Long‐term efficacy of biologics in the treatment of psoriasis: what do we really know?

Psoriasis is a chronic inflammatory condition that often requires life-long treatment. Conventional therapies have not fully met the needs of psoriatic patients, because of limited efficacy, adverse effects with cumulative use, and patient inconvenience. In the past decade, biologic immunotherapies have become accepted treatments for psoriasis as a result of perceived efficacy and safety on the part of patients and practitioners. However, most data on these medications come from relatively limited short-term trials. In this review, we will focus on the available long-term data on the efficacy of the biologic agents. We will emphasize the strengths and weakness of the available data of the biologic agents that are Food and Drug Administration (FDA)-approved for the treatment of moderate to severe psoriasis (alefacept, efalizumab, * etanercept, infliximab, and adalimumab), with the inclusion of a newer agent currently under FDA evaluation (ustekinumab).     

Trichloroacetic acid accumulates in murine amniotic fluid after tri- and tetrachloroethylene inhalation

The distribution of trichloroethylene (Tri) and tetrachloroethylene (Tetra) and their metabolites have been studied in pregnant mice by means of whole-body autoradiography (14C-labelled Tri and Tetra) and gas chromatography, with special emphasis on possible uptake and retention in the foetoplacental unit. Volatile (non-metabolized) activity appeared at short intervals after a 10 min. or 1 hr inhalation period in foetus and amniotic fluid. Most notable, however, was a strong accumulation and retention (peak at 4 hrs) in amniotic fluid of the metabolite trichloroacetic acid (TCA) after inhalation of either of the solvents. The main metabolite of Tri, trichloroethanol (TCE) (or conjugates), did not accumulate specifically as compared to maternal plasma. TCA infused intravenously in the maternal plasma was accumulated in amniotic fluid, but less pronounced than after Tri and Tetra inhalation, indicating that some metabolism of Tri and Tetra to TCA may occur in the foetoplacental unit. The results suggest that TCA may be transported to the foetus partly paraplacentally through foetal membranes and amniotic fluid, with the possibility of foetal swallowing or absorption through the skin. Foetal urinary activity also suggests that circulation between foetus and amniotic fluid may contribute to the long-term retention in the foetoplacental unit. In the mother, after inhalation exposures, and in intraperitoneally injected newborn mice, non-extractable radioactivity was found in the respiratory tract, liver, and kidney, indicating binding to these organs through metabolism.     

Covalent binding of four DDD isomers in the mouse lung: lack of structure specificity

Previous studies have shown that o,p'-DDD is activated and covalently bound in the mouse lung. In order to examine the structure dependency of the selective lung binding, the 14C-labelled DDD isomers p,p'-DDD, m,p'-DDD and o,m'-DDD were injected intravenously into female C57B1 mice and covalent binding was measured. Autoradiography of solvent-extracted tape-sections showed that all isomers were selectively and covalently bound in the lung alveolar region. As determined by exhaustive extraction of homogenized tissue, maximal binding was observed 4 hr after injection, although the lung/liver concentration ratio increased for 12 days. Covalent protein binding was also observed in vitro, implying that the activation of DDD to a reactive metabolite takes place in the target organ. Since the aryl-chlorine substitution pattern did not change the selective lung binding, bioactivation of DDD may take place at the ethane side-chain.     

Extrahepatic sites of metabolism of halothane in the rat

Rats were given 14C-halothane intravenously and whole-body autoradiography with freeze-dried sections, or with sections extracted in trichloroacetic acid, water, and organic solvents, was carried out to trace tissues accumulating halothane metabolites. In vitro incubations of tissue homogenates were performed to examine the capacity by the various organs to form tissue-bound 14C from the 14C-halothane. Autoradiography of isolated organs after incubation with 14C-halothane was performed to study the tissue localization of halothane metabolites formed under in vitro conditions. A localization of halothane metabolites was observed in several extrahepatic tissues in vivo, and the in vitro experiments showed a capacity by the same tissues to transform 14C-halothane to metabolites that bind strongly to tissue components. In addition to the liver, the other tissues shown to have a marked halothane-metabolizing capacity were the nasal mucosa, lateral nasal gland, mucosa of the tongue, cheek, soft palate (but not the hard palate), pharynx, larynx, oesophagus, and the tracheo-bronchial mucosa. The in vivo data obtained indicated a diffusion of the halothane over the walls of the large intestine and the caecum, followed by the formation of apparently reductive metabolites by intestinal microbes and a binding of the metabolites to the intestinal contents. The localization of halothane metabolites in the upper alimentary and respiratory pathways is correlated to the presence of cytochrome P-450 at these sites.     

Isolated Ultrafiltration in the Treatment of Dialysis Ascites

Three patients with dialysis ascites improved markedly after treatment with isolated ultrafiltrations. This simple, noninvasive technique should be applied first to patients with dialysis ascites before resorting to more drastic therapeutic measures.