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Renin Angiotensin System (renin + angiotensin_system)
Selected AbstractsAtrial fibrillation: insights from clinical trials and novel treatment optionsJOURNAL OF INTERNAL MEDICINE, Issue 6 2007Y. Blaauw Abstract., Blaauw Y, Crijns HJGM (University Hospital Maastricht, Maastricht, The Netherlands). Atrial fibrillation: insights from clinical trials and novel treatment options (Review). J Intern Med 2007; 262: 593,614. Atrial fibrillation (AF) is the most common encountered sustained arrhythmia in clinical practice. The last decade the result of large ,rate' versus ,rhythm' control trials have been published that have changed the current day practise of AF treatment. It has become clear that rate control is at least equally effective as a rhythm control strategy in ameliorating morbidity as well as mortality. Moreover, in each individual patient the risk of thromboembolic events should be assessed and antithrombotic treatment be initiated. There have also been great advances in understanding the mechanisms of AF. Experimental studies showed that as a result of electrical and structural remodelling of the atria, ,AF begets AF'. Pharmacological prevention of atrial electrical remodelling has been troublesome, but it seems that blockers of the renin angiotensin system, and perhaps statins, may reduce atrial structural remodelling by preventing atrial fibrosis. Clinical studies demonstrated that the pulmonary veins exhibit foci that can act as initiator and perpetuator of the arrhythmia. Isolation of the pulmonary veins using radiofrequency catheter ablation usually abolishes AF. The most promising advances in the pharmacological treatment of AF include atrial specific antiarrhythmic drugs and direct thrombin inhibitors. In the present review we will describe the results of recent experimental studies, discuss the latest clinical trials, and we will focus on novel treatment modalities. [source] Human brain aminopeptidase A: biochemical properties and distribution in brain nucleiJOURNAL OF NEUROCHEMISTRY, Issue 1 2008Nadia De Mota Abstract Aminopeptidase A (APA) generated brain angiotensin III, one of the main effector peptides of the brain renin angiotensin system, exerting a tonic stimulatory effect on the control of blood pressure in hypertensive rats. The distribution of APA in human brain has not been yet studied. We first biochemically characterized human brain APA (apparent molecular mass of 165 and 130 kDa) and we showed that the human enzyme exhibited similar enzymatic characteristics to recombinant mouse APA. Both enzymes had similar sensitivity to Ca2+. Kinetic studies showed that the Km (190 ,mol/L) of the human enzyme for the synthetic substrate- l -glutamyl-,-naphthylamide was close from that of the mouse enzyme (256 ,mol/L). Moreover, various classes of inhibitors including the specific and selective APA inhibitor, (S)-3-amino-4-mercapto-butyl sulfonic acid, had similar inhibitory potencies toward both enzymes. Using (S)-3-amino-4-mercapto-butyl sulfonic acid, we then specifically measured the activity of APA in 40 microdissected areas of the adult human brain. Significant heterogeneity was found in the activity of APA in the various analyzed regions. The highest activity was measured in the choroids plexus and the pineal gland. High activity was also detected in the dorsomedial medulla oblongata, in the septum, the prefrontal cortex, the olfactory bulb, the nucleus accumbens, and the hypothalamus, especially in the paraventricular and supraoptic nuclei. Immunostaining of human brain sections at the level of the medulla oblongata strengthened these data, showing for the first time a high density of immunoreactive neuronal cell bodies and fibers in the motor hypoglossal nucleus, the dorsal motor nucleus of the vagus, the nucleus of the solitary tract, the Roller nucleus, the ambiguus nucleus, the inferior olivary complex, and in the external cuneate nucleus. APA immunoreactivity was also visualized in vessels and capillaries in the dorsal motor nucleus of the vagus and the inferior olivary complex. The presence of APA in several human brain nuclei sensitive to angiotensins and involved in blood pressure regulation suggests that APA in humans is an integral component of the brain renin angiotensin system and strengthens the idea that APA inhibitors could be clinically tested as an additional therapy for the treatment of certain forms of hypertension. [source] Latest news and product developmentsPRESCRIBER, Issue 22 2007Article first published online: 28 DEC 200 Glitazones: benefits outweigh the risks Following a review of the safety of rosiglitazone and pioglitazone, the European Medicines Agency (EMEA) has concluded that their benefits outweigh their risks in the approved indications. The review was prompted by reports of an increased risk of fractures in women and, in patients taking rosiglitazone, ischaemic heart disease. The EMEA concluded that prescribing information for rosiglitazone should now include a warning that, in patients with ischaemic heart disease, it should only be used after careful evaluation of each patient's individual risk, and the combination of rosiglitazone and insulin should only be used in exceptional cases and under close supervision. No change was considered necessary to the prescribing information for pioglitazone. Modern dressings no better? A systematic review has found only weak evidence that modern dressings are better than saline gauze or paraffin gauze for healing acute and chronic wounds (Arch Dermatol 2007;143: 1297-304). The analysis, which included 99 studies, found that only hydrocolloids were demonstrably better than older dressings for healing chronic wounds, and alginates were superior to other modern dressings for debriding necrotic wounds. There was no evidence that modern dressings offered superior overall performance to the older alternatives. Hospital inflation twice primary care level The cost of drugs prescribed in secondary care but dispensed in the community increased by 6.4 per cent in 2006 - twice the rate of inflation in primary care - according to the latest statistics on hospital prescribing in England. The increase follows a reduction in costs in 2005 after the introduction of the new PPRS scheme. Data from The Information Centre (www.ic.nhs.uk) show that hospital medicines make up about 24 per cent of the NHS drugs budget. Secondary care has a consistently better record than primary care in prescribing lower-cost alternatives within therapeutic categories, eg simvastatin and pravastatin among the statins, omeprazole and lansoprazole among PPIs, and ACE inhibitors among drugs acting on the renin angiotensin system. The most expensive drug prescribed by hospital specialists and dispensed in the community is interferon beta. MHRA limits the use of fibrates The Medicines and Healthcare products Regulatory Agency (MHRA) has advised that fibrates should now be reserved for the treatment of isolated severe hypertriglyceridaemia. They should be considered for hypercholesterolaemia only when a statin or other treatment is contraindicated or not tolerated. In the latest Drug Safety Update, the MHRA says there is insufficient evidence of long-term benefits from fibrates, and first-line use is no longer justified because the evidence for the benefits of statins is robust. The MHRA also warns that some breastfeeding infants have increased susceptibility to the adverse effects of codeine taken by their mother, and that St John's wort may affect the hepatic metabolism of any anticonvulsant. Annual zoledronic acid infusion cuts mortality after hip fracture Once-yearly infusion of zoledronic acid (Aclasta) after hip fracture reduces deaths over a two-year period by 28 per cent compared with placebo, US investigators say (N Engl J Med 2007;357:1799-809). The HORIZON Recurrent Fracture Trial randomised 2127 men and women (mean age 75) within 90 days of surgery for hip fracture to zoledronic acid 5mg yearly or placebo. Mortality over 1.9 years of follow-up was 9.6 per cent with zoledronic acid and 13.3 per cent with placebo. Zoledronic acid also significantly reduced the rate of any new clinical fractures (by 35 per cent) and new clinical vertebral fractures(by 45 per cent),but the lower rate of hip fracture (2.0 vs 3.5 per cent with placebo) was not statistically significant. Rivastigmine patch for mild to moderate AD Rivastigmine (Exelon) is now available as a transdermal patch for the treatment of mild to moderate Alzheimer's disease. Applied once daily, the patch delivers 9.5mg per 24 hours and, says manufacturer Novartis, is associated with a lower incidence of nausea and vomiting than a comparable oral dose. The patch is available in two strengths: 4.6mg per 24hr is equivalent to oral doses of 3 or 6mg per day, and the 9.5mg per 24hr patch is equivalent to 9 or 12mg per day orally. The recommended dose of the patch is 9.5mg per day; both strengths cost £83.84 for 30 patches. Women more aspirin resistant than men? The cardioprotective effect of low-dose aspirin may be lower in women than men, say Canadian investigators (BMC Medicine 2007;5:29 doi: 10.1186/1741-70155-29). Their meta-analysis of 23 randomised trials involving a total of 113 494 participants found that aspirin significantly reduced the risk of nonfatal but not fatal myocardial infarction (MI). About one-quarter of the variation in its effects on nonfatal MI was accounted for by the sex mix of the trial population. Separating the results by sex showed the reduction in risk with aspirin use was statistically significant in men (relative risk, RR, 0.62) but not in women (RR 0.87). Look after physical health of mentally ill GPs and other primary care workers should take more responsibility for the physical health of their mentally ill patients, say advocacy groups. Mind and Body: Preventing and Improving Physical Health Problems in Patients With Schizophrenia points out that the mental health needs of patients with schizophrenia are met in secondary care, but their physical health needs should be met in primary care. In particular, the metabolic effects of antipsychotics may lead to obesity, diabetes and cardiovascular disease, and weight gain in particular is a frequent reason for nonadherence to treatment. The Mind and Body Manifesto was developed by SANE, The Mental Health Nurses Association, The National Obesity Forum and The Disability Rights Commission and sponsored by Bristol-Myers Squibb Pharmaceuticals Limited and Otsuka Pharmaceuticals (UK) Ltd. Copies are available from elizabeth.green@ ogilvyhealthworld.com. Health eCard costs Some costs quoted in our article on the Health eCard (The Health eCard: the way ahead for medical records?,5 October issue, pages 28-9) have been revised: the card and initial download will cost patients £39.50, and GPs will be entitled to charge patients £10 per annum for subsequent downloads. NICE appraisals of cytokine inhibitors in RA NICE has endorsed the use of the anti-TNF agents adalimumab (Humira), etanercept (Enbrel) and infliximab (Remicade), normally in conjunction with methotrexate, for the treatment of active RA when methotrexate and another DMARD have failed (also see New from NICE below). NICE has provisionally concluded, subject to consultation, that abatacept (Orencia) should not be recommended for the treatment of RA. Boots and BMJ launch health advice site www.askbootshealth.com is a new website providing information about health and medicines for the public produced by Boots using information provided by the BMJ Publishing Group. The website covers many of the topics already available from NHSDirect, with perhaps more information about available treatments. Diabetes care shows small improvement The third National Diabetes Audit in England and Wales has found that more people with diabetes were achieving the targets set by NICE for cholesterol levels, glycaemic control and blood pressure in 2005/06 - but younger patients were doing less well. Overall, the HbA1C target of ,7.5 per cent was achieved in 60 per cent of people with diabetes compared with 58 per cent in 2004/05. However, HbA1C was >9.5 per cent in 30 per cent of children and young people, of whom 9 per cent experienced at least one episode of ketoacidosis. More topics for NICE New topics referred to NICE include clinical guidelines on ovarian cancer, coeliac disease and stable angina, public health guidance on preventing cardiovascular disease, and technology appraisals on insulin detemir (Levemir) for type 1 diabetes, several treatments for cancer and hepatic and haematological disorders, and biological therapies for juvenile arthritis. New from NICE NICE appraisal on anti-TNFs for RA Since NICE published its first appraisal of agents acting against tumour necrosis factor-alpha (anti-TNFs) for the treatment of RA in 2002, the product licences for etanercept (Enbrel) and infliximab (Remicade) have changed and a new agent, adalimumab (Humira), has been introduced. The anti-TNFs act in different ways. Infliximab is a chimeric monoclonal antibody that binds to TNF-alpha, neutralising its activity. Etanercept, a recombinant human TNF-alpha receptor fusion protein, and adalimumab, a human-sequence antibody, both bind to TNF-alpha and block its interaction with cell surface receptors. Adalimumab also modulates some biological responses induced or regulated by TNF-alpha. These agents are recommended for adults with severe active RA (defined as a disease activity score - DAS28 - greater than 5.1) who have already tried two disease-modifying drugs, including methotrexate (if not contraindicated). Prior treatment should have been of at least six months' duration, including two months at the standard dose (unless limited by toxicity). Anti-TNFs should normally be prescribed with methotrexate; when this is not appropriate, etanercept and adalimumab may be prescribed as monotherapy. Treatment with an anti-TNF should be continued beyond six months only if there is an adequate response (defined as an improvement in DAS28 of at least 1.2). Data from the British Rheumatology Society Biologics register show that, after six months, 67 per cent of patients met NICE criteria for an adequate response; this declined to 55 per cent at 18 months. The basic annual cost of treatment is £9295 for adalimumab 40mg on alternate weeks or etanercept 25mg twice weekly; infliximab costs £3777 for a loading dose, then £7553-£8812 depending on dose. Assuming no progression of disability, the incremental costs per QALY (compared with sequential DMARDs) were £30 200 for adalimumab, £24 600 for etanercept and £39 400 for infliximab. There are no direct comparative trials of the anti-TNFs, and their clinical trial findings are not directly comparable. Unless other factors determine treatment choice, NICE therefore recommends the least expensive. If the first anti-TNF is withdrawn within six months due to an adverse event, a second may be tried. [source] SEQUENTIAL ACTIVATION OF THE REACTIVE OXYGEN SPECIES/ANGIOTENSINOGEN/RENIN,ANGIOTENSIN SYSTEM AXIS IN RENAL INJURY OF TYPE 2 DIABETIC RATSCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 8 2008Kayoko Miyata SUMMARY 1The present study was performed to test the hypothesis that the reactive oxygen species (ROS),angiotensinogen (AGT),renin angiotensin system (RAS) axis is sequentially activated in the development of diabetic nephropathy in Zucker diabetic fatty (ZDF) obese rats. 2Genetic pairs of male ZDF obese and control ZDF lean rats (n = 12 of each species) were killed every 3 weeks from 12 to 21 weeks of age (n = 6 at each time point). 3The ZDF obese rats developed diabetes mellitus at 12 weeks. At that time, urinary excretion rates of 8-isoprostane were similar between the groups; however, urinary 8-isoprostane levels were significantly increased at 15 weeks in ZDF obese rats compared with controls (36 ± 6 vs 15 ± 2 ng/day, respectively). At 15 weeks, protein levels of cortical angiotensinogen were similar between groups; however, cortical angiotensinogen levels were significantly increased at 18 weeks in ZDF obese rats compared with controls (relative ratio of 2.32 ± 0.21 vs 1.00 ± 0.20, respectively). At 12 weeks, angiotensin (Ang) II-like immunoreactivity was similar between groups in both the glomeruli and tubules; however, AngII-like immunoreactivity was increased significantly at 21 weeks in ZDF obese rats compared with controls (relative ratios of 1.98 ± 0.55 vs 1.00 ± 0.03, respectively, for glomeruli and 1.58 ± 0.16 vs 1.00 ± 0.13, respectively, for tubules). Moreover, at 21 weeks, the desmin-positive area in the glomeruli (0.63 ± 0.08 vs 0.22 ± 0.05%) and Masson's trichrome stain-positive area in the interstitium (4.97 ± 0.05 vs 3.18 ± 0.41%) were significantly increased in ZDF obese rats compared with controls, even though these differences had not been observed earlier. 4These data suggest that the sequential activation of the ROS,AGT,RAS axis plays an important role in the development of diabetic nephropathy in ZDF obese rats. [source] ANGIOTENSIN CONVERTING ENZYME 2 IN THE KIDNEYCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 4 2008A Koitka SUMMARY 1Angiotensin converting enzyme 2 (ACE2) is an important homeostatic component of the renin angiotensin system (RAS). ACE2 both degrades the vasoconstrictor, angiotensin II and generates the potent vasodilator peptide, angiotensin 1,7. These actions counterbalance those of ACE. 2ACE2 is highly expressed in the healthy kidney, particularly in the proximal tubules, where it colocalizes with ACE and angiotensin receptors. 3Kidney disease and subtotal nephrectomy is associated with a reduction in renal ACE2 expression, possibly facilitating the damaging effects of angiotensin II in the failing kidney. Acquired or genetic ACE2 deficiency also appears to exacerbate renal damage and albuminuria in experimental models, supporting this hypothesis. 4ACE2 also has an important role in blood pressure control. Many models of hypertension are associated with reduced ACE2 expression. Although ACE2 KO animals are normotensive, in states associated with activation of the RAS, ACE2 overexpression improves blood pressure control and reduces angiotensin responsiveness. [source] IMPORTANCE OF SLEEP BLOOD PRESSURECLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 4 2008Trefor Morgan SUMMARY 1Blood pressure varies throughout the day and night and is maintained at different times by different control systems. 2During the awake interval, the sympathetic nervous system is preeminent but during sleep the renin angiotensin system is the controller. 3Sleep blood pressure is a more powerful predictor of non-haemorrhagic cerebro- and cardiovascular events in animals and humans, despite the sleep value being lower than the day value. 4Drugs that act independently of the hormonal or neural systems, such as diuretics and calcium channel blockers, have similar effects during sleep and awake intervals. Beta-blockers have little effect during sleep when the activity of the sympathetic is low while drugs that interfere with the action of the renin angiotensin system have a greater blood pressure lowering effect during sleep. 5One aim of therapy should be to ensure that blood pressure is low during sleep and drugs should be used in doses that lower blood pressure throughout the 24 h period. [source] | ||||||||||