Drugs online research references
J Renin Angiotensin Aldosterone Syst. 2003 Sep;4(3):191-6.
Effect of chronic treatment with the vasopeptidase inhibitor AVE 7688 and ramipril on endothelial function in atherogenic diet rabbits.
Weckler N, Leitzbach D, Kalinowski L, Malinski T, Busch AE, Linz W.
DG Cardiovascular Diseases, Aventis Pharma, Frankfurt, 65926, Germany.
Cardiovascular disease is the major cause of death in Western nations, although improved possibilities regarding diagnosis and therapy now exist. Endothelial dysfunction is triggered by cardiovascular risk factors such as hypercholesterolaemia, hypertension, adiposity and smoking, contributing to the common endpoint of atherosclerosis. This study examined the pharmacological effects of angiotensin-converting enzyme (ACE) and combined ACE-neutral endopeptidase (NEP) (vasopeptidase) inhibitors on endothelial dysfunction in the model of hyperlipidaemic rabbits. The focus of the study was to assess endothelial function after treatment with the ACE-NEP inhibitor AVE 7688 (30 mg/kg/day) in comparison to the ACE inhibitor (ACE-I) ramipril (1 mg/kg/day). Different parameters, such as endothelial function, blood pressure (BP), expansion of plaques, endothelial nitric oxide (NO) and superoxide (O2-) release and plasma levels of various lipidaemic parameters were analysed. Control groups consisted of one group fed only with normal diet, one group fed only with atherogenic diet and the direct control group fed with varied diets (six weeks atherogenic diet followed by 12 weeks normal diet). Since for the treatment of atherosclerosis, a change in feeding is absolutely necessary, in the present study, at the start of the treatments with AVE 7688 and ramipril, the rabbits food was changed to a normal diet. At the end of the study, mean arterial blood pressure (MAP) was measured in the anaesthetised animals. The values in standard, atherogenic and varied diet-fed rabbits were around 73 2 mmHg. Angiotensin I (Ang I) given intravenous (i.v.) induced a strong increase in MAP of about 20%. In both the treated groups Ang I-induced BP increase was inhibited. In contrast, i.v. bradykinin led to a strong reduction in MAP in both the treated groups of around 50%. Six weeks feeding with an atherogenic diet in the rabbits induced an enduring endothelial dysfunction despite the food subsequently being changed to a normal chow. All measured parameters indicated a significant favourable effect on endothelial dysfunction as a result of the two treatment regimens. Endothelial function measured in the organ chamber showed somewhat greater improvement in the ACE-NEP treated group than in the ACE-I treated group. The treatment with ramipril, as well as with AVE 7688, restored endothelial function by increasing the ratio of NO to O2- concentration and bioavailability of NO. In this study, a similar protective effect on endothelial function was shown by ACE-NEP inhibition as already seen with ACE inhibitors in an animal model of atherosclerosis.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14608526&dopt=Abstract
Nephron Clin Pract. 2003;95(2):c47-59.
Chronic nephropathies: individual risk for progression to end-stage renal failure as predicted by an integrated probabilistic model.
Dimitrov BD, Ruggenenti P, Stefanov R, Perna A, Remuzzi G.
Clinical Research Center for Rare Diseases Aldo e Cele Dacco, Mario Negri Institute for Pharmacological Research, Villa Camozzi, Ranica, Bergamo, Italy.
BACKGROUND/AIMS: To predict risk of end-stage renal disease (ESRD) in individual patients with chronic nephropathy. METHODS: Sequential use of univariate analyses and Cox regression to identify risk factors, artificial neural network to quantify their relative importance and Bayesian analysis to address uncertainty of relationships and incorporate ESRD prevalence information in 344 patients with chronic nephropathy enrolled in the Ramipril Efficacy In Nephropathy study. RESULTS: Serum creatinine (SC), 24-hour urinary protein excretion (UPE) and calcium-phosphorus (Ca*P) product were, in this order, the strongest time-adjusted ESRD predictors. Individual risk of ESRD ranged from near zero when SC and UPE were <1.66 mg/dl and <3 g/24 h, to 69% when SC, UPE and Ca*P were > or =2.41 mg/dl, > or =3 g/24 h and > or =32.64 mg2/dl2, respectively. Receiver operating characteristic curves showed that within lowest, middle and highest tertiles of basal SC (0.90-1.65, 1.66-2.40 and 2.41-6.30 mg/dl, respectively) the model accurately predicted ESRD (AUC = 0.80, 0.72 and 0.65; p = 0.0003, 0.0001 and 0.0022, respectively), quality of life or treatment costs. CONCLUSION: Integrated use of regression analysis and probabilistic models allows computation of individual risk of progression to ESRD and related utilities. This may help in optimizing care and costs in nephrology and other medical areas and designing trials in high-risk patients. Copyright 2003 S. Karger AG, Basel
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14610330&dopt=Abstract
aventis.com
BACKGROUND: Blocking the renin-angiotensin system is an established therapeutic principle in diabetic nephropathy. We investigated whether inhibition of both neutral endopeptidase and ACE (vasopeptidase inhibition) can prevent functional and morphological features of nephropathy in the Zucker diabetic fatty (ZDF) rat, an animal model of type II diabetes. METHODS: Homozygous (fa/fa) ZDF rats (each n=15) aged 10 weeks were treated with placebo, ramipril (1 mg/kg/day in drinking water), or the vasopeptidase inhibitor AVE7688 (45 mg/kg/day in chow). Metabolic parameters and renal function (metabolic cages) were assessed at baseline (age 10 weeks), and at age 17, 27, and 37 weeks. Twenty heterozygous animals (fa/-) served as lean, nondiabetic controls. At age 37 weeks, the animals were sacrificed and the kidneys analyzed histopathologically. RESULTS: Overt diabetes mellitus (blood glucose >20 mmol/l) was established at age 17 weeks in all homozygous ZDF rats. In the placebo group, urinary protein excretion increased progressively from 8+/-1 (baseline) to 342+/-56 mg/kg/day (week 37) whereas diabetes and proteinuria were absent in the lean control group. Ramipril tended to reduce albuminuria and morphological damage (p=ns) but AVE7688 virtually prevented albuminuria (33+/-12 mg/kg/day, p<0.05 vs. ZDF placebo) and drastically reduced the incidence and severity of glomerulosclerosis and tubulointerstitial damage. CONCLUSIONS: In ZDF rats, development of diabetes mellitus is accompanied by functional and morphological kidney damage that resembles human diabetic nephropathy. Diabetic nephropathy can be prevented by chronic vasopeptidase inhibition.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14613875&dopt=Abstract
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