The effect of partial inhibition of monoamine oxidase on the steady-state rate of deamination of 3H-catecholamines in two metabolizing systems

Two different "deaminating systems" were compared (i.e., intact tissues in which an uptake process translocates the 3H-catecholamine from the extracellular space to the intracellular MAO): the adrenergic nerve endings of the rat vas deferens exposed to 10 nmol/l 3H-(-)-noradrenaline, and the extraneuronal deaminating system of the rat heart perfused with 50 nmol/l 3H-(-)-adrenaline. Vesicular uptake and COMT were inhibited. In both systems MAO was partially inhibited by pargyline, and the steady-state tissue content of the 3H-catecholamine was determined as well as the steady-state rate of deamination. Rat vas deferens (preincubated with 10-40 nmol/l pargyline for 30 min). Inhibition of neuronal MAO caused not more than a moderate decrease of the steady-state rate of deamination of 3H-(-)-noradrenaline, but the steady-state tissue content was greatly increased. Determinations of the activity of MAO in homogenates of vasa deferentia showed that preincubation with 10 and 20 nmol/l pargyline inhibited the enzyme by 80 to 95%. Rat heart (of animals pretreated with 1 to 30 mg/kg pargyline). Inhibition of extraneuronal MAO caused a steep decline of the steady-state rate of deamination of 3H-(-)-adrenaline, but only a small rise in the steady-state tissue content. The decisive difference between the two deaminating systems lies in the fact that the ratio "kmao/kout" (where the two k-values characterize the activity of the unsaturated intracellular MAO and the ability of the 3H-catecholamine to leave the relevant cells, respectively) is much higher for the neuronal deaminating system exposed to 3H-(-)-noradrenaline than for the extraneuronal deaminating system exposed to 3H-(-)-adrenaline.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evaluation of anticancer drug schedule dependency using an in vitro human tumor clonogenic assay

Summary A human tumor clonogenic assay (HTCA) has been used to evaluate standard and experimental anticancer drugs with respect to thrir inhibition of clonogenicity of both fresh human cancers and human tumor cell lines. By comparing the inhibitory effect on tumor colony-forming unit (TCFU) growth of 1-h and continuous drug exposures in the HTCA we were able to identify and separate schedule-dependent (e.g., bleomycin, vinblastine, and etoposide) and schedule-independent drugs (e.g., actinomycin D, adriamycin, basantrene, and cis-platinum). Vinblastine, bleomycin, and etoposide, which are known to have cell cycle-specific characteristics, caused exponential reduction in tumor colony formation when given by continuous exposure, whereas when given with a short exposure each of these drugs caused plateau-type dose-response curves. For comparison of the relative efficacy of the two dosing schedules, a ratio (1-h versus continuous exposures) was calculated of the drug concentrations which reduced growth of TCFU to 50% of the control values (ID₅₀) for fresh human tumors and human tumor cell lines. For fresh tumors, ID₅₀ ratios for adriamycin, actinomycin D, and bisantrene ranged between 2 and 60 (median 14), whereas the ID₅₀ ratios for bleomycin, vinblastine, and etoposide ranged between 100 and 3,000 (median 600). The fact that actinomycin D, adriamycin, and bisantrene (a new anthracene-type drug) had similarly shaped dose-response curves and very low ID₅₀ ratios suggests that the cytotoxicity of these compounds may not be schedule-dependent. On the other hand, the steep dose-survival curves we observed after continuous drug exposure and the high ID₅₀ ratios of bleomycin, vinblastine, and etoposide suggest that these drugs may possess schedule-dependent cytotoxicity characteristics. Before final conclusions are drawn concerning a drug's schedule dependency it is essential to evaluate its in vitro stability and protein-binding characteristics. Finally, it must be emphasized that unlike the results obtained with 1-h exposure studies, the in vitro continuous exposure schedules have yet to be shown to be predictive of clinical response for any agent or tumor type.     

Altersspezifische Trends des risikoreichen Alkoholkonsums in Deutschland: Parallele oder unterschiedliche Verläufe?

Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz - Nach der Collectivity-of-Drinking-Cultures-Theorie von Skog finden Veränderungen des Alkoholkonsums in allen...     

Changes in causes and age of death in an eastern German county over a period of 14 years. Comparison of rural and urban populations. Focus on COPD and ischemic heart disease

Journal of Public Health - We aimed to determine whether the causes of death, age of death and burden of disease have changed in the last years and whether there are differences between males and...     

Intraspinal anomalies in myelomeningocele

This study reports the results of MRI analysis of the spinal cord in 83 patients with myelomeningocele. 63 patients had a "tethered cord" or a "suspected tethered cord". In 14 cases we found a "hydro-/syringomyelia". In only 2 cases there were no pathological findings. The influence especially of the "tethered cord" and the "hydro-/syringomyelia" on the development of deformities of the locomotor apparatus is discussed. Concerning this problem the experience reported in the literature is not sufficient enough to make final statements. However, in cases of deterioration of the neurological status in patients with myelomeningocele the influence of intraspinal anomalies should be considered giving rise to further diagnostic examinations.     

Antitumor-activity and toxicity of continuous-infusion versus bolus administration of bleomycin in 2 heterotransplanted human testicular cancer cell-lines

The continuous infusion of the glycopeptide antibiotic cytotoxic agent bleomycin in comparison to bolus application has been postulated to be associated with increased antitumour activity and decreased toxicity, particularly pulmonary fibrosis. In the treatment of patients with testicular cancer, bleomycin is an essential agent and is currently used in continuous infusion and bolus application schedules in cisplatin-based combination therapy regimens. The current study addresses the antitumour activity and general toxicity of bleomycin given as continuous intraperitoneal infusion versus bolus application in human testicular cancer cell lines heterotransplanted into nude mice. Maximally tolerated doses for each administration route, defined as being the LD20 were applied (8.7 or 17.5 mg/kg days 1-7 continuous intraperitoneal infusion via osmotic mini pump or 40 mg/kg intraperitoneal bolus application on days 1, 5, 9). Bleomycin demonstrated antitumour efficacy at all concentrations used in comparison to untreated controls. There was no significant difference in antitumour activity between continuous or bolus application of bleomycin when the same cumulative doses were compared. Neither was there any difference with respect to bleomycin toxicity with 11 +/- 4 or 12 +/- 5% losses of body weight for continuous infusion regimens compared to 13 +/- 3% for bolus application. In a small subgroup of mice histological examination of the lungs demonstrated no signs of pulmonary fibrosis. In summary, using an established testicular cancer xenograft model in nude mice bolus application of bleomycin was as active as continuous infusion of this drug with no apparent difference in overall toxicity. Current standard treatment regimens using bolus application of bleomycin should not be altered without necessary reasons. Bleomycin pulmonary toxicity needs to be studied in clinical trials taking into account possible drug interactions in combination chemotherapy regimens and additional risk factors for pulmonary toxicity.     

Effects of various HTK solution regimens on proteinuria after renal transplantation in dogs

Investigations were carried out by means of an autologous, heterotopic model for kidney transplantation applied to dogs. Duration of cold ischemia was 48 h. Four experimental groups were arranged. During the first 20 min following revitalization of the transplanted kidney, group 1 (HTK solution/80 cm perfusion height) showed a significant glomerular and tubular malfunction. In group 2 (HTK solution/120 cm perfusion height), only four urinary proteins with molecular weights of 25 kDa, 67 kDa, 100 kDa and >100 kDa were found. The excretion of higher molecular proteins receded over the 20-min period of observation. In both group 3 (HTK/aspartate solution) and group 4 (HTK/tryptophan solution) the quantity of excreted glomerular and tubular protein was well above that of group 2. As opposed to the Tryptophan group, a complete restoration of renal function was observed in the Aspartate group after 4 weeks. In general, the standard HTK protective solution delivered with 120 cm perfusion pressure gave the most favorable results, with the lowest levels of proteinuria and a satisfactory recovery of renal function after revitalization.     

Oocyte quality and treatment outcome in intracytoplasmic sperm injection cycles of polycystic ovarian syndrome patients

Patients with polycystic ovarian syndrome (PCOS) have higher miscarriage rates. It is postulated that this is caused by a lower rate of mature oocytes, and a lower quality of embryos. Retrospectively we analysed 51 intracytoplasmic sperm injection (ICSI) cycles of 31 PCOS patients. These data were compared to age-matched controls (105 cycles) during the same period. All patients of both groups received gonadotrophin-releasing hormone (GnRH) agonists prior to gonadotrophin treatment. The rate of metaphase II oocytes (MII) was not different. However, the mean absolute number of normally fertilized oocytes was significantly higher in PCOS patients (5.00 versus 3.56, P < 0.01), due to a higher number of oocytes retrieved. More embryos were transferred by cycle in the PCOS group (2.69 versus 2.17, P < 0.05), with a higher cumulative embryo score. The overall and multiple pregnancy rate showed no differences and the clinical abortion rate was lower (21 versus 41.67%, P < 0.05) in the controls. Our findings demonstrate that negative factors unconnected to oocyte morphology must be present in PCOS patients. It is possible that only cytoplasmic, not nuclear, maturity is influenced in these patients.