CN1072485C - 夫马菌醇及其衍生物用于制备抗肠道感染药物的用途 - Google Patents
夫马菌醇及其衍生物用于制备抗肠道感染药物的用途 Download PDFInfo
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Abstract
本发明涉及夫马菌醇和由夫马菌醇与饱和的或不饱和的(C1-C12)烷基羧酸或(C1-C12)烷基二羧酸形成的酯及其药学上可接受的盐的用途，它用于制备抑制微小孢子和/或隐小孢子所致肠道感染的药物。
Description
本发明涉及fumagillol(夫马菌醇)及其衍生物，特别是烟曲霉素的一种新用途。
烟曲霉素是一种抗菌素，首见于1951年(Merck索引第11版，4199号)，尤其是用于预防或控制养鱼和养蜂过程中的寄生虫疾病，并且也用于人的局部治疗，如用于Encephalitozoon hellem所致的角膜结膜炎的洗眼剂(眼科杂志，1993,115,293)。但是，已发现它是一种无效的溶癌剂(抗菌素年刊，1958-1959,541-546)。
现已发现如果将夫马菌醇和由这种化合物形成的某些酯配制成药物，特别是口服药时，能消除微小孢子或隐小孢子所致的极严重的肠道感染性疾病。
还意外地发现，夫马菌醇和由夫马菌醇以及饱和的或不饱和的(C1-C12)烷基羧酸或(C1-C12)烷基二羧酸所形成的酯能根除感染人免疫缺损病毒患者的Enterocytozoon bieneusi。这一发现既意外而又肯定，因为目前还不知道有关这类感染的治疗方法，此类感染包括95％因微小孢子而致的肠道感染，它最终导致艾滋病患者的恶病质和死亡。
因此，依照其特征之一，本发明涉及将夫马菌醇或由夫马菌醇和饱和的或不饱和的(C1-C12)烷基羧酸或(C1-C12)烷基二羧酸所形成的酯，及其药学上可接受的盐，用于制备抑制微小孢子和/或隐小孢子而致的肠道感染的药物的用途。
更为特殊且突出的是，根据其优选特征，本发明涉及将夫马菌醇或由夫马菌醇和饱和的或不饱和的(C1-C12)烷基羧酸或(C1-C12)烷基二羧酸所形成的酯，及其药学上可接受的盐，用于制备抑制主要因寄生虫Enterocytozoon bieneusi所致的肠道感染的药物的用途。
一般认为“饱和的或不饱和的(C1-C12)烷基羧酸或(C1-C12)烷基二羧酸”意思是指直链或支链烷基羧酸或二羧酸，它可能是含一个或多个双键的上述烷基。
这些酸的例子有乙酸，丙酸，丁酸，戊酸，新戊酸，丙二酸，丁二酸，丙烯酸，巴豆酸，异巴豆酸，油酸，马来酸，富马酸和2,4,6,8-十四烯双酸。
特别优选的化合物为夫马菌醇和2,4,6,8-十四烯双酸的酯，烟曲霉素。
通过将夫马菌醇与适合的酸在文献所述的普通酯化条件下反应，可以容易地得到本发明的酯。
可以将夫马菌醇或者其类似物或与(C1-C12)烷基羧酸或(C1-C12)烷基二羧酸的酯化物以游离酸的形式或者以它们的的某一种盐的形式与药物可接受的基质一起给药。
为给患有微小孢子或隐小孢子感染的病人用药，通常将fumagilllol及其形成的酯与常用的药物赋形剂混合以制备药物制剂，优选口服给药。
有益的是，本发明的化合物是按单位剂量有效成分配制，例如，片剂或胶囊，每单位剂量含有效成分1-200mg，优选2-100mg，更优选5-50mg，或者最佳优选7.5-30mg。
本发明的另一个目的是提供口服的药物组合物。
在本发明的口服药物组合物中，可以将有效成分以上述的单位给药形式并与常用的药物载体混合给药，以治疗上述疾病。适合的单位给药形式包括口服剂型如片剂(可以有划痕)，明胶胶囊，粉末，颗粒以及口服溶液或悬浮剂。
如果将固体组合物制备成优选剂型之一的片剂，是将主要有效成分与药物赋形剂如明胶，淀粉，乳糖，硬脂酸镁，滑石，阿拉伯树胶等混合。可将片剂用蔗糖或其它合适的物质包衣，或者进行处理以便具有延长或延迟活性，以及持续释放预计数量的有效成分。这种延迟作用或控释片剂代表另一种非常优越的剂型。
明胶胶囊型制剂是另一种特别优越的剂型，它是将有效成分与稀释剂混合，再将所得的混合物倾注成软明胶胶囊或硬明胶胶囊而得到的。
糖浆或酏剂型制剂可以包括有效成分和优选不合卡路里的增甜剂，用作防腐剂的对羟苯甲酸甲酯和对羟苯甲酸丙酯，以及调味剂和适当的着色剂。
水分散性颗粒或粉剂可以包括有效成分和分散剂或润湿剂或者悬浮剂如聚乙烯吡咯烷酮，也可包括增甜剂或矫味剂。
有效成分也可任选与一种或多种载体或添加剂配制成微胶囊。
本发明的药物组合物中，有效成分也可是存在于环糊精，其醚或其酯中的包合配合物的形式。
本发明的另一个目的是提供口服的药物组合物，其含有作为有效成分的1-200mg，优选2-100mg,5-50mg，或7.5-30mg夫马菌醇，由夫马菌醇和上述一种酸形成的酯，特别是烟曲霉素，或者它们的一种药学上可接受的盐，剂型可选择片剂，延迟作用片剂，控释片剂和明胶胶囊。
本发明的化合物可以与其他通常用于艾滋病的药物一同给药，也可与其它杀寄生虫药或抗菌素或与抗人免疫缺损病毒作用的药物联合配制。
通过给患有严重免疫缺损且平均CD4含量为66(11-158)的男性同性恋患者服用不同剂量的实施例1的药物组合物，来证实本发明化合物的治疗作用。其中三例为艾滋病，一例为ARC(艾滋病相关综合症)。平均年龄为40岁。
包埋之前，对所有这些患者进行连续性大便检查，确认为微小孢子阳性。其中两例伴有隐小孢子所致的肠道感染。所有患者中尿微小孢子试验持续阴性，这些因素支持Enterocytozoon bieneusi感染的诊断。
用活检对所有患者进行十二指肠纤维检查。有三例患者的组织学和直接寄生虫学的活检，以及电子显微术证实有微小孢子。第四例仅电子显微术表明有Enterocytozoon bieneusi存在。
给四例患者服用20mg烟曲霉素，一天三次，即，60mg/天，用21天。
治疗15,17和21天后，对比检查发现所有患者的大便中均无寄生虫。停止治疗后一个月患者的大便中仍未发现微小孢子。
包埋前其中有两例患者大便中出现隐小孢子，仅有一例大便暂时为阴性，停止治疗后一个月又出现隐小孢子。
对所有患者进行对比十二指肠纤维检查以确定组织中寄生虫的消除。而且，其中有两例组织学为阴性结果，直接寄生虫学中持续出现极稀少的微小孢子(可能是微小孢子的尸骸)。电子显微术研究证实了所有四例患者中均没有Enterocytozoon bieneusi。
对另一组患者再进行耐药量/毒理学研究。给24例患者服用剂量分别为10,20,40和60mg的烟曲霉素(每一剂量水平六个人)。
治疗耐药性极好。特别是没出现肝脏毒生，心脏毒性(心电图)或肾脏毒生(肌酸酐血)。观察到血清碱性磷酸酶含量下降极少，这可能与对微小孢子所致胆囊炎的治疗有效相关。
所观察到的不利的副作用是血液学方面的，即血小板减少症，它的程度不同但绝不会很严重(除上组四例患者停止服药的情况外)，停止治疗后10-14天又自动消退了。这种副作用，它不是免疫学上的，而仅仅是由于对血小板的直接毒生，它可以通过适当选择起始治疗来纠正。
最后，在这种机会致病菌感染中首次发现大便中的寄生虫不见了，在停止治疗后这种情况至少维持一个月，并且似乎十二指肠活检时寄生虫也没有了。使用其他抗寄生虫剂从未得到这种结果。
从多重相关感染和进行的症状性治疗方面来看难以估计这些患者中的临床有益效果。不过已进行治疗的患者出现了极显著的临床效果，他们治疗结束时均增重了几公斤，且腹泻也好了。
因此，对艾滋病过程中的Enterocytozoon bieneusi感染使用烟曲霉素可得到特别的寄生虫学结果，同时某些病例临床效果极好。
实施例1明胶胶囊型的药物组合物，每枚胶囊含2 0mg烟曲霉素酸
用需要量胶体硅石(AEROSIL)将14g纯化且预筛过的烟曲霉素酸逐渐稀释至210ml体积。将所得到的粉剂彻底混合，再将按此方法制成的均匀粉剂分配至3号不透明硬明胶胶囊中。这样便得到700枚明胶胶囊，每枚胶囊含20mg烟曲霉素酸。
Claims (10)
1．夫马菌醇或由夫马菌醇和饱和的或不饱和的(C1-C12)烷基羧酸或(C1-C12)烷基二羧酸形成的一种酯，及其药学上可接受的盐的用途，其特征是用于制备抑制由微小孢子和/或隐小孢子所致肠道感染的药物。
2．根据权利要求1所述的用途，其中上述酯为烟曲霉素。
3．根据权利要求1所述的夫马菌醇或由夫马菌醇和饱和的或不饱和的(C1-C12)烷基羧酸或(C1-C12)烷基二羧酸形成的一种酯，及其药学上可接受的盐的用途，其特征是制备抑制主要由寄生虫Enterocytozoonbieneusi所致肠道感染的药物。
4．根据权利要求3所述的用途，其中上述酯为烟曲霉素。
5．根据权利要求1或2所述的用途，其特征是用于制备口服药物。
6．根据权利要求3或4所述的用途，其特征是用于制备片剂，明胶胶囊或延迟作用片剂或控释片剂形式的药物。
7．口服的药物组合物，其含有作为有效成分的由夫马菌醇和饱和的或不饱和的(C1-C12)烷基羧酸或(C1-C12)烷基二羧酸形成的一种酯，或其药学上可接受的一种盐。
8．根据权利要求7所述的药物组合物，其中上述酯为烟曲霉素。
9．根据权利要求7或8所述的药物组合物，它包括1-200mg有效成分。
10．根据权利要求9所述的药物组合物，它包括7.5-30mg有效成分。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9503549 | 1995-03-27 | ||
| FR95/03549 | 1995-03-27 |
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| Publication Number | Publication Date |
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| CN1179715A CN1179715A (zh) | 1998-04-22 |
| CN1072485C true CN1072485C (zh) | 2001-10-10 |
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| CN96192923A Expired - Lifetime CN1072485C (zh) | 1995-03-27 | 1996-03-26 | 夫马菌醇及其衍生物用于制备抗肠道感染药物的用途 |
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| Country | Link |
|---|---|
| US (1) | US5900431A (zh) |
| EP (1) | EP0817626B1 (zh) |
| JP (1) | JP3260378B2 (zh) |
| KR (1) | KR100286920B1 (zh) |
| CN (1) | CN1072485C (zh) |
| AP (1) | AP646A (zh) |
| AT (1) | ATE172641T1 (zh) |
| AU (1) | AU706161B2 (zh) |
| CA (1) | CA2216623C (zh) |
| CZ (1) | CZ286821B6 (zh) |
| DE (1) | DE69600879T2 (zh) |
| DK (1) | DK0817626T3 (zh) |
| EA (1) | EA000150B1 (zh) |
| ES (1) | ES2128846T3 (zh) |
| FR (1) | FR06C0014I2 (zh) |
| HU (1) | HU224028B1 (zh) |
| IS (1) | IS2048B (zh) |
| NO (1) | NO315968B1 (zh) |
| NZ (1) | NZ304906A (zh) |
| OA (1) | OA10515A (zh) |
| PL (1) | PL183378B1 (zh) |
| SK (1) | SK283883B6 (zh) |
| TR (1) | TR199701048T1 (zh) |
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| US2791530A (en) * | 1953-08-31 | 1957-05-07 | Abbott Lab | Stabilized fumagillin compositions |
| JPH0629278B2 (ja) * | 1985-06-26 | 1994-04-20 | 藤沢薬品工業株式会社 | オキサスピロオクタン化合物 |
| US5135920A (en) * | 1988-11-16 | 1992-08-04 | Takeda Chemical Industries, Ltd. | Angiostatic agents |
| WO1992002240A2 (en) * | 1990-07-27 | 1992-02-20 | Repligen Corporation | Novel methods and compositions for treatment of angiogenic diseases |
| US5328930A (en) * | 1993-03-01 | 1994-07-12 | Emory University | Treatment of microsporidial and acanthamoeba keratoconjunctivitis with topical fumagillin |
| US5900431A (en) * | 1995-03-27 | 1999-05-04 | Sanofi | Use of fumagillol and derivatives thereof for preparing medicaments against intestinal infections |
| EP0799616A1 (en) * | 1996-04-01 | 1997-10-08 | Takeda Chemical Industries, Ltd. | Oral composition comprising a fumagillol derivative |
| CA2210600A1 (en) * | 1996-07-17 | 1998-01-17 | Takashi Houkan | Inhibitor of tumor metastasis or recurrence |
| AU3968597A (en) * | 1996-08-02 | 1998-02-25 | Children's Medical Center Corporation | Method of regulating the female reproductive system through angiogenesis inhibitors |
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