H. Kewitz

Hospital Admissions Due to Adverse Drug Reactions: A Comparative Study from Jerusalem and Berlin

SummaryA comparative study of adverse drug reactions (ADR) leading to hospital admission showed that 103 (4.1%) out of 2499 medical admissions in Jerusalem and 167 (5.7%) out of 2933 admissions in Berlin were due to such reactions. Sex distribution in the two patient — populations was almost equal but the Jerusalem patients were younger. The most frequent ADRs were digitalis intoxication (in Berlin) and reactions to antibiotics (in Jerusalem). Other important differences were noted in the relative frequencies of ADRs associated anticoagulants, hypoglycemic agents and oral contraceptives. They were probably related to differences in drug usage in the two countries. The most common major side effects were arrhythmias, allergic reactions, bleeding, congestive heart failure, bronchospasm and hypoglycemia. The following risk factors were identified in both cities: old age, female sex, impaired renal function, previous history of ADR and polypragmasia.

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.

Pharmacokinetic interaction between cyclosporin and diltiazem

SummaryPrevious 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 noncompetitve 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.

Determination of thiamine in human plasma and its pharmacokinetics

SummaryA sensitive assay for thiamine suitable for clinical use has been developed. It is based on precolumn oxidation of thiamine to thiochrome followed by HPLC-separation and fluorescence detection. The assay is applicable to various biological materials, including human plasma.The minimum amount detectable was 5 fmol, minimum plasma concentration 0.5 nmol/l and minimum sample volume 0.3 ml plasma. Each chromatographic run took 3 min.Inter- and intra-assay relative standard deviations (RSD) were 8.3% and 6.3%, respectively, at a stock plasma concentration of 10.8 nmol/l. At 38.8 nmol/l, interassay RSD was reduced to 3.4%. The recovery of 5 nmol/l added thiamine was 102 (SD±17)%, that of 30 nmol/l was 94±5%.Plasma levels in 91 volunteers ranged from 6.6 to 43 nmol/l, showing a log normal distribution with a median of 11.6 nmol/l.Thiamine kinetics were studied in plasma and urine from 8 men after intravenous and oral doses of 50, 100 and 200 mg thiamine hydrochloride. In all individuals, nonlinear renal elimination kinetics were demonstrated by plotting the fractional amount of thiamine excreted unchanged in urine against the corresponding area under the plasma concentration — time curve.

Effects of diuretics on plasma lipoproteins in healthy men

SummaryThe fasting level of plasma very low density lipoproteins (VLDL) was increased by 30 to 50% in 12 healthy male volunteers treated with daily oral doses of hydrochlorothiazide 100 mg, chlorthalidone 100 mg or furosemide 80 mg for 3 weeks in a cross-over trial. Hydrochlorothiazide and chlorthalidone, but not furosemide, caused a 10% increase in cholesterol in the low density lipoproteins (LDL), whereas triglycerides and phospholipids in this fraction remained unchanged. High density lipoproteins (HDL) were not affected by any of the diuretics. Free palmitic and oleic acid in plasma were also increased during the treatment, perhaps because of an accumulation of cyclic 3′5′-AMP due either to the inhibitory action of diuretics on phosphodiesterase, or to secondary activation of the sympathetic nervous systems. This would activate lipolysis in fat tissue, which in turn may induce VLDL synthesis in the liver. Each of the diuretics caused a similar rise of 20 to 30% in the mean plasma uric acid, the which could not be correlated with either triglycerides or cholesterol. Plasma sodium was increased by 2% only by furosemide, whereas potassium was decreased by 15 and 19% by hydrochlorothiazide and chlorthalidone, respectively, but not by furosemide. Mean plasma creatinine rose by 3.5% on treatment with furosemide, and by 6% with the other two diuretics. Mean body weight was reduced by 1,4 to 2,0% during treatment. No change in fasting blood sugar, plasma protein level or hematocrit was found.

Stereoselectivity of cholinesterase inhibition by galanthamine and tolerance in humans

SummaryThe 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.

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)

Reserpine and breast cancer in women in germany.

SummaryExposure to reserpine was compared in 181 women interviewed prior to biopsy and found to have breast cancer and 307 women found to have a benign disorder of the breast. The age-adjusted relative risk of breast cancer in those who had taken reserpine was 0.6 (95% confidence limits: 0.4 and 1.1). When the 181 breast cancer patients were compared with a second control group of 101 women with a benign condition requiring surgery, the relative risk was 0.9 (95% confidence limits: 0.4 and 1.7). Neither long-term exposure nor its timing, gave any evidence of an association with breast cancer. The findings in this study do not support the hypothesis that rauwolfia derivatives initiate or promote breast cancer.

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.

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 in 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.