Access to Care in France for Elderly Immigrants from North Africa: Influence of Socio-cultural Factors (the MATC Survey).

France is faced with an ageing migrant population, and in the institutions for elderly, migrants represent only 4% and very few come from the Maghreb. Is it the result of a kind of discrimination or of other factors such as culture and traditions? In France migrants have access to aid and prevention of dependency plans. The reluctance to enter into institutions is maintained by the fear of cultural abuse and/or language barriers, and difficulties in financial and administrative matters. From the interviews of the MATC survey, we have pointed out the importance of culture and the tradition of filial piety. Nevertheless, solidarity in the family is decreasing but remains the basis of the care support to the elderly. The will to keep them in the family may limit both the diagnosis and the access to specific care. This attitude contributes to a kind of self-discrimination.

[Ethical and legal aspects of biological sample banks: synthesis, practical questions and proposals]. / Aspects éthiques et réglementaires des collections d'échantillons biologiques: synthèse, questions pratiques et propositions.

The overview of the numerous ethical questions and complex legal framework regarding biological sample collections leads to present in this synthesis 1) tables of the principal ethical recommendations and French or supranational reglementary texts in this domain, with their internet access; 2) to detail the procedures to follow in some practical situations; 3) to underline the still open questions and current debates, as the ethical and legal framework of human biobanks is in deep evolution.

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This double-blind dose-response crossover study was designed to compare the efficacy and tolerability of sustained-release (SR) and conventional diltiazem over 4 weeks in patients with stable angina pectoris. Following a 2-week placebo run-in period, 26 patients were randomised into 3 parallel groups to receive either diltiazem SR (180, 240 or 300mg once daily) or conventional diltiazem 60mg three times daily for 2 weeks. Treatments were then crossed over for a further 2-week study period. Antianginal efficacy was evaluated using submaximal treadmill exercise testing. At baseline, all 3 treatment groups were comparable for all parameters. Treatment with both conventional and SR formulations improved exercise time and reduced intensity of ischaemia, but the difference between groups at the end of each 2-week treatment phase was not statistically significant. The results did not suggest a dose-response relationship. Adverse reactions necessitated treatment discontinuation in two patients being treated with conventional diltiazem and in one patient receiving diltiazem SR 240mg. In conclusion, this study demonstrated that diltiazem SR 180, 240 and 300mg did not differ from the conventional formulation in terms of anti-ischaemic efficacy.

Hemodynamic Effects of Dilevalol Following Acute and Long-Term Administration in Normal and Hypertensive Subjects.

Forearm hemodynamics using pulsed Doppler flowmetry were studied in 12 healthy volunteers and 20 patients with mild to moderate hypertension before and after acute and long-term oral administration of the beta-blocking agent dilevalol. The study was performed using a double-blind design versus placebo. Both 200-mg and 400-mg dosages produced a significant acute blood pressure reduction in normotensive and hypertensive subjects. In hypertensive subjects, forearm vascular resistance was poorly modified, brachial artery diameter decreased significantly but only with long-term administration of the 400-mg dosage. A significant reduction in brachial artery tangential tension was consequently observed. The study provides evidence that Dilevalol produced a significant decrease in blood pressure in normotensive and hypertensive subjects in association with a decrease in brachial artery tangential tension.

Pharmacokinetics of fluvoxamine maleate in patients with liver cirrhosis after single-dose oral administration.

The pharmacokinetics of fluvoxamine maleate were investigated in 13 patients with biopsy-proven liver cirrhosis. They received a single oral 100mg dose as an enteric-coated tablet, and plasma samples were collected up to 168h after administration. Geometric mean values for peak plasma concentrations and area under the plasma concentration-time curves (AUC) were 39 micrograms/L and 1338 micrograms.h/L, respectively. Mean (+/- SD) elimination half-life (t1/2) was 25 +/- 11h, and increased with higher plasma bilirubin levels, although no relationship between bilirubin and AUC was observed. AUC was about 50% higher in patients than in healthy volunteers from another similar study. This was mainly because of a longer t1/2. Although there is a great overlap between AUC values of fluvoxamine in patients and healthy volunteers, it is nevertheless concluded that in patients with signs of active liver disease, e.g. raised bilirubin, it is wise to lower the initial daily dose and to carefully monitor the patient during subsequent upward dose adjustments.

Microgravity and orthostatic intolerance: carotid hemodynamics and peripheral responses.

A ground-based model [24 h of bed rest (BR) with head-down tilt (HDT)] was used to investigate the cardiovascular deconditioning responsible for orthostatic intolerance, frequently observed after weightlessness flights. This experimental deconditioning is shown to be distinguished by an increase of mean blood pressure (P < 0.05), with increased total peripheral resistances (TPRs). Systolic tangential tension of the carotid arterial wall, cardiac output and frequency (spectral analysis), and plasma norepinephrine and epinephrine were not significantly altered, while plasma dopamine was increased (P < 0.05). Cardiovascular homeostasis was challenged before and after 24 h of BR with HDT through -40 mmHg lower body negative pressure (LBNP). Systolic tangential tension of the carotid wall was decreased, with a decrease of systolic pressure and cardiac output; increased heart rate was likely due to an increase of sympathetic drive with a decrease of vagal braking. The overall picture was not changed after 24 h of BR with HDT, except for a lack of increase of TPRs: their increase (+13.7%, P < 0.05) before was no longer observed after (-2.6%) 24 h of BR with HDT. This apparent deficiency cannot be explained. However, a heterogeneity in the response of TPR should be considered because the magnitude of the increase of blood pressure to cold pressor test was the same after 24 h of BR with HDT as it was before.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of lansoprazole in patients with renal or liver disease of varying severity.

The pharmacokinetics of lansoprazole (L) after a single oral dose of 30 mg was determined in 18 healthy volunteers, 17 renal failure patients and 24 hepatic failure patients; 8 hepatitis and 16 with compensated (CC) or uncompensated (UCC) cirrhosis. In renal failure, the absorption of L was unchanged, its half-life being similar to that in healthy subjects; a small change seen in mild renal failure patients (creatinine clearance between 40 and 60 ml/min) was attributed to the age of the patients. Urinary elimination, essentially as metabolites of lansoprazole, was decreased, in relation to the degree of renal impairment. In hepatitis patients, the AUC and t1/2 of L were doubled, without any change in Cmax. In cirrhotics tmax was prolonged, the AUC was increased (P < 0.001) and there was prolongation of t1/2 (6.1 h in CC and 7.2 h in UCC compared to 1.4 h in healthy subjects). These changes resulted from a decrease in the clearance of L. There was also an increase in its sulphone metabolite (Cmax, Rm) and a decrease in the hydroxylated metabolite (Cmax, Rm) in relation to the degree of liver disease, and reflecting a decrease in hydroxylation and biliary elimination. Thus, renal failure had no effect on the pharmacokinetics of L, but severe hepatic failure caused marked changes. A repeated dosing study would be necessary to evaluate the repercussions of the possible accumulation in cirrhotic patients.

Hemodynamic effects of carvedilol after acute oral administration in hypertensive and normal subjects.

Forearm hemodynamics using pulsed Doppler flowmetry were studied in nine healthy volunteers and 12 patients with mild-to-moderate hypertension before and after acute oral administration of the beta-blocking and vasodilating agent carvedilol. Both the 25- and the 50-mg dose produced a significant blood pressure reduction by comparison with placebo in normotensive and hypertensive subjects. Only the 50-mg dose caused a decrease in forearm vascular resistance in hypertensive subjects. The decrease disappeared after wrist occlusion. Although brachial artery diameter did not change, a significant decrease in tangential tension was observed. This study provides evidence that carvedilol produced arteriolar dilation within the forearm of hypertensive subjects in association with a decrease in brachial artery tangential tension.

Dose ranging study of lansoprazole, a new proton pump inhibitor, in patients with high gastric acid secretion.

The effects of single doses and of 7 days of lansoprazole 10, 20 and 30 mg PO versus placebo on gastric acid secretion have been evaluated in 8 patients with high gastric acid secretion. The double blind crossover period was followed by a simple blind 7 days on placebo to detect any rebound phenomenon. After the first dose lansoprazole did not modify basal acid output (BAO) but it significantly and dose dependently inhibited peak acid output (PAO) and increased the time during which nocturnal intragastric pH was greater than 3. After 7 days of treatment the same significant, dose-dependent suppression of gastric acid was found, but BAO was also blocked. One week after cessation of lansoprazole administration no rebound increase in gastric acid-secretion was observed. The plasma gastrin concentration remained unchanged throughout the study.

Twenty-four hours of bed rest with head-down tilt: venous and arteriolar changes of limbs.

The hemodynamic changes after 24 h of bed rest with -5 degree head-down tilt were studied in six normal subjects as a condition causing an intrathoracic shift of blood volume with a resulting urinary sodium and water loss and a subsequent reduction in total intravascular volume. Vascular resistance and venous tone of the upper and the lower limbs were investigated as were systemic hemodynamics throughout the procedure. Whereas systemic hemodynamic parameters did not change significantly, vascular resistance and venous tone of the upper and lower limbs decreased significantly up to the sixth h and then returned toward baseline values at 24 h. Systemic and forearm vasoconstriction responses to lower body negative pressure (LBNP) were studied just before and at the end of the study period. With LBNP, -5, -10, and -15 mmHg pressure levels were used to investigate mechanoreceptors in the low-pressure system, whereas the -40 mmHg pressure level was used to explore baroreceptors both in low and high pressure systems. Changes in vascular resistance in response to LBNP did not differ at the beginning and at the end of the head-down tilt, whereas an exaggerated heart rate response was observed at -40 mmHg at the end of 24 h of bed rest. The study showed that after 24 h of bed rest with -5 degree head-down tilt, the adaptative changes in venous tone and vascular resistance to blood volume reduction were altered. A dissociation between cardiac and vascular baroreflex response was observed in situations simulating tilting.

Plasma and urine aluminium concentrations in healthy subjects after administration of sucralfate.

1. Sucralfate (basic sucrose aluminium sulphate), a topical intestinal agent, was administered in suspension or granule form to 25 healthy subjects at a total dose of 4 g day-1 for 21 days. Aluminium in plasma and 24 h urine samples was assayed before, during and after administration of sucralfate by inductively coupled plasma optical emission spectrometry. 2. Sucralfate produced significant increases in plasma and urine aluminium concentrations. On average, plasma aluminium increased from about 2 micrograms 1-1 to more than 5 micrograms 1-1 and 24 h urine aluminium increased from less than 5 micrograms to more than 30 micrograms. Both plasma and urine aluminium concentrations decreased rapidly after sucralfate was stopped. However, urinary aluminium concentrations remained higher than normal 5 and 10 days after discontinuation of sucralfate administration. Moreover subjects receiving sucralfate granules had significantly higher average urinary excretion of aluminium than subjects receiving the suspension. 3. The small but significant increase in plasma and urine aluminium following sucralfate administration in therapeutic doses may reflect intestinal absorption of aluminium. Although such absorption would appear to be moderate in healthy subjects, it is suggested that aluminium-based treatments should be used only intermittently, especially in patients with renal disorders.

Stereoselective protection of exogenous and endogenous atrial natriuretic factor by enkephalinase inhibitors in mice and humans.

We compared the relative potencies of sinorphan and retorphan, the S- and R-enantiomers of acetorphan a potent inhibitor of enkephalinase (EC 3.4.34.11), to inhibit membrane metalloendopeptidase in vivo and to protect exogenous and endogenous ANF after oral administration. In mice, sinorphan was 2-3 fold as potent as retorphan in inhibiting the specific in vivo binding of [3H]acetorphan to kidney enkephalinase. The same potency ratio was found for the enhancement of trichloroacetic acid-precipitated radioactivity in kidneys of mice that had received 125I-ANF, which is used as a test for the protection of the hormone against inactivation in vivo. In nine healthy human volunteers who had received a low oral dosage of sinorphan or retorphan in a double-blind, placebo-controlled, randomized trial, sinorphan was also 2-3 fold more potent than retorphan in inhibiting plasma enkephalinase activity. These effects were accompanied by a related rise in plasma ANF immunoreactivity, which also reflected the difference in the effectiveness of the two compounds. Sinorphan was also more potent than retorphan in enhancing urinary cyclic GMP excretion and sodium excretion in five of these subjects. These data indicate that, in humans as in rodents, enkephalinase plays a crucial role in the inactivation of ANF, its partial inhibition in vivo being accompanied by a significant protection of the exogenous or endogenous hormone as well as by typical ANF-like responses. Thus orally administered sinorphan appears to be a promising compound for therapeutic use in cardiovascular and renal diseases in which ANF has been postulated to exert beneficial effects.

[Current practice of drug trials in healthy volunteers]. / Pratique actuelle des essais de médicaments sur volontaires sains.

It is impossible to extrapolate for men the animal's data. Pre-therapeutical studies are a necessity to state precisely in man ADME for a new drug and to confirm pharmacological properties seen in animals. Very often, the only healthy volunteers are useful for Phase 1 studies: The selection of volunteers keeps physical and metabolic status, and psychological motivation. True but restricted information is necessary for "free and informed consent". Rights and duties must be clearly defined in written convention. Financial advantages are in agreement of trouble but not of hazard in the study. The safety is the main point in human studies. That means a safe methodology and a protocol approved by independent ethical committee. The monitoring of these studies must be precisely conducted with many clinical and laboratory examinations. Healthy volunteers studies are required by French Ministry of Health, rejected by medical law, condemned by civil law but covered by legal insurances. In French mind is illicit that is not specifically permitted by law. We need special legislation as we refuse medical and ethical responsibility.

Peripheral haemodynamic effects of smoking in habitual smokers. A methodological study.

The effect of smoking on forearm haemodynamics was studied in four groups of healthy subjects, who had all smoked cigarettes (10-15 cigarettes/day) on average for 10 years. Changes in heart rate, blood pressure, forearm blood flow, forearm vascular resistance and pulse wave velocity were determined before and every 15 min for 75 min after smoking two cigarettes within 10 min. The inhaled nicotine was about 2.2 mg. There was no significant difference between the four groups in any haemodynamic variable before or after smoking, which indicated adequate reproducibility of the parameters studied and so made it possible to pool the results from all 30 subjects. Smoking significantly increased blood pressure, heart rate and pulse wave velocity and decreased forearm blood flow. Forearm vascular resistance remained unchanged. The rises in systolic blood pressure and pulse wave velocity were transient and both peaked (7% and 28%, respectively) 15 min after smoking. In contrast, heart rate and diastolic blood pressure remained significantly elevated and forearm blood flow was significantly decreased throughout the 75 min follow-up. The maximal changes were: heart rate +34%, diastolic blood pressure +17%, and forearm blood flow -24%. It is concluded that smoking produces statistically significant changes in forearm haemodynamics affecting both small and large arteries. The reproducibility of the study design means that it can be used to evaluate substances which may antagonize the haemodynamic effects of tobacco smoking.

Effects of twenty-four hours of bed rest with head-down tilt on cardiopulmonary baroreflex control: preliminary study.

The cardiopulmonary baroreflex response was studied before and after 24 h bed rest with head-down tilt (-5 degrees) in six normal male subjects, through lower body negative pressure (-5, -10, -15 mmHg) and passive leg raising. The reflex response was assessed (using plethysmography) by changes in forearm vascular resistance. During the lower body negative pressure and leg raising, forearm vasoconstriction and vasodilation were similar before and after head-down tilt. The study shows that orthostatic intolerance following head-down tilt is not explained by an abnormality in the response of low pressure baroreceptors.

[Evaluation of the effectiveness of a cicletanine-enalapril combination in hypertensive patients]. / Evaluation de l'efficacité d'une association ciclétanine-énalapril chez des patients hypertendus.

In this multicentre controlled single blind trial the effectiveness and safety of cicletanine (100 mg/day) were compared with those of enalapril (20 mg/day) and of the combination of both drugs in the same doses in 72 patients (41 men, 31 women, mean age 64.1 +/- 8.3 years) with permanent moderate essential hypertension without severe cardiovascular complications. In the course of the trial, one patient in each of the three therapeutic groups was excluded either for insufficient effectiveness in monotherapy or for photosensitization under the combined treatment. After two months of treatment, the fall in blood pressure and the number of patients with normalized BP were similar in the groups treated with cicletanine or enalapril alone. In contrast, the cicletanine-enalapril combination produced a significantly greater fall of diastolic arterial pressure than cicletanine alone. In addition, there was a greater reduction of functional symptoms associated with arterial hypertension. Apart from the lone case of photosensitization observed with the combined treatment, only minor side-effects were encountered, including an episode of diarrhoea and a case of extrasystoles with the combination, and a case or nausea with lipothymia under cicletanine alone. There were no significant variations of biochemical values.

Protection of atrial natriuretic factor against degradation: diuretic and natriuretic responses after in vivo inhibition of enkephalinase (EC 3.4.24.11) by acetorphan.

Atrial natriuretic factor (ANF) might be beneficial in several cardiovascular disorders, but its poor oral absorption and rapid inactivation in vivo have so far prevented its use in therapeutics. We have assessed the role of enkephalinase (membrane metallo-endopeptidase, EC 3.4.24.11) in the in vivo inactivation of ANF in mice and healthy human volunteers by evaluating the effects of acetorphan, a potent inhibitor. In mice, the degradation of 125I-labeled ANF was markedly delayed, as shown by the levels of the intact peptide in the plasma and the kidney, a major target organ. The effect of acetorphan was due to the inhibition of enkephalinase activity, since it occurred at an ED50 very close to this drug's ID50 for the inhibition of the specific binding of radioactive material to the kidney or lung peptidase that was measured after administration of [3H]acetorphan. The effects of acetorphan were also studied in eight healthy human volunteers by using a randomized double-blind, placebo-controlled design. Oral administration of acetorphan elicited a lasting elevation of plasma ANF-like immunoreactivity, with a time course parallel to that of the inhibition of plasma enkephalinase activity. These effects were accompanied by significant increases in urinary volume and sodium excretion, two well-established renal responses to ANF peptides. These results indicate that enkephalinase plays a critical role in ANF degradation in vivo and that its inhibition enhances the levels of circulating endogenous ANF, which, in turn, results in diuresis and natriuresis. Enkephalinase inhibition may constitute another therapeutic approach to the treatment of cardiovascular diseases, such as congestive heart failure or essential hypertension, on which ANF is postulated to have a beneficial effect.

Calcium blocker lacidipine and carotid arteriolar vasodilation in healthy volunteers.

Systemic and carotid hemodynamics were studied in 10 healthy male volunteers before and after short-term administration of a 4 mg dose of the calcium entry-blocker lacidipine in a placebo-controlled, double-blind, crossover study. Hemodynamic parameters of the right common carotid artery were measured before and at 1 1/2 and 3 hours after dose administration by means of pulsed Doppler flowmetry. In addition, systemic hemodynamic parameters were calculated from cardiac impedance measurements at the same time. In comparison with placebo, lacidipine produced a significant decrease in blood pressure, together with systemic and carotid arteriolar dilatation. Heart rate increased sharply, whereas carotid arterial diameter and tangential tension did not change. The study provided evidence that the calcium entry-blocker lacidipine produces systemic and carotid arteriolar vasodilation and that the heart rate baroreflex response after administration of calcium inhibitor is not associated with a significant modification of the geometry of carotid arterial wall.