CN1557303A - 匹多莫德在制备治疗乙肝药物中的应用 - Google Patents
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Abstract
本发明涉及匹多莫德在制备治疗乙肝药物中的应用。匹多莫德商品名为万适宁，英文名为Pidotimod，化学名为(R)－3－[(S)－(5－氧代－2－吡咯烷基)羰基]－四氢噻唑－4－羧酸，分子式为C9H12N2O4S，分子量为244.26，化学结构式如图：匹多莫德作为一种全化学合成的二肽类免疫药物，适合临床慢性乙型肝炎治疗的需求。匹多莫德通过调节慢性乙型肝炎患者的免疫系统，增强慢性乙型肝炎患者对于目前的抗病毒药物的疗效，具有重要的临床实际应用前景。匹多莫德作为一种新型的免疫调节剂，使用方便，价格便宜，机理清楚，因而具有可操作性。本发明提供了一种新型的慢性乙型肝炎治疗药物。
Description
技术领域
本发明涉及匹多莫德在制备治疗乙肝药物中的应用。
背景技术
乙型肝炎是由乙型肝炎病毒引起的肝脏炎性损害，是世界上最严重的传染病之一，也是世界上人类的第九大死亡原因。全世界的乙型肝炎患者约有3.5亿，占世界人口的5％。乙型肝炎也是我国当前流行最广泛、危害最严重的一种传染病，有资料表明，我国人口中约半数感染过乙肝病毒或正在感染中，其中有一亿多人口有慢性感染，其中有现症的慢性乙型肝炎约为3000万人。
慢性乙型肝炎是临床上常见的难治性疾病，往往由于诸多原因久治不愈，反复发作，很容易出现慢性肝炎一肝硬化一肝癌这一恶性演变，所以临床上强调早期、综合、长期治疗。治疗的原则是以保护肝细胞，抗乙肝病毒，调节机体的免疫功能，抗纤维化为主要环节。
目前临床上应用于慢性乙型肝炎治疗的药物很多，如干扰素、拉米夫定、阿昔洛韦等抗病毒药物。其中拉米夫定与干扰素联合应用已成为慢性乙型肝炎活动期治疗用药的标准方案。但干扰素应用有较严格的适应指征：拉米夫定必须有相当长的疗程，又易发生特定的耐药病毒变异，而且存在治疗费用高昂的缺点。选用合适的免疫调节药物进行联合治疗，有助于提高治疗效率和延迟耐药性的发生，并且可能阻止或改变疾病的发展。但在众多可采用的免疫调节药物，如胸腺肽(包括胸腺肚α、胸腺5肽)、中草药中，尚缺乏一种作用持续稳定、疗效确切、安全性好、口服方便、费用适中的免疫调节药物。
匹多莫德为免疫促进剂，既能促进非特性免疫反应又能促进特异性免疫反应。匹多莫德可促进巨噬细胞及中性粒细胞的吞噬活性，提高其趋化性；激活自然杀伤细胞；促进有丝分裂原引起的淋巴细胞增殖，使免疫功能低下时降低的辅助性T细胞(CD+4)与抑制性T细胞(CD+8)的比值升高恢复正常；通过刺激白介素-2和γ-干扰素促进细胞免疫反应。动物试验及临床试验均表明匹多莫德尽管无直接的抗菌及抗病毒活性，但通过对肌体的免疫功能的促进可发挥显著的治疗细菌(肺炎双球菌、大肠杆菌、绿脓杆菌、变形杆菌等)及病毒(流感病毒、单纯疱、装腔作势病毒、鼠脑心肌炎病毒及门果病毒等)感染的疗效。以往匹多莫德用于治疗反复发作的上下呼吸道感染如咽炎、气管炎、支气管炎、扁桃体炎；反复发作的感染如鼻炎、鼻窦炎、耳炎；泌尿系感染和妇科感染。未见匹多莫德用于治疗乙型肝炎的报道。
本发明的目的在于提供一种匹多莫德在制备治疗乙肝药物中的应用。
匹多莫德商品名为万适宁，英文名为Pidotimod，化学名为(R)-3-[(S)-(5-氧代-2-吡咯烷基)羰基]-四氢噻唑-4-羧酸，分子式为C9H12N2O4S，分子量为244.26，化学结构式如下：
匹多莫德作为一种全化学合成的二肽类免疫药物，适合临床慢性乙型肝炎治疗的需求。
乙型肝炎是病毒性疾病，但病变主要是宿主免疫应答的结果，免疫应答很大程度上决定了感染的发展和结局。急性乙型肝炎属于自限性疾病，仅需对症和辅助治疗，但慢性乙型肝炎的治疗，除了采用抑制病毒药物降低病毒本身复制量外，更重要的是纠正患者普遍存在的免疫功能低下或紊乱，依靠患者自身的免疫功能才能最终清除病毒。在这方面，匹多莫德的药理作用均符合近年来对慢性乙型肝炎免疫机理研究的进展：
1.肝炎患者肝脏内吞噬细胞(Kuffer细胞)吞噬能力和抗原递呈能力下降，对坏死肝细胞及释放病毒的清除以及T淋巴细胞的激活作用都明显降低，而匹多莫德具有迅速激活吞噬细胞活性，增强吞噬细胞吞噬和抗原递呈的能力。
2.匹多莫德能促进多种内源性细胞因子的释放，具中包括IL-2、IFNγ、TNFα等，研究表明这些细胞因子可经过非细胞毒性途径，抑制病毒基因的表达和复制，增强了免疫应答的保护效应。
3.机体对乙肝病毒感染细胞的清除以T细胞诱导分化的CFL细胞对肝细胞的细胞毒效应为主。而在慢性乙型肝炎患者中，受感染细胞表面抗原表达具有低亲和性，抗原提呈效率低，诱导的CD4T细胞以Th2亚型占优势，相应Th1减弱，从而CTL应答低下，IL-2、IFNγ减少，使宿主清除病毒的能力降低。研究表明匹多莫德可以提高IL-12，抑制IL-4产生，有助于T细胞向Th1类型转化，长期应用可以纠正患者存在的Th1/Th2失衡，提高Th1型的抗病毒活性。以往匹多莫德对Th1/Th2的作用同样体现出对门哥病毒、单纯疱疹病毒和流感病毒等的预防治疗效果，进一步证明匹多莫德对病毒性感染疾病治疗的可能性。
4.树突状细胞在抗乙肝病毒免疫中起着非常重要的地位，它具备较强的激活T细胞的能力，并且能捕获被致敏的外来抗原将其传递给B细胞，在乙肝免疫治疗中处于起动整个链条的关键作用。研究表明匹多莫德能刺激树突状细胞提高其抗原提呈能力。
5.此外，匹多莫德不经过肝脏代谢，有利于减轻肝脏负担；作为化学合成的免疫药物，匹多莫德还具有结构稳定、组织分布广、渗透力强的特点，除了对慢性乙型肝炎治疗有作用外，还可用于肝炎患者合并细菌感染的预防和治疗，应用更为广泛。
关于匹多莫德联合拉米夫定提高抗病毒疗效的现象具有十分重要的意义。一方面干扰素a(IFN a)利核苷类似物如拉米夫定等对于一部分患者具有抗病毒疗效，但是效果不满意。慢性乙型肝炎的发病机制主要是机体感染了乙型肝炎病毒(HBV)后导致机体免疫系统的紊乱，因此从免疫调节角度进行探索具有广阔的空间。匹多莫德通过调节慢性乙型肝炎患者的免疫系统，增强慢性乙型肝炎患者对于目前的抗病毒药物的疗效，具有重要的临床实际应用前景。另一方面，匹多莫德作为一种新型的免疫调节剂，使用方便，价格便宜，机理清楚，因而具有可操作性。本发明用匹多莫德提高拉米夫定的抗HBV治疗效果，开辟了一种新型的慢性乙型肝炎治疗药物。
下面通过临床疗效报告进一步说明本发明。
匹多莫德联合拉米夫定治疗慢性乙型肝炎的临床疗效报告：
目的：观察匹多莫德对慢性乙型肝炎患者的临床疗效
方法：
1、病例：58例慢性乙型肝炎活动期住院患者，诊断符合2000年第十次全国病毒性肝炎与肝病学术会议(西安)修定的《病毒性肝炎防治方案》的诊断标准。其中48例为男性，女性10例，年龄18-50岁，病程1-13年。
2、治疗方法：感染未控制前：拉米夫定100mg，qd+匹多莫德800mg，Bid+抗生素；由于在临床治疗感染的过程中发现此三联疗法较以往单用抗生素控制感染效果明显，见效快，且匹多莫德在以往治疗中具协同抗病毒效果，因此为了观察匹多莫德是否对慢性乙型肝炎患者也有抗病毒疗效，继续将所有病例随机分为实验组和对照组，治疗方法如下
实验组：拉米夫定100mg，qd+匹多莫德800mg，Bid
对照组：单服拉米夫定100mg，qd
治疗过程中未再使用其他免疫促进剂。
3、疗程：均为6个月。
4、检查：治疗开始前，治疗6个月后，检测肝功、血、尿常规及HBVM五项，治疗前及治疗后各定量检测血清中的HBV DNA一次。
结果：
1、病毒复制指标
治疗开始前两组病毒指标情况
| 病例数 | HBsAg | HBeAg | HBeAb | HBVDNA | |
| + | + | + | + |
| 实验组 | 30 | 30 | 28 | 2 | 29 |
| 对照组 | 28 | 28 | 26 | 1 | 27 |
治疗6个月后病毒指标情况
| 病例数 | HBsAg | HBeAg | HBeAb | HBVDNA | |
| + | + | + | + | ||
| 实验组 | 30 | 27 | 16 | 5 | 2 |
| 对照组 | 28 | 28 | 16 | 2 | 1 |
2、血清生化检测
两组治疗前和治疗6个月后ALT/AST的变化情况
| 实验组(30例) | 对照组(28例) | |||
| 正常 | 异常 | 正常 | 异常 | |
| 治疗前 | 4 | 26 | 3 | 25 |
| 治疗6个月后 | 19 | 11 | 12 | 16 |
3、不良反应
治疗前后血、尿常规及血清肌苷均在正常范围内。
4、在随访6个月的观察中，实验组3例病人HBsAg阴转，另有6例病人HBeAg转阴；对照组无HBsAg阴转现象，但有2例病人HBeAg阴转，HBV DNA在实验组和对照组各有2和1例持续阳性。
结论：
在此初步观察中，发现拉米夫定联用匹多莫德比单用拉米夫定治疗慢性乙型肝炎患者疗效明显好转，HBeAg的阴转率在实验组可达43％，显著高于对照组38％(P＜0.05)，并且联合用药组ALT正常化比率在治疗后可达63％、HBV DNA恢复正常的时间和平稳率要强于单服拉米夫定组。
总结：
匹多莫德作为一种免疫促进剂，可能是通过调节机体的内在免疫系统达到抑制病毒的目的；并且免疫药物与抗病毒药物的联合用药方案已得到了临床相关专家的基本共识，匹多莫德为口服安全、较便宜的药物，本发明为患者提供一个可供选择的联用药品，而且临床数据表明匹多莫德与拉米夫定联用要明显优于单用拉米夫定。实验组的疗程继续延长，乙型肝炎病毒的各项指标上继续好转，从试验结果的观察看，匹多莫德还有一定的治疗后效应，对于控制病情进展也有一定的作用。
匹多莫德用于治疗乙肝的用法与用量：
成人：
急性期用药：开始两周每次0.8g，一日二次。随后减为每次0.8g，一日一次。预防期用药：每次0.8g，一日一次，连续用药60天。
儿童：
急性期用药：开始两周，每次0.4g，一日二次，随后减为每次0.4g，一日一次，连续用药60天。
预防期用药：每次0.4g，一日一次，连续用药60天。
如直接吞服不便时，可将药片溶入适量温水中(迅速溶解成混悬液)服用。
Claims (1)
1、具有下述结构式(I)的化合物匹多莫德Pidotimod在制备治疗乙肝药物中的应用。
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| CN 200410000692 CN1225245C (zh) | 2004-01-16 | 2004-01-16 | 匹多莫德在制备治疗乙肝药物中的应用 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2015036370A1 (en) * | 2013-09-10 | 2015-03-19 | Polichem S.A. | Pidotimod for use in the treatment of inflammation-associated diseases |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015036370A1 (en) * | 2013-09-10 | 2015-03-19 | Polichem S.A. | Pidotimod for use in the treatment of inflammation-associated diseases |
| WO2015036009A1 (en) * | 2013-09-10 | 2015-03-19 | Polichem S.A. | Pidotimod for use in the treatment of inflammation-associated diseases |
| CN105555267A (zh) * | 2013-09-10 | 2016-05-04 | 波利化学公司 | 匹多莫德用于治疗炎症相关疾病的用途 |
| EP3146966A1 (en) * | 2013-09-10 | 2017-03-29 | Polichem S.A. | Pidotimod for use in the treatment of inflammation-associated diseases |
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