The medicinal chemistry implications of the anticancer effects of aspirin and other NSAIDs.

The regular intake of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with decreased incidence of certain types of cancer particularly those with an inflammatory component. The protective effects of these drugs in colorectal cancer are particularly marked, with a 40-50% reduction in risk. Research in this area has focussed on understanding and optimising these cytoprotective effects. NSAIDs are believed to operate by inhibiting COX-2, an enzyme that appears to be involved in a number of cancer promoting processes. This hypothesis is consistent with the observation that the COX-2 selective inhibitors dramatically decrease tumour formation in human and animal studies. Surprisingly aspirin, which is selective for COX-1 over COX-2, and sulindac, which is an equipotent inhibitor of the COX isoenzymes, appear to have a similar anticancer profile to the COX-2 selective NSAIDs. A number of mechanisms have been proposed to explain the anomalous effects of aspirin. The first of these relates to the unique mode of action of aspirin, which acetylates the COX-2 enzyme and generates the cancer-suppressing 15R-hydroxyeicosatetraenoic acid at the site of a potential tumour. The alternative rationale relates to the metabolism of aspirin to salicylic acid, which has a cyclooxygenase independent anti-inflammatory mechanism, preventing the inflammatory response at the gene transcription level. A new generation of drugs could evolve from approaches to improving the therapeutic index of aspirin or by modifications to known therapies such as sulindac and celecoxib.

The effects of propranolol on cognitive function and quality of life: a randomized trial among patients with diastolic hypertension.

PURPOSE: We sought to determine whether propranolol has adverse effects on cognitive function, depressive symptoms, and sexual function in patients treated for diastolic hypertension. SUBJECTS AND METHODS: We performed a placebo-controlled trial among 312 men and women, 22 to 59 years of age, who had untreated diastolic hypertension (90 to 104 mm Hg). Patients were randomly assigned to treatment with propranolol (80 to 400 mg/day) or matching placebo tablets. Thirteen tests of cognitive function were assessed at baseline, 3 months, and 12 months. Five tests measured reaction time to, or accuracy in, interpreting visual stimuli; one test measured the ability to acquire, reproduce, and change a set of arbitrary stimulus-response sets; and seven tests measured memory or learning verbal information. Depressive symptoms and sexual function were assessed by questionnaires at baseline and 12 months. RESULTS: There were no significant differences by treatment assignment for 11 of the 13 tests of cognitive function at either 3 or 12 months of follow-up. Compared with placebo, participants treated with propranolol had slightly fewer correct responses at 3 months (33 +/- 3 [mean +/- SD] versus 34 +/- 2, P = 0.02) and slightly more errors of commission at 3 months (4 +/-5 versus 3 +/- 3, P = 0.04) and at 12 months (4 +/- 4 versus 3 +/- 3, P = 0.05). At 12 months, depressive symptoms and sexual function and desire did not differ by treatment assignment. CONCLUSIONS: Treatment of hypertension with propranolol had limited adverse effects on tests of cognitive function that were of questionable clinical relevance, and there were no documented adverse effects on depressive symptoms or sexual function. Selection of beta-blockers for treatment of hypertension should be based on other factors.

Comparison of a lifestyle modification program with propranolol use in the management of diastolic hypertension.

OBJECTIVE: To compare the management of mild diastolic hypertension (90 to 104 mm Hg) using a nonpharmacologic intervention with that using propranolol or placebo. DESIGN: Randomized, placebo-controlled trial with a 2 x 2 factorial design. SETTING: University-based ambulatory care center. PARTICIPANTS: Two hundred seven men and 105 women, 22 to 59 years of age, 73% white, who had mild diastolic hypertension untreated for at least eight weeks. INTERVENTIONS: 1) a multicomponent lifestyle modification intervention (lifestyle focus group, or LFG) administered in eight weekly meetings + placebo, 2) LFG + propranolol, 3) propranolol alone, and 4) placebo alone, followed for 12 months. MEASUREMENTS: Systolic blood pressure (SBP), diastolic blood pressure (DBP), and self-reported adverse effects at each of nine follow-up visits; fasting total cholesterol, triglycerides, and glucose at baseline and 12 months; 24-hour urine sodium (Na+) and potassium (K+), three-day food records and physical activity questionnaire at three and 12 months; and a quality of life questionnaire at 12 months. MAIN RESULTS: The mean decreases in DBP at 12 months were: 8.5 mm Hg in the LFG + propranolol group; 7.7 mm Hg in the propranolol-only group; 5.9 mm Hg in the placebo-only group; and 5.4 mm Hg in the LFG + placebo group. Repeated-measures analysis of covariance showed that level of baseline DBP (p < 0.0001), time of follow-up (p < 0.0001), and propranolol use (p < 0.0001) were significantly associated with a decrease in DBP at 12 months. Despite reductions in urinary Na+ (-35 mEq; 95% CI = -50, -19), dietary Na+ (-521 mg; 95% CI = -710, -332), total calories ingested (-238; 95% CI = -335, -140), and weight (-1.4 lb; 95% CI = -3.7, +0.8), and significant increases in dietary K+ (+294 mg; 95% CI = +107, +480) and in mets-minutes of exercise (+43; 95% CI = +20, +67) at three months, assignment to the LFG intervention had no effect on DBP at three or 12 months. The subjects assigned to take propranolol more frequently reported fatigue during ordinary activities, sleep disturbance, decrease in sexual activity, and depressed feelings, when compared with the subjects taking placebo, but the numbers of study withdrawals did not differ by drug assignment. No significant difference in total cholesterol and glucose levels was observed by group assignment. Triglycerides increased significantly in the subjects assigned to propranolol (mean difference = +20 mg/dL; 95% CI of difference +1.5, +39). There was no difference in the responses to 21 quality of life items between the subjects assigned to propranolol and those assigned to placebo. CONCLUSIONS: This multicomponent lifestyle modification intervention was unable to promote persistent behavior changes and thus was inferior to propranolol therapy for the treatment for mild diastolic hypertension. Future research should focus on single modifiable factors to lower blood pressure.

The effects of mild diastolic hypertension on the results of tests of cognitive function in adults 22 to 59 years of age.

OBJECTIVE: To test the hypothesis that mild diastolic hypertension (90 to 104 mm Hg) may induce asymptomatic impairment of cognitive function. DESIGN: Cross-sectional. SETTING: Community participants recruited to a university-based ambulatory care center. PARTICIPANTS: Three hundred twelve men and women with untreated essential hypertension and 47 normotensive subjects, 22 to 59 years of age. MEASUREMENTS AND MAIN RESULTS: Cognitive function tests measured reaction time to and accuracy in interpreting predetermined visual stimuli, the ability to acquire, reproduce, and change a set of arbitrary stimulus-response associations, and memory and learning of verbal information. These tests were selected to detect subtle differences in performances as opposed to differentiating neurologically normal persons from brain-damaged persons. After controlling for age, gender, and education, results showed that there was no significant difference between the normotensive and hypertensive subjects in two measures of reaction time to and four measures of accuracy in interpreting predetermined visual stimuli, in the measure of arbitrary stimulus-response associations, or in seven memory and learning variables. Although confidence intervals for the differences between means were wide, clinically significant differences were not likely to be present. Younger age was associated with faster reaction times, fewer errors, and better performance on memory and learning tasks, independent of diastolic blood pressure. CONCLUSIONS: The few detectable effects of untreated mild hypertension on cognitive function reported in the literature may be due to chance and are of questionable clinical significance.