Shinichi Tokunaga

Pharmacokinetics of Temocapril and Enalapril in Patients with Various Degrees of Renal Insufficiency

SummaryTemocapril is a novel ACE inhibitor that is cleared via dual excretion routes in humans. Borderline or mildly hypertensive patients with normal renal function [group 1, creatinine clearance (CLcr) >70 ml/min (4.2 L/h), n = 12], moderate renal impairment [group 2, CLcr 30 to 70 ml/min (1.8 to 4.2 L/h), n = 12] or severe renal impairment [group 3, CLcr <30 ml/min (1.8 L/h), n = 12] received a single oral dose of either temocapril 1mg (n = 6, each group) or enalapril 5mg (n = 6, each group).These 2 drugs gave similar values for the area under the plasma concentration-time curve (AUC) of the active diacids. The maximum plasma concentration of enalapril diacid was increased 2- and 6-fold in moderate and severe renal impairment, respectively, whereas that of temocapril diacid was not altered. The AUC of enalapril diacid increased 13-fold at CLcr values <30 ml/min, but that of temocapril diacid increased only 2-fold.The duration of plasma ACE inhibition due to enalapril was greatly prolonged by the impairment of renal function, whereas that due to temocapril was affected very little. Urinary recovery of temocapril diacid was decreased markedly in patients with severe renal dysfunction, most probably because the diacid was excreted through the biliary route. On the other hand, urinary recovery of enalapril diacid remained fairly high even in patients with severe renal impairment, because of extremely high plasma diacid concentrations resulting from the lack of biliary excretion. These observations suggest that temocapril is beneficial in the treatment of hypertension in patients with severely impaired renal function.

Effects of a Selective Thromboxane Synthetase Inhibitor OKY-046 on Experimental Diabetic Nephropathy

To examine the effects of endogenous thromboxane A2 on the development of diabetic nephropathy, we administered OKY-046, an inhibitor of thromboxane synthesis, to streptozotocin-induced diabetic rats. Animals were divided into three groups; nondiabetic control, diabetic, and diabetic with OKY-046, and were sacrificed 16 weeks after experimental procedures. The chronic oral administration of OKY-046 to diabetic rats significantly decreased plasma and urinary thromboxane B2 levels. Urinary protein excretion and serum glucose levels were significantly lower in the OKY-046-treated diabetic rats than in the untreated diabetics (60.8 +/- 23.2 vs. 94.1 +/- 33.4 mg/day in the 16th week, p less than 0.05 and 424.4 +/- 93.3 vs. 614.4 +/- 102.3 mg/dl in the 16th week, p less than 0.01, respectively). Platelet aggregation was inhibited by OKY-046. Blood urea nitrogen was unaffected. Ultrastructural examination revealed that the thickness of glomerular basement membrane was markedly thinner in the OKY-046-treated diabetic rats than in the untreated diabetics (197.4 +/- 29.6 vs. 288.6 +/- 46.9 nm, p less than 0.01). These results suggest that thromboxane A2 may play an important role in the development and progression of diabetic nephropathy in rats.

Erythrocytosis complicated by multiple paraganglioma

We report the case of a 22-year-old woman with onset of erythrocytosis at the age of 9 years. Endocrinological and radiological examinations revealed an elevated catecholamine level and the presence of multiple abdominal tumors. After the removal of the tumors, the catecholamine level normalized, whereas erythropoietin remained at the same level and erythrocytosis persisted. The tumor lysate contained considerable amounts of catecholamine but not erythropoietin. Moreover, no erythropoietin mRNA was detected in the tumor by in situ hybridization. These data suggest that this paraganglioma did not produce erythropoietin. A review of the literature showed the existence of patients with early-onset erythrocytosis complicated with paraganglioma, whose erythrocytosis was not relieved even after the resection of paraganglioma.

Antihypertensive Effects and Pharmacokinetics of Temocapril, an Angiotensin Converting Enzyme Inhibitor with Preferential Biliary Excretion, in Patients with Impaired Renal Function

Since the discovery of captopril, the first angiotensin converting enzyme (ACE) inhibitor, by Ondetti et al. in 1977, many ACE inhibitors have been developed (Hui et al. 1991; Ondetti et al. 1977). However, almost all ACE inhibitors currently available, with the exception of fosinopril (Gavras & Gavras 1988), are excreted mainly in the urine through the kidneys. Therefore, in order to prevent an unnecessary increase in plasma concentrations in patients with impaired renal function, careful attention should be paid to the dose, the dose interval and the choice of drug (Oizumi et al. 1988; Suzuki et al. 1992). Temocapril is a novel ACE inhibitor that has been shown in experimental animals and man to be primarily excreted in faeces through the bile (Nakashima et al. 1992; Oguchi et al. 1993). A pharmacokinetic study of a single dose of temocapril has been performed in patients with impaired renal function (Nakashima et al. 1992; Oguchi et al. 1993), and showed that the pharmacokinetics of the drug were similar to those in patients with normal renal function. Another pharmacokinetic study has shown that temocapril is eliminated preferentially through the biliary route and that its bioactivity is hardly affected in patients with liver dysfunction (Furuta et al. 1993). The present study was conducted to evaluate the pharmacokinetics and antihypertensive effects of temocapril in hypertensive patients with severely impaired renal function during administration of temocapril for 7 consecutive days.

Two cases of hepatitis C virus infection caused by needlestick injury at hemodialysis units.

透析業務中の針刺傷事故で, HCV抗体陽性の透析患者血に暴露した後, C型急性肝炎を発症し, その後慢性肝炎へ進展したの2症例を経験した. 2例とも, HCV抗体陽性で肝機能が正常の透析患者に使用した注射針を誤って手掌に穿刺した. 1例は針事故後1か月後より全身倦怠感の出現とともにトランスアミナーゼの上昇を認め, 6か月後にはHCV抗体が陽性となった. 他の1例は特に自覚症状の出現はなく, 針事故後4か月目にトランスアミナーゼの上昇を認め, 6か月後にHCV抗体が陽性となった. 2例とも, 肝機能の悪化と改善を繰り返し, 針事故後, 9か月目と15か月目の肝生検による肝組織学的検査では, chronic persistent hepatitisの所見を示した. 2例ともにβ-インターフェロンの投与によりトランスアミナーゼは正常化した.

Three cases of acute pancreatitis in long-term hemodialysis

慢性腎不全患者に膵障害の発生率の高いことが剖検により報告されているが, 本邦での慢性透析患者に急性膵炎を発症した報告例は比較的少ない. 我々は慢性血液透析の経過中に急性膵炎を発症した3例を経験したので報告する. 3症例は臨床症状 (嘔気, 嘔吐, 心窩部痛, 発熱), 血清膵酵素の上昇 (アミラーゼ700SU以上, 膵成分80%以上), および膵腫大 (腹部超音波検査, CT) より急性膵炎と診断された. 2症例は中心静脈栄養, 短時間頻回透析 (5と7日間) を施行した. 3例とも抗生物質, 蛋白分解酵素阻害剤の投与を行なった. 2例は完全寛解したが1例は膵炎再発後11日にグラム陽性菌による心筋炎に伴う心不全のため死亡した. 急性膵炎発症の成因の可能性としては2例で高カルシウム血症が, 1例で副甲状腺機能亢進症が疑われた. 以上, 血液透析患者に発生した急性膵炎の3例を提示した. 透析療法の長期化に伴い種々の合併症の増加が予測され, 急性膵炎もそのひとつと考えられる. その成因についてはいまだ不明の点も多いが, 血液透析患者には膵炎発症の誘因が多数存在し, また膵炎は発症すると重症化する例もあるため, 発症の早期発見と充分な治療が必要と思われた.