凝血酶受体拮抗剂的研究进展

血栓栓塞性疾病严重威胁人类健康,应用抗血小板药物是当前主要的治疗手段之一。研究证明,凝血酶受体(又称蛋白酶激活受体-1,PAR-1)被凝血酶激活后,可诱导血小板活化。此外,PAR-1主要参与病理性血栓的形成,对人体正常的止血过程影响很小。因此,PAR-1已成为抗血小板药物研发的新兴靶点。目前,已有多个PAR-1拮抗剂如vorapaxar、F16618、F16357、ML161、RWJ-58259、PZ-128已上市或进入临床研究。综述了PAR-1的结构和作用机制以及小分子拮抗剂和多肽类拮抗剂的研究进展。     

蛋白酶激活受体-3在大鼠体内外脑缺血模型中的作用研究

目的研究蛋白酶激活受体-3(PAR-3)在大鼠体内外脑缺血模型中的作用。方法以PAR-3激活肽(AP)为工具药,采用大脑中动脉阻塞和氧糖剥夺法分别建立大鼠和大鼠胚胎脑皮质神经元缺血模型,观察PAR-3在缺血损伤中的作用及表达变化。用肌动描记器记录PAR-3对大鼠大脑中动脉(MCA)血管张力的影响,用蛋白印迹法研究PAR-1对PAR-3表达的影响。结果 PAR-3在缺血侧大脑皮质和神经元中无显著改变,PAR-1 AP和拮抗剂对PAR-3的表达无影响。缺血前给予PAR-3 AP SFNGGP-NH2显著改善了体内缺血模型导致的损伤,但对体外缺血模型导致的损伤无影响,它能够显著收缩来自正常或缺血大鼠的MCA。结论 SFNGGP-NH_2有望作为预防性治疗脑缺血疾病的靶点进行研究,但不是通过受体数量的调节起作用,胶质细胞或其他类型细胞可能在保护机制中起到更重要的作用。     

欧盟批准默沙东 PD-1免疫疗法 Keytruda 用于晚期黑色素瘤成人患者

近日,欧盟已批准默沙东在研 PD-1免疫疗法 Keytruda 用于晚期（不可切除性或转移性）黑色素瘤成人患者,包括一线治疗及既往已接受治疗的晚期黑色素瘤。使Keytruda成为Opdivo之后第二个进入欧洲市场的PD-1免疫疗法。     

蛋白酶激活受体-2在大鼠体内体外脑缺血模型中的作用研究

目的研究蛋白酶激活受体-2(PAR-2)在大鼠体内外脑缺血模型中的作用。方法以PAR-2激活肽(AP)和拮抗剂(Anta)为工具药,使用大脑中动脉阻塞和氧糖剥夺的方法分别建立大鼠和大鼠胚胎脑皮质神经元的缺血模型,观察PAR-2在缺血损伤中的作用及表达变化。用肌动描记器记录PAR-2对正常或来自脑缺血大鼠的大脑中动脉(MCA)血管张力的影响。结果蛋白质印迹法表明PAR-2在缺血侧大脑皮质中表达增多,缺血前给予PAR-2 AP(SLIGRL-NH2)显著改善了体内和体外模型缺血导致的损伤,且能够被PAR-2 Anta(ENMD-1068)所抑制。PAR-2 AP能够使MCA产生一氧化氮依赖性舒张,但是不能被ENMD-1068所抑制。结论 PAR-2有望作为预防性治疗脑缺血疾病的靶点进行研究,ENMD-1068能够抑制SLIGRL-NH2对脑缺血的保护作用。     

特瑞普利单抗治疗转移性恶性黑色素瘤1例

恶性黑色素瘤发病率低, 致死率高、生存期短, 早期以手术治疗为主, 晚期多予以应用化学药物治疗, 但有效率不高。免疫治疗在多种恶性肿瘤治疗中取得进阶性、突破性发展, 同时也在临床中被证实可延长恶性黑色素瘤患者的生存时间。本文分享暨南大学附属第一医院1例特瑞普利单抗治疗转移性恶性黑色素瘤并获得较佳疗效的病例。     

重组人血管内皮抑素联合DP方案化疗治疗转移性恶性黑色素瘤临床研究

<正>本研究自2002年1月至2014年7月对我科收治的35例转移性恶性黑色素瘤(MM)患者,通过对治疗结果回顾分析发现重组人血管内皮抑素(恩度)联合DP方案化疗治疗转移性恶性黑色素瘤效果显著,现报告如下。1资料与方法1.1临床资料:收集我科自2002年1月至2014年7月经病理诊断确诊为转移性恶性黑色素瘤患者35例,KPS评分>60分。其中2002年1月至     

足甲床恶性黑色素瘤胃底部转移 1例

目的提高内镜下对肢端恶性黑色素瘤转移至胃底部诊断的重视。方法报告中国人民解放军陆军第八十一集团军医院 2018年 5月收治的原发于足甲床恶性黑色素瘤电子胃镜下胃底部不典型转移灶 1例。结果胃部转移性恶性黑色素瘤罕见,通过分析该病例电子胃镜下诊断过程,提高了对该类疾病认识。结论重视胃部转移性恶性黑色素瘤电子胃镜下表现,以期做到早发现、早治疗,提高疗效。     

速览

多西他赛、替莫唑胺和顺铂治疗转移性黑色素瘤多西他赛、替莫唑胺和顺铂联合方案对于转移性黑色素瘤患者来说是耐受的,而且是一种有前景的新型治疗方案。     

胃肠道转移性恶性黑色素瘤6例临床病理观察及误诊分析

目的探讨胃肠道转移性恶性黑色素瘤的临床病理特征,讨论需要鉴别诊断的疾病并吸取误诊教训。方法收集胃肠道转移性恶性黑色素瘤6例,回顾性分析其临床资料、HE、免疫组化及病理诊断结果。结果 6例中除了2例因临床及病理特征典型首次活检即被确诊外,其余4例均被误诊。2例误诊为非霍奇金淋巴瘤,1例误诊为低分化腺癌,1例误诊为胃肠间质瘤。结论胃肠道转移性恶性黑色素瘤少见,无色素胃肠道转移性恶性黑色素瘤易误诊,遇到分化较差的胃肠道恶性肿瘤应行免疫组化检查。     

国外药物研发动态一瞥

注射用聚乙二醇化干扰素α-2b获准用于治疗淋巴结转移性黑色素瘤 [关键词]聚乙二醇化干扰素α-2b;黑色素瘤;对乙酰氨基酚 [中图分类号]R979．1 默克（Merck）公司开发的皮下注射用聚乙二醇化干扰素α-2b（商品名为Sylatron）于2011年4月获美国FDA批准用于淋巴结转移性黑色素瘤（node—positive melanoma）的辅助治疗。本品适应证为在确定性手术切除（包括淋巴结清扫术）后84天内显微镜活检可见淋巴结转移的黑色素瘤。     

Systemic chemotherapy in the treatment of malignant melanoma

Different postsurgical therapies are used for the treatment of metastatic melanoma. This article reviewes the use of chemotherapeutic agents in the treatment of patients with metastatic malignant melanoma. A variety of single chemotherapy agents have been evaluated, although the most widely used chemotherapeutic in the treatment of metastatic melanoma is dacarbazine. In order to improve the rate and duration of responses, combination chemotherapy was developed. The most common combined chemotherapy regimens used as standard for the treatment of metastatic melanoma are Dartmouth regimen, CVD (cisplatin + vinblastine + dacarbazine) and BOLD (bleomycin + vincristine + lomustine + dacarbazine). However, Phase III trials have failed to demonstrate a significant benefit in survival in patients treated with polychemotherapy compared to those treated with dacarbazine alone. The use of classical systemic chemotherapy still has a role in the treatment of patients with metastatic melanoma. Immunotherapy and biochemotherapy have no additional advantage over chemotherapy.     

肺转移性恶性黑色素瘤误诊为透明细胞瘤的分析

目的探讨肺转移性恶性黑色素瘤误诊的原因。方法对1例肺转移性恶性黑色素瘤误诊为肺透明细胞瘤作回顾性分析。结果肿瘤细胞呈巢状分布,胞浆透明或粉染,间质有薄壁的窦状血管,免疫组化染色结果显示：瘤细胞S-100、HMB45、Melan-A均阳性,与肺透明细胞瘤的组织学改变及免疫组化表型极为相似。由于患者曾有皮肤背部色素痣的切除史,且现发现原皮肤活检处存在肿瘤原发灶,应诊断为肺转移性恶性黑色素瘤。结论恶性黑色素瘤的临床特点多样,组织学形态复杂,诊断时应仔细观察病理切片,同时详细了解临床病史,并结合临床相关辅助检查,以减少误诊。     

Systemic chemotherapy in the treatment of malignant melanoma

Different postsurgical therapies are used for the treatment of metastatic melanoma. This article reviews the use of chemotherapeutic agents in the treatment of patients with metastatic malignant melanoma. A variety of single chemotherapy agents have been evaluated, although the most widely used chemotherapeutic in the treatment of metastatic melanoma is dacarbazine. In order to improve the rate and duration of responses, combination chemotherapy was developed. The most common combined chemotherapy regimens used as standard for the treatment of metastatic melanoma are Dartmouth regimen, CVD (cisplatin + vinblastine + dacarbazine) and BOLD (bleomycin + vincristine + lomustine + dacarbazine). However, Phase III trials have failed to demonstrate a significant benefit in survival in patients treated with polychemotherapy compared to those treated with dacarbazine alone. The use of classical systemic chemotherapy still has a role in the treatment of patients with metastatic melanoma. Immunotherapy and biochemotherapy have no additional advantage over chemotherapy.     

G-protein coupled receptor antagonists-1: protease activated receptor-1 (PAR-1) antagonists as novel cardiovascular therapeutic agents

Inhibition of thrombin receptor (PAR-1) is a promising therapeutic approach for the treatment of various cardiovascular disorders such as unstable angina, acute myocardial infarction, stroke, and restenosis. Since a PAR-1 antagonist is specific for the cellulalr actions of thrombin, and does not interfere with fibrin generation, it is expected to have less bleeding liability than the currently available treatments. Several peptide and non-peptide PAR-1 antagonists with potent inhibition of platelet aggregation have been reported. Antithrombotic effect of a PAR-1 antibody has been demonstrated in a baboon thrombosis model and the antirestenosis property of a PAR-1 antagonist has been demonstrated in a rat model.     

Characterization of protease-activated receptors in rat peritoneal mast cells

Activation of protease-activated receptor (PAR)-1 or PAR-2 elicits inflammation most probably via mast cell degranulation in vivo. The present study aimed at characterizing PARs in rat peritoneal mast cells (PMC). Messenger RNA for PAR-1, but not for PAR-2, was detected in PMC. Thrombin, the PAR-1 agonist SFLLR-NH2 or the PAR-2 agonist SLIGRL-NH2 failed to induce histamine release from PMC. Surprisingly, the PAR-2-inactive control peptide LSIGRL-NH2 triggered histamine release from PMC. Thus, PAR-1, but not PAR-2, are expressed in PMC, whereas neither PAR-1 nor PAR-2 are considered to be involved in degranulation of PMC. LSIGRL-NH2 does not appear to be appropriate as a control peptide for PAR-2 in inflammation studies.     

Proteinase-activated receptor-1 agonists attenuate nociception in response to noxious stimuli

Proteinase-activated receptor-1 (PAR-1) is activated by thrombin and can be selectively activated by synthetic peptides (PAR-1-activating peptide: PAR-1-AP) corresponding to the receptor's tethered ligand. PAR-1 being expressed by afferent neurons, we investigated the effects of PAR-1 agonists on nociceptive responses to mechanical and thermal noxious stimuli. Intraplantar injection of selective PAR-1-AP increased nociceptive threshold and withdrawal latency, leading to mechanical and thermal analgesia, while control peptide had no effect. Intraplantar injection of thrombin also showed analgesic properties in response to mechanical, but not to thermal stimulus. Co-injection of PAR-1-AP with carrageenan significantly reduced carrageenan-induced mechanical and thermal hyperalgesia, while thrombin reduced carrageenan-induced mechanical but not thermal hyperalgesia. The fact that thrombin is not a selective agonist for PAR-1 may explain the different effects of thrombin and PAR-1-AP. These results identified analgesic properties for selective PAR-1 agonists that can modulate nociceptive response to noxious stimuli in normal and inflammatory conditions.