内源性大麻素系统调节瘙痒的研究进展

背景 很多药物和疾病都能引起瘙痒,但目前有关瘙痒的病理生理学还不完全清楚.研究发现,内源性大麻素系统在调节瘙痒中起着重要的作用,影响着瘙痒的发生与发展.目的 就近年来国内外有关内源性大麻素系统调节瘙痒的文献作一综述. 内容 大麻素受体1 (cannabinoid receptor 1,CB1)激动剂缓解瘙痒,拮抗剂诱发瘙痒.大麻素受体2(cannabinoid receptor 2,CB2)拮抗剂、内源性大麻素类化合物和脂肪酰胺水解酶(fatty acid amide hydrolase,FAAH)间接抑制瘙痒.此外,内源性大麻素的止痒作用可能部分是通过瞬时受体电位香草类受体(transient receptor potential vanilloid type,TRPV)介导的.趋向 内源性大麻素系统可能成为将来各种病因学全身性瘙痒的止痒靶点,但其调节瘙痒的机制还不十分清楚,需要进一步的研究和探讨.     

内源性大麻素系统的研究进展

内源性大麻素物质及其受体在人体内有广泛的生理学作用,与镇痛、免疫调节、心血管、能量代谢等有关,并参与一些疾病的病理过程。对内源性大麻素系统的研究不仅能阐明一些疾病的病理机制,还有助于新药的研发,为相关疾病的治疗提供新的方向。     

大麻素受体及其配体对骨量和骨改建的调节作用

内源性大麻素(CB)系统至少有2种受体,在体内均存在相应的配体和特定的合成及代谢通路,均属G蛋白偶联超家族成员.CB1受体主要分布在中枢神经系统,CB2受体主要分布于外周免疫细胞表面,两者受激动均可产生特定的生理反应.研究表明一些CB类物质可在体内抑制类风湿性关节炎的炎症病变.近来对CB受体基因敲除的小鼠研究显示,CB1受体、CB2受体及其配体,其激动剂可在体内外调节破骨细胞及成骨细胞的功能,从而对骨量和骨改建起调节作用.进一步研究其对骨细胞的作用机制,可为临床应用该类药物提供理论依据.     

大麻素受体和配体对胃肠运动及分泌的影响

内源性大麻素系统有几种受体,在体内均存在相应的配体和特定的合成及代谢通路,均属G蛋白耦联超家族成员.近来的一些研究显示,大麻素受体激活后可影响胃肠运动及分泌.本文介绍大麻素的种类,其受体、配体、拮抗剂以及它们对胃肠运动和胃肠分泌的影响,为进一步研究内源性大麻素系统对胃肠运动及分泌的作用机制提供资料,并为临床应用该类药物...     

内源性大麻素系统对慢性脑低灌注患者认知功能障碍的调控作用

慢性脑低灌注诱导神经细胞变性,是导致患者认知功能障碍和社会能力低下的重要因素之一,脑血管疾病的病理发生有密切的关系。内源性大麻毒素(ECS)包括G蛋白耦联受体CB1、CB2,内源性配基AEA、2-AG及其内源性配基失活系统AEA水解酶FAAH等,国内外研究表明ECS在中枢神经系统具有多种内源性生理性调节作用并介导哺乳动物的神经保护作用,其主要表现在受体水平、失活系统、免疫应答及突触可塑性等方面;现就内源性大麻素系统(ECS)对慢性脑低灌注患者认知功能障碍的调控作用作一综述。     

大鼠骨酪椎间盘累积损伤性炎症反应中大麻素受体的表达及意义的初步研究

目的 通过检测大麻素（CB)1、2型受体(CB-1R、CB-2R)在大鼠累积损伤性椎间盘炎症反应过程中的表达来探讨其中大麻素的参与过程及作用机制。方法 清洁级Wistar大鼠随机分成实验组与对照组,根据Jill A. Ulrich制作方法准备实验组,以切皮后即缝合为对照组,在术后第3、7、10 d,实验组与对照组每次各取6只,取出相应椎间盘,进行形态学观察,应用 RealTime -PCR技术检测CB-1R、CB-2R的表达水平;利用Western Blot方法检测CB-2R蛋白含量。结果 与对照组相比,实验组10 d可见刺伤所致纤维环断裂,髓核内出血。在椎间盘累积性损伤后,CB-1R、CB-2R呈时间依赖性增高趋势。3、7、10 d组 CB-2R蛋白表达与对照组相比明显增高(P <0. 01)。结论 在骨骼椎间盘反复损伤及其后炎症反应阶段,CB类物质参与了炎症反应的发展过程,从而抑制骨骼椎间盘的退变。     

内源性大麻素系统与神经保护

内源性大麻素系统包括大麻素受体、内源性配体以及参与其降解的酶类。内源性大麻素系统在中枢神经系统的许多病理和生理过程中都扮演重要的角色。大麻素不仅在动物实验研究中被发现具有神经保护作用。在细胞水平,也同样能够促进神经元的存活,大麻素通过许多不同的通路发挥其神经保护作用。包括减少细胞钙内流,抑制谷氨酸能神经传递、抗氧化以及抗炎作用等。本文基玗现有的研究报道,就内源性大麻素系统及其神经保护作用机制进行综述,以便更清楚地认识大麻素在神经保护方面的药理学作用和临床意义。     

大麻素类物质应用于骨关节炎疼痛治疗

骨关节炎是一种可导致关节慢性疼痛、畸形和活动障碍的疾病.其中,慢性疼痛是影响患者生活质量的重要原因之一.然而,治疗骨关节炎慢性疼痛的药物并不能令人完全满意.大麻素类物质用于治疗疼痛已有数千年历史,其主要包括内源性大麻素、植物源性大麻素和人工合成大麻素.临床前研究表明,大麻素类物质在骨关节炎疼痛动物模型中具有良好治疗效果...     

内源性大麻素的中枢镇痛位点

内源性大麻素(endocannabinoids,EC)在机体具有广泛的生理作用,其中EC通过作用于中枢和外周神经系统的CB1受体可产生镇痛效应.现综述内源性大麻素系统(endocannabinoid system,ECS)的特性在慢性痛和应激性镇痛(stressinduced analgesia,SIA)中的作用,以及支持EC在棘上水平导水管周围灰质(periaqueductal graymatter,PAG)、延脑头端腹内侧区(rostral ventromedial medulla,RVM)和杏仁核镇痛的行为学、神经生理学和神经解剖学证据.     

内源性大麻素系统对老年骨质疏松症的影响

骨质疏松症是一种常见的老年疾病, 影响着全球数百万患者, 现已成为阻滞健康老龄化进程的主要问题, 研发新的治疗老年骨质疏松症的药物具有重要意义。内源性大麻素系统包含大麻素配体、内源性大麻素受体及合成和降解内源性大麻素所需的酶, 在骨代谢中起着重要的作用。在动物模型和体外实验中使用基于内源性大麻素系统疗法的临床前研究表明内源性大麻素系统可以预防老年骨质疏松症, 并显示出了其对老年骨质疏松症的治疗潜力。通过检索PubMed、ScienceDirect、中国知网及万方数据库收录的有关内源性大麻素系统和骨质疏松症相关研究的文章, 分析老年骨质疏松症的发病机制(如钙、活性维生素D3缺乏或不足、性激素缺乏、细胞功能衰退及慢性疾病继发引起等), 综述近年来内源性大麻素系统的各种成分、其通过调节成骨细胞和破骨细胞的功能影响骨稳态以及在骨质疏松症治疗中的应用进展, 为老年骨质疏松症的临床治疗提供新的方向。     

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.     

A comparison of the inhibitory effects of four volatile anaesthetics on the metabolism of chlorzoxazone, a substrate for CYP2E1, in rabbits

Background: Halothane inhibits in vitro and in vivo activity of cytochrome P-450 (CYP) 2E1. There are several fluorinated volatile anaesthetics besides halothane, and most of them are defluorinated by CYP2E1. It is unclear whether other fluorinated anaesthetics inhibit the in vivo activity of CYP2E1.
Methods: We compared the inhibitory effects of therapeutic concentrations of four inhalational anaesthetics, halothane, enflurane, isoflurane, and sevoflurane, on chlorzoxazone metabolism in rabbits receiving artificial ventilation.
Results: All four inhalational anaesthetics decreased arterial blood pressure and increased plasma chlorzoxazone concentration. However, no significant differences in the plasma chlorzoxazone concentration were found between the four anaesthetics. The estimated chlorzoxazone clearance increased after beginning inhalation with all four agents, but no significant difference in clearance was noted between agents.
Conclusions: At therapeutic concentrations, the in vivo inhibitory effect on chlorzoxazone metabolism was similar for all four inhalational anaesthetics examined, even though their chemical characteristics and extent of hepatic metabolism differ considerably.     

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.     

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.     

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.     

Synergistic interaction between the effects of propofol and midazolam with fentanyl on phrenic nerve activity in rabbits

Background: It has been shown that the depressive effects of both propofol and midazolam on consciousness are synergistic with opioids, but the nature of their interactions on other physiological systems, e. g. respiration, has not been fully investigated. The present study examined the effect of propofol and midazolam alone and in combination with fentanyl on phrenic nerve activity (PNA) and whether such interactions are additive or synergistic. Methods: PNA was recorded in 27 anaesthetised and artificially ventilated rabbits. In three groups, propofol, fentanyl and midazolam were administered intravenously in incremental doses to construct dose-response curves for the depressant effects of each one on PNA. In another two groups, the effect of pretreatment with either fentanyl 1 μg · kg^?1 i. v. or midazolam 0.05 mg · kg^?1 i. v. on the effects of propofol and fentanyl respectively on PNA were studied. Results: Propofol and fentanyl caused a dose-dependent depression of PNA with complete abolition at the highest total doses of 16 mg · kg^?1 i. v. and 32 μg · kg^?1 i. v., respectively. In contrast, midazolam in incremental doses to a total of 0.8 mg · kg^?1 reduced mean PNA by 63%, but approximately 12% of PNA remained at a total dose as high as 6.4 mg · kg^?1. The mean ED₅₀s, calculated from dose-response curves, were 5.4 mg · kg^?1, 3.9 μg · kg^?1 and 0.4 mg · kg^?1 for propofol, fentanyl and midazolam, respectively. Initial doses of either fentanyl 1 μg · kg^?1 i. v. or midazolam 0.05 mg · kg^?1 i. v. acted synergistically with subsequent doses of either propofol or fentanyl to abolish PNA at total doses of 8 mg · kg^?1 and 8 μg · kg^?1, respectively. Conclusion: Fentanyl has a synergistic interaction with both propofol and midazolam on PNA and hence potentially on respiration.     

Influence of dopexamine hydrochloride on haemodynamics and regulators of circulation in patients undergoing major abdominal surgery

Background: Catecholaminergic support is often used to improve haemodynamics in patients undergoing major abdominal surgery. Dopexamine is a synthetic vasoactive catecholamine with beneficial microcirculatory properties. Methods: The influence of perioperative administration of dopexamine on cardiorespiratory data and important regulators of macro- and microcirculation were studied in 30 patients undergoing Whipple pancreaticduodenectomy. The patients received randomized and blinded either 2 μg · kg^?1 · min^?1 of dopexamine (n=15) or placebo (n=15, control group). The infusion was started after induction of anaesthesia and continued until the morning of the first postoperative day. Endothelin-1 (ET-1), vasopressin, atrial natriuretic peptide (ANP), and catecholamine plasma levels were measured from arterial blood samples. Measurements were carried out after induction of anaesthesia, 2 h after onset of surgery, at the end of surgery, 2 h after surgery, and on the morning of the first postoperative day. Results: Cardiac index (CI) increased significantly in the dopexamine group (from 2.61±0.41 to 4.57±0.78 1 · min^?1 · m^?2) and remained elevated until the morning of the first postoperative day. Oxygen delivery index (DO₂I) and oxygen consumption index (VO₂I) were also significantly increased in the dopexamine group (DO₂I: from 416±91 to 717±110 ml/m² · m²; VO₂I: from 98±25 to 157±22 ml/m² · m²), being significantly higher than in the control group. pHi remained stable only in the dopexamine patients, indicating adequate splanchnic perfusion. Vasopressive regulators of circulation increased significantly only in the untreated control patients (vasopressin: from 4.37±1.1 to 35.9±12.1 pg/ml; ET-1: from 2.88±0.91 to 6.91±1.20 pg/ml). Conclusion: Patients undergoing major abdominal surgery may profit from prophylactic perioperative administration of dopexamine hydrochloride in the form of improved haemodynamics and oxygenation as well as beneficial influence on important regulators of organ blood flow.     

Systemic analgesia adapted to the children's condition

A concept of balanced analgesia using nonsteroidal anti-inflammatory drugs (NSAIDs), paracetamol (acetaminophen), opioids, and corticosteroids can also be used in patients with pre-existing illnesses. NSAIDs are the most effective treatment for acute pain of moderate intensity in children; however, these drugs should be avoided in patients at increased risk for serious side effects, e.g. patients with renal impairment, bleeding tendency, or extreme prematurity. NSAIDs can be given with minimal risks to the younger child with mild to moderate asthma, and, in these patients, the use of steroids can be encouraged; in addition to their antiemetic and analgesic action, a beneficial effect on asthma symptoms can be expected. In the non-intubated child with cerebral trauma, exaggerated sedation caused by opioids and increased bleeding tendency caused by NSAIDs must be avoided. In neonates and small infants, the oral administration of sucrose or glucose is helpful to minimize pain reaction during short uncomfortable interventions.