Rock H. Johnson
Active Member
SLIDES: COVID19 Presentation Nelson Vergel March 23 2020.pdf
SLIDES April 21, 2020: Hydrochloroquine and COVID-19 Emerging Data and Placebo-Controlled Studies
Update on April 4, 2020 from Medscape (RCT's:Randomized Clinical Trials)
HydroxyChloroquine RCTs | ||||
|---|---|---|---|---|
Chloroquine, azithromycin | 1500 | Canada "+ international" | September 30, 2020 | |
Hydroxychloroquine | COVID-19 PEP: Post-Exposure Prophylaxis / Preemptive Therapy for SARS-Coronavirus-2 | 3000 | Canada, US | April 21, 2020 |
Hydroxychloroquine | Efficacy and Safety of Hydroxychloroquine for Treatment of Pneumonia Caused by 2019-nCoV (HC-nCoV ) | 30 | China | February 25, 2020 |
Hydroxychloroquine | Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial | 62 | China | February 28, 2020 |
Hydroxychloroquine | 1600 | US | March 1, 2021 | |
Hydroxychloroquine, azithromycin | 440 | Brazil | August 30, 2020 |
April 21 Update by George Carter
Note Date: April 20, 2020
In memory of Kurt Behnke
URL: POTENTIAL COVID TX
ANTIVIRALS
Drug | Target | Model | Data | Refs. |
Favipiravir, Favilavir, Avigan | Polymerase | COV19 | Open label study showed improved chest image; faster viral clearance; lop/rit arm not as effective; RCT showed no strong benefit vs arbidol for venting, only swifter fever/cough, dyspnea relief | 1,2,3, |
Galidesivir (BCX4430) | Polymerase (adenosine) | Yellow fever, WNV, Zika, Marburg | Phase I for COV19 | 6,7 |
Remdesivir (RDV) | Polymerase | COV19 | Ongoing studies, phase III results in April; NCT04257656, NCT04252664; possibly ineffective in severe disease; small very weak study with debatably positive results8 | 9,10,11 |
Chloroquine (CQ) | Endocytic vesicles | COV19 | Hu data; safe to use; HCQ better; Brazilian study stopped early due to higher mortality in very high dose arm (12g/10 days). | 12,13,14 |
Hydroxychloroquine (HCQ) | Endocytic vesicle | COV19, SARS | Several studies; better/safer than CQ, in vitro dosing; see systematic review; n=11 French study, no benefit; n=62 Chinese study saw reduced symptoms, no progression, shortened remission but some side effects. No benefit in viral clearance or symptom duration in open-label RCT at 28 days, n=150, mild-to-moderate disease; 30% w/AE vs 8.8% in standard-of-care group; greater reduction in CRP in HQ and greater alleviation of sx at wk 2 | 15,16,17, 18,19,20 |
Macrolide/ azithromycin | Secondary infection; antinflammatory | COV19 | Combo with HCQ; QT problems potential with combo | 21,22 |
Ascorbic acid (Vitamin C) | Inflammation | COV | IV; efficacy in sepsis, ARDS; NCT04264533, NCT04328961 (oral) | 23,24, |
Cholecalciferol (Vitamin D3) | Prophylactic | Lower respiratory infection | Reduced number of infections, esp. for those with baseline low level; large bolus doses not helpful | 27 |
Zinc (sulfate, picolinate, amino acid bound) | Ionophores; polymerase | SARS, animal | Cell culture studies; diarrhea in calves with viral infections (DBPC) | 28,29 |
Micronutrients | Health | Prophylaxis, Treatment | Combinations of multivitamin, vitamin C, D3, NAC, probiotics, CoQ10, glutamine | 30,31 |
Potassium | Hypokalemia | COV | Urinary loss offset by supplementation; nearly 2/3 had hypokalemia, correlated with disease severity; monitor ECG; avg dose, 3 g/day; pts treated also with lop/rit, IFNα and arbidol | 32 |
Quercetin | Protease; ACE2 inhibition | Ebola, Zika, coronavirus, dengue, SARS | Clinical trials underway? (McGill)33; some efficacy with flu in vitro | 34,35, |
N-Acetylcysteine (NAC) | ROS; Iron chelation? | PEDV, thalassemia | COV/MERS bind hemoglobin; low RBC, elevated ALT, myalgia as risks for vent; various chelators38 (hemoglobin binding)39 | 40,41, |
Glycyrrhizin | Adsorption; other | SARS | In vitro work; EC50 316-625 mg/L; used in HIV, Hep C; porcine alphacoronavirus diarrhea | 44,45 |
ARB, ACE inhibitors | ACE2 receptor | COV | Retrospective, multi-center study; 60% lower risk of death; good news for those treating hypertension | 46 |
Camostat mesylate | TMPRSS2 (hu) | COV | Phase II in Denmark, 100 mg tid | 47 |
Ribavirin | Polymerase | SARS, MERS | Not good as mono; ltd efficacy with other drugs (IFN-alpha) | 48 |
Nitazoxanide | Secondary inf. | MERS | In vitro; suppresses inflammatory cytokines | 49 |
Corticosteroids | Inflammation | SARS,COV | Limitations—see guidelines; probably NOT a good idea for most | 50 |
Lianhuaqingwen/ TCM | Various | COV, flu | I.v.; hu studies better than oseltamivir; various other Chinese herbal medicines as adjunctive or early treatment | 51,52, |
Artemisia | ? | Herpesviruses, HCV, HIV | Mostly i.v. and animal; reduced CMV viral load (artesenuate) | 55 |
Oseltamivir | Polymerase? | SARS | (no effect, i.v.); used in combination | 56 |
Umifenovir (Arbidol) | ? | COV | Phase IV NCT04260594, NCT04254874, | 57,5,58 |
EIDD-2801 | Polymerase | COV | Emory U study; mouse studies; oral | 59,60,61 |
GC376 | 3CL protease | COV, FIPV | I.v., mouse | 62 |
ASC09F | 3CL protease | COV | Phase III NCT04261270 with oseltamivir | 57 |
Lopinavir/ritonavir | Protease | COV | Failed as monotherapy; combo? | 63 |
Teicoplanin | Inhibits spike cleavage | COV | I.v.; antibiotic for Staph., gram pos. | 64 |
Aviptadil | ARDS | COV | Vasoactive intestinal peptide; NCT04311697; unclear rationale | ? |
Colchicine | Cytokine storm | COV | COLCORONA study | 65 |
Ivermectin | IMPα/β1 | COV | I.v.; 5000-fold reduction in viral RNA; caution that in Thailand, drug was safe but no benefit for dengue | 66,67 |
Tenofovir | polymerase? | COV | I.v.; fleximers?; no benefit in vitro | 68,7 |
Disulfiram | Protease | ? | Lacking clinical data | 57 |
Darunavir | ? protease | COV | Trial CT04252274 w/cobicistat; no benefit in vitro compared to RDV | 69 |
Sildenafil (Viagra) | Blood flow | COV symptoms | NCT04304313, n=10 but phase 3? | |
Nitric oxide | Lung function (avoid vent) | COV, MERS | Non-invasive CPAP admin of NO; NCT04305457, NCT04312243, NCT04306393. Study in Hong Kong (NCT04285801) completed—no results? | 70 |
CQ – chloroquine; DBPC – double-blind, placebo-controlled; FIPV – Feline infectious peritonitis virus; HCQ – hydroxychloroquine; I.v. – in vitro; 3CL – 3C-like protease; ROS – reactive oxygen species
Protease inhibitor candidates (SARS): The compounds identified include zinc or mercury conjugates [26,27], C2-symmetric diols [28,29], peptidomimetic α,β-unsaturated esters [30], anilides [31], benzotriazole [32], N-phenyl-2-(2-pyrimidinylthio)acetamide [33], biphenyl sulfone [34], glutamic acid and glutamine peptides possessing a trifluoromethylketone group [35], pyrimidinone [36], and pyrazole analogues that can also inhibit 3Cpro of picornaviruses CVB3 (coxsackievirus), EV-71 (enterovirus) and RV- 14 (rhinovirus) (coronavirus and picornavirus dual inhibitors).71
BIOLOGICS
Drug | Target | Model | Data | Refs. |
Alpha interferon (IFNα) | SARS | I.v., human | IFNα-n1 and n3 active (not 2a and 2b) | 56 |
Beta Interferon (IFNβ) | SARS | I.v. | IFNβ-1b (but not 1a) active i.v. | 56 |
IVIG; (heparin also for high d-Dimer) | COV | Theoretical; some data in SARS, flu | Calming cytokine storm; high dose 5-days (0.3-0.5 mg/kg) | 72 |
Tocilizumab | IL6/COV19 | Human studies; NCT04310228 | Experimental; osteonecrosis of jaw? | 73 |
Sarilumab (Kevzara) | IL6R | Used for RA; study with severe COV; site also in Phase III for RDV | Study by Northwell Health, Long Island | 74 |
Baracitinib | JAK inhibitor; cell entry | COV/Theoretical | AP2-associated protein kinase 1 (AAK1); 2 mg or 4 mg/day | 75 |
Convalescent plasma | COV19 | Hu studies; first 5 cases, 3 discharged after ARDS, 2 stable | NCT04325672, NCT04323800, NCT04292340; n=10 saw clinical improvement in 3 days and undetectable virus at 7 | 76,77, |
Monoclonal antibodies (MAbs) | COV19, SARS, MERS | Passive immunotherapy; see also VACCINES list below; potential lack of binding to COV w/SARS MAb80 | Review paper provides mech of action list of MAbs, SARS, MERS | 81 |
BCG Vaccine | Innate immune response | Healthcare workers | Study in Australia | 82 |
PRO140 (leronlimab) | Cytokine storm, CCR5r | Theoretical | IND provided | 83 |
APNO1 | ACE2 | rhACE2; phase I safety study, no serious AE but dose-dependent; limited effect? | European phase II initiated (press releases only!) | 84 |
PLX cells | Treg, M2 macrophages | Placental expanded mesenchymal cells | 6 seriously ill covid pts saw improvement (Israel) | 85 |
AE – adverse event; RA – rheumatoid arthritis; rh – recombinant, human
COMBINATION STUDIES
Drug | Target | Model | Data | Refs. |
Favipiravir+IFNα | COV19 | ? | ||
Favipiravir+CQ | COV19 | Human | NCT04319900 | |
Favipiravir+Tocilizumab | COV19 | Human | NCT04310228 | |
HCQ/azithromycin | COV19 | Open label study | Viral clearance in 6; survival? | 15 |
Nitazoxanide/oseltamivir or zanamivir | Coronavirus | I.v., synergy with antivirals | Hu: NTZ alone not good in flu | 2 |
Ribavirin/IFNα | MERS | Macaque | No dyspnea, low inflame markers in treated | 86 |
Ribavirin/IFN | MERS | Retrospective analysis; critically ill | No benefit on mortality or viral clearance with rIFN-α2a, rIFN-α2b, or rIFN-β1a | 87 |
Ribavirin/IFN | COV19 | Trial | Underway ChiCTR2000029387 | 57 |
Lop/rit+IFNα+arbidol (nebulized IFN) | COV19 | Treatment experience | If not effective, use CQ; | 88 |
Lopinavir/ritonavir+IFNβ | MERS | Human/mouse | Trial underway; Gilead mouse study showed IFNβ+rem better | 89,90 |
Mixed combinations, Lop, HCQ, oseltamivir, darunavir, favipiravir[1] | COV19 | Human | Thai study; NCT04303299 | |
Chinese medicine/herbs | COV2 | Human | Various, pt-dependent; NCT04295551 w/Xiyanping injection, extract of Andrographis paniculate: 9-dehydro-17-hydro-andrographolide and sodium 9-dehydro-17-hydro-andrographolide-19-yl sulfate | 91 |
[to be continued] | ||||
VACCINES
Drug | Target | Model | Data | Refs. |
4 vaccine candidates w/ or w/o alum adjuvant | SARS | Mouse | 1-whole, inactivated with formalin, UV; 2-whole inactivated with propiolactone w/alum; 3-spike subunit induced neutralizing Abs; 4-virus-like particle with spike, nucleocapsid, env and membrane proteins; mice challenged with virus experienced lung disease (Th2 immunopathology) | 92 |
siRNA, aerosolized | I.v., animal | Alnylam | 93 | |
siRNA, nebulizer | Preclin | Sirnaomics | ||
IgG1 MAbs | Isolated from recovered pts | 500 abs so far | Abcellera Biologics | |
IgG1 Mab | Complement factor 5a | Phase I, China | Beijing Defengrei | |
Situximab | IL6 | Case control, sx pts | EUSA Pharma | |
IgG1 Mab (47D11) | COVID19 spike (S) | Chimeric Mab | Harbour Biomed | |
IgG1 Mab | Multiple epitopes | Derived from animal models then humanized | ImmunoPrecise Abs | |
IgG1 Mab | Comp factor 5a | Appd for trial, China | InflaRx | |
IgG1 | Polyclonal against SARS-Cov2 | MAbs also against ACE2; preclinical | Vir Biotech | |
S bound to virucidal nanomicelle | w/PEG; targets virus | Testing in culture | NanoViricides | |
Aplidin | Elongation factor 1A | In vitro studies completed | Pharmamar | |
Clearly, this table needs work! | See AVAC link in Clinical Trials below for more. |
Clinical Trial Lists
AVAC Ongoing studies: Ongoing Studies for the Treatment and Prevention of the COVID-19 Virus
NLM: Search of: Coronavirus - List Results - ClinicalTrials.gov
Drug Toxicities Notes
Identification of adverse drug reactions88
It has been demonstrated that the incidence of abnormal liver function is 51.9% in COVID-19 patients who have received lopinavir/ritonavir combined arbidol antiviral treatment. Multivariate analysis revealed that antiviral agents and more concomitant medications are two independent risk factors of abnormal liver function. Therefore, monitoring of the adverse drug reactions should be strengthened; the unnecessary drug combinations should be reduced. The main adverse reactions of antiviral agents include:
(1) Lopinavir /ritonavir and darunavir/cobicistat: diarrhea, nausea, vomit, the increase of serum aminotransferase, jaundice, dyslipidemia, the increase of lactic acid. Symptoms will recover after drug withdrawal.
(2) Arbidol: the increase of serum aminotransferase and jaundice. When combined with lopinavir, the incidence rate is even higher. The symptoms will recover after drug withdrawal. Sometimes a slowdown of the heart could be induced; thus it is necessary to avoid the combination of arbidol with β–receptor inhibitors such as metoprolol and propranolol. We suggest to stop taking the drugs when the heart rate drops below 60/min.
(3) Fapilavir: elevation of plasma uric acid, diarrhea, neutropenia, shock, fulminant hepatitis, acute kidney injury. The adverse reactions were commonly seen in elderly patients or patients complicated with cytokine storm.
(4) Chloroquine phosphate: dizziness, headache, nausea, vomit, diarrhea, different kinds of skin rash. The most severe adverse reaction is cardiac arrest. The main adverse reaction is the ocular toxicity. An electrocardiogram needs to be examined before taking the drug. The drug should be prohibited for patients with arrhythmia (e.g., conduction block), retinal disease, or hearing loss.
Resources
WHO Multinational, multi-therapy trial:
WHO to launch multinational trial to jumpstart search for coronavirus drugs
WHO Vaccines list: https://www.who.int/blueprint/priority-diseases/key-action/novel-coronavirus-landscape-ncov.pdf
Therapeutics Tracker: COVID-19 therapeutics tracker
Infectious Disease Society recommendations: Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19
Diagnostics list: SARS-CoV-2 diagnostic pipeline - FIND
Testing: Testing Resources for COVID-19
Open Source R&D for Covid-19: COVID-19 | Knowledge Portal
Supplement Evidence: Which supplements can help against colds and the flu?
Overriding Patents for Access: Drugs That Could Be Used to Beat COVID-19 Have Another Barrier – Patents
Treatment list: Coronavirus outbreak: Top coronavirus drugs and vaccines in development
“Every” vaccine/treatment (for-profit): Every Vaccine and Treatment in Development for COVID-19, So Far
Drugs list: Chemicals for Pharmaceutical Research for the Novel Coronavirus, COVID-19 - LKT Labs
Contact
Use gmail extension with “gmcfiar” to reach me. Also, contact tab at www.fiar.us
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[1] A 6-Week Prospective, Open label, Randomized, in Multicenter Study of, Oseltamivir 300mg per day plus Hydroxychloroquine 800 mg per day versus Combination of Lopipinavir 800mg (or 10 mg/kg ) per day and Ritonavir 200 mg ( or 2.5 mg/kg ) per day plus Oseltamivir 300 mg ( or 4-6 mg /kg ) per day versus Combination of Darunavir 400 mg every 8 hours plus ritonavir 200 mg (or 2.5 mg/kg ) per day plus Oseltamivir 300mg ( or 4-6 mg /kg ) per day plus Hydroxychloroquine 400 mg per day in mild COVID 19 and Combination of Lopipinavir 800 mg (or 10 mg/kg ) per day and Ritonavir 200 mg ( or 2.5 mg/kg ) per day plus Oseltamivir 300 mg ( or 4-6 mg /kg ) per day versus Favipiravir 2400 mg, 2400 mg, and 1200 mg every 8 h on day 1, and a maintenance dose of 1200 mg twice a day plus Lopipinavir 800 mg ( or 10 mg/kg ) per day and Ritonavir 200 mg ( or 2.5 mg/kg ) per day versus Combination of Darunavir 400 mg every 8 hours plus ritonavir 200 mg (or 2.5 mg/kg ) plus Oseltamivir 300 mg (or 4-6 mg /kg ) per day plus Hydroxychloroquine 400 mg per day versus Favipiravir 2400 mg, 2400 mg, and 1200 mg every 8 h on day 1, and a maintenance dose of 1200 mg twice a day plus Darunavir 400 mg every 8 hours Ritonavir 200 mg ( or 2.5 mg/kg ) per day plus Hydroxychloroquine 400 mg per day in moderate to critically illness in COVID 19.
