Biomedical subjects

K Weisser

Publications and source records attributed to K Weisser.

At least 19 recordsLinked to original sources

PubMed2004

[Thiomersal and immunisations].

Thiomersal was used in the 1930s for the first time for the preservation of vaccines to prevent bacterial and fungal contamination. Thiomersal is an organic compound containing 49% mercury (Hg) by weight. It is generally well known that mercury and its compounds, including thiomersal, ethylmercury, and methylmercury, act as nephro- and neurotoxicants, however, at much higher doses than used in vaccines. In the 1990s the question of toxicity of thiomersal in vaccines was reassessed since the numbers of vaccines recommended for routine administration to infants and children, and therefore the cumulative thiomersal dose in children, increased in some countries. Various international committees (European Agency for the Evaluation of Medicinal Products, EMEA, US Public Health Service/American Academy of Pediatrics, Institute of Medicine, IOM) concluded after an extensive risk/benefit analysis that scientific evidence is inadequate to reject or explicitly recommend thiomerosal-containing vaccines for children. However (in line with the global goal of reducing exposure to mercury), they recommended promoting the elimination of thiomerosal from paediatric vaccines. This has largely been achieved in Germany. Today a child in Germany can be immunised in accordance with the official recommendations (STIKO) almost without the administration of thiomerosal (residual amounts). Results of new pharmacokinetic and epidemiological studies are discussed. The evidence available to date does not support the hypothesis of a potential relationship between neurodevelopmental disorders and thiomersal-containing vaccines.

Adverse Drug Reaction Reporting Systems↗

PubMed2002

In vitro determination of specific toxicity in tetanus vaccines.

Tetanus vaccine is prepared from detoxified tetanus neurotoxin. To ensure the absence of residual toxin activity or to exclude the reversion to toxicity reliable control testing is based on in vivo methods, because no in vitro assay provides the required specificity and sensitivity. Tetanus neurotoxin is a 150 kDa protein produced by Clostridium tetani. The 50 kDa light chain of this neurotoxin belongs to the family of zinc metalloproteases. It cleaves synaptobrevin, a small synaptic vesicle protein, which is involved in neuroexocytosis, at the single Q76-F77 peptide bond. To develop a sensitive in vitro assay capable of quantifying the proteolytic activity of this toxin, we used as substrate a recombinant fragment of synaptobrevin2 (1-97). For detecting the cleavage products a peptide antibody raised against the N-terminal cleavage site was used. In Western Blot analysis only the cleaved substrate was detected while the uncleaved substrate showed no signal. In different approaches, recombinant synaptobrevin was either (i) bound to a microtitre plate, reduced toxin was added and the N-terminal cleavage product was detected by a specific antibody or (ii) the cleavage was performed in test tubes, the samples were transferred to a microtitre plate and immobilised cleavage products were detected. When toxoid or crude toxin is used, non-specific cleavage of synaptobrevin substrate occurs. Depending on the toxoid used different patterns of degradation of substrate are visible in Western Blots. Different protease inhibitors and reaction conditions seem to have an effect on the inhibition of this non-specific cleavage.

Amino Acid Sequence↗

PubMed1995

Dose-effect and kinetic-dynamic relationships of the beta-adrenoceptor blocking properties of various doses of talinolol in healthy humans.

Twelve healthy subjects were investigated on six separate occasions at least 1 week apart when they either received a single oral dose of 80 mg propranolol; 25, 50, 100, or 400 mg talinolol; or placebo (double-blinded, period-balanced six-way cross-over design). The subjects were investigated during supine rest and performed supine bicycle ergometry 0200, 0500, 0730, 1000, and 2400 h after dosing. Isoprenaline (ISO) and epinephrine (EPI) were infused intravenously (i.v.) at a constant infusion rate of 1 microgram/min for 10 min, at 0315 and 0400 h after dosing, respectively. At various timepoints, blood was drawn for the high-performance liquid chromatography (HPLC) determination of the plasma concentrations of talinolol's enantiomers and for the ex vivo in vitro determination of beta 1- and beta 2-adrenoceptor binding and related concentrations by radioreceptor assay (RRA). Talinolol was confirmed to bind to beta-adrenoceptors with moderate affinity but to act as a highly selective and efficient beta 1-adrenoceptor antagonist in terms of the relative degree and duration of its ergometric effects. At doses < or = 100 mg talinolol hardly altered the reduction of estimated vascular total peripheral resistance (TPR) in response to the intravenous infusion of ISO and EPI. Only at doses of 400 mg did talinolol more closely approximate the effects of propranolol, which lead to a loss of the vasodilatory actions of EPI ("EPI reversal"). On the average, there was a smoothly linear relationship between the ergometric treatment effects and log-transformed dose, the logtransformed concentrations of the S(-)-enantiomer measured by HPLC, and the RRA-derived estimated occupancies beta 1-adrenoceptors.

Adrenergic beta-Antagonists↗

PubMed1994

Pharmacokinetics and pharmacodynamics of lisinopril in advanced renal failure. Consequence of dose adjustment.

To prevent drug accumulation and adverse effects the dose of hydrophilic angiotensin-converting enzyme (ACE) inhibitors, e.g. lisinopril, must be reduced in patients with renal failure. To obtain a rational basis for dose recommendations, we undertook a prospective clinical trial. After 15 days of lisinopril treatment pharmacokinetic and pharmacodynamic parameters were determined in patients with advanced renal failure (n = 8; endogenous creatinine clearance [CLCR]: 18 ml.min-1.1.73 m-2) and in healthy subjects with normal renal function (n = 16; CLCR: 107 ml.min-1.1.73 m-2). The volunteers received 10 mg lisinopril once daily, the daily dose in patients (1.1-2.2 mg) was adjusted to the individual CLCR according to the method of Dettli [13]. After 15 days of lisinopril treatment the mean maximal serum concentration (Cmax) in patients was lower than in volunteers (30.7 vs 40.7 ng.ml-1, while the mean area under the concentration-time curve (AUC0-24 h) was higher (525 vs 473 ng.h-1.ml-1). ACE activity on day 15 was almost completely inhibited in both groups. Plasma renin activity, angiotensin I and angiotensin II levels documented marked inhibition of converting enzyme in volunteers and patients. Furthermore, average mean arterial blood pressure in patients decreased by 5 mmHg and proteinuria from 3.9-2.7 g per 24 h after 15 days of treatment with the reduced dose of lisinopril. Adjustment of the dose of lisinopril prevents significant accumulation of the drug in patients with advanced renal failure during chronic therapy. Mean serum levels did not exceed this in subjects with normal renal function receiving a standard dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1993

Cardiovascular effects, pharmacokinetics, and converting enzyme inhibition of enalapril after morning versus evening administration.

The cardiovascular effects and pharmacokinetics of once-daily enalapril were studied after single-dose and subchronic treatment in eight patients with hypertension by use of ambulatory blood pressure monitoring. Enalapril, 10 mg, was given at either 7 AM or 7 PM in a randomized crossover design. In addition, inhibition of serum converting enzyme was studied. Subchronic treatment at 7 AM significantly reduced blood pressure during the day but was less effective at night. Subchronic dosing at 7 PM significantly further decreased nighttime blood pressure followed by a slow increase during the day, with no effect on elevated afternoon values. Peak concentrations of enalaprilat were found 3.5 hours (morning) and 5.6 hours (evening) after drug intake (p < 0.05), whereas peak effects occurred 7.4 hours (morning) and 12 hours (evening) after drug administration. In conclusion, 24-hour blood pressure profiles in patients with hypertension were significantly influenced by the time of enalapril dosing. Differences in effect profiles could not be attributed to similar changes in pharmacokinetics or to different time courses of angiotensin converting enzyme inhibition.

Adult↗

PubMed1992

The influence of hydrochlorothiazide on the pharmacokinetics of enalapril in elderly patients.

In a randomized, cross-over, single-dose study of 19 elderly hypertensive patients (aged 62-84 y, SBP greater than 160 mmHg, DBP greater than 100 mmHg, creatinine clearance 11-93 ml.min-1) we have studied the pharmacokinetics of the angiotensin converting enzyme (ACE) inhibitor enalapril after a single oral dose of either 10 mg enalapril or 10 mg enalapril + 25 mg hydrochlorothiazide. The pharmacokinetics of enalapril were unaffected by hydrochlorothiazide, but there was a significant reduction in renal clearance and a significant increase in AUC(0-24 h) of enalaprilat after hydrochlorothiazide, resulting in higher serum concentrations of the active drug. This was independent of the individual degree of renal impairment and might be due either to an initial reduction of GFR by hydrochlorothiazide or to interference with the tubular secretion of enalaprilat. The relationships between serum enalaprilat and serum ACE activity were similar after both treatments, both consistent with a value for Ki of enalaprilat of about 0.1 nmol.l-1. Thus, serum ACE activity was not affected by hydrochlorothiazide but completely reflected the pharmacokinetics of enalaprilat in both treatments.

Administration, Oral↗

PubMed1991

The role of enzyme and substrate concentration in the evaluation of serum angiotensin converting enzyme (ACE) inhibition by enalaprilat in vitro.

The relationship between serum angiotensin converting enzyme (ACE) activity and concentration of the ACE inhibitor enalaprilat was determined in vitro in the presence of different concentrations (S = 4-200 mM) of the substrate Hip-Gly-Gly. From Henderson plots, a competitive tight-binding relationship between enalaprilat and serum ACE was found yielding a value of approximately 5 nM for serum ACE concentration (Et) and an inhibition constant (Ki) for enalaprilat of approximately 0.1 nM. A plot of reaction velocity (Vi) versus total inhibitor concentration (It) exhibited a non-parallel shift of the inhibition curve to the right with increasing S. This was reflected by apparent Hill coefficients greater than 1 when the commonly used inhibitory sigmoid concentration-effect model (Emax model) was applied to the data. Slopes greater than 1 were obviously due to discrepancies between the free inhibitor concentration (If) present in the assay and It plotted on the abscissa and could, therefore, be indicators of tight-binding conditions. Thus, the sigmoid Emax model leads to an overestimation of Ki. Therefore, a modification of the inhibitory sigmoid Emax model (called "Emax tight model") was applied, which accounts for the depletion of If by binding, refers to It and allows estimation of the parameters Et and IC50f (free concentration of inhibitor when 50% inhibition occurs) using non-linear regression analysis. This model could describe the non-symmetrical shape of the inhibition curves and the results for Ki and Et correlated very well with those derived from the Henderson plots. The latter findings confirm that the degree of ACE inhibition measured in vitro is, in fact, dependent on the concentration of substrate and enzyme present in the assay. This is of importance not only for the correct evaluation of Ki but also for the interpretation of the time course of serum ACE inhibition measured ex vivo. The non-linear model has some advantages over the linear Henderson equation: it is directly applicable without conversion of the data and avoids the stochastic dependency of the variables, allowing non-linear regression of all data points contributing with the same weight.

Amino Acid Sequence↗

PubMed1991

Pharmacokinetics and converting enzyme inhibition after morning and evening administration of oral enalapril to healthy subjects.

Possible circadian changes in the pharmacokinetics and effect on serum angiotensin-converting enzyme (ACE) activity of the ACE inhibitor enalapril have been studied in 8 healthy subjects after oral ingestion of 10 mg enalapril maleate either at 08.00 h or 20.00 h. The time to peak serum concentration (tmax) of enalapril was increased after administration at 20.00 h compared to 08.00 h (2.4 h versus 1.3 h), whereas other kinetic parameters were not significantly altered. The 24 h-kinetics of the active metabolite enalaprilat did not differ significantly between the two treatments, but the area under the curve (AUC (0-24] and the peak serum concentration (Cmax) were slightly higher after intake at 20.00 h. The relationship between the measured serum enalaprilat level and the degree of inhibition of serum ACE was the same after both treatments. Overall, the evening and morning administration of enalapril did not differ markedly in the pharmacokinetics and the time course of ACE inhibition.

Administration, Oral↗

PubMed1986

Analysis of histone gene expression in adult tissues of the sea urchins Strongylocentrotus purpuratus and Lytechinus pictus: tissue-specific expression of sperm histone genes.

We analyzed the histone mRNA population found in several adult tissues of the sea urchin Strongylocentrotus purpuratus and in testis of Lytechinus pictus. Unique species of H1 and H2b mRNAs encoding the sperm-specific histone subtypes can be found exclusively in testis RNA. S. purpuratus contains two distinct testis-specific H1 transcripts, while L. pictus contains one such transcript. Each of these mRNAs is larger than either early or late embryonic H1 mRNAs. Other somatic adult tissues contain transcripts derived from members of the late embryonic H1 histone gene family. S. purpuratus contains one H2b transcript found exclusively in testis, while L. pictus contains two such H2b mRNAs. Similarly, in tissues other than testis, late H2b transcripts were found. While there is no sperm-specific H2a protein, a limited set of late histone H2a genes encoding primarily the H2a-beta subtype is expressed in testis. The majority of the H2a protein found in diploid adult tissues is also the H2a-beta subtype; however, the size of the H2a transcripts differs between testis and other tissues. We conclude that different members of the late H2a gene family are differentially expressed in embryos and adult tissues. We prepared and characterized cDNA clones encoding the sperm-specific H2b protein as well as the H2a-beta protein found in testis.

Amino Acid Sequence↗

PubMed1973