Cardiovascular safety of sublingual apomorphine in patients on stable doses of oral antihypertensive agents and nitrates.

Sublingual (SL) apomorphine (2 to 6 mg) has been shown to be effective for treatment of male erectile dysfunction. Many patients with erectile dysfunction are also being treated for systemic hypertension and/or cardiovascular disease. In a double-blind, randomized, placebo-controlled, crossover trial, SL apomorphine 5 mg and placebo were administered on alternate days to 162 men who were on long-term therapy (> or =4 weeks) with angiotensin-converting enzyme inhibitors, beta blockers, diuretics, calcium channel blockers, alpha(1) blockers, or short- or long-acting nitrates. Blood pressure and heart rate were measured before and after dosing; cardiac rhythm was recorded by 4-hour Holter monitoring. The only potentially clinically significant interactions between SL apomorphine and the antihypertensive agents or short-acting nitrates were greater orthostatic decreases in systolic blood pressure in the alpha-blocker and calcium channel blocker groups (-10 and -6 mm Hg vs placebo, respectively). Administration of SL apomorphine after dosing with long-acting nitrates resulted in significant decreases in blood pressure when patients were standing (mean systolic change, -5 to -9 mm Hg 30 to 60 minutes postdose, p <0.05; mean diastolic change, -3 to -4 mm Hg 50 to 60 minutes postdose, p <0.05). The most common adverse events with SL apomorphine were dizziness, nausea, and headache. Syncope occurred in 1 patient in the beta-blocker group; symptomatic hypotension occurred in 2 patients each in the short- and long-acting nitrate groups. Thus, in patients receiving common antihypertensive agents and short-acting nitrates, as well as in most patients receiving long-acting nitrates, SL apomorphine at higher than recommended doses produced no clinically significant changes in heart rate or blood pressure greater than changes seen with SL apomorphine alone.

Effects of candesartan cilexetil in patients with systemic hypertension. Candesartan Cilexetil Study Investigators.

The objectives of this double-blind, multicenter, randomized, parallel-arm, placebo-controlled study were to evaluate the dose-related efficacy, tolerability, and safety of candesartan cilexetil, a potent, AT1 selective, long-acting angiotensin II receptor blocker, in 365 adult patients with systemic hypertension and mean sitting diastolic blood pressure (BP) of 95 to 114 mm Hg. Patients received either placebo or candesartan cilexetil 2, 4, 8, 16, or 32 mg once daily for 8 weeks. All doses of candesartan cilexetil reduced trough (24 hours after treatment) sitting diastolic and systolic BP significantly compared with placebo (p < 0.005). A significant (p < or = 0.0001) dose response was evident, with greater decreases in BP at higher doses. Mean changes in BP were -10.7/-7.8 mm Hg and -12.6/-10.2 mm Hg in the 16- and 32-mg groups, respectively, versus -0.3/-2.6 mm Hg in the placebo group. The 16- and 32-mg doses were consistently significantly superior to placebo in antihypertensive effect with regard to all BP measurements, including peak (6 hours after treatment), trough, sitting, and standing measurements of diastolic and systolic BP. Responder rates (trough sitting diastolic BP < 90 or > or = 10 mm Hg BP decrease) were 54% and 64% for the 16- and 32-mg groups, respectively. Tolerability and safety profiles were similar to placebo at all doses. In conclusion, candesartan cilexetil administered once daily effectively reduces BP in a dose-related manner while maintaining safety and tolerability; doses of 16 and 32 mg are most effective for treatment of hypertension.

Blood pressure reduction and tolerability of felodipine ER in older and younger hypertensive patients. The Felodipine ER in the Elderly versus Young Working Group.

OBJECTIVE: To evaluate and compare blood pressure reduction and tolerability of felodipine ER (extended-release), in younger and older patients. DESIGN: A multicenter, double-blind, placebo-controlled, parallel group study. SETTING: Nineteen study sites; approximately half of the sites were at academic medical centers and half were in private primary care practices. Patients were non-hospitalized and free-living. PATIENTS: There were 243 younger (< or = 61 years) and older (> or = 64 years) patients, age range 26 to 83, with sitting diastolic blood pressure (SDBP) of 95-115 mm Hg (higher stage 1 to lower stage 3) on placebo. Patients volunteered for the study. INTERVENTIONS: After a 2 to 4 week, single-blind, placebo baseline period, patients with SDBP of 95-115 mm Hg were randomized to treatment with felodipine ER 2.5 mg qd or placebo at a ratio of 3:1, felodipine:placebo. The dose of felodipine ER was increased to 5 mg qd after 3 weeks and to 10 mg qd after 6 weeks if the SDBP was greater than 90 mm Hg. MEASUREMENTS: The main outcome measure was change in SDBP. Secondary Outcome measures were change in sitting systolic blood pressure (SSBP) and percent of responders, defined as SDBP less than 90 mm Hg or a > or = 10 mm Hg reduction. Other measurements included heart rate, weight, routine laboratory values, and self-reported adverse events. RESULTS: By Week 9, felodipine ER reduced blood pressure in the older subjects (n = 77) by 13/12 mm Hg; in the younger patients, (n = 102), the reduction was 12/8 mm Hg. All reductions were significantly different from placebo (P < or = .003). The reduction in diastolic, but not systolic, blood pressure was significantly greater in the older than in the younger patients (P = .004 and P = .188, respectively). The percentage of patients reporting a clinical adverse experience was similar for felodipine ER and placebo treatment groups. The incidence of side effects was similar between old and young patients. Discontinuation occurred in 9% of the felodipine-treated patients and 19% of the placebo-treated patients. Older patients required lower doses of felodipine ER to achieve equivalent blood pressure control. CONCLUSIONS: Felodipine ER is effective in lowering blood pressure and is well tolerated in both young and old people.

Stimulatory as well as inhibitory effects of ethinyloestradiol on the metabolic clearances of propranolol in young women.

1. The metabolism of a single 80 mg oral dose of propranolol was determined in nine young women before and after administration of ethinyloestradiol alone (EE2) or in combination with norethindrone (OC). 2. Whereas the total clearance of propranolol (2713 +/- 404 ml min-1 (mean +/- s.e.mean)) was not significantly altered by either EE2 (3365 +/- 347 ml min-1) or the combined OC (2905 +/- 345 ml min-1), significant changes in all three primary metabolic pathways were observed. 3. The clearance through side-chain oxidation decreased from 345 +/- 55 ml min-1 to 262 +/- 33 ml min-1 after EE2 (P < 0.05). A similar reduction of cytochrome P450 metabolism by EE2 has been observed for other drugs. 4. The clearance through glucuronidation increased from 364 +/- 61 ml min-1 to 625 +/- 117 ml min-1 after EE2 (P < 0.01). Similar stimulation of glucuronic acid conjugation by EE2 has also been observed for other drugs. 5. The clearance through ring oxidation increased from 697 +/- 109 ml min-1 to 1280 +/- 162 ml min-1 after EE2 (P < 0.01). This observation appears to be a novel finding with EE2 and cytochrome P450 metabolism. 6. The treatment with OC produced changes in propranolol's metabolic clearances which were qualitatively similar to those generated by EE2.

Treatment of mild hypertension with low once-daily doses of a sustained-release capsule formulation of verapamil.

The efficacy and safety of a low dose (120 mg) of a sustained-release capsule formulation of verapamil administered once daily in the treatment of 42 patients with mild hypertension were assessed in this clinical trial. After a 4-week placebo washout period (baseline), patients with diastolic clinic blood pressures of 91 to 100 mm Hg inclusive were treated for 4 weeks with once-daily verapamil sustained-release 120 mg capsules. Clinic blood pressure was measured and 24-hour ambulatory blood pressure monitoring was performed at the end of both the baseline and the 4-week treatment periods. Twenty-four hour, day, and night systolic and diastolic ambulatory blood pressure were significantly (P < 0.01) reduced in the entire study population (24-hour, -5/-4 mm Hg; day, -6/-4 mm Hg; night, -4/-3 mm Hg). On the basis of mean daytime (6 AM to 6 PM) ambulatory diastolic blood pressure, patients were stratified into subgroups of patients with confirmed (> 85 mm Hg) and unconfirmed mild hypertension (< or = 85 mm Hg). The magnitude of the mean change in systolic and diastolic blood pressure was greater in the group of patients with confirmed mild hypertension than the group with unconfirmed hypertension. The incidence of adverse experiences was low in frequency and events were of mild severity; quality of life scores improved (P = 0.02). Low daily doses (120 mg) of verapamil sustained-release capsules provide a well-tolerated and sustained antihypertensive effect over 24 hours in patients with mild hypertension.

Efficacy and tolerability of extended-release felodipine and extended-release nifedipine in patients with mild-to-moderate essential hypertension.

The efficacy and tolerability of extended-release felodipine (felodipine-ER) and nifedipine gastrointestinal therapeutic system (nifedipine GITS) were compared in a multicenter, prospective, open-label clinical trial of 277 patients with mild-to-moderate uncomplicated essential hypertension (sitting diastolic blood pressure [SiDBP] > or = 95 and < or = 115 mm Hg). After a 3-week washout period, patients were randomized to receive felodipine-ER (5 mg once daily) or nifedipine GITS (30 mg once daily); during a subsequent 6-week titration phase, the once-daily felodipine-ER dose could be increased to 10 mg and the nifedipine GITS dose to 60 or 90 mg in an attempt to achieve adequate blood pressure response (SiDBP < or = 90 mm Hg, or < 100 mm Hg with a > 10-mm Hg reduction from baseline, as measured 24 hours after dosing [trough]). At the end of titration, the mean daily doses of felodipine-ER and nifedipine GITS were 8 and 50 mg, respectively. Mean changes in sitting systolic blood pressure (SiSBP)/SiDBP were -14/-12 and -16/-13 mm Hg, respectively. All reductions were significant when compared with baseline (P < 0.01), but there were no significant differences between treatment groups. Adequate blood pressure response occurred in 77% of the felodipine-ER group and 80% of the nifedipine GITS group; this difference was not significant. Blood pressure changes were similar among sex and race subgroups. A higher percentage of older patients (> 55 years of age) than younger patients (< or = 55 years of age) reached goal SiDBP with both drugs. Patients with adequate SiDBP response continued receiving their assigned medication for an additional 6-week maintenance period. Reductions in SiDBP and SiSBP from baseline continued to be significant in both treatment groups. No clinically important changes in heart rate were noted. A total of 28 patients (15 in the felodipine-ER group and 13 in the nifedipine GITS group) withdrew from the study because of inadequate blood pressure response. At least one adverse experience occurred in 55% of the felodipine-ER group and 63% of the nifedipine GITS group, prompting withdrawal of 14 patients (10%) and 16 patients (11%), respectively. Headache and edema were the most common adverse experiences. The incidence and pattern of adverse experiences did not differ significantly between treatments. The results of this study demonstrate that once-daily felodipine-ER and nifedipine GITS are similarly highly effective and generally well tolerated in patients with essential hypertension.

The influence of gender and sex steroid hormones on the plasma binding of propranolol enantiomers.

1. Plasma binding of tritium-labelled racemic propranolol (P) was measured by equilibrium dialysis. The unbound enantiomers were separated by h.p.l.c. after chiral derivatization. The binding of (-)-P was higher than that of (+)-P. 2. Contrary to previous suggestions, a sex difference in the plasma binding of the P enantiomers (9 young women, 12 young men) was not observed. The unbound percentage of (-)-P was 9.2 +/- 1.8 (mean +/- s.d.) in women vs 9.1 +/- 1.7 in men; for (+)-P it was 10.8 +/- 1.8 vs 10.8 +/- 2.1. 3. In the nine women, the binding did not change with fluctuating plasma oestradiol concentrations during the menstrual cycle. Testosterone cypionate doubled the circulating concentrations of testosterone in eight men but had no effect on P binding. 4. Ethinyl oestradiol (50 micrograms day-1) alone or together with norethindrone (OCD) in eight of the women produced an increase in the unbound percentage of both (-)-P (11.4 +/- 2.6 vs 9.5 +/- 1.6 for control; P < 0.001) and (+)-P (13.2 +/- 2.5 vs 11.2 +/- 1.5 for control; P < 0.001). This was due to a decrease in the plasma concentrations of alpha 1-acid glycoprotein from 0.54 +/- 0.11 mg ml-1 in control to 0.37 +/- 0.08 mg ml-1 (P < 0.001) during ethinyl oestradiol treatment. 5. Enantioselectivity in the unbound fraction of P increased with increasing total binding from a (-)/(+)-ratio of 0.93 at 84% binding to a (-)/(+)-ratio of 0.78 at 94% binding (P < 0.001).

Sustained-release nicardipine in mild-to-moderate hypertension.

STUDY OBJECTIVE: To evaluate the antihypertensive effects and tolerability of a sustained release preparation of nicardipine (NIC SR), a dihydropyridine calcium channel antagonist. DESIGN AND INTERVENTIONS: After at least 1 week without receiving antihypertensive medications and 2 weeks of single-blind placebo treatment, the patients were randomized to receive in a double-blind fashion, either placebo or NIC SR 30, 45, or 60 mg twice daily at 12-h intervals for 12 weeks. Supine and standing blood pressure were measured in all patients and 24-h ambulatory blood pressure monitoring was performed in a subset of 75 patients at baseline during treatment with single-blind placebo and during the double-blind treatment period. SETTING: Academic and private hypertension research clinics. PATIENTS: Two hundred sixty-four patients with supine diastolic blood pressures of 95 to 114 mm Hg, ranging in age from 22 to 75 years and in weight from 50 to 137 kg, approximately evenly divided by gender; one third were black. RESULTS: In comparison with placebo, all doses of NIC SR significantly reduced systolic and diastolic blood pressures, with a trend toward greater effects from 45 to 60 mg twice daily than with 30 mg twice daily. At all doses, reduction of blood pressure from baseline levels was fully apparent within the first 2 weeks of therapy and was maintained throughout the remaining 10 weeks of the trial. Ambulatory blood pressure monitoring demonstrated that the antihypertensive effect was maintained throughout the dosing interval. Adverse effects were primarily extensions of pharmacologic activity (eg, pedal edema, flushing). Six percent of the placebo group and 10 percent of the combined NIC SR groups experienced at least one adverse event that was judged to be probably related to therapy. Withdrawals due to unacceptably high blood pressure totaled 5 percent of the combined NIC SR groups and 25 percent of the placebo group. CONCLUSIONS: Sustained-release nicardipine at a dose of 30 to 60 mg every 12 h provided effective and generally well-tolerated antihypertensive control throughout the day in most patients with mild-to-moderate essential hypertension.

Application of ambulatory blood pressure monitoring in differentiating between antihypertensive agents.

PURPOSE: This multicenter, double-blind, parallel group study assessed the usefulness of the ambulatory blood pressure monitoring (ABPM) technique in differentiating between the once-daily administration of the beta blockers bisoprolol (10 to 20 mg) and atenolol (50 to 100 mg) in terms of efficacy and duration of action. PATIENTS AND METHODS: The study population consisted of 659 patients with essential hypertension and an average office diastolic blood pressure (BP) between 95 and 115 mm Hg after 4 weeks of placebo treatment. Office BPs were recorded at the end of the 24-hour dosing interval (trough). ABPM was performed in 11 of the 28 institutions participating in this study in a total of 203 patients. These procedures were performed at the end of the placebo phase and again after 8 weeks of active treatment. RESULTS: With the use of conventionally measured office BPs, the two drugs significantly (p < 0.001) decreased trough systolic and diastolic BPs to a similar extent. By 24-hour monitoring, bisoprolol demonstrated a 33% greater reduction in whole-day average diastolic BP than did atenolol (11.6 +/- 0.7 mm Hg versus 8.7 +/- 0.8 mm Hg, p < 0.01). Significant treatment differences in systolic (p < 0.05) and diastolic (p < 0.01) BPs were also noted for bisoprolol compared with atenolol during the final 4 hours of the dosing interval (-13.2 +/- 1.5/-10.9 +/- 1.0 mm Hg versus -8.9 +/- 1.6/-7.3 +/- 1.1 mm Hg, respectively), and over the time period 6:00 AM to noon (-14.2 +/- 1.3/-11.5 +/- 0.9 mm Hg versus -9.9 +/- 1.4/-7.7 +/- 0.9 mm Hg). CONCLUSIONS: Whereas conventional BP measurements did not detect differences in the antihypertensive effects of the beta blockers bisoprolol and atenolol, ABPM revealed significant treatment differences in both the efficacy and duration of action of these two agents. These findings indicate the power of this technique to discriminate potentially important differences between apparently similar antihypertensive drugs.

Prospective study of the safety and financial benefit of ketoconazole as adjunctive therapy to cyclosporine after heart transplantation.

In a prospective study of the relative safety and potential benefit of concomitant ketoconazole and cyclosporine after heart transplantation, 15 transplant recipients were followed up for up to 1 year (mean, 10.7 months) after ketoconazole was added to their immunosuppressive regimen of cyclosporine, prednisone, and azathioprine, and these patients were compared with a matched cohort over the same time. There was an 88% reduction in the mean (+/- SD) dose of cyclosporine, from 394 (115) mg/day to 47 (21) mg/day (p less than 0.0005) in the ketoconazole group, compared with an insignificant change in the control group. The projected annual cost of cyclosporine was reduced by 88%, with a 72% reduction in the projected cost of immunosuppressive drugs and prophylactic antifungal therapy, from a mean of $6800 to $1862 per year per transplant recipient in the ketoconazole-treated group. Other beneficial effects found over the study period included a significant reduction in the mean and diastolic systemic arterial pressure and a significant reduction in serum cholesterol. The mean total serum cholesterol fell from 265 (44) to 204 (38) mg/dl in the ketoconazole group but did not change significantly in the control group (p less than 0.005). Low-density lipoprotein cholesterol also fell from a mean of 167 (32) mg/dl to 112 (28) mg/dl (p less than 0.005). Renal function was not significantly affected by ketoconazole when compared with the control group. Ketoconazole and other drugs of potential use in organ transplant recipients should be evaluated for financial as well as for other potential clinical benefits in the long-term management of these patients.

Diltiazem: its place in the antihypertensive armamentarium.

In 15 randomized, double-blind studies with blood pressure measured at the end of the dosing interval, diltiazem sustained-release or conventional tablets were found to be equal in efficacy to hydrochlorothiazide, beta-blockers, angiotensin-converting enzyme inhibitors, and other calcium-channel antagonists. The total number of patients with adverse effects and those who drop out due to adverse effects are similar for diltiazem and the other drugs. Combination therapy with diltiazem and captopril showed additive effects, and combination of diltiazem with hydrochlorothiazide or atenolol showed additional, but perhaps less than additive, effects. Six studies in older and younger patients have shown no overall effect of age on the antihypertensive effect of diltiazem. Two studies showed no difference in mean antihypertensive response between black and non-black patients. In contrast to diuretics and beta-blockers, diltiazem does not have adverse metabolic effects on electrolytes, carbohydrate metabolism, and lipid metabolism. Diltiazem is an excellent antianginal agent. It has been shown in one study to decrease proteinuria as effectively as lisinopril, and it may have renal protective effects. The antihypertensive efficacy of diltiazem as monotherapy is equal to that of all other antihypertensive classes, and it is tolerated as well or better than most other antihypertensive drugs. Diltiazem is particularly indicated in patients with hypertension and concurrent angina pectoris, diabetes, hyperlipidemias, and, perhaps, chronic renal disease.

Relationship between age and the cardiovascular response to meals.

In 82 healthy normotensive and hypertensive subjects aged 19-79, blood pressure and heart rate were measured for 1 hour before and 2 hours after a meal. Mean blood pressure decreased from 147/93 to 139/83 mmHg supine and from 148/101 to 142/94 mmHg standing (all p less than .001). Older subjects had higher premeal blood pressures. There were significant correlations between age and the reductions in supine systolic and diastolic blood pressures and standing systolic blood pressure, i.e., older patients had greater reductions. However, after statistical correction for premeal blood pressure, there was no longer any significant relationship between age and the cardiovascular response to meals. The greater blood pressure reduction after meals in older patients may be due to decreased baroreflex sensitivity in association with higher arterial pressures. The changes in blood pressure due to meals may confound the diagnosis of hypertension and interfere with the interpretation of the response to antihypertensive treatment.

Clinical review of histamine2 receptor antagonists.

Histamine2 receptor antagonists are beneficial in treating gastric and duodenal ulcers, gastroesophageal reflux, and hypersecretory states. Histamine2 receptor antagonists are helpful for the prevention of stress ulceration and recurrence of gastric and duodenal ulcer. Four histamine2 blockers are approved for clinical use: cimetidine, famotidine, ranitidine, and nizatidine. This review compares these agents in three areas: efficacy, adverse drug reactions, and drug interactions. Although limited published data exist for famotidine and nizatidine, both are as effective as the better-studied ranitidine and cimetidine when administered appropriately. Subtle differences exist among the four agents in the areas of drug interactions and adverse effects. Individual practitioners may decide if these differences are important enough to affect drug choice.

Nicardipine and hydrochlorothiazide in essential hypertension.

Nicardipine is an investigational dihydropyridine calcium channel blocking agent. One hundred fifty-one patients with hypertension received either 30 mg nicardipine t.i.d. or 25 mg hydrochlorothiazide b.i.d. in a double-blind, randomized, multicenter trial. After 4 weeks of therapy and at the end of the dosing interval, nicardipine reduced arterial pressure by 10/6 mm Hg and 12/6 mm Hg in the supine and standing positions, respectively (all p less than 0.01). In the hydrochlorothiazide group, the reductions were 12/6 mm Hg and 14/6 mm Hg, respectively (all p less than 0.01). The maximum reduction in blood pressure of 16/14 mm Hg supine and 20/15 mm Hg standing occurred within 1 hour after administration of nicardipine. The mean reduction in the hydrochlorothiazide group after 1 hour was 14/11 mm Hg supine and 16/12 mm Hg standing. Neither drug affected autonomic reflexes associated with maximum exercise. Nicardipine increased urinary sodium excretion during the 4-hour period after the first dose. Adverse effects of nicardipine were primarily extensions of its vasodilator effect and included flushing, headache, and edema.