The role of recombinant cytokines and other immunomodulators on engraftment following allogeneic bone marrow transplantation in mice.

BALB/c mice were conditioned by total body irradiation (TBI) with a suboptimal (475 cGy) or optimal (600 cGy) radiation dose for induction of chimerism subsequent to administration of 10(7) (BALB/c x C57BL/6) F1 (F1) bone marrow cells in order to test whether a variety of recombinant cytokines and other immunomodulators caused positive or negative effects on engraftment at different time intervals post-bone marrow transplantation (BMT). Engraftment in recipient mice conditioned by the minimal dose of TBI permitting 100% induction of chimerism (600 cGy) was not impaired following treatment with recombinant human interleukin 2 (IL2) (10(4) Cetus Units x 3/day i.p.), alpha interferon (alpha IFN) (10(4) units/day i.p.), gamma interferon (gamma IFN) (10(4) U/day i.p.) and combinations of IL2 + alpha IFN as well as IL2 + gamma IFN given either 5 days prior to or 5 days following BMT. Likewise, neither PGE2 (50 micrograms x 2/day i.p.) nor indomethacin (25 micrograms x 2/day i.p.) given either immediately prior to or immediately following BMT for 3 consecutive days had any detectable effect on chimerism. To investigate the putative beneficial effects of IL2 in enhancing marrow engraftment, BALB/c mice were irradiated with a suboptimal dose of TBI (475 cGy) followed by reconstitution with 10(7) F1 marrow cells supplemented with 2 x 10(6) F1 spleen cells. IL2 (10(4) U x 3/day i.p. x 5 days) was administered either prior to TBI, between TBI and BMT, immediately following BMT, or starting 2 weeks post-BMT.(ABSTRACT TRUNCATED AT 250 WORDS)

Carpipramine metabolism in the rat, rabbit and dog and in man after oral administration.

Carpipramine administered orally is excreted via the urine and faeces in rat, rabbit, dog and man. Many metabolites are formed, including several conjugates in the urine. A total of 20-25 metabolites was detected by t.l.c. and h.p.l.c., 16 of which were isolated and identified. Three metabolic pathways were observed: hydroxylation of the iminodibenzyl ring to a phenol or alcohol without modification of the side-chain, hydroxylation of the terminal piperidine of the 2-piperidinol side-chain, and cyclization and dehydrogenation of the same 2-piperidinol group.

Disposition of 14C-oltipraz in animals. Pharmacokinetics in mice, rats and monkeys. Comparison of the biotransformation in the infected mouse and in the schistosomes.

14C-labelled 4-methyl-5(2-pyrazinyl)-1,2-dithiole-3-thione (14C-oltipraz, 35 972 R.P.) was orally administered to rhesus monkeys (20 mg/kg), rats (50 mg/kg) and female mice infected with Schistosoma mansoni (100 and 250 mg/kg). The absorption of oltipraz varied with the animal species and the dose administered. In each species, the pharmacokinetics of oltipraz in the plasma and red blood cells were generally similar. 40 to 57% of the radioactive dose was excreted in urine, depending on the animal species and dose levels. In the mouse, there was negligible elimination of radioactivity as 14CO2. Whole-body autoradiographic studies in mice showed that, during the first 24 h, radioactivity was present mainly in the gastro-intestinal tract, bile, urine, liver and kidneys. In the male and female worms, the nature and amounts of radioactive products present differed.

Comparison of the metabolism of oltipraz in the mouse, rat and monkey and in man. Distribution of the metabolites in each species.

4-Methyl-5-(2-pyrazinyl)-1,2-dithiole-3-thione (35 972 R.P., oltipraz) and its metabolites were extracted from human urine and from mouse, rat and monkey urine using Amberlite XAD4 resin. The metabolites were identified by GLC, TLC and HPLC and isolated by preparative TLC or HPLC. The structures of 11 compounds were determined by spectroscopic examination (MS, IR, NMR). Six of the principal metabolites isolated in sufficient quantity from human urine were administered to the mouse, confirming the metabolic pathways of oltipraz.

High-performance liquid chromatographic determination of pipotiazine in human plasma and urine.

A high-performance liquid chromatographic method has been developed for the determination of pipotiazine in human plasma and urine. After selective extraction, pipotiazine and the internal standard (7-methoxypipotiazine) and chromatographed on a column packed with Spherosil XOA 600 (5 micrometers) using a 7:3 (v/v) mixture of diisopropyl either--isooctane (1:1, v/v + 0.2% triethylamine and diisopropyl ether--methanol (1:1, v/v) + 0.2% triethylamine + 2.6% water. The eluted compounds are measured by fluorescence detection. The sensitivity of the method was established at 0.25 ng/ml pipotiazine in plasma and 2 ng/ml pipotiazine in urine (C.V. less than 5%). The method has been successfully applied to a pharmacokinetic study following a single oral administration of 10 mg of pipotiazine.

[Pharmacokinetics of isosorbide dinitrate administered by intravenous infusion to hypertensive patients (author's transl)]. / Pharmacocinétique du dinitrate d'isosorbide. Approche après perfusion intraveineuse chez le patient hypertendu.

The pharmacokinetics of intravenous isosorbide dinitrate was investigated in 11 patients with labile hypertension and with normal renal and hepatic functions. The mode of administration (constant rate infusion without loading dose) was chosen in order to minimize side-effects and to approximate clinical conditions. Isosorbide dinitrate levels were measured by electron-capture gas chromatography. The volume of distribution during steady state (Vd beta = 318 +/- 117 I) and the elimination half-life (t1/2 beta = 64.8 +/- 30.5 min) were similar to those found after perlingual and oral administration. Systemic clearance (Cls = 3.80 +/- 1.48 I/min) was high for a drug given intravenously, presumably because of active hepatic extraction, intensive pre-systemic degradation and very active extra-hepatic metabolism. These findings should be compared with the considerable inter-individual variations observed in theoretical plasma concentrations during steady state and with the presence of two pharmacokinetic models (one -- and two -- compartments) in the patients under study. Comparison of the results obtained by the intravenous route with previously published results after perlingual and oral administration indicates the following bioavailability ratios: perlingual/i.v. = 31%, oral/i.v. = 20%, and oral/perlingual = 63%.

A priori lithium dosage regimen using population characteristics of pharmacokinetic parameters.

The important problem of initiation of long-term lithium treatment is tackled by means of the selection of an a priori dosage regimen based on the presumed efficacy of lithium and absence of toxicity. The pharmacokinetics of Li+ ion is represented by a four-compartment open model including the supposed first-order processes for the release of the active compound from the dosage form and its absorption. Experimental protocols for measurements of serum concentrations and of urinary amounts after single and multiple dosing to healthy volunteers were derived with several oral dosage forms. Estimation of the pharmacokinetic parameters for each subject made it possible to validate the model for the various dosage forms. The interindividual variability of these parameters is taken into account by estimating the characteristics of the statistical distribution for the whole population. A dosage regimen is considered optimum when serum concentration profiles at steady state range from the threshold of efficacy (0.8 mmol/liter) to the threshold of toxicity (2.0 mmol/liter). When the number of daily intakes is fixed, the search for the optimum dose for the whole population is effected by minimizing the expected value of the random variable which characterizes the risks of excursion out of the therapeutic range. By this means universal dosages are shown to be unsatisfactory. However, certain dosage regimens individualized with respect to the renal clearance value of lithium and based on two or three daily intakes can give excellent results even when conventional dosage forms are used.