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Evaluation of the efficacy and safety of oral N‐acetylcysteine in patients with COVID‐19 receiving the routine antiviral and hydroxychloroquine protocol: A randomized controlled clinical trial

Atefi et al., Immunity, Inflammation and Disease, doi:10.1002/iid3.1083, IRCT20200623047897N1
Nov 2023  
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Mortality 85% Improvement Relative Risk Azithromycin  Atefi et al.  LATE TREATMENT Is late treatment with azithromycin beneficial for COVID-19? Retrospective 60 patients in Iran Lower mortality with azithromycin (not stat. sig., p=0.31) c19early.org Atefi et al., Immunity, Inflammation a.., Nov 2023 Favorsazithromycin Favorscontrol 0 0.5 1 1.5 2+
RCT 60 hospitalized COVID-19 patients evaluating the efficacy and safety of adding oral N-acetylcysteine (NAC) at 600mg three times daily to standard antiviral treatment regimens. There was lower mortality for patients that received azithromycin, without statistical significance.
risk of death, 85.1% lower, RR 0.15, p = 0.31, treatment 0 of 18 (0.0%), control 4 of 42 (9.5%), NNT 10, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm).
Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
Atefi et al., 20 Nov 2023, retrospective, Iran, peer-reviewed, 10 authors, trial IRCT20200623047897N1. Contact: goodarzi.a@iums.ac.ir, azadeh_goodarzi1984@yahoo.com.
This PaperMiscellaneousAll
Evaluation of the efficacy and safety of oral N‐acetylcysteine in patients with COVID‐19 receiving the routine antiviral and hydroxychloroquine protocol: A randomized controlled clinical trial
Najmolsadat Atefi, Azadeh Goodarzi, Taghi Riahi, Niloofar Khodabandehloo, Mahshid Talebi Taher, Niloufar Najar Nobari, Farnoosh Seirafianpour, Zeinab Mahdi, Amir Baghestani, Rohollah Valizadeh
Immunity, Inflammation and Disease, doi:10.1002/iid3.1083
Background: The current absence of gold-standard or all-aspect favorable therapies for COVID-19 renders a focus on multipotential drugs proposed to prevent or treat this infection or ameliorate its signs and symptoms vitally important. The present well-designed randomized controlled trial (RCT) sought to evaluate the efficacy and safety of N-acetylcysteine (NAC) as adjuvant therapy for 60 hospitalized Iranian patients with COVID-19. Methods: Two 30-person diets, comprising 15 single diets of Kaletra (lopinavir/ritonavir) + hydroxychloroquine (HCQ) with/without NAC (600 mg TDS) and atazanavir/ritonavir + HCQ with/without NAC (600 mg TDS), were administered in the study. Results: At the end of the study, a further decrease in C-reactive protein was observed in the NAC group (P = 0.008), and no death occurred in the atazanavir/ritonavir + HCQ + NAC group, showing that the combination of these drugs may reduce mortality. The atazanavir/ritonavir + HCQ and atazanavir/ritonavir + NAC groups exhibited the highest O 2 saturation at the end of the study and a significant rise in O 2 saturation following intervention commencement, including NAC (P > 0.05). Accordingly, oral or intravenous NAC, if indicated, may enhance O 2 saturation, blunt the inflammation trend (by reducing C-reactive protein), and lower mortality in hospitalized patients with COVID-19.
AUTHOR CONTRIBUTIONS Azadeh Goodarzi and Najmolsadat Atefi conceived and planned the intervention. Taghi Riahi, Niloofar Khodabandehloo, Mahshid Talebi Taher and Niloufar Najar Nobari carried out the intervention. Zeinab Mahdi and Amir Baghestani gathering the datas. Amir Baghestani, Zeinab Mahdi, Rohollah Valizadeh, and Farnoosh Seirafianpour contributed to the interpretation of the results. Rohollah Valizadeh analyzed the data. Farnoosh Seirafianpour took the lead in writing the manuscript. All authors contributed to the preparation of data and the finalization of this article. All the figures have been produced by the authors of this article and are personal data. CONFLICT OF INTEREST STATEMENT The authors declare no conflict of interest.
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The present well‐designed randomized controlled trial ' '(RCT) sought to evaluate the efficacy and safety of N‐acetylcysteine (NAC) as adjuvant ' 'therapy for 60 hospitalized Iranian patients with ' 'COVID‐19.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Two 30‐person ' 'diets, comprising 15 single diets of Kaletra (lopinavir/ritonavir) + hydroxychloroquine (HCQ) ' 'with/without NAC (600 mg TDS) and atazanavir/ritonavir + HCQ with/without NAC (600 mg TDS), ' 'were administered in the ' 'study.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>At the end of the ' 'study, a further decrease in C‐reactive protein was observed in the NAC group ' '(<jats:italic>P</jats:italic>\u2009=\u20090.008), and no death occurred in the ' 'atazanavir/ritonavir + HCQ + NAC group, showing that the combination of these drugs may ' 'reduce mortality. 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'article-title': 'MNa theory: triple therapy to COVID‐19: minocycline, N‐acetylcysteine ' 'and aspirin', 'volume': '5', 'author': 'Hamad MNM', 'year': '2020', 'journal-title': 'Saudi J Biomed Res'}, { 'key': 'e_1_2_10_20_1', 'doi-asserted-by': 'crossref', 'DOI': '10.1016/j.mehy.2020.110133', 'article-title': 'N‐acetycysteine: a potential therapeutic agent in COVID‐19 infection', 'volume': '144', 'author': 'Jaiswal N', 'year': '2020', 'journal-title': 'Med Hypotheses'}, { 'issue': '10', 'key': 'e_1_2_10_21_1', 'doi-asserted-by': 'crossref', 'first-page': '2668', 'DOI': '10.1021/acs.chemrestox.0c00299', 'article-title': 'Protective role of glutathione against peroxynitrite‐mediated DNA ' 'damage during acute inflammation', 'volume': '33', 'author': 'Ahmed N', 'year': '2020', 'journal-title': 'Chem Res Toxicol'}, { 'key': 'e_1_2_10_22_1', 'doi-asserted-by': 'crossref', 'DOI': '10.1016/j.mehy.2020.109778', 'article-title': 'N‐acetyl‐cysteine may prevent COVID‐19‐associated cytokine storm and ' 'acute respiratory distress syndrome', 'volume': '140', 'author': 'Assimakopoulos SF', 'year': '2020', 'journal-title': 'Med Hypotheses'}, { 'issue': '4', 'key': 'e_1_2_10_23_1', 'doi-asserted-by': 'crossref', 'DOI': '10.5812/iji.106361', 'article-title': 'N‐acetylcysteine in severe COVID‐19: the possible mechanism', 'volume': '7', 'author': 'Hasan MJ', 'year': '2020', 'journal-title': 'Int J Infect'}, { 'issue': '9', 'key': 'e_1_2_10_24_1', 'first-page': '122', 'article-title': 'N‐acetyl cysteine (NAC) and COVID‐19 treatment: new hopes in old ' 'medication', 'volume': '3', 'author': 'Hatami N', 'year': '2020', 'journal-title': 'Int J Multidiscip Res Anal'}, { 'key': 'e_1_2_10_25_1', 'doi-asserted-by': 'crossref', 'first-page': '1047', 'DOI': '10.2147/TCRM.S273700', 'article-title': 'N‐acetylcysteine to combat COVID‐19: an evidence review', 'volume': '16', 'author': 'Shi Z', 'year': '2020', 'journal-title': 'Ther Clin Risk Manag'}, { 'key': 'e_1_2_10_26_1', 'unstructured': 'Van HeckeO LeeJ.N‐acetylcysteine: a rapid review of the evidence for ' 'effectiveness in treating COVID‐19.2020.'}, { 'key': 'e_1_2_10_27_1', 'doi-asserted-by': 'crossref', 'DOI': '10.1016/j.mehy.2020.109862', 'article-title': 'N‐acetylcysteine: a potential therapeutic agent for SARS‐CoV‐2', 'volume': '143', 'author': 'Poe FL', 'year': '2020', 'journal-title': 'Med Hypotheses'}, { 'issue': '2', 'key': 'e_1_2_10_28_1', 'doi-asserted-by': 'crossref', 'first-page': '130', 'DOI': '10.31053/1853.0605.v77.n2.28410', 'article-title': 'COVID‐19 neurologic manifestation', 'volume': '77', 'author': 'Ocampo Rojas SJ', 'year': '2020', 'journal-title': 'Rev Fac Cien Med Univ Nac Cordoba'}, { 'issue': '11', 'key': 'e_1_2_10_29_1', 'doi-asserted-by': 'crossref', 'first-page': '1166', 'DOI': '10.1002/phar.2464', 'article-title': 'Acetylcysteine for the treatment of suspected remdesivir‐associated ' 'acute liver failure in COVID‐19: a case series', 'volume': '40', 'author': 'Carothers C', 'year': '2020', 'journal-title': 'Pharmacotherapy'}, { 'issue': '4', 'key': 'e_1_2_10_30_1', 'doi-asserted-by': 'crossref', 'first-page': 'A1002', 'DOI': '10.1016/j.chest.2020.08.932', 'article-title': 'Corona virus disease‐19‐induced acute liver failure leading to severe ' 'metabolic acidosis', 'volume': '158', 'author': 'Sarkar S', 'year': '2020', 'journal-title': 'Chest'}, { 'issue': '1', 'key': 'e_1_2_10_31_1', 'doi-asserted-by': 'crossref', 'first-page': '8293', 'DOI': '10.1038/s41598-018-26033-z', 'article-title': 'The effect of N‐acetyl‐l‐cysteine (NAC) on liver toxicity and clinical ' 'outcome after hematopoietic stem cell transplantation', 'volume': '8', 'author': 'El‐Serafi I', 'year': '2018', 'journal-title': 'Sci Rep'}, { 'issue': '255', 'key': 'e_1_2_10_32_1', 'first-page': '140', 'article-title': '[The application of N‐acetylcysteine in optimization of specific ' 'pharmacological therapies]', 'volume': '43', 'author': 'Hołyńska‐Iwan I', 'year': '2017', 'journal-title': 'Pol Merkur Lekarski'}, { 'issue': '1', 'key': 'e_1_2_10_33_1', 'doi-asserted-by': 'crossref', 'first-page': '149', 'DOI': '10.1186/s12902-020-00626-0', 'article-title': 'Repurposing existing drugs for COVID‐19: an endocrinology perspective', 'volume': '20', 'author': 'Cadegiani FA', 'year': '2020', 'journal-title': 'BMC Endocr Disord'}, { 'issue': '10', 'key': 'e_1_2_10_34_1', 'doi-asserted-by': 'crossref', 'first-page': '13185', 'DOI': '10.1096/fj.202001807', 'article-title': 'Rationale for the use of N‐acetylcysteine in both prevention and ' 'adjuvant therapy of COVID‐19', 'volume': '34', 'author': 'De Flora S', 'year': '2020', 'journal-title': 'FASEB J'}, { 'issue': '1', 'key': 'e_1_2_10_35_1', 'doi-asserted-by': 'crossref', 'first-page': '635', 'DOI': '10.21873/invivo.12302', 'article-title': 'Breast cancer surgery in the COVID‐19 pandemic: validation of a ' 'preventive program for patients and health care workers', 'volume': '35', 'author': 'Fregatti P', 'year': '2021', 'journal-title': 'In Vivo'}, { 'issue': '11', 'key': 'e_1_2_10_36_1', 'doi-asserted-by': 'crossref', 'first-page': 'e736', 'DOI': '10.1093/cid/ciaa1443', 'article-title': 'Double‐blind, randomized, placebo‐controlled trial with ' 'N‐acetylcysteine for treatment of severe acute respiratory syndrome ' 'caused by coronavirus disease 2019 (COVID‐19)', 'volume': '72', 'author': 'Alencar JCG', 'year': '2021', 'journal-title': 'Clin Infect Dis'}, { 'issue': '9', 'key': 'e_1_2_10_37_1', 'article-title': 'Spontaneous intraparenchymal hepatic hemorrhage as a sequela of ' 'COVID‐19', 'volume': '12', 'author': 'Daid SS', 'year': '2020', 'journal-title': 'Cureus'}, { 'issue': '10', 'key': 'e_1_2_10_38_1', 'doi-asserted-by': 'crossref', 'first-page': '2238', 'DOI': '10.1002/jmv.26113', 'article-title': 'First case of focal epilepsy associated with SARS‐coronavirus‐2', 'volume': '92', 'author': 'Elgamasy S', 'year': '2020', 'journal-title': 'J Med Virol'}, { 'issue': '1', 'key': 'e_1_2_10_39_1', 'doi-asserted-by': 'crossref', 'first-page': '69', 'DOI': '10.1080/15563650.2020.1758327', 'article-title': 'Truncated IV acetylcysteine treatment duration has potential to safely ' 'preserve resources during the COVID‐19 pandemic', 'volume': '59', 'author': 'Goodnough R', 'year': '2021', 'journal-title': 'Clin Toxicol'}, { 'issue': '1', 'key': 'e_1_2_10_40_1', 'doi-asserted-by': 'crossref', 'first-page': '78', 'DOI': '10.1080/15563650.2020.1813298', 'article-title': 'Response to comment on truncated IV acetylcysteine treatment duration ' 'has potential to safely preserve resources during the COVID‐19 pandemic', 'volume': '59', 'author': 'Goodnough R', 'year': '2021', 'journal-title': 'Clin Toxicol'}, { 'key': 'e_1_2_10_41_1', 'doi-asserted-by': 'crossref', 'DOI': '10.1016/j.mehy.2020.109851', 'article-title': 'Three novel prevention, diagnostic, and treatment options for COVID‐19 ' 'urgently necessitating controlled randomized trials', 'volume': '143', 'author': 'Horowitz RI', 'year': '2020', 'journal-title': 'Med Hypotheses'}, { 'key': 'e_1_2_10_42_1', 'doi-asserted-by': 'crossref', 'DOI': '10.1016/j.clim.2020.108544', 'article-title': 'Therapeutic blockade of inflammation in severe COVID‐19 infection with ' 'intravenous N‐acetylcysteine', 'volume': '219', 'author': 'Ibrahim H', 'year': '2020', 'journal-title': 'Clin Immunol'}, { 'issue': '9', 'key': 'e_1_2_10_43_1', 'doi-asserted-by': 'crossref', 'first-page': '515', 'DOI': '10.1038/s41577-020-0407-1', 'article-title': 'Tissue damage from neutrophil‐induced oxidative stress in COVID‐19', 'volume': '20', 'author': 'Laforge M', 'year': '2020', 'journal-title': 'Nat Rev Immunol'}, { 'issue': '3', 'key': 'e_1_2_10_44_1', 'doi-asserted-by': 'crossref', 'first-page': '268', 'DOI': '10.2174/1389557520666201027160833', 'article-title': 'Perspectives for the use of N‐acetylcysteine as a candidate drug to ' 'treat COVID‐19', 'volume': '21', 'author': 'Luo P', 'year': '2021', 'journal-title': 'Mini Rev Med Chem'}, { 'issue': '2', 'key': 'e_1_2_10_45_1', 'first-page': '94', 'article-title': 'Immune competence and minimizing susceptibility to COVID‐19 and other ' 'immune system threats', 'volume': '26', 'author': 'Meletis CD', 'year': '2020', 'journal-title': 'Altern Ther Health Med'}, { 'key': 'e_1_2_10_46_1', 'doi-asserted-by': 'crossref', 'first-page': '768', 'DOI': '10.1016/j.toxrep.2020.06.003', 'article-title': 'Reactive oxygen species as an initiator of toxic innate immune ' 'responses in retort to SARS‐CoV‐2 in an ageing population, consider ' 'N‐acetylcysteine as early therapeutic intervention', 'volume': '7', 'author': 'Nasi A', 'year': '2020', 'journal-title': 'Toxicol Rep'}, { 'issue': '1', 'key': 'e_1_2_10_47_1', 'doi-asserted-by': 'crossref', 'first-page': '77', 'DOI': '10.1080/15563650.2020.1809667', 'article-title': 'Comment on truncated IV acetylcysteine treatment duration has potential ' 'to safely preserve resources during the COVID‐19 pandemic', 'volume': '59', 'author': 'Wong A', 'year': '2021', 'journal-title': 'Clin Toxicol'}, { 'key': 'e_1_2_10_48_1', 'doi-asserted-by': 'crossref', 'first-page': '1584', 'DOI': '10.2174/18734316MTEyyNzY6y', 'article-title': 'The potential mechanism of N‐acetylcysteine in treating COVID‐19', 'volume': '2', 'author': 'Zhou N', 'year': '2021', 'journal-title': 'Curr Pharm Biotechnol'}, { 'issue': '6', 'key': 'e_1_2_10_49_1', 'first-page': '2802', 'article-title': 'Therapeutic potential of N‐acetyl cysteine (NAC) in preventing cytokine ' 'storm in COVID‐19: review of current evidence', 'volume': '25', 'author': 'Mohanty RR', 'year': '2021', 'journal-title': 'Eur Rev Med Pharmacol Sci'}, { 'issue': '14', 'key': 'e_1_2_10_50_1', 'doi-asserted-by': 'crossref', 'first-page': '1207', 'DOI': '10.1089/ars.2020.8247', 'article-title': 'N‐acetylcysteine and hydrogen sulfide in coronavirus disease 2019', 'volume': '35', 'author': 'Bourgonje AR', 'year': '2021', 'journal-title': 'Antioxid Redox Signal'}, { 'issue': '12', 'key': 'e_1_2_10_51_1', 'doi-asserted-by': 'crossref', 'DOI': '10.1111/ijcp.14720', 'article-title': 'Severe and life‐threatening COVID‐19‐related mucocutaneous eruptions: a ' 'systematic review', 'volume': '75', 'author': 'Mashayekhi F', 'year': '2021', 'journal-title': 'Int J Clin Pract'}, { 'key': 'e_1_2_10_52_1', 'article-title': 'Efficacy of glutathione therapy in relieving dyspnea associated with ' 'COVID‐19 pneumonia: a report of 2 cases', 'volume': '30', 'author': 'Horowitz RI', 'year': '2020', 'journal-title': 'Respir Med Case Rep'}, { 'key': 'e_1_2_10_53_1', 'first-page': '123', 'article-title': 'Geriatric challenges in the new coronavirus disease‐19 (COVID‐19) ' 'pandemic: a systematic review', 'volume': '34', 'author': 'Mohamadi M', 'year': '2020', 'journal-title': 'Med J Islam Repub Iran'}, { 'issue': '4', 'key': 'e_1_2_10_54_1', 'doi-asserted-by': 'crossref', 'DOI': '10.1111/dth.13733', 'article-title': 'Treatment of COVID‐19 with pentoxifylline: could it be a potential ' 'adjuvant therapy?', 'volume': '33', 'author': 'Seirafianpour F', 'year': '2020', 'journal-title': 'Dermatol Ther'}, { 'issue': '2', 'key': 'e_1_2_10_55_1', 'doi-asserted-by': 'crossref', 'DOI': '10.34172/ipp.2021.36', 'article-title': 'Accuracy of chest computed tomography and reverse transcription ' 'polymerase chain reaction in diagnosis of 2019 novel coronavirus ' 'disease; a systematic review and meta‐analysis', 'volume': '7', 'author': 'Shokraee K', 'year': '2021', 'journal-title': 'Immunopathol Persa'}, { 'issue': '1', 'key': 'e_1_2_10_56_1', 'first-page': '9', 'article-title': 'Systemic retinoids in the COVID‐19 era–are they helpful, safe, or ' 'harmful? A comprehensive systematized review', 'volume': '23', 'author': 'Sadeghzadeh‐Bazargan A', 'year': '2020', 'journal-title': 'Iran J Dermatol'}, { 'issue': '1', 'key': 'e_1_2_10_57_1', 'first-page': '13', 'article-title': 'Cytokine storm and probable role of immunoregulatory drugs in COVID‐19: ' 'a comprehensive review', 'volume': '23', 'author': 'Sadeghzadeh‐Bazargan A', 'year': '2020', 'journal-title': 'Iranian J Dermatol'}, { 'key': 'e_1_2_10_58_1', 'first-page': '4', 'article-title': 'A comprehensive review on COVID‐19 infection and comorbidities of ' 'various organs', 'author': 'Goodarzi A', 'year': '2021', 'journal-title': 'Acta Med Iranica'}, { 'issue': '1', 'key': 'e_1_2_10_59_1', 'first-page': '865', 'article-title': 'The effect of influenza vaccine on severity of COVID‐19 infection: an ' 'original study from Iran', 'volume': '35', 'author': 'Kalantari S', 'year': '2021', 'journal-title': 'Med J Islam Repub Iran'}, { 'issue': '1', 'key': 'e_1_2_10_60_1', 'first-page': '481', 'article-title': 'Histopathologic survey on lung necropsy specimens of 15 patients who ' 'died from COVID‐19: a large study from Iran with a high rate of ' 'anthracosis', 'volume': '35', 'author': 'Kooranifar S', 'year': '2021', 'journal-title': 'Med J Islam Repub Iran'}, { 'key': 'e_1_2_10_61_1', 'doi-asserted-by': 'crossref', 'DOI': '10.1016/j.bios.2020.112752', 'article-title': 'COVID‐19 diagnosis—a review of current methods', 'volume': '172', 'author': 'Yüce M', 'year': '2021', 'journal-title': 'Biosens Bioelectron'}, { 'issue': '1', 'key': 'e_1_2_10_62_1', 'first-page': '81', 'article-title': 'Histopathologic changes and cellular events of organs systems in ' 'COVID‐19', 'volume': '6', 'author': 'Nobari NN', 'year': '2021', 'journal-title': 'J Cell Mol Anesth'}, { 'issue': '5', 'key': 'e_1_2_10_63_1', 'article-title': 'Obesity as an independent risk factor for COVID‐19 severity and ' 'mortality', 'volume': '5', 'author': 'Tadayon Najafabadi B', 'year': '2023', 'journal-title': 'Cochrane Database Syst Rev'}, { 'issue': '1', 'key': 'e_1_2_10_64_1', 'first-page': '870', 'article-title': 'The effect of opium on severity of COVID‐19 infection: an original ' 'study from Iran', 'volume': '35', 'author': 'Riahi T', 'year': '2021', 'journal-title': 'Med J Islam Repub Iran'}], 'container-title': 'Immunity, Inflammation and Disease', 'original-title': [], 'language': 'en', 'link': [ { 'URL': 'https://onlinelibrary.wiley.com/doi/pdf/10.1002/iid3.1083', 'content-type': 'unspecified', 'content-version': 'vor', 'intended-application': 'similarity-checking'}], 'deposited': { 'date-parts': [[2023, 11, 21]], 'date-time': '2023-11-21T21:42:42Z', 'timestamp': 1700602962000}, 'score': 1, 'resource': {'primary': {'URL': 'https://onlinelibrary.wiley.com/doi/10.1002/iid3.1083'}}, 'subtitle': [], 'short-title': [], 'issued': {'date-parts': [[2023, 11]]}, 'references-count': 63, 'journal-issue': {'issue': '11', 'published-print': {'date-parts': [[2023, 11]]}}, 'alternative-id': ['10.1002/iid3.1083'], 'URL': 'http://dx.doi.org/10.1002/iid3.1083', 'relation': {}, 'ISSN': ['2050-4527', '2050-4527'], 'subject': ['Immunology', 'Immunology and Allergy'], 'container-title-short': 'Immunity Inflam &amp;amp; Disease', 'published': {'date-parts': [[2023, 11]]}, 'assertion': [ { 'value': '2023-06-13', 'order': 0, 'name': 'received', 'label': 'Received', 'group': {'name': 'publication_history', 'label': 'Publication History'}}, { 'value': '2023-10-31', 'order': 1, 'name': 'accepted', 'label': 'Accepted', 'group': {'name': 'publication_history', 'label': 'Publication History'}}, { 'value': '2023-11-20', 'order': 2, 'name': 'published', 'label': 'Published', 'group': {'name': 'publication_history', 'label': 'Publication History'}}]}
Late treatment
is less effective
Please send us corrections, updates, or comments. c19early involves the extraction of 100,000+ datapoints from thousands of papers. Community updates help ensure high accuracy. Treatments and other interventions are complementary. All practical, effective, and safe means should be used based on risk/benefit analysis. No treatment or intervention is 100% available and effective for all current and future variants. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. FLCCC and WCH provide treatment protocols.
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