Objective. Despite widespread use of colchicine, the evidence basis for oral colchicine therapy and dosing in acute gout remains limited. The aim of this trial was to compare low-dose colchicine (abbreviated at 1 hour) and high-dose colchicine (prolonged over 6 hours) with placebo in gout flare, using regimens producing comparable maximum plasma concentrations in healthy volunteers.Methods. This multicenter, randomized, doubleblind, placebo-controlled, parallel-group study compared self-administered low-dose colchicine (1.8 mg total over 1 hour) and high-dose colchicine (4.8 mg total over 6 hours) with placebo. The primary end point was >50% pain reduction at 24 hours without rescue medication.Results. There were 184 patients in the intent-totreat analysis. Responders included 28 of 74 patients (37.8%) in the low-dose group, 17 of 52 patients (32.7%) in the high-dose group, and 9 of 58 patients (15.5%) in the placebo group (P ‫؍‬ 0.005 and P ‫؍‬ 0.034, respectively, versus placebo). Rescue medication was taken within the first 24 hours by 23 patients (31.1%) in the low-dose group (P ‫؍‬ 0.027 versus placebo), 18 patients (34.6%) in the high-dose group (P ‫؍‬ 0.103 versus placebo), and 29 patients (50.0%) in the placebo group. The low-dose group had an adverse event (AE) profile similar to that of the placebo group, with an odds ratio (OR) of 1.5 (95% confidence interval [95% CI] 0.7-3.2). High-dose colchicine was associated with significantly more diarrhea, vomiting, and other AEs compared with low-dose colchicine or placebo. With high-dose colchicine, 40 patients (76.9%) had diarrhea (OR 21.3 [95% CI 7.9-56.9]), 10 (19.2%) had severe diarrhea, and 9 (17.3%) had vomiting. With low-dose colchicine, 23.0% of the patients had diarrhea (OR 1.9 [95% CI 0.8-4.8]), none had severe diarrhea, and none had vomiting.Conclusion. Low-dose colchicine yielded both maximum plasma concentration and early gout flare efficacy comparable with that of high-dose colchicine, ClinicalTrials.gov identifier: NCT00506883.

BACKGROUND: Tocilizumab, an IL-6 receptor antagonist, can be used to treat cytokine release syndrome (CRS), with observed improvements in a coronavirus disease 2019 (COVID-19) case series. RESEARCH QUESTION: The goal of this study was to determine if tocilizumab benefits patients hospitalized with COVID-19.

Objective. Drug-drug interactions can limit the safety of colchicine for treating rheumatic diseases. Seven separate drug-drug interaction (DDI) studies were performed to elucidate the in vivo effects of concomitant treatment with colchicine and known inhibitors of cytochrome P450 3A4 (CYP3A4)/P-glycoprotein (cyclosporine, ketoconazole, ritonavir, clarithromycin, azithromycin, verapamil ER [extended release]), and diltiazem ER) on the pharmacokinetics of colchicine. The objective was to develop colchicine-dosing algorithms with improved safety. Methods.All studies were open-label, nonrandomized, single-center, one-sequence, two-period DDI experiments, using two 0.6-mg doses of colchicine, separated by a minimum 14-day washout period, followed by administration of the approved on-label regimen of known CYP3A4/P-glycoprotein inhibitors. Plasma concentrations of colchicine, but not the reference CYP3A4/P-glycoprotein inhibitors, were determined, and the pharmacokinetic parameters were calculated.Results. The ratios of the maximum concentration and area under the curve from time 0 to infinity for colchicine plus CYP3A4/P-glycoprotein inhibitors versus colchicine alone were >125% across all studies, with the exception of studies involving azithromycin. Significant DDIs were present when single doses of colchicine were coadministered with most of the selected CYP3A4/ P-glycoprotein inhibitors. Recommended colchicine dose reductions of 33-66% for the treatment of acute gout and 50-75% for prophylaxis were calculated for concomitant therapy with each agent, with the exception of no dose adjustment when colchicine is used in combination with azithromycin.Conclusion. These studies provide quantitative evidence regarding drug interactions and necessary adjustments in the dose of colchicine if colchicine treatment is continued during therapy with multiple CYP3A4/Pglycoprotein inhibitors. We demonstrated the need for specific reductions in the dose of colchicine when it is used in combination with 2 broadly prescribed calcium channel blockers (verapamil ER and diltiazem ER) and that the dose of colchicine does not need to be adjusted when it is used in combination with azithromycin.Despite the widespread use of colchicine for the treatment and prophylaxis of gout flares (1-5) and the ClinicalTrials

Objective. To assess the effectiveness of the lidocaine patch 5% (Lidoderm ® ), a targeted peripheral analgesic, in reducing pain intensity/interference with quality of life (QOL) among patients with postherpetic neuralgia (PHN).Design. Open-label, nonrandomized, effectiveness study; up to three patches applied to area of greatest pain for 12 hours per day for 28 days.Setting. Forty-two centers consisting of large institutional primary care programs and academic centers, including pain centers, neurologists, and pain specialists affiliated with a university. Patients. Patients with PHN (N ϭ 332).Outcome Measures. Patients completed the Brief Pain Inventory Short Form and global pain assessments at baseline, Days 7 and 14, and study conclusion. Physicians completed global assessments at baseline and study conclusion.Results. The mean time from onset of herpes zoster to treatment was 28 months. Use of the lidocaine patch 5% was associated with reductions in all mean pain intensity, pain interference with QOL, and composite scores at all time points ( P ϭ 0.0001). Overall, 66% of patients reported improvement in pain intensity, and 74% reported improved QOL by Day 7; approximately 43% who did not respond by Day 7 experienced improvement in pain intensity by Day 14. For all measures of pain intensity, relief, and interference with QOL, improvements from baseline were equally significant regardless of time since shingles onset. In all, approximately 60% of patients reported moderate to complete pain relief at final evaluation. The lidocaine patch 5% was well tolerated.Conclusions. Based on results of previous randomized, controlled trials and the current study, designed to gauge response in the clinical practice setting, the lidocaine patch 5% should be considered a firstline therapy, alone or in combination with other agents, for PHN due to its efficacy, safety, minimal systemic side effects and drug interactions, and ease of administration. Although the lidocaine patch 5% was equally effective in longstanding PHN, it would appear prudent to begin therapy as early in the course of PHN as possible.

The SARS-CoV-2 virus has emerged and rapidly evolved into a current global pandemic. Although bacterial and fungal coinfections have been associated with COVID-19, little is known about parasitic infection. We report a case of a COVID-19 patient who developed disseminated strongyloidiasis following treatment with high-dose corticosteroids and tocilizumab. Screening for Strongyloides infection should be pursued in individuals with COVID-19 who originate from endemic regions before initiating immunosuppressive therapy.

A series of peptidyl alpha-ketoheterocycles were synthesized and evaluated for their in vitro inhibition of human neutrophil elastase (HNE). Several heterocycles, including oxazoline and benzoxazole, afforded extremely potent inhibitors of HNE (1p-r) with nanomolar to subnanomolar Ki values. The structure-activity relationships revealed that for compounds with a Ki < 1000 nM potency tends to be positively correlated with the sigma I value of the heterocycle. Furthermore, the results in this study support the hypothesis that, in the covalent enzyme-inhibitor adduct, the azole nitrogen atom of the inhibitor heterocycle participates in a hydrogen-bonding interaction with the active-site His-57.

BACKGROUND Fibrous septae play a role in contour alterations associated with cellulite. OBJECTIVE To assess collagenase clostridium histolyticum-aaes (CCH) for the treatment of cellulite. MATERIALS AND METHODS Two identically designed phase 3, double-blind, randomized studies (RELEASE-1 and RELEASE-2) were conducted. Adult women with moderate/severe cellulite (rating 3–4 on the Patient Reported Photonumeric Cellulite Severity Scale [PR-PCSS] and Clinician Reported PCSS [CR-PCSS]) on the buttocks received up to 3 treatment sessions of subcutaneous CCH 0.84 mg or placebo per treatment area. Composite response (≥2-level or ≥1-level improvement from baseline in both PR-PCSS and CR-PCSS) was determined at Day 71. RESULTS Eight hundred forty-three women received ≥1 injection (CCH vs placebo: RELEASE-1, n = 210 vs n = 213; RELEASE-2, n = 214 vs n = 206). Greater percentages of CCH-treated women were ≥2-level composite responders versus placebo in RELEASE-1 (7.6% vs 1.9%; p = .006) and RELEASE-2 (5.6% vs 0.5%; p = .002) and ≥1-level composite responders in RELEASE-1 (37.1% vs 17.8%; p < .001) and RELEASE-2 (41.6% vs 11.2%; p < .001). Most adverse events (AEs) in the CCH group were injection site related; few CCH-treated women discontinued because of an AE (≤4.3%). CONCLUSION Collagenase clostridium histolyticum-aaes significantly improved cellulite appearance and was generally well tolerated.

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