CN110934874B - 一种ccr4受体拮抗剂在制备药疹药物中的应用 - Google Patents

一种ccr4受体拮抗剂在制备药疹药物中的应用 Download PDF

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CN110934874B
CN110934874B CN201911314847.6A CN201911314847A CN110934874B CN 110934874 B CN110934874 B CN 110934874B CN 201911314847 A CN201911314847 A CN 201911314847A CN 110934874 B CN110934874 B CN 110934874B
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李玉叶
况轶群
唐俊婷
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First Affiliated Hospital of Kunming Medical University
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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
    • 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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    • 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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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract

本发明公开了一种CCR4受体拮抗剂的用途，该物质用于制备治疗药疹的药物中的应用。作用好于醋酸泼尼松，起效时间快，更迅速的缓解患者痛苦，特别是对于发疹性药疹或者是荨麻疹型药疹，见效更快有助于快速缓解病人的痛苦。其中CCR4受体拮抗剂是AZD2098时，对药疹有较好的疗效，特别是药疹为发疹性药疹，CCR4受体拮抗剂是Compound22时，对药疹有较好的疗效，特别是药疹为荨麻疹型药疹效果更佳。

Description

一种CCR4受体拮抗剂在制备药疹药物中的应用
技术领域
本发明涉及一种CCR4受体拮抗剂在制备药疹药物中的应用，特别是AZD2098和Compound22在治疗药疹中的应用。
背景技术
皮炎（dermatitis）是指由各种内、外部感染或非感染性因素导致的皮肤炎症性疾患的一个泛称，并非一独立疾病，其病因和临床表现复杂多样，且反复发作，临床治疗较为困难。药疹(drug eruption)亦称药物性皮炎(dermatitis medicamentosa)，是药物通过口服、注射、吸入、栓剂、外用药物吸收等各种途径进入人体后引起的皮肤黏膜炎症反应。药疹可分为轻型和重型，轻型药疹包括:发疹型药疹 (maculopapular exanthema, MPE)、多形红斑型药疹(erythema multiforme, EM)、 固定型药疹(fixed drug eruption, FDE)、荨麻疹型药疹(urticarial drug eruption)、 痤疮型药疹(acniform eruption)、紫癜型药疹(purpuric drug eruption)等。重型药疹包括重症多形红斑型药疹(Steven-Johnsonsyndrome, SJS )、大疱性表皮坏死松解型药疹(toxic epidermal necrolysis, TEN)、剥脱性皮炎型药疹(drug-induced exfolialive dermatitis)及药物超敏反应综合征(drug-induced hypersensitivity syndrome，DHIS)，重型药疹病死率高。2010-2015 年我国药疹的发生率在 1.95‰-3.5‰。
由于药疹发生率高，且重型药疹患者病死率高，因此，及时控制药疹是关键。目前临床治疗药疹的方法有：1.抗组胺药物治疗；2.糖皮质激素抗炎、抗过敏治疗；3.丙种球蛋白治疗；4.TNF- α拮抗剂治疗；上述治疗疗效均有缓解症状的作用，但抗组胺药物控制重型药疹疗效不佳，糖皮质激素，TNF- α拮抗剂等药物易出现感染等不良反应。AZD2098和Compound22是CCR4受体抑制剂。该药物目前可用于治疗哮喘。
发明内容
本发明的目的是提供CCR4受体拮抗剂在在制备治疗药疹中的新应用，特别是AZD2098和Compound22在制备治疗药疹中的应用。
本发明的目的是这样实现的：一种CCR4受体拮抗剂的用途用于制备治疗药疹的药物中的应用。其中药疹为发疹性药疹或者是荨麻疹型药疹效果更佳。所述的CCR4受体拮抗剂是AZD2098，所述的药疹为发疹性药疹，效果较好。所述的CCR4受体拮抗剂是Compound22，药疹为荨麻疹型药疹，效果较好。该药物可以制作为片剂、注射剂或者外用剂。图1 AZD2098的结构式，图2 Compound22的结构式。AZD2098分子式为C11H9Cl2N3O3S，Compound22分子式为C18H15Cl2N6R（((R)-(4-(4-[(2,4-二氯苯)氨基]）。
本发明优点：
1、本发明中的药物对于药疹的作用好于醋酸泼尼松，起效时间快，更迅速的缓解患者痛苦，特别是对于发疹性药疹或者是荨麻疹型药疹，见效更快有助于快速缓解病人的痛苦。
附图说明
图1 AZD2098的结构式示意图；
图2 Compound22的结构式示意图；
图3患者在发疹第3，5，11，14天外周血清中细胞因子IL-4和lgE 的变化情况,Compound47即为AZD2098。
具体实施方式
下面结合附图对本发明作进一步详细说明，但所述内容不应看作对本发明的限制，本实施例中方法如无特殊说明的均按常规方法操作，所用试剂如无特殊说明的采用常规试剂或按常规方法配置的试剂。
本发明所述的CCR4受体拮抗剂的用途是所述的CCR4受体拮抗剂用于制备治疗药疹的药物中的应用。
所述的药疹为发疹性药疹或者是荨麻疹型药疹。
所述的CCR4受体拮抗剂是AZD2098，所述的药疹为发疹性药疹。
所述的CCR4受体拮抗剂是Compound22，药疹为荨麻疹型药疹。
所述的药物可以制作为片剂、注射剂或者外用剂。
下面以具体实验对本发明做进一步说明：
AZD2098和Compound22治疗药疹的患者实验，具体操作如下：
1、入选标准：年龄大于18岁，确诊为药疹的患者，患者全身出现密集红斑、丘疹伴瘙痒；自愿签署知情同意书，并能保证接受随访；在试验进行过程中无计划迁离当前的试验地点；50例受试者口服AZD2098，平均年龄43岁，患者未使用抗组胺药、糖皮质激素等治疗；50例受试者口服Compound22对照组，平均年龄39岁，患者未使用抗组胺药、糖皮质激素等治疗；50例受试者口服醋酸泼尼松龙（对照组），平均年龄43岁，患者未使用抗组胺药等治疗；50例体检中心健康患者，平均年龄40岁，患者无过敏性疾病。
2、实验流程：筛选出符合方案要求的受试者后，在发疹第1天开始治疗：① 按研究方案给予AZD2098和Compound22治疗；每日50-100mg，分2次服用，治疗2周；在发疹第3、5、11、14天抽血进行细胞因子检测，评估疗效，记录不良反应；完成疗程，停药1月后随访，再次评估疗效、并记录不良反应；② 按研究方案给予醋酸泼尼松龙治疗；每日40mg，分2次服用，治疗5天；在发疹第3、5、11、14天抽血进行细胞因子检测，评估疗效，记录不良反应。
3、疗效观察：皮疹消退，无瘙痒等症状。
患者在发疹第3，8，11，14天外周血清中细胞因子IL-4和lgE的变化情况见图3，表1AZD2098化合物治疗药疹患者治疗情况，表2 Compound22化合物治疗药疹患者治疗情况，表3标准药物醋酸泼尼松治疗药疹患者治疗情况。
Figure 826504DEST_PATH_IMAGE002
Figure 816414DEST_PATH_IMAGE004
Figure 596151DEST_PATH_IMAGE006
实验结果显示：药疹患者使用CCR4拮抗剂治疗后，皮疹逐渐消退，无不良反应，皮疹未复发。药疹患者使用醋酸泼尼松龙治疗后，皮疹逐渐消退，无不良反应，皮疹未复发。其中AZD2098对于发疹性药疹的治疗，效果好转较快。快于醋酸泼尼松龙，可以优选用于治疗发疹性药疹。其中Compound22对于荨麻疹型药疹效，果好转较快快于醋酸泼尼松龙，可以优选用于治疗发疹性药疹。
发疹第3天，AZD2098和Compound22和醋酸泼尼松龙治疗组患者IgE水平高于对照组。AZD2098, Compound22和醋酸泼尼松龙治疗以后，皮疹第11天和第14天检测的细胞因子IL-4均低于第5天，提示治疗有效果。
因此，AZD2098 和Compound22具有治疗药疹的疗效，且无复发，副作用小，使用简单方便；具有临床推广应用的前景。

Claims (4)

1.一种CCR4受体拮抗剂的用途，其特征在于用于制备治疗药疹的药物中的应用；所述的CCR4受体拮抗剂为AZD2098。
2.根据权利要求1所述的CCR4受体拮抗剂的用途，其特征在于所述的药疹为发疹性药疹或者是荨麻疹型药疹。
3.根据权利要求1所述的CCR4受体拮抗剂的用途，其特征在于所述的CCR4受体拮抗剂是AZD2098，所述的药疹为发疹性药疹。
4.根据权利要求1所述的制备治疗药疹的药物中的用途，其特征在于所述的药物可以制作为片剂、注射剂或者外用剂。
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Citations (1)

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WO2019161684A1 (zh) * 2018-02-23 2019-08-29 中国科学院生物物理研究所 Ccr4的n端重组蛋白及其用途

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WO2019161684A1 (zh) * 2018-02-23 2019-08-29 中国科学院生物物理研究所 Ccr4的n端重组蛋白及其用途

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CCL17/CCR4轴介导药疹的免疫机制研究;唐俊婷;《昆明医科大学博士论文》;20210215;1-143 *
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