CN1193911A - 用于降低神经酰胺水平的碱性氨基酸和衍生物的应用 - Google Patents
用于降低神经酰胺水平的碱性氨基酸和衍生物的应用 Download PDFInfo
- Publication number
- CN1193911A CN1193911A CN96196528A CN96196528A CN1193911A CN 1193911 A CN1193911 A CN 1193911A CN 96196528 A CN96196528 A CN 96196528A CN 96196528 A CN96196528 A CN 96196528A CN 1193911 A CN1193911 A CN 1193911A
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- Prior art keywords
- acid
- basic amino
- amino acid
- purposes
- ceramide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- YDNKGFDKKRUKPY-JHOUSYSJSA-N C16 ceramide Natural products CCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)C=CCCCCCCCCCCCCC YDNKGFDKKRUKPY-JHOUSYSJSA-N 0.000 title claims abstract description 55
- CRJGESKKUOMBCT-VQTJNVASSA-N N-acetylsphinganine Chemical compound CCCCCCCCCCCCCCC[C@@H](O)[C@H](CO)NC(C)=O CRJGESKKUOMBCT-VQTJNVASSA-N 0.000 title claims abstract description 55
- 229940106189 ceramide Drugs 0.000 title claims abstract description 55
- ZVEQCJWYRWKARO-UHFFFAOYSA-N ceramide Natural products CCCCCCCCCCCCCCC(O)C(=O)NC(CO)C(O)C=CCCC=C(C)CCCCCCCCC ZVEQCJWYRWKARO-UHFFFAOYSA-N 0.000 title claims abstract description 55
- VVGIYYKRAMHVLU-UHFFFAOYSA-N newbouldiamide Natural products CCCCCCCCCCCCCCCCCCCC(O)C(O)C(O)C(CO)NC(=O)CCCCCCCCCCCCCCCCC VVGIYYKRAMHVLU-UHFFFAOYSA-N 0.000 title claims abstract description 55
- 229940093740 amino acid and derivative Drugs 0.000 title 1
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- 238000011282 treatment Methods 0.000 claims abstract description 13
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- PHIQHXFUZVPYII-ZCFIWIBFSA-N (R)-carnitine Chemical compound C[N+](C)(C)C[C@H](O)CC([O-])=O PHIQHXFUZVPYII-ZCFIWIBFSA-N 0.000 claims description 13
- 229940079593 drug Drugs 0.000 claims description 8
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- IGQBPDJNUXPEMT-SNVBAGLBSA-N isovaleryl-L-carnitine Chemical compound CC(C)CC(=O)O[C@H](CC([O-])=O)C[N+](C)(C)C IGQBPDJNUXPEMT-SNVBAGLBSA-N 0.000 claims description 5
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- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
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- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 3
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 claims description 3
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 3
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- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
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- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 2
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
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- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
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Classifications
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Abstract
本发明公开了碱性氨基酸、酰化的碱性氨基酸和它们的药用盐的治疗应用,用于制备预防疾病或者治疗性处理伴随有高神经酰胺水平的细胞疾病的药物。
Description
本发明涉及碱性氨基酸、酰化的碱性氨基酸和它们的药用盐的新的治疗应用,用于疾病的预防或者治疗性处理伴随有高神经酰胺水平的细胞疾病。具体地说,本发明涉及L-肉毒碱、L-肉毒碱酰基衍生物和其药用盐的应用,用于疾病的预防或者治疗性处理伴随有高神经酰胺水平的细胞疾病。
神经酰胺是神经鞘脂类结构和其代谢物的碱性分子。所有的神经鞘脂类都含有神经酰胺作为主要的亲水组分并且是由神经酰胺通过生物合成途径产生的,在该合成中主要修饰了分子结构的1-羟基位置,而神经鞘脂类在跨细胞膜的信号转导中起着重要的作用。
神经酰胺在跨细胞膜的信号转导中起着重要的作用。能够对胞内受体(如钙三醇)或跨膜受体[如γ-干扰素(IFN-γ)、白细胞介素-1(IL-1)和神经生长因子(NGF)]起作用的分子将神经磷脂水解成为神经酰胺。神经酰胺活化磷酸酶和蛋白激酶,并且由生物学的观点看,能够诱导细胞的编程性细胞死亡、生长和细胞的分化,调整环氧酶和磷脂酶的表达和kB核因子(NFkB)的活性[Kuno,K.等,J.Leukoc Biol.,56(5):542-7;Cifone,M.G.等,J.Exp.Med.,180(4):1547-52;Kolesnick R.,Mol.Chem.Neuropathol.,21(2-3):287-97;Jarvis,W.D.等,Proc.Natl.Acad.Sci.U.S.A.,91(1):73-7;Obeid,L.M.等,Science,259(5102):1769-71]。
已经发现神经酰胺浓度或代谢的变化对导致许多疾病起作用或者会诱导代谢细胞失调。不幸地是,到目前为止还没有办法降低体内的神经酰胺水平。
相应的,本发明的一个目的是提供碱性氨基酸、酰化的碱性氨基酸和其药用盐用于降低体内神经酰胺水平的新用途。
本发明的第二个目的是提供碱性氨基酸、酰化的碱性氨基酸和其药用盐在疾病的预防或者治疗性处理伴随有高神经酰胺水平的细胞疾病方面的新用途。
事实上,已经发现施用大剂量的碱性氨基酸、低分子量的碱性化合物或其酰基衍生物和其药用盐可降低神经酰胺水平并且这些化合物可被用于治疗以高神经酰胺水平为特征的疾病。
具体地说,已经发现碱性氨基酸如精氨酸、赖氨酸、组氨酸、鸟氨酸和肉毒碱,或其酰基衍生物和其药用盐可用于治疗以高神经酰胺水平为特征的疾病。
按照本发明,提供了碱性氨基酸、碱性氨基酸酰基衍生物和其药用盐降低体内神经酰胺水平的新用途。
适当的碱性氨基酸包括带有碱性电荷的任何氨基酸,例如精氨酸、赖氨酸、组氨酸、鸟氨酸和肉毒碱。这些化合物是可以买到的。优选的,是使用L-氨基酸。更优选的,是使用肉毒碱。这些化合物可以游离氨基酸或其药用盐的形式使用。
在本发明中也可以使用碱性氨基酸的酰基衍生物。可以使用直链或支链的C2-6酰基氨基酸。对药理学家和药学技术领域的熟练人员而言这些酸是熟知的。特别优选的酰基基团是乙酰基、丙酰基、丁酰基、戊酰基和异戊酰基。
适当的药用盐可以是由上述碱性氨基酸和任何常规的阴离子形成的,这些阴离子例如氯、溴、碘、或酸天门冬氨酸如天门冬氨酸根、酸性柠檬酸根如柠檬酸根、酸性酒石酸根如酒石酸根、酸性磷酸根如磷酸根、酸性富马酸根、糖磷酸根如葡糖磷酸根、酸性乳酸根、酸性马来酸根、乳清酸、酸性草酸根,特别是草酸,硫酸、特别优选硫酸根、三氯乙酸根、三氟乙酸根和甲磺酸根。
以升高的神经酰胺水平为特征的疾病或失调的实例包括炎性肠疾病、播散性血管内凝血、发烧、蛋白质分解代谢和/或脂类消耗、与感染或代谢性肝疾病有关的肝脾肿大、心肌内膜炎、内皮细胞和白细胞激活、毛细血管血栓形成、由于传染物引起的脑膜脑炎、器官移植、类风湿关节炎和***的疾病,以及自身免疫疾病、甲状腺机能亢进、放射和/或化学治疗损伤以及慢性疲劳综合症。
由于使用某些药物也会产生高水平的神经酰胺,因此本发明也考虑了降低使用这些药物的患者的神经酰胺水平。例如,按照本发明的碱性氨基酸可以和下述药品一起用药以防止神经酰胺水平提高:皮质类甾醇(如***)、抗炎药(如吲哚美辛)、抗病毒药(如干扰素)、免疫抑制剂(如环孢菌素)、化学治疗剂(如阿霉素(adriamicin))、免疫强化剂(如免疫球蛋白和疫苗)和内分泌制剂(如metimazole)。
健康人正常的神经酰胺水平取决于个体的年龄、大小和体重,但是通常在5至50微微摩尔/106细胞(优选的是外周血的淋巴细胞)的范围内。高于50微微摩尔/106细胞时被认为是高水平。应用本发明的碱性氨基酸、酰化的碱性氨基酸和其药用盐至少可使此高水平降低25%。
一般来说,以至少可使神经酰胺水平降低25%的浓度给予本发明的碱性氨基酸。适当的,通过口服或肠胃外给予50mg至大约15g/天碱性氨基酸可得到此结果。优选的,应该大剂量的给予这些碱性氨基酸,例如每天的剂量大于1g,或大于2g;特别优选每天4-10g。
监测神经酰胺水平可以通过直接监测细胞中(如淋巴细胞)的神经酰胺水平,或者可以间接地监测细胞中神经酰胺代谢物的浓度。优选的,为了评价减少的数量,在施用碱性氨基酸之前和之后监测患者的神经酰胺水平。监测可在用药后的任何时间开始,但是适当的是开始于用药后3小时以得到准确的结果。监测可无限期的延长。
神经酰胺水平可用下述方法直接测定:由患者的外周血分离出淋巴细胞,然后离心细胞除去清液,并由细胞沉淀中除去脂类,按照“DAG激酶试验”方法对含有神经酰胺的有机相进行试验,以使神经酰胺磷酰化,然后用放射性自显影法进行检测[Cifone,M.G.等,J.Exp.Med.,180(4):1547-52]。
在对本发明进行了一般的描述之后,参考下面提供的一些具体的实施例可进一步地理解本发明,除非另有说明,这些实施例仅仅是说明而不限制本发明。
实施例1
用常规的方法分离出外周血的淋巴细胞,该细胞与L-肉毒碱或异戊酰基L-肉毒碱(200mcg/ml)于37℃一起孵化30分钟,然后与抗Fas单克隆抗体一起孵化30分钟,离心细胞,除去清液,将细胞沉淀脱脂。按照“DAG激酶试验”方法对有机相(含有神经酰胺)进行试验,使神经酰按磷酰化,然后用放射性自显影法进行检测。
结果列于下表1。
表1
神经酰胺
(微微摩尔/106细胞)对照 20对照+抗Fas抗体 81.6对照+抗Fas抗体+L-肉毒碱(100mcg/ml) 7.3对照+抗Fas抗体+异戊酰基L-肉毒碱(50mcg/ml) 8.6对照+抗Fas抗体+异戊酰基L-肉毒碱(100mcg/ml) 7.3
已经知道适当的刺激细胞(例如用Fas-L,白细胞介素-1等)产生神经酰胺。用抗Fas抗体可增加神经酰胺生成,将基础数值(每106细胞中20微微摩尔)提高到每106细胞中81.6微微摩尔。
由此看出L-肉毒碱和异戊酰基L-肉毒碱能够在体外抑制神经酰胺的合成。
实施例2
使两名神经肌病(慢性疲劳综合症)的患者每天口服3克(g)L-肉毒碱。共服用2个月以进行治疗。
在用药之前和之后测定肌肉中的神经酰胺。
结果列于下表2。
表2
神经酰胺 神经酰胺
治疗前 治疗后
(每mg蛋白质微微摩尔) (每mg蛋白质微微摩尔)患者1 76 28患者2 142 46
实施例3
四名甲状腺机能亢进的患者,他们已经用metimazole(每天口服15mg)治疗8个月以上,这些患者以每天口服8g L-肉毒碱。共服用4周进行治疗。
在治疗之前和之后测定与淋巴细胞相关的神经酰胺。
结果列于下表3。
表3
神经酰胺 神经酰胺
治疗前 治疗后
(微微摩尔/106细胞) (微微摩尔/106细胞)患者1 73 26患者2 45 27患者3 111 36患者4 69 18
实施例4
对三名由于丙型病毒肝炎引起肝脾肿大的患者通过静脉用4g L-肉毒碱药团进行治疗。
在输注前和输注后3和48小时测定与淋巴细胞相关的神经酰胺。
结果列于下表4。
表4
患者1 患者1 患者3
神经酰胺 神经酰胺 神经酰胺
(微微摩尔/106细胞) (微微摩尔/106细胞) (微微摩尔/106细胞)治疗前 65 77 793小时后 12 32 2448小时后 31 21 23
很显然在输注L-肉毒碱药团3小时之后就已经抑制了神经酰胺水平的提高。其作用至少保持了2天。
实施例5
对两名由于结核感染造成的蛋白质分解代谢和脂类消耗的患者进行治疗,每天通过肠胃外给予8g L-肉毒碱。共给药2周。
在用药之前和之后测定与外周血淋巴细胞相关的神经酰胺。
结果列于下表5。
表5
神经酰胺 神经酰胺
治疗前 治疗后
(微微摩尔/106细胞) (微微摩尔/106细胞)患者1 127 59患者2 265 77患者3 301 152患者4 78 54
现在,对本发明已经做了清楚的描述,显然对本领域普通技术人员而言在不脱离如下文要求保护的本发明的实质和范围的情况下可以对其进行很多变化和改进。
Claims (15)
1.碱性氨基酸、酰化的碱性氨基酸和它们的药用盐在制备预防疾病或治疗伴有高神经酰胺水平的细胞疾病的药物中的用途。
2.根据权利要求1的用途,其中以高水平的神经酰胺为特征的疾病或失调包括炎性肠疾病、播散性血管内凝血、发烧、蛋白质分解代谢和/或脂类消耗、与感染或代谢性肝疾病有关的肝脾肿大、心肌内膜炎、内皮细胞和白细胞激活、毛细血管血栓形成、由于传染物引起的脑膜脑炎、器官移植、类风湿关节炎和***的疾病,以及自身免疫疾病、甲状腺机能亢进、放射和/或化学治疗损伤以及慢性疲劳综合症。
3.根据权利要求1或2的用途,其中碱性氨基酸、酰化的碱性氨基酸或它们的药用盐可与皮质类甾醇、抗炎药、抗病毒药、免疫抑制剂、细胞抑制剂、免疫强化剂和内分泌制剂一起用药。
4.根据前述任意一项权利要求的用途,其中的碱性氨基酸是精氨酸、赖氨酸、组氨酸、鸟氨酸和肉毒碱。
5.根据权利要求4的用途,其中的碱性氨基酸是L-肉毒碱。
6.根据权利要求1-3中任意一项的用途,其中所述碱性氨基酸的酰基基团选自乙酰基、丙酰基、丁酰基、戊酰基和异戊酰基。
7.根据权利要求6的用途,其中的所述的酰化碱性氨基酸是异戊酰基L-肉毒碱。
8.根据权利要求1-3中任意一项的用途,其中所述药用盐的阴离子选自氯、溴、碘、或酸性天门冬氨酸根、酸性柠檬酸根、酸性酒石酸根、酸性磷酸根、酸性富马酸根、糖磷酸根、酸性乳酸根、酸性马来酸根、乳清酸根、酸性草酸根和硫酸根。
9.根据权利要求8的用途,其中所述阴离子是硫酸根、三氯乙酸根、三氟乙酸根或甲磺酸根。
10.根据权利要求1的用途,其中口服或肠胃外给药的日剂量是50mg至15g。
11.根据权利要求10的用途,其中口服或肠胃外给药的日剂量是4至10g。
12.用于预防疾病或治疗伴有高神经酰胺水平的细胞疾病的口服或肠胃外给药的药物组合物,该组合物包括能有效的降低神经酰胺水平的活性组分量的碱性氨基酸、酰化的碱性氨基酸或它们的药用盐,和至少一种药学上可接受的赋形剂。
13.根据权利要求12的口服或肠胃外给药的药物组合物,其中以高水平的神经酰胺为特征的疾病或失调包括炎性肠疾病、播散性血管内凝血、发烧、蛋白质分解代谢和/或脂类消耗、与感染或代谢性肝疾病有关的肝脾肿大、心肌内膜炎、内皮细胞和白细胞激活、毛细血管血栓形成、由于传染物引起的脑膜脑炎、器官移植、类风湿关节炎和***的疾病,以及自身免疫疾病、甲状腺机能亢进、放射和/或化学治疗损伤和慢性疲劳综合症。
14.根据权利要求12或13的组合物,适于口服或肠胃外给药的剂量是50mg至15g/天碱性氨基酸。
15.根据权利要求12或13的组合物,适于口服或肠胃外给药的剂量是4g至10g/天碱性氨基酸。
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WO2002060431A1 (fr) * | 2001-01-30 | 2002-08-08 | Ajinomoto Co., Inc. | Medicaments therapeutiques/prophylactiques contre des maladies inflammatoires |
US20080145424A1 (en) * | 2002-10-24 | 2008-06-19 | Enos Phramaceuticals, Inc. | Sustained release L-arginine formulations and methods of manufacture and use |
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IL156670A0 (en) * | 2003-06-26 | 2004-01-04 | Zvi Zolotariov | Aloe suppositories |
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JP2007055900A (ja) * | 2003-12-15 | 2007-03-08 | Ajinomoto Co Inc | 炎症性疾患の治療及び予防用医薬組成物 |
US20050232911A1 (en) * | 2004-04-19 | 2005-10-20 | Schreiber Brian D | Prevention and treatment of metabolic abnormalities associated with excess intramyocellular lipid |
EA019268B1 (ru) * | 2010-12-01 | 2014-02-28 | Общество С Ограниченной Ответственностью "Анвилаб" | Комбинированное средство, обладающее гепатопротекторным действием |
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AU518617B2 (en) * | 1977-04-29 | 1981-10-08 | Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. | Therapeutic application of acetyl-d, 1-carnitine |
DE2946563A1 (de) * | 1979-11-17 | 1981-05-21 | B. Braun Melsungen Ag, 3508 Melsungen | Aminosaeureloesung zur parenteralen infusion |
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JPH02124822A (ja) * | 1988-11-02 | 1990-05-14 | Eisai Co Ltd | セファロスポリン含有注射用組成物 |
IT1224842B (it) * | 1988-12-27 | 1990-10-24 | Sigma Tau Ind Farmaceuti | Uso di derivati della l-carnitina nel trattamento terapeutico delle alterazioni degenerative del sistema nervoso |
US6294520B1 (en) * | 1989-03-27 | 2001-09-25 | Albert T. Naito | Material for passage through the blood-brain barrier |
EP0400547A1 (en) * | 1989-06-02 | 1990-12-05 | Abbott Laboratories | Parenteral nutrition product |
IT1244636B (it) * | 1991-01-04 | 1994-08-08 | Sigma Tau Ind Farmaceuti | Uso dell'acetil l-carnitina nel trattamento terapeutico del coma e composizioni farmaceutiche utili in tale trattamento. |
IT1248321B (it) * | 1991-05-15 | 1995-01-05 | Sigma Tau Ind Farmaceuti | Uso di esteri di acil l-carnitine con l'acido gamma-idrossibutirrico per produrre composizioni farmaceutiche per il trattamento di epatopatie |
IT1254136B (it) * | 1992-01-16 | 1995-09-08 | Sigma Tau Ind Farmaceuti | Esteri di acil carnitine con alcooli alifatici a lunga catena e composizioni farmaceutiche che li contengono, ad attivita' antimicotica. |
AU6922994A (en) * | 1993-06-21 | 1995-01-17 | Bernardini, Attilio | Use of acylcarnitin to treat illnesses caused by aids |
IT1277897B1 (it) | 1995-08-03 | 1997-11-12 | Mendes Srl | Uso della l-carnitina,di suoi derivati e di loro sali farmaceuticamen- te accettabili in combinazione con farmaci antiretrovirali per ridurre |
IT1277898B1 (it) | 1995-08-03 | 1997-11-12 | Mendes Srl | Uso di amminoacidi basici, di acil derivati di amminoacidi basici e di loro sali farmaceuticamente accettabili per la profilassi di malattie |
IT1283951B1 (it) * | 1996-03-15 | 1998-05-07 | Mendes Srl | Uso della acetil l-carnitina o dei suoi sali farmacologicamente accettabili per il trattamento terapeutico o la profilassi di |
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1995
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- 1996-07-19 CN CNB961965282A patent/CN1138539C/zh not_active Expired - Fee Related
- 1996-07-19 BR BR9610106A patent/BR9610106A/pt not_active Application Discontinuation
- 1996-07-19 DK DK96924125T patent/DK0844875T3/da active
- 1996-07-19 RU RU98103503/14A patent/RU2179850C2/ru not_active IP Right Cessation
- 1996-07-19 KR KR10-1998-0700816A patent/KR100423760B1/ko not_active IP Right Cessation
- 1996-07-19 PT PT96924125T patent/PT844875E/pt unknown
- 1996-07-19 EP EP96924125A patent/EP0844875B1/en not_active Expired - Lifetime
- 1996-07-19 WO PCT/IT1996/000147 patent/WO1997005862A2/en active IP Right Grant
- 1996-07-19 JP JP9508283A patent/JPH11510182A/ja not_active Ceased
- 1996-07-19 DE DE69636792T patent/DE69636792T2/de not_active Expired - Lifetime
- 1996-07-19 US US09/000,203 patent/US6114385A/en not_active Expired - Fee Related
- 1996-07-19 CA CA002228281A patent/CA2228281C/en not_active Expired - Fee Related
- 1996-07-19 ES ES96924125T patent/ES2279523T3/es not_active Expired - Lifetime
- 1996-07-19 AT AT96924125T patent/ATE349206T1/de not_active IP Right Cessation
- 1996-07-20 TW TW085108859A patent/TW434011B/zh not_active IP Right Cessation
- 1996-08-02 AR ARP960103845A patent/AR003473A1/es not_active Application Discontinuation
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1999
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CA2228281C (en) | 2008-03-25 |
US6350782B1 (en) | 2002-02-26 |
TW434011B (en) | 2001-05-16 |
WO1997005862A3 (en) | 1997-04-17 |
ITRM950545A0 (it) | 1995-08-03 |
EP0844875B1 (en) | 2006-12-27 |
IT1277898B1 (it) | 1997-11-12 |
KR100423760B1 (ko) | 2004-08-25 |
HK1015274A1 (en) | 1999-10-15 |
DE69636792T2 (de) | 2007-10-04 |
PT844875E (pt) | 2007-02-28 |
CN1138539C (zh) | 2004-02-18 |
AU6469196A (en) | 1997-03-05 |
AU713207B2 (en) | 1999-11-25 |
ATE349206T1 (de) | 2007-01-15 |
DK0844875T3 (da) | 2007-04-10 |
ES2279523T3 (es) | 2007-08-16 |
KR19990036148A (ko) | 1999-05-25 |
US6114385A (en) | 2000-09-05 |
MX9800916A (es) | 1998-10-31 |
DE69636792D1 (de) | 2007-02-08 |
CA2228281A1 (en) | 1997-02-20 |
JPH11510182A (ja) | 1999-09-07 |
AR003473A1 (es) | 1998-08-05 |
EP0844875A2 (en) | 1998-06-03 |
ITRM950545A1 (it) | 1997-02-03 |
BR9610106A (pt) | 1999-02-23 |
RU2179850C2 (ru) | 2002-02-27 |
WO1997005862A2 (en) | 1997-02-20 |
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