Hisao Shibata

A Combination Therapy With Simvastatin and Ursodeoxycholic Acid Is More Effective for Cholesterol Gallstone Dissolution Than Is Ursodeoxycholic Acid Monotherapy

Inhibitors of 3-hydroxy,3-methylglutaryl coenzyme A (HMG-CoA) reductase have been reported to decrease the cholesterol saturation index (CSI) in duodenal bile in humans and to prevent formation of cholesterol gallstones in animal studies. We performed a prospective study to evaluate the role of HMG-CoA reductase inhibitors as gallstone-dissolving agents. Fifty patients with radiolucent gallstones in a gallbladder opacifying at drip infusion cholecystography were treated with either 10 mg/day simvastatin plus 600 mg/day ursodeoxycholic acid (group 1, n=26) or 600 mg/day ursodeoxycholic acid alone (group 2, n=24) for 12 months. The ratio of solitary to multiple gallstone cases was 21:29. Plasma lipid levels were assessed and ultrasonographic examination of the gallbladder was performed at baseline and at 3-month intervals during treatment. Duodenal bile sampling was performed in five patients in each group at baseline and after 12 months of treatment. Plasma cholesterol decreased significantly in group 1 but not in group 2. In solitary gallstone cases, no significant difference in dissolution rates was observed between groups 1 (3 of 9, 33%) and 2 (4 of 12, 33%). In contrast, the dissolution rate in multiple gallstone cases was significantly higher in group 1 (12 of 17, 71%) than in group 2 (3 of 12, 25%) (p < 0.01). Bile cholesterol saturation index was significantly decreased (p < 0.01) but did not significantly differ between the two groups. These results suggest that combination therapy with simvastatin and ursodeoxycholic acid is more effective for cholesterol gallstone dissolution than ursodeoxycholic acid monotherapy in patients with multiple gallstones.

The Pharmacokinetics and Pharmacodynamics of a New Thromboxane Synthetase Inhibitor, 6-(1-Imidazolylmethyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (DP-1904), in Man after Single Oral Administration

The pharmacokinetics of DP‐1904, a new potent and selective thromboxane synthetase inhibitor and its effects on ex‐vivo prostanoid formation were studied in Japanese normal male volunteers, who received orally a single 10, 20, 50, 100, 200, 400 or 800 mg dose. The drug was well tolerated by all subjects without evidence of any adverse reactions. The absorption of DP‐1904 from gastro‐intestinal tract was rapid. After oral doses of 10–800 mg of the drug given to volunteers in the fasted state, the mean maximum drug concentrations in plasma (Cmax) (mean ± s.e., n = 5) of 0·215 (± 0·041), 0·399 (± 0·037), 1·47 (± 0·22), 2·86 (±0·22), 4·66 (±0·58), 7·28(±0·72) and 16·9 (±2·6) μgmL−1 were reached within 1 h. DP‐1904 concentrations declined monophasically after Cmax with half lives of 30–40 min. These half lives were independent of the administered doses. The mean area under the concentration‐time curves (AUCs) increased from 0·398 (±0·038) to 30·0 (±2·7) μgh. mL−1 as the dose increased from 10 to 800 mg. Linear relations between the doses and Cmax and AUCs were observed. The correlation coefficients for Cmax and AUC were 0·930 and 0·960, respectively. The apparent oral clearance (CL/F) and renal clearance (CLR) did not change significantly as dose increased from 10 to 800 mg. The kinetics of DP‐1904 proved to be linear in the dose range studied. The urinary excretion of DP‐1904 was also independent of the administered dose, and about half of the dose was recovered in urine as unchanged form within 48 h after administration. The elimination of the drug was fast and almost complete within 6 h after dosing. On the other hand, only 0·5% of the dose was excreted into faeces as intact DP‐1904 up to 48 h after 400 mg oral dose. Food intake delayed the absorption of DP‐1904 but did not significantly modify its pharmacokinetics. Serum thromboxane B2 levels (the stable metabolite of thromboxane A2) were reduced more than 90% within 0·5 h after all doses studied. DP‐1904 had a long duration of inhibitory activity and there was still more than 80, 90 and 95% suppression at 12 h after 200, 400, and 800 mg doses, respectively.

Inhibitory effect of noradrenaline on acute liver injury induced by carbon tetrachloride in the rat

The effect of exogenous noradrenaline (NA) on acute liver injury was investigated in rats receiving a single dose of carbon tetrachloride (CCl4). Animals were divided into the following groups: (I) no treatment, used for plasma catecholamine assay; (II) received CCl4 only; (III) treated with CCl4 plus noradrenaline (NA). Plasma levels of catecholamine (CA) were elevated in both groups II and III, particularly in NA: average value at 33 h after the exposure of CCl4 increased to 290-fold of the control in group II and to 513-fold in group III. Subsequently, the levels of NA decreased with time, and were comparatively well-preserved in the rats of group III. Hepatic changes observed in the animals of group II were as follows: destruction with reduced number in rough endoplasmic reticulum; destruction and disappearance of cristae in mitochondria, and numerous fat droplets (shown by electron microscopy); histologically observed marked centrilobular necrosis with steatosis followed by progression with time; and microangiographically demonstrated deranged intrahepatic microvasculature. By contrast, these changes were successfully prevented by NA treatment (group III). Furthermore, histologically observed centrilobular change was restored with time. It was concluded that, in a deranged state, NA takes a form quite dissimilar to ordinary state: Na exerts for hapatoprotective and is highly involved in liver injury.

Microcirculatory responses to estradiol benzoate in chronic liver damage induced by carbon tetrachloride in the rat

SummaryMicrocirculatory responses to estradiol benzoate (ES) under condition of chronic liver damage induced by long-term administration of carbon tetrachloride (CC14) was investigated in the rat. One hundred and five male rats were divided into the following groups receiving 0.1 mg/100 g body weight ES injected intraperitoneally 5 times per week: (1) controls, exposed to CC14 alone; (2) rats treated with ES from the fourth week of CCl4 exposure; (3) animals treated with ES from the 11th week of CC14 exposure. In rats receiving CC14 alone, liver cirrhosis was induced by 10 consecutive weeks of exposure. Microangiograms of the liver demonstrated conspicuous rarefaction of the vascular tree. On the other hand, animals treated with ES had neither atrophic liver nor rarefaction of the intrahepatic vascular tree. ES produced also intrahepatic neovascular proliferation in the cirrhotic liver. After long-term CCl4 administration, ES treated rats had extremely enlarged nodules with tumor-stain like findings, giving rise to a structure differing from hepatocellular carcinoma which latter generally displays a broom-swept appearance. It is concluded that in providing potent angiogenesis in the liver, ES protects the liver against microcirculatory derangement and parenchymal damage induced by CC14.

Inhibitory effects of autologous hepatic tumor suspension on the development of liver cell carcinoma in rats

SummaryInoculation with a crude suspension prepared from autologous liver cell carcinoma inhibited the development of liver tumor in cirrhotic rats exposed to 3′-methyl-4-diethylaminoazobenzene (3′-Me-DAB). The suspension had also an inhibitory effect on the growth of tumor in rats bearing liver cell carcinoma. The results obtained suggest that a close relationship exists between tumor-associated antigens and onco-development.

Studies on Hypercholinesterasenemia

Cholinesterase (ChE) (Acylcholine acylhydrolase) (3, 1, 1, 8)はAcylcholineを分解してコリンと酸を生ずる酵素であるが生体内ではいわゆるTrue cholinesterase (Acetyl cholinehydrolase (3, 1, 1, 7)と異り主として肝,血清に存在する.この酵素が肝疾患において減少することは1950年Alcalde1)の報告以来知られ,肝機能検査の1つとして特に我国ではよく用いられている.しかしこれまでのこの酵素の利用はネフローゼの場合を除き肝機能障害を始めとする各種疾患において低下することを見るのが主眼であった.著者の一人柴田は数年前よりChEの測定法について検討し,各種のThiocholine2)を用いて本酵素並にTrue choline esteraseの測定を試み3)オートアナライザーにてAcetylthiocholineでChE, propionyl thiocholineにてTrue cholinesteraseの測定をすることがすぐれていることを報告している.そして当時異常に高いChE活性を有する1例を経験し,肝生検により脂肪肝であったことを報告した8)がその後ChEの高い症例に遭遇したのでこれらを合せて一括報告検討を加える.一般にChEは低値のみが強調されネフローゼ以外の高値症例は従来問題にされなかったが,我々は高ChE血症の中に一つは脂肪肝に関連した場合と,もう一つは脂肪肝にあまり関係がないように見えるが何らかの肝障害に関係ある一連のものがあると考えている.

A Case of Liver Dysfunction Associated with Long-Term Methotrexate Therapy

本邦では,メソトレキセートによる長期治療例は少ないが,欧米では数年前から乾癬に対して長期投与され,肝障害をきたす例が注目されてきている.ここに報告する症例は58歳の男性で,乾癬に対して約6年間メソトレキセートを投与されたが,腹水と肝障害のため入院した.肝生検の結果は,肝細胞は核の大小不同,pleomorphismが目立ち,幅の狭い線維性間質が小葉間を分割するように走っているが,未だ偽小葉を形成するには至らない肝線維症の所見であり,この肝障害はメソトレキセートによるものと思われた.メソトレキセートによる重篤な肝障害には肝線維症と肝硬変症があるが,それらはDose dependentであることが示唆されている.メソトレキセートによる肝障害および乾癬との関係について,若干の文献的考察を加えた.