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43.
Rolf W. Hartmann Martin Frotscher Dorothea Ledergerber Gerald A. Wchter Gertrud L. Grün Tom F. Sergejew 《Archiv der Pharmazie》1996,329(5):251-261
In search of potential drugs for the treatment of estrogen- and androgen-dependent cancer as well as the prophylaxis of metastases, tetralones, tetralins, and dihydronaphthalenes bearing a OCH3 substituent at the benzene nucleus and an imidazol-4-yl, imidazol-1-yl, or 1,2,4-triazol-1-yl substituent in 2-position were synthesized with and without C1-spacer between the rings (compounds 2 – 26 ). The compounds were tested in vitro for inhibition of the three target enzymes P450 arom (human placental microsomes), P450 17 (rat testicular microsomes), and P450 TxA2 (citrated human whole blood). To examine selectivity, some compounds were further tested in vitro for inhibition of P450 18 (bovine adrenal mitochondria), P450 see (bovine adrenal mitochondria) and corticoid formation (aldosterone, corticosterone; ACTH stimulated rat adrenal tissue). In vivo, selected compounds were examined in Sprague Dawley rats regarding P450 TxA2 inhibition, reduction of plasma testosterone concentration, antiuterotrophic activity (inhibition of the uterotrophic activity of androstenedione), reduction of plasma estradiol concentration (pregnant mares' serum gonadotropin-primed rats), and mammary tumor inhibiting activity (dimethylbenzanthracene-induced tumor; pre- and postmenopausal model). In the series of imidazol-4-yl compounds, which represent a novelty in the field of azole inhibitors of steroidogenic P450 enzymes, strong inhibitors of P450 arom and/or P450 17 were found: 7-OCH3-2-(imidazol-4-ylmethylene)-1-tetralone ( 4 ) and 7-OCH3-2-(imidazol-4-ylmethyl)-tetralin ( 12 ) are among the most potent inhibitors of P450 arom in vitro known so far. Compound 4 is a selective inhibitor, whereas 12 shows in addition strong inhibition of P450 17. In contrast to 12 , the 6-OCH3 derivative (compound 11 ) is a selective inhibitor of P450 17, being 50 times more potent than ketoconazole. Some imidazol-1-yl compounds show a marked inhibition of P450 TxA2: 2-(imidazol-1-ylmethyl)-1-tetralone ( 13 ) is a selective inhibitor of P450 TxA2, whereas 7-OCH3-2-(imidazol-1-ylmethyl)-tetralin ( 17 ) as well as 2-(imidazol-1-ylmethyl)-tetralin ( 16 ) and 7-OCH3-2-imidazol-1-yl-3,4-dihydronaphthalene ( 25 ) additionally show strong inhibition of P450 arom and P450 17. Regarding the other steroidogenic P450 enzymes as well as corticosterone formation, the compounds show only little inhibitory activity. Aldosterone formation, however, is inhibited at low concentrations. Nevertheless, 4 and 12 are more selective, i.e. inhibit aldosterone synthesis less than the well known inhibitor of P450 arom fadrozole. The compounds show activity in the aforementioned in vivo tests. 相似文献
44.
Effects of chronic infusions of alpha-trinositol on regional and cardiac haemodynamics in conscious rats. 总被引:3,自引:3,他引:0 下载免费PDF全文
1. Male, Long Evans rats (350-450 g) were chronically instrumented for the measurement of renal, mesenteric and hindquarters haemodynamics, and were given three consecutive, 24 h infusions of vehicle (sterile saline at 0.3 ml h-1, n = 8) or alpha-trinositol (D-myo-inositol-1,2,6-triphosphate) at 5, 20 and 80 mg kg-1 h-1 (0.3 ml h-1; n = 9). During infusion of alpha-trinositol at 5 or 20 mg kg-1 h-1, cardiovascular changes were little different from those seen during saline infusion. However, during infusion of alpha-trinositol at 80 mg kg-1 h-1 there were increases in hindquarters vascular conductance, renal flow and vascular conductance, that were all significantly different from the changes seen in the saline group. Infusion of alpha-trinositol at the high dose in naive rats (n = 8) had even more marked vasodilator effects. 2. Two groups of rats (n = 8 in each), chronically instrumented for the measurement of cardiac haemodynamics, were given 48 h infusions of saline (0.3 ml h-1) or alpha-trinositol (2 mg kg-1 bolus, 80 mg kg-1 h-1 infusion at 0.3 ml h-1). During the infusion of saline, there were slight reductions in heart rate, cardiac index, peak aortic flow, dF/dtmax and central venous pressure. In the animals receiving alpha-trinositol, with the exception of central venous pressure, all the above variables, together with total peripheral conductance, increased. 3. These results, collectively, indicate that incremental infusions of alpha-trinositol do not reveal its full vasodilator potential, possibly due to concurrent activation of counter-regulatory vasoconstrictor mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
45.
Protein components specifically associated with prespliceosome and spliceosome complexes. 总被引:40,自引:2,他引:38
We have carried out a systematic analysis of the protein composition of highly purified mammalian spliceosomes. We show that > 30 distinct proteins, including 20 previously unidentified components [designated spliceosome-associated proteins (SAPs)], are specifically associated with the spliceosome in a salt-resistant complex. In contrast to these spliceosome-specific proteins, we show that hnRNP proteins are not tightly associated with purified prespliceosome and spliceosome complexes. The splicing factor U2AF65, U1 snRNP-specific proteins, and several SAPs are present in the earliest prespliceosome complex (E). A set of 10 proteins is then added to the first ATP-dependent prespliceosome complex (A), and concomitantly, a significant decrease in the level of U2AF65 is observed. The fully assembled spliceosome is formed by the addition of 12 proteins in a reaction that requires ATP and both the 5' and 3' splice sites. 相似文献
46.
47.
Clinical correlates of high signal lesions on magnetic resonance imaging in Alzheimer's disease 总被引:1,自引:0,他引:1
David A. Bennett David W. Gilley Robert S. Wilson Michael S. Huckman Jacob H. Fox 《Journal of neurology》1992,239(4):186-190
Summary The pathophysiology and clinical significance of high signal lesions, visualized on magnetic resonance imaging (MRI) in patients with Alzheimer's disease (AD), remain controversial. Since they are known to correlate with vascular disease and vascular risk factors, we reviewed the clinical correlates of periventricular high signal (PVH) and subcortical white matter lesions (WML) in a sample of 106 patients with probable AD, excluding persons with treated vascular risk factors or symptomatic cerebrovascular and cardiovascular disease. Grade 2 PVH were seen in 26 (25%) and scattered WML were identified in 29 (18%). PHV were associated with advancing age and gait disturbance. WML were associated with gait disturbance and incontinence. Neither radiologic finding was related to dementia severity. The findings suggest that these lesions are common in patients with AD even when those with evidence of cerebrovascular disease are excluded; their presence, therefore, should not preclude a diagnosis of AD. Additionally, the data suggest that HSL on MRI may be one of many risk factors associated with functional disability in persons with probable AD. 相似文献
48.
Gerald F. Powell MD Barbara A. Bettes PhD 《Child psychiatry and human development》1992,22(3):185-198
A controversy exists regarding the classification of nonorganic failure to thrive within the psychiatric nomenclature. There are a number of DSM-III-R diagnoses that may be applied to NOFTT, including Reactive Attachment Disorder of Infancy (RADI) and Major Depressive Disorder (MDD). The behaviors characteristic of NOFTT are symptomatic of depression, and are similar to those exhibited by infants with anaclitic depression as well as those of the adult with depression. The correspondence of the behaviours of NOFTT and the DSM-III-R criteria for Major Depression are reviewed, as are the conceptual and therapeutic reasons to view NOFTT infants as suffering from Depression. 相似文献
49.
Adverse mortality experience of a southwestern American Indian community: overall death rates and underlying causes of death in Pima Indians 总被引:1,自引:0,他引:1
As part of an ongoing epidemiologic study, the death rate and causes of death during 1975 through 1984 were determined in Pima Indians who resided in the Gila River Indian Community (GRIC) in 1965 and later. Death certificates were available for 677 of the 681 deaths. In 78% of the deaths, the underlying cause recorded on the death certificate agreed with the cause determined after review of all available relevant records. The age- and sex-adjusted average annual death rate for the GRIC population (1639/100,000) was 1.9 times (95% CI 1.7-2.0) the 1980 rate for the U.S. all races (878/100,000). In Pima males, whose death rate was substantially higher than that of Pima females, the age-adjusted death rate was 2.3 times that in U.S. males, all races. Moreover among males 25-34 years of age, the Pima death rate was 6.6 times that for the U.S. all races. Diseases of the heart and malignant neoplasms caused 59% of U.S. deaths in 1980, but only 19% of GRIC deaths. By contrast, the age- and sex-adjusted mortality rate in the GRIC Pima was 5.9 times the rate of the U.S. all races for accidents, 6.5 times for cirrhosis, 7.4 times for homicide, 4.3 times for suicide, and 11.9 times for diabetes. Tuberculosis and coccidioidomycosis were important causes of death in the Pima, for whom infectious diseases was the tenth leading cause of death. The findings indicate that programs to improve the adverse mortality experience of the GRIC population should emphasize factors related to fatal accidents, alcoholic cirrhosis, homicide, suicide, diabetes mellitus, and infectious diseases. Young Pimas, especially the males, should be the primary focus of such preventive efforts. These findings and recommendations probably apply to many Native American populations. 相似文献
50.
The comparison of trends in perinatal mortality in small areas 总被引:1,自引:0,他引:1
Year to year changes in perinatal mortality rates for small populations are difficult to interpret. Because local rates are based on small numbers of events, they are subject to apparently large fluctuations. A technique for analysing trends in mortality, for detecting changes in trends and comparing variations in trends between areas is described. It is illustrated by an analysis of perinatal mortality rates for Area Health Authorities in the West Midlands Region of England from 1974-1981, but the same techniques could be used to analyse trends at other times and in other places. 相似文献