A novel transdermal formulation of fentanyl-containing dipropylene glycol droplets dispersed in a silicone matrix with a rate-controlling membrane was developed. Healthy male subjects (n = 24) received repeated 72-hour applications of fentanyl (50 mug/h) as the novel matrix and the conventional reservoir formulations in a randomized, 2-way crossover study. Blood samples were collected, and serum concentrations of fentanyl were assayed using liquid chromatography with mass spectrometry detection. The mean area under the curve (AUCtau) and peak concentrations (C(max)) of the matrix formulation were 84 838 pg.h/mL and 1680 pg/mL, respectively. Ratio and 90% confidence intervals of AUCtau and C(max) between the 2 formulations were within 80% to 125%. Adherence of the matrix formulation was higher than the reservoir formulation (62.5 vs 56.2%, P < .0001), without affecting skin irritation. Vital signs and adverse events of the 2 formulations were similar in nature and frequency. The novel matrix formulation displayed enhanced adherence and resulted in similar pharmacokinetics and tolerability as the reservoir formulation.
Imreg (Tyr-Gly-Gly) is a well-known immunostimulant. However, it possesses a short half-life. Stabilized analogues of Imreg were prepared by a regioselective insertion in which peptide
bonds at position 1,2 or 2,3 were replaced by thioamide linkages. This was achieved by using
new thioacylating agents based on thioacyl-fluoro-N-benzimidazolone. The synthesis and
properties of these reagents are described herein. This peptide modification enhanced
significantly the half-life of the thioanalogues relative to Imreg in blood. The thioanalogues
and Imreg were tested in vitro in T and B cell proliferation assays and for their ability to
stimulate cytotoxic T-lymphocytes (CTLs). Only thiotyrosyl glycyl glycine 11 displayed some
activity as evidenced by a weak stimulation of CTLs. On the basis of this activity and the
increased stability, an in vivo immunological evaluation was undertaken. Immunophenotyping
of 11 revealed a significant increase in activated CTL and NK cell populations in the spleen.
This expansion was also accompanied by a significant stimulation of NK cells and the B cell
proliferative response. Thioanalogues of Imreg were generally nontoxic, as exemplified by 11.
The latter is a promising immunostimulant which may be targeted for cancer and viral
infections, where CTLs and NK cells play an important role, or as a vaccine adjuvant where
stimulation of antibody-producing B cells is important.
The pharmacokinetics of 150 mg lamivudine, 300 mg zidovudine, and 200 mg nevirapine were assessed following single oral administration of a fixed-dose combination tablet and coadministration of the separate innovator products in healthy male subjects (n = 64) under fasting conditions in an open-label, randomized, 2-way crossover study. Multiple blood samples were collected up to 72 hours and plasma concentrations of antiretrovirals were assayed using liquid chromatography/tandem mass spectrometry methods. Pharmacokinetic parameters were calculated using noncompartmental methods, and bioequivalence was assessed using an analysis of variance model. The ratio of the least squares mean (fixed-dose combination to individual products) and 90% confidence intervals of AUC(0-t), AUC(0-infinity), and C(max) for lamivudine, zidovudine, and nevirapine were all within 80.0% to 125.0%, suggesting a similar rate and extent of antiretroviral exposure in the bloodstream. Mean oral clearance (CL/F) values of lamivudine, zidovudine, and nevirapine for the fixed-dose combination were 23.7, 127, and 1.65 L/h, respectively. The fixed-dose combination and individual products were equally safe and well tolerated, with only a few subjects experiencing drug-related adverse events. The current fixed-dose combination of lamivudine, zidovudine, and nevirapine is expected to provide a similar efficacy/safety profile as coadministration of the individual products, a better adherence to treatment, and considerable cost savings in the treatment of HIV.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.