Cardiome (Canada)

:Atrial fibrillation (AF) is a common clinically significant cardiac arrhythmia. This phase 3 randomized, double-blind, placebo-controlled trial assessed the efficacy and safety of vernakalant hydrochloride for the pharmacological conversion of AF to sinus rhythm in patients with recent-onset (>3 hours to ≤7 days) symptomatic AF from the Asia–Pacific region. Patients received an infusion of vernakalant (3 mg/kg) or placebo for 10 minutes. If AF had not been terminated 15 minutes later, a second infusion of vernakalant (2 mg/kg) or placebo for 15 minutes was administered. The primary efficacy end point was conversion of AF to sinus rhythm for >1 minute within 90 minutes. The study was terminated early for administrative reasons; 123 patients from Korea, Taiwan, and India were randomized to receive vernakalant (n = 55) or placebo (n = 56). A greater proportion of patients who received vernakalant (52.7%) than placebo (12.5%) met the primary end point (P < 0.001), and cardioversion was faster in the vernakalant group than in the placebo group (P < 0.001). Vernakalant was generally well tolerated; the incidence of treatment-emergent adverse events was similar between the groups. We conclude that vernakalant is efficacious in the rapid cardioversion of recent-onset AF in patients from the Asia–Pacific region.

Vernakalant hydrochloride is a novel, predominantly atrial-selective antiarrhythmic drug that effectively and rapidly terminates atrial fibrillation (AF). Plasma vernakalant concentration data from 5 phase 2 and 3 clinical trials of vernakalant in patients with AF or atrial flutter and a phase 1 study in healthy volunteers were used to construct a population pharmacokinetic model. Plasma vernakalant concentration-time data were best fit by a 2-compartment mammillary model, with rapid first-order elimination from the central compartment. Median systemic clearance was 0.35 L/h/kg (or 28 L/h for an 80-kg patient), with intersubject variability estimated to be 40%. Clearance was significantly influenced by CYP2D6 genotype, age, serum creatinine concentration, and subject status (patient vs volunteer). The intercompartmental clearance was also influenced by subject status, whereas the volumes of the central compartment and peripheral compartment were unaffected by any covariates. Based on the final pharmacokinetic model, the area under the plasma vernakalant concentration-time curve from 0 to 90 minutes was estimated to be 15% higher in CYP2D6 poor metabolizers than extensive metabolizers, with age and serum creatinine having much smaller influences on exposure. These data suggest that dose adjustments based on patient characteristics, including use of concomitant drugs, are unnecessary for intravenous vernakalant.

Abstract In general, mutations in oncogenes and tumor suppressor genes are believed to represent the fundamental cause of carcinogenesis. Mitochondrial deficiency (Warburg effect) may be a direct or indirect consequence of these mutations. Accordingly, tumor cells depend on glycolysis rather than mitochondrial oxidative metabolism as energy source for their survival and proliferation. Targeting this kind of metabolism could offer a possibility for cancer treatment. Erythrose was used as an alternative energy source to test its inhibitory effect on several tumor cell lines in vitro and in vivo. Cancer cell lines (breast BT474 and MCF-7, brain U87mg, pancreas Panc-1, HEL, LL-2 Lewis lung, and colorectal CT26 and SW480 lines) were grown in DMEM + 10% FBS media with different concentrations of D-erythrose and cell growth was tested with the Trypan blue assay. In general, 70% of cancer cells did not survive after 24 hrs of culture with 500mg/L D-erythrose. Addition of ZnCl2 (40µM) doubled the cancer killing effect at 400mg/L D-erythrose. In addition, LL-2 Lewis lung cells were subcutaneously introduced into the immunocompetent C57BL/6 mice. After allowing tumor growth to 2.7±0.4mm wide diameters, a daily subcutaneous injection beside the tumor with D-erythrose (∼1g/kg bw) was administered for 25 days; controls received a PBS injection instead. Tumor growth in erythrose-treated mice was inhibited more than 90% by weight. We hypothesize that the administration of erythrose leads to CO2 production from oxidation in cytosol or mitochondria. Carbonic acid is formed from CO2 and water, accelerated by carbonic anhydrase (a zinc enzyme), which can convert lactate to lactic acid, and cause intracellular acidosis and cancer death since cancer cells have increased lactate production. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4548.