We have previously shown that low-density (LDL) and high-density (HDL) lipoprotein from healthy subjects can promote in vitro prostaglandin (PG) release by murine macrophages. In this pilot study, we have measured PG production induced by lipoproteins of six diabetic patients with poor metabolic control, compared to five healthy controls. Plasma lipoprotein levels were similar in both groups. Lipoprotein fractions were purified by sequential ultracentrifugation. After lipoprotein incubation with cells, supernatants were extracted and PG quantified by HPLC. In presence of LDL, in control subjects, there was an increase in total PG production, mainly due to thromboxane B2 (TxB2). In diabetic patients, the secretion pattern was similar. In presence of HDL, in control subjects, total PG secretion was also increased, but it was balanced between TxB2 and prostacyclin. In diabetic patients, at low HDL concentration (10 mg/l) the secretion was mainly due to TxB2, while at higher HDL concentrations (100 mg/l). the secretion was balanced between TxB2 and prostacyclin. Comparison of means of areas under curve for the two groups studied showed that LDL increased all PG secretion in diabetic patients compared to controls (P < 0.05 for PGF2alpha), while HDL increased all PG secretion in controls compared to diabetic patients, except PGF2alpha. Our work suggests a key role of LDL in TxB2 secretion in diabetic patients, which is a major proaggregant and vasoconstrictive agent. There was also an increased secretion of all PG in diabetic patients.

Summary— Research into the biological basis of lens transparency has demonstrated the implication of lens sugar stress in the diabetic cataract whereas senile cataract is the result of natural degeneration which is enhanced by various external factors such as cosmic and ionizing rays, or oxidative processes. Drugs have been developed which are aimed at being effective on lens pathological physiology and metabolism, concurrently. Such molecules: aldose reductase inhibitors (ARIs: sorbinil, AD‐5467, CT‐112 and imirestat), acetyl salicylic acid (ASA), salicylate (SA) and sodium monomethyl trisilanol orthohydroxybenzoate (SMB, a prodrug for salicylate) have undergone pharmacodynamic, pharmacokinetic and/or clinical studies which are presented here. ARIs have shown efficacy in slowing down and preventing the progression of experimental sugar cataracts; sorbinil can partially reverse the very early morphological signs of sugar cataract. Sorbinil and imirestat have also demonstrated anti‐oxidant properties. ARIs administration (per os or by topical instillation) generally results in lens levels compatible with concentrations that are efficient on biochemical mechanisms of cataract formation. However, at the present time, clinical evaluations are in progress and as yet, there is no confirmation of their efficacy in man. ASA and SA can prevent various mechanisms of lens protein denaturation; they inhibit AR and prevent, in vitro , the formation of some pigments found in the aged cataractous lens. Extrapolation of the ASA ocular pharmacokinetics results in animal to man, suggest that ASA administration per os could result in efficacious levels in the lens. This is also sustained by the observation of a reduced frequency of cataracts in ASA treated diabetic rhumatoid arthritis patients. SMB pharmacokinetic studies have shown small but persistent levels of the active principle in the lens. They suggest that the capsule slows down SA diffusion into the lens and that, on the contrary, lens epithelium facilitates its penetration. Preliminary results of pharmacodynamic studies are given.

Macrophages have been shown to play a key-role in the development of atherosclerotic lesions. Monocyte attraction and activation in the arterial wall lead to foam cell formation, cholesterol accumulation and secretion of inflammation mediators. Among macrophage secretions, prostacyclin and thromboxane are prostaglandins involved in the regulation of coagulation and vascular permeability. In this study, we have evaluated the effects of human native low-density and high-density lipoproteins on macrophage prostaglandin production (P388D1 mouse cell line). Lipoprotein fractions were purified from venous blood of healthy volunteers by sequential ultracentrifugation. After lipoprotein incubation with cells, supernatants were extracted and prostaglandins quantified by high-performance liquid chromatography. Our technique allows the determination of the main classes of prostaglandins. In the presence of low-density lipoproteins, time-course study showed an increase in total prostaglandin production within 10 min (50 times basal secretion level). This increase was dose-dependent. A steady-state was obtained at 20 mg protein LDL/1. Stimulation of thromboxane B2 and prostacyclin was predominant, with a main effect on the proaggregant thromboxane. Production of the proinflammatory PGF2 alpha and the immunoregulatory PGE2 was lower. In the presence of high-density lipoproteins, P388D1 cells also increased their total prostaglandin secretion at 30 min, in a dose-dependent manner. This increase was directly related to a stimulation of prostacyclin, with no significant effect on thromboxane. Our results demonstrate that normal low-density lipoproteins can stimulate macrophage prostaglandin secretions, with putative deleterious effects on the arterial wall, in particular thrombus formation. On the other hand, high-density lipoproteins, by mainly stimulating prostacyclin, could theoretically have a beneficial influence.

Verapamil is a calcium channel blocker widely used as an antihypertensive agent, and its pharmacological effects may partly be due to some degree of beta blockade. In order to evaluate the changes occurring in beta-2 adrenoceptor density, 40 patients with mild to moderate hypertension received verapamil 240 mg (once a day) or captopril 20 mg (twice a day) during 30 days, in a double-blind randomized study, after a placebo run-in period. The lymphocytic membrane beta-2 adrenoceptor density (Bmax) was determined before the administration of active drugs and after a 15-day treatment. After a month of treatment, most patients showed a marked reduction of their diastolic blood pressure: from 98.2 +/- 3.2 mmHg to 81.2 +/- 4.0 mmHg (p < 0.05), in the verapamil group, and from 95.0 +/- 6.0 mmHg to 82.5 +/- 4.8 mmHg (p < 0.05) in the captopril group. After 15 days of treatment, verapamil induced an up-regulation of beta-2 adrenoceptors from 39.5 +/- 8.3 fmol/mg protein to 58.5 +/- 12.0 fmol/mg protein (p < 0.05), whereas the Bmax in the captopril group did not significantly change. No significant change occurred in the two dissociation constants. This up-regulation phenomenon, common among beta-2 blockers, supports the hypothesis of verapamil's beta blockade potency.

Summary— Slow calcium channel antagonists are widely used among transplanted patients suffering from hypertension, although some of them tend to reduce hepatic blood flow. The aim of our study was to determine the pharmacological properties of nicardipine in transplanted patients with hypertension. Ten hours after liver transplantation, six patients (three men, three women) received 5 mg of intravenous nicardipine to prevent high blood pressure during intensive care. Prior to the administration and during the study (at the completion of the infusion, 3, 5, 10, 15, 20, 30, 45, and 60 min after infusion), the systemic and splanchnic parameters were measured (Swan Ganz catheter). Blood samples were drawn simultaneously from radial artery and free hepatic veins, in order to obtain the hepatic extraction of nicardipine. The hepatic extraction ratio was around 70% for the first 3 min, then decreased and remained stable thereafter, around 45%, showing a non linear first‐pass metabolism pattern. Plasma hepatic clearance of nicardipine (699–850 ml/min) was close to total plasma clearance throughout the study (978 ± 222 ml/min, from 71 to 87%) and half of the estimated hepatic plasma flow values at the same times (1467–1770 ml/min, from 44 to 51%). No statistically significant changes were observed in cardiac output and hepatic blood flow during the study, although there was a decrease in mean arterial blood pressure from 87 ± 6 mm Hg baseline level to 76 ± 3 mmHg, 60 min after administration. Nicardipine chlorhydrate seems to be appropriate in post operative liver transplant patients when blood pressure must be decreased. Nicardipine safely lowers peripheral resistance, and does not induce changes in hepatic blood flow. Its extraction remains stable, after a hepatic saturation phenomenon.

Calcium is involved in several biochemical atherogenesis processes and its activity is antagonised in cell and animal experimental models by all classes of slow channel calcium inhibitors. However, the doses required in animals to slow the development of atherosclerotic lesions are above therapeutically acceptable doses in man. The clinical relevance of their antiatherosclerotic activity in the few clinical studies undertaken is difficult to assess because of the variable criteria of judgment used.

The authors report on an acute suicidal arsenic intoxication (di-arsenic-trioxide). Death can occur one week after ingestion, despite intensive care. The forensic, anatomopathological and toxicologic aspects are reported. Forty titrations are realized at the level of the biologic fluid in viscera, by absorption spectrophotometry. These data are compared with those in standing literature, especially with the rates determined in normal subjects, following simple environmental impregnation.

Le role du calcium dans la formation de la plaque atheromateuse est important et peu specifique. Il intervient dans de nombreuses etapes biochimiques, et son action est antagonisee par les inhibiteurs des canaux calciques, quelle qu'en soit la classe, sur les modeles experimentaux cellulaires et animaux. Toutefois, les doses utilisees chez l'animal pour inhiber la progression des plaques par rapport au controle sont nettement superieures aux doses therapeutiques utilisees chez l'homme. Les etudes humaines, sont difficiles a interpreter, par la grande disparite des criteres de jugement

Calcium is involved in several biochemical atherogenesis processes and its activity is antagonised in cell and animal experimental models by all classes of slow channel calcium inhibitors. However, the doses required in animals to slow the development of atherosclerotic lesions are above therapeutically acceptable doses in man. The clinical relevance of their anti-atherosclerotic activity in the few clinical studies undertaken is difficult to assess because of the variable criteria of judgment used.

A placebo is a pharmacologically inactive substance that can have a therapeutic effect if administered to a patient who believes that he or she is receiving an effective treatment. It is generally admitted that the placebo effect decreases blood pressure in 20% to 30%, when evaluated by casual sphygmomanometer or ambulatory systems. In order to evaluate the occurrence of a placebo effect in cardiovascular pharmacology, we analysed two studies. One study included ten mild-to-moderate hypertensive patients, and consisted of two submaximal exercise tests separated by a single oral administration of the placebo. The other study included six healthy volunteers, receiving an oral placebo during ten days. The placebo was in both case presented as an effective antihypertensive agent. Any change on blood pressure and heart rate, both at rest and during exercise, was observed before and three hours after the placebo. After ten days of placebo administration, no statistically significant change in blood pressure or heart rate was obtained. Nor was any statistical difference observed in catecholamine plasma levels, either three hours or ten days after oral administration of the placebo. The second study did not show any evidence of changes in lymphocytic beta-adrenoceptor density after ten days of placebo. The results of these pilot studies suggest that the use of a placebo group in cardiovascular clinical pharmacology should be reconsidered. The real occurrence and characteristics of a placebo effect should be evaluated by a complementary study.

Because pruritus, erythema and tachycardia are observed in some patients during chemonucleolysis, a prospective study was designed to investigate the plasma levels of histamine and catecholamines occurring after an injection of chymopapain. Thirteen patients (11 men and 2 women), mean age 38 +/- 11 years, were studied. They all had negative prick skin tests, human basophil degranulation tests (HBDT) and radio-absorbent tests (RAST) to chymopapain. The patients were premedicated with 100 mg hydroxyzine and 3 g tranexamic acid. Sedation was carried out using 0.1 mg.kg-1 droperidol and 0.02 mg.kg-1 phenoperidine. The nucleosus pulposus was visualized with 3 ml of contrast medium (lopamiron 300); 2 ml of chymopapain were then injected. Blood samples were obtained at T1 (after the contrast medium, but before the chymopapain), and then 5, 10, 15, 20 and 30 minutes after the chymopapain. The usual haemodynamic parameters were recorded at the same times. Four patients had clinical signs (group I), whereas the other nine (group II) did not. There was an increase in histamine levels in three patients from group 1, as well as in two in group II (up to 33 nmol.l-1). However, mean histamine and catecholamines levels were comparable in both groups at all times, and between times, of sampling. There therefore was no relationship between clinical signs and the release of histamine or catecholamines. The premedication with an antihistamine may have protected the patients, but the signs reported by four patients may also be due to the chymopapain itself.

The evaluation of mild to moderate hypertension must be carried out under the conditions in which treatments are usually prescribed, i.e., in general practice. After specific training of the physicians in the methods used, we evaluated the efficacy and safety of a new formulation of verapamil by comparing it with a reference drug: captopril. The main assessment criterion was the restoration of normal blood pressure in mildly to moderately hypertensive patients (blood pressure in excess of 160/95 mmHg). Blood pressure was evaluated by two methods: a mercury column sphygmomanometer, after the patient had rested in a half-sitting position for 10 minutes, and the ambulatory measurement of blood pressure (AMBP) using the SpaceLabs system. The results of this study involving 40 patients followed up for 3 months by 8 GPs in collaboration with our blood pressure unit were as follows: on verapamil, 47% of patients recovered normal values after 30 days of treatment and 71% after 60 days (with no change in dosage). On captopril, the normalization rates were 22 and 27% respectively. The highly significant reduction of blood pressure found by the <<occasional>> measurement for both treatments (p < 0.001) was only faintly reflected by AMBP. Verapamil induced a reduction of nighttime blood pressure with no significant impact on heart rate. The clinical, paraclinical and electrocardiographic safety of both treatments was good.

Au cours de la chimionucléolyse pour le traitement des hernies discales, certains patients présentent des manifestations cliniques de type tachycardie, hypotension, érythème et paresthésies, malgré un bilan immunologique préalable négatif (prick-test, TDBH, RAST). Le but de ce travail a été de vérifier si ces manifestations pouvaient être en rapport avec une histaminolibération non-spécifique ou une sécrétion accrue de catécholamines. Treize patients (2 femmes et 11 hommes) ont été étudiés. Le protocole a toujours été le même : une préparation par hydroxyzine et acide tranéxamique pendant les trois jours précédant la chimionucléolyse, une prémédication avec les mêmes produits, puis une sédation avec dropéridol et phénopéridine. Au cours de la chimionucléolyse des prélèvements successifs d'histamine et de catécholamines plasmatiques ont été pratiqués, ainsi que des mesures hémodynamiques (fC, Pasys, Padia) aux mêmes moments. Quatre patients ont présenté des manifestations cliniques (groupe I), les autres (groupe II) n'ont présenté aucune symptomatologie. Aucune relation n'est trouvée entre l'apparition des signes cliniques après injection de chymopapaïne, et les taux d'histamine et de catécholamines. Par ailleurs, des taux élevés d'histamine ont été retrouvés (33 nmol · l−1) sans qu'aucune manifestation clinique n'apparaisse. Cette dissociation clinicobiologique rend improbable le seul rôle de l'histaminolibération dans la genése des manifestations cliniques survenant au cours de la chimionucléolyse.

Dilevalol is a vasodilating beta-blocker with proven antihypertensive activity. In this study, 28 patients with mild-to-moderate uncomplicated hypertension underwent 2 submaximal exercise tests, each consisting of progressive steps of 20 watts for 2 minutes or up to 85% theoretical maximum heart rate. Five minutes after the first test, patients received either placebo or dilevalol 200 mg, 400 mg or 600 mg. The second exercise test was performed 3 hours later. Diastolic blood pressure, systolic blood pressure, heart rate and norepinephrine plasma levels were assessed before and after exercise. Dilevalol at all doses caused a significant decrease in heart rate and blood pressure both at rest and during exercise, compared to placebo. Dilevalol 600 mg had a greater effect on diastolic blood pressure than dilevalol 200 mg and 400 mg. Administration of dilevalol 200 mg and 400 mg enabled 42% of patients to increase their maximal exercise level by 20 to 60 watts. Dilevalol increased plasma norepinephrine levels at the 100 watts exercise levels from 5.1 +/- 4.0 nmol/l to 7.6 +/- 4.3 nmol/l (p less than 0.05). No adverse effects were observed during dilevalol treatment. This study shows that dilevalol is an effective antihypertensive agent that blunts heart rate and blood pressure risings during exercise.

UNLABELLED:The administration of placebo (a pharmacologically inactive substance) is justified in clinical trials of antihypertensive drugs in order to exclude the placebo effect. The evaluation of antihypertensive treatments during exercise is an interesting end point, since aerobic exercise is part of antihypertensive treatment. The aim of this study is to determine the placebo effect on blood pressure, heart rate and catecholamine secretion profiles during exercise testing.METHOD:10 patients with untreated mild to moderate essential hypertension participated in a single blind study consisting of two successive submaximal exercise tests (85% of maximal predicted heart rate), separated by a single oral administration of placebo. Blood pressure and heart rate were measured after 10 minutes of rest and at the end of each effort step (2 min, 20 Watts), both before and after placebo. Blood samples (5 ml) were collected at rest and during maximal exercise before and after placebo, in order to determine the effect of placebo on circulating catecholamines.RESULTS:There were no significant difference between the "control" and after placebo exercise tests, neither in blood pressure or heart rate profiles, nor in values of circulating catecholamines (noradrenaline at rest: 1.88 +/- 0.96, effort: 6.43 +/- 1.93 nm/l before placebo, 1.65 +/- 0.83 nm/l and 5.71 +/- 2.12 nm/l after placebo respectively [NS]).CONCLUSION:The placebo effect, which is generally determined from blood pressure at rest by sphygmomanometry, seems devoid of any influence on blood pressure, heart rate or catecholamine profiles during exercise in patients with mild to moderate essential hypertension. Thus, antihypertensive treatments can be evaluated during exercise by comparison to baseline cardiovascular parameters without need of a placebo group.