Hayao Ueno

Pharmacokinetics of once-a-month injectable microspheres of leuprolide acetate.

The pharmacokinetic parameters of leuprolide acetate, a potent analogue of LH-RH, were determined in rats and dogs after i.v. and s.c. dosing with leuprolide solution. The effective human dose of once-a-month injectable microspheres of leuprolide was estimated to be about 3.2 to 8.1 mg analogue/month using these parameters. After microsphere injection at three different doses in rat serum leuprolide concentrations were sustained for over 4 weeks, and the AUCs and mean serum levels were linearly correlated with the dose. The serum levels and urinary excretion of the analogue in rats after repeated s.c. injection of the microspheres every 4 weeks exhibited similar profiles after each injection; no changes of the absorption and excretion of the analogue after the repeated injection could be demonstrated. The serum levels of the analogue metabolite (M-I) were 21% of the intact form 3 hr after injection of the microspheres but very low at the steady state after 1 to 4 weeks.

Elevated levels of plasma endothelin-1 in young patients with pulmonary hypertension caused by congenital heart disease are decreased after successful surgical repair.

R E F E R E N C E S 1. Hill PE. Complications of permanent transvenous car: diac pacing: a 14-year review of all transvenous pacemakers inserted at one community hospital. PACE Pacing Clin Electrophysiol 1987;10:564-70. 2. Ellis GL. Pacemaker twiddlers syndrome: a case report. Am J Emerg Med 1990;8:48-50. 3. Roberts JS, Wenger NK. Pacemaker twiddlers syndrome. Am J Cardiol 1989;63:1013-6. 4. Lal RB, Avery Rd. Aggressive pacemaker twiddlers syndrome: dislodgement of an active fixation ventricular pacing electrode. Chest 1990;97:756-7.

Influence of pulmonary blood pressure and flow on endothelin-1 production in humans

Summary: To investigate the regulation of endothelin-1 (ET-1) production, cardiac catheterization was performed in young patients with congenital heart disease (27 ± 5 months old, mean ± SEM), and plasma levels of ET-1 in the inferior vena cava were measured by a sandwich-enzyme immunoassay. Plasma ET-1 levels of age-matched healthy controls were 1.55 ± 0.07 pg/ml (n = 6). In patients with atrial septal defect [without pulmonary hypertension (PH)] who had volume but not pressure overload to the pulmonary circulation (PC), plasma ET-1 levels were significantly lower than in controls. In patients with PH due to ventricular septal defect (VSD) who had both volume and pressure overload to PC, the levels were significantly higher than in controls. In patients with PH and severe pulmonary congestion due to pulmonary venous stenosis (PVS), plasma ET-1 levels were significantly higher than in those with VSD, suggesting that ET-1 production is also augmented by pulmonary congestion. The present findings suggest that ET-1 production is increased by pressure overload to PC but decreased by volume overload to PC.

High-performance liquid chromatography followed by radioimmunoassay for the determination of a luteinizing hormone-releasing hormone analogue, leuprorelin, and its metabolite

A sensitive method for the determination of leuprorelin (TAP-144), a luteinizing hormone-releasing hormone analogue, and its C-terminal metabolite, M-I, in serum and urine has been developed. Leuprorelin and M-I were extracted from serum or urine samples with Sep-Pak C18 cartridges, and separated completely by high-performance liquid chromatography and determined by radioimmunoassay using [125I]leuprorelin as the labelled antigen. The detection limit of the method was 0.05 ng/ml for leuprorelin and M-I, and the recovery of the compounds added to serum and urine was over 88% with a coefficient of variation (within-assay) of less than 5%. The method was applied to the determination of leuprorelin and M-I-like immunoreactivity in serum or urine after administration of once-a-month injectable microspheres of leuprorelin acetate (TAP-144-SR) to patients with prostate cancer.

A new fluorometric analysis of citric acid

Abstract A new fluorometric method for analysis of citric acid in blood and plasma was established, where the citric acid react with o -aminothiophenol in 35% phosphoric acid solution, at 125°C, for 15 hr. The fluorescent substance was extracted by ethylacetate and measured with excitation at 415 nm and emission at 450 nm. Only 0.05 ml of human blood or plasma is required.

Chromatographic separation and chemical analysis of polymers formed by penicillin g

To elucidate the chemical structures of penicillin polymers that may elicit an allergic reaction, a 25% aqueous solution of penicillin G potassium was kept standing in the dark at room temperature for 14 days and was then separated by gel filtration chromatography on Sephadex G-25. The fractions of Kav 0.0-0.3, 0.3-0.55 and 0.55-0.75 were designated fractions A, B and C, respectively. Chemical and spectral data indicated that fractions A and B had almost similar chemical structures, but differed in molecular weight. They consisted of equimolar phenylacetyl and thiazolidine moieties and showed a C:N:S ratio almost equal to that of penicillin G. Their degrees of polymerization were 10 for A and 3.2 for B. Comparison of 1H NMR and IR spectra and thin-layer chromatographic RF values with those of authentic standards showed that the main components of fraction C were N- formylpenicillamine , benzylpenilloic acid, benzylpenicilloic acid and benzylpenillic acid.

Eliciting IgE-mediated passive cutaneous anaphylactic reaction by synthetic D-benzylpenilloic acid analogs

The ability of various D-benzylpenilloic acid analogs to evoke the passive cutaneous anaphylactic (PCA) reaction was tested in rats sensitized with mouse IgE antibodies to a benzylpenicillin preparation. D-benzylpenilloic acid synthesized chemically from materials that had no potency to evoke the PCA reaction showed almost the same antigenicity in eliciting the reaction as that prepared from benzylpenicillin. Changes in the chemical structures of the side-chain and thiazolidine ring of D-benzylpenilloic acid resulted in a reduction in the activity, but the removal of either alpha- or beta-methyl did not greatly affect it. From these results, it was concluded that benzyl and amidomethyl at C-2, the D-configuration at C-4, and dimethyl at C-5 on the thiazolidine ring have a significant effect on the PCA reaction.