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Systematic Review

Experimental drugs in randomized controlled trials for long-COVID: what’s in the pipeline? A systematic and critical review

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Pages 655-667 | Received 03 May 2023, Accepted 26 Jul 2023, Published online: 04 Aug 2023

References

  • Choutka J, Jansari V, Hornig M, et al. Unexplained post-acute infection syndromes. Nat Med. 2022 May;28(5):911–923. doi: 10.1038/s41591-022-01810-6
  • Stefano GB. Historical insight into infections and disorders associated with neurological and psychiatric sequelae similar to long COVID. Med Sci Monit. 2021 Feb 26;27:e931447. doi: 10.12659/MSM.931447
  • Pearce JM. Disease, diagnosis or syndrome? Pract Neurol. 2011 Apr;11(2):91–97. doi: 10.1136/jnnp.2011.241802
  • Jablonski S. Syndrome–a changing concept. Bull Med Libr Assoc. 1992 Oct;80(4):323–327.
  • Honigsbaum M, Krishnan L. Taking pandemic sequelae seriously: from the Russian influenza to COVID-19 long-haulers. Lancet. 2020 Oct 31;396(10260):1389–1391. doi: 10.1016/S0140-6736(20)32134-6
  • McCall S, Vilensky JA, Gilman S, et al. The relationship between encephalitis lethargica and influenza: a critical analysis. J Neurovirol. 2008 May;14(3):177–185. doi: 10.1080/13550280801995445
  • Acheson ED. The clinical syndrome variously called benign myalgic encephalomyelitis, Iceland disease and epidemic neuromyasthenia. Am J Med. 1959 Apr;26(4):569–595. doi: 10.1016/0002-9343(59)90280-3
  • Sapra A, Bhandari P. Chronic fatigue syndrome. Treasure Island (FL): StatPearls; 2022.
  • Carruthers BM, Jain AK, De Meirleir KL, et al. Myalgic encephalomyelitis/chronic fatigue syndrome. J Chronic Fatigue Syndr. 2003;11(1):7–115. doi: 10.1300/J092v11n01_02
  • Hu B, Guo H, Zhou P, et al. Characteristics of SARS-CoV-2 and COVID-19. Nat Rev Microbiol. 2021 Mar;19(3):141–154. doi: 10.1038/s41579-020-00459-7
  • Yong SJ. Long COVID or post-COVID-19 syndrome: putative pathophysiology, risk factors, and treatments. Infect Dis. 2021 Oct;53(10):737–754. doi: 10.1080/23744235.2021.1924397
  • Shah W, Hillman T, Playford ED, et al. Managing the long term effects of covid-19: summary of NICE, SIGN, and RCGP rapid guideline. BMJ. 2021 Jan 22;372:n136. doi: 10.1136/bmj.n136
  • Soriano JB, Murthy S, Marshall JC, et al. A clinical case definition of post-COVID-19 condition by a Delphi consensus. Lancet Infect Dis. 2022 Apr;22(4):e102–e107. doi: 10.1016/S1473-3099(21)00703-9
  • The Centers for Disease Control and Prevention. Long COVID or post-COVID conditions; 2022 [cited 2023 Jul 8]. Available from: https://www.cdc.gov/coronavirus/2019-ncov/long-term-effects/index.html
  • Yong SJ, Liu S. Proposed subtypes of post-COVID-19 syndrome (or long-COVID) and their respective potential therapies. Rev Med Virol. 2021 Dec;9:e2315. doi: 10.1002/rmv.2315
  • Alkodaymi MS, Omrani OA, Fawzy NA, et al. Prevalence of post-acute COVID-19 syndrome symptoms at different follow-up periods: a systematic review and meta-analysis. Clin Microbiol Infect. 2022 May;28(5):657–666. doi: 10.1016/j.cmi.2022.01.014
  • Owens B. How “long covid” is shedding light on postviral syndromes. BMJ. 2022 Sep 21;378:o2188. doi: 10.1136/bmj.o2188
  • Toogood PL, Clauw DJ, Phadke S, et al. Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): where will the drugs come from? Pharmacol Res. 2021 Mar;165:105465.
  • Ledford H. Long-COVID treatments: why the world is still waiting. Nature. 2022 Aug;608(7922):258–260. doi: 10.1038/d41586-022-02140-w
  • Rubin R. As their numbers grow, COVID-19 “Long haulers” stump experts. JAMA. 2020;324(14):1381–1383. doi: 10.1001/jama.2020.17709
  • Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ. 2009 Jul 21;339(jul21 1):b2535. doi: 10.1136/bmj.b2535
  • Methley AM, Campbell S, Chew-Graham C, et al. PICO, PICOS and SPIDER: a comparison study of specificity and sensitivity in three search tools for qualitative systematic reviews. BMC Health Serv Res. 2014 Nov 21;14(1):579. doi: 10.1186/s12913-014-0579-0
  • Sterne JAC, Savovic J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019 Aug 28;366:l4898. doi: 10.1136/bmj.l4898
  • Yong SJ, Halim A, Halim M, et al. Inflammatory and vascular biomarkers in post-COVID-19 syndrome: a systematic review and meta-analysis of over 20 biomarkers. Rev Med Virol. 2023 Mar;33(2):e2424. doi: 10.1002/rmv.2424
  • Davis HE, McCorkell L, Vogel JM, et al. Long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol. 2023 Mar;21(3):133–146. doi: 10.1038/s41579-022-00846-2
  • Yong SJ. Persistent brainstem dysfunction in long-COVID: a hypothesis. ACS Chem Neurosci. 2021 Feb 17;12(4):573–580. doi: 10.1021/acschemneuro.0c00793
  • Barros C, Freire RS, Frota E, et al. Short-course of methylprednisolone improves respiratory functional parameters after 120 days in hospitalized COVID-19 patients (metcovid trial): a randomized clinical trial. Front Med. 2021;8:758405.
  • Bazdyrev E, Panova M, Brachs M, et al. Efficacy and safety of Treamid in the rehabilitation of patients after COVID-19 pneumonia: a phase 2, randomized, double-blind, placebo-controlled trial [Article]. J Transl Med. 2022;20(1). doi:10.1186/s12967-022-03660-9
  • Bramante CT, Buse JB, Liebovitz D, et al. Outpatient treatment of covid-19 with metformin, ivermectin, and fluvoxamine and the development of long covid over 10-month follow-up. medRxiv. 2022 Dec 23.
  • Nevalainen OPO, Horstia S, Laakkonen S, et al. Effect of remdesivir post hospitalization for COVID-19 infection from the randomized SOLIDARITY Finland trial. Nat Commun. 2022 Oct 18;13(1):6152. doi: 10.1038/s41467-022-33825-5
  • Patel VK, Shirbhate E, Patel P, et al. Corticosteroids for treatment of COVID-19: effect, evidence, expectation and extent. Beni-Suef Univ J Basic Appl Sci. 2021;10(1). doi: 10.1186/s43088-021-00165-0
  • Wang X, Wen D, He Q, et al. Effect of corticosteroids in patients with COVID-19: a Bayesian network meta-analysis. Int J Infect Dis. 2022 Dec;125:84–92.
  • Baratella E, Ruaro B, Marrocchio C, et al. Interstitial lung disease at high resolution CT after SARS-CoV-2-related acute respiratory distress syndrome according to pulmonary segmental anatomy. J Clin Med. 2021 Sep 2;10(17):3985. doi: 10.3390/jcm10173985
  • Bramante CT, Huling JD, Tignanelli CJ, et al. Randomized trial of metformin, ivermectin, and fluvoxamine for Covid-19. N Engl J Med. 2022 Aug 18;387(7):599–610. doi: 10.1056/NEJMoa2201662
  • Crisafulli E, Clini EM. Measures of dyspnea in pulmonary rehabilitation. Multidiscip Respir Med. 2010 Jun 30;5(3):202–210. doi: 10.1186/2049-6958-5-3-202
  • Vladimirovna Pakhomova A, Nebolsin VE, Victorovna Pershina O, et al. Antidiabetic effects of bisamide derivative of dicarboxylic acid in metabolic disorders. Int J Mol Sci. 2020 Feb 3;21(3):991. doi: 10.3390/ijms21030991
  • Skurikhin E, Nebolsin V, Widera D, et al. Antifibrotic and regenerative effects of treamid in pulmonary fibrosis. Int J Mol Sci. 2020 Nov 8;21(21):8380. doi: 10.3390/ijms21218380
  • Mitra S, Chakraborty AJ, Tareq AM, et al. Impact of heavy metals on the environment and human health: novel therapeutic insights to counter the toxicity. J King Saud Univ Sci. 2022;34(3):101865. doi: 10.1016/j.jksus.2022.101865
  • McCormack J, Vandermeer B, Allan GM. How confidence intervals become confusion intervals. BMC Med Res Methodol. 2013 Oct 31;13(1):134. doi: 10.1186/1471-2288-13-134
  • Cuijpers P, Li J, Hofmann SG, et al. Self-reported versus clinician-rated symptoms of depression as outcome measures in psychotherapy research on depression: a meta-analysis. Clin Psychol Rev. 2010 Aug;30(6):768–778. doi: 10.1016/j.cpr.2010.06.001
  • Jeong H, Yim HW, Lee SY, et al. Discordance between self-report and clinical diagnosis of internet gaming disorder in adolescents. Sci Rep. 2018 Jul 4;8(1):10084. doi: 10.1038/s41598-018-28478-8
  • Burvill AJ, Murray K, Knuiman MW, et al. Comparing self-reported and measured hypertension and hypercholesterolaemia at standard and more stringent diagnostic thresholds: the cross-sectional 2010-2015 Busselton Healthy Ageing study. Clin Hypertens. 2022 Jun 1;28(1):16. doi: 10.1186/s40885-022-00199-1
  • Nasri H, Rafieian-Kopaei M. Metformin: current knowledge. J Res Med Sci. 2014 Jul;19(7):658–664. doi: 10.12659/MSMBR.889344
  • Corcoran C, Jacobs TF. Metformin. Treasure Island (FL): StatPearls; 2023.
  • Karam BS, Morris RS, Bramante CT, et al. mTOR inhibition in COVID-19: a commentary and review of efficacy in RNA viruses. J Med Virol. 2021 Apr;93(4):1843–1846. doi: 10.1002/jmv.26728
  • Zhou J, Massey S, Story D, et al. Metformin: an old drug with new applications. Int J Mol Sci. 2018 Sep 21;19(10):2863. doi: 10.3390/ijms19102863
  • Parthasarathy H, Tandel D, Siddiqui AH, et al. Metformin suppresses SARS-CoV-2 in cell culture. Virus Res. 2022 Nov 20;323:199010. doi: 10.1016/j.virusres.2022.199010
  • Schaller MA, Sharma Y, Dupee Z, et al. Ex vivo SARS-CoV-2 infection of human lung reveals heterogeneous host defense and therapeutic responses. JCI Insight. 2021 Sep 22;6(18). doi: 10.1172/jci.insight.148003
  • Sun X, Liu Y, Huang Z, et al. SARS-CoV-2 non-structural protein 6 triggers NLRP3-dependent pyroptosis by targeting ATP6AP1. Cell Death Differ. 2022 Jun;29(6):1240–1254. doi: 10.1038/s41418-021-00916-7
  • Boglione L, Meli G, Poletti F, et al. Risk factors and incidence of long-COVID syndrome in hospitalized patients: does remdesivir have a protective effect? QJM. 2022 Jan 9;114(12):865–871. doi: 10.1093/qjmed/hcab297
  • Eastman RT, Roth JS, Brimacombe KR, et al. Remdesivir: a review of its discovery and development leading to emergency use authorization for treatment of COVID-19. ACS Cent Sci. 2020 May 27;6(5):672–683. doi: 10.1021/acscentsci.0c00489
  • Kokic G, Hillen HS, Tegunov D, et al. Mechanism of SARS-CoV-2 polymerase stalling by remdesivir. Nat Commun. 2021 Jan 12;12(1):279. doi: 10.1038/s41467-020-20542-0
  • Strayer DR, Carter WA, Stouch BC, et al. A double-blind, placebo-controlled, randomized, clinical trial of the TLR-3 agonist rintatolimod in severe cases of chronic fatigue syndrome. Plos One. 2012;7(3):e31334. doi: 10.1371/journal.pone.0031334
  • Mitchell WM. Efficacy of rintatolimod in the treatment of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). Expert Rev Clin Pharmacol. 2016 Jun;9(6):755–770. doi: 10.1586/17512433.2016.1172960
  • Strayer DR, Young D, Mitchell WM, et al. Effect of disease duration in a randomized phase III trial of rintatolimod, an immune modulator for myalgic encephalomyelitis/chronic fatigue syndrome. Plos One. 2020;15(10):e0240403. doi: 10.1371/journal.pone.0240403
  • Kedor C, Freitag H, Meyer-Arndt L, et al. A prospective observational study of post-COVID-19 chronic fatigue syndrome following the first pandemic wave in Germany and biomarkers associated with symptom severity. Nat Commun. 2022 Aug 30;13(1):5104. doi: 10.1038/s41467-022-32507-6
  • Mustafa DAM, Saida L, Latifi D, et al. Rintatolimod induces antiviral activities in human pancreatic cancer cells: opening for an anti-COVID-19 opportunity in cancer patients? Cancers (Basel). 2021 Jun 9;13(12):2896. doi: 10.3390/cancers13122896
  • Mitchell WM, Nicodemus CF, Carter WA, et al. Discordant biological and toxicological species responses to TLR3 activation. Am J Pathol. 2014 Apr;184(4):1062–1072. doi: 10.1016/j.ajpath.2013.12.006
  • Chen MC, Korth CC, Harnett MD, et al. A randomized phase 1 evaluation of deupirfenidone, a novel deuterium-containing drug candidate for interstitial lung disease and other inflammatory and fibrotic diseases. Clin Pharmacol Drug Dev. 2022 Feb;11(2):220–234. doi: 10.1002/cpdd.1040
  • Pirali T, Serafini M, Cargnin S, et al. Applications of deuterium in medicinal chemistry. J Med Chem. 2019 Jun 13;62(11):5276–5297. doi: 10.1021/acs.jmedchem.8b01808
  • Tanvir M, Wagay I, Ahmed R, et al. Early intervention with anti-fibrotic pirfenidone is effective than corticosteroids in preventing pulmonary fibrosis in severe COVID pneumonia patients. Curr Med Res Pract. 2022;12(2):53. doi: 10.4103/cmrp.cmrp_110_21
  • Boshra MS, Abou Warda AE, Sayed MA, et al. Effect of pirfenidone on risk of pulmonary fibrosis in COVID-19 patients experiencing cytokine storm. Healthcare. 2022 Nov 28;10(12):2387. doi: 10.3390/healthcare10122387
  • Sahoo BM, Ravi Kumar BVV, Sruti J, et al. Drug Repurposing Strategy (DRS): emerging approach to identify potential therapeutics for treatment of novel coronavirus infection. Front Mol Biosci. 2021;8:628144. doi: 10.3389/fmolb.2021.628144
  • Szefler SJ, Ebling WF, Georgitis JW, et al. Methylprednisolone versus prednisolone pharmacokinetics in relation to dose in adults. Eur J Clin Pharmacol. 1986;30(3):323–329. doi: 10.1007/BF00541537
  • Waddell AW, Currie AR. A comparison of the effects of prednisolone and methylprednisolone on human lymphoblastoid cells. Biochem J. 1977 Nov 15;168(2):323–324. doi: 10.1042/bj1680323
  • Utrero-Rico A, Ruiz-Ruigomez M, Laguna-Goya R, et al. A short corticosteroid course reduces symptoms and immunological alterations underlying long-COVID. Biomedicines. 2021 Oct 26;9(11):1540. doi: 10.3390/biomedicines9111540
  • Day CW, Baric R, Cai SX, et al. A new mouse-adapted strain of SARS-CoV as a lethal model for evaluating antiviral agents in vitro and in vivo. Virology. 2009 Dec 20;395(2):210–222. doi: 10.1016/j.virol.2009.09.023
  • Li HH, Moldovan D, Bernstein JA, et al. Recombinant human-C1 inhibitor is effective and safe for repeat hereditary angioedema attacks. J Allergy Clin Immunol Pract. 2015 May;3(3):417–423. doi: 10.1016/j.jaip.2014.12.013
  • Riedl MA, Bernstein JA, Li H, et al. Recombinant human C1-esterase inhibitor relieves symptoms of hereditary angioedema attacks: phase 3, randomized, placebo-controlled trial. Ann Allergy Asthma Immunol. 2014 Feb;112(2):163–169 e1. doi: 10.1016/j.anai.2013.12.004
  • Howard JF Jr., Nowak RJ, Wolfe GI, et al. Clinical effects of the self-administered subcutaneous complement inhibitor zilucoplan in patients with moderate to severe generalized myasthenia gravis: results of a phase 2 randomized, double-blind, placebo-controlled, multicenter clinical trial. JAMA Neurol. 2020 May 1;77(5):582–592. doi: 10.1001/jamaneurol.2019.5125
  • De Leeuw E, Van Damme KFA, Declercq J, et al. Efficacy and safety of the investigational complement C5 inhibitor zilucoplan in patients hospitalized with COVID-19: an open-label randomized controlled trial. Respir Res. 2022 Aug 9;23(1):202. doi: 10.1186/s12931-022-02126-2
  • Kubera M, Maes M, Budziszewska B, et al. Inhibitory effects of amantadine on the production of pro-inflammatory cytokines by stimulated in vitro human blood. Pharmacol Rep. 2009 Nov;61(6):1105–1112. doi: 10.1016/S1734-1140(09)70173-2
  • Lim S-Y, Guo Z, Liu P, et al. Anti-SARS-CoV-2 activity of adamantanes in vitro and in animal models of infection. Covid. 2022;2(11):1551–1563. doi: 10.3390/covid2110111
  • Plioplys AV, Plioplys S. Amantadine and L-carnitine treatment of chronic fatigue syndrome. Neuropsychobiology. 1997;35(1):16–23. doi: 10.1159/000119325
  • Pilling K, Butterworth RF. Amantadine for the treatment of fatigue in multiple sclerosis: systematic review and summary of the evidence base. J Mult Scler. 2021;8(10):272.
  • Sochocka M, Zaczynska E, Leszek J, et al. Effect of donepezil on innate antiviral immunity of human leukocytes. J Neurol Sci. 2008 Oct 15;273(1–2):75–80. doi: 10.1016/j.jns.2008.06.021
  • Oka N, Shimada K, Ishii A, et al. SARS-CoV-2 causes brain inflammation via impaired neuro-immune interactions. bioRxiv. 2022.
  • Irons J. Fluvoxamine in the treatment of anxiety disorders. Neuropsychiatr Dis Treat. 2005 Dec;1(4):289–299.
  • Sukhatme VP, Reiersen AM, Vayttaden SJ, et al. Fluvoxamine: a review of its mechanism of action and its role in COVID-19. Front Pharmacol. 2021;12:652688. doi: 10.3389/fphar.2021.652688
  • Ter Borg PC, van Os E, van den Broek WW, et al. Fluvoxamine for fatigue in primary biliary cirrhosis and primary sclerosing cholangitis: a randomised controlled trial [ISRCTN88246634]. BMC Gastroenterol. 2004 Jul 13;4:13. doi: 10.1186/1471-230X-4-13
  • Xiong HL, Cao JL, Shen CG, et al. Several FDA-Approved drugs effectively inhibit SARS-CoV-2 Infection in vitro. Front Pharmacol. 2020;11:609592. doi: 10.3389/fphar.2020.609592
  • Xiao X, Wang C, Chang D, et al. Identification of potent and safe antiviral therapeutic candidates against SARS-CoV-2. Front Immunol. 2020;11:586572. doi: 10.3389/fimmu.2020.586572
  • Vikarenko M, Vorokhta Y, Muratova T. Clinical effectiveness of vortioxetine in postcovid syndrome. Neurosci Appl. 2022;1:100316. doi: 10.1016/j.nsa.2022.100316
  • Won E, Kim YK. An oldie but goodie: lithium in the treatment of bipolar disorder through neuroprotective and neurotrophic mechanisms. Int J Mol Sci. 2017 Dec 11;18(12):2679. doi: 10.3390/ijms18122679
  • Soriano-Torres O, Noa Romero E, Gonzalez Sosa NL, et al. Lithium salts as a treatment for COVID-19: pre-clinical outcomes. Biomed Pharmacother. 2022 May;149:112872.
  • Spuch C, Lopez-Garcia M, Rivera-Baltanas T, et al. Efficacy and safety of lithium treatment in SARS-CoV-2 infected patients. Front Pharmacol. 2022;13:850583. doi: 10.3389/fphar.2022.850583
  • Wermuth HR, Badri T, Takov V. Montelukast. Treasure Island (FL): StatPearls; 2023.
  • Durdagi S, Avsar T, Orhan MD, et al. The neutralization effect of montelukast on SARS-CoV-2 is shown by multiscale in silico simulations and combined in vitro studies. Mol Ther. 2022 Feb 2;30(2):963–974. doi: 10.1016/j.ymthe.2021.10.014
  • Huynh T, Wang H, Luan B. In silico exploration of the molecular mechanism of clinically oriented drugs for possibly inhibiting SARS-CoV-2‘s main protease. J Phys Chem Lett. 2020 Jun 4;11(11):4413–4420. doi: 10.1021/acs.jpclett.0c00994
  • Khan AR, Misdary C, Yegya-Raman N, et al. Montelukast in hospitalized patients diagnosed with COVID-19. J Asthma. 2022 Apr;59(4):780–786. doi: 10.1080/02770903.2021.1881967
  • Mohamed Hussein AAR, Ibrahim MEAA, Makhlouf HA, et al. Value of montelukast as a potential treatment of post-COVID-19 persistent cough: a non-randomized controlled pilot study. Egypt J Bronchol. 2022;16(1). doi: 10.1186/s43168-022-00154-6
  • Lam C, Patel P. Nirmatrelvir/Ritonavir. Treasure Island (FL): StatPearls; 2023.
  • Xie Y, Choi T, Al-Aly Z. Association of treatment with nirmatrelvir and the risk of post–COVID-19 condition. JAMA Intern Med. 2023 Mar 23;183(6):554. doi: 10.1001/jamainternmed.2023.0743
  • Gendreau RM, Clauw D, Gendreau J, et al. Thu0322 TNX-102 SL for treatment of fibromyalgia: approaches to pain measurement. Ann Rheumatic Dis. 2015;74(Suppl 2):312. doi: 10.1136/annrheumdis-2015-eular.2099
  • Violi F, Calvieri C, Ferro D, et al. Statins as antithrombotic drugs. Circulation. 2013 Jan 15;127(2):251–257. doi: 10.1161/CIRCULATIONAHA.112.145334
  • Investigators I-S. Atorvastatin versus placebo in patients with COVID-19 in intensive care: randomized controlled trial. BMJ. 2022 Jan 7;376:e068407.
  • Torramade-Moix S, Palomo M, Vera M, et al. Apixaban downregulates endothelial inflammatory and prothrombotic phenotype in an in vitro model of endothelial dysfunction in uremia. Cardiovasc Drugs Ther. 2021 Jun;35(3):521–532. doi: 10.1007/s10557-020-07010-z
  • Connors JM, Brooks MM, Sciurba FC, et al. Effect of antithrombotic therapy on clinical outcomes in outpatients with clinically stable symptomatic COVID-19: the ACTIV-4B randomized clinical trial. JAMA. 2021 Nov 2;326(17):1703–1712. doi: 10.1001/jama.2021.17272
  • Mark RT, Carrol G, Baillie JK, et al. Apixaban following discharge in hospitalised adults with COVID-19: preliminary results from a multicentre, open-label, randomised controlled platform clinical trial. medRxiv. 2022. 2022.12.07.22283175.
  • Campbell N, Kalabalik-Hoganson J, Frey K. Vericiguat: a novel oral soluble guanylate cyclase stimulator for the treatment of heart failure. Ann Pharmacother. 2022 May;56(5):600–608. doi: 10.1177/10600280211041384
  • Armstrong PW, Pieske B, Anstrom KJ, et al. Vericiguat in patients with heart failure and reduced ejection fraction. N Engl J Med. 2020 May 14;382(20):1883–1893. doi: 10.1056/NEJMoa1915928
  • Slifer ZM, Krishnan BR, Madan J, et al. Larazotide acetate: a pharmacological peptide approach to tight junction regulation. Am J Physiol Gastrointest Liver Physiol. 2021;320(6):G983–G989. doi: 10.1152/ajpgi.00386.2020
  • Di Micco S, Musella S, Sala M, et al. Peptide derivatives of the zonulin inhibitor larazotide (AT1001) as potential anti SARS-CoV-2: molecular modelling, synthesis and bioactivity evaluation. Int J Mol Sci. 2021 Aug 30;22(17):9427. doi: 10.3390/ijms22179427
  • Li Z, Peng M, Chen P, et al. Imatinib and methazolamide ameliorate COVID-19-induced metabolic complications via elevating ACE2 enzymatic activity and inhibiting viral entry. Cell Metab. 2022 Mar 1;34(3):424–440 e7. doi: 10.1016/j.cmet.2022.01.008
  • Strobelt R, Adler J, Paran N, et al. Imatinib inhibits SARS-CoV-2 infection by an off-target-mechanism. Sci Rep. 2022 Apr 6;12(1):5758. doi: 10.1038/s41598-022-09664-1
  • Duijvelaar E, Schippers JR, Smeele PJ, et al. Long-term clinical outcomes of COVID-19 patients treated with imatinib. Lancet Respir Med. 2022 Apr;10(4):e34–e35. doi: 10.1016/S2213-2600(22)00052-2
  • Li Z, You Y, Griffin N, et al. Low-dose naltrexone (LDN): a promising treatment in immune-related diseases and cancer therapy. Int Immunopharmacol. 2018 Aug;61:178–184.
  • O’Kelly B, Vidal L, McHugh T, et al. Safety and efficacy of low dose naltrexone in a long covid cohort; an interventional pre-post study. Brain Behav Immun Health. 2022 Oct;24:100485.
  • Basharat S, Chao YS, McGill SC. Subtypes of post–COVID-19 condition: a review of the emerging evidence. Can J Health Technol. 2022;2(12). doi: 10.51731/cjht.2022.516
  • Goldhaber NH, Kohn JN, Ogan WS, et al. Deep dive into the long haul: analysis of symptom clusters and risk factors for post-acute sequelae of COVID-19 to inform clinical care. Int J Environ Res Public Health. 2022 Dec 15;19(24):16841. doi: 10.3390/ijerph192416841
  • Wong-Chew RM, Rodriguez Cabrera EX, Rodriguez Valdez CA, et al. Symptom cluster analysis of long COVID-19 in patients discharged from the temporary COVID-19 hospital in Mexico City. Ther Adv Infect Dis. 2022 Jan;9:20499361211069264. doi: 10.1177/20499361211069264

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