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Biomedical subjects

B Lemmer

Publications and source records attributed to B Lemmer.

At least 127 records · Page 7Linked to original sources
PubMed1989

Circadian rhythm of the in vitro stimulation of adenylate cyclase in rat heart tissue.

Adenylate cyclase activity in rat heart ventricles displayed a circadian rhythm with a maximum around 8:00 h and a minimum around 20:00 h. In vitro stimulation with 0.1 mM of isoprenaline, Gpp(NH)p or forskolin increased the 24-h-mean basal adenylate cyclase activity by 1.7-, 2.7- and 10.7-fold, respectively. The magnitude of the drug-induced stimulation varied significantly with the time of day. However, the drugs did not affect the timing of the circadian maximum or the amplitude (as % of 24-h-mean) of the basal rhythm. The data are the first to show that the response to the in vitro stimulation of the cardiac adenylate cyclase also displays a pronounced circadian rhythm.

Adenylyl Cyclases↗
PubMed1989

Circadian changes in stimulus threshold and in the effect of a local anaesthetic drug in human teeth: studies with an electronic pulptester.

An electronic pulptester with constant testing current was used to study the stimulus threshold in human teeth of 28 healthy volunteers and the duration of local anaesthesia by articaine plus epinephrine in 55 patients with caries who underwent a filling therapy. In 21 out of the 28 volunteers, significant daily variations in stimulus threshold were detected by cosinor analysis. Acrophases, however, were scattered over the 24-hr scale. In patients, the local anaesthetic effect was studied at four different times of day (0800, 1100, 1400 and 1700 hr). The electronic device allowed one to accurately determine the time to peak effect (Tmax), duration of effect (Emax, time to return to baseline threshold (Tret) and the area under the time-effect curve (AUC) as a measure of the total local anaesthetic effect. Significant diurnal variations in AUC and Emax were found in 36 patients with the 0.8 ml dose, with peak and trough values at 1400 and 1700 hr, respectively. No differences in effect were found with the low dose of 0.4 ml applied to 19 patients either at 1400 or 1700 hr giving evidence for a circadian phase-dependency in the dose-response relationship of a local anaesthetic drug. The results clearly demonstrate that this electronic device is suitable for exact evaluation of circadian changes in local anaesthetic effects. Under drug-free control conditions, however, the low stimulus frequency of 5 Hz of this device obviously does not allow to discriminate between stimuli modified by pain perception and/or alertness.

Adolescent↗
PubMed1989

Reduced cAMP-signal transduction in postmortem hippocampus of demented old people.

The basal as well as the stimulated activity of the adenylate cyclase was determined in postmortem hippocampi. The tissue probes were obtained from 12 demented individuals (10 Alzheimer-type dementia; 1 Down's syndrome; 1 argyrophilic grains syndrome) and from 15 age-matched controls. The diagnoses were done in accordance with histopathological criteria. Adenylate cyclase was stimulated by isoprenaline, Gpp(NH)p, or forskolin. The amount of cAMP formed was determined by the protein binding method using a radioimmuno assay. In tissues of controls as well as of demented patients adenylate cyclase was stimulated in the rank order of isoprenaline less than Gpp (NH) p less than forskolin. In hippocampal tissues of demented individuals a significant reduction (50%, p less than 0.01) in basal as well as stimulated adenylate cyclase activity was found. This reduction in cAMP signal transduction is not caused by simple cell loss.

Adenylyl Cyclases↗
PubMed1989

Clinical chronopharmacology of oral nitrates.

The clinical-chronopharmacological investigations with oral nitrates (ISDN, IS-5-MN) demonstrate that the drugs' pharmacokinetics and/or hemodynamic effects are circadian phase-dependent. For both an immediate-release and a sustained-release preparation of IS-5-MN peak drug concentrations coincided with peak drug effects after morning but not after evening drug application. Results indicate a circadian phase-dependency in the dose-response relationship of oral nitrates.

Administration, Oral↗
PubMed1988

Circadian changes in the pharmacokinetics and cardiovascular effects of oral propranolol in healthy subjects.

Four subjects were synchronized with activity from 07 to 23 h and were given a single oral dose of 80 mg racemic propranolol at fixed times (08, 14, 20 and 02 h) at weekly intervals. ANOVA revealed significant circadian changes in the peak propranolol concentration (Cmax), with a maximum at 08 h and a minimum at 02 h after drug intake; tmax was not dependent on the circadian phase. The elimination half-life varied significantly with the time of day, being shortest at 08 h (3.3 h) and longest at 20 h (4.9 h). The stereospecificity of the propranolol pharmacokinetics was not dependent on the time of drug intake. No circadian variation was found in the maximum decrease in heart rate, but the time to peak effect was dependent on the time of drug intake; tmax was 2.3 h at 08 h and 7.0 h at 02 h. Thus, the time to peak drug concentration did not coincide with the time to peak effect on heart rate at different times of day. Circadian changes were also found in the systolic blood pressure and in the double product. The results show a significant daily variation in the pharmacokinetics and cardiovascular effects of propranolol. However, chronokinetics cannot explain the circadian changes in the effects of the drug. It is concluded that circadian variation in sympathetic tone and vascular reactivity is mainly responsible for the circadian changes in the effects of propranolol.

Administration, Oral↗
PubMed1987

On the daily variation in the beta-receptor-adenylate cyclase-cAMP-phosphodiesterase system in rat forebrain.

In rat forebrain tissue of single rats beta-adrenoceptor density (Bmax) and affinity (Kd) were determined by saturation isotherms in receptor binding studies with the antagonist ligand (3H)-dihydroalprenolol at 8 different times of day in May. Rats were on a controlled 12L:12D photoperiod. In addition, the cAMP content, the formation of cAMP from ATP by the adenylate cyclase and the hydrolysis of the second messenger by the phosphodiesterase were determined at the same time points. No significant (ANOVA) daily variations were found in the total number of 3H-DHA binding sites (Bmax) nor in the affinity (Kd). In contrast, basal cAMP content as well as basal formation and hydrolysis of cAMP displayed significant rhythms. The peak value in cAMP was at the beginning of light. At that time the daily trough value in cAMP formation was found. Hydrolysis of cAMP by the phosphodiesterase displayed a 12-hr rhythm with trough values occurring at the early light and early dark period. The results demonstrate pronounced rhythmic changes in basal formation, content and hydrolysis of cAMP which are, however, not paralleled by changes in receptor number and/or affinity in the same tissue.

Adenosine Triphosphate↗
PubMed1987

Chronopharmacology and chronotherapeutics: definitions and concepts.

Most knowledge of medications has been derived from single- and multiple-dose investigations in which pharmacokinetic and pharmacodynamic phenomena have been evaluated following one, usually, daytime drug administration. Chronopharmacologic studies involving the evaluation of such phenomena after each of several different clock-hour treatments during the day- and nighttime reveal that biological rhythmic processes, such as those of 24 hr, can profoundly affect the kinetics and effects of various medications. Several new concepts have arisen based on findings from chronopharmacologic investigations, such as chronokinetics, chronesthesy and chronergy. These are defined and discussed herein using illustrative examples. A major goal of chronopharmacologic research is to devise chronotherapeutic interventions. Chronotherapeutics is the optimization of drug effects and/or minimization of toxicity by timing medications with regard to biological rhythms. Chronotherapeutics takes into account predictable administration-time-dependent variation in the pharmacokinetics of drugs as well as the susceptibility of target tissues due to temporal organization of physiochemical processes and functions of the body as circadian and other rhythms. The unequally divided and once-daily theophylline treatment schedules for the clinical management of nocturnal asthma, which are discussed in this issue, represent steps toward a chronotherapy.

Animals↗
PubMed1987

Circadian phase dependency of the effects of different beta-receptor blocking drugs on motor activity of rats. Importance of drug lipophilicity.

The effects of seven beta-receptor blocking drugs differing in lipophilicity by 3.5 orders of magnitude (propranolol, bupranolol, oxprenolol, metoprolol, sotalol, practolol, atenolol) were studied on the circadian rhythm in motor activity of light-dark-synchronized (light (L): 7-19 h, dark (D): 19-7 h) male rats. Motor activity after i.p. injection of saline or of the racemic mixtures of all drugs and the isomers of propranolol, bupranolol and practolol was measured in groups of 5 rats with a motimeter. Two doses of either drug were injected either at 7:30 a.m. in L or at 7:30 p.m. in D. In L the drugs did either not affect motor activity or even increased motility in comparison to saline. No dosage-dependency was observed in the drug effects in L. In contrast, during D a dosage-dependent decrease in motor activity was found for all compounds. ED50-values of decrease in motility during D were negatively correlated with lipophilicity (partition coefficient) of the compounds. No significant difference was found in the ED50-values of the isomers studied. The results clearly demonstrate a circadian phase dependency in the effects of beta-receptor blocking drugs on motor activity of rats. A dosage-dependent central depressant effect of the drugs could be observed only in D. It is concluded that the central depressant effects of beta-receptor blocking drugs are mainly due to the non-specific, lipophilic property of the drugs and not brought about by a specific blockade of central beta-adrenoceptors.

Adrenergic beta-Antagonists↗
PubMed1985

Chronopharmacokinetics of beta-receptor blocking drugs of different lipophilicity (propranolol, metoprolol, sotalol, atenolol) in plasma and tissues after single and multiple dosing in the rat.

Comparative pharmacokinetic studies with the beta-receptor blocking drugs propranolol, metoprolol, sotalol and atenolol, differing greatly in lipophilicity, and their main route of elimination were performed in light-dark-synchronized rats after equimolar single (6 mumoles/kg) or multiple (6 X 6 mumoles/kg) drug application. Drug concentrations were determined in plasma and various target organs of the drugs, e.g. heart, muscle, lung and brain, after drug application in the light period (L) and dark period (D), respectively. After single drug administration pharmacokinetic parameters of all drugs depended on the L and D conditions. Elimination half-lives in plasma and organs were shorter during D than during L. No L-D-differences were found in initial drug concentrations of the hydrophilic drugs sotalol and atenolol. In contrast, C0-values of the lipophilic propranolol in highly perfused organs (muscle, lung, brain) and of metoprolol in muscle tissue were significantly higher in D than in L. No obvious temporal dependency was found in other pharmacokinetic parameters (AUC, plasma clearance, Vd beta) with the exception in Vd beta of propranolol. Due to the different physico-chemical properties of the compounds inter-drug-differences in pharmacokinetic parameters including drug accumulation into lung and brain tissue were observed. Multiple drug dosing abolished the circadian-phase-dependency in the elimination half-lives of the drugs due to an increase in D. Only for the highly lipophilic propranolol half-lives in highly perfused organs were still shorter in D than in L.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1985

Evidence for two specific affinity states of 3H-antagonist binding to cardiac beta-adrenergic receptors and influence of Gpp(NH)p.

Binding of the lipophilic antagonist ligand 3H-DHA and the hydrophilic antagonist ligand 3H-CGP 12177 to beta-adrenergic receptors of rat heart ventricular membranes was studied. Quantitative analysis of the binding data indicated the existence of two specific affinity states of the beta-adrenergic receptor population aside from a third non-specific binding site for 3H-DHA. In order to exclude that the biphasic saturation isotherm may be due to retained endogenous agonist, crude membranes as well as modified membranes were used. In the latter a 99% reduction of noradrenaline concentration was obtained by washing and preincubation or by catecholamine depletion. Two affinity states of antagonist binding could be demonstrated independently from the kind of membrane suspension. A biphasic dissociation of 3H-DHA by unlabelled (-)-alprenolol was also found in kinetic studies. In crude or washed membranes of untreated rats the guanine nucleotide Gpp(NH)p affected saturation and antagonist competition curves. However, this was not observed in catecholamine-depleted membranes of reserpine-treated rats. Stereoselectivity of the high and the low affinity state was demonstrated in competition experiments with (-) - and (+) -alprenolol in catecholamine-depleted membranes. The data are best explained by assuming a ternary complex model (1) in which antagonists, instead of passively occupying binding sites, play an active role in receptor mechanisms. Based on this model, it is assumed that beta-adrenergic antagonists bind with high affinity to the free form of the receptor and with low affinity to the precoupled form. Furthermore, an interaction of Gpp(NH)p with the regulatory component is proposed.

Alprenolol↗
PubMed1984

Circadian-phase-dependency in [3H]-dihydroalprenolol binding to rat heart ventricular membranes.

Binding studies with the beta-adrenoceptor antagonist ligand [3H]-dihydroalprenolol ([3H]-DHA, spec. act, 90-102 Ci/mmol) were performed with ventricular membranes L-D-synchronized (L:0.7-19 hr, D:-07 hr) male rats, sacrificed either at 08 hr or at 20 hr. Saturation experiments with crude or washed and preincubated membranes revealed two affinity states of specific [3H]-DHA binding which were abolished after addition of the guanine nucleotide Gpp(NH)p. In crude membranes the apparent Bmax-value at 20 hr was about 40% higher than at 08 hr, in washed and preincubated membranes the nocturnal increase in the apparent Bmax-value was not observed. Pretreatment of rats with isoprenaline (50 mg/kg, i.p.) decreased and catecholamine depletion (reserpine plus inhibition of tyrosine-hydroxylase) increased Bmax-values in crude membranes. The circadian-stage-dependent and the drug-induced effects on the apparent number of beta-adrenoceptors are assumed to be due to circadian or drug-induced variations in the turnover of cardiac noradrenaline.

Alprenolol↗