Angiotensin II Receptor Blockers Inhibit the Generation of Epoxyeicosatrienoic Acid from Arachidonic Acid in Recombinant CYP2C9, CYP2J2 and Human Liver Microsomes

Cytochrome P450 (CYP) 2C9, CYP2C8 and CYP2J2 enzymes, which metabolize arachidonic acid (AA) to epoxyeicosatrienoic acids, have cardioprotective effects including anti‐inflammation and vasodilation. We have recently shown that some angiotensin II receptor blockers (ARBs) may inhibit AA metabolism via CYP2C8. Using recombinant CYP2C9, CYP2J2 and human liver microsomes (HLMs), the aim was now to compare the ability of six different clinically used ARBs to inhibit AA metabolism in vitro. The rank order of the ARBs for the 50% inhibitory concentration (IC₅₀) of AA metabolism was losartan <telmisartan <irbesartan <candesartan <olmesartan <valsartan via CYP2C9, and telmisartan <irbesartan <olmesartan <losartan <candesartan and valsartan via CYP2J2. The order for the HLMs was losartan <telmisartan <irbesartan <olmesartan <candesartan <valsartan. Some ARBs having lower concentration of IC₅₀ indicate that these ARBs might inhibit the AA metabolism in the liver.     

Cost Effectiveness of Angiotensin Receptor Blocker Monotherapy in Patients with Hypertension in the Netherlands

Background and Objective

Health gains and related cost savings achieved by optimizing treatment in hypertensive patients is highly important. The aim of this study was to evaluate the costs and cost effectiveness of treatment with angiotensin II receptor antagonists (angiotensin II receptor blockers [ARBs]) in patients with essential hypertension and to compare within-trial with real-life dosing of ARBs.

Methods

Cost effectiveness was estimated based on a published clinical trial comparing the BP-lowering effects of olmesartan, losartan, valsartan, and irbesartan. BP lowering after 8 weeks of treatment was entered into the Framingham risk functions to estimate cardiovascular complications after 1 and 5 years, using an international health economics model that was adapted to the Netherlands. Dutch costs (2006 values) and complications derived from the model were discounted at 4% and 1.5%, respectively, and cost effectiveness was expressed in net costs per cardiovascular complication averted. In a drug-utilization study, pharmacy dispensing records were used to evaluate differences between within-trial and daily-practice dosing and related costs for treatment in the Netherlands.

Results

After 8 weeks, the trial-based analysis showed that treatment with olmesartan versus losartan, valsartan, and irbesartan resulted in a significantly larger decrease in BP (11.5 vs 8.2, 7.9 and 9.9 mmHg [p<0.05], respectively) and consequently more complications averted. Cost effectiveness for olmesartan, losartan, valsartan, and irbesartan was estimated at €39 100, €77 100, €70 700, and €50 900 per cardiovascular complication averted, respectively. The incremental cost-effectiveness analysis indicated the most favorable cost-effectiveness outcome for olmesartan, with lower costs and less cardiovascular complications for olmesartan compared with the other three ARBs. The drug-utilization analysis showed that the dosing followed within clinical trials was not found in daily practice. On average, losartan, valsartan, and irbesartan were administered at doses above those used in clinical trials, whereas olmesartan was dosed lower than in clinical trials, resulting in relatively lower costs.

Conclusion

Based on the exact trial data, olmesartan was estimated to be the most favorable option of the four ARBs based on within-trial decreases in BP levels after 8 weeks and in terms of cost-effectiveness for this particular Dutch setting. However, for definite conclusions to be drawn, this hypothesis-generating study requires confirmation from further prospective studies comparing ARBs based on comparable BP control and including hard endpoints.     

Antihypertensive Effects of Olmesartan Compared with Other Angiotensin Receptor Blockers

Objectives: Angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]) have been shown to be effective and well tolerated in hypertensive patients. Olmesartan is the seventh angiotensin receptor blocker licensed by the US Food and Drug Administration. The aim of this meta-analysis was to determine the efficacy and tolerability of olmesartan medoxomil in comparison with other ARBs. Data Sources: Reports of randomized controlled trials (RCTs) of olmesartan versus other ARBs were identified through a systematic search of PubMed (up to July 2010), EMBASE (1980 to July 2010), SinoMed (up to July 2010), and the Cochrane Central Register of Controlled Trials (Cochrane Library Issue 7, 2010). Review Methods: Pertinent studies were selected through extensive searches of PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and SinoMed. Two of the authors abstracted data from the identified studies independently. Criteria for inclusion in our meta-analyses were randomized clinical trials in which patients were receiving an ARB and outcome data for blood pressure reduction or the incidence of adverse events were available. Quantitative and qualitative analyses of data from all RCTs meeting the criteria were performed. Our meta-analysis was undertaken according to the Quality of Reporting Meta-analyses (QUOROM) statement. Results: Twenty-two studies with data from 4892 patients were considered for analyses. Olmesartan provided greater diastolic blood pressure (DBP) and systolic blood pressure (SBP) reductions compared with losartan (DBP: 95% confidence interval [CI] 0.59, 2.62; SBP: 95% CI 0.46, 5.92). Olmesartan provided greater SBP reductions compared with valsartan (95% CI 0.29, 3.16). Similar blood pressure response rates and incidence of adverse events were found with losartan, valsartan, candesartan, and irbesartan. Conclusion: Olmesartan provides better antihypertensive efficacy than losartan and valsartan and has no association with an increased risk of adverse events in comparison with losartan, valsartan, candesartan, and irbesartan.     

The value of irbesartan in the management of hypertension

Elevated blood pressure levels are highly prevalent and are a major reason for cardiovascular events and thus place a significant financial burden on healthcare systems worldwide. Guidelines recommend five first-line anti-hypertensive drug classes, but compelling indications may indicate favoring one drug class over another. Angiotensin receptor blockers (ARBs) have demonstrated a blood pressure lowering efficacy which is at least comparable with other drug classes, including ACE inhibitors (ACE-I), β-blockers, calcium channel blockers and diuretics. They have, in addition, a lower side effect profile than other drug classes and patients on ARBs are more persistent with therapy. Compelling indications for the use of ARBs are heart failure, post-myocardial infarction, diabetic nephropathy, proteinuria/microalbuminuria, left ventricular hypertrophy, atrial fibrillation, metabolic syndrome and ACE-I induced cough. The ARB irbesartan has demonstrated a high efficacy in lowering blood pressure, which has been shown to be at least comparable with ACE-Is and superior to other ARBs such as losartan and valsartan. This translated into a better cost-effectiveness for irbesartan than for valsartan and losartan in the treatment of hypertension. In addition, irbesartan has been shown to be effective in both early and late stage diabetic nephropathy. It has further demonstrated considerable cost savings over standard therapy including β-blockers, diuretics and non-dihydropyridine calcium channel blockers at all stages of kidney disease. Based on efficacy data from the Irbesartan Diabetic Nephropathy Trial and Reduction of Endpoints in NIDDM (non insulin dependant diabetes melitis) with the Angiotensin II Antagonist Losartan Study, it has also demonstrated cost savings over losartan in late stage renal disease. While both losartan and irbesartan are registered for the treatment of late stage diabetic nephropathy, irbesartan is also registered for early stage diabetic nephropathy in the EU. In summary, the data from randomized clinical trials on the efficacy of antihypertensive drugs provides an indication of their real value to patients. In addition observational data from clinical practice and proven end-organ protection in diabetic nephropathy provides further evidence of the true value of irbesartan compared to other ARBs in the treatment of hypertension.     

A French cost-consequence analysis of the renoprotective benefits of irbesartan in patients with type 2 diabetes and hypertension

ABSTRACT

Objectives: We performed a cost-consequence analysis in a French setting of the renoprotective benefit of irbesartan in hypertensive type 2 diabetes patients over a 25-year period.

Research design and methods: A previously published Markov model simulated progression from microalbuminuria to overt nephropathy, doubling of serum creatinine, end-stage renal disease and death. Three treatment strategies with analogous blood pressure control were compared: (A) control – conventionally medicated antihypertensive therapy (excluding angiotensin converting enzyme inhibitors, other angiotensin-2-receptor antagonists and dihydropyridine calcium channel blockers) initiated at microalbuminuria; (B) early irbesartan – (300?mg daily added to control, initiated with microalbuminuria) and (C) late irbesartan – (300?mg daily, initiated with overt nephropathy). Probabilities came from the Irbesartan in Reduction of Microalbuminuria-2 study, Irbesartan in Diabetic Nephropathy Trial and other sources. Clinical and economic outcomes were projected over 25 years. Annual discount rates were 3%.

Results: Compared to control, early use of irbesartan added (mean ± standard deviation) 1.51 ± 0.08 undiscounted life years (discounted: 0.94 ± 0.05 years), while late irbesartan added 0.07 ± 0.01 (0.04 ± 0.01) years/patient. Early irbesartan added 1.03 ± 0.06 discounted quality-adjusted life years (QALYs), while late irbesartan added 0.06 ± 0.01 QALYs. Early and late irbesartan treatments were projected to save €22?314 ± 1273 and €6619 ± 820/patient, respectively versus control. Sensitivity analysis showed that even over short time horizons both irbesartan treatments were superior to the control group.

Conclusions: In France, early irbesartan treatment improved quality and length of life and reduced costs in hypertensive patients with type 2 diabetes and microalbuminuria. Late irbesartan therapy is beneficial, but earlier irbesartan leads to better outcomes.     

Palatability of angiotensin II antagonists among nephropathic children

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * Among children, medication palatability is crucial for adherence to therapeutic regimen. * Several studies have measured the palatability of antimicrobial suspensions in paediatric patients by means of a visual analogue scale palatability score. WHAT THIS STUDY ADDS: * This is the first analysis comparing the taste and smell acceptability of angiotensin II receptor blockers among paediatric patients with kidney disease. * From the perspective of the child with kidney disease, the taste of pulverized candesartan is significantly superior to that of pulverized irbesartan, losartan, telmisartan or valsartan. AIM: Angiotensin II receptor blockers are widely prescribed in kidney disease. Among children, medication palatability is crucial for adherence. METHODS: Taste and smell acceptability of five angiotensin II receptor blockers were compared among 21 nephropathic children using a visual analogue scale palatability score. RESULTS: The score assigned to pulverized tablets of candesartan cilexetil was significantly higher than that assigned to pulverized tablets of irbesartan, losartan, telmisartan and valsartan. CONCLUSIONS: From the perspective of the nephropathic child, the taste of pulverized candesartan cilexetil is superior to that of irbesartan, losartan, telmisartan or valsartan.     

Relationship between the receptor occupancy profile and pleiotropic effects of angiotensin II receptor blockers

Aim

To investigate whether (i) angiotensin receptor occupying profiles of angiotensin II receptor blockers (ARBs) vary among the drugs and (ii) such differences contribute to the degree of their pleiotropic effects.

Methods

In a randomized, three phase crossover study, nine hypertensive patients received repeated doses (each recommended starting dose for 7 days and then each maximum recommended dose for 20 days) of irbesartan, valsartan and candesartan. The time course profiles and trough level of receptor occupancy were determined on days 7 and 28, respectively. The pleiotropic effect related parameters were measured on days 0 and 28 in each trial.

Results

Of the pleiotropic effect related parameters investigated, urinary 8-isoprostane, fasting serum insulin and homeostasis model assessment of insulin resistance index were more suppressed after 4 weeks treatment with irbesartan than after candesartan and valsartan therapy, respectively. The maximum, area under the curve and trough values of receptor occupancy significantly differed between the ARBs [geometric mean (and 95% CI) of trough value 18.1 (12.9, 25.3) for irbesartan, 9.6 (6.0, 15.3) for valsartan and 5.5 (2.8, 10.8) for candesartan, respectively] and were negatively correlated with the change in urinary 8-isoprostane (r = −0.46 − −0.55, P < 0.05), but not the markers of insulin resistance (r = 0.02–0.15, P = 0.46–0.94).

Conclusions

Our results demonstrate that the receptor occupying profiles are different among the ARBs. This class of drugs might have both receptor occupancy dependent and independent pleiotropic effects.     

Investigation of Carcinogenic Impurities of N-Nitrosamines in Sartan Pharmaceutical Products Marketed in Brazil: Development and Validation of Method Based on High-Performance Liquid Chromatography-Tandem Mass Spectrometry

N-nitrosamines (NA) impurities have unexpectedly been found in sartan products, angiotensin II receptor antagonists that are used to control hypertension, representing an urgent concern for industry, global regulators and for the patients. In this study, an HPLC-MS/MS method was developed and validated for the quantification of six NA (N-nitrosodimethylamine, N-Nitroso-N-methyl-4-aminobutyric acid, N-Nitrosodiethylamine, N-ethyl-N-nitroso-2-propanamine, N-nitroso-diisopropylamine and N-nitroso-di-n-butylamine) in losartan, valsartan, olmesartan, irbesartan, candesartan and telmisartan products. The method was validated in terms of sensitivity, linearity, accuracy, precision, robustness and stability. The limits of quantification were 100, 31.25, 250, 33, 312.5 and 125 µg kg⁻¹ in losartan, valsartan, olmesartan, irbesartan, candesartan and telmisartan samples, respectively, which met the sensitivity requirements for the limits set by Food and Drug Administration of the United States. The standard curves showed good linearity. The recoveries ranged from 93.06 to 102.23% in losartan matrix, 83 to 85.9% in valsartan, 96.1 to 101.2% in olmesartan, 89.2 to 97.5% in irbesartan, 93.4 to 132.0% in candesartan and 62.3 to 106.2% in telmisartan matrix. The other parameters met the validation criteria, the good sensitivity and precision, high accuracy and simple and fast analysis provides a reliable method for quality control of NA in sartan pharmaceutical products. The developed method was successfully applied for the determination of N-nitrosamines in 71 sartan products marketed in Brazil.     

全国多中心564 711例高血压患者RAS抑制剂药物利用分析

目的：分析2017年全国8个城市口服RAS抑制剂的高血压患者特征和药品使用特征,为临床合理用药提供参考。方法：基于2017年《医院处方分析项目》随机抽取的处方数据,采用WHO推荐的药物利用分析方法,对ACEI和ARBs使用情况进行分析。结果：共抽得8个城市101家医院的564 711例的口服ACEI和ARBs类降血压药高血压患者。北京地区患者最多,占26.20%。男女比例为1.17。中位年龄64岁。老年患者占比49.90%。患者主要于门诊购药,占89.10%。处方科室以内科为主,占89.40%。303例患者存在潜在超适应证用药风险。ARBs处方数量占78.71%,处方金额占83.05%。处方数量和处方金额最大的3种药品依次为：缬沙坦、厄贝沙坦和氯沙坦;其PDD/DDD值均大于1：缬沙坦（1.32±0.53）、厄贝沙坦（1.33±0.87）和氯沙坦（1.70±0.65）;合并肾病、肝病及同时合并肾病和肝病患者的PDD/DDD值高于患者平均水平。结论：ARBs是临床更常用的RAS抑制剂,特别是缬沙坦、厄贝沙坦和氯沙坦;仍须规范ARBs和ACEIs类药物的适应证,且重视高血压合并肾病、肝病患者的药物剂量管理。     

In vitro inhibition screening of human hepatic P 450 enzymes by five angiotensin-II receptor antagonists

Objective: Metabolic interactions at the level of drug-metabolising enzymes are important for drug therapy. We investigated potential interactions of losartan, irbesartan, valsartan, eprosartan and candesartan with cytochrome P ₄₅₀ (CYP) enzymes in human liver microsomes. Methods: In incubations with human liver microsomes in vitro, the inhibitory potency of angiotensin-II receptor antagonists (sartans) on CYP-specific model activities were compared by measuring the IC₅₀ and, with respect to more potent inhibition, K _i values. Results: None of the five sartans inhibited CYP2A6-, CYP2D6- or CYP2E1-associated activities (coumarin 7-hydroxylation, dextromethorphan O-demethylation and chlorzoxazone 6-hydroxylation, respectively) to any significant extent. Losartan and irbesartan inhibited the CYP2C9-associated tolbutamide methylhydroxylation more potently (K _i values 4.1 μM and 24.5 μM), than valsartan, candesartan or eprosartan (K _i values 135 μM, 155 μM and >1000 μM, respectively). Losartan and irbesartan inhibited CYP1A2- and CYP3A4-associated activities (ethoxyresorufin O-deethylation and testosterone 6β-hydroxylation) with relatively weak affinities (IC₅₀ values between 200 μM and 500 μM). CYP2C19-associated S-mephenytoin 4′-hydroxylation activity was inhibited by losartan (IC₅₀ value 138 μM) and much less or not at all by the other sartans tested. Conclusion: All sartans except eprosartan have at least some affinity for CYP2C9, but only losartan has an affinity for CYP2C19. Losartan and irbesartan have modest affinity for CYP1A2 and CYP3A4. This would suggest that the theoretical potential for drug interactions is likely to be quite low, with the possible exceptions of losartan and irbesartan for CYP2C9. Based on these findings, further studies on the interaction potential of losartan and irbesartan are warranted. Received: 27 October 1999 / Accepted in revised form: 10 February 2000     

Substrate recognition of renally eliminated angiotensin II receptor blockers by organic anion transporter 4

Organic anion transporter (OAT) 4, which is localized at the apical membrane of human renal proximal tubules, transports olmesartan, an angiotensin II receptor blocker (ARB). Many ARBs, including olmesartan, undergo partial tubular secretion as active forms, and inhibit OAT4-mediated uptake activity. Here, we examined the substrate recognition of various ARBs by OAT4 in order to assess whether OAT4 might be involved in the renal handling of ARBs. Concentration-dependent OAT4-mediated uptake of azilsartan, candesartan, carboxylosartan, losartan, and valsartan was observed with K_m values of 6.6, 31, 7.2, 13, and 1.7 μM, respectively, in the absence of extracellular Cl⁻. In the presence of extracellular Cl⁻, OAT4-mediated uptake of dianionic ARBs (azilsartan, candesartan, carboxylosartan, and valsartan) was lower and reached a steady state faster than in the absence of extracellular Cl⁻. Thus, OAT4 is proposed to use extracellular Cl⁻ as a counterpart for anion efflux. Our results suggest that OAT4 may play a role in the excretion of azilsartan, candesartan, carboxylosartan, and valsartan, as well as olmesartan. In contrast, OAT4-mediated uptake of losartan, a monoanionic ARB, was little affected by extracellular Cl⁻, suggesting that only OAT4-mediated dianion transport is Cl⁻-sensitive.     

Angiotensin II Receptor Antagonists Alone and Combined with Hydrochlorothiazide

Angiotensin II receptor antagonists (angiotensin receptor blockers; ARBs) and thiazide diuretics have an accepted place in the management of hypertension. Most patients require combination therapy with two or more drugs to adequately control blood pressure to targets recommended by European and international guidelines. ARBs and the thiazide diuretic hydrochlorothiazide have complementary modes of action. Fixed-dose combinations of an ARB and low-dose hydrochlorothiazide provide a convenient and effective treatment option for patients who do not achieve blood pressure targets on monotherapy, without compromising the placebo-like tolerability of ARBs. In Europe, fixed-dose combinations with hydrochlorothiazide currently are available for the ARBs candesartan, eprosartan, irbesartan, losartan, telmisartan, and valsartan. Recently, a number of studies have focused on the use of ARBs in monotherapy and in combination therapy, in conditions including congestive heart failure, post-myocardial infarction management, hypertension with cardiovascular risk factors, and diabetic and non-diabetic nephropathy. Evidence from these studies suggests a beneficial role beyond the antihypertensive effect of these therapies in providing protection against cardiovascular, renovascular, and cerebrovascular events.     

Modelling the economic and health consequences of cardiac resynchronization therapy in the UK

ABSTRACT

Objective: Clinical evidence supports the use of cardiac resynchronization therapy (CRT) in advanced heart failure, but its cost-effectiveness is still unclear. This analysis assessed the economic and health consequences in the UK of implanting a CRT in patients with NYHA class III-IV heart failure.

Methods: A discrete event simulation of heart failure was used to compare the course over 5 years of 1000 identical pairs of patients – one receiving both CRT and optimum pharmacologic treatment (OPT), the other OPT alone. All inputs were obtained from the data collected in the CArdiac REsynchronization in Heart Failure (CARE-HF) trial and a hospital in the UK. Direct medical costs (in 2004 £) from the perspective of the National Health Service were considered. Both costs and benefits were discounted at 3.5%. Sensitivity analyses addressed all model inputs and multivariate analyses were performed by varying key parameters simultaneously.

Results: The model predicted 471 deaths and 2263 hospitalizations over 5 years with OPT alone and 348 deaths and 1764 hospitalizations with CRT, equivalent to a 26% reduction in mortality and 22% in hospitalizations, at a discounted cost of £11?423 per patient with CRT vs. £4900 with OPT alone. CRT was predicted to increase quality-adjusted survival by 0.43 QALYs per patient, resulting in an incremental cost-effectiveness ratio of £15?247 per QALY gained (range: £12?531–£23?184). Sensitivity analyses revealed that this outcome was most sensitive to time horizon and cost of implantation.

Conclusion: Based on these 5‐year analyses, CRT is expected to yield substantial health benefits at a reasonable cost.     

Identification and determination of selected angiotensin II receptor antagonist group drugs by HPLC method

Losartan potassium, valsartan, telmisartan, irbesartan, eprosartan mesylate and candesartan cilexitil, the angiotensin II receptor antagonists, were analyzed in bulk substances and in tablets: Lorista tablets 50 mg, Diovan tablets 160 mg, Micardis tablets 20 mg, Aprovel tablets 300 mg, Teveten tablets 600 mg and Blopress tablets 16 mg. The conditions for identification by HPLC method in a gradient system and for determination of those compounds in isocratic systems were developed. The determination was carried out using Zorbax SB-Phenyl column with UV-VIS detector set at 230 nm and the following mobile phases: 0.1 mol/L sodium acetate (pH = 5.5) - acetonitrile - methanol in 35:9:6 v/v/v ratio for eprosartan mesylate and valsartan, in 15:6:4 v/v/v ratio for losartan potassium and irbesartan and in 10:9:6 v/v/v ratio for telmisartan and candesartan cilexitil. The recovery from simulated tablets was determined and amounted to: for eprosartan mesylate - 99.04%, valsartan - 100.0%, losartan potassium - 100.03%, irbesartan - 100.35%, telmisartan - 100.06% and candesartan cilexitil - 100.40%.     

Candesartan cilexetil – a review of effects on cardiovascular complications in hypertension and chronic heart failure

ABSTRACT

Therapeutic interventions that block the renin–angiotensin–aldosterone system (RAAS) have an important role in slowing the progression of cardiovascular risk factors to established cardiovascular diseases. In recent years, angiotensin receptor blockers (ARBs) have emerged as effective and well-tolerated alternatives to an angiotensin-converting enzyme inhibitor (ACEi) for RAAS blockade. The ARB candesartan was initially established as an effective once-daily antihypertensive treatment, providing 24?h blood pressure (BP) control with a trough:peak ratio close to 100%.

Scope: A Medline literature search was undertaken to identify randomised, controlled trials that examined the efficacy and cardiovascular outcomes associated with candesartan cilexetil in hypertension and chronic heart failure (CHF).

Findings: Compared with other ARBs, candesartan demonstrates the strongest binding affinity to the angiotensin II type 1 receptor. Clinical trials have demonstrated that candesartan is well tolerated in combination with diuretics or calcium channel blockers (CCBs), making it a suitable treatment option for patients whose hypertension is not adequately controlled by monotherapy. Subsequently, candesartan became the only ARB licensed in the UK to treat patients with CHF and left ventricular ejection fraction ≤ 40% as add-on therapy to an ACEi or when an ACEi is not tolerated. Studies in patients with symptomatic HF have indicated that candesartan treatment was associated with significant relative risk reductions in cardiovascular mortality and hospitalisation due to CHF.

Conclusions: There are clear indications that the clinical benefits of candesartan may extend beyond its proven antihypertensive effects to a wider range of complica­tions across the cardiovascular continuum, including diabetes, left ventricular hypertrophy, atherosclerosis and stroke. Such results suggest that candesartan treatment may offer significant patient benefits as well as practical advantages over conventional treatment.     

Efficacy and safety of valsartan 160/HCTZ 25 mg in fixed combination in hypertensive patients not controlled by candesartan 32 mg plus HCTZ 25 mg in free combination

ABSTRACT

Objective: Free combination hypertension medication is associated with a lower compliance and less persistence compared to fixed combination therapy and can, there­fore, be associated with insufficient blood pressure reductions. This non-randomized study investigated whether valsartan 160?mg/ hydrochlorothiazide 25?mg (Val 160/HCTZ 25) in fixed dose combination could provide additional blood pressure control in hypertensive patients not adequately controlled by the free combination of candesartan 32?mg plus HCTZ 25?mg.

Research design and methods: One hundred and ninety-seven patients with a mean sitting diastolic blood pressure (MSDBP) between 100 and 110?mmHg entered a 4-week treatment phase with 32?mg of candesartan in free combination with 25?mg of HCTZ once daily. One hundred and thirty-eight patients with uncontrolled BP at Week 4, entered a second 4-week treatment phase with Val160/ HCTZ 25 once daily.

Main outcome measures: The primary efficacy parameter was the reduction in MSDBP at trough between Week 4 and Week 8 in the intent-to-treat population.

Results: At baseline, MSDBP was 103.0 ± 2.8?mmHg. After Week 4, MSDBP had decreased to 93.8 ± 4.5?mmHg. Subsequent treatment with Val 160/HCTZ 25 for 4 weeks reduced MSDBP to 88.7 ± 8.6?mmHg. This represented an additional decrease in MSDBP of 5.1 ± 7.9?mmHg (?p < 0.0001). Val 160/ HCTZ 25 reduced mean sitting systolic BP by 3.4 ± 13.0?mmHg (?p = 0.0029).

Conclusions: The fixed dose combination of valsartan 160/HCTZ 25?mg provided a statistically and clinically significant additional BP reduction in patients not controlled by the free combination of candesartan 32?mg and HCTZ 25?mg.     

An economic evaluation of sevelamer in patients new to dialysis

ABSTRACT

Objective: The overall objective of this study was to estimate the costs and outcomes associated with treatment with sevelamer for hyperphosphataemia compared with calcium-based binders.

Methods: Using published data on mortality and hospitalisation rates, a Markov model was developed to predict health outcomes and associated costs for the treatment of hyperphosphataemia using either sevelamer or calcium binders in chronic kidney disease patients who had recently started haemodialysis. Patient outcomes were modelled for 5 years, and incremental cost-effective ratios (ICERs) were calculated for sevelamer relative to calcium carbonate and calcium acetate binders. The perspective adopted was that of the UK National Health Service.

Results: The total 5-year discounted treatment cost for patients treated with sevelamer is £24?216, while for the calcium carbonate group total cost was £17?695. This is an incremental cost of £6521 per sevelamer-treated patient over 5 years. Patients receiving sevelamer can be expected to experience 2.70 quality-adjusted life years (QALYs) compared to 2.46 for those treated with calcium carbonate (i.e. an incremental gain of 0.24 QALYs). This results in an incremental cost per QALY of £27?120 and an incremental cost per life year gained of £15?508. Results were similar with calcium acetate.

Conclusion: Together with the unique morbidity and mortality benefits, this study suggests that treatment with sevelamer confers clinical benefits with a modest investment of additional economic resources.     

Telmisartan has the strongest binding affinity to angiotensin II type 1 receptor: comparison with other angiotensin II type 1 receptor blockers

There is a growing body of evidence that the renin-angiotensin system (RAS) plays a pivotal role in the pathogenesis of cardiovascular diseases. Indeed, large clinical trials have demonstrated a substantial benefit of the blockade of this system for cardiovascular-organ protection. Although several types of angiotensin II type 1 (AT1) receptor blockers (ARBs) are commercially available for the treatment of patients with hypertension, comparisons of the binding affinity to AT1 receptor among them remain to be elucidated. In this study, we examined the dissociation rate of several ARBs from AT1 receptor in vitro. Angiotensin II time-dependently dissociated telmisartan, olmesartan, candesartan, valsartan, losartan and an active metabolite of losartan, EXP3174, from membrane components containing human AT1 receptor The dissociation rate constant of each ARB was 0.003248, 0.004171, 0.005203, 0.009946, 0.01027 and 0.008561 min(-1), with corresponding half-lives of 213, 166, 133, 70, 67 and 81 min, respectively. These results demonstrate that telmisartan has the strongest binding affinity to AT1 receptor among various ARBs examined herein. The rank order of affinity was telmisartan > olmesartan > candesartan > EXP3174 > or = valsartan > or = losartan. The present findings suggest that telmisartan (Micardis) may have long-lasting blood pressure-lowering effects and superior cardioprotective properties in patients with hypertension due to its strongest AT1 receptor antagonistic ability.