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Biomedical subjects

H J Dengler

Publications and source records attributed to H J Dengler.

At least 37 records · Page 2Linked to original sources
PubMed1987

Chromosomal assignment of human cytochrome P-450 (debrisoquine/sparteine type) to chromosome 22.

In order to determine on which chromosome the gene controlling human cytochrome P-450 (debrisoquine/sparteine type) is located a linkage study of polymorphic sparteine oxidation (PSO) to various polymorphic markers was carried out. Positive information for linkage between PSO and the P1 blood group was obtained with a maximal LOD-score of LOD = 3.35 for both male and female recombination fraction estimates of theta m = theta f = 0.0. The P1 blood group has been recently mapped to the long arm of chromosome 22. Thus it can be concluded that the gene controlling human cytochrome P-450 (debrisoquine/sparteine) is situated on the long arm of chromosome 22 in close vicinity to P1.

Alleles↗
PubMed1987

Evidence for polymorphic oxidation of sparteine in Japanese subjects.

The metabolism of sparteine which exhibits a genetic polymorphism in Caucasians was studied in 84 unrelated Japanese subjects. In contrast to a recent study where debrisoquine was used as a probe and no poor metabolizers could be observed in Japanese involving 100 subjects, two subjects had a urinary metabolic ratio of sparteine greater than 20 and thus were poor metabolizers of sparteine. The incidence of poor metabolizer phenotype of sparteine oxidation of 2% seems to be lower in Japanese as compared with various Caucasian populations where 5 to 10% are poor metabolizers of sparteine. However, this is not conclusive, because the 95% confidence interval of the observed frequency, 0.6 to 8%, covers the range reported in the literature for Caucasians.

Adult↗
PubMed1987

FcR-mediated clearance in thrombopenic and non-thrombopenic patients with hemophilia A and possible relation of thrombopenia to HIV seropositivity.

As morbidity of thrombopenia in hemophilia A patients is increasing, the pathogenetic influence of the reticuloendothelial system (RES) was measured using autologous anti-Rh0(D)-coated erythrocytes (EA) in 17 patients with or without thrombopenia. Mean survival of EA in patients was reduced to 53% of healthy controls (53.2 +/- 46.1 min vs 100.5 +/- 12.2 min; patients vs controls, mean +/- S.D.). Survival of EA was not significantly different either in thrombopenic vs non-thrombopenic nor anti-HIV (human immunodeficiency virus) positive vs negative patients. Thrombopenia, elevated serum IgG and circulating immune complexes were related to the presence of anti-HIV antibodies. EA survival was also decreased in the absence of anti-HIV antibodies. This indicates activation of RES by a mechanism different from retroviral infection by HIV (1).

Acquired Immunodeficiency Syndrome↗
PubMed1986

Immunomodulating properties of the uremic pentapeptide H-Asp-Leu-Trp-Glu-Lys-OH in vitro.

A pentapeptide originally isolated by Abiko and coworkers from the ultrafiltrate of a uremic patient was synthesized and studied for its in vitro effects on normal human peripheral blood mononuclear cells. The SRBC-rosette forming capacity of T cells was significantly reduced after preincubation of the cells with the peptide, whereas the viability and the percentage of SRBC-receptor positive cells as determined with a monoclonal antibody remained unchanged. The PHA and ConA induced proliferation of T cells as well as the induction of suppressor cells by ConA were decreased, while the proliferative responses to PWM and specific antigens were enhanced. MLC experiments with separated and reconstituted lymphocyte populations pointed to the T cell as the main target. The data presented demonstrate that at least some of the effects described for so-called middle molecules are reproducible with this peptide at concentrations eventually occurring in patients with chronic renal failure.

Dose-Response Relationship, Drug↗
PubMed1985

In vitro--in vivo correlation of dissolution, a time scaling problem? Transformation of in vitro results to the in vivo situation, using theophylline as a practical example.

Two principal approaches to demonstrating the continuous in vivo relevance of an in vitro dissolution test are outlined. The first uses the convolution technique to predict the concentration-time course in vivo; the second uses deconvolution as a mathematical tool to estimate the in vivo dissolution profile. The weighting function must be known to utilise either technique. Defined by the aim of the analysis the dose-normalized response to the oral solution is regarded as the weighting function (Impulse Response). In both cases the essential step is continuous comparison of the predicted time dependent data with actual readings of the same class. To permit the prediction of concentration-time data from in vitro dissolution data the basic equations for the transformation of the time base from in vitro to in vivo conditions are developed. The transformation is essential, since one cannot assume that the time scales for the in vitro and the in vivo experiment are definitely the same. The estimated in vivo dissolution profile using the deconvolution technique gives a hypothetical image of the true in vivo dissolution curve. Comparison with in vitro dissolution test results, using one of the equivalence testing procedures, reveals how closely and for how long the in vitro dissolution test simulates the in vivo dissolution process. For the formulation of theophylline studied, equivalence of the in vitro and the estimated in vivo dissolution profiles was not confirmed for the entire period of observation, but it was demonstrated for approximately the first 5 h. The later inequivalence is not due to possible non-linear or time-dependent kinetics of theophylline. There is a discussion of whether a change in pH, agitation of the formulation, diffusion conditions or the absorption rate constant along the gastrointestinal tract might explain the biphasic linear correlation of the in vitro and in vivo data observed.

Adult↗
PubMed1983

Endogenous ligand(s) decrease drug--protein binding in uremic sera: a fluorescence probe study.

Human serum albumin (HSA) was isolated and purified (greater than 97% purity) from normal sera, from sera of patients with severe chronic renal insufficiency and from sera to which a strongly protein bound acidic drug--clofibrinic acid--was added as a model ligand. The binding properties were evaluated using dansylglycine as a fluorescent probe. Data were analyzed according to Scatchard, the binding constants were calculated by least square approximation. The binding of dansylglycine to HSA from uremic sera was substantially decreased, reflected mainly by a lower product n1 . K1, as was the binding of dansylglycine to HSA from model sera containing clofibrinic acid. The binding was restored to almost normal when HSA was treated with charcoal. It is concluded that the impaired binding of many mostly acidic drugs to HSA in uremia is due to the presence of endogenous ligands. In addition a minor contribution by changes in HSA structure cannot be excluded.

Adult↗
PubMed1982

[Incidence of hepatotoxic side effects during antituberculous therapy (INH, RMP, EMB) in relation to the acetylator phenotype (author's transl)].

In 95 patients with active tuberculosis, we investigated in a prospective study the influence of the acetylator phenotype on the hepatotoxic side effects of the antituberculous regimen isoniazid (INH) 10 mg/kg, rifampicin (RMP) 10 mg/kg, and ethambutol (EMB) 25 mg/kg. Besides a much higher incidence of isoniazid hepatitis (SGOT, SGPT greater than 200 U/l) in 12.6% of patients treated--as compared to the incidence reported in large chemoprophylaxis trials with isoniazid monotherapy in the range of 0.5%-1% (IUAT 1969, U.S.P.H.S. 1971)--we observed a significant, higher risk of isoniazid-induced hepatotoxicity in slow acetylators (p less than 0.01): in 26 of 56 slow acetylators (= 46.4%), but only in 4 of 30 rapid acetylators (=13.3%) were transaminases in the serum elevated greater than 50 U/l. The 12 patients with the most severe hepatotoxic side effects (SGOT, SGPT greater than 200 U/l) were all slow acetylators. Women developed severe hepatic injury more often than men (p less than 0.05). In cases with isoniazid hepatitis, triple therapy was either stopped or reduced to a combination RMP, EMB. In cases with less severe liver injury, triple therapy was continued. In all patients transaminases normalized within 2-4 weeks. On return to full triple therapy, none of the patients developed new elevation of transaminases. The constant occurrence of isoniazid hepatitis during the 2nd-4th week (19 +/- 7 days) as well as the normalization without any new hepatotoxic reaction suggest that there may be an interaction between RMP and isoniazid metabolism limited to the early phase of chemotherapy.

Acetylation↗
PubMed1982

Dihydroergotamine increases the bioavailability of orally administered etilefrine.

Etilefrine undergoes considerable first-pass metabolism through conjugation in the gut wall. In six volunteers bioavailability was reduced to 35% for a fast release tablet and to 17% for a sustained release preparation. The addition of dihydroergotamine (DHE) to the sustained release preparation surprisingly increased bioavailability to 61%. The plasma levels of the main metabolite formed during the passage through the gut wall indicated an increase in the rate of enteric absorption and therefore also in bioavailability by DHE. This might be due to the influence of DHE upon the vascular resistance of the vessels in the gut wall or a change in gastro-intestinal motility with a prolongation of drug contact time within the absorbing gut segment.

Administration, Oral↗
PubMed1982

Diazepam absorption: effects of age, sex, and Billroth gastrectomy.

The kinetics of diazepam absorption were assessed in 37 healthy volunteers, aged 19--79 years, who ingested a single 5-mg tablet in the fasting state. Diazepam plasma concentrations were measured by gas chromatography in multiple samples drawn over the next 72 hr. After a lag time averaging 12 min elapsed between tablet ingestion and the start of absorption, first-order absorption proceeded with a mean half-life of 19 min (range: 0--96 min), with peak plasma concentrations reached 0.9 hr after dosage (range: 0.25--2.5 hr). Age and sex did not influence absorption kinetics. Peak plasma concentrations averaged 157 ng/ml, and tended to be higher in women than in men because of lower body weights in women. Peak levels also declined with age, probably due to increased volume of distribution of diazepam in the elderly. Absolute systemic availability of oral diazepam was evaluated in seven of the subjects who received intravenous diazepam on another occasion. Based on areas under the oral versus intravenous plasma concentration curve, bioavailability of diazepam averaged 97%. Six male patients, at least 2 years after undergoing Billroth gastrectomy, also participated in the diazepam absorption study. Absorption kinetic parameters were nearly identical to those in six healthy age-matched male volunteers without gastrointestinal disease. Thus absorption of oral diazepam in the fasting state is rapid and nearly complete, and is minimally influenced by age, sex, or Billroth gastrectomy.

Administration, Oral↗
PubMed1981

Clinical implications of serum digoxin concentrations.

Factors influencing serum digoxin concentrations, and the relation of these levels to classical electrocardiographic (ECG) and clinical manifestations of toxicity, were assessed in a series of 463 consecutively hospitalized patients of mean age 58 years. The majority of patients were receiving beta-acetyldigoxin or beta-methyldigoxin. Age, sex, creatinine clearance, and weight-corrected dose collectively explained less than 7% of overall variability in serum digoxin concentrations; creatinine clearance, which declined significantly with age (r=-0.36, p less than 0.001) was the most important of these determinants. ST-segment depression was present in the majority of patients and became more common at higher serum digoxin concentrations. However, PR interval, QRS durations, QT interval, or the presence of AV block were not associated with serum levels. Among 75 patients with atrial fibrillation, ventricular rate did not decline with increasing digoxin concentrations. The presence of gastrointestinal, neuromuscular, or psychiatric symptoms classically attributed to digitalis toxicity was not associated with serum digoxin concentration. Serum levels of digoxin appear to be of limited value in assessing the degree of digitalization.

Acetyldigoxins↗
PubMed1981

[The Bonn Cooperative Tumor Aftercare Model. A contribution to the amelioration of tumor patient care in the practitioner's office (author's transl)].

Problems of aftercare of tumor patients are so involved that one doctor cannot cope with them single-handed. Every doctor who has care of tumor patients is dependent on the cooperation of doctors of various faculties as with scarcely any other disease. The experience of a specialized multidisciplinary medical team is as indispensable in aftercare as the general medical supervision of the family doctor. In an action financed by the Federal Minister of Health a cooperative model was worked out intended to enable a qualitatively high level of aftercare for tumor patients over a wide field, making full use of the existing medical welfare structure.

Aftercare↗
PubMed1981

Superiority of stable isotope techniques in the assessment of the bioavailability of drugs undergoing extensive first pass elimination. Studies of the relative bioavailability of verapamil tablets.

Although the absorption of verapamil is almost complete after oral administration, its bioavailability is low due to extensive hepatic first-pass metabolism. Besides large interindividual differences in first-pass metabolism, pronounced day-to-day intraindividual variations in first-pass metabolism are observed, leading to erroneous results in relative bioavailability studies. Stable isotope techniques, which permit simultaneous administration of a solution and a tablet, can successfully be used to overcome these difficulties. The method has the advantage that two experiments can be carried out in a single test. Furthermore, the number of subjects required in bioavailability studies can be greatly reduced. Using this technique the bioavailability of verapamil tablets (Isoptin 80) relative to a stable labelled solution of verapamil was found to be 108.1%, with a 95% confidence interval between 89.1 and 127.1%.

Adult↗
PubMed1981

Simultaneous determination of the intravenous and oral pharmacokinetic parameters of D,L-verapamil using stable isotope-labelled verapamil.

Following i.v. administration, the plasma concentration-time curve of verapamil could best be described by either a mono- or biexponential equation. Total plasma clearance (1.26 1/min) approached liver blood flow (1.51/min), so it can be concluded that its clearance is liver blood flow-dependent. Although absorption was almost complete after oral administration, absolute bioavailability (20%) was low, due to extensive hepatic first-pass metabolism. The approach using stable isotope-labelled and unlabelled drug permits simultaneous administration by the intravascular and extravascular routes, thus allowing determination of absolute bioavailability in a single experiment.

Administration, Oral↗
PubMed1981

Diazepam interaction with antituberculosis drugs.

The influence of antituberculosis drugs on diazepam disposition was assessed in a series of volunteers and patients who received single intravenous doses of diazepam. In study 1, nine healthy subjects received diazepam in the drug-free control state and again during treatment with isoniazid (INH), 180 mg/day. INH did not alter diazepam volume of distribution (Vd) or protein binding, but prolonged mean elimination half-life (t1/2) from 34 to 45 hr (p less than 0.02), and reduced total clearance from 0.54 to 0.40 ml/min/kg (p less than 0.02). In study 2, diazepam disposition in a group of seven tuberculous patients on triple therapy with INH, ethambutol (EMB), and rifampin (RIF) was compared with that in healty drug-free controls matched for age and sex. Diazepam Vd and protein binding were nearly identical between groups, but mean t1/2 among patients (14 hr) was significantly shorter than in controls (58 hr, p less than 0.01) and total clearance correspondingly increased (to 1.50 from 0.37 ml/min/kg, p less than 0.01). Study 3 compared six newly diagnoses tuberculous patients receiving initial therapy with EMB alone with age- and sex-matched controls. Diazepam unbound fraction in patients tended to be higher than in controls, and diazepam Vd and clearance tended to be lower but the differences were not statistically significant. Thus, diazepam clearance is impaired and t1/2 prolonged by administration of INH alone. Markedly increased clearance and shortened t1/2 in triple-therapy patients is probably due to enzyme-inducing effects of RIF. Dosage of diazepam may require adjustment in patients with tuberculosis on chemotherapy.

Adult↗
PubMed1981

Diazepam kinetics in relation to age and sex.

27 male volunteers aged 20 to 91 years, and 13 female volunteers aged 21 to 33 years, received single 5 to 10 mg doses of diazepam intravenously. Diazepam pharmacokinetics were determined from concentrations measured in multiple plasma samples drawn during 7 days after each dose. Diazepam elimination half-life among males (mean: 66 h) increased significantly with age (r = 0.53, p less than 0.005). Volume of distribution (mean: 1.39 liters/kg) also increased significantly with age (r = 0.67, p less than 0.001). Clearance of total diazepam in males (mean: 0.42 ml/min/kg) tended to decline with age (r = 0.32), but the association was of borderline significance (p = 0.1). Diazepam was extensively bound to plasma protein, with a mean free fraction among male subjects of 1.34%. Free fraction tended to increase with age (r = 0.14). Correction of volume of distribution and clearance for individual differences in binding did not alter the conclusions. Compared to young males, young females had larger volumes of distribution (1.87 vs. 1.34 liters/kg) and higher total clearance (0.63 vs. 0.49 ml/min/kg). These differences were even greater after correction for sex-related changes in protein binding. Elimination half-life did not differ between sexes. Since both age and sex can influence diazepam disposition, both should be considered as independent variables in studies of diazepam pharmacokinetics.

Adult↗
PubMed1981

HPLC determination of antipyrine metabolites.

A high-performance liquid chromatography method is described which allows for the simultaneous determination of antipyrine, 4-hydroxyantipyrine, norantipyrine and 3-hydroxyantipyrine. Hydrolysis conditions with respect to source glucuronidase, amount of glucuronidase, pH of incubation and addition of antioxidant to the incubation medium proved to be very critical for norantipyrine and to a lesser extent 4-hydroxyantipyrine. The method is of good sensitivity, accuracy and reproducibility. Thus, the method is well suited for detailed metabolic studies.

Antioxidants↗