








key: cord-288733-c51lfwd6
authors: Kavanagh, Oisín; Marie Healy, Anne; Dayton, Francis; Robinson, Shane; O'Reilly, Niall J.; Mahoney, Brian; Arthur, Aisling; Walker, Gavin; Farragher, John P.
title: Inhaled Hydroxychloroquine to Improve Efficacy and Reduce Harm in the Treatment of COVID-19
date: 2020-07-15
journal: Med Hypotheses
DOI: 10.1016/j.mehy.2020.110110
sha: 
doc_id: 288733
cord_uid: c51lfwd6

Current formulations and dose regimens of hydroxychloroquine (HCQ) put patients at risk of harm. An analysis of clinical trials registered on ClinicalTrials.gov revealed that this may continue as many studies combine HCQ with agents that prolong the QT interval. Further, almost all of the trials registered do not consider dosage adjustment in the elderly, a patient population most likely to require HCQ treatment. Here we describe an inhaled formulation of HCQ which has passed safety studies in clinical trials for the treatment of asthma and discuss how this approach may reduce side-effects and improve efficacy. As this simple formulation progressed to phase II studies, safety data can be used to immediately enable phase II trials in COVID-19.

2 25 The COVID-19 (SARS-CoV-2) pandemic has had devastating health consequences 26 worldwide 1 , and life has been brought to a standstill as the world awaits a vaccine. Meanwhile, 27 many patients continue to fall critically ill and, in the absence of a vaccine, antivirals and other 28 treatments to alleviate the effects of the disease are urgently sought. 29 30 In recent months, since the outbreak of COVID-19, a large number of clinical trials have been 31 registered on ClinicalTrials.gov with the aim of repurposing medicines to reduce the severity 32 of the disease 2 . Chloroquine and hydroxychloroquine (HCQ) were two of the earliest drugs to 33 receive attention as possible repurposable treatment options for COVID-19 3 . Indeed, a number 34 of studies investigated their anti-SARS-CoV activity as early as 2003 4-6 . However, the 35 potential efficacy of HCQ must be balanced against its side-effects, particularly those 36 associated with QT elongation, which is exacerbated by age, comorbidities and administration 37 with other agents (such as azithromycin) that prolong the QT interval 7 . A recent analysis of 38 NHS (UK) electronic health records revealed that the most striking risk factors for COVID-19 39 death were age and male gender 8 , and those same risk factors have been identified previously 40 in the context of drug induced QT elongation 9,10 . Concerns associated with severe side effects 41 are such that the FDA and EMA now formally recommend against taking HCQ for COVID- 

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OpenSAFELY: factors associated 189 with COVID-19-related hospital death in the linked electronic health records of 17 190 million adult NHS patients

Detailed analysis of the impact of age on the 192 QT interval

Aging effects on QT interval: Implications for cardiac safety of 194 antipsychotic drugs

COVID-19: reminder of risk of serious side effects with 196 chloroquine and hydroxychloroquine

FDA Drug Safety Communication: FDA cautions 199 against use of hydroxychloroquine or chloroquine for COVID-19 outside of the 200 hospital setting or a clinical trial due to risk of heart rhythm problems

Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory 204

Syndrome Coronavirus 2 (SARS-CoV-2)

Hydroxychloroquine for treatment of SARS-CoV-2 infection? 206 Improving our confidence in a model-based approach to dose selection

Optimizing hydroxychloroquine 210 dosing for patients with COVID-19: An integrative modeling approach for effective 211 drug repurposing

The Aging Kidney: Physiological Changes. Adv. Chronic 214 Kidney Dis

The species Severe acute respiratory 216 syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2

219 The novel coronavirus 2019 (2019-nCoV) uses the SARS-coronavirus receptor ACE2 220 and the cellular protease TMPRSS2 for entry into target cells

Hydroxychloroquine as an aerosol might 224 markedly reduce and even prevent severe clinical symptoms after SARS-CoV-2 225 infection

Development of an inhaled hydroxychloroquine 229 sulfate product using the AERx ® system to treat asthma

Clinical Study Report: A two-part, randomised, 231 double-blind, placebo-controlled, ascending-dose study to evaluate the safety, 232 tolerance and pharmacokinetics of orally inhaled hydroxychloroquine sulfate via the

Evaluation of an Immediate-244

Release Formulation of Hydroxychloroquine Sulfate With an Interwoven Pediatric 245 Taste-Masking System

Comprehensive evidence-based review on European antitussives

Effect of taste sensation on cough reflex sensitivity

Sweet taste and menthol increase cough reflex 251 thresholds

Development and palatability 253 assessment of norvir® (Ritonavir) 100 mg powder for pediatric population



