Salicylsalicylic acid (SAL) and sal-PC compositions and methods of use in the treatment of inflammatory conditions

Abstract

The present disclosure relates, inter alia, to medical treatments and compositions for medical treatment and, more particularly, to methods and compositions for treating subjects afflicted with medical conditions.

Description

SALICYLSALICYLIC ACID (SAL) AND SAL-PC COMPOSITIONS AND METHODS OF USE IN THE TREATMENT OF INFLAMMATORY CONDITIONSCROSS REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims the benefit of priority from U.S. Provisional Application No. 63 / 716,956, filed November 6, 2024, the contents of which are hereby incorporated by reference in their entirety for all purposes.FIELD

[0002] The present disclosure relates, inter alia, to medical treatments and compositions for medical treatment and, more particularly, to methods and compositions for treating subjects afflicted with medical conditions.BACKGROUND

[0003] Hutchinson Gilford Progeria Syndrome (HGPS) and related laminopathies are a group of extremely rare genetic disorders. HGPS affects approximately 400 individuals in the world (Gordon 2023). In nearly all cases, patients progress to death by age 17 due to accelerated aging conditions such as strokes and myocardial infarction. Currently there is only one medication approved by regulatory agencies such as the US Food and Drug Administration (FDA) as well as the European Medicines Agency (EMA). That drug is called lonafarnib, a chemotherapy agent, and it is associated with serious toxicities (see package insert for ZOKINVY, revised November 2020; https: / / www.accessdata.fda.gov / drugsatfda_docs / label / 2020 / 213969s0001bl.pdf). These adverse effects may negatively impact a patient’s quality of life due to potentially significant side effects (Dhillon 2021).

[0004] Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a genetic disorder affecting approximately 150,000 individuals in the United States with an estimated prevalence of clinically diagnosed cases of 42.6 cases per 100,000 individuals (Aung 2021). In all cases patients progress to end stage renal disease requiring dialysis or kidney transplant. Currently there is only one medication approved by regulatory agencies such as the US Food and Drug Administration (FDA) as well as the European Medicinal Agency (EMA). That drug is called tolvaptan and it is associated with serious liver toxicities as well as significant other side effects such as aquaresis, polyuria and polydipsia. These adverse effects may negatively impact a patient’s quality of life due to potentially significant side effects (Weimbs 2018).

[0005] Traumatic brain injury (TBI) is a significant public health problem that can lead to chronic neurodegenerative disorders such as Alzheimer's disease and chronic traumatic encephalopathy (CTE) and often results in long-term disability or death. Apart from the primary immediate damage to brain tissue, the pathophysiology of TBI involves secondary injury resulting from a cascade of biochemical changes at the cellular and molecular levels that exacerbate the tissue damage as a part of the host response to primary injury. Secondary injury cascades such as oxidative stress, endoplasmic reticulum stress, and neuroinflammation contribute to lasting damage within the brain and can be induced by several different risk factors. Since neuroinflammation is one of the key players in the development of secondary injury post- TBI, there is a need to develop and identify new therapies and more effective therapeutic agents to reduce neuroinflammation resulting from TBI.

[0006] As can be seen, there is a need for improved treatments that address the above therapeutic needs.BRIEF DESCRIPTION OF THE DRAWINGS

[0007] Figures 1A and IB are diagrams showing the solvent accessibility of Salicylic Acid (SA), according to aspects of the present disclosure;

[0008] Figure 2 is a diagram of the chemical structure of salicylsalicylic acid (SAL), according to aspects of the present disclosure;

[0009] Figure 3 is a diagram of the chemical structure of phosphatidylcholine (PC), according to aspects of the present disclosure;

[0010] Figure 4 is a graph of light scattering of a sample of SAL-PC, according to aspects of the present disclosure;

[0011] Figure 5 is a diagram of the effects of SAL on molecules, according to aspects of the present disclosure; and

[0012] Figure 6 is a diagram of an effect of SAL to reduce endotheliopathy and atherosclerosis, according to aspects of the present disclosure.

[0013] Figure 7 is an experimental design for Sal-PC efficacy against TBI-induced neurological and cognitive dysfunction.

[0014] Figures 8 A-C show neurological assessments. Wistar Han IGS adult male rats (N=19) were acclimated and baseline assessments obtained for mNSS (A), rotarod (B), and TFL (C) 1-3 days prior to surgery. On day 0, rats received a controlled cortical impact; beginning 60 min post- TBI, 8 rats received a PBS vehicle, and 11 rats received Sal-PC (50 mg / kg) daily via i.p. route for 5 successive days (days 0, 1, 2, 3, 4) as indicated by the light green box. Treatmentgroup differences at each time point were determined by a Mann-Whitney test; * represents p<0.05.

[0015] Figures 9 A-E show spatial learning and memory and object recognition assessments. On days 12-14 post-TBI rats received 3-4 training trials / day on the Barnes maze to find the escape hole (A-C); memory of the location of the escape hole was tested on the probe day (D; day 15-post-TBI). Ability to discern a novel object on day 17 post-TBI (E) from the original object exposed to on the previous day utilized the novel object recognition test. Treatment group differences at each time point were determined using the Mann-Whitney test.

[0016] Figure 10 shows the live cell multiplex and NFKB antagonist-mode assays described in Example 3.

[0017] Figure 11 shows the increased efficacy of Sal-PC vs. SAL in reducing cellular expression of nuclear factor kappa b in human embryonic kidney cells.DETAILED DESCRIPTION OF THE DISCLOSURE

[0018] The following detailed description is of the best currently contemplated modes of carrying out exemplary embodiments of the disclosure. The description is not to be taken in a limiting sense but is made merely for the purpose of illustrating the general principles of the disclosure.Hutchinson Gilford Progeria Syndrome (HGPS)

[0019] HGPS has been reported to be due to a congenital birth defect related to an exaggerated accumulation of cellular damage or the inefficient ability to respond to stress which causes progeroid syndromes, characterized by a precocious manifestation of several features related to human aging (Burtner and Kennedy 2010). Most progeroid syndromes are caused by defective DNA repair mechanisms or by alterations in the nuclear lamina (Hoeijmakers 2009). The nuclear lamina is a complex structure that surrounds and protects the nuclear content, playing important roles in genome regulation, organization, and maintenance (Dechat et al. 2008). Covering the inner face of the nuclear membrane, the nuclear lamina forms a protein network that provides a scaffold for nuclear envelope proteins and chromatin (Gruenbaum 2005; Mekhail and Moazed 2010).

[0020] Genetic inhibition of nuclear factor kappa b (NF-KB) extends longevity in Zmspte24- deficient mice (an accepted model of HGPS) (Osario 2012). The IKK / NF-KB signaling pathway has been proposed to be one of the key mediators of aging (Tilstra 2011). It is activated by genotoxic, oxidative, and inflammatory stresses and regulates expression ofcytokines, growth factors, and genes that regulate apoptosis, cell cycle progression, cell senescence, and inflammation. (Tilstra 2011). Therefore, a safe molecule that inhibits NF-KB represents a therapeutic target for extending mammalian lifespan and especially so in HGPS patients and those with related laminopathies. Using motif mapping, NF-KB was determined to be the transcription factor most associated with aging (Adler 2007). Inducible genetic blockade of NF-KB for 2 weeks in the epidermis of chronologically aged mice reverted the tissue characteristics and global gene expression programs to those of young mice. Agespecific NF-KB blockade and orthogonal cell cycle interventions revealed that NF-KB controls cell cycle exit and gene expression signature of aging in parallel but not sequential pathways (Adler 2007). These results identify a conserved network of regulatory pathways underlying mammalian aging and show that NF-KB is continually required to enforce many features of aging in a tissue-specific manner (Adler 2007). Sodium salicylate is an anti-inflammatory drug that at high doses is able to efficiently inhibit the IKK complex and has been satisfactorily used to reduce NF-KB activation in animal models of muscular dystrophy (Cai 2004).

[0021] In one example study, Zmpste-24-deficient mice vs control wild type mice were treated with sodium salicylate (200 mg / kg per day), were weighted and observed during their lifetimes. Salicylate-treated Zmpste24- / - mice showed improved body weights (Figures 5A and 5B from Osario 2012) and extended life spans as compared with nontreated Zmpste24-deficient mice (Osario 2012). The mean survival of salicylate-treated Zmpste24- / - mice was extended from 123 to 148 days, and the maximum survival was extended from 151 to 243 days (P < 0.01). NF-KB EMSA analysis of livers from treated and untreated mice demonstrated the targeted effect of salicylate on NF-KB activation as treated mice showed decreased amounts of RelA dimers in the nucleus as well as reduced degradation of the NF-KB inhibitor IKBU. (Osario 2012). Salicylate-treated Zmpste24 mice showed an increase in cell proliferation, subcutaneous fat layer thickness, and normal hair follicles in the skin (Osario 2012). Moreover, this treatment also prevented thymic and spleen involution, with these organs having a size similar to wildtype organs (Osario 2012). Treated Zmpste24-deficient mice showed significantly improved cortical regions (Osario 2012). In summary, these data demonstrate that salicylate treatment is effective at inhibiting NF-KB activation in vivo and significantly extended the longevity of progeroid Zmpste24-deficient mice. Unfortunately, the use of oral salicylic acid in humans is often associated with severe gastrointestinal intolerance with nausea and vomiting reported as very common adverse events leading to high discontinuation rate, poor tolerability and poor compliance. Aspirin was invented in 1898 to reduce the frequency of the intolerablegastrointestinal side effects or oral salicylic acid, but aspirin is associated with severe risks of bleeding and it also an unacceptable choice for patients with HGPS and related laminopathies.

[0022] Salicylic acid (SA) as shown in Figure 1 is the one and only active metabolite of the prodrug referred to in this document as salicylsalicylic acid (SAL). SAL is also known as "salsalate" and by other acronyms such as SSA. SAL has been prescribed in the US as an unapproved yet marketed drug used for treatment of rheumatismal disorders since its introduction in the US by Boehringer Mannheim in 1908 and marketed by Merck and Co.

[0023] For patients with the rapidly aging conditions such as HGPS and related laminopathies, Applicant has found that SAL and complexes thereof (e.g., SAL-PC, a 1 : 1 complex of SAL and PC)) can be used to slow the aging process in humans and animals as well. Without being bound by theory, it is proposed that the origin of HGPS is an abnormal over farneslyation of the intranuclear protein known as progerin (Chen 2022). There is a strong focus on the clinical utility of IKK-kinase beta, which when phosphorylated leads to a release of excessive expression of nuclear factor kappa b. Abnormal levels of farnesylated progerin are suspected to contribute to an abnormal inner nuclear membrane, leading to changes in the size and shape of the nucleus of cells in HGPS patients, leading to release of toxic concentrations of intracellular nuclear factor kappa b which then leads to overexpression and release of toxic cytokines such as interleukins as well as tumor necrosis factor b. HGPS is always a slowly progressing, chronic disease and thus any therapy will have to continue over years and decades. Systemically distributed drugs are likely to lead to potentially prohibitive side effects during extended treatment. As subjects with HGPS will require a lifetime of treatment with agents designed to slow progression of their accelerated aging, any such medication must have an acceptable risk / benefit ration over such a prolonged period of treatment.

[0024] Specific molecules in the treatment of HGPS target kinase enzymes such as IKK-kinase beta are expected to improve the quality and quantity of life in such patients. A molecule that can accomplish both of these functions with an acceptable safety profile for long term use would be highly desirable.

[0025] Unlike anti-inflammatory agents such as non-steroidal anti-inflammatory drugs (NSAIDs), SAL or complexes of SAL with phosphatidyl choline (SAL-PC), unlike SA, do not cause bleeding or increase the risks of gastrointestinal lesions such as ulcers or erosions (Cryer 1990), nor does SAL or SAL-PC increase the risk of cardiovascular or cerebrovascular complications (Hauser 2016). Salicylic acid is the only active moiety of SAL and SAL-PC. Yet, unlike SA, SAL, in studies of duration as long as 30 months does not lead to worsening glomerular filtration rate (GFR) or changes in plasma C-cystatin both important markers ofrenal function (Hauser 2016). Salicylsalicylic acid, because of its limited aqueous solubility is used almost exclusively as an orally administered drug to treat inflammatory conditions.

[0026] SAL is particularly beneficial compared to other sources of salicylate (e.g., acetylsalicylic acid (aka aspirin) due to its decreased effects on the mucosal lining after oral administration. For example, Cryer et al (Gastroenterology, vol. 99, issue 6, December 1990, pp. 1616-1621) found that equivalent doses of aspirin or SAL (3.9 g / d and 3.0 g / d, respectively) produced roughly identical serum salicylate concentrations (approx. 15 mg / dL), but the aspirin- treated subjects showed considerable mucosal injury compared to SAL-treated subjects or placebo-treated subjects. Aspirin was also shown to reduce mucosal prostaglandin F2a and E2 levels by greater than 90% compared to no significant effect for the SAL-treated subjects. Aspirin also reduced plasma prostaglandin F2a by about 58% versus only about 11% for SAL- treated subjects. Thus, SAL provides plasma salicylate concentrations similar to other sources of salicylate such as aspirin, it has significantly lower adverse effects on gastroduodenal mucosa and protaglandin synthesis. Accordingly SAL provides significant benefits when dosed over long periods of time for conditions such as HGPS (or ADPKD, TBI, and conditions associated with NF-kB activation as described herein).

[0027] The role of metabolic reprogramming has emerged as a potential therapeutic target in the pathogenesis of HGPS (Dhillon 2021). An animal study has shown that use of intraperitoneal salicylic acid delivered as the sodium salt called sodium salicylate at a dose of 200 g / kg / day targets the metabolic alterations in HGPS and slowed the accelerated aging in such animal models of HGPS (Osario 2012). However, as indicated herein, the side-effects of SA make it problematic for daily dosing over a prolonged period, as would be required for treating HGPS and other conditions as described herein. Therefore, targeting such abnormal pathways created by pathologic levels of intracellular progerin using SAL or SAL-PC is a novel therapeutic approach to patients with HGPS and related laminopathies as well as to slow down the aging process in normal subjects. Salicylsalicylic acid or SAP-PC via their active moiety salicylic acid (SA) are pleiotropic drugs with multiple mechanisms of actions. SA has direct binding on the enzyme IkB kinase (MIKK) (Figure 1) (Yin 1998, Matsushita 2013, Hawley 2012). This binding results in decreased released of nuclear factor kappa b with reduction in release of cytokines (Figure 5). Few approaches have been described to counteract the altered downstream pathways caused by progerin accumulation, including nuclear shape abnormalities, ROS generation, accumulation of oxidized proteins, mitochondrial dysfunction (Viteri 2010, Richards 2011), cell senescence and NF-kB activation, leading to the secretion of high levels of the proinflammatory cytokines IL-6, CXCL1, and TNF-a (Osario 2012,Tilstra2011). In one embodiment of the present disclosure, HGPS can be effectively treated by orally administering to a patient suffering from HGPS a therapeutically effective amount of SAL or SAL-PC. In addition embodiments, SAL or SAL-PC can also be administered by intravenous, intramuscular, ocular, subcutaneous, intraperitoneal, intraarticular, intranasal, topical or rectal administration. By treating HGPS, we mean reducing the severity or slowing the progression of symptoms associated with HGPS, including reducing the severity or slowing the progression of symptoms associated with accelerated aging (e.g., thin, wrinkled skin, baldness or thinning hair, joint stiffness and dislocations, brittle bones, atherosclerosis, stroke, etc.), and in increasing the life span of such patients.

[0028] In some embodiments, treatment of a population of HGPS patients with SAL or SAL- PC as described herein provides improved life expectancy as compared to an otherwise similar population of HGPS patients not treated with SAL or SAL-PC. The improvement in life expectancy ranges from about 10% to about 100%, including at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 100%, including all ranges between any of these values.

[0029] in other embodiments, after one month of treatment of an HGPS patient with SAL or SAL-PC as described herein, the patient experiences a reduction of plasma levels of Progerin of about 10% to about 90%, including about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90%, including all ranges between any of these values.

[0030] Suitable daily doses of SAL for treating HGPS range from about 50 mg / kg to about 100 mg / kg, including about 50 mg / gk, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, or about 100 mg / kg, inclusive of all ranges between any of these values. In various embodiments, the daily dose of SAL is divided into two doses (e.g., a 50 mg / kg daily dose can be administered as two 25 mg / kg doses, e.g, about 8 hours apart). In various embodiments, the HGPS patient is initially administered a daily dose of SAL of about 50 mg / kg for approximately 1 week. If the plasma concentration of salicylate is less than about 1 mM / L (123 meg / mL), the dose of SAL is increased by about 10 mg / kg. Titration of SAL in 10 mg / kg increments in this manner is continued until the plasma concentration of salicylate is about 1 mM / L. In some embodiments, the SAL is administered in the form of a caplet or a powder dissolved in water.

[0031] Suitable daily doses of SAL-PC for treating HGPS range from about 150 mg / kg to about 300 mg / kg, including about 150 mg / gk, about 180 mg / kg, about 210 mg / kg, about 240mg / kg, about 270 mg / kg, or about 300 mg / kg, inclusive of all ranges between any of these values. In various embodiments, the daily dose of SAL is divided into two doses (e.g., a 150 mg / kg daily dose can be administered as two 75 mg / kg doses, e.g., about 8 hours apart). In various embodiments, the HGPS patient is initially administered a daily dose of SAL-PC of about 150 mg / kg for approximately 1 week. If the plasma concentration of salicylate is less than about 1 mM / L (123 meg / mL), the dose of SAL-PC is increased by about 30 mg / kg. Titration of SAL-PC in 30 mg / kg increments in this manner is continued until the plasma concentration of salicylate is about 1 mM / L.Table 1. Solubility of Salicylsalicylic Acid After Redissolving According to the Methods of the Present Disclosure

[0032] A lipid film or powder (which can be generated by methods known in the art, e.g., adding a bulking agent such as sucrose) which contains the SAL or SAL-PC will be stored under conditions which prevent oxidation. Pharmaceutical compositions of orally-administered SAL or SAL-PC can include, depending on the formulation desired, pharmaceutically- acceptable, non-toxic GRAS excipients, which are defined as vehicles commonly used to formulate pharmaceutical compositions for animal or human administration. Suitable orally administrable forms comprising SAL or SAL-PC include, but are not limited to tablets, capsules, wafers, troches, solutions, and suspensions. Further guidance regarding formulations that are suitable for various types of administration can be found in Remington's Pharmaceutical Sciences, Mace Publishing Com-pany, Philadelphia, Pa., 17th ed. (1985). For a brief review of methods for drug delivery, see. Langer, Science 249: 1527-1533 (1990). Toxicity and therapeutic efficacy of the active agent can be determined according to standard pharmaceutical procedures in cell cultures and / or experimental animals, including, for example, determining the LD50 (the dose lethal to 50% of the studied animal population) andthe ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50 / ED50. The components used to formulate the pharmaceutical compositions are preferably of high purity and are substantially free of potentially harmful contaminants (e.g., at least National Formulary (NF) grade, generally at least analytical grade, and more typically at least pharmaceutical grade). To the extent that SAL or SAL complexes (e.g., SAL-PC) must be synthesized prior to use, the resulting product is typically substantially free of any potentially toxic agents, particularly any endotoxins, which may be present during the synthesis or purification process. Compositions for oral administration are made under current Good Manufacturing Practice (c-GMP) conditions. The oral SAL or SAL complexes (e.g., SAL-PC) are offered to children either as tablets / capsules / caplets or in liquid form.

[0033] In embodiments, a process for preparing compositions comprising SAL or SAL-PC include new procedures to solubilize SAL or SAL-PC in an aqueous medium. Maintaining a stable solution of SAL or SAL-PC is pH dependent as is a stable suspension of SAL or SAL- PC. The pH of the salsalate in physiologically buffered saline (PBS) was observed to drop to pH 4, with undissolved salsalate solid in the test tube, and virtually no salsalate in solution. A surprising discovery is that, by increasing the pH of the previously insoluble salsalate in PBS when mixed with sodium hydroxide (NaOH), the salsalate or SAL-PC readily goes into solution at 15 mg / ml which ti the knowledge of applicant is a novel and never before reported discovery. Any such salsalate solution that has a pH of less than 6.0 falls out of the solution. Current product data sheets of salsalate state salsalate is not soluble in aqueous solutions.

[0034] In embodiments, solutions or suspensions of SAL or SAL complexes (e.g., SAL-PC) can be prepared using PBS. This step simplifies the process of dissolving salsalate in aqueous media because there is no need to utilize any organic solvents and by simply adding PBS to SAL, the result is a unique solution. The process results in a 50 mM solution of SAL at a pH 7.5. If a precipitate appears in the container upon storage, that indicates that the pH has dropped below 6.0. In this case, the precipitate can be redissolved to form a solution without a precipitate by simply adding NaOH. In embodiments, the process involves maintaining a pH in a range of approximately 6.0 to approximately 10.0 and preferably approximately 7.2 to approximately 7.5. Maintaining the proper pH can be controlled, for example, by the use of pharmaceutically acceptable buffers known in the art such as phosphate buffers (e.g, PBS), Tris buffers, and zwitterionic buffers such as HEPES, MOPS, and TES.

[0035] The exact dosage required to reach a therapeutic level of SAL's active moiety, salicylic acid, will be determined by any competent pediatric clinician or pharmacist. Such a therapeuticlevel of plasma salicylate is defined as a plasma level no less than 1 mM / L and no greater than 2.5 mM / L, including 1 mM / L, 1.1 mM / L, 1.2 mM / L, 1.3 mM / L, 1.4 mM / L, 1.5 mM / L, 1.6 mM / L, 1.7 mM / L, 1.8 mM / L, 1.9 mM / L, 2.0 mM / L, 2.1 mM / L, 2.2 mM / L, 2.3 mM / L, 2.4 mM / L, or 2.5 mM / L, inclusive of all ranges between any of these values. In one embodiment, the starting dose in children would be 20-30 mg / kg per day in two equally divided doses. It is expected that the patient with HGPS and those with the related laminopathies would be required to take the oral SAL or SAL complexes (e.g., SAL-PC) for their lifetime.Autosomal Dominant Polycystic Kidney Disease (ADPKD)

[0036] With regard to the use of SAL-PC for the treatment of ADPKD, one of the theories proposed for the origin of the cystic enlargement of the renal tubules relates to uncontrolled inflammation of the renal parenchyma and surrounding tissues (Song 2023, Kanhai 2023, Leonard 2019). There is a strong focus on the clinical utility with respect to the mammalian target of rapamycin and kinase inhibitors, compounds that target inflammation and histone deacetylases, compounds that affect the renal cysts (Song 2023, Kanhai 2023, Leonard 2019). ADPKD is always a slowly progressing, chronic disease and any therapy will have to continue over years and decades. Systemically distributed drugs are likely to lead to potentially prohibitive extra-renal side effects during extended treatment. As subjects with ADPKD will require a lifetime of treatment with agents designed to slow progression of their renal insufficiency, any such medication must have an acceptable risk / benefit ration over such a prolonged period of treatment.

[0037] Specific molecules useful in the treatment of ADPKD target mTOR and kinase enzymes are referred to as catalytic mTOR inhibitors and kinase inhibitors. A molecule that can accomplish both of these functions with an acceptable safety profile for long term use would be highly desirable.

[0038] The anti-inflammatory agent known as salicylsalicylic acid or salsalate (SAL) has such dual properties (Song 2023, Kanhai 2023, Leonard 2019, Yin 1998), but has not been recognized in the art as having any potential utility in treating symptoms associated with ADPKD. SAL has been used an analgesic / anti-inflammatory in the United States since it was introduced in 1908 for treatment of rheumatological disorders such as osteoarthritis and rheumatoid arthritis (Singelton 1980, McPherson 1984). Since its introduction in the US it has been safely used by hundreds of thousands of individuals with a record of long-term safety. Unlike anti-inflammatory agents such as the non-steroidal anti-inflammatory drugs (NSAIDs) and SA, SAL does not cause bleeding or increase the risks of gastrointestinal lesions such asulcers or erosions (Cryer 1990). Nor does SAL increase the risk of cardiovascular or cerebrovascular complications (Hauser 2016). Furthermore, SAL in studies of duration as long as 30 months, does not lead to worsening glomerular filtration rate (GFR) or changes in plasma C-cystatin both important markers of renal function (Hauser 2016).

[0039] The role of metabolic reprogramming has emerged as a potential therapeutic target in the pathogenesis of autosomal dominant polycystic kidney disease (Leonhard 2019). Various animal studies have shown that targeting the metabolic alterations in ADPKD may arrest the renal cyst progression as well as slow renal cell loss in both in-vitro studies and in animal models of ADPKD. Therefore, targeting such metabolic pathways is a novel therapeutic approach to patients with ADPKD. (Bergmann 2019, Leonhard 2019). Key molecular signaling pathways involved in ADPKD related metabolic dysfunction include the mechanistic target of rapamycin complex 1 (mTORCl) signaling (Novalic 2012, Takiar 2011, Rowe 2013, Leonhard 2019, Perna 2016, Mei 2020) as well as the activity of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel (Persu 2000), both of which are regulated by the enzyme AMP-activated protein kinase (AMPK). AMPK enzyme has multiple functions such as an energy sensing as well as a functioning as a “master metabolic regulator of the cell” (Leonard 2019).

[0040] AMPK is an upstream inhibitor of the mTORCl pathway and is a ubiquitously expressed heterotrimeric enzyme complex (consisting of a, P and y isoforms) (Steinberg 2019). Various studies have been conducted to assess the efficacy of indirect AMPK activators, such as metformin in slowing renal cyst growth through modulating mitochondrial function (Leonard 2019, Takiar 2011, Seliger 2018). However clinical translation of metformin as a promising disease modifying agent in the treatment of ADPKD is limited due to its reduced bioavailability (-50-60%), limited maximum dose (2250 mg / day), and when coupled with a high hepatic first-pass effect, may result in an insufficient AMPK activation for clinical efficacy. Thus, there is an unmet need to develop a more effective AMPK-based therapeutic which can be used to treat patients with ADPKD. Currently, the only FDA drug approved drug Jynarque (tolvaptan), a vasopressin V2 receptor (V2R) antagonist, has a suspected underlying key mechanism of increasing cAMP signaling and it has been shown clinically to slow renal cyst growth as well as delay declining renal function (Torres 2017).

[0041] Salsalate, via its active moiety salicylic acid, is a pleiotropic drug with multiple mechanisms of actions and has direct binding on the enzyme AMPK resulting in decreased mTORlc expression as well as effects on mitochondrial respiration (Yin 1998, Matsushita 2013, Hawley 2012, Leonhard 2019).

[0042] Salsalate has a long history (>100 years) of clinical use in arthritis as a safe antiinflammatory agent, with pleiotropic actions along with multiple salicylic acid binding target protein (SABP) (Kiessig 2014). Bleeding into the multiple cysts of patients with ADPKD is a serious complication in such patients. Use of any NSAID is medically contraindicated due to the bleeding risks. Salsalate has a hematological safety profile even in patients with hemophilia due to lack of effect on COX-1 in platelets (Sweeney 1991, Stevens 1995, Estes 1980). This gives the additional potential benefit of pain reduction as well as slowing of disease progression by using salsalate in adults with ADPKD. Given the efficacy, unique pleiotropic actions on multiple molecular signaling pathways of inflammation and cyst growth and cystic fluid secretions, its long and safe clinical use, SAL or SAL complexes (e.g., SAL-PC) are novel candidates for the treatment of patients diagnosed with ADPKD.

[0043] SAL and SAL-PC are a novel therapeutic approach to treating patients with ADPKD. SAL has been found to safe and effective in the animal model of ADPKD (Song 2023, Kanhai 2023, Leonard 2019).

[0044] By treating ADPKD, we mean reducing the severity or slowing the progression of symptoms associated with ADPKD, including slowing the loss of kidney function, slowing the growth of kidney cysts, reducing the rate of decrease in glomerular filtration rates, reducing the severity or slowing the progression of symptoms associated with ADPKD such as frequent urination, high blood pressure, pain, kidney stones, bloating, swelling, shortness of breath, etc.

[0045] Suitable daily doses of SAL for treating ADPKD range from about 50 mg / kg to about 100 mg / kg, including about 50 mg / gk, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, or about 100 mg / kg, inclusive of all ranges between any of these values. In various embodiments, the daily dose of SAL is divided into two doses (e.g., a 50 mg / kg daily dose can be administered as two 25 mg / kg doses, e.g., about 8 hours apart). In various embodiments, the ADPKD patient is initially administered a daily dose of SAL of about 50 mg / kg for approximately 1 week. If the plasma concentration of salicylate is less than about 1 mM / L (123 meg / mL), the dose of SAL is increased by about 10 mg / kg. Titration of SAL in 10 mg / kg increments in this manner is continued until the plasma concentration of salicylate is about 1 mM / L. In some embodiments, the SAL is administered in the form of a caplet or a powder dissolved in water.

[0046] Suitable daily doses of SAL-PC for treating ADPKD range from about 150 mg / kg to about 300 mg / kg, including about 150 mg / gk, about 180 mg / kg, about 210 mg / kg, about 240 mg / kg, about 270 mg / kg, or about 300 mg / kg, inclusive of all ranges between any of these values. In various embodiments, the daily dose of SAL is divided into two doses (e.g., a 150mg / kg daily dose can be administered as two 75 mg / kg doses, e.g., about 8 hours apart). In various embodiments, the ADPKD patient is initially administered a daily dose of SAL-PC of about 150 mg / kg for approximately 1 week. If the plasma concentration of salicylate is less than about 1 mM / L (123 meg / mL), the dose of SAL-PC is increased by about 30 mg / kg. Titration of SAL-PC in 30 mg / kg increments in this manner is continued until the plasma concentration of salicylate is about 1 mM / L.

[0047] In various embodiments, administration of SAL or SAL-PC as described herein, to patients suffering from ADPKD slows the annual decline in estimated glomerular filtration rate (eGFR) by no more than about 0.5 mL / min / 1.73 m2up to about 5.0 mL / min / 1.73 m2(e.g., about 0.5, about 1.0, about 1.5, about 2.0, about 2.5, about 3.0, about 3.5, about 4.0, about 4.5, or about 5.0 mL / min / 1.73 m2, including all ranges between any of these values) compared to standard care in eligible ADPKD patients (e.g., treatment with tolvaptan). This effect may vary by age and disease stage, but will slow the annual decline in eGFR by an average of about 1.27 to about 1.66 mL / min / 1.73 m2annually (including an average of about 1.27, about 1.3, about 1.33, about 1.36, about 1.39, about 1.42, about 1.45, about 1.48, about 1.51, about 1.54, about 1.57, about 1.60, about 1.66, or about 1.66 mL / min / 1.73 m2, including all ranges between any of these values) with a more significant effect in younger individuals and earlier stages of the disease. Cumulative effect: The 5-year cumulative slowing in eGFR decline will be about 7 to about 10 mL / min / 1.73 m2, including about 7, about 7.5, about 8.0, about 8.5, about 9, about 9.5, or about 10 mL / min / 1.73 m2, including all ranges between any of these values). Stagespecific effects: The drugs SAL and SAL-PC will show significant slowing of eGFR decline in patients with baseline eGFRs of 45 to 59, 30 to 44, and 25 to 29 mL / min / 1.73 m2

[0048] The compositions comprising SAL or SAL complexes with phosphatidylcholine (SAL- PC) described herein provide improved compositions for administering SAL to patients in need thereof.Traumatic Brain Injury (TBI)

[0049] SAL or SAL-PC are a novel approach to treating patients with traumatic brain injury, post-operative pain, and in to treating patients with diabetes and wound healing from bum injuries.

[0050] Traumatic brain injury (TBI) is associated with elevated levels of a post-translationally modified protein called acetylated tau (ac-tau). Elevated ac-tau levels are detected in the plasma of patients admitted to the hospital after sustaining a TBI. Elevated plasma and brain levels of acetylated tau are reported in various murine models of TBI. The recent discovery ofac-tau in the brains of chronic traumatic encephalopathy (CTE) patients has confirmed the long-term presence of ac-tau many years after a TBI.

[0051] Salsalate (salicyl ester of salicylic acid) been used orally for the past 100+ years to treat inflammation and pain primarily caused by arthritis. Sodium salicylate has been used intravenously since the first report in 1923 for the treatment of rheumatological conditions. Salsalate because of its limited aqueous solubility is used almost exclusively as an orally administered drug to treat inflammatory conditions. The most recent report of the use of intravenous sodium salicylate in patients was in 1987 when administered to heroin addicts to determine sodium salicylate effects on glucose metabolism. Salsalate although readily available as a prescription drug under the brand names, Disalcid, Salsitab, Mono-Gesic and Salflex have never received FDA approval for any condition.

[0052] Broadly, an embodiment of the present disclosure provides methods and compositions for effectively reducing a level of acetylated tau in a patient with an severity of TBI (mild, moderate and / or severe) as well as improving the clinical outcomes of patients who have sustained any severity of TBI. SAL or SAL-PC are administered in an intravenous or in an oral formulation to reduce acetylated tau plasma, cerebrospinal fluid and brain tissue levels in patients suffering from symptoms of TBI. SAL or SAL-PC are expected to improve the clinical outcomes of TBI victims even in the absence of reducing acetylated tau in any bodily fluid or brain tissue. In addition to the above routes of administration, SAL or SAL-PC can also be administered by subcutaneous, intraperitoneal, intramuscular, epidural, intrathecal infusions as well as by intranasal, topical or rectal administration.

[0053] An effect of SAL or SAL-PC is to reduce acetylated tau and / or to cause neuroinflammation suppression in a human brain, according to aspects of the present disclosure. In embodiments, an effective amount of intravenous SAL or SAL-PC can be delivered to a patient to treat symptoms of TBI. An effective amount of intravenous SAL or SAL complexes (e.g., SAL-PC) is an amount that is effective to ameliorate at least one symptom of a TBI, e.g., to alleviate an adverse symptom and / or to increase a normal function that was impaired as a result of the TBI with our without elevated plasma acetylated tau levels. The therapeutic plasma levels of SAL or SAL-PC’ s active moiety salicylic acid in the successful treatment of TBI ranges from about 0.1 mM / L to about 4.0 mM / L, including about 0.1m about 0.2m about 0.3, about 0.4, about 0.5, about 1.0, about 1.5, about 2.0, about 2.5, about 3.0, about 3.5, or about 4.0 mM / L, including all ranges between any of these values. Symptoms of TBI include, but are not limited to headache, nausea and vomiting, dizziness orloss of balance, confusion or disorientation, seizures, weakness or numbness in limbs, blurred vision, ringing in the ears, or sensitivity to light or sound.

[0054] SAL-PC can be prepared by initially dissolving SAL in a polar solvent such as acetone under moderate heat (25-45°C). Once in solution, increasing amounts phosphatidylcholine (PC) are added to the solvent up to an amount where PC and SAL are present in equimolar concentration until fully in solution. Other suitable polar solvents include, but are not limited to: ethyl acetate: ethanol; methyl ethyl ketone) The polar solvent is then quantitatively removed by methods known in the art such as evaporation under inert gas (e.g., nitrogen) or other methods known in the art which prevent or minimize oxidation. Suitable alternative methods include rotary evaporation, lyophilization, spray drying, vacuum distillation, forced gas evaporation or related methods to facilitate the volatilization of the polar solvent. The resulting lipid film or powder (which can be generated by adding a bulking agent such as sucrose, mannitol, lactose, dextrose, etc.) which comprises the SAL or SA conjugate ( / .< ., SAL-PC complex) is stored under conditions which prevent or minimize oxidation. In various embodiments, the complex so produced has an average particle size in the range of about 50- 80 nm, including about 50 nm, about 55 nm, about 60 nm, about 65 nm, about 70 nm, about 75 nm, or about 80 nm, inclusive of all ranges between any of these values. See, for example, Figure 4.

[0055] Prior to administration, the SAL or SAL-PC is dispersed in a biologically suitable sterile delivery solution such as saline, 5% dextrose in deionized / distilled water, Lactated Ringers, phosphate buffered saline, etc. Full dispersion of the SAL or SAL-PC may be facilitated by sonication or the like followed by one of a number of methods to sterilize the aqueous lipidic suspension such as passing it through a 0.22 micron filter.

[0056] The toxicity and therapeutic efficacy of the active agent can be determined according to standard pharmaceutical procedures in cell cultures and / or experimental animals, including, for example, determining the LDso (the dose lethal to 50% of the population) and the EDso (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50 / ED50.

[0057] The components used to formulate the pharmaceutical compositions of the present disclosure are preferably of high purity and are substantially free of potentially harmful contaminants (e.g., at least National Food (NF) grade, generally at least analytical grade, and more typically at least pharmaceutical grade). Moreover, compositions intended for in vivo use are sterile. To the extent that salicylic acid or salsalate must be synthesized prior to use, the resulting intravenous product is typically substantially free of any potentially toxic agents,particularly any endotoxins, which may be present during the synthesis or purification process. Compositions for parental administration are also sterile, substantially isotonic and made under Good Manufacturing Practice (c-GMP) conditions.

[0058] In embodiments, individuals with mild, moderate or severe TBI are administered SAL or SAL-PC within 24 hours of the TBI using a rapid bolus intravenous delivery over a 5-10 second period. Dosing is done using a total of no less than about 250 mg and no more than about 2,000 mg (e.g., about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650. mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 110 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, or about 2000 mg, inclusive of all ranges between any of these values) followed by a continuous infusion of SAL or SAL-PC at a dose range no less than about 1.0 mg / hour and no more than about 200 mg / hour (e.g., about 1.0 mg / hour, about 2.0 mg / hour, about 3.0 mg / hour, about 4.0 mg / hour, about 5.0 mg / hour, about 6.0 mg / hour, about 7.0 mg / hour, about 8.0 mg / hour, about 9.0 mg / hour, about 10 mg / hour, about 20 mg / hour, about 30 mg / hour, about 40 mg / hour, about 50 mg / hour, about 60 mg / hour, about 70 mg / hour, about 80 mg / hour, about 90 mg / hour, about 100 mg / hour, about 110 mg / hour, about 120 mg / hour, about 130 mg / hour, about 140 mg / hour, about 150 mg / hour, about 160 mg / hour, about 170 mg / hour, about 180 mg / hour, about 190 mg / hour, or about 200 mg / hour, inclusive of all ranges between any of these values) in order to maintain a therapeutic plasma salicylate level of no less than about 0.1 millimole / liter and no greater than about 4 millimole / liter (e.g., about 0.1 millimole / liter, about 0.2 millimole / liter, about 0.3 millimole / liter, about 0.4 millimole / liter, about 0.5 millimole / liter, about 0.6 millimole / liter, about 0.7 millimole / liter, about 0.8 millimole / liter, about 0.9 millimole / liter, about 1.0 millimole / liter, about 1.1 millimole / liter, about 1.2 millimole / liter, about 1.3 millimole / liter, about 1.4 millimole / liter, about 1.5 millimole / liter, about 1.6 millimole / liter, about 1.7 millimole / liter, about 1.8 millimole / liter, about 1.9 millimole / liter, about 2.0 millimole / liter, about 2.1 millimole / liter, about 2.2 millimole / liter, about 2.3 millimole / liter, about 2.4 millimole / liter, about 2.5 millimole / liter, about 2.6 millimole / liter, about 2.7 millimole / liter, about 2.8 millimole / liter, about 2.9 millimole / liter, about 3.0 millimole / liter, about 3.1 millimole / liter, about 3.2 millimole / liter, about 3.3 millimole / liter, about 3.4 millimole / liter, about 3.5 millimole / liter, about 3.6 millimole / liter, about 3.7 millimole / liter, about 3.8 millimole / liter, about 3.9 millimole / liter, about 4.0 millimole / liter, inclusive of all ranges between any of these values). Doses, as expressed herein for SAL and SAL-PC are expressed as a doses which provide theindicated amount of SAL. That is, a dose of e.g., 250 mg of SAL-PC is a dose that would be equivalent to 250 mg of SAL.

[0059] While the above describes one example of treatment, the effective amount of SAL or SAL complexes (e.g., SAL-PC)to be given to a particular patient can depend on a variety of factors, several of which will be different from patient to patient. A competent clinician will be able to determine an effective amount of an active agent to administer to a patient to treat TBI. The data obtained from animal studies can be used in formulating a range of dosages for humans. The dosage of the active agent typically lines within a range of circulating concentrations that include the EDso with low toxicity. The dosage can vary within this range depending upon the dosage form employed and the route of administration utilized.

[0060] As noted above, TBI is associated with elevated levels of ac-tau in the plasma or brain of the patient with TBI. In various embodiments, administration of therapeutically effective amounts of SAL or SAL-PC as described herein provide reductions of ac-tau present in the blood or spinal fluid in the range of about 20% to about 90% after about 1 month of treatment, including about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90%, inclusive of all ranges between any of these values.

[0061] An individual skilled in the art of treating TBI or in reducing acetylated tau would not find it obvious nor recognize that the active moiety of salsalate, namely salicylic acid is the molecule responsible for reduction of acetylated tau in TBI mice models or potentially in humans with moderate to severe TBI. In neither Lagraoui or Shin’s papers do they discuss that the active moiety of salsalate, namely salicylic acid, is responsible for the beneficial effects of salsalate in TBI murine models.Use of SAL-PC to treat Metabolic Disorders Mediated by NFkB

[0062] In embodiments, SAL or SAL complexes e.g., SAL-PC) can be used for the treatment of metabolic dysfunction-associated steatohepatitis (MASH) which is inflammation of the liver caused by excess fat cells in it (steatotic liver disease). As SAL or SAL-PC are molecules with anti-inflammatory properties, the chronic inflammation that causes progressive liver damage are reduced with clinical to the patient.

[0063] In embodiments, the SAL or SAL complexes (e.g., SAL-PC) can be delivered via a nasal delivery system.

[0064] In embodiments, the SAL or SAL-PC compositions of the present disclosure can include other additives such as antioxidants. For example, the SAL or SAL-PC compositions of the present disclosure can include Beta carotene & retinol (Vit A).

[0065] The present applicant has discovered an unexpected finding related to the utility of salsalate phosphatidylcholine (SAL-PC) in treating various diseases and conditions as disclosed herein, based on / / / -vitro studies using human embryonic kidney (HEK 293) cells(see attached report). Upon treating activated HEK cells (using a phorbol ester) with various concentrations of SAL-PC versus salsalate without PC. an unexpected and surprising 40% better reduction on nuclear factor kappa b was demonstrated (see tables xxx and figures 1 and 2) with SAL-PC compared to salsalate without the PC added to the molecule of salsalate.

[0066] In view of the many reported diseases associated with elevated nuclear factor kappa b levels (see below) and in conjunction with the numerous adverse events (toxicities) associated with all the current treatments for such diseases associated with elevated nuclear factor kappa b levels, SAL or SAL complexes (e.g., SAL-PC) can be used to treat conditions associated with elevated nuclear factor kappa b levels, as SAL-PC offers improved safety with equal or improved therapeutic benefits compared to current treatments.

[0067] The following Tables 2 and 3 provide non-limiting examples of diseases in which activation of NF-kB has been implicated, and for which the compositions and methods of the present disclosure are suitable for treating or managing the symptoms of such diseases. For general reviews on the role of NF-kB in disease, see Aradhya & Nelson (2001), Kumar et al(2004), Yamamoto& Gaynor (2002) or Baldwin (2001). For specific diseases see the listed references, which can be found either on this application (under References) or at PubMed(through the linked references).Table 2: General DiseasesDisease Review / PaperAgeing Chung et al, 2002; Adler, 2007; Csizar, 2008Allergies Cousins et al, 2008Headaches Reuter et al, 2003Pain Tegeder et al, 2004; Niederberger & Geisslinger, 2008Complex Regional Pain Syndro Hettne et al, 2007Cardiac Hypertrophy Purcell & Molkentin, 2003; Freund et al, 2005; Sen &Roy, 2005Muscular Dystrophy (type 2A) Baghdiguian et al, 1999Muscle wasting Hasselgren, 2007Catabolic disorders Holmes-McNary, 2002Diabetes mellitus, Type 1 Ho & Bray, 1999; Eldor et al, 2006Diabetes mellitus, Type 2 Yuan 2001; Lehrke et al, 2004; Chen, 2005Obesity Gil et al, 2007Fetal Growth Retardation Mammon et al, 2005Hypercholesterolemia Wilson et al, 2000Atherosclerosis Ross et al, 2001 ; Li & Gao, 2005Heart Disease Valen et al, 2001Chronic Heart Failure Frantz, 2003; Gong et al, 2007Ischemia / reperfusionToledo-Pereyraet al, 2004; Nichols, 2004;Ridder & Schwaninger, 2008Stroke Herrmann et al, 2005Cerebral aneurysm Aoki et al, 2007; 2009 Angina Pectoris Ritchie, 1998 Pulmonary Disease Christman et al, 2000Cystic Fibrosis Pollard et al, 2005; Carrabino et al, 2006; Rottner et al, 2007Acid-induced Lung Injury Madjdpour et al, 2003 Pulmonary hypertension Sawada et al, 2007Chronic Obstructive Pulmonary Disease Barnes, 2002 ; Rahman & Kilty, 2006Hyaline Membrane Disease Cheah et al, 2005Kidney DiseaseGuijarro & Egido, 2001; Camici, 2006; Guzik & Harrison, 2007Glomerular Disease Zheng et al, 2005Alcoholic Liver Disease Zima & Kalousova, 2005Leptospirosis renal disease Yang et al, 2001 Gut Diseases Neurath et al, 1998Peritoneal endometriosis Gonzalez-Ramos et al, 2007Skin Diseases Bell et al, 2003Nasal sinusitis Xu et al, 2006Anhidrotic Ecodermal Dysplasia-ID Puel et al, 2005Behcet’s Disease Todaro et al, 2005Incontinentia pigmenti Courtois & Israel, 2000Tuberculosis Zea et al, 2006Asthma Pahl & Szelenyi, 2002ArthritisRoshak et al, 2002 ; Roman-Blas & Jimenez, 2006; Aud & Peng, 2006; Okamoto, 2006Crohn’s Disease Pena & Penate, 2002Colitis (rat) Chen et al, 2005Ocular Allergy Bielory et al, 2002Glaucoma Zhou et al, 2005Appendicitis Pennington et al, 2000Paget’s Disease Lin et al, 2007Pancreatitis Weber & Adler, 2001 ; Gray et al, 2006Periodonitis Nichols et al, 2001; Ambili et al, 2005Endometriosis Guo, 2006; Celik et al, 2008Inflammatory Bowel Disease Dijkstra et al, 2002; Atreya et al, 2008Inflammatory Lung Disease Park & Christman, 2006Sepsis Wratten et al, 2001; Abraham, 2003Silica-induced Chen & Shi, 2002Sleep apnoea Lavie, 2003AIDS (HIV-1) Hi scott et al., 2001Autoimmunity Hayashi & Faustman, 2000; Bacher & Schmitz, 2004Antiphospholipid Syndrome Lopez -Pedrera et al, 2005LupusKammer & Tsokos, 2002 ; Okamoto, 2006; Oikonomidou et al, 2007Lupus nephritis Zheng et al, 2006, 2008Chronic Disease Syndrome Maes et al, 2007Familial Mediterranean Fever Onen, 2005Hereditary Periodic Fever Syndrome Jeru et al, 2008Psychosocial stress diseases Bierhaus et al, 2004 Neuropathological DiseasesCechetto, 2001; Mattson &Camandola,2001; Pizzi & Spano, 2006Familial amyloidotic polyneuropathy, inflammoneuropathyMazzeo et al, 2004Traumatic brain injury Hang et al, 2005 Spinal cord injury Brambilla et al, 2005 Parkinson Disease Soos et al, 2004, Mogi et al, 2006Multiple Sclerosis Satoh et al, 2007Rheumatic Disease Okamoto, 2006; Greetham et al, 2007Alzheimer’s Disease Mattson & Camandola, 2001; Collister & Albensi, 2005Amyotrophic lateral sclerosis Xu et al, 2006Huntington’s Disease Khoshnan et al, 2004Retinal Disease Kitaoka et al, 2004Cataracts Yang et al, 2006Hearing loss Merchant et al, 2005; Lang et al, 2006Cancer Gilmore et al, 2002; Karin et al, 2002: Lee et al, 2007(see Table 2, below)Table 3: Constitutive activation of NF-kB in human cancer cellsCancer type ReferenceA: Primary tumors and tumor cell linesSolid tumors Pacifico & Leonardi, 2006Breast Nakshatri, 1997; Sovak, 1997; Ahmed, 2006Cervix Nair , 2003; Kumar et al, 2005; Shehata, 2005; Ramdass 2006Ovary Dejardin, 1999; Huang et al, 2000Vulva Seppanen & Vihko, 2000Prostate Huang, 2001; Palayoor,1999; Fradet et al, 2004; Lessard, 2006; Paule, 2007Kidney Oya et al, 2001, 2003Bladder Horiguchi et al, 2003; Kadhim et al, 2006; Levidou, 2008LungTichelaar, 2004; Tang, 2006; Zhang, 2007; Motadi, 2007; Stathopoulos, 2008Mesothelioma Bertino et al, 2007; Carbone & Bedrossian, 2006Non small-cell lung Zhang 2006; Tew , 2007; Jin , 2008LiverTai, 2000, Arsura & Cavin, 2005; Qiao et al, 2006; Seki & Brenner, 2007Pancreas Wang 1999; Sclabas , 2003; Xiong, 2004; Jackson & Evers, 2006;Zhang & Rigas,2006; Sarkar ,2006; Weichert et al, 2007; Sebens ,2008;Holcomb, 2008Esophageal / gastrSutter, 2004; Lee, 2005; Abdel-Latif , 2005, 2008; Jackson & Evers, 2006: Levidou, 2007Laryngeal Zhu et al, 2004; Pan et al, 2005Stomach Sasaki 2001; Wu 2007Colon Lind, 2001; Schottelius & Dinter, 2006; Aranha, 2007Thyroid Visconti, 1997; Pacifico, 2004; Gombos, 2007Parathyroid Corbetta et al, 2004Melanoma Yang & Richmond, 2001; Torabian & Kashani -S abet, 2005;Amiri & Richmond, 2005; Ueda & Richmond, 2006; Van den Oord, 2007Squamous cell carcinoma Loercher, 2004; Kobielak & Fuchs, 2006Head and neck Ondrey, 1999; Chung, 2006; Allen, 2007;Jackson-Bernitsas 2007Endometrial (Uterus) Pallares, 2004; Domenyuk, 2007Cylindromatosis Kovalenko, 2003; Brummelkamp, 2003; Trompouki, 2003Brooke-Spiegler, Trichoepithelioma Almeida, 2007Hilar Cholangiocarcinoma Chen, 2005Oral carcinomaNakayama, 2001; Bindhu , 2006; Mishra, 2006; Sawhney, 2007Min, 2007Astrocytoma / glioblastoma Hayahsi et al, 2001; Garkavtsev et al, 2004Neuroblastoma Bian , 2002; Brown, 2007; Widera, 2007Glioblastoma Raychaudhuri , 2007; Smith , 2007Hodgkin’s lymphoma Bargou, 1996, 1997; Staudt, 2000Acute lymphoblastic leukemia Kordes, 2000; Munzert, 2004Acute myelogenous leukemia Guzman, 2001; Fabre, 2007Acute T-cell leukemia (+ / -HTLV-1) Arima & Tei, 2001; Horie, 2006Acute Non-lymphocytic leukemia Lei & Zhao, 2007Chronic lymphocytic leukemiaFurman et al, 2000 ; Pickering, 2006; Herwamana,2008Burkitts Lymphoma (EBV) Knecht, 2001 Mantle cell lymphoma Martinez, 2003 Myelodysplastic syndrome Fabre, 2007 Multiple myeloma Berenson, 2001; Gilmore, 2007Diffuse large B-cell lymphoma Davis, 2001; Shaffer, 2002 MALT lymphoma Sagaert, 2007; Inagaki, 2007; Du, 2007Waldenstrom macroglobulinemia Leleu, 2008

[0068] As used in the description herein and throughout the claims that follow, “a”, “an”, and “the” include plural references unless the context clearly dictates otherwise. Also, as used in the description herein and throughout the claims that follow, the meaning of “in” includes “in” and “on” unless the context clearly dictates otherwise. While the above is a complete description of specific examples of the disclosure, additional examples are also possible. Thus, the above description should not be taken as limiting the scope of the disclosure which is defined by the appended claims along with their full scope of equivalents.

[0069] The foregoing disclosure encompasses multiple distinct examples with independent utility. While these examples have been disclosed in a particular form, the specific examples disclosed and illustrated above are not to be considered in a limiting sense as numerous variations are possible. The subject matter disclosed herein includes novel and non-obvious combinations and sub-combinations of the various elements, features, functions and / or properties disclosed above both explicitly and inherently. Where the disclosure or subsequently filed claims recite “a” element, “a first” element, or any such equivalent term, the disclosure or claims is to be understood to incorporate one or more such elements, neither requiring nor excluding two or more of such elements. As used herein regarding a list, “and” forms a group inclusive of all the listed elements. For example, an example described as including A, B, C, and D is an example that includes A, includes B, includes C, and also includes D. As used herein regarding a list, “or” forms a list of elements, any of which may be included. For example, an example described as including A, B, C, or D is an example that includes any of the elements A, B, C, and D. Unless otherwise stated, an example including a list of alternatively-inclusive elements does not preclude other examples that include various combinations of some or all of the alternatively-inclusive elements. An example described using a list of alternatively-inclusive elements includes at least one element of the listed elements. However, an example described using a list of alternatively-inclusive elements does not preclude another example that includes all of the listed elements. And, an example described using a list of alternatively-inclusive elements does not preclude another example that includes a combination of some of the listed elements. As used herein regarding a list, “and / or” forms a list of elements inclusive alone or in any combination. For example, an example described as including A, B, C, and / or D is an example that may include: A alone; A and B; A, B and C; A, B, C, and D; and so forth. The bounds of an “and / or” list are defined by the complete set of combinations and permutations for the list.

[0070] It should be understood, of course, that the foregoing relates to exemplary embodiments of the disclosure and that modifications can be made without departing from the spirit and scope of the disclosure as set forth in the following claims. All documents (e.g., journal citations, books, websites, etc. cited herein are incorporated by reference in their entirety for all purposes.ExamplesExample 1 : Efficacy of SAL-PC compared to PBSMethods

[0071] Controlled Cortical Impact (CCI): CCI was performed as previously described (Al Yacoub et al., 2024). Anesthetized rats (Wistar Han IGS adult male rats, 4% isoflurane with medical air induction; 2 - 2.5 % maintenance) underwent stereotaxic surgery under aseptic conditions with a midline incision, exposure of the skull using a skin-retractor and assignment of Bregma as a reference using the stereotaxic manipulator (Stoelting Co., Wood Dale, IL).

[0072] On day 0, rats received a 7-9 mm craniectomy using a hand-held drill over the left parietal cortex followed by a moderate controlled cortical impact with stereotaxic coordinates (1.8 mm posterior, 3.0 mm lateral to the left of the Bregma) using the Impact One device (Leica Biosystems, IL) and the following actuator settings: Impactor flat tip diameter (5 mm), velocity (6 m / sec) at 20 degree angle, dwell time (200 ms) and impact depth (3 mm). After impact, the bone flap was sealed in place with sterile bone wax and incision sutured followed by topical antibiotic ointment treatment. Righting reflex time (275 ± 102 sec) was recorded for each rat and defined as the time it took to come up on all 4 paws once anesthesia was discontinued. Body temperature (maintained between 36 C and 37.5 C) and breathing were monitored throughout the surgery. Experimental timeline is shown in Fig. 7. Beginning 60 min post-TBI, 8 received PBS vehicle and 11 received Sal-PC (50 mg / kg) daily via i.p. route for 5 successive days (days 0, 1, 2, 3, 4) as indicated by a light green box in Fig. 7 and in the shaded box inFigs. 8 A-C

[0073] Rotarod: Rotarod test was performed as previously described (Al Yacoub et al., 2024). Briefly, after habituation to the apparatus and training over 3 days, rats were given three 3- minute trials continuously increasing rotation speed from 4-30 rpm with 15-minute inter-trial intervals. Baseline was determined based on average time spent on the rotarod over 4 trials on the final training day. Three-minute test trials were performed on days 1, 3, 7, and 14 post-TBI. Values are presented as mean ± SEM.

[0074] Modified neurological severity score (mNSS): The mNSS (Chen et al., 2001) was used to validate the severity of injury as a measure of overall neurological function at baseline and on days 1, 3, 7 and 14 following surgery. The evaluation indices include a battery of motor (raising rat by the tail (0-3); walking on floor (0-3)), sensory (proprioceptive test (0-1); visual and tactile test (0-1)), Reflex : Pinna reflex (0-1); Corneal reflex (0-1); Startle reflex (0-1), resting movement (seizures, myoclonus, my ody stony (0-1)), and beam balance (0-6) tests, where normal function receives a value of 0. Neurological deficit was categorized based upon cumulative score: Severe = 13-18, moderate = 6-12, mild = 1-6 (Chen et al., 2001). Rats lacking neurological deficits score less than 1. Values are presented as mean ± SD.

[0075] Nociceptive sensitivity to thermal stimuli was assessed by measuring tail flick latency (TFL) from radiant heat using a tail flick test analgesia meter apparatus (IITC Life Sciences, Inc., Woodland Hills, CA). Thermal sensitivity was assessed prior to TBI (i.e., baseline) and on testing days (2, 4, and 8) post- TBI. Rats were acclimated to the testing room for at least 30 min. Latency to withdraw from an infrared light beam (25% active intensity) directed toward the tail (maximum 12 s to prevent tissue damage) was assessed in triplicate on each day. A decrease in TFL indicates increased pain sensitivity. Values are presented as mean ± SEM.

[0076] Barnes Maze test for cognitive spatial learning and memory is a 122 cm diameter circle of blue plexiglass with 20 holes equally spaced around the perimeter of the maze with roughly 1" from the edge of the hole to the edge of the maze. The platform is ~ 36" from the ground. One hole (“escape hole”) has an opening to a "goal" box mounted under the maze for escape from the open maze top. The other 19 holes end in a false bottom that isn't distinguishable to the rat, but they prevent the rat from falling through non-goal box holes onto the ground. For all testing days the escape of the rat from the center of the maze to the goal box is solely motivated by escape from the open maze with light (-600 lux) and sound (85dB, 2kHz). Video recording from above is used to assess activity during the trials and analyzed using ANY-maze software. Rats are habituated for 30-60 min to the testing room prior to testing each day. When the rat is on the maze top (regardless of day), a buzzer sounds until the rat enters the goal box.

[0077] Training / Acquisition occurs for 3 days with up to 4 trials per day with at least 15 minutes between trials. The rat begins in the middle of the maze under a small opaque container for 15 seconds. The container is removed, the buzzer is begun, and the rodent has 3 minutes to explore the maze and find the goal box. When the rat enters the goal box, the buzzer is discontinued, and the rat remains in the dark goal box for 1 minute before being returned to the holding cage. If the rat does not find the escape hole and goal box it is gently guided to the goal and allowed to stay in the goal box for one minute before being returned to the home cage.

[0078] Probe Trial: 24-48 hours after the last training day, learning was assessed in a single trial. The escape / goal box hole was closed, like the other 19 holes, for this trial. The rat was first placed under the opaque container in the center of the maze as before. Upon removal of the container, the buzzer was started and activity of the rat on the maze measured for 3 minutes. At the end of the 3 minutes, the buzzer was turned off, the rat removed from the maze top and placed back in the holding cage. A second probe trial 7 days later can be run to determine longterm memory and will be identical to the initial probe trial (but this has not been used in the current paradigm). Data are presented as mean ± SD for probe trial and SEM for training trials.

[0079] Novel Object Recognition (NOR) test was conducted as previously reported to evaluate non-spatial, hippocampal-mediated memory (Clark et al., 2000; Cohen et al., 2015). The apparatus consists of an open field (50 cm x 50 cm) with two imaginary circular zones located in two diagonally opposite quadrants. Two identical cylindrical objects were positioned in the centers of these two circular zones and the rat was allowed to freely explore for 5 minutes. Activity was recorded by video camera connected to ANY-maze software. Object exploration was identified and measured by the software only when the rat's head was within the circular zone (~1 cm radius) where the object was located. Rats were then removed to their holding cage and returned to their home cage for the day. Novel object recognition was tested the next day by substituting a novel object for one of the familiar training objects. Task performance was assessed by analyzing the differences in time spent exploring each object. Because rodents inherently prefer to explore novel objects, a preference for the novel object indicates intact memory for the familiar object. Data are presented as mean ± SD.

[0080] Statistical Analysis. All groups were assessed for normality using the Kolmogorov- Smirnov test, and as a result the nonparametric Mann-Whitney test was utilized for most comparisons between Sal-PC and PBS-treated groups at each time point; normally distributed data sets were analyzed by unpaired two-way student’ s t-test.Results

[0081] Generalized neurological scores were assessed four times following TBI using mNSS (Fig. 8A). Compared to the TBI / PBS group (red circles), Sal-PC-treated rats (blue triangles) had lower scores on days 3, 7 and 14 (*p<0.05), indicating improved neurological function, even after Sal-PC injections ended. Vestibulomotor function was assessed using the rotarod apparatus (Fig. 8B). In contrast to mNSS, TBI / Sal-PC rats appeared to fall off the rotarod earlier than TBI / PBS-treated rats the pre-TBI baseline levels being similar in both groups, but there was no significant difference between groups at any time point. Thermal sensitivity to heat was assessed using the tail flick latency test. TBI-induced only a slight increase in thermalsensitivity at day 8 in the TBI / PBS group, but TBI / Sal-PC rats did not exhibit this hyperalgesia (Fig. 8C). Note that no treatments were received after day 4 post-TBI.

[0082] Learning and memory often are impaired following TBI. The Barnes maze test was used to assess changes in spatial learning and memory. The Barnes maze is a circle with 20 holes, but only one hole is open as an escape. Rats are trained in 4 trails / day over three days (days 12-14 post-TBI) to see how quickly they learn where to find the escape hole. On the fourth day (probe day; day 15 post-TBI), the escape hole was closed and the time spent in the area around the escape hole is calculated; this is considered a spatial memory test. Both groups learned at a similar rate on the first day (Fig. 9A). Though it appears that Sal-PC rats learned more quickly on the second day, no differences between groups were noted (Fig. 9B). Both groups had learned to find the escape hole by the third day of training, so only 3 trials were assessed on that day (Fig. 9C). Though there were several rats in the Sal-PC group that spent more time in the escape hole area than any PBS-treated rats during the memory probe test on the fourth day of Barnes maze testing (Fig. 9D), there was no significant difference between the two groups (p=0.49).

[0083] The ability to remember an object instead of a location in space is assessed using a novel object recognition test. For that test, rats were exposed to two identical objects on the first day (day 16 post-TBI). On the second day of the test (day 17 post-TBI), one of the objects was removed and a novel object was substituted. Normally rats will spend more than 50% of the time exploring the novel object, but after TBI the preference for the novel object is lost (preference index = 0.5 as noted in Fig. 9E).

[0084] TBI produced neurological impairment as determined by the increased mNSS score in both groups 1 day post-TBI compared to baseline (Fig. 8A) and reduced TFL compared to baseline values in the TBI / PBS group (Fig. 8C). Unfortunately, we saw little decrease in time on the rod in the rotarod test (Fig. 8B), which was very different from what we noted previously (Al Yacoub et al., 2024).

[0085] Little differences between groups were found for the two different learning and memory tests, because these tests were performed 8-13 days past the last drug administration day.Example 2: Preparation of SAL-PC

[0086] Combinations of SAL with phospholipids such as phosphatidyl choline (PC) can be prepared by the following method. Approximately 10 g of salsalate is dissolved in 80 mL of acetone in a round bottomed flask at 40 °C. Once the salsalate is fully dissolved, 22-30 g of pure soy PC (SOYA PC100-C from Avanti / Croda Pharma) are added, and allowed to fullydissolve. The round bottomed flask is then affixed to a rotary evaporator, and the acetone is removed under vacuum to provide a lipidic film of the SAL-PC complex. An aqueous buffer such as phosphate buffered saline (PBS) is then added to the lipidic film of SAL-PC, for example to provide a SAL-PC concentration of 5-20 mg / mL. The SAL-PC is resuspended using sonication at 40 °C. The resulting suspended SAL-PC is in the form of suspended liposomes.

[0087] If desired, the liposomal form of SAL-PC can be converted to a self-emulsifying drug delivery system (SEDDS) by combining the liposomal form of SAL-PC with an appropriate mixture of phospholipids and neutral lipids. The skilled artisan will understand that the PC component, being amphoteric, acts as a surfactant.Example 3: Inhibition of human NF-kB

[0088] SAL and SAL-PC were evaluated for inhibition of human NFKB transcription factor. Reporter cells were treated with EC 80 concentration of the reference activator PMA and eight concentrations of each test compound, starting at 5mM and following a 2-fold dilution series. All treatment concentrations were performed in duplicate. Assay performance was validated using the reference antagonist Chromomycin A3. The Live Cell Multiplex (LCM) assay was performed to assess compound-induced cytotoxicity. Staurosporine was used as a positive control cytotoxicant.Assay Methods

[0089] Reporter Cells. As summarized in Table 4, Reporter Cells used in the assay express the native transcription factor. The reporter gene, firefly luciferase, is functionally linked to upstream transcription factor-specific genetic response elements (GRE).Table 4. Reporter Cells used in the NF-KP assays express the native transcription factor. The reporter gene, firefly luciferase, is functionally linked to an upstream transcription factorspecific genetic response element (GRE). The cell line background is indicated, as is the reference compound used to confirm the performance of the assays.

[0090] Compound Handling. The compounds were stored as directed by the manufacturer.

[0091] Setup of Assays. Receptor assays were performed as depicted in Figure 10. In brief, the steps carried out are as follow:

[0092] Step 1 : A suspension of Reporter Cells was prepared in Cell Recovery Medium (CRM), and 200 pL of the Reporter Cell suspension was dispensed into wells of a white 96-well assay plate. Assay plates were incubated at 37°C, 5% CO2 and -70% humidity for 18 hours.

[0093] Step 2 : After 18 hours incubation, the cell recovery medium was discarded, and 100 pL of Compound Screening Medium (CSM; containing 10% charcoal-stripped FBS) supplemented with 2x-EC80 concentration of the reference activator PMA, was added to each well.

[0094] Step 3: Immediately prior to assay setup, test compound master stocks were serially diluted in PBS. These intermediate stocks were subsequently diluted directly into Compound Screening Medium (containing 10% charcoal-stripped FBS) to generate ‘2x-concentration’ treatment media. 100 pL of each prepared treatment medium was dispensed into duplicate assay wells pre-dispensed with a 100 pL CSM supplemented with 2x-EC80 concentration of the reference activator PMA, thereby achieving the desired final treatment concentrations. PBS concentration across treatment groups were normalized to a final concentration of 10% in the assay wells. Assay plates were incubated at 37°C, 5% CO2 and -70% humidity for 6 hours.

[0095] Step 4: Following the incubation period, wells were rinsed once with LCM Buffer, then LCM substrate was added. Following incubation at room temperature for 15 min, LCM substrate was discarded and 100 pL / well of Luciferase Detection Reagent was added. Subsequently, fluorescence was measured to determine the relative number of live cells per assay well. RLU values were quantified after a 10-minute incubation period at room temperature to determine nuclear receptor activities.

[0096] Assay Validation

[0097] The reference antagonist Chromomycin A3 was utilized to confirm the performance of the specific lot of Reporter Cells treated with the Sponsor's test compounds. Reference Compound and Test Compound assays were performed at the same time and, hence, were exposed to the same assay reagents and environmental conditions. Reference and test compound groups always include their corresponding 'Vehicle' control to determine background activities in the assay and to calculate corresponding values of fold-inhibition and percent-inhibition of receptor activities.Data Reduction

[0098] Microsoft Excel was used to manage and archive assay data, as well as to calculate average RLU values + / - Standard Deviation (SD), Fold-inhibition, Percent-inhibition, Percent Coefficients of Variation (%CV), and Z' values.

[0099] Antagonist Assays:

[0100] ■ Fold-Inhibition: [Ave RLUVehicle / Ave RLUTest Cmpd]

[0101] ■ Percent-Inhibition: The theoretical minimum inhibition (0% inhibition) derives from Vehicle treatment only, no treatment cmpd. % Inhibition is calculated as:100*(l - [Ave RLUTest Cmpd / Ave RLUVehicle])

[0102] ■ Z' for Reference Antagonist:1 - [(3 * [SD RT 11 C&0 agonist | gQref antagonist]) / (RT jEC80 agonist > R jref antagonist )]

[0103] Live Cell Multiplex (LCM) Assays:

[0104] ■ Average Percent Live Cells Assays: 100*[Ave RFUTest CmPd / Ave RFUVehlcleGraphical Data Methods

[0105] Dose-response curve analyses of reference and test compounds were performed via nonlinear curve-fitting of % Inhibition vs. Logio [Cmpd],

[0106] All graphical manipulations were carried out using GraphPad Prism software.Results

[0107] The results of these assays are found in Figure 11, Table 5, and as discussed below.

[0108] Salsalate displayed compound-induced cytotoxicity at the highest test concentrations and borderline toxicity at the second highest test concentration. Inhibition > 50% was observed at two test concentration (1,250 and 2,500 pM). An IC50 value was obtained for this test compound.

[0109] Salsalate-PC displayed compound-induced cytotoxicity at the highest test concentration (5,000 pM). Inhibition activities > 50% were observed at three test concentrations (625, 1,250 and 2,500 pM). An IC50 value was obtained for this test compound.Table 5: Summary of Antagonist and Live Cell Multiplex Assay Results.

[0110] Antagonist data values of > 50% inhibition (i.e., > 2-fold inhibition; highlighted with light grey) are typically found to be statistically significant. The Live Cell Multiplex (LCM) assay was performed. Values <85% live cells (highlighted with dark grey) are strong indicators of emerging cytotoxicity in the treated assay wells. Calculated values of % Inhibition, IC50 and % Live Cells are recorded to either three significant figures or three decimal places, whichever comes first.DocumentsAdler A, Sinha, S., Kawahara, TLA., Zhang, JY., Segal, E., Chang, HY. (2007). Motif module map reveals enforcement of aging by continual NF-kB activity. Genes Dev, 21. Burtner CR, Kennedy BK. Progeria syndromes and ageing: what is the connection? Nat Rev Mol Cell Biol. 2010 Aug;l l(8):567-78. doi: 10.1038 / nrm2944. PMID: 20651707.Cai D, Frantz JD, Tawa NE Jr, Melendez PA, Oh BC, Lidov HG, Hasselgren PO, Frontera WR, Lee J, Glass DJ, Shoelson SE. 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Claims

CLAIMSWhat is claimed is:

1. A pharmaceutically acceptable composition comprising a suspension comprising SAL-PC, and a pharmaceutically acceptable buffer, wherein the pH of said composition is about 7.2 to about 7.5.

2. A method for treating the symptoms of a disease or condition in a patient with a pharmaceutical composition according to claim 1, wherein the disease or condition is selected from the group consisting of HGPS, ADPKD, and TBI.

3. The method of claim 2, wherein the disease or condition is HGPS, and wherein after daily administration of about 150 mg / kg to about 300 mg / kg of SAL-PC for one month, the plasma Progerin levels of the patient are reduced by at least about 10%.

4. The method of claim 2, wherein the disease or condition is ADPKD, and wherein after 1 year of treatment with about 150 mg / kg to about 300 mg / kg of SAL-PC, the annual decline of eGFR of the patient is no more than about 0.5 mL / min / 1.73 m25. The method of claim 2, wherein the disease or condition is TBI, and wherein after 1 month of treatment with about 150 mg / kg to about 300 mg / kg of SAL-PC, the plasma ac-tau levels of the patient decreases by about 20% to about 90%.

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