Jinsaku Sakakibara

Contribution of cytosolic ionic and energetic milieu change to ischemia- and reperfusion-induced injury in guinea pig heart: fluorometry and nuclear magnetic resonance studies.

The contribution of cytosolic ion and energy milieu changes to ischemia/reperfusion injury was investigated in isolated guinea-pig hearts and mitochondria, with fluorometry and 31P nuclear magnetic resonance (NMR). The fura-2 Ca2+ signal during ischemia in the guinea-pig Langendorff heart changed triphasically (phases I, II, and III) and rapidly returned to the control level after the reperfusion. These triphasic changes during ischemia were affected by various agents that affect the cytosolic ion milieu: the combination of asebotoxin-III and dihydroouabain (which increase intracellular Na+) caused an increase in Ca2+ levels in the final stage (phase III) with a manifestation of contracture after the reperfusion of the heart. Inhibitors of the H+-Na+ exchange such as 5-(N-ethyl-N-isopropyl)-amiloride (EIPA) produced a significant restorative effect on the contractility of the reperfused heart with increased proton and decreased Na+ and Ca2+ in the cytosol. The mitochondrial matrix Ca2+ ([Ca2+]m) preloaded with abnormally high Ca2+ levels was markedly increased by perfusion with either a physiologic concentration of Ca2+ or an acidified perfusate. These [Ca2+]m increases were reduced by the H+-Na+ and H+-K+ exchange inhibitor (EIPA; omeprazole), respectively. These findings will help to explain the Ca paradox at the mitochondria level (i.e., mitochondria for Ca2+ pumping play an essential role in the cellular homeostasis of Ca2+ for the maintenance of cell functions of the heart, acting like a Ca2+ scavenger in the cytosol). Factors that induce Ca2+ overload on mitochondria via sarcolemmal Ca2+ influx and any exchange mechanisms with Na+, K+, Ca2+, and H+ will lead to a loss of contractility, associated with the extremely reduced level of free energy change predicted from the reduced ATP x PCr/Pi ratio by 31P NMR.

Studies on the Chemical Tranformations of Rotenoids. III. Ring Conversations of Methyl Rotenononate and b-Rotenonone

Reactions avec des amines primaires ou des hydrazines; transposition de Beckmann des cetoximes

Photochemistry of bufadienolide: occurrence of three tautomers in the photolysis of resibufogenin

The photolysis of resibufogenin (1) in MeOH was found to give a fairly labile mixture of three tautomers (2a-c) by the 1 H nmr spectral analysis including difference NOE experiments

Synthesis of the diterpenoid grayanol B from grayanotoxin II

Treatment of grayanotoxin II (1) with thallium (III) acetate in acetic acid at room temperature, followed by alkaline hydrolysis, yields grayanol B (3b).

One-step synthesis of the diterpenoid leucothol D from grayanotoxin-II

Treatment of grayanotoxin-II (1b) with palladium acetate in methanol at room temperature gave leucothol D (2).

Exploring Risk Factors that Contribute to the Onset of Ritodrine-Associated Serious Adverse Drug Reactions

Background: Ritodrine is a drug used for threatened premature labor. The severe adverse drug reactions associated with ritodrine are known to be pneumonedema, leukopenia, and rhabdomyolysis, but there have been few investigations on the risk factors. We performed a case-control study and selected case reports as a case group and healthy pregnant women in clinical practice as a control group. Methods: We extracted the onsets of pneumonedema, leukopenia, and rhabdomyolysis associated with ritodrine from case reports in Japan as a case group. We selected healthy pregnant women with ritodrine administration in clinical practice as a control group. We investigated their age, medical history; Pregnancy Induced Hypertension (PIH), multiple pregnancies, concomitant drugs administered, and maximum rate of ritodrine infusion, and examined the association with those factors with the onset of adverse drug reactions by logistic regression analysis. Results: The results of the case group showed: pneumonedema (28 cases); leukopenia (25 cases); rhabdomyolysis (21 cases). The risk factors significantly associated with pneumonedema are a medical history of the cardiovascular system, PIH, multiple pregnancy, and concomitant treatment with steroids, which all match with the precautions in ritodrine’s package insert. The factors associated with leukopenia are its administration longer than 7 days and the concomitant treatment with Mg. The factors associated with rhabdomyolysis are multiple pregnancies and a concomitant treatment with Mg. Conclusion: Risk factors for the onset of pneumonedema match the descriptions in the ritodrine package insert, and can be explained by pharmacological actions. Thus, this study could elucidate the risk factors for rare adverse drug reactions limited to pregnant women. The onsets of leukopenia and rhabdomyolysis were caused by physiological changes by pregnancy and its progression of disease state and ritodrine’s pharmacological action, and were suggested the possibility of risk factors.

X-Ray structure of lyofoligenic acid, a novel B-homotriterpene

The structure of lyofoligenic acid has been determined as 3α,24,25-trihydroxy-9(10 → 19)-abeo-lanost-5(10)-en-32-oic acid (II) by chemical and spectroscopic studies as well as by X-ray crystallographic analysis of the p-bromobenzoate methyl ester(III) or (II).