WO2022049414A1

WO2022049414A1 - Nitazoxanide for use to treat covid-19

Info

Publication number: WO2022049414A1
Application number: PCT/IB2020/058317
Authority: WO
Inventors: Octavio Alejandro ENRÍQUEZ LARA; Antonio RODRÍGUEZ BAZÁN
Original assignee: Siegfried Rhein, S.A. De C.V.
Priority date: 2020-09-07
Filing date: 2020-09-07
Publication date: 2022-03-10
Also published as: MX2023002773A; MX2021008353A

Abstract

The present description relates to the use of nitazoxanide, alone or in combination with an anti-inflammatory agent and/or an additional active agent, to treat coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Description

NITAZOXANIDE FOR USE IN THE TREATMENT OF COVID-19

FIELD OF THE INVENTION

The present invention relates to nitazoxanide alone or in combination with an anti-inflammatory agent and/or an additional active agent for use in the treatment of coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 ( SARS-CoV-2).

BACKGROUND OF THE INVENTION

Coronaviruses (CoVs) are positive-sense, single-stranded RNA viruses of the Coronaviridae family (Coronavirinaé subfamily) that infect a wide range of hosts to cause illnesses ranging from the common cold to severe illness. In late December 2019, a group of patients were admitted to hospitals with an initial diagnosis of pneumonia of unknown aetiology. These patients were epidemiologically linked to a seafood market in Wuhan, Hubei province, China. The new virus was initially named “2019-nCoV” and was later changed to “SARS-CoV-2” by the International Committee on Taxonomy of Viruses (ICTV) Coronavirus Study Group (Dhama K, Sharun K, Tiwari R, Dadar M, Malik YS, Singh KP, et al.COVID-19, an emerging coronavirus infection: advances and prospects in designing and developing vaccines, immunotherapeutics, and therapeutics.Hum Vaccines Immunother., 2020; 1-7; Rothan HA, Byrareddy SN. The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak. J Autoimmun. 2020;102433; Bogoch, Watts A., Thomas-Bachli A., Huber C., Kraemer MUG, Khan K. Pneumonia of unknown etiology in Wuhan, China: potential for international spread via commercial air travel. J. Trav. Med. 2020).

The first step in infection by CoVs is the interaction of host cells with the Spike (S) glycoprotein of the viral envelope. SARS-CoV-2 employs two routes for host cell entry, which depend on the location of proteases required for S-protein activation. The binding of SARS-CoV-2 to the cellular receptor, the angiotensin 2 (ACE2), can cause uptake of virions into endosomes, where protein S is activated by the pH-dependent cysteine protease cathepsin B and L (cathepsin B/L). Alternatively, protein S can be activated by the serine protease TMPRSS2, which results in fusion of the viral membrane with the plasma membrane. Viral fusion and release of genetic components is highly dependent on the endosomal pathway and particularly on pH. After the viral infection has spread in the body and due to the incredibly high viral loads, the non-specific endosomal pathway is primarily used for further virus replication. (Markus D, Gottfried L, Markus M, Marina R, Dario B, Danielle de V. A SARS-CoV-2 Prophylactic and Treatment; A Counter Argument Against The Sole Use of Chloroquine. 2020 - 8(4). Posted 9 April 2020).

With the global spread of SARS-CoV-2 infection, it is increasingly urgent to develop a vaccine to prevent COVID-19, as well as effective drugs to treat it. Most of the therapeutic options that are available to manage COVID-19 are based on previous experiences in the treatment of SARS- and MERS-CoV.

Possible candidates for the prevention and treatment of coronavirus infection are peptides or low molecular weight chemical compounds that block the membrane-associated enzyme ACE2, or alternatively TMPRSS2 inhibitors, such as for example camostat mesylate, nafamostat mesylate , ambroxol and bromhexine. Treatment with virustatics, such as oseltamivir, darunavir, and umifenovir, is also under investigation; protease inhibitors such as lopinavir have been used in conjunction with low dose ritonavir; as well as remdesivir, a nucleoside analog. The action of different substances against SARS-CoV-2 in vitro has been reported, for example remdesivir has an EC ₅ o = 0.77 pM, chloroquine has an EC ₅ o = 1.1 pM, nitazoxanide has an EC ₅ o = 2.1 pM, nafamostat has an EC ₅ o = 22 pM, favipiravir an EC ₅ o = 62 pM, penciclovir has an EC ₅ o = 96 pM, and ribavirin an EC ₅ o = 109 pM (Ralf Stahlmann, Hartmut Lode Medication for COVID-19 — an Overview of Approaches Currently Under Study Dtsch Arztebl Int 2020;117:213-9).

Nitazoxanide (2-[(5-nitro-1,3-thiazol-2-yl)carbamoyl]phenyl ethanoate or also known as 2-(5-nitrothiazol-2-ylcarbamoyl)phenyl acetate) is an anti-infective thiazolide used originally to treat intestinal infections. Treatment of systemic infections in animal models and in humans has been challenging due to the very low solubility of the drug and its short elimination half-life. Following oral administration, the active pharmaceutical ingredient nitazoxanide is absorbed from the intestinal tract and rapidly hydrolyzed by plasma esterases to form tizoxanide, its active circulating metabolite, which is then conjugated by glucuronidation in the liver. The drug is eliminated in the urine and bile as tizoxanide and tizoxanide glucuronide. The half-life of tizoxanide in plasma is only about 1.3 hours. More than 99.9% of circulating tizoxanide is bound to plasma proteins.

Nitazoxanide and its active metabolite tizoxanide (2-hydroxy-A/-(5-nitrothiazol-2-yl)benzamide) have the following chemical structures:

Tizoxanide

Nitazoxanide and its active metabolite, thiazoxanide, have a broad spectrum of antiviral activity against DNA and RNA viruses, good pharmacokinetic properties, and a very favorable safety profile (M. Krátky and J. Vinsová. Antiviral Activity of Substituted Salicylanilides - A Review. Mini-Reviews in Medicinal Chemistry, 2011, 11, 956-967). Nitazoxanide is an immunomodulator that interferes with host-regulated pathways involved in viral replication, amplifying cytoplasmic RNA sensing and type I IFN pathways (Serap §¡M§EK YAVUZ1 , Serhat ÜNAL. Antiviral treatment of COVID- 19. Turkish Journal of Medical Sciences (2020) 50: 611-619. Published April 15, 2020; Jean-Franpois Rossignol. Nitazoxanide: A first-in-class broad-spectrum antiviral agent. Antiviral Research 110 (2014) 94-103. Published August 7, 2014).

The inhibition of the activity of the serine protease TMPRSS2 has been described as a potential therapeutic target for antiviral treatment for COVID-19, based on the fact that the entry of the SARS-CoV-2 virus into the host cell depends on the activation of the protein S of the viral envelope by the serine protease TMPRSS2. Virus entry into cells has been shown to be reduced by camostat mesylate, a non-selective inhibitor of TMPRSS2. Bromhexine, a licensed mucolytic cough suppressant drug, has been identified as a selective inhibitor of TMPRSS. Available data further suggest that ambroxol, a metabolite of bromhexine, is a potent inducer of surfactant synthesis in AT2 cells. Due to these lung-protective properties, bromhexine, in addition to direct antiviral effects, could also provide indirect protective effects. Bromhexine has been reported to have no significant in vitro cell entry or replication inhibition effect on influenza viruses. However, influenza viruses have also been shown to use, unlike SARS-CoV-2, a host extracellular protease other than TMPRSS2 for priming.

To date, no treatment against COVID-19 has proven to be effective, so there is still a need to find a drug for the treatment of a SARS-CoV-2 infection, which helps raise oxygen saturation to normal levels, because this is a parameter that helps to evaluate respiratory function and activity, including hypoxia, that is, that some patients develop dangerously low blood oxygenation, reaching in some critical cases up to 50 percent.

BRIEF DESCRIPTION OF THE INVENTION

The present invention is based on the finding that nitazoxanide or tizoxanide, alone or together with an anti-inflammatory agent and/or an additional active agent, allow the oxygenation level to be raised to normal levels of 90 percent or more in oxygen saturation, therefore the use of nitazoxanide or tizoxanide alone or together with an anti-inflammatory agent and/or an additional active agent according to the present invention is useful in the treatment of COVID-19 caused by SARS-CoV-2.

A further aspect of the invention provides the use of an effective amount of nitazoxanide or tizoxanide alone or in combination with an effective amount of an anti-inflammatory agent and/or an effective amount of a further active agent according to the present invention in the manufacture of a medicine for the treatment of COVID-19 caused by SARS-CoV-2.

Another aspect of the invention provides a method of treating a disease, disorder, or condition in a subject, comprising administering to the subject an effective amount of nitazoxanide or tizoxanide alone or in combination with an anti-inflammatory agent and/or an effective amount of an active agent. further according to the present invention, wherein the disease, disorder or condition is selected from COVID-19.

A further aspect of the invention provides the use of an effective amount of nitazoxanide or tizoxanide alone or in combination with an effective amount of a TMPRSS2 serine protease inhibitor agent in the manufacture of a medicament for the treatment of COVID-19 caused by SARS-CoV-2.

Another aspect of the invention provides a method of treating a disease, disorder, or condition in a subject, comprising administering to the subject an effective amount of nitazoxanide or tizoxanide alone or in combination with an effective amount of a TMPRSS2 serine protease inhibitor, wherein the disease, disorder or condition is selected from COVID-19.

DETAILED DESCRIPTION OF THE INVENTION

In a first aspect, the present invention relates to nitazoxanide or tizoxanide for use in the treatment of COVID-19, an infection caused by SARS-CoV-2.

Single-dose plasma concentrations of tizoxanide are proportional to dose, but higher exposures are observed with single-dose administration with food at doses of 1,000 mg, 2,000 mg, 3,000 mg, and 4,000 mg. For example, at a 1000 mg dose, the maximum concentration ( _Cmax ) is approximately 12,300 ng/mL in the fasted state, while the Cmax is approximately _15,900 ng/mL with food. The pharmacokinetics of tizoxanide have also been evaluated for 7 days after oral administration at 500 mg and 1000 mg twice daily with food.

Pharmacokinetics are not influenced by repeated dosing at 500 mg twice daily (C _max 10,400 ng/mL after a single dose compared to 12,200 ng/mL on day 7) but are markedly increased after administration of repeated doses at 1000 mg twice daily (C _max 16,800 ng/mL after a single dose vs. 26,400 ng/mL on day 7). All reported C _max values for tizoxanide exceed the reported in vitro EC ₅ of nitazoxanide for SARS-CoV-2 [651 ng/mL (2.1 pM)]. The concentration of nitazoxanide has also been specifically predicted to exceed its EC ₅ o for SARS-CoV-2 by 3.1-fold in the lung. This EC ₅ value was reported for nitazoxanide, but previous studies have shown similar activity for its human metabolite, tizoxanide, against various strains of influenza.

According to the above, the effective amount of nitazoxanide according to the present invention includes single doses of 1000 mg, 2000 mg, 3000 mg and 4000 mg orally; oral doses of 500 mg and 1000 mg two, three, or four times a day, with or without food. Doses of 500 mg every 12 hours for 3 to 21 days, 500 mg every 8 hours for 7 days, 500 mg every 6 hours for 7 days, or 500 mg every 6 hours for 2 days, then 500 mg every 6 hours for 7 days are preferred. mg every 8 hours without suspension until further assessment. Preferably, a dose of 500 mg every 12 hours for 5 to 21 days, more particularly for 5 to 14 days and even more particularly for 5 to 7 days.

Nitazoxanide can also be administered in patients aged 1 to 3 years at a dose of 100 mg every 12 hours, in patients aged 4 to 11 years at a dose of 200 mg, and in patients older than 12 years at a dose of 500 mg every 12 hours. , for 3 days up to 7 days of treatment. In children under 12 years of age, it is recommended to use the oral suspension.

Nitazoxanide has been shown to have a favorable overall safety profile, with no significant differences in the occurrence of total adverse events, serious adverse events, or gastrointestinal events compared to other antimicrobial regimens or placebo control. Additional evidence is required regarding specific hepatorenal and cardiovascular effects, as well as the potential for teratogenicity, but the existing evidence does not provide particular cause for concern. However, caution and careful monitoring have been recommended in patients with hepatic impairment.

In a second aspect, the present invention relates to nitazoxanide or tizoxanide together with an anti-inflammatory agent and/or an additional active agent for use in the treatment of COVID-19, an infection caused by SARS-CoV-2.

The anti-inflammatory agents of the present invention may be selected from both steroidal anti-inflammatory agents and non-steroidal anti-inflammatory agents.

Within the steroidal anti-inflammatory drugs, for the present invention, natural corticosteroids are included, such as the hormones produced by the adrenal cortex, or semi-synthetic ones. Nonsteroidal anti-inflammatory drugs (NSAIDs) can be selected from the group consisting of: salicylates, paraaminophenols, pyrazolones, indoles, arylacetic or phenylacetic, pyrrolacetic, pyranoacetic, fenamate or arylanthranilic, propionic acid derivatives, oxicames, nicotinic acid derivatives, naphthylalkone derivatives , derivatives of heterocyclic acids, derivatives of sulfonanilides, derivatives of benzoxazocines, including NSAIDs that act to a greater or lesser extent on different enzymes involved in the biochemical mechanisms for the production of substances such as prostaglandins from arachidonic acid; non-selective inhibitors and selective inhibitors of cyclooxygenase 2 (or COX-2) or others such as clomethacin.

According to the present invention, salicylates may be selected from the group including acetylsalicylic acid, salicylic acid, Usina acetylsalicylate, diflunisal, sulfazalazine or salicylazosulfapyridine, sodium salicylate and salicylamide; para-aminophenols can be selected from the group including acetaminophen or paracetamol; pyrazolones can be selected from the group including dipyrone, oxyphenbutazone, gamma-ketophenylbutazone, pyrazinobutazone, or feprazone or prenazone, clofenazone, bumadizone, suxibuzone, and azapropazone; indoles can be selected from indomethacin, benzydamine, sulindac, acemetacin, proglumetacin, and talmethacin; arylcetics can be selected from diclofenac sodium, diclofenac potassium, aceclofenac, alclofenac, methiazinic acid, fenclofenac and fentiazac; pyrrolacetics can be selected from the group including ketorolac and tolmetin; pyranoacetics include etodolac; the fenamates or arylanthranilics can be selected from the group including mefenamic, flufenamic, niflumic, aluminum flufenamate, talniflumate, floctafenin, glafenin, meclofenamate, tolfenamic acid, meclofenamic and tolfenamic acid; the propionic acid derivatives may be selected from the group including ibuprofen, ketoprofen, naproxen, indoprofen, procetofen, fenbufen, pyroprofen, suprofen, flurbiprofen, fenoprofen lysine phenylpropionate and tiaprofenic acid; oxicams can be selected from the group including piroxicam, tenoxicam, sudoxicam, isoxicam, and meloxicam; nicotinic acid derivatives may be selected from the group including lysine and isonixin clonixinate; Naphthylalkanone derivatives include nabumetone; heterocyclic acid derivatives include oxaprozin; sulfonanilide derivatives include nimesulide; benzoxazocine derivatives include nefopam.

Paracetamol is an analgesic and antipyretic drug that is used in adult doses of 325 mg to 1000 mg every four hours, up to a maximum of 4 grams per day. In the present invention, he prefers a dose of 500 mg every 8 hours for 5 days. In children under 12 years of age, the dose can be between 40 mg to 480 mg every 4 to 6 hours, depending on the age of the patient.

The steroidal anti-inflammatory drugs according to the present invention preferably include the group of glucocorticoids, which can be administered orally, intravenously, intramuscularly, intrasynovially, intraarticularly or intralesionally. This group includes betamethasone, cortisol (hydrocortisone), cortisone, prednisone, prednisolone, methylprednisone, dexamethasone (and its derivatives, dexamethasone sodium phosphate and dexamethasone acetate), triamcinolone, beclomethasone, and fluticasone.

At present, betamethasone, methylprednisolone or dexamethasone, also including their pharmaceutically acceptable esters, are preferred as steroidal anti-inflammatories. Pharmaceutically acceptable esters of betamethasone include betamethasone phosphate, betamethasone sodium phosphate, betamethasone valerate, betamethasone divalerate, betamethasone dipropionate, betamethasone acetate, betamethasone acibutate, betamethasone adamantoate, betamethasone succinate, betamethasone valeroacetate, benzoate of betamethasone, betamethasone salicylate or a mixture thereof, with a mixture of betamethasone dipropionate and betamethasone sodium phosphate being preferred. Pharmaceutically acceptable esters of methylprednisolone include methylprednisolone aceponate, methylprednisolone acetate, methylprednisolone cyclopentylpropionate, methylprednisolone phosphate, methylprednisolone succinate, methylprednisolone sodium suctionate, or methylprednisolone suleptanate, and combinations thereof. Pharmaceutically acceptable esters of dexamethasone include dexamethasone acefurate, dexamethasone acetate, dexamethasone cipecylate, dexamethasone diethylaminoacetate, dexamethasone dipropionate, dexamethasone isonicotinate, dexamethasone linoleate, dexamethasone metasulfobenzoate, dexamethasone palmitate, dexamethasone phosphate, dexamethasone pivalitate dexamethasone, dexamethasone sodium phosphate, dexamethasone sodium sulfate, dexamethasone suctionate, dexamethasone sulfate, dexamethasone terbutate, dexamethasone troxundate, dexamethasone valerate, or a mixture thereof.

In a preferred embodiment, the present invention also relates to nitazoxanide or tizoxanide together with one or more anti-inflammatory agents for use in the treatment of an infection caused by SARS-CoV-2 or COVID-19, wherein the anti-inflammatory agent is selected from methylprednisolone or an acceptable ester thereof.

The dosage and frequency of administration of methylprednisolone vary according to the severity of the condition and the therapeutic response of the patient. Methylprednisolone can be administered parenterally, as an intravenous (IV) or intramuscular (IM) injection, with the intravenous route being preferred in emergency situations. The parenteral dose is 10 to 250 mg IM or IV every 4 hours (adults) and 0.03 to 0.2 mg/kg or 1 to 6.25 mg/m ² IM or IV over 24 hours in divided doses (children). The suggested dose for patients in shock is 100 to 250 mg IV at intervals of 2 to 6 hours (adults); and from 0.03 to 0.2 mg/kg or 1 to 6.25 mg/m ² IM or IV for 24 hours in divided doses (children). The oral dose in adults is 2 to 60 mg per day divided every 6 to 24 hours and in children 0.5 to 1.7 mg/kg/day, in divided doses every 6 to 12 hours. For the maintenance dose, it is necessary to adjust or maintain the initial dose until a satisfactory response is obtained; then gradually in small decrements at appropriate intervals taper to the lowest dose that maintains an adequate clinical response.

Methylprednisolone can also be given at doses of 1.6 to 3.2 mg/kg/day IV in divided doses for 7 to 14 days. Alternatively, a reduced dose (2 mg/kg/day on days 1 to 14; 1 mg/kg/day on days 15 to 21; 0.5 mg/kg/day on days 22 to 28; 0.25 mg/kg /day on days 29 to 30; 0.125 mg/kg/day on days 31 to 32). Start IV, given in 4 divided doses, and oral doses are given as a single daily dose. Alternatively, doses of 1 mg/kg IV every 8 hours for 5 days, followed by 1 mg/kg IV every 12 hours for 5 days, and followed by prednisolone to complete a 21-day corticosteroid regimen can be used.

Fluticasone is also a preferred synthetic corticosteroid in the present invention which is administered at doses of 50 pg, 125 pg, or 250 pg fluticasone (as propionate), equivalent to a delivered dose of 44 pg, 110 pg, or 220 pg fluticasone propionate. fluticasone, two or three times a day.

Deflazacort is a preferred glucocorticoid in the present invention which at 6 mg is equivalent in anti-inflammatory activity to about 5 mg of prednisolone. It is administered orally at an initial dose of up to 120 mg/day, the maintenance dose is 3 to 18 mg/day. In children, doses of 0.25 to 1.5 mg/kg/day have been used. In the present invention, a dose of 6 mg every hour for 5 days is preferred.

The present invention also relates to nitazoxanide or tizoxanide together with one or more anti-inflammatory agents for use in treating an infection caused by SARS-CoV-2 or COVID-19, wherein the anti-inflammatory agent is selected from betamethasone or a salt or derivative thereof, preferably selected from a mixture of betamethasone dipropionate and betamethasone sodium phosphate.

The dosage and frequency of administration of betamethasone depend on the severity of the condition and the therapeutic response of the patient. The initial dose of betamethasone for adults can reach up to 8 mg of betamethasone per day, depending on the specific disease being treated, particularly it may be necessary to administer a dose of 4 to 8 mg of betamethasone, intramuscularly, intravenously or intramuscularly. in soft tissues. In particular, betamethasone can be administered at a dose of 4 to 8 mg, intramuscularly every 12 hours, for 24 to 48 hours (2 to 4 doses). The pediatric dose ranges from 0.02 to 0.125 mg per kg of body weight per day.

The usual initial pediatric intramuscular dose ranges from 0.02 to 0.125 mg per kg of body weight per day. In infants, the same doses and considerations should be observed as in the case of adults, with the same proportions indicated by age or body weight. Although betamethasone can be administered by various routes, in emergency situations it is recommended to resort to the intravenous route. Betamethasone can also be given by intravenous drip, together with isotonic saline or dextrose solution in the desired amount of solution. In these cases, betamethasone should be added to the solution at the time of administration. When a favorable clinical response is observed, the appropriate maintenance dose should be determined by reducing the initial dose by small amounts at appropriate intervals until the lowest effective dose is reached. The patient's exposure to stressful situations unrelated to the disease being treated may necessitate an increase in the dose of Betamethasone. If the drug is discontinued after prolonged treatment, the dose should be gradually reduced.

The anti-inflammatory agent according to this embodiment is preferably selected from a mixture of betamethasone dipropionate and betamethasone sodium phosphate, where betamethasone dipropionate is in an amount equivalent to 5.0 mg of betamethasone and betamethasone sodium phosphate is in an amount equivalent to 2.0 mg of betamethasone. Furthermore, the anti-inflammatory agent according to this embodiment may be selected from betamethasone sodium phosphate, in an amount equivalent to 4.0 mg of betamethasone. In one embodiment the invention consists of nitazoxanide or tizoxanide, betamethasone or methylprednisone and an additional active agent, for use in the treatment of COVID-19, an infection caused by SARS-CoV-2.

According to this modality, nitazoxanide is in an amount of 500 mg and betamethasone is in an amount of 4.0 mg, preferably nitazoxanide is administered every 12 hours for 3 to 7 days, every 8 hours for 7 days, every 6 hours for 7 days, or every 6 hours for 2 days and then 500 mg every 8 hours for 5 days.

The additional active agent is selected from the group consisting of: antibiotics, antitussives, expectorants, mucolytics, anticholinergics, p2-adrenergic agonists, nonselective competitive phosphodiesterase inhibitors, antacids, antiflatulents, demulcents, antihistamines, and antivirals.

Preferred antibiotics in the present invention are selected from the group that includes: clarithromycin, levofloxacin, cefaxone, azithromycin and cefixime, their pharmaceutically acceptable salts and combinations of these.

In a preferred embodiment, the additional active agent is clarithromycin. Clarithromycin is an antibiotic of the macrolide group that is used at a dose in the range of 250 mg to 500 mg every 12 to 24 hours, orally with or without food for 6 to 14 days, the dose can be doubled. Preferably, clarithromycin is used at a dose of 500 mg every 12 hours for 10 days. It is well absorbed from the gastrointestinal tract, regardless of the presence of food, so it can be administered without gastric protectors, it has a bioavailability of 50% and produces an active metabolite which maintains a peak 3 hours after administration. Its long half-life is due to the production of its active metabolite, which allows dosing twice a day and is extensively metabolized in the liver by cytochrome P450, and its excretion is renal.

Levofloxacin is a broad-spectrum antibiotic from the group of fluoroquinolones. It is used at a dose of 500 mg to 750 mg once a day for 5 to 14 days. Preferably, in the present invention it is used in an oral dose of 750 mg every 24 hours for 7 days. Cefaxone is a long-acting bactericidal antibiotic for parenteral use with broad spectrum, which is used as ceftriaxone disodium hemiheptahydrate or ceftriaxone sodium can be used at a dose equivalent to ceftriaxone 500 mg or 1000 mg. In adults, the daily dose is 1 to 2 g per day (or divided into two doses per day), not to exceed 4 g. In children, the dose is 50 to 75 mg/kg of weight per day (or divided into two doses per day) without exceeding 2 g per day. In the present invention, the dose of 1 g every 24 hours for 6 days is preferred.

Azithromycin is a broad-spectrum macrolide antibiotic used at a dose of 500 mg azithromycin once daily for 3 consecutive days, the total dose being 1,500 mg azithromycin, or 1,000 mg orally. as a single dose. In the present invention, the dose of 500 mg every 24 hours for 6 days is preferred.

Cefixime is an antibiotic of the third-generation cephalosporin family that is administered in doses of 400 mg daily, as a single dose or two divided doses for 5 to 7 days.

The preferred antitussives in the present invention are selected from the group that includes: dropropizine, levodropropizine and hedera helix, their pharmaceutically acceptable salts and combinations of these.

Preferred expectorants and mucolytics in the present invention are selected from the group including: bromhexine and ambroxol, their pharmaceutically acceptable salts, and combinations thereof.

Dropropizine and levodropropizine are antitussives that can be administered together with bromhexine or bromhexine hydrochloride or ambroxol. The preferred dose of dropropizine is 15 mg and the preferred dose of bromhexine is 8 mg, both every 8 hours for 6 days.

Ambroxol an expectorant and mucolytic used as ambroxol hydrochloride, in solution or tablets, at doses of 60 to 180 mg per day, in three divided doses. In children, the suggested doses are from 2 to 5 years: 15 to 30 mg/day; 5 to 12 years old: 30 to 45 mg/day; 12 years and older: 60 to 90 mg/day. In the present invention, the dose of 7.5 mg every 8 hours is preferred.

Hederá helix is used in the form of syrup as a mucolytic, spasmodic and antitussive that contains 0.7 ml of dried ivy leaf extract solution per 100 ml. doses are used in adults from 5 ml to 7.5 ml 3 times a day, and in children under 5 years of age, 2.5 ml 2 to 3 times a day.

Acetylcysteine is a mucolytic drug at a dose of 600 mg per day, orally, in a single daily dose or divided into 3 daily doses.

Preferred anticholinergics in the present invention may be short-acting or long-acting. Short-acting anticholinergics are preferably selected from the group including: ipratropium or its pharmaceutically acceptable salts, such as ipratropium bromide; long-acting anticholinergics are selected from the group that includes: tiotropium, umeclidinium, aclidinium or their pharmaceutically acceptable salts, such as for example tiotropium bromide.

Ipratropium or ipratropium bromide is a derivative of atropine that is administered by the inhalation route as a bronchodilator, which is used at a dose of 2 aerosol inhalations with 0.018 mg of ipratropium or 0.020 mg of ipratropium bromide 3 to 4 times a day. , with the maximum dose in adults being 0.216 mg (equivalent to 12 inhalations) in 24 hours. It is also possible to use it in solution for nebulization, the dose in adults being 0.5 mg 3 or 4 times a day through a nebulizer. Doses should be spaced 6 to 8 hours apart.

The p2-adrenergic agonists in the present invention may be short-acting p2-adrenergic agonists, long-acting p2-adrenergic agonists, ultra-long-acting p2-adrenergic agonists, and p2-adrenergic agonists with unknown duration of action, and combinations thereof.

Short-acting p2-adrenergic agonists can be selected from the group consisting of: bitolterol, fenoterol, isoprenaline, levosalbutamol, orciprenaline, pirbuterol, procaterol, ritodrine, salbutamol, terbutaline and albuterol, or their pharmaceutically acceptable salts. Salbutamol is preferred in the present invention.

Salbutamol or albuterol is a short-acting p2-adrenergic agonist that can be administered by inhalation to produce a direct effect on the smooth muscle of the bronchi, but can also be used in syrup or suspension form. The dose in adults is 2 to 4 mg, 3 or 4 times a day, which can be gradually increased to 8 mg.

Long-term p2 adrenergic agonists can be selected from the group that consists of: arformoterol, bambuterol, clenbuterol, formoterol and salmeterol, or their pharmaceutically acceptable salts. Salmeterol is preferred in the present invention.

Salmeterol may be co-administered with fluticasone or fluticasone propionate, a corticosteroid. It is administered in adult doses of two inhalations of 25 pg salmeterol (as xinafoate) and 50 pg, 125 pg, or 250 pg fluticasone (as propionate), equivalent to a delivered dose of 21 pg salmeterol and 44 pg, 110 pg or 220 pg of fluticasone propionate, two or three times a day.

The preferred nonselective competitive inhibitor of phosphodiesterase in the present invention is theophylline. In intravenous doses, 10 pg/ml to 20 pg/ml are used, although levels of 5-10 pg/ml can be effective in some patients. When formulated as a syrup, the dose can be individualized according to the needs of the patient, 7 mg/kg/day divided into 3 doses. The dose can be adjusted by measuring the concentrations of serum theophylline (5-15 pg/mL), the increase in the dose is taking into account that 1 mg/kg of theophylline increases approximately 2 pg/mL of serum concentration. In the present invention, low doses of anhydrous theophylline of 35 mg every 8 hours for 10 days are preferred.

In the present invention, aluminum hydroxide, magnesium hydroxide and simethicone are used as preferred antacids, antiflatulents and demulcents. Doses range from 400 mg to 800 mg of magnesium hydroxide, 306 mg to 612 mg of aluminum hydroxide, and 30 mg to 60 mg of simethicone, between meals and at bedtime. In the present invention, the dose of 600 mg of magnesium hydroxide, 459 mg of aluminum hydroxide and between 45 mg of simethicone is preferred.

The preferred antihistamine in the present invention is loratadine, a second generation antihistamine used at a dose of 10 mg once daily and at a weight dose of 0.2 mg/kg/day.

The additional active agent according to this aspect of the invention may be selected from the combination of clarithromycin, fluticasone and salmeterol, wherein the dose of clarithromycin is 500 mg every 12 hours for 10 days, the dose of fluticasone is 2 inhalations of 50 pg, 125 pg or 250 pg every 8 hours and the dose of salmeterol is 2 inhalations of 25 pg every 8 hours.

The additional active agent can also be selected from the combination of clarithromycin, dropropizine and bromhexine, where the dose of clarithromycin is 500 mg every 12 hours for 10 days, the dose of dropropizine is 15 mg every 8 hours for 6 days and the dose of bromhexine is 8 mg every 8 hours for 6 days.

In another embodiment, the additional active agent is the combination of ipratropium, dropropizine and bromehexine, where the dose of ipratropium is 2 aerosol inhalations with 0.018 mg ipratropium or 0.020 mg ipratropium bromide 3 to 4 times a day, the dropropizine dose is 15 mg every 8 hours for 6 days and bromhexine dose is 8 mg every 8 hours for 6 days.

In a further embodiment, the additional active agent can be selected from the combination of levofloxacin, dropropizine and bromhexine, where the dose of levofloxacin is 750 mg every 24 hours for 7 days, the dose of dropropizine is 15 mg every 8 hours for 6 days and the dose of bromhexine is 8 mg every 8 hours for 6 days.

Also, the present invention relates to nitazoxanide or tizoxanide, betamethasone and an additional active agent, for use in the treatment of COVID-19, an infection caused by SARS-CoV-2, wherein the additional active agent is selected from the combination of cefaxone, dropropizine and bromhexine, where the dose of cefaxone is 1 g every 24 hours for 6 days, the dose of dropropizine is 15 mg every 8 hours for 6 days and the dose of bromhexine is 8 mg every 8 hours for 6 days, and where deflazacort and paracetamol are included as additional anti-inflammatories, in a dose of deflazacort of 6 mg every 8 hours for 5 days and in a dose of paracetamol of 500 mg every 8 hours for 5 days.

The additional active agent may be selected from an antiviral which is selected from the group including camostat, chloroquine, hydroxychloroquine, oseltamivir, darunavir, umifenovir, lopinavir/ritonavir, remdesivir, nafamostat, favipiravir, penciclovir and ribavirin.

In another aspect, the present invention relates to nitazoxanide or tizoxanide and a further active agent, for use in the treatment of COVID-19, an infection caused by SARS-CoV-2.

According to this aspect of the invention, the additional active agent is selected from the group consisting of: antibiotics, antitussives, expectorants, mucolytics, and TMPRSS2 serine protease inhibitors.

In accordance with this aspect of the invention, the additional active agent is selected preferably from the group consisting of TMPRSS2 serine protease inhibitors.

In a preferred embodiment, the dose of nitazoxanide is 500 mg every 12 hours and the additional active agent may be selected from the combination of camostat mesylate, nafamostat mesylate, ambroxol and bromhexine.

In a preferred embodiment, the dose of nitazoxanide is 500 mg every 12 hours for 6 days and the additional active agent can be selected from the combination of levofloxacin, dropropizine, ambroxol and bromhexine, where the dose of levofloxazin is 750 mg every 24 hours. hours for 7 days, the dropropizine dose is 15 mg every 8 hours for 6 days, the ambroxol dose is up to 40 mg daily, and the bromhexine dose is 8 mg every 8 hours for 6 days.

In the present invention, bromhexine is also used as a prophylactic and for the treatment of disease caused by SARS-CoV2 virus infection, since bromhexine at an effective dose to selectively inhibit the TMPRSS2 receptor inhibits specific viral entry via TMPRSS2 and , therefore, it is effective against SARS-CoV-2.

According to the above, a combination of bromhexine with nitazoxanide, which is (among other functions) a broad-spectrum antiviral drug, is a favorable combination for prophylactic use, as well as for the treatment of mild, moderate and severe cases of COVID-19. . This combination makes it possible to decrease virus entry into the host cell by blocking entry mediated by protein S activation (through bromhexine) and by amplifying the host's antiviral innate immune response (through nitazoxanide).

In a further aspect, the present invention relates to nitazoxanide or tizoxanide with ibuprofen, optionally together with a further active agent, for use in the treatment of COVID-19, an infection caused by SARS-CoV-2.

According to this aspect, the dose of nitazoxanide is 500 mg every 12 hours for 6 days and the dose of ibuprofen is 400 mg every 12 hours for 6 to 7 days.

The additional active agent according to this fifth aspect of the invention is selected from an antibiotic, particularly clarithromycin, which is used at a dose of 500 mg every 12 hours for 10 days. In a further aspect, the present invention relates to nitazoxanide or tizoxanide, betamethasone, ibuprofen, optionally together with a further active agent, for use in the treatment of COVID-19, an infection caused by SARS-CoV-2.

According to this aspect of the invention, the nitazoxanide dose is 500 mg every 12 hours for 6 days, the betamethasone dose is 4.0 to 7.0 mg per day, and the ibuprofen dose is 400 mg every 12 hours.

The additional active agent may be selected in this regard from the group consisting of: antibiotics, antitussives, expectorants, mucolytics, anticholinergics, antihistamines, P2-adrenergic agonists, and non-selective competitive phosphodiesterase inhibitors.

In a preferred embodiment, the additional active agent is selected from clarithromycin at a dose of 500 mg every 12 hours for 10 days, optionally together with the combination of dropropizine and bromhexine, where the dose of dropropizine is 15 mg every 8 hours for 6 days and the dose of bromhexine is 8 mg every 8 hours for 6 days; or optionally together with hedera helix, ipratropium or acetylcysteine.

Alternatively, the additional active agent is selected from clarithromycin, ceflixime and hedera helix, wherein clarithromycin has a dose of 500 mg every 12 hours for 10 days and cefixime has a dose of 400 mg every 24 hours.

In another preferred embodiment, the additional active agent is selected from levofloxacin, optionally together with the combination of dropropizine, bromhexine and loratadine, where the dose of levofloxacin is 750 mg every 24 hours for 7 days, the dose of dropropizine is 15 mg every 8 hours for 6 days and the dose of bromhexine is 8 mg every 8 hours for 6 days.

In another embodiment, the additional active agent is selected from the combination of levofloxacin, ipratropium bromide, salmeterol, ambroxol hydrochloride and anhydrous theophylline, where the dose of levofloxacin is 750 mg every 24 hours for 7 days, the dose of bromide The dose of ipratropium is 2 aerosol inhalations with 0.020 mg of ipratropium bromide 3 times a day, the dose of salbutamol is 2 mg every 8 hours, the dose of ambroxol hydrochloride is 7.5 mg every 8 hours for 10 days, and the dose of Anhydrous theophylline dose is 35 mg every 8 hours for 10 days. The additional active agent is selected from the combination of levofloxacin, aluminum hydroxide, magnesium hydroxide and simethicone, where the dose of levofloxacin is 750 mg every 24 hours for 7 days, the dose of 600 mg magnesium hydroxide, 459 mg of aluminum hydroxide and 45 mg of simethicone.

The additional active agent according to this embodiment may be selected from the combination of azithromycin, dropropizine and bromhexine, wherein the dose of azithromycin is 500 mg every 24 hours for 6 days, the dose of dropropizine is 15 mg every 8 hours for 6 days and the dose of bromhexine is 8 mg every 8 hours for 6 days.

In a further embodiment, the additional active agent is selected from the combination of dropropizine and bromhexine, wherein the dose of dropropizine is 15 mg every 8 hours for 6 days and the dose of bromhexine is 8 mg every 8 hours for 6 days. .

The additional active agent according to this embodiment is selected from ipratropium or ipratropium bromide, where 2 aerosol inhalations with 0.018 mg ipratropium or 0.020 mg ipratropium bromide are used 3 to 4 times a day.

EXAMPLES

EXAMPLE 1 :

A group of 6 patients presented with one or more of the following symptoms: cough, dyspnea, fever, malaise, sore throat, hyaline rhinorrhea, headache, abdominal pain, anosmia, crackles, cyanosis, accessory muscles, bilateral crackles, arthralgia, myalgia and diaphoresis. A chest X-ray was taken from each patient at the beginning of treatment, confirming pulmonary involvement with lesions compatible with COVID-19, such as focal opacity, faint focal opacity, slight diffuse increase in density, focal or diffuse interstitial pattern, alveolar pattern. - Focal or diffuse interstitial, ruling out lesions not suggestive of COVID-19, such as lymphadenopathy, pleural effusion or nodule.

The patients followed a treatment with nitazoxanide 500 mg every 12 hours for 6 days with a anti-inflammatory, such as betamethasone 1 ml daily with or without ibuprofen 400 mg every 12 hours, optionally together with an antibiotic such as clarithromycin 500 mg every 12 hours for 10 days or levofloxacin 750 mg every 24 hours for 7 days. During the course of treatment, the patients had a good evolution, towards improvement, without any “accelerated” events due to cytokine storm. A chest X-ray was performed at the end of their treatment, resulting in a score/classification of Normal. No adverse reactions were reported. The oxygen saturation (O ₂ ) at the beginning and at the end of the treatment is presented in the following table:

Table 1.

* 2 inhalations every 8 hours, ** 15 ml every 8 hours.

The results show that treatment with nitazoxanide, an anti-inflammatory agent such as betamethasone and/or ibuprofen, and an antibiotic such as clarithromycin or levofloxacin allow the oxygenation level to be raised to normal levels of 90 percent or more in oxygen saturation, so a drug containing these active ingredients it is useful in the treatment of COVID-19 caused by SARS-CoV-2.

EXAMPLE 2:

A group of 12 patients presented with one or more of the following symptoms: cough, dyspnea, fever, malaise, odynophagia, hyaline rhinorrhea, headache, abdominal pain, anosmia, crackling rales, cyanosis, accessory muscles, bilateral crackles, arthralgia, myalgia and diaphoresis. A chest X-ray was taken from each patient at the beginning of treatment, confirming pulmonary involvement with lesions compatible with COVID-19, such as focal opacity, faint focal opacity, slight diffuse increase in density, focal or diffuse interstitial pattern, alveolar pattern. - Focal or diffuse interstitial, ruling out lesions not suggestive of COVID-19, such as lymphadenopathy, pleural effusion or nodule.

Patients were treated with nitazoxanide 500 mg every 12 hours for 6 days with bromhexine or ambroxol with or without an anti-inflammatory, such as betamethasone 1 mL daily with or without ibuprofen 400 mg every 12 hours, optionally together with an additional active agent.

During the course of treatment, the patients had a good evolution, towards improvement, without any “accelerated” events due to cytokine storm. All patients underwent a chest X-ray at the end of their treatment, resulting in a score/classification of Normal. No adverse reactions were reported. The oxygen saturation (02) at the beginning and at the end of the treatment is shown in the following table:

Table 2.

¹ DALVEAR (dropropizine /bromhexine), 5 ml every 8 hours for 6 days; ² AMINOEFEDRISON NF (ambroxol / theophylline) 5ml every 8 hours for 10 days; ³ 6 mg every 8 hours for 5 days; ^4,500 mg every 8 hours for 5 days; ⁵ 1 every 24 hours 6 days. ⁶ every 24 for 6 days.

The results show that a treatment with nitazoxanide and bromhexine or ambroxol, together with an anti-inflammatory agent such as betamethasone, with or without ibuprofen, allows to raise the level of oxygenation to normal levels of 90 percent or more in oxygen saturation, for so a drug containing these active ingredients is useful in the treatment of COVID-19 caused by SARS-CoV-2. As used in this specification and appended claims, singular articles such as "a""an" and "the" may refer to a single object or to multiple objects unless the context clearly indicates otherwise. Thus, for example, reference to a composition containing "an anti-inflammatory agent" may include a single anti-inflammatory agent. or two or more anti-inflammatory agents. The foregoing description is intended to be illustrative and not exhaustive. Various embodiments will be apparent to those skilled in the art upon reading the foregoing description. Accordingly, the scope of the invention should be determined with reference to the appended claims, and includes the full scope of equivalents attached to such claims. Descriptions of all items and references cited in the description, including patents, publications, and patent applications, are hereby incorporated by this reference for all purposes.

Claims

23 CLAIMS

1. Nitazoxanide or the active metabolite thiazoxanide for use in the treatment of COVID-19 caused by SARS-CoV-2, where the dose of nitazoxanide is 500 mg every 12 hours.

2. Nitazoxanide for use according to claim 1, wherein the nitazoxanide is used in combination with an anti-inflammatory agent and/or an additional active agent.

3. Nitazoxanide for use according to claim 2, wherein the anti-inflammatory agent is selected from the group that includes methylprednisolone, dexamethasone, betamethasone, ibuprofen, deflazacort and fluticasone, or a combination thereof.

4. Nitazoxanide for use according to claim 2, wherein the additional active agent is selected from the group consisting of: antibiotics, antitussives, expectorants, mucolytics, anticholinergics, p2 adrenergic agonists, non-selective competitive phosphodiesterase inhibitors, antacids, antiflatulents, demulcents, antihistamines and antivirals, serine protease inhibitors or a combination thereof.

5. Nitazoxanide for use according to claim 4, wherein the additional active agent comprises azithromycin, clarithromycin or levofloxacin.

6. Nitazoxanide for use according to any of claims 2 to 5, wherein the anti-inflammatory agent is a combination of betamethasone and ibuprofen, wherein the additional active agent comprises clarithromycin, wherein the dose of betamethasone is from 4.0 to 7.0 mg per day, ibuprofen dose is 400 mg every 12 hours and clarithromycin dose is 500 mg every 12 hours.

7. Nitazoxanide for use according to any of claims 2 to 5, wherein the anti-inflammatory agent is a combination of betamethasone and ibuprofen, wherein the additional active agent comprises levofloxacin, wherein the dose of betamethasone is from 4.0 to 7.0 mg per day, ibuprofen dose is 400 mg every 12 hours and levofloxazin dose is 750 mg every 24 hours.

8. Nitazoxanide for use according to any of claims 2 to 7, wherein the additional active agent comprises bromhexine or its active metabolite ambroxol at a dose of 8 mg every 8 or 12 hours of bromhexine, or ambroxol at a dose of 20 mg to 40 mg every 8 or 24 hours.