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F Verdier

Publications and source records attributed to F Verdier.

At least 37 records · Page 2Linked to original sources
PubMed1995

Short report: pefloxacin does not potentiate quinine efficacy against Plasmodium falciparum malaria.

Twenty-four patients presenting with severe Plasmodium falciparum infection at the Kamenge Hospital in Burundi were enrolled in a double-blind study comparing the efficacy of a seven-day regimen of intravenous quinine alone or in combination with pefloxacin. The aim of this study was to assess whether pefloxacin modified chloroquine efficacy or its uptake by infected erythrocytes as shown with other antimalarials. Pefloxacin did not modify the antimalarial activity of quinine, in terms of speed of parasite or fever clearance. Moreover, pefloxacin does not appear to interact with quinine uptake by erythrocytes in humans.

Adult↗
PubMed1995

[Role of modulators in Plasmodium falciparum resistance to antimalarials].

Modulating agents that circumvent the Plasmodium falciparum resistance to antimalarials are components without any intrinsic antimalarial activity but able, in association with a standard antimalarial drug, to restore the sensitivity of Plasmodium falciparum to this drug. Two hypotheses are forwarded about their possible mechanisms of action : the mechanisms involving the inhibition of the drug efflux and the mechanisms involving the inhibition of antimalarial drug metabolic degradation. None of these mechanisms is able to alone explain the effect of all modulating agents. The future use prospects of these compounds are limited by their in vivo toxicity. That relevant to the calcium channels blockers seems to be circumvented by the use of dextro-enantiomers. A toxicity relevant to a possible accumulation of the antimalarial in healthy, non target cells must be also suspected. Moreover the use of these agents evidences a socio-economic problem : a complete new development of the association (antimalaria plus modulatin drugs) is needed and that, in developing countries. Nevertheless, the agents modulating the Plasmodium falciparum resistance are a new approach for the treatment of resistant malaria which might give a recrudescence of activity to the old antimalarials as chloroquine.

Animals↗
PubMed1994

Anaphylaxis models in the guinea-pig.

Immediate hypersensitivity (or anaphylactic) reactions can be caused by large molecules which are directly immunogenic or by smaller molecules which bind to macromolecular carriers and act as haptens. To reproduce these reactions in animals, either systemic or local models are used in actively or passively sensitized animals, respectively. Several attempts have been made to detect the potential of new drugs and chemicals to induce anaphylactic reactions. Protocols using the inhalation of reactive low-molecular-weight compounds produced clinical symptoms in the guinea-pig. An intralaboratory validation study was initiated using a panel of six positive and one negative model compounds in a guinea-pig model combining systemic and local anaphylaxis. Anaphylactic reactions to positive model compounds were obtained only when the molecular weight was approximately 3000 or more. Overall, published results indicate that the potential to induce immediate hypersensitivity reactions can be detected as far as large-molecular-weight molecules are concerned--in contrast to the majority of low-molecular-weight drugs and chemicals.

Administration, Cutaneous↗
PubMed1994

The pharmacokinetics of chloroquine in healthy and Plasmodium chabaudi-infected mice: implications for chronotherapy.

The schizogony of malarial parasite is a typical cyclic phenomenon where the different stages of parasite development appear at regular time intervals. Each of the stages is specifically sensitive to different antimalarial drugs. Knowledge of the details of the cycle, drug susceptibility and the pharmacokinetics of drugs, could allow the improvement of drug action by the chronotherapeutic approach: treatment at the time of appearance of the drug sensitive stage with a drug that displays rapid pharmacokinetics. Since murine malarias serve as preferable models for in vivo drug testing, the pharmacokinetics of subcutaneously (sc) administered chloroquine (CQ) were tested in the whole blood of healthy mice and in animals slightly (1.5-3.5% parasitemia) or heavily infected (21-25% parasitemia) with Plasmodium chabaudi chabaudi. The half-time of absorption was around 5 min and almost independent of parasitemia. The apparent half-time of drug concentration decay was around 40 min in healthy animals, about 90 min at low parasitemia and about 410 min in heavy infection, indicating that the concentration of CQ is a typical spike, that is prolonged by asymptomatic disease, and considerably more by the active accumulation of CQ in infected cells. The latter is confirmed by the 3-fold higher peak blood [CQ] at the trophozoite stage and < 1.5-fold increase during schizogony. In conjunction with our previous experiments which showed that a single sc injection of 5 mg/kg CQ is sufficient to eliminate the drug susceptible mid-term trophozoite stage, the present results seem to justify to propose the chronotherapeutic approach for the treatment of malaria.

Animals↗
PubMed1994

Morphology of popliteal lymph node responses in Brown-Norway rats.

The popliteal lymph node (PLN) assay has been proposed as a tool to predict in rodents those xenobiotics likely to induce autoimmune reactions in humans. To further validate this assay and to study the mechanisms involved, histologic changes in PLNs from rats injected with streptozotocin, diphenylhydantoin, pure acetone, or 50% ethanol were compared to a local graft-versus-host (GvH) reaction. This study suggests that routine histology of PLNs is instrumental to discard primary irritants. In addition, the hypothesis of a GvH-like mechanism in positive PLN responses is supported by the finding that the reference compounds streptozotocin and diphenylhydantoin produced histologic changes similar to a "true" local GvH reaction.

Acetone↗
PubMed1994

Pharmacokinetics and metabolism of amopyroquin after administration of two doses of 6 mg/kg im 24 h apart to healthy volunteers.

Twelve healthy volunteers received two doses of amopyroquin 6 mg/kg im 24 h apart. Blood and plasma concentrations of amopyroquin and two metabolites were assayed by HPLC from 0 to 48 h. Half-life values for amopyroquin, calculated from 0 to 48 h whole-blood and plasma samples were 13.9 +/- 9.1 and 18.3 +/- 6.8 h respectively. Two metabolites were detected in blood and they had very low in-vitro activity against Plasmodium falciparum compared with the parent drug. Neither hypotension nor lengthening of QRS complex were observed in any volunteers and hepatic enzymes remained in the normal range despite a transitory increase. These results confirm that unchanged amopyroquin accounts for antimalarial activity in vivo and that two doses of 6 mg/kg are well tolerated.

Adult↗
PubMed1994

Antimalarial 4-aminoquinolines: mode of action and pharmacokinetics.

In the last ten years, the widespread increase in Plasmodium falciparum resistance to chloroquine has prompted research into antimalarial 4-aminoquinolines, empirically used up to now. The mechanism of action of 4-aminoquinolines is characterized by the concentration of the drug in the digestive vacuole of the intraerythrocytic parasite. Various hypotheses have been advanced to explain the specificity of action on the parasite; the most recent one is the inhibition of the haem polymerase of the parasite, leading to the accumulation of soluble haem toxic for the parasite. Chloroquine-resistant parasites accumulate the drug to a lesser extent than do sensitive parasites. Recent findings have shown that chloroquine resistance can be reversed by various tricyclic drugs, which are able to restore the effective concentrations of chloroquine in the infected erythrocyte, but intrinsic mechanisms of action of these reversing agents are unknown. Four-aminoquinolines are extensively distributed in tissues and characterized by a long elimination half-life. Despite similarities in their chemical structures, these drugs show differences in their biotransformation and routes of elimination: chloroquine is partly metabolized into a monodesethylderivative and eliminated mainly by the kidney. In contrast, amodiaquine is a prodrug and amopyroquine is poorly metabolized; both drugs are excreted mainly in the bile. The understanding of the pharmacokinetics of 4-aminoquinolines has led to an improvement in empirically defined therapeutic regimens. Finally, the emergence of severe adverse-effects after prolonged prophylaxis with amodiaquine and the lack of cross resistance of Plasmodium falciparum between chloroquine and amopyroquine, have led to a proposal for the use of intramuscular amopyroquine as an alternative for the treatment of chloroquine-resistant malaria.

Aminoquinolines↗
PubMed1994

Comparison of popliteal lymph node responses in various strains of rats.

Outbred (namely Wistar and Sprague-Dawley) and inbred (Wistar-Furth, Lewis, Fisher 344 and Brown-Norway) strains of rats were screened for their responses to reference compounds in the popliteal lymph node (PLN) assay. Streptozotocin and diphenylhydantoin gave positive responses as evidenced by increased weight and cellularity indices in all strains used whereas procainamide, isoniazid and barbital consistently gave negative responses. Although these findings overall are in agreement with previous investigations involving these compounds, the lack of marked interstrain differences in PLN responses argues against a strong immunogenetically controlled mechanism as could be assumed in presumably auto-immune reactions. The question is raised whether drug-induced side-effects predicted by the PLN assay are basically non-autoimmune as suggested by clinical and immunological findings in man.

Animals↗
PubMed1993

Popliteal lymph node response to procainamide and isoniazid. Role of beta-naphthoflavone, phenobarbitone and S9-mix pretreatment.

The popliteal lymph node assay (PLNA) was proposed for the preclinical prediction of xenobiotics-induced autoimmune reactions in humans. Among the substances so far tested in this model, procainamide and isoniazid gave negative PLNA responses despite reports of lupus syndromes in man. To confirm the hypothesis that a metabolite instead of the parent molecule is involved, rats were pretreated with phenobarbital or beta-naphthoflavone, then injected with procainamide or isoniazid. In additional groups of animals, procainamide or isoniazid were injected together with S9-mix following various incubation times. Pretreated rats had a positive PLNA response when injected with procainamide, whereas preincubation with S9-mix resulted in a positive response to isoniazid. These results further support the validity of the PLNA.

Animals↗
PubMed1993

Efficacy of intramuscular amopyroquin for treatment of Plasmodium falciparum malaria in the Gabon Republic.

The efficacy of a 12-mg/kg (of body weight) intramuscular amopyroquin (ApQ) regimen (two successive 6-mg/kg injections at a 24-h interval), previously established from kinetic studies on healthy volunteers and multicenter studies on patients with malaria, was investigated in 152 patients (children and adults) in Gabon with Plasmodium falciparum malaria. All children in the present study (ages, 1 to 14 years) showed higher degrees of parasitemia and temperatures and lower hematocrit values than did adults at the time of admission. No major side effects in the patients were observed. On day 7, all patients were apyretic; clearance of parasites was obtained in 143 of 152 patients (94%); a low level of parasitemia was observed in nine patients, all of whom were children (6%). In vitro chemosusceptibility tests carried out on P. falciparum isolates from patients demonstrated 51% of resistance to chloroquine (Cq). A correlation was found between the in vitro chemosusceptibilities to Cq and ApQ, but no relationship between the in vitro activity and the in vivo efficacy of ApQ could be found. Concentrations of ApQ in blood assayed by high-performance liquid chromatography on day 2 did not differ significantly between the groups in whom therapy was a success or a failure, although the mean ApQ concentration in blood for the group that failed therapy was 31% lower. Concentrations greater than 100 nmol of self-prescribed Cq and amodiaquine per liter, which were assayed simultaneously with ApQ, were observed in 78 patients (51%). They did not correlate with degrees of parasitemia compared with ApQ alone, which did. Successful treatment by day 7 was obtained in 69 of 74 patients (93%) who had no other 4-aminoquinolines in their blood. The results of the present study show that an ApQ regimen of 12 mg/kg over 2 days may be an alternative for the treatment of Cq-resistant malaria, at least in adult patients, in the field.

Adolescent↗
PubMed1992

Activation of CD4+ and CD8+ lymphocyte subsets by streptozotocin in murine popliteal lymph node (PLN) test.

Time-related and dose-related popliteal lymph node (PLN) enlargement and lymphocyte subset alterations owing to subcutaneous (s.c.) injection of streptozotocin (STZ) into the foot pad were determined in (C57BL/6 x DBA/2)F1 [B6D2F1] mice. Early cell activation and time-related changes in T and B lymphocyte subsets were monitored during the onset of STZ-induced lymphoproliferative reaction by flow cytometry and immunophenotyping of lymphocyte subsets stained with a panel of monoclonal antibodies. Examination of cell size and chromatin decondensing for T and B cell subsets revealed differences in their activation profiles during the early phase of STZ-induced lymph node enlargement. The kinetics of the reaction showed initial activation and proliferation of CD4+ cells associated with accumulation of CD8+ and B cells. Subsequently CD8+ cells were activated and proliferated, but there was no evidence of early or late B cell activation as shown by the lack of increase in cell size or nuclear decondensation and the low and transient synthesis of immunoglobulins. The activation characteristics for CD4+ and CD8+ cell subsets in STZ-induced node enlargement were found to be analogous with T cell activation in acute allogeneic graft-versus-host (GVH) reaction in which the F1 recipient differed from the parent at both class I and II MHC loci. Our data support a central role for T cell activation in the induction of STZ-related PLN enlargement and suggest that recirculatory host B cells can play a major role in early node enlargement.

Animals↗
PubMed1992

In vitro antimalarial activity and chloroquine potentiating action of two bisbenzylisoquinoline enantiomer alkaloids isolated from Strychnopsis thouarsii and Spirospermum penduliflorum.

The bisbenzylisoquinolines 7-O-demethyltetrandrine and limacine, respectively, isolated from Strychnopsis thouarsii Baill. and Spirospermum penduliflorum Thou. were evaluated for their intrinsic antimalarial activity in vitro and chloroquine potentiating action against the chloroquine-resistant Plasmodium falciparum FCM 29 originating from Cameroon. They both showed significant antiplasmodial potency in vitro with very similar IC50 values of respectively, 740 nM and 789 nM (IC50 = 214 nM for chloroquine used as standard drug), which demonstrated that the stereochemistry of the C-1 and C-1' configuration likely plays a role in the chloroquine potentiating effect of these drugs. If confirmed in vivo, these results may account for the traditional use of the two plants as antimalarials and adjuvant to chloroquine in Madagascan folklore remedies.

Alkaloids↗
PubMed1992

Popliteal lymph node assay as a tool to predict drug-induced GvH-like reactions.

The popliteal lymph node (PLN) assay was proposed to study a panel of drug-induced clinical manifestations, e.g. lupus syndrome, serum sickness-like disease, lymphadenopathy, scleroderma-like reaction, the mechanism of which was suggested as being similar to a graft-versus-host (GvH) reaction, hence the term GvH-like reaction. This assay can readily be performed in either the mouse or rat. The commonest endpoint is PLN weight, but cellularity and lymphocyte-phenotype analysis can also be determined. Experiments so far show that most drugs and chemicals known to induce such complications in man can be detected by the PLN assay and false-positive responses are extremely few. Interestingly, preliminary results indicate that cimetidine, an immuno-enhancing agent, can increase the response to phenytoin, a positive reference compound in the PLN assay. Thus, in addition to predicting those drugs with the capacity to induce GvH-like reactions and investigating the mechanism involved, the PLN assay may also prove useful in the pre-clinical assessment of immunomodulating agents.

Animals↗
PubMed1991

Immunotoxicity of bis(tri-n-butyltin) oxide in the rat.

Previous studies in the rat have shown that bis(tri-n-butyltin) oxide (TBTO), used as a biocide, was immunotoxic at dose levels that did not affect other organs. In order to determine a no-effect level, weanling rats were treated for at least 28 consecutive days with TBTO at 0, 0.5, 2, 5, or 50 mg/kg of diet. Studies on clinical chemistry, hematology, pathology, and immune function, that is, plaque-forming cell (PFC) assay, delayed-type hypersensitivity (DTH) response, and the splenic clearance of Listeria monocytogenes, were performed at the end of treatment. No treatment-related effects were noted on clinical chemistry and hematology parameters and on PFC and DTH response, whereas thymic atrophy and impaired clearance of L. monocytogenes were noted only at a dietary concentration of 50 mg/kg. These results confirm the thymus as a target organ of TBTO immunotoxicity. Under the conditions of these experiments the dietary concentration of 5 mg/kg, equivalent to a dose of 0.5 mg/kg body weight, represents a no observed effect level (NOEL) for immunotoxicity in the Sprague-Dawley rat.

Administration, Oral↗
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↗