Investigation of the interactions between methadone and elvitegravir-cobicistat in subjects receiving chronic methadone maintenance.

Interactions between HIV and opioid dependence therapies are known to occur. We sought to determine if such interactions occurred between methadone and elvitegravir boosted with cobicistat (EVG/COBI). We performed a within-subject open-label pharmacokinetic and pharmacodynamic study of 11 HIV-seronegative subjects stabilized on at least 2 weeks of methadone. Subjects underwent baseline and steady-state evaluation of the effect of elvitegravir 150 mg once a day (QD) boosted with 150 mg QD of cobicistat (EVG/COBI) on methadone pharmacokinetic parameters. Safety and pharmacodynamics were monitored throughout the study. Compared to baseline values, the R-methadone mean area under the concentration-time curve to the end of the dosing period (AUCtau) (5,550 versus 6,210 h · ng/ml) and mean maximum concentration of drug in serum (Cmax) (316 versus 337 ng/ml) did not significantly increase in the presence of EVG/COBI. Compared to baseline values, the S-methadone mean AUCtau (7,040 versus 7,540 h · ng/ml) and mean Cmax (446 versus 452 ng/ml) did not significantly increase in the presence of EVG/COBI. The AUCtau, Cmax, and Ctau of elvitegravir and cobicistat did not significantly differ from those of historical controls. Opioid withdrawal or overdose was not observed among subjects in this study. The addition of EVG/COBI to stabilized patients receiving methadone did not affect methadone pharmacokinetics and pharmacodynamics. These two agents can be safely coadministered.

Correction to: HTX-011 reduced pain intensity and opioid consumption versus bupivacaine HCl in herniorrhaphy: results from the phase 3 EPOCH 2 study.

In Abstract, under the section "Results", the first and third p values are incorrect. The correct p values should be p = 0.0004 and p < 0.0001 respectively.

HTX-011 reduced pain intensity and opioid consumption versus bupivacaine HCl in herniorrhaphy: results from the phase 3 EPOCH 2 study.

PURPOSE: Currently available local anesthetics have not demonstrated sufficient analgesia beyond 12-24 h postoperatively. The purpose of the study was to assess the safety and efficacy of HTX-011 (bupivacaine and meloxicam in Biochronomer® polymer technology), a long-acting investigational anesthetic, in reducing both postoperative pain over 72 h and postoperative opioid use compared to bupivacaine hydrochloride (HCl). METHODS: A phase 3, randomized, double-blind, active-controlled multi-center study (EPOCH 2; NCT03237481) in subjects undergoing unilateral open inguinal herniorrhaphy with mesh placement was performed. Subjects randomly received a single intraoperative dose of HTX-011, immediate-release bupivacaine HCl, or saline placebo prior to closure. RESULTS: The study evaluated 418 subjects, and the primary and all key secondary efficacy endpoints were in favor of HTX-011. HTX-011 reduced mean pain intensity by 23% versus placebo (primary endpoint; p < 0.001) and by 21% versus bupivacaine HCl (p < 0.001) with significant reductions in the number of patients experiencing severe pain. Opioid consumption over 72 h was reduced by 38% versus placebo (p < 0.001) and 25% versus bupivacaine HCl (p = 0.024). Overall, 51% of HTX-011 subjects were opioid-free through 72 h (versus 22% for placebo [p < 0.001] and 40% for bupivacaine HCl [p = 0.049]). HTX-011 was generally well-tolerated with fewer opioid-related adverse events reported compared to the bupivacaine HCl and placebo and no evidence of local anesthetic systemic toxicity. CONCLUSIONS: HTX-011 demonstrated significant improvement in postoperative pain control and a clinically meaningful reduction in opioid consumption when compared to the most widely used local anesthetic, bupivacaine HCl.

Novel partial 5HT3 agonist pumosetrag reduces acid reflux events in uninvestigated GERD patients after a standard refluxogenic meal: a randomized, double-blind, placebo-controlled pharmacodynamic study.

BACKGROUND: Low basal lower esophageal sphincter (LES) pressure and transient LES relaxations are major causes of gastroesophageal reflux disease (GERD). Pumosetrag, a novel selective partial 5HT3 receptor agonist, showed a promising effect on reducing reflux events in health. We aimed to evaluate the effect of pumosetrag on changes in reflux episodes, lower esophageal sphincter pressure (LESP), and specific symptoms in patients with GERD receiving a refluxogenic meal. METHODS: Patients with GERD, who developed heartburn and/or regurgitation after ingestion of a refluxogenic meal, were randomized to 1 of 3 dose levels of pumosetrag (0.2, 0.5, or 0.8 mg) or placebo. Before and after 7 days of treatment, patients underwent manometry, intraesophageal multichannel, intraluminal impedance and pH after a standard refluxogenic meal. KEY RESULTS: A total of 223 patients with GERD [125 (56%) women, mean (SD) age = 36 (12) years] were enrolled. No overall treatment effects were detected for the total number of reflux episodes (acidic and weakly acidic) (p > 0.5); however, significant treatment effects (p < 0.05) on the number of acid reflux episodes were observed with lower values on pumosetrag 0.2 mg (10.8 ± 1.1), 0.5 mg (9.5 ± 1.1), and 0.8 mg (9.9 ± 1.1) compared with placebo (13.3 ± 1.1). Significant treatment effects (p < 0.05) were also observed for the percentage of time pH was <4, with less time for pumosetrag at 0.5 mg (10%) and 0.8 mg (10%) compared with placebo (16%). CONCLUSIONS & INFERENCES: In GERD, the partial 5HT3 agonist pumosetrag significantly reduced the rate of acid reflux events but did not result in a significant change in LESP or symptomatic improvement over a 1-week treatment period.

Biliary interleukin-6 and tumor necrosis factor-alpha in patients undergoing endoscopic retrograde cholangiopancreatography.

Cytokines are low-molecular-weight protein mediators that possess a wide spectrum of inflammatory, metabolic, and immunomodulatory properties. Cytokines have been shown to be produced by monocytes/macrophages, lymphocytes, fibroblasts, endothelial cells, and more recently, hepatocytes and biliary epithelium. The aim of this study was to define biliary levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) in patients undergoing endoscopic retrograde cholangiopancreatography (ERCP) in various disease states. Fifty-four patients undergoing ERCP comprised the study group. IL-6 and TNF-alpha were measured in aspirated bile using an ELISA technique. Levels of both TNF-alpha and IL-6 were significantly higher in patients with cholangitis (P < 0.00001). Moreover, IL-6 was 100% specific for cholangitis since none of the patients without bacterial cholangitis-including patients with biliary obstruction secondary to cholangiocarcinoma or pancreatic carcinoma-had measurable IL-6 in their bile. Low levels of biliary TNF-alpha were detectable in five patients without cholangitis; the sensitivity and specificity of TNF-alpha for cholangitis were 100% and 82%, respectively. There was a strong statistical correlation between biliary IL-6 and TNF-alpha levels (r = 0.819, P < 0.0001). In contrast, the correlations between biliary cytokines and serum biochemical parameters were weak. These results suggest that IL-6 and TNF-alpha are sensitive markers for cholangitis and may differentiate it from other types of biliary tract disease.

Increased granulocyte-macrophage colony-stimulating factor mRNA instability in cord versus adult mononuclear cells is translation-dependent and associated with increased levels of A + U-rich element binding factor.

The level of granulocyte-macrophage colony-stimulating factor (GM-CSF) mRNA is fourfold lower in phorbol myristate acetate (PMA) + phytohemagglutinin (PHA)-activated mononuclear cells (MNC) from newborns compared with adults. The GM-CSF transcription rate is similar in umbilical cord and adult MNC, but transcript half-life is threefold lower in cord activated MNC. Interaction of RNA binding proteins, such as the cloned adenosine + uridine-rich element, binding factor, AUF1, with eight AUUUA motifs in the human GM-CSF mRNA 3'-untranslated region (GM-3'-UTR) has been implicated in regulating transcript stability. Translational inhibition by cycloheximide (CHX) significantly increased GM-CSF mRNA accumulation and half-life by three-fold in activated cord MNC, but had a minimal effect in activated adult MNC as compared with PMA + PHA alone. Electrophoretic mobility-shift assays with a 32P-labeled, 305-nucleotide RNA comprising the GM-3'-UTR revealed two RNaseT1-resistant, bound complexes that were almost twice as abundant in cord than in adult MNC extracts. Mobility-shift competition assays and RNaseT1 mapping localized the binding site of both complexes to a 52-nucleotide region containing seven of eight AUUUA motifs. Inclusion of AUF1 antiserum produced a supershifted complex at 35-fold higher levels in cord than in adult MNC extracts. Extracts from the carcinoma cell line 5637, with extended GM-CSF mRNA half-life, also had very low levels of anti-AUF1 supershifted complex. Anti-AUF1 immunoblotting showed significantly higher levels of two AUF1 protein isoforms and lower levels of one in cord than in adult MNC or 5637 extracts. These results suggest that destabilization of GM-CSF mRNA in cord MNC is translation-dependent and that increased levels of specific AUF1 isoforms in cord MNC may target transcripts for increased degradation, which could account in part for dysregulation of neonatal phagocytic immunity.