The role of complement activation in tumour necrosis factor-induced lethal hepatitis.

Injection of tumour necrosis factor (TNF) in animals causes severe liver cell toxicity, especially when D-(+)-galactosamine (GalN) is co-administered. After challenge with TNF/GalN, serum complement activity (CH50 and APCH50) decreased dramatically, suggesting strong activation of both the classical and the alternative pathways. TNF or GalN alone had no such effect.

The subtype-selective alpha 2-adrenoceptor antagonists BRL 44408 and ARC 239 also recognize 5-HT1A receptors in the rat brain.

Several alpha 2-adrenoceptor compounds have been reported to recognize 5-HT1A receptors. The interaction of the alpha 2A/D- and alpha 2B/C-adrenoceptor antagonists BRL 44408 (2-[2H-(1-methyl-1,3-dihydroisoindole) methyl]-4,5-dihydroimidazole) and ARC 239 (2-[2-[4-(o-methoxyphenyl)piperazin-1-yl] ethyl]-4,4-dimethyl-1,3-(2H,4H)-isoquinolinedione) with 5-HT1A receptors was evaluated in rat brain. Competition experiments in cortex with both compounds against the specific binding of the 5-HT1A receptor radioligand [3H]8-OH-DPAT (8-hydroxy-2-(n-dipropyl-amine)-tetralin) yielded Ki values in the nanomolar range, fairly close to their previously reported affinities for alpha 2-adrenoceptors.

Alpha 2-adrenoceptor subtypes in the human brain: a pharmacological delineation of [3H]RX-821002 binding to membranes and tissue sections.

In order to study the characterization and localization of [3H]RX-821002 (2-methoxy-idazoxan) binding to alpha 2-adrenoceptor subtypes in several regions of the human brain, we have carried out competition studies using both autoradiography and membrane binding assays. The alpha 2A-adrenoceptor subtype was found to be predominant in the different layers of the frontal cortex, cerebellum and hippocampal formation, while in the neostriatum it was the non-alpha 2A- (alpha 2B- and alpha 2C-) adrenoceptor subtype. In the frontal cortex, in addition to binding to the alpha 2A-adrenoceptor subtype, [3H]RX-821002 bound also to a small portion of alpha 2B- and alpha 2C-adrenoceptors in layer III, and to an unidentified binding site in the external layers.

Inhibition of and sensitization to the lethal effects of tumor necrosis factor.

The extension of the positive results obtained with tumor necrosis factor (TNF) in the locoregional treatment of cancer to systemic treatments requires the selective inhibition of its shock-inducing properties. In this paper, recent data regarding the mechanisms by which infections and tumors render mice extremely sensitive to the lethal effects of TNF as well as regarding the inhibition of the dose-limiting toxicities, hypotension and hepatotoxicity, are summarized. An interleukin-12 (IL-12) driven induction of interferon-gamma (IFN-gamma), probably in synergism with endogenous TNF, was found to mediate infection-induced sensitization.