Effect of disulfiram-mediated CYP2E1 inhibition on the disposition of vesnarinone

Vesnarinone is an orally administered inotropic agent that is metabolized in vitro by the cytochrome P450 (CYP) isozymes CYP3A4 and CYP2E1. The purpose of this study was to assess the contribution of CYP2E1 activity to the disposition of vesnarinone in humans by characterizing the pharmacokinetics before and after disulfiram-mediated CYP2E1 inhibition. The pharmacokinetics of vesnarinone 60 mg were determined in normal healthy volunteers (N = 7) before and after daily disulfiram administration (250 mg). Chlorzoxazone 250 mg was also administered before, during, and after disulfiram administration to serve as a positive control for CYP2E1 inhibition. Disulfiram treatment decreased 6-hydroxychlorzoxazone formation clearance by nearly 95% but effected only a modest decrease in vesnarinone apparent oral clearance (5.7 +/- 1.0 vs. 5.0 +/- 0.5 ml/min; p = 0.022). In contrast to the modest effect on the parent drug, disulfiram treatment substantially increased plasma concentrations of the primary metabolite OPC-18692. The Cmax of OPC-18692 was increased approximately 7-fold, and the area under the plasma concentration-time curve was increased 18-fold (2.9 +/- 0.9 vs. 53.7 +/- 33.2 micrograms.h/ml; p = 0.006). The results indicate that CYP2E1 inhibition has only a modest, clinically insignificant effect on vesnarinone disposition but markedly increases plasma concentrations of the OPC-18692 metabolite. The pharmacological properties of this metabolite have not been fully defined; thus, the clinical importance of this observation depends on whether this metabolite contributes to any of the toxicity associated with vesnarinone administration.     

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In a study of the epidemiological significance of serum DDT concentration, three groups of men with descending degrees of occupational pesticide exposure gave bimonthly blood samples throughout 1968. The groups contained 38, 32, and 28 men, respectively. Their serums were analyzed by gas-liquid chromatography. There was no clear relationship between degree of occupational DDT exposure and total serum DDT concentration. All three groups experienced sixfold increases in total serum DDT concentration between April and August. Concomitantly, in all groups there was a relative decrease in serum concentration of DDE, a degradation product of DDT. The results suggested that local agricultural and municipal insecticide applications increased the DDT exposure of all subjects regardless of their degree of occupational pesticide exposure, and that DDT appeared in their serums soon after absorption from the external environment.     

Comparison of two doses and dosing regimens of tolvaptan in congestive heart failure

Fluid retention and extracellular volume expansion are frequently encountered complications of congestive heart failure (HF) that can cause morbidity and mortality. Tolvaptan (Otsuka) is an orally administered nonpeptide vasopressin (VP) V2 receptor antagonist that inhibits water reabsorption in the kidney by competitively blocking VP binding, resulting in water diuresis without significantly changing total electrolyte excretion. In the 24-hour period following a 30-mg dose of tolvaptan, urine excretion rate increases and declines as plasma concentrations rise and fall; this uneven effect results in 80% of daily urine output in the first 12 hours. Therefore, the current study was designed to assess the pharmacodynamic effects, pharmacokinetics, and clinical safety of tolvaptan 30 mg QD plus placebo versus 15 mg BID over 7 days in patients with NYHA Class II/III heart failure and persistent fluid overload, SBP > or = 90 mm Hg, and a serum creatinine < or = 3.0 mg/dL. Patients were withdrawn from diuretics for 48 hours before randomization. Statistics were performed with ANCOVA for continuous variables and Mantel-Haenszel mean score test stratified by center for categorical variables. Thirty-nine of 40 patients completed days 1 and 7. There were no significant clinical, pharmacokinetic, or pharmacodynamic differences between the dosing regimens over time. Based on these findings, tolvaptan 30 mg was chosen as the comparator for placebo in a large phase 3 survival trial.     

The plight of the not-for-profit

Recent controversies in the hospital sector have questioned whether the levels of charity care, community benefit, and executive compensation provided by not-for-profit hospitals are consistent with mandates of their tax-exempt status and mission statements. This article demonstrates that these recent controversies stem from a combination of historical influences, regulatory inequities, and competitive disadvantages, which are suffocating many not-for-profit hospitals across the nation. Once the current environment is described, the article discusses each threat and offers actionable recommendations to quell current attacks faced by the industry. First, to address the current probe by the Internal Revenue Service, hospitals must begin to link their executive compensation with their organizational mission. Second, to address recent lawsuits, the article presents a standardized definition of community benefit and recommends an alternative model to classify charity care. Finally, to address recent congressional hearings, the article offers a plan for hospitals to gauge their expected benefit to the community they serve.     

Catanionic mixtures involving a drug: a rather general concept that can be utilized for prolonged drug release from gels

The aim of this work was to study at what extent mixtures of drug substances and oppositely charged surfactants form catanionic aggregates and to apply these as a means of obtaining prolonged drug release from a gel. The properties of traditional catanionic mixtures are relatively well known, but only recently we found that not only traditional surfactants form these mixtures, but also structurally more complex surface active drug compounds. In this study, several different compositions of catanionic mixtures were studied visually, by cryogenic transmission electron microscopy (cryo-TEM) and rheologically using a Bohlin VOR Rheometer. Some of the catanionic vesicle and micelle phases were incorporated in and released from gels using the USP paddle method. The drug compounds investigated were lidocaine, ibuprofen, naproxen, alprenolol, propranolol, and orphenadrine. Of the six drug molecules used in this study, five, both positively and negatively charged, were capable of forming catanionic vesicles and/or micelles with oppositely charged surfactants. The drug release studies show that catanionic drug surfactant mixtures are beneficial for obtaining prolonged release from gels, as the drug release using catanionic vesicles and micelles was prolonged between 10 and 100 times compared to the release of pure drug substance from the gel.     

Long-term outcome of right ventricular outflow tract reconstruction with bicuspidalized homografts

Objective: Given the shortage of small-sized cryopreserved homografts for right ventricle (RV) to pulmonary artery (PA) reconstructions, more readily available larger-sized homografts can be used after size reduction by bicuspidalization. The aim of our study was to determine and compare function over time of standard and bicuspidalized homografts in infants younger than 12 months, including patients with a Ross or extended Ross procedure. Methods: All consecutives infants under the age of 1 year, who underwent a surgical procedure in which a homograft was placed in the RV-PA position between January 1994 and April 2009, were included. Prospectively collected data from serial, standardized echocardiography from all patients were extracted from the database, and hospital records were retrospectively reviewed. Results: A total of 40 infants had a valved homograft conduit placed in the RV-PA position. In 20 of those patients, a bicuspidalized homograft was used. Twelve patients underwent a Ross procedure, of whom seven had an additional Konno-type aortic annulus enlargement. Median follow-up was 146 months (interquartile range (IQR), 117–170; total patient years: 178) in the group with standard use of the homograft and 95 months (IQR, 11–104; total patient years: 78) in the group with bicuspidalized conduits. Freedom from re-intervention (re-operation or percutaneous) was not different in the standard and bicuspidalized groups for all and Ross or Konno–Ross procedures (Tarone-Ware, p = 0.65 and p = 0.47, respectively). Consecutive echocardiographic maximum velocities in the right ventricular outflow tract were similar in the standard and bicuspidalized groups. Conclusion: When proper sized cryopreserved homografts for placement in the RV-PA position in Ross, Konno–Ross, and other procedures in infants under the age of 1 year are not readily available, bicuspidalized homografts provide an acceptable alternative.