PF-04691502, a potent and selective oral inhibitor of PI3K and mTOR kinases with antitumor activity

Deregulation of the phosphoinositide 3-kinase (PI3K) signaling pathway such as by PTEN loss or PIK3CA mutation occurs frequently in human cancer and contributes to resistance to antitumor therapies. Inhibition of key signaling proteins in the pathway therefore represents a valuable targeting strategy for diverse cancers. PF-04691502 is an ATP-competitive PI3K/mTOR dual inhibitor, which potently inhibited recombinant class I PI3K and mTOR in biochemical assays and suppressed transformation of avian fibroblasts mediated by wild-type PI3K γ, δ, or mutant PI3Kα. In PIK3CA-mutant and PTEN-deleted cancer cell lines, PF-04691502 reduced phosphorylation of AKT T308 and AKT S473 (IC(50) of 7.5-47 nmol/L and 3.8-20 nmol/L, respectively) and inhibited cell proliferation (IC(50) of 179-313 nmol/L). PF-04691502 inhibited mTORC1 activity in cells as measured by PI3K-independent nutrient stimulated assay, with an IC(50) of 32 nmol/L and inhibited the activation of PI3K and mTOR downstream effectors including AKT, FKHRL1, PRAS40, p70S6K, 4EBP1, and S6RP. Short-term exposure to PF-04691502 predominantly inhibited PI3K, whereas mTOR inhibition persisted for 24 to 48 hours. PF-04691502 induced cell cycle G(1) arrest, concomitant with upregulation of p27 Kip1 and reduction of Rb. Antitumor activity was observed in U87 (PTEN null), SKOV3 (PIK3CA mutation), and gefitinib- and erlotinib-resistant non-small cell lung carcinoma xenografts. In summary, PF-04691502 is a potent dual PI3K/mTOR inhibitor with broad antitumor activity. PF-04691502 has entered phase I clinical trials.     

Dose effects associated with rivastigmine transdermal patch in patients with mild-to-moderate Alzheimer's disease

Aim: The cholinesterase inhibitor rivastigmine is available in both oral and transdermal forms. The efficacy of oral rivastigmine appears to be dose‐dependent. The current analysis investigates the effect of dose on the efficacy of the rivastigmine transdermal patch. Methods: This was a retrospective analysis of a large, international, 24‐week, randomised, placebo‐ and active‐controlled trial (IDEAL, CENA713D2320) of rivastigmine in patients with mild‐to‐moderate Alzheimer’s disease (AD). Patients received the 9.5 mg/24 h rivastigmine patch, the 17.4 mg/24 h rivastigmine patch, 12 mg/day rivastigmine capsules or placebo. Changes from baseline at week 24 on the AD Assessment Scale–cognitive subscale (ADAS‐cog), AD Cooperative Study–Clinical Global Impression of Change (ADCS‐CGIC) and the AD Cooperative Study–Activities of Daily Living (ADCS‐ADL) scale were calculated based on the patient’s mode and last prescribed patch dose. The analysis included the 4.6 mg/24 h and 13.3 mg/24 h patch doses, for which efficacy data have not previously been reported. Results: Significant differences (p < 0.05 vs. placebo) were seen on the ADAS‐cog and ADCS‐ADL for all mode rivastigmine patch doses (except 4.6 mg/24 h) and all last prescribed rivastigmine patch doses (except 4.6 mg/24 h and 13.3 mg/24 h). Patients with a last prescribed/mode patch dose of 9.5 mg/24 h and 13.3 mg/24 h showed significant improvements (p < 0.05 vs. placebo) on the ADCS‐CGIC. Conclusion: Rivastigmine patch doses higher than 9.5 mg/24 h may offer additional benefits. The 13.3 mg/24 h patch is worthy of further investigation.     

老龄鼻窦炎患者鼻内镜手术的围手术期处理

目的：总结老龄鼻窭炎患者进行鼻内镜手术的围手术期处理的经验，以降低手术风险。提高安全性。方法：回顾性分析76例经鼻内镜手术治疗的老龄鼻窦炎患者的病例资料，总结鼻内镜手术的围手术期处理，包括药物选择、麻醉方式、术中、术后心电和血氧监护等。结果：所有患者均未出现严重并发症，安全度过围手术期。结论：老龄鼻窭炎患者经过有效的围手术期处理，即选择合适的用药、彻底的术中止血、良好的术后监护等，可以有效降低鼻内镜手术并发症的发生率。获得良好的手术效果，提高老龄患者的生活质量。     

Novel powder formulations for controlled delivery of poorly soluble anticancer drug: application and investigation of TPGS and PEG in spray-dried particulate system.

Biodegradable poly (lactic-co-glycolic acid) (PLGA), D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) and/or polyethylene glycol (PEG) were combined as pharmaceutical excipient to fabricate microparticles containing sparingly soluble drug paclitaxel by spray-drying technique with successful achievement. The effect of formulation variety on particle morphology, surface composition, thermal property, drug entrapped capability, and drug release profile was investigated. The result indicated that the use of the appropriate mixtures of PLGA, TPGS and/or PEG produced paclitaxel-loaded microparticles characterised by acceptable pharmaceutical properties. Atomic force microcopy (AFM) and scanning electron microscopy (SEM) showed that the produced microparticles were spherical in shape with dimples or pores. The particle size ranged from 0.88 to 2.44 microm with narrow distribution. The combination of TPGS and PEG in the formulation resulted in a narrow particle size distribution in general although the influence of the formulation on the particle size was not significant. Differential scanning calorimetry (DSC) study implied that all those components in consideration were compatible well in the blend formulation systems. The paclitaxel entrapped in the particles existed in an amorphous or disordered-crystalline status in the matrices and was independent of the PLGA/TPGS/PEG ratio. X-ray photoelectron spectroscope (XPS) analysis revealed that after incorporation the particle's surface was dominated with PLGA due to its hydrophobic property. The formulation variety had an important impact on the drug release that was reduced with the presence of large fraction of TPGS resulting from a strong hydrophobic interaction between various matrix materials and the drug inside the particle. A zero order release could be yielded by optimising the ratio of PLGA/TPGS/PEG. The combination of PLGA/TPGS/PEG as safe pharmaceutical excipient to formulate particulate delivery system is beneficial in improving the pharmaceutical properties for further powder dosage application.     

汉防己甲素联合屈洛昔芬逆转K562/A02细胞耐药与诱导凋亡相关性的研究

本研究旨在探讨汉防己甲素(tetrandrine，Tet)联合屈洛昔芬(droloxifene，DRL)对耐药细胞系K562／A02的逆转作用与诱导凋亡有无相关性。采用Annexin V/PI法测定耐药调节剂汉防己甲素、屈洛昔芬单独或联合应用后细胞凋亡的情况。结果发现0.62ug/ml汉防己甲素或1/94ug/ml屈洛昔芬单独作用于K562细胞48小时后均可诱导一定比例的细胞凋亡，作用呈时间依赖性，两者联合应用作用增强。0.62ug/ml汉防己甲素或1.94ug/ml屈洛昔芬单独作用于K562／A02细胞均不能诱导细胞凋亡，两者联合应用72小时可诱导小部分细胞凋亡。结论：汉防己甲素，屈洛昔芬逆转耐药的机理与诱导K562／A02细胞凋亡无关。     

Attenuation of brain response to heroin correlates with the reinstatement of heroin-seeking in rats by fMRI

Thirty male Sprague-Dawley rats were divided into two groups and trained to self-administer either saline (n = 14) or heroin (0.1 mg/kg per injection, n = 16) for 10-12 days until a stable self-administration (SA) behavior was achieved. After 8-9 days of withdrawal, each group was divided into two subgroups for reinstatement tests and functional magnetic resonance image (fMRI) scanning, respectively, to determine the neural correlates of the reinstatement of heroin-seeking behavior. For reinstatement testing, heroin-SA rats (n = 10) displayed robust reinstatement of drug-seeking behavior triggered by an acute heroin priming injection, whereas saline control rats (n = 8) did not show such a behavioral response. Regional positive or negative blood oxygen level-dependent (BOLD) signals, induced by heroin priming injection, were observed in both groups of rats during fMRI scanning. However, such heroin-induced positive BOLD signal primarily in the prefrontal cortex and parietal cortex was significantly attenuated in heroin-SA rats (n = 6) when compared to saline control rats (n = 6). Similarly, the heroin-induced negative BOLD signal in the subcortical regions, such as in the nucleus accumbens and hippocampus, was also significantly attenuated in both signal intensity and number of brain voxels activated in heroin-SA rats. These data demonstrate that heroin-induced reinstatement of drug-seeking behavior coincides with a significant, enduring reduction in opiate-induced brain activity in heroin-SA rats, suggesting a possible role of opiate tolerance in mediating reinstatement of drug-seeking behavior.     

新辅助化疗在老年乳腺癌治疗中的意义

目的：探讨新辅助化疗在老年乳腺癌患者治疗中的意义。方法：35例老年乳腺癌患者术前用CTF方案化疗1疗程，化疗后1周手术。结果：无完全缓解病例，部分缓解4例（占11．43％），轻度缓解20例（占57．14％），无变化11例（占31．43％），无临床进展病例。病理组织学观察20例镜下见肿瘤细胞有小点片状坏死。1例因白细胞降低推迟手术，其余患者按计划手术。全组随访1～6年，在随访期间发现5例局部复发，2例骨转移，2例有肺和脑转移。6例在随访期间因本病死亡，3例因其它合并症死亡，余均健在。结论：新辅助化疗对老年乳腺癌可缩小肿瘤，增加手术机会，提高治疗效果，并可能减少术中血行转移。     

Association of serum levels of glycated albumin, C-reactive protein and tumor necrosis factor-alpha with the severity of coronary artery disease and renal impairment in patients with type 2 diabetes mellitus

OBJECTIVES: This study aimed to determine whether elevated serum levels of glycated albumin, high-sensitivity C-reactive protein (hsCRP) and tumor necrosis factor (TNF)-alpha were related to an increased risk for coronary artery disease (CAD) and renal insufficiency in patients with type 2 diabetes mellitus (T2DM). DESIGN AND METHODS: Serum levels of glycated albumin, hsCRP, TNF-alpha and blood glycosylated hemoglobin A1c (HbA1c) were measured in 317 consecutive patients with T2DM and 309 normal controls. Patients with T2DM were grouped based upon coronary angiographic findings (Group I: 151 patients with normal coronary arteries; Group II: 166 patients with significant coronary stenosis [>70% luminal diameter narrowing]) and renal functional status evaluated by estimated creatinine clearance (CrCl) (normal renal function group: 187 patients with CrCl >90 mL/min; mild renal insufficiency group: 103 patients with CrCl 60-90 mL/min; moderate renal insufficiency group: 27 patients with CrCl 30-60 mL/min). Multivariate analysis was performed to determine independent risk factors for CAD and renal insufficiency in patients with T2DM. RESULTS: Serum levels of glycated albumin, hsCRP and TNF-alpha were significantly higher in Group II than in controls (P<0.01) and Group I (P<0.01). A significant difference was found in glycated albumin, hsCRP and TNF-alpha levels among diabetic patients with mild, moderate renal insufficiency and normal renal function (P<0.05). These biochemical measurements correlated significantly with number of diseased coronary vessels (P<0.01) and status of renal function (P<0.05). No difference existed in HbA1c levels between Group II and Group I, and among patients with various CrCL stages. Multivariate analysis revealed that male gender, old age and serum levels of glycated albumin, hsCRP, TNF-alpha and lipoprotein (a) were independent risk factors for CAD, and older age, hypertension and glycated albumin were for CrCl <60 mL/min in diabetes. CONCLUSIONS: Increased serum levels of glycated albumin, hsCRP and TNF-alpha are associated with the presence and severity of CAD and renal impairment in patients with T2DM.     

含盐酸二甲双胍联合方案治疗再生障碍性贫血的短期疗效观察

目的采用临床生物信息学方法筛选治疗再生障碍性贫血(AA)的新型药物并评估其临床疗效。方法首先建立AA的人类全基因组表达谱,与药物基因组学数据库进行相似性分析,筛选可能有效的药物。纳入难治性AA患者[接受过免疫抑制剂和(或)雄激素治疗时间超过6个月无效]作为研究对象评估疗效,6个月后评估临床疗效和不良反应。结果临床生物信息学筛选结果显示盐酸二甲双胍可能对AA有治疗作用。纳入43例难治性AA患者(其中15例为重型AA),采用包含盐酸二甲双胍、环孢素A(CsA)和司坦唑醇的联合方案进行治疗,结果显示:27例输血依赖患者在治疗6个月后全部(100%)停止输血;40例贫血患者中,37例(92.5%)血红蛋白完全恢复正常;30例血小板低于20×109/L的患者中,28例(93.3%)升至50×109/L以上;35例白细胞低于2.5×109/L的患者中,31例(88.6%)升至3.5×109/L以上。40例贫血患者中,1例出现肾功能异常,停用环孢素A后恢复正常;18例出现转氨酶升高,加用保肝药物并减少司坦唑醇用量后恢复正常。所有患者均未出现低血糖反应。结论盐酸二甲双胍、环孢素A和司坦唑醇联合方案治疗难治性AA有效。     

Using Onyx in endovascular embolization of internal carotid artery large or giant aneurysms

Background and purpose

Internal carotid artery (ICA) large or giant saccular aneurysms is challenging for endovascular coil embolization and surgical clipping with a high recanalization and rebleeding rate. We report our results using Onyx in the endovascular treatment of ICA large or giant saccular aneurysms.

Methods

During 2008–2010, 5 patients with 5 large or giant saccular aneurysms in ICA were treated with a liquid embolic agent (Onyx; Micro Therapeutics, Irvine, CA). One aneurysm was small (<10 mm), 2 were large (≥10 mm, <25 mm) and 2 were giant saccular aneurysms (≥25 mm). Of 3 female and 2 male patients, 3 were incidental and 2 had bleeding. Selective embolization was performed with Onyx alone or a combination with coils. Clinical and anatomic outcomes were assessed with the Modified Glasgow Outcome Scale and follow-up angiography was performed at 4–21 months (mean 12.2 months).

Results

Complete aneurysm occlusion was obtained in all of the aneurysms on immediate control angiogram. There was not any procedure-related complication. No recanalization was observed at the follow- up periods. There were 2 ICA occlusions in giant ICA aneurysms. The 5 patients were all clinically asymptomatic at follow-up.

Conclusion

Endovascular embolization with Onyx is a useful treatment for ICA large or giant aneurysms, which is unsuitable for coiling or surgical treatment.