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Biomedical subjects

E Benoit

Publications and source records attributed to E Benoit.

At least 19 recordsLinked to original sources
PubMed1992

Identification of a benzhydrolic metabolite of ketoprofen in horses by gas chromatography-mass spectrometry and high-performance liquid chromatography.

A benzhydrolic metabolite of ketoprofen, formed by reduction of the keto group of the drug, has been identified by gas chromatography-mass spectrometry in equine plasma and urine. After partial synthesis, its structure has been confirmed by UV, IR and 1H NMR spectroscopy. The kinetics of ketoprofen and this metabolite have been monitored in plasma by high-performance liquid chromatography. The two products were quantified in plasma up to 4 and 3 h, respectively, and were detected in urine up to 72 and 24 h, respectively, after a single intravenous administration to horses at the dose of 2.2 mg/kg. Simultaneous detection of both compounds increases the reliability of antidoping control analysis.

Animals↗
PubMed1992

Purified ciguatoxin-induced modifications in excitability of myelinated nerve fibre.

The effects of external applications of 0.22-1.12 nM of purified ciguatoxin (CTX-1B), extracted from the moray-eel, were studied on frog current and voltage clamped node of Ranvier. CTX-1B induced spontaneous action potentials at a frequency of 70-100 Hz, suppressed by 50 microM lidocaine, which resulted from a toxin-induced maintained (late) inward Na current representing about 5.5% of peak Na current. Peak and late currents showed different voltage characteristics but were similarly affected by 50-500 microM lidocaine. It is concluded that the effects of CTX-1B are qualitatively but not quantitatively similar to those previously studied of partially purified toxin (2).

Action Potentials↗
PubMed1992

Effect of repeated doses of albendazole on enantiomerism of its sulfoxide metabolite in goats.

Five adult Saanen goats were dosed orally 3 times with albendazole (2.5 mg/kg of body weight) at 24-hour intervals, and blood samples were taken by jugular venapuncture at standardized intervals. Plasma was analyzed to determine concentrations of S-oxidation metabolites, and a chiral column was used for enantiomeric discrimination of the sulfoxide metabolite of albendazole. Marked changes were evident between the first and subsequent plasma profiles concerning, on one hand, the proportions of sulfoxide and sulfone metabolites concentrations and, on the other hand, the enantiomeric balance of sulfoxide metabolite. These correlated phenomena may be explained by the following arguments: the enzyme responsible for sulfoxidation is mainly a flavine-containing monooxygenase, whereas the enzyme responsible for sulfonation is a cytochrome-dependent monooxygenase; the latter, but not the former, is induced by albendazole; the enantioselectivities of both enzymic systems are opposite, the flavine produces the (+) sulfoxide, whereas the cytochromes can use as a substrate, specifically, the (-) sulfoxide.

Albendazole↗
PubMed1991

Riluzole specifically blocks inactivated Na channels in myelinated nerve fibre.

The effects of 0.15-250 microM riluzole, a novel psychotropic agent with anticonvulsant properties, were studied on voltage-clamped nodes of Ranvier of isolated nerve fibres of the frog. When added to the external solution, the drug rapidly and reversibly inhibited both K and Na currents with an apparent dissociation constant of 0.09 mM. The riluzole-induced decrease of these currents was not "use-dependent". At concentrations up to 100 microM, the drug had no noticeable effect on the time course of Na current inactivation nor on the shape and the position along voltage axis of the Na conductance/voltage relationship. On the other hand, it induced substantial shifts towards negative voltages of the steady-state Na inactivation/voltage curve. From these results, according to the modulated-receptor model, an apparent dissociation constant of 0.29 microM could be calculated for riluzole-induced blockage of inactivated Na channels. The recovery from Na current inactivation was also affected by the drug. It is concluded that riluzole is a highly specific blocker of inactivated Na channels, which is more than 300 times more effective on these channels than on K or resting Na channels.

Animals↗
PubMed1991

Chiral behaviour of the metabolite albendazole sulphoxide in sheep, goats and cattle.

Three sheep, three goats and three cattle were dosed orally with 5.0, 7.5 and 10 mg albendazole kg-1 bodyweight, respectively. Blood samples were taken at intervals for 48 hours after administration. The enantiomeric ratio of the metabolite albendazole sulphoxide (SO.ABZ) was determined by liquid chromatography on chiral stationary phases. At To, the plasma concentration ratio (+)SO.ABZ/(-)SO.ABZ was estimated at 3.0 in sheep, 1.5 in goats and 4.0 in cattle. The proportion of the (+) enantiomer then increased linearly as a function of time during the course of the kinetics. In comparison to the area under the curve for total SO.ABZ, the (+) enantiomer represented 86 per cent in sheep, 80 per cent in goats and 91 per cent in cattle. The specific behaviour of the two enantiomers is probably the result of the enantioselectivity of the flavine adenosine dinucleotide and cytochrome P450 dependent enzymatic systems which are involved in the sulphoxidation and the sulphonation of ABZ.

Administration, Oral↗
PubMed1991

Comparative enantioselectivity in the sulphoxidation of albendazole in man, dogs and rats.

1. H.p.l.c. analyses were performed to investigate the plasma kinetics of albendazole (ABZ), the sulphoxide (SO.ABZ) and sulphone (SO2ABZ) metabolites, as well as the chirality vs time of SO.ABZ, after oral administration to rats, dogs and man of prochiral sulphide antiparasitic drug ABZ. 2. In all three species the initial plasma concentration ratio of the enantiomers, as soon as SO.ABZ could be detected in plasma, was that of a racemate. 3. Subsequently, the ratio (+)/(-) increased linearly with time, reaching values of 13.1 and 9.3 in man and dogs, respectively, while it decreased to 0.6 in rats. 4. The (+) enantiomer represents 80%, 70% and 41% of the area under the curve of the total SO.ABZ in man, dogs and rats, respectively.

Albendazole↗
PubMed1990

Species differences in the generation of the chiral sulfoxide metabolite of albendazole in sheep and rats.

The prochiral anthelmintic drug albendazole was administered orally to sheep and rats. Blood samples were taken at standardized intervals during the time course of the plasma kinetics: 18 h in rats and 48 h in sheep. The enantiomeric ratio of the sulfoxide metabolite was determined by means of HPLC on a chiral stationary phase, the chiral selector of which was a N-3,5-dinitrobenzoyl derivative of (S)-tyrosine. Two enantiomers were detected in both animal species but their ratios were inverted in rat vs. sheep. The evolution of the ratio is turned from a racemate at 15 min to 60(-):40(+) at 12 h in rats, while it moved from 23(-):77(+) at 3 h to 4(-):96(+) at 36 h after administration in sheep.

Albendazole↗
PubMed1990

Chirality of the sulphoxide metabolites of fenbendazole and albendazole in sheep.

Two prochiral sulphide drugs, fenbendazole (FBZ) and albendazole (ABZ) were administered orally to sheep. Blood samples were analysed for parent drug and S-oxidation metabolites and the chirality of the sulphoxide metabolites was determined. The plasma concentrations of the enantiomers of the sulphoxides were never a racemate. On the contrary, the ratios were greater than 1 as soon as the sulphoxide compounds could be detected in plasma. They subsequently increased linearly throughout the time course of the kinetics, reaching the level 86:14 after FBZ and 95:5 after ABZ treatment. The major enantiomer represented 74% and 86% of the total AUC of SO.FBZ and SO.ABZ, respectively.

Albendazole↗
PubMed1990

Adrenal cortical response in clinically normal dogs before and after adaptation to a housing environment.

58 dogs (29 males and 29 females) selected as healthy on clinical and biochemical evaluations were subjected to an ACTH adrenal function test 2 days after their admission to a veterinary hospital (t + 0). Basal female serum cortisol concentrations were significantly higher than concentrations in males (77 nmol/l versus 43 nmol/l; P less than 0.01). Concentrations post stimulation were not statistically different (P greater than 0.05) between males and females: 306 (+/- 69) nmol/l versus 291 (+/- 73) nmol/l, respectively. Twelve dogs (6 males and 6 females), randomly selected from the 58, were subjected to the same test 5 weeks later (t + 5) and 12 weeks later (t + 12). Basal cortisol concentrations were lower at t + 5 or at t + 12 than at t + 0. Post stimulation mean cortisol concentrations were lower in males than in females at t + 5 (162 versus 232 nmol/l; P less than 0.05) but not at t + 0 (262 versus 320 nmol/l; P greater than 0.05) and t + 12 (188 versus 233 nmol/l; P greater than 0.05). These findings are indicating an increased susceptibility of bitches to environmental stress.

Adaptation, Psychological↗
PubMed1990

Pharmacokinetics in sheep and cattle of albendazole administered by an intraruminal slow release capsule.

Forty sheep and 40 heifers were dosed with an intraruminal slow release capsule (IRSRC) constructed to deliver albendazole (ABZ) at a low daily dosage for three months. Blood samples were collected at standardised intervals for 110 days and analysed by high performance liquid chromatography for the quantification of the two main metabolites sulphoxide (SO.ABZ) and sulphone (SO2ABZ). The plasma profiles show sustained concentrations of the active metabolite SO.ABZ for 105 days in sheep (m = 0.06 +/- 0.032 micrograms ml-1) and 85 days in cattle (m = 0.10 +/- 0.019 micrograms ml-1). In both species, the proportions of the metabolites were inverted compared to that observed after a single dosage. The bioavailability of ABZ after the administration of the IRSRC compared with a drench was reduced in sheep but increased in cattle. The IRSRC exhibited a preventive and therapeutic effect for at least three months.

Albendazole↗
PubMed1989

Membrane currents in lizard motor nerve terminals and nodes of Ranvier.

Presynaptic membrane currents were recorded by external electrodes and nodal membrane currents were obtained by the voltage clamp technique in motor nerve endings and nodes of Ranvier of the lizard Anolis carolinensis. Although of compact shape, lizard motor endings display relatively long terminal branches; they exhibit, in agreement with previous findings in mouse and frog motor terminals, Na, Ca and K conductances, the latter consisting of a voltage- and a Ca-dependent type. Lizard nodes of Ranvier, like those of the frog, but unlike those of the mouse, exhibit a K conductance. These observations provide an explanation for the differences and similarities in presynaptic wave form configuration between the lizard and the other two species.

Animals↗
PubMed1988

Mechanism of action of a structural analog of alphaxalone on myelinated nerve fibre.

The action of alphadolone acetate (0.05-5 mM), a steroid anaesthetic and structural analog of alphaxalone, was investigated on frog myelinated axons under voltage-clamp conditions. When applied externally, alphadolone acetate reduced K and Na currents, with apparent dissociation constants of 0.70 and 1.74 mM, respectively, and without noticeable modification in their time course. In addition, Na conductance-voltage and steady-state inactivation-voltage curves were shifted towards negative voltages. This effect was more pronounced on the steady-state inactivation-voltage relationship. These results suggest that alphadolone acetate blocked K channels indifferently in their resting or open state, and Na channels preferentially in their inactivated state. Alphaxalone has been shown to preferentially block open K and inactivated Na channels (Benoit et al., 1988, Br. J. Pharmacol. 94, 635). Thus, a structural change of a steroid molecule can lead to differences in its mechanism of action. This supports the hypothesis of direct interactions between steroid molecules and target membrane proteins with resulting anaesthetic activity.

Anesthetics↗
PubMed1988

Inducing effect of albendazole on rat liver drug-metabolizing enzymes and metabolite pharmacokinetics.

Albendazole (ABZ), methyl (5-(propylthio)-1H-benzimidazol-2-yl)carbamate, is a broad spectrum anthelmintic drug. S-oxidation to the sulfoxide (SO-ABZ) and the sulfone (SO2-ABZ) are the first steps of its bioconversion. SO-ABZ is pharmacologically active and embryotoxic in rats. In the present study, rat liver microsomal drug-metabolizing enzymes were assayed after 10 days oral administration with 40 mumol ABZ/kg per day. The activities of 4-nitroanisole O-demethylase, benzo[a]pyrene hydroxylase, 7-ethoxycoumarin O-deethylase, and 7-ethoxyresorufin O-deethylase increased 6-, 7-, 8-, and 30-fold, respectively. By immunoblotting an increase in cytochrome P-448 was observed. UDP-glucuronosyltransferase (GT) type 1 activities (1-naphthol, 7-hydroxycoumarin, 4-nitrophenol, and 4-methylumbelliferone) were significantly higher than in control microsomes (3- to 4-fold), while GT type 2 activities and bilirubin-GT remained unchanged. Microsomal epoxide hydrolase (benzo[a]pyrene oxide) increased 2-fold. Microsomal gamma-glutamyltransferase activity was unchanged. The in vivo SO-ABZ plasma level was decreased when the SO2-ABZ plasma level was increased. In vitro sulfoxidation and sulfonation were, however, unchanged. Although a range of imidazole derivatives, including benzimidazole itself, were commonly reported as inhibitors of monooxygenase activities, ABZ behaved as an inducer of cytochrome P-448, GT1, and epoxide hydrolase.

Administration, Oral↗
PubMed1988

Interactions between molecules of a steroid anaesthetic (alphaxalone) and ionic channels of nodal membrane in voltage-clamped myelinated nerve fibre.

1. The effects of the anaesthetic alphaxalone (0.05 to 1 mM) on the node of Ranvier of isolated myelinated nerve fibres of the frog were studied under voltage-clamp conditions. 2. When added to the solution bathing voltage-clamped nodes, alphaxalone modified neither linear leakage nor capacitative currents but rapidly and reversibly blocked K and Na currents. The blocking effects of the anaesthetic on both types of current were not dependent on the frequency of stimulation of the nerve fibres between 0.7 and 10 Hz. 3. The kinetics of the Na current were not modified by alphaxalone but, in the presence of the drug, the K current showed an apparent fast inactivation. 4. Alphaxalone rapidly and reversibly shifted towards negative voltages both the steady-state K conductance-voltage and the peak Na steady-state inactivation-voltage relationships, without noticeable modification of their shape. In contrast, the anaesthetic reversibly decreased the slope of the peak Na conductance-voltage curve. 5. The reduction of the K current induced by alphaxalone was voltage-dependent with an apparent dissociation constant first decreasing from about 0.25 to 0.08 mM between -20 mV and +20 mV and then remaining constant above +20 mV. In contrast, the apparent dissociation constant for the Na current was almost constant with increasing voltages and equalled about 0.30 mM. Hill coefficient values for both K and Na currents were noticeably less than one. 6. It is concluded that, at higher concentrations than those attainable in the brain or in the plasma during surgical anaesthesia in man, alphaxalone has a 'local anaesthetic-like' action on the peripheral nervous system in that it specifically and differentially interacts with K and Na channel gating systems: it is suggested that the anaesthetic would preferentially modify open K and inactivated Na channels.

Anesthetics↗
PubMed1987

Pharmacokinetics of oxfendazole in goats: a comparison with sheep.

In goats, there was a linear correlation of area under the plasma concentration-time curve (AUC) with dose in the range 0-20 mg/kg as single dosages of oxfendazole (OFZ). The bioavailability of OFZ after oral administration was lower in goats than in sheep. The repetition of three administrations at 24 h intervals produced significant increase in the AUC in comparison with a single administration equivalent to the total dosage (1 X 5.0 and 3 X 1.7 mg/kg). Infection with O. circumcincta produced a 33% decrease in the bioavailability of OFZ.

Administration, Oral↗