CN104582701B - 减轻体重的方法 - Google Patents
减轻体重的方法 Download PDFInfo
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- CN104582701B CN104582701B CN201380033658.6A CN201380033658A CN104582701B CN 104582701 B CN104582701 B CN 104582701B CN 201380033658 A CN201380033658 A CN 201380033658A CN 104582701 B CN104582701 B CN 104582701B
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- methazolamide
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Abstract
本公开内容一般地涉及醋甲唑胺在治疗中的用途。本公开内容特别地涉及在患有或易患不期望的高血糖水平所涉及或参与之疾病及相关病症(例如糖尿病、综合征X、高血糖、血管病和肾病)的患者中调节葡萄糖内稳态和减轻体重。本公开内容还涉及用于在治疗方法中使用的化合物及其药剂和组合物。
Description
技术领域
本公开内容一般地涉及醋甲唑胺在治疗中的用途。本公开内容特别涉及在患有或易患不期望的高血糖水平涉及或参与的疾病及相关病症的患者中减轻体重。本公开内容还涉及用于在治疗中使用的化合物及其药剂和组合物。
背景技术
本说明书中引用的任何现有出版物(或从其来源的信息)或任何已知内容不是且不应被认为是认可或承认或任何形式地建议所述现有出版物(或从其来源的信息)或已知内容形成了本说明书涉及之努力领域中的公知常识的一部分。
葡萄糖是机体的优选能量来源。血糖源自从饮食吸收的葡萄糖和由肝产生并释放到血流中的葡萄糖(产生肝葡萄糖)的组合。一旦进入血流中，葡萄糖需要胰岛素的协助以进入肝细胞、肌细胞和脂肪细胞，从而被储存或利用。胰岛素的另一主要作用是抑制肝葡萄糖产生。在健康个体中，葡萄糖内稳态主要受胰岛素控制。当血糖水平上升时(例如在饮食后)，胰腺内的特化β-细胞释放胰岛素，其抑制肝葡萄糖产生并促进机体靶组织的葡萄糖摄取、细胞内代谢和糖原合成。因此，在健康个体中，血糖浓度一般被严格控制在80至110mg/dL的范围内。然而，当胰腺不产生充足的胰岛素应答，或靶细胞不对产生的胰岛素适当应答时，这会导致葡萄糖在血流中迅速积累(高血糖)。
随着时间的推移，高的血糖水平可导致心血管疾病、视网膜损伤、肾衰竭、神经损伤、勃起功能障碍和坏疽(具有截肢的风险)。此外，在不存在可获得的葡萄糖的情况下，细胞转向将脂肪作为替代能源。得到的酮体(脂肪水解的产物)可在血流中积累从而导致低血压和休克、昏迷、甚至死亡。
糖尿病是以慢性升高的血糖水平(大于约126mg/dL或7.0mmol/L)为特征的代谢疾病，而慢性升高的血糖水平是由胰岛素分泌不足(1型糖尿病)和/或机体组织对胰岛素作用的不适当应答或敏感性(2型糖尿病)引起的。糖尿病的主要诊断特征之一是个体失去对葡萄糖内稳态的控制，致使餐后血糖水平在餐后保持升高并且可在长时间内保持较高。糖尿病可以持续高血糖、多尿、烦渴和/或饮食过量、慢性微血管并发症(例如视网膜病、肾病和神经病)和大血管并发症(例如高血脂和高血压)为特征，其可导致失明、末期肾病、截肢和心肌梗死。高血糖水平和胰岛素抗性还与可发展成慢性炎症、纤维化和肝硬化的脂肪性肝病相关。
三种最常见的糖尿病类型为1型糖尿病、2型糖尿病和妊娠糖尿病。
1型糖尿病，也称为胰岛素依赖型糖尿病(insulin dependent diabetesmellitus，IDDM)或青少年发作型糖尿病，占所有糖尿病病例的10％至15％。1型糖尿病最常在儿童和青少年中被诊断出，但是其也可发生在年轻成人中。1型糖尿病以导致胰岛素分泌功能丧失的β-细胞破坏为特征。大多数病例与β-细胞的自身免疫破坏相关。通过注射胰岛素进行治疗，并且必须要无限期地持续下去。
2型糖尿病，也称为非胰岛素依赖型糖尿病(non-insulin dependent diabetesmellitus，NIDDM)或迟发型糖尿病，胰岛素水平初始正常，但是机体靶细胞丧失其对胰岛素的应答。这也称为胰岛素抗性或胰岛素不敏感性。为了补偿这种抗性，胰腺分泌过量的胰岛素。随着时间的推移，胰腺产生足够胰岛素的能力变弱，从而导致慢性高血糖。2型糖尿病的初始症状一般比1型糖尿病温和，并且该疾病在很多年内不能被确诊，直至观察到更严重的症状。生活方式(吸烟、饮食不良和不运动)被认为是2型糖尿病发生的主要决定因素，但是遗传倾向提高了发生该疾病的风险。
所有妊娠者的约2％至5％发生妊娠糖尿病。妊娠糖尿病是暂时的，但是如果不经治疗的话其可导致胎儿并发症。大多数患者在分娩后完全恢复。但是，一部分发生妊娠糖尿病的女性继续发展成2型糖尿病。
糖尿病的另一些不常见病因包括β-细胞的遗传缺陷、遗传上相关的胰岛素抗性、胰腺疾病、激素缺乏、营养不良以及化学或药物影响。
糖耐量减低和空腹血糖异常是与2型糖尿病紧密相关的前驱型2型糖尿病状态，并且发生在血糖水平高于正常但是又不足够高以归类为糖尿病(约100至125mg/dL；5.6至6.9mmol/L)时。与2型糖尿病一样，机体产生胰岛素，但是其量不足够，或者靶组织不对所产生的胰岛素应答。
糖耐量减低、空腹血糖异常和胰岛素抗性是综合征X(Syndrome X)(也称为胰岛素抗性综合征(Insulin Resistance Syndrome，IRS)或代谢综合征)的组成部分，其是心脏疾病的风险因素集群(cluster of risk factors)，所述风险因素集群还包括肥胖、动脉粥样硬化、高甘油三酯血症、低HDL胆固醇、高胰岛素血症、高血糖以及高血压。因此，显而易见的是胰岛素抗性或不敏感性在糖尿病及其他高血糖相关的病症中发挥重要作用。
在过去二十年内，2型糖尿病的发病率增加了一倍多，并且继续以惊人的速率增长。世界卫生组织(World Health Organization，WHO)估计，在世界范围内，有3.46亿人患有2型糖尿病(约是世界人口的4.9％)，其中至少50％的糖尿病人群未意识到他们的病症(World Health Organization.Diabetes.Fact sheet N°312August 2011，(www.who.int))。估计每年会有另外的7百万人成为糖尿病患者。在世界范围内，糖尿病发病率的升高在儿童中特别受关注：30年前，1％至2％的儿童被诊断患有2型糖尿病，但是现在其占已报道的儿科糖尿病病例的高达80％。目前，印度具有最高的糖尿病人数，随后是中国、美国、俄罗斯和德国。约170万澳大利亚人(人口的7.5％)患有2型糖尿病，并且每天有275个澳大利亚成人成为糖尿病患者。另有200万澳大利亚人患有前驱糖尿病，并且具有发生2型糖尿病的风险(Diabetes Australia-Vic(www.diabetesvic.o rg.au/health-professionals/diabetes-facts))。在美国，估计有2580万人(人口的8.3％)患有糖尿病，并且另有7900万人为前驱糖尿病患者(U.S.Department 0f Health and Human Services，Centers for Disease Control and Prevention(2011).National diabetes factsheet：national estimates and general information 0n diabetes and prediabetesin the United States(www.cdc.gov/diabetes))。在美国，每年新诊断出190万成人糖尿病病例，并且至少一种预测表明，目前已诊断和未诊断糖尿病患者的增长意味着到2020年，50％的美国人口可能成为糖尿病患者或前驱糖尿病患者(UnitedHealth Group’s Centerfor Health Reform和Modernization.The United States of Diabetes.Working paper5.November，2010)。糖尿病及相关病症的经济费用是显著的。据估计，澳大利亚医疗保健系统估算的糖尿病的直接和间接费用为至少30亿澳元。与美国相比，这显得相形见绌，据估计，2007年美国糖尿病的直接费用为1160亿美元，间接费用占另外580亿美元。如果美国糖尿病发病率的预测增加继续下去，那么医疗保健费用可达到3.35万亿美元(至少为总医疗保健支出的10％)。
理想地，通过改变生活方式(特别是饮食和运动)来治疗2型糖尿病。综合临床和流行病学研究证明，体重减轻5-11kg可使糖尿病风险降低50％，体重减轻≥10kg与糖尿病相关死亡之30％至40％的降低相关。对很多患者而言，体重减轻20-30kg可治疗糖尿病和高血压(Labib M.，(2003)The investigation and management of obesity.J ClinPathol.56：17-25)。
遗憾的是，大多数患者不能保持这种生活方式改变，因此需要药物介入来适当地控制葡萄糖。目前，国际治疗指导方针包括二甲双胍以及饮食和运动作为2型糖尿病的一线治疗(Inzucchi SE等(2012)Medical management of hyperglycemia in type2diabetes：a patient-centered approach.Position statement of the AmericanDiabetes Association(ADA)and the European Association for the Study ofDiabetes(EASD).Diabetes Care 35：1364-79；在印刷前以电子文档公开，2012年4月19日)。糖尿病病理学的多因素性质意味着大多数患者将进展为需要进行联合治疗以在其有生之年保持有效的葡萄糖控制。如果二甲双胍和改变生活方式不足以建立葡萄糖控制，表明需要添加磺酰脲类、DPP4抑制剂(例如西他列汀)、GLP-1激动剂(例如利拉鲁肽)(二线)或三药组合(三线)。先前已推荐将噻唑烷二酮类(thiazolidinedione，ZD)胰岛素敏化剂罗格列酮和匹格列酮作为二线治疗剂；然而目前，显著的安全问题严重限制了它们的应用。使用联合治疗不能保持葡萄糖控制的患者将最终需要使用胰岛素。尽管先前胰岛素被认为是糖尿病的末线治疗，但是医生越来越愿意将基础胰岛素添加为二线治疗。
目前，糖尿病治疗常常受较差的安全性特征的限制。一线治疗二甲双胍导致包括剂量限制性腹泻在内的胃肠副作用。二线治疗磺酰脲类(其提高胰岛素分泌)以及美格列奈类可导致危险的低血糖并加速胰腺β-细胞破坏。随着时间的推移，磺酰脲类、美格列奈类和二甲双胍均经受耐受并丧失效力。TZD胰岛素敏化剂与严重水肿、体重增长、骨折、心血管副作用(包括心肌梗死的死亡风险升高)、膀胱癌以及糖尿病性黄斑水肿的风险升高相关。就急性胰腺炎以及潜在致命的变态反应Stevens-Johnson综合征而言，已对DPP4抑制剂西他列汀发出了安全警告。已表明，相关分子维格列汀升高肝酶水平。用GLP-1激动剂艾塞那肽治疗可导致恶心、胰腺炎和低血糖。产生针对艾塞那肽的抗体同样可限制其在部分患者中的应用。GLP-1激动剂利拉鲁肽具有较高的胃肠副作用(包括恶心和呕吐)发病率，并且导致在临床相关暴露的大鼠和小鼠发生剂量依赖型和治疗持续依赖型甲状腺C-细胞肿瘤。对于更新的治疗，费用同样是一个显著问题。例如，西他列汀在降低血糖水平方面并不比二甲双胍有效，但是却比其贵20倍(VanDeKoppel S等(2008)Managed care perspective onthree new agents for type 2diabetes.J Manag Care Pharm 14：363-80.)。
当前非胰岛素糖尿病药物存在的局限性表明迫切需要开发具有如下特征之经济有效的新治疗：改善的安全性和有效性、高患者依从性以及保持/改善β-细胞功能和延迟二次治疗失败的可能性。特别需要新型安全的胰岛素敏化剂来替代TZD。此外，对新型糖尿病治疗的治疗和监管要求是改善关键的健康参数，理想的是减轻体重和改善心血管健康(USFDA.Guidance for Industry：Diabetes Mellitus-Evaluating Cardiovascular Risk inNew Antidiabetic Therapies to Treat Type 2Diabetes.December，2008)。最近，WO2008/089521公开了醋甲唑胺(一种起初被批准治疗青光眼的药物)用于治疗糖尿病和其他前驱糖尿病病症的用途。临床前研究已确定醋甲唑胺是一类新的胰岛素敏化剂。本公开内容描述了醋甲唑胺的新的且意想不到的在糖尿病患者中减轻体重的作用。
发明概述
现在出人意料地观察到，对于先前已开始使用抗糖尿病剂(例如二甲双胍)治疗的患者，随后共施用醋甲唑胺导致额外的意想不到的体重减轻。出乎意料的是，在先前未使用抗糖尿病剂的患者中未观察到这种作用。本公开内容涉及醋甲唑胺在接受过抗糖尿病或血糖调节治疗的患者中使体重减轻的用途。因此，在一些实施方案中，通过改善胰岛素抗性、增强血糖控制和减轻体重，醋甲唑胺可被有利地用作用于接受过抗糖尿病剂治疗之患者的辅助治疗。体重减轻可降低抗糖尿病或其他治疗药物的所需剂量。
因此，本公开内容涉及在此前已开始且正接受用抗糖尿病剂治疗的患者中使体重减轻的方法，所述方法包括向所述患者进一步施用醋甲唑胺的步骤。
在另一实施方案中，本公开内容涉及在患者中使体重减轻的方法，其包括：
(i)开始用抗糖尿病剂进行治疗；
(ii)继续用所述抗糖尿病剂进行治疗；以及
(iii)随后开始用醋甲唑胺进行额外的治疗。
在一些实施方案中，当患者的血糖水平通过抗糖尿病剂得到稳定时，开始用醋甲唑胺进行治疗。
本公开内容还涉及醋甲唑胺，其用于在此前已开始且正接受用抗糖尿病剂治疗的患者中使体重减轻。
本公开内容还涉及用于在此前已开始且正接受用抗糖尿病剂治疗的患者中使体重减轻的组合物，所述组合物包含醋甲唑胺以及一种或更多种可药用添加剂。
本公开内容还涉及醋甲唑胺在制备用于在此前已开始且正接受用抗糖尿病剂治疗的患者中使体重减轻的药物中的用途。
本公开内容还涉及用于在此前已开始且正接受用抗糖尿病剂治疗的患者中使体重减轻的组合，所述组合包含醋甲唑胺和抗糖尿病剂。
在一些实施方案中，醋甲唑胺以每日少于100mg(例如每日90、80、70、60或50mg)的量施用。
在一些实施方案中，所述抗糖尿病剂为胰岛素敏化剂，例如二甲双胍或其可药用盐。
在一些实施方案中，醋甲唑胺和抗糖尿病剂同时或分开地经口施用。
在一些实施方案中，所述患者的BMI为至少25。
在一些实施方案中，所述患者的腰围大于94cm(成年男性)或大于80cm(成年女性)。
附图说明
图1图示了同时进行醋甲唑胺治疗对降低糖尿病患者的体重的影响，所述患者在进行醋甲唑胺治疗之前已用二甲双胍稳定至少3个月。在24周研究期间，经醋甲唑胺和二甲双胍治疗的患者比其初始体重减轻2％，而经二甲双胍和安慰剂治疗的患者体重未显著改变。出乎意料的是，在未使用二甲双胍的经醋甲唑胺与经安慰剂治疗的患者间未观察到差异。通过改变饮食，这些新诊断的糖尿病患者均减轻了相当量的体重。
发明详述
除非上下文另有要求，否则在本说明书通篇以及所附的权利要求书中，词语“包含”及其变化形式(例如“包括”和“含有”)应被理解为指包括/包含所述整数或步骤或整数组，但不排除其他任何整数或步骤或整数组。
除非上下文另有明确指出，否则没有数量词修饰的名词表示一个/种或更多个/种。
术语“发明”包括本文中所述的所有方面、实施方案和实例。
醋甲唑胺被批准用于治疗降低眼内压可具有治疗益处的眼部病症，例如慢性开角型青光眼、继发性青光眼，以及在手术前用于需要手术前降低眼内压的急性闭角型青光眼。尽管通常将其描述为利尿剂，但是醋甲唑胺仅具有弱的短暂利尿活性，并且产品标签明确声明其不应用作利尿剂。醋甲唑胺通过抑制酶碳酸酐酶来发挥其对眼部病症的作用，然而，这似乎并非其作为糖尿病中胰岛素敏化剂之活性的机制。醋甲唑胺的治疗有效的(碳酸酐酶抑制的)眼内压降低剂量为50ma至100-150ma，每日2或3次，即每日100ma至450ma。一些代谢酸中毒和电解质失衡可随使用碳酸酐酶抑制有效量而发生，但是甚至在剂量处于标准剂量范围的较低端时，可发生导致不适、疲劳、体重减轻、抑郁和厌食的过度酸中毒(Epstein和Grant，Arch.Opthamol.，95，1380，1977)。
根据本公开内容以及根据期望的给药方案，醋甲唑胺以有效降低体重的量施用。在一些实施方案中，施用量(例如与抗糖尿病剂以协同或相加的方式)还应足以降低升高的血糖水平或者维持正常的或期望的血糖水平。在一些实施方案中，本文中公开的醋甲唑胺减轻体重的效果可通过如下剂量获得，所述剂量使得它们可避免或最小化临床上有意义的碳酸酐酶抑制，例如，治疗性治疗眼部病症所需的剂量，同时使用的剂量还避免或最小化可与标准碳酸酐酶抑制有效剂量方案相关之临床上有意义的酸中毒。因此，在一些实施方案中，醋甲唑胺有利地以每日少于100ma的剂量率施用。在另一些实施方案中，醋甲唑胺以每日约90、80或75ma或更少，或每日约50ma或更少的剂量率施用。在另一些实施方案中，醋甲唑胺以每日约40ma或更少的剂量率施用。在另一些实施方案中，醋甲唑胺以每日约30ma或更少的剂量率施用。在另一些实施方案中，醋甲唑胺以每日约25ma或更少的剂量率施用。在另一些实施方案中，醋甲唑胺以每日约20ma或更少(例如每日约15、10或5ma)的剂量率施用。这些剂量中任意剂量的施用可作为单次剂量每日一次，或者作为分次剂量，例如每日两次或三次或根据主治医生确定的任意其他给药方案。醋甲唑胺的合适单位剂量可包含约1.0、2.5、5.0、10、20、25、30、40、50、60、75、80或90mg的醋甲唑胺。
本文中考虑的患者患有糖尿病或前驱糖尿病病症，其包括由胰岛素抗性或细胞或组织摄取葡萄糖异常引起或这些发挥重要作用或显示这些的任意疾病或病症，或其症状或致病因素，所述疾病可利用使用开出的抗糖尿病剂(本文中也称为抗高血糖剂)治疗来进行治疗。糖尿病或前驱糖尿病病症、症状和致病因素的非限制性实例包括：NIDDM(2型糖尿病)、妊娠糖尿病、糖耐量减低、空腹血糖异常、综合征X、高血糖、动脉粥样硬化、高甘油三酯血症、血脂异常、高胰岛素血症、肾病、神经病、缺血、卒中和脂肪性肝疾病。一般地，所述疾病或病症为NIDDM、妊娠糖尿病、糖耐量减低、空腹血糖异常、综合征X或高血糖。
虽然并非总是如此，但是患有或易患糖尿病或前驱糖尿病病症的患者一般具有升高的体重指数(body mass index，BMI)。将BMI为25至29.9归类为“超重”或“前期肥胖”。将BMI为30或更大归类为“肥胖”。另一些亚类进一步对肥胖的程度进行了限定(肥胖类别I、II和III)。在一些实施方案中，患者的BMI可为25或更大，例如25至27、或27至29.9、或30至33或33至34.9或大于35或40。根据本公开内容的治疗对25或更大或30或更大的升高的BMI的患者特别有效。腰围提高是2型糖尿病的另一风险标志，腰围越大，提高的风险越大，并且大量的糖尿病或前驱糖尿病患者可能具有提高的腰围(其可能但并非一定与BMI大于25相关)。因此，在一些实施方案中，本文中所考虑的患者的腰围大于94cm或102cm(成年男性)或者大于80cm或88cm(成年女性)。
本公开内容所考虑的患者已被诊断为患有或易患上述考虑的病症，并且已建立使用抗糖尿病剂(例如二甲双胍或其可药用盐)的治疗方案。在一些实施方案中，所述患者在开始进行醋甲唑胺治疗前至少1或2周，已开始用抗糖尿病剂进行治疗。在另一些实施方案中，所述患者在开始进行醋甲唑胺治疗前至少4周(或1个月)，已开始用抗糖尿病剂进行治疗。在另一些实施方案中，所述患者在开始进行醋甲唑胺治疗前至少6、8、10或12周(例如至少约2或3个月)，已开始用抗糖尿病剂进行治疗。在一些实施方案中，对患者有利的是患者在开始进行醋甲唑胺治疗之前已用抗糖尿病剂稳定，也就是说，已确定并开始进行给药方案使得已获得稳定的或控制的期望血糖水平，如主治医生所确定的。例如，二甲双胍(作为盐酸盐)的开始剂量可由主治医生确定，并且可更根据有效性和耐受性个体化，一般情况下，以每日一次或两次500或850mg的日剂量开始，如有必要，可对其进行调整以获得稳定的或控制的血糖水平。一旦确定了剂量，对于成年患者而言，该剂量可以是每日约1000至1500mg，最多每日的最大剂量为约2500mg。血糖水平可通过本领域中常用的任意合适的方法测量，例如空腹血糖，HbA1c水平等。示例性的稳定水平包括HbA1c水平低于6.5％，或空腹状态血糖水平低于约6.1mmol/L(110mg/dL)。
用于治疗相关病症(例如心血管疾病)的药剂(例如抗高血压剂)还可与抗糖尿病剂和醋甲唑胺联合施用(同时或分开)。如主治医生所确定的，任何这样的相关症状或病症均可用合适的药剂(例如诸如利尿剂、ACE抑制剂或β-阻断剂的抗高血压剂)来治疗。在一些实施方案中，通过本文中的公开内容实现的体重减轻可有利地避免对所述药剂剂量的需要或降低所述药剂的剂量。因此，应当理解的是，患者可不必患有或发生与糖尿病或前驱糖尿病疾病或病症相关的所有症状或疾病，或者所述疾病未严重到需要进行额外的治疗性治疗，特别是如果该疾病或病症在早期阶段检测到并进行治疗。
醋甲唑胺可与抗糖尿病治疗剂同时或先后(之前或之后)共施用，在同时施用的情况下，每种药剂可分开配制，或者两者可一起配制成紧密组合物。合适的抗糖尿病剂可包括胰岛素敏化剂、胰岛素促分泌葡萄糖吸收/摄取抑制剂、以及US2005/0037981(特别是其表2)中鉴定的类别和化合物，其内容整体并入本文。使用的药剂的一些实例包括双胍类、磺酰脲类、美格列奈类、胰岛素和胰岛素类似物以及噻唑烷二酮类。其他的非限制性实例包括噻唑烷二酮类(包括罗格列酮和匹格列酮)、二甲双胍、胰岛素、磺酰脲类(包括格列美脲、格列本脲、格列吡嗪、氯磺丙脲、妥拉磺脲和甲苯磺丁脲)、美格列奈类(包括瑞格列奈和那格列奈)、α-葡萄糖苷酶抑制剂(包括阿卡波糖和米格列醇)、GLP类似物(例如艾塞那肽)以及DPPIV抑制剂(例如西他列汀)。
在一些实施方案中，所述抗糖尿病剂为胰岛素敏化剂。其一个实例为二甲双胍。
在一些实施方案中，与初始单药治疗相比，一旦患者建立使用抗糖尿病剂(例如二甲双胍)的治疗，通过共施用醋甲唑胺可随后降低抗糖尿病剂的剂量。这可有利地避免、改善或以其他方式降低与用于单药治疗的剂量和方案相关的不期望副作用和缺点的严重程度、风险或发生。因此，在一些实施方案中，一旦开始进行醋甲唑胺治疗或已进行一段时间，可对在进行醋甲唑胺治疗之前开始的抗糖尿病剂的剂量方案进行调整。
当在涉及葡萄糖内稳态时使用时，本文所用的术语“调控”或“调节”及其变化形式指调节或控制所述葡萄糖水平，在特定实施方案中，指调节或保持正常的血糖水平。因此，“调控/调节葡萄糖内稳态”包括调节或控制血糖水平以降低高血糖，或有利地获得或维持正常的空腹状态、血糖水平。正常的空腹状态血糖水平一般低于6.1mmol/L(110mgd/L)。高血糖水平(本文中也称为升高的血糖水平)指空腹血糖水平大于或等于6.1mmol/L(110mgd/L)。
空腹血糖异常(impaired fasting glycemia，IFG)的特征在于空腹血浆葡萄糖浓度大于或等于6.1mmol/L(110mgd/L)，但是低于7.0mmol/L(126mgd/L)，并且口服葡萄糖耐量试验(oral glucose tolerance test，OGTT)期间的2小时血浆葡萄糖浓度(如测定的话)低于7.8mmol/L(140mgd/L)。糖耐量减低(impaired glucose tolerance，IGT)的特征在于空腹血浆葡萄糖浓度低于7.0mmol/L(126mgd/L)，并且OGTT期间的2小时血浆葡萄糖浓度大于或等于7.8mmol/L(140mgd/L)，但是低于11.1mmol/L(200mgd/L)。糖尿病的特征在于空腹血浆葡萄糖浓度大于或等于7.0mmol/L(126mgd/L)；或OGTT期间的2小时血浆葡萄糖浓度大于11.1mmol/L(200mgd/L)。
本文中所考虑的患者包括哺乳动物对象：人、灵长类动物、家畜动物(包括牛、马、绵羊、猪和山羊)、伴侣动物(包括狗、猫、兔、豚鼠)和捕获的野生动物。还包括诸如兔、小鼠、大鼠、豚鼠和仓鼠的实验室动物，因为它们可提供方便的测试系统。特别地考虑人患者。
如上所述，与公知的二甲双胍治疗，特别是二甲双胍单药治疗相比，根据本发明的使用二甲双胍或其可药用盐的组合可有利地允许降低二甲双胍(或其可药用盐)的剂量。在一些实施方案中，组合的剂量应为使得它们可提供相加或协同效果。合适的剂量和给药方案可由主治医生确定，并且可取决于所治疗的特定疾病、疾病的严重程度，以及对象的一般年龄、健康状况和体重。
一旦开始进行醋甲唑胺治疗，可保持开始的或已建立的使用抗糖尿病剂的治疗，或者在必要时还可对其进行调整。在本发明的一些实施方案中，降低抗糖尿病剂例如二甲双胍(或可药用盐，例如盐酸盐)的施用日剂量。在一些实施方案中，可将该剂量调整为等于或低于初始或稳定的单药治疗所需日剂量的约90％。在另一些实施方案中，该剂量等于或低于二甲双胍单药治疗所需剂量的约80％、70％、60％或50％。针对成人之二甲双胍的示例性日剂量可以是每日约100mg至约1500或2000mg的活性物，例如约250mg、500mg、750mg、850mg、1000mg、1100mg或1250mg。针对儿科患者(10至16岁)的示例性日剂量可以是每日约50mg至1000mg或1500mg，例如每日约100mg、250mg、500mg、750mg、850mg、1100mg或1250mg。抗糖尿病剂可以单次剂量或一系列剂量施用。合适的剂型可包含约50、75、100、150、200、250、500、750、850或1000mg的二甲双胍。
尽管醋甲唑胺与抗糖尿病剂可在不存在任何其他药剂或添加剂的情况下施用，但是优选使每种药剂以与一种或更多种可药用添加剂的组合物的形式，或者一起以与一种或更多种可药用添加剂的紧密组合物的形式存在。
此类组合物的制剂是本领域技术人员公知的，参见例如Remington′sPharmaceutical Sciences，第21版。所述组合物可包含任何合适的添加剂，例如载体、稀释剂或赋形剂。这些包括所有常规溶剂、分散介质、填充剂、固体载体、包衣剂、抗真菌剂、抗细菌剂、皮肤渗透剂、表面活性剂、等张剂和吸收剂等。应当理解的是，本发明的组合物还可包含其他补充的生理活性剂。
载体必须是可药用的，即与组合物中的其他成分相容并且对对象无害。组合物包括适于经口、经直肠、吸入、经鼻、局部(包括皮肤、口腔和舌下)、经阴道或肠胃外(包括皮下、肌内、静脉内和皮内)施用的这些组合物。组合物可方便地以单位剂型的形式存在，并且可通过药学领域中公知的任意方法制备。
适于经口施用之本公开内容的组合物可以呈现为分散的单位(例如每个包含预定量活性成分的胶囊剂、药袋剂(sachet)或片剂)、散剂或颗粒剂、水性液体或非水性液体中的溶液剂或混悬剂，或水包油液体乳剂或油包水液体乳剂。
片剂可通过任选地与一种或更多种辅助成分压制或模制来制备。压制片剂可通过在合适的机器内压制任选地与诸如以下混合之自由流动形式的活性成分(例如粉末或颗粒)来制备：黏合剂(例如惰性稀释剂)、防腐剂崩解剂(例如羟乙酸淀粉钠、交联的聚乙烯吡咯烷酮、交联的羧甲基纤维素钠)、表面活性剂或分散剂。模制片剂可通过在合适的机器内模制润湿的粉末化合物与惰性液体稀释剂的混合物来制备。所述片剂可被任选地包衣或刻痕，并且可利用合适的包衣(例如不同比例的羟丙基甲基纤维素)将其配制成能够减慢或控制其中活性成分的释放以提供期望的释放特性。片剂可任选地具有肠溶包衣，使得其能够在除胃之外的消化道部分中释放。
适于经肠胃外施用的组合物包括可包含抗氧化剂、缓冲剂、杀菌剂以及使所述组合物与预期接受者的血液等张的溶质的水性或非水性等渗无菌注射溶液，和可包含助悬剂和增稠剂的水性和非水性无菌混悬剂。组合物可存在于单位剂量或多剂量密封容器(例如，安瓿瓶和小瓶)中，并且可储存于冷冻干燥(冻干)条件下，仅需在临用前加入无菌液体载体(例如注射用水)即可。即用注射溶液和混悬剂可由先前所述种类的无菌粉末、颗粒和片剂制备。
应当理解的是，除上文特别提及的活性成分之外，本公开内容的组合物还可包含与所讨论组合物类型相关的领域中常规的其他试剂，例如，适于经口施用的这些组合物可包含如下其他试剂，例如黏合剂、甜味剂、增稠剂、矫味剂、崩解剂、包衣剂、防腐剂、润滑剂和/或延时剂。合适的甜味剂包括蔗糖、乳糖、葡萄糖、阿斯巴特或糖精。合适的崩解剂包括玉米淀粉、甲基纤维素、聚乙烯吡咯烷酮、黄原胶、膨润土、褐藻酸或琼脂。合适的矫味剂包括薄荷油、冬青油、樱桃、橙子或覆盆子矫味剂。合适的包衣剂包括丙烯酸和/或甲基丙烯酸和/或其酯的聚合物或共聚物、蜡、脂肪醇、玉米蛋白、虫胶或谷蛋白。合适的防腐剂包括苯甲酸钠、维生素E、α-生育酚、抗坏血酸、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯或亚硫酸氢钠。合适的润滑剂包括硬脂酸镁、硬脂酸、油酸钠、氯化钠或滑石。合适的延时剂包括单硬脂酸甘油酯或二硬脂酸甘油酯。
根据本公开内容，在适当时，用于施用的化合物可任选地以可药用盐或前药的形式存在。
术语“前药”以其最广泛的含义使用，并且涵盖经酶解或水解在体内转化为本发明化合物的那些衍生物。本领域技术人员很容易想到这些衍生物，其包括，例如游离巯基或羟基转化为酯(例如，醋酸酯或硫酯)或游离氨基转化为酰胺的化合物。酰化本发明化合物(例如以制备酯和酰胺前药)的方法是本领域中公知的，所述方法可包括在存在合适的催化剂或碱的情况下，用合适的羧酸、酸酐或氯化物来处理所述化合物。还包括羧酸(羧基)基团的酯。合适的酯包括C1-6烷基酯、C1-6烷氧基甲基酯(例如，甲氧基甲基酯或乙氧基甲基酯)、C1-6烷酰氧基甲基酯(例如新戊酰氧基甲基酯)、酞基酯(phthalidyl ester)、C3-8环烷氧基羰基C1-6烷基酯(例如1-环己基羰氧基乙基酯)、1，3-二氧杂环戊烯-2-酮基甲基酯(例如5-甲基-1，3-二氧杂环戊烯-2-酮基甲基酯)以及C1-6烷氧基羰氧基乙基酯(例如1-甲氧基羰氧基乙基酯)。氨基官能团的前药包括酰胺(参见，例如，Adv.BioSci.，1979，20，369，Kyncl，J.等)、烯胺(参见，例如，J.Pharm.Sci.，1971，60，1810，Caldwell，H.等)、Schiff碱(参见，例如，美国专利No2,923,661和Antimicrob.Agents Chemother.，1981，19，1004，Smyth，R.等)、唑烷(参见，例如，J.Pharm.Sci，1983，72，1294，Johansen，M.等)、Mannich碱(参见，例如，J.Pharm.Sci.1980，69，44，Bundgaard，H.等和J.Am.Chem.Soc.，1959，81，1198，Gottstein，W.等)、羟甲基衍生物(参见，例如，J.Pharm.Sci，1981，70，855，Bansal，P.等)和N-(酰氧基)烷基衍生物和氨基甲酸酯(参见，例如，J.Med.Chem.，1980，23，469，Bodor，N.等，J.Med.Chem.，1984，27，1037，Firestone，R.等，J.Med.Chem.，1967，10，960，Kreiger，M.等，美国专利No5,684,018以及J.Med.Chem.，1988，31，318-322，Alexauder，J.等)。用于选择和制备合适的前药的其他常规方法是本领域中公知的，并且在例如以下中进行了描述：例如WO 00/23419；Design of Prodrugs，H.Bundgaard编著，Elsevier Science Publishers，1985；Methods in Enzymology，42：309-396，K.Widder编著，Academic Press，1985；ATextbook of Drug Design and Development，Krogsgaard-Larsen和H.Bundgaard编著，第5章，第113-191页(1991)；Advanced Drug Delivery Reviews，8；1-38(1992)；Journal ofPharmaceutical Sciences，77；285(1988)，H.Bundgaard，等；Chem Pharm Bull，32692(1984)，N.Kakeya等和The Organic Chemistry of Drug Desig and Drug Action，第8章，第352-401页，Academic press，Inc.，1992。
合适的可药用盐包括但不局限于可药用无机酸的盐，所述无机酸例如盐酸、硫酸、磷酸、硝酸、碳酸、硼酸、氨基磺酸和氢溴酸，或者可药用有机酸的盐，所述有机酸例如醋酸、丙酸、丁酸、酒石酸、马来酸、羟基马来酸、富马酸、马来酸、柠檬酸、乳酸、黏酸、葡糖酸、苯甲酸、琥珀酸、草酸、苯乙酸、甲磺酸、甲苯磺酸、苯磺酸、水杨酸、对氨基苯磺酸、天冬氨酸、谷氨酸、乙二胺四乙酸、硬脂酸、棕榈酸、油酸、月桂酸、泛酸、单宁酸、抗坏血酸、芬地柞酸(fendizoic acid)、4-4’-亚甲基双-3-羟基-2-萘甲酸、0-(对-羟基苯甲酰基)苯甲酸、4’-4”-二羟基三苯基甲烷-2-羧酸和戊酸。碱盐包括但不局限于与诸如以下可药用阳离子形成的那些盐：钠离子、钾离子、锂离子、钙离子、镁离子、铵离子和烷基铵离子。碱性含氮基团可以被诸如以下试剂季铵化，例如低级烷基卤化物(例如甲基、乙基、丙基和丁基氯化物、溴化物、碘化物)、二烷基硫酸盐(如二甲基和二乙基硫酸盐)等。
本发明的化合物还可应用于兽医组合物中。所述组合物可通过本领域中已知的任何的合适方法制备。所述组合物的实例包括适用于以下的这些组合物：
(a)经口施用，例如用于与饲料混合的片剂、大丸剂(bolus)、散剂、颗粒剂、丸粒剂，用于向舌头施用的糊剂，包括水性和非水性溶液剂或混悬剂的兽用顿服药(drench)；
(b)肠胃外施用，例如皮下、肌内或静脉内注射的无菌溶液剂或混悬剂。现在将参考下述实施例对本发明进行描述，所述实施例是出于举例说明本发明的实施方案的目的而提供，不应解释为是对上文所述一般性的限制。
实施例
在24周随机的、安慰剂对照的、双盲临床试验中评价醋甲唑胺(每日两次，施用40mg)作为2型糖尿病的潜在治疗的安全性和有效性。临床试验的主要疗效终点是在治疗24周后，相对于安慰剂，使用醋甲唑胺时，HbA1c从基线降低(ΔHbA1c)。次要疗效终点包括体重减轻和改善心血管量度，例如血压。主要安全性量度是与安慰剂相比，醋甲唑胺对静脉血气体参数的影响，即酸中毒的量度。
起初参与临床试验的是在进入试验前未经历过任何抗糖尿病剂治疗的(NAIVE)2型糖尿病患者。试验扩展到包括在进入试验前(MET)已经二甲双胍治疗至少3个月并且已有至少8周的稳定二甲双胍剂量的受试者。在整个试验期间，不改变二甲双胍剂量。受试者基线人口统计数据提供于表1中。
向临床试验中随机分配的受试者施用日剂量的醋甲唑胺(40mgb.i.d.)或安慰剂，持续24周。在早餐和晚餐时，以每剂量1×30mg胶囊剂和1×10mg胶囊剂摄取醋甲唑胺。以相同形式施用安慰剂(微晶纤维素)。在到诊所初次随机化访视(第0天)后，受试者在第1、2、4、8、12、18和24周返回诊所以进行身体检查、实验室分析、体内组合物测量、血糖参数(空腹血糖、空腹胰岛素、HbA1c)评价和静脉血气体分析测量。
醋甲唑胺和安慰剂对HbA1c、体重和BMI的影响示于表2中。体重随时间的平均变化示于图1中。
在整个研究期间，接受过安慰剂的经二甲双胍治疗之患者的体重在很大程度上保持稳定。出乎意料的是，在24周期间内，经二甲双胍治疗，并进一步经醋甲唑胺治疗的患者平均减轻2.2kg(为患者初始体重的2％)。在未接受过治疗的患者中未观察到醋甲唑胺的这种额外作用，其中醋甲唑胺组和安慰剂组两者的体重减轻是由于新诊断的糖尿病患者的一般饮食发生了变化。因此，观察到醋甲唑胺对经二甲双胍治疗的患者具有意想不到的选择性的影响。
表1：醋甲唑胺(MTZ)临床试验受试者的基线(第0天)人口统计数据
an＝38。bn＝18。在随机化前筛选就诊时，bHbA1c＝6.5％。在随机化前筛选就诊时，dHbA1c为8.4％。MTZ＝醋甲唑胺；Met＝二甲双胍
表2：从基线(第0天)到第24周的HbA1c、体重(BW)和体重指数(BMI)以及这些参数的变化(ΔHbA1c、ΔBW、ΔBMI)
＊相对于安慰剂+MET，p＜0.05(未配对的2侧t-检验)。MTZ＝醋甲唑胺；Met＝二甲双胍。
Claims (6)
1.醋甲唑胺在制备用于在先前已开始且正接受用抗糖尿病剂治疗的患者中使体重减轻的药物中的用途，其中所述抗糖尿病剂为二甲双胍。
2.根据权利要求1所述的用途，其中所述醋甲唑胺配制成用于当所述患者的血糖水平通过所述抗糖尿病剂得到稳定时施用。
3.根据权利要求1或权利要求2所述的用途，其中所述醋甲唑胺以每日少于100mg的量施用。
4.根据权利要求1或权利要求2所述的用途，其中所述醋甲唑胺和抗糖尿病剂配制成用于同时或分开地经口施用。
5.根据权利要求1或权利要求2所述的用途，其中所述患者的BMI为至少25。
6.根据权利要求1或权利要求2所述的用途，其中所述患者是腰围大于94cm的成年男性或腰围大于80cm的成年女性。
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