Anti-tumor Necrosis Factor-α Agents Research Articles

Histoplasmosis and Anti-TNF-α Therapies -- Reason for Pause?

Two antitumor necrosis factor-α (TNF-α) agents have been approved by the FDA: infliximab for the treatment of rheumatoid arthritis and Crohn disease,

Current and emerging therapies for rheumatoid arthritis, with a focus on infliximab: clinical impact on joint damage and cost of care in Canada

Background: Rheumatoid arthritis (RA) is a physically debilitating disease that places an enormous burden not only on individuals and their families but also on the economy. Affecting ∼1% of the Canadian population, RA is characterized by pain and swelling of joints. Without effective treatment, RA results in joint destruction that often requires surgery. Objective: This review summarizes the effect of current and new RA treatments on joint damage, with a focus on infliximab. The health-economic repercussions and potential impact of arresting the joint destruction of RA are discussed. Methods: Information for inclusion in this review was identified through searches of the MEDLINE and HealthStar databases from 1995 to 2000. Search terms included rheumatoid arthritis, treatment guidelines, economics, and individual drug names. Results: Standard initial RA drug therapy has been aimed at reducing pain and inflammation, whereas use of the more potent disease-modifying antirheumatic drugs (DMARDs) has been reserved for later stages of disease. More aggressive RA treatment involves introducing DMARDs at the earliest stage. The largest single direct cost of RA involves hospital admissions for the correction of joint deformities. Among newer therapies, the anti—tumor necrosis factor-α agent infliximab has been shown to arrest radiographic measures of disease progression. Conclusions: With early and aggressive treatment involving new drugs and drug combinations, it may be possible to ameliorate the physical, social, and economic effects of RA.

The hydroxyl radical scavengers dimethylsulfoxide and dimethylthiourea protect rats against thioacetamide-induced fulminant hepatic failure

Background/Aims: Reactive oxygen species, proinflammatory cytokines, glutathione depletion and nitric oxide have all been implicated in the pathogenesis offulminant hepatic failure. The aim of the present study was to examine the respective roles of these factors in the pathogenesis of thioacetamide-induced fulminant hepatic failure in rats. Methods: Fulminant hepatic failure was induced by 3 consecutive intraperitoneal injections of thioacetamide (400 mg/kg) at 24-h intervals. Rats were pretreated with one of the following agents: the free radical scavengers dimethylsulfoxide (4 g/kg every 6 h) or dimethylthiourea (200 mg/kg every 12 h), the glutathione donor, N-acetylcysteine (130 or 200 mg/kg every 6 h), or the anti-tumor necrosis factor-α agents pentoxifylline (100 and 200 mg/kg) and soluble tumor necrosis factor receptor (100 or 1000 μg/rat). The nitric oxide synthase inhibitor N-mono-methyl arginine ester (L-NAME, 0.1 mg/ml) was administered in the drinking water, starting 7 days prior to thioacetamide administration. Results: Serum levels of liver enzymes, blood ammonia and prothrombin time and the stage of hepatic encephalopathy were significantly improved in rats treated with dimethylsulfoxide or dimethylthiourea compared to the other treatment groups ( p<0.001). Liver histology and the survival rate in these rats were not adversely affected by thioacetamide administration ( p<0.001), while in all the other treatment groups those parameters were similar to control rats with fulminant hepatic failure. Furthermore, dimethylsulfoxide ameliorated liver damage and improved survival even when its administration was initiated 8 and 16 h after the first thioacetamide injection. The hepatic concentration of methanesulfinic acid, which is produced after direct interaction of dimethylsulfoxide with hydroxyl radicals, was increased five-fold in rats treated with thioacetamide+dimethylsulfoxide ( p<0.001), suggesting a role for hydroxyl radical scavenging in the protection from fulminant hepatic failure in this model. In the group of thioacetamidetreated rats that were pretreated with L-NAME, liver enzymes, blood ammonia levels and the mortality rate were higher than in the control group, treated with thioacetamide only. Conclusions: In thioacetamide-induced fulminant hepatic failure, the hydroxyl radical scavengers dimethylsulfoxide and dimethylthiourea prevent liver injury. Neither N-acetylcysteine nor antagonists of tumor necrosis factor-α are protective in this rat model. Inhibition of nitric oxide formation aggravates liver damage and reduces the survival of rats with thioacetamide-induced liver damage.