The protective effect of α-glucosidase inhibitor (GI) by once a day administration against the increase of postprandial blood glucose (ΔPBG) was examined. Using a control group of 5 hospitalized patients with non-insulin-dependent diabetes mellitus (NIDDM) consisting who received only dietary treatment, we demonstrated the effect of GI while considering the influence of an inproved of living environment during hospitalization. The effects on the blood glucose level were studied using the GI treatment group, which consisted of 8 hospitalized NIDDM patients who received medical treatment with GI, and compared the findings before and after GI treatment. In addition, we also compared two GI treatment groups, one which received treatment 3 times a day and the other which was treated only once a day. Blood samples were obtained at 30 min before and 2h after each meal, before sleep and early the next morning. The increase in the postprandial blood glucose levels decreased significantly by the once a day administration of GI, but no significant changes were observed in the control group. The in crease in (ΔPBG) level was also reduced by the once a day administration of GI, and the effect was also similar to that after the 3 times a day administration.Our findings in this small group of patients suggest that good glycemic control can be obtained all day long by the once a day administration of GI.

テオ フィリン(TP)は 日本アレルギー学会 に よるアレルギー治療ガイ ドライン1)において,気 管支喘息に対 して軽症か ら重症 までの幅広い段階 に治療薬 として位置づけられてお り,気 管支喘息 や閉塞性肺疾患に対 して汎用されている薬剤であ る.し かし,有 効血中濃度域が狭 く2),また種々の 薬剤 と相互作用を示す3)ことや,嗜 好や病態,疾 患 などによって,そ の体内動態が異なる4,5)ことが知 られており,TDMが 必要な薬剤 とされている.当 院 にお いて も日常業 務 としてTPのTDMを 行っているが,投 与方法に変更がないにもかかわ らず,入 院後の病状の変化 とともにその体内動態 が変化 し,血 中濃度が変動する場合が多々見 うけ られる.今 回,う っ血性心不全 と気管支喘息を併 発 している患者のTDMを 行 った ところ,う っ血 状態の改善に伴いTPの 血中濃度が上昇 した症例 を経験 したので若干の考察を加 え報告す る.

症例は70歳男性. 呼吸困難を主訴に当院受診し, 胸部X線写真で左胸水を認めた. 胸膜生検診は低分化型腺癌で, 癌性胸膜炎と診断した. 入院翌日には急速な胸水の貯留がみられ, その後胸腔ドレナージにて計12L (挿入後5日間で) の排液を得るも呼吸困難は改善せず, 抗癌剤投与もできないまま約2週間後に永眠された. 経過中明らかな細菌感染が認められないのにもかかわらず, 白血球数は27,800/mm3まで増加し, 血清中および胸水中のG-CSF濃度が高値を示し, G-CSF産生腫瘍が疑われたが, 抗G-CSFモノクローナル抗体による胸膜腫瘍の免疫染色では明らかな陽性所見を認めなかった. 癌性胸膜炎としては特異な経過と思われ, 白血球増多症が何らかの影響を与えたのではないかと推察された.

Proliferation of vascular smooth muscle cells (VSMC) has been shown to play a key role in the atherosclerotic lesions. It has been demonstrated that serum-derived peptidic growth factors, such as insulin, platelet-derived growth factor (PDGF), or epidermal growth factor (EGF), provide mitogenic signals in VSMC and that the interplay of Ca2+ and other messengers is necessary for triggering proliferation. Since Ca2+ channel blockers act on the voltage-dependent Ca2+ channel to inhibit Ca2+ influx, it is conceivable that they affect the proliferative action of growth factors. In this study we have evaluated the effects of diltiazem, a 1,5-benzothiazepine-derived Ca2+ channel blocker, on [3H]thymidine incorporation into DNA stimulated by insulin, insulinlike growth factor I (IGF-I), or PDGF in cultured VSMC from rat aorta. We have also investigated the effects of insulin, IGF-I, and PDGF on Ca2+ uptake in VSMC. After exposure to insulin (10−10 to 8×10−6 M) or IGF-I (10−10 to 10−7 M) for 48 hours, VSMC incorporated [3H]thymidine to 200–280% of maximum (with insulin or IGF-I alone) compared to control. The effect of IGF-I was approximately 10–100 times more potent than that of insulin. PDGF (0.5–15 ng/ml) also induced an increase in [3H]thymidine incorporation into DNA of VSMC. Additivity is observed between PDGF with insulin or IGF-I, but not between insulin and IGF-I. Sixty minute treatment with insulin (5×10−8 to 10−6 M), IGF-I (10−8 to 10−6 M), or PDGF (1.0–15.0 ng/ml) increased the unidirectional45Ca2+ uptake during a 5 minute period. The 30 minute45Ca2+ uptake of insulin (10−7 to 10−6 M)- or IGF-I (10−8 to 10−7 M)-treated cells was significantly greater than that of nontreated cells; 3.5 ng/ml PDGF accelerated45Ca2+ uptake more than 10−6 M insulin or 10−7 M IGF-I. Diltiazem (10−9 to 2×10−5 M) inhibited not only the increase in [3H]thymidine incorporation but also that of the45Ca2+ uptake stimulated by insulin, IGF-I, or PDGF in a dose-dependent manner. These data suggest that coordinate control of VSMC proliferation by insulin or IGF-I and PDGF may play a cardinal role in the development of atherosclerosis and that a Ca2+ channel blocker may suppress atheroma formation by inhibiting VSMC proliferation evoked by serum-derived growth factors through a mechanism that attenuates the increase of intracellular Ca2+ concentration. Furthermore, the effects of insulin, IGF-I, and PDGF on proliferation of VSMC may be coupled to an increase of Ca2+ influx.

Neutral cholesteryl ester hydrolase (NCEH) is an enzyme that mediates the intracellular hydrolysis of cholesteryl ester in cytoplasm. It has been shown to play an important role in the regulation of cholesterol metabolism in the liver. Recently, it has been reported that high-density lipoprotein (HDL)associated cholesterol is processed via a pathway different from that of low-density lipoprotein (LDL) metabolism and that degradation of HDL occurs in a non-lysosomal pathway. In the present study, we examined whether hepatic NCEH activity in H-35 rat hepatoma cells is affected by HDL.NCEH activity was increased when the cells were incubated with increasing concentrations of HDL (from 25 to 100μg protein/ml) for 20 hours. Approximately two-fold increases of NCEH activity were obtained with 100μg protein/ml of HDL. NCEH activity was elevated significantly when the cells were incubated with HDL for more than 10 hours. Moreover, NCEH activity was enhanced by dimyristoyl phosphatidylcholine (DMPC)/cholesteryl oleate (CO)/apoHDL compex, as well as native HDL, but not by DMPC/apoHDL or DMPC/CO complexes. In contrast, neither LDL nor VLDL affected NCEH activity. In addition, HDL induced increases in NCEH activity were not inhibited by coincubation with 50μM of chloroquine, which is regarded as an inhibitor of lysosomal hydrolases.These findings suggest that uptaken HDL-CE is delivered to a cytoplasmic compartment in a manner distinct from the lysosomal pathway, and is hydrolyzed by NCEH in H-35 rat hepatoma cells.

Ca2+ regulates a variety of cellular mechanisms in vascular cells as well as in platelets. Nicorandil interacts with the intracellular Ca2+-activated processes in vascular smooth muscle cells, while Ca2+ channel blockers such as verapamil and diltiazem block voltage-dependent Ca2+ channels. The effects of nicorandil are due to the hyperpolarization of the membrane, interference with mobilization of Ca2+ from the intracellular storage sites, and blockade of receptor-operated Ca2+ channels. In the present study, the effects of nicorandil on cell proliferation and cholesteryl ester accumulation in rat arterial smooth muscle cells in culture were compared to Ca2+ channel blockers. Smooth muscle cells were prepared from rat thoracic aorta, and the rate of proliferation was determined by measuring the cell number and by [3H]-thymidine incorporation into cellular DNA. The effect of nicorandil on cholesteryl ester content in smooth muscle cells was determined by thin-layer chromatography of the cell extracts. Nicorandil at concentrations of 10−6 to 10−4 M, as well as Ca2+ channel blockers (verapamil and diltiazem) inhibited the proliferation and DNA synthesis of cultured smooth muscle cells. The acute inhibitory effects on cell proliferation were observed significantly 16 hours after the addition of the three agents in serum-stimulated cells. These effects were dose dependent, both in acute and in chronic treatment with the three agents. Addition of 10−5 M nicorandil to medium supplemented with 10% serum resulted in a decrease of the net cholesteryl ester content by 18±1%, while cellular free cholesterol content was the same as control. Similar results were also obtained in the presence of verapamil and diltiazem. These data suggest that nicorandil may suppress atheroma formation, not only by inhibiting cell proliferation but also by decreasing cholesteryl ester accumulation in arterial smooth muscle cells.

Clinofibrate (1200mg/day) and probucol (500mg/day: used as a control drug) were administered orally for a period of four years in 106 cases of type-II hyperlipidemia (total cholesterol, TC, 220-300mg/dl: and triglyceride, TG, over 150mg/dl), including 47 cases associated with mild grade diabetes, to evaluate their influence on blood lipids, and the incidence of coronary heart disease (CHD) as determined from patient complaints and ECG findings. No other antihyperlipidemic drugs were administered during the study period. In the clinofibrate group (57 cases, including 27 diabetics), significant improvements in TC (10-15% reduction at 13 measurements), TG (35-50% reduction), HDL-cholesterol, HDL-C, concentration (mean 7.8% increase), and the atherogenic index (25% reduction), as defined by (TC-HDL-C)/HDL-C, were found. In contrast, the probucol group (49 cases, including 21 diabetics) showed a more pronounced reduction in TC (17-20%) with less reduction in TG (0-30%) and deterioration of the HDL-C level (10% reduction). These changes coincide with those previously obtained through a variety of short-term administrative studies. Furthermore, an improved tendency in fasting blood glucose and HbA1 was noticed in the clinofibrate group, but not in the probucol group. CHD episodes occurred in only two cases in both groups, and ECG findings in patients at rest remained almost unchanged in the 38 cases (clinofibrate group: 21 cases; and probucol group: 17 cases) examined.

1) 進行肺癌症例に対する化学療法施行時にOK-432・5KE皮内投与 (週2～3回) を併用し, 骨髄抑制に対する効果を検討した.2) OK-432投与群では末梢血の白血球および顆粒球のNadirが非投与群と比較して有意に高かった.3) 小細胞肺癌例では化学療法施行後の血小板のNadirも非投与群と比較して有意に高かった.4) 白血球数2000/mm3未満, あるいは血小板数50000/mm3未1黄を示す症例はOK-432投与群で明らかに少なく, 更にその期間は短かった.5) 白血球のNadirから正常白血球数 (4000/mm3以上) に復するまでの期間はOK-432投与群が有意に短かった.

The effects of casein or soybean protein on plasma lipid levels and lipoprotein lipid distribution were investigated in non-insulin dependent diabetic male rats whose condition was induced by a neonatal injection of streptozotocin (90mg/kg of body weight) intraperitoneally 2 days after birth. Plasma levels of total cholesterol in the diabetic rats fed the control diets were as high as in the control rats. However, in the diabetic rats fed the cholesterol-rich (1% of cholesterol) diet containing casein, plasma cholesterol was significantly elevated compared to the control rats fed the cholesterol-rich diet containing casein (TCh 337.8±37mg/dl vs 214.8±19, 8mg/dl, p<0.05). Plasma cholesterol levels of diabetic rats fed the cholesterol-rich diet containing soybean were not different from those of the control rats fed the cholesterol-rich diet containing soybean. Difference in plasma cholesterol level, between the casein group and soybean group in diabetic and control rats, was mainly reflected in the very lowdensity lipoprotein (VLDL) fraction. The present study showed that soybean protein attenuated the augumented response of plasma cholesterol to cholesterol-rich diet in the NIDDM model rats.

To investigate the effect of leukocyte and platelet depletion on reperfusion injury using a leukocyte-platelet removal filter (LRF), several cardiovascular variables were examined in the rabbits during ischemia followed by reperfusion. The rabbits underwent cytoapheresis with LRF (n=S) and were compared with controls without LRF (n=S). LRF was composed of a nonwoven polyester fabric (1.8,um, 4.6 gm). Removal of leukocytes and platelets by LRF was 98% for both. A period of 30 min equilibration was allowed before any experimental intervention, at which time the diagonal artery was occluded for 20 min and then reperfused. All arrhythmias were defined and quantified in accordance with the Lambeth Convention. Regional wall thickening was examined by a pulsed Doppler dimension system. No significant differences were observed in hemodynamic variables between the two groups; however, rabbits treated with a LRF demonstrated greater regional wall thickening (LRF group: 17.0 ± 0.9%, control group: 11.0 ± 0.3%, p < 0.01), as well as significant improvement in the frequency of ventricular arrhythmias (LRF group: 12.5%, control group: 47.2%, p < 0.01). The data suggest that LRF may help prevent arrhythmias and preserve left ventricular contraction during and after intracoronary thrombolysis.

Monosodium glutamate (MSG)投与による実験的肥満ラット肝の1H-および31P-MRスペクトロスコピー(MRS)を測定し肝組織像,肝臓中トリグリセライド(TG)含量と比較,検討した.MSGラットでは8週齢頃より脂肪肝を発症し,加齢とともに,肝臓中TG含量が増加していた.1H-MRSでは水と脂肪のピークが認められ,水と脂肪のピークの面積の和に対する脂肪のピークの面積の比は,脂肪肝の進行とともに増加し,肝臓中TG含量との間に強い正の相関関係が認められた.31P-MRSではPhosphomonoester,無機リン(Pi), Phosphodiester,α, β, γのATPのピークが認められた.20週齢において,MSGラットではPi/α-ATPが増加していた.細胞内pHの指標となるα-ATPに対するPiのchemical shiftがMSGラットで低値を示し,アシドーシスの傾向にあると考えられた.以上より,1H-および31P-MRSは脂肪肝における脂肪蓄積の評価と代謝異常の検出に有用であると考えられた.