SR146131: a new potent, orally active, and selective nonpeptide cholecystokinin subtype 1 receptor agonist. II. In vivo pharmacological characterization.

SR146131 is a potent and selective agonist at cholecystokinin subtype 1 (CCK1) receptors in vitro. The present study evaluates the activity of the compound in vivo. SR146131 completely inhibited gastric and gallbladder emptying in mice (ED50 of 66 and 2.7 micrograms/kg p.o., respectively). SR146131 dose dependently reduced food intake in fasted rats (from 0.1 mg/kg p.o.), in nonfasted rats in which food intake had been highly stimulated by the administration of neuropeptide Y (1-36) (from 0.3 mg/kg p.o.), in fasted gerbils (from 0.1 mg/kg p.o.), and in marmosets maintained on a restricted diet (from 3 mg/kg p.o.). SR146131 (10 mg/kg p.o.) also increased the number of Fos-positive cells in the hypothalamic paraventricular nucleus of rats. Locomotor activity of mice was reduced by orally administered SR146131 (from 0.3 mg/kg p.o.). When administered intrastriatally, SR146131 elicited contralateral turning behavior in mice. Furthermore, orally administered SR146131 (0.3-10 mg/kg), also reduced the levels of cerebellar cyclic GMP. Finally, SR146131 (0.1 microgram/kg to 1 mg/kg, p.o.) significantly and dose dependently antagonized fluphenazine-induced mouth movements in rats. The CCK1 antagonist SR27897B prevented all the effects of SR146131. Conversely, SR146131 was unable to elicit any agonist or antagonist effects in a model of CCK2 receptor stimulation in vivo. SR146131 is a very potent and selective nonpeptide CCK1 agonist in vivo. SR146131 is more potent than any other CCK1 agonists reported to date. Because pharmacodynamic studies suggest that SR146131 should have a high absolute bioavailability, it may be a promising drug for the treatment of eating and motor disorders in humans.

Biochemical and pharmacological activities of SR 26831, a potent and selective elastase inhibitor.

SR 26831 ([[5-(2-chloro-benzyl-2-(terbutyloxycarbonyl)]-4,5,6,7- tetrahydrothieno(3,2-c)pyridine]N-oxide) is the first member of a new class of human leukocyte elastase inhibitors. SR 26831 inhibited in a dose-dependent manner elastases from human leukocytes or pancreas with IC50 values of 80 +/- 2.6 nM and 4.8 +/- 0.12 microM, respectively. Steady-state studies revealed that SR 26831 behaved like a noncompetitive, irreversible inhibitor of both types of enzymes. SR 26831 inhibited in a dose-dependent manner degradation of [3H]elastin and [3H]collagens (types I and IV) by human leukocyte elastase (IC50 values were between 1.2 and 1.8 microM). In this respect, SR 26831 was 3- to 20-fold more active than alpha-1-antitrypsin. SR 26831 was also highly selective for elastases inasmuch as it did not inhibit pepsin, collagenase, trypsin, alpha-chymotrypsin, factor Xa, plasmin, kallikrein, cathepsins B, C, D and G and thrombin. In the rabbit, SR 26831 was cleared rapidly from blood after i.v. injection, but affected intracellular leukocyte elastase activity shortly after either i.v. or p.o. administration. In the rat, i.v. or p.o. administration of SR 26831 prevented in a dose-dependent manner acute lung injury induced by intratracheal instillation of human leukocyte elastase. SR 26831 (1 mg/kg) was still efficient when it was administered 90 min before elastase instillation and was also able to limit further hemorrhage development in response to elastase, after it had begun. SR 26831 may therefore be of therapeutic value in the treatment of diseases such as rheumatoid arthritis or pulmonary emphysema thought to be due to the destructive action of leukocyte elastase.

Characterization of specific binding sites for [3H]-staurosporine on various protein kinases.

Binding of [3H]-staurosporine to different protein kinases was time-dependent, reversible and saturable. Scatchard analysis of saturation isotherms indicated one class of binding sites for [3H]-staurosporine with dissociation constants (KD) of 9.6, 2.0, 3.0 and 7.4 nM for protein kinase C, cAMP-dependent protein kinase, tyrosine protein kinase and calcium/calmodulin-dependent protein kinase respectively. [3H]-staurosporine binding was fully displaced by unlabelled staurosporine or the related compound K-252a whereas other protein kinase inhibitors (H-7, H-8 and W-7) did not compete with [3H]-staurosporine. These data confirm that sataurosporine shows no selectivity for different protein kinases and suggest the putative existence of distinct, specific binding sites for [3H]-staurosporine on these enzymes.

[Kawasaki syndrome]. / Le syndrome de Kawasaki.

Recent studies support the hypothesis that Kawasaki disease is due to a hyperimmune vasculitis, probably of infectious origin. In addition, current data highlight the frequency of atypical (oligosymptomatic) aspects of the disease which may not be recognized, thereby worsening its cardiovascular prognosis. The types of cardiac lesions encountered, notably those of the coronary arteries, have now been well established by sequential echocardiographic studies. Several therapeutic trials have confirmed the effectiveness of gammaglobulins (400 mg/kg.day) and acetylsalicylic acid in preventing the formation of coronary aneurysms. These recent advances in the understanding and treatment of Kawasaki disease may lead to a reappraisal of its diagnostic and prognostic criteria and open the way to multiple lines of research.