[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.

Sympathetic nervous system activation in postextrasystolic potentiation: role of catecholamine release in enhancement of ventricular function.

The role of catecholamines in postextrasystolic potentiation was assessed in 30 patients during continuous coupled right ventricular pacing. Hemodynamic data were recorded in 15 patients (group 1); in the other 15 patients (group 2), coronary blood flow and metabolic variables, including catecholamines, were measured. Data were recorded in the control state and after 10 minutes of coupled pacing. Both groups had similar control pulse rates and mean aortic pressures: these variables decreased abruptly by 32 beats/min and 12 mm Hg, respectively, (p less than 0.001 for each) after the initiation of coupled pacing. In group 1, all indexes of left ventricular function and contractility increased during coupled pacing (p less than 0.001 for each), thus confirming postextrasystolic potentiation. In group 2, coupled pacing increased coronary blood flow, myocardial oxygen consumption and free fatty acid uptake (p less than 0.001 for each) but not lactate extraction. Plasma epinephrine was unchanged, but norepinephrine levels increased in arterial (421 +/- 27 to 576 +/- 41 ng/liter) and coronary sinus plasma (611 +/- 46 to 836 +/- 46 ng/liter) (p less than 0.001 for both). Indirectly calculated norepinephrine release within the myocardium increased from 25.6 +/- 2.8 to 39.7 +/- 5.2 ng/min (SEM) (p less than 0.05), suggesting a sympathetic nervous system activation. It is argued that coupled pacing acutely lowered mean aortic pressure, leading to baroreflex sympathetic activation which may contribute to augmented cardiac contractility in postextrasystolic potentiation.

Estimation of sympathetic activity in essential hypertension.

The estimation of sympathetic nervous activity by measurement of plasma norepinephrine (NE) concentration assumes a constant relation between this and the synaptic cleft concentration. This assumption would be incorrect if the clearance of plasma NE could be varied without affecting its removal from the synaptic cleft, so we compared the clearance of plasma NE in mild hypertensives and normal subjects by measurement of its plasma concentration during a 0.5-hr infusion at 0.07 microgram/kg/min; there were no differences. The simultaneous infusion of isoproterenol, 0.02 microgram/kg/min, led to an increase in heart rate and NE clearance. There was partial inhibition of catechol-O-methyltransferase by a single oral dose of alpha-methyldopa, 250 mg, which reduced the clearance of both catecholamines (CAs) by about 20%. After the end of the infusions containing isoproterenol, the tachycardia persisted for more than 1 hr and declined more slowly in the hypertensives than the normals. In contrast, plasma concentrations of both CAs returned to basal values within a few minutes. The persistent tachycardia may be due to rerelease of isoproterenol into the synaptic cleft, since stimulation of sympathetic activity by assumption of the erect posture was associated with an exaggerated increase in heart rate (by 48/min after infusion and 23/min before infusion). The study therefore suggests that synaptic cleft and plasma CA concentrations can be independently manipulated and the relation between them may be different in hypertensive patients and normal control subjects.

Diseases and drug protein binding.

In a number of pathological states a decrease in the plasma protein binding of drugs is observed. This may be due to many factors related either to the protein, or the ligand (drug), or to the binding conditions. The most important of these disease states quantitatively are probably hypoalbuminaemia, conditions resulting in modification of the albumin compartment volume and the presence on albumin binding sites of pathological inhibitors of drug binding. A decrease in the extent of drug plasma protein binding does not necessarily lead to enhanced drug effects and therefore raises two important therapeutic questions. Firstly, does reduced protein binding have a clinically significant influence on the pharmacological effects of the drug? Secondly, if it does, is it preferable to modify the dosage regimen of the drug or to correct the plasma protein concentration prior to the administration of the drug? At present, only tentative answers can be given.

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.

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.

The role of drug-induced illness in admissions to an intensive care unit.

All patients admitted during a 33-month period to a multidisciplinary intensive care unit were prospectively studied in order to determine the incidence and severity of drug-induced illness leading to the admission. The role of underlying diseases was assessed and the avoidability of drug-induced illness considered. Out of 1651 patients, 97 (5.88%) were admitted because of drug-induced illness; 74 of these had serious underlying diseases. 13 (13.4%) of the 97 patients died, but underlying diseases accounted for 4 of the 13 fatalities. In nearly half of the cases, the drug-induced illness appeared potentially avoidable.

Decreased plasma epinephrine concentrations after glucose ingestion in humans.

Plasma levels of norepinephrine (NE), epinephrine (E), immunoreactive insulin (IRI), and glucose were measured in six healthy volunteers after glucose consumption and in six volunteers after a water solution. Ingestion of the glucose (100 g) solution significantly decreased E levels from 46.7 +/- 8.0 to 20.8 +/- 1.9 pg/mL (P less than 0.01). Three hours after the glucose ingestion, plasma E levels nearly returned to basal values. Plasma IRI and glucose levels peaked at 45 minutes after glucose consumption (P less than 0.01), then declined toward basal values. Plasma NE levels were unaffected by glucose consumption. There were no changes in glucose, IRI, NE, or E levels in the control group. These results suggest that E behaves as a counter-regulatory hormone to insulin under stimulation by glucose.

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)

Beta-adrenergic blockade and atrio--ventricular conduction impairment.

Atrio--ventricular conduction and its modifications induced by six Beta-adrenergic blocking agents have been investigated in the dog. Premature atrial stimuli (St2) were applied at variable intervals following regular stimuli (St1) ensuring atrial pacing; atrial (AERP), nodoventricular (NERP) and global (GERP) effective refractory periods as well as global functional refractory period (GFRP) were determined before and after administration of each of the six drugs. When Beta-blockade was produced with d,1-propranolol which hwas membrane stabilizing effects (MSE) but no intrinsic sympathomimetic activity (ISA) or with sotalol, which has neither MSE nor ISA, all parameters were significantly increased. When Beta-blockade was achieved with pindolol or practolol, which have only a poor Beta-adrenolytic potency and no ISA. Alprenolol showed intermediate effects. Thus, it appears that Beta-blockade and not MSE, is responsible for the onset of A-V conduction impairment but that ISA, probably through a metabolic mechanism, affords protection against this impairment. On the other hand, measurement of ventricular effective refractory period (VERP) has shown that at the Purkinje-free junction, it is MSE which is mainly involved in conduction impairment.

Isoprenaline and canine cardiac refractory periods.

Atrioventricular refractory periods and their modifications induced by variable doses of sioprenaline have been investigated in dogs. Premature atrial stimuli (St2) were applied at variable intervals following regular stimuli (St1) which ensured atrial pacing. Atrial (AERP), nodoventricular (NERP) and global (GERP) effective refractory periods, as well as the global functional refractory period (GFRP) were determined before, during and after infusion of the drug. In low doses, isoprenaline did not significantly alter these various parameters. This confirms its lack of dromotropic effect on the healthy heart. In contrast, high doses of the drug significantly reduced the refractory periods, probably by simple correction of the negative dromotropic effects resulting from overstimulation. Also when the infusion was stopped, marked but reversible conduction depression was observed. It would appear that this reflects 'exhaustion' of cell metabolism induced by the drug.

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.

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.

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)

Erythromycin pharmacokinetics in man.

This study shows that high serum concentrations are reached after either ethylsuccinate or lactobionate erythromycin administration. But the short elimination half-life implies repetitive administration to obtain efficacy, the ideal being represented by continuous infusion.

[Role of the adrenal medulla in the effect of antihypertensive drugs]. / Rôle de la médullosurrénale dans l'effet de divers médicaments antihypertenseurs.

Recent studies have suggested a role for adrenaline in the pathogenesis of essential hypertension. In the present study, the effects of several anti-hypertensive agents were compared in normal (plasma adrenaline concentration: 0.267 + 0.040 ng/ml) and adrenomedullectomised (plasma adrenaline concentration: 0.063 + 0.011 ng/ml; p less than 0.01) dogs. The hypotensive and tachycardic effects of phentolamine (1.5 mg/kg i.v.) or dihydralazine (1 mg/kg i.v.) were the same in the two groups of dogs. Verapamil (0.2 mg/kg i.v.)-induced hypotension was less pronounced in dogs without adrenal medulla. In these adrenomedullectomised dogs, clonidine (10 micrograms/kg i.v. or 1 microgram/kg i.c.) elicited tachycardia and its hypotensive properties were delayed. In dogs with neurogenic hypertension, the antihypertensive properties of propranolol (1 mg/kg i.v.) remained unchanged. These results show the importance of adrenal medulla in the antihypertensive action of clonidine, or verapamil. These agents (but not dihydralazine, propranolol or phentolamine) could reduce adrenaline secretion from the adrenal medulla.

[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.

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.