Hisaaki Koie

A prostacyclin analogue reduces free radical generation in heart-lung transplantation

The mechanism by which prostacyclin acts to prevent in vivo reperfusion injury is still uncertain. This study was therefore undertaken to assess the effect of a stable prostacyclin analogue (OP 41483-alpha-CD [OP]) on oxygen-derived free radicals after heart-lung transplantation. OP was administered to the heart-lung graft through the pulmonary artery for 25 minutes encompassing the reperfusion process. Free radicals were directly measured by electron spin resonance spectroscopy. The radical intensities of pulmonary venous blood were significantly lower in the OP group than in the control group, suggesting that fewer free radicals were generated in the lungs of the OP group. The cardiac and respiratory function were better in the OP group than in the control group. The lung is the primary source of oxygen free radical attack, and the beneficial action of OP on free radical generation is almost exclusively restricted to the lung and does not apply to the heart. This result suggested that OP probably is effective in inhibiting free radical generation from the endothelium.

The Influence of Liver Dysfunction on Cyclosporine Pharmacokinetics —A Comparison between 70 per cent Hepatectomy and Complete Bile Duct Ligation in Dogs—

The influence of experimentally induced hepatic dysfunction on the pharmacokinetics of Cyclosporine A (CsA) was determined in dogs. The pharmacokinetics of oral (PO) and intravenous (IV) CsA were studied before and after 70 per cent hepatectomy or complete bile duct ligation (CBDL). Changes in liver function were monitored by serial measurements of serum bilirubin, and by the maximum removal rate (Rmax) and plasma disappearance rate (ICG-K) of indocyanine green (ICG). Concentrations of CsA in whole blood were measured by HPLC. Seventy per cent hepatectomy caused significant liver dysfunction: the ICG-Rmax decreased by 47.7±7.1 per cent (mean±SD) and the ICG-K decreased by 61.3±9.7 per cent during the first week after hepatectomy. At the same time, the systemic clearance (CLs) of IV-CsA decreased by 43.9±8.2 per cent, the area under the concentration curve (AUC) of IV-CsA increased by 35.4±20.8 per cent and the bioavailability of CsA decreased by 26.4±14.8 per cent. CBDL also induced significant liver dysfunction: the ICG-Rmax decreased by 39.1±12.8 per cent and the ICG-K decreased by 65.6±3.6 per cent in the second week after the operation. During the same period, the AUC of PO-CsA decreased by 69.9±10.7 per cent and the bioavailability of CsA also decreased markedly by 73.9±15.6 per cent. These data indicate that hepatic impairment significantly influences the pharmacokinetics of CsA, not only by the changes in intestinal absorption, but also by those in hepatic, metabolism. Dose adjustment is therefore necessary in the presence of hepatic dysfunction in order to maintain an adequate blood concentration of CsA without causing side effects.

The effect of thymectomy on myasthenia gravis, thrombocytopenia, and granulocytopenia associated with thymoma: Report of a case

We report the case of a 47-year-old woman with thymoma who developed myasthenia gravis, thrombocytopenia, and granulocytopenia, simultaneously, the concurrent association of these four disorders being extremely rare. Thymectomy was performed, and, during the post-thymectomy course, there were surprising findings concerning the recovery of not only the myasthenia gravis but also of the hematologic disorders. Immediately after thymectomy, the myasthenic symptoms completely disappeared, and the granulocyte and platelet counts recovered to within the normal range within a few days. The laboratory data revealed no difference between pre- and post-thymectomy in the release of cytokines (tumor necrosis factor; TNF, interleukin; IL-2, and IL-6), anti-acetylcholine receptor antibody, or platelet-associated IgG. On the other hand, the serum level of anti-neutrophil cytoplasmic antibody (p-ANCA), against the myeloperoxidase of the granulocytes was dramatically decreased, after thymectomy, showing a significant correlation with the granulocyte count. According to our survey of the literature, this is the first report to show that the removal of a thymoma led to the dramatic resolution not only of myasthenia gravis but also of other associated diseases. It is possible that p-ANCA may be regulated by thymoma, thus causing severe granulocytopenia.

Glomerular endothelial changes in cyclosporine A-treated rats: scanning and transmission electron microscopic studies.

This study focused on the glomerular structural changes observed after cyclosporine A (CsA)-induced nephrotoxicity. Renal structural changes were examined in rats treated with oral CsA, given as a daily dose of 50 mg/kg for periods of up to 49 days. By means of scanning electron microscopy and morphometry, we first demonstrated that the most conspicuous and reproducible ultrastructural changes could be detected in the endothelial cells of the glomerular capillaries. These changes included a reduction in the fenestral pore size and partial disappearance of endothelial fenestration, the appearance of microvilli-like projections on the endothelial surface, and flattening and widening of the cytoplasmic folds. We believe that the ultrastructural changes observed in this study are partially responsible for the alterations in renal function seen in the cyclosporine A-treated model, and that these alterations are caused by CsA-induced vasospasm.

A Case of Primary Cardiac Angiosarcoma.

原発性心臓腫瘍のなかで血管肉腫はまれな疾患で, 比較的若年男子に好発し予後が著しく不良な疾患である. 今回われわれは右心室穿孔による心タンポナーデを初発症状として発症した本疾患の1例を経験した. 穿孔部の心筋の病理組織学的検索では原因不明で, そのまま退院となった. しかし1か月後に突然, 多量の喀血をきたし緊急来院した. 気管支鏡で右B6からの大量の出血があり, 止血困難と判断し緊急手術で右肺下葉切除を行った. 出血巣の病理組織学的検索で血管肉腫と診断された. 前回の右室心筋を再検討したところ, 肺病巣と同一な腫瘍細胞が検出され, この時点で心臓穿孔は心臓の血管肉腫によるものと判明した. 患者は再入院時にすでに両肺野に多発性の転移を認めており, 化学療法を主体とした治療を行わざるをえなかった. 一時寛解したが1か月後に再び多数の転移性陰影を認めるようになり, 呼吸困難を呈し発症後9か月で死亡した. 本疾患の確定診断は悪性腫瘍細胞を証明することであり, 術前診断は非常に難かしい. もし生前に診断が可能であっても有効な治療手段がなく, 今後の有効治療の開発が待たれる.