法舒地尔治疗AECOPD相关性肺动脉高压的临床分析

目的 评价法舒地尔治疗AECOPD相关性肺动脉高压患者的临床近期疗效.方法 将60例AECOPD并肺动脉高压患者随机分为治疗组和对照组各30例,对照组作常规治疗,治疗组在常规治疗基础上联合法舒地尔.结果 治疗组经治疗10 d临床症状改善,肺动脉收缩压及6min步行试验距离有所改善且优于对照组（P＜0.05）;治疗组和对照组治疗后肺动脉收缩压及6mnin步行试验距离差异有统计学意义（P＜0.05）.结论 法舒地尔能改善运动耐量,降低肺动脉高压,增加6min步行试验距离;改善慢性阻塞性肺疾病急性加重期相关性肺动脉高压患者的近期疗效.     

HPLC法测定盐酸法舒地尔注射液的含量

目的建立高效液相色谱法测定盐酸法舒地尔注射液含量的方法。方法采用Welch Ultimate XB-C8色谱柱(4.6 mm×250 mm,5μm),流动相为0.03 mol.L-1磷酸氢二铵溶液-乙腈=76:24(用磷酸调节pH值至4.5),检测波长为275 nm,流速为1.0 mL.min-1。结果盐酸法舒地尔在90.04～210.08μg.mL-1的浓度范围内线性关系(r=0.999 9)良好,平均回收率为99.87%,RSD为0.24%。结论本方法专属强、准确度高,可用于盐酸法舒地尔注射液的质量控制。     

法舒地尔联合鼠神经生长因子对急性脑梗死患者血浆Lp-PLA2和MCP-1的影响

目的探讨法舒地尔联合鼠神经生长因子对急性脑梗死患者血浆脂蛋白相关磷脂酶A2（Lp-PLA2）和单核细胞趋化因子一1（MCP-1）的影响。方法 206例急性脑梗死患者随机分为三组,A组62例,B组54例,C组90例。A组在常规治疗的基础上加用法舒地尔,B组在常规治疗的基础加用鼠生长因子,C组在常规治疗的基础上联合加用法舒地尔和鼠生长因子。三组患者共治疗21 d。测定患者治疗前后血浆的Lp-PLA2和MCP-1。结果 A组总有效率为87.1%,B组总有效率为87%,C组总有效率为97.8%,A组和B组之间无明显差异（P〉0.05）,C组总有效率明显高于A组、B组（P〈0.05）。三组治疗后患者血浆Lp-PLA2和MCP-1均有明显降低,A组和B组治疗后血浆Lp-PLA2和MCP-1无明显差异（P〉0.05）,但C组比A、B组血浆Lp-PLA2和MCP-1均明显降低（P〈0.05）。结论联合应用法舒地尔和鼠神经生长因子降低急性脑梗死患者血浆Lp-PLA2和MCP-1更明显。     

Fasudil,a clinically safe ROCK inhibitor,decreases disease burden in a Cbl/Cbl-b deficiency-driven murine model of myeloproliferative disorders

Objectives: Mutations in Cbl or Cbl-b gene occur in 10% of myeloproliferative disorder (MPD) patients and are associated with poor prognosis. Hematopoietic Cbl/Cbl-b double knockout (DKO) leads to a disease in mice phenotypically similar to human MPDs. The aim of this study was to evaluate the anti-MPD activity of a clinically safe drug, Fasudil, identified in an in vitro kinase inhibitor as an inhibitor of proliferation of DKO mouse hematopoietic stem/progenitor cells (HSPCs).

Methods: Fasudil exhibited relatively selective anti-proliferative activity against Cbl/Cbl-b DKO vs. control murine bone marrow HSPCs. We established a mouse model with uniform time of MPD onset by transplanting Cbl/Cbl-b DKO HSPCs into busulfan-conditioned NOD/SCID/gamma chain-deficient mice. Four weeks post-transplant, mice were treated with 100 mg/kg fasudil (13 mice) or water (control, 8 mice) daily by oral gavage, followed by blood cell count every 2 weeks.

Results: By 2 weeks of treatment, total white cell and monocyte counts were significantly lower in mice treated with fasudil. We observed a trend towards improved survival in fasudil-treated mice that did not reach statistical significance. Notably, prolonged survival beyond 27 weeks was observed in two fasudil-treated mice, nearly twice the 16-week average life-span in the Cbl/Cbl-b DKO MPD model.

Conclusions: Our results suggest a therapeutic potential for fasudil, a clinically safe drug with promising results in vascular diseases, in the treatment of MPDs or other mutant Cbl-driven myeloid disorders.     

Fasudil alleviates brain damage in rats after carbon monoxide poisoning through regulating neurite outgrowth inhibitor/oligodendrocytemyelin glycoprotein signalling pathway

Carbon monoxide (CO) poisoning can lead to many serious neurological symptoms. Currently, there are no effective therapies for CO poisoning. In this study, rats exposed to CO received hyperbaric oxygen therapy, and those in the Fasudil group were given additional Fasudil injection once daily. We found that the escape latency in CO poisoning group (CO group) was significantly prolonged, the T₁/T_total was obviously decreased, and the mean escape time and the active escape latency were notably extended compared with those in normal control group (NC group, P < 0.05). After administration of Fasudil, the escape latency was significantly shortened, T₁/T_total was gradually increased as compared with CO group (>1 week, P < 0.05). Ultrastructural damage of neurons and blood‐brain barrier of rats was serious in CO group, while the structural and functional integrity of neuron and mitochondria maintained relatively well in Fasudil group. Moreover, we also noted that the expressions of neurite outgrowth inhibitor (Nogo), oligodendrocyte‐myelin glycoprotein (OMgp) and Rock in brain tissue were significantly increased in CO group, and the elevated levels of the three proteins were still observed at 2 months after CO poisoning. Fasudil markedly reduced their expressions compared with those of CO group (P < 0.05). In summary, the activation of Nogo‐OMgp/Rho signalling pathway is associated with brain injury in rats with CO poisoning. Fasudil can efficiently down‐regulate the expressions of Nogo, OMgp and Rock proteins, paving a way for the treatment of acute brain damage after CO poisoning.     

Treatment with a Rho Kinase Inhibitor Improves Survival from Graft-Versus-Host Disease in Mice after MHC-Haploidentical Hematopoietic Cell Transplantation

Acute graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic cell transplantation (HCT) and the main cause of nonrelapse mortality during the first 100 days post-transplant. Although GVHD can be prevented by extensive removal of mature donor T cells from the donor hematopoietic stem cell population, doing so eliminates any potential allogeneic graft-versus-tumor (GVT) effect also mediated by donor T cells and results in unacceptable rates of cancer relapse. One potential solution to this problem of separating GVHD development from a GVT response is to prevent T cell–mediated GVHD in the intestinal tract (IT) while preserving systemic antihost alloreactivity of donor T cells that target residual tumor cells expressing host alloantigens. We examined the ability of the anti-inflammatory rho kinase inhibitor, fasudil, given orally and intraperitoneally, to prevent GVHD in a C3H → B6C3F₁ mouse model of MHC-haploidentical bone marrow transplantation. Fasudil-treated recipients of anti-thy-1 mAb + C′ treated bone marrow (ATBM) cells plus T cells had a 73% 90-day survival compared with 25% among untreated ATBM + T cell recipients (P < .0001). Severe initial weight loss was similar in the 2 groups, but less diarrhea was observed among treated animals, and fasudil-treated survivors recovered more weight than untreated survivors. Skin inflammation occurred and resolved between weeks 2 and 8 with similar severity and kinetics in both treated and untreated surviving animals, indicating persistent alloreactivity. Day 10 post-transplantation splenocytes from fasudil-treated mice, containing mature donor T cells, and day 98 splenocytes, containing mature donor and de novo thymus-derived T cells, exhibited alloreactivity against host parental antigens, as assessed by in vitro IFN-γ production and rounds of allostimulated proliferation, respectively. These data support the idea that targeted treatment of the IT with rho kinase inhibitors can ameliorate lethal GVHD while preserving systemic alloreactivity. The results also suggest that similar mechanisms of IT-specific tolerance or resistance to GVHD operate in fasudil-treated and untreated long-term survivors of allogeneic ATBM + T cells.     

盐酸法舒地尔对冠心病心力衰竭患者心室重构和心功能的影响

目的：探讨盐酸法舒地尔对冠心病心力衰竭患者心室重构及心功能的影响。方法：冠心病心力衰竭患者80例,左室射血分数≤40%,心功能Ⅱ-Ⅳ级,常规治疗基础上随机分为治疗组和对照组,治疗3个月,观察法舒地尔对心室重构、心功能的影响。结果：经过3个月治疗,与对照组相比,法舒地尔组左室射血分数明显升高（P〈0.01）,左室收缩末容量指数、左室舒张末容量指数、左室重量指数均显著降低（P〈0.01）。结论：在常规治疗基础上,应用法舒地尔能显著改善冠心病心力衰竭患者的心功能,改善心室重构。     

盐酸法舒地尔治疗肺动脉高压疗效观察

目的评价盐酸法舒地尔治疗肺动脉高压的临床近期疗效及安全性。方法将60例各型肺动脉高压患者随机分为治疗组和对照组,对照组30例作常规治疗,治疗组30例在常规治疗基础上加法舒地尔治疗。结果治疗组临床症状、动脉血氧饱和度、动脉氧分压、超声心动图估测肺动脉收缩压（SPAP）、6 min步行试验距离有改善（P〈0.05）,且优于对照组（P〈0.05）。结论盐酸法舒地尔能改善运动耐量,提高肺动脉氧分压和动脉血氧饱和度,降低SPAP,增加6 min步行试验距离,对肺动脉高压治疗安全、有效。     

盐酸法舒地尔与奥扎格雷钠注射剂体外配伍稳定性考察

目的:考察盐酸法舒地尔与奥扎格雷钠注射液的配伍稳定性。方法:采用HPLC法测定室温(25℃)条件下配伍溶液放置8 h两药的含量变化,并考察配伍前后外观、性状、pH及不溶性微粒的变化。结果:注射用盐酸法舒地尔与奥扎格雷钠配伍后在室温下放置8 h,配伍溶液的外观、性状、pH及不溶性微粒无明显变化,两药的含量仍在97%以上。结论:盐酸法舒地尔注射液与奥扎格雷钠注射液配伍8 h内未发现明显变化。     

法舒地尔对慢性阻塞性肺疾病急性加重期合并肺动脉高压患者安全性及有效性评价的研究

目的 探索法舒地尔对慢性阻塞性肺疾病急性加重期合并肺动脉高压患者肺循环血流动力学及氧动力学影响,从而评价法舒地尔在此类患者中的安全性和有效性.方法 对10例慢性阻塞性肺疾病急性加重期合并肺动脉高压患者给予静脉注射法舒地尔,行漂浮导管监测血流动力学及氧动力学变化.结果 10例患者用药前平均肺动脉压为(39.60±9.4) mmHg,在静脉注射法舒地尔48 h后可降至(32.63±6.05) mmHg,P＜0.05;72 h后降至(33.71±4.99) mmHg,P＜0.05;肺血管阻力指数仅表现存在下降趋势,由基线值(746.8±509.49) dyn·s·m2·cm-5下降为72 h时肺血管阻力指数为(482.43±198.21) dyn·s·m2·cm5,P＞0.05.其中3例患者在用药过程中发生血压降低,因而减小法舒地尔用量或暂停.心率、心脏指数、右室每搏功和肺动脉楔顿压等其他血流动力学参数无显著变化.用药后氧动力学指标提示氧摄取率、氧消耗指数、氧输送指数存在升高趋势,分流率存在降低趋势,但差异均无统计学意义.结论 静脉注射法舒地尔早期可降低慢性阻塞性肺疾病急性加重期合并肺动脉高压患者的肺动脉压力及肺血管阻力,改善缺氧,但仍需进一步评价其安全性.