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Hydroxychloroquine (HCQ) and chloroquine (CQ) are well‐established medications used in treating systemic lupus erythematosus and rheumatoid arthritis, as well as skin conditions such as cutaneous lupus erythematosus. In rare cases, arrhythmias and conduction system abnormalities, as well as cardiomyopathy, have been reported in association with HCQ/CQ use. Recently, however, the corrected QT interval (QTc)–prolonging potential of these medications, and risk of torsade de pointes (TdP) in particular, have been highlighted in the setting of their experimental use for COVID‐19 infection. This report was undertaken to summarize the current understanding of HCQ/CQ cardiac toxicity, describe QTc prolongation and TdP risks, and discuss areas of priority for future research. A working group of experts across rheumatology, cardiology, and dermatology performed a nonsystematic literature review and offered a consensus‐based expert opinion. Current data clearly indicate that HCQ and CQ are invaluable medications in the management of rheumatic and dermatologic diseases, but they are associated with QTc prolongation by directly affecting cardiac repolarization. Prescribing clinicians should be cognizant of this small effect, especially in patients taking additional medications that prolong the QTc interval. Long‐term use of HCQ/CQ may lead to a cardiomyopathy associated with arrhythmias and heart failure. Risk and benefit assessment should be considered prior to initiation of any medication, and both initial and ongoing risk–benefit assessments are important with regard to prescription of HCQ/CQ. While cardiac toxicity related to HCQ/CQ treatment of rheumatic diseases is rarely reported, it can be fatal. Awareness of the potential adverse cardiac effects of HCQ and CQ can increase the safe use of these medications. There is a clear need for additional research to allow better understanding of the cardiovascular risk and safety profile of these therapies used in the management of rheumatic and cutaneous diseases. [ABSTRACT FROM AUTHOR]

Background and Objectives: Chloroquine and its analog hydroxychloroquine are derivatives of 4-aminoquinoline and are regularly used in the treatment of malaria and autoimmune diseases. Among the side effects of these drugs, alterations associated with the auditory system are frequently mentioned. Thus, the aim of this systematic review is to systematically review publications on hearing disorders and chloroquine or hydroxychloroquine use. Materials and Methods: Inclusion criteria were observational or interventional studies on audiological assessment in participants who were using chloroquine or hydroxychloroquine. The methodological quality was independently assessed by two reviewers using the Meta-Analysis of Statistics: assessment and review Instrument. The certainty of the evidence was assessed using the GRADE tool. Results: A total of 1,372 non-duplicate papers were screened, out of which 17 were included in the final qualitative synthesis, and 5 studies in the meta-analysis. The odds ratio for the two subgroups evaluated did not show significance with no heterogeneity between the effects observed between the different diseases (I²=0%) and obtaining the global estimate of 0.76 (95% confidence interval [CI]=0.41-1.39; p>0.05). Despite the inclusion of papers with different disease samples, the heterogeneity observed in the analysis was low (I²= 0%) and prediction interval (95% PI=0.32-1.80; p>0.05) remained close to that estimated by the CI (95% CI=0.41-1.39; p>0.05). The certainty of the evidence assessed by the GRADE tool was considered very low due to the risk of bias, indirect evidence, and imprecision. Conclusions: The findings of this study suggest that the use of chloroquine/hydroxychloroquine is not associated with hearing disorders. [ABSTRACT FROM AUTHOR]

Background: Chloroquine (CQ) resistance is conferred by mutations in the Plasmodium falciparum CQ resistance transporter (pfcrt). Following CQ withdrawal for anti-malarial treatment, studies across malaria-endemic countries have shown a range of responses. In some areas, CQ sensitive parasites re-emerge, and in others, mutant haplotypes persist. Active surveillance of resistance mutations in clinical parasites is essential to inform treatment regimens; this effort requires fast, reliable, and cost-effective methods that work on a variety of sample types with reagents accessible in malaria-endemic countries. Methods: Quantitative PCR followed by High-Resolution Melt (HRM) analysis was performed in a field setting to assess pfcrt mutations in two groups of clinical samples from Southwestern Uganda. Group 1 samples (119 in total) were collected in 2010 as predominantly Giemsa-stained slides; Group 2 samples (125 in total) were collected in 2015 as blood spots on filter paper. The Rotor-Gene Q instrument was utilized to assess the impact of different PCR-HRM reagent mixes and the detection of mixed haplotypes present in the clinical samples. Finally, the prevalence of the wild type (CVMNK) and resistant pfcrt haplotypes (CVIET and SVMNT) was evaluated in this understudied Southwestern region of Uganda. Results: The sample source (i.e. Giemsa-stained slides or blood spots) and type of LCGreen-based reagent mixes did not impact the success of PCR-HRM. The detection limit of 10− 5 ng and the ability to identify mixed haplotypes as low as 10 % was similar to other HRM platforms. The CVIET haplotype predominated in the clinical samples (66 %, 162/244); however, there was a large regional variation between the sample groups (94 % CVIET in Group 1 and 44 % CVIET in Group 2). Conclusions: The HRM-based method exhibits the flexibility required to conduct reliable assessment of resistance alleles from various sample types generated during the clinical management of malaria. Large regional variations in CQ resistance haplotypes across Southwestern Uganda emphasizes the need for continued local parasite genotype assessment to inform anti-malarial treatment policies. [ABSTRACT FROM AUTHOR]

A statement of consensus was formulated after reviewing available literature on pediatric treatment strategies for COVID-19 by the Steering and Scientific Committee of the Italian Society of Infectious Pediatric Diseases in connection with the Italian Society of Paediatrics. [ABSTRACT FROM AUTHOR]

Drug-resistant malaria parasites pose a threat to global malaria control efforts, and it is important to know the extent of these drug-resistant mutations in each region to determine appropriate control measures. Chloroquine (CQ) was widely used in Cameroon for decades, but its declining clinical efficacy due to resistance prompted health authorities in 2004 to resort to artemisinin-based combination therapy (ACT) as the first-line treatment for uncomplicated malaria. Despite numerous efforts to control malaria, it persists, and the emergence and spread of resistance to ACTs make the development of new drugs or the possible reintroduction of discontinued drugs increasingly urgent. Malaria-positive blood samples were collected from 798 patients on Whatman filter paper to determine the status of resistance to CQ. DNA was extracted by boiling in Chelex and analysis of Plasmodium species. Four hundred P. falciparum monoinfected samples, 100 per study area, were amplified by nested PCR, and allele-specific restriction analysis of Pfmdr1 gene molecular markers was performed. Fragments were analyzed using a 3% ethidium bromide-stained agarose gel. P. falciparum was the most abundant Plasmodium species, accounting for 87.21% of P. falciparum monoinfections only. No infection with P. vivax was detected. The majority of samples contained the wild type for all 3 SNPs evaluated on the Pfmdr1 gene with N86, Y184, and D1246 accounting for 45.50%, 40.00%, and 70.00%, respectively. The most abundant haplotype observed was the Y184D1246 double wild type at 43.70%. The results suggest that P. falciparum is the major infecting species and that P. falciparum species with the susceptible genotype are gradually recapturing the parasite population. [ABSTRACT FROM AUTHOR]

The paper analyses how post-truth could be related to the identification processes in the context of the pandemic in Brazil. Fact-checking articles published by the agencies "Lupa" and "Aos Fatos" were taken as examples. The corpus was analysed in order to describe the conflicting narratives on the chloroquine and hydroxychloroquine efficacy for Covid-19 treatments. The hypothesis is that those pieces of disinformation under journalistic scrutiny are not accidental messages - they belong in the bigger picture of cultural practices which can be found among social and political groups tied to the supporters of president Bolsonaro's discourse. [ABSTRACT FROM AUTHOR]

Autophagy has been of novel interest since it was first demonstrated to have effect in Burkitt's lymphoma. Since that time, the autophagy agents chloroquine and hydroxychloroquine have become the only FDA (Food and Drug Administration)-approved autophagy inhibitors. While not approved for cancer therapy, there are ongoing clinical trials to evaluate their safety and efficacy. Pevonedistat has emerged as a novel inhibitor through the neddylation pathway and is an autophagy activator. This paper summarizes and presents current clinical trials for hydroxychloroquine (HCQ), chloroquine (CQ), and Pevonedistat for the clinician. [ABSTRACT FROM AUTHOR]

Background: The COVID-19 pandemic has affected the world extraordinarily. This disease has a potential to cause a significantly severe course of disease leading to respiratory complications, multiple organ failure and possibly death. In the fight against this pandemic-causing disease, medical professionals around the world are searching for pharmacological agents that could treat and prevent disease progression and mortality. To speed the search of promising treatment options, already existing pharmacological agents are repurposed for the potential treatment of COVID-19 and tested in clinical trials. The aim of this literature review is to investigate the efficacy and safety of repurposed pharmacological agents for the treatment of COVID-19 at different pathophysiologic stages of the disease. For this literature review, online-databases PubMed and Google Scholar were utilised. Keywords "COVID-19", "SARS-CoV-2", "pathogenesis", "drug targets", "pharmacological treatment", "cytokine storm", "coagulopathy" and individual drug names were used. Scientific articles, including reviews, clinical trials, and observational cohorts, were collected and analysed. Furthermore, these articles were examined for references to find more clinical trials testing for the potential treatment of COVID-19. In total, 97 references were used to conduct this research paper.Results: The most beneficial pharmacological agent for the treatment of COVID-19 are corticosteroids, especially dexamethasone, for the treatment of mechanically ventilated COVID-19 patients. Other promising agents are remdesivir for the treatment of patients with COVID-19 pneumonia requiring minimal supplemental oxygen therapy, and IL-6 receptor antagonist monoclonal antibodies in severe COVID-19. Lopinavir/ritonavir, as well as chloroquine or hydroxychloroquine with or without azithromycin demonstrate the least efficacy in the treatment of COVID-19. The clinical benefits of the treatment of a COVID-19-specific coagulopathy with increased dosing of anticoagulation need further research and confirmation of randomised controlled trials.Conclusion: The search for pharmacological treatment of COVID-19 has elicited great controversy. Whereas drugs like chloroquine, hydroxychloroquine, and lopinavir/ritonavir have not shown proven benefit, the agents remdesivir and dexamethasone are recommended for clinical use for the treatment of COVID-19. Further randomised trials for other pharmacological treatment strategies are awaited. [ABSTRACT FROM AUTHOR]

Adult T-cell leukemia/lymphoma (ATLL) originates from human T-cell leukemia virus type 1 (HTLV-1) infection due to the activation of the nuclear factor-κB (NF-κB) signaling pathway to maintain proliferation and survival. An important mechanism of the activated NF-κB signaling pathway in ATLL is the activation of the macroautophagy (herafter referred to as autophagy in the remainder of this manuscript)-lysosomal degradation of p47 (NSFL1C), a negative regulator of the NF-κB pathway. Therefore, we considered the use of chloroquine (CQ) or hydroxychloroquine (HCQ) (CQ/HCQ) as an autophagy inhibitor to treat ATLL; these drugs were originally approved by the FDA as antimalarial drugs and have recently been used to treat autoimmune diseases, such as systemic lupus erythematosus (SLE). In this paper, we determined the therapeutic efficacy of CQ/HCQ, as NF-κB inhibitors, in ATLL mediated by blockade of p47 degradation. Administration of CQ/HCQ to ATLL cell lines and primary ATLL cells induced cell growth inhibition in a dose-dependent manner, and the majority of cells underwent apoptosis after CQ administration. As to the molecular mechanism, autophagy was inhibited in CQ-treated ATLL cells, and activation of the NF-κB pathway was suppressed with the restoration of the p47 level. When the antitumor effect of CQ/HCQ was examined using immunodeficient mice transplanted with ATLL cell lines, CQ/HCQ significantly suppressed tumor growth and improved the survival rate in the ATLL xenograft mouse model. Importantly, HCQ selectively induced ATLL cell death in the ATLL xenograft mouse model at the dose used to treat SLE. Taken together, our results suggest that the inhibition of autophagy by CQ/HCQ may become a novel and effective strategy for the treatment of ATLL. [ABSTRACT FROM AUTHOR]

This paper explores the feasibility of functionalizing mango stones with iron oxide magnetic nanoparticles (MS-Fe 3 O 4) by coprecipitation in batch adsorption processes. The synthesized material was characterized and applied in chloroquine (CQN) and sertraline hydrochloride (SER) removal from contaminated waters. The biosorbent was subjected to a regenerative study and treatment using a synthetic mixture of contaminants to evaluate its applicability in real effluents. The biosorbent was analyzed by transmission electron microscopy images, scanning electron microscopy, dispersive X-ray spectroscopy, Fourier transform infrared spectra, and zeta potential to characterize its chemical and morphology properties. The techniques applied showed the effectiveness of the proposed modification. In the adsorption experiments, the optimal adsorbent dosage was 0.01 g for both contaminants. The pH strongly influenced the adsorption of the drugs on MS-Fe 3 O 4 , and the best results were obtained in the pH range of 5–6. Kinetic data showed a better fit to the pseudo-second-order model, and the equilibrium time was achieved in 16 h for CQN and 4 h for SER. Isotherm studies revealed maximum adsorptive capacities of 49.42 and 64.79 mg g−1, respectively, for CQN and SER, at 318 K, demonstrating that the increase in temperature is a favorable factor, and the Sips model better describes the process. The thermodynamic parameters indicate an endothermic (ΔH° >0), spontaneous (ΔG° <0), and reversible (ΔS° >0) nature of the adsorption. This process is essentially governed by physical forces, such as hydrogen and π-π bonds. However, it is also valid to consider the presence of electrostatic forces due to the ionizing nature of CQN and SER. The MS-Fe 3 O 4 biosorbent showed good performance when evaluated in a synthetic mixture of four contaminants, with an overall removal efficiency of approximately 86% and the regenerative capacity of three reusing cycles. [Display omitted] • Reutilization of agro-industrial wastes contributes to circular economy perspective. • The evaluated biosorbent is a promising material for wastewater treatment. • MS-Fe 3 O 4 obtained q máx of 49.42 and 64.79 mg g−1 for chloroquine and sertraline hydrochloride adsorption. • The biosorbent demonstrated a global removal efficiency of 86% in synthetic mixture of contaminants. [ABSTRACT FROM AUTHOR]

Background: Artesunate plus sulfadoxine-pyrimethamine (ASP) is first-line treatment for uncomplicated Plasmodium falciparum malaria in most of India, except for six North-eastern provinces where treatment failure rates were high. In Ujjain, central India, the frequency of mutations associated with increased drug tolerance, but not overt resistance to sulfadoxine and pyrimethamine were 9% and > 80%, respectively, in 2009 and 2010, just prior to the introduction of ASP. The frequency of drug resistance associated mutations in Ujjain in 2015-2016 after 3-4 years of ASP use, are reported. Methods: Blood samples from patients with P. falciparum mono-infection verified by microscopy were collected on filter-paper at all nine major pathology laboratories in Ujjain city. Codons pfdhfr 16-185, pfdhps 436-632 and K13 407-689 were identified by sequencing. Pfcrt K76T and pfmdr1 N86Y were identified by restriction fragment length polymorphism. Results: Sulfadoxine-pyrimethamine resistance-associated pfdhfr 108 N and 59R alleles were found in 100/104 (96%) and 87/91 (96%) samples, respectively. Pfdhps 437G was found in 10/105 (10%) samples. Double mutant pfdhfr 59R + 108 N were found in 75/81 (93%) samples. Triple mutant pfdhfr 59R + 108 N and pfdhps 437G were found in 6/78 (8%) samples. Chloroquine-resistance-associated pfcrt 76T was found in 102/102 (100%). Pfmdr1 N86 and 86Y were identified in 83/115 (72%) and 32/115 (28%) samples, respectively. Conclusion: The frequency of P. falciparum with reduced susceptibility to sulfadoxine-pyrimethamine remained high, but did not appear to have increased significantly since the introduction of ASP. No polymorphisms in K13 associated with decreased artemisinin susceptibility were found. ASP probably remained effective, supporting continued ASP use. [ABSTRACT FROM AUTHOR]

Background: Actual level of knowledge of treatment of COVID-19 disease caused by a type of coronavirus is that the disease cannot at present be cured by targeted therapy. Worldwide research is aiming to find a specific treatment, such as a vaccine or drug, for this type of coronavirus; this may help improve the situation, but it is highly expensive and time-consuming. The purpose of this paper is to review drug therapies approved in different parts of the world to treat COVID-19 and draw attention to ototoxicity as one of the adverse side-effects. Material and methods: Review of current literature was done in the scientific databases PubMed, ResearchGate, GoogleScholar, and Science-Direct. Studies were reviewed with reference to the inclusion criteria, then graded to assess the internal and external validity, leaving 50 studies for review. Results: According to scientific reports, possible antiviral pharmacological agents to treat COVID-19 consist of chloroquine, hydroxychloroquine, azitromycine, oseltamivir, and tocilizumab. In some cases, certain combinations may lead to additive ototoxicity as an adverse effect. Ototoxicity may be manifested by sensory and nervous hearing loss, tinnitus, imbalance, and cochlear-mandibular symptoms, which are sometimes temporary but sometimes permanent. Conclusion: Drug ototoxicity is well known as a cause of cochlear hearing loss, and so the use of new pharmacotherapy methods and drug combinations in the fight against the new coronavirus may have harmful effects. Ototoxicity needs to be taken into account. [ABSTRACT FROM AUTHOR]

Optimal lysosome function requires maintenance of an acidic pH maintained by proton pumps in combination with a counterion transporter such as the Cl−/H+ exchanger, CLCN7 (ClC-7), encoded by CLCN7. The role of ClC-7 in maintaining lysosomal pH has been controversial. In this paper, we performed clinical and genetic evaluations of two children of different ethnicities. Both children had delayed myelination and development, organomegaly, and hypopigmentation, but neither had osteopetrosis. Whole-exome and -genome sequencing revealed a de novo c.2144A>G variant in CLCN7 in both affected children. This p.Tyr715Cys variant, located in the C-terminal domain of ClC-7, resulted in increased outward currents when it was heterologously expressed in Xenopus oocytes. Fibroblasts from probands displayed a lysosomal pH approximately 0.2 units lower than that of control cells, and treatment with chloroquine normalized the pH. Primary fibroblasts from both probands also exhibited markedly enlarged intracellular vacuoles; this finding was recapitulated by the overexpression of human p.Tyr715Cys CLCN7 in control fibroblasts, reflecting the dominant, gain-of-function nature of the variant. A mouse harboring the knock-in Clcn7 variant exhibited hypopigmentation, hepatomegaly resulting from abnormal storage, and enlarged vacuoles in cultured fibroblasts. Our results show that p.Tyr715Cys is a gain-of-function CLCN7 variant associated with developmental delay, organomegaly, and hypopigmentation resulting from lysosomal hyperacidity, abnormal storage, and enlarged intracellular vacuoles. Our data supports the hypothesis that the ClC-7 antiporter plays a critical role in maintaining lysosomal pH. [ABSTRACT FROM AUTHOR]

Antimalarial drugs (AD) are a group of widespread therapeutic agents in multiple rheumatic indications. Although the effect of AD is mild and extended in time, low toxicity is their appreciated value. This paper describes the current state of knowledge on the mechanism of action, use, toxicity and pleiotropic effects of AD in the pharmacotherapy of autoimmune diseases. [ABSTRACT FROM AUTHOR]

Chloroquine (CQ) and hydroxychloroquine (HCQ) are well-known 4-aminoquinoline antimalarial agents. Scientific evidence also supports the use of CQ and HCQ in the treatment of cancer. Overall, preclinical studies support CQ and HCQ use in anti-cancer therapy, especially in combination with conventional anti-cancer treatments since they are able to sensitise tumour cells to a variety of drugs, potentiating the therapeutic activity. Thus far, clinical results are mostly in favour of the repurposing of CQ. However, over 30 clinical studies are still evaluating the activity of both CQ and HCQ in different cancer types and in combination with various standard treatments. Interestingly, CQ and HCQ exert effects both on cancer cells and on the tumour microenvironment. In addition to inhibition of the autophagic flux, which is the most studied anti-cancer effect of CQ and HCQ, these drugs affect the Toll-like receptor 9, p53 and CXCR4-CXCL12 pathway in cancer cells. In the tumour stroma, CQ was shown to affect the tumour vasculature, cancer-associated fibroblasts and the immune system. The evidence reviewed in this paper indicates that both CQ and HCQ deserve further clinical investigations in several cancer types. Special attention about the drug (CQ versus HCQ), the dose and the schedule of administration should be taken in the design of new trials. [ABSTRACT FROM AUTHOR]

Background: Recent work has perfected yeast-based methods for measuring drug transport by the Plasmodium falciparum chloroquine (CQ) resistance transporter (PfCRT). Methods: The approach relies on inducible heterologous expression of PfCRT in Saccharomyces cerevisiae yeast. In these experiments selecting drug concentrations are not toxic to the yeast, nor is expression of PfCRT alone toxic. Only when PfCRT is expressed in the presence of CQ is the growth of yeast impaired, due to inward transport of chloroquine (CQ) via the transporter. Results: During analysis of all 53 known naturally occurring PfCRT isoforms, two isoforms (PH1 and PH2 PfCRT) were found to be intrinsically toxic to yeast, even in the absence of CQ. Additional analysis of six very recently identified PfCRT isoforms from Malaysia also showed some toxicity. In this paper the nature of this yeast toxicity is examined. Data also show that PH1 and PH2 isoforms of PfCRT transport CQ with an efficiency intermediate to that catalyzed by previously studied CQR conferring isoforms. Mutation of PfCRT at position 160 is found to perturb vacuolar physiology, suggesting a fitness cost to position 160 amino acid substitutions. Conclusion: These data further define the wide range of activities that exist for PfCRT isoforms found in P. falciparum isolates from around the globe. [ABSTRACT FROM AUTHOR]

Background: Acquired drug resistance is becoming common during cancer chemotherapy and leads to treatment failure in clinic. To conquer acquired drug resistance, nanotechnology has been employed to deliver drug. In this paper, we prepared chitosan nanoparticles (CS NPs) capable of entrapping Gefitinib and chloroquine (CQ) for multiple drugs combinational therapy. Results: The results showed that Gefitinib/CQ-NPs were characterized of small particle size about 80.8 ± 9.7 nm and positive zeta potential about 21.3 ± 1.56 mV, and drug controlled to release slowly on a biphasic pattern. Compared with free Gefitinib and Gefitinib loaded NPs, Gefitinib and CQ co-delivery by CS nanoparticles showed the higher inhibition rates and enhanced cell apoptosis. Through western blot analysis, we found that Gefitinib could promote LC3 expression, which is the marker of autophagosomes. So, the acquired drug resistance may be associated with autophagy. CQ as an inhibitor of autophagolysosomes formation could overcome autophagy in the resistant cells. Conclusions: These findings demonstrated that chitosan nanoparticles entrapping Gefitinib and chloroquine have the potential to overcome acquired resistance and improve cancer treatment efficacy, especially towards resistant strains. [ABSTRACT FROM AUTHOR]

Background: Plasmodium falciparum resistance to chloroquine (CQ) denied healthcare providers access to a cheap and effective anti-malarial drug. Resistance has been proven to be due to point mutations on the parasite's pfcrt gene, particularly on codon 76, resulting in an amino acid change from lysine to threonine. This study sought to determine the prevalence of the pfcrt K76T mutation 13 years after CQ cessation in Msambweni, Kenya. Methods: Finger-prick whole blood was collected on 3MM Whatman® filter paper from 99 falciparum malaria patients. Parasite DNA was extracted via the Chelex method from individual blood spots and used as template in nested PCR amplification of pfcrt. Apo] restriction enzyme was used to digest the amplified DNA to identify the samples as wild type or sensitive at codon 76. Prevalence figures of the mutant pfcrt 76T gene were calculated by dividing the number of samples bearing the mutant gene with the total number of samples multiplied by 100 %. Chi square tests were used to test the significance of the findings against previous prevalence figures. Results: Out of 99 clinical samples collected in 2013, prevalence of the mutant pfcrt 76J gene stood at 41 %. Conclusion: The results indicate a significant [χ#178; test, P ≤ 0.05 (2006 vs 2013)] reversal to sensitivity by the P. falciparum population in the study site compared to the situation reported in 2006 at the same study site. This could primarily be driven by diminished use of CQ in the study area in line with the official policy. Studies to establish prevalence of the pfcrt 76T gene could be expanded countrywide to establish the CQ sensitivity status and predict a date when CQ may be re-introduced as part of malaria chemotherapy. [ABSTRACT FROM AUTHOR]

Purpose: To report an unusual fundus autofluorescence aspect in a patient with suspected hydroxychloroquine retinal toxicity. Method: Case report of an unusual presentation of a patient treated for 9 consecutive years with a therapeutically recommended dose of hydroxychloroquine. Result: We report the case of a 53-year-old Caucasian female treated with 400 mg hydroxychloroquine for rheumatoid arthritis over 9 years, currently on methotrexate and folinic acid, who stopped treatment 3 years ago. The cumulative dose is estimated at 1.314 kg. She recently noticed a reduction of vision in both eyes to 0.34 logMAR, with colour vision problems and major distortion in central vision. Fundus autofluorescence revealed minimal foveal pigmentary changes and more pronounced changes in the retina elsewhere. Foveal changes were confirmed by optical coherence tomography in both eyes. The patient did not report any colour perception difficulties or night vision problems and has no family history of any eye condition. Her visual field tested by an optician was full, with some central changes. Conclusion: Retinal toxicity from hydroxychloroquine can present in a different aspect than the commonly known retinal toxicity, and it happens even after years of cessation of the drug. The role of cumulative dose in toxicity is supported in this paper. [ABSTRACT FROM AUTHOR]

Background Malaria caused by Plasmodium vivax was long considered to have a low mortality, but recent reports from some geographical areas suggest that severe and complicated vivax malaria may be more common than previously thought. Methods The primary objective of this systematic review and meta-analysis was to describe the reported clinical characteristics and the geographical variation in prevalence of reported severe vivax malaria and its change over time derived from English-language articles published since 1900. Medline and Scopus databases were searched for original papers on severe vivax malaria, using as inclusion criteria modified 2010 WHO criteria for the diagnosis of severe falciparum malaria. Articles before 1949 were identified through reference lists in journals, textbooks, and personal collections of colleagues. Results A total of 77 studies with reported severe vivax malaria and 63 studies with no reported severe vivax malaria (totaling 46,411 and 6,753 vivax malaria patients, respectively) were included. The 77 studies with reported severe vivax malaria were mainly from India (n = 33), USA (n = 8), Indonesia (n = 6), and Pakistan (n = 6). Vivax endemic countries not reporting severe vivax malaria beyond individual case reports included: the Greater Mekong Sub-region, China, North Korea, Bangladesh, Afghanistan, Middle East (except Qatar), the horn of Africa, and Madagascar. Only 17/77 reports were from before 2000. Vivax mono-infection was confirmed by PCR in 14 studies and co-morbidities were ruled out in 23 studies. Among the 77 studies reporting severe vivax malaria, severe thrombocytopenia (<50,000/mm³) was the most common "severe" manifestation (888/45,775 with pooled prevalence of 8.6%).. The case fatality was 0.3% (353/46,411). Severity syndromes varied widely between different geographical areas, with severe anaemia being most prominent in areas of high transmission and chloroquine resistance. Conclusion Plasmodium vivax can cause severe and even fatal disease, but there is recent increase in reports over the past 15 years with larger series restricted to a limited number of geographical areas. The biological basis of these variations is currently not known. More detailed epidemiological studies are needed which dissociate causation from association to refine the definition and estimate the prevalence of severe vivax malaria. [ABSTRACT FROM AUTHOR]

COVID-19 has spread around the world and caused serious public health and social problems. Although several vaccines have been authorized for emergency use, new effective antiviral drugs are still needed. Some repurposed drugs including Chloroquine, Hydroxychloroquine and Remdesivir were immediately used to treat COVID-19 after the pandemic. However, the therapeutic effects of these drugs have not been fully demonstrated in clinical studies. In this paper, we found an antimalarial drug, Naphthoquine, showed good broad-spectrum anti-coronavirus activity. Naphthoquineinhibited HCoV-229E, HCoV-OC43 and SARS-CoV-2 replication in vitro, with IC50 = 2.05 ± 1.44 μM, 5.83 ± 0.74 μM, and 2.01 ± 0.38 µM, respectively. Time-of-addition assay was also performed to explore at which stage Naphthoquine functions during SARS-CoV-2 replication. The results suggested that Naphthoquine may influence virus entry and post-entry replication. Considering the safety of Naphthoquine was even better than that of Chloroquine, we think Naphthoquine has the potential to be used as a broad-spectrum drug for coronavirus infection. [ABSTRACT FROM AUTHOR]

Background After years of disuse of chloroquine (CQ) as first-line anti-malarial drug in Ghana, reports from molecular studies conducted in parts of the country indicate varying prevalence of T76 mutation in the pfcrt gene. This situation has several health implications, one being that mutations that confer resistance to CQ have been reported to show substantial cross-resistance to other anti-malarial drugs. It is important to identify some of the factors contributing to the continuous presence of CQ resistance markers in the country. This study determined the prevalence of T76 mutation in pfcrt gene of Plasmodium falciparum isolates collected from selected areas of the Central region of Ghana and correlated with the level of CQ use in these areas. Methods Plasmodium falciparum DNA was extracted from collected blood-blot filter paper samples in the study sites. The prevalence of T76 point mutation in pfcrt gene was assessed using nested PCR followed by RFLP. CQ from pharmacy and chemical shops was obtained using mystery buying method. The extent of CQ use by the participants was determined by measuring the level of the drug in their urine samples using the Saker-Solomon method. Results Of the 214 P. falciparum isolates analysed, 71.9% were found to have T76 mutation of pfcrt gene. The study revealed that 14.49% of community pharmacies and chemical shops had stocks of CQ for sale while 16.9% of the participants had CQ in their urine samples. There is five times more risks of becoming infected with CQ resistant strain for staying in an area where CQ is stocked for sale [RR = 0.20, p < 0.0001] and thirteen times more risks of having CQ-resistant mutant from those who still use CQ than non-users [OR = 0.08, p < 0.0001]. Conclusion This study has shown that high variation in the prevalence of T76 mutations of P. falciparum is linked with the level of CQ stocking and usage within study area. [ABSTRACT FROM AUTHOR]

The rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has created a severe global health crisis. In this paper, we used docking and simulation methods to identify potential targets and the mechanism of action of chloroquine (CQ) and hydroxychloroquine (HCQ) against SARS-CoV-2. Our results showed that both CQ and HCQ influenced the functionality of the envelope (E) protein, necessary in the maturation processes of the virus, due to interactions that modify the flexibility of the protein structure. Furthermore, CQ and HCQ also influenced the proofreading and capping of viral RNA in SARS-CoV-2, performed by nsp10/nsp14 and nsp10/nsp16. In particular, HCQ demonstrated a better energy binding with the examined targets compared to CQ, probably due to the hydrogen bonding of the hydroxyl group of HCQ with polar amino acid residues. [ABSTRACT FROM AUTHOR]

Fluorescence quenching, very often, has been employed as a suitable technique for characterization of the immediate environment of a fluorophore. This paper reports the absorption and fluorescence characteristics of an antimalarial drug, chloroquine, in presence of the salt copper chloride (CuCl 2) in aqueous and micellar systems. Chloroquine fluorescence was quenched considerably by the copper ion (Cu2+); quenching ability of Cu2+ in micellar solution of the cationic surfactant cetyltrimethylammonium chloride (CTAC) is higher than that in water while for the nonionic surfactant polyoxyethylene (20) cetyl ether (Brij 58) it has much lower quenching efficiency. Downward deviations in Stern-Volmer (SV) plots were observed for all the systems. Possibly, the chloroquine molecules are inserted somewhat deeper inside the micelles of Brij 58 as compared to the CTAC micelles and in Brij 58 micelles the fluorophore might be less exposed to the aqueous phase to become available for the metal ion quenching. • Quenching of chloroquine fluorescence by copper ion in aqueous/micellar solutions • Location sites of fluorophore/quencher are influenced by polarity of micellar interface. • This study can provide deep insight into structure-property relationship of fluorophore with amphiphiles. [ABSTRACT FROM AUTHOR]

Background: A reversal of chloroquine (CQ) resistance following a period of withdrawal has raised the possibility of its re-introduction. This study evaluated the current prevalence of Pfcrt and Pfmdr1 alleles in Plasmodium falciparum isolates, 11 years after CQ withdrawal in Southeast Nigeria. Methods: Filter-paper blood samples were collected from 725 non-febrile individuals, comprising 250 children (≤ 12 years), 250 pregnant women and 225 other adults, between October 2014 and February 2015 in Nnewi town, Southeast Nigeria. Nested PCR followed by direct sequencing was employed for the genotyping of Pfcrt and Pfmdr1 genes. Results: A total of 103 parasites-positive samples were recovered, comprising of 48 (19.20%) among children, 20 (20.00%) among pregnant women and 35 (15.50%) among other adults cohort. The frequency of the mutant genotype of Pfcrt 76T, 75E and 74I was 94.50% each. Parasite isolates from children had a frequency of 100% for mutant alleles in all Pfcrt codons while isolates from pregnant women and other adults had a frequency of 91% each in all codons. Haplotype distribution of pfcrt gene were 5.45, 0.00 and 76.37% for CVMNK, SVMNT and CVIET, respectively. For Pfmdr1 gene, the frequency of 86Y, 184F and 1246Y mutant alleles were 8.54, 29.27 and 3.66%, respectively. Amongst the Pfmdr1 haplotypes analysed, NFD had the highest frequency of 24.4%, followed by YFD at 6.10%. NYF and NYY occurred the least (1.20%). Conclusion: The high level of Pfcrt mutations is suggestive of a sustained CQ pressure on P. falciparum isolates in the study area, despite the change of first line treatment from CQ to artemisinin combination therapy for 11 years. A new strategy to ensure the complete withdrawal of CQ from the country is recommended. [ABSTRACT FROM AUTHOR]

This paper describes a continuation of our efforts in the pursuit of novel antiplasmodial agents with optimized properties. Following our previous discovery of biologically potent asymmetric primaquine (PQ) and halogenaniline fumardiamides (1–6), we now report their significant in vitro activity against the hepatic stages of Plasmodium parasites. Furthermore, we successfully prepared chloroquine (CQ) analogue derivatives (11–16) and evaluated their activity against both the hepatic and erythrocytic stages of Plasmodium. Our results have shown that PQ fumardiamides (1–6) exert both higher activity against P. berghei hepatic stages and lower toxicity against human hepatoma cells than the parent drug and CQ derivatives (11–16). The favourable cytotoxicity profile of the most active compounds, 5 and 6, was corroborated by assays performed on human cells (human breast adenocarcinoma (MCF-7) and non-tumour embryonic kidney cells (HEK293T)), even when glucose-6-phosphate dehydrogenase (G6PD) was inhibited. The activity of CQ fumardiamides on P. falciparum erythrocytic stages was higher than that of PQ derivatives, comparable to CQ against CQ-resistant strain PfDd2, but lower than CQ when tested on the CQ-sensitive strain Pf3D7. In addition, both sets of compounds showed favourable drug-like properties. Hence, quinoline fumardiamides could serve as a starting point towards the development of safer and more effective antiplasmodial agents. [ABSTRACT FROM AUTHOR]