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Biomedical subjects

R Gugler

Publications and source records attributed to R Gugler.

At least 55 records · Page 3Linked to original sources
PubMed1985

Factors predicting the therapeutic outcome of duodenal ulcer treatment with H2-receptor antagonists.

In a prospective trial 37 duodenal ulcer patients were treated daily with 1 g cimetidine. Personal and clinical data were obtained for all patients, acid secretion studies performed before and during treatment, and pharmacokinetic parameters of cimetidine determined. The healing rate after 4 weeks was 64.9% (24 patients). Non-Responders included a higher proportion of smokers, patients with a history of ulcer and previous treatment with H2-receptor antagonists than Responders. Basal acid output (BAO) and peak acid output (PAO) values were not different between the two groups, nor was the reduction of BAO and PAO under cimetidine. However, more Responders had complete suppression of BAO than Non-Responders. A correlation existed in both groups between cimetidine plasma concentration and PAO suppression but not with BAO suppression. Regular drug intake (compliance) was found in about 90% in both groups. Cimetidine bioavailability parameters were identical in both groups, but Non-Responders had a higher peak concentration and a shorter time of peak concentration. Discriminant analysis enabled a prediction of treatment response in 89.2% of the patients by using five factors: time of peak concentration of cimetidine, previous H2-receptor-antagonist treatment, peak concentration, smoking, and alcohol use. Prediction of treatment response is increased by use of drug related variables.

Adult↗
PubMed1985

Cimetidine interaction with liver microsomes in vitro and in vivo. Involvement of an activated complex with cytochrome P-450.

The O-deethylation of 7-ethoxycoumarin was inhibited in a mixed type manner by cimetidine in vitro and in microsomes isolated from rats treated with cimetidine in vivo. It was found that the inhibition was even greater if cimetidine was preincubated with the microsomal suspension in the presence of an NADPH-generating system prior to the addition of substrate. In vitro the decrease in activity was accompanied by a decrease in cytochrome P-450 content. This decrease was unaffected by the addition of EDTA to the microsomal suspensions, eliminating the possibility that free radical production was responsible for the decrease in cytochrome P-450. The decrease in activity and cytochrome P-450 content following preincubation of microsomal suspensions with cimetidine could be attenuated if potassium ferricyanide was added to the suspensions. The deethylation activity and cytochrome P-450 content of liver microsomes prepared from cimetidine-treated rats was decreased compared to control animals. The activity and cytochrome P-450 content of microsomes from cimetidine-treated rats could also be restored if microsomes were washed with potassium ferricyanide prior to incubation with substrate. It is proposed that an intermediate complex of cimetidine and cytochrome P-450 could be involved in the inhibition of microsomal metabolism by cimetidine.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1985

Serum-cholesterol-lowering effect of metronidazole and possible mechanisms of action.

In five patients with Crohn's disease long-term therapy with metronidazole (400 mg b.i.d.) was followed by a significant reduction of total serum cholesterol from 179 mg/dl to 156 mg/dl, 134 mg/dl, and 143 mg/dl, after 2-4 months, 6 months, and 9-12 months, respectively. Lipoprotein analysis before and after 3 weeks of administration of metronidazole (400 mg/day) to five normolipemic volunteers revealed that LDL-cholesterol was reduced by 21% (P less than 0.05), whereas HDL-cholesterol remained unchanged. Biliary secretion of cholesterol and bile acids were reduced by 13% and 20% (P less than 0.05), respectively, which might suggest a decreased sterol synthesis. The amount and percentage of intestinal cholesterol absorption were decreased by 33% and 22% (P less than 0.05). Thus, a possible decrease in sterol synthesis and a reduction of cholesterol absorption might be responsible for the serum-cholesterol-lowering effect of metronidazole. However, caution should be taken when considering metronidazole for long-term treatment of patients with hypercholesterolemia due to possible side effects.

Bile↗
PubMed1985

Cimetidine pharmacokinetics and dosage requirements in children.

The pharmacokinetics of cimetidine (10 mg/kg) were investigated in 11 children following an oral dose and in 9 children following an intravenous dose. The children ranged in age from 4-13 years and were undergoing radiology for upper gastrointestinal tract pain. Compared with a group of adults, the children had a higher total body clearance (11.6 +/- 3.4 versus 7.0 +/- 2.5 ml/min per kg; P less than 0.005), a larger apparent volume of distribution (1.24 +/- 0.40 versus 0.80 +/- 0.24 l/kg; P less than 0.005) and a shorter elimination half-life (83 +/- 26 versus 122 +/- 16 min; P less than 0.001) of cimetidine. Renal clearance in children comprised 70% of total body clearance, more than double that of adults (9.0 +/- 1.9 versus 4.2 +/- 2.1 ml/min per kg; P less than 0.001). The area under the cimetidine plasma concentration: time curve after the oral dose was on average 42% in children compared with adults. The mechanism for the increased elimination of cimetidine in children is suggested to be an increase in the renal tubular secretory transport of cimetidine in the kidney. A statistically significant negative correlation was observed between age and cimetidine renal clearance. A cimetidine dosage regimen of approximately 30 mg/kg per day in three to four divided doses would be an appropriate dose in children.

Administration, Oral↗
PubMed1985

Current diagnosis and selection of patients for treatment of peptic ulcer disease.

The introduction of fiberoptic endoscopy has altered the relative importance of ulcer symptoms in the diagnosis of peptic ulcer disease. Interestingly, we now realize that 50% of ulcer patients do not have the classical ulcer symptoms and that 25% of peptic ulcers are asymptomatic. Modern forward-viewing endoscopes of small diameter enable precise diagnosis with little discomfort in 95% of all duodenal ulcer patients. A biopsy is only recommended in rare cases (giant ulcers) because the malignancy rate is only 0.024% in duodenal ulcers. The diagnostic accuracy of endoscopy in detecting gastric ulcer is as high as that for duodenal ulcer, but for this ulcer type it is absolutely necessary to exclude malignancy by obtaining a minimum of six biopsies (four from the ulcer margin and two from the ulcer base), since approximately 10% of all gastric ulcers are actually carcinomas. Whereas in duodenal ulcer repeat endoscopy is seldom necessary, it is mandatory in gastric ulcer since ulcer healing is not proof of a benign ulcer. In experienced hands endoscopy is superior to radiography in duodenal and in gastric ulcer, although there is still a place for radiography as a supplementary investigation or if the patient rejects endoscopy. When selecting patients for treatment of peptic ulcer the following aspects must be considered: natural history of the disease, effectiveness of treatment, and risks and costs of treatment. Treatment goals (relief of symptoms, ulcer healing) can be achieved as far as the acute ulcer is concerned but as yet we have no evidence that we can cure chronic ulcer disease.

Diagnosis, Differential↗
PubMed1985

Interaction between metronidazole and drugs eliminated by oxidative metabolism.

Single-dose kinetics of 0.1 mg/kg intravenous diazepam, 10 mg/kg oral antipyrine, and 300 mg oral phenytoin were followed in healthy subjects before and after 400 mg metronidazole twice a day for 5 days. When data before metronidazole dosing were compared with those after metronidazole dosing, there were no changes in total plasma clearance of diazepam (0.53 and 0.65 ml/min/kg), antipyrine (39.0 and 38.0 ml/min/kg), or phenytoin (0.56 and 0.55 ml/min/kg). Plasma t 1/2s and volumes of distribution of the three drugs tested were not affected by metronidazole, but urinary excretion of 4-hydroxyantipyrine decreased after metronidazole dosing. There was no change in the elimination of phenytoin as its hydroxylated metabolite after metronidazole. It is concluded that, at therapeutic concentrations, metronidazole does not significantly inhibit oxidative drug metabolism.

Administration, Oral↗
PubMed1985

Omeprazole inhibits oxidative drug metabolism. Studies with diazepam and phenytoin in vivo and 7-ethoxycoumarin in vitro.

The effect of treatment with omeprazole, a substituted benzimidazole, on the elimination of diazepam and phenytoin was studied in two groups of 8 subjects. Omeprazole given orally in a daily dose of 40 mg over 7 days decreased diazepam plasma clearance from 22.4 +/- 2.8 to 10.1 +/- 1.5 ml/kg X h and prolonged the half-life of diazepam from 36.9 +/- 4.1 to 85.0 +/- 14.7 h. Plasma concentrations of desmethyldiazepam, a diazepam metabolite, were reduced after omeprazole treatment. Omeprazole also reduced the plasma clearance of phenytoin from 25.1 +/- 2.0 to 21.4 +/- 1.8 ml/kg X h and prolonged its half-life from 20.7 +/- 1.9 to 26.3 +/- 2.7 h. Renal excretion of the major metabolite of phenytoin (p-hydroxyphenyl-phenyl-hydantoin) was not changed. Omeprazole did not affect the volume of distribution and the plasma protein binding of either diazepam or phenytoin. In vitro studies with human liver microsomes showed that omeprazole in equimolar concentrations (0.5 mM) was a stronger inhibitor than cimetidine of 7-ethoxycoumarin deethylase activity. These data confirm that omeprazole interferes with the elimination of other drugs by an inhibition of the drug-metabolizing monooxygenase system of the human liver.

Adult↗
PubMed1984

The inhibition of drug metabolism by cimetidine in patients with liver cirrhosis.

The effect of cimetidine treatment, 1 g daily over 6 days, on the disposition of theophylline was studied in nine patients with liver cirrhosis and in nine patients without liver disease. Plasma elimination half-life tended to increase from 14.6 +/- 8.2 h to 24.3 +/- 14.1 h in the cirrhotic patients (P greater than 0.05) and from 8.3 +/- 4.2 h to 10.3 +/- 4.1 h in the control patients (P less than 0.05). Total plasma clearance decreased from 0.50 +/- 0.23 ml/kg/min to 0.41 +/- 0.21 ml/kg/min (P less than 0.05) in the cirrhotics and from 0.77 +/- 0.34 ml/kg/min to 0.58 +/- 0.18 ml/kg/min (P less than 0.05) in the controls. Pretreatment clearance values were also significantly reduced in the cirrhosis group. No change was observed in the volume of distribution of theophylline. The degree of inhibition of theophylline metabolism did not depend on whether the patients were smokers, or whether they had low pretreatment clearance values. In liver cirrhosis, inhibition of drug metabolism by cimetidine varies widely and is unpredictable in the individual patient.

Adult↗
PubMed1984

[Whipple's disease: an important differential diagnosis in polyarthritis and fever].

Whipple's disease is frequently recognised only after numerous diagnostic sidetracks. As demonstrated by four patients polyarthritis and fever are characteristic early symptoms for many years. Early consideration of this differential diagnosis and subsequent small intestinal biopsy permit early diagnosis of the disease. Intermittent or long-term antibiotic treatment successfully removes intestinal marasmus and its accompanying symptoms.

Adult↗
PubMed1984

Double-blind comparison of once-daily bopindolol, pindolol and atenolol in essential hypertension.

The efficacy of once-daily bopindolol, a nonselective beta-adrenoceptor blocking agent with partial agonist activity, and of pindolol and atenolol in the treatment of essential hypertension has been compared. 369 patients were investigated in a double-blind parallel-group study. The treatment period was 10 weeks. Blood pressure normalisation (diastolic BP equal to or less than 90 mmHg) was to be achieved by a stepwise increase in the dose of the test drugs, and, if required, by addition of a diuretic. Normalisation of blood pressure was achieved in 71 to 76% of the subjects, with no significant differences between bopindolol, pindolol, and atenolol. Special attention was given to evaluation of side effects by using two methods for registration of all adverse events during the study. A low incidence of drug-induced side effects was observed, with no significant difference between bopindolol, pindolol, and atenolol. There was no evidence of unsuspected adverse reactions due to bopindolol.

Adrenergic beta-Antagonists↗
PubMed1984

Effect of clofibrate on the metabolism of bilirubin, bromosulphophthalein and indocyanine green and on the biliary lipid composition in Gilbert's syndrome.

Clofibrate (20 mg day-1 kg-1 body weight) given orally for 2 weeks to 18 subjects with Gilbert's syndrome reduced the total serum bilirubin concentration from 44.4 (22.1-71.7) mumol/l (median, range) to 15.0 (7.9-28.9) mumol/l, mainly by decreasing the 'indirect' fraction to 34.5% of pretreatment values. In contrast to treatment with phenobarbitone, clofibrate did not change the ratio of bilirubin mono- to di-conjugates in bile. The initial plasma disappearance rate of indocyanine green and of bromosulphophthalein did not show consistent changes during clofibrate treatment but the 'apparent' maximal biliary secretion capacity of bromosulphophthalein (Tm) decreased in most of the patients studied, whereas the relative storage capacity (S) tended to increase. As expected, the cholesterol saturation of bile increased in all subjects. These results suggest that clofibrate increases mainly the glucuronidation of bilirubin, promoting as such the overall hepatic transport in Gilbert's syndrome. However, it decreases the maximal biliary secretion of bromosulphophthalein, possibly by an increased hepatic retention. These phenomena might be linked to the augmented content of Z protein in the liver.

Adult↗
PubMed1984

Protein binding of valproic acid in maternal and umbilical cord serum.

The serum valproic acid levels of 18 maternity patients at the time of delivery were compared with the valproic acid levels in the umbilical cord serum. The levels in the umbilical cord serum were 1.1-4.6 times higher than those in the maternal serum, with a mean value of 1.38. One explanation for this difference apparently is an increased protein binding of valproic acid in the infant's serum. Protein binding was determined in nine patients, in six by equilibrium dialysis and in three by ultrafiltration. The median value of the free fraction of valproic acid was 9.1% (range, 5.8-16.4%) in the umbilical cord serum (equilibrium dialysis) and 15% (range, 12.7-35.3%) in the maternal serum. The difference between the infant and the maternal serum is significant.

Adolescent↗