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Biomedical subjects

S Harder

Publications and source records attributed to S Harder.

At least 91 records · Page 5Linked to original sources
PubMed1995

Fluctuations in Parkinson's disease. Pathogenetic significance of levodopa's cerebral pharmacokinetics and pharmacodynamics.

The pathogenetic mechanisms which are responsible for the clinical manifestation of motor-fluctuations are poorly understood. Peripheral pharmacokinetics do obviously not play a significant role. For a better understanding of fluctuations exact knowledge and precise characterization of the levodopa induced motor-response (MR) might be useful. In a number of studies it has been demonstrated that this MR follows the "all or none" rule after a levodopa threshold concentration has been exceeded. Such a threshold is considered to exist in the plasma-compartiment as well as in the cerebral effect-compartiment. The specific character of the MR can be modified by the coadministration of dopamine-agonists. Dopamine-agonists lower the levodopa threshold and they reduce the time-lag between levodopa plasmaconcentration and MR. The duration of the MR can be prolonged but the intensity (amplitude) of the MR cannot be augmented. Most of these data to levodopa pharmacodynamics can be explained by a model which is presented in this paper and which is mainly based on cerebral pharmacokinetic mechanisms.

Antiparkinson Agents↗
PubMed1994

Modulation of adhesion molecule expression on endothelial cells by verapamil and other Ca++ channel blockers.

Cytokine-induced expression of adhesion molecules on leukocytes and endothelial cells (EC) is a crucial point in the process of organ transplant rejection. It has been shown that protein kinase C (PKC) is involved in this activation process. Verapamil and other calcium channel blockers seem to possess immunosuppressive qualities in vivo and in vitro; some authors suggested that this is due to PKC- or calmodulin-antagonism. Thus our objectives were to further investigate the second-messenger systems involved in the stimulation of EC and to analyze whether the beneficial influence of calcium channel blockers on the outcome of transplantation is due to impaired expression of adhesion molecules on EC. Our results, obtained in an in vitro model using human umbilical vein EC, show that IL-1-induced expression of intercellular adhesion molecule-1 (ICAM-1) is in part mediated by PKC and that parallel activation of calmodulin is required. Expression of ICAM-1 was reduced to 38.5% by PKC-inhibitor H7 and to 77.2% by calmodulin-inhibitor W7. In addition, data on the intracellular events in TNF-alpha-induced expression of vascular cell adhesion molecule-1 (VCAM-1) is presented, showing that both PKC and, to a higher extent, calmodulin, are involved in this process. Expression of VCAM-1 was reduced to 63.7% by H7 and to 27.7% by W7. IL-1-induced expression of endothelial leukocyte adhesion molecule-1 (ELAM-1) is PKC-dependent but insensitive to blocking of calmodulin. Though activation of adhesion molecule expression utilizes PKC and/or calmodulin as second-messenger pathways the investigated calcium channel blockers verapamil (R- and S-enantiomers), diltiazem and Ro 40-5967 failed to inhibit adhesion molecule expression. Surprisingly, higher concentrations of verapamil (> 12.5 micrograms/ml) or Ro 40-5967 (5 micrograms/ml) significantly enhanced IL-1-induced expression of ELAM-1. ICAM-1-expression was also enhanced by verapamil, but not by Ro 40-5967 or diltiazem. This enhancement was only seen if verapamil was added maximally one hour after the cytokine stimulus indicating that transcriptional modulation is responsible for the observed effects. Our findings indicate that calcium channel blockers have an immunomodulating effect independent of adhesion molecule expression.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1994

Absorption of ipsapirone along the human gastrointestinal tract.

Isapirone-HCl (5 mg) was administered orally, rectally and locally, by a remote control drug delivery device (HF-capsule) into different segments of the gastrointestinal tract, to four young healthy male adults. The relative systemic bioavailability of the drug from the colon and rectum was 2-3-fold greater than that from the upper gastrointestinal tract. This supports a rationale for a prolonged-release formulation.

Administration, Oral↗
PubMed1994

Respiratory responses to repeated prolonged exposure to 0.12 ppm ozone.

Repeated exposure to high concentrations of ozone results first in augmentation (typically on the second day) and then attenuation of pulmonary response in humans. To determine the effects of repeated prolonged low-concentration ozone exposure, we exposed 17 healthy nonsmoking male subjects to 0.12 ppm ozone for 6.6 h on 5 consecutive days. Subjects were also exposed once to filtered air. Volunteers exercised at a ventilation of approximately 39 L/min for 50 min of each hour during the exposure. Spirometry, plethysmography, and symptom responses were obtained before, during, and after each exposure. Nasal lavage and aerosol bolus dispersion were obtained before and after exposure. Spirometry decreased and symptoms increased on the first day. Responses were less on the second day compared with those on the first day, and they were absent compared with control values on the subsequent 3 days of ozone exposure. Percent change in FEV1 after ozone exposure compared with that after air exposure averaged -12.79, -8.73, -2.54, -0.6, +0.18% for Days 1 to 5 of ozone exposure, respectively. FEV1 responses ranged from a zero to 34% decrease on Days 1 and 2. After each exposure, we determined the ratio of SRaw after inhaling a fixed dose of methacholine to SRaw after inhaling saline aerosol, as an index of airway responsiveness. Airway responsiveness was significantly increased after each ozone exposure. The mean ratios were 2.22, 3.67, 4.55, 3.99, 3.24, and 3.74 for filtered air and ozone Days 1 to 5, respectively. Symptoms of cough and pain on deep inspiration increased significantly on ozone Day 1 only.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1994

Drug utilization review on a surgical intensive care unit.

Drug use reviews (DUR) provide information about drug prescription patterns. At the surgical intensive care unit (SICU) of the University Hospital Frankfurt/Main we recorded the indication related administration of blood products and pharmaceuticals (which were responsible for 60% of the total costs at the SICU in the year before) over a 4-month investigation period. Data were recorded and analyzed using a notebook-PC. 207 Patients were included, and recorded total expenditures came to $551,592. The 10 leading substances, represented by antibiotics and blood-products, caused more than 70% of total costs. The usage of these high-cost substances and the most expensive complications are identified and discussed. We concluded that DURs are useful for obtaining information about drug usage patterns and for identifying high cost drugs, which are of economic interest. Furthermore, the indications for the application of these substances can be identified. Our results suggest, that blood and blood-products should always be included in DURs. In our opinion, especially the usage of blood-products represents a field where considerable cost savings may be expected. As certain complications during the postoperative course (e.g. sepsis) may increase costs, they should be considered in the reimbursement negotiations between hospitals and health insurance.

Adult↗
PubMed1994

Effects of flupirtine coadministration on phenprocoumon plasma concentrations and prothrombin time.

The influence of flupirtine, a non-opioid, centrally acting analgesic agent on phenprocoumon plasma levels and protein binding as well as prolongation of prothrombin time has been investigated in 12 healthy male volunteers. Subjects received phenprocoumon 1.5 mg od over 28 days. From day 15 to 28 oral flupirtine 100mg tid was added. Phenprocoumon plasma levels and prothrombin time (Quick time), measured at trough before the morning drug intake, were chosen as primary pharmacokinetic and pharmacodynamic variables. In addition, phenprocoumon protein binding and the eudismic ratio of phenprocoumon were determined. The mean values from data obtained on day 12 to 15 (i.e. measurements under phenprocoumon alone) and the mean values from those data obtained from day 25 to 28 (i.e. under comedication with flupirtine) were subject to subsequent statistical procedures. Phenprocoumon plasma concentrations came to 1.38 +/- 0.28 micrograms/ml on day 12 to 15 and were not significantly altered under flupirtine coadministration with 1.48 +/- 0.36 micrograms/ml on day 25 to 28 (95% confidence interval: 1.02-1.11, point estimator: 1.06). The average Quick time came to 68 +/- 10% on day 12-15 and 73 +/- 15% on day 25-28. The nonparametric 95%-confidence interval for the ratio ranged between 0.96 and 1.14, the point estimator was determined to 1.04. Protein binding of phenprocoumon was determined to 88.8% +/- 0.5 on day 14 and to 88.9 +/- 0.5% on day 28. The ratio of S/R-phenprocoumon was 1:0.84 on day 14 and 1:0.84 on day 28. These results do not provide any evidence for a pharmacokinetic and/or pharmacodynamic interaction between flupirtine and phenprocoumon.

Administration, Oral↗
PubMed1994

Concentration/effect relationship of bunazosin, a selective alpha 1-adrenoceptor antagonist in hypertensive patients after single and multiple oral doses.

The concentration/effect relationship of bunazosin, a selective alpha-1-adrenoceptor antagonist of the quinazoline class, was established in hypertensive patients after a first dose of bunazosin and after 8 weeks of chronic dosing. The study was part of a placebo controlled, multicenter dose-finding trial with parallel group design. After a wash-out period and a 2-week placebo run-in phase, each 4 patients received either placebo, 3 mg, 6 mg or 12 mg bunazosin o.d. in a slow-release formulation. Concentration/effect analysis based on a sigmoidal Emax-model and the drop in the mean arterial blood pressure application of this model was feasible in 9/11 patients. The EC50 after the first dose was 4.6 +/_ 2.0 ng/ml and increased to 9.1 +/- 7.3 ng/ml at steady-state. The decrease in the average of the responsiveness parameter was mainly due to about three-fold, right-shift in the concentration/effect curves at steady-state in 3 patients, the remaining patients showed no or considerably lesser changes of the EC50. Whereas a significant correlation was observed between the pretreatment mean arterial blood pressure and the height of the maximal effect under bunazosin, no relationship appears between the bunazosin dose, the resulting plasma levels at trough and the corresponding effect.

Administration, Oral↗
PubMed1994

[In vitro studies on immunosuppression with verapamil].

UNLABELLED: AIMS OF THE INVESTIGATION: It is known that Verapamil and other calcium channel blockers possess immunosuppressive properties. It has been suggested that they exert their effects by antagonising protein kinase C (PKC) or calmodulin. Our aim was to investigate whether the adhesion of lymphocytes to allogenic endothelial cells and lymphocyte migration are impaired in the presence of Verapamil. The role of PKC and calmodulin during expression of adhesion molecules, the expression of adhesion molecules under the influence of Verapamil and lymphocyte motility on endothelial cell monolayers were investigated. METHODS: Human endothelial cells (EC) were obtained from umbilical chord veins and incubated as dissociate primary cultures. Expression of adhesion molecules on EC was determined by quantitative immunofluorescence using the CytoFluor 2300-system. Studies on lymphocyte motility were performed by phase contrast microscopy using video scope analysis. RESULTS: Expression of Intercellular Adhesion Molecule 1 (ICAM-1), Vascular Cell Adhesion Molecule (VCAM-1) and Endothelial Leukocyte Adhesion Molecule I (ELAM-1) was dose-dependently reduced by the application of PKC-inhibitor H7. Expression of ICAM-1 and VCAM-1 was also inhibited by the calmodulin-antagonist W7. Surprisingly, neither R- nor S-Verapamil inhibited adhesion molecule expression, we even observed significant enhancement of ELAM-1- and ICAM-1-expression. Nevertheless, lymphocyte motility on allogenic EC monolayers was impaired in the presence of R-verapamil, the enantiomer that is inactive as a calcium channel blocker. CONCLUSION: Verapamil reduces lymphocyte motility and is therefore effective in impairing lymphocyte-endothelial cell-interactions. These effects seem to be independent of calcium channel blockade and are probably not due to inhibition of PKC or calmodulin.

Calmodulin↗
PubMed1994

Antihypertensive efficacy of a slow release nifedipine tablet formulation given once daily in patients with mild to moderate hypertension. A placebo-controlled, double-blind parallel-group trial.

In a double-blind, randomized parallel-group, multi-center study the antihypertensive efficacy of a slow release tablet containing 60 mg nifedipine (Aprical long, CAS 21829-25-4) has been investigated. After two-weeks wash-out of previous antihypertensive medication and a two-weeks placebo run-in period, 88 patients of both gender with a diastolic blood pressure between 95 and 115 mmHg received either nifedipine or placebo for 8 weeks. Blood pressure was measured at the end of the dose interval at rest by a semi-automatic, auscultatory device. Control measurements were recorded using a standard cuff sphygmomanometer. Primary efficacy criterion was the drop in diastolic blood pressure (DBP, measured semi-automatically) after 8 weeks therapy. 88 patients were randomized to nifedipine or placebo. 86 patients completed the protocol (42 nifedipine, 44 placebo). However, only in 73 patients BP measurements were recorded appropriately with the semi-automatic device (36 nifedipine, 37 placebo). In the nifedipine group, blood pressure fell from 152 (+/- 18)/102 (+/- 6) mmHg to 139 (+/- 16)/91 (+/- 10) mmHg. Blood pressure under placebo was determined to 149 (+/- 20)/102 (+/- 8) mmHg before treatment and 146 (+/- 18)/100 (+/- 10) mmHg at the end of the study. Heart rate was not affected under both treatments. The 90% confidence interval of the difference between the mean fall in DBP ranged from 5.0 to 12.5 mmHg, the point estimator was 8.8 mmHg. At the end of the study, 21 of 36 patients under nifedipine and 10 of 37 patients under placebo had a DBP below 90 mmHg and/or a decrease in DBP > 10 mmHg.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1993

Lack of a pharmacokinetic interaction between carvedilol and digitoxin or phenprocoumon.

The possibility of a pharmacokinetic interaction between carvedilol and digitoxin (Study I) or phenprocoumon (Study II) has been evaluated in groups of 12 healthy volunteers. The bioavailability (Cmax, tmax, AUC) of digitoxin and phenprocoumon were assessed after a single dose, given once alone and once on day 6 of treatment with carvedilol 25 mg o.d. Cmax, tmax, AUC and Ut of carvedilol and desmethylcarvedilol were also investigated after the fifth dose of carvedilol and after the sixth dose given concomitantly with digitoxin or phenprocoumon. In Study I, the 95% confidence intervals of the ratio test versus the reference findings were; digitoxin Cmax 0.80-1.20, tmax 0.56-1.14, AUC 0.97-1.33, and for carvedilol Cmax 0.81-1.22; tmax 0.66-1.23; AUC 0.91-1.17. Formation of the active metabolite desmethylcarvedilol and the urinary recovery of carvedilol and desmethylcarvedilol were not influenced by digitoxin. In Study II Cmax and AUC of phenprocoumon were not changed after carvedilol. Cmax of carvedilol was decreased after phenprocoumon. The kinetic parameters of phenprocoumon were Cmax 0.80-1.05, tmax 0.47-2.00, AUC 0.78-1.05, and for carvedilol Cmax 0.59-1.06, tmax 0.71-1.73; AUC 0.80-1.08, respectively. The plasma levels of desmethylcarvedilol and the urinary recovery of carvedilol and desmethylcarvedilol were not influenced by phenprocoumon. The blood pressure and heart rate after carvedilol alone were not affected by concomitant administration of digitoxin or phenprocoumon.

Adult↗
PubMed1993

Effect of D,L-verapamil, verapamil enantiomers and verapamil metabolites on the binding of vincristine to alpha 1-acid glycoprotein.

Vincristine binding to solutions of alpha 1-acid glycoprotein (AGP, 2 mg/ml) and the effect of D,L-verapamil, verapamil enantiomers and the verapamil metabolites norverapamil and D617 were investigated in vitro using equilibrium dialysis and 3H-labelled vincristine. Vincristine binding to AGP (52.3 +/- 3.6%) was concentration independent over the range 0.002-2.0 micrograms/ml. The displacement of vincristine from AGP varied between 25.1 and 81.3% with D,L-verapamil and verapamil enantiomers added at concentrations in the range 5-50 micrograms/ml. In contrast, the displacement by D617 (5-100 micrograms/ml) was weaker and varied between 0 and 47%. The displacement at 20 micrograms/ml produced by D,L-verapamil, R-verapamil, S-verapamil and norverapamil was 53.1%, 56.8%, 58.9% and 53.9%, respectively, was more than double that for D617 (25%; P = 0.002). It is concluded that vincristine, D,L-verapamil and verapamil isomers and metabolites interact at binding sites on AGP. These interactions may be clinically important in multidrug resistance, for example in cancer patients with elevated levels of AGP undergoing treatment with verapamil and vinca alkaloids.

Nitriles↗
PubMed1993

Concentration/effect analysis of verapamil: evaluation of different approaches.

Plasma concentration and PR-interval prolongation were correlated after a single dose of 80 mg verapamil (trial A) and at steady-state during one dose interval (80 mg verapamil t.i.d.) on day 7 (trial B) and day 14 (trial C) and the subsequent dose interval at the afternoon on day 14 (trial D). The pharmacokinetic parameters of verapamil indicated a two-fold increase in AUC and Cmax at trial B and C when compared with the single dose application, but AUC and Cmax were considerably lesser during the afternoon dosing interval (trial D). For each subject, concentration/effect analysis was established: according to a linear and a sigmoidal model, and using a plasma concentration vs effect approach (1) and a semiparametric effect-site concentration vs effect approach (2). The comparison of the two different approaches and models showed that in general, the concentration/effect analysis based on the linear model and with approach 2 gave the best description of the dromotropic response to verapamil for the majority of the individuals. However, approach 1 accounts for 30 to 50% of the concentration/effect curve established in the data subsets of trial A to D, and about 40% of all curves in trial A, B and C can be more precisely described with the Emax-model, whereas almost all curves obtained in trial D were best described by a linear model. A decrease in the responsiveness to verapamil at steady-state was indicated by both models, but more precisely described by the parameters of the Emax-model.

Adult↗
PubMed1993

Plasma concentrations of S-verapamil after single doses of two different galenic formulations of racemic verapamil.

The results of enantioselective analysis of verapamil (CAS 52-53-9) in plasma samples obtained at tmax after single dose applications of a 80 mg fast dissoluting (IR) tablet, a controlled release (CR) formulation (240 mg) and an intravenous injection of 5 mg verapamil are reported. The mean fraction of S-verapamil obtained in samples containing the Cmax of racemic verapamil was somewhat smaller after application of the IR-form than observed with the CR formulation. (IR = 15.8 +/- 3.8%; CR = 18.8 +/- 2.0%; p < 0.01), after the intravenous application the mean S-fraction was 32.8 +/- 1.4%. In vitro dissolution tests of the two oral preparations prove that the isomers were released as racemate.

Administration, Oral↗
PubMed1992

Intra-individual variability of caffeine elimination in healthy subjects.

Caffeine is a popular test substance for assessing the activity of hepatic drug metabolizing enzymes in vivo and in vitro. A correct estimation of the relative magnitudes of intra-individual and inter-individual variations in caffeine elimination is significant for the use of the elimination parameter of caffeine to characterize the biotransformation capacity of a specific form of cytochrome P-450 (1AII) in vivo. The purpose of this study is to demonstrate the magnitudes of fluctuation of caffeine-clearance and half-life as well as inter- and intra-individual comparison in 12 healthy male subjects. Compared to the high reproducibility of caffeine decay curves in each healthy male, caffeine elimination varied more extensively between subjects. The distribution of variance amounted to: intra-individual 21.4%, inter-individual 78.6%. The knowledge of variance provided precise evidence of the sample size, which is necessary to prove previously defined differences.

Adult↗
PubMed1992

Concentration/effect relationship and enantioselective analysis of verapamil in hypertensive patients.

The concentration/effect relationship of verapamil was analyzed in 9 hypertensive patients using concentrations of racemic verapamil and the corresponding decrease in mean arterial blood pressure (MBP) in a sigmoidal Emax model. Concentration/effect data were obtained after a first dose (240 mg sustained release preparation) and at steady state after stepwise dose adjustment to obtain satisfactory BP control (less than 90/150 mm Hg). Emax (MBP) ranged from 15 to 40 mm Hg, and EC50 averaged 81 +/- 40 ng/ml (mean +/- SD). The fraction of S-verapamil in the overall racemic verapamil concentrations was measured in two patients by chiral high-performance liquid chromatography (HPLC) and showed a slight increase at steady state from 12.2 +/- 1.5 to 14.4 +/- 1.4% and from 14.0 +/- 1.3 to 16.3 +/- 0.6%. Concentration/effect curves for S-verapamil concentrations were similar to those obtained with racemic verapamil concentrations.

Administration, Oral↗