Valacyclovir and celecoxib for the treatment of Alzheimer's disease and COVID-19

Abstract

The present disclosure relates to methods of treating symptoms of Alzheimer's disease, diseases and / or conditions associated with Covid-19 infection, including Long COVID, acute post-infectious syndrome, or orthostatic intolerance, comprising administering a therapeutically effective combination of a COX-2 inhibitor and an antiviral compound.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 407,224, filed September 16, 2022, and U.S. Provisional Patent Application No. 63 / 524,391, filed June 30, 2023. The entire disclosures of the applications identified in this paragraph are incorporated herein by reference.

[0002] The present disclosure relates to methods for treating human diseases, including treating Alzheimer's disease, treating or ameliorating a disease or condition associated with SARS-CoV2 infection, and / or treating or ameliorating acute post-infectious syndrome. [Background technology]

[0003] SARS-CoV2 infection was first reported around November 2019. Since then, the virus has spread worldwide, causing the disease known as "COVID-19." Estimates suggest that 14% to 19% of COVID-19 patients develop long-term symptoms. [Logue, et al., J. Am. Med. Assoc. (2020); Garrigues et al., J. Infect. 81(6):e4-e6(2020)] This chronic condition is commonly known as "long COVID" or "long-haul COVID." Evidence suggests that long COVID is significantly underreported. Currently, there is no established FDA-approved treatment for long COVID.

[0004] Alzheimer's disease and long COVID may share similar viral etiologies and symptoms with fibromyalgia and other somatic symptom disorders. In particular, Alzheimer's disease, long COVID, and fibromyalgia present with fatigue, cognitive impairment ("brain fog"), sleep disorders, muscle weakness, pain, and mood disorders. Persistent herpesvirus infection has been theorized as a possible cause of fibromyalgia and Alzheimer's disease. Many symptoms of long COVID overlap with those of fibromyalgia and somatic symptom disorders. HSV-1 downregulates inflammatory cytokines, such as IL-1, IL-6, and TNF-α. These cytokines correlate with the onset and severity of fibromyalgia and may play a similar role in Alzheimer's disease and long COVID.

[0005] Post-acute infectious syndrome (PAIS) can be a sequela following viral or bacterial infection. PAIS can cause severe chronic fatigue, exercise intolerance, autonomic dysfunction, unrestful sleep, memory impairment, and mood changes. See Choutka, et al. (Nat Med, May 2022; 28:911-923). In some cases, PAIS can lead to complex multisystem disorders such as ME / CFS, fibromyalgia, and irritable bowel syndrome. See Komaroff, et al. (Front Med, Jan 2021; 7).

[0006] The combination of an antiviral compound (e.g., famciclovir or valacyclovir) with a COX-2 inhibitor (e.g., celecoxib) for the treatment of functional somatic syndromes (FSS) and fibromyalgia is believed to have a synergistic effect in inhibiting the virus and is described in U.S. Pat. No. 8,809,351. Summary of the Invention

[0007] In one embodiment, the method of treating a subject susceptible to or suffering from Alzheimer's disease is A method is provided for treating rheumatoid arthritis, the method comprising administering to a subject a therapeutically effective combination of a COX-2 inhibitor (which may also inhibit COX-1) and an antiviral compound.

[0008] In one embodiment, a method of treating a subject susceptible to or suffering from COVID-19, including Long COVID-19, is provided, the method comprising administering to the subject a therapeutically effective combination of a COX-2 inhibitor and an antiviral compound.

[0009] In one embodiment, a method of treating a subject susceptible to or suffering from PAIS is provided, the method comprising administering to the subject a therapeutically effective combination of a COX-2 inhibitor and an antiviral compound.

[0010] In one embodiment, a method of treating symptoms of orthostatic intolerance in a subject with PAIS is provided, the method comprising administering to the subject a therapeutically effective combination of a COX-2 inhibitor and an antiviral compound.

[0011] Further areas of applicability will become apparent from the description provided herein. This summary description and specific examples are intended for purposes of illustration only and are not intended to limit the scope of the present disclosure. [Brief explanation of the drawings]

[0012] [Figure 1] Figure 1 shows the change in PROMIS fatigue T-score from baseline for both combination therapy and SOC control at week 14. [Figure 2] Figure 2 shows the change in NRS fatigue score from baseline for both combination therapy and SOC control at week 14. [Figure 3] Figure 3 shows the change in NRS pain scale from baseline for both the combination therapy and the SOC control at week 14. [Figure 4] Figure 4 shows the PGIC response rate at 14 weeks. [Figure 5]Figure 5 shows the change from baseline in OISA, OISAS for both combination therapy and SOC control at week 14. [Figure 6] Figure 6 shows the change in OIDAS from baseline for both combination therapy and SOC control at week 14. DETAILED DESCRIPTION OF THE INVENTION

[0013] The following description is merely illustrative and is not intended to limit the present disclosure, its application, or uses.

[0014] A.Definition The term "pharmaceutically acceptable" means suitable for use in pharmaceutical preparations, generally considered safe for such use, officially approved by a national or state government regulatory agency for such use, or listed in the United States Pharmacopoeia or other generally recognized pharmacopoeias for use in animals, and more specifically in humans.

[0015] The term "therapeutically effective amount" refers to the amount of a compound that, when administered to a subject for treating a disease, is effective in treating the disease. A "therapeutically effective amount" can vary depending on the compound, the disease and its severity, the subject being treated, such as age, weight, etc.

[0016] The term "COX-2 inhibitor" refers to a cyclooxygenase-2 inhibitor, which is a pharmaceutically acceptable compound that inhibits the enzyme cyclooxygenase-2.

[0017] The term "COX-1 inhibitor" refers to a cyclooxygenase-1 inhibitor, which is a pharmaceutically acceptable compound that inhibits the enzyme cyclooxygenase-1.

[0018] The term "HSV-1" refers to herpes simplex virus type 1.

[0019] The terms "prevent," "prevention," or "preventing" refer to either preventing the onset of a preclinically evident condition altogether, or preventing the onset of a preclinically evident stage of a condition in a subject. Prevention includes, but is not limited to, prophylactic treatment of a subject at risk of developing a condition.

[0020] The term "treat" (and the corresponding terms "treatment" and "treating") includes palliative, restorative, and prophylactic treatment of a subject. The term "palliative treatment" refers to treatment that alleviates or reduces the impact or intensity of a condition in a subject without curing the condition. The term "prophylactic treatment" (and the corresponding term "prophylactic treatment") refers to treatment that prevents the occurrence of a condition in a subject. The term "restorative treatment" refers to treatment that halts the progression of a condition in a subject, reduces pathological symptoms, or completely eliminates them.

[0021] Alzheimer's disease (AD) is a medical disorder characterized by progressive neurodegeneration, severe cognitive decline, short-term memory loss, language impairment, and the inability to perform common daily tasks.

[0022] COVID-19 refers to severe acute respiratory syndrome caused by infection with the RNA virus SARS-CoV-2. "Long COVID," also known as "long-haul COVID," refers to a condition in which a subject experiences prolonged (e.g., months or years) effects of infection after recovery from initial SARS-CoV-2 infection. Such long-term effects include, but are not limited to, severe chronic fatigue that significantly interferes with daily life and is not due to continued exercise or medical condition.

[0023] The term "CFS" refers to chronic fatigue syndrome. In some embodiments, the CFS is myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS).

[0024] The term "cognitive impairment," also known as "brain fog," "mental fog," or "cognitive disability," refers to a loss or impairment of intellectual function (such as thinking, remembering, or reasoning) that is severe enough to interfere with daily life.

[0025] The terms "famcyclovir" and "famciclovir" refer to the same antiviral compound.

[0026] The terms "valacyclovir" and "valaciclovir" refer to the same antiviral compound.

[0027] The terms "acyclovir" and "aciclovir" refer to the same antiviral compound.

[0028] The term "QD" refers to once daily.

[0029] The term "BID" refers to twice a day.

[0030] The term "TID" refers to three times a day.

[0031] The term "QID" refers to four times a day.

[0032] The term PO refers to oral administration.

[0033] The term "Likert survey" (and the corresponding term "Likert scale") refers to a questionnaire that uses a 5-point scale to ask subjects to indicate the extent to which they agree or disagree with a certain statement.

[0034] The term "combination therapy" (or "cotherapy"), as used herein to define the use of an antiviral compound and a COX-2 inhibitor, is intended to encompass the sequential administration of each agent in a regimen that provides the beneficial effect of the drug combination. It is also intended to encompass the coadministration of these agents in a substantially simultaneous manner, e.g., by oral administration of a single capsule containing a set ratio of the active ingredients or by the ingestion of multiple separate capsules for each ingredient. "Combination therapy" also includes simultaneous or sequential administration by intravenous, intramuscular, or other parenteral routes, including direct absorption through mucosal tissues, such as those found in the paranasal sinuses. Sequential administration also includes drug combinations in which the individual components are administered at different times and / or by different routes, but which act in combination to provide a beneficial effect. This combination therapy of an antiviral compound and a COX-2 inhibitor is expected to result in a co-action between the antiviral compound and the COX-2 inhibitor, resulting in a pharmacokinetic or pharmacodynamic interaction, or both, and the compounds are administered simultaneously or sequentially to enable such co-action.

[0035] B. Clinical Observations The present invention is understood to encompass the treatment of Alzheimer's disease and COVID-19, including long COVID. U.S. Patent No. 8,809,351 reports that a combination of a COX-2 inhibitor and an antiviral agent (e.g., famciclovir and celecoxib, or valacyclovir and celecoxib) is useful for treating functional somatic syndromes (FSS), including but not limited to fibromyalgia, as well as the pain and related functional symptoms associated with fibromyalgia. Patients with fibromyalgia have been observed to exhibit a variety of symptoms, including but not limited to fatigue, insomnia, depression, allodynia, headache, irritable bowel syndrome, photosensitivity, numbness, and anxiety. Stress often exacerbates symptoms. While the etiology and condition of FSS are not clearly understood, a combination of interactions between external stressors, neurotransmitters, hormones, the immune system, and the sympathetic nervous system is thought to be involved. In particular, herpes viruses are hypothesized to play a major role in fibromyalgia and related functional somatic syndromes.

[0036] Many of the symptoms of fibromyalgia overlap with those of chronic fatigue syndrome (CFS), which is often misdiagnosed as CFS, which in addition to the symptoms of fibromyalgia includes sore throat, swollen lymph nodes, new headaches, difficulty thinking or remembering, and unexplained muscle pain.

[0037] Herpes viruses, including HSV-1 and HSV-2, have the unique property that after initial infection, they may remain latent in tissues until conditions are sufficient for reactivation. Physiological stressors associated with this reactivation process can trigger the synthesis and release of host peptides and hormones from the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis. These viruses rarely reactivate. Both HSV-1 and HSV-2 reactivate frequently enough to create the environment necessary for the development of chronic, debilitating disease. HSV-2 reactivates only once or twice a year, making it unlikely to cause chronic disease. However, HSV-1 reactivates frequently enough, on average four times a year and as frequently as monthly, to cause slowly developing, debilitating disease. Without wishing to be bound by theory, U.S. Patent No. 8,809,351 hypothesizes that after multiple reactivations, neuronal cell bodies die by apoptosis and ganglia are destroyed in the area that innervates the initial inoculation site.

[0038] The presence of herpesvirus in one or more ganglia can directly or indirectly affect the central nervous system (CNS), the hypothalamic-pituitary axis (HPA), and the immune system. Dysregulation of pain processing within the CNS can lead to the amplification of the perception of pain and other sensory stimuli. This phenomenon, often referred to as central sensitization or potentiation, results from changes in the properties of neurons within the CNS, such that pain is no longer linked to the presence, intensity, or duration of noxious peripheral stimuli, as is the case with acute nociceptive pain. Neurotransmitters such as glutamate, substance P, serotonin, norepinephrine, dopamine, brain-derived neurotrophic factor (BDNF), and gamma-aminobutyric acid (GABA) are activated in chronic pain and depression. Substance P, cerebrospinal fluid levels, and serum BDNF concentrations are consistently elevated in fibromyalgia patients compared with controls. Fibromyalgia patients also exhibit abnormal dopamine responses to pain. Recent data suggest that inflammatory cytokines, including interleukin-1β, tumor necrosis factor-α (TNFα), IL-6, and IL-8, play a putative role in regulating the pathogenesis and symptoms of fibromyalgia [M. DiFranco et al., Ann. NY Acad. Sci. 1193(1), 84-90 (2010)]. Thus, the pain that is a defining feature of fibromyalgia is not due to tissue damage or inflammation, making it fundamentally different from rheumatic diseases and many other pain conditions that cause inflammation in joints and tissues. Herpesviruses have developed various immune evasion mechanisms that pose special challenges to the immune system. Cytokines and cytokine-inducible genes are critical for any organism's ability to mount an antiviral response. Understanding immune mediators and their potential role in fibromyalgia may be the most challenging obstacle to understanding this disease. Gur and Oktayoglu [A. Gur and P. Oktayoglu, Curr. Pain Headache Rep. 12(3), 175-181 (2008)] explain that cytokines associated with acute or repeated tissue injury can cause long-term activation of spinal glia and dorsal horn neurons, thereby leading to central sensitization.The immune system responds to stressors by inducing specific immune cells to secrete the pro-inflammatory cytokines IL-1 and IL-6. Both cytokines are involved in inflammation, and IL-6 is thought to exacerbate the symptoms of autoimmune diseases and fibromyalgia [L. Vanderhaeghe, Total Health 23, 34-35 (2001)]. Both IL-1 and IL-6 are correlated with the onset and severity of Alzheimer's disease [Su et al., Neurosci. Bull., 32 (5), 469-480 (2016)].

[0039] Various studies have confirmed that COX-1 and COX-2 isoforms are important for efficient viral replication. In one study, Ray and Enquist showed that simultaneous inhibition of COX-1 and COX-2 resulted in a dramatic reduction in viral yield after HSV-1 infection [N. Ray and L. Enquist, J. Virol. 78, 3489-3501 (2004)]. Hill et al. used microarrays to analyze gene expression in the trigeminal ganglia of mice infected with latent HSV-1 and found that COX-2 gene expression significantly increased after reactivation [J. Hill et al., Virus Genes 23, 273-280 (2001)]. Gebhardt reported that the selective COX-2 inhibitor celecoxib can suppress heat stress-induced herpes virus reactivation in the nervous system of mice [B. Gebhardt et al., J. Ocul. Pharmacol. Ther. 21, 114-120 (2005)].

[0040] Functional somatic syndromes (FSS) are defined as "a structural or other condition that cannot be adequately explained by appropriate testing." FSS can be defined as a condition "characterized by a pattern of persistent somatic complaints in the absence of any other specific pathology" [P. Henningsen et al. (2007) Lancet 369, 946-954]. A variety of conditions have been commonly described as FSS, including fibromyalgia, irritable bowel syndrome, chronic fatigue syndrome, premenstrual syndrome, nonulcer dyspepsia, chronic pain, chronic pelvic pain, hypoglycemia, low back pain, sick building syndrome, Gulf War syndrome, tension headaches, temporomandibular joint disorder, repetitive strain injury, multiple chemical sensitivity, interstitial cystitis, chronic Lyme disease, depression, post-traumatic stress disorder (PTSD), chronic anxiety disorder, food sensitivities, and brain fog or cognitive dysfunction.

[0041] Despite the wide variety of FSS conditions, these conditions may share a common etiology rather than being distinct syndromes. Based on a literature review, Wessely et al. concluded that there is considerable overlap between these conditions, with more similarities than differences, and proposed the concept of a general functional somatic syndrome [S. Wessely et al. (1999) Lancet 354, 936-939]. The common etiology of FSS has also been discussed by Bland, who pointed out that when allostatic load, i.e., combined external and internal stressors, exceed the patient's ability to maintain allostasis, functional changes occur and symptomatic FSS develops [J. Bland (2008) Alt. Therapies 14, 14-16]. Somatic syndrome disorders further classify conditions such as IBS, fibromyalgia, and ME / CFS.

[0042] U.S. Patent No. 8,809,351 further supports the concept that herpes viruses are a common etiologic stressor causing fibromyalgia and FSS. Briefly, U.S. Patent No. 8,809,351 discloses the presence of HSV-1 DNA in 18 of 19 patients with fibromyalgia. HSV-1 infection was confirmed by detection of the viral protein ICP8 in biopsies from positive patients. U.S. Patent No. 8,809,351 further demonstrates that combined administration of famciclovir and celecoxib effectively treated fibromyalgia, brain fog, inflammatory bowel disease (IBS), chronic fatigue syndrome (CFS), chronic pain, and brain fog.

[0043] Herpesviruses significantly reduce both natural killer (NK) cell activity and CD8+ T cell activity, both of which are important components of the immune response to viral infection. Thus, herpesviruses may be immunosuppressive infections. Downregulation of NK and CD8+ T cell activity has been shown in chronic pain, ME / CFS, and long COVID. Without being bound by theory, it is hypothesized that after acute SARS-CoV2 infection, subsequent herpesvirus infection (or coinfection with herpesvirus and SARS-CoV2) persists as a mild nociceptive illness leading to long COVID. Given the similarities between the symptoms of long COVID and ME / CFS, it is theorized that administration of antivirals and COX-2 inhibitors may be an effective treatment for long COVID.

[0044] C. Pharmaceutical Compositions The compound of the present invention can be administered in a unit dosage form.If desired, this unit dosage form can be administered multiple times a day to increase the total daily dosage.The combination of COX-2 inhibitor and antiviral compound is disclosed in U.S. Patent No. 8,809,351, which is incorporated herein by reference.Specific embodiments include the combination of celecoxib and valacyclovir, and the combination of celecoxib and famciclovir.

[0045] In another embodiment, there is provided a pharmaceutical composition described herein, wherein the amount of antiviral compound is from about 250 mg to about 2,000 mg per unit dosage form.

[0046] In another embodiment, there is provided a pharmaceutical composition described herein, wherein the amount of antiviral compound is from about 250 mg to about 1,000 mg per unit dosage form.

[0047] In another embodiment, there is provided a pharmaceutical composition described herein, wherein the amount of antiviral compound is from about 250 mg to about 500 mg per unit dosage form.

[0048] In another embodiment, there is provided a pharmaceutical composition described herein, wherein the antiviral compound is a guanine analog antiviral compound.

[0049] In another embodiment, there is provided a pharmaceutical composition described herein, wherein the antiviral compound is selected from the group consisting of famciclovir, valacyclovir, and acyclovir.

[0050] In another embodiment, there is provided a pharmaceutical composition as described herein, wherein the antiviral compound is famciclovir.

[0051] In another embodiment, there is provided a pharmaceutical composition as described herein, wherein the amount of famciclovir is from about 250 mg to about 1,000 mg per unit dosage form.

[0052] In another embodiment, there is provided a pharmaceutical composition as described herein, wherein the antiviral compound is valacyclovir.

[0053] In another embodiment, there is provided a pharmaceutical composition as described herein, wherein the amount of valacyclovir is from about 1,000 mg to about 2,000 mg per unit dosage form.

[0054] In another embodiment, there is provided a pharmaceutical composition described herein, wherein the antiviral compound is acyclovir.

[0055] In another embodiment, there is provided a pharmaceutical composition as described herein, wherein the amount of acyclovir is from about 400 mg to about 1,600 mg per unit dosage form.

[0056] In another embodiment, there is provided a pharmaceutical composition as described herein, wherein the amount of COX-2 inhibitor is from about 7.5 mg to about 600 mg per unit dosage form.

[0057] In another embodiment, there is provided a pharmaceutical composition as described herein, wherein the amount of COX-2 inhibitor is from about 15 mg to about 300 mg per unit dosage form.

[0058] In another embodiment, there is provided a pharmaceutical composition as described herein, wherein the amount of COX-2 inhibitor is from about 50 mg to about 200 mg per unit dosage form.

[0059] In another embodiment, there is provided a pharmaceutical composition as described herein, wherein the COX-2 inhibitor is selected from the group consisting of celecoxib, meloxicam, and diclofenac-misoprostol combination.

[0060] In another embodiment, there is provided a pharmaceutical composition described herein, wherein the COX-2 inhibitor is celecoxib.

[0061] In another embodiment, there is provided a pharmaceutical composition as described herein, wherein the amount of celecoxib is from about 50 mg to about 600 mg per unit dosage form.

[0062] In another embodiment, there is provided a pharmaceutical composition described herein, wherein the COX-2 inhibitor is meloxicam.

[0063] In another embodiment, there is provided a pharmaceutical composition as described herein, wherein the amount of meloxicam is from about 7.5 mg to about 15 mg per unit dosage form.

[0064] In another embodiment, there is provided a pharmaceutical composition as described herein, wherein the COX-2 inhibitor is a diclofenac-misoprostol combination.

[0065] In another embodiment, there is provided a pharmaceutical composition as described herein, wherein the amount of diclofenac is from about 50 mg to about 200 mg per unit dosage form and the amount of misoprostol is from about 200 μg to about 800 μg per unit dosage form.

[0066] In one embodiment, there is provided a combination comprising a therapeutically effective amount of valacyclovir and a therapeutically effective amount of celecoxib, wherein the amount of valacyclovir is from about 750 mg to about 2000 mg per unit dosage form and the amount of celecoxib is from about 200 mg to about 800 mg per unit dosage form.

[0067] In another embodiment, there is provided a combination as described herein, wherein the amount of valacyclovir is from about 750 mg to about 1050 mg per unit dosage form.

[0068] In another embodiment, there is provided a combination as described herein, wherein the amount of valacyclovir is from about 1050 mg to about 1500 mg per unit dosage form.

[0069] In another embodiment, there is provided a combination as described herein, wherein the amount of valacyclovir is selected from the group consisting of about 750 mg, about 1050 mg, about 1250 mg, about 1500 mg, and about 2000 mg per unit dosage form.

[0070] In another embodiment, there is provided a combination as described herein, wherein the amount of valacyclovir is about 750 mg or about 1250 mg per unit dosage form.

[0071] In another embodiment, there is provided a combination as described herein, wherein the amount of celecoxib is from about 100 mg to about 400 mg per unit dosage form.

[0072] In another embodiment, there is provided a combination as described herein, wherein the amount of celecoxib is from about 400 mg to about 800 mg per unit dosage form.

[0073] In another embodiment, there is provided a combination as described herein, wherein the amount of celecoxib is selected from the group consisting of about 100 mg, about 200 mg, about 400 mg, and about 800 mg per unit dosage form.

[0074] In another embodiment, there is provided a combination as described herein, wherein the amount of celecoxib is about 200 mg or about 400 mg per unit dosage form.

[0075] In another embodiment, there is provided a combination as described herein, wherein the amount of valacyclovir is about 750 mg or about 1250 mg per unit dosage form and the amount of celecoxib is about 200 mg or about 400 mg per unit dosage form.

[0076] In one embodiment, the kit comprises a first unit dosage form containing a therapeutically effective amount of a dispersible A kit is provided, comprising a first and second unit dosage form containing clovir or famciclovir and a therapeutically effective amount of celecoxib in a second unit dosage form, the first and second unit dosage forms being separately enclosed in one or more containers and disposed in a single package or dispensing device, and optionally including instructions on how to use the kit components to obtain a therapeutic effect.

[0077] In another embodiment, there is provided a kit form as described herein, wherein the amount of valacyclovir or famciclovir is from about 750 mg to about 2000 mg per unit dosage form and the amount of celecoxib is from about 100 mg to about 800 mg per unit dosage form.

[0078] In another embodiment, a dosage form is provided in which the amount of drug is from about 0.05% to about 95% by weight, more typically from about 2% to about 50% by weight.

[0079] To treat the conditions described herein, the compounds described herein can be administered as described below.

[0080] Oral administration The compounds of the invention may be administered orally, including by swallowing, so that the compound enters the gastrointestinal tract or is absorbed into the blood stream directly from the oral cavity (eg, buccal or sublingual administration).

[0081] Compositions suitable for oral administration include solid dosage forms such as tablets, troches and capsules, which may contain liquids, gels or powders.

[0082] Compositions for oral administration may be formulated for immediate or sustained release (including delayed or extended release) and may optionally be enteric coated.

[0083] Liquid formulations may include solutions, syrups, and suspensions, which may be used in soft or hard capsules. Such formulations may contain pharmaceutically acceptable carriers, such as water, ethanol, polyethylene glycol, cellulose, or oils. Additionally, the formulations may contain one or more emulsifying agents and / or suspending agents.

[0084] Tablets may contain a disintegrant, comprising from about 0.5% to about 35% by weight of the dosage form, more typically from about 2% to about 25% by weight of the dosage form. Examples of disintegrants include methylcellulose, sodium or calcium carboxymethylcellulose, croscarmellose sodium, polyvinylpyrrolidone, hydroxypropylcellulose, and starch.

[0085] Suitable lubricants for use in tablets may be present in amounts from about 0.1% to about 5% by weight and include calcium stearate, zinc stearate, or magnesium stearate, sodium stearyl fumarate, and the like.

[0086] Binders suitable for use in tablets include gelatin, polyethylene glycol, sugars, gums, starch, hydroxypropyl cellulose, etc. Diluents suitable for use in tablets include mannitol, xylitol, lactose, dextrose, sucrose, sorbitol, starch.

[0087] Suitable surfactants and lubricants for use in tablets may be present in amounts of about 0.1% to about 3% by weight and include polysorbate 80, sodium dodecyl sulfate, talc, and silicon dioxide.

[0088] Parenteral administration The compounds of the present invention can be administered directly into the bloodstream, muscle, or an internal organ. Suitable means for parenteral administration include intravenous, intramuscular, subcutaneous intra-arterial, intraperitoneal, intrathecal, intracranial, etc. Suitable devices for parenteral administration include syringes (including needle and needleless syringes) and infusion techniques.

[0089] Compositions for parenteral administration may be formulated as immediate release or sustained release formulations, including delayed or extended release.

[0090] Most parenteral formulations are aqueous solutions containing excipients, including salts, buffers, and carbohydrates.

[0091] Parenteral formulations may also be prepared in dehydrated form (e.g., by lyophilization) or as sterile non-aqueous solutions. These formulations may be used with a suitable vehicle such as sterile water. Solubility enhancers may also be used to prepare parenteral solutions.

[0092] Topical administration The compounds of the present invention can be administered topically or transdermally to the skin. Formulations for topical administration may include lotions, solutions, creams, gels, hydrogels, ointments, foams, implants, patches, etc. Pharmaceutically acceptable carriers for topical administration formulations may include water, alcohol, mineral oil, glycerin, polyethylene glycol, etc. Topical administration can also be achieved by electroporation, iontophoresis, phonophoresis, etc.

[0093] Compositions for topical administration may be formulated as immediate release or sustained release, including delayed or extended release.

[0094] kit The compound combination of the present invention, where component A is an antiviral compound and component B is a COX-2 inhibitor as described herein, may be provided in kit form, comprising an arrangement of components A and B associated with one another, such as in a single package or pharmaceutical dispensing device. Such kit form for patient use may be dispensed by a hospital formulary, a retail pharmacist, or a prescribing physician.

[0095] In one example, the kit may comprise a single package in which therapeutically effective doses of components A and B, in tablet or capsule form, are held separately in separate containers (e.g., bottles), such as trays, and held together, for example, using shrink wrap, tape, or a plastic or cardboard box enclosing the components.

[0096] In another example, therapeutically effective doses of combination components A and B may be provided co-packaged in a single blister pack in the form of tablets or capsules.

[0097] In another example, the kit form may provide therapeutically effective doses of combination components A and B in tablet or capsule form, which are co-dispensed from a device that delivers the components from a reservoir, e.g., using one or more levers to co-dispense individual dosage forms of the combinedly administered components A and B.

[0098] The kit may also be used for parenteral administration of dosage forms of components A and B. For example, individual doses of components A and B in the form of lyophilized powders may be administered separately or in therapeutically effective doses. A and B are mixed together and placed into a package that also includes a separately placed vial of sterile water or buffer and, optionally, a sterile packaged syringe for administration of the dose combination after dissolution.

[0099] Kit forms may further include instructions for how to use the kit components suitable for administration to achieve a therapeutic result, in accordance with instructions approved by a government agency (e.g., the U.S. FDA).

[0100] D. Treatment method The present disclosure further provides a method of treating a condition in a subject having or susceptible to having such a condition by administering to the subject a therapeutically effective amount of the compound. In one embodiment, the treatment is preventative treatment. In another embodiment, the treatment is palliative treatment. In yet another embodiment, the treatment is restorative treatment.

[0101] In one embodiment, there is provided a method of treating a subject susceptible to or suffering from a condition selected from the group consisting of fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, chronic pain, chronic headache, chronic neck pain, chronic back pain, chronic depression, chronic clinical anxiety disorder, post-traumatic stress disorder (PTSD), brain fog, cognitive dysfunction, and chronic interstitial cystitis, the method comprising administering to the subject a therapeutically effective amount of an antiviral compound and a therapeutically effective amount of a COX-2 inhibitor, in a dose weight ratio of the COX-2 inhibitor to the antiviral compound ranging from about 1:1 to about 500:1.

[0102] In one embodiment, a method is provided for treating a subject susceptible to or afflicted with Alzheimer's disease, the method comprising administering to the subject a therapeutically effective amount of a COX-2 inhibitor in a dose weight ratio of the COX-2 inhibitor to the antiviral compound ranging from about 1:1 to about 500:1. In a specific embodiment, the COX-2 inhibitor is celecoxib and the antiviral compound is famciclovir. In another specific embodiment, the COX-2 inhibitor is celecoxib and the antiviral compound is valacyclovir.

[0103] In one embodiment, a method of treating a subject susceptible to or suffering from long COVID is provided. The method comprises administering to the subject a therapeutically effective amount of a COX-2 inhibitor, wherein the COX-2 inhibitor to antiviral compound dose weight ratio ranges from about 1:1 to about 500:1. In a specific embodiment, the COX-2 inhibitor is celecoxib and the antiviral compound is famciclovir. In another specific embodiment, the COX-2 inhibitor is celecoxib and the antiviral compound is valacyclovir.

[0104] In another embodiment, a method of treating a subject susceptible to or suffering from COVID-19 sequelae, including post-acute infectious syndrome (PAIS), is provided. In various embodiments, the method is used to treat PAIS, a sequela of an infection selected from the group consisting of SARS-CoV-2 infection, Epstein-Barr virus infection, Ross River virus infection, human herpesvirus 6 infection, varicella-zoster virus infection, Ebola virus infection, West Nile virus infection, dengue virus infection, parvovirus infection, Borrelia burgdorferi infection, Coxiella burnetii infection, and Mycoplasma pneumoniae infection. The method may comprise administering to the subject a therapeutically effective amount of a COX-2 inhibitor, wherein the dose weight ratio of the COX-2 inhibitor to the antiviral compound ranges from about 1:1 to about 500:1. In certain embodiments, the COX-2 inhibitor is celecoxib and the antiviral compound is famciclovir. In another specific embodiment, the COX-2 inhibitor is celecoxib and the antiviral compound is valacyclovir.

[0105] In another embodiment, a method of treating symptoms of orthostatic intolerance in a subject with PAIS. In various embodiments, the method is used to treat PAIS, a sequela of an infection selected from the group consisting of SARS-CoV-2 infection, Epstein-Barr virus infection, Ross River virus infection, human herpesvirus 6 infection, varicella-zoster virus infection, Ebola virus infection, West Nile virus infection, dengue virus infection, parvovirus infection, Borrelia burgdorferi infection, Coxiella burnetii infection, and Mycoplasma pneumoniae infection. Symptoms include dizziness, near-fainting, unsteadiness, pre-existing loss of consciousness, blurred vision, tunnel vision, spotting, weakness, fatigue, difficulty concentrating, head and neck discomfort, difficulty standing up for a short period of time, difficulty standing up for a long period of time, difficulty walking for a short period of time, and / or difficulty walking for a long period of time. The method may include administering to a subject a therapeutically effective amount of a COX-2 inhibitor, wherein the dose weight ratio of the COX-2 inhibitor to the antiviral compound ranges from about 1:1 to about 500:1. In a specific embodiment, the COX-2 inhibitor is celecoxib and the antiviral compound is famciclovir. In another specific embodiment, the COX-2 inhibitor is celecoxib and the antiviral compound is valacyclovir.

[0106] In another embodiment, there is provided a method as described herein, wherein the dose weight ratio of the antiviral compound to the COX-2 inhibitor ranges from about 1:1 to about 100:1.

[0107] In another embodiment, there is provided a method described herein, wherein the dose weight ratio of the antiviral compound to the COX-2 inhibitor ranges from about 1:1 to about 50:1.

[0108] In another embodiment, there is provided a method described herein, wherein the dose weight ratio of the antiviral compound to the COX-2 inhibitor ranges from about 1:1 to about 20:1.

[0109] In another embodiment, there is provided a method described herein, wherein the dose weight ratio of the antiviral compound to the COX-2 inhibitor ranges from about 1:1 to about 5:1.

[0110] In another embodiment, there is provided a method according to the present invention, wherein the amount of antiviral compound is from about 250 mg to about 2000 mg per unit dosage form.

[0111] In another embodiment, there is provided a method according to the present invention, wherein the amount of antiviral compound is from about 250 mg to about 1000 mg per unit dosage form.

[0112] In another embodiment, there is provided a method according to the present invention, wherein the amount of antiviral compound is from about 250 mg to about 500 mg per unit dosage form.

[0113] In another embodiment, there is provided a method described herein, wherein the amount of famciclovir is from about 250 mg to about 1000 mg per unit dosage form.

[0114] In another embodiment, there is provided a method as described herein, wherein the amount of valacyclovir is from about 1000 mg to about 2000 mg per unit dosage form.

[0115] In another alternative embodiment, there is provided a method as described herein, wherein the antiviral compound is acyclovir.

[0116] In another alternative embodiment, there is provided a method according to the present invention, wherein the amount of acyclovir is from about 400 mg to about 1600 mg per unit dosage form.

[0117] In another embodiment, the methods described herein, wherein the amount of the COX-2 inhibitor is a unit dose A method is provided in which the dosage form is about 7.5 mg to about 600 mg per dosage form.

[0118] In another embodiment, there is provided a method as described herein, wherein the amount of COX-2 inhibitor is from about 15 mg to about 300 mg per unit dosage form.

[0119] In another embodiment, there is provided a method as described herein, wherein the amount of COX-2 inhibitor is from about 50 mg to about 200 mg per unit dosage form.

[0120] In another alternative embodiment, provided herein is a method wherein the COX-2 inhibitor is meloxicam or a diclofenac-misoprostol combination.

[0121] In another embodiment, there is provided a method described herein, wherein the amount of celecoxib is from about 50 mg to about 600 mg per unit dosage form.

[0122] In another embodiment, there is provided a method as described herein, wherein the COX-2 inhibitor is meloxicam.

[0123] In another embodiment, the method described herein, wherein the amount of meloxicam is from about 7.5 mg to about 15 mg per unit dosage form.

[0124] In another embodiment, there is provided a method as described herein, wherein the COX-2 inhibitor is a diclofenac-misoprostol combination.

[0125] In another embodiment, provided herein is a method, wherein the amount of diclofenac is from about 50 mg to about 200 mg per unit dosage form and the amount of misoprostol is from about 200 μg to about 800 μg per unit dosage form.

[0126] In one embodiment, a method of treating a subject susceptible to or suffering from Alzheimer's disease is provided, comprising administering to the subject a therapeutically effective combination of famciclovir and celecoxib, wherein the famciclovir is administered in a total daily dose of about 250 mg to about 1000 mg and the celecoxib is administered in a total daily dose of about 200 mg to about 800 mg, and the administration of the combination does not produce substantial adverse events.

[0127] In one embodiment, a method of treating a subject susceptible to or suffering from Alzheimer's disease is provided, comprising administering to the subject a therapeutically effective combination of valacyclovir and celecoxib, wherein the valacyclovir is administered in a total daily dose of about 750 mg to about 2000 mg and the celecoxib is administered in a total daily dose of about 200 mg to about 800 mg, and the administration of the combination does not produce substantial adverse events.

[0128] In one embodiment, a method of treating a subject susceptible to or suffering from long COVID is provided, comprising administering to the subject a therapeutically effective combination of famciclovir and celecoxib, wherein the famciclovir is administered in a total daily dose of about 250 mg to about 1000 mg and the celecoxib is administered in a total daily dose of about 200 mg to about 800 mg, and the administration of the combination does not produce substantial adverse events.

[0129] In one embodiment, a method of treating a subject susceptible to or suffering from long COVID is provided, comprising administering to the subject a therapeutically effective combination of valacyclovir and celecoxib, wherein the valacyclovir is administered in a total daily dose of about 750 mg to about 2000 mg and the celecoxib is administered in a total daily dose of about 200 mg to about 800 mg, and the administration of the combination does not result in substantial adverse events.

[0130] In one embodiment, a method of treating a subject susceptible to or suffering from PAIS is provided, comprising administering to the subject a therapeutically effective combination of famciclovir and celecoxib, wherein the famciclovir is administered in a total daily dose of about 250 mg to about 1000 mg and the celecoxib is administered in a total daily dose of about 200 mg to about 800 mg, and the administration of the combination does not produce substantial adverse events.

[0131] In one embodiment, a method of treating a subject susceptible to or suffering from PAIS is provided, comprising administering to the subject a therapeutically effective combination of valacyclovir and celecoxib, wherein the valacyclovir is administered in a total daily dose of about 750 mg to about 2000 mg and the celecoxib is administered in a total daily dose of about 200 mg to about 800 mg, and the administration of the combination does not produce substantial adverse events.

[0132] In one embodiment, a method for treating symptoms of orthostatic intolerance in a subject suffering from PAIS is provided, comprising administering to the subject a therapeutically effective combination of valacyclovir and celecoxib, wherein the valacyclovir is administered in a total daily dose of about 750 mg to about 2000 mg and the celecoxib is administered in a total daily dose of about 200 mg to about 800 mg, and the administration of the combination does not produce substantial adverse events.

[0133] E. Subject Suitable subjects for treatment according to the present invention include mammals. Mammals of the present invention include, but are not limited to, humans, dogs, cats, cows, goats, horses, sheep, pigs, rodents, lagomorphs, primates, and the like, including mammals in utero. Subjects may be of either sex and at any stage of development. In certain embodiments, the subject is human.

[0134] F. Combinations and Combination Therapies The antiviral compounds and COX-2 inhibitors of the present invention can be used as described herein or in combination with other pharmacologically active compounds to treat the conditions already described above. The antiviral compounds and COX-2 inhibitors of the present invention and the other pharmacologically active compounds can be administered simultaneously (in the same dosage form or in separate dosage forms) or sequentially. Thus, in one embodiment, the present invention includes a method for treating a condition by administering to a subject therapeutically effective amounts of the antiviral compounds and COX-2 inhibitors of the present invention and one or more additional pharmacologically active compounds.

[0135] In another embodiment, there is provided a pharmaceutical composition comprising an antiviral compound and a COX-2 inhibitor that is a compound of the present invention, one or more additional pharmacologically active compounds, and a pharmaceutically acceptable carrier.

[0136] In another embodiment, one or more additional pharmacologically active compounds are administered in any order with the antiviral compound and COX-2 inhibitor of the present invention, or simultaneously. When administered simultaneously, the multiple therapeutic agents may be provided in a single, unified form or in multiple forms (e.g., a single tablet, or two or more separate tablets). [Example]

[0137] The following examples are illustrative only and are not intended to limit the present disclosure in any way.

[0138] Example 1: Human Clinical Trials the purpose Celecoxib and famciclovir combination therapy for myalgic encephalomyelitis / chronic fatigue syndrome (ME / To investigate the effectiveness of this treatment in treating patients diagnosed with Chronic Fever (CFS).

[0139] Study design Thirty-three patients diagnosed with ME / CFS were administered valacyclovir (mean dose 2264 mg / day) and celecoxib (400 mg / day).

[0140] Patient population and diagnostic criteria: Adult men and women with a documented diagnosis of ME / CFS were selected. Screening assessment included a medical and psychological history and a physical examination.

[0141] ME / CFS The US Centers for Disease Control's diagnostic criteria for CFS require the following three requirements: i) Severe chronic fatigue for six or more consecutive months that is not due to continuous exertion or another medical condition that causes fatigue ii) Fatigue that significantly interferes with daily activities and work iii) Having four or more of the following eight symptoms at the same time: (a) Post-exertional fatigue lasting more than 24 hours (b) Unrestful sleep (c) Significant impairment of short-term memory or concentration (d) Muscle pain (e) Joint pain without swelling or redness (f) new type, pattern, or severity of headache (g) Tender lymph nodes in the neck or axilla (h) Frequent or recurring sore throat

[0142] These symptoms must persist or recur for at least 6 consecutive months and must not precede the fatigue. (Chronic fatigue syndrome: General information. Centers for Disease Control and Prevention. www.cdc.gov / cfs / general)

[0143] Cognitive dysfunction or impairment Cognitive dysfunction or impairment, also known as brain fog or mental fog, is a decline in intellectual functions (thinking, memory, reasoning, etc.) that interferes with daily life. People with cognitive impairment have problems with verbal recall, basic calculations, and concentration.

[0144] Patient improvement was quantified using the Mental Clutter Scale (Leavitt et al., Psychological Reports 109, 445-452, 2011).

[0145] fatigue Fatigue is a loss of energy, a strong desire for rest or sleep, and / or a feeling of constant exhaustion that can interfere with normal daily activities. Fatigue can be assessed by surveying patients receiving combination antiviral and COX-2 inhibitor therapy, in which patients report the presence and severity of fatigue. Improvement in fatigue is assessed by first asking patients whether their fatigue has improved and, if so, by having them report the degree of improvement in their overall fatigue over the course of treatment.

[0146] result The results shown in the table below show the relative improvements in fatigue and cognitive function. The results of the clinical trials are shown in Table 1. Table 2 shows the mean dose and mean improvement.

[0147] [Table 1-1]

[0148] Table 1 continued [Table 1-2]

[0149] [Table 2]

[0150] Example 2: Human Clinical Trial Protocol for Treatment of Long COVID: Objective: To investigate the safety and efficacy of antiviral drugs (famciclovir or valacyclovir) plus celecoxib compared with placebo in the treatment of long COVID.

[0151] Study design A 14-week, single-center, open-label study was designed to investigate the safety and efficacy of valacyclovir plus celecoxib for the treatment of long-term symptoms of COVID-19 in adult female patients. Treatment consisted of daily administration of valacyclovir and celecoxib. Treated patients received 1.5 g of valacyclovir and 200 mg of celecoxib in addition to standard of care for long-term COVID treatment. Coxib was administered twice daily (BID) for 14 weeks. A comparison cohort matched with patients receiving standard of care was also enrolled; the comparison cohort received only standard of care to treat Long COVID. Standard of care was defined as current care provided by a center provider, unless the Long COVID patient was not a center patient. In that case, standard of care was defined as ongoing care provided by a primary care physician (PCP) or other Long COVID clinic.

[0152] Women were enrolled according to the inclusion criteria and assigned to receive either combination therapy (standard of care plus valacyclovir / celecoxib) (n=22) or placebo (standard of care alone) (n=17).

[0153] Eligible patients had primary long COVID (exhibiting one or more of the following symptoms: fatigue, persistent muscle weakness, decreased lung function, and a 6-minute walk test result below baseline [see Kuehn, JAMA, 325(11)(2021)] and no other infections or other conditions that could compromise the interpretation of the study results.

[0154] Patients underwent an initial screening procedure followed by washout of excluded medications, if necessary. Patients who were dependently using opioids or narcotic medications for pain management were not enrolled in the study.

[0155] Because the treatment included celecoxib, patients in the treatment group discontinued all other regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) at randomization. Acetaminophen was used at a dose not exceeding 3250 mg daily for the duration of the study. Patients continued low-dose aspirin (<325 mg / day) for cardiovascular protection, triptans and ergotamines for migraine, dopamine agonists for restless legs syndrome, as well as muscle relaxants, sleep aids, and benzodiazepines (in the absence of evidence of abuse or dependence).

[0156] The metabolic profile of each patient's concomitant medications was evaluated to ensure there was no risk of significant drug interactions. For drugs metabolized by CYP2C9, concomitant use with fluconazole, a potent CYP2C9 inhibitor, was avoided.

[0157] After confirming that all inclusion criteria were met and washout was complete, patients returned for baseline assessment and randomization. The day of baseline assessment was designated Day 0. Patients began study medication with either the evening dose on Day 0 or the morning dose on the following day (Day 1), and continued treatment twice daily for the duration of the study.

[0158] Inclusion Criteria: 1. Able to read, understand, and sign the informed consent form. 2. Be female and between the ages of 18 and 65 (inclusive). 3. Each female patient must have a negative urine pregnancy test at screening and baseline unless postmenopausal. 4. Women of childbearing potential must be willing to use effective contraception during the study period. 5. Have been diagnosed with primary long COVID. 6. A urine drug screen administered at the screening visit will be negative for drugs of abuse, including methamphetamine, cocaine, phencyclidine (PCP), and undisclosed amphetamines / opioids / opiates. 7. Eligible patients with mild to moderate depression must be clinically stable for 3 months and not at risk for suicidal ideation or behavior. Permitted antidepressant medication doses must be stable for at least 3 months prior to screening. 8. In the opinion of the investigator, the patient is willing and able to comply with all requirements set forth in the protocol.

[0159] Exclusion criteria: 1. Being breastfeeding or pregnant. 2. Have been diagnosed with post-spinal surgery syndrome, infectious arthritis, rheumatoid arthritis, systemic lupus erythematosus, or other systemic autoimmune diseases. 3. The presence of a clinically significant, uncontrolled, or unstable medical, psychiatric, or surgical condition that, in the opinion of the investigator, may affect ability to participate in the study or compromise patient safety during the study. 4. History of serious adverse reactions or allergies to the study drug. 5. History of suicide attempt or other suicidal behavior within the past two years. 6. Planned surgery that may confound the study results or interfere with ability to comply with the protocol. 7. Symptomatic or other clinically significant cardiac disease. 8. Have an acute non-COVID systemic infection (e.g., HIV, hepatitis) or other active viral / bacterial infection during the screening period or at the baseline visit. 9.Currently receiving chronic systemic corticosteroids (greater than 5 mg prednisone equivalent daily or equivalent). 10. Uncontrolled sleep apnea, but patients who have been successfully treated with CPAP or other devices are eligible. 11. Use of chronic nucleoside analogue antiviral suppressive therapy within 1 month prior to the screening visit or requiring, on average, one or more acute treatment courses every 2 months. 12.Currently using celecoxib in combination with valacyclovir or famciclovir. 13. Having undergone malabsorptive weight loss surgery (e.g., Roux-en-Y or other bypass surgery). 14. Severe IBS-C or colonic inertia with bowel movements occurring more than 7 days apart. 15. Have evidence of clinically significant laboratory abnormalities based on clinical test results at screening and / or medical history, as judged by the investigator.

[0160] Test drug: The study medications used in this study were commercially available generic valacyclovir tablets and celecoxib capsules. Patients in the treatment group received a 45-day supply of study medication at baseline, followed by 30-day supplies at weeks 6 and 10. Each dose of study medication consisted of one 200 mg capsule of celecoxib and 1.5 g of valacyclovir. Patients were instructed to take the medication twice daily (BID).

[0161] result: Efficacy endpoints: The primary endpoint was the change from baseline to week 14 in PROMIS Fatigue 8a T-score.

[0162] Secondary endpoints included: · Change in PROMIS Fatigue 8a T-score from baseline to weeks 6, 10, and 14; · Change in self-reported NRS fatigue score from baseline to weeks 6, 12, and 14; · Change in self-reported mean pain intensity score from baseline to weeks 6, 10, and 14; Patients' overall condition measured by two PGIC scales at weeks 6, 10, and 14 ; · Change from baseline to weeks 6, 10, and 14 in the HADS anxiety domain and HADS depression domain; Changes in orthostatic tolerance tests from baseline to weeks 6, 10, and 14.

[0163] Safety endpoints: Safety assessments included vital signs (sitting blood pressure, heart rate, oral temperature, and weight), adverse events, and clinical tests.

[0164] Statistical analysis: The primary efficacy endpoint for assessing treatment efficacy was the change from baseline in long COVID symptoms. Changes were calculated by comparing baseline long COVID symptoms with those at weeks 6, 10, and 14.

[0165] The mean changes from baseline in the combination treatment group were compared with those calculated in the placebo treatment group over the 16-week treatment period using mixed-effects models (MMRM). The null hypothesis was that there would be no difference between the treatment groups in the mean changes from baseline. Rejection of this hypothesis demonstrated the efficacy of the combination treatment.

[0166] result Tables 3 and 4 show the PROMIS fatigue scores and NRS fatigue scores, respectively, for subjects receiving the combination of valacyclovir 1.5 g and celecoxib 200 mg (denoted "IMC-2"). The "Within-group p-value" column indicates the statistical significance of the score change compared to baseline. The "Comparative p-value" column indicates the statistical significance of the score change between the treatment group (e.g., patients receiving the valacyclovir and celecoxib combination) and the standard of care (SOC) group (e.g., patients not receiving the valacyclovir and celecoxib combination). The addition of the valacyclovir / celecoxib combination to standard of care resulted in a statistically significant improvement in fatigue compared to baseline (measured on both the PROMIS and NRS scales). In contrast, subjects receiving standard of care alone did not demonstrate significant improvement in fatigue from baseline. Furthermore, significant differences were observed between the treatment and control groups for many fatigue scores. Figure 1 shows the change from baseline in PROMIS fatigue T-scores for the combination therapy and SOC control groups at week 14. Figure 2 shows the change from baseline in NRS fatigue scores for the combination therapy and SOC control groups at week 14.

[0167] [Table 3]

[0168] [Table 4]

[0169] Table 5 shows the NRS pain scale for subjects receiving the combination of valacyclovir 1.5 g and celecoxib 200 mg (denoted "IMC-2"). The addition of the valacyclovir / celecoxib combination to standard of care resulted in a statistically significant improvement in pain compared to the control group. Figure 3 shows the change from baseline in the NRS pain scale for the combination therapy group and the SOC control group at week 14.

[0170] [Table 5]

[0171] Tables 6 and 7 show the scores on the Patient Image of Change (PGIC) 1-7 scale and PGIC improved 0-10 scale for subjects receiving the combination of valacyclovir 1.5 g and celecoxib 200 mg (denoted "IMC-2"). The addition of the valacyclovir / celecoxib combination to standard of care resulted in statistically significant improvements in both the PGIC and PGIC improved scales compared with the control group. Figure 4 shows the PGIC responder rate at week 14. Tables 8 and 9 show the percentage of subjects who reported a "good outcome" based on the PGIC and PGIC Improved scales. A "good outcome" on the PGIC 1-7 scale refers to subjects achieving a PGIC score of 5, 6, or 7 relative to their initial score. A "good outcome" on the PGIC 0-10 scale refers to subjects achieving a score of less than 4 relative to their initial score.

[0172] [Table 6]

[0173] [Table 7]

[0174] [Table 8]

[0175] [Table 9]

[0176] Tables 10 and 11 show the Hospital Anxiety and Depression Scale (HADS) depression and anxiety scores, respectively, for subjects receiving the combination of valacyclovir 1.5 g and celecoxib 200 mg (denoted "IMC-2"). The addition of the valacyclovir / celecoxib combination to standard of care resulted in statistically significant improvements in HADS depression scores at week 6 and HADS anxiety scores at week 14 compared to the control group.

[0177] [Table 10]

[0178] [Table 11]

[0179] Tables 12 and 13 show the Orthostatic Tolerance Symptom Assessment Scale (OISA, OISA) scores for subjects receiving the combined valacyclovir 1.5 g and celecoxib 200 mg (denoted as "IMC-2"). The Orthostatic Intolerance Daily Activities Impact Scale (OIDAS) and Orthostatic Intolerance Daily Activities Impact Scale (OISA) are shown in Figure 1. Adding valacyclovir / celecoxib combination to standard of care resulted in statistically significant improvements compared to baseline in intolerance symptoms (measured by OISA and OISAS) and daily activities (measured by OIDAS) compared to the control group. In contrast, subjects receiving standard of care alone did not experience statistically significant improvements compared to baseline in any of the OISA, OISAS, or OIDAS scores. Furthermore, statistically significant improvements in OISA, OISAS, and OIDAS scores were observed between the treatment and control groups. Figure 5 shows the change in OISA and OISAS from baseline at week 14 for the combination group and the SOC control group. Figure 6 shows the change in OIDAS from baseline at week 14 for the combination group and the SOC control group.

[0180] [Table 12]

[0181] [Table 13]

[0182] The results, shown in Table 3-11 and Figure 1-5, demonstrate that the combination of valacyclovir and celecoxib provides statistically significant improvements in the following compared to standard of care for long COVID: · PROMIS fatigue at weeks 6 and 14; · NRS fatigue scale at weeks 10 and 14; · Global PGIC1-7 scale serial analysis at weeks 6 and 14; Global PGIC1-7 scale responder analysis at weeks 6 and 14; ·Continuous analysis of global PGIC0-10 scale at weeks 6 and 14; Global PGIC0-10 responder analysis at weeks 6 and 14; · Orthostatic Intolerance Symptom Assessment (OISA) at weeks 6 and 14; Orthostatic Intolerance Impact of Daily Activities (OIDAS) at weeks 6 and 14; NRS pain scale at 10 and 14 weeks. · HADS Anxiety and Depression Scale.

[0183] Example 3: Treatment of Alzheimer's Disease Objective: To investigate the efficacy of a combination of celecoxib and famciclovir in treating patients diagnosed with Alzheimer's disease.

[0184] A 67-year-old adult male presented with mild cognitive decline, including short- and long-term memory loss, confusion and disorganized thinking, and difficulty speaking, reading, and organizing his thoughts. The patient was prescribed celecoxib 200 mg twice daily and valacyclovir twice daily. The dose of valacyclovir was 1 g for 6 months, 1.5 g from months 6 to 9, and 2 g at month 9. After 9 months of treatment, the patient fully recovered. Short- and long-term memory function returned to normal. The confusion and disorganized thinking, as well as the difficulty speaking, reading, and organizing his thoughts, also resolved.

[0185] Example 4: Human Clinical Trial Protocol for the Treatment of Alzheimer's Disease: Objective: To investigate the safety and efficacy of celecoxib in combination with an antiviral drug (famciclovir or valacyclovir) compared with placebo in the treatment of Alzheimer's disease.

[0186] Study design: This randomized, double-blind, placebo-controlled, 26-week study evaluated the safety and efficacy of combination therapy with an antiviral (famciclovir or valacyclovir) and celecoxib in patients with Alzheimer's disease. Patients receive a loading dose (twice the maintenance dose) of the antiviral (famciclovir or valacyclovir) twice daily (BID) for the first week of treatment, followed by a maintenance dose of the antiviral (famciclovir or valacyclovir) BID for 25 weeks. Depending on the patient population in the study arm, the use of a loading dose greater than 1,000 mg / day is optional. The celecoxib dose (also BID) will remain stable throughout the 26-week treatment period.

[0187] Patients will be randomly assigned to either the combination therapy group or a placebo group.

[0188] Eligible patients must have primary Alzheimer's disease (defined as experiencing one or more of the following: progressive amyloid deposition, mild cognitive impairment (including memory loss and / or other thinking disorders), memory impairment, word-finding difficulties, and / or visual / spatial impairments [see the National Institutes of Aging Alzheimer's Disease Diagnostic Guidelines (www.nia.nih.gov / health / alzheimers-disease-diagnostic-guideline)]) and be free of other conditions that may impair the interpretation of study results.

[0189] Patients will undergo initial screening procedures followed by washout of excluded medications as needed. Patients dependent on opioids or narcotic analgesics for pain management will not be included in this study.

[0190] Regular use of other nonsteroidal anti-inflammatory drugs (NSAIDs) was to be discontinued at randomization due to the inclusion of celecoxib. NSAIDs were to be used at doses not exceeding 3250 mg per day for the duration of the study. Patients may also continue to receive low-dose aspirin (<325 mg / day) for cardiovascular protection, triptans and ergotamines for migraine headaches, dopamine agonists for restless leg syndrome, as well as muscle relaxants, sleep aids, and benzodiazepines (provided there are no signs of abuse or dependence).

[0191] The metabolic profile of each patient's concomitant medications should be evaluated to ensure there is no risk of significant drug interactions with either of the study drugs. For drugs metabolized by CYP2C9, concomitant use with fluconazole, a strong CYP2C9 inhibitor, should be avoided.

[0192] After meeting all inclusion criteria and successfully completing washout, patients will return for baseline assessment and randomization. The day of baseline assessment will be designated Day 0. Patients will begin taking the study medication either in the evening on Day 0 or in the morning on the following day (Day 1), and will continue to receive the medication BID throughout the study.

[0193] Blood samples will be collected at the screening visit for safety assessment and exploratory cytokine analysis (e.g., IL-1β, IL-4, IL-6, IL-8, IL-10, TNF-α, IFN-α, IFN-β, IFN-γ). A second sample for cytokine analysis will be collected at the baseline / randomization visit. Follow-up blood samples for safety and cytokine analysis will be collected at Week 8 and 1. At the Week 6 visit (or in case of early discontinuation), a standard urine panel will be included as part of the safety testing collected at the Week 8 and Week 16 screenings.

[0194] To maintain double-blindness, the study medication is over-encapsulated, and patients in the study medication and placebo groups receive identical-looking study medication. Study medication is provided in two-week bottles; therefore, patients receive one, two, or three separate bottles of each medication (or matching placebo) at each visit, depending on the number of weeks until the next visit. For the first week only, patients receive a third bottle containing an additional antiviral medication (famciclovir or valacyclovir) to provide a one-week loading dose. Patients take one capsule from each of their three assigned bottles twice daily (with meals) during the first week, followed by one capsule from each of their two provided bottles twice daily. Patients receive study medication for a total of 21 weeks, with treatment visits scheduled at weeks 2, 8, 16, 22, and 26, or upon early discontinuation.

[0195] Inclusion Criteria: 1. Able to read, understand, and sign the informed consent form. 2. Applicants must be male or female and between the ages of 18 and 70 (inclusive). 3. Each female patient must have a negative urine pregnancy test at screening and baseline unless postmenopausal. 4. Women of childbearing potential must be willing to use effective contraception during the study period. 5. Have been diagnosed with primary Alzheimer's disease. 6. In the opinion of the investigator, the patient is willing and able to comply with all requirements set forth in the protocol.

[0196] Exclusion criteria: 1. Being breastfeeding or pregnant. 2. Use of an investigational drug within 30 days of screening. 3. Have been diagnosed with post-spinal surgery syndrome, infectious arthritis, rheumatoid arthritis, systemic lupus erythematosus, or other systemic autoimmune diseases. 4. The presence of a clinically significant, uncontrolled, or unstable medical, psychiatric, or surgical condition that, in the opinion of the investigator, may affect ability to participate in the study or compromise patient safety during the study. 5.Currently have a systemic infectious disease (e.g., HIV, hepatitis). 6. History of serious adverse reactions or allergies to study drugs. 7. Have evidence of clinically significant laboratory abnormalities based on clinical test results at screening and / or medical history, as judged by the investigator.

[0197] Test drug: As described herein, each of the test agents being evaluated in the combination has been extensively studied in humans and animals. The doses and durations of administration evaluated in this study are consistent with the current FDA-approved product labeling for each agent.

[0198] Study medications will be blinded by overencapsulation. Each medication will be provided in a separate bottle, clearly labeled in a blinded manner. Placebo will be provided in the same capsule and bottle as the active study medication. All patients will take one capsule from each assigned bottle twice daily with meals.

[0199] result: Efficacy endpoints: The primary endpoint will be the change in ADAS-Cog score from baseline to week 26.

[0200] Secondary endpoints included: Changes in ADAS-Cog scores from baseline to weeks 8, 16, and 22 Changes in self-reported NRS fatigue scores from baseline to weeks 8, 16, 22, and 26 Changes in PROMIS sleep disturbance 8aT scores from baseline to weeks 8, 16, 22, and 26 The proportion of patients who achieved a PGIC rating of "very much improved" or "much improved" at weeks 8, 16, 22, and 26

[0201] Safety endpoints: Safety assessments included vital signs (sitting blood pressure, heart rate, oral temperature, and weight), adverse events, and clinical tests.

[0202] Statistical analysis: The primary efficacy endpoint for assessing treatment efficacy was the change from baseline in Alzheimer's disease symptoms as measured by the ADAS-Cog assessment. Changes were calculated by comparing baseline Long COVID symptom scores with those measured at weeks 6, 10, and 14. Changes from baseline were calculated by comparing baseline Alzheimer's disease symptoms with those measured at weeks 8, 16, 22, and 26.

[0203] The mean change from baseline in the combination treatment group will be compared to the change calculated in the placebo treatment group over the 16-week treatment period using a mixed-effects model (MMRM). The null hypothesis is that there is no difference between the treatment groups in the mean change from baseline. Rejection of this hypothesis indicates efficacy of the combination treatment.

[0204] All documents mentioned in this specification are deemed to be incorporated herein by reference. When describing elements of the present invention or exemplary embodiments thereof, the articles "a," "an," "the," and "said" are each intended to mean that there are one or more elements. Additionally, the terms "comprising," "including," and "having" are used inclusively, meaning that there may be additional elements other than the listed elements. Although the present invention has been described with reference to specific embodiments, the details of these embodiments should not be construed as limitations.

Claims

1. 1. A method of treating a subject susceptible to or suffering from Alzheimer's disease, comprising: A method comprising administering to said subject a therapeutically effective amount of an antiviral compound and a therapeutically effective amount of a COX-2 inhibitor.

2. 10. The method of claim 1, wherein the antiviral compound is famciclovir or valacyclovir.

3. 3. The method of claim 1 or 2, wherein the COX-2 inhibitor is celecoxib.

4. The method of any one of claims 1 to 3, wherein the antiviral compound is famciclovir and the COX-2 inhibitor is celecoxib.

5. 5. The method of claim 4, wherein famciclovir is administered in a total daily dose range of about 750 mg to about 1500 mg, and celecoxib is administered in a total daily dose range of about 200 mg to about 800 mg.

6. 2. The method of claim 1, wherein the antiviral compound is valacyclovir and the COX-2 inhibitor is celecoxib.

7. 7. The method of claim 6, wherein valacyclovir is administered in a total daily dose range of about 750 mg to about 2000 mg, and celecoxib is administered in a total daily dose range of about 200 mg to about 800 mg.

8. 1. A method of treating a subject susceptible to or suffering from long COVID, comprising: A method comprising administering to said subject a therapeutically effective amount of an antiviral compound and a therapeutically effective amount of a COX-2 inhibitor.

9. 9. The method of claim 8, wherein the antiviral compound is famciclovir or valacyclovir.

10. 10. The method of claim 8 or 9, wherein the COX-2 inhibitor is celecoxib.

11. The method of any one of claims 8 to 10, wherein the antiviral compound is famciclovir and the COX-2 inhibitor is celecoxib.

12. 12. The method of claim 11, wherein famciclovir is administered in a total daily dose range of about 750 mg to about 1500 mg, and celecoxib is administered in a total daily dose range of about 200 mg to about 800 mg.

13. 9. The method of claim 8, wherein the antiviral compound is valacyclovir and the COX-2 inhibitor is celecoxib.

14. 14. The method of claim 13, wherein valacyclovir is administered in a total daily dose range of about 750 mg to about 2000 mg, and celecoxib is administered in a total daily dose range of about 200 mg to about 800 mg.

15. 1. A method of treating a subject susceptible to or suffering from post-acute infectious syndrome (PAIS), comprising: A method comprising administering to said subject a therapeutically effective amount of an antiviral compound and a therapeutically effective amount of a COX-2 inhibitor.

16. 16. The method of claim 15, wherein the PAIS is a sequela of an infection selected from the group consisting of SARS CoV-2 infection, Epstein-Barr virus infection, Ross River virus infection, human herpesvirus 6 infection, varicella-zoster virus infection, Ebola virus infection, West Nile virus infection, dengue virus infection, parvovirus infection, Borrelia burgdorferi infection, Coxiella burnetii infection, and Mycoplasma pneumoniae infection.

17. 17. The method of claim 15 or 16, wherein the antiviral compound is famciclovir or valacyclovir.

18. The method of any one of claims 15 to 17, wherein the COX-2 inhibitor is celecoxib.

19. 16. The method of claim 15, wherein the antiviral compound is famciclovir and the COX-2 inhibitor is celecoxib.

20. 20. The method of claim 19, wherein famciclovir is administered in a total daily dose range of about 750 mg to about 1500 mg, and celecoxib is administered in a total daily dose range of about 200 mg to about 800 mg.

21. 16. The method of claim 15, wherein the antiviral compound is valacyclovir and the COX-2 inhibitor is celecoxib.

22. 22. The method of claim 21, wherein valacyclovir is administered in a total daily dose range of about 750 mg to about 2000 mg, and celecoxib is administered in a total daily dose range of about 200 mg to about 800 mg.

23. 1. A method of treating symptoms of orthostatic intolerance in a subject with post-acute infectious syndrome (PAIS), comprising: A method comprising administering to said subject a therapeutically effective amount of an antiviral compound and a therapeutically effective amount of a COX-2 inhibitor.

24. 24. The method of claim 23, wherein the PAIS is a sequela of an infection selected from the group consisting of SARS CoV-2 infection, Epstein-Barr virus infection, Ross River virus infection, human herpesvirus 6 infection, varicella-zoster virus infection, Ebola virus infection, West Nile virus infection, dengue virus infection, parvovirus infection, Borrelia burgdorferi infection, Coxiella burnetii infection, and Mycoplasma pneumoniae infection.

25. 24. The method of claim 23, wherein the symptom is selected from the group consisting of dizziness, near fainting, lightheadedness, pre-loss of consciousness, blurred vision, tunnel vision, seeing spots, weakness, fatigue, difficulty concentrating, head and neck discomfort, difficulty standing up briefly, difficulty standing up for a long time, difficulty walking for a short time, and difficulty walking for a long time.

26. The method of any one of claims 23 to 25, wherein the antiviral compound is famciclovir or valacyclovir.

27. 27. The method of any one of claims 23 to 26, wherein the COX-2 inhibitor is celecoxib.

28. 28. The method of any one of claims 23 to 27, wherein the antiviral compound is famciclovir and the COX-2 inhibitor is celecoxib.

29. 29. The method of claim 28, wherein famciclovir is administered in a total daily dose range of about 750 mg to about 1500 mg, and celecoxib is administered in a total daily dose range of about 200 mg to about 800 mg.

30. 24. The method of claim 23, wherein the antiviral compound is valacyclovir and the COX-2 inhibitor is celecoxib.

31. 31. The method of claim 30, wherein valacyclovir is administered in a total daily dose range of about 750 mg to about 2000 mg, and celecoxib is administered in a total daily dose range of about 200 mg to about 800 mg.

32. A composition for treating symptoms of Alzheimer's disease, long COVID, post-acute infectious syndrome (PAIS) or orthostatic intolerance in a subject with PAIS, comprising a therapeutically effective amount of an antiviral compound and a therapeutically effective amount of a COX-2 inhibitor.

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