Antihypertensive effects of a new sustained-release formulation of nifedipine

The blood pressure response to a new sustained-release formulation of nifedipine was evaluated in an 8-week, double-blind, placebo-controlled study. Twenty-nine patients with mild essential hypertension were randomized to receive placebo (N = 9), 30 mg nifedipine (N = 10), or 60 mg nifedipine (N = 10). During treatment, 30-mg and 60-mg doses of nifedipine administered once daily decreased office blood pressures from 137/98 +/- 8/2 mm Hg and 141/98 +/- 15/2 mm Hg at baseline, respectively, to 126/89 +/- 9/7 mm Hg and 126/86 +/- 6/7 mm Hg (P less than .005). Noninvasive automatic ambulatory blood pressure monitoring demonstrated a marginally significant (P less than .10) reduction in the mean 24-hour blood pressure of 2/6 +/- 8/8 mm Hg and 5/6 +/- 9/9 mm Hg for patients taking 30 mg and 60 mg nifedipine once daily, respectively. Diastolic blood pressure load (the percentage of ambulatory diastolic blood pressure readings greater than 90 mm Hg) during 24 hours was decreased by 41% and 35%, with 30 mg and 60 mg nifedipine administered once daily, respectively. No significant dose response to nifedipine at these dose levels was observed. Although the once-daily formulation of nifedipine achieved effective control of office blood pressure, similar control was not observed in awake and 24-hour periods in all patients.     

Beneficial effects of the calcium antagonist PN 200-110 in patients with congestive heart failure

We studied the acute hemodynamic effects of PN 200-110, a newly available calcium antagonist, in 12 patients with severe congestive heart failure. Measurements of cardiac performance were obtained by a right heart catheter before and after administration of 5 and 15 mg of PN. Peak drug effects occurred 1-2 h following the administration of PN 200-110 and were dose related. The 15-mg dose reduced mean arterial pressure (MAP) from 90 +/- 11 to 75 +/- 6 mm Hg (mean +/- SD) (p less than 0.001) and decreased systemic vascular resistance (SVR) from 1,740 +/- 500 to 995 +/- 300 dynes X s X cm-5 (p less than 0.01). Stroke volume index (SVI) increased from 26 +/- 7 to 36 +/- 10 ml/m2 (p less than 0.001), and cardiac index (CI) rose from 2.1 +/- .3 to 2.8 +/- .6 L/m2 (p less than 0.01). Pulmonary arterial wedge pressure (PAW) changed insignificantly. Seven patients performed graded supine exercise at identical workloads before and after treatment. When peak exercise values were compared, the addition of PN 200-110 further reduced SVR from 1,282 +/- 461 to 936 +/- 356 dynes X s X cm-5 (p less than 0.01) and increased CI from 3.3 +/- 1.1 to 4.3 +/- 1.3 L/m2 (p less than 0.01). Only minor, self-limiting side effects were noticed during acute administration. Of the seven patients discharged on PN 200-110 and followed for at least 6 months, six reported substantial relief of symptoms.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute haemodynamic effects of ibopamine in patients with severe congestive heart failure.

Ten patients with congestive heart failure (CHF), in III and IV NYHA Class, were treated orally with a single dose of ibopamine ranging from 1.2-3.3 mg/kg, and were studied using the Swan-Ganz catheter and thermodilution technique. Cardiac index (CI) and stroke volume index (SVI) were increased, and mean pulmonary pressure (PAP), systemic vascular resistances (SVR) were lowered. Ibopamine increased CI (+33%) and SVI (+26%), and decreased PAP (-17%) and SVR (-24%). All changes were statistically significant. The maximum haemodynamic effect occurred 180 min after ibopamine administration. Blood pressure and heart rate were unaffected. Tolerability was good. This study shows that ibopamine when orally administered to human subjects improves cardiac performance and further investigations on its use as a therapeutic agent in the long term treatment of CHF are recommended.     

Acute neurohormonal and hemodynamic response to a new peak III phosphodiesterase inhibitor (ICI 153,110) in patients with chronic heart failure.

Peak III phosphodiesterase (PDE) inhibitors have combined positive inotropic and vasodilator effects. We studied 10 patients with chronic heart failure during and after infusion of intravenous (i.v.) ICI 153,110, an investigational peak III PDE inhibitor. Maximum hemodynamic response for the group occurred after cessation of infusion at a lower plasma drug concentration. At maximum hemodynamic response, cardiac index (CI) increased (2.4 +/- 0.5 vs. 3.2 +/- 0.37 L/min/m2, p less than 0.05) with a decrease in mean arterial pressure (MAP 91 +/- 5 vs. 80 +/- 3 mm Hg, p less than 0.05), pulmonary capillary wedge pressure (PCWP 25 +/- 2 vs. 17 +/- 3.1 mm Hg, p less than 0.01), systemic vascular resistance (SVR 1,422 +/- 106 vs. 983 +/- 97 dynes.s.cm-5, p less than 0.05) and pulmonary vascular resistance (PVR 227 +/- 39 vs. 16 +/- 31 dynes.s.cm-5, p less than 0.05). During the infusion, plasma renin activity (PRA) decreased from 6.34 +/- 2.53 to 3.6 +/- 3 ng/ml/h (NS). The five patients with high baseline PRA had a significant decrease (11.2 +/- 2.5 vs. 5.4 +/- 1.67 ng/ml/h, p less than 0.01) that preceded changes in CI and SVR by 1-2 h. These data suggest that reduction in PRA may have contributed to the hemodynamic effects of this peak III PDE inhibitor.     

静脉输入消心痛治疗严重充血性心力衰竭的急性血液动力学效应

对7例严重充血性心力衰竭患者观察了静脉输入消心痛的急性血液动力学效应。以4mg/小时的速度静脉输入消心痛。结果显示,肺楔压和右心房压明显下降,肺动脉压和外周血管阻力轻度下降,心指数、每搏功指数及每搏容积指数均增加,心率和平均动脉血压无明显变化。本研究表明静脉输入消心痛以降低前负荷为主,亦有减轻后负荷作用,用于严重充血性心力衰竭可使心功能得到改善。     

Antiischemic and hemodynamic effects of intravenous isradipine, a new calcium antagonist, in coronary heart disease: a comparative double-blind cross-over study with nifedipine.

In a double-blind cross-over study, 10 patients with stable angina pectoris owing to coronary heart disease were investigated in supine position during rest and bicycle exercise for the effect of 0.4 mg of intravenous (i.v.) isradipine in comparison to 2 mg i.v. nifedipine on cardiac hemodynamics and myocardial ischemia. At rest, both drugs significantly decreased total peripheral resistance (TPR) and mean arterial blood pressure (MAP), whereas heart rate (HR) increased. The pressures and resistance of the pulmonary circulation remained uninfluenced at rest. During symptom limited-exercise, both medications reduced TPR despite an unchanged MAP. Mean pulmonary artery pressure decreased significantly after both medications, whereas right atrial pressure (RAP), pulmonary capillary wedge pressure (PCWP), and pulmonary vascular resistance (PVR) decreased significantly only after nifedipine. The improvement of mean ischemic ST-segment depression averaged 44 +/- 6% (mean +/- SEM, p less than or equal to 0.01) after nifedipine and 45 +/- 7% (p less than or equal to 0.01) after isradipine. The time until angina appeared increased after isradipine by 89 +/- 28% (p less than or equal to 0.05) and after nifedipine by 105 +/- 42% (p less than or equal to 0.01). Significant differences between the two medications appeared only for cardiac output (CO) at rest (p less than or equal to 0.05), during which state the increase after isradipine was higher than after nifedipine, and for exercise HR (p less than or equal to 0.01), during which state only nifedipine induced a significant increase in frequency. We conclude that at the chosen dosages the hemodynamic and antiischemic effects of isradipine are similar to the effects that occur after nifedipine.     

Pharmacodynamics and pharmacokinetics of nifedipine in patients with congestive heart failure

Twenty-seven cases of congestive heart failure (CHF) were treated with nifedipine (Nif) 20 mg po. Significant improvements in resting hemodynamics were found in 22 cases. The higher the basal systemic vascular resistance (SVR) and pulmonary artery end diastolic pressure (PAEDP) were, the greater the magnitudes of reduction found (r = 0.84 and 0.77, P less than 0.01, respectively). Exercise hemodynamic investigation showed that Nif led to a lowering of SVR, PAEDP and pulmonary vascular resistance (PVR), with increases in SV and concentration of 5-10 ng/ml, with a maximum being observed at the concentration of 20 ng/ml. No further vasodilation was found when the plasma concentration exceeded 20 ng/ml. No remarkable deviations from the normal ranges of Nif pharmacokinetics were found in CHF patients. The plasma norepinephrine level decreased markedly 2 and 7 h after Nif. Thus, it is concluded that oral Nif is beneficial in severe CHF patients having low cardiac output and high SVR.     

Oral nifedipine in the long-term management of severe chronic heart failure

We evaluated the hemodynamic effects of nifedipine in 10 symptomatic patients with chronic refractory heart failure due to idiopathic cardiomyopathy. Nifedipine significantly increased cardiac index (from 1.80 +/- 0.4 to 3 +/- 0.6 L/min/m2), stroke volume index (from 21 +/- 6 to 33 +/- 8 ml/beat/m2), and stroke work index (from 17.9 +/- 7 to 25.5 +/- 7 g-m/m2). The drugs also produced a significant decrease in left ventricular filling pressure (from 24.6 +/- 3 to 19 +/- 2 mm Hg), mean blood pressure (from 86 +/- 9 to 74 +/- 5 mm Hg), mean pulmonary arterial pressure (from 31.9 +/- 5 to 25.6 +/- 3 mm Hg), total systemic vascular resistance (from 2,104 +/- 329 to 1,088 +/- 249 dyn/s/cm-5), and pulmonary vascular resistance (from 200 +/- 71 to 107 +/- 50 dyn/s/cm-5). Heart rate remained unchanged. In all patients maintained on nifedipine therapy, repeat hemodynamic studies at 2 months revealed sustained effects, and all patients had symptomatic improvement of at least one New York Heart Association (NYHA) functional class. Long-term treatment was well tolerated. Forty-eight hours after discontinuation of nifedipine administration the hemodynamic benefits were lost. We conclude that nifedipine may be of value for long-term ambulatory therapy of severe chronic heart failure.     

Effect of beta-adrenergic receptor antagonism on chloralose-induced hemodynamic changes in newborn lambs.

alpha-Chloralose is an anesthetic commonly used in cardiovascular research. Using a chronically instrumented neonatal lamb model, we previously determined that chloralose has important effects on basal hemodynamics and arterial oxygen tension as compared with those of paired conscious control lambs. We wished to determine whether beta-adrenergic receptor stimulation accounted for chloralose-induced hemodynamic effects and to investigate the influence of chloralose and beta-adrenergic receptor antagonism on oxygen metabolism. In paired studies, five lambs were given chloralose intravenously (30 mg/kg i.v.) after propranolol (1 mg/kg i.v.) or saline control. The group pretreated with propranolol had reduced heart rate (HR 206 +/- 12 vs. 244 +/- 10 beats/min, p = 0.04) and cardiac output (CO 253 +/- 29 vs. 302 +/- 40 ml/min/kg, p = 0.005) 30 min after chloralose as compared with control; pretreatment with propranolol also attenuated the systemic hypertensive response to chloralose (77 +/- 8 vs. 89 +/- 5 mm Hg, p = 0.055). No difference in the response of stroke volume (SV), atrial or pulmonary arterial pressures, or pulmonary and systemic vascular resistances (PVR, SVR) were observed between treatment groups. No differences between propranolol and saline treatment groups were observed in arterial and mixed venous oxygen contents, arteriovenous (A-V) oxygen difference, oxygen extraction, or oxygen consumption; a reduction in oxygen delivery observed after propranolol as compared with saline was not altered by chloralose. We conclude that tachycardia and increase in CO induced by chloralose in lambs probably are mediated by beta-adrenergic receptor stimulation, which may be direct or indirect.(ABSTRACT TRUNCATED AT 250 WORDS)     

Depside salts from Salvia miltiorrhiza improve myocardial microperfusion in rats using laser Doppler flowmetry

Aim： To investigate the effects of depside salts from Salvia miltiorrhiza on myocardial microperfusion and systemic hemodynamics in open-chest anaesthetized Sprague-Dawley rats. Methods： Myocardial microperfusion was measured by laser Doppler flowmetry with a needle probe; cardiac output （CO） was determined using ultrasonic Doppler flowmetry. Other hemodynamic parameters, including femoral artery blood pressure, cardiac inotropy, and systemic vascular resistance （SVR） were simultaneously recorded by the PowerLab system. Results： Intravenous administration of S miltiorrhiza depside salts resulted in a significant imme- diate increase in CO and cardiac inotropy, but a fall in SVR. S miltiorrhiza depside salts （30 mg/kg and 60 mg/kg） promoted cardiac index （CI） by 12.2%±6.3% （P〈0.01 vs baseline） and 20.1%±3.5% （P〈0.01）, respectively. Myocardial microperfusion maximally increased by 6.3%±2.9% （P〈0.01） and 9.6%±4.0% （P〈0.01） for 30 mg/kg and 60 mg/kg S miltiorrhiza depside salts, respectively. Conclusion： These results indicated that S miltiorrhiza depside salts improved myocardial microperfusion, as well as CO.     

Effect of calcium channel antagonists on the cardiac vagal tone response to submaximal exercise

Reductions in cardiac vagal tone have been shown to correlate with a greater susceptibility to ventricular fibrillation. Calcium antagonists have been shown to protect against malignant arrhythmias probably as the result of direct actions on cardiac muscle. However, these drugs could also reflexively alter cardiac vagal tone as a consequence of reductions in arterial pressure. Therefore, the effects of various calcium channel antagonists on cardiac vagal tone, both at rest and during exercise, were investigated. The R-R interval was recorded in chronically instrumented mongrel dogs (n = 39) and the amplitude of the respiratory sinus arrhythmia (0.24–1.04 Hz) was calculated using time-series analysis techniques. Before exercise, verapamil (n = 17, 250 μg/kg), nifedipine (n = 5, 10 μg/kg; n = 9, 100 μg/kg), diltiazem (n = 10, 100 mg/kg), Ro 40-5967 (n = 14, 1,000 μg/kg), and magnesium sulfate (n = 10, 100 mg/kg) significantly increased heart rate, while flunarizine (n = 11, 2.5 mg/kg) and a lower dose of Ro 40-5967 (n = 5, 250 μg/kg) did not affect heart rate. During exercise, nifedipine (high dose) increased heart rate, while Ro 40-5967 (high dose) decreased heart rate. All six drugs reduced vagal tone before exercise; magnesium and nifedipine (high dose) elicited the greatest reduction, while flunarizine produced the smallest decrease. The vagal tone response to exercise was not affected by flunarizine and Ro 40-5967 (low dose), but it was accentuated by magnesium, nifedipine, and verapamil. Intermediate responses were noted for Ro-40-5967 (high dose) and diltiazem. Pronounced hemodynamic effects were noted for flunarizine, magnesium, nifedipine, and verapamil, but not for Ro 40-5967. Thus, calcium antagonists have variable hemodynamic profiles and can elicit pronounced reductions in cardiac vagal tone, presumably due to activation of the baroreceptor reflex. © 1992 Wiley-Liss, Inc.     

Inhibition of exercise-induced asthma by nifedipine: a dose-response study.

1. The effect of three single doses of nifedipine on exercise-induced asthma has been examined in 11 asthmatic subjects. 2. On four separate days patients undertook 6 min of exercise on a treadmill 30 min after taking placebo or nifedipine 10, 20 or 30 mg administered double-blind and in random order. 3. Nifedipine had no significant effect on resting FEV1 measurements. 4. Nifedipine, in doses of 10, 20 and 30 mg, inhibited exercise induced bronchoconstriction, reducing the maximum fall in FEV1 from 30.8 +/- 3.5% after placebo to 21.9 +/- 3.4% (NS), 13 +/- 3.4% (P less than 0.01) and 15 +/- 3.9% (P less than 0.01) respectively. 5. This study has shown that the protective effect of nifedipine against exercise-induced asthma is dose related with the maximum inhibitory effect being observed with a single dose of 20 mg.     

Correlation of plasma levels of nifedipine and cardiovascular effects after sublingual dosing in normal subjects

Only limited work has been reported about the relationships of cardiovascular effects and plasma concentrations of the calcium-channel blocker nifedipine. In this study, placebo and nifedipine in 10-, 20-, 30-, and 40-mg doses were administered sublingually to ten normal subjects with at least three days between dosing periods. Blood pressure and heart rate were monitored every 30 minutes for two hours, and blood samples were taken after each measurement for determination of plasma nifedipine concentration by a sensitive and specific gas chromatographic method. Systolic blood pressure fell significantly (P less than 0.05) although briefly after 10 mg, but the effect persisted with larger doses. Diastolic blood pressure fell significantly only after 30- or 40-mg dosing. Heart rate increased significantly after all doses of nifedipine with the effect lasting longer with higher doses. Systolic blood pressure measurements were significantly related to the log of the concurrently measured plasma nifedipine concentrations (r = -.82, P less than 0.001). Diastolic blood pressure was also related to log nifedipine concentration (r = -.69, P less than 0.01). Heart rate, too, was linearly related to the log of nifedipine plasma levels (r = .75, P less than 0.001). These data indicate that the hemodynamic effects observed after acute nifedipine administration may be used to estimate whether or not significant quantities of the drug are being absorbed and that the intensity of the hemodynamic effects may, therefore, serve as a bioassay to evaluate the appearance of drug in plasma in therapeutic quantities.     

Long-acting lacidipine versus short-acting nifedipine in the treatment of asymptomatic acute blood pressure increase

We compared antihypertensive efficacy and safety of a single administration of equipotent doses of lacidipine versus nifedipine in the hypertensive urgencies. Twenty-nine asymptomatic essential hypertensive patients (nine men, 20 women) with a mean age of 55.03+/-11.19 years and baseline diastolic blood pressure (DBP) of > or =120 mm Hg after resting 30 min, not taking antihypertensive drugs for the last 24 h, were randomized in a single-blind fashion to receive lacidipine, 4 mg (LCD, 15 patients) or short-acting nifedipine, 20 mg (NFD, 14 patients) in a single dose. Blood pressure (BP) and heart rate (HR) were taken every 30 min during the first 8 h and every 2 h until 24 h of follow-up. Baseline BP values were similar in the two groups (LCD, 222.5+/-32.8/124.6+/-8.4 mm Hg vs. NFD, 215.9+/-20.6/128+/-7.7 mm Hg; p = NS). Both drugs promoted a significant reduction of systolic blood pressure (SBP; 169.6+/-27.8 vs. 170.6+/-25.3 mm Hg) and diastolic blood pressure (DBP; 104.1+/-16 vs. 102.9+/-12.4 mm Hg) after 8 h. However, either SBP (165+/-27.3 vs. 190.6+/-18.2 mm Hg; p = 0.008) and DBP (99.9+/-12.3 vs. 117.2+/-11.4 mm Hg; p = 0.001) were significantly higher in the NFD group after 24-h dosing. Eleven patients in the LCD group had a decrease in BP >25% of the baseline value both 8 and 24 h after the dose. Although 10 patients showed the same response in the NFD group 8 h after the dose, only four patients maintained these values at 24 h. One patient treated with NFD had a transient cerebrovascular ischemic attack. No adverse effects were observed in the LCD group. We conclude that the long-acting calcium antagonist lacidipine was more effective than the short-acting nifedipine in both controlling BP and maintaining this BP reduction over 8 h in essential hypertensive patients with acute asymptomatic BP increase.     

Determinants of acute hemodynamic and electrophysiologic effects of verapamil in humans: role of myocardial drug uptake.

To examine the relationship between myocardial verapamil content (MVC) and acute effects in humans, coronary sinus catheterization was used in 22 patients to determine myocardial uptake of verapamil after bolus intravenous (i.v.) verapamil (4 mg) injection. Verapamil-induced effects on hemodynamic and electrophysiologic parameters were measured simultaneously and correlated with MVC per unit baseline coronary sinus blood flow (MVC:F). Myocardial uptake of verapamil was rapid: peak MVC (1.2 +/- 0.2% of injected dose) occurred at 5.4 +/- 0.4 min; at 30 min, residual MVC was 71.1 +/- 3.4% of maximum. Peak MVC:F in individual patients was inversely related to the extent of coronary artery disease (p less than 0.005) but not to left ventricular (LV) systolic function. Verapamil produced significant (p less than 0.001) early reductions in arterial pressure and systemic vascular resistance (SVR); cardiac index (CI) increased, left ventricular (LV) positive dP/dt was unchanged. Verapamil prolonged (p less than 0.01) PR and AH intervals (maximum at 12-18 min) and atrioventricular (AV) nodal effective and functional refractory periods (ERP, FRP) (maximum at 30 min). In individual patients, the extent of changes in AH intervals (r = 0.69; p less than 0.05) and LV dP/dt (r = 0.62; p less than 0.05) correlated with peak MVC:F. We conclude that after i.v. injection, verapamil uptake by the human myocardium is rapid and more extensive in patients with minor coronary artery disease. Despite the hysteresis between MVC and drug effects, MCV is a determinant of inotropic and electrophysiologic effects of verapamil.     

Effect of single and repeat doses of casopitant on the pharmacokinetics of CYP450 3A4 substrates midazolam and nifedipine

AIM

To evaluate the impact of single and repeated doses casopitant on the pharmacokinetics of single dose midazolam and nifedipine (CYP3A substrates) in healthy subjects. The effect on debrisoquine metabolism (CYP2D6 substrate) was also assessed.

METHODS

Three open-label studies were conducted in healthy subjects. In the first study subjects received single dose 50 or 100 mg oral casopitant, single dose 5 mg oral midazolam and single dose 10 mg oral debrisoquine. In the other two studies subjects received repeated doses of 10 mg (study 2), 30, or 120 mg oral casopitant and single doses of 5 mg oral midazolam (study 2) and single doses of 10 mg oral nifedipine (study 3). Plasma concentration–time data were analyzed using standard non-compartmental methods. The effect of casopitant on all probes was assessed using geometric means ratios and corresponding 90% confidence intervals (CIs).

RESULTS

The AUC(0,∞) of midazolam was increased 1.44-fold (90% CI 1.35, 1.54) and 1.52-fold (90% CI 1.41, 1.65) after co-administration with a single dose of 50 or 100 mg casopitant, respectively. Debrisoquine metabolism was unchanged. After 3 days of casopitant administration, midazolam AUC(0,∞) was increased 1.45- (90% CI 1.32, 1.59), 2.02- (90% CI 1.75, 2.32), and 2.67-fold (90% CI 2.18, 3.27) after co-administration with 10, 30 or 120 mg casopitant, respectively. After 14 days of casopitant administration, midazolam AUC(0,∞) was increased 1.51- (90% CI 1.40, 1.63) to 3.49-fold (90% CI 2.98, 4.08). After 3 days of casopitant administration, nifedipine AUC(0,∞) was increased 1.56- (90% CI 1.37, 1.78) and 1.77-fold (90% CI 1.54, 2.04) after co-administration with 30 or 120 mg casopitant, respectively. Similar increases in nifedipine exposure were observed after 14 days of casopitant administration.

CONCLUSIONS

Casopitant is a dose- and duration-dependent weak to moderate inhibitor of CYP3A.     

Drug interactions: the new phosphodiesterase inhibitor enoximone and the calcium channel blocker nifedipine in coronary surgery patients--influence on hemodynamics and plasma concentrations.

The calcium channel blocker nifedipine and the new phosphodiesterase (PDE) inhibitor enoximone are used in the treatment of cardiovascular diseases. Since both substances are acting on slow calcium channels and because systemic elimination of these two agents is dependent on oxidative drug metabolizing enzyme activity, this study was performed in order to investigate hemodynamic changes and effects on plasma levels when both substances are given simultaneously. Forty-five patients undergoing aortocoronary bypass grafting were randomly subdivided into three groups: (a) group (n = 15) received 0.3 micrograms/kg/min of nifedipine as an infusion (N patients); (b) group (n = 15) received 0.5 mg/kg of enoximone as a bolus (E patients); and (c) group (n = 15) received nifedipine and enoximone in the same dosages (E + N patients). In addition to various hemodynamic variables, plasma levels of nifedipine, enoximone, and enoximone sulfoxide were measured until the end of the operation. Injection of enoximone was followed by an increase in cardiac index and right ventricular ejection fraction, decrease in pulmonary artery pressure, pulmonary capillary pressure, and systemic vascular resistance, whereas heart rate and mean arterial pressure remained almost unchanged. These changes were comparable for E and E + N patients. Plasma concentrations of enoximone and enoximone sulfoxide were not affected by nifedipine infusion and showed a comparable course in E and E + N patients. Nifedipine plasma level dropped to values less than 15 ng/ml at the end of extracorporeal circulation in N and E + N patients. It can be concluded that enoximone improved hemodynamics even in patients pretreated with nifedipine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Development of tolerance to nifedipine in patients with stable angina pectoris.

1. The possibility of development of tolerance to the anti-ischaemic and anti-anginal effects of nifedipine during sustained administration for 2 months was studied in 15 patients with stable angina pectoris by means of repeated exercise tests on a treadmill. 2. After acute administration of nifedipine (20-30 mg) substantial anti-ischaemic and anti-anginal effects lasted for at least 4 h in all patients. 3. During sustained nifedipine treatment with a dose schedule which provided continuous anti-ischaemic effect during a day (mean daily dose 82.7 +/- 6.0 mg, range 60-120 mg) a substantial attenuation of this effect was registered. The duration of the anti-ischaemic effect was 5.4 +/- 0.3 h after acute administration, decreasing significantly to 3.6 +/- 0.4 h during sustained administration. 4. The attenuation of the nifedipine effect was not associated with worsening of the patients' condition. 5. Plasma concentrations of nifedipine and its metabolite were similar after acute administration and during sustained treatment. Protein binding of nifedipine also remained constant during the study. 6. There was marked interindividual variation in the degree of attenuation of the nifedipine effect during sustained administration. In five patients nearly complete loss of nifedipine efficacy was registered. Eight to ten days after stopping regular administration of nifedipine only partial restoration of nifedipine effect was observed. 7. We conclude that during sustained nifedipine administration tolerance to its anti-ischaemic, anti-anginal and circulatory effects develops in a substantial number of patients with stable angina pectoris.     

Rosiglitazone has no clinically significant effect on nifedipine pharmacokinetics

To examine the effects of repeat oral dosing of rosiglitazone on the pharmacokinetics of nifedipine, a prototype CYP3A4 substrate, a randomized, open-label, crossover study was performed with two treatment phases separated by a washout period of at least 14 days. Twenty-eight healthy male volunteers received either a single 20 mg oral nifedipine dose or rosiglitazone 8 mg orally once daily for 14 days with a single 20 mg oral nifedipine dose administered on day 14. Plasma nifedipine concentrations were determined over the 24-hour period following administration of the nifedipine doses. Lack of effect was defined as the demonstration that the 90% CI was contained entirely within a symmetrical 30% range either side of unity on the loge-scale. Following rosiglitazone + nifedipine administration, the area under the nifedipine concentration-time curve from time zero to infinity (AUC(0-infinity)) was 13% lower than that after administration of nifedipine alone. This difference in nifedipine AUC(0-infinity) was not deemed to be clinically significant since the 90% CI was contained within the protocol-defined 30% range (point estimate for ratio of geometric means 0.87; 90% CI: 0.79, 0.96). Rosiglitazone had no marked effect on nifedipine peak plasma concentration (point estimate: 0.99; 90% CI: 0.73, 1.34) or time to peak concentration compared with nifedipine alone. Rosiglitazone coadministration produced a small decrease in the mean nifedipine half-life (point estimate: -0.77; 90% CI: mean difference -1.29 h, -0.25 h). Both treatment regimens were well tolerated and associated with a favorable safety profile. Rosiglitazone, at the highest dose used in clinical studies, produced a small, clinically insignificant decrease in nifedipine exposure. The very small effect on nifedipine pharmacokinetics suggests that rosiglitazone is an extremely weak inducer of CYP3A4, a characteristic that distinguishes rosiglitazone from troglitazone.     

Amifostine improves hemodynamic parameters in doxorubicin-pretreated rabbits

Amifostine reduces nephrotoxicity and myelotoxicity of alkylating agents. Little is known about its role in preventing cardiotoxicity. We studied if amifostine could affect the hemodynamic parameters in doxorubicin-pretreated rabbits. The animals were divided into six groups consisting of 6 rabbits each. Group 1--doxorubicin iv 2 mg/kg of body weight 4 times every 14 days (cumulative dose 8 mg/kg); group 2--a dose of doxorubicin was 3 mg/kg (cumulative dose 12 mg/kg); groups 3 and 4--amifostine iv 30 mg/kg 15 min prior to doxorubicin 2 and 3 mg/kg, respectively, groups 5 and 6--amifostine- and physiological saline-treated controls. Two-three weeks after the last dose the animals were anesthetized and cardiac index (CI) i.e. cardiac output/body weight, and total peripheral resistance (TPR) were calculated using the method of human I(125) albumin dilution. Mean CI was 71.4 +/- 40.5 ml/min/kg in group 2, 135.8 +/- 41.2 in group 5 (p < 0.001), and 116.4 +/- 47.8 in group 6 (p < 0.001), TPR was 4.7 +/- 3.3 kPa x s/l, 1.1 +/- 1.2 (p < 0.001), and 1.9 +/- 1.1 (p < 0.001), respectively. In group 4, CI was 135.4 +/- 33.2, and TPR was 1.1 +/- 0.6. The differences in CI and TPR between groups 2 and 4 were statistically significant (p < 0.001). In conclusion, pretreatment with doxorubicin at the total dose of 12 mg/kg significantly reduced CI and increased TPR. Amifostine improved CI and TPR in doxorubicin-pretreated rabbits.