Clinical and statistical assessment of suicidal ideation and behavior in pharmaceutical trials.

In the past two decades, the potential association between the risk of suicidal ideation and behavior and the clinical use of pharmaceutical products has been debated among industry, regulators, and academia. A better understanding of the possible effects-favorable, unfavorable, or neutral-of pharmaceuticals on the risk of suicidal ideation and behavior may be required, especially for trials typically designed for other primary objectives. Here, a cross-industry statistical team provides recommendations that address the assessment, statistical analysis, interpretation, and utility of suicide-related data in pharmaceutical clinical trials. These recommendations are to evaluate suicidal ideation, suicidal behavior, and the two combined as end points; utilize standard scales to collect data prospectively; and analyze the data using several statistical methods. A more accurate assessment of the potential association between the use of pharmaceutical products and risk of suicide-related events will contribute to estimating the benefit/risk ratio and result in safer medicines for patients.

Endothelial function, insulin action and cardiovascular risk factors in young healthy adult offspring of parents with Type 2 diabetes: effect of vitamin E in a randomized double-blind, controlled clinical trial.

BACKGROUND AND AIMS: Endothelial dysfunction, insulin resistance and oxidative stress are believed to be central and associated mechanisms in atherogenesis. We aimed to determine the effect of the antioxidant vitamin E on endothelial function, insulin action and cardiovascular risk markers in young healthy adult offspring of parents with Type 2 diabetes. METHODS: Healthy, glucose-tolerant adults (18-38 years), 14 (12 male/2 female) with at least one parent with Type 2 diabetes, and 14 (12 male/2 female) subjects with no family history of diabetes (controls) were studied. Insulin action was assessed by euglycaemic hyperinsulinaemic clamp (1 mU/kg/min). Endothelial function was assessed by forearm blood flow (FBF) responses to intra-brachial artery infusions of acetylcholine (ACh) (endothelium-dependent vasodilation), sodium nitroprusside (SNP) (endothelium-independent vasodilation) and N(G)-monomethyl L-arginine (LNMMA) (nitric oxide synthase inhibition). Thirteen offspring (18-38 years, 11 male/2 female, BMI < 30 kg/m2) completed a randomized, double-blind, crossover trial (12 weeks vitamin E 800 IU/day or placebo, 6-week washout). RESULTS: Exogenous glucose infusion rates to maintain euglycaemia were positively associated with response to acetylcholine in offspring (r = 0.61, P < 0.05), and were linked with triglycerides. Vitamin E had no effect on endothelial function, insulin action or cardiovascular risk markers in healthy adult offspring of parents with Type 2 diabetes. CONCLUSIONS: Our results support a positive association between insulin action and endothelial-dependent vasodilation in young healthy adult offspring of parents with Type 2 diabetes, but indicate no effect of vitamin E on these parameters.

Vitamin C improves endothelial function in healthy estrogen-deficient postmenopausal women.

OBJECTIVE: Estrogen deficiency is associated with increased cardiovascular risk and endothelial dysfunction. Improvements in endothelial function with antioxidants, including vitamin C, have been reported. We aimed to determine the acute effect of vitamin C on endothelial function in healthy women with established menopause. SUBJECTS: Subjects (aged 47-59 years) were at least 1 year postmenopause. Ten (serum estradiol < 50 pmol/l) were not receiving hormone replacement therapy, while eight hysterectomized subjects received subcutaneous estradiol. DESIGN: Forearm blood flow (FBF; strain-gauge plethysmography) responses to intrabrachial artery infusions of incremental doses of acetylcholine (endothelium-dependent vasodilation) and sodium nitroprusside (endothelium-independent vasodilation) were determined at baseline, and following 1.5 g vitamin C given intravenously. RESULTS: At baseline, estrogen-treated subjects had a lower index of insulin resistance (homeostasis model assessment, HOMA) and lower fibrinogen than those of estrogen deficient subjects. There was a trend towards higher baseline FBF and larger baseline FBF response to acetylcholine in estrogen-treated subjects. FBF responses to acetylcholine were significantly enhanced after vitamin C in estrogen-deficient subjects (area under the dose-response curve (AUC): estrogen-deficient 9.9 +/- 2.6 vs. 15.1 +/- 3.2 (mean +/- SEM), p = 0.02; estrogen-treated 17.0 +/- 2.9 vs. 21.0 +/- 3.2, p = 0.07). Resting FBF and response to sodium nitroprusside were unchanged in either group by vitamin C. Plasminogen activator inhibitor-1 levels fell after vitamin C in the estrogen-deficient group (17.0 +/- 1.6 vs. 14.7 +/- 0.9 IU/ml, p = 0.03). CONCLUSIONS: These results indicate that endothelial function may be improved acutely by antioxidant treatment in postmenopausal women with established estrogen deficiency.

Dextromethorphan and pain after total abdominal hysterectomy.

Dextromethorphan is an N-methyl-D-aspartate (NMDA) receptor antagonist which has been shown to inhibit the development of cutaneous secondary hyperalgesia after tissue trauma. We studied 60 ASA I-II patients undergoing total abdominal hysterectomy in a randomized, double-blind, placebo-controlled study. Patients received either dextromethorphan 27 mg capsules, two doses before operation and three doses in the first 24 h after operation, or placebo. Visual analogue pain scores (VAS) at 24 and 48 h were assessed at rest, on coughing and on sitting up, and were not significantly different between groups. Morphine consumption from a patient-controlled analgesia (PCA) device was also not significantly different between groups. Evidence of secondary hyperalgesia was assessed with von Frey hairs 10 cm above the Pfannenstiel incision. Both groups of patients exhibited evidence of secondary hyperalgesia after 24 and 48 h but there were no significant differences between groups. There was also no difference between groups in VAS scores at 1 month.

Efficacy of acrivastine plus pseudoephedrine for symptomatic relief of seasonal allergic rhinitis due to mountain cedar.

BACKGROUND: Acrivastine is a second-generation H1-antagonist chemically related to triprolidine, but more polar and with less central nervous system penetration than triprolidine. OBJECTIVE: The efficacy of the antihistamine-decongestant combination product (Semprex-D capsules) containing acrivastine 8 mg plus pseudoephedrine HCl 60 mg was evaluated for the treatment of seasonal allergic rhinitis symptoms. METHODS: A total of 676 patients sensitive to mountain cedar pollen was enrolled into a 6-center, randomized, double-blind, placebo-controlled, parallel, 4-group study designed to compare acrivastine + pseudoephedrine, acrivastine, pseudoephedrine, and placebo. Patients with demonstrable diary symptom scores at baseline took study medication (4 doses/day) and recorded symptom scores twice daily for 2 weeks. The effectiveness of the acrivastine + pseudoephedrine combination was examined relative to the individual components and placebo in terms of changes in diary symptom scores. RESULTS: Over the 2-week period, the combination of acrivastine plus pseudoephedrine was significantly more effective than (1) acrivastine, pseudoephedrine, and placebo (P < .001) for relief of all symptoms; (2) pseudoephedrine (P < .001) for relieving allergy symptoms, ie, running nose, sneezing, itchy nose/throat and tearing; and (3) acrivastine (P < .001) for reducing nasal congestion. Relative to placebo, small increases in adverse experience rates were observed with acrivastine + pseudoephedrine for dry mouth, insomnia, somnolence, and headache. CONCLUSION: These findings in a large clinical trial demonstrate (1) the efficacy of acrivastine and (2) that each component of the combination of acrivastine 8 mg plus pseudoephedrine HCl 60 mg contributes to the overall efficacy, thereby supporting the conclusion that the combination is rational, safe, and effective for the treatment of allergic rhinitis.

Economic evaluation of a randomized clinical trial comparing vinorelbine, vinorelbine plus cisplatin, and vindesine plus cisplatin for non-small-cell lung cancer.

PURPOSE: To estimate the comparative cost-effectiveness of three regimens for metastatic non-small-cell lung cancer (NSCLC). METHODS: Results from a randomized clinical trial of 612 European patients with NSCLC, and cost data from an academic cancer center, the Medical College of Virginia, were analyzed. In this post-hoc economic analysis, we compared vinorelbine alone, vinorelbine plus cisplatin, and a common regimen of vindesine plus cisplatin. RESULTS: Vinorelbine plus cisplatin resulted in the longest mean survival time of the three regimens, 49.6 weeks, followed by vindesine plus cisplatin, 44.3 weeks, and vinorelbine, 41.6 weeks. Compared with vinorelbine alone, vinorelbine plus cisplatin added 56 days at a cost of $2,700, resulting in a cost-effectiveness ratio of $17,700 per year of life gained. Similarly, vindesine plus cisplatin added 19 days at a cost of $1,150, or $22,100 per year of life gained. Compared with vindesine plus cisplatin, vinorelbine plus cisplatin added 37 days at a cost of $1,570, or $15,500 per year of life gained. CONCLUSION: The most effective regimen of vinorelbine plus cisplatin added substantial benefit compared with vinorelbine alone or another common treatment, vindesine plus cisplatin, at a cost-effectiveness within accepted limits for medical interventions. Vindesine plus cisplatin also added benefit at an acceptable cost per year of life gained. If vinorelbine is preferred because of its toxicity profile, the additional effectiveness of cisplatin added substantial benefit at an acceptable cost. Compared with other common medical interventions, chemotherapy for NSCLC has acceptable efficacy and cost-effectiveness and should not be arbitrarily denied based on clinical or economic grounds.

Semantic activation and implicit memory in Alzheimer disease.

Patients with Alzheimer disease (AD) invariably display pronounced deficits in verbal memory when retention is tested explicitly. The present study examined the possibility that tasks which require memory only implicitly would be performed normally. Moderately demented patients with probable AD were severely impaired in free recall of a word list. On a subsequent word association test, the AD patients were less likely than normals to give items from the recall list as their word associations. The results suggest that implicit verbal memory, as well as explicit memory, is impaired in AD. While the magnitude of the activation effect was significantly reduced in AD patients, it was uncorrelated with recall performance or a measure of global cognitive functioning. Memory activation may thus depend on neural circuitry outside the traditional (i.e. temporo-limbic) memory system.

Methylene dianilene: a new toxic cause of visual failure with hepatitis.

A 28-year-old man ingested methylene dianilene in potassium carbonate and gamma-butyrolactone. He developed toxic optic neuritis, with severe visual dysfunction (not previously reported in humans), prolonged toxic hepatitis, with disturbed liver-function tests 18 months after the incident, and other more transient effects. The course of his illness is described and the literature on methylene dianilene toxicity is reviewed.

Effects of propranolol and metoprolol on the peripheral circulation.

The effects of single doses of propranolol and metoprolol on skin temperature and skin and muscle blood flow were compared in 10 normal subjects and four patients with essential hypertension. In normal subjects the mean skin temperature fell by 1.30 +/- 0.62 degrees C 90 minutes after 80 mg propranolol and 0.15 +/- 0.05 degrees C after 100 mg metoprolol. Skin blood flow and resting muscle blood flow were not affected by metoprolol but fell significantly after propranolol. Both drugs reduced post-exercise muscle hyperaemia, propranolol by more than metoprolol. Similar changes were seen in the hypertensive patients. Propranolol should be used with care in patients with known vascular disease.

A comparison of methods for measurement of rectal potential difference in man: effects of rectal infusion of amiloride.

1. Two methods for measurement of rectal potential difference in man were compared. A saline-filled catheter technique gave more reproducible results and was better tolerated by patients than the solid probe technique. 2. Infusion of amiloride at a concentration of 4 x 10(-6) mol/l in saline produced a variable fall of potential difference in six normal subjects. Dose-response curves in two subjects showed that complete inhibition of rectal difference occurred at 4 x 10(-5) mol/l and 4 x 10(-6) mol/l respectively. 3. This finding provides additional evidence that rectal potential difference in man results from electrogenic ion transport across the mucosal epithelial cell.