亚胺培南肾毒性和西司他丁肾保护的基础和临床研究进展

亚胺培南是一种碳青霉烯类抗生素,在临床上和西司他丁组成复方制剂,用于多重耐药和重症感染的治疗。肾毒性是亚胺培南的常见不良反应,在儿童和老年等肾功不全群体中,应用亚胺培南导致肾脏毒性的风险更大。西司他丁具有肾保护活性,可降低顺铂、万古霉素、环孢素A等药物的肾毒性。本文对近年来亚胺培南肾毒性和西司他丁肾保护作用的研究进展进行综述,从基础研究和临床应用的角度,揭示亚胺培南和西司他丁在肾脏产生不同效应的可能机制,为亚胺培南和西司他丁的临床安全合理应用提供理论基础和科学建议。     

右美托咪定在多模式镇痛中应用的研究进展

围手术期镇痛的目的是缓解手术造成的疼痛及其带来的不良反应,防止外周及中枢敏化的发生。近年来,随着医疗行业的飞速发展和众多新型药物的不断出现,常联合不同作用机制的镇痛药物,或不同的镇痛措施,通过多种机制产生镇痛作用,即多模式镇痛以获得更好的镇痛效果,而使药物副作用减到最低。右美托咪定是一种选择性α2肾上腺素受体激动剂,其镇痛作用已被证实可以作为麻醉剂佐剂应用于临床。可与局部麻醉药或阿片类药物配伍、可应用于静脉注射或应用于各种神经阻滞等方式达到多模式镇痛。对右美托咪定在多模式镇痛中的应用进行综述。     

布托啡诺在胸科手术后多模式镇痛的临床研究

目的观察布托啡诺在胸科手术术后多模式镇痛的效果及不良反应。方法选择40例,ASAⅠ～Ⅱ级的胸外科手术患者,随机分为两组,试验组(M组,n=20)术后采用硬膜外注射布托啡诺1 mg+布托啡诺PCIA的镇痛方法,对照组(C组,n=20)使用单纯布托啡诺PCIA镇痛。记录并比较术后2、4、8、12、24、48 h的VAS镇痛评分、镇静评分(Ramsay)、有效按压次数、不良反应、术后康复情况及患者的满意程度。结果术后各时间点C组的VAS、Ramsay镇静评分均高于M组,有效PCIA按压次数明显多于M组,不良反应发生率均较低、均未出现呼吸抑制,术后48 h患者满意度评分M组明显好于C组,以上均P0.05。结论布托啡诺多模式镇痛方法的应用能有效的减轻术后疼痛及相关副作用。     

多模式镇痛在胸科手术术后镇痛应用的临床观察

目的对多模式镇痛对于胸科手术术后镇痛效果和不良反应进行观察,以期找到更为安全有效的胸科手术术后镇痛方式。方法将60例择期接受胸科手术的患者随机分为实验组和对照组,每组30例,实验组患者在关胸前由手术者使用罗哌卡因进行肋间神经的阻滞,在手术结束之前30min静脉注射帕瑞昔布钠,并于手术结束时给予舒芬太尼以自控镇痛;对照组在手术结束时给予舒芬太尼以自控镇痛。于患者经静脉给药自控镇痛（PCIA）开始后第2、4、6、8、12、24、48、72h对镇静（Ramsay评分）和镇痛（VAS评分）效果观察记录,同时对不良反应发生情况进行观察。结果相较于对照组,实验组患者PCA有效按压次数、舒芬太尼用量、舒适状态评分、静止和活动状态下VAS评分明显下降,对照组PCA按压次数较实验组上升（P〈0．05）;两组患者在术后胸闷、皮肤瘙痒、恶心呕吐、排气时间、镇静评分、生命体征等副作用发生率均没有显著差异（P〉0．05）。结论多模式镇痛对于胸科手术术后镇痛效果良好,有临床推广价值。     

临床生化指标在新药临床前研究中的毒理学意义

临床生化指标主要用来检测碳水化合物、脂类、蛋白质、尿液、肝胆、心血管、肌肉、胃肠道系统的代谢。临床检验的个体或汇总数据要在病理报告中分析并在实验报告中述及。阐明了临床生化指标在药物临床前研究中的毒理学和生物学意义,从而考察和反映了临床生化指标对动物机体总的代谢、营养和健康状态的影响,同时为建立和定期更新实验室各实验动物临床检验的背景值提供了参考与比较。     

奈福泮和阿片类药物在硬膜外自控镇痛中的应用

目的：比较奈福泮与阿片类药物用于子宫切除术后患者的镇痛效果。方法：90例ASA Ⅰ-Ⅱ级择期手术的患者，随机分为奈福泮组（Ⅰ组）、芬太尼组（Ⅱ组）和吗啡组（Ⅲ组），每组30例，含药量分别为奈福泮0．4g／L、芬太尼2mg／L、吗啡0．1g／L，均加0．1％罗比卡因，总量100mL，并设置为2mL/h，自控按压次数（PCA）为0．5mL／次，锁定时间为15min，镇痛时间24—48h。观察患者镇痛效果（VAS评分）、镇静评分（SS评分）及不良反应。结果：镇痛评分Ⅰ组与Ⅱ、Ⅲ组差别无统计学意义（P〉0．05），组内I组术后4h明显高于16，24，48h（P〈0．05）；SS评分Ⅰ组与Ⅱ、Ⅲ组差别有统计学意义（P〈0．01）。不良反应发生率Ⅱ、Ⅲ组明显高于Ⅰ组（P〈0．01）。结论：奈福泮镇痛效果满意，不良反应比吗啡和芬太尼更低．且作用强度随时间的延长而明显增强。     

Targeting apoptosis in solid tumors: the role of bortezomib from preclinical to clinical evidence

The ubiquitin–proteasome pathway is the main proteolytic system present in the nucleus and cytoplasm of all eukaryotic cells. Apoptosis activation induced by ubiquitin–proteasome pathway inhibition makes the proteasome a new target of anticancer therapy. Bortezomib is the first proteasome inhibitor to be approved by the US FDA; in 2003 as a third line and in 2005 as a second line therapy for the treatment of multiple myeloma only. This review focuses on the use of bortezomib, not only in its therapeutic role but also, more specifically, in its biologic role and discusses the most recent applications of the drug in solid tumors, both at a preclinical and clinical level.     

生长抑素及其拮抗剂对小鼠吗啡镇痛的影响(英文)

AIM: To study the effects of somatostatin (SST) andits antagonist cyclo- (7 - aminoheptanoyl- Phe-D-Trp-Lys-Thr [Bzl]) (SSA) on morphine-induced analgesia.METHODS: The pain assays were the hot plate andthe tail flick test. RESULTS: SST or SSA per seadministered intracerebrally at the doses of 0.1 and Img/mouse did not change the pain threshold of miceboth in the hot plate and in the tail flick test.However, at the higher dose (10 mg/mouse), SST andSSA decreased the pain threshold in the tail flick test     

Agmatine: Biological role and therapeutic potentials in morphine analgesia and dependence

Agmatine is an amine that is formed by decarboxylation of L-arginine by the enzyme arginine decarboxylase (ADC) and hydrolyzed by the enzyme agmatinase to putrescine. Agmatine binds to several target receptors in the brain and has been proposed as a novel neuromodulator. In animal studies, agmatine potentiated morphine analgesia and reduced dependence/withdrawal. While the exact mechanism is not clear, the interactions with N-methyl-D-aspartate (NMDA) receptors, alpha2-adrenergic receptors, and intracellular cyclic adenosine monophosphate (cAMP) signaling have been proposed as possible targets. Like other monoamine transmitter molecules, agmatine is rapidly metabolized in the periphery and has poor penetration into the brain, which limits the use of agmatine itself as a therapeutic agent. However, the development of agmatinase inhibitors will offer a useful method to increase endogenous agmatine in the brain as a possible therapeutic approach to potentiate morphine analgesia and reduce dependence/withdrawal. This review provides a succinct discussion of the biological role/therapeutic potential of agmatine during morphine exposure/pain modulation, with an extensive amount of literature cited for further details.     

Axitinib: from preclinical development to future clinical perspectives in renal cell carcinoma

Introduction: Based on extensive preclinical data and abundant evidence for clinical activity, vascular endothelial growth factor receptor (VEGFR) inhibitors are currently standard of care for metastatic renal cell carcinoma (mRCC). Axitinib is one of the most selective molecules in the class of anti-angiogenic agents, which confers an optimal profile between its safety and anti-cancer activity spectrum.

Area covered: In this review, the authors discuss the different stages that lead to the approval of axitinib in the clinic as well as the current perspectives for its clinical use with other promising therapies in mRCC such as immune checkpoint inhibitors and vaccines.

Expert opinion: In 2015, axitinib has emerged as one of the major agents used in mRCC. Based on robust preclinical data, this highly specific VEGFR inhibitor continues to be evaluated in different indications, including the adjuvant setting but also sequential administration with other molecularly targeted agents or combinations with immune therapies.     

Nefopam reduces thermal hypersensitivity in acute and postoperative pain models in the rat

The activity of nefopam, a centrally acting compound, not structurally related to other analgesics, was examined in acute and postoperative thermal pain models in the rat. Its antinociceptive potency was evaluated using heat noxious stimuli either in intact or in injured animals after skin and muscular incisions. In the hot plate and in the plantar tests, nefopam after acute administration by different routes exhibited a dose-dependent attenuation of the nociceptive responses at 10-30 mg x kg(-1) by intraperitoneal or subcutaneous administration, at 60 mg x kg(-1) by oral dosing, and from 3 mg x kg(-1) after intravenous injection. In the postoperative pain model, at 30 mg x kg(-1) nefopam augmented the endpoint to thermal threshold, 60 and 90 minutes after administration compared to the threshold recorded after the incision. In the same conditions, morphine and tramadol displayed antinociceptive activities. As the plantar test provides a good index of nociception in humans, these results point out the usefulness of nefopam for attenuating moderate to severe pain, and for postoperative analgesia. In conclusion, nefopam has shown potent properties to reduce thermal hypersensitivity after acute or postoperative pain in rats.     

多模式超前镇痛在妇科腹腔镜手术中的应用

目的：探讨多模式超前镇痛在妇科腹腔镜手术的术后镇痛作用。方法80例择期行妇科腹腔镜手术患者,ASAⅠ～Ⅱ级,年龄25～64岁,随机双盲分为对照组（C 组）、地佐辛组（D 组）、帕瑞昔布钠组（P 组）、多模式镇痛组（PM组）,每组20例,分别于麻醉诱导前5 min 给予生理盐水、地佐辛10 mg、帕瑞昔布钠40 mg 及地塞米松10 mg、地佐辛10 mg,复合帕瑞昔布钠40 mg 静脉注射。各组麻醉维持采用异丙酚和瑞芬太尼静脉麻醉,统计各组术中瑞芬太尼用量（RFC）,记录术后患者拔除喉罩后0、1、2、4、8、12、24 h（T 1－7）的疼痛视觉模拟评分（VAS 评分）,记录术后各组补救镇痛的时间和剂量,观察术后不良反应。结果C 组术中瑞芬太尼用量多于其他各组。拔除喉罩后0、1、2、4、8、12 h 的 VAS 评分,D 组、P 组均低于 C 组（P ＜0．05）,PM组低于 D 组、P 组、C 组（P ＜0．05）。各组中患者于拔出喉罩后1、2、4 h 需要补救镇痛的例数,C 组多于 D 组、P 组（P ＜0．05）,而 PM组不需要补救镇痛（P ＜0．05）。其他不良反应无明显差异。结论多模式超前镇痛在妇科腹腔镜手术有更好的镇痛效果,明显优于单一用药。     

Combined treatment with atypical antipsychotics and antidepressants in treatment-resistant depression: preclinical and clinical efficacy

Several clinical reports have documented a beneficial effect of adding atypical antipsychotic drugs to ongoing treatments with antidepressants, particularly selective serotonin reuptake inhibitors, in ameliorating drug-resistant depression. The aim of this paper was to summarize some preclinical evidence describing the mechanism responsible for the therapeutic action of combined treatment with antidepressants and atypical antipsychotics and also some clinical data supporting the efficacy and safety of the augmentation strategy for improving antidepressant-resistant depression using atypical antipsychotics. This analysis is based on five microdialysis studies and nine behavioral studies assessing the impact of combined atypical antipsychotic and antidepressant treatments on extracellular levels of dopamine, serotonin and noradrenaline in the prefrontal cortex of freely moving rats and on antidepressant-induced effects, respectively. In addition, clinical data demonstrating the efficacy and safety of augmentation strategies for treatmentresistant depression using atypical antipsychotics were included. Combined treatment of rats with all studied atypical antipsychotics (olanzapine, risperidone, clozapine and quetiapine) and antidepressants (citalopram, fluoxetine and fluvoxamine) increased the extracellular level of dopamine in the prefrontal cortex compared to a respective drug given alone; in addition, a combination of olanzapine or quetiapine plus fluoxetine or fluvoxamine increased the levels of dopamine and noradrenaline. Moreover, atypical antipsychotics administered in a low dose enhanced the antidepressant-like activity of antidepressants, with (among other mechanisms) the serotonin 5-HT_1A, 5-HT_2A and adrenergic a₂ receptors likely playing an important role in their action. The results support the conclusion that atypical antipsychotics may be effective as adjunctive therapy in treatment-resistant depression; however, their adverse effect profile may be unfavorable in some patients.     

HPLC法同时测定盐酸奈福泮萘普生胶囊中2种成分的含量

目的 建立同时测定盐酸奈福泮萘普生胶囊中盐酸奈福泮和萘普生含量的高效液相色谱方法.方法 采用Apollo C18色谱柱,以庚烷磺酸钠溶液-乙腈(53:47)为流动相,流速为1.0 mL·min-1,检测波长为215 nm.结果 盐酸奈福泮浓度在15.8～47.5 μg·mL-1范围内与峰面积线性关系良好(r=0.9997),平均回收率为99.43％,RSD为1.31％(n=3);萘普生在54.7～164.2 μg·mL-1范围内线性关系良好(r=0.9999),平均回收率为99.72％,RSD为0.80％(n=3).结论 该方法操作简便,结果准确,精密度高,可用于控制盐酸奈福泮萘普生胶囊的质量.     

不同方式超前镇痛对儿童腹腔镜术后多模式镇痛效果的影响

目的 观察不同方式超前镇痛对儿童腹腔镜术后多模式镇痛安全性及效果的影响.方法 选择在全身麻醉下接受择期腹腔镜手术的患儿90例,年龄5～ 14岁,美国麻醉医师协会（ASA）分级Ⅰ～Ⅱ级.采用完全随机双盲法均分为对乙酰氨基酚栓塞肛组（A组）、布托啡诺喷鼻组（B组）和空白对照组（C组）.A组患儿全身麻醉后予对乙酰氨基酚栓40 mg/kg塞肛;B组患儿予布托啡诺20μg/kg喷鼻;C组于手术开始前10 min缓慢静脉注射生理盐水2 ml.监测三组患儿术后的心率（HR）、平均动脉压（MAP）、血氧饱和度（SpO2）、拔管时间和在PACU停留时间.记录患儿的VAS评分、Ramsay镇静评分及不良反应.结果 A组和B组苏醒期躁动评分显著低于C组（P＜0.01）.B组镇静评分显著高于A组和C组（P＜0.01）,A组也高于C组（P＜0.05）.术后1、4hA组、B组VAS评分显著低于C组（P＜0.01）,术后8 h VAS评分低于C组（P＜0.05）;术后1、4、8hB组VAS评分低于A组（P＜0.05）.C组术后首次按压镇痛泵的时间早于A组和B组（P＜0.01）,且按压总次数明显多于A组和B组（P＜ 0.01）.结论 对乙酰氨基酚栓塞肛和布托啡诺喷鼻均可为儿童腹腔镜手术提供同样安全、有效的超前镇痛效果,但前者不良反应更少,较适合在基层中推广使用.     

氯诺昔康用于术后患者自控镇痛的临床疗效和安全性

目的:评价非甾体抗炎药氯诺昔康用于妇科全子宫切除术后患者自控镇痛(PCA)的疗效及安全性。方法:60例全身麻醉下行全子宫切除术术后出现中度以上疼痛的患者随机分为氯诺昔康组和吗啡组。患者根据需要启动PCA泵(氯诺昔康0.8mg/次,吗啡1mg/次,锁定时间5min)。由疼痛缓解程度(PAR)、疼痛缓解总和(TOT-PAR)和患者24h镇痛总体效果来评价镇痛效果,同时监测血小板聚集率、肝、肾功能,并观察胃肠道反应等。结果:氯诺昔康组和吗啡组的TOTPAR和镇痛总体印象评分无显著性差异(P>0.05)。吗啡组起效早于氯诺昔康 组。氯诺昔康组的恶心呕吐的发生率明显低于吗啡组。2组血小板聚集率无显著性差异(P>0.05)。结论:氯诺昔康用于妇科全子宫切除术后PCA镇痛,其镇痛效应与吗啡相近,不良反应较少。     

利鲁唑对吗啡镇痛、耐受和依赖作用的影响(英文)

目的　研究利鲁唑对阿片镇痛、耐受及躯体功能的调节。方法　采用冰醋酸扭体 ,5 5℃热板法和热辐射甩尾法观察利鲁唑对小鼠痛阈及吗啡镇痛效应的影响 ;采用小鼠急性和慢性吗啡耐受模型及小鼠吗啡依赖模型 ,观察利鲁唑对吗啡耐受和依赖的作用。结果　单独皮下注射利鲁唑 2 .5～ 10mg·kg- 1在以上 3种模型无镇痛作用 ,然而能剂量依赖性地增强吗啡镇痛效应。利鲁唑 2 .5～ 10mg·kg- 1剂量依赖性地对抗吗啡引起的急性和慢性耐受。在小鼠吗啡依赖模型中 ,利鲁唑 2 .5～ 10mg·kg- 1剂量依赖性地抑制吗啡戒断症状的产生。结论　利鲁唑自身无镇痛作用 ,但能显著增强吗啡镇痛效应 ,并能预防吗啡所引起的耐受和依赖     

Opioid-sparing effect of cannabinoids for analgesia: an updated systematic review and meta-analysis of preclinical and clinical studies

Cannabinoid co-administration may enable reduced opioid doses for analgesia. This updated systematic review on the opioid-sparing effects of cannabinoids considered preclinical and clinical studies where the outcome was analgesia or opioid dose requirements. We searched Scopus, Cochrane Central Registry of Controlled Trials, Medline, and Embase (2016 onwards). Ninety-two studies met the search criteria including 15 ongoing trials. Meta-analysis of seven preclinical studies found the median effective dose (ED₅₀) of morphine administered with delta-9-tetrahydrocannabinol was 3.5 times lower (95% CI 2.04, 6.03) than the ED₅₀ of morphine alone. Six preclinical studies found no evidence of increased opioid abuse liability with cannabinoid administration. Of five healthy-volunteer experimental pain studies, two found increased pain, two found decreased pain and one found reduced pain bothersomeness with cannabinoid administration; three demonstrated that cannabinoid co-administration may increase opioid abuse liability. Three randomized controlled trials (RCTs) found no evidence of opioid-sparing effects of cannabinoids in acute pain. Meta-analysis of four RCTs in patients with cancer pain found no effect of cannabinoid administration on opioid dose (mean difference −3.8 mg, 95% CI −10.97, 3.37) or percentage change in pain scores (mean difference 1.84, 95% CI −2.05, 5.72); five studies found more adverse events with cannabinoids compared with placebo (risk ratio 1.13, 95% CI 1.03, 1.24). Of five controlled chronic non-cancer pain trials; one low-quality study with no control arm, and one single-dose study reported reduced pain scores with cannabinoids. Three RCTs found no treatment effect of dronabinol. Meta-analyses of observational studies found 39% reported opioid cessation (95% CI 0.15, 0.64, I² 95.5%, eight studies), and 85% reported reduction (95% CI 0.64, 0.99, I² 92.8%, seven studies). In summary, preclinical and observational studies demonstrate the potential opioid-sparing effects of cannabinoids in the context of analgesia, in contrast to higher-quality RCTs that did not provide evidence of opioid-sparing effects.Subject terms: Preclinical research, Translational research     

Multimodal analgesia in moderate-to-severe pain: a role for a new fixed combination of dexketoprofen and tramadol

Background: Untreated and under-treated pain represent one of the most pervasive health problems, which is worsening as the population ages and accrues risk for pain. Multiple treatment options are available, most of which have one mechanism of action, and cannot be prescribed at unlimited doses due to the ceiling of efficacy and/or safety concerns. Another limitation of single-agent analgesia is that, in general, pain is due to multiple causes. Combining drugs from different classes, with different and complementary mechanism(s) of action, provides a better opportunity for effective analgesia at reduced doses of individual agents. Therefore, there is a potential reduction of adverse events, often dose-related. Analgesic combinations are recommended by several organizations and are used in clinical practice. Provided the two agents are combined in a fixed-dose ratio, the resulting medication may offer advantages over extemporaneous combinations.

Conclusions: Dexketoprofen/tramadol (25?mg/75?mg) is a new oral fixed-dose combination offering a comprehensive multimodal approach to moderate-to-severe acute pain that encompasses central analgesic action, peripheral analgesic effect and anti-inflammatory activity, together with a good tolerability profile. The analgesic efficacy of dexketoprofen/tramadol combination is complemented by a favorable pharmacokinetic and pharmacodynamic profile, characterized by rapid onset and long duration of action. This has been well documented in both somatic- and visceral-pain human models. This review discusses the available clinical evidence and the future possible applications of dexketoprofen/tramadol fixed-dose combination that may play an important role in the management of moderate-to-severe acute pain.     

病人自控镇痛中吗啡的药物动力学及血药浓度监测

目的：研究病作人镇痛（ＰＣＡ）时吗啡（Ｍｏｒ）的药物动力学,在硬膜外麻醉病人自控镇痛时以负荷剂量－持续注射（ＬＣＰ）模式给药时血药浓度的波动要用放射免疫法测定Ｍｒｏ血药浓度。结果：Ｍｏｒｉｖ时符合开放型二室模型。在ＬＣＰ模式给药时,Ｍｏｒ的平均血药浓度在２７３．９４～７４．５μｇ／Ｌ之间,此时镇痛效果良好,病人无明显不良反应结论：本实验为Ｍｏｒ应用于ＬＣＰ模式中的安全性提供一定的理论依据。