Predicting possible zonisamide hypersensitivity syndrome.

UNLABELLED: Zonisamide (ZNS) is an anticonvulsant (AC) that contains a sulpha moiety potentially triggering hypersensitivity syndrome reactions (HSR). The lymphocyte toxicity assay (LTA) is an in vitro drug rechallenge test, which is believed to reflect a decreased capacity of the individual to detoxify reactive metabolites. The study examined whether cross-reactivity is present between ZNS and other AC and/or sulphonamides and if this HSR may be predicted using the LTA. The second aim was to determine age-related differences in ZNS-induced HSR. LTA was previously validated in patients who received sulphamethoxazole (SMX) or AC. METHODS: Forty adult patients who displayed clinical HSR to SMX (20) or AC (20) participated in the study. Each group was represented with an equal number of individuals above and below the age of 60. LTA-SMX, LTA-AC and LTA-ZNS from 20 patients who previously presented a clinical reaction to one of the drugs and who had a positive LTA result to the specific drug were compared with 20 individuals who received the same drugs but did not present reactions. Binary logistic regression was used to evaluate the statistical significance. RESULTS: In vitro results correlated with the clinical diagnosis. LTA presented a significant difference (P < 0.0001) between control and hypersensitive patients. In each age group, only a single patient had a severe clinical manifestation of SMX-HSR. These individuals tested positive to both SMX and ZNS. CONCLUSIONS: Sulphamethoxazole-HSR but not AC-HSR patients may present a cross-reactivity to ZNS-HSR. The use of LTA to predict a possible ZNS reaction is recommended for SMX-sensitive individuals who prescribed ZNS.

Ethanol signals for apoptosis in cultured skin cells.

Ethanol is commonly used in cosmetic and pharmaceutical preparations. To test whether ethanol may cause apoptosis in skin cells, we treated A431 epidermoid skin cells and neonatal human primary skin cells with different concentrations of ethanol, for different time periods. Ethanol was toxic to cells in both a dose- and time-dependent manner and increased the percentage of cells undergoing apoptosis. Treatment of cells with 40 and 100 mM ethanol increased release of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) into culture medium and increased its expression in cells. The TNF-alpha was toxic to A431 epidermoid skin cells at concentrations similar to those released by cells on exposure to ethanol. Ethanol-treated cells examined by electron microscopy showed organelle damage, condensed chromatin, and apoptotic bodies. Therefore, even at low concentrations, ethanol may induce apoptosis in skin cells by enhancing the effects of TNF-alpha.

Immunopathogenesis of hypersensitivity syndrome reactions to sulfonamides.

Cytokines play a role in the immunopathological and molecular mechanisms of sulfonamide-induced hypersensitivity reactions (HSRs). The objective of this study was to analyze the reliability and correlation between the clinical symptoms observed in affected patients (n = 86) because of a sulfonamide-induced HSR and their lymphocyte toxicity assay (LTA) values. Another goal was to determine the cytokine secretion in the patient's sera and their expression in the peripheral blood mononuclear cells (PBMCs) and to explore whether a correlation exists among positive LTA score, cytokine levels, and HSR occurrence. The final goal is to determine whether these measures could be used to predict the likelihood of a patient to experience an HSR during sulfonamide treatment. Such a predictive ability would be valuable to the clinician to know whether the patient would tolerate sulfonamides or whether an alternative antibiotic should be prescribed. The LTA showed a good correlation with the clinical involvement of patients with hypersensitivity syndromes. In addition, the pro-inflammatory cytokines presented significant differences in patients that had rash, fever, and organ involvement than in control patients or any of the other patient groups. Expression of tumor necrosis factor alpha (TNF-alpha) is significantly higher in patients presenting rash, fever, and organ involvement versus all other groups. It is concluded that a positive LTA is a predictor for sulfonamide-induced true HSR. In addition, T-helper cell 1 cytokines [TNF-alpha, interleukins (ILs) 1 and 2] as well as the chemokine regulated upon activation, normal T-cell expressed and secreted (RANTES) control the pathogenesis of sulfonamide-induced HSR and may be used in early diagnosis of the syndrome.

Cytokine--chemokine and apoptotic signatures in patients with hepatitis C.

Cytokines and chemokines are proteins that play a critical role in the regulation of immunity and inflammation in patients with chronic Hepatitis C. The aim of our study was to correlate serum cytokines, chemokines and apoptosis in non-treated chronic hepatitis C patients with various degrees of inflammation and fibrosis. We studied 778 patients: 59 had low Knodell fibrosis score and low Knodell histological activity index; 372 had mild fibrosis and low histological activity index; 270 had moderate fibrosis and moderate histological activity index; and, 77 had high fibrosis and high histological activity index on their biopsy. Serum cytokines, chemokines and apoptosis were measured by enzyme-linked-immunosorbent-assay. Multivariate analysis was employed for statistical purposes. A positive correlation was seen between the degree of inflammation and tumor necrosis factor-alpha (TNF-alpha) levels (r = 0.92) in non-cirrhotic patients and between interleukin 2 in all patients (r = 0.85). Interleukin-8 increased significantly at higher histological activity indices and continued to increase in patients with cirrhosis. Transforming growth factor-beta (TGF-beta) levels increased significantly with the severity of fibrosis, but decreased in cirrhotics. In conclusion, cytokines, chemokines and apoptosis levels reflect the progression of inflammation and fibrosis in hepatitis C infected patients, but their signatures differ.

Monitoring adverse drug reactions to sulfonamide antibiotics in human immunodeficiency virus-infected individuals.

Patients infected with the human immunodeficiency virus (HIV) are at higher risk for adverse drug reactions from trimethoprim-sulfamethoxazole (TMP-SMX) than the HIV-negative population. Studying the HIV-positive population the authors aimed to validate the predictive and diagnostic value of the lymphocyte toxicity assay (LTA) for adverse drug reactions. Patient lymphocytes were analyzed for toxicity to SMX and TMP. Of 35 enrolled HIV patients, 18 had TMP-SMX hypersensitivity syndrome reaction (HSR); 10 tolerated the drug; and 5 had never received the drug. When cases with HSR were compared with controls that tolerated the drugs, cytotoxicity was higher for cases: 29.5% +/- 10.1% versus 19.3% +/- 11.2% for SMX (P < 0.022) and 25.0% +/- 11.9% versus 16.3% +/- 11.0% for TMP (P < 0.04). The authors' proposed threshold value for assigning positive results for TMP and SMX hypersensitivities was 22.5%. The LTA has a strong potential for use as a diagnostic tool to assess TMP-SMX hypersensitivity in HIV-infected individuals. Larger patient populations, as well as in vitro studies are needed to further address the reasons for elevated results in immunocompromised patients and to validate the usefulness of the test.