A marker for Stevens-Johnson syndrome ...: ethnicity matters.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but severe cutaneous adverse drug reactions, which can be caused by a certain number of specific drugs among which is carbamazepine, an antiepileptic agent. A very strong association of carbamazepine-induced SJS with HLA-B*1502 has recently been described in the Han Chinese population. Here in, we report preliminary results from a European study (RegiSCAR) of 12 carbamazepine-induced SJS/TEN cases (nine French and three German). Among these only four had a HLA-B*1502 allele. Remarkably, these four patients had an Asian ancestry, whereas the others did not as far as we have ascertained. This shows that although the HLA region may contain important genes for SJS, the HLA-B*1502 allele is not a universal marker for this disease and that ethnicity matters.

[Adverse cutaneous reaction to celecoxib: 6 cases]. / Toxidermies au célécoxib: 6 cas.

INTRODUCTION: Our objective was to characterize adverse cutaneous reactions to celecoxib, a new non steroidal anti-inflammatory drug. PATIENTS AND METHODS: A retrospective study of 6 consecutive patients. RESULTS: The average delay before the onset of the reaction was 10.2 days for patients taking the medication for the first time and 48 hours for one patient taking the drug for the second time. Two patients had fever. Patients presented with an exanthema and in most cases an edema of the face. Buccal mucosa was involved in two patients, and one patient had minimal blister lesions. In five of the six patients, minor and transitory biological abnormalities were found. The intrinsic imputability of the celecoxib was I3 (C3S2) in all the cases. DISCUSSION: Our cases are similar to those reported by the French drug regulatory agency (Pharmacovigilance). Usually the adverse cutaneous reactions were not too severe, with maculo-papulo exanthema and edema of the face. The reactions due to celecoxib are more frequent than those due to other non steroidal anti-inflammatory drugs (7.5% versus 4.1%), but severe cases are rarely reported. Besides, an allergic history to sulphonamide contraindicates celecoxib. However celecoxib does not have the aromatic amine common to antibacterial sulphonamides, and there is no proof of cross reactions between these two families. Furthermore, this amine is usually associated with drug reaction severity, which could explain why severe cases due to celecoxib are rare.

[The acetylator polymorphism in a Khmer population: clinical consequences]. / Polymorphisme d'acétylation dans une population khmère: conséquences cliniques.

The great variability of slow acetylator (SA) and/or rapid acetylator (RA) frequency is mainly due to ethnic-racial origin. Using the urinary elimination ratio of three metabolites of caffeine--acetylamino formylamino methyluracil (AFMU) to AFMU + 1-methyl urate (1U) + 1-methyl xanthine (1X)--we settled the acetylation phenotype in 54 independent subjects of Khmer and 70 independent subjects of Caucasian origin. Using DNA from peripheral leucocytes, we determined by PCR, in 32 Khmer and 122 Caucasian subjects, the frequencies of wild-type alleles (NAT-2 *4) and of mutated alleles (NAT-2 *5A, *6A, *7A). The frequency of SA was respectively 28 per cent and 61 per cent in Khmer and Caucasian subjects. The antimode of the distribution of the ratio was different in the two populations: 0.07 in Khmers and 0.18 in Caucasians showing a reduced acetylation capacity in the Khmer population in spite of a higher frequency of RA. The frequencies of alleles were also different between the two populations. Between Khmers and Caucasians respectively: *4: 48.4-23.8 per cent *5A: 15.6-44.2 per cent. *6A: 29.7-32.0 per cent. *7A: 6.3-0 per cent. These differences might be taken into account to define a therapeutic strategy in the treatment of tuberculosis by isoniazide.

Caffeine metabolism before and after liver transplantation.

AIM: To study drug metabolism in patients before and after liver transplantation using caffeine as a probe drug. Forty-five patients undergoing liver transplantation for various liver diseases and who had well documented dossiers were selected for the study. Before the liver transplantation and 1 month, 1 year, and 6 years after liver transplantation, they were given 200 mg of caffeine by the oral route in the morning after voiding their bladder. Twenty-four-hour urine samples were collected and caffeine and metabolites were determined by HPLC: 1-methylurate (1U), 1-methylxanthine (1X), 1.7-dimethylurate (17U), 1.7-dimethylxanthine (17X), 7-methylxanthine (7X), 3-methylxanthine (3X), 1.3-dimethylurate (13U), 3.7-dimethylxanthine (37X), 1.3-dimethylxanthine (13X), 1.3.7-trimethylxanthine = caffeine (137X). Indices of enzyme activities were calculated from the following urinary elimination ratios: (AFMU+1U+1X)/17U for CYP1A2, 17U/17X for CYP2A6, 1U/1X for xanthine oxidase (XO), AFMU/(AFMU+1U+1X) for N-acetyltransferase (NAT-2). RESULTS: Compared with results obtained in a group of 70 healthy subjects, caffeine metabolism before liver transplantation was deeply depressed with a decreased elimination rate in the case of all metabolites and a decreased CYP1A2 activity. Caffeine metabolism began to return to the control values one month after transplantation. One year and 6 years after liver transplantation, quantitatively, the metabolism of caffeine was stable and not different from control, but with qualitative modifications. CYP1A2 activity was decreased with reduced urinary elimination rates of 1X and 17X. XO and CYP2A6 activities and 1U and 17U urinary elimination rates were increased. Immunosuppressive treatment was possibly responsible for the metabolic pathway changes. Almost the same modifications were observed in 9 patients after bone marrow transplantation who had been treated with the same immunosuppressive drugs, cyclosporine and azathioprine. During severe rejection phases in 6 of the liver transplant patients, caffeine metabolism was progressively decreased when the usual liver function tests showed moderate but uniform changes. CONCLUSION: Despite an apparent normal drug-metabolic function, immunosuppressive treatment induces stable variations in drugmetabolic pathways after liver transplantation which can be detected from the changes in caffeine metabolism.

Caffeine metabolism in a group of 67 patients with primary biliary cirrhosis.

OBJECTIVE: To evaluate the polygenic regulated caffeine metabolism in a group of 67 patients with a documented primary biliary cirrhosis (PBC) classified according to the histologic stage proposed by Scheuer. METHODS: Over a 14-year period, drug liver metabolism, using caffeine as a probe drug, has been systematically carried out in addition to the usual clinical, histological and biochemical investigations performed in patients with PBC. The "Caffeine test" consisted of a 200 mg caffeine oral intake. Urines were collected over 24 hours: caffeine (137X), 1-7-dimethylxanthine (17X), 1-3-dimethylxanthine (13X), 1-3-dimethylurate (13U), 3-7-dimethylxanthine (37X), 1-7-dimethylurate (17U), 1-methylxanthine (1X), 1-methylurate (1U), 7-methylxanthine (7X), 3-methylxanthine (3X), and 5-acetylamino-6-formylamino-3-methyluracyl (AFMU) were analyzed by high performance liquid chromatography (HPLC). Total and individual metabolite urinary elimination rates were expressed in micromol/24 hours. Enzyme activities were evaluated from the following urinary metabolite ratios: (AFMU+1U+1X)/17U for CYP1A2, 17U/17X for CYP2A6, AFMU/(AFMU+U+ 1X) for NAT-2, 1U/1X for XO. RESULTS: Compared to healthy subjects, patients with PBC presented a reduced metabolism of caffeine due to a decreased CYP1A2 activity, all the more important since the patients had an advanced histological stage. This picture was nearly identical to the observed picture in chronic liver diseases from various origins. PBC affected the various metabolic pathways of caffeine in a differential manner. CYP1A2 activity was decreased but XO and mainly CYP2A6 activities were increased as shown by the raised urinary ratio 17U/total metabolite elimination. In contrast to the described loss of bimodality of the NAT-2 index distribution in patients with alcoholic cirrhosis, we found a clear-cut, bimodal distribution in patients with PBC, without a high incidence of slow acetylator status. CONCLUSION: Metabolism of caffeine is strongly and differentially disturbed in patients with PBC and apparently not exactly in the same way as that in alcoholic cirrhosis which is more often taken as an index of chronic liver disease. This suggests the need for caution with medicines whose metabolism is under polygenic regulation. Because of the relationships between caffeine metabolism modifications and histological stages, the caffeine test might be used along with the usual tests to safely follow-up the evolution of the disease.

Relationship between the severity of alcoholic liver cirrhosis and the metabolism of caffeine in 226 patients.

OBJECTIVES: To evaluate the polygenic regulated caffeine metabolism in a group of 226 patients with liver alcoholic cirrhosis classified according to the Child score. METHODS: Over a 14-year period an hepatic function test, using caffeine as probe drug, has been systematically associated to the usual clinical and biochemical investigations performed in patients with liver alcoholic cirrhosis. "Caffeine test" consisted in a 200 mg caffeine oral intake. Urines were collected over 24 hours: caffeine (137X), 1-7 dimethylxanthine (17X), 1-3 dimethylxanthine (13X), 1-3 dimethylurate (13U), 3-7 dimethylxanthine (37X), 1-7 dimethylurate (17U), 1-methylxanthine (1X), 1-methylurate (1U), 7-methylxanthine (7X), 3-methylxanthine (3X), and 5-acetylamino-6-formylamino-3-methyluracyl (AFMU) were analyzed by high performance liquid chromatography (HPLC). Total and individual metabolite urinary elimination rates were expressed in micromol/24 hours. Enzyme activities were evaluated from the following urinary metabolites ratios: (AFMU+1U+1X)/17U for CYPIA2, 17U/17X for CYP2A6, AFMU/(AFMU+ 1U+1X) for NAT-2, 1U/1X for XO. RESULTS: Compared to healthy subjects, whatever the Child score, caffeine metabolism was reduced by half in patients with alcoholic cirrhosis. The main cause was the decreased CYP1A2 activity. On the other hand, XO and CYP2A6 activities were increased and NAT-2 activity remained unchanged in slow acetylators (SA) and decreased in rapid acetylators (RA) Child B and C. Bimodality of NAT-2 distribution was unclear, but a right assignment of RA and SA phenotype in cirrhotic patients, confirmed by comparison with genotype, was obtained, using the antimode value of NAT-2 distribution used in healthy subjects. At last, there was an interindividual variability in caffeine metabolism as great as in the usual laboratory parameters. CONCLUSION: Metabolism of caffeine is decreased in patients with alcoholic liver cirrhosis. This decrease paralleled the modifications of the usual laboratory tests and does not bring additional information on the severity of the disease. But the equilibrium between the various metabolic pathways of caffeine is impaired. Beyond the changes of a specific enzymatic activity, this must be taken into account particularly for drugs whose metabolism is of the polygenic regulation type.

Caffeine metabolism differences in acute hepatitis of viral and drug origin.

The 24-h urinary excretion rate of caffeine metabolites following 200 mg caffeine intake has been proved to be a valuable safe quantitative test of liver function. The pathological mechanism of acute hepatitis of viral and drug origin is different. In both diseases, the patient's caffeine metabolic capacity during the acute and the recovery period was compared. In the acute period, in both diseases, the strongly reduced metabolism of caffeine paralleled the variations of the usual biochemical tests. During the recovery period, in viral hepatitis, caffeine metabolism and biochemical tests returned to the normal values. In drug-induced hepatitis during the recovery period, caffeine metabolism remained severely impaired at a time when biochemical tests were back to the control levels. This discrepancy might be due to the histological or molecular toxic effects of the drug(s), irrespective of cytolysis. After drug-induced hepatitis, a caffeine test might be used to check the total recovery or to choose an adapted dosage of medicines.