CN1176652C - 褪黑激素在治疗疾病方面的应用 - Google Patents

褪黑激素在治疗疾病方面的应用 Download PDF

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CN1176652C
CN1176652C CNB008081069A CN00808106A CN1176652C CN 1176652 C CN1176652 C CN 1176652C CN B008081069 A CNB008081069 A CN B008081069A CN 00808106 A CN00808106 A CN 00808106A CN 1176652 C CN1176652 C CN 1176652C
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纳瓦·奇撒贝尔
姆士·劳丹
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Neurim Pharmaceuticals 1991 Ltd
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Abstract

本发明涉及一种抑制或治疗患者的迟发性运动障碍症状的方法，通过给予一种有效剂量的褪黑激素来达到此目的；还涉及一种药物组合物，它包含至少一种具有安定作用的化合物，其剂量为能有效地在需要接受这种治疗的患者身上产生具有安定作用的效应，和一种褪黑激素，其剂量为能有效地改善或抑制患者患有的迟发性运动障碍症状。

Description

褪黑激素在治疗疾病方面的应用
发明所属技术领域和背景技术
本发明涉及一种治疗迟发性运动障碍的方法和药物组合物。
迟发性运动障碍(TD)是一种无意识的运动失调，在曾经接受过安定药物治疗的病人中有很高的发病率。现有文献中列举有大量的文章，提出褪黑激素分泌物与TD症状的发生率之间存在反比关系。但是，据我们最了解的是，只在一种实例中，用外生的褪黑激素给药来试图确定这种关系，在该实例中发现，用氟哌啶醇对做过松果腺体切除术的老鼠进行治疗会比未进行手术的老鼠明显地导致了更严重的运动失调，随后服用褪黑激素(例如4mg)，在1小时内并没有明显地减少运动障碍的严重性(Sandyk，R.，et al.，Int.J.Neurosci.，1989，48(3-4)：303-8)。在这个不明显的结果中所用的褪黑激素的量相当于70公斤体重的人服用大于1000mg的量。因此，在后来的TD治疗试验中避免使用外生的褪黑激素是不奇怪的。例如在Sandyk，R.的美国专利5,691,324中，TD是多种条件之一，涉及到血液中的复合胺不充分传递和削弱褪黑激素的作用，通过向患者提供一种混合剂，然后对大脑施加一个磁场，以提高血液中复合胺的神经传递。美国专利5,691,324的全部内容被引用作为参考文献。
目前令人惊奇地发现，关于迟发性运动障碍，在外生的褪黑激素的用量比上述Int.J.Neurosci.报告中所用的至少下降一个数量级(考虑到人的平均体重与实验动物的关系)的剂量水平下，对人体产生了一种显著的治疗效果。
发明概述
一方面，本发明提供了一种药物组合物，该组合物包括除了至少一种载体、稀释剂或辅剂外，至少一种具有安定作用的化合物，其用量对需要接受这种治疗的患者能有效地发挥安定作用，和褪黑激素，其用量为能有效地改善或抑制患者患有的迟发性运动障碍症状。
另一方面，本发明涉及褪黑激素在用于制备抑制或治疗患者迟发性运动障碍症状的药物制剂的应用。该药物制剂优选采用药物组合物的形式，它包含下面的附加组分(a)和(b)中的至少一种：(a)至少一种载体、稀释剂或辅剂。(b)至少一种具有安定作用的化合物，其用量为对需要这种治疗的患者能有效地发挥安定作用。进一步地，本发明涉及一种抑制或治疗患者的迟发性运动障碍症状的方法，包含对表现出这种症状或其它有发生这种症状倾向的患者施用褪黑激素，其剂量为能有效地改善或抑制患者所患有的迟发性运动障碍症状。
本发明的详细描述
本发明的药物制剂/药物组合物可以按任一种方便的形式给药，例如口服、直肠、非肠道或通过皮肤给药。也可以，例如可以以单形式给药，其中，褪黑激素优选是在事先预定的控制速率下释放。
目前试图用于抑制或治疗迟发性运动障碍的褪黑激素的剂量将是为此目的找到的有效量，目前据信，在口服给药的情况下，每天的给药量大于0.5mg但不超过100mg，例如0.5-50mg，优选为2.5-20mg，对于非肠道给药或通过皮肤给药，给药量在0.1至50mg之间。依据本发明，褪黑激素的有效量可以是例如与有效剂量的一种具有安定作用的药物进行组配。目前药物制剂/药物组合物也可以包含至少一种褪黑激素接受体改性剂和/或褪黑激素分布改性剂。
一旦本发明的使用褪黑激素治疗或抑制TD的概念按照本发明公开，为本发明的目的确定褪黑激素的有效剂量范围以及各种各样的给药方式不需要经过创造性的劳动。如果所述的药物组合物包含至少一种具有安定作用的化合物，这种化合物例如可以从至少一种下列的环系物的化合物中选取，即，哌啶、哌嗪(pirperazine)、对氧氮己环，5，6，7，8-四氢吲哚、吩噻嗪和噻吨。代表性的具有安定作用的化合物包括氯丙嗪，三氟丙嗪、甲砜哒嗪、哌乙酰嗪、甲硫哒嗪、乙酰奋乃静、氟非那嗪、奋乃静、三氟吡啦嗪、氯丙硫蒽、氨砜噻吨、氟哌啶醇、克塞平、莫林酮(参见下页表1)、和氯噻平、氯氮平、欧兰扎平(olanzapine)、利哌酮(risperidone)和祖克罗朋西克素(zuclopenthixol)的醋酸盐，及其药物学可接受的盐。
表1：具有安定作用的化合物
化合物      每日剂量*可能范围                通常范围 给药模式   肌肉注射单次用量*
氯丙嗪+ 25-2000  300-800 口服给药；非肠道给药，直肠给药，SR  20-50
三氟丙嗪+ 25-300  100-150 口服给药；非肠道给药  20-60
甲砜哒嗪besylate 25-300  75-300 口服给药；非肠道给药  25
哌乙酰嗪 5-200  20-600 口服给药  ---
甲硫哒嗪+ 20-800  200-600 口服给药  ---
乙酰奋乃静马来酸盐 20-600  60-120 口服给药  ---
氟非那嗪+ 0.5-30  1-20 口服给药；非肠道给药  1.25-2.5
奋乃静 4-64  8-32 口服给药；非肠道给药，SR  5-10
三氟吡啦嗪 2-60  6-20 口服给药；非肠道给药  1-2
氯丙硫蒽 30-600  50-400 口服给药；非肠道给药  25-50
氨砜噻吨+ 6-60  6-30 口服给药；非肠道给药  2-4
氟哌啶醇 1-100  6-20 口服给药；非肠道给药  2-5
克塞平琥珀酸盐 20-250  60-100 口服给药；非肠道给药  12.5-50
莫林酮+ 12-225  50-100 口服给药  ---
*mg+盐酸盐，SR＝缓释剂(口服)
本发明由下面的实施例加以说明。
                      实施例1
将下面的组分混合在一起，该混合物在7mm圆柱形冲床上，在2.5吨压力下压缩，以制成缓释药片：盐酸氯丙嗪(275mg/片)、褪黑激素(5mg/片)及重量比例为1∶1的EudragitTMRS 100丙烯酸树脂载体(Rohm Pharma)和乳糖。尽管这种药物组合物应该按照医嘱服用，建议在睡觉前2小时服用两个这样的药片。
                      实施例2
将下面的组分混合在一起，该混合物在7mm圆柱形冲床上，在2.5吨压力下压缩，以制成缓释药片：奋乃静(10mg/片)、褪黑激素(5mg/片)和重量比例为2∶1∶2.5的EudragitTMRSPO丙烯酸树脂载体(Rohm Pharma)、乳糖和磷酸氢钙。尽管这种药物组合物应该按照医嘱服用，建议在睡觉前2小时服用两个这样的药片。
                      实施例3
褪黑激素对迟发性运动障碍的效果是由对22个患者的实验确定的，其中6人是精神分裂症，16人是偏执狂精神分裂症。所有的患者都接受了长期的安定药物的治疗，其病症是根据DSM IV确诊的。病人中有11个男性和11个女性，年龄在39±15岁，年龄范围在17-61岁，其中19人完成了实验并计入结果中。以随机的、双盲的、交叉的方式，每天按缓释药物组合物给予受治疗者2×5mg的褪黑激素(CircadinTM，Neurim Pharmaceuticals，以色列)，或相同外形的安慰剂，在睡觉前2小时服用，6周为一个疗程，在两个疗程中有4周时间安慰剂完全失败。除了褪黑激素或安慰剂外，每个患者分别接受了下面具有安定作用的日常用量(mg)，或在两种情况下没有用安定药物：氯丙嗪(5、15或20)、氯噻平(20、80或160)、氯氮平(200、400或550)、氟哌啶醇(5、15或20)、olanzapine(10或15)、奋乃静(4、8、12、32或32)、利哌酮(4)、zuclopenthixol的醋酸盐(4或20)。在每个疗程的最后一周，用异常无意识运动等级(AIMS)对TD严重性进行评估，并对安慰剂或褪黑激素治疗与基准进行比较。结果显示于表2和表3中。
             表2  各种AIMS参数的T-测试结果
AIMS子等级 参数 T-测试(t21)§ p
1 脸部和口腔的运动 -1 0.33
2 唇和胸部 -3.92 ＜0.001*
3 鄂 -1.14 0.27
4 舌 -0.81 0.43
5 手臂，手 -1.78 0.09
6 腿，膝 -2.81 ＜0.01*
7 颈，肩 -2.49 0.02*
8 异常运动的严重性 -1.82 0.08
9 异常运动的含义 -1.14 0.27
10 患者的意识 δ＝0
11 牙的问题 δ＝0
§基准/给药差别的比较，安慰剂对褪黑激素
*显著的结果
 表3  褪黑激素对迟发性运动障碍效应的研究结果
AIMS子等级                        运动强度(标准偏差)
 基准 安慰剂 基准 褪黑激素
1  2.14(0.89) 2.00(0.82) 2.18(0.80) 1.91(0.87)
2  3.27(0.70) 3.27(0.70) 3.50(0.74) 3.00(0.98)
3  3.00(1.07) 2.73(1.12) 3.09(1.11) 2.68(1.13)
4  3.55(0.67) 3.32(0.65) 3.50(0.67) 3.18(0.80)
5  1.73(0.83) 1.64(0.79) 1.91(0.92) 1.50(0.74)
6  1.23(0.53) 1.23(0.53) 1.55(0.91) 1.27(0.63)
7  1.18(0.50) 1.14(0.47) 1.55(1.06) 1.27(0.70)
8  3.36(0.73) 3.27(0.70) 3.50(0.74) 3.27(0.88)
9  3.09(0.81) 2.95(0.79) 3.00(0.87) 2.73(0.88)
10  1.73(0.70) 1.73(0.70) 1.73(0.70) 1.73(0.70)
11  1.91(0.29) 1.91(0.29) 1.91(0.29) 1.91(0.29)
结论
本发明的研究，在服用褪黑激素之后与安慰剂(分别为-3±2.1和-1±1.3)进行比较，迟发性运动障碍有非常显著的(p＜0.0001，方差的多元分析)下降，即能改善病人的迟发性运动障碍。
尽管通过一些具体的实施例对本发明进行了详细说明，但是对于本领域的普通技术人员来说，可以对本发明进行各种各样的修正和改进。所以本发明并不受这些实施例的限制，本发明的精神和保护范围由下面的权利要求来限定。

Claims (7)

1、一种用于抑制或治疗迟发性运动障碍的药物组合物，该组合物除了含有载体、稀释剂或辅剂外，还含有至少一种具有安定作用的化合物，该化合物的剂量为能有效地在需要接受这种治疗的患者身上产生具有安定作用的效应，和一种褪黑激素，该褪黑激素的剂量为每单位剂量包含2.5-20mg，其中所述至少一种具有安定作用的化合物是从下列环化合物中选择的至少一种：哌啶、哌嗪、对氧氮己环、5，6，7，8-四氢吲哚、吩噻嗪和噻吨。
2、按照权利要求1所述的药物组合物，其还具有下列特征中的至少一种：
(1)适于口服、直肠、非肠道或通过皮肤给药；
(2)为单位剂量的形式，每个单位剂量包含的褪黑激素在2.5-20mg的范围内；
(3)为缓释配方的形式，其中褪黑激素按事先确定的控制速率释放；
(4)包含至少一种褪黑激素受体改性剂和/或褪黑激素分布改性剂。
3、按照权利要求1或2的药物组合物，其中所述的具有安定作用的化合物选自氯丙嗪、三氟丙嗪、甲砜哒嗪、哌乙酰嗪、甲硫哒嗪、乙酰奋乃静、氟非那嗪、奋乃静、三氟吡啦嗪、氯丙噻蒽、氨砜噻吨、氟哌啶醇、克塞平、莫林酮、氯噻平、氯氮平、欧兰扎平、利哌酮、祖克罗朋西克素的醋酸盐，以及它们的药物学上可接受的盐。
4、褪黑激素在制备用于抑制或治疗患者的迟发性运动障碍症状的药物制剂产的应用，其中所述药物制剂中每个单位剂量包含的褪黑激素在2.5-20mg的范围内。
5、按照权利要求4所述的应用，其中所述的药物制剂为药物组合物的形式，包含至少一种下列的附加组分(a)和(b)：(a)至少一种载体、稀释剂或辅剂；(b)至少一种具有安定作用的化合物，其剂量为能有效地在需要接受这种治疗的患者身上产生一种具有安定作用的效应。
6、按照权利要求5所述的应用，其中所述的药物组合物还具有下列特征中的至少一种：
(1)适于口服、直肠、非肠道或通过皮肤给药；
(2)为单位剂量的形式，每个单位剂量包含的褪黑激素在2.5-20mg的范围内；
(3)为缓释配方的形式，其中褪黑激素按事先确定的控制速率释放；
(4)包含至少一种褪黑激素受体改性剂和/或褪黑激素分布改性剂；
(5)所述的具有安定作用的化合物是从下列环化合物中选择的至少一种：哌啶、哌嗪、对氧氮己环、5，6，7，8-四氢吲哚、吩噻嗪和噻吨。
7、按照权利要求5或6所述的应用，其中所述的具有安定作用的化合物选自氯丙嗪、三氟丙嗪、甲砜哒嗪、哌乙酰嗪、甲硫哒嗪、乙酰奋乃静、氟非那嗪、奋乃静、三氟吡啦嗪、氯丙噻蒽、氨砜噻吨、氟哌啶醇、克塞平、莫林酮、氯噻平、氯氮平、欧兰扎平、利哌酮、祖克罗朋西克素的醋酸盐，以及它们的药物学上可接受的盐。
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