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Biomedical subjects

A Benakis

Publications and source records attributed to A Benakis.

At least 19 recordsLinked to original sources
PubMed1998

Plasma levels of artesunate and dihydroartemisinin in children with Plasmodium falciparum malaria in Gabon after administration of 50-milligram artesunate suppositories.

A thermostable suppository of artesunate (artesunic acid) has been developed. In Gabon, 12 children with Plasmodium falciparum malaria received two administrations of this suppository in a 4-hr interval. Parasitemia and fever were then measured and the plasma levels of artesunate and its active metabolite, dihydroartemisinin, were determined by means of a reversed phase high-pressure liquid chromatography method using reductive electrochemical detection. Substantial parasite clearance (97-100%) was noted 24 hr after the beginning of the treatment and body temperature had returned to normal. Absorption, metabolism, and elimination of artesunate were rapid. Mean values of maximum plasma levels (Cmax) and maximum concentration peak times (tmax) were evaluated. The Cmax of dihydroartemisinin (0.18 +/- 0.10 microg/ml [mean +/- SE]) was higher than the Cmax of artesunate (0.09 +/- 0.04 microg/ml) and the tmax of dihydroartemisinin (1.13 +/- 0.58 hr) was higher than the tmax of artesunate (0.58 +/- 0.19 hr). Plasma levels 30 min after the second suppository administration were not consistently higher than those found 30 min after the first administration.

Absorption↗
PubMed1997

Pharmacokinetics of artemisinin and artesunate after oral administration in healthy volunteers.

This study was designed to determine the pharmacokinetic parameters of a new pharmaceutical form of artemisinin (a natural substance extracted from the Artemisia annua L. plant) and of one of its derivatives, artesunate, a semisuccinate of 12-hydroxy-artemisinin. These two compounds are widely used in the treatment of malaria. The new oral forms of these two compounds, in 250-mg tablets, were used in two parallel pharmacokinetic studies. For artemisinin, the mean pharmacokinetic parameters were maximum drug concentration (Cmax) = 0.36 microgram/ml; peak time (tmax) = 100 min; appearance half-life (t1/2 max) = 0.62 hr; distribution half-life (t1/2 alpha) = 2.61 hr; decline half-life (t1/2 beta) = 4.34 hr; and total area under the concentration-time curve (AUC) = 1.19 micrograms.hr/ml. For artesunate, its main metabolite, dihydroartemisinin, was measurable in the plasma. The mean pharmacokinetic parameters for dihydroartemisinin were appearance rate constant (Ka) = 2.11 hr-1; elimination rate constant (Ke) = 1.18 hr-1; biotransformation half-life = 0.33 hr; elimination half-life = 0.65 hr; and AUC = 0.74 microgram.hr/ml. Both pharmaceutical forms were well-tolerated and no undesirable side effects were observed in any of the subjects.

Administration, Oral↗
PubMed1994

Vecuronium neuromuscular blockade reflects liver function during hepatic autotransplantation in pigs.

BACKGROUND: Rapid assessment of hepatic function early after reperfusion of the liver graft is of great importance, because it may allow for prompt detection of incipient hepatic graft failure. The current study was undertaken to determine whether the continuous recording of neuromuscular transmission could be used as an on-line assessment of hepatic function during liver transplantation when a muscle relaxant with high hepatic uptake is used. METHODS: We quantified and compared the effect of liver exclusion and graft reperfusion on the level of vecuronium-induced neuromuscular blockade in nine pigs studied twice within 3 days. During the 1st day (control session), an intravenous infusion of vecuronium was administered to maintain a constant 90-95% twitch depression during 180 min. The twitch response was then allowed to recover spontaneously to 75% of its prerelaxant value. Neuromuscular transmission was continuously measured on the right anterior leg using an acceleration transducer. During the same time period, the metabolic rate of 14C-labeled aminopyrine (a well-established quantitative test of the liver microsomal function) was determined by measuring the excretion of 14CO2 in expired air after administration of an intravenous bolus of 14C-labeled aminopyrine. Two days later, the pigs underwent a hepatic autotransplantation, during which vecuronium was administered to maintain a constant 90-95% twitch depression. After reperfusion of the liver graft, the vecuronium infusion rate was maintained at its anhepatic level, and the recovery index of the neuromuscular blockade (the time from 25% to 75% recovery of twitch height) was calculated. The aminopyrine breath test was performed during the last 30 min of the anhepatic phase, and during 3 h after reperfusion of the liver graft. RESULTS: During control studies, the mean infusion rate of vecuronium was 1.30 +/- 0.33 mg.kg-1.h-1 and the recovery index was 3.4 +/- 0.5 min. During liver dissection, the infusion rate of vecuronium was similar to the control value (1.18 +/- 0.16 mg.kg-1.h-1), then considerably decreased to 0.05 +/- 0.03 mg.kg-1.h-1 during the anhepatic phase. After reperfusion of the liver graft, the recovery index was markedly prolonged to 35.5 +/- 15.8 min, indicating a prolongation of the recovery of neuromuscular blockade by a factor of 10.4. Excretion of 14CO2 was equal to zero during the anhepatic phase and then increased to 0.19 +/- 0.11% during the 1st h after reperfusion of the liver graft, an excretion rate corresponding to 11.2% of control conditions. The relationship between individual changes in the recovery index of the neuromuscular blockade and 14CO2 excretion in expired air after reperfusion of the liver graft showed a strong significant correlation (r2 = 0.71). CONCLUSIONS: These results indicate that, compared with the control studies, there is a similar decrease in the recovery rate of vecuronium-induced neuromuscular blockade and in the metabolic rate of 14C-labeled aminopyrine during the progressive recovery of hepatic function immediately after unclamping of the liver vessels. Metabolism of 14C-labeled aminopyrine increased progressively during the reperfusion phase. Therefore, recording of neuromuscular transmission during liver transplantation could serve as a continuous and easy to perform assessment of liver graft function provided that a muscle relaxant with a high hepatic uptake is used for neuromuscular blockade.

Aminopyrine↗
PubMed1994

The interaction of artemisinin with red cell membranes.

Artemisinin (qinghaosu) and its derivatives are endoperoxide-containing compounds that are an important new class of antimalarial drugs. Tritiated dihydroartemisinin is taken up and concentrated by isolated red cell membranes but not by intact erythrocytes. More than half of the membrane-associated drug can be released by treatment with phospholipase A2 followed by extraction with ethyl acetate. The remaining drug appears to be bound to the major red cell membrane proteins. There is no association of the drug with either the membrane or cytoplasm of intact red cells. Thus dihydroartemisinin appears to be taken up by isolated membranes, where it associates with proteins but not via intact red cells.

Antimalarials↗
PubMed1993

Morphologic effects of artemisinin in Plasmodium falciparum.

Ultrastructural changes induced in Plasmodium falciparum by artemisinin were studied in vitro. Electron microscopic autoradiography was performed on infected erythrocytes that were exposed in vitro to 3H-dihydroartemisinin and 14C-artemisinin. These drugs consistently were located in food vacuoles and mitochondria. Two hours after administration, changes were observed in parasite mitochondria, rough endoplasmic reticulum, and nuclear envelope. At four hours, in addition to the earlier changes, nuclear membranes and, to a lesser extent, some plasma membranes formed myelin figures. In addition, there was a disappearance of ribosomes, and a destruction of food vacuole membranes. These changes may lead to the total disorganization of the parasites. Approximately 30% of the parasites manifested these alterations.

Animals↗
PubMed1992

[Aminopyrine breath test in hepatic auto-transplantation in pigs].

The aminopyrine breath test (ABT) was performed during hepatic autotransplantation in the pig. The test is reproducible in this animal and only hepatic cytochromes perform the demethylation of aminopyrine. Ischemia, varying from 90 to 200 minutes, generated a major decrease in the elimination of the 14CO2 and a marked change in the elimination curve. In this specific model it was not possible to assess survival of the animal by the ABT.

Aminopyrine↗
PubMed1990

Dose requirements and plasma concentrations of pipecuronium during bilateral renal exclusion and orthotopic liver transplantation in pigs.

We have studied five pigs undergoing bilateral clamping of the renal pedicles, seven pigs undergoing orthotopic liver transplantation and three control animals without surgery in order to examine the roles of the kidney and liver in the plasma clearance of pipecuronium. An i.v. infusion of pipecuronium was controlled to maintain a constant 90-95% twitch depression throughout the investigation. The right sciatic nerve was stimulated continuously with supramaximal stimuli at 0.1 Hz and the force of the corresponding evoked isometric muscle contraction was recorded continuously. Control pigs needed an infusion rate of pipecuronium 8-10.7 micrograms kg-1 min-1. In the renal group, it was necessary to reduce the infusion rate of pipe-curonium by about 25% after clamping both renal vascular pedicles (P less than 0.05 compared with controls); in pigs undergoing liver transplantation, it was necessary to reduce the rate by approximately 80% after clamping hepatic vessels (P less than 0.05 compared with controls and from the period after clamping of renal vessels). After hepatic recirculation, the infusion rate of pipecuronium was increased progressively to a rate which corresponded to 50% of baseline values (P less than 0.05 compared with the anhepatic phase and from controls). Plasma concentrations of pipecuronium were comparable in the three animal groups and did not change significantly during the study. These data suggest that the liver plays a more important role than the kidney in the plasma clearance of pipecuronium in pigs.

Androstane-3,17-diol↗
PubMed1990

Plasma concentrations of laudanosine, but not of atracurium, are increased during the anhepatic phase of orthotopic liver transplantation in pigs.

To quantify the changes in plasma concentrations of atracurium and laudanosine induced by the lack of hepatic function and circulation, the authors studied nine domestic pigs (22-25 kg) undergoing an orthotopic liver transplantation, and three control animals without surgery, using atracurium as the muscle relaxant. After intubation facilitated by isoflurane 2-3%, anesthesia was maintained with isoflurane (0.5% in oxygen) and fentanyl (4 micrograms.kg-1.hr-1). Ventilation was controlled to keep end-tidal CO2 at 35-40 mmHg, body temperature maintained at 35.5-37.5 degrees C, and arterial pH at 7.35-7.50. The right sciatic nerve was stimulated with a nerve stimulator delivering a single twitch at 0.1 Hz with 0.2-ms duration, at supramaximal stimulation. The force of the corresponding evoked isometric muscle contraction was continuously measured by a force-displacement transducer. A single iv bolus of atracurium (2 mg/kg) was given to obtain a 90-95% twitch depression, followed 5 min later by a constant-rate iv infusion of atracurium at 120 micrograms.kg-1.min-1 maintained during the entire investigation. Blood samples for plasma atracurium and laudanosine concentrations were drawn every 15 min. In the control group, plasma concentrations of atracurium remained stable between 6.5-8.0 micrograms/ml following initial bolus injection; plasma concentrations of laudanosine increased during the first 60 min, then remained stable between 0.69-0.74 micrograms/ml up to the end of the study. In animals undergoing transplantation, plasma concentrations of atracurium remained stable between 10-12 micrograms/ml, despite a 90-min duration of liver exclusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1979

Motility and stereotyped behaviour induced by amphetamine and apomorphine on hypophysectomized and on thyroidectomized rats.

The reduction of the hypermotility and stereotyped behaviour induced by amphetamine and apomorphine was used as a criterion for the effectiveness of neuroleptics. Considering the impact of neuroleptics on the hypophysis as well as the relationship between the hypophysis and the thyroid, motility and stereotyped behaviour induced by amphetamine and apomorphine was studied in both hypophysectomized and thyroidectomized rats. In the hypophysectomized rat, amphetamine-induced hypermotility, observed between 1 and 3 hours after administration, was almost 3 times greater than in normal animals. Thyroidectomy resulted in a reversal of the motility effect induced by amphetamine. The stereotyped behaviour induced by apomorphine was practically abolished in both hypophysectomized and thyroidectomized animals.

Amphetamine↗
PubMed1979

Comparative study of the inductive effect of two psychomoderators--tetrabamate and complexe 1656--and of phenobarbital on liver microsomal enzymes in rats.

Tetrabamate (Atrium) and Complexe 1656, two psychosedative drugs, are complexes formed by phenobarbital with its N-substituted derivatives. We have studied the induction effect of all these compounds on the microsomal liver enzymes in male rats. Tetrabamate and Complexe 1656 were found to be equally effective in increasing the amount of microsomal proteins, cytochrome P-450 and the in vitro aniline p-hydroxylation and amino-pyrine N-demethylation activity. These effects were similar to those obtained after a treatment with an equivalent dose of phenobarbital. Febarbamate and difebarbamate had no significanteffect on microsomal enzymes. The inductive effect of tetrabamate and of its analogue seems essentially due to the phenobarbital content of these complexes.

Animals↗
PubMed1977

Induction of hepatic microsomal enzymes by diuron, phenobenzuron, and metabolites in rats.

Microsomal liver enzymes are induced in rats which are fed a diet containing 1000 ppm of phenobenzuron, a phenylurea herbicide, for 7 days: All parameters measured are about 50% higher than control values. This increase is lower after 14 feeding days. Diuron and 3,4-dichloroaniline have a similar, although lower, effect than phenobenzuron. Two other metabolites have no action on microsomal enzymes. The transitory and weak inducing effect of these phenylureas is interesting when compared to other organochlorine pesticides.

Animals↗
PubMed1977

[Liver extract effect on liver microsomal system and on an experimental model of intoxication].

A lyophilized liver extract (FLR) lengthens hexobarbital action in control rats ; it decreases slightly the induction of hepatic microsomal enzymes and normalizes diphenylhydantoin protection against electroshock seizure in phenobarbital-treated animals ; in the event of a CC14 intoxication, this extract reestablishes values close to normal for mebubarbital metabolism in mice and for BSP clearance in rats. FLR could act in regularizing drug metabolism.

Animals↗
PubMed1975

Pharmacokinetic study of maleate acid of 2-(N,N-dimethylaminoethanol-14C1)-cyclohexylpropionate (cyprodenate) and of N,N-dimethylaminoethanol-14C1 in animals.

The localization, distribution, and elimination of maleate acid 2-(N,N-dimethylaminoethanol-14C1)-cyclohexylpropionate (14C-cyprodenate, Actebral) was studied in rats and pigs. Beside this, dimethylaminoethanol-14C (DMAE) was also administered to rats enabling a comparison of the pharmacokinetics of the two 14C-labelled molecules to be made. The study of the localization by autoradiography and the study of the quantitative distribution of the radioactivity showed that cyprodenate, a psychotonic drug, diffused more rapidly than DMAE through the hemo-encephalic barrier. However, it was also observed that the radioactivity found in the brain rises continually as a function of time, regardless of the product administered. The two labelled products were primarily excreted in the urine (30-35 per cent of the dose in 72 h in rats and 6 per cent of the dose in 48 h in pigs) following oral administration of cyprodenate. Radioactivity found in the feces was practically nil and in rats the biliary elimination of the drug was very weak. Thus, whichever animal is used, it was found that 14C-cyprodenate is totally absorbed. Radioactivity expired as 14CO2 was negligible (around 1 per cent of the administered dose in 8 h), however, this value increases as a function of time, becoming 4 per cent in 24 h. In rats the maximum radioactivity in the blood was found at 45 min to 1 h after oral administration of 14C-cyprodenate. These values decrease slowly until 3 h when they begin to increase again. The rising of the blood level values is practically the same for pigs, the maximum being attained at 1 h. Therefore, whatever route of administration, whichever dose or animal, we always found a progressive elevation of the protein binding to the plasma proteins for these two labelled products in vivo.

Animals↗