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of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished.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 We systematically identified unpublished RCTs (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, Cochrane COVID-registry up to June 11, 2020), and published RCTs (PubMed,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 We included 14 unpublished trials (1308 patients) and 14 publications/preprints (9011 patients).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

Cisplatin is one of the most widely used agents in the treatment of solid tumors, but its clinical utility is limited by toxicity. The development of less toxic, liposomal formulations of cisplatin has been hampered by the low water solubility and low lipophilicity of cisplatin, resulting in very low encapsulation efficiencies. We describe a novel method allowing the efficient encapsulation of cisplatin in a lipid formulation; it is based on repeated freezing and thawing of a concentrated solution of cisplatin in the presence of negatively charged phospholipids. The method is unique in that it generates nanocapsules, which are small aggregates of cisplatin covered by a single lipid bilayer. The nanocapsules have an unprecedented drug-to-lipid ratio and an in vitro cytotoxicity up to 1000-fold higher than the free drug. Analysis of the mechanism of nanocapsule formation suggests that the method may be generalized to other drugs showing low water solubility and lipophilicity.The clinical use of cis-diamminedichloroplatinum(II) (cisplatin) and many of its analogs faces three major problems: 1) serious dose-limiting toxicities in particular nephrotoxicity and neurotoxicity; 2) rapid inactivation of the drug as a result of complexation to plasma and tissue proteins; and 3) the frequent occurrence of platinum resistance [1][2][3][4][5] . In general, these problems can be reduced by shielding of a drug from the extracellular environment by means of a lipid coating. However, in many cases this approach fails because of inefficient encapsulation of the drug in lipid formulations resulting in low drug uptake by the tumor 6 . This is particularly true for cisplatin: the low water solubility and low lipophilicity of cisplatin result in lipid formulations with a very low drug-to-lipid ratio 7-9 . One approach is to synthesize lipophilic derivatives of cisplatin that can be efficiently encapsulated in large multilamellar liposomes 10 . Here, we describe a new method to efficiently encapsulate native, non-derivitized cisplatin in a lipid formulation. Nanocapsules of cisplatinOur method involves hydration of a dry lipid film composed of equimolar amounts of dioleoyl-phosphatidylserine (PS) and dioleoyl-phosphatidylcholine (PC), with a buffered solution (pH 7.4) of 5 mM cisplatin followed by 10 freeze-thaw (FT) cycles, and removal of free (extravesicular) cisplatin by centrifugation. The cisplatincontaining lipid suspension (cisPt-PS/PC) was extremely cytotoxic (Fig. 1a) with a typical IC 50 (the drug concentration at which cell growth is inhibited by 50%) of approximately 2 nM as compared with 0.5 µM for the free drug (conventional cisplatin). A lipid suspension not loaded with cisplatin (blank) was not cytotoxic, and mixing conventional cisplatin with the blank lipid suspension did not increase the cytotoxicity of cisplatin.Omitting the freeze-thaw step, or leaving out the negatively charged PS in the lipid mixture, resulted in a dramatic decrease in cytotoxicity (Fig. 1b). This decrease in cytotoxicity was paralleled by a sim...

ARTICLEaugmentation of the headgroup size. We expect that the next compounds in the series with n = 6À8 will exhibit more promising behavior as drug delivery systems.' ASSOCIATED CONTENT b S Supporting Information. Input files (*.itp) for CG and AA simulations of C 12 E 5 ; Figure S1, RDF of the distance between tailÀtail COM in system 1; and Figure S2, evolution of cluster size distribution (A,B) and cluster number (C,D) for C 12 E 5 in diluted system with 360 surfactants at χ = 0.19 (A,C) and concentrated system with 780 surfactants at χ = 0.33 (B,D). This material is available free of charge via the Internet at http:// pubs.acs.org.

Background: Substantial COVID-19 research investment has been allocated to randomized clinical trials (RCTs) on hydroxychloroquine/chloroquine, which currently face recruitment challenges or early discontinuation. We aimed to estimate the effects of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished. Methods: Rapid meta-analysis of ongoing, completed, or discontinued RCTs on hydroxychloroquine or chloroquine treatment for any COVID-19 patients (protocol: https://osf.io/QESV4/). We systematically identified published and unpublished RCTs by September 14, 2020 (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, PubMed, Cochrane COVID-19 registry). All-cause mortality was extracted (publications/preprints) or requested from investigators and combined in random-effects meta-analyses, calculating odds ratios (ORs) with 95% confidence intervals (CIs), separately for hydroxychloroquine/chloroquine. Prespecified subgroup analyses included patient setting, diagnostic confirmation, control type, and publication status. Results: Sixty-two trials were potentially eligible. We included 16 unpublished trials (1596 patients) and 10 publications/preprints (6317 patients). The combined summary OR on all-cause mortality for hydroxychloroquine was 1.08 (95%CI: 0.99, 1.18; I-square=0%; 24 trials; 7659 patients) and for chloroquine 1.77 (95%CI: 0.15, 21.13, I-square=0%; 4 trials; 307 patients). We identified no subgroup effects. Conclusions: We found no benefit of hydroxychloroquine or chloroquine on the survival of COVID-19 patients. For hydroxychloroquine, the confidence interval is compatible with increased mortality (OR 1.18) or negligibly reduced mortality (OR 0.99). Findings have unclear generalizability to outpatients, children, pregnant women, and people with comorbidities.

PK/PD similarity of Sandoz proposed biosimilar pegfilgrastim and reference pegfilgrastim was confirmed. No clinically meaningful differences in safety, tolerability and immunogenicity were observed in healthy subjects.