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SMTP-7 ( Stachybotrys microspora triprenyl phenol-7), a small molecule that promotes plasminogen activation through the modulation of plasminogen conformation, has excellent therapeutic activity against cerebral infarction in several rodent models. Detailed evaluations of SMTP-7 in a primate stroke model are needed for effective, safe drug development. Here we evaluated SMTP-7 in a monkey photochemical-induced thrombotic middle cerebral artery (MCA) occlusion model ( n=6), in which MCA occlusion was followed by recanalization/reocclusion. SMTP-7 (10 mg/kg, intravenous infusion) significantly increased the postinfusion MCA recanalization rate (32.5-fold, P=0.043) and ameliorated the post-24-h neurologic deficit (by 29%, P=0.02), cerebral infarct (by 46%, P=0.033), and cerebral hemorrhage (by 51%, P=0.013) compared with the vehicle control animals. In normal monkeys, SMTP-7 did not affect general physiologic or hemostatic variables, including coagulation and platelet parameters. Investigations in rodent models of transient and permanent focal cerebral ischemia, as well as arterial thrombosis and bleeding tests, suggest a role for SMTP-7's regulated profibrinolytic action and neuroprotective properties in the monkey MCA occlusion model. In conclusion, SMTP-7 is effective in treating thrombotic stroke in monkeys. SMTP-7 is thus a promising candidate for the development of alternative therapy for ischemic stroke.

The disposition of pitavastatin and pitavastatin lactone, which are mutually converted in the circulatory system, was investigated after intravenous administration of pitavastatin in dogs equipped with chronic bile-duct catheters. The plasma concentration of pitavastatin declined three-exponentially after dosing in the dogs with both diverted and non-diverted bile-flow. The terminal elimination half-life (T1/2) of pitavastatin in the diverted and non-diverted conditions was 3.12 and 5.01 hr, and that of pitavastatin lactone 4.50 and 7.23 hr, respectively. The diverted bile-flow decreased the AUC0-24 hr for pitavastatin and its lactone to 66 and 64%, respectively. In the dogs with the diverted bile-flow, 56.1% and 4.2% of the dose was recovered in the bile as pitavastatin and its lactone, respectively. The biliary clearance (CLb) of pitavastatin and its lactone was 32.5 and 6.8 mL/min, respectively, and the CLb of pitavastatin was about 4.8-fold that of its lactone. In the dogs whose bile-flow was not diverted, the cumulative biliary excretion of pitavastatin and its lactone was estimated from the AUC0-24 hr and CLb of both forms of pitavastatin. The estimated amount was increased by 46% compared with that in the dogs with the diverted bile-flow. This indicates that the increase reflects the actual contribution of the enterohepatic circulation.

Wurtzite—CdSe epitaxial layers on GaAs(1 1 1)A and B substrates were grown by molecular beam epitaxy using elemental Cd and Se beams. A distinct RHEED oscillation of a specular spot intensity was observed during ALE growth of CdSe on GaAs(1 1 1)B, but the oscillation on GaAs(1 1 1)A was poor. A GaAs(1 1 1)B substrate is superior to GaAs(1 1 1)A substrate for the layer-by-layer growth of wurtzite CdSe. The activation energy of Se desorption from the GaAs(1 1 1)B surface was determined as 1.2 ± 0.1 eV by analyzing the temporal specular beam intensity. The crystallographic and luminescence properties are also presented.

UK-1745, a derivative of furoindolinone, is a novel cardiotonic agent that was designed to have both β -adrenoceptor-blocking and cardiotonic activity. The aim of this study was to clarify the mode of action of UK-1745 in the canine and rabbit myocardium. UK-1745 elicited a weak but definite concentration-dependent positive inotropic effect in association with a decrease in the total duration of contraction: in particular, a decrease in the relaxation time in isolated canine right ventricular trabeculae. The maximum positive inotropic effect of UK-1745 was achieved at 3×10 −5 m and amounted to approximately 15% of the maximum response to isoproterenol. The EC 50 for the positive inotropic effect of UK-1745 was 3.3×10 −6 m . Carbachol, a muscarinic receptor agonist, at 3×10 −6 m completely inhibited the positive inotropic effect of UK-1745. UK-1745 shifted the concentration-response curve for isoproterenol to the right with pA 2 value of 5.70. By contrast, UK-1745 at 3×10 −7 to 3×10 −5 m shifted the concentration-response curve for forskolin to the left. In aequorin-loaded ventricular trabeculae, UK-1745 induced a positive inotropic effect that was accompanied by an increase in Ca 2+ transients. It did not affect the relationship between the amplitude of Ca 2+ transients and peak force as compared with that associated with elevation of the extracellular concentration of Ca 2+ ions ([Ca 2+ ] o ). The level of cyclic AMP in tissue was not significantly increased at 3×10 −5 m UK-1745. The present results indicate that UK-1745 exerts a positive inotropic effect mainly via a cyclic AMP-dependent mechanism but, in addition, it has β -adrenoceptor-blocking activity over the same range of concentrations. A drug with such a pharmacological profile might have the potential advantage of avoiding Ca 2+ overload and superfluous oxygen consumption, which may contribute to the unfavorable effects of novel cardiotonic agents that act purely by inhibition of phosphodiesterase III.

Effects of levosimendan on myocardial contractility and Ca2+ transients were assessed in the ventricular myocardium of the rabbit. Levosimendan at and above 0.1 microM had a concentration-dependent positive inotropic effect (PIE) on isolated papillary muscles that had been loaded with aqeuorin. The maximum inotropic response to levosimendan at 3 microM was approximately 20% of the maximum response to isoproterenol (ISOmax), whereas the maximum increase in the amplitude of Ca2+ transients was approximately 11% of ISOmax. For a given PIE, levosimendan increased the amplitude of Ca2+ transients much less than an elevation of [Ca2+]o. Levosimendan did not prolong the relaxation time. Similar results were obtained in single ventricular cardiomyocytes that had been loaded with indo-1. In the presence of the muscarinic receptor agonist carbachol, both the PIE and the increase in the Ca2+ transient induced by levosimendan were markedly attenuated. During wash-out of both carbachol and levosimendan, the contractile force increased conspicuously with little change in the amplitude of Ca2+ transients, an indication that the increase in myofibrillar sensitivity to Ca2+ ions elicited by levosimendan was susceptible to carbachol. Levosimendan at and above 0.03 microM shifted the concentration-response curve for isoproterenol to the left. Levosimendan had a positive chronotropic effect at 0.01 microM and higher in the isolated right atrium of the rabbit. These findings indicate that, in addition to the increase by levosimendan of the sensitivity of contractile proteins to Ca2+ ions, the accumulation of cyclic AMP due to the phosphodiesterase-inhibitory action of levosimendan might contribute to the PIE of this drug.

Thrombomodulin (TM) is a thrombin receptor on the endothelial cell surface, effective as an anticoagulant by changing procoagulant thrombin to an anticoagulant one. As rabbit TM with glycosaminoglycan (GAG) has a more potent anticoagulant activity than that without GAG, we expressed recombinant GAG-modified urinary thrombomodulin (GAG-UTM) in C-127 cells. The effect of an additional GAG chain on anticoagulant activity was investigated in comparison with unmodified recombinant UTM (r-UTM). In vitro, the activity of cleavage of fibrinogen by thrombin or prothrombinase activity was more potently depressed by GAG-UTM than by r-UTM, and the generation of activated protein C by TM-thrombin complex was accelerated by GAG modification. The acceleration of antithrombin III-dependent anticoagulant activity was shown only by GAG-UTM. Parameters like thrombin time, prothrombin time and activated partial thromboplastin time in human plasma were prolonged by GAG-UTM more than by r-UTM. In vivo, the effect of GAG-UTM and r-UTM in endotoxin-induced disseminated intravascular coagulation (DIC) rats was investigated using hematological parameters. GAG-UTM and r-UTM significantly reduced the decrease in fibrinogen and platelet number induced by endotoxin at the dosage of 0.1 and 1.0 mg/kg/h, respectively, suggesting that the antithrombotic effect of GAG-UTM in endotoxin-induced DIC rats was 10-fold as potent as that of r-UTM. GAG-UTM reduced the prolongation of the bleeding time induced by endotoxin, while r-UTM accelerated it. These results suggest that the addition of a GAG chain may increase availability as an anticoagulant.

6-Isobutyrylbenzocycloalken-5-ones (4) exist in the enol form in solution. The seven- and eight-membered enolic 1,3-diketones (4c) and (4d) underwent photoketonization and subsequent type II reaction to generate biradicals which were trapped by oxygen to yield the furanones (5) and (6), and the peroxide (7)[only formed from (4c)] in various solvents in the presence of oxygen, whereas the six-membered enolic 1,3-diketone (4a) underwent oxidative dehydrogenation to yield the naphthol (10). Photoreaction of the six-membered enolic 1,3-diketone (4b) in the presence of oxygen gave the naphthalenone (11) and the epoxide (12).

6-Isobutyrylbenzocycloalken-5-ones (4) exist in the enol form in solution. The seven- and eight-membered enolic 1,3-diketones (4c) and (4d) underwent photoketonization and subsequent type II reaction to generate biradicals which were trapped by oxygen to yield the furanones (5) and (6), and the peroxide (7)[only formed from (4c)] in various solvents in the presence of oxygen, whereas the six-membered enolic 1,3-diketone (4a) underwent oxidative dehydrogenation to yield the naphthol (10). Photoreaction of the six-membered enolic 1,3-diketone (4b) in the presence of oxygen gave the naphthalenone (11) and the epoxide (12).