Design of Group IIA Secreted/Synovial Phospholipase A2 Inhibitors: An Oxadiazolone Derivative Suppresses Chondrocyte Prostaglandin E2 Secretion

Group IIA secreted/synovial phospholipase A2 (GIIAPLA2) is an enzyme involved in the synthesis of eicosanoids such as prostaglandin E2 (PGE2), the main eicosanoid contributing to pain and inflammation in rheumatic diseases. We designed, by molecular modeling, 7 novel analogs of 3-{4-[5(indol-1-yl)pentoxy]benzyl}-4H-1,2,4-oxadiazol-5-one, denoted C1, an inhibitor of the GIIAPLA2 enzyme. We report the results of molecular dynamics studies of the complexes between these derivatives and GIIAPLA2, along with their chemical synthesis and results from PLA2 inhibition tests. Modeling predicted some derivatives to display greater GIIAPLA2 affinities than did C1, and such predictions were confirmed by in vitro PLA2 enzymatic tests. Compound C8, endowed with the most favorable energy balance, was shown experimentally to be the strongest GIIAPLA2 inhibitor. Moreover, it displayed an anti-inflammatory activity on rabbit articular chondrocytes, as shown by its capacity to inhibit IL-1β-stimulated PGE2 secretion in these cells. Interestingly, it did not modify the COX-1 to COX-2 ratio. C8 is therefore a potential candidate for anti-inflammatory therapy in joints

Kolik bei Arabischen Pferden - Retrospektive Studie aus dem Patientengut von 11 Tierkliniken in Deutschland, Österreich und der Schweiz, 1995-2000

The subjects of this investigation were 338 Arabian horses which were presented to 11 renowned medical centres in Germany, Austria and Switzerland between the years 1995-2000, suffering from colic as a result of morbid changes in the gastrointestinal tract. Parameters of the preliminary examination are analyzed for significance and prognostic relevance for the survival rate of the presented horses. A further question was whether any of these parameters give a reliable indication for the necessity of surgical intervention. PCV (p=0,0007) and abdominocentesis (p=0,005) proved themselves to be distinguishing features between Arabs that survived and Arabs that died. The heart rate (p=0,02) contributed to the decision for or against surgical intervention. The analysis was based on the following data which were recorded in a compulsory protocol: anamnesis, clinic admission, diagnosis, treatment and the result of treatment. This comprehensive evaluation gives an overview of gender and age distribution as well as the frequency of the respective colic forms. Of the 338 horses in the study, 230 received conservative treatment and 108 had surgical correction. 76,96% of conservatively and 53,70% of the surgically treated horses were released as healthy. The clinic stay amounted to an average of 5 days for conservatively treated horses and 10 days for those horses with surgical correction. The most frequently affected intestinal segment was the large intestine (65,77%), followed by the small intestine (26,92%) and the stomach (7,31%). The most frequent cause of colic was obstipation, the second-most frequent displacement and the third-most frequent enteritis. The PCV-value of the blood even termed haematocrit was a very important parameter for a success of treatment. The purpose of this work was to determine whether Arabian horses can have their susceptibility for colic minimized by changes in their exogenic management