CN1723026A - 海绵核苷(2－甲氧腺苷)在治疗疼痛,特别是痛觉过敏中的用途 - Google Patents
海绵核苷(2－甲氧腺苷)在治疗疼痛,特别是痛觉过敏中的用途 Download PDFInfo
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- CN1723026A CN1723026A CNA2003801055073A CN200380105507A CN1723026A CN 1723026 A CN1723026 A CN 1723026A CN A2003801055073 A CNA2003801055073 A CN A2003801055073A CN 200380105507 A CN200380105507 A CN 200380105507A CN 1723026 A CN1723026 A CN 1723026A
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Abstract
描述了海绵核苷(2－甲氧腺苷)作为镇痛剂的用途，特别是用于治疗痛觉过敏。
Description
本发明涉及一种镇痛剂并且涉及使用该镇痛剂预防、治疗或改善疼痛的方法。
疼痛有两种组元，各自涉及感觉神经元的激活。当感觉神经元被刺激，例如作为皮肤上的加热或压力的结果时，第一种组元是早期或即时期。第二种组元是使先前受损伤的组织受神经支配的感觉机制增加的敏感性的结果。这第二种组元被称为痛觉过敏(hyperlagesia)，并涉及由组织损伤引起的慢性疼痛的所有形式，但不涉及疼痛知觉的早期或即时期。
因此，痛觉过敏是一种由组织损伤引起的升高的疼痛知觉的状况。这种状况是神经系统的自然反应，该神经系统显然被设计促使受损伤的个体保护受损害的组织，给组织修复发生以时间。有两种已知的这种状况的潜在原因，即感觉神经元活性的增加和发生于脊髓中的感受伤害信息的神经元处理的变化。在慢性炎症(例如类风湿性关节炎)的状况中和当感觉神经损伤发生时(即神经病性疼痛)，痛觉过敏可被衰弱。
已知两大类镇痛剂：(i)非甾族抗炎药物(NSAIDs)和有关的COX-2抑制剂；以及(ii)基于吗啡的阿片剂。两类镇痛剂在控制正常即时疼痛，或感受伤害疼痛中都是有效的。然而，他们对抗一些类型的痛觉过敏，例如神经病性疼痛则较少有效。因为由施用这些化合物引起的副作用，以及患者可能对它们上瘾的可能性，许多医师不愿意以影响神经病性疼痛所需要的高剂量开阿片剂处方。NSAIDs比阿片剂作用弱许多，因此需要甚至更高剂量的这些化合物。然而，这是不受欢迎的，因为这些化合物引起胃肠道的刺激。
已知腺苷A1受体激动剂起强力镇痛剂的作用(Sawynok，Eur JPharmacol.(1998)347，1-11)，以及已知腺苷A2A受体激动剂起抗炎剂的作用。然而，一般排除了基于腺苷的疗法的开发，因为它们有不可接受的副作用。选择性A1受体激动剂引起心动过缓，以及A2A受体激动剂引起普遍的血管舒张，随之发生低血压和心动过速。
因此，存在提供镇痛剂的需要，该镇痛剂足够强效以控制神经病性综合征、炎性综合征和其它痛觉过敏综合征中的疼痛知觉，并且没有严重的副作用或使患者对它们成瘾。
海绵核苷为一种化合物，1945年首先从热带海洋海绵Cryptotethia crpta中将它分离出来(Bergmann和Feeney，J.Org.Chem.(1951)16，981，Ibid(1956)21，226)。海绵核苷为第一种在自然界中发现的甲氧嘌呤，并且也被称为2-甲氧腺苷，或9H-嘌呤-6-胺，9-α-D-阿糖呋喃-2-甲氧基。
Bartlett等描述了海绵核苷的第一种生物学活性(J.Med.Chem.(1981)24，947-954)，他显示这种化合物在大鼠中具有肌肉松弛、低温、低血压和抗炎的活性(通过角叉菜胶诱导的大鼠足水肿的抑制来评价抗炎活性)。
海绵核苷对大鼠腺苷A1和A2A受体的亲和力已被测定。获得的Kd值对A1受体是340nM，对A2A受体是1.4μM(Daly等，Pharmacol.(1993)46，91-100)。在豚鼠中，在分离的心脏制备物中检测了海绵核苷的功效，并且获得的EC50值对腺苷A1和A2A受体分别为10μM和0.7μM(Ueeda等，J Med Chem(1991)34，1334-1339)。在二十世纪九十年代早期，其它的腺苷受体(A2B和A3受体)被克隆，但从未研究海绵核苷在这些受体上的活性。随着越来越多强效和受体选择性新化合物被合成，这种化合物的低效能和差受体选择性导致它很大程度上被忽视。
令人惊奇地发现，海绵核苷当被给予哺乳动物时，在增加的疼痛敏感性的状况(例如神经病性和炎性痛觉过敏)中引起显著的疼痛减轻，不引起对使用嘌呤受体激活剂预期的显著副作用。
根据本发明，提供了海绵核苷在制备用于预防、治疗或改善疼痛的药物中的用途。
在本说明书中使用术语“海绵核苷”以包括海绵核苷游离碱，或海绵核苷的药学上可接受的盐。
根据本发明的海绵核苷的用途，特别地涉及除如上所述疼痛的早期或即时期以外的疼痛的预防、治疗或改善，并且尤其涉及痛觉过敏的预防、治疗或改善。
根据本发明，还提供了一种预防、治疗或改善疼痛(特别是痛觉过敏)的方法，该方法包括对需要这样的预防、治疗或改善的受试者施用海绵核苷。
令人惊奇地发现，即使当以预期产生很低于已知激活腺苷受体的那些浓度的浓度的剂量被施用时，海绵核苷在抑制患有神经病性和炎性疼痛的哺乳动物中的疼痛知觉中有效。因此，海绵核苷能治疗神经病性和炎性疼痛而不引起与施用其它腺苷受体激动剂有关的显著副作用。
在施用海绵核苷后，没有观察到对正常生理学伤害感受的镇痛效果。
因为痛觉过敏是直接对感觉神经，或对受感觉神经支配的组织的组织损害的结果，所以有许多其中疼痛知觉包括痛觉过敏的组元的疾病或状况。
可以将海绵核苷作为抗痛觉过敏药使用，用于预防、治疗或改善作为神经病的结果引起的痛觉过敏，包括肠疼痛、背疼痛、癌疼痛、HIV疼痛、幻肢疼痛、手术后疼痛、糖尿病性神经病、多发性神经病、疱疹后神经痛和三叉神经痛。
涉及损害含有神经病性疼痛组元的感觉神经的其他疾病或状况包括胰腺疼痛、骨盆/会阴疼痛、下背疼痛、胸疼痛、心脏疼痛、骨盆疼痛/PID、关节疼痛(例如，与肌腱炎、滑囊炎、急性关节炎有关的)，颈疼痛、产科疼痛(分娩或剖腹产术部位)、慢性神经病性疼痛、失败的背部外科疼痛、身体创伤后疼痛(包括由枪伤、道路交通事故或烧伤引起的疼痛)、疤痕组织疼痛、急性带状疱疹疼痛、急性胰腺炎贯穿疼痛(癌)、或用于预防、治疗或改善神经病性疼痛或由纤维肌痛、肌筋膜(myofascial)疼痛综合征、骨关节炎、类风湿性关节炎、坐骨神经痛或腰神经根病、椎管狭窄、颞下颌关节障碍、肾绞痛、痛经/子宫内膜异位症引起或与它们有关的其它疼痛。
可以将海绵核苷作为抗痛觉过敏药使用，用于预防、治疗或改善作为炎性疾病的结果引起的痛觉过敏，包括肠疼痛、背疼痛、癌疼痛、纤维肌痛、手术后疼痛、骨关节炎和类风湿性关节炎。
因为它们与慢性炎症有关，其中痛觉过敏在疼痛知觉中起突出作用的其它疾病或状况包括其它的关节炎状况例如类风湿性脊椎炎、痛风性关节炎或哮喘、慢性阻塞性肺病、纤维变性、多发性硬化、脓毒症、脓毒性休克、内毒素性休克、革兰氏阴性休克、中毒性休克、出血性休克、成人呼吸窘迫综合征、脑型疟、器官移植排斥、癌继发性疼痛、HIV、慢性肺炎性疾病、矽肺、肺肉瘤病、骨吸收病、再灌注损伤、移植物对宿主排斥、多发性硬化、重症肌无力、同种异体移植物排斥、由于感染引起的发热和肌痛、AIDS有关的综合征(ARC)、瘢痕疙瘩形成、瘢痕组织形成、局限性回肠炎、溃疡性结肠炎和pyresis、应激性肠综合征、骨质疏松、脑型疟、细菌性脑膜炎、或来自两性霉素B治疗、白细胞介素-2治疗、OKT3治疗或GM-CSF治疗的不良作用。
与上面疾病或状况中许多种有关的疼痛相对地对NSAIDs和阿片制剂耐受。
将理解，海绵核苷可与药学上可接受的载体、赋形剂或稀释剂一起被施用。
海绵核苷的合适剂量将随着被治疗者的年龄、性别和体重，以及施用途径而变化。
优选地以一定的剂量施用海绵核苷，所述剂量引起的血浆浓度是在与将被给予所述剂量的受试者同种的动物中引起心动过缓、低血压或心动过速副作用的海绵核苷最小血浆浓度的五分之一到千分之一，优选地五分之一到百分之一。
或者，优选以在与将施用所述剂量的受试者同种的动物中引起心动过缓、低血压或心动过速副作用的海绵核苷的最小剂量的五分之一到五十分之一，优选五分之一到十分之一的剂量施用海绵核苷。
优选地以少于6mg/kg，并且优选地至少0.01mg/kg，更优选地至少0.05mg/kg，最优选地至少0.1mg/kg的剂量施用海绵核苷。更优选地以0.1到1mg/kg，或0.2到1mg/kg的剂量施用海绵核苷。
因此，对70kg人类受试者的优选的剂量为少于420mg，优选地至少0.7mg，更优选地至少3.5mg，最优选地至少7mg。更优选地7到70mg，或14到70mg。
可以通过任何合适的途径，优选口服，胃肠外，舌下，透皮，鞘内或透粘膜施用海绵核苷。
优选地以每日2或3次的频率施用海绵核苷。
也发现，如果海绵核苷与另一种镇痛剂一起被施用，可以获得加和的镇痛效果。因此，可以施用海绵核苷和其它镇痛剂，以获得期望水平的镇痛效果，各自以比如果单独施用其中一种药剂达到该水平所需剂量更低的剂量。因为可以施用更低剂量的每一种药剂，与更高剂量所述药剂施用有关的副作用减少。或者，可以通过以更高剂量施用海绵核苷和另一种镇痛剂获得增加水平的镇痛效果。
当与另一种镇痛剂一起被施用时，海绵核苷的优选剂量比上面详细说明的单独施用海绵核苷的优选剂量更低。
认为，如果另一种镇痛剂不以与海绵核苷相同的方式起作用，可以达到加和的镇痛效果。可以与海绵核苷一起被施用的合适的其它镇痛剂包括阿片受体激动剂和部分激动剂(例如吗啡、二乙酰吗啡、芬太尼、丁丙诺啡、可待因或其衍生物)、环加氧酶抑制剂(例如阿斯匹林、扑热息痛、布洛芬、双氯芬酸或其衍生物)、钠或钙通道调节剂(例如利多卡因或加巴喷丁)或选择性5-羟色胺再摄取抑制剂(SSRI’s)(例如帕罗西丁)。
下面的实施例4显示，海绵核苷的抗痛觉过敏特性不受共同施用阿片受体拮抗剂纳洛酮的影响，表明海绵核苷不通过阿片受体起作用。下面的实施例5证明了共同施用海绵核苷和加巴喷丁的加和镇痛效果。加巴喷丁对抗神经病性疼痛是有效的。预期被设计用于治疗神经病性疼痛的其它镇痛剂与海绵核苷可能具有加和的镇痛效果。这样的药剂包括托吡酯，普加巴林，齐可替定(ziconitide)，和大麻素衍生物。
参照附图在下列实施例中描述本发明的实施方案，其中：
图1显示海绵核苷(0.6mg/kg口服)对角叉菜胶诱导的痛觉过敏的抗痛觉过敏作用。A：时程(5小时间海绵核苷和IND(Dunnett’s)对赋形剂(Sidak’s)*p＜0.05，**p＜0.01，对BL p＞0.05；)B：抗痛觉过敏效果的剂量依赖性；
图2显示海绵核苷(0.6mg/kg口服)在神经病性疼痛的慢性狭窄损伤模型中的抗痛觉过敏作用(对赋形剂(ANOVA Sidak’s)*p＜0.05，**p＜0.01)；
图3显示海绵核苷(0.6mg/kg口服)对A：正常大鼠的血压；B：心率的效果；
图4显示在纳洛酮存在或不存在时，海绵核苷(0.6mg/kg口服)在神经病性疼痛的慢性狭窄损伤模型中的效果；和
图5显示海绵核苷和加巴喷丁在神经病性疼痛的慢性狭窄损伤模型中的加和效果。
实施例
实施例1
图1：A.海绵核苷(0.624mg/kg口服)抑制角叉菜胶(CGN)诱导的热痛觉过敏(CITH)具有与消炎痛(3mg/kg口服)相当的功效。B.在给药后3小时海绵核苷的浓度-反应关系。将角叉菜胶(2％，10微升)施用到右后脚爪中。将热源放于靠近处理和未处理的后脚爪，并显示在脚爪缩回潜伏期的差异。在与角叉菜胶相同的时间施用海绵核苷。
实施例2
图2：海绵核苷(0.624mg/kg口服)抑制由大鼠坐骨神经的慢性狭窄损伤引起的热痛觉过敏。在麻醉下，暴露右腿的坐骨神经，并且将四根松的结扎线围绕神经束扎住。大约两星期后，如通过右脚爪和左脚爪的脚爪缩回潜伏期的差异判断的，大鼠手术的腿出现热痛觉过敏。如通过缩回潜伏期的差异的减少所显示的，海绵核苷的施用减轻了痛觉过敏。海绵核苷与卡马西平(CBZ，100mg/kg皮下)同样或更加有效。
实施例3
图3：海绵核苷(0.624mg/kg口服)对血压或心率没有显著的影响。将一种可植入的无线电遥测装置放在每组6只大鼠的腹腔中。将装置的压力导管插入腹主动脉，并且两支电极在导联II位置(腹腔的左侧/右肩)皮肤下面穿洞(tunnel)。将个体大鼠放置在用于数据获得的无线接受器(DSI)上面的它们自己的笼中。A：血压，B：心率。
实施例4
图4：在纳洛酮(1mg/kg皮下)存在或不存在时，海绵核苷(1.2mg/kg口服)抑制由大鼠坐骨神经的慢性狭窄损伤引起的静态异常性疼痛。在麻醉下，暴露右腿的坐骨神经，并且将四根松的结扎线围绕神经束扎住。大约两星期后，如通过右脚爪和左脚爪的脚爪缩回阈的差异判断的，大鼠手术的腿中出现静态异常性疼痛。如通过在纳洛酮存在和不存在下增加的脚爪缩回阈(PWT)所显示的，海绵核苷的施用减轻了痛觉过敏。Veh：赋形剂。
实施例5
图5：海绵核苷和加巴喷丁抑制由大鼠坐骨神经的慢性狭窄损伤引起的静态异常性疼痛。如在图中所指出的，海绵核苷和加巴喷丁以不同的比例施用(口服)。施用的总剂量显示于水平轴，而脚爪缩回阈(PWT)在垂直轴。用(●)显示预计的抗痛觉过敏效果(来源于从每种药剂单独获得的剂量反应曲线)如果两种化合物的效果是加和的。观察到的效果通过(■)显示。明显的是，观察到的效果与通过加和性预计的效果没有显著差异。
即使当以期望产生很低于已知激活腺苷受体的浓度的浓度的剂量施用时，海绵核苷在抑制患有神经病性和炎性疼痛的哺乳动物中的疼痛知觉中是有效的。在这些剂量下，可以看到心脏A1受体和血管A2A受体二者都没有被足够地刺激以引起动物心血管状态的变化。
因此可以将海绵核苷用作抗痛觉过敏药，其可以经口施用，用于治疗作为神经病或炎性疾病的结果引起的痛觉过敏，包括肠疼痛、背疼痛、癌疼痛、纤维肌痛、HIV疼痛、幻肢疼痛、骨关节炎、类风湿性关节炎、疱疹后神经痛、三叉神经痛、多发性神经病、糖尿病性神经病和手术后疼痛。
Claims (31)
1.海绵核苷在制备用于预防、治疗或改善疼痛的药物中的用途。
2.根据权利要求1的用途，其中所述疼痛为痛觉过敏。
3.根据权利要求2的用途，其中所述痛觉过敏为神经病性疼痛。
4.根据任一前述权利要求的用途，其中所述疼痛由造成感觉神经元损伤的疾病引起或与造成感觉神经元损伤的疾病有关。
5.根据任一前述权利要求的用途，用于预防、治疗或改善肠疼痛、胰腺疼痛、骨盆/会阴疼痛、背疼痛、下背疼痛、胸疼痛、心脏疼痛、骨盆疼痛/PID、关节疼痛(例如，与肌腱炎、滑囊炎、急性关节炎有关的)、颈疼痛、产科疼痛(分娩或剖腹产术部位)、癌疼痛、HIV疼痛、幻肢疼痛、手术后疼痛、慢性神经病性疼痛、失败的背部外科疼痛、身体创伤后疼痛(包括由枪伤、道路交通事故、或烧伤引起的疼痛)、疤痕组织疼痛、急性带状疱疹疼痛、急性胰腺炎贯穿疼痛(癌)、疱疹后神经痛、或三叉神经痛，或用于预防、治疗或改善神经病性疼痛或由糖尿病性神经病、多发性神经病、纤维肌痛、肌筋膜疼痛综合征、骨关节炎、类风湿性关节炎、坐骨神经痛或腰神经根病、椎管狭窄、颞下颌关节障碍、肾绞痛、痛经/子宫内膜异位症引起或与它们有关的其它疼痛。
6.根据权利要求2的用途，其中所述痛觉过敏为炎性疼痛。
7.根据权利要求1，2或6任一项的用途，其中所述疼痛由炎性或免疫性疾病引起或与炎性或免疫性疾病有关。
8.根据权利要求1、2、6或7的用途，用于预防、治疗或改善肠疼痛、背疼痛、癌疼痛、纤维肌痛、手术后疼痛，或用于预防、治疗或改善炎性疼痛或由关节炎状况例如骨关节炎、类风湿性关节炎、类风湿性脊椎炎、痛风性关节炎或哮喘引起或与它们有关的其他疼痛、慢性阻塞性肺病、纤维变性、多发性硬化、脓毒症、脓毒性休克、内毒素性休克、革兰氏阴性休克、中毒性休克、出血性休克、成人呼吸窘迫综合征、脑型疟、器官移植排斥、癌继发性疼痛、HIV、慢性肺炎性疾病、矽肺、肺肉瘤病、骨吸收病、再灌注损伤、移植物对宿主排斥、多发性硬化、重症肌无力、同种异体移植物排斥、由感染引起的发热和肌痛、AIDS有关的综合征(ARC)、瘢痕疙瘩形成、瘢痕组织形成、局限性回肠炎、溃疡性结肠炎和pyresis，应激性肠综合征、骨质疏松、脑型疟、细菌性脑膜炎或来自两性霉素B治疗，白细胞介素-2治疗，OKT3治疗或GM-CSF治疗的不良作用。
9.根据任一前述权利要求的用途，其中海绵核苷与另一种镇痛剂一起被使用。
10.根据权利要求9的用途，其中所述另一种镇痛剂为阿片受体激动剂或部分激动剂、环加氧酶抑制剂、钠或钙通道调节剂、选择性5-羟色胺再摄取抑制剂(SSRI)或治疗神经病性疼痛的药剂。
11.一种预防、治疗或改善疼痛的方法，该方法包括对需要这样的预防、治疗或改善的受试者施用海绵核苷。
12.根据权利要求11的方法，其中所述疼痛为痛觉过敏。
13.根据权利要求12的方法，其中所述痛觉过敏为神经病性疼痛。
14.根据权利要求11至13任一项的方法，其中所述疼痛由造成感觉神经元损伤的疾病引起或与造成感觉神经元损伤的疾病有关。
15.根据权利要求11至14任一项的方法，用于预防、治疗或改善肠疼痛、胰腺疼痛、骨盆/会阴疼痛、背疼痛、下背疼痛、胸疼痛、心脏疼痛、骨盆疼痛/PID、关节疼痛(例如，与肌腱炎、滑囊炎、急性关节炎有关的)、颈疼痛、产科疼痛(分娩或剖腹产术部位)、癌疼痛、HIV疼痛、幻肢疼痛、手术后疼痛、慢性神经病性疼痛、失败的背部外科疼痛、身体创伤后疼痛(包括由枪伤、道路交通事故、或烧伤引起的疼痛)、疤痕组织疼痛、急性带状疱疹疼痛、急性胰腺炎贯穿疼痛(癌)、疱疹后神经痛、或三叉神经痛，或用于预防、治疗或改善神经病性疼痛或由糖尿病性神经病、多发性神经病、纤维肌痛、肌筋膜疼痛综合征、骨关节炎、类风湿性关节炎、坐骨神经痛或腰神经根病、椎管狭窄、颞下颌关节障碍、肾绞痛、痛经/子宫内膜异位症引起与它们有关的其它疼痛。
16.根据权利要求12的方法，其中所述痛觉过敏是炎性疼痛。
17.根据权利要求11、12或16的方法，其中所述疼痛由炎性或免疫性疾病引起或者与炎性或免疫性疾病有关。
18.根据权利要求11、12、16或17的方法，用于预防、治疗或改善肠疼痛、背疼痛、癌疼痛、纤维肌痛、手术后疼痛，或用于预防、治疗或改善炎性疼痛或由关节炎状况例如骨关节炎、类风湿性关节炎、类风湿性脊椎炎、痛风性关节炎或哮喘引起或与它们有关的其他疼痛、慢性阻塞性肺病、纤维变性、多发性硬化、脓毒症、脓毒性休克、内毒素性休克、革兰氏阴性休克、中毒性休克、出血性休克、成人呼吸窘迫综合征、脑型疟、器官移植排斥、癌继发性疼痛、HIV、慢性肺炎性疾病、矽肺、肺肉瘤病、骨吸收病、再灌注损伤、移植物对宿主排斥、多发性硬化、重症肌无力、同种异体移植物排斥、由于感染引起的发热和肌痛、AIDS有关的综合征(ARC)、瘢痕疙瘩形成、瘢痕组织形成、局限性回肠炎、溃疡性结肠炎和pyresis、应激性肠综合征、骨质疏松、脑型疟、细菌性脑膜炎或来自两性霉素B治疗、白细胞介素-2治疗、OKT3治疗或GM-CSF治疗的不良作用。
19.根据权利要求11至18任一项的方法，其中以一定的剂量施用海绵核苷，所述剂量引起的血浆浓度是在与将被给予所述剂量的受试者同种的动物中引起心动过缓、低血压或心动过速副作用的海绵核苷最小血浆浓度的五分之一至千分之一。
20.根据权利要求19的方法，其中所述剂量是引起所述副作用最小剂量的五分之一至百分之一。
21.根据权利要求11至18任一项的方法，其中以在与将被给予所述剂量的受试者同种的动物中引起心动过缓、低血压或心动过速副作用的海绵核苷最小剂量的五分之一至五十分之一的剂量施用海绵核苷。
22.根据权利要求21的方法，其中所述剂量是引起所述副作用最小剂量的五分之一至十分之一。
23.根据权利要求11至18任一项的方法，其中以少于6mg/kg的剂量施用海绵核苷。
24.根据权利要求11至18任一项或权利要求23的方法，其中以至少0.01mg/kg，优选地至少0.05mg/kg的剂量施用海绵核苷。
25.根据权利要求11至18任一项或权利要求23的方法，其中以至少0.1mg/kg的剂量施用海绵核苷。
26.根据权利要求25的方法，其中以0.1至1mg/kg，或0.2至1mg/kg的剂量施用海绵核苷。
27.根据权利要求11至18任一项的方法，其中用海绵核苷和另一种镇痛剂给予受试者。
28.根据权利要求27的方法，其中所述另一种镇痛剂为阿片受体激动剂或部分激动剂、环加氧酶抑制剂、钠或钙通道调节剂、选择性5-羟色胺再摄取抑制剂(SSRI)或治疗神经病性疼痛的药剂。
29.根据权利要求11至28任一项的方法，其中口服、胃肠外、舌下、透皮、鞘内或透粘膜施用海绵核苷。
30.根据权利要求11至29任一项的方法，其中以每天2或3次的频率施用海绵核苷。
31.根据权利要求11至30任一项的方法，其中所述受试者为人类受试者。
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| GB0305149D0 (en) | 2003-03-07 | 2003-04-09 | Cambridge Biotechnology Ltd | Compounds for the treatment of pain |
| EA011099B1 (ru) | 2004-03-05 | 2008-12-30 | Кембридж Байотекнолоджи Лимитед | Терапевтические соединения |
| US8407664B2 (en) | 2005-12-30 | 2013-03-26 | Sap Ag | Software model business objects |
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- 2003-12-09 CA CA002507918A patent/CA2507918A1/en not_active Abandoned
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- 2003-12-09 KR KR1020057010441A patent/KR101122495B1/ko not_active IP Right Cessation
- 2003-12-09 AT AT03780370T patent/ATE430572T1/de active
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113999281A (zh) * | 2016-02-04 | 2022-02-01 | 约翰霍普金斯大学 | 平衡型核苷转运蛋白1的抑制剂Rapadocin及其用途 |
Also Published As
| Publication number | Publication date |
|---|---|
| JP4836454B2 (ja) | 2011-12-14 |
| CN101264097B (zh) | 2011-10-05 |
| DK1581235T3 (da) | 2009-08-31 |
| GB2396108B (en) | 2005-08-03 |
| ATE430572T1 (de) | 2009-05-15 |
| HK1086186A1 (en) | 2006-09-15 |
| SI1581235T1 (sl) | 2009-10-31 |
| CN100471503C (zh) | 2009-03-25 |
| US20070010475A1 (en) | 2007-01-11 |
| AU2003288451B2 (en) | 2009-06-04 |
| EP1581235A1 (en) | 2005-10-05 |
| CN101264097A (zh) | 2008-09-17 |
| GB0228723D0 (en) | 2003-01-15 |
| WO2004052377A1 (en) | 2004-06-24 |
| CA2507918A1 (en) | 2004-06-24 |
| AU2003288451A1 (en) | 2004-06-30 |
| CY1109229T1 (el) | 2013-09-04 |
| NO20053042L (no) | 2005-06-21 |
| JP2011132229A (ja) | 2011-07-07 |
| DE60327557D1 (de) | 2009-06-18 |
| ES2326532T3 (es) | 2009-10-14 |
| GB0328548D0 (en) | 2004-01-14 |
| KR20050089815A (ko) | 2005-09-08 |
| NZ540353A (en) | 2006-11-30 |
| GB2396108A (en) | 2004-06-16 |
| KR101122495B1 (ko) | 2012-03-15 |
| JP2006514638A (ja) | 2006-05-11 |
| EP1581235B1 (en) | 2009-05-06 |
| US20110184065A1 (en) | 2011-07-28 |
| US8252766B2 (en) | 2012-08-28 |
| PT1581235E (pt) | 2009-07-07 |
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