CN111184718A - 法罗培南在制备治疗初治病原学阳性肺结核药物中的用途 - Google Patents
法罗培南在制备治疗初治病原学阳性肺结核药物中的用途 Download PDFInfo
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
- A61K31/431—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems containing further heterocyclic rings, e.g. ticarcillin, azlocillin, oxacillin
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- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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Abstract
本发明属于医药技术领域,涉及法罗培南的新用途,具体涉及法罗培南在制备治疗初治病原学阳性肺结核药物中的新用途。与现有标准方案相比,本发明即为包含法罗培南的药物组合物在用于治疗初治病原学阳性肺结核时,效果显著、起效迅速、副作用小、安全性高,有效克服了结核病治疗疗程长,毒副反应大的缺点。
Description
技术领域
本发明属于医药技术领域,涉及法罗培南的新用途,具体涉及法罗培南在制备治疗初治病原学阳性肺结核药物中的新用途。
背景技术
结核病是一种传染性疾病,其中在痰中能够查出结核杆菌的肺结核患者具有传染性,可以通过空气传播;每个传染性肺结核患者,平均每人每年可以传染10-15人;每秒钟全球都会有人感染结核杆菌。据世界卫生组织报道,目前全球有近1/3的人已感染结核杆菌。全球有活动性肺结核病人约2000万,每年新发结核病人约800-1000万,每年约有300万人死于结核病。
卫生服务体系的不力,耐药结核的传播加剧了结核病对人类的威胁。据估计,如果不能有效控制结核病,2000年到2020年间,将有10亿人感染结核菌,2亿人将发展为结核病,3500万人将死于结核病。结核病已成为全世界成人因传染病而死亡的主要疾病之一。我国是全球第三大结核病高负担国家,在法定传染病中结核病的报告发病率与病死率始终处于前2位。在有效疫苗出现前,早期诊断和治疗仍是结核病防治最主要的手段。现阶段,结核病治疗疗程长、毒副反应大,寻找更有效的新型抗结核药物是防治工作者的重要使命。
法罗培南是一个非典型的β-内酰胺抗生素,属于青霉烯类衍生物,通过与青霉素结合蛋白(PBP)结合,阻断细菌细胞壁的合成,从而发挥杀菌作用。其主要用于治疗由葡萄球菌、链球菌、肺炎球菌、肠球菌、卡他莫拉克氏菌、大肠杆菌、柠檬酸杆菌、克雷白氏杆菌、肠杆菌、奇异变形杆菌、流感嗜血杆菌、消化链球菌、痤疮丙酸杆菌、拟杆菌等敏感菌所致的感染性疾病。
初治病原学阳性肺结核患者是指首次诊断为肺结核,病原学鉴定为阳性且并未接受任何抗结核药物治疗,或发现肺结核后虽经不规则、不合理抗结核治疗,但疗程不超过1个月的病人。此阶段结核杆菌的活跃度较大,传染性较强,如果在此阶段得不到较好的治疗,不仅对周围人群构成强大威胁,而且会造成肺结核进入下一个病情更为复杂的肺结核复治阶段。
随着抗生素的广泛使用以及不合理使用,结核杆菌已经对常用的异烟肼和利福平等药物出现耐药性。虽然在后续的药物研究过程中喹诺酮类和氨基糖苷类药物对肺结核药物有一定的疗效,但是缺乏特异性,疗效有限,尤其目前药物针对结核病的治疗广泛出现了疗程长、毒副作用大等缺陷,所以,目前缺乏针对治疗初治病原学阳性肺结核安全有效的药物。
发明内容
为克服现有技术中结核病治疗疗程长、毒副反应大等缺陷,本发明提供了法罗培南在制备治疗初治病原学阳性肺结核药物中的用途。
所述初治病原学阳性肺结核是指初次发现,病原学鉴定为阳性且并未接受任何抗结核药物治疗,或发现肺结核后虽经不规则、不合理抗结核治疗,但治疗疗程不超过1个月的疾病。
为实现如上的技术方案,本发明采用的技术方案为:
法罗培南在制备治疗初治病原学阳性肺结核药物中的用途。体外试验结果表明:法罗培南对标准菌株H37Rv的MIC值为2ug/ml,小于吡嗪酰胺及利福片(4ug/ml和16ug/ml),说明法罗培南对H37Rv具有更好的抑制效果,进而对由H37Rv引起的肺结核具有更好的治疗效果。
优选的是,法罗培南在制备治疗初治病原学阳性肺结核强化期药物中的用途。特别的是,本发明为包含法罗培南的药物组合物在制备治疗初治病原学阳性肺结核药物中的用途。临床试验结果表明:与对照组相比,治疗组的痰涂片、痰培养转阴更快,胸部CT病灶吸收、空洞缩小更快,证明治疗组对肺结核进行治疗时起效快、用时短、治愈率高;此外,治疗组的肝肾功能、血常规发生异常的程度明显较对照组轻,出现严重异常的时间较对照组晚,不良反应发生率更低,说明用法罗培南对肺结核进行治疗时更安全。
优选的是,上述所述包含法罗培南的药物组合物为法罗培南、利福平、异烟肼、吡嗪酰胺。
上述所述的法罗培南的每日人用剂量为10mg-1000mg。
优选的是,上述所述的法罗培南的每日人用剂量为100mg-800mg。
最优选的是,上述所述的法罗培南的每日人用剂量为600mg。
所述利福平的每日人用剂量为15mg-1000mg。
优选的是,所述利福平的每日人用剂量为450mg-600mg。
所述异烟肼的每日人用剂量为15mg-1000mg。
优选的是,所述异烟肼的每日人用剂量为150mg-300mg。
上述所述的吡嗪酰胺的每日人用剂量为500mg-5000mg。
优选的是,所述的吡嗪酰胺的每日人用剂量为1500mg-2000mg。
所述的包含法罗培南的药物组合物的用法为:第一阶段强化期服用法罗培南、利福平、异烟肼、吡嗪酰胺;第二阶段巩固期服用利福平、异烟肼。其中,第一阶段时间为3-6个月;第二阶段时间为2-4个月,优先的是上述第一阶段为4个月,第二阶段为2个月。
与现有技术相比,本发明法罗培南及包含法罗培南的药物组合物在治疗初治病原学阳性肺结核药物具有如下优势:
1.起效快、疗效显著,治愈率高
与对照组相比,治疗组的痰涂片、痰培养转阴更快,胸部CT病灶吸收、空洞缩小更快,疗效显著,治愈率高。
2.副作用小、安全性高
治疗组的肝肾功能、血常规发生异常的程度明显较对照组轻,不良反应发生率更低。
3.体外试验及临床试验效果显著
体外试验结果表明:法罗培南对标准菌株H37Rv的MIC值为2ug/ml,小于吡嗪酰胺及利福片(4ug/ml和16ug/ml),说明法罗培南对H37Rv具有更好的抑制效果,进而对由H37Rv引起的肺结核具有更好的治疗效果。
临床试验结果表明:与对照组相比,治疗组的痰涂片、痰培养转阴更快,胸部CT病灶吸收、空洞缩小更快,证明治疗组对肺结核进行治疗时起效快、用时短、治愈率高;此外,治疗组的肝肾功能、血常规发生异常的程度明显较对照组轻,出现严重异常的时间较对照组晚,不良反应发生率更低,说明用法罗培南对肺结核进行治疗时更安全。
具体实施例
以下通过具体实施例进一步说明本发明,但本领域技术人员应当知晓本发明的具体实施例并不以任何方式限制本发明,且在本发明基础上所作出的任何等同替换均落入本发明的保护范围。
实施例1各药物对结核分枝杆菌MIC的测定
人型结核杆菌标准菌株H37Rv(购于山东省结核病防治研究所,批号:170308)接种于罗氏斜面培养基,37℃培养4周。取适量培养物离心后与生理盐水混匀,沉淀25分钟后取上层菌液,点于含不同浓度药物的罗氏斜面培养基,接种浓度为106CFU/点,37℃培养至生长对照管有菌落形成时,观察记录结果。
其中含药物的罗氏斜面培养基制备方法与普通罗氏斜面培养基制备方法相同,药物在培养基加入试管前加入培养基。
实验组所用药物分别为:法罗培南、吡嗪酰胺及利福片,每种药物均设定多个浓度;对照组细菌接种于不含任何药物的罗氏斜面培养基,其中罗氏斜面培养基购于上海研拓生物科技有限公司,接种浓度为1×106CFU/点。
试验指标包括各种药物的最低抑菌浓度(MIC)和各组H37Rv细胞的形态学特征。
结果如表1所示:
表1不同药物对标准菌株H37Rv的MIC值
药物 | MIC(ug/ml) |
法罗培南 | 2 |
吡嗪酰胺 | 4 |
利福片 | 16 |
采用琼脂平板扩散法和二倍稀释法分别测定法罗培南、吡嗪酰胺及利福片对标准菌株H37Rv的MIC值,上表中的结果表明:法罗培南对标准菌株H37Rv的MIC值为2ug/ml,小于吡嗪酰胺及利福片(4ug/ml和16ug/ml),说明法罗培南对H37Rv具有更好的抑制效果,进而对由H37Rv引起的肺结核具有更好的治疗效果。
实施例2临床试验考察法罗培南对初治病原学阳性肺结核的治疗作用
1.病例纳入
(1)病例纳入标准
1)首次诊断为肺结核且病原学鉴定阳性患者,包括痰涂片阳性、痰培养阳性、GeneXpert阳性,其中痰涂片阳性、痰培养阳性经过菌种鉴定为结核分枝杆菌者。
2)年龄18至80岁。
3)痰菌药敏证实无异烟肼和利福平耐药。
4)肝肾功能正常。
5)影像学可见肺部结核病灶。
6)无HIV感染。
(2)病例排除标准:
1)肺结核合并肺外结核病。
2)对方案中任何药物有过敏史。
3)合并肝、肾、代谢、自身免疫性疾病、神经、精神或内分泌疾病、血液系统疾病、恶性肿瘤、长期服用免疫抑制剂或HIV/AIDS患者等。
4)根据研究者判断,患者有任何不适合参加本研究的或可能使患者不能全程参加本研究的任何疾病。
5)同时参加其他临床研究者。
6)曾经入组后中途放弃和退出者,参与其他临床试验但依从性不良。
7)病例如符合以上情况中的任何一条,则不能入组。
(3)退组标准:
1)治疗开始后,发现不符合选例标准者,如经菌种鉴定为非结核分枝杆菌等。
2)痰菌药敏证实为耐多药或耐药结核杆菌。
3)因各种原因不能继续使用规定方案或中途停药连续2周以上者。
4)未按规定方案进行治疗和随访的患者。
5)因严重不良事件不能继续治疗者。
2.分组治疗
(1)分组
将入院治疗的360例肺结核患者按随机分组的方法分为如下两组:
A组为方案组:2法罗培南、利福平、异烟肼、吡嗪酰胺/4利福平、异烟肼,共180例;
B组为对照组:2乙胺丁醇、利福平、异烟肼、吡嗪酰胺/4利福平、异烟肼,共180例。
(2)药品名称、每日用量、使用方法
表3.药品名称、每日用量、使用方法
(3)治疗时间
A组和B组均分为两个阶段,第一阶段为强化期,第二阶段为巩固期,药品的剂量应根据患者体重而定,如表3。
A组:第一阶段为强化期,服用法罗培南、利福平、异烟肼、吡嗪酰胺,每日用药,时间为2个月,第二阶段为巩固期,服用利福平、异烟肼,每日用药,时间为4个月。
B组:第一阶段为强化期,服用乙胺丁醇、利福平、异烟肼、吡嗪酰胺,每日用药,时间为2个月,第二阶段为巩固期,服用利福平、异烟肼,每日用药,时间为4个月。
3.治疗监测
(1)症状评分:咳嗽、咳痰、咯血、发热、气促、乏力、盗汗评分,具体标准见表4:
表4临床症状评分标准表
(2)痰抗酸染色
1)痰标本留取运送和保存
留取清晨咳痰标本3-5ml,如咳痰量太少时,可收集当日晚至次日清晨咳出的全部痰液。痰盒为广口、直径4cm、高2cm有盖密闭的塑料盒或蜡纸盒,盒上标明姓名,初诊时门诊序号(或随访病人登记号或化验单号)及送检日期。痰标本留取后,痰盒切勿倒置、严防痰液外溢,应立即送检。由专人送至痰检实验室。当天不能检查的痰标本置4℃保存
2)痰涂片检查:直接涂片法
用折断的竹签毛茬端挑取干酪样或脓性痰部分0.05-0.1ml,涂于载物玻片右2/3处,均匀涂抹2.0×2.5cm大小的卵圆形痰膜,待自然干燥,微火焰固定,染色镜检,载物玻片应清洁无划痕,一次性使用,每张玻片只涂一份标本。
3)镜检与报告:萋一纳氏染色法
在淡蓝色背景下,抗酸杆菌呈红色,其它细菌和细胞呈蓝色。显微镜物镜100×所见结果按下列标准报告:
萋一纳氏染色抗酸杆菌阴性(-):0条/300视野。
萋一纳氏染色报告抗酸杆菌数:1-8条/300视野。
萋一纳氏染色抗酸杆菌(1+):3-9条/100视野。
萋一纳氏染色抗酸杆菌(2+):1-9条/10视野。
萋一纳氏染色抗酸杆菌(3+):1-9条/每视野。
萋一纳氏染色抗酸杆菌(4+):>10条/每视野。
(3)分枝杆菌培养
1)前处理方法
碱处理法:痰液中加2%NaOH 2-4倍量,振荡器振荡5-10min或置室温30min,其间振荡2-3次,使痰液化。
2)接种方法
取前处理消化后痰液0.1ml,无菌操作接种于培养基斜面上,每份标本同时接种两支酸性改良罗氏培养基,置37℃孵育。
3)结果与报告
接种后3天、7天观察,此后,每周观察一次菌落生长情况,有菌落生长需经抗酸染色确认是否为分枝杆菌。若至第八周仍无菌落生长方可报告阴性结果。分枝杆菌培养报告方式:
分枝杆菌培养阴性(-):斜面无菌落生长。
分枝杆菌培养阳性(1+):菌落占斜面面积1/4。
分枝杆菌培养阳性(2+):菌落占斜面面积1/2。
分枝杆菌培养阳性(3+):菌落占斜面面积3/4。
分枝杆菌培养阳性(4+):菌落布满全斜面。
菌落占斜面面积不足1/4者实报菌落数。
(4)肺部CT
(5)药物安全性检查:治疗期间第1、2周末、第1、2、3、4、5、6月末进行肝、肾功能、血常规检查。血生化异常分级标准见表5:
表5血生化异常分级标准
血生化指标 | 轻度 | 中度 | 重度 |
血红蛋白(g/L) | 9.5-10.9 | 8.0-9.4 | <8 |
白细胞(×10<sup>9</sup>/L) | 3.0-3.9 | 2.0-2.9 | <2.0 |
中性粒细胞(×10<sup>9</sup>/L) | 1.5-2.9 | 1.0-1.4 | <1 |
血小板(×10<sup>9</sup>/L) | 75-99 | 50-74 | <50 |
谷丙转氨酶(ULN)<sup>*</sup> | 1.26-2.5 | 2.6-5 | >5 |
胆红素(ULN)<sup>*</sup> | 1.26-2.5 | 2.6-5 | >5 |
尿素氮(mmol/L) | 7.5-14.28 | 14.64-21.42 | >21.42 |
肌酐(mmol/L) | 114.92-176.8 | 185.64-353.6 | >353.6 |
QTc | 450-479 | 480-500 | >500 |
尿蛋白 | + | ++ | +++ |
注:*ULN是指高于正常的倍数
不良反应症状程度分级
(1)轻度:反应轻微,易耐受,不干扰日常活动。
(2)中度:反应足以干扰日常活动。
(3)重度:反应导致患者失能,阻碍患者的日常活动。
4.治疗过程各检测项目结果
治疗过程中,在规定的检测时间点对需要检测的项目进行监测,并根据检测结果进行效果评定。结果见表6:
表6各项目监测结果
注:症状评分、痰涂片、痰培养、肝肾功能、血常规结果均为本组患者得分的平均值;肺部CT/X片取大部分患者结果;不良反应轻、中、重为开始出现轻度、中度和重度不良反应。
从表4中可以看出:与B组相比,A组的痰涂片、痰培养转阴更快,胸部CT病灶吸收、空洞缩小更快,证明A组对肺结核进行治疗时起效快、用时短、治愈率高;此外,A组的肝肾功能、血常规发生异常的程度明显较对照组轻,出现严重异常的时间较对照组晚,不良反应发生率更低,说明用法罗培南对肺结核进行治疗时更安全。
5.治疗效果比较
(1)疗效判定标准
1)治愈
涂阳肺结核患者完成规定的疗程,疗程结束时病原学阴性,且至少为连续2次病原学检查阴性(两次病原学检查间隔时间至少1月),症状消失,肺部影像学吸收稳定;
2)完成疗程
涂阳肺结核患者完成规定的6个月疗程,最近一次痰检病原学结果阴性,完成疗程时无痰,或完成疗程时痰检结果阴性,症状消失,肺部影像学吸收稳定。
3)死亡
活动性肺结核患者因病变进展或并发咯血、自发性气胸、肺心病、全身衰竭或肺外结核等原因死亡。
4)丢失
疗程中病人中断治疗2个月以上无法取得联系。
5)中断治疗
疗程中因毒副反应等中断治疗,但仍能保持联系的病人。
(2)治疗结果
A、B两组治疗初治病原学阳性肺结核的结果比较如表7所示:
表7对治疗初治病原学阳性肺结核结果比较
组别 | n | 治愈 | 完成疗程 | 死亡 | 丢失 | 中断 |
A组 | 180 | 124(69%) | 50(28%) | 0(0) | 2(1%) | 4(2%) |
B组 | 180 | 84(47%) | 59(33%) | 2(1%) | 8(4%) | 27(15%) |
从上表结果可以看出,包含法罗培南的治疗组相比对照组具有更高的治愈率,并且疗程中因毒副反应等中断治疗的病人要明显少于对照组(p<0.05),说明包含法罗培南的药物组合物不仅疗效显著,而且不良反应要明显轻于现有技术。
以上结果充分说明了:包含法罗培南的标准抗结核方案的有效性、可行性和安全性均优于标准方案,法罗培南可以用于初治病原学阳性肺结核的治疗。
Claims (10)
1.法罗培南在制备治疗初治病原学阳性肺结核药物中的用途。
2.法罗培南在制备治疗初治病原学阳性肺结核强化期药物中的用途。
3.如权利要求1或2所述的用途,其特征在于,包含法罗培南的药物组合物在制备治疗初治病原学阳性肺结核药物中的用途。
4.如权利要求3所述的用途,其特征在于,包含法罗培南的药物组合物为法罗培南、利福平、异烟肼、吡嗪酰胺。
5.如权利要求4所述的用途,其特征在于,所述法罗培南的每日人用剂量为10mg-1000mg。
6.如权利要求5所述的用途,其特征在于,所述法罗培南的每日人用剂量为100mg-800mg。
7.如权利要求6所述的用途,其特征在于,所述法罗培南的每日人用剂量为600mg。
8.如权利要求4所述的用途,其特征在于,所述利福平的每日人用剂量为15mg-1000mg;优选的,所述利福平的每日人用剂量为450mg-600mg。
9.如权利要求4所述的用途,其特征在于,所述异烟肼的每日人用剂量为15mg-1000mg;优选的,所述异烟肼的每日人用剂量为150mg-300mg。
10.如权利要求4所述的用途,其特征在于,所述吡嗪酰胺的每日人用剂量为500-5000mg;优选的,所述吡嗪酰胺的每日人用剂量为1500mg-2000mg。
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