Effects of ramipril and rosiglitazone on cardiovascular and renal outcomes in people with impaired glucose tolerance or impaired fasting glucose: results of the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) trial.

OBJECTIVE: Impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG) are risk factors for diabetes, cardiovascular disease (CVD), and kidney disease. We determined the effects of ramipril and rosiglitazone on combined and individual CVD and renal outcomes in people with IGT and/or IFG in the Diabetes REduction Assessment With ramipril and rosiglitazone Medication (DREAM) trial. RESEARCH DESIGN AND METHODS: A total of 5,269 people aged >or=30 years, with IGT and/or IFG without known CVD or renal insufficiency, were randomized to 15 mg/day ramipril versus placebo and 8 mg/day rosiglitazone versus placebo. A composite cardiorenal outcome and its CVD and renal components were assessed during the 3-year follow-up. RESULTS: Compared with placebo, neither ramipril (15.7% [412 of 2,623] vs. 16.0% [424 of 2,646]; hazard ratio [HR] 0.98 [95% CI 0.84-1.13]; P = 0.75) nor rosiglitazone (15.0% [394 of 2,635] vs. 16.8% [442 of 2,634]; 0.87 [0.75-1.01]; P = 0.07) reduced the risk of the cardiorenal composite outcome. Ramipril had no impact on the CVD and renal components. Rosiglitazone increased heart failure (0.53 vs. 0.08%; HR 7.04 [95% CI 1.60-31.0]; P = 0.01) but reduced the risk of the renal component (0.80 [0.68-0.93]; P = 0.005); prevention of diabetes was independently associated with prevention of the renal component (P < 0.001). CONCLUSIONS: Ramipril did not alter the cardiorenal outcome or its components. Rosiglitazone, which reduced diabetes, also reduced the development of renal disease but not the cardiorenal outcome and increased the risk of heart failure.

Risk factor identification and assessment in hypertension and diabetes (RIAHD) study.

The RIAHD (Risk factor Identification and Assessment in Hypertension and Diabetes) study was conducted as a non-interventional study in 699 patients with hypertension without additional risk factors (low-risk) or with additional risk factors (high-risk), primarily diabetes and/or micro/macroalbuminuria (MA/A). The RIAHD study aimed to assess novel cardiovascular risk factors (RFs) such as blood viscosity, inflammatory markers and selected genetic polymorphisms. In addition, the RIAHD study also aimed to examine home versus office blood pressures (BPs), objective cardiovascular risk according to ESH/ESC Systematic Coronary Risk Evaluation systems (SCORE) and subjectively expressed risk (clinical judgment) by physicians and patients. The health economic impact of other RFs, associated clinical conditions and target organ damage was also studied by evaluating healthcare utilization and sick leave in high-risk patients. In terms of circulating RFs, measured and calculated whole blood viscosity did not differ between the high and low-risk patient groups. Fibrinogen was significantly increased in the high-risk group, while hsCRP did not differ between the two groups. Self-measured BPs at home differed from BPs measured in the office. The average systolic home BPs was 11.8 mmHg lower in the low-risk group and 6.7 mmHg lower in the high-risk group. The diastolic home BPs averages differed 7.1 mm Hg and 4.1 mmHg from office BPs in the low-risk and high-risk groups, respectively. A higher home BP compared with the office BP, i.e. masked high BP values, was found in 21% of patients in the low-risk group and 32% of patients in the high-risk group. Global CV risk assessment (high-risk or low-risk) by the physicians corresponded well to objective risk evaluation (ESH/ESC) in the high-risk hypertensive patients, while physicians tended to underestimate the patients CV risk in the low-risk group (without diabetes and/or MA/A). Proper global risk assessment by judgement is often difficult in cardiovascular patients. The RIAHD study emphasizes the importance of performing a more extended RF assessment in hypertensive patients with as well as without diabetes and/or micro/macroalbuminuria in order to expose the full RF profile.

Haplotype association analysis of the polymorphisms Arg16Gly and Gln27Glu of the adrenergic beta2 receptor in a Swedish hypertensive population.

The Arg16Gly and the Gln27Glu polymorphisms in the gene for the beta2-adrenergic receptor (beta2AR) have been linked to an increased risk for cardiovascular disease. The aim of the present study was to evaluate the significance of these haplotypes for development of myocardial infarction (MI) as well as other cardiovascular phenotypes. In a prospective study cohort (CAPPP), 522 hypertensive patients (174 MI and 348 matched controls) were analysed for the Arg16Gly and the Gln27Glu polymorphisms by dynamic allele-specific hybridisation. The haplotype could successfully be determined in 516 patients. Haplotype was not significantly associated with MI. Systolic blood pressure (SBP) was higher in patients with Arg16Gly+Gln27Gln and lower in patients with Arg16Gly+Gln27Glu as compared with the other haplotypes. Haplotype was not associated with body mass index, diastolic blood pressure, cholesterol, LDL, HDL triglycerides or a diagnosis of diabetes mellitus. The present study found no evidence that haplotype for the two most common polymorphisms in the beta2AR are associated with development of MI in a Swedish hypertensive population, but haplotype may be associated with SBP.

Pharmacokinetics and tolerability of different doses of fentanyl following sublingual administration of a rapidly dissolving tablet to cancer patients: a new approach to treatment of incident pain.

AIMS: It is estimated that two-thirds of cancer patients will at some point during their illness experience breakthrough pain. In this study, the pharmacokinetics of a novel sublingual dosage form of fentanyl developed for breakthrough pain was evaluated. METHODS: Eleven Caucasian patients (seven male and 4 female, aged 34-75 years, median 60 years) with metastatic malignant disease were recruited initially, but three patients withdrew. Prior to the study all patients were on continuous nonfentanyl opiate medication. The study was a double-blind, cross-over trial, consisting of three 1-day treatment periods. A new rapidly dissolving preparation of fentanyl, was administered sublingually in single doses of 100, 200 and 400 microg, respectively, on three separate occasions. Plasma fentanyl concentrations were determined using liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). Pharmacokinetic parameters were calculated by noncompartment analysis. Tolerability and the occurrence of adverse events were monitored throughout the study by patient questionnaire. RESULTS: The data from nine subjects who completed at least two periods were used in the analysis of variance. There were no significant differences between doses (100, 200 and 400 microg) for dose adjusted AUC (F = 0.42, P = 0.6660), dose adjusted C(max) (F = 0.08, P = 0.9206) and Tmax (F = 0.94, P = 0.4107). Thus, these parameters showed dose proportionality. The differences (400-100microg) in dose adjusted AUC from the three-period crossover analysis was -0.016 min.ng/ml (t = 0.71, P = 0.8718). Interindividual variability in systemic exposure to fentanyl was fairly small (25-40%), which may be related to a good in vivo biopharmaceutical performance of the sublingual tablet, and a relatively small fraction of the dose being swallowed. The first detectable plasma concentration of fentanyl was observed between 8 and 11 min after administration. t(max) increased from 39.7 +/- 17.4 to 48.7 +/- 26.3 and 56.7 +/- 24.6 min for the 100, 200 and 400 microg doses, respectively. Adverse events were few and did not increase with increasing dose. CONCLUSION: With this rapidly dissolving fentanyl formulation, the first detectable plasma concentration of fentanyl was observed at 8-11 min after administration. The pharmacokinetics of the drug showed dose proportionately. This formulation of fentanyl seemed to be well tolerated by the patients.

A common polymorphism in the interleukin-6 gene promoter is associated with overweight.

OBJECTIVE: Human body fat mass is to a large extent genetically determined, but little is known about the susceptibility genes for common obesity. Interleukin-6 (IL-6) suppresses body fat mass in rodents, and IL-6 treatment increases energy expenditure in both rodents and humans. The -174 G/C single-nucleotide polymorphism (SNP) in the IL-6 gene promoter is common in many populations, and -174 C-containing promoters have been found to be weaker enhancers of transcription. Moreover, a SNP at position -572 in the IL-6 promoter has recently been reported to affect transcription. The objective was to investigate the association between the IL-6 gene promoter SNPs and obesity. DESIGN: Trans-sectional association study of IL-6 gene promoter SNPs and indices of obesity. SUBJECTS: Two study populations, the larger one consisting of hypertensive individuals (mean age 57 y, 73% males, n=485) and the other consisting of 20 y younger nonobese healthy females (n=74). MEASUREMENTS: Genotyping for the -174 IL-6 G/C and the -572 G/C SNPs, body mass index (BMI), serum leptin levels, serum IL-6 levels, C-reactive protein, fasting blood glucose and various blood lipids. RESULTS: The common -174 C allele (f(C)=0.46), but not any -572 allele, was associated with higher BMI and higher serum leptin levels in both study populations. In the larger population, there were significant odds ratios for the association of CC (2.13) and GC (1.76) genotypes with overweight (BMI>25 kg/m(2)). Moreover, as the C allele was common, it accounted for a significant population-attributable risk of overweight (12%; CI 2-21%), although its average effect was modest in this sample. CONCLUSION: Genetically determined individual differences in production of IL-6 may be relevant for the regulation of body fat mass.

Characteristics, clinical effect profile and tolerability of a nasal spray preparation of Artemisia abrotanum L. for allergic rhinitis.

A nasal spray formulation containing an extract of Artemisia abrotanum L. was developed for therapeutic use in patients with allergic rhinitis and other upper airway disorders. The nasal spray preparation used contains a mixture of essential oils (4 mg/ml) and flavonols (2.5 microg/ml), of which some components have been shown to possess antiinflammatory, expectorant, spasmolytic as well as antiseptic and antimicrobial activities. The most important constituents in the essential oil fraction of the preparation are 1,8-cineole, linalool and davanone, while the flavonol fraction contains centauredin, casticin and quercetin dimethyl-ethers. No trace of thujon was observed in the essential oil of the Artemisia abrotanum L. genotype "Tycho" used for the manufacture of the nasal spray preparation. In 12 patients with diagnoses of allergic rhinitis, allergic conjunctivitis and/or bronchial obstructive disease, the nasal spray was given immediately after the appearance of characteristic allergic nasal symptoms. In 10 of the 12 patients, allergic rhinitis with nasal congestion, sneezing and rhinorrhea was dominant. After administration of the nasal spray, all patients experienced a rapid and significant symptom relief of nasal symptoms, comparable to the effect of antihistamine and chromoglicate preparations which several of the patients had used previously. The effect was present within 5 minutes after the administration and lasted for several hours. In 7 of the 10 rhinitis patients with concomitant symptoms of allergic conjunctivitis, a significant subjective relief of eye symptoms was also experienced. In 3 of the 6 patients who had a history of characteristic symptoms of endogenous, exogenous or exercise induced bronchial obstructive disease, there was a bronchial symptom relief by the nasal spray preparation which was experienced as rapid and clinically significant. It is concluded from the present proof of concept study, that a nasal spray formulation containing an extract characterised by a mixture of essential oils and flavonols from the Artemisia abrotanum L. genotype "Tycho", appears to be clinically useful and suitable for the prophylactic and therapeutic management of patients with allergic rhinitis and adjuvant symptoms.

Hyperhomocysteinaemia is not associated with increased levels of asymmetric dimethylarginine in patients with ischaemic heart disease.

BACKGROUND: Elevated plasma total homocysteine appears to be related to endothelial dysfunction and impaired nitric oxide production. We aimed to investigate [1] whether elevated levels of plasma total homocysteine are associated with high plasma levels of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, and [2] whether reduction of plasma total homocysteine levels by folate and vitamin B supplementation lowers plasma concentration of asymmetric dimethylarginine. MATERIALS AND METHODS: Sixty patients with ischaemic heart disease and with plasma total homocysteine levels of 15.0 micromol L-1 were randomized to open therapy with folic acid, pyridoxine and cyancobalamin for 3 months (n = 30) or to no treatment (n = 30). Samples were also obtained from 34 patients with plasma total homocysteine levels of 8.0 micromol L-1 on admission. RESULTS: Plasma asymmetric dimethylarginine concentrations in patients with elevated total homocysteine levels were not significantly higher (0.68 +/- 0.19 micromol L-1) than in patients with low total homocysteine levels (0.61 +/- 0.10 micromol L-1; P = 0.08). Plasma asymmetric dimethylarginine level in the vitamin supplemented group was 0.65 +/- 0.12 micromol L-1 before, and 0.64 +/- 0.12 micromol L-1 after 3 months of vitamin supplementation (NS). Plasma asymmetric dimethylarginine levels were correlated with serum cystatin C levels (P < 0.001). CONCLUSION: A nonsignificant trend to increased plasma levels of asymmetric dimethylarginine in patients with high plasma total homocysteine levels may be explained by concomitant subtle renal dysfunction. Substantial reduction of plasma total homocysteine did not affect the level of plasma asymmetric dimethylarginine.

Similar cardiovascular effects of growth hormone and insulin-like growth factor-I in rats after experimental myocardial infarction.

Accumulating data show that growth hormone (GH) and insulin-like growth factor-I (IGF-I) have major effects on the cardiovascular system. In the present study we have directly compared GH and IGF-I in an in vivo rat model of experimental myocardial infarction. Four weeks after ligation of the left coronary artery, male rats were treated with recombinant human (rh) GH 1.1 mg/kg per day, rhIGF-I 3.0 mg/kg per day or saline s.c. for 2 weeks. Transthoracic echocardiography was performed before and after the treatment period. Both GH and IGF-I reduced total peripheral resistance (P< 0.01), end-systolic wall stress (P< 0.01) and end-systolic short-axis area (P< 0.001 and P< 0.05). GH also increased area fractional shortening (P< 0.05). Stroke volume (SV) and SV index were improved by IGF-I (P< 0.0001), and SV tended to be increased by GH (P= 0.12). In conclusion, GH and IGF-I had similar beneficial effects on systolic function and peripheral resistance after experimental myocardial infarction.

Reduced cardiovascular morbidity and mortality in hypertensive diabetic patients on first-line therapy with an ACE inhibitor compared with a diuretic/beta-blocker-based treatment regimen: a subanalysis of the Captopril Prevention Project.

OBJECTIVE: The Captopril Prevention Project (CAPPP) evaluated the effects of an ACE inhibitor-based therapeutic regimen on cardiovascular mortality and morbidity in hypertension. One planned subanalysis of the CAPPP was to evaluate the outcome in the diabetic patient group. RESEARCH DESIGN AND METHODS: In the CAPPP, 572 (4.9% of 10,985 hypertensive patients) had diabetes at baseline and were studied according to a prospective, randomized, open, blinded, end point trial design. Patients aged 25-66 years with diastolic blood pressure > or =100 mmHg were included and randomized to receive either captopril or conventional antihypertensive treatment (diuretics and/or beta-blockers). RESULTS: The primary end point, fatal and nonfatal myocardial infarction and stroke as well as other cardiovascular deaths, was markedly lower in the captopril than in the conventional therapy group (relative risk [RR] = 0.59; P = 0.018). Specifically, cardiovascular mortality, defined as fatal stroke and myocardial infarction, sudden death, and other cardiovascular death, tended to be lower in the captopril group (RR = 0.48; P = 0.084), and no difference was observed between the study groups for stroke (RR = 1.02; P = 0.96). Myocardial infarctions were less frequent in the captopril group than in the conventional therapy group (RR = 0.34; P = 0.002). Furthermore, total mortality was lower in the captopril as compared with the conventional therapy group (RR = 0.54; P = 0.034). Patients with impaired metabolic control seemed to benefit the most from ACE inhibitor-based therapy. CONCLUSIONS: Captopril is superior to a diuretic/beta-blocker antihypertensive treatment regimen in preventing cardiovascular events in hypertensive diabetic patients, especially in those with metabolic decompensation.

Relation between drug treatment and cancer in hypertensives in the Swedish Trial in Old Patients with Hypertension 2: a 5-year, prospective, randomised, controlled trial.

BACKGROUND: Is cancer related to hypertension and blood pressure? Do antihypertensive drugs promote cancer? Do antihypertensive drugs protect against cancer? We previously analysed the frequency of cardiovascular mortality and morbidity in elderly people who participated in the Swedish Trial in Old Patients with Hypertension 2 (STOP-Hypertension-2). We have also looked at the frequency of cancer in these patients. METHODS: We randomly assigned 6614 elderly patients with hypertension (mean age 76 years, median time of follow-up 5.3 years) to one of three treatment strategies: conventional drugs (diuretics or b-blockers), calcium antagonists, or ACE inhibitors. We matched the patients to the Swedish Cancer Registry and compared our findings with expected values based on age, sex, and calendar-year-specific reference frequencies for the general Swedish population. We also compared the number of cancers between the three treatment groups. FINDINGS: At baseline, 607 (9%) patients had previous malignant disease. Diagnoses were closely similar to the distribution of cancer types that might be seen in elderly patients. During follow-up, there were 625 new cases of cancer in 590 patients. The frequency of cancer did not differ significantly between the treatment strategies, including all cancers and those at individual sites. The standardised incidence ratios (SIRs) for all cancers were also close to unity: 0.92 (95% CI 0.80-1.06) for conventional drugs, 0.96 (0.83-1.10) for calcium antagonists, and 0.99 (0.86-1.13) for ACE inhibitors. INTERPRETATIONS: No difference in cancer risk was seen between patients randomly assigned to conventional drugs, calcium antagonists, or ACE inhibitors. Thus, the general message to the practising physician is that more attention should be given to getting the blood pressure down than to the risk of cancer.

The effect duration of candesartan cilexetil once daily, in comparison with enalapril once daily, in patients with mild to moderate hypertension.

OBJECTIVE: To determine the antihypertensive efficacy, effect duration and safety of the angiotensin II type 1 receptor blocker candesartan cilexetil and the angiotensin converting enzyme inhibitor enalapril once daily in patients with mild to moderate hypertension. METHODS: A multicenter, randomised, double-blind parallel group study was performed in Finland, France, the Netherlands, Spain and Sweden. Three-hundred-and-ninety-five men and women in the age range 20-80 years with primary hypertension were randomised to an 8-week double-blind treatment period with either candesartan cilexetil 8-16 mg or enalapril 10-20 mg once daily, with forced dose titration after 4 weeks. Non-invasive ambulatory blood pressure was measured for 36 h at baseline and after 8 weeks. The primary efficacy variable was the change in mean diastolic and systolic ambulatory blood pressure 22-24 h post-dose. RESULTS: There was a significant difference in the adjusted mean difference for the change from baseline to week 8 between candesartan cilexetil and enalapril 22-24 h post-dose by -3.5 mmHg (95% confidence interval, CI: -6.8 to -0.3 mmHg; p < 0.032) in ambulatory systolic blood pressure and -3.0 mmHg (95% CI: -5.1 to -0.8 mmHg; p < 0.008) in ambulatory diastolic blood pressure. There was a significant difference in adjusted mean daytime ambulatory blood pressure 24-36 h post-dose by -4.2 mmHg (95% CI: -6.8 to -1.6 mmHg; p < 0.002)/-3.5 mmHg (95% CI: -5.1 to -1.8 mmHg; p < 0.001). Both drugs were generally well tolerated. CONCLUSION: The results of the present study suggest that advantages may be attributed to the use of candesartan cilexetil, as compared to enalapril in the treatment of patients with essential hypertension. In comparison with enalapril 20 mg, candesartan cilexetil 16 mg more effectively lowered blood pressure at trough and in particular on the day following the day after the last dose.

Enhanced endothelin-1-induced contractions in mesenteric arteries from rats with congestive heart failure: role of ET(B) receptors.

Studies of congestive heart failure (CHF) in man and in experimental CHF have demonstrated elevated circulating levels of endothelin (ET). In order to examine whether there are concomitant ET receptor alterations, the vasomotor effects of endothelin-1 (ET-1) and sarafotoxin 6c (S6c) were examined in endothelium-intact and -denuded isolated mesenteric arteries from rats with CHF. CHF was induced by ligation of the left anterior descending coronary artery. Vasomotor responses were studied using small mesenteric arteries (approx. 250 microm in diameter, determined after normalisation). The antagonists IRL2500 and FR139317 were used in order to characterise the ET-1-induced response. In mesenteric arteries with intact endothelium, ET-1-induced contractions were more potent in CHF as compared to sham (pEC(50) 9.6+/-0.2 and 9.1+/-0.1, respectively, P<0.01). In endothelium-denuded arteries, there was no difference in potency of ET-1 between CHF and sham arteries, or in maximum contraction. In the presence of IRL2500, a selective ET(B)-receptor antagonist, ET-1 was more potent in endothelium-denuded arteries of CHF rats, while this difference was not seen in sham arteries. S6c had no consistent contractile or dilatory effect in CHF and sham rats. The results indicate that the enhanced contractile effects of ET-1 noted in CHF might be due to an attenuated endothelial function and that inhibition of smooth muscle cell ET(B) receptors increase the effects of contractile ET(A) receptors in CHF rats.

Enhanced Ca2+-induced contractions and attenuated alpha-adrenoceptor responses in resistance arteries from rats with congestive heart failure.

AIM: The aim of the present study was to examine the role of Ca2+-mediated contractile responses in isolated mesenteric resistance arteries from rats with congestive heart failure (CHF). METHODS: Heart failure was induced by ligation of the left coronary artery. Rats exposed to the same surgical procedure except ligation served as controls (Sham). The following experiments were conducted: (1) passive increase in radial stretch (the length-tension relationship) in Ca2+-free and in depolarizing high K+-solution; (2) the contractile responses to external application of Ca2+ and high K+-solutions in the presence of nifedipine and phentolamine; and (3) a histological evaluation of CHF and Sham vessels. RESULTS: The length-tension induced response in Ca2+-free buffer solution was significantly lower in arteries from CHF rats, starting at a very low tension (0.9+/-0.2 mN/mm for heart failure and 1.7+/-0.2 mN/mm for Sham). This difference, but at a higher degree of stretch, was also present in K+-activated vessels. The external application of Ca2+ in K+-depolarized vascular segments in the presence of phentolamine (1 microM) induced an enhanced contractile response in arteries from CHF rats compared with Sham (4.8+/-0.3 mN/mm and 3.6+/-0.6 mN/mm, respectively, P=0.059). In the absence of phentolamine the reverse response was found (4.0+/-0.4 mN/mm and 5.7+/-0.3 mN/mm for CHF vs. Sham respectively, P=0.035). Application of increasing concentrations of K+-solution induced a stronger contractile response in Sham compared with CHF arteries (Sham 4.9+/-0.4 and heart failure 4.0+/-0.3, P=0.04). Microscopic examination of vessels yielded no difference in gross morphology, media thickness or wall to lumen ratio between CHF and Sham arteries. CONCLUSION: The results indicate an attenuation of alpha-adrenoceptors and a difference of Ca2+-mediated vascular contractility in resistance arteries of congestive heart failure rats.

Amelioration of arterial properties with a perindopril-indapamide very-low-dose combination.

BACKGROUND: Epidemiological studies have shown that increased arterial stiffness and wave reflections, major determinants of systolic and pulse pressure, are associated with morbidity and mortality. Therapeutic trials based on cardiovascular mortality have recently shown that reduction of systolic blood pressure (SBP) requires normalization of both large-artery stiffness and wave reflections. AIMS: To compare the antihypertensive effects of the very-low-dose combination of perindopril (2 mg) and indapamide (0.625 mg) (one or two tablets per day) with the beta-blocking agent atenolol (50 mg; one or two tablets per day) in order to determine whether the combination decreased SBP and pulse pressure more than did atenolol, and whether this decrease occurred in relation to a reduction in arterial stiffness [aortic pulse wave velocity (PWV)] or a decrease in the intensity of, or delay in, wave reflections (augmentation index, measured by applanation tonometry) or a combination of both. MATERIAL AND METHODS: This was a double-blind randomized study in 471 individuals with essential hypertension followed for 12 months. Arterial pressure was measured in the brachial artery (mercury sphygmomanometer) and in the carotid artery (applanation tonometry). RESULTS: For the same reduction in diastolic blood pressure (DBP), the combination of perindopril and indapamide decreased brachial SBP and pulse pressure significantly more than did atenolol (adjusted differences between groups -6.2 +/- 1.5 and -5.5 +/- 1.0 mmHg, respectively; P < 0.001). This difference was even more pronounced for the carotid than for the brachial artery. Whereas both antihypertensive agents similarly decreased PWV, only the combination significantly attenuated wave reflections. CONCLUSION: Normalization of SBP, pulse pressure and arterial function--a haemodynamic profile known to improve survival significantly in hypertensive populations at high cardiovascular risk--was achieved to a greater extent with a very-low-dose combination of perindopril and indapamide than with atenolol.