FLCCC Alliance MATH+ ascorbic acid and I-MASK+ ivermectin protocols for COVID-19 -a brief review
M.Sc Mika Turkia
An alliance of established experts on critical care, Front Line Covid-19 Critical Care Alliance (FLCCC), has published two protocols for treatment of COVID-19. The first one, MATH+, is intended for hospital and intensive care unit treament of pulmonary phases of the disease. It is based on affordable, commonly available components: anti-inflammatory corticosteroids (methylprednisolone, "M"), high-dose vitamin C infusion (ascorbic acid, "A"), vitamin B1 (thiamine, "T"), anticoagulant heparin ("H"), antiparasitic agent ivermectin, and supplemental components ("+") including melatonin, vitamin D, elemental zinc and magnesium. The MATH+ protocol has received scarce attention due to the World Health Organization advising against the use of corticosteroids in the beginning of the pandemic. In addition, randomized controlled clinical trials were required as a condition for adoption of the protocol. As the hospital mortality rate of MATH+ treated patients was less than a quarter of the rate of patients receiving a standard of care, the authors of the protocol considered performing such trials unethical. Later, other parties have performed clinical trials with e.g. corticosteroids and anticoagulants which has led to their more widespread adoption. Other essential components of the protocol remain unadopted. In October 2020, ivermectin was upgraded from an optional component to an essential component of the protocol. According to the authors, ivermectin is considered the first agent effective for both prophylaxis (prevention) of COVID-19 and for treatment of all phases of COVID-19 including outpatient treatment of the early symptomatic phase. Therefore, at the end of October 2020, a separate ivermectin-based I-MASK+ protocol for prophylaxis and early outpatient treatment of COVID-19 was published.
References
Anderson, Unofficial translation of the Shanghai 2019 coronavirus disease comprehensive treatment expert consensus
Arvinte, Singh, Marik, Serum Levels of Vitamin C and Vitamin D in a Cohort of Critically Ill COVID-19 Patients of a North American Community Hospital Intensive Care Unit in May 2020: A Pilot Study, Medicine in Drug Discovery,
doi:10.1016/j.medidd.2020.100064
Barabutis, Khangoora, Marik, Catravas, Hydrocortisone and Ascorbic Acid Synergistically Prevent and Repair Lipopolysaccharide-Induced Pulmonary Endothelial Barrier Dysfunction, Chest,
doi:10.1016/j.chest.2017.07.014
Behera, Patro, Singh, Role of ivermectin in the prevention of COVID-19 infection among healthcare workers in India: A matched case-control study, medRxiv,
doi:10.1101/2020.10.29.20222661
Benefield, Skrip, Clement, Althouse, Chang et al., SARS-CoV-2 viral load peaks prior to symptom onset: a systematic review and individual-pooled analysis of coronavirus viral load from 66 studies, medRxiv,
doi:10.1101/2020.09.28.20202028
Biancatelli, Berrill, Catravas, Marik, Quercetin and Vitamin C: An Experimental Synergistic Therapy for the Prevention and Treatment of SARS-CoV-2 Related Disease (COVID-19), Frontiers in Immunology,
doi:10.3389/fimmu.2020.01451
Biancatelli, Berrill, Mohammed, Marik, Melatonin for the treatment of sepsis: the scientific rationale, Journal of Thoracic Disease,
doi:10.21037/jtd.2019.12.85
Bier, Astrup, Observations of the most remarkable occurences
Buijsers, Yanginlar, Maciej-Hulme, De, Van Der et al., Beneficial non-anticoagulant mechanisms underlying heparin treatment of COVID-19 patients, EBioMedicine,
doi:10.1016/j.ebiom.2020.102969
Chahrazed, Hassina, Soumya, Beneficial effects of ascorbic acid on ivermectin repeated high-dose therapy in rabbits: biochemical and histopathological investigations, European Journal of Biological Research,
doi:10.5281/zenodo.4116306
Chamie, Real-World Evidence: The Case of Peru
Cheng, Can early and high intravenous dose of vitamin C prevent and treat coronavirus disease 2019 (COVID-19)?, Medicine in Drug Discovery,
doi:10.1016/j.medidd.2020.100028
Chiscano-Camón, Ruiz-Rodriguez, Ruiz-Sanmartin, Roca, Ferrer, Vitamin C levels in patients with SARS-CoV-2-associated acute respiratory distress syndrome, Critical Care,
doi:10.1186/s13054-020-03249-y
Ci, Li, Yu, Avermectin exerts anti-inflammatory effect by downregulating the nuclear transcription factor kappa-B and mitogen-activated protein kinase activation pathway, Fundamental & Clinical Pharmacology,
doi:10.1111/j.1472-8206.2009.00684.x
Cohen, Kupferschmidt, A very, very bad look' for remdesivir, Science
Dabbagh-Bazarbachi, Clergeaud, Quesada, Ortiz, Sullivan et al., Zinc ionophore activity of quercetin and epigallocatechin-gallate: from Hepa 1-6 cells to a liposome model, Journal of Agricultural and Food Chemistry,
doi:10.1021/jf5014633
Dinicolantonio, Barroso, Mccarty, Ivermectin may be a clinically useful anti-inflammatory agent for late-stage COVID-19, Open Heart,
doi:10.1136/openhrt-2020-001350
Fowler, Syed, Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis, Journal of Translational Medicine,
doi:10.1186/1479-5876-12-32
Fowler, Truwit, Hite, Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial, JAMA
Gandhi, Beyrer, Goosby, Masks Do More Than Protect Others During COVID-19: Reducing the Inoculum of SARS-CoV-2 to Protect the Wearer, Journal of General Internal Medicine,
doi:10.1007/s11606-020-06067-8
Garcia, Fumeaux, Guerci, Prognostic factors associated with mortality risk and disease progression in 639 critically ill patients with COVID-19 in Europe: Initial report of the international RISC-19-ICU prospective observational cohort, EClinicalMedicine,
doi:10.1016/j.eclinm.2020.100449
Garrigues, Janvier, Kherabi, Post-discharge persistent symptoms and health-related quality of life after hospitalization for COVID-19, Journal of Infection,
doi:10.1016/j.jinf.2020.08.029
Glinsky, Tripartite Combination of Candidate Pandemic Mitigation Agents: Vitamin D Quercetin, and Estradiol Manifest Properties of Medicinal Agents for Targeted Mitigation of the COVID-19 Pandemic Defined by Genomics-Guided Tracing of SARS-CoV-2 Targets in Human Cells, Biomedicines,
doi:10.3390/biomedicines8050129
Hashim, Maulood, Rasheed, Fatak, Kabah et al., Controlled randomized clinical trial on using Ivermectin with Doxycycline for treating COVID-19 patients in Baghdad Iraq, medRxiv,
doi:10.1101/2020.10.26.20219345
Heidary, Gharebaghi, Ivermectin: a systematic review from antiviral effects to COVID-19 complementary regimen, The Journal of Antibiotics,
doi:10.1038/s41429-020-0336-z
Hemilä, Chalker, Vitamin C may reduce the duration of mechanical ventilation in critically ill patients: a meta-regression analysis, Journal of Intensive Care,
doi:10.1186/s40560-020-0432-y
Hu, Guan, -Jie, Bi, Efficacy and safety of Lianhuaqingwen capsules a repurposed Chinese herb, in patients with coronavirus disease 2019: A multicenter, prospective, randomized controlled trial, Phytomedicine,
doi:10.1016/j.phymed.2020.153242
Jans, Wagstaff, The broad spectrum host-directed agent ivermectin as an antiviral for SARS-CoV-2? Biochemical and Biophysical Research Communications,
doi:10.1016/j.bbrc.2020.10.042
Khan, Al-Ghanem, Bamefleh, Bronchiolitis obliterans organizing pneumonia: Pathogenesis clinical features, imaging and therapy review, Annals of Thoracic Medicine,
doi:10.4103/1817-1737.39641
Kory, Kanne, SARS-CoV-2 organising pneumonia: 'Has there been a widespread failure to identify and treat this prevalent condition in COVID-19?, BMJ Open Respiratory Research,
doi:10.1136/bmjresp-2020-000724
Labate, The Therapeutic Use of Ayahuasca
Li, Chen, Cao, Zhu, Zheng et al., Extraordinary GU-rich single-strand RNA identified from SARS coronavirus contributes an excessive innate immune response, Microbes and Infection,
doi:10.1016/j.micinf.2012.10.008
Li, Zhao, Zhan, Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin benefiting for COVID-19 treatment, Journal of Cellular Physiology,
doi:10.1002/jcp.30055
Liang, Handbook of COVID-19 Prevention and Treatment
Liu, Hong, Yang, A Single Large Dose of Vitamin D Could be Used as a Means of Coronavirus Disease 2019 Prevention and Treatment, Drug Design Development and Therapy,
doi:10.2147/dddt.s271754
Mao, Intensive management of severe acute pancreatitis, Annals of Translational Medicine
Marik, Hydrocortisone Ascorbic Acid and Thiamine (HAT Therapy) for the Treatment of Sepsis. Focus on Ascorbic Acid, Nutrients,
doi:10.3390/nu10111762
Marik, Kory, Varon, Iglesias, Meduri, MATH+ protocol for the treatment of SARS-CoV-2 infection: the scientific rationale, Expert Review of Anti-infective Therapy,
doi:10.1080/14787210.2020.1808462
Marik, Payen, CITRIS-ALI: How statistics were used to obfuscate the true findings. Anaesthesia, Critical Care & Pain Medicine,
doi:10.1016/j.accpm.2019.10.004
Mousavi, Bereswill, Heimesaat, Immunomodulatory and antimicrobial effects of vitamin C, European Journal of Microbiology and Immunology,
doi:10.1556/1886.2019.00016
Navarro, Camprubí, Requena-Méndez, Safety of high-dose ivermectin: a systematic review and meta-analysis, Journal of Antimicrobial Chemotherapy,
doi:10.1093/jac/dkz524
Nchioua, Kmiec, Müller, SARS-CoV-2 Is Restricted by Zinc Finger Antiviral Protein despite Preadaptation to the Low-CpG Environment in Humans, mBio,
doi:10.1128/mbio.01930-20
News, How a Grass Roots Health Movement Led to Acceptance of Ivermectin as a COVID-19 Therapy in Peru
Palhano-Fontes, Barreto, Onias, Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial, Psychological Medicine,
doi:10.1017/s0033291718001356
Paranjpe, Fuster, Lala, Association of Treatment Dose Anticoagulation With In-Hospital Survival Among Hospitalized Patients With COVID-19, Journal of the American College of Cardiology,
doi:10.1016/j.jacc.2020.05.001
Perera, Tso, Tsang, SARS-CoV-2 virus culture from the upper respiratory tract: Correlation with viral load subgenomic viral RNA and duration of illness, medRxiv,
doi:10.1101/2020.07.08.20148783
Perico, Benigni, Casiraghi, Ng, Renia et al., Immunity endothelial injury and complement-induced coagulopathy in COVID-19, Nature Reviews Nephrology,
doi:10.1038/s41581-020-00357-4
Rajter, Sherman, Fatteh, Vogel, Sacks et al., Use of Ivermectin Is Associated With Lower Mortality in Hospitalized Patients With Coronavirus Disease, Chest,
doi:10.1016/j.chest.2020.10.009
Reaz, Clinical Trial of Ivermectin Plus Doxycycline for the Treatment of Confirmed Covid-19
Rizzo, Ivermectin, antiviral properties and COVID-19: a possible new mechanism of action, Naunyn Schmiedebergs Arch Pharmacol,
doi:10.1007/s00210-020-01902-5
Runfeng, Yunlong, Jicheng, Lianhuaqingwen exerts anti-viral and anti-inflammatory activity against novel coronavirus (SARS-CoV-2), Pharmacological Research,
doi:10.1016/j.phrs.2020.104761
Salton, Confalonieri, Meduri, Prolonged Low-Dose Methylprednisolone in Patients With Severe COVID-19 Pneumonia, Open Forum Infectious Diseases,
doi:10.1093/ofid/ofaa421
Shen, Yang, Wang, Diagnosis treatment, and prevention of 2019 novel coronavirus infection in children: experts' consensus statement, World Journal of Pediatrics,
doi:10.1007/s12519-020-00343-7
Stafford, Bokil, Achard, Metal ions in macrophage antimicrobial pathways: emerging roles for zinc and copper, Bioscience Reports,
doi:10.1042/bsr20130014
The, Group, Dexamethasone in Hospitalized Patients with Covid-19 -Preliminary Report, New England Journal of Medicine,
doi:10.1056/nejmoa2021436
Trunfio, Cabodi, Anti-Xa monitoring improves low-molecular-weight heparin effectiveness in patients with SARS-CoV-2 infection, Thrombosis Research,
doi:10.1016/j.thromres.2020.09.039
Velthuis Ajw Te, She Van Den, Sims, Baric, Snijder et al., Zn2+ Inhibits Coronavirus and Arterivirus RNA Polymerase Activity In Vitro and Zinc Ionophores Block the Replication of These Viruses in Cell Culture, PLoS Pathogens,
doi:10.1371/journal.ppat.1001176
Waheed, Prophylactic Ivermectin in COVID-19 Contacts
Wang, Jiang, He, A retrospective cohort study of methylprednisolone therapy in severe patients with COVID-19 pneumonia, Signal Transduction and Targeted Therapy,
doi:10.1038/s41392-020-0158-2
Xu, Baylink, Chen, The importance of vitamin d metabolism as a potential prophylactic immunoregulatory and neuroprotective treatment for COVID-19, Journal of Translational Medicine,
doi:10.1186/s12967-020-02488-5
Yang, Islam, Wang, Li, Chen, Traditional Chinese Medicine in the Treatment of Patients Infected with 2019-New Coronavirus (SARS-CoV-2): A Review and Perspective, International Journal of Biological Sciences,
doi:10.7150/ijbs.45538
Young, Ong, Ng, Viral Dynamics and Immune Correlates of Coronavirus Disease 2019 (COVID-19) Severity, Clinical Infectious Diseases,
doi:10.1093/cid/ciaa1280