Chloroquine ameliorates adriamycin-induced testicular damage by suppressing the inflammation and apoptosis in rats: a histological, immunohistochemical and biochemical study / La cloroquina mejora el daño testicular inducido por la adriamicina al suprimir la inflamación y la apoptosis en ratas: un estudio histológico, inmunohistoquímico y bioquímico

SUMMARY: Adriamycin (ADR) is an anthracycline antibiotic used for treatment of many types of cancer. However, its applications may damage to healthy tissues. Chloroquine (CLQ) is an anti-inflammatory agent used in treatment of many inflammation associated diseases such as malaria and rheumatoid arthritis. Moreover, it is used in the treatment of pneumonia caused by COVID-19. The aim of this study is to determine possible therapeutic effects of Chloroquine on Adriamycin-induced testicular toxicity in rats. We investigated the effect of CLQ on testicular injury caused by ADR. Rats were divided into four groups: Control, ADR, CLQ, ADR+CLQ. After administrations, animals were sacrificed, and testis tissues were extracted from the animals for the further examinations. Histopathological changes in testis tissues were evaluated and TNF-α and IL-6 immunostaining were performed to determine the expression levels of these cytokines. TUNEL method were used for evaluation of apoptotic index. Moreover, serum testosterone levels were measured by ELISA assay. We observed that ADR group showed histopathological deterioration when compared to the Control group and CLQ treatment ameliorated this damage induced by Adriamycin.An increase in TNF-α and IL-6 immunoreactivities and in the number of apoptotic cells and a decrease in serum testosterone levels were determined in the ADR group compared to the Control and CLQ group. Furthermore, our examinations showed an improvement in testicular tissue in ADR+CLQ group in terms of these parameters when compared to the ADR group. We suggest that CLQ can be used as a protective agent to reduce the toxic effects of Adriamycin as a result of its anti-inflammatory and anti-apoptotic properties.

RESUMEN: La adriamicina (ADR) es un antibiótico de antraciclina que se usa para el tratamiento de muchos tipos de cáncer. Sin embargo, sus aplicaciones pueden dañar los tejidos sanos. La cloroquina (CLQ) es un agente antiinflamatorio que se utiliza en el tratamiento de enfermedades asociadas a la inflamación, tal como la malaria y la artritis reumatoide. También se utiliza en el tratamiento de la neumonía causada por COVID-19. El objetivo de este estudio fue determinar los posibles efectos terapéuticos de la cloroquina sobre la toxicidad testicular inducida por adriamicina en ratas. Investigamos el efecto de CLQ sobre la lesión testicular causada por ADR. Las ratas se dividieron en cuatro grupos: Control, ADR, CLQ, ADR + CLQ. Después de las administraciones, se sacrificaron los animales y se extrajeron los testículos de los animales para los exámenes adicionales. Se evaluaron los cambios histopatológicos en los tejidos testiculares y se realizó la inmunotinción de TNF-α e IL-6 para determinar los niveles de expresión de estas citocinas. Se utilizó el método TUNEL para la evaluación del índice apoptótico. Además, los niveles de testosterona en suero se midieron mediante un ensayo ELISA. El grupo ADR mostró un deterioro histopatológico en comparación con el grupo Control y observamos que el tratamiento con CLQ mejoró el daño inducido por Adriamicina. Un aumento en las inmunorreactividades de TNF-α e IL-6 y en el número de células apoptóticas además de una disminución en los niveles séricos de testosterona se determinaron en el grupo de ADR en comparación con el grupo de control y CLQ. Además, nuestros exámenes mostraron una mejora en el tejido testicular en el grupo ADR + CLQ en términos de estos parámetros en comparación con el grupo ADR. Sugerimos que CLQ se puede utilizar como agente protector para reducir los efectos tóxicos de la Adriamicina, gracias a sus propiedades antiinflamatorias y antiapoptóticas.

Torsade de pointes associated with chloroquine, hydroxychloroquine, and azithromycin: a retrospective analysis of individual case safety reports from VigiBase.

PURPOSE: To analyze the cases of torsade de pointes (TdP) and related symptoms reported in association with chloroquine (CQ), hydroxychloroquine (HCQ), and azithromycin (AZT) to the World Health Organization (WHO) global database of individual case safety reports (ICSRs) for drug monitoring (VigiBase) using qualitative and quantitative pharmacovigilance approaches. METHODS: The main characteristics of the ICSRs reporting TdP with CQ, HCQ, and AZT have been summarized. Co-reported drugs with risk to cause QT prolongation have been described. Reporting odds ratios (RORs) as a measure of disproportionality for reported TdP and individual drugs have been calculated. RESULTS: One hundred seventy ICSRs reporting TdP in association with the drugs of interest were identified (CQ: 11, HCQ: 31, CQ + HCQ: 1, HCQ + AZT: 27, AZT: 100). From these, 41 (24.3%) were received during the pandemic period (December 2019 to February 2021). The median age of the patients was 63, 53, and 63 years old for CQ, HCQ, and AZT, respectively. Reports included concomitant use of other QT-prolonging drugs (CQ 25.0%, HCQ 71.2%, AZT 64.6%). A proportion of the cases were fatal (CQ 25.0%, HCQ 8.6%, AZT 16.1%). Increased disproportionality has been found for the individual drugs and TdP: CQ (ROR: 7.41, 95% confidence interval (CI): 3.82, 12.96), HCQ (ROR: 8.49, 95% CI: 6.57, 10.98), azithromycin (ROR: 8.06, 95% CI: 6.76, 9.61). Disproportionality was also found for other related symptoms, Standardized MedDRA Query for torsade de pointes/QT prolongation (narrow): CQ (ROR: 11.95, 95% CI: 10.04-14.22); HCQ (ROR: 20.43, 95% CI: 19.13, 21.83), AZT (ROR: 7.78, 95% CI: 7.26, 8.34). CONCLUSIONS: The prescription of CQ, HCQ, and AZT should be restricted to therapeutic indications with established positive benefit/risk profile. Doctors and patients should be aware of this potential adverse reaction especially when several risk factors are present.

Pulmonary Delivery of Aerosolized Chloroquine and Hydroxychloroquine to Treat COVID-19: In Vitro Experimentation to Human Dosing Predictions.

In vitro screening for pharmacological activity of existing drugs showed chloroquine and hydroxychloroquine to be effective against severe acute respiratory syndrome coronavirus 2. Oral administration of these compounds to obtain desired pulmonary exposures resulted in dose-limiting systemic toxicity in humans. However, pulmonary drug delivery enables direct and rapid administration to obtain higher local tissue concentrations in target tissue. In this work, inhalable formulations for thermal aerosolization of chloroquine and hydroxychloroquine were developed, and their physicochemical properties were characterized. Thermal aerosolization of 40 mg/mL chloroquine and 100 mg/mL hydroxychloroquine formulations delivered respirable aerosol particle sizes with 0.15 and 0.33 mg per 55 mL puff, respectively. In vitro toxicity was evaluated by exposing primary human bronchial epithelial cells to aerosol generated from Vitrocell. An in vitro exposure to 7.24 µg of chloroquine or 7.99 µg hydroxychloroquine showed no significant changes in cilia beating, transepithelial electrical resistance, and cell viability. The pharmacokinetics of inhaled aerosols was predicted by developing a physiologically based pharmacokinetic model that included a detailed species-specific respiratory tract physiology and lysosomal trapping. Based on the model predictions, inhaling emitted doses comprising 1.5 mg of chloroquine or 3.3 mg hydroxychloroquine three times a day may yield therapeutically effective concentrations in the lung. Inhalation of higher doses further increased effective concentrations in the lung while maintaining lower systemic concentrations. Given the theoretically favorable risk/benefit ratio, the clinical significance for pulmonary delivery of aerosolized chloroquine and hydroxychloroquine to treat COVID-19 needs to be established in rigorous safety and efficacy studies. Graphical abstract.

Translational Modeling of Chloroquine and Hydroxychloroquine Dosimetry in Human Airways for Treating Viral Respiratory Infections.

PURPOSE: Chloroquine and hydroxychloroquine are effective against respiratory viruses in vitro. However, they lack antiviral efficacy upon oral administration. Translation of in vitro to in vivo exposure is necessary for understanding the disconnect between the two to develop effective therapeutic strategies. METHODS: We employed an in vitro ion-trapping kinetic model to predict the changes in the cytosolic and lysosomal concentrations of chloroquine and hydroxychloroquine in cell lines and primary human airway cultures. A physiologically based pharmacokinetic model with detailed respiratory physiology was used to predict regional airway exposure and optimize dosing regimens. RESULTS: At their reported in vitro effective concentrations in cell lines, chloroquine and hydroxychloroquine cause a significant increase in their cytosolic and lysosomal concentrations by altering the lysosomal pH. Higher concentrations of the compounds are required to achieve similar levels of cytosolic and lysosomal changes in primary human airway cells in vitro. The predicted cellular and lysosomal concentrations in the respiratory tract for in vivo oral doses are lower than the in vitro effective levels. Pulmonary administration of aerosolized chloroquine or hydroxychloroquine is predicted to achieve high bound in vitro-effective concentrations in the respiratory tract, with low systemic exposure. Achieving effective cytosolic concentrations for activating immunomodulatory effects and adequate lysosomal levels for inhibiting viral replication could be key drivers for treating viral respiratory infections. CONCLUSION: Our analysis provides a framework for extrapolating in vitro effective concentrations of chloroquine and hydroxychloroquine to in vivo dosing regimens for treating viral respiratory infections.

Review of Emerging Pharmacotherapy for the Treatment of Coronavirus Disease 2019.

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has evolved into an emergent global pandemic. Coronavirus disease 2019 (COVID-19) can manifest on a spectrum of illness from mild disease to severe respiratory failure requiring intensive care unit admission. As the incidence continues to rise at a rapid pace, critical care teams are faced with challenging treatment decisions. There is currently no widely accepted standard of care in the pharmacologic management of patients with COVID-19. Urgent identification of potential treatment strategies is a priority. Therapies include novel agents available in clinical trials or through compassionate use, and other drugs, repurposed antiviral and immunomodulating therapies. Many have demonstrated in vitro or in vivo potential against other viruses that are similar to SARS-CoV-2. Critically ill patients with COVID-19 have additional considerations related to adjustments for organ impairment and renal replacement therapies, complex lists of concurrent medications, limitations with drug administration and compatibility, and unique toxicities that should be evaluated when utilizing these therapies. The purpose of this review is to summarize practical considerations for pharmacotherapy in patients with COVID-19, with the intent of serving as a resource for health care providers at the forefront of clinical care during this pandemic.

Risk factors for prolonged virus shedding of respiratory tract and fecal in adults with severe acute respiratory syndrome coronavirus-2 infection.

BACKGROUND: The dynamic alteration and comparative study of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA shedding pattern during treatment are limited. This study explores the potential risk factors influencing prolonged viral shedding in COVID-19. METHODS: A total of 126 COVID-19 patients were enrolled in this retrospective longitudinal study. A multivariate logistic regression analysis was carried out to estimate the potential risk factors. RESULTS: 38.1% (48/126) cases presented prolonged respiratory tract viral shedding, and 30 (23.8%) cases presented prolonged rectal swab viral shedding. Obesity (OR, 3.31; 95% CI, 1.08-10.09), positive rectal swab (OR, 3.43; 95% CI, 1.53-7.7), treatment by lopinavir/ritonavir with chloroquine phosphate (OR, 2.5; 95% CI, 1.04-6.03), the interval from onset to antiviral treatment more than 7 days (OR, 2.26; 95% CI, 1.04-4.93), lower CD4+ T cell (OR, 0.92; 95% CI, 0.86-0.99) and higher NK cells (OR, 1.11; 95% CI, 1.02-1.20) were significantly associated with prolonged respiratory tract viral shedding. CD3-CD56+ NK cells (OR, 0.87; 95% CI, 0.76-0.99) were related with prolonged fecal shedding. CONCLUSIONS: Obesity, delayed antiviral treatment, and positive SARS-CoV-2 for stool were independent risk factors for prolonged SARS-CoV-2 RNA shedding of the respiratory tract. A combination of LPV/r and abidol as the initial antiviral regimen was effective in shortening the duration of viral shedding compared with LPV/r combined with chloroquine phosphate. CD4+ T cell and NK cells were significantly associated with prolonged viral shedding, and further studies are to be warranted to determine the mechanism of immunomodulatory response in virus clearance.

Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials.

Substantial COVID-19 research investment has been allocated to randomized clinical trials (RCTs) on hydroxychloroquine/chloroquine, which currently face recruitment challenges or early discontinuation. We aim to estimate the effects of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished. We present a rapid meta-analysis of ongoing, completed, or discontinued RCTs on hydroxychloroquine or chloroquine treatment for any COVID-19 patients (protocol: https://osf.io/QESV4/ ). We systematically identified unpublished RCTs (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, Cochrane COVID-registry up to June 11, 2020), and published RCTs (PubMed, medRxiv and bioRxiv up to October 16, 2020). All-cause mortality has been extracted (publications/preprints) or requested from investigators and combined in random-effects meta-analyses, calculating odds ratios (ORs) with 95% confidence intervals (CIs), separately for hydroxychloroquine and chloroquine. Prespecified subgroup analyses include patient setting, diagnostic confirmation, control type, and publication status. Sixty-three trials were potentially eligible. We included 14 unpublished trials (1308 patients) and 14 publications/preprints (9011 patients). Results for hydroxychloroquine are dominated by RECOVERY and WHO SOLIDARITY, two highly pragmatic trials, which employed relatively high doses and included 4716 and 1853 patients, respectively (67% of the total sample size). The combined OR on all-cause mortality for hydroxychloroquine is 1.11 (95% CI: 1.02, 1.20; I² = 0%; 26 trials; 10,012 patients) and for chloroquine 1.77 (95%CI: 0.15, 21.13, I² = 0%; 4 trials; 307 patients). We identified no subgroup effects. We found that treatment with hydroxychloroquine is associated with increased mortality in COVID-19 patients, and there is no benefit of chloroquine. Findings have unclear generalizability to outpatients, children, pregnant women, and people with comorbidities.

Chloroquine and hydroxychloroquine - safety profile of potential COVID-19 drugs from the rheumatologist's perspective.

INTRODUCTION AND OBJECTIVE: The COVID-19 pandemic causes vital concerns due to the lack of proved, effective, and safe therapy. Chloroquine and hydroxychloroquine seem to be useful, but recently serious concerns regarding their adverse events have risen. The aim of the study was to broaden the general perspective of chloroquine and hydroxychloroquine use in COVID-19 treatment, based on an analysis of their current safety profile among patients with rheumatic diseases. MATERIAL AND METHODS: The study was based on a group of 152 patients with rheumatic diseases, aged 20-78 years, treated either with chloroquine or hydroxychloroquine. Analyzed data included age, gender, comorbidities, type of drug, dosage, treatment duration, and reported adverse events. Cases of drug withdrawal related to adverse events were also recorded. RESULTS: The dosage was consistent in both groups: 250 mg of chloroquine or 200 mg of hydroxychloroquine daily. 77.6% of patients did not experience any adverse reactions to the treatment. Hydroxychloroquine showed better safety profile, with 10.9% of patients reporting side-ffects, compared to 28.9% in patients treated with chloroquine. The overall incidence of ophthalmic complications was 6.6%. For both drugs, no statistically significant correlation between adverse events and age, chronic heart or liver disease, or hypertension was found. CONCLUSIONS: Chloroquine and hydroxychloroquine at lower doses, as used in rheumatic diseases, prove to be relatively safe. Data from the literature show that high dosage as recommended in COVID-19 treatment may pose a risk of toxicity and require precise management, but prophylactic, long-term use of lower, safe doses might be a promising solution.

COVID-19 infection in pediatric subjects: study of 36 cases in Conakry.

The aim of this study was to evaluate the main clinical and evolutionary features of SARS-CoV-2 infection in children aged 0-18 years who were suspected and diagnosed for COVID-19 during routine consultations in the pediatric ward of the Ignace Deen National Hospital in Conakry. This retrospective study targeted all children admitted to the Pediatrics Department during the study period and focused on children whose clinical examination and/or history indicated a suspicion of SARS-CoV-2 infection. Only children with a positive reverse transcriptase-polymerase chain reaction (RT-PCR) test were included. Clinical and paraclinical data were rigorously analyzed. Anonymity and respect for ethical rules were the norm. Medical records were used as the data source and a questionnaire was developed for collection. The analysis was done using STATA/SE version 11.2 software. The mean age of the patients observed was 9.66±1.32 years, with a sex ratio of 1.25. The history of the patients found that 36.11 had already been in contact with a COVID-19 positive subject, of which 8 or 22 had close relatives treated for COVID-19 and 5 had been with classmates treated for COVID-19. Fever and physical asthenia, runny nose and throat pain were respectively found in 58.33%, 50% and 30.55% of patients with irritability in 25%. Asymptomatic children were 30.55%. The diagnosis was confirmed after a positive RT-PCR test. Thoracic computed tomography (CT) scan was normal in 80.55% of the children. They were given mostly azithromycin 15mg/kg, zinc and chloroquine sulfate 5mg/kg. The mean age of the patients observed was 9.66 years, with a sex ratio of 1.25. The history of the patients found that 36.11 had already been in contact with a COVID-19 positive subject, of which 8 or 22 had close relatives treated for COVID-19 and 5 had been with classmates treated for COVID-19. Fever and physical asthenia, runny nose and throat pain were respectively found in 58.33%, 50% and 30.55% of patients with irritability in 25%. Asymptomatic children were 30.55%. The diagnosis was confirmed after a positive RT-PCR test. Thoracic computed tomography (CT) scan was normal in 80.55% of the children. They were given mostly azithromycin 15mg/kg, zinc and chloroquine sulfate 5mg/kg.

Cardiotoxic Potential of Hydroxychloroquine, Chloroquine and Azithromycin in Adult Human Primary Cardiomyocytes.

Substantial efforts have been recently committed to develop coronavirus disease-2019 (COVID-19) medications, and Hydroxychloroquine alone or in combination with Azithromycin has been promoted as a repurposed treatment. Although these drugs may increase cardiac toxicity risk, cardiomyocyte mechanisms underlying this risk remain poorly understood in humans. Therefore, we evaluated the proarrhythmia risk and inotropic effects of these drugs in the cardiomyocyte contractility-based model of the human heart. We found Hydroxychloroquine to have a low proarrhythmia risk, whereas Chloroquine and Azithromycin were associated with high risk. Hydroxychloroquine proarrhythmia risk changed to high with low level of K+, whereas high level of Mg2+ protected against proarrhythmic effect of high Hydroxychloroquine concentrations. Moreover, therapeutic concentration of Hydroxychloroquine caused no enhancement of elevated temperature-induced proarrhythmia. Polytherapy of Hydroxychloroquine plus Azithromycin and sequential application of these drugs were also found to influence proarrhythmia risk categorization. Hydroxychloroquine proarrhythmia risk changed to high when combined with Azithromycin at therapeutic concentration. However, Hydroxychloroquine at therapeutic concentration impacted the cardiac safety profile of Azithromycin and its proarrhythmia risk only at concentrations above therapeutic level. We also report that Hydroxychloroquine and Chloroquine, but not Azithromycin, decreased contractility while exhibiting multi-ion channel block features, and Hydroxychloroquine's contractility effect was abolished by Azithromycin. Thus, this study has the potential to inform clinical studies evaluating repurposed therapies, including those in the COVID-19 context. Additionally, it demonstrates the translational value of the human cardiomyocyte contractility-based model as a key early discovery path to inform decisions on novel therapies for COVID-19, malaria, and inflammatory diseases.

Chloroquine may induce endothelial injury through lysosomal dysfunction and oxidative stress.

COVID-19 is a pandemic with no end in sight. There is only one approved antiviral agent but global stocks are deemed insufficient. Despite in vitro antiviral activity, clinical trials of chloroquine and hydroxychloroquine were disappointing, and they may even impair outcomes. Chloroquine causes zebroid deposits reminiscent of Fabry disease (α-galactosidase A deficiency) and endothelial cells are key targets of COVID-19. We have explored the effect of chloroquine on cultured endothelial cells and its modulation by recombinant α-galactosidase A (agalsidase). Following dose-response studies, 0.5 µg/mL chloroquine was added to cultured human endothelial cells. Neutral red and Lysotracker were used to assess lysosomes. Cytotoxicity was evaluated by the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide) - MTT assay and cell stress by assessing reactive oxygen species (ROS) and nitric oxide (NO). In endothelial cells, chloroquine induced dose-dependent cytotoxicity at in vitro test concentrations for COVID-19 therapy. At a sublethal concentration, chloroquine significantly induced the accumulation of acid organelles (P < 0.05), increased ROS levels, and decreased NO production (P < 0.05). These adverse effects of chloroquine on endothelial cell biology were decreased by agalsidase-ß (P < 0.05). Chloroquine-induced endothelial cell cytotoxicity and stress is attenuated by agalsidase-ß treatment. This suggests that endothelial cell injury may contribute to the failure of chloroquine as therapy for COVID-19 and may be at least in part related to causing dysfunction of the lysosomal enzyme α-galactosidase A.

COVID-19 infection in known epileptic and non-epileptic children: what is the place of chloroquine sulfate? (a case report).

The coronavirus 19 (COVID-19) disease, which was declared in China in December 2019, very early on became a pandemic, claiming more than 28 million victims worldwide to date. Its impact on the central nervous system is still poorly understood. The objective of this work is to assess the involvement of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in the aggravation of seizures in children known to have epilepsy and in the epileptogenesis of children hitherto seizure-free. Prior to conducting this work, we had obtained informed consent from patients and parents. We report the cases of three (3) patients, one known epileptic and the other two apparently healthy, who presented a febrile seizure in a context of COVID-19 infection. The aggravation of the epileptic seizure was indicative of a SARS-CoV-2 infection in the first patient, while the seizure occurred after induction of chloroquine sulfate treatment in the 2 other patients. Although our current concern is to limit the spread of the disease to COVID-19, it is crucial to address its possible complications. Notably, the worsening of seizures in children with epilepsy and the occurrence of first seizures in children without epilepsy following drug treatment. Equipping our COVID-19 patient management facilities with electroencephalogram (EEG) equipment could facilitate continuous electroencephalographic monitoring of children for proper management.

Challenges of autoimmune rheumatic disease treatment during the COVID-19 pandemic: A review.

Since December 2019, the COVID-19 pandemic has become a major public health problem. To date, there is no evidence of a higher incidence of COVID in patients with autoimmune rheumatic diseases and we support the approach of maintaining chronic rheumatological treatments. However, once infected there is a small but significant increased risk of mortality. Among the different treatments, NSAIDs are associated with higher rates of complications, but data for other drugs are conflicting or incomplete. The use of certain drugs for autoimmune inflammatory rheumatisms appears to be a potentially interesting options for the treatment. The rationale for their use is based on the immune system runaway and the secretion of pro-inflammatory cytokines (Il1, IL6, TNFα) in severe forms of the disease. Notably, patients on chloroquine or hydroxychloroquine as a treatment for their autoimmune rheumatic disease are not protected from COVID-19.

Chloroquine and hydroxychloroquine in the management of COVID-19: Much kerfuffle but little evidence.

Chloroquine and hydroxychloroquine are drugs that have shown in vitro activity on the replication of certain coronaviruses. In the context of the SARS-Cov-2 epidemic, the virus responsible for the novel coronavirus disease (COVID-19), these two drugs have been proposed as possible treatments. The results of the first clinical studies evaluating the effect of hydroxychloroquine do not support any efficacy of this drug in patients with COVID-19, due to major methodological weaknesses. Yet, these preliminary studies have aroused considerable media interest, raising fears of massive and uncontrolled use. In the absence of evidence of clinical benefits, the main risk is of exposing patients unnecessarily to the well-known adverse effects of hydroxychloroquine, with a possibly increased risk in the specific setting of COVID-19. In addition, widespread use outside of any recommendation risks compromising the completion of good quality clinical trials. The chloroquine hype, fueled by low-quality studies and media announcements, has yielded to the implementation of more than 150 studies worldwide. This represents a waste of resources and a loss of opportunity for other drugs to be properly evaluated. In the context of emergency, rigorous trials are more than ever needed in order to have, as soon as possible, reliable data on drugs that are possibly effective against the disease. Meanwhile, serious adverse drug reactions have been reported in patients with COVID-19 receiving hydroxychloroquine, justifying to limit its prescription, and to perform suitable cardiac and therapeutic drug monitoring.

Unusual association of COVID-19, pulmonary tuberculosis and human immunodeficiency virus, having progressed favorably under treatment with chloroquine and rifampin.

Infection with the new coronavirus has been declared an international health emergency. Its curative treatment is unknown and is the subject of several clinical trials. In addition, the concomitant association of COVID-19 with tuberculosis and the human immunodeficiency virus, hitherto never described, is potentially fatal. We report the illustrative case of a 32-year-old patient who presented this trifecta of infections and who did well under treatment with chloroquine and anti-mycobacterial drugs. This patient arrived at the ER with respiratory discomfort that had been evolving over a month with symptoms of flu and deterioration of her general condition. A chest CT scan revealed an aspect of lung miliary tuberculosis with isolation of Koch's bacilli in the sputum. A polymerization chain reaction (PCR) was positive for COVID-19 on a nasopharyngeal swab. HIV serology was positive. The course was marked by a spectacular clinical improvement and two negative COVID-19 PCR controls at the end of treatment (at days 9 and 10). Anti-tubercular drugs (especially, rifampin) are powerful enzyme inducers that can reduce the effectiveness of chloroquine in our patient. This therapeutic success may be linked to the effect of anti-tubercular drugs against SARS ncov-2, especially rifampin, inhibiting the formation of messenger RNAs of SARS ncov-2 or to the synergistic effect of chloroquine and rifampin. Researchers should explore the effect of these drugs on SARS ncov-2.

Clinical characteristics of COVID-19 patients hospitalized at Clinique Ngaliema, a public hospital in Kinshasa, in the Democratic Republic of Congo: A retrospective cohort study.

OBJECTIVES: To describe the clinical characteristics of patients infected with SARS-CoV-2 at Clinique Ngaliema, a public hospital, in Kinshasa, in the Democratic Republic of Congo (DRC). METHODS: This retrospective study analyzed medical records including socio-demographics, past medical history, clinical manifestation, comorbidities, laboratory data, treatment and disease outcome of 160 hospitalized COVID-19 patients, with confirmed result of SARS-CoV-2 viral infection. RESULTS: The median age of patients was 54 years (IQR: 38-64), and there was no significant gender difference (51% of male). The most common comorbidities were hypertension (55 [34%]), diabetes (31 [19%]) and obesity (13 [8%]). Fever (93 [58%]), cough (92 [57%]), fatigue (87 [54%]), shortness of breath (72 [45%]) and myalgia (33 [21%]) were the most common symptoms, upon admission. Patients were categorized into mild (92 [57%]), moderate (19 [12%]) and severe (49 [31%]). Severe patients were older and were more likely to have comorbidities, compared to mild ones. The majority of patients (92% [147 of 160]) patients received hydroxychloroquine or chloroquine phosphate. Regression model revealed that older age, lower SpO2, higher heart rate and elevated AST at admission were all risk factors associated with in-hospital death. The prevalence of COVID-19 and malaria co-infection was 0.63% and 70 (44%) of all patients received antimalarial treatment before hospitalization. CONCLUSION: Our findings indicated that the epidemiological and clinical feature of COVID-19 patients in Kinshasa are broadly similar to previous reports from other settings. Older age, lower SpO2, tachycardia, and elevated AST could help to identify patients at higher risk of death at an early stage of the illness. Plasmodium spp co-infection was not common in hospitalized COVID-19 patients.

Therapeutic Effectiveness of Interferon Alpha 2b Treatment for COVID-19 Patient Recovery.

A previous report on 814 patients who were coronavirus disease 2019 (COVID-19) positive provided preliminary therapeutic efficacy evidence with interferon-α2b (IFN-α2b) in Cuba, from March 11 to April 14, 2020. This study re-evaluates the effectiveness of IFN-α2b during the period from March 11 to June 17, 2020. Patients received a combination of oral antivirals (lopinavir/ritonavir and chloroquine) with intramuscular or subcutaneous administration of IFN-α2b. The primary endpoint was the proportion of patients discharged from the hospital; the secondary endpoint was the case fatality rate, and several outcomes related to time variables were also evaluated. From March 11 to June 17, 2,295 patients had been confirmed to be severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive in Cuba, 2,165 were treated with Heberon® Alpha R, and 130 received the approved protocol without IFN. The proportion of fully recovered patients was higher in the IFN-treated compared with the non-IFN-treated group. Prior IFN treatment decreases the likelihood of intensive care and increases the survival after severe or critical diseases. Benefits of IFN were significantly supported by time variables analyzed. This second report confirmed our preliminary evidence about the therapeutic effectiveness of IFN-α2b in SARS-CoV-2 infection and postulated Heberon Alpha R as the main component within antiviral drugs used in the Cuban protocol COVID-19.

Cardiotoxicity induced by the combination therapy of chloroquine and azithromycin in human embryonic stem cell-derived cardiomyocytes.

Combination therapy using chloroquine (CQ) and azithromycin (AZM) has drawn great attention due to its potential anti-viral activity against SARS-CoV-2. However, clinical trials have revealed that the co-administration of CQ and AZM resulted in severe side effects, including cardiac arrhythmia, in patients with COVID-19. To elucidate the cardiotoxicity induced by CQ and AZM, we examined the effects of these drugs based on the electrophysiological properties of human embryonic stem cellderived cardiomyocytes (hESC-CMs) using multi-electrode arrays. CQ treatment significantly increased the field potential duration, which corresponds to prolongation of the QT interval, and decreased the spike amplitude, spike slope, and conduction velocity of hESC-CMs. AZM had no significant effect on the field potentials of hESC-CMs. However, CQ in combination with AZM greatly increased the field potential duration and decreased the beat period and spike slope of hESC-CMs when compared with CQ monotherapy. In support of the clinical data suggesting the cardiovascular side effects of the combination therapy of CQ and AZM, our results suggest that AZM reinforces the cardiotoxicity induced by CQ in hESC-CMs. [BMB Reports 2020; 53(10): 545-550].