No abstract

Patients with drug-induced hepatocellular jaundice have 11.7% chance of progressing to death or transplantation. Amoxicillin-clavulanate stands out as the most common drug related to DILI.

Drug-induced idiosyncratic liver disease (DIILD) depends largely on host susceptibility factors. Small studies support the genetic influence of human leukocyte antigen (HLA) class II molecules on the predisposition to DIILD. We sought associations between HLA-DRB and -DQB alleles and DIILD considered collectively or according to the biochemical expression of liver damage. We studied a total of 140 patients with a definitive or probable diagnosis of DIILD, as assessed with the Council for International Organizations of Medical Sciences scale, with 635 volunteer bone marrow and blood donors serving as controls. HLA-DRB1* and -DQB1* genotyping was performed by hybridization with sequencespecific oligonucleotides after genomic amplification. The group with DIILD did not differ from control subjects with regard to the distribution of HLA-DRB and -DQB antigens. The frequencies of alleles DRB1*15 (35.4% vs. 18.6% of controls; P ‫؍‬ .002; odds ratio [OR] 2.31) and DQB1*06 (61.5% vs. 40.8%; P ‫؍‬ .001; OR 2.32) were significantly increased in patients with the cholestatic/mixed type of liver damage in comparison to healthy subjects. By contrast, frequencies of alleles DRB1*07 (16.9% vs. 35.4%; P ‫؍‬ .003; OR 0.37) and DQB1*02 (32.3% vs. 55.8%; P ‫؍‬ .0003; OR 0.39) were significantly decreased. In conclusion, there is no association between any specific HLA allele and the propensity to develop DIILD. However, the genetic influence associated with HLA class II alleles appears to play a role in the biochemical expression of liver injury in cholestatic/mixed hepatotoxicity and may explain why a given drug may cause different patterns of liver damage.

Nonselective ␤-blockers are very effective in preventing first variceal bleeding in patients with cirrhosis. Treatment with isosorbide-5-mononitrate (IS-MN) plus propranolol achieves a greater reduction in portal pressure than propranolol alone. The present multicenter, prospective, double-blind, randomized, controlled trial evaluated whether combined drug therapy could be more effective than propranolol alone in preventing variceal bleeding. A total of 349 consecutive cirrhotic patients with gastroesophageal varices were randomized to receive propranolol ؉ placebo (n ‫؍‬ 174) or propranolol ؉ IS-MN (n ‫؍‬ 175). There were no significant differences in the 1-and 2-year actuarial probability of variceal bleeding between the 2 groups (propranolol ؉ placebo, 8.3% and 10.6%; propranolol ؉ IS-MN, 5% and 12.5%). The only independent predictor of variceal bleeding was a variceal size greater than 5 mm. However, among patients with varices greater than 5 mm (n ‫؍‬ 196), there were no significant differences in the incidence of variceal bleeding between the 2 groups. Survival was also similar. Adverse effects were significantly more frequent in the propranolol ؉ IS-MN group due to a greater incidence of headache. There were no significant differences in the incidence of new-onset or worsening ascites or in impairment of renal function. V ariceal bleeding is one of the more severe complications of patients with cirrhosis and portal hypertension. More than 40% of cirrhotic patients already have esophageal varices at diagnosis. Nearly 30% of those patients with large esophageal varices will bleed at 2 years. 1 Nonselective ␤-blockers are an effective therapy for the prophylaxis of first variceal bleeding in patients with cirrhosis. [2][3][4] This beneficial effect of ␤-blockers is mainly due to its ability to reduce portal pressure. 5,6 Complete protection from variceal bleeding is achieved when the portal pressure gradient is reduced to less than 12 mm Abbreviation:

The variability and possible factors modifying the free plasma fraction of phenytoin were investigated in 134 patients with epilepsy undergoing long-term treatment. The total and free plasma concentrations of phenytoin were determined using fluorescent polarisation immunoassay. Concentrations of albumin, bilirubin and creatinine were also obtained. The free plasma concentration was separated by ultrafiltration, at 25 degrees C, using Centrifree((R)) filters. Factors related to the free plasma fraction of phenytoin (free plasma concentration/total plasma concentration) were gender, age, dose, therapeutic regimen, total plasma concentration and the biochemical parameters mentioned. The mean of free plasma fraction was 9.1% with a very high variability (between 3.3 and 37%). No significant relationship was found between the free plasma fraction and dose, age, gender, total plasma concentration or the biochemical data. The only variable with a significant effect (p < 0.05) on the free plasma fraction was polytherapy with valproic acid. The variability in the free plasma fraction of phenytoin was high in epileptic patients, and was poorly related to the clinical or analytical variables studied. In the absence of pathologies that modify phenytoin binding (uraemia, hypoalbuminaemia), the only factor predictive of a possible alteration in the binding of phenytoin to plasma proteins was polytherapy with valproic acid.