[Trust-based economics with medicine outcome-based pricing]. / Médicament : économie de la confiance et contrat de résultats.

In recent decades, the pharmaceutical industry as built a high level of confidence thanks to innovative medicines that improve both duration and quality of life. Some recent scandals have however discredited this industry, now suspected of cheating or bribery. Even the scientific progresses are challenged on the ground of possible conflicts of interests and value uncertainty. This situation is deleterious. Simultaneously the economic crisis exacerbates the payers' expectations in terms of clinical value and value/price ratio. It also stimulates the demand for outcomes in real life. This induces a new economic approach for the market access of highly expensive reimbursable drugs. It consists in paying only for drugs actually proven effective in terms of actual outcomes, with a full or partial refund of the payer in case of failure, according to accurate and simple criteria in so called "performance agreement". Confidence is restored accordingly.

Is uranyl scavenger hexakis(3,6-anhydro) tetrakis(2A,B,D,E-O-octyl) cyclomaltohexaose (OCT) relevant with biosystems?

Hexakis(3,6-anhydro)tetrakis(2A,B,D,E-O-octyl) cyclomatohexaose (OCT) has been recently shown as a powerful cryptant for lead, mercury, and especially for uranyl. As previous results have been obtained in an organic solvent (methanol), a similar evaluation of OCT complex formation was achieved in aqueous medium and in the presence of membrane-mimicking systems such as phospholipid vesicles, liposomes and micelles. It was found that OCT, while completely insoluble in water, forms solid gel structures when in equimolar mixtures of water and methanol. Moreover, OCT exhibits detergent properties. Finally, OCT was successfully introduced in detergent solutions while keeping. Uranyl complexing properties. Possible applications of such models were also discussed.

1H-NMR study of heavy metals complexation with hexakis(3,6-anhydro) tetrakis(2A,B,D,E-O-octyl) cyclomaltohexaose (OCT).

The selection of the cations bound by hexakis (3,6-anhydro) tetrakis (2A,B,D,E-O-octyl) cyclomatohexaose (OCT) was performed by thin layer chromatography. The three cations selected, UO(2)2+, Pb2+ and Hg2+ were then studied by 1H-NMR. A 2:1 OCT/cation stoichiometry was identified in the cases of UO(2)2+ and Pb2+. While UO(2)2+ binding (logK around 6) followed a fast exchange kinetics, a slow or intermediate complexation was found with Pb2+ (logK = 5.6) and Pb2+, respectively. In the latter case, the poor solubility of Hg2+ precluded to propose neither a stoichiometry nor an estimation of the affinity constant.

[Postoperative analgesia after ligamentoplasty of the knee. Comparison of epidural morphine and intravenous nalbuphine]. / Analgésie postopératoire après ligamentoplastie de genou. Comparaison de la morphine péridurale et de la nalbuphine intraveineuse.

Surgery of the anterior cruciate ligament causes severe postoperative pain. This study aimed to compare efficacy and side effects of two postoperative analgesia methods, during 24 hours. Twenty healthy patients were assigned to two groups (n = 10): the patients of the first group were given by an epidural catheter 3 mg of morphine hydrochloride, every twelve hours. The patients of the second group received 2 mg h-1 of intravenous nalbuphine. The degree of pain was studied with a visual analogue scale. After the third postoperative hour, it was significantly higher in the second group, but the nalbuphine dose was low. The incidence of respiratory depression, nausea, pruritus was not statistically different between the groups, but 7/10 patients in the first group suffered of urinary retention (the first micturition was obtained 10.5 hours after the end of surgery in the first group and 5.3 h in the second one). Two patients needed an uretral catheter. These results might tend to show a greater efficactly of epidural morphine, with a higher incidence of urinary side effects.

Head injury: clonidine decreases plasma catecholamines.

Seven patients who had suffered head injury 3 to 5 days before the study was undertaken received clonidine (2.5 micrograms/kg iv over 10 min). This resulted in a reduction of plasma norepinephrine (p less than .05) and in normalization of plasma epinephrine (p less than .05). Neither common carotid blood flow nor diastolic blood flow as index of global cerebral perfusion as measured by pulsed Doppler changed. The reduction of sympathetic overactivity, probably due to the specific action of clonidine on alpha 2-adrenoceptors within the rostral ventrolateral medulla, may be of interest in the management of head injury because of the maintenance of cephalic hemodynamics.

Private companies for phase I studies?

In France, the debate is still open regarding where phase I studies should take place. According to its strict definition, very few phase I studies are performed per year in our country. Because they are usually carried out on healthy volunteers, ethics and safety are intimately mixed in with such studies. Safety in these highly specific investigations is founded on 2 bases, first on the independence of the investigator and secondly on the laboratory environment. The economic independence and total lack of responsibility in this respect on the part of the investigator ensure that all ethical considerations including safety are focused on the personal interest of the volunteer who participates in the study.

Decreased cardiac response to isoproterenol infusion in acute and chronic hypoxia.

The hypothesis of a blunted chronotropic response of cardiac beta-adrenergic receptors in altitude hypoxia was tested in nine subjects at sea level (SL) by infusion of isoproterenol. Observations were made at SL, in acute hypoxia (2 days at 4,350 m, condition H1), in more prolonged hypoxia [13 days between 850 and 4,800 m, condition H2] and in chronic hypoxia [21 days at 4,800 m, condition H3]. Resting heart rate was higher in all hypoxic conditions. Resting norepinephrine concentrations were found to be significantly higher in conditions H2 (1.64 +/- 0.59) and H3 (1.74 +/- 0.76) than at SL (0.77 +/- 0.18 ng/ml). Isoproterenol, diluted in saline, was infused at increasing doses of 0.0, 0.02, 0.04, and 0.06 micrograms.kg-1.min-1. For the highest dose, there was a significantly smaller increase in heart rate in conditions H1 (35 +/- 9), H2 (33 +/- 11), and H3 (31 +/- 11) than at SL (45 +/- 8 min-1). The increase in pulse (systolic/diastolic) pressure, considered as the vascular response to isoproterenol infusion, was smaller in condition H3 (29 +/- 16) than at SL (51 +/- 24 mmHg). There was a significant increase in the dose of isoproterenol required to increase heart rate by 25 min-1 and decrease in slope of heart rate increase vs. log(dose) relationship in conditions H2 and H3. Thus an hypoxia-related attenuated response of beta-adrenergic receptors to exogenous stimulation was found in humans.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute hypoxia decreases cardiac response to catecholamines in exercising humans.

Cardiac chronotropic response to adrenergic activity at rest and exercise has been studied in 8 sea-level natives on the first two days of exposure to high altitude hypoxia (3823 m, 473 mmHg). Maximal O2 uptake (VO2max) was determined at low altitude (day 0:D0) and high altitude (day 2:D2). Submaximal exercise tests were performed at low altitude (day 1:D1) and high altitude (days 3 and 4: D3, D4). Plasma venous norepinephrine (NE) and epinephrine (E) concentrations were determined at rest and at the end of submaximal exercise. From D0 to D2, maximal heart rate decreased by 7% (p less than 0.01), and VO2max decreased by 17% (p less than 0.01). During submaximal exercise, plasma NE did not vary significantly (D1: 1.36 +/- 0.57, D3: 1.48 +/- 0.51, D4: 1.31 +/- 0.54 ng.ml-1). In contrast, relative work load decreased at high altitude (% VO2max at D1, D3 and D4 were respectively: 90.2 +/- 6.1, 83.3 +/- 9.8, 76.9 +/- 8.2). Linear relationships were found, both at low and high altitudes, between NE and VO2, NE and % VO2max, and between the increases in NE and heart rate during exercise. Covariance analysis indicates that these relations shifted to the left at high altitude:for the same NE or increase in NE, VO2 or increase in heart rate was lower at high altitude. Variations in E were similar but not significant. We conclude that hypoxia induced a decrease in cardiac chronotropic response to adrenergic activation during submaximal exercise.

Cardiovascular and central nervous system effects of rilmenidine (S 3341) in rats.

Rilmenidine (S 3341) is a new alpha 2 agonist, with antihypertensive properties. Pharmacologic data concerning its hemodynamic and central nervous system effects in the rat are described in this report. In the anesthetized or conscious spontaneously hypertensive rat, rilmenidine was found effective and potent as an antihypertensive agent, lowering blood pressure in a dose-dependent manner after intravenous and oral administration. These effects are related to a reduction in sympathetic tone as seen by the decrease in plasma catecholamines induced by rilmenidine in the spontaneously hypertensive rat. Studies in the normotensive pithed rat (electrical stimulation and adrenalectomization) confirmed the presynaptic alpha 2-stimulating properties of rilmenidine and suggested that a component of the antihypertensive activity of rilmenidine could be exerted through these peripheral receptors. A study of the central effects of rilmenidine was performed using classic neuropharmacologic tests. No effect was observed on the pentobarbitone-induced sleeping time in the rat. Rilmenidine caused only a minimal and non-dose-dependent inhibition of the righting reflex in the chick. In the rat, rilmenidine did not decrease the motor activity at concentrations up to 50 times higher than the antihypertensive dose. These results confirmed the contrast between rilmenidine and clonidine and suggest that a dissociation between sedative and antihypertensive effects could occur with rilmenidine.

Inhibition of (-) [125I]-iodocyanopindolol binding to rat lung beta adrenoceptors by uremic plasma ultrafiltrates.

Numerous data have suggested that beta-adrenoceptor-mediated responses were decreased in uremia and that parathormone could be implicated in this phenomenon. In a previous paper we have shown that the beta2 receptor density of mononuclear cells of uremic patients is significantly increased despite a significant increase in plasma epinephrine, suggesting that an endogenous substance could interfere and disregulate the beta 2 receptor density. In order to further evaluate this phenomenon we have firstly studied the influence of one non uremic and five uremic plasma ultrafiltrates on the binding of (-)-[125I]iodocyanopindolol using rat lung beta adrenoceptors. The results show that uremic plasma ultrafiltrates induce a decrease in the Bmax value without any variation on the Kd value. In a second step we have assessed the ability of human synthetic 1-34 and 53-84 parathormone to interact directly with beta-adrenoceptors. No variation in the (-)-[125I]iodocyanopindolol binding parameters was observed. These results suggest that an uremic endogenous substance might interfere on the beta adrenergic receptors and that the alteration in the beta-adrenergic response in uremia is probably not due to a direct action of parathormone on the beta-adrenoceptors.

The effects of cremophor EL in the anaesthetized dog.

The effects of cremophor EL were studied in 13 anaesthetized, paralyzed and ventilated dogs. Twenty per cent cremophor EL in a dose of 4.3 +/- 0.92 ml was infused at a rate of 30 ml X hr-1. In seven dogs, thoracopulmonary compliance, heart rate, systemic arterial pressure (SAP), pulmonary pressures (PAP, PCWP, RAP), cardiac output (CO) and platelet and white cell counts, were measured before the injection of cremophor EL, at the end of infusion and 5, 10, 30 and 150 minutes after the end of infusion. In six dogs, SAP, CO, and blood volume were measured before the injection of cremophor EL, at the end of infusion and 10, 30, 90 and 150 minutes after the end of infusion. Plasma histamine and catecholamines were assayed before the injection of cremophor EL and 2, 5, 10, 30, 90 and 150 minutes after starting the infusion. Cremophor EL induced a marked, sustained and significant decrease in SAP at the end of infusion and at 5, 10 and 30 minutes after the completion of the infusion (-68, -71, -70 and -43 per cent respectively), in PCWP, RAP and CO (-78 per cent at the end of infusion, -32 per cent 150 minutes after the end of infusion). Heart rate and systemic vascular resistance did not vary significantly. Pulmonary vascular resistance increased at the end of infusion, five and ten minutes after the end of infusion (+734, +548 and +439 per cent respectively). Plasma volume decreased 10 and 30 minutes after the end of infusion (-28 and -30.5 per cent respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Hormonal response to captopril pre-treatment during sodium nitroprusside-induced hypotension in man.

To assess the hormonal response to captopril pre-treatment during sodium nitroprusside (SNP) -induced hypotension, 12 patients were studied during a spinal surgical procedure. Haemodynamic data, plasma-renin activity, aldosterone, adrenaline and noradrenaline levels were measured. Patients were randomly allocated to two groups: Group I, control patients; Group II, 3 mg kg-1 captopril pre-treated patients. SNP requirement for the same level (mean arterial pressure (MAP) = 55 mmHg) and duration of hypotension (88.5 +/- 28.7 vs. 95.2 +/- 22.5 min) was significantly lower in Group II than in Group I (16.5 +/- 14.2 mg vs. 39.3 +/- 16.7 mg; P less than 0.05) and a lower SNP infusion rate was required to induce and to maintain hypotension. In Group II patients, MAP remained significantly lower than the control and Group I values for 30 min after SNP withdrawal. Cardiac index (CI) remained stable in both groups. Heart rate was not modified in Group II during hypotension. Plasma-renin activity rose more dramatically in Group II patients than in Group I both during hypotension (13.9 +/- 7.5 vs. 2.8 +/- 0.9 ng ml-1 h-1; P less than 0.05) and after hypotension (23.4 +/- 15.4 vs. 2.2 +/- 0.8 ng ml-1 h-1; P less than 0.05). Plasma catecholamine levels increased in both groups during hypotension and remained raised in captopril patients after SNP withdrawal. It can be concluded that recovery from hypotension may be delayed when using captopril and that sympathoadrenal activity induced by hypotension is not substantially altered by captopril pre-treatment, suggesting that sympathetic blockade might not be the mechanism by which captopril reduces SNP requirement during controlled hypotension for surgical procedure in man.

Effects of pergolide on the cardiovascular responses to sinoaortic deafferentation in dogs with intact or surgically decentralized adrenal glands.

In pentobarbital-anesthetized dogs with decentralized adrenal glands, sinoaortic baroreceptor deafferentation produced an increase in mean aortic blood pressure which reached a maximum (42 +/- 5 mm Hg, n = 6) within 5 min and then waned entirely within the subsequent 25 min. In contrast, in sham-operated dogs, the maximal pressor response due to deafferentation was of greater magnitude (63 +/- 6 mm Hg, n = 8) and of much longer duration (44 +/- 4 mm Hg, 60 min after deafferentation). Heart rate was only augmented slightly in both preparations. A marked elevation of epinephrine plasma concentration occurred 5 min after deafferentation and the magnitude of this effect was 8 times greater in dogs with innervated than denervated adrenal glands. Norepinephrine plasma concentration increased moderately and similarly in the two preparations. Administration of pergolide (30.0 micrograms/kg i.v.) 15 min before undertaking the deafferentation procedure induced a small, short-lasting increase in blood pressure and a small fall in heart rate in dogs in which the innervation to the adrenal glands was left either intact (sham-operated) or removed surgically. In dogs with adrenal gland denervated, pergolide blocked entirely the pressor response and the small elevation in plasma concentration of catecholamines evoked by sinoaortic deafferentation in the matched, saline-pretreated group. However, in sham-operated dogs (intact adrenal innervation), pergolide reduced partially (by 41%) the increase in blood pressure and plasma epinephrine concentration caused by deafferentation. The decrease in heart rate, produced by pergolide, was abolished by deafferentation in sham-operated and adrenal decentralized dogs.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiopulmonary effects of ketanserin infusion in human pulmonary embolism.

The release of platelet-derived vasoactive substances, particularly serotonin (5-HT), have been implicated in the pulmonary vasoconstrictor response following acute pulmonary embolism. Therefore, we studied the effects of infusing ketanserin, a 5-HT blocking agent, upon pulmonary and systemic hemodynamics and gas exchange in 10 patients with severe acute pulmonary embolism. These patients evidenced 45 +/- 17% mean angiographic pulmonary vascular obstruction. Ketanserin significantly decreased the mean pulmonary arterial pressure from 26 +/- 6 to 23 +/- 5 mm Hg (p less than 0.001). The total pulmonary vascular resistance decreased from 9.1 +/- 3.2 to 8.3 +/- 2.5 mm Hg/L X min X m2 (p less than 0.001). However, the mean cardiac index was unchanged. The systemic arterial and right atrial pressures were significantly decreased after ketanserin. The PaO2 increased in all patients from 60.5 +/- 12.6 to 66.5 +/- 13.6 mm Hg (p less than 0.05), whereas the venous admixture was unchanged. This was attributed to an increased PVO2 (27 +/- 7 to 30 +/- 5 mmHg, p less than 0.01) secondary to a reduction of calculated peripheral oxygen consumption during ketanserin infusion. The results indicate ketanserin is a mild pulmonary vasodilator and can reduce the pulmonary hypertension and increase the PaO2 after pulmonary embolism.

Cardiovascular characterization of the DA2 dopamine receptor agonist quinpirole in rats.

In normotensive anesthetized rats, 15-min IV infusions of quinpirole (2.5-40.0 micrograms/kg/min) produced dose-related, rapidly appearing, and long-lasting decreases in mean carotid artery BP and HR. Hemodynamically, the hypotensive effects of quinpirole (10.0 micrograms/kg/min) were due to a fall in total peripheral vascular resistance inasmuch as CO did not undergo significant changes. Mesenteric, hindquarter, and renal blood flows were, respectively, reduced, unchanged, and increased by quinpirole; thus, the renal vascular resistance fell more than either the total peripheral or hindquarter vascular resistance. Biochemically, the hypotensive effects of quinpirole were accompanied by a decrease in the plasma level of norepinephrine and plasma renin activity. The peak fall in blood pressure produced by quinpirole was not significantly modified by atenolol, idazoxan, ranitidine, SCH 23390 (DA1 dopamine receptor antagonist), enalapril, or SK&F 100273 (V1 vasopressin receptor antagonist), but was entirely blocked by S-sulpiride or removal of autonomic nerve drive to the cardiovascular system with chlorisondamine. The effect of quinpirole on systemic and regional vascular resistances was antagonized by S-sulpiride. Furthermore, SK&F 100273 prevented the fall in mesenteric flow produced by quinpirole. Intracerebroventricular injection of quinpirole (10.0 micrograms/kg over 2 min) in saline- or SK&F 100273-pretreated rats produced the same hypotensive effects as an identical IV dose of the compound. In pithed rats, quinpirole (10 micrograms/kg/min IV over 15 min) decreased pressor responses to electrical stimulation of spinal cord outflow without affecting those to exogenously injected angiotensin II, B-HT 920, cirazoline, norepinephrine, or 5-hydroxytryptamine. This inhibitory effect was antagonized by S-sulpiride. The bradycardia produced by quinpirole in intact rats was mediated by the autonomic nervous system inasmuch as it was slightly modified by bilateral vagotomy, partly reduced by atenolol, and entirely prevented by pithing even when the low HR of the last preparation had been raised by IV infusion of isoprenaline. Furthermore, S-sulpiride, but not SCH 23390 or idazoxan, antagonized this effect. In pithed rats, quinpirole similarly inhibited the tachycardic responses elicited by electrical stimulation of either the spinal cord outflow (preganglionic) or postganglionic cardioaccelerator nerve fibers. This effect of quinpirole was susceptible to S-sulpiride but not idazoxan blockade. Finally, in conscious spontaneously hypertensive rats (SHR) but not in normotensive rats, quinpirole (10 micrograms/kg/min IA over 15 min) lowered blood pressure.(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of ketanserin on cardiovascular, sympatho-adrenal and endocrine systems during physical exercise in man.

Blood pressure, heart rate, oxygen consumption, plasma concentrations of catecholamines, renin, aldosterone and lactate were measured in 6 normotensive volunteers during a randomized cross-over study of oral ketanserin (20 mg X 7) and placebo; measurements were made at rest and during maximal dynamic exercise on a bicycle ergometer. At rest ketanserin reduced blood pressure without modifying heart rate or plasma noradrenaline and adrenaline. Duration of exercise and blood lactate levels did not differ between the ketanserin and the control group. During exercise only systolic blood pressure was significantly decreased on ketanserin at maximal work rate whereas heart rate did not change. Plasma noradrenaline was significantly increased and plasma aldosterone significantly decreased during exercise in ketanserin-treated subjects whereas plasma renin activity and plasma adrenaline remained unchanged. Finally, under ketanserin oxygen consumption during exercise was reduced. The results suggest that ketanserin might interfere with the sympathetic nervous system and aldosterone secretion in man.

[Laser-Doppler velocimetry: a new technic for evaluating of microcirculation. A reproducibility study]. / La vélocimétrie laser-doppler: nouvelle technique d'évaluation de la microcirculation. Etude de la reproductibilité.

The recent introduction of the laser-Doppler technique to measure capillary flow velocity offers new prospects in clinical pharmacology. We used this technique in 45 healthy volunteers (23 women and 22 men) to study the capillary network at the distal end of the third finger of the non-dominant hand. Each subject was tested twice at one-week interval. The results showed that the data concerning flow velocity and amplitude were perfectly reproducible, under standard conditions, after one week in each subject. No correlation was found between the microcirculation parameters and the subjects age, weight and, paradoxically, blood pressure and heart rate. We would suggest that this innocuous, sensitive and reproducible technique be used more systematically to evaluate the haemodynamic effects of drugs on capillary blood flow.

Impaired regulation of beta 2-adrenergic receptor density in mononuclear cells during chronic renal failure.

Previous investigations have suggested that beta-adrenoceptor-mediated responses were decreased in uremia. To evaluate this phenomenon further, beta 2-receptor density in mononuclear cells, plasma catecholamines and plasma parathyroid hormone were studied in two groups of normotensive patients: group U, twenty-five chronic uremic patients with end-stage renal failure; group C, twenty-eight control subjects. Each group was divided into three age and sex-matched subgroups. Beta 2-receptor density was determined using (-)125 iodocyanopindolol. Despite a significant increase in plasma epinephrine in the group of uremic patients, there was a significant increase in beta 2-adrenoceptor density. On the other hand the uremic state did not influence (-)125 iodocyanopindolol binding affinity and plasma norepinephrine. Parathyroid hormone, as expected, was significantly elevated in all the uremic subgroups. It can be concluded that the uremic state is associated with an unexpected upregulation of beta 2-receptor density in mononuclear cells. The role of an endogenous beta-blocking substance is suggested.