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J Howes

Publications and source records attributed to J Howes.

At least 37 records · Page 2Linked to original sources
PubMed1992

Pharmacokinetic characterization and tissue distribution of the new glucocorticoid soft drug loteprednol etabonate in rats and dogs.

Loteprednol etabonate, a new glucocorticoid soft drug with a characteristic chloromethyl ester function in the 17 beta-position, is currently in the early phases of clinical development. As the basis for human trials, this study describes a new reversed-phase high-performance liquid chromatographic method for the determination of levels of drug in plasma and urine samples and assesses the pharmacokinetic properties of loteprednol etabonate in dogs and rats. Intravenous administration of loteprednol etabonate (5 mg/kg) to dogs revealed a terminal half-life of 2.8 h, a volume of distribution of 3.7 L/kg, and a total body clearance of 0.9 L/h/kg. Intact loteprednol etabonate was not detectable in the urine. After oral administration of the drug (5 mg/kg) to dogs, only metabolites, but no intact drug, were found in the plasma, an indication for a high first-pass effect. A pronounced binding of the drug to plasma protein (> 90%) and a high erythrocyte-buffer partition coefficient of 7.8 were determined in vitro. Preliminary information about tissue distribution and possible metabolic pathways were obtained in rats after oral administration of a 14C-labeled loteprednol etabonate suspension (5 mg/kg). pH-selective extraction into ethyl acetate revealed three distinguishable fractions: (1) a neutral lipophilic fraction, presumably intact drug, (2) an acidic, lipophilic fraction, and (3) a hydrophilic nonextractable fraction. Levels of intact drug and metabolites were highest in liver and kidney, whereas significantly lower levels were found in other investigated organs (lung, brain, heart).(ABSTRACT TRUNCATED AT 250 WORDS)

Androstadienes↗
PubMed1987

Nalmefene: safety and kinetics after single and multiple oral doses of a new opioid antagonist.

The aim of these two studies was to evaluate the safety and pharmacokinetics of oral nalmefene, a new orally effective opioid antagonist. In the first study, single ascending doses of 50, 100, 200, and 300 mg of nalmefene HCl were administered in double-blind fashion to four groups of healthy men. There were six subjects in each group; four received nalmefene and two received placebo. The drug was well tolerated at all dose levels with only mild and transient side effects, such as lightheadedness, at the higher doses. Model-independent pharmacokinetic analysis of the plasma concentration-time data showed that nalmefene was rapidly absorbed and had an elimination half-life that ranged from seven to 15 hours (mean, 10.7 hr). There was a good linear relationship (r = .97) between administered dose and total area under the curve at each dose level. Only about 4% of the dose was excreted in the urine as unchanged nalmefene, whereas up to 60% was excreted as a beta-glucuronidase/sulfatase hydrolysable conjugate(s) of nalmefene. In the second study, six healthy men were initially administered a single 50-mg dose of drug, and plasma samples were obtained at selected time intervals for 48 hours. A dosing schedule of 20 mg q12h was then started and continued for seven days. Plasma samples were collected immediately before each dose and at selected times for up to 48 hours after the last dose. The drug was well tolerated by all subjects, and no clinically significant adverse effects were observed during the seven-day administration period.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1986

Nalmefene: intravenous safety and kinetics of a new opioid antagonist.

In a placebo-controlled, double-blind study we evaluated the safety and kinetics of a new narcotic antagonist, nalmefene, after 2, 6, 12, and 24 mg intravenous doses to healthy men. At each dose level four subjects received active drug and two received placebo. The drug was well tolerated at all dose levels with only mild and transient side effects, the most common of which was lightheadedness. The plasma concentration-time data were best fit with a triexponential equation, and the terminal elimination phase had a harmonic mean t1/2 of 8 to 9 hours. Only about 5% of the dose was excreted in the urine as intact nalmefene, with up to 60% excreted as nalmefene glucuronide. Although intersubject differences were noted, mean or dose-normalized mean kinetic parameters such as clearance, steady-state volume of distribution, terminal t1/2, and AUC showed no consistent trends related to increasing doses, indicating that nalmefene has linear pharmacokinetics.

Adult↗
PubMedDate not supplied

Genetic discrimination.

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Discrimination, Psychological↗