CN1330301C - L－肉碱、乙酰l－肉碱和丙酰l－肉碱在制备治疗精子减少精子活力不足畸形精子的联合药物中的应用 - Google Patents
L－肉碱、乙酰l－肉碱和丙酰l－肉碱在制备治疗精子减少精子活力不足畸形精子的联合药物中的应用 Download PDFInfo
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- RDHQFKQIGNGIED-MRVPVSSYSA-N O-acetyl-L-carnitine Chemical compound CC(=O)O[C@H](CC([O-])=O)C[N+](C)(C)C RDHQFKQIGNGIED-MRVPVSSYSA-N 0.000 title claims description 39
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Classifications
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- A—HUMAN NECESSITIES
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- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
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- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
Abstract
本发明描述了L-肉碱、乙酰L-肉碱和丙酰L-肉碱或其可药用盐之一用于制备治疗任何起因的精子减少精子活力不足畸形精子的药物的用途。
Description
在此描述的发明涉及联合使用L-肉碱、乙酰L-肉碱和丙酰L-肉碱制备用于治疗任何起因的精子减少精子活力不足畸形精子(oligoasthenoteratospermia)的药物：炎性、特发性、激素性或与精索静脉曲张相关。
所有这些形式的不育症的最终共同途径是局部积聚氧自由基(Pasqualotto F.F.等，Fertil.Steril.73：459-464，1999)。为了对抗这种积聚，可使用抗氧化药物。
大多数目前在药物市场上可得到的抗氧化剂(维生素E、谷胱甘肽、NADH)的作用方式与三羧酸循环无关，因此，其作用方式仅仅与药物剂量而不与细胞代谢相关。
人类精子发生的实质上的局部解剖和时间的异质性(在相同睾丸内)(Silber S.J.，Clin.Obstet.Gynaecol.43：843-888，1999)使得不可能建立抗氧化剂的“固定”剂量，因为这会导致服药过量和不足。
过度降低氧自由基导致对顶体和精子的获能反应的抑制(Ochenforf F.R.，Hum.Reprod.Update.5：399-402，1999)，而太高的浓度则导致精子本身的形态异常(Gattuccio F.等，Varicocele 2000，Cofese Editore，Palermo 2000)。
在Human Reprod.13：3090-3093，1998中，提出了基于US多普勒结果区分阻塞性和非阻塞性精子缺乏的半定量评分体系。
在Human.Reprod.15：2554-2558，2000中，报道了在非阻塞性精子缺乏患者中跨纵隔的睾丸动脉的抵抗力指数显著大于对照和精子减少精子活力不足患者。
在Fertil.Steril.75：1088-1094，2001中，报道了在阻塞性精子缺乏中睾丸动脉的搏动指数高于非阻塞性精子缺乏。
在J.Urol.163：135，2000中，报道了在患有精子发生成熟停滞(也就是说患有生殖细胞发育不良)的对象中，睾丸内血流和血流速率显著降低。
精子在睾丸中产生，并在附睾中经历性腺后成熟，以获得其受精能力。
在血浆中，高分子量蛋白质和小分子如游离肉碱促进配子成熟成为有能力的功能性细胞。
来自血浆的附睾L-肉碱对精子具有有益的作用。其通过被动扩散进入精子，并且只在成熟精子中被乙酰化。
游离和乙酰化肉碱的内源性库与精子活力的累进百分比之间的关系表明与鞭毛运动相关的更为重要的代谢功能。
因此，在附睾中精子活动的开始可能不依赖于肉碱系统，而乙酰L-肉碱的能量特性在“能量危机”情形中有关。
游离肉碱在成熟精子的胞质中的积聚不得不被认为是线粒体代谢的一种保护形式，其对这些分离细胞的存活有用。
已知L-肉碱、乙酰L-肉碱和丙酰L-肉碱的联合应用。
在欧洲专利EP 0 973 415中，描述了一种饮食营养组合物，其由L-肉碱、乙酰L-肉碱和丙酰L-肉碱组成，用于经受强体力劳动的运动员，或者用于衰弱的个体。
在专利申请WO 99/17623中，描述了一种饮食营养组合物，其由L-肉碱、乙酰L-肉碱和丙酰L-肉碱组成，用于治疗酒精戒断综合征。
还已知L-肉碱和烷酰基L-肉碱用于治疗男性不育症的用途。
在Drugs Exptl.Clin.Res.XXI(4)：157-159，1995中，报道了在患有特发性精子活力不足的一组患者中施用L-肉碱在所治疗的47名患者中的37名患者中改善精子活力并增加精子计数。
在Dermatol.Monatschr.169：572-575，1983中，证实了相同的结果。
在Andrologia，26：155-159，1994中，报道了在不育症患者中施用L-肉碱使精子活力在量和质上都有显著改善。
在Fertilitt4：1-4，1988中，报道了在不育症患者中L-肉碱治疗使精子中的肉碱水平升高并且同时增加精子活力和精子计数。
Loumbakis P.等(European Association of Urology第12次会议，Paris，1-4 September，1996)报道了初步的数据，表明施用L-肉碱对精子质量可能具有积极作用。
在Acta Eur.Fertil.23(5)：221-224，1992中，报道了在患有特发性精子减少精子活力不足的患者中使用乙酰L-肉碱对精子密度没有作用，但诱导精子活力的进行性增加。
在US 6,090,848中，报道了L-肉碱和乙酰L-肉碱的组合可用于治疗精子减少精子活力不足畸形精子。
上面提及的已知的化合物无疑被认为是好的治疗剂，但仍然表现出一些缺点。
事实上，如上所述，在Drugs Exptl.Clin.Res.XXI(4)：157-159，1995中，报道了向患有特发性精子减少精子活力不足畸形精子的一组患者施用L-肉碱在47名治疗患者中的37名患者中改善精子计数并增加精子活力，而在Acta Eur.Fertil.23(5)：221-224，1992中，报道了在患有特发性精子减少精子活力不足的患者中使用乙酰L-肉碱对精子密度没有影响。
在US 6,090,848中描述的组合被认为是迄今为止已知的最好一种组合，其在研究本发明组合物的活性期间被用作参照化合物。所获得的结果报道于下文，证实了在US 6,090,848中描述的组合物的活性，但也令人惊奇和出人意料之外地证实了本发明的组合比US 6,090,848中描述的组合物更具活性。
在医学领域，仍然强烈感到需要获得用于治疗精子减少精子活力不足畸形精子的组合物，其不表现出上述已知化合物的缺点，或者其改进用目前使用的已知组合物中最好的组合物所获得的结果。
现已发现，联合使用L-肉碱、乙酰L-肉碱和丙酰L-肉碱或其可药用盐之一被证实在对所有形式的精子减少精子活力不足畸形精子的治疗中能发挥惊人的协同作用。
因此，本发明的一个目的是L-肉碱、乙酰L-肉碱和丙酰L-肉碱内盐或其可药用盐用于制备治疗精子减少精子活力不足畸形精子的药物的用途。
本发明的另一目的是L-肉碱、乙酰L-肉碱和丙酰L-肉碱内盐或其可药用盐用于制备治疗精子减少的药物的用途。
本发明的另一目的是L-肉碱、乙酰L-肉碱和丙酰L-肉碱内盐或其可药用盐用于制备治疗精子活力不足的药物的用途。
本发明的另一目的是L-肉碱、乙酰L-肉碱和丙酰L-肉碱内盐或其可药用盐用于制备治疗畸形精子的药物的用途。
本发明的另一目的是L-肉碱、乙酰L-肉碱和丙酰L-肉碱或其可药用盐用于制备治疗精子减少精子活力不足畸形精子的营养组合物的用途。
本发明的另一目的是L-肉碱、乙酰L-肉碱和丙酰L-肉碱或其可药用盐用于制备治疗精子减少的营养组合物的用途。
本发明的另一目的是L-肉碱、乙酰L-肉碱和丙酰L-肉碱或其可药用盐用于制备治疗精子活力不足的营养组合物的用途。
本发明的另一目的是L-肉碱、乙酰L-肉碱和丙酰L-肉碱或其可药用盐用于制备治疗畸形精子的营养组合物的用途。
已发现，本发明的组合比上面提及的L-肉碱与乙酰L-肉碱的组合在改善男性精子计数和精子活力方面更具活性。
L-肉碱、乙酰L-肉碱和丙酰L-肉碱可以是适于对男性进行口服或胃肠外给药的任何形式。
L-肉碱、乙酰L-肉碱和丙酰L-肉碱可以配制在一起，作为混合物，或者可以分别单独配制(分别单独包装)，采用已知的方法。L-肉碱、乙酰L-肉碱和丙酰L-肉碱可以配制成混合物或配制成单独包装而施用于个体。
基于各种不同的因素，诸如活性成分的浓度或患者的一般情况，本发明的组合可以上市作为健康食物补充剂、营养补充剂或作为需要或不需要医学处方而出售的治疗产品。
根据本发明，L-肉碱与乙酰L-肉碱和丙酰L-肉碱或其可药用盐之一的摩尔比范围从2.48∶0.098∶0.092-0.186∶0.98∶0.92。
可供选择的摩尔比包括范围从2.48∶0.49∶0.46-0.62∶0.49∶0.46的摩尔比。
可供选择的摩尔比包括范围从2.48∶0.98∶0.92-1.24∶0.49∶0.23的摩尔比。
根据本发明的组合制剂，当为单位剂型时，含有4.0g-0.30g的L-肉碱内盐，0.20-2.0g的乙酰L-肉碱内盐和0.20g-2.0g的丙酰L-肉碱内盐，或等摩尔量的其可药用盐之一。
单位剂型的优选的组合制剂含有2g的L-肉碱内盐，1g的乙酰L-肉碱内盐和0.5g的丙酰L-肉碱内盐，或等摩尔量的其可药用盐之一。
但是，现已发现，尽管待施用的上述活性成分的日剂量取决于患者的年龄、体重和一般情况，采用专业经验通常可建议以单剂或以多剂施用大约0.3-4.0g/天的L-肉碱、大约0.20-2.0g/天的乙酰L-肉碱和大约0.20-2.0g/天的丙酰L-肉碱，或等摩尔量的其可药用盐之一。
由于所述活性成分的毒性极低，可以施用更大的剂量。
下文报道的是为评价与用L-肉碱加上乙酰L-肉碱进行的联合治疗相比本发明的组合是否改善精子活力而进行的临床试验。
征募的患者必须满足以下入选/排除标准。
入选标准：年轻的不育症男性患者，患有精子活力不足-活精子存在，认为其是之前至少2年期间不育症的唯一原因；在至少两份样本中必须满足的精液标准是：精子浓度(M/ml)从10-20，活力(％)在2小时＞20＜40，快速线性行进(％)在2小时＜20。对患者取病史，进行双侧阴囊回声-彩色多普勒，体检，激素测定(游离和总睾酮，FSH，LH，17β雌二醇，孕酮，催乳素)和精子发生图(WHO 1999)。
排除标准：急性生殖器炎症，精子浓度＜5,000,000/ml。所有患者对参与该开放试验知情同意。总共被检查的患者为8名精索静脉曲张患者(6名II级，2名III级)，12名性腺慢性炎症患者，12名精索静脉曲张(8名II级，4名III级)+性腺慢性炎症患者，25名原因不明的精子减少精子活力不足患者，2名促性腺激素不足性性腺功能减退患者，1名高催乳素血症患者，4名手术史(3例单侧隐睾，1例双侧隐睾)患者，和2名双侧睾丸外伤患者。
在禁欲至少4天之后通过手淫获得精液。在射精1小时之内对精液样本分析所有参数，采用WHO(1987)推荐的标准方法。对至少两份样本采用计算机化活动性分析仪研究精子活力。
在用研究化合物治疗之前和用其进行4个月治疗之后，进行精液分析和活力评价。
以2g/天(2×500mg片剂，每天2次，午餐后)的剂量施用L-肉碱4个月；以1g/天的剂量施用乙酰L-肉碱4个月；以500mg/天的剂量施用丙酰L-肉碱4个月。
与用L-肉碱加上乙酰L-肉碱组合治疗相比，本发明的组合显著增加精子浓度和活力以及具有快速线性行进的精子的百分比，不论精子减少精子活力不足畸形精子的原因为何，甚至在激素异常患者中也是如此。
在后者中，与文献中报道的数据相比，本发明的组合使得促性腺激素和抗催乳素血症药物的剂量减小。
在此描述的本发明的药物可通过将活性成分(L-肉碱内盐，乙酰L-肉碱内盐和丙酰L-肉碱内盐或其可药用盐之一)与对于配制肠道(特别是口服)或胃肠外(特别是肌内或静脉内)给药的组合物而言合适的赋形剂相混合而制备。药学技术的专家熟悉所述赋形剂。
上述活性成分的可药用盐包括通过向L-肉碱、乙酰L-肉碱和丙酰L-肉碱内盐加入酸而制备的，并且不产生不想要的毒性作用或副作用的所有可药用盐。通过酸加成形成盐在药学技术领域中是广为人知的。
这种盐的实例为(尽管不只有这些)：氯化物、溴化物、乳清酸盐、天冬氨酸盐、酸式天冬氨酸盐、柠檬酸盐、酸式柠檬酸盐、柠檬酸镁、磷酸盐、酸式磷酸盐、富马酸盐、酸式富马酸盐、富马酸镁、甘油磷酸盐、乳酸盐、马来酸盐和酸式马来酸盐、粘酸盐、草酸盐、酸式草酸盐、双羟萘酸盐、酸式双羟萘酸盐、硫酸盐、酸式硫酸盐、葡萄糖磷酸盐、酒石酸盐、酸式酒石酸盐、酒石酸镁、2-氨基乙磺酸盐、2-氨基乙磺酸镁、甲磺酸盐、胆碱酒石酸盐、三氯乙酸盐和三氟乙酸盐。
Claims (12)
1.L-肉碱、乙酰L-肉碱和丙酰L-肉碱内盐或其可药用盐用于制备治疗精子减少精子活力不足畸形精子的药物的用途。
2.权利要求1的用途，用于制备治疗精子减少的药物。
3.权利要求1的用途，用于制备治疗精子活力不足的药物。
4.L-肉碱、乙酰L-肉碱和丙酰L-肉碱或其可药用盐用于制备治疗精子减少精子活力不足的营养组合物的用途。
5.权利要求4的用途，用于制备治疗精子减少的营养组合物。
6.权利要求4的用途，用于制备治疗精子活力不足的营养组合物。
7.权利要求1或4的用途，其中所述可药用盐选自氯化物、溴化物、乳清酸盐、天冬氨酸盐、酸式天冬氨酸盐、柠檬酸盐、酸式柠檬酸盐、柠檬酸镁、磷酸盐、酸式磷酸盐、富马酸盐、酸式富马酸盐、富马酸镁、甘油磷酸盐、乳酸盐、马来酸盐和酸式马来酸盐、粘酸盐、草酸盐、酸式草酸盐、双羟萘酸盐、酸式双羟萘酸盐、硫酸盐、酸式硫酸盐、葡萄糖磷酸盐、酒石酸盐、酸式酒石酸盐、酒石酸镁、2-氨基乙磺酸盐、2-氨基乙磺酸镁、甲磺酸盐、胆碱酒石酸盐、三氯乙酸盐和三氟乙酸盐。
8.权利要求1或4的用途，其中L-肉碱与乙酰L-肉碱和丙酰L-肉碱或其可药用盐的摩尔比范围从2.48∶0.098∶0.092-0.186∶0.98∶0.92。
9.权利要求1或4的用途，其中L-肉碱与乙酰L-肉碱和丙酰L-肉碱或其可药用盐的摩尔比范围从2.48∶0.49∶0.46-0.62∶0.49∶0.46。
10.权利要求1或4的用途，其中L-肉碱与乙酰L-肉碱和丙酰L-肉碱或其可药用盐的摩尔比范围从2.48∶0.98∶0.92-1.24∶0.49∶0.23。
11.权利要求8的用途，其中单位剂型所述药物或营养组合物含有4.0g-0.30g的L-肉碱内盐，0.20-2.0g的乙酰L-肉碱内盐，和0.20g-2.0g的丙酰L-肉碱内盐，或等摩尔量的其可药用盐。
12.权利要求11的用途，其中所述单位剂型含有2g的L-肉碱内盐，1g的乙酰L-肉碱内盐和0.5g的丙酰L-肉碱内盐或等摩尔量的其可药用盐。
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| EP2429299B1 (en) * | 2009-05-01 | 2016-06-01 | Celloxess Llc | Treating male infertility secondary to sperm oxidative stress |
| US20110015154A1 (en) * | 2009-07-20 | 2011-01-20 | Kellermann Gottfried H | Supporting acetylcholine function |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0539336A1 (en) * | 1991-10-21 | 1993-04-28 | Sigma-Tau Industrie Farmaceutiche Riunite S.p.A. | Use of L-carnitine or of acyl L-carnitine for the treatment of idiopathic oligoasthenospermias |
| CN1284871A (zh) * | 1997-12-01 | 2001-02-21 | 希格马托保健科学股份公司 | 增加人类精子的浓度和运动性的组合物及方法 |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109999042A (zh) * | 2019-05-16 | 2019-07-12 | 北京华睿鼎信科技有限公司 | 包含脱氢表雄酮或其硫酸酯、左卡尼汀、乙酰左卡尼汀或它们的可药用盐的组合物及其应用 |
| CN109999042B (zh) * | 2019-05-16 | 2021-05-18 | 北京华睿鼎信科技有限公司 | 包含脱氢表雄酮或其硫酸酯、左卡尼汀、乙酰左卡尼汀或它们的可药用盐的组合物及其应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| DK1492521T3 (da) | 2010-11-22 |
| DE60333742D1 (de) | 2010-09-23 |
| PL372924A1 (en) | 2005-08-08 |
| EP1492521B1 (en) | 2010-08-11 |
| SI1492521T1 (sl) | 2010-12-31 |
| WO2003084526A1 (en) | 2003-10-16 |
| KR20040098005A (ko) | 2004-11-18 |
| ATE476974T1 (de) | 2010-08-15 |
| US20050107470A1 (en) | 2005-05-19 |
| EP1492521A1 (en) | 2005-01-05 |
| ITRM20020194A0 (it) | 2002-04-09 |
| CA2478674C (en) | 2010-10-19 |
| JP2006505499A (ja) | 2006-02-16 |
| AU2003224443A1 (en) | 2003-10-20 |
| JP4663987B2 (ja) | 2011-04-06 |
| BR0309055A (pt) | 2005-02-22 |
| US8415392B2 (en) | 2013-04-09 |
| PT1492521E (pt) | 2010-11-11 |
| AU2003224443B2 (en) | 2008-09-11 |
| US20090012169A1 (en) | 2009-01-08 |
| CY1111273T1 (el) | 2015-08-05 |
| MXPA04009763A (es) | 2004-12-13 |
| PL214859B1 (pl) | 2013-09-30 |
| ITRM20020194A1 (it) | 2003-10-09 |
| CN1638754A (zh) | 2005-07-13 |
| CA2478674A1 (en) | 2003-10-16 |
| ES2350338T3 (es) | 2011-01-21 |
| HK1078460A1 (en) | 2006-03-17 |
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