CN111249275A - 一种治疗间日疟的药物的配伍方案及其使用方法 - Google Patents
一种治疗间日疟的药物的配伍方案及其使用方法 Download PDFInfo
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Abstract
本发明提出了一种治疗间日疟的药物的配伍方案,包括如下比例的药物原料:青蒿素17.5mg/kg、萘酚喹7mg/kg、伯喹0.9mg/kg;同时提出了其使用方法:青蒿素份、萘酚喹份、伯喹份,每天各1次,3天连续分服。此方案治疗时间短,只需三至五天就完成,病人依从性高。
Description
技术领域
本发明属于治疗用药物领域,具体涉及一种治疗间日疟的药物的配伍方案及其使用方法。
背景技术
世界卫生组织2019年报道目前全球有31个国家有疟疾流行,2018年有2.28亿人患疟疾,有40.5万人死于疟疾。感染人类疟原虫有5种,流行最广是间日疟,是WHO美洲区域的主要疟原虫虫种,占疟疾病例的75%。间日疟和卵形疟都会在人体肝脏内长期潜伏形成休眠体引起复发,目前能够杀灭肝期疟原虫的抗疟药只有8-氨基喹啉类,磷酸伯氨喹啉和他非诺喹(Tafenoquine)。根治和阻断间日疟的传播极为困难,专家认为目前的间日疟治疗方案并不恰当,需要研发新药和新治疗方案以解决间日疟疾治疗效果、安全性、耐受性和依从性等问题。尽管目前英国已成功地研究出了另一种8氨基喹啉类抗疟药“他非诺喹(Tafenoquine)”,但临床试验结果显示,与伯喹相比,除疗程短(一次顿服300mg)外,其它方面并无明显优势,更为危险的是他非诺喹在人体蓄积时间比伯喹长,如果有G6PD缺乏病人对8氨基喹啉类药物有溶血反应,从临床上清除此药物的时间和方法都比伯喹困难,这给G6PD缺乏的疟疾病人带来更大的风险,这也许是中国未注册应用的主要原因。新抗疟药或新治疗方案的设计研究原则是要能同时快速有效地杀灭血液期疟原虫(裂殖体)以控制临床症状并遏制抗药性,有效地杀灭组织期(肝期)疟原虫达到根治目的。在目前伯喹服药时间长,病人耐受性和依从性差等,导致只有73.2%病人治愈,复发率达26.8%的情况下,我们计划以世界卫生组织(WHO)推荐的一线间日疟治疗方案氯喹加伯喹十四日疗法作对照,快速裂殖体杀灭剂青蒿素类药物配伍磷酸萘酚喹加服2天伯喹治疗间日疟的新方案。设计假设为,即使青蒿素和萘酚喹均不能杀灭肝期疟原虫,但萘酚喹在人体内吸收快,半衰期长(15天左右),体内存留时间长(40天左右),而云南省及周边间日疟原虫94.9%为短潜期,(12.2±1.9天),服药后体内残留的萘酚喹可及时反复杀灭从肝脏释放到血液中的短潜伏期复发病例释放的裂殖子,以达到根治目的,同时加服伍3天伯喹来快速杀灭配子体,阻断传播,并提高根治效果。以克服国家方案服用8天和世界卫生组织方案服用14天伯喹的服药时间长,病人耐受性和依从性差等问题;另外服用伯喹对葡萄糖-6-磷酸脱氢酶(G6PD)缺乏症的疟疾病人有急性溶血性贫血的风险,据WHO报道全球有3.5亿人,热带地区患病此病的人达3-35%,但伯喹溶血一般出现在服用伯喹3天后,加服3天伯喹这个剂量下,不管病人的G6PD状态如何,伯氨喹都是可以耐受。
G6PD缺乏症是一种遗传性X连锁疾病,G6PD缺乏症病人服用8-氨基喹啉类药物后会发生药物引起的剂量依赖性急性溶血性贫血,这种情况普遍存在,在全球范围内影响了3.5亿人,热带地区的患病率为3-35%,云南省是多民族省份,少数民族G6PD缺乏者比例较高,傣族为25%;G6PD缺乏的病人服用伯喹3天后极易发生急性溶血性贫血。G6PD是红细胞中的一种关键的内务酶,通过产生还原形式的烟酰胺腺嘌呤二核苷酸磷酸(NADPH)来对抗氧化挑战,红细胞对G6PD依赖的NADPH的产生没有替代途径。对于间日疟原虫疟疾的治疗,世卫组织建议使用标准抗疟药物,然后使用14天的伯氨喹方案,以防止疟疾复发。虽然伯氨喹是非常有效的,但病人需要在整整两周的时间内每天服用该药。因此,治疗依从性是一个挑战。
一种新药,他非诺喹(Tafenoquine),英国研究成功的另一种8氨基喹啉类抗疟药,最近刚获得美国食品和药物管理局(FDA)和澳大利亚16岁及以上成人治疗用品管理局两个监管机构的批准。但临床试验结果显示,与伯喹相比,除疗程短(一次顿服300mg)外,其它方面并无明显优势,更为危险的是他非诺喹在人体停留数天,如果有G6PD缺乏病人对8氨基喹啉类药物有溶血反应,从临床上清除此药物的时间和方法都比伯喹困难,这给G6PD缺乏的疟疾病人带来更大的风险。
发明内容
为了解决现有技术中存在的问题,本发明提出了一种治疗间日疟的药物的配伍方案及其使用方法,具体是通过以下技术方案来实现的:
一种治疗间日疟的药物的配伍方案,包括如下比例的药物原料:青蒿素17.5mg/kg、萘酚喹7mg/kg、伯喹0.9mg/kg。
一种治疗间日疟的药物的使用方法,青蒿素份、萘酚喹份、伯喹份,每天各1次,3天连续分服。
进一步的,服药后多喝开水,并注意观察病人尿量及颜色,一旦病人尿的颜色呈咖啡或酱油色立即停止给下一次药并住院观察。
本发明的有益效果:
(1)在无条件开展G6PD检测的医疗机构,开展间日疟的治疗更安全。
(2)治疗时间短,一般3天即可完成。
(3)更安全,更经济。
(4)延缓伯氨抗药性的产生。
附图说明
图1为本发明的技术线路图。
具体实施方式
为使本发明的目的、技术方案和优点更加清楚,下面将结合具体实施方式作进一步地详细描述。
实施例1
1、病例对照研究
如图1所示,病例对照研究纳入人数比(病例数:对照数)为1:2,即一个病例选择2非疟疾病人作对照。根据95%可信度,80%把握度,计算所得最小样本量为病例组162人,对照组325人。病例为医疗机构发热病人疟原虫镜检阳性者,对照为到相同机构就医的非疟疾病人(疟原虫镜检阴性)。为排除年龄、性别和健康状况等混杂因素的影响.,以性别相同,年龄(+/-5岁)和健康状况相似配对。作为质量控制,对病例组和对照组的血样进行PCR检测,病例组PCR实验阴性和对照组PCR阳性者,将从研究对象中踢出。
由研究组成员或经培训能够开展工作的医疗卫生机构的医生,对病例和对照组人员开展个人深度访谈。问卷将包括有关调查对象基本情况和潜在危险因素的30个左右问题,问卷内容将涉及病例和对照组人员在境内外的房屋及住宿条件,自然生态环境,社会经济状况,疟疾知识、防护意识和行为,出境情况和在境内外的活动等。调查对象的社会经济状况将通过调查对象家庭的房屋,财产和交通工具等的具体调查资料来计算财富指数。
2、复方青蒿素萘酚喹伍用伯喹(ANQ-PQ)三日疗法和氯伯喹(CQ-PQ)8日/14日疗法治疗间日疟随机对比试验
(1)病例选择和排除标准
a)采用厚薄血膜涂片,姬姆萨染色,显微镜油镜确定为单一间日疟原虫感染者。
b)年龄在1~65岁且体重大于10公斤(妊娠期与哺乳期妇女除外)。
c)血中无性体疟原虫密度≥500个/μl。
d)近2周内未服过任何抗疟药物或具有抗疟作用(如磺胺药物)的其他药物。
e)无严重肝、肾、心脏功能障碍。
f)无脑型、超高热型(体温超过41℃)、休克等严重并发症。
(2)药品和病人分组
磷酸伯氨喹(伯喹)片将由上海中西药厂提供,每片含磷酸伯喹基质7.5mg;复方青蒿素萘酚喹片由昆明制药厂提供,每片含青蒿素125mg和磷酸萘酚喹50mg。
复方青蒿素类萘酚喹片加伯喹(ANQ-PQ)与氯伯喹(CQ-PQ)对比试验病人分组治疗:确诊病人通过抽签,随机分配到ANQ-PQ治疗试验组和氯伯喹治疗对照组(CQ-PQ组)。ANQ-PQ试验组每天1次,连服3天,总剂量复方青蒿素类萘酚喹片24.5mg/kg(萘酚喹7mg/kg,青蒿素17.5mg/kg,伯喹0.9mg/kg);CQ-PQ对照组国内病人按国家推荐的氯喹加伯喹8日疗法,缅甸籍按世界卫生组织推荐的氯喹加伯喹14日方案治疗。
(3)病人追踪和实验检查
病人在纳入时测量体温、耳垂取血,同时制备厚薄血膜,血膜干炒后采用甲醇固定薄血膜,使用吉姆萨法染色。用缓冲液把吉氏原染液稀释为3-5%的工作液,染色30分钟后晾干镜检。每张血片镜检厚血膜200个视野以上,不能发现疟原虫者方能定为阴性。计数镜检到500个白细胞的疟原虫数,以每微升血8000个白细胞计算疟原虫密度。
在头3天内每8小时检查一次,直到退热和疟原虫清除后48小时。然后分别在第7、14、21和28天进行随访并涂制厚薄血膜镜检疟原虫。28天后改为每个月随访一次,随访一年(365天)。同时每10天通过电话与病人联系一次,要求病人任何时候感觉不适(特别是发热),回原诊治点血检,检查到疟原虫者给予抗疟药治疗。在第1、2,3、7、14、21和28天的随访中,通过深度访谈,问卷调查病人对治疗方案的不良反应和依从性。
3、数据管理和统计分析
使用Epidata 3.1二次数据录入,建立数据库。根据分析目的,把数据库转入Epi Info 2000(美国疾控中心)软件进行统计学分析。
(1)病例对照研究数据统计分析.
以配对分析为基础,统计分析疟疾感染与潜在危险因素之间的相关性。首先计算病例组和对照组中各假设危险因素的发生频度和比例及其95%可信区间,并进行卡方检验;然后选择与疟疾感染可能相关的因素(P<0.25),作为配对单因素和多因素分析的变量,进行logistic回归分析。
(2)复方青蒿素类萘酚喹加伯喹(ANQ-PQ)与氯伯喹(CQ-PQ)对比试验数据统计分析.
根据经验,每组治愈率90%,5%精准度(precision),两种治疗方案治愈率相差10%,退出和失访率10%计算,每组最小样本量为120例。使用Wilson检验治疗反应的差异度及其双侧的95%的可信区间(CI),Yates校正卡方比较百分比,方差分析比较平均退热和原虫清除时间。
分析结果的P<0.05为具有统计学意义,同时使用95%可信区间显示联系程度及其显著性水平。
实验结果:1、纳入病人的比例较低,只有28.8%(330/1147),当病人知道需要住院观察14天及随访1年后,多数病人不愿意加入;发热血检30189人,1147是间日疟阳性病人,330个病人加入此研究,按2:1的比例随机进入实验组(青蒿素+萘酚喹+伯喹)和对照组(氯喹+伯喹),实验组有220例及对照组有110例随机进入临床研究,实验室组有205人,对照组有101人完成28天随访,实验组和对照组完成1年随访分别为160和81人,最后进入统计处理,实验组完全治愈率为77.8%,对照组为81.2%,两者没有统计学差异(P值>0.05),此方案和现有的标准的治疗方案比较两者在统计学上没有差异,治愈率稍稍低于对照组,但它第一解决了伯喹用量大于3天溶血发生率增加的风险,在疟疾流行的区域多数属于经济、交通和医疗欠发达地区,8日或14日方案对G6PD中、重度缺乏的病人溶血发生率概率增高,且溶血病人的救治条件极为有限,此方案大大提高了间日疟根治的安全性;第二提高了病人的依从性,多数间日疟病人通常服药2天后症状完全消失,第3天基本恢复到健康状态,再让病人住院或随访5-11天,许多病人不愿意,特别是在农忙季节;第三为病人节约了支出,三天的花费通常比八天或十四天少一半以上;第四延缓间日疟对伯喹的敏感性,伯喹是中国目前注册的唯一治疗间日疟肝期和血液期配子体药物,延缓其敏感性极为重要,因为长期、反复使用均可以产生耐药性,而且时间越长,产生耐药性越多越重。
2、血中疟原虫清除时间实验组平均为27.1小时,对照组为37.8小时,两者有显著性差异(P<0.001)。
3、严重不良反应退出研究病例数分别为实验组0,对照组5。
此方案可以用于G6PD(葡萄糖-6磷酸脱氢酶)缺乏的间日疟病人:云南省是少数民族大省,全省有26种少数名族,少数名族G6PD缺乏比较高,目前在治疗疟疾前还没有常规开展G6PD检测;即使开展了G6PD检测结果为严重性缺乏的间日疟病人也没有其它治疗方案可以替代氯喹+伯喹14日(或8日)方案,氯喹治疗时间都超过8天,而在此研究中5例溶血反应分别发生在第四天2例,第五天3例,都在疗程时间范围内。
此方案治疗时间短,只需三至五天就完成,病人依从性高。具体服用时,依据表1剂量进行服用。
表1
以上所述,仅为本发明的具体实施方式,但本发明的保护范围并不局限于此,任何不经过创造性劳动想到的变化或替换,都应涵盖在本发明的保护范围之内。因此,本发明的保护范围应该以权利要求书所限定的保护范围为准。
Claims (3)
1.一种治疗间日疟的药物的配伍方案,其特征在于,包括如下比例的药物原料:青蒿素17.5mg/kg、萘酚喹7mg/kg、伯喹0.9mg/kg。
2.基于权利要求1中的一种治疗间日疟的药物的使用方法,其特征在于,青蒿素份、萘酚喹份、伯喹份,每天各1次,3天连续分服。
3.根据权利要求2所述的使用方法,其特征在于,服药后多喝开水,并注意观察病人尿量及颜色,一旦病人尿的颜色呈咖啡或酱油色立即停止给下一次药并住院观察。
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