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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., (© 2021, American College of Rheumatology.)

Background: The return of chloroquine-sensitive Plasmodium falciparum in sub-Saharan Africa countries offers the opportunity for the reintroduction of chloroquine (CQ) either in combination with other drugs or as a single therapy for the management of malaria. This study assesses the influence of individual study sites on the selection of CQ sensitive P. falciparum markers in the Central region of Ghana., Methods: Genomic DNA was extracted from an archived filter paper blood blot from Cape Coast, Elmina, Assin Fosu, and Twifo Praso using the Chelex DNA extraction method. The age metadata of the patients from whom the blood spots were taken was collected. The prevalence of CQ-sensitive markers of pfcrt K76 and pfmdr1 N86 was performed using nested PCR and RFLP. The data were analysed using Chi-square and Odd ratio., Results: The overall prevalence of CQ-sensitive P. falciparum markers, pfcrt K76 and pfmdr1 N86 in the Central Region of Ghana were 142 out of 184 (77.17%) and 180 out of 184 (97.83%), respectively. The distribution of pfcrt K76 was assessed among the age groups per the individual study sites. 12 out of 33 (36.36%), 8 out of 33 (24.24%) and 6 out of 33 (18.18%) of pfcrt K76 CQ-sensitive marker were isolated from age 0 to 5 years, 16 to 30 years and 31 to 45 years old respectively at Cape Coast. Assin Fosu and Twifo Praso had the highest pfcrt K76 prevalence in 0-5 years, followed by 16-30 years and 6-15 years of age. The results showed that there was a significant prevalence of pfcrt K76 in all study sites; Cape Coast (χ 2  = 26.48, p < 0.0001), Assin Fosu (χ 2  = 37.67, p < 0.0001), Twifo Praso (χ 2  = 32.25, p < 0.0001) and Elmina (χ 2  = 17.88, p < 0.0001). Again, the likelihood to detect pfcrt K76 (OR (95% CI) was 7.105 (3.118-17.14), p < 0.0001 and pfmdr1 (2.028 (1.065-3.790), p < 0.001) among P. falciparum isolates from Cape Coast to be seven times and two times, respectively., Conclusion: The study showed a significant selection and expansion of chloroquine-sensitive P. falciparum markers in all the selected study areas in the Central region. This finding has a significant implication for the future treatment, management, and control of P. falciparum malaria., (© 2021. The Author(s).)

Background: Anti-malarial resistance is, and continues to be a significant challenge in the fight against malaria and a threat to achieving malaria elimination. In Zambia, chloroquine (CQ), a safe, affordable and well-tolerated drug, was removed from use in 2003 due to high levels of resistance evidenced with treatment failure. This study sought to investigate the prevalence of chloroquine resistance markers in Southern and Western Provinces of Zambia 14 years after the withdrawal of CQ., Methods: Data from a cross-sectional, all-age household survey, conducted during the peak malaria transmission season (April-May 2017) was analysed. During the all-age survey, socio-demographic information and coverage of malaria interventions were collected. Consenting individuals were tested for malaria with a rapid diagnostic test and a spot of blood collected on filter paper to create a dried blood spot (DBS). Photo-induced electronic transfer-polymerase chain reaction (PET-PCR) was used to analyse the DBS for the presence of all four malaria species. Plasmodium falciparum positive samples were analysed by high resolution melt (HRM) PCR to detect the presence of genotypic markers of drug resistance in the P. falciparum chloroquine resistance transporter (Pfcrt) and P. falciparum multi-drug resistance (Pfmdr) genes., Results: A total of 181 P. falciparum positive samples were examined for pfcrt K76T and MDR N86. Of the 181 samples 155 successfully amplified for Pfcrt and 145 for Pfmdr N86. The overall prevalence of CQ drug-resistant parasites was 1.9% (3/155), with no significant difference between the two provinces. No N86Y/F mutations in the Pfmdr gene were observed in any of the sample., Conclusion: This study reveals the return of CQ sensitive parasites in Southern and Western Provinces of Zambia 14 years after its withdrawal. Surveillance of molecular resistant markers for anti-malarials should be included in the Malaria Elimination Programme so that resistance is monitored country wide.

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 Pf Dd2, but lower than CQ when tested on the CQ-sensitive strain Pf 3D7. 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., Competing Interests: The authors declare no conflict of interest.

Activation of the NLRP3 inflammasome, which catalyzes maturation of proinflammatory cytokines like IL-1 β and IL-18, is implicated and essentially involved in many kinds of inflammatory disorders. Chloroquine (CQ) is a traditional antimalarial drug and also possesses an anti-inflammatory property. In this study, we investigated whether CQ suppresses NLRP3 inflammasome activation and thereby confers protection against murine endotoxic shock. CQ attenuated NF- κ B and MAPK activation and prohibited expression of IL-1 β , IL-18, and Nlrp3 in LPS treated murine bone marrow-derived macrophages (BMDMs), demonstrating its inhibitory effect on the priming signal of NLRP3 activation. Then, CQ was shown to inhibit caspase-1 activation and ASC specks formation in BMDMs, which indicates that CQ also suppresses inflammasome assembly, the second signal for NLRP3 inflammasome activation. In a murine endotoxic shock model, CQ effectively improved survival and markedly reduced IL-1 β and IL-18 production in serum, peritoneal fluid, and lung tissues. Moreover, CQ reduced protein levels of NLRP3 and caspases-1 p10 in lung homogenates of mice with endotoxic shock, which may possibly explain its anti-inflammatory activity and life protection efficacy in vivo. Overall, our results demonstrate a new role of CQ that facilitates negative regulation on NLRP3 inflammasome, which thereby confers protection against lethal endotoxic shock., Competing Interests: The authors declare that there are no competing interests regarding the publication of this paper.

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. Apo1 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 76T gene stood at 41 %., Conclusion: The results indicate a significant [χ(2) 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.

Bacterial and malaria co-infections are common in malaria endemic countries and thus necessitate co-administration of antibiotics and antimalarials. There have long been anecdotal clinical reports of interactions between penicillins and antimalarial agents, but the nature and mechanisms of these interactions remain to be investigated. In this study, we employed antimicrobial interaction testing methods to study the effect of two antimalarials on the antibacterial activity of ampicillin in vitro. Paper strip diffusion, a modified disc diffusion and checkerboard methods were used to determine the nature of interactions between ampicillin and quinoline antimalarials, chloroquine and quinine, against Gram-positive and Gram-negative bacteria. The impact of antimalarials and ampicillin-antimalarial drug combinations on cell integrity of test bacteria were determined by measuring potassium release. The tested antimalarials did not show substantial antibacterial activity but quinine was bactericidal at high concentrations. Chloroquine and quinine increased ampicillin activity, with increasing concentrations extending the antibacterial's inhibition zones by 2.7-4.4 mm and from 1.1 to over 60 mm, respectively. Observed interactions were largely additive with Fractional Inhibitory Concentration Indices of >0.5-1 for all ampicillin-antimalarial combinations. Quinine and, to a lesser extent, chloroquine increase the activity of ampicillin and potentially other β-lactams, which has implications for combined clinical use. [ABSTRACT FROM AUTHOR]

Background: Chloroquine (CQ) which is one of the 4-aminoquinolines was once the mainstay of malaria treatment before it was officially withdrawn due to widespread resistance to it by Plasmodium species. It is one of the cheapest, safest, easily produced antimalarial compounds and has one of the longest half-lives among the antimalarial drugs which are also safe for use in pregnancy. Reversal of CQ resistance back to sensitivity has been documented after a period of withdrawal, and this may be a great relief in achievement of effective antimalarial chemotherapy at a relatively cheaper cost in Nigeria. This study investigated the characterization of markers of CQ resistance in Plasmodium falciparum infection among pregnant women in Oyo State following several years of official CQ withdrawal for treatment in Nigeria. Materials and Methods: Thick and thin blood films were made from venous blood collected from 316 consenting pregnant women and dispensed into ethylenediaminetetraacetic acid bottles after initial screening with SD Bioline RDT kit. The blood films were processed for malaria microscopy using 10% Giemsa stain. Dry blood spots on Whatman no. 1 filter paper were used for parasite DNA extraction and subsequent detection of CQ resistance markers using restriction fragment length polymorphism. Results: Eighty-two out of the 316 samples were positive for P. falciparum and subjected to molecular analysis for the detection of Pfcrt and Pfmdr1 mutant genes. Out of the 82 positive cases, 75 and 80 expressed mutant Pfcrt and Pfmdr1 genes, respectively, while 73 expressed both Pfcrt and Pfmdr1 genes. Conclusion: The high prevalence of the two major molecular markers of CQ resistance in this study, portends a concern in achieving resurgence of sensitivity after years of official withdrawal, thus official malaria management protocols should be strictly adhered to by ensuring testing before drug use while also avoiding self-medication. [ABSTRACT FROM AUTHOR]

Background: Malaria continues to wreak havoc on the well-being of the community. Resistant parasites are jeopardizing the treatment. This is a wake-up call for better medications. Folk plants are the key starting point for antimalarial drug discovery. After crushing and mixing the leaves of Coriandrum sativum with water, one cup of tea is drunk daily for a duration of three to five days as a remedy for malaria by local folks in Ethiopia. Additionally, in vitro experiments conducted on the plant leaf extract elsewhere have also demonstrated the plant's malaria parasite inhibitory effect. There has been no pharmacologic research to assert this endowment in animals, though. This experiment was aimed at evaluating the antimalarial efficacy of C. sativum in Plasmodium berghei infected mice. Methods: The plant's leaf was extracted using maceration with distilled water. The extract was examined for potential acute toxicity. An evaluation of secondary phytoconstituents was done. Standard antimalarial screening models (prophylactic, chemosuppressive, curative tests) were utilized to assess the antiplasmodial effect. In each test, thirty mice were organized into groups of five. To the three categories, the test substance was given at doses of 100, 200 and 400 mg/kg/day before or after the commencement of P. berghei infection. Positive and negative control mice were provided Chloroquine and distilled water, respectively. Rectal temperature, parasitemia, body weight, survival time and packed cell volume were ultimately assessed. Analysis of the data was performed using Statistical Package for Social Sciences. Results: No toxicity was manifested in mice. The extract demonstrated a significant inhibition of parasitemia (p < 0.05) in all the models. The inhibition of parasite load was highest with the upper dose in the suppressive test (82.74%) followed by the curative procedure (78.49%). Likewise, inhibition of hypothermia, weight loss hampering, improved survival and protection against hemolysis were elicited by the extract. Conclusions: The results of our experimental study revealed that the aqueous crude leaf extract of C. sativum exhibits significant antimalarial efficacy in multiple in vivo models involving mice infected with P. berghei. Given this promising therapeutic attribute, in depth investigation on the plant is recommended. [ABSTRACT FROM AUTHOR]

Multiple methodologies have been developed to identify and predict adverse events (AEs); however, many of these methods do not consider how patient population characteristics, such as diseases, age, and gender, affect AEs seen. In this study, we evaluated the utility of collecting and analyzing AE data related to hydroxychloroquine (HCQ) and chloroquine (CQ) from US Prescribing Information (USPIs, also called drug product labels or package inserts), the FDA Adverse Event Reporting System (FAERS), and peer-reviewed literature from PubMed/EMBASE, followed by AE classification and modeling using the Ontology of Adverse Events (OAE). Our USPI analysis showed that CQ and HCQ AE profiles were similar, although HCQ was reported to be associated with fewer types of cardiovascular, nervous system, and musculoskeletal AEs. According to EMBASE literature mining, CQ and HCQ were associated with QT prolongation (primarily when treating COVID-19), heart arrhythmias, development of Torsade des Pointes, and retinopathy (primarily when treating lupus). The FAERS data was analyzed by proportional ratio reporting, Chi-square test, and minimal case number filtering, followed by OAE classification. HCQ was associated with 63 significant AEs (including 21 cardiovascular AEs) for COVID-19 patients and 120 significant AEs (including 12 cardiovascular AEs) for lupus patients, supporting the hypothesis that the disease being treated affects the type and number of certain CQ/HCQ AEs that are manifested. Using an HCQ AE patient example reported in the literature, we also ontologically modeled how an AE occurs and what factors (e.g., age, biological sex, and medical history) are involved in the AE formation. The methodology developed in this study can be used for other drugs and indications to better identify patient populations that are particularly vulnerable to AEs. [ABSTRACT FROM AUTHOR]

Background: Chemotherapies target the PfEMP-1 and PfPKG proteins in Plasmodium falciparum, the parasite that causes malaria, in an effort to prevent the disease's high fatality rate. This work identified the phytochemical components of Nauclea latifolia roots and docked the chemical compounds against target proteins, and examined the in vivo antiplasmodial effect of the roots on Plasmodium berghei-infected mice. Methods: Standard protocols were followed for the collection of the plant's roots, cleaning, and drying of the roots, extraction and fraction preparation, assessment of the in vivo antiplasmodial activity, retrieval of the PfEMP-1 and PfPKG proteins, GCMS, ADME, and docking studies, chromatographic techniques were employed to separate the residual fraction's components, and the Swis-ADME program made it possible to estimate the drug's likeness and pharmacokinetic properties. The Auto Dock Vina 4.2 tool was utilized for molecular docking analysis. Results: The residual fraction showed the best therapeutic response when compared favorably to amodiaquine (80.5%) and artesunate (85.1%). It also considerably reduced the number of parasites, with the % growth inhibition of the parasite at 42.8% (D2) and 83.4% (D5). Following purification, 25 compounds were isolated and characterized with GCMS. Based on their low molecular weights, non-permeation of the blood–brain barrier, non-inhibition of metabolizing enzymes, and non-violation of Lipinski's criteria, betulinic and ursolic acids were superior to chloroquine as the best phytochemicals. Hence, they are lead compounds. Conclusion: In addition to identifying the bioactive compounds, ADME, and docking data of the lead compounds as candidates for rational drug design processes as observed against Plasmodium falciparum target proteins (PfEMP-1 and PfPKG), which are implicated in the pathogenesis of malaria, the study has validated that the residual fraction of N. latifolia roots has the best antiplasmodial therapeutic index. [ABSTRACT FROM AUTHOR]

Background: Duchenne muscular dystrophy (DMD), a severe degenerative skeletal and cardiac muscle disease, has a poor prognosis, and no curative treatments are available. Because decreased autophagy has been reported to contribute to skeletal muscle degeneration, therapies targeting autophagy are expected to improve skeletal muscle hypofunction. However, the role of this regulatory mechanism has not been evaluated clearly in DMD cardiomyocytes. Methods: In this present study, we evaluated myocardial fibrosis and its mechanism in mdx mice, a model of DMD, and also evaluated changes in cardiac function. Results: As assessed by LC3 immunohistochemistry, a small number of autophagosomes were detected in cardiomyocytes of both mdx mice and control wild-type (WT) mice. The number of autophagosomes was significantly enhanced by 4 weeks of isoproterenol-induced cardiac stress in cardiomyocytes of mdx but not WT mice. Simultaneously, isoproterenol increased cardiomyocyte fibrosis in mdx but not WT mice. Administration of chloroquine significantly decreased cardiomyocyte fibrosis in mdx mice, even after isoproterenol treatment. Left ventricle size and function were evaluated by echocardiography. Left ventricular contraction was decreased in mdx mice after isoproterenol treatment compared with control mice, which was alleviated by chloroquine administration. Conclusions: Heart failure in DMD patients is possibly treated with chloroquine, and the mechanism probably involves chloroquine's anti-inflammatory effects. [ABSTRACT FROM AUTHOR]

Malaria is a global health challenge with endemicity in sub-Saharan Africa, where there are multiple drug-resistant strains and limited access to modern health care facilities, especially in rural areas. Studies indicate that African traditional medicine could make a substantial contribution to the reduction of malaria-related deaths and achievement of universal health coverage (UHC), particularly in these regions. Thus, this study evaluated the curative antimalarial effects of Chromolaena odorata leaf extract using mouse model. Forty-five (45) albino mice weighing between 18 and 22 g were grouped into nine groups of 5 animals each. Animals in groups 2–9 were infected with the chloroquine-resistant strain of Plasmodium berghei, while animals in groups 3–9 were subsequently treated with 10 mg/kg chloroquine, a combination of 1.4 mg/kg artemether and 8.75 mg/kg lumefantrine (Coartem), and varying concentrations of the fraction from the aqueous leaf extract of C. odorata at day 3 post-infection. The findings from this study indicate that treatment with 400 mg/kg of the ethanolic fraction of the crude extract resulted in a significant decrease in parasite load (97.6%), which was comparable to the activities of the conventional drugs chloroquine (98.6%) and Coartem (98.8%). The ethyl acetate and ethanolic fractions at 400 mg/kg also ameliorated the significant alterations in the red blood cells, white blood cells, and platelets of the infected animals. The high antimalarial activity displayed by the ethanolic fraction could be due to the presence of quercetin and kaempferol, as detected by high performance liquid chromatography (HPLC) analysis. The findings suggest that the fractions from C. odorata could serve as an alternative source of malaria therapy, particularly in sub-Saharan Africa. [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: 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]

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: The plants Aloe weloensis, Lepidium sativum, and Lobelia gibberoa have been used in Ethiopian folklore medicine to treat various diseases including malaria. Method: The in vitro anti-plasmodial activity of the three crude extracts was evaluated using parasite lactate dehydrogenase assay against the chloroquine (CQ)-sensitive D10 and the chloroquine (CQ)-resistant W2 strains. Result: The methanolic extract of L. gibberoa roots showed the highest in vitro anti-plasmodial effect against both D10 and W2 Plasmodium falciparum strains with IC50 value of 103.83 ± 26.17 µg/mL and 47.11 ± 12.46 µg/mL, respectively. However, the methanolic extract of L. sativum seeds and the leaf latex of A. weloensis were not active with an IC50 value > 200 µg/mL against both D10 and W2 strains. Conclusion: The methanolic extract of L. gibberoa roots showed a promising in vitro anti-plasmodial activity against the CQ-sensitive (D10) and CQ-resistant (W2) strains of P. falciparum. Thus, the anti-plasmodial activity of this plant partly justifies and may also support the traditional use against malaria. However, the methanolic extract of L. sativum seeds and the leaf latex of A. weloensis did not exert suppressive activity on the growth of P. falciparum strains. [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]

In Nigeria, Annona muricata L. has been used to treat a variety of ailments. The mechanism of the antimalarial activity of ethanolic leaf extract of Annona muricata (EEAML) was investigated using both an in vivo and an in silico approach. The experimental mice were divided into five groups: A-F. The mice in groups B-F were inoculated with Plasmodium berghei NK-65 and treated accordingly. Groups A and B are the negative and positive controls (infected and untreated), respectively. Group C received 10 mg/kg chloroquine (standard drug), whereas groups D-F received 100, 200, and 300 mg/kg body weight of the extract orally respectively. The mice were euthanized eight days after infection, and their liver and blood were collected and used in biochemical tests. Molecular docking was performed using the extract's HPLC compounds and Plasmodium falciparum proteins. In the suppressive, prophylactic, and curative tests, there was a significant decrease (p < 0.05) in parasitemia levels in groups treated with the extract compared to the positive control and standard drug. When compared to the positive control, there was a significant (p < 0.05) reduction in liver MDA, total cholesterol, and total triglyceride levels. The binding energies of luteolin and apigenin- pf protein complexes were significantly (p < 0.05) higher compared to their respective references. The anti-plasmodial activity of the extract may result from its hypolipidemic effect, which deprives the parasite of essential lipid molecules needed for parasite growth, as well as from the inhibitory effects of apigenin and luteolin on specific proteins required for the Plasmodium metabolic pathway. [ABSTRACT FROM AUTHOR]

Objective: To describe the pattern and risk factors for antimalarial (AM)‐induced retinopathy in patients with rheumatic diseases. Methods: A retrospective chart review was conducted at an urban Canadian center for patients with AM use of more than 3 months and documented retinopathy screening. Univariate and multivariate regression analyses were performed to determine risk factors for retinopathy. Sensitivity analyses included stratification of analysis by method of screening and by hydroxychloroquine (HCQ) versus chloroquine (CQ). Results: A total of 613 patients were included in the final analysis, with systemic lupus erythematosus (SLE) (n = 259) as the most common diagnosis. Definite AM‐induced retinal toxicity was observed in 12 patients, 11 of whom had SLE. The earliest diagnosis of toxicity occurred after 5.4 years of AM therapy, and the prevalence beyond 5 years was 3.1%. In univariate analysis, a diagnosis of SLE (P = 0.009; odds ratio [OR]: 15.66; 95% confidence interval [CI]: 2.01‐122.05), the daily weight‐based dose of HCQ (P = 0.044; OR: 1.49; 95% CI: 1.01‐2.20), cumulative CQ dose (P = 0.014; OR: 4.80; CI: 1.37‐16.84), and daily CQ weight‐based dose (P = 0.0001; OR: 5.70; 95% CI: 2.41‐13.49) were significantly associated with toxicity. In multivariate analysis, diagnosis of SLE (P = 0.022; OR: 12.14; 95% CI: 1.44‐102.44) and daily CQ weight‐based dose (P = 0.005; OR: 1.83; 95% CI: 1.83‐26.75) were significant after adjusting for standard covariates. Conclusion: The risk of AM‐induced retinopathy increases after 5 years of therapy. There may be higher rates of toxicity in patients with SLE because of longer duration of treatment, higher weight‐based dosages, and more CQ use in this population, and SLE may be an independent risk factor. [ABSTRACT FROM AUTHOR]

Background. Malarial infection has significant negative impact on the health of the world population. It is treated by modern and traditional medicines. Among traditional medicinal plants, Acacia tortilis is used by different communities as antimalarial agent. Therefore, the objective of this study is to validate antimalarial activity of the stem bark of Acacia tortilis in mice. Methods. To evaluate antimalarial activity of the plant, 4-day suppressive, curative, and prophylactic antimalarial test models were used. Parasitemia, packed cell volume (PCV), survival time, rectal temperature, and body weight were used to evaluate the effect of the plant extracts. Data were analyzed using SPSS version 26 followed by Tukey's post hoc multiple comparison test. Results. The crude extract and dichloromethane fraction significantly suppressed the level of parasitemia (p < 0.001) and increased mean survival time (p < 0.01) at all tested doses. Similarly, significant effects were observed in mean survival time, % change of PCV, weight, and temperature in both curative and prophylactic antimalarial test models. Conclusions. The methanolic extract and solvent fractions of the stem bark of Acacia tortilis has shown antimalarial activity, and the finding supports the traditional use and the in vitro studies. Thus, this study can be used as an initiation for researchers to find the most active phytochemical entity and to conduct additional safety and efficacy tests. [ABSTRACT FROM AUTHOR]

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The aim of this study was to discuss the therapeutic mechanism of action of antimalarials, in particular hydroxychloroquine (HCQ), in patients with lupus erythematosus. It examines the results of recent studies indicating the need to revise the indications, dosage and duration of safe therapy, thus limiting the possibility of adverse effects. Historically, HCQ was recommended for patients with arthritis as a predominant symptom, whereas today, it is recommended for all lupus patients, even those with lupus nephritis and pregnant women; it has a favourable therapeutic profile, particularly regarding its effect on the activity of the disease, and the possibility of prolonging survival time and preventing organ damage and dysfunction. Antimalarials are basic, disease-modifying antirheumatic drugs, which not only relieve the symptoms of inflammation, but also affect the underlying processes; therefore, they should be administered chronically, and the expected effects may sometimes take a long time to become apparent. In the past, the recommended dose was 6.5 mg/kg ideal body weight, whereas today it is up to 5.0 mg/kg real body weight. A very important aspect of long-term therapy is the strict adherence to the medical prescription; hence, the introduction of a new formulation containing 400 mg of hydroxychloroquine sulphate per tablet is an interesting proposal. [ABSTRACT FROM AUTHOR]

Malaria remains a significant global health problem, but the development of effective antimalarial drugs is challenging due to the parasite's complex life cycle and lack of knowledge about the critical specific stages. Medicinal plants have been investigated as adjuvant therapy for malaria, so this systematic review summarizes 46 primary articles published until December 2020 that discuss curcumin and piperine as antimalarial agents. The selected articles discussed their antioxidant, anti-inflammatory, and antiapoptosis properties, as well as their mechanism of action against Plasmodium species. Curcumin is a potent antioxidant, damages parasite DNA, and may promote an immune response against Plasmodium by increasing reactive oxygen species (ROS), while piperine is also a potent antioxidant that potentiates the effects of curcumin. Hence, combining these compounds is likely to have the same effect as chloroquine, that is, attenuate and restrict parasite development, thereby reducing parasitemia and increasing host survival. This systematic review presents new information regarding the development of a curcumin-piperine combination for future malaria therapy. [ABSTRACT FROM AUTHOR]

Chloroquine phosphate (CQ) the antimalarial drug and suggested to treat the pandemic disease coronavirus (COVID-19) is often adulterated with some of the non-steroidal anti-inflammatory drugs (NSAIDs) such as paracetamol, aspirin (ASP), or both. The purpose of this study is to detect such counterfeited drugs, using a reversed phase high pressure liquid chromatography (RP-HPLC) method with fluorescence detection. Analysis was divided into three phases. In the first phase, a Plackett-Burman design (PBD) was used to screen five independent factors, namely, buffer pH, buffer concentration (mM), acetonitrile content (%), flow rate (mL/min) and triethylamine (TEA) content in the buffer preparation (%). The selected dependent variables were (resolution, symmetry of peaks and run time). The objective of the second phase was to optimize the method performance using Box-Behnken design (BBD) and desirability function for multiple response optimization to obtain the best chromatographic performance with the shortest run time. Optimal chromatographic separation was achieved on a YMC-pack pro C18 ODS-A column (15 cm × 4.6 mm, 5 µm) at room temperature The optimum mobile phase consisted of acetonitrile and 5 mM sodium dihydrogen phosphate buffer containing 0.5% triethyamine (30:70, v/v) with the pH adjusted to 3.5 using an orthophosphoric acid solution. The flow rate was maintained at 1 mL/min, and the detection was performed with a fluorescence detector fixed at 380 nm (λemission) after excitation at 335 nm (λexcitation). The third phase was method validation according to ICH guidelines, providing to be specific, precise, accurate, and robust. The method is linear over a range of 0.4–8 µg/mL for chloroquine and ASP, while for paracetamol it is linear over 16–48 µg/mL. The developed RP-HPLC method was used for quantitation of the three drugs in chloroquine dosage form samples. The method shows a great tendency in the classification between the genuine chloroquine and the adulterated ones in pharmaceutical preparations and breast milk. [ABSTRACT FROM AUTHOR]

Background: Anti-malarial drug resistance may be limited by decreased fitness in resistant parasites. Important contributors to resistance are mutations in the Plasmodium falciparum putative drug transporter PfMDR1. Methods: Impacts on in vitro fitness of two common PfMDR1 polymorphisms, N86Y, which is associated with sensitivity to multiple drugs, and Y184F, which has no clear impact on drug sensitivity, were evaluated to study associations between resistance mediators and parasite fitness, measured as relative growth in competitive culture experiments. NF10 P. falciparum lines engineered to represent all PfMDR1 N86Y and Y184F haplotypes were co-cultured for 40 days, and the genetic make-up of the cultures was characterized every 4 days by pyrosequencing. The impacts of culture with anti-malarials on the growth of different haplotypes were also assessed. Lastly, the engineering of P. falciparum containing another common polymorphism, PfMDR1 D1246Y, was attempted. Results: Co-culture results were as follows. With wild type (WT) Y184 fixed (N86/Y184 vs. 86Y/Y184), parasites WT and mutant at 86 were at equilibrium. With mutant 184 F fixed (N86/184F vs. 86Y/184F), mutants at 86 overgrew WT. With WT N86 fixed (N86/Y184 vs. N86/184F), WT at 184 overgrew mutants. With mutant 86Y fixed (86Y/Y184 vs. 86Y/184F), WT and mutant at 86 were at equilibrium. Parasites with the double WT were in equilibrium with the double mutant, but 86Y/Y184 overgrew N86/184F. Overall, WT N86/mutant 184F parasites were less fit than parasites with all other haplotypes. Parasites engineered for another mutation, PfMDR1 1246Y, were unstable in culture, with reversion to WT over time. Thus, the N86 WT is stable when accompanied by the Y184 WT, but incurs a fitness cost when accompanied by mutant 184F. Culturing in the presence of chloroquine favored 86Y mutant parasites and in the presence of lumefantrine favored N86 WT parasites; piperaquine had minimal impact. Conclusions: These results are consistent with those for Ugandan field isolates, suggest reasons for varied haplotypes, and highlight the interplay between drug pressure and fitness that is guiding the evolution of resistance-mediating haplotypes in P. falciparum. [ABSTRACT FROM AUTHOR]

Malaria is a great concern for global health and accounts for a large amount of morbidity and mortality, particularly in Africa, with sub-Saharan Africa carrying the greatest burden of the disease. Malaria control tools such as insecticide-treated bed nets, indoor residual spraying, and antimalarial drugs have been relatively successful in reducing the burden of malaria; however, sub-Saharan African countries encounter great challenges, the greatest being antimalarial drug resistance. Chloroquine (CQ) was the first-line drug in the 20th century until it was replaced by sulfadoxine–pyrimethamine (SP) as a consequence of resistance. The extensive use of these antimalarials intensified the spread of resistance throughout sub-Saharan Africa, thus resulting in a loss of efficacy for the treatment of malaria. SP was replaced by artemisinin-based combination therapy (ACT) after the emergence of resistance toward SP; however, the use of ACTs is now threatened by the emergence of resistant parasites. The decreased selective pressure on CQ and SP allowed for the reintroduction of sensitivity toward those antimalarials in regions of sub-Saharan Africa where they were not the primary drug for treatment. Therefore, the emergence and spread of antimalarial drug resistance should be tracked to prevent further spread of the resistant parasites, and the re-emergence of sensitivity should be monitored to detect the possible reappearance of sensitivity in sub-Saharan Africa. [ABSTRACT FROM AUTHOR]

Malaria is still a serious cause of mortality and morbidity. Moreover, the emergence of malaria parasite resistance to antimalarial drugs has prompted the search for new, effective, and safe antimalarial agents. For this reason, the study of medicinal plants in discovering new antimalarial drugs is important and remains a crucial step in the fight against malaria. Hence, this study is aimed at investigating the antimalarial activity of Gymnema inodorum leaf extract (GIE) in Plasmodium berghei infected mice. Aqueous crude extract of G. inodorum leaves was prepared in distilled water (DW) and acute toxicity in mice was carried out. The antimalarial activity was assessed in the five groups of ICR mice employing the 4-day suppressive and curative tests. Untreated and positive controls were given DW along with 10 mg/kg of chloroquine, respectively. Any signs of toxicity, behavioral changes, and mortality were not observed in mice given GIE up to 5,000 mg/kg. GIE significantly (P < 0.05) suppressed parasitemia by 25.65%, 38.12%, and 58.28% at 10, 50, and 100 mg/kg, respectively, in the 4-day suppressive test. In the curative test, the highest parasitemia inhibition of 66.78% was observed at 100 mg/kg of GIE. Moreover, GIE prevented packed cell volume reduction and body weight loss compared to the untreated control. Additionally, GIE was able to prolong the mean survival time of infected mice significantly. The results obtained in this study confirmed the safety and promise of G. inodorum as an important source of new antimalarial agents and justify its folkloric use for malaria treatment. [ABSTRACT FROM AUTHOR]

Background and Purpose: Efficacy of current antimalarial treatments is declining as a result of increasing antimalarial drug resistance, so new and potent antimalarial drugs are urgently needed. Azithromycin, an azalide antibiotic, was found useful in malaria therapy, but its efficacy in humans is low.Experimental Approach: Four compounds belonging to structurally different azalide classes were tested and their activities compared to azithromycin and chloroquine. in vitro evaluation included testing against sensitive and resistant Plasmodium falciparum, cytotoxicity against HepG2 cells, accumulation and retention in human erythrocytes, antibacterial activity, and mode of action studies (delayed death phenotype and haem polymerization). in vivo assessment enabled determination of pharmacokinetic profiles in mice, rats, dogs, and monkeys and in vivo efficacy in a humanized mouse model.Key Results: Novel fast-acting azalides were highly active in vitro against P. falciparum strains exhibiting various resistance patterns, including chloroquine-resistant strains. Excellent antimalarial activity was confirmed in a P. falciparum murine model by strong inhibition of haemozoin-containing trophozoites and quick clearance of parasites from the blood. Pharmacokinetic analysis revealed that compounds are metabolically stable and have moderate oral bioavailability, long half-lives, low clearance, and substantial exposures, with blood cells as the preferred compartment, especially infected erythrocytes. Fast anti-plasmodial action is achieved by the high accumulation into infected erythrocytes and interference with parasite haem polymerization, a mode of action different from slow-acting azithromycin.Conclusion and Implications: The hybrid derivatives described here represent excellent antimalarial drug candidates with the potential for clinical use in malaria therapy. [ABSTRACT FROM AUTHOR]

COVID-19 has been announced pandemic by WHO and over 17,000,000 people infected (Till April 21st 2020). The disease is currently under control in China, with a curative rate of 86.8%. Chloroquine (CQ) is an old anti-malarial drug with good tolerability, which had proved to be effective in previous SARS-coronavirus, which spread and disappeared between 2002-2003. In vitro studies demonstrated the efficacy of CQ in curing COVID-19. Consequently, via analytical PBPK modeling, a further preliminary clinical trial has proved the efficacy and safety of CQ in China., and multiple clinical trials were registered and approved to investigate the activity of other analogs of CQ against COVID-19. We have listed all the clinical trials and made a meta-analysis of published data of hydroxychloroquine (HCQ). HCQ could increase the CT improvement and adverse reactions (ADRs) significantly though there was considerable heterogeneity among current researches. Actually, CQ and its analogs have unique pharmacokinetic characteristics, which would induce severe side effects in some circumstances. We have then summarized pharmacological considerations for these drugs so as to provide to the busy clinicians to avoid potential side effects when administered CQ or its analogs to COVID-19 patients, especially in the elderly, pediatrics, and pregnancies. [ABSTRACT FROM AUTHOR]

Background: Chloroquine (CQ) and its derivative hydroxychloroquine (HCQ) have recently emerged as potential antiviral and immunomodulatory options for the treatment of 2019 coronavirus disease (COVID-19). To examine the safety profiles of these medications, we systematically evaluated the adverse events (AEs) of these medications from published randomized controlled trials (RCTs). Methods: We systematically searched MEDLINE, the Cochrane library, the Cochrane Central Register of Controlled Trials (CENTRAL), and the ClinicalTrials.gov for all the RCTs comparing CQ or HCQ with placebo or other active agents, published before June 20, 2020. The random-effects or fixed-effects models were used to pool the risk estimates relative ratio (RR) with 95% confidence interval (CI) for the outcomes. Results: The literature search yielded 23 and 19 studies for CQ and HCQ, respectively, that satisfied our inclusion criteria. Of these studies, we performed meta-analysis on 6 studies for CQ and 18 studies for HCQ. We did not limit our analysis to published records involving viral treatment alone; data also included the usage of either CQ or HCQ for the treatment of other diseases. The trials for the CQ consisted of a total of 2,137 participants (n = 1,077 CQ, n = 1,060 placebo), while the trials for HCQ involved 2,675 participants (n = 1,345 HCQ and n = 1,330 control). The overall mild and total AEs were significantly higher in CQ-treated non–COVID-19 patients, HCQ-treated non–COVID-19 patients, and HCQ-treated COVID-19 patients. The AEs were further categorized into four groups and analyses revealed that neurologic, gastrointestinal (GI), dermatologic, and sensory AEs were higher in participants taking CQ compared to placebo, while GI, dermatologic, sensory, and cardiovascular AEs were higher in HCQ-treated COVID-19 patients compared to control patients. Moreover, subgroup analysis suggested higher AEs with respect to dosage and duration in HCQ group. Data were acquired from studies with perceived low risk of bias, so plausible bias is unlikely to seriously affect the main findings of the current study. Conclusions: Taken together, we found that participants taking either CQ or HCQ exhibited more AEs than participants taking placebo or control. Precautionary measures should be taken when using these drugs to treat COVID-19. The meta-analysis was registered on OSF (https://osf.io/jm3d9). Registration: The meta-analysis was registered on OSF (https://osf.io/jm3d9). [ABSTRACT FROM AUTHOR]

Background Early studies have led to the repositioning of a subgroup of antimalarial agents (e.g. chloroquine and hydroxychloroquine) as antiviral treatment in coronavirus disease 2019 (COVID-19) patients. These drugs are now being prescribed based on small non-controlled studies, but larger controlled studies have yet to demonstrate the positive effect of these drugs. In addition, these drugs are also known for their QT interval-prolonging effect associated with significant morbidity and mortality. Case summary We present a case of a 66-year-old female admitted to the intensive care unit with respiratory failure due to COVID-19. She was treated with chloroquine (QTc interval at baseline was 429 ms). Despite cessation of chloroquine, but after the start of erythromycin, she developed severe QTc interval prolongation (QTc interval 550 ms) and 'Torsade de Pointes'. Two weeks after cessation of all QTc interval-prolonging drugs, the QTc interval was restored. Discussion The elimination half-life of chloroquine ranges from days up to weeks. Even after discontinuation of chloroquine, ECG monitoring in COVID-19 patients is warranted. We recommend observation of the QT interval after cessation of chloroquine in cases where other potentially QT interval-prolonging drugs are introduced. [ABSTRACT FROM AUTHOR]

Background: A new coronavirus SARS-CoV-2 has been identified as the etiological agent of the severe acute respiratory syndrome, COVID-19, the source and cause of the 2019– 20 coronavirus pandemic. Hydroxychloroquine and chloroquine have gathered extraordinary attention as therapeutic candidates against SARS-CoV-2 infections. While there is growing scientific data on the therapeutic effect, there is also concern for toxicity of the medications. The therapy of COVID-19 by hydroxychloroquine and chloroquine is off-label. Studies to analyze the personalized effect and safety are lacking. Methods: A review of the literature was performed using Medline/PubMed/Embase database. A variety of keywords were employed in keyword/title/abstract searches. The electronic search was followed by extensive hand searching using reference lists from the identified articles. Results: A total of 126 results were obtained after screening all sources. Mechanisms underlying variability in drug concentrations and therapeutic response with chloroquine and hydroxychloroquine in mediating beneficial and adverse effects of chloroquine and hydroxychloroquine were reviewed and analyzed. Pharmacogenomic studies from various disease states were evaluated to elucidate the role of genetic variation in drug response and toxicity. Conclusion: Knowledge of the pharmacokinetics and pharmacogenomics of chloroquine and hydroxychloroquine is necessary for effective and safe dosing and to avoid treatment failure and severe complications. [ABSTRACT FROM AUTHOR]

The rapid spread, severity, and lack of specific treatment for COVID-19 resulted in hasty drug repurposing. Conceptually, trials of antivirals were well-accepted, but twentieth century antimalarials sparked an impassioned global debate. Notwithstanding, antiviral and immunomodulatory effects of aminoquinolines have been investigated in vitro, in vivo and in clinical trials for more than 30 years. We review the mechanisms of action of (hydroxy)chloroquine on immune cells and networks and discuss promises and pitfalls in the fight against SARS-CoV-2, the agent of the COVID-19 outbreak. [ABSTRACT FROM AUTHOR]

In December 2019, a severe outbreak of a novel coronavirus (COVID-19) occurred in the whole world, posing a great threat to people's health. With the outbreak and development of the epidemic, how to improve the cure rate, find effective drugs against this virus, has been the most urgent problem. Chloroquine (CQ) was verified effective against COVID-19 in vitro. As CQ's analogue, hydroxychloroquine (HCQ) was also reminded as a potential candidate for treating COVID-19. This review summarizes the latest clinical trials of CQ and HCQ against COVID-19 and its therapeutic regimen in China aiming to share their current usage to the whole world and provide insight into its appropriate future use in the treatment of COVID-19. Through searching the CNKI and Wangfang databases in Chinese language and PubMed, EMBASE, and Ovid databases in English language to identify published reports with the keywords including "coronavirus/COVID, chloroquine, hyroxychloroquine" in alone or combined, we found out the potential preclinical or clinical evidence for using CQ and HCQ against COVID-19. Consequently, we also searched the website of Chinese Clinical Trial Registry (http://www.chictr.org.cn/) till the day on 27th, June, 2020. This review found that there are 23 programs aimed to treat the different phases under COVID-19 pipeline in clinic with CQ and HCQ, totally. The inclusion criteria, exclusion criteria and therapeutic regimen were all shared to consult. Among them, seven have been canceled due to lack of patients or other objective factors. There are two trials have completed, which the potential relationship between usage and adverse reactions was discussed emphatically. Through literature research, we suggested that paid close attention to retinal toxicity and ophthalmologic adverse symptom of CQ and HCQ. And the outcome of HCQ in clinic shows better than CQ especially in protective effect with low dosage. [ABSTRACT FROM AUTHOR]

Background: Plasmodium falciparum parasites, which could harbour anti-malaria drug resistance genes, are commonly detected in blood donors in malaria-endemic areas. Notwithstanding, anti-malaria drug resistant biomarkers have not been characterized in blood donors with asymptomatic P. falciparum infection.Methods: A total of 771 blood donors were selected from five districts in the Greater Accra Region, Ghana. Each donor sample was screened with malaria rapid diagnostic test (RDT) kit and parasitaemia quantified microscopically. Dried blood spots from malaria positive samples were genotyped for P. falciparum chloroquine resistance transporter (Pfcrt), P. falciparum multi-drug resistance (Pfmdr1), P. falciparum dihydropteroate-synthetase (Pfdhps), P. falciparum dihydrofolate-reductase (Pfdhfr) and Kelch 13 propeller domain on chromosome 13 (Kelch 13) genes.Results: Of the 771 blood donors, 91 (11.8%) were positive by RDT. Analysis of sequence reads indicated successful genotyping of Pfcrt, Pfmdr1, Pfdhfr, Pfdhps and Kelch 13 genes in 84.6, 81.3, 86.8, 86.9 and 92.3% of the isolates respectively. Overall, 21 different mutant haplotypes were identified in 69 isolates (75.8%). In Pfcrt, CVIET haplotype was observed in 11.6% samples while in Pfmdr1, triple mutation (resulting in YFN haplotype) was detected in 8.1% of isolates. In Pfdhfr gene, triple mutation resulting in IRNI haplotype and in Pfdhps gene, quintuple mutation resulting in AGESS haplotype was identified in 17.7% parasite isolates. Finally, five non-synonymous Kelch 13 alleles were detected; C580Y (3.6%), P615L (4.8%), A578S (4.8%), I543V (2.4%) and A676S (1.2%) were detected.Conclusion: Results obtained in this study indicated various frequencies of mutant alleles in Pfcrt, Pfmdr1, Pfdhfr, Pfdhps and Kelch 13 genes from P. falciparum infected blood donors. These alleles could reduce the efficacy of standard malaria treatment in transfusion-transmitted malaria cases. Incorporating malaria screening into donor screening protocol to defer infected donors is therefore recommended. [ABSTRACT FROM AUTHOR]

Mutations in the Plasmodium falciparum chloroquine resistance transporter (PfCRT) confer resistance to several antimalarial drugs such as chloroquine (CQ) or piperaquine (PPQ), a partner molecule in current artemisinin-based combination therapies. As a member of the Drug/Metabolite Transporter (DMT) superfamily, the vacuolar transporter PfCRT may translocate substrate molecule(s) across the membrane of the digestive vacuole (DV), a lysosome-like organelle. However, the physiological substrate(s), the transport mechanism and the functional regions of PfCRT remain to be fully characterized. Here, we hypothesized that identification of evolutionary conserved sites in a tertiary structural context could help locate putative functional regions of PfCRT. Hence, site-specific substitution rates were estimated over Plasmodium evolution at each amino acid sites, and the PfCRT tertiary structure was predicted in both inward-facing (open-to-vacuole) and occluded states through homology modeling using DMT template structures sharing <15% sequence identity with PfCRT. We found that the vacuolar-half and membrane-spanning domain (and especially the transmembrane helix 9) of PfCRT were more conserved, supporting that its physiological substrate is expelled out of the parasite DV. In the PfCRT occluded state, some evolutionary conserved sites, including positions related to drug resistance mutations, participate in a putative binding pocket located at the core of the PfCRT membrane-spanning domain. Through structural comparison with experimentally-characterized DMT transporters, we identified several conserved PfCRT amino acid sites located in this pocket as robust candidates for mediating substrate transport. Finally, in silico mutagenesis revealed that drug resistance mutations caused drastic changes in the electrostatic potential of the transporter vacuolar entry and pocket, facilitating the escape of protonated CQ and PPQ from the parasite DV. [ABSTRACT FROM AUTHOR]

Background: Malaria is a complex disease and main community health problem in Africa and the top leading cause of outpatient visits, admissions, and deaths in Ethiopia. Its effective management is possible through early diagnosis and immediate treatment employing antimalarials. The quality of these drugs has to be good enough to attain their intended purpose. However, there are treatment failures resulted from the consumption of falsified and substandard antimalarials. Therefore, the current study was undertaken to evaluate the quality of two commonly used antimalarial drugs [chloroquine phosphate and quinine sulfate tablets] and to determine whether the quality of these drugs was affected by the origin, brand and sample collection sites in South-West Ethiopia. Methods: Random sampling based on Ethiopian malaria eco-epidemiological strata map, with different levels of medicines outlets, was applied to select sampling sites. Results: Sixty samples were bought from 43 drug retails (pharmacy, drug store, and drug vendor) in twelve different geographical locations of South-West Ethiopia between June and July 2016. Visual inspection was done for all samples before the lab experiment. A 28.3%, 31.7%, and 6.8% of samples failed to comply with the Pharmacopoeial quality standards for visual inspection, hardness and weight variation tests, respectively. Statistical analysis revealed that origin and geography from which samples were collected significantly affects the active pharmaceutical content of both drugs at P < 0.05 level. Significant variation was observed for chloroquine samples within batches of the same manufacturing and between origins. Conclusion: This study indicated that all the chloroquine and quinine tablets met the quality specification concerning friability, dissolution and assay. Out-of-specification results for weight variation, hardness and visual inspection tests for the chloroquine tablets are signs of substandard/spurious/falsely labeled/falsified/counterfeit actions that may compromise the quality of these drugs. Besides, within the acceptance limit, the origin of drugs and collection sites have found to determine the quality which raises good manufacturing practice and storage (drug supply chain system) issues to be evaluated. [ABSTRACT FROM AUTHOR]

Background and Purpose: Chloroquine is a traditional medicine to treat malaria. There is increasing evidence that chloroquine not only induces phagocytosis but regulates vascular tone. Few reports investigating the effect of chloroquine on vascular responsiveness of coronary arteries have been made. In this study, we examined how chloroquine affected endothelium-dependent relaxation in coronary arteries under normal and diabetic conditions.Experimental Approach: We isolated coronary arteries from mice and examined endothelium-dependent relaxation (EDR). Human coronary endothelial cells and mouse coronary endothelial cells isolated from control and diabetic mouse (TALLYHO/Jng [TH] mice, a spontaneous type 2 diabetic mouse model) were used for the molecular biological or cytosolic NO and Ca2+ measurements.Key Results: Chloroquine inhibited endothelium-derived NO-dependent relaxation but had negligible effect on endothelium-derived hyperpolarization (EDH)-dependent relaxation in coronary arteries of control mice. Chloroquine significantly decreased NO production in control human coronary endothelial cells partly by phosphorylating eNOSThr495 (an inhibitory phosphorylation site of eNOS) and attenuating the rise of cytosolic Ca2+ concentration after stimulation. EDR was significantly inhibited in diabetic mice in comparison to control mice. Interestingly, chloroquine enhanced EDR in diabetic coronary arteries by, specifically, increasing EDH-dependent relaxation due partly to its augmenting effect on gap junction activity in diabetic mouse coronary endothelial cells.Conclusions and Implications: These data indicate that chloroquine affects vascular relaxation differently under normal and diabetic conditions. Therefore, the patients' health condition such as coronary macrovascular or microvascular disease, with or without diabetes, must be taken account into the consideration when selecting chloroquine for the treatment of malaria. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) are thought to be important in cell-cell communication and have elicited extraordinary interest as potential biomarkers of disease. However, quantitative methods to enable elucidation of mechanisms underlying release are few. Here, we describe a cell-based assay for monitoring EV release using the EV-enriched tetraspanin CD63 fused to the small, ATP-independent reporter enzyme, Nanoluciferase. Release of CD63-containing EVs from stably expressing cell lines was monitored by comparing luciferase activity in culture media to that remaining in cells. HEK293, U2OS, U87 and SKMel28 cells released 0.3%-0.6% of total cellular CD63 in the form of EVs over 5 hrs, varying by cell line. To identify cellular machinery important for secretion of CD63-containing EVs, we performed a screen of biologically active chemicals in HEK293 cells. While a majority of compounds did not significantly affect EV release, treating cells with the plecomacrolides bafilomycin or concanamycin, known to inhibit the V-ATPase, dramatically increased EV release. Interestingly, alkalization of the endosomal lumen using weak bases had no effect, suggesting a pH-independent enhancement of EV release by V-ATPase inhibitors. The ability to quantify EVs in small samples will enable future detailed studies of release kinetics as well as further chemical and genetic screening to define pathways involved in EV secretion. [ABSTRACT FROM AUTHOR]

Although modern fluorescence microscopy produces detailed three-dimensional (3D) datasets, colocalization analysis and region of interest (ROI) selection is most commonly performed two-dimensionally (2D) using maximum intensity projections (MIP). However, these 2D projections exclude much of the available data. Furthermore, 2D ROI selections cannot adequately select complex 3D structures which may inadvertently lead to either the exclusion of relevant or the inclusion of irrelevant data points, consequently affecting the accuracy of the colocalization analysis. Using a virtual reality (VR) enabled system, we demonstrate that 3D visualization, sample interrogation and analysis can be achieved in a highly controlled and precise manner. We calculate several key colocalization metrics using both 2D and 3D derived super-resolved structured illumination-based data sets. Using a neuronal injury model, we investigate the change in colocalization between Tau and acetylated α-tubulin at control conditions, after 6 hours and again after 24 hours. We demonstrate that performing colocalization analysis in 3D enhances its sensitivity, leading to a greater number of statistically significant differences than could be established when using 2D methods. Moreover, by carefully delimiting the 3D structures under analysis using the 3D VR system, we were able to reveal a time dependent loss in colocalization between the Tau and microtubule network as an early event in neuronal injury. This behavior could not be reliably detected using a 2D based projection. We conclude that, using 3D colocalization analysis, biologically relevant samples can be interrogated and assessed with greater precision, thereby better exploiting the potential of fluorescence-based image analysis in biomedical research. [ABSTRACT FROM AUTHOR]

A 66‐year‐old woman diagnosed clinical manifestation of extensive hard palate hyperpigmentation is presented. Due to historic of rheumatoid arthritis and use of chloroquine phosphate for 3 years, exogenous hyperpigmentation associated with the drug was included among the possible diagnoses. Incisional biopsy was performed and the histopathological exam confirmed exogenous hyperpigmentation compatible with chloroquine use. The patient was referred to the rheumatologist and the ophthalmologist for evaluation of the continuity of the chloroquine use. After one year of follow‐up, no changes were seen in the hyperpigmentation nor other clinical changes. Hyperpigmentation of the hard palate by the use of chloroquine is one of the adverse effects of the chronic use of this drug and does not require specific treatment. The adequate anamnesis and the knowledge about the adverse effects of the drug allowed an adequate therapeutic approach in the case. [ABSTRACT FROM AUTHOR]

Tenovin-6 is the most studied member of a family of small molecules with antitumour activity in vivo. Previously, it has been determined that part of the effects of tenovin-6 associate with its ability to inhibit SirT1 and activate p53. However, tenovin-6 has also been shown to modulate autophagic flux. Here we show that blockage of autophagic flux occurs in a variety of cell lines in response to certain tenovins, that autophagy blockage occurs regardless of the effect of tenovins on SirT1 or p53, and that this blockage is dependent on the aliphatic tertiary amine side chain of these molecules. Additionally, we evaluate the contribution of this tertiary amine to the elimination of proliferating melanoma cells in culture. We also demonstrate that the presence of the tertiary amine is sufficient to lead to death of tumour cells arrested in G1 phase following vemurafenib treatment. We conclude that blockage of autophagic flux by tenovins is necessary to eliminate melanoma cells that survive B-Raf inhibition and achieve total tumour cell kill and that autophagy blockage can be achieved at a lower concentration than by chloroquine. This observation is of great relevance as relapse and resistance are frequently observed in cancer patients treated with B-Raf inhibitors. [ABSTRACT FROM AUTHOR]

Background. In Ethiopia, stem bark of Periploca linearifolia is used for the treatment of malaria by the local community and demonstrated antimalarial activity in vitro. Despite its in vitro antimalarial activity, no scientific study has been carried out to verify its activity in vivo. Therefore, the aim of the study was to evaluate the antimalarial activity of Periploca linearifolia stem bark extract in mice. Methods. The dried stem bark of Periploca linearifolia was extracted with 80% methanol and evaluated for its antimalarial activity on both early and established Plasmodium berghei infected mice. The extract was prepared at graded doses of 200, 400, and 600 mg/kg. Chloroquine and distilled water were administered to the positive and negative control groups, respectively. Results. The crude extract, at all tested doses, suppressed parasitemia significantly (p<0.05) for 200 and 400 mg/kg and (p<0.001) for 600 mg/kg. The suppression values at these doses were 56.98, 43.33, and 38.17 percent, respectively. Periploca linearifolia extract also demonstrated schizonticidal activity in the established malaria infection. Conclusion. The plant Periploca linearifolia has a promising antimalarial activity in mice, supporting its in vitro finding. Thus, it could be considered as a potential source to develop new antimalarial agent. [ABSTRACT FROM AUTHOR]

Background: Tafenoquine is an investigational 8-aminoquinoline for the prevention of Plasmodium vivax relapse. Tafenoquine has a long half-life and the potential for more convenient dosing, compared with the currently recommended 14-day primaquine regimen. Methods: This randomized, active-control, double-blind trial was conducted in Bangkok, Thailand. Seventy patients with microscopically confirmed P. vivax were randomized (2:1) to tafenoquine 400 mg once daily for 3 days or 2500 mg total dose chloroquine phosphate (1500 mg chloroquine base) given over 3 days plus primaquine 15 mg daily for 14 days. Patients were followed to day 120. Results: Day 28 adequate clinical response rate in the per-protocol population was 93% (40/43) (90%CI 83–98%) with tafenoquine, and 100% (22/22) (90%CI 87–100%) with chloroquine/primaquine. Day 120 relapse prevention was 100% (35/35) with tafenoquine (90%CI 92–100%), and 95% (19/20) (90%CI 78–100%) with chloroquine/primaquine. Mean (SD) parasite, gametocyte and fever clearance times with tafenoquine were 82.5 h (32.3), 49.1 h (33.0), and 41.1 h (31.4) versus 40.0 h (15.7), 22.7 h (16.4), and 24.7 h (17.7) with chloroquine/primaquine, respectively. Peak methemoglobin was 1.4–25.6% (median 7.4%, mean 9.1%) in the tafenoquine arm, and 0.5–5.9% (median 1.5%, mean 1.9%) in the chloroquine/primaquine arm. There were no clinical symptoms of methemoglobinemia in any patient. Discussion: Although there was no difference in efficacy in this study, the slow rate of parasite, gametocyte and fever clearance indicates that tafenoquine should not be used as monotherapy for radical cure of P. vivax malaria. Also, monotherapy increases the potential risk of resistance developing to this long-acting agent. Clinical trials of single-dose tafenoquine 300 mg combined with standard 3-day chloroquine or artemisinin-based combination therapy are ongoing. Trial registration: Clinicaltrials.gov [ABSTRACT FROM AUTHOR]

Background: Trema orientalis (T. orientalis Linn) has been used in the management of malaria in the western part of Nigeria and despite its application in ethnomedicine, there is dearth of scientific evidence to justify the acclaimed prophylactic antimalarial usage of the plant. The aim of this study is to assess the in vitro antiplasmodial cell-free assay and chemopreventive efficacy of the methanol extract of the stem bark of T. orientalis and its fractions as a prophylactic regimen for malaria prevention. Also, the antimicrobial activities of the extract and the fractions were investigated. Method: Vacuum liquid chromatography was used to obtain dichloromethane, ethylacetate and methanol fractions from the methanol extract of T. orientalis. The fractions were tested for their prophylactic and cell-free antimalarial activity using murine models and β-hematin formation assay respectively. Disc diffusion method was used to determine the antibacterial activity of the extract and its fractions against both Gram-positive and Gram-negative bacteria. Results: In the prophylactic experiment, dichloromethane (DCMF), methanol fraction (MF) and extract (ME) (in this order) showed significant chemopreventive effects against P. berghei invasion of the red blood cells when compared with both Sulfadoxine-Pyrimethamine (SP) and untreated controls. Results of the in vitro study showed that the DCMF had the highest effect in preventing the formation of β-hematin when compared with other fractions. The DCMF also had the highest percentage inhibition of β-hematin formation when compared with chloroquine. The extract and fractions showed a concentration dependent antibacterial activity. Methanol extract had a pronounced inhibitory effect on Enterobacter cloaca ATCC 13047 and Enterococcus faecalis ATCC 29212. Serratia mercescens ATCC 9986 and Pseudomonas aeruginosa ATCC 19582 were the most susceptible bacteria. Conclusion: The results obtained showed that both extract and fractions of T. orientalis possessed antiplasmodial and antimicrobial activity. [ABSTRACT FROM AUTHOR]

Background: Chloroquine (CQ) was the cornerstone of anti-malarial treatment in Africa for almost 50 years, but has been widely withdrawn due to the emergence and spread of resistance. Recent reports have suggested that CQsusceptibility may return following the cessation of CQ usage. Here, we monitor CQ sensitivity and determine the prevalence of genetic polymorphisms in the CQ resistance transporter gene (pfcrt) of Plasmodium falciparum isolates recently imported from Africa to China. Methods: Blood samples were collected from falciparum malaria patients returning to China from various countries in Africa. Isolates were tested for their sensitivity to CQ using the SYBR Green I test ex vivo, and for a subset of samples, in vitro following culture adaptation. Mutations at positions 72-76 and codon 220 of the pfcrt gene were analyzed by sequencing and confirmed by PCR-RFLP. Correlations between drug sensitivity and pfcrt polymorphisms were investigated. Results: Of 32 culture adapted isolates assayed, 17 (53.1%), 6 (18.8%) and 9 (28.1%) were classified as sensitive, moderately resistant, and highly resistant, respectively. In vitro CQ susceptibility was related to point mutations in the pfcrt gene, the results indicating a strong association between pfcrt genotype and drug sensitivity. A total of 292 isolates were typed at the pfcrt locus, and the prevalence of the wild type (CQ sensitive) haplotype CVMNK in isolates from East, South, North, West and Central Africa were 91.4%, 80.0%, 73.3%, 53.3% and 51.7%, respectively. The only mutant haplotype observed was CVIET, and this was almost always linked to an additional mutation at A220S. Conclusions: Our results suggest that a reduction in drug pressure following withdrawal of CQ as a first-line drug may lead to a resurgence in CQ sensitive parasites. The prevalence of wild-type pfcrt CQ sensitive parasites from East, South and North Africa was higher than from the West and Central areas, but this varied greatly between countries. Further surveillance is required to assess whether the prevalence of CQ resistant parasites will continue to decrease in the absence of widespread CQ usage. [ABSTRACT FROM AUTHOR]

Background: Primaquine (PQ) is the only currently licensed antimalarial that prevents Plasmodium vivax (Pv) relapses. It also clears mature P. falciparum (Pf) gametocytes, thereby reducing post-treatment transmission. Randomized PQ treatment in a treatment-to-reinfection cohort in Papua New Guinean children permitted the study of Pv and Pf gametocyte carriage after radical cure and to investigate the contribution of Pv relapses. Methods: Children received radical cure with Chloroquine, Artemether-Lumefantrine plus either PQ or placebo. Blood samples were subsequently collected in 2-to 4-weekly intervals over 8 months. Gametocytes were detected by quantitative reverse transcription-PCR targeting pvs25 and pfs25. Results: PQ treatment reduced the incidence of Pv gametocytes by 73%, which was comparable to the effect of PQ on incidence of blood-stage infections. 92% of Pv and 79% of Pf gametocyte-positive infections were asymptomatic. Pv and to a lesser extent Pf gametocyte positivity and density were associated with high blood-stage parasite densities. Multivariate analysis revealed that the odds of gametocytes were significantly reduced in mixed-species infections compared to single-species infections for both species (ORPv = 0.39 [95% CI 0.25–0.62], ORPf = 0.33 [95% CI 0.18–0.60], p<0.001). No difference between the PQ and placebo treatment arms was observed in density of Pv gametocytes or in the proportion of Pv infections that carried gametocytes. First infections after blood-stage and placebo treatment, likely caused by a relapsing hypnozoite, were equally likely to carry gametocytes than first infections after PQ treatment, likely caused by an infective mosquito bite. Conclusion: Pv relapses and new infections are associated with similar levels of gametocytaemia. Relapses thus contribute considerably to the Pv reservoir highlighting the importance of effective anti-hypnozoite treatment for efficient control of Pv. Trial registration: ClinicalTrials.gov [ABSTRACT FROM AUTHOR]