Products and therapeutic compositions for treating, ameliorating, or preventing viral infections and methods for making and using them

Abstract

In alternative embodiments, provided are therapeutic combinations of pharmaceutical compositions and drugs, including articles of manufacture and kits, and methods for making and using the same, for treating, preventing, or ameliorating (e.g., reducing symptoms or reducing mortality) a viral infection, e.g., a coronavirus infection, such as COVID-19 or a variant thereof. In alternative embodiments, provided are articles of manufacture and kits for delivering the therapeutic combinations of pharmaceutical compositions and drugs provided herein, e.g., provided are transdermal delivery devices, such as patches, that can have multiple compartments for simultaneous transdermal delivery of different drugs.

Description

[Technical Field]

[0001]

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. (USSN) 63 / 452,399, filed March 15, 2023, the entire disclosure of which is incorporated herein by cross-reference.

[0002]

[0002] The present invention relates generally to infectious diseases and medicine. In alternative embodiments, provided are pharmaceutical compositions and therapeutic drug combinations, including articles of manufacture and kits, and methods for making and using the same, for treating, preventing, or ameliorating (e.g., reducing symptoms or reducing mortality) viral infections, e.g., coronavirus infections, such as COVID-19 or variants thereof. In alternative embodiments, provided are articles of manufacture and kits for delivering the pharmaceutical compositions and therapeutic drug combinations provided herein. [Background technology]

[0003]

[0003] Several active single agents exist that inhibit coronavirus replication. However, when used alone, these agents do not eradicate infections quickly enough, and many patients still develop a cytokine storm, may be admitted to intensive care, and a small percentage die. Therefore, there is a great need to find a method to effectively inhibit viral replication intracellularly.

[0004]

[0004] Many of the products included in such therapies must be used early, before the onset of massive cytokine release, and therefore are ineffective because they are either monotherapies (e.g., molnupiravir, or LAGEVRIO (trademark)) or two-drug therapies, such as the combination of nilmatrervir and ritonavir, as in PAXLOVID (trademark). Summary of the Invention

[0005] In an alternative embodiment, provided is a pharmaceutical composition or therapeutic combination of drugs comprising: (a)(i) metformin (or GLUCOPHAGE™) and / or (ii) a 3C-like (3CL) protease (also known as main protease (M), also known as C30 endopeptidase or 3-chymotrypsin-like protease) inhibitor, optionally ensitrevir (or XOCOVA™), or ensitrevir fumarate; wherein optionally, metformin is formulated or dosed at between about 100 mg and 4000 mg per unit dose (optionally per tablet); or metformin is formulated or dosed at between about 0.1 ml and 25 ml of liquid metformin / day; wherein optionally, the ensitrevir or ensitrevir fumarate is formulated or dosed at between about 100 mg and 500 mg per unit dose, or at about 100 mg, 125 mg, or 150 mg per unit dose (optionally per tablet); and (b) If only metformin or a 3CLpro inhibitor is included, any two of the following drugs or drug combinations, or if both metformin and a 3CLpro are included, any one (or at least one) of the following drugs or drug combinations: (i) Avermectin drugs or Ivermectin (or STROMECTOL™); (ii) an avermectin drug or ivermectin and an antibiotic (optionally, doxycycline or azithromycin); (iii) avermectins or ivermectin; antibiotics (optionally, doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol (optionally with or without vitamin C); (iv) antibiotics; (v) ivermectin; and an antibiotic (optionally, doxycycline or azithromycin), at least one vitamin, and zinc; (vi) opaganib or YELIVA™; (vii) opaganib and an avermectin drug or ivermectin; an antibiotic (optionally, doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (viii) plitidepsin (also known as dehydrodidemnin B), or APLIDIN™; (ix) plitidepsin and an avermectin drug or ivermectin; an antibiotic (optionally, doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol, and optionally also vitamin D or cholecalciferol; (x) lopinavir, ritonavir (or NORVIR™), and / or oseltamivir; (xi) lopinavir, ritonavir, and / or oseltamivir with an avermectin or ivermectin; an antibiotic (optionally, doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xii) nilmatrervir and ritonavir (or PAXLOVID™), (xiii) Nilmatrevir and ritonavir (or Paquilobid™) with an avermectin drug or ivermectin; an antibiotic (optionally, doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xiv) chloroquine (optionally ARALEN™), chloroquine phosphate, chloroquine diphosphate, hydroxychloroquine (optionally PLAQUENIL™); (xv) chloroquine, chloroquine phosphate, chloroquine diphosphate, hydroxychloroquine, and an avermectin or ivermectin; an antibiotic (optionally, doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xvi) abacavir, optionally acyclovir, (ACICLOVIR™), adefovir, amantadine, ampligen, amprenavir (optionally AGENERASE™), aprepitant, arbidol, atazanavir, atripla, balavir, baloxavir marboxil (XOFLUZA™), bepotastine, bevirimat, bictegravir, bictarvy, brilacidin, cidofovir, caspofungin, lamivudine, and zidovir Vudine (optionally COMBVIR™), cobicstat, colisitin, cocaine, delavirdine, descovy, didanosine, docosanol, dolutegravir, ecoliever, edoxudine, elvitegravir, enfuvirtide, entecavir, epirubicin, epoprostenol, etravirine, famciclovir, homovirsen, fosamprenavir, foscarnet, fosfonet, galidesivir, ibacitabine, icatibant, idoxuridine, ife amprozil, imiquimod, imunovir, indinavir, inosine, interferon (optionally type I interferon, type II interferon, and / or type III interferon), lamivudine, loviride, ledipasvir, leronlimab, maraviroc, methisazone, moroxydine, nexavir, norvir, nucleoside analogues (optionally brincidofovir, didanosine, favipiravir (also known as T-705, avigan, or favipiravir, Fujifilm Toyama Chemical, Japan), vidarabine galidesivir (optionally BCX4430, IMMUCILLIN-A™), cytarabine, gemcitabine, lamivudine, zalcitabine, abacavir, acyclovir, entecavir, stavudine, telbivudine, zidovudine, idoxuridine, and / or trifluridine, or any combination thereof), oseltamivir (or TAMIFLU™), peginterferon alfa-2a, penciclovir, peramivir (optionally RAPIVAB™), perphenazine,Pleconaril, prulifloxacin, podophyllotoxin, pyramidine, raltegravir, rifampicin, rilpivirine, rimantadine, ritonavir, saquinavir, sofosbuvir, stavudine, telaprevir, tegobuv, tipranavir, trifluridine, trizivir, tromantadine, truvada, valacyclovir (optionally VALTREX™), valganciclovir, valrubicin, vapreotide, vicriviroc, vidarabine, viramidine, velpatasvir, vivecon, zalcitabine, zanamivir (optionally RELENZA™), zidovudine, or any combination thereof; (xvii) Any one or more of the drugs in (xiv) above; an avermectin drug or ivermectin; an antibiotic (optionally, doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xviii) molnupiravir, emtricitabine (or EMTRIVA™), efavirenz (or SUSTIVA™), or tenofovir; or molnupiravir and emtricitabine and tenofovir (or ATRIPLA™); (xix) molnupiravir, emtricitabine, efavirenz, or tenofovir with an avermectin or ivermectin; an antibiotic (optionally, doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xx) zanamivir (or Relenza®); (xxi) zanamivir and an avermectin or ivermectin; an antibiotic (optionally, doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxii) efavirenz (optionally, Sustiva®); (xxiii) efavirenz and an avermectin or ivermectin; an antibiotic (optionally, doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxiv) nelfinavir (VIRACEPT™) or oseltamivir (or Tamiflu™), (xxv) nelfinavir (Viracept™) or oseltamivir (or Tamiflu™) with an avermectin drug or ivermectin; an antibiotic (optionally, doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxvi) a drug of the thiazolide class, optionally nitazoxanide (optionally ALINIA™, or NIZONIDE™) or tizoxanide (or 2-hydroxy-N-(5-nitro-2-thiazolyl)benzamide); (xxvii) a drug of the thiazolide class, optionally with nitazoxanide and an avermectin drug or ivermectin; an antibiotic (optionally with doxycycline or azithromycin), and zinc, and optionally also with vitamin D or cholecalciferol; (xxviii) remdesivir (optionally GS-5734™, Gilead Sciences, or VEKLURY™); (xxix) molnupiravir (or LAGEVRIO™); (xxx) molnupiravir and an avermectin or ivermectin; an antibiotic (optionally, doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxi) nevirapine (or VIRAMUNE™); (xxxii) nevirapine (or Viramune™) with an avermectin drug or ivermectin; an antibiotic (optionally, doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxiii) tenofovir alafenamide, tenofovir disoproxil, or tenofovir; (xxxiv) tenofovir alafenamide, tenofovir disoproxil, or tenofovir with an avermectin or ivermectin; an antibiotic (optionally, doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxv) selamectin (or SELEHOLD™, REVOLT™, SELARID™, or SENERGY™); (xxxvi) selamectin and an avermectin drug or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxvii) inhibitors of S-phase kinase-associated protein 2 (SKP2), or dioscin, or niclosamide, or NICLOCIDE™, FENASAL™, or PHENASAL™; (xxxviii) an inhibitor of S-phase kinase-associated protein 2 (SKP2), or dioscin, or niclosamide, and an avermectin drug or ivermectin; an antibiotic (optionally, doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxix) ribavirin or tribavirin (or COPEGUS™, REBETOL™, or VIRAZOLE™); (xxxx) Ribavirin or tribavirin with an avermectin or ivermectin; an antibiotic (optionally, doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxxi) a viral, or coronavirus, or COVID-19 protease inhibitor, optionally ASC09 (CAS Registry Number 1000287-05-7) (Janssen Research and Development, LLC), ritonavir, or ASC09 and ritonavir, or a JAK1 / 2 inhibitor (optionally baricitinib), optionally compound 11r (University of Lübeck, Germany; see Zhang et al. J. Med Chem 2020, February 11, 2020), or darunavir (or PREZISTA™), cobicistat (or TYBOST™), or darunavir and cobicistat; (xxxxii) Virus, or coronavirus, or COVID-19 protease inhibitors, ritonavir, JAK1 / 2 inhibitors (optionally baricitinib), or darunavir (or Plezista™) or cobicistat, with avermectins or ivermectin; antibiotics (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxxiii) mucolytic therapy or medication, optionally acetylcysteine, ambroxol, bromhexine, carbocysteine, erdosteine, mecysteine, or dornase alfa, or expectorant, optionally guaifenesin; (xxxxiv) mucolytic therapy or medication with an avermectin drug or ivermectin; an antibiotic (optionally, doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxxv) angiotensin-converting enzyme 2 (ACE2) inhibitors, optionally captopril, enalapril, lisinopril, benazepril, fosinopril, quinapril, ramipril, perindopril, moexipril, or trandolapril; (xxxxvi) angiotensin-converting enzyme 2 (ACE2) inhibitor and an avermectin or ivermectin; an antibiotic (optionally, doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxxvii) an anti-vascular endothelial growth factor (VEGF) (optionally, VEGF-A) drug or antibody, optionally bevacizumab (or AVASTIN™); (xxxxviii) anti-vascular endothelial growth factor (VEGF) drug or antibody, or bevacizumab, with an avermectin drug or ivermectin; an antibiotic (optionally, doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxxix) a protease inhibitor, optionally danoprevir, optionally a serine protease inhibitor, optionally camostat (or FOIPAN™) or narlaprevir (optionally ARLANSA™) (xxxxx) A protease inhibitor, danoprevir, a serine protease inhibitor, camostat, or narlaprevir, and an avermectin or ivermectin; an antibiotic (optionally, doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxxxi) an anti-PD-1 checkpoint inhibitor, optionally camrelizumab, or a PD-1 inhibitor (or cemiplimab, dostallimab, pembrolizumab, or nivolumab), or a PD-L1 inhibitor (or atezolizumab, avelumab, cosibelimab, or durvalumab); (xxxxxii) anti-PD-1 checkpoint inhibitor, or camrelizumab, or a PD-1 inhibitor, or a PD-L1 inhibitor with an avermectin or ivermectin; an antibiotic (optionally, doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxxxiii) thalidomide, or thalidomide and glucocorticoids (optionally low-dose glucocorticoids), or and thalidomide and celecoxib; (xxxxxiv) thalidomide, or thalidomide and a glucocorticoid (optionally, a low-dose glucocorticoid) with an avermectin or ivermectin; an antibiotic (optionally, doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxxxv) a compound or antibody capable of binding to complement factor C5 and inhibiting membrane attack complex formation, or eculizumab; (xxxxxvi) a compound or antibody capable of binding to complement factor C5 and inhibiting membrane attack complex formation, or eculizumab, together with an avermectin drug or ivermectin; an antibiotic (optionally, doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxxxvii) a cathepsin inhibitor, optionally a cathepsin K, B, or L inhibitor, or relacatib or baricatib; (xxxxxviii) a cathepsin inhibitor, or relacatib or baricatib, with an avermectin or ivermectin; an antibiotic (optionally, doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxxxix) a synthetic nucleoside analogue or derivative, or N4-hydroxycytidine, or a prodrug of N4-hydroxycytidine, optionally molnupiravir (Merck), or favipiravir (also known as T-705 or Avigan™), or Favilavir, Japan, Fujifilm Toyama Chemical, or FABIFLU™ (Glenmark Pharmaceuticals), optionally dosed at 800 mg bid; (xxxxxx) synthetic nucleoside analogues or derivatives with avermectins or ivermectin; antibiotics (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; wherein the synthetic nucleoside analog or derivative, or N4-hydroxycytidine, or prodrug of N4-hydroxycytidine, optionally molnupiravir or favipiravir, is administered at between about 10 mg and 3 gm per dose, or between about 10 mg and 3 gm per day, or can be dosed as a single dose, or administered once, twice, three or four times daily, or 200-800 mg twice daily, or 200, 400, 600 or 800 mg, or 200-800 mg three times a day, or 200, 400, 600, or 800 mg three times a day, or 200-800 mg three times a day for about 2-15 days, or for about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 days, optionally with lower dosages used when combined with other drugs, optionally with 100 or 200 mg three times a day for about 5-15 days, or for about 7, 8, 9, 10, 11, or 12 days; (xxxxxxi) an antiandrogen drug, optionally wherein the antiandrogen drug is bicalutamide, or CASODEX™, or dutasteride (or AVODART™), optionally wherein the antiandrogen drug comprises a 5α-reductase inhibitor, optionally wherein the 5α-reductase inhibitor comprises finasteride (or PROSCAR™, PROPECIA™, or FINIDE™); (xxxxxxii) an antiandrogen drug, optionally where the antiandrogen drug is bicalutamide, or Casodex™, or dutasteride (or Avodart™), an avermectin drug or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxxxxiii) an antimalarial drug, wherein optionally the antimalarial drug comprises mefloquine (or LARIAM™, MEPHAQUIN™, or MEFLIAM™), wherein optionally the mefloquine is optionally formulated for oral administration in tablet or capsule form, optionally as 200 mg, 250 mg, or 300 mg tablets; (xxxxxxiv) an antimalarial drug and an avermectin or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxxxxv) Peroxisome Proliferator-Activated Receptor (PPAR) agonists, wherein optionally the PPAR agonist comprises fenofibrate, or TRICOR™, FENOBRAT™, FENOGLIDE™, or LIPofen™, and optionally the PPAR agonist comprises a combination of fenofibrate and pravastatin, or PRAVAFENIX™, or the PPAR agonist comprises bezafibrate or BEZALI™. P)™, or a combination of bezafibrate and chenodeoxycholic acid, or HEPACONDA™, or clofibrate aluminum, or alfibrate, or ciprofibrate, or clinofibrate or LIPOCLIN™, or clofibrate or Atromid-S™, or clofibrate, or gemfibrozil or LOPID™, or lonifibrate, or simfibrate or CHOLESOLVIN™, or any combination thereof, (xxxxxxvi) a peroxisome proliferator-activated receptor (PPAR) agonist and an avermectin drug or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxxxxvii) An acetaldehyde dehydrogenase inhibitor, optionally formulated as a sustained-, extended-, or delayed-release disulfiram formulation, optionally disulfiram, or ANTABUS™, or ANTABUSE™, optionally sustained-, extended-, or delayed-release disulfiram formulated as a tablet, capsule, or in an injectable, amphiphilic, absorbable, depot-forming drug delivery system (DDS); (xxxxxxviii) an acetaldehyde dehydrogenase inhibitor and an avermectin or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxxxxix) a nicotinic antagonist, dopamine agonist, or non-competitive N-methyl-D-aspartate (NMDA) antagonist, optionally formulated as a tablet or capsule, optionally dosed at between about 100-200 mg per dose, optionally amantadine, or GOCOVRI™, or SYMADINE™, or SYMMETREL™; (xxxxxxx) a nicotinic antagonist, dopamine agonist, or noncompetitive N-methyl-D-aspartate (NMDA) antagonist with an avermectin or ivermectin; an antibiotic (optionally, doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxxxxxi) mitochondrial sensitivity agents, optionally proguanil or chlorguanide (or PALUDRINE™), or malarial cytochrome bc1 complex inhibitors, optionally atovaquone (or MEPRON™), or a combination of proguanil and atovaquone (or MALARONE™); Optionally, proguanil, atovaquone, or the combination of proguanil and atovaquone is formulated for oral administration, optionally as a tablet, and optionally the unit dose of atovaquone is 250 mg, 300 mg, 350 mg, 400 mg, 500 mg, or 1 gram and the unit dose of proguanil is 100 mg, 250 mg, 300 mg, 350 mg, or 400 mg; (xxxxxxxii) mitochondrial insulators or malarial cytochrome bc1 complex inhibitors with avermectins or ivermectin; antibiotics (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxxxxxiii) dendrimers, optionally astodrimer sodium (Starpharma, Melbourne, Australia); (xxxxxxxiv) a dendrimer and an avermectin drug or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxxxxxv) Antihistamine class drugs, optionally azelastine, or ASTELIN™, OPTIVAR™, ALLERGODIL™, bepotastine (or TALION™, BEPREVE™), brompheniramine, fexofenadine or ALLEGRA™, pheniramine or AVIL™, or chlorpheniramine; (xxxxxxxvi) Antihistamine class drugs and avermectins or ivermectin; antibiotics (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxxxxxvii) a drug of the selective serotonin reuptake inhibitor (SSRI) class, optionally fluvoxamine, or LUVOX™, FAVERIN™, FLUVOXIN™; a peroxisome proliferator-activated receptor (PPAR) agonist, optionally wherein the PPAR agonist comprises fenofibrate, or Tricor™, Fenobrat™, Fenoglide™, or Lipofen™, optionally wherein the PPAR agonist comprises a combination of fenofibrate and pravastatin, or prasugrel including Bafenix™, or PPAR agonists include bezafibrate, or Bezalip™, or a combination of bezafibrate and chenodeoxycholic acid, or Hepaconda™, or clofibrate aluminum, or alfibrate, or ciprofibrate, or clinofibrate or Lipocrine™, or clofibrate or Atromid-S™, or clofibride, or gemfibrozil or Lopid™, or lonifibrate, or simfibrate or Cholesorbin™, or any combination thereof; (xxxxxxxviii) Selective serotonin reuptake inhibitor (SSRI) class drugs and avermectins or ivermectin; antibiotics (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxxxxxix) clofazimine, or LAMPENE™, optionally dosed at about 100 mg per day, or between about 50 mg and 150 mg per day, and / or colchicine (or COLCRYS™, MITIGARE™), optionally dosed at about 0.1 mg to 5 mg per day; (xxxxxxxx) Clofazimine or colchicine with an avermectin or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxxxxxxi) Selective estrogen receptor modulators (SERMs), or toremifene (or FARESTON™), or clomiphene or clomiphene (or CLOMID™, SEROPHENE™); (xxxxxxxxii) A selective estrogen receptor modulator (SERM), or toremifene, or clomiphene or clomiphene, with an avermectin or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxxxxxxiii) alpha-ketoamides (α-ketoamides), where optionally the alpha-ketoamide is a structure described by Zhang et al., J. Med. Chem. 2020, 63, 9, 4562-4578, or Meng et al., Chem. Sci. (2019) Vol. 10, p. 5156 (optionally, structure KAM-2); (xxxxxxxxiv) alpha-ketoamide and an avermectin or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxxxxxxv) acylsulfonamide inhibitors of NS3-4A serine protease, or paritaprevir, or ombitasvir, or paritaprevir and ombitasvir and ritonavir (TECHNIVIE™); (xxxxxxxxvi) Paritaprevir (or VERUPREVIR™), or ombitasvir, or paritaprevir and ombitasvir and ritonavir, and an avermectin or ivermectin; an antibiotic (optionally, doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxxxxxxvii) at least one vitamin, optionally the at least one vitamin comprising vitamin B3 (or pyridine-3-carboxylic acid, niacin, or nicotinic acid, or vitamin B3 or niacin administered in a sustained release form (or NIASPAN FCT™), vitamin D (optionally, D2, or ergocalciferol), or vitamin D3 or cholecalciferol, optionally administered at about 1000-4000 ugm / day; vitamin B12, vitamin B6 (or pyridoxine); vitamin K; vitamin A; vitamin E; and / or vitamin C (optionally administered at 500 mg bid); (xxxxxxxxviii) at least one vitamin and an avermectin drug or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc; (xxxxxxxxix) a compound, drug, or preparation that reduces gastric acid production or lowers gastric pH, optionally wherein the compound, drug, or preparation comprises famotidine or PEPCID™, optionally wherein the famotidine is administered at a dosage of between about 10-60 mg per day, or between about 20-40 mg per day; (xxxxxxxxx) Famotidine and an avermectin or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc; (xxxxxxxxxi) an immunosuppressant drug, wherein optionally the immunosuppressant drug comprises tocilizumab or atlizumab, or ACTEMRA™, or ROACTEMRA, or a calcineurin inhibitor (CNI), wherein the CNI comprises cyclosporin (or cyclosporine or cyclosporin), or NEORAL™, or SANDIMMUNE™, or tacrolimus, or PROTOPIC™, or PROGRAF™; (xxxxxxxxxii) immunosuppressant drugs or calcineurin inhibitors and avermectins or ivermectin; antibiotics (optionally doxycycline or azithromycin), and zinc; (xxxxxxxxxiii) an anti-inflammatory therapy or at least one anti-inflammatory therapeutic drug, wherein optionally the anti-inflammatory therapy or drug is a sphingosine kinase-2 (SK2) selective inhibitor (optionally opaganib (optionally Eriva™)), sirolimus, a JAK1 / 2 / TYK2 inhibitor (optionally ruxolitinib), an anti-CD47 mAb (optionally meplasmab), a cyclooxygenase (COX) (optionally COX2) inhibitor, an anti-inflammatory agent, including a glucocorticoid (optionally a synthetic glucocorticoid, hydrocortisone, dexamethasone (or DEXTENZA™, OZURDEX™, or NEOFORDEX™) or cortisol, or CORTEF™), plitidepsin or dehydrodidemnin B, or Aplidine™; and / or (xxxxxxxxxiv) an anti-inflammatory therapy or at least one anti-inflammatory therapy drug, including an avermectin drug or ivermectin; an antibiotic (optionally, doxycycline or azithromycin), and zinc; wherein optionally the avermectin drug comprises ivermectin (or Stromectol™), moxidectin (or CYDECTIN™, EQUEST™, QUEST™), selamectin (or STRONGHOLD™), milbemycin (optionally milbemectin, milbemycin oxime, moxidectin, or nemadectin), doramectin (or DECTOMAX™), eprinomectin, or abamectin; Optionally, the avermectin or ivermectin is dosed at between about 50-2000 μgm / kg body weight per day, optionally 200 μgm / kg per day, or about 14 mg / day, optionally 220, 225, 150, 275, or 300 μgm / kg per day, or optionally 12, 14, 16, 18, 20, 22, 24, or 26 mg per day, or optionally between about 10-30 mg per day, for administration; Optionally, the avermectin or ivermectin is dosed at between about 5 and 480 mg or between about 3 and 500 mg per day for administration; Optionally, the avermectin drug (optionally ivermectin) is formulated or dosed at between about 15-150 mg / kg, or about 18, 24, 30, 35, 40, 35, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, or 120 mg / kg or more; Optionally, the antibiotic comprises a tetracycline class drug, optionally the tetracycline class drug is tetracycline, doxycycline, chlortetracycline, oxytetracycline, glycylcycline, fluorocycline, or demeclocycline, tetracycline or SUMYCIN™; chlortetracycline or AUREOMYCIN™; oxytetracycline; demeclocycline or DECLOMYCIN™, DECLOSTATIN™, LEDERMYCIN™, BIOTERCICLIN™, DEGANOL™, DETECLO (TM), DETRAVIS™, MECICLIN™, MEXOCINE™, CLORTETRIN™; lymecycline; meclocycline; methacycline; minocycline or MINOCIN™; rolitetracycline; doxycycline or DORYX™; DOXYHEXA™, DOXYLIN™; tigecycline or TYGACIL™; eravacycline or XERAVA™; sarecycline or SEYSARA™; omadacycline or NUZYRA™; or any combination thereof, Optionally, the therapeutic combination comprises about 25 mg to about 600 mg of a drug of the tetracycline class, or tetracycline, doxycycline, chlortetracycline, oxytetracycline, or demeclocycline; Optionally, the antibiotic comprises a macrolide drug, optionally the macrolide drug is azithromycin (optionally ZITHROMAX™, or AZITHROCIN™, optionally an oral sustained or delayed release formulation of azithromycin, or ZMAX™), clarithromycin (optionally BIAXIN™), erythromycin (optionally ERYTHROCIN™), or fidaxomicin (optionally dextromethorphan), optionally dosed at between about 50 mg and about 2000 mg per dose or per day. DIFICID™ or DIFICLIR™), troleandomycin (optionally TEKMISIN™), tylosin (optionally TYLOCINE™ or TYLAN™), solithromycin (optionally SOLITHERA™), oleandomycin (or SIGMAMYCINE™), midecamycin, roxithromycin, kitasamycin or tulimicin, josamycin, carbomycin or magnamycin, and / or spiramycin; Optionally, the antibiotic comprises azithromycin, and optionally the therapeutic combination comprises between about 50 mg and about 2000 mg of azithromycin, or optionally, the azithromycin comprises an oral sustained-release formulation of azithromycin; Optionally, the antibiotic comprises a nitroimidazole, or 2-, 4-, and / or 5-nitroimidazole, or 5-nitronitroimidazole, including metronidazole, tinidazole, nimorazole, dimetridazole, pretomanid, ornidazole, megazole, and / or azanidazole, or 2-nitroimidazole, including benznidazole; Optionally, the antibiotic comprises a β-lactam antibiotic, such as a penicillin class drug or a cephalosporin class drug; Optionally, the cephalosporin class drug comprises cefalexin, cefadroxil, cefazolin, cefapirin, cephalothin, cefradine, cefprozil, cefuroxime, ceftolozane, cefonicid, or cefaclor; Optionally, the penicillin class drug comprises penicillin V, penicillin G, cloxacillin, dicloxacillin, flucloxacillin, methicillin, nafcillin, oxacillin, ampicillin, amoxicillin, pivampicillin, bacampicillin, metampicillin, talampicillin, hetacillin, carbenicillin, ticarcillin, temocillin, mezlocillin, piperacillin, azlocillin, clavulanic acid, sulbactam, or tazobactam; Optionally, the antibiotic comprises an antibiotic of the quinolone class, such as a fluoroquinolone, or comprises ciprofloxacin, garenoxacin, gatifloxacin, gemifloxacin, levofloxacin, or moxifloxacin; Optionally, the antibiotic comprises an ansamycin class drug, or rifampicin, also known as rifampin, bedaquiline; Optionally, the antibiotic comprises artemisinin, amodiaquine, proguanil, sulfadoxine, sulfamethoxypyridazine, pyrimethamine, linezolid, quinine, quinidine, cinchonine, cinchonidine (or quinimax), hydroxychloroquine, or chloroquine; Optionally, the at least one vitamin comprises vitamin D or cholecalciferol, or vitamin C, or vitamin D or cholecalciferol and vitamin C, wherein the vitamin D or cholecalciferol is dosed at between about 3,000 and about 100,000 units of vitamin D or cholecalciferol; optionally, the therapeutic combination comprises between about 10,000 and about 50,000 units of vitamin D or cholecalciferol; and optionally, the vitamin comprises vitamin C, optionally formulated or administered at a dosage of between about 500 and 5000 units (U) per dose; optionally, the zinc comprises or is formulated as a zinc salt, zinc chelate, zinc sulfate, zinc acetate, zinc gluconate, or zinc picolinate; and optionally, the therapeutic combination comprises between about 1 mg and 250 mg of zinc, zinc sulfate, zinc acetate, zinc gluconate, or zinc picolinate, or optionally zinc oxide nanoparticles in a dose between about 1 mg and 250 mg; Optionally, the pharmaceutical composition or therapeutic combination further comprises copper, optionally administered or formulated at a dosage of between about 1 and 200 mg per day, wherein optionally the copper is administered or formulated as cupric chloride and formulated at about 0.4 mg / ml and administered intravenously; Optionally, the pharmaceutical composition or therapeutic combination further comprises selenium, optionally administered as selenite formulated at about 65.4 mcg / ml (or μg / ml), and optionally the selenium is administered at a dosage of between about 50-100 μg / ml, optionally between about 60-100 μgm per day administered to adults, and no more than 60 μgm per day administered to pediatric patients in a pharmaceutical composition or therapeutic combination of drugs.

[0006] In an alternative embodiment, provided is an article of manufacture comprising a pharmaceutical composition or therapeutic combination of drugs provided herein, Optionally, the article of manufacture comprises a pharmaceutical formulation, or a dressing or skin patch, or an implant; Optionally, the pharmaceutical composition or therapeutic combination is formulated as a gel, liquid, aerosol, spray, mist, lotion, cream, powder, tablet, capsule, pill, geltab, enema, suppository, transdermal or buccal patch, or an injectable, subcutaneous, intramuscular (IM), or intravenous (IV) formulation to produce a pharmaceutical formulation.

[0007]

[0007] In an alternative embodiment, provided is a kit comprising the pharmaceutical composition or therapeutic combination of drugs provided herein or the product provided herein, optionally for delivering both oral and transdermal drugs as needed.

[0008] In an alternative embodiment, provided is a virus, optionally a virus of the subfamily Ortho-coronavirus, or a virus of the family Coronaviridae, Arteriviridae, Roniviridae, and / or Mesoniviridae, or a virus of the subfamilies Letovirinae and Orthocoronavirinae; or a virus of the order Nidovirales, or a virus of the genera Alphacoronavirus, Betacoronavirus, Gammacoronavirus, or Use of a pharmaceutical composition or therapeutic combination of drugs provided herein, or a product of manufacture provided herein, or a kit provided herein, for treating, preventing, or ameliorating (optionally reducing symptoms or reducing mortality) an infection caused by a virus of the genus Deltacoronavirus or Deltacoronavirus, or Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) virus or a variant thereof, optionally wherein the SARS-CoV-2 is an omicron variant, or a B.1.1.529, BA.1, BA.1.1, BA.2, BA.3, BA.4, and BA.5 lineage variant; or optionally wherein the SARS-CoV-2 is an alpha, beta, gamma, delta, epsilon, eta, iota, kappa, mu, or zeta variant; optionally, the coronavirus infection is a viral infection caused by COVID-19 or a variant, alternative lineage branch, or subtype thereof, or a Middle East Respiratory Syndrome Virus (MERS-CoV) infection, and optionally, the coronavirus infection is so-called "Long COVID" or Post-COVID Conditions (PCC), or Post-Acute Sequelae of SARS CoV-2 Infection (PASC); Optionally, the viral infection is a virus that causes the common cold, influenza virus (optionally influenza A, B, or C), hepatitis virus, Rous sarcoma virus (RSV), Paramyxoviridae or measles virus, Paramyxovirus or mumps virus, herpes simplex virus (HSV), Cytomegalovirus (CMV), Rubivirus or rubella virus, enterovirus Enterovirus, viral meningitis, rhinovirus, human immunodeficiency virus (HIV), varicella zoster or chickenpox virus, orthopoxvirus or variola or smallpox virus, Epstein-Barr virus (EBV), adenovirus, hantavirus, flaviviridae or dengue virus, zika virus, or chikungunya virus infection).

[0009] In an alternative embodiment, provided is a virus, optionally a virus of the subfamily Ortho-coronavirus, or a virus of the family Coronaviridae, Arteriviridae, Roniviridae, and / or Mesoniviridae, or a virus of the subfamilies Letovirinae and Orthocoronavirinae; or a virus of the order Nidovirales, or a virus of the genera Alphacoronavirus, Betacoronavirus, Gammacoronavirus, or Delcoronavirus. Use of a pharmaceutical composition or therapeutic combination of drugs provided herein, or a product of manufacture provided herein, or a kit provided herein, for the manufacture of a medicament for treating, preventing, or ameliorating (optionally reducing symptoms or reducing mortality) an infection caused by a virus of the genus deltacoronavirus, or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus or a variant thereof, optionally wherein the SARS-CoV-2 is an omicron variant, or a B.1.1.529, BA.1, BA.1.1, BA.2, BA.3, BA.4, and BA.5 lineage variant; or optionally wherein the SARS-CoV-2 is an alpha, beta, gamma, delta, epsilon, eta, iota, kappa, mu, or zeta variant; optionally, the coronavirus infection is a viral infection caused by COVID-19 or a variant, alternative lineage branch, or subtype thereof, or a Middle East Respiratory Syndrome Virus (MERS-CoV) infection, and optionally, the coronavirus infection is so-called "long COVID" or post-COVID condition (PCC), or post-acute sequelae of SARS CoV-2 infection (PASC); Optionally, the viral infection is a virus that causes the common cold, influenza virus (optionally influenza A, B, or C), hepatitis virus, Rous sarcoma virus (RSV), Paramyxoviridae or measles virus, Paramyxovirus or mumps virus, herpes simplex virus (HSV), Cytomegalovirus (CMV), Rubivirus or rubella virus, enterovirus Enterovirus, viral meningitis, rhinovirus, human immunodeficiency virus (HIV), varicella zoster or chickenpox virus, orthopoxvirus or variola or smallpox virus, Epstein-Barr virus (EBV), adenovirus, hantavirus, flaviviridae or dengue virus, zika virus, or chikungunya virus infection).

[0010] In an alternative embodiment, provided is a virus, optionally a virus of the subfamily Ortho-coronavirusae, or a virus of the family Coronaviridae, Arteriviridae, Roniviridae, and / or Mesoniviridae, or a virus of the subfamilies Letovirinae and Orthocoronavirinae; or a virus of the order Nidovirales, or a virus of the genera Alphacoronavirus, Betacoronavirus, Gammacoronavirus, or A pharmaceutical composition or therapeutic combination of drugs provided herein, or a product provided herein, or a kit provided herein, for use in treating, preventing, or ameliorating (optionally reducing symptoms or reducing mortality) an infection caused by a virus of the genus Deltacoronavirus, or Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) virus or a variant thereof, optionally wherein SARS-CoV-2 is an omicron variant, or a B.1.1.529, BA.1, BA.1.1, BA.2, BA.3, BA.4, and BA.5 lineage variant; or optionally wherein SARS-CoV-2 is an alpha, beta, gamma, delta, epsilon, eta, iota, kappa, mu, or zeta variant; (Optionally, the coronavirus infection is a viral infection caused by COVID-19 or a variant, alternative lineage branch, or subtype thereof, or a Middle East Respiratory Syndrome Virus (MERS-CoV) infection; Optionally, the viral infection is a virus that causes a cold, influenza virus (optionally influenza A, B, or C), hepatitis virus, Rous sarcoma virus (RSV), Paramyxoviridae or measles virus, Paramyxovirus or mumps virus, herpes simplex virus (HSV), mumps virus (MuV), human papillomavirus (HPV), cytomegalovirus (CMV), Rubivirus or rubella virus, Enterovirus, viral meningitis, caused by vaccinia virus, rhinovirus, human immunodeficiency virus (HIV), varicella zoster or chickenpox virus, orthopoxvirus or variola or smallpox virus, Epstein-Barr virus (EBV), adenovirus, hantavirus, flaviviridae or dengue virus, ebola virus, zika virus, pneumonia virus, norovirus, rotavirus, viruses of the genus enterovirus or poliovirus, or chikungunya virus infection).

[0011] In an alternative embodiment, provided is a virus, optionally a virus of the subfamily Orthocoronavirinae, or a virus of the family Coronaviridae, Arteriviridae, Roniviridae, and / or Mesoniviridae, or a virus of the subfamilies Letovirinae and Orthocoronavirinae; or a virus of the order Nidovirales, or a virus of the genera Alphacoronavirus, Betacoronavirus, Gammacoronavirus, 1. A method for treating, preventing, or ameliorating (optionally reducing symptoms or reducing mortality from) an infection caused by a virus of the gammacoronavirus or deltacoronavirus genus, or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus or a variant thereof, optionally wherein the SARS-CoV-2 is an omicron variant, or a B.1.1.529, BA.1, BA.1.1, BA.2, BA.3, BA.4, and BA.5 lineage variant; or optionally wherein the SARS-CoV-2 is an alpha, beta, gamma, delta, epsilon, eta, iota, kappa, mu, or zeta variant; (Optionally, the coronavirus infection is a viral infection caused by COVID-19 or a variant, alternative lineage branch, or subtype thereof, or a Middle East Respiratory Syndrome Virus (MERS-CoV) infection; Optionally, the viral infection is a virus that causes the common cold, influenza virus (optionally influenza A, B, or C), hepatitis virus, Rous sarcoma virus (RSV), Paramyxoviridae or measles virus, Paramyxovirus or mumps virus, herpes simplex virus (HSV), Cytomegalovirus (CMV), Rubivirus or rubella virus, enterovirus Enterovirus, viral meningitis, rhinovirus, human immunodeficiency virus (HIV), varicella zoster or chickenpox virus, orthopoxvirus or variola or smallpox virus, Epstein-Barr virus (EBV), adenovirus, hantavirus, flaviviridae or dengue virus, zika virus, or chikungunya virus infection), A method comprising the step of administering a pharmaceutically effective amount of a pharmaceutical composition or drug therapeutic combination provided herein, or a product provided herein, or a kit provided herein to an individual in need thereof.

[0012]

[0012] In an alternative embodiment of the method provided herein, Avermectins (optionally ivermectin) (a)(i) in or as a loading dose containing an avermectin drug (optionally, ivermectin); (1) For adults, daily doses of about 300 μg / kg to 30 mg / kg (or 30 mg per 2.2 pounds (lb)) or about 18 mg to 1800 mg at 60 kg (about 132 lb), or 50 μg / kg, 75 μg / kg, 100 μg / kg, or 500 μg / kg, or a dose between about 50 μg / kg and 500 μg / kg, or an avermectin drug (any optionally, a loading dose of ivermectin between about 300 μg / kg to 30 mg / kg to 60 mg / kg per day, or between about 18 mg to about 1200 mg, or 1600 mg to 1800 mg, or between about 300 μg (mcg) to about 40 to 70 mg / kg, or 60 to 120 mg to about 1600 to 1800 mg in a 60 kg (about 132 lb) human; or (2) In adults, a loading dose containing an avermectin drug (optionally, ivermectin) in a dose of between about 18 mg and 50 mg, or between about 18 mg, 24 mg, 30 mg, 36 mg, or 40 mg, or between about 50 mg and 100 mg, or between 60 mg and 120 mg, up to a maximum of about 1600 mg to 1800 mg. , and is administered or administered, wherein optionally the loading dose is administered once, daily, periodically, optionally every 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 or more days; (ii) after administration of the loading dose of (i), a maintenance dose of ivermectin of between about 20 mcg / kg (μ / kg) and 5000 mcg / kg (μ / kg), or between about 200 and 2000 mcg / kg (μ / kg) per dose (where 200 mcg / kg corresponds to a 12 mg dose for a 60 kg adult, and 2000 mcg / kg corresponds to 120 mg per dose), or about 50 μg / kg, 75 μg / kg, or 100 μg / kg; wherein optionally, the maintenance dose is administered every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days, or every 3 weeks, or every month, or every 2 or more months after the initial loading dose; wherein optionally, the maintenance doses are administered every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days, every 3 weeks, or monthly for 4 to 8 weeks, 6 to 10 weeks, 8 to 12 weeks, 10 to 20 weeks, 15 to 30 weeks, or 20 to 52 weeks or more after the initial or loading dose is administered; wherein optionally, an antibiotic or antiviral is administered with a loading dose of an avermectin (optionally ivermectin); and zinc (optionally a zinc chelate, zinc salt, or zinc sulfate) is administered with a loading dose of an avermectin (optionally ivermectin); Optionally, a drug combination, optionally formulated as a single dosage form (e.g., a tablet capsule), includes ivermectin, doxycycline, and a zinc chelate, or optionally includes 12 mg ivermectin, 100 mg doxycycline, and 25 mg zinc chelate, administered once or twice daily; or (b) as a drug, formulation, or therapeutic combination of drugs comprising an avermectin drug (optionally, ivermectin), (i) In adults, a dose of about 300 μg / kg to 30 mg / kg (or 30 mg per 2.2 pounds (lb)) or about 18 mg to 1800 mg at 60 kg (about 132 lb), or 50 μg / kg, 75 μg / kg, or 100 μg / kg, or a loading dose of ivermectin between about 30 μg / kg and 60 mg / kg, or in a 60 kg (about 132 lb) human, a dose of about 18 mg to about 1200 mg, or 1600 mg to 1800 mg, or between about 40 to 70 mg / kg, or a dose of 60 to 120 mg to about 1600 to 1800 mg, or 50 μg / kg, 75 μg / kg, 100 μg / kg, or 500 μg / kg, or a dose of about 50 μg / kg to 500 μg / kg, or (ii) daily doses for adults of between about 18 mg and 50 mg, or between about 18 mg, 24 mg, 30 mg, 36 mg, or 40 mg, or between about 50 mg and 100 mg, or between 60 mg and 120 mg and about 1600 mg and 1800 mg; is administered at One or more additional drugs are dosed or administered together with metformin and / or a 3C-like (3CL) protease or ensitrevir, and the one or more additional drugs are (a) an avermectin drug (optionally ivermectin), optionally also including colchicine (optionally dosed at between about 30-80 mg per day, or between about 36-60 mg per day), clofazimine (optionally dosed at about 100 mg or 150 mg per day, or between about 50 mg and 200 mg per day), and zinc (optionally zinc sulfate, zinc acetate, zinc gluconate, or zinc picolinate, or zinc oxide nanoparticles, optionally in a dosage of between about 1 mg and 250 mg per day, or about 50 mg per day); (b) a combination of clofazimine (optionally dosed at about 100 mg or 150 mg per day, or between about 50 mg and 200 mg per day), fluvoxamine, and zinc (optionally zinc sulfate, zinc acetate, zinc gluconate, or zinc picolinate, or zinc oxide nanoparticles, optionally at a dose of between about 1 mg and 250 mg per day, or about 50 mg per day), optionally also containing colchicine; or (c) optionally, an avermectin drug (optionally including colchicine; hydrocortisone or cortisol (optionally Cortef™, SOLUCORTEF™), optionally hydrocortisone sodium succinate or hydrocortisone acetate, or dexamethasone (optionally Dextenza™, Ozurdex™, Neofoldex™), further comprising zinc (optionally zinc sulfate, zinc acetate, zinc gluconate, or zinc picolinate, or zinc oxide nanoparticles, optionally at a dosage of between about 1 mg and 250 mg per day); , ivermectin) (optionally between about 10-100 mg per day, or between about 12-80 mg per day, or between about 36-60 mg per day), clofazimine (optionally dosed at about 100 mg or 150 mg per day, or between about 50 mg and 200 mg per day), fluvoxamine, and at least one vitamin, optionally administered at about 1000-4000 ugm / day, vitamin B3 (or pyridine-3-carboxylic acid, niacin, or nicotinic acid, or a sustained release form (or NIASPAN Vitamin B3 or niacin, vitamin D (optionally D2, or ergocalciferol), or vitamin D3 or cholecalciferol administered as FCT™; vitamin B12, vitamin B6 (or pyridoxine); vitamin K; vitamin A; vitamin E; and / or vitamin C (optionally administered at 500 mg bid); The pharmaceutical compositions or therapeutic combinations provided herein, or the articles of manufacture provided herein, or the kits provided herein, formulated as, administered as, containing or manufactured as a pharmaceutical preparation, or a dressing or skin patch, or an implant; Optionally, the pharmaceutical composition or therapeutic combination is formulated as a gel, liquid, aerosol, spray, mist, lotion, cream, powder, tablet, capsule, pill, geltab, enema, suppository, transdermal or buccal patch, or an injectable, subcutaneous, intramuscular (IM), or intravenous (IV) preparation to produce a pharmaceutical formulation; (a) an antibiotic or macrolide drug, optionally doxycycline or azithromycin, optionally starting with a loading dose of between about 400 mg and 500 mg and 1 g, or about 500 mg, given orally, IV, or IM, optionally with follow-up doses continuing for about 1 week to 1 month, optionally daily, every 4 to 10 days, or every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or up to 20 or more days, at a lower dose of between about 100 gm and 300 mg, or about 250 mg total daily dose; (b) azithromycin (optionally Zithromax™, or Azithlosin™) is administered at a loading dose of 500 mg bid on day 1, then 500 mg in the morning (MANE) on days 2, 3, and 4, after which azithromycin is discontinued and replaced with doxycycline (optionally Doryx™, Doxyhex™, Doxylin™) 100 mg bid for the remainder of the treatment period (10 or 11 days); or (c) azithromycin (optionally Zithromax™, or Azithlosin™) is administered initially at a loading dose of 500 mg bid on day 1, then 500 mg in the morning (MANE) on days 2, 3, and 4, after which azithromycin is discontinued and doxycycline 100 mg bid (or between about 25 and 500 mg bid) (optionally Dorix™, Doxyhexa™, Doxylin™) is administered daily for the entire duration of treatment (10 or 11 days or more); The administration or treatment of a pharmaceutical composition or drug therapeutic combination provided herein, or a product provided herein, or a kit provided herein, lasts for about 10 days to 3 weeks, or 11 days to 2 weeks, or about 10, 11, 12, 13, or 14 days, or about 1 month to 1 year; and / or Zinc, optionally zinc sulfate or a zinc chelate, is administered at a dose of 100 mg MANE or between about 50 mg and 150 mg per day of treatment or administration.

[0013]

[0013] In an alternative embodiment, provided is a transdermal device manufactured to contain or have a plurality or multiple drug-containing or drug-storage compartments (or cells or wells), each compartment being sealed or having adjacent walls such that when a drug formulation (optionally a liquid, liposomal, gel, or hydrogel drug formulation) is placed into one of the plurality or multiple drug-containing or drug-storage compartments or cells or wells, the liquid or gel drug formulation is contained within that compartment, the compartments being open on one side to a removable (and optionally flexible) release liner that can be removed by the user, and an adhesive (optionally comprising an acrylate polymer or a pressure-sensitive adhesive (PSA)) being affixed to the flexible, removable release liner on the same side of the transdermal device as the open side of the compartment or cell or well (or the side covered by the release liner) to affix the transdermal device to the skin surface, the adhesive remaining covered until the removable release liner is removed. In alternative embodiments, the transdermal device has 2 to 10 separate or individual drug-containing or drug-storage cells or compartments, optionally with each of the multiple compartments (or cells or wells) having a storage volume of between about 5 μl and 1000 μl (or 1 ml), or between about 20 μl and 500 μl, or between about 50 μl and 5 ml. In alternative embodiments, the transdermal device includes three separate or individual drug-containing or drug-storage cells or compartments.

[0014] In an alternative embodiment, the first compartment contains an avermectin drug (optionally ivermectin), the second compartment contains an antibiotic (optionally doxycycline or azithromycin), and the third compartment contains zinc (optionally a zinc chelate, e.g., zinc sulfate, zinc acetate, zinc gluconate, or zinc picolinate, or zinc oxide nanoparticles). In an alternative embodiment, the first compartment contains ivermectin, the second compartment contains doxycycline, and the third compartment contains a zinc chelate. In an alternative embodiment of the transdermal devices described herein, the first compartment contains 48 mg of ivermectin, the second compartment contains 300 mg of doxycycline, and the third compartment contains 50 mg of a zinc chelate.

[0015]

[0015] In an alternative embodiment, provided is a method for treating, preventing, or ameliorating (optionally reducing symptoms or reducing mortality) a coronavirus infection caused by COVID-19, or a variant, alternative lineage branch, or subtype thereof, comprising administering a transdermal device described herein to an individual in need thereof.

[0016]

[0016] In an alternative embodiment, provided is a transdermal device described herein for use in treating, preventing, or ameliorating (optionally reducing symptoms or reducing mortality) a coronavirus infection caused by COVID-19, or a variant, alternative lineage branch, or subtype thereof.

[0017]

[0017] In an alternative embodiment, provided is the use of a transdermal device described herein for the manufacture of a medicament for treating, preventing, or ameliorating (optionally reducing symptoms or reducing mortality) a coronavirus infection caused by COVID-19, or a variant, alternative lineage branch, or subtype thereof.

[0018]

[0018] The details of one or more exemplary embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.

[0019]

[0019] All publications, patents, and patent applications cited herein are expressly incorporated herein by reference in their entirety for all purposes. DETAILED DESCRIPTION OF THE INVENTION

[0020] In alternative embodiments, provided are therapeutic combinations of pharmaceutical compositions and drugs, including articles of manufacture and kits, and methods for making and using the same, for treating, preventing, or ameliorating (e.g., reducing symptoms or reducing mortality) a viral infection, e.g., a coronavirus infection, such as COVID-19 or a variant thereof. In alternative embodiments, the coronavirus infection is the so-called "long COVID" syndrome, or post-COVID state (PCC), or post-acute sequelae of SARS CoV-2 infection (PASC). In alternative embodiments, provided are articles of manufacture, kits, and transdermal devices for delivering the therapeutic combinations of pharmaceutical compositions and drugs provided herein.

[0021]

[0021] Active single and dual agents exist that inhibit coronavirus proliferation; however, when used alone, the active single and dual agents have not eradicated the viral infection quickly enough, resulting in many coronavirus-infected patients becoming ill with cytokine storm and / or being admitted to intensive care, and a small percentage dying.

[0022] To address this weakness, the inventors have discovered that a combination of at least three or more drugs at appropriate doses is required to adequately inhibit coronavirus (e.g., COVID-19) virus replication within cells and prevent hospitalization and / or death. The inventors have discovered a drug combination effective in treating, ameliorating, and / or preventing "long COVID" or post-COVID state (PCC), or post-acute sequelae of SARS-CoV-2 infection (PASC). The inventors have discovered a drug combination including metformin (or Glucophage™) and / or a 3C-like (3CLpro) protease (also known as main protease (Mpro), also known as C30 endopeptidase or 3-chymotrypsin-like protease) inhibitor, such as ensitrevir (or Zocova™), that may lead to a cure even with delayed or delayed initiation of treatment. The inventors have further discovered that transdermal delivery of any drug or drug combination, e.g., a drug combination or formulation provided herein (e.g., metformin and / or a 3C-like (3CLpro) protease inhibitor, e.g., ensitrervir, and at least one, two, three, or more other drugs); or zinc, ivermectin, and doxycycline (e.g., ZIVERDOX™) is effective in treating, ameliorating, and / or preventing coronavirus (e.g., COVID-19). Products and kits

[0023]

[0023] Provided are articles of manufacture and kits for practicing the methods provided herein, and optionally, the articles of manufacture and kits may further include instructions for practicing the methods provided herein.

[0024]

[0024] Provided are compositions, formulations, and / or kits, including preparations, that include a combination of ingredients, e.g., a therapeutic combination of a pharmaceutical composition and a drug described herein. In alternative embodiments, the therapeutic combination of a pharmaceutical composition and a drug described herein can be mixed and administered together, or alternatively, they can be individual members of a packaged combination of ingredients, e.g., a liquid component and a solid product component, manufactured in separate compartments, packages, kits, or containers, e.g., where all or a subset of the combination of ingredients are manufactured in separate compartments, packages, or containers. In alternative aspects, the package, kit, or container comprises a blister package, clamshell, tray, shrink wrap, or the like.

[0025] In one embodiment, the package, kit, or container comprises a "blister package" (also called a blister pack or bubble pack). In one embodiment, the blister package is composed of two separate elements: a clear plastic cavity molded to fit the product and its blister board backing. These two elements are then joined by a heat sealing process, which allows the product to be hung or displayed. Exemplary types of "blister packages" include face seal blister packages, gang run blister packages, mock blister packages, interactive blister packages, and slide blister packages.

[0026]

[0026] A blister pack, clamshell, or tray is a form of packaging used for an article. Thus, provided is a blister pack, clamshell, or tray containing a drug combination or formulation provided herein, or a drug combination, pharmaceutical preparation, or pharmaceutical composition used to practice the methods provided herein. Blister packs, clamshells, or trays can be designed to be non-reclosable, allowing the consumer to know if the package has been opened. They are used to package for sale articles where product tampering is a concern, such as the pharmaceuticals provided herein. In one embodiment, a blister pack comprises a molded PVC base covered by a foil laminate with raised portions ("blisters") for containing tablets, pills, etc., including the drug combination, drug combination, or formulation, pharmaceutical preparation, or pharmaceutical composition used in the methods provided herein. Tablets, pills, etc. can be removed from the pack by peeling back the foil or by pressing the blister, forcing the tablet to break the foil. In one embodiment, a specialized form of blister pack is a strip pack. In one embodiment, in the UK, blister packs comply with British Standard 8404.

[0027] In one embodiment, provided is a method of packaging in which a composition comprising a combination of ingredients (e.g., a pharmaceutical composition and therapeutic drug combination provided herein) is contained between a card and clear PVC. The PVC can be transparent, allowing for easy viewing of the item (pills, tablets, gel tabs, etc.), and in one aspect, can be vacuum-formed around a mold, allowing the PVC to tightly contain the item and allow room for opening at the time of purchase. In one aspect, the card is brightly colored and designed according to the item (pills, tablets, gel tabs, etc.), and the PVC is attached to the card using a pre-formed tab coated with adhesive. The adhesive can be strong enough to allow the pack to be hung on a peg, yet weak enough to allow the seam to be torn open and the item to be accessed. When large items or a large number of pills, tablets, gel tabs, etc. are enclosed, the card may have a perforated window for access. In one embodiment, a higher security blister pack is used for items such as pills, tablets, gel tabs, etc., and may comprise two vacuum-formed PVC sheets interlocked together at the edges with an information card inside. These can be difficult to open by hand and may require a pair of scissors or a sharp knife to open.

[0028] In one embodiment, the blister package includes at least two or more components: a thermoformed "blister" containing the multi-component combination provided herein, and a "blister card," which is a printed card with a front-side adhesive coating. During the assembly process, the blister components, most commonly made of PVC, are attached to the blister card using a blister machine. This machine introduces heat to the flange area of ​​the blister, activating the glue on the card in that specific area, ultimately securing the PVG blister firmly to the printed blister card. The thermoformed PVG blister and printed blister card can be made as small or large as desired, although oversized blister cards present limitations and cost considerations. Conventional blister packs can also be sealed using standard heat-seal tooling (e.g., AERGO 8 DUO™, SCA Consumer Packaging, Inc., DeKalb IL). This alternative embodiment using heat-seal tooling can seal common types of thermoformed packaging.

[0029] In alternative embodiments, the pharmaceutical compositions and therapeutic combinations of drugs described herein are formulated, e.g., as powders, e.g., as lyophilized materials, e.g., as lyophilized encapsulated products, e.g., for practicing the methods provided herein, and may be packaged, alone or in combination, e.g., as a "blister package" or multiple pouches including a lidded blister package, a lidded blister or blister card, or a small packet or packet, or in shrink wrap.

[0030] In an alternative embodiment, laminated aluminum foil blister packs are used, for example, for preparing the therapeutic combinations or formulations provided herein, or for pharmaceutical preparations or compositions used in the methods provided herein. The product or kit includes aqueous solution(s) dispensed (e.g., by measured dose) into containers. The tray can be lyophilized to form tablets shaped like blister pockets. An alufoil laminate on both the tray and lid fully protects any hygroscopic and / or sensitive individual doses. In one aspect, the pack incorporates a child-resistant peel-open security laminate. In one aspect, this system provides an identification mark on the tablet by embossing a design into the alufoil pocket, which is incorporated into the tablet when it changes from an aqueous to a solid state. In one aspect, individual "push-through" blister packs / pouches are used, for example, using hard temper aluminum or aluminum (e.g., Alufoil) lid materials. In one aspect, a sealed high-barrier aluminum or aluminum (e.g., Alufoil) laminate is used. In one aspect, the product comprises a kit or blister pack, and uses foil laminates as well as strip packs, stick packs, sachets, and pouches, peelable and non-peelable laminates combining foil, paper, or film for high barrier packaging.

[0031] In an alternative embodiment, the multi-component product, including the kit or blister pack provided herein, includes a memory aid to help the patient remember when and how to take the therapeutic combination. This protects the effectiveness of the therapeutic combination by protecting each tablet, gel tab, or pill until it is taken, and provides portability of the product or kit, facilitating taking a dose anytime, anywhere. Dosages and packaging for therapeutic or prophylactic purposes

[0032]

[0032] In alternative embodiments, provided are therapeutic combinations of the pharmaceutical compositions and drugs described herein, as well as drug combinations and drug delivery devices containing these combinations for therapeutic and / or prophylactic (preventative) purposes.

[0033] In an alternative embodiment, a therapeutic or prophylactic drug or ingredient combination "package" (which may be a blister pack, clamshell, or nebulizer, inhaler, respirator, or CPAP insert, etc.) is designed so that a particular drug or ingredient combination (e.g., a drug or ingredient combination having two, three, four, five, or six ingredients or active agents, one, some, or all formulated separately or in a single delivery agent, such as a capsule or gel tab, or in a nebulizer, inhaler, respirator, or CPAP insert) is taken by the user daily, every other day, weekly, every two weeks, or every four weeks (i.e., monthly). In an alternative embodiment, the therapeutic or prophylactic drug combination "package" is designed (e.g., instructs the user) to take the drug combination as staggered doses, e.g., one dose of the drug combination is given on two or three consecutive days, followed by a one-week staggering before starting the next two- or three-day dosing cycle again. Formulations and Pharmaceutical Compositions

[0034] In alternative embodiments, provided are pharmaceutical formulations or compositions for use in in vivo, in vitro, or ex vivo methods for treating, preventing, ameliorating, and / or ameliorating a viral infection, e.g., a coronavirus (optionally, COVID-19), and optionally, the drug combinations provided herein are effective in treating, ameliorating, and / or preventing "long COVID" or post-COVID condition (PCC), or post-acute sequelae of SARS CoV-2 infection (PASC).

[0035] In alternative embodiments, the pharmaceutical compositions provided herein or used to practice the methods provided herein may be administered parenterally, topically, orally, or by local administration, such as by aerosol, mist, powder, or the like, bucally, or transdermally. These pharmaceutical compositions may be formulated in any manner and may be administered in a variety of unit dosage forms depending on the condition or disease and severity of the illness, the general medical condition of each patient, and the resulting preferred method of administration. Details of formulation and administration techniques are fully described in the scientific and patent literature; see, for example, the latest edition of Remington's Pharmaceutical Sciences, Maack Publishing Co., Easton PA ("Remington's"). For example, in alternative embodiments, the pharmaceutical compositions or therapeutic combinations provided herein are formulated in buffer solutions, saline solutions, powders, emulsions, vesicles, liposomes, nanoparticles, nanolipoparticles, and the like. In alternative embodiments, the pharmaceutical compositions or therapeutic combinations provided herein can be formulated in any manner and applied in various concentrations and forms depending on the desired in vivo, in vitro, or ex vivo conditions, the desired method of in vivo, in vitro, or ex vivo administration, etc. Details of techniques for in vivo, in vitro, or ex vivo formulation and administration are well described in the scientific and patent literature. The formulations and / or carriers used to practice the methods provided herein can be in the form of tablets, pills, powders, capsules, liquids, gels, syrups, slurries, suspensions, etc., and are suitable for in vivo, in vitro, or ex vivo application.

[0036]

[0036] In an alternative embodiment, the pharmaceutical compositions or therapeutic combinations provided herein or used to practice the methods provided herein can comprise a pharmaceutically acceptable carrier, e.g., a solution of the composition disposed or dissolved in an acceptable vehicle; solvents that can be used include water, Ringer's solution, and isotonic saline. Additionally, sterile, fixed oils can be used as a solvent or suspending medium. For this purpose, any fixed oil containing synthetic monoglycerides or diglycerides, or fatty acids such as oleic acid, can be used. In one embodiment, the solutions and preparations used to practice the present invention can be prepared to be sterile and generally free of undesirable matter. In one embodiment, these solutions and preparations are sterilized by conventional, well-known sterilization techniques.

[0037]

[0037] The pharmaceutical compositions or drug therapeutic combinations provided herein, and the solutions and formulations provided herein or used to practice the methods provided herein, can contain auxiliary substances as needed to approximate physiological conditions, such as pH adjusting and buffering agents, toxicity adjusting agents, such as sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, etc. The concentration of the active agent in these formulations can vary widely and can be selected primarily based on fluid volume, viscosity, etc., according to the particular mode of in vivo, in vitro, or ex vivo administration selected and the desired result.

[0038] The therapeutic combinations of pharmaceutical compositions and drugs provided herein or used to practice the methods provided herein can be delivered by the use of liposomes. Liposomes, particularly those whose surface carries a ligand specific for target cells (e.g., damaged or diseased neurons or CNS tissue) or that are otherwise preferentially targeted to a particular tissue or organ type, can be used to focus delivery of active agents to target cells in in vivo, in vitro, or ex vivo applications. Nanoparticles, nanolipoparticles, and liposomes

[0039] Also provided are nanoparticles, nanolipoparticles, vesicles, and liposomal membranes comprising the therapeutic combinations of pharmaceutical compositions and drugs provided herein or used to practice the methods provided herein, which nanoparticles, nanolipoparticles, vesicles, and liposomal membranes can be delivered transdermally to an individual in need thereof using the transdermal delivery devices provided herein.

[0040] In an alternative embodiment, provided are multilamellar liposomes containing a therapeutic combination of a pharmaceutical composition and drug provided herein or used to practice the methods provided herein, such as those described in Park et al., U.S. Patent Application Publication No. 20070082042. The multilamellar liposomes can be prepared to a particle size of about 200-5000 nm using a mixture of oil phase components including squalane, sterols, ceramides, neutral lipids or oils, fatty acids, and lecithin, to entrap the compositions used to practice the methods provided herein.

[0041]

[0041] Liposomes can be made using any method, such as that described in Park et al., U.S. Patent Application Publication No. 20070042031, including a method of making liposomes by encapsulating an active agent, comprising the steps of providing an aqueous solution to a first reservoir; providing an organic lipid solution to a second reservoir, and then mixing the aqueous solution and the organic lipid solution in a first mixing region to form a liposome solution, wherein the organic lipid solution mixes with the aqueous solution to substantially immediately form liposomes encapsulating the active agent; and then immediately mixing the liposome solution with a buffer solution to form a diluted liposome solution.

[0042]

[0042] In one embodiment, the liposome composition used to practice the methods provided herein comprises a substituted ammonium and / or polyanion, such as those described in U.S. Patent Application Publication No. 20070110798, for targeting the delivery of compounds.

[0043]

[0043] Provided are nanoparticles comprising a therapeutic combination of a pharmaceutical composition and a drug provided herein or used to practice a method provided herein, e.g., in the form of an active agent-containing nanoparticle (e.g., a second nanoparticle) described in U.S. Patent Application Publication No. 20070077286. In one embodiment, provided are nanoparticles comprising a lipid-soluble active drug or a lipid-solubilized water-soluble active agent interacting with a divalent or trivalent metal salt.

[0044] In one embodiment, the compositions used to practice the methods provided herein can be formulated using solid lipid suspensions and delivered to mammalian cells in vivo, in vitro, or ex vivo, for example, as described in U.S. Patent Application Publication No. 20050136121. Inhalers, Nebulizers, Puffers, and Nasal Sprays

[0045] In an alternative embodiment, a drug delivery device including an inhalation device or inhaler or an aerosol or nasal spray device, such as a nebulizer, puffer (for asthma), or modified hair dryer, is used to deliver the drug therapeutic combination, pharmaceutical dosage form, or formulation provided herein. In an alternative embodiment, provided is a method for administering a drug therapeutic combination, pharmaceutical dosage form, or formulation provided herein using an inhalation device, nebulizer, puffer, or inhaler, or a nasal spray device, for example, for delivering metformin and / or a 3C-like (3CLpro) protease inhibitor, such as ensitrevir, and at least one, two, three, or more other drugs.

[0046] In an alternative embodiment, the inhaler, nebulizer, puffer, or nasal spray device is a handheld or otherwise portable (e.g., worn around the neck) inhaler or nasal spray device, and optionally the inhaler or nasal spray device is a metered or dose-counting inhaler or nasal spray device. In an alternative embodiment, the inhaler or nasal spray device is a device such as those described in, for example, U.S. Pat. Nos. 10,583,261 or 10,561,809 (which describe a breath-actuated dry powder inhaler with one air circulation chamber for deagglomeration of the incorporated powdered medicament), or U.S. Pat. No. 10,561,807 (which describe an inhaler device configured to use up a predetermined volume and produce an aerosol spray, mist, or flavored aerosol, a sensor configured to detect a predefined variable, an interface configured to notify the inhaler of the aerosol, spray, or mist, and a controller), or U.S. Pat. No. 3,815 (describing a dry powder inhaler that may include a powder storage area, an inlet channel, a dispersion chamber, and an outlet channel); or U.S. Patent Application Publication No. 20200069897 (describing an inhaler having a breath-activated trigger mechanism that responds to inhalation flow to trigger the release of an inhaled substance); or U.S. Patent Application Publication No. 20200061314 (describing a smart inhalation device having a cartridge receptacle that can accommodate a cartridge, a flow path including a flow meter, a pump, and a vaporizer; a wireless communication module; and at least one sensor for obtaining identification information about the cartridge); or U.S. Patent Application Publication No. 2020004691 (describing a pulmonary tube tract) and a replaceable cartridge containing dry powder for local or systemic delivery through the lungs); or No. 20200046916 (describes an inhaler having a patient port; a canister that delivers a dose of medicinal drug to the patient port, actuable by a reusable assembly; and a refill assembly that includes a sleeve that is selectively actuable by the user, independently of the reusable assembly, to actuate the canister and deliver the dose of medicinal drug);or a device described in U.S. Patent No. 20200046029 (which describes an apparatus for generating an aerosol, spray or mist, and / or vapor in an inhaler device, including: a reservoir for storing a supply of liquid; a heating system fluidly connected to the reservoir for receiving the liquid and configured to heat the liquid and generate an aerosol, spray or mist, and / or vapor therefrom; a pump system configured to pump the liquid from the reservoir to the heating system; and a valve device for regulating flow from the pump system to the heating system); or U.S. Patent No. 20200016345 (which describes a dry powder inhaler having a first chamber with an opening for holding dry powder and gas, and a second chamber directly connected to the first chamber by at least one passageway for receiving dry powder in aerosolized form from the first chamber and delivering the aerosolized dry powder to a user). The inhaler provided herein or used in the methods provided herein may include the use of a dose counter, for example, as described in U.S. Patent No. 10,561,808.

[0047]

[0047] In an alternative embodiment, the inhaler or nasal spray device is a handheld or otherwise portable inhaler or nasal spray device used or intended for use on public transportation, e.g., buses, trams, trains, airplanes, and / or boats, or in commercial locations, e.g., stores, bars, sporting events, cinemas, theatres, music events, or any place where people gather.

[0048]

[0048] In an alternative embodiment, the drug or drug combination or formulation provided herein is delivered as a liquid, powder, spray, or mist through an inhalation device such as an oxygen tube or a CPAP (continuous positive air pressure) device, such as those used in the treatment of sleep apnea, a respirator, or a ventilator.

[0049]

[0049] In alternative embodiments, a CPAP device for delivering the drugs or drug combinations provided herein may include components, be manufactured, or be used as described in, for example, U.S. Patent Nos. 10,595,814; 10,549,057 (which describes a ventilator system including a mask that fits over the wearer's face); 10,543,333 (which describes a venting device for a mask or associated conduit for venting exhaled gases from the mask); and / or 10,406,312 (which describes a CPAP flow driver for using a nebulizer with a CPAP device).

[0050] In alternative embodiments, the medical device for inhalation delivery of a drug or agent or combination provided herein comprises a dry powder inhaler (e.g., a dry powder disc inhaler, such as a DISKUS™ device, optionally having a dose counter window so that the user knows how many doses are remaining), e.g., the powder is dispensed in doses by (using) a disposable, refillable, or replaceable cassette, sachet, or disc; dispensing of the dry powder can be breath-actuated, e.g., Examples include the AEROLIZER™, FLEXHALER™, PRESSAIR™, DISKUS™, HANDIHALER™, TWISTHALER™, ELLIPTA™, NEOHALER™, RESPICLICK™, ROTAHALER™, or TUBUHALER™ devices.

[0051] In an alternative embodiment, the antiviral drug combination or medicament provided herein (e.g., metformin and / or a 3C-like (3CLpro) protease inhibitor, e.g., ensitrevir, and at least one, two, three, or more other drugs) is formulated as a powder (e.g., dry powder), microparticles or nanoparticles, or an aerosol, spray, or mist. In an alternative embodiment, the powder can be an agglomerate of powder particles or an agglomerate having an irregular shape, such as width, diameter, and length. In an alternative embodiment, the dry powder can be formulated as granules of physiologically acceptable excipients used as carriers for dry powder formulations for inhalation, e.g., as described in U.S. Pat. No. 10,583,085.

[0052] In an alternative embodiment, chloroquine (optionally Alarene™), chloroquine phosphate, chloroquine diphosphate, or hydroxychloroquine (optionally Plaquenil™) is formulated as a liquid or aqueous formulation at a concentration of between about 50% and 100%. In an alternative embodiment, chloroquine (optionally Alarene™), chloroquine phosphate, chloroquine diphosphate, or hydroxychloroquine (optionally Plaquenil™) is formulated and delivered in a dosing regimen of between about 0.2 mg / kg and about 150 mg / kg per dose.

[0053] In alternative embodiments, methods of delivery of drug combinations provided herein (e.g., metformin and / or a 3C-like (3CLpro) protease inhibitor, e.g., ensitrervir and at least one, two, three, or more other drugs) include treatment regimens in which the drugs, agents, or drug combinations are administered hourly, every other hour, or once, twice, three, four, five, six, seven, eight, nine, ten, eleven, or twelve times daily. In alternative embodiments, the length of time of treatment or the exact dosing or dosing regimen is determined by a clinician, or administration is initiated shortly after potential exposure to an individual with (or exposed to another individual with) a viral infection, e.g., a coronavirus infection such as COVID-19 or a variant thereof, or an infection caused by a virus of the subfamily Orthocoronavirinae, or the family Coronaviridae, or the order Nidoviridae.

[0054] In an alternative embodiment, the drugs (e.g., metformin and / or a 3C-like (3CLpro) protease inhibitor, e.g., ensitrevir, and at least one, two, three, or more other drugs) are formulated as a liquid or aqueous formulation at a concentration of between about 50% and 100%, which can be used as an aerosol, spray, or mist and / or administered orally. In an alternative embodiment, the drugs are formulated and delivered (e.g., by inhalation and / or orally) in a dosage regimen of about 0.2 mg / kg to about 150 mg / kg per dose. Transdermal Drug Delivery Devices

[0055]

[0055] In alternative embodiments, provided are transdermal delivery devices, e.g., bandages, skin patches, or dressings for transdermal delivery of any drug or drug combination, e.g., a drug combination or formulation provided herein (e.g., metformin and / or a 3C-like (3CLpro) protease inhibitor, e.g., ensitrevir, and at least one, two, three, or more other drugs); or zinc, ivermectin, and doxycycline (e.g., Zybardox™).

[0056] In an alternative embodiment, any drug or drug combination, such as the drug combinations provided herein, is included in a transdermal delivery device such that it can pass through a drug- or formulation-permeable surface of a bandage, skin patch, or dressing, which is placed on the skin of an individual in need thereof. In other words, the skin patch or dressing has one surface that is permeable to the drug combination or formulation provided herein. The drug combination or formulation can be formulated in the form of a gel or hydrogel.

[0057]

[0057] In an alternative embodiment, the transdermal delivery devices provided herein, e.g., bandages, skin patches, or dressings, have (one) outer surface, layer, or covering or laminate (e.g., a "release liner") that is removable by the user (e.g., an individual in need thereof) before being placed on the skin.

[0058] In an alternative embodiment, the transdermal delivery devices provided herein, e.g., bandages, skin patches, or dressings, adhere to the skin, wherein the skin-adhesive composition is positioned around the entire periphery of the drug combination or formulation compartment, such that the drug combination or formulation (e.g., formulated as a gel or hydrogel) does not leak or migrate from the dressing, but rather is contained between the skin patch or dressing and the skin, thereby ensuring that the drug combination or formulation is in contact only with the skin beneath the skin-adhesive dressing or patch.

[0059] In an alternative embodiment, the transdermal delivery device is comprised of an acrylate polymer, optionally an acrylate polymer that is a pressure sensitive adhesive (PSA), for example, the transdermal delivery device can include, be made with, or have an adhesive that includes: Ethylene vinyl acetate copolymers, as described in U.S. Patent No. 7,396,976; Methacrylate Copolymers: These copolymers have excellent adhesive and cohesive strength and the ability to form clear, transparent films.

[0060] Acrylate-vinyl acetate copolymers: These copolymers have a good balance of adhesion, cohesion, flexibility, and durability.

[0061] Acrylate-acrylonitrile copolymers: These copolymers have high adhesion to a wide range of substrates and good resistance to ultraviolet light and weathering.

[0062] Acrylate-butadiene copolymers: These copolymers have strong adhesion, good flexibility, and resistance to heat and aging.

[0063] In an alternative embodiment, the adhesive is contained in microcapsules, such as those described in US Pat. No. 7,396,976.

[0064] In alternative embodiments, the transdermal delivery device, e.g., a bandage, patch, or dressing, includes a skin adhesive, which can be made from a combination of materials to provide the necessary adhesion to the skin, as well as protection and comfort, for example, the transdermal delivery devices provided herein include or are manufactured to have: The adhesive material can be a medical grade, skin-friendly substance that can stick to the skin and hold the bandage in place; for example, a pressure sensitive adhesive (PSA) made from an acrylate polymer, as described above; a backing material that provides a base for the adhesive and protects the wound from further damage, and can include materials such as cloth, plastic film, or nonwoven fabric; Optionally, it may also have an absorbent pad made from a material containing cellulose or hydrocolloid to absorb exudate from the wound; Optionally, it may also have a release liner made of, for example, paper or plastic film, which protects the adhesive until the bandage is ready to be used; In an alternative embodiment, the transdermal delivery device includes or uses a non-irritating adhesive for attachment to the skin, e.g., human skin, including, for example: Hypoallergenic tape designed for sensitive skin, less likely to cause skin irritation or allergic reactions; cloth bandages, which can have a soft, cloth-like backing that is gentle on the skin and less likely to cause irritation; Hydrocolloid bandages, which can have a gel-like substance that helps protect and heal the skin while also providing a non-irritating adhesive; Silicone adhesive bandages, which may have a silicone-based adhesive that is gentle on the skin and less likely to cause irritation or leave residue; In an alternative embodiment, the transdermal delivery devices provided herein are manufactured as hydrocolloid dressings or bandages, which may be made from a combination of materials and chemicals, including, for example: a hydrocolloid material that contains a gel-forming substance that helps protect and heal wounds and can be made from a mixture of polymers such as pectin or carboxymethylcellulose and a gel-forming agent such as sodium carboxymethylcellulose or sodium polyacrylate; Adhesives that can be used for medical purposes, are non-irritating, gentle on the skin, and are skin-friendly; a backing material, which can be a semi-permeable material such as polyurethane or polyethylene, to allow air and moisture to circulate and help prevent the bandage from sticking to the wound; In alternative embodiments, the transdermal delivery devices provided herein may be manufactured as silicone adhesive dressings or bandages and may be made from the following materials: Silicone adhesive: can be soft and flexible, helping to reduce friction and minimize skin irritation; The backing material can be a soft, flexible material, such as polyurethane, that conforms to the skin and helps minimize irritation; Optionally, a wound pad comprising an absorbent material such as cotton or nonwoven fabric to help absorb exudate from the wound.

[0065]

[0065] The silicone adhesives used to manufacture the transdermal delivery devices provided herein may include a combination of polymeric compounds and fillers, such as: Polydimethylsiloxane (PDMS), a linear, flexible polymer typically used in silicone adhesives, which provides good adhesion and elasticity and is also known for its resistance to thermal and chemical degradation; Silicone resins: these are cross-linked silicone polymers that give silicone adhesives strength and stability, and they are often used in combination with PDMS to improve adhesive performance; Silicone adhesives may contain fillers such as silica to improve their physical properties and may contain activators or catalysts to accelerate the curing process.

[0066] In alternative embodiments, the transdermal delivery devices provided herein are divided into a region or multiple compartments (or cells or wells), optionally each containing (and storing prior to delivery) a different drug, for example, an exemplary transdermal delivery device provided herein is divided into three regions or compartments (or cells or wells), each containing one of zinc, ivermectin, and doxycycline; or four regions or compartments, each containing one of vitamin D, zinc, ivermectin, and doxycycline. By having separate regions or compartments, the drugs can be formulated separately, for example, each can have a different dosage, carrier, and / or formulation.

[0067] In alternative embodiments, each of the multiple compartments (or cells, or wells) has a storage volume of between about 5 μl and 1000 μl (or 1 ml), or between about 20 μl and 500 μl. Medication delivery in transdermal devices

[0068] In an alternative embodiment, the drug combination or formulation, such as the drug combination or formulation provided herein, is formulated at a higher concentration in a formulation for delivery by the transdermal delivery device provided herein. In an alternative embodiment, the drug combination or formulation is formulated in a gel or hydrogel to allow the drug active agent that contacts the skin to penetrate into or through the skin.

[0069]

[0069] For example, in the formulations in one or more compartments of the transdermal delivery devices provided herein, drugs such as metformin, ensitrevir, avermectin, antibiotics (e.g., doxycycline or azithromycin), zinc, or vitamins (e.g., vitamins D and / or C) are formulated or dispensed in dosages that are 2-fold, 5-fold, 10-fold, or 20-fold greater (or optionally between about 2-50-fold greater).

[0070]

[0070] For example, one compartment, or cell, or well of the transdermal delivery device provided herein contains or stores an avermectin drug, such as ivermectin, which is dispensed or formulated in that compartment at a concentration high enough to provide effective delivery to an individual (patient) in need thereof of a dose of between about 50 and 2000 μgm / kg body weight per day, optionally dispensed at 200 μgm / kg per day, or about 14 mg / day, optionally dispensed at 220, 225, 150, 275, or 300 μgm / kg per day, optionally dispensed at 12, 14, 16, 18, 20, 22, 24, or 26 mg per day, or optionally dispensed at between about 10 and 30 mg per day.

[0071]

[0071] In an alternative embodiment, ivermectin, doxycycline, and zinc chelate are each formulated at a higher dosage (48 mg ivermectin, 400 mg doxycycline, 100 mg zinc chelate) than the dosages formulated when the same drug combination is administered orally (which would be 12 mg ivermectin, 100 mg doxycycline, and 25 mg zinc chelate). In one embodiment, one compartment, or cell, or well of the transdermal delivery device provided herein contains or stores an avermectin drug, such as ivermectin, that is dispensed or formulated in that compartment at a concentration high enough to provide effective delivery to an individual (patient) in need thereof of a dosage of about 48 mg / day, optionally dosed at 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, or 60 mg per day, or optionally dosed at between about 30 and 60 mg per day.

[0072] In alternative embodiments, the drug combination or formulation is formulated in a delivery vehicle that facilitates transdermal delivery (e.g., formulated in a skin penetration enhancer), for example, the drug combination or formulation in the transdermal delivery device provided herein is formulated in a lipid or liposome or lipid vesicle, azone (optionally laurocapram), a sulfoxide such as dimethyl sulfoxide or DMSO, an alcohol (optionally ethanol, decanol), a polyol (optionally propylene glycol), an alkane, a fatty acid (optionally oleic acid), an ester, an amine or amide (optionally urea, dimethylacetamide, dimethylformamide, and / or a pyrrolidone, e.g., 2-pyrrolidone), a terpene, a cyclodextrin, a surfactant, e.g., a nonionic or cationic surfactant, or a chemical penetration enhancer (CPE). In alternative embodiments, the drug combination or formulation in the transdermal delivery device provided herein is formulated in water with a gelling agent. Pressure cuff or band

[0073] In alternative embodiments, the drug combination or formulation is formulated in a delivery vehicle, or transdermal device, or provided is a delivery vehicle or transdermal device provided herein further comprising a pressure cuff or band, wherein the delivery vehicle or transdermal device is placed, affixed, glued, or sutured onto a cuff or band designed or manufactured to be worn around the arm (or upper arm or forearm) or leg, and the cuff or band is designed or manufactured so that the user can tighten the cuff around the arm or leg, optionally by use of hook-and-loop fasteners (a straight strip of fabric with small hooks that can interlock with another strip of fabric with small loops and provide a temporary attachment until pulled apart) (or VELCRO™), or the cuff is designed or manufactured so that it can be fastened around the arm or leg by inflation (such as with a sphygmomanometer, or The cuff or band is designed or manufactured to be fastened around the arm or leg, such as a blood pressure cuff, and the cuff or band is wrapped around the arm or upper arm and inflated, and optionally the cuff is manufactured or designed as described in U.S. Pat. Nos. 7,390,301; 7,544,168 (which describe an automatic cuff-based blood pressure measurement device); 10,398,325 (which describe a cuff including a first bladder having a width and a length transverse to the width; the cuff also includes a second bladder connected to the first bladder and a port fluidly connected to at least one of the first and second bladders); or U.S. Patent Application Publication No. 20130060147A1 (which describes the use of compressible materials to fasten the cuff or band).

[0074] In alternative embodiments, the cuff or band is manufactured using cotton, nylon, or polyester. Drugs and Drug Combinations

[0075] In alternative embodiments, the transdermal delivery devices provided herein include any pharmaceutical composition or therapeutic combination of drugs, for example, the transdermal delivery devices provided herein include any one, two, three, four, or five or more of the following: (a) (i) metformin (or Glucophage™) and / or (ii) a 3C-like (3CLpro) protease (also known as main protease (Mpro), also known as C30 endopeptidase or 3-chymotrypsin-like protease) inhibitor, optionally ensitrevir (or Zocova™), or ensitrevir fumarate, wherein optionally metformin is administered in an amount of 100 mg / kg per unit dose (optionally 100 mg / kg per unit dose). or metformin is formulated or dosed at between about 0.1 ml and 25 ml of liquid metformin / day; wherein optionally, ensitrevir or ensitrevir fumarate is formulated or dosed at between about 100 mg and 500 mg per unit dose, or about 100 mg, 125 mg, or 150 mg per unit dose (optionally per tablet); and (b) (i) an avermectin or ivermectin (or Stromectol™); (ii) an avermectin or ivermectin and an antibiotic (optionally, doxycycline or azithromycin); (iii) an avermectin or ivermectin; an antibiotic (optionally, doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol (optionally with or without vitamin C); (c) an antibiotic, or ivermectin; and an antibiotic (optionally doxycycline or azithromycin), at least one vitamin, and zinc; (d) opaganib or eriva®; (e) opaganib and an avermectin or ivermectin; an antibiotic (optionally, doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (f) plitidepsin (also known as dehydrodidemnin B), or Aplidine™; (g) plitidepsin and an avermectin drug or ivermectin; an antibiotic (optionally, doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol, and optionally also vitamin D or cholecalciferol; (h) lopinavir, ritonavir (or Norvir™), and / or oseltamivir; (i) lopinavir, ritonavir, and / or oseltamivir with an avermectin or ivermectin; an antibiotic (optionally, doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (j) nilmatrervir and ritonavir (or Paquilobid™), (k) Nilmatrevir and ritonavir (or Paquilobid™) with an avermectin drug or ivermectin; an antibiotic (optionally, doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (l) chloroquine (optionally, Alaren™), chloroquine phosphate, chloroquine diphosphate, hydroxychloroquine (optionally, Plaquenil™); (m) chloroquine, chloroquine phosphate, chloroquine diphosphate, hydroxychloroquine, and avermectins or ivermectin; antibiotics (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (n) Abacavir, optionally acyclovir, (Acyclovir™), adefovir, amantadine, Ampligen, amprenavir (optionally Agenerase™), aprepitant, arbidol, atazanavir, atripla, baravir, baloxavir marboxil (Xofluza™), bepotastine, Bevirimat, bictegravir, bictarvy, brilacidin, cidofovir, caspofungin, lamivudine and zidovudine (optionally Convir™), cobixstat, colicitin, cocaine, delavirdine, desiccant Bis, didanosine, docosanol, dolutegravir, ecoliebel, edoxudine, elvitegravir, enfuvirtide, entecavir, epirubicin, epoprostenol, etravirine, famciclovir, homovirsen, fosamprenavir, foscarnet, phosphonet, galidesivir, ibacitabine, icatibant, idoxuridine, ifenprodil, imiquimod, immunovir, indinavir, inosine, interferon (optionally type I interferon, type II interferon, and / or type III interferon), Lamivudine, loviride, ledipasvir, leronlimab, maraviroc, methisazone, moroxydine, nexavir, norvir, nucleoside analogues (optionally brincidofovir, didanosine, favipiravir (also known as T-705, Avigan, or Favilavir, Fujifilm Toyama Chemical, Japan), vidarabine, galidesivir (optionally BCX4430, Immucillin-A™), cytarabine, gemcitabine, lamivudine, zalcitabine, abacavir, acyclovir, entecavir, stavudine, telbivudine, zidovudine, iodoxamic acid uridine, and / or trifluridine, or any combination thereof), oseltamivir (or Tamiflu™), peginterferon alfa-2a, penciclovir, peramivir (optionally Rapivir™), perphenazine, pleconaril, prulifloxacin, podophyllotoxin, pyramidine, raltegravir, rifampicin, rilpivirine, rimantadine, ritonavir, saquinavir, sofosbuvir, stavudine, telaprevir, tegovab, tipranavir, trifluridine, trizivir, tromantadine, Truvada,Valacyclovir (optionally Valtrex™), valganciclovir, valrubicin, vapreotide, vicriviroc, vidarabine, viramidine, velpatasvir, vibecon, zalcitabine, zanamivir (optionally Relenza™), zidovudine, or any combination thereof; (o) Any one or more of the drugs in (xiv); an avermectin drug or ivermectin; an antibiotic (optionally, doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (p) molnupiravir, emtricitabine (or Emtriva™), efavirenz (or Sustiva™), or tenofovir; or molnupiravir and emtricitabine and tenofovir (or Atripla™); (q) molnupiravir, emtricitabine, efavirenz, or tenofovir with an avermectin or ivermectin; an antibiotic (optionally, doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (r) zanamivir (or Relenza™); (s) zanamivir and an avermectin or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (t) efavirenz (optionally, Sustiva™); (u) efavirenz and an avermectin or ivermectin; an antibiotic (optionally, doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (v) nelfinavir (Viracept™) or oseltamivir (or Tamiflu™), (w) nelfinavir (Viracept™) or oseltamivir (or Tamiflu™) with an avermectin drug or ivermectin; an antibiotic (optionally, doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (x) a drug of the thiazolide class, optionally nitazoxanide (optionally Alinia™, or Nizonide™) or tizoxanide (or 2-hydroxy-N-(5-nitro-2-thiazolyl)benzamide); (y) a drug of the thiazolide class, optionally with nitazoxanide and an avermectin drug or ivermectin; an antibiotic (optionally with doxycycline or azithromycin), and zinc, and optionally also with vitamin D or cholecalciferol; (z) remdesivir (optionally GS-5734™, Gilead Sciences, or Veklury™); (aa) molnupiravir (or LaGebrio™); (bb) molnupiravir and an avermectin or ivermectin; an antibiotic (optionally, doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (cc) nevirapine (or Viramune™); (dd) nevirapine (or Viramune™) with an avermectin drug or ivermectin; an antibiotic (optionally, doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (ee) tenofovir alafenamide, tenofovir disoproxil, or tenofovir; (ff) tenofovir alafenamide, tenofovir disoproxil, or tenofovir with an avermectin or ivermectin; an antibiotic (optionally, doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (gg) selamectin (or Cerehold™, Revolt™, Ceralid™, or Senergy™); (hh) selamectin and an avermectin or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (ii) an inhibitor of S-phase kinase-associated protein 2 (SKP2), or dioscin, or niclosamide, or nicloside™, or fenasal™, or fenasal™; (jj) an inhibitor of S-phase kinase-associated protein 2 (SKP2), or dioscin, or niclosamide, and an avermectin drug or ivermectin; an antibiotic (optionally, doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (kk) ribavirin or tribuvirin (or Copegus™, Rebetol™, or Virazol™); (ll) ribavirin or tribavirin with an avermectin or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (mm) a viral, or coronavirus, or COVID-19, protease inhibitor, optionally ASC09 (CAS Registry Number 1000287-05-7) (Janssen Research and Development, LLC), ritonavir, or ASC09 and ritonavir, or a JAK1 / 2 inhibitor (optionally baricitinib), optionally compound 11r (University of Lübeck, Germany, optionally see Zhang et al. J. Med Chem 2020, February 11, 2020), or darunavir (or Prezista™), cobicistat (or Tyvost™), or darunavir and cobicistat; (nn) a protease inhibitor of a virus, or coronavirus, or COVID-19, such as ritonavir, a JAK1 / 2 inhibitor (optionally baricitinib), or darunavir (or Plezista™) or cobicistat, with an avermectin or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (oo) mucolytic therapy or medication, optionally acetylcysteine, ambroxol, bromhexine, carbocysteine, erdosteine, mecysteine, or dornase alfa, or expectorant, optionally guaifenesin; (pp) mucolytic therapy or medication with avermectins or ivermectin; antibiotics (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (qq) angiotensin-converting enzyme 2 (ACE2) inhibitors, optionally captopril, enalapril, lisinopril, benazepril, fosinopril, quinapril, ramipril, perindopril, moexipril, or trandolapril; (rr) angiotensin-converting enzyme 2 (ACE2) inhibitors and avermectins or ivermectin; antibiotics (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (ss) an anti-vascular endothelial growth factor (VEGF) (optionally, VEGF-A) drug or antibody, optionally bevacizumab (or Avastin™); (tt) an anti-vascular endothelial growth factor (VEGF) drug or antibody, or bevacizumab, with an avermectin drug or ivermectin; an antibiotic (optionally, doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (uu) a protease inhibitor, optionally danoprevir, optionally a serine protease inhibitor, optionally camostat (or Foipan™) or narlaprevir (optionally Allansa™) (vv) a protease inhibitor, danoprevir, a serine protease inhibitor, camostat, or narlaprevir, and an avermectin or ivermectin; an antibiotic (optionally, doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (ww) an anti-PD-1 checkpoint inhibitor, optionally camrelizumab, or a PD-1 inhibitor (or cemiplimab, dostallimab, pembrolizumab, or nivolumab), or a PD-L1 inhibitor (or atezolizumab, avelumab, cosibelimab, or durvalumab); (xx) anti-PD-1 checkpoint inhibitor, or camrelizumab, or a PD-1 inhibitor, or a PD-L1 inhibitor with an avermectin or ivermectin; an antibiotic (optionally, doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (yy) thalidomide, or thalidomide and glucocorticoids (optionally low-dose glucocorticoids), or and thalidomide and celecoxib; (zz) thalidomide, or thalidomide and a glucocorticoid (optionally a low-dose glucocorticoid) with an avermectin or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (aaa) a compound or antibody capable of binding to complement factor C5 and inhibiting membrane attack complex formation, or eculizumab; (bbb) a compound or antibody capable of binding to complement factor C5 and inhibiting membrane attack complex formation, or eculizumab, with an avermectin drug or ivermectin; an antibiotic (optionally, doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (ccc) a cathepsin inhibitor, optionally a cathepsin K, B, or L inhibitor, or leracatib or valicatib; (ddd) a cathepsin inhibitor, or relacatib or baricatib, with an avermectin or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (eee) a synthetic nucleoside analogue or derivative, or N4-hydroxycytidine, or a prodrug of N4-hydroxycytidine, optionally molnupiravir (Merck), or favipiravir (also known as T-705 or Avigan™), or Favilavir, Japan, Fujifilm Toyama Chemical, or FabiFlu™ (Glenmark Pharmaceuticals), optionally dosed at 800 mg bid; (fff) a synthetic nucleoside analogue or derivative with an avermectin drug or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; wherein the synthetic nucleoside analog or derivative, or N4-hydroxycytidine, or prodrug of N4-hydroxycytidine, optionally molnupiravir or favipiravir, is administered at between about 10 mg and 3 gm per dose, or between about 10 mg and 3 gm per day, or can be dosed as a single dose, or administered once, twice, three or four times daily, or 200-800 mg twice daily, or 200, 400, 600 or 800 mg, or 200-800 mg three times a day, or 200, 400, 600, or 800 mg three times a day, or 200-800 mg three times a day for about 2-15 days, or for about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 days, optionally with lower dosages used when combined with other drugs, optionally with 100 or 200 mg three times a day for about 5-15 days, or for about 7, 8, 9, 10, 11, or 12 days; (ggg) an antiandrogen drug, optionally wherein the antiandrogen drug is bicalutamide, or Casodex™, or dutasteride (or Avodart™), optionally wherein the antiandrogen drug comprises a 5α-reductase inhibitor, optionally wherein the 5α-reductase inhibitor comprises finasteride (or Proscar™, Propecia™, or Finide™); (hhh) an antiandrogen drug, optionally wherein the antiandrogen drug is bicalutamide, or Casodex™, or dutasteride (or Avodart™), an avermectin drug or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (iii) an antimalarial drug, where optionally the antimalarial drug comprises mefloquine (or Lariam™, Mefaquine™, or Mefriam™), where optionally the mefloquine is optionally formulated for oral administration in tablet or capsule form, optionally as 200 mg, 250 mg, or 300 mg tablets; (jjj) an antimalarial drug and an avermectin or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (lll) Peroxisome Proliferator-Activated Receptor (PPAR) agonists, wherein optionally the PPAR agonist comprises fenofibrate, or TRICOR™, FENOBRAT™, FENOGLIDE™, or LIPofen™, and optionally the PPAR agonist comprises a combination of fenofibrate and pravastatin, or PRAVAFENIX™, or the PPAR agonist comprises bezafibrate, or bezalip (B EZALIP™, or a combination of bezafibrate and chenodeoxycholic acid, or HEPACONDA™, or aluminum clofibrate, or alfibrate, or ciprofibrate, or clinofibrate or LIPOCLIN™, or clofibrate or Atromid-S™, or clofibrate, or gemfibrozil or LOPID™, or lonifibrate, or simfibrate or Cholesorbin™, or any combination thereof; (mmm) a peroxisome proliferator-activated receptor (PPAR) agonist and an avermectin drug or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (nnn) an acetaldehyde dehydrogenase inhibitor, optionally formulated as a sustained-, extended-, or delayed-release disulfiram formulation, optionally disulfiram, or Antabuse™, or Antabuse™, optionally the sustained-, extended-, or delayed-release disulfiram formulated as a tablet, capsule, or in an injectable, amphiphilic, absorbable, depot-forming drug delivery system (DDS); (ooo) an acetaldehyde dehydrogenase inhibitor and an avermectin drug or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (ppp) a nicotinic antagonist, dopamine agonist, or non-competitive N-methyl-D-aspartate (NMDA) antagonist, optionally formulated as a tablet or capsule, optionally dosed at between about 100-200 mg per dose, optionally amantadine, or Gocobri™, or Simazine™, or Symmetrel™; (qqq) a nicotinic antagonist, dopamine agonist, or noncompetitive N-methyl-D-aspartate (NMDA) antagonist with an avermectin or ivermectin; an antibiotic (optionally, doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (rrr) a mitochondrial sensitizer, optionally proguanil or chlorguanide (or Paludrin™), or a malarial cytochrome bc1 complex inhibitor, optionally atovaquone (or Mepron™), or a combination of proguanil and atovaquone (or Malarone™); Optionally, proguanil, atovaquone, or the combination of proguanil and atovaquone is formulated for oral administration, optionally as a tablet, and optionally the unit dose of atovaquone is 250 mg, 300 mg, 350 mg, 400 mg, 500 mg, or 1 gram and the unit dose of proguanil is 100 mg, 250 mg, 300 mg, 350 mg, or 400 mg; (sss) a mitochondrial sensor or malarial cytochrome bc1 complex inhibitor with an avermectin or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (ttt) dendrimers, optionally astodrimer sodium (Starpharma, Melbourne, Australia); (uuu) a dendrimer and an avermectin drug or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (vvv) drugs of the antihistamine class, optionally azelastine, or Asterin™, Optivar™, Allergodil™, bepotastine (or Talion™, Veprive™), brompheniramine, fexofenadine or Allegra™, pheniramine or Avil™, or chlorpheniramine; (www) Antihistamine class drugs and avermectins or ivermectin; antibiotics (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxx) a drug of the selective serotonin reuptake inhibitor (SSRI) class, optionally fluvoxamine, or Luvox™, Faverine™, Fluvoxin™; a peroxisome proliferator-activated receptor (PPAR) agonist, optionally wherein the PPAR agonist comprises fenofibrate, or Tricor™, Fenobrat™, Fenoglide™, or Lipofen™, optionally wherein the PPAR agonist comprises a combination of fenofibrate and pravastatin, or Pravafenix™; or PPAR agonists include bezafibrate, or Bezalip™, or a combination of bezafibrate and chenodeoxycholic acid, or Hepaconda™, or clofibrate aluminum, or alfibrate, or ciprofibrate, or clinofibrate or Lipocrine™, or clofibrate or Atromid-S™, or clofibride, or gemfibrozil or Lopid™, or lonifibrate, or simfibrate or Cholesorbin™, or any combination thereof; (yyy) a drug of the selective serotonin reuptake inhibitor (SSRI) class and an avermectin drug or ivermectin; an antibiotic (optionally, doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (zzz) clofazimine, or Rampen™, optionally dosed at about 100 mg per day, or between about 50 mg and 150 mg per day, and / or colchicine (or Colcrys™, Mitigare™), optionally dosed at about 0.1 mg to 5 mg per day; (aaaa) clofazimine or colchicine with an avermectin or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (bbbb) Selective estrogen receptor modulators (SERMs), or toremifene (or Fairston™), or clomiphene or clomiphene (or Clomid™, Serophen™); (cccc) a selective estrogen receptor modulator (SERM), or toremifene, or clomiphene, or clomiphene, with an avermectin or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (dddd) alpha-ketoamides (α-ketoamides), where optionally the alpha-ketoamides are the structures described by Zhang et al., J. Med. Chem. 2020, 63, 9, 4562-4578, or Meng et al., Chem. Sci. (2019) Vol. 10, p. 5156 (optionally, structure KAM-2); (eeee) an alpha-ketoamide and an avermectin drug or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (ffff) acylsulfonamide inhibitors of NS3-4A serine protease, or paritaprevir, or ombitasvir, or paritaprevir and ombitasvir with ritonavir (Technivy™); (gggg) Paritaprevir (or Belprevir™), or ombitasvir, or paritaprevir and ombitasvir and ritonavir, and an avermectin drug or ivermectin; an antibiotic (optionally, doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (hhhh) at least one vitamin, optionally the at least one vitamin comprising vitamin B3 (or pyridine-3-carboxylic acid, niacin, or nicotinic acid, or vitamin B3 or niacin administered in sustained release form (or Niaspan FCT™), vitamin D (optionally D2, or ergocalciferol), or vitamin D3 or cholecalciferol, optionally administered at about 1000-4000 ugm / day; vitamin B12, vitamin B6 (or pyridoxine); vitamin K; vitamin A; vitamin E; and / or vitamin C (optionally administered at 500 mg bid); (iiii) at least one vitamin and an avermectin drug or ivermectin; an antibiotic (optionally, doxycycline or azithromycin), and zinc; (jjjj) a compound, drug, or preparation that reduces gastric acid production or lowers gastric pH, optionally wherein the compound, drug, or preparation comprises famotidine or PEPCID™, optionally wherein the famotidine is administered at a dosage of between about 10-60 mg per day, or between about 20-40 mg per day; (kkkk) Famotidine and an avermectin or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc; (llll) immunosuppressant drugs, wherein optionally the immunosuppressant drugs include tocilizumab or atlizumab, or Actemra™, or RoActemra, or calcineurin inhibitors (CNIs), wherein the CNIs include cyclosporin (or cyclosporine or cyclosporin), or Neoral™, or Sandimmune™, or tacrolimus, or Protopic™, or Prograf™; (mmmm) immunosuppressant drugs or calcineurin inhibitors and avermectins or ivermectin; antibiotics (optionally doxycycline or azithromycin), and zinc; (nnnn) an anti-inflammatory therapy or at least one anti-inflammatory therapeutic drug, wherein optionally the anti-inflammatory therapy or drug comprises a sphingosine kinase-2 (SK2) selective inhibitor (optionally opaganib (optionally Eriva™), sirolimus, a JAK1 / 2 / TYK2 inhibitor (optionally ruxolitinib), an anti-CD47 mAb (optionally meplasmab), a cyclooxygenase (COX) (optionally COX2) inhibitor, a glucocorticoid (optionally a synthetic glucocorticoid, hydrocortisone, dexamethasone (or Dextenza™, Ozurdex™, or Neofoldex™) or cortisol, or Cortef™), plitidepsin or dehydrodidemnin B, or Aplidine™; and / or (oooo) an anti-inflammatory therapy or at least one anti-inflammatory therapy drug and an avermectin drug or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc; wherein optionally the avermectin drug comprises ivermectin (or Stromectol™), moxidectin (or Cidectin™, Equest™, Quest™), selamectin (or Stronghold™), milbemycin (optionally milbemectin, milbemycin oxime, moxidectin, or nemadectin), doramectin (or Dectomax™), eprinomectin, or abamectin; Optionally, the avermectin or ivermectin is dosed at between about 50-2000 μgm / kg body weight per day, optionally 200 μgm / kg per day, or about 14 mg / day, optionally 220, 225, 150, 275, or 300 μgm / kg per day, or optionally 12, 14, 16, 18, 20, 22, 24, or 26 mg per day, or optionally between about 10-30 mg per day, for administration; Optionally, the avermectin or ivermectin is dosed at between about 5 and 480 mg or between about 3 and 500 mg per day for administration; Optionally, the avermectin drug (optionally ivermectin) is formulated or dosed at between about 15-150 mg / kg, or about 18, 24, 30, 35, 40, 35, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, or 120 mg / kg or more; Optionally, the antibiotic comprises a tetracycline class drug, optionally the tetracycline class drug is tetracycline, doxycycline, chlortetracycline, oxytetracycline, glycylcycline, fluorocycline, or demeclocycline, tetracycline or Sumycin™; chlortetracycline or Aureomycin™; oxytetracycline; demeclocycline or Declomycin™, Decrostatin™, Redamycin™, Biotercyclin™, Deganol™, Deteclo™ doxycycline or Doryx™; Doxyhexa™, Doxylin™; Tigecycline or Tygacil™; Eravacycline or Zerava™; Sarecycline or Seysara™; Omadacycline or Nuzila™; or any combination thereof, Optionally, the therapeutic combination comprises about 25 mg to about 600 mg of a drug of the tetracycline class, or tetracycline, doxycycline, chlortetracycline, oxytetracycline, or demeclocycline; Optionally, the antibiotic comprises a macrolide drug, optionally the macrolide drug is azithromycin (optionally Zithromax™, or Azithrocin™, optionally an oral sustained or delayed release formulation of azithromycin, or ZMAX™), clarithromycin (optionally Biaxin™), erythromycin (optionally Erythrocin™), or Fidakis, optionally dosed at between about 50 mg and 2000 mg per dose or per day. somycin (optionally Difficid™ or Difficlea™), troleandomycin (optionally Tekmicin™), tylosin (optionally Tylosin™ or TYLAN™), solithromycin (optionally Solitella™), oleandomycin (or Sigmamycin™), midecamycin, roxithromycin, kitasamycin or tulimicin, josamycin, carbomycin or magnamycin, and / or spiramycin, Optionally, the antibiotic comprises azithromycin, and optionally the therapeutic combination comprises between about 50 mg and about 2000 mg of azithromycin, or optionally, the azithromycin comprises an oral sustained-release formulation of azithromycin; Optionally, the antibiotic comprises a nitroimidazole, or 2-, 4-, and / or 5-nitroimidazole, or 5-nitronitroimidazole, including metronidazole, tinidazole, nimorazole, dimetridazole, pretomanid, ornidazole, megazole, and / or azanidazole, or 2-nitroimidazole, including benznidazole; Optionally, the antibiotic comprises a β-lactam antibiotic, such as a penicillin class drug or a cephalosporin class drug; Optionally, the cephalosporin class drug comprises cefalexin, cefadroxil, cefazolin, cefapirin, cephalothin, cefradine, cefprozil, cefuroxime, ceftolozane, cefonicid, or cefaclor; Optionally, the penicillin class drug comprises penicillin V, penicillin G, cloxacillin, dicloxacillin, flucloxacillin, methicillin, nafcillin, oxacillin, ampicillin, amoxicillin, pivampicillin, bacampicillin, metampicillin, talampicillin, hetacillin, carbenicillin, ticarcillin, temocillin, mezlocillin, piperacillin, azlocillin, clavulanic acid, sulbactam, or tazobactam; Optionally, the antibiotic comprises an antibiotic of the quinolone class, such as a fluoroquinolone, or comprises ciprofloxacin, garenoxacin, gatifloxacin, gemifloxacin, levofloxacin, or moxifloxacin; Optionally, the antibiotic comprises an ansamycin class drug, or rifampicin, also known as rifampin, bedaquiline; Optionally, the antibiotic comprises artemisinin, amodiaquine, proguanil, sulfadoxine, sulfamethoxypyridazine, pyrimethamine, linezolid, quinine, quinidine, cinchonine, cinchonidine (or quinimax), hydroxychloroquine, or chloroquine; Optionally, the at least one vitamin comprises vitamin D or cholecalciferol, or vitamin C, or vitamin D or cholecalciferol and vitamin C, wherein the vitamin D or cholecalciferol is dosed at between about 3,000 and about 100,000 units of vitamin D or cholecalciferol; optionally, the therapeutic combination comprises between about 10,000 and about 50,000 units of vitamin D or cholecalciferol; and optionally, the vitamin comprises vitamin C, optionally formulated or administered at a dosage of between about 500 and 5000 units (U) per dose; optionally, the zinc comprises or is formulated as a zinc salt, zinc chelate, zinc sulfate, zinc acetate, zinc gluconate, or zinc picolinate; and optionally, the therapeutic combination comprises between about 1 mg and 250 mg of zinc, zinc sulfate, zinc acetate, zinc gluconate, or zinc picolinate, or optionally zinc oxide nanoparticles in a dose between about 1 mg and 250 mg; Optionally, the pharmaceutical composition or therapeutic combination further comprises copper, optionally administered or formulated at a dosage of between about 1 and 200 mg per day, wherein optionally the copper is administered or formulated as cupric chloride and formulated at about 0.4 mg / ml and administered intravenously; Optionally, the pharmaceutical composition or therapeutic combination further comprises selenium, optionally administered as selenite formulated at about 65.4 mcg / ml (or μg / ml), optionally the selenium is administered at a dosage of between about 50-100 μg / ml, optionally between about 60-100 μgm per day administered to adults, and no more than 60 μgm per day administered to pediatric patients.

[0076] In one embodiment, the transdermal delivery device provided herein comprises a first compartment containing an avermectin drug (optionally ivermectin), a second compartment containing an antibiotic (optionally doxycycline or azithromycin), and a third compartment containing zinc (optionally a zinc chelate, e.g., zinc sulfate, zinc acetate, zinc gluconate, or zinc picolinate, or zinc oxide nanoparticles). In one embodiment, the transdermal delivery device provided herein comprises a first compartment containing ivermectin, a second compartment containing doxycycline, and a third compartment containing a zinc chelate. In one embodiment, the transdermal delivery device provided herein comprises a first compartment containing between about 24 mg and about 150 mg of ivermectin, a second compartment containing between about 25 mg and about 600 mg of doxycycline, and a third compartment containing between about 1 mg and 250 mg of zinc. In one embodiment, the transdermal delivery device provided herein comprises a first compartment containing between about 30 mg and about 60 mg of ivermectin, a second compartment containing between about 100 mg and about 500 mg of doxycycline, and a third compartment containing between about 25 mg and about 125 mg of zinc. In one embodiment, the transdermal delivery device provided herein comprises a first compartment containing between about 40 mg and about 50 mg of ivermectin, a second compartment containing between about 200 mg and about 450 mg of doxycycline, and a third compartment containing between about 50 mg and about 100 mg of zinc. In one embodiment, the transdermal delivery device provided herein comprises a first compartment containing 48 mg of ivermectin, a second compartment containing 300 mg of doxycycline, and a third compartment containing 50 mg of zinc chelate.

[0077] Any of the above aspects and embodiments may be combined with any other aspect or embodiment disclosed herein in the Summary and / or Detailed Description sections.

[0078]

[0078] As used in this specification and claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0079]

[0079] Unless otherwise specified or obvious from the context, in this specification the term "or" is understood to be inclusive and covers both "or" and "and."

[0080]

[0080] Unless otherwise specified or apparent from the context, the term "about" as used herein is understood to mean within normal tolerances in the art, e.g., within two standard deviations of the mean. About (use of the term "about") can be understood to mean within 20%, 19%, 18%, 17%, 16%, 15%, 14%, or 0.01% of the stated value. Unless otherwise apparent from the context, all numerical values ​​provided herein are modified by the term "about."

[0081]

[0081] Unless otherwise specified or apparent from the context, as used herein, the terms "substantially all," "substantially most," "substantially all," or "the majority" include at least about 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% or more of a reference amount of a composition.

[0082] Each patent, patent application, publication, and document referenced herein is incorporated by reference in its entirety. Citation of the above patents, patent applications, publications, and documents is not an admission that any of them is relevant prior art, nor does it constitute any admission as to the contents or date of these publications or documents. The incorporation by reference of any of these documents alone should not be construed as a claim or admission that any portion of the contents of any document is believed to be essential material to satisfy any national or local statutory disclosure requirements for patent applications. Nevertheless, the right of an examining authority or court to rely on any such documents, as appropriate, to provide samples believed essential to the claimed subject matter is reserved.

[0083]

[0083] Modifications can be made in the foregoing without departing from the essential aspects of the invention. While the present invention has been described in considerable detail with reference to one or more specific embodiments, those skilled in the art will recognize that changes can be made to the embodiments specifically disclosed herein, and that these modifications and improvements will still be within the scope and spirit of the invention. The invention illustratively described herein can be suitably practiced in the absence of elements not specifically disclosed herein. Thus, for example, anywhere in this specification, any of the terms "comprising," "consisting essentially of," and "consisting of" can be replaced with either of the other two terms. Accordingly, the terms and expressions used are used as terms of description rather than of limitation, and equivalents of the features or portions thereof shown and described are not excluded, recognizing that various modifications are possible within the scope of the invention. Embodiments of the invention are set forth in the following claims.

[0084]

[0084] Various features of the embodiments of the invention disclosed herein are, for brevity, described in the context of a single embodiment, but may also be provided separately or in any suitable subcombination. All combinations of embodiments are specifically embraced by the exemplary embodiments disclosed herein as if each and every combination were individually and expressly disclosed. Furthermore, all subcombinations listed in embodiments describing such variables are also specifically embraced by the present compositions and are disclosed herein as if each and every subcombination were individually and expressly disclosed herein.

[0085]

[0085] While the present invention will be further described with reference to the examples described herein, it will be understood that the invention is not limited to such examples. [Example]

[0086] Example 1: Exemplary Transdermal Device for Treating Long Term COVID

[0086] This example describes the use of the transdermal devices provided herein to treat or ameliorate so-called "long COVID" or post-COVID condition (PCC), or post-acute sequelae of SARS CoV-2 infection (PASC).

[0087]

[0087] Several patients present to the clinic complaining of a variety of symptoms, including difficulty thinking or concentrating (sometimes called "brain fog"); headaches; sleep problems; dizziness or lightheadedness when standing; pins-and-needles feeling; change or loss of smell or taste; and / or depression or anxiety. Medical history includes acute COVID infection.

[0088]

[0088] Each patient will receive a transdermal device (applied to the arm, chest, abdomen, upper back, or lower back) designed to deliver Zyverdox™ or the therapeutic drug combination of zinc, ivermectin, and doxycycline.

[0089]

[0089] The transdermal device has three separate compartments, each containing one of zinc, ivermectin, and doxycycline, each formulated at a higher dose (48 mg ivermectin, 400 mg doxycycline, 100 mg zinc chelate) than the dose at which the same drug combination would be formulated if administered orally (which would be 12 mg ivermectin, 100 mg doxycycline, and 25 mg zinc chelate).

[0090]

[0090] Zinc, ivermectin, and doxycycline are formulated separately in DMSO and contained in separate compartments of the transdermal device.

[0091]

[0091] Each patient is given 7 to 10 transdermal devices to self-apply once daily. The surface of the transdermal delivery device to be applied to the skin has one outer surface, layer, covering or laminate (a "release liner") that is removable by the patient immediately before being placed on the skin.

[0092]

[0092] Removal of the release liner also exposes the adhesive on the transdermal device, which holds the transdermal device on the skin without causing irritation and prevents the transdermally delivered drug from leaking out of the transdermal device. The adhesive can include an acrylate polymer or any pressure-sensitive adhesive (PSA).

[0093] Example 2: Exemplary Transdermal Devices for Preventing Severe Clinical COVID

[0093] This example describes the use of the transdermal device provided herein to prevent severe COVID infection.

[0094]

[0094] Individuals who anticipate being exposed to a potentially infectious environment, such as traveling on an airplane or subway, are given a transdermal device (applied to the arm, chest, abdomen, upper back, or lower back) designed to deliver Zybardox™ or the therapeutic drug combination of zinc, ivermectin, and doxycycline.

[0095]

[0095] The transdermal device has three separate compartments, each containing one of zinc, ivermectin, and doxycycline, each formulated at a higher dose (48 mg ivermectin, 400 mg doxycycline, 100 mg zinc chelate) than the dose at which the same drug combination would be formulated if administered orally (which would be 12 mg ivermectin, 100 mg doxycycline, and 25 mg zinc chelate).

[0096]

[0096] Zinc, ivermectin, and doxycycline are formulated separately in DMSO and contained in separate compartments of the transdermal device.

[0097]

[0097] These transdermal devices can be self-applied prior to an individual's exposure, but not more than once daily.

[0098]

[0098] The surface of the transdermal delivery device that is applied to the skin has one outer surface, layer, or covering or laminate (a "release liner") that is removable by the patient immediately prior to placement on the skin.

[0099]

[0099] Removal of the release liner also exposes the adhesive on the transdermal device, which holds the transdermal device on the skin without causing irritation and prevents the transdermally delivered drug from leaking out of the transdermal device. The adhesive can include an acrylate polymer or any pressure-sensitive adhesive (PSA).

[0100] Example 3 [000100] A 64-year-old patient with diabetes and hypertension was diagnosed with COVID-19 infection by PCR. He had a sore throat and cough, and his oxygen level by oximetry dropped to 82. He was treated with a transdermal patch containing high doses of active antiviral drugs: 48 mg ivermectin, 300 mg doxycycline, and 50 mg zinc chelate. The transdermal patch had three separate compartments, each containing one of ivermectin, doxycycline, and zinc chelate. Each active ingredient was formulated with a gelling agent and water. The patch remained on the left side of the chest for three days. Blood levels of ivermectin, doxycycline, and zinc chelate increased, peaking at 10 hours. The patient's cough persisted but gradually resolved, and he experienced no shortness of breath. The areas under the curve for each of ivermectin, doxycycline, and zinc chelate were greater than those for a single oral agent and persisted for 6 days versus 48 hours in the orally treated patient. The patient's oxygen saturation improved within 2 days, rising to 96% by oximetry.

[0101] [000101] This example led to the prophylactic use of such patches. None of the three patients contracted Covid-19 while living with someone infected with Covid-19.

[0102] [000102] Several embodiments of the present invention have been described. Nevertheless, it will be understood that various modifications can be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims.

Claims

1. 1. A pharmaceutical composition or therapeutic combination of drugs, comprising: (a)(i) metformin (or Glucophage™) and / or (ii) a 3C-like (3CLpro) protease (also known as main protease (Mpro), also known as C30 endopeptidase or 3-chymotrypsin-like protease) inhibitor, optionally ensitrevir (or Zocova™) or ensitrevir fumarate; wherein optionally, metformin is formulated or dosed at between about 100 mg and 4000 mg per unit dose (optionally per tablet); or metformin is formulated or dosed at between about 0.1 ml and 25 ml of liquid metformin / day; wherein optionally, ensitrevir or ensitrevir fumarate is formulated or dosed at between about 100 mg and 500 mg per unit dose, or about 100 mg, 125 mg, or 150 mg per unit dose (optionally per tablet); and (b) When only metformin or a 3CLpro inhibitor is included, any two of the following drugs or drug combinations, or when both metformin and 3CLpro are included, any one (or at least one) of the following drugs or drug combinations: (i) Avermectin drugs or Ivermectin (or Stromectol™); (ii) an avermectin or ivermectin and an antibiotic (optionally doxycycline or azithromycin); (iii) an avermectin or ivermectin; an antibiotic (optionally, doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol (optionally with or without vitamin C); (iv) Antibiotics (v) ivermectin; and an antibiotic (optionally doxycycline or azithromycin), at least one vitamin, and zinc; (vi) opaganib or Eriva™; (vii) opaganib with an avermectin drug or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (viii) plitidepsin (also known as dehydrodidemnin B), or Aplidine™; (ix) plitidepsin and an avermectin drug or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol, and optionally also vitamin D or cholecalciferol; (x) lopinavir, ritonavir (or Norvir™), and / or oseltamivir; (xi) lopinavir, ritonavir, and / or oseltamivir with an avermectin or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xii) nilmatrervir and ritonavir (or Paquilobid™), (xiii) Nilmatrervir and ritonavir (or Paquilobid™) with an avermectin drug or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xiv) chloroquine (optionally Alaren™), chloroquine phosphate, chloroquine diphosphate, hydroxychloroquine (optionally Plaquenil™); (xv) chloroquine, chloroquine phosphate, chloroquine diphosphate, hydroxychloroquine, and an avermectin or ivermectin; an antibiotic (optionally, doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xvi) abacavir, optionally acyclovir, (Acyclovir™), adefovir, amantadine, Amplgen, amprenavir (optionally Agenerase™), aprepitant, arbidol, atazanavir, atripla, baravir, baloxavir marboxil (Xofluza™), bepotastine, bevirimat, bictegravir, bictarvy, brilacidin, cidofovir, caspofungin, lamivudine and zidovudine (optionally Convir™), cobixstat, colicitin, cocaine, delavirdine, deciclovir Cobi, didanosine, docosanol, dolutegravir, ecolievel, edoxudine, elvitegravir, enfuvirtide, entecavir, epirubicin, epoprostenol, etravirine, famciclovir, homovirsen, fosamprenavir, foscarnet, fosfonet, galidesivir, ibacitabine, icatibant, idoxuridine, ifenprodil, imiquimod, immunovir, indinavir, inosine, interferon (optionally type I interferon, type II interferon, and / or type III interferon) , lamivudine, loviride, ledipasvir, leronlimab, maraviroc, methisazone, moroxydine, nexavir, norvir, nucleoside analogues (optionally brincidofovir, didanosine, favipiravir (also known as T-705, Avigan, or Favilavir, Fujifilm Toyama Chemical, Japan), vidarabine, galidesivir (optionally BCX4430, Immucillin-A™), cytarabine, gemcitabine, lamivudine, zalcitabine, abacavir, acyclovir, entecavir, stavudine, telbivudine, zidovudine, iodoxamic acid uridine, and / or trifluridine, or any combination thereof), oseltamivir (or Tamiflu™), peginterferon alfa-2a, penciclovir, peramivir (optionally Rapivir™), perphenazine, pleconaril, prulifloxacin, podophyllotoxin, pyramidine, raltegravir, rifampicin, rilpivirine, rimantadine, ritonavir, saquinavir, sofosbuvir, stavudine, telaprevir, tegovab, tipranavir, trifluridine, trizivir, tromantadine, Truvada,Valacyclovir (optionally Valtrex™), valganciclovir, valrubicin, vapreotide, vicriviroc, vidarabine, viramidine, velpatasvir, vibecon, zalcitabine, zanamivir (optionally Relenza™), zidovudine, or any combination thereof; (xvii) Any one or more of the drugs in (xiv) with: an avermectin drug or ivermectin; an antibiotic (optionally, doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xviii) molnupiravir, emtricitabine (or EMTRIVA™), efavirenz (or SUSTIVA™), or tenofovir; or molnupiravir and emtricitabine and tenofovir (or ATRIPLA™); (xix) molnupiravir, emtricitabine, efavirenz, or tenofovir with an avermectin or ivermectin; an antibiotic (optionally, doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xx) zanamivir (or Relenza™); (xxi) zanamivir with an avermectin or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxii) efavirenz (optionally Sustiva™); (xxiii) efavirenz and an avermectin drug or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxiv) nelfinavir (Viracept™) or oseltamivir (or Tamiflu™), (xxv) nelfinavir (Viracept™) or oseltamivir (or Tamiflu™) with an avermectin drug or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxvi) a drug of the thiazolide class, optionally nitazoxanide (optionally Alinia™, or Nizonide™) or tizoxanide (or 2-hydroxy-N-(5-nitro-2-thiazolyl)benzamide); (xxvii) a drug of the thiazolide class, optionally with nitazoxanide and an avermectin drug or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxviii) remdesivir (optionally GS-5734™, Gilead Sciences, or Veklury™); (xxix) molnupiravir (or LAGEVRIO™); (xxx) molnupiravir and an avermectin or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxi) nevirapine (or VIRAMUNE™); (xxxii) nevirapine (or Viramune™) with an avermectin drug or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxiii) tenofovir alafenamide, tenofovir disoproxil, or tenofovir; (xxxiv) tenofovir alafenamide, tenofovir disoproxil, or tenofovir with an avermectin or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxv) selamectin (or Cerehold™, Revolt™, Ceralid™, or Senergy™); (xxxvi) selamectin and an avermectin drug or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxvii) inhibitors of S-phase kinase-associated protein 2 (SKP2), or dioscin, or niclosamide, or nicloside™, phenasal™, or phenasal™; (xxxviii) an inhibitor of S-phase kinase-associated protein 2 (SKP2), or dioscin, or niclosamide, with an avermectin drug or ivermectin; an antibiotic (optionally, doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxix) ribavirin or tribavirin (or Copegus™, Rebetol™, or Virazol™); (xxxx) ribavirin or tribavirin with an avermectin or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxxi) a viral, or coronavirus, or COVID-19, protease inhibitor, optionally ASC09 (CAS Registry Number 1000287-05-7) (Janssen Research and Development, LLC), ritonavir, or ASC09 and ritonavir, or a JAK1 / 2 inhibitor (optionally baricitinib), optionally compound 11r (University of Lübeck, Germany; see Zhang et al. J. Med Chem 2020, February 11, 2020), or darunavir (or Prezista™), cobicistat (or Tyvost™), or darunavir and cobicistat; (xxxxii) a viral, or coronavirus, or COVID-19 protease inhibitor, ritonavir, a JAK1 / 2 inhibitor (optionally baricitinib), or darunavir (or PREZISTA™) or cobicistat with an avermectin or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxxiii) mucolytic therapy or medication, optionally acetylcysteine, ambroxol, bromhexine, carbocysteine, erdosteine, mecysteine, or dornase alfa, or an expectorant, optionally guaifenesin; (xxxxiv) mucolytic therapy or drug with an avermectin drug or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxxv) angiotensin-converting enzyme 2 (ACE2) inhibitors, optionally captopril, enalapril, lisinopril, benazepril, fosinopril, quinapril, ramipril, perindopril, moexipril, or trandolapril; (xxxxvi) an angiotensin-converting enzyme 2 (ACE2) inhibitor and an avermectin or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxxvii) anti-vascular endothelial growth factor (VEGF) (optionally VEGF-A) drugs or antibodies, optionally bevacizumab (or Avastin™); (xxxxviii) an anti-vascular endothelial growth factor (VEGF) drug or antibody, or bevacizumab, with an avermectin drug or ivermectin; an antibiotic (optionally, doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxvix) protease inhibitor, optionally danoprevir, optionally a serine protease inhibitor, optionally camostat (or Foipan™) or narlaprevir (optionally Allansa™) (xxxxx) a protease inhibitor, danoprevir, a serine protease inhibitor, camostat, or narlaprevir, and an avermectin or ivermectin; an antibiotic (optionally, doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxxi) an anti-PD-1 checkpoint inhibitor, optionally camrelizumab, or a PD-1 inhibitor (or cemiplimab, dostallimab, pembrolizumab, or nivolumab), or a PD-L1 inhibitor (or atezolizumab, avelumab, cosibelimab, or durvalumab); (xxxxxii) an anti-PD-1 checkpoint inhibitor, or camrelizumab, or a PD-1 inhibitor, or a PD-L1 inhibitor with an avermectin or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxxxiii) thalidomide, or thalidomide and glucocorticoid (optionally low-dose glucocorticoid), or and thalidomide and celecoxib; (xxxxxiv) thalidomide, or thalidomide and a glucocorticoid (optionally a low-dose glucocorticoid) with an avermectin or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxxxv) a compound or antibody capable of binding to complement factor C5 and inhibiting membrane attack complex formation, or eculizumab; (xxxxxvi) a compound or antibody capable of binding to complement factor C5 and inhibiting membrane attack complex formation, or eculizumab, with an avermectin drug or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxxxvii) a cathepsin inhibitor, optionally a cathepsin K, B, or L inhibitor, or relacatib or valicatib; (xxxxviii) a cathepsin inhibitor, or relacatib or baricatib, with an avermectin or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxxxix) synthetic nucleoside analogue or derivative, or N4-hydroxycytidine, or a prodrug of N4-hydroxycytidine, optionally molnupiravir (Merck), or favipiravir (also known as T-705 or Avigan™), or Favilavir, Japan, Fujifilm Toyama Chemical, or FabiFlu™ (Glenmark Pharmaceuticals), optionally dosed at 800 mg bid; (xxxxxx) synthetic nucleoside analogues or derivatives with avermectins or ivermectin; antibiotics (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; wherein the synthetic nucleoside analog or derivative, or N4-hydroxycytidine, or prodrug of N4-hydroxycytidine, optionally molnupiravir or favipiravir, is administered at between about 10 mg and 3 gm per dose, or between about 10 mg and 3 gm per day, or can be dosed as a single dose, or administered once, twice, three or four times daily, or 200-800 mg twice daily, or 200, 400, 600 or 800 mg, or 200-800 mg three times a day, or 200, 400, 600, or 800 mg three times a day, or 200-800 mg three times a day for about 2-15 days, or for about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 days, optionally with lower dosages used when combined with other drugs, optionally with 100 or 200 mg three times a day for about 5-15 days, or for about 7, 8, 9, 10, 11, or 12 days; (xxxxxxi) an antiandrogen drug, optionally wherein the antiandrogen drug is bicalutamide, or CASODEX™, or dutasteride (or AVODART™), optionally wherein the antiandrogen drug comprises a 5α-reductase inhibitor, optionally wherein the 5α-reductase inhibitor comprises finasteride (or PROSCAR™, PROPECIA™, or FINIDE™); (xxxxxxii) an antiandrogen drug, optionally an avermectin drug or ivermectin when the antiandrogen drug is bicalutamide, or Casodex™, or dutasteride (or Avodart™); an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxxxxiii) an antimalarial drug, where optionally the antimalarial drug comprises mefloquine (or Lariam™, Mefaquine™, or Mefriam™), where optionally the mefloquine is optionally formulated for oral administration in tablet or capsule form, optionally as 200 mg, 250 mg, or 300 mg tablets; (xxxxxxiv) an antimalarial drug and an avermectin or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxxxxv) Peroxisome Proliferator-Activated Receptor (PPAR) agonists, wherein optionally the PPAR agonist comprises fenofibrate, or TRICOR™, FENOBRAT™, FENOGLIDE™, or LIPOFEN™, and optionally the PPAR agonist comprises a combination of fenofibrate and pravastatin, or PRAVAFENIX™, or the PPAR agonist is bezafibrate or bezalip. (BEZALIP™), or a combination of bezafibrate and chenodeoxycholic acid, or HEPACONDA™, or clofibrate aluminum, or alfibrate, or ciprofibrate, or clinofibrate or LIPOCLIN™, or clofibrate or Atromid-S™, or clofibrate, or gemfibrozil or LOPID™, or lonifibrate, or simfibrate or colsorbin™, or any combination thereof; (xxxxxxvi) a peroxisome proliferator-activated receptor (PPAR) agonist and an avermectin drug or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxxxxvii) an acetaldehyde dehydrogenase inhibitor, optionally formulated as a sustained-, extended-, or delayed-release disulfiram formulation, optionally disulfiram, or Antabuse™, or Antabuse™, optionally sustained-, extended-, or delayed-release disulfiram formulated as a tablet, capsule, or in an injectable, amphiphilic, absorbable, depot-forming drug delivery system (DDS); (xxxxxxviii) an acetaldehyde dehydrogenase inhibitor and an avermectin or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxxxxix) a nicotinic antagonist, dopamine agonist, or non-competitive N-methyl-D-aspartate (NMDA) antagonist, optionally dosed at between about 100-200 mg per dose, optionally formulated as a tablet or capsule, optionally amantadine, or Gocobri™, or Simazine™, or Symmetrel™; (xxxxxx) a nicotinic antagonist, dopamine agonist, or non-competitive N-methyl-D-aspartate (NMDA) antagonist with an avermectin or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxxxxxi) a mitochondrial sensor, optionally proguanil or chlorguanide (or Paludrine™), or a malarial cytochrome bc1 complex inhibitor, optionally atovaquone (or Mepron™), or a combination of proguanil and atovaquone (or Malarone™); Optionally, proguanil, atovaquone, or a combination of proguanil and atovaquone is formulated for oral administration, optionally as a tablet, and optionally the unit dose of atovaquone is 250 mg, 300 mg, 350 mg, 400 mg, 500 mg, or 1 gram and the unit dose of proguanil is 100 mg, 250 mg, 300 mg, 350 mg, or 400 mg; (xxxxxxii) a mitochondrial sensor or malarial cytochrome bc1 complex inhibitor with an avermectin or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxxxxiii) Dendrimer, optionally astodrimer sodium (Starpharma, Melbourne, Australia); (xxxxxxiv) a dendrimer and an avermectin drug or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxxxxv) a drug of the antihistamine class, optionally azelastine, or Asterin™, Optivar™, Allergodil™, bepotastine (or Talion™, Beprive™), brompheniramine, fexofenadine or Allegra™, pheniramine or Avil™, or chlorpheniramine; (xxxxxxvi) a drug of the antihistamine class and an avermectin drug or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxxxxvii) a drug of the selective serotonin reuptake inhibitor (SSRI) class, optionally fluvoxamine, or Luvox™, Faverine™, Fluvoxin™; a peroxisome proliferator-activated receptor (PPAR) agonist, optionally wherein the PPAR agonist comprises fenofibrate, or Tricor™, Fenobrat™, Fenoglide™, or Lipofen™, optionally wherein the PPAR agonist comprises a combination of fenofibrate and pravastatin, or Pravafenix™. or the PPAR agonist comprises bezafibrate, or Bezalip™, or a combination of bezafibrate and chenodeoxycholic acid, or Hepaconda™, or clofibrate aluminum, or alfibrate, or ciprofibrate, or clinofibrate or Lipocrine™, or clofibrate or Atromid-S™, or clofibrate, or gemfibrozil or Lopid™, or lonifibrate, or simfibrate or Cholesorbin™, or any combination thereof; (xxxxxxviii) a drug of the selective serotonin reuptake inhibitor (SSRI) class and an avermectin drug or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxxxxix) clofazimine, or Lampen™, optionally dosed at about 100 mg per day, or between about 50 mg and 150 mg per day, and / or colchicine (or Colcrys™, Mitigare™), optionally dosed at about 0.1 mg to 5 mg per day; (xxxxxxxxx) clofazimine or colchicine with an avermectin or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxxxxxi) selective estrogen receptor modulators (SERMs), or toremifene (or Fairston™), or clomiphene or clomiphene (or Clomid™, Serophen™); (xxxxxxxxii) a selective estrogen receptor modulator (SERM), or toremifene, or clomiphene or clomiphene with an avermectin or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxxxxxxxiii) alpha-ketoamides (α-ketoamides), where optionally the alpha-ketoamide is a structure described by Zhang et al., J. Med. Chem. 2020, 63, 9, 4562-4578, or Meng et al., Chem. Sci. (2019) Vol. 10, p. 5156 (optionally, structure KAM-2); (xxxxxxxxiv) alpha-ketoamide and an avermectin or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxxxxv) acylsulfonamide inhibitors of NS3-4A serine protease, or paritaprevir, or ombitasvir, or paritaprevir and ombitasvir with ritonavir (Technivy™); (xxxxxxvi) paritaprevir (or Belprevir™), or ombitasvir, or paritaprevir and ombitasvir with ritonavir and an avermectin or ivermectin; an antibiotic (optionally, doxycycline or azithromycin), and zinc, and optionally also vitamin D or cholecalciferol; (xxxxxxxxxvii) at least one vitamin, optionally wherein the at least one vitamin comprises vitamin B3 (or pyridine-3-carboxylic acid, niacin, or nicotinic acid, or vitamin B3 or niacin administered in a sustained release form (or NIASPAN FCT™), vitamin D (optionally D2, or ergocalciferol), or vitamin D3 or cholecalciferol, optionally administered at about 1000-4000 ugm / day; vitamin B12, vitamin B6 (or pyridoxine); vitamin K; vitamin A; vitamin E; and / or vitamin C (optionally administered at 500 mg bid); (xxxxxxxxxviii) at least one vitamin and an avermectin drug or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc; (xxxxxxxxxix) a compound, drug, or preparation that reduces gastric acid production or lowers gastric pH, optionally wherein the compound, drug, or preparation comprises famotidine or PEPCID™, optionally wherein famotidine is administered at a dosage of between about 10-60 mg per day, or between about 20-40 mg per day; (xxxxxxxxx) famotidine and an avermectin or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc; (xxxxxxxxxxi) an immunosuppressant drug, wherein optionally the immunosuppressant drug comprises tocilizumab or atlizumab, or Actemra™, or RoActemra, or a calcineurin inhibitor (CNI), wherein the CNI comprises cyclosporine (or cyclosporine or cyclosporine), or Neoral™, or Sandimmune™, or tacrolimus, or Protopic™, or Prograf™; (xxxxxxxxxii) an immunosuppressant drug or calcineurin inhibitor and an avermectin drug or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc; (xxxxxxxxxiii) an anti-inflammatory therapy or at least one anti-inflammatory therapeutic drug, wherein optionally the anti-inflammatory therapy or drug comprises a sphingosine kinase-2 (SK2) selective inhibitor (optionally opaganib (optionally Eriva™), sirolimus, a JAK1 / 2 / TYK2 inhibitor (optionally ruxolitinib), an anti-CD47 mAb (optionally meplasmab), a cyclooxygenase (COX) (optionally COX2) inhibitor, a glucocorticoid (optionally a synthetic glucocorticoid, hydrocortisone, dexamethasone (or Dextenza™, Ozurdex™, or Neofoldex™) or cortisol, or Cortef™), plitidepsin or dehydrodidemnin B, or Aplidine™; and / or (xxxxxxxxxiv) an anti-inflammatory therapy or at least one anti-inflammatory therapy drug, including an avermectin drug or ivermectin; an antibiotic (optionally doxycycline or azithromycin), and zinc; Optionally, the avermectin drug comprises ivermectin (or Stromectol™), moxidectin (or Cidectin™, Equest™, Quest™), selamectin (or Stronghold™), milbemycin (optionally milbemectin, milbemycin oxime, moxidectin, or nemadectin), doramectin (or Dectomax™), eprinomectin, or abamectin; Optionally, the avermectin or ivermectin is dosed at between about 50-2000 μgm / kg of body weight per day, optionally 200 μgm / kg per day, or about 14 mg / day, optionally 220, 225, 150, 275, or 300 μgm / kg per day, or optionally 12, 14, 16, 18, 20, 22, 24, or 26 mg per day, or optionally between about 10-30 mg per day, for administration; Optionally, the avermectin or ivermectin is dosed at between about 5-480 mg or between about 3-500 mg per day for administration; Optionally, the avermectin drug (optionally ivermectin) is formulated or dosed at between about 15-150 mg / kg, or about 18, 24, 30, 35, 40, 35, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, or 120 mg / kg or more; Optionally, the antibiotic comprises a tetracycline class drug, and optionally the tetracycline class drug is tetracycline, doxycycline, chlortetracycline, oxytetracycline, glycylcycline, fluorocycline, or demeclocycline, tetracycline or SUMYCIN™; chlortetracycline or AUREOMYCIN™; oxytetracycline; demeclocycline or DECLOMYCIN™, DECLOSTATIN™, LEDERMYCIN™, BIOTERCICLIN™, DEGANOL™, DETECLO (trademark), DETRAVIS (trademark), MECICLIN (trademark), MEXOCINE (trademark), CLORTETRIN (trademark); lymecycline; meclocycline; methacycline; minocycline or MINOCIN (trademark); rolitetracycline; doxycycline or DORYX )™; DOXYHEXA™, DOXYLIN™; tigecycline or TYGACIL™; eravacycline or XERAVA™; sarecycline or SEYSARA™; omadacycline or NUZYRA™; or any combination thereof, Optionally, the therapeutic combination comprises about 25 mg to about 600 mg of a drug of the tetracycline class, or tetracycline, doxycycline, chlortetracycline, oxytetracycline, or demeclocycline; Optionally, the antibiotic comprises a macrolide drug, optionally the macrolide drug is azithromycin (optionally ZITHROMAX™, or AZITHROCIN™, optionally an oral sustained or delayed release formulation of azithromycin, or ZMAX™), clarithromycin (optionally BIAXIN™), erythromycin (optionally ERYTHROCIN™), or fidaxomicin (optionally dextromethorphan), optionally dosed at between about 50 mg and 2000 mg per dose or per day. DIFICID™ or DIFICLIR™), troleandomycin (optionally TEKMISIN™), tylosin (optionally TYLOCINE™ or TYLAN™), solithromycin (optionally SOLITHERA™), oleandomycin (or SIGMAMYCINE™), midecamycin, roxithromycin, kitasamycin or turimycin, josamycin, carbomycin or magnamycin, and / or spiramycin; Optionally, the antibiotic comprises azithromycin, and optionally, the therapeutic combination comprises between about 50 mg and about 2000 mg of azithromycin, or optionally, the azithromycin comprises an oral sustained release formulation of azithromycin; Optionally, the antibiotic comprises a nitroimidazole, or a 2-, 4-, and / or 5-nitroimidazole, or a 5-nitronitroimidazole, including metronidazole, tinidazole, nimorazole, dimetridazole, pretomanid, ornidazole, megazole, and / or azanidazole, or a 2-nitroimidazole, including benznidazole; Optionally, the antibiotic comprises a β-lactam antibiotic, such as a penicillin class drug or a cephalosporin class drug; Optionally, the cephalosporin class drug comprises cephalexin, cefadroxil, cefazolin, cephapirin, cephalothin, cephradine, cefprozil, cefuroxime, ceftolozane, cefonicid, or cefaclor; Optionally, the penicillin class drug comprises penicillin V, penicillin G, cloxacillin, dicloxacillin, flucloxacillin, methicillin, nafcillin, oxacillin, ampicillin, amoxicillin, pivampicillin, bacampicillin, metampicillin, talampicillin, hetacillin, carbenicillin, ticarcillin, temocillin, mezlocillin, piperacillin, azlocillin, clavulanic acid, sulbactam, or tazobactam; Optionally, the antibiotic comprises an antibiotic of the quinolone class, such as a fluoroquinolone, or comprises ciprofloxacin, garenoxacin, gatifloxacin, gemifloxacin, levofloxacin, or moxifloxacin; Optionally, the antibiotic comprises an ansamycin class drug, or rifampicin, also known as rifampin, bedaquiline; Optionally, the antibiotic comprises artemisinin, amodiaquine, proguanil, sulfadoxine, sulfamethoxypyridazine, pyrimethamine, linezolid, quinine, quinidine, cinchonine, cinchonidine (or quinimax), hydroxychloroquine, or chloroquine; optionally, the at least one vitamin comprises vitamin D or cholecalciferol, or vitamin C, or vitamin D or cholecalciferol and vitamin C, wherein the vitamin D or cholecalciferol is dosed at between about 3,000 and about 100,000 units of vitamin D or cholecalciferol; optionally, the therapeutic combination comprises between about 10,000 and about 50,000 units of vitamin D or cholecalciferol; optionally, the vitamin comprises vitamin C, wherein the vitamin C is formulated or administered at a dosage of between about 500 and 5000 units (U) per dose; optionally, the zinc comprises or is formulated as a zinc salt, zinc chelate, zinc sulfate, zinc acetate, zinc gluconate, or zinc picolinate, and optionally, said therapeutic combination comprises between about 1 mg and 250 mg of zinc, zinc sulfate, zinc acetate, zinc gluconate, or zinc picolinate, or optionally zinc oxide nanoparticles in a dose between about 1 mg and 250 mg; Optionally, the pharmaceutical composition or therapeutic combination further comprises copper, optionally administered or formulated at a dosage of between about 1-200 mg per day, wherein optionally the copper is administered or formulated as cupric chloride, formulated at about 0.4 mg / ml and administered intravenously; Optionally, said pharmaceutical composition or therapeutic combination further comprises selenium, optionally administered as selenite formulated at about 65.4 mcg / ml (or μ / ml), and optionally the selenium is administered at a dosage of between about 50-100 μ / ml, optionally between about 60-100 μgm per day administered to adults, and no more than 60 μgm per day administered to pediatric patients.

2. 10. An article of manufacture comprising the pharmaceutical composition or therapeutic drug combination of claim 1, Optionally, the article of manufacture comprises a pharmaceutical formulation, or a dressing or skin patch, or an implant; Optionally, the pharmaceutical composition or therapeutic combination is formulated as a gel, liquid, aerosol, spray, mist, lotion, cream, powder, tablet, capsule, pill, geltab, enema, suppository, transdermal or buccal patch, or an injectable, subcutaneous, intramuscular (IM), or intravenous (IV) formulation to produce a pharmaceutical formulation.

3. 10. A kit comprising the pharmaceutical composition or therapeutic drug combination of claim 1 or the product of claim 2, optionally for delivery of both oral and transdermal drugs as required.

4. a virus, optionally of the subfamily Orthocoronavirinae, or of the families Coronaviridae, Arteriviridae, Roniviridae, and / or Mesoniviridae, or of the subfamilies Letovirinae and Orthocoronavirinae; or of the order Nidovirales, or of the genera Alphacoronavirus, Betacoronavirus, 10. Use of the pharmaceutical composition or therapeutic drug combination of claim 1, or the product of claim 2, or the kit of claim 3, for treating, preventing, or ameliorating (optionally reducing symptoms or reducing mortality) an infection caused by a virus of the genus B.navirus, gammacoronavirus, or deltacoronavirus, or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus or a variant thereof, optionally wherein SARS-CoV-2 is an Omicron variant, or one of B.1.1.529, BA.1, BA.1.1, BA.2, BA.3, BA.4, and BA.

5. 5 lineage variant; or optionally, the SARS-CoV-2 is an alpha, beta, gamma, delta, epsilon, eta, iota, kappa, mu, or zeta variant; Optionally, the coronavirus infection is a viral infection caused by COVID-19 or a variant, alternative lineage branch, or subtype thereof, or a Middle East Respiratory Syndrome Virus (MERS-CoV) infection; Optionally, the viral infection is a virus that causes the common cold, influenza virus (optionally influenza A, B, or C), hepatitis virus, Rous sarcoma virus (RSV), Paramyxoviridae or measles virus, Paramyxovirus or mumps virus, herpes simplex virus (HSV), Cytomegalovirus (CMV), Rubivirus or rubella virus, Enterovirus, viral meningitis, 4. Use of the pharmaceutical composition or therapeutic combination of drugs according to claim 1, or the product of claim 2, or the kit of claim 3, for an infection caused by rhinovirus, human immunodeficiency virus (HIV), varicella zoster or chickenpox virus, orthopoxvirus or variola or smallpox virus, Epstein-Barr virus (EBV), adenovirus, hantavirus, flaviviridae or dengue virus, zika virus, or chikungunya virus infection.

5. a virus, optionally of the subfamily Orthocoronavirinae, or of the families Coronaviridae, Arteriviridae, Roniviridae, and / or Mesoniviridae, or of the subfamilies Letovirinae and Orthocoronavirinae; or of the order Nidovirales, or of the genera Alphacoronavirus, Betacoronavirus, 1. The pharmaceutical composition or therapeutic combination of drugs of claim 1, or the product of claim 2, or the kit of claim 3, for use in treating, preventing, or ameliorating (optionally reducing symptoms or reducing mortality) an infection caused by a virus of the genus B.irus, gammacoronavirus, or deltacoronavirus, or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus or a variant thereof, optionally wherein the SARS-CoV-2 is an Omicron variant, or one of B.1.1.529, BA.1, BA.1.1, BA.2, BA.3, BA.4, and BA.

5. 5 lineage variant; or optionally, the SARS-CoV-2 is an alpha, beta, gamma, delta, epsilon, eta, iota, kappa, mu, or zeta variant; Optionally, the coronavirus infection is a viral infection caused by COVID-19 or a variant, alternative lineage branch, or subtype thereof, or a Middle East Respiratory Syndrome Virus (MERS-CoV) infection; Optionally, the viral infection is a virus that causes the common cold, influenza virus (optionally influenza A, B, or C), hepatitis virus, Rous sarcoma virus (RSV), Paramyxoviridae or measles virus, Paramyxovirus or mumps virus, herpes simplex virus (HSV), mumps virus (MuV), human papillomavirus (HPV), cytomegalovirus (CMV), Rubivirus or rubella virus, enterovirus, viral meningitis, vaccinia virus, rhinovirus, human 10. The pharmaceutical composition or therapeutic combination of drugs according to claim 1, or the product of claim 2, or the kit of claim 3, caused by an immunodeficiency virus (HIV), varicella zoster or chickenpox virus, orthopoxvirus or smallpox or variola virus, Epstein-Barr virus (EBV), adenovirus, hantavirus, flaviviridae or dengue virus, ebola virus, zika virus, pneumonia virus, norovirus, rotavirus, virus of the genus enterovirus or poliovirus, or chikungunya virus infection.

6. a virus, optionally of the subfamily Orthocoronavirinae, or of the families Coronaviridae, Arteriviridae, Roniviridae, and / or Mesoniviridae, or of the subfamilies Letovirinae and Orthocoronavirinae; or of the order Nidovirales, or of the genus Alphacoronavirus; avirus), betacoronavirus, gammacoronavirus, or deltacoronavirus, or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus or a variant thereof, wherein optionally the SARS-CoV-2 is an omicron variant, or one of B.1.1.529, BA.1, BA.1.1, BA.2, BA.3, BA.4, and BA.

5. 5 lineage variant; or optionally, the SARS-CoV-2 is an alpha, beta, gamma, delta, epsilon, eta, iota, kappa, mu, or zeta variant; Optionally, the coronavirus infection is a viral infection caused by COVID-19 or a variant, alternative lineage branch, or subtype thereof, or a Middle East Respiratory Syndrome Virus (MERS-CoV) infection, and optionally, the coronavirus infection is so-called "long COVID" or post-COVID condition (PCC), or post-acute sequelae of SARS CoV-2 infection (PASC); Optionally, the viral infection is a virus that causes the common cold, influenza virus (optionally influenza A, B, or C), hepatitis virus, Rous sarcoma virus (RSV), Paramyxoviridae or measles virus, Paramyxovirus or mumps virus, herpes simplex virus (HSV), cytomegalovirus (CMV), Rubivirus or rubella virus, endometrial ... caused by Enterovirus, viral meningitis, rhinovirus, human immunodeficiency virus (HIV), varicella zoster or chickenpox virus, orthopoxvirus or smallpox or variola virus, Epstein-Barr virus (EBV), adenovirus, hantavirus, flaviviridae or dengue virus, zika virus, or chikungunya virus infection, A method comprising the step of administering a pharmaceutically effective amount of the pharmaceutical composition or drug therapeutic combination of claim 1, or the product of claim 2, or the kit of claim 3 to an individual in need thereof.

7. Avermectins (optionally ivermectin) (a)(i) with or as a loading dose comprising an avermectin drug (optionally ivermectin); (1) For adults, at a dose of about 300 μg / kg to 30 mg / kg (or 30 mg per 2.2 pounds (lb)) or at a dose of about 18 mg to 1800 mg per 60 kg (about 132 lb) per day, or at a dose of 50 μg / kg, 75 μg / kg, 100 μg / kg, or 500 μg / kg, or at a dose between about 50 μg / kg and 500 μg / kg, or an avermectin drug a loading dose of (optionally ivermectin) between about 300 μg / kg to 30 mg / kg to 60 mg / kg per day, or in a 60 kg (about 132 lb) human, between about 18 mg to about 1200 mg, or 1600 mg to 1800 mg, or between about 300 μg (mcg) to about 40-70 mg / kg, or dosages of 60-120 mg to about 1600-1800 mg; or (2) For adults, a dose of between about 18 mg and 50 mg, or about 18 mg, 24 mg, 30 mg, 36 mg, or 40 mg, or between about 50 mg and 100 mg, or 60 mg and 120 mg, up to a maximum of about 1600 mg to 1800 mg. Medications or administration are given at wherein, optionally, the loading dose is administered once, daily, periodically, optionally every 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 or more days; (ii) after administration of the loading dose of (i), a maintenance dose of ivermectin of between about 20 mcg / kg (μ / kg) and 5000 mcg / kg (μ / kg), or between about 200 and 2000 mcg / kg (μ / kg) per dose (where 200 mcg / kg corresponds to a 12 mg dose for a 60 kg adult and 2000 mcg / kg corresponds to 120 mg per dose), or about 50 μg / kg, 75 μg / kg, or 100 μg / kg; wherein optionally, the maintenance dose is administered every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days, or every 3 weeks, or every month, or every 2 or more months after the initial loading dose; wherein optionally, the maintenance doses are administered every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days, every 3 weeks, or monthly for 4-8 weeks, 6-10 weeks, 8-12 weeks, 10-20 weeks, 15-30 weeks, or 20-52 weeks or more after the initial or loading dose is administered; wherein optionally, an antibiotic or antiviral is administered with a loading dose of an avermectin (optionally ivermectin); and zinc (optionally a zinc chelate, zinc salt, or zinc sulfate) is administered with a loading dose of an avermectin (optionally ivermectin); Optionally, a drug combination, optionally formulated as a single dosage form (e.g., a tablet capsule), includes ivermectin, doxycycline, and a zinc chelate, or optionally includes 12 mg ivermectin, 100 mg doxycycline, and 25 mg zinc chelate administered once or twice daily; or (b) as a drug, formulation, or therapeutic combination of drugs comprising an avermectin drug (optionally ivermectin), (i) in adults, about 300 μg / kg to 30 mg / kg (or 30 mg per 2.2 pounds (lb)), or about 18 mg to 1800 mg at 60 kg (about 132 lb), or a dosage of 50 μg / kg, 75 μg / kg, or 100 μg / kg, or a loading dose of ivermectin between about 30 μg / kg and 60 mg / kg, or in a 60 kg (about 132 lb) human, about 18 mg to about 1200 mg, or 1600 mg to 1800 mg, or about 40 to 70 mg / kg, or a dosage of 60 to 120 mg to about 1600 to 1800 mg, or 50 μg / kg, 75 μg / kg, 100 μg / kg, or 500 μg / kg, or a dosage between about 50 μg / kg and 500 μg / kg, or (ii) daily doses for adults of between about 18 and 50 mg, or about 18 mg, 24 mg, 30 mg, 36 mg, or 40 mg, or between about 50 mg and 100 mg, or 60-120 mg to about 1600-1800 mg; 7. The method of claim 6, wherein the patient is administered

8. One or more additional drugs are dosed or administered together with metformin and / or 3C-like (3CLpro) protease or ensitrevir, and the one or more additional drugs are (a) an avermectin drug (optionally ivermectin), optionally also including colchicine (optionally dosed at between about 30-80 mg per day, or between about 36-60 mg per day), clofazimine (optionally dosed at about 100 mg or 150 mg per day, or between about 50 mg and 200 mg per day), and zinc (optionally zinc sulfate, zinc acetate, zinc gluconate, or zinc picolinate, or zinc oxide nanoparticles, optionally in a dosage of between about 1 mg and 250 mg per day, or about 50 mg per day); (b) a combination of clofazimine (optionally dosed at about 100 mg or 150 mg per day, or between about 50 mg and 200 mg per day), fluvoxamine, and zinc (optionally zinc sulfate, zinc acetate, zinc gluconate, or zinc picolinate, or zinc oxide nanoparticles, optionally at a dosage of between about 1 mg and 250 mg per day, or about 50 mg per day), optionally also containing colchicine; or (c) optionally further comprising zinc (optionally zinc sulfate, zinc acetate, zinc gluconate, or zinc picolinate, or zinc oxide nanoparticles, optionally at a dosage of between about 1 mg and 250 mg per day), and optionally also comprising colchicine; hydrocortisone or cortisol (optionally Cortef™, Solcortef™), optionally hydrocortisone sodium succinate or hydrocortisone acetate, or dexamethasone (optionally Dextenza™, Ozurdex™, Neofoldex™); a combination of clofazimine (optionally dosed at about 100 mg or 150 mg per day, or between about 50 mg and 200 mg per day), fluvoxamine, and at least one vitamin, optionally administered at about 1000-4000 ugm / day; vitamin B3 (or pyridine-3-carboxylic acid, niacin, or nicotinic acid, or in a sustained release form (or NIASPAN); 8. The method of claim 6 or 7, comprising a combination comprising vitamin B3 or niacin, vitamin D (optionally D2, or ergocalciferol), or vitamin D3 or cholecalciferol administered as FCT™; vitamin B12, vitamin B6 (or pyridoxine); vitamin K; vitamin A; vitamin E; and / or vitamin C (optionally administered at 500 mg bid).

9. 10. The pharmaceutical composition or therapeutic drug combination of claim 1, or the product of claim 2, or the kit of claim 3, formulated as, administered as, or comprising a pharmaceutical preparation, or a dressing or skin patch, or an implant; 9. The method of any one of claims 6 to 8, wherein optionally the pharmaceutical composition or therapeutic combination is formulated as a gel, liquid, aerosol, spray, mist, lotion, cream, powder, tablet, capsule, pill, geltab, enema, suppository, transdermal or buccal patch, or an injectable, subcutaneous, intramuscular (IM), or intravenous (IV) formulation to produce a pharmaceutical formulation.

10. (a) administering an antibiotic or macrolide drug, optionally doxycycline or azithromycin, optionally starting with a loading dose of between about 400 mg and 500 mg and 1 g, or about 500 mg oral, IV, or IM doses, optionally daily, every 4-10 days, or every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or up to 20 or more days, at a lower dose of between about 100 gm and 300 mg, or about 250 mg total daily dose, optionally continuing for about 1 week to 1 month; (b) azithromycin (optionally Zithromax™, or Azithlosin™) is administered at a loading dose of 500 mg bid on day 1, then 500 mg in the morning (MANE) on days 2, 3, and 4, after which azithromycin is discontinued and replaced with doxycycline (optionally Doryx™, Doxyhex™, Doxylin™) 100 mg bid for the remainder of the treatment period (10 or 11 days); or (c) The method of any one of claims 6-9, wherein azithromycin (optionally Zithromax™, or Azithlosin™) is administered initially at a loading dose of 500 mg bid on day 1, then 500 mg in the morning (MANE) on days 2, 3, and 4, after which azithromycin is discontinued and doxycycline 100 mg bid (or between about 25-500 mg bid) (optionally Dorix™, Doxyhex™, Doxylin™) is administered daily for the entire duration of treatment (10 or 11 days or more).

11. 11. The method of any one of claims 6 to 10, wherein the administration of the pharmaceutical composition or drug therapeutic combination of claim 1, or the product of claim 2, or the kit of claim 3, or treatment lasts for about 10 days to 3 weeks, or 11 days to 2 weeks, or about 10, 11, 12, 13, or 14 days, or about 1 month to 1 year.

12. 11. The method of any one of claims 6 to 10, wherein zinc, optionally zinc sulfate or a zinc chelate, is administered at a dosage of 100 mg MANE or between about 50 mg and 150 mg per day of treatment or administration.

13. 1. A transdermal device manufactured to contain or have a plurality or multiple drug-containing or drug-storage compartments (or cells or wells), each compartment having a sealed or adjacent wall such that when a drug formulation (optionally a liquid, liposomal, gel, or hydrogel drug formulation) is placed into one of the plurality or multiple drug-containing or drug-storage compartments or cells or wells, the liquid or gel drug formulation is contained within that compartment, the compartments being open on one side to a removable (and optionally flexible) release liner that can be removed by a user, and an adhesive (optionally comprising an acrylate polymer or a pressure-sensitive adhesive (PSA)) affixed to the flexible, removable release liner on the same side of the transdermal device as the open side of the compartments or cells or wells (or the side covered by the release liner) to affix the transdermal device to a skin surface, the adhesive remaining covered until the removable release liner is removed.

14. 14. The transdermal device of claim 13, wherein the transdermal device has 2 to 10 separate or individual drug-containing or drug-storage cells or compartments, optionally each of the multiple compartments (or cells or wells) having a storage volume of between about 5 μl and 1000 μl (or 1 ml), or between about 20 μl and 500 μl, or between about 50 μl and 5 ml.

15. 14. The transdermal device of claim 13, further comprising a pressure cuff, wherein the transdermal device is placed, affixed, glued, or sutured onto a cuff or band designed or manufactured to be worn around the arm (or upper arm or forearm) or leg, the cuff or band optionally designed or manufactured to allow a user to fasten the cuff or band around the arm or leg by use of hook-and-loop fasteners (straight strips of fabric with small hooks that can interlock with another strip of fabric with small loops, temporarily attaching until pulled apart) (or Velcro™), or the cuff or band is designed or manufactured to fasten around the arm or leg by inflation (like a blood pressure monitor or blood pressure cuff), the cuff or band being wrapped around the arm or upper arm and inflated, and optionally the cuff or band being manufactured or designed as described in U.S. Pat. No. 10,398,325.

16. 15. The transdermal device of claim 13 or 14, comprising three separate or individual drug-containing or drug-storage cells or compartments.

17. 17. The transdermal device of claim 16, wherein a first compartment contains an avermectin drug (optionally ivermectin), a second compartment contains an antibiotic (optionally doxycycline or azithromycin), and a third compartment contains zinc (optionally a zinc chelate, e.g., zinc sulfate, zinc acetate, zinc gluconate, or zinc picolinate, or zinc oxide nanoparticles).

18. 18. The transdermal device of claim 16 or 17, wherein the first compartment comprises ivermectin, the second compartment comprises doxycycline, and the third compartment comprises a zinc chelate.

19. 19. The transdermal device of claim 17 or 18, wherein the first compartment contains 48 mg of ivermectin, the second compartment contains 300 mg of doxycycline, and the third compartment contains 50 mg of zinc chelate.

20. 20. A method for treating, preventing, or ameliorating (optionally reducing symptoms or reducing mortality) a coronavirus infection caused by COVID-19, or a variant, alternative lineage branch, or subtype thereof, comprising administering to an individual in need thereof the transdermal device of any one of claims 13 to 19.

21. 20. Use of the transdermal device of any one of claims 13 to 19 for the manufacture of a medicament for preventing or ameliorating (optionally reducing symptoms or reducing mortality) a coronavirus infection caused by COVID-19, or a variant, alternative lineage branch, or subtype thereof.

22. 20. The transdermal device of any one of claims 13 to 19 for use in treating, preventing or ameliorating (optionally reducing symptoms or reducing mortality) a coronavirus infection caused by COVID-19, or a variant, alternative lineage branch, or subtype thereof.

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