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Biomedical subjects

U Klotz

Publications and source records attributed to U Klotz.

At least 19 recordsLinked to original sources
PubMed1992

Characterization of peripheral-type benzodiazepine binding sites on human lymphocytes and lymphoma cell lines and their role in cell growth.

Peripheral-type benzodiazepine binding sites (PBRs) are ubiquitous in mammalian tissues. However, the physiological role of PBRs has not yet been clarified. In this study we characterized a saturable and high affinity binding site for [3H]Pk 11195 (isoquinoline carboxamide derivative) on human lymphocytes and different lymphoma cell lines. Binding parameters of the human T-lymphoma cell line CCRF-CEM came closest to values for lymphocyte binding. Thus, the CCRF-CEM cell line appears to be a suitable lymphocyte cell model for further study of PBRs. To evaluate the pharmacological specificity of binding to human lymphocytes and CCRF-CEM cells we investigated the potency of different ligands to displace [3H]Pk 11195 from its binding site. Pk 11195 was found to be the most potent inhibitor followed by 4'-chlorodiazepan (Ro5-4864) and diazepam (range of inhibition constants from 6.7 x 10(-9) M to 3.6 x 10(-7) M), whereas ligands specific for the central-type receptor like clonazepam and flumazenil had no displacing potency in the tested concentration range (10(-10)-10(-4) M). Since it was assumed that PBRs might be involved in the regulation of cell growth and differentiation, we studied the influence of PBR ligands on cell growth and survival using a quantitative colorimetric assay (MTT). Ligands which bind selectively to PBRs inhibited cell multiplication in vitro. However, half-effective concentrations (EC50) were in the micromolar range and above therapeutic in vivo concentrations (range of EC50 values from 2.4 x 10(-5) M to 1.5 x 10(-4) M). Clonazepam and flumazenil had no inhibiting potency in the tested concentration range (10(-10)-10(-4) M). Although the difference between values for displacing potency and ability to inhibit cell multiplication cannot be explained as yet, it is interesting that all PBR-ligands followed the same sequence in displacing [3H]Pk 11195 and inhibiting cell multiplication and that central type ligands were ineffective in both assays. This association suggest a mediating role of PBR binding in cell growth.

Adult↗
PubMed1992

Glucuronidation of drugs. A re-evaluation of the pharmacological significance of the conjugates and modulating factors.

Glucuronides of drugs are considered to be generally inactive and rapidly eliminated. Therefore, these metabolites are often not taken into account in evaluating drug effects. The present review describes examples of both direct and indirect contributions of glucuronides to net drug effects. Multiple lines of evidence indicate that morphine-6-glucuronide has analgesic activity. This compound has a high affinity to the mu-receptor, is capable of penetrating the blood/brain barrier and is a potent analgesic after administration to patients. Indirect activity of glucuronides may consist of a systemic cycle in which an active parent compound is derived from the glucuronide by enzymatic action. Such systemic cycling has been demonstrated for clofibric acid. In addition, some acyl glucuronides are subject to intramolecular rearrangement and the resulting metabolites are resistant to beta-glucuronidase. Covalent protein binding of glucuronides by different mechanisms may contribute to drug toxicity and immune responses. If glucuronides are accepted as potential modifiers of net drug action it is important to determine what factors modulate disposition of these compounds. Therefore, the later section of this review describes glucuronidation under different pathophysiological conditions. Examples for alterations of the rate and/or extent of glucuronidation by concurrent diseases processes, age and coadministration of other drugs are provided.

Age Factors↗
PubMed1992

A method to simultaneously investigate histamine-induced cyclic AMP and aminopyrine accumulation in isolated gastric mucosal cells from human biopsies.

A method has been developed to simultaneously measure two parameters of histamine-induced gastric secretion, cyclic AMP and aminopyrine accumulation, in gastric mucosal cells from human biopsies. Histamine stimulated cyclic AMP and aminopyrine accumulation with different time courses. Cyclic AMP production reached a maximum at 30 min, whereas maximal aminopyrine accumulation was obtained after the cells had been incubated for 90 min in presence of 100 mcM histamine. Histamine was more potent in stimulating aminopyrine than cyclic AMP accumulation. The ED50 values for histamine-induced aminopyrine accumulation were estimated to be 0.88 +/- 0.02 and 25.53 +/- 8.75 mcM for cyclic AMP production, respectively. The aminopyrine accumulation was more than half-maximally increased at 1 mcM histamine without significant effects on the cyclic AMP basal level. It remains to be elucidated whether this finding indicates, besides cyclic AMP, the involvement of calcium in histamine stimulus. The histamine H2-receptor antagonists cimetidine and ranitidine inhibited both in vitro parameters, whereas the gastric proton pump inhibitor omeprazole only affected aminopyrine accumulation. Our method might be a valuable tool for in vitro pharmacological and clinical investigations on histamine-induced gastric secretion in human biopsies.

Adult↗
PubMed1979

Alterations in the disposition of differently cleared drugs in patients with cirrhosis.

We have compared the disposition of antipyrine orally (15 mg/kg) and the new antiarrhythmic drug lorcainide intravenously (1.5 mg/kg) in 8 patients with alcoholic cirrhosis. Antipyrine (AP) serves as a model drug for drugs which are eliminated independently of liver blood flow and lorcainide (L) elimination as a model for drugs which depend on liver blood flow. Since in healthy subjects elimination half-life (t 1/2) of L increased with age (r = 0.68, p less than 0.01) due to parallel change in the volume of distribution (r = 0.52, p less than 0.05), its disposition had to be compared to age-matched controls. Elimination of both AP and L was impaired in cirrhotic patients, expressed either in terms (mean +/- SD) of t 1/2 (AP = 26.8 +/- 15.0 hr and 12.3 +/- 1.8; L = 12.5 +/- 4.5 hr and 7.7 +/- 2.2 hr, p = 0.002) or of clearance (Cl) (AP = 21.9 +/- 7.9 ml/min and 41.7 +/- 5.5 ml/min; L = 814 +/- 144 and 1002 +/- 304 ml/min, p = 0.06). While the alterations in plasma Cl were great for AP, they were smaller for L. This suggests that elimination of drugs in cirrhotic patients is associated with relatively more impairment of enzyme activity than of hepatic blood flow. The slightly decreased Cl of L in patients with alcoholic cirrhosis would suggest that L should be carefully handled in patients with dysfunction of the liver.

Acetanilides↗
PubMed1979

Effect of age on levels of diazepam in plasma and brain of rats.

The pharmacokinetics and distribution in brain and cerebellum of diazepam after a single dose were studied in middle aged (6 months) and old (18 months) rats. Following the single intravenous bolus of 5 mg/kg diazepam was eliminated more slowly in old rats (T 1/2 (beta) = 3.1 H) than in middle aged rats (1.4H). This was due to an increase in the apparent volume of distribution Vd beta from 11.0 l/kg (control rats) to 29.5 l/kg. Concentrations of diazepam in brain and cerebellum were in the same range (0.5-1.1 ng/mg) in both groups after this dose. We conclude that the distribution of diazepam is age-dependent which might be due to an altered body composition.

Aging↗
PubMed1979

Disposition and antiarrhythmic effect of lorcainide.

The disposition and the antiarrhythmic effect of lorcainide (R 15,889) were investigated in 11 patients with ventricular premature beats (VPB) after a single intravenous dose of 100 mg or 2 mg/kg and after multiple intravenous and oral dosing. Pharmacokinetic parameters were computed according to the two-compartment open model. The half-life of the initial phase, t 1/2 (alpha), was calculated as 0.3 +/- 0.1 hr (mean +/- SD) and the terminal half-life, t 1/2 (beta), varied independently of the dose and route of administration between 5.8 and 12.5 hr (7.8 +/- 2.5 hr). After the single intravenous dose total plasma clearance (Cl) ranged from 570 to 1670 ml/min (988 +/- 425 ml/min) while after multiple dosing Cl decreased to 666 +/- 27 ml/min. Comparison of the area under the curves during steady state (ss) indicated a complete bioavailability of multiple oral doses. After the single intravenous dose, VPB were diminished or reduced for about 4 hr if the plasma concentrations exceeded 120 to 150 ng/ml. During ss-therapy plasma levels fluctuated between 200 and 550 ng/ml with an effective prevention of arrhythmias. Thus, the new drug demonstrates a therapeutic range of approximately 150 to 400 ng/ml and oral therapy seems to be effective with 100 mg t. i. d.

Acetanilides↗
PubMed1978

[Clinical pharmacokinetics of diazepam and its biologically active metabolites (author's transl)].

The pharmacokinetics of diazepam and its biologically active metabolites desmethyldiazepam and oxazepam is critically evaluated from a clinically relevant point of view. The slow elimination of diazepam is dependent on the degree of plasma protein binding, the duration of the medication, the age and the liver function of the patient. While the normal half-life (T1/2(beta)) varies between 1 and 2 days, it can be increased to up to 80--100 h in subjects over 60 years of age. In patients with liver disease T1/2(beta) is about doubled, which is caused by a reduction (factor 2) of the normal hepatic clearance of 26 ml/min. After subchronic treatment with diazepam the elimination rate is reduced about 20--70% in healthy subjects, but liver patients exhibit only a slightly further prolongation in T1/2(beta). The major metabolite desmethyldiazepam has a T1/2(beta) of 51 h and a Cl of 11 ml/min and accumulates after multiple doses of diazepam since its elimination is much slower than that of its parent compound. The elimination of this drug is also impaired (factor 2) in patients with liver disease. In contrast to these findings oxazepam is excreted as glucuronide in the urine relatively fast and independently of the liver function with a T1/2(beta) of 5.5 h and a Cl of 130 ml/min.

Biotransformation↗
PubMed1978

The bioavailability of alpha-acetyldigoxin from Card-Hydergin--a fixed combination of Hydergine and acetyldigoxin.

In six healthy volunteers the bioavailability of alpha-acetyldigoxin in solution and tablet form was compared with a tablet which in addition to alpha-acetyldigoxin contained the DH-ergot alkaloid Hydergine in identical galenic formulation. After a single dose, bioavailability was measured from the areas under the plasma level time curves and from the cumulative amount of digoxin excreted into the urine. The addition of Hydergine did not change the plasma level/time profile and the bioavailability of alpha-acetyldigoxin. When this parameter was compared to the solution, a relative bioavailability of approximately 80% could be calculated for both tablets. Relating this data to a previously published infusion experiment, their absolute bioavailabilities amounted to about 70%.

Adult↗