Biomedical subjects
Publications and source records attributed to A Dresse.
It has been shown previously that cefoxitin was not detectable in the milk following an intramuscular injection of 1 Gm to mothers. In the present study, using a more sensitive HPLC method, we have shown in five women that low concentrations of cefoxitin (0.25 to 0.65 micrograms/ml) are measured in the milk after the intramuscular injection of 2 Gm.
Sulmazol (AR-L 115 BS) is a new inotropic drug which has arterial and venous vasodilating properties. We used it in seven patients with severe refractory heart failure to determine the effective plasma concentration levels and the most effective bolus dose on haemodynamics. The haemodynamic monitoring included a Swan-Ganz catheter in the pulmonary artery and a radial catheter. Haemodynamic measurements and plasma concentration determinations were performed before sulmazol injection and at 5, 10 and 30 min after a bolus 0.25, 0.50, 0.75 mg/kg. We observed a gradual increase in cardiac index and decrease in pulmonary wedge pressure when plasma concentration levels rose but the beneficial effects were mainly observed for sulmazol plasma concentrations above 1 microgram/ml. A bolus injection of 0.75 mg/kg was effective in all cases: a significant increase of cardiac index (1.9 to 2.5 1 min-1 m-2; P less than 0.001) and a significant decrease in pulmonary wedge pressure (30 to 25 mm Hg; P less than 0.005) and right atrial pressure (13 to 10 mm Hg, P less than 0.01) were observed. In these patients sulmazol improved the severely deteriorated left ventricular function without affecting heart rate and blood pressure.
Sulmazol (AR-L 115 BS) is a new positively inotropic drug with arterial and venous vasodilating properties. We studied the effects of sulmazol (three-day infusion) on clinical tolerance, hemodynamics, and blood gas levels in ten patients with severe chronic heart failure. The hemodynamic monitoring included a Swan-Ganz catheter in the pulmonary artery and a radial catheter. Blood gas levels were determined on samples of arterial and mixed venous blood. After 24 hours of infusion, there was a significant increase in cardiac index (2 to 2.5 L/min/sq m; p less than 0.005) and a significant decrease in pulmonary wedge pressure (28 to 19 mm Hg; p less than 0.001) and in right atrial pressure (7 to 4 mm Hg; p less than 0.001) without significant changes in heart rate and systolic blood pressure. These beneficial effects lasted during the three days of infusion. Oxygen delivery was significantly increased (350 to 443 ml/min/sq m; p less than 0.005) without significant change in arterial oxygen tension. The side effects included nausea, vomiting, anorexia, and mild thrombocytopenia. We conclude that sulmazol is a potent drug which may improve severely deteriorated left and right ventricular function in patients with chronic refractory heart failure without affecting the heart rate and the systolic blood pressure.
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The principal neurochemical property of tricyclic antidepressants is the blockade of noradrenaline (NA) and/or 5-hydroxytryptamine (5-HT) uptake into monoaminergic nerve endings. Electrophysiological studies show that these drugs also decrease the firing rate of the noradrenergic neurones of the locus coeruleus (L.C.) and of the serotonergic neurones of the dorsal raphe (D.R.). In order to assess the relation between the two phenomena, the influence of five tricyclic antidepressants on NA and 5-HT uptake was studied in vitro. The concentrations required to produce a 50% inhibition (IC50) were determined and correlated with the respective doses required to reduce to 50% (ID50) the firing rate of L.C. and D.R. neurones. Ex vivo experiments were also performed to study the influence of the tricyclic antidepressants on NA and 5-HT uptake when administered i.v. at the doses decreasing to 50% the firing rate of L.C. and D.R. cells. The inhibition of the NA uptake by tricyclic antidepressants can account, at least in part, for the inhibition of the firing rate of L.C. neurones observed after acute i.v. administration. In the case of serotonergic neurons, the results do not allow a firm conclusion.
Two preparations of dipyridamole have been studied by oral administration to 11 normal volunteers. The plasma levels of dipyridamole and its glucuronide were determined simultaneously by high performance liquid chromatography. The instant form (I.F., 100 mg) was administered four times daily and the slow release preparation (SRP, 200 mg) twice daily, for 3 days. Multiple blood samples were collected on Days 1-4 to provide plasma for assay, and simultaneously, platelet rich plasma was prepared for ex vivo study of the effect of dipyridamole on platelet uptake of adenosine. The pharmacokinetics of absorption and distribution of dipyridamole were described using a two compartment model with lag time and prolonged absorption. Strong inhibition of the platelet adenosine uptake was observed at therapeutic plasma levels. The inhibition of platelet adenosine uptake may be related to some of the pharmacological properties of dipyridamole.
1 The aim of this study was to evaluate the influence of renal insufficiency on the plasma pharmacokinetics of mexiletine, a new antiarrhythmic agent, in human beings. 2 Mexiletine was administered orally three times daily for 10 days to 15 patients with chronic renal failure (creatinine clearance lower than 30 ml/min) and to 9 subjects with normal renal function. 3 The use of low doses of mexiletine was possible owing to the development of a new fluorescence h.p.l.c. method with a limit of sensitivity lower than 20 gn/ml. 4 Our results clearly indicate that the plasma kinetics of mexiletine are not modified when the renal clearance of creatinine is higher than 10 ml/min.
The firing rate of central noradrenergic, serotonergic and dopaminergic neurons was recorded in rats anaesthetized with chloral hydrate. The i.v. perfusion of amineptine decreased the frequency of discharge of noradrenergic and dopaminergic neurons but had no effect on serotonergic cells. Quantitatively amineptine was a more potent inhibitor of dopaminergic than of noradrenergic neurons. These experiments in vivo confirm biochemical studies in vitro reporting a selective action of amineptine on dopaminergic systems.
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In former investigations on human focal epilepsy and on experimental epilepsy by cobalt implantation, the authors have demonstrated the signaletic importance of "activated astrocytes": cortical astrocytes endowed with a modified metabolism and an accelerated turnover. The present study concerns the results of the intra-amygdaloid injections of kainic acid, a strong excitatory and neurotoxic amino acid. Injections in semi-chronic conditions in the rat lead to electrical and motor seizures and to the production of activated astrocytes not only in regions that might trigger off epileptic seizures (cerebral cortex, amygdala, possibly hippocampus), but also in the neostriatum. Stimulation of this last region results in a Huntington chorea-like syndrome. Thus, the importance of activated astrocytes must be extended to include other conditions of intense hyperactivity of neurons than epilepsy.
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Mexiletine (Mexitil) is an effective antiarrhythmic drug for the treatment of ventricular dysrhythmias. The therapeutic plasma level is situated between 0.75 and 2 microgram/ml. For concentrations higher than 2 microgram/ml, the percentage of severe side effects is rapidly increasing without improvement of the therapeutic efficacy. The main pharmacokinetics parameters of mexiletine are reviewed in the first part of this publication. Contrary to lidocaine, mexiletine may be administrated orally (or intravenously). It is largely and rapidly distributed in the body. The apparent volume of distribution (Vd) is greater than 500 1. The plasma half-time is 10 to 12 hours in healthy volunteers with a 70% plasma protein fixation. Mexiletine is largely metabolized to conjugates after N-methylation and hydroxylation. In the second part of the work, the influence of renal insufficiency on the plasma half-time of mexiletine has been investigated in 11 patients presenting a creatinine clearance situated between 2 and 38 ml/min. The mean plasma half-time for these patients is 11.1 +/- 1.7 hours after a single i.v. injection of 1.5 mg/kg. This value is comparable to the normal values found in the literature. Our control group containing convalescents from acute myocardial infarct has a plasma half-time of only 5.9 hours. In conclusion, the renal insufficiency has not modified the plasma elimination half-time of mexiletine after a single i.v. injection.
1 The uricosuric effect of diflunisal was studied in eleven normal subjects. 2 Urine and serum uric acid levels were measured and used to assess the effect. 3 Diflunisal caused statistically significant decreases in serum uric acid levels and increases in uric acid clearance at 250 and 375 mg twice daily. 4 Diflunisal taken on an empty stomach caused epigastric discomfort in the high dose group which was obviated when the drug was taken with meals. 5 Diflunisal caused no abnormalities in the measured haematological, urological or biochemical parameters.