PubMed Health⌕ Search

Biomedical subjects

E Musch

Publications and source records attributed to E Musch.

51 records · Page 3Linked to original sources
PubMed1987

[Fulminant liver failure in tuberculostatic therapy. A contribution to clinical aspects and pharmacokinetics].

A 23-year old female patient on a prolonged regimen of tuberculostatic chemotherapy finally developed fulminant hepatic failure shortly after addition of hormonal contraception. The pathophysiology of this almost fatal drug reaction is described as a pharmacokinetic interaction: the inherent hepatotoxicity of prothionamide-the drug finally prescribed during convalescence-was significantly potentiated by the Cyt-P-450-inducing effect of the progestagen component of the hormonal contraceptive. Potentiation of hepatotoxicity in connection with tuberculostatic regimes containing rifampicin is well known and this pharmacokinetic phenomenon also pertains to the combination with other Cyt-P-450-inducing drugs such as, for instance, anticonvulsants. However, since the maximum of rifampicin-related Cyt-P-450-inducing effect is limited to the initial 2-3 weeks of therapy, the hepatotoxic risk triggered by this rifampicin-related induction may decline during continuation of therapy. This, unfortunately, does not pertain to the other Cyt-P-450-inducers, whose inductive effect is not time-limited. Progressive severe hepatic damage may follow from such interaction as demonstrated in this case report.

Adult↗
PubMed1985

Pharmacokinetics of oral and intravenous rifampicin during chronic administration.

We investigated the pharmacokinetics of rifampicin and its major metabolites, 25-desacetylrifampicin and 3-formylrifampicin, in two groups of six patients with active pulmonary tuberculosis, who received either multiple oral or intravenous rifampicin therapy in combination with intravenous isoniazid and ethambutol. Serum concentrations of rifampicin were each determined after a single oral and intravenous test dose of 600 mg rifampicin at the beginning and after 1 and 3 weeks of tuberculostatic treatment. Analysis of rifampicin and its metabolites was performed by high-pressure liquid chromatography. It was found that, due to autoinduction of its metabolizing hepatic enzymes, the systemic clearance of rifampicin increased from 5.69 to 9.03 l/h after 3 weeks of multiple dosing. The volume of distribution of the drug was constant over the period of this study. The bioavailability of the active, orally administered rifampicin decreased from 93% after the first single oral dose to 68% after 3 weeks of oral and intravenous rifampicin therapy. Relating to the increase in systemic (hepatic) clearance, a bioavailability no lower than 90% can be predicted. The reduction to 68% indicates that, in addition to an increase of hepatic metabolism, an induction of a prehepatic "first-pass" effect resulted from multiple rifampicin doses. Our study of rifampicin metabolites confirm that prehepatic metabolism was induced, since a higher metabolic ratio resulted after the oral doses than after the intravenous rifampicin test doses. A preabsorptive process can therefore be excluded as a cause of reduced bioavailability.

Administration, Oral↗
PubMed1985

Determination of isoniazid, acetylisoniazid, acetylhydrazine and diacetylhydrazine in biological fluids by high-performance liquid chromatography.

A high-performance liquid chromatographic assay for the determination of isoniazid, acetylisoniazid, acetylhydrazine and diacetylhydrazine (plasma and urine) was developed. The m-chlorobenzoyl derivatives of isoniazid, acetylhydrazine and the internal standard propionylhydrazine were prepared, separated on a RP-18 column and detected at 220 nm. Acetylisoniazid, diacetylhydrazine and the internal standard dipropionylhydrazine were converted to isoniazid, acetylhydrazine, and propionylhydrazine by acidic hydrolysis and subsequently derivatized with m-fluorobenzoyl chloride, separated on a RP-18 column and detected at 220 nm. The lower limits of detection in plasma are acetylhydrazine 0.5 nmol/ml, isoniazid 1.0 nmol/ml, diacetylhydrazine 1.0 nmol/ml and acetylisoniazid 2.0 nmol/ml, and in urine, acetylhydrazine 10 nmol/ml, isoniazid 15 nmol/ml, diacetylhydrazine 20 nmol/ml and acetylisoniazid 40 nmol/ml. This method is sensitive, reproducible, accurate and precise; therefore, it is well suited for detailed pharmacokinetic studies.

Body Fluids↗
PubMed1985

[Acute isoniazid poisoning].

Acute isoniazid intoxication is characterised by high mortality and vomiting, seizures, coma and metabolic acidosis as main symptoms. Besides isoniazid, its metabolites may also cause neurotoxicity, as demonstrated in a patient. Delayed onset of neurotoxicity should be considered. The therapy of intoxication with special emphasis on high-dose vitamin B6 application is discussed.

Acidosis↗
PubMed1983

[Metabolic effects of antacids and interactions with other drugs].

The incidence of side effects from antacids is low, but patients with renal insufficiency are at risk to develop alkalosis with high doses of calcium carbonate or magnesium hydroxides, or to develop hypercalcemia due to insufficient calcium elimination by the kidneys.--A great potential exists for drug interactions with antacids. In most instances, the effectiveness of other drugs is decreased in the presence of antacids, but effectiveness may be increased for L-dopa (less degradation in stomach) or quinidine (renal elimination reduced). Interactions at the absorption level can be avoided by administering the antacid one hour after intake of the other drugs (one hour after meals) which is also the optimum dosing schedule to ensure good antacid effect. Interactions through changes of urine pH are not eliminated by observing special dosing time schedules, but by modifying the dose or by selecting alternative drug treatment.

Absorption↗
PubMed1982

[Incidence of hepatotoxic side effects during antituberculous therapy (INH, RMP, EMB) in relation to the acetylator phenotype (author's transl)].

In 95 patients with active tuberculosis, we investigated in a prospective study the influence of the acetylator phenotype on the hepatotoxic side effects of the antituberculous regimen isoniazid (INH) 10 mg/kg, rifampicin (RMP) 10 mg/kg, and ethambutol (EMB) 25 mg/kg. Besides a much higher incidence of isoniazid hepatitis (SGOT, SGPT greater than 200 U/l) in 12.6% of patients treated--as compared to the incidence reported in large chemoprophylaxis trials with isoniazid monotherapy in the range of 0.5%-1% (IUAT 1969, U.S.P.H.S. 1971)--we observed a significant, higher risk of isoniazid-induced hepatotoxicity in slow acetylators (p less than 0.01): in 26 of 56 slow acetylators (= 46.4%), but only in 4 of 30 rapid acetylators (=13.3%) were transaminases in the serum elevated greater than 50 U/l. The 12 patients with the most severe hepatotoxic side effects (SGOT, SGPT greater than 200 U/l) were all slow acetylators. Women developed severe hepatic injury more often than men (p less than 0.05). In cases with isoniazid hepatitis, triple therapy was either stopped or reduced to a combination RMP, EMB. In cases with less severe liver injury, triple therapy was continued. In all patients transaminases normalized within 2-4 weeks. On return to full triple therapy, none of the patients developed new elevation of transaminases. The constant occurrence of isoniazid hepatitis during the 2nd-4th week (19 +/- 7 days) as well as the normalization without any new hepatotoxic reaction suggest that there may be an interaction between RMP and isoniazid metabolism limited to the early phase of chemotherapy.

Acetylation↗
PubMedDate not supplied

Lipid peroxides in the polychemotherapy of cancer patients.

There is evidence that a variety of anticancer drugs exert their cytotoxic activity by a free-radical-mediated mechanism. These drugs include anthracyclines such as adriamycin, daunorubicin, 4-epi-adriblastin as well as bleomycin, procarbazine, vincristin, cyclophosphamide, etoposide and mitomycin C. The aim of this study was to investigate whether cancer patients who underwent polychemotherapy (n = 44) show more signs of oxidative stress in plasma than a group of healthy controls (n = 52). As an index of free radical generation, plasma concentrations of thiobarbituric-acid-reactive substances (TBARS), well-accepted as markers for oxidative stress, were determined by fluorometric detection after separation by high-performance liquid chromatography. In 12 cases, the TBARS were measured both before and after a chemotherapy course. After chemotherapy, 10 of 12 patients showed a marked increase in plasma TBARS concentration compared to values measured before therapy [9.02 +/- 1.84 nmol/ml (n = 12) vs. 11.58 +/- 2.49 nmol/ml (n = 12); p = 0.002, t-test for paired observations]. Tumor patients in general had significantly larger amounts of TBARS in plasma in comparison with a control group [mean 11.88 +/- 3.51 nmol/ml (n = 44) vs. 7.51 +/- 2.14 nmol/ml (n = 52); p < 0.001, t test]. Our results are evidence that repetitive polychemotherapy with radical-generating compounds may exceed the antioxidative capacities of cancer patients and may lead to oxidative stress.

Adult↗
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↗