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101.
1. The sensitivity of the soluble guanylate cyclase (sGC)-cyclic guanosine-3',5'-monophosphate (cyclic GMP) system to nitric oxide (NO) was investigated in mouse aorta from wild type (WT) and NO synthase (NOS) knockout (KO) animals. 2. The NO donor, spermine-NONOate (SPER-NO) was more potent in aortas from eNOS KO mice compared to WT (pEC50 7.30+/-0.06 and 6.56+/-0.04, respectively; n=6; P<0.05). In contrast, the non-NO based sGC activator, YC-1 was equipotent in vessels from eNOS WT and KO mice. The sensitivity of aortas from nNOS and iNOS KO animals to SPER-NO was unchanged. Forskolin (an adenylate cyclase activator), was equipotent in vessels from eNOS WT and KO animals. 3. The cyclic GMP analogue, 8-Br-cGMP was equipotent in eNOS WT and KO mice (pEC50 4. 38+/-0.04 and 4.40+/-0.05, respectively; n=5; P>0.05). Zaprinast (10-5 M) a phosphodiesterase type V (PDE V) inhibitor, had no effect on the response to SPER-NO in vessels from eNOS WT or KO mice. 4. The NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 3x10-4 M) increased the potency of SPER-NO in aortas from WT mice (pEC50 6. 64+/-0.02 and 7.37+/-0.02 in the absence and presence of L-NAME, respectively; n=4; P<0.05). 5. In summary, there is increased sensitivity of vessels from eNOS KO animals to NO. Cyclic AMP-mediated dilatation is unchanged, consistent with a specific up-regulation of sGC - cyclic GMP signalling. The functional activity of cyclic GMP-dependent protein kinase (G-kinase) and PDE V was also unchanged, suggesting that sGC is the site of up-regulation. These alterations in the sensitivity of the sGC - cyclic GMP pathway might represent a mechanism for the dynamic regulation of NO bioactivity. 相似文献
102.
S J O'Connor K J Barr L Wang B K Sorensen A S Tasker H Sham S C Ng J Cohen E Devine S Cherian B Saeed H Zhang J Y Lee R Warner S Tahir P Kovar P Ewing J Alder M Mitten J Leal K Marsh J Bauch D J Hoffman S M Sebti S H Rosenberg 《Journal of medicinal chemistry》1999,42(18):3701-3710
The synthesis and evaluation of analogues of previously reported farnesyltransferase inhibitors, pyridyl benzyl ether 3 and pyridylbenzylamine 4, are described. Substitution of 3 at the 5-position of the core aryl ring resulted in inhibitors of equal or less potency against the enzyme and decreased efficacy in a cellular assay against Ras processing by the enzyme. Substitution of 4 at the benzyl nitrogen yielded 26, which showed improved efficacy and potency and yet presented a poor pharmacokinetic profile. Further modification afforded 30, which demonstrated a dramatically improved pharmacokinetic profile. Compounds 26 and 29 demonstrated significant in vivo efficacy in nude mice inoculated with MiaPaCa-2, a human pancreatic tumor-derived cell line. 相似文献
103.
The purpose of this study was to investigate the medium-term effects of methotrexate (MTX) and indomethacin on the growth of young rats. Four equal groups of Sprague-Dawley male rats (four animals in each group; mean+/-S.D. body weight, 183+/-13 g, in their rapid growth phase) were subjected to the following drug treatment: one group was given MTX (0.2 mg kg(-1) body weight) subcutaneously on every fourth day, another received indomethacin (2.5 mg kg(-1) body weight) subcutaneously daily and the third group was given both of these drugs (MTX on every fourth day and indomethacin daily). The fourth group was injected subcutaneously with physiological saline every day to serve as a control group. Total body weight, food and water consumption by animals in each group were monitored every second day for a period of 10 weeks. After this period, liver, spleen and kidneys were excised, weighed and analysed for MTX and dihydrofolate reductase activity. Compared with the groups, which received MTX alone, indomethacin alone, or physiological saline, mean increase (17+/-11 g) in body weight of rats was minimal in the group receiving both MTX and indomethacin. The difference was statistically significant (p=0.001) when the values of mean increase in body weight of rats in different treatment groups after a 10-week treatment were compared. The mean weights of liver and spleen in this group receiving both MTX and indomethacin were also found to be significantly less than the weights of these organs in the control group (p<0.01). There also appears to be a decline in food consumption in this group (p<0.05). This negative effect on growth of animals in this group appears to be not only due to decreased food consumption but also due to increased inhibition of de novo pathway of DNA synthesis. This is supported by increased accumulation of MTX and decreased dihydrofolate reductase activity in this group receiving both MTX and indomethacin, as compared with the group receiving MTX alone. The data indicate an additive effect of MTX and indomethacin on the suppression of growth in young rats, alluding to the notion that patients suffering from juvenile rheumatoid arthritis or acute lymphoblastic leukaemia receiving these two drugs concomitantly over a long period of time might be at a risk of experiencing short-term suppression of growth. 相似文献
104.
Raghavan Krishnaswamy S. Gray David B. Scholz Thomas H. Nemeth Gregory A. Hussain Munir A. 《Pharmaceutical research》1996,13(12):1815-1820
Purpose. The objective was to evaluate the degradation profile of the elastase inhibitor DMP 777 and lay the foundation for formulation development.
Methods. The pKa was determined by potentiometric titration in mixed-aqueous solvents. The degradation kinetics were studied as a function of pH, buffer concentration, ionic strength, methanol concentration and temperature using a stability-indicating HPLC assay. The degradation products were identified by LC-MS, NMR, and by comparison with authentic samples.
Results. The pKa for the protonated piperazine nitrogen was estimated to be 7.04. The pH-rate profile is described by specific acid-, water-, and specific base-catalyzed pathways. The pH of maximum stability is in the range of 4 to 4.5 where water is the principal catalyst in the reaction. Buffer catalysis, primary salt effects and medium effects were observed. The proposed mechanism for acid catalyzed degradation is the rarely observed AAL1 which involves alkyl-nitrogen heterolysis. The driving force for the reaction appears to lie in the stability of the benzylic carbocation. The proposed mechanism for base catalyzed degradation is BAC2 which involves -lactam ring opening. The -lactam ring of DMP 777, a monolactam, appears to be as reactive as that in benzylpenicillin in the k
OH controlled region where a similar mechanism of hydrolysis should be operative. A contributing factor to this increased reactivity may lie in the reduced basicity of the -lactam nitrogen making it a good leaving group.
Conclusions. The degradation profile indicates that development of a solution dosage form of DMP 777 with adequate shelf-life stability at room temperature is feasible. 相似文献
105.
Honn KV Aref A Chen YQ Cher ML Crissman JD Forman JD Gao X Grignon D Hussain M Porter AT Pontes JE Powell I Redman B Sakr W Severson R Tang DG Wood DP 《Pathology oncology research : POR》1996,2(1-2):98-109
Rates of prostate cancer (PCa) have increased so dramatically over the last decade that the age adjusted incidence rate for PCa is now greater than that any other cancer among men in the United States. This review, published as a three part series, provides a state-of-art assessment of the PCa problem in its divergent aspects.Part 1 covers epidemiology, incidence and progression. Several epidemiological studies have demostrated that first degree male relatives of men with PCa are at increased risk of developing the disease. Familial and genetic factors as well as medical, anthropometric, dietary, hormonal and occupational factors involved in PCa are discussed. Postmortem examination of the prostate in men without evidence of PCa documented a high frequency of adenocarcinoma. Latent disease occurred as early as the second decade of life. Although there is no significant difference in incidence between Caucasian and African-American males, high grade prostatic intraepithelial neoplasia (HGPIN) is higher in the latter group. While dietary fat, androgens and certain environmental factors may be determinants for PCa, the exact mechanism of tumorigenesis is still relatively unknown. The current thinking of the role of genomic instability, chromosomal alterations, tumor suppressor genes and the androgen receptor are explored. 相似文献
106.
Objectives
To compare the incidence and severity of acetabular fractures and associated injuries before and after seatbelt legislation.Design
A retrospective study.Setting
Two major trauma centres, which are teaching hospitals.Patients
Three hundred and ninety-three patients who sustained acetabular fractures during the 5 years before and 5 years after seatbelt legislation was enacted. Of these, the fractures in 198 patients (50.4%) resulted from a motor vehicle accident.Main Outcome Measures
The number and severity of acetabular fractures and associated injuries.Results
There has been a significant reduction in the number of acetabular fractures (p = 0.005) since seatbelt use became mandatory, and the complexity of the fractures has decreased. There has also been a marked reduction in associated injuries, such as fractures of other bones, and head, chest and abdominal injuries (p < 0.001).Conclusion
The seatbelt law has been a useful preventive measure, resulting in a reduction in the incidence of acetabular fractures and associated injuries. 相似文献107.
BACKGROUND: Health professionals should take an active role against smoking, so it is relevant to have information on their smoking habits and their attitudes towards smoking, especially with a view to identifying and offering help to those smokers who wish to stop. Staff in Llandough Hospital were surveyed to determine their smoking habits and attitudes, and the findings were compared with those of a similar survey at Llandough in 1987. METHODS: In October 1991 a questionnaire was sent to each member of staff employed half time or more requesting data on age, sex, department, smoking habit, attitudes to smoking in various areas of the hospital, and attitudes to access to smoking rest rooms for patients, staff, and visitors. Smokers were asked whether they would like to join a "quit smoking" group. Non-responders were sent a reminder four weeks later and all replies returned by 31 December 1991 were analysed. RESULTS: The response rate was 82%; of the respondents, 65% were non-smokers, 15% ex-smokers, and 20% current smokers. The prevalence of current smokers was 5% among doctors, 20% among nurses, 18% among administrative and clerical staff, and 40-42% among domestics, catering, and portering staff. Thirty eight per cent of responders wished smoking to be completely forbidden in all areas of the hospital and 90% in certain areas such as wards, offices, cafeteria, and laboratories. Nearly half wanted smoking to be allowed in rest rooms and over 60% wanted a 24 hour facility for smoking for staff, 56% for patients, and 44% for visitors. Only 39% of smokers wished to join a "quit smoking" support group. In comparison with the 1987 survey, the response rate in this study was higher (82% v 70%), the proportion of non-smokers had increased (65% v 59%), and more smokers wanted help (39% v 26%). Fewer wanted 24 hour access to smoking areas for staff and for visitors. CONCLUSION: This hospital should capitalise on these changes of attitude among staff and proceed more rapidly with the implementation of policies to further reduce smoking among staff, visitors, and patients. As a first step a smoking cessation counsellor has been appointed. 相似文献
108.
A comparison was made between the survival of fetal suprachiasmatic nucleus (SCN) grafted either in tissue pieces or as tissue suspension. Donor tissue was obtained from day 15, 16 or 17 Wistar fetuses, and stereotaxically placed in the dorsal thalamus of the brain of vasopressin(VP)-deficient Brattleboro adult rats. One month post-grafting, the suspension grafts largely failed to show the immunocytochemical presence of VP- and vasoactive intestinal polypeptide(VIP)-producing SCN cells, but solid piece grafts did. In the suspension grafts only a few tiny clusters of surviving VP SCN neurons were seen and hardly any VIP cells. This suggests that intrinsic contacts are necessary for SCN cells to survive and/or to express their genotype. Efferent VP fiber growth was observed to run from the tissue piece derived SCN grafts towards the periventricular area of the thalamus, a nearby SCN projection area. However, the number of VP efferents was very limited and not consistently present. Surprisingly, magnocellular VP neurons, also present in the fetal SCN grafts, showed an opposite survival pattern. Several of such cells were seen in day 15 suspension grafts, whereas hardly any were found in day 15 tissue piece grafts. These results indicate that the type of graft preparation might be important when survival of particular cells is desired. 相似文献
109.
110.