CN109223781B - 一种治疗锂盐所致肾损伤的药物及其用途 - Google Patents
一种治疗锂盐所致肾损伤的药物及其用途 Download PDFInfo
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- 229910003002 lithium salt Inorganic materials 0.000 title claims abstract description 32
- 159000000002 lithium salts Chemical class 0.000 title claims abstract description 32
- 206010061481 Renal injury Diseases 0.000 title claims abstract description 30
- 239000003814 drug Substances 0.000 title claims abstract description 27
- 208000037806 kidney injury Diseases 0.000 title claims abstract description 19
- 229940079593 drug Drugs 0.000 title abstract description 10
- FNGGIPWAZSFKCN-ACRUOGEOSA-N tabersonine Chemical compound N1C2=CC=CC=C2[C@]2([C@H]34)C1=C(C(=O)OC)C[C@]3(CC)C=CCN4CC2 FNGGIPWAZSFKCN-ACRUOGEOSA-N 0.000 claims abstract description 47
- JSLDLCGKZDUQSH-RTBUJCADSA-N 19-epivindolinine Natural products O=C(OC)[C@H]1[C@@]23[C@H](C)[C@]4([C@@H]5N(CC=C4)CC[C@]25c2c(N3)cccc2)C1 JSLDLCGKZDUQSH-RTBUJCADSA-N 0.000 claims abstract description 45
- KILNDJCLJBOWAN-UHFFFAOYSA-N Tabersonine Natural products CCC12CC(=C3N(C)c4cc(OC)ccc4C35CCN(CC=C1)C25)C(=O)OC KILNDJCLJBOWAN-UHFFFAOYSA-N 0.000 claims abstract description 45
- FNGGIPWAZSFKCN-UHFFFAOYSA-N xi-tabersonine Natural products N1C2=CC=CC=C2C2(C34)C1=C(C(=O)OC)CC3(CC)C=CCN4CC2 FNGGIPWAZSFKCN-UHFFFAOYSA-N 0.000 claims abstract description 45
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- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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Abstract
本发明属于医药领域,具体涉及一种治疗锂盐所致肾损伤的药物及其用途。所述治疗锂盐所致肾损伤的药物的活性成分为它波宁和一种巯基抗氧化剂,其中巯基抗氧化剂优选为N‑乙酰半胱氨酸。所述药物优选为口服片剂,药用辅料优选为乳糖、微晶纤维素、羟丙纤维素、羧甲淀粉钠、硬脂酸镁、聚乙二醇6000、聚维酮。上述药物对锂盐所致肾损伤的肾脏病理改变及具体症状均具有改善作用。
Description
技术领域
本发明属于医药领域,具体涉及一种治疗锂盐所致肾损伤的药物及其用途。
背景技术
金属盐类药物已在人类疾病治疗中得到广泛应用,如铁盐、钙盐、锂盐等。其中锂盐如碳酸锂的口服制剂已被批准用于治疗躁狂症,对躁狂、抑郁交替发作的双相情感障碍性精神病有很好的治疗和预防作用,对反复发作抑郁症也有预防发作作用,也可用于治疗***-情感性精神病。
对于精神类疾病的治疗而言,药物往往需要长期使用,以维持对精神活动的控制效果。而药物长期使用往往会对脏器产生损伤。早在1876年,人类已经注意到锂对肾脏的影响,随后关于锂引起急性肾损伤如肾衰竭的报道逐渐增多。锂制剂引起慢性肾损害的报道最早见于1977年。
锂盐所致肾损伤医学上也称为锂肾病(lithium nephropathy),其具体表现包括多尿、小管细胞变性和坏死等。据统计,长期服用锂制剂的患者中,约50%的患者会出现尿浓缩功能障碍,约20%的患者出现多尿症,甚至出现肾小球滤过率受损。
急性锂中毒可通过催吐、血液透析等进行紧急处理。锂盐所致急性肾损伤往往在停药后可以自行恢复,但对于长期服用锂制剂导致的慢性损伤如肾损伤,目前尚缺乏针对性的治疗药物。大多数药物仅能够缓解锂制剂所致损伤的某部分病理变化或临床症状。如对于锂盐所致肾损伤,N-乙酰半胱氨酸能够改善肌酐、尿素氮、肾小球滤过率等指标和肾小管坏死等病理改变,但对锂盐所致肾损伤伴随的多尿症却缺乏治疗作用。乙酰唑胺被证明能够改善锂盐所致肾损伤伴随的多尿症,但对尿浓缩功能无改善作用。
基于上述原因,目前临床上仍需要针对锂盐所致肾损伤的肾脏保护药物,以便提高患者的用药安全。
发明内容
针对上述现有技术,本发明的目的之一是提供一种治疗锂盐所致肾损伤的药物。
为实现上述的目的,本发明采用的技术方案为:
一种治疗锂盐所致肾损伤的药物,由它波宁、一种巯基抗氧化剂和医药学上可接受的药用辅料制成。
优选的,所述巯基抗氧化剂为N-乙酰半胱氨酸。
优选的,所述治疗锂盐所致肾损伤的药物的制剂剂型为口服片剂。
优选的,所述治疗锂盐所致肾损伤的药物中它波宁和N-乙酰半胱氨酸的重量份比为它波宁1重量份、N-乙酰半胱氨酸10~20重量份。
优选的,所述治疗锂盐所致肾损伤的药物中它波宁和N-乙酰半胱氨酸的重量份比为它波宁1重量份、N-乙酰半胱氨酸10重量份。
优选的,所述治疗锂盐所致肾损伤的药物中它波宁和N-乙酰半胱氨酸的重量份比为它波宁1重量份、N-乙酰半胱氨酸15重量份。
优选的,所述治疗锂盐所致肾损伤的药物中它波宁和N-乙酰半胱氨酸的重量份比为它波宁1重量份、N-乙酰半胱氨酸20重量份。
优选的,所述口服片剂的医药学上可接受的药用辅料包括乳糖、微晶纤维素、羟丙纤维素、羧甲淀粉钠、硬脂酸镁、聚乙二醇6000、聚维酮。
优选的,所述口服片剂中乳糖的用量为它波宁重量的28倍、微晶纤维素的用量为它波宁重量的16倍、羟丙纤维素的用量为它波宁重量的4倍、羧甲淀粉钠的用量为它波宁重量的2.4倍、硬脂酸镁的用量为它波宁重量的3.6倍、聚乙二醇6000的用量为它波宁重量的3.2倍。
本发明的另一方面,还提供了上述治疗锂盐所致肾损伤的药物在制备锂盐所致肾损伤治疗药物中的用途。
本发明的技术方案中 “它波宁”,也称为它勃宁,英文名称为Tabersonine,CAS号为4429-63-4;本发明的技术方案中 “N-乙酰半胱氨酸”;即N-乙酰-L-半胱氨酸,CAS号为616-91-1;本发明的技术方案中“羧甲淀粉钠” 也称为羧甲基淀粉钠、淀粉乙醇酸钠等,在片剂中常用作崩解剂、黏合剂等;本发明的技术方案中“聚乙二醇6000” 在片剂中常用作粘合剂;本发明的技术方案中“聚维酮”也称为聚乙烯吡咯烷酮,通常片剂中使用的是聚维酮K30、聚维酮K32、聚维酮K25、聚维酮K90,在片剂中可用作粘合剂,一般先配置成3%~5%的水溶液(W/W)然后用于片剂制备。
实验研究显示,它波宁对锂盐所致肾损伤具有一定的改善效果,包括对多尿症状的显著改善以及对肾脏病理改变的改善。N-乙酰半胱氨酸则对锂盐所致肾脏病理改变具有改善作用,对多尿症状缺乏效果。二者联合使用对锂盐所致肾损伤的外显症状及微观病理改变均具有显著的改善效果。。对于锂盐所致肾损伤患者,推荐的人体口服剂量为它波宁每次2.5mg,每日1至2次、N-乙酰半胱氨酸每次25~50 mg,每日1至2次。
具体实施方式
下面结合实施例对本发明作进一步的解释。应当理解的是,以下实施例仅用于解释本发明,而不是限制本发明的保护范围。
实施例1 治疗锂盐所致肾损伤的口服片剂
组方:
它波宁 25g
N-乙酰半胱氨酸 250g
乳糖 700g
微晶纤维素 400g
羟丙纤维素 100g
羧甲淀粉钠 60g
硬脂酸镁 90g
聚乙二醇6000 80g
聚维酮K30 61g
取处方量它波宁、N-乙酰半胱氨酸、乳糖、微晶纤维素、羟丙纤维素、羧甲淀粉钠、硬脂酸镁、聚乙二醇6000、聚维酮K30分别粉碎过80目筛;
取处方量聚维酮K30加水配制成浓度为5%的水溶液;
取处方量它波宁、N-乙酰半胱氨酸、乳糖、羟丙纤维素、聚乙二醇6000和200g微晶纤维素混合均匀,然后用聚维酮K30水溶液制备软材,过40目筛制粒,60℃烘干,然后与200g微晶纤维素、处方量羧甲淀粉钠和处方量硬脂酸镁混合压成10000片。
实施例2 治疗锂盐所致肾损伤的口服片剂
组方:
它波宁 25g
N-乙酰半胱氨酸 375g
乳糖 700g
微晶纤维素 400g
羟丙纤维素 100g
羧甲淀粉钠 60g
硬脂酸镁 90g
聚乙二醇6000 80g
聚维酮K30 61g
取处方量它波宁、N-乙酰半胱氨酸、乳糖、微晶纤维素、羟丙纤维素、羧甲淀粉钠、硬脂酸镁、聚乙二醇6000、聚维酮K30分别粉碎过80目筛;
取处方量聚维酮K30加水配制成浓度为5%的水溶液;
取处方量它波宁、N-乙酰半胱氨酸、乳糖、羟丙纤维素、聚乙二醇6000和200g微晶纤维素混合均匀,然后用聚维酮K30水溶液制备软材,过40目筛制粒,60℃烘干,然后与200g微晶纤维素、处方量羧甲淀粉钠和处方量硬脂酸镁混合压成10000片。
实施例3 治疗锂盐所致肾损伤的口服片剂
组方:
它波宁 25g
N-乙酰半胱氨酸 500g
乳糖 700g
微晶纤维素 400g
羟丙纤维素 100g
羧甲淀粉钠 60g
硬脂酸镁 90g
聚乙二醇6000 80g
聚维酮K30 61g
取处方量它波宁、N-乙酰半胱氨酸、乳糖、微晶纤维素、羟丙纤维素、羧甲淀粉钠、硬脂酸镁、聚乙二醇6000、聚维酮K30分别粉碎过80目筛;
取处方量聚维酮K30加水配制成浓度为5%的水溶液;
取处方量它波宁、N-乙酰半胱氨酸、乳糖、羟丙纤维素、聚乙二醇6000和200g微晶纤维素混合均匀,然后用聚维酮K30水溶液制备软材,过40目筛制粒,60℃烘干,然后与200g微晶纤维素、处方量羧甲淀粉钠和处方量硬脂酸镁混合压成10000片。
实施例4 对锂盐所致肾损伤的改善作用研究
一、造模、分组及给药
Sprague Dawley 大鼠,体重200g~250g,雄性。大鼠分笼饲养,在第1周,每日将饮用水换为浓度为15%的LiCl水溶液(W/W),每只大鼠每日给予15mL LiCl水溶液,待LiCl水溶液消耗完毕再更换为蒸馏水,如此饲喂7天。第2周采用蒸馏水作为大鼠饮用水,正常饲喂7天;第3周,每日将饮用水换为浓度为7%的LiCl水溶液(W/W),每只大鼠每日给予15mL LiCl水溶液,待LiCl水溶液消耗完毕再更换为蒸馏水,如此饲喂7天。
第4周开始将存活大鼠随机分为5组,每组6只:
第1组为模型组,灌胃给予生理盐水,每只大鼠每次1mL,每日两次(早6时、晚18时);
第2组为它波宁组,灌胃给予它波宁生理盐水混悬液,每只大鼠每次1mL,每日两次(早6时、晚18时),每次每只大鼠给予它波宁0.05mg。
第3组为N-乙酰半胱氨酸组,灌胃给予N-乙酰半胱氨酸生理盐水溶液,每只大鼠每次1mL,每日两次(早6时、晚18时),每次每只大鼠给予N-乙酰半胱氨酸2mg。
第4组为它波宁+N-乙酰半胱氨酸组(1:10),灌胃给予含它波宁和N-乙酰半胱氨酸的生理盐水混悬液,每只大鼠每次1mL,每日两次(早6时、晚18时),每次每只大鼠给予它波宁0.05 mg、N-乙酰半胱氨酸0.5mg。
第5组为它波宁+N-乙酰半胱氨酸组(1:20),灌胃给予含它波宁和N-乙酰半胱氨酸的生理盐水混悬液,每只大鼠每次1mL,每日两次(早6时、晚18时),每次每只大鼠给予它波宁0.05 mg、N-乙酰半胱氨酸1mg。
第5周,每日将饮用水换为浓度为5%的LiCl水溶液(W/W),每只大鼠每日给予15mLLiCl水溶液,待LiCl水溶液消耗完毕再更换为蒸馏水,如此饲喂7天。然后将各组大鼠分别合笼饲养。
各组大鼠均连续给药4周,即自第4周开始,每日给药2次,直至第7周,共给药28天。
二、指标及观察和测定方法
1.尿量的计量
第8周第1天即最后一次给药后次日,大鼠禁食禁水24小时;第8周第2天大鼠自由摄食摄水,并收集大鼠24小时尿液,计算各组大鼠24小时内的平均尿液体积(mL)。
2.肾脏病理改变评价
第8周第3天将各组大鼠处死,取肾脏,由病理技术人员常规制备石蜡切片,苏木精-伊红染色,光镜下对各组大鼠肾脏病理改变进行观察。400倍视野下,随机选取一个视野,按照肾小管坏死面积占肾小管总面积的百分比进行评分。0分::肾小管坏死面积<5%;1分:肾小管坏死面积<20%但≥5%;2分:肾小管坏死面积<40%但≥20%;3分:肾小管坏死面积<60%但≥40%;4分:肾小管坏死面积<80%但≥60%;5分:肾小管坏死面积≥80%。每组大鼠的肾脏病理评分以该组每只大鼠的肾脏病理评分均值表示。
各组大鼠尿液体积及肾脏病理评分的组间比较采用t检验,P<0.05视为差异具有统计学意义。
四、实验结果
各组大鼠尿液体积及肾脏病理评分统计结果见下表。
表中,a表示与第1组相比p<0.05,b表示与第1组相比p<0.01。
由上表可见:从尿液体积分析,第3组即N-乙酰半胱氨酸组尿液体积与模型组无显著差异(p>0.05),其他各组尿液体积均显著低于第1组即模型组(p<0.01)。说明N-乙酰半胱氨酸对氯化锂所致慢性肾损伤的多尿症状无显著改善作用,但它波宁以及它波宁与N-乙酰半胱氨酸的组合物能够显著减少模型大鼠的多尿症状。从肾脏病理评分分析,第2、3组即它波宁和N-乙酰半胱氨酸单独给药组的肾脏病理评分均显著低于第1组(p<0.05),第4、5组的病理评分更低,说明它波宁和N-乙酰半胱氨酸单独或联合给药均可降低氯化锂所致的肾脏病理改变,二者联合使用的效果更优。
Claims (1)
1.一种组合物在制备单纯由锂盐所致肾损伤的治疗药物中的用途,其特征在于,所述组合物由它波宁、N-乙酰半胱氨酸和医药学上可接受的药用辅料制成,所述组合物中它波宁和N-乙酰半胱氨酸的重量份比为它波宁1重量份、N-乙酰半胱氨酸10~20重量份,所述组合物的制剂剂型为口服片剂。
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