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Biomedical subjects

E Pussard

Publications and source records attributed to E Pussard.

At least 55 records · Page 3Linked to original sources
PubMed1991

Efficacy of a loading dose of oral chloroquine in a 36-hour treatment schedule for uncomplicated plasmodium falciparum malaria.

The efficacy of a loading dose of 20 mg of chloroquine per kg of body weight per os given at intervals during the first day was evaluated in 27 patients in Madagascar with Plasmodium falciparum malaria. The conventional regimen of 25 mg/kg over 3 days (schedule 1) was thus compared with a regimen of 30 mg/kg over 2 days (schedule 2; one dose of 10 mg/kg followed by two doses of 5 mg/kg at 6-h intervals on the first day and two doses of 5 mg/kg at 12-h intervals on the second day) in terms of their clinical and parasitological efficacies, tolerance, and drug concentration-time curves. At 24 h schedule 2 gave higher chloroquine levels in blood, which induced a more rapid decrease in parasitemia. The time required for a 50% decrease in the initial parasitemia was shorter in patients on schedule 2 (14.3 +/- 1.6 h) than it was in patients on schedule 1 (35.5 +/- 5.4 h; P less than 0.01). Moreover, negative blood smears were obtained more rapidly with schedule 2 (50.8 +/- 3.7 h) than with schedule 1 (72 +/- 8.7 h). As predicted by the drug concentration-time curve, no high, potentially toxic peak drug concentration appeared and no adverse effects were observed with the loading dose regimen (schedule 2). These findings support the idea that a loading dose of 20 mg/kg given at intervals during the first 12 h is well tolerated and can be used to obtain a more rapid decrease in parasitemia and to shorten the treatment time of uncomplicated chloroquine-susceptible falciparum malaria in the field.

Administration, Oral↗
PubMed1991

Lidocaine and cardiovascular reflex responses to simulated orthostatic stress in normal volunteers.

The interactions of lidocaine with baroreceptor reflexes during simulated orthostatic stress or moderate volume depletion were investigated in healthy volunteers using the lower body negative pressure (LBNP) test. Cardiopulmonary baroreceptors were selectively unloaded at low levels of LBNP (-15 mm Hg) since the central venous pressure (CVP) decreased (-1.4 +/- 0.3 mm Hg) without changes in arterial pressure (AP) and heart rate (HR) but significant increases in forearm vascular resistance (FVR) and plasma noradrenaline (PNA). Cardiopulmonary as well as arterial baroreflexes were both unloaded at higher levels of LBNP (-40 mm Hg) since the CVP (-3.4 +/- 0.4 mm Hg) and systolic AP (-10 +/- 3 mm Hg) decreased whereas FVR, PNA, and plasma renin activity (PRA) increased further (all p less than 0.05). Following lidocaine infusion (serum level of 3.8 +/- 0.2 micrograms/ml), the AP, HR, FVR, and PNA increased and CVP decreased (p less than 0.05). Compared to LBNP performed under saline, lidocaine did not alter the LBNP (-15 mm Hg)-induced changes in cardiovascular and biological parameters but significantly decreased the induced rises in HR, FVR, PNA, and PRA at a LBNP of -40 mm Hg (p less than 0.05). In an additional study, it was also demonstrated that lidocaine significantly decreased the sensitivity of the reflex-mediated bradycardia following phenylephrine injection and attenuated the vasoconstrictor response to the cold pressor test taken as a nonspecific somatic pressor reflex.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Relationships between plasma atrial natriuretic peptide concentrations and hemodynamics and hematocrit in patients with cirrhosis.

We studied the relationships in 29 patients with cirrhosis between pulmonary arterial atrial natriuretic peptide concentrations and the following: systemic and splanchnic hemodynamics, the hematocrit, arterial oxyhemoglobin saturation, oxygen tension and the severity of cirrhosis. Plasma atrial natriuretic peptide concentrations ranged from 21 to 208 pg/ml and averaged 78 +/- 8 pg/ml (mean +/- S.E.M.). Simple regression analysis showed significant correlations between plasma atrial natriuretic peptide concentration and the following: hematocrit, mean pulmonary arterial pressure, wedged hepatic venous pressure, free hepatic venous pressure, pulmonary wedged pressure and serum bilirubin concentrations. No significant correlations were found between plasma atrial natriuretic peptide concentrations and all other hemodynamic values, arterial oxyhemoglobin saturation and oxygen tension. Multiple stepwise regression analysis showed that the hematocrit, mean pulmonary arterial pressure and wedged hepatic venous pressure were significant and independent predictors of pulmonary artery plasma atrial natriuretic peptide concentrations (R2 = 0.69). Partial regression coefficients were -0.74 (p less than 0.001), 0.61 (p less than 0.001) and 0.44 (p less than 0.05) for the hematocrit, the mean pulmonary arterial pressure and the wedged hepatic venous pressure, respectively. In conclusion, in patients with cirrhosis, increased plasma atrial natriuretic peptide concentrations were related to the degree of hemodilution, increased pulmonary arterial pressure and the degree of portal hypertension. Plasma atrial natriuretic peptide concentrations were not influenced by the arterial oxygenation levels.

Arteries↗
PubMed1990

Absence of effect of chloroquine in vivo on neutrophil oxidative metabolism in human subjects.

High levels of antimalarial drugs have been shown to be inhibitory to the oxidative metabolism of human neutrophils in vitro. In this study, chemiluminescence of, and chloroquine concentrations in, neutrophils from volunteers treated with prophylactic or therapeutic malaria regimens were assessed. Although detectable chloroquine levels were found in neutrophils, their chemiluminescence was not reduced at prophylactic or at therapeutic drug levels, in comparison with controls without chloroquine treatment. At these clinically achievable concentrations, chloroquine was not found to interfere with the oxidative metabolism of neutrophils.

Administration, Oral↗
PubMed1990

Hemodynamic and cardiac effects of spiraprilat in normal and sodium depleted conscious dogs.

The cardiac and hemodynamic effects of 3 doses (0.1, 0.3 and 1 mg/kg, iv) of spiraprilat, the diacid active metabolite of the new angiotensin I converting enzyme inhibitor spirapril, have been investigated and compared to those of saline in chronically implanted conscious dogs at rest. Under a normal sodium diet, spiraprilat, 1 mg/kg, induced significant (at least P less than 0.05) decreases in mean arterial pressure (MAP, -11%), total peripheral resistance (TPR, -21%), left ventricular end diastolic pressure (LVEDP, -15%) and increases in heart rate (HR, +12%) and cardiac output (CO, +16%) whereas dP/dtmax remained unchanged. Spiraprilat-induced tachycardia was not modified by propranolol pre-treatment but was abolished by previous administration of the propranolol-N-methylatropine combination. Spiraprilat, 0.1 mg/kg, did not affect any parameter, but spiraprilat, 0.3 mg/kg, showed intermediate effects. Finally, sodium depletion strongly potentiated spiraprilat effects on MAP, TPR, LVEDP, HR and CO. We conclude that: a), in conscious dogs under normal sodium diet, spiraprilat reduces TPR and MAP through peripheral vasodilating properties; b), spiraprilat-induced tachycardia is mainly related to parasympathetic tone withdrawal, possibly in relation with high and low pressure baroreceptors deactivation; and c), sodium depletion considerably potentiates spiraprilat cardiac and hemodynamic effects.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1990

Role of atrial peptide in the acute natriuretic response to uninephrectomy.

Unilateral nephrectomy (UNX) is associated with an immediate natriuretic response of the remaining kidney. The role of atrial natriuretic peptide (ANP), as assessed by right atrial appendectomy (APX), was investigated in euvolemic anaesthetized rats. In sham APX rats, UNX resulted in a twofold increase in urinary sodium and potassium excretion (1.03 +/- 0.11 to 2.08 +/- 0.17 and 1.39 +/- 0.05 to 2.26 +/- 0.08 mueq/min, respectively) and a doubling of urinary excretion of guanosine 3',5'-cyclic monophosphate (cGMP). No significant change in glomerular filtration rate, renal plasma flow, and lithium clearance occurred in response to UNX. APX totally prevented the UNX-induced natriuresis and diuresis as well as the rise in urinary cGMP. Post-UNX plasma concentration of ANP was higher in sham-operated compared with APX rats (45 +/- 9 vs. 20 +/- 2 fmol/ml). In sham APX rats, UNX was associated with a transient (less than 15 min) rise in arterial pressure; in APX rats, this immediate increase in arterial pressure was of similar magnitude but of longer (greater than 30 min) duration. The observed stimulation of ANP release after UNX and the blunting of the natriuretic response to UNX by APX suggest that ANP may be an important mediator of the renal response to contralateral renal ablation.

Animals↗
PubMed1990

[Suppression of the immediate pressive response to unilateral nephrectomy by atrial natriuretic peptide in the rat].

Unilateral nephrectomy (UNX) is associated with an immediate and transient increase in arterial pressure and in prompt natriuresis from the remaining kidney. The hypothesis that atrial natriuretic peptide (ANP) is involved in the acute adaptation to unilateral nephrectomy was tested in euvolemic anesthetized Sprague-Dawley rats. In a first series of experiments, an increase in circulating ir-ANP levels (from 23.5 +/- 3.6 to 66.3 +/- 12.8 fmol/ml; p less than 0.01) was found within 2 minutes following renal exclusion. In a second set of experiments, the ANP response was inhibited by performing a right atrial appendectomy, in order to eliminate the major source of ANP, or by intravenous administration of monoclonal antibodies directed against ANP. When UNX was performed in the control groups (sham atrial appendectomy and administration of non specific monoclonal antibodies), mean arterial pressure rose immediately (maximal about 12% within 4 minutes) and transiently (return to pre-UNX values within 20 minutes) after UNX. At the same time, central venous pressure, monitored in the right atrium, tended to decrease slightly. In rats pretreated by right atrial appendectomy or by monoclonal antibodies directed against ANP, arterial pressure increased to the same extent as observed in control groups; this increase however was significantly more prolonged. In control groups, urinary cGMP excretion, the biological marker of ANP, increased twofold in parallel with the natriuretic response. These two responses were blunted in right atrial appendectomized rats and in rats receiving antibodies against-ANP. These results suggest that atrial natriuretic peptide plays a major role in the immediate functional adaptation to unilateral nephrectomy by blunting the increase in blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Pharmacokinetics of intramuscular amopyroquin in healthy subjects and determination of a therapeutic regimen for Plasmodium falciparum malaria.

The disposition of amopyroquin was investigated in 10 healthy volunteers after a single 2-mg/kg (body weight) intramuscular dose of amopyroquin base. The major form of the drug in plasma and in whole blood was nonmetabolized amopyroquin, and only very low levels of its primary amine derivative were detected. After a rapid absorption phase (15 min), levels in plasma declined, following a tri-exponential model with a terminal elimination half-life of 129.6 +/- 92.5 h. The apparent volume of distribution (V/F) and the systemic clearance (CL/F) were 238 +/- 75 liters/kg and 2,063 +/- 1,159 ml/min, respectively. The renal clearance, calculated by using urine excreted during the first 48 h, was 119 +/- 99 ml/min and represented about 6% of the systemic clearance. About 1.2 and 0.2% of the amopyroquin dose was excreted in the urine during the first 48 h as nonmetabolized amopyroquin and its primary amine metabolite, respectively. Twenty-two Plasmodium falciparum malaria patients were studied after treatment with one of the following regimens of intramuscularly injected amopyroquin base: 3 mg/kg (body weight), 6 mg/kg, or 6 mg/kg followed by 3 mg/kg 24 h later. Parasitemia was cleared at day 7 in one of six, four of seven, and seven of nine patients, respectively. On the basis of this study, a regimen of 12 mg/kg (body weight) administered in two or three injections is suggested.

Adolescent↗
PubMed1988

Evaluation of the natriuretic and beta-adrenoceptor-blocking effects of tienoxolol in normal volunteers.

The beta-adrenoceptor blocking and diuretic properties of tienoxolol (150 mg and 300 mg) were investigated and compared to those of a placebo in a double-blind, cross-over trial in six healthy volunteers. Heart rate (HR), systolic and diastolic blood pressures, peak expiratory flow rate (PEFR) at rest and during vigorous exercise, plasma renin activity (PRA) and aldosterone levels at rest, and diuresis and urinary electrolyte excretion values were measured before and at intervals up to 24 h after oral administration of the drugs. In addition, the clearances of electrolytes, uric acid, and creatinine were calculated, as well as the fractional sodium excretion (Fe Na%) before and 4 h and 24 h after drug intake. Finally, tienoxolol plasma levels were measured. Tienoxolol significantly and dose-dependently reduced exercise-induced tachycardia. This effect started 1 h after drug administration, peaked between 4 h and 6 h (-12% and -17% from control values at 150 mg and 300 mg, respectively), and lasted at least 12 h. Resting HR was decreased at 300 mg (P less than 0.05), PRA was decreased at both doses (P less than 0.05), but PEFR was not drug-affected. 24-h cumulative sodium excretion was increased (+24% at 150 mg [NS], +38% at 300 mg [P less than 0.01]) as compared to placebo, and Fe Na% did not change, regardless of the dose administered. 24-h cumulative diuresis was moderately increased by tienoxolol (NS), whereas creatinine clearance rose after the 300-mg dose, suggesting that tienoxolol might increase glomerular filtration rate. Plasma aldosterone levels remained unchanged. Finally, the elimination half-life of tienoxolol was 7.5 h. Thus, in healthy volunteers, tienoxolol behaves as an early acting and relatively long-lasting selective beta 1-adrenoceptor blocking drug endowed with significant natriuretic properties.

Adrenergic beta-Antagonists↗
PubMed1988

Disposition of amopyroquin in rats and rabbits and in vitro activity against Plasmodium falciparum.

The disposition of amopyroquin was studied in rats after a single 50-mg/kg (body weight) oral dose of amopyroquin base. After a rapid absorption phase, the drug concentrations decreased in the plasma, with a terminal half-life of 14.5 h. The drug was widely distributed in the liver and lungs and, to a lesser extent, in the kidneys and spleen. In rabbits, the kinetic parameters were compared after a single 10-mg/kg dose of amopyroquin base through intravenous, intramuscular (i.m.), and oral routes. The similar bioavailability values (0.67 and 0.69) suggested that the drug could be used through i.m. or oral administration. Clearance and distribution volume did not differ significantly among the three modes of administration, and the terminal half-lives were 18.1 +/- 3.3, 23.9 +/- 6.7, and 25.7 +/- 5.4 h for intravenous, i.m., and oral routes, respectively. The ratio of concentrations in erythrocytes and plasma was about 5 in rats and rabbits. Three metabolites were detected in both animal species (one was tentatively identified as the primary amine derivative). The amopyroquin in vitro activity was tested against four chloroquine-susceptible and 11 chloroquine-resistant African Plasmodium falciparum strains. For all isolates, the 50% inhibitory concentrations of amopyroquin were much lower than those of chloroquine and monodesethylamodiaquine.

Absorption↗
PubMed1987

Disposition of monodesethylamodiaquine after a single oral dose of amodiaquine and three regimens for prophylaxis against Plasmodium falciparum malaria.

The disposition of monodesethylamodiaquine was studied in four healthy subjects after a single oral dose of 10 mg/kg amodiaquine base. Amodiaquine was not found in any sample, but the major metabolite monodesethylamodiaquine was detected and was assumed to be the sole derivative that contributed significantly to antimalarial activity in the blood. The best fit for the decay of the metabolite was obtained with a three-compartment model. The half-lives of the first two phases were 3.2 to 11.4 h for t1/2 alpha 1 and 22.7 to 50.3 h for t1/2 alpha 2 in plasma. The half-life of the terminal phase (t1/2 beta) was between 9 and 18.2 days. The concentration in whole blood was 4- to 6-times higher than in plasma. Three schedules (alternate days, weekly, daily) of the conventional prophylactic dose of 10 mg/kg per week were compared in six other healthy subjects. There were significant differences in the plasma monodesethylamodiaquine levels between the three schedules.

Adult↗
PubMed1986

Simultaneous determination of chloroquine, amodiaquine and their metabolites in human plasma, red blood cells, whole blood and urine by column liquid chromatography.

A column liquid chromatographic method for the simultaneous determination of chloroquine, amodiaquine and their monodesethyl metabolite in human plasma, red blood cells, whole blood and urine is described. The drugs and internal standard were extracted as bases with methylene dichloride and then re-extracted into an acid aqueous phase. Separation was obtained using a reversed-phase column and a mobile phase of phosphate buffer (pH 3.0)-acetonitrile (88:12). The absorbance of the drugs was monitored at 340 nm with a sensitivity limit of 10 pmol/ml. No endogenous compound interfered at this wavelength. The mean overall recovery from each biological fluid was greater than 75%. This method can be applied to therapeutic, pharmacokinetic and epidemiological studies. The metabolism of these two amino-4-quinolines in humans is compared.

Amodiaquine↗
PubMed1985

[Pharmacokinetics of amodiaquine and prevention of Plasmodium falciparum malaria].

Amodiaquine might appear as an alternative in prophylaxis of chloroquine-resistant P. falciparum malaria. In an attempt to explain the discrepancy between its in vivo-in vitro activity, a pharmacokinetic study was conducted in healthy subjects with HPLC assays. The results showed that: amodiaquine was no more detected in the blood, a main metabolite (monodesethyl derivative) appeared as the active form of the drug in vivo, metabolite's half-life had a mean value of 15.6 +/- 5.4 days. This study shows that monodesethylamodiaquine (and not amodiaquine) must be monitored in vitro. Furthermore the high individual variations of blood levels and half-life's values suggest that the weekly prophylactic schedule must be eventually re-evaluated.

Adult↗
PubMed1985

[Biotransformation of amiodaquine and prophylaxis of Plasmodium falciparum malaria].

The authors have devised a specific HPLC method for amodiaquine assay which demonstrated that the drug disappeared rapidly from the blood of subjects under prophylaxis for malaria (10 mg/kg/week in a single oral dose). The main metabolite was identified as the monodesethyl derivative which is the only active form of the drug. The low erythrocytic levels of the metabolite, observed at day +7, might account for the failure in the prophylaxis of P. falciparum malaria with amodiaquine in a few cases. The in vitro activity of monodesethyl amodiaquine should be evaluated during the chemosensitivity tests and the chemoprophylaxis schedule, re-evaluated.

Amodiaquine↗