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Rationale for use of an exercise end point and design for the ADVANCE (a dose evaluation of a vasopressin antagonist in CHF patients undergoing exercise) trial

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AMERICAN HEART JOURNAL 2003年第1期145卷 179-186页

作者： Russell, SD Selaru, P Pyne, DA Ghazzi, MM Massey, KD Pressler, M Serikoff, A Coats, AJS Duke Univ Med Ctr Dept Med Div Cardiol Durham NC 27710 USA Pfizer Global Res & Dev Ann Arbor MI USA Yamanouchi Europe BV Leiderdorp Netherlands Univ London Imperial Coll Sci Technol & Med Natl Heart & Lung Inst London England

Background Exercise intolerance is a primary characteristic of chronic congestive heart failure. Exercise testing is therefore widely used to evaluate the degree of functional impairment, prognosis of underlying cardiac disease, and response to treatment. Historically, studies that used exercise tolerance as an end point to evaluate the efficacy of pharmacologic interventions have been confounded by methodologic differences involving protocols, exercise end points, absence or misuse of gas exchange data, and study design. Methods The purpose of this study was to outline the methodology and rationale of a unique cardiopulmonary exercise trial. The design was based on prior experience from evaluation of ACE inhibitors and other interventions. The ADVANCE (A Dose evaluation of a Vasopressin ANtagonist in CHF patients undergoing Exercise) trial is a multicenter, double-blind, placebo-controlled, randomized trial investigating the effects of a vasopressin antagonist, conivaptan, on functional capacity in patients with heart failure. Results The primary end point is change in the exercise time to reach 70% of peak oxygen consumption during an incremental exercise test. Secondary end points include changes in peak oxygen consumption and other exercise parameters as well as quality-of-life indicators. The study incorporates several unique features to lessen potential methodological errors of exercise testing in heart failure, including,use of a core laboratory to evaluate exercise tests, a computer program to determine the exercise end points, and validation of each site before patient enrollment. Conclusions The results of this study will have value not only for the further use of vasopressin antagonists for heart failure therapy but also for the use of exercise testing and gas exchange determination for the evaluation of new drug therapies.

关键词：投药口服苯丙氮|艹卓|类/投药和剂量双盲法运动试验/药物作用氧耗量/药物作用肺换气/药物作用受体血管升压素/拮抗剂和抑制剂研究设计成年人老年人老年人 80以上女(雌)性人类男(雄)性中年人

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Vasopressin: A new target for the treatment of heart failure

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AMERICAN HEART JOURNAL 2003年第1期146卷 9-18页

作者： Lee, CR Watkins, ML Patterson, JH Gattis, W O'Connor, CM Gheorghiade, M Adams, KF Univ N Carolina Sch Med Dept Med Div Cardiol Chapel Hill NC 27599 USA Univ N Carolina Sch Med Dept Radiol Chapel Hill NC 27599 USA Univ N Carolina Sch Pharm Chapel Hill NC 27599 USA Duke Clin Res Inst Durham NC USA Northwestern Univ Sch Med Chicago IL USA GlaxoSmithKline Res Triangle Pk NC USA

Background Arginine vasopressin is a peptide hormone that modulates a number of processes implicated in the pathogenesis of heart failure. Numerous vasopressin antagonists are currently under development for the treatment of this syndrome. Methods Preclinical and clinical data describing the effects of vasopressin and the vasopressin antagonists on both normal physiology and heart failure were reviewed. Results Through activation of V-1a and V-2 receptors, vasopressin regulates various physiological processes including body fluid regulation, vascular tone regulation, and cardiovascular contractility. Vasopressin synthesis is significantly and chronically elevated in patients with heart failure despite the volume overload and reductions in plasma osmolality often observed in these patients. Vasopressin also appears to adversely effect hemodynamics and cardiac remodeling, while potentiating the effects of norepinephrine and angiotensin II. The selective V-2 and dual V-1a/V-2 receptor antagonists tolvaptan and conivaptan, respectively, substantially increase free water excretion and plasma osmolality, reduce body weight, improve symptoms of congestion, and moderately increase Serum sodium concentrations in patients with heart failure who present with symptoms of fluid overload. Tolvaptan effectively normalizes serum sodium concentrations in hyponatremic heart failure patients. Conivaptan significantly reduces pulmonary capillary wedge pressure without affecting systemic vascular resistance or cardiac output. The clinical significance of V-1a receptor antagonism requires further investigation. Conclusions Current preclinical and clinical findings with the vasopressin antagonists appear promising, however further evaluation in phase III clinical trials is necessary to define the role of vasopressin antagonism in the treatment of heart failure.

关键词：精氨酸加压素/拮抗剂和抑制剂精氨酸加压素/血液精氨酸加压素/生理学体液/生理学心排血量低/药物疗法心脏扩大/病因学肌张力/生理学肌平滑血管/生理学心肌收缩/生理学神经递质药/生理学受体血管升压素/拮抗剂和抑制剂受体血管升压素/生理学动物人类大鼠

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Rationale and study design for a multicenter, randomized, double-blind, placebo-controlled study of the effects of tolvaptan on the acute and chronic outcomes of patients hospitalized with worsening congestive heart failure

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AMERICAN HEART JOURNAL 2003年第2期145卷 S51-S54页

作者： Gheorghiade, M Gattis, WA Barbagelata, A Adams, KF Elkayam, U Orlandi, C O'Connor, CM Northwestern Univ Feinberg Sch Med Div Cardiol Chicago IL 60611 USA Duke Clin Res Inst Durham NC USA Inst Cardiol & Cirugia Buenos Aires DF Argentina Univ N Carolina Chapel Hill NC USA Univ So Calif Los Angeles CA USA Otsuka Maryland Res Inst Baltimore MD USA

Am Heart J 2003;145:S51-4.

关键词：精氨酸加压素/血液精氨酸加压素/生理学苯丙氮|艹卓|类/治疗应用疾病恶化双盲法住院病人遴选前瞻性研究受体血管升压素/拮抗剂和抑制剂受体血管升压素/生理学研究设计人类

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Selective vasopressin, angiotensin II, or dual receptor blockade with developing congestive heart failure

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第3期293卷 852-860页

作者： Clair, MJ King, MK Goldberg, AT Hendrick, JW Nisato, R Gay, DM Morrison, AE McElmurray, JH Krombach, RS Bond, BR Cazaubon, C Nisato, D Spinale, FG Med Univ S Carolina Div Cardiothorac Surg Charleston SC 29425 USA Sanofi Synthelabo Cardiovasc Thrombosis Res Dept Montpellier France

With developing congestive heart failure (CHF), activation of the vasopressin V-1a and angiotensin II type 1 (AT(1)) receptors can occur. In the present study, we examined the direct effects of V-1a receptor blockade (V-1a block), selective AT(1) receptor blockade (AT(1) block), and dual V-1/a/AT(1) receptor blockade (dual block) with respect to left ventricular (LV) function and contractility during the progression of CHF. LV and myocyte functions were examined in pigs with pacing CHF (rapid pacing, 240 beats/min, 3 weeks, n = 10), pacing CHF with concomitant V-1a block (SR49059, 60 mg/kg, n = 8), pacing CHF with concomitant AT(1) block (irbesartan, 30 mg/kg, n = 7), or pacing CHF with dual block (n = 7). LV end-diastolic dimension and peak wall stress were reduced in all receptor blockade groups compared with CHF values. However, LV fractional shortening was increased only in the dual block group compared with CHF values (29 +/- 3 versus 21 +/- 2, P < .05). Basal LV myocyte percent shortening increased in the dual block group compared with CHF values (3.44 +/- 0.23 versus 2.88 +/- 0.11, P < .05). Although V-1a or AT, block reduced LV loading conditions, only dual block resulted in improved LV and myocyte shortening.

关键词：血管紧张素Ⅱ/血液血管紧张素Ⅱ/药理学心钠素/血液血压/药物作用心肌收缩/药物作用受体血管紧张素 1型受体血管紧张素 2型受体血管紧张素/拮抗剂和抑制剂受体血管升压素/拮抗剂和抑制剂钠/血液猪血管升压素类/血液血管升压素类/药理学心室功能左/药物作用动物男(雄)性

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A molecular model of agonist and nonpeptide antagonist binding to the human V₁ vascular vasopressin receptor

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第1期294卷 195-203页

作者： Thibonnier, M Coles, P Conarty, DM Plesnicher, CL Shoham, M Case Western Reserve Univ Sch Med Dept Med Div Clin & Mol Endocrinol Cleveland OH 44106 USA Case Western Reserve Univ Sch Med Dept Biochem Cleveland OH 44106 USA

The affinity of the nonpeptide antagonist OPC-21268 is greater for the rat V-1 arginine vasopressin (AVP) receptor (V1R) than for the human V1R. Site-specific mutagenesis was carried out to identify the residues that determine interspecies selectivity for nonpeptide antagonist binding. The introduction of rat amino acids in position 224, 310, 324, or 337 of the human V1R sequence dramatically altered OPC-21268 affinity for the receptor, whereas binding of AVP, the peptide V1R antagonist d(CH2)(5)Tyr(Me)AVP, and the nonpeptide V1R antagonist SR49059 was not altered by these mutations. Computer modeling explained the mutagenesis results. Docking of OPC-21268 onto a homology-built model of the V1R receptor yielded a model for the bound ligand in which the hydrophobic part is deeply embedded in the transmembrane region, whereas the polar part is located on the surface of the extracellular side. The increased affinity of the G337A mutant is due to two additional van der Waals contacts of the alanine methyl group with carbon atoms on the antagonist. The I310V mutant reduces the hydrophobicity in the vicinity of the polar oxygen atom of the antagonist. The I224V mutant relieves overcrowding in a hydrophobic binding pocket involving the aromatic residues Trp(175), Phe(179), Phe(307), and Trp(304). Finally, the E324D mutant enables the formation of a hydrogen bond of the carboxylate side chain with the amide side chain of Gln(311), which in turn forms a hydrogen bond with the N57 nitrogen atom of OPC-21268. Thus, a few residues, distinct from those involved in agonist binding, control interspecies selectivity toward OPC-21268 nonpeptide antagonist binding.

关键词：氨基酸序列精氨酸加压素/代谢模型分子分子序列数据诱变定点哌啶类/代谢喹诺酮类/代谢放射配体测定受体血管升压素/激动剂受体血管升压素/拮抗剂和抑制剂受体血管升压素/化学动物人类大鼠

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Long-term aquaretic efficacy of a selective nonpeptide V₂-vasopressin receptor antagonist, SR121463, in cirrhotic rats

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第1期295卷 83-90页

作者： Jiménez, W Serradeil-Le Gal, C Ros, J Cano, C Cejudo, P Morales-Ruiz, M Arroyo, V Pascal, M Rivera, F Maffrand, JP Rodés, J Univ Barcelona Hosp Clin Univ Inst Invest Biomed August Pi & Sunyer Hormonal Lab E-08036 Barcelona Spain Univ Barcelona Hosp Clin Univ Inst Invest Biomed August Pi & Sunyer Liver Unit Barcelona Spain Inst Reina Sofia Invest Nefrol Barcelona Spain Sanofi Synthelabo Toulouse France

Water retention in experimental cirrhosis can be reversed by blocking V-2-vasopressin (AVP) receptors with the non-peptide antagonist OPC-31260 or by using the kappa-opioid receptor agonist niravoline, a compound inhibiting central AVP release. However, reluctance to use these drugs in human beings has emerged because the former loses aquaretic efficacy in rats after 2 days of treatment and the latter may have adverse effects in humans. Recently, a new potent and selective non-peptide V-2-AVP receptor antagonist, SR121463, has been developed that could be useful for the treatment of dilutional hyponatremia in human cirrhosis. The current study assessed the aquaretic efficacy of 10-day chronic oral administration of SR121463 (0.5 mg/kg/day) in cirrhotic rats with ascites and impaired water excretion after a water load (minimum urinary osmolality >160 mOsm/kg and percentage of water load excreted <60%). Urine volume (UV), osmolality (UOsmV), and sodium excretion (UNaV) were measured daily. At the end of the 10-day treatment, mean arterial pressure also was measured. In basal conditions cirrhotic rats showed ascites, sodium retention, and impaired water excretion. UV, UOsmV, and UNaV did not change throughout the study in cirrhotic rats receiving the vehicle. In contrast, SR121463 increased UV and reduced UOsmV during the 10-day treatment. This resulted in a greater renal ability to excrete a water load and normalization in serum sodium and osmolality. During the first 6 days of treatment, SR121463 also increased UNaV without affecting mean arterial pressure. These data suggest that SR121463 could be of therapeutical value for chronic management of human cirrhosis.

关键词：身体水份/代谢肝硬化实验性/药物疗法肝硬化实验性/代谢吗啉类/治疗应用大鼠 Wistar 受体血管升压素/拮抗剂和抑制剂钠/代谢螺环化合物/治疗应用动物男(雄)性大鼠

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Effects of the V₂-receptor antagonist OPC-41061 and the loop diuretic furosemide alone and in combination in rats

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第1期292卷 288-294页

作者： Hirano, T Yamamura, Y Nakamura, S Onogawa, T Mori, T Otsuka Pharmaceut Co Ltd Tokushima Inst New Drug Res 2 Kawaguchi Tokushima 7710192 Japan

This study was conducted to characterize the diuretic effect of OPC-41061, a nonpeptide vasopressin V-2-receptor antagonist, and furosemide by administering each alone and in combination in conscious male rats. OPC-41061 at 1 and 10 mg/kg and furosemide at 10 and 100 mg/kg dose-dependently increased urine volume to the same extent. The high dose of OPC-41061 (10 mg/kg) markedly elevated electrolyte-free water clearance (E-CH2O) to a positive value. In contrast to OPC-41061, furosemide elevated only electrolyte clearance but not E-CH2O. The differences in diuretic profile reflected the changes in serum sodium and hormone levels. OPC-41061 dose-dependently elevated serum sodium concentration, but furosemide tended to decrease it. The high dose of furosemide (100 mg/kg) significantly elevated serum renin activity and aldosterone concentration, indicating that furosemide activated the renin-angiotensin-aldosterone system (RAA-system). On the other hand, OPC-41061 did not affect these parameters. When OPC-41061 was administered concomitantly with furosemide, OPC-41061 significantly increased urine volume and E-CH2O, and decreased urinary osmolality compared with furosemide alone. OPC-41061 dose-dependently elevated serum osmolality and sodium concentration even when administered in combination with the high dose of furosemide. These results suggest that OPC-41061 produces aquaresis leading to increased serum sodium without affecting the RAA-system. On the other hand, furosemide produced natriuresis, leading to decreased serum sodium level and activation of the RAA-system. It was also demonstrated that OPC-41061 produced an additive diuretic effect and elevated serum sodium level in the presence of furosemide.

关键词：醛固酮/尿苯丙氮|艹卓|类/药理学利尿/药物作用利尿药/药理学剂量效应关系药物药物相互作用药物疗法联合电解质/尿呋塞米/药理学激素类/血液容积渗克分子浓度随机分配大鼠 Sprague-Dawley 受体血管升压素/拮抗剂和抑制剂肾素/尿钠/血液水/代谢动物男(雄)性大鼠

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Vasopressin receptor antagonism - a therapeutic option in heart failure and hypertension

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EXPERIMENTAL PHYSIOLOGY 2000年第Sup1期85卷 259S-265S页

作者： Burrell, LM Risvanis, J Johnston, CI Naitoh, M Balding, LC Univ Melbourne Austin & Repatriat Med Ctr Dept Med Heidelberg Vic Australia

The precise role of vasopressin in the pathophysiology of cardiovascular disease is controversial, but this peptide hormone is important for several reasons. Firstly, circulating concentrations of vasopressin are elevated in heart failure and some forms of hypertension. Secondly, there is evidence that vasopressin is synthesized not only in the hypophysial-pituitary axis but also in peripheral tissues including the heart where it acts as a paracrine hormone. Thirdly, vasopressin has vasoconstrictor, mitogenic, hyperplastic and renal fluid retaining properties which, by analogy with angiotensin II, may have deleterious effects when present in chronic excess. Finally, the availability of orally active non-peptide vasopressin receptor antagonists allows vasopressin receptor antagonism to be considered as a therapeutic option in cardiovascular disease.

关键词：苯丙氮|艹卓|类/治疗应用高血压/药物疗法高血压/病理生理学吗啉类/治疗应用受体血管升压素/拮抗剂和抑制剂受体血管升压素/生理学螺环化合物/治疗应用人类

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Discovery and design of novel vasopressin hypotensive peptide agonists

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JOURNAL OF RECEPTOR AND SIGNAL TRANSDUCTION RESEARCH 1999年第1-4期19卷 631-644页

作者： Manning, M Stoev, S Cheng, LL Wo, NC Chan, WY Med Coll Ohio Dept Biochem & Mol Biol Toledo OH 43614 USA Cornell Univ Coll Med Dept Pharmacol New York NY 10021 USA

This presentation will trace the serendipitous discovery of novel vasopressin (VP) hypotensive agonists d(CH(2))(5)[D-Tyr(Et)(2),X(3)]VAVP (where X = Arg, Lys). These peptides were uncovered as part of an ongoing program aimed at the design of potent and selective VP antidiuretic (V(2) receptor) antagonists. We will also present highlights of our subsequent preliminary studies seeking (i) to design high affinity radioiodinatable ligands for the localization and characterization of the putative VP vasodilatory (V(1c) ?) receptor;(ii) to identify the structural features of selective and non-selective cyclic and linear VP and oxytocin (OT) antagonists of the V(2) receptor, the vascular (V(1a)) receptor and of the uterine (OT) receptor required for hypotensive agonism and;(iii) to enhance hypotensive potency. These novel VP hypotensive agonists could serve as valuable research tools in studies on the roles of VP in blood pressure regulation and may also lead to the development of a new class of therapeutically useful antihypertensives.

关键词：亲和力标记物氨基酸序列抗高血压药/化学合成抗高血压药/化学抗高血压药/药理学精氨酸加压素/类似物和衍生物精氨酸加压素/化学精氨酸加压素/药理学药物设计受体催产素/拮抗剂和抑制剂受体血管升压素/拮抗剂和抑制剂构效关系血管升压素类/激动剂动物女(雌)性大鼠

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V_1a- and V₂-type vasopressin receptors mediate vasopressin-induced Ca²⁺ responses in isolated rat supraoptic neurones

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JOURNAL OF PHYSIOLOGY-LONDON 1999年第3期517卷 771-779页

作者： Gouzènes, L Sabatier, N Richard, P Moos, FC Dayanithi, G CNRS UPR 9055 CCIPE F-34094 Montpellier 05 France

1. The pharmacological profile of receptors activated by vasopressin (AVP) in freshly dissociated supraoptic magnocellular neurones mas investigated using specific V-1a- nnd V-2-type AVP receptor agonists and antagonists. 2. In 97% of AVP-responding neurones (1-3000 nM) V-1a or V-2 receptor type agonists (F-180 and dDAVP, respectively) elicited dose-dependent [Ca2+](i) transients that were suppressed by removal of external Ca2+. 3. The [Ca2+](i) response induced by 1 mu M F-180 or dDAVP JP was selectively blocked by 10 nM of V-1a and V-2 antagonists (SR 49059 and SR 121463A, respectively). The response to V-1a agonist was maintained in the presence of the V-2 antagonist, and the V-2 agonist-induced response persisted in the presence of the V-1a antagonist. 4. The [Ca2+](i) response induced by 1 mu M AVP was partially (61%) blocked by 10 nM SR 121463A. This blockade was increased by a further 31% with the addition, of 10 nM SR 49059. Similarly, the AVP-induced response was partially (47%) decreased by SR 49059, and a further inhibition of 33% was achieved in the presence of SR 121463A. 5. We demonstrate that AVP acts: on the magnocellular neurones via two distinct types of AVP receptors that exhibit the pharmacological profiles of V-1a and V-2 types. However, since V-2 receptor mRNA is not expressed in the supraoptic nucleus (SON), and since V-1b receptor transcripts are observed in the SON, we propose that the V-2 receptor agonist and antagonist act on a 'V-2-like' receptor or a new type of AVP receptor that remains to be elucidated. The possibility that V-2 ligands act on the V-1b receptor cannot be excluded.

关键词：精氨酸加压素/药理学钙/代谢脱氨基精氨酸血管升压素/药理学吲哚类/药理学动力学吗啉类/药理学神经元/药物作用神经元/生理学吡咯烷类/药理学大鼠 Wistar 受体血管升压素/拮抗剂和抑制剂受体血管升压素/遗传学受体血管升压素/生理学螺环化合物/药理学视上核/细胞学视上核/生理学转录遗传血管收缩药/药理学血管升压素类动物男(雄)性大鼠

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