Investigating the TNP-OVA and direct popliteal lymph node assays for the detection of immunostimulation by drugs associated with anaphylaxis in humans.

Using current animal models, it is not possible to identify low-molecular-weight compounds (LMWCs) that are likely to be associated with anaphylaxis. It is generally accepted that the ultimate effector mechanism involves drug-induced IgE antibody. The objective of the present study was to determine if diclofenac, zomepirac and glafenine, which are associated with anaphylaxis in humans, have immunostimulating potential in the murine TNP-OVA (trinitrophenyl-ovalbumin) popliteal lymph node assay (PLNA), and more specifically to determine if the immunostimulation caused by these LMWCs results in IgE antibody production. These LMWCs were chosen because both zomepirac and glafenine were removed from the market due to high association with anaphylaxis, and diclofenac, which remains on the market, is frequently associated with anaphylaxis. In addition to conducting a TNP-OVA PLNA, the immunostimulating potential of these compounds was examined in the direct PLNA. When co-administered with TNP-OVA, all three LMWCs caused dose-dependent (0.25, 0.50, 1.00 and 1.25 mg) increases in popliteal lymph node (PLN) weight and cellularity that were observed beginning with the 0.25-mg dose. In addition, beginning with the 0.25-mg dose, all three compounds caused dose-dependent increases in TNP-OVA specific IgM and IgG(1) antibody-forming cells (AFCs). Diclofenac induced an isotype switch and caused a dose-dependent increase in the number of IgE AFCs with no detectable IgG(2a) AFCs and minimal high-dose-only IgG(2b) AFCs. Zomepirac induced IgE, IgG(2a) and IgG(2b) AFCs following the injection of 0.50 mg only, and glafenine induced IgE, IgG(2a) and IgG(2b) AFCs following the injection of 0.50-1.00 mg. In the direct PLNA, diclofenac caused dose-dependent increases in PLN weight and cellularity that were observed beginning with dose of 0.50 mg, whereas zomepirac failed to increase any PLN parameter and glafenine only increased the PLN weight. These results suggest that diclofenac, zomepirac and glafenine are immunostimulating LMWCs in the TNP-OVA PLNA with the potential to induce IgE antibody against a co-administered hapten-conjugate. Furthermore, these results suggest that the TNP-OVA PLNA offered significant advantages over the direct PLNA. Although it is not realistic to suggest that a single assay, based on a low number of test compounds, can identify all LMWCs with the potential to cause anaphylaxis in humans, these observations do demonstrate the potential utility of the PLNAs in examining LMWC-induced immunomodulation and support further development and investigation of the assays.

[Anaphylactic shock complicated by myocardial infarction: side effect of glaphenine?]. / Choc anaphylactique compliqué d'un infarctus du myocarde: effet indésirable de la glafénine? A propos d'un cas.

The authors report a case of anaphylactic shock complicated by coronary spasm and infarction attributed to glafenine medication in a 43-year-old male patient. The outcome was positive and coronary angiography showed healthy coronary vessels. The ergonovine maleate was negative. A review of the literature confirms the rarity of this complication of anaphylactic shock and study the ECG changes induced by this type of reaction and to analyze the mechanisms responsible for this coronary spasm in this situation. These consists basically of histamine release and prostaglandin-synthesis inhibition.

[Severe immunoallergic hemolytic anemia caused by a glafenine metabolite]. / Anémie hémolytique immuno-allergique grave provoquée par un métabolite de la glafénine.

Three weeks after a surgical operation, a 74-year old woman was admitted to hospital for severe haemolytic anaemia. A strongly positive IgG type direct Coombs test pointed to a iatrogenic origin, but a search for anti-molecule antibodies directed against all medicines taken by the patient after surgery was negative. We extended our immunological investigations and were able to demonstrate the presence of IgG type antibodies directed against an ex vivo metabolite of glafenine.

Drug induced red blood cell autoantibodies co-developed with drug specific antibodies causing haemolytic anaemias.

Four individuals with anti-glafenine, anti-latamoxef and anti-teniposide antibodies were found to have an associated red blood cell autoantibody. The two components could be separated by selective absorption and showed distinct time course patterns. In three patients a well-defined blood group antigen was recognized as the receptor for both auto- and drug specific antibodies. Similarities between this type of immune response to drugs and the well-known hapten and carrier specificities developed in animals immunized by hapten-carrier conjugates are discussed.

Value of oral provocation tests to aspirin and food additives in the routine investigation of asthma and chronic urticaria.

Nonsteroidal anti-inflammatory drugs and certain food or drug additives are known to induce acute bronchospasms, angioneurotic edema, and urticaria in susceptible patients. Thirty-four patients (17 with asthma and 17 with urticaria), whose case history suggested such intolerance, were challenged orally with increasing doses of seven compounds: acetylsalicylic acid, glafenine, sodium benzoate, sulfur dioxide, potassium sorbate, sodium glutamate, and tartrazine. Among 162 oral provocation tests, 38 were positive (20% decrease in peak flow rate or appearance of acute urticaria/angioneurotic edema). Twenty-four of the 34 patients (nine with asthma and 15 with urticaria) were intolerant to at least one compound. However, no serious reaction was observed. In 20 of these 24 patients (six with asthma and 14 with urticaria), a diet free of additives and nonsteroidal anti-inflammatory drugs resulted, within 5 days, in a marked improvement of symptoms, which persisted 8 to 14 mo after starting the diet. Age, prevalence of IgE-mediated allergy, and nasal polyposis were similar in patients with or without reactions of intolerance. Under the conditions used, oral provocation tests proved to be feasible, safe, and useful in many patients not helped by existing methods.

[Anti-glafenine circulating antibodies: demonstration and frequency in acute renal insufficiency following intake of glafenine in toxic doses]. / Anticorps circulants anti-glafénine: mise en évidence at fréquence dans l'insuffisance rénale aiguë après absorption de glafénine à doses toxiques.

From 1970 to 1981, acute glafenineeeeeeee poisoning was observed in 106 patients, including 37 with acute renal insufficiency (ARI). From 1977 to 1982, the search for anti-glafenin antibodies was carried out systematically by direct and indirect tests for antiglobulin on erythrocytes, and by leucoagglutination and complement fixation tests on platelets in the presence of glafenin. An antibody was detected in only one of the 17 ARI patients studied. This antibody, IgM, has been studied along with glafenin, floctafenin, antrafenin and their metabolites. The rareness of such an antibody confirms the direct nephrotoxic action of glafenin, a drug responsible for half of the renal insufficiencies observed in an intensive care unit specialized in toxicology.

Leucocyte migration test and hypersensitivity to glafenin.

The leucocyte migration test (LMT) was performed on 20 patients with an intolerance to glafenin--a non-narcotic analgesic drug. LMT was found to be positive in 50% of the subjects with intolerance, a highly significant percentage as compared with the control groups. HSA-glafenin was found to be the most appropriate method for presenting the antigen, but glafenin and its hydroxylated metabolites were only found to induce a migration inhibition in the subjects intolerant to glafenin.