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 January 14, 2021, the entire contents of which are incorporated herein by reference.

[0002] 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, amyotrophic lateral sclerosis (ALS), Parkinson's disease, other diseases and trauma, and combinations thereof. Related therapeutic methods and pharmaceutical compositions are also disclosed. [Background technology]

[0003] Physiological fatigue is familiar to most people and is mainly due to exercise, i.e. the inability to continue exercising at the same intensity, resulting in reduced 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, disturbed 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 greater than tiredness (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 is not improved by bed rest and can be exacerbated by physical or mental activity.

[0004] Physiological fatigue is caused by neurological changes, calcium level changes, decreases in blood flow and oxygen levels, ATP energy levels and glycogen levels, as well as increases in intracellular metabolites such as H+, lactate, Pi and ROS, 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). Most importantly, these physiological changes are reversed by rest.

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

[0006] A specific example of this includes the disorder Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME / CFS). Because ME / CFS can be triggered by many different insults to the body, the disorder is based on the ongoing symptoms rather than the cause of the disorder. The disorder is characterized by persistent fatigue and other specific symptoms that last for a minimum of six months in adults (and three months in children or adolescents), and the fatigue is not relieved by bed rest. The disease is also referred to as Systemic Exercise Intolerance Disease (SEID), Post-Viral Fatigue Syndrome (PVFS), and Chronic Fatigue Immune Dysfunction Syndrome (CFIDS).

[0007] Patients with ME / CFS have persistent and debilitating fatigue, diffuse musculoskeletal pain, sleep disorders, neuropsychiatric symptoms, and cognitive impairments such as brain fog that cannot be explained by an underlying medical condition. The symptoms of ME / CFS are not caused by ongoing exercise and are not relieved by rest.

[0008] ME / CFS is a symptom-based or clinical diagnosis without distinguishing between physical or routine laboratory findings. Although infectious, immunological, neuroendocrine, sleep and psychiatric mechanisms have been investigated, a unified etiology of ME / CFS remains unclear. The majority of ME / CFS cases begin suddenly, usually with a "flu-like illness," but a significant proportion of cases begin within a few months of severe adverse stress (Afari N et al(2003),Am J Psychiatr 160(2):221-36). There is often a course of remission and relapse of symptoms that makes the disease difficult to manage. People who feel well for a period of time may become overactive, which can result in relapse of the disease and worsening of symptoms.

[0009] Viral infections have been causally implicated in cases of ME / CFS. 40% of people infected with the coronavirus SARS had chronic fatigue after infection, and 27% of these patients met the Centers for Disease Control and Prevention criteria for ME / CFS. 11% 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 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, in fact, 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 treatments 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 status 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 disease itself. Fatigue persists even when the cancer is no longer present and the patient is not undergoing chemotherapy.

[0011] ME / CFS often occurs together with other disorders such as fibromyalgia (FM), multiple chemosensitivity, irritable bowel syndrome and temporomandibular joint disorders. In particular, comorbidity with fibromyalgia has been studied (Afari N et al, supra). Fibromyalgia is a non-rheumatoid arthritis syndrome characterized by myalgia and multiple focal muscle tender points (trigger points) to palpation. Patients with FM often experience muscle pain that is exacerbated by inactivity or exposure to cold. The condition is often associated with common symptoms such as sleep disturbance, fatigue, stiffness, headaches, anxiety, perceived stress and occasionally depression.

[0012] Despite contrasting definitions, 20-70% of patients with fibromyalgia also meet criteria for chronic fatigue syndrome, and conversely, 35-70% of patients with a chronic fatigue syndrome-like illness have concurrent fibromyalgia (Afari N et al, supra).

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

[0014] Many patients suffering from ME / CFS experience significant functional impairment. Nearly all patients with ME / CFS, in addition to other undesirable consequences of the illness, notice a decrease in social relationships, about one-third are unable to work or study, and a further one-third are only able to work part-time (Afari N et al, supra). Many patients suffering from ME / CFS also experience depressive symptoms and are diagnosed with clinical depression, and similarly, patients suffering from depression often experience symptoms of debilitating fatigue.

[0015] Currently, patients with ME / CFS are treated with cognitive behavioral therapy (CBT) or graded exercise therapy (GET), which have shown moderate effectiveness 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, drugs play a minor role in disease management (Van Houdenhove B et al (2010) Expert opinion on pharmacotherapy 11(2):215-23).

[0016] Additionally, 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 infection 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 cytostatic therapy, depression, and combinations thereof. None of these fatigues are from overexertion of muscle tissue, and rest does not provide a cure for this type of fatigue.

[0017] Muscle fatigue is easily remedied by rest, allowing nutrients to be taken up by the muscles and waste products such as lactate to be removed by normal cellular processes. In fatigue due to injury, whether due to viral or bacterial infection, trauma, disease or other cellular attack, the cellular metabolic changes do not necessarily reset after providing energy for the body's defense / repair. The inability of the metabolism to reset to a normal state results in continued mental and physical fatigue, which can persist for years even after the original injury to the body has been resolved.

[0018] Various metabolic mechanisms are turned on by damage to the body, and these ongoing metabolic changes can cause persistent fatigue if not reprogrammed back to a normal metabolic state. One such metabolic change is increased glycolysis in the cytoplasm of cells. Using a very ancient metabolic feature, cells can increase their consumption of glucose and ferment glucose in the cytosol to lactate to increase energy production over that produced by mitochondria alone. Typically, in unstressed healthy cells, mitochondria burn glucose by oxidative phosphorylation rather than fermenting glucose in the cytosol. Burning glucose in mitochondria is much more efficient than fermentation in the cytosol and creates less toxic end products. However, stressed unhealthy cells often turn to increased glycolysis / fermentation for extra energy when it is perceived to be needed. This metabolic shift was first described by Otto Warburg in 1930 and is named the "Warburg effect." Warburg described a metabolic energy shift associated with cancer cells, and in fact, almost all cancers exhibit this change in energy metabolism. However, Otto Warburg believed that once a cell has changed to this different way of producing energy, it cannot change back to a normal cell. This change in energy pathways can lead to pathological fatigue. (Warburg O. On the origin of cancer cells. Science. 1956;123(3191):309-14).

[0019] The Warburg effect is not only present in cancer cells, but also in adaptive immune cells of the myeloid and lymphoid lineages, 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 shows this shift towards 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 seen in fatigued patients is a decrease in the ratio of the pyridine nucleotide nicotinamide adenine dinucleotide (NAD+) to its reduced state NADH in the cytoplasm, also known as a change in cellular "redox". NAD+ levels in cells act as a signaling molecule that drives specific metabolic states. A review of the importance of NAD+ levels to 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 of this, Graham et.al (1978) found that muscle NAD+ levels decreased with exercise at 65% and 100% of maximal oxygen uptake (VO2max), and that increased muscle water accounted for approximately 73% of this decrease, but NAD+ levels were still reduced 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 reduced 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] Yet another metabolic change that occurs in response to cellular stress / injury is the translocation of the protein complex nuclear factor kappa light-chain-enhancer of activated B cells (NF-κB) from the cytoplasm to the nuclear compartment. This translocation allows for interaction with chromatin and the production of inflammatory proteins for tissue defense / repair. This response is important to keep us healthy, but in some people, such as COVID-19 patients with long-haul symptoms, the response is not shut off and cellular energy is constantly tied up in 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).Alterations in this inflammatory pathway may lead to persistent fatigue and are found 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 most of the energy during normal cellular function. Increased energy demands to fight infection and repair tissues can increase the production of reactive oxygen species (ROS) in mitochondria and impair mitochondrial function. Mitochondrial dysfunction has been implicated in 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] Yet another metabolic change that occurs in response to cellular stress / injury is a decrease in activation of the AMPK protein and the resulting decrease in glucose uptake by tissues. This has been seen directly in cells 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 decrease in fuel available to 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 in an "off-label" manner. Each of these drugs has significant side effects. For example, for each of these drugs, animal reproduction studies have shown adverse effects on the fetus, and there are no adequate and well-controlled studies in humans on fatigue (world wide web at drugs.com / condition / fatigue.html January 5, 2020).

[0025] Caffeine has often been touted to improve cognitive attention (Repantis D, Bovy L, Ohla K, Kuhn S, Dresler M. Cognitive enhancing 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 has minimal effects on muscle performance (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 reported improved endurance in bench press exercise but 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 decrease muscle fatigue in normal cells with fatigue stimulated by muscle overuse by an electrical 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 resulting from viral infection, bacterial infection, disease or trauma, as the fatigue from those conditions is different from the muscle fatigue seen from simple muscle overuse.

[0027] Thus, there is a great need for, and thus the provision of, novel therapies and treatments for alleviating physical and mental fatigue symptoms following tissue damage due to viral infection, bacterial infection, trauma, cancer, and other diseases remains a matter of substantial interest in the art.

[0028] The use of oxaloacetate is disclosed in U.S. Pat. No. 9,050,306, U.S. Pat. No. 9,561,199, U.S. Pat. No. 10,016,385, U.S. Pat. No. 10,137,099, and U.S. Patent Application Publication No. 20190321315A1, 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 aspects, 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 amount 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, fatigue associated with cancer with or without cytostatic treatment. In some embodiments, the oxaloacetate compound is anhydrous enol-oxaloacetate. In some embodiments, the oxaloacetate is comprised of the group of enol-oxaloacetate, keto-oxaloacetate, hydrated oxaloacetate, or oxaloacetate salt. 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 agent is administered at a dose of about 100-6,000 mg. In some embodiments, the oxaloacetate agent is administered at a dose of 200 mg-3,000 mg. In some embodiments, the oxaloacetate agent is administered once, twice, or three times daily. In some embodiments, the oxaloacetate compound is in a pharmaceutical composition.

[0031] In some aspects, the present invention provides a method for treating one or more symptoms of a disorder characterized by debilitating fatigue in a subject, comprising administering to the subject a therapeutic amount of a compound to reverse metabolic dysfunction, the dysfunction being selected from the group consisting of increased glycolysis, chronic activation of NF-kB, decreased NAD+ / NADH ratio, mitochondrial dysfunction, decreased activation of AMPK, 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 salt. 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, debilitating fatigue associated with Parkinson's disease, debilitating fatigue associated with Alzheimer's disease, multiple sclerosis, and post-cancer fatigue. In some embodiments, the oxaloacetate compound is administered at a dose of about 100 to about 6,000 mg. In some embodiments, the oxaloacetate compound is administered at a dose 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 in a pharmaceutical composition. [Brief description of the drawings]

[0032] [Figure 1] Figure 1 shows the results of treatment of COVID-19 fatigue with oxaloacetate. Statistical analysis was performed by Student's T-test. [Diagram 2] Figure 1 shows the results of treatment of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME / CFS) with oxaloacetate. Statistical analysis was performed by Student's T-test. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0033] It is an object of the present disclosure to provide new and effective treatments for patients suffering from disorders characterized by persistent and debilitating pathological fatigue.

[0034] It is an object of the present disclosure to provide a pharmaceutical agent for use in treating said patient.

[0035] Another object of the present disclosure is to provide a method for treating a disorder characterized by debilitating fatigue in a patient in need thereof.

[0036] These and other objects apparent to one skilled in the art from this disclosure are met by the different aspects of the invention as claimed in the appended claims and generally disclosed herein.

[0037] The inventors have unexpectedly found that the clinical outcome of treating disorders characterized by debilitating pathological fatigue can be significantly improved by restoring multiple metabolic pathways to normal (pre-injury) function.Therefore, as a therapeutic method, strategies, compounds or combinations of compounds that modify metabolism in the following pathways also treat pathological fatigue: 1) Improvement of abnormal energy production by reversing the "Warburg effect", reducing glycolysis and decreasing the fermentative production of lactate in the cytoplasm of cells. 2) Increasing the NAD+ / NADH levels in the cell makes NAD+ more available so that cytoplasmic lactate can be converted back to pyruvate. The NAD+ level is 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 the protein nuclear factor kappa light-chain-enhancer of activated B cells (NF-kB) from the cytosol to the nucleus to stop or reduce the production of inflammatory responses and cytokine storms. 4) Increased mitochondrial biogenesis, as well as higher mitochondrial density, could provide a greater capacity to process incoming glucose and replace damaged mitochondria. 5) Activation of 5' adenosine monophosphate-activated protein kinase (AMPK), an enzyme involved in energy homeostasis that activates the uptake and oxidation of glucose and fatty acids when cellular energy is low. Increased glucose uptake provides additional fuel to cells.

[0038] The method of treatment may involve one or more of the identified modifications to the metabolism to ameliorate pathological fatigue. Strategies, compounds or combinations of compounds to achieve this method of treatment 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 can also be part of a salt, such as sodium oxaloacetate or magnesium oxaloacetate. Enol-oxaloacetate is also known as hydroxyfumarate. Other names for oxaloacetate include oxaloacetic acid, 2-oxosuccinic acid, ketosuccinic acid, oxosuccinic acid, 2-ketosuccinic acid, butanedioic acid, oxo-, oxaloacetate, butanedioic acid, 2-oxo-, 2-oxo-butanedioic acid, oxaloethanoic acid, NSC77688, UNII-2F399MM81J, alpha-ketosuccinic acid, EINECS ... 206-329-8, MFCD00002592, OAA, CHEBI:30744;2F399MM81J, 2-ketosuccinate, ketosuccinate, oxaloethanoate, a-ketosuccinate, 2-oxosuccinate, 4cts, alpha-ketosuccinate, a-ketosuccinate, 3-carboxy-3-oxopropanoic acid, oxaloacetic acid, oxaloacetate, oxobutanedioate, 2-oxobutanedioic acid, oxaloacetate(2-), oxosuccinate, keto-oxaloacetate, 149-63-3, butanedioic acid, oxo-, ion(2-), oxoacetic acid dianion, oxobutanedioic acid, ion(2-).

[0040] Oxaloacetate supplementation affects the following dysfunctional metabolic pathways that can be treated by the metabolic treatments identified above for the improvement of pathological fatigue. Specifically, these dysfunctional metabolic pathways are outlined below: 1) Abnormal energy production due to increased glycolysis in the "Warburg effect". Cells from individuals with disabling fatigue show abnormal energy production, with energy being produced in the cytoplasm by increased glycolysis and fermentation. Oxaloacetate has been shown to reverse this trend, decreasing both glycolysis and the formation of lactate. Our 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 neither clear nor suggested by cellular studies, nor does it represent a surprising novel finding. 2) Cells 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, reduce inflammation and stimulates neurogenesis. Hum Mol Genet. 2014; 23(24): 6528-41). Our efforts to reverse the NAD+ / NADH ratio have been shown 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 is not clear or suggested by the preclinical studies. Other literature shows that oxaloacetate supplementation increases NAD+ and decreases NADH, but the effect on fatigue is not clear or suggested by the literature, and does not represent a surprising novel finding. 3) Reduction of NF-kB inflammation. Cells from humans with disabling fatigue show increased activation of NF-kB, which leads to a "cytokine storm." Oxaloacetate has been shown to reduce NF-kB 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-kB pathway with oxaloacetate supplementation was found, the effect on fatigue was not evident or suggested by animal studies. 4) Mitochondrial damage is common in fatigued patients. Oxaloacetate turns on biomolecular pathways that lead 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 effect of increased mitochondria on fatigue was not expected or suggested in the prior art. 5) Decreased AMPK activation. Cells from individuals with disabling fatigue show impaired ability to activate AMPK and impaired stimulation of glucose uptake. Oxaloacetate has been shown to increase glucose uptake in clinical trials in diabetic and Alzheimer's patients (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 was not clear from clinical trials. Furthermore, the work done in diabetic patients would not be used to treat ME / CFS patients or other fatigue sufferers.

[0041] The "Warburg effect" refers to a form of altered cellular metabolism often seen in cancer cells, but also in other cells that tend to use specialized fermentation of pyruvate to lactate in the cytoplasm rather than the aerobic respiratory pathway that burns pyruvate in the mitochondria used by most cells in the body under non-pathological conditions. Fermentation does not produce adenosine triphosphate (ATP) in high yields compared to the oxidative phosphorylation of the citric acid cycle and aerobic respiration, but it converts such nutrients to biomass more efficiently by avoiding the unnecessary catabolic oxidation of nutrients such as glucose and glutamine to carbon dioxide, preserving carbon-carbon bonds, and facilitating 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 highly advantageous for the body in recovering from a pathological event, but at the conclusion of the event (such as the end of an infection), if it is not switched off, it can affect fatigue levels. Patients with chronic fatigue syndrome have been shown to activate this alternative energy pathway and increase the amount of energy produced by glycolysis in the cytosol following 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 redox state of the cell.

[0043] Nuclear factor kappa light-chain-enhancer of activated B cells (NF-κB) is a protein complex located mostly in the cytoplasm of cells under non-stress conditions. Upon activation by a stress event (such as infection), NF-κB translocates to the nucleus where it controls DNA transcription, leading to cytokine production. NF-κB plays an important role in regulating the immune response to infection.

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

[0045] Thus, in an aspect of the disclosure, an oxaloacetate agent for treating pathological fatigue is provided, said oxaloacetate being 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 of oxaloacetate detailed herein

[0046] According to one embodiment, the oxaloacetate agent for use in the treatments described herein is in the pure oxaloacetate form.

[0047] According to one embodiment, the oxaloacetate agent for use in the treatments described herein is in the form of a pharma- ceutically acceptable salt thereof.

[0048] The use and preparation of oxaloacetate agents are described in U.S. Patent Nos. 10,137,099, 10,016,385, 9,561,199, and 9,050,306.

[0049] As mentioned above, oxaloacetate agent can be a pharmaceutically acceptable salt.The term "pharmaceutically acceptable salt" as used herein means the 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 salt includes the salt of the basic group present in the compound of the present invention.

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

[0051] In one embodiment, the administration of oxaloacetate is at a dose of about 100 to about 6,000 mg per day, the dose depending on both the severity of fatigue and the time the body is in a pathologically fatigued state. In some embodiments, the dose of oxaloacetate is at about 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 about 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 per day.

[0052] In one embodiment, the administration of oxaloacetate is titrated at a lower starting dose of about 100 to about 400 mg per day and increased to about 1,000 to about 6,000 mg per day. In one embodiment, the administration of oxaloacetate is titrated at a lower starting dose of about 100 mg, about 200 mg, about 300 mg, or about 400 mg per day and increased to about 1,000, about 2000 mg, about 3000 mg, about 4000 mg, about 5000 mg, or about 6,000 mg per day. Some patients with altered metabolism associated with fatigue may have problems sleeping when initially taking large doses of oxaloacetate, as they may have problems dissipating the excess energy they receive from oxaloacetate, causing restless sleep. These patients may be titrated up at a lower dose, for example 200 mg / day, held until the sleep pattern stabilizes at a minimum number of hours, then increased to a higher level and held again until the sleep pattern stabilizes at a minimum number of hours. This dosage increase procedure may be repeated to increase the dosage multiple times, and may be particularly important in ME / CFS patients who have been fatigued for several years.

[0053] In one embodiment, the dose of oxaloacetate is administered at about 1,000 mg to about 3,000 mg per day, and then reduced to a "maintenance dose" of about 100 to about 300 mg per day. In one embodiment, the dose of oxaloacetate is administered at about 1,000 mg, about 2000 mg, or about 3,000 mg per day, and then reduced to a "maintenance dose" of about 100 mg, about 200 mg, or about 300 mg per day. Discontinuation of the highest dose, e.g., 1,000 mg / day, of oxaloacetate may be indicated if a patient-derived fatigue questionnaire, such as the Chalmers Fatigue Questionnaire, Fatigue Severity Scale, or PROMISE Fatigue Short Form 7A, indicates a decrease in fatigue that correlates with normal levels of fatigue seen in normal control groups. Fatigue can then continue to improve with lower dose maintenance levels, e.g., 200 mg of oxaloacetate per day. Maintenance doses may be particularly important to prevent the recurrence of the pathological fatigue observed in some patients.

[0054] In order to obtain high patient compliance, i.e., the degree to which patients follow medical advice accurately, it is generally believed that treatment regimens should not be complicated so that patients can easily follow them. For example, it may be preferable that the administration of drugs is once, twice or three times a day, for example twice or once a day. Thus, in one embodiment, oxaloacetate is provided for use as described herein, said oxaloacetate is administered once, twice or three times a day, for example once or twice a day. For clarity, oxaloacetate dosage may be orally administered twice a day, for example at a dosage of 500 mg, to obtain a daily dosage of 1,000 mg. It will be understood that said oxaloacetate may be administered at different 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 disturbance 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 lasting at least 6 months, diffuse musculoskeletal pain, sleep disturbance, neuropsychiatric symptoms and cognitive impairment. ME / CFS often occurs together with other diseases such as fibromyalgia (FM), multiple chemosensitivity, irritable bowel syndrome and temporomandibular joint disorder. In addition, several other disorders are also characterized by disabling fatigue. A non-limiting list of such diseases 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, post-viral fatigue, post-bacterial infection fatigue, and combinations thereof.Furthermore, fatigue may be associated with cancer with or without cytostatic treatment.Physical trauma may also cause fatigue that may be improved with oxaloacetate agents.Those skilled in the art will understand that the disorder characterized by disabling fatigue may be a fatigue disorder or a pain disorder.

[0056] Thus, in one embodiment there is provided an oxaloacetate agent as described herein for use in the treatment of a disorder characterized by persistent and debilitating fatigue, said 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, post-viral fatigue, post-bacterial fatigue, post-bacterial fatigue and fatigue associated with cancer with or without cytostatic treatment, depression and combinations thereof.

[0057] In one embodiment, the fatigue disorder is characterized by at least one of the conditions 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 of the conditions 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 disorders, such as 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 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 appreciate that the embodiments described above in relation to the first aspect of the disclosure are equally relevant and applicable to multiple aspects disclosed herein.

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

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

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

[0062] In one embodiment, a pharmaceutical composition as described herein is provided that comprises oxaloacetate in an amount of about 100 mg to about 6,000 mg, e.g., about 200 to about 3,000 mg, e.g., about 500 mg to about 1,000 mg. In some embodiments, a pharmaceutical composition as described herein is provided that comprises oxaloacetate in an amount of about 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. In some embodiments, the pharmaceutical composition comprises any of about 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 mentioned 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, where the medicament is formulated for oral administration, the pharmaceutical composition comprises about 100 mg to 6,000 mg, e.g., 200 to 3,000 mg, e.g., about 500 mg to 1,000 mg, of oxaloacetate. In some embodiments, the pharmaceutical composition formulated for oral administration comprises about 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 of oxaloacetate. In some embodiments, a pharmaceutical composition formulated for oral administration contains between about 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 of oxaloacetate.

[0065] When the medicament is formulated for subcutaneous or intramuscular administration, it may be preferable that the administered dose corresponds to about half of the oral dose. Thus, in one embodiment where the medicament is formulated for subcutaneous or intramuscular administration, the pharmaceutical composition comprises about 50 mg to 3,000 mg, such as 100 to 1,500 mg, such as 250 mg to 500 mg of oxaloacetate. In some embodiments, the pharmaceutical composition formulated for subcutaneous or intramuscular administration comprises about 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, 1000 mg, 2000 mg or 3000 mg of oxaloacetate. In some embodiments, a pharmaceutical composition formulated for subcutaneous or intramuscular administration contains either about 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 of oxaloacetate.

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

[0067] In one embodiment, there is provided a pharmaceutical composition formulated as a pill, tablet, capsule, dragee, liquid, gel capsule, syrup, slurry or suspension, such as a pill.

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

[0069] In a further aspect of the disclosure, there is provided the use of an oxaloacetate agent as defined herein for the manufacture of a medicament for the treatment of a disorder characterized by persistent and debilitating fatigue, such as those disclosed herein.

[0070] Pharmaceutical Compositions Pharmaceutical Preparations and Methods of Administration Oxaloacetate can be administered to an individual in a therapeutically effective dose 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 infection fatigue, bacterial infection fatigue, and combinations thereof.

[0071] As used herein, "oxaloacetate or OAA" includes oxaloacetic acid, acid salts, or oxaloacetate in buffered solutions, anhydrous enol-oxaloacetate, enol-oxaloacetate in solution, keto-oxaloacetate in solution, hydrated oxaloacetate in solution, and mixtures thereof. It also includes synonyms of oxaloacetate as provided herein.

[0072] Effective Dose A therapeutically effective dose refers to that amount of oxaloacetate sufficient to produce a desired effect, such as amelioration of symptoms associated with fatigue.

[0073] The toxicity and therapeutic efficacy of oxaloacetate are discussed, for example, in LD 50(a dose lethal to 50% of the population) and ED 50 The dose that is therapeutically effective in 50% of the population can be determined by standard pharmaceutical procedures in cell cultures or experimental animals. The dose ratio between toxic and therapeutic effects is the therapeutic index, and the LD 50 / ED 50 The LD of oxaloacetate can be expressed as 50 exceeds 5 g / kg body weight. The "No Observable Adverse Effect Level" (NOAEL) in a 90-day subchronic rat study was 500 mg / kg (the highest dose tested). Oxaloacetate has very low toxicity, as would be expected from a chemical involved in the citric acid cycle in all cells.

[0074] A toxicological study of oxaloacetate on rats conducted in Japan in 1968 showed that a level of 83 mg / kg body weight of oxaloacetate caused changes in the pancreatic islets. Some islets were reduced in size and hyperemic, and the alpha cells were atrophic, while the beta cells were enlarged and stained darker. At a lower dose of 41 mg / kg body weight, a proportion of the pancreas demonstrated only islet cell proliferation and hyperplasia. The liver, pituitary, adrenal glands and gonads showed no particular changes (Yoshikawa, Anti-diabetic effect of sodium oxaloacetate, 1968 Tohoku Journal of Experimental Medicine).

[0075] Doses of anhydrous enol-oxaloacetate up to 6,000 mg / day in patients for one year have not resulted in negative side effects.

[0076] An example of an effective dose of oxaloacetate administered by intravenous injection is about 0.5 mg to about 1 g of oxaloacetate per kg of body weight. In a preferred embodiment, the effective dose of oxaloacetate is about 2.0 mg to about 40 mg per kg of body weight. In some embodiments, the effective dose of the oxaloacetate compound is about 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 continuously. Effective oral dosing similarly ranges from about 0.5 mg to about 1 g of oxaloacetate per kg of body weight, with a preferred effective dosage range of about 2 mg to about 40 mg of oxaloacetate per kg of body weight. For example, an adult male weighing about 80 kg is orally administered about 150 mg to about 3.5 g of oxaloacetate per day. For skin, topical formulations containing oxaloacetate at concentrations of about 0.5 to 16 mM are effective. Caloric restriction (CR) studies have shown that restricting calories every other day produces the same beneficial results as daily CR. Similarly, in some embodiments, oxaloacetate is administered every other day, as the anti-fatigue effects persist 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 according to the present invention can be formulated in a conventional manner using one or more physiologically acceptable carriers or additives.Thus, oxaloacetate and its physiologically acceptable salts and solvates can be formulated for administration by inhalation or insufflation (either through the mouth or nose) or by oral, buccal, topical, transdermal, parenteral, or rectal administration.

[0078] Oxaloacetate is acidic. The acidity is unlikely to affect the organism that ingests the compound in beneficial amounts, since the internal conditions of the stomach are also very acidic. The acidity may affect other tissues, including but not limited to the skin or lungs, that can benefit from direct application of oxaloacetate. Thus, in another embodiment, the composition of matter can be made by mixing oxaloacetate with a buffer solution or base, or can be used as a salt of oxaloacetate, so that the compound delivered is not caustic. This allows a higher concentration of oxaloacetate to be safely delivered to the organism, especially when oxaloacetate is not delivered by oral ingestion.

[0079] For oral administration, the pharmaceutical composition may take the form of a tablet or capsule prepared by conventional means with pharma- ceutically acceptable additives, such as binders (e.g., pregelatinized maize starch, polyvinylpyrrolidone, or hydroxypropylmethylcellulose), 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, non-aqueous solutions, syrups, or suspensions, or may be provided as a dry product for constitution with water or other suitable vehicle (due to concerns about decarboxylation) immediately prior to use. Water acts as a catalyst to allow the conversion of solid enol-oxaloacetate to liquid keto-oxaloacetate form, which spontaneously decarboxylates to pyruvate and carbon dioxide. Such non-aqueous liquid preparations may be prepared by conventional means using pharma- ceutically acceptable additives, such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats), emulsifying agents (e.g., lecithin or acacia), non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils), preservatives (e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid), etc. The preparations may also contain buffer salts, flavoring, coloring and sweetening agents as appropriate.

[0080] Absorption of oxaloacetate from the gut increases oxaloacetate levels throughout the organism, but the immediate exposure of oxaloacetate to cells of the gut allows it to preferentially contact gut cells, allowing for a reduction in gastric diseases such as colon cancer, even if the intake of oxaloacetate is insufficient to provide benefit to the organism as a whole.

[0081] Preparations for oral administration can be suitably formulated to give controlled release of active compound.For buccal administration, the composition can take the form of tablets or lozenges formulated in conventional manner.For administration by inhalation, the compound for use according to the present invention is conveniently delivered in the form of aerosol spray from pressurized pack or nebulizer using suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.For pressurized aerosol, dosage unit can be determined by providing a valve to deliver a metered amount.Capsules and cartridges of, for example, gelatin for use in inhaler or insufflator can be formulated to contain a powder mix of the compound and a suitable powder base, for example, 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 can include several types of pharmaceutical or cosmetic carrier systems, including, but are not limited to, solutions, emulsions, gels, and solids. The topical pharmaceutical and cosmetic compositions of the present invention formulated as solutions typically include a pharma- ceutically acceptable organic solvent. The term "pharmaceutical acceptable organic solvent" refers to a solvent in which oxaloacetate can be dissolved and which has acceptable safety characteristics (e.g., irritation and sensitization properties). Examples of suitable pharma- ceutically 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 the present disclosure are formulated as aerosols and applied to the skin as a spray, a propellant is added to the solution composition.

[0083] The type of product that can be formulated from the solution carrier system is a cream or ointment. The ointment can include a simple base of animal or vegetable oil or semi-solid hydrocarbon (oleaginous). The ointment can include about 0.1% to about 2% of a thickening agent. Examples of suitable thickening agents include cellulose derivatives (e.g., methylcellulose and hydroxypropylmethylcellulose), synthetic high molecular weight polymers (e.g., carboxyvinyl polymers and polyvinyl alcohol), vegetable hydrocolloids (e.g., karaya gum and tragacanth gum), clay thickeners (e.g., colloidal magnesium aluminum silicate and bentonite), and carboxyvinyl polymers (CARBOPOLS.RTM, available from 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 thickening agents 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 comprises 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, although other types can be used.

[0084] The emulsion carrier system useful for the topical pharmaceutical and cosmetic compositions of the present 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 mono fatty acid (commercially available under the trade name Tween) or other non-ionic material, and about 7% to about 20% water. This carrier system is combined with the above-mentioned therapeutic agent, and oxaloacetate is carried in the non-aqueous portion.

[0085] The topical pharmaceutical and cosmetic compositions of the present disclosure may also include a safe and effective amount of a penetration enhancer.Other conventional skin care 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, soybean saponin, 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, pantothenic acid, vitamin D, and mixtures thereof may be used.

[0086] In yet further embodiments of the invention, topically delivered oxaloacetate can be mixed with a penetration enhancer, such as dimethylsulfoxide (DMSO), a combination of sucrose fatty acid esters with sulfoxides or phosphate oxides, or eugenol, which allows for faster movement of oxaloacetate into the skin tissue and then into deeper cellular tissues.

[0087] In one embodiment, the disclosed compounds are administered through a topical delivery system. Implantable or injectable polymer matrices and transdermal formulations that slowly release active ingredients are also well known and can be used in the disclosed methods. The above-mentioned controlled release components can be used as a means to deliver the disclosed compounds. The composition can further include components adapted to improve the stability or effectiveness 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, which are 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 to complex or absorb oxaloacetate. Controlled delivery can be achieved by selecting appropriate polymers such as polyesters, polyamino acids, polyvinylpyrrolidones, ethylene vinyl acetate, methyl cellulose, carboxymethyl cellulose and protamine sulfate, the concentrations of these polymers and the method of incorporation are selected to control the release of the active compound.

[0089] In another embodiment, transdermal patches, steady-state reservoirs sandwiched between an impermeable backing and a membrane surface, and transdermal formulations can also be used to deliver oxaloacetate. Transdermal delivery systems are well known in the art. Occlusive transdermal patches for administration of active agents to the skin or mucosa are described in U.S. Pat. Nos. 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 through which the active ingredient diffuses into the skin. Such transdermal patches are described in U.S. Pat. Nos. 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 at a dose of about 2 mg to 40 mg per day.

[0090] Current transdermal patch systems are designed to deliver smaller doses over extended periods of time, up to several days to several weeks. A rate-controlling outer microporous membrane, or micropockets of the disclosed oxaloacetate dispersed throughout a silicone polymer matrix, can be used to control the release rate. Such rate-controlling 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 about 20 to 30 minutes or less.

[0091] These transdermal patches and formulations can be used with or without the use of penetration enhancers such as dimethylsulfoxide (DMSO), sucrose fatty acid esters in combination with sulfoxides or phosphates, or 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. Patent Nos. 5,474,527, 5,336,168 and 5,328,454, the entire contents of which are incorporated herein by reference.

[0092] Oxaloacetate may be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. Injected oxaloacetate may be mixed with other beneficial agents prior to 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, the immediate contact of high levels of oxaloacetate with vascular cells results in a reduction in age-related diseases, such as arterial hardening. Injectable formulations may be provided in unit dosage form, for example, in ampoules or multi-dose containers, with added preservatives. The compositions may take the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing, and / or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, for example, sterile pyrogen-free water, immediately before use.

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

[0094] In addition to the above-mentioned preparation, oxaloacetate can also be formulated as long-acting preparation.Such long-acting preparation can be administered by implantation (for example, subcutaneous or intramuscular) or intramuscular injection.Thus, for example, compound can be formulated with suitable polymer or hydrophobic material (for example, as emulsion in acceptable oil) or ion exchange resin, or as poorly soluble derivative, for example as poorly soluble salt. The composition may be, if desired, in a pack or dispenser device that may contain one or more unit dosage forms containing the active ingredient. The pack may, for example, comprise 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 can be either formulated as part of the animal's food or administered separately as a supplement to the animal's food. As 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 the main ingredient, there are typically one or two grains, commonly corn, wheat and / or rice. In addition, for protein sources, they may contain poultry meal, by-product meat, meat and bone meal, or other animal or fish meal by-products. Sometimes, grain protein supplements such as corn gluten, soybean meal or other oilseed meal can also be added. In addition to an effective amount of oxaloacetate of about 0.01% to 0.1% by weight of the chow, the animal chow of the present invention further comprises: typical nutrient contents in the food dry matter include crude protein of 14% to 50%, usually 20% to 25%, crude fat of 5% to 25%, crude fiber is usually present in the range of about 3% to 14%, usually about 5% to 7%, and total minerals or ash is in the range of 3% to 10%, usually 4% to 7%. The important point is not the exact formulation of the pet food, as many conventional satisfactory ones are available on the market for use in combination with the present invention. Rather, the key to success is the addition of sufficient oxaloacetate components to the pet food ration, whatever formulation is used, to provide the range of oxaloacetate activity levels required for AMPK activation to aid in the prevention or treatment of disorders involving pathological fatigue in animals.

[0096] Clinical outcome measures As described in the Examples section below, the clinical outcome of administering an oxaloacetate agent to a subject suffering from a disorder described herein can be assessed by the following tests and questionnaires. Those skilled in the art will recognize the applicability of these tests for the assessment of fatigue and depression-related symptoms.

[0097] As used herein, the term "Clinical Global Impressions" (CGI) refers to a rating scale commonly used to measure symptom severity, treatment response and treatment effectiveness in treatment studies of patients with psychiatric disorders (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 Global Impression of Change" (CGI-C) (also known as the Clinical Global Impression-Improvement (CGI-I)) scale is a 7-point scale that requires clinicians to rate how much a patient's illness has improved or worsened compared to the baseline condition at the start of an intervention. Ratings are as follows: 1, very much improved; 2, much improved; 3, very little improved; 4, no change; 5, slightly worse; 6, much worse; or 7, very much 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 outcome of the treatment can be assessed using the FF scale, the Beck / BDI scale, the VAS pain scale and by neuropsychological testing.

[0101] As used herein, the term "FF scale" or "FF" refers to the fibromyalgia and chronic fatigue syndrome rating scale, also known as the fibromyalgia and chronic fatigue syndrome rating scale, described by Zachrisson and co-workers (Zachrisson O, et al, (2002) J Psychosom Res Jun;52(6):501-9). The fibromyalgia and chronic fatigue syndrome rating scale is an observer rating scale with 12 items that measure the subjective experience of pain, muscle tension, fatigue, difficulty concentrating, memory impairment, irritability, sadness, sleep disturbance, as well as autonomic neuropathy and irritable bowel, headache and infection.

[0102] As used herein, the terms "Beck / BDI scale" and "BD" refer to the Beck Depression Inventory, created 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 inventory and is one of the most widely used instruments for measuring the severity of depression. The BDI questionnaire is designed for individuals aged 13 years and older and consists of items related 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 lack of interest in 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 characteristic. The VAS scale is a psychometric response scale and is often used in questionnaires. It is a measurement instrument for subjective characteristics or attitudes that cannot be measured directly. When responding to a VAS item, the respondent specifies their level of agreement with a statement by indicating their location along a continuum between the two end points.

[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, but not necessarily, a set of tasks or problems that the respondent must solve, and the respondent's maximum performance must be measured.

[0105] As used herein, the term "Chalder Fatigue Scale" refers to a 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 a 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) that 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. (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, 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 recognize and know how to use the tests used herein. Any deviations from standard calculation procedures are explained 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 populations are the same against an alternative hypothesis, in particular that certain populations tend to have larger values ​​than other populations.

[0112] Two-way interaction analysis (also known as two-way analysis of variance (ANOVA)) is a test 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 effect of each independent variable, but also to assess whether there is any interaction between them.

[0113] Three-way interaction analysis (three-way analysis of variance (ANOVA)) is a test to examine whether there are two-way interactions that vary across the levels of a third variable.

[0114] Spearman's rank correlation coefficient is a nonparametric measure of statistical dependence between two variables. It evaluates how well the relationship between two variables can be described using a monotonic function. In the absence of repeated data values, a perfect Spearman correlation of +1 or -1 occurs when each of the variables 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 a Student's t-distribution under the null hypothesis. A 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 recognize that various modifications can be made and elements thereof can be substituted with equivalents without departing from the scope of the present invention. Accordingly, the present invention is not limited to any particular embodiment contemplated, but rather the invention is intended to include all embodiments that fall within the scope of the appended claims.

[0117] definition For purposes of interpreting this specification, the following definitions shall apply, and where appropriate, terms used in the singular shall include the plural and vice versa. In the event that a definition set forth below conflicts with any document incorporated herein by reference, the definition set forth shall control.

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

[0119] As used herein, the terms "comprising," "having," "containing," and "including," as well as their grammatical equivalents, are intended to be equivalent in meaning and open-ended in that the item or items following any one of these words are not meant to be an exhaustive enumeration of such item or items, or are not limited to only the item or items listed. For example, an article "comprising" components A, B, and C can consist of (i.e., contain only) components A, B, and C, or can contain not only components A, B, and C, but also one or more other components. Thus, "comprising" and similar forms thereof, as well as grammatical equivalents, are intended and understood to include disclosure of embodiments that "consist essentially of" or "consist of."

[0120] Where a range of values ​​is provided, unless the context clearly dictates otherwise, it is understood that each intervening value, to the tenth of the unit of the lower limit between the upper and lower limits of that range, and any other stated or intervening value within that stated range, is encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure.

[0121] The term "about" as used herein refers to the normal error range of each value, which is readily known to those skilled in the art. Reference to "about" a value or parameter herein includes (and describes) an embodiment that is directed to the value or parameter itself. For example, the description "about X" includes the description of "X".

[0122] As used herein, "treatment" or "treating" is an approach to obtain beneficial or desired results, including clinical results. For purposes of the present invention, beneficial or desired clinical results include, but are not limited to, one or more of the following: alleviation of one or more symptoms caused by the disease, reduction in the extent of the disease, stabilization of the disease (e.g., preventing or slowing the progression of the disease (e.g., metastasis), preventing or slowing the recurrence of the disease, slowing or slowing the progression of the disease, improving the condition of the disease, providing remission (partial or total) of the disease, reducing the dose of one or more other drugs required to treat the disease, slowing the progression of the disease, improving or improving the quality of life, increasing weight gain, and / or prolonging survival. The methods of the present invention contemplate any one or more of these aspects of treatment.

[0123] As used herein, the term "prophylactic treatment" refers to treatment in which an individual is known to have or suspected to have, or is at risk of having, a disorder, but does not exhibit symptoms or minimal symptoms of the disorder. An individual receiving prophylactic treatment may be treated prior to the onset of symptoms.

[0124] As used herein, "combination therapy" means that a first agent is administered in conjunction with another agent. "In conjunction with" refers to administering one therapeutic modality in addition to another therapeutic modality, for example, administering the composition of nucleated cells described herein in addition to administering the immunoconjugate described herein to the same individual. Thus, "in conjunction with" refers to administering one therapeutic modality before, during, or after the delivery of the other therapeutic modality to an individual.

[0125] As used herein, the term "co-administration" means that the first and second therapies in a combination therapy are administered at a time interval of about 15 minutes or less, such as about 10, 5, or 1 minute or less. When the first and second therapies are administered at the same time, the first and second therapies can be contained in the same composition (e.g., a composition that includes both the first and second treatments) or in separate compositions (e.g., the first therapy in one composition and the second therapy are contained in another composition).

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

[0127] As used herein, the term "co-administration" means that the administration of a first therapy and a second therapy in a combination therapy overlap with each other.

[0128] As used herein, "pharmacologically acceptable" or "pharmacologically compatible" means a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. A pharma-ceutically acceptable carrier or excipient preferably meets the required standards of toxicological and manufacturing testing and / or is included in the Inactive Ingredients Guide prepared by the U.S. Food and Drug Administration.

[0129] Exemplary embodiments Embodiment 1. A method of treating one or more symptoms of a disorder characterized by debilitating fatigue in a subject, comprising administering to the subject a therapeutic amount of an oxaloacetate compound, 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, fatigue associated with cancer with or without cytostatic treatment.

[0130] Embodiment 2. The method of embodiment 1, wherein the oxaloacetate compound is anhydrous enol-oxaloacetate.

[0131] Embodiment 3. The method of embodiment 1, wherein the oxaloacetate is comprised of the group of enol-oxaloacetate, keto-oxaloacetate, hydrated oxaloacetate, or an oxaloacetate salt.

[0132] Embodiment 4. The method of 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 of any one of embodiments 1 to 4, wherein the oxaloacetate agent is administered at a dose of about 100 to 6,000 mg.

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

[0135] Embodiment 7. The method of any one of embodiments 1 to 6, wherein the oxaloacetate agent is administered once, twice or three times daily.

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

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

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

[0139] Embodiment 11. The method of 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 of embodiment 10 or 11, wherein the oxaloacetate compound is anhydrous enol oxaloacetate.

[0141] Embodiment 13. The method of 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 of any one of embodiments 10 to 13, wherein the oxaloacetate compound is administered at a dose of about 100 to about 6,000 mg.

[0143] Embodiment 15. The method of any one of embodiments 10 to 14, wherein the oxaloacetate compound is administered at a dose of about 200 mg to about 3,000 mg.

[0144] Embodiment 16 The method of any one of embodiments 10-15, wherein the oxaloacetate compound is administered once, twice, or three times daily.

[0145] Embodiment 17 The method of any one of embodiments 9 to 16, wherein the compound for reversing metabolic dysfunction is in a 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, of course, should not be construed as limiting its scope.

[0147] Example 1. Parkinson's patients have significant fatigue. It is their number one complaint. Here is some text taken from the Parkinson:Org website, the leading organization for Parkinson's patients resolving Parkinson's fatigue, on January 5, 2020: Does a person with Parkinson's disease (PD) or their family member feel physically or mentally exhausted? Could this be fatigue? Deep tiredness that does not improve with rest. Nearly half of people with PD report fatigue as their main problem, and a third say fatigue is their most disabling symptom. Fatigue is distinct from sleepiness, however, a fatigued person may feel exhausted but not necessarily want to sleep. Fatigue is common early in the course of PD but can occur at any time and can occur whether motor symptoms are mild or severe. It can be confused with other symptoms that can make a person sleepy or tired, such as sleep problems or pain. Fatigue is also a symptom of depression, but a person can be fatigued without being depressed. Stress can make fatigue worse. No specific cause has been shown to cause fatigue in PD. Motor symptoms such as tremor and stiffness may contribute to muscle fatigue. However, fatigue may also have causes other than Parkinson's disease. It is important to identify and treat non-PD-related diseases or drugs that cause fatigue. The exhaustion associated with fatigue can cause people to reduce time at work or retirement, or avoid social activities. Understanding fatigue as a symptom of drug-induced PD and finding ways to address it is essential to maintain a good quality of life. Symptoms · Physical fatigue: Feeling extremely tired or worn out may be exacerbated by "off" fluctuations. Mental fatigue: Mental fatigue that makes it difficult to concentrate. Therapy Few therapies have been tested for fatigue in PD. None have been proven effective for fatigue alone. Motor symptom therapies do not appear to help fatigue.

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

[0149] The present inventors have set up a series of early case studies to investigate the effects of oxaloacetate on Parkinson's disease. Several of the case study participants reported reduced fatigue with the use of "benaGene", an oxaloacetate dietary supplement manufactured and distributed by the present inventors. Testimonials from such individuals are shown below: Dear Alan, I will try to answer all your questions as clearly as possible. I take benaGene at breakfast and dinner, so they are about 10-12 hours apart, and I take magnesium at about the same time as the benaGene. The Mg2+ is in oxide form, and each capsule has 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 see a neurologist (beginning in early fall 2009) because I felt like I was having memory problems beyond the normal age-related memory loss. This presented a great challenge, as I was a faculty member at KU and had taught cardiovascular pharmacology for many years. I noticed that my speech was becoming very halting and slow, as I was searching for words. At about the same time, I began to have violent muscle twitches while sleeping. This phenomenon is known as REM Sleep Without Atonia (RSWA) or REM Sleep Paraactivity, which is being studied by scientists at the Mayo Clinic in Minnesota. As I recall, the next problem that presented itself was a significant disruption of visuo-spatial coordination, which convinced Eli that I needed to stop driving. My balance was also worsening, and I fell several times. So in December 2009, I went to the neurology clinic at the medical center, thinking I might have Alzheimer's. The neurologist was an expert on Alzheimer's, and I wondered if Alzheimer's was 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 who specializes in movement disorders. Although he did not think that the symptoms were very severe at that point, he put me on Sinemet (4 tablets per day) (100mg L-DOPA, 25mg carbidopa), a commonly used drug that contains levodopa and carbidopa, and that treatment certainly seemed to help me maintain better balance for a while. However, I began to develop 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 could not read my handwriting and had great difficulty grasping silverware and eating. The neurologist continued to increase my dose of Sinemet I (up to 7 tablets / day), but the 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 up to 8 Sinemet tablets / day and still had not achieved any improvement.On April 14th I visited the neurologist and he was convinced that I would definitely need a walker as I could only stand for 2.3 seconds without leaning back into my chair. Eli had been reviewing the literature on PD and had drawn attention to the idea that mitochondrial dysfunction is a major contributor to the pathogenesis of PD. He also knew that magnesium has a very beneficial effect in animal models of various central nervous system problems and may counter abnormal calcium surges in neurons. A neurologist friend who studies mitochondria alerted him to Oxaloacetate and Terra Biologicals. So on May 9, 2011, I started taking benaGene and magnesium along with Sinemet (7.5 tablets / day). After 4 weeks on the benaGene / Mg combination, my balance and posture had improved enough for me to consider going to a scientific conference in Europe again, something that would have been completely impossible before this treatment regimen was started. Both my balance and flexibility improved. The tremor gradually began to subside and had subsided almost completely by the time of my return from Europe (early August). Both the tremor and vision problems had subsided to the point where I was able to abandon my voice-activated computer programs. The improvement in visuospatial function allowed me to start driving a car by the end of August. I am now able to type on the computer, attend meetings with my research staff, and work on scientific papers. I am continuing the same benaGene / Mg regimen and Sinemet 7 tablets / day. I hope this gives a good picture of the reversal of many PD symptoms with benaGene / Mg treatment. If you have any further questions, please feel free to contact me. Mary

[0150] As can be seen, this person experienced improvement in pathological muscle fatigue and reduced tremors that may result from muscle fatigue. A single patient's testimony is important, especially in a disease such as Parkinson's disease, where there is no cure. However, to better examine efficacy, the inventor then conducted a retrospective study of the effect of the dietary supplement benaGene (a combination of 100 mg oxaloacetate and 150 mg vitamin C) on the inventor's customer base, including some Parkinson's disease patients. Each participant with Parkinson's disease was asked to complete a 39-question "Parkinson's Quality of Life (PDQ)" survey (PDQ-39) and score their past Parkinson's disease status before taking benaGene (oxaloacetate) and then again after taking benaGene for at least three months. Pre / post data was received from 13 customers and the scores were tallied.

[0151] 53.8% of people with Parkinson's disease taking benaGene (oxaloacetate) responded well with an improvement in quality of life as measured by a pre- and post-PDQ-39 survey. Among patients who responded well, the improvement in quality of life was greater than 50%, with some patients showing up to 90% cessation of symptoms, including pathological fatigue. Improvements in quality of life include improvements in fatigue.

[0152] Example 2 Based on the findings of the present inventors, a clinical trial was carried out 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 a valid method for clinically measuring pathological fatigue in patients with Parkinson's disease. The fatigue questions were as follows: 1.13 Fatigue Over the course of a week, have you generally felt tired? This feeling is not part of sleepiness or sadness. 0: Normal: No fatigue 1: Minor: Fatigue occurs, but it doesn't interfere with doing things or being with people. 2: Mild: Fatigue makes it slightly difficult to do things or be with people. 3: Moderate: Fatigue causes a lot of trouble doing things or being with people, but it doesn't stop you from doing anything. 4: Severe: Fatigue prevents you from doing things or being with people.

[0153] Twenty-six patients completed the phase 2 study, 13 patients in the placebo group and 13 patients in the oxaloacetate group.

[0154] Our initial data to support clinical trials in Parkinson's patients came from our "benaGene" study discussed in Example 1 herein. benaGene is a dietary supplement of 100 mg oxaloacetate and 150 mg ascorbic acid (vitamin C) in a vegetable capsule shell. As it was not known whether the benefits seen in Example 1 above were due to ascorbic acid or oxaloacetate, ascorbic acid (vitamin C) was chosen as a placebo at 250 mg, but the active substance tested was a 100 mg oxaloacetate / 150 mg ascorbic acid capsule (benaGene).

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

[0156] After 4 months, the oxaloacetate group showed a statistically significant improvement in fatigue problems on the MDS-UPDRS scale over 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 non-significant P value of P=0.71.

[0157] 200mg of oxaloacetate has been clinically proven to significantly reduce pathological fatigue in a double-blind, placebo-controlled clinical trial of Parkinson's disease patients using oxaloacetate supplied by the present inventor. 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% continued to have long-term pathological fatigue. (Mandal S, Barnett J, Brill SE, Brown JS, Denneny EK, Hare SS, et al.'Long-COVID': a cross-sectional study of persisting symptoms, biomarker and imaging abnormalities following hospitalization for COVID-19. Thorax. 2020). Experts in the field of pathological fatigue have detailed their own experiences with significant persistent pathological fatigue after COVID-19. A physician contracted COVID-19 and experienced extreme fatigue after the resolution of the viral infection. Her fatigue was measured using a validated fatigue measurement survey 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 6 weeks, her fatigue had resolved. Her scores are shown in Table 1 below. TIFF2024503435000002.tif48170

[0159] The physician provided the inventor with a testimony of her experience: I took a trial of Oxaloacetate because I had been suffering from extreme fatigue for a few weeks. I was skeptical at first because of the nausea it caused, but decided to go ahead and I have to say I am glad I did. By the end of the 6 weeks, my energy was through the roof and I have never felt so happy, motivated, energized or clear-headed. My life has improved for the better. Thank you! LI

[0160] Extreme fatigue after COVID-19 can take up to several months to resolve (if at all), so for clinicians to completely reverse severe fatigue in a period of less than six weeks is an unexpected and novel event.

[0161] Example 4 A physician client of the present inventor used 5 capsules of benaGene (oxaloacetate) BID on a patient with post-COVID-19 infection pathological fatigue. The physician provided this report to the present inventor: I just received a positive report from a 50 year old woman who survived COVID-19 but remained debilitated with post-viral fatigue that lasted for 4 months. I had her try benaGene [AEO] and within 3 days she said the effects were dramatic. Yesterday she was feeling as if she was back to her pre-COVID self. I have asked her to update me again in a month. I will let you know how she is after taking benaGene / hydroxyfumarate a little longer.

[0162] The inventors checked in with the physician after 30 days to confirm the patient. Physician's report: She is still going strong....she is the wife of another MD.

[0163] It is unexpected and novel that 4-month-long post-COVID-19 fatigue can be improved within 3 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. The fever then dissipated, but she experienced extreme fatigue and had difficulty walking to the bathroom. She began taking 500 mg of anhydrous enol-oxaloacetate BID for 45 days. Within 3 days, 80% of the fatigue had resolved. After 30 days, 100% of the fatigue had resolved.

[0165] The reduction in post-COVID-19 fatigue by 80% after 3 days and 100% after 30 days is unexpected and novel.

[0166] Example 6 Patients with amyotrophic lateral sclerosis (ALS) commonly 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 has been conducted by the inventors supplying the anhydrous enol-oxaloacetate drug. Typically, Phase 1 clinical trials focus on the safety of the proposed drug, but the efficacy of patient response is also important and noted. We present two testimonials from patients who saw improvement in pathological fatigue in patients who were 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 14th, 2020. I was offered this clinical trial of Oxaloacetate at 1500mg twice daily for 28 days by Dr. Jawdat. Going into the trial, my symptoms included slurred speech, my tongue was not working well, and my left hand and arm were noticeably atrophied. I had muscle fasciculations at times, almost all over my body, almost all the time. The first 4-5 days of taking the supplement, it felt like it intensified 1-2 hours after taking it, and it lasted about 1 or 2 hours. After 4 or 5 days, it went back to normal strength. About the third week of taking the supplement, I started to notice that my tongue movement had a better range of motion. I could see my tongue pushing out the side of my cheek, where it never got there before. I also felt like my left hand had gained a little strength, a better grip, and I felt like I had a little strength in my left wrist. However, I feel like most things are still declining, but because I have been trying the supplements for so short a time, I want to keep taking them to see if I can continue to improve / change. I am not currently taking any ALS medications, but I am taking some vitamins. Patient 2. My husband, Nathan, was part of a study with oxaloacetate for ALS. When he started the supplement [1500 mg oxaloacetate BID], we did not expect a big difference. However, within a few days, he was feeling much better. Before taking oxaloacetate, he had a hard time getting out of bed and was always tired. He worked during the day but slept in a recliner most nights. After a week on the drug, my 18-year-old son commented that his dad was waking up at night and talking to him. He said that whatever he was doing was making a big difference. It really shocked me. With the trial over, we returned to Nathan struggling to get up and move. My children and I talk almost daily about how we feel oxaloacetate has made a positive difference in 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) commonly 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 has been 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 evidence that they have observed improvement in muscle fatigue in patients who were taking 1000 mg of anhydrous enol-oxaloacetate BID. Hello, my name is Matthew Grzesik. I recently participated in the TOALS study at the KU ALS Clinic. Specifically, I was in the first group of the 2000mg dose. Typically, I had to get 2-4 long sleeps a day to combat the constant fatigue from ALS, and also moderate how much physical activity I did to keep from exhausting myself. I was only 28 years old and a competitive powerlifter as well as a strength and conditioning coach, so limiting my physical activity was difficult for me. I was planning to renovate my lawn while participating in the study and was trying to take my time, so I didn't push myself. About a week into the study, I noticed that my energy levels were much higher than they had been in over a year, 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, eventually dropping to zero. It felt like a gift to feel that good for that month. The only side effect I noticed was an upset stomach when I took the dose without food, which went away as soon as I ate something. While I want more oxaloacetate so I can continue to take it and enjoy as much life as possible, I also wanted to share something positive with you all. I appreciate the time and thoughtfulness of working with Dr. Jawdat on this study. I look forward to seeing how this supplement can benefit others, whether they have ALS or other diseases.

[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 did not experience any decline in function and had stable fatigue / muscle function after 8 months of supplementation. This is surprising and welcome news, since for ALS, the expected rate of decline over this period 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 Email: "Hi Alan, I am writing to ask for more oxaloacetate for my husband, Darrell. He has been taking the drug since May 2021 and has not experienced any loss of mobility or strength. We are very pleased! Can we have some more? Thank you!"

[0174] Example 8 The inventors have provided anhydrous enol-oxaloacetate for post-pneumonia fatigue. Pneumonia patients often suffer from physiological fatigue. In a retrospective study of 506 adults with clinical and radiological evidence of pneumonia, 51% of patients suffered from 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). Below is a testimonial from a patient who found benefit from 500 mg of oxaloacetate daily. I resumed taking oxaloacetate immediately after being released from the hospital and skilled nursing care. The biggest difference oxaloacetate made for me was in relieving the crushing fatigue associated with pneumonia. The American Lung Association indicates that the basis of fatigue is not understood, and the scientific literature certainly does not demonstrate any solid understanding of the biological causes of fatigue. The fatigue I experienced can only be described as "crushing." Example: Shortly after being released to go home, I got in the car (not driving) to drop someone off at the airport, stopped for lunch afterwards, and found myself completely exhausted and needing two full days to recover. When I queried nurses and physiotherapists about this response, the universal answer was "typical." Speaking to people who had pneumonia at different ages (which I acknowledge was anecdotal), I got consistent stories of extreme fatigue and slow recovery that took years to reach previous energy levels, even in teenagers who were physically active at the time. I was in the hospital for 2 weeks and then in skilled care for about 6 weeks, putting me in the 40% of the population that doesn't avoid hospitalization, however, I wasn't in the ICU so I wasn't in the worst situation. When I took the first Oxaloacetate capsule, I felt immediate relief from a sensation I hadn't even realized I had -- a heavy, oppressive feeling in the center of my chest. The sensation went away, never to return. For the first few months, I chose to take multiple capsules throughout the day. Oxaloacetate immediately boosted my energy levels and enabled me to work from home. I found that if I went to the office, I could function fine for a few hours, and when I did get fatigued, Oxaloacetate would keep me from collapsing too quickly. Of course, there is no way to determine whether the use of oxaloacetate accelerated my recovery, but I can tell you with certainty that it played a remarkable role in making the recovery process less painful.

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

[0176] Example 9 A phase 2 trial to treat mental and physical fatigue in breast cancer survivors with an oxaloacetate agent is currently underway, helping to inform methods of treating pathological mental and physical fatigue in cancer patients. In the trial, fatigue is assessed by the Multidimensional Fatigue Symptom Inventory. Scores are summarized as means, and standard deviations and confidence intervals are calculated. Changes are also summarized as effect sizes.

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

[0178] Exclusion criteria: · Have 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 would interfere with cognitive function, such as medications for sleep, narcotics for anxiety, pain, illegal drugs or cannabis use. Participants cannot be receiving any other investigational drugs. History of allergic reactions caused by compounds with a similar chemical or biological composition to oxaloacetate. Uncontrolled intercurrent illness, including but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina, cardiac arrhythmias, or psychiatric / social conditions that would limit compliance with study requirements Pregnant or lactating women are excluded from this study because the safety of oxaloacetate in this setting is unknown. Pregnancy testing will be performed on all women with an intact uterus and ovaries who are not determined to be postmenopausal.

[0179] Primary outcome measures: 1. Change in Functional Assessment of Cancer Therapy-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. Response rates are further characterized using point estimates and 95% exact binomial confidence intervals.

[0181] Secondary outcome measures: 1. Incidence of adverse events [Time frame: up to 57 days] Adverse events will be assessed using the Common Terminology Criteria for Adverse Events version 4.

[0182] 2. Fatigue [Timeframe: Day 57] Fatigue will be assessed by the Multidimensional Fatigue Symptom Inventory. Scores will be summarized as means, and standard deviations and confidence intervals will be calculated. Changes will also be summarized as effect sizes to support the design of future clinical trials.

[0183] 3. Insomnia [Timeframe: Day 57] Insomnia severity index. Scores will be summarized as means, with standard deviations and confidence intervals calculated. Changes will also be summarized as effect sizes to support the design of future clinical trials.

[0184] 4. Depressive symptoms [Time frame: Day 57] Patient-reported outcome measures will be assessed by the Patient-Reported Outcome Measures Information System. Scores will be summarized as means, and standard deviations and confidence intervals will be calculated. Changes will also be summarized as effect sizes to support the design of future clinical trials.

[0185] 5. Neurocognitive testing [Time frame: up to day 57] Subjects will be assessed with the California Verbal Learning Test-2nd Edition, Brief Visuospatial Memory Test-Revised, Golden Stroop, Rail Making Test, Verbal Fluency, and Conners Continuous Performance Test-II. All scales listed have individual scores transformed by using published normative data, so that the units of measurement are the same for the tests listed, and higher scores indicate better performance.

[0186] The clinical trial provides an example of how the drug oxaloacetate can be used to treat cognitive and muscle fatigue in breast cancer patients, 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 by the Calder Fatigue Scale, Fatigue Severity Scale, and PROMIS Fatigue Short Form 7a. Scores are summarized as means, with standard deviations and confidence intervals calculated. Changes are also summarized as effect sizes. The study is being run as a double-blind, placebo-controlled trial, with half of the patients receiving the active drug and the other half receiving a placebo. The trial is being conducted in compliance with the International Conference on Harmonization (ICH) guidelines on Good Clinical Practice (GCP). All patients provided written informed consent to participate in the study before screening.

[0188] Inclusion Criteria: 4.1.1 Women with resolved primary COVID-19 infection at least 2 months after having evidence of viral resolution as measured by rRT PCR. 4.1.2 No evidence of active / recurrent COVID-19 or other severe chronic illness. 4.1.3 Have significant fatigue complaints defined as a bimodal score of 4 or greater on the Fatigue Questionnaire. 4.1.4 Be geographically accessible or able to complete the forms virtually and be able to participate in the study of 6-10 week duration. 4.1.5> 18 years of age and under 65 years of age. 4.1.6 Ability to complete assessment surveys in English. 4.1.7 The effect of oxaloacetate on the developing human fetus at the recommended therapeutic dose is unknown. For this reason, women of childbearing potential must agree to use appropriate contraception (barrier birth control methods; IUDs; abstinence) prior to and during study participation. Women of any age who have had their ovaries and / or uterus removed are not at risk for pregnancy and do not require contraception. If a woman becomes pregnant or suspects she is pregnant while participating in this study, she should inform the study physician immediately. Menopausal status is established as follows: women aged 55 years or older who are not menstruating are considered postmenopausal and not at risk for pregnancy. Women under 55 who are menstruating are considered premenopausal and require contraception. Women under 55 who have an intact uterus and ovaries, are not menstruating, and have not had a menstrual period within the past two years have FSH and estradiol measured. If the values ​​are in the postmenopausal range, the woman is considered postmenopausal and not at risk for 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 Not taking oxaloacetate supplements.

[0189] Exclusion criteria: 4.2.1 Have 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 would interfere with cognitive function, such as medications for sleep, narcotics for anxiety, pain, illegal medical foods or cannabis use. 4.2.3 Participants may not be receiving any other investigational products. 4.2.4 History of allergic reactions due to compounds of similar chemical or biological composition to oxaloacetate. 4.2.5 Uncontrolled intercurrent illness, including but not limited to ongoing or active infection with COVID-19 or any other virus, symptomatic congestive heart failure, unstable angina, cardiac arrhythmias, or psychiatric / social circumstances that would limit compliance with study requirements. 4.2.6 Pregnant or lactating women are excluded from this study as the safety of oxaloacetate in this setting is unknown. Perform pregnancy testing on all women with an intact uterus and ovaries who are not determined to be postmenopausal as described in section 4.1.7.

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

[0191] Eighteen patients suffering from "long-haul" fatigue after COVID-19 for an average of 6 months were recruited into the clinical trial. Each patient received 500 mg of oxaloacetate BID orally for 6 weeks. At 6 weeks, fatigue was reduced by 45% from baseline as measured by the Calder Fatigue Scale (P<0.005). Other fatigue scales supported this finding. The Fatigue Severity Scale showed a 15% reduction in fatigue from baseline (P<0.005). The Visual Analog Fatigue Scale showed a 56% reduction (P<0.05). The PROMIS Fatigue Short Form 7a showed a 21% reduction in fatigue compared to baseline (P<0.005). The results of the clinical trial data are shown in Figure 1.

[0192] There were no significant adverse events during the trial. These patients had been fatigued for an average of 6 months, so they meet the criteria for ME / CFS. The placebo effect for ME / CFS patients has been established as a very low effect, 5.9% as measured by the Calder fatigue score with oral medication. (Cho HJ,Hotopf M,Wessely SThe placebo response in the treatment of chronic fatigue syndrome:a systematic review and meta-analysisPsychosom Med2005;67(2):301-13.) Improvement in long-haul COVID-19 patients with persistent fatigue was 7 times higher than could be expected with a placebo in the past. Thus, oxaloacetate has been shown to be effective in treating long-haul COVID-19 residual fatigue.

[0193] Example 11 A phase 1 trial is being planned to evaluate the response of patients with myasthenia gravis fatigue treated with oxaloacetate. Fatigue will be assessed by the Calder Fatigue Scale, Fatigue Severity Scale, and PROMIS Fatigue Short Form 7a. Scores will be summarized as means, and standard deviations and confidence intervals will be calculated. Changes will also be summarized as effect sizes.

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

[0195] Example 12 A phase 2 trial is underway to evaluate the response of patients with ME / CFS. Fatigue will be assessed by the Calder Fatigue Scale, Fatigue Severity Scale, and PROMIS Fatigue Short Form 7a. Scores will be summarized as means, with standard deviations and confidence intervals calculated. Changes will also be summarized as effect sizes. The study is being run as a double-blind, placebo-controlled trial, with half of the patients receiving the active drug and the other half receiving a placebo. The trial is being conducted in accordance with the International Conference on Harmonization (ICH) guidelines on Good Clinical Practice (GCP). All patients 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 diagnosing ME was 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 population Patients will be recruited in the United States, initially including a total of 80 women aged 18 to 70 years.

[0199] Exclusion criteria Drugs that are known / determined not to interfere with oxaloacetate were not permitted. Drugs that were not permitted were antiepileptics or antipsychotics.

[0200] Patients with active substance abuse, pregnant women, women of childbearing age not taking contraceptives, and patients with abnormal laboratory parameters judged to be clinically significant (e.g., Hb, white blood cell count, electrolytes, liver and kidney function tests, TSH, T4, B12, folate) will not be admitted.

[0201] Unstable therapy is not permitted, but stable therapy is acceptable. Stable therapy is defined as having begun at least 6 months prior to the study and remaining unchanged throughout the study period. An example of such therapy is treatment with antidepressants. Other stable therapies with hypnotics and anxiolytics were also permitted if they were given at the doses recommended by the manufacturers.

[0202] Additionally, NSAIDs, analgesics such as acetylsalicylic acid, paracetamol, and duloxetine, as well as stable antihypertensive therapy are permitted. Acute or chronic medications for other medical conditions are permitted based on clinical judgment.

[0203] Occasional over-the-counter (OTC) use will be permitted at the investigator's discretion.

[0204] Be mindful of all concomitant medications, whether OTC or prescription.

[0205] The clinical trial provides an example of a novel use of oxaloacetate, a method of using the drug to treat cognitive and muscle fatigue in patients with myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS) fatigue.

[0206] Sixty-nine patients with ME / CFS were enrolled in a clinical trial that examined three dosage levels of oral oxaloacetate. ·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 time 9.1 years, 86.4% female

[0207] FIG. 2 graphically depicts the results of measurable fatigue versus dose level and time.

[0208] All dose levels demonstrated significant reductions in fatigue at 2 weeks as measured by the validated Calder Fatigue Scale. Equally important, successive dosing of oxaloacetate further reduced fatigue. Mean fatigue reductions ranged from a 15.3% reduction from baseline fatigue at 2 weeks with the low dose of 500 mg BID to a 17.5% reduction in fatigue with the high dose of 1,000 mg TID, showing improvement with higher doses. At 6 weeks, mean improvements ranged from a 21.9% reduction in fatigue with 500 mg BID to a 30.2% reduction in fatigue with 1,000 mg BID.

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

[0210] Historical data from ME / CFS patients were used as placebo comparison. (Cho HJ,Hotopf M,Wessely SThe placebo response in the treatment of chronic fatigue syndrome:a systematic review and meta-analysisPsychosom Med2005;67(2):301-13.) Oral placebo treatment of fatigue in ME / CFS patients showed a placebo effect of 5.9% as measured by the Calder Fatigue Scale. Many other studies have shown that the placebo effect in ME / CFS patients is very small. 76.8% of patients in the study improved over their previous placebo. The average of all improvements seen with oxaloacetate ranged from 3-5 times that of the previous placebo, so oxaloacetate has been shown to be effective in treating pathological fatigue in ME / CFS.

[0211] Based on the data from this study, a commercial "medical food" product providing 500 mg oxaloacetate capsules has been marketed 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 continued, taking 6,000 mg of oxaloacetate daily improved the cancer-related fatigue before the disease resolved. The patient continued on this dose for a year without any significant adverse events.

[0213] Pathological fatigue is common in cancer, so this is an unexpected and novel use of oxaloacetate to ameliorate fatigue in cancer patients.

[0214] Example 14 A cancer patient with stage 2 primary prostate cancer experienced significant fatigue. A daily dose of 1,000 mg of oxaloacetate improved the pathological fatigue. The patient has now been fatigue-free for 4 years and is continuing on the dose. This patient experienced no side effects with this dose.

[0215] Example 15 A cancer patient with stage 4 primary hepatocellular carcinoma experienced significant fatigue and was hospitalized due to progression of the cancer. The patient was started on oxaloacetate at a dose of 3,000 mg per day and noted a significant decrease 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 was started on oxaloacetate at a dose of 1,000 mg per day and noticed a significant decrease in fatigue after 3 days. The patient was able to continue the oxaloacetate dose for 2 years.

[0217] Example 17 A cancer patient with stage 3 colon cancer experienced pathological fatigue. He was started on oxaloacetate at a dose of 1,000 mg per day (500 mg BID) and noted a significant decrease in fatigue. The patient continued to be fatigue-free, with his cancer in remission and no fatigue.

[0218] Example 18 The patient with Alzheimer's disease experienced significant muscle and mental fatigue. A testimonial for the patient from the patient's caregiver / daughter / healthcare professional indicates that oxaloacetate significantly reduces the patient's mental and physical fatigue. The testimonial is 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 showed calorie restriction as one possible treatment, but this did not seem like an appealing course of action for my mother. I was led to realize by Alan Cash's research that oxaloacetate would work to mimic calorie restriction without interfering with my mother's diet. I started my mother on "benaGene," an over-the-counter product I obtained from Cash. After 3 months of taking 2 grams / day (20 capsules per day) of oxaloacetate, the following positive events were observed: · Her memory and mood have improved, for example, she now remembers to thank me from time to time and apologizes when necessary. This is new, this behavior had not existed for over a year. She also started crossing out dates on her wall calendar again, something she hadn't done in a while. These are just a few examples. She is just generally doing better, not huge changes but to me as her caregiver it is important and makes my life so much easier. After another month, I noticed the following changes: -Good at remembering where things are -Remember future events well · Less angry (probably due to confusion) - Expressing gratitude and apologizing when necessary (something I didn't do before) · Be aware of the needs of others - He can now enjoy himself without my help Improved personal hygiene These things are hard to measure, but I see her every day and can tell the difference: she sounds better and is more like the way she used to be. After 2 years on oxaloacetate (benaGene), she regressed, so I stopped the treatment. This did not cure her Alzheimer's, but putting her on benaGene delayed her entry into memory care by 24 months, saving our family at least $18,000. I was able to help my mother with oxaloacetate (benaGene) no doubt because of the work of Alan Cash, who showed that oxaloacetate acts as a mimetic of caloric restriction, and caloric restriction was known to improve Alzheimer's disease. Sincerely, Christine Peterson Date: September 21, 2015 TIFF2024503435000003.tif19170

[0219] The above examples demonstrate efficacy in reducing pathological mental fatigue.

[0220] Example 19 A patient diagnosed with fibromyalgia had significant fatigue. Upon initiation of oxaloacetate, she noticed improvement with 2 capsules of 100 mg oxaloacetate per day. She increased the dosage to 6 capsules per day and saw a greater than 50% improvement in fatigue.

Claims

1. 1. A medicament for treating one or more symptoms of a disorder characterized by debilitating fatigue in a subject, comprising a therapeutic amount of an oxaloacetate compound, 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 fatigue associated with cancer with or without cytostatic treatment.

2. The method of claim 1, wherein the oxaloacetate compound is anhydrous enol-oxaloacetate.

3. The method of claim 1, wherein the oxaloacetate is selected from the group consisting of enol-oxaloacetate, keto-oxaloacetate, hydrated oxaloacetate, or oxaloacetate salt.

4. The pharmaceutical agent according to any one of claims 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, debilitating fatigue associated with Parkinson's disease, debilitating fatigue associated with Alzheimer's disease, multiple sclerosis, and post-cancer fatigue.

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

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

7. 7. The method of claim 1, wherein the oxaloacetate compound is administered once, twice or three times daily.

8. The method of claim 1 , wherein the oxaloacetate compound is in a pharmaceutical composition.

9. 1. A medicament for treating one or more symptoms of a disorder characterized by debilitating fatigue in a subject, comprising a therapeutic amount of a compound that ameliorates a metabolic dysfunction, said dysfunction being selected from the group consisting of increased glycolysis, chronic activation of NF-kB, decreased NAD+ / NADH ratio, mitochondrial dysfunction, decreased activation of AMPK, and combinations thereof.

10. The method of claim 9, wherein the compound is an oxaloacetate compound.

11. The method of claim 10, wherein the oxaloacetate compound is selected from the group consisting of enol-oxaloacetate, keto-oxaloacetate, hydrated oxaloacetate and oxaloacetate salts.

12. The method of claim 10 or 11, wherein the oxaloacetate compound is anhydrous enol-oxaloacetate.

13. The medicament according to any one of claims 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, debilitating fatigue associated with Parkinson's disease, debilitating fatigue associated with Alzheimer's disease, multiple sclerosis, and post-cancer fatigue.

14. The method of any one of claims 10 to 13, wherein the oxaloacetate compound is administered in a dose of about 100 mg to about 6,000 mg.

15. The method of any one of claims 10 to 14, wherein the oxaloacetate compound is administered in a dose of about 200 mg to about 3,000 mg.

16. 16. The method of any one of claims 10 to 15, wherein the oxaloacetate compound is administered once, twice or three times daily.

17. The method of any one of claims 9 to 16, wherein the compound for ameliorating metabolic dysfunction is in a pharmaceutical composition.

Images