The utility of diffusion chambers as models for the description of drug disposition.

Tissue cages were employed to explore the diffusion processes of several cephalosporins into extravascular fluids. Concentrations of cefotaxime in serum and in subcutaneous chambers increased proportionally to the amount of the drug injected. Administration of single equal doses of cephalothin, cephaloridine and cefotaxime resulted in different concentration-time courses in the serum and in diffusion chambers. These observations suggest that diffusion chambers are linked to the tissue at the implantation site. None of the classical compartmental approaches can be applied to evaluate the kinetics of drug diffusion into tissue cages. Correlations of total or non-protein bound drug concentrations in tissue cages to those in the peripheral compartment assumed concentration and time dependent diffusion processes. No specific diffusion constant based on the law of Fick could be derived for the diffusion chambers used in this study. Concentration-time courses in serum and interstitial fluid can be simultaneously evaluated according to pharmacokinetic-pharmacodynamic models. Based on the equation describing the effect site this model can be used to simulate drug concentrations in tissue cages by varying the dose size or the dose interval.

Tiamulin, a new antibiotic for eliminating mycoplasmas from bovine serum 1. Investigations on Spermatozoal Toxicity.

Tiamulin, a new diterpene antibiotic, was investigated for toxicity to spermatozoa. The compound was added to ejaculates via semen extender at a concentration of 50 to 90 mg per 100 ml of total liquid. Motility and the proportion of non-viable spermatozoa were used as criteria of the drug's effect. Tiamulin proved to be safe up to doses of 70 mg per 100 ml of semen extender.

[Monitoring of cardiac function during doxorubicin therapy in metastasized breast cancer. Measuring systolic time interval]. / Uberwachung der Herzfunktion bei Doxorubicintherapie des metastasierten Mammakarzinoms.

Assessment of systolic time interval represents an uncomplicated, sufficiently precise and cheap possibility in clinical practice of cardiac monitoring during treatment with doxorubicin (adriamycin) if the ratio between pre-ejection period interval (PEPI) and left ventricular ejection time interval (LVETI) ("Weissler index") for evaluation of left ventricular cardiac function is used. In an investigation of 352 female patients with metastatic carcinoma of the breast statistically ascertained dose-response relationships could be established as regards electrocardiographic disorders of repolarisation and the systolic time interval (P less than 0.001). Pre-irradiated patients showed more ECG changes (P less than 0.001) and higher PEPI : LVETI values (P less than 0.001) than patients without prior irradiation. There was no general influence of cytostatic treatment on systolic and diastolic blood pressure values. The upper limit of a therapeutic risk in evaluation of the systolic time interval for cardiac monitoring of doxorubicin treatment should be 0.45-0.50 for PEPI : LVETI. Above this borderline value precise cardiac evaluation including invasive methods should be attempted if continuation of treatment is indicated. This regime could help prevent the occurrence of life-threatening cardiac crises during treatment with doxorubicin.

Noninvasive methods for the early detection of doxorubicin-induced cardiomyopathy.

Ninety-eight female patients (mean age 54 years) who underwent doxorubicin therapy because of metastatic breast cancer were submitted to radionuclide angiography at rest. Left ventricular ejection fractions (LVEFs) were found to decrease significantly with the increasing cumulative doxorubicin dosage. Patients with prior local radiotherapy showed lower LVEFs at the same dosage level than nonirradiated patients, but the difference was not statistically significant. In a further study, 52 patients (mean age 56 years) were followed up regularly for their history and systolic time intervals prior to each doxorubicin treatment course. Before starting treatment, LVEF values were normal in all cases. Fifteen of these patients complained of dyspnea at some time during the treatment period before the critical cumulative dosage level of 550 mg/m2 was reached. Nine of these 15 patients showed an increase of the PEPI:LVETI ratio (greater than or equal to 0.40) and 12 patients a decrease of the LVEF values at rest at the same time. The rest of the patients did not complain of cardiac symptoms and did not show any significant alterations in systolic-time-interval measurements until the borderline dosage level (550 mg/m2) was attained. To evaluate myocardial function with greater accuracy, these 15 patients were submitted to right-heart catheterization and radionuclide angiography at rest and during exercise. As a result, doxorubicin treatment had to be discontinued in three of these patients because of heart failure of stage III or IV and treatment with methyl digoxin and nifedipine was started. In these three patients cardiotonic medication could produce more or less complete cardiac recompensation. We conclude from our findings that signs of stage-III heart failure in radionuclide angiography performed while the patient is at rest and exercising should be regarded as the upper limit of the therapeutic risk, where further doxorubicin treatment is contraindicated. Cardiotonic medication during cytostatic courses should be avoided, however, because the true functional condition of the myocardium could be masked during a potentially cardiotoxic therapy.