Treatment with antiviral compounds and spirolactones

Abstract

The present disclosure relates to methods of treating virus-induced functional disorder (VIFD), functional somatic syndrome (FSS), and / or the herpes family virus by administering a therapeutically effective combination of an antiviral compound and a spirolactone. The disclosure further relates to pharmaceutical compositions comprising a combination of an antiviral compound and a spirolactone.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 63 / 427,049, filed on November 21, 2022, and U.S. Provisional Application No. 63 / 437,406, filed on January 6, 2023, both of which are incorporated herein by reference in their entireties. Technical Field

[0003] The present disclosure relates to methods for treating viral-induced functional disorders (VIFD), functional somatic syndromes (FSS) and / or herpes family viruses by administering a therapeutically effective combination of an antiviral compound and spironolactone. The present disclosure further relates to pharmaceutical compositions comprising a combination of an antiviral compound and spironolactone. Background Art

[0004] Virus-induced functional disorders (VIFD) are disorders with viral etiologies. Viruses have been shown to play a role in many disorders. In particular, the herpes family of DNA viruses has been found to be associated with many disorders or to have a causal effect in many disorders. For example, multiple studies have shown that patients with chronic fatigue syndrome (CFS) have a high incidence of latent infection or chronic infection caused by herpes family viruses. Similarly, extensive laboratory and clinical studies have shown that herpes type 1, i.e., herpes labialis virus, plays a key role in the development of Alzheimer's disease. Therefore, the literature teaches that VIFD may have common causal factors.

[0005] Functional disorders involve one or more organ systems, have ambiguous or uncertain etiologies, and impair a person's function. These various disorders are grouped under the category of functional somatic syndrome (FSS), which shares overlapping characteristics of physical discomfort, functional disorders of body systems, and fatigue. FSS can be defined as a condition "characterized by a pattern of persistent physical discomfort for which adequate examination does not adequately reveal an explanatory structural pathology or other specified pathology" [P. Henningsen et al., (2007) Lancet 369, 946-954]. Most people with one FSS have additional symptoms or meet the full criteria for another FSS disorder. For example, 20-65% of people with irritable bowel syndrome (IBS) have fibromyalgia, 36-63% have CFS, and 16% have temporomandibular joint disorder (Wiehle and Henningsen, 2014). Similarly, 35-92% of CFS patients have IBS (Wiehle and Henningsen, 2014).

[0006] There remains an unmet need for effective treatment options for VIFD and FSS. Summary of the Invention

[0007] Provided herein are methods and compositions for treating a functional disorder in a subject, wherein the functional disorder is functional somatic syndrome (FSS), viral-induced functional disorder (VIFD), and / or a disease caused by a herpes family virus.

[0008] In one aspect of the present disclosure, provided herein is a pharmaceutical composition comprising a therapeutically effective dose of an antiviral compound, spironolactone, or a combination thereof, formulated for administration to a subject suffering from a functional disorder.

[0009] Another aspect of the present disclosure provides a method of treating a human subject suffering from viral-induced functional disorder (VIFD), functional somatic syndrome (FSS), herpes family virus infection, or a combination thereof, comprising administering a pharmaceutical composition comprising a therapeutically effective dose of an antiviral compound, spironolactone, or a combination thereof.

[0010] These and other features, objects, and advantages of the present disclosure will be better understood from the following description. In the description, reference is made to the accompanying drawings, which form a part hereof and in which embodiments of the present disclosure are shown by way of illustration and not limitation. The description of the preferred embodiments is not intended to limit the present disclosure to encompass all modifications, equivalents, and alternatives. Therefore, when interpreting the scope of the present disclosure, reference should be made to the claims set forth herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] Figure 1 The molecular structure of spironolactone is shown.

[0012] Figure 2 The hierarchy of viral-induced functional disorders (VIFD) is shown. Shown are the genitourinary, gastrointestinal, central nervous, peripheral nervous, immune, and musculoskeletal systems.

[0013] Figure 3 The interactions of the major organ systems in functional somatic syndrome (FSS) are shown. The primary symptom of FSS is fatigue, which is shown as a circle that includes all other symptoms and syndromes.

[0014] Figure 4A-4B The course and timing of FSS and VIFD responses to treatment are shown. Figure 4AThe course and timing of the response of FSS and VIFD to treatment are shown. Three individual cases are shown in line graphs. For each individual case, the duration of symptoms before the start of treatment is shown as a bar, which is divided to show the passage of time. Duration in years is provided in the text. The course of response to antiviral treatment with antiviral guanine analogs is shown as a solid line. On the vertical axis, the response is expressed as a percentage of the baseline FSS or VIFD symptom severity before the start of treatment. The duration is shown in months, with each tick mark on the horizontal axis representing one month. Case 1 shows a patient with a 20-year history of symptoms before the start of treatment. Case 2 shows a patient with a 5-year history of symptoms. Case 3 shows a patient with a 4-year history of symptoms. Figure 4B The composite response across multiple patients is shown. Baseline symptom severity is shown with a gray shaded bar (100%). Symptom severity with the guanine analog antiviral regimen is shown with a vertical striped bar (set to 100%). Symptom severity with the combination of spironolactone plus guanine analog antiviral regimen is shown with a black solid bar. DETAILED DESCRIPTION

[0015] For the purpose of promoting an understanding of the principles of the present disclosure, reference will now be made to embodiments and specific language will be used to describe them. It will nevertheless be understood that the scope of the present disclosure is not thereby intended to be limited in any way, and it should be understood that such changes and further modifications to the disclosure as described herein would normally occur to one skilled in the art to which the present disclosure pertains.

[0016] As used herein, the articles "a" and "an" refer to one or more than one (ie, at least one) of the grammatical object of the article. For example, "an element" means at least one element and may also include more than one element.

[0017] Unless expressly stated or obvious from the context, as used herein, the term "about" should be understood as within the normal tolerance range in the art, for example, within 2 standard deviations of the mean. "About" can be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05% or 0.01% of the stated value. Unless otherwise clear from the context, all numerical values ​​provided herein are modified by the term "about."

[0018] Throughout this specification, unless the context requires otherwise, the words “comprise” and “include” and variations thereof (for example, “comprises”, “comprising”, “includes”, “including”) will be understood to imply the inclusion of a stated component, feature, element or step or group of components, features, elements or steps but not the exclusion of any other integer or step or group of integers or steps.

[0019] As used herein, "and / or" means and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations explained in the alternative ("or").

[0020] Unless otherwise indicated herein, recitation of numerical ranges herein is intended merely as a concise method of individually referring to each separate value falling within the range. Moreover, each separate value is incorporated into this specification as if it were individually recited herein. For example, if a range is stated as 1 to 50, it is intended that values ​​such as 2 to 4, 10 to 30, or 1 to 3 are expressly enumerated in this disclosure. These are merely examples of what is specifically intended, and all possible combinations of values ​​between the lowest value and the highest value (inclusive) recited are considered to be expressly enumerated in this disclosure.

[0021] Unless otherwise defined, all technical terms used herein have the meanings commonly understood by those of ordinary skill in the art to which the present disclosure belongs. The following references provide general definitions of many of the terms used in the present disclosure for technicians: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd edition, 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th edition, R. Rieger et al. (eds.), Springer Verlag (1991); and Hale and Marham, The Harper Collins Dictionary of Biology (1991). As used herein, unless otherwise indicated, the following terms have the meanings assigned to them below.

[0022] As used herein, the term "functional somatic syndrome (FSS)" refers to a condition characterized by a pattern of persistent physical discomfort and in which adequate examination of the physical discomfort does not adequately reveal an explanatory structural pathology or other specified pathology. The methods disclosed herein can be used to treat FSS, including but not limited to: irritable bowel syndrome (IBS), chronic fatigue syndrome (CFS), myalgic encephalomyelitis, fibromyalgia, multiple chemical sensitivity, muscle pain, joint pain, nonspecific chest pain, premenstrual syndrome, non-ulcer dyspepsia, repetitive strain injury, headache, temporomandibular joint disorder, chronic pain, chronic pelvic pain, atypical facial pain, low back pain, sick building syndrome, Gulf War syndrome, interstitial cystitis, chronic Lyme disease, depression, post-traumatic stress disorder (PTSD), chronic anxiety disorders, brain fog or cognitive dysfunction, poor sleep, insomnia, vertigo, tinnitus, and long COVID.

[0023] Symptoms and syndromes can be specific to a given organ system. For example, headaches, brain fog, and Alzheimer's disease are syndromes specific to the central nervous system, cystitis and vaginal pain are specific to the genitourinary system, and joint pain and muscle pain are specific to the musculoskeletal system. More commonly, symptoms and syndromes that characterize FSS involve multiple major organ systems. For example, sick building syndrome, Gulf War syndrome, long COVID, and fibromyalgia have been shown to involve the immune system, central nervous system, peripheral nervous system, and other organ systems.

[0024] As used herein, the term "virus-induced functional disorder (VIFD)" refers to an acute, chronic, latent, or recurrent condition caused by a viral infection. The virus causing the condition can be a member of the herpes family (HSV1, HSV2, herpes type 3 or varicella, herpes type 4 or Epstein-Barr virus, herpes type 5 or cytomegalovirus, herpes type 6, herpes type 7, herpes type 8, herpes type 9, herpes type 10, herpes type 11, herpes type 12) or other viral families. The functional disorder caused by these viral infections can affect any organ system, including but not limited to the central nervous system, peripheral nervous system, immune system, musculoskeletal system, gastrointestinal system, cardiovascular system, and genitourinary system. VIFD can induce various systemic changes in multiple systems.

[0025] As used herein, the term "long COVID" refers to a range of symptoms experienced by patients following COVID infection (both symptomatic and asymptomatic). Long COVID is also known as long haul COVID, post-acute COVID-19, post-acute sequelae of SARS CoV-2 infection (PASC), long-term effects of COVID, and chronic COVID. Symptoms of long COVID may include, but are not limited to, chronic fatigue, loss of smell or taste, insomnia, dizziness, brain fog, difficulty thinking, or a combination thereof.

[0026] As used herein, the term "chronic fatigue syndrome (CFS)" refers to a variety of symptoms including, but not limited to, fatigue, dizziness, difficulty concentrating, pain, post-exertional malaise, or a combination thereof. CFS is also known as myalgic encephalomyelitis.

[0027] As used herein, the term "subject" refers to humans and non-human animals, particularly mammals.

[0028] As used herein, the term "treatment" or "treat" refers to both therapeutic treatment and prophylactic or preventative measures.

[0029] As used herein, the term "administration" or "administering" refers to providing, contacting, and / or delivering a compound or composition by any suitable route to achieve a desired effect. Administration can include, but is not limited to, oral, sublingual, parenteral (e.g., intravenous, subcutaneous, intradermal, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, or intracranial injection), transdermal, topical, buccal, rectal, vaginal, nasal, ocular, via inhalation, or using an implant.

[0030] As used herein, the term "total administration" or "combination" refers to the simultaneous or sequential administration of multiple compounds or compositions. The first compound or composition can be administered before, simultaneously, or after the administration of the second compound or composition. The first compound or composition and the second compound or composition can be administered simultaneously or sequentially on the same day, or can be administered sequentially within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, or 1 month of each other. In some embodiments, compound or composition is administered altogether during the period in which each of these compounds or compositions plays at least some physiological role and / or has a residual effect.

[0031] A "therapeutically effective dose" or "therapeutic dose" is an amount sufficient to achieve a desired clinical result (ie, to achieve therapeutic efficacy). A therapeutically effective dose can be administered in one or more administrations.

[0032] As used herein, the term "pharmaceutical composition" or "therapeutic composition" refers to a compound or composition capable of inducing a desired therapeutic effect when properly administered to a subject.

[0033] As used herein, the term "pharmaceutically acceptable carrier" or "physiologically acceptable carrier" refers to one or more formulation materials suitable for achieving or enhancing the delivery of one or more antibodies of the present disclosure.

[0034] In some embodiments, provided herein is a method of treating VIFD in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of each of an antiviral compound and spironolactone.

[0035] In some embodiments, provided herein is a method of treating FSS in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of each of an antiviral compound and spironolactone.

[0036] In some embodiments, provided herein is a method of treating a herpes family virus in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of each of an antiviral compound and spironolactone.

[0037] The herpes family viruses all share similar viral DNA polymerases, so antiviral guanine analogs are effective against all members of the herpes family: herpes simplex type 1 (herpes type 1), genital herpes (herpes type 2), varicella-zoster (herpes type 3), Epstein-Barr virus (herpes type 4), cytomegalovirus (herpes type 5), human herpes type 6 (herpes type 6), human herpes type 7 (herpes type 7), and human herpes type 8 (herpes type 8). The guanine analogs are also expected to be effective against any unnamed or unidentified herpes virus.

[0038] In some embodiments, the antiviral compound is an antiviral guanine analog. These agents inhibit viral replication by replacing guanine at the viral thymidine kinase. This competitively inhibits viral DNA polymerase and terminates DNA replication, leading to the failure of DNA replication.

[0039] In further embodiments, the antiviral compound is valacyclovir, acyclovir, famciclovir, ganciclovir, valganciclovir, or a combination thereof.

[0040] In some embodiments, the therapeutically effective dose of the antiviral agent will vary depending on the subject's weight, body surface area, organ size, age, and / or health.

[0041] In one embodiment, the amount of the antiviral compound is present in a unit dosage form of about 250 mg to about 6000 mg.

[0042] In another embodiment, the amount of the antiviral compound is present in a unit dosage form of about 250 mg to about 4000 mg.

[0043] In yet another embodiment, the amount of the antiviral compound is present in a unit dosage form of about 250 mg to about 2000 mg.

[0044] In a further embodiment, the amount of the antiviral compound is present in a unit dosage form of 1000 mg or about 1000 mg.

[0045] In yet further embodiments, the amount of the antiviral compound is present in a unit dosage form of at or about 2000 mg.

[0046] In one embodiment, the antiviral compound or combination of antiviral compounds comprises famciclovir.

[0047] In some embodiments, famciclovir is present in a unit dosage form of about 250 mg to about 4000 mg.

[0048] In some embodiments, famciclovir is present in a unit dosage form of about 250 mg or about 500 mg.

[0049] In some embodiments, the amount of famciclovir is present in a unit dosage form of about 125 mg to about 500 mg.

[0050] In some embodiments, the amount of famciclovir is present in a unit dosage form of about 500 mg to about 1000 mg.

[0051] In some embodiments, the amount of famciclovir is present in a unit dosage form of about 125 mg, about 250 mg, about 500 mg, or about 1000 mg.

[0052] In a specific embodiment, the amount of famciclovir is present in a unit dosage form of 500 mg.

[0053] In another specific embodiment, the amount of famciclovir is present in a unit dosage form of 1000 mg.

[0054] In one embodiment, the antiviral compound or combination of antiviral compounds comprises valacyclovir.

[0055] In some embodiments, valacyclovir is present in a unit dosage form of about 1000 mg to about 6000 mg.

[0056] In some embodiments, valacyclovir is present in a unit dosage form of 1000 mg.

[0057] In some embodiments, valacyclovir is present in a unit dosage form of 2000 mg.

[0058] In some embodiments, valganciclovir is present in a unit dosage form of about 400 mg to about 1800 mg.

[0059] In a specific embodiment, the amount of valganciclovir is present in a unit dosage form of 450 mg.

[0060] In another specific embodiment, the amount of valganciclovir is present in a unit dosage form of 900 mg.

[0061] In all embodiments, spironolactone is combined with one or more antiviral compounds. Spironolactone is a mineralocorticoid activity inhibitor that has been used to treat hypertension, edema and acne since 1959. Unlike the effect on mineralocorticoid receptors, spironolactone inhibits the production of herpes family virus capsids. Structurally similar molecules and mineralocorticoid inhibitors lack this antiviral effect. Spironolactone has no effect on early viral gene replication; on the contrary, it inhibits a regulatory protein (Verma D, Thompson J and Swaminathan S, Spironolactone blacks Epstein-Barr virus (EBV) production by inhibiting EBVSM protein function. Proc. Nat. Acad. Sci. V113: 3609-3614, 2016, which is incorporated herein by reference in its entirety) that is responsible for expressing and producing viral capsid proteins (including major viral capsid antigens). In culture, spironolactone prevents the production of viable viral particles. In short, spironolactone inhibits viral replication by preventing the formation of protein capsids rather than inhibiting the synthesis of viral DNA.

[0062] The synergistic combination of using antiviral guanine analogs to inhibit viral gene replication and using spironolactone to prevent viral protein capsid formation is a unique and effective antiviral combination.

[0063] In some embodiments, the therapeutically effective dose of spironolactone will vary depending on the subject's weight, body surface area, organ size, age, and / or health.

[0064] In one embodiment, the amount of spironolactone is present in a unit dosage form of about 10 mg to about 2000 mg.

[0065] In another embodiment, the amount of spironolactone is present in a unit dosage form of about 50 mg to about 1000 mg.

[0066] In yet another embodiment, the amount of spironolactone is present in a unit dosage form of about 10 mg to about 500 mg.

[0067] In some embodiments, the amount of spironolactone is present in a unit dosage form of about 10, about 25 mg, about 50 mg, about 75 mg, or about 100 mg.

[0068] In one embodiment, the amount of spironolactone is present in a unit dosage form of about 100 mg to about 500 mg.

[0069] In one embodiment, the amount of spironolactone is present in a unit dosage form of about 500 mg to about 1000 mg.

[0070] In a specific embodiment, the amount of spironolactone is present in a unit dosage form of 500 mg.

[0071] In a specific embodiment, the unit dosage form of spironolactone is 25 mg.

[0072] In a specific embodiment, the unit dosage form of spironolactone is 100 mg.

[0073] In one embodiment, the antiviral compound and spironolactone are administered in a dosage weight ratio ranging from about one to one to about two thousand to one of the antiviral compound to spironolactone.

[0074] In another embodiment, the antiviral compound and spironolactone are administered in a dosage weight ratio of antiviral compound to spironolactone ranging from about one to one to about one thousand to one.

[0075] In yet another embodiment, the antiviral compound and spironolactone are administered in a dosage weight ratio ranging from about one to one to about five hundred to one of the antiviral compound to spironolactone.

[0076] In further embodiments, the antiviral compound and spironolactone are administered in a dosage weight ratio ranging from about one to one to about one hundred to one of the antiviral compound to spironolactone.

[0077] In yet further embodiments, the antiviral compound and spironolactone are administered in a dosage weight ratio range of about one to one to about fifty to one of antiviral compound to spironolactone.

[0078] In one embodiment, the antiviral compound or compound and spironolactone are co-administered to a subject twice a day, wherein the amount of the antiviral compound is present in a unit dosage form of 450 mg, and wherein the amount of spironolactone is present in a unit dosage form of 25 mg.

[0079] In another embodiment, an antiviral compound and spironolactone are co-administered to a subject twice a day, wherein the amount of the antiviral compound is present in a unit dosage form of 500 mg, and wherein the amount of spironolactone is present in a unit dosage form of 50 mg.

[0080] In yet another embodiment, an antiviral compound and spironolactone are co-administered to a subject twice a day, wherein the amount of the antiviral compound is present in a unit dosage form of 900 mg, and wherein the amount of spironolactone is present in a unit dosage form of 25 mg.

[0081] In a further embodiment, an antiviral compound and spironolactone are co-administered to a subject twice a day, wherein the amount of the antiviral compound is present in a unit dosage form of 900 mg, and wherein the amount of spironolactone is present in a unit dosage form of 50 mg.

[0082] In yet a further embodiment, an antiviral compound and spironolactone are co-administered to a subject twice a day, wherein the amount of the antiviral compound is present in a unit dosage form of 1000 mg, and wherein the amount of spironolactone is present in a unit dosage form of 25 mg.

[0083] In an even further embodiment, the antiviral compound and spironolactone are co-administered to the subject twice a day, wherein the amount of the antiviral compound is present in a unit dosage form of 1000 mg, and wherein the amount of spironolactone is present in a unit dosage form of 50 mg.

[0084] In one embodiment, an antiviral compound and spironolactone are co-administered to a subject twice a day, wherein the amount of the antiviral compound is present in a unit dosage form of 2000 mg, and wherein the amount of spironolactone is present in a unit dosage form of 25 mg.

[0085] In another embodiment, an antiviral compound and spironolactone are co-administered to a subject twice a day, wherein the amount of the antiviral compound is present in a unit dosage form of 2000 mg, and wherein the amount of spironolactone is present in a unit dosage form of 50 mg.

[0086] In yet another embodiment, an antiviral compound and spironolactone are co-administered to a subject twice a day, wherein the first administration of the antiviral compound is in a 1000 mg unit dosage form and the second administration of the antiviral compound is in a 2000 mg unit dosage form, and wherein the amount of spironolactone is present in a 25 mg unit dosage form.

[0087] In a further embodiment, an antiviral compound and spironolactone are co-administered to a subject twice a day, wherein the first administration of the antiviral compound is in a 1000 mg unit dosage form and the second administration of the antiviral compound is in a 2000 mg unit dosage form, and wherein the amount of spironolactone is present in a 50 mg unit dosage form.

[0088] In yet a further embodiment, the antiviral compound is administered twice a day and spironolactone is administered to the subject once a day, wherein the amount of the antiviral compound is present in a unit dosage form of 450 mg and wherein the amount of spironolactone is present in a unit dosage form of 25 mg.

[0089] In an even further embodiment, the antiviral compound is administered twice a day and spironolactone is administered to the subject once a day, wherein the amount of the antiviral compound is present in a unit dosage form of 500 mg and wherein the amount of spironolactone is present in a unit dosage form of 50 mg.

[0090] In one embodiment, the antiviral compound is administered twice a day and spironolactone is administered to the subject once a day, wherein the amount of the antiviral compound is present in a unit dosage form of 900 mg and wherein the amount of spironolactone is present in a unit dosage form of 25 mg.

[0091] In another embodiment, the antiviral compound is administered twice a day and spironolactone is administered to the subject once a day, wherein the amount of the antiviral compound is present in a unit dosage form of 900 mg and wherein the amount of spironolactone is present in a unit dosage form of 50 mg.

[0092] In yet another embodiment, the antiviral compound is administered twice a day and spironolactone is administered to the subject once a day, wherein the amount of the antiviral compound is present in a unit dosage form of 1000 mg and wherein the amount of spironolactone is present in a unit dosage form of 25 mg.

[0093] In a further embodiment, the antiviral compound is administered twice a day and spironolactone is administered to the subject once a day, wherein the amount of the antiviral compound is present in a unit dosage form of 1000 mg and wherein the amount of spironolactone is present in a unit dosage form of 50 mg.

[0094] In yet a further embodiment, the antiviral compound is administered twice a day and spironolactone is administered to the subject once a day, wherein the amount of the antiviral compound is present in a unit dosage form of 2000 mg and wherein the amount of spironolactone is present in a unit dosage form of 25 mg.

[0095] In another further embodiment, the antiviral compound is administered twice a day and spironolactone is administered to the subject once a day, wherein the amount of the antiviral compound is present in a unit dosage form of 2000 mg and wherein the amount of spironolactone is present in a unit dosage form of 50 mg.

[0096] In yet a further embodiment, the antiviral compound is administered twice a day and spironolactone is administered to the subject once a day, wherein the first administration of the antiviral compound is in a 1000 mg unit dosage form and the second administration of the antiviral compound is in a 2000 mg unit dosage form, and wherein the amount of spironolactone is present in a 25 mg unit dosage form.

[0097] In another even further embodiment, the antiviral compound is administered twice a day and spironolactone is administered to the subject once a day, wherein the first administration of the antiviral compound is in a 1000 mg unit dosage form and the second administration of the antiviral compound is in a 2000 mg unit dosage form, and wherein the amount of spironolactone is present in a 50 mg unit dosage form.

[0098] In some embodiments, the antiviral compound is administered once a day.

[0099] In another embodiment, the antiviral compound is administered twice a day.

[0100] In yet another embodiment, the antiviral compound is administered more than twice a day.

[0101] In some embodiments, when administered more than once a day, the unit dosage form of the antiviral compound is the same for each administration.

[0102] In another embodiment, when administered more than once a day, the unit dosage form of the antiviral compound is different at each administration.

[0103] In some embodiments, the unit dosage form of the antiviral compound is 500 mg.

[0104] In some embodiments, the unit dosage form of the antiviral compound is 1000 mg.

[0105] In some embodiments, the unit dosage form of the antiviral compound is 2000 mg.

[0106] In some embodiments, spironolactone is administered once a day.

[0107] In another embodiment, spironolactone is administered twice a day.

[0108] In yet another embodiment, spironolactone is administered more than twice a day.

[0109] In some embodiments, when administered more than once a day, the unit dosage form of spironolactone is the same for each administration.

[0110] In another embodiment, when administered more than once a day, the unit dosage form of spironolactone is different at each administration.

[0111] In some embodiments, the unit dosage form of spironolactone is 25 mg.

[0112] In some embodiments, the unit dosage form of spironolactone is 50 mg.

[0113] In some embodiments, the unit dosage form of spironolactone is 100 mg.

[0114] In some embodiments, the antiviral compound and spironolactone are administered for a two week treatment period, a four week treatment period, a six week treatment period, an eight week treatment period, a twelve week treatment period, a twenty-four week treatment period, a thirty-six week treatment period, a forty-eight week treatment period, a sixty week treatment period, a seventy-two week treatment period, or a treatment period of one year or longer.

[0115] In another embodiment, the antiviral compound and spironolactone are administered chronically or continuously over an extended period of time (months to years).

[0116] In some embodiments, spironolactone is co-administered to a subject with one or more antiviral agents to treat VIFD, FSS, and / or herpes family viruses.

[0117] In some embodiments, VIFD is a disorder affecting the genitourinary system, gastrointestinal system, central nervous system, immune system, musculoskeletal system, peripheral nervous system, or a combination thereof.

[0118] In certain embodiments, the disorder is a disorder of the genitourinary system.

[0119] In some embodiments, genitourinary disorders include, but are not limited to, cystitis and vaginal pain.

[0120] In specific embodiments, the VIFD is a disorder of the gastrointestinal system.

[0121] In some embodiments, gastrointestinal disorders include but are not limited to IBS, ulcerative colitis, and colitis.

[0122] In certain embodiments, the VIFD is a disorder of the central nervous system.

[0123] In some embodiments, central nervous system disorders include, but are not limited to, headaches, brain fog, Parkinson's disease, Alzheimer's disease, dementia, depression, anxiety, and CFS.

[0124] In certain embodiments, the VIFD is a disorder of the immune system.

[0125] In some embodiments, immune system disorders include but are not limited to a compromised immune system, CFS, and fibromyalgia.

[0126] In specific embodiments, the VIFD is a disorder of the musculoskeletal system.

[0127] In some embodiments, musculoskeletal disorders include, but are not limited to, joint pain, muscle pain, and fatigue.

[0128] In specific embodiments, VIFD is a disorder of the peripheral nervous system.

[0129] In some embodiments, peripheral nervous system disorders include, but are not limited to, pain, numbness, and complex regional pain syndrome.

[0130] In certain embodiments, the methods described herein result in a decrease in the administration of at least one additional therapeutic compound previously administered to a subject. In some embodiments, the compound previously administered to a subject is gabapentin, clonazepam, pregabalin, duloxetine, milnacipran, amitriptyline, fluoxetine, paroxetine, sertraline, citalopram, escitalopram, levodopa, carbidopa, pramipexole, ropinirole, donepezil, galantamine, memantine, a COX-2 inhibitor, a nonsteroidal anti-inflammatory drug, tramadol, morphine, a sleep aid, and / or a muscle relaxant.

[0131] In one embodiment, provided herein is a pharmaceutical composition comprising a pharmaceutically acceptable carrier in combination with a therapeutically effective amount of an antiviral compound and a therapeutically effective amount of spironolactone.

[0132] In some embodiments, the antiviral compound in the pharmaceutical composition is an antiviral guanine analog. In some embodiments, the antiviral compound is valacyclovir, acyclovir, famciclovir, ganciclovir, or valganciclovir.

[0133] In specific embodiments, the weight ratio of the antiviral compound to spironolactone in the pharmaceutical composition ranges from about one to one to about five hundred to one.

[0134] In specific embodiments, the weight ratio of the antiviral compound to spironolactone ranges from about one hundred to one, about fifty to one, about twenty to one, or about five to one.

[0135] In one embodiment, the amount of the antiviral compound is present in the pharmaceutical composition in a unit dosage form of about 250 mg to about 6000 mg.

[0136] In another embodiment, the amount of the antiviral compound is present in a unit dosage form of about 250 mg to about 4000 mg.

[0137] In yet another embodiment, the amount of the antiviral compound is present in a unit dosage form of about 250 mg to about 2000 mg.

[0138] In a further embodiment, the amount of the antiviral compound is present in a unit dosage form of 1000 mg.

[0139] In yet a further embodiment, the amount of the antiviral compound is present in a unit dosage form of 2000 mg.

[0140] The compositions of the present disclosure can be administered orally, including by swallowing so that the compositions enter the gastrointestinal tract, or absorbed directly from the oral cavity into the bloodstream (e.g., buccal administration or sublingual administration). Suitable compositions for oral administration include solid formulations such as tablets, lozenges, and capsules, which may contain liquids, gels, or powders.

[0141] Compositions for oral administration may be formulated to be immediate or modified release, including delayed or sustained release, optionally with an enteric coating.

[0142] Liquid preparations can include solutions, syrups and suspensions, which can be used in soft capsules or hard capsules. Such preparations can include pharmaceutically acceptable carriers, such as water, ethanol, polyethylene glycol, cellulose or oil. Preparations can also include one or more emulsifiers and / or suspending agents.

[0143] Tablets may contain a disintegrant, which comprises from about 0.5% to about 35% by weight of the dosage form, more typically from about 2% to about 25% by weight. Examples of disintegrants include methylcellulose, sodium or calcium carboxymethylcellulose, crosslinked sodium carboxymethylcellulose, polyvinyl pyrrolidone, hydroxypropyl cellulose, starch, and the like.

[0144] Suitable lubricants for use in tablets may be present in an amount of about 0.1% to about 5% by weight and include calcium stearate, zinc or magnesium stearate, sodium stearyl fumarate, and the like.

[0145] Suitable binders for use in tablets include gelatin, polyethylene glycol, sugars, gums, starch, hydroxypropylcellulose, etc. Suitable diluents for use in tablets include mannitol, xylitol, lactose, dextrose, sucrose, sorbitol and starch.

[0146] Suitable surfactants and glidants for use in tablets may be present in amounts of about 0.1% to about 3% by weight and include polysorbate 80, sodium lauryl sulfate, talc, and silicon dioxide.

[0147] Compositions of the present disclosure can be directly administered into the bloodstream, muscle or internal organs. Suitable means for parenteral administration include intravenous, intramuscular, subcutaneous intra-arterial, intraperitoneal, intrathecal, intracranial, etc. Suitable devices for parenteral administration include syringes (including needle syringes and needleless syringes) and infusion methods. Compositions for parenteral administration can be formulated into immediate release or modified release, including delayed release or sustained release. Most parenteral preparations are aqueous solutions containing excipients, and the excipients include salts, buffers and carbohydrates. Parenteral preparations can also be prepared into dehydrated forms (for example, by lyophilization) or prepared into sterile non-aqueous solutions. These preparations can be used together with suitable carriers such as sterile water. Solubility enhancers can also be used in the preparation of parenteral solutions.

[0148] Compositions of the present disclosure can be topically applied to the skin or transdermally applied. Preparations for such topical application can include lotions, solutions, creams, gels, hydrogels, ointments, foams, implants, patches, etc. Pharmaceutically acceptable carriers for topical preparations can include water, alcohol, mineral oil, glycerol, polyethylene glycol, etc. Topical application can also be carried out by electroporation, iontophoresis, sonophoresis, etc. Compositions for topical application can be formulated to release immediately or to modify release, including delayed release or sustained release.

[0149] In some embodiments, provided herein is a kit comprising an antiviral compound and spironolactone associated with each other, such as in a single package or in a drug dispensing device. Such a kit for use by a subject can be dispensed by a hospital formulary, a retail pharmacist, or a prescribing physician.

[0150] In one embodiment, the kit includes a single package having therapeutically effective doses of an antiviral compound and spironolactone in the form of tablets or capsules in separate containers (e.g., bottles) that are stored individually (e.g., in a tray) and included together in a single package using, for example, shrink wrap, tape, or a plastic or cardboard box to enclose the components.

[0151] In another embodiment, separate therapeutically effective doses of an antiviral compound in tablet or capsule form and spironolactone are co-packaged in a single blister pack.

[0152] In another embodiment, the kit includes an antiviral compound and spironolactone in tablet or capsule form that are co-dispensed from a device that delivers the components from storage containers using, for example, one or more operating rods to co-dispense separate dosage forms of the antiviral compound and spironolactone for combined administration.

[0153] The kit is also useful for parenteral administration of dosage forms of the antiviral compound and spironolactone. For example, individual doses of the antiviral compound and spironolactone in the form of lyophilized powders (alone, or mixed together in a therapeutically effective dose) are arranged in a package that also includes a separately contained vial of sterile water or buffer solution and, optionally, a sterile packaged syringe for administering the combined dose upon dissolution.

[0154] The kit may further include instructions consistent with approval by a governmental agency (eg, the U.S. FDA) on how to use the kit components for administration to achieve a therapeutic result.

[0155] Various exemplary embodiments of the compositions and methods according to the present disclosure are now described in the following non-limiting examples. These examples are for illustrative purposes only and are not intended to limit the scope of the present disclosure in any way. In fact, various modifications of the present disclosure, except those shown and described herein, will become apparent to those skilled in the art from the foregoing description and the following examples, and fall within the scope of the appended claims.

[0156] Example

[0157] The following examples illustrate specific embodiments of the present disclosure and various uses thereof. They are set forth for illustrative purposes only and should not be construed as limiting the scope of the present invention in any way.

[0158] Example 1: Chronic Fatigue Syndrome

[0159] An elderly woman presented with a 20-year history of fatigue, brain fog, anxiety, and disability. These symptoms were consistent with chronic fatigue syndrome (CFS). She reported daily naps and was confined to her home due to exhaustion after exertion and discomfort with any physical activity. When she attempted simple tasks, such as going to the grocery store, she could only complete them for about 15 minutes before "crashing" and remaining bedridden for two or three days due to exhaustion and malaise. Viral laboratory tests confirmed persistent infection with herpes simplex virus types 4 and 6. Antiviral therapy with valacyclovir, 1000 mg orally twice daily, was initiated. While the patient experienced modest improvement in fatigue, she continued to experience daily naps, brain fog, and fatigue that prevented her from performing daily activities. Spironolactone, 25 mg orally once daily, was added to her regimen. Within a month, she reported significant improvement in fatigue, brain fog, and energy. The spironolactone dose was increased to 50 mg orally once daily. The patient experienced a significant improvement in energy, brain fog, and fatigue. After years of not leaving her home, she was able to go to the grocery store and restaurants. She calls July 3rd her "miracle day," when she was able to complete tasks without feeling exhausted. After a year using the combination regimen, she has increased her energy, is able to perform daily tasks, participate in social activities, and feel clear-headed. She says, "I'm thrilled! You've given me my life back."

[0160] Example 2: Virus-Induced Functional Disorder (VIFD)

[0161] An adult woman complained of multiple VIFD symptoms involving multiple organ systems. She experienced fatigue, weakness after exertion, brain fog, and poor sleep consistent with CFS. Symptoms consistent with fibromyalgia included muscle and joint pain, accompanied by trigger point pain. She experienced headaches, sore throat, lymph node pain, depression, anxiety, numbness, and generalized pain. These symptoms involved the central nervous system, genitourinary system, gastrointestinal system, immune system, musculoskeletal system, and peripheral nervous system. Laboratory testing revealed evidence of ongoing infection with herpes simplex virus (HEV) types 4 and 6. The patient was started on oral valacyclovir 1000 mg twice daily, and over a three-month period, her symptoms showed slight improvement. Spironolactone 25 mg was then added orally once daily. There was no response. The dose of spironolactone was increased to 50 mg once daily. The patient showed significant signs of improvement, with less pain and more energy. The dose of spironolactone was increased to 50 mg orally twice daily. Over the following 12 months, the patient showed significant improvement in symptoms. She stated, "You have changed my life."

[0162] Example 3: Anxiety, Depression and Fatigue

[0163] A late middle-aged woman complained of anxiety, depression, and fatigue. Cognitive testing also revealed mild cognitive impairment. She described confused thinking, poor memory, and difficulty working full days as a computer programmer due to exhaustion. If she overexerted herself, she would experience "crashes" and need to sleep for hours. Sometimes, these "crashes" would last one or two days. Single-photon emission computed tomography (SPECT) revealed patchy hypoperfusion consistent with infection, distinct from a pattern consistent with early dementia or depression. Viral testing showed evidence of herpes 4, 5, and 6. The patient was started on oral valacyclovir, 1000 mg twice daily. After six months, the patient showed modest improvement in mood and energy, but overall fatigue and anxiety remained. She rated her energy level as having increased by 35%. The antiviral medication was switched to famciclovir, another guanine analog, 1000 mg orally twice daily. Within three months, the patient reported a steady and incremental improvement in her energy. Her cognitive abilities also improved, and she no longer experienced brain fog. She reported a significant improvement in her mood and anxiety. She could work, shop, or run errands all day without "crashing" and needing hours of sleep. After six months, the patient voluntarily chose to stop taking famciclovir. Within a few weeks, she experienced the return of severe fatigue, brain fog, anxiety, and low mood. The patient restarted taking famciclovir and felt more energetic, clear-headed, with improved mood and less anxiety. However, she did not reach her pre-illness energy level. She felt she had only 65% ​​of her baseline energy. At that time, spironolactone was added, 25 mg daily. After a few weeks, the patient felt her energy had improved. She reported that she could exercise regularly. Within two months, she began practicing Aikido twice a week and did not experience "crashes." She reported that her mental function was better than before. Her anxiety and depression symptoms had resolved.

[0164] Example 4: Chronic Fatigue Syndrome

[0165] A middle-aged woman presented with a nearly 20-year history of CFS symptoms. Prior to her onset, she had run marathons and exercised regularly. After the onset of CFS, she experienced worsening exercise intolerance. She could no longer run marathons. She could no longer exercise without experiencing muscle pain, severe fatigue, and a "crash." She then experienced tachycardia and palpitations even at rest. As this condition progressed, she could no longer stand in line at the grocery store without experiencing tachycardia and a "crash." She experienced memory problems and confusion, or "brain fog." Notably, she also developed irritable bowel syndrome, which caused multiple episodes of diarrhea daily. She also suffered from genitourinary symptoms of painful and frequent urination. As her condition became increasingly impaired, she became depressed. Viral testing tested positive for herpes serotypes 4, 5, and 6. The patient was started on valacyclovir 2000 mg daily. Over a six-month period, she experienced modest improvement. Her mental clarity improved, and she felt less depressed. She gained a desire to engage in various activities and tasks, but her energy levels remained low. The valacyclovir dose was increased to 3000 mg / day. Her brain fog resolved completely. Her mood improved. Her mental and physical stamina improved, allowing her to complete household chores and some errands. She also reported improvement in her gastrointestinal symptoms. Her diarrhea decreased. She was able to engage in light exercise and resume playing her flute. However, she still easily collapsed if she overexerted herself. At this time, she was started on spironolactone 25 mg / day. Within three weeks, her energy improved. She reported that she could exercise for longer periods without collapsing. She was able to resume cycling. Her tachycardia and palpitations resolved. Her mental clarity improved further. The spironolactone dose was increased to 50 mg / day. The patient reported further improvement in her mood and energy. Her symptoms of painful and frequent urination resolved. She now maintains a regular exercise schedule, runs errands, and plays her flute in ensembles without collapsing. She said, "I'm a little surprised!"

[0166] Example 5: Brain Fog

[0167] An adult male university professor presented for evaluation with memory problems, fatigue, post-exertional malaise, and brain fog. Laboratory testing revealed evidence of persistent herpes type 1 and herpes type 4 infection. The patient was started on antiviral therapy with valacyclovir 2000 mg orally twice daily. After six months, the patient experienced only slight improvement in his symptoms. Valacyclovir was discontinued and valganciclovir 450 mg orally twice daily was initiated. One month later, valganciclovir was increased to 900 mg orally twice daily. Two months later, the patient showed additional, but slight, improvement in his fatigue, brain fog, and post-exertional malaise symptoms. Spironolactone was added to his regimen at a dose of 25 mg orally twice daily. Within three months of using the combination of valganciclovir and spironolactone, his energy had improved dramatically, and his memory and cognitive function had improved significantly.

[0168] Example 6: Focus

[0169] A 20-year-old male college student complained of fatigue, exhaustion, exercise intolerance, difficulty concentrating, memory loss, and "brain fog." Viral testing revealed herpes serotypes 4, 5, and 6. The patient was started on oral valacyclovir 2000 mg / day. After two months, the patient showed only modest improvement. He estimated his energy had improved by 20%, but he continued to have difficulty cognition, which led to difficulties in learning. The valacyclovir dose was increased to 3000 mg / day. After six weeks, the patient reported additional modest improvement and estimated his energy was 40% better. Spironolactone 25 mg orally daily was started. Within three weeks, the patient experienced a substantial improvement in his symptoms. His "brain fog" disappeared, and he could concentrate fully. His energy increased to 100% of his baseline. He resumed exercise and, within a few weeks, was running 2 miles every morning. His academic performance and memory returned to baseline. He was admitted to a highly competitive graduate program in biochemistry.

[0170] Example 7: Long COVID

[0171] A 42-year-old man presented with a 25-year history of chronic fatigue syndrome. He reported having had mononucleosis at age 15, followed by fatigue symptoms at age 17. His symptoms included fatigue, poor sleep, brain fog, memory difficulties, frequent headaches, and mild joint pain. In 2021, he contracted COVID-19, after which his symptoms worsened significantly. He experienced extreme fatigue and required multiple naps daily. If he exerted himself mentally or physically, he would experience a "crash." His joint pain became more severe. He developed muscle pain. His cognitive symptoms of brain fog and impaired memory worsened, and he could no longer concentrate. His headaches worsened in intensity and frequency. Due to his disability, he could no longer work. Viral testing was positive for herpes 4 and 6. COVID PCR was negative, but the patient showed COVID antibodies. The patient was started on oral valacyclovir 2000 mg / day. After two months of little improvement, valganciclovir was increased to 900 mg / day. Over the next two months, the patient showed some improvement and more energy. The patient reduced his naps to once or twice a day. He was able to cook a meal or do some chores without "crashing." Spironolactone 25 mg orally daily was started. Within a month, the patient saw significant improvement. The patient reported that his headaches and his joint pain had greatly decreased. His "brain fog" had lessened. The patient reported that he had not been able to focus as well as he could in years. The patient reported improved energy. He only needed to take one nap a day and could work for four hours at a time. The spironolactone dose was increased to 50 mg orally daily. Within a few weeks, the patient again saw significant improvement. He reported a significant increase in energy. His joint pain and muscle pain had largely resolved. He reported that his concentration and memory had greatly improved and that he no longer felt foggy. The patient was able to find part-time work.

[0172] Example 8: Irritable Bowel Syndrome

[0173] A 36-year-old doctoral student was referred by his psychiatrist because of recent onset of severe fatigue, excessive sleepiness, joint pain, irritable bowel symptoms (IBS), headaches, depressed mood, and confusion. Symptoms had suddenly developed eight months prior to the examination. The patient had been actively exercising, running several miles daily and lifting weights three times a week. He was also working on his doctoral dissertation, which required considerable time. Viral laboratory tests revealed herpes serotypes 4, 5, and 6, with evidence of active replication of herpes serotype 4. The patient was started on oral valacyclovir 2000 mg twice daily. After five months, the patient reported improved energy. He was able to complete a demanding work schedule and his dissertation writing project. His mood improved. His gastrointestinal symptoms improved. However, he had no energy for exercise and "crashed" when he tried. Famciclovir was added to 500 mg orally twice daily. One month later, famciclovir was increased to 1000 mg twice daily, combined with valacyclovir 2000 mg twice daily. The patient was able to exercise gently and continue his work duties. He defended his dissertation and began writing a paper based on the data from his dissertation. However, he continued to experience mild fatigue. He was also unable to exercise at the same level as before the onset of the disease. Spironolactone, 25 mg orally daily, was started. One month later, the patient reported, "Oh my goodness—the fog in my head has lifted!" He reported a significant increase in mental energy, better concentration, and the feeling that he could think more clearly. He also reported being more creative. The patient also reported an improvement in his mood and that he was less irritable. The patient was able to resume running and weightlifting without experiencing a "crash," and slowly increased the distance and weights in his physical training regimen.

[0174] Example 9: Results

[0175] Three individuals were treated with spironolactone and antiviral therapy ( Figure 4A-4B Case 1 shows a patient with a 20-year history of symptoms before treatment ( Figure 4B ). Antiviral therapy alone resulted in significant improvement in symptoms. One month after the addition of spironolactone to the guanine analog regimen, a significant reduction in the severity of symptoms occurred. Subsequently, the severity of symptoms continued to decrease more gradually on an ongoing basis. Case 2 shows a patient with a 5-year history of symptoms. After 6 months of combined treatment, the patient achieved an almost symptom-free state (20%). The patient then discontinued spironolactone. Over the next three months, symptoms rapidly worsened. When the patient restarted the combination therapy of spironolactone and the guanine analog regimen, the severity of symptoms rapidly decreased. With this combination, the patient achieved complete remission of symptoms. Case 3 shows a patient with a 4-year history of symptoms ( Figure 4AAntiviral therapy alone resulted in modest improvement in symptoms. One month after adding spironolactone to the guanine analog regimen, the severity of symptoms was significantly reduced. Subsequently, the severity of symptoms continued to decrease more gradually on an ongoing basis.

[0176] As shown in the bar chart ( Figure 4B ), with baseline symptom severity of 100% without any treatment. The average symptom severity for patients taking the guanine analog antiviral regimen alone was 60%. Symptom severity was reduced to an average of 20% for all three patients who took the combination of spironolactone and a guanine analog antiviral.

Claims

1. A pharmaceutical composition comprising a therapeutically effective dose of an antiviral compound, spironolactone, or a combination thereof, formulated for administration to a subject suffering from a functional disorder.

2. The pharmaceutical composition of claim 1, wherein the functional disorder is virus-induced functional disorder (VIFD).

3. The pharmaceutical composition of claim 1, wherein the VIFD is a disorder affecting the genitourinary system, gastrointestinal system, central nervous system, immune system, musculoskeletal system, peripheral nervous system, or a combination thereof.

4. The pharmaceutical composition as claimed in claim 3, wherein the VIFD is a disorder of the genitourinary system.

5. The pharmaceutical composition as claimed in claim 4, wherein the disorders of the genitourinary system are cystitis and vaginal pain.

6. The pharmaceutical composition as claimed in claim 3, wherein the VIFD is a disorder of the gastrointestinal system.

7. The pharmaceutical composition as claimed in claim 6, wherein the disorder of the gastrointestinal system is irritable bowel syndrome (IBS), ulcerative colitis or colitis.

8. The pharmaceutical composition as claimed in claim 3, wherein the VIFD is a disorder of the central nervous system.

9. The pharmaceutical composition of claim 8, wherein the disorder of the central nervous system is headache, brain fog, Parkinson's disease, Alzheimer's disease, dementia, depression, anxiety or chronic fatigue syndrome (CFS).

10. The pharmaceutical composition of claim 3, wherein the VIFD is a disorder of the immune system.

11. The pharmaceutical composition of claim 10, wherein the VIFD is a compromised immune system, CFS or fibromyalgia.

12. The pharmaceutical composition as claimed in claim 3, wherein the VIFD is a disorder of the musculoskeletal system.

13. The pharmaceutical composition as claimed in claim 12, wherein the disorder of the musculoskeletal system is joint pain, muscle pain or fatigue.

14. The pharmaceutical composition as claimed in claim 3, wherein the VIFD is a disorder of the peripheral nervous system.

15. The pharmaceutical composition of claim 14, wherein the disorder of the peripheral nervous system is pain, numbness or complex regional pain syndrome.

16. The pharmaceutical composition of claim 1, wherein the functional disorder is functional somatic syndrome (FSS).

17. The pharmaceutical composition of claim 16, wherein the FSS is one or more of irritable bowel syndrome (IBS), chronic fatigue syndrome (CFS), fibromyalgia, multiple chemical sensitivity, muscle pain, joint pain, nonspecific chest pain, premenstrual syndrome, non-ulcer dyspepsia, repetitive strain injury, headache, temporomandibular joint disorder, chronic pain, chronic pelvic pain, atypical facial pain, low back pain, sick building syndrome, Gulf War syndrome, long COVID, interstitial cystitis, chronic Lyme disease, depression, post-traumatic stress disorder (PTSD), chronic anxiety disorder, brain fog, cognitive dysfunction, poor sleep, insomnia, vertigo, tinnitus, or a combination thereof.

18. The pharmaceutical composition of claim 1, wherein the functional disorder is a herpes family virus.

19. pharmaceutical compositions as described in claim 16, wherein said herpes family virus is one or more in herpes simplex type 1 (herpes type 1), genital herpes (herpes type 2), varicella-zoster (herpes type 3), Epstein-Barr virus (herpes type 4), cytomegalovirus (herpes type 5), human herpes type 6 (herpes type 6), human herpes type 7 (herpes type 7) or human herpes type 8 (herpes type 8).

20. The pharmaceutical composition of claim 1, wherein the antiviral compound is an antiviral guanine analog.

21. The pharmaceutical composition of claim 1, wherein the antiviral compound is valacyclovir, acyclovir, famciclovir, ganciclovir, valganciclovir, or a combination thereof.

22. The pharmaceutical composition of claim 1, wherein the antiviral compound is present in an amount of about 250 mg to about 6000 mg.

23. The pharmaceutical composition of claim 1, wherein the antiviral compound is present in an amount of about 1000 mg.

24. The pharmaceutical composition of claim 1, wherein the antiviral compound is present in an amount of about 2000 mg.

25. The pharmaceutical composition of claim 1, wherein spironolactone is present in an amount of about 10 mg to about 2000 mg.

26. The pharmaceutical composition of claim 1, wherein the spironolactone is present in an amount of about 10 mg to about 2000 mg.

27. The pharmaceutical composition of claim 24, wherein spironolactone is present in an amount of 100 mg.

28. The pharmaceutical composition of claim 24, wherein spironolactone is present in an amount of 50 mg.

29. The pharmaceutical composition of claim 24, wherein spironolactone is present in an amount of 25 mg.

30. The pharmaceutical composition of claim 1, wherein the ratio of the antiviral compound to spironolactone is a dose weight ratio of about 1:1 to about 2000:

1.

31. The pharmaceutical composition of claim 30, wherein the ratio of the antiviral compound to spironolactone is about 1000:1 dose weight ratio.

32. The pharmaceutical composition of claim 30, wherein the ratio of the antiviral compound to spironolactone is about 50:1 dose weight ratio.

33. A method of treating a human subject suffering from a viral-induced functional disorder (VIFD), a functional somatic syndrome (FSS), a herpes family virus, or a combination thereof, the method comprising administering to the subject a composition as described in claim 1.

34. The method of claim 33, wherein the human subject suffers from VIFD.

35. The method of claim 33, wherein the human subject suffers from FSS.

36. The method of claim 33, wherein the human subject has a herpes family virus.

37. The method of claim 33, wherein the antiviral compound is an antiviral guanine analog.

38. The method of claim 33, wherein the antiviral compound is valacyclovir, acyclovir, famciclovir, ganciclovir, valganciclovir, or a combination thereof.

39. The method of claim 33, wherein the antiviral compound is present in an amount of about 250 mg to about 6000 mg.

40. The method of claim 33, wherein the antiviral compound is present in an amount of 1000 mg.

41. The method of claim 33, wherein the antiviral compound is present in an amount of 2000 mg.

42. The method of claim 33, wherein spironolactone is present in an amount of about 10 mg to about 2000 mg.

43. The method of claim 42, wherein spironolactone is present in an amount of 100 mg.

44. The method of claim 42, wherein spironolactone is present in an amount of 50 mg.

45. The method of claim 42, wherein spironolactone is present in an amount of 25 mg.

46. ​​The method of any one of claims 33-41, wherein the ratio of the antiviral compound to spironolactone is a dose weight ratio of about 1:1 to about 500:

1.

47. The method of claim 33, wherein the antiviral compound is administered to the human subject twice a day.

48. The method of claim 33, wherein spironolactone is administered twice a day.

49. The method of claim 33, wherein spironolactone is administered once a day.

50. The method of claim 33, wherein the VIFD is a disorder affecting the genitourinary system, gastrointestinal system, central nervous system, immune system, musculoskeletal system, peripheral nervous system, or a combination thereof.

51. The method of claim 33, wherein the FSS is irritable bowel syndrome (IBS), chronic fatigue syndrome (CFS), fibromyalgia, multiple chemical sensitivity, muscle pain, joint pain, nonspecific chest pain, premenstrual syndrome, non-ulcer dyspepsia, repetitive strain injury, headache, temporomandibular joint disorder, chronic pain, chronic pelvic pain, atypical facial pain, low back pain, sick building syndrome, Gulf War syndrome, long COVID, interstitial cystitis, chronic Lyme disease, depression, post-traumatic stress disorder (PTSD), chronic anxiety disorder, brain fog, cognitive dysfunction, poor sleep, insomnia, vertigo, tinnitus, or a combination thereof.

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