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R Gugler

Publications and source records attributed to R Gugler.

157 records · Page 9Linked to original sources
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In vivo interactions between H2-receptor antagonists and ethanol metabolism in man and in rats.

The influence of a 7-day medication of either cimetidine (1,000 mg per day) or ranitidine (300 mg per day) on serum ethanol concentrations after a single oral dose of ethanol (0.8 gm per kg body weight) was investigated in a randomized placebo-controlled study in eight male volunteers. Compared with the placebo, cimetidine but not ranitidine produced a significant increase in both the peak serum ethanol concentration (85.9 +/- 3.5 vs. 73.0 +/- 3.2 mg dl-1, p less than 0.02) and in the area under the serum ethanol concentration time curve (350 +/- 19 vs. 304 +/- 25 mg dl-1 hr-1, p less than 0.05). However, the ethanol elimination rate was not affected by cimetidine. When ethanol (1.0 gm per kg body weight) was administered intravenously, cimetidine failed to induce a change in ethanol metabolism. Furthermore, the effect of H2-receptor antagonists was studied in animal experiments. Female Sprague-Dawley rats received a single dose of ethanol (7 or 3 gm per kg body weight) together with an intraperitoneal injection of either cimetidine (120 mg per kg body weight), ranitidine (120 mg per kg body weight) or isotonic saline. After alcohol absorption, ethanol elimination was significantly inhibited by both cimetidine (3.99 +/- 0.39 vs. 5.68 +/- 0.23 mmoles kg-1 hr-1, p less than 0.02) and ranitidine (4.21 +/- 0.14 vs. 5.68 +/- 0.23 mmoles kg-1 hr-1, p less than 0.02) at high ethanol concentrations (60 to 20 mM) but not at blood ethanol concentrations below 20 mM.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
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Pharmacokinetics and bioavailability of cimetidine in gastric and duodenal ulcer patients.

The pharmacokinetics and bioavailability of cimetidine after 200 mg given intravenously and orally was studied in 6 gastric and 6 duodenal ulcer patients aged between 28 and 64 years. There were no differences in any of the pharmacokinetic parameters between the two ulcer groups, but there was considerable variation which was mainly age-related. Bioavailability was not complete, but was about 60% based on the plasma concentration data. The volume of distribution at steady-state was about 80% of body weight, and the plasma clearance value of 495 ml/min was mainly due to renal clearance (293 ml/min). The elimination half-life was approximately 2 hours. These pharmacokinetic parameters together with the percentage of dose excreted unchanged in urine following intravenous administration were all highly age correlated; all decreasing with age except the elimination half-life which increased with age. Of clinical importance is the finding that the time for which the plasma concentration exceeded 0.5 microgram/ml following oral administration was also highly age-dependent, increasing by more than 2-fold in the elderly (53 to 64y) compared with the younger (28 to 45y) patients.

Adult↗
PubMedDate not supplied

Clinical pharmacokinetics of cimetidine.

Cimetidine is the first histamine H2-receptor antagonist with wide clinical application. It is a weak base and a highly water-soluble compound which can be measured in biological fluids by a number of high-pressure liquid chromatographic methods. Following intravenous administration, the plasma concentration profile follows multicompartmental characteristics. The total systemic clearance is high (500 to 600 ml/min) and is mainly determined by renal clearance. The volume of distribution (Vd beta or Vdss) is of the order of 1 L/kg and this about equals bodyweight. Elimination half-life is approximately 2 hours. Following oral administration of cimetidine, 2 plasma concentration peaks are frequently observed, probably due to discontinuous absorption in the intestine. The absolute bioavailability in healthy subjects is about 60%. In patients with peptic ulcer disease, bioavailability is around 70%, but the variation is much greater than in healthy subjects. Absorption and clearance of cimetidine are linear after 200 and 800mg doses. Mean steady-state plasma concentrations on a standard 1000mg daily dose are 1.0 microgram/ml (range 0.64-1.64 micrograms/ml) and are reproducible after treatment periods of up to 2 years. When taken with food, the extent of absorption is unaltered, but a delay occurs and only 1 peak in the plasma concentration curve is apparent. Partial gastrectomy (Billroth I, II) causes an increase in systemic availability of cimetidine by an unclear mechanism. Distribution of cimetidine leads to extensive uptake into kidney, lung and muscle tissues. It distributes into the cerebrospinal fluid (CSF) at a ratio of 0.1 to 0.2 compared with plasma. The mean saliva to plasma ratio is 0.2 (range 0.1-0.55). Plasma protein binding is 20%, and there is no relevant effect of changes in binding on the pharmacokinetics of cimetidine. Uptake of cimetidine into red blood cells leads to concentrations equal to those in plasma. Between 50 and 80% of the dose administered intravenously is recovered in urine as unchanged cimetidine. This fraction is less after oral doses, but is independent of the amount of the dose. In ulcer patients, 40% is recovered unchanged in urine after oral administration. Biliary excretion of cimetidine accounts for only 2% of the dose.(ABSTRACT TRUNCATED AT 400 WORDS)

Aging↗
PubMedDate not supplied

Phase II clinical trial of combined natural interferon-beta plus recombinant interferon-gamma treatment of chronic hepatitis B.

BACKGROUND/AIMS: Alpha-interferon (IFN-alpha) is an effective treatment for chronic hepatitis B but only 25-40% of patients will profit from a long-term beneficial response to the currently recommended schedule of 3-6 MU given 3 times a week for 6 months. Clinical trials are therefore needed to investigate alternative modifications of interferon therapy, including combinations of different antivirals or immune modulators in order to improve the therapeutic approach to chronic hepatitis B infection. In a phase II trial we evaluated whether a combination of natural interferon-beta (nIFN-beta) with strong antiviral activity plus recombinant interferon-gamma (rIFN-gamma) with a predominantly immunomodulatory activity is able to increase the response rate compared to historical controls treated with IFN-alpha in a conventional regimen. METHODOLOGY: Forty patients with chronic hepatitis B were included in this trial of combined interferon therapy at a dosage of 6 MU nIFN-beta during week 1 followed by 3 MU for weeks 2-4 plus rIFN-gamma at a daily subcutaneous (s.c.) injection of 150 microg during the entire 4 weeks of the treatment period. Patients entered the trial on the basis of the following criteria: hepatitis B surface antigen (HBsAG), HBeAG and HBV-DNA positive for at least 6 months, HDV, EBV, CMV, anti-HIV negative, and chronic hepatitis proven on biopsy taken within 4 weeks of entry as well as 6 and/or 12 months after interferon therapy. The final diagnosis and classification of chronic hepatitis has been based on guidelines according to a revised classification of chronic hepatitis (Desmet 1994). The post-treatment follow-up was 12 months. RESULTS: The combined interferon therapy achieved complete responses with seroconversion from HBeAG to anti-HBe and a negative HBV-DNA (dot blot) test, as well as normalization of ALT activity in 15 patients, and partial response with negativation of HBV-DNA concomitant to a decrease in aminotransferase activity to near normal levels in 6 patients. Nineteen patients showed no response to viral markers but showed relief of clinical symptoms as well as pronounced decrease of serumtransaminase activity. Grading of liver biopsies demonstrated an improvement of histologic parameters after the interferon regimen in half of the evaluable patients (n=22). Histological response has been quantified by a reduction in the score of histological activity (HAI-index) from 12.6 before to 7.6 after interferon therapy, and in the inflammation and cellular degeneration score (ICD) from 9.9 to 5.2. Histological response, however, failed to show a consistent correlation with serologic response. This medium-dose combination of interferon-beta and interferon-gamma was tolerated very well by the patients, this good tolerability being explained by tachyphylaxis in response to daily interferon doses. No serious side effects or decompensation of liver function were observed during the 4-week period of therapy or the follow-up, despite the special clinical situation where 60% of the patients included in the study presented with histologically proven cirrhosis (35% of them with clinical manifestation of mildly decompensated cirrhosis). CONCLUSIONS: This short-term regimen of combined nIFN-beta + rIFN-gamma therapy in patients with chronic hepatitis B proved to be equieffective to long-term treatment with interferon-alpha and combines high clinical tolerability with good practicability, as it can be administered on an in-patient basis, ensuring close patient monitoring.

Adolescent↗