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Biomedical subjects

U Quast

Publications and source records attributed to U Quast.

At least 109 records · Page 6Linked to original sources
PubMed1987

Effect of the K+ efflux stimulating vasodilator BRL 34915 on 86Rb+ efflux and spontaneous activity in guinea-pig portal vein.

The effect of BRL 34915 on 86Rb+ efflux and myogenic activity was studied simultaneously in guinea-pig portal vein. 86Rb+ was used as a tracer ion for K+. BRL 34915 inhibited myogenic activity with an IC50 value of 12 +/- 2 nM by reducing primarily the frequency of spontaneous contractions. Washout of the substance was followed by hyperreactivity of the vessel. 86Rb+ efflux was slightly reduced by concentrations of BRL 34915 below 100 nM; above 300 nM efflux was increased in a concentration-dependent manner. Above 10 microM BRL 34915, a slow desensitization of the effect on flux was observed during the 10 min application period of the agonist. The Ca2+ entry blocker, isradipine (PN 200-110, 200-500 nM) did not modify BRL 34915-stimulated 86Rb+ efflux at any BRL 34915 concentration tested, indicating that the influx of extracellular Ca2+ through dihydropyridine-sensitive Ca2+ channels is not necessary for this effect. However, by abolishing spontaneous activity, it allowed the 86Rb+ efflux promoting effect of BRL 34915 to be observed at a concentration of 60 nM. The K+ channel blockers tetraethylammonium and 3,4 diaminopyridine inhibited the BRL 34915-induced 86Rb+ efflux with IC50 values of 13 and 3 mM, respectively. Cell permeable derivatives of cyclic AMP and cyclic GMP had no major effect on BRL 34915-induced 86Rb+ flux, indicating that cyclic nucleotide-induced phosphorylation does not play an important modulatory role here. In conclusion, there is an at least 5 fold difference between the concentrations of BRL 34915 necessary to inhibit myogenic activity and those needed to stimulate 86Rb+ efflux. This may be explained by a primary effect of BRL 34915 on the pacemaker cells of the portal vein. explained by a primary effect of BRL 34915 on the pacemaker cells of the portal efflux. This may be

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1987

Calmodulin and troponin C as targets for drug action.

In this study, ligands from various chemical classes were investigated with respect to their relative affinities to calmodulin (CaM) and troponin C (TnC), using the fluorescent dye 3,3'-dipropylthiocarbocyanine iodide (diS-C3-5'). In parallel, functional tests were carried out determining the effects of the ligands on the CaM activated cyclic nucleotide phosphodiesterase (PDE) activity and the TnC mediated Ca-sensitivity of skinned myocardial fibres and cardiac myofibrils. The following results were obtained: 1) As a rule, most of the ligands tested had higher affinities to CaM than to TnC. 2) Even within one and the same pharmacological class (e.g. phenothiazines) the relative affinities for CaM and TnC varied considerably, trifluoperazine (TFP) or levomepromazine (LMP) showing low or no CaM specificity, methophenazine (MP) on the other hand being highly selective for CaM by a factor of more than 200. 3) In all cases tested, the functional tests were in good quantitative agreement with the binding data, showing inhibition of CaM stimulated PDE activity and Ca-sensitizing effects in concentrations corresponding well with the respective drug affinities to CaM and TnC, respectively. 4) It is concluded that a) interaction of ligands with TnC can lead to Ca-sensitization of the cardiac contractile system and a positive inotropic effect without a concomitant elevation of the intracellular level of activator Ca. This may result in a novel cardiotonic principle avoiding the common side effects of 'classical' positive inotropic agents due to Ca-overload. b) drug selectivity for TnC or CaM appears chemically achievable.

Animals↗
PubMed1987

Metofenazate as a more selective calmodulin inhibitor than trifluoperazine.

The interaction of several phenothiazines, benzodiazepines, butyrophenones, polycyclic neuroleptics and tricyclic antidepressants with calmodulin and troponin C was investigated using the fluorescent dye 3,3'-dipropylthiocarbocyanine iodide. In the presence of Ca2+, trifluoperazine (2-trifluoromethyl-10-[3-(1-methylpiperazinyl-4)propyl]-phenothiaz ine dihydrochloride, TFP), which is commonly used as a selective calmodulin inhibitor, half maximally increased the fluorescence of the complex formed of the fluorescent dye with calmodulin at a concentration of 4 mumol/l, and with troponin C at 24 mumol/l. TFP completely inhibited the calmodulin dependent stimulation of cyclic nucleotide phosphodiesterase with a Ki of 4 mumol/l and decreased the maximum Ca2+ dependent troponin C mediated activation of actomyosin ATPase by 35% at a concentration of 100 mumol/l. Metofenazate (3,4,5-trimethoxybenzoate-2-chlor-10-(3-[(beta-oxyethyl) piperazinyl-4]-propyl)phenothiazine diethanesulfonate, methophenazine, MP) produced half maximal fluorescence enhancement of the calmodulin dye complex at a concentration of 6 mumol/l and did not influence the fluorescence of the troponin C dye complex at concentrations of up to 1000 mumol/l. MP also completely inhibited the calmodulin dependent stimulation of phosphodiesterase with a Ki of 7 mumol/l but it had not effect on maximum Ca2+ stimulation of actomyosin ATPase. MP increased the Ca2+ sensitivity of skinned cardiac muscle with an about 10fold lower potency than TFP. In view of these results, we propose MP as a useful tool for distinction between processes mediated by either calmodulin or troponin C.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1986

[Tetanus vaccination--tolerance and prevention of side effects].

Data collected over a 15-year period concerning the side effects directly reported following administration of Tetanol were evaluated and it was found that the tetanus vaccination exhibited an extremely high degree of tolerance, with only 27 cases of side effects for 1 million doses. In over 80% of those cases with side effects the intolerance took the form of a painful reddening and/or swelling at the site of injection. This reaction to the vaccination, though not uncommon, was thus greater than is to be expected. General reactions, particularly malaise and an increase in body temperature, accounted for 10% of the cases reported; 3% involved skin reactions beyond the injection site. Symptoms involving the cardiac, circulatory, respiratory, locomotor, or nervous system occurred in fewer than 3 cases per 1 million doses, i.e., in fewer than 5% of the reported cases. It proved highly improbable that an allergic-anaphylactic or anaphylactoid reaction was involved and the complete picture of anaphylactic shock was never observed. Young and middle-aged adults with several tetanus pre-vaccinations accounted for the majority of side effects reported and in most cases hyperimmunization was suspected as a cause. As they were mainly restricted to the site of application and in 75% of cases occurred within 2-48 h, they can be interpreted as type III reactions (Arthus type). Furthermore it can be assumed that other causes of the reactions will have included unintentional intravascular and subcutaneous administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1986

Evidence for different receptor sites for the novel cardiotonic S-DPI 201-106, ATX II and veratridine on the cardiac sodium channel.

DPI 201-106 (4-[3-(4-diphenylmethyl-1-piperazinyl)-2-hydroxypropoxy]-1 H-indole-2-carbonitrile, DPI) is a novel cardiotonic which prolongs the open state of the cardiac sodium channel. The interactions of the sea anemone toxin ATX II and of veratridine with the active enantiomer of (racemic) DPI, S-DPI, were investigated by making electrophysiologic measurements in guinea-pig papillary muscles. The prolongation of the action potential duration (APD) by S-DPI was potentiated in the presence of ATX II, suggesting that the two agents bound to different sites. Veratridine alone increased APD slowly over 4 h. S-DPI greatly accelerated and potentiated the effect of veratridine. Conversely, veratridine increased the efficacy of S-DPI but decreased its potency, both about 4-fold. All effects were TTX-sensitive. It is concluded that the three agents bind to different sites at the cardiac Na+ channel and that these sites are allosterically coupled.

Action Potentials↗
PubMed1986

Total body irradiation in Essen--dosimetry and physical treatment planning.

Since 1975, in Essen 109 patients received total body irradiation (TBI) prior to bone marrow transplantation. About 80 patients were treated by bilateral 5.7 MeV photon beams. Three new TBI techniques were developed providing precise, homogeneous, reliable and reasonable a. p./p. a. TBI for adults and children. Systematic TBI dosimetry and the beam-zone method enable for individual treatment planning.

Acute Disease↗
PubMed1986

Bone marrow transplantation in severe aplastic anemia and acute or chronic leukemia.

In Essen 121 bone marrow transplantations were carried out. The indications were severe aplastic anemia (n = 18), acute leukemia in relapse (n = 20), acute leukemia in remission (n = 46) or chronic myeloid leukemia (n = 37). The conditioning regimen consisted of cyclophosphamide or the combination of cyclophosphamide and total body irradiation. All patients were treated under strict gnotobiotic care. To mitigate the risk of CMV infections intravenous CMV-hyperimmunoglobulin and CMV-negative blood products have been applied routinely since two years. MTX was used as prophylaxis against GVH-disease. In case of severe aplastic anemia 13 patients (72%) are still alive with a median observation time of 24 months. In the prognostically unfavourable group of acute leukemia in relapse only one patient showed long term survival. In this patient leukemic relapse occurred six years after transplantation. The survival rate of AML patients grafted during the first remission is 55% (15/27) with a median observation time of 40 months. For patients grafted in first or consecutive remission of ALL the survival rate is 42% (5/12) with a maximal observation time of 29 months. Out of 37 patients grafted because of CML, eight were in an advanced stage of the disease. 13 patients are still alive, the maximal observation time is 37 months. The overall incidence of GVHD in patients at risk was 28% in aplastic anemia, 26% in AML, 9% in ALL and 63% in CML. In aplastic anemia no patient developed an interstitial pneumonia. In leukemia the risk of fatal interstitial pneumonia was 34%.

Acute Disease↗
PubMed1986

Physical problems of total body irradiation.

In the concept of combined treatment of acute leukemias the whole body has to be irradiated as precisely and homogeneously as reasonably achieveable. In fulfillment of these radiobiological requirements, total body irradiation (TBI) means a very special challenge to medical physicists. Very large, uniform high energy photon beams have to be realized and applied. The dose at any relevant reference point has to be determined, regarding all influences of the TBI treatment situation. The dose distribution has to be modified - if necessary - verified and recorded. The lungs - the vital organs at risk in TBI - have to be shielded to tolerable doses. Optimization of TBI demands to understand all physical limitations and to utilize all technical possibilities. These physical problems encountered with TBI dosimetry, treatment planning and treatment performance are discussed.

Acute Disease↗
PubMed1986

Problems of dose modification in total body irradiation.

Physical treatment planning of total body irradiation (TBI) has the goal to optimize the spatial distribution of dose, taking radiobiological requirements and technical possibilities into account. In order to improve the dose homogeneity in the target volume or to reduce dose and dose rate in organs at risk dose modifications are needed to raise or to lower the local dose. Treatment optimization demands to know possible techniques, the methods of individual planning and calculation as well as the limitations of beam modifying aids.

Humans↗
PubMed1986

Side effects of BCG vaccination with strain Copenhagen 1331.

In the Federal Republic of Germany a BCG vaccine of strain Copenhagen 1331 is used. This vaccine was delivered with a content of 100,000 to 200,000 viable units per dose. Even in this small range one can see a relationship between spontaneously reported side effects, especially suppurated lymphadenitis in newborns. The lower the dosage the rarer the side effects. A diminution of viable units to a concentration of 100,000 to only 150,000 per dose shows a better compatibility though the conversion rate is still greater than 90%. Relevant side effects in schoolchildren or adults were not registered.

Adolescent↗
PubMed1985

DPI 201-106, a novel cardioactive agent. Combination of cAMP-independent positive inotropic, negative chronotropic, action potential prolonging and coronary dilatory properties.

The in vitro cardiac effects of DPI 201-106, a novel piperazinyl-indole, were investigated. DPI 201-106 produced concentration-dependent positive inotropic effects in guinea-pig and rat left atria, kitten, rabbit and guinea-pig papillary muscles and Langendorff perfused hearts of rabbits between 10(-7) and 3 X 10(-6) mol/l. During isometric twitches, contraction and relaxation phases were prolonged in guinea-pig left atria and right ventricular papillary muscles from kitten and guinea-pigs. Spontaneous sinus rate was decreased in right atria of guinea-pigs and rats. Coronary flow increased in rabbit isolated hearts. Functional refractory period was increased in left atria from guinea-pigs and rats with EC50 values of 1.7 and 0.24 mumol/l respectively. In electrophysiological measurements, DPI 201-106 prolonged the action potential duration (APD70) in guinea-pig papillary muscles up to 70% and in rabbit atria up to 120% at 3 mumol/l. Other action potential characteristics were not changed in guinea-pig papillary muscles but Vmax was decreased in rabbit left atria. The electrophysiological as well as the positive inotropic effects were stereoselective with the activity residing in the S-enantiomer. DPI 201-106 increased the Ca2+-sensitivity of skinned fibres from porcine trabecula septomarginalis with an EC50 of 0.2 nmol/l. DPI 201-106 dit not change cAMP levels in guinea-pig atria and rabbit papillary muscles. Slow action potentials were not induced by DPI 201-106 in partially depolarized guinea-pig papillary muscles. Phosphodiesterase activity of rat hearts was not inhibited by DPI 201-106 at pharmacologically relevant concentrations. The presence of propranolol did not influence the inotropic potency of DPI 201-106 in guinea-pig atria. In conclusion, DPI 201-106 represents a novel type of positive inotropic agents with a synergistic sarcolemmal and intracellular mechanism of action.

Action Potentials↗
PubMed1984

Stopped-flow kinetics of the interaction of the fluorescent calcium indicator Quin 2 with calcium ions.

The kinetics of the Quin 2-Ca2+ interaction have been studied using stopped-flow fluorimetry. Mixing the Quin 2-Ca2+ complex with a large excess of EGTA, EDTA or MgCl2 resulted in first order dissociation kinetics. The observed dissociation rate increased slightly with increasing EGTA concentration yielding a limiting value of 83 +/- 4 s-1 for the dissociation rate constant (k-) at pH 7.2, 37 degrees C, +/- 3mM Mg2+. The temperature dependence of the dissociation was weak (activation energy = 22 +/- 1 kJ/mol) and around neutral pH the pH dependence was negligible. The association reaction was too fast to be monitored directly. From this and the instrument dead-time, the second order rate constant k+ was estimated to be greater than or equal to 10(9) M-1s-1, in agreement with the calculation from k+ = k-/K. These data should be useful in evaluating the potential of Quin 2 to measure fast intracellular Ca2+ transients.

Aminoquinolines↗
PubMed1984

Binding of beta-adrenoceptor antagonists to rat and rabbit lung: special reference to levobunolol.

Binding of 3H-dihydroalprenolol (3H-DHA) to beta-adrenoceptors in homogenates from rat and rabbit lung was homogeneous and of high affinity (KD = 0.6 and 1.1 nmol/l at 20 degrees C; 1.1 and 2.2 nmol/l at 37 degrees C). The beta 1-selective antagonists betaxolol, metoprolol, bevantolol and acebutolol displaced 3H-DHA in a biphasic manner. From these data, the beta-adrenoceptor subtype distribution in rat lung homogenates was estimated to be 80% beta 2 (at 20 and 37 degrees C) as compared to 25% beta 2 in rabbit lung homogenates. In general, binding of beta-adrenoceptor antagonists (selective and nonselective) was slightly (less than 2 X) weaker in rabbit than in rat lung homogenates. In rat lung, binding of cardioselective beta-blockers to beta 1-receptors seemed to be more temperature-sensitive than binding to beta 2-receptors or binding of nonselective beta-blockers. Levobunolol, a potent non-cardioselective beta-blocker in pharmacological experiments, displaced 3H-DHA in a homogeneous manner (indicative of non-selectivity). In rat lung homogenates KD values were 0.8 nmol/l at 20 degrees C and 2.1 nmol/l at 37 degrees C. Similar values were found for the metabolites dihydrolevobunolol and hydroxylevobunolol. Surprisingly, d-bunolol, the dextrarotatory enantiomer of bunolol, showed a biphasic displacement curve, the fraction of high affinity sites being 83% in rat lung homogenates and 23% in rabbit lung. This ratio of sites is expected for a beta 2-adrenoceptor preferring ligand. High affinity binding (i.e. supposedly binding to beta 2-receptors) was about 50 times weaker than binding of levobunolol, in agreement with known stereospecificity of beta-adrenoceptor binding.

Adrenergic beta-Antagonists↗
PubMed1983

Modulation of [3H]muscimol binding in rat cerebellar and cerebral cortical membranes by picrotoxin, pentobarbitone, and etomidate.

Modulation of [3H]muscimol binding by picrotoxin, pentobarbitone, and etomidate was investigated in rat cerebellar and cerebral cortical membranes. In cerebellum, at 37 degrees C in the presence of chloride ions (150 mM), picrotoxin and picrotoxinin decreased specific [3H]muscimol binding to 43 +/- 3% of control, with an EC50 of 1.2 +/- 0.1 microM. [3H]Muscimol saturation experiments in the presence and absence of picrotoxin indicated that the picrotoxin effect was primarily due to a loss of high-affinity muscimol sites with KD approximately equal to 10 nM. Pentobarbitone enhanced specific [3H]muscimol binding to 259 +/- 3% of control, with EC50 = 292 +/- 37 microM, and etomidate increased binding to 298 +/- 18%, with EC50 = 7.1 +/- 1.0 microM. The influence of temperature and chloride ion concentration on these effects was investigated by comparing experiments at 37 and 0 degrees C in the presence or absence of chloride at constant ionic strength. The results indicate that studies at 0 degrees C underestimate the coupling between GABA receptors and barbiturate sites and that they greatly overestimate the importance of chloride ions in this phenomenon. In cerebral cortical membranes (37 degrees C, 150 mM Cl-), the effect of picrotoxin was similar to that observed in cerebellum, whereas the effects of pentobarbitone and etomidate were greater, but occurred at higher concentrations.

Animals↗
PubMed1982

Interaction of [3H]flunitrazepam with the benzodiazepine receptor: evidence for a ligand-induced conformation change.

The interaction of [3H]flunitrazepam with benzodiazepine receptors in rat brain homogenates was studied in the presence of 2 micro M endogenous GABA at 0 degrees at pH 7.2. Equilibrium binding experiments showed a dominant component of high affinity with an equilibrium dissociation constant K = 0.86 +/- 0.07 nM which accounted for 75% of total binding and another component of lower affinity (K = 30 nM). The dissociation kinetics of the [3H]flunitrazepam complex at the high affinity site were strictly monophasic with a rate constant Koff = (7.7 +/- 0.3 X 10(-4)/sec. The association kinetics with the high affinity sites were studied with ligand concentrations [L]0 in large excess over binding sites. The kinetics were in accordance with a single exponential with a reaction rate r-1. In the higher concentration range [L]0 greater than or equal to 10 nM, r-1 as a function of [L]0 deviated from linearity and started to level off. The data are compatible with a two-step mechanism where R and L rapidly combine to form a pre-complex RL which then slowly isomerizes to the final complex C: (see formula in text) where K1 = ([R][L]/([RL] and [RL]/[C] = k-2/k2 = k2. Nonlinear parameter estimation yielded K1 = 24.2 +/- 7.1 nM, k2 = (2.8 +/- 0.5) X 10(-2)/sec and K-2 = (9 +/- 2) X 10(-4)/sec. The isomerization step might reflect ligand-induced conformation change of the high affinity site which is involved in the potentiation of GABA-ergic transmission produced by the benzodiazepines.

Animals↗