Treatment of pathological fatigue with oxaloacetate

Abstract

The present disclosure relates to therapeutic methods and compositions for treating pathological fatigue caused by physical injury or disease. Pathological fatigue refers to physical and mental fatigue caused by viral infection, bacterial infection, trauma, disease, or genetic changes, which results in fatigue that is not improved by bed rest and can be exacerbated by physical or mental activity. Such pathological fatigue occurs in myalgic encephalomyelitis (ME) / chronic fatigue syndrome (CFS) and other disorders such as post-COVID-19 fatigue, post-viral fatigue, fibromyalgia (FM), cancer, Parkinson's disease, other diseases and trauma, and combinations thereof. Related therapeutic methods and pharmaceutical compositions are also disclosed.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of U.S. Provisional Application No. 63 / 137,524, filed on January 14, 2021, the entire content of which is incorporated herein by reference.

[0002] The present disclosure relates to treatment methods and compositions for treating pathological fatigue caused by physical injury or disease. Pathological fatigue refers to physical and mental fatigue caused by viral infections, bacterial infections, trauma, diseases, or genetic changes, which results in fatigue that is not improved by bed rest and can be worsened by physical or mental activity. Such pathological fatigue occurs in myalgic encephalomyelitis (ME) / chronic fatigue syndrome (CFS) and other disorders, such as post - COVID - 19 fatigue, post - viral fatigue, fibromyalgia (FM), cancer, amyotrophic lateral sclerosis (ALS), Parkinson's disease, other diseases and traumas, and combinations thereof. Related treatment methods and pharmaceutical compositions are also disclosed.

Background Art

[0003] Physiological fatigue is well known to most people and is primarily caused by exercise, i.e., the inability to sustain exercise at the same intensity, resulting in decreased performance (Evans WJ, Lambert CP. Physiological basis of fatigue. Am J Phys Med Rehabil. 2007;86(1 Suppl):S29-46.). It can also be caused by sleep loss or prolonged wakefulness, disrupted circadian rhythms, or increased workload (Lock AM, Bonetti DL, Campbell ADK. The psychological and physiological health effects of fatigue. Occup Med (Lond). 2018;68(8):502-11). In contrast, pathological fatigue or pathological exhaustion is more significant than fatigue (Barnett R. Fatigue. Lancet. 2005;366(9479):21) and refers to physical and mental fatigue caused by viral infection, bacterial infection, trauma, disease, overeating, overtraining, or genetic changes, which results in physical and mental fatigue that does not improve with bed rest and can be aggravated by physical or mental activity.

[0004] Physiological fatigue, as summarized in Wan, et al. (2017) (Wan JJ, Qin Z, Wang PY, Sun Y, Liu X. Muscle fatigue: general understanding and treatment. Exp Mol Med. 2017;49(10):e384), is caused by neurological changes, changes in calcium levels, decreased blood flow and oxygen levels, decreased ATP energy levels and glycogen levels, and increased intracellular metabolites such as H+, lactate, Pi, and ROS. Most importantly, these physiological changes are reversed by rest.

[0005] In contrast, while pathological fatigue may involve some of the same physiological changes seen in physiological fatigue, there are many further metabolic changes that occur in pathological fatigue, including impaired energy production pathways, cellular redox reactions, inflammatory responses, mitochondrial dysfunction, and reduced AMPK activation (and associated glucose tissue uptake). Unlike physiological fatigue, the metabolic changes in pathological fatigue are not reversed by rest, and fatigue may persist for a long time after a virus has been overcome, a bacterial invasion has been thwarted, or damaged tissue has been repaired.

[0006] This specific example includes a disorder called myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS). ME / CFS can be triggered by many different injuries to the body, so the disorder is based on the ongoing symptoms rather than the cause of the disorder. This disorder is characterized by persistent fatigue and other specific symptoms that last for at least six months in adults (and three months in children or adolescents), and this fatigue is not relieved by bed rest. This disorder is also known as systemic exercise intolerance disorder (SEID), post-viral fatigue syndrome (PVFS), and chronic fatigue immunodeficiency syndrome (CFIDS).

[0007] ME / CFS patients experience persistent and debilitating fatigue, diffuse musculoskeletal pain, sleep disturbances, neuropsychiatric symptoms, and cognitive impairments such as cerebral fog that cannot be explained by their underlying medical condition. The symptoms of ME / CFS are not triggered by ongoing exercise and are not relieved by rest.

[0008] ME / CFS is a symptom-based or clinical diagnosis, without distinguishing between physical examination and routine laboratory findings. While infectious, immunological, neuroendocrine, sleep, and psychiatric mechanisms have been investigated, the unified etiology of ME / CFS remains unclear. The majority of ME / CFS cases have a sudden onset, usually accompanied by an "influenza-like illness," although a significant proportion of cases begin within months of severe adverse stress (Afari N et al (2003), Am J Psychiatr 160(2):221-36). Often, there is a course of remission and relapse of symptoms that makes disease management difficult. Individuals who feel well for a period may become overactive, potentially leading to a relapse and worsening of symptoms.

[0009] Viral infections have been linked as a cause of ME / CFS cases. 40% of people infected with the coronavirus SARS developed chronic fatigue post-infection, and 27% of these patients met the Centers for Disease Control and Prevention's criteria for ME / CFS. Eleven percent of people diagnosed with Ross River virus, Epstein-Barr virus, or Q fever virus were diagnosed with ME / CFS six months later. (Hickie I, Davenport T, Wakefield D, Vollmer-Conna U, Cameron B, Vernon SD, et al. Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study. BMJ. 2006;333(7568):575). There is a great concern that the current COVID-19 pandemic will lead many patients to ME / CFS (Perrin R, Riste L, Hann M, Walther A, Mukherjee A, Heald A. Into the looking glass: Post-viral syndrome post COVID-19. Med Hypotheses. 2020;144:110055.)(7), and indeed, in one study affecting 55% of the patient population, pathological fatigue is one of the most common symptoms of COVID-19 (Jacobs LG, Gourna Paleoudis E, Lesky-Di Bari D, Nyirenda T, Friedman T, Gupta A, et al. Persistence of symptoms and quality of life at 35 days after hospitalization for COVID-19 infection. PLoS One. 2020;15(12):e0243882.)(8)

[0010] Cancer and cancer treatment often cause persistent fatigue, even when patients are in remission from the disease. The prevalence of pathological fatigue ranges from 59% to nearly 100%, depending on the clinical state of the cancer. (Weis J. Cancer-related fatigue: prevalence, assessment and treatment strategies. Expert Rev Pharmacoecon Outcomes Res. 2011;11(4):441-6). Cancer-related fatigue can be more distressing and longer-lasting than the fatigue caused by the disease itself. The fatigue persists even when cancer is no longer present and the patient is not receiving chemotherapy.

[0011] ME / CFS often occurs in conjunction with other conditions such as fibromyalgia (FM), multiple chemosensitivity, irritable bowel syndrome, and temporomandibular joint disorders. In particular, the comorbidity with fibromyalgia has been studied (Afari N et al, cited above). Fibromyalgia is a non-arthritis rheumatic syndrome characterized by myalgia and multiple focal muscle tender points (trigger points) on palpation. Patients with FM often experience myalgia that worsens with inactivity or exposure to cold. This condition is often associated with common symptoms such as sleep disturbances, fatigue, rigidity, headaches, anxiety, perceived stress, and occasional depression.

[0012] Despite contrasting definitions, 20–70% of patients with fibromyalgia also meet the criteria for chronic fatigue syndrome, and conversely, 35–70% of patients with chronic fatigue syndrome-like disorders have synchronous fibromyalgia (Afari N et al, cited above).

[0013] ME / CFS is a common disorder. The estimated prevalence of ME / CFS ranges from 0.07% to 2.8% in the general adult population, and is lower in children and adolescents (Afari N et al, cited above). The prevalence of related fibromyalgia (FM) is 2–4%. This means that in the United States, at least 230,000 people have ME / CFS and 6.5 million have FM (see Zachrisson O (2002); Fatigue Syndrome-aspects on biology, treatment and symptom evaluation. ISBN 91-628-5386-4. University of Gothenburg).

[0014] Many patients with ME / CFS experience significant functional impairment. Almost all patients with ME / CFS notice a reduction in social connections, in addition to other undesirable consequences of the disease, with about one-third unable to work or study, and another one-third only able to work part-time (Afari N et al, cited above). Many patients with ME / CFS also experience depressive symptoms and are diagnosed with clinical depression, and similarly, patients with depression often experience symptoms of exhaustion.

[0015] Currently, patients with ME / CFS are treated with cognitive behavioral therapy (CBT) or graded exercise therapy (GET), which have shown moderate efficacy in several randomized controlled trials, but many patients do not recover (Rimes KA et al (2005), (10) Occupational Medicine 55(1):32-39; Chambers D et al (2006). Journal of the Royal Society of Medicine 99(10):506-20). Currently, medication plays a small role in disease management (Van Houdenhove B et al (2010) Expert opinion on pharmacotherapy 11(2):215-23).

[0016] Furthermore, many disorders, in addition to ME / CFS and FM, are characterized by symptoms of debilitating fatigue. Such disorders include post-COVID-19 fatigue, post-viral fatigue, post-bacterial fatigue, mental fatigue, post-stroke fatigue, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis, narcolepsy, post-cancer fatigue, fatigue associated with cancer with or without cell division arrest therapy, depression, and combinations thereof. None of these fatigues stem from excessive muscle activity, and rest does not provide relief for this type of fatigue.

[0017] Muscle fatigue is easily healed by rest, with nutrients being absorbed by the muscles and waste products such as lactate being removed by normal cellular processes. In fatigue caused by injury, whether resulting from viral or bacterial infection, trauma, disease, or other cellular attack, cellular metabolic changes are not necessarily reset after supplying energy for the body's defense / repair. The inability of metabolism to reset to a normal state leads to persistent mental and physical fatigue, which can last for years, even after the original injury to the body has healed.

[0018] Various metabolic mechanisms are activated by damage to the body, and these ongoing metabolic changes can lead to persistent fatigue if they are not reprogrammed to their original, normal metabolic state. One such metabolic change is an increase in glycolysis in the cytoplasm of cells. Using a very old metabolic feature, cells can increase glucose consumption and ferment glucose in the cytosol into lactate, increasing energy production beyond what is produced by mitochondria alone. Typically, in healthy cells that are not under stress, mitochondria burn glucose by oxidative phosphorylation rather than fermenting it in the cytosol. Burning glucose in mitochondria is far more efficient than fermentation in the cytosol and produces less toxic end products. However, stressed, unhealthy cells often turn to increased glycolysis / fermentation for extra energy when perceived as needed. This metabolic shift was first described in 1930 by Otto Warburg and named the "Warburg effect." Warburg described the metabolic energy shift associated with cancer cells, and indeed, almost all cancers exhibit this change in energy metabolism. However, Otto Warburg hypothesized that once cells change to this different energy production method, they cannot revert back to normal cells. This change in energy pathway can lead to pathological fatigue. (Warburg O. On the origin of cancer cells. Science. 1956;123(3191):309-14).

[0019] The Warburg effect is present not only in cancer cells but also in myeloid and lymphoid adaptive immune cells characterized by a transition to aerobic glycolysis. (Kornberg MD. The immunologic Warburg effect: Evidence and therapeutic opportunities in autoimmunity. Wiley Interdiscip Rev Syst Biol Med. 2020;12(5):e1486). The Warburg effect is present in the replication of viruses such as MERS-CoV and SARS-CoV-2. (Icard P,Lincet H,Wu Z,Coquerel A,Forgez P,Alifano M, et al. The key role of Warburg effect in SARS-CoV-2 replication and associated inflammatory response. Biochimie. 2020;180:169-77. Clinical work in ME / CFS patients demonstrates this shift to Warburg effect metabolism, generating the majority of the energy currency ATP from non-mitochondrial sources. (Lawson N,Hsieh CH,March D,Wang X. Elevated Energy Production in Chronic Fatigue Syndrome Patients. J Nat Sci. 2016;2(10)).

[0020] Another metabolic change observed in fatigued patients is a decrease in the ratio of nicotinamide adenine dinucleotide (NAD+) to its reduced state NADH in the cytoplasm of pyridine nucleotides, also known as cellular "redox" changes. Cellular NAD+ levels act as signaling molecules that drive specific metabolic states. A review of the importance of NAD+ levels for metabolism and skeletal muscle function is outlined in White et al. (2012). (White AT, Schenk S. NAD(+) / NADH and skeletal muscle mitochondrial adaptations to exercise. Am J Physiol Endocrinol Metab. 2012;303(3):E308-21). In humans, muscle use reduces NAD+ levels. As an example, Graham et al. (1978) found that muscle NAD+ levels decreased with exercise at 65% and 100% of maximal oxygen uptake (VO2max), with increased muscle water accounting for approximately 73% of this decrease, but NAD+ levels still decreased when assessed on a dry weight basis (Graham T, Sjogaard G, Lollgen H, Saltin B. NAD in muscle of man at rest and during exercise. Pflugers Arch. 1978;376(1):35-9). NADH levels also increased (Sahlin K, Katz A, Henriksson J. Redox state and lactate accumulation in human skeletal muscle during dynamic exercise. Biochem J. 1987;245(2):551-6), which further decreased the NAD+ / NADH ratio.Sweetman et al. (2020) calculated that NADH levels were higher in peripheral blood mononuclear cells of patients with ME / CFS (Sweetman E, Kleffmann T, Edgar C, de Lange M, Vallings R, Tate WA SWATH-MS analysis of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome peripheral blood mononuclear cell proteomes reveals mitochondrial dysfunction. J Transl Med. 2020;18(1):365).

[0021] Another metabolic change that occurs in response to cellular stress / damage is the translocation of the nuclear factor-κ light chain enhancer (NF-κB), a protein complex of activated B cells, from the cytoplasm to the nuclear compartment. This translocation enables interaction with chromatin and the production of inflammatory proteins for tissue defense / repair. While this response is important for keeping us healthy, in some individuals, such as COVID-19 patients with long-haul symptoms, the response is not blocked, and cellular energy is constantly tied to the immune response (Afrin LB, Weinstock LB, Molderings GJ. Covid-19 hyperinflammation and post-Covid-19 illness may be rooted in mast cell activation syndrome. Int J Infect Dis. 2020;100:327-32).This alteration of inflammatory pathways can lead to persistent fatigue and is observed in diseases with fatigue as a common determinant (Gupta SC, Kim JH, Kannappan R, Reuter S, Dougherty PM, Aggarwal BB. Role of nuclear factor kappaB-mediated inflammatory pathways in cancer-related symptoms and their regulation by nutritional agents. Exp Biol Med (Maywood). 2011;236(6):658-71; Bower JE, Ganz PA, Irwin MR, Arevalo JM, Cole SW. Fatigue and gene expression in human leukocytes: increased NF-kappaB and decreased glucocorticoid signaling in breast cancer survivors with persistent fatigue. Brain Behav Immun. 2011;25(1):147-50.; Morris G, Maes M. Increased nuclear factor-kappaB and loss of p53 are key mechanisms in Myalgic Encephalomyelitis / chronic fatigue syndrome(ME / CFS).Med Hypotheses.2012;79(5):607-13).

[0022] Mitochondria are organelles that produce the majority of energy during normal cellular function. Increased energy demands for fighting infection and tissue repair can increase the production of reactive oxygen species (ROS) within mitochondria, potentially damaging mitochondrial function. Mitochondrial dysfunction is associated with fatigued patients (Filler K, Lyon D, Bennett J, McCain N, Elswick R, Lukkahatai N, et al. Association of Mitochondrial Dysfunction and Fatigue: A Review of the Literature. BBA Clin. 2014;1:12-23).

[0023] Another metabolic change that occurs in response to cellular stress / injury is a decrease in AMPK protein activation and the resulting decrease in glucose uptake by tissues. This is directly observed in cells derived from ME / CFS patients (Brown AE, Jones DE, Walker M, Newton JL. Abnormalities of AMPK activation and glucose uptake in cultured skeletal muscle cells from individuals with chronic fatigue syndrome. PLoS One. 2015;10(4):e0122982). The reduction in available fuel for cells may be a direct cause of fatigue.

[0024] Treatment options for fatigue are extremely limited. No medications are approved for the treatment of fatigue. Modafinil, methylphenidate, amantadine, amphetamine, and dextroamphetamine have been used "off-label." Each of these drugs has serious side effects. For example, animal reproductive studies have shown adverse effects on the fetus for each of these drugs, and there are no adequate and well-controlled human studies on fatigue (world wide web at drugs.com / condition / fatigue.html January 5, 2020).

[0025] Caffeine has often been promoted for its ability to improve cognitive attention (Repantis D, Bovy L, Ohla K, Kuhn S, Dresler M. Cognitive enhancement effects of stimulants: a randomized controlled trial testing methylphenidate, modafinil, and caffeine. Psychopharmacology (Berl). 2020.; Herden L, Weissert R. The Effect of Coffee and Caffeine Consumption on Patients with Multiple Sclerosis-Related Fatigue. Nutrients. 2020; 12(8)), but its impact on muscle performance is minimal (Harty PS, Stratton MT, Escalante G, Rodriguez C, Dellinger JR, Williams AD, et al. Effects of Bang(R) Keto Coffee Energy Drink on Metabolism and Exercise Performance in Resistance-Trained Adults: A Randomized, double-blind, placebo-controlled, crossover study. J Int Soc Sports Nutr. 2020;17(1):45. A meta-review of caffeine studies reported improvements in endurance during bench press exercises, but also reported conflicting effects in the lower body (Ferreira TT, da Silva JVF, Bueno NB. Effects of caffeine supplementation on muscle endurance, maximum strength, and perceived exertion in adults submitted to strength training: a systematic review and meta-analyses. Crit Rev Food Sci Nutr. 2020:1-14).

[0026] Oxaloacetate, a human energy metabolite, has been shown to increase muscle endurance and reduce muscle fatigue in normal cells with fatigue stimulated by overuse of muscle due to an electric current applied to the muscle (Nogueira L. Acute Oxaloacetate Exposure Enhances Resistance to Fatigue in in vitro Mouse Soleus Muscle. FASEB Journal. 2011;25(1104.5)), but it has not been shown that oxaloacetate can be used to treat pathological fatigue caused by viral infection, bacterial infection, disease or trauma, because the fatigue from those conditions is different from the muscle fatigue seen from simple overuse of muscle.

[0027] Therefore, there is a great need for new therapies and treatments to relieve physical and mental pathological fatigue symptoms after tissue damage caused by viral infection, bacterial infection, trauma, cancer, and other diseases, and thus the provision thereof remains a matter of substantial interest in the art.

[0028] The use of oxaloacetate is disclosed in U.S. Patent No. 9,050,306, U.S. Patent No. 9,561,199, U.S. Patent No. 10,016,385, U.S. Patent No. 10,137,099 and U.S. Patent Application Publication No. 2019 / 0321315A1, all of which are incorporated herein by reference.

[0029] All references cited herein, including patent applications and publications, are incorporated by reference in their entirety. SUMMARY OF THE INVENTION

[0030] In some embodiments, the present invention provides a method for treating one or more symptoms of a disorder characterized by debilitating fatigue of a subject, comprising administering a therapeutic dose of an oxaloacetate compound to the subject, wherein the disorder is selected from the group consisting of post-COVID-19 fatigue, post-viral fatigue, myalgic encephalomyelitis / chronic fatigue syndrome, fibromyalgia, mental fatigue, post-stroke fatigue, amyotrophic lateral sclerosis, myasthenia gravis, Huntington's disease, debilitating fatigue associated with Parkinson's disease, debilitating fatigue associated with Alzheimer's disease, multiple sclerosis, narcolepsy, post-cancer fatigue, and cancer-related fatigue with or without cell division arrest therapy. In some embodiments, the oxaloacetate compound is anhydrous enol-oxaloacetate. In some embodiments, the oxaloacetate consists of the group consisting of enol-oxaloacetate, keto-oxaloacetate, hydrated oxaloacetate, or oxaloacetate salts. In some embodiments, the disorder is selected from the group consisting of fibromyalgia, mental fatigue, myalgic encephalomyelitis / chronic fatigue syndrome, fibromyalgia, Huntington's disease, post-COVID-19 fatigue, post-viral fatigue, amyotrophic lateral sclerosis, myasthenia gravis, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, multiple sclerosis, and post-cancer fatigue. In some embodiments, the oxaloacetate is administered in doses of about 100 to 6,000 mg. In some embodiments, the oxaloacetate is administered in doses of 200 to 3,000 mg. In some embodiments, the oxaloacetate is administered once, twice, or three times a day. In some embodiments, the oxaloacetate compound is present in the pharmaceutical composition.

[0031] In some embodiments, the present invention provides a method for treating one or more symptoms of a disorder characterized by debilitating fatigue in a subject, comprising administering a therapeutic dose of a compound to the subject to reverse a metabolic dysfunction, wherein the dysfunction is selected from the group consisting of increased glycolysis, chronic activation of NF-κB, decreased NAD+ / NADH ratio, mitochondrial dysfunction, decreased AMPK activation, and combinations thereof. In some embodiments, the compound is an oxaloacetate compound. In some embodiments, the oxaloacetate compound is selected from the group consisting of enol-oxaloacetate, keto-oxaloacetate, hydrated oxaloacetate, and oxaloacetate salts. In some embodiments, the oxaloacetate compound is anhydrous enol-oxaloacetate. In some embodiments, the disorder is selected from the group consisting of fibromyalgia, mental fatigue, myalgic encephalomyelitis / chronic fatigue syndrome, fibromyalgia, Huntington's disease, post-COVID-19 fatigue, post-viral fatigue, amyotrophic lateral sclerosis, myasthenia gravis, wasting fatigue associated with Parkinson's disease, wasting fatigue associated with Alzheimer's disease, multiple sclerosis, and post-cancer fatigue. In some embodiments, the oxaloacetate compound is administered in doses of about 100 to about 6,000 mg. In some embodiments, the oxaloacetate compound is administered in doses of about 200 mg to about 3,000 mg. In some embodiments, the oxaloacetate compound is administered once, twice, or three times daily. In some embodiments, the compound for reversing metabolic dysfunction is present in the pharmaceutical composition. [Brief explanation of the drawing]

[0032] [Figure 1] This figure shows the results of treating COVID-19 fatigue with oxaloacetate. Statistical analysis was performed using Student's t-test. [Figure 2] This figure shows the results of treating myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS) with oxaloacetate. Statistical analysis was performed using Student's t-test. [Modes for carrying out the invention]

[0033] The purpose of this disclosure is to provide novel and effective treatments for patients suffering from disorders characterized by persistent and debilitating pathological fatigue.

[0034] The purpose of this disclosure is to provide a pharmaceutical product for use in the treatment of the aforementioned patient.

[0035] Another object of this disclosure is to provide a method for treating a disorder characterized by depleting the pathological fatigue of a patient who requires it.

[0036] These and other objectives, which are obvious to those skilled in the art from this disclosure, are satisfied by different embodiments of the invention claimed in the appended claims and generally disclosed herein.

[0037] The inventors unexpectedly found that clinical outcomes in the treatment of disorders characterized by debilitating pathological fatigue are significantly improved by restoring multiple metabolic pathways to normal (pre-injury) function. Therefore, strategies, compounds, or combinations of compounds that modify metabolism in the following pathways also treat pathological fatigue. 1) Improvement of abnormal energy production, reduction of glycolysis, and reduction of lactate fermentation production in the cytoplasm of cells, through the reversal of the "Warburg effect." 2) An increase in NAD+ / NADH levels in the cell makes NAD+ more available, which in turn allows cytoplasmic lactate to be converted back into pirubate. NAD+ levels are the rate-limiting part of the reaction: Lactate and NAD+ are converted to pyruvate and NADH in the presence of the enzyme lactate dehydrogenase. 3) Decreased translocation of activated B-cell protein nuclear factor κ light chain enhancer (NF-κB) from the cytosol to the nucleus, thereby stopping or reducing the production of inflammatory responses and cytokine storms. 4) Increased mitochondrial biosynthesis can provide a greater capacity to process incoming glucose and replace damaged mitochondria as mitochondrial density increases. 5) Activation of 5'-adenosine monophosphate-activated protein kinase (AMPK), an enzyme involved in energy homeostasis, which activates glucose and fatty acid uptake and oxidation when cellular energy is low. Increased glucose uptake provides cells with additional fuel.

[0038] The treatment method may include one or more specific modifications to metabolism to alleviate pathological fatigue. Strategies, compounds, or combinations of compounds to achieve this treatment method include:

[0039] The energy metabolite "oxaloacetate" can be a single compound and can be used to modify metabolism in all of the metabolic modifications listed above. This metabolite can be in several forms: anhydrous enol-oxaloacetate, enol-oxaloacetate in solution, keto-oxaloacetate in solution, and hydrated oxaloacetate in solution, as well as combinations thereof. Oxaloacetate may also be part of a salt such as oxaloacetate sodium or oxaloacetate magnesium. Enol-oxaloacetate is also known as hydroxyfumarate. Other names for oxaloacetate include, according to the National Library of Medicine, National Center for Biotechnology Information "PubChem" Worldwide Web, reviewed on January 3, 2021 (pubchem.ncbi.nlm.nih.gov / compound / Oxalacetate#section=Depositor-Supplied-Synonyms), oxaloacetate, 2-oxosuccinate, ketosuccinate, oxosuccinate, 2-ketosuccinate, butanediic acid, oxo-, oxaloacetate, butanediic acid, 2-oxo-, 2-oxo-butanediic acid, oxaloethaneic acid, NSC77688, UNII-2F399MM81J, alpha-ketosuccinate, EINECS 206-329-8, MFCD00002592, OAA, CHEBI:30744;2F399MM81J, 2-ketosuccinate, ketosuccinate, oxaloaethanolate, α-ketosuccinate, 2-oxosuccinate, 4cts, alpha-ketosuccinate, α-ketosuccinate, 3-carboxy-3-oxopropanoic acid, oxaloacetate, oxaloacetate, oxobutanediate, 2-oxobutanediate, 2-oxobutanediate, oxaloacetate(2-), oxosuccinate, keto-oxaloacetate, 149-63-3, butanediic acid, oxo-, ion(2-), oxaoacetate dianion, oxobutanediic acid, ion(2-).

[0040] Oxaloacetate supplementation affects the following dysfunctional metabolic pathways that can be treated by the metabolic therapies identified above to improve pathological fatigue. Specifically, these dysfunctional metabolic pathways are outlined below: 1) Abnormal energy production due to increased glycolysis in the "Warburg effect." Cells derived from individuals with physical fatigue exhibit abnormal energy production, with energy being produced in the cytoplasm through increased glycolysis and fermentation. Oxaloacetate has been shown to reverse this trend, reducing both glycolysis and lactate formation. The inventors' efforts to reverse abnormal energy production have even been shown in cancer cells (Ijare O, Conway D, Cash A, Baskin D, Pichumani K. CBMT-49. OXALOACETATE ALTERS GLUCOSE METABOLISM IN GLIOBLASTOMA:13C ISOTOPOMER STUDY. Neuro-Oncology. 2019;21(Supplement_6):vi43-vi4), but the effect on fatigue is not clear, nor is it suggested by cell studies, nor does it represent any surprising novel findings. 2) Cells derived from patients with fatigue show significantly lower NAD+ / NADH levels. Oxaloacetate increases the NAD+ / NADH ratio. (Wilkins HM, Harris JL, Carl SM, EL, Lu J, Eva Selfridge J, et al. Oxaloacetate activates brain mitochondrial biogenesis, enhances the insulin pathway, reduces inflammation and stimulates neurogenesis. Hum Mol Genet. 2014;23(24):6528-41). The inventors' efforts to reverse the NAD+ / NADH ratio have been demonstrated in preclinical studies (Williams DS, Cash A, Hamadani L, Diemer T. Oxaloacetate supplementation increases lifespan in Caenorhabditis elegans through an AMPK / FOXO-dependent pathway. Aging Cell. 2009;8(6):765-8), but the effect on fatigue was not clear and was not suggested in preclinical studies. Other literature shows that oxaloacetate supplementation increases NAD+ and decreases NADH, but the effect on fatigue is not clear, not suggested in the literature, and does not represent any surprising novel findings. 3) Reduction of NF-κB inflammation. Human-derived cells with physical fatigue show increased NF-κB activation, which leads to a "cytokine storm." Oxaloacetate has been shown to reduce NF-κB activation by up to 70% in animal models (Wilkins HM, Harris JL, Carl SM, EL, Lu J, Eva Selfridge J, et al. Oxaloacetate activates brain mitochondrial biogenesis, enhances the insulin pathway, reduces inflammation and stimulates neurogenesis. Hum Mol Genet. 2014;23(24):6528-41). Although a reduction in the NF-κB pathway was found with oxaloacetate supplementation, its effect on fatigue was not clear and was not suggested in animal studies. 4) Mitochondrial damage is common in fatigued patients. Oxaloacetate activates a biomolecular pathway that leads to increased mitochondrial production and density. (Wilkins HM, Koppel S, Carl SM, Ramanujan S, Weidling I, Michaelis ML, et al. Oxaloacetate Enhances Neuronal Cell Bioenergetic Fluxes and Infrastructure. J Neurochem. 2016). This mitochondrial increase effect on fatigue was unexpected and not suggested by prior art. 5) Reduced AMPK activation. Cells derived from individuals with physical fatigue show impaired ability to activate AMPK and impaired stimulation of glucose uptake. Oxaloacetate has been shown to increase glucose uptake in clinical trials of patients with diabetes and Alzheimer's disease (Yoshikawa K. Studies on the anti-diabetic effect of sodium oxaloacetate. Tohoku J Exp Med. 1968;96(2):127-41.; Vidoni ED, Choi IY, Lee P, Reed G, Zhang N, Pleen J, et al. Safety and target engagement profile of two oxaloacetate doses in Alzheimer's patients. Alzheimers Dement. 2020), but its effect on fatigue has not been evident from clinical trials. Furthermore, the work performed on patients with diabetes is unlikely to be used to treat ME / CFS patients or other fatigue patients.

[0041] The "Warburg effect" refers to a modified form of cellular metabolism often seen in cancer cells, but also found in other cells, where there is a tendency to use a specific fermentation of piruvate to lactate in the cytoplasm rather than the aerobic respiratory pathway that burns piruvate in the mitochondria, which is used by most cells in the body under non-pathological conditions. Fermentation does not produce adenosine triphosphate (ATP) in high yield compared to the oxidative phosphorylation of the citric acid cycle and aerobic respiration, but it converts nutrients such as glucose and glutamine into biomass more efficiently by avoiding unwanted catabolic oxidation to carbon dioxide, preserving carbon-carbon bonds, and promoting assimilation. (Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324(5930):1029-33). This alternative energy pathway can be very beneficial to the body when recovering from a pathological event, but if not switched off at the end of the event (e.g., the end of an infection), it can affect fatigue levels. Studies have shown that patients with chronic fatigue syndrome activate this alternative energy pathway, increasing the amount of energy produced by glycolysis in the cytosol following the onset of the pathological event. (Lawson N, Hsieh CH, March D, Wang X. Elevated Energy Production in Chronic Fatigue Syndrome Patients. J Nat Sci. 2016;2(10); Morris G, Maes M. Oxidative and Nitrosative Stress and Immune-Inflammatory Pathways in Patients with Myalgic Encephalomyelitis (ME) / Chronic Fatigue Syndrome (CFS). Curr Neuropharmacol. 2014;12(2):168-85).

[0042] Nicotinamide adenine dinucleotide (NAD+) is a central cofactor in metabolism. NAD exists in two forms, oxidized and reduced, abbreviated as NAD+ and NADH, respectively. NAD participates in redox reactions, transporting electrons from one reaction to another. The NAD+ / NADH ratio in cells is a measure of the cell's redox state.

[0043] The nuclear factor-κ light chain enhancer (NF-κB) in activated B cells is a protein complex that is mostly located in the cytoplasm of the cell under non-stress conditions. When activated by a stress event (such as infection), NF-κB translocates to the nucleus, where it regulates DNA transcription and leads to cytokine production. NF-κB plays a crucial role in regulating the immune response to infection.

[0044] AMP protein-activated kinase (AMPK) is a sensor and regulator of cellular energy homeostasis, acting as a master switch that regulates glucose and lipid metabolism as well as AMPK activation, resulting in many beneficial effects. (Misra, et al, The role of AMP kinase in diabetes, Indian J Med Res 125:389-398 (2007)).

[0045] Accordingly, aspects of this disclosure provide oxaloacetate agents for treating pathological fatigue, wherein the oxaloacetate is selected from the group consisting of: Oxaloacetate anion (in salt) and / or Oxaloacetate and / or Enol-oxaloacetate and / or Keto-oxaloacetate and / or Hydrated oxaloacetate and / or Anhydrous enol-oxaloacetate, or other synonyms for oxaloacetate as detailed herein

[0046] According to one embodiment, the oxaloacetate preparation for use in a treatment as described herein is in the form of pure oxaloacetate.

[0047] According to one embodiment, the oxaloacetate preparation for use in a treatment as described herein is in the form of a pharmaceutically acceptable salt thereof.

[0048] The use and manufacture of oxaloacetate preparations are described in U.S. Patents No. 10,137,099, No. 10,016,385, No. 9,561,199, and No. 9,050,306.

[0049] As described above, oxaloacetate preparations may be pharmaceutically acceptable salts. As used herein, the term “pharmaceutically acceptable salt” means a salt of the compound of the present disclosure that is safe and effective for oral, subcutaneous, intramuscular, or intravenous administration in mammals and has the desired biological activity. Pharmaceutically acceptable salts include salts of basic groups present in the compounds of the present invention.

[0050] As stated above, this disclosure is based on the unexpected finding that supplementation with oxaloacetate compounds significantly improves clinical outcomes in the treatment of disorders characterized by pathological fatigue.

[0051] In one embodiment, the dose of oxaloacetate is approximately 100 to 6,000 mg per day, and the dose depends on both the severity of fatigue and the duration of the pathological fatigued state. In some embodiments, the dose of oxaloacetate is any of approximately 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 2000 mg, 3000 mg, 4000 mg, 5000 mg, or 6000 mg per day. In some embodiments, the dose of oxaloacetate is one of the following per day: approximately 100-200 mg, 200-300 mg, 300-400 mg, 400-500 mg, 500-600 mg, 600-700 mg, 700-800 mg, 800-900 mg, 900-1000 mg, 1000-2000 mg, 2000-3000 mg, 3000-4000 mg, 4000-5000 mg, or 5000-6000 mg.

[0052] In one embodiment, the dose of oxaloacetate is gradually increased from a lower starting dose of about 100 to about 400 mg per day to about 1,000 to about 6,000 mg per day. In another embodiment, the dose of oxaloacetate is gradually increased from a lower starting dose of about 100 mg, about 200 mg, about 300 mg or about 400 mg per day to about 1,000, about 2,000 mg, about 3,000 mg, about 4,000 mg, about 5,000 mg or about 6,000 mg per day. Some patients with altered fatigue-related metabolism may have sleep problems when initially taking a large dose of oxaloacetate, as the excess energy received from the oxaloacetate may dissipate, potentially causing restless sleep. These patients may be given a lower dose, e.g., 200 mg / day, gradually increasing until the sleep pattern stabilizes to the minimum number of hours, and then increasing to a higher level, again until the sleep pattern stabilizes to the minimum number of hours. This dose-increasing procedure can be repeated many times to increase the dose, which may be particularly important in ME / CFS patients who have been fatigued for several years.

[0053] In one embodiment, the oxaloacetate is administered at approximately 1,000 mg to approximately 3,000 mg per day, and then reduced to a “maintenance dose” of approximately 100 to approximately 300 mg per day. In another embodiment, the oxaloacetate is administered at approximately 1,000 mg, approximately 2,000 mg, or approximately 3,000 mg per day, and then reduced to a “maintenance dose” of approximately 100 mg, approximately 200 mg, or approximately 300 mg per day. Discontinuation of the highest dose, e.g., 1,000 mg / day of oxaloacetate, may be suggested when patient-derived fatigue questionnaires, such as the Chalmers Fatigue Questionnaire, Fatigue Severity Scale, or PROMISE Fatigue Short Form 7A, show a reduction in fatigue that correlates with normal levels of fatigue seen in a normal control group. Subsequently, fatigue can be continuously improved with a lower dose maintenance level, e.g., 200 mg of oxaloacetate per day. Maintenance doses may be particularly important to prevent the recurrence of pathological fatigue observed in some patients.

[0054] To achieve high patient compliance, i.e., the degree to which patients accurately follow medical advice, it is generally considered that treatment regimens should not be complex so that patients can easily follow them. For example, it may be preferable for drug administration to be once, twice, or three times a day, for example, once or twice a day. Accordingly, in one embodiment, an oxaloacetate for use as described herein is provided, said oxaloacetate is administered once, twice, or three times a day, for example, once or twice a day. For clarity, the dose of oxaloacetate may be, for example, 500 mg orally twice a day to obtain a daily dose of 1,000 mg. It will be understood that said oxaloacetate may be administered at different numbers of times a day.

[0055] As disclosed in the Examples section of this disclosure, oxaloacetate agents may be useful in treating disorders characterized by debilitating fatigue, which often include symptoms such as persistent and / or recurrent debilitating fatigue, diffuse musculoskeletal pain, sleep disturbances, and subjective cognitive impairment. Non-limiting examples of such disorders include myalgic encephalomyelitis (ME), also known as chronic fatigue syndrome (CFS), which refers to a group of debilitating medical conditions in adults characterized by persistent and debilitating fatigue, diffuse musculoskeletal pain, sleep disturbances, neuropsychiatric symptoms, and cognitive impairment lasting at least six months. ME / CFS often occurs in conjunction with other conditions such as fibromyalgia (FM), polychemosensory malformations, irritable bowel syndrome, and temporomandibular joint disorders. Furthermore, several other disorders also feature debilitating fatigue. A non-exclusive list of such disorders includes FM, mental fatigue, post-stroke fatigue, Huntington's disease, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis, myasthenia gravis, narcolepsy, cancer, post-cancer fatigue, ADHD, depression, post-viral fatigue, viral fatigue, post-bacterial fatigue, bacterial infection fatigue, and combinations thereof. Furthermore, fatigue may be associated with cancer with or without cell division arrest therapy. Physical trauma can also cause fatigue that can be improved with oxaloacetate. Those skilled in the art will understand that disorders characterized by physical fatigue may be fatigue disorders or pain disorders.

[0056] Accordingly, in one embodiment, an oxaloacetate agent described herein is provided for use in the treatment of a disorder characterized by persistent and debilitating fatigue, the disorder being selected from the group consisting of myalgic encephalomyelitis / chronic fatigue syndrome, fibromyalgia, mental fatigue, post-stroke fatigue, Huntington's disease, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, myasthenia gravis, narcolepsy, cancer, post-cancer fatigue, ADHD, post-viral fatigue depression, viral fatigue, post-bacterial fatigue, post-bacterial fatigue and fatigue associated with cancer with or without cell division arrest therapy, depression and fatigue associated with combinations thereof.

[0057] In one embodiment, the fatigue disorder is characterized by at least one condition selected from fibromyalgia, mental fatigue, myalgic encephalomyelitis / chronic fatigue syndrome, and depression. In another embodiment, the disorder is a pain disorder characterized by at least one condition selected from fibromyalgia, mental fatigue, myalgic encephalomyelitis / chronic fatigue syndrome, and depression. In one embodiment, the disorder is ME / CFS. In one embodiment, the disorder is mental fatigue. In one embodiment, the disorder is depression, and in another embodiment, the disorder is fibromyalgia. In one embodiment, the disorder is a combination of two or more of the above-mentioned disorders, for example, a combination of myalgic encephalomyelitis / chronic fatigue syndrome and fibromyalgia, a combination of myalgic encephalomyelitis / chronic fatigue syndrome and mental fatigue, a combination of myalgic encephalomyelitis / chronic fatigue syndrome and depression, a combination of mental fatigue and depression, a combination of fibromyalgia and depression, and a combination of mental fatigue and fibromyalgia. In one embodiment, the combination is selected from the following: a combination of myalgic encephalomyelitis / chronic fatigue syndrome, mental fatigue, and fibromyalgia; a combination of myalgic encephalomyelitis / chronic fatigue syndrome, mental fatigue, and depression; a combination of myalgic encephalomyelitis / chronic fatigue syndrome, depression, and fibromyalgia; and a combination of depression, mental fatigue, and fibromyalgia.

[0058] Those skilled in the art will understand that the embodiments described above in relation to the first aspect of this disclosure are equally relevant to and applicable to the various aspects disclosed herein.

[0059] In another aspect of the present disclosure, a pharmaceutical compound agent is provided for normalizing metabolism after injury or disease, wherein the dysfunction is selected from the group consisting of increased glycolysis, chronic activation of NF-κB, decreased NAD+ / NADH ratio, mitochondrial dysfunction, and decreased AMPK activation.

[0060] In one embodiment, the pharmaceutical composition further comprises at least one pharmaceutically acceptable additive or carrier. Non-limiting examples of additives include diluents, disintegrants, binders, lubricants, flow enhancers, and agents that modify the release of active agents, such as polymers. Those skilled in the art will know suitable additives and carriers.

[0061] In another embodiment, the pharmaceutical composition further comprises at least one additional activator. In one embodiment, the additional agent is a stimulant, such as a caffeine-based stimulant, or an anti-fatigue agent such as a central nervous system stimulant, such as methylphenidate and various amphetamine derivatives.

[0062] In one embodiment, a pharmaceutical composition according to this specification is provided, comprising an amount of oxaloacetate ranging from about 100 mg to about 6,000 mg, for example, about 200 to about 3,000 mg, for example, about 500 mg to about 1,000 mg. In some embodiments, a pharmaceutical composition according to this specification is provided, comprising any amount of oxaloacetate ranging from about 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1,000 mg, 2,000 mg, 3,000 mg, 4,000 mg, 5,000 mg, or 6,000 mg. In some embodiments, the pharmaceutical composition contains any of the following: approximately 100 mg to 200 mg, 200 mg to 300 mg, 300 mg to 400 mg, 400 mg and 500 mg, 500 mg to 600 mg, 600 mg to 700 mg, 700 mg to 800 mg, 800 mg to 900 mg, 900 mg to 1000 mg, 1000 mg to 2000 mg, 2000 mg to 3000 mg, 3000 mg to 4000 mg, 4000 mg to 5000 mg, or 5000 mg to 6000 mg.

[0063] In one embodiment, the pharmaceutical composition is formulated for oral, subcutaneous, intramuscular, buccal, sublingual, suppository, transdermal, or intravenous administration. As described above, it will be understood that non-invasive administration may generally be preferred. In one embodiment, the pharmaceutical composition is formulated for oral administration.

[0064] In one embodiment in which the pharmaceutical is formulated for oral administration, the pharmaceutical composition contains about 100 mg to 6,000 mg, for example, 200 to 3,000 mg, for example, about 500 mg to 1,000 mg of oxaloacetate. In some embodiments, the pharmaceutical composition formulated for oral administration contains any of about 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1,000 mg, 2,000 mg, 3,000 mg, 4,000 mg, 5,000 mg, or 6,000 mg of oxaloacetate. In some embodiments, the pharmaceutical composition formulated for oral administration contains one of the following amounts of oxaloacetate: approximately 100 mg to 200 mg, 200 mg to 300 mg, 300 mg to 400 mg, 400 mg to 500 mg, 500 mg to 600 mg, 600 mg to 700 mg, 700 mg to 800 mg, 800 mg to 900 mg, 900 mg to 1000 mg, 1000 mg to 2000 mg, 2000 mg to 3000 mg, 3000 mg to 4000 mg, 4000 mg to 5000 mg, or 5000 mg to 6000 mg.

[0065] When the pharmaceutical formulation is prepared for subcutaneous or intramuscular administration, it may be preferable that the administered dose be approximately half the oral dose. Therefore, in one embodiment in which the pharmaceutical formulation is prepared for subcutaneous or intramuscular administration, the pharmaceutical composition contains approximately 50 mg to 3,000 mg, for example, 100 to 1,500 mg, for example, 250 mg to 500 mg of oxaloacetate. In some embodiments, the pharmaceutical composition prepared for subcutaneous or intramuscular administration contains any of approximately 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1,000 mg, 2,000 mg, or 3,000 mg of oxaloacetate. In some embodiments, the pharmaceutical composition formulated for subcutaneous or intramuscular administration contains one of the following amounts of oxaloacetate: approximately 50 mg to 100 mg, 100 mg to 150 mg, 150 mg to 200 mg, 200 mg to 250 mg, 250 mg to 300 mg, 350 mg to 400 mg, 400 mg to 450 mg, 450 mg to 500 mg, 500 mg to 600 mg, 600 mg to 700 mg, 700 mg to 800 mg, 800 mg to 900 mg, 900 mg to 1000 mg, 1000 mg to 2000 mg, or 2000 mg to 3000 mg.

[0066] In another embodiment where the pharmaceutical composition is formulated for intravenous administration, the pharmaceutical composition comprises about 100 to 500 mg of oxaloacetate. In some embodiments, the pharmaceutical composition formulated for intravenous administration comprises about 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, or 500 mg of oxaloacetate. In some embodiments, the pharmaceutical composition formulated for oral administration comprises about 100 mg to 150 mg, 150 mg to 200 mg, 200 mg to 250 mg, 250 mg to 300 mg, 300 mg to 400 mg, 400 mg to 450 mg, or 450 mg to 500 mg of oxaloacetate.

[0067] In one embodiment, a pharmaceutical composition is provided that is formulated as a pill, tablet, capsule, sugar-coated tablet, liquid, gel capsule, syrup, slurry, or suspension, for example, as a pill.

[0068] In one embodiment, a pharmaceutical composition is provided that is formulated for administration once, twice, or three times a day, for example, once or twice a day.

[0069] Further aspects of this disclosure provide the use of oxaloacetate agents as defined herein for manufacturing pharmaceuticals for treating disorders characterized by persistent and debilitating fatigue, such as the disorders disclosed herein.

[0070] Pharmaceutical composition Pharmaceutical preparations and methods of administration Oxaloacetate can be administered to individuals in therapeutically effective doses to prevent or treat fatigue disorders, including ME / CFS, FM, mental fatigue, post-stroke fatigue, Huntington's disease, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis, myasthenia gravis, narcolepsy, cancer, post-cancer fatigue, ADHD, depression, post-viral fatigue, viral fatigue, post-bacterial fatigue, bacterial fatigue, and combinations thereof.

[0071] As used herein, “oxaloacetate or OAA” includes oxaloacetic acid, salts of the acid, or oxaloacetate in buffered solution, anhydrous enol-oxaloacetate, enol-oxaloacetate in solution, keto-oxaloacetate in solution, hydrated oxaloacetate in solution, and mixtures thereof. It also includes synonyms for oxaloacetate as shown herein.

[0072] Effective dose The therapeutically effective dose refers to the amount of oxaloacetate sufficient to produce the desired effect, such as improvement of fatigue-related symptoms.

[0073] The toxicity and therapeutic efficacy of oxaloacetate are, for example, LD 50(A lethal dose in 50% of the population) and ED 50 The dose effective in 50% of the population can be determined by standard pharmaceutical procedures in cell cultures or experimental animals. The dose ratio between the toxic effect and the therapeutic effect is the therapeutic index, or ratio LD50. 50 / ED 50 It can be expressed as the LD of oxaloacetate. 50 The dose exceeds 5 g / kg body weight. In a 90-day subchronic rat study, the "no observable adverse effect level" (NOAEL) was 500 mg / kg (the highest dose in the study). Oxaloacetate has very low toxicity, as expected from a chemical involved in the citric acid cycle of any cell.

[0074] A 1968 toxicity study of oxaloacetate in rats conducted in Japan showed that a level of oxaloacetate of 83 mg / kg body weight induced changes in the pancreatic islets. Some islets were reduced in size and congested, with alpha cells being atrophic, while beta cells were hypertrophic and darkly stained. At a lower dose of 41 mg / kg body weight, a percentage of the pancreas demonstrated only proliferation and hyperplasia of the pancreatic islet cells. The liver, pituitary gland, adrenal gland, and gonads showed no particular changes (Yoshikawa, Anti-diabetic effect of sodium oxaloacetate, 1968 Tohoku Journal of Experimental Medicine).

[0075] A one-year dose of anhydrous enol-oxaloacetate up to 6,000 mg / day in patients did not result in negative side effects.

[0076] An example of an effective dose of oxaloacetate administered by intravenous injection is approximately 0.5 mg to 1 g of oxaloacetate per kg of body weight. In preferred embodiments, the effective dose of oxaloacetate is approximately 2.0 mg to 40 mg per kg of body weight. In some embodiments, the effective dose of the oxaloacetate compound is one of approximately 2 mg / kg to 5 mg / kg, 5 mg / kg to 10 mg / kg, 10 mg / kg to 15 mg / kg, 15 mg / kg to 20 mg / kg, 20 mg / kg to 25 mg / kg, 25 mg / kg to 30 mg / kg, 30 mg / kg to 35 mg / kg, or 35 mg / kg to 40 mg / kg of body weight. Due to the acidity of the compound, the effective dose may be administered in multiple injections over several hours or consecutively. Effective oral administration ranges from approximately 0.5 mg to 1 g of oxaloacetate per kg of body weight, with a preferred effective dose range of approximately 2 mg to 40 mg of oxaloacetate per kg of body weight. For example, an adult male weighing approximately 80 kg would receive approximately 150 mg to 3.5 g of oxaloacetate orally per day. Topical formulations containing oxaloacetate at concentrations of approximately 0.5 to 16 mM are effective for skin application. Calorie restriction (CR) studies have shown that restricting calories every other day yields the same beneficial results as daily CR. Similarly, in some embodiments, oxaloacetate is administered every other day because the anti-fatigue effect lasts for at least two days once metabolism is renormalized. In other embodiments, oxaloacetate is administered three times a day after each meal.

[0077] formulation Pharmaceutical compositions for use in accordance with the present invention can be formulated in the conventional manner using one or more physiologically acceptable carriers or additives. Accordingly, oxaloacetate and its physiologically acceptable salts and solvates can be formulated for administration by inhalation or inhalation (through either the mouth or nose) or by oral, buccal, topical, transdermal, parenteral, or rectal administration.

[0078] Oxaloacetate is acidic. Its acidity is unlikely to affect organisms ingesting beneficial amounts of the compound, given that the internal conditions of the stomach are also highly acidic. However, its acidity may affect other tissues, including the skin or lungs, which could benefit from direct application of oxaloacetate. Therefore, in another embodiment, a composition of the substance can be prepared by mixing oxaloacetate with a buffer solution or a base, or it can be used as a salt of oxaloacetate, so that the delivered compound is not caustic. This allows for the safe delivery of higher concentrations of oxaloacetate to organisms, particularly when oxaloacetate is not delivered by oral ingestion.

[0079] For oral administration, the pharmaceutical composition may take the form of tablets or capsules prepared by conventional means using pharmaceutically acceptable additives such as binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone, or hydroxypropyl methylcellulose), fillers (e.g., lactose, microcrystalline cellulose, or calcium hydrogen phosphate), lubricants (e.g., magnesium stearate, talc, or silica), disintegrants (e.g., potato starch or sodium starch glycolate), or wetting agents (e.g., sodium lauryl sulfate). Tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, a non-aqueous solution, a syrup, or a suspension, or may be provided as a dry product to be mixed with water or another suitable vehicle immediately before use (due to concerns about decarboxylation). Water acts as a catalyst, enabling the conversion of solid enol-oxaloacetate to liquid keto-oxaloacetate, from which it spontaneously decarboxylates to pirubate and carbon dioxide. Such non-aqueous liquid preparations may be prepared by conventional means using pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives, or hydrogenated edible fats), emulsifiers (e.g., lecithin or acacia), non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol, or fractionated vegetable oils), and preservatives (e.g., methyl or propyl-p-hydroxybenzoate or sorbic acid). The preparations may also optionally contain buffer salts, flavoring agents, coloring agents, and sweeteners.

[0080] While absorption of oxaloacetate from the gastrointestinal tract increases the overall oxaloacetate level in the organism, immediate contact of oxaloacetate with gastrointestinal cells preferentially allows for a reduction in gastric diseases such as colon cancer, even if the amount of oxaloacetate ingested is insufficient to provide overall benefits to the organism.

[0081] Preparations for oral administration can be appropriately formulated to provide controlled release of the active compound. For buccal administration, the composition may take the form of tablets or lozenges formulated in a conventional manner. For inhalation administration, the compound for use according to the present invention is conveniently delivered in the form of an aerosol spray from a pressurized pack or nebulizer using a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of pressurized aerosols, the dose unit may be determined by providing a valve for delivering a measured amount. Capsules and cartridges, for example, gelatin capsules and cartridges for use in inhalers or injectors may be formulated containing a powder mixture of the compound and a suitable powder base such as lactose or starch.

[0082] The topical pharmaceutical and cosmetic compositions of the present invention can be in a wide variety of product types. These include, but are not limited to, lotions, creams, beach oils, gels, sticks, sprays, ointments, pastes, mousses, and cosmetics. These product types may include, but are not limited to, several types of pharmaceutical or cosmetic carrier systems, including solutions, emulsions, gels, and solids. The topical pharmaceutical and cosmetic compositions of the present invention, formulated as solutions, typically contain a pharmaceutically acceptable organic solvent. The term "pharmaceutically acceptable organic solvent" refers to a solvent in which oxaloacetate can be dissolved and which has acceptable safety properties (e.g., irritation and sensitization properties). Examples of suitable pharmaceutically acceptable organic solvents include, for example, monohydric alcohols such as ethanol and polyhydric alcohols such as glycols. When the topical pharmaceutical and cosmetic compositions of this disclosure are formulated as aerosols and applied to the skin as a spray, a propellant is added to the solution composition.

[0083] The types of products that can be formulated from solution carrier systems are creams or ointments. Ointments may contain a simple base of animal oil, vegetable oil, or semi-solid hydrocarbon (oily). Ointments may contain about 0.1% to about 2% of a thickener. Examples of suitable thickeners include cellulose derivatives (e.g., methylcellulose and hydroxypropylmethylcellulose), synthetic high molecular weight polymers (e.g., carboxyvinyl polymers and polyvinyl alcohol), plant hydrophilic colloids (e.g., karaya gum and tragacanth gum), clay thickeners (e.g., colloidal magnesium aluminum silicate and bentonite), and carboxyvinyl polymers (CARBOPOLS.RTM, sold by BFGoodrich Company, such polymers are described in detail in Brown, U.S. Patent No. 2,798,053, issued July 2, 1975). A more complete disclosure of thickeners useful herein can be found in Sagarin, Cosmetics, Science and Technology, 2nd Edition, Vol. 1, pp. 72-73 (1972). When the carrier is formulated as an emulsion, about 1% to about 10%, e.g., about 2% to about 5%, of the carrier system contains an emulsifier. Suitable emulsifiers include nonionic, anionic, or cationic emulsifiers. Exemplary emulsifiers are disclosed, for example, in McCutcheon's Detergents and Emulsifiers, North American Edition, pages 317-324 (1986). Preferred emulsifiers are anionic or nonionic, but other types may also be used.

[0084] An emulsion carrier system useful for the topical pharmaceutical and cosmetic compositions of this disclosure is a microemulsion carrier system. Such a system preferably comprises about 9% to about 15% squalane, about 25% to about 40% silicone oil, about 8% to about 20% fatty alcohol, about 15% to about 30% polyoxyethylene sorbitan monofatty acid (commercially available under the trade name Tween) or other nonionic substance, and about 7% to about 20% water. This carrier system is combined with the therapeutic agent described above, and the oxaloacetate is supported in the non-aqueous portion.

[0085] The topical pharmaceutical and cosmetic compositions of this disclosure may also contain safe and effective amounts of penetration enhancers. Other conventional skincare product additives may also be included in the compositions of the present invention. For example, collagen, elastin, hydrolysates, primrose oil, jojoba oil, epidermal growth factor, soy saponins, mucopolysaccharides, and mixtures thereof may be used. Various vitamins may also be included in the compositions of the present invention. For example, vitamin A and its derivatives, vitamin B2, biotin, pantothene, vitamin D, and mixtures thereof may be used.

[0086] In further embodiments of the present invention, locally delivered oxaloacetate can be mixed with a penetration enhancer, such as dimethyl sulfoxide (DMSO), a combination of sucrose fatty acid esters and sulfoxides or phosphate oxides, or eugenol, thereby enabling faster movement of oxaloacetate into skin tissue and then further into deeper cell tissue.

[0087] In one embodiment, the disclosed compound is administered via a local delivery system. Implantable or injectable polymer matrices and transdermal formulations in which the active ingredient is slowly released are also known and can be used in the disclosed manner. The controlled-release components described above can be used as a means of delivering the disclosed compound. The composition may further include components adapted to improve the stability or efficacy of the applied formulation, such as preservatives, antioxidants, skin penetration enhancers, and sustained-release materials. Examples of such components are described in the following references incorporated herein by reference: Martindale--The Extra Pharmacopoeia (Pharmaceutical Press, London 1993) and Martin (ed.), Remington's Pharmaceutical Sciences.

[0088] Controlled release preparations can be achieved using polymers that complex or absorb oxaloacetate. Controlled delivery can be carried out by selecting appropriate polymers such as polyesters, polyamino acids, polyvinylpyrrolidone, ethylene vinyl acetate, methylcellulose, carboxymethylcellulose, and protamine sulfate, where the concentration and method of incorporation of these polymers are selected to control the release of the active compound.

[0089] In another embodiment, transdermal patches, a steady-state reservoir sandwiched between an impermeable backing and a membrane surface, and transdermal formulations can also be used to deliver oxaloacetate. Transdermal administration systems are well known in the art. Occlusive transdermal patches for the administration of active agents to the skin or mucous membranes are described in U.S. Patents 4,573,996, 4,597,961 and 4,839,174, which are incorporated herein by reference. One type of transdermal patch is a polymer matrix in which the active agent is dissolved in a polymer matrix into which the active ingredient diffuses to the skin. Such transdermal patches are described in U.S. Patents 4,839,174, 4,908,213 and 4,943,435, which are incorporated herein by reference. In one embodiment, the steady-state reservoir carries a dose of oxaloacetate in the range of approximately 2 mg to 40 mg per day.

[0090] Current transdermal patch systems are designed to deliver smaller doses over longer periods, ranging from several days to several weeks. The release rate can be controlled using a rate-controlled outer microporous membrane or micropockets of the oxaloacetate of this disclosure dispersed throughout a silicone polymer matrix. Such rate-controlled means are described in U.S. Patent No. 5,676,969, which is incorporated herein by reference. In another embodiment, the oxaloacetate is released from the patch into the patient's skin in approximately 20–30 minutes or less.

[0091] These transdermal patches and formulations can be used with or without the use of dimethyl sulfoxide (DMSO), a combination of sucrose fatty acid esters and sulfoxides or phosphoroxides, or a penetration enhancer such as eugenol. The use of electrolytic transdermal patches is also within the scope of the methods disclosed herein. Electrolytic transdermal patches are described in U.S. Patents 5,474,527, 5,336,168 and 5,328,454, the entire contents of which are incorporated herein by reference.

[0092] Oxaloacetate can be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. Injected oxaloacetate can be mixed with other beneficial agents before injection, including but not limited to antibiotics and other drugs, saline, plasma, and other fluids. Even if the amount of oxaloacetate is insufficient to provide age-related benefits to the entire organism, immediate contact of high levels of oxaloacetate with vascular cells results in a reduction of age-related diseases such as arteriosclerosis. Injectable formulations may be provided in unit dose forms, such as ampoules or multi-dose containers, with added preservatives. The composition may take the form of a suspension, solution, or emulsion in an oily or aqueous vehicle and may contain compounding agents such as suspending agents, stabilizers, and / or dispersants. Alternatively, the active ingredient may be in powder form for composition with a suitable vehicle, such as sterile water free of pyrogens, before immediate use.

[0093] Oxaloacetate can also be formulated into rectal compositions such as suppositories or retained enemas containing conventional suppository bases, such as cocoa butter or other glycerides.

[0094] In addition to the formulations described above, oxaloacetate can also be formulated as a sustained-release formulation. Such long-acting formulations can be administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Therefore, for example, the compound can be formulated with a suitable polymer or hydrophobic material (e.g., as an emulsion in an acceptable oil) or an ion exchange resin, or as a sparingly soluble derivative, for example, as a sparingly soluble salt. The composition may be present in a pack or dispenser device that may contain, if desired, one or more unit dose forms containing the active ingredient. The pack may include, for example, metal or plastic foil such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration.

[0095] In yet another embodiment, oxaloacetate can be mixed with animal food to treat fatigue in animals. Oxaloacetate may be formulated as part of the animal's food or administered separately as a supplement to the animal's food. As is known to those skilled in the art, dry pet food, typically dry dog ​​food, usually contains protein, fat, fiber, non-fiber carbohydrates, minerals, vitamins, and moisture components. For example, as major components, there are typically one or two grains, generally corn, wheat, and / or rice. In addition, if protein sources, they may contain poultry meal, by-product meat, meat and bone meal, or by-products of other animal or fish meal. Sometimes, grain protein supplements such as corn gluten, soy meal, or other oilseed meal may be added. In addition to an effective amount of oxaloacetate of approximately 0.01% to 0.1% by weight in the solid feed, the animal solid feed of the present invention further comprises: a typical nutrient content in the food dry matter of 14% to 50%, typically 20% to 25% crude protein, 5% to 25% crude fat, typically 3% to 14%, typically in the range of 5% to 7%, and total mineral or ash content of 3% to 10%, typically in the range of 4% to 7%. The important point is that there is no precise formulation of pet food, as many conventional satisfactory products are available on the market for use in combination with the present invention. Rather, the key to success is to add sufficient oxaloacetate components to the pet food feed, regardless of which formulation is used, in order to provide oxaloacetate activity levels within the range necessary for AMPK activation to help prevent or treat disorders accompanied by pathological fatigue in animals.

[0096] Scale of clinical outcomes As described in the Examples section below, the clinical outcomes of administering oxaloacetate to subjects suffering from the disorders described herein may be evaluated by the following tests and questionnaires. Those skilled in the art will recognize the applicability of these tests for evaluating fatigue and depression-related symptoms.

[0097] As used herein, the term “Clinical Global Impressions” (CGI) refers to an assessment scale commonly used in the treatment of patients with mental disorders to measure the severity of symptoms, response to treatment, and effectiveness of treatment (Guy W: Clinical Global Impressions (CGI) Scale. Modified From: Rush J, et al.: Psychiatric Measures, APA, Washington DC, 2000).

[0098] As used herein, the "Clinical General Impression of Change" (CGI-C) (also known as Clinical General Impression - Improvement (CGI-I)) scale is a seven-point scale that requires clinicians to assess how much a patient's condition has improved or worsened compared to their baseline state at the start of an intervention. The assessments are as follows: 1, very significant improvement; 2, significant improvement; 3, little improvement; 4, no change; 5, slightly worse; 6, significantly worse; or 7, very significant worse.

[0099] As used herein, the term "MFS" refers to the Mental Fatigue Self-Assessment Questionnaire (Johansson B et al (2010) Brain Injury 2010;24:2-12).

[0100] Furthermore, the clinical outcomes of treatment can be assessed using the FF scale, Beck / BDI scale, VAS pain scale, and neuropsychological tests.

[0101] As used herein, the term “FF Scale” or “FF” refers to the Fibromyalgia and Chronic Fatigue Syndrome Assessment Scale, also known as the Fibromyalgia and Chronic Fatigue Syndrome Assessment Scale, described by Zachrisson and collaborators (Zachrisson O, et al, (2002) J Psychosom Res Jun;52(6):501-9). The Fibromyalgia and Chronic Fatigue Scale is an observer-assessment scale with 12 items that measure subjective experiences of pain, muscle tone, fatigue, difficulty concentrating, memory impairment, irritability, sadness, sleep disturbances, as well as autonomic dysfunction and irritable bowel syndrome, headaches and infections.

[0102] As used herein, the terms “Beck / BDI scale” and “BD” refer to the Beck Depression Item, developed by Aaron T. Beck (Beck AT et al., (1961) Arch. Gen. Psychiatry 4(6):561-71). It is a 21-question multiple-choice self-report questionnaire and one of the most widely used means of measuring the severity of depression. The BDI questionnaire is designed for individuals aged 13 years and older and consists of items relating to depressive symptoms such as helplessness and irritability, cognitions such as feelings of guilt or punishment, and physical symptoms such as fatigue, weight loss, and apathy for sex.

[0103] As used herein, the term “VAS pain scale” refers to a visual analog scale for measuring a patient’s pain intensity or other characteristics. A VAS scale is a psychometric response scale, often used in questionnaires. It is a means of measurement for subjective characteristics or attitudes that cannot be directly measured. When responding to VAS items, respondents indicate their level of agreement to a statement by indicating their position along a continuous line between two endpoints.

[0104] As used herein, the term “neuropsychological test” refers to a test designed to measure an unobserved construct, also known as a latent variable. A psychological test is typically, though not always, a set of tasks or problems that a respondent must solve and that must measure the respondent’s best performance.

[0105] As used herein, the term “Calder Fatigue Scale” refers to the Fatigue Questionnaire (Cella, M and T. Chalder (2010). “Measuring fatigue in clinical and community settings.” J Psychosom Res 69(1):17-22), which is a validated patient self-assessment of fatigue.

[0106] As used herein, the term “fatigue severity scale” refers to the Fatigue Questionnaire (Kleinman, L., Zodet, MW, Hakim, Z., Aledort, J., Barker, C., Chan, K., Krupp, L., & Revicki, D. (2000). Psychometric evaluation of the fatigue severity scale for use in chronic hepatitis C. Quality of Life Research, 9, 499-508), which is a validated patient self-assessment of fatigue.

[0107] As used herein, the term “PROMIS fatigue short form 7a” refers to the fatigue questionnaire (Christodoulou C, Schneider S, Junghaenel DU, Broderick JE, Stone AA. Measuring daily fatigue using a brief scale adapted from the Patient-Reported Outcomes Measurement Information System (PROMIS) Quality of Life Research. 2014;23:1245-1253.doi:10.1007 / s11136-013-0553-z), which is a validated patient self-assessment of fatigue.

[0108] As used herein, the term "PDQ-39" refers to the "Parkinson's Disease Quality of Life 39-Questionnaire Survey" (Fitzpatrick R, Jenkinson C, Peto V, Hyman N, Greenhall R. Desirable properties for instruments assessing quality of life: evidence from the PDQ-39. J Neurol Neurosurg Psychiatry. 1997;62(1):104).

[0109] As used herein, the term “MDS-UPDRS” refers to the “Movement Disorder Society-Sponsored Revision of the United Parkinson's Disease Rating Scale (MDS-UPDRS): Scale Presentation and Clinimetric Testing Results” (Goetz et al, Movement Disorders Vol.23, No.15, 2008, pp.2129-2170).

[0110] statistical analysis Various studies have used statistical evaluation of the data obtained. Those skilled in the art will understand and be aware of how to use the tests used herein. Any deviations from standard calculation procedures are described in the Examples section of this disclosure. Briefly, the statistical tests used herein are as follows:

[0111] The Mann-Whitney U test (also known as the Mann-Whitney-Wilcoxon (MWW), Wilcoxon-rank-sum test (WRS), or Wilcoxon-Mann-Whitney test) is a nonparametric test of the null hypothesis that two groups are the same for a given alternative hypothesis, particularly the null hypothesis that a particular group tends to have larger values ​​than other groups.

[0112] Two-way interaction analysis (two-way analysis of variance (ANOVA)) is a study that examines the effects of two different categorical independent variables on one continuous dependent variable. Two-way ANOVA aims not only to assess the main effects of each independent variable but also to determine if there are any interactions between them.

[0113] Three-way interaction analysis (three-way analysis of variance (ANOVA)) is a test that examines whether there is a two-way interaction that varies across the level of a third variable.

[0114] Spearman's rank correlation coefficient is a nonparametric measure of the statistical dependence between two variables. It assesses how well a monotonic function can describe the relationship between two variables. A perfect Spearman correlation of +1 or -1 occurs when there are no repeated data values ​​and each variable is a perfect monotonic function of the other.

[0115] The Student's t-test is a statistical hypothesis test in which the test statistic follows Student's t-distribution under the null hypothesis. The t-test can be used, for example, to determine whether the means of two sets of data are significantly different from each other.

[0116] While the present invention has been described with reference to various exemplary aspects and embodiments, those skilled in the art will understand that various modifications can be made and elements can be replaced with equivalents without departing from the scope of the invention. Therefore, the present invention is not limited to any particular embodiment contemplated, and is intended to include all embodiments that fall within the scope of the appended claims.

[0117] definition For the purposes of interpreting this Specified, the following definitions apply, and wherever used in the singular, the plural form is also included, and vice versa. In the event of any conflict between the following definitions and any documents incorporated herein by reference, the following definitions shall prevail.

[0118] As used herein, the singular forms "a," "an," and "the" include plural references unless otherwise indicated.

[0119] As used herein, the terms “comprising,” “having,” “containing,” and “including,” as well as their grammatical equivalents, are semantically equivalent and open-ended in that the one or more items following any one of these words do not mean an exhaustive list of such one or more items, nor do they mean that the list is limited to only the one or more items listed. For example, an article “comprising” components A, B, and C may consist of (i.e., contain only) components A, B, and C, or may contain one or more other components in addition to components A, B, and C. Accordingly, “comprising” and its similar forms, as well as their grammatical equivalents, are intended and understood to include disclosures of embodiments of “consisting essentially of” or “consisting of.”

[0120] Where a range of values ​​is provided, unless explicitly indicated in the context, each intervening value up to one-tenth of the lower limit between the upper and lower limits of that range, and any other stated values ​​or intervening values ​​within that stated range, are understood to be included in this disclosure, subject to any specifically excluded limits within the stated range. If the stated range includes one or both limits, the range excluding either or both of those limits is also included in this disclosure.

[0121] As used herein, the term “about” refers to the normal range of error for each value, which is readily known to those skilled in the art. References to “about” a value or parameter herein include (and describe) embodiments relating to that value or parameter itself. For example, “about X” includes a description of “X”.

[0122] As used herein, “treatment” or “to treat” refers to a method for obtaining beneficial or desired outcomes, including clinical outcomes. For the purposes of the present invention, beneficial or desired clinical outcomes include, but are not limited to, one or more of the following: relief of one or more symptoms caused by the disease; reduction of the severity of the disease; stabilization of the disease (e.g., prevention or delay of disease exacerbation); prevention or delay of disease progression (e.g., metastasis); prevention or delay of disease recurrence; delay or slowing of disease progression; improvement of the condition; provision of remission (partial or complete) of the disease; reduction of the dose of one or more other drugs necessary for the treatment of the disease; delay of disease progression; improvement or enhancement of quality of life; increased weight gain; and / or extension of survival. The methods of the present invention aim to achieve one or more of these aspects of treatment.

[0123] As used herein, the term “preventive treatment” refers to treatment in which an individual is known to have, suspected to have, or at risk of having a disability, but is not exhibiting symptoms or minimal symptoms of the disability. Individuals receiving preventive treatment may be treated before symptoms develop.

[0124] As used herein, “combination therapy” means that a first drug is administered in combination with another drug. “In combination with” means that one mode of therapy is administered in addition to another mode of therapy, for example, administering the nucleated cell composition described herein in addition to administering the immunoconjugate described herein to the same individual. Thus, “in combination with” means that one mode of therapy is administered before, during, or after the delivery of the other mode of therapy to the individual.

[0125] As used herein, the term “concurrent administration” means that the first and second therapies in combination therapy are administered within a time interval of about 15 minutes or less, for example, about 10, 5, or 1 minute or less. When the first and second therapies are administered concurrently, the first and second therapies may be contained in the same composition (e.g., a composition containing both the first and second therapies) or in separate compositions (e.g., the first and second therapies in one composition are contained in another composition).

[0126] As used herein, the term “sequential administration” means that the first and second therapies in a combination therapy are administered at time intervals exceeding approximately 15 minutes, for example, more than approximately 20, 30, 40, 50, or 60 minutes. Either the first or second therapy may be administered first. The first and second therapies are contained in separate compositions, which may be contained in the same or different packages or kits.

[0127] As used herein, the term “concurrent administration” means that the administration of the first therapy and the administration of the second therapy in combination therapy overlap with each other.

[0128] As used herein, “pharmaceutically acceptable” or “pharmaceutically compatible” means a material that is not biologically or otherwise undesirable, for example, a material that can be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effect or without interacting in a harmful manner with any of the other components of the composition in which it is contained. Pharmaceutically acceptable carriers or additives preferably meet the required standards of toxicological and manufacturing testing and / or are included in the Inactive Ingredients Guide created by the U.S. Food and Drug Administration.

[0129] Exemplary Embodiments Embodiment 1. A method for treating one or more symptoms of a disorder characterized by debilitating fatigue of a subject, comprising administering a therapeutic dose of an oxaloacetate compound to the subject, wherein the disorder is selected from the group consisting of post-COVID-19 fatigue, post-viral fatigue, myalgic encephalomyelitis / chronic fatigue syndrome, fibromyalgia, mental fatigue, post-stroke fatigue, amyotrophic lateral sclerosis, myasthenia gravis, Huntington's disease, Parkinson's disease, Alzheimer's disease, multiple sclerosis, narcolepsy, post-cancer fatigue, and cancer-related fatigue with or without cell division arrest therapy.

[0130] Embodiment 2. The method according to Embodiment 1, wherein the oxaloacetate compound is an anhydrous enol-oxaloacetate.

[0131] Embodiment 3. The method according to Embodiment 1, wherein the oxaloacetate is composed of the group consisting of enol-oxaloacetate, keto-oxaloacetate, hydrated oxaloacetate, or oxaloacetate salts.

[0132] Embodiment 4. The method according to any one of Embodiments 1 to 3, wherein the disorder is selected from the group consisting of fibromyalgia, mental fatigue, myalgic encephalomyelitis / chronic fatigue syndrome, fibromyalgia, Huntington's disease, post-COVID-19 fatigue, post-viral fatigue, amyotrophic lateral sclerosis, myasthenia gravis, Parkinson's disease, Alzheimer's disease, multiple sclerosis, and post-cancer fatigue.

[0133] Embodiment 5. The method according to any one of Embodiments 1 to 4, wherein the oxaloacetate is administered in a dose of approximately 100 to 6,000 mg.

[0134] Embodiment 6. The method according to any one of Embodiments 1 to 5, wherein the oxaloacetate is administered in a dose of 200 mg to 3,000 mg.

[0135] Embodiment 7. The method according to any one of Embodiments 1 to 6, wherein the oxaloacetate is administered once, twice, or three times a day.

[0136] Embodiment 8. The method according to any one of Embodiments 1 to 7, wherein the oxaloacetate compound is present in the pharmaceutical composition.

[0137] Embodiment 9. A method for treating one or more symptoms of a disorder characterized by debilitating fatigue in a subject, comprising administering a therapeutic dose of a compound to reverse metabolic dysfunction in the subject, wherein the dysfunction is selected from the group consisting of increased glycolysis, chronic activation of NF-κB, decreased NAD+ / NADH ratio, mitochondrial dysfunction, decreased AMPK activation, and combinations thereof.

[0138] Embodiment 10. The method according to Embodiment 9, wherein the compound is an oxaloacetate compound.

[0139] Embodiment 11. The method according to Embodiment 10, wherein the oxaloacetate compound is selected from the group consisting of enol-oxaloacetate, keto-oxaloacetate, hydrated oxaloacetate, and oxaloacetate salts.

[0140] Embodiment 12. The method according to Embodiment 10 or 11, wherein the oxaloacetate compound is an anhydrous enol oxaloacetate.

[0141] Embodiment 13. The method according to any one of Embodiments 9 to 12, wherein the disorder is selected from the group consisting of fibromyalgia, mental fatigue, myalgic encephalomyelitis / chronic fatigue syndrome, fibromyalgia, Huntington's disease, post-COVID-19 fatigue, post-viral fatigue, amyotrophic lateral sclerosis, myasthenia gravis, Parkinson's disease, Alzheimer's disease, multiple sclerosis, and post-cancer fatigue.

[0142] Embodiment 14. The method according to any one of Embodiments 10 to 13, wherein the oxaloacetate compound is administered in a dose of about 100 to about 6,000 mg.

[0143] Embodiment 15. The method according to any one of Embodiments 10 to 14, wherein the oxaloacetate compound is administered in a dose of approximately 200 mg to approximately 3,000 mg.

[0144] Embodiment 16. The method according to any one of Embodiments 10 to 15, wherein the oxaloacetate compound is administered once, twice, or three times a day.

[0145] Embodiment 17. The method according to any one of Embodiments 9 to 16, wherein a compound for reversing metabolic dysfunction is present in the pharmaceutical composition. [Examples]

[0146] Those skilled in the art will recognize that several embodiments are possible within the scope and spirit of the present invention. The present invention will be described in more detail with reference to the following non-limiting examples. The following examples further illustrate the present invention, but should not be construed as limiting its scope.

[0147] Example 1. Patients with Parkinson's disease experience significant fatigue. It is their number one complaint. The following text is taken from the Parkinson's Association website, January 5, 2020: (The leading organization for Parkinson's patients addressing pathological fatigue in Parkinson's disease) Do people with Parkinson's disease (PD) or their families feel physically or mentally exhausted? Could this be fatigue? Deep fatigue that does not improve with rest. About half of people with PD report fatigue as their primary problem, and the third most common symptom of their disability. Fatigue is different from sleepiness. However, while fatigued people may feel exhausted, they don't necessarily feel like sleeping. Fatigue is common in the early stages of Parkinson's disease, but can occur at any time, whether motor symptoms are mild or severe. It can be confused with other symptoms that cause drowsiness or fatigue, such as sleep disturbances or pain. Fatigue is a symptom of depression, but a person may experience fatigue without becoming depressed. Stress can worsen fatigue. No specific cause of fatigue in Parkinson's disease (PD) has been identified. Motor symptoms such as tremors and rigidity may contribute to muscle fatigue. However, fatigue can also have causes other than Parkinson's disease. It is important to identify and treat any non-PD-related illnesses or medications that may be causing fatigue. Fatigue can lead people to reduce their working or retirement time, or to avoid social activities altogether. Understanding fatigue as a symptom of drug-induced disease and finding ways to cope with it is essential for maintaining a good quality of life. Symptoms • Physical fatigue: Feeling extremely tired or exhausted may worsen with “off” fluctuations. • Mental fatigue: Mental exhaustion that makes it difficult to concentrate. therapy Few therapies have been tested for fatigue in Parkinson's disease (PD). None have been proven effective for fatigue alone. Therapies for motor symptoms do not appear to help with fatigue.

[0148] Retrieved from the World Wide Web on January 5, 2020, at Parkinson.org / Understanding-Parkinsons / Symptoms / Non-Movement-Symptoms / Fatigue

[0149] The inventors set up an initial series of case studies to investigate the effects of oxaloacetate on Parkinson's disease. Several individuals in the case studies reported a reduction in fatigue with the use of "benaGene," an oxaloacetate dietary supplement manufactured and distributed by the inventors. Certificates from such individuals are shown below: Dear Alan, I will do my best to answer all your questions as clearly as possible. I take benaGene with breakfast and dinner respectively, so there is about 10-12 hours between them, and I take magnesium at roughly the same time as benaGene. The Mg2+ is in oxide form, and each capsule contains 400mg. Obviously, the oxide is not the best absorbed form, but it is the only oxide I could find at the pharmacy. I first went to a neurologist because I felt I was experiencing memory problems beyond typical age-related memory impairment (starting in early fall 2009). This presented significant challenges for me, as I was a KU employee and had taught cardiovascular pharmacology for many years. I noticed my speech becoming very slow and paused as I searched for words. Almost simultaneously, I began experiencing severe muscle spasms during sleep. This phenomenon is known as REM sleep without athenia (RSWA), or REM sleep disorder behavior, which scientists at the Mayo Clinic in Minnesota are studying. Recall, the next problem that emerged was a significant disruption of visuospatial coordination, which led Mr. Eli to convince me to stop driving. My balance also deteriorated, and I fell several times. So, in December 2009, I went to the neurology clinic at the medical center, suspecting I might have Alzheimer's disease. The neurologist was an Alzheimer's specialist, and I suspected that Alzheimer's disease might be my problem. However, he felt it was more likely that I had a form of Parkinson's disease and arranged for me to see a neurologist specializing in movement disorders. He didn't think my symptoms were very severe at that point, but prescribed me Sinemet (4 tablets per day) (100 mg L-DOPA, 25 mg carbidopa), a commonly used medication containing levodopa and carbidopa. And that treatment certainly seemed to help me maintain a better balance for a while. However, I began to experience tremors in my hands and could no longer type on a computer keyboard, carry something without spilling it, button my clothes, or comb my hair. I couldn't read my handwriting and it was extremely difficult to pick up silverware and eat. The neurologist continued to increase my dosage of Sinemet I (up to 7 tablets / day), but my symptoms only got worse over time. In late March and early April, I had several bad falls, one of which resulted in a fractured hand. By April 14th, I was taking up to 8 Sinemet tablets a day, and still hadn't achieved any improvement.When I visited a neurologist on April 14th, he was convinced I would definitely need a walker because I could only stand for 2-3 seconds without leaning back in a chair. Eli was reviewing the literature on Parkinson's disease (PD) and was drawn to the idea that mitochondrial dysfunction is a major cause of PD's pathogenesis. He also knew that magnesium had very beneficial effects in animal models of various central nervous system problems and could counteract abnormal calcium surges in neurons. A neurologist friend who studies mitochondria warned him about oxaloacetate and Terra Biologicals. So, on May 9, 2011, he began taking benaGene and magnesium along with Sinemet (7.5 tablets / day). After four weeks on the benaGene / Mg combination, my balance and posture had improved enough that I could consider going to a scientific conference in Europe again. This would have been absolutely impossible in my condition before this treatment regimen was started. Both my balance and flexibility improved. The tremor began to subside gradually and was almost completely gone by the time I returned from Europe (early August). Both the tremor and visual problems had subsided to the point where I could abandon my voice-activated computer programs. The improvement in visuospatial function allowed me to start driving a car by the end of August. Now I can type on my computer, attend meetings with my research staff, and work on scientific papers. I am continuing the same benaGene / Mg therapy and taking 7 tablets of Sinemet per day. I hope this will result in many good pictures of the reversal of PD symptoms with benaGene / Mg treatment. Please feel free to contact me if you have any further questions. Mary

[0150] As can be seen, this person showed improvement in pathological muscle fatigue and a reduction in tremors that could result from muscle fatigue. A single patient's testimonial is important, especially in diseases such as Parkinson's disease, which have no cure. However, to better investigate efficacy, the inventors subsequently conducted a retrospective study on the effects of the nutritional supplement benaGene (a combination of 100 mg oxaloacetate and 150 mg vitamin C) on the inventors' customer base, including some Parkinson's disease patients. Each participant with Parkinson's disease was given the "Quality of Life with Parkinson's Disease (PDQ)" questionnaire (PDQ-39) using 39 questions and asked to score their past Parkinson's disease status before taking benaGene (oxaloacetate) and again after taking benaGene for at least 3 months. Pre / post data were received from 13 customers and the scores were compiled.

[0151] 53.8% of Parkinson's disease patients taking benaGene (oxaloacetate) responded well, along with improvements in quality of life, as measured by pre- and post-treatment assessments using the PDQ-39. Among those who responded well, over 50% experienced improvements in quality of life, and some patients showed up to 90% reduction in symptoms, including pathological fatigue. Improvements in quality of life included reduced fatigue.

[0152] Example 2 Based on the inventors' findings, a clinical trial was conducted on patients with Parkinson's disease. In this trial, the MDS-UPDRS (Goetz et al, Movement Disorder Society-Sponsored Revision of the United Parkinson's Disease Rating Scale (MDS-UPDRS): Scale Presentation and Clinimetric Testing Results, Movement Disorders Vol.23, No.15, 2008, pp.2129-2170) (45) was used as an effective method for clinically measuring pathological fatigue in patients with Parkinson's disease. The fatigue questions were as follows: 1.13 Fatigue Have you been feeling tired for the past week? This feeling isn't related to sleepiness or sadness. 0: Normal: No fatigue 1: Mild: Fatigue occurs. However, it does not interfere with doing things or being with people. 2: Mild: Fatigue causes some difficulty in doing things or being with people. 3: Moderate: Fatigue significantly impairs the ability to do things or be with people. However, it does not prevent you from doing anything. 4: Severe: Fatigue prevents you from doing things or being with people.

[0153] Twenty-six patients completed the Phase 2 trial, with 13 patients in the placebo group and 13 patients in the oxaloacetate group.

[0154] The inventors' initial data supporting clinical trials in Parkinson's disease patients were obtained from the inventors' “benaGene” study discussed in Example 1 of this specification. benaGene is a dietary supplement containing 100 mg of oxaloacetate and 150 mg of ascorbic acid (vitamin C) in a vegetable capsule shell. Since it was unclear whether the benefits observed in Example 1 were due to ascorbic acid or oxaloacetate, ascorbic acid (vitamin C) was selected as a 250 mg placebo, but the active substance tested was a 100 mg oxaloacetate / 150 mg ascorbic acid capsule (benaGene).

[0155] In a double-blind, placebo-controlled clinical trial, the effects of two capsules of benaGene (oxaloacetate) per day were measured in Parkinson's disease patients for four months.

[0156] After four months, the oxaloacetate group showed a significant statistical improvement in fatigue issues on the MDS-UPDRS scale compared to the initial baseline measurement. The oxaloacetate score for fatigue improved by 28.7%, with a p-value of <0.05. In contrast, the ascorbic acid placebo group showed only a 10.4% improvement in fatigue, with a p-value of P=0.71, which was not statistically significant.

[0157] 200 mg of oxaloacetate was clinically demonstrated to significantly reduce pathological fatigue in Parkinson's disease patients in a double-blind, placebo-controlled clinical trial using oxaloacetate supplied by the inventors. Therefore, oxaloacetate supplementation is a novel method for improving pathological fatigue in Parkinson's disease.

[0158] Example 3 In one study of 384 patients discharged after COVID-19 infection, 69% experienced persistent long-term pathological fatigue. (Mandal S, Barnett J, Brill SE, Brown JS, Denney EK, Hare SS, et al. 'Long-COVID': a cross-sectional study of persistent symptoms, biomarker and imaging abnormalities following hospitalization for COVID-19. Thorax. 2020). A person skilled in the art of pathological fatigue details their own experience with significant persistent pathological fatigue after COVID-19. The physician contracted COVID-19 and experienced extreme fatigue after the resolution of the viral infection. Her fatigue was measured using valid fatigue measurement surveys including the Calder fatigue score, fatigue severity score, visual fatigue score and PROMIS fatigue short form 7a. All measurements indicated severe fatigue. The physician was placed on a course of 500 mg anhydrous enol-oxaloacetate BID for 45 days. Her fatigue score was obtained after 2 weeks and showed slight improvement. After a total of six weeks, her fatigue was relieved. Her scores are shown in Table 1 below. TIFF0007882855000001.tif48170

[0159] The doctor provided the inventor with a certificate of her experience: I participated in a clinical trial for oxaloacetate because I had been suffering from extreme fatigue for several weeks. I was initially skeptical because of the nausea it caused, but I decided to go for it, and I must say I'm so glad I did. By the end of the six weeks, my energy seemed limitless, and I've never felt so happy, motivated, energetic, and mentally sharp. My life has been improving more and more. Thank you! LI

[0160] Extreme fatigue after COVID-19 can take up to several months to resolve (if it exists at all), so a doctor completely reversing severe fatigue in less than six weeks is unexpected and a novel phenomenon.

[0161] Example 4 A physician customer of the inventor used 5 capsules of benaGene (oxaloacetate) BID for a patient with pathological fatigue following COVID-19 infection. The physician provided this report to the inventor: I just received a positive report from a 50-year-old woman who had survived COVID-19 but remained weakened by post-viral fatigue that lasted for four months. I had her try benaGene [AEO], and after three days she said the effect was dramatic. Yesterday she felt like she was back to her pre-COVID self. I asked her to give me an update in a month. I will let you know about her after taking benaGene / hydroxyfumarate for a little longer.

[0162] The inventors consulted a physician 30 days later to confirm the patient's condition. Physician's report: She's still doing well... She's the wife of another MD.

[0163] It is unexpected and novel that post-COVID-19 fatigue, which persists for four months, can be improved within three days with oxaloacetate supplementation.

[0164] Example 5 The inventor's 29-year-old daughter contracted COVID-19 in late February 2020 and had a fever for 26 days. After the fever subsided, she experienced extreme fatigue, making it difficult for her to even walk to the toilet. She began taking 500 mg of anhydrous enol-oxaloacetate BID for 45 days. Within 3 days, 80% of her fatigue was gone. After 30 days, 100% of her fatigue was gone.

[0165] The unexpected and novel finding that extreme fatigue after COVID-19 decreased by 80% in 3 days and 100% in 30 days is noteworthy.

[0166] Example 6 Patients with amyotrophic lateral sclerosis (ALS) generally experience pathological fatigue. (Gibbons C, Pagnini F, Friede T, Young CA. Treatment of fatigue in amyotrophic lateral sclerosis / motor neuron disease. The Cochrane database of systematic reviews. 2018;1:CD011005).

[0167] A Phase 1 clinical trial was conducted by the inventors supplying the anhydrous enol-oxaloacetate drug. Typically, Phase 1 clinical trials focus on the safety of the proposed drug, but efficacy in patient response is also important and noteworthy. The inventors present two testimonials from patients who observed improvement in pathological fatigue in patients taking 1500 mg of anhydrous enol-oxaloacetate BID. Patient 1. My name is Kevin Fairchild. I was diagnosed with bulbar-onset ALS by Dr. Jawdat at KU Medical Center in Kansas City, KS on October 14, 2020. Dr. Jawdat proposed this clinical trial of oxaloacetate, taking 1500 mg twice daily for 28 days. Upon joining the clinical trial, my symptoms included slurred speech, poor tongue movement, and significant atrophy of my left hand and arm. I occasionally experienced muscle fasciculations that affected almost my entire body, and were mostly constant. For the first 4-5 days of taking the supplement, I felt them intensify 1-2 hours after taking it, and it lasted for about 1 or 2 hours. After 4 or 5 days, it returned to normal strength. Around the third week of taking the supplement, I began to notice that my tongue movement had a better range of motion. I could see my tongue pushing against the side of my cheek, which it hadn't reached before. I also felt that my left hand gained a little strength, and I felt like I had more grip strength, and I also felt a little strength in my left wrist. However, most things still feel like they're declining, but because I've only been trying the supplement for a very short time, I want to continue taking it to see if I can continue to improve / change. I am not currently taking any ALS medication, but I am taking some vitamins. Patient 2. My husband, Nathan, was part of a study using oxaloacetate for ALS. When he started the supplement [1500mg oxaloacetate BID], we didn't expect a huge difference. However, within a few days, he was much more energetic. Before taking oxaloacetate, he struggled to get out of bed and was always exhausted. He worked during the day but slept mostly in his recliner at night. After taking the medication for a week, my 18-year-old son commented that his dad was getting up at night to talk to him. He said it was making a huge difference to whatever he was doing. That really shocked me. Now that the trial was over, we were back to Nathan struggling to get up and to move. My child and I talk almost every day about how we feel oxaloacetate has made a positive difference to my husband's quality of life.

[0168] There are no approved drugs to improve muscle fatigue in ALS patients; therefore, this result with oxaloacetate supplementation is unexpected and novel.

[0169] Example 7 Patients with amyotrophic lateral sclerosis (ALS) generally experience pathological fatigue. (Gibbons C, Pagnini F, Friede T, Young CA. Treatment of fatigue in amyotrophic lateral sclerosis / motor neuron disease. The Cochrane database of systematic reviews. 2018;1:CD011005).

[0170] A Phase 1 clinical trial was conducted by the inventors supplying the anhydrous enol-oxaloacetate drug. Typically, Phase 1 trials focus on the safety of the proposed drug, but patient response is also important. The inventors present a certificate showing improvement in muscle fatigue in patients taking 1000 mg of anhydrous enol-oxaloacetate BID. Hi, my name is Matthew Grzesik. I recently participated in the TOALS study at the KU ALS Clinic. Specifically, I was in Group 1, receiving a 2000mg dose. Typically, I had to take 2-4 long sleeps a day to combat the constant fatigue from ALS, and also moderate the amount of physical activity I did to avoid exhausting myself. I am only 28 years old, a powerlifting athlete, and also a strength and conditioning instructor, so limiting physical activity was difficult for me. I was planning a turf renovation project during my participation in the study and was trying to take my time with it, so I didn't push myself too hard. About a week into the study, I noticed my energy levels were much higher than they had been over a year ago, and I was able to complete a project that would have taken a month in a week and a half. Not only was I able to do more physically, but I only needed one nap a day, and eventually it dropped to zero. That month felt like a gift to have felt so good. The only side effect I noticed was stomach upset when taking the dose without food, but that disappeared as soon as I ate something. I wanted to share something positive with you all, as I would like to seek more oxaloacetate so that I can continue taking it and enjoy life as much as possible. I am grateful to Dr. Jawdat for collaborating with me on this research and for his time and consideration. I look forward to seeing how this supplement can benefit other people, whether they have ALS or other illnesses.

[0171] There are no approved drugs to improve muscle fatigue in ALS patients; therefore, this result with oxaloacetate supplementation is unexpected and novel.

[0172] ALS patients taking 3,000 mg of oxaloacetate daily experienced no functional decline and maintained stable fatigue / muscle function eight months after supplementation. This is remarkable and welcome news, as the expected rate of decline during this period in ALS ranges from 12% to 43%, as measured by the ALSFRS. (Ong ML, Tan PF, Holbrook JD. Predicting functional decline and survival in amyotrophic lateral sclerosis. PLoS One. 2017;12(4):e0174925. Published 2017 Apr 13. doi:10.1371 / journal.pone.0174925).

[0173] Patient's email address: "Hello Alan, I am writing to request additional oxaloacetate for my husband, Darrell. He has been taking the medication since May 2021 and has not experienced any decrease in exercise or strength. We are very pleased! Could you please give him a little more medication? Thank you!"

[0174] Example 8 The inventors supplied anhydrous enol-oxaloacetate for post-pneumonia fatigue. Patients with pneumonia often suffer from physiological fatigue. In a retrospective study of 506 adults with clinical and radiological evidence of pneumonia, 51% of patients experienced fatigue 90 days after diagnosis. (Metlay JP, Fine MJ, Schulz R, Marrie TJ, Coley CM, Kapoor WN, et al. Measuring symptomatic and functional recovery in patients with community-acquired pneumonia. J Gen Intern Med. 1997;12(7):423-30). The following are testimonials from patients who found benefit from 500 mg of oxaloacetate daily. I resumed taking oxaloacetate shortly after being released from hospital and skilled nursing care. The biggest difference oxaloacetate made for me was the alleviation of collapse fatigue associated with pneumonia. The American Lung Association indicates that the basis of fatigue is not understood, and the scientific literature certainly does not offer any firm understanding of the biological causes of fatigue. The fatigue I experienced can only be described as "crushing." For example, immediately after being released to go home, I got into a car (not driving) to drop someone off at the airport, and then stopped for lunch, only to find myself completely exhausted, requiring two full days to recover. When I inquired about this response with nurses and physiotherapists, the universal answer was that it was "typical." Speaking with people who had pneumonia at different ages (which I acknowledge is a case in itself), I got consistent stories of extreme fatigue and slow recovery, even from teenagers who were physically active at the time, requiring several years to return to their previous energy levels. I was hospitalized for two weeks, followed by about six weeks of expert care, and I was among the 40% of the group that couldn't avoid hospitalization. However, I wasn't in the ICU, so it wasn't the worst-case scenario. The first time I took the oxaloacetate capsule, I immediately felt relieved from a sensation I hadn't even realized I had. It was a heavy, oppressive feeling in the center of my chest. That feeling disappeared and never returned. For the first few months, I chose to take multiple capsules a day. Oxaloacetate immediately boosted my energy levels, allowing me to work from home. When I went to the office, I found I could work energetically for several hours, and when I did get tired, oxaloacetate prevented me from rapidly becoming exhausted. Of course, there's no way to determine if using oxaloacetate accelerated my recovery. However, I can confidently say that it played a significant role in alleviating the pain of the recovery process.

[0175] The rapid dissipation of fatigue following oxaloacetate supplementation after pneumonia is unexpected and novel.

[0176] Example 9 A Phase 2 trial using oxaloacetate to treat mental and physical fatigue in breast cancer survivors is currently underway and is helping to teach a method for treating pathological mental and physical fatigue in cancer patients. In the trial, fatigue is assessed using a multidimensional fatigue symptom item. Scores are summarized as mean values, and the standard deviation and confidence interval are calculated. Changes are also summarized as effect size.

[0177] Inclusion criteria for this clinical trial: Women who have been diagnosed with early-stage breast cancer (stages 0, I, II, or IIIa), have undergone surgery, chemotherapy, or radiation therapy at least 12 months ago, may have received endocrine therapy or HER-2 targeted therapy, and have been diagnosed with breast cancer within the last 5 years. • No evidence of active / recurrent breast cancer or other serious chronic disease. • Patient-Reported Outcome Scale Information System (PROMIS) Adult Version (v) 2.0 - Cognitive Function 4a: Having a significant cognitive complaint defined as a score of <12. • Geographically accessible and able to participate in a study lasting 8-10 weeks. • Ability to complete assessment surveys in English The effect of oxaloacetate on developing human fetuses at the recommended therapeutic dose is unknown. For this reason, women of potential pregnancy must agree to use appropriate contraception (contraception barrier; intrauterine device [IUD]; abstinence from alcohol) before and during participation in the study. Women of any age who have had their ovaries and / or uterus removed are not at risk of pregnancy and do not require contraception. If a woman becomes pregnant or suspects she may be pregnant while participating in this study, she should immediately inform the research physician. Menopausal status is established as follows: Women who are 55 years of age or older and have not menstruated are considered postmenopausal and are not at risk of pregnancy. Women under 55 years of age who are menstruating are considered premenopausal and require contraception. Women under 55 years of age with an intact uterus and ovaries, who have not menstruated and have not had a menstrual period in the past two years, have measured follicle-stimulating hormone (FSH) and estradiol levels. If the values ​​are in the postmenopausal range, the woman is considered postmenopausal and is not at risk of pregnancy. • The ability to understand and sign a written informed consent document.

[0178] Exclusion criteria: Having another serious or chronic medical or psychiatric condition that contributes to a substantial physical or emotional impairment that would prevent participation in the planned study. • Taking chronic medications that may interfere with cognitive function, such as sleep medications, narcotics for anxiety or pain, or the use of illegal drugs or cannabis. Participants are not permitted to receive any other investigational drugs. • A medical history of allergic reactions caused by compounds with a chemical or biological composition similar to oxaloacetate. • Uncontrolled comorbidities, including but not limited to ongoing or active infections, symptomatic congestive heart failure, unstable angina, cardiac arrhythmias, or mental / social conditions that would limit compliance with research requirements. • Pregnant or breastfeeding women are excluded from this study because the safety of oxaloacetate in this setting is unknown. Pregnancy tests are performed on all women with intact uteruses and ovaries who are not determined to be postmenopausal.

[0179] Primary outcome measure: 1. Functional assessment of cancer therapy - Changes in cognitive function and perceived cognitive impairment (FACT-CogPCI) score [Time frame: Baseline up to day 57]

[0180] Patients with at least a 4-point improvement in FACT-Cog PCI are considered to have a positive response. The response rate is further characterized using point estimates and 95% accurate binomial confidence intervals.

[0181] Secondary outcome scale: 1. Incidence of adverse events [Time frame: up to day 57] The evaluation will be conducted according to the Common Terminology Criteria for Adverse Events, version 4.

[0182] 2. Fatigue [Time frame: Day 57] Fatigue symptoms are assessed using a multidimensional fatigue symptom questionnaire. Scores are summarized as mean values, and the standard deviation and confidence interval are calculated. Changes are also summarized as effect sizes to support the design of future clinical trials.

[0183] 3. Insomnia [Time frame: Day 57] Insomnia severity is assessed using an insomnia severity index. The score is summarized as a mean, and the standard deviation and confidence interval are calculated. Changes are also summarized as effect size to support the design of future clinical trials.

[0184] 4. Symptoms of depression [Time frame: Day 57] Patient-reported outcome scales are evaluated using an information system. Scores are summarized as mean values, and the standard deviation and confidence interval are calculated. Changes are also summarized as effect sizes to support the design of future clinical trials.

[0185] 5. Neurocognitive Test [Timeframe: up to 57 days] The subjects will be assessed using the California Language Learning Test, 2nd Edition, the Simplified Visuospatial Memory Test—Revised, the Golden Stroop Test, the Railmaking Test, Verbal Fluency, and the Connors Continuity Performance Test—II. All listed scales have individual scores converted using published reference data, so the units of measurement are the same for the listed tests, and higher scores indicate better performance.

[0186] The clinical trial provides an example of the use of oxaloacetate to treat cognitive and muscle fatigue in breast cancer patients, representing a novel use of oxaloacetate.

[0187] Example 10 A clinical trial is currently underway to evaluate the response of patients with post-COVID-19 fatigue treated with oxaloacetate. Fatigue is assessed using the Calder Fatigue Scale, the Fatigue Severity Scale, and the PROMIS Fatigue Short Form 7a. Scores are summarized as mean values, and the standard deviation and confidence interval are calculated. Changes are also summarized as effect size. This study is being conducted as a double-blind, placebo-controlled trial, with half of the patients receiving the active drug and the other half receiving a placebo. This trial is being conducted in accordance with the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines on Good Practices for the Use of Pharmaceuticals. All patients provided written informed consent to participate in the trial prior to screening.

[0188] Inclusion criteria: 4.1.1 Women who have recovered from an initial COVID-19 infection, at least two months after viral clearance was confirmed by rRT PCR. 4.1.2 No evidence of active / relapsing COVID-19 or other serious chronic disease. 4.1.3 The patient has significant fatigue complaints, defined as a biphasic score of 4 or higher on the Fatigue Questionnaire. 4.1.4 Geographically accessible or practically able to complete the form and participate in the study for a period of 6 to 10 weeks. 4.1.5> The age of 18 and under 65. 4.1.6 Ability to complete assessments and surveys in English. 4.1.7 The effect of oxaloacetate at the recommended therapeutic dose on developing human fetuses is unknown. Therefore, women of potential pregnancy must agree to use appropriate contraception (contraception barrier; IUD; abstinence from alcohol) before and during participation in the study. Women of any age who have had an oophorectomy and / or hysterectomy are not at risk of pregnancy and do not require contraception. If a woman becomes pregnant or suspects she may be pregnant while participating in this study, she should immediately inform the research physician. Menopausal status is established as follows: Women aged 55 or older who are abstaining from menstruation are considered postmenopausal and at no risk of pregnancy. Women under 55 who are menstruating are considered premenopausal and require contraception. Women under 55 who have an intact uterus and ovaries, are abstaining from menstruation, and have not had a menstrual period in the past two years have measured FSH and estradiol levels. If the values ​​are in the postmenopausal range, the woman is considered postmenopausal and at no risk of pregnancy. 4.1.8 Ability to understand and willingness to sign a written informed consent document. 4.1.9 No diagnosis of clinical depression 4.1.10 I am not taking oxaloacetate supplements.

[0189] Exclusion criteria: 4.2.1 Having another serious or chronic medical or psychiatric condition that contributes to a substantial physical or emotional impairment that would prevent participation in the planned study. 4.2.2 Taking chronic medications that may interfere with cognitive function, such as sleep medications, narcotics for anxiety or pain, or the use of illegal medical foods or cannabis. 4.2.3 Participants are not permitted to receive any other investigational drugs. 4.2.4 A medical history of allergic reactions caused by compounds with a chemical or biological composition similar to oxaloacetate. 4.2.5 Uncontrolled comorbidities, including but not limited to ongoing or active infection with COVID-19 or other viruses, symptomatic congestive heart failure, unstable angina, cardiac arrhythmias, or mental / social conditions that would limit compliance with research requirements. 4.2.6 Pregnant or breastfeeding women are excluded from this study because the safety of oxaloacetate in this setting is unknown. Pregnancy tests are performed on all women with intact uteruses and ovaries who are not determined to be postmenopausal, as described in Section 4.1.7.

[0190] This clinical trial provides an example of the use of oxaloacetate to treat cognitive and muscle fatigue in patients with post-COVID-19 fatigue, representing a novel use of oxaloacetate.

[0191] Eighteen patients with an average of six months of "long-haul" fatigue after COVID-19 were recruited for a clinical trial. Each patient received 500 mg of oxaloacetate BID orally for six weeks. As measured by the Calder Fatigue Scale, fatigue decreased by 45% from baseline over six weeks (P<0.005). Other fatigue scales supported this result. The Fatigue Severity Scale showed a 15% decrease in fatigue from baseline (P<0.005). The Visual Analog Fatigue Scale showed a 56% decrease (P<0.05). The PROMIS Fatigue Short Form 7a showed a 21% decrease in fatigue compared to baseline (P<0.005). The results of the clinical trial data are shown in Figure 1.

[0192] No significant adverse events occurred during the trial. These patients met the criteria for ME / CFS, having experienced fatigue for an average of six months. The placebo effect in ME / CFS patients has been established as very low, at 5.9% when measured by the Calder fatigue score using oral medication (Cho HJ, Hotopf M, Wessley S: The placebo response in the treatment of chronic fatigue syndrome: a systematic review and meta-analysis Psychosom Med 2005;67(2):301-13). Improvement in long-haul COVID-19 patients with persistent fatigue was seven times higher than previously expected with placebo. Therefore, oxaloacetate has been shown to be effective in treating long-haul COVID-19 residual fatigue.

[0193] Example 11 A Phase 1 clinical trial is planned to evaluate the response of patients with myasthenic fatigue treated with oxaloacetate. Fatigue will be assessed using the Calder Fatigue Scale, the Fatigue Severity Scale, and the PROMIS Fatigue Short Form 7a. Scores will be summarized as mean values, and the standard deviation and confidence interval will be calculated. Changes will also be summarized as effect size.

[0194] This clinical trial provides an example of the use of oxaloacetate to treat cognitive and muscle fatigue in patients with myasthenia gravis fatigue, representing a novel use of oxaloacetate.

[0195] Example 12 A Phase 2 trial is underway to evaluate the response of patients with ME / CFS. Fatigue is assessed using the Calder Fatigue Scale, Fatigue Severity Scale, and PROMIS Fatigue Short Form 7a. Scores are summarized as mean values, and the standard deviation and confidence interval are calculated. Changes are also summarized as effect size. This study is being conducted as a double-blind, placebo-controlled trial, with half of the patients receiving the active drug and the other half receiving a placebo. This trial is being conducted in accordance with the International Conference on Harmonisation of Registration of Pharmaceuticals for Human Use (ICH) guidelines on Good Practices for the Use of Medicinal Products. All patients will provide written informed consent to participate in the study before screening.

[0196] Inclusion Criteria The Fukuda Criteria and the International Consensus Criteria (ICC) for the Diagnosis of ME / CFS were applied as inclusion criteria in this study.

[0197] The ICC for diagnostic ME is presented in the Journal of Internal Medicine (International Consensus Criteria, ICC, Carruthers et al (2011) Volume 270, Issue 4 Pages 295-400) (49), and is an update of the previously used Fukuda (Fukuda et al (1994) Annals of Internal Medicine; 121:953-959) (50) and Canadian Criteria (Carruthers et al (2003) Journal of Chronic Fatigue Syndrome 11(1):7-115). (51).

[0198] Patient group The patients will be recruited in the United States, initially consisting of 80 women aged 18 to 70.

[0199] Exclusion criteria Drugs known / determined not to interfere with oxaloacetate are not permitted. The drugs that were not permitted were antiepileptic or antipsychotic drugs.

[0200] Patients who have abused active substances, pregnant women, women of childbearing age who are not taking birth control pills, and patients with abnormal laboratory parameters deemed clinically significant (e.g., Hb, white blood cell count, electrolytes, liver and kidney function tests, TSH, T4, B12, folic acid) are not accepted.

[0201] Unstable therapies are not acceptable, but stable therapies are. A stable therapy is defined as one that was initiated at least six months prior to the study and remained unchanged throughout the study period. An example of such a therapy is treatment with antidepressants. Other stable therapies using hypnotics and anxiolytics were also acceptable if they were administered at the doses recommended by the manufacturers.

[0202] Furthermore, analgesics such as NSAIDs, acetylsalicylic acid, paracetamol, and duloxetine, as well as stable antihypertensive therapy, are acceptable. Acute or chronic medications for other medical conditions are acceptable on a clinical basis.

[0203] The use of over-the-counter (OTC) medications may be permitted occasionally at the discretion of the principal investigator.

[0204] Whether it's an over-the-counter (OTC) or prescription drug, pay attention to all concomitant medications.

[0205] The clinical trial provides an example of a novel use of oxaloacetate, specifically for treating cognitive and muscle fatigue in patients with myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS).

[0206] Sixty-nine patients with ME / CFS were enrolled in a clinical trial. Three dose levels of oral oxaloacetate were investigated. ·500mg twice daily (BID) N=22, mean disease time 6.7 years, 68% female ·1,000mg twice daily (BID) N=25, average disease time 5.7 years, 80% female • 1,000 mg three times daily (TID), N=22, mean disease duration 9.1 years, 86.4% female.

[0207] Figure 2 shows a graph of the results for measurable fatigue versus dose level and time.

[0208] All dose levels showed a significant reduction in fatigue over two weeks, as measured by the validated Calder fatigue scale. Equally important, continuous dosing of oxaloacetate further reduced fatigue. Mean fatigue reductions ranged from a 15.3% reduction from baseline fatigue over two weeks at the low dose of 500 mg BID to a 17.5% reduction at the high dose of 1,000 mg TID, demonstrating improvement with higher doses. Over six weeks, mean improvements ranged from a 21.9% reduction in fatigue at 500 mg BID to a 30.2% reduction at 1,000 mg BID.

[0209] No serious adverse effects were recorded in the study. Four patients experienced indigestion, which was resolved by taking oxaloacetate with food. One patient experienced insomnia, which was resolved by shifting the medication schedule from dinner to breakfast and lunch.

[0210] Historical data from ME / CFS patients were used as a placebo comparison. (Cho HJ, Hotopf M, Wessley S. The placebo response in the treatment of chronic fatigue syndrome: a systematic review and meta-analysis. Psychosom Med 2005;67(2):301-13.) The placebo effect of oral placebo-assisted fatigue treatment in ME / CFS patients was measured using the Calder Fatigue Scale, and the placebo effect was shown to be 5.9%. Many other studies have shown that the placebo effect in ME / CFS patients is very small. 76.8% of patients in the study improved compared to previous placebo treatments. The average improvement observed with oxaloacetate ranged from 3 to 5 times that of previous placebo treatments, indicating that oxaloacetate is effective in treating pathological fatigue in ME / CFS.

[0211] Based on the data from this study, a commercially available "medical food" product containing 500 mg of oxaloacetate capsules was launched by the inventors. Further information can be found at http: / / OxaloacetateCFS.com.

[0212] Example 13 A cancer patient with recurrent stage 4 glioblastoma multiforme experienced significant fatigue as part of the ongoing disease. Although the cancer persisted, daily administration of 6,000 mg of oxaloacetate improved the cancer-related fatigue to the same extent as the disease's resolution. The patient continued this dosage for one year without any significant adverse events.

[0213] Pathological fatigue is common in cancer, making the use of oxaloacetate to alleviate fatigue in cancer patients an unexpected and novel application.

[0214] Example 14 A cancer patient with stage 2 primary prostate cancer experienced severe fatigue. Daily administration of 1,000 mg of oxaloacetate improved the pathological fatigue. The patient has been free from pathological fatigue for four years and continues to receive the same dosage. No side effects were observed in this patient with this dosage.

[0215] Example 15 A cancer patient with stage 4 primary hepatocellular carcinoma experienced severe fatigue and was hospitalized due to cancer progression. The patient started oxaloacetate at a dose of 3,000 mg per day and noticed a significant reduction in fatigue. The patient was able to continue this dose for 10 months without side effects.

[0216] Example 16 A cancer patient with stage 4 breast cancer experienced pathological fatigue. She started taking oxaloacetate at a dose of 1,000 mg per day and noticed a significant reduction in fatigue after 3 days. The patient was able to continue taking oxaloacetate for 2 years.

[0217] Example 17 A cancer patient with stage 3 colon cancer experienced pathological fatigue. He started taking oxaloacetate (500 mg BID) at a dose of 1,000 mg per day and noticed a significant reduction in fatigue. The patient remained fatigue-free, his cancer went into remission, and he never experienced fatigue again.

[0218] Example 18 Patients with Alzheimer's disease experienced significant muscle and mental fatigue. Certificates from patients' caregivers / daughters / healthcare professionals indicate that oxaloacetate significantly reduces patients' mental and physical pathological fatigue. The certificates are shown below. My name is Christine Peterson. I am the founder and CEO of HealthActivator. I was looking for ways to treat my mother, who had been diagnosed with Alzheimer's disease. My literature review indicated that calorie restriction was one possible treatment, but this did not seem like an appealing course of action for my mother. I learned from Alan Cash's research that oxaloacetate works to mimic calorie restriction without interfering with my mother's diet. I started giving my mother the commercially available "benaGene" that I obtained from Mr. Cash. After taking 2 grams / day (20 capsules per day) of oxaloacetate for 3 months, the following positive events were observed: Her memory and mood have improved. For example, she now remembers to thank me occasionally and apologizes when necessary. This is a new development, as such behavior had disappeared for over a year. She also started drawing lines on the dates on her wall calendar again, something she hadn't done in a while. These are just a few examples. She is simply getting better overall, not a huge change, but it is important to me as her caregiver and makes my life so much easier. A month later, I noticed the following changes: • I have a good memory of where things are. • I remember future events well. • I've become less angry (probably due to the confusion). • Express gratitude and apologies frequently as needed (I used to stop doing this). • Be mindful of the needs of others. • I've become able to enjoy myself without my help. • Individual hygiene awareness has improved. These things are difficult to measure, but since I see her every day, I can notice the difference. I can hear her voice better, and she's often more like she used to be. Two years after she started taking oxaloacetate (benaGene), she regressed, so I stopped the treatment. This didn't cure her Alzheimer's, but taking benaGene delayed her entering memory care by 24 months, and our family was able to save at least $18,000. I was undoubtedly able to help my mother with oxaloacetate (benaGene) thanks to the research by Alan Cash, which showed that oxaloacetate acts as a mimic of calorie restriction, and calorie restriction is known to improve Alzheimer's disease. Sincerely, Christine Peterson Date: September 21, 2015 TIFF0007882855000002.tif19170

[0219] The above example demonstrates effectiveness in reducing pathological mental fatigue.

[0220] Example 19 A patient diagnosed with fibromyalgia experienced significant fatigue. Upon starting oxaloacetate, she noticed improvement with two 100mg capsules of oxaloacetate per day. She increased the dosage to six capsules per day and found a more than 50% improvement in fatigue.

Claims

1. A pharmaceutical for treating disease-related debilitating fatigue in a subject, comprising a therapeutic dose of an oxaloacetate compound, wherein the subject has a disease selected from the group consisting of cancer, COVID-19, myalgic encephalomyelitis / chronic fatigue syndrome, fibromyalgia, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer's disease, and pneumonia.

2. The pharmaceutical product according to claim 1, wherein the oxaloacetate compound is an anhydrous enol-oxaloacetate.

3. The pharmaceutical product according to claim 1, wherein the oxaloacetate compound is selected from the group consisting of enol-oxaloacetate, keto-oxaloacetate, hydrated oxaloacetate, and oxaloacetate salts.

4. The pharmaceutical product according to any one of claims 1 to 3, wherein the oxaloacetate compound is administered in a dose of about 100 mg to about 6,000 mg.

5. The pharmaceutical product according to any one of claims 1 to 4, wherein the oxaloacetate compound is administered in a dose of about 200 mg to about 3,000 mg.

6. The pharmaceutical product according to any one of claims 1 to 5, wherein the oxaloacetate compound is administered once, twice, or three times a day.

7. A pharmaceutical product according to any one of claims 1 to 6, wherein an oxaloacetate compound is present in the pharmaceutical composition.

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