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Biomedical subjects

Frederick R Cobb

Publications and source records attributed to Frederick R Cobb.

8 recordsLinked to original sources
PubMed2006

The novel phosphodiesterase inhibitor NM-702 improves claudication-limited exercise performance in patients with peripheral arterial disease.

OBJECTIVES: The current study tested the hypothesis that NM-702 improves treadmill exercise performance in peripheral arterial disease patients with claudication-limited exercise performance. BACKGROUND: Patients with claudication experience significant disability, owing to their exercise limitation. Therapeutic options to improve exercise performance in these patients are limited. NM-702 is a novel drug that inhibits phosphodiesterase as well as thromboxane A2 synthase. METHODS: This study was a randomized, multi-center, placebo-controlled, double-blind trial. Patients were randomized to receive 24 weeks of twice-daily treatment with either placebo (intent to treat population, n = 130), 4 mg NM-702 (n = 126), or 8 mg NM-702 (n = 130). RESULTS: After 24 weeks of treatment, 8 mg NM-702 was associated with a statistically significant increased peak walking time on a graded treadmill as compared with placebo (p = 0.004). Peak walking time after 24 weeks was increased by 17.1 +/- 49.0% in the placebo arm, 22.1 +/- 60.1% in the 4-mg NM-702 arm, and 28.1 +/- 50.5% in the 8-mg NM-702 arm. NM-702 at the 8-mg dose for 24 weeks was associated with statistically significant improvements in the treadmill claudication onset time as compared with placebo. In addition, as compared with placebo, NM-702 improved the physical component and physical functioning scores of the Medical Outcomes Study 36-Item Short Form and the walking distance and stair climbing domains of the Walking Impairment Questionnaire. NM-702 was generally well tolerated, but adverse events typical of vasodilators were common. CONCLUSIONS: NM-702 used for 24 weeks by patients with claudication was associated with improvements in laboratory- and ambulatory-based exercise performance.

Aged↗
PubMed2006

Total nitrogen oxide following exercise testing reflects endothelial function and discriminates health status.

Nitric oxide (NO) bioavailability is important in vascular health, but unsuitable as a clinical measure due to biological oxidation. Total nitrogen oxides (NO(x)) are stable but background nitrate levels make it difficult to detect disease-based variation. We investigated the clinical discriminatory value of NO(x) as it relates to exercise capability (VO(2peak)) and brachial artery reactivity (BAR, an NO-dependent measure of endothelial health), in healthy (H), increased risk (RF), and known cardiovascular disease (CVD) subjects. BAR was measured using forearm occlusion/hyperemia stimulus. Subjects performed a maximal graded exercise test (GXT). Blood at rest, exercise termination, and 10 min into recovery was mixed equally with 0.1 M NaOH at 4 degrees C, filtered, and stored at -70 degrees C. NO(x) was measured by chemiluminescence. Seven of the RF group then exercise-trained for 6 months prior to retesting. The H group (n = 12) was younger, had higher VO(2peak), HDL levels, and baseline NO(x) values than the RF (n = 15) and CVD (n = 10) groups. NO(x) increased from baseline to recovery in the H group only (75.85 +/- 19.04 microM vs 97.76 +/- 31.93 microM; P <or= 0.01). BAR was greater in the H versus CVD group (7.24 +/- 3.78% vs 2.59 +/- 3.53%; P <or= 0.01). The relation between VO(2peak) and NO(x) recovery was significant across groups (r = 0.71, P <or= 0.01). Following training the RF subjects (n = 7) increased VO(2peak) (29.98 +/- 6.74 to 33.08 +/- 5.57 ml kg(-1) min(-1); P <or= 0.05), BAR (3.19 +/- 3.96 to 6.86 +/- 4.81%; P <or= 0.05), and recovery NO(x) (18.29 +/- 6.46 to 66.48 + 21.11 microM; P <or= 0.01). These findings suggest that plasma NO(x) following GXT discriminate cardiovascular disease status, are related to regional endothelial function, and respond favorably to exercise training.

Adult↗
PubMed2005

Regional and whole-body markers of nitric oxide production following hyperemic stimuli.

The measurement of nitric oxide (NO) bioavailability is of great clinical interest in the assessment of vascular health. However, NO is rapidly oxidized to form nitrite and nitrate and thus its direct detection in biological systems is difficult. Venous plasma nitrite (nM concentrations) has been shown to be a marker of forearm NO production following pharmacological stimulation of the endothelium utilizing acetylcholine (Ach). In the present study, we demonstrate, within 15 apparently healthy subjects (34.1 +/- 7.3 years), that reactive hyperemia of the forearm, a physiological endothelial stimulus, results in a 52.5% increase in mean plasma nitrite concentrations (415 +/- 64.0 to 634 +/- 57.1 nM, P = 0.015). However, plasma nitrite is readily oxidized to nitrate within plasma, and thus its utility as a marker of NO production within the clinical setting may be limited. Alternatively, NOx (predominantly nitrate) is relatively stable in plasma (microM concentrations), but is produced by sources other than the vasculature and has been shown to be unsuitable as a measure of localized NO production. We reasoned that the principle source of NOx generation during exercise is NO production and thus have examined the change in NOx following treadmill exercise stress. In this study, 12 apparently healthy subjects showed an increase (from baseline) in venous NOx at peak effort and during recovery (12 +/- 9.1 and 17 +/- 15.3 microM respectively, P < 0.05). In contrast, 10 subjects with cardiovascular disease showed no significant increases. Additionally, a correlation between VO(2peak) and the change in circulating NOx (r(2) = 0.4585, P < or = 0.01) indicated the subjects who could exercise hardest also produced the most NO.

Aged↗
PubMed2004

Role of mitochondrial aldehyde dehydrogenase in nitroglycerin-induced vasodilation of coronary and systemic vessels: an intact canine model.

BACKGROUND: It has recently been shown that mitochondrial aldehyde dehydrogenase 2 (mtALDH) catalyzes the formation of 1,2-glyceryl dinitrate and nitrite from nitroglycerin (glyceryl trinitrate [GTN]) within mitochondria, leading to production of cGMP and vasorelaxation. However, whether this mechanism operates in the systemic and coronary beds that subserve the antianginal action of GTN is not known. In this study, we address this question in an intact canine model. METHODS AND RESULTS: Fourteen healthy mongrel dogs (weight, 20 to 25 kg) were studied. Coronary blood flow and hemodynamics were continuously monitored by a pulse Doppler flow probe implanted around the left circumflex coronary artery and with catheters in left ventricle and aorta, respectively. Each dog was given a 1-mL bolus injection of GTN, sodium nitroprusside (SNP), or adenosine through a catheter in the left atrium before and 30 minutes after infusion of cyanamide (17 mg/kg), an inhibitor of mtALDH. Cyanamide significantly inhibited both the classic dehydrogenase and GTN reductase activities of mtALDH in situ and attenuated the coronary blood flow increase and declines in blood pressure and left ventricular end-diastolic pressure produced by GTN in vivo. In contrast, mtALDH inhibition had no effect on the coronary and systemic effects of SNP and adenosine. CONCLUSIONS: Our data suggest that mtALDH contributes to GTN biotransformation in vivo and thus at least partly underlies the antianginal mechanism of drug action. Our findings also highlight the differences in biometabolism of clinically relevant nitrosovasodilators.

Adenosine↗
PubMed2004

The effect of vitamin therapy on the progression of coronary artery atherosclerosis varies by haptoglobin type in postmenopausal women.

OBJECTIVE: Antioxidant trials have not demonstrated efficacy in slowing cardiovascular disease but could not rule out benefit for specific patient subgroups. Antioxidant therapy reduces LDL oxidizability in haptoglobin 1 allele homozygotes (Hp 1-1), but not in individuals with the haptoglobin 2 allele (Hp 2-1 or Hp 2-2). We therefore hypothesized that haptoglobin type would be predictive of the effect of vitamin therapy on coronary atherosclerosis as assessed by angiography. RESEARCH DESIGN AND METHODS: We tested this hypothesis in the Women's Angiographic Vitamin and Estrogen (WAVE) trial, a prospective angiographic study of vitamins C and E with or without hormone replacement therapy (HRT) in postmenopausal women. Haptoglobin type was determined in 299 women who underwent baseline and follow-up angiography. The annualized change in the minimum luminal diameter (MLD) was examined in analyses stratified by vitamin use, haptoglobin type, and diabetes status. RESULTS: We found a significant benefit on the change in MLD with vitamin therapy as compared with placebo in Hp 1-1 subjects (0.079 +/- 0.040 mm, P = 0.049). This benefit was more marked in diabetic subjects (0.149 +/- 0.064 mm, P = 0.021). On the other hand, there was a trend toward a more rapid decrease in MLD with vitamin therapy in Hp 2-2 subjects, which was more marked in diabetic subjects (0.128 +/- 0.057 mm, P = 0.027). HRT had no effect on these outcomes. CONCLUSIONS: The relative benefit or harm of vitamin therapy on the progression of coronary artery stenoses in women in the WAVE study was dependent on haptoglobin type. This influence of haptoglobin type seemed to be stronger in women with diabetes.

Aged↗
PubMed2002

Effects of hormone replacement therapy and antioxidant vitamin supplements on coronary atherosclerosis in postmenopausal women: a randomized controlled trial.

CONTEXT: Hormone replacement therapy (HRT) and antioxidant vitamins are widely used for secondary prevention in postmenopausal women with coronary disease, but no clinical trials have demonstrated benefit to support their use. OBJECTIVE: To determine whether HRT or antioxidant vitamin supplements, alone or in combination, influence the progression of coronary artery disease in postmenopausal women, as measured by serial quantitative coronary angiography. DESIGN, SETTING, AND PATIENTS: The Women's Angiographic Vitamin and Estrogen (WAVE) Trial, a randomized, double-blind trial of 423 postmenopausal women with at least one 15% to 75% coronary stenosis at baseline coronary angiography. The trial was conducted from July 1997 to January 2002 in 7 clinical centers in the United States and Canada. INTERVENTIONS: Patients were randomly assigned in a 2 x 2 factorial design to receive either 0.625 mg/d of conjugated equine estrogen (plus 2.5 mg/d of medroxyprogesterone acetate for women who had not had a hysterectomy), or matching placebo, and 400 IU of vitamin E twice daily plus 500 mg of vitamin C twice daily, or placebo. MAIN OUTCOME MEASURE: Annualized mean (SD) change in minimum lumen diameter (MLD) from baseline to concluding angiogram of all qualifying coronary lesions averaged for each patient. Patients with intercurrent death or myocardial infarction (MI) were imputed the worst rank of angiographic outcome. RESULTS: The mean (SD) interval between angiograms was 2.8 (0.9) years. Coronary progression, measured in mean (SD) change, worsened with HRT by 0.047 (0.15) mm/y and by 0.024 (0.15) mm/y with HRT placebo (P =.17); and for antioxidant vitamins by 0.044 (0.15) mm/y and with vitamin placebo by 0.028 (0.15) mm/y (P =.32). When patients with intercurrent death or MI were included, the primary outcome showed an increased risk for women in the active HRT group (P =.045), and suggested an increased risk in the active vitamin group (P =.09). Fourteen patients died in the HRT group and 8 in the HRT placebo group (hazard ratio [HR], 1.8; 95% confidence interval [CI], 0.75-4.3), and 16 in the vitamin group and 6 in the vitamin placebo group (HR, 2.8; 95% CI, 1.1-7.2). Death, nonfatal MI, or stroke occurred in 26 HRT patients vs 15 HRT controls (HR, 1.9; 95% CI, 0.97-3.6) and in 26 vitamin patients and 18 vitamin controls (HR, 1.5; 95% CI, 0.80-2.9). There was no interaction between the 2 treatment interventions. CONCLUSION: In postmenopausal women with coronary disease, neither HRT nor antioxidant vitamin supplements provide cardiovascular benefit. Instead, a potential for harm was suggested with each treatment.

Aged↗
PubMed2002

Women's angiographic vitamin and estrogen trial: design and methods.

The Women's Angiographic Vitamin and Estrogen trial was a randomized, double-blind, placebo-controlled study designed to test the efficacy of estrogen replacement and antioxidant vitamins for preventing angiographic progression of coronary artery disease. Postmenopausal women with one or more angiographically documented coronary stenoses of 15-75% at baseline were assigned in a 2 x 2 factorial randomization to active hormone replacement therapy (conjugated estrogens for women who had had a hysterectomy or conjugated estrogens with medroxyprogesterone for women with intact uteri) or placebo and to active vitamins E and C or their placebos. Seven clinical centers, five in the United States and two in Canada, randomized 423 women between July 1997 and July 1999. Quantitative coronary angiography was performed at baseline and repeated after projected mean follow-up of 3 years.

Antioxidants↗