The effect of pindolol on exercise-induced cardiac acceleration in relation to plasma levels in man.

The correlation between the beta receptor blocking activity of pindolol and plasma level was studied in 8 subjects after a 10-mg oral dose. Exercise tachycardia was markedly reduced over a period of at least 6 hr. Significant effects were recorded 30 min after the drug. For each individual there was a close correlation between log plasma level and beta blockade. The regression lines were parallel as shown by analysis of covariance; the intercepts, however, were significantly different. It can be concluded that there is a correlation between plasma level and beta adrenergic blockade by pindolol, but the data failed to establish in different individuals the blood levels necessary to achieve effective adrenergic blockade.

Diazepam interaction with antituberculosis drugs.

The influence of antituberculosis drugs on diazepam disposition was assessed in a series of volunteers and patients who received single intravenous doses of diazepam. In study 1, nine healthy subjects received diazepam in the drug-free control state and again during treatment with isoniazid (INH), 180 mg/day. INH did not alter diazepam volume of distribution (Vd) or protein binding, but prolonged mean elimination half-life (t1/2) from 34 to 45 hr (p less than 0.02), and reduced total clearance from 0.54 to 0.40 ml/min/kg (p less than 0.02). In study 2, diazepam disposition in a group of seven tuberculous patients on triple therapy with INH, ethambutol (EMB), and rifampin (RIF) was compared with that in healty drug-free controls matched for age and sex. Diazepam Vd and protein binding were nearly identical between groups, but mean t1/2 among patients (14 hr) was significantly shorter than in controls (58 hr, p less than 0.01) and total clearance correspondingly increased (to 1.50 from 0.37 ml/min/kg, p less than 0.01). Study 3 compared six newly diagnoses tuberculous patients receiving initial therapy with EMB alone with age- and sex-matched controls. Diazepam unbound fraction in patients tended to be higher than in controls, and diazepam Vd and clearance tended to be lower but the differences were not statistically significant. Thus, diazepam clearance is impaired and t1/2 prolonged by administration of INH alone. Markedly increased clearance and shortened t1/2 in triple-therapy patients is probably due to enzyme-inducing effects of RIF. Dosage of diazepam may require adjustment in patients with tuberculosis on chemotherapy.

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.

Endogenous ligand(s) decrease drug--protein binding in uremic sera: a fluorescence probe study.

Human serum albumin (HSA) was isolated and purified (greater than 97% purity) from normal sera, from sera of patients with severe chronic renal insufficiency and from sera to which a strongly protein bound acidic drug--clofibrinic acid--was added as a model ligand. The binding properties were evaluated using dansylglycine as a fluorescent probe. Data were analyzed according to Scatchard, the binding constants were calculated by least square approximation. The binding of dansylglycine to HSA from uremic sera was substantially decreased, reflected mainly by a lower product n1 . K1, as was the binding of dansylglycine to HSA from model sera containing clofibrinic acid. The binding was restored to almost normal when HSA was treated with charcoal. It is concluded that the impaired binding of many mostly acidic drugs to HSA in uremia is due to the presence of endogenous ligands. In addition a minor contribution by changes in HSA structure cannot be excluded.

Evidence for extratumoural storage of catecholamines in pheochromocytoma patients.

Following the removal of a pheochromocytoma in three female patients the daily excretion of catecholamines and their metabolites was still considerably elevated for about one week. The excretion rates declined during this period with half-lives of 1.8 to 10.9 days for catecholamines and 2.1 to 4.7 days for metanephrines, vanilmandelic acid, and vanilglycol. The cumulative urinary excretion of catecholamines and their metabolites following surgical removal of the tumour was nearly as high as the catecholamine content of the pheochromocytomas. This large amount of catecholamines must have been located outside the tumour, most probably within the sympathetic nerve, where it is subject to release following physiological stimuli. Furthermore, this fact may provide an explanation for hypertensive crises in pheochromocytoma patients.

[Polymorphisms and deficient drug metabolism as triggers of toxic reactions (author's transl)]. / Polymorphismen und Defekte des Arzneimittelstoffwechesels als Ursache toxischer Reaktionen.

The influences of polymorphisms and pharmacokinetic defects of drug metabolism as causes of toxic drug reactions are presented. The different mechanisms of toxic side effects mediated by alterations of the metabolism and excretion of drugs are discussed.

Sensitive high-performance liquid chromatographic assay for the determination of eugenol in body fluids.

The high-performance liquid chromatographic assay described permitted a simple, rapid, sensitive, selective and precise quantitative determination of eugenol in body fluids (serum, urine and bile) without derivatization. Amounts in the range 0.02-100 micrograms of eugenol per millilitre of body fluid were determined with intra-assay coefficients of variation below 4% (3.72-1.13%). The short analysis time for each sample and the selectivity even at low concentrations made this assay suitable for pharmacokinetic studies. Eugenol undergoes a pronounced first-pass effect; in serum, unconjugated eugenol was not detected after an oral dose of 150 mg. The kinetics of eugenol conjugates were measured. More than 80% of the dose was excreted within 6 h after oral administration.

[Chronic fatigue syndrome]. / Das "Chronische Müdigkeitssyndrom" ("Chronic Fatigue Syndrome").

Reports on conditions of chronic fatigue associated with other somatopsychic symptoms after acute viral infections have led to the hypothesis of a "chronic fatigue syndrome" (CFS). Historical disease descriptions, like e.g. "myalgic encephalomyelitits", were updated by means of modern virological diagnostic techniques and data analysis. Several viral agents like enteroviruses, Epstein-Barr virus, Human-Herpesvirus 6 and other herpesviruses have been implicated for possible underlying infections. A preliminary disease definition by the Center for Disease Control (CDC) seeks to provide a rational basis for further etiological studies. In fact, there is growing consensus that the syndrome comprises various separate disease entities and causative agents. Today we can tentatively differentiate a "chronic mononucleosis" after infection with Epstein-Barr virus, an etiologically undetermined "postviral fatigue syndrome" and a fatigue syndrome of the myalgic type after Coxsackie-B virus infection. Furthermore, a valid diagnosis of CFS must be based on the exclusion of defined other diseases and the awareness of dealing with a hypothetical concept. As a result, current knowledge does not yet allow specific therapeutic recommendations.

Absorption of oral tetracycline in patients with Billroth-II gastrectomy.

The bioavailability of a single 250-mg oral dose of tetracycline hydrochloride was studied in seven patients following Billroth-II gastrectomy in comparison with seven control subjects matched for age and body weight. There were no significance differences between control subjects and gastrectomized patients in the apparent lag time prior to the start of absorption (23.6 vs. 22.8 min), peak serum tetracycline concentration (1.72 vs. 1.75 microgram/ml), the time of attainment of peak concentrations (3.35 vs. 3.42 hr), the apparent first-order absorption half-life (1.8 vs. 1.4 hr), or the apparent first-order elimination half-life (8.0 vs. 8.7 hr). Completeness of tetracycline absorption, as judged by area under the 24-hr serum concentration curve, did not differ significantly between the two groups, nor did 24-hr urinary excretion of tetracycline. Thus the abnormalities of gastrointestinal structure and function produced by Billroth-II gastrectomy do not result in impairment of the rate and completeness of tetracycline absorption.

Defective N-oxidation of sparteine in man: a new pharmacogenetic defect.

Sparteine, an antiarrhythmic and oxytocic drug, is metabolised by N1-oxidation. The sparteine-N1-oxide rearranges with loss of water to 2- and 5-dehydrosparteine. 18 (i.e., 5%) out of 360 subjects were unable to metabolise the drug. These persons, who were designated as nonmetabolisers, excreted almost 100% of the administered dose in urine as unchanged drug. The defective metabolism of sparteine was found to have a genetic basis. Sparteine-N1-oxidation appears to be determined by two allelic genes at a single locus where nonmetabolisers are homozygous for an autosomal recessive gene.