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Biomedical subjects

D D Breimer

Publications and source records attributed to D D Breimer.

At least 217 records · Page 12Linked to original sources
PubMed1985

Central effects during the continuous osmotic infusion of a benzodiazepine (triazolam).

The effects of relatively constant plasma levels of a rapidly eliminated benzodiazepine (triazolam) were studied in young healthy males to determine whether tolerance to certain effects may develop over a relatively short period of time. The drug was given over a period of 30 h (2 days and 1 night) at zero-order rate using a rectal osmotic pump. Performance was measured at 2 hourly intervals during the day and was continuously impaired during the infusion, though there was a rapid recovery when the infusion ceased. All tasks were affected, in particular mental arithmetic and letter cancellation, but there was some improvement in performance during the second day. The normal circadian improvement in performance may have contributed to this effect, but some degree of tolerance to the effect of the drug cannot be excluded. Overnight there was a marked reduction in wakefulness, suppression of slow wave sleep, and delay to the onset and reduction in the duration of rapid eye movement sleep. During the night after infusion there was less slow wave sleep and increased wakefulness. The experimental design may prove useful in the study of tolerance to drugs.

Adult↗
PubMed1985

Antipyrine clearance and metabolite formation in children with congenital adrenal hyperplasia.

Antipyrine salivary clearance and half-life and the rate of formation of three principal metabolites of antipyrine (4-hydroxyantipyrine, 3-hydroxymethylantipyrine and norantipyrine) were assessed in nine children with congenital adrenal hyperplasia, six of whom were salt-losers and three of whom were non-salt-losers. No differences were found in comparison with data obtained in normal children.

Adolescent↗
PubMed1985

Route- and dose-dependent pharmacokinetics of hexobarbitone in the rat: a re-evaluation of the use of sleeping times in metabolic studies.

The metabolic clearance (CL) and half-life of racemic hexobarbitone and sleeping time were studied in rats following intra-arterial (i.a.), intraperitoneal (i.p.) and oral (p.o.) administration, at dose levels of 25 and 100 mg kg-1 of its sodium salt. CLp.o. was higher than CLi.a. at both 25 and 100 mg kg-1. CLi.a. and CLi.p. values were much lower, but CLi.p. was higher than CLi.a. at 25 mg kg-1 and lower than CLi.a. at 100 mg kg-1. There was no distinct dependency of the half-lives on route of administration, but a slight increase upon increasing the dose was observed. Hexobarbitone blood concentrations at which the rats awoke were significantly higher after 100 mg kg-1 i.p. than after 100 mg kg-1 i.a., although there was only a small difference in sleeping time. It is postulated that the rate of uptake of the barbiturates into the portal system after i.p. administration is so high that transient saturation of hepatic first-pass metabolism occurs. Therefore neither CLi.p. nor sleeping times can be used as an accurate reflection of drug-metabolizing enzyme activity in the rat; instead CLp.o. should be used.

Animals↗
PubMed1985

Dose-dependent elimination of theophylline in rats.

The effect of different doses on the rate of metabolism of theophylline in rats was investigated. After doses of 52 or 115 mg/kg, the initial concn. decayed according to a first-order process with an apparent half-life of about four hours. However, after four to eight hours the slope of the curves declined, resulting in elimination half-lives of about 70 min. Similar half-lives of 70 min were also found after doses of 6 or 11 mg/kg. The AUC increased disproportionately with dose, indicating capacity-limited elimination. No differences were observed in capacity-limited elimination of the two major metabolites of theophylline: the ratio between the amounts of 1,3-dimethyluric acid and 1-methyluric acid formed was independent of the dose of theophylline. The initial apparent first-order decay after higher doses resulted from a combination of capacity-limited metabolism and compensatory increased diuresis of unchanged theophylline. It is concluded that linear pharmacokinetics of theophylline in rats apply only to doses not exceeding 10 mg/kg.

Animals↗
PubMed1985

Correlation between antipyrine metabolite formation and theophylline metabolism in humans after simultaneous single-dose administration and at steady state.

To nine healthy male volunteers two model substrates for oxidative drug-metabolizing enzyme activity, viz, antipyrine (A) and theophylline (T) were administered simultaneously by the p.o. route. To six of them, the same two drugs were also administered simultaneously at zero-order rate with an osmotic rectal drug delivery system in order to obtain steady-state plasma concentrations. Plasma A and T concentrations were measured simultaneously by a high-performance liquid chromatographic method and urinary excretions of the major metabolites arising from A (4-hydroxyantipyrine, norantipyrine and 3-hydroxymethylantipyrine) and from T (3-methylxanthine, 1-methyluric acid and 1,3-methyluric acid) were also measured by high-performance liquid chromatography. Correlations between total plasma clearance and metabolic clearances of A and T and clearances for production of the various metabolites were investigated in order to determine whether the metabolic pathways of A and T are mediated by the same or closely related forms of the cytochrome P-450 system. Total plasma clearances of the two drugs were found to correlate reasonably well (r = 0.72) but not well enough to be of useful predictive value. The strongest correlations (r = 0.91) were found between the clearance for production of 4-hydroxyantipyrine and both total and metabolic clearances of T. The clearances for production of all metabolites of T also correlated better with the clearance for production of 4-hydroxyantipyrine (r ranging from 0.79-0.86) than with the clearance of norantipyrine and 3-hydroxymethylantipyrine (r ranging from 0.42-0.58).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1984

Cytosolic glutathione S-transferases in Drosophila melanogaster.

Post-microsomal supernatants from Drosophila melanogaster and rat liver homogenates were investigated with respect to their glutathione S-transferase (GST) activity. It appeared that the Drosophila transferase did not conjugate the epoxides styrene-7,8-oxide and 1,2 epoxy-3(p-nitrophenoxy)-propane. Attempts to isolate the Drosophila GST isozymes by means of the well-documented method for the purification of the rat liver transferases failed, because the Drosophila transferases did not bind to CM-cellulose. Purification by subsequent ion exchange on DEAE-cellulose, molecular sieving on Sephadex G-100 and hydroxylapatite chromatography, revealed three active fractions from Drosophila cytosol and five active fractions from rat liver cytosol, using 1-chloro-2,4-dinitrobenzene as the electrophilic substrate. None of the Drosophila active fractions catalyzed the conjugation of glutathione with the epoxides mentioned. It is concluded that there are important differences between the GST systems of both species, resulting in differences in the metabolic fate of chemicals that are substrates for glutathione conjugation. This has to be taken into account in the evaluation of genotoxicity testing in Drosophila of potentially harmful compounds.

Animals↗
PubMed1984

Liquid chromatographic determination of nifedipine in plasma and of its main metabolite in urine.

A high-performance liquid chromatographic method was developed for the assay of nifedipine in plasma and its main metabolite (M-I) in urine. After liquid-liquid extraction nifedipine was chromatographed in a reversed-phase system with ultraviolet detection at 238 nm. The method was sensitive to 2 ng nifedipine per ml plasma and the standard curve was linear to at least 400 ng/ml. Standard deviations did not exceed 8.5%. There was no interference with photodecomposition products or metabolites. M-I was determined in urine after liquid-liquid extraction by ion-pair chromatography with ultraviolet detection at 290 nm. The method was sensitive to 0.02 micrograms M-I per ml urine and the standard curve was linear to at least 5 micrograms/ml. Standard deviations did not exceed 5.0%. The methods were used to study nifedipine disposition in healthy volunteers.

Chromatography, Liquid↗
PubMed1984

Antipyrine metabolism in patients with disseminated testicular cancer and the influence of cytostatic treatment.

Antipyrine plasma clearance and rates of metabolite formation were measured on four occasions in eight patients with disseminated nonseminomatous testicular cancer. Antipyrine tests were performed before, during (2X), and after treatment with a combination of cisplatin (P), vinblastin (V), and bleomycin (B). Pretreatment values were compared with a male control group (n = 14) matched for age and body weight. Antipyrine plasma clearance was 20% higher in patients with testicular cancer (first experiment) than in the control group. This difference was mainly due to a 35% higher clearance for production of 3-hydroxymethylantipyrine (HMA), while clearance for production of norantipyrine (NORA) and 4-hydroxyantipyrine (OHA) was not significantly different from the control group. A reduction in CLHMA was observed after complete remission (fourth experiment), indicating that the presence of the tumor may be related to a selective increase of HMA formation. Treatment with the PVB combination resulted in a 30% increase in antipyrine plasma clearance (second and third experiments), whereas the rates of formation of the main metabolites of antipyrine were all increased to the same extent. These accelerating effects of PVB treatment persisted for at least 6 weeks after the start of the last treatment cycle. The data presented in this paper demonstrate that the presence of a testicular tumor and the use of cytostatics can have an accelerating and partially selective effect on oxidative drug-metabolizing enzyme activity in man.

Adolescent↗
PubMed1984

Influence of alaproclate on antipyrine metabolite formation in man.

Alaproclate, a selective serotonin reuptake inhibitor, presently undergoing clinical trial for the treatment of major depressive disorders, has been shown to inhibit hexobarbital metabolism in mice. In the present study the influence of oral alaproclate on the total plasma clearance of antipyrine and on the formation of its metabolites was investigated in 10 healthy volunteers. The peak level of alaproclate was reached after about 1.5 h, and after a distribution phase, its plasma elimination half-life was between 3.0 and 3.5 h. Antipyrine tests were performed before treatment, during the first four doses and after the seventh dose of alaproclate 200 mg/day. During treatment, total plasma antipyrine clearance and the clearance for production of all antipyrine metabolites were reduced by 30%, indicating non-selective inhibition of oxidative drug-metabolizing enzyme activity in man by alaproclate. After the last dose of alaproclate, antipyrine plasma clearance and the clearance to its metabolites returned to control values. In order to allow more detailed evaluation of the results, the time course of the clearances for production of metabolites was investigated. This revealed that the extent of inhibition of metabolite formation by alaproclate was dependent on the plasma alaproclate level, indicating a rapidly reversible inhibition.

Adult↗
PubMed1984

Rationale for rate-controlled drug delivery of cardiovascular drugs by the transdermal route.

If the therapeutic effects of a drug are to be maximized and maintained while the side effects are minimized, an optimal concentration of drug in blood plasma must be sustained continuously. Conventional dosage forms such as tablets, capsules, or elixirs describe a peak-and-valley curve when their dosage intervals are charted, demonstrating great fluctuations in the safety and effectiveness of a drug during the dosage interval. The need for certain drugs to be delivered at a constant, or zero-order, rate has led to the development of rate-controlled drug delivery systems, which by definition deliver drug in precise quantities over time. One such system uses the transdermal route, which is discussed here in terms of convenience, compliance, reliability, and potential as a vehicle for cardiovascular agents.

Cardiovascular Agents↗
PubMed1984

Strain-differences and inducibility of microsomal oxidative enzymes in Drosophila melanogaster flies.

Some basic characteristics of the enzyme system involved in the oxidative metabolism of xenobiotic compounds were investigated in Drosophila melanogaster flies. Attention was focussed on (1) the normal levels of these enzymes and their activities in whole flies, in different parts of the fly's body and in different sexes, (2) the changes in levels and activities of the enzymes elicited by pretreatment of the flies with known enzyme inducers and (3) differences between strains. Four commonly used wild-type (WT) strains, three insecticide resistant strains (IR) and one white-eyed mutant strain were employed. Except in those experiments on sex differences and in spatial distribution in the fly's body of the enzymatic activities, microsomes were isolated from whole-body homogenates of mixtures of female and male flies. Microsomal cytochrome P-450, benzo[a]pyrene (BP) hydroxylation, p-nitroanisole (pNA) demethylation and aminopyrine (AP) demethylation were measured in control flies and in flies pretreated with Aroclor 1254 (AC), phenobarbital (PB) or butylated hydroxytoluene (BHT). In flies of the WT strain Berlin-K, there were no significant differences in BP hydroxylation activity and its inducibility between the two sexes. In males, inducibility of BP hydroxylation activity was similar in the head, thorax and abdomen, but significantly lower in testis. Considerable differences in some enzyme activities were found between the strains. pNA demethylation and AP demethylation were substantially higher in all IR strains, while no correlation could be found between their increased insecticide resistance and BP hydroxylating capacity or cytochrome P-450 content of the microsomes. Response to enzyme inducing compounds was found to be strain-dependent. PB proved to be a more efficient inducer of BP hydroxylation than AC, which does induce pNA demethylation. BHT has inducing properties that are intermediate between PB and AC. IR strain Hikone-R turned out to be an exception, possessing very low BP hydroxylating capacity and a low degree of inducibility of mixed-function oxidase activities. Differential temperature dependence was found for BP hydroxylation as compared with pNA demethylation. While BP hydroxylation was doubled when raising the temperature from 25 degrees C to 35 degrees C, pNA demethylation was reduced by 50%.

Aminopyrine N-Demethylase↗
PubMed1984

The direct mutagenic activity of alpha, omega-dihalogenoalkanes in Salmonella typhimurium. Strong correlation between chemical properties and mutagenic activity.

A series of 18 alpha, omega-dihalogenoalkanes (kappa(CH2)n kappa with n = 1-6 and kappa = Cl, Br, I) was tested for direct mutagenic activity in Salmonella strains TA1530, TA1535 and TA100 using spot-test procedures. The results indicate that the mutagenic behaviour of these compounds is strongly dependent upon the carbon chain length as well as the type of halogen involved. This behaviour correlates with the leaving group ability and the degree of neighbouring group participation in nucleophilic displacement reactions of the different halogen atoms.

Hydrocarbons, Halogenated↗
PubMed1984

Nifedipine: kinetics and dynamics in healthy subjects.

Kinetics and pharmacologic effects of three formulations of nifedipine were examined in six healthy young men in a crossover design. Each subject received intravenous nifedipine, 0.015 mg/kg body weight, 20 mg in a capsule, and 20 mg in a slow-release tablet. Changes in heart rate (HR), blood pressure, heart dimensions, and plasma norepinephrine levels (PNE) were examined serially. Plasma concentrations of nifedipine (Cp) and urinary metabolite concentrations were measured by liquid chromatography. After intravenous injection the elimination t1/2 was 1.7 +/- 0.4 hr, systemic clearance was 26.7 +/- 5.4 l/hr, and volume of distribution was 0.8 +/- 0.2 l/kg. After the capsule, Cp rose rapidly, to a maximum concentration (Cmax) of 117 +/- 15 ng/ml at a maximum time (tmax) of 1.4 +/- 0.5 hr. After the sustained release tablet tmax was 4.2 +/- 0.7 hr and Cmax was 26 +/- 10 ng/ml. Nifedipine bioavailability was 56% +/- 25% for the capsule and 52% +/- 13% for the tablet, but there were large interindividual differences. Urinary excretion was 58% +/- 13% 24 hr after intravenous injection, and after 32 hr was 55% +/- 13% after capsules and 32% +/- 8% after tablets. HR increased briefly after intravenous injection and after capsules (15 to 20 bpm), but not significantly after tablets. Diastolic blood pressure (DBP) fell briefly after capsules (8 to 10 mm Hg), but there was a sustained effect after tablets. Cardiac dimensions were unchanged. PNE levels paralleled plasma drug levels in the three experiments.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1984

Nifedipine kinetics and dynamics during rectal infusion to steady state with an osmotic system.

Nifedipine steady-state kinetics and dynamics were investigated in a placebo-controlled study of six healthy subjects. Nifedipine was given rectally through an osmotic system at a zero-order rate for 24 hr. Steady-state plasma concentrations of approximately 20 ng/ml were achieved within 6 to 8 hr. Nifedipine lowered diastolic blood pressure (DBP) and increased forearm blood flow (FBF) and plasma norepinephrine concentration. On the other hand, heart rate (HR) and systolic blood pressure were not affected. Changes in DBP and FBF were closely related to nifedipine plasma concentrations during and immediately after the infusion period. Our data indicate that nifedipine lowers blood pressure in subjects with normotension and that it is possible by infusing the drug at a relatively low rate to dissociate its effect on blood pressure from that on HR.

Absorption↗
PubMed1984

Rectal and intravenous propranolol infusion to steady state: kinetics and beta-receptor blockade.

The effects of intravenous propranolol infusion for 24 hr was compared with those of zero-order rectal administration by an osmotic delivery system in six healthy subjects. In plasma and urine, levels of propranolol, 4-OH-propranolol (4-OH-P), and conjugates were determined just before and at 6 hr and at 20 hr during drug administration. With the rectally applied osmotic delivery system providing zero-order release, fairly constant steady-state levels of propranolol in plasma were produced within 12 to 15 hr (four to five times elimination t1/2). The mean steady-state levels were 25 ng/ml after 1.1 micrograms/min/kg rectally and 60 ng/ml after 0.8 micrograms/min/kg IV. The mean rectal systemic availability was 33%; the elimination t1/2s for the two routes did not differ. The results of analysis of plasma for metabolites indicate that after rectal propranolol different metabolic pathways are followed and that there is partial avoidance of first-pass elimination. The isoproterenol challenge resulted in a reproducible assessment of beta-receptor blockade that was closely related to the propranolol concentration in plasma in all subjects and for both routes of administration. With rate-controlled release of propranolol from an osmotic delivery device, the rectal route provides an alternative to intravenous infusion to achieve constant steady-state propranolol concentrations. This may be useful for research purposes or during the perioperative period in surgical patients.

Adult↗