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Biomedical subjects

J Bircher

Publications and source records attributed to J Bircher.

At least 55 records · Page 3Linked to original sources
PubMed1986

Treatment of liver disease with malotilate. A pharmacokinetic and pharmacodynamic phase II study in cirrhosis.

Malotilate, a sulphur-containing compound with antifibrotic and hepatoprotective properties in several animal models, has been investigated in cirrhotic patients. Nine patients with cirrhosis of various aetiologies and severity, and 4 healthy volunteers, participated in a pharmacokinetic study. After a single dose of 500 mg malotilate p.o. peak malotilate plasma concentration measured by GC-MS was 35 times higher in patients (median 0.70 micrograms/ml) than in controls (median 0.019 micrograms/ml). The median apparent oral clearance was approximately 50 times lower in cirrhotics (median 2.21/min) than in healthy volunteers (1181/min). The apparent oral clearance was significantly correlated with indicators of portal-systemic shunting, such as the 2-h postprandial serum bile acids and the bioavailability of oral nitroglycerine. Urinary output of the glucuronidated metabolite-(M3), measured by HPLC, was normal in patients, whereas recovery of metabolite-M6 (resulting from ring opening and loss of sulphur) was reduced. Six patients in an open 6-month trial received malotilate 200 mg t.i.d. for 2 months and 400 mg t.i.d. for 4 months. The thrombocyte count increased and serum ferritin level fell in all patients, and serum cholinesterase rose and IgA decreased in 5 of 6. The other indicators of liver function did not show a significant change. Dry skin was the only possible adverse effect. It is concluded that first-pass elimination of malotilate is dramatically reduced in cirrhotics, and that a smaller amount of the drug reaches the liver in such patients. Malotilate was well tolerated, even in patients with advanced disease.

Adult↗
PubMed1986

Treatment of hydatid disease with high oral doses of mebendazole. Long-term follow-up of plasma mebendazole levels and drug interactions.

Plasma mebendazole levels were analysed retrospectively in patients treated for inoperable infections with Echinococcus multilocularis or granulosus. In 10 patients receiving mebendazole at 4 dose levels there was no relation between dose and plasma concentration. In 17 patients followed on the same dose for more than 18 months, the plasma levels varied with individual coefficients of variation ranging from 27 to 72%. The data reveal the limitations of single measurements of plasma mebendazole and emphasize the need for repeated monitoring. Coadministration of phenytoin and carbamazepine seemed to lower plasma levels, presumably as a result of enzyme induction. It was not possible appreciably to raise the mebendazole concentrations by inhibition of drug metabolizing enzymes with cimetidine.

Adult↗
PubMed1986

Ciclosporin concentration in the rabbit aqueous humor and cornea following subconjunctival administration. Importance of anatomical site of injection.

The model compound lidocaine was used in the rabbit to investigate different sites of subconjunctival injection for the achievement of reproducible drug concentrations in the aqueous humor. Only epibulbar injections were satisfactory, but not parabulbar or injections under the lower fornix. After epibulbar administration of 0.8 ml 5% ciclosporin, median concentrations in the aqueous humor were 360, 700 and 200 ng/ml after 2, 8, and 24 h, respectively. Corresponding levels in the cornea were 32, 27, and 12 ng/ml. It appears that drug concentrations resulting from epibulbar injections may be therapeutically useful.

Animals↗
PubMed1985

Treatment of cystic echinococcosis (Echinococcus granulosus) with mebendazole: assessment of bound and free drug levels in cyst fluid and of parasite vitality in operative specimens.

Chemotherapy of the larval stage of Echinococcus granulosus in man with high oral doses of mebendazole has only been partly successful. In order to improve effective pharmacotherapy of this disease with mebendazole, the optimal time for blood sampling has been assessed and the mebendazole concentrations acting on the parasite have been compared with their viability. The optimal time for blood sampling was analysed in 14 patients during longterm treatment with mebendazole. The plasma level 4 h after the morning dose exhibited the best correlation with the average 24-h concentration, suggesting that the plasma level should be monitored 4 h after the morning dose. In 22 patients undergoing surgery for hydatid disease, the mebendazole concentration in cyst fluid was significantly correlated with its plasma level 4 h after the morning dose. In 13 of them the free drug concentration was determined by equilibrium dialysis and it was almost identical with the free mebendazole concentration in plasma. Results of viability tests in 12 cases revealed viable cysts in 6 cases and possibly viable cysts in 6 other cases. Even patients treated for more than 12 months still had viable cysts.

Adult↗
PubMed1985

Pharmacokinetics of amiodarone, desethylamiodarone and other iodine-containing amiodarone metabolites.

In 23 patients treated with the iodine-containing antiarrhythmic drug amiodarone, the plasma concentrations of amiodarone, desethylamiodarone and iodine have been studied. Besides amiodarone and desethylamiodarone, a pool of iodine-containing substances, NANDAI (non-amiodarone-, non-desethylamiodarone-iodine), was present. At steady state the iodine content of NANDAI amounted to 64% and the iodine content of amiodarone plus desethylamiodarone to 36% of total serum iodine. At steady state 26% of the NANDAI fraction was made up of inorganic iodide, the average plasma concentration of which was at least 40 times above the upper limit of the normal range. The serum elimination half-life of NANDAI of 57-160 days exceeded that of amiodarone (35-68 days) and of desethylamiodarone (31-110 days). At steady state the serum concentration of desethylamiodarone appears to be related to the concentration of amiodarone by a Michaelis-Menten type function, yielding a Km of amiodarone of 2.45 mumol/l and a maximal desethylamiodarone concentration of 3.61 mumol/l.

Adolescent↗
PubMed1985

The portacaval and splenocaval shunt in the normal rat. A morphometric and functional reevaluation.

Consequences of a portacaval and a distal splenocaval shunt on the liver were examined in normal male rats with measurements of the fractional clearance of ICG, of aminopyrine demethylation and of the hepatic ultrastructure with morphometric techniques. Twenty days after a portacaval shunt liver weight/100 g body weight was 30% smaller than in sham-operated controls. The most pronounced reduction of 50% occurred with surface area of the RER, whereas hepatocyte volumes, SER-surface area, mitochondria and peroxisomes were reduced between 30 and 40% hepatogenic lysosomes and non-hepatocytes/100 g b.wt. remained unchanged. The loss of liver mass is therefore compatible with the hypothesis, that it is the consequence of a decrease in synthetic and an increase in catabolic processes. The rate of elimination of ICG from plasma was proportional to the liver weight (r = 0,79, n = 20) and 14C-exhalation derived from [14C]aminopyrine was correlated with the surface of the SER (r = 0.72, n = 20), confirming that the morphometrically observed changes are functionally relevant. The lack of morphological and functional sequelae following distal splenocaval shunt suggests that blood drained by the splenic vein is not essential for the integrity of the liver in rats.

Aminopyrine↗
PubMed1985

High oral doses of mebendazole interfere with growth of larval Echinococcus multilocularis lesions.

The natural development of the larval stage of Echinococcus multilocularis in man has been studied in 7 patients after presumed radical operation 2 8/12-11 2/12 years prior to detection of a relapse. The volumes of the recurring lesions were assessed by CT-scanning, and assuming linear growth a median increase of 14.8 ml/year (range 3.8-220 ml/year) was calculated. In 6 patients treated for a median duration of 4 5/12 years with high oral doses of mebendazole a median growth rate of -3.0 ml/year (range-470- + 10.2 ml/year) was found, which differed significantly from the natural growth rate (P less than 0.01). Although the patients improved clinically, there was evidence of persistent infection. These data are the first controlled evidence that high oral doses of mebendazole may be parasitostatic in alveolar echinococcosis in man. Although not curative, this pharmacological effect appears to be clinically beneficial.

Adult↗
PubMed1985

Polymorphic dextromethorphan metabolism: co-segregation of oxidative O-demethylation with debrisoquin hydroxylation.

Dextromethorphan hydrobromide, 25 mg po, was given to 268 unrelated Swiss subjects to study urinary drug and metabolite profiles. Rates of O-demethylation yielding the main metabolite dextrorphan were expressed by the urinary dextromethorphan/dextrorphan metabolic ratio. We found a bimodal distribution of this parameter in our population study, which indicates that there are two phenotypes for dextromethorphan O-demethylation. The antimode at a metabolic ratio of 0.3 separated the poor metabolizer (PM; n = 23; prevalence of 9%) from extensive metabolizer (EM) phenotypes. Urinary output of dextrorphan was less than 6% of the dose in all PMs and was 50% in the 245 EMs. Pedigree analysis of 14 family studies revealed an autosomal-recessive transmission of deficient dextromethorphan O-demethylation. In these families, 37 heterozygous genotypes could be identified; however, through use of the urinary drug and metabolite analysis it was not possible to identify the heterozygous genotypes within the EM phenotype group. Co-segregation of dextromethorphan O-demethylation with debrisoquin 4-hydroxylation was also studied. Complete concordance of the two phenotypic assignments was obtained, with a Spearman rank correlation coefficient of rs = 0.78 (n = 62; P less than 0.0001) for dextromethorphan and debrisoquin metabolic ratios. Presumably the two drug oxidation polymorphisms are under the same genetic control. Thus the innocuousness and ubiquitous availability of dextromethorphan render it attractive for worldwide pharmacogenetic investigations in man.

Administration, Oral↗
PubMed1985

Amiodarone-induced vasculitis and polyserositis.

A dose-dependent cutaneous leukocytoclastic vasculitis developed in a 34 year old man who was given amiodarone for supraventricular tachycardias resistant to other drugs. This adverse reaction disappeared within 2 weeks after discontinuation of amiodarone despite its very long half-life of 52 days in this patient. During previous treatment periods with amiodarone, the patient had experienced photosensitivity and dose-dependent polyserositis. Since high doses of amiodarone have been recently proposed for the treatment of resistant cardiac arrhythmias, dose-dependent adverse effects as described here may be encountered with increasing frequency.

Adult↗
PubMed1985

Increased ethanol consumption and blood ethanol levels in rats with portacaval shunts.

In a series of experiments, it was demonstrated that male rats with end-to-side portacaval shunts (PCS) consumed more ethanol and exhibited higher blood ethanol levels than sham-operated control animals in chronic tests with 2% ethanol and water ad libitum. Ethanol intake in the 6 h prior to blood sampling was 2-5 times and blood ethanol 10-50 times higher in PCS than control rats. These effects were not due to the feminization of male rats occurring after a PCS, since female PCS rats exhibited comparable increases of ethanol intake and blood ethanol. In both sexes ethanol elimination rate and alcohol dehydrogenase activity per total liver were lower after PCS than in control rats, explaining the disproportionate increase in blood ethanol relative to ethanol intake. Interestingly, ethanol intake was not abnormal in PCS rats fed a low-protein, low-tryptophan diet (corn) alone or as a supplement to the usual chow diet. Such dietary modulation of ethanol preference in this animal model of chronic liver dysfunction merits further attention.

Alcohol Drinking↗
PubMed1985

Effect of plasma mebendazole concentrations in the treatment of human echinococcosis.

High oral doses of mebendazole were given for a mean period of 23 months to 22 patients with inoperable alveolar or cystic echinococcosis (Echinococcus multilocularis n = 18, E. granulosus n = 4). Clinical, morphological, biochemical and serological findings and plasma mebendazole levels were monitored. Clinical and biochemical improvement or stabilization was observed in 17 patients but the parasitic lesions did not decrease in size in most instances. One patient died shortly after onset of therapy with hemorrhage of esophageal varices. Three patients with alveolar and one with cystic echinococcosis had evidence of progressive disease such as increase of cholestasis, destruction of lumbar vertebrae and growth of an intraperitoneal cyst. The plasma mebendazole levels (4 hr after the morning dose) of the latter 4 patients were 0.09 +/- SD 0.02 mumol/l, while in those with clinical stabilization or improvement it was 0.30 +/- SD 0.14 mumol/l (P less than 0.001). These preliminary data indicate 1) a good clinical response to chemotherapy in most patients despite unchanged size of the parasitic lesions, and 2) a direct correlation of clinical response with plasma mebendazole levels.

Adult↗
PubMed1985

Absolute bioavailability of glyceryl trinitrate from a transdermal system, assessed by digital plethysmography.

The absolute bioavailability of glyceryl trinitrate from a transdermal therapeutic system (Nitroderm TTS, 20 cm2) was assessed with a new method in 6 healthy volunteers. Instead of measuring plasma concentrations the pharmacological effects of glyceryl trinitrate were followed by digital plethysmography. Each experiment consisted of the establishment of an intravenous dose response curve which was followed by a 1-hour application of the transdermal system and a second intravenous dose response curve. The investigations were repeated after pretreatment of each subject with 0.4 mg pindolol i.v. The results show a satisfactory overall consistency of the data and indicate a release rate of 4.4 +/- SD 1.7 micrograms/min of bioavailable glyceryl trinitrate during the first hour of application of this transdermal system. This corresponds to 75 +/- 29% of the release rate obtained by analysis of residual amounts in the TTS.

Administration, Topical↗
PubMed1984

[Mebendazole therapy in echinococcosis. Long-term study and course parameters in 8 patients].

Eight patients with inoperable echinococcosis, four each with the cystic or alveolar form, had received mebendazole (Vermox) at a daily dose of 1.5 g for an average of 27 months. In six patients with clinical symptoms the number of fever attacks fell by 60% and of hospital admissions by 54%, cholangitic and/or icteric attacks disappearing completely. Two patients had no recognizable symptoms, either before or after treatment. One woman with multilocular disease died of bleeding from esophageal varices. The immunological and morphological findings did not reveal any relationship to the clinical course. Apart from reversible leukopenia in one patient there were no serious side effects. These observations indicate a satisfactory effect of long-term treatment of inoperable echinococcosis with mebendazole.

Adult↗
PubMed1984

Lack of effect of haemodialysis on mebendazole kinetics: studies in a patient with echinococcosis and renal failure.

The effect of haemodialysis on mebendazole kinetics has been studied in a patient receiving both mebendazole therapy and haemodialysis. The procedure of haemodialysis did not influence the plasma concentration-time profiles or the mean daily plasma levels. The arterio-venous difference in the dialyser was negligible and no mebendazole could be detected in the dialysate. Protein binding of mebendazole was 90% before dialysis and 88% during dialysis and not significantly different from the binding in patients without renal disease (91.4 +/- 1.9%, n = 22).

Adult↗
PubMed1984

[Automatic finger plethysmography as a human pharmacologic research tool. A methodologic study].

In view of the use of an electronically processed digital plethysmography as a noninvasive pharmacological tool - particularly to measure effects of organic nitrates - 9 healthy young volunteers were examined. The purpose of the investigation was to study baseline recordings and to assess the effects of several well defined exogenous influences. The electronic processor calculated the D/H-ratio of each plethysmographic pulse wave, where D represents the depth of the dicrotic minimum measured from the apex of the systolic maximum and H the total hight of the plethysmographic wave. The D/H-ratio was not significantly influenced by a hot beverage, but fell after a cold drink. In undisturbed volunteers the D/H-ratio had a tendency to fall slightly during a 3-h period of observation. This tendency could be eliminated by small doses of pindolol or dihydroergotamine, but individual fluctuations of the curves were still visible. It appears therefore that a fully automated evaluation of plethysmographic recordings yields best results if the findings in a group of volunteers are averaged.

Adult↗
PubMed1984

[Chemotherapy of human echinococcosis].

In human echinococcosis, today as in the past, surgical removal of the parasite remains the treatment of choice. Beside certain conditions, adjuvant chemotherapy with Vermox is indicated for echinococcus multilocularis as well as echinococcus granulosus. A substantial decrease of the echinococcal parasite mass under Mebendazole is not yet known. Nevertheless jaundiced patients with diffuse liver infestation with echinococcus multilocularis became jaundice-free and able to work. Mebendazole toleration is very good. A closely interrelated medical control of patients under Mebendazole therapy ought to be interdisciplinarily carried through between internists and surgeons.

Administration, Oral↗