Biomedical subjects
Publications and source records attributed to J M Alexandre.
Cyclosporin is a nephrotoxic immunosuppressant metabolized in the liver and requiring drug monitoring. Numerous pharmacokinetic and pharmacodynamic drug interactions have occurred with this compound. Some of them are well substantiated while others are merely suspected. The major interactions must definitely be prevented of corrected, whereas the others need no more than careful drug monitoring.
A randomized, double-blind, placebo-controlled trial was conducted with 32 elderly patients (aged 75-97 years) with uncomplicated essential hypertension, to evaluate the efficacy and tolerance of enalapril, an angiotensin-converting enzyme inhibitor. It was given over an 8-week period in doses from 20 to 40 mg/day and was compared with an identical placebo. Enalapril caused a significant reduction in systolic blood pressure (SBP) and diastolic blood pressure (DBP) by the 2nd week, an effect that persisted through to the 8th week (190 +/- 16/102 +/- 7 to 151 +/- 19/85 +/- 11 mm Hg); 67% of patients had their pressures normalized (less than 160/95 mm Hg). BP was also significantly decreased by the 8th week under placebo (183 +/- 16/101 +/- 9 to 165 +/-21/91 +/- 13 mm Hg), but only 35% of patients attained a normal pressure. Heart rate did not change with treatment. Enalapril caused an increase in plasma renin activity (1.22 +/- 0.08 to 3.66 +/- 2.50 ng/ml/h), whereas aldosterone levels remained unchanged. There was a mild, significant elevation of creatinine level with enalapril but other laboratory parameters, including serum potassium, were unaltered. Two deaths occurred in the enalapril group, but were not considered to be treatment-related. The drug was otherwise well tolerated. Serum enalapril concentration was assessed in 10 patients taking 20 mg/day over an 8-day period. At equilibrium, the level was 22.3 +/- 5.0 ng/l and it correlated both with converting enzyme inhibition and with renal function. Enalapril is shown to be an effective and well-tolerated antihypertensive medication in elderly patients.
A patient with congestive heart failure and moderate renal insufficiency developed severe reversible non-oliguric renal failure while on frusemide and enalapril. Renal failure developed when enalapril was given in the presence of pronounced sodium depletion. When positive sodium balance was restored the plasma creatinine concentration began to fall while angiotensin converting enzyme inhibition remained effective and blood pressure was stable. These observations suggest that the degree of sodium depletion plays an important role in the tendency for angiotensin converting enzyme inhibitors to induce renal failure in patients with congestive heart failure and moderate renal insufficiency. Restoration of a positive sodium balance promotes the recovery of renal function after the combined administration of angiotensin converting enzyme inhibitors and diuretics.
The effects of a single oral dose of enalapril (20 mg) on blood pressure (BP), heart rate (HR) plasma renin activity (PRA) aldosterone (PA), converting enzyme inhibition (CEI) and enalaprilat (E, active metabolite) were investigated during 96 h in 3 groups of 5 hypertensive patients with (1) normal renal function (creatinine clearance: Clcr greater than 80 ml.min-1); (2) moderate chronic renal failure: 80 greater than or equal to Clcr greater than 30 ml.min-1; (3) severe chronic renal failure: 30 greater than or equal to Clcr greater than 10 ml.min-1. Results are as follows (mean +/- SEM): (Table: see text) CEmax: maximal plasma concentration; TEmax: delay corresponding to CEmax; TE 1/2: plasma elimination half-life; AUCE: area under plasma level versus time curve. a: p less than 0.01; b: p less than 0.001; versus (1). In the 3 groups, CEI reached 87-94% as early as the 3rd h; however, at 96 h, CE1 was higher in (3) than in (1) and (2): 77.6 +/- 3.3% versus 6.0 +/- 1.6 and 17.7 +/- 4.8 (p less than 0.001 respectively). In (3). PRA increased at the 1st h and remained elevated: at 96 h, delta PRA was + 3.0 +/- 2.9 ng.ml-1 -.h-1 in (3) versus + 0.10 +/- 0.06 and + 0.25 +/- 0.17 ng.ml-1.h-1 .n (1) and (2) [(3) versus (1): p less than 0.01]; delta PA was lower in (3): -4.56 +/- 2.01 ng. 100 ml-1 versus -0.54 +/- 0.31 and -2.50 +/- 0.38 ng. 100 ml-1 [(3) versus (1): p less than 0.05].(ABSTRACT TRUNCATED AT 250 WORDS)
A quality assurance system for clinical trials entails the definition, prior to the trial, of a number of procedures (the "good clinical practices") ensuring that it will be correctly conducted and the verification that these procedures have been respected. Setting up a clinical trial quality assurance system involving the manufacturer, university staff and public authorities should result in trials that are better performed. The role and responsibilities of each party are discussed, together with the consequences to be expected from the introduction of good clinical practices in France.
The purpose of this study was to investigate the effectiveness and safety of enalapril in elderly people. A double-blind, randomized, placebo-controlled trial was carried out in 32 subjects aged from 75 to 97 years (mean: 86 years) with blood pressure values equal or superior to 160/90 mmHg. After 8 weeks of treatment with enalapril in doses of 20 to 40 mg/day, the systolic pressure was lowered from 190 +/- 16 to 151 +/- 19 mmHg (P less than 0.0001) and the diastolic pressure from 102 +/- 7 to 85 +/- 11 mmHg (P less than 0.0001). Systolic and diastolic pressures were also significantly reduced in subjects under placebo (from 183 +/- 16 to 165 +/- 21 mmHg, P less than 0.001; and from 101 +/- 9 to 91 +/- 13 mmHg, P less than 0.001, respectively), but the degree of reduction was significantly superior with enalapril (systolic: 39 +/- 25 vs 18 +/- 19 mmHg, P less than 0.005; diastolic: 17 +/- 13 vs 11 +/- 12, P less than 0.001); blood pressure was inferior to 160/90 mmHg in 67% of the subjects treated, as against 35% of those under placebo. Two patients under enalapril died: one on the 27th, the other on the 47th day of treatment. No relation could be established between these deaths and the drug, and this figure of 2 is not significantly different for the number of deaths expected over the same period in a population of that age-group. Among the patients under placebo, one had pulmonary embolism on the 34th day and another had a sudden increase in blood pressure on the 6th day, requiring discontinuation of treatment. It is concluded that enalapril administered alone is effective and well tolerated. Long-term studies are needed to find out whether this angiotensin-converting enzyme inhibitor is superior to a diuretic as initial treatment of arterial hypertension.
Experiments were performed in urethane-anaesthetized rabbits using ventriculo-cisternol perfusion. Central infusion of angiotensin II (50 ng/kg/min) induced a rise in blood pressure which was accompanied by an increase in the noradrenaline concentration of the cerebrospinal fluid. Both effects were highly correlated. Conversely, an i.v. infusion of noradrenaline (5 micrograms/kg/min) which caused a similar increase in arterial pressure did not affect the cerebrospinal fluid catecholamine levels. These results suggest that peripheral cardiovascular effects of centrally administered angiotensin II are related to the activation of noradrenaline structures in the brain.
Extracellular fluid volume (EFV), total blood volume (TBV), and renal indices were determined in 53 permanent essential hypertensive patients with normal renal function and balanced sodium intake and urinary output. In comparison with normal subjects, hypertensives had normal EFV values while TBV and the TBV/EFV ratio were significantly reduced (p less than 0.001). In hypertensives, a significant negative relationship (r = -0.40; p less than 0.005) was observed between the TBV/EFV ratio and diastolic arterial pressure. No correlation existed between TBV and diastolic pressure, whereas EFV (and also interstitial fluid volume) was positively related to diastolic arterial pressure (r = +0.41; p less than 0.005). Extracellular fluid volume and interstitial fluid volume were both directly correlated to the renal filtration fraction (r = +0.45; p less than 0.005). The study suggests that, in the disturbed partition of the extracellular fluid of hypertensives, changes in the interstitial space are involved and are related to variations in the renal indices.
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A method for the determination of mexiletine in human plasma by gas-liquid chromatography with electron-capture detection is described. Plasma samples are extracted at pH 12 with dichloromethane after addition of the internal standard, the 2,4-methyl analogue of mexiletine. A derivative is obtained using heptafluorobutyric anhydride; according to gas chromatography-mass spectrometry it is a monoheptafluorobutyryl compound. The minimum detectable amount of mexiletine is 5 pg. Accurate determinations of human plasma levels were performed after oral or intravenous treatment.
In anaesthetized rats, the intracisternal injection of clonidine (1 microgram/kg) reduced mean arterial pressure (MAP), increased plasma renin concentration (PRC) while naphazoline (5 microgram/kg) was ineffective. The i.v. administration of clonidine (30 microgram/kg) still lowered MAP, but in this case, the drug decrease PRC, naphazoline (45 microgram/kg, i.v.) also reduced PRC. It is suggested that i.v. clonidine and naphazoline reduce renin release through activation of alpha-adrenoceptors within the kidney.
1 Hepatic blood flow was determined before and during (+)- and (+/-)-propranolol plasma concentration plateaus in 19 patients with suspected renal hypertension and normal liver function. 2 Hepatic blood flow significantly decreased (P less than 0.001) during (+/-)-propranolol administration and remained unchanged during (+)-propranolol administration. 3 Hepatic extraction ratio was 74 +/- 1% (+/-)-propranolol and 79 +/- 2% for (+)-propranolol. 4 Total propranolol clearances were determined during the steady-state achieved by a constant infusion. A highly significant positive relationship was observed (r = +0.86; P less than 0.01) between hepatic blood flow and (+)-propranolol clearance. The slope of the curve was 1.05 +/- 0.27. 5 The result implies that the total clearance of (+)-propranolol constitutes an accurate estimation of basal hepatic blood flow in subjects with normal liver function.
Total effective compliance, hemodynamic parameters, extracellular fluid volume, cardiopulmonary (CPBV) and total blood (TBV) volumes were determined in 32 men, including 14 normotensive controls and 18 sustained essential hypertensive patients. The effective compliance was calculated from the changes in central venous pressure recorded simultaneously with the changes in blood volume obtained after a rapid Dextran infusion. In normotensive controls, compliance was 2.08 +/- 0.09 ml/mm Hg/kg and was positively correlated with plasma (r = 0.79) and extracellular fluid (r = 0.84) volumes. In hypertensives, compliance was significantly reduced (1.49 +/- 0.06 ml/mm Hg/kg; P is less than 0.001) and was correlated negatively with the CPBV/TBV ratio (r = -0.75) and positively with the plasma volume/interstitial fluid volume ratio (r = 0.84). These results suggest that in normotensives, there is a regulatory mechanism between volume and compliance and that this contributes to maintaining filling pressure and cardiac output within normal ranges. In hypertensives, the reduced compliance could participate in the maintenance of normal values of cardiac output and extracellular fluid volume by influencing the partition of intravascular and extracellular fluid volumes.
The electrophysiological properties of Mexiletine were investigated by endocavitary His Bundle recording and programmed electrical stimulation of the heart in 30 patients. Differing dosage (2, 2.7 and 3.4 mg/kg) were given intravenously in 3 groups of 10 patients. The effects on the length of the sinus cycle, conduction intervals and cardiac refractory periods were observed and the following results obtained : 1. Sinus rhythm increased at all dosages but this effect was much more pronounced with 3.4 mg/kg dosage (--12.8% +/- 2.81% : : % shortening of sinus cycle with respect to the basal cycle +/- SD, p less than 0.005); 2. Atrioventricular nodal conduction time (A-H interval) decreased, the effect being more marked with the larger dose regimes; 3.His-Pirkinje conduction time (H-V interval) unaltered except in 3 cases where it increased by 5 ms after injection of 2.7 mg/kg; 4. Relative refractory period of His-Parkinje system shortened, this effect also being more pronounced with the larger doses ( --3.75 +/- 0.25% :2.7 mg/kg, p less than 0,001; -- 7 +/- 1.46% 3.4 mg/kg, p less than 0.005). In conclusion, the changes observed in the His-Purkinje system after mexiletine were similar to those of Lignocaine and Diphenylhydantoin. The drug also appears to have a marked vagal inhibitory effect as shown by the acceleration of the sinus rhythm and reduced atrioventricular conduction times.
The decrease of sympathetic activity by the beta-blocking drug, as demonstrated by the decreased electric activity of the splanchnic nerve and by the decreased urinary catecholamine reponse to tilt as well as by the decreased levels of plasma dopamine beta-hydroxylase exists not only in hypertension with elevated PRA but also in hypertension with normal or low PRA. In these latter cases the antihypertensive effect is better explained by the decrease in the sympathetic nervous system activity than by the decrease of PRA. This effect seems to be indirect and probably, as suggested by Lewis, as a result of damping sensory input to the central nervous system from the heart, whose capacity to respond to exercice and stress is blunted by beta-adreno-receptor blockade.
In borderline and permanent hypertensives after rapid i.v. injection of dl-propranolol 0.2 mg/kg plasma levels were measured and were fitted to a two-compartment open-model. In borderline patients, characterized by a high basal cardiac output (CO), plasma levels were always lower than in permanent hypertensives. The biological half-life was reduced and the central volume of distribution, volume of distribution at pseudo-equilibrium and total clearance (TC) were markedly increased. In the overall population, there was a significant positive correlation between CO and TC. Rapid achievement of a predetermined plateau in each group constituted experimental proof of the validity of the two-compartment open-model for kinetic analysis of propranolol i.v. If kinetic parameters from permanent hypertensive were applied to borderline hypertensives a lower plateau was obtained. Thus, in so far as beta-blockade is related to plasma level of propranolol, an increased intravenous dose may be required in patients with high CO.
1. Acebutolol, a beta1-receptor blocker, has, at a daily dose of 800 mg, a mild but significant anti-hypertensive effect in moderate sustained essential hypertension with normal or low plasma renin activity. 2. Prediction of its anti-hypertensive effect is better based on the evaluation of the sympathetic nervous system responsiveness to head-up tilt than on the evaluation of plasma renin activity or dopamine-beta-hydroxylase. 3. The anti-hypertensive effect of acebutolol is better explained on the basis of inhibition of the sympathetic nervous system activity than on the basis of suppression of plasma renin activity. 4. A positive correlation between plasma renin activity and dopamine-beta-hydroxylase in patients on diuretics suggests the common dependence of these two variables on sympathetic overactivity.
Cardiac output, cardiopulmonary (CPBV) and total (TBV) blood volumes, vascular reactivity to norepinephrine and dopamine B hydroxylase (DBH) were determined in 41 borderline hypertensives patients in comparison with 28 normal subjects. Cardiac output (P less than 0.001) and CPBV/TBV ratio (P less than 0.01) were significantly increased. The ratio was directly correlated to the pressor-response to norepinephrine (P less than 0.01) and the DBH level (P less than 0.005). The results suggest that sympathetic overactivity plays a dominant role in the cardiac output elevation of borderline hypertensive patients.