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H Kewitz

Publications and source records attributed to H Kewitz.

At least 19 recordsLinked to original sources
PubMed1999

The O-demethylation of the antidementia drug galanthamine is catalysed by cytochrome P450 2D6.

Galanthamine proved effective in symptomatic treatment of senile dementia of Alzheimer's type. The aim of this study was to elucidate the metabolism of galanthamine. Two novel metabolites of galanthamine have been isolated from the urine of eight young men after single doses of 10-15 mg. Some 19.8% of the doses were excreted as O-demethylgalanthamine glucuronide, 5% as N-demethylgalanthamine, 25.1% as galanthamine, and 0.8% as epigalanthamine. After coadministration of quinidine hydrogen sulfate, which inhibits cytochrome P450 2D6 (CYP2D6) selectively, O-demethylgalanthamine glucuronide was highly diminished in urine. In vitro, human liver microsomes metabolized galanthamine to O-demethylgalanthamine with Vmax 5.2 nmol/mg protein/h and Km 187 microM. Ki of quinidine to inhibit O-demethylation was 28 nM. To inhibit cholinesterases, O-demethylgalanthamine was 10-fold more selective for acetylcholinesterase (AChE) versus butyrylcholinesterase (BuChE) than galanthamine. After glucuronidation, O-demethylgalanthamine failed to inhibit AChE and BuChE. N-Demethylgalanthamine inhibited cholinesterases less potently than galanthamine.

Acetylcholinesterase↗
PubMed1992

Effect of the cholinesterase inhibiting substance galanthamine on human EEG and visual evoked potentials.

The action of galanthamine (GAL), a cholinesterase inhibiting substance, on resting EEG and on flash visual evoked potentials (VEPs) was tested in 9 healthy subjects. Alpha power was increased significantly in 4 of 8 subjects after the infusion of 10 mg, which provided a median inhibition of 47% of acetylcholinesterase in erythrocytes. Mean alpha frequency and peak alpha frequency decreased significantly in 5 of the 8 subjects by 0.22-0.98 Hz. Alpha power increase and alpha frequency decrease were not accompanied by changes in theta power. The amplitudes of the late components of the flash VEP were increased in 8 of 9 subjects receiving doses of 10-35 mg of GAL, while the early components remained unaffected. Increase of late VEP components was significantly correlated with the strength of cholinesterase inhibition. The synchronizing effect of GAL in these healthy volunteers obviously contrasts with the known desynchronizing effect of physostigmine in animal experiments.

Adult↗
PubMed1992

The effect of the new immunosuppressive drug FK506 on the formation of secondary metabolites of cyclosporin A.

Interactions of FK506 with the cyclosporin A (CsA) metabolism are described. These interactions were not differentiated between the primary and secondary part of metabolism. The combination-therapy with cyclosporin A and diltiazem has shown, that not only the blood levels of CsA were increased, but also the blood levels of the primary CsA-metabolite M17. In the presented in in-vitro-investigations 1.7 microM tritium-labelled CsA was incubated for 90 min with human liver microsomes. The inhibitory effect of FK506 (6 microM) was observed with coincubation under the same conditions. The metabolites were quantified by detection of radioactivity of the elution-fractions after HPLC. The results showed strong inhibition on the formation of both, the primary and secondary CsA-metabolites by FK506. With the same concentration diltiazem and erythromycin exhibited only an inhibition of the formation of secondary CsA-metabolites. In clinical investigations with FK506 in combination with CsA it is necessary to control blood levels of CsA and also its primary metabolites.

Biotransformation↗
PubMed1991

System analysis in multiple dose kinetics: evidence for saturable tubular reabsorption of the organic cation N1-methylnicotinamide in humans.

The renal clearance of N1-methylnicotinamide (NMN) was studied in 8 young women at physiological steady state and at steady state following a combined loading bolus and iv infusion. Urinary NMN concentrations were determined using a new HPLC method, plasma levels by a conventional fluorescence method. At physiological levels net tubular secretion of NMN was evident due to a renal fractional excretion, i.e., a ratio of renal NMN clearance to creatinine clearance, above unity. Increasing plasma concentrations lead to an increase in the fractional excretion, indicating saturation of the underlying tubular reabsorption process. Binding to plasma proteins was excluded by ultra-filtration experiments. Clearances measured at physiological levels were about one half of the maximum renal clearance attained following the infusion. This maximum value was approximately six times the creatinine clearance and may be a useful approximation of the renal plasma flow. System analysis, including a novel method to calculate the net response following a multiple input, was used to determine the pharmacokinetic system parameters.

Absorption↗
PubMed1991

Galanthamine: pharmacokinetics, tissue distribution and cholinesterase inhibition in brain of mice.

Galanthamine was determined in plasma and tissue extracts of mice, after the application of 4, 6 and 8 mg/kg (i.v.), by reverse phase HPLC, with fluorescence detection. A biexponential decline of concentrations in plasma, with a terminal half-life of 43.3 min, was observed after the dose of 4 mg/kg. The volume of distribution (Vss) of 2.17 l/kg was similar to that found in other species, including man. Metabolism to the inactive diastereomer, epigalanthamine, was very limited. There was a rapid accumulation of galanthamine in tissues, which was most pronounced in the kidney (10-fold compared to plasma) and liver (5-fold). In brain, accumulation was similar to other parenchymatous organs (diaphragm, lung) and amounted to 2.10-fold. Red blood cells showed a concentration 1.34-fold greater than plasma. The accumulation of galanthamine in tissue, with the exception of liver and kidney, can be explained by passive distribution according to differences in pH, between intra- and extracellular compartments. Extraction of galanthamine from blood to brain tissue was complete, indicated by a clearance in the range of cerebral blood flow (1.05 ml min-1 g-1). The concentration-time course of galanthamine in brain tissue was parallel to that in plasma during the terminal elimination phase. Measurement of inhibition of acetylcholinesterase (AChE) in the same samples from brain revealed a maximum apparent inhibition of 43% in the homogenate of brain (1:4 w/v in phosphate buffer, 4 mg/kg, 5 min after injection).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Pharmacokinetics of galanthamine in humans and corresponding cholinesterase inhibition.

Measurements were done to determine the plasma concentrations of galanthamine and two of its metabolites, as well as the corresponding inhibition of acetylcholinesterase activity in erythrocytes after applying 5 and 10 mg galanthamine hydrobromide as a constant-rate intravenous infusion for 30 minutes and single oral doses of 10 mg in eight healthy male volunteers. The data obtained revealed first-order pharmacokinetics, complete oral bioavailability, and a mean terminal half-life of 5.68 hours (95% confidence interval, 5.17 to 6.25 hours). Renal clearance accounted for only 25% of the total plasma clearance (CL = 0.34 L.kg-1.hr-1). Only negligible quantities of the putative metabolites, epigalanthamine and galanthaminone, were detected in blood and urine. The inhibition of acetylcholinesterase activity was closely correlated with the pharmacokinetics of galanthamine, a median maximal value of 53% being achieved by applying 10 mg galanthamine intravenously. Analysis of in vitro and ex vivo concentration responses revealed no differences, indicating that no metabolites of galanthamine exert additional inhibition of acetylcholinesterase activity.

Acetylcholinesterase↗
PubMed1991

Different modulation of the perioperative stress hormone response under neurolept-anaesthesia or enflurane for cholecystectomy.

Two groups of 13 patients, randomly allocated to receive either enflurane or neurolept anaesthesia for cholecystectomy, were compared in their cardiovascular and neuroendocrine response to surgery and in the postoperative period. There were no significant differences in blood pressure or heart rate. Catecholamine values were higher under neurolept anaesthesia towards the end of surgery and postoperatively. Median values for adrenaline during suture of peritoneum were 342 pg/ml and 88 pg/ml, respectively, P less than 0.05. In contrast, ACTH and cortisol rose to higher levels in enflurane treated patients. At the end of surgery median ACTH values were 75 pg/ml in NLA patients and 322 pg/ml in enflurane patients (P less than 0.01). Vasopressin increments during surgery were similar under both regimens, while prolactin was higher following induction of neurolept anaesthesia. It is discussed whether the differences in stress hormone secretion patterns under either form of anaesthesia reflect different stress protective properties or direct pharmacological effects of certain anaesthetics. We conclude that the hormonal stress response to surgery is critically dependent on the type of anaesthesia and may be discordant in different hormonal systems.

Adrenocorticotropic Hormone↗
PubMed1991

Inhibition of acetylcholinesterase activity in human brain tissue and erythrocytes by galanthamine, physostigmine and tacrine.

Galanthamine, physostigmine and 9-amino-1,2,3,4-tetrahydroacridine (tacrine) were evaluated as inhibitors of human acetylcholinesterase activity from samples of postmortem human brain, fresh brain cortex biopsies and human erythrocytes. Acetylcholinesterase activity was most effectively inhibited in all tissues by physostigmine, followed by tacrine and galanthamine. The respective inhibitor concentrations exerting a half maximal effect (IC50) on acetylcholinesterase in postmortem human brain frontal cortex were 14 nmol/l, 1.0 mumol/l and 3.2 mumol/l versus 15 nmol/l, 1.1 mumol/l and 2.8 mumol/l in the hippocampus region. In addition, the inhibition of acetylcholinesterase by galanthamine was similar in postmortem brain and brain cortical biopsies from patients submitted to brain-tumour removal, indicating that postmortem changes up to 28 h after death probably did not influence the measurement of acetylcholinesterase inhibition. While physostigmine and tacrine acted equally on acetylcholinesterase from different sources, galanthamine was 10-fold less potent in inhibiting the enzyme activity from human brain that from human erythrocytes. Comparison with issues from mice revealed that galanthamine was selectively more potent in suppressing acetylcholinesterase in human erythrocytes. The results are discussed in the light of pharmacokinetic data, and conclusions are drawn for further clinical studies.

Acetylcholinesterase↗
PubMed1990

Pharmacokinetic interaction between cyclosporin and diltiazem.

Previous reports have indicated that administration of the calcium antagonist diltiazem results in major changes in the pharmacokinetics of cyclosporin A (CyA). A new clinical trial was undertaken in 22 renal transplant patients receiving a constant dose of cyclosporin to further explore this interaction. Coadministration of diltiazem for one week produced an increase in the blood concentration of CyA and its metabolites 17 and 18 in almost all patients, but no increase in CyA metabolites 1 and 21. The mean whole blood CyA trough level determined by HPLC rose from 117 ng.ml-1 to 170 ng.ml-1 after one week on diltiazem, and the mean trough level of metabolite 17 rose similarly from 184 ng.ml-1 before to 336 ng.ml-1. Based on experiments with microsomes from human liver the effect of diltiazem was due to noncompetitive inhibition of CyA-metabolism by diltiazem, and the increased concentration of metabolite 17 might have been due to stronger inhibition of its secondary metabolism steps.

Adult↗
PubMed1990

Stereoselectivity of cholinesterase inhibition by galanthamine and tolerance in humans.

The effect of galanthamine (GAL) and its 2 major metabolites on human cholinesterases has been explored. Epigalanthamine, a diastereomer of GAL, was 130-times less potent in vitro in its effect on acetylcholinesterase (AChE) in erythrocytes than the parent compound, and it did not differ significantly from the ketone galanthaminone. In vivo, the maximal 36-55% inhibition of AChE was approached 30 min after oral administration of 10 mg GAL. The duration of the catalytic inhibition corresponded to an elimination half-life of approximately 5-7 h. GAL was well tolerated in 8/8 healthy volunteers, and 3/4 Alzheimer patients tolerated the drug up to a daily dose of 40 mg.

Administration, Oral↗
PubMed1990

Selective inhibition of human acetylcholinesterase by galanthamine in vitro and in vivo.

We investigated the inhibition of human cholinesterases by galanthamine, an alkaloid of the common snowdrop (galanthus nivalis). In vitro, the compound showed potent enzyme inhibition and 50-fold selectivity for acetylcholinesterase (EC 3.1.1.7) as opposed to butyrylcholinesterase (EC 3.1.1.8). There was no difference between enzyme inhibition by galanthamine in whole blood and separated fractions of plasma and erythrocytes. We conclude that galanthamine does not accumulate in large amounts in red blood cells. In vivo, administration of galanthamine in a healthy volunteer and in a patient who underwent long-term treatment confirmed the selectivity of galanthamine for acetylcholinesterase.

Administration, Oral↗
PubMed1989

A suitable method to monitor inhibition of cholinesterase activities in tissues as induced by reversible enzyme inhibitors.

A radiometric method has been used to estimate in vivo activities of cholinesterases in various tissues in the presence of reversible inhibitors. Determination of the samples was performed with the lowest possible degree of dilution to avoid reactivation of the enzyme which would prevent reliable calculation. Dose-response curves and concentration-response curves were performed using physostigmine and tetrahydroacridine, two reversible anticholinesterases in clinical use. Specific inhibition of acetyl- and butyrylcholinesterase was performed using BW284C51 and iso-OMPA, respectively.

Acetylcholinesterase↗
PubMed1988

Estimation of cholinesterase activity (EC 3.1.1.7; 3.1.1.8) in undiluted plasma and erythrocytes as a tool for measuring in vivo effects of reversible inhibitors.

In vivo effects of reversible inhibitors of cholinesterase activity were determined radiometrically in undiluted samples of erythrocytes and plasma. [14C]acetylcholine at substrate saturation, 25 degrees C and pH 7.4 permitted rapid and precise determination of butyrylcholinesterase (EC 3.1.1.8) and acetylcholinesterase (EC 3.1.1.7) activities. Reference values for acetylcholinesterase and butyrylcholinesterase were estimated in the plasma and erythrocyte haemolysate of 102 healthy volunteers. The time course of in vitro inhibition was monitored, starting immediately after addition of 9-amino-1,2,3,4-tetrahydroacridine (tacrine), eserine or pyridostigmine to undiluted human plasma. Maximal inhibition (in vitro) was seen within 60 min with tacrine and eserine, in contrast to 180 min with pyridostigmine. The inhibition remained constant for more than 10 h except with eserine, from which enzyme activity showed an early recovery. Concentration response experiments were performed in undiluted human plasma and undiluted human erythrocyte haemolysate. Ki-values of tacrine, eserine and pyridostigmine were estimated. In contrast to pyridostigmine and eserine, tacrine was found to have a higher affinity for butyrylcholinesterase than for acetylcholinesterase. Tacrine at 2.5 mumol/l resulted in complete inhibition of butyrylcholinesterase and 70% inhibition of acetylcholinesterase activity. Dilution of these samples up to 100-fold was accompanied by almost complete recovery of acetylcholinesterase and by 50% recovery of butyrylcholinesterase.

Acetylcholinesterase↗