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81.
Design of monocyclic (1-3) and dicyclic (1-3/4-10) gonadotropin releasing hormone (GnRH) antagonists
Rivier JE Porter J Cervini LA Lahrichi SL Kirby DA Struthers RS Koerber SC Rivier CL 《Journal of medicinal chemistry》2000,43(5):797-806
Careful analysis of the NMR structures of cyclo(4-10)[Ac-Delta(3)Pro(1),DFpa(2),DTrp(3),Asp(4),DNal (6), Dpr(10)]GnRH, dicyclo(4-10/5-8)[Ac-DNal(1),DCpa(2),DTrp(3), Asp(4), Glu(5),DArg(6),Lys(8),Dpr(10)]GnRH, and dicyclo(4-10/5, 5'-8)[Ac-DNal(1),DCpa(2),DPal(3),Asp(4), Glu(5)(Gly),DArg(6),Dbu(8), Dpr(10)]GnRH showed that, in the N-terminal tripeptide, a type II beta-turn around residues 1 and 2 was probable along with a gamma-turn around DTrp(3)/DPal(3). This suggested the possibility of constraining the N-terminus by the introduction of a cyclo(1-3) scaffold. Optimization of ring size and composition led to the discovery of cyclo(1-3)[Ac-DAsp(1),DCpa(2),DLys(3),DNal(6), DAla(10)]GnRH (5, K(i) = 0.82 nM), cyclo(1,1'-3)[Ac-DAsp(1)(Gly), DCpa(2),DOrn(3),DNal(6),DAla(10)]GnRH (13, K(i) = 0.34 nM), cyclo(1, 1'-3)[Ac-DAsp(1)(Gly),DCpa(2),DLys(3),DNal(6),DA la(10)]GnRH (20, K(i) = 0.14 nM), and cyclo(1,1'-3)[Ac-DAsp(1)(betaAla), DCpa(2), DOrn(3),DNal(6),DAla(10)]GnRH (21, K(i) = 0.17 nM), which inhibited ovulation significantly at doses equal to or lower than 25 microgram/rat. These results were particularly unexpected in view of the critical role(s) originally ascribed to the side chains of residues 1 and 3.(1) Other closely related analogues, such as those where the [DAsp(1)(betaAla), DOrn(3)] cycle of 21 was changed to [DOrn(1)(betaAla), DAsp(3)] of cyclo(1,1'-3)[Ac-DOrn(1)(betaAla), DCpa(2),DAsp(3),DNal(6),DAla(10)]GnRH (22, K(i) = 2.2 nM) or where the size of the cycle was conserved and [DAsp(1)(betaAla), DOrn(3)] was replaced by [DGlu(1)(Gly), DOrn(3)] as in cyclo(1, 1'-3)[Ac-DGlu(1)(Gly),DCpa(2),DOrn(3),DNal(6),DA la(10)]GnRH (23, K(i) = 4.2 nM), were approximately 100 and 25 times less potent in vivo, respectively. Analogues with ring sizes of 18 ?cyclo(1, 1'-3)[Ac-DGlu(1)(Gly),DCpa(2),DLys(3),DNal(6),DA la(10)]GnRH (24)? and 19 ?cyclo(1,1'-3)[Ac-DGlu(1)(betaAla),DCpa(2),DLys( 3),DNal(6), DAla(10)]GnRH (25)? atoms were also less potent than 21 with slightly higher K(i) values (1.5 and 2.2 nM, respectively). These results suggested that the N-terminal tripeptide was likely to assume a folded conformation favoring the close proximity of the side chains of residues 1 and 3. The dicyclic analogue dicyclo(1-3/4-10)[Ac-DAsp(1),DCpa(2),DLys(3),Asp (4),DNal(6), Dpr(10)]GnRH (26) was fully active at 500 microgram, with a K(i) value of 1 nM. The in vivo potency of 26 was at least 10-fold less than that of monocyclic cyclo(1-3)[Ac-DAsp(1),DCpa(2),DLys(3),DNal(6), DAla(10)]GnRH (5); this suggested the existence of unfavorable interactions between the now optimized and constrained (1-3) and (4-10) cyclic moieties that must interact as originally hypothesized. Tricyclo(1-3/4-10/5-8)[Ac-DGlu(1),DCpa(2), DLys(3),Asp(4),Glu(5), DNal(6),Lys(8),Dpr(10)] GnRH (27) was inactive at 500 microgram/rat with a corresponding low affinity (K(i) = 4.6 nM) when compared to those of the most potent analogues (K(i) < 0.5 nM). 相似文献
82.
J. A. Sugden J. I. Davies M. D. Witham A. D. Morris A. D. Struthers 《Diabetic medicine》2008,25(3):320-325
Aims To test whether a single large dose of vitamin D2 can improve endothelial function in patients with Type 2 diabetes mellitus and low serum 25‐hydroxyvitamin D levels. Methods Double‐blind, parallel group, placebo‐controlled randomized trial. A single dose of 100 000 IU vitamin D2 or placebo was administered to patients with Type 2 diabetes over the winter, when levels of circulating 25‐hydroxyvitamin D were likely to be lowest. Patients were enrolled if their baseline 25‐hydroxyvitamin D level was < 50 nmol/l. Endothelial function and blood pressure were measured and fasting blood samples were taken at baseline and 8 weeks after administration of vitamin D. Results Forty‐nine per cent of subjects screened had 25‐hydroxyvitamin D levels < 50 nmol/l. Thirty‐four subjects completed the study, with a mean age of 64 years and a baseline 25‐hydroxyvitamin D level of 38.3 nmol/l. Vitamin D supplementation increased 25‐hydroxyvitamin D levels by 15.3 nmol/l relative to placebo and significantly improved flow mediated vasodilatation (FMD) of the brachial artery by 2.3%. The improvement in FMD remained significant after adjusting for changes in blood pressure. Vitamin D supplementation significantly decreased systolic blood pressure by 14 mmHg compared with placebo; this did not correlate with change in FMD. Conclusions Vitamin D insufficiency is common in patients with Type 2 diabetes during winter in Scotland. A single large dose of oral vitamin D2 improves endothelial function in patients with Type 2 diabetes and vitamin D insufficiency. 相似文献
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85.
J J McMurray P H Seidelin R A Brown A D Struthers 《British journal of clinical pharmacology》1989,27(1):7-12
1. The effects of noradrenaline (0.025 micrograms kg-1 min-1) and atrial natriuretic factor (0.04 micrograms kg-1 min-1) alone, and in combination, were studied in eight healthy salt replete men. 2. Atrial natriuretic factor increased urinary sodium excretion and flow rate without changing glomerular filtration rate or systemic haemodynamics. 3. Noradrenaline decreased urinary sodium excretion without changing glomerular filtration rate, urinary flow rate or systemic haemodynamics. 4. When atrial natriuretic factor was administered against a background infusion of noradrenaline the natriuretic response to the peptide was significantly attenuated. 5. Further analysis showed that this attenuation was due to the additive antinatriuretic effect of noradrenaline rather than to a specific interaction between atrial natriuretic factor and noradrenaline. 6. The possible significance of this interplay between noradrenaline and atrial natriuretic factor is discussed in the context of experimental evidence for an important role of the sympathetic nervous system in modulating the renal effects of atrial natriuretic factor in animals. 相似文献
86.
The effect of angiotensin II and noradrenaline alone and in combination on renal sodium excretion in man. 下载免费PDF全文
P H Seidelin J J McMurray R A Brown A D Struthers 《British journal of clinical pharmacology》1989,27(6):803-809
1. The renin-angiotensin-aldosterone-system is important for the maintenance of sodium balance in man. Recent animal evidence suggests the angiotensin II can modulate the effect of the renal sympathetic nervous system on renal function. We have investigated the possible interaction of physiological doses of angiotensin II and noradrenaline on sodium excretion in man. 2. Seven normal volunteers were studied on four occasions during maximum water diuresis sustained by oral hydration. Samples were obtained during a baseline and four subsequent 20 min periods (A-E). Placebo or noradrenaline was infused over periods B-E, and angiotensin II infused over period C. 3. There was no change in systemic blood pressure, heart rate or creatinine clearance caused by infusion of either angiotensin II, noradrenaline or both in combination. 4. Noradrenaline alone caused a significant fall in absolute and fractional sodium excretion. Angiotensin II when infused with placebo caused a 37% fall in absolute sodium excretion and a 32% fall when infused with noradrenaline (no significant difference between the 2 days). Similar changes were seen for urinary flow and fractional sodium excretion. 5. We have therefore found no evidence to support a postsynaptic interaction of low doses of angiotensin II and noradrenaline on renal sodium excretion in man. 相似文献
87.
Percutaneous drainage access: a simplified coaxial technique 总被引:1,自引:0,他引:1
vanSonnenberg E; Wittich GR; Schiffman HR; Cabrera OA; Willson SA; Quinn SF; Casola G; Hayne LA; Polansky AD 《Radiology》1986,159(1):266-268
We describe an access technique that we have used in 150 nephrostomy and biliary drainage procedures and for access to some abscesses and viscera. The system provides safe coaxial access with a 22-gauge removable hub needle, which then acts as a guide wire and is replaced by an 18-gauge cannula. A major advantage is that only one guide wire is used (0.038-inch) for the entire drainage procedure. No significant complications have occurred to date with this method. 相似文献
88.
A prospective evaluation of color flow mapping and real-time ultrasound was performed to determine if pseudoaneurysms could be distinguished from other causes of masses surrounding vascular grafts of the lower extremities. Twelve palpable pulsatile masses were imaged. Diagnoses were confirmed at angiography (n = 11), computed tomography (n = 7), aspiration biopsy (n = 5), and operative intervention (n = 6). A swirling pattern of blood flow was seen in six of seven cases of pseudoaneurysm. Lack of flow signals was noted in four of the five collections representing hematoma (n = 2) or infection (n = 2). The seventh case was later shown to be an infected, thrombosed pseudoaneurysm. The single false-positive diagnosis was made early in the series when the flow signals detected were due to transmitted arterial pulsations. The authors conclude that color Doppler flow imaging is useful in the differential diagnosis of pulsatile masses associated with prosthetic grafts. Prosthetic graft pseudoaneurysms have a specific appearance of swirling blood flow arising from a wide neck and are distinguishable from traumatic or iatrogenic pseudoaneurysms of the native vascular tree. 相似文献
89.
Association between allopurinol and mortality in heart failure patients: a long‐term follow‐up study
L. Wei T. Fahey A. D. Struthers T. M. MacDonald 《International journal of clinical practice》2009,63(9):1327-1333
Aims: The aim of the study was to explore the long‐term effect of allopurinol on mortality and cardiovascular hospitalisations in heart failure (HF) patients. Methods: This is a population‐based cohort study using a record‐linkage database in Tayside, Scotland. A total of 4785 HF patients (4260 non‐users, 267 incident users and 258 prevalent users) were studied between 1993 and 2002. Results: Compared with non‐users, low‐dose users in the incident group had a significant increased risk of all‐cause mortality, cardiovascular mortality and cardiovascular recurrence (adjusted HR, 1.60, 95%CI 1.26–2.03; 1.70, 1.29–2.23 and 1.44, 1.01–2.07). For the prevalent users, the adjusted HR were 1.27, 0.98–1.64; 1.43, 1.07–1.90 and 1.27, 0.91–1.76 respectively. There was no increased risk of outcome for high‐dose users when compared with non‐users (adjusted HR, 1.18, 0.84–1.66; 1.14, 0.76–1.71 and 1.36, 0.88–2.10 for the incident users, and 0.86, 0.64–1.15; 0.90, 0.64–1.26; and 1.27, 0.93–1.74 for the prevalent users respectively). High‐dose allopurinol was associated with reduced risk of all‐course mortality for prevalent users when compared with low‐dose (adjusted HR 0.65, 95%CI 0.42–0.99). Conclusions: The prevalent high‐dose allopurinol use had a lower risk of mortality than the prevalent low‐dose use suggesting that allopurinol may be of benefit in HF patients. 相似文献
90.
D Pathirana A Nast AD Ormerod N Reytan P Saiag CH Smith P Spuls B Rzany 《Journal of the European Academy of Dermatology and Venereology》2010,24(12):1458-1467
Background The development of evidence based guidelines is a demanding and time consuming process. Therefore it is important to share the knowledge and discuss the structure of these guidelines in detail. Objectives To present a method report on the development process of the European evidence based guidelines on the systemic treatment of psoriasis vulgaris with the aim to offer guidance to other guidelines groups with lesser experience and to critically appraise the methodology of the guidelines development process. Methods The guidelines are based on the previously evaluated literature from three European national evidence based guidelines and an additional systematic search and evaluation of new literature. Further steps included a structured consensus conference and a DELPHI procedure to develop the recommendations, as well as several internal and external reviews. All steps were coordinated by the Division of evidence based medicine in cooperation with a group of methodologists. Results A total of 114 studies were included, serving as base for the efficacy chapters of the intervention. The recommendations, based on the efficacy and the level of evidence of the included studies were discussed and finally consented by the guidelines group. After subsequent reviews the guidelines were presented to the European Dermatology Forum, European Academy of Dermatology and Venereology and Union Européenne des Médicins Spécialistes for approval and published in October 2009. Conclusion The development of European evidence based guidelines requires a coordinated structure which can be achieved by the integration of an experienced group of methodologists. Nevertheless further improvements are imaginable and might be considered for an update or other European evidence based guidelines. 相似文献