WO2021216562A1

WO2021216562A1 - Zinc for treating covid-19

Info

Publication number: WO2021216562A1
Application number: PCT/US2021/028174
Authority: WO
Inventors: Eric FINZI
Original assignee: Finzi Eric
Priority date: 2020-04-21
Filing date: 2021-04-20
Publication date: 2021-10-28

Abstract

Methods are provided for treating a SARS-CoV-2 infection in a subject. These methods include selecting a subject with a SARS-CoV-2 infection; and administering to the subject with the SARS-CoV-2 infection an effective amount of elemental zinc, such as in the form of a zinc salt, thereby treating the SARS-CoV-2 infection in the subject. The subject can have long COVID.

Description

ZINC FOR TREATING COVID-19

CROSS REFERENCE TO RELATED APPLICATIONS

This claims the benefit of U.S. Provisional Application No. 63/013,431, filed April 21, 2020, which is incorporated herein by reference in its entirety.

FIELD OF THE DISCLOSURE

This relates to SARS Coronavirus-2 (SARS-CoV-2), specifically to methods for treating a subject with COVID-19.

BACKGROUND

Coronaviruses are enveloped, positive-sense single-stranded RNA viruses. They have the largest genomes (26-32 kb) among known RNA viruses, and are phylogenetically divided into four genera (a, b, g, d), with betacoronaviruses further subdivided into four lineages (A, B, C, D). Coronaviruses infect a wide range of avian and mammalian species, including humans.

In 2019, a novel coronavirus (designated SARS-CoV-2 by the World Health Organization) was identified as the causative agent of a coronavirus epidemic that appears to have originated in Wuhan, China. The disease caused by this coronavirus is called COVID-19. The high case-fatality rate, vaguely defined epidemiology, and absence of prophylactic measures against coronaviruses have created an urgent need for an effective therapeutic agent.

SUMMARY OF THE DISCLOSURE

Methods are disclosed herein for treating a SARS-CoV-2 infection in a subject, These methods include selecting a subject with a SARS-CoV-2 infection, and administering to the subject with the SARS-CoV-2 infection an effective amount of elemental zinc, such as in the form of a zinc salt, thereby treating the SARS-CoV-2 infection in the subject. In some non limiting examples, the zinc salt is zinc acetate, zinc citrate, zinc gluconate, zinc sulfate, or any combination thereof. The subject can have long COVID.

In some embodiments, the method also includes administering to the subject with the SARS-CoV-2 infection an effective amount of a zinc ionophore. In specific non-limiting examples, the zinc ionophore is quercetin, epigallocatechin gall ate (EGCE), pyrithione, hinokitiol, or pyrrolidine-dithiocarbamate (PDTC).

In further embodiments, the zinc is administered with other therapeutic agents. In a specific non-limiting example, the therapeutic agent is L-lysine. In another specific non-limiting example, the therapeutic agent is echinacea purpura. In another specific non-limiting example, the therapeutic agent is Vitamin C.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows self-monitored Pa02 by pulse oximetry of Subject 3 from Example 1. The arrow indicates the start of high dose zinc lozenges.

FIG. 2 shows self-monitored daily oral temperature of Subject 3 from Example 1. The arrow indicates the start of high dose zinc lozenges.

FIG. 3 shows COVID-19 symptom score over time of case 18 from Example 2. The arrow indicates the start of zinc lozenges.

The foregoing and other features and advantages of the invention will become more apparent from the following detailed description of several embodiments.

DETAILED DESCRIPTION OF SEVERAL EMBODIMENTS

Methods are disclosed herein for treating a SARS-CoV-2 infection in a subject, These methods include selecting a subject with a SARS-CoV-2 infection, and administering to the subject with the SARS-CoV-2 infection an effective amount of elemental zinc in the form of a zinc salt. The disclosed methods were effective in human subjects, as disclosed in the Examples. The disclosed methods are of use for treating long COVID.

I. Summary of Terms

Unless otherwise noted, technical terms are used according to conventional usage. Definitions of common terms in molecular biology may be found in Benjamin Lewin, Genes X, published by Jones & Bartlett Publishers, 2009; and Meyers el al. (eds.), The Encyclopedia of Cell Biology and Molecular Medicine, published by Wiley-VCH in 16 volumes, 2008; and other similar references.

As used herein, the singular forms “a,” “an,” and “the,” refer to both the singular as well as plural, unless the context clearly indicates otherwise. For example, the term “a zinc salt” includes single or plural zinc salts and can be considered equivalent to the phrase “at least one zinc salt.” As used herein, the term “comprises” means “includes.” It is further to be understood that any and all base sizes or amino acid sizes, and all molecular weight or molecular mass values, given for nucleic acids or polypeptides are approximate, and are provided for descriptive purposes, unless otherwise indicated. Although many methods and materials similar or equivalent to those described herein can be used, particular suitable methods and materials are described herein. In case of conflict, the present specification, including explanations of terms, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. To facilitate review of the various embodiments, the following explanations of terms are provided:

About: Unless context indicated otherwise, “about” refers to plus or minus 5% of a reference value. For example, “about” 100 refers to 95 to 105.

Administration: The introduction of an agent, such as a disclosed therapeutic agent, such a Zn²⁺, into a subject by a chosen route. Administration can be local or systemic. For example, if the chosen route is intranasal, the agent is administered by introducing the composition into the nasal passages of the subject. Exemplary routes of administration include, but are not limited to, oral, injection (such as subcutaneous, intramuscular, intradermal, intraperitoneal, and intravenous), sublingual, rectal, transdermal (for example, topical), intranasal, vaginal, and inhalation routes. In some embodiments, administration is oral.

Control: A reference standard. In some embodiments, the control is a negative control sample obtained from a healthy patient. In other embodiments, the control is a positive control sample obtained from a patient diagnosed with a coronavirus infection, such as SARS-CoV-2 (also known as 2019-nCoV). In still other embodiments, the control is a historical control or standard reference value or range of values (such as a previously tested control sample, such as a group of patients infected with SARS-CoV-2 with known prognosis or outcome, or group of samples that represent baseline or normal values).

A difference between a test sample and a control can be an increase or conversely a decrease. The difference can be a qualitative difference or a quantitative difference, for example a statistically significant difference. In some examples, a difference is an increase or decrease, relative to a control, of at least about 5%, such as at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 150%, at least about 200%, at least about 250%, at least about 300%, at least about 350%, at least about 400%, at least about 500%, or greater than 500%.

Coronavirus: A family of positive-sense, single-stranded RNA viruses that are known to cause severe respiratory illness. Viruses currently known to infect human from the coronavirus family are from the alphacoronavirus and betacoronavirus genera. Additionally, it is believed that the gammacoronavirus and deltacoronavirus genera may infect humans in the future.

Non-limiting examples of betacoronaviruses include SARS-CoV-2 (also known as 2019- nCoV), Middle East respiratory syndrome coronavirus (MERS-CoV), Severe Acute Respiratory Syndrome coronavirus (SARS-CoV), Human coronavirus HKU1 (HKUl-CoV), Human coronavirus OC43 (OC43-CoV), Murine Hepatitis Virus (MHV-CoV), Bat SARS-like coronavirus WIV1 (WIVl-CoV), and Human coronavirus HKU9 (HKU9-CoV). Non-limiting examples of alphacoronaviruses include human coronavirus 229E (229E-CoV), human coronavirus NL63 (NL63-CoV), porcine epidemic diarrhea virus (PEDV), and Transmissible gastroenteritis coronavirus (TGEV). A non-limiting example of a deltacoronaviruses is the Swine Delta Coronavirus (SDCV).

The viral genome is capped, polyadenylated, and covered with nucleocapsid proteins. The coronavirus virion includes a viral envelope containing type I fusion glycoproteins referred to as the spike (S) protein. Most coronaviruses have a common genome organization with the replicase gene included in the 5'-portion of the genome, and structural genes included in the 3'- portion of the genome.

Effective Amount: A quantity of a specific substance, such as a zinc salt, sufficient to achieve a desired effect in a subject to whom the substance is administered. For instance, this can be the amount necessary to inhibit a SARS-CoV-2 infection, such as the amount necessary to inhibit SARS-CoV-2 from infecting cells in a subject or to measurably alter outward symptoms of the SARS-CoV-2 infection.

The effective amount of a compound, such as a zinc salt, that is administered to a subject to inhibit SARS-CoV-2 will vary depending upon a number of factors associated with that subject, for example the overall health and/or weight of the subject. An effective amount can be determined by varying the dosage and measuring the resulting response, such as, for example, a reduction in pathogen titer. Effective amounts also can be determined through various in vitro , in vivo or in situ immunoassays.

An effective amount encompasses a fractional dose that contributes in combination with previous or subsequent administrations to attaining an effective response. For example, an effective amount of an agent can be administered in a single dose, or in several doses, for example hourly, daily, during a course of treatment lasting several days or weeks. However, the effective amount can depend on the subject being treated, the severity and type of the condition being treated, and the manner of administration. A unit dosage form of the agent can be packaged in an amount, or in multiples of the effective amount, for example, in a vial ( e.g ., with a pierceable lid), tablet, or other form.

Inhibiting or treating a disease: Inhibiting the full development of a disease or condition, for example, in a subject who is at risk for a disease such as a SARS-CoV-2 infection, namely COVID-19. “Treatment” refers to a therapeutic intervention that ameliorates a sign or symptom of a disease or pathological condition after infection, when the disease has begun to develop. The disease can be long COVID. The term “ameliorating,” with reference to a disease or pathological condition, refers to any observable beneficial effect of the treatment. Inhibiting a disease can include reducing the viral infection. The beneficial effect can be evidenced, for example, by a delayed onset of clinical symptoms of the disease in a susceptible subject, a reduction in severity of some or all clinical symptoms of the disease, a slower progression of the disease, a reduction in the viral load, an improvement in the overall health or well-being of the subject, or by other parameters that are specific to the particular disease. A “prophylactic” treatment is a treatment administered to a subject who does not exhibit signs of a disease or exhibits only early signs for the purpose of decreasing the risk of developing pathology. In some embodiments, the disclosed methods are therapeutic and not prophylactic.

Ionophore: A chemical species that reversibly binds ions. An ionophore can be a lipid- soluble entity that transport ions across a cell membrane. These compounds catalyze ion transport across hydrophobic membranes such as liquid polymeric membranes (carrier-based ion selective electrodes) or lipid bilayers found in the living cells. Cholorquine, pyrithione, quercetin and epigailocatechin-gallate are exemplary zinc ionophores.

Long COVID: Symptoms resulting from a SARS-CoV-2 infection that include, but not limited to, fatigue, headaches, fever, shortness of breath, weakness, dizziness, cognitive dysfunction, malaise, memory deficits, nausea, vomiting, diarrhea, loss of taste/smell, muscle aches and autonomic dysfunction, that persist greater than 30 days after the onset of symptomatic disease.

Lozenge: A small, typically medicated tablet intended to be dissolved slowly in the mouth hat delivers an active agent orally. Generally lozenges a disc or rhomboid shaped and composed of solidifying paste containing an astringent, antiseptic, or active agent, such as zinc. They are used for local treatment of the mouth or throat, the lozenge being held in the mouth until dissolved. However, lozenges can also be flat circular, octagonal biconvex or rod shaped. The vehicle or base can be sugar, made adhesive by admixture with acacia or tragacanth, fruit paste, made from black or red currants, confection of rose, or balsam of tolu. Molded lozenges are called pastilles while compressed lozenges are called troches.

Pharmaceutically acceptable carriers: The pharmaceutically acceptable carriers of use are conventional. Remington ’s Pharmaceutical Sciences , by E. W. Martin, Mack Publishing Co., Easton, PA, 19th Edition, 1995, describes compositions and formulations suitable for pharmaceutical delivery of the disclosed immunogens.

In general, the nature of the carrier will depend on the particular mode of administration being employed. For instance, parenteral formulations usually comprise injectable fluids that include pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like as a vehicle. For solid compositions ( e.g. , powder, pill, tablet, or capsule forms), conventional non-toxic solid carriers can include, for example, pharmaceutical grades of mannitol, lactose, starch, or magnesium stearate. In addition to biologically neutral carriers, pharmaceutical compositions (such as immunogenic compositions) to be administered can contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, preservatives, and pH buffering agents and the like, for example sodium acetate or sorbitan monolaurate. In particular embodiments, suitable for administration to a subject the carrier may be sterile, and/or suspended or otherwise contained in a unit dosage form containing one or more measured doses of the composition suitable to induce the desired immune response. It may also be accompanied by medications for its use for treatment purposes. The unit dosage form may be, for example, in a sealed vial that contains sterile contents, a syringe for injection into a subject, lyophilized for subsequent solubilization and administration, in a solid or controlled release dosage, or in an oral lozenge form.

SARS-CoV-2: Also known as Wuhan coronavirus or 2019 novel coronavirus, SARS- CoV-2 is a positive-sense, single stranded RNA virus of the genus betacoronavirus that has emerged as a highly fatal cause of severe acute respiratory infection. The viral genome is capped, polyadenylated, and covered with nucleocapsid proteins. The SARS-CoV-2 virion includes a viral envelope with large spike glycoproteins. The SARS-CoV-2 genome, like most coronaviruses, has a common genome organization with the replicase gene included in the 5'- two thirds of the genome, and structural genes included in the 3'-third of the genome. The SARS-CoV-2 genome encodes the canonical set of structural protein genes in the order 5' - spike (S) - envelope (E) - membrane (M) and nucleocapsid (N) - 3'. Symptoms of SARS-CoV-2 infection include fever and respiratory illness, such as dry cough and shortness of breath. Cases of severe infection can progress to severe pneumonia, multi-organ failure, and death. The time from exposure to onset of symptoms is approximately 2 to 14 days. The acute disease resulting from a SARS-CoV-2 infection is called COVID-19. SARS-CoV-2 can also cause long COVID

Standard methods for detecting viral infection may be used to detect SARS-CoV-2 infection, including but not limited to, assessment of patient symptoms and background and genetic tests such as reverse transcription-polymerase chain reaction (rRT-PCR). The test can be done on patient samples such as respiratory or blood samples. SARS-CoV-2 is the causative agent for COVID-19 and long COVID.

Subject: Living multi-cellular vertebrate organisms, a category that includes human and non-human mammals, such as non-human primates, pigs, camels, bats, sheep, cows, dogs, cats, rodents, and the like. In an example, a subject is a human. In a particular example, the subject is a human. In an additional example, a subject is selected that is in need of inhibiting a SARS- CoV-2 infection. For example, the subject is either uninfected and at risk of the SARS-CoV-2 infection or is infected and in need of treatment.

Zinc (elemental): A chemical element with the symbol Zn and the atomic number 30. There is only one oxidation state (+2). Zinc salts include zinc acetate, zinc citrate, zinc gluconate, zinc picolinate, and zinc sulfate.

II. Methods of Treatment and Pharmaceutical Compositions

Methods and pharmaceutical compositions are disclosed for the treatment of a SARS- CoV-2 infection in a subject. In some embodiments, a subject can be selected for treatment that has an existing SARS-CoV-2 infection, for example because of exposure to the virus.

Following administration of a disclosed pharmaceutical composition, the subject can be monitored for infection, such as by detecting the virus, or symptoms associated with a SARS- CoV-2 infection.

The disclosed methods and pharmaceutical compositions are used to treat an existing SARS-CoV-2 infection. The subject can be selected for the treatment based on a positive diagnostic test for the virus, or that exhibits symptoms of infection with the SARS-CoV-2 virus. The subject can have long COVID, wherein the symptoms persist for greater than about 30 days. The symptoms can have persisted for about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months. The symptoms can have persisted for about 1, 2, 3, 4, or 5 years. Without being bound by theory, the disclosed methods do not prevent an infection in subjects that are not SARS-CoV-2 infected. Thus, in some embodiments, the disclosed methods and compositions are not used for prophylaxis.

Typical subjects intended for treatment with the therapeutics and methods of the present disclosure include humans, as well as non-human primates and other animals, such as cats and tigers. To identify subjects for treatment according to the methods of the disclosure, accepted screening methods are employed to determine risk factors associated with a targeted or suspected disease or condition, or to determine the status of an existing disease or condition in a subject. These screening methods include, for example, conventional work-ups to determine environmental, familial, occupational, and other such risk factors that may be associated with a poor outcome of an infection, as well as diagnostic methods, such as various ELISA and other immunoassay methods to detect and/or characterize coronavirus infection. The subject can be selected based on contact history and/or symptoms. These and other routine methods allow the clinician to select patients in need of therapy using the methods and pharmaceutical compositions of the disclosure. In accordance with these methods and principles, a composition can be administered according to the teachings herein, or other conventional methods, as an independent treatment program, or as a follow-up, adjunct or coordinate treatment regimen to other treatments.

A pharmaceutical composition that includes an effective amount of elemental zinc, such as in the form of a zinc salt, is provided at or after the onset of a symptom of infection, for example, after development of a symptom of SARS-CoV-2 infection or after diagnosis with the SARS-CoV-2 infection. In some embodiments, the pharmaceutical composition can be administered to the subject within about 1 to about 5 years of onset of symptoms or diagnosis of SARS-CoV-2 infection. The zinc salt can be administered 1, 1.5, 2, 2.5, 3, 3.5, 4, or 4.5 years of onset of the SARS-CoV-2 infection.

In some embodiments, the subject has a fever and/or a dry cough. In some embodiments, the pharmaceutical composition can attenuate the anticipated severity, duration or extent of an infection and/or associated disease symptoms, after exposure or suspected exposure to the SARS-CoV-2, or after the actual initiation of an infection.

The pharmaceutical compositions are provided to a subject in an amount effective to decrease the viral infection in the subject, preferably a human. The actual dosage will vary according to factors such as the disease indication and particular status of the subject (for example, the subject’s age, size, fitness, extent of symptoms, susceptibility factors, and the like), time and route of administration, other drugs or treatments being administered concurrently, as well as the specific pharmacology of the composition for eliciting the desired activity or biological response in the subject. Dosage regimens can be adjusted to provide an optimum therapeutic response.

In some embodiments, the effective amount of elemental zinc, such as in the form of a zinc salt, is an amount that improves one or more symptoms of SARS-CoV-2 infection (e.g. fever, partial pressure of oxygen (PaC ) of arterial blood, cough, shortness of breath, diarrhea, viral load) within hours of initiation of treatment, for example, within about 8 hours, within about 10 hours, within about 12 hours, within about 24 hours, within about 48 hours, or within about 72 hours of initiation of treatment. The effective amount of elemental zinc can improve the one or more symptoms about 8 to about 72 hours, about 8 to about 24 hours, about 8 to about 36 hours, or about 8 to about 48 hours, following treatment. The effective amount of elemental zinc can improve the one or more symptoms about 10 to about 72 hours, about 10 to about 24 hours, about 10 to about 36 hours, or about 10 to about 48 hours, following treatment. The elemental zinc can improve the one or more symptoms. The effective amount of elemental zinc can improve the one or more symptoms about 12 to about 72 hours, about 12 to about 24 hours, about 12 to about 36 hours, or about 12 to about 48 hours, following treatment. The elemental zinc can be in the form of zinc salt. The zinc salt can be zinc gluconate.

In some embodiments, the effective amount of elemental zinc is an amount that improves one or more symptoms (e.g. fever, partial pressure of oxygen (PaCh) of arterial blood, cough, shortness of breath, diarrhea, viral load) of SARS-CoV-2 infection with days of initiation of treatment, for example, within about 3 days, within about 4 days, within about 5 days, within about 6 days, within about 7 days, within about 8 days, within about 9 days, or within about 10 days. The effective amount of elemental zinc can improve the one or more symptoms within about 2 to about 3 days, about 2 to about 4 days, about 2 to about 5 days, about 2 to about 6 days, about 2 to about 7 days, about 2 to about 8 days, about 2 to about 9 days, about 2 to about 10 days, about 3 to about 5 days, about 3 to about 10 days, or about 5 to about 10 days, following treatment. In some embodiments, the effective amount of elemental zinc is an amount that resolves one or more symptoms of SARS-CoV-2 infection within about 2 to about 5 days of initiation of treatment. The elemental can be in the form of a zinc salt. The zinc salt can be zinc gluconate.

In some embodiments, the effective amount of elemental zinc is an amount that improves shortness of breath (SOB) in the subject due to SARS-CoV-2 infection within about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9 or about 10 days of initiation of treatment. In other embodiments, the effective amount of elemental zinc is an amount that improves shortness of breath (SOB) in the subject due to SARS-CoV-2 infection within about 1 to about 7 days of treatment, such as within about 2 to about 6 days of treatment. In a specific non-limiting example, the effective amount of elemental zinc is an amount that improves shortness of breath (SOB) in the subject due to SARS-CoV-2 infection within 7 days of initiation of treatment. The elemental zinc can be in the form of a zinc salt. The zinc salt can be zinc gluconate.

In some embodiments, the subject is human, such as an elderly subject of about 65 years of age or more. In some embodiments, the subject is greater than about 70, 71, 72, 73, 74, 75,

76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 91, 93, 94, 95, 96, 97, 98, 99 100 years of age. The elderly human subject can be about 65 to about 95 years of age, about 65 to about 85 years of age, about 65 to about 80 years of age, about 65 to about 75 years of age, or about 65 to about 70 years of age.

The human subject can be an adult human subject that is greater than about 18 years of age. In some embodiments, the adult human subject that is greater than about 20 years of age, greater than about 25 years of age, greater than about 30 years of age, greater than about 35 years of age, greater than about 40 years of age, greater than about 45 years of age, greater than about 50 years of age, greater than about 55 years of age, or greater than about 60 years of age. The subject can be, for example, about 18 to about 64 years of age, about 20 to about 60 years of age, about 30 to about 60 years of age, about 40 to about 60 years of age, or about 50 to about 60 years of age. The subject can be, for examples, greater than about 55 years of age, such as about 55 to about 64 years of age.

The human subject can be a child, that is 1 to about 17 years of age. In some embodiments, the child as about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17 years of age. The subject can be about 5 to about 17 years of age, such as about 10 to about 17 years of age. In the context of age, “about” indicates within 5%.

The human subject can be an infant, that is less than one year of age. The infant can be, for example, about 1 month to about 11 months of age, such as about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 months of age. The infant can be, for example, about 1 to about 10 months of age, about 1 to about 8 months of age, or about 1 to about 6 months of age.

The disclosed methods use pharmaceutical compositions including elemental zinc. Elemental zinc can be provided as inorganic salts, such as chlorides, sulfates, and the like, as organic salts and other bioavailable forms, such as amino acid chelates or combinations thereof. Examples of such zinc compounds of use include salicylates, fumarates, benzoates, glutarates, lactates, citrates, malonates, acetates, glycolates, thiosalicylates, adipates, succinates, gluconates, aspartates, glycinates, tartarates, malates, maleates, ascorbates, chlorides, sulphates, nitrates, phosphates, fluorides, iodides, pidolates, and mixtures thereof. Non-limiting examples of zinc compounds of use include any soluble zinc salt capable of providing freely available zinc ions when dissolved in water. For example, zinc chloride, zinc acetate, zinc citrate, zinc gluconate, zinc picolinate, zinc lactate, zinc salicylate, zinc sulfate, zinc nitrate, and any possible combination thereof may be used. In a particular embodiment, zinc acetate, zinc citrate, zinc gluconate, zinc picolinate, or zinc sulfate, alone or in any combination, are used. Amino acid chelated zinc is also of use. In some embodiments, the zinc salt is zinc acetate, zinc citrate, zinc gluconate, zinc picolinate, zinc sulfate, or any combination thereof. Liquid zinc drops can be used repeated doses, such as by application to the tongue.

In some embodiments, combinations of zinc salts are used. Combinations of 2, 3, 4, or 5 types of zinc salt are also of use in the disclosed methods. Exemplary suitable combinations are zinc acetate and zinc citrate, zinc gluconate and zinc citrate, zinc gluconate and zinc acetate, or zinc sulfate and zinc acetate. In one non-limiting example, the zinc salt is zinc citrate and zinc acetate. In another non-limiting example, the zinc salt is zinc acetate and zinc gluconate. In a further non-limiting example, the zinc salt is zinc citrate and zinc gluconate.

When two types of zinc salt are used, they can be present at a ratio, for example, of 1 : 1, 1:2, 1:3, 1:4, 4:1, 3:1, 2: 1 or 1:1. Non-limiting examples include zinc acetate and zinc gluconate, in a 1:1 ratio., or zinc citrate and zinc gluconate in a 1 :3 ratio.

In some embodiments, per day, about 1 to about 200 mg of elemental zinc (Zn²⁺) is administered to the subject. In some embodiments, per day, about 1 to about 100 mg of the elemental zinc is administered to the subject, such as about 1 to about 90 mg, about 1 to about 80 mg, about 1 to about 70 mg, about 1 to about 60 mg, about 1 to about 50 mg, about 1 to about 40 mg, about 1 to about 30 mg, about 1 to about 20 mg, or about 1 to about 10 mg, of the elemental zinc is administered to the subject. In other embodiments, about 10 to about 100 mg of the elemental zinc is administered to the subject, such as about 10 to about 90 mg, about 10 to about 80 mg, about 10 to about 70 mg, about 10 to about 60 mg, about 10 to about 50 mg, about 10 to about 40 mg, about 10 to about 30 mg, or about 10 to about 20 mg of the elemental zinc is administered to the subject. In further embodiments, about 20 mg about 100 mg of the elemental zinc is administered to the subject, such as about 20 to about 90 mg, about 20 to about 80 mg, about 20 to about 70 mg, about 20 to about 60 mg, about 20 to about 50 mg, about 20 to about 40 mg, or about 20 to about 30 mg, of the elemental zinc is administered to the subject. In other embodiments, about 30 mg about 100 mg of the elemental zinc is administered to the subject, such as about 30 to about 90 mg, about 30 to about 80 mg, about 30 to about 70 mg, about 30 to about 60 mg, about 30 to about 50 mg, about 30 to about 40 mg is administered to the subject. In more embodiments, about 40 mg about 100 mg of the elemental zinc is administered to the subject, such as about 40 to about 90 mg, about 40 to about 80 mg, about 40 to about 70 mg, about 40 to about 60 mg, or about 40 to about 50 mg is administered to the subject. In additional embodiments, about 50 mg about 100 mg of the elemental zinc is administered to the subject, such as about 50 to about 90 mg, about 50 to about 80 mg, about 50 to about 70 mg, about 50 to about 60 mg of the elemental zinc is administered to the subject. In yet other embodiments, about 60 mg about 100 mg of the zinc salt is administered to the subject, such as about 60 to about 90 mg, about 60 to about 80 mg, or about 60 to about 70 mg of the elemental zinc is administered to the subject. In further embodiments, about 70 mg about 100 mg of the elemental zinc is administered to the subject, such as about 70 to about 90 mg, or about 70 to about 80 mg of the elemental zinc is administered to the subject. In some embodiments, about 80 mg about 100 mg of the elemental zinc is administered to the subject, such as about 80 to about 90 mg of the elemental zinc is administered to the subject. In another embodiment, about 90 mg to about 100 mg of the elemental zinc is administered to the subject. The zinc can be in the form of ionic liquid zinc. The zinc can be in the form of a zinc salt. The doses can be divided. In this context, “about” indicates within five percent.

In some embodiments, 100 mg of the elemental zinc, or more, per day is administered to the subject. In some embodiments, per day, about 100 mg to about 200 mg, about 110 mg to about 200 mg, about 120 mg to about 200 mg, about 130 mg to about 200 mg, about 140 mg to about 200 mg, or about 150 to about 200 mg, about 160 mg to about 200 mg, about 170 mg to about 200 mg, about 180 mg to about 200 mg, or about 190 mg to about 200 mg of elemental zinc is administered to the subject. In other embodiments, about 100 to about 200 mg of the elemental zinc is administered to the subject, such as about 100 to about 190 mg, about 100 to about 180 mg, about 100 to about 170 mg, about 100 to about 160 mg, about 100 to about 150 mg, about 100 to about 140 mg, about 100 to about 130 mg, or about 100 to about 120 mg, or about 100 to about 110 mg of the elemental zinc is administered to the subject. In more embodiments, about 110 to about 200 mg of the elemental zinc is administered to the subject, such as about 110 to about 190 mg, about 110 to about 180 mg, about 110 to about 170 mg, about 110 to about 160 mg, about 110 to about 150 mg, about 110 to about 140 mg, about 110 to about 130 mg, or about 110 to about 120 mg of the elemental zinc is administered to the subject. In further embodiments, about 120 mg about 200 mg of the elemental zinc is administered to the subject, such as about 120 to about 190 mg, about 120 to about 180 mg, about 120 to about 170 mg, about 120 to about 160 mg, about 120 to about 150 mg, about 120 to about 140 mg, or about 120 to about 130 mg, of the elemental zinc is administered to the subject. In other embodiments, about 130 mg about 200 mg of the elemental zinc is administered to the subject, such as about 130 to about 190 mg, about 130 to about 180 mg, about 130 to about 170 mg, about 130 to about 160 mg, about 130 to about 150 mg, or about 130 to about 140 mg is administered to the subject. In more embodiments, about 140 mg about 200 mg of the elemental zinc is administered to the subject, such as about 140 to about 190 mg, about 140 to about 180 mg, about 140 to about 170 mg, about 140 to about 160 mg, or about 140 to about 150 mg of the elemental zinc is administered to the subject. In additional embodiments, about 50 mg about 100 mg of the elemental zinc is administered to the subject, such as about 150 to about 190 mg, about 150 to about 180 mg, about 150 to about 170 mg, about 150 to about 160 mg of the elemental zinc is administered to the subject. In yet other embodiments, about 160 mg about 200 mg of the elemental zinc is administered to the subject, such as about 160 to about 190 mg, about 160 to about 180 mg, or about 160 to about 170 mg of the elemental zinc is administered to the subject. In further embodiments, about 170 mg about 200 mg of the elemental zinc is administered to the subject, such as about 170 to about 190 mg, or about 170 to about 180 mg of the elemental zinc is administered to the subject. In some embodiments, about 180 mg about 200 mg of the elemental zinc is administered to the subject, such as about 180 to about 190 mg of the elemental zinc is administered to the subject. In another embodiment, about 190 mg to about 200 mg of the elemental zinc is administered to the subject. The zinc can be in the form of ionic liquid zinc. The zinc can be in the form of a zinc salt. The doses can be divided. In this context, “about” indicates within five percent.

A composition comprising a zinc salt can be utilized. The amount of a zinc salt for administration can be determined based on the molecular weight of zinc in the salt.

In some embodiments, per day, about 1 to about 100 mg of a zinc salt is administered to the subject, such as about 1 to about 90 mg, about 1 to about 80 mg, about 1 to about 70 mg, about 1 to about 60 mg, about 1 to about 50 mg, about 1 to about 40 mg, about 1 to about 30 mg, about 1 to about 20 mg, or about 1 to about 10 mg, of the zinc salt is administered to the subject. In other embodiments, about 10 to about 100 mg of the zinc salt is administered to the subject, such as about 10 to about 90 mg, about 10 to about 80 mg, about 10 to about 70 mg, about 10 to about 60 mg, about 10 to about 50 mg, about 10 to about 40 mg, about 10 to about 30 mg, or about 10 to about 20 mg of the zinc salt is administered to the subject. In further embodiments, about 20 mg about 100 mg of the zinc salt is administered to the subject, such as about 20 to about 90 mg, about 20 to about 80 mg, about 20 to about 70 mg, about 20 to about 60 mg, about 20 to about 50 mg, about 20 to about 40 mg, or about 20 to about 30 mg, of the zinc salt is administered to the subject. In other embodiments, about 30 mg about 100 mg of the zinc salt is administered to the subject, such as about 30 to about 90 mg, about 30 to about 80 mg, about 30 to about 70 mg, about 30 to about 60 mg, about 30 to about 50 mg, about 30 to about 40 mg is administered to the subject. In more embodiments, about 40 mg about 100 mg of the zinc salt is administered to the subject, such as about 40 to about 90 mg, about 40 to about 80 mg, about 40 to about 70 mg, about 40 to about 60 mg, or about 40 to about 50 mg is administered to the subject. In additional embodiments, about 50 mg about 100 mg of the zinc salt is administered to the subject, such as about 50 to about 90 mg, about 50 to about 80 mg, about 50 to about 70 mg, about 50 to about 60 mg of the zinc salt is administered to the subject. In yet other embodiments, about 60 mg about 100 mg of the zinc salt is administered to the subject, such as about 60 to about 90 mg, about 60 to about 80 mg, or about 60 to about 70 mg of the zinc salt is administered to the subject. In further embodiments, about 70 mg about 100 mg of the zinc salt is administered to the subject, such as about 70 to about 90 mg, or about 70 to about 80 mg of the zinc salt is administered to the subject. In some embodiments, about 80 mg about 100 mg of the zinc salt is administered to the subject, such as about 80 to about 90 mg of the zinc salt is administered to the subject. In another embodiment, about 90 mg to about 100 mg of the zinc salt is administered to the subject. In these embodiments, the zinc salt can be zinc acetate, zinc citrate, zinc gluconate, zinc, zinc sulfate, or any combination thereof. The doses can be divided. In this context, “about” indicates within five percent.

In some embodiments, 100 mg of the zinc salt, or more, per day is administered to the subject. In some embodiments, per day, about 100 mg to about 200 mg, about 110 mg to about 200 mg, about 120 mg to about 200 mg, about 130 mg to about 200 mg, about 140 mg to about 200 mg, or about 150 to about 200 mg, about 160 mg to about 200 mg, about 170 mg to about 200 mg, about 180 mg to about 200 mg, or about 190 mg to about 200 mg. In other embodiments, about 100 to about 200 mg of the zinc salt is administered to the subject, such as about 100 to about 190 mg, about 100 to about 180 mg, about 100 to about 170 mg, about 100 to about 160 mg, about 100 to about 150 mg, about 100 to about 140 mg, about 100 to about 130 mg, or about 100 to about 120 mg, or about 100 to about 110 mg of the zinc salt is administered to the subject. In more embodiments, about 110 to about 200 mg of the zinc salt is administered to the subject, such as about 110 to about 190 mg, about 110 to about 180 mg, about 110 to about 170 mg, about 110 to about 160 mg, about 110 to about 150 mg, about 110 to about 140 mg, about 110 to about 130 mg, or about 110 to about 120 mg of the zinc salt is administered to the subject. In further embodiments, about 120 mg about 200 mg of the zinc salt is administered to the subject, such as about 120 to about 190 mg, about 120 to about 180 mg, about 120 to about 170 mg, about 120 to about 160 mg, about 120 to about 150 mg, about 120 to about 140 mg, or about 120 to about 130 mg, of the zinc salt is administered to the subject. In other embodiments, about 130 mg about 200 mg of the zinc salt is administered to the subject, such as about 130 to about 190 mg, about 130 to about 180 mg, about 130 to about 170 mg, about 130 to about 160 mg, about 130 to about 150 mg, about 130 to about 140 mg is administered to the subject. In more embodiments, about 140 mg about 200 mg of the zinc salt is administered to the subject, such as about 140 to about 190 mg, about 140 to about 180 mg, about 140 to about 170 mg, about 140 to about 160 mg, or about 140 to about 150 mg is administered to the subject. In additional embodiments, about 50 mg about 100 mg of the zinc salt is administered to the subject, such as about 150 to about 190 mg, about 150 to about 180 mg, about 150 to about 170 mg, about 150 to about 160 mg of the zinc salt is administered to the subject. In yet other embodiments, about 160 mg about 200 mg of the zinc salt is administered to the subject, such as about 160 to about 190 mg, about 160 to about 180 mg, or about 160 to about 170 mg of the zinc salt is administered to the subject. In further embodiments, about 170 mg about 200 mg of the zinc salt is administered to the subject, such as about 170 to about 190 mg, or about 170 to about 180 mg of the zinc salt is administered to the subject. In some embodiments, about 180 mg about 200 mg of the zinc salt is administered to the subject, such as about 180 to about 190 mg of the zinc salt is administered to the subject. In another embodiment, about 190 mg to about 200 mg of the zinc salt is administered to the subject. In these embodiments, the zinc salt can be zinc acetate, zinc citrate, zinc gluconate, zinc picolinate, zinc sulfate, or any combination thereof. In some embodiments, a zinc ionophore, vitamin C, L-lysine and/or echinacea is administered.

In some embodiments, the subject is administered about 1 to about 100 mg of the zinc about every hour in a day, but not exceeding about 200 mg of elemental zinc in a day. In other embodiments, the subject is administered about 10 to about 100 mg of the zinc about every hour in a day, but not exceeding 200 mg of elemental zinc in a day. In further embodiments the subject is administered about 20 to about 100 mg of the zinc about every hour in a day, but not exceeding 900 mg of a zinc salt in a day. In more embodiments, the subject is administered about 30 to about 100 mg of the zinc about every hour in a day, but not exceeding 900 mg of the zinc salt in a day. In yet other embodiments, the subject is administered about 40 to about 100 mg of the zinc salt about every hour in a day, but not exceeding 900 mg of the zinc salt in a day. In some embodiments, the subject is administered about 50 to about 100 mg of the zinc about every hour in a day, but not exceeding 900 mg of the zinc salt in a day. In further embodiments, the subject is administered about 60 to about 100 mg of the zinc about every hour in a day, but not exceeding 900 mg of the zinc salt in a day. In yet other embodiments, the subject is administered about 70 to about 100 mg of the zinc about every hour in a day, but not exceeding 900 mg of the zinc salt in a day. In more embodiments, the subject is administered about 80 to about 100 mg of the zinc about every hour in a day, but not exceeding 900 mg of the zinc salt in a day. In more embodiments, the subject is administered about 90 to about 100 mg of the zinc about every hour in a day, but not exceeding 900 mg of the zinc salt in a day. In some embodiments, a zinc ionophore, vitamin C, L-lysine and/or echinacea is administered every hour.

In more embodiments, the subject is administered about 20 to about 100 mg of the zinc about every hour in a day, but not exceeding 1400 mg of a zinc salt in a day. In more embodiments, the subject is administered about 30 to about 100 mg of the zinc about every hour in a day, but not exceeding 1400 mg of the zinc salt in a day. In yet other embodiments, the subject is administered about 40 to about 100 mg of the zinc salt about every hour in a day, but not exceeding 1400 mg of the zinc salt in a day. In some embodiments, the subject is administered about 50 to about 100 mg of the zinc about every hour in a day, but not exceeding 1400 mg of the zinc salt in a day. In further embodiments, the subject is administered about 60 to about 100 mg of the zinc about every hour in a day, but not exceeding 1400 mg of the zinc salt in a day. In yet other embodiments, the subject is administered about 70 to about 100 mg of the zinc about every hour in a day, but not exceeding 1400 mg of the zinc salt in a day. In more embodiments, the subject is administered about 80 to about 100 mg of the zinc about every hour in a day, but not exceeding 1400 mg of the zinc salt in a day. In more embodiments, the subject is administered about 90 to about 100 mg of the zinc about every hour in a day, but not exceeding 1400 mg of the zinc salt in a day. In some embodiments, a zinc ionophore, vitamin C, L-lysine and/or echinacea is administered every hour. The zinc salt can be in the form of ionic liquid zinc. The zinc salt can be zinc gluconate. The doses can be divided.

In some embodiments, the zinc salt is administered in an amount not to exceed 200 mg of elemental zinc in a day. Without being bound by theory, this avoids toxicity.

In some embodiments, the total daily adult dose is between about 100 mg and 200 mg of elemental zinc per day, in divided doses. In some examples, the total daily adult dose is about 2 to about 2.5 mg per kilogram body weight of elemental zinc per day. The total daily adult dose can be, for example, about 2, about 2.1 about 2.2 about 2.3, about 2.4 or about 2.5 mg of elemental zinc per kilogram body weight per day. In other embodiments, the daily dose for children is reduced proportionate to their weight. The zinc salt can be in the form of ionic liquid zinc. The zinc salt can be zinc gluconate. The zinc salt can be zinc gluconate.

In some embodiments, the method also includes administering to the subject with the SARS-CoV-2 infection an effective amount of a zinc ionophore. In specific non-limiting embodiments, the zinc ionophore is quercetin (in non-limiting example, administered at about 500 to about 1000 mg a day), epigallocatechin gall ate (EGCE) (in a non-limiting example, administered at about 100 to about 400 mg daily), pyrithione (in a non-limiting example, used at about 1 to about 500 mg daily), hinokitiol (in a non-limiting example, administered at about 0,2 to about 0.5mg/kg), or pyrrolidine-dithiocarbamate (PDTC) (in a non-limiting example, administered at about 1 to about 200 mg/kg per day). The method can include administration of one or more of quercetin, epigallocatechin gall ate (EGCE), pyrithione), hinokitiol, orpyrrolidine-dithiocarbamate (PDTC), and also an effective amount of hydroxychloroquine (in a non-limiting example, administered at about 200 to about 400mg per day). In separate embodiments, a zinc ionophore is not administered to the subject.

The zinc, optionally with the zinc ionophore, can be administered repeatedly. For example, the zinc and/or the zinc ionophore can be administered every 30 minutes, hourly, every 90 minutes, every two hours, or every four hours. In other examples, the zinc and/or zinc ionophore is administered repeatedly, for example, about every 1 to 4 hours, about every 2 to 4 hours, or about every 3 to 4 hours. In some examples, the zinc and/or ionophore is administered repeatedly over several days, for example, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 14 days, or longer.

In a specific non-limiting example, the zinc, such as in the form of a zinc salt, for example zinc gluconate, is administered about every 2 to about every 4 hours for at least 10 days. In some examples, the zinc and/or ionophore is only administered while the subject is awake. The zinc salt can be zinc gluconate.

The administration can be provided for about several days, about 1 week or about two weeks, such as for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 days.

In some embodiments, the zinc salt, and optionally the zinc ionophore, is administered for at least 2 days or at least 3 days. In other embodiments, the zinc, and optionally the zinc ionophore, is administered for at least 4 days or at least 5 days. In further embodiments, the zinc, and optionally the zinc ionophore, is administered for at most 4, 5, 6, or 7 days. In yet other embodiments, the zinc, and optionally the zinc ionophore, is administered for at least 8, 9, 10, 11, 12, 13, or 14 days. The zinc can be elemental zinc, such as in the form of a zinc salt.

In some embodiments, the zinc is administered as an oral lozenge that dissolves on the tongue. In some embodiments, the lozenge dissolves over a period of about 15 to about 30 minutes, such as about 20 to about 30 minutes, such as over 15, 16, 17 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 20 or 30 minutes. The lozenge can be administered repeatedly. In some embodiments, the lozenge is administered every 15 minutes, every 30 minutes, every hour, every 90 minutes, every 2 hours, or every 4 hours. This can be performed over, for example, 6, 7, 8, 9, 10, 11 or 12 hours.

In some embodiments, the same amount of zinc is provided at each repeated administration. However, different amounts of zinc can be provided at different time points to the subject. Similarly, the same or different amounts of the zinc ionophore can be administered to the subject at each repeated administration.

Repeated administration can be provided for about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours in a day. In some embodiments, repeated administration is for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours per day. In more embodiments, repeated administration is provided for at most 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 hours in a day. In more embodiments, the repeated administration is provided for at most 5, 6, 7, or 8 hours in a day. In some embodiments, the repeated administration is hourly. In specific non-limiting examples, repeatedly administering the zinc salt, and optionally the zinc ionophore comprises administering to the zinc salt about every hour for at least about 8, 9 or 10, 11, 12, 13, 14, 15,

16, 17, 18, 19, 20, 21 or 22 hours per day.

In one non-limiting example, the zinc and/or zinc ionophore is administered to the subject about every hour for at least 5 hours per day for at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 14 days, or longer. The zinc and/or zinc ionophore can be administered about every 2 hours to about every four hours per day, at least 6 times per day, for at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, or longer. In some examples, the zinc is administered about 6 to about 12 times per day for at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, or longer. In a specific embodiment, the zinc is administered for no more than two weeks. The zinc can be in the form of a zinc salt. The zinc salt can be zinc gluconate.

In further embodiments, the zinc is administered for 2, 3, 4, 5, 6, 7, 8, 9, or 10 days. In more embodiments, the zinc is administered for 5, 10, 15, 20, 25 or 30 days. In some embodiments, the zinc is administered for no more than two weeks. In yet other embodiments, the zinc is administered for 2-30 days, such as for about 2-10 days, about one week, about two weeks, about three weeks, or for about a month. In one non-limiting example, the zinc is administered for up to 30 days. The zinc can be in the form of a zinc salt. The zinc salt can be zinc gluconate. The zinc gluconate can be administered, for example, for at least 7 days, such as, but not limited to, about every two hours to about every 4 hours for at least 7 days.

The zinc, and optionally the zinc ionophore, is administered at each repeated administration. In one embodiment, both the zinc and the zinc ionophore are administered at each administration. The zinc ionophore can be is quercetin, epigallocatechin gal Sate (EGCE), pyrithione, hinokitiol, or pyrrolidine-dithiocarbamate (PDTC). Combinations of these ionophores are also of use in the disclosed methods.

In further embodiments, the zinc is administered at each repeated administration, but the zinc ionophore, is administered in accordance only in accordance with standard dosing. The zinc ionphore is quercetin, epigallocatechin gal late (EGCE), pyrithione, hinokitiol, and pyrrolidine-dithiocarbamate (PDTC) can also be administered in accordance with standard dosing. In some embodiments, the zinc ionophore is quercetin (in non-limiting example, administered at about 500 to about 1000 mg a day), epigallocatechin galiate (EGCE) (in a non- limiting example, administered at about 100 to about 400 mg daily), pyrithione (in a non limiting example, used at about 1 to about 500 mg daily), hinokitiol (in a non-limiting example, administered at about 0,2 to about 0.5mg/kg), or pyrrolidine-dithiocarbamate (PDTC) (in a non limiting example, administered at about 1 to about 200 mg/kg per day). The method can include administration of one or more of quercetin, epigallocatechin galiate (EGCE), pyrithione), hinokitiol, and orpyrrolidine-dithiocarbamate (PDTC). In separate embodiments, a zinc ionophore is not administered to the subject.

In further embodiments, Vitamin C is also administered to the subject. An exemplary non-limiting dose of Vitamin C is about lOOmg. Vitamin C can be administered at dosages of about 10 mg to about 100 mg per dose, such as about 20 mg to about 100 mg per dose, about 30 mg to about 100 mg per dose, about 40 mg to about 100 mg per dose, about 50 mg to 100 mg per dose, about 60 mg to about 100 mg per dose, about 70 to about 100 mg per dose, about 80 to about 100 mg per dose or about 90 to about 100 mg per dose. The composition can include about 25 to about 100, about 50 to about 100, or about 75 to about 100 mg of vitamin C.

In some embodiments, L-lysine is also administered to the subject. An exemplary non limiting dose of L-lysine is 1 to 200 mg per dose. The composition can include about 1 to about 20, about 1 to about 30, about 1 to about 40, about 1 to about 50, about 1 to about 60, about 1 to about 70, about 1 to about 80, about 1 to about 90, about 1 to about 100, about 1 to about 110, about 1 to about 120, about 1 to about 130, about 1 to about 140, about 1 to about 150, about 1 to about 160, about 1 to about 170, about 1 to about 180, or about 1 to about 190 mg of echinacea. The composition can include about 50 to about 200, about 100 to about 200, or about 150 to about 200 mg of echinacea.

In further embodiments, echinacea is administered to the subject. An exemplary non limiting dose of echinacea is about 1 to about 20 mg per dose. The composition can include about 1 to about 2, about 1 to about 3, about 1 to about 4, about 1 to about 5, about 1 to about 6, about 1 to about 7, about 1 to about 8, about 1 to about 9, about 1 to about 10, about 1 to about 11, about 1 to about 12, about 1 to about 13, about 1 to about 14, about 1 to about 15, about 1 to about 16, about 1 to about 17, about 1 to about 18, or about 1 to about 19 mg of echinacea. The composition can include about 5 to about 20, about 10 to about 20, or about 15 to about 20 mg of echinacea. In more embodiments, the subject is administered an effective amount of vitamin C, L-lysine and/or echinacea.

A pharmaceutical composition is provided that includes both an effective amount of the zinc and an effective amount of the zinc ionophore in a pharmaceutically acceptable carrier. Optionally, the pharmaceutical composition can include an effective amount of a zinc, a first zinc ionophore that is not hydroxychloroquine, and an effective amount of hydroxychloroquine. The zinc can be elemental zinc. The zinc can be a zinc salt.

Thus, one or more suitable unit dosage forms comprising zinc and/or a zinc ionophore can be administered by a variety of routes including oral, parenteral (including subcutaneous, intravenous, intramuscular and intraperitoneal), intrathoracic, intrapulmonary and intranasal (respiratory) routes. In one embodiment, the route is oral. The formulations may, where appropriate, be conveniently presented in discrete unit dosage forms and may be prepared by any of the methods well known to the pharmaceutical arts. Such methods may include the step of mixing a zinc and/or a zinc ionophore with liquid carriers, solid matrices, semi-solid carriers, finely divided solid carriers or combinations thereof, and then, if necessary, introducing or shaping the product into the desired delivery system. The zinc can be in the form of a zinc salt.

When zinc, such as in the form of a zinc salt, and/or a zinc ionophore is prepared for oral administration, it is generally combined with a pharmaceutically acceptable carrier, diluent or excipient to form a pharmaceutical formulation, or unit dosage form. For oral administration, the composition may be present as a powder, a granular formulation, a solution, a suspension, an emulsion or in a natural or synthetic polymer or resin for ingestion of zinc, or an oral lozenge that dissolves slowly on the tongue, and/or a zinc ionophore from a chewing gum. The active ingredients may also be presented as a bolus, electuary or paste. Lozenge formulations are disclosed, for example, in Maheshwari et al, “A review on lozenges,” British Biomed. Bull. ISSN-2347-5447, 2013, incorporated by reference. Orally administered zinc and/or a zinc ionophore can also be formulated for sustained release. For example, zinc and/or a zinc ionophore, can be coated, can be micro-encapsulated, or otherwise placed within a sustained delivery device, for example, in order to avoid salivary bacteria degradation. The total N of zinc and/or a zinc ionophore in such formulations comprises from 0.1 to 99.9% by weight of the formulation. Zinc, such as in the form of a zinc salt, can be formulated for sustained release over about 10, 15, 20, 25, 30, 35, 40, or 45 minutes. In some embodiments, the zinc, such as a zinc salt, is formulated for release over about 15 to about 25 minutes, such as in about 20 minutes.

Pharmaceutical formulations containing zinc and/or a zinc ionophore can be prepared by procedures known in the art using well-known and readily available ingredients. For example, zinc salts and ionoophores can be formulated with common excipients, diluents, or carriers, and formed into tablets, capsules, solutions, suspensions, powders, aerosols and the like. Examples of excipients, diluents, and carriers that are suitable for such formulations include buffers, as well as fillers and extenders such as sorbitol, fructose, magnesium stearate, starch, cellulose, sugars, mannitol, and silicic derivatives. Binding agents can also be included such as carboxymethyl cellulose, hydroxymethylcellulose, hydroxypropyl methylcellulose and other cellulose derivatives, alginates, gelatin, and polyvinyl-pyrrolidone. Moisturizing agents can be included such as glycerol, disintegrating agents such as calcium carbonate and sodium bicarbonate.

Agents for retarding dissolution can also be included, such as paraffin. In some embodiment, the zinc salt is formulated for slow dissolution, such as in about 15 to about 60 minutes, such as in about 20 to about 50 minutes, such as in about 20 to about 40 minutes, such as in about 20 to about 30 minutes. In some embodiments, dissolution occurs in about 20 to about 30 minutes, such as about 20, about 25 or about 30 minutes. The zinc salt can be zinc gluconate.

Resorption accelerators such as quaternary ammonium compounds can also be included.

Surface active agents such as acetyl alcohol and glycerol monostearate can be included. Adsorptive carriers such as kaolin and bentonite can be added. Lubricants such as talc, calcium and magnesium stearate, and solid polyethyl glycols can also be included. Preservatives may also be added.

In some embodiments, the composition can include an antioxidants, such as Vitamin C. An exemplary non-limiting dose of Vitamin C is about lOOmg. Vitamin C can be administered at dosages of about 10 mg to about 100 mg per dose, such as about 20 mg to about 100 mg per dose, about 30 mg to about 100 mg per dose, about 40 mg to about 100 mg per dose, about 50 mg to 100 mg per dose, about 60 mg to about 100 mg per dose, about 70 to about 100 mg per dose, about 80 to about 100 mg per dose or about 90 to about 100 mg per dose. The composition can include about 25 to about 100, about 50 to about 100, or about 75 to about 100 mg of vitamin C.

In some embodiments, the composition can include L-lysine. An exemplary non limiting dose of L-lysine is 1 to 200 mg per dose. The composition can include about 1 to about 20, about 1 to about 30, about 1 to about 40, about 1 to about 50, about 1 to about 60, about 1 to about 70, about 1 to about 80, about 1 to about 90, about 1 to about 100, about 1 to about 110, about 1 to about 120, about 1 to about 130, about 1 to about 140, about 1 to about 150, about 1 to about 160, about 1 to about 170, about 1 to about 180, or about 1 to about 190 mg of echinacea. The composition can include about 50 to about 200, about 100 to about 200, or about 150 to about 200 mg of echinacea.

In further embodiments, the composition can include echinacea, such as about 1 to about 20 mg per dose. The composition can include about 1 to about 2, about 1 to about 3, about 1 to about 4, about 1 to about 5, about 1 to about 6, about 1 to about 7, about 1 to about 8, about 1 to about 9, about 1 to about 10, about 1 to about 11, about 1 to about 12, about 1 to about 13, about 1 to about 14, about 1 to about 15, about 1 to about 16, about 1 to about 17, about 1 to about 18, or about 1 to about 19 mg of echinacea. The composition can include about 5 to about 20, about 10 to about 20, or about 15 to about 20 mg of echinacea.

The compositions can also contain thickening agents such as cellulose and/or cellulose derivatives. The composition can also contain gums such as xanthan, guar or carbo gum or gum arabic, or alternatively polyethylene glycols, bentones and montmorillonites, and the like.

For example, tablets or caplets containing zinc, such as a zinc salt, and/or a zinc ionophore can include buffering agents such as calcium carbonate, magnesium oxide and magnesium carbonate. Caplets and tablets can also include inactive ingredients such as cellulose, pre-gelatinized starch, silicon dioxide, hydroxy propyl methyl cellulose, magnesium stearate, microcrystalline cellulose, starch, talc, titanium dioxide, benzoic acid, citric acid, com starch, mineral oil, polypropylene glycol, sodium phosphate, and the like. Hard or soft gelatin capsules containing a zinc salt and/or a zinc ionophore can contain inactive ingredients such as gelatin, microcrystalline cellulose, sodium lauryl sulfate, starch, talc, and titanium dioxide, and the like, as well as liquid vehicles such as polyethylene glycols (PEGs) and vegetable oil. Moreover, enteric-coated caplets or tablets containing a zinc salt and/or a zinc ionophore are designed to resist disintegration in the stomach and dissolve in the more neutral to alkaline environment of the duodenum.

Zinc, such as in the form of a zinc salt, and/or a zinc ionophore can also be formulated as an elixir or solution for convenient oral administration or as a solution appropriate for parenteral administration, for instance by intramuscular, subcutaneous, intraperitoneal or intravenous routes. The pharmaceutical formulations can also take the form of an aqueous or anhydrous solution or dispersion, or alternatively the form of an emulsion or suspension. The zinc, such as in the form of a zinc salt, can be included in a lozenge for delivery on the tongue. An intravenous solution can also be administered to a subject.

A composition may be formulated for parenteral administration (e.g., by injection, for example, bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion containers or in multi-dose containers. As noted above, preservatives can be added to help maintain the shelve life of the dosage form. The zinc and/or zinc ionophore, and other ingredients such as vitamin C, echinacea and/or L-lysine, may form suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, a zinc salt and/or zinc ionophore, and other ingredients may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.

These formulations can contain pharmaceutically acceptable carriers, vehicles and adjuvants that are well known in the art. It is possible, for example, to prepare solutions using one or more organic solvent(s) that is/are acceptable from the physiological standpoint, chosen, in addition to water, from solvents such as acetone, ethanol, isopropyl alcohol, glycol ethers such as the products sold under the name “DOWANOL™,” polyglycols and polyethylene glycols, C 1 -C4 alkyl esters of short-chain acids, ethyl or isopropyl lactate, fatty acid triglycerides such as the products marketed under the name “MIGLYOL™,” isopropyl myristate, animal, mineral and vegetable oils and polysiloxanes.

It is possible to add other ingredients such as antioxidants, surfactants, other preservatives, film-forming, keratolytic or comedolytic agents, perfumes, flavorings and colorings. Antioxidants such as t-butylhydroquinone, butylated hydroxyanisole, butylated hydroxytoluene and a-tocopherol and its derivatives can be added. In one embodiment, N- acetylcysteine is added to the composition.

The composition can be administered in a food supplement or incorporated into food or drink item such as a nutritional bar, snack bar, cookie, candy, cereal, pudding, ice cream, frozen confectionary, chewing gum, drink mix, soda pop, liquid supplement, sauce, salad dressing, gravy, jelly, jam, spread, margarine, peanut butter, nut spread, frosting, and the like. In essence, it can be used in any food, composition or supplement in which sugar is employed. Flavoring agents can also be added.

Such food supplements, drinks and food items can include any other food ingredient including, for example, flour, oil, cream, butter, sugar, salt, spices and the like. In addition, the food supplements, drinks and food items can include vitamins and other nutrients commonly found in other nutritional supplements.

EXAMPLES

Coronaviruses are positive-sense RNA viruses of which SARS Coronavirus-2 (SARS- CoV-2) is the most recently identified member and cause of COVID-19. All coronaviruses are unified in requiring a RNA-dependent RNA polymerase (RdRp) that is a core enzyme in their RNA-synthesizing machinery. As such, RdRp’s are key targets of antiviral research. Previous work has shown that increased intracellular Zn²⁺ concentrations can interfere with proteolytic processing of polyproteins in many RNA viruses. In addition, increased Zn²⁺ levels directly inhibit isolated RdRp complexes and purified recombinant RdRps, as well as coronavirus replication in tissue culture.

Example 1

Case Report for Subjects Receiving High Dose Zinc Lozenges

Zinc lozenges were tried in four patients with significant clinical COVID-19 disease.

Subject 1

The subject was a 23 year-old male who complained of fatigue and diarrhea 5 days after spending an evening with an individual who later developed fever and a cough. The individual subsequently tested positive for COVID-19. The fatigue and diarrhea persisted in case 1 for 10 days. Case 1 lived with case 2 and 3. This individual was not treated with Zn²⁺, and is a control.

Subject 2

The subject was a 63 year-old male physician who was in a state of good health until 3 days after the onset of diarrhea in case 1. At 5 pm of the evening of Subject 2’s first day of illness he developed severe muscle aches in the mid and lower back. Later that evening his face flushed before he went to sleep. He awoke around 4 am, sweating profusely and feeling feverish. His temperature was 100.5 orally. In the past he had noted a very positive response to oral zinc lozenges when he felt a cold coming on, so he took three 23mg zinc citrate lozenges that he dissolved on his tongue. He assumed that he might have COVID-19, given his symptoms and his history of influenza type B three months prior.

Over the next three days he avoided any medication for fever reduction. His temperature varied from 100.3 on day two to 99.0 on day 3. Each morning he felt significantly worse with sweats and body aches. He would then take one lozenge an hour until he felt improvement, which usually happened by midday. His total dose of Zn²⁺ over the first seven days averaged 184 mg per day. His symptoms gradually improved over the next 10 days. He was afebrile after day 3.

Subject 3

The subject was a 57 year-old female partner of case 2. She developed mild symptoms of diarrhea, fatigue and low-grade temperature elevation (under 100.5) 2 days after Subject 2’s symptoms began. She took only one or at most two zinc lozenges daily, since she did not feel that unwell, and was concerned about interaction of zinc with her thyroid medication. On day 5 she developed a dry cough without fever. She also developed a feeling of constriction about the upper chest. She was slightly winded after climbing stairs. The cough stayed mild until day 9 when, in late evening, she suddenly developed a severe dry cough along with fever, shortness of breath, and a severe headache. The chest constriction was now very painful and her face and neck were flushed and warm. She was unable to sleep due to coughing and breathlessness.

Over the next four hours she took one 23 mg zinc lozenge every hour. After a total of 7 zinc lozenges her coughing and shortness of breath had mostly disappeared by the afternoon of the next day. On day 11 she only took 2 lozenges and the cough started again. After 3 more lozenges she felt better again. She continued to improve over the next 7 days while taking 3 or 4 zinc lozenges daily.

Subject 4

A 41 year-old female worked in a pediatric office and was exposed to COVID-19 through a patient. On day 1 she developed body aches, cough and sinus pain, without fever. On day 2, her fatigue, cough, and headache worsened. On day 3, her fever rose to 101.5, she experienced severe body aches, worsening cough and tested positive for COVID-19. On days 4 and 5, her fever to 101 continued. Her pulse oxygenation dropped to 94% on room air (FIG. 1), chest pain started, and her cough worsened. On day 6, she was unable to sleep, short of breath, and experienced back pain, a fever to 100.5, and had a pulse oximeter reading of 93%. Her physician started her on hydroxychloroquine, 200 mg orally twice a day. On days 7-9 she reported severe fatigue, feeling very weak, almost passed out, fever up to 102. She had a cough and severe body aches, and was able to eat and drink very little. There was an overall worsening in her condition.

On the evening of day 9, she started zinc citrate/gluconate 23 mg lozenges, every 4 hours, 138 mg daily. On day 10 she felt better; her Pa02 and fever began improving one day after zinc was initiated (FIGS. 1 and 2) From day 10 to 13 she was afebrile and gradually improved each day. On days 14 -19, she continued zinc lozenges every 4 hours. She felt well and ready to return to work on day 19. Subject 5

A 26 year-old female acquired COVID-19 through contact with a health care employee of an emergency room. She developed fever, cough and severe body aches. The subject was confined to home after the first day. During week 2, she developed shortness of breath and severe fatigue. The subject reported sleeping 14-18 hours daily. By week 3 the subject still had a significant cough and severe fatigue and body aches. Shortness of breath was improved and she was afebrile. However, she still complained of severe fatigue, slept most of the day, and continued to cough and have body aches. On day 21 she began 15 mg zinc acetate lozenges, every 1-2 hours, 10 lozenges a day, for a total dose of 150mg daily. On day 22 the cough and body aches and fatigue began to improve, and by day 25 her body aches were gone and her cough was much improved. She continued zinc acetate lozenges and was feeling close to normal one week later.

Several lines of evidence suggest that zinc lozenges assisted in disease recovery from COVID-19 in all four subjects. In Subject 2, the symptoms significantly improved after 100 mg of zinc over a few hours. In addition, Subject 2 reported significantly worse symptoms in the morning, after a 9 hour sleep without Zn²⁺ dosing, and improved each morning after Zn²⁺.

Furthermore, for Subject 3, the disease was relatively mild until day 9, when she took a sudden turn for the worse, a common occurrence in COVID-19. The improvement after institution of high dose Zn²⁺ was dramatic, with reversal of severe symptoms in less than 10 hours. This time course of rapid disease improvement after severe worsening is very unusual, and suggestive of a therapeutic response to Zn²⁺.

In the case of Subject 4, the subject experienced worsening of symptoms over 9 days, with high fevers, body aches, cough and shortness of breath, until she began zinc lozenges.

Similarly, Subject 5 experienced persistent body aches, fatigue and coughing (3 weeks), until she began high dose Zn²⁺, after which time she began improving daily.

There is evidence suggesting that zinc lozenges in the correct dosing and formulation can shorten the duration of the common cold, and direct evidence for Zn²⁺ inhibition of coronavirus RNA dependent polymerase. Free Zn²⁺ is the active ingredient in zinc lozenges which shortens the duration of the common cold. Without being bound by any particular theory, zinc acetate or gluconate theoretically releases the most free Zn²⁺; Zinc citrate releases less. Therefore, zinc acetate or gluconate may be combined with zinc citrate for treatment. The zinc lozenges can be selected such that sufficient ionic zinc is released. In some examples, frequent dosing (for example, but not limited to, every 2-4 hours), adequate dosing (for example, about 200mg daily), and slow dissolution on the tongue (for example, 20 -30 min) can be important factors, see Finzi (2020) Int J Infect Dis 99:307-309, herein incorporated by reference in its entirety.

Example 2

A Retrospective Review of Outpatient Zinc Treatment of COVID-19

The following describes a retrospective review of consecutive cases of laboratory confirmed COVID-19 (26 cases), or CDC case definition (2 cases), who were started on zinc gluconate/citrate lozenges (23 mg of elemental zinc, 21 patients) or zinc acetate lozenges (15 mg of elemental zinc, 7 patients), at a total dosage of 2 to 2.5 mg/kg/day.

Patients were instructed to place one lozenge on their tongue every 2-4 hours while awake, for a minimum of 10 days. Depending on weight, patients took between 6 and 12 lozenges daily. The median number of days between symptom onset and initiation of zinc was 4 days, ranging from 1 to 21 days after onset of symptoms. The mean age was 40; the group included 17 female, 11 male, 3 Hispanic, 3 Asian, 1 African-American and 21 Caucasian.

Patients were contacted daily for symptom evaluation and for side effects. Ten symptoms were scored according to a COVID-19 symptom checklist and categorized on a 3 point scale: 0-no symptoms, 1 -mild, 2-moderate, 3- severe. Fever and shortness of breath were further defined as follows: Fever 0 -< 98.6, 1- > 98.6-100.0, 2- >100.0 - 102.0, 3- > 102.0. Shortness of breath (SOB) 1= moderate intensity exercise, 2= with walking on flat surface, 3= with any movement or at rest. Cough, nausea/vomiting, diarrhea, sore throat, headache, muscle/body aches, fatigue and loss of smell/taste were also assessed.

All 28 patients showed improvement after 7 days of zinc. Symptomatic improvement began a mean of 1.6 days after zinc treatment. Patients 40 or older took an average of 2.1 days to improve vs 1.4 days for those under 40 (p< 0.05, t-test). The mean COVID-19 score at 7 days was not different for >40 aged patients, vs < 40 aged patients. The time to improvement did not correlate with the number of days since the onset of symptoms. Nine patients were symptomatic with fever, cough and SOB, prior to zinc. The mean COVID-19 symptom score pretreatment was 8.6, versus 1.6 post-treatment (p <.001, Wilcoxon signed rank test). No patients were hospitalized after zinc treatment. Four patients complained of nausea after taking zinc (3 with acetate, 1 with gluconate). Zinc acetate was associated with vomiting in 2 patients when ingested on an empty stomach; thereafter only zinc gluconate was used, after food.

A comparison of COVID-19 checklist scores before and after 7 days of zinc is seen in Table 1. Three weeks after initiation of zinc lozenges, two patients were still fatigued; otherwise, all were asymptomatic.

Table 1

The clinical course of case 18 is shown in FIG. 3. After two days of the initiation of zinc lozenges, symptoms began to improve.

These data show that initiation of zinc lozenges was followed by symptomatic and objective improvement in 28 consecutive COVID-19 patients. Zinc gluconate or acetate were initially chosen because they have the most theoretical and experimental effectiveness in the treatment of the common cold (see e.g. Eby (2010) Med Hypotheses 74(3):482-92). Zinc gluconate was found to be better tolerated than zinc acetate in our patients.

The frequent and high dose regimen was chosen for three reasons. First, if zinc directly inhibits SARS-CoV-2 replication, frequent dosing may be required. Second, two weeks of 200mg zinc daily has negligible toxicity. Third, trials of zinc for the common cold that failed were underdosed (Eby (2010) Med Hypotheses 74(3):482-92). The present use of zinc differs significantly from a previous retrospective report in frequency (every 2-4 hours vs. once daily), length of dosage (>10 days vs. 5 days), and type of zinc salt (zinc gluconate/acetate vs. sulfate) (Carlucci etal. (2020) .Journal of Medical Microbiology 69:1228-34).

Without being bound to any particular mechanism or theory, for COVID-19 patients, zinc may help through direct inhibition of viral replication, improvement of mucociliar clearance of SARS-CoV-2, reduction of secondary bacterial infection, improvement of lung and kidney tissue healing after ischemia, modulation of T and B lymphocytes, and/or restoration of interferon-alpha production (Wessels et al. (2020) Front Immunol 11:1712, and Prasad et al. (2007) AM J Clin Nutr 85:837-44). In addition, mild zinc deficiency is often present in groups at the highest risk of COVID-19; namely, the elderly, diabetic, obese, and hypertensive (Wessels et al. (2020) Front Immunol 11:1712).

In mild cases of COVID-19 about 80 % of patients begin improving after day 10; 20% worsen the second week. Zinc treated patients began improvement after 1.6 days on average. Patients older than 40 began recovery slightly later than under 40; however, the clinical outcome at 7 days was the same, which is not the typical COVID-19 course. A recent report by the CDC showed that among symptomatic adult COVID-19 outpatients, 35% were still symptomatic 2-3 weeks after testing positive (Tenforde et al. (2020) MMWR Morb Mortal Wkly Rep 69:993-998). For those with SOB, one-third experienced these symptoms weeks later. By contrast, all 9 of the patients who were SOB began improving after 2 days, and none were SOB after 7 days. Except for fatigue, all 28 patients were symptom free after 3 weeks. Finzi and Harrington (2021) JMed Virol. DOI: 10.1002/jmv.26812, is incorporated by reference in its entirety. Example 3

Treatment of Long COVID

A 33 year-old female was in her usual state of good health until she became infected with SARS-CoV-2 in February 2020, and developed classic symptoms of Covid-19, including fever, headache, profound fatigue, muscle aches, sore throat, shortness of breath and dizziness. One month after the onset of symptoms she still suffered from profound fatigue, shortness of breath, malaise, cognitive dysfunction, headaches, muscle aches, weakness, memory deficits and hypersomnia. She was unable to walk more than 20 feet without becoming short of breath. The profound fatigue, memory deficits, weakness, dizziness and cognitive dysfunction forced her to discontinue her work as a university lecturer. One year later she was still completely disabled, with persistent profound fatigue, weakness, memory deficits, dizziness and cognitive dysfunction. She slept more than 12 hours daily.

She was started on the high dose zinc gluconate regimen disclosed herein, see Example 2. Two weeks after completing the zinc regimen her symptoms had improved sufficiently that she was able to return to work. She still suffered from some fatigue and what she described as "brain fog", but her symptoms were improved enough to resume some of her previous duties.

Six weeks after completing the zinc regimen she had maintained her improvement.

In view of the many possible embodiments to which the principles of our invention may be applied, it should be recognized that illustrated embodiments are only examples of the invention and should not be considered a limitation on the scope of the invention. Rather, the scope of the invention is defined by the following claims. We therefore claim as our invention all that comes within the scope and spirit of these claims.

Claims

It is claimed:

1. A method of treating a SARS-CoV-2 infection in a subject, comprising selecting a subject with a SARS-CoV-2 infection; and administering to the subject with the SARS-CoV-2 infection an effective amount of elemental zinc, wherein the effective amount is about 100 mg or more of elemental zinc daily, thereby treating the SARS-CoV-2 infection in the subject.

2. The method of claim 1, wherein the elemental zinc is in the form of a zinc salt.

3. The method of claim 2, wherein zinc salt is zinc acetate, zinc citrate, zinc gluconate, zinc sulfate, or any combination thereof.

4. The method of any one of claims 1-3, further comprising administering to the subject with the SARS-CoV-2 infection an effective amount of a zinc ionophore.

5. The method of claim 4, wherein the zinc ionophore is quercetin, epigailocatechin gal late (EGCE), pyrithione, hinokitiol, or pyrrolidine-dithiocarbamate (PDTC).

6. The method of claim 5, wherein the zinc ionophore is quercetin.

7. The method of any one of claims 1-5, comprising repeatedly administering to the subject about 1 to about 200 mg of the elemental zinc per day.

8. The method of claim 7, comprising repeatedly administering to the subject about 1 to about 100 mg of the elemental zinc about every hour, and not exceeding about 200 mg elemental zinc per day.

9. The method of claim 7 or claim 8, wherein repeatedly administering the elemental zinc comprises administering the elemental zinc every hour for at least 5 hours per day to the subject, and wherein said administering occurs for at least 2 days.

10. The method of any one of claims 7-9, wherein repeatedly administering comprises administering the elemental zinc to the subject about every hour for at most 9 hours.

11. The method of any one of claims 1-10, wherein the elemental zinc is administered to the subject every about 2 to about 4 hours at a total daily dose of about 2 to about 2.5 mg/kg.

12. The method of any one of claims 1-11, wherein the elemental zinc is administered to the subject for at least 3 days.

13. The method of any one of claims 1-12, wherein the zinc salt is administered to the subject for at least 7 days.

14. The method of any one of claims 1-13, wherein the elemental zinc is formulated for sustained release over a period of at least 20 minutes.

15. The method of claim 14, wherein the elemental zinc is in the form of a zinc salt, and wherein the zinc salt is zinc gluconate, zinc citrate, or a combination thereof.

16. The method of any one of claims 1-15, wherein the elemental zinc is administered as orally.

17. The method of claim 16, wherein the zinc is formulated as a lozenge.

18. The method of any one of claims 1-17, comprising administering the elemental zinc to the subject for a maximum of two weeks.

19. The method of any one of claims 1-19, further comprising administering to the subject an effective amount of vitamin C, L-lysine and/or echinacea.

20. The method of any one of claims 1-19, wherein the subject has long COVID.

21. The method of any one of claims 1-20, wherein the subject is human.

22. The method of claim 21, wherein the human is an adult.

23. The method of claim 22, wherein the adult is greater than 55 years of age or greater than 65 years of age.

24. A pharmaceutical composition comprising an effective amount of a zinc salt and a zinc ionophore.

25. The pharmaceutical composition of claim 24, further comprising vitamin C, L-lysine and/or echinacea.

24. The pharmaceutical composition of claim 24 or claim 25, for use in the method of any one of claims 1-23.