促甲状腺素释放激素类似物YM14673对小鼠学习记忆的影响

采用小鼠跳台法评价促甲状腺素释放激素类似物ＹＭ１４６７３（ｉｐ１ｍｇ·ｋｇ－１）对正常成年小鼠被动回避学习记忆成绩的影响．结果表明ＹＭ１４６７３对东莨菪碱，氯霉素和乙醇造成的小鼠记忆获得，巩固及再现障碍均有明显的改善作用．     

抗人DR5单抗-阿霉素交联物的制备及其细胞毒作用

目的：介绍抗人DR5单抗YM366EC-阿霉素结合物的制备及其细胞毒作用,以探讨YM366EC作为内源性导向载体的可能性。方法：采用氧化葡聚糖（Dex）T-40作为中介载体,联结抗人DR5YM366EC与阿霉素（ADR）制备交联物366EC-Dex-ADR,交联物中ADR与366EC的克分子比为71：1。经ELISA测定交联物的抗体活性大部分保持。MTT法体外测定其细胞毒性。结果：交联物对表达DR5受体的肿瘤细胞处理24小时的IC50是游离ADM的5倍,并且和肿瘤细胞DR5受体表达相关。结论：YM366EC具有良好的导向作用,结合物对肿瘤细胞有选择性杀伤作用。     

Treat cancers by targeting survivin: Just a dream or future reality?

Since the discovery of survivin (BIRC5) as a cancer-related molecule by Grazia Ambrosini and Dario C. Altieri at 1997, our knowledge related to the function of this molecule has been extended from simple apoptosis inhibition to complicated, interlinked processes that involve interference of mitosis, apoptosis, autophagy, and even DNA repair recently. However, despite the growing amount of knowledge related to survivin in the last ten years, the development of survivin inhibitors or survivin-related molecular therapies is surprisingly and relatively slow as compared to other therapeutic inhibitors for cancer treatment. Here, the molecular functions of survivin and the progress of development of survivin-targeting therapies are discussed in detail. Functional differences between different survivin-specific inhibitors are discussed from both structural and biochemical point of views. This review also reveals different challenges that scientists are currently facing in the development of survivin inhibitors for clinical application. Finally, future directions for the development of survivin-targeted therapies are discussed in this review.     

Suppression of Rotenone-Treated Human Breast Cancer Stem Cell Survival Using Survivin Inhibitor YM155 is Associated to Oxidative Stress Modulation

Background: Despite recent progress in molecular-targeted therapies, breast cancer remains the primary leading cause of cancer related death among women worldwide. Breast cancer stem cells (BCSCs) are believed to be responsible for therapy resistance and cancer recurrence. We recently demonstrated that human BCSCs (CD24-/CD44+) could survive better than their counterpart non-BCSCs (CD24-/CD44-) when treated with rotenone, possibly due to lower levels of reactive oxygen species (ROS) production, high expression of antioxidant manganese superoxide dismutase (MnSOD), and anti-apoptotic survivin. The aim of this study was to verify the role of survivin on human BCSCs survival under oxidative stress modulation by suppressing its expression using YM155, a survivin inhibitor. Methods: Human BCSCs (ALDH+ cells) were treated with YM155 for 24 h prior to treatment with rotenone for a further 6 h. We determined intracellular superoxide levels were determined using dihydroethidium assay, survivin and MnSOD expression using qRT-PCR, survivin protein level using ELISA, as well as cell viability using trypan blue exclusion and acridine orange/ethidium bromide apoptosis assay. Results: Suppression of survivin expression using YM155 could reduce the survival of rotenone-treated BCSCs, which may be associated with oxidative stress modulation, as shown by increased ROS levels and decreased MnSOD expression. We confirm that survivin is responsible for maintaining BCSCs survival under oxidative stress modulation. Furthermore, YM155 could modulate oxidative stress in BCSCs by reducing MnSOD expression and increasing ROS levels. Conclusion: YM155 treatment could be used to overcome BCSCs resistance to oxidative stress-based anticancer therapies.     

Solifenacin appears effective and well tolerated in patients with symptomatic idiopathic detrusor overactivity in a placebo- and tolterodine-controlled phase 2 dose-finding study

OBJECTIVES: To evaluate the dose-response relationship and safety/tolerability of solifenacin succinate (YM905) in the treatment of overactive bladder (OAB), and to compare its efficacy and safety/tolerability with tolterodine 2 mg twice daily. PATIENTS AND METHODS: This multicentre study included a 2-week single-blind placebo run-in, a 4-week double-blind placebo-controlled active treatment phase, and a 2-week follow-up. Men and women with an OAB and urodynamic evidence of detrusor overactivity were randomized to placebo or solifenacin 2.5, 5, 10 or 20 mg once daily, or tolterodine 2 mg twice daily. RESULTS: Of 265 patients enrolled, 225 were randomized and 192 completed the study. Solifenacin 5, 10 and 20 mg produced statistically significant (P < 0.05) improvements in voids/24 h vs placebo, whereas tolterodine did not; the mean change with tolterodine was between those with solifenacin 2.5 and 5 mg. The outcome was similar for the mean change from baseline to endpoint in mean volume voided/void. For incontinence and urgency episodes/24 h the solifenacin dose groups showed numerically superior changes vs placebo; the mean effects with tolterodine were generally smaller than with solifenacin. Most of the efficacy effect of solifenacin was evident at 2 weeks. Quality-of-life outcomes supported the efficacy results. Solifenacin 5 and 10 mg were well tolerated; there were no serious treatment-related adverse events. The incidence of dry mouth was 14% for solifenacin 5 and 10 mg, 2.6% for placebo and 24% for tolterodine. CONCLUSION: In this study, the 5- and 10-mg doses of solifenacin appeared to be the most clinically effective for treating OAB, considering the balance between efficacy, quality of life and tolerability. From the results of this study solifenacin 5 and 10 mg were selected for further evaluation in large-scale phase 3 studies.     

Effect of YM928, a novel AMPA receptor antagonist,on seizures in EL mice and kainate-induced seizures in rats

Kainate-induced seizures and seizures induced by tossing stimulation in epilepsy-prone EL mice are considered as models of complex partial seizures. We used these models to evaluate the anticonvulsive effects of 2-[N-(4-chlorophenyl)-N-methylamino]-4H-pyrido[3.2-e]-1,3-thiazin-4-one (YM928), a novel -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist. In the kainate-induced seizure test in rats, wet-dog shakes (WDS) were reduced by oral administration of YM928 at doses of 7.5 mg/kg and 30 mg/kg. YM928 (15 mg/kg) reduced the number of WDS within the first 80 min, but then prolonged the time of occurrence compared with the other groups. Significant reduction in kainate-induced motor seizure was observed with 4–30 mg/kg. YM928 did not induce apparently abnormal behaviour at doses of 2–15 mg/kg but did induce sedation at 30 mg/kg. Carbamazepine (40 or 80 mg/kg), valproate (600 mg/kg), diazepam (2.5 mg/kg), and phenobarbital (20 or 40 mg/kg) exerted anticonvulsant effects against motor seizures, but only valproate, at a dose that also caused sedation, suppressed WDS. Phenytoin and ethosuximide did not show significant anti-kainate effects. In the tossing stimulation test in EL mice, i.p. injection of YM928 at 5 mg/kg or 10 mg/kg significantly increased the number of stimulations required to elicit generalized seizure. Carbamazepine (4 or 8 mg/kg), phenytoin (8 or 16 mg/kg), valproate (100–400 mg/kg), diazepam (0.5 mg/kg), phenobarbital (1.3 or 2.5 mg/kg) and ethosuximide (75–300 mg/kg) exerted significant anticonvulsant effects against these seizures. These results indicate that YM928 has anticonvulsant effects on seizure models that are characteristic of partial onset seizures in humans. YM928 is expected to have beneficial effects against human complex partial seizure with secondary generalization or temporal lobe epilepsy.     

Effects of ATP-sensitive K+ channel openers and tolterodine on involuntary bladder contractions in a pig model of partial bladder outlet obstruction

AIMS: To compare in vivo the efficacy, potency, and bladder-vascular selectivity of ATP-sensitive potassium channel openers (KCOs), YM934 and (-)-cromakalim to a muscarinic antagonist, tolterodine in a novel partial outlet obstructed pig model. METHODS: Partially obstructed female Landrace pigs were implanted with telemetry transmitters to allow the continuous measurement of intravesical, abdominal and arterial pressures. A subcutaneous port catheter was used to adjust bladder volume. Bladder and arterial pressure were simultaneously monitored under isoflurane anesthesia before and after increasing i.v. doses of test compounds. RESULTS: Under anesthesia, voiding was completely inhibited, but spontaneous, nonvoiding bladder contractions were observed with mean amplitude of 16 +/- 1 cm H(2)O, duration of 35 +/- 2 seconds, and intercontraction interval of 43 +/- 4 seconds (n = 25). YM934 and (-)-cromakalim both caused dose-dependent decreases in bladder contraction area under the curve (AUC) with effective doses to inhibit AUC by 35% of 3.6 and 14.9 nmol/kg, i.v., respectively. However, concomitant reductions in mean arterial pressure of 12 and 13% were also observed. Tolterodine did not inhibit spontaneous bladder contractions at doses up to 100 nmol/kg, i.v. corresponding to plasma concentrations up to 41 ng/mL. CONCLUSIONS: The superior efficacy of KCOs to inhibit spontaneous bladder contractions relative to tolterodine support the hypothesis that KCOs may provide an alternate therapeutic mechanism to treat symptoms of overactive bladder if bladder-vascular selectivity can be sufficiently improved. The minimally invasive model described herein appears useful in the preclinical evaluation of potential therapeutics targeted to treat the overactive bladder.     

YM461, a PAF antagonist, blocks antigen-induced late airway responses and airway hyperresponsiveness in allergic sheep

We examined the effect of an orally active antagonist, YM461, of platelet activating factor (PAF) on antigen-induced early and late airway responses and on the development of airway hyperresponsivenss 24 h after challenge in allergic sheep. Early and late airway responses were determined by measuring specific lung resistance (SR_L) before and periodically after challenge. Airway responsiveness was determined from the slopes of dose-response curves of SR_L vs. increasing doses of carbachol aerosol. The sheep were challenged with Ascaris suum antigen once after vehicle treatment (control) and once 1 h after oral administration of 3 or 10 mg/kg YM461 (each trial was 14 days apart). Airway responsiveness to carbachol was determined 1–3 days prior to and 24 h after antigen challenge. In control 1 and control 2 trials antigen challenge caused significant peak early (288 and 292%, respectively) and peak late (103 and 124%, respectively) increases over baseline in SR_L. SR_L returned to baseline 24 h after challenge but the sheep developed airway hyperresponsiveness as indicated by the 2.6-fold increases in the slopes of the carbachol dose-response curves in the control trials. YM461, 3 and 10 mg/kg p.o., significantly inhibited the late responses (66 and 82%, respectively) and blocked the development of airway hyperresponsiveness at 24 h. The early responses were not significantly reduced in either trial. These results suggest that PAF contributes to the antigen-induced late airway responses and associated airway hyperresponsiveness in allergic sheep.     

促甲状腺素释放激素类似物YM14673对大鼠脑外伤后脑水肿及血脑屏障通透性的影响

目的观察促甲状腺素释放激素 (TRH)类似物YM 14 673对脑外伤后血脑屏障的影响。方法制作大鼠急性脑外伤模型 ,外伤前静脉注入伊文氏蓝。大鼠分为假手术组、生理盐水组、给药组Ⅰ ( 0 1mg/kg)、给药组Ⅱ ( 1mg/kg)。伤后 2 4h处死 ,测定脑水含量及脑组织和血浆中的伊文氏蓝含量。结果大鼠脑外伤后 ,生理盐水组脑组织脑水含量明显高于假手术组 (P <0 0 1) ,遭受直接打击的左侧半球脑水含量明显高于右半球 (P <0 0 1)。经药物YM 14 673处理后 ,左右半球的脑水含量均下降 (P <0 0 5 ) ,而不同剂量治疗组之间脑水含量无显著性差异 (P >0 0 5 )。急性脑外伤后 ,脑组织中伊文氏蓝含量明显升高 ,YM 14 673对其没有影响。结论YM 14 673可减轻急性脑外伤引起的脑水肿 ,但对血脑屏障通透性没有影响。     

Effect of YM218, a nonpeptide vasopressin V(1A) receptor-selective antagonist, on rat mesangial cell hyperplasia and hypertrophy

Mesangial cell growth constitutes a key feature of progressive glomerular injury. Vasopressin (AVP), a potent peptide vasoconstrictor, acts on mesangial cells through the V(1A) receptors, inducing contraction and cell proliferation. This study examined the effects of YM218, a nonpeptide AVP V(1A) receptor-selective antagonist, on the mitogenic and hypertrophic effects of AVP in rat mesangial cells. When added to mesangial cells whose growth was arrested, AVP concentration-dependently induced hyperplasia and hypertrophy. YM218 potently prevented AVP-induced hyperplasia and hypertrophy of these cells. Furthermore, AVP stimulated endothelin (ET)-1 secretion from mesangial cells in a concentration-dependent manner and this effect was potently inhibited by YM218. ET-1 also induced hyperplasia and hypertrophy in mesangial cells and this effect was completely abolished by ET(A) receptor-selective antagonist YM598. In addition, AVP-induced hyperplasia and hypertrophy were partly inhibited by YM598. These results suggest that AVP may modulate mesangial cell growth not only by its direct action but also through the stimulation of ET-1 secretion. YM218 displays high potency in inhibiting the AVP-induced physiologic responses of mesangial cells via the V(1A) receptors and is a potent pharmacologic probe for investigating the physiologic and pathophysiologic roles of AVP in several renal diseases.