Relationship between age and effect of early and long-term captopril treatment in patients with acute myocardial infarction

Objective To analyse the relationship between age and treatment with captopril after acute myocardial infarction (AMI). Methods In a randomized trial, 822 patients with a first AMI received conventional medic al treatment, including intravenous thrombolytic therapy and oral aspirin or metoprolol, and then were randomly allocated to captopril ［dosage fr om the first 6.25 mg to 25 mg/t.i.d, 209 younger patients (≤64 years), 269 elderly patients (65-75 years)］ or conventional treatment only (131 younger p atients, 213 elderly). Survival in the four groups was calculated with the Kapl an-Meier method. Multivariate analysis was performed to understand the degree that multi-variables (including age) affect survival in patients taking captopr il in the hospital or during long term follow-up. Results The survival of patients who took captopril correlated significantly with age ( P<0.001). The survival of the elderly patients on captopril treatment did increase (P<0.0001), but not of the younger ones (P>0.05) during hosp italization. During follow-up, the survival of patients who took captopril cor related insignificantly with age (P>0.05), but both the elderly and the you n ger patients have good survival rates (all P<0.01) and lower cardiac events (all P<0.01) when they took captopril.Conclusions Captopril exerts a weak effect on the younger patients but a beneficial effect o n the elderly patients during hospitalization after AMI. However, there is no d ifference between the younger and the elderly in the prognosis, both having good survival and lower cardiac events when they take captopril long term during fol low-up.     

脑室注射左旋硝基精氨酸对短暂性前脑缺血时迟发性神经元坏死的影响

目的 研究一氧化氮合酶抑制剂在短暂笥前脑缺血再灌注损伤中的作用。方法 钳夹沙土鼠的双侧颈总动脉制造脑缺血模型,应用尼氏染色观察迟发性神经元坏死的分布与。结果 短暂性前脑缺血导致海马ＣＡ１区锥体细胞迟发性神经元坏死,一氧化氮合酶抑制剂左旋硝基精氨酸（Ｌ－ＮＮＡ）明显地减少了迟发性神经元坏死。结论Ｌ－ＮＮＡ可能通过抑制ＮＯＳ对脑缺血起保护作用。     

抑制血管生成对颊粘膜鳞癌微血管构筑的影响

目的 了解抑制血管生成对颊癌微血系统空间配布的影响,进而了解对肿瘤局部生长、浸润及转移的作用。方法 应用鱼精蛋白进行实验治疗,结合扫描电镜肿瘤生血管系统的变化规律。结果 鱼精蛋白确有抑制智力;这生成的作用,主要表现为延缓肿瘤血管生成的发和因管空间结构的建立,促进血管成熟,因此而抑制肿瘤生长、浸润和转移。结论 通过抑制血和生成有可效地阻止肿瘤生长和转移所依赖的血和系统建立和发展,从而限制肿瘤细胞局部     

Effect of protease inhibitors on degradation of recombinant human epidermal growth factor in skin tissue

Recombinant human epidermal growth factor (rhEGF), a polypeptide of 53 amino acid residues, is subject to degradation by numerous enzymes, especially proteases, when it is applied on the skin for the treatment of open wound. Amastatin, aprotinin, bestatin, EDTA, EGTA, gabexate, gentamicin, leupeptin, and TPCK were investigated for the possible protease inhibitors, which may use to protect rhEGF from degradation by the enzymes in the skin. Skin homogenates containing protease inhibitors and rhEGF were incubated at 37°C for 30 minutes. After the reaction was stopped with trifluoroacetic acid, the amount of rhEGF remaining in the sample was determined with an HPLC method. The percentages of rhEGF degraded, at the skin/PBS ratio of 0.25, in the mouse, rat, and human skin homogenate were 85%, 70%, and 46%, respectively. The degree of degradation of rhEGF in the cytosolic fraction was higher than that in the membrane fraction and these enzyme reactions were completed in 30 minutes. Bestatin, EGTA, and TPCK showed significant inhibitory effects on the degradation of rhEGF in the two fractions (p<0.05), while the other protease inhibitors had no significant inhibitory effects or, even resulted in deleterious effects. Therefore, the formulation containing one or several inhibitors among these effective inhibitors would be a promising topical preparation of rhEGF for the treatment of open wound.     

Inhibition of inflammatory angiogenesis in rats by loco-regional administration of hydrocortisone and protamine

We have studied the antiangiogenetic effects of hydrocortisone and protamine given intra-arterially. The cornea of male, Sprague-Dawley rats were cauterized with silver nitrate. The following treatments were given :30 g hydrocortisone topical (t.p.), b.i.d., 50 mg/kg/day intraperitoneally (i.p.) or intra-arterially (i.a.), 10 mg/ kg/day protamine i.p. or i.a. Saline was administered to the control groups. In separate experiments we also evaluated the anti-inflammatory effects of hydrocortisone, i.p., on the cauterized corneas.Five days after cauterization, the animals were killed, exsanguinated and India ink was injected to show the network of neovessels. The percentage area of the cornea covered by neovessels was measured morphometrically and evaluated statistically. Hydrocortisone t.p. (–84%), i.a. (–60%) and protamine i.a. (–44%) significantly inhibited angiogenesis in the cauterized cornea. Either drugs, i.p., had any antiangiogenetic effects, but hydrocortisone significantly reduced cell infiltration of the corneas. The results suggest that locoregional administration of antiangiogenetic drugs might be clinically useful.     

Epimerization and Hydrolysis of Dalvastatin,a New Hydroxymethylglutaryl Coenzyme A (HMG-CoA) Reductase Inhibitor

In aqueous solutions, dalvastatin (1) undergoes epimerization as well as hydrolysis. The transformation of the drug was studied as a function of pH at 25°C in aqueous solutions containing 20% acetonitrile. At all pH values, first-order plots for the conversion are biphasic, indicating rapid equilibration of 1 with its epimer (2) and slower hydrolysis of 1 to the corresponding -hydroxy acid (3). Apparent first-order rate constants for the biexponential equation are given as a function of pH. The alkyl–oxygen cleavage of the lactone ring results in the epimerization of 1 to 2, whereas the acyl–oxygen cleavage results in the hydrolysis of 1 to 3. The epimerization is an S_N1 reaction reaching an equilibrium of [l] _eq/[2] _eq = 1.27. The epimerization rate is increased with an increase in the water content of the solvent. The hydrolysis of 1 to 3 is acid and base catalyzed. The hydrolysis is reversible in acidic media and irreversible in neutral and basic media. At pH values greater than 9, the hydrolysis reaction proceeds more rapidly than the epimerization.     

抗病毒红藻多糖的提取与测定

从我国沿海红灌中撮的粗多糖,经ＤＥＡＥ－纤维素柱层析得到红藻多糖ＲＰ１实验证实有明显抗病毒作用。通过气相色谱、红外光谱、Ｙａｐｈｅ测定方法,证明红藻多糖ＲＰ１含硫酸基是一种硫酸酯化多糖,其单糖组成为半乳糖和３,６－内醚半乳糖,定量分析含量分别为半乳糖７０．０４％、３,６－内醚半乳糖９．５６％１硫酸基１７．３０％。     

Tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) stimulate osteoclastic bone resorption

As both tissue inhibitor of metalloproteinases-1 (TIMP-1) and TIMP-2 have been reported to inhibit bone resorption, we examined whether TIMP-1 or TIMP-2 in fetal calf serum (FCS), with which culture media were supplemented, affected osteoclastic bone resorption in vitro. Contrary to our expectation, almost complete suppression of osteoclastic bone resorption was observed when both TIMP-1 and TIMP-2 were removed from the FCS. Bone resorption was, however, almost fully restored by the addition of recombinant TIMPs. TIMPs stimulate bone resorption at significantly lower concentrations (∼ng/ml) than those (∼μg/ml) required to inhibit bone resorption. To understand the mechanism of TIMP-dependent bone resorption, we counted and compared the number of tartrate-resistant acid phosphatase-(TRAP-) positive and multinuclear cells in cultures containing either 10% FCS or TIMP-1-free and/or TIMP-2-free FCS. There was essentially no difference in number among these, suggesting that the TIMP role seems to be related to the functional expression of osteoclasts. Metallo-proteinase inhibitors, either BE16627B[l-N-(N-hydroxy-2-isobutylsuccinynamoyl)-seryl-l-valine] or R94138 {N-methyl-(3S)-2-[(2R)-2-hydroxycarbamoylmethylundecanoyl] hexahydropyridazine-3-carboxamide}, could not replace TIMPs, suggesting that the osteoclast-stimulating activity of TIMPs cannot be ascribed to merely their inhibitory effect on matrix metalloproteinases. Received: Oct. 15, 1998 / Accepted: April 5, 1999     

晶状体上皮细胞PAI—1蛋白酶mRNA的表达

研究从转录水平确定晶状体上皮细胞是否能够合成纤麦原激活物抑制物－１蛋白酶。方法体外培养的牛晶状体上皮细胞,当细胞生长融合后,抽提ＲＮＡ;采用Ｎｏｔｈｅｒｎｂｌｏｔ分析技术,对抽提得到的牛晶状体上皮细胞ＲＮＡ用特异的ｃＤＮＡ探针进行检测。结果在牛晶状体上皮细胞的基因转录产物中存在有ＰＡＩ－１ｍＲＮＡ的表达,所表达的ＰＡＩ－１ｍＲＮＡ碱基长度为２．３ｋｂ。结论牛晶状体上皮细胞能够分泌ＰＡＩ－１蛋白酶：     

Specific inhibition of epidermal growth factor receptor tyrosine kinase by 4-anilinoquinazolines

Summary Since the mitogenic action of EGF is mediated by ligand-induced autophosphorylation of the EGF receptor (EGFR), and EGFR is commonly overexpressed in solid human tumours, inhibitors of receptor tyrosine kinase activity (RTK) could prove to be effective antitumour agents. Screening of a compound library using an EGF-RTK enzyme prepared from human tumour derived A431 cells identified a series of potent (IC₅₀<1µM) enzyme inhibitors. These inhibitors are quinazolines bearing a variety of substituted anilines at the 4-position. The most potent 4-anilinoquinazolines (IC₅₀ 20nM) have small non-polar meta substituents on the aniline ring, and are competitive with ATP and non-competitive with substrate. The growth inhibitory activity of these agents was assessed in vitro using KB cells (human oral squamous tumour) grown in the absence or presence of EGF. A selected compound, 4-(3-chloroanilino)quinazoline (CAQ), inhibited EGF-stimulated growth in a concentration dependent manner and complete blockade was observed at concentrations (1–10 µM) which had no effect on basal growth. Selectivity of growth inhibition by CAQ was further exemplified in IGF1-stimulated KB cells where no effect was detected at concentrations which completely blocked EGF-stimulated growth. Similarly, CAQ blocked TGF-stimulated growth in MCF-7 human breast cancer cells without affecting insulin-stimulated growth. These studies define a novel class of EGF-RTK inhibitors which are also potent and selective inhibitors of EGF-stimulated human tumour cell growthin vitro. Presented at the symposium "New Approaches in the Therapy of Breast Cancer", Georgetown University Medical Center, Washington DC, October 1994, generously supported by an education grant from Bristol-Myers Squibb.