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61.
62.
Kekewska A Hübner H Gmeiner P Pertz HH 《The Journal of pharmacology and experimental therapeutics》2011,338(1):381-391
Fibrotic valvular heart disease (VHD) has been observed in patients with Parkinson's disease treated with dopamine receptor agonists such as pergolide and cabergoline. 5-Hydroxytryptamine(2B) receptor (5-HT(2B)R) agonism is the most likely cause, but other 5-HT receptors may also play a role in VHD. We aimed at characterizing the molecular fragment of cabergoline responsible for agonism at 5-HT(2B)R and 5-HT(2A)R. Cabergoline with an allyl substituent at N(6) behaved as a potent 5-HT(2B)R full agonist in relaxation of porcine pulmonary arteries and as a weaker 5-HT(2A)R partial agonist in contraction of coronary arteries. The same was true for cabergoline derivatives with cyclopropylmethyl, propyl, or ethyl at N(6). However, agonism was converted into antagonism, when the N(6) substituent was methyl. 6-Methylcabergoline retained agonism compared with cabergoline at human dopamine D(2LONG) and human dopamine D(2SHORT) receptors as determined by guanosine 5'-O-(3-[(35)S]thio)triphosphate binding. In porcine aortic valve cusps, 5-HT-induced contractions were inhibited by ketanserin (5-HT(2A/2C)R antagonist) but not by N-(1-methyl-1H-5-indolyl)-N'-(3-methyl-5-isothiazolyl)urea (SB204741) (5-HT(2B)R antagonist). In porcine valvular interstitial cells, cabergoline-induced activation of extracellular signal-regulated kinase (ERK) 1/2, an initiator of cellular proliferation and activity, was blocked by (R)-(+)-4-(1-hydroxy-1-(2,3-dimethoxyphenyl)methy1)-N-2-(4-fluorophenylethyl)piperidine (MDL100907) (5-HT(2A)R antagonist) and N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-1,1'-biphenyl-4-carboxamide (GR127935) (5-HT(1B)R antagonist), whereas the stimulatory effect on [(3)H]proline and [(3)H]glucosamine incorporations (indices of extracellular matrix collagen and glycosaminoglycan) was blocked by MDL100907. We conclude that the bulky N(6) substituent of cabergoline is responsible for 5-HT(2A)R and 5-HT(2B)R agonism. The increased ERK1/2 phosphorylation and production of extracellular matrix by cabergoline are mediated by 5-HT(2A)Rs. However, the moderate potency of cabergoline at native 5-HT(2A)Rs suggests that these are not the preferential target in VHD in vivo. 相似文献
63.
Enhanced pulmonary vasoconstriction in response to injuries of the central nervous system and hypoxia result in pulmonary edema due to increased sympathetic activation. This study aimed to characterize α(2)-adrenoceptor (AR)-mediated responses in porcine pulmonary arteries. α(2)-AR-mediated vasoconstriction was studied using a tissue bath protocol. α(2)-AR protein was determined by Western blotting. UK14304 (α(2)-AR agonist) elicited only a slight contraction in pulmonary arteries compared to veins. Verapamil (voltage-operated Ca(2+) channel blocker), 2-APB (store-operated Ca(2+) channel inhibitor), and P1075 (K(ATP) channel opener) induced a marked decrease of the basal tone in veins, but not in arteries. The UK14304-induced contraction in arteries was enhanced by (S)-(-)-Bay K 8644 (L-type Ca(2+) channel activator), N (ω)-nitro-L: -arginine methyl ester hydrochloride (L-NAME, eNOS inhibitor), and (S)-(-)-Bay K 8644 plus L-NAME to the same extent. Endothelium denudation failed to affect the UK14304 response. (S)-(-)-Bay K 8644 did not increase the maximal noradrenaline (non-selective α-AR agonist) or phenylephrine (α(1)-AR agonist) response. The rightward shift of the concentration-response curve to noradrenaline by prazosin (α(1)-AR antagonist) plus (S)-(-)-Bay K 8644 was smaller and non-parallel compared to that in the presence of prazosin alone. UK14304 responses were inhibited by MK912 (α(2C)-AR antagonist). Affinity of MK912 (pA(2) 9.76) and Western blotting analysis argue for an involvement of α(2C)-ARs in noradrenaline-induced contraction of pulmonary arteries. It is concluded that postjunctional α(2C)-ARs predominantly mediate contraction in porcine pulmonary arteries when the cytosolic Ca(2+) concentration is elevated. α(2C)-AR antagonists may be beneficial in the treatment of pulmonary edema. 相似文献
64.
生物制剂可用于治疗各种疾病,包括肿瘤、风湿、胃肠道疾病、皮肤科疾病、呼吸道疾病、激素缺乏症和感染。尽管近来批准了很多生物制品,但有关其药物间相互作用临床研究还不多。单克隆抗体是最主要的一类治疗性生物制品,本文介绍评价其药物间相互作用的风险评估策略,指出了评估中的关键因素,并建议将相互作用风险评估作为治疗性生物制品综合药物开发的一部分。 相似文献
65.
Hofmann C Penner U Dorow R Pertz HH Jähnichen S Horowski R Latté KP Palla D Schurad B 《Clinical neuropharmacology》2006,29(2):80-86
OBJECTIVES: The high incidence of fibrotic cardiac valvulopathies reported in association with the 8beta-ergoline dopamine (DA) agonist, pergolide, and also case reports for cabergoline and bromocriptine have made it necessary to review the theoretical basis and actual findings in the case of another DA agonist, the 8alpha-ergoline lisuride (used since the 1970s for migraine prophylaxis as well as since the 1980s for its prolactin-lowering and anti-Parkinson activity). METHODS: We have reviewed the pharmacology of lisuride in relation to other DA agonists, and we have performed a throughout literature search as well as a search of our own and other adverse drug reaction databases for a possible relationship of lisuride with cardiac valvulopathy or for any reports of fibrosis in other locations. RESULTS: Our review of the pharmacology and the literature strongly suggests that drug-induced cardiac valvulopathies are always related to a stimulatory drug effect on trophic 5-HT(2B) receptors. As lisuride is devoid of such an effect, but on the contrary is an extremely potent 5-HT(2B) antagonist, an association of lisuride therapy with cardiac valvulopathies seems to be highly unlikely. In agreement with this hypothesis, not a single report of a cardiac valvulopathy associated with lisuride therapy has been identified in any database so far.Furthermore, against a background of an estimated 360,000 patient years, we have found only a very small number of cases of any other form of fibrosis (1x retroperitoneal, 2x pleural, 2x pulmonary, 1x interstitial pulmonary changes), in part combined with other risk factors and confounding variables. This closely matches 4 reports available from WHO (1x retroperitoneal, 3x pleural fibrosis). In addition, only 5 other possibly related conditions (3x pleural effusion, 1x pleuritis, 1x pericarditis) were identified in the lisuride adverse drug reaction database of Schering, Berlin. CONCLUSIONS: No link has been found between lisuride use and fibrotic cardiac valvulopathy, in agreement with the 5-HT(2B) receptor antagonist effect of this drug. The very low incidence of spontaneous reports of any other fibrosis could be even compatible with an association by chance in the population exposed to lisuride. Although close monitoring for this kind of side effects is still to be recommended in the therapy with lisuride, our data do not support the concept of a class effect suggesting that all ergot-derived drugs and especially DA receptor agonists with some chemical similarity to the ergot structure will cause or facilitate cardiac valvulopathies as observed with pergolide. 相似文献
66.
MA Islam RI Chowdhury N Chakraborty W Bari HH Akhter 《The European journal of contraception & reproductive health care》2013,18(4):203-213
Objectives There are only a few studies on maternal morbidity, delivery complications and maternal mortality in Bangladesh. This study analyzes data from a follow-up study conducted by the Bangladesh Institute of Research for Health and Technologies (BIRPERHT) on maternal morbidity in rural Bangladesh in 1993. Methods A total of 1020 pregnant women were interviewed in the follow-up component of the study. The survey collected information on socioeconomic and demographic characteristics, pregnancy-related care and practice, morbidity during the period of follow-up as well as in the past, information concerning complications at the time of delivery and during the postpartum period. For the purpose of this study, we selected 993 pregnant women with at least one antenatal follow-up. Both bivariate and multivariate analyses were conducted to identify the potential risk factors for complication during delivery and duration of labor. Results and conclusions It appears that complications during the antenatal period can result in various complications at the time of delivery. Some of the important findings are: hemorrhage during the antenatal period increases the risk of excessive hemorrhage during delivery, the risk of obstructed labor increases significantly if abdominal pain is observed during the antenatal period, prolonged labor appears to be significantly higher for the first pregnancy, and pregnancies suffering from abdominal pain during pregnancy tend to have a higher risk of prolonged labor during delivery. The duration of labor appears to be negatively associated with the number of previous pregnancies, being longest for the first pregnancies. The duration of labor pain is significantly higher for the respondents who reported the index pregnancy as undesired, and, similarly, the respondents who were reported to be involved with gainful employment would have a shorter duration of labor pain than those having no involvement with gainful employment. 相似文献
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68.
Cathy CROMBIE W Ivon BURNS Christos KARAPETIS Ray M LOWENTHAL Fred KIRSTEN J Andrew DAVIDSON Fiona ABELL William HH REECE Jose IGLESIAS Paul DE SOUZA 《Asia-Pacific Journal of Clinical Oncology》2009,5(1):24-31
Aim: Two 21-day gemcitabine–carboplatin schedules were evaluated in patients with advanced non-small cell lung cancer in order to assess the effect of timing of the carboplatin dose on toxicity and efficacy.
Methods: Patients were randomized to gemcitabine (1000 mg/m2 on days 1 and 8 of a 21-day cycle) and carboplatin (AUC 5, on day 1) (Carbo d1 arm) or the same gemcitabine schedule with carboplatin given on day 8 (Carbo d8 arm). Twenty patients with Stage IIIB or IV non-small-cell lung cancer were enrolled in each arm.
Results: The achieved dose intensities of both gemcitabine and carboplatin were significantly higher in the Carbo d1 arm. The total rates of grade 3 or 4 hematological and non-hematological toxicities (any toxicity, any cycle) were 80% and 65%, respectively, with no significant differences between the two arms. Nine patients in the Carbo d1 arm, but only one patient in the Carbo d8 arm, required a platelet transfusion. There were 10 partial responses (four Carbo d1 arm, six Carbo d8 arm), giving an overall response rate of 25% (95% CI 13–41%).
Conclusion: Administration of carboplatin on day 8 of this regimen confers no clear advantage compared with day 1 carboplatin, with similar toxicity but lower dose intensity. A formula for the prediction of thrombocytopenia is proposed. 相似文献
Methods: Patients were randomized to gemcitabine (1000 mg/m
Results: The achieved dose intensities of both gemcitabine and carboplatin were significantly higher in the Carbo d1 arm. The total rates of grade 3 or 4 hematological and non-hematological toxicities (any toxicity, any cycle) were 80% and 65%, respectively, with no significant differences between the two arms. Nine patients in the Carbo d1 arm, but only one patient in the Carbo d8 arm, required a platelet transfusion. There were 10 partial responses (four Carbo d1 arm, six Carbo d8 arm), giving an overall response rate of 25% (95% CI 13–41%).
Conclusion: Administration of carboplatin on day 8 of this regimen confers no clear advantage compared with day 1 carboplatin, with similar toxicity but lower dose intensity. A formula for the prediction of thrombocytopenia is proposed. 相似文献
69.