The involvement of oxygen free radicals in the development of the ethanol-induced gastric mucosal damage has been investigated. We found that oral administration of superoxide dismutase reduced the incidence of ethanol-induced mucosal lesions. Reduction of superoxide dismutase activity by diethyldithiocarbamate led to a pronounced aggravation of mucosal damage. Inhibition of the chloride-bicarbonate channel by a stilbene derivative also aggravated the ethanol-induced hemorrhagic lesions. Neither glutathione peroxidase, catalase, nor ceruloplasmin were capable of inhibiting the development of mucosal damage. Compounds with scavenging properties such as thiourea, 1-phenyl-3-(2-thiazolyl)-2-thiourea, dimethyl sulfoxide, various inorganic compounds (elements of the first and second subgroups and of the sixth group of the periodic table) and sulfhydryl-containing substances protected the gastric mucosa against ethanol-induced injury in a dose-related manner. Naturally occurring antioxidants such as alpha-tocopherol, beta-carotene, and coenzyme Q10 were ineffective. The present results suggest that superoxide free radicals are involved in the development of ethanol-induced gastric mucosal lesions, probably via an interaction with cellular membranes.

A modification of the distention ulcer was studied in albino rats and a new possibility of testing ulcerogenic side effects of drugs was described. The distention alone was not sufficient to produce lesions. The severity of ulcer lesions was highly dependent on the volume of the acid solution. Large volumes of 0.1 N HC1 evoked severe ulcers within 1 h. Small amounts of weak acid solution did not cause any ulceration. Anti-inflammatory drugs administered in therapeutic doses, which did not yet produce any ulcers in animals, increased the sensitivity of the gastric mucosa against the aggresive factor, the acid. In animals pretreated by anti-inflammatory drugs in toxic doses an earlier development of ulceration was observed by distention with acid. Stress also accelerated and aggravated the formation of distention ulcers.

Flupirtine was developed long before K(V)7 (KCNQ) channels were known. However, it was clear from the beginning that flupirtine is neither an opioid nor a nonsteroidal anti-inflammatory analgesic. Its unique muscle relaxing activity was discovered by serendipity. In the meantime, broad and intensive research has resulted in a partial clarification of its mode of action. Flupirtine is the first therapeutically used K(V)7 channel activator with additional GABA(A)ergic mechanisms and thus the first representative of a novel class of analgesics. The presently accepted main mode of its action, potassium K(V)7 (KCNQ) channel activation, opens a series of further therapeutic possibilities. One of them has now been realized: its back-up compound, the bioisostere retigabine, has been approved for the treatment of epilepsy.

1 IL-13 is an important mediator in in¯ammatory diseases such as asthma. IL-13 is mainly produced by T cells. However, signalling pathways leading to induction of this cytokine are not wellcharacterized. We analysed the regulation of IL-13 in human peripheral blood mononuclear cells and CD4 + T cells. 2 Cyclosporine (CsA) and FK-506 inhibited IL-13 synthesis, when cells were stimulated by TPA/ ionomycin. However, stimulation by a-CD3/a-CD28 led to an enhanced IL-13 synthesis. 3 NF-kB inhibitor N-tosyl-L-lysine chloromethylketone (TLCK) inhibited IL-13 synthesis more eectively after TPA/ionomycin stimulation. After a-CD3/a-CD28 stimulation, only 300 mM TLCK inhibited IL-13 synthesis. Dexamethasone inhibited IL-13 equally eective after a-CD3/a-CD28 and TPA/ionomycin stimulation. 4 p38 MAPK inhibitor SB203580 inhibited IL-13 synthesis only partially. MEK inhibitor U0126 inhibited TPA/ionomycin induced IL-13 synthesis very eectively, whereas a-CD3/a-CD28 stimulated IL-13 induction was resistant to this drug. 5 These results were con®rmed in puri®ed CD4 + T cells. In dierence to PBMCs a-CD3/a-CD28 stimulated IL-13 synthesis was eectively inhibited by CsA, FK-506 and U0126. 6 Therefore U0126 was tested in an animal model of allergic asthma. We could demonstrate for the ®rst time that inhibition of the MEK ± ERK cascade is a therapeutic option for asthma. Intraperitoneal administration of 10 mg kg 71 U0126 reduced lung eosinophilia in ovalbuminchallenged Brown Norway rats by 44%. 7 These results demonstrate that dierent signalling pathways are involved in regulating IL-13 synthesis in primary human T cells. Characterizing highly potent inhibitors of IL-13 synthesis can be exploited to identify new drugs to treat immunological diseases such as asthma.

Due to the continuous increase in prevalence and morbidity in asthma, there is an urgent need to improve present therapy by drugs with new modes of actions. In contrast to many human diseases, allergic asthma does not occur in the animal world. Therefore, we have to mimic some characteristic feature of asthma in animals. For this reason, a wide variety of animal models have been developed and are employed in the search for new chemical entities for asthma therapy. In the present paper, the experimental models of the most characteristic asthma symptoms are critically reviewed.