Dose finding studies with imidapril--a new ACE inhibitor.

1. We describe an approach involving a smaller, shorter study, leading onto a longer, larger study in which the antihypertensive effects of ascending doses of imidapril, a new ACE inhibitor, were investigated. Both studies were planned prospectively, assuming a clinically useful fall in BP to be 8 mm Hg (s.d. = 9). The studies included patients with mild to moderate essential hypertension (baseline sitting diastolic blood pressure (SDBP) 95-115 mm Hg). After a placebo run-in of 2-3 weeks patients received either placebo or imidapril 2.5, 5, 10 or 20 mg in the 2 week study (n = 91) or imidapril 5, 10, 20 or 40 mg in the 4 week study (n = 162). 2. The overall mean baseline SDBP was 103.4 mm Hg (s.d. 0.62) in the initial study and 101.5 mm Hg (s.d. 0.41) in the 4 week study. 3. Compared with placebo, imidapril 10, 20 and 40 mg significantly reduced SDBP. There was no significant difference between these doses, suggesting that 10 mg achieved maximal ACE inhibition in most patients. The 2.5 mg dose showed no significant effect. The 5 mg dose gave an intermediate effect. In both studies the overall incidence of adverse events was similar in the imidapril and placebo groups, and was not worrying.

Digoxin pharmacokinetics and perindopril in heart failure patients.

The influence of chronic perindopril treatment on digoxin pharmacokinetics was investigated in 10 patients with mild chronic heart failure under stable diuretic and digitalis treatment and normal renal function. Digoxin was administered at a dose of 0.125 mg/day (n = 2) or 0.250 mg/day (n = 8). The 24-hour steady-state digoxin profile was assessed before and after concomitant administration of perindopril for 1 month at doses of 2 mg once a day for the first 8 days and 4 mg once a day for the remaining 21 days. Chronic treatment with perindopril produced no significant effect on mean (+/- standard deviation) digoxin serum area under the curve for 24 hours (17.9 +/- 7.4 versus 16.3 +/- 4.4 ng/mL.h), peak digoxin concentration (1.3 +/- 0.54 versus 1.2 +/- 0.36 ng/mL), time to peak concentration (3 versus 4 hours), and apparent oral clearance of digoxin (237.7 +/- 109.6 versus 237.4 +/- 79.5 mL/min). Clinical and biologic tolerance of perindopril was good throughout the study. Chronic administration of perindopril did not alter steady-state digoxin kinetics in patients with mild chronic heart failure and normal renal function, indicating that no adaptation of the digoxin dose is required during co-prescription with perindopril in such patients.

Sustained-release verapamil and nifedipine in exercise-induced angina pectoris.

In a randomised, double-blind, crossover study of oral sustained-release verapamil 360 mg o.d. ('SR-verapamil') and oral nifedipine 20 mg t.d.s. in 19 patients with chronic stable angina pectoris, significantly greater improvement from baseline was seen with SR-verapamil than with nifedipine. Mean exercise duration was 380 +/- 108 s with SR-verapamil and 343 +/- 130 s with nifedipine (P less than 0.05); mean time to onset of angina was 326 +/- 79 s with SR-verapamil and 239 +/- 79 s with nifedipine (P less than 0.01); median time to 1 mm ST depression was 252 s (range 114-579) with SR-verapamil and 182 s (range 84-582) with nifedipine (P less than 0.01); mean ST depression at maximum exercise was 1.65 +/- 0.56 mm with SR-verapamil and 2.17 +/- 0.98 mm with nifedipine (P less than 0.05). Ambulatory ECG recordings indicated a trend in favour of SR-verapamil (median ST-time integral 0.00 [range 0-24.16] mm h-1 with SR-verapamil, 1.15 [range 0-12.50] mm h-1 with nifedipine, not significant). Median glyceryl trinitrate consumption was significantly lower (P less than 0.05) with SR-verapamil (0.21; range 0-1.25 per day) than with nifedipine (0.31; range 0-1.32 per day), but there was no significant difference between angina attack frequency. Adverse events were reported by two patients with SR-verapamil and nine with nifedipine. Once-daily sustained-release verapamil 360 mg has a significantly better effect on exercise tolerance than nifedipine 20 mg t.d.s. and also appears to be better-tolerated.

A large scale comparative study in general practice with nitroglycerin spray and tablet formulations in elderly patients with angina pectoris.

In an 8-week comparative study, 410 patients were treated with nitroglycerin spray and 387 with conventional 500 mcg sublingual tablets. Data were analysed to compare the two treatments and to compare the results in older patients (greater than or equal to 65 y) with younger patients (less than 65 y). Spray was significantly superior to tablets in terms of number of patients helped, speed of pain relief and reduction in the number of attacks from pre-study levels. The occurrence of headache was significantly less in the spray group. There was no significant difference in the number or nature of adverse events but more spray patients reported taste disturbance. The clinical advantages seen in the entire population were maintained when the two age categories were considered separately. Further, 95% of patients found the spray convenient. The authors conclude that improved efficacy together with improved stability of the spray without loss of convenience makes Nitrolingual spray an acceptable alternative to tablets irrespective of patients' age.

A study of the potential pharmacokinetic interaction of lisinopril and digoxin in normal volunteers.

1. The pharmacokinetics of single oral doses of 20 mg lisinopril and 0.25 mg digoxin, given alone and together, have been studied in 12 normal young male volunteers. 2. Peak serum conc of lisinopril occurred at 6 to 8 h and were slightly higher during combined treatment. Subsequent elimination proceeded moderately rapidly in both cases, concn declining to approx. 25% of peak values in 24 h. The AUC of lisinopril was similarly slightly higher during combined treatment. 3. After lisinopril alone, urinary elimination of unchanged lisinopril was 13% dose in 72 h, and after combined therapy was 17% dose. 4. Although there were no statistically significant differences in lisinopril pharmacokinetics during single or combined treatment, serum and urinary parameters suggest that bioavailability may be enhanced slightly during combined treatment. 5. Plasma concentrations of digoxin were slightly lower and urinary excretion slightly higher during combined treatment, the mean renal clearance being 20% higher.

Efficacy and tolerability of cefuroxime axetil in patients with upper respiratory tract infections.

A study was carried out in general practice to assess the clinical effectiveness and tolerability of the oral cephalosporin, cefuroxime axetil, in the treatment of 369 patients presenting with acute infections of the upper respiratory tract. The main diagnoses were tonsillitis, pharyngitis, sinusitis and otitis media. Patients were treated for 7 days with 1 tablet of 250 mg cefuroxime axetil twice daily. Details of fever and signs and symptoms of infection such as pain, sinus tenderness and reddening of the eardrum were recorded before and after treatment. Response was assessed by the physician on the basis of the clinical findings (the microbiological findings will be reported separately), and by patients on their satisfaction with their therapy. The results indicated an overall clinical improvement rate of 89%: all clinical parameters showed significant improvement and most patients were symptom-free when seen after treatment. Only 2 patients were classified as treatment failures and withdrawn from the study. Complete resolution of the infection was seen more often in patients with tonsillitis and pharyngitis than in those with sinusitis or otitis media. Over 80% of patients expressed their satisfaction with therapy. Adverse events reported were few, even though patients were prompted with a non-leading question, and were mainly mild in nature. The most frequently reported were diarrhoea (5%) and loose motions (3%).

Enalapril in moderate to severe hypertension: a comparison with atenolol.

Patients with moderate to severe essential hypertension (mean untreated supine blood pressure 190/112 mm Hg) received once daily enalapril 20-40 mg or atenolol 50-100 mg, supplemented if required by hydrochlorothiazide 25-100 mg, in a randomized observer-blind trial. Both regimens produced a highly significant reduction in supine and standing blood pressure. There was no significant difference in the antihypertensive effects of enalapril and atenolol when they were used as monotherapy. After hydrochlorothiazide was added to patients not achieving 'target' blood pressure, the fall in systolic pressure was significantly greater in the enalapril group than in the atenolol group, despite similar dosage of hydrochlorothiazide in the two groups. At the end of 6 months' treatment, a supine diastolic blood pressure of 90 mm Hg or below was achieved in 74% of patients on enalapril plus hydrochlorothiazide and 56% of patients on atenolol plus hydrochlorothiazide. This difference was not statistically significant. A small rise in plasma urea and creatinine was observed in the enalapril group and a small rise of urea only in the atenolol group. These changes were statistically significant but of uncertain clinical importance. This study confirms that once daily enalapril and atenolol, both alone and in combination with hydrochlorothiazide, are effective drugs in the management of moderate to severe hypertension.

Pharmacokinetics of enalapril in normal subjects and patients with renal impairment.

The pharmacokinetics of enalaprilat were studied after administration of single and multiple doses of enalapril maleate to people with normal and impaired renal function. Renal impairment was associated with higher serum concentrations of enalaprilat, longer times to peak concentrations, slower decline of serum concentrations and with reduced urinary elimination. Urinary elimination of enalaprilat was closely related to renal function. In patients with severe renal impairment (GFR values below 30 ml min-1 1.73 m-2) significantly smaller doses of enalapril maleate will be required than in patients with normal or less severely impaired renal function.

Enalapril in the treatment of hypertension associated with impaired renal function.

This pilot study was undertaken to examine the safety and efficacy of enalapril in the treatment of hypertension associated with impaired renal function. Forty-one patients with glomerular filtration rate (GFR) < or = 50 ml/min received enalapril for up 12 weeks. Blood pressure, renal function, biochemistry and haematology were monitored weekly for 4 weeks and then monthly. Blood pressure was effectively reduced within 4 weeks; this reduction was maintained for at least 12 weeks. Renal function remained stable and there was no significant sustained alteration in any biochemical or haematological parameter. Requirement for additional antihypertensive drugs was reduced during enalapril therapy. These data suggest that enalapril may have a useful role in the management of hypertension associated with renal impairment.