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Biomedical subjects

B Lemmer

Publications and source records attributed to B Lemmer.

At least 19 recordsLinked to original sources
PubMed1992

[Rhythm analysis of individual 24-hour blood pressure profiles of patients with essential hypertension].

Circadian rhythms in ambulatory blood pressure profiles of eight primary hypertensive patients were analyzed by nonlinear fit of a combined cosine function. Significant circadian variation in systolic blood pressure was found in each patient, and in diastolic blood pressure in seven out of eight patients. The eight primary hypertensive subjects revealed typical circadian blood-pressure profiles with two daytime maxima and a single nighttime minimum. Whereas daytime maxima differed between the subjects, all nighttime minima occurred within a narrow range of 1:54 a.m. to 4:42 a.m. The PHARMFIT-program allows to analyze in more detail the circadian blood pressure profiles obtained by ABPM in single patients as well as in a group of hypertensives.

Adult↗
PubMed1992

[PHARMFIT--a program for the evaluation of digitally collected cardiovascular parameters].

The PHARMFIT program allows the non-linear fit of simple and combined cosine functions to data from long-term monitoring of cardiovascular parameters and the statistical evaluation of the quality of fit. With the SYNOPS utility a statistical comparison of different fit models can be achieved. As an example, the systolic blood-pressure data obtained in a hypertensive subject by ambulatory blood-pressure monitoring (ABPM) over a period of 36 h is used. The program demonstrates that the fit of a combined cosine function including a 24-h and a 12-h period describes the data better than a simple 24-h cosine function. The quality of fit is significantly improved by inclusion of the first harmonics. The PHARMFIT program can help to get a better analysis of ABPM data.

Blood Pressure↗
PubMed1991

Dose-dependent stimulation of adenylate cyclase in rat hippocampal tissue by isoprenaline, Gpp(NH)p and forskolin: lack of circadian phase-dependency.

In rat hippocampal tissue the basal as well as drug-stimulated adenylate cyclase (AC) activity was studied after sacrificing the animals at 9 different circadian times (01.00, 04.00, 07.00, 10.00, 13.00, 16.00, 19.00, 22.00, 01.00 h). The AC was stimulated in vitro either via the beta-adrenoceptor by isoprenaline (IPN, 0.01-100 mumol/l plus GTP 0.005-50 mumol/l, via the GTP-binding protein by Gpp(NH)p (0.03-100 mumol/l) or via the catalytic unit of the AC by forskolin (0.1-600 mumol/l). For each drug dose-response curves could be constituted in single hippocampal tissues at each of the time points of sacrifice. Whereas maximal stimulation by forskolin was not achieved with the highest dose used (600 mumol/l, EC50-, Emax-values and Hill-coefficients could be calculated for both IPN and Gpp(NH)p, respectively. Thus, the rank order of drug stimulated AC activity was forskolin > Gpp(NH)p > IPN. However, no circadian phase-dependency in basal as well as drug-stimulated AC activity was found.

Adenylyl Cyclases↗
PubMed1991

Reduced basal and stimulated (isoprenaline, Gpp(NH)p, forskolin) adenylate cyclase activity in Alzheimer's disease correlated with histopathological changes.

Cyclic adenosine monophosphate (cAMP) is an adenylate cyclase borne second messenger involved in basic metabolic events. The beta-adrenoceptor sensitive adenylate cyclase was studied in post-mortem hippocampi of controls and Alzheimer patients. Virtually identical subsets of each hippocampus homogenate were stimulated by 100 mumol isoprenaline, Gpp(NH)p and forskolin, respectively, in presence of an ATP-regenerating system. The determination of cAMP formed was carried out by means of a radioassay. The observed significant 50% reduction in basal as well as in stimulated adenylate cyclase activity in Alzheimer's disease is negatively correlated with semiquantitative evaluations of amyloid plaques (P less than 0.05) but not with neuritic plaques, neurofibrillary tangles or neuropil threads. This reduction in enzyme activity is obviously not due to simple cell loss alone. It is likely that the crucial point of the observed functional disturbance is at the level of the catalytic unit of the adenylate cyclase, since the same degree of reduction is maintained at all steps of the signal cascade.

Adenylyl Cyclases↗
PubMed1991

Clinical chronopharmacology of oral sustained-release isosorbide-5-mononitrate in healthy subjects.

In 10 healthy male subjects the pharmacokinetics and haemodynamic effects of sustained-release isosorbide-5-mononitrate 60 mg (IS-5-MN) were studied after oral administration at two different times in the day (08.00 h and 20.00 h). Effects on blood pressure and heart rate after 3 min standing upright were measured in relation to the individual circadian control values. The pharmacokinetic parameters (Cmax, tmax, AUC, t 1/2) did not differ after morning and after evening dosing, tmax being 5.2 h and 4.9 h, respectively. In contrast, the cardiovascular effects of IS-5-MN were clearly circadian phase-dependent. The maximum decrease in blood pressure decrease and increase in heart rate occurred significantly earlier after the evening (BPsys 2.8 h; BPdia 2.9 h; HR 3.8 h) than after the morning dose (BPsys 5.0 h; BPdia 6.0 h; HR 5.2 h). Thus, the peak haemodynamic effects coincided with the peak drug concentration after the morning dose, whereas the peak effect was in advance of the peak drug concentration after the evening dose of IS-5-MN. The data provide evidence of circadian phase-dependency in the dose-response relationship of oral IS-5-MN.

Administration, Oral↗
PubMed1991

Rhythms in second messenger mechanisms.

In this chapter circadian rhythms in the beta-adrenoceptor/adenylate cyclase/phosphodiesterase system are presented and discussed. Daily variation in total number and affinity of beta-adrenoceptors in rat forebrain and rat heart ventricles seem to be of minor importance in the circadian regulation of the cAMP concentration in these tissues. Pronounced and significant circadian rhythms in cAMP formation by the adenylate cyclase and cAMP degradation by the phosphodiesterases could be demonstrated in either rat forebrain or heart ventricles. Also the accessibility of cardiac adenylate cyclase to different stimuli was circadian-phase-dependent. Furthermore, data are presented which indicate that the catalytic unit of the adenylate cyclase must undergo qualitative changes with age.

Adenylyl Cyclases↗
PubMed1991

The cardiovascular system and daily variation in response to antihypertensive and antianginal drugs: recent advances.

This review contains recent data on the pharmacokinetics and the hemodynamic effects on heart rate and blood pressure of three different groups of drugs (beta-blockers: propranolol; oral nitrates: isosorbide-dinitrate (ISDN), isosorbide-5-mononitrate (IS-5-MN); calcium channel blockers: nifedipine) which were investigated in healthy volunteers or in hypertensive patients after drug application at different times of the day. In the case of IS-5-MN and nifedipine two different galenic formulations were studied. The results clearly demonstrate chronopharmacokinetics for propranolol, ISDN, and the immediate-release formulations of IS-5-MN and nifedipine, whereas no pharmacokinetic daily variations were observed with the sustained-release formulations. However, all drugs exhibited daily variations in their hemodynamic effects. These data greatly support the view that pharmacokinetics and drug effects should be studied simultaneously when chronopharmacologic studies are performed.

Adrenergic beta-Antagonists↗
PubMed1991

Circadian changes in estimated hepatic blood flow in healthy subjects.

Intravenous injections of indocyanine green (ICG) were given to 10 healthy supine subjects at 02.00, 08.00, 14.00 and 20.00 h. ICG plasma half-life, plasma clearance and estimated hepatic blood flow (EHBF), but not volume of distribution, varied significantly with time of day with EHBF being greatest at 08.00 h. This circadian rhythm in EHBF should be considered when evaluating the kinetics of high-clearance drugs at different times of day.

Adult↗
PubMed1991

Chronopharmacology of oral nitrates in healthy subjects.

The pharmacokinetics and the hemodynamic effects (blood pressure, heart rate) of oral organic nitrates have been investigated in healthy subjects after oral single-dose application either in the morning or in the evening. Isosorbide-5-monitrate (IS-5-MN, 60 mg) was administered as an immediate-release tablet or as a slow-release formulation. Isosorbide dinitrate (ISDN, 20 mg) was ingested as an immediate-release tablet. After administration of IS-5-MN as an immediate-release tablet, the drug was more rapidly absorbed in the morning (tmax of 0.9 h) than in the evening (tmax of 2.1 h). The rapid absorption led to more pronounced effects in the morning, at which time maximum drug concentrations occurred at the same time as peak effects were observed. After evening administration, however, peak effects were in advance of the maximum drug concentrations. No chronokinetics were observed after application of the slow-release formulation of IS-5-MN. In accordance with the results of the immediate-release formulation, peak effects of the slow-release preparation occurred significantly earlier than peak drug concentrations after evening than after morning dosing. ISDN bioavailability was higher after morning than after evening administration and hemodynamic effects were more pronounced in the evening than in the morning. These results show that daily variations in pharmacokinetics and/or hemodynamic effects can be observed with oral nitrates. In addition, galenic formulation can influence the time-specified pharmacokinetics of IS-5-MN.

Administration, Oral↗
PubMed1991

Circadian rhythm of blood pressure in congestive heart failure and effects of ACE inhibitors.

In 33 patients with heart failure (NYHA II-III), the 24-h blood pressure rhythm was examined before and after the titration period of two ACE inhibitors. Blood pressure was measured by the oscillometric method using the blood pressure monitor 90202 from SpaceLabs, Inc. The measurements were taken from 06:00 to 22:00 h every 20 min and from 22:00 to 06:00 h every hour. Patients were randomized to therapy with either captopril (group 1, n = 17) or enalapril (group 2, n = 16). The average daily dosage of captopril was 41 +/- 3 mg given in three divided doses (08:00, 12:00, and 17:00 h). The mean dose of enalapril was 8 +/- 1 mg once daily (08:00 h). Serum electrolytes, serum creatinine, and plasma renin activity were measured before and during therapy with both ACE inhibitors. Twenty-four-hour blood pressure measurements were taken before and on the fifth day of treatment with ACE inhibitors. Both groups were not different with respect to the degree of heart failure, the concomitant medication, and the 24-h profiles of blood pressure and heart rate before initiation of ACE inhibition. The 24-h blood pressure values on day 5 were consistently below the pretreatment values (p less than 0.005) in both groups. Both groups did not differ significantly during ACE inhibition in their 24-h blood pressure and heart rate profiles. In both groups, the mesor of the systolic and diastolic blood pressure decreased significantly by the same degree (by 4.7/5.1 mmg Hg in group 1 and 6.4/4.1 mm Hg in group 2). The systolic/diastolic blood pressure amplitude decreased slightly in both groups. Before treatment, serum sodium, potassium, and creatinine were within the normal range. The increase in potassium (0.5 +/- 0.1 mmol/L) reached statistical significance (p less than 0.01) only in the captopril group, whereas it was not significant in the enalapril group (0.1 +/- 0.1 mmol/L). Serum creatinine was not significantly altered by both ACE inhibitors. No relationship could be found between the changes in serum potassium or creatinine and the mean of the 24-h blood pressure values during ACE inhibition. Captopril and enalapril showed comparable blood pressure profiles and similar effects on renal function at the end of the titration on day 5. It can therefore be concluded that the effects on blood pressure rhythm and renal function are similar with a single daily dose of enalapril compared to captopril given three times daily.

Blood Pressure↗
PubMed1991

PHARMFIT--a nonlinear fitting program for pharmacology.

A new program is presented for nonlinear fitting of data from pharmacological and chronobiological investigations. It contains functions for calculating data from ligand-binding studies and competition experiments, for the analysis of dose-response curves, for pharmacokinetic calculations, and for cosine analysis of harmonic and overlapping rhythms. In addition, it is possible to implement general equations by the user. The program allows data exchange with most spreadsheet, database, and graphics presentation programs, and accepts data from two widely used ambulatory 24-h blood-pressure monitoring systems. The fitting procedure uses the Marquardt-Levenberg algorithm. It calculates the weighted or the unweighted fit together with a great variety of statistics for estimation of goodness of fit. A graphics module permits graphical presentation of the fitted curve. Moreover, fitting of data to different models can be compared for the most likely fit and model discrimination statistics for improvement of further experiments are provided. To demonstrate the chronobiological application of the fitting program PHARMFIT, the analysis of telemetric heart rate data from rats is presented.

Binding Sites↗
PubMed1991

Chronopharmacokinetics and cardiovascular effects of nifedipine.

Circadian phase dependency in pharmacokinetics and hemodynamic effects on blood pressure and heart rate of different galenic formulations of nifedipine (immediate-release, sustained-release, and i.v. solution) were studied in healthy subjects or in hypertensive patients. Pharmacokinetics of immediate-release but not sustained-release and i.v. nifedipine were dependent on time of day: immediate-release nifedipine had higher Cmax (peak concentration) and shorter tmax (time-to-peak concentration) after morning than evening application, and bioavailability in the evening was reduced by about 40%. Circadian rhythm in estimated hepatic blood flow as determined by indocyanine green kinetics may contribute to these chronokinetics. A circadian time dependency was also found in nifedipine-induced effects on blood pressure and heart rate as monitored by 24-h ambulatory blood pressure measurements. In conclusion, the dose response relationship of oral nifedipine is influenced by the circadian organization of the cardiovascular system as well as by the galenic drug formulation.

Administration, Oral↗
PubMed1991

Effects of amlodipine on circadian rhythms in blood pressure, heart rate, and motility: a telemetric study in rats.

In male Wistar rats [light(L): 07:00-19:00 h, dark(D): 19:00-07:00 h], the effects of the calcium channel blocker amlodipine (1, 3, 10 mg/kg i.p.) on blood pressure, heart rate, and motor activity were studied by telemetric monitoring. Amlodipine was injected either at 07:00 h or at 19:00 h. Systolic and diastolic blood pressure were dose-dependently decreased with more pronounced effects in the dark span, ED50 values in D were about seven times lower than in L. In contrast, the dose-dependent increase in heart rate was more pronounced in L than in D. No significant effects of amlodipine were found on motor activity. The study gives evidence for a circadian phase-dependency in the cardiovascular effects amlodipine in rats.

Amlodipine↗
PubMed1991

Chronopharmacokinetics of imipramine and desipramine in rat forebrain and plasma after single and chronic treatment with imipramine.

Daily variations in the pharmacokinetics of imipramine (IMI) could contribute to circadian phase-dependent effects of the drug. Therefore, the chronopharmacokinetics of IMI and its metabolite, desipramine (DMI), were studied after single and chronic application. Male rats were synchronized to a 12:12 hour light:dark (L:D) regimen with lights on from 07:00 to 19:00 (dark, 19:00-07:00). In single-dose experiments rats were injected with IMI (10 mg/kg) i.p. or i.v. at 07:30 or 19:30 and groups of rats were killed 0-22 hours thereafter. After chronic application of IMI in drinking water (approximately 15 mg/kg/d) groups of rats were killed during the 14th day of treatment at 02:00, 08:00, 14:00, and 20:00, respectively. Brain and plasma concentrations of IMI and DMI were determined by reversed-phase high-performance liquid chromatography with ultraviolet detection. After single i.p. application of IMI, maximal brain concentrations (Cmax) of IMI and DMI were nearly twofold higher in darkness (IMI, 4.8 micrograms/g; DMI, 1.8 micrograms/g) than in light (IMI, 2.85 micrograms/g; DMI, 0.85 microgram/g). Also, the area under the curve (AUC) (0-22 hours) was about 1.6-fold greater in darkness than in light for IMI and DMI; half-lives were not circadian phase dependent. After i.v. injection of IMI, the AUC in brain was also about 30% greater in darkness than in light. After chronic application of IMI in drinking water, brain concentrations of IMI and DMI varied more than threefold within 24 hours. The data demonstrate that the pharmacokinetics of IMI and DMI are circadian phase dependent. It is assumed that circadian variations in drug distribution are more likely to contribute to the drug's chronopharmacokinetics than variations in the drug's metabolism. The 24-hour variations in the drug's concentrations after chronic IMI application in drinking water can be explained by the drinking behavior of the rats, which by itself is altered by IMI.

Analysis of Variance↗