WO2021068203A1 - 一种氯喹或衍生物羟氯喹的用途 - Google Patents

一种氯喹或衍生物羟氯喹的用途 Download PDF

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WO2021068203A1
WO2021068203A1 PCT/CN2019/110630 CN2019110630W WO2021068203A1 WO 2021068203 A1 WO2021068203 A1 WO 2021068203A1 CN 2019110630 W CN2019110630 W CN 2019110630W WO 2021068203 A1 WO2021068203 A1 WO 2021068203A1
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chloroquine
hydroxychloroquine
derivative
ofs
preparation
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李延兵
郭衍
李海
陈雪莹
陈雨馨
管洪宇
刘烈华
肖海鹏
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中山大学附属第一医院
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents

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  • the invention belongs to the field of biomedical technology, and relates to a new use of chloroquine or a derivative of hydroxychloroquine, and more specifically, to a use of chloroquine or a derivative of hydroxychloroquine in a medicine for treating Graves' ophthalmopathy.
  • Chloroquine (CQ) has been used clinically since 1944; it was first used to treat malaria, but its use gradually expanded. In 1951, it was used to treat rheumatoid arthritis with chloroquine, with a certain effect.
  • Graves ophthalmopathy is the most common extrathyroid manifestation of Graves disease, accounting for about 50%, manifesting as blepharoplasty, exophthalmia, pain, redness and swelling, and even lead to optic nerve compression, causing blindness, and seriously affecting the health and quality of life of patients .
  • the effective rate of clinical application of glucocorticoids is 63% (oral) to 88% (intravenous shock), but it is often only targeted at acute or moderate to severe patients, and cannot reverse the infiltrating exophthalmos of GO.
  • Side effects such as edema, obesity, bone Porosity also limits its application, and surgery and radiotherapy are only supplementary treatments.
  • Orbital fibroblasts excessively proliferate, differentiate into adipocytes, and secrete hydrophilic mucopolysaccharides, which increase the contents of the orbit and increase the pressure in the orbit. At the same time, it secretes inflammatory factors to recruit inflammatory cells, which causes exophthalmos and The core factor of inflammatory infiltration, but the current drugs for OFs to reduce exophthalmos are very limited. At present, only IGF-1 receptor monoclonal antibody Teprotumumab has been found to alleviate exophthalmos while inhibiting inflammation, but the high price limits its wide application.
  • the technical problem to be solved by the present invention is to overcome the above-mentioned defects and technical deficiencies in the prior art, and to provide a new application of chloroquine or a derivative of hydroxychloroquine in the treatment of Graves' ophthalmopathy.
  • chloroquine or a derivative of hydroxychloroquine which is an application of chloroquine or a derivative of hydroxychloroquine in the preparation of a medicine for treating and/or alleviating Graves' ophthalmopathy.
  • a use of chloroquine or its derivative hydroxychloroquine is characterized in that: the application of the chloroquine or its derivative hydroxychloroquine in the preparation of drugs for inhibiting the proliferation of OFs.
  • a use of chloroquine or a derivative of hydroxychloroquine characterized in that: the application of the chloroquine or a derivative of hydroxychloroquine in the preparation of drugs for inhibiting the adipogenic differentiation of OFs.
  • a use of chloroquine or its derivative hydroxychloroquine is characterized in that: the application of the chloroquine or its derivative hydroxychloroquine in the preparation of drugs for inhibiting the synthesis and secretion of OFs hyaluronic acid.
  • chloroquine or its derivative hydroxychloroquine is prepared into a pharmaceutical preparation in the form of a tablet, a capsule or a sustained-release agent.
  • the content of chloroquine is 250 mg/tablet of chloroquine phosphate; the content of hydroxychloroquine phosphate is 200 mg/tablet.
  • the present invention takes fibroblasts isolated and extracted from the periorbital adipose tissue of patients with Graves ophthalmopathy as the research object. Under the action of chloroquine or its derivative, hydroxychloroquine, the hyperproliferation, adipogenic differentiation and hyalurin of fibroblasts are found Acid synthesis is significantly inhibited, and these effects superimposed to demonstrate the effective regulation of chloroquine and its derivative hydroxychloroquine on the pathophysiology of fibroblasts, the leading factor in the pathology of Graves ophthalmopathy.
  • the present invention is different from the current existing treatment of hyperthyroidism exophthalmia.
  • Chloroquine and its derivative hydroxychloroquine act on the pathophysiological mechanism of orbital fibroblasts, and have a certain immunomodulatory effect instead of immunosuppressive effect, and are clinically It has been used for many years, with high safety and low price.
  • the invention regulates all the pathogenesis of hyperthyroidism exophthalmos, and the raw materials are easily available, and have been widely used in other clinical diseases.
  • the new use as an old medicine is of great significance to saving social resources and the like.
  • Figures 1A-1C show that chloroquine and its derivative hydroxychloroquine inhibit the proliferation of fibroblasts.
  • Figures 2A-3B show that chloroquine and its derivative hydroxychloroquine inhibit the adipogenic differentiation of fibroblasts.
  • Figures 3A-3B show that chloroquine and its derivative hydroxychloroquine inhibit the synthesis and secretion of hyaluronic acid in fibroblasts.
  • the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the technical field.
  • the reagents and materials used in the present invention are all commercially available.
  • Proliferation medium DMEM-F12 containing 10% (vol/vol) fetal bovine serum (Gibco Laboratories, USA)
  • CCK-8 Cell counting kit-8 (CCK-8) cell proliferation kit (KGI, Guangzhou, China); EdU DNA synthesis detection kit (Ribo, Guangzhou, China)
  • Chloroquine raw material powder and ultrapure water to make a 100mM stock solution, dilute to 5 ⁇ M and 10 ⁇ M in a certain proportion to treat cells in vitro
  • Hydroxychloroquine raw material (TCI, Shanghai, China): Hydroxychloroquine Sulfate (Hydroxychloroquine Sulfate) powder is mixed with ultrapure water to make a 50mM stock solution, which is diluted to 2.5 ⁇ M and 5 ⁇ M in a certain proportion to treat cells in vitro.
  • Example 1 Chloroquine and its derivative hydroxychloroquine inhibit the proliferation of OFs in GO patients
  • OFs of GO patients were extracted and passaged to P2 in the proliferation medium for experiments. They were divided into chloroquine group (0, 0.5, 1, 5, 10, 25, 50, 100 ⁇ M) and hydroxychloroquine group (0 , 0.5, 1, 5, 10, 25, 50, 100 ⁇ M), add the same concentration of CCK8 for 3 consecutive days after starting the treatment and read the absorbance (450nm) after incubating for 4 hours.
  • chloroquine and hydroxychloroquine concentration is greater than 10uM and there is greater cytotoxicity, and the drug concentration in the human body of patients taking chloroquine or hydroxychloroquine is generally less than or equal to 10uM, so follow-up experiments use chloroquine (10uM) or hydroxychloroquine (5uM). Further using EdU (5-ethynyl-2'-deoxyuridine) cell proliferation experiments to detect DNA synthesis, it was found that 10 ⁇ M chloroquine or 5 ⁇ M hydroxychloroquine significantly inhibited the DNA synthesis of OFs, respectively, as shown in Figure 1C.
  • Example 2 Chloroquine and its derivative hydroxychloroquine inhibit the adipogenic differentiation of OFs in GO patients
  • the exophthalmia of GO patients is mainly caused by the adipogenic differentiation of OFs and compression of periorbital tissue.
  • chloroquine and its derivative hydroxychloroquine affect this process, we induced differentiation and culture of OFs in GO patients, while using chloroquine (10 ⁇ M) or Hydroxychloroquine (5 ⁇ M) treated or untreated controls were used to detect the adipogenic differentiation ability of OFs by oil red staining and western blotting. It was found that chloroquine could inhibit the formation of lipid droplets. See Figure 2A.
  • Example 3 Chloroquine inhibits the synthesis and secretion of OFs hyaluronic acid in GO patients
  • Hyaluronic acid is the main hydrophilic mucopolysaccharide in the orbit of GO patients, which promotes the increase of periorbital content and compression of surrounding tissues, and the secretion of inflammatory factor IL-1 ⁇ is significantly increased. Therefore, we tested whether chloroquine treatment can regulate the secretion of hyaluronic acid. ELISA showed that chloroquine and its derivative hydroxychloroquine significantly inhibited the secretion of hyaluronic acid regardless of the presence or absence of IL-1 ⁇ , as shown in Figure 3A.
  • the present invention finds for the first time that chloroquine and its derivatives, hydroxychloroquine, as autophagy inhibitors can simultaneously act on various pathological mechanisms of orbital fibroblasts in patients with hyperthyroidism, including proliferation, differentiation and hyaluronic acid formation, which determine chloroquine and its derivatives The potential therapeutic effect of hydroxychloroquine in future clinical applications.

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Abstract

一种氯喹或其衍生物羟氯喹在制备治疗Graves眼病的药物中的用途。氯喹或其衍生物羟氯喹对成纤维细胞的过度增殖、成脂分化及透明质酸合成有明显抑制作用。

Description

一种氯喹或衍生物羟氯喹的用途 技术领域
本发明属于生物医学技术领域，涉及氯喹或衍生物羟氯喹药物的新用途，更具体地，涉及一种氯喹或衍生物羟氯喹在治疗Graves眼病的药物中的用途。
背景技术
氯喹(Chloroquine，CQ)从—1944年开始应用于临床；最初用来治疗疟疾，以后用途逐渐扩大。1951年，用于治疗氯喹类风湿关节炎，有一定效果。
Graves眼病(Graves ophthalmopathy，GO)是Graves病最常见的甲状腺外表现，约占50％，表现为睑挛缩、突眼、疼痛、红肿，甚至导致视神经压迫，引起失明，严重影响患者健康与生活质量。目前临床应用糖皮质激素有效率为63％(口服)到88％(静脉冲击)，但常常只针对急性期或中重度患者，且无法逆转GO的浸润性突眼，副作用如水肿、肥胖、骨质疏松等也限制其应用，而手术及放射治疗仅作为其补充治疗，因此亟需探索针对病因的治疗新策略[1,2]。眼眶成纤维细胞(Orbital fibroblasts，OFs)过度地增殖、成脂分化、分泌亲水性粘多糖，使眼眶内容物增多，眶内压力增大，同时分泌炎症因子募集炎症细胞，是造成突眼及炎症浸润的核心因素，但目前针对OFs减缓突眼的药物很有限。目前仅发现IGF-1受体单抗Teprotumumab能缓解突眼同时抑制炎症反应，但昂贵的价格限制了其广泛应用。
研究发现自噬在OFs的增殖及分化早期起到至关重要的调控作用，而氯喹及其衍生物羟氯喹作为被美国FDA通过的安全老药，是最具有临床价值的一种自噬抑制剂，且价格低廉。我们以GO患者手术切除的眶周脂肪组织中分离提取的OFs为研究对象，证实氯喹(Chloroquine，CQ)及其衍生物羟氯喹(Hydroxychloroquine，HCQ)显著抑制OFs的各方面病理机理包括增殖、分化及透明质酸分泌，有望成为GO的新疗法，具有重要的科学意义与社会意义。
发明内容
本发明要解决的技术问题是克服上述现有技术中的缺陷和技术不足，提供一种氯喹或衍生物羟氯喹在治疗Graves眼病的药物中的新用途。
本发明的技术方案如下：
一种氯喹或衍生物羟氯喹的用途，所述用途是氯喹或衍生物羟氯喹在制备治疗和/或缓解Graves眼病的药物中的应用。
一种氯喹或衍生物羟氯喹的用途，其特征在于：所述氯喹或衍生物羟氯喹在制备抑制OFs的增殖的药物中的应用。
一种氯喹或衍生物羟氯喹的用途，其特征在于：所述氯喹或衍生物羟氯喹在制备抑制OFs的成脂分化的药物中的应用。
一种氯喹或衍生物羟氯喹的用途，其特征在于：所述氯喹或衍生物羟氯喹在制备抑制OFs透明质酸的合成及分泌的药物中的应用。
另外，上述方案中，将氯喹或衍生物羟氯喹制备成药物制剂，其制剂形式为为片剂、胶囊或缓释剂。
所述的药物制剂中，氯喹的含量为磷酸氯喹250mg/片；衍生物羟氯喹的含量为磷酸羟氯喹200mg/片。
本发明以Graves眼病患者手术切除的眶周脂肪组织中分离提取的成纤维细胞为研究对象，在氯喹或其衍生物羟氯喹的作用下，发现成纤维细胞的过度增殖、成脂分化及透明质酸合成受到明显抑制，这些效果叠加展示了氯喹及其衍生物羟氯喹对Graves眼病病理主导因素——成纤维细胞病理生理的有效调控。
本发明具有以下有益效果：
本发明与目前现有甲亢突眼的的疗法不同，氯喹及其衍生物羟氯喹针对眼眶成纤维细胞的病理生理机制发挥作用，有一定的免疫调节作用，而非免疫抑制作用，且在临床上应用多年，安全性高，价格低廉。
本发明针对甲亢突眼的全部发病机制进行调控，且原料易得，在临床上其他疾病中已有过广泛应用，作为老药新用对节省社会资源等有重大意义。
附图说明
图1A-1C为氯喹及其衍生物羟氯喹抑制成纤维细胞增殖。
图2A-3B为氯喹及其衍生物羟氯喹抑制成纤维细胞的成脂分化。
图3A-3B为氯喹及其衍生物羟氯喹抑制成纤维细胞透明质酸合成和分泌。
具体实施方式
以下结合说明书附图和具体实施例来进一步说明本发明，但实施例并不对本发明做任何形式的限定。除非特别说明，本发明采用的试剂、方法和设备为本技术领域常规试剂、方法和设备。除非特别说明，本发明所用试剂和材料均为市购。
所用材料及试剂盒
1)增殖培养基：含10％(vol/vol)胎牛血清的DMEM-F12(Gibco Laboratories，美国)
2)分化培养基及油红O染色液：商品化诱导成脂培养基(赛莱拉，广州，中国)
3)增殖相关实验试剂盒：Cell counting kit‐8(CCK‐8)细胞增殖试剂盒(凯基，广州，中国)；EdU DNA合成检测试剂盒(锐博，广州，中国)
4)RNA逆转录试剂盒(Promega,美国)
5)透明质酸ELISA试剂盒(Echelon Bioscience Inc.，美国)
6)氯喹原料(sigma，美国)：粉末加超纯水配成浓度100mM原液，以一定比例稀释成5μM及10μM在体外处理细胞
7)羟氯喹原料(TCI，上海，中国)：硫酸羟基氯喹(Hydroxychloroquine Sulfate)粉末加超纯水配成浓度50mM原液，以一定比例稀释成2.5μM及5μM在体外处理细胞。
实施例1氯喹及其衍生物羟氯喹抑制GO患者OFs的增殖
方法步骤：
A)提取GO患者OFs(n＝6)，在增殖培养基中传代至P2进行实验，分为氯 喹组(0，0.5，1，5，10，25，50，100μM)及羟氯喹组(0，0.5，1，5，10，25，50，100μM)，开始处理后连续3天加入相同浓度的CCK8培养4h后读取吸光度(450nm)，随着氯喹或羟氯喹浓度增加及作用时间延长，细胞活性逐渐下降；B)提取GO患者OFs(n＝6)，在增殖培养基中传代至P2进行实验，分为羟氯喹组(0，0.5，1，5，10，25，50，100μM)，开始处理后连续3天加入相同浓度的CCK8培养4h后读取吸光度(450nm)，随着氯喹或羟氯喹浓度增加及作用时间延长，细胞活性逐渐下降；
C)提取GO患者眼眶的OFs(n＝3)，在增殖培养基中传代至P2进行实验，用基础培养基进行同步化处理后，分为对照组，氯喹组(10μM)及羟氯喹组(5μM)共3组，随后加入EdU 37℃孵育18h，固定细胞后进行染色，用荧光显微镜拍照，统计EdU阳性比例，氯喹或羟氯喹相比对照组差异具有统计学意义。
结果：
OFs的过度增殖是GO的病理生理机制之一，为验证氯喹及羟氯喹是否影响其增殖，我们提取GO患者OFs，在增殖培养基中初步分别用不同浓度的氯喹和羟氯喹处理后进行CCK8细胞活性实验发现氯喹对成脂肪细胞的增殖有抑制作用，且呈时间和浓度依赖性，见图1A及图1B。上述可得当氯喹及羟氯喹浓度超过10uM出现较大细胞毒性，且服用氯喹或羟氯喹的患者人体内药物浓度一般为小于等于10uM，因此后续实验使用氯喹(10uM)或羟氯喹(5uM)。进一步用EdU(5-ethynyl-2’-deoxyuridine)细胞增殖实验检测DNA合成，发现氯喹10μM或羟氯喹5μM均分别显著抑制OFs的DNA合成，见图1C。
实施例2：氯喹及其衍生物羟氯喹抑制GO患者OFs的成脂分化
方法步骤：
A)取GO患者OFs(n＝3)，在增殖培养基中传代至P3，待细胞密度达90％以上开始换用诱导培养基，分为对照组，氯喹组(10μM)及羟氯喹组(5μM) 共3组，10天后固定细胞，用光学显微镜拍摄普通相差图像及油红O染色后图像(100×)。
B)诱导分化4天成功后收集各组细胞提取RNA，进行实时荧光定量PCR实验，检测成脂肪分化相关标志物的变化。
结果：
GO患者的突眼主要由OFs的成脂分化压迫眶周组织导致，为验证氯喹及其衍生物羟氯喹是否影响这一过程，我们对GO患者OFs进行诱导分化培养，同时用氯喹(10μM)或羟氯喹(5μM)处理或无处理对照，通过油红染色法及免疫印迹实验检测OFs的成脂分化能力，发现氯喹可以抑制脂滴形成。见图2A。
同时成脂前期及中期的标志物PPARγ，Perilipin-1，FABP4，c/EBPα/β在mRNA水平被氯喹及其衍生物羟氯喹下调，如图2B。
实施例3：氯喹抑制GO患者OFs透明质酸的合成及分泌
方法步骤：
取GO患者OFs(n＝4)，在增殖培养基中传代至P3进行实验，分为IL-1β处理组和非处理组，进一步分为对照组，氯喹组(10μM)及羟氯喹组(5μM)共3组，处理细胞48h，取培养基上清，4℃离心去除死细胞后用透明质酸酶联免疫吸附测定(Enzyme-linked immunosorbent assay，ELISA)试剂盒检测透明质酸浓度，剩下的细胞用于提取RNA检测HAS2表达。
结果：
透明质酸是GO患者眼眶中主要的亲水性粘多糖，促进眶周内容物增多及压迫周围组织，且在炎症因子IL-1β的刺激下分泌显著增多。因此我们检测氯喹处理是否会调节透明质酸的分泌。ELISA表明无论在有无IL-1β作用下，氯喹及其衍生物羟氯喹均显著抑制透明质酸分泌，见图3A。
实时荧光定量PCR结果表明无论是否在IL-1β作用下，氯喹及其衍生物羟氯喹都能明显抑制透明质酸合成酶HAS2的表达，参考图3B。
本发明首次发现氯喹及其衍生物羟氯喹作为自噬抑制剂可以同时作用于甲亢眼病患者眼眶成纤维细胞的各种病理机制，包括增殖、分化及透明质酸形成，决定了氯喹及其衍生物羟氯喹在将来临床应用上的潜在治疗作用。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (7)

  1. 一种氯喹或衍生物羟氯喹的用途，所述用途是氯喹或衍生物羟氯喹在制备治疗和/或缓解Graves眼病的药物中的应用。
  2. 一种氯喹或衍生物羟氯喹的用途，其特征在于：所述氯喹或衍生物羟氯喹在制备抑制OFs的增殖的药物中的应用。
  3. [根据细则26改正31.10.2019]　
    一种氯喹或衍生物羟氯喹的用途，其特征在于：所述氯喹或衍生物羟氯喹在制备抑制OFs的成脂分化的药物中的应用。
  4. [根据细则26改正31.10.2019]　
    一种氯喹或衍生物羟氯喹的用途，其特征在于：所述氯喹或衍生物羟氯喹在制备抑制OFs透明质酸的合成及分泌的药物中的应用。
  5. [根据细则26改正31.10.2019]　
    根据权利要求1-4任一项所述氯喹或衍生物羟氯喹的用途，其特征在于：将氯喹或衍生物羟氯喹制备成药物制剂，其制剂形式为为片剂、胶囊或缓释剂。
  6. [根据细则26改正31.10.2019]　
    根据权利要求5所述的氯喹或衍生物羟氯喹的用途，其特征在于，所述的药物制剂中，氯喹在制剂中的含量为磷酸氯喹250mg/片。
  7. [根据细则26改正31.10.2019]　
    根据权利要求5所述的氯喹或衍生物羟氯喹的用途，其特征在于，所述的药物制剂中，衍生物羟氯喹在制剂中的含量为磷酸羟氯喹200mg/片。
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011146732A1 (en) * 2010-05-19 2011-11-24 Beth Israel Deaconess Medical Center Methods for treating inflammatory autoimmune disorders
CN106860459A (zh) * 2015-12-11 2017-06-20 成都夸常科技有限公司 喹啉类物质在治疗甲状腺和乳腺疾病中的应用、方法以及药物组合物
EP3520803A1 (en) * 2018-01-31 2019-08-07 Zarodex Therapeutics Limited Novel uses

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011146732A1 (en) * 2010-05-19 2011-11-24 Beth Israel Deaconess Medical Center Methods for treating inflammatory autoimmune disorders
CN106860459A (zh) * 2015-12-11 2017-06-20 成都夸常科技有限公司 喹啉类物质在治疗甲状腺和乳腺疾病中的应用、方法以及药物组合物
EP3520803A1 (en) * 2018-01-31 2019-08-07 Zarodex Therapeutics Limited Novel uses

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEN, SHU ET AL.: "Clinical Observation of Chinese Produced Chlorovaline for Treating Endocrine Exophthalmos or Hyperthyroidism and Exophthalmos of Degree III or Higher Caused by Graves’ Disease", MEDICAL TECHNOLOGY, no. 3, 30 September 2002 (2002-09-30), pages 22 - 23, XP009527372, ISSN: 1672-6170 *
SOLTANI, A. MOAYYERI, A. AZIZI, F.: "Combination therapy of chloroquine and methimazole in Graves' disease: A pilot randomized controlled trial", BIOMEDICINE AND PHARMACOTHERAPY., ELSEVIER, FR, vol. 61, no. 4, 9 May 2007 (2007-05-09), FR, pages 241 - 243, XP022067326, ISSN: 0753-3322, DOI: 10.1016/j.biopha.2007.01.001 *

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