Systemic toxicity of chloroquine and hydroxychloroquine: prevalence, mechanisms, risk factors, prognostic and screening possibilities

Müller, R.

doi:10.1007/s00296-021-04868-6

Cited by 22 publications

(18 citation statements)

References 139 publications

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“…[ 16 ]. Cardiotoxicity is the main concern with prolonged use, especially in patients with hepatic or renal dysfunction [ 45 , 46 ]. This may in turn hamper the successful reuse of chloroquine for other clinical applications (e.g., COVID-19).…”

Section: Resultsmentioning

confidence: 99%

Intratracheal Administration of Chloroquine-Loaded Niosomes Minimize Systemic Drug Exposure

et al. 2021

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Pulmonary administration provides a useful alternative to oral and invasive routes of administration while enhancing and prolonging the accumulation of drugs into the lungs and reducing systemic drug exposure. In this study, chloroquine, as a model drug, was loaded into niosomes for potential pulmonary administration either via dry powder inhalation or intratracheally. Chloroquine-loaded niosomes have been prepared and extensively characterized. Furthermore, drug-loaded niosomes were lyophilized and their flowing properties were evaluated by measuring the angle of repose, Carr’s index, and Hausner ratio. The developed niosomes demonstrated a nanosized (100–150 nm) spherical morphology and chloroquine entrapment efficiency of ca. 24.5%. The FT-IR results indicated the incorporation of chloroquine into the niosomes, whereas in vitro release studies demonstrated an extended-release profile of the drug-loaded niosomes compared to the free drug. Lyophilized niosomes exhibited poor flowability that was not sufficiently improved after the addition of lactose or when cryoprotectants were exploited throughout the lyophilization process. In vivo, intratracheal administration of chloroquine-loaded niosomes in rats resulted in a drug concentration in the blood that was 10-fold lower than the oral administration of the free drug. Biomarkers of kidney and liver functions (i.e., creatinine, urea, AST, and ALT) following pulmonary administration of the drug-loaded nanoparticles were of similar levels to those of the control untreated animals. Hence, the use of a dry powder inhaler for administration of lyophilized niosomes is not recommended, whereas intratracheal administration might provide a promising strategy for pulmonary administration of niosomal dispersions while minimizing systemic drug exposure and adverse reactions.

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Section: Resultsmentioning

confidence: 99%

Intratracheal Administration of Chloroquine-Loaded Niosomes Minimize Systemic Drug Exposure

et al. 2021

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“…Furthermore, severe cardiac toxicity due to prolonged use of HCQ included cardiomyopathy. The mechanism of cardiotoxicity probably due to the alkalization of cardiomyocyte lysosomes and thus inhibition of the activity of alpha-galactosidase A, which leads to intracellular accumulation of polysaccharides [11]. Clinically HCQinduced cardiomyopathy manifested as diffusely thickened restrictive or dilated cardiomyopathy or with conduction system abnormalities including atrioventricular block and bundle branch block [12].…”

Section: Discussionmentioning

confidence: 99%

Myocardial Involvement in Systemic Lupus Erythematosus: Not only A Problem of Epicardial Coronary Artery

Spigno¹

2022

Curr Res Emerg Med

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42-year-old woman, active smoker, with an history of arterial hypertension and SLE, treated with Prednisone and Hydroxychloroquine, was admitted to the Emergency Department (ED) complaining of severe chest pain. Electrocardiogram revealed normofrequent sinus rhythm with negative/diphasic T waves in Infero-lateral leads. Bedside Transthoracic Echocardiogram (TTE) showed mild impairment of ventricular systolic function (EF 50%) in presence of hypokinesia of the anterior wall in mid- basal segment. Cardiac biomarkers were elevated and a diagnosis of acute coronary syndrome without persistent ST Elevation Myocardial Infarction (ASC N-STEMI) was performed. The patient underwent for coronary angiography that revealed coronary arteries free from significant atherosclerotic lesions. Moreover, Cardiac Magnetic Resonance (CMR) showed signs of hypertrophic cardiomyopathy along with T2 hyperintensity and mesocardial Late Gadolinium Enhancement (LGE) in the basal segment of postero- lateral wall consistent with acute myocarditis.

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“…10 11 22 23 Recent investigation of the functions mediated by HCQ has extended understanding of its beneficial and harmful effects (figure 1). [23][24][25][26][27] As weak bases, HCQ and chloroquine, derivatives of 4-aminoquinoline, accumulate in intracellular acidic endolysosomes and neutralise their pH, potentially altering protein processing and antigen presentation on major histocompaticility complex (MHC) class II molecules and inhibiting TLR signalling and the resultant production of type I interferon, proinflammatory cytokines and differentiation of autoantibody-producing B cells. 23 25 26 Beyond its effects on endosomal pH, HCQ directly binds to nucleic acids, favouring binding to the guanosinecytosine-rich sequences in the major groove of DNA and thereby potentially blocking the interaction of DNA with TLR9.…”

Section: Editorialmentioning

confidence: 99%

“…The observed inhibition of cytokine secretion by HCQ may be attributable to its Golgi alkalinisation, impairing protein secretion. 25 The potential for patients treated with HCQ to experience toxicity from that drug is primarily a function of daily dose, reflected in blood levels, and duration of treatment. 25 For patients treated with HCQ for less than 5 years, it would appear that the mechanisms that abrogate production or secretion of type I interferon and other cytokines and are purported to limit antigen presentation are likely to outweigh the mechanisms that contribute to the toxicity of HCQ, most notably those that may impact vision.…”

Section: Editorialmentioning

confidence: 99%

“…25 The potential for patients treated with HCQ to experience toxicity from that drug is primarily a function of daily dose, reflected in blood levels, and duration of treatment. 25 For patients treated with HCQ for less than 5 years, it would appear that the mechanisms that abrogate production or secretion of type I interferon and other cytokines and are purported to limit antigen presentation are likely to outweigh the mechanisms that contribute to the toxicity of HCQ, most notably those that may impact vision. The risk of retinal toxicity is estimated to be <2% in the first 10 years in patients taking HCQ of 5 mg/ kg of their actual weight.…”

Section: Editorialmentioning

confidence: 99%

See 1 more Smart Citation

Hydroxychloroquine and lupus flare: a good drug, but we need to do better

Crow

Kirou

2022

Ann Rheum Dis

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Systemic toxicity of chloroquine and hydroxychloroquine: prevalence, mechanisms, risk factors, prognostic and screening possibilities

Cited by 22 publications

References 139 publications

Intratracheal Administration of Chloroquine-Loaded Niosomes Minimize Systemic Drug Exposure

Intratracheal Administration of Chloroquine-Loaded Niosomes Minimize Systemic Drug Exposure

Myocardial Involvement in Systemic Lupus Erythematosus: Not only A Problem of Epicardial Coronary Artery

Hydroxychloroquine and lupus flare: a good drug, but we need to do better

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