Pacritinib (SB1518), a JAK2/FLT3 inhibitor for the treatment of acute myeloid leukemia

FMS-like tyrosine kinase 3 (FLT3) is the most commonly mutated gene found in acute myeloid leukemia (AML) patients and its activating mutations have been proven to be a negative prognostic marker for clinical outcome. Pacritinib (SB1518) is a tyrosine kinase inhibitor (TKI) with equipotent activity against FLT3 (IC₅₀=22 n) and Janus kinase 2 (JAK2, IC₅₀=23 n). Pacritinib inhibits FLT3 phosphorylation and downstream STAT, MAPK and PI3 K signaling in FLT3-internal-tandem duplication (ITD), FLT3-wt cells and primary AML blast cells. Oral administration of pacritinib in murine models of FLT3-ITD-driven AML led to significant inhibition of primary tumor growth and lung metastasis. Upregulation of JAK2 in FLT3-TKI-resistant AML cells was identified as a potential mechanism of resistance to selective FLT3 inhibition. This resistance could be overcome by the combined FLT3 and JAK2 activities of pacritinib in this cellular model. Our findings provide a rationale for the clinical evaluation of pacritinib in AML including patients resistant to FLT3-TKI therapy.     

Dedicated bifurcation stents – Mechanistic,hardware, and technical aspects

Percutaneous coronary intervention (PCI) in bifurcation lesions is associated with lower success rate, higher acute complication rates and higher event rates in follow-up.The reason for this higher than usual complication rate relates to the relationship between anatomy, flow, and atheroma distribution in bifurcation lesions.Further, stenting these lesions can be a prolonged procedure and can be technically more demanding. The most common complication is the loss of significant side branch (SB). Main vessel (MV) stenting may enhance the carina displacement and atheroma shift across the SB ostium leading to SB ostium narrowing.Finally, complications, if they occur, are more difficult to manage. Dedicated bifurcation stent has been developed to overcome the number of limitations associated with conventional bifurcation PCI. The main advantage of most dedicated bifurcation stents is to allow the operator to perform the procedure on a bifurcation lesion without the need to rewire the SB.     

p38MAPK抑制剂对兔脑血管痉挛病理变化的影响

目的 观察兔脑血管痉挛(CVS)后基底动脉病理学改变、p38MAPK的表达及其抑制剂SB203580对脑血管痉挛的影响,以探讨蛛网膜下腔出血(SAH)后CVS细胞信号通路转导机制.方法 ①采用二次枕大池注血建立兔CVS模型.②采用免疫组织化学技术动态观察兔基底动脉血管壁组织病理改变,观察使用SB203580干预后对病理...     

鞘内注射p38 MAPK抑制剂对神经病理性疼痛大鼠脊髓背角脑源性神经营养因子表达的影响

目的 观察鞘内注射p38 MAPK抑制剂SB203580对坐骨神经压缩性损伤(CCI)神经病理性疼痛大鼠的镇痛效果及脊髓背角p38丝裂原活化蛋白激酶(p38 MAPK)、脑源性神经营养因子(BDNF)的表达,探讨大鼠神经病理性疼痛可能的发生机制。 方法 30只SD雄性大鼠随机分为3组(n=10):假手术组、对照组(CCI组)、SB203580组(CCI术前30 min及术后第1~3天鞘内注射SB203580,剂量为0.1 ml/kg)。于CCI术前2 h以及术后第4~14天测定大鼠右足机械痛阈值;术后第14天取损伤侧腰段脊髓,采用免疫组化方法观察脊髓背角p38 MAPK及BDNF的表达。结果 与术前相比,假手术组术后机械痛阈值差异无统计学意义,对照组、SB203580组在CCI术后机械痛阈值明显降低(P<0.05);与假手术组相比,CCI术后,对照组、SB203580组机械痛阈值明显降低(P<0.05);与对照组相比,CCI术后第4~14天SB203580组机械痛阈值明显升高(P<0.05)。与假手术组相比,对照组、SB203580组脊髓背角p38 MAPK表达及BDNF释放明显增加(P<0.05);与对照组相比,SB203580组损伤侧脊髓背角p38 MAPK表达及BDNF释放明显降低(P<0.05)。结论 鞘内注射p38 MAPK抑制剂可能通过降低损伤侧脊髓背角p38 MAPK表达,抑制BDNF释放,从而缓解CCI大鼠慢性神经病理性疼痛。     

SB203580对肾缺血/再灌注损伤时细胞凋亡及p38MAPK影响的实验研究

目的　探讨不同时间及不同浓度p38MAPK特异性抑制剂SB2 0 35 80对肾缺血 /再灌注损伤过程中肾功能、细胞凋亡及 p38MAPK活性、表达量、p38MAPK底物的影响。 方法　 4 9只大鼠按缺血 /再灌注及给药时间的不同 ,随机分为 7组 ,每组7只大鼠按正交拉丁方表的顺序 ,经尾静脉注射相同体积、不同剂量的SB ,使其在大鼠体内达到不同的浓度。测定BUN和Scr;用TUNEL试剂盒检测细胞凋亡情况 ;Westernblot技术用于蛋白定性及半定量分析。结果　SB可显著减轻大鼠肾缺血 /再灌注损伤造成的Scr和BUN的升高、肾小管上皮细胞的凋亡及 p38MAPK的激活 ,但存在模型、剂量及给药时机的差异 (P<0 .0 5 ) ,缺血前 3h之前给药 ,使其体内血药浓度达到 5 μmol/L左右可取得较好的效果。 结论　SB可显著减轻大鼠肾缺血 /再灌注损伤 ,在缺血前 3h之前给药 ,同时使其血药浓度达到 5 μmol/L左右可取得最佳效果。     

Intravenous Lipid Emulsions in the Prevention and Treatment of Liver Disease in Intestinal Failure

The development of intestinal failure-associated liver disease (IFALD) in pediatric and adult patients on parenteral nutrition is usually multifactorial in nature due to nutritional and non-nutritional causes. The role of lipid therapy as a contributing cause is well-established with the pathophysiological pathways now better understood. The review focuses on risk factors for IFALD development, biological effects of lipids, lipid emulsions and the mechanisms of lipid toxicity observed in laboratory animals followed by a synopsis of clinical studies in pediatric and adult patients. The introduction of fish oil-based lipid emulsions that provide partial or complete lipid replacement therapy has resulted in resolution of IFALD that had been associated with soybean oil-based therapy. Based on case reports and cohort studies in pediatric and adult patients who were at risk or developed overt liver disease, we now have more evidence that an early switch to partial or complete fish oil–based lipid therapy should be implemented in order to successfully halt and reverse IFALD.     

Mimicking the Impact of Infant Tongue Peristalsis on Behavior of Solid Oral Dosage Forms Administered During Breastfeeding

An in vitro simulation system was developed to study the effect of an infant's peristaltic tongue motion during breastfeeding on oral rapidly disintegrating tablets in the mouth, for use in rapid product candidate screening. These tablets are being designed for use inside a modified nipple shield worn by a mother during breastfeeding, a proposed novel platform technology to administer drugs and nutrients to breastfeeding infants. In this study, the release of a model compound, sulforhodamine B, from tablet formulations was studied under physiologically relevant forces induced by compression and rotation of a tongue mimic. The release profiles of the sulforhodamine B in flowing deionized water were found to be statistically different using 2-way ANOVA with matching, when tongue mimic rotation was introduced for 2 compression levels representing 2 tongue strengths (p = 0.0013 and p < 0.0001 for the lower and higher compression settings, respectively). Compression level was found to be a significant factor for increasing model compound release at rotational rates representing nonnutritive breastfeeding (p = 0.0162). This novel apparatus is the first to simulate the motion and pressures applied by the tongue and could be used in future infant oral product development.     

p38MAPK抑制剂SB203580减轻罗哌卡因对PC12细胞的毒性

目的：探讨p38MAPK抑制剂SB203580对罗哌卡因诱发大鼠肾上腺嗜铬细胞瘤细胞(PC12)的毒性的影响及 其机制。方法：将PC12细胞分为对照组(N组)、罗哌卡因组(R组,15 mmol/L盐酸罗哌卡因)、罗哌卡因+SB203580组 (R+S组,15 mmol/L盐酸罗哌卡因+10 μmol/L SB203580)。培养48 h后行3组细胞计数并采用MTT法检测细胞存活率; 采用蛋白质印迹法检测各组磷酸化p38(p-p38)、活化的caspase-3的表达以及细胞质中细胞色素C(cytochrome C,Cyt C) 的含量。结果：与N组比较,R组和R+S组的PC12细胞数目及细胞存活率均显著减少(均P<0.05);且R+S组的PC12细胞 数目和存活率较R组显著上升(均P<0.05)。与N组比较,R组和R+S组p-p38,活化的caspase-3的表达以及细胞质中Cyt C 的含量显著增加(均P<0.05);与R组比较,R+S组p-p38,活化的caspase-3的表达以及细胞质中Cyt C的含量明显减少(均 P<0.05)。结论：抑制p38磷酸化可减轻罗哌卡因对PC12细胞的毒性作用,其机制可能与减少释放入细胞质的Cyt C和 caspase-3的活化有关。     

中西医结合治疗重症肝炎58例疗效观察

重症肝炎病死率高 ,目前尚无特效治疗方法。我院近年来采用综合疗法加促肝细胞生长素、配合中草药治疗重症肝炎 5 8例 ,取得了较好疗效 ,现总结如下。1　材料与方法1.1　病例选择5 8例重症肝炎均为我院 1998年 3月～ 2 0 0 1年 10月间住院病人 ,诊断符合 1995年全国肝病会议标准 ,其中 5例经肝脏穿刺病理检查证实。男 4 8例 ,女 10例 ;年龄 10～ 84岁 ;5 8例病人入院时均有重度黄疸 ,同时伴有明显胃肠道症状、腹胀、高度乏力 ,血清总胆红素 (ＳＢ) >171ｕｍｏｌ/Ｌ ,凝血酶原活动度 (ＰＴＡ) <4 0 % ;部分病例伴有腹水、肝性脑病等。5 8例重…     

Correlation between Molecular Architecture,Morphology, and Deformation Behaviour of Styrene/Butadiene Block Copolymers

The correlation between the molecular architecture, morphology, and micromechanical deformation behaviour of styrene/butadiene (SB) block copolymers with different architectures (linear and star block copolymers, total styrene content, Φ_ST = 0.74) was studied using dynamic mechanical analysis (DMA), uniaxial tensile testing, scanning force microscopy (SFM), and high voltage electron microscopy (HVEM). Deformation of the individual phases under uniaxial strain at the molecular level was monitored by Fourier transform infrared (FT‐IR) spectroscopy. It was demonstrated that the morphology and deformation behaviour of these block copolymers are strongly influenced by their molecular topology, block symmetry, and the nature of the interface between the component blocks. While the cylindrical morphology (hexagonal polybutadiene (PB) cylinders in polystyrene (PS) matrix) was observed in a symmetric SBS triblock copolymer with Φ_ST = 0.74, a “two‐component three‐phase” morphology was found in an asymmetric star block copolymer having an equivalent chemical composition and an SBS arm structure. Likewise, an SBS triblock copolymer with a composition identical to the former ones but with highly asymmetric PS end blocks revealed a lamellar morphology. While no locally confined deformation zones were observed in the lamellar block copolymers, the cylindrical block copolymer was found to deform through the formation of highly localised craze‐like deformation zones.

SFM phase images showing lamellae‐like morphology of the star block copolymer ST2, phase difference 25 degrees.