Long-term changes in the response of conductance and resistance coronary vessels to endothelium-dependent and independent vasodilators. A double-blind placebo-controlled study of the effect of a 6-month treatment with cilazapril.

BACKGROUND: The aim of this study was to assess the effect of a 6-month treatment with the inhibitor of the angiotensin-converting enzyme cilazapril on the response of conductance and resistance vessels to endothelium-dependent and independent vasodilators, in a randomized placebo-controlled parallel group single center study. METHODS: Quantitative angiographic and Doppler flow time-averaged peak velocity measurements were performed in an artery with < 30% diameter stenosis after sequential selective intracoronary injection of papaverine (7 mg), acetylcholine (0.036, 0.36 and 3.6 microg/ml at 2 ml/min) and isosorbide dinitrate. Repeated assessment was performed after a 6-month treatment with cilazapril 20 mg/day or placebo. Thirty-four patients were enrolled in the study undergoing elective percutaneous coronary interventions for stable angina. Main outcome measures were percent differences from baseline and absolute measurements of mean coronary cross-sectional area, coronary flow time-averaged peak velocity and flow resistance in the initial study and at follow-up for the placebo and the treated group. RESULTS: No significant differences between the placebo and the treated group were observed in the modifications of cross-sectional area after acetylcholine and isosorbide dinitrate and in the response of time-averaged peak velocity to papaverine. After the maximal concentration of acetylcholine a high but statistically not significant increase in flow and a decrease in flow resistance were observed in the treated group (medians: 45% increase vs 4% increase for coronary flow, and 44% decrease vs 1% increase for flow resistance in the cilazapril and in the treated group, respectively, p = NS). CONCLUSIONS: In patients with coronary artery disease, a 6-month treatment with 20 mg of cilazapril/day did not modify the response to endothelium-independent and dependent vasodilators of epicardial arteries without any significant stenoses but induced a consistent, although not significant, increase in flow and decrease in flow resistance after acetylcholine.

Effects of recombinant human interleukin-12 on eosinophils, airway hyper-responsiveness, and the late asthmatic response.

BACKGROUND: Interleukin-12 (IL-12) is a macrophage-derived cytokine that modulates T lymphocyte responses and has the capacity to suppress allergic and eosinophilic inflammation. METHODS: We carried out a double-blind, randomised, parallel group clinical study, in which patients with mild allergic asthma were given subcutaneous recombinant human IL-12 at increasing weekly injections of 0.1, 0.25, 0.5 microg/kg (n=19), or placebo (n=20). We compared responses to inhaled allergen challenge 24 h before the first injection and 24 h after the final injection. Airways hyper-responsiveness and concentrations of peripheral blood eosinophils and sputum eosinophils were also assessed. FINDINGS: IL-12 caused a significant decrease from baseline in the main peripheral blood eosinophil count 24 h after the fourth injection compared with placebo (p=0.0001). Sputum eosinophils were also significantly decreased 24 h after allergen challenge when treated with IL-12 compared with placebo (p=0.024). IL-12 caused a non-significant trend towards improvement in airway hyper-responsiveness to histamine, but had no significant effect on the late asthmatic reaction after inhaled allergen challenge. After administration of IL-12, four of 19 patients withdrew prematurely; two with cardiac arrhythmias, one with abnormal liver function, and a single patient with severe flu-like symptoms. INTERPRETATION: We have shown that IL-12 lowers numbers of blood and sputum eosinophils, but without any significant effects on airway hyper-responsiveness or the late asthmatic reaction. This questions the role of eosinophils in mediating these reactions, and has important implications for development of new anti-inflammatory treatments.

Effects of angiotensin-converting enzyme inhibition versus beta-adrenergic blockade on aortic stiffness in essential hypertension.

We assessed the effects of 6 months of treatment with an angiotensin-converting enzyme (ACE) inhibitor (cilazapril) or a beta 1-adrenergic blocker (atenolol) on aortic stiffness in essential hypertension. Forty patients (16 women) aged 47 +/- 9 years (mean +/- SD) with baseline systolic and diastolic blood pressures of 162 +/- 15 and 105 +/- 5 mm Hg, respectively, were entered into a double-blind, parallel-group study with cilazapril, 5 mg once daily, or atenolol, 100 mg once daily. The treatment period was preceded by a 4-week placebo washout phase. Aortic elastic modulus (Ep) was determined by cine magnetic resonance imaging (MRI) and indirect brachial artery blood pressure measurements prior to and after 3 weeks and 6 months of therapy. The reductions in systolic and diastolic blood pressures from baseline to 6 months averaged -17 +/- 13 and -10 +/- 6 mm Hg, respectively, with cilazapril and -23 +/- 16 and -14 +/- 6 mm Hg with atenolol. Concomitantly, Ep of the ascending aorta decreased with cilazapril from a median of 2,234 10(3)dyn/cm2 (interquartile range, 866-3,740) to 868 10(3)dyn/cm2 (515-1,486) and with atenolol from a median of 1,611 10(3)dyn/cm2 (895-2,790) to 1,054 10(3)dyn/cm2 (616-1,860). In repeated-measurements analysis of variance, the change in Ep with time was statistically significant (p < 0.001) but the group x time interaction was not. We conclude that 6 months of treatment with either cilazapril or atenolol reduces the stiffness of the ascending aorta in essential hypertension. No statistically significant differences between the effects of the two drugs were observed. The mechanisms and clinical significance of improved aortic distensibility with antihypertensive therapy deserve further study.

Oral pharmacokinetics of bisoprolol in resting and exercising healthy volunteers.

The effects of exercise on bisoprolol oral pharmacokinetics were studied in eight healthy male volunteers in an open, randomized, three-period, crossover trial. Oral bisoprolol (20 mg) was given either at rest during 24 h or with iterative stress tests before and 2.5, 5, 10, and 24 h after dosing. Exercise tests were repeated on a third placebo period. Bisoprolol was assayed in plasma and urines, and plasma catecholamines were measured before and after stress tests, Cmax, Tmax, elimination t1/2, and renal clearance of bisoprolol were not significantly modified by exercise. AUC0-infinity significantly decreased by 7.5% (p less than 0.05) with stress test resulting in an increase in apparent oral clearance. The beta-blocking effect peaked at 2.5 h, lasted greater than 24 h, and was related to plasma levels. The exercise-induced increase in plasma norepinephrine levels was significantly augmented with bisoprolol. These results suggest that repeated exercise tests exerted only limited effects on the oral pharmacokinetics of bisoprolol.

Pharmacokinetics of intravenous and oral pentoxifylline in healthy volunteers and in cirrhotic patients.

The pharmacokinetics of pentoxifylline were investigated in six healthy volunteers and in 10 patients with alcoholic cirrhosis. After a 100 mg intravenous infusion, pentoxifylline elimination half-life was prolonged in cirrhotic patients (2.12 +/- 1.22 hours versus 0.83 +/- 0.29 hours, p less than 0.05) because of a decrease in its plasma clearance (1.44 +/- 0.46 L.hr-1.kg-1 in patients with cirrhosis versus 3.62 +/- 0.75 L.hr-1.kg-1 in volunteers, p less than 0.001). The elimination half-life of the metabolite (5-hydroxypentoxifylline) was similar to that of the parent compound. After oral administration of a 400 mg sustained-released tablet, absolute bioavailability of pentoxifylline increased in cirrhotic patients (0.71 +/- 0.24 versus 0.33 +/- 0.13, p less than 0.01). Although plasma concentrations of pentoxifylline and hydroxypentoxifylline were significantly increased in cirrhotic patients, the AUCpentoxifylline/AUChydroxypentoxifylline ratio remained unchanged in both groups after either intravenous or oral administration. These findings show that liver cirrhosis profoundly alters the pharmacokinetics of pentoxifylline. However the formation of hydroxypentoxifylline is not modified in these patients, suggesting an extrahepatic metabolism.