Deuterium-rich pirfenidones and methods of use thereof

Abstract

Disclosed herein are deuterium-rich pirfenidones, optionally in combination with one or more additional therapeutic agents, and methods of use thereof; and deuterium-rich pirfenidones, optionally in combination with one or more additional therapeutic agents; pharmaceutical compositions comprising the compounds, processes for the preparation of the compounds; and methods of using the compounds. The compounds and compositions are useful, for example, in the treatment of diseases, disorders, or conditions such as edema.

Description

[0001] This application is a divisional application of patent application No. 201980074434.7, filed on September 16, 2019, entitled "Deuterium-rich pirfenidone and its method of use". Technical Field

[0002] This invention relates to substituted deuterium-rich N-arylpyridones, their pharmaceutically acceptable salts and prodrugs, the chemical synthesis of said compounds, and the use of such compounds for the treatment and / or management of diseases, symptoms, or ailments.

[0003] Cross-references to related applications

[0004] This application claims the benefits of U.S. Provisional Patent Application No. 62 / 731,570, filed September 14, 2018; U.S. Provisional Patent Application No. 62 / 750,377, filed October 25, 2018; U.S. Provisional Patent Application No. 62 / 839,256, filed April 26, 2019; and U.S. Provisional Patent Application No. 62 / 884,984, filed August 9, 2019; each of which is incorporated herein by reference in its entirety. Background Technology

[0005] Fibrosis is a common feature of most chronic diseases, and it is estimated to cause 45% of deaths in the United States (Wynn, Nat Rev Immunol. 2004 Aug; 4(8):583-594). In epithelial organs such as the lungs, liver, skin, and kidneys, normal cells and tissues are remodeled by scar tissue composed of collagen and other extracellular matrix molecules, eventually leading to organ dysfunction and ultimately organ failure. Pulmonary fibrosis, renal fibrosis, and cirrhosis are the most common fibrotic diseases, and together they represent a huge unmet clinical need.

[0006] Idiopathic pulmonary fibrosis (IPF) has garnered significant attention due to its severe course. Drug development efforts in IPF have provided insights into its potential transformation into other fibrotic diseases and raised awareness of the commonalities among fibrotic diseases of various origins. For example, the TGF-β pathway is known to be a major mediator of fibrosis initiation and maintenance in many fibrotic diseases (Friedman et al., SciTransl Med. 2013 Jan 9; 5(167):167sr1). In vitro mechanistic studies, preclinical animal studies, and strong evidence of upregulation of this pathway in human diseases suggest that targeting the TGF-β pathway may be therapeutic for fibrosis. Numerous drugs are currently under development, including antibodies targeting TGF-β or other pathway molecules such as αvβ6 integrin, and are being evaluated in clinical trials for the treatment of diseases such as advanced focal segmental glomerulosclerosis, scleroderma, and IPF. However, even though elevated TGF-β signaling is an important component of fibrotic diseases, cytokines also perform important normal homeostatic activities, including immune regulation and tumor suppression. Therefore, the design of clinical studies must take into account and minimize the potential side effects of systemic inhibition of TGFβ activity.

[0007] Lymphedema is a chronic, debilitating disease caused by fibrosis and inflammation. In developed countries like the United States, it is most commonly a complication of cancer treatment. In this case, lymphedema results from iatrogenic damage to the lymphatic system, usually due to lymph node dissection or biopsy. Larger skin excisions and radiation-assisted therapy can also cause lymphedema. See, for example, Szuba et al., Cancer 95:2260-2267 (2002); Tsai et al., Ann. Surg. Oncol. 16:1959-72 (2009); Purushotham et al., J. Clin. Oncol. 23:4312-4321 (2005). It is estimated that 1 in 3 patients who undergo lymph node dissection will later develop lymphedema. Conservative estimates suggest that up to 50,000 new patients are diagnosed each year. See, for example, DiSipio et al., Lancet Oncol. 14:500-515 (2013); Petrek et al., Cancer 83:2776-2781 (1998). Because lymphedema is an incurable disease, the number of people affected is increasing annually, currently estimated at 5-6 million Americans (Rockson et al., Ann. NY Acad. Sci. 1131:147-154 (2008)), and over 200 million globally. This number is likely to continue to rise in the future due to the near-linear relationship between the development of lymphedema and cancer survival rates, and because known risk factors for lymphedema, such as obesity and radiation exposure, are increasingly prevalent. See, for example, Erickson et al., J. Natl. Cancer Inst. 93:96-111 (2001).

[0008] Lymphedema is debilitating and debilitating; patients experience persistent swelling, heaviness, pain, discomfort, skin lesions, fibrosis, recurrent infections, limited mobility, and a decreased quality of life in the affected limb. See, for example, Hayes et al., Cancer 118:2237-2249 (2012). Severe symptoms can limit self-care. When lymphedema first develops, the skin may appear pitted or pitted, and as the disease progresses, with thickening and fibrosis, the skin may develop a leathery texture. This non-pitted edema indicates an irreversible stage of lymphedema, with a lichenified or cobblestone (hyperkeratosis) appearance. Fat deposition is a defining feature of late-stage lymphedema. Skin in chronic lymphedema is particularly prone to fissuring and recurrent cellulitis. Complicated skin ulcers, bacterial and fungal infections, and impetigo (a skin disease that causes erythematous sores) are also common. Lymphatic exudation, i.e., the leakage of lymph fluid, is also frequently observed. Over time, it can develop into elephantiasis, causing severe deformities of the body parts. The facial deformities caused by lymphedema are difficult to conceal. Patients with lymphedema often suffer from social and psychological stigma due to impaired mobility, difficulty dressing, and deformities of the limbs and genitals, leading to feelings of inferiority, depression, anxiety, and low body image.

[0009] In addition, there is a 10% risk of developing angiosarcoma, a highly aggressive malignant tumor, in patients with chronic lymphedema lasting more than 10 years, which has a poor prognosis and a low 5-year survival rate. Other cancers are also associated with lymphedema.

[0010] Once lymphedema develops, it is usually progressive. Although lymphedema is common and highly pathological, there is currently no cure, and treatment is palliative, aiming to prevent disease progression rather than restore lymphatic function (Beaulac et al., Arch. Surg. 137; 1253-1257 (2002)). As a result, patients are required to wear tight, uncomfortable clothing for the rest of their lives to prevent lymph fluid buildup in the affected limb and undergo intensive and time-consuming physical therapy (Koul et al., Int. J. Radiat. Oncol. Biol. Phys., 67: 841-846 (2007)). Furthermore, despite continued long-term care, some patients remain in severe condition with progressive swelling and frequent infections in the lymphedematous limb.

[0011] Currently, there are no approved drug therapies for the treatment of lymphedema. Furthermore, there are no known drug treatments that can halt the progression of lymphedema or promote its resolution (Cormier et al., Ann. Surg. Oncol. 19:642-651 (2012)). Moreover, progress in developing effective treatments for lymphatic diseases has been minimal. Therefore, the development of targeted therapies for lymphedema is an important goal and represents an unmet biomedical need. Summary of the Invention

[0012] The compounds described herein are designed to target underlying fibrosis and inflammation found in fibrosis-mediated and / or collagen-mediated conditions. They are also designed to target underlying fibrosis and inflammation found in the lymphatic system to improve lymphatic function and alleviate symptoms of lymphedema and other lymphatic system disorders, such as those described herein.

[0013] In one aspect, the present invention relates to a method for treating, preventing, and / or improving a disease, symptom, or illness. The method comprises administering an effective amount of deuterium-rich pirfenidone to a subject in need. The deuterium-rich pirfenidone has the structure shown in Formula I:

[0014]

[0015] Or its pharmaceutically acceptable salt. 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 and R 11 Selected from hydrogen and deuterium. R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 and R 11 At least one of them is deuterium. When R 7 R 8 R 9 R 10 and R 11 When it is deuterium, R 1 R 2 R 3 R 4 R 5 and R 6 At least one of them is deuterium.

[0016] In some implementation schemes, R 1 R 2 and R 3 At least one of them is deuterium. In some embodiments, R 1 R 2 and R3 At least one of them independently has a deuterium enrichment of not less than about 90%. In some embodiments, R 1 R 2 and R 3 It is deuterium.

[0017] Deuterium-rich pirfenidone can have the following structure:

[0018]

[0019] Or its pharmaceutically acceptable salt.

[0020] In some embodiments, the disease, condition, or ailment is selected from inflammation-mediated conditions, fibrosis-mediated conditions, collagen-mediated conditions, and fibrosis-mediated and collagen-mediated conditions, or any combination of these conditions. In some implementations, the disease, condition, or ailment is selected from idiopathic pulmonary fibrosis, pneumoconiosis, silicosis, diatomaceous earth disease, asbestosis, anthrax, lymphedema (primary and / or secondary), systemic sclerosis (scleroderma) or scleroderma-related ailments, scleroderma interstitial lung disease, focal segmental glomerulosclerosis, juvenile systemic sclerosis (J-SSC), diabetic nephropathy, lupus nephritis, polycystic kidney disease, ANCA vasculitis, membranous nephropathy, minimal change disease, chronic kidney disease, myocardial fibrosis, keloids, polymyositis cutanea, fibrotic sarcoidosis, graft-versus-host disease, medical device or implant rejection, fatty liver, non-alcoholic steatohepatitis (NASH), and hepatitis C fibrosis. In some implementations, the disease, condition, or disorder is selected from neurofibromatosis, Hermansky-Pudlak syndrome, diabetic nephropathy, renal fibrosis, hypertrophic cardiomyopathy (HCM), hypertension-associated nephropathy, glomerulosclerosis (FSGS), radiation-induced fibrosis, multiple sclerosis (including secondary progressive multiple sclerosis), uterine leiomyomas (fibroids), alcoholic liver disease selected from hepatic steatosis, liver fibrosis, and cirrhosis, proliferative diseases selected from angiogenesis-mediated diseases, cancers selected from glioma, glioblastoma, breast cancer, colon cancer, melanoma, and pancreatic cancer, fibrotic diseases, interstitial lung disease, atrial fibrillation (AF), and organ transplant rejection. Scleroderma and skin-related fibrotic disorders, endotoxin-induced liver injury after partial hepatectomy or hepatic ischemia, allogeneic transplant injury after organ transplantation, cystic fibrosis, atrial fibrosis, neutropenia, dermatomyositis, cirrhosis, diffuse parenchymal lung disease, mediastinal fibrosis, tuberculosis, splenic fibrosis caused by sickle cell anemia, rheumatoid arthritis, pulmonary fibrosis associated with systemic sclerosis, sarcoidosis, pulmonary fibrosis associated with sarcoidosis, pulmonary fibrosis caused by infection, asbestos-induced pulmonary fibrosis, silica-induced pulmonary fibrosis, environmentally induced pulmonary fibrosis, radiation-induced pulmonary fibrosis, lupus-induced pulmonary fibrosis, drug-induced pulmonary fibrosis and hypersensitivity pneumonia, and / or any condition that can be improved by modulating fibrosis and / or collagen infiltration into tissues.

[0021] In some embodiments, the disease, condition, or ailment is selected from idiopathic pulmonary fibrosis, edema (primary and / or secondary), lymphedema (primary and / or secondary), and systemic sclerosis (scleroderma) or symptoms associated with scleroderma. In some embodiments, the disease, condition, or ailment is scleroderma and at least one related ailment selected from interstitial lung disease, tight skin, joint pain, overreaction to cold (Raynaud's disease), and heartburn. In some embodiments, the disease, condition, or ailment is selected from nonalcoholic steatohepatitis (NASH), fatty liver disease, or hepatitis C fibrosis.

[0022] Deuterium-rich pirfenidone has the structure shown in Formula I or a pharmaceutically acceptable salt thereof. In some embodiments, deuterium-rich pirfenidone has the structure shown in Formula I and is administered orally. In some embodiments, deuterium-rich pirfenidone has the structure shown in Formula I and is administered topically. In some embodiments, deuterium-rich pirfenidone has the structure shown in Formula I and is administered intravenously.

[0023] In some embodiments, deuterium-rich pirfenidone has a structure shown as LYT-100:

[0024]

[0025] Or its pharmaceutically acceptable salt.

[0026] In some embodiments, deuterium-rich pirfenidone has the following structure:

[0027]

[0028] Or its pharmaceutically acceptable salts may be taken orally.

[0029] In some embodiments, deuterium-rich pirfenidone has the following structure:

[0030]

[0031] Or its pharmaceutically acceptable salts may be administered intravenously.

[0032] In some embodiments, deuterium-rich pirfenidone has the following structure:

[0033]

[0034] Or its pharmaceutically acceptable salts may be applied topically.

[0035] In some embodiments, deuterium-rich pirfenidone has the following structure:

[0036]

[0037] Or its pharmaceutically acceptable salt, administered twice daily.

[0038] In some embodiments, deuterium-rich pirfenidone has the following structure:

[0039]

[0040] Or its pharmaceutically acceptable salt, administered once daily.

[0041] In some embodiments, deuterium-rich pirfenidone has the following structure:

[0042]

[0043] Or its pharmaceutically acceptable salt, administered three times daily.

[0044] In another aspect, the present invention is characterized by a method for reducing inflammation and / or fibrosis in subjects with insufficient lymphatic flow. The method comprises administering to the subject in need an effective amount of deuterium-rich pirfenidone having the structure shown in Formula I:

[0045]

[0046] Or its pharmaceutically acceptable salt. 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 and R 11 Selected from hydrogen and deuterium. R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 and R 11 At least one of them is deuterium. When R 7 R 8 R 9 R 10 and R 11 When it is deuterium, R 1 R 2 R 3 R 4 R 5 and R 6At least one of them is deuterium.

[0047] In some implementation schemes, R 1 R 2 and R 3 At least one of them is deuterium. In some embodiments, R 1 R 2 and R 3 At least one of them independently has a deuterium enrichment of not less than about 90%. In some embodiments, R 1 R 2 and R 3 It is deuterium.

[0048] Deuterium-rich pirfenidone can have the following structure:

[0049]

[0050] Or its pharmaceutically acceptable salt.

[0051] In another aspect, the present invention is characterized by a method for regulating and / or maintaining interstitial fluid balance and / or lymphatic flow in a subject in need. The method comprises administering to the subject an effective amount of a deuterium-rich pirfenidone having the structure shown in Formula I:

[0052]

[0053] Or its pharmaceutically acceptable salt. 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 and R 11 Selected from hydrogen and deuterium. R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 and R 11 At least one of them is deuterium. When R 7 R 8 R 9 R 10 and R 11 When it is deuterium, R 1 R 2 R 3R 4 R 5 and R 6 At least one of them is deuterium.

[0054] In some implementation schemes, R 1 R 2 and R 3 At least one of them is deuterium. In some embodiments, R 1 R 2 and R 3 At least one of them independently has a deuterium enrichment of not less than about 90%. In some embodiments, R 1 R 2 and R 3 It is deuterium.

[0055] In some implementations, deuterium-rich pirfenidone has the following structure:

[0056]

[0057] Or its pharmaceutically acceptable salt.

[0058] In another aspect, the present invention relates to a method for treating edema. The method comprises administering to a subject in need an effective amount of a deuterium-rich pirfenidone having the following structure:

[0059]

[0060] Or its pharmaceutically acceptable salt. 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 and R 11 Selected from hydrogen and deuterium. R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 and R 11 At least one of them is deuterium. When R 7 R 8 R 9 R 10 and R 11 When it is deuterium, R 1 R2 R 3 R 4 R 5 and R 6 At least one of them is deuterium. In some embodiments, the deuterium-rich pirfenidone has the following structure:

[0061]

[0062] Or its pharmaceutically acceptable salt.

[0063] In some implementations, the edema is lymphedema. In some implementations, the lymphedema is secondary lymphedema. In some implementations, the lymphedema is primary lymphedema.

[0064] In some implementations, the progression of a disease or ailment, such as edema, ceases in the subject. In some implementations, a reduction in stage is observed in the subject. In some implementations, treatment includes reducing swelling, reducing inflammation, reducing fibrosis, reducing pain, increasing range of motion, reducing heaviness, reducing tightness, reducing skin thickening, and / or improving lymphatic function. In some implementations, treatment includes improvements in ailments such as edema as measured by: water content, limb volume, tissue stiffness, Visual Analogue Scale (VAS) score, Upper Limb Lymphedema Score (ULL27), Lymphedema Life Impact Scale (LLIS) score, Functional Assessment of Cancer Therapy – Breast Cancer Specific Quality of Life Tool Score (FACT-B+4), Lymphedema Quality of Life Score (LYMQOL), Arm, Shoulder, and Hand Disability Score (DASH), and / or Lymphedema Quality of Life Questionnaire (LQOLI).

[0065] Improvement in the water content of a subject with edema is a reduction in water content. Therefore, in some embodiments, the water content in the extremities of a subject with edema is reduced. In some embodiments, the water content in the extremities of a subject with edema is reduced by at least 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or more. In some embodiments, for example, the water content in the extremities of a subject with edema is reduced by at least 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more as measured by bioelectrical impedance spectrometry (BIS). In some embodiments, the water content in the extremities of a subject with edema, as measured by tissue dielectric constant (TDC), is reduced by at least 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more. In some embodiments, the limb volume in a subject with edema is stable or reduced by at least 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or more. In some embodiments, the limb volume is stable or reduced by at least 2%. In some embodiments, the tissue stiffness of subjects with edema increases by at least 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or more. In some embodiments, the tissue stiffness, as measured by intraocular tonometry, increases by 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 30%, 35%, 40%, 45%, 50%, or more. In some embodiments, the tissue stiffness, as measured by intraocular tonometry, increases by at least 20%.

[0066] In some embodiments, at least one of the locations denoted as D independently has a deuterium enrichment of not less than about 95%. In some embodiments, at least one of the locations denoted as D independently has a deuterium enrichment of not less than about 98%. In some embodiments, at least one of the locations denoted as D independently has a deuterium enrichment of not less than about 99%.

[0067] In some implementations, an effective amount of deuterium-rich pirfenidone is maintained at the site of lymphedema in the subject.

[0068] In some implementations, the subject has received cancer treatment, and the lymphedema is related to the cancer treatment or diagnosis. In some implementations, the subject has breast cancer-related arm lymphedema. In some implementations, the subject has mild to moderate breast cancer-related arm lymphedema. In some implementations, the subject is receiving or may have received chemotherapy or radiation therapy.

[0069] In some embodiments, deuterium-rich pirfenidone is applied topically twice daily. In some embodiments, deuterium-rich pirfenidone is applied topically once daily. In some embodiments, deuterium-rich pirfenidone is applied topically three times daily.

[0070] In another aspect, the present invention is characterized by a method for treating interstitial lung disease (ILD). The method comprises administering to a subject in need an effective amount of deuterium-rich pirfenidone having the following structure:

[0071]

[0072] Or its pharmaceutically acceptable salt. 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 and R 11 Selected from hydrogen and deuterium. R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 and R 11 At least one of them is deuterium. When R 7 R 8 R 9 R 10 and R 11 When it is deuterium, R 1 R 2 R 3 R 4 R 5 and R 6 At least one of them is deuterium. ILD is treated in subjects.

[0073] In some implementations, deuterium-rich pirfenidone has the following structure:

[0074]

[0075] Or its pharmaceutically acceptable salt.

[0076] In some implementations, ILD is idiopathic pulmonary fibrosis (IPF). Deuterium-rich pirfenidone can be taken orally twice daily at a total daily dose of 1000 mg. In some implementations, the initial dose is titrated from 250 mg to 1000 mg over 2 weeks.

[0077] In some implementations, subjects experience a reduction of at least 5% or 10% in their predicted percentage of forced vital capacity (%FVC).

[0078] In another aspect, the present invention is characterized by a method for treating fibrosis or collagen infiltration disorders. The method comprises administering to a subject in need an effective amount of deuterium-rich pirfenidone having the following structure:

[0079]

[0080] Or its pharmaceutically acceptable salt. 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 and R 11 Selected from hydrogen and deuterium. R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 and R 11 At least one of them is deuterium. When R 7 R 8 R 9 R 10 and R 11 When it is deuterium, R 1 R 2 R 3 R 4 R 5 and R 6 At least one of them is deuterium. It is used to treat fibrosis or collagen infiltration in subjects.

[0081] In some implementations, deuterium-rich pirfenidone has the following structure:

[0082]

[0083] Or its pharmaceutically acceptable salt.

[0084] In another embodiment, the method includes measuring or monitoring biomarkers, such as inflammatory markers, in the subject. In some embodiments, the biomarkers are one or more selected from the following: G-CSF, MIG, FGF-2, IL-4, IL-10, lymphotoxin-α / TNF-β, leptin, IL-6, IL-1β, TNF-α, TGF-β1, MMP-9, TIMP-1, and MCP-1. In some embodiments, the biomarkers are monitored to monitor the subject's treatment. Attached Figure Description

[0085] Figure 1A The single-dose pharmacokinetics of LYT-100 at a dose of 801 mg and pirfenidone at a dose of 801 mg are shown over 24 hours. Figure 1B The single-dose pharmacokinetics of LYT-100 at a dose of 801 mg and pirfenidone at a dose of 801 mg in individuals over 48 hours are shown. Figure 1C The model is based on LYT-100 (total daily dose of 1000 mg) administered twice daily at a dose of 500 mg on day 7 and its metabolites. Figure 1D The model was based on LYT-100 administered twice daily at a dose of 750 mg on day 7 (total daily dose of 1500 mg) and its metabolites. Figure 1E yes Figure 1D The model of the first 7 days of drug administration showed accumulation to a steady state. Figure 1F The model is based on a 750 mg dose of LYT-100 once daily on day 7 (total daily dose of 750 mg) and its metabolites. Figure 1G yes Figure 1F The model of the first 7 days of drug administration showed accumulation to a steady state.

[0086] Figure 2 Representative micrographs depicting liver sections stained with Sirius-red show that LYT-100 significantly reduces the area of ​​fibrosis.

[0087] Figure 3 The percentage of fibrosis area of ​​LYT-100 relative to the medium and control group is shown.

[0088] Figure 4A This indicates that LYT-100 does not induce the survival of primary mouse lung fibroblasts (PMFL). Figure 4B andFigure 4C The results show that LYT-100 reduces TGF-β-induced total collagen levels in PMFL in 6-well and 96-well formats, respectively; and Figure 4D and Figure 4E The study showed that LYT-100 reduced TGF-β-induced levels of soluble fibronectin and soluble collagen.

[0089] Figure 5A This indicates that LYT-100 does not affect the survival of L929 cells. Figure 5B This indicates that LYT-100 inhibits TGF-induced collagen synthesis. Figure 5C This indicates that LYT-100 significantly inhibits TGF-β-induced total collagen levels. Figure 5D This is a graph illustrating that LYT-100 significantly inhibits TGF-β-induced soluble collagen levels. Figure 5E This indicates that LYT-100 significantly reduces soluble fibronectin levels in both the absence and presence of TGF-β induction. Detailed Implementation

[0090] 1. General Description of Certain Aspects of the Invention

[0091] Deuterium-enriched pirfenidone

[0092] Certain N-arylpyridones of the present invention, including deuterium-rich pirfenidone compounds, are described in WO 2008 / 157786, WO 2009 / 035598, WO 2012 / 122165 and WO 2015 / 112701, which are incorporated herein by reference in their entirety.

[0093] Pirfenidone CAS#53179-13-8, Pirespa, AMR-69, Pirfenidona, Pirfenidonum, Esbriet, Pirfenex, 5-methyl-1-phenyl-1H-pyridin-2-one, 5-methyl-1-phenyl-2-(1H)-pyridinone, 5-methyl-1-phenylpyridin-2(1H)-one, is an oral antifibrotic agent. Pirfenidone is currently approved for idiopathic pulmonary fibrosis (IPF) in the United States and elsewhere.

[0094]

[0095] The metabolism of pirfenidone is only partially understood. For example, to avoid being bound by theory, it is assumed that the methyl group is readily oxidized, producing the corresponding hydroxymethyl metabolite "M1". It is believed that M1 is further oxidized to the carboxylic acid metabolite "M2" (Wang et al., Biomedical Chromatography 2006, 20, 1375-1379). A third detected metabolite is believed to be a phase II product possibly derived from M1 or M2. Pirfenidone has a very short half-life in the human body.

[0096] Deuterium kinetic isotope effect

[0097] To remove foreign substances from the circulatory system, animal tissues express various enzymes, such as cytochrome P400. 450 Enzymes, or CYPs, esterases, proteases, reductases, dehydrogenases, and monoamine oxidases, react with these foreign substances and convert them into more polar intermediates or metabolites for excretion via the kidneys. Some of the most common metabolic reactions of drug compounds involve the oxidation of carbon-hydrogen bonds (CH) to carbon-oxygen (CO) or carbon-carbon (CC) π bonds. The resulting metabolites may be stable or unstable under physiological conditions and may have fundamentally different pharmacokinetics, pharmacodynamics, and acute and long-term toxicities relative to the parent compound. For most drugs, this oxidation is typically rapid, ultimately requiring multiple daily or high-dose administration to maintain therapeutically effective levels of the drug in the patient's body.

[0098] The relationship between activation energy and reaction rate can be quantitatively expressed by the Arrhenius equation, k = Ae^(-k / A ... -Eact / RT, where E act Here, is the activation energy, T is the temperature, R is the molar gas constant, k is the reaction rate constant, and A (frequency factor) is a constant specific to each reaction, depending on the probability that molecules collide in the correct direction. The Arrhenius equation states that the portion of molecules with sufficient energy to overcome the energy barrier—that is, those molecules with energy at least equal to the activation energy—depends exponentially on the ratio of activation energy to thermal energy (RT), i.e., the average thermal energy possessed by the molecule at a given temperature.

[0099] The transition state in a reaction is a transient state along the reaction pathway (approximately 10). -14 (seconds), during which the original bonds have stretched to their limit. By definition, the activation energy E of the reaction is... actThe activation energy is the energy required to reach the transition state of the reaction. Reactions involving multiple steps necessarily have many transition states, in which case the activation energy of the reaction is equal to the energy difference between the reactants and the least stable transition state. Once the transition state is reached, the molecules can recover, either reforming the original reactants or forming new bonds to produce products. This dichotomy is possible because both the forward and reverse pathways result in the release of energy. Catalysts facilitate reaction processes by lowering the activation energy that leads to the transition state. Enzymes are examples of biological catalysts that lower the energy required to achieve a specific transition state.

[0100] A carbon-hydrogen bond is essentially a covalent chemical bond. This type of bond forms when two atoms with similar electronegativity share some of their valence electrons, creating a force that holds the atoms together. The strength of this force, or bond, can be quantified and expressed in units of energy; therefore, various types of covalent bonds between atoms can be classified according to how much energy must be applied to break the bond or separate the two atoms.

[0101] Bond strength is proportional to the absolute value of the bond's ground-state vibrational energy. This vibrational energy, also known as the zero-point vibrational energy, depends on the mass of the atoms forming the bond. The absolute value of the zero-point vibrational energy increases with the mass of one or both atoms constituting the bond. Since deuterium (D) has twice the mass of hydrogen (H), a CD bond is stronger than the corresponding CH bond. Compounds with CD bonds are generally stable indefinitely in H₂O and have been widely used in isotope studies. If the CH bond breaks in the rate-determining step of a chemical reaction (i.e., the step with the highest transition state energy), replacing hydrogen with deuterium will result in a decrease in the reaction rate, and the process will slow down. This phenomenon is called the deuterium kinetic isotope effect (DKIE) and ranges from about 1 (without the isotope effect) to very large numbers, such as 50 or greater, meaning that a reaction may be 50 times or more slower when hydrogen is replaced by deuterium. Higher DKIE values ​​may be partly attributed to a phenomenon called tunneling, a consequence of the uncertainty principle. Tunneling is attributed to the small size of hydrogen atoms, and it occurs because a transition state involving a proton can sometimes form in the absence of the required activation energy. Deuterium is larger, and statistically, this phenomenon is much less likely to occur. Replacing hydrogen with tritium produces stronger bonds than deuterium and has a greater numerical isotopic effect.

[0102] Deuterium (D), discovered by Urey in 1932, is a stable and non-radioactive isotope of hydrogen. It was the first isotope to be isolated from an element in its pure form, and its mass is twice that of hydrogen, accounting for approximately 0.02% of the total mass of hydrogen on Earth (in this usage, all hydrogen isotopes are represented). When two deuterium atoms bond with one oxygen atom, they form deuterium oxide (D₂O, or "heavy water").

[0103] Deuterated pyridinone derivatives

[0104] Pirfenidone is a substituted pyridone-based regulator of fibrosis and / or collagen infiltration. The carbon-hydrogen bonds of pirfenidone contain a naturally occurring hydrogen isotopic distribution. 1 H or protium (approximately 99.9844%) 2 H or deuterium (approximately 0.0156%) and 3 H or tritium (in every 10) 18 (The number of tritium atoms in each protium atom ranges from approximately 0.5 to 67). Increased deuterium incorporation levels can produce detectable kinetic isotope effects (KIE) compared to compounds with naturally occurring levels of deuterium, which can affect the pharmacokinetic, pharmacological, and / or toxicological characteristics of such fibrosis regulators and / or collagen infiltration regulators.

[0105] Pirfenidone is likely metabolized in the human body via methyl oxidation. Other sites on the molecule may also undergo transformations, resulting in metabolites with unknown pharmacological / toxicological properties. Limiting the production of these metabolites could potentially reduce the risks of administering such drugs and might even allow for increased dosage and consequently, increased efficacy. All of these transformations can occur via polymorphically expressed enzymes, thus exacerbating inter-patient variability.

[0106] Various deuteration modalities can be used to a) reduce or eliminate unwanted metabolites, b) increase the half-life of the parent drug, c) reduce the dose required to achieve the desired effect, d) reduce the amount of dose required to achieve the desired effect, e) increase the formation of active metabolites (if any), and / or f) reduce the production of harmful metabolites in specific tissues, and / or produce more effective and / or safer drugs for compound drugs, whether or not the compound drug is intentionally produced. Deuteration methods have a strong potential to slow down metabolism through various oxidation and racemic mechanisms.

[0107] In one aspect, the present invention provides a deuterium-rich pirfenidone having the structure shown in Formula I:

[0108]

[0109] Or its pharmaceutically acceptable salt, wherein:

[0110] R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 and R 11 Selected from hydrogen and deuterium; and R 1 R2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 and R 11 At least one of them is deuterium. In some embodiments, when R 7 R 8 R 9 R 10 and R 11 When it is deuterium, R 1 R 2 R 3 R 4 R 5 and R 6 At least one of them is deuterium.

[0111] In some implementation schemes, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 and R 11 At least one of them independently has a deuterium enrichment of not less than about 1%, not less than about 5%, not less than about 10%, not less than about 20%, not less than about 50%, not less than about 70%, not less than about 80%, not less than about 90%, not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.1%, not less than about 99.2%, not less than about 99.3%, not less than about 99.4%, not less than about 99.5%, not less than about 99.6%, not less than about 99.7%, not less than about 99.8%, or not less than about 99.9%. In some embodiments, including any deuterium-rich pirfenidone described below and in other parts of this document, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 and R 11At least one of them independently has a deuterium enrichment of 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, 100%, or any increasing numerical fraction within the deuterium enrichment.

[0112] In yet another implementation scheme, R 1 R 2 and R 3 At least one of them is deuterium.

[0113] In yet another implementation scheme, R 1 R 2 and R 3 At least two of them are deuterium.

[0114] In yet another implementation scheme, R 1 R 2 and R 3 It is deuterium.

[0115] In yet another implementation scheme, R 4 It is deuterium.

[0116] In yet another implementation scheme, R 5 and R 6 At least one of them is deuterium.

[0117] In yet another implementation scheme, R 5 and R 6 It is deuterium.

[0118] In yet another implementation scheme, R 5 and R 6 For deuterium; and R 1 R 2 R 3 R 4 R 7 R 8 R 9 R 10 and R 11 At least one of them is deuterium.

[0119] In yet another implementation scheme, R 7 R 8 R 9 R 10 and R 11 At least one of them is deuterium.

[0120] In yet another implementation scheme, R 7 R 8 R 9 R10 and R 11 It is deuterium.

[0121] In yet another implementation scheme, R 7 R 8 and R 9 For deuterium, and R 1 R 2 R 3 R 4 R 5 R 6 R 10 and R 11 At least one of them is deuterium.

[0122] In yet another implementation scheme, R 1 R 2 and R 3 At least one of them is deuterium; and R 4 R 5 R 6 R 7 R 8 R 9 R 10 and R 11 It is hydrogen.

[0123] In yet another implementation scheme, R 1 R 2 and R 3 At least two of them are deuterium; and R 4 R 5 R 6 R 7 R 8 R 9 R 10 and R 11 It is hydrogen.

[0124] In yet another implementation scheme, R 1 R 2 and R 3 For deuterium; and R 4 R 5 R 6 R 7 R 8 R 9 R 10 and R 11 It is hydrogen.

[0125] In yet another implementation scheme, R 4 For deuterium; and R 1 R 2 R 3 R 5 R 6 R7 R 8 R 9 R 10 and R 11 It is hydrogen.

[0126] In yet another implementation scheme, R 5 and R 6 At least one of them is deuterium; and R 1 R 2 R 3 R 4 R 7 R 8 R 9 R 10 and R 11 It is hydrogen.

[0127] In yet another implementation scheme, R 5 and R 6 For deuterium; and R 1 R 2 R 3 R 4 R 7 R 8 R 9 R 10 and R 11 It is hydrogen.

[0128] In yet another implementation scheme, R 1 R 2 R 3 R 4 R 5 and R 6 At least one of them is deuterium; and R 7 R 8 R 9 R 10 and R 11 It is hydrogen.

[0129] In yet another implementation scheme, R 1 R 2 R 3 R 4 R 5 and R 6 For deuterium; and R 7 R 8 R 9 R 10 and R 11 It is hydrogen.

[0130] In yet another implementation scheme, R 7 R 8 R 9 R10 and R 11 At least one of them is deuterium; and R 1 R 2 R 3 R 4 R 5 and R 6 It is hydrogen.

[0131] In yet another implementation scheme, R 7 R 8 R 9 R 10 and R 11 For deuterium; and R 1 R 2 R 3 R 4 R 5 and R 6 At least one of them is deuterium.

[0132] In other implementations, R 1 It is hydrogen. In other embodiments, R 2 It is hydrogen. In other embodiments, R 3 It is hydrogen. In other embodiments, R 4 It is hydrogen. In some implementations, R 5 It is hydrogen. In other embodiments, R 6 It is hydrogen. In other embodiments, R 7 It is hydrogen. In other embodiments, R 8 It is hydrogen. In some implementations, R 9 It is hydrogen. In other embodiments, R 10 It is hydrogen. In other embodiments, R 11 It is hydrogen.

[0133] In other implementation schemes, R 1 For deuterium. In other implementations, R 2 For deuterium. In other implementations, R 3 For deuterium. In other implementations, R 4 For deuterium. In some implementations, R 5 For deuterium. In other implementations, R 6 For deuterium. In other implementations, R 7 For deuterium. In other implementations, R 8 For deuterium. In some implementations, R 9 For deuterium. In other implementations, R 10 For deuterium. In other implementations, R 11 It is deuterium.

[0134] In some embodiments, the deuterium-rich pirfenidone is LYT-100, or a pharmaceutically acceptable salt thereof. LYT-100 has the following structure:

[0135]

[0136] In some embodiments, the deuterium-rich pirfenidone is a compound or a pharmaceutically acceptable salt thereof, or a metabolite thereof, as described herein in its entirety in WO2008 / 157786, WO 2009 / 035598, WO 2012 / 122165 or WO 2015 / 112701, which are incorporated herein by reference.

[0137] In one aspect, the present invention provides the deuterium-rich compounds shown in Table 1, or pharmaceutically acceptable salts thereof:

[0138] Table 1: Exemplary Compounds

[0139]

[0140]

[0141]

[0142] In some embodiments, the present invention provides compounds as depicted in Table 1 above, or pharmaceutically acceptable salts thereof.

[0143] In some embodiments, the present invention provides compounds as depicted in Table 1 above, or pharmaceutically acceptable salts thereof, wherein at least one of the positions designated as D independently has a deuterium enrichment of not less than about 1%, not less than about 5%, not less than about 10%, not less than about 20%, not less than about 50%, not less than about 70%, not less than about 80%, not less than about 90%, not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.1%, not less than about 99.2%, not less than about 99.3%, not less than about 99.4%, not less than about 99.5%, not less than about 99.6%, not less than about 99.7%, not less than about 99.8%, or not less than about 99.9%. In other embodiments, at least one of the positions denoted as D independently has a deuterium enrichment of 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, 100%, or any increasing numerical fraction within the deuterium enrichment.

[0144] In another embodiment, the compound is substantially a single enantiomer, a mixture of about 90% by weight or more of (-)-enantiomer and about 10% by weight or less of (+)-enantiomer, a mixture of about 90% by weight or more of (+)-enantiomer and about 10% by weight or less of (-)-enantiomer, substantially a single diastereomer, or a mixture of about 90% by weight or more of a single diastereomer and about 10% by weight or less of any other diastereomer.

[0145] In some embodiments, the compounds disclosed herein contain about 60 wt% or more of the (-)-enantiomers of the compound and about 40 wt% or less of the (+)-enantiomers of the compound. In some embodiments, the compounds disclosed herein contain about 70 wt% or more of the (-)-enantiomers of the compound and about 30 wt% or less of the (+)-enantiomers of the compound. In some embodiments, the compounds disclosed herein contain about 80 wt% or more of the (-)-enantiomers of the compound and about 20 wt% or less of the (+)-enantiomers of the compound. In some embodiments, the compounds disclosed herein contain about 90 wt% or more of the (-)-enantiomers of the compound and about 10 wt% or less of the (+)-enantiomers of the compound. In some embodiments, the compounds disclosed herein contain about 95 wt% or more of the (-)-enantiomers of the compound and about 5 wt% or less of the (+)-enantiomers of the compound. In some embodiments, such as the compounds disclosed herein, there are about 99% by weight or more of the (-)-enantiomer of the compound and about 1% by weight or less of the (+)-enantiomer of the compound.

[0146] In some embodiments, the compounds disclosed herein contain about 60% by weight or more of the (+)-enantiomers of the compound and about 40% by weight or less of the (-)-enantiomers of the compound. In some embodiments, the compounds disclosed herein contain about 70% by weight or more of the (+)-enantiomers of the compound and about 30% by weight or less of the (-)-enantiomers of the compound. In some embodiments, the compounds disclosed herein contain about 80% by weight or more of the (+)-enantiomers of the compound and about 20% by weight or less of the (-)-enantiomers of the compound. In some embodiments, the compounds disclosed herein contain about 90% by weight or more of the (+)-enantiomers of the compound and about 10% by weight or less of the (-)-enantiomers of the compound. In some embodiments, the compounds disclosed herein contain about 95% by weight or more of the (+)-enantiomers of the compound and about 5% by weight or less of the (-)-enantiomers of the compound. In some embodiments, the compounds disclosed herein contain about 99% by weight or more of the (+)-enantiomer of the compound and about 1% by weight or less of the (-)-enantiomer of the compound.

[0147] The deuterated compounds disclosed herein may also contain isotopes of other less common elements, including but not limited to carbon. 13 C or 14 C-, nitrogen 15 N and oxygen 17 O or 18 O.

[0148] Isotopic hydrogen can be introduced into compounds such as those disclosed herein using synthetic techniques employing deuterating agents, where the incorporation ratio is predetermined; and / or through exchange techniques, where the incorporation ratio is determined by equilibrium conditions and can vary considerably depending on reaction conditions. Synthetic techniques involving the direct and specific insertion of tritium or deuterium using tritating or deuterating agents with known isotopic abundances can yield high tritium or deuterium abundances, but are limited by the desired chemical reactions. Furthermore, depending on the severity of the synthetic reaction used, the labeled molecule may be altered. On the other hand, exchange techniques can produce lower tritium or deuterium incorporation, typically with the isotope distributed at many sites on the molecule, but offer the advantage of not requiring a separate synthetic step and being less likely to disrupt the structure of the labeled molecule.

[0149] The compounds disclosed herein can be prepared by methods known to those skilled in the art, with their conventional modifications, and / or by procedures found in: Esaki et al., Tetrahedron 2006, 62, 10954-10961; Smith et al., Organic Syntheses 2002, 78, 51-56; U.S. Patent No. 3,974,281; U.S. Patent No. 8,680,123; WO 2003 / 014087; WO 2008 / 157786; WO 2009 / 035598; WO 2012 / 122165; or WO 2015 / 112701; the entire contents of each of which are incorporated herein by reference, along with the references cited therein and their conventional modifications.

[0150] Methods, compositions, and administration for treating fibrosis-mediated and / or collagen-mediated conditions.

[0151] This document discloses methods for treating, preventing, and / or improving fibrosis-mediated conditions and / or collagen-mediated conditions and / or inflammatory conditions, the methods comprising administering to a subject in need a deuterium-rich pirfenidone compound disclosed herein, such as compounds of formula I, such as those listed in Table 1, including, for example, LYT-100. This document discloses methods for treating, preventing, and / or improving one or more symptoms of fibrosis-mediated conditions and / or collagen-mediated conditions and / or inflammatory conditions, the methods comprising administering to a subject in need a deuterium-rich pirfenidone compound disclosed herein, such as compounds of formula I, such as those listed in Table 1, including, for example, LYT-100. This document discloses methods for treating, preventing, and / or improving fibrosis-mediated conditions, the methods comprising administering to a subject in need a deuterium-rich pirfenidone compound disclosed herein, such as compounds of formula I, such as those listed in Table 1, including, for example, LYT-100. This document discloses methods for treating, preventing, and / or improving one or more symptoms of fibrosis-mediated conditions, the methods comprising administering to a subject in need a deuterium-rich pirfenidone compound disclosed herein, such as compounds of formula I, such as those listed in Table 1, including, for example, LYT-100. This document also discloses methods for treating, preventing, and / or improving collagen-mediated conditions, the methods comprising administering to a subject in need a deuterium-rich pirfenidone compound disclosed herein, such as compounds of formula I, such as those listed in Table 1, including, for example, LYT-100. Finally, this document discloses methods for treating, preventing, and / or improving one or more symptoms of collagen-mediated conditions, the methods comprising administering to a subject in need a deuterium-rich pirfenidone compound disclosed herein, such as compounds of formula I, such as those listed in Table 1, including, for example, LYT-100. This document discloses methods for treating, preventing, and / or improving inflammatory conditions, the methods comprising administering to a subject in need a deuterium-rich pirfenidone compound disclosed herein, such as compounds of formula I, such as those listed in Table 1, including, for example, LYT-100. This document also discloses methods for treating, preventing, and / or improving one or more symptoms of an inflammatory condition, the methods comprising administering to a subject in need a deuterium-rich pirfenidone compound disclosed herein, such as compounds of formula I, such as those listed in Table 1, including, for example, LYT-100.

[0152] Fibrosis-mediated conditions and / or collagen-mediated conditions include, but are not limited to, idiopathic pulmonary fibrosis, uterine fibroids, multiple sclerosis, renal fibrosis, diabetic kidney disease, endotoxin-induced liver injury after partial hepatectomy or liver ischemia, allogeneic transplant injury after organ transplantation, cystic fibrosis, atrial fibrosis, neutropenia, scleroderma, dermatomyositis, cirrhosis, diffuse parenchymal lung disease, mediastinal fibrosis, pulmonary tuberculosis, splenic fibrosis caused by sickle cell anemia, rheumatoid arthritis, edema, lymphedema, and / or any condition that can be improved by regulating fibrosis and / or collagen infiltration into tissues.

[0153] In some embodiments, the deuterium-rich pirfenidone compound used in the disclosed method has at least one of the following properties: a) reduced inter-individual variability in plasma levels of the compound or its metabolites compared to non-isotopically enriched compounds; b) increased mean plasma levels per dose unit of the compound compared to non-isotopically enriched compounds; c) decreased mean plasma levels per dose unit of at least one metabolite of the compound compared to non-isotopically enriched compounds; d) increased mean plasma levels per dose unit of at least one metabolite of the compound compared to non-isotopically enriched compounds; and e) improved clinical efficacy per dose unit during treatment in subjects compared to non-isotopically enriched compounds. Therefore, this document discloses methods for treating subjects who have or are suspected of having fibrosis-mediated and / or collagen-mediated conditions (such as any of the conditions disclosed herein), including humans, or for preventing such conditions in subjects susceptible to said conditions; said methods include administering to said subject a therapeutically effective amount of a deuterium-rich pirfenidone compound, such as those disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; to achieve one or more of a)-e) above compared to corresponding non-isotopically enriched compounds during treatment of the condition. In some embodiments, the deuterium-rich pirfenidone compound has at least two of the properties a) to e) above. In some embodiments, the deuterium-rich pirfenidone compound has at least three of the properties a) to e) above.

[0154] In one embodiment, a method is provided for treating, preventing, or improving one or more symptoms of fibrosis-mediated and / or collagen-mediated conditions. Fibrosis-mediated and / or collagen-mediated conditions include, but are not limited to, idiopathic pulmonary fibrosis, uterine fibroids, multiple sclerosis, renal fibrosis, diabetic kidney disease, endotoxin-induced liver injury following partial hepatectomy or hepatic ischemia, allogeneic transplant injury after organ transplantation, cystic fibrosis, atrial fibrosis, neutropenia, scleroderma, dermatomyositis, cirrhosis, diffuse parenchymal lung disease, mediastinal fibrosis, pulmonary tuberculosis, splenic fibrosis due to sickle cell anemia, rheumatoid arthritis, and / or any condition that can be improved by modulating fibrosis and / or collagen infiltration into tissues.

[0155] This document discloses methods for treating subjects who have or are suspected of having fibrosis-mediated and / or collagen-mediated conditions (such as any of the conditions disclosed herein), including humans, or for preventing such conditions in subjects susceptible to said conditions; said methods include administering to said subject a therapeutically effective amount of a deuterium-rich pirfenidone compound, such as that disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; to achieve a reduction in inter-individual variability in plasma levels of the compound or its metabolites during treatment of the condition compared to corresponding non-isotopically enriched compounds. In some embodiments, the inter-individual variability in plasma levels of the compound or its metabolites, such as that disclosed herein, is reduced by more than about 2%, more than about 5%, more than about 10%, more than about 15%, more than about 20%, more than about 25%, more than about 30%, more than about 40%, or more than about 50% (including any numerical increments between the listed percentages) compared to corresponding non-isotopically enriched compounds.

[0156] This document discloses methods for treating subjects who have or are suspected of having fibrosis-mediated and / or collagen-mediated conditions (such as any of the conditions disclosed herein), including humans, or for preventing such conditions in subjects susceptible to said conditions; said methods include administering to said subject a therapeutically effective amount of a deuterium-rich pirfenidone compound, such as that disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; such that, compared to a corresponding non-isotopically enriched compound, the mean plasma level of the compound per dose unit is increased or the mean plasma level of at least one metabolite of the compound is decreased. In some embodiments, the mean plasma level of the compound, such as that disclosed herein, is increased by more than about 2%, more than about 5%, more than about 10%, more than about 15%, more than about 20%, more than about 25%, more than about 30%, more than about 40%, or more than about 50% (including any numerical increments between the listed percentages) compared to a corresponding non-isotopically enriched compound. In some embodiments, the average plasma levels of metabolites of compounds such as those disclosed herein are reduced by more than about 2%, more than about 5%, more than about 10%, more than about 15%, more than about 20%, more than about 25%, more than about 30%, more than about 40%, or more than about 50% (including any numerical increments between the listed percentages) compared to corresponding non-isotopically enriched compounds.

[0157] Plasma levels of compounds or their metabolites disclosed herein can be measured using the methods described by Li et al. (Rapid Communications in Mass Spectrometry 2005, 19, 1943-1950).

[0158] In some embodiments, compared to the non-isotope-enriched compound, each dose unit of the compound in the subject contains at least one polymorphically expressed cytochrome P. 450 The isoform reduces the metabolism of the compound.

[0159] In some implementations, cytochrome P 450 Isotypes are selected from CYP2C8, CYP2C9, CYP2C19 and CYP2D6.

[0160] In some embodiments, the compound is characterized in that, compared to non-isotope-enriched compounds, each dose unit of the compound provides an effect on at least one cytochrome P in the subject. 450 Or the inhibitory effect of monoamine oxidase isoforms may be reduced.

[0161] In some implementations, cytochrome P 450Or monoamine oxidase isoforms selected from CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2G1, CYP2J2, CYP2R1, CYP2S1, CYP3A4, CYP3A5, CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11, CYP4B1, CYP 4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4X1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1, CYP11A1, C YP11B1, CYP11B2, CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, CYP27A1, CYP27B1, CYP39, CYP46, CYP51, MAO A and MAO B .

[0162] In some embodiments, the deuterium-rich pirfenidone compound has at least one of the following properties: a) a half-life exceeding 2.5 hours; b) reduced pill burden; c) increased patient tolerability; d) lower effective dose; e) increased bioavailability; f) increased Cmax; and g) increased systemic exposure of the subject per dose unit of the compound during treatment compared to non-isotope-rich compounds. This document discloses methods for treating subjects with or suspected of having fibrosis-mediated and / or collagen-mediated conditions (such as any of the conditions disclosed herein), including humans, or for preventing such conditions in subjects susceptible to them; the methods comprising administering to the subject a therapeutically effective amount of a deuterium-rich pirfenidone compound, such as those disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; to achieve one or more of a)-g) above compared to corresponding non-isotope-rich compounds during treatment of the condition.

[0163] This document discloses methods for treating subjects who have or are suspected of having fibrosis-mediated and / or collagen-mediated conditions (such as any of the conditions disclosed herein), including humans, or for preventing such conditions in subjects susceptible to said conditions; said methods include administering to said subject a therapeutically effective amount of a deuterium-rich pirfenidone compound, such as that disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, to achieve a longer half-life. In some embodiments, the half-life of a deuterium-rich pirfenidone compound, such as that disclosed herein, or its metabolites, is increased by more than about 2%, more than about 5%, more than about 10%, more than about 15%, more than about 20%, more than about 25%, more than about 30%, more than about 40%, more than about 50%, more than about 60%, more than about 70%, more than about 80%, more than about 90%, or more than about 100% (including any numerical increments between the listed percentages) compared to the corresponding non-isotopically enriched compounds. In some embodiments, the half-life of deuterium-rich pirfenidone compounds or their metabolites, such as those disclosed herein, is increased by about 1.5 times, about 2 times, more than about 2 times, more than about 3 times, more than about 4 times, more than about 5 times, more than about 10 times or more (including any numerical increments between the listed percentages) compared to the corresponding non-isotopically enriched compounds.

[0164] This document discloses methods for treating subjects who have or are suspected of having fibrosis-mediated and / or collagen-mediated conditions (such as any of the conditions disclosed herein), including humans, or for preventing such conditions in subjects susceptible to said conditions; said methods include administering to said subject a therapeutically effective amount of a deuterium-rich pirfenidone compound, such as that disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; in order to reduce pill burden, for example, to achieve a pill burden of fewer than nine (9) capsules per day (TID) of the compound or its metabolites during treatment of the condition, compared to the corresponding non-isotope-enriched compound.

[0165] In some embodiments, the pill burden of compounds such as those disclosed herein is reduced by more than about 2%, more than about 5%, more than about 10%, more than about 15%, more than about 20%, more than about 25%, more than about 30%, more than about 40%, or more than about 50% (including any numerical increments between the listed percentages) compared to corresponding non-isotopically enriched compounds.

[0166] This document discloses methods for treating subjects with or suspected of having fibrosis-mediated and / or collagen-mediated conditions (such as any of the conditions disclosed herein), including humans, or for preventing such conditions in subjects susceptible to said conditions; said methods include administering to said subject a therapeutically effective amount of a deuterium-rich pirfenidone compound, such as those disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; to achieve increased patient tolerability of the compound or its metabolites during treatment of the condition compared to corresponding non-isotopically enriched compounds. In some embodiments, patient tolerability is increased by altering pharmacokinetics, for example by increasing bioavailability (to use a lower dose) and / or by prolonging the half-life of the compound and / or by other means of reducing the side effects of pirfenidone.

[0167] In some embodiments, patient tolerability is increased by more than about 2%, more than about 5%, more than about 10%, more than about 15%, more than about 20%, more than about 25%, more than about 30%, more than about 40%, more than about 50%, more than about 60%, more than about 70%, more than about 80%, more than about 90%, or more than about 100% (including any numerical increments between the listed percentages) compared to corresponding non-isotopically enriched compounds. In some embodiments, patient tolerability is increased by about 1.5 times, more than 2 times, more than about 2 times, more than about 3 times, more than about 4 times, more than about 5 times, more than about 10 times, or more (including any numerical increments between the listed percentages) compared to corresponding non-isotopically enriched compounds.

[0168] This document discloses methods for treating subjects who have or are suspected of having fibrosis-mediated and / or collagen-mediated conditions (such as any of the conditions disclosed herein), including humans, or for preventing such conditions in subjects susceptible to said conditions; said methods include administering to said subject a therapeutically effective amount of a deuterium-rich pirfenidone compound, such as those disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; to achieve a lower effective dose of the compound or its metabolites per dose compared to corresponding non-isotope-enriched compounds during treatment of the condition.

[0169] In some embodiments, the effective dose of each dose of the compound or its metabolites disclosed herein is reduced by more than about 2%, more than about 5%, more than about 10%, more than about 15%, more than about 20%, more than about 25%, more than about 30%, more than about 40%, more than about 50%, more than about 60%, more than about 70%, more than about 80%, more than about 90%, or more than about 100% (including any numerical increments between the listed percentages) compared to the corresponding non-isotopically enriched compounds. In some embodiments, the effective dose of each dose of the compound or its metabolites disclosed herein is reduced by about 1.5 times, more than 2 times, more than about 2 times, more than about 3 times, more than about 4 times, more than about 5 times, more than about 10 times, or more (including any numerical increments between the listed percentages) compared to the corresponding non-isotopically enriched compounds.

[0170] This document discloses methods for treating subjects who have or are suspected of having fibrosis-mediated and / or collagen-mediated conditions (such as any of the conditions disclosed herein), including humans, or for preventing such conditions in subjects susceptible to said conditions; said methods include administering to said subject a therapeutically effective amount of a deuterium-rich pirfenidone compound, such as those disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; in order to increase the bioavailability of each dose of the compound or its metabolites during treatment of the condition compared to corresponding non-isotopically enriched compounds.

[0171] In some embodiments, the bioavailability of each dose of the compound or its metabolites disclosed herein is increased by more than about 2%, more than about 5%, more than about 10%, more than about 15%, more than about 20%, more than about 25%, more than about 30%, more than about 40%, more than about 50%, more than about 60%, more than about 70%, more than about 80%, more than about 90%, or more than about 100% (including any numerical increments between the listed percentages) compared to the corresponding non-isotopically enriched compounds. In some embodiments, the bioavailability of each dose of the compound or its metabolites disclosed herein is increased by about 1.5-fold, decreased by about 2-fold, more than about 2-fold, more than about 3-fold, more than about 4-fold, more than about 5-fold, more than about 10-fold, or more (including any numerical increments between the listed percentages) compared to the corresponding non-isotopically enriched compounds.

[0172] This document discloses methods for treating subjects who have or are suspected of having or are suspected of having fibrosis-mediated and / or collagen-mediated conditions (such as any of the conditions disclosed herein), including humans, or for preventing such conditions in subjects susceptible to said conditions; said methods include administering to said subject a therapeutically effective amount of a deuterium-rich pirfenidone compound, such as those disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; to affect systemic exposure per unit dose of the compound by an increase compared to the corresponding non-isotopically enriched compound.

[0173] In some embodiments, the systemic exposure per dose of the compound or its metabolites disclosed herein is increased by more than about 10%, more than about 15%, more than about 20%, more than about 25%, more than about 30%, more than about 35%, more than about 40%, more than about 45%, or more than about 50% (including any numerical increments between the listed percentages) compared to the corresponding non-isotopically enriched compound. In one embodiment, the systemic exposure per dose of the compound disclosed herein is increased by more than about 35% compared to the corresponding non-isotopically enriched compound. In one embodiment, the systemic exposure per dose of the compound disclosed herein is increased by about 35% compared to the corresponding non-isotopically enriched compound.

[0174] This document discloses methods for treating subjects who have or are suspected of having or are suspected of having fibrosis-mediated and / or collagen-mediated conditions (such as any of the conditions disclosed herein), including humans, or for preventing such conditions in subjects susceptible to said conditions; said methods include administering to said subject a therapeutically effective amount of a deuterium-rich pirfenidone compound, such as those disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; such that the Cmax of the compound per dose unit increases compared to the corresponding non-isotopically enriched compound.

[0175] In some embodiments, the Cmax of each dose of the compound or its metabolites disclosed herein is increased by more than about 10%, more than about 15%, more than about 20%, more than about 25%, more than about 30%, more than about 35%, more than about 40%, more than about 45%, or more than about 50% (including any numerical increments between the listed percentages) compared to the corresponding non-isotopically enriched compound. In one embodiment, the Cmax of each dose of the compound disclosed herein is increased by more than about 25% compared to the corresponding non-isotopically enriched compound. In one embodiment, the Cmax of each dose of the compound disclosed herein is increased by about 25% compared to the corresponding non-isotopically enriched compound.

[0176] In some embodiments, the method treats the condition while reducing or eliminating harmful changes in diagnostic hepatobiliary function endpoints compared to corresponding non-isotopically enriched compounds such as pirfenidone. This document discloses methods for treating subjects with or suspected of having fibrosis-mediated and / or collagen-mediated conditions (such as any of the conditions disclosed herein), including humans, or for preventing such conditions in subjects susceptible to said conditions; said methods include administering to said subject a therapeutically effective amount of a compound such as those disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; to reduce or eliminate harmful changes in diagnostic hepatobiliary function endpoints compared to corresponding non-isotopically enriched compounds. In some implementations, diagnostic hepatobiliary function endpoints are selected from alanine aminotransferase (“ALT”), serum glutamate-pyruvate transaminase (“SGPT”), aspartate aminotransferase (“AST”, “SGOT”), ALT / AST ratio, serum aldolase, alkaline phosphatase (“ALP”), ammonia level, bilirubin, gamma-glutamyl transferase (“GGTP”, “γ-GTP”, “GGT”), leucine aminopeptidase (“LAP”), liver biopsy, liver ultrasound, hepatic smear, 5'-nucleotidase, and serum proteins.

[0177] This document discloses methods for treating, preventing, and / or improving fibrosis-mediated and / or collagen-mediated conditions, and methods for treating, preventing, and / or improving one or more symptoms of fibrosis-mediated and / or collagen-mediated conditions, said methods comprising administering to a subject in need a deuterium-rich pirfenidone compound disclosed herein, such as compounds of formula I, such as those listed in Table 1, including, for example, LYT-100, and further comprising administering one or more additional therapeutic agents selected from anti-T-cell agents, anti-inflammatory agents, anti-TGF-βI agents, and anti-angiotensin agents. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent. In some embodiments, the additional therapeutic agent is an anti-T-cell agent. In some embodiments, the additional therapeutic agent is an anti-TGF-βI agent. In some embodiments, the additional therapeutic agent is an anti-angiotensin agent.

[0178] In some embodiments, the therapeutic agent is deuterium-rich pirfenidone, or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutic agent is LYT-100, or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutic agent is deuterium-rich pirfenidone, or a pharmaceutically acceptable salt thereof, in combination with one or more other therapeutic agents, such as any other therapeutic agents disclosed herein.

[0179] In any of the above embodiments, a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally twice daily for a total daily dose of 100-1500 mg. In some embodiments, the daily dose is 100, 200, 250, 300, 400, 500, 600, 700, 750, 800, 900, 1000, or 1500 mg. In some embodiments, the daily dose is 1500 mg. In some embodiments, the daily dose is 1000 mg. In some embodiments, the daily dose is 750 mg. In some embodiments, the daily dose is 500 mg. In some embodiments, the daily dose is 250 mg. In some embodiments, 750 mg of deuterium-rich pirfenidone is taken orally twice daily. In some embodiments, 500 mg of deuterium-rich pirfenidone is taken orally twice daily. In some embodiments, 250 mg of deuterium-rich pirfenidone is taken orally twice daily.

[0180] In some embodiments, a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally once daily at a total daily dose of 100-1500 mg. In some embodiments, the daily dose is 100, 200, 250, 300, 400, 500, 600, 700, 750, 800, 900, 1000, or 1500 mg. In some embodiments, the daily dose is 1500 mg. In some embodiments, the daily dose is 1000 mg. In some embodiments, the daily dose is 750 mg. In some embodiments, the daily dose is 500 mg. In some embodiments, the daily dose is 250 mg. In some embodiments, 1500 mg of deuterium-rich pirfenidone is taken orally once daily. In some embodiments, 1000 mg of deuterium-rich pirfenidone is taken orally once daily. In some embodiments, 750 mg of deuterium-rich pirfenidone is taken orally once daily. In some implementations, 500 mg of deuterium-rich pirfenidone is taken orally once daily. In some implementations, 250 mg of deuterium-rich pirfenidone is taken orally once daily.

[0181] In any of the above embodiments, a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally three times daily for a total daily dose of 100-1500 mg. In some embodiments, the daily dose is 100, 200, 250, 300, 400, 500, 600, 700, 750, 800, 900, 1000, or 1500 mg. In some embodiments, the daily dose is 1500 mg. In some embodiments, the daily dose is 1000 mg. In some embodiments, the daily dose is 750 mg. In some embodiments, the daily dose is 500 mg. In some embodiments, the daily dose is 250 mg. In some embodiments, 500 mg of deuterium-rich pirfenidone is taken orally three times daily. In some embodiments, 333 mg of deuterium-rich pirfenidone is taken orally three times daily. In some embodiments, 166 mg of deuterium-rich pirfenidone is taken orally three times daily.

[0182] In some embodiments, deuterium-enriched pirfenidone is in tablet form. In some embodiments, deuterium-enriched pirfenidone is taken orally with food.

[0183] Therefore, this document provides methods for treating, preventing, and / or improving fibrosis-mediated and / or collagen-mediated conditions, the methods comprising administering to a subject in need a deuterium-rich pirfenidone compound, such as compounds of formula I, such as those listed in Table 1, including, for example, LYT-100, wherein the deuterium-rich pirfenidone compound is orally administered twice daily for a total daily dose of 100-1500 mg. In some embodiments, this document provides methods for treating, preventing, and / or improving fibrosis-mediated and / or collagen-mediated conditions, the methods comprising administering to a subject in need LYT-100, wherein LYT-100 is orally administered twice daily for a total daily dose of 100-1500 mg. In some embodiments, the daily dose of the deuterium-rich pirfenidone compound, such as LYT-100, is 1500 mg. In some embodiments, the daily dose of the deuterium-rich pirfenidone compound, such as LYT-100, is 1000 mg. In some embodiments, the daily dose of a deuterium-rich pirfenidone compound, such as LYT-100, is 750 mg. In some embodiments, the daily dose of a deuterium-rich pirfenidone compound, such as LYT-100, is 500 mg. In some embodiments, the daily dose of a deuterium-rich pirfenidone compound, such as LYT-100, is 250 mg. In some embodiments, 750 mg of a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally twice daily. In some embodiments, 500 mg of a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally twice daily. In some embodiments, 250 mg of a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally twice daily.

[0184] In some embodiments, this document provides methods for treating, preventing, and / or improving fibrosis-mediated and / or collagen-mediated conditions, the methods comprising administering to a subject in need a deuterium-rich pirfenidone compound, such as compounds of formula I, such as those listed in Table 1, including, for example, LYT-100, wherein the deuterium-rich pirfenidone compound is taken orally once daily for a total daily dose of 100-1500 mg. In some embodiments, this document provides methods for treating, preventing, and / or improving fibrosis-mediated and / or collagen-mediated conditions, the methods comprising administering to a subject in need LYT-100, wherein LYT-100 is taken orally once daily for a total daily dose of 100-1500 mg. In some embodiments, the daily dose of the deuterium-rich pirfenidone compound, such as LYT-100, is 1500 mg. In some embodiments, the daily dose of the deuterium-rich pirfenidone compound, such as LYT-100, is 1000 mg. In some embodiments, the daily dose of a deuterium-rich pirfenidone compound, such as LYT-100, is 750 mg. In some embodiments, the daily dose of a deuterium-rich pirfenidone compound, such as LYT-100, is 500 mg. In some embodiments, the daily dose of a deuterium-rich pirfenidone compound, such as LYT-100, is 250 mg. In some embodiments, a 1500 mg dose of a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally once daily. In some embodiments, a 1000 mg dose of a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally once daily. In some embodiments, a 750 mg dose of a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally once daily. In some embodiments, a 500 mg dose of a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally once daily. In some implementations, 250 mg of a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally once daily.

[0185] Therefore, this document provides methods for treating, preventing, and / or improving fibrosis-mediated and / or collagen-mediated conditions, the methods comprising administering to a subject in need a deuterium-rich pirfenidone compound, such as compounds of formula I, such as those listed in Table 1, including, for example, LYT-100, wherein the deuterium-rich pirfenidone compound is orally administered three times daily for a total daily dose of 100-1500 mg. In some embodiments, this document provides methods for treating, preventing, and / or improving fibrosis-mediated and / or collagen-mediated conditions, the methods comprising administering to a subject in need LYT-100, wherein LYT-100 is orally administered three times daily for a total daily dose of 100-1500 mg. In some embodiments, the daily dose of the deuterium-rich pirfenidone compound, such as LYT-100, is 1500 mg. In some embodiments, the daily dose of the deuterium-rich pirfenidone compound, such as LYT-100, is 1000 mg. In some embodiments, the daily dose of a deuterium-rich pirfenidone compound, such as LYT-100, is 750 mg. In some embodiments, the daily dose of a deuterium-rich pirfenidone compound, such as LYT-100, is 500 mg. In some embodiments, the daily dose of a deuterium-rich pirfenidone compound, such as LYT-100, is 250 mg. In some embodiments, 500 mg of a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally three times daily. In some embodiments, 333 mg of a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally three times daily. In some embodiments, 166 mg of a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally twice daily.

[0186] In other embodiments, the deuterium-rich pirfenidone compound is administered orally at a total daily dose of 100-2500 mg. In some embodiments, the deuterium-rich pirfenidone compound is administered orally at a total daily dose of 100-2000 mg. In some embodiments, the deuterium-rich pirfenidone compound is administered orally at a total daily dose of 100-1500 mg. In some embodiments, the deuterium-rich pirfenidone compound is administered orally at a total daily dose of 100-1000 mg. In some embodiments, the deuterium-rich pirfenidone compound is administered orally at a total daily dose of 100-500 mg. In some embodiments, the daily dose is selected from 100, 200, 250, 300, 400, 500, 600, 700, 750, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, and 2500 mg / day. In some embodiments, the deuterium-rich pirfenidone compound is taken orally three times daily (TID). In some embodiments, the deuterium-rich pirfenidone compound is taken orally twice daily (BID). In some embodiments, the deuterium-rich pirfenidone compound is taken orally once daily (QD). In any of these embodiments, the deuterium-rich pirfenidone compound has the structure of Formula I, such as the compounds listed in Table 1, including, for example, LYT-100.

[0187] Methods, compositions, and dosing for treating edema

[0188] As used herein, the term "edema" refers to an abnormal accumulation of fluid beneath the skin and within body cavities, including but not limited to the extremities, hands / feet, upper body (chest / chest wall, shoulders, back), lower body (buttocks, abdomen), genitals (scrotum, penis, vulva), head, neck, or face. Abnormal fluid accumulation can occur when capillary filtration exceeds lymphatic drainage. Thus, all edema has a lymphatic component. Edema includes lymphedema, lymphatic dysfunction, lymphoid fibrosis, idiopathic edema, peripheral edema, and ocular edema. Edema includes acute edema, chronic edema, postoperative edema, progressively developing edema, primary edema, and secondary edema. Chronic edema is edema that has been present for more than three months and may include lymphedema (primary lymphatic developmental failure and secondary lymphatic injury), venous edema, chronic swelling due to immobility, edema associated with advanced cancer, chronic swelling associated with lymphedema, chronic swelling associated with obesity, and chronic swelling associated with rare vascular malformations (such as Klippel-Trenaunay syndrome). Symptoms of edema may include the accumulation of fluid under the skin and within body cavities, swelling, fullness or edema of tissues, inflammation, fibrosis, heaviness, pain, reduced range of motion, aches, recurrent infections, thickened or uncomfortable skin. In some implementations, "edema" does not include pulmonary edema or cerebral edema. In some implementations, edema is lymphedema. In some implementations, lymphedema is primary lymphedema. In some implementations, lymphedema is secondary lymphedema.

[0189] Lymphedema is a chronic condition that afflicts thousands of people, characterized by severe swelling of parts of the body (usually the arms or legs) due to the accumulation of lymph fluid, along with inflammation, fibrosis, and fat deposits. Lymph fluid is a clear liquid collected from the body's tissues that transports fats and proteins through the small intestine, removes bacteria, viruses, toxins, and certain proteins from tissues, and delivers white blood cells, particularly lymphocytes, into the bloodstream to help fight infections and other diseases. Lymphedema is a chronic, debilitating disease caused by fibrosis and inflammation, and in developed countries like the United States, it is most commonly a complication of cancer treatment. Therefore, secondary lymphedema is the most common form of lymphedema, which can develop after surgery, infection, or trauma, and is often caused by cancer, cancer treatments (such as radiation and chemotherapy), trauma, or infection that results in damage to or removal of lymph nodes. As a complication of cancer treatment, lymphedema is caused by iatrogenic damage to the lymphatic system, usually due to lymph node dissection. It is estimated that one in three patients who undergo lymph node dissection will later develop lymphedema. Larger skin excisions and radiation-assisted therapy can also cause lymphedema. In addition, obesity and radiation exposure are known risk factors for the development of lymphedema.

[0190] In areas endemic for lymphatic filariasis, leg lymphedema and its later form known as elephantiasis are significant causes of disability and morbidity, with an estimated 14 million people infected worldwide (Stocks et al., PLoS Negl Trop Dis. 2015 Oct 23; 9(10):e0004171). More than 1.1 billion people globally are at risk of lymphatic filariasis (Walsh et al., PLoS Negl Trop Dis. 2016 Aug 22; 10(8):e0004917). Lymphatic filariasis is distributed in Latin America, Central Africa, South Asia, and the Pacific Islands. Filariasis is mosquito-borne, but efforts to control transmission based solely on mosquito control have had limited success (Lammie et al., Ann NY Acad Sci. 2002 Dec; 979:131-42; Discussion 188-96). Wuchereria bancrofti (Wb) is the most widespread of the three known nematodes causing lymphatic filariasis (LF), the other two being Brucella malayi and Brucella timori. Wuchereria bancrofti is responsible for 90% of lymphatic filariasis cases in humans. Filariasis infection can cause a variety of clinical manifestations, including lymphedema of the extremities, genital diseases (hydroscrotal hydrops, chylous cysts of the scrotum, and swelling of the scrotum and penis), and recurrent acute attacks. These acute attacks are caused by secondary infections that trigger lymphatic damage in the lower extremities, resulting in extreme pain and fever. Most infected individuals are asymptomatic, but in reality, all of them suffer from subclinical lymphatic damage, and up to 40% develop kidney damage, accompanied by proteinuria and hematuria.

[0191] Lymphedema is a serious condition with severe health consequences, including physical deformities and weakness. Patients experience persistent swelling, heaviness, pain, discomfort, skin lesions, fibrosis, recurrent infections, limited mobility, and a decreased quality of life in the affected limb.

[0192] Dysfunction of the lymphatic system remains largely untreated or poorly addressed by current therapies. There are currently no approved drug treatments for lymphedema. Furthermore, there are no known drug treatments that can halt the progression of lymphedema or promote its resolution. The current standard of care for lymphedema is management, primarily through compression and physical therapy to control swelling. These methods are cumbersome, uncomfortable, and not curative, and do not address the underlying condition, especially in patients with more severe lymphedema. Even with management, some patients progress from mild to moderate lymphedema to more severe forms. At later stages, patients may seek ablation procedures, including liposuction or fat reduction. These procedures reduce volume but do not restore lymphatic fluid flow, leading to dependence on compression. Given the current lack of drug treatments addressing the underlying cause of lymphedema, the development of targeted therapies for lymphedema represents an unmet need in biomedicine.

[0193] Progress in developing meaningful treatments for lymphatic diseases has been minimal. Previous experimental treatments for lymphedema have focused on the delivery of lymphangiogenic cytokines. (Skobe et al., Nat. Med. 7:192-198 (2001)). For example, some previous studies have focused on repairing damaged lymphatic vessels using lymphangiogenic cytokines such as vascular endothelial growth factor-c (VEGF-C) (Tammela et al., Nat. Med. 13:1458-1466 (2007); Baker et al., Breast Cancer Res. 12:R70 (2010)). However, since these same mechanisms regulate tumor growth and metastasis, increasing the risk of cancer metastasis or recurrence, the application of this approach, particularly for cancer patients, may be untenable.

[0194] In some embodiments, this disclosure provides a method for treating edema, the method comprising administering to a subject in need a deuterium-rich pirfenidone compound disclosed herein, such as compounds of formula I, such as those listed in Table 1, including, for example, LYT-100. In some embodiments, this disclosure provides a method for treating lymphedema, the method comprising administering to a subject in need a deuterium-rich pirfenidone compound disclosed herein, such as compounds of formula I, such as those listed in Table 1, including, for example, LYT-100. In some embodiments, this disclosure provides a method for treating secondary lymphedema, the method comprising administering to a subject in need a deuterium-rich pirfenidone compound disclosed herein, such as compounds of formula I, such as those listed in Table 1, including, for example, LYT-100. In some embodiments, this disclosure provides a method for treating primary lymphedema, the method comprising administering to a subject in need a deuterium-rich pirfenidone compound disclosed herein, such as compounds of formula I, such as those listed in Table 1, including, for example, LYT-100.

[0195] In some embodiments, lymphedema occurs in one or both arms, such as in the hand, wrist, forearm, elbow, upper arm, shoulder, arm, or a combination of arm regions or the entire arm. In some embodiments, lymphedema occurs in one or both legs, such as in the foot, ankle, leg, knee, upper leg or thigh, groin, buttock, or a combination of leg regions or the entire leg. In some embodiments, lymphedema occurs in other areas of the head, neck, jaw, chest, breast, thoracic cavity, abdomen, pelvis, genitals, or body cavity. In some embodiments, lymphedema occurs in one or more limbs, or one or more limbs and another area of ​​the body.

[0196] In some implementations, lymphedema is caused by vascular defects, including venous insufficiency, venous malformations, arterial malformations, capillary malformations, lymphovascular malformations, or cardiovascular diseases.

[0197] In some implementations, the subject has or has had cancer, such as cancer containing a solid tumor. In some implementations, the subject has or has had breast cancer or cancer affecting the female reproductive organs, skin system, musculoskeletal system, soft tissues of the limbs or trunk, male reproductive system, urinary system, or head and neck. In some implementations, the subject has undergone axillary lymph node dissection. In some implementations, the subject has received cancer treatment, and edema, lymphedema, or lymph node damage is related to the cancer treatment or diagnosis. For example, the subject may be receiving or may have received chemotherapy or radiation therapy for cancer treatment or other indications, or may have had one or more lymph nodes surgically removed during cancer treatment or diagnosis.

[0198] In some implementations, the subject has persistent lymphatic damage (e.g., caused by the removal, ligation, or obstruction of lymph nodes or lymphatic vessels, or lymphoid fibrosis), or the subject is obese or has had or has had an infection that causes edema, such as lymphedema. In some implementations, the infection is a skin infection or a history of skin infection associated with lymphedema or lymphatic damage. In some implementations, the infection is a parasitic infection that obstructs lymphatic fluid flow or damages the lymphatic system. In some implementations, the subject has persistent lymphatic damage due to joint replacement, trauma, burns, radiation, or chemotherapy.

[0199] In some embodiments, this disclosure provides a method for preventing edema, the method comprising administering to a subject in need a deuterium-rich pirfenidone compound disclosed herein, such as compounds of formula I, such as those listed in Table 1, including, for example, LYT-100. In some embodiments, this disclosure provides a method for preventing lymphedema, the method comprising administering to a subject in need a deuterium-rich pirfenidone compound disclosed herein, such as compounds of formula I, such as those listed in Table 1, including, for example, LYT-100. In some embodiments, this disclosure provides a method for preventing secondary lymphedema, the method comprising administering to a subject in need a deuterium-rich pirfenidone compound disclosed herein, such as compounds of formula I, such as those listed in Table 1, including, for example, LYT-100. In some embodiments, this disclosure provides a method for preventing primary lymphedema, the method comprising administering to a subject in need a deuterium-rich pirfenidone compound disclosed herein, such as compounds of formula I, such as those listed in Table 1, including, for example, LYT-100.

[0200] In some embodiments, lymphedema occurs in one or both arms, such as in a combination of the hand, wrist, forearm, elbow, upper arm, shoulder, armpit, or arm area, or throughout the entire arm. In some embodiments, lymphedema occurs in one or both legs, such as in a combination of the foot, ankle, leg, knee, upper leg or thigh, groin, buttock, or leg area, or throughout the entire leg. In some embodiments, lymphedema occurs in other areas of the head, neck, jaw, chest, breast, thoracic cavity, abdomen, pelvis, genitals, or body cavity. In some embodiments, lymphedema occurs in one or more limbs, or one or more limbs and another area of ​​the body.

[0201] In some implementations, lymphedema is caused by vascular defects, including venous insufficiency, venous malformations, arterial malformations, capillary malformations, lymphovascular malformations, or cardiovascular diseases.

[0202] In some embodiments, this disclosure provides methods for improving one or more symptoms of edema, the methods comprising administering to a subject in need a deuterium-rich pirfenidone compound disclosed herein, such as compounds of formula I, such as those listed in Table 1, including, for example, LYT-100. In some embodiments, this disclosure provides methods for improving one or more symptoms of lymphedema, the methods comprising administering to a subject in need a deuterium-rich pirfenidone compound disclosed herein, such as compounds of formula I, such as those listed in Table 1, including, for example, LYT-100. In some embodiments, this disclosure provides methods for improving one or more symptoms of lymphedema, the methods comprising administering to a subject in need a deuterium-rich pirfenidone compound disclosed herein, such as compounds of formula I, such as those listed in Table 1, including, for example, LYT-100. In some embodiments, this disclosure provides a method for improving one or more symptoms of primary lymphedema, the method comprising administering to a subject in need a deuterium-rich pirfenidone compound disclosed herein, such as compounds of formula I, such as those listed in Table 1, including, for example, LYT-100.

[0203] In some embodiments, lymphedema occurs in one or both arms, such as in a combination of the hand, wrist, forearm, elbow, upper arm, shoulder, armpit, or arm area, or throughout the entire arm. In some embodiments, lymphedema occurs in one or both legs, such as in a combination of the foot, ankle, leg, knee, upper leg or thigh, groin, buttock, or leg area, or throughout the entire leg. In some embodiments, lymphedema occurs in other areas of the head, neck, jaw, chest, breast, thoracic cavity, abdomen, pelvis, genitals, or body cavity. In some embodiments, lymphedema occurs in one or more limbs, or one or more limbs and another area of ​​the body.

[0204] In some implementations, lymphedema is caused by vascular defects, including venous insufficiency, venous malformations, arterial malformations, capillary malformations, lymphovascular malformations, or cardiovascular diseases.

[0205] In any of the above methods for treating, preventing, or improving one or more symptoms of edema or lymphedema, a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally twice daily for a total daily dose of 100-1500 mg. In some embodiments, the daily dose is 100, 200, 250, 300, 400, 500, 600, 700, 750, 800, 900, 1000, or 1500 mg. In some embodiments, the daily dose is 1500 mg. In some embodiments, the daily dose is 1000 mg. In some embodiments, the daily dose is 750 mg. In some embodiments, the daily dose is 500 mg. In some embodiments, the daily dose is 250 mg. In some embodiments, 750 mg of deuterium-rich pirfenidone is taken orally twice daily. In some embodiments, 500 mg of deuterium-rich pirfenidone is taken orally twice daily. In some embodiments, 250 mg of deuterium-rich pirfenidone is taken orally twice daily.

[0206] In some embodiments, a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally once daily at a total daily dose of 100-1500 mg. In some embodiments, the daily dose is 100, 200, 250, 300, 400, 500, 600, 700, 750, 800, 900, 1000, or 1500 mg. In some embodiments, the daily dose is 1500 mg. In some embodiments, the daily dose is 1000 mg. In some embodiments, the daily dose is 750 mg. In some embodiments, the daily dose is 500 mg. In some embodiments, the daily dose is 250 mg. In some embodiments, 1500 mg of deuterium-rich pirfenidone is taken orally once daily. In some embodiments, 1000 mg of deuterium-rich pirfenidone is taken orally once daily. In some embodiments, 750 mg of deuterium-rich pirfenidone is taken orally once daily. In some implementations, 500 mg of deuterium-rich pirfenidone is taken orally once daily. In some implementations, 250 mg of deuterium-rich pirfenidone is taken orally once daily.

[0207] In any of the above embodiments, a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally three times daily for a total daily dose of 100-1500 mg. In some embodiments, the daily dose is 100, 200, 250, 300, 400, 500, 600, 700, 750, 800, 900, 1000, or 1500 mg. In some embodiments, the daily dose is 1500 mg. In some embodiments, the daily dose is 1000 mg. In some embodiments, the daily dose is 750 mg. In some embodiments, the daily dose is 500 mg. In some embodiments, the daily dose is 250 mg. In some embodiments, 500 mg of deuterium-rich pirfenidone is taken orally three times daily. In some embodiments, 333 mg of deuterium-rich pirfenidone is taken orally three times daily. In some embodiments, 166 mg of deuterium-rich pirfenidone is taken orally three times daily.

[0208] In some embodiments, deuterium-enriched pirfenidone is in tablet form. In some embodiments, deuterium-enriched pirfenidone is taken orally with food.

[0209] Therefore, this document provides a method for treating, preventing, and / or improving edema, such as lymphedema, the method comprising administering to a subject in need a deuterium-rich pirfenidone compound, such as a compound of formula I, such as those listed in Table 1, including, for example, LYT-100, wherein the deuterium-rich pirfenidone compound is taken orally twice daily for a total daily dose of 100-1500 mg. In some embodiments, this document provides a method for treating, preventing, and / or improving edema, such as lymphedema, the method comprising administering to a subject in need LYT-100, wherein the deuterium-rich pirfenidone compound is taken orally twice daily for a total daily dose of 100-1500 mg. In some embodiments, the daily dose of the deuterium-rich pirfenidone compound, such as LYT-100, is 1500 mg. In some embodiments, the daily dose of the deuterium-rich pirfenidone compound, such as LYT-100, is 1000 mg. In some embodiments, the daily dose of a deuterium-rich pirfenidone compound, such as LYT-100, is 750 mg. In some embodiments, the daily dose of a deuterium-rich pirfenidone compound, such as LYT-100, is 500 mg. In some embodiments, the daily dose of a deuterium-rich pirfenidone compound, such as LYT-100, is 250 mg. In some embodiments, 750 mg of a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally twice daily. In some embodiments, 500 mg of a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally twice daily. In some embodiments, 250 mg of a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally twice daily.

[0210] In some embodiments, this document provides a method for treating, preventing, and / or improving edema, such as lymphedema, the method comprising administering to a subject in need a deuterium-rich pirfenidone compound, such as a compound of formula I, such as those listed in Table 1, including, for example, LYT-100, wherein the deuterium-rich pirfenidone compound is taken orally once daily for a total daily dose of 100-1500 mg. In some embodiments, this document provides a method for treating, preventing, and / or improving edema, such as lymphedema, the method comprising administering to a subject in need LYT-100, wherein the deuterium-rich pirfenidone compound is taken orally once daily for a total daily dose of 100-1500 mg. In some embodiments, the daily dose of the deuterium-rich pirfenidone compound, such as LYT-100, is 1500 mg. In some embodiments, the daily dose of the deuterium-rich pirfenidone compound, such as LYT-100, is 1000 mg. In some embodiments, the daily dose of a deuterium-rich pirfenidone compound, such as LYT-100, is 750 mg. In some embodiments, the daily dose of a deuterium-rich pirfenidone compound, such as LYT-100, is 500 mg. In some embodiments, the daily dose of a deuterium-rich pirfenidone compound, such as LYT-100, is 250 mg. In some embodiments, a 1500 mg dose of a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally once daily. In some embodiments, a 1000 mg dose of a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally once daily. In some embodiments, a 750 mg dose of a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally once daily. In some embodiments, a 500 mg dose of a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally once daily. In some implementations, 250 mg of a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally once daily.

[0211] Therefore, this document provides a method for treating, preventing, and / or improving edema, such as lymphedema, the method comprising administering to a subject in need a deuterium-rich pirfenidone compound, such as a compound of formula I, such as those listed in Table 1, including, for example, LYT-100, wherein the deuterium-rich pirfenidone compound is orally administered three times daily for a total daily dose of 100-1500 mg. In some embodiments, this document provides a method for treating, preventing, and / or improving edema, such as lymphedema, the method comprising administering to a subject in need LYT-100, wherein LYT-100 is orally administered three times daily for a total daily dose of 100-1500 mg. In some embodiments, the daily dose of the deuterium-rich pirfenidone compound, such as LYT-100, is 1500 mg. In some embodiments, the daily dose of the deuterium-rich pirfenidone compound, such as LYT-100, is 1000 mg. In some embodiments, the daily dose of a deuterium-rich pirfenidone compound, such as LYT-100, is 750 mg. In some embodiments, the daily dose of a deuterium-rich pirfenidone compound, such as LYT-100, is 500 mg. In some embodiments, the daily dose of a deuterium-rich pirfenidone compound, such as LYT-100, is 250 mg. In some embodiments, 500 mg of a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally three times daily. In some embodiments, 333 mg of a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally three times daily. In some embodiments, 166 mg of a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally twice daily.

[0212] In other embodiments, the deuterium-rich pirfenidone compound is administered orally at a total daily dose of 100-2500 mg. In some embodiments, the deuterium-rich pirfenidone compound is administered orally at a total daily dose of 100-2000 mg. In some embodiments, the deuterium-rich pirfenidone compound is administered orally at a total daily dose of 100-1500 mg. In some embodiments, the deuterium-rich pirfenidone compound is administered orally at a total daily dose of 100-1000 mg. In some embodiments, the deuterium-rich pirfenidone compound is administered orally at a total daily dose of 100-500 mg. In some embodiments, the daily dose is selected from 100, 200, 250, 300, 400, 500, 600, 700, 750, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, and 2500 mg / day. In some embodiments, the deuterium-rich pirfenidone compound is taken orally three times daily (TID). In some embodiments, the deuterium-rich pirfenidone compound is taken orally twice daily (BID). In some embodiments, the deuterium-rich pirfenidone compound is taken orally once daily (QD). In any of these embodiments, the deuterium-rich pirfenidone compound has the structure of Formula I, such as the compounds listed in Table 1, including, for example, LYT-100.

[0213] In some embodiments, this disclosure provides a method for treating edema, such as lymphedema, the method comprising administering to a subject in need a deuterium-rich pirfenidone compound disclosed herein, such as compounds of formula I, such as those listed in Table 1, including, for example, LYT-100. In some embodiments, the method comprises administering an effective amount of a deuterium-rich pirfenidone, such as a deuterium-rich pirfenidone compound having the following structure:

[0214]

[0215] Or its pharmaceutically acceptable salt, wherein it is used to treat edema, such as lymphedema, in subjects.

[0216] In some embodiments, lymphedema is secondary lymphedema. Secondary lymphedema can develop after surgery, infection, or trauma, and is often caused by cancer, cancer treatments (e.g., surgery, biopsy, radiation, and chemotherapy), trauma, or infection resulting in lymph node damage or removal. Therefore, in some embodiments, this disclosure provides a method for treating edema, the method comprising administering to a subject in need a deuterated pirfenidone compound having the following structure:

[0217]

[0218] In some embodiments, this disclosure provides a method for treating lymphedema, the method comprising administering to a subject in need a deuterated pirfenidone compound having the following structure:

[0219]

[0220] In some embodiments, this disclosure provides a method for treating secondary lymphedema, the method comprising administering to a subject in need a deuterated pirfenidone compound having the following structure:

[0221]

[0222] In some embodiments, this disclosure provides a method for treating primary lymphedema, the method comprising administering to a subject in need a deuterated pirfenidone compound having the following structure:

[0223]

[0224] In some embodiments, this disclosure provides a method for preventing edema, such as lymphedema, the method comprising administering to a subject in need a deuterium-rich pirfenidone compound disclosed herein, such as compounds of formula I, such as those listed in Table 1, including, for example, LYT-100. In some embodiments, the method comprises administering an effective amount of a deuterium-rich pirfenidone, such as a deuterium-rich pirfenidone compound having the following structure:

[0225]

[0226] Or a pharmaceutically acceptable salt thereof, wherein edema, such as lymphedema, is prevented in a subject. In some embodiments, the lymphedema is secondary lymphedema. Secondary lymphedema can develop after surgery, infection, or trauma, and is often caused by cancer, cancer treatments (e.g., surgery, biopsy, radiation, and chemotherapy), trauma, or infection resulting in lymph node damage or removal. Therefore, in some embodiments, this disclosure provides a method for preventing edema, the method comprising administering to a subject in need a deuterated pirfenidone compound having the following structure:

[0227]

[0228] In some embodiments, this disclosure provides a method for preventing lymphedema, the method comprising administering to a subject in need a deuterated pirfenidone compound having the following structure:

[0229]

[0230] In some embodiments, this disclosure provides a method for preventing secondary lymphedema, the method comprising administering to a subject in need a deuterated pirfenidone compound having the following structure:

[0231]

[0232] In some embodiments, this disclosure provides a method for preventing primary lymphedema, the method comprising administering to a subject in need a deuterated pirfenidone compound having the following structure:

[0233]

[0234] In some embodiments, this disclosure provides a method for improving one or more symptoms of edema, such as lymphedema, said method comprising administering to a subject in need a deuterium-rich pirfenidone compound disclosed herein, such as compounds of formula I, such as those listed in Table 1, including, for example, LYT-100. In some embodiments, said method comprises administering an effective amount of a deuterium-rich pirfenidone, such as a deuterium-rich pirfenidone compound having the following structure:

[0235]

[0236] Or a pharmaceutically acceptable salt thereof, wherein one or more symptoms of edema, such as lymphedema, are improved in a subject. In some embodiments, the lymphedema is secondary lymphedema. Secondary lymphedema can develop after surgery, infection, or trauma, and is often caused by cancer, cancer treatment (e.g., radiation and chemotherapy), trauma, or infection resulting in damage to or removal of lymph nodes. Therefore, in some embodiments, this disclosure provides a method for improving one or more symptoms of edema, the method comprising administering to a subject in need a deuterated pirfenidone compound having the following structure:

[0237]

[0238] In some embodiments, this disclosure provides a method for improving one or more symptoms of lymphedema, the method comprising administering to a subject in need a deuterated pirfenidone compound having the following structure:

[0239]

[0240] In some embodiments, this disclosure provides a method for improving one or more symptoms of secondary lymphedema, the method comprising administering to a subject in need a deuterated pirfenidone compound having the following structure:

[0241]

[0242] In some embodiments, this disclosure provides a method for improving one or more symptoms of primary lymphedema, the method comprising administering to a subject in need a deuterated pirfenidone compound having the following structure:

[0243]

[0244] In any of the above implementation methods, the improvement of one or more symptoms is selected from: fluid accumulation under the skin and in body cavities, swelling, fullness or edema of tissues, inflammation, fibrosis, heaviness, pain, disfigurement, reduced range of motion, aches, recurrent infections, thickened or uncomfortable skin.

[0245] In any of these embodiments used to treat various forms of lymphedema, lymphedema may occur in one or both arms, such as in a combination of the hand, wrist, forearm, elbow, upper arm, shoulder, armpit, or arm area, or throughout the entire arm. In some embodiments, lymphedema occurs in one or both legs, such as in a combination of the foot, ankle, leg, knee, upper leg or thigh, groin, buttock, or leg area, or throughout the entire leg. In some embodiments, lymphedema occurs in other areas of the head, neck, jaw, chest, breast, thoracic cavity, abdomen, pelvis, genitals, or body cavity. In some embodiments, lymphedema occurs in one or more limbs, or one or more limbs and another area of ​​the body.

[0246] In any of these embodiments used to treat lymphedema, the lymphedema may be caused by vascular defects, including venous insufficiency, venous malformations, arterial malformations, capillary malformations, lymphovascular malformations, or cardiovascular diseases.

[0247] Cellulitis is a serious, potentially life-threatening infection that can affect patients with lymphedema. Cellulitis can exacerbate inflammation and further worsen lymphedema. Patients with lymphedema may experience recurrent and progressive episodes of cellulitis, requiring intravenous antibiotics. Prophylactic antibiotics are the only available intervention to attempt to reduce cellulitis. In some embodiments, this document provides a method for reducing cellulitis in a subject, the method comprising administering to a subject in need a deuterium-rich pirfenidone compound disclosed herein, such as compounds of formula I, such as those listed in Table 1, including, for example, LYT-100. In some embodiments, cellulitis episodes are reduced by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more. In some embodiments, the severity of the infection is reduced from severe to moderate or moderate to mild. In some embodiments, the use of treatment-related or prophylactic antibiotics is reduced.

[0248] In any of the above methods for treating, preventing, or improving one or more symptoms of edema or lymphedema, a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally twice daily for a total daily dose of 100-1500 mg. In some embodiments, the daily dose is 100, 200, 250, 300, 400, 500, 600, 700, 750, 800, 900, 1000, or 1500 mg. In some embodiments, the daily dose is 1500 mg. In some embodiments, the daily dose is 1000 mg. In some embodiments, the daily dose is 750 mg. In some embodiments, the daily dose is 500 mg. In some embodiments, the daily dose is 250 mg. In some embodiments, 750 mg of deuterium-rich pirfenidone is taken orally twice daily. In some embodiments, 500 mg of deuterium-rich pirfenidone is taken orally twice daily. In some embodiments, 250 mg of deuterium-rich pirfenidone is taken orally twice daily.

[0249] In some embodiments, a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally once daily at a total daily dose of 100-1500 mg. In some embodiments, the daily dose is 100, 200, 250, 300, 400, 500, 600, 700, 750, 800, 900, 1000, or 1500 mg. In some embodiments, the daily dose is 1500 mg. In some embodiments, the daily dose is 1000 mg. In some embodiments, the daily dose is 750 mg. In some embodiments, the daily dose is 500 mg. In some embodiments, the daily dose is 250 mg. In some embodiments, 1500 mg of deuterium-rich pirfenidone is taken orally once daily. In some embodiments, 1000 mg of deuterium-rich pirfenidone is taken orally once daily. In some embodiments, 750 mg of deuterium-rich pirfenidone is taken orally once daily. In some implementations, 500 mg of deuterium-rich pirfenidone is taken orally once daily. In some implementations, 250 mg of deuterium-rich pirfenidone is taken orally once daily.

[0250] In any of the above embodiments, a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally three times daily for a total daily dose of 100-1500 mg. In some embodiments, the daily dose is 100, 200, 250, 300, 400, 500, 600, 700, 750, 800, 900, 1000, or 1500 mg. In some embodiments, the daily dose is 1500 mg. In some embodiments, the daily dose is 1000 mg. In some embodiments, the daily dose is 750 mg. In some embodiments, the daily dose is 500 mg. In some embodiments, the daily dose is 250 mg. In some embodiments, 500 mg of deuterium-rich pirfenidone is taken orally three times daily. In some embodiments, 333 mg of deuterium-rich pirfenidone is taken orally three times daily. In some embodiments, 166 mg of deuterium-rich pirfenidone is taken orally three times daily.

[0251] In some embodiments, deuterium-enriched pirfenidone is in tablet form. In some embodiments, deuterium-enriched pirfenidone is taken orally with food.

[0252] Therefore, this document provides a method for treating, preventing, and / or improving edema, such as lymphedema, the method comprising administering to a subject in need a deuterium-rich pirfenidone compound, such as a compound of formula I, such as those listed in Table 1, including, for example, LYT-100, wherein the deuterium-rich pirfenidone compound is taken orally twice daily for a total daily dose of 100-1500 mg. In some embodiments, this document provides a method for treating, preventing, and / or improving edema, such as lymphedema, the method comprising administering to a subject in need LYT-100, wherein the deuterium-rich pirfenidone compound is taken orally twice daily for a total daily dose of 100-1500 mg. In some embodiments, the daily dose of the deuterium-rich pirfenidone compound, such as LYT-100, is 1500 mg. In some embodiments, the daily dose of the deuterium-rich pirfenidone compound, such as LYT-100, is 1000 mg. In some embodiments, the daily dose of a deuterium-rich pirfenidone compound, such as LYT-100, is 750 mg. In some embodiments, the daily dose of a deuterium-rich pirfenidone compound, such as LYT-100, is 500 mg. In some embodiments, the daily dose of a deuterium-rich pirfenidone compound, such as LYT-100, is 250 mg. In some embodiments, 750 mg of a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally twice daily. In some embodiments, 500 mg of a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally twice daily. In some embodiments, 250 mg of a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally twice daily.

[0253] In some embodiments, this document provides a method for treating, preventing, and / or improving edema, such as lymphedema, the method comprising administering to a subject in need a deuterium-rich pirfenidone compound, such as a compound of formula I, such as those listed in Table 1, including, for example, LYT-100, wherein the deuterium-rich pirfenidone compound is taken orally once daily for a total daily dose of 100-1500 mg. In some embodiments, this document provides a method for treating, preventing, and / or improving edema, such as lymphedema, the method comprising administering to a subject in need LYT-100, wherein the deuterium-rich pirfenidone compound is taken orally once daily for a total daily dose of 100-1500 mg. In some embodiments, the daily dose of the deuterium-rich pirfenidone compound, such as LYT-100, is 1500 mg. In some embodiments, the daily dose of the deuterium-rich pirfenidone compound, such as LYT-100, is 1000 mg. In some embodiments, the daily dose of a deuterium-rich pirfenidone compound, such as LYT-100, is 750 mg. In some embodiments, the daily dose of a deuterium-rich pirfenidone compound, such as LYT-100, is 500 mg. In some embodiments, the daily dose of a deuterium-rich pirfenidone compound, such as LYT-100, is 250 mg. In some embodiments, a 1500 mg dose of a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally once daily. In some embodiments, a 1000 mg dose of a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally once daily. In some embodiments, a 750 mg dose of a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally once daily. In some embodiments, a 500 mg dose of a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally once daily. In some implementations, 250 mg of a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally once daily.

[0254] Therefore, this document provides a method for treating, preventing, and / or improving edema, such as lymphedema, the method comprising administering to a subject in need a deuterium-rich pirfenidone compound, such as a compound of formula I, such as those listed in Table 1, including, for example, LYT-100, wherein the deuterium-rich pirfenidone compound is orally administered three times daily for a total daily dose of 100-1500 mg. In some embodiments, this document provides a method for treating, preventing, and / or improving edema, such as lymphedema, the method comprising administering to a subject in need LYT-100, wherein LYT-100 is orally administered three times daily for a total daily dose of 100-1500 mg. In some embodiments, the daily dose of the deuterium-rich pirfenidone compound, such as LYT-100, is 1500 mg. In some embodiments, the daily dose of the deuterium-rich pirfenidone compound, such as LYT-100, is 1000 mg. In some embodiments, the daily dose of a deuterium-rich pirfenidone compound, such as LYT-100, is 750 mg. In some embodiments, the daily dose of a deuterium-rich pirfenidone compound, such as LYT-100, is 500 mg. In some embodiments, the daily dose of a deuterium-rich pirfenidone compound, such as LYT-100, is 250 mg. In some embodiments, 500 mg of a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally three times daily. In some embodiments, 333 mg of a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally three times daily. In some embodiments, 166 mg of a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally twice daily.

[0255] In other embodiments, the deuterium-rich pirfenidone compound is administered orally at a total daily dose of 100-2500 mg. In some embodiments, the deuterium-rich pirfenidone compound is administered orally at a total daily dose of 100-2000 mg. In some embodiments, the deuterium-rich pirfenidone compound is administered orally at a total daily dose of 100-1500 mg. In some embodiments, the deuterium-rich pirfenidone compound is administered orally at a total daily dose of 100-1000 mg. In some embodiments, the deuterium-rich pirfenidone compound is administered orally at a total daily dose of 100-500 mg. In some embodiments, the daily dose is selected from 100, 200, 250, 300, 400, 500, 600, 700, 750, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, and 2500 mg / day. In some embodiments, the deuterium-rich pirfenidone compound is taken orally three times daily (TID). In some embodiments, the deuterium-rich pirfenidone compound is taken orally twice daily (BID). In some embodiments, the deuterium-rich pirfenidone compound is taken orally once daily (QD). In any of these embodiments, the deuterium-rich pirfenidone compound has the structure of Formula I, such as the compounds listed in Table 1, including, for example, LYT-100.

[0256] Lymphedema typically progresses through multiple stages, accompanied by fibrosis, increased limb volume, and tissue changes. An estimated 250,000 Americans are diagnosed with breast cancer each year, and up to one in five of them will develop secondary lymphedema. Besides breast cancer, lymphedema can occur in up to 15% of cancer survivors, with malignancies ranging from melanoma to sarcoma. Some patients with lymphedema will also experience cellulitis, a bacterial skin infection that can enter through wounds in the lymphedema-affected skin. Cellulitis usually requires hospitalization and treatment with intravenous antibiotics, and about half of patients with cellulitis will experience a recurrence. In rare cases, patients with chronic lymphedema may develop lymphangiosarcoma, a malignant tumor. Lymphedema is classified by clinical stage and severity, as shown in the table below.

[0257]

[0258] In some implementations, the subject or patient has stage I lymphedema. In some implementations, the subject or patient has stage II lymphedema. In some implementations, the subject or patient has stage III lymphedema. In some implementations, the subject or patient recovers from stage III to stage II or I, or recovers from stage II to stage I.

[0259] The International Society of Lymphology classifies lymphedema limbs according to stages describing the condition of the limb. As the disease progresses to later stages, the affected limb acquires a "woody" texture due to fibrosis. In addition to clinical staging, clinicians use measurements of limb swelling to assess the severity of the disease. Cancer treatments result in new cases of lymphedema each year, most of whom will develop mild lymphedema: over 70% of patients with secondary lymphedema have a milder form, while the remainder have moderate to severe lymphedema. The table below summarizes the percentage of breast cancer-related secondary lymphedema patients who experience different stages and degrees of lymphedema severity.

[0260]

[0261] Therefore, in some implementations, the patient has mild, moderate, or severe secondary lymphedema. In some implementations, the patient has mild to moderate secondary lymphedema. In some implementations, the patient has moderate to severe secondary lymphedema. In some implementations, the patient has mild to severe secondary lymphedema.

[0262] The natural history of lymphedema is that of a chronic and progressive disease, reflected in the increasing severity of swelling in the limb. The relative increase in limb volume of the affected limb compared to the unaffected limb worsens over time. In patients with mild lymphedema, approximately 48% will progress to a more severe stage within the first five years of follow-up. Due to the progressive nature of the disease, many patients will progress to a point where bandaging and compression cannot reduce limb volume. The potential loss of limb movement and range of function, the risk of secondary infections and complications, and disfiguring effects contribute to the physical and psychological suffering of cancer survivors. Secondary lymphedema is a lifelong condition, and the affected population is increasing each year due to improved survival times for cancer patients and changes in patient and disease factors, including obesity, an aging population, and increased use of radiation therapy.

[0263] Millions of patients suffer from lymphedema beyond breast cancer-related arm lymphedema. The deuterium-rich pirfenidone compounds disclosed in this article, such as LYT-100, may be used to treat other forms of secondary or primary lymphedema, including potential mechanisms of lymphatic filariasis.

[0264] The deuterium-rich pirfenidone compounds disclosed herein, such as LYT-100, can be used to treat various forms of lymphedema. In some embodiments, the lymphedema to be treated occurs in one or both arms, such as in a combination of the hand, wrist, forearm, elbow, upper arm, shoulder, armpit, or arm region, or the entire arm. In some embodiments, the lymphedema occurs in one or both legs, such as in a combination of the foot, ankle, leg, knee, upper leg or thigh, groin, buttock, or leg region, or the entire leg. In some embodiments, the lymphedema occurs in other areas of the head, neck, jaw, chest, breast, thoracic cavity, abdomen, pelvis, genitals, or body cavity. In some embodiments, the lymphedema occurs in one or more limbs, or one or more limbs and another area of ​​the body.

[0265] In any of these embodiments used to treat lymphedema, the lymphedema may be caused by vascular defects, including venous insufficiency, venous malformations, arterial malformations, capillary malformations, lymphovascular malformations, or cardiovascular diseases.

[0266] The deuterium-rich pirfenidone compounds disclosed herein, such as LYT-100, can be used to treat cellulitis, a serious and potentially life-threatening infection that can affect patients with lymphedema. In some embodiments, this document provides a method for reducing cellulitis in a subject, the method comprising administering to a subject in need a deuterium-rich pirfenidone compound disclosed herein, such as compounds of formula I, including, for example, those listed in Table 1, such as LYT-100.

[0267] In some embodiments, the patient underwent breast cancer surgery at least 3, 6, 9, or 12 months prior and completed radiation therapy at least one, two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve months prior due to breast cancer. In some embodiments, they have been cancer-free for more than 6 months after breast cancer surgery. In some embodiments, the patient is a patient with pockmarked edema and has at least one of the following: a relative limb volume increase of 10-20% as measured by the circumferential tape measure, or a bioimpedance measurement > +6.5 L-Dex. In some embodiments, the patient is also under standard care compression, or has a relative limb volume >10% or L-Dex >14 compared to pre-surgery and / or pre-radiation volume. Therefore, in some embodiments, this disclosure provides a method for treating lymphedema, the method comprising administering LYT-100 to a subject in need, wherein the subject's relative limb volume has increased by at least 10% compared to pre-treatment limb volume. Therefore, in some embodiments, this disclosure provides a method for treating lymphedema, the method comprising administering LYT-100 to a subject in need, wherein the subject's relative limb volume increases by 10-20% compared to the pre-treatment limb volume. In some embodiments, this disclosure provides a method for treating lymphedema, the method comprising administering LYT-100 to a subject in need, wherein the subject's relative limb volume increases by more than 20% compared to the pre-treatment limb volume. In some embodiments, this disclosure provides a method for treating lymphedema, the method comprising administering LYT-100 to a subject in need, wherein the subject's relative limb volume increases by 20%-40% compared to the pre-treatment limb volume. In some embodiments, this disclosure provides a method for treating lymphedema, the method comprising administering LYT-100 to a subject in need, wherein the subject's relative limb volume increases by more than 40% compared to the pre-treatment limb volume. In some embodiments, this disclosure provides a method for treating lymphedema, the method comprising administering LYT-100 to a subject in need, wherein the subject has a bioimpedance measurement of at least +6.5 L-Dex compared to the volume of the limb before treatment. In some embodiments, this disclosure provides a method for treating lymphedema, the method comprising administering LYT-100 to a subject in need, wherein the subject has a bioimpedance measurement of at least +14 L-Dex compared to the volume of the limb before treatment.

[0268] In some embodiments, this disclosure provides a method for treating edema, such as lymphedema, the method comprising administering to a subject in need a deuterium-rich pirfenidone compound, such as a compound of formula 1, including those listed in Table 1, wherein treatment is demonstrated in a subject by improvement in one or more measurements selected from: a) bioimpedance (e.g., measured by BIS), b) limb volume (e.g., measured by a perimeter or measuring tape), c) local tissue water content (e.g., measured by tissue dielectric constant), d) tissue stiffness (e.g., measured by a tonometer), e) fibrosis (e.g., measured by tissue... f) stiffness measurement, g) pain, h) swelling, h) discomfort, i) function, j) visual analog scale for pain, h) upper extremity lymphedema score (ULL27), i) lymphedema impact on life scale (LLIS), j) functional assessment score for cancer therapy (FACT-B+4), k) lymphedema quality of life scale (LYMQOL); l) disability score of arm, shoulder and hand (DASH); m) lymphedema quality of life scale (LQOLI), n) granulocyte colony-stimulating factor (G-CSF), o) skin histology (CHA); and p) skin thickness (e.g., measured by calipers).

[0269] In some embodiments, this disclosure provides a method for improving one or more symptoms of edema, such as lymphedema, said method comprising administering LYT-100 to a subject in need, wherein improvement of one or more symptoms is demonstrated by a subject having improved one or more measurements selected from: a) bioimpedance (e.g., measured by BIS), b) limb volume (e.g., measured by a perimeter or measuring tape), c) local tissue water content (e.g., measured by tissue dielectric constant), d) tissue stiffness (e.g., measured by a tonometer), e) fibrosis (e.g., measured by tissue stiffness). f) Pain, g) Swelling, h) Discomfort, i) Function, j) Visual analog scale for pain, h) Upper extremity lymphedema score (ULL27), i) Lymphedema Impact on Life Scale (LLIS), j) Functional Assessment of Cancer Therapy (FACT-B+4), k) Lymphedema Quality of Life Scale (LYMQOL); l) Arm, shoulder and hand disability score (DASH); m) Lymphedema Quality of Life Scale (LQOLI), n) Granulocyte colony-stimulating factor (G-CSF), o) Skin histology (CHA); and p) Skin thickness (e.g., measured by calipers).

[0270] Bioimpedance, or water content, can be measured by bioelectrical impedance spectroscopy (BIS). Multifrequency bioelectrical impedance spectroscopy (BIS) provides accurate relative measurements of protein-rich fluid in a patient's upper limb. BIS is a non-invasive technique that involves passing a very small current through the body and measuring the impedance (or resistance) to this current. The current is primarily conducted by water within the body. BIS quantifies the amount of protein-rich fluid in lymphedema by comparing the affected and unaffected limbs. In some embodiments, this disclosure provides a method for reducing bioimpedance in a subject's limb, the method comprising administering to the subject a deuterium-rich pirfenidone compound disclosed herein, such as compounds of formula I, such as those listed in Table 1. In some embodiments, the deuterium-rich pirfenidone compound is LYT-100. Therefore, in some embodiments, this disclosure provides a method for reducing bioimpedance in a subject suffering from edema, such as lymphedema, the method comprising administering an effective amount of LYT-100. In some embodiments, this document provides a method for treating lymphedema, the method comprising administering a deuterium-rich pirfenidone compound, such as LYT-100, to a subject having lymphedema in at least one limb, wherein the bioimpedance in the subject's limb is reduced compared to the bioimpedance in the subject's limb prior to administration of the deuterium-rich pirfenidone compound, such as LYT-100. In some embodiments, the bioimpedance is significantly reduced over 3 months, 4 months, or 6 months. In some embodiments of the disclosed method, the bioimpedance is reduced by 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% (and any numerical increments between) or more in the subject's limb compared to the bioimpedance in the subject's limb prior to administration of the deuterium-rich pirfenidone compound. In some embodiments, this reduction is visible within 3 months, 4 months, or 6 months. Therefore, in some embodiments, this disclosure provides a method for reducing bioimpedance in a subject's limb, the method comprising administering LYT-100 to the subject, wherein bioimpedance is reduced. In some embodiments, this disclosure provides a method for reducing bioimpedance in a subject's limb, the method comprising administering LYT-100 to the subject, wherein bioimpedance is reduced compared to bioimpedance in the subject's limb before administration of LYT-100. In some embodiments, this disclosure provides a method for reducing bioimpedance in a subject's limb, the method comprising administering LYT-100 to the subject, wherein bioimpedance is reduced by at least 2% compared to bioimpedance in the subject's limb before administration of LYT-100.In some embodiments, this disclosure provides a method for reducing bioimpedance in a subject's limb, the method comprising administering LYT-100 to the subject, wherein the bioimpedance in the subject's limb is reduced by at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, or at least 20% compared to before the administration of LYT-100. In some embodiments, this disclosure provides a method for reducing bioimpedance in a subject's limb, the method comprising administering LYT-100 to the subject, wherein the bioimpedance in the subject's limb is reduced by more than 20% compared to before the administration of LYT-100.

[0271] Limb volume (circumference method). Relative limb volume can be measured using a circumferential tape measure via a truncated cone method. The circumference method is a non-invasive technique involving a perimeter system that uses infrared light to scan the limb and obtain a measurement of the limb circumference. In some embodiments, this disclosure provides a method for reducing the limb volume of a subject's limb, the method comprising administering to the subject a deuterium-rich pirfenidone compound disclosed herein, such as compounds of formula I, such as those listed in Table 1. In some embodiments, the deuterium-rich pirfenidone compound is LYT-100. Therefore, in some embodiments, this disclosure provides a method for reducing the limb volume of a subject suffering from edema, such as lymphedema, the method comprising administering an effective amount of LYT-100. In some embodiments, this document provides a method for treating lymphedema, the method comprising administering a deuterium-rich pirfenidone compound, such as LYT-100, to a subject having lymphedema in at least one limb, wherein the limb volume of the subject's limb is reduced compared to the limb volume of the subject's limb before administration of the deuterium-rich pirfenidone compound, such as LYT-100. In some embodiments, the limb volume is reduced by at least 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more compared to the limb volume of the subject's limb before administration of the deuterium-rich pirfenidone. In some embodiments, the severity is reduced from severe to moderate or from moderate to mild. In some embodiments, this reduction in limb volume is visible within 3 months, 4 months, or 6 months. Therefore, in some embodiments, this disclosure provides a method for reducing the volume of a subject's limb, the method comprising administering LYT-100 to the subject, wherein the limb volume is reduced. In some embodiments, this disclosure provides a method for reducing the volume of a subject's limb, the method comprising administering LYT-100 to the subject, wherein the limb volume is reduced compared to the limb volume of the subject's limb before the administration of LYT-100. In some embodiments, this disclosure provides a method for reducing the volume of a subject's limb, the method comprising administering LYT-100 to the subject, wherein the limb volume is reduced by at least 2% compared to the limb volume of the subject's limb before the administration of LYT-100.In some embodiments, this disclosure provides a method for reducing the volume of a subject's limb, the method comprising administering LYT-100 to the subject, wherein the limb volume is reduced by at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, or at least 20% compared to the limb volume of the subject's limb before the administration of LYT-100. In some embodiments, this disclosure provides a method for reducing the volume of a subject's limb, the method comprising administering LYT-100 to the subject, wherein the limb volume is reduced by more than 20% compared to the limb volume of the subject's limb before the administration of LYT-100. In some embodiments, this disclosure provides a method for reducing the volume of a subject's limb, the method comprising administering LYT-100 to the subject, wherein the limb volume is reduced by 20%-40% compared to the limb volume of the subject's limb before the administration of LYT-100. In some embodiments, this disclosure provides a method for reducing the limb volume of a subject's limb, the method comprising administering LYT-100 to the subject, wherein the limb volume is reduced by more than 40% compared to the limb volume of the subject's limb before the administration of LYT-100.

[0272] Tissue dielectric constant (MoistureMeterD). The tissue dielectric constant measures the water content of a localized tissue beneath the skin at various depths, from the skin to the subcutaneous tissue. The results are converted to a scale of 0-100% to reflect subcutaneous fluid accumulation that may occur in early lymphedema. In some embodiments, this disclosure provides a method for reducing the tissue dielectric constant in a subject, the method comprising administering to the subject a deuterium-rich pirfenidone compound disclosed herein, such as compounds of formula I, such as those listed in Table 1. In some embodiments, the deuterium-rich pirfenidone compound is LYT-100. In some embodiments, this disclosure provides a method for treating lymphedema, the method comprising administering to a subject having lymphedema in at least one limb a deuterium-rich pirfenidone compound, such as LYT-100, wherein the tissue dielectric constant in the subject's limb is reduced compared to the tissue dielectric constant in the subject's limb prior to the administration of the deuterium-rich pirfenidone compound, such as LYT-100. Therefore, in some embodiments, this disclosure provides a method for reducing the tissue dielectric constant in a limb of a subject suffering from edema, such as lymphedema, said method comprising administering an effective amount of LYT-100. In some embodiments, the tissue dielectric constant is reduced by 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more compared to the tissue dielectric constant in the subject's limb before administration of deuterium-rich pirfenidone. In some embodiments, this disclosure provides a method for reducing the tissue dielectric constant in a subject's limb, said method comprising administering LYT-100 to said subject, wherein the tissue dielectric constant is reduced. In some embodiments, this disclosure provides a method for reducing the tissue dielectric constant in a subject's limb, said method comprising administering LYT-100 to said subject, wherein the tissue dielectric constant is reduced compared to the tissue dielectric constant in the subject's limb before administration of LYT-100. In some embodiments, this disclosure provides a method for reducing the tissue dielectric constant in a subject's limb, the method comprising administering LYT-100 to the subject, wherein the tissue dielectric constant is reduced by at least 2% compared to the tissue dielectric constant in the subject's limb before the administration of LYT-100. In some embodiments, this disclosure provides a method for reducing the tissue dielectric constant in a subject's limb, the method comprising administering LYT-100 to the subject, wherein the tissue dielectric constant is reduced by at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, or at least 20% compared to the tissue dielectric constant in the subject's limb before the administration of LYT-100.In some embodiments, this disclosure provides a method for reducing the tissue dielectric constant in a subject's limb, the method comprising administering LYT-100 to the subject, wherein the tissue dielectric constant in the subject's limb is reduced by more than 20% compared to the tissue dielectric constant before the administration of LYT-100.

[0273] Tissue stiffness (tonometer / SkinFibroMeter). A tonometer device is pressed into the skin to measure the force required to create an indentation in the tissue. The resulting measurement can assess the degree of subcutaneous stiffness or fibrosis (tissue scarring) to evaluate the severity of lymphedema. In some embodiments, this disclosure provides a method for reducing tissue stiffness in a subject's limb, the method comprising administering to the subject a deuterium-rich pirfenidone compound disclosed herein, such as compounds of formula I, such as those listed in Table 1. In some embodiments, the deuterium-rich pirfenidone is LYT-100. Therefore, in some embodiments, this disclosure provides a method for reducing tissue stiffness in a subject's limb suffering from edema, such as lymphedema, the method comprising administering an effective amount of LYT-100. In some embodiments, this document provides a method for treating lymphedema, the method comprising administering a deuterium-rich pirfenidone compound, such as LYT-100, to a subject having lymphedema in at least one limb, wherein the tissue stiffness of the subject's limb is reduced compared to the tissue stiffness of the subject's limb before administration of the deuterium-rich pirfenidone compound, such as LYT-100. In some embodiments, the tissue stiffness is reduced by 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more compared to the tissue stiffness of the subject's limb before administration of the deuterium-rich pirfenidone compound. In some embodiments, this disclosure provides a method for reducing the tissue stiffness of a subject's limb, the method comprising administering LYT-100 to the subject, wherein the tissue stiffness is reduced. In some embodiments, this disclosure provides a method for reducing tissue stiffness of a subject's limb, the method comprising applying LYT-100 to the subject, wherein the tissue stiffness of the subject's limb is reduced compared to the tissue stiffness of the subject's limb before the application of LYT-100. In some embodiments, this disclosure provides a method for reducing tissue stiffness of a subject's limb, the method comprising applying LYT-100 to the subject, wherein the tissue stiffness of the subject's limb is reduced by at least 2% compared to the tissue stiffness of the subject's limb before the application of LYT-100. In some embodiments, this disclosure provides a method for reducing tissue stiffness of a subject's limb, the method comprising applying LYT-100 to the subject, wherein the tissue stiffness is reduced by at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, or at least 20% compared to the tissue stiffness of the subject's limb before the application of LYT-100.In some embodiments, this disclosure provides a method for reducing tissue stiffness of a subject's limb, the method comprising administering LYT-100 to the subject, wherein the tissue stiffness of the subject's limb is reduced by more than 20% compared to the tissue stiffness of the subject's limb before the administration of LYT-100.

[0274] The Visual Analogue Scale (VAS) assesses pain, swelling, discomfort, and function. This graphical scale has a straight line with endpoints from 0 to 10, marked by the patient, relating to their limits of pain, swelling, discomfort, and function, ranging from “none” to “as severe as possible.” Higher marks on the line indicate a worse condition. In some embodiments, this disclosure provides a method for reducing one or more VAS pain scores in a subject, the method comprising administering to the subject a deuterium-rich pirfenidone compound disclosed herein, such as compounds of Formula I, such as those listed in Table 1. In some embodiments, the deuterium-rich pirfenidone compound is LYT-100. Thus, in some embodiments, this disclosure provides a method for reducing one or more VAS pain scores in a subject suffering from edema, such as lymphedema, the method comprising administering an effective amount of LYT-100. In some embodiments, this document provides a method for treating lymphedema, the method comprising administering a deuterium-rich pirfenidone compound, such as LYT-100, to a subject suffering from lymphedema, wherein one or more of the subject's visual analog scale (VAS) scores are reduced compared to the subject's VAS scores prior to administration of the deuterium-rich pirfenidone compound, such as LYT-100. In some embodiments, one or more VAS scores are reduced by 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more compared to the corresponding VAS scores in the subject prior to administration of the deuterium-rich pirfenidone compound. In some embodiments, this disclosure provides a method for reducing one or more VAS scores in a subject, the method comprising administering LYT-100 to the subject, wherein one or more VAS scores are reduced. In some embodiments, this disclosure provides a method for reducing one or more visual analog pain scores in a subject, the method comprising administering LYT-100 to the subject, wherein one or more visual analog pain scores in the subject are reduced compared to those prior to the administration of LYT-100. In some embodiments, this disclosure provides a method for reducing one or more visual analog pain scores in a subject, the method comprising administering LYT-100 to the subject, wherein one or more visual analog pain scores in the subject are reduced by at least 2% compared to those prior to the administration of LYT-100.In some embodiments, this disclosure provides a method for reducing one or more visual analog pain scores in a subject, the method comprising administering LYT-100 to the subject, wherein the one or more visual analog pain scores in the subject are reduced by at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, or at least 20% compared to the visual analog pain scores in the subject before the administration of LYT-100. In some embodiments, this disclosure provides a method for reducing one or more visual analog pain scores in a subject, the method comprising administering LYT-100 to the subject, wherein the one or more visual analog pain scores are reduced by more than 20% compared to the visual analog pain scores in the subject before the administration of LYT-100.

[0275] The Upper Limb Lymphedema Score 27 (ULL27) is a self-report tool consisting of 27 questions used to assess arm lymphedema and related symptoms in breast cancer survivors. Responses are given on a 5-point Likert scale, ranging from “never” to “always”. At least the following areas must be addressed: physical (15 items), psychological (7 items), and social (5 items), with scores ranging from 0 to 100 (100 being the highest possible score). Lower scores indicate higher quality of life. In some embodiments, this disclosure provides a method for reducing ULL27 in a subject, the method comprising administering to the subject a deuterium-rich pirfenidone compound disclosed herein, such as compounds of formula I, such as those listed in Table 1. In some embodiments, the deuterium-rich pirfenidone is LYT-100. Thus, in some embodiments, this disclosure provides a method for reducing ULL27 in a subject suffering from edema, such as lymphedema, the method comprising administering an effective amount of LYT-100. In some embodiments, this document provides a method for treating lymphedema, the method comprising administering a deuterium-rich pirfenidone compound, such as LYT-100, to a subject having lymphedema in at least one limb, wherein the subject's ULL27 score is reduced compared to the subject's ULL27 score prior to administration of the deuterium-rich pirfenidone compound, such as LYT-100. In some embodiments, ULL27 is reduced by 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more compared to the subject's ULL27 prior to administration of the deuterium-rich pirfenidone compound. In some embodiments, this disclosure provides a method for reducing a subject's ULL27, the method comprising administering LYT-100 to the subject, wherein ULL27 is reduced. In some embodiments, this disclosure provides a method for reducing ULL27 in a subject, the method comprising administering LYT-100 to the subject, wherein ULL27 is reduced compared to the subject's ULL27 prior to the administration of LYT-100. In some embodiments, this disclosure provides a method for reducing ULL27 in a subject, the method comprising administering LYT-100 to the subject, wherein ULL27 is reduced by at least 2% compared to the subject's ULL27 prior to the administration of LYT-100.In some embodiments, this disclosure provides a method for reducing ULL27 in a subject's limb, the method comprising administering LYT-100 to the subject, wherein ULL27 is reduced by at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, or at least 20% compared to the subject's ULL27 before the administration of LYT-100. In some embodiments, this disclosure provides a method for reducing ULL27 in a subject's limb, the method comprising administering LYT-100 to the subject, wherein ULL27 is reduced by more than 20% compared to the subject's ULL27 before the administration of LYT-100.

[0276] The Lymphedema Life Impact Scale (LLIS) is a comprehensive instrument specifically designed for lymphedema, used to measure impairment, activity limitation, and participation limitation in patients with lymphedema of any extremity. It is an assessment tool comprising 18 questions across physical, psychological, and functional domains. The Life Impact Scale is intended to be used in conjunction with an injury calculator to determine the severity of the impairment. In some embodiments, this disclosure provides a method for reducing or lowering the LLIS of a subject (e.g., reducing the severity of the impairment), said method comprising administering to said subject a deuterium-rich pirfenidone compound disclosed herein, such as compounds of formula I, such as those listed in Table 1. In some embodiments, the deuterium-rich pirfenidone is LYT-100. Thus, in some embodiments, this disclosure provides a method for reducing the LLIS of a subject with edema, such as lymphedema, said method comprising administering an effective amount of LYT-100. In some embodiments, this document provides a method for treating lymphedema, the method comprising administering a deuterium-rich pirfenidone compound, such as LYT-100, to a subject having lymphedema in at least one limb, wherein the subject's LLIS is reduced compared to the subject's LLIS prior to administration of the deuterium-rich pirfenidone compound, such as LYT-100. In some embodiments, the LLIS is reduced by 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more compared to the subject's LLIS prior to administration of the deuterium-rich pirfenidone compound. In some embodiments, this disclosure provides a method for reducing LLIS in a subject, the method comprising administering LYT-100 to the subject, wherein LLIS is reduced. In some embodiments, this disclosure provides a method for reducing LLIS in a subject, the method comprising administering LYT-100 to the subject, wherein the LLIS is reduced compared to the subject's LLIS prior to the administration of LYT-100. In some embodiments, this disclosure provides a method for reducing LLIS in a subject, the method comprising administering LYT-100 to the subject, wherein the LLIS is reduced by at least 2% compared to the subject's LLIS prior to the administration of LYT-100. In some embodiments, this disclosure provides a method for reducing LLIS in a subject, the method comprising administering LYT-100 to the subject, wherein the LLIS is reduced by at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, or at least 20% compared to the subject's LLIS prior to the administration of LYT-100.In some embodiments, this disclosure provides a method for reducing LLIS in a subject, the method comprising administering LYT-100 to the subject, wherein the LLIS is reduced by more than 20% compared to the subject's LLIS prior to the administration of LYT-100.

[0277] The Functional Assessment of Cancer Therapy for Breast Cancer-Specific Quality of Life Tool (FACT-B+4) is a five-point Likert scale where a higher quality of life corresponds to a higher score once a negative phrase score is reversed. The score is calculated by adding subscale scores from physical health, social health, emotional health, functional health, and the breast cancer-related concern subscale. In some embodiments, this disclosure provides a method for increasing a subject's FACT-B+4 score (e.g., improving quality of life), the method comprising administering to the subject a deuterium-rich pirfenidone compound disclosed herein, such as compounds of Formula I, such as those listed in Table 1. In some embodiments, the deuterium-rich pirfenidone is LYT-100. Therefore, in some embodiments, this disclosure provides a method for increasing a subject's FACT-B+4 score with edema, such as lymphedema, the method comprising administering an effective amount of LYT-100. In some embodiments, this document provides a method for treating lymphedema, the method comprising administering a deuterium-rich pirfenidone compound, such as LYT-100, to a subject suffering from lymphedema, wherein the subject's FACT-B+4 score increases compared to the subject's FACT-B+4 score prior to administration of the deuterium-rich pirfenidone compound, such as LYT-100. In some embodiments, the FACT-B+4 score increases by 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more compared to the subject's FACT-B+4 score prior to administration of the deuterium-rich pirfenidone compound. In some embodiments, this disclosure provides a method for increasing a subject's FACT-B+4, the method comprising administering LYT-100 to the subject, wherein FACT-B+4 increases. In some embodiments, this disclosure provides a method for increasing a subject's FACT-B+4, the method comprising administering LYT-100 to the subject, wherein FACT-B+4 is increased compared to the subject's FACT-B+4 level before LYT-100 administration. In some embodiments, this disclosure provides a method for increasing a subject's FACT-B+4, the method comprising administering LYT-100 to the subject, wherein FACT-B+4 is increased by at least 2% compared to the subject's FACT-B+4 level before LYT-100 administration.In some embodiments, this disclosure provides a method for increasing FACT-B+4 in a subject, the method comprising administering LYT-100 to the subject, wherein FACT-B+4 is increased by at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, or at least 20% compared to the subject's FACT-B+4 before the administration of LYT-100. In some embodiments, this disclosure provides a method for increasing FACT-B+4 in a subject, the method comprising administering LYT-100 to the subject, wherein FACT-B+4 is increased by more than 20% compared to the subject's FACT-B+4 before the administration of LYT-100.

[0278] The Lymphedema Quality of Life Measure (LYMQOL) for limb lymphedema encompasses four domains: symptoms, body image / appearance, function, and mood. It also includes an overall quality of life rating. Subjects with more severe limb dysfunction score higher and correspond to lower quality of life. In some embodiments, this disclosure provides a method for reducing the overall LYMQOL of a subject, the method comprising administering to the subject a deuterium-rich pirfenidone compound disclosed herein, such as compounds of formula I, such as those listed in Table 1. In some embodiments, the deuterium-rich pirfenidone is LYT-100. Therefore, in some embodiments, this disclosure provides a method for reducing the overall LYMQOL of a subject suffering from edema, such as lymphedema, the method comprising administering an effective amount of LYT-100. In some embodiments, this document provides a method for treating lymphedema, the method comprising administering a deuterium-rich pirfenidone compound, such as LYT-100, to a subject having lymphedema in at least one limb, wherein the subject's LYMQOL is reduced compared to the subject's LYMQOL prior to administration of the deuterium-rich pirfenidone compound, such as LYT-100. In some embodiments, the LYMQOL is reduced by 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more compared to the subject's overall LYMQOL prior to administration of the deuterium-rich pirfenidone compound. In some embodiments, this document provides a method for treating lymphedema, the method comprising administering a deuterium-rich pirfenidone compound, such as LYT-100, to a subject having lymphedema in at least one limb, wherein the subject's LYMQOL is reduced compared to the subject's LYMQOL prior to administration of the deuterium-rich pirfenidone compound, such as LYT-100. In some embodiments, the LYMQOL is reduced by 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more compared to the subject's LYMQOL prior to administration of the deuterium-rich pirfenidone compound. In some embodiments, this disclosure provides a method for reducing LYMQOL in a subject, the method comprising administering LYT-100 to the subject, wherein LYMQOL increases. In some embodiments, this disclosure provides a method for reducing LYMQOL in a subject, the method comprising administering LYT-100 to the subject, wherein the subject's LYMQOL is reduced compared to the subject's LYMQOL level before the administration of LYT-100.In some embodiments, this disclosure provides a method for reducing LYMQOL in a subject, the method comprising administering LYT-100 to the subject, wherein LYMQOL is reduced by at least 2% compared to the subject's LYMQOL level before administration of LYT-100. In some embodiments, this disclosure provides a method for reducing LYMQOL in a subject, the method comprising administering LYT-100 to the subject, wherein LYMQOL is reduced by at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, or at least 20% compared to the subject's LYMQOL level before administration of LYT-100. In some embodiments, this disclosure provides a method for reducing LYMQOL in a subject, the method comprising administering LYT-100 to the subject, wherein LYMQOL is reduced by more than 20% compared to the subject's LYMQOL level before administration of LYT-100.

[0279] The Arm, Shoulder, and Hand Disability Scale (DASH) is a 30-item disability / symptom scale, rated from 0 (no disability) to 100. Each item has five response options. The scale score is then calculated using the scores from all items, ranging from 0 (no disability) to 100 (most severe disability). The items inquire about the degree of difficulty in performing various physical activities due to arm, shoulder, or hand problems (21 items), the severity of each pain symptom, activity-related pain, tingling, weakness, and stiffness (5 items), and the impact of the problem on social activities, work, sleep, and self-image (4 items). In patients with upper limb musculoskeletal disorders, DASH can detect and distinguish changes in the size of the disability over time post-surgery. A difference of 10 points in the mean DASH score is considered a significant change indicating treatment effectiveness. DASH scores can be scored as raw scores, converted to a 0-100 scale, or converted to a logarithmic scale. In some embodiments, this disclosure provides a method for reducing a subject's DASH score (e.g., reducing disability / symptoms), the method comprising administering to the subject a deuterium-rich pirfenidone compound disclosed herein, such as compounds of formula I, such as those listed in Table 1. In some embodiments, the deuterium-rich pirfenidone is LYT-100. Thus, in some embodiments, this disclosure provides a method for reducing a subject suffering from edema, such as lymphedema, the method comprising administering an effective amount of LYT-100. In some embodiments, this disclosure provides a method for treating lymphedema, the method comprising administering to a subject having lymphedema in at least one limb a deuterium-rich pirfenidone compound, such as LYT-100, wherein the subject's DASH score is reduced compared to the subject's DASH score prior to administration of the deuterium-rich pirfenidone compound, such as LYT-100. In some embodiments, compared to the subject's DASH score before administration of the deuterium-rich pirfenidone compound, the subject's DASH score decreased by 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more over a period of three, six, nine, or twelve months. In some embodiments, this disclosure provides a method for reducing a subject's DASH score, the method comprising administering LYT-100 to the subject, wherein the DASH score is reduced. In some embodiments, this disclosure provides a method for reducing a subject's DASH score, the method comprising administering LYT-100 to the subject, wherein the subject's DASH score is reduced compared to the subject's DASH score before administration of LYT-100.In some embodiments, this disclosure provides a method for reducing a subject's DASH score, the method comprising administering LYT-100 to the subject, wherein the subject's DASH score is reduced by at least 5 points compared to the subject's DASH score before administration of LYT-100. In some embodiments, this disclosure provides a method for reducing a subject's DASH score, the method comprising administering LYT-100 to the subject, wherein the subject's DASH score is reduced by at least 10 points compared to the subject's DASH score before administration of LYT-100. In some embodiments, this disclosure provides a method for reducing a subject's DASH score, the method comprising administering LYT-100 to the subject, wherein the subject's DASH score is reduced by 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more over a period of three months, six months, nine months, or twelve months compared to the subject's DASH score before administration of a deuterium-rich pirfenidone compound. Compared to the subject's DASH score before administration of LYT-100. In some embodiments, this disclosure provides a method for reducing a subject's DASH score, the method comprising administering LYT-100 to the subject, wherein the subject's DASH score is reduced by more than 10% compared to the subject's DASH score before administration of LYT-100.

[0280] The Lymphedema Quality of Life Inventory (LQOLI) is the only HRQOL tool developed and tested for patients with different types of lymphedema. The questionnaire consists of three parts: physical, psychosocial, and practical. In some embodiments, this disclosure provides a method for reducing the LQOLI of a subject, the method comprising administering to the subject a deuterium-rich pirfenidone compound disclosed herein, such as compounds of formula I, such as those listed in Table 1. In some embodiments, the deuterium-rich pirfenidone is LYT-100. Therefore, in some embodiments, this disclosure provides a method for reducing the LQOLI of a subject suffering from edema, such as lymphedema, the method comprising administering an effective amount of LYT-100. In some embodiments, the LQOLI is reduced compared to the subject's LQOLI before administration of the deuterium-rich pirfenidone. Therefore, in some embodiments, this disclosure provides a method for reducing the overall LQOLI of a subject suffering from edema, such as lymphedema, the method comprising administering an effective amount of LYT-100. In some embodiments, this document provides a method for treating lymphedema, the method comprising administering a deuterium-rich pirfenidone compound, such as LYT-100, to a subject suffering from lymphedema, wherein the subject's LQOLI is reduced compared to the LQOLI prior to administration of the deuterium-rich pirfenidone compound, such as LYT-100. In some embodiments, this disclosure provides a method for reducing the LQOLI of a subject, the method comprising administering LYT-100 to the subject, wherein the LQOLI is reduced. In some embodiments, this disclosure provides a method for reducing the LQOLI of a subject, the method comprising administering LYT-100 to the subject, wherein the subject's LQOLI is reduced compared to the LQOLI prior to administration of LYT-100. In some embodiments, this disclosure provides a method for reducing the LQOLI of a subject, the method comprising administering LYT-100 to the subject, wherein the LQOLI is reduced by at least 2% compared to the LQOLI prior to administration of LYT-100. In some embodiments, this disclosure provides a method for reducing LQOLI in a subject, the method comprising administering LYT-100 to the subject, wherein the LQOLI is reduced by more than 20% compared to the subject's LQOLI before the administration of LYT-100.

[0281] Systemic inflammatory mediator granulocyte colony-stimulating factor (G-CSF) is an inflammatory cytokine used to measure a patient's systemic inflammatory response. It can be assessed by Luminex-bead inflammasome analysis of plasma samples before and after treatment. In some embodiments, this disclosure provides a method for reducing G-CSF in a subject, the method comprising administering to the subject a deuterium-rich pirfenidone compound disclosed herein, such as compounds of formula I, such as those listed in Table 1. In some embodiments, the deuterium-rich pirfenidone is LYT-100. Therefore, in some embodiments, this disclosure provides a method for reducing G-CSF in a subject suffering from edema, such as lymphedema, the method comprising administering an effective amount of LYT-100. In some embodiments, this document provides a method for treating lymphedema, the method comprising administering a deuterium-rich pirfenidone compound, such as LYT-100, to a subject suffering from lymphedema, wherein the subject's G-CSF is reduced compared to the subject's G-CSF prior to administration of the deuterium-rich pirfenidone compound, such as LYT-100. In some embodiments, systemic inflammatory mediator granulocyte colony-stimulating factor (G-CSF) is significantly reduced. In some embodiments, the reduction is at least 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more, compared to the subject's G-CSF prior to administration of the deuterium-rich pirfenidone compound. In some embodiments, this disclosure provides a method for reducing a subject's G-CSF, the method comprising administering LYT-100 to the subject, wherein the G-CSF is reduced. In some embodiments, this disclosure provides a method for reducing G-CSF in a subject, the method comprising administering LYT-100 to the subject, wherein the G-CSF is reduced compared to the subject's G-CSF prior to the administration of LYT-100. In some embodiments, this disclosure provides a method for reducing G-CSF in a subject, the method comprising administering LYT-100 to the subject, wherein the G-CSF is reduced by at least 2% compared to the subject's G-CSF prior to the administration of LYT-100. In some embodiments, this disclosure provides a method for reducing G-CSF in a subject, the method comprising administering LYT-100 to the subject, wherein the G-CSF of the subject is reduced by at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, or at least 20% compared to the subject's G-CSF before the administration of LYT-100.In some embodiments, this disclosure provides a method for reducing G-CSF in a subject, the method comprising administering LYT-100 to the subject, wherein the G-CSF of the subject is reduced by more than 20% compared to the subject's G-CSF before the administration of LYT-100.

[0282] In some embodiments, based on histological specimens of lymphedema skin before and after treatment with LYT-100, the skin histological structure (CHA) shows a significant change compared to baseline. This score is based on a scoring system assessing skin thickness (0-5), internal mucin content (0-5), deep dermal collagen content (0-5), and perivascular infiltration (0-5), with a total score of 0-20. In some embodiments, this disclosure provides a method for reducing a subject's CHA score, the method comprising administering to the subject a deuterium-rich pirfenidone compound disclosed herein, such as compounds of formula I, such as those listed in Table 1. In some embodiments, the deuterium-rich pirfenidone is LYT-100. Therefore, in some embodiments, this disclosure provides a method for reducing a subject suffering from edema, such as lymphedema, the method comprising administering an effective amount of LYT-100. In some embodiments, this document provides a method for treating lymphedema, the method comprising administering a deuterium-rich pirfenidone compound, such as LYT-100, to a subject suffering from lymphedema, wherein the subject's CHA score is reduced compared to the subject's CHA score prior to administration of the deuterium-rich pirfenidone compound, such as LYT-100. In some embodiments, the CHA score is reduced by at least 50%. In some embodiments, the CHA score is reduced by at least 40%, at least 30%, at least 25%, at least 20%, at least 15%, at least 10%, at least 5%, at least 2%, or at least 1% compared to the subject's CHA score prior to administration of the deuterium-rich pirfenidone compound, such as LYT-100. In some embodiments, this reduction is visible within 3 months, 4 months, or 6 months. In some embodiments, this disclosure provides a method for reducing a subject's CHA score, the method comprising administering LYT-100 to the subject, wherein the CHA score is reduced. In some embodiments, this disclosure provides a method for reducing a subject's CHA score, the method comprising administering LYT-100 to the subject, wherein the CHA score is reduced compared to the subject's CHA score before the administration of LYT-100. In some embodiments, this disclosure provides a method for reducing a subject's CHA score, the method comprising administering LYT-100 to the subject, wherein the CHA score is reduced by at least 2% compared to the subject's CHA score before the administration of LYT-100.In some embodiments, this disclosure provides a method for reducing a subject's CHA score, the method comprising administering LYT-100 to the subject, wherein the CHA score is reduced by at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, or at least 20% compared to the subject's CHA score before the administration of LYT-100. In some embodiments, this disclosure provides a method for reducing a subject's CHA score, the method comprising administering LYT-100 to the subject, wherein the CHA score is reduced by more than 20% compared to the subject's CHA score before the administration of LYT-100.

[0283] In some embodiments, this disclosure provides a method for reducing skin thickness in a subject, the method comprising administering to the subject a deuterium-rich pirfenidone compound disclosed herein, such as compounds of formula I, such as those listed in Table 1. In some embodiments, the deuterium-rich pirfenidone is LYT-100. Thus, in some embodiments, this disclosure provides a method for reducing skin thickness in a subject suffering from edema, such as lymphedema, the method comprising administering an effective amount of LYT-100. In some embodiments, this disclosure provides a method for treating lymphedema, the method comprising administering to a subject suffering from lymphedema a deuterium-rich pirfenidone compound, such as LYT-100, wherein the subject's skin thickness is reduced compared to the skin thickness of the subject before administration of the deuterium-rich pirfenidone compound, such as LYT-100. In some embodiments, the skin thickness, as measured by calipers, is reduced by at least 50% compared to the skin thickness of the subject before administration of the deuterium-rich pirfenidone compound, such as LYT-100. In some embodiments, skin thickness, measured by calipers, is reduced by at least 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, or 5% compared to the skin thickness of the subject before application of a deuterium-rich pirfenidone compound, such as LYT-100. In some embodiments, skin thickness is reduced by 25% compared to the skin thickness of the subject before application of a deuterium-rich pirfenidone compound, such as LYT-100. In some embodiments, this reduction is visible within 3 months, 4 months, or 6 months. In some embodiments, this disclosure provides a method for reducing the skin thickness of a subject, the method comprising applying LYT-100 to the subject, wherein the skin thickness is reduced. In some embodiments, this disclosure provides a method for reducing the skin thickness of a subject, the method comprising applying LYT-100 to the subject, wherein the skin thickness is reduced compared to the skin thickness of the subject before application of LYT-100. In some embodiments, this disclosure provides a method for reducing the skin thickness of a subject, the method comprising applying LYT-100 to the subject, wherein the skin thickness is reduced by at least 10% compared to the skin thickness of the subject before the application of LYT-100. In some embodiments, this disclosure provides a method for reducing the skin thickness of a subject, the method comprising applying LYT-100 to the subject, wherein the skin thickness is reduced by at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 35%, or at least 40% compared to the skin thickness of the subject before the application of LYT-100.In some embodiments, this disclosure provides a method for reducing the skin thickness of a subject, the method comprising applying LYT-100 to the subject, wherein the skin thickness is reduced by at least 20% compared to the subject's skin thickness before the application of LYT-100.

[0284] In some embodiments, this disclosure relates to the use of deuterium-rich pirfenidone for the treatment, prevention, and / or improvement of one or more symptoms associated with edema. In some embodiments, the deuterium-rich pirfenidone is LYT-100 or a pharmaceutically acceptable salt thereof. In some embodiments, this disclosure provides a method for treating, preventing, and / or improving one or more symptoms of edema, the method comprising administering to a subject in need an effective amount of deuterium-rich pirfenidone, such as a compound of formula I, such as the compounds in Table 1. In some embodiments, the deuterium-rich pirfenidone is LYT-100 or a pharmaceutically acceptable salt thereof.

[0285] In some embodiments, this disclosure relates to the use of deuterium-rich pirfenidone for the treatment, prevention, and / or improvement of one or more symptoms of lymphedema. In some embodiments, the deuterium-rich pirfenidone is LYT-100 or a pharmaceutically acceptable salt thereof. In some embodiments, this disclosure provides a method for treating, preventing, and / or improving one or more symptoms of lymphedema, the method comprising administering to a subject in need an effective amount of deuterium-rich pirfenidone, such as a compound of formula I, such as the compounds in Table 1. In some embodiments, the deuterium-rich pirfenidone administered to the subject in need is LYT-100 or a pharmaceutically acceptable salt thereof.

[0286] In some embodiments, this disclosure relates to the use of deuterium-rich pirfenidone for the treatment, prevention, and / or improvement of one or more symptoms of secondary lymphedema. In some embodiments, the deuterium-rich pirfenidone is LYT-100 or a pharmaceutically acceptable salt thereof. In some embodiments, this disclosure provides a method for treating, preventing, and / or improving one or more symptoms of secondary lymphedema, the method comprising administering to a subject in need an effective amount of deuterium-rich pirfenidone, such as a compound of formula I, such as the compounds in Table 1. In some embodiments, the deuterium-rich pirfenidone administered to the subject in need is LYT-100 or a pharmaceutically acceptable salt thereof.

[0287] In some embodiments, this disclosure relates to the use of deuterium-rich pirfenidone for the treatment, prevention, and / or improvement of one or more symptoms of breast cancer-related arm lymphedema. In some embodiments, the deuterium-rich pirfenidone is LYT-100 or a pharmaceutically acceptable salt thereof. In some embodiments, this disclosure provides a method for treating, preventing, and / or improving one or more symptoms of breast cancer-related arm lymphedema, the method comprising administering to a subject in need an effective amount of deuterium-rich pirfenidone, such as a compound of formula I, such as the compounds in Table 1. In some embodiments, the deuterium-rich pirfenidone administered to the subject in need is LYT-100 or a pharmaceutically acceptable salt thereof.

[0288] In some embodiments, this disclosure relates to the use of deuterium-rich pirfenidone for the treatment, prevention, and / or improvement of one or more symptoms of lymphedema other than breast cancer-related arm lymphedema. In some embodiments, the deuterium-rich pirfenidone is LYT-100 or a pharmaceutically acceptable salt thereof. In some embodiments, this disclosure provides a method for treating, preventing, and / or improving one or more symptoms of lymphedema other than breast cancer-related arm lymphedema, the method comprising administering to a subject in need an effective amount of deuterium-rich pirfenidone, such as a compound of formula I, such as the compounds in Table 1. In some embodiments, the deuterium-rich pirfenidone administered to the subject in need is LYT-100 or a pharmaceutically acceptable salt thereof.

[0289] In some embodiments, this disclosure relates to the use of deuterium-rich pirfenidone for the treatment, prevention, and / or improvement of one or more symptoms of primary lymphedema. In some embodiments, the deuterium-rich pirfenidone is LYT-100 or a pharmaceutically acceptable salt thereof. In some embodiments, this disclosure provides a method for treating, preventing, and / or improving one or more symptoms of primary lymphedema, the method comprising administering to a subject in need an effective amount of deuterium-rich pirfenidone, such as a compound of formula I, such as the compounds in Table 1. In some embodiments, the deuterium-rich pirfenidone administered to the subject in need is LYT-100 or a pharmaceutically acceptable salt thereof.

[0290] In some embodiments, this disclosure relates to the use of deuterium-rich pirfenidone for the treatment, prevention, and / or improvement of one or more symptoms of lymphatic filariasis. In some embodiments, the deuterium-rich pirfenidone is LYT-100 or a pharmaceutically acceptable salt thereof. In some embodiments, this disclosure provides a method for treating, preventing, and / or improving one or more symptoms of lymphatic filariasis, the method comprising administering to a subject in need an effective amount of deuterium-rich pirfenidone, such as a compound of formula I, such as the compounds in Table 1. In some embodiments, the deuterium-rich pirfenidone administered to the subject in need is LYT-100 or a pharmaceutically acceptable salt thereof.

[0291] In some embodiments, this disclosure relates to the use of deuterium-rich pirfenidone for the treatment, prevention, and / or improvement of one or more symptoms of other lymphatic and / or fibrotic disorders. Inflammation and fibrosis affect lymphatic flow, thus the pirfenidone agents described herein, such as deuterium-rich pirfenidone, can be used to treat other lymphatic flow disorders. As discussed herein, patients suffer from lymphedema other than breast cancer-related arm lymphedema, and the basic mechanism by which the pirfenidone agents described herein, such as deuterium-rich pirfenidone, can be used to treat other forms of secondary or primary lymphedema. In some embodiments, the pirfenidone agents described herein, such as deuterium-rich pirfenidone, have anti-inflammatory and / or anti-fibrotic activity and can be used to treat fibrotic diseases, including IPF and FSGS. In some embodiments, the deuterium-rich pirfenidone is LYT-100 or a pharmaceutically acceptable salt thereof. In some embodiments, this disclosure provides a method for treating, preventing, and / or improving one or more symptoms of other lymphatic and / or fibrotic conditions, the method comprising administering an effective amount of deuterium-rich pirfenidone to a subject in need. In some embodiments, the deuterium-rich pirfenidone administered to the subject in need is LYT-100, or a pharmaceutically acceptable salt thereof.

[0292] Lymphatic vessels are present in most tissues of the human body. These vessels consist of an extensive network of thin-walled blood vessels that drain protein-rich lymph from the extracellular space. The main functions of the lymphatic system include maintaining tissue fluid homeostasis, fatty acid absorption, and, under normal circumstances, mediating immune responses. The lymphatic system also plays a crucial role in diseases such as lymphedema, fibrosis, and inflammation. In such lymphatic disorders, lymphatic fluid flow is altered and the balance of interstitial fluid is disrupted. Therefore, maintaining or restoring tissue fluid balance and / or maintaining or restoring lymphatic fluid flow constitutes a method of treating these disorders. Without being bound by theory, administering agents that regulate, for example, increase lymphatic fluid flow to subjects with lymphatic disorders may alleviate, treat, or prevent the condition.

[0293] In some embodiments, this document provides methods for regulating and / or maintaining interstitial fluid balance and / or lymphatic flow in a subject with a need. In some embodiments, regulating lymphatic flow in a subject with a need includes increasing lymphatic flow in the subject. In some embodiments, the method includes administering an effective amount of a compound, such as an effective amount of a deuterium-rich pirfenidone having the structure shown in Formula I. In some embodiments, the compound is LYT-100. In some embodiments, this document provides methods for treating the lymphatic disorders described herein, the methods including regulating and / or maintaining interstitial fluid balance and / or lymphatic flow. In some embodiments, the method includes increasing lymphatic flow in a subject with a need. In some embodiments, the method includes administering an effective amount of a compound, such as an effective amount of a deuterium-rich pirfenidone having the structure shown in Formula I. In some embodiments, the compound is LYT-100.

[0294] This document provides further methods comprising reducing inflammation and / or fibrosis in subjects with insufficient lymphatic flow, the methods comprising administering to a subject in need an effective amount of a deuterium-rich pirfenidone having the structure shown in Formula I. In some embodiments, the compound is LYT-100. In some embodiments, this document provides methods for treating the lymphatic disorders described herein, the methods comprising reducing inflammation and / or fibrosis in subjects with insufficient lymphatic flow. In some embodiments, the methods comprise administering an effective amount of a compound, such as an effective amount of a deuterium-rich pirfenidone having the structure shown in Formula I. In some embodiments, the compound is LYT-100.

[0295] In some embodiments, the deuterium-rich pirfenidone compounds disclosed herein have the ability to achieve one or more of the following: a) reduce tissue swelling, b) reduce lymphatic stasis or “blockage”, c) reduce tissue fibrosis, d) reduce tissue inflammation, e) reduce leukocyte infiltration, f) reduce macrophage infiltration, g) reduce infiltration of immature and differentiated T cells, h) reduce TGF-β1 expression and reduce the expression and / or activation of downstream mediators (e.g., pSmad3), i) reduce angiotensin and / or ACE levels, j) reduce collagen deposition and / or scar formation, k) improve or increase lymphatic function, l) improve or increase lymphatic transport (e.g., lymphatic flow), m) improve or increase lymphangiogenesis, and / or n) improve or increase lymphatic pulsation frequency.

[0296] Therefore, the methods disclosed herein are used to treat subjects who have or are suspected of having edema, such as lymphedema, including human subjects, or to prevent such edema in subjects susceptible to the condition; the methods include administering to the subject a therapeutically effective amount of a deuterium-rich pirfenidone compound (e.g., a compound of formula I, including, for example, LYT-100), or a pharmaceutically acceptable salt, solvate, or prodrug thereof; to achieve one or more of a)-n) above during the treatment of the condition.

[0297] Therefore, this document discloses a method for treating subjects who have or are suspected of having edema, such as lymphedema, including human subjects, or for preventing edema, such as lymphedema, in subjects prone to edema; said method comprising administering to said subject a therapeutically effective amount of a deuterium-rich pirfenidone compound as disclosed herein (e.g., a compound of formula I, including, for example, LYT-100), or a pharmaceutically acceptable salt, solvate, or prodrug thereof; to achieve one or more of a)-n) above during treatment of edema, such as lymphedema.

[0298] In some embodiments, this disclosure provides methods for reducing tissue swelling in subjects who have or are suspected of having edema, such as lymphedema, including human subjects, or for preventing tissue swelling in subjects prone to edema or lymphedema; said methods include administering to said subject a therapeutically effective amount of a deuterium-rich pirfenidone compound as disclosed herein, such as compounds of formula I, such as those listed in Table 1, such as LYT-100, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the deuterium-rich pirfenidone is LYT-100.

[0299] In some embodiments, this disclosure provides methods for reducing lymphatic stasis or pooling in subjects who have or are suspected of having edema, such as lymphedema, including human subjects, or for preventing lymphatic stasis or pooling in subjects prone to edema or lymphedema; said methods include administering to said subject a therapeutically effective amount of a deuterium-rich pirfenidone compound as disclosed herein, such as a compound of formula I, such as compounds listed in Table 1, such as LYT-100, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the deuterium-rich pirfenidone is LYT-100.

[0300] In some embodiments, this disclosure provides methods for improving or increasing lymphatic transport (e.g., increasing lymphatic flow) in subjects who have or are suspected of having edema, such as lymphedema, including human subjects, or for improving or increasing lymphatic transport (e.g., increasing lymphatic flow) in subjects prone to edema or lymphedema; said methods include administering to said subject a therapeutically effective amount of a deuterium-rich pirfenidone compound as disclosed herein, such as a compound of formula I, such as compounds listed in Table 1, such as LYT-100, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the deuterium-rich pirfenidone is LYT-100.

[0301] In some embodiments, this disclosure provides methods for reducing tissue fibrosis in subjects who have or are suspected of having edema, such as lymphedema, including human subjects, or for preventing tissue fibrosis in subjects prone to edema or lymphedema; said methods include administering to said subject a therapeutically effective amount of a deuterium-rich pirfenidone compound as disclosed herein, such as compounds of formula I, such as those listed in Table 1, such as LYT-100, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the deuterium-rich pirfenidone is LYT-100.

[0302] In some embodiments, this disclosure provides a method for reducing tissue inflammation in subjects who have or are suspected of having edema, such as lymphedema, including human subjects, or for preventing tissue inflammation in subjects prone to edema or lymphedema; said method comprising administering to said subject a therapeutically effective amount of a deuterium-rich pirfenidone compound as disclosed herein, such as a compound of formula I, such as compounds listed in Table 1, such as LYT-100, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the deuterium-rich pirfenidone is LYT-100.

[0303] In some embodiments, this disclosure provides methods for reducing leukocyte infiltration in subjects who have or are suspected of having edema, such as lymphedema, including human subjects, or for preventing leukocyte infiltration in subjects prone to edema or lymphedema; said methods include administering to said subject a therapeutically effective amount of a deuterium-rich pirfenidone compound as disclosed herein, such as a compound of formula I, such as compounds listed in Table 1, such as LYT-100, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the deuterium-rich pirfenidone is LYT-100.

[0304] In some embodiments, this disclosure provides methods for reducing macrophage infiltration in subjects who have or are suspected of having edema, such as lymphedema, including human subjects, or for preventing macrophage infiltration in subjects prone to edema or lymphedema; said methods include administering to said subject a therapeutically effective amount of a deuterium-rich pirfenidone compound as disclosed herein, such as a compound of formula I, such as compounds listed in Table 1, such as LYT-100, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the deuterium-rich pirfenidone is LYT-100.

[0305] In some embodiments, this disclosure provides methods for reducing nascent and differentiated T-cell infiltration in subjects who have or are suspected of having edema, such as lymphedema, including human subjects, or for preventing nascent and differentiated T-cell infiltration in subjects prone to edema or lymphedema; said methods include administering to said subject a therapeutically effective amount of a deuterium-rich pirfenidone compound as disclosed herein, such as a compound of formula I, such as compounds listed in Table 1, such as LYT-100, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the deuterium-rich pirfenidone is LYT-100.

[0306] In some embodiments, this disclosure provides methods for reducing TGF-β1 expression and reducing the expression and / or activation of downstream mediators (e.g., pSmad3) in subjects who have or are suspected of having edema, such as lymphedema, including human subjects, or for preventing TGF-β1 expression and preventing the expression and / or activation of downstream mediators (e.g., pSmad3) in subjects prone to edema or lymphedema; said methods include administering to said subject a therapeutically effective amount of a deuterium-rich pirfenidone compound as disclosed herein, such as a compound of formula I, such as compounds listed in Table 1, such as LYT-100, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the deuterium-rich pirfenidone is LYT-100.

[0307] In some embodiments, this disclosure provides methods for reducing angiotensin and / or ACE levels in subjects who have or are suspected of having edema, such as lymphedema, including human subjects, or for preventing angiotensin and / or ACE levels in subjects prone to edema or lymphedema; said methods include administering to said subject a therapeutically effective amount of a deuterium-rich pirfenidone compound as disclosed herein, such as a compound of formula I, such as compounds listed in Table 1, such as LYT-100, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the deuterium-rich pirfenidone is LYT-100.

[0308] In some embodiments, this disclosure provides methods for improving or increasing lymphatic function in subjects who have or are suspected of having edema, such as lymphedema, including human subjects, or for improving or increasing lymphatic function in subjects prone to edema or lymphedema; said methods include administering to said subject a therapeutically effective amount of a deuterium-rich pirfenidone compound as disclosed herein, such as compounds of formula I, such as those listed in Table 1, such as LYT-100, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the deuterium-rich pirfenidone is LYT-100.

[0309] In some embodiments, this disclosure provides methods for reducing collagen deposition and / or scar formation in subjects who have or are suspected of having edema, such as lymphedema, including human subjects, or for preventing collagen deposition and / or scar formation in subjects prone to edema or lymphedema; said methods include administering to said subject a therapeutically effective amount of a deuterium-rich pirfenidone compound as disclosed herein, such as a compound of formula I, such as compounds listed in Table 1, such as LYT-100, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the deuterium-rich pirfenidone is LYT-100.

[0310] In some embodiments, this disclosure provides a method for improving or increasing lymphangiogenesis in subjects who have or are suspected of having edema, such as lymphedema, including human subjects, or for improving or increasing lymphangiogenesis in subjects prone to edema or lymphedema; said method comprising administering to said subject a therapeutically effective amount of a deuterium-rich pirfenidone compound as disclosed herein, such as a compound of formula I, such as compounds listed in Table 1, such as LYT-100, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the deuterium-rich pirfenidone is LYT-100.

[0311] In some embodiments, this disclosure provides methods for increasing or enhancing the frequency of lymphatic pulsation in subjects who have or are suspected of having edema, such as lymphedema, including human subjects, or for increasing or enhancing the frequency of lymphatic pulsation in subjects prone to edema or lymphedema; said methods include administering to said subject a therapeutically effective amount of a deuterium-rich pirfenidone compound as disclosed herein, such as compounds of formula I, such as those listed in Table 1, such as LYT-100, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the deuterium-rich pirfenidone is LYT-100.

[0312] This article provides methods for treating, preventing, and / or improving edema, such as lymphedema, wherein cellulitis is reduced, the methods comprising administering to a subject in need a deuterium-rich pirfenidone compound, such as a compound of formula I, such as the compounds listed in Table 1, including, for example, LYT-100.

[0313] This article provides a method for treating, preventing and / or improving cellulitis, the method comprising administering to a subject in need a deuterium-rich pirfenidone compound, such as a compound of formula I, such as the compounds listed in Table 1, including, for example, LYT-100.

[0314] In any of the above methods for treating, preventing, or improving one or more symptoms of edema or lymphedema, a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally twice daily for a total daily dose of 100-1500 mg. In some embodiments, the daily dose is 100, 200, 250, 300, 400, 500, 600, 700, 750, 800, 900, 1000, or 1500 mg. In some embodiments, the daily dose is 1500 mg. In some embodiments, the daily dose is 1000 mg. In some embodiments, the daily dose is 750 mg. In some embodiments, the daily dose is 500 mg. In some embodiments, the daily dose is 250 mg. In some embodiments, 750 mg of deuterium-rich pirfenidone is taken orally twice daily. In some embodiments, 500 mg of deuterium-rich pirfenidone is taken orally twice daily. In some embodiments, 250 mg of deuterium-rich pirfenidone is taken orally twice daily.

[0315] In some embodiments, a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally once daily at a total daily dose of 100-1500 mg. In some embodiments, the daily dose is 100, 200, 250, 300, 400, 500, 600, 700, 750, 800, 900, 1000, or 1500 mg. In some embodiments, the daily dose is 1500 mg. In some embodiments, the daily dose is 1000 mg. In some embodiments, the daily dose is 750 mg. In some embodiments, the daily dose is 500 mg. In some embodiments, the daily dose is 250 mg. In some embodiments, 1500 mg of deuterium-rich pirfenidone is taken orally once daily. In some embodiments, 1000 mg of deuterium-rich pirfenidone is taken orally once daily. In some embodiments, 750 mg of deuterium-rich pirfenidone is taken orally once daily. In some implementations, 500 mg of deuterium-rich pirfenidone is taken orally once daily. In some implementations, 250 mg of deuterium-rich pirfenidone is taken orally once daily.

[0316] In any of the above embodiments, a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally three times daily for a total daily dose of 100-1500 mg. In some embodiments, the daily dose is 100, 200, 250, 300, 400, 500, 600, 700, 750, 800, 900, 1000, or 1500 mg. In some embodiments, the daily dose is 1500 mg. In some embodiments, the daily dose is 1000 mg. In some embodiments, the daily dose is 750 mg. In some embodiments, the daily dose is 500 mg. In some embodiments, the daily dose is 250 mg. In some embodiments, 500 mg of deuterium-rich pirfenidone is taken orally three times daily. In some embodiments, 333 mg of deuterium-rich pirfenidone is taken orally three times daily. In some embodiments, 166 mg of deuterium-rich pirfenidone is taken orally three times daily.

[0317] In some embodiments, deuterium-enriched pirfenidone is in tablet form. In some embodiments, deuterium-enriched pirfenidone is taken orally with food.

[0318] Therefore, this document provides a method for treating, preventing, and / or improving edema, such as lymphedema, the method comprising administering to a subject in need a deuterium-rich pirfenidone compound, such as a compound of formula I, such as those listed in Table 1, including, for example, LYT-100, wherein the deuterium-rich pirfenidone compound is taken orally twice daily for a total daily dose of 100-1500 mg. In some embodiments, this document provides a method for treating, preventing, and / or improving edema, such as lymphedema, the method comprising administering to a subject in need LYT-100, wherein the deuterium-rich pirfenidone compound is taken orally twice daily for a total daily dose of 100-1500 mg. In some embodiments, the daily dose of the deuterium-rich pirfenidone compound, such as LYT-100, is 1500 mg. In some embodiments, the daily dose of the deuterium-rich pirfenidone compound, such as LYT-100, is 1000 mg. In some embodiments, the daily dose of a deuterium-rich pirfenidone compound, such as LYT-100, is 750 mg. In some embodiments, the daily dose of a deuterium-rich pirfenidone compound, such as LYT-100, is 500 mg. In some embodiments, the daily dose of a deuterium-rich pirfenidone compound, such as LYT-100, is 250 mg. In some embodiments, 750 mg of a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally twice daily. In some embodiments, 500 mg of a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally twice daily. In some embodiments, 250 mg of a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally twice daily.

[0319] In some embodiments, this document provides a method for treating, preventing, and / or improving edema, such as lymphedema, the method comprising administering to a subject in need a deuterium-rich pirfenidone compound, such as a compound of formula I, such as those listed in Table 1, including, for example, LYT-100, wherein the deuterium-rich pirfenidone compound is taken orally once daily for a total daily dose of 100-1500 mg. In some embodiments, this document provides a method for treating, preventing, and / or improving edema, such as lymphedema, the method comprising administering to a subject in need LYT-100, wherein the deuterium-rich pirfenidone compound is taken orally once daily for a total daily dose of 100-1500 mg. In some embodiments, the daily dose of the deuterium-rich pirfenidone compound, such as LYT-100, is 1500 mg. In some embodiments, the daily dose of the deuterium-rich pirfenidone compound, such as LYT-100, is 1000 mg. In some embodiments, the daily dose of a deuterium-rich pirfenidone compound, such as LYT-100, is 750 mg. In some embodiments, the daily dose of a deuterium-rich pirfenidone compound, such as LYT-100, is 500 mg. In some embodiments, the daily dose of a deuterium-rich pirfenidone compound, such as LYT-100, is 250 mg. In some embodiments, 1500 mg of a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally once daily. In some embodiments, 1000 mg of a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally once daily. In some embodiments, 750 mg of a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally once daily. In some embodiments, 500 mg of a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally once daily. In some embodiments, 250 mg of a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally once daily.

[0320] Therefore, this document provides a method for treating, preventing, and / or improving edema, such as lymphedema, the method comprising administering to a subject in need a deuterium-rich pirfenidone compound, such as a compound of formula I, such as those listed in Table 1, including, for example, LYT-100, wherein the deuterium-rich pirfenidone compound is orally administered three times daily for a total daily dose of 100-1500 mg. In some embodiments, this document provides a method for treating, preventing, and / or improving edema, such as lymphedema, the method comprising administering to a subject in need LYT-100, wherein LYT-100 is orally administered three times daily for a total daily dose of 100-1500 mg. In some embodiments, the daily dose of the deuterium-rich pirfenidone compound, such as LYT-100, is 1500 mg. In some embodiments, the daily dose of the deuterium-rich pirfenidone compound, such as LYT-100, is 1000 mg. In some embodiments, the daily dose of a deuterium-rich pirfenidone compound, such as LYT-100, is 750 mg. In some embodiments, the daily dose of a deuterium-rich pirfenidone compound, such as LYT-100, is 500 mg. In some embodiments, the daily dose of a deuterium-rich pirfenidone compound, such as LYT-100, is 250 mg. In some embodiments, 500 mg of a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally three times daily. In some embodiments, 333 mg of a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally three times daily. In some embodiments, 166 mg of a deuterium-rich pirfenidone compound, such as LYT-100, is taken orally twice daily.

[0321] In other embodiments, the deuterium-rich pirfenidone compound is administered orally at a total daily dose of 100-2500 mg. In some embodiments, the deuterium-rich pirfenidone compound is administered orally at a total daily dose of 100-2000 mg. In some embodiments, the deuterium-rich pirfenidone compound is administered orally at a total daily dose of 100-1500 mg. In some embodiments, the deuterium-rich pirfenidone compound is administered orally at a total daily dose of 100-1000 mg. In some embodiments, the deuterium-rich pirfenidone compound is administered orally at a total daily dose of 100-500 mg. In some embodiments, the daily dose is selected from 100, 200, 250, 300, 400, 500, 600, 700, 750, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, and 2500 mg / day. In some embodiments, the deuterium-rich pirfenidone compound is taken orally three times daily (TID). In some embodiments, the deuterium-rich pirfenidone compound is taken orally twice daily (BID). In some embodiments, the deuterium-rich pirfenidone compound is taken orally once daily (QD). In any of these embodiments, the deuterium-rich pirfenidone compound has the structure of Formula I, such as the compounds listed in Table 1, including, for example, LYT-100.

[0322] In some embodiments, the method described herein includes escalating the dose of deuterium-rich pirfenidone over a period of time until a full maintenance dose is reached. In some embodiments, the escalation period is 7 days. In some embodiments, the escalation period is 14 days. In some embodiments, the escalation period is 21 days. In some embodiments, the method described herein includes dose reduction. In any of these embodiments, the daily dose is administered as a single dose, or divided into two or three doses, i.e., administered once, twice, or three times daily.

[0323] In some embodiments, the daily dose is increased from 250 mg to 500 mg. In some embodiments, the daily dose is increased from 250 mg to 750 mg, optionally including 500 mg increments. In some embodiments, the daily dose is increased from 250 mg to 1000 mg, optionally including 500 mg increments and / or 750 mg increments. In some embodiments, the daily dose is increased from 250 mg to 1500 mg, optionally including 500 mg increments and / or 750 mg increments and / or 100 mg increments. In some embodiments, the daily dose is increased from 500 mg to 750 mg. In some embodiments, the daily dose is increased from 500 mg to 1000 mg, optionally including 750 mg increments. In some embodiments, the daily dose is increased from 500 mg to 1500 mg, optionally including 750 mg increments and / or 100 mg increments. In any of these implementations, the daily dose is administered as a single dose, or divided into two or three doses, i.e., once, twice, or three times a day.

[0324] In some embodiments, the daily dose is increased from 250 mg to 500 mg over 5 days. In some embodiments, the daily dose is increased from 250 mg to 750 mg over 5 days, optionally including 500 mg increments. In some embodiments, the daily dose is increased from 250 mg to 1000 mg over 5 days, optionally including 500 mg increments and / or 750 mg increments. In some embodiments, the daily dose is increased from 250 mg to 1500 mg over 5 days, optionally including 500 mg increments and / or 750 mg increments and / or 100 mg increments. In some embodiments, the daily dose is increased from 500 mg to 750 mg over 5 days. In some embodiments, the daily dose is increased from 500 mg to 1000 mg over 5 days, optionally including 750 mg increments. In some embodiments, the daily dose is increased from 500 mg to 1500 mg over a 5-day period, optionally including 750 mg increments and / or 100 mg increments. In any of these embodiments, the daily dose is administered as a single dose, or divided into two or three doses, i.e., administered once, twice, or three times daily.

[0325] In some embodiments, the daily dose is increased from 500 mg to 250 mg over 5 days. In some embodiments, the daily dose is decreased from 750 mg to 250 mg over 5 days, with 500 mg increments. In some embodiments, the daily dose is decreased from 1000 mg to 250 mg over 5 days, optionally including 750 mg increments and / or 500 mg increments. In some embodiments, the daily dose is decreased from 1500 mg to 250 mg over 5 days, optionally including 1000 mg increments and / or 750 mg increments and / or 500 mg increments. In some embodiments, the daily dose is decreased from 750 mg to 500 mg over 5 days. In some embodiments, the daily dose is decreased from 1000 mg to 500 mg over 5 days, optionally including 750 mg increments. In some embodiments, the daily dose is reduced from 1500 mg to 500 mg over a 5-day period, optionally including 100 mg increments and / or 750 mg increments. In any of these embodiments, the daily dose is administered as a single dose, or divided into two or three doses, i.e., administered once, twice, or three times daily.

[0326] In some embodiments, the daily dose is increased from 250 mg to 500 mg over 14 days. In some embodiments, the daily dose is increased from 250 mg to 750 mg over 14 days, optionally including 500 mg increments. In some embodiments, the daily dose is increased from 250 mg to 1000 mg over 14 days, optionally including 500 mg increments and / or 750 mg increments. In some embodiments, the daily dose is increased from 250 mg to 1500 mg over 14 days, optionally including 500 mg increments and / or 750 mg increments and / or 100 mg increments. In some embodiments, the daily dose is increased from 500 mg to 750 mg over 14 days. In some embodiments, the daily dose is increased from 500 mg to 1000 mg over 14 days, optionally including 750 mg increments. In some embodiments, the daily dose is increased from 500 mg to 1500 mg over a 14-day period, optionally including 750 mg increments and / or 100 mg increments. In any of these embodiments, the daily dose is administered as a single dose, or divided into two or three doses, i.e., administered once, twice, or three times daily.

[0327] In some embodiments, the daily dose is increased from 250 mg to 500 mg from day 1 to day 7, and then from 500 mg to 1000 mg from day 7 to day 14. In some embodiments, the increase from 500 mg to 1000 mg comprises 750 mg increments. In some embodiments, the daily dose is increased from 500 mg to 750 mg from day 1 to day 7, and then from 750 mg to 1000 mg from day 7 to day 14. In any of these embodiments, the daily dose is administered as a single dose, or divided into two or three doses, i.e., administered once, twice, or three times daily.

[0328] In some embodiments, the daily dose is increased from 250 mg to 500 mg over 21 days. In some embodiments, the daily dose is increased from 250 mg to 750 mg over 21 days, optionally including 500 mg increments. In some embodiments, the daily dose is increased from 250 mg to 1000 mg over 21 days, optionally including 500 mg increments and / or 750 mg increments. In some embodiments, the daily dose is increased from 250 mg to 1500 mg over 21 days, optionally including 500 mg increments and / or 750 mg increments and / or 100 mg increments. In some embodiments, the daily dose is increased from 500 mg to 750 mg over 21 days. In some embodiments, the daily dose is increased from 500 mg to 1000 mg over 21 days, optionally including 750 mg increments. In some embodiments, the daily dose is increased from 500 mg to 1500 mg over a 21-day period, optionally including 750 mg increments and / or 100 mg increments. In any of these embodiments, the daily dose is administered as a single dose, or divided into two or three doses, i.e., administered once, twice, or three times daily.

[0329] In some embodiments, the daily dose is increased from 250 mg to 500 mg from day 1 to day 7, then from 500 mg to 750 mg from day 7 to day 14, and then from 750 mg to 1000 mg from day 14 to day 21. In some embodiments, the daily dose is increased from 500 mg to 750 mg from day 1 to day 7, then from 750 mg to 1000 mg from day 7 to day 14, and then from 1000 mg to 1500 mg. In any of these embodiments, the daily dose is administered as a single dose, or divided into two or three doses, i.e., once, twice, or three times daily.

[0330] In a precautionary manner, the pharmaceutical composition of the present invention may be administered at any time before or after an event that would put a subject at risk of lymphatic injury or susceptibility to lymphatic injury and / or edema (e.g., radiotherapy, chemotherapy, or surgical lymph node dissection). In some embodiments, the pharmaceutical composition is administered prophylactically about one week before the event, for example, 1, 2, 3, 4, 5, 6, or 7 days before the event. In some cases, the pharmaceutical composition is administered prophylactically on the same day the event occurs. In some embodiments, the pharmaceutical composition is administered prophylactically within six weeks of the event, for example, within about 1, 2, 3, 4, 5, or 6 days after the event, or within about 1, 2, 3, 4, 5, or 6 weeks after the event. In some embodiments, the pharmaceutical composition is administered prophylactically for about 2-4 weeks or about 1, 2, 3, 4, 5, or 6 weeks.

[0331] In one embodiment, this document provides a method for treating lymphedema in a subject, the method comprising administering LYT-100, wherein the duration of treatment is selected from 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, and 25 weeks, and any increments thereof.

[0332] In one embodiment, this document provides a method for treating lymphedema in a subject, the method comprising administering LYT-100, wherein the duration of treatment is selected from 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, and any increments thereof. In another embodiment, this document provides a method for treating lymphedema in a subject, the method comprising administering LYT-100, wherein the duration of treatment is one year, 2 years, 3 years, 4 years, 5 years, or longer.

[0333] In some embodiments, LYT-100 may be administered with or without food. In some embodiments, LYT-100 is administered with food. In some embodiments, LYT-100 is not administered with food.

[0334] In some embodiments, the pharmaceutical composition is applied topically once a day or at least once a day. In another embodiment, the pharmaceutical composition is applied topically twice a day or at least twice a day. When the pharmaceutical composition or method relates to the prevention of edema, particularly the prevention of lymphedema, the composition may be applied within approximately six weeks of the lymphatic injury, for example, within approximately two weeks of the lymphatic injury.

[0335] In some embodiments, the pharmaceutical composition is taken orally once a day or at least once a day. In another embodiment, the pharmaceutical composition is taken orally twice a day or at least twice a day. When the pharmaceutical composition or method relates to the prevention of edema, particularly the prevention of lymphedema, the composition may be administered within approximately six weeks of lymphatic injury, for example, within approximately two weeks of lymphatic injury.

[0336] Methods, compositions, and dosing for treating interstitial lung disease

[0337] In the United States, idiopathic pulmonary fibrosis (IPF) affects approximately 100,000 people, with nintedanib and pirfenidone being the only available treatments. In preclinical studies, LYT-100 demonstrated good antifibrotic and anti-inflammatory activity compared to pirfenidone.

[0338] Therefore, this article provides a method for treating interstitial lung disease (ILD), the method comprising administering to a subject in need an effective amount of deuterium-rich pirfenidone having the following structure:

[0339]

[0340] Or a pharmaceutically acceptable salt thereof, wherein ILD is treated in subjects.

[0341] In some implementations, ILD is idiopathic pulmonary fibrosis (IPF). In some implementations, ILD is chILD.

[0342] Clinical advantages of deuterium-rich pirfenidone

[0343] Pirfenidone is a small molecule with anti-fibrotic and anti-inflammatory effects. Recent studies have shown that this activity is at least partly due to the inhibition of TGF-β production and activity. (Iyer et al., J. Pharmacol. Exp. Ther. 291:367-373 (1999); Tada et al., Clin. Exper. Pharmacol. Physiol. 28:522-527 (2001); Oku et al., Eur. J. Pharmacol. 590:400-408 (2008)). It is currently approved for oral use in the United States and elsewhere for the treatment of idiopathic pulmonary fibrosis (IPF). Taniguchi et al., Eur. Respir. J. 35:821-829 (2010); Noble et al., Lancet 377:1760-1769 (2011); King et al., N. Engl. J. Med. 370:2083-2092 (2014). Idiopathic pulmonary fibrosis (IPF) is a debilitating, progressive, and fatal fibrotic lung disease with a median survival of approximately 2–5 years from diagnosis. IPF is one of the most common interstitial lung diseases (ILD), and its incidence and prevalence are rising worldwide. Pirfenidone is one of two approved therapies for the treatment of IPF. Randomized controlled clinical trials and subsequent post-hoc analyses have shown that pirfenidone reduces lung function decline, lowers mortality, and improves progression-free survival.

[0344] However, pirfenidone has a very short half-life in the human body, so it needs to be administered relatively frequently. The recommended daily maintenance dose of pirfenidone is 801 mg (2403 mg·day-1) three times a day (a total of nine (9) tablets per day) with a 14-day titration period after the start of treatment.

[0345] In addition, to ensure that patients with IPF receive the maximum benefit from pirfenidone treatment, it is necessary to manage pirfenidone-related adverse events (AEs). The most common AEs are gastrointestinal (GI) and skin-related adverse events, such as nausea, rash, diarrhea, fatigue, dyspepsia, anorexia, dizziness, gastroesophageal reflux disease, decreased appetite, weight loss, photosensitivity, and cough. Several treatment emergencies, including upper respiratory tract infections and bronchitis, have also been reported. A recent study in patients treated with pirfenidone under a compassionate use program showed that 44% of patients experienced adverse reactions to pirfenidone, and only half continued taking pirfenidone after dose reduction. Raghu and Thickett. Thorax; 68:605-608 (2013). Common adverse reactions at a daily dose of 2403 mg pirfenidone include nausea, rash, fatigue, diarrhea, vomiting, dyspepsia, photosensitivity, and anorexia. Noble et al. Lancet; 377:1760-69 (2011).

[0346] Lancaster et al., Eur Resp Rev 2017:26:170057 summarized the results of several extended clinical trials reporting treatment-emergent adverse events (TEAEs) at a rate per 100 PEY (equivalent to the frequency physicians might expect for these TEAEs if 100 IPF patients were followed for 1 year). It should be noted that the most frequently reported adverse events leading to discontinuation were nausea, fatigue, diarrhea, and / or rash, with frequencies as high as 62.1 per 100 PEY (nausea), 27.6 per 100 PEY (diarrhea), and 52.4 per 100 PEY (fatigue). In a single-center retrospective observational study of 351 patients receiving pirfenidone, 75% of reported AEs were related to GI, with anorexia (17%) and nausea / vomiting (15%) being the most common, similar to results observed in phase III trials. Anorexia and nausea / vomiting were the most frequent reasons for discontinuation. The incidence of AEs and discontinuation increased with age. The proportion of patients with ADRs leading to dose adjustment / interruption or discontinuation increases with age: 32.7% of patients aged ≥80 years and 18.0% of patients aged <65 years experienced ADRs leading to dose adjustment / interruption, while 20.9% of patients aged ≥80 years and 7.5% of patients aged <65 years experienced ADRs leading to discontinuation.

[0347] Several approaches to managing pirfenidone-related adverse events (AEs) have been proposed, including altering the dose titration schedule through slower titrations, and employing dose adjustments including reduction or interruption (dose reduction and interruption occurred in 46% and 41% of patients receiving pirfenidone, respectively, with median durations of 28 days and 14 days, in phase III trials). Overall, in phase III trials, 30% of pirfenidone patients underwent dose adjustments, and 29% permanently discontinued the drug due to AEs. Additionally, dietary changes are necessary when adjusting pirfenidone doses. Taking pirfenidone with large amounts of food, especially taking the full dose at the end of a large meal or distributing it as three capsules during a meal, may reduce pirfenidone absorption and mitigate the occurrence of GI-related AEs.

[0348] Although slower titration and dose adjustment may help resolve adverse events (AEs) in patients, such measures have significant therapeutic effects. Notably, patients receiving 1197 mg / day of pirfenidone were reported to experience greater decline in lung function than those receiving the full dose of 2403 mg / day.

[0349] Furthermore, pirfenidone treatment affects liver function, therefore monitoring liver function is important during pirfenidone treatment. In phase III clinical trials, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels increased to more than 3 times the upper limit of normal (ULN) (3.2%), which can be managed by adjusting the dose or discontinuing the drug. If AST and ALT elevations (>3 times to ≤5 times ULN) occur without symptoms or hyperbilirubinemia, the dose can be reduced or interrupted until normal levels are achieved. However, in cases of AST and ALT elevations (>3 times to ≤5 times ULN) accompanied by hyperbilirubinemia, or if the patient's levels exceed 5 times ULN, pirfenidone must be permanently discontinued.

[0350] In addition, drug-drug interactions must be monitored in patients, as patients taking other oral medications concurrently may experience significant effects on pirfenidone metabolism by inhibiting or inducing hepatic enzyme systems (cytochrome P450 1A2 (CYP1A2), CYP3A4, and P-glycoprotein). For example, for potent CYP1A2 inhibitors such as fluvoxamine and enoxacin, pirfenidone should be reduced to 267 mg three times daily (801 mg / day). For intermediate-potency CYP1A2 inhibitors, such as ciprofloxacin, the dose of pirfenidone should be reduced from 750 mg twice daily to 534 mg three times daily (1602 mg / day). Patients' GI tolerance, skin reactions, and elevated hepatic enzymes should also be assessed.

[0351] Therefore, pirfenidone treatment requires a variety of AE management strategies, including slower dose titration at the start of treatment, administration of pirfenidone with large meals, use of intermittent capsules throughout meals, dietary adjustments, weight-based dosing regimens, dose reduction and interruption, and continuous liver function monitoring.

[0352] Therefore, the limitations of pirfenidone include: a half-life of only about 2.5 hours; a high pill burden (9 capsules per day (TID)); poor tolerability, including nausea, diarrhea, and photosensitivity; the high doses required for efficacy may induce side effects; and significant variability among patients.

[0353] Conversely, deuterium-rich pirfenidone compounds can resolve the defects associated with pirfenidone. The metabolism of pirfenidone is only partially understood. For example, to avoid being bound by theory, it is assumed that the methyl group is readily oxidized, which would produce the corresponding hydroxymethyl metabolite "M1". It is believed that M1 is further oxidized to the carboxylic acid metabolite "M2" (Wang et al., Biomedical Chromatography 2006, 20, 1375-1379). A third detected metabolite is believed to be a phase II product possibly derived from M1 or M2.

[0354] Pirfenidone is a substituted pyridone-based fibrillation regulator and / or collagen infiltration regulator. The C-H bonds of pirfenidone contain a naturally occurring hydrogen isotope distribution: 1H or protium (approximately 99.9844%), 2H or deuterium (approximately 0.0156%), and 3H or tritium (ranging from approximately 0.5 to 67 tritium atoms per 10¹⁸ protium atoms). The increased deuterium incorporation level produces a detectable kinetic isotope effect (KIE) compared to compounds with naturally occurring deuterium levels, which can affect the pharmacokinetic, pharmacological, and / or toxicological characteristics of such fibrillation regulators and / or collagen infiltration regulators.

[0355] Pirfenidone is likely metabolized in the human body via methyl oxidation. Other sites on the molecule may also undergo transformations, resulting in metabolites with unknown pharmacological / toxicological properties. Limiting the production of these metabolites could potentially reduce the risks of administering such drugs and might even allow for increased dosage and consequently, increased efficacy. All of these transformations can occur via polymorphically expressed enzymes, thus exacerbating inter-patient variability.

[0356] Therefore, various deuteration modalities can be used to a) reduce or eliminate unwanted metabolites, b) increase the half-life of the parent drug, c) reduce the dose required to achieve the desired effect, d) reduce the amount of dose required to achieve the desired effect, e) increase the formation of active metabolites (if any), and / or f) reduce the production of harmful metabolites in specific tissues, and / or produce more effective and / or safer drugs for compound drugs, whether or not the compound drug is intentionally produced. Deuteration methods have a strong potential to slow down metabolism through various oxidation and racemic mechanisms.

[0357] In one embodiment, the deuterated compounds disclosed herein, such as LYT-100, retain the beneficial aspects of the corresponding non-isotopically enriched molecules while substantially increasing the maximum tolerated dose, reducing toxicity, increasing half-life (T1 / 2), reducing the maximum plasma concentration (Cmax) of the minimum effective dose (MED), reducing the effective dose, thereby reducing mechanism-independent toxicity, and / or reducing the likelihood of drug-drug interactions.

[0358] In some embodiments, the deuterium-rich pirfenidone compound used in the disclosed method has at least one of the following properties: a) reduced inter-individual variability in plasma levels of the compound or its metabolites compared to non-isotopically enriched compounds; b) increased mean plasma levels per dose unit of the compound compared to non-isotopically enriched compounds; c) decreased mean plasma levels per dose unit of at least one metabolite of the compound compared to non-isotopically enriched compounds; d) increased mean plasma levels per dose unit of at least one metabolite of the compound compared to non-isotopically enriched compounds; and e) improved clinical efficacy per dose unit during treatment in subjects compared to non-isotopically enriched compounds. Therefore, this document discloses methods for treating subjects with or suspected of having edema, such as lymphedema, including humans, or for preventing such edema in subjects susceptible to said condition; said methods include administering to said subject a therapeutically effective amount of a deuterium-rich pirfenidone compound, as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; to achieve one or more of a)-e) above compared to corresponding non-isotope-enriched compounds during treatment of the condition. In some embodiments, the deuterium-rich pirfenidone compound has at least two of the above properties a) to e). In some embodiments, the deuterium-rich pirfenidone compound has at least three of the above properties a) to e).

[0359] In one implementation, it is a method for treating, preventing, or improving one or more symptoms of edema, such as lymphedema.

[0360] This document discloses methods for treating subjects with or suspected of having edema, such as lymphedema, including humans, or for preventing such edema in subjects susceptible to the condition; the methods comprising administering to the subject a therapeutically effective amount of a deuterium-rich pirfenidone compound, as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; to achieve a reduction in inter-individual variability in plasma levels of the compound or its metabolites during treatment of the condition compared to corresponding non-isotopically enriched compounds. In some embodiments, the inter-individual variability in plasma levels of the compound, as disclosed herein, or its metabolites is reduced by more than about 2%, more than about 5%, more than about 10%, more than about 15%, more than about 20%, more than about 25%, more than about 30%, more than about 40%, or more than about 50% (including any numerical increments between the listed percentages) compared to corresponding non-isotopically enriched compounds.

[0361] This document discloses methods for treating subjects with or suspected of having edema, such as lymphedema, including humans, or for preventing such edema in subjects susceptible to said condition; said methods include administering to said subject a therapeutically effective amount of a deuterium-rich pirfenidone compound, as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; such that, compared to a corresponding non-isotopically enriched compound, the mean plasma level of the compound per dose unit is increased or the mean plasma level of at least one metabolite of the compound is decreased. In some embodiments, the mean plasma level of the compound, as disclosed herein, is increased by more than about 2%, more than about 5%, more than about 10%, more than about 15%, more than about 20%, more than about 25%, more than about 30%, more than about 40%, or more than about 50% (including any numerical increments between the listed percentages) compared to a corresponding non-isotopically enriched compound. In some embodiments, the average plasma levels of metabolites of compounds such as those disclosed herein are reduced by more than about 2%, more than about 5%, more than about 10%, more than about 15%, more than about 20%, more than about 25%, more than about 30%, more than about 40%, or more than about 50% (including any numerical increments between the listed percentages) compared to corresponding non-isotopically enriched compounds.

[0362] Plasma levels of compounds or their metabolites disclosed herein can be measured using the methods described by Li et al. (Rapid Communications in Mass Spectrometry 2005, 19, 1943-1950).

[0363] In some embodiments, compared to the non-isotope-enriched compound, each dose unit of the compound in the subject contains at least one polymorphically expressed cytochrome P. 450 The isoform reduces the metabolism of the compound.

[0364] In some implementations, cytochrome P 450 Isotypes are selected from CYP2C8, CYP2C9, CYP2C19 and CYP2D6.

[0365] In some embodiments, the compound is characterized in that, compared to non-isotope-enriched compounds, each dose unit of the compound provides an effect on at least one cytochrome P in the subject. 450 Or the inhibitory effect of monoamine oxidase isoforms may be reduced.

[0366] In some implementations, cytochrome P 450 Or monoamine oxidase isoforms selected from CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2G1, CYP2J2, CYP2R1, CYP2S1, CYP3A4, CYP3A5, CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11, CYP4B1, CYP 4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4X1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1, CYP11A1, C YP11B1, CYP11B2, CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, CYP27A1, CYP27B1, CYP39, CYP46, CYP51, MAO A and MAO B .

[0367] In some embodiments, the deuterium-rich pirfenidone compound has at least one of the following properties: a) a half-life exceeding 2.5 hours; b) reduced pill burden; c) increased patient tolerability; d) lower effective dose; e) increased bioavailability; f) increased Cmax; and g) increased systemic exposure of the subject per dose unit of the compound during treatment compared to non-isotope-rich compounds. This document discloses methods for treating subjects with or suspected of having edema, such as lymphedema, including humans, or for preventing such edema in subjects susceptible to the condition; the methods comprising administering to the subject a therapeutically effective amount of a deuterium-rich pirfenidone compound as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; to achieve one or more of a)-g) above compared to corresponding non-isotope-rich compounds during treatment of the condition.

[0368] This document discloses methods for treating subjects with or suspected of having edema, such as lymphedema, including humans, or for preventing such edema in subjects susceptible to said condition; said methods include administering to said subject a therapeutically effective amount of a deuterium-rich pirfenidone compound, as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, to achieve a longer half-life. In some embodiments, the half-life of a deuterium-rich pirfenidone compound, as disclosed herein, or its metabolites, is increased by more than about 2%, more than about 5%, more than about 10%, more than about 15%, more than about 20%, more than about 25%, more than about 30%, more than about 40%, more than about 50%, more than about 60%, more than about 70%, more than about 80%, more than about 90%, or more than about 100% (including any numerical increments between the listed percentages) compared to corresponding non-isotopically enriched compounds. In some embodiments, the half-life of deuterium-rich pirfenidone compounds or their metabolites, such as those disclosed herein, is increased by about 1.5 times, about 2 times, more than about 2 times, more than about 3 times, more than about 4 times, more than about 5 times, more than about 10 times or more (including any numerical increments between the listed percentages) compared to the corresponding non-isotopically enriched compounds.

[0369] This document discloses methods for treating subjects who have or are suspected of having edema, such as lymphedema, including humans, or for preventing such edema in subjects susceptible to said edema; said methods include administering to said subject a therapeutically effective amount of a deuterium-rich pirfenidone compound, as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; in order to reduce pill burden, for example, to achieve a pill burden of fewer than nine (9) capsules per day (TID) of the compound or its metabolites during treatment of the edema, compared to the corresponding non-isotope-enriched compound.

[0370] In some embodiments, the pill burden of compounds such as those disclosed herein is reduced by more than about 2%, more than about 5%, more than about 10%, more than about 15%, more than about 20%, more than about 25%, more than about 30%, more than about 40%, or more than about 50% (including any numerical increments between the listed percentages) compared to corresponding non-isotopically enriched compounds.

[0371] This document discloses methods for treating subjects with or suspected of having edema, such as lymphedema, including humans, or for preventing such edema in subjects susceptible to the condition; the methods include administering to the subject a therapeutically effective amount of a deuterium-rich pirfenidone compound, as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; to achieve increased patient tolerability of the compound or its metabolites during treatment of the condition compared to corresponding non-isotopically enriched compounds. In some embodiments, patient tolerability is increased by altering pharmacokinetics, for example by increasing bioavailability (to use a lower dose) and / or by prolonging the half-life of the compound and / or by other means of reducing the side effects of pirfenidone.

[0372] In some embodiments, patient tolerability is increased by more than about 2%, more than about 5%, more than about 10%, more than about 15%, more than about 20%, more than about 25%, more than about 30%, more than about 40%, more than about 50%, more than about 60%, more than about 70%, more than about 80%, more than about 90%, or more than about 100% (including any numerical increments between the listed percentages) compared to corresponding non-isotopically enriched compounds. In some embodiments, patient tolerability is increased by about 1.5 times, more than 2 times, more than about 2 times, more than about 3 times, more than about 4 times, more than about 5 times, more than about 10 times, or more (including any numerical increments between the listed percentages) compared to corresponding non-isotopically enriched compounds.

[0373] This document discloses methods for treating subjects who have or are suspected of having edema, such as lymphedema, including humans, or for preventing such edema in subjects susceptible to said condition; the methods include administering to the subject a therapeutically effective amount of a deuterium-rich pirfenidone compound, as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; to achieve a lower effective dose of the compound or its metabolite per dose during treatment of the condition compared to corresponding non-isotope-enriched compounds.

[0374] In some embodiments, the effective dose of each dose of the compound or its metabolites disclosed herein is reduced by more than about 2%, more than about 5%, more than about 10%, more than about 15%, more than about 20%, more than about 25%, more than about 30%, more than about 40%, more than about 50%, more than about 60%, more than about 70%, more than about 80%, more than about 90%, or more than about 100% (including any numerical increments between the listed percentages) compared to the corresponding non-isotopically enriched compounds. In some embodiments, the effective dose of each dose of the compound or its metabolites disclosed herein is reduced by about 1.5 times, about 2 times, more than about 2 times, more than about 3 times, more than about 4 times, more than about 5 times, more than about 10 times, or more (including any numerical increments between the listed percentages) compared to the corresponding non-isotopically enriched compounds.

[0375] This document discloses methods for treating subjects with or suspected of having edema, such as lymphedema, including humans, or for preventing such edema in subjects susceptible to the condition; the methods comprising administering to the subject a therapeutically effective amount of a deuterium-rich pirfenidone compound, as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; in order to increase the bioavailability of each dose of the compound or its metabolites during treatment of the condition compared to corresponding non-isotopically enriched compounds.

[0376] In some embodiments, the bioavailability of each dose of the compound or its metabolites disclosed herein is increased by more than about 2%, more than about 5%, more than about 10%, more than about 15%, more than about 20%, more than about 25%, more than about 30%, more than about 40%, more than about 50%, more than about 60%, more than about 70%, more than about 80%, more than about 90%, or more than about 100% (including any numerical increments between the listed percentages) compared to the corresponding non-isotopically enriched compounds. In some embodiments, the bioavailability of each dose of the compound or its metabolites disclosed herein is increased by about 1.5-fold, decreased by about 2-fold, more than about 2-fold, more than about 3-fold, more than about 4-fold, more than about 5-fold, more than about 10-fold, or more (including any numerical increments between the listed percentages) compared to the corresponding non-isotopically enriched compounds.

[0377] This document discloses methods for treating subjects who have or are suspected of having or are suspected of having edema, such as lymphedema, including humans, or for preventing such edema in subjects susceptible to said condition; said methods include administering to said subject a therapeutically effective amount of a deuterium-rich pirfenidone compound, such as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; such that the systemic exposure per dose unit of the compound is increased compared to the corresponding non-isotopically enriched compound.

[0378] In some embodiments, the systemic exposure per dose of the compound disclosed herein, or its metabolites, is increased by more than about 10%, more than about 15%, more than about 20%, more than about 25%, more than about 30%, more than about 35%, more than about 40%, more than about 45%, or more than about 50% (including any numerical increments between the listed percentages) compared to the corresponding non-isotopically enriched compound. In one embodiment, the systemic exposure per dose of the compound disclosed herein is increased by more than about 35% compared to the corresponding non-isotopically enriched compound. In another embodiment, the systemic exposure per dose of the compound disclosed herein is increased by about 35% compared to the corresponding non-isotopically enriched compound.

[0379] This document discloses methods for treating subjects who have or are suspected of having or are suspected of having edema, such as lymphedema, including human subjects, or for preventing such edema in subjects susceptible to said condition; said methods include administering to said subject a therapeutically effective amount of a deuterium-rich pirfenidone compound, such as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; such that the Cmax of the compound per dose unit increases compared to the corresponding non-isotopically enriched compound.

[0380] In some embodiments, the Cmax of each dose of the compound disclosed herein or its metabolites is increased by more than about 10%, more than about 15%, more than about 20%, more than about 25%, more than about 30%, more than about 35%, more than about 40%, more than about 45%, or more than about 50% (including any numerical increments between the listed percentages) compared to the corresponding non-isotopically enriched compound. In one embodiment, the Cmax of each dose of the compound disclosed herein is increased by more than about 25% compared to the corresponding non-isotopically enriched compound. In one embodiment, the Cmax of each dose of the compound disclosed herein is increased by about 25% compared to the corresponding non-isotopically enriched compound.

[0381] In some embodiments, the method treats the condition while reducing or eliminating harmful changes in diagnostic hepatobiliary function endpoints compared to corresponding non-isotopically enriched compounds such as pirfenidone. This document discloses methods for treating subjects with or suspected of having edema, such as lymphedema, including humans, or for preventing such edema in subjects susceptible to the condition; the methods comprising administering to the subject a therapeutically effective amount of a compound as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; to reduce or eliminate harmful changes in diagnostic hepatobiliary function endpoints compared to corresponding non-isotopically enriched compounds. In some implementations, diagnostic hepatobiliary function endpoints are selected from alanine aminotransferase (“ALT”), serum glutamate-pyruvate transaminase (“SGPT”), aspartate aminotransferase (“AST”, “SGOT”), ALT / AST ratio, serum aldolase, alkaline phosphatase (“ALP”), ammonia level, bilirubin, gamma-glutamyl transferase (“GGTP”, “γ-GTP”, “GGT”), leucine aminopeptidase (“LAP”), liver biopsy, liver ultrasound, hepatic smear, 5'-nucleotidase, and serum proteins. In some implementations, the disease, condition, or disorder is selected from idiopathic pulmonary fibrosis, pneumoconiosis, silicosis, diatomaceous earth disease, asbestosis, anthrax, lymphedema (primary and / or secondary), systemic sclerosis (scleroderma) or a disorder associated with scleroderma, juvenile systemic sclerosis (J-SSC), interstitial lung disease, scleroderma-interstitial lung disease, focal segmental glomerulosclerosis (FSGS), diffuse lung disease (e.g., diffuse parenchymal lung disease), diabetic nephropathy, lupus nephritis, polycystic kidney disease, ANCA vasculitis, membranous nephropathy, minimal change disease, chronic kidney disease, myocardial fibrosis, keloids, polymyositis cutanea, fibrotic sarcoidosis, rejection of medical devices or implants (e.g., breast capsular contracture), fatty liver disease (e.g., non-alcoholic steatohepatitis (NASH)), and hepatitis C fibrosis.

[0382] In some embodiments, the disease, condition, or ailment is selected from idiopathic pulmonary fibrosis, lymphedema (primary and / or secondary), systemic sclerosis (scleroderma), juvenile systemic sclerosis (J-SSC), scleroderma-associated interstitial lung disease, or scleroderma-related ailments. In some embodiments, the disease, condition, or ailment is myocardial fibrosis. In some embodiments, the disease, condition, or ailment is keloid scarring.

[0383] In some embodiments, the disease, condition, or disorder is cutaneous polymyositis. Cutaneous polymyositis (also known as PM / DM) is a family of myositis disorders that includes polymyositis and dermatomyositis. In some embodiments, the disease, condition, or disorder is selected from dermatomyositis, juvenile dermatomyositis polymyositis, and inclusion body myositis.

[0384] In some implementations, the disease, condition, or ailment is scleroderma, progressive systemic sclerosis, mixed connective tissue disease, or CREST syndrome.

[0385] In some implementations, the disease, condition, or ailment is fibrotic sarcoidosis.

[0386] In some implementations, the disease, symptom, or ailment is surgical implant rejection, such as an immune response to an implanted medical device, or capsular contracture, such as breast capsular contracture.

[0387] The compounds and combinations of the present invention can be used to treat a variety of diseases, conditions, and ailments. In some embodiments, the diseases, conditions, or ailments are selected from idiopathic pulmonary fibrosis, neurofibromatosis, Hermansky-Pudrag syndrome, diabetic nephropathy, renal fibrosis, hypertrophic cardiomyopathy (HCM), hypertension-associated nephropathy, glomerulosclerosis (FSGS), radiation-induced fibrosis, multiple sclerosis (including secondary progressive multiple sclerosis), uterine leiomyomas (fibroids), alcoholic liver disease (including hepatic steatosis, liver fibrosis, and cirrhosis), scarring, hepatitis C virus (HCV) infection, proliferative diseases (including angiogenesis-mediated conditions), cancers (including glioma, glioblastoma, breast cancer, colon cancer, melanoma, and pancreatic cancer), fibrotic conditions, interstitial lung disease, atrial fibrillation (AF), organ transplant rejection, and scleroderma and skin-associated fibrotic disorders.

[0388] In some implementations, the disease, condition, or disorder is diabetic nephropathy, Kimmelstiel-Wilson disease or syndrome, diabetic nephropathy, diabetic nephritis, or intercapillary or intracapillary glomerulosclerosis.

[0389] In some embodiments, the method of the present invention is used to treat patients in need of a disease or condition selected from the following: idiopathic pulmonary fibrosis, neurofibromatosis, Hermansky-Pudler syndrome, diabetic nephropathy, renal failure, hypertrophic cardiomyopathy (HCM), glomerulosclerosis (FSGS), radiation-induced fibrosis, multiple sclerosis, and uterine leiomyomas (fibroids).

[0390] In another specific embodiment, the method of the present invention is used to treat patients in need of renal fibrosis, liver fibrosis, uterine leiomyomas, scarring, multiple sclerosis, radiation-related fibrosis, organ transplant rejection, or cancer.

[0391] In yet another specific embodiment, the method is used to treat idiopathic pulmonary fibrosis in patients in need. In yet another specific embodiment, the method of the invention is used to treat secondary progressive multiple sclerosis in patients in need. In yet another specific embodiment, the method of the invention is used to treat pancreatic cancer in patients in need. In yet another more specific embodiment, the method of the invention is used to treat renal fibrosis in patients in need. More specifically, the method is used to treat renal fibrosis caused by diabetic nephropathy, glomerulonephropathy / FSGS, or hypertension-related nephropathy. In yet another embodiment, a certain amount of the compound of the invention is administered to treat liver fibrosis in patients in need. Other diseases, conditions, and ailments that can be treated according to the invention include those described herein and below.

[0392] In some embodiments, the present invention provides a method for treating, preventing, or improving a disease, condition, or disorder selected from fibrosis-mediated conditions, collagen-mediated conditions, or a combination of both, said method comprising administering to a subject in need an effective amount of deuterium-rich pirfenidone or a pharmaceutically acceptable salt thereof. In some embodiments, said method further comprises administering an effective amount of an additional therapeutic agent, such as those described below.

[0393] In some implementations, the deuterium-rich pirfenidone is a compound of formula I or a pharmaceutically acceptable salt thereof.

[0394] In some implementations, the deuterium-rich pirfenidone is LYT-100 or a pharmaceutically acceptable salt thereof.

[0395] In some implementations, deuterium-rich pirfenidone is co-administered with one or more other therapeutic agents, such as those described herein.

[0396] In some embodiments, the disease, condition, or ailment is selected from systemic sclerosis, systemic sclerosis-associated pulmonary fibrosis, sarcoidosis, sarcoidosis-associated pulmonary fibrosis, infection-induced pulmonary fibrosis, asbestos-induced pulmonary fibrosis, silica-induced pulmonary fibrosis, environment-induced pulmonary fibrosis, radiation-induced pulmonary fibrosis, lupus-induced pulmonary fibrosis, drug-induced pulmonary fibrosis and hypersensitivity pneumonia, and / or any condition that can be improved by modulating fibrosis and / or collagen infiltration into tissues.

[0397] In some embodiments, the disease, condition, or disorder is selected from idiopathic pulmonary fibrosis, uterine fibroids, multiple sclerosis, renal fibrosis, diabetic kidney disease, endotoxin-induced liver injury after partial hepatectomy or liver ischemia, allogeneic transplant injury after organ transplantation, cystic fibrosis, atrial fibrosis, neutropenia, scleroderma, dermatomyositis, cirrhosis, diffuse parenchymal lung disease, mediastinal fibrosis, pulmonary tuberculosis, splenic fibrosis due to sickle cell anemia, rheumatoid arthritis, and / or any condition that can be improved by regulating fibrosis and / or collagen infiltration into tissues.

[0398] In some implementations, the disease, condition, or ailment is selected from idiopathic pulmonary fibrosis, uterine fibroids, multiple sclerosis, renal fibrosis, diabetic nephropathy, endotoxin-induced liver injury after partial hepatectomy or liver ischemia, allogeneic transplant injury after organ transplantation, cystic fibrosis, atrial fibrosis, neutropenia, scleroderma, dermatomyositis, cirrhosis, diffuse parenchymal lung disease, mediastinal fibrosis, pulmonary tuberculosis, splenic fibrosis caused by sickle cell anemia, and rheumatoid arthritis.

[0399] In some embodiments, this disclosure relates to the use of deuterium-rich pirfenidone for the treatment or prevention of inflammatory diseases, conditions, or disorders. In some embodiments, the deuterium-rich pirfenidone is LYT-100. In some embodiments, this disclosure provides a method of treating or preventing inflammatory diseases, conditions, or disorders, the method comprising administering an effective amount of deuterium-rich pirfenidone to a subject in need. In some embodiments, the deuterium-rich pirfenidone is LYT-100, or a pharmaceutically acceptable salt thereof.

[0400] In some embodiments, this disclosure relates to the use of deuterium-rich pirfenidone for the treatment or prevention of fibrotic diseases, conditions, or disorders. In some embodiments, the deuterium-rich pirfenidone is LYT-100. In some embodiments, this disclosure provides a method of treating or preventing fibrotic diseases, conditions, or disorders, the method comprising administering an effective amount of deuterium-rich pirfenidone to a subject in need. In some embodiments, the deuterium-rich pirfenidone is LYT-100, or a pharmaceutically acceptable salt thereof.

[0401] In some embodiments, this disclosure relates to the use of deuterium-rich pirfenidone for the treatment or prevention of idiopathic pulmonary fibrosis. In some embodiments, the deuterium-rich pirfenidone is LYT-100.

[0402] In some embodiments, this disclosure provides a method for treating or preventing idiopathic pulmonary fibrosis, the method comprising administering an effective amount of deuterium-rich pirfenidone to a subject in need. In some embodiments, the deuterium-rich pirfenidone is LYT-100, or a pharmaceutically acceptable salt thereof.

[0403] In some embodiments, the disease, condition, or ailment is idiopathic pulmonary fibrosis (IPF). In some embodiments, the disease, condition, or ailment is chronic fibrotic alveolitis, fibrotic alveolitis, pulmonary fibrotic alveolitis, fibrotic lung disease, Hamman-Rich syndrome, or alveolar fibrosis.

[0404] In some implementations, the disease, condition, or ailment is systemic sclerosis (scleroderma) and / or related interstitial lung disease.

[0405] In some embodiments, the disease, condition, or disorder is childhood interstitial lung disease (CHILD). In some embodiments, childhood interstitial lung disease is selected from surfactant dysfunction mutations, childhood lung developmental disorders such as alveolar capillary dysplasia, abnormal lung growth, neonatal neuroendocrine cell proliferation (NEHI), pulmonary interstitial glycogen hyperplasia (PIG), idiopathic interstitial pneumonia (e.g., nonspecific interstitial pneumonia, cryptogenic histiocytosis, acute interstitial pneumonia, desquamative interstitial pneumonia, lymphocytic interstitial pneumonia), alveolar hemorrhage syndrome, aspiration syndrome, hypersensitivity pneumonia, infectious or post-infectious diseases. (Occlusive bronchiolitis), eosinophilic pneumonia, pulmonary alveolar proteinosis, pulmonary infiltrates with eosinophilia, pulmonary lymphatic diseases (lymphangiopathy, lymphangiectasia), pulmonary vascular diseases (angiomatosis), interstitial lung diseases associated with the progression of systemic diseases (e.g., connective tissue diseases, histiocytic hyperplasia, lung diseases associated with malignancies, sarcoidosis, storage diseases), or immune system disorders (e.g., opportunistic infections, diseases associated with treatment interventions, lung diseases associated with lung and bone marrow transplantation, diffuse alveolar damage of unknown cause).

[0406] Various types of childhood interstitial lung disease (CHILD) can affect many parts of the lungs, including alveoli (air sacs), bronchi (airways), and capillaries.

[0407] In some embodiments, the disease, condition, or disorder is scleroderma and at least one related disorder selected from interstitial lung disease, tight skin, joint pain, overreaction to cold (Raynaud's disease), and heartburn.

[0408] In some implementations, the disease, condition, or ailment is selected from abnormal wound healing, skin ulcers or scars, pulmonary fibrosis, fibrosis of the lungs, liver, kidneys, or skin, or Dupuytren's contracture.

[0409] In some embodiments, the inflammatory disease is selected from inflammatory diseases of the liver or inflammatory diseases affecting liver function. In some embodiments, the inflammatory disease is selected from non-alcoholic steatohepatitis (NASH), fatty liver disease, or hepatitis C fibrosis.

[0410] In some embodiments, a method of treating, preventing, or improving one or more symptoms of a subject’s fibrosis-mediated condition and / or collagen-mediated condition includes administering a therapeutically effective amount of a compound as disclosed herein.

[0411] In some implementations, fibrosis-mediated conditions and / or collagen-mediated conditions are selected from idiopathic pulmonary fibrosis, uterine fibroids, multiple sclerosis, renal fibrosis, diabetic kidney disease, endotoxin-induced liver injury after partial hepatectomy or liver ischemia, allogeneic transplant injury after organ transplantation, cystic fibrosis, atrial fibrosis, neutropenia, scleroderma, dermatomyositis, cirrhosis, diffuse parenchymal lung disease, mediastinal fibrosis, pulmonary tuberculosis, splenic fibrosis caused by sickle cell anemia, and rheumatoid arthritis.

[0412] In some embodiments, fibrosis-mediated symptoms and / or collagen-mediated symptoms can be reduced, alleviated, or prevented by modulating fibrosis. In some embodiments, collagen infiltration can be modified to reduce, alleviate, or prevent fibrosis-mediated symptoms and / or collagen-mediated symptoms.

[0413] In some embodiments, the treatment and / or prevention methods described herein may be combined with one or more other treatment and / or prevention methods for edema or lymphedema known in the art, such as treatments involving the administration of other therapeutic agents and / or treatments involving surgery, massage, pressure therapy, drainage therapy, acupuncture, laser or any other suitable treatment.

[0414] Definitions

[0415] Although the terminology used herein is considered to be well understood by one of ordinary skill in the art, definitions are provided herein to aid in the explanation of the subject matter currently disclosed.

[0416] The term "pharmaceutical composition" refers to a formulation in which the biological activity of the active ingredient is permitted and which does not contain any other components that would have unacceptable toxicity to a subject to whom the composition will be administered. Pharmaceutical compositions can be in many dosage forms, such as tablets, capsules, liquids, solutions, soft gels, suspensions, emulsions, syrups, elixirs, tinctures, films, powders, hydrogels, ointments, pastes, creams, lotions, gels, mousses, foams, varnishes, sprays, aerosols, inhalers, nebulizers, eye drops, patches, suppositories, and / or enemas. Pharmaceutical compositions typically contain a pharmaceutically acceptable carrier and may contain one or more buffers (e.g., acetate, phosphate, or citrate buffers), surfactants (e.g., polysorbate), stabilizers (e.g., human albumin), preservatives (e.g., benzyl alcohol), penetration enhancers, bioavailability enhancers, and / or other conventional solubilizers or dispersants. The choice of dosage form and excipients depends on the active agent to be delivered and the disease or condition to be treated or prevented, and is routine to those skilled in the art.

[0417] The term "deuterium enrichment" refers to the percentage of hydrogen ion incorporated into a molecule by deuterium replacing hydrogen at a given position. For example, 1% deuterium enrichment at a given position means that 1% of the molecules in a given sample contain deuterium at that specified location. Since the natural distribution of deuterium is approximately 0.0156%, the deuterium enrichment at any position in a compound synthesized using unenriched starting materials is approximately 0.0156%. Deuterium enrichment can be determined using conventional analytical methods such as mass spectrometry and nuclear magnetic resonance spectroscopy.

[0418] The term "is / is deuterium," when used to describe a given variable position in a molecule or molecular formula, or the symbol "D," when used to indicate a given position in a molecular structure diagram, signifies that the specific position is rich in deuterium, exceeding the natural distribution of deuterium. In some embodiments, the deuterium enrichment at the specified position is not less than about 1%, not less than about 5%, not less than about 10%, not less than about 20%, not less than about 50%, not less than about 70%, not less than about 80%, not less than about 90%, not less than about 98%, or in some embodiments not less than about 99%. In some embodiments, the deuterium enrichment at each specified position is greater than 90%. In some embodiments, the deuterium enrichment at each specified position is greater than 95%. In some embodiments, the deuterium enrichment at each specified position is about 99%.

[0419] The term "isotope enrichment" refers to the percentage of a less common isotope of an element replacing a more common isotope of an element at a given position in a molecule.

[0420] The term "non-isotope enriched" refers to molecules in which the percentages of various isotopes are substantially the same as those of naturally occurring molecules.

[0421] The term "fibrosis" refers to the development of excessive fibrotic connective tissue within an organ or tissue.

[0422] The term "collagen infiltration" refers to the entry of collagen from connective tissue into cells or into the extracellular matrix surrounding cells. This occurs naturally and normally in organs and tissues, but can occur excessively and be associated with or cause disease.

[0423] The term "collagen-mediated disorder" refers to a disorder characterized by abnormal or undesirable collagen infiltration, meaning that altering collagen infiltration activity elicits a desired response, depending on the route of administration and the desired end result. Collagen-mediated disorders can be fully or partially mediated by modulating collagen infiltration. Specifically, a collagen-mediated disorder is a condition in which the modulation of collagen infiltration activity causes some effect on the underlying disease; for example, administration of a collagen infiltration modulator elicits some improvement in at least some of the treated patients.

[0424] The term "fibrosis-mediated disease" refers to a disease characterized by abnormal or undesirable fibrotic activity, meaning that altering fibrotic activity elicits a desired response, depending on the route of administration and the desired end result. Fibrosis-mediated diseases can be fully or partially mediated by modulating fibrosis. Specifically, fibrosis-mediated diseases are those in which the modulation of fibrotic activity causes some effect on the underlying disease; for example, administration of a fibrosis modulator leads to some improvement in at least some of the treated patients.

[0425] The terms “fibrosis modulator” or “modulatory fibrosis” are interchangeable and refer to the ability of the compounds disclosed herein to alter the occurrence and / or amount of fibrosis. A fibrosis modulator can increase the occurrence or level of fibrosis, or increase or decrease the occurrence and / or amount of fibrosis depending on the concentration of the compound exposed to adrenergic receptors, or decrease the occurrence and / or amount of fibrosis. Such activation or inhibition may depend on the occurrence of specific events, such as activation of signal transduction pathways, and / or may be manifested only in specific cell types.

[0426] The terms "collagen infiltration regulator" or "regulator of collagen infiltration" are interchangeable and refer to the ability of the compounds disclosed herein to alter the occurrence and / or amount of collagen infiltration. Fibrosis regulators can increase the occurrence or level of collagen infiltration, can increase or decrease the occurrence and / or amount of collagen infiltration depending on the concentration of the compound exposed to adrenergic receptors, or can decrease the occurrence and / or amount of collagen infiltration. Such activation or inhibition may depend on the occurrence of specific events, such as activation of signal transduction pathways, and / or may be manifested only in specific cell types.

[0427] The “effective amount” of the compositions disclosed herein is an amount sufficient to achieve the specifically stated purpose. The “effective amount” can be determined empirically and in accordance with conventional methods, and is related to the stated purpose, route of administration and dosage form.

[0428] Terms such as “treating,” “treatment,” “to treat,” “alleviating,” or “to alleviate” refer to therapeutic measures that can cure, slow, relieve, or reduce one or more symptoms, halt their progression, and / or alleviate or reduce a diagnosed pathological disease or condition. Therefore, people requiring treatment include those who already have the condition. In some embodiments, treatment may be administered after one or more symptoms have occurred. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to susceptible individuals before the onset of symptoms (e.g., based on a history of symptoms and / or based on genetic or other susceptibility factors). Treatment may also continue after symptom relief, for example, to prevent or delay recurrence. In some embodiments, a subject’s disease or condition is successfully “treated” according to the methods provided herein if the patient shows all, part, or temporary relief or elimination of symptoms, such as those related to the disease or condition. For example, “treating edema” may include, but is not limited to, reducing swelling, reducing inflammation, reducing fibrosis, reducing pain, increasing range of motion, reducing heaviness, reducing tightness, reducing skin thickening, and / or improving lymphatic function.

[0429] "Prevention" or "prevention" refers to preventive or preventative measures that stop, delay, and / or slow the development of one or more symptoms of a target pathological disease or condition or state. Therefore, those requiring prevention include individuals at risk or susceptible to the disease. Subjects at risk or susceptible to lymphedema include, but are not limited to, cancer patients undergoing radiotherapy, chemotherapy, and / or surgical lymph node dissection. In some embodiments, the method provided herein is considered to have successfully prevented the disease or condition if, compared to patients who have not received the method of the invention, a patient transiently or permanently develops, for example, fewer or less severe symptoms associated with the disease or condition, or symptoms associated with the disease or condition appear later.

[0430] Anti-T cell agents are molecules that reduce T cell-mediated inflammation, T cell activation, T cell differentiation, and / or T cell proliferation. Types of anti-T cell agents include calcineurin inhibitors and IL-2 inhibitors. Examples of small-molecule anti-T cell agents include tacrolimus, teriflunomide, leflunomide, cyclosporine, and pimecrolimus. Examples of large-molecule anti-T cell agents include denileukin diftitox and basiliximab.

[0431] "Anti-TGF-β1 agents" are molecules that inhibit the expression, secretion, activation, signal transduction, or activity of transforming growth factor β1. Pirfenidone and deuterium-rich pirfenidone are examples of small-molecule anti-TGF-β1 agents.

[0432] "Angiotensin inhibitors" are molecules that inhibit the activity of Ang I or Ang II, or molecules that inhibit the conversion of Ang I to Ang II (e.g., ACE inhibitors or ACE agonists). Examples of antiangiotensin drugs include captopril, zofenopril, enalapril, lisinopril, ramipril, quinapril, perindopril, benazepril, imidapril, trandolapril, cilazapril, fosinopril, losartan, irbesartan, olmesartan, candesartan, telmisartan, valsartan, fimasartan, diminazene aceturate, xanthenone, and AVE 099.

[0433] The compounds of this invention include those generally described herein, and are further illustrated by the categories, subclasses, and species disclosed herein. Unless otherwise indicated, the following definitions will apply as used herein. For the purposes of this invention, chemical elements are identified according to the periodic table, Handbook of Chemistry and Physics, 98th edition. Furthermore, the general principles of organic chemistry are described in the following: “Organic Chemistry,” Thomas Sorrell, University Science Books, Sausalito: 1999, and March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, MBSmith and J. March, 7th edition, John Wiley & Sons, 2013, the entire contents of which are incorporated herein by reference.

[0434] As used herein, the term "pharmaceutically acceptable salt" refers to salts that, within reasonable medical judgment, are suitable for use in contact with tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SMBerge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19 (incorporated herein by reference). Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic acids and bases and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts include salts of amino groups (or other basic groups) formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or salts formed by other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include: adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, besylate, hydrogen sulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanepropionate, diglucuronate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucono-heptate, glyceryl phosphate, gluconate, hemisulfate, heptahydrate, hydroiodate, 2-hydroxyethanesulfonate, lacturonate, lactate, laurate, dodecyl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, p-pentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc.

[0435] Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and nitrogen. + (C 1-4 Alkyl salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Other pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0436] Unless otherwise stated, the structures described herein are also intended to include all isomers (e.g., enantiomers, diastereomers, and geometric (or conformations)) of the structure; for example, R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers of the compounds of the present invention, as well as enantiomers, diastereomers, and mixtures of geometric (or conformations), are within the scope of the present invention. Unless otherwise stated, all tautomers of the compounds of the present invention are within the scope of the present invention. Furthermore, unless otherwise stated, the structures described herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structure of the present invention but with hydrogen replaced by deuterium or tritium, or with carbon enriched. 13 C or 14 Compounds in which carbon is substituted for carbon are within the scope of this invention. Such compounds can be used, for example, as analytical tools, as probes in biological assays, or as therapeutic agents according to the invention.

[0437] The disclosed compounds, as well as pharmaceutically acceptable compositions comprising the disclosed compounds and pharmaceutically acceptable excipients, adjuvants, diluents, or carriers, may be used to treat a variety of diseases, conditions, and disorders. Such diseases, conditions, and disorders include those described herein.

[0438] Those skilled in the art will recognize that each therapeutic agent described herein is known to be associated with the treatment of one or more diseases, conditions, or disorders. Therefore, it should be understood that in some embodiments, the present invention provides a method of treating a disease, condition, or disorder in a patient in need, the method comprising administering to the patient an effective amount of the disclosed compound, combination of compounds, or pharmaceutical composition thereof.

[0439] Other active agents

[0440] In some embodiments, the present invention provides systemic (e.g., IV or oral) or local (e.g., topical or transdermal) administration of anti-T-cell, anti-TGF-β1, and / or anti-angiotensin agents, such as tacrolimus, deuterium-rich pirfenidone, teriflunomide, leflunomide, or captopril, or pharmaceutically acceptable salts thereof. In some embodiments, when administered to mammalian subjects, administration of this combination improves lymphedema and lymphatic function and has a variety of other beneficial biological effects, including stimulation of lymphangiogenesis. Furthermore, because these agents act at different steps in the fibrotic pathway, in some embodiments, the combination of anti-T-cell agents, anti-TGF-β1 agents, and / or anti-angiotensin agents is more effective than the administration of a single agent. In some embodiments, the combination exhibits a synergistic effect. In some embodiments, the present invention provides systemic or local administration of anti-TGF-β and / or anti-TNF-α agents, such as deuterium-rich pirfenidone. In some embodiments, this document discloses a method for treating diseases such as edema, the method comprising administering LYT-100 and pirfenidone, wherein LYT-100 and pirfenidone together provide an effective amount of the active substance to treat the disease.

[0441] Tacrolimus is an anti-T-cell agent approved by the FDA for topical use in the treatment of inflammatory / fibrotic skin diseases, including atopic dermatitis (Ruzicka et al., N. Engl. J. Med. 337:816-821 (1997)), psoriasis (Wang et al., J. Cutan. Med. Surg. 18:8-14 (2014)), and localized scleroderma (Mancuso et al., Br. J. Dermatol. 152:180-182 (2005)). Tacrolimus is a macrolide produced by the soil bacterium *Streptomyces tsukubaensis* and is well-tolerated when used to prevent transplant rejection and treat various autoimmune diseases. It exerts its anti-T-cell properties by binding to FK-506-binding protein 12 (FKBP-12), thereby inhibiting calcineurin and ultimately reducing IL-2 expression. Clipstone et al., Nature 357:695-697 (1992). Due to IL-2's role in T cell activation and CD4... + T cell differentiation is crucial, therefore calcineurin inhibitors have potent CD4 inhibitors. + Cellular immunosuppression. Liao et al., Immunity 38:13-25 (2013); Rautajoki et al., Ann. Med. 40:322-335 (2008).

[0442] Teriflunomide is an immunosuppressant that reduces T-cell inflammatory responses. Oral teriflunomide has been approved by the FDA for the treatment of multiple sclerosis. Williamson et al., J. Biol. Chem. 270:22467-22472 (1995); Davis et al., Biochem. 35:1270-1273 (1996); Iglesias-Bregna et al., J. Pharmacol. Exp. Ther. 347:203-211 (2013). Teriflunomide is the active metabolite of leflunomide and inhibits the synthesis of neopyrimidines by blocking valproate dehydrogenase. Teriflunomide also shows inhibition of the activation of signal transducers and STAT-6 activators, STAT-6 being a key regulator of Th2 differentiation. Olsan et al., Proc. Natl. Acad. Sci. USA 108:18067-18072 (2011). As a result of these mechanisms, teriflunomide can inhibit the active division of Th2 cells and reduce the inflammatory response.

[0443] Captopril is an angiotensin-converting enzyme (ACE) inhibitor approved by the FDA for oral treatment of hypertension and certain types of heart failure and diabetic nephropathy. ACE works by acting on the renin-angiotensin system (RAS), converting angiotensin I (AngI) to angiotensin II (AngII) and causing vasoconstriction, inhibiting vasodilation, and indirectly regulating intravascular fluid volume. Therefore, ACE inhibition has long been a primary treatment for hypertension. Recent studies have shown that AngII is also a key regulator of fibrosis in various organ systems, including the kidneys, liver, and lungs. Langham et al., Diabetes Care 29:2670-2675 (2006); Alves de Albuquerque et al., Kidney Intl. 65:846-859 (2004); Osterreicher et al., Hepatology. 50:929-938 (2009); Mak et al., Mol. Ther. 23:1434-1443 (2015); Wang et al., Cell Physiol. Biochem. 36:697-711 (2015). The pro-fibrotic effect of AngII is mediated by multiple mechanisms, including the production of reactive oxygen species, chemokines and cytokines, increased expression of adhesion molecules, and regulation of TGF-β expression / activity. Conversely, AngI exhibits anti-proliferative and anti-fibrotic activity by activating its cell surface receptors. Mas. Clarke et al., Int. J. Hypertens. 2012:307315 (2011). As a result, inhibitors of ACE and / or AngII, such as captopril, losartan and other similar drugs, have been proposed as potential treatment options for fibrotic diseases of the lungs, kidneys and liver.

[0444] In one aspect, the present invention provides a pharmaceutical composition comprising a combination of deuterium-rich pirfenidone and one or more anti-T cell agents, anti-TGF-β1 agents and / or anti-angiotensin agents and / or anti-inflammatory agents.

[0445] In some embodiments, the anti-T-cell agent is selected from tacrolimus, terflunomide, leflunomide, cyclosporine, pimecrolimus, denile interleukin, and balithimab. In some embodiments, the anti-TGF-β1 agent or anti-angiotensin agent is selected from pirfenidone, deuterium-rich pirfenidone, captopril, zolfenpril, enalapril, lisinopril, ramipril, quinapril, perindopril, benazepril, imidapril, trandopril, cilazapril, fosinopril, losartan, irbesartan, olmesartan, candesartan, telmisartan, valsartan, and femasartan. In some embodiments, the anti-angiotensin agent is an ACE agonist, such as an ACE-2 agonist. The composition can be formulated for systemic or topical administration. In some embodiments, the composition is formulated for topical application.

[0446] The pharmaceutical compositions of the present invention may comprise any combination of anti-T cell agents, anti-TGF-β1 agents, and / or anti-angiotensin agents.

[0447] In some embodiments, the composition comprises a deuterium-rich pirfenidone, such as a compound of formula I, such as those listed in Table 1, including, for example, LYT-100; and one or more anti-T cell agents. In some embodiments, the composition comprises a deuterium-rich pirfenidone, such as a compound of formula I, such as those listed in Table 1, including, for example, LYT-100; and one or more anti-T cell agents selected from tacrolimus, terflunomide, leflunomide, cyclosporine, piromemus, deniformin, and baliximab. For example, in some embodiments, the composition comprises a deuterium-rich pirfenidone, such as a compound of formula I, such as those listed in Table 1, including, for example, LYT-100; and tacrolimus. In another example, in some embodiments, the composition comprises a deuterium-rich pirfenidone, such as a compound of formula I, such as those listed in Table 1, including, for example, LYT-100; and terflunomide.

[0448] In some embodiments, the composition comprises a deuterium-rich pirfenidone, such as a compound of formula I, such as those listed in Table 1, including, for example, LYT-100; and one or more anti-TGF-β1 agents. Non-limiting examples of anti-TGF-β1 agents include LY550410 and LY580276, SB-505124, or galunisertib (LY2157299 monohydrate) or, for example, deuterium-rich pirfenidones other than LYT-100 as described herein. In some embodiments, the composition comprises a deuterium-rich pirfenidone, such as a compound of formula I, such as those listed in Table 1, including, for example, LYT-100; and one or more anti-TGF-β1 agents selected from LY550410 and LY580276, SB-505124 or Grunise (LY2157299 monohydrate) or, for example, those described herein, other than LYT-100, such as those that are deuterium-rich pirfenidones. In some embodiments, the composition comprises a deuterium-rich pirfenidone, such as a compound of formula I, such as those listed in Table 1, including, for example, LYT-100; and, for example, a second type of deuterium-rich pirfenidone other than LYT-100, such as a compound of formula I, such as those listed in Table 1.

[0449] In some embodiments, the composition comprises a deuterium-rich pirfenidone, such as a compound of formula I, such as those listed in Table 1, including, for example, LYT-100; and one or more antiangiotensin agents selected from: captopril, zolfenpril, enalapril, lisinopril, ramipril, quinapril, perindopril, benazepril, imidapril, quinalazapril, fosinopril, losartan, irbesartan, olmesartan, candesartan, telmisartan, valsartan, femasartan, diazonamide acetylglycine, oxoxonone, and AVE 099. For example, in some embodiments, the composition comprises a deuterium-rich pirfenidone, such as a compound of formula I, such as those listed in Table 1, including, for example, LYT-100; and captopril.

[0450] In some embodiments, the composition comprises a deuterium-rich pirfenidone, such as a compound of formula I, such as those listed in Table 1, including, for example, LYT-100; and one or more anti-inflammatory agents. Non-limiting examples of anti-inflammatory agents include etodolac, famotidine, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, lansoprazole, mefenamic acid, meloxicam, misoprostol, nabumetone, naproxen, oxaprozin, piroxicam, sulindac, and tolmetin. Anti-inflammatory agents also include Cox-2 inhibitors, including but not limited to celecoxib, apricoxib, robenacoxib, valdecoxib, anitrazafine, tilmacoxib, flumizole, cimicoxib, rofecoxib, mavacoxib, and firocoxib. In some embodiments, the composition comprises a deuterium-rich pirfenidone, such as a compound of formula I, including, for example, compounds listed in Table 1, such as LYT-100; and one or more anti-inflammatory agents selected from: etodoxacin, famotidine, fenolofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, lansoprazole, mefenamic acid, meloxicam, misoprostol, nabumetone, naproxen, oxapazine, piroxacin, sulindac, tometine, celecoxib, aricoxoxib, robecoxib, vardicoxib, anizafen, temicoxib, flumidazole, cimeticoxib, rofecoxib, movacoxib, and ferocoxib. For example, in some embodiments, the composition comprises a deuterium-rich pirfenidone, such as a compound of formula I, including, for example, compounds listed in Table 1, such as LYT-100; and ibuprofen.

[0451] In some embodiments, the composition comprises a deuterium-rich pirfenidone, such as a compound of formula I, such as those listed in Table 1, including, for example, LYT-100; one or more anti-T cell agents and optionally one or more anti-angiotensin agents. In some embodiments, the composition comprises a deuterium-rich pirfenidone, such as a compound of formula I, such as those listed in Table 1, including, for example, LYT-100; and one or more anti-T cell agents selected from tacrolimus, terflunomide, leflunomide, cyclosporine, piromemus, deniformin, and balithimab, and optionally one or more anti-angiotensin agents. In some embodiments, one or more antiangiotensin agents are selected from captopril, zolfenpril, enalapril, lisinopril, ramipril, quinapril, perindopril, benazepril, imidapril, trandopril, cilazapril, fosinopril, losartan, irbesartan, olmesartan, candesartan, telmisartan, valsartan, femasartan, diazonamide acetylglycine salt, oxoxanone, and AVE 099. For example, in some embodiments, the composition comprises a deuterium-rich pirfenidone, such as a compound of formula I, such as those listed in Table 1, including, for example, LYT-100; and tacrolimus and one or more antiangiotensin agents, such as captopril. In another instance, in some embodiments, the composition comprises a deuterium-rich pirfenidone, such as a compound of formula I, such as those listed in Table 1, including, for example, LYT-100; terflunomide; and one or more antiangiotensin agents, such as captopril.

[0452] In some embodiments, the composition comprises a deuterium-rich pirfenidone, such as a compound of formula I, such as those listed in Table 1, including, for example, LYT-100; one or more anti-T cell agents; and optionally one or more anti-inflammatory agents. In some embodiments, the composition comprises a deuterium-rich pirfenidone, such as a compound of formula I, such as those listed in Table 1, including, for example, LYT-100; and one or more anti-T cell agents selected from tacrolimus, terflunomide, leflunomide, cyclosporine, piromemus, deniformin, and balithimab; and one or more anti-inflammatory agents. In some embodiments, one or more anti-inflammatory agents are selected from etodoxacin, famotidine, fenprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, lansoprazole, mefenamic acid, meloxicam, misoprostol, nabumetone, naproxen, oxapazine, piroxicam, sulindac, tometine, celecoxib, aricoxox, robecoxib, vardicoxib, anizafen, temicoxib, flumidazole, cimeticoxib, rofecoxib, movacoxib, and ferocoxib. For example, in some embodiments, the composition comprises a deuterium-rich pirfenidone, such as a compound of formula I, such as those listed in Table 1, including, for example, LYT-100; tacrolimus and ibuprofen. In another instance, in some embodiments, the composition comprises a deuterium-rich pirfenidone, such as a compound of formula I, such as those listed in Table 1, including, for example, LYT-100; and terflunomide and ibuprofen.

[0453] In some embodiments, the composition comprises a deuterium-rich pirfenidone, such as a compound of formula I, such as those listed in Table 1, including, for example, LYT-100; one or more anti-TGF-β1 agents; and optionally one or more anti-angiotensin agents. In some embodiments, the composition comprises a deuterium-rich pirfenidone, such as a compound of formula I, such as those listed in Table 1, including, for example, LYT-100; and one or more anti-TGF-β1 agents selected from LY550410, LY580276, SB-505124, Grunic (LY2157299 monohydrate), and, as described herein, deuterium-rich pirfenidones other than LYT-100; and optionally one or more anti-angiotensin agents. In some embodiments, the antiangiotensin agent is selected from captopril, zolfenpril, enalapril, lisinopril, ramipril, quinapril, perindopril, benazepril, imidapril, trandopril, cilazapril, fosinopril, losartan, irbesartan, olmesartan, candesartan, telmisartan, valsartan, femasartan, diazonamide acetylglycine salt, oxoxanone, and AVE 099. For example, in some embodiments, the composition comprises a deuterium-rich pirfenidone, such as a compound of formula I, such as those listed in Table 1, including, for example, LYT-100; and one or more anti-TGF-β1 agents, such as, for example, a second type of deuterated pirfenidone other than LYT-100; and one or more antiangiotensin agents, such as captopril.

[0454] In some embodiments, the composition comprises a deuterium-rich pirfenidone, such as a compound of formula I, such as those listed in Table 1, including, for example, LYT-100; one or more anti-TGF-β1 agents and optionally one or more anti-inflammatory agents. In some embodiments, the composition comprises a deuterium-rich pirfenidone, such as a compound of formula I, such as those listed in Table 1, including, for example, LYT-100; and one or more anti-TGF-β1 agents selected from LY550410, LY580276, SB-505124 (LY2157299 monohydrate) and, for example, those described herein, such as those other than LYT-100, deuterium-rich pirfenidone; and one or more anti-inflammatory agents. In some embodiments, one or more anti-inflammatory agents are selected from etodoxacin, famotidine, fenprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketoroxyprofen, lansoprazole, mefenamic acid, meloxicam, misoprostol, nabumetone, naproxen, oxapazine, piroxicam, sulindac, tometine, celecoxib, aricoxox, robecoxib, vardicoxib, anizafen, temicoxib, flumidazole, cimeticoxib, rofecoxib, movacoxib, and ferocoxib. For example, in some embodiments, the composition comprises a deuterium-rich pirfenidone, such as a compound of formula I, such as those listed in Table 1, including, for example, compounds of formula I, such as those listed in Table 1, including, for example, LYT-100; one or more anti-TGF-β1 agents, such as, for example, deuterium-rich pirfenidones described herein other than LYT-100; and ibuprofen.

[0455] In some embodiments, the composition comprises a deuterium-rich pirfenidone, such as a compound of formula I, including, for example, compounds listed in Table 1, such as LYT-100; one or more anti-T cell agents; and optionally an anti-angiotensin agent. In some embodiments, the composition comprises a deuterium-rich pirfenidone, such as a compound of formula I, including, for example, compounds listed in Table 1, such as LYT-100; and one or more anti-T cell agents selected from tacrolimus, terflunomide, leflunomide, cyclosporine, piromemus, deniformin, and balithimab. In some embodiments, the antiangiotensin agent is selected from captopril, zolfenpril, enalapril, lisinopril, ramipril, quinapril, perindopril, benazepril, imidapril, trandopril, cilazapril, fosinopril, losartan, irbesartan, olmesartan, candesartan, telmisartan, valsartan, femasartan, diazonamide acetylglycine salt, oxoxonone, and AVE 099. For example, in some embodiments, the composition comprises a deuterium-rich pirfenidone, such as a compound of formula I, such as those listed in Table 1, including, for example, LYT-100; tacrolimus and optionally captopril. In some embodiments, the composition comprises a deuterium-rich pirfenidone, such as a compound of formula I, such as those listed in Table 1, including, for example, LYT-100; terflunomide and optionally captopril.

[0456] The aforementioned pharmaceutical compositions or combinations of two or more therapeutic agents may be used to treat diseases, symptoms, or ailments, such as those described below.

[0457] The compounds and combinations of the present invention are used to treat diseases, symptoms and ailments.

[0458] In one aspect, the present invention relates to the use of deuterium-rich pirfenidone, such as compounds of formula I, such as those listed in Table 1, including, for example, compounds of formula I, such as those listed in Table 1, including, for example, LYT-100, in combination with one or more agents selected from anti-TGF-β1 agents, anti-T cell agents, and / or anti-angiotensin agents, for the treatment of diseases, conditions, or disorders such as edema, fibrotic diseases, or inflammatory conditions. In another aspect, this disclosure relates to the use of deuterated pirfenidone, such as compounds of formula I, such as those listed in Table 1, including, for example, LYT-100, in combination with anti-inflammatory and / or anti-fibrotic therapeutic agents for the treatment of diseases, conditions, or disorders such as edema, fibrotic diseases, or inflammatory conditions.

[0459] This article provides methods for treating, preventing, and / or improving fibrosis-mediated and / or collagen-mediated conditions, the methods comprising administering to a subject in need a deuterium-rich pirfenidone compound, such as compounds of formula I, such as those listed in Table 1, including, for example, LYT-100, in combination with one or more anti-T-cell agents, anti-TGF-β1 agents, anti-angiotensin agents, and / or anti-inflammatory agents. In one aspect, the invention relates to methods for treating, preventing, and / or improving edema, such as lymphedema, the methods comprising administering to a subject in need a deuterium-rich pirfenidone compound, such as compounds of formula I, such as those listed in Table 1, including, for example, LYT-100, in combination with one or more anti-T-cell agents, anti-TGF-β1 agents, anti-angiotensin agents, and / or anti-inflammatory agents. In one aspect, the present invention relates to a method for treating, preventing, and / or improving one or more symptoms of edema, such as lymphedema, the method comprising administering to a subject in need a deuterium-rich pirfenidone compound, such as compounds of formula I, such as those listed in Table 1, including, for example, LYT-100, in combination with one or more anti-T-cell agents, anti-TGF-β1 agents, anti-angiotensin agents, and / or anti-inflammatory agents. In another aspect, the present invention relates to a method for treating, preventing, and / or improving one or more symptoms of idiopathic pulmonary fibrosis (IPF) and / or IPF, the method comprising administering to a subject in need a deuterium-rich pirfenidone compound, such as compounds of formula I, such as those listed in Table 1, including, for example, LYT-100, in combination with one or more anti-T-cell agents, anti-TGF-β1 agents, and / or anti-angiotensin agents.

[0460] This document provides methods for treating, preventing, and / or improving fibrosis-mediated and / or collagen-mediated conditions, the methods comprising administering to a subject in need a deuterium-rich pirfenidone compound, such as compounds of formula I, such ...

Claims

1. Use of deuterium-rich pirfenidone or a pharmaceutically acceptable salt thereof having the following structure in the preparation of a medicament for the treatment of edema: Where R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 and R 11 Selected from hydrogen and deuterium; and R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 and R 11 At least one of them is deuterium; and when R 7 R 8 R 9 R 10 and R 11 When it is deuterium, R 1 R 2 R 3 R 4 R 5 and R 6 At least one of them is deuterium.

2. The use according to claim 1, wherein the deuterium-rich pirfenidone has the following structure: Or its pharmaceutically acceptable salt.

3. The use according to claim 1 or 2, wherein the edema is lymphedema.

4. The use according to claim 3, wherein the lymphedema is secondary lymphedema.

5. The use according to any one of the preceding claims, wherein the subject has received cancer treatment and the lymphedema is related to the cancer treatment or diagnosis.

6. The use according to any one of the preceding claims, wherein the subject suffers from breast cancer-related arm lymphedema.

7. The use according to any one of the preceding claims, wherein the subject suffers from mild to moderate breast cancer-related lymphedema.

8. The use according to any one of the preceding claims, wherein the subject is receiving or has received chemotherapy or radiation therapy.

9. The use according to any one of the preceding claims, wherein at least one of the positions denoted as D independently has a deuterium enrichment of not less than about 95%.

10. The use according to any one of the preceding claims, wherein at least one of the positions denoted as D independently has a deuterium enrichment of not less than about 98%.

11. The use according to any one of the preceding claims, wherein at least one of the positions denoted as D independently has a deuterium enrichment of not less than about 99%.

12. The use according to any one of the preceding claims, wherein the deuterium-rich pirfenidone is administered orally at a total daily dose of 250-2500 mg.

13. The use according to claim 12, wherein the deuterium-rich pirfenidone is administered orally at a total daily dose of 500-1500 mg.

14. The use according to claim 13, wherein the deuterium-rich pirfenidone is administered orally at a total daily dose of 750-1000 mg.

15. The use according to claim 13, wherein the deuterium-rich pirfenidone is administered orally twice daily at a total daily dose of 1500 mg.

16. The use according to claim 13, wherein the deuterium-rich pirfenidone is administered orally twice daily at a total daily dose of 1000 mg.

17. The use according to claim 13, wherein the deuterium-rich pirfenidone is administered orally twice daily at a total daily dose of 500 mg.

18. The use according to claim 13, wherein the deuterium-rich pirfenidone is administered orally once daily at a total daily dose of 1500 mg.

19. The use according to claim 13, wherein the deuterium-rich pirfenidone is administered orally once daily at a total daily dose of 1000 mg.

20. The use according to claim 13, wherein the deuterium-rich pirfenidone is administered orally once daily at a total daily dose of 750 mg.

21. The use according to claim 13, wherein the deuterium-rich pirfenidone is administered orally once daily at a total daily dose of 500 mg.

22. The use according to any one of the preceding claims, wherein the deuterium-rich pirfenidone is administered with food.

23. The use according to any one of the preceding claims, wherein the deuterium-rich pirfenidone is not administered with food.

24. The use according to any one of the preceding claims, wherein the deuterium-rich pirfenidone is in tablet form.

25. Use of deuterium-rich pirfenidone or a pharmaceutically acceptable salt thereof having the following structure in the preparation of a medicament for the treatment of interstitial lung disease: Where R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 and R 11 Selected from hydrogen and deuterium; and R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 and R 11 At least one of them is deuterium; and when R 7 R 8 R 9 R 10 and R 11 When it is deuterium, R 1 R 2 R 3 R 4 R 5 and R 6 At least one of them is deuterium.

26. The use according to claim 18, wherein the deuterium-rich pirfenidone has the following structure: Or its pharmaceutically acceptable salt.

27. The use according to claim 25 or 26, wherein the interstitial lung disease is idiopathic pulmonary fibrosis.

28. The use according to any one of claims 25-27, wherein at least one of the positions represented as D independently has a deuterium enrichment of not less than about 95%.

29. The use according to any one of claims 25-28, wherein at least one of the positions denoted as D independently has a deuterium enrichment of not less than about 98%.

30. The use according to any one of claims 25-29, wherein at least one of the positions represented as D independently has a deuterium enrichment of not less than about 99%.

31. The use according to any one of claims 25-30, wherein the deuterium-rich pirfenidone is administered orally at a total daily dose of 250-2500 mg.

32. The use according to any one of claims 25-30, wherein the deuterium-rich pirfenidone is administered orally at a total daily dose of 500-1500 mg.

33. The use according to any one of claims 25-30, wherein the deuterium-rich pirfenidone is administered orally at a total daily dose of 750-1000 mg.

34. The use according to any one of claims 25-31, wherein the deuterium-rich pirfenidone is administered orally at a total daily dose of 1600-2500 mg.

35. The use according to claim 34, wherein the deuterium-rich pirfenidone is administered orally at a total daily dose of 2400-2500 mg.

36. The use according to claim 35, wherein the total daily dose of 2400-2500 mg is administered orally three times daily in equal amounts.

37. The use according to any one of claims 25-30, wherein the deuterium-rich pirfenidone is administered orally at a total daily dose of 1500 mg.

38. The use according to any one of claims 25-30, wherein the deuterium-rich pirfenidone is administered orally at a total daily dose of 1000 mg.

39. The use according to any one of claims 25-30, wherein the deuterium-rich pirfenidone is administered orally at a total daily dose of 750 mg.

40. The use according to any one of claims 25-30, wherein the deuterium-rich pirfenidone is administered orally at a total daily dose of 500 mg.

41. The use according to any one of claims 25-40, wherein the deuterium-rich pirfenidone is administered with food.

42. The use according to any one of claims 25-40, wherein the deuterium-rich pirfenidone is not administered with food.

43. The use according to any one of claims 25-36, wherein the deuterium-rich pirfenidone is taken in an oral dose form selected from capsules or tablets.

44. Use of deuterium-rich pirfenidone or pharmaceutically acceptable salts thereof having the following structures in the preparation of medicaments for the treatment of fibrosis or collagen infiltration disorders: Where R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 and R 11 Selected from hydrogen and deuterium; and R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 and R 11 At least one of them is deuterium; and when R 7 R 8 R 9 R 10 and R 11 When it is deuterium, R 1 R 2 R 3 R 4 R 5 and R 6 At least one of them is deuterium.

45. The use according to claim 24, wherein the deuterium-rich pirfenidone has the following structure: Or its pharmaceutically acceptable salt.

46. ​​The use according to any one of claims 44-45, wherein at least one of the positions represented as D independently has a deuterium enrichment of not less than about 95%.

47. The use according to claim 46, wherein at least one of the positions represented as D independently has a deuterium enrichment of not less than about 98%.

48. The use according to claim 47, wherein at least one of the positions represented as D independently has a deuterium enrichment of not less than about 99%.

49. The use according to any one of claims 44-48, wherein the deuterium-rich pirfenidone is administered orally at a total daily dose of 250-2500 mg.

50. The use according to any one of claims 44-48, wherein the deuterium-rich pirfenidone is administered orally at a total daily dose of 500-1500 mg.

51. The use according to any one of claims 44-48, wherein the deuterium-rich pirfenidone is administered orally at a total daily dose of 750-1000 mg.

52. The use according to any one of claims 44-48, wherein the deuterium-rich pirfenidone is administered orally at a total daily dose of 1500 mg.

53. The use according to any one of claims 44-48, wherein the deuterium-rich pirfenidone is administered orally at a total daily dose of 1000 mg.

54. The use according to any one of claims 44-48, wherein the deuterium-rich pirfenidone is administered orally at a total daily dose of 500 mg.

55. The use according to any one of claims 44-48, wherein the deuterium-rich pirfenidone is administered orally at a total daily dose of 1500 mg.

56. The use according to any one of claims 44-48, wherein the deuterium-rich pirfenidone is administered orally at a total daily dose of 1000 mg.

57. The use according to any one of claims 44-48, wherein the deuterium-rich pirfenidone is administered orally at a total daily dose of 750 mg.

58. The use according to any one of claims 44-48, wherein the deuterium-rich pirfenidone is administered orally at a total daily dose of 500 mg.

59. The use according to any one of claims 44-58, wherein the deuterium-rich pirfenidone is administered with food.

60. The use according to any one of claims 44-58, wherein the deuterium-rich pirfenidone is not administered with food.

61. The use according to any one of claims 44-60, wherein the deuterium-rich pirfenidone is in tablet form.

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