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J Descotes

Publications and source records attributed to J Descotes.

At least 37 records · Page 2Linked to original sources
PubMed1997

Drug-induced autoimmunity: experience of the French pharmacovigilance system.

Spontaneous reporting of suspected adverse drug reactions to a pharmacovigilance structure is a reasonable tool to detect new associations between drugs and a given toxic effect. An analysis of the French national database of pharmacovigilance was undertaken to evaluate how such a system is relevant to survey and/or detect drug-associated autoimmune disorders. Only 0.2% of reports were coded with terms suggestive of systemic autoimmune diseases. Drugs most frequently found were cardiovascular drugs, antiepileptic drugs and slow-acting anti-inflammatory drugs. Most of reports involved drugs previously recognized as a possible cause of autoimmune disorders. Minocycline or HMG-CoA reductase inhibitors were suggested to be involved in several reports and represented possible new cases of drug-associated autoimmune disorders. In conclusion, drugs are infrequently reported as a cause of systemic autoimmune disorders compared to other adverse drug reactions and may not represent a critical health problem for drug regulatory agencies to deal with.

Adverse Drug Reaction Reporting Systems↗
PubMed1997

The popliteal lymph node assay in 1996.

The popliteal lymph node (PLN) assay is based on the assumption that a mechanism similar to a graft-versus-host (GvH) reaction is involved in 'GvH-like' drug-induced side-effects, including generalized lymphadenopathy, serum sickness-like disease, scleroderma-like reaction and the lupus syndrome. An increased PLN weight 7-10 days after injection of the test article into the footpad is generally held as a positive response. Most, if not all compounds reported to induce pseudo-GvH side-effects in man (namely positive model compounds) have been shown to induce positive PLN responses in mice and/or rats. Reproducible results have been obtained in several laboratories, in some instances blindly. However, positive responses have also been obtained with the negative model compounds acetone and imipramine. Flow cytometry analysis and conventional histology failed to help differentiate between a true GvH response and a primary irritative effect. In order to confirm the potential value of the PLN assay to predict the risk for drug-induced GvH-like reactions, mechanistic studies are urgently needed.

Animals↗
PubMed1997

Autoantibodies in conventional toxicity testing.

A number of drugs and chemicals can induce autoimmune disorders. The use of autoantibody assays in toxicology has been evaluated as a tool to predict and explain autoimmune reactions. Autoantibodies are divided between organ-specific and ubiquitous autoantibodies and several mechanisms have been proposed for their pathogenesis. Assay methods depend on the autoantibody investigated and the specificity of the assay required. There is only a partial correlation between the presence of autoantibodies in humans or animals and the risk of developing an autoimmune disease. Responses in animals vary according to genetic influence and extrapolation to humans is difficult. Therefore, autoantibody assays were not considered absolutely predictive of the potential of a new drug to trigger autoimmune diseases. However assays such as the Coombs test for hemolytic anemia or anti-thyroid antibody assay for thyroiditis, can be useful for explaining the possible mechanisms of autoimmune reactions which occur during toxicology studies.

Animals↗
PubMed1997

Antibiotic-associated hepatitis: update from 1990.

OBJECTIVE: To review the literature on the recent available evidence of antibiotic-associated acute liver injury. DATA SOURCES: All published articles from January 1990 to July 1995 were extracted from the monthly updated HEPATOX database. Additional articles were found using MEDLINE, EMBASE, and PASCAL searches. Hepatic injuries associated with antituberculous, antimycotic, antiviral, antiprotozoal, and antiseptic compounds were excluded form this review. STUDY SELECTION: As the amount of literature was large, only case reports, series and epidemiologic data were used. Results from clinical trials were reviewed only when other information was available. DATA EXTRACTION: Original articles were reviewed to select relevant material. Information regarding the clinical description, histologic features, severity, outcome, and possible risk factors was extracted. Data on incidence were provided by epidemiologic studies or spontaneous reporting to regulatory agencies. DATA SYNTHESIS: Antibiotic-associated acute injury is rare, with an incidence not exceeding 1 case 10,000 users for most drugs. Among beta-lactams, amoxicillin/clavulanic acid and penicillinase-resistant penicillins are associated with predominant and sometimes protracted cholestasis. The hepatotoxic potential of all available erythromycin salts is confirmed, and recent evidence suggests that roxithromycin could be added to the list of antibiotic-induced liver injury. Among fluoroquinolones, only ciprofloxacin has been associated with serious hepatitis. Trimethoprim/sulfamethoxazole-induced hepatitis often reported, but trimethoprim alone also appears as a possible cause of acute liver injury. Finally, acute bile duct injuries and ductopenia have been described with several antibiotics. CONCLUSIONS: The most important recent information is the possibility of protracted liver cholestasis with bile duct injuries induced by several antibiotics, particularly penicillinase-resistant penicillins, and the identification of new potentially hepatotoxic antibiotics, namely, roxithromycin, ciprofloxacin, and trimethoprim.

4-Quinolones↗
PubMed1997

Increases in the effects of albendazole on Echinococcus multilocularis metacestodes by the dipeptide methyl ester (Phe-Phe-OMe).

Three months after infection with Echinococcus multilocularis, Mongolian gerbils were given either the dipeptide methyl ester (Phe-Phe-OMe) or a combination of Phe-Phe-OMe plus albendazole to treat alveolar echinococcosis. Each drug was given orally at the daily dose of 50 mg/kg of body weight following various administration regimens. Histologic and ultrastructural studies of parasites recovered from infected gerbil tissues showed that the dipeptide methyl ester increases the effect of albendazole.

Albendazole↗
PubMed1996

Clinical immunotoxicity of pesticides.

Because of the wide use of pesticides for domestic and industrial purposes, the evaluation of their immunotoxic effects is of major concern for public health. Despite the large amount of experimental data describing pesticide-induced immunosuppression, evidence that pesticides may severely impair immune functions in humans is lacking or scarce. Contact hypersensitivity is a well-identified immunotoxic effect of pesticides but remains a rare complaint in pesticide-exposed workers. By contrast, immunologically mediated systemic reactions have been described only as debatable case reports. The association between autoimmune diseases and pesticide exposure has more recently been suggested. Despite the lack of convincing human data, a potential risk for the immune system should not be excluded, especially during chronic exposure to pesticides or in otherwise (immuno) compromised patients (malnutrition, children, old patients). Epidemiological studies including markers of exposure and the assessment of immune competence in exposed individuals, or registries of sentinel diseases related to immunosuppression (e.g., non-Hodgkin's lymphoma, opportunistic infections) or autoimmunity (e.g. lupus erythematosus, rheumatoid arthritis), are warranted.

Autoimmune Diseases↗
PubMed1996

Suboptimal non-inflammatory concentrations of haptens may elicit a contact sensitivity reaction when used as a mix.

Contact dermatitis is a cutaneous inflammatory reaction mediated by hapten-specific T cells. We used a murine model to investigate the contact sensitivity reaction elicited by different concentrations (optimal and suboptimal) of the haptens DNFB and oxazolone applied singly or in combination. The simultaneous application of DNFB and oxazolone at optimal concentrations (0.2% and 0.4% respectively) did not significantly increase the ear swelling response induced by each of the allergens when applied singly. No contact sensitivity response was observed when the haptens were tested individually at subthreshold concentrations (0.05% and 0.1% respectively). However, mixing the 2 molecules at the same concentrations gave rise to a clinical contact sensitivity reaction. The simultaneous application of the haptens at a 2 x higher, but still suboptimal concentrations (0.1% and 0.2% respectively), elicited an inflammatory response that was significantly greater than the responses elicited by either of the haptens when applied separately. These results suggest that a "false-positive" reaction to a mix may reveal a genuine sensitization to the constituents.

Animals↗
PubMed1996

Influence of cimetidine on the toxicity and toxicokinetics of diazinon in the rat.

1. The influence of cimetidine on diazinon toxicity and toxicokinetics was investigated in male Wistar rats. 2. The acute toxicity of diazinon, as well as brain acetylcholinesterase and carboxylesterase inhibition, were potentiated by pretreating rats with cimetidine (80 mg kg-1, i.p.) 1 and 24 h prior to diazinon application (50 mg kg-1, i.p.). 3. Comparison of toxicokinetic parameters between control and cimetidine-treated animals, showed a significant decrease in diazinon total body clearance and a marked increase in the area under the plasma concentration-time curve following cimetidine. 4. These results indicate that a major cause of the potentiation of diazinon may be related to the increase in the amount of diazinon in the systemic circulation as well as in the brain.

Acetylcholinesterase↗
PubMed1996

Acute hexogen poisoning after occupational exposure.

BACKGROUND: Hexogen (cyclonite, RDX) nitrate explosive is an infrequent cause of poisoning. CASE REPORT: A 42-year-old man with no prior history of epilepsy experienced grand mal seizures after sieving fine hexogen (RDX) powder for four hours in an ammunition plant. Physical examination was normal on arrival at the emergency room but recurrent seizures occurred six hour after admission. EEG, CT scan and MRI were normal and the patient recovered uneventfully. CONCLUSIONS: The available toxicological data on this rare occupational poisoning are reviewed.

Adult↗
PubMed1996

Diazinon toxicokinetics, tissue distribution and anticholinesterase activity in the rat.

The toxicokinetics, tissue distribution, and anticholinesterase (antiChE) activity of diazinon were investigated in the rat. Plasma concentrations most adequately fitted a two-compartment open model after i.v. administration of 10 mg/kg and a one-compartment model after oral administration of 80 mg/kg. Diazinon elimination half-life following i.v. and oral dosing was 4.70 and 2.86 h, respectively. The oral bioavailability was found to be low (35.5%). Hepatic extraction ratios after i.v. administration of 5 or 10 mg/kg were 54.8% and 47.7%, respectively, suggesting that low systemic oral bioavailability can be explained by a first-pass effect in the liver. Diazinon was found to be approximately 89% protein-bound in plasma within the concentration range 0.4-30 ppm. The highest concentration of diazinon after i.v. administration was found in the kidneys, when comparing to liver, kidney, brain. Both red blood cell (RBC) acetylcholinesterase (AChE) and plasma ChE activities were inhibited rapidly (44% and 17% at 10 min, and 36% and 13% min for i.v. and oral administration, respectively), but inhibition of RBC AChE was greater than that of plasma ChE.

Acetylcholinesterase↗
PubMed1995

Immune-mediated side-effects of cytokines in humans.

A large body of clinical experience on the adverse consequences of cytokine administration has accumulated since the last decade. Side-effects reported after the therapeutic use of cytokines has provided evidence that activation of the immune response may sometimes have deleterious consequences. Several effects appeared as a direct consequence of the immune activation induced by cytokines, e.g. flu-like reactions, vascular leak syndrome. Cytokine-induced exacerbation of underlying diseases or immune dysregulation were other complications of growing concern. Interferon-alpha (IFN-alpha) treatment has now been clearly linked with the exacerbation or the occurrence of several types of autoantibodies or autoimmune diseases (thyroiditis, systemic lupus erythematosus, hematologic disorders, insulin-dependent diabetes mellitus) or diseases involving altered cell-mediated immune functions (inflammatory dermatologic diseases, nephritis, pneumonitis, colitis). By contrast immunological side-effects of IFN-beta and IFN-gamma have been seldom reported. However, the extent of clinical experience with both of these cytokines is still very limited. Interleukin-2 (IL-2) has also been implicated in various conditions that may involve immunopathological processes (thyroid disorders, rheumatoid arthritis, dermatological diseases, interstitial nephritis). Growth factors have been more specifically linked with the development or the exacerbation of dermatological inflammatory diseases through neutrophils, monocytes/macrophages or eosinophils activation (e.g. cutaneous vasculitis and generalized cutaneous eruption, Sweet's syndrome, bullous eruption, psoriasis). Exacerbation of autoimmune thyroiditis was described with granulocyte-macrophage colony-stimulating factor (GM-CSF) only. The immunogenicity of cytokines is also of great relevance and the occurrence of antibodies binding IFN-alpha and IFN-beta, IL2 and GM-CSF have been reported. While the clinical significance of non-neutralizing antibodies is not clearly established, an absence of response or reversal of clinical efficacy has been described in patients developing neutralizing antibodies. Finally, several isolated reports have recently suggested that IFN-alpha treatment may be associated with several immunosuppressive effects while IL-2 is clinically associated with an increased incidence of infectious complications.

Autoantibodies↗
PubMed1995

Determination of lymphocyte subsets and cytokine levels in cynomolgus monkeys.

Lymphocyte subset counts and cytokine assays are useful to investigate the interactions of pharmaceuticals, particularly new biotechnology products, with the immune system. As no specific reagents are available to label monkey lymphocytes or to assay monkey cytokines by ELISA, cross reactivities of a panel of monoclonal antibodies specific for human lymphocytes or cytokines were studied in the Cynomolgus monkey. The proportions of B, T, CD4+ and CD8+ cells were determined by flow cytometry using a whole blood technique with at least one monoclonal antibody for each subset. Background data were obtained for more than 300 samples. Monkey and human cultured white blood cells were stimulated with standard mitogens. PHA + LPS in humans and Con A + PWM in monkeys triggered the greatest proliferation. IL-1 beta IL-2, IL-6, IL-8, TNF-alpha, TNF-beta and IFN-gamma, but not IL-1 alpha, were detected in the monkey using human reagents. In addition, the cytokine profile and the kinetics of cytokine production compared well in humans and Cynomolgus monkeys.

Animals↗
PubMed1995

Effect of serotonin on the chemiluminescence response of rat peripheral blood leucocytes.

Serotonin (5-HT) has been shown to exert various immunomodulatory effects. In this study, the effects of 5-HT, 5-hydroxy-DL-tryptophan (5-HTP) and DL-p-chlorophenylalanine (PCPA) on the chemiluminescence (CL) responses of rat peripheral blood leucocytes (PBL) activated by phorbol myristate acetate (PMA), opsonized zymosan or latex beads were assessed. The CL responses were measured following in vitro treatment with 0.01-100 microM 5-HT, and either 1 h after the last i.p. administration of 5-HT (0.05, 0.5, 1, 2.5, 5 or 10 mg/kg for 4 days), 5-HTP (25 or 100 mg/kg for 4 days) or PCPA (200 mg/kg for 4 days, n = 5), or 48 h after a single 200 mg/kg PCPA injection. A concentration-dependent decrease in CL responses was noted following in vitro 5-HT treatment. In vivo treatment of rats with 5-HT produced a reverse bell-curve inhibiting effects on the CL response with a maximal inhibition in rats receiving 1 mg/kg/day 5-HT and a weaker response of PMA-activated PBL. In vivo treatment with high-dose 5-HTP increased CL response of opsonized zymosan-activated PBL, while low-dose 5-HTP decreased CL response of opsonized zymosan and latex beads-activated PBL. No effect was observed in PMA-activated PBL from rats treated with 5-HTP. By contrast, in vivo treatment with PCPA increased CL responses induced by PMA or latex beads, whereas CL responses using opsonized zymosan were not significantly affected. These results suggest that 5-HT modulates the CL response of rat leucocytes to particulate stimuli.

5-Hydroxytryptophan↗
PubMed1995

Competitive ELISA to evaluate the immunogenicity of double-virus-inactivated factor VIII in rabbits.

Viral inactivation is a critical step during the manufacture of factor VIII formulations for use in humans. Indeed, viral inactivation procedures may alter the three-dimensional structure of factor VIII resulting in the formation of new epitopes which, in turn, may lead to the synthesis of inhibiting antibodies, and hence to a decreased therapeutic activity. A rabbit model was used to compare the immunogenicity of a solvent/detergent (SD)-inactivated formulation with a double-inactivated (SD plus heating in solution, SDP) formulation of factor VIII. Two groups of five rabbits were immunized by six s.c. injections of each formulation. The serum of each animal was incubated with various amounts of the competing antigens, e.g. factor VIII SD or factor VIII SDP. The remaining free polyclonal antibodies were assayed by ELISA. Curves obtained with both antigens were compared for each serum. Both factor VIII SD and factor VIII SDP decreased the amount of antibodies raised to either formulation in a dose-dependent manner without observable differences. These results suggest that no new epitopes were present on factor VIII SDP as compared with factor VIII SDP as compared with factor VIII SD and that no epitope deletions occurred, supporting the view that the double-inactivation procedure does not change the immunogenicity of factor VIII SD. This model is proposed as a tool to detect changes in the immunogenicity of proteins which may be modified.

Animals↗