结直肠癌药物开发的现状与前景——从临床证据到机制探索

氟尿嘧啶类药物、伊立替康、奥沙利铂、抗血管内皮生长因子（VEGF）单抗和抗表皮生长因子受体（EGFR）单抗是目前结直肠癌治疗中的5类基础药物.根据不同的临床证据,其各自定位和彼此组合亦不相同.目前,结直肠癌药物治疗领域内的热点问题包括：（1）开发新药与新型药物组合;（2）评估分子靶向治疗药物在结直肠癌辅助治疗中的价值;（3）优化分子靶向治疗药物的最佳配伍方案;（4）探索分子标志物指导下的个体化治疗模式.现结合2011年美国临床肿瘤学会胃肠道肿瘤大会（ASCO-GICS）的相关数据,分别就以上问题作一简介,以示抛砖之意.     

结直肠癌药物开发的现状与前景——从临床证据到机制探索

氟尿嘧啶类药物、伊立替康、奥沙利铂、抗血管内皮生长因子(VEGF)单抗和抗表皮生长因子受体(EGFR)单抗是目前结直肠癌治疗中的5类基础药物.根据不同的临床证据,其各自定位和彼此组合亦不相同.目前,结直肠癌药物治疗领域内的热点问题包括:(1)开发新药与新型药物组合;(2)评估分子靶向治疗药物在结直肠癌辅助治疗中的价值;(3)优化分子靶向治疗药物的最佳配伍方案;(4)探索分子标志物指导下的个体化治疗模式.现结合2011年美国临床肿瘤学会胃肠道肿瘤大会(ASCO-GICS)的相关数据,分别就以上问题作一简介,以示抛砖之意.     

奥沙利铂长循环脂质体的制备及其对人结直肠癌SW480细胞活性的影响

目的 观察奥沙利铂长循环脂质体的制备以及对结直肠癌SW480细胞活性的影响.方法 通过逆向旋转蒸发法制备奥沙利铂长循环脂质体,检测脂质体的粒径、电位、包封率及外观形态;分析奥沙利铂长循环脂质体对细胞活性的影响.结果 脂质体粒径、电位分别为(151.56±15.57)nm,(-23.68±2.35)mV;包封率为(42.96±6.45)%;细胞对脂质体的摄入在2 h可观察到,平均荧光强度在2 12、24 h分别为198、443、642;2.60 mmol/L的空载脂质体、28.0 mg/L游离奥沙利铂及2.60 mmol/L的奥沙利铂脂质体(含28.00 mg/L奥沙利铂)分别与细胞作用12 h,细胞的活力分别是(84.73±1.73)%、(70.72±2.66)%和(57.69±3.33)%(F=104.428,P＜0.01),同时细胞集落数量减少.结论 奥沙利铂长循环脂质体具有增强对结直肠癌SW480细胞毒性作用.

Abstract：

Objective To investigate the preparation of oxaliplatin long-circulating liposomes and its effect on activity of human colorecal cancer SW480 cells. Methods The rverse-phase evaporation vesicles (REV) method was used to prepare the oxaliplatin long-circulating liposomes. The particle size, electric potential, entrapment efficiency and face shape were analyzed, and the effects of liposomes on activity of cells were also analyzed. Results The particle size and electric potential were ( 151.56 ± 15. 57 ) nmand ( - 23.68 ± 2. 35) mV resepctively. Entrapment efficiency was (42. 96 ± 6. 45 ) %. At 2 h, the uptake of liposomes by cells was observed. At 2, 12, 24 h, immunofluorescent intensity was 198,443 and642 respectively. After cells were treated with 2. 60 mmol/L blank liposomes, 28.00 mg/L free oxaliplatin and 2. 60 mmol/L liposomal oxaliplatin (containing 28 mg/L oxaliplatin), activity of cells was (84. 73 ±1.73 ) %, (70. 72 ± 2, 66 ) % and (57. 69 ± 3. 33 ) % respectively ( F = 104. 428, P ＜ 0. 01 ). Additionally, the number of cell colonies was reduced. Conclusion Oxaliplatin long-circulating liposomes were successfully prepared, and could enhance cytotoxic effects against colorecal cancer SW480 cells.     

奥沙利铂联合希罗达治疗对结直肠癌患者血糖的影响

目的探讨奥沙利铂联合希罗达治疗对结直肠癌患者血糖的影响,总结相关临床经验。方法回顾性分析本院收治的100例结直肠癌患者作为研究对象,时间为2016年5月至2017年12月,根据化疗用药不同分为两组,对照组50例患者接受多西他赛联合希罗达治疗,观察组50例患者接受奥沙利铂联合希罗达治疗,对比两组的治疗效果。结果观察组患者中有6例发生继发性高血糖、发生率为12.00%,对照组患者中有13例发生继发性高血糖、发生率为26.00%,相比之下,观察组患者的继发高血糖发生率较低,差异具有统计学意义(P0.05);化疗前两组患者的空腹血糖水平比较差异无统计学意义(P0.05);化疗后观察组患者各个时期的血糖水平均明显高于对照组,差异均有统计学意义(均P0.05)。结论对结直肠癌患者实施不同的化疗方案,对患者血糖水平的影响也不同,奥沙利铂联合希罗达治疗会让结直肠癌患者的血糖水平升高,临床应注意观察患者血糖水平变化。     

COX-2在结直肠肿瘤中的表达及治疗意义

结直肠癌是西方发达国家主要病死原因之一，在我国的发病率也正逐年增高。新一代化疗药物如奥沙利铂及伊利替康（开普拓）改善了结直肠癌患者的临床疗效，但每年全世界仍有50万人死于结直肠癌。随着对发病研究的深入，不断发现肿瘤预防及治疗的新靶点，从而能够开发新型的有效药物。     

结直肠癌干细胞的调控机制及靶向干预研究进展

正结直肠癌是我国最常见的消化道恶性肿瘤之一,2016年国家癌症中心发布的中国最新癌症数据显示,城市地区大肠癌发病率位居男性的第5位、女性的第3位~([1])。由于进展期结直肠癌潜在微转移灶的存在,约有近一半的患者接受规范治疗后仍出现肿瘤复发。在新一代的铂类药物(奥沙利铂)与生物靶向药物(西妥昔单抗、贝伐单抗)的应用以来,仍有部分肠癌患者能从现有的外科手段与内科药物中获益~([2])。如何进一步杀灭逃离原发病灶且化疗耐药的     

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2012年美国国家癌症综合网(National Comprehensive Cancer Network,NCCN)指南中结直肠癌新辅助和解救化疗方案出现了一些变更。由于在两项Ⅲ期随机对照研究中西妥昔单抗无法在奥沙利铂化疗的基础上进一步延长病人生存期,FOLFOX联合西妥昔单抗的方案被从KRAS野生型晚期结直肠癌病人的解救化疗和非转化性新辅助化疗中剔除。但在转化性新辅助化疗中,EGFR单抗联合奥沙利铂为基础的化疗方案仍具有合理性。卡培他滨联合贝伐珠单抗具有良好安全性增加为不能耐受高强度化疗的进展期或转移性结直肠癌的一种初始治疗选择。Ⅱ/Ⅲ期直肠癌术前同步放化疗首选卡培他滨或静脉输注氟尿嘧啶联合放疗。3项研究结果表明,在直肠癌新辅助同步放化疗中卡培他滨或静脉输注5-FU联合放疗为目前首选方案,增加奥沙利铂并不能进一步增加近期疗效。     

脂质体作为骨靶向药物载体的应用研究进展

目的：通过探究脂质体作为骨靶向药物载体的研究进展，以促进其作为特异性骨靶向给药系统进入临床应用。方法应用计算机检索PubMed、中国期刊全文数据库（ CNKI）的相关文献，选择文章内容与骨靶向脂质体相关者，同一领域文献则选择近期发表在权威杂志的文章。结果根据纳入标准选择22篇文献进行综述。结论脂质体作为药物载体，因其制备简单、无毒、无免疫原性、易携载和释放各种药物等特点而备受关注。脂质体经修饰后可通过被动靶向、主动靶向和双重靶向三种靶向方式携带药物沉积于骨中，从而使药物能选择性地作用于骨组织，这将解决一些治疗骨病的药物疗效低、不良反应大的问题。迄今为止研究最多的是主动骨靶向脂质体，即通过对脂质体表面进行化学修饰，使脂质体具有骨趋向性。目前，脂质体作为骨靶向递药系统的研究已取得较大进展，这些研究初步解决了药物骨靶向性的问题，但是脂质体要作为一个理想的骨靶向性药物载体进入临床应用尚有许多待解决的问题。     

热敏脂质体载抗癌药物的作用研究

热敏脂质体在高于相变温度的条件下，所包封的药物释放于加热部位而产生靶向性。本研究在前期成功制备热敏脂质体工作的基础上，进一步探讨其包封药物结合射频热疗在提高抗癌药物活性方面的作用，为肿瘤的药物靶向性治疗提供实验依据。     

结直肠癌肝转移转化治疗中靶向药物合理应用的专家指导意见

肝转移灶完整切除是结直肠癌肝转移获得潜在治愈的唯一机会。转化治疗对提高结直肠癌肝转移患者手术切除率,延长生存时间和改善预后具有重要意义。转化治疗的目标应该是尽量应用具有最高效率的治疗方案,以期获得尽可能高的转化切除率。为进一步规范靶向药物在结直肠癌肝转移转化治疗的合理应用,中国抗癌协会大肠癌专业委员会组织肝脏外科、结直肠外科和消化道肿瘤内科专家,结合该领域国内外最新进展,提出结直肠癌肝转移转化治疗中靶向药物合理应用的专家指导意见,旨在为我国外科医生的临床实践提供参考。     

Vasopressor hormone response following mesenteric traction during major abdominal surgery

Background : We investigated the vasopressor hormone response following mesenteric traction (MT) with hypotension due to prostacyclin (PGI₂) release in patients undergoing abdominal surgery with a combined general and epidural anesthesia. Methods : In a prospective, randomized, placebo-controlled study we administered 400 mg ibuprofen (i.v.) in 42 patients scheduled for abdominal surgery. General anesthesia was combined with epidural anesthesia (T4-L1). Before as well as 5, 15, 30, 45, and 90 min after MT we recorded plasma osmolality, hemodynamics and measured 6-keto-PGFlα (stabile metabolite of PGI₂), TXB₂ (stabile metabolite of thromboxane A₂) active renin, and arginine vasopressin (AVP) plasma concentrations by radioimmunoassay. Catecholamine levels were assessed by high-pressure liquid chromatography (HPLC) with electrochemical detection. Results : Following MT, arterial hypotension occurred along with a substantial PGI₂ release. This was completely abolished by ibuprofen administration. Although plasma levels of 6-keto-PGF_1α (1133 (708) vs. 60 (3) ng/L, median (median absolute deviation), P=0.0001, placebo vs. ibuprofen) remained significantly elevated, blood pressure was restored within 30 min after MT in the placebo group. At the same point in time plasma concentrations of TXB² (164 (87) vs. 58 (1) ng/L, P=0.0001), epinephrine (46 (33) vs. 14 (6) ng/L, P=0.001), AVP (41 ± (18) vs. 12 (7) ng/L, P=0.0004), and active renin (27 (12) vs. 12 (4) ng/L, P = 0.001) were significantly higher in placebo-treated patients. Conclusion : Under combined general and epidural anesthesia arterial hypotension following MT due to endogenous PGI₂ release is associated with enhanced release of AVP, active renin, epinephrine and thromboxane A₂, presumably contributing to hemodynamic stability within 30 min after MT.     

A Teaspoon Pump for Pumping Blood with High Hydraulic Efficiency and Low Hemolysis Potential

Abstract: Virtually all blood pumps contain some kind of rubbing, sliding, closely moving machinery surfaces that are exposed to the blood being pumped. These valves, internal bearings, magnetic bearing position sensors, and shaft seals cause most of the problems with blood pumps. The original teaspoon pump design prevented the rubbing, sliding machinery surfaces from contacting the blood. However, the hydraulic efficiency was low because the blood was able to "slip around" the rotating impeller so that the blood itself never rotated fast enough to develop adequate pressure. An improved teaspoon blood pump has been designed and tested and has shown acceptable hydraulic performance and low hemolysis potential. The new pump uses a nonrotating "swinging" hose as the pump impeller. The fluid enters the pump through the center of the swinging hose; therefore, there can be no fluid slip between the revolving blood and the revolving impeller. The new pump uses an impeller that is comparable to a flexible garden hose. If the free end of the hose were swung around in a circle like half of a jump rope, the fluid inside the hose would rotate and develop pressure even though the hose impeller itself did not "rotate"; therefore, no rotating shaft seal or internal bearings are required.     

Is the recovery profile of mivacurium independent of the rate of decay of its plasma concentration in patients with normal plasma cholinesterase activity?

Background: The duration of action of muscle relaxants is poorly correlated to the rate of decay of their plasma concentration. The plasma concentration of mivacurium may rapidly decrease below its active concentration because of the extensive hydrolysis of mivacurium. By inflating a tourniquet on one upper limb for 3 min after the administration of atracurium, mivacurium or vecuronium, we studied the influence of the initial decline of their plasma concentration on their effect. Methods: In 50 patients anaesthetised with thiopental, isoflurane and fentanyl, the effect of bolus doses of 0.15 or 0.25 mg . kg^?1 mivacurium (MIV 15, MIV 25), 0.3 or 0.5 mg . kg^?1 atracurium (ATR 30, ATR 50) and 0.06 or 0.1 mg . kg^?1 vecuronium (VEC 06, VEC 10) were measured on both arms (evoked response of the adductor pollicis to train-of-four stimulation every 12 s), a tourniquet being applied on one arm just before and during 3 min after the muscle relaxant bolus. Results: Tourniquet inflation of 3 min almost abolished the neuromuscular effect of mivacurium. In the vecuronium groups and in the ATR 50 group, tourniquet inflation did not modify the maximum degree of depression of the twitch response. Also, the duration of action of vecuronium was unaffected by the tourniquet. In the ATR 30 group, times to return of the twitch response to 25% (duration 25%) and 75% (duration 75%) of control response were significantly shorter in the cuffed arm, 23 min vs 27 min, and 41 min vs 45 min, respectively. In the ATR 50 group, only duration 25% was significantly shorter in the cuffed arm (41 min vs 45 min). Conclusion: The results suggest that the rate of decline of the plasma concentration of mivacurium is so rapid, that a very low and almost clinically ineffective concentration is present as soon as 3 min after its administration. The results also indicate that the recovery from a mivacurium-induced neuromuscular blockade is not influenced by the rate of decay of its plasma concentration in patients with genotypically normal plasma cholinesterase.     

Membranes in Artificial Organs

Abstract: Membrane processes play a pivotal and enabling role in modern replacement therapy for acute and chronic organ failure and in the management of immunologic diseases. In fact, virtually all contemporary extracorporeal blood purification methods employ membrane devices, and the next generation of artificial organs and tissue engineering therapies are almost certain to be similarly grounded in membrane technology. In this short essay, we comment on the similarities and differences among synthetic membranes and their natural counterparts and also provide a critical overview of the demographics and technology of hemodialysis, hemofiltration, apheresis, oxygenation, and emerging membrane technologies and applications.     

Microspheres Based Detoxification System: A New Method in Convective Blood Purification

Abstract: A variety of protein-bound or hydrophobic substances, accumulating as a result of pathologic conditions such as exogenous or endogenous intoxications, are removed poorly by conventional detoxification methods because of low accessibility (hemodialysis), insufficient adsorption capabilities (hemosorption), low efficiency (peritoneal dialysis), or economic limitations (high-volume plasmapheresis). Combining advantages of existing methods with microspheric technology, a module-based system was designed. Major operating parameters of the latter can be modified to allow for adjustment to individual clinical situations. An extracorporeal blood circuit including a plasmafilter is combined with a secondary high-velocity plasma circuit driven by a centrifugal pump. Different microspheric adsorbers can be combined in one circuit or applied in sequence. Thus, a prolonged treatment can be tailored using specially designed selective adsorber materials. Comparing this system with existing methods (high-flux hemodialysis, molecular adsorbent recycling system), results from our in vitro studies and animal experiments demonstrate the superior efficiency of substance removal.     

Tissue perfusion in relation to cardiac output during continuous positive-pressure ventilation and administration of propranolol or verapamil

Background : Our objective was to determine whether administration of propranolol or verapamil modifies the hemodynamic adaptation to continuous positive-pressure ventilation (CPPV), in particular the regional distribution of cardiac output (CO).
Methods : General hemodynamics and regional blood flows assessed by microsphere technique (15 (μm) were recorded in 16 anesthetized pigs during spontaneous breathing (SB) and CPPV with 8 cm H₂O end-expiratory pressure (CPPV8) before and after intravenous administration of propranolol (0.3 mg · kg⁻¹ followed by 0.15 mg · kg⁻¹ · h⁻¹, n=8) or verapamil (0.1 mg · kg⁻¹ followed by 0.3 mg · kg⁻¹ · h⁻¹, n=8).
Results : CPPV8 depressed CO by 25% without shifts in its relative distribution with the exception of a noteworthy increase in adrenal perfusion. Propranolol increased arterial blood pressure, and due to a fall in heart rate, CO dropped by 25%. The kidneys and, to a lesser extent, the splanchic region and central nervous system received increased fractions of the remaining CO at the expense of skeletal muscle flow. Similar patterns were seen during SB and CPPV8 such that the combination of propranolol and CPPV8 depressed CO by 50%. The circulatory effects of verapamil were less evident but myocardial perfusion tended to increase.
Conclusions : The combination of propranolol or verapamil with CPPV does not result in any specific hemodynamic interaction in anesthetized pigs, except that the combined effect of propranolol and CPPV may severely reduce CO.     

Volatile anaesthetics reduce adhesion of blood platelets under low-flow conditions in the coronary system of isolated guinea pig hearts

Background : Inhibitory effects of volatile anaesthetics on platelet aggregation have been demonstrated in several studies. However, the influence of volatile anaesthetics on intracoronary platelet adhesion has not been elucidated so far.
Methods : Isolated hearts of guinea pigs were perfused with buffer in the absence or presence of volatile anaesthetics (0.5 and 1 MAC) at constant coronary flow rates of 5 ml/min for 25 min, then 1 ml/min for 30 min and again 5 ml/min for 10 min. Before, during and after low-flow perfusion, a bolus of human platelets was applied into the coronary system. To simulate thrombogenic conditions, 0.3 U/ml human thrombin was infused during low-flow perfusion and reperfusion. The number of platelets sequestered to the endothelium was calculated from the difference between coronary in- and output of platelets. The myocardial production of lactate and consumption of pyruvate and coronary perfusion pressure were also determined.
Results : At a flow rate of 5 ml/min only about 3% of the applied platelets did not emerge from the coronary system, in any group. In contrast, 13.1±1.2% (mean±SEM) of infused platelets became adherent in low-flow perfusion in the control group without anaesthetic. The adherence was reduced with each 1 MAC isoflurane (to 6.2±1.2%), sevoflurane (to 4.4±0.9%) or halothane (to 3.2±1.5%) (each P <0.05 vs. control). Volatile anaesthetic, 0.5 MAC, did not inhibit platelet adhesion to a statistically significant extent in any case. Perfusion pressure and metabolic parameters were not statistically different between the control and the hearts exposed to anaesthetics.
Conclusion : Volatile anaesthetics in a concentration of 1 MAC can reduce the adhesion of platelets in the coronary system under reduced flow conditions. This action does not arise from vasodilation or inhibition of ischaemic stress.     

Bariatric Surgery in Some "Central and East-European (former Eastern bloc)"Countries - Current Status and Prediction for the Next Millennium

Background: Obesity is increasing globallly, including in the formerly "Eastern Bloc" countries. Methods: A survey was made of obesity and bariatric surgery. Results: In the 8 East and Central European countries studied, with total population 300 million, roughly 43% of the population was overweight (BMI 25-30), 23% obese (BMI > 30), with about 15 million people morbidly obese (BMI > 40). From 0-10 morbidly obese individuals/100,000/year undergo bariatric surgery. Conclusion: Most countries were found to provide inadequate treatment for obesity.The majority of the morbidly obese are not treated effectively. However, health-care awareness of obesity and bariatric surgeons are slowly increasing.     

Dilemma of Membrane Biocompatibility and Reuse

Abstract: Numerous articles have been published on the multiple use of dialyzers and on the effect of different reprocessing chemicals and techniques on the dialyzer biocompatibility and performance. The results often appear contradictory, especially those comparing standard biocompatibility parameters. Despite this confusion, a discerning review of the published works allows certain limited conclusions to be drawn. Reprocessing of used hemodialyzers changes the biocompatibility profile of a dialyzer as defined by the parameters complement activation. leukopenia, and cytokine release. The effect of reprocessing depends on the chemicals and reprocessing technique applied and also on the type of membrane polymer being subjected to the reprocessing procedure. Reports of pyrogenic reactions indicate that the flux of the membrane also influences how suitable it is for safe reuse. An increased risk of allergic and pyrogenic reactions appears to be associated with dialyzer reuse. Furthermore, there has been a lack of investigations into the immunologic effect of the layer of adsorbed and chemically altered proteins that remains on the inner surface of reprocessed dialyzers. We conclude that the clinical benefit of dialyzer reuse cannot be generally accepted from a biocompatibility point of view.     

The analgesic effect of racemic ketamine in patients with chronic ischemic pain due to lower extremity arteriosclerosis obliterans

Background : Ketamine in sub-dissociative doses has been shown to have analgesic and phantom-Limb pain, where conventional treatment has often failed. Chronic ischemic pain due to lower extremity arteriosclerosis obliterans often responds poorly to analgesics, and the pain-generating mechanisms are not well understood.
Methods : Eight patients with rest pain in the lower extremity due to arteriosclerosis obliterans were given sub-dissociative doses of 0.15, 0.30, or 0.45 mg/kg racemic ketamine and morphine 10 mg as a 5-min infusion on four separate days in a cross-over, double-blind, randomised protocol. Plasma levels of (S)- and (R)-ketamine and their nor-metabolites were analysed with an enantioselective high-performance liquid chromatography (HPLC) method. Pain levels were evaluated with a visual analogue scale (VAS).
Results : Individual pain levels were highly variable during and after all the infusions but the pooled pain levels showed a dose-dependent analgesic effect of ketamine with a transient but complete pain relief in all patients at the highest dose (0.45 mg/ kg). Side-effects, mainly disturbed cognition and perception, were pronounced and dose-dependent. Morphine 10 mg had an analgesic peak at 20 min and 5/8 patients had complete pain relief. The remaining 3 patients also had high baseline pain scores, indicating a higher analgesic potency for the 0.30 and 0.45 mg/ kg ketamine doses than for morphine 10 mg.
Conclusion : We have demonstrated a potent dose-dependent analgesic effect of racemic ketamine in clinical ischemic pain. Due to a narrow therapeutic window, this analgesic effect is probably best utilised in combination with other analgesics.