Biomedical subjects

Alan L Hinderliter

Publications and source records attributed to Alan L Hinderliter.

31 records · Page 2Linked to original sources

PubMed2003

Differences in flurbiprofen pharmacokinetics between CYP2C91/1, 1/2, and 1/3 genotypes.

OBJECTIVE: This study was conducted to examine differences in flurbiprofen metabolism among individuals with the CYP2C9*1/*1, *1/*2, and *1/*3 genotypes. METHODS: Fifteen individuals with the CYP2C9*1/*1 ( n=5), *1/*2 ( n=5), and *1/*3 ( n=5) genotypes received a single 50-mg oral dose of flurbiprofen. Plasma and urine samples were collected over 24 h, and flurbiprofen and 4'-hydroxyflurbiprofen pharmacokinetic data were compared across genotypes. RESULTS: CYP2C9 genotype was a significant predictor of flurbiprofen metabolism and accounted for 59% of the variability in flurbiprofen AUC(0- infinity ), and approximately 50% of the variability in flurbiprofen oral clearance, formation clearance to 4'-hydroxyflurbiprofen, and the 0 to 24-h urinary metabolic ratio of flurbiprofen to 4'-hydroxyflurbiprofen. Flurbiprofen AUC(0- infinity )was significantly higher and all measures of flurbiprofen clearance were significantly lower in the CYP2C9*1/*3 individuals than in those with *1/*1. Significant differences in these parameters were not detected between *1/*2 subjects and *1/*1 subjects. CONCLUSIONS: CYP2C9 genotype is a significant predictor of flurbiprofen disposition in humans by altering CYP2C9-mediated metabolism and reducing systemic clearance. The effects are most pronounced in individuals carrying the *3 allele.

Adolescent↗

PubMed2003

Assessing endothelial function as a risk factor for cardiovascular disease.

The vascular endothelium plays a key role in the prevention of atherosclerosis. Endothelial dysfunction is an antecedent of clinical cardiovascular disease and can be viewed as the final pathway between coronary risk factors and the development of atherosclerosis. The development of a noninvasive method of assessing endothelial health (ie, measurement of flow- mediated dilation of the brachial artery) has enabled investigators to evaluate the effects of dietary patterns on vascular function. Emerging evidence indicates that dietary fats may acutely impair endothelial function, but this effect is dependent on the type of fat and on the other nutrients consumed. Although inconclusive, studies in cohorts of modest size suggest that antioxidants, L-arginine, and folic acid may modulate endothelial function. Additional research is needed to define the impact of complex, long-term dietary patterns on the vascular endothelium.

Antioxidants↗

PubMed2003

Tolbutamide, flurbiprofen, and losartan as probes of CYP2C9 activity in humans.

The metabolic activity of CYP2C9 in 16 subjects expressing four different genotypes (CYP2C9*1/*1, *1/*2, *1/*3, and *2/*2) was evaluated. Single oral doses of tolbutamide, flurbiprofen, and losartan were administered in a randomized, crossover design. Plasma and urine were collected over 24 hours. The urinary metabolic ratio and amount of metabolite(s) excreted were correlated with formation clearance. The formation clearance of tolbutamide to its CYP2C9-mediated metabolites demonstrated a stronger association with genotype compared to flurbiprofen and losartan, respectively (r2 = 0.64 vs. 0.53 vs. 0.42). A statistically significant correlation was observed between formation clearance of tolbutamide and the 0- to 12-hour urinary amount of 4'-hydroxytolbutamide and carboxytolbutamide (r = 0.84). Compared to tolbutamide, the correlations observed between the respective measures of flurbiprofen and losartan metabolism were not as strong. Tolbutamide is a better CYP2C9 probe than flurbiprofen and losartan, and the 0- to 12-hour amount of 4'-hydroxytolbutamide and carboxytolbutamide is the best urinary measure of its metabolism.

Adult↗

PubMed2003

Sympathoadrenergic mechanisms in reduced hemodynamic stress responses after exercise.

PURPOSE: This study examines the acute effects of moderate aerobic exercise on 1) hemodynamic and sympathetic activity during behavioral stress and 2) beta-adrenergic receptor responsivity in a biracial sample of 24 sedentary adults. METHODS: Before and after exercise, blood pressure (BP), impedance-derived cardiovascular measures, and plasma norepinephrine (NE) and epinephrine (EPI) were assessed during mental arithmetic and active speech tasks, and beta-adrenergic receptor responsivity was assessed using a standard isoproterenol challenge procedure. RESULTS: After exercise, BP, NE, and EPI responses to stress were reduced (0.0001 < P < 0.08), preejection period (PEP) was elongated (P < 0.0001), and beta(1)- and beta(2)-receptor responsivity (P < 0.02) was enhanced. Approximately 65% of the prepost exercise mean arterial pressure response difference could be accounted for by changes in sympathetic factors, with change in NE and PEP being the single best predictors. CONCLUSIONS: Reduced BP responses to stress after acute exercise are strongly linked to a decrease in sympathetic drive, as evidenced by reduced NE responses and elongation of the PEP. Coincident with this overall dampening of the hemodynamic response to stress, increases in cardiac and vascular beta-adrenergic receptor responsivity occur. These findings may have important implications for future translational studies that seek to articulate the mechanisms through which regular aerobic exercise reduces the risks of hypertensive and coronary heart disease.

Adult↗

PubMed2003

Losartan and E3174 pharmacokinetics in cytochrome P450 2C91/1, 1/2, and 1/3 individuals.

STUDY OBJECTIVE: To determine if differences in the pharmacokinetics of losartan and its pharmacologically active E3174 metabolite exist among individuals expressing the cytochrome P450 (CYP) 2C9*1/*1, *1/*2, and *1/*3 genotypes. DESIGN: Single-dose pharmacokinetic study. SETTING: University general clinical research center. SUBJECTS: Fifteen healthy volunteers, five from each genotype: CYP2C9*1/*1, *1/*2, and *1/*3. INTERVENTION: A single oral dose of losartan 50 mg. MEASUREMENTS AND MAIN RESULTS: Plasma and urine samples were collected for 24 hours, and losartan and E3174 pharmacokinetic data were compared across the three genotypes. Orthostatic blood pressure was measured over 12 hours after dosing. No significant differences were observed among the three groups in losartan or E3174 area under the plasma concentration-time curve, losartan or E3174 elimination half-life, or losartan oral clearance. A significant association between CYP2C9 genotype and losartan to E3174 formation clearance was observed, such that 50% of the variability was accounted for by the genotype. No significant relationship between that genotype and blood pressure was observed at any time. CONCLUSION: Differences in the pharmacokinetics of losartan and its active E3174 metabolite were not observed in healthy subjects with the genotype of CYP2C9*1/*2 and *1/*3 compared with those expressing *1/*1. Alterations in losartan dosing in CYP2C9*1/*2 and *1/*3 individuals does not appear necessary.

Adolescent↗

PubMed2002

Echocardiographic predictors of adverse outcomes in primary pulmonary hypertension.

OBJECTIVES: The aim of this study was to evaluate the relationships between echocardiographic findings and clinical outcomes in patients with severe primary pulmonary hypertension (PPH). BACKGROUND: Primary pulmonary hypertension is associated with abnormalities of right heart structure and function that contribute to the poor prognosis of the disease. Echocardiographic abnormalities associated with PPH have been described, but the prognostic significance of these findings remains poorly characterized. METHODS: Echocardiographic studies, invasive hemodynamic measurements and 6-min walk tests were performed and outcomes prospectively followed in 81 patients with severe PPH. Subjects were participants in a 12-week randomized trial examining the effects of prostacyclin plus conventional therapy compared with conventional therapy alone. RESULTS: During the mean follow-up period of 36.9 +/- 15.4 months, 20 patients died and 21 patients underwent transplantation. Pericardial effusion (p = 0.003) and indexed right atrial area (p = 0.005) were predictors of mortality. Pericardial effusion (p = 0.017), indexed right atrial area (p = 0.012) and the degree of septal shift in diastole (p = 0.004) were predictors of a composite end point of death or transplantation. In multivariable analyses incorporating clinical, hemodynamic and echocardiographic variables, pericardial effusion and an enlarged right atrium remained predictors of adverse outcomes. Six-minute walk results, mixed venous oxygen saturation and initial treatment randomization were also independently associated with a poor prognosis. CONCLUSIONS: Pericardial effusion, right atrial enlargement and septal displacement are echocardiographic abnormalities that reflect the severity of right heart failure and predict adverse outcomes in patients with severe PPH. These characteristics may help identify patients appropriate for more intensive medical therapy or earlier transplantation.

Adult↗

PubMed2002

Changes in hemodynamics and left ventricular structure after menopause.

To evaluate the cardiovascular changes associated with menopause, we studied hemodynamics at rest, ambulatory blood pressure, and left ventricular structure in a biracial cohort of pre- and postmenopausal women of similar age, race, weight, and blood pressure. Despite similar levels of blood pressure, postmenopausal women had a higher indexed peripheral resistance (2,722 +/- 757 vs 2,262 +/- 661 dynes.s.m(2)/cm(5), p <0.01) and a lower cardiac index (2.64 +/- 0.73 vs 3.10 +/- 0.71 L/min.m(2), p <0.01) than premenopausal women. Postmenopausal women also had less nocturnal decreases in both systolic (15 +/- 8 vs 19 +/- 8 mm Hg, p <0.01) and diastolic (12 +/- 6 vs 15 +/- 6 mm Hg, p = 0.05) pressures during ambulatory monitoring and higher levels of hematocrit (40 +/- 2% vs 38 +/- 3%, p <0.01). In association with this greater hemodynamic load, postmenopausal women had evidence of early concentric left ventricular remodeling, manifested by a greater relative wall thickness (0.38 +/- 0.06 vs 0.35 +/- 0.06, p <0.01) than that observed in premenopausal women. Differences between pre- and postmenopausal women in hemodynamics, diurnal blood pressure variation, and left ventricular structure were observed in white and African-American subjects. These results suggest that menopause is associated with hemodynamic changes and left ventricular remodeling, which may contribute to the enhanced cardiovascular risk observed in postmenopausal women.

Black or African American↗

PubMed2002

Nighttime blood pressure dipping: the role of the sympathetic nervous system.

There is a marked diurnal variation in blood pressure (BP), with BP dipping to its lowest levels during nighttime sleep. A day-night dip in systolic BP (SBP) of <10% has been used to characterize individuals as nondippers, and is associated with an increased risk for cardiovascular disease. The present study examined the contribution of the sympathetic nervous system (SNS) to BP dipping in a biracial sample of 172 men and women aged 25 to 45 years. Assessments included 24-h ambulatory BP monitoring and both waking and sleeping urinary catecholamines. In addition, cardiovascular alpha- and beta-adrenergic receptor (AR) responsiveness was determined by the doses of isoproterenol and phenylephrine required to attain an increase in heart rate of 25 points (CD25) and BP (PD25), respectively. Compared with dippers (n = 116), nondippers (n = 56) were more likely to be African American and to have a family history of hypertension as well as a higher body mass index (BMI). The nighttime fall in both norepinephrine (NE) and epinephrine (EPI) excretion rates was reduced in nondippers compared with dippers (NE dip 9.3 v 13.1 microg/mg; EPI dip 2.7 v 4.0 microg/mg; both P < .05). Nondippers also were characterized by heightened alpha1-AR responsiveness compared with dippers (PD25 = 252 v 321 microg, P < .05). These data suggest that the SNS may contribute to individual differences in nighttime BP dipping, and appears to account in part for blunted BP dipping in African Americans.

Adult↗

PubMed2002

Evaluation of cytochrome P4502C9 metabolic activity with tolbutamide in CYP2C91 heterozygotes.

OBJECTIVES: Multiple single-nucleotide polymorphisms in the gene encoding cytochrome P450 (CYP) 2C9 have been identified, but the functional significance of the various putative defective genotypes in humans merits further study. METHODS: Using tolbutamide as a probe of CYP2C9 activity, we evaluated CYP2C9 phenotype in 15 healthy individuals expressing the CYP2C9(*)1/(*)1, (*)1/(*)2, and (*)1/(*)3 genotypes (n = 5 per group). CYP2C9 genotype was determined by polymerase chain reaction-restriction fragment length polymorphism methods. Subjects received 500 mg of tolbutamide, with plasma and urine collected over a 24-hour period. Plasma tolbutamide and urinary tolbutamide, 4'-hydroxytolbutamide, and carboxytolbutamide concentrations were determined by an HPLC method. RESULTS: Tolbutamide area under the plasma concentration-time curve from time zero to infinity [AUC(0- infinity )] significantly increased by 1.5-fold and 1.9-fold, respectively, in subjects expressing the CYP2C9(*)1/(*)2 and (*)1/(*)3 genotypes compared with (*)1/(*)1 subjects. Statistically significant reductions in tolbutamide oral clearance (29% and 48%) and formation clearance (38% and 56%) were detected in the (*)1/(*)2 and (*)1/(*)3 individuals, respectively, compared with (*)1/(*)1 subjects. The increases in AUC(0- infinity) and decreases in oral clearance observed in the (*)1/(*)3 individuals were also significantly greater than those expressing the (*)1/(*)2 genotype (P <.05). The amount of urinary 4'-hydroxytolbutamide and carboxytolbutamide excreted in the 0- to 12-hour and 6- to 12-hour collection intervals was significantly less in (*)1/(*)2 and (*)1/(*)3 individuals compared with (*)1/(*)1 subjects. With tolbutamide used as a CYP2C9 probe, CYP2C9 genotype was the major determinant of CYP2C9 phenotype (r(2) = 0.77). CONCLUSIONS: CYP2C9 activity was significantly reduced in (*)1 heterozygotes compared with (*)1 homozygotes, and metabolism was more severely impaired in (*)1/(*)3 individuals compared with those expressing (*)1/(*)2.

Adolescent↗

PubMedDate not supplied

Relationship of clinic, ambulatory, and laboratory stress blood pressure to left ventricular mass in overweight men and women with high blood pressure.

OBJECTIVE: This study was designed to evaluate the relationship between left ventricular (LV) mass and blood pressure (BP) recorded in the following contexts: in the clinic, using standard auscultatory procedures, during a typical day using ambulatory BP monitoring, and in the laboratory environment during behavioral stress testing. METHODS: Ninety-seven men and women with clinic systolic blood pressure (SBP) of 130 to 180 mm Hg and/or diastolic blood pressure (DBP) of 85 to 110 mm Hg and mild to moderate obesity were included in the study. Laboratory stressors included the following tasks: Public Speaking; Anger Interview; Mirror Trace; and Cold Pressor. LV mass was measured using echocardiography and adjusted for body size by dividing by height(2.7) to yield LV mass index (LVMI). RESULTS: LVMI was positively correlated with clinic SBP (r = 0.24, p <.05), ambulatory SBP (r = 0.34, p <.01), and aggregated laboratory stress SBP (r = 0.28, p <.01). Of the individual stressors, only SBP responses to the Mirror Trace and Cold Pressor tasks were independently correlated with LVMI (r = 0.35 and 0.34, respectively, p values <.01). Hierarchical regression analyses revealed that laboratory stress SBP remained a significant predictor of LVMI, after controlling for BMI and clinic pressure. CONCLUSIONS: These findings suggest that cardiovascular responses to behavioral stress are associated with individual differences in LVMI in men and women with high blood pressure who are overweight. Laboratory studies of behavioral stress may help promote our understanding of the pathophysiology of LVH.

Adult↗

PubMedDate not supplied

Hostility, social support, and adrenergic receptor responsiveness among African-American and white men and women.

OBJECTIVE: We examined the relationship between beta-adrenergic receptor responsiveness and hostility and social support in African American and white men and women. METHODS: The participants were 149 men and women, aged 25 to 45 years with SBP < 160 and DBP < 105. Hostility and social support were assessed with standardized self-report measures. An isoproterenol challenge was used to evaluate beta-adrenergic receptor responsiveness, and a phenylephrine challenge was used to evaluate alpha-adrenergic receptor responsiveness. RESULTS: Hostility and social support were unrelated to alpha-adrenergic receptor responsiveness. Hostility and satisfaction with perceived social support predicted beta-adrenergic receptor responsiveness in multiple linear regression analyses controlling for race, gender, age, SBP, and resting heart rate. High hostility was associated with reduced cardiac beta-adrenergic receptor function among both white and African American men. Low levels of satisfaction with social support were associated with reduced cardiac beta-adrenergic receptor responsiveness among men and women. Hostility and satisfaction with social support shared some variance in models predicting beta-adrenergic receptor responsiveness. CONCLUSIONS: Reduced beta-adrenergic receptor responsiveness is associated with higher levels of hostility among men, and is associated with lower levels of satisfaction with social support among men and women. Impaired beta-adrenergic receptor function, which is a common characteristic of cardiovascular disease, may be a marker of increased cardiovascular disease risk among individuals high in hostility and low in social support.

Adrenergic alpha-Agonists↗

PubMedDate not supplied

Biological correlates of abuse in women with premenstrual dysphoric disorder and healthy controls.

OBJECTIVE: To examine the biological correlates associated with histories of sexual or physical abuse in women meeting DSM criteria for premenstrual dysphoric disorder (PMDD) and in healthy, non-PMDD controls. METHODS: Twenty-eight women with prospectively confirmed PMDD were compared with 28 non-PMDD women for cardiovascular and neuroendocrine measures at rest and in response to mental stressors, and for beta-adrenergic receptor responsivity, during both the follicular and luteal phase of the menstrual cycle. Structured interview was used to assess psychiatric history and prior sexual and physical abuse experiences. All subjects were free of current psychiatric comorbidity and medication use. RESULTS: More PMDD women had prior sexual and physical abuse experiences than controls (20 vs. 10, respectively). Relative to nonabused PMDD women, PMDD women with prior abuse (sexual or physical) exhibited significantly lower resting norepinephrine (NE) levels and significantly greater beta1- and beta2-adrenoceptor responsivity and greater luteal phase NE reactivity to mental stress. For non-PMDD control women, abuse was associated with blunted cortisol, cardiac output, and heart rate reactivity to mental stress relative to nonabused controls. CONCLUSIONS: The results of this initial study suggest that a history of prior abuse is associated with alterations in physiological reactivity to subsequent mental stress in women, but that the biological correlates of abuse may be different for PMDD vs. non-PMDD women.

Adult↗

PubMedDate not supplied

Hostility is related to blunted beta-adrenergic receptor responsiveness among middle-aged women.

OBJECTIVE: Based on previous findings in men, the hypothesis that hostility would be associated with blunted responsiveness of cardiovascular beta-adrenergic receptors was tested in a study sample of middle-aged women. The roles of the sympathetic nervous system and of social support in this putative relationship were also evaluated. METHODS: Subjects were 80 healthy women (n = 23 African American; n = 57 white), aged 47 to 55 years. Hostility was assessed using the Cook-Medley Hostility Scale and social support was assessed with the Brief Social Support Questionnaire. Intravenous isoproterenol challenge was used to evaluate cardiac and vascular beta-adrenergic receptor responsiveness. Twenty-four-hour urinary catecholamine excretion was used to index sympathetic nervous system activity. RESULTS: Hostility was related to blunted cardiac (R = 0.33, p <.01) and vascular (R = 0.23, p <.05) beta-adrenergic receptor responsiveness in simple correlation analysis and in hierarchical regression analyses controlling for race, menopausal status, weight, and resting heart rate. Low social support was also related to blunted beta-adrenergic receptor responsiveness (R = 0.3, p <.01). Twenty-four-hour norepinephrine excretion was related both to hostility (R = 0.32, p <.01) and to cardiac (R = 0.25, p <.05) and vascular (R = 0.24, p <.05) beta-adrenergic receptor responsiveness. CONCLUSIONS: These observations replicate and extend previous findings in men by demonstrating that higher levels of hostility and low levels of social support are associated with blunted beta-adrenergic receptor responsiveness in middle-aged women. They also suggest that heightened sympathetic nervous system activity associated with hostility may contribute to beta-adrenergic receptor blunting. Because blunted beta-adrenergic receptor sensitivity is a characteristic feature of a broad range of cardiovascular diseases, these findings may reflect an early preclinical manifestation of pathophysiology accompanying hostility and low social support.

Adrenergic beta-Agonists↗