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In regions with high malaria endemicity, the withdrawal of chloroquine (CQ) as first-line treatment ofPlasmodium falciparuminfections has typically led to the restoration of CQ susceptibility through the reexpansion of the wild-type (WT) allele K76 of the chloroquine resistance transporter gene (pfcrt) at the expense of less fit mutant alleles carrying the CQ resistance (CQR) marker K76T. In low-transmission settings, such as South America, drug resistance mutations can attain 100% prevalence, thereby precluding the return of WT parasites after the complete removal of drug pressure. In French Guiana, despite the fixation of the K76T allele, the prevalence of CQR isolates progressively dropped from >90% to <30% during 17 y after CQ withdrawal in 1995. Using a genome-wide association study with CQ-sensitive (CQS) and CQR isolates, we have identified a single mutation inpfcrtencoding a C350R substitution that is associated with the restoration of CQ susceptibility. Genome editing of the CQR reference strain 7G8 to incorporate PfCRT C350R caused a complete loss of CQR. A retrospective molecular survey on 580 isolates collected from 1997 to 2012 identified all C350R mutant parasites as being CQS. This mutation emerged in 2002 and rapidly spread throughout theP. falciparumpopulation. The C350R allele is also associated with a significant decrease in piperaquine susceptibility in vitro, suggesting that piperaquine pressure in addition to potential fitness costs associated with the 7G8-type CQRpfcrtallele may have selected for this mutation. These findings have important implications for understanding the evolutionary dynamics of antimalarial drug resistance.

In this historical study, Leo B. Slater shows the roots and branches of an enormous drug development project during World War II. Fighting around the globe, American soldiers were at high risk for contracting malaria, yet quinineùa natural cureùbecame harder to acquire.

Chloroquine — an approved malaria drug — is known in nanomedicine research for the investigation of nanoparticle uptake in cells, and may have potential for the treatment of COVID-19.

COVID-19 (coronavirus disease 2019) is a public health emergency of international concern. As of this time, there is no known effective pharmaceutical treatment, although it is much needed for patient contracting the severe form of the disease. The aim of this systematic review was to summarize the evidence regarding chloroquine for the treatment of COVID-19. PubMed, EMBASE, and three trial Registries were searched for studies on the use of chloroquine in patients with COVID-19. We included six articles (one narrative letter, one in-vitro study, one editorial, expert consensus paper, two national guideline documents) and 23 ongoing clinical trials in China. Chloroquine seems to be effective in limiting the replication of SARS-CoV-2 (virus causing COVID-19) in vitro. There is rationale, pre-clinical evidence of effectiveness and evidence of safety from long-time clinical use for other indications to justify clinical research on chloroquine in patients with COVID-19. However, clinical use should either adhere to the Monitored Emergency Use of Unregistered Interventions (MEURI) framework or be ethically approved as a trial as stated by the World Health Organization. Safety data and data from high-quality clinical trials are urgently needed. •No specific pharmacological treatments are available to date for COVID-19.•Chloroquine is a widely used, safe and cheap, effective in viral infections in pre-clinical studies.•Specific pre-clinical evidence and expert opinions suggest potential use against SARS-CoV-2.•A search in trial registries shows that 23 clinical trials are ongoing in China.•There is a urgent need of high-quality clinical data from different geographic areas.

There is no specific antiviral therapy recommended for coronavirus disease 2019 (COVID-19). In vitro studies indicate that the antiviral effect of chloroquine diphosphate (CQ) requires a high concentration of the drug. To evaluate the safety and efficacy of 2 CQ dosages in patients with severe COVID-19. This parallel, double-masked, randomized, phase IIb clinical trial with 81 adult patients who were hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was conducted from March 23 to April 5, 2020, at a tertiary care facility in Manaus, Brazilian Amazon. Patients were allocated to receive high-dosage CQ (ie, 600 mg CQ twice daily for 10 days) or low-dosage CQ (ie, 450 mg twice daily on day 1 and once daily for 4 days). Primary outcome was reduction in lethality by at least 50% in the high-dosage group compared with the low-dosage group. Data presented here refer primarily to safety and lethality outcomes during treatment on day 13. Secondary end points included participant clinical status, laboratory examinations, and electrocardiogram results. Outcomes will be presented to day 28. Viral respiratory secretion RNA detection was performed on days 0 and 4. Out of a predefined sample size of 440 patients, 81 were enrolled (41 [50.6%] to high-dosage group and 40 [49.4%] to low-dosage group). Enrolled patients had a mean (SD) age of 51.1 (13.9) years, and most (60 [75.3%]) were men. Older age (mean [SD] age, 54.7 [13.7] years vs 47.4 [13.3] years) and more heart disease (5 of 28 [17.9%] vs 0) were seen in the high-dose group. Viral RNA was detected in 31 of 40 (77.5%) and 31 of 41 (75.6%) patients in the low-dosage and high-dosage groups, respectively. Lethality until day 13 was 39.0% in the high-dosage group (16 of 41) and 15.0% in the low-dosage group (6 of 40). The high-dosage group presented more instance of QTc interval greater than 500 milliseconds (7 of 37 [18.9%]) compared with the low-dosage group (4 of 36 [11.1%]). Respiratory secretion at day 4 was negative in only 6 of 27 patients (22.2%). The preliminary findings of this study suggest that the higher CQ dosage should not be recommended for critically ill patients with COVID-19 because of its potential safety hazards, especially when taken concurrently with azithromycin and oseltamivir. These findings cannot be extrapolated to patients with nonsevere COVID-19. ClinicalTrials.gov Identifier: NCT04323527.

Use of these drugs is premature and potentially harmful

Key Points Macroautophagy (known as autophagy) is a highly regulated multi-step process that is involved in the bulk degradation of cellular proteins and organelles to provide macromolecular precursors that are recycled or that are used to fuel metabolic pathways. Autophagy can be targeted for both stimulation and inhibition. Stimulation can be achieved through cellular stress (nutrient deprivation) and mTOR inhibition, and inhibition can be achieved through multiple targets both upstream (ULK1, Beclin 1 and VPS34 inhibitors) and downstream of the site of lysosomal fusion with the autophagosome. Early clinical trials have demonstrated the feasibility and potential benefit of clinically inhibiting autophagy in multiple cancer types, including glioblastoma, pancreatic cancer, melanoma, sarcoma and multiple myeloma. Ongoing studies are developing novel clinical biomarkers that can be used to monitor autophagy in patients, including electron microscopy evaluation of autophagosome number in peripheral blood mononuclear cells and tumour samples, LC3II and ATG13 puncta by immunohistochemistry, and novel imaging techniques that use positron emission tomography and metabolomics profiles. The role of autophagy in regulating tumour immune responses is unclear, with arguments both for and against autophagy inhibition. Further research is needed to define the safety and utility of autophagy inhibition while also maximizing tumour immune responses for improved clinical outcomes. Markers of autophagy dependence have the potential to identify patients who will best respond to autophagy inhibition therapy. Such markers include altered RAS signalling, BRAF mutations, signal transducer and activator of transcription 3 (STAT3) activation, autophagy-dependent secretion of interleukins and p53 status. Autophagy can be an effective cancer escape mechanism and has been implicated in the development of resistance in multiple cancer types, including BRAF-mutated central nervous system (CNS) tumours and melanoma, non-small-cell lung cancer (NSCLC), bladder cancer and thyroid cancer. Combination therapy with autophagy inhibition in these cancers has the potential to reduce and reverse resistance to therapy. Autophagy is a process that delivers cytoplasmic components to lysosomes for degradation. This Review discusses clinical interventions to target autophagy in cancer and explains how understanding the context-dependent role of autophagy in cancer should dictate future clinical trial design. Autophagy is a mechanism by which cellular material is delivered to lysosomes for degradation, leading to the basal turnover of cell components and providing energy and macromolecular precursors. Autophagy has opposing, context-dependent roles in cancer, and interventions to both stimulate and inhibit autophagy have been proposed as cancer therapies. This has led to the therapeutic targeting of autophagy in cancer to be sometimes viewed as controversial. In this Review, we suggest a way forwards for the effective targeting of autophagy by understanding the context-dependent roles of autophagy and by capitalizing on modern approaches to clinical trial design.

The coronavirus disease 2019 (COVID-19) pandemic, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been associated with more than 780,000 deaths worldwide (as of 20 August 2020). To develop antiviral interventions quickly, drugs used for the treatment of unrelated diseases are currently being repurposed to treat COVID-19. Chloroquine is an anti-malaria drug that is used for the treatment of COVID-19 as it inhibits the spread of SARS-CoV-2 in the African green monkey kidney-derived cell line Vero 1 – 3 . Here we show that engineered expression of TMPRSS2, a cellular protease that activates SARS-CoV-2 for entry into lung cells 4 , renders SARS-CoV-2 infection of Vero cells insensitive to chloroquine. Moreover, we report that chloroquine does not block infection with SARS-CoV-2 in the TMPRSS2-expressing human lung cell line Calu-3. These results indicate that chloroquine targets a pathway for viral activation that is not active in lung cells and is unlikely to protect against the spread of SARS-CoV-2 in and between patients. Expression of TMPRSS2—a protease that activates SARS-CoV-2 for entry into cells—renders SARS-CoV-2 insensitive to chloroquine.

The widely used antimalarial combination therapy dihydroartemisinin + piperaquine (DHA + PPQ) has failed in Cambodia. Here, we perform a genomic analysis that reveals a rapid increase in the prevalence of novel mutations in the Plasmodium falciparum chloroquine resistance transporter PfCRT following DHA + PPQ implementation. These mutations occur in parasites harboring the K13 C580Y artemisinin resistance marker. By introducing PfCRT mutations into sensitive Dd2 parasites or removing them from resistant Cambodian isolates, we show that the H97Y, F145I, M343L, or G353V mutations each confer resistance to PPQ, albeit with fitness costs for all but M343L. These mutations sensitize Dd2 parasites to chloroquine, amodiaquine, and quinine. In Dd2 parasites, multicopy plasmepsin 2 , a candidate molecular marker, is not necessary for PPQ resistance. Distended digestive vacuoles were observed in pfcrt -edited Dd2 parasites but not in Cambodian isolates. Our findings provide compelling evidence that emerging mutations in PfCRT can serve as a molecular marker and mediator of PPQ resistance. Increasing resistance of Plasmodium falciparum strains to piperaquine (PPQ) in Southeast Asia is of concern and resistance mechanisms are incompletely understood. Here, Ross et al. show that mutations in the P . falciparum chloroquine resistance transporter are rapidly increasing in prevalence in Cambodia and confer resistance to PPQ.