PubMed Health⌕ Search

Biomedical subjects

M Hollmann

Publications and source records attributed to M Hollmann.

At least 55 records · Page 3Linked to original sources
PubMed1989

Cloning by functional expression of a member of the glutamate receptor family.

We have isolated a complementary DNA clone by screening a rat brain cDNA library for expression of kainate-gated ion channels in Xenopus oocytes. The cDNA encodes a single protein of relative molecular mass (Mr) 99,800 which on expression in oocytes forms a functional ion channel possessing the electrophysiological and pharmacological properties of the kainate subtype of the glutamate receptor family in the mammalian central nervous system.

Amino Acid Sequence↗
PubMed1989

Glutamate transport and not glutamate receptor binding is stimulated by gangliosides in a Ca2+-dependent manner in rat brain synaptic plasma membranes.

Crude as well as purified synaptic plasma membrane (SPM) preparations were analyzed for the influence of the ganglioside galactosyl-N-acetylgalactosaminyl-(N-acetylneuraminyl)-galactosylgluc osyl ceramide (GM1) on high-affinity binding of L-[3H]glutamate. Assayed in two different buffer systems, SPM consistently exhibited increased (40-50%) binding upon incubation with GM1 plus Ca2+, as compared to controls without GM1. Incorporation experiments with 3H-labeled GM1 proved trypsin-stable insertion of GM1 into SPM, with a maximum incorporation of four times the endogenous amount (35 nmol/mg of protein). The observed increase in glutamate binding was not due to a change in the affinity of the binding sites, but to a change in the number of binding sites, and it was absolutely dependent on the presence of Ca2+. A pharmacological profile of the GM1/Ca2+-stimulated glutamate binding is presented. The original classification of the stimulatory effect as an effect on glutamate receptor binding had to be revised to take into account the observed temperature sensitivity of the ganglioside effect, its sensitivity to high osmolarity and to ultrasonication, and the lack of binding stimulation after detergent treatment of membranes or after receptor solubilization. Vesicular space measured in both SPM preparations was found to be around 7 microliters/mg of protein, in ganglioside-treated as well as in control membranes. From the data, it is concluded that a special, Na+- and Cl- -independent form of glutamate transport into resealed membrane vesicles is stimulated by gangliosides in the presence of Ca2+.

Animals↗
PubMed1989

Metabolism of the calcium antagonist gallopamil in man.

The metabolism of gallopamil (5-[(3,4-dimethoxyphenyl)methylamino]-2-(3,4,5-trimethoxyphenyl) -2- isopropylvaleronitrile hydrochloride, Procorum, G) was studied after single administration (2 mg i.v., 50 mg p.o.) of unlabelled and labelled G (14G, 2H). TLC, HPLC, GLC, MS and RIA were used for assessment of G and its metabolites in plasma, urine and faeces. G clearance is almost completely metabolic, with only minimal excretion of unchanged drug. Metabolites represent most of the plasma radioactivity after p.o. administration. They are formed by N-dealkylation and O-demethylation with subsequent N-formylation, or glucuronidation, respectively. Compound A, derived by loss of the 3,4-dimethoxyphenethyl moiety of G is the main metabolite in plasma and urine (about 20% of the dose). This metabolite is accompanied by its N-formyl derivative (C), by the N-demethylated compound (H) and the acid (F), formed by oxidative deamination of A. Only 3 unconjugated monphenoles from several O-demthylated products showed distinct plasma levels which were nevertheless lower than metabolite A. These metabolites had no relevance to the pharmacodynamic action. Conjugated monophenolic and diphenolic products represented the major part in plasma and were excreted predominantly via the bile: they represented almost the whole faecal metabolite fraction. Less than 1% of the dose was recovered unchanged in the urine. About 50% of the dose is excreted by urine and 40% by faeces.

Administration, Oral↗
PubMed1988

Calcium ions induce glutamate transport into rat brain membrane vesicles in the absence of sodium and chloride. Evidence for a novel uptake site?

Evidence is presented that glutamate binding to rat brain synaptic plasma membranes measured in Cl(-)- and Na+-free but Ca2+-supplemented buffers is partly due to uptake of glutamate into resealed membrane vesicles. An intravesicular volume of 7.9 microliter/mg protein was measured. Ca2+-induced glutamate binding to synaptic plasma membranes was found to be sensitive to low temperatures as well as to an increase in osmolarity and was abolished by short pulses of ultrasonication. None of several glutamate receptor agonists tested discriminated between basal and Ca2+-induced binding, but 4 out of 5 glutamate uptake inhibitors did. The Ca2+-induced increase in glutamate binding was the same irrespective of whether calcium acetate, calcium sulfate or calcium gluconate in either Tris-acetate of Tris-citrate buffer was used.

Animals↗
PubMed1988

Comparative pharmacokinetics and clinical pharmacology of propafenone enantiomers after oral administration to man.

The pharmacodynamic and pharmacokinetic behavior of (R)- and (S)-propafenone was investigated in a group of seven healthy volunteers, one of whom belonged to the phenotype of poor debrisoquine hydroxylators. Each volunteer received 250 mg of either enantiomer as a solution in randomized order with a washout period of one week in between. The pharmacodynamic evaluation comprised cardiovascular parameters (HR, PQ, QRS, QT, BP) and tolerability (self-assessment questionnaire, hematology, clinical chemistry). For pharmacokinetic purposes plasma levels of the parent compounds (R, S) and their 5-hydroxylated metabolites (5-R, 5-S) were measured. As expected, there was a small but distinct increase of PQ interval with a maximum 2 h after drug intake. No difference was observed between both enantiomers tested. In the poor hydroxylator prolongation of PQ interval was less compared to extensive metabolizers, though plasma concentrations of the unchanged drug were considerably higher. Inspection of the individual concentration time profiles in the other subjects provided additional evidence that the 5-OH-metabolite also contributes to this effect. Other ECG parameters, heart rate and blood pressure remained unaffected. Both enantiomers were well tolerated: no drug-related side effects concerning general well-being and laboratory parameters were observed. In contrast to pharmacodynamic effects (on ECG) a distinct enantioselectivity of metabolic and/or distributive processes can be observed in the group of efficient hydroxylators manifesting itself in a lower clearance for R (ratio 0.50 +/- 0.19, probability of error less than 1%), in spite of a higher terminal elimination rate constant (ratio 1.64 +/- 0.63, probability of error less than 10%). This difference cannot be accounted for by the different degrees of protein binding of the enantiomers (fu(R) = 0.076; fu(S) = 0.049). The experience obtained with one poor hydroxylator seems to indicate that enantioselectivity in terms of oral clearance Cl/F might be lost in this phenotype. The distinctly lower clearance values for the poor hydroxylator when compared to the corresponding data for efficient hydroxylators, seem to be the reflection of the lower metabolic capacity of this phenotype.

Adult↗
PubMed1987

Pharmacokinetic-dynamic study on different oral biperiden formulations in volunteers.

The pharmacodynamic and kinetic profiles of two oral biperiden formulations (tablet with instant-release and sugar-coated tablet with slow-release) were studied in a total of 12 healthy subjects after the administration of a 4 mg dose and compared in part to placebo. Biperiden as slow-release formulation showed much slower absorption than the instant-release tablet; whereas plasma levels peaked as early as 1-2 h after administration of the tablet, with the slow-release formulation a first peak was seen approximately 4.5 h after intake in the majority of the subjects. In some subjects this was followed by a trough, in others by formation of a shoulder at around 0.5 ng/ml. In all subjects a peak of about 1.0 ng/ml was reached after 10-12 h. The instant-release tablet and the slow-release formulation showed comparable bioavailability. Plasma concentrations for the slow-release formulation at 24 h were around 0.5 ng/ml, about twice as high as those for the instant-release formulation. The ratio of peak to 24 h values showed the marked reduction which is characteristic for a slow-release formulation compared with the instant-release tablet. The subjective well-being of the volunteers was not influenced by the slow-release formulation, whereas after the instant-release tablet slight CNS effects (dizziness, drowsiness and fatigue) were reported up to 6 h after ingestion. Furthermore, objectively quantifiable pharmacodynamic ocular parameters (near-point accomodation, pupil size) and the secretion of saliva proved to be less affected by the slow-release formulation than by the instant-release tablet, or not affected at all.

Accommodation, Ocular↗
PubMed1986

Gangliosides modulate glutamate receptor binding in rat brain synaptic plasma membranes.

The influence of gangliosides on the binding of L-[3H]glutamate (Glu) to its receptor(s) on isolated rat brain synaptic plasma membranes was investigated in two different buffer systems using an in vitro filter binding assay. It was found that the tested pure monosialogangliosides GM1 and GM2 as well as the polysialogangliosides GT1b and GD1a enhanced binding by up to about 100%, but only in the presence of 5 mM calcium. The binding site involved was sensitive to quisqualate but insensitive to N-methyl-D-aspartate and kainate. GM1 did exert its stimulating effect by increasing the number of binding sites on the membranes whereas the receptor's affinity for L-Glu was unchanged. Regional differences in rat brain were found: while the hippocampus and cortex exhibited significant Ca/GM1-induced stimulation of Glu binding, the cerebellum was unaffected. Our results suggest modulation of at least one subtype of the Glu receptor by gangliosides.

Animals↗
PubMed1986

Pharmacokinetic and pharmacodynamic studies following the intravenous and oral administration of the antiparkinsonian drug biperiden to normal subjects.

The pharmacokinetics and pharmacodynamics (changes in pupil size and salivary flow) of biperiden following a single oral and intravenous dose were investigated in six normal subjects. After the injection plasma concentrations declined biphasically, with half-times of 1.5 h for the rapid phase and 24 h for the terminal phase. Clearance and apparent volume of distribution were high (12 ml X min-1 X kg-1 and 24 l X kg-1 respectively). Absorption was rapid but the systemic availability was incomplete (33%), probably due to first-pass metabolism. Central nervous system (CNS) adverse effects and changes in pupil size were observed after both routes of administration while salivary flow was affected only by the injection.

Administration, Oral↗
PubMed1985

Monoclonal antibody-defined circulating human tumor-associated antigen with epitope shared by cytokeratins.

Sera of human colonic carcinoma xenografted rnu/nu rats were used to immunize rnu/+rats in order to obtain an immune response against circulating human tumor-associated components. After fusion of rat spleen cells with mouse myeloma cells monoclonal antibody MAB 108 could be established which reacted with two 40 and 45 kD cytokeratins as well as with vimentin, with a soluble 37 kD protein apparently derived from the 45 kD protein and with a 37 kD protein released by tumor cells. The MAB 108-specific epitope was also detected in tissue polypeptide antigen (TPA), a human tumor-associated antigen originally described by Björklund et al. (22).

Animals↗
PubMed1984

Biperiden effects and plasma levels in volunteers.

The pharmacokinetics of biperiden was studied and compared with pharmacodynamics (pupil size, accommodation, self-rating mood scale) in 6 healthy volunteers. A single-blind cross-over design was employed with placebo and biperiden (4 mg as commercially available tablets). After a lag time of 0.5 h, biperiden was rapidly absorbed with a half-life of 0.3 h, plasma peak levels of 5 ng/ml being reached after 1.5 h. Biperiden showed good tissue penetration (distribution half-life 0.6 h; ratio of total to central distribution volume 9.6), the terminal half-life time of plasma concentration was 18 h, and the oral clearance was 146 l/h. The pharmacodynamic maximum lagged behind the plasma peak concentration by 1 (self-rating) to 4 h (accommodation).

Accommodation, Ocular↗
PubMed1984

Simultaneous determination of propafenone and 5-hydroxypropafenone in plasma by means of high pressure liquid chromatography.

A high pressure liquid chromatographic (HPLC) method with internal analogue standardization for the simultaneous determination of propafenone and 5-hydroxypropafenone in plasma is described. The method comprises extraction from plasma at pH 9 with toluene/dichloromethane/isopropanol, derivatization with dansylhydrazine and subsequent elimination of fluorescent byproducts via silica gel disposable columns followed by quantification by means of fluorescence detection after HPLC separation using a normal phase. With a sample volume of 1 ml the lower limit of detection for propafenone and 5-hydroxypropafenone is approximately 0.2 ng/ml, the limit of determination (precision limit 10%) is approximately 1 ng/ml. The variation coefficients decrease from approximately 10% in the low range to 6-9% for propafenone and 3-7% for 5-hydroxypropafenone at 2 ng/ml and above. For both substances a mean weighted relative error of 6% has to be expected.

Adrenergic beta-Antagonists↗
PubMed1983

Beta-blocking and electrophysiological effects of propafenone in volunteers.

The chemical structure of propafenone (P) and certain experimental findings suggest that this antiarrhythmic compound could possess beta-blocking properties. To evaluate the clinical relevance of the latter cardiovascular effects of P during exercise were studied. After oral administration of P 150 and 300 mg in solution, six healthy volunteers were subjected to graded exercise. These doses of P, which are usually effective against arrhythmias, decreased exercise-induced tachycardia, whereas the systolic blood pressure was lowered but only at rest, and the diastolic pressure was slightly raised. However, taking into account dose ratio, and the intensity and duration of the reduction in exercise tachycardia, this effect of P was only about 5% at its maximum compared to propranolol and similar active beta-blocking compounds. The reduction in heart rate produced by P was not correlated with the plasma level nor did it show dose dependency, in contrast to beta-blocking agents, and also in contrast to its electrophysiological effects on the PQ interval.

Adult↗
PubMed1983

Investigations on the pharmacokinetics of propafenone in man.

The pharmacokinetics of propafenone (Rytmonorm) was studied in 19 healthy volunteers. Propafenone was given intravenously (commercial ampoules of 70 mg) and orally in different doses (150, 300, 450 mg) and forms (solution, commercial film tablets). The results show a dose dependence of bioavailability and maximum plasma concentrations after oral application with over-proportionate increase at higher dose levels yielding bioavailabilities up to 40-50% with single applications of 450 mg. This is interpreted as saturability of a presystemic mechanism during invasion (most probably of the metabolizing enzyme systems of the liver). The mean rate constant of elimination after intravenous application is beta = 0.28 h-1 (95% confidence limits: 0.24-0.33 h-1) corresponding to a half-life of 2.5 h. There are no significant differences in these values after oral application and different dosages. The total plasma clearance of 1.0 1/min (95% confidence limits: 0.9-1.1 1/min) is almost exclusively metabolic. After 12 days of oral dosing (2 tablets of 150 mg propafenone daily) no statistically significant changes of kinetic parameters could be demonstrated although with some volunteers the total clearance decreased. It is considered that in some persons with relatively low clearance the plasma concentrations may reach levels at which a saturation of enzymatic reactions of metabolism may become relevant even after application of such low single doses as 150 mg.

Administration, Oral↗
PubMed1983

The pharmacokinetics of ameziniummetilsulfate in man. Single and repetitive oral administration of a therapeutically effective dose.

The pharmacokinetics of the antihypotensive drug 4-amino-6-methoxy-1-phenyl-pyridazinium methyl sulfate (ameziniummetilsulfate, LU 1631, Regulton), in the following briefly called amezinium, has been investigated in 8 healthy volunteers. Plasma concentrations were determined by means of a high pressure liquid chromatographic method after single oral administration of a therapeutic dose (10 mg), during repetitive dosing (10 mg b.i.d., 13 days) and following the last dose. The results demonstrate for amezinium rapid absorption (half-life about 0.6 h), good tissue penetration (distribution) with about 3.0 h half-life and comparably slow elimination (half-life about 12.0 h). Considering the results before and after multiple dosing and those of earlier studies (using higher dosages), none of the kinetic parameters showed any indication of dose dependency or changes by chronic dosing. These properties and the characteristics of amezinium with respect to absorption, bioavailability and elimination are considered favourable for safe and effective handling of the drug.

Adult↗
PubMed1980

Chemotherapeutic-bacteriological interdependences observed by use of a clinical anti-infective drug monitoring system.

The relationships between the extent and type of clinical antibacterial chemotherapy and bacteriological findings were investigated, both retrospectively and contemporaneously, by study of pharmacy deliveries and analysis of patient records and the results of bacteriological examination of urine. Initially, with a high proportion of tetracycline use and relatively little of ampicillin, co-trimoxazole and cephalosporins, E. coli was frequently found and seldom Klebsiella/Enterobacter; the in-vitro efficacy of tetracyclines was low against all bacteria tested. Deliberate restraint in the use of tetracyclines and promotion of co-trimoxazole as well as a spontaneous rise in ampicillin use, were correlated with a decrease in E. coli and increase in Klebsiella/Enterobacter. The in vitro susceptibility of Klebsiella to all the chemotherapeutics tested was relatively low, but it improved markedly after use of cefuroxime was begun. This resulted in a decrease in the incidence of Klebsiella/Enterobacter in urine specimens. Restraint in tetracycline usage was accompanied by an increase in its in vitro efficacy against E. coli. The study shows that continuous monitoring of antibacterial chemotherapy under routine conditions enables the clinical pharmacologist to recognize transient and locally specific circumstances and to define guidelines or corrective recommendations as a basis for and to aid control of real therapeutic decisions.

Anti-Bacterial Agents↗