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Biomedical subjects

P Gayral

Publications and source records attributed to P Gayral.

At least 19 recordsLinked to original sources
PubMed1998

Epoxyethane-/ethynesulfonamides with antifilarial activities. Degradation kinetics and inhibitory effect on filarial malate dehydrogenase and lactate dehydrogenase.

Some epoxyethane-/ethynesulfonamides had shown strong filaricidal activity with inconstant reproducibility as a result of a lack of stability in aqueous solution. The degradation in hydroxylic and aprotic solutions of two epoxyethanesulfonamides and one ethynesulfonamide was investigated using TLC, HPLC, GC and mass spectrometry. For both epoxydes, the degradation rate followed first-order kinetics and was more rapid in hydroxylic than in aprotic solutions. The degradation increased with the temperature whereas it was not modified with and without light exposure. Four kinds of degradation products were found: the first one involved the oxidation of the epoxyde bond, the second the breaking of the N-S bond, the third a desulfonation product and the fourth was not identified. In contrast, the stability of ethynesulfonamide was better than those of epoxyethanesulfonamide. These results suggest that epoxyethanesulfonamides should be kept at +4 degrees C before being injected to animals during the study of biological activity. Since epoxyde compounds are known to have inhibitory effects on parasite energy metabolism enzymes, the compunds were evaluated on two major filarial enzymes: lactate dehydrogenase (LDH) and cytoplasmic malate dehydrogenase (MDH). Both epoxyethanesulfonamides showed only a slight inhibitory effect on filarial LDH and MDH confirming the evidence that the main mode of action of these compounds remains to discover. Moreover, ethynesulfonamide and the degradation products of both epoxyethane-sulfonamides had no effect on LDH and MDH.

Animals↗
PubMed1998

[Fluctuations of serotonin and its metabolites in the lung and intestinal mucosa in the rat infected with Nippostrongylus brasiliensis].

The influence of parasitism on host biogenic amine levels was investigated in Nippostrongylus brasiliensis infected rats. Amine levels were estimated in tissues surrounding Nematods in their biological environment: the lung and intestinal mucus. D0 being the day of infestation, tissues were obtained at 24, 30 and 45 hrs, and every day between D4 and D14 (when the rat was completely deparasited by the self-cure phenomenon). Biogenic amines belonging to the serotoninergic pathway were quantified by HPLC with electrochemical detection. In the lungs and mucus, parasitism resulted in an important decrease in serotonine (5-HT) and 5-hydroxyindolacetic acid (5-HIAA) levels, as opposed to the immediate 5-HT precursor, the 5-hydroxy-tryptophane (5-HTP). Host response to parasitism is translated by serotoninergic pathway levels. This leads to two hypotheses: 5-HT turn-over may be accelerated, but the inhibition of 5-HT synthetic enzyme, 5-hydroxytryptophane hydroxylase, by the parasite present in the host seems more probable.

Animals↗
PubMed1997

Levels of biogenic amines in larvae and adults of the rat hookworm, Nippostrongylus brasiliensis (Nematoda).

Norepinephrine, 5-hydroxytryptophan, octopamine, dihydroxyphenylacetic acid, N-acetyldopamine, dopamine, 5-hydroxyindoleacetic acid, N-acetylserotonin, tyramine, tryptophan and serotonin in larvae (third free stage and parasitic stages) and adult males and females (at defined ages during the intestinal phase) of the parasitic nematode Nippostrongylus brasiliensis were quantified simultaneously by high-performance liquid chromatography with electrochemical detection. Biogenic amine levels depended on the stage, the age and the sex of parasites and on environmental conditions. Their physiological roles in reproductively competent adults of this nematode are discussed in relation to exuviation and egg laying. Parallel fluctuations in free ecdysteroids and norepinephrine were observed in females from the same worm populations.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1997

Tissue distribution and metabolism in rat of an ethynesulphonamide with filaricidal activity.

1. The tissue distribution and metabolism of a new filaricidal agent P903 (N-[(2-phenylethynyl)sulfonyl]morpholine) were studied in rat. 2. After s.c. administration of 14C and 13C P903, the Tmax in the blood was observed on day 2. Elimination was slow and > 95% was bound to protein. Radioactivity was distributed in the whole organism but particularly in erythrocytes and the lymphatic channel. Four days later, > 60% of the radioactivity was excreted in urine and faeces at equal amounts and 15% remained at the injection point. 3. In all biological fluids tested no P903 was found but only its metabolites. 4. One principal metabolite, the N-[(2-phenyloxo-2-ethane) sulphonyl] morpholine or oxosulphonamide was identified in blood, urine and faeces as compared with the reference compound by GC/MS and NMR. This latter molecule was detected following hydrolysis by hydrochloric acid but not with beta glucuronidase/sulphatase. 5. Unconjugated and conjugated oxosulphonamide represented > 85% of the radioactivity at all times tested in blood but only 38 and 35% respectively of urinary and faecal radioactivity on day 1 after the administration of the labelled drug. 6. Thus, P903 is rapidly converted to a reactive metabolite, probably an oxirene, which is then conjugated with endogenous components to form conjugated oxosulphonamide and an unknown metabolite. The role of this reactive metabolite in antifilarial activity seems to be very important in understanding the mechanism of action of P903.

Animals↗
PubMed1997

[Experimental studies of filaricides].

Several chemical compounds have shown filarical activities, which are presented and compared in this presentation: diethylcarbamazin, ivermectin, benzimidazoles and original compounds as epoxy and ethynesulphonamide, or carboxamides. Their metabolism and tissue distribution are depending of the host, and whether hosts are parasitized or not. Reference compounds have filaricidal activities depending of the stage of Filaria, and of the experimental model. The necessity of a good model is essential to extrapolate the results. Biochemical targets which can be identified from these animals models may be inappropriate for use in human filariasis; that is why fundamental research is still necessary in this area.

Animals↗
PubMed1996

Presence of norepinephrine and other biogenic amines in stonefish venom.

Although fish venoms exert a cardiovascular effect, the presence of adrenergic substances was not previously demonstrated. Chromatographic analysis with electrochemical detection showed the presence of substances co-migrating with norepinephrine, dopamine and tryptophan. Serotonin, which was thought to be implicated in the intense pain following fish envenomation, was not detected. Norepinephrine was identified as a component of the stonefish Synanceia verrucosa venom by gas chromatography-mass spectrometry.

Adrenergic alpha-Agonists↗
PubMed1996

[Leponex: experience of the hospital pharmacist].

Clozapine's monitoring, with a co-responsibility between psychiatrists and pharmacists, is very efficient for the prevention of neutropenia's side effects. This intensive drug safety has lowered the cases of agranulocytosis in France to a 0.5% prevalence. However the cost of clozapine led to a strict estimation for health expenditures. Our study, performed in a university department of psychiatry in Sainte-Anne Hospital (Paris), has included 14 patients treated with clozapine for at least 12 months and has displayed a decrease of 10% in their annual global cost, comparing with the same group of patients treated by classical neuroleptics during the preceding year. This global cost includes the treatment, the blood monitoring and the cost of different hospital or community cares. Quality of life, in the clozapine group, was much improved, as illustrated by the shortened full time hospitalization which was followed at an earlier stage by community care and earlier social readaptation.

Antipsychotic Agents↗
PubMed1995

[Leponex: experience of the hospital pharmacist].

Clozapine's monitoring, with a co-responsibility between psychiatrists and pharmacists, was very efficient for the prevention of neutropenia's side effects. This intensive drug safety has lowered the agranulocytosis' cases in France to a 0.5% prevalence. However the cost of clozapine led to a strict estimation for Health expenditures. Our study, trained in an university department of psychiatry in Sainte-Anne Hospital (Paris), has included 14 patients treated with clozapine during at least 12 months and has displayed a decrease of 10% in their annual global cost, comparing to the same group of patients treated by classical neuroleptics during the preceding year. This global cost includes the treatment, the blood monitoring and the cost of different hospital or community cares. Quality of life, in clozapine group, was much improved as illustrated by lowing full time hospitalization relayed earlier by community care and precocious social readaptation.

Agranulocytosis↗
PubMed1995

In vitro and in vivo antifilarial activity of ethynesulfonamides, epoxyethanesulfonamides and carboxamide analogues.

A series of 2-substituted trans-1,2-epoxyethanesulfonamides (1T), ethynesulfonamides (2), and their carboxamide analogues 3 (cis and trans) and 4 were evaluated for their antifilarial activity, first in vitro against the infective larvae of the filaria Molinema dessetae, then in vivo against the same filaria in Proechimys oris, its natural host. On the whole, compounds 2 displayed a high level of activity in vitro, while 4 showed a wider range and 3 were virtually inactive. The modest activity found within the series 1T was assumed to be due, in part, to the instability of the products under the conditions of the biological tests. Five new compounds within the series 1T, 2 and 4 showed a macrofilaricidal activity in vivo. There is no clear correlation between in vivo and in vitro data. It was observed, however, that within the series 2 and 4 all the compounds active in vivo were among the most potent compounds in vitro. Nevertheless, the in vitro model, although of limited value, could help in selecting compounds for further evaluation within a given series.

Aedes↗
PubMed1994

Inhibitory activity of saccharomyces yeasts on the adhesion of Entamoeba histolytica trophozoites to human erythrocytes in vitro.

Adhesion to target cells represents the first step in infection by Entamoeba histolytica. Binding of axenic amoeba (HMI strain) to human red cells in vitro was employed as a model of the adhesion process. The influence of precontact of trophozoites with suspensions of live Saccharomyces boulardii yeasts, their fractions (membranes and yeast-content supernatant before and after filtration to eliminate the membrane) or yeast culture medium before and after fermentation was investigated. N-Acetylgalactosamine (GalNAC) was employed as the reference inhibitory sugar. The percentage of amoebae bearing red cells after pretreatment of amoebae with the various suspensions and derivates was determined. Adhesion was also evaluated by scanning electron microscopy (SEM). Pretreatment of amoebae with the live yeast suspension led to a significant reduction in the percentage of adhesion [32% vs 70% in the phosphate-buffered saline (PBS) control]. Reduced adhesion was also observed with the filtered and unfiltered supernatant of the yeast suspension homogenate [32% and 34%, respectively, vs 69% in the PBS control], yeast culture medium at the end of fermentation [49% vs 76% in the PBS control] and GalNAC [32% vs 72% in the PBS control]. SEM showed a decrease in the number of amoebae bearing red cells and a reduction in the number of red cells adhering to amoebae. We conclude that substances produced by the yeasts compete with red cells for adhesion sites on amoebae.

Acetylgalactosamine↗
PubMed1994

Activity of albendazole-ivermectin combination and other filaricidal drugs against infective larvae, preadult, microfilariae and adult worms of Molinema dessetae in the rodent Proechimys oris.

The efficacy of albendazole-ivermectin combination was tested an adult and developing stages of Molinema dessetae in the rodent Proechimys oris. Albendazole and ivermectin, both given alone, suramin and diethylcarbamazine were used as reference compounds. The drug combination (albendazole at 10 mg/kg/ day x 5 days and Ivermectin at 0.04 mg/kg/day x 5 days) was effective against infective larvae and preadult worms, and substantially reduced the number of live adult worms. The known filaricidal agents, diethylcarbamazine (400 mg/kg twice daily x 5 days), ivermectin (0.2 mg/kg/day x 5 days), and suramin (40 mg/kg/day x 5 days), as well as albendazole (50 mg/kg/day x 5 days) were active on infective larvae, preadult worms, microfilariae and adult worms. All drugs had the same level of efficacity on infective larvae. Albendazole had the highest efficacy against adult and preadult worms and diethylcarbamazine was the most active on microfilariae. Although the drug combination was not as effective against preadult and adult worms as albendazole alone, the results indicate that albendazole-ivermectin combination at a low dose had prophylactic effect and suggest a possible macrofilaricidal activity.

Administration, Oral↗
PubMed1994

Study of lymphotropic targeting and macrofilaricidal activity of a melphalan prodrug on the Molinema dessetae model.

This study deals with the design of a new macrofilaricidal drug derived from melphalan and having a lymphotropism to avoid the hepatic first pass effect and enhance bioavailability after oral administration. Melphalan was linked to a ligand leading to a prodrug called 1,3-dp-melphalan which has structural analogy to triglycerides. The Molinema dessetae/Proechimys oris model was used for antiparasitic evaluation. Melphalan was macrofilaricidal in vitro against Molinema dessetae at 1mM, inactive in vivo after an oral single dose at 164 mumol/kg while the prodrug 1,3-dp-melphalan was active against adult worms after a single dose at 82 mumol/kg. After an oral administration of the prodrug to rats, the maximum concentration and the cumulated quantities of melphalan in lymph were about 45-fold higher than those observed with the free drug under the same conditions. Moreover, the plasma concentration of melphalan was 2-fold higher than those observed after the administration of the free drug. These results are in favor of lymphotropic targeting as a novel approach to develop new orally active macrofilaricides.

Animals↗
PubMed1994

Synthesis and orally macrofilaricidal evaluation of niclosamide lymphotropic prodrugs.

The development of new macrofilaricidal drugs is described following a strategy for the promotion of the lymphatic transport of anthelminthic drugs by-passing the liver. The selected compound was niclosamide (CAS 50-65-7) which is very effective in vitro against infective larvae but has no significant antifilarial activity when orally administered at 200 mumol/kg. To estimate the interest of such an approach, the synthesis of 5 prodrugs was achieved in a first stage. The intrinsic antifilarial activity and the delayed effect of these compounds were evaluated in vitro. Then, in vivo tests were performed with Molinema dessetae infective larvae to select the best ligands. The prodrug V 1,3-dihexadecanamido-2-[4-chloro(2- chloro-4-nitroanilinocarbonyl)phenyloxy-carbonylpropanoyl oxy]propane (having a diamide function) was responsible for an in vitro delayed effect and an orally in vivo activity (200 mumol/kg when administered in a single dose). The biological improvement of this easily micellizable prodrug which is stable to intestinal enzymes in respect to Niclosamide confirms such a strategy.

Animals↗