Antimykotische Wirkstoffe, 20. Mitt.: Bioisostere 6-Arylpyrimidin-Derivate

Antimycotic Agents, XX Bioisosteric 6-Arylpyrimidine Derivatives Condensation of N-(2-hydroxyethyl)-N-methylguanidine-sulfate ( 1 ) with the β-diketones 4a - e bearing 1-aryl substituents leads to the bioisosteric 2-[(2-hydroxyethyl)-methylamino]-6-arylpyrimidines 5a - e . Compounds 5a - c exhibit significant antimycotic in vivo and in vitro activities.     

Folic acid in the treatment of acute watery diarrhoea in children: a double-blind, randomized, controlled trial

One-hundred and six male children aged 6-23 months with a history of acute watery diarrhoea of less than 72 h duration were randomized to receive either folic acid in a dose of 5 mg at 8-h intervals or placebo for 5 d. There were 54 children in the folic acid group and 52 in the placebo group. The admission characteristics were comparable between the two groups. No significant differences were observed in the intake of oral rehydration solution or stool output between the groups. The mean ± SD of total stool output (g kg⁻¹) was 532 ± 476 vs 479 ± 354 and the duration (h) of diarrhoea was 108 ± 68 vs 103 ± 53 in the folic acid vs placebo group, respectively. The findings, therefore, should have a positive influence on preventing the inappropriate use of folic acid in acute diarrhoea.     

Direct inhibition of rat granulosa cell inhibin production by epidermal growth factor in vitro

The effect of epidermal growth factor (EGF) on inhibin production by rat granulosa cells has been investigated using a recently developed inhibin radioimmunoassay (RIA). Granulosa cells from intact immature diethylstilbestrol (DES)-treated rats were exposed to EGF (1-100 ng/ml) in the presence or absence of FSH for varying periods in vitro. An inhibitory effect of EGF on basal inhibin secretion was evident at day 2 of culture and was sustained over the subsequent 2 days. This action on basal inhibin secretion was dose-dependent, and maximal inhibition to 50% of control was observed at a dose of 100 ng EGF/ml at day 4. EGF also inhibited basal progesterone secretion in a similar manner. EGF caused a dose-dependent inhibition of FSH-stimulated inhibin secretion, with an ID50 (0.5 ng/ml, 0.08 nM) about one-eighth that in the absence of FSH. In addition, EGF also inhibited the stimulation of inhibin production by 8-Br-cAMP and prostaglandin E2. To exclude the possibility that EGF was toxic to the granulosa cells, several biochemical parameters related to cell growth were measured. EGF treatment did not alter cell number but slightly increased [3H]thymidine incorporation into cellular DNA. The effect of EGF on [35S]methionine incorporation into cellular protein was biphasic, being stimulatory at doses less than 10 ng/ml but inhibitory at 100 ng/ml. The present data have demonstrated a direct inhibitory effect of EGF on basal and FSH-stimulated inhibin production by granulosa cells suggesting an important regulatory role of this growth factor in the differentiation of ovarian function.     

Effects of rifampicin on the peripheral turnover kinetics of thyroid hormones in mice and in men

The induction of mixed function hepatic oxygenases by rifampicin is known to increase the metabolic clearance rate (MCR) of T4. By performing T3 and rT3 kinetics we have shown that rifampicin also increases the MCR of T3 and rT3. Using the fall of serum T4 during TSH suppression as an indirect marker of the production rate (PR) of T4, we have demonstrated that there was no major change in monodeiodination nor any shift to either 5'- or 5-monodeiodination. Rifampicin stimulates in mice the mixed function hepatic oxygenases. However, we were unable to increase hepatic deiodinase activity (deiodinase type I) in this species. It is therefore possible that the increased MCR of T4 in man is not mediated by an increased conversion rate either. As mixed function hepatic oxygenases are known to increase hepatic conjugation it is suggested that rifampicin increases the biliary excretion of iodothyronine conjugates.     

Induction of ovulation with gonadotrophin-releasing hormone--life-table analysis of 50 courses of treatment

Ovulation induction by means of the pulsatile subcutaneous administration of gonadotrophin-releasing hormone by way of an infusion pump is described. The clinical outcome in 50 courses of treatment, which totalled 116 treatment cycles, was analysed and was compared with the pregnancy rates that were obtained with the administration of human pituitary gonadotrophins. We found that the pregnancy rates for these two treatments were similar. We also have shown that for those women who ovulated as a result of such treatment the conception rates were similar to those in ovulatory women who had discontinued contraception. We conclude that gonadotrophin-releasing hormone has an important place among the ovulation-induction agents.     

Cervical Cancer with Paraaortic Metastases: Significance of Residual Paraaortic Disease after Surgical Staging

Cervical carcinoma frequently metastasizes to the paraaortic region, necessitating extended field radiotherapy to effect a cure. As imaging modalities are unreliable in identifying all cases of paraaortic nodal metastases (PAN), surgical staging is often utilized prior to radiotherapy. This study was aimed at identifying factors predictive of survival in women with cervical carcinoma and paraaortic metastases. In particular, survival based on extent of paraaortic disease was examined. The study group consisted of 43 women (stages IB–IVB) identified between 1982 and 1993 who were treated with extended field radiation for cervical carcinoma with histologically confirmed paraaortic metastases. The estimated 5-year survival for the study population was 24% with a median survival of 18 months. Pelvic tumor size had a significant impact on survival with the median survival being 34 months if the primary lesion was <6 cm compared to 14 months if ≥6 cm (P= 0.01). Eight of the 26 (31%) women without residual PAN disease after surgical staging remain alive and disease free (mean follow-up, 74 months). In contrast, only 1 of the 17 (6%) women with gross residual PAN is alive 71 months after treatment (P= 0.05). However, a comparison of Kaplan–Meier survival curves did not show a statistically significant advantage to the surgical excision of grossly involved PAN (P= 0.98). Although long-term survival among women with grossly involved, unresected paraaortic metastases is uncommon, further study is necessary to elucidate the role of surgical excision of bulky aortic disease in women with cervical cancer.     

Further experience utilizing the Gildenberg technique for computed tomography-guided stereotactic biopsies

Initial experience using the Gildenberg technique for computed tomography-guided stereotactic biopsies is reviewed. Of 50 patients, adequate tissue was obtained in 49. In one patient, the stereotactic frame was unable to reach the selected biopsy site. In 32 of 49 patients, the diagnosis was obtained with one biopsy; in the remainder, two to five samples were required. In 4 cases, a subsequent craniotomy was performed; these provided similar histopathological tissue and in no case was the diagnosis altered. The lesions were categorized by CT as ring-enhancing lesions (REL), enhancing lesions with surrounding low density (ELLD), and low density lesions with and without peripheral areas of enhancement. Of the REL, 21 of 23 were primary tumors. Of the ELLD, 5 of 13 were primary tumors; the remainder had a wide spectrum of disease. Of the low density lesions without enhancement, 6 were primary tumors and 1 was an inflammatory process. Three patients had low density lesions with peripheral areas of enhancement and proved to have malignant primary tumors. The remaining patients had multiple lesions with both primary and metastatic disease. Twelve RELs were biopsied in multiple sites. An accurate diagnosis was best obtained by performing the first biopsy in the enhancing rim with additional biopsies as needed in the low density center. Homogeneous lesions could be biospied with target selection based upon a primary regard for safety rather than imaging characteristics. Three patients had transiently increased hemiparesis and one had a transient decrease in level of consciousness after biopsy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cell kinetics of oligodendroglioma and oligo-astrocytoma--Ki-67 PaP study

In order to determine the principal histologic features in distinguishing the "anaplastic" from the "well differentiated" oligodendroglioma and mixed glioma (oligo-astrocytoma), correlations between the growth fraction, and histologic grade and 6 histologic variables (vascular proliferation, cytologic pleomorphism, calcification, necrosis, cellularity, mitotic index) were studied in 24 patients. The growth fraction was calculated as the percentage of Ki-67-immunostained nuclei in frozen sections using Ki-67 monoclonal antibody. 6 histologic variables were checked with HE stain of paraffin-embedded tissue sections. The growth fraction was in general agreement with the histologic grade, in order of decreasing mean percentage, ranging from 11.1% (anaplastic mixed glioma) to 5.3% (anaplastic oligodendroglioma), 2.8% (isomorphic oligo.) and 1.9% (mixed, grade II). There was a significant association between the growth fraction and 3 histologic variables (vascular proliferation, cytologic pleomorphism, mitotic index) out of 6. Thus, even though there exist some gaps between these parameters in paraffin-embedded tissues and those in frozen sections, the percentage of Ki-67-immunostained nuclei is likely to be very valuable as a supplement information of histological grading and a prognostic indicator.     

Topographic anatomy and CT correlations in the untreated glioblastoma multiforme

To provide baseline information for the "local" therapy of the glioblastoma multiforme (GBM), whole-brain histological sections of 15 untreated GBM's were studied to determine the distribution of neoplastic cells. These findings were then compared with the computerized tomography (CT) scans in 11 cases in order to determine the extent to which the peripheral portion of the neoplasm can be estimated by the presence of a low-density area without contrast enhancement. The results of the histological study confirmed the marked heterogeneity of GBM's and disclosed a great variability in the geometry, extent, and character of the peripheral "infiltrating" margin. In spite of the widely held concept that glioblastomas are localized within 2 cm of the contrast-enhanced rim, there were three cases in this two-dimensional study in which this distance was exceeded, and it seems likely that three-dimensional reconstructions would have detected additional cases in which neoplastic cells extended beyond this arbitrary limit. Only three of the 15 GBM's were restricted to the distribution of one internal carotid or one vertebral artery. To the extent that the neoplasms in the present series are representative, this suggests that glioblastomas will be difficult to treat successfully by intra-arterial therapy using existing therapeutic agents. Correlations of histological sections with the CT scans revealed that the vast majority of the neoplastic tissue was contained within the contrast-enhancing and "peritumoral" areas of low density, but that in five cases fingers of neoplasm extended for short distances beyond the outer margin of the latter region. This indicates that the distribution of cells of a GBM cannot be inferred from CT images since the "peritumoral" area of low density can over- or underestimate the extent of the lesion.     

Association between hormonal changes at menopause and the risk of a coronary event: a longitudinal study

OBJECTIVE: To investigate the association of hormone levels at menopause, lifestyle variables, and body composition with the predicted 10-year risk of a coronary event, calculated using the PROCAM scoring system, in a population-based sample of Australian-born, middle-aged women. DESIGN: A 9-year prospective study of 438 Australian-born women, who at baseline were aged 45 to 55 years and had menstruated in the prior 3 months. Interviews, fasting blood, and physical measurements were taken annually. The risk of an acute coronary event was calculated using the PROCAM scoring system (includes: age, low-density lipoprotein cholesterol, smoking, high-density lipoprotein cholesterol, systolic blood pressure, family history of premature myocardial infarction, diabetes mellitus, and triglycerides). RESULTS: Retention rate after 8 years of follow-up was 88% (n = 387). In women not using hormone therapy (HT): higher than average body mass index (BMI) (P < 0.001), BMI that increased (P < 0.005), lower than average estradiol levels (P < 0.005), estradiol levels that decreased (P < 0.001), and high free testosterone levels (P < 0.05) were associated with increased risk of a coronary event. There was a trend for high exercise frequency to be associated with a decreased risk (P < 0.07). After BMI and lifestyle variables were taken into account, use of HT did not have a significant effect on risk of a coronary event. CONCLUSION: In this longitudinal observational study of middle-aged Australian-born women, high BMI, an increase in BMI, high free testosterone, low estradiol, and a decrease in estradiol levels were the main determinants of increased risk of an acute coronary event, based on the PROCAM scoring system calculation. More frequent exercise tended to lower the risk.