Stimulation of human monocytic THP-1 cells by metabolic activation of hepatotoxic drugs.

Drug-induced liver injury (DILI) is thought to be involved in the participation of drugs that either directly affect the cell viability or elicit an immune response. However, there is limited information about the immune responses induced by drugs, including those drugs that are metabolically activated. In this study, we constructed an in vitro assay system to assess the involvement of immune-related factors induced by metabolic activation of drugs. To investigate whether CYP3A4-mediated metabolism of 10 hepatotoxic drugs is associated with immune-related responses, human monocytic leukemia THP-1 cells were co-incubated with CYP3A4 Supersomes. Cluster of differentiation (CD) 86 and CD54 expression levels on THP-1 cells were upregulated by treatment with albendazole and amiodarone (AMD), respectively, in the presence of CYP3A4. Additionally, N-desethylamiodarone (DEA), a major metabolite of AMD, upregulated the CD54 expression of THP-1 cells with CYP3A4. The release of interleukin (IL)-8 and tumor necrosis factor (TNF) α from THP-1 cells was significantly increased by the treatment of AMD or DEA with CYP3A4. Similarly, IL-8 and TNFα were also upregulated by the treatment of AMD and DEA with human liver microsomes, but were inhibited by adding ketoconazole to the cell culture. In this study, we first report that albendazole, AMD and DEA activate immune reaction when metabolically activated.

Amiodarone-induced severe hepatitis mediated by immunological mechanisms.

A 64-year-old man developed a fulminant hepatitis 4 days after initiation of amiodarone treatment and a total dose of 7.1 g. The direct Coombs test was positive and became negative again soon after stopping treatment. Immediately after stopping treatment the extremely increased parameters of hepatic failure returned to normal again. A rechallenge with 200 mg of amiodarone was accompanied by a positive Coombs test which again became negative after several days. We conclude that the occurrence of an acute hepatitis soon after initiation of amiodarone treatment is mediated by immunological mechanisms. There should be high vigilance with respect to this rare life-threatening adverse drug reaction.

[Hyperthyroidism and immune hemolytic anemia following amiodarone therapy]. / Hyperthyroïdie et anémie hémolytique immune après traitement par amiodarone.

We report the cases of two patients who, after prolonged amiodarone therapy developed hyperthyroidism and immune haemolytic anaemia. Antibodies were of the IgG type and non-specific at elution. A search for other causes of haemolytic anaemia with positive Coombs' test gave negative results. Antiamiodarone antibodies have recently been discovered; they reflect an immunological disturbance due to this drug and might be responsible for some of the undersirable effects of amiodarone. In our patients, hyperthyroidism and haemolytic anaemia were induced by a dual mechanism: accumulation of amiodarone and induction of an effect of this drug on the immune system.

Amiodarone-induced pulmonary toxicity. Immunoallergologic tests and bronchoalveolar lavage phospholipid content.

Amiodarone (A) is a widely-used antiarrhythmic drug. Pulmonary toxicity is the most serious adverse effect with an estimated mortality of 1 to 33 percent. In order to determine an element helpful for diagnosis, we examined four patients with amiodarone-induced pulmonary toxicity, three patients treated with A, without evidence of pulmonary toxicity but with a main underlying pulmonary disease, and four healthy volunteers. Daily and cumulative doses or duration of treatment were similar in the first two groups. Pulmonary function tests (spirometry, CO-diffusing capacity, arterial blood gases), roentgenographic examinations, pulmonary biopsies or immunoallergologic tests (skin reaction, lymphoblastic transformation test and human basophile degranulation test) did not provide any discriminatory element. In APT+, we observed an increased cellularity of the bronchoalveolar lavage. Neither the differential cell count nor the presence of foamy macrophages were distinguishable between APT+ and APT-. The phospholipid composition of BAL fluid showed a decreased total phospholipid and phospholipid/protein ratio in all patients compared to normal subjects. These changes reflect more the severity of pulmonary disease than the specificity of the causative agent. However, we observed that the unique PL which decreases in APT- and remains normal in APT+ is phosphatidyl-serine + phosphatidylinositol (PS + PI). This has to be confirmed and should be evaluated at different stages of the disease to determine an eventual specific element. We conclude that there are no data currently available to establish the diagnosis of APT except perhaps for the analysis of BAL PL content.

Anti-amiodarone antibodies: detection and relationship to the development of side effects.

PURPOSE: It has become evident in the past few years that amiodarone, a powerful antiarrhythmic agent, induces considerable side effects. These may be due to an amiodarone-elicited lipid storage disease and to the iodine content of amiodarone, but might also be causally related to amiodarone-induced immune reactions. The latter possibility prompted us to develop a sensitive anti-amiodarone antibody detection assay based on the immunodot technique. PATIENTS AND METHODS: Sera were obtained from 10 untreated control subjects and 33 patients receiving amiodarone. Using serum dilutions of 1:500 and 1:1,000, the lower detection limit was 0.3 microgram/ml of anti-amiodarone antibodies as calculated from a simultaneously performed IgG standard curve. RESULTS: Screening of sera from the untreated control subjects and amiodarone-treated patients revealed that the untreated subjects had no anti-amiodarone antibodies, that only one of 16 patients without clinical side effects had elevated anti-amiodarone antibodies, but that seven of 12 patients with amiodarone-induced thyroid disease and four of five patients with other side effects had elevated anti-amiodarone antibody titers (1.2 to 2.5 micrograms/ml). The combined evaluation of anti-amiodarone antibody titers and cumulative dose was found to be a highly reliable indicator of side effects, as all patients with more than 100-g cumulative dose of amiodarone and more than 0.6 microgram/ml of anti-amiodarone antibodies had side effects. CONCLUSION: The detection of anti-amiodarone antibodies in patients with amiodarone-elicited side effects underscores the possible contribution of immunologic reactions to the development of certain side effects.