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Renin Inhibitors (renin + inhibitor)

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Medical Sciences	90%

Selected Abstracts

Renin Inhibitors in Chronic Heart Failure: The Aliskiren Observation of Heart Failure Treatment Study in Context

CLINICAL CARDIOLOGY, Issue 9 2010
FESC, FRACP, Henry Krum PhD
Renin-angiotensin aldosterone system (RAAS) activation is a key neurohormonal contributor to the progression of chronic heart failure. Strategies that block this activation have consistently demonstrated major beneficial impacts on morbidity and mortality in this setting. Direct renin inhibitors (DRIs) present a novel opportunity to block at an additional or alternative step in this pathway, that being conversion of angiotensinogen to angiotensin I. Theoretical benefits of blocking at the level of renin include: inhibition of the reflex activation of plasma renin activity induced by conventional downstream RAAS blockers. Minimization of angiotensin II and/or aldosterone escape and blocking upstream at the rate-limiting step of angiotensin I production. Preclinical and early-phase clinical studies have largely supported this hypothesis. In the Aliskiren Observation of Heart Failure Treatment study, patients with systolic chronic heart failure receiving background angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers and ,-blockers benefited from aliskiren in reduction vs placebo of plasma levels of brain natriuretic peptide, the primary efficacy endpoint of that study. Large-scale outcome trials are, however, required to definitively determine the benefits of a DRI strategy additional to, or as an alternative to, conventional approaches such as ACE inhibitors in the systolic chronic heart failure setting. Copyright © 2010 Wiley Periodicals, Inc. The authors have no funding, financial relationships, or conflicts of interest to disclose. [source]

Renin inhibitors: an important advance in hypertension treatment?

INTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 11 2006
A. Ferro
No abstract is available for this article. [source]

Treatment of diabetic hypertension

DIABETES OBESITY & METABOLISM, Issue 5 2009
David S. H. Bell
Insulin resistance and hyperglycaemia combine to make hypertension more prevalent in the type 2 diabetic patient. Blood pressure goals below those for the non-diabetic subject have been shown to be more effective in lowering mortality and cardiovascular events in the diabetic patient. To achieve these goals in most cases, three to five antihypertensives from different therapeutic groups need to be utilized. Suppression of the renin,angiotensin system (RAS) with angiotensin-converting enzyme inhibitors, angiotensin 2 receptor blockers or a renin inhibitor should be the primary therapy. A second goal should be suppression of the sympathetic nervous system utilizing a beta-blocker that does not increase insulin resistance. The addition of a diuretic, calcium channel blocker or a vasodilator to suppressors of the RAS and sympathetic nervous system aid in achieving hypertensive goals in the diabetic patient. Achieving hypertensive goals with suppression of the RAS and sympathetic nervous system should result in a decrease in mortality and cardiovascular events in the diabetic hypertensive patient. In this review article, the benefits and disadvantages of the different antihypertensive therapies in the diabetic patient are discussed. [source]

Latest news and product developments

PRESCRIBER, Issue 20 2007
Article first published online: 26 NOV 200
GPs and pharmacists to work more closely Closer working between GPs and community and primary-care pharmacists ,could further improve prescribing quality and therapeutic outcomes for patients', according to a report by the London School of Pharmacy and Alliance Boots. The report suggests that the expansion of primary-care centres and the increasing complexity of care they offer mean that community pharmacists will increasingly need to take on some GP roles. It foresees an increase in shared premises and calls for closer interdisciplinary working between GPs, pharmacists and nurses. Variation in PCT commissioning of enhanced services from pharmacies has resulted in ,a fragmented system of postcode pharmaceutical care rationing'. Full read-write access to patients' records will be essential if the benefits of electronic prescribing are to be realised. How pharmacists can support commissioners The NHS Alliance and Primary Care Pharmacists' Association have published a guide for practice-based commissioners on making the most of primary-care pharmacists. Prescribing Support and Prescribing Advice for Practice Based Commissioners , A Guide for Commissioning Groups and GPs illustrates how pharmacists can support commissioners at all levels of medicines use. Copies are free to NHS Alliance members and cost £10 for others. Directory website aids diabetes management The National Diabetes Support Team is developing a website that brings together different datasets and tools for diabetes management. The Diabetes Data Directory (www.yhpho.org.uk/diabetesdatadirectory/introddd.asp) summarises what other online databases can provide and lists the tools that can be used to answer specific questions. The first edition is now online, providing direct links to the appropriate sites. Flu vaccine efficacy in older people challenged US reviewers have questioned the effectiveness of flu vaccine in older people (Lancet Infect Dis online: 24 September; doi: 10.1016/ S1473-3099(07)70236-0). They were unable to confirm a reduction in flu mortality since 1980, concluding that biased patient selection and nonspecific end-points such as all-cause mortality may have exaggerated the benefits of vaccination in clinical trials. The Department of Health is encouraging younger people in at-risk groups to be vaccinated against flu this winter; last year, 58 per cent of under-65s at risk were not vaccinated. OC cervical cancer risk probably overestimated Recent evidence that oral contraceptives may be associated with a small increase in the incidence of cervical cancer probably overestimates the risk, says the Clinical Effectiveness Unit of the Faculty of Family Planning and Reproductive Health Care (www.ffprhc.org.uk). A recent study in the BMJ reported a 12 per cent reduced overall risk of cancer associated with oral contraceptives but an increased risk of cervical cancer of 38 per 100 000 woman-years after at least eight years' use. The FFPRHC says this study was conducted before the UK cervical screening programme was established, and at a time when the average Inhaled insulin ,unlikely to be cost effective' Inhaled insulin (Exubera) is safe and effective but costs so much more than injected insulin that it is unlikely to be cost effective, according to a new Health Technology Assessment (2007;11:No.33.www.hta.nhsweb.nhs.uk). The review included nine trials (seven of Exubera), in which the only significant difference between inhaled and injected soluble insulin was in patient preference. However, most of the trials used syringes for insulin injection rather than pens. The extra cost of inhaled insulin is put at between £600 and £1000 per year. New topics for NICE The Secretary of State for Health has referred the novel antihypertensive aliskiren (Rasilez) for appraisal by NICE; aliskiren is the first direct renin inhibitor to be introduced. Other referrals to NICE include five clinical guidelines (multiple pregnancy, transient loss of consciousness, lower UTI in men, post-ITU rehabilitation and colorectal and anal cancer). Topics for technology appraisals include cetuximab (Erbitux) for colorectal and head and neck cancers. QOF statistics for 06/07 GPs in England averaged 96.3 per cent of the maximum points available for the clinical domain of the Quality and Outcomes Framework in 2006/07 compared with 97.1 per cent previously, official statistics show. Mean practice scores for most clinical areas were in the mid-90 per cent range, but highest for obesity (100 per cent) and lowest for depression (81 per cent), palliative care (90 per cent), mental health and epilepsy (<95 per cent). NICE consulting on type 2 diabetes guideline NICE is consulting on its draft clinical guideline for the management of type 2 diabetes. Comments should be submitted online by 22 November; publication is scheduled for April 2008. The drug of first choice for glycaemic control is metformin, which should be considered even for patients who are not overweight; a sulphonylurea is an alternative or adjunctive agent if glycaemic control is not achieved with metformin alone. If these regimens fail, a glitazone may be added. Exenatide (Byetta) is recommended only for obese patients for whom other oral treatments have failed. The guidance will update and replace clinical guidelines E, F, G and H, and technology appraisals 53, 60 and 63. Glitazones increase risk of HF but not CV death A new meta-analysis , this time of seven trials involving a total of 20 191 patients with type 2 diabetes or impaired glucose tolerance treated with a glitazone , has concluded that these agents are associated with an increased risk of heart failure but not cardiovascular death (Lancet 2007;370:1129,36). Compared with comparator drugs, glitazones were associated with an increased risk of congestive heart failure (2.3 vs 1.4 per cent; relative risk, RR, 1.72; number needed to harm over 30 months, 107). There was no heterogeneity between studies, showing that this is a class effect. However, the risk of cardiovascular death was not increased for either rosiglitazone (Avandia) or pioglitazone (Actos). Copyright © 2007 Wiley Interface Ltd [source]

Latest news and product developments

PRESCRIBER, Issue 19 2007
Article first published online: 22 NOV 200
UK data suggest OCs may reduce cancer risk The latest analysis of the RCGP oral contraception (OC) study suggests that oral contraceptives may be associated with an overall reduction in the risk of cancer (Br Med J online: 11 September 2007; doi:10.1136/bmj.39289. 649410.55). The cohort of 46 000 women provided 744 000 woman-years for ever use of an oral contraceptive and 339 000 woman-years of never use. Longer use was associated with increasing risks of cervical (RR 2.73), and pituitary or CNS (RR 5.51) cancers, but decreasing risks of uterine (RR 0.57) and ovarian (RR 0.38) cancers. OC use was also associated with a lower overall risk of colorectal cancers. The overall risk of any cancer was reduced by 12 per cent (RR 0.88). CombAT two-year data Two-year data revealed at the 29th Congress of the Société Internationale d'Urologie in Paris in September show that dutasteride (Avodart) and tamsulosin combination therapy provides significantly improved symptom control in BPH compared with either therapy alone. The Combination therapy with Avodart (dutasteride) and tamsulosin (CombAT) study took over 4800 eligible men (age ,50 years with a prostate volume ,30cc, serum PSA level ,1.5-10ng per ml and IPSS ,12) who received placebo for four weeks before being randomised in a 1:1:1 ratio to either dutasteride monotherapy (0.5mg per day), tamsulosin monotherapy (0.4mg per day) or a combination of both drugs. At two years the primary efficacy end-point was achieved: combination therapy was significantly more effective than either monotherapy, and continuous improvement could be observed throughout the two years. The combination therapy was also well tolerated, although drug-related adverse events were more common with combination therapy (24 per cent) than either monotherapy (dutasteride 18 per cent, tamsulosin 14 per cent). Dutasteride, a 5-, reductase inhibitor, has been shown to be more effective for long-term use in men than tamsulosin, while tamsulosin, an alpha blocker, has been shown to be effective in the short term. CombAT is the first study to demonstrate that the combination therapy of both drugs could lead to greater symptom improvement over time than an alpha blocker alone. Aliskiren - new class of antihypertensive Novartis has introduced aliskiren (Rasilez), the first direct renin inhibitor for the treatment of hypertension. It is likely to be used in combination with other agents but is also licensed as monotherapy. The commonest adverse effect is diarrhoea. At the recommended dose of 150-300mg per day, a month's treatment costs £19.80-£23.80. MHRA updates drug safety advice The balance of benefit and risks from HRT may be more favourable for younger women, the MHRA says in its monthly bulletin, Drug Update (September 2007). GPs considering prescribing HRT should evaluate the potential risks and benefits for each individual, the MHRA says. The bulletin summarises the risks of cardiovascular events and cancers associated with HRT. Cardiovascular risk is a particular concern for women over 60, whose baseline risk is high; although evidence for the safety of HRT in younger women is limited, their baseline risk is lower. Overall, the lowest dose of HRT should be used for the shortest possible time, and HRT should be prescribed to prevent osteoporosis only when alternatives are not suitable. The MHRA also advises in the bulletin that: Individual risk of stroke, breast cancer and endometrial cancer should be considered before prescribing tibolone (Livial). Nasal formulations of desmopressin are no longer indicated for primary nocturnal enuresis; prescribers are reminded to adhere to product guidance on fluid intake. Patients and carers should be warned of the risk of psychiatric effects associated with corticosteroids; symptoms may develop within a few days or weeks in children and adults, and may be more common at higher doses. Patients taking steroids for more than three weeks are reminded not to stop treatment abruptly. A list of questions and answers for patients is available at www.mhra.gov.uk. The use of parenteral B vitamins plus ascorbic acid (Pabrinex) may rarely be associated with severe allergic reactions, but this should not preclude its use for patients who need it. Study claims statin switch may increase CV morbidity Switching patients from atorvastatin (Lipitor) to simvastatin may increase the risk of cardiovascular events, according to a UK study presented at the European Society of Cardiology Congress in Vienna. The analysis, from The Health Improvement Network database, included 11 520 patients taking atorvastatin for at least six months, of whom 2511 were switched to simvastatin. Switching was associated with a 30 per cent increase in the relative risk of cardiovascular events, though absolute figures have not been reported. Patients who were switched were also more likely to discontinue treatment (21 vs 8 per cent of those continuing atorvastatin). Details of the conduct of the study, which will be published in the British Journal of Cardiology, are not available. Glitazones controversy rumbles on New systematic reviews have fuelled the controversy over the cardiac safety of rosiglitazone and pioglitazone. A meta-analysis of four trials involving 14 291 patients and lasting one to four years found that rosiglitazone was associated with a significantly increased risk of myocardial infarction (relative risk, RR, 1.42) and heart failure (RR 2.09) but not cardiovascular mortality (RR 0.90) (J Am Med Assoc 2007;298:1189-95). The second review included 19 trials of pioglitazone involving 16 390 patients, with follow-up from four months to 3.5 years. Pioglitazone was associated with a lower risk of composite events (death, myocardial infarction, stroke; hazard ratio, HR, 0.82) but an increased risk of serious heart failure (HR 1.41) (J Am Med Assoc 2007;298: 1180-8). Neither review reported significant heterogeneity between the included studies. Another systematic review of eight controlled and cohort studies concluded that metformin is the only antidiabetic drug not associated with an increased risk of harm in patients with diabetes and heart failure (Br Med J Online First 30 August; doi:10.1136/bmj.39314. 620174.80). The Canadian authors found methodological problems with all studies, and concluded that results for sulphonylureas were conflicting due to differences between the studies. Asthma prescribing education Health professionals need more education about rational prescribing for children with asthma, say researchers from Australia (Arch Dis Child online: 4 September 2007; doi: 10. 1136/adc.2007.119834). Analysing trends in asthma medication prescriptions for children in the UK between 2000 and 2006, they found the proportion of steroid inhalers prescribed as combinations increased from 2.7 per cent in 2000 to 25 per cent in 2006. The authors say this excessive increase is inconsistent with guidance that steroid-only inhalers should be the mainstay for most people with asthma. Copyright © 2007 Wiley Interface Ltd [source]

The Nonchiral Bislactim Diethoxy Ether as a Highly Stereo-Inducing Synthon for Sterically Hindered, , -Branched , -Amino Acids: A Practical, Large-Scale Route to an Intermediate of the Novel Renin Inhibitor Aliskiren

HELVETICA CHIMICA ACTA, Issue 8 2003
Richard Göschke
The diastereoselective synthesis of the sterically hindered, , -branched , -amino acid derivative (2S,4S)- 24a and its N -[(tert -butoxy)carbonyl](Boc)-protected alcohol (2S,4S)- 19, both key intermediates of a novel class of nonpeptide renin inhibitors such as aliskiren (1), is described. Initially, the analogous methyl ester (2S,4S)- 17 was obtained by alkylation of the chiral Schöllkopf dihydropyrazine (R)- 12a with the dialkoxy-substituted alkyl bromide (R)- 11a, which proceeded with explicitly high diastereofacial selectivity (ds ,98%) to give (2S,5R,2,S)- 13a (Scheme,4), followed by mild acid hydrolysis and N -Boc protection (Scheme,5). Conversely, the complete lack of stereocontrol and poor yields for the reaction of (R)- 11a with the enantiomeric (S)- 12b suggested, in addition to the anticipated shielding effect by the iPr group at C(2) of the auxiliary, steric repulsion between the MeOC(6) and the bulky residues of (R)- 11a in the proposed transition state, which would strongly disfavor both the Si and Re attack of the electrophile (see Fig.). Based on this rationale, alkylation of the readily accessible achiral diethoxy-dihydropyrazine 21 with (R)- 11a was found to provide a 95,:,5 mixture of diastereoisomers (2S,2,S)- 22a and (2R,2,S)- 23a in high yield (Scheme,6), which afforded in two steps and after recrystallization enantiomerically pure (2S,4S)- 24a. Similarly, the stereochemical course for the alkylation reactions of the related alkyl bromides (S)- 28a and (R)- 28b with both (R)- 12a and (S)- 12b as well as with the achiral 21 was investigated (Schemes,7,9). The precursor bromides (R)- 11a, (S)- 11b, (R)- 28a, and (S)- 28b were efficiently synthesized via the diastereoselective alkylation of the Evans 3-isovaleroyloxazolidin-2-ones (R)- 7a and (S)- 7b either with bromide 6 or with benzyl chloromethyl ether, and subsequent standard transformations (Schemes,3 and 7). A practical and economical protocol of the preparation of (2S,4S)- 24a on a multi-100-g scale is given. This is the first report of the application of an achiral dihydropyrazine, i.e., in form of 21, as a highly stereo-inducing synthon providing rapid access to a N -protected , -branched , -amino acid with (2S) absolute configuration. [source]

Plasma renin and the antihypertensive effect of the orally active renin inhibitor aliskiren in clinical hypertension

INTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 9 2007
J. Nussberger
Summary Background:, Aliskiren is the first in a new class of orally effective renin inhibitors for the treatment of hypertension. Methods:, In 569 patients with mild-to-moderate hypertension, blood pressure (BP), plasma renin activity (PRA) and plasma renin concentration (PRC) were measured before and after 8 weeks of double-blind treatment with once-daily oral doses of aliskiren (150, 300 or 600 mg), irbesartan 150 mg or placebo. Results:, Aliskiren 150, 300 and 600 mg and irbesartan 150 mg significantly reduced mean cuff sitting systolic BP (SBP) from baseline (p < 0.001 vs. placebo). Aliskiren 150, 300 and 600 mg significantly reduced geometric mean PRA by 69%, 71% and 75% from baseline respectively (p < 0.05 vs. placebo). Irbesartan 150 mg significantly increased PRA by 109% (p < 0.05 vs. placebo). Aliskiren dose-dependently increased PRC from baseline by 157%, 246% and 497%, at 150, 300 and 600 mg respectively, compared with a 9% decrease with placebo (p < 0.05). PRC increased significantly more with aliskiren 300 and 600 mg compared with irbesartan 150 mg (105%; p < 0.05). Regression analysis showed no significant correlations between baseline PRA and changes in SBP in any of the treatment groups, but interestingly, the slopes of the regression lines between changes in SBP and log-transformed baseline PRA were +2.0 for placebo and ,1.5, ,1.8 and ,2.3 for aliskiren 150, 300 and 600 mg respectively. The slope for irbesartan 150 mg (,1.4) was similar to that for aliskiren 150 mg. Conclusions:, Aliskiren reduces SBP and PRA and increases PRC dose-dependently. In contrast, irbesartan reduces SBP but increases both PRC and PRA. As PRA is a measurement of angiotensin I-generating capacity, PRA can be used for measuring the ability of an antihypertensive agent to prevent the generation or action of Ang II, either directly (renin inhibitors, beta-blockers, central ,2 -agonists) or indirectly (AT1 -receptor blockers, ACE inhibitors). [source]

Renin-angiotensin system revisited

JOURNAL OF INTERNAL MEDICINE, Issue 3 2008
F. Fyhrquist
Abstract. New components and functions of the renin-angiotensin system (RAS) are still being unravelled. The classical RAS as it looked in the middle 1970s consisted of circulating renin, acting on angiotensinogen to produce angiotensin I, which in turn was converted into angiotensin II (Ang II) by angiotensin-converting enzyme (ACE). Ang II, still considered the main effector of RAS was believed to act only as a circulating hormone via angiotensin receptors, AT1 and AT2. Since then, an expanded view of RAS has gradually emerged. Local tissue RAS systems have been identified in most organs. Recently, evidence for an intracellular RAS has been reported. The new expanded view of RAS therefore covers both endocrine, paracrine and intracrine functions. Other peptides of RAS have been shown to have biological actions; angiotensin 2,8 heptapeptide (Ang III) has actions similar to those of Ang II. Further, the angiotensin 3,8 hexapeptide (Ang IV) exerts its actions via insulin-regulated amino peptidase receptors. Finally, angiotensin 1,7 (Ang 1,7) acts via mas receptors. The discovery of another ACE2 was an important complement to this picture. The recent discovery of renin receptors has made our view of RAS unexpectedly complex and multilayered. The importance of RAS in cardiovascular disease has been demonstrated by the clinical benefits of ACE inhibitors and AT1 receptor blockers. Great expectations are now generated by the introduction of renin inhibitors. Indeed, RAS regulates much more and diverse physiological functions than previously believed. [source]