Inhibitory effect of DS-4574, a peptidoleukotriene antagonist with mast cell stabilizing action,on compound 48/80-induced gastric mucosal lesions in rats

We evaluated the inhibitory effect of DS-4574, a peptidoleukotriene antagonist with mast cell stabilizing action, on rat gastric mucosal lesions induced by compound 48/80 (C48/80: a mast cell degranulator), in comparison with those of disodium cromoglycate (DSCG: a mast cell stabilizer), LY171883 (a peptidoleukotriene antagonist) and cimetidine (a histamine H₂ receptor antagonist). Subcutaneous administration of C48/80 (1 mg/kg) once daily for four consecutive days produced extensive gastric lesions in the fundic mucosa. DS-4574 (20, 50 and 100 mg/kg/day, oral) and DSCG (200 mg/kg/day, intraperitoneal) treatment markedly inhibited formation of these mucosal lesions, but LY171883 (100 and 200 mg/kg/day, oral) and cimetidine (400 mg/kg/day, oral) treatment did not. Moreover, DS-4574 and DSCG significantly suppressed both hyperhistaminemia and histamine release from rat peritoneal mast cells induced by C48/80. These results indicate that the inhibitory effect of DS-4574 on gastric lesions induced by C48/80 may be related to its mast cell stabilizing action, but to neither its antisecretory nor its peptidoleukotriene antagonistic activity.     

腕式BPro6000和袖带式DS-250动态血压120例对比分析

目的 把BPro6000腕式ABPM与DS-250袖带式ABPM采集的数据进行临床对比研究.探讨其准确性.方法 计算两种ABPM的SBP和DBP昼夜平均值、平均误差值.分别进行方差齐性检验和t检验.对其准确性进行评级.结果 120例志愿者SBP及DBP昼夜平均值经方差齐性检验,平均误差值经t检验,P均大于0.05,无统计学差异.SBP和△ DBP分别为-1.84±14.32 mmHg、-1.61±9.20 mmHg,按照BHS标准SBP和DBP的准确性级别分别为D级和C级,未通过AAMI标准.结论 BPro6000腕式ABPM准确性不高.     

Resorption of cementum by cementocyte activity (“Cementolysis”)

Cementum resorption (cementolysis) comparable to osteocytic osteolysis and concomitant with cementocyte maturation has been observed in alpharadiographs of rat molars. This phenomenon was enhanced by administration of parathyroid extract (Para-Thormone, Lilly) and retarded by feeding a diet containing 1% MgO for 48 days. ³H-thymidine-labeled rats have shown cells with radioactive nuclei at the cementodentinal junction 3 days later and none thereafter, pointing to a turnover of young cementum comparable to that of trabecular bone.

---

Zusammenfassung Eine Resorption des Zements (Zementolyse), vergleichbar mit einer durch Osteocyten verursachte Osteolyse, und begleitet von einer Zementocytenreifung wurde anhand von Alpha-Radiographien von Rattenbackenzähnen beobachtet.Dieser Vorgang wurde durch Verabreichung von Parathyroid-Extrakt (Para-Thormone, Lilly) gesteigert und durch 48tägige Verfütterung einer 1% MgO enthaltenden Diät verlangsamt.Ratten, die mit³H-Thymidin markiert sind, zeigten Zellen mit radioaktivem Nuclei an der zemento-dentinalen Übergangsstelle, und zwar nur nach 3 Tagen — später nicht mehr. Dies weist auf einen Umsatz von jungem Zement hin, ähnlich jenem der Knochenbälkchen.

---

Résumé L'existence d'un phénomène de résorption comparable à l'ostéolyse péri-ostéocytaire au niveau des cementocytes adultes du rat a été mise en évidence par l'alpharadiographie. Cette «cémentolyse» a été stimulée par l'administration d'extrait parathyroîdien et retardée chez des rats dont la diète contenait 1% de MgO.La thymidine tritiée a été retrouvée par radioautographie dans des noyaux de cellules situées à la jonction cément-dentine, 3 jours aprés l'injection, démontrant ainsi un «turnover» du cément des jeunes rats, comparable à celui de l'os trabéculaire.

     

Comprehensive preclinical pharmacokinetic evaluations of trastuzumab deruxtecan (DS-8201a), a HER2-targeting antibody-drug conjugate,in cynomolgus monkeys

1. Trastuzumab deruxtecan (DS-8201a) is an antibody-drug conjugate (ADC) composed of a monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2) conjugated to a topoisomerase I inhibitor (DXd) at a drug-to-antibody ratio (DAR) of 7-8. Here, we examined the pharmacokinetic (PK) profiles of DS-8201a and DXd in cynomolgus monkeys, a cross-reactive species.

2. Following intravenous (iv) administration of DS-8201a, the linker was stable in plasma, and systemic DXd exposure was low. DXd was rapidly cleared following iv dosing. Biodistribution studies revealed that intact DS-8201a was present mostly in the blood without tissue-specific retention. The major pathway of excretion for DXd was the faecal route following iv administration of radiolabelled DS-8201a. The only detectable metabolite in the urine and faeces was unmetabolized DXd. DXd is a substrate of organic anion transporting polypeptides, P-gp, and breast cancer resistance protein.

3. In conclusion, the stable linker in circulation and the high clearance of DXd upon release resulted in the low systemic exposure to DXd. Furthermore, the minimal tissue-specific retention and rapid excretion of DXd into faeces as its unmetabolized form with potentially limited impact on drug???drug interaction as a victim were also critical elements of the PK profile of DS-8201a.

     

DS-1226对慢性睡眠干扰所致小鼠抑郁行为的改善作用

目的 研究人参皂苷水解产物DS-1226对慢性睡眠干扰小鼠的抗抑郁作用,为抗抑郁药物的研发提供科学依据。方法 将72只雄性ICR小鼠分为空白对照组、模型组、阳性对照组（盐酸帕罗西汀,10 mg/kg）、DS-1226低剂量组（20 mg/kg）、中剂量组（40 mg/kg）、高剂量组（80 mg/kg）。除空白组外,其他组小鼠先进行3 d的滚筒适应,然后连续进行14 d睡眠干扰。采用体重监测、自主活动实验、悬尾实验、强迫游泳实验等实验方法,评价DS-1226的抗抑郁作用。结果 连续进行14 d睡眠干扰后,与空白对照组相比,模型组体重显著下降,悬尾和强迫游泳不动时间显著增长。与模型组相比,DS-1226中剂量组显著逆转睡眠干扰所致的体重下降,其他各给药组均未能显著逆转睡眠干扰所致的体重下降;阳性药组的悬尾不动时间极显著减少,强迫游泳不动时间有减少趋势;DS-1226中剂量悬尾不动时间显著减少,强迫游泳不动时间有明显减少趋势;DS-1226高剂量组悬尾和强迫游泳不动时间均显著减少。结论 DS-1226具有改善慢性睡眠干扰小鼠抑郁样行为的作用。     

DS-1227改善东莨菪碱致小鼠学习记忆障碍的研究

【摘要】 目的 研究人参皂苷水解产物DS-1227（Dammarane Sapogenins-1227）对东莨菪碱致小鼠学习记忆障碍的改善作用,为老年痴呆等疾病的药物研究提供科学数据。方法 将60只ICR小鼠随机分为空白对照组、模型组、阳性对照组、DS-1227低、中、高剂量组共6组,每组10只。连续灌胃给药2周后,检测自主活动,第15天开始除空白对照组腹腔注射生理盐水,其他各组均腹腔注射东莨菪碱（0.75mg/kg）,阳性对照组在注射东莨菪碱5min后另腹腔注射毒扁豆碱（0.3mg/kg）,给药完成20min后进行物体认知实验和Morris水迷宫实验检测动物的学习记忆能力。结果 DS-1227对小鼠的自主活动无显著性影响。腹腔注射东莨菪碱后,小鼠的相对辨别指数降低,水迷宫定位航行实验中Day1、Day2、Day3、Day4和Day5潜伏期均明显延长。DS-1227低、中、高剂量和给予M受体激动剂毒扁豆碱均能不同程度增加东莨菪碱致学习记忆障碍模型小鼠的相对辨别指数,缩短水迷宫定位航行潜伏期。结论 DS-1227有改善东莨菪碱致小鼠学习记忆障碍的作用。     

Histamine as an autocrine growth factor in experimental mammary carcinomas

The antisecretory effect of DS-4574, a mast cell stabilizer with peptidoleukotriene antagonism, on the hypersecretion of gastric acid stimulated by several secretagogues was examined in the pig. Goettingen miniature pigs with chronic gastric fistula were used. Intramuscular injection of carbachol (60 g/kg), tetragastrin (50 g/kg) or histamine (200 g/kg)-induced gastric acid hypersecretion. Intraduodenal administration of DS-4574 (10 and 20 mg/kg) significantly inhibited both the hypersecretion induced by carbachol and that by tetragastrin. On the other hand, DS-4574 (50 mg/kg, intraduodenal) did not suppress histamine-induced hypersecretion. In thein vitro study, no effect on hog gastric K⁺-dependent ATPase activity was found at concentrations of DS-4574 from 10^–7 to 10^–4 M. These results were highly similar to those in the rat. The suppression of histamine release from histamine-containing cells in the gastric mucosa of the rat was concluded to be an antisecretory effect of DS-4574.     

丹参素（DS—182）对大鼠心肌线粒体氧自由基损伤的保护作用

本实验用产生OH·体系(Fe~(2+)/抗坏血酸)直接损伤大鼠心肌线粒体,观察丹参素的保护作用。实验结果表明丹参素对线粒体ADP/O,RCR(respiratory control rate,呼吸控制率)、细胞色素氧化酶活性有保护作用,提示丹参素为良好的OH·清除剂。     

丹参酮ⅡA磺酸钠对人肾间质成纤维细胞体外增殖和形态的影响

目的探讨丹参酮ⅡA磺酸钠(sodium tanshinoneⅡ-A sulfonate,DS-201)对肾间质纤维化来源的人肾间质成纤维细胞(human renal interstitial fibroblast,HRIF)体外增殖和形态的影响。方法组织块体外培养HRIF,MTT比色法分别检测对照组及不同浓度DS-201组(0.5mg/ml、1.00mg/ml和2.00mg/ml)HRIF,在体外培养第1、3、5、7、9d的吸光光度值,并计算各实验组抑制率的均值(average of inhibition rate,IRA);倒置相差显微镜观察对照组及DS-201作用下HRIF形态的改变。结果随培养时间的延长和DS-201药物浓度的升高,IRA值升高。用药后HRIF形态由均一的梭形变成圆形或细长不规则条状。结论DS-201对HRIF体外增殖具有时间和浓度依赖性的抑制作用,并使体外培养的HRIF出现形态异常。