Katsuhisa Tsuji

Trimethadione tolerance tests for the assessment of feasible size of hepatic resection in patients with hepatocellular carcinoma.

Pre‐operative evaluation of the quantity of functional remnant hepatic parenchyma after hepatectomy was carried out to predict the optimal amount of hepatic resection using the trimethadione (TMO) tolerance test. This test is an estimate based on serum diamethadione (DMO)/TMO ratio (DMO is the only metabolite of TMO) 4 h after oral administration of TMO, and computed tomography (CT) scans of the liver in patients with hepatocellular carcinoma (HCC). The percentage of remnant hepatic parenchyma was calculated pre‐operatively from the remaining non‐cancerous portion and the whole hepatic parenchyma, excluding the HCC portion, using the CT scans. Presumptive remnant DMO/TMO ratio was calculated by multiplying the percentage of remnant hepatic parenchyma and pre‐operative serum DMO/TMO ratio in 45 patients with HCC undergoing resection. The presumptive remnant DMO/TMO ratios were 0.31 ± 0.10 (mean ±s.d.) in 42 patients who survived hepatectomy and 0.13 ± 0.02 (below 0.15) in the three patients who died from postoperative hepatic failure. Of these surviving patients, two patients who had the presumptive remnant DMO/TMO ratios under 0.15 developed postoperative severe complications. Thus, hepatectomy may not be indicated in patients where presumptive remnant DMO/TMO ratio is 0.15 and lower.

Age-related changes in hepatic drug-oxidizing activity using trimethadione as a probe drug in human

Objective: The purpose of this study was to examine the changes in trimethadione (TMO) metabolism over seven stages from neonates to elderly adults. Methods: The subjects were divided into seven groups according to age: neonates (<4 weeks; n=5), infants (<12 months; n=12), children (<10 years; n=21), adolescents (<20 years; n=3), young adults (<40 years; n=20), mature adults (<65 years; n=20) and elderly adults (⩾65 years; n=40). The metabolism of TMO following oral administration (4 mg/kg) was studied in 21 healthy volunteers and 100 patients. Results: The serum albumin, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were always within normal ranges. The serum dimethadione (DMO) versus TMO ratio (DMO/TMO) at 4 h after administration of TMO was low in neonates (mean±S.E.M.: 0.12±0.01). In infants, however, it reached approximately 95% of the peak observed in adolescents (0.64±0.09), and gradually decreased thereafter. Conclusion: These findings indicate that the metabolic rate of TMO varies according to the stage in life. Using TMO as a probe drug may be of value in determining changes in overall hepatic drug-oxidizing activity throughout the human life-span, thereby allowing evaluation of drug–drug interactions and clinically significant risks associated with drug therapy.

Effect of cigarette smoking on caffeine and trimethadione N-demethylation catalyzed by different cytochrome P450 isozymes in patients with cirrhosis

Abstract It has been reported that caffeine (CA) metabolism in humans is catalyzed by cytochrome P450(CYP)1A2. Recently, we reported that human CYP3A4 and 2C, but not 1A2, contribute to trimethadione (TMO) N-demethylation in the human liver. In this study we simultaneously administered two indicators, CA (2 mg/kg) and TMO (4 mg/kg), which have different patterns of metabolism, to patients with cholelithiasis (control) or cirrhosis. The serum levels of CA and TMO, and their individual metabolites, were determined by high-performance liquid chromatography and gas chromatography, respectively. The metabolism of CA and TMO was significantly inhibited in patients with cirrhosis as compared with controls. The ratios of serum paraxanthine (PX)/CA and DMO/TMO at 4 h after administration of the two probe drugs were also significantly decreased in patients with cirrhosis. The PX/CA ratios of the smoking patients with cirrhosis were higher than those of non-smokers. No differences in serum DMO/TMO ratios were observed between the smokers and non-smokers. These results suggest that different estimations of hepatic oxidizing capacity, catalysed mainly by CYP2C and 3A4, are possible in humans.

Trimethadione tolerance test for the quantitative assessment of liver function in rats

The quantitative estimation of the hepatic functional volume in rats was attempted using the serum dimethadione (DMO)/trimethadione (TMO) ratio in a single blood sampling after oral administration of TMO, which we call the TMO tolerance test, in order to develop a means of pre‐operatively assessing hepatic resectability.

A Case of Small Bowel Obstruction due to Mycobacterium Avium Intracellulare Associated with the Acquired Immunodeficiency Syndrome.

AIDSが誘因となった播種性非定型感染症にて腸閉塞をきたした1例を経験した. 症例は48歳の男性. 主訴は腹痛と嘔吐であった. 開腹既往歴なし. 1996年カリニ肺炎にてAIDS発症, その後サイトメガロ網膜炎, 陰部ヘルペス, 頸部リンパ節腫脹を伴う播種性非定型抗酸菌感染症を発症し当院外来にて加療中であった. 2000年に左下腹部痛を主訴に当院を受診した. 身体所見上左下腹部圧痛を認め, 諸検査にて腸閉塞と診断され, 入院した. 入院3日後症状増悪し緊急開腹手術を施行した. 開腹所見にて, 横行結腸と癒着しarch を形成する上部空腸腸間膜リンパ節の著明な腫大を認め, 空腸が陥入し腸閉塞となっていた. Archを解除し陥入する小腸を引き出したところ, 腸管の色調は著明に改善を認めたために腸切除を行うことなく手術を終了した. 術後25日目に退院したが, 術後123日目にAIDSの増悪にて死亡した. AIDSが誘因となった腸閉塞は本邦でも今後増加する可能性があり, 文献的考察を加え報告する.

Correlationships between Liver Function Tests and Morphometric Cytological Parameters in Liver Cirrhosis.

肝硬変併存肝癌例の耐術評価に用いられている肝機能検査が, いかなる肝の形態的所見を反映しているか, 画像解析装置を用いて検討した. 肝硬変併存肝癌16例の肝実質の数か所から得た組織切片から単位体積あたりの肝細胞数と肝実質比を測定した. それにCT像から求めた肝容積とを組み合わせて肝細胞量や肝実質量および肝細胞総量を算出して形態的所見の定量化を試みた. さらに, これらの指標とICG負荷試験値 (ICGR15) や一般肝機能検査値とを比較検討した. ICGR15と, 実質比や単位体積あたりの細胞数および細胞量とは, r=-0.506 (p<0.01), r=-0.655 (p<0.003), r=-0.620 (p<0.01) とそれぞれ相関したが, 肝実質細胞総量とは相関しなかった.以上より, 肝硬変の病理形態的特徴を定量化することにより, 肝実質比や単位体積あたりの肝細胞数および肝細胞量などの組織形態所見から肝機能をある程度, 推測することが可能であった.

The estimation of the functional activity of the reticuloendothelial system using 99mTc-phytate in hepatectomized rat.

RES機能の診断に応用するために肝のシンチグラフィー用試薬99mTc-フチン酸を用いたRES機能総量の測定法について薬物動力学的解析による基礎的検討を行った.99mTc-フチン酸静注後の循環血中のγ線量の減衰はα相とβ相からなる二相性を示し,2-コンパートメントオープンモデルで解析された.β値は肝切除群や肝障害群そしてDIC群などに関係なくほぼ一定であった.そこで静注直後に出現する分布相(α相)の消失速度定数であるα値をもってRES機能総量の値とした.肝切除モデルの検討では,RES機能は肝切除後の残存肝容積に近似した変動を示した.またDICモデルや急性肝障害モデルにおけるRES機能は低下した.また慢性肝障害モデルでは脾のフチン酸の取り込みは増加したが,全身のRES機能は低下した.本測定法は,臨床例におけるRES機能の診断に応用可能と思われた.