WO2023286104A1 - Therapeutic - Google Patents
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- WO2023286104A1 WO2023286104A1 PCT/JO2022/050011 JO2022050011W WO2023286104A1 WO 2023286104 A1 WO2023286104 A1 WO 2023286104A1 JO 2022050011 W JO2022050011 W JO 2022050011W WO 2023286104 A1 WO2023286104 A1 WO 2023286104A1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Definitions
- the present invention relates to repurposing of an existing therapeutic for use in treating an individual suffering from a condition selected from the group comprising viral infections, autoimmune diseases and diseases arising from hyperinflammatory states.
- the invention also includes inter alia methods of treatment of such individuals for said conditions.
- Mebendazole is an orally prescribed therapeutic with over 50 years use. It is a synthetic, highly effective, broad-spectrum antihelmintic indicated for the treatment of nematode infestations, including roundworm, hookworm, whipworm, threadworm, pinworm, and the intestinal form of trichinosis prior to its spread into the tissues beyond the digestive tract. Mebendazole works by selectively inhibiting the synthesis of microtubules via binding to colchicine binding site of b-tubulin, thereby blocking polymerisation of tubulin dimers in intestinal cells of parasites. Disruption of cytoplasmic microtubules leads to blocking the uptake of glucose and other nutrients, resulting in the gradual immobilization and eventual death of the helminths.
- Mebendazole has been approved at high dose 40-50mg/kg/day for the treatment of cystic and alveolar echinococcosis (a parasitic lung infection caused by the fox tapeworm) for at least 3-6 months and up to two years. It has neverbefore, hitherto been prescribed for any other medical indication other than as an antihelmintic.
- the 2019 novel Coronavirus otherwise known as COVID-19 is a pathogenic virus that targets the human respiratory system with viral pneumonia-like symptoms. It is the third beta coronavirus in the last two decades to be implicated in respiratory infections after the Severe Acute Respiratory Syndrome (SARS-CoV-1) and the most recent Middle East Respiratory Syndrome (MERS-CoV).
- SARS-CoV-1 Severe Acute Respiratory Syndrome
- MERS-CoV Middle East Respiratory Syndrome
- COVID-19 is a contagious virus with a high rate of spread with few if any clinically proven treatments. Morbidity and mortality vary widely among patients and appears related to age and co-morbid conditions. The repurposing of approved drugs provides cost and time- effective therapeutic options in the on-going efforts to combat the COVID-19 pandemic. Several antivirals and immune modulators are currently used to enhance the recovery and reduce the mortality in symptomatic COVID-19 patients. The main pathogenesis of severe COVID- 19 infection as a respiratory system targeting virus is severe pneumonia, combined with the incidence of ground-glass opacities, and acute cardiac injury.
- cytokines and chemokine’s have been observed in patients with COVID-19 infection including ILI-b, IL1RA, IL7, IL8, IL9, IL10, basic FGF2, GCSF, GMCSF, IFNy, IP10, MCP1, MIP1a, MIP1 b, PDGFB, TNFa, and VEGFA.
- Some of the severe cases that were admitted to the intensive care unit showed high levels of pro-inflammatory cytokines including IL2, IL7, IL10, GCSF, IP10, MCP1, MIP1a, and TNFa that have previously been shown to promote disease severity.
- COVID-19 infections have presented with unique clinical features such as targeting the lower airways as shown by sneezing, rhinorrhea and sore throat.
- CQ chloroquine phosphate
- Remdesivir are two other drugs that were investigated for inhibiting the viral activity of COVID-19. The former is the first-line choice for the treatment of malaria and so far the results of the clinical trials are negative or inconclusive.
- Remdesivir is a nucleoside analogue used in Coronavirus-COV2 infection and is currently being investigated for the treatment of COVID-19 patients with initial promising data.
- another study highlighted the use of nitric oxide inhalers for the treatment of respiratory failure.
- nitric oxide gas has not been studied specifically in vitro for the treatment of COVID-19, however, it is suggested to exhibit anti-inflammatory effects in acute respiratory distress syndrome.
- RNA viruses such as coronavirus family
- ER endoplasmic reticulum
- coronaviruses are known to suppress the innate immune response of the host by disrupting interferon production and may lead to Acute Lung Injury (ALI). Therefore, a potential treatment for coronaviruses should focus on disrupting the viral replication, interaction with the ER, increases the interferon production and inhibit cytokine storm target genes.
- ALI Acute Lung Injury
- mebendazole at a daily body load of between 50 to 4000 g per day that attains a mebendazole plasma concentration of between 300-500 nM, for use in the treatment and/or prophylaxis of a condition selected from the group comprising viral infections, autoimmune diseases and diseases arising from hyperinflammatory states.
- mebendazole can be used alone or in combination with other appropriate anti viral medicaments.
- the viral infection is a symptomatic COVID-19 infection.
- mebendazole is used to treat an individual who exhibits signs of lower respiratory tract pneumonia like symptoms, shortness of breath and blood oxygen saturation above and including 94% or below and including 94%.
- mebendazole is used alone or in combination with other appropriate medicaments used to treat an autoimmune disease wherein the autoimmune disease is selected from the group comprising type 1 diabetes, systemic lupus erythematosus, rheumatoid arthritis, psoriasis/psoriatic arthritis, multiple sclerosis, inflammatory bowel disease, Addison’s disease, Graves’ disease, Sjogren’s syndrome, Hashimoto’s thyroiditis, myasthenia gravis, autoimmune vasculitis, pernicious anaemia and other autoimmune diseases. More preferably, the autoimmune disease is a type I hypersensitivity reaction/allergy.
- mebendazole is used alone or in combination with other appropriate medicaments for the treatment of extrinsic asthma.
- mebendazole is used alone or in combination with other appropriate medicaments for the treatment of allergic and perennial rhinitis, allergic conjunctivitis, chronic urticaria, atopic dermatitis and/or laryngeal oedema
- mebendazole is used alone or in combination with other appropriate medicaments, for the treatment of a condition arising from a hyperinflammatory state selected from the group comprising a bacterial or viral infection, diabetes mellitus, arterial and venous thromboembolism and chronic fatigue syndrome.
- a hyperinflammatory state selected from the group comprising a bacterial or viral infection, diabetes mellitus, arterial and venous thromboembolism and chronic fatigue syndrome.
- mebendazole is administered orally as capsules, tablets, lozenges, slow-release preparations or as liquid preparation.
- mebendazole is administered topically, as eye droplets or nasally as a spray.
- mebendazole is administered at least two to three times per day.
- mebendazole when used to treat a viral infection, it is administered at least two to three times per day with fatty food until lower respiratory symptoms return to normal parameters.
- mebendazole is used at a dose sufficient to inhibit Ran-GTP.
- mebendazole at a daily body load of between 50 to 4000 mg per day that attains a mebendazole plasma concentration of between 300-500 nM, for the manufacture of a medicament for the treatment and/or prophylaxis of a condition selected from the group comprising viral infections, autoimmune diseases and diseases arising from hyperinflammatory states.
- a method of treating/ and/or prophylaxis of a human individual having a condition selected from the group comprising a viral infection, an autoimmune disease and a disease arising from a hyperinflammatory state comprising administering mebendazole at a daily body load of between 50 to 4000 mg per day that attains a mebendazole plasma concentration of between 300-500 nM.
- FIG. 1 shows the hypothesis explaining the difference between mebendazole (MBZ) and other tubulin binding agents (TBAs) for MAPK activation.
- TBAs are known to activate MAPK signalling, however, mainly through SAP/JNK.
- MBZ but no other benzimidazoles activate ERK. Additionally, MBZ inhibits DYRKIb which can lead to ERK activation, as well as potently inhibits BRAF which in cells with wild type RAF leads to paradoxical ERK activation.
- FIG. 2 shows Ran-GTP signalling. This diagram shows the overall mechanism of nuclear import and export. Ran assists in both of these processes by forming and dissociating complexes. This is also enabled by regulatory proteins RCC1, RanGAP, and RanBP1/2.
- Figure 3 shows immuno-blotting for Ran-GTP and Actin in the lysate obtained from MCF- 10A cells treated with Control (DMSO) and 100 nM, 300 nM and 500 nM MBZ.
- DMSO Control
- Figure 4 shows the effect of MBZ on coronavirus 02 mRNA expression.
- FIG. 5 shows MCF-10A cells infected by coronavirus SARS-CoV-1 and treated by MBZ.
- C5a and its target gene IL-8 mRNA were down-regulated at 500nM MBZ.
- FIG. 6 shows MCF-10A cells infected by SARS-CoV-1 and treated by MBZ.
- C5a and its target gene IL-8 mRNA were down-regulated at 500nM MBZ.
- FIG. 7 shows a comparison between the two study groups at day 3.
- FIG 8 shows a comparison of CRP levels between the two days in the drug and placebo groups. CRP levels are significantly decreased in the third day as compared to baseline levels in the mebendazole group (A) but not in the placebo group (B) with p values of ⁇ 0.001 and 0.250, respectively.
- Figure 9 shows significant reduction in Mean values of cyle threshold (CT) in the third day than baseline day in the mebendazole group (A) but not changed in the placebo group (B).
- CT Mean values of cyle threshold
- Figure 10 shows the significant reduction in nonocytes in the mebendazole (A) and placebo (B) groups in the two days of trial.
- MBZ therapy 40-50 mg/kg body weight for the treatment of lung parasitic conditions transmitted via fox tapeworms has been shown to induce the levels of interferon-alpha and gamma by 4 to 5-fold higher (Zingg et al. , 2004, Infection, 32, No 4, 299-302).
- MBZ has a well-established safety profile and an established positive benefit to risk in addition to ease of administration and low cost.
- MBZ exerts an immunomodulating effect by inducing interferon levels, and it’s potent up regulation of pro-inflammatory M1 -phenotype genes encoding cytokines.
- MBZ resulted in strong up regulation of pro- inflammatory M1 -phenotype genes encoding cytokines (such as TNF, IL8 and IL6) surface markers (CD80 and CD 86) and T-cell-attracting chemokines, whereas no up regulation was observed for M2 markers.
- cytokines such as TNF, IL8 and IL6
- CD80 and CD 86 surface markers
- T-cell-attracting chemokines T-cell-attracting chemokines
- MBZ was able to induce pro-inflammatory M1-type cytokines release in both THP-1 monocytes and THP-1 cells differentiated into macrophages (Blom et al 2017, Immunopharmacology and Immunotoxicology, 39, 4).
- Human cell lines MCF-10A and viral packaging cell lines HEK 293T were obtained from the American Type Culture Collection (ATCC), Manassas, VA, US and maintained as monolayer cultures in Dulbecco’s Modified Eagle’s Medium-High Glucose (DMEM-Hi) medium (Gibco BRL, Grand Island, NY, USA) supplemented with 10% fetal bovine serum (Gibco BRL, Grand Island, NY) and 1% penicillin-streptomycin (Gibco BRL) at 37 °C in a humidified atmosphere (5% CO2).
- AdEM-Hi Modified Eagle’s Medium-High Glucose
- DMEM-Hi Modified Eagle’s Medium-High Glucose
- Gibco BRL fetal bovine serum
- penicillin-streptomycin Gabco BRL
- the Java application sscMap which was bundled with over 6000 reference gene expression profiles for over 1000 compounds as its core database, was queried to identify compounds that had significant connections to immune modulatory effect of the RanGTP immune target genes in the human infected by SARS-CoV-1.
- These 1000 distinct small molecule perturbagens selected to represent a broad range of activities, include U.S. Food and Drug Administration (RELEASE)-approved drugs and nondrug bioactive “tool” compounds.
- the top candidate compounds that had significant connections to Ran expression are selected.
- RNA and protein were isolated from three independent experiments using the RNA STAT-60 Total RNA isolation reagent according to the manufacturer's instructions. Total RNA (5 pg) was sent to Roach Affymetrix for cDNA synthesis, cRNA synthesis, fragmentation, and hybridization onto Affymetrix microarrays.
- Transfection was performed using GeneJuice ® (Promega, Southampton, UK) according to the manufacturer’s instructions.
- SARS-CoV-1 cDNA (OriGene, USA) were used by viral infection as described in the literature.
- MTT 3- (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
- Interferons also stimulate intra- and intercellular networks for regulating innate and acquired immunity, resistance to viral infections, and normal and tumor cell survival and death. Interferons are proteins produced by cells in response to infection by many different viruses. A number of investigations have suggested that high expression of interferon induces cells to synthesize a new, intracellular, antiviral protein which in turn, inhibits the replication of a wide range of DNA and RNA viruses without affecting normal cellular synthetic activities. In fact, IFN has been shown to be a potent inhibitor of Coronavirus-CoV replication in vitro.
- MBZ This positions MBZ as a strong candidate for the treatment of COVID 19 infected patients. Recently, it has been shown that MBZ activates the MEK-ERK pathway and. MBZ has also been shown to be a strong activator for M1 macrophages (Andersson et al, 2020, Sci Rep, 10, 13124). MBZ has an advantage over the other interferon inducers that restore cells homeostasis and did not drive cell to apoptosis as shown in Figure 1.
- Figure 1 shows the hypothesis explaining the difference between mebendazole (MBZ) and other tubulin binding agents (TBAs) for MAPK activation. TBAs are known to activate MAPK signalling, however, mainly through SAP/JNK.
- MBZ but no other benzimidazoles activate ERK. Additionally, MBZ inhibits DYRKIb which can lead to ERK activation, as well as potently inhibits BRAF which in cells with wild type RAF leads to paradoxical ERK activation.
- MBZ has a Hypoxia-inducible factors (HIFs) stabilizing effect by binding to tubulin (data not shown).
- HIFs Hypoxia-inducible factors
- pVHL Von Hippel-Lindau tumour suppressor protein
- the overlapping of hypoxia and interferon signalling can be explained by the fact that both can lead to the increased level of cytosolic nuclear DNA or mitochondrial DNA causing the activating the cytoplasmic DNA sensor (cGAS).
- the potential mechanisms of antiviral action of MBZ and interferon signalling is postulated to be that, in addition, MBZ is causing the stabilization of the cytosolic DNA released via nuclear double-strand breaks or via mitochondrial damage.
- TREX1 a cytosolic DNA endonuclease that can degrade cytoplasmic DNA to reduce cytosolic DNA concentrations.
- Inhibition of TREX causes the activation of cGAS synthase increasing the level of 2’, 5’ cGAMP, an atypical cyclic dinucleotide second messenger that leads to the activation of the ER scaffold protein, stimulator of interferon genes (STING).
- STING stimulator of interferon genes
- MBZ could bind directly to STING to recruit TANK-binding kinase I (TBK1), and activating the transcription factor IRF3.
- IRF3 activation leads to induction of the innate immune response, including Type I interferon response genes.
- MBZ works as antiviral agent by different mechanisms including inhibiting virus replication, stimulating the cell to contain virus apoptosis and increasing the expression of immune target genes.
- the bidirectional transport of macromolecules between the nucleus and cytoplasm is a selective process that occurs exclusively through nuclear pore complexes (NPC).
- NPC nuclear pore complexes
- the NPC allows the passive diffusion of small molecules, including ions, metabolites, and globular proteins of up to ca. 60 kDa, without energy consumption.
- transport of larger proteins between the cytoplasmic and nuclear compartments is an active process and facilitated by specific soluble carrier proteins that are collectively referred to as “karyopherins”, with “importins” and “exportins”.
- the energy for nuclear transport is provided by Ran (a small Ras family of GTPases), which cycles between a GTP- and a GDP-bound state.
- Ran-GTP and Ran-GDP An asymmetric distribution of Ran-GTP and Ran-GDP between the nucleus and the cytoplasm controls the cargo import and export, and this gradient is maintained by various Ran associated regulatory factors.
- Ran is a small Ras-related GTPase that controls the nucleocytoplasmic exchange of macromolecules across the nuclear envelope ( Figure 2). Like other GTPases, Ran relies on the cycling between GTP-bound and GDP-bound conformations to interact with effector proteins and regulate these processes.
- Ran shuttles across the nuclear envelope through nuclear pores. It is concentrated in the nucleus by an active import mechanism where it generates a high concentration of Ran-GTP by nucleotide exchange. It controls the assembly and disassembly of a range of complexes that are formed between Ran-binding proteins and cellular cargo such as RNA of the Coronavirus to maintain rapid nuclear transport.
- Nucleocytoplasmic trafficking pathways are involved in Coronaviruses infection, where hijacking or alteration of function of key transporter proteins, such as Ran-GTP is observed. Overexpression of Ran-GTP is evident in viral infection and several solid and hematological malignancies. Interestingly, Ran-GTP-mediated nuclear export of viral components is crucial in various stages of the viral lifecycle and assembly.
- NPC nuclear pore complex
- HAV human immunodeficiency virus
- Coronaviruses exploit the nucleocytoplasmic pathway to export its RNA transcripts across the NPC to the cytoplasm.
- Active transport of viral proteins is mediated by nuclear localization signals (NLS), which were first identified in Simian Virus 40 large T antigen and had subsequently been identified in a large number of viral proteins such as SARS-CoV-1.
- Ran-GTP inhibitor could be a successful treatment for patients vulnerable to the lethal inflammatory storm induced by COVID-19 infections.
- MBZ The effect of MBZ on SARS-CoV-1 mRNA and immune target genes was investigated. Sensitivity of the MBZ drug was examined in MCF-10A cells infected with SARS-CoV-1 cDNA and treated with or without MBZ. The effect of MBZ on Ran-GTP protein expression and on the SARS-CoV-1 mRNA was assessed using Western and Real-Time Polymerase Chain Reaction (RT-PCR), respectively ( Figures 3 & 4).
- RT-PCR Real-Time Polymerase Chain Reaction
- affiymatrex RNA microarray By using Roche affiymatrex RNA microarray we have identified MBZ immune target genes. We used affiymatrex RNA microarray to identify transcripts that were differentially expressed between infected SARS-CoV-1 MCF-10A cells which treated with and without mebendazole (MBZ). Then we validated affiymatrex RNA microarry data by measured the mRNA expression levels by using Real-Time polymerase Chain Reaction (RT-PCR) of target genes such as Ran-GTP, immune response target genes including C5a, cytokines and T-Cell factor.
- RT-PCR Real-Time polymerase Chain Reaction
- RNA microarray was performed. MBZ Immune signaling target genes were identified and C5a and its target genes (cytokine storm) were down- regulated and T-cell factor up regulated by MBZ. In addition, we have validated the RNA microarray by treating the SARS-CoV-1 infected MCF-10A cells with and without 500 nM MBZ.
- MBZ significantly reduced C5a ( Figure 5) and cytokine target genes induced by SARS- CoV-1 including IL-1 alpha, IL-1 beta, IL-1 gamma, IL8 expression but upregulated T-Cell facot (T-Factor) ( Figure 6). These results showed the MBZ capable of down regulating C5a gene-mediated cytokines storm and immune paralysis and MBZ upregulated T-Cell Factor which stimulate the production and development of T-cells.
- MBZ as an inhibitor of the SARS-CoV-1 mRNA.
- SARS-CoV severe acute respiratory syndrome coronavirus
- BACs bacterial artificial chromosomes
- MBZ inhibits Ran-GTP expression at 300 nanomolar concentration which inhibited the nuceo-cytoplasmic translocation of the SARS-CoV-1 viral RNA, therefore, MBZ strongly inhibits the virus replication by downregulation of Ran-GTP.
- importin a/b translocate the Viral protein to the nucleus in the inhibitory complex which required Ran-GTP to release the viral protein to complete the cycle. Therefore, by silencing Ran-GTP, MBZ inhibits also the virus replication cycle by inhibiting viral protein release from importin a/b receptors and keeping it in inactive complex.
- Phase 1 clinical study was conducted and had adequate sample size and is adequately powered to determine if MBZ administered orally for the hospital stay in COVID-19 patients, namely PCR positive with symptoms (moderate to severe) other than patients in the ICU or on mechanical ventilation, at a dose determined from the 3 + 3 dose finding study (started with 600 mg three times daily then measuring the MBZ plasma level and finding out MBZ dose that attains MBZ plasma level between 300-500 nM and titrating the dose up and down according to MBZ plasma level) will be effective in reducing the duration and severity of COVID-19 virus disease course, thereby reducing patients morbidity and mortality.
- MBZ will be given in addition to conventional treatment.
- Inclusion and exclusion criteria The participants were considered outpatients and were chosen based on inclusion and exclusion criteria. Among the inclusion criteria are the following: 1) subjects with SARS-CoV- 2 infection who do not require hospitalization; 2) subjects willing and able to provide written informed consent prior to enrollment in the study; and 3) PCR-positive test within 72 hours of signing the consent form.
- the exclusion criteria are 1) participants under the age of 18 and 2) pregnant or nursing mothers.
- This study is a randomized controlled trial with two arms consisting of placebo-controlled and drug-treated participants. To ensure data confidentiality, the generated randomization list was kept with the pharmacist responsible for blinding and drug distribution. To maintain blindness, the packaging and labeling of the drug and control treatments were identical. Participants, researchers, and study staff were unaware of the treatment assignments. A total of 58 patients (29 in the Mebendazole group and 29 in the placebo control group) were required to obtain a mean effect size of 50 % with error of 0.05 and Beta error not exceeding 0.15.
- COVID- 19 outpatients were recruited and divided into two groups: drug group (Mebendazole with standard COVID- 19 therapy) and control group (with only standard therapy of COVID- 19).
- drug group Mebendazole with standard COVID- 19 therapy
- control group with only standard therapy of COVID- 19.
- a matching placebo will be administered in accordance with the study's randomization plan.
- the placebo will be paired with a Mebendazole dose of 2 Vermox 500 mg tablets three times daily.
- the standard of care included all or some of the following COVID-19 repurposed medications: acetaminophen (500 mg), vitamin C (1000 mg twice/day), zinc (75-125 mg/day), vitamin D3 (5000 lU/day), azithromycin (250 mg/day for 5 days), levofloxacin (500 mg once orally for 5 days), desloratadine (5 mg once daily), and dexamethasone (6 mg/day or methyl. 138 patients were initially screened and selected to participate in the study between January 11 and March 12, 2022. Due to the exclusion criteria, a total of 69 patients received the assigned treatment and were enrolled in the study (34 in the drug group and 35 in the placebo group).
- the primary endpoint of the clinical study was the time from treatment initiation to a PCR- negative result at day 3, as described in the procedures, as well as the changes in CBC with differential panel over the study timeframes.
- the primary safety endpoint is the occurrence of any adverse event from the initial dose through the conclusion of the study, including any abnormalities in liver and kidney function tests measured on days 1 and 3. Changes in C- reactive protein and PCR cycle threshold between days 1 and 3 represented the secondary efficacy endpoint.
- ALT alanine transaminase
- AST aspartate transaminase
- urea urea
- creatinine sodium, and potassium
- CRP C-reactive protein
- CT cycle threshold
- SD standard deviation
- Table 6 Correlation analysis between lymphocytes and CT levels in the two study groups at day 3 of the trial.
- Lymphocytes and CT values are significantly and positively correlated at day 3 only in the mebendazole group.
- antiviral agents capable of managing COVID- 19 hospitalizations have been investigated, including remdesivir, ritonavir, interferon, corticosteroids, cytokine storm blockers, and monoclonal antibodies with similar results in mild to moderate COVID 19 patients. Since no pharmacological agent has a well-established COVID-19 eradication effect that is effective, rapid, and inexpensive, it was crucial to evaluate new potential antivirals such as mebendazole in a prospective setting.
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Abstract
The present invention relates to repurposing of an existing therapeutic, mebendazole, for use in treating an individual suffering from a condition selected from the group comprising viral infections, autoimmune diseases and diseases arising from hyperinflammatory states.
Description
THERAPEUTIC
The present invention relates to repurposing of an existing therapeutic for use in treating an individual suffering from a condition selected from the group comprising viral infections, autoimmune diseases and diseases arising from hyperinflammatory states. The invention also includes inter alia methods of treatment of such individuals for said conditions.
BACKGROUND
Mebendazole is an orally prescribed therapeutic with over 50 years use. It is a synthetic, highly effective, broad-spectrum antihelmintic indicated for the treatment of nematode infestations, including roundworm, hookworm, whipworm, threadworm, pinworm, and the intestinal form of trichinosis prior to its spread into the tissues beyond the digestive tract. Mebendazole works by selectively inhibiting the synthesis of microtubules via binding to colchicine binding site of b-tubulin, thereby blocking polymerisation of tubulin dimers in intestinal cells of parasites. Disruption of cytoplasmic microtubules leads to blocking the uptake of glucose and other nutrients, resulting in the gradual immobilization and eventual death of the helminths. Mebendazole has been approved at high dose 40-50mg/kg/day for the treatment of cystic and alveolar echinococcosis (a parasitic lung infection caused by the fox tapeworm) for at least 3-6 months and up to two years. It has neverbefore, hitherto been prescribed for any other medical indication other than as an antihelmintic.
The 2019 novel Coronavirus, otherwise known as COVID-19 is a pathogenic virus that targets the human respiratory system with viral pneumonia-like symptoms. It is the third beta coronavirus in the last two decades to be implicated in respiratory infections after the Severe Acute Respiratory Syndrome (SARS-CoV-1) and the most recent Middle East Respiratory Syndrome (MERS-CoV). Evidence supports that coronaviruses are of zoonotic origin as previous investigations found that the Coronavirus-CoV was transmitted from civet cats to humans and MERS-CoV from dromedary camels to humans.
COVID-19 is a contagious virus with a high rate of spread with few if any clinically proven treatments. Morbidity and mortality vary widely among patients and appears related to age and co-morbid conditions. The repurposing of approved drugs provides cost and time- effective therapeutic options in the on-going efforts to combat the COVID-19 pandemic. Several antivirals and immune modulators are currently used to enhance the recovery and reduce the mortality in symptomatic COVID-19 patients.
The main pathogenesis of severe COVID- 19 infection as a respiratory system targeting virus is severe pneumonia, combined with the incidence of ground-glass opacities, and acute cardiac injury. In addition, significantly higher blood levels of cytokines and chemokine’s have been observed in patients with COVID-19 infection including ILI-b, IL1RA, IL7, IL8, IL9, IL10, basic FGF2, GCSF, GMCSF, IFNy, IP10, MCP1, MIP1a, MIP1 b, PDGFB, TNFa, and VEGFA. Some of the severe cases that were admitted to the intensive care unit showed high levels of pro-inflammatory cytokines including IL2, IL7, IL10, GCSF, IP10, MCP1, MIP1a, and TNFa that have previously been shown to promote disease severity. Furthermore, in comparison to other beta coronaviruses, COVID-19 infections have presented with unique clinical features such as targeting the lower airways as shown by sneezing, rhinorrhea and sore throat.
To date, there is no clinically proven treatment for COVID-19 infection. Few antiviral drugs have been investigated for their efficacy but no conclusive results were obtained. Using an artificial intelligence (Al) program, a group of researchers found potential therapeutic candidates that could inhibit clathrin-mediated endocytosis and thus inhibit viral infection. Such drugs could be used as potential therapeutics against COVID-19. Baricitinib, Fedratinib, and ruxolitinib are the drugs predicted to be of high importance in the treatment of COVID-19. These drugs are potent and selective JAK inhibitors approved for indications such as rheumatoid arthritis. All three are powerful anti-inflammatories that, as JAK-STAT signalling inhibitors, are likely to be effective against the consequences of the elevated levels of cytokines (including interferon-g) typically observed in people with COVID-19. Likewise, chloroquine phosphate (CQ) and Remdesivir are two other drugs that were investigated for inhibiting the viral activity of COVID-19. The former is the first-line choice for the treatment of malaria and so far the results of the clinical trials are negative or inconclusive.
Remdesivir is a nucleoside analogue used in Coronavirus-COV2 infection and is currently being investigated for the treatment of COVID-19 patients with initial promising data. Interestingly, another study highlighted the use of nitric oxide inhalers for the treatment of respiratory failure. Although nitric oxide gas has not been studied specifically in vitro for the treatment of COVID-19, however, it is suggested to exhibit anti-inflammatory effects in acute respiratory distress syndrome.
The replication of positive-strand RNA viruses, such as coronavirus family is closely linked to the cellular membrane compartment of the host cells especially the endoplasmic reticulum (ER). Moreover, coronaviruses are known to suppress the innate immune response of the host by disrupting interferon production and may lead to Acute Lung Injury (ALI). Therefore, a potential treatment for coronaviruses should focus on disrupting the viral replication,
interaction with the ER, increases the interferon production and inhibit cytokine storm target genes.
There is a need for further therapeutics for the treatment of an individual suffering from a condition selected from the group comprising viral infections, autoimmune diseases and diseases arising from hyperinflammatory states.
There is also a need for further and safe therapeutics for the treatment of an individual suffering from symptomatic coronavirus COVID-19 infections.
BRIEF SUMMARY OF THE DISCLOSURE
According to a first aspect of the invention there is provided mebendazole, at a daily body load of between 50 to 4000 g per day that attains a mebendazole plasma concentration of between 300-500 nM, for use in the treatment and/or prophylaxis of a condition selected from the group comprising viral infections, autoimmune diseases and diseases arising from hyperinflammatory states.
Preferably, mebendazole can be used alone or in combination with other appropriate anti viral medicaments.
Preferably, the viral infection is a symptomatic COVID-19 infection.
Preferably, mebendazole, is used to treat an individual who exhibits signs of lower respiratory tract pneumonia like symptoms, shortness of breath and blood oxygen saturation above and including 94% or below and including 94%.
Preferably, mebendazole is used alone or in combination with other appropriate medicaments used to treat an autoimmune disease wherein the autoimmune disease is selected from the group comprising type 1 diabetes, systemic lupus erythematosus, rheumatoid arthritis, psoriasis/psoriatic arthritis, multiple sclerosis, inflammatory bowel disease, Addison’s disease, Graves’ disease, Sjogren’s syndrome, Hashimoto’s thyroiditis, myasthenia gravis, autoimmune vasculitis, pernicious anaemia and other autoimmune diseases. More preferably, the autoimmune disease is a type I hypersensitivity reaction/allergy.
Preferably, mebendazole is used alone or in combination with other appropriate medicaments for the treatment of extrinsic asthma.
Preferably, mebendazole is used alone or in combination with other appropriate medicaments for the treatment of allergic and perennial rhinitis, allergic conjunctivitis, chronic urticaria, atopic dermatitis and/or laryngeal oedema
Preferably, mebendazole is used alone or in combination with other appropriate medicaments, for the treatment of a condition arising from a hyperinflammatory state selected from the group comprising a bacterial or viral infection, diabetes mellitus, arterial and venous thromboembolism and chronic fatigue syndrome.
Preferably, mebendazole is administered orally as capsules, tablets, lozenges, slow-release preparations or as liquid preparation.
In some embodiments, mebendazole is administered topically, as eye droplets or nasally as a spray.
Preferably, mebendazole is administered at least two to three times per day.
Preferably, when mebendazole is used to treat a viral infection, it is administered at least two to three times per day with fatty food until lower respiratory symptoms return to normal parameters.
Preferably, mebendazole is used at a dose sufficient to inhibit Ran-GTP.
According to a further aspect of the invention there is provided use of mebendazole, at a daily body load of between 50 to 4000 mg per day that attains a mebendazole plasma concentration of between 300-500 nM, for the manufacture of a medicament for the treatment and/or prophylaxis of a condition selected from the group comprising viral infections, autoimmune diseases and diseases arising from hyperinflammatory states.
According to a further aspect of the invention there is provided a method of treating/ and/or prophylaxis of a human individual having a condition selected from the group comprising a viral infection, an autoimmune disease and a disease arising from a hyperinflammatory state comprising administering mebendazole at a daily body load of between 50 to 4000 mg per day that attains a mebendazole plasma concentration of between 300-500 nM.
It will be appreciated that preferred features ascribed to one aspect of the invention applies mutatis mutandis to each and every aspect of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
Embodiments of the invention are further described hereinafter with reference to the accompanying drawings, in which:
Figure 1 shows the hypothesis explaining the difference between mebendazole (MBZ) and other tubulin binding agents (TBAs) for MAPK activation. TBAs are known to activate MAPK signalling, however, mainly through SAP/JNK. MBZ but no other benzimidazoles activate ERK. Additionally, MBZ inhibits DYRKIb which can lead to ERK activation, as well as potently inhibits BRAF which in cells with wild type RAF leads to paradoxical ERK activation.
Figure 2 shows Ran-GTP signalling. This diagram shows the overall mechanism of nuclear import and export. Ran assists in both of these processes by forming and dissociating complexes. This is also enabled by regulatory proteins RCC1, RanGAP, and RanBP1/2.
Figure 3 shows immuno-blotting for Ran-GTP and Actin in the lysate obtained from MCF- 10A cells treated with Control (DMSO) and 100 nM, 300 nM and 500 nM MBZ.
Figure 4 shows the effect of MBZ on coronavirus 02 mRNA expression.
Figure 5 shows MCF-10A cells infected by coronavirus SARS-CoV-1 and treated by MBZ. C5a and its target gene IL-8 mRNA were down-regulated at 500nM MBZ.
Figure 6 shows MCF-10A cells infected by SARS-CoV-1 and treated by MBZ. C5a and its target gene IL-8 mRNA were down-regulated at 500nM MBZ.
Figure 7 shows a comparison between the two study groups at day 3. CRP levels (A) and CT values (B) are significantly different between mebendazole and placebo groups at the third day of intervention, P<0.001 and P=0.046, respectively.
Figure 8 shows a comparison of CRP levels between the two days in the drug and placebo groups. CRP levels are significantly decreased in the third day as compared to baseline levels in the mebendazole group (A) but not in the placebo group (B) with p values of <0.001 and 0.250, respectively.
Figure 9 shows significant reduction in Mean values of cyle threshold (CT) in the third day than baseline day in the mebendazole group (A) but not changed in the placebo group (B).
Figure 10 shows the significant reduction in nonocytes in the mebendazole (A) and placebo (B) groups in the two days of trial. detailed description
MBZ therapy (40-50 mg/kg body weight) for the treatment of lung parasitic conditions transmitted via fox tapeworms has been shown to induce the levels of interferon-alpha and gamma by 4 to 5-fold higher (Zingg et al. , 2004, Infection, 32, No 4, 299-302). MBZ has a well-established safety profile and an established positive benefit to risk in addition to ease of administration and low cost. MBZ exerts an immunomodulating effect by inducing interferon levels, and it’s potent up regulation of pro-inflammatory M1 -phenotype genes encoding cytokines.
In previous studies, we have shown that MBZ resulted in strong up regulation of pro- inflammatory M1 -phenotype genes encoding cytokines (such as TNF, IL8 and IL6) surface markers (CD80 and CD 86) and T-cell-attracting chemokines, whereas no up regulation was observed for M2 markers. MBZ exposure induced I L-1 b secretion, while no effect on I L-1 b release was observed in response to other benzimidazoles or vincristine. MBZ revealed to be a potent inhibitor of DYRK1B (ICso360 nM). MBZ was able to induce pro-inflammatory M1-type cytokines release in both THP-1 monocytes and THP-1 cells differentiated into macrophages (Blom et al 2017, Immunopharmacology and Immunotoxicology, 39, 4).
Materials and Methods
Human Cell Lines
Human cell lines MCF-10A and viral packaging cell lines HEK 293T were obtained from the American Type Culture Collection (ATCC), Manassas, VA, US and maintained as monolayer cultures in Dulbecco’s Modified Eagle’s Medium-High Glucose (DMEM-Hi) medium (Gibco BRL, Grand Island, NY, USA) supplemented with 10% fetal bovine serum (Gibco BRL, Grand Island, NY) and 1% penicillin-streptomycin (Gibco BRL) at 37 °C in a humidified atmosphere (5% CO2).
Connectivity map (Map) analysis
The Java application sscMap, which was bundled with over 6000 reference gene expression profiles for over 1000 compounds as its core database, was queried to identify compounds that had significant connections to immune modulatory effect of the RanGTP immune target genes in the human infected by SARS-CoV-1. These 1000 distinct small molecule perturbagens, selected to represent a broad range of activities, include U.S. Food and Drug Administration (RELEASE)-approved drugs and nondrug bioactive “tool” compounds. The top candidate compounds that had significant connections to Ran expression are selected. MBZ was the drug that was predicted to have inhibitory effects on the expression of both Ran, SARS-CoV-1 and cytokines storm. MBZ was highly ranked (P = 0.00001, z-score = - 4.8028) compared to other drugs.
Microarray analysis
Cells were treated or untreated with 300 nmol/L MBZ for 24 h were analyzed to identify those genes that are constitutively dysregulated between treated and untreated cells. Total RNA and protein were isolated from three independent experiments using the RNA STAT-60 Total RNA isolation reagent according to the manufacturer's instructions. Total RNA (5 pg) was sent to Roach Affymetrix for cDNA synthesis, cRNA synthesis, fragmentation, and hybridization onto Affymetrix microarrays.
Transfection
Transfection was performed using GeneJuice® (Promega, Southampton, UK) according to the manufacturer’s instructions. SARS-CoV-1 cDNA (OriGene, USA) were used by viral infection as described in the literature.
MTT cell proliferation and in Vitro IC50 assay
Cells were seeded at a cell density of 3000 cells/well in a 96-well plate in triplicates and allowed to grow for 24 hours and before MBZ at different doses was added. The MTT (3- (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) dye uptake method was used to assess cell survival 24, 48 and 72 hours post-treatment.
Western blot analysis
Western blotting was performed as previously described. Briefly, cells were lysed in RIPA buffer containing protease inhibitors. The samples were separated by SDS-PAGE and transferred onto a nitrocellulose membrane (Millipore, Watford, UK). The membranes were blocked with 5% (v/v) nonfat dried milk in PBS and subsequently incubated anti-Ran (1:2000) or housekeeping gene beta-actine from Millipore, overnight at 4° C. Bound
antibodies were detected by horseradish peroxidases-conjugated secondary antibodies at 1:10000 at RT for 1 hour with enhanced chemiluminescence (Amersham Pharmacia Biotech, Chalfont, UK) for detection. Densitometry on scanned immunoblot images was performed using the ImageJ software.
Real-time polymerase chain reaction
RNA was extracted using Trizol (Invitrogen, Paisley, UK) and reverse transcription was performed using Superscript™ III first strand synthesis system (Invitrogen) according to the manufacturer's instructions. Real-time PCR was performed according to the manufacturer's instructions (Applied Biosystem, Foester City, CA) using a SYBR® Green assay for SARS- CoV-1 (https://w,'Jvw.sigmaaidhch.com/technica[-documents/protocois/bioloqy)
Statistical analysis
Data are presented as the mean ± standard deviation (SD) for three independent experiments. The Student’s f-test and one-way ANOVA were used to assess the significance of independent experiments.
EXAMPLE 1
It has been shown that MBZ can activate a component of the hypoxic adaptive response, specifically the stabilization of HIF-1a and its downstream targets. Interferons (IFNs) also stimulate intra- and intercellular networks for regulating innate and acquired immunity, resistance to viral infections, and normal and tumor cell survival and death. Interferons are proteins produced by cells in response to infection by many different viruses. A number of investigations have suggested that high expression of interferon induces cells to synthesize a new, intracellular, antiviral protein which in turn, inhibits the replication of a wide range of DNA and RNA viruses without affecting normal cellular synthetic activities. In fact, IFN has been shown to be a potent inhibitor of Coronavirus-CoV replication in vitro. This positions MBZ as a strong candidate for the treatment of COVID 19 infected patients. Recently, it has been shown that MBZ activates the MEK-ERK pathway and. MBZ has also been shown to be a strong activator for M1 macrophages (Andersson et al, 2020, Sci Rep, 10, 13124). MBZ has an advantage over the other interferon inducers that restore cells homeostasis and did not drive cell to apoptosis as shown in Figure 1. Figure 1 shows the hypothesis explaining the difference between mebendazole (MBZ) and other tubulin binding agents (TBAs) for MAPK activation. TBAs are known to activate MAPK signalling, however, mainly through SAP/JNK. MBZ but no other benzimidazoles activate ERK. Additionally, MBZ inhibits
DYRKIb which can lead to ERK activation, as well as potently inhibits BRAF which in cells with wild type RAF leads to paradoxical ERK activation.
EXAMPLE 2
We have demonstrated that MBZ has a Hypoxia-inducible factors (HIFs) stabilizing effect by binding to tubulin (data not shown). Von Hippel-Lindau tumour suppressor protein (pVHL) is known to regulate HIF-1a exportation to the cytoplasm. The overlapping of hypoxia and interferon signalling can be explained by the fact that both can lead to the increased level of cytosolic nuclear DNA or mitochondrial DNA causing the activating the cytoplasmic DNA sensor (cGAS). The potential mechanisms of antiviral action of MBZ and interferon signalling is postulated to be that, in addition, MBZ is causing the stabilization of the cytosolic DNA released via nuclear double-strand breaks or via mitochondrial damage. This stabilization is expected to be due to the inhibition of TREX1, a cytosolic DNA endonuclease that can degrade cytoplasmic DNA to reduce cytosolic DNA concentrations. Inhibition of TREX causes the activation of cGAS synthase increasing the level of 2’, 5’ cGAMP, an atypical cyclic dinucleotide second messenger that leads to the activation of the ER scaffold protein, stimulator of interferon genes (STING). Alternatively, MBZ could bind directly to STING to recruit TANK-binding kinase I (TBK1), and activating the transcription factor IRF3. IRF3 activation leads to induction of the innate immune response, including Type I interferon response genes. In conclusion, MBZ works as antiviral agent by different mechanisms including inhibiting virus replication, stimulating the cell to contain virus apoptosis and increasing the expression of immune target genes.
EXAMPLE 3
The bidirectional transport of macromolecules between the nucleus and cytoplasm is a selective process that occurs exclusively through nuclear pore complexes (NPC). The NPC allows the passive diffusion of small molecules, including ions, metabolites, and globular proteins of up to ca. 60 kDa, without energy consumption. However, transport of larger proteins between the cytoplasmic and nuclear compartments is an active process and facilitated by specific soluble carrier proteins that are collectively referred to as “karyopherins”, with “importins” and “exportins”. The energy for nuclear transport is provided by Ran (a small Ras family of GTPases), which cycles between a GTP- and a GDP-bound state. An asymmetric distribution of Ran-GTP and Ran-GDP between the nucleus and the cytoplasm controls the cargo import and export, and this gradient is maintained by various Ran associated regulatory factors.
Ran is a small Ras-related GTPase that controls the nucleocytoplasmic exchange of macromolecules across the nuclear envelope (Figure 2). Like other GTPases, Ran relies on the cycling between GTP-bound and GDP-bound conformations to interact with effector proteins and regulate these processes. In nucleocytoplasmic transport, Ran shuttles across the nuclear envelope through nuclear pores. It is concentrated in the nucleus by an active import mechanism where it generates a high concentration of Ran-GTP by nucleotide exchange. It controls the assembly and disassembly of a range of complexes that are formed between Ran-binding proteins and cellular cargo such as RNA of the Coronavirus to maintain rapid nuclear transport.
Nucleocytoplasmic trafficking pathways are involved in Coronaviruses infection, where hijacking or alteration of function of key transporter proteins, such as Ran-GTP is observed. Overexpression of Ran-GTP is evident in viral infection and several solid and hematological malignancies. Interestingly, Ran-GTP-mediated nuclear export of viral components is crucial in various stages of the viral lifecycle and assembly.
It has been also shown that MBZ was able to stimulate antitumoral immune response by polarization of macrophages. Molecular traffic between the nucleus and the cytoplasm is regulated by the nuclear pore complex (NPC), which acts as a highly selective channel perforating the nuclear envelope in eukaryotic cells. Most viruses such as the human immunodeficiency virus (HIV) and Coronaviruses exploit the nucleocytoplasmic pathway to export its RNA transcripts across the NPC to the cytoplasm. Active transport of viral proteins is mediated by nuclear localization signals (NLS), which were first identified in Simian Virus 40 large T antigen and had subsequently been identified in a large number of viral proteins such as SARS-CoV-1. Usually, they contain short stretches of lysine or arginine residues. These signals are recognized by the importin super-family (importin a and b) proteins that mediate the transport across the nuclear envelope through Ran-GTP. In contrast, only one class of the leucine-rich nuclear export signal (NES) on viral proteins is known at present. Chromosome region maintenance 1 (CRM1) protein mediates the nuclear export of hundreds of viral proteins through the recognition of the leucine-rich NES. This mechanism is vital for the virus to translocate its mRNA to cytoplasm for translation its protein. On other hand once the protein trans located in cytoplasm, it bind to importin receptors in inhibitory complex to translocate to nucleus. In the nucleus Ran-GTP bind to imprtin a/b receptors to release the virus protein. Therefore, by inhibiting Ran-GTP the nucleocytoplasmic transport will be deregulated, therefore, inhibiting Covid-19 replication.
As Ran-GTP is involved in more than one type of innate immune response by modulating the proinflammatory cytokines across the board, it also plays an important role in host innate
immune response induced by COVID-19. Therefore, Ran-GTP inhibitor (MBZ) could be a successful treatment for patients vulnerable to the lethal inflammatory storm induced by COVID-19 infections.
EXAMPLE 4
The effect of MBZ on SARS-CoV-1 mRNA and immune target genes was investigated. Sensitivity of the MBZ drug was examined in MCF-10A cells infected with SARS-CoV-1 cDNA and treated with or without MBZ. The effect of MBZ on Ran-GTP protein expression and on the SARS-CoV-1 mRNA was assessed using Western and Real-Time Polymerase Chain Reaction (RT-PCR), respectively (Figures 3 & 4).
By using Roche affiymatrex RNA microarray we have identified MBZ immune target genes. We used affiymatrex RNA microarray to identify transcripts that were differentially expressed between infected SARS-CoV-1 MCF-10A cells which treated with and without mebendazole (MBZ). Then we validated affiymatrex RNA microarry data by measured the mRNA expression levels by using Real-Time polymerase Chain Reaction (RT-PCR) of target genes such as Ran-GTP, immune response target genes including C5a, cytokines and T-Cell factor. Regulation of the above target genes mRNA expression were assessed in human cell lines including MCF-10A MDA-MB 231 cells that were infected by SARS-CoV-1 and treated with or without MBZ. All statistical tests were two-sided. MCF-10A cells infected by SARS-CoV-1 and treated by MBZ. RNA microarray was performed. MBZ Immune signaling target genes were identified and C5a and its target genes (cytokine storm) were down- regulated and T-cell factor up regulated by MBZ. In addition, we have validated the RNA microarray by treating the SARS-CoV-1 infected MCF-10A cells with and without 500 nM MBZ. MBZ significantly reduced C5a (Figure 5) and cytokine target genes induced by SARS- CoV-1 including IL-1 alpha, IL-1 beta, IL-1 gamma, IL8 expression but upregulated T-Cell facot (T-Factor) (Figure 6). These results showed the MBZ capable of down regulating C5a gene-mediated cytokines storm and immune paralysis and MBZ upregulated T-Cell Factor which stimulate the production and development of T-cells.
This data also suggested that MBZ by inhibiting Ran-GTP which could inhibit both coronavirus replication and the cytokine storm. We have also shown that MBZ induce cell apoptosis in the human cells containing active virus which it is addicted to high Ran-GTP, but not normal cells (data not shown here). The addiction of cells to high expression of Ran- GTP allows them to cope with extreme/high speed Coronavirus replications.
EXAMPLE 5
Using the engineering of a full-length infectious cDNA clone and a functional replicon of the severe acute respiratory syndrome coronavirus (SARS-CoV) Urbani strain as bacterial artificial chromosomes (BACs) we examined MBZ as an inhibitor of the SARS-CoV-1 mRNA. To investigate the IC50 of MBZ, we treated human invasive breast cancer MCF-10A, MDA- MB-231 and lung adenocarcinoma A549 cells with this drug at different doses for 24 or 48 hours, and cell viability was assessed after treatment with different doses of MBZ after 48 hours (Table 1).
Human MCF-10A cells were infected with SARS-CoV-1 cDNA which cloned in pKLO vector and then treated the cells with the vehicle (DMSO) or MBZ at the indicated concentrations. Samples were taken at day 0 and day 3 post-infection for Western blot of Ran-GTP expression. This data showed that reduced Ran-GTP expression by MBZ at IC5o=300nM concentration. Quantitation of viral load using RT-PCR of cell-associated virus using Sigma RT-PCR probe for the SARS-CoV-1. MBZ at 300nM concentration reduced SARS-CoV-1 mRNA by > 90% compared to the DMSO treated control. This data showed that MBZ reduced multiplicity of Infection (MOI) of SARS-CoV-1 by 6300 compared to the DMSO treated control. Results represent the mean ± SD of three independent experiments.
Our data showed that MBZ inhibits Ran-GTP expression at 300 nanomolar concentration which inhibited the nuceo-cytoplasmic translocation of the SARS-CoV-1 viral RNA, therefore, MBZ strongly inhibits the virus replication by downregulation of Ran-GTP. On the other hand, importin a/b translocate the Viral protein to the nucleus in the inhibitory complex which required Ran-GTP to release the viral protein to complete the cycle. Therefore, by silencing Ran-GTP, MBZ inhibits also the virus replication cycle by inhibiting viral protein release from importin a/b receptors and keeping it in inactive complex. We have shown previously that silencing Ran-GTP in hyperactive but not in normal cells led to reduced cell proliferation and induced programmed cell death (apoptosis) in vitro (only in abnormal cells but not in normal cells). These results showed that MBZ inhibited Ran-GTP and inhibited coronavirus SARS-CoV-1 replication at 300nM.
In conclusion, MBZ has a significant impact on the immunodeficiency state that has been induced using SARS-CoV-1. The work included examining the effect of mebendazole (MBZ) on cell immunity responsible genes, on SARS-CoV-1 replication and on Ran-GTPase. The results showed the MBZ down regulated C5a gene-mediated cytokines storm and immune paralysis and up regulated T-Cell Factor which stimulated the production and development of T-cells. These results showed that MBZ inhibited Ran-GTP and inhibited coronavirus SARS-CoV-1 replication at 300nM. Thus concluded that MBZ inhibited Ran-GTP and consequently inhibited both coronavirus replication and the cytokine storm. We have also shown that MBZ induced cell apoptosis in human cells containing active virus which it is addicted to high Ran-GTP, but not normal cells (data not shown here). The addiction of cells to high expression of Ran-GTP allows them to cope with extreme/high speed Coronavirus replications.
EXAMPLE 6
Phase 1 clinical study was conducted and had adequate sample size and is adequately powered to determine if MBZ administered orally for the hospital stay in COVID-19 patients, namely PCR positive with symptoms (moderate to severe) other than patients in the ICU or on mechanical ventilation, at a dose determined from the 3 + 3 dose finding study (started with 600 mg three times daily then measuring the MBZ plasma level and finding out MBZ dose that attains MBZ plasma level between 300-500 nM and titrating the dose up and down according to MBZ plasma level) will be effective in reducing the duration and severity of COVID-19 virus disease course, thereby reducing patients morbidity and mortality. MBZ will be given in addition to conventional treatment.
Phase 2 clinical study was also conducted from January to March 2022 at the emergency room of the Amman Field Hospital in Amman, Jordan.
Study participants
Subjects were recruited from the emergency room of Amman Field Hospital as symptomatic COVID-19 patients with a positive PCR test and sent home for treatment. The study was conducted in accordance with the Declaration of Helsinki and its amendments as well as the Guidelines for Good Clinical Practices issued by the European Union Committee for Medicinal Products (CPMP). Price Hamza Hospital and the Jordan Food and Drug Administration granted ethical approval. All study participants provided their written informed consent. The work has been reported according to CONSORT (Consolidated Standards of Reporting Trials) guidelines (19).
Inclusion and exclusion criteria
The participants were considered outpatients and were chosen based on inclusion and exclusion criteria. Among the inclusion criteria are the following: 1) subjects with SARS-CoV- 2 infection who do not require hospitalization; 2) subjects willing and able to provide written informed consent prior to enrollment in the study; and 3) PCR-positive test within 72 hours of signing the consent form. The exclusion criteria are 1) participants under the age of 18 and 2) pregnant or nursing mothers. 3) patients with any liver abnormalities or current transaminases > 3 times the upper normal limit; 4) patients with any kidney abnormalities or current serum creatinine >1.5 mg/dL; 5) patients with known myopathy or elevated baseline creatinine kinase; 6) patients requiring sedation for mechanical ventilation; 7) patients requiring admission to the ICU; 8) patients with allergy to Mebendazole or typical signs of hypersensitivity (rash, fever); and 9) patients currently
Blinding, randomization, and sample size calculation
This study is a randomized controlled trial with two arms consisting of placebo-controlled and drug-treated participants. To ensure data confidentiality, the generated randomization list was kept with the pharmacist responsible for blinding and drug distribution. To maintain blindness, the packaging and labeling of the drug and control treatments were identical. Participants, researchers, and study staff were unaware of the treatment assignments. A total of 58 patients (29 in the Mebendazole group and 29 in the placebo control group) were required to obtain a mean effect size of 50 % with error of 0.05 and Beta error not exceeding 0.15.
Recruitment of study participants
COVID- 19 outpatients were recruited and divided into two groups: drug group (Mebendazole with standard COVID- 19 therapy) and control group (with only standard therapy of COVID- 19). In addition to the conventional treatment according to the Jordanian national protocol for the treatment of COVID-19 for ten days or until the first negative PCR, a matching placebo will be administered in accordance with the study's randomization plan. The placebo will be paired with a Mebendazole dose of 2 Vermox 500 mg tablets three times daily. The standard of care included all or some of the following COVID-19 repurposed medications: acetaminophen (500 mg), vitamin C (1000 mg twice/day), zinc (75-125 mg/day), vitamin D3 (5000 lU/day), azithromycin (250 mg/day for 5 days), levofloxacin (500 mg once orally for 5 days), desloratadine (5 mg once daily), and dexamethasone (6 mg/day or methyl. 138 patients were initially screened and selected to participate in the study between January 11 and March 12, 2022. Due to the exclusion criteria, a total of 69 patients received the assigned treatment and were enrolled in the study (34 in the drug group and 35 in the placebo group).
Trial procedure
Participants in the study were randomly assigned to receive Mebendazole 1000 g (two tablets) three times daily for a total of ten days, or until the first negative PCR. On the first day of drug administration, a research coordinator initiated daily phone calls for the duration of study participation. The other objective of the follow-up is to assess patient adherence and the occurrence of adverse events. After signing the consent form and before starting the medication, each patient underwent home visits from the lab technician on days 3, 6, and 10 to collect blood samples for the following biochemical tests: COVID-19 PCR, liver function tests, kidney function tests, complete blood cell count (CBC) with differential, C- reactive protein, and mebendazole plasma level.
Efficacy and safety assessment
The primary endpoint of the clinical study was the time from treatment initiation to a PCR- negative result at day 3, as described in the procedures, as well as the changes in CBC with differential panel over the study timeframes. The primary safety endpoint is the occurrence of any adverse event from the initial dose through the conclusion of the study, including any abnormalities in liver and kidney function tests measured on days 1 and 3. Changes in C- reactive protein and PCR cycle threshold between days 1 and 3 represented the secondary efficacy endpoint.
Statistical analysis
All data collection, processing, and analysis was performed using version 22.0 of IBM SPSS for Microsoft Windows (SPSS Inc, Chicago, IL, US). The Chi-square test was used to examine categorical (discrete) variable differences. Continuous data were presented as mean standard deviation (SD) and subjected to the normality test (Shapiro-Wilk); data that passed the normality test (followed a Gaussian distribution) were analyzed using parametric tests, while data that were not normally distributed were analyzed using nonparametric methods. For dependent data (outcomes before and after clinical intervention), paired student t-test and Wilcoxon test are used, whereas unpaired student t-test and Mann- Whitney U test are used for independent data (outcomes between mebendazole group and placebo group). Using Pearson's correlation coefficient, linear correlation was determined. Less than 0.05 probability (P) values were considered statistically significant. P < 0.05 is considered statistically significant for mean differences. Utilizing G*Power 3.1, statistical power analyses and sample size calculations were conducted.
Results
Study participants
According to Table 2, the mebendazole and placebo groups were comparable with regard to gender (P>0.05). Age, CBC with differential, and liver and kidney function tests at baseline were matched between both study groups (Table 3). Since the subjects were recruited during the Omicron COVID-19 variant, the majority of them became PCR negative on day 5 and did not exhibit any symptoms. Therefore, it was decided to compare all variables between the baseline day and the third day of drug administration.
Table 2. The study groups are matched for males and females numbers.
Hematological and biochemical results for mebendazole and placebo groups at baseline day. All data are presented as meanistandard deviation (SD). CRP, C-reactive protein; CT, cycle threshold; AST, aspartate aminotransferase; ALT, alanine aminotransferase. * The difference is significant if P<0.05.
Drug safety
Seven patients in the drug group and two patients in the control group experienced adverse events, but none were considered serious according to the protocol definition. There was one case of diarrhea, four cases of nausea, one case of vomiting, one case of headache, one case of cough, one case of flu-like symptoms, and four cases of abdominal pain. Some of these adverse effects were only observed in the drug group and led to the study's termination. Mebendazole-related gastrointestinal symptoms, including nausea, vomiting, and diarrhea, accounted for the majority of discontinuations. As shown in Table 4, there were no statistically significant differences between baseline day and day 3 for any safety measurements in the mebendazole group: alanine transaminase (ALT), aspartate transaminase (AST), urea, creatinine, sodium, and potassium (p value not significant between the two days).
All data are presented as meanistandard deviasion (SD). * Nonsignificant difference in the kidney and liver function tests between baselione day and day 3 in the mebendazole- administered group. AST, aspartate aminotransferase; ALT, alanine aminotransferase Mebendazole efficacy
On the basis of primary and secondary clinical outcomes, the efficacy of mebendazole in COVID-19 patients was compared to that of a placebo drug. The primary endpoints of this study are the time from treatment initiation to negative PCR, the increase in PCR cycle threshold (CT), and the differential changes in WBC over the study timeframes. Changes between baseline and day 3 in C-reactive protein levels were the secondary efficacy endpoint. Table 5 revealed that there was no statistically significant difference between the baseline CRP and CT levels of the drug group and the control group. Third-day comparisons of CRP and CT levels between the two groups revealed significant differences, with lower CRP (2.031.45 vs. 5.45, P0.001) and higher CT levels (27.21±3.81 vs. 24.40±3.09, P=0.046) in the mebendazole group than in the placebo group (Figure 7).
* Nonsignificant difference between mebendazole and placebo groups at baseline day. CRP, C-reactive protein; CT, cycle threshold; SD, standard deviation.
Outcomes comparison between the groups of the study in the two timeframes As shown in Figure 8, there was no statistically significant difference in CRP levels between day three and the baseline day in the control group (P=0.25), whereas in the drug group there was a statistically significant difference between day three and the baseline day, with a dramatic decrease in CRP on day three compared to the baseline day (P0.001). In Figure
9, CT levels increased significantly on the third day compared to the day of baseline in the mebendazole group (P = 0.008) but not in the placebo group (P = 0.70). As shown in Figure
10, for all variables except the monocyte count, there is no statistically significant difference between day 3 and baseline in both study groups for the other primary endpoints, which include CBC with differential measures.
Relationship of different parameters in the drug and placebo groups Various parameters in the drug and placebo groups were subjected to a correlation analysis. The correlations between lymphocytes and CT levels in the study groups on the third day of the trial were showed in Table 6. In the mebendazole group, there was a significant inverse correlation between lymphocutes and CT levels (r= -0.491, P=0.039), whereas no such correlation was observed in the placebo group (r=0.051, P=0.888).
Table 6: Correlation analysis between lymphocytes and CT levels in the two study groups at day 3 of the trial.
* Lymphocytes and CT values are significantly and positively correlated at day 3 only in the mebendazole group.
Discussion
The results revealed a small number of adverse events comparable to those of other antiviral agents. Mebendazole's safety as an antihelmintic is well-established. Monitoring liver toxicity is among the most important adverse effects. Long-term, high-dose (40 mg/kg per day) mebendazole usage was reported in the treatment of hydated echinococcosis in adults and children, with granulocytopenia, alopecia, pruritus, skin abscess, and arthritis being the most common side effects. In this clinical trial, mebendazole was well tolerated by COVID-19 patients with normal liver enzyme levels and renal function parameters at baseline and day 3. The daily dosage prescribed is 1000 mg three times a day (6 tablets). Such a quantity of pills with substantial benefits may be preferable due to fewer difficulties in organizing drug administration and the possibility of adverse effects.
The efficacy of mebendazole in COVID-19 patients was evaluated using PCR cycle threshold (CT) elevation, CRP levels, and differential changes in WBC on day 3 between the drug group and the placebo group. On day 3, lower CRP and higher CT levels were observed in the mebendazole group, but not in the control group; these changes were not observed on day zero in either group. In this double-blind, placebo-controlled, randomized trial, the administration of mebendazole at the onset of COVID-19 symptoms was not associated with a negative PCR test. Several antiviral agents capable of managing COVID- 19 hospitalizations have been investigated, including remdesivir, ritonavir, interferon, corticosteroids, cytokine storm blockers, and monoclonal antibodies with similar results in mild to moderate COVID 19 patients. Since no pharmacological agent has a well-established COVID-19 eradication effect that is effective, rapid, and inexpensive, it was crucial to evaluate new potential antivirals such as mebendazole in a prospective setting.
Changes in the primary clinical endpoints (CT, WBC with differential) suggest a faster viral clearance in the mebendazole group than in the placebo group. In addition, the reduction and normalization of monocytes may indicate a more rapid eradication of the infection and its associated inflammation. As for the secondary clinical endpoint (CRP), which indicates the inflammatory status of the body, the drug group demonstrated a more rapid normalization of the elevated CRP levels, which favors a low incidence of COVID-19
complications. This is the first double-blind, placebo-controlled, randomized trial to evaluate the efficacy of mebendazole in the treatment of outpatients with COVID-19, to our knowledge.
Throughout the description and claims of this specification, the words “comprise” and “contain” and variations of them mean “including but not limited to”, and they are not intended to (and do not) exclude other moieties, additives, components, integers or steps. Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.
Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.
The reader's attention is directed to all papers and documents which are filed concurrently with or previous to this specification in connection with this application and which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference.
Claims
1. Mebendazole, at a daily body load of between 50 to 4000 mg per day that attains a mebendazole plasma concentration of between 300-500 nM, for use in the treatment and/or prophylaxis of a condition selected from the group comprising viral infections, autoimmune diseases and diseases arising from hyperinflammatory states.
2. The use of mebendazole, according to claim 1, alone or in combination with other appropriate medicaments wherein the viral infection is a symptomatic COVID-19 infection.
3. The use of mebendazole, according to claim 2 wherein an individual in need of treatment exhibits signs of lower respiratory tract pneumonia like symptoms, shortness of breath and blood oxygen saturation above and including 94% or below and including 94%.
4. The use of mebendazole, according to claim 1, alone or in combination with other appropriate medicaments wherein the autoimmune disease is a type I hypersensitivity reaction/allergy.
5. The use of mebendazole, according to claim 1, alone or in combination with other appropriate medicaments wherein the autoimmune disease is selected from the disease is selected from the group comprising type 1 diabetes, systemic lupus erythematosus, rheumatoid arthritis, psoriasis/psoriatic arthritis, multiple sclerosis, inflammatory bowel disease, Addison’s disease, Graves’ disease, Sjogren’s syndrome, Hashimoto’s thyroiditis, myasthenia gravis, autoimmune vasculitis, pernicious anaemia and other autoimmune diseases.
6. The use of mebendazole, according to claim 1, alone or in combination with other appropriate medicaments for the treatment of extrinsic asthma.
7. The use of mebendazole, according to claim 1, alone or in combination with other appropriate medicaments for the treatment of allergic and perennial rhinitis, allergic conjunctivitis, chronic urticaria, atopic dermatitis and/or laryngeal oedema
8. The use according to claim 1 of mebendazole, alone or in combination with other appropriate medicaments, for the treatment of a condition arising from a hyperinflammatory
state selected from the group comprising a bacterial or viral infection, diabetes mellitus, arterial and venous thromboembolism and chronic fatigue syndrome.
9. The use according to any preceding claim wherein mebendazole is administered orally as capsules, tablets, lozenges, slow-release preparations or as liquid preparation.
10. The use according to any of claims 1 to 8 wherein mebendazole is administered topically, as eye droplets or nasally as a spray.
11. The use according to any preceding claim wherein mebendazole is administered at least two to three times per day.
12. The use according to any one of claims 1 to 3 or 11 , wherein the condition is a viral infection and is administered at least two to three times per day with fatty food until lower respiratory symptoms return to normal parameters.
13. The use according to any preceding claim wherein mebendazole is used at a dose sufficient to inhibit Ran-GTP.
14.
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1748679A (en) * | 2004-09-14 | 2006-03-22 | 郑文婕 | Mebendazole new form for treating allergic rhinitis |
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US20210015797A1 (en) * | 2017-12-19 | 2021-01-21 | Repos Pharma Ab | Treatment For Inflammatory Disease |
-
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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US20210015797A1 (en) * | 2017-12-19 | 2021-01-21 | Repos Pharma Ab | Treatment For Inflammatory Disease |
CN112138133A (en) * | 2020-10-23 | 2020-12-29 | 成都中医药大学附属医院 | Pharmaceutical composition for preventing and/or treating novel coronavirus pneumonia and preparation method and application thereof |
Non-Patent Citations (2)
Title |
---|
FARAG AYMAN, WANG PING, BOYS IAN N., L. EITSON JENNIFER, OHLSON MAIKKE B., FAN WENCHUN, MCDOUGAL MATTHEW B., AHMED MAHMOUD, W. SCH: "Identification of Atovaquone, Ouabain and Mebendazole as FDA Approved Drugs Tar-geting SARS-CoV-2 (Version 4)", 14 May 2020 (2020-05-14), XP093025897, Retrieved from the Internet <URL:https://chemrxiv.org/engage/api-gateway/chemrxiv/assets/orp/resource/item/60c74bee9abda2184cf8d194/original/identification-of-atovaquone-ouabain-and-mebendazole-as-fda-approved-drugs-tar-geting-sars-co-v-2-version-4.pdf> [retrieved on 20230221], DOI: 10.26434/chemrxiv.12003930.v4 * |
VAN DER LINDE CARMEN, WANG XU, LEISEGANG KRISTIAN: "The Use of Probiotics in the Primary Prevention of Atopic Dermatitis: A Systemic Review of the Literature in Light of the Hygiene Hypothesis", XP093025899, Retrieved from the Internet <URL:https://repository.uwc.ac.za/xmlui/bitstream/handle/10566/6573/Probiotics%20for%20primary%20prevention%20of%20atopicdermatitis.pdf?sequence=1&isAllowed=y> [retrieved on 20230221] * |
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