Craniovascular selectivity of eletriptan and sumatriptan in human isolated blood vessels.
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Blood Vessels↗
Biomedical subjects
R Salonen
Publications and source records attributed to R Salonen.
Cardiovascular fitness as a predictor of mortality in men.
OBJECTIVE: To examine the relations of cardiorespiratory fitness, as measured by maximal oxygen uptake and exercise test duration at the initiation of the study, with overall, cardiovascular disease (CVD)-related, and non-CVD-related mortality. METHODS: A population-based cohort study of 1294 men with no CVD, pulmonary disease, or cancer at baseline in Kuopio and surrounding communities in eastern Finland. During an average follow-up of 10.7 years, there were 124 overall, 42 CVD-related, and 82 non-CVD-related deaths. RESULTS: The relative risk of overall death in unfit men (maximal oxygen uptake <27.6 mL/kg per minute) was 2.76 (95% confidence interval, 1.43-5.33) (P =.002), and the relative risk of CVD-related death was 3.09 (95% confidence interval, 1.10-9.56) (P =.05), compared with fit men (maximal oxygen uptake >37.1 mL/kg per minute) after adjusting for age, examination years, smoking, and alcohol consumption. The relative risk of non-CVD-related death in unfit men was almost the same magnitude as for overall death. Furthermore, adjustment for serum lipid levels, blood pressure, plasma fibrinogen level, diabetes, and fasting serum insulin level did not weaken these associations significantly. Exercise test duration also had a strong inverse relation to overall, CVD-related, and non-CVD-related mortality. Poor cardiorespiratory fitness was comparable with elevated systolic blood pressure, smoking, obesity, and diabetes in importance as a risk factor for mortality. CONCLUSIONS: Cardiorespiratory fitness had a strong, graded, inverse association with overall, CVD-related, and non-CVD-related mortality. Maximal oxygen uptake and exercise test duration represent the strongest predictors of mortality.
Adult↗
Abdominal obesity is associated with accelerated progression of carotid atherosclerosis in men.
Abdominal obesity increases the risk of clinical atherosclerotic diseases, but whether it accelerates the progression of preclinical atherosclerosis is unknown. We studied whether waist-to-hip ratio (WHR) and waist circumference are associated with 4-year increase in indicators of common carotid atherosclerosis, assessed by B-mode ultrasonography, in 774 Finnish men aged 42-60 years without atherosclerotic diseases. Men with WHR of <0.91, 0.91-0.96 and >0.96 (thirds) had increase in maximal intima-media thickness (IMT) of 0.230, 0.255 and 0.281 mm/4 years (P=0.007 for linear trend; P=0.025 for difference) and plaque height of 0.241, 0.254 and 0.291 mm/4 years (P=0.005, P=0.013) adjusting for age, body mass index and technical covariates. Men with waist circumference of <85, 85-93 and >93 cm (thirds) had increase in maximal IMT of 0.227, 0.251 and 0.290 mm/4 years (P=0.011, P=0.035) and plaque height of 0.229, 0.263 and 0.296 mm/4 years (P=0.003, P=0.013). These associations were stronger in men with high (> or =3.8 mmol/l) than lower serum LDL cholesterol (P<0.05 for interaction). This is the first documentation that abdominal obesity is associated with accelerated progression of atherosclerosis, and supports the view that it is an important cardiovascular risk factor. This study emphasizes the role of avoiding abdominal obesity to prevent atherosclerotic diseases.
Abdomen↗
Cardiorespiratory fitness and the progression of carotid atherosclerosis in middle-aged men.
BACKGROUND: Good cardiorespiratory fitness has been associated with reduced risk for clinical events of atherosclerotic vascular diseases, but whether it is related to slower progression of early atherosclerosis is unclear. OBJECTIVE: To study the association between cardiorespiratory fitness and the progression of early carotid atherosclerosis. DESIGN: 4-year follow-up study. SETTING: Eastem Finland. PARTICIPANTS: Population-based sample of 854 men 42 to 60 years of age. MEASUREMENTS: Maximal oxygen uptake (VO2max [mL/kg per minute]) was measured directly by using respiratory gas exchange in a cycle ergometer exercise test. Carotid atherosclerosis was assessed by using B-mode ultrasonography. RESULTS: After adjustments for age, technical covariates, and cigarette smoking, VO2max had strong, inverse, and graded associations with 4-year increases in maximal intima-media thickness (IMT) (standardized regression coefficient beta = -0.120; P = 0.002), plaque height (beta = -0.140; P < 0.001), surface roughness (beta = -0.147; P < 0.001), and mean IMT (beta = -0.080; P = 0.035). These associations weakened but remained statistically significant after additional adjustment for systolic blood pressure, serum levels of apolipoprotein B, diabetes, and plasma fibrinogen levels. The increases in maximal IMT, surface roughness, and mean IMT (23%, 31%, and 100%, respectively) were larger among men in the lowest quartile of VO2max (<26.1 mL/kg per minute) than among those in the highest quartile (>36.2 mL/kg per minute). CONCLUSIONS: Good cardiorespiratory fitness is associated with slower progression of early atherosclerosis in middle-aged men. These findings are important because they emphasize that middle-aged men can be evaluated for cardiorespiratory fitness to estimate their future risk for atherosclerotic vascular diseases. Additional research is warranted to investigate a possible causal relationship between cardiorespiratory fitness and atherosclerosis.
Adult↗
Leucine7 to proline7 polymorphism in the preproneuropeptide Y is associated with the progression of carotid atherosclerosis, blood pressure and serum lipids in Finnish men.
A rather common leucine7-to-proline7 (Leu7Pro) polymorphism in the preproneuropeptide Y (prepro-NPY) gene signal peptide may be important in blood pressure regulation, cholesterol metabolism and the pathogenesis of atherosclerosis in humans. We examined the associations of the Leu7Pro polymorphism with carotid atherosclerotic progression, blood pressure and serum lipids in a population-based sample of 966 men aged 42-60 years in Finland. The Pro7 substitution (carrier frequency 12.2%) was associated with accelerated four-year increase in the mean (P=0.01) and maximal (P=0.007) common carotid intima-media thickness (IMT) and with slightly increased systolic (P=0.03) and diastolic (P=0.02) blood pressures, adjusted for other major risk factors. Men with Pro7 substitution had 30.6% (95% CI 6.9-54.0%) greater increase in the mean IMT and 20.0% (95% CI 5.3-34.4%) greater increase in the maximal IMT than men with Leu7/Leu7 genotype. The Pro7 substitution was also related to increased serum total cholesterol (P=0.01) and LDL cholesterol (P=0.02) in obese (body mass index (BMI)>30 kg/m(2)) men. This study provides important evidence suggesting that the Pro7 substitution in the prepro-NPY is an important risk factor for accelerated atherosclerotic progression, increased blood pressure and increased serum cholesterol in humans.
Adult↗
Effect of encapsulation on absorption of sumatriptan tablets: data from healthy volunteers and patients during a migraine.
BACKGROUND: Some comparative trials of selective serotonin 1B/ID-agonists in migraine have reported -15% lower efficacy for sumatriptan tablets than that reported in placebo-controlled trials. OBJECTIVE: This study was designed to test the hypothesis that the encapsulation methods used to mask active drug may delay absorption of sumatriptan from dosing to 2 hours after dosing (the traditional end point in clinical trials of migraine treatment), an effect that may be enhanced by migraine-associated gastric stasis. METHODS: Two randomized, open-label, 2-way crossover trials were conducted to evaluate the absorption and bioequivalence of conventional 50-mg sumatriptan tablets and encapsulated 50-mg sumatriptan tablets in supine, fasted, healthy volunteers (Glaxo Wellcome protocol SUM40270) and supine patients experiencing a migraine (Glaxo Wellcome protocol SUM40268). Absorption was assessed by calculating the area under the plasma concentration-time curve from dosing to 2 hours after dosing (AUC2) and the times to first measurable plasma concentration, 10 ng/mL, 20 ng/mL, and maximum plasma concentration. Data for the AUC from time zero to infinity and maximum plasma concentration were used to assess standard bioequivalence, which is considered to occur when the 90% CIs for the geometric mean treatment ratios (test/reference) fall between 0.8 and 1.25. RESULTS: Study 1 included 26 healthy subjects (73% men, 27% women; mean age, 39.1 years), and study 2 included 30 patients with migraine (67% women, 33% men; mean age, 42.7 years). Sumatriptan absorption was delayed with the encapsulated tablet compared with the conventional tablet 0 to 2 hours after dosing, particularly during a migraine. AUC2 values with encapsulated sumatriptan compared with the conventional tablet were 21% lower in healthy volunteers (ratio of capsule/tablet, 0.79; 90% CI, 0.588-1.050) and 27% lower in patients experiencing a migraine (ratio of capsule/tablet, 0.73; 90% CI, 0.519-1.023). Standard bioequivalence was demonstrated in both healthy volunteers and patients experiencing a migraine. CONCLUSIONS: Encapsulation delayed absorption of sumatriptan 0 to 2 hours after dosing, particularly during a migraine. This delay in absorption of the encapsulated form may account for the lower efficacy of sumatriptan in some comparative studies.
Adult↗
An insertion/deletion polymorphism in the alpha2B-adrenergic receptor gene is a novel genetic risk factor for acute coronary events.
OBJECTIVES: Our aim was to study whether an insertion/deletion (I/D) polymorphism in the alpha2B-adrenoceptor gene is associated with the risk for cardiovascular diseases. BACKGROUND: alpha2-adrenoceptors mediate contraction of vascular smooth muscle and induce coronary vasoconstriction in humans. The alpha2-adrenoceptor subtype B mediates vasoconstriction in mice. A variant of the human alpha2B-adrenoceptor gene that encodes a D of three residues in an intracellular acidic motif has been shown to confer decreased receptor desensitization. This receptor variant could, therefore, be involved in diseases associated with enhanced vasoconstriction. METHODS: This study was part of a prospective population-based study investigating risk factors for cardiovascular diseases in a cohort of middle-aged men from eastern Finland. Nine hundred twelve men aged 46 to 64 years were followed for an average time of 4.5 years. RESULTS: In this study population, 192 men (21%) had the D/D genotype; 256 (28%) had the I/I genotype, and 464 (51%) had a heterozygous genotype. In a Cox model adjusting for other coronary risk factors, men with the D/D genotype had 2.2 times (95% confidence interval: 1.1 to 4.4, p = 0.02) the risk to experience an acute coronary event (n = 15 for D/D, 10 for I/I and 12 for I/D) compared with men carrying either of the other two genotypes. The alpha2B-adrenoceptor genotype was not associated with hypertension in this study population. CONCLUSIONS: The D/D genotype of the alpha2B-adrenoceptor is a novel genetic risk factor for acute coronary events, but not for hypertension.
Analysis of Variance↗
Exercise-induced silent myocardial ischemia and coronary morbidity and mortality in middle-aged men.
OBJECTIVES: We investigated the prognostic significance of exercise-induced silent myocardial ischemia in both high and low risk men with no prior coronary heart disease (CHD). BACKGROUND: Silent ischemia predicts future coronary events in patients with CHD, but there is little evidence of its prognostic significance in subjects free of CHD. METHODS: We investigated the association of silent ischemia, as defined by ST depression during and after maximal symptom-limited exercise test, with coronary risk in a population-based sample of men with no prior CHD followed for 10 years on average. RESULTS: Silent ischemia during exercise was associated with a 5.9-fold (95% CI 2.3 to 11.8) CHD mortality in smokers, 3.8-fold (95% CI 1.9 to 7.9) in hypercholesterolemic men and 4.7-fold (95% CI 2.4 to 9.1) in hypertensive men adjusting for other risk factors. The respective relative risks (RRs) of any acute coronary event were 3.0 (95% CI 1.7 to 5.1), 1.9 (95% CI 1.2 to 3.1) and 2.2 (95% CI 1.4 to 3.5). These associations were weaker in men without these risk factors. Furthermore, silent ischemia after exercise was a stronger predictor for the risk of acute coronary events and CHD death in smokers and in hypercholesterolemic and hypertensive men than in men without risk factors. CONCLUSIONS: Exercise-induced silent myocardial ischemia was a strong predictor of CHD in men with any conventional risk factor, emphasizing the importance of exercise testing to identify asymptomatic high risk men who could benefit from risk reduction and preventive measures.
Coronary Disease↗
The sumatriptan difference.
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Administration, Intranasal↗
Fetal nuchal translucency and normal chromosomes: a long-term follow-up study.
OBJECTIVE: To assess the impact of increased nuchal translucency observed during early pregnancy on the subsequent health of children with normal chromosomes, with special attention to cardiac anatomy and function. METHODS: Clinical examination and detailed cardiac evaluation were carried out in 50 chromosomally normal children at the age of 2.4-7.1 years who had had a nuchal translucency measurement of > or = 3 mm at 13-15 weeks' gestation. The data of two babies who died of heart defects were also included. RESULTS: Major cardiac defects were identified in four (8%) of the children. The growth of all children was within normal limits. One child had Noonan syndrome, one had a cleidocranial dysplasia and a third had a developmental delay together with an unrecognized syndrome. Webs in the neck region were noticed in two children, with no associated pathology. CONCLUSIONS: In chromosomally normal fetuses with increased nuchal translucency, fetal echocardiography is necessary to identify major cardiac defects. In general, the parents can be reassured that, in the great majority, postnatal development is normal.
Child↗
Low serum lycopene concentration is associated with an excess incidence of acute coronary events and stroke: the Kuopio Ischaemic Heart Disease Risk Factor Study.
A number of epidemiological studies have shown an association between beta-carotene and the risk of cardiovascular diseases, whereas only a few studies are available concerning the association of lycopene with the risk of coronary events, and no studies have been undertaken concerning lycopene and stroke. Thus, we tested the hypothesis that low serum levels of lycopene are associated with increased risk of acute coronary events and stroke in middle-aged men previously free of CHD and stroke. The subjects were 725 men aged 46-64 years examined in 1991-3 in the Kuopio Ischaemic Heart Disease Risk Factor Study. Forty-one men had either a fatal or a non-fatal acute coronary event or a stroke by December 1997. In a Cox' proportional hazard's model adjusting for examination years, age, systolic blood pressure and three nutritional factors (serum folate, beta-carotene and plasma vitamin C), men in the lowest quarter of serum lycopene levels (< or =0.07 micromol/l) had a 3.3-fold (95 % CI 1.7, 6.4, risk of acute coronary events or stroke compared with the others. Our study suggests that a low serum level of lycopene is associated with an increased risk of atherosclerotic vascular events in middle-aged men previously free of CHD and stroke.
Adult↗
Supplementation with vitamin E but not with vitamin C lowers lipid peroxidation in vivo in mildly hypercholesterolemic men.
Although the use of vitamin E supplements has been associated with a reduction in coronary events, assumed to be due to lowered lipid peroxidation, there are no previous long-term clinical trials into the effects of vitamin C or E supplementation on lipid peroxidation in vivo. Here, we have studied the long-term effects of vitamins C and E on plasma F2-isoprostanes, a widely used marker of lipid peroxidation in vivo. As a study cohort, a subset of the "Antioxidant Supplementation in Atherosclerosis Prevention" (ASAP) study was used. ASAP is a double-masked placebo-controlled randomized clinical trial to study the long-term effect of vitamin C (500 mg of slow release ascorbate daily), vitamin E (200 mg of D-alpha-tocopheryl acetate daily), both vitamins (CellaVie), or placebo on lipid peroxidation, atherosclerotic progression, blood pressure and myocardial infarction (n = 520 at baseline). Lipid peroxidation measurements were carried out in 100 consecutive men at entry and repeated at 12 months. The plasma F2-isoprostane concentration was lowered by 17.3% (95% CI 3.9-30.8%) in the vitamin E group (p = 0.006 for the change, as compared with the placebo group). On the contrary, vitamin C had no significant effect on plasma F2-isoprostanes as compared with the placebo group. There was also no interaction in the effect between these vitamins. In conclusion, long-term oral supplementation of clinically healthy, but hypercholesterolemic men, who have normal vitamin C and E levels with a reasonable dose of vitamin E lowers lipid peroxidation in vivo, but a relatively high dose of vitamin C does not. This observation may provide a mechanism for the observed ability of vitamin E supplements to prevent atherosclerosis.
Aged↗
Migraine revolution and sumatriptan.
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Capsules↗
Role of nephrin in cell junction formation in human nephrogenesis.
Nephrin is a cell adhesion protein located at the slit diaphragm area of glomerular podocytes. Mutations in nephrin-coding gene (NPHS1) cause congenital nephrotic syndrome (NPHS1). We studied the developmental expression of nephrin, ZO-1 and P-cadherin in normal fetal kidneys and in NPHS1 kidneys. We used in situ hybridization and immunohistochemistry at light and electron microscopic levels. Nephrin and zonula occludens-1 (ZO-1) were first expressed in late S-shaped bodies. During capillary loop stage, nephrin and ZO-1 localized at the basal margin and in the cell-cell adhesion sites between developing podocytes, especially in junctions with ladder-like structures. In mature glomeruli, nephrin and ZO-1 concentrated at the slit diaphragm area. P-cadherin was first detected in ureteric buds, tubules, and vesicle stage glomeruli. Later, P-cadherin was seen at the basal margin of developing podocytes. Fetal NPHS1 kidneys with Fin-major/Fin-major genotype did not express nephrin, whereas the expression of ZO-1 and P-cadherin was comparable to that of control kidneys. Although early junctional complexes proved structurally normal, junctions with ladder-like structures and slit diaphragms were completely missing. The results indicate that nephrin is dispensable for early development of podocyte junctional complexes. However, nephrin appears to be essential for formation of junctions with ladder-like structures and slit diaphragms.
Cadherins↗
Mercury accumulation and accelerated progression of carotid atherosclerosis: a population-based prospective 4-year follow-up study in men in eastern Finland.
Basic research and our previous studies have suggested that mercury exposure enhances lipid peroxidation and the risk of myocardial infarction, but there are no studies concerning the association between mercury accumulation and atherosclerosis. We therefore investigated whether high hair mercury content is associated with accelerated progression of carotid atherosclerosis, determined by ultrasonographic assessment of common carotid intima-media thickness (IMT), in a prospective study among 1014 men aged 42-60 years. In a linear regression model adjusting for other atherosclerotic risk factors, high hair mercury content was one of the strongest predictors of the 4-year increase in the mean IMT (P2.81 microg/g (fifths) had an IMT increase of 0.105, 0.102, 0.113, 0.107 and 0.140 mm/4 years, respectively (P=0.041 for heterogeneity between groups). The IMT increase was 0.034 mm/4 years (31.9%) greater in the highest fifth than in the other fifths (P<0.05 for the difference). These findings suggest that mercury accumulation in the human body is associated with accelerated progression of carotid atherosclerosis.
Adult↗
Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) study: a randomized trial of the effect of vitamins E and C on 3-year progression of carotid atherosclerosis.
OBJECTIVES: To study the efficacy of vitamin E and C supplementation on the progression of carotid atherosclerosis, hypothesizing an enhanced preventive effect in men and in smokers and synergism between vitamins. DESIGN AND SUBJECTS: Double-masked two-by-two factorial trial, randomization in four strata (by gender and smoking status) to receive twice daily either 91 mg (136 IU) of d-alpha-tocopherol, 250 mg of slow-release vitamin C, a combination of these or placebo for three years. A randomized sample of 520 smoking and nonsmoking men and postmenopausal women aged 45-69 years with serum cholesterol >/= 5.0 mmol L-1 were studied. SETTING: The population of the city of Kuopio in Eastern Finland. INTERVENTION: Twice daily either a special formulation of 91 mg of d-alpha-tocopherol, 250 mg of slow-release vitamin C, a combination of these (CellaVie(R)) or placebo for three years. MEASUREMENTS: Atherosclerotic progression, defined as the linear regression slope of ultrasonographically assessed common carotid artery mean intima-media thickness (IMT), was calculated over semi-annual assessments. RESULTS: The average increase of the mean IMT was 0.020 mm year-1 amongst men randomized to placebo and 0.018 mm year-1 in vitamin E, 0.017 mm year-1 in vitamin C and 0.011 mm year-1 in the vitamin combination group (P = 0.008 for E + C vs. placebo). The respective means in women were 0.016, 0.015, 0.017 and 0.016 mm year-1. The proportion of men with progression was reduced by 74% (95% CI 36-89%, P = 0.003) by supplementation with the formulation containing both vitamins, as compared with placebo. CONCLUSIONS: Our study shows that a combined supplementation with reasonable doses of both vitamin E and slow-release vitamin C can retard the progression of common carotid atherosclerosis in men. This may imply benefits with regard to other atherosclerosis-based events.
Aged↗
Drug comparisons: why are they so difficult?
Comparing therapeutic agents in a drug class can be difficult. This article examines the ways in which the triptans can be and have been compared and evaluates the advantages and disadvantages of the approaches. Direct comparative trials are clearly the best method for evaluating the triptans, however, there is a scarcity of this type of data on the currently available compounds. Indirect comparison such as meta-analysis is a second method of comparing these agents but only serves as an estimate of relative efficacy or safety based on a comparison of pooled data derived from a number of different trials for each agent. Comparison of the data found in the regulatory documents represents another type of indirect comparison that can be done so long as the data is presented in a consistent format across products.
Clinical Trials as Topic↗
Inter-laboratory comparison of flow-volume curve measurements as quality control procedure in the framework of an international epidemiological study (PEACE project).
The aim of this work was to describe the results of a simple quality control procedure for the flow-volume curve adopted in a multicentre epidemiological study (PEACE). In 14 centres, 8-15 individuals (n = 157) performed forced vital capacity (FVC) manoeuvres following a standard protocol with both the local spirometer/pneumotachograph and a portable spirometer (i.e. the 'reference instrument' for this study). Deviances of measurements were assessed by computing the differences (delta) between the former and the latter, the ratios of such differences on portable spirometer values (delta %) and the coefficients of variation (CV). The portable spirometer yielded lower mean AFVC and deltaFEV1 (forced in 1 sec) than local instruments (except for two and four centres, respectively). In most instances, differences were statistically significant. Absolute mean A%FVC ranged from 4.9-18.2%, while delta%FEV1 ranged from 2.3-18.5%. The Bland and Altman analysis showed a good agreement between the portable and local instruments, except for two centres, where a systematic trend towards higher individual absolute deltaFVC and deltaFEV1 was observed. The overall variability, assessed by CV, was within 6.2% and 5.1% for FVC and FEV1, respectively: it was similar to other quality control studies ranging from 2.0-5.5% for FVC and 2.2-5.8% for FEV1. Our results point out the importance of performing interlaboratory comparisons as a quality control procedure in multicentre epidemiological studies on lung function, and of stimulating manufacturers to extend the accuracy and precision of the instruments.
Adolescent↗