Bune Aj

Effects of Indomethacin, Sulindac, Naproxen, Aspirin, and Paracetamol in Treated Hypertensive Patients

Four placebo controlled, randomised crossover studies were carried out to investigate the effects of non-steroidal anti-inflammatory drugs and analgesics on blood pressure control in treated hypertensive patients. Twelve patients completed one study comparing indomethacin, 25 mg tds, with placebo in 2 six week phases; there were increases in mean blood pressure (p less than 0.01) of 9 mm Hg (casual), 8 mm Hg (supine) and 10 mm Hg (standing) in the indomethacin phase accompanied by a 50% reduction in plasma renin activity (p less than 0.05) and a 47% decrease in plasma aldosterone concentration (p less than 0.05). Similar studies on aspirin-SR, 650 mg daily (19 patients), and paracetamol, 1 g 8th hourly (20 patients), revealed only small changes in blood pressure, with a 2 mm Hg increase in supine diastolic blood pressure during aspirin therapy and a 4 mm Hg increase in supine and standing systolic blood pressure during paracetamol therapy (p less than 0.05 for both). Nineteen patients completed a study with 4 three week phases, taking placebo, naproxen 250 mg mane and 500 mg nocte, sulindac 200 mg bd, and aspirin-SR 1950 mg bd. All three active agents depressed plasma renin activity and plasma aldosterone concentration. Neither sulindac nor aspirin caused any significant increases in blood pressure, and naproxen had little effect, though it did cause a 4 mm Hg increase in standing systolic pressure (p less than 0.05). We conclude that the effects of indomethacin on control of blood pressure in treated hypertensive patients are not exhibited to the same extent by other drugs investigated, and that they are not dependent on the concomitant decreases in plasma renin activity or plasma aldosterone concentration. The importance of inhibition of prostaglandin synthesis remains unclear.

Relationship between antihypertensive drug therapy and cognitive function in elderly hypertensive patients with memory complaints.

Objective To evaluate the relationship between antihypertensive treatments and cognitive function in elderly hypertensive patients with memory complaints. Methods The association between cognitive function and antihypertensive drug therapy was studied in 1241 hypertensive elderly patients with memory complaints attending a geriatric outpatient clinic. Cognitive function was assessed using the Mini Mental State Examination (MMSE) and validated neuropsychological tests (Cognitive Efficiency Profile; CEP). Patients were classified into four categories according to their cognitive status: normal cognitive function, mild cognitive impairment (MCI), Alzheimers disease (AD) or vascular dementia (VaD). Results In this population aged 78 ± 8 years, with a mean blood pressure of 152 ± 19/86 ± 12 mmHg, antihypertensive treatment was prescribed for 57% of patients. After adjustment for age, sex and education, treated hypertensive patients had better cognitive function than untreated patients (MMSE score 23.9 ± 5.6/30 versus 22.7 ± 6.4/30, P < 0.001, CEP score 49.1 ± 24.9/100 versus 45.4 ± 23.7/100, P < 0.001). This association was observed independently of the cognitive status, both in normal, MCI, AD and VaD hypertensive patients. The odds ratio (OR) for AD was 0.58 [95% confidence interval (CI) 0.42–0.81] in treated compared with untreated hypertensive patients. In patients on antihypertensive therapy, higher cognitive function was observed in patients using calcium antagonists compared with those without calcium antagonists (CEP 52.9 ± 24.6/100 versus 46.4 ± 23.4/100, P < 0.001; OR for AD 0.67; 95% CI 0.45–0.99), independently of blood pressure level. Conclusions Antihypertensive therapy was associated with a lower risk of cognitive impairment and AD. In particular, the use of calcium antagonists was associated with a decreased risk of cognitive impairment and AD independently of the blood pressure level, suggesting a specific neuroprotective effect of these antihypertensive agents.

Effects of timolol and hydrochlorothiazide on blood-pressure and plasma renin activity. Double-blind factorial trial.

The effects of timolol (10 mg thrice daily) and hydrochlorothiazide (50 mg/day) have been compared in a double-blind factorial trial in 20 patients with essential hypertension. There were four randomised test phases of 8 weeks each during which patients received timolol alone, hydrochlorothiazide alone, timolol plus hydrochlorothiazide, and no treatment (placebo). Blood-pressure was measured weekly, alternately at the outpatient clinic and at the patients home. Supine mean arterial pressure fell from 119 mm Hg in the placebo phase to 110 mm Hg in the hydrochlorothiazide phase, 106 mm Hg in the timolol phase, and 101 mm Hg in the combined timolol plus hydrochlorothiazide phase. Factorial analysis revealed that these effects of the two drugs were additive without any potentiation or antagonism. Mean plasma-renin activity (P.R.A.) was 5-02 ng/ml/3 h in the placebo phase falling to 1-79 in the timolol phase and rising to 9-54 in the diuretic phase, but remaining unchanged in the combined treatment phase (5-40 ng/ml/3 h). The data suggest that the hypotensive action of timolol is not dependent on the concomitant fall in P.R.A. The methods described provide a valuable tool for quantitating the effects of a given drug, and hence a valid basis for objective comparison.

Enalapril and Atenolol in Essential Hypertension: Attenuation of Hypotensive Effects in Combination

In 16 patients with essential hypertension the effects of enalapril 20 mg once daily were compared with those of atenolol 50 mg once daily, with the two drugs in combination and with placebo using a double-blind cross-over design with allocation of treatment order by randomised Latin squares. For each patient there were four treatment phases, each of four weeks duration, which together comprised a 2 x 2 factorial experiment. All blood pressure parameters were reduced in the three active treatment phases compared to placebo (p less than 0.001). Supine blood pressures (group means) were 171/97 (placebo), 147/85 (enalapril), 154/84 (atenolol) and 144/78 (enalapril plus atenolol) (S.E.M. +/- 2/+/- 1-ANOVA), and standing blood pressures were 170/105 (placebo), 146/92 (enalapril), 154/92 (atenolol) and 147/86 (enalapril plus atenolol) (S.E.M. +/- 3/+/- 1). In the combination phase there was an additional hypotensive response but the potential fully additive effects of the two agents were attenuated by 30-50%. The mechanism of the attenuated hypotensive effect of the combined agents has not been determined. Plasma atrial natriuretic peptide (ANP) concentration was doubled in the presence of atenolol (P less than 0.01) suggesting that ANP may contribute to the hypotensive effect of the beta-blocker.

THE EFFECTS OF INDOMETHACIN IN TREATED HYPERTENSIVE PATIENTS

1. Twelve treated hypertensive patients (ages 58–71 years) who had also been treated for joint disease participated in a randomized double‐blind crossover placebo‐controlled study to investigate the effects of indomethacin (25 mg three times daily) on blood pressure and biochemical parameters over a 6‐week period.

Low-dose diuretic and/or dietary sodium restriction when blood pressure is resistant to ACE inhibitor.

AIM To compare the efficacy of indapamide (1.25 mg daily) and low-salt diet (<100 mmol/day) separately and in combination in essential hypertensive patients with inadequate BP response to perindopril. DESIGN AND METHODS Randomized double-blind, double-dummy, crossover design. The randomized treatments were indapamide 1.25 mg daily, sodium chloride 80 mmol daily, the combination of indapamide and sodium chloride and placebo. All patients received perindopril 4 mg daily and maintained a low-sodium diet. RESULTS 19 patients entered and 17 completed the study. Prior to randomization, average clinic sitting blood pressure was 162/101 mm Hg and average 24-h urine sodium excretion was 157 mmol/day. Compared to the phase in which patients received perindopril with sodium repletion, clinic and ambulatory BPs were significantly reduced (p<0.01) in all the other phases. Indapamide had a greater effect on BP than dietary sodium restriction, and in combination their effects were additive. The effect of indapamide on ambulatory BP persisted throughout 24 h, but the effect of the low-salt diet was predominantly observed during waking hours. CONCLUSIONS In hypertensives with BP resistant to the angiotensin converting enzyme (ACE) inhibitor perindopril, the diuretic indapamide had greater additional efficacy and longer duration of action than dietary sodium restriction. In combination they had additive effects on BP.

Felodipine, Metoprolol and Their Combination Compared with Placebo in Isolated Systolic Hypertension in the Elderly

This study compared with placebo the efficacy and tolerability of optimised doses of felodipine 5-20 mg daily, metoprolol 50-200 mg daily and their combination in subjects 60 years or over with isolated systolic hypertension. The study employed a randomised double-blind crossover design with allocation of treatment order within subjects by Latin squares. For each subject, after a single-blind run-in placebo phase, there were four randomised treatment phases each of six weeks duration, with a dose titration step at three weeks if necessary. Twenty-eight subjects entered the randomised phases of the study and twenty-one completed all four phases--13 male, 8 female (ages: median 71, range 59-85 years). At the end of both the felodipine and metoprolol phases systolic and diastolic pressure were reduced at 2 hours postdose compared with the placebo phase (p < 0.001), the blood pressure reduction with felodipine (-40/-20 mmHg) being greater than that with metoprolol (-15/-9 mmHg) (p < 0.01). Immediately predose (12 hours postdose) there was a persisting reduction of supine systolic blood pressure (-17 mmHg) with felodipine (p < 0.001), but there was no significant effect of metoprolol. At both measurement times the two drugs when in combination had an additive effect on blood pressure. There was a 20% increase in reported symptoms during each of the active treatment phases. Four subjects withdrew during the randomised phases because of probable drug-related adverse events and six subjects required dosage reductions during the felodipine or combination phases.(ABSTRACT TRUNCATED AT 250 WORDS)

Mono- and Combination Therapy with Felodipine or Enalapril in Elderly Patients with Systolic Hypertension

Using a randomised double-blind crossover design with Latin square allocation of treatments in 20 subjects (7 male, 13 female-ages: 61-87 years) with systolic hypertension, we investigated the efficacy and tolerability of once daily felodipine (extended release) 5-20 mg, enalapril 5-20 mg and their combination compared with placebo in four treatment phases each of 6 weeks duration. During each phase, doses were titrated to achieve a predose clinic supine systolic blood pressure of 140 mmHg or to a predetermined maximum dose. In both the felodipine and combination phases, predose supine and standing systolic and diastolic pressures were significantly reduced compared with the placebo phase (decrease in supine pressure: -13/-5 and -18/-7, respectively). Only predose supine diastolic pressure was significantly reduced (-3 mmHg) compared to placebo in the enalapril phase. In combination the effects of the two drugs on predose blood pressure were additive. There was a 40-60% increase in reported symptoms in the felodipine and combination phases compared with the placebo and enalapril phases. Thus, in elderly subjects with systolic hypertension, felodipine effectively reduces blood pressure throughout the dose interval but with vasodilator adverse effects. In contrast, enalapril is well tolerated but is less effective in reducing blood pressure throughout the whole dose interval.

Diltiazem and atenolol in essential hypertension : additivity of effects on blood pressure and cardiac conduction with combination therapy

In 15 patients with mild to moderate essential hypertension, the effects of diltiazem (120 mg twice daily) were compared with those of atenolol (50 mg once daily), the two drugs in combination, and placebo in a randomized double-blind cross-over study with treatment phases of 4 weeks duration. Blood pressure was reduced in the active treatment phases (supine blood pressure: diltiazem, 172/92 mmHg; atenolol, 172/92 mmHg; diltiazem plus atenolol, 164/88 mmHg; pooled estimate of s.e.m. by analysis of variance = 3/1) compared with placebo (180/101 mmHg). Factorial analysis confirmed fully additive antihypertensive effects of the drugs in combination. The time interval from the beginning of the P wave to the beginning of the QRS complex (P-R interval) was longer during combination therapy (0.184s) compared with either diltiazem (0.175s) or atenolol (0.174s) alone, or placebo (0.164s); s.e.m. by analysis of variance = 0.003. No clinically significant conduction disturbances occurred. Plasma atrial natriuretic peptide was elevated by atenolol but not diltiazem. Thus, in subjects with uncomplicated essential hypertension, diltiazem and atenolol had equal antihypertensive efficacy when used alone, and fully additive effects in combination, on both blood pressure and cardiac conduction.

Effect of Indomethacin on Blood Pressure Control during Treatment with Nitrendipine

This study tested the hypothesis that treatment with a nonsteroidal anti-inflammatory drug will not alter the hypotensive effect of a dihydropyridine calcium channel antagonist. Fifteen essential hypertensives (ages 58-80 years) had a supine diastolic blood pressure (DBP) < 100 mmHg after 4 weeks monotherapy with nitrendipine 5-20 mg twice daily. They entered a double-blind randomised crossover study in which the addition of indomethacin 25 mg three times daily was compared with placebo in treatment phases each of 4 weeks duration. Subjects were seen weekly and measurements in the last 2 weeks of each phase were compared. Supine blood pressure (mean +/- SE) was higher in the indomethacin phase (158 +/- 4/80 +/- 2) than in the placebo phase (154 +/- 4/76 +/- 3) (p < 0.01 for DBP). In 6/15 (40%) of subjects the increase in supine diastolic blood pressure with indomethacin was > 5 mmHg. Plasma urea was also increased in the indomethacin phase: 7.6 +/- 0.6 mmol/l compared with placebo: 6.3 +/- 0.5 mmol/l (p < 0.001). The study has demonstrated that concurrent treatment with the NSAID indomethacin impairs the blood pressure lowering effect of the dihydropyridine calcium channel antagonist nitrendipine. This increase in blood pressure with indomethacin in subjects treated with nitrendipine may represent either an independent pressor effect of indomethacin or a reduced vasodilator prostanoid contribution to the hypotensive effect of nitrendipine. This blood pressure increase may be sufficient to interfere significantly with clinical blood pressure control in some subjects.