Clinical evidence for repurposing chloroquine and hydroxychloroquine as antiviral agents: a systematic review

BackgroundRepurposing hydroxychloroquine (HCQ) and chloroquine (CQ) as antiviral agents is a re-emerging topic with the advent of new viral epidemics.AimsTo summarize evidence from human clinical studies for using HCQ or CQ as antiviral agents for any viral infection.SourcesPubMed, EMBASE, Scopus, Web of Science for published studies without time or language restrictions; Cochrane Clinical Trial Registry and Chinese Clinical Trials Registry for trials registered after 2015; MedRxiv for preprints within the last 12 months.ContentStudy eligibility criteria were interventional and prospective observational studies (with or without a control group). Participants were adults and children with a confirmed viral infection. Interventions included the use of CQ or HCQ as antiviral agent in one or more groups of the study. Two authors independently screened abstracts, and all authors agreed on eligible studies. A meta-analysis was planned if studies were available which were similar in terms of participants, intervention, comparator and outcomes. Nineteen studies (including two preprints) were eligible (HIV 8, HCV 2, dengue 2, chikungunya 1, COVID-19 6). Nine and ten studies assessed CQ and HCQ respectively. Benefits of either drug for viral load suppression in HIV are inconsistent. CQ is ineffective in curing dengue (high-certainty evidence) and may have little or no benefit in curing chikungunya (low-certainty evidence). The evidence for COVID-19 infection is rapidly evolving but at this stage we are unsure whether either CQ or HCQ has any benefit in clearing viraemia (very-low-certainty evidence).ImplicationsUsing HCQ or CQ for HIV/HCV infections is now clinically irrelevant as other effective antivirals are available for viral load suppression (HIV) and cure (HCV). There is no benefit of CQ in dengue, and the same conclusion is likely for chikungunya. More evidence is needed to confirm whether either HCQ or CQ is beneficial in COVID-19 infection.     

Accelerating the clearance of mutant huntingtin protein aggregates through autophagy induction by europium hydroxide nanorods

Autophagy is one of the well-known pathways to accelerate the clearance of protein aggregates, which contributes to the therapy of neurodegenerative diseases. Although there are numerous reports that demonstrate the induction of autophagy with small molecules including rapamycin, trehalose and lithium, however, there are few reports mentioning the clearance of aggregate-prone proteins through autophagy induction by nanoparticles. In the present article, we have demonstrated that europium hydroxide [Eu^III(OH)₃] nanorods can reduce huntingtin protein aggregation (EGFP-tagged huntingtin protein with 74 polyQ repeats), responsible for neurodegenerative diseases. Again, we have found that these nanorods induce authentic autophagy flux in different cell lines (Neuro 2a, PC12 and HeLa cells) through the expression of higher levels of characteristic autophagy marker protein LC3-II and degradation of selective autophagy substrate/cargo receptor p62/SQSTM1. Furthermore, depression of protein aggregation clearance through the autophagy blockade has also been observed by using specific inhibitors (wortmannin and chloroquine), indicating that autophagy is involved in the degradation of huntingtin protein aggregation. Since [Eu^III(OH)₃] nanorods can enhance the degradation of huntingtin protein aggregation via autophagy induction, we strongly believe that these nanorods would be useful for the development of therapeutic treatment strategies for various neurodegenerative diseases in near future using nanomedicine approach.     

Chloroquine sensitizes biofilms of Candida albicans to antifungal azoles

Biofilms formed by Candida albicans, a human pathogen, are known to be resistant to different antifungal agents. Novel strategies to combat the biofilm associated Candida infections like multiple drug therapy are being explored. In this study, potential of chloroquine to be a partner drug in combination with four antifungal agents, namely fluconazole, voriconazole, amphotericin B, and caspofungin, was explored against biofilms of C. albicans. Activity of various concentrations of chloroquine in combination with a particular antifungal drug was analyzed in a checkerboard format. Growth of biofilm in presence of drugs was analyzed by XTT-assay, in terms of relative metabolic activity compared to that of drug free control. Results obtained by XTT-metabolic assay were confirmed by scanning electron microscopy. The interactions between chloroquine and four antifungal drugs were determined by calculating fractional inhibitory concentration indices. Azole resistance in biofilms was reverted significantly (p < 0.05) in presence of 250 μg/mL of chloroquine, which resulted in inhibition of biofilms at very low concentrations of antifungal drugs. No significant alteration in the sensitivity of biofilms to caspofungin and amphotericin B was evident in combination with chloroquine. This study for the first time indicates that chloroquine potentiates anti-biofilm activity of fluconazole and voriconazole.     

Inhibition of autophagy by chloroquine makes chemotherapy in nasopharyngeal carcinoma more efficient

Objectives

A combination of platinum-based chemotherapy and radiotherapy is the standard treatment for nasopharyngeal carcinoma (NPC). However, the efficacy of chemotherapy has reached a plateau. Many autophagy studies suggest that autophagy can either promote or suppress to cancer progression. Thus, a role of autophagy in the acquisition of chemoradioresistance has recently been a notable event. Therefore, we examined the relationship between autophagy and chemotherapy in NPC.

Efficacy and Toxicity Profile of Methotrexate Chloroquine Combination in Treatment of Active Rheumatoid Arthritis

Background

The present study was conducted to study the efficacy and toxicity profile of methotrexate chloroquine combination in treatment of active rheumatoid arthritis.

Methods

24 patients of rheumatoid arthritis confirming to revised American Rheumatism Association (ARA) criteria were studied prospectively for twenty months. Clinical evaluation was made every 3 months. Clinical disease variables measured at each visit were number of joints with swelling, number of joints with tenderness and pain, duration of morning stiffness and physician and patient assessment of disease activity. Blood counts, liver function tests and other adverse effects due to drugs were monitored every 2 months.

Results

10 patients demonstrated more than 50% improvement. 4 patients withdrew from study, 2 because of excessive nausea and vomiting and 2 because of noncompliance. Other side effects noted were hyperpigmentation, photosensitivity, skin rashes, raised transaminases and stomatitis.

Conclusion

Methotrexate chloroquine combination has good efficacy and toxicity profile. Gastrointestinal side effects are most common and usually responsible for the discontinuation of the drugs.Key Words: Rheumatoid arthritis, Methotrexate, Chloroquine, Efficacy, Toxicity     

感染食蟹猴疟原虫的恒河猴口服咯萘啶的疗效观察

When pyronaridine was given ig to 2 infected monkeys at a single dose of 6 mg (base)/kg, parasitemia was not cleared, but it was cleared in three of four monkeys treated at dosages of 6 mg/kg/d×3. With chloroquine at a single dose of 6 mg/kg, parasitemia of 2 monkeys turned negative, so did the parasitemia of 4 other monkeys treated at dosages of 6 mg/kg/d×3. Five of 6 monkeys treated with pyronaridine at 30 mg/kg recrudesced whereas only 1 of the 6 monkeys receiving the same dose of chloroquine recrudesced.     

硫鸟嘌呤类化合物的合成及其抗疟作用

自发现恶性疟原虫对氯喹产生了耐药性后,寻找新的抗疟药物已成为当务之急。据报道,氯喹对正常疟原虫的作用,主要是在体内阻断了疟原虫红内期DNA的合成。又见报道,抗肿瘤代谢药物硫鸟嘌呤是抑制肿瘤DNA的合成。作者设想,能否将抑制肿瘤DNA合成的硫鸟嘌呤类化合物应用到抗疟方面,以寻找新型抗疟药物。我们首先进行了硫     

蒿甲醚对小鼠血清IgG及脾重的影响

青蒿素与青蒿酯钠的某些免疫作用已有报道。本文报道应用单向免疫扩散测定技术,测定了蒿甲醚对小鼠血清IgG含量的影响,还观察了蒿甲醚对脾脏重量的影响。动物用20～25g JCR纯种小鼠,按雌雄各半随机分组。蒿甲醚(桂林制药厂提供)与氯喹(重庆制药厂生产)均混悬于1％西黄蓍胶,供灌胃用。兔抗小鼠IgG抗血清及标准JCR小鼠血清抗原均为本实验室制备。     

In vitro activity of quinolines against Plasmodium falciparum in Gabon

The assessment of drug sensitivity of Plasmodium falciparum to antimalarial drugs is of vital interest for malaria endemic regions. We conducted a follow-up study to monitor the in vitro activity of the most commonly used quinolines against fresh P. falciparum isolates in Lambaréné, Gabon by measuring schizont maturation inhibition in 2002. Mean 50% effective concentration levels for chloroquine, quinine, and mefloquine were 5.5micromol/l blood, 286nmol/l blood medium mixture (BMM), and 1.1micromol/l blood, respectively. All isolates (n=40) were found to be highly resistant to chloroquine. One isolate was resistant to mefloquine and five isolates were presenting borderline-resistance. All isolates were inhibited by quinine concentrations below the threshold of resistance (n=43).Besides the observation of an increasing number of borderline resistant isolates to mefloquine, an extremly high parasite resistance to chloroquine-still officially the first line antimalarial in Gabon-seems to be of particular concern.     

Cytochrome P450 2C8 and CYP3A4/5 are involved in chloroquine metabolism in human liver microsomes

Chloroquine has been used for many decades in the prophylaxis and treatment of malaria. It is metabolized in humans through the N-dealkylation pathway, to desethylchloroquine (DCQ) and bisdesethylchloroquine (BDCQ), by cytochrome P450 (CYP). However, until recently, no data are available on the metabolic pathway of chloroquine. Therefore, the metabolic pathway of chloroquine was evaluated using human liver microsomes and cDNA-expressed CYPs. Chloroquine is mainly metabolized to DCQ, and its Eadie-Hofstee plots were biphasic, indicating the involvement of multiple enzymes, with apparent Km and Vmax values of 0.21 mM and 1.02 nmol/min/mg protein 3.43 mM and 10.47 nmol/min/mg protein for high and low affinity components, respectively. Of the cDNA-expressing CYPs examined, CYP1A2, 2C8, 2C19, 2D6 and 3A4/5 exhibited significant DCQ formation. A study using chemical inhibitors showed only quercetin (a CYP2C8 inhibitor) and ketoconazole (a CYP3A4/5 inhibitor) inhibited the DCQ formation. In addition, the DCQ formation significantly correlated with the CYP3A4/5-catalyzed midazolam 1-hydroxylation (r = 0.868) and CYP2C8-catalyzed paclitaxel 6alpha-hydroxylation (r = 0.900). In conclusion, the results of the present study demonstrated that CYP2C8 and CYP3A4/5 are the major enzymes responsible for the chloroquine N-deethylation to DCQ in human liver microsomes.