The influence of two types of meal on the pharmacokinetics of a modified-release formulation of nifedipine (Adalat Retard).

OBJECTIVE: The effect of two different types of meal on the absorption of a modified-release formulation of nifedipine (Adalat Retard) was studied. RESULTS: A light breakfast produced a delay in gastric emptying (indicated by the rate of paracetamol absorption) compared with the fasting state but did not alter the tmax or Cmax for nifedipine significantly. After a cooked breakfast, there was less delay in gastric emptying and again no delay in tmax for nifedipine. However, the Cmax for nifedipine was significantly higher than in the fasting state. Neither meal influenced the bioavailability of nifedipine. CONCLUSION: The results suggest that the nature of the meal has an important influence on the absorption profile of this formulation of nifedipine, probably by an effect on its dissolution. This study illustrates the importance of considering the effects of different types of meal before concluding that food does not affect the pattern of drug absorption.

Angiotensin converting enzyme inhibitors in Raynaud's phenomenon.

Patients with Raynaud's phenomenon exhibit reversible digital vasospasm, often in response to cold. While this condition often responds to simple physical measures, in severe cases, symptoms may require drug treatment. Arterial vasodilators have usually been tried in clinical practice, but recently ACE inhibitors have been tested in clinical trials of this condition. Case studies, noncomparative and placebo-controlled studies have shown mixed results of ACE inhibitor therapy in Raynaud's phenomenon. While these drugs reduced symptoms in some patients, the results were not consistent. On objective measures of improvement, such as evaluation of digital blood flow patterns, consistent statistically significant changes have also not been shown. However, well conducted dose-titration studies have not been performed in patients with Reynaud's phenomenon, and the objective methods of assessing this condition require refinement. The mode of action of ACE inhibitors is promising and these agents do not have significant adverse effects in this population. While at present ACE inhibitors cannot be recommended for the routine treatment of Reynaud's phenomenon, further controlled studies with newer ACE inhibitors, which may have improved peripheral activity, may change this view.

The influence of dose and ethnic origins on the pharmacokinetics of nifedipine.

The pharmacokinetics of nifedipine capsules was investigated in healthy young Caucasian and South Asian subjects. Both the area under the plasma concentration-time curve (AUC) and terminal half-life of nifedipine were significantly higher in South Asians compared with Caucasian subjects after single oral doses of 10 and 20 mg. The AUC and half-life values of the nitropyridine metabolite were also higher in South Asians than in Caucasian subjects. The serum protein binding of nifedipine was similar in the two groups. The pharmacokinetics were essentially linear in both Caucasian subjects (0 to 30 mg; n = 27) and South Asians (0 to 20 mg; n = 16). There was no indication of a separate subgroup of Caucasian subjects with high AUC values equivalent to the poor metabolizers reported previously. Pharmacodynamic modeling for South Asians gave estimates comparable to those previously reported in Caucasian subjects. Patients of South Asian origin may require lower doses of nifedipine.

The influence of posture on the pharmacokinetics of orally administered nifedipine.

1. Nifedipine (20 mg as capsules) and soluble paracetamol (1 g) were co-administered to eight healthy young volunteers on three separate occasions, following which in random order they stood, lay on their left side or lay on their right side for 4 h. 2. The time to maximum plasma concentration of paracetamol was significantly lower when standing or lying on the right side compared with recumbent left, indicating more rapid gastric emptying. 3. The times to maximum plasma concentrations of nifedipine and its metabolite produced at first pass were reduced when standing or lying on the right side. These postures were associated with significantly higher peak plasma concentrations and AUC values of nifedipine but not of its nitropyridine metabolite. 4. The increase in heart rate following nifedipine administration was significantly greater when lying on the right side compared with the left. 5. The data are consistent with transient saturation of first pass metabolism of nifedipine with postures which favour rapid gastric emptying. The results demonstrate the importance of defining the precise posture in studies in which pharmacokinetic and pharmacodynamic measurements are made on drugs which are absorbed rapidly and are subject to presystemic elimination.

Is xamoterol safe in chronic airflow obstruction?

We have demonstrated in a group of 10 patients with CAO that treatment with xamoterol (200 mg b.i.d. for 7 days) did not alter lung function or respiratory symptoms. These results suggest that xamoterol can be used to treat mild heart failure in patients with CAO.

The effect of acute hypoxia on right ventricular function in healthy adults.

Right ventricular ejection fraction and right ventricular volumes were derived in 12 healthy male subjects using krypton-81m equilibrium radionuclide ventriculography whilst subjects breathed 30% (high inspired oxygen) and then 8-12% oxygen in nitrogen mixture (hypoxia). 'Physiological' tricuspid valve regurgitation was identified in 7 of the subjects by Doppler echocardiography, and right ventricular peak systolic pressure was estimated during high inspired oxygen and during hypoxia. Mean right ventricular peak systolic pressure was 24.1 +/- 3.3 mmHg during high inspired oxygen and increased to 41.3 +/- 8.4 mmHg during hypoxia (P less than 0.01). Mean right ventricular ejection fraction was 0.612 +/- 0.075 during high inspired oxygen and was unchanged at 0.590 +/- 0.073 during hypoxia. There was no significant change in right ventricular end-diastolic volume or stroke volume in response to hypoxia. The systolic performance of the normal right ventricle is well-maintained during an acute rise in afterload induced by hypoxia.

Ethnic differences in the pharmacokinetics of oral nifedipine.

1. The pharmacokinetics of a single oral dose of 20 mg nifedipine, given as capsules, has been compared in five South Asian volunteers with data for 27 Caucasian volunteers. 2. The area under the plasma concentration-time curve (AUC) of nifedipine was three fold higher in South Asians (989 +/- 166 ng ml-1 h) than in Caucasians (323 +/- 116 ng ml-1 h). 3. The ratio of the AUC of nifedipine to that of the nitropyridine analogue, which is formed largely as a first pass metabolite, was significantly higher in South Asians (4.6 +/- 1.9) than in Caucasians (2.3 +/- 1.1) indicating a lower first pass metabolism in South Asians. 4. The terminal half-lives of nifedipine and the nitropyridine metabolite were significantly greater in South Asians than in Caucasians. 5. Consumption of a spicy curry diet for 3 days by Caucasians did not significantly affect the pharmacokinetics of a single oral dose of nifedipine. 6. The treatment of patients of South Asian origin with nifedipine should be initiated with lower doses than would be given to Caucasians.

Subjective and objective assessment of enalapril in primary Raynaud's phenomenon.

1. The efficacy and acceptability of enalapril were assessed in a double-blind, randomised, placebo controlled cross-over study in 21 patients with primary Raynaud's phenomenon. 2. Skin temperature was assessed by thermocouples in response to a 15 degrees C cold water challenge as an index of digital blood flow. 3. Following enalapril there were no significant changes in the number and severity of Raynaud's attacks, and no subjective benefit from treatment as measured by visual analogue scales, 5 point rating scales, and skin temperature response to cold challenge when compared with placebo. 4. Enalapril in a dose of 20 mg daily is ineffective in the management of primary Raynaud's phenomenon.

Effects of nifedipine and propranolol on whole blood platelet aggregation.

The effects of nifedipine and propranolol, alone and in combination, on collagen-induced platelet aggregation were studied in healthy volunteers using whole blood impedance aggregometry. No significant inhibition of platelet aggregation was found after the in vitro addition of propranolol, nifedipine or nifedipine vehicle or after nifedipine ex vivo. No interaction was found between in vitro propranolol and nifedipine, either in vitro or ex vivo.

The combination of slow-release nifedipine and atenolol for stable angina.

Beta-adrenoceptor antagonists, such as atenolol and the dihydropyridine calcium antagonist nifedipine, have antianginal actions that should prove complementary when the drugs are used in combination. Atenolol acts primarily by reducing myocardial oxygen demand, while the vasodilator effects of nifedipine can both reduce demand and increase oxygen supply. The slow-release tablet formulation of nifedipine (Nifedipine Retard) provides more persistent plasma concentrations than the conventional capsule formulation, which may prolong the duration of action. There is increasing evidence that the plasma nifedipine concentration is closely related to efficacy, although the absolute concentration required to improve exercise tolerance in patients with angina varies between individuals. Clinical studies indicate that for many patients the duration of action of slow-release nifedipine, particularly when added to atenolol, is less than 12 hours. This reflects the extensive but variable first-pass metabolism of nifedipine, leading to subtherapeutic trough concentrations. To achieve 24-hour symptom relief, slow-release nifedipine will often need to be given three times daily to patients with angina.

81mKr equilibrium radionuclide ventriculography for the assessment of right heart function.

Right heart 81mKr equilibrium radionuclide ventriculography was used to derive right ventricular ejection fraction (RVEF) in 12 healthy male volunteers. Anatomical lung subtraction using 99mTc-MAA perfusion scintigraphy was compared with conventional background correction and the effect of imaging projection on the techniques of image analysis evaluated. Both intra and inter observer variability were reduced by anatomical lung subtraction when compared to conventional background correction. In the right anterior oblique (RAO) projection, background corrected RVEF was lower than lung subtracted RVEF - 0.544 +/- 0.05 and 0.612 +/- 0.08 (mean +/- SD) (P less than 0.02). Lung subtracted RVEF in the anterior projection was lower than that with background correction (P less than 0.05) and lower than lung subtracted RVEF in the RAO projection (P less than 0.001). We conclude that optimal separation of right heart structures is achieved in the RAO projection and that reproducibility of the analytical technique is improved by anatomical lung subtraction.

Platelet Aggregation in Primary Raynaud's Phenomenon and the Effect of Enalapril Administration.

Platelet aggregation using a single platelet counting technique in whole blood, was determined on 18 patients with primary Raynaud's phenomenon and 17 age-matched controls. Platelet aggregation in the Raynaud's patients was also assessed during a double-blind, crossover trial to investigate the efficacy of the angiotensin converting enzyme (ACE) inhibitor, enalapril. There were no differences in platelet aggregation to collagen, arachidonic acid, ADP or PAF, or in plasma levels of beta-thromboglobulin (BTG), platelet factor 4 (PF4) or thromboxane B(2) (TxB(2)) between the Raynaud's group and the normal controls. Similarly, there were no differences in these parameters in the Raynaud's group during treatment with enalapril when compared to placebo. It is concluded that patients with primary Raynaud's phenomenon have no evidence of abnormal platelet aggregation or increased platelet activation, and that platelet aggregation is not affected by enalapril.

Slow release nifedipine plus atenolol in chronic stable angina pectoris.

1. The effects of adding slow release nifedipine in doses of 20 mg and 40 mg twice daily to atenolol therapy (50 mg twice daily) were assessed in 18 patients with chronic stable angina. 2. The addition of the lower dose of nifedipine to atenolol did not significantly alter the weekly consumption of glyceryl trinitrate or the mean number of anginal attacks as assessed by diary cards. However, 2 h after dosing there was a significant prolongation during stress testing in the time to onset of both 1 mm ST depression on the ECG (by 28%) and to angina (by 37%) compared with atenolol alone, but no benefit was apparent by 12 h after dosing. 3. At a dose of 40 mg twice daily, nifedipine significantly reduced glyceryl trinitrate consumption by 25% and the number of anginal attacks by 36%. The times to onset of ST depression and angina were increased by 37% and 55% respectively at 2 h and by 24% and 26% respectively 12 h after dosing. 4. Analysis of the frequency distribution of anginal attacks showed decreasing efficacy with time after administration of nifedipine. The overall results also suggest a relationship between efficacy and the plasma nifedipine concentration, with a mean 20% improvement in time to development of angina occurring at a nifedipine plasma concentration of approximately 30-40 ng ml-1. 5. In conclusion, the reduction of effort-related angina by nifedipine is related to its plasma concentration and the effective duration of action of the 20 mg slow release formulation is less than 12 h.

Beta-adrenoceptor antagonists plus nifedipine in the treatment of chronic stable angina pectoris.

The antianginal effects of beta-adrenoceptor antagonists are achieved by a reduction in myocardial oxygen demand. This is a rational approach to treatment in patients whose angina is caused by a fixed stenosis. However, dynamic coronary vasospasm is an important factor in patients with chronic stable angina. Nifedipine increases myocardial oxygen supply by reducing coronary vascular tone and is a logical approach to treatment in these patients. For monotherapy of angina, nifedipine is less effective than the beta-adrenoceptor antagonists, but the combination has additive effects in reducing the frequency of anginal episodes and improving exercise tolerance. Plasma concentrations of nifedipine are closely related to clinical efficacy, and the variable first-pass metabolism of the drug leads to wide interindividual differences in peak concentrations and duration of action. Increasing the size of individual doses of nifedipine carries a risk of enhanced side effects due to high peak plasma concentrations. Optimal treatment may be more appropriately achieved in some patients by a slow release formulation, but with an increased frequency of administration.

Vibrotactile sensation and response to nifedipine dose titration in primary Raynaud's phenomenon.

The clinical response to two doses of sustained-release nifedipine was assessed during a double-blind, randomized, placebo-controlled trial in 22 patients with primary Raynaud's phenomenon. Nifedipine at doses of 20 mg and 40 mg daily reduced the mean number of attacks by 40% compared with placebo with no significant differences between the two doses in the number of attacks or their severity. Unwanted effects were more common and more persistent with the higher dose of nifedipine. Fingertip vibrotactile thresholds measured at 31.5 and 125 Hz were unchanged by treatment with nifedipine. There was, however, a correlation between the pretreatment threshold at 125 Hz and the response to treatment with nifedipine, the most favorable responses occurring in patients with the lowest thresholds.

The pharmacokinetics of oral nifedipine--a population study.

1. The pharmacokinetics and metabolism of nifedipine have been studied in a population of 59 young male volunteers following administration of a 10 mg capsule. 2. The area under the plasma concentration-time curves (AUC) for nifedipine demonstrated a skewed but not a bimodal distribution (mean 154 ng ml-1 h; range 54-306 ng ml-1h). 3. Calculation of the ratio of the AUC of nifedipine to the AUC of its nitropyridine metabolite did not separate those individuals with high AUC values of nifedipine from the remainder of the population. 4. Similarly there was no evidence for bimodality in the excretion of the major urinary metabolite. Those subjects with high plasma AUC values for nifedipine excreted similar amounts to the remainder of the population. 5. In contrast to a previous study using a 20 mg oral dose, there was no evidence of polymorphism in the pharmacokinetics or metabolism of nifedipine following a single 10 mg oral dose.

The effect of nisoldipine on whole blood platelet aggregation in patients with Raynaud's phenomenon.

1. Whole blood platelet aggregation was measured by electrical impedance in 28 controls and 28 patients with primary Raynaud's phenomenon. 2. The patients were entered into a double-blind, placebo-controlled cross-over trial of the calcium antagonist nisoldipine, in which they received, in random order, three, 4 week treatments with placebo and nisoldipine (5 and 10 mg day-1). 3. Platelet aggregation responses to two concentrations (5.0 and 0.5 micrograms ml-1) of collagen were determined before treatment and at the end of each treatment phase. 4. There were no differences in aggregation response to either collagen concentration between controls and patients with primary Raynaud's phenomenon, or between placebo and active treatment phases. 5. These data do not support the suggestion that nisoldipine has a significant anti-platelet effect.

Relative efficacy of oral verapamil and digoxin alone and in combination for the treatment of patients with chronic atrial fibrillation.

1. The efficacy of verapamil alone, or in combination with digoxin, was compared with digoxin alone in eight patients with chronic atrial fibrillation in this double-blind placebo-controlled study. 2. After 2 weeks on each treatment regimen, heart rate at rest and during progressive load treadmill exercise, left ventricular function at rest and nocturnal heart rate were measured. 3. Oral verapamil alone at a dose of 80 mg three times daily, or 40 mg of verapamil three times daily in combination with 0.25 mg of digoxin daily, was superior to digoxin alone in doses associated with high serum digoxin concentrations (mean +/- SEM 1.6 +/- 0.3 micrograms/l). This superiority manifested as greater control of heart rate during work rates equivalent to regular daily activities, and was not associated with deterioration in left ventricular function or worsening nocturnal bradycardia. 4. We conclude that the treatment of choice in patients with chronic atrial fibrillation is either 80 mg of verapamil three times daily or 40 mg of verapamil three times daily in combination with digoxin.