CN100574804C - 治疗胃肠不适的医药组合物 - Google Patents
治疗胃肠不适的医药组合物 Download PDFInfo
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- CN100574804C CN100574804C CN200510108030A CN200510108030A CN100574804C CN 100574804 C CN100574804 C CN 100574804C CN 200510108030 A CN200510108030 A CN 200510108030A CN 200510108030 A CN200510108030 A CN 200510108030A CN 100574804 C CN100574804 C CN 100574804C
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Abstract
一种治疗和/或预防个体急性与慢性胃肠不适的组合物与方法，上述胃肠不适包括免疫缺陷或接受化疗和/或放射治疗疗程的个体的恶心，呕吐，乳糖不耐症，阻塞症状，下痢，粘膜炎，出血，减轻体重，及营养不良。上述方法包括给予该个体一组蛋白脱乙酰基酶抑制剂，或其与一第二药剂的组合。同时提供一种使用组蛋白脱乙酰基酶抑制剂的组合物与方法以保护正常组织免受化疗和/或放射治疗引发的损伤，而不会损及癌症治疗的效果。更提供一种治疗和/或预防恶病质，癌症相关疲劳，或慢性疲劳症候群的组合物与方法。
Description
技术领域
本发明涉及使用组蛋白脱乙酰基酶的抑制剂(inhibitors ofhistone deacetylase，简称HDAC)治疗或预防急性及慢性胃肠不适(gastrointestinal(GI)distress)，上述胃肠不适是由化疗及放射治疗所引发的恶心，呕吐，乳糖不耐症，阻塞症状，下痢，粘膜炎，出血，减轻体重，及营养不良。
背景技术
A.化疗与放射治疗所引发急性胃肠不适如恶心与呕吐
化疗及放射治疗所引发的恶心与呕吐会造成生活品质及身体与认知功能的显著下降，导致延缓或中断潜在治疗。
事实上，化疗及放射治疗所引发的恶心与呕吐可以严重到使病患拒绝进一步的治疗。有五种恶心与呕吐的情形与使用化疗剂和/或放射治疗有关：(1)急性化疗及放射治疗所引发的恶心与呕吐，在治疗头24小时内发生；(2)延迟型化疗及放射治疗所引发的恶心与呕吐，在治疗24小时以后发生；(3)预先型(anticipatory)化疗及放射治疗所引发的恶心与呕吐，在治疗前发生；(4)突破型(breakthrough)化疗及放射治疗所引发的恶心与呕吐，尽管病患开始预防治疗仍发生；(5)抗性(refractory)化疗及放射治疗所引发的恶心与呕吐，当在早期疗程中以止吐剂进行预防性或挽救性治疗失败时，会在后续治疗疗程中发生。
化疗及放射治疗所引发的恶心与呕吐的机制并没有明确的界线，但证据显示化疗及放射治疗所引发的恶心与呕吐有部分是经由衬在胃肠道粘膜上的肠嗜铬细胞(enterochromaffin cells)反应于细胞损伤(粘膜炎)，而释放出血清素及其它神经活化剂，上述血清素及其它神经活化剂结合至胃肠道传入迷走神经上的受体，并递送神经冲动至呕吐中枢(vomiting center，简称VC)及化学受体触发区(chemoreceptor trigger zone，简称CTZ)，其分别位于脑干侧髓区的小细胞性网状结构以及中枢神经系统(CNS)近第四脑室的最后区(area postrema)(Navari RM.J.Supp.Oncol.1：89-92，2003；Grunberg SM.J.Supp.Oncol.2：1-12，2004)。CTZ的活化也可以驱动神经传导物质的释放而进一步活化VC。被认为与化疗及放射治疗所引发的恶心与呕吐有关的CTZ神经传导物质，包括，但不限于，多巴胺(dopamine)，血清素(serotonin)，组胺(histamine)及正肾上腺素(norepinephrine)。CNS高级中枢与VC/CTZ间有直接连结存在。第V、VII、及IX对脑神经的传出分支及迷走神经与交感神经干会接着产生一套复杂协调动作，包括肌肉收缩，心血管反应及反蠕动，特征为呕吐。
有数种药剂在临床上使用于治疗化疗及放射治疗所引发的恶心与呕吐。这些药剂包括抗胆碱剂(anticholinergics)、抗组胺(antihistamines)、吩噻嗪类(phenothiazines)、丁酰苯类(butyrophenones)、大麻碱(cannabinoids)、苯甲酰胺类(benzamides)、糖皮质激素(glucocorticoids)、苯二氮平(benzodiazepines)、5-HT3受体拮抗剂(5-HT3 receptorantagonists)及三环抗忧郁剂(tricyclic antidepressants)。然而，仍有需要改善治疗药剂。
例如，锥体外路症候群(extrapyramidal symptoms)，如肌张力不全(dystonia)及静坐困难(akathisia)，镇静，抗胆碱作用及起坐性低血压(orthostatic hypote nsion)，使得吩噻嗪类成为较不欲使用的治疗法。嗜睡为抗胆碱剂显著的副作用；镇静与抗胆碱作用则为抗组胺的主要缺点。丁酰苯类的副作用包括静坐困难，肌张力不全及低血压。大麻碱则显示有限的效力以及副作用如异常欣快(euphoria)、晕眩、偏执意念(paranoid ideation)及嗜睡。苯二氮平的副作用包括知觉障碍(perceptual disturbances)、尿失禁(urinary incontinence)、低血压、下痢、镇静及健忘。类固醇作为单独给药时仅有很小的效力，且有如高血糖、异常欣快、失眠及直肠痛等副作用。三环抗忧郁剂的抗胆碱作用中比较不想发生的副作用包括口干、便秘、视力模糊、尿液滞留、增重、高血压、心悸及心律不齐。使用5-HT3受体拮抗剂如恩丹西酮(ondansetron)、格拉司琼(granisetron)及曲匹西龙(tropisetron)已显示对于延迟型恶心与呕吐的效果不如对于急性症状。5-HT3受体拮抗剂的效力显示对于中度呕吐原性(emetogenic)化疗的效果低于对于含顺铂的疗法。5-HT3受体拮抗剂对于恶心的控制显然低于对于呕吐的控制。此外，5-HT3受体拮抗剂的效力会随着重复天数与重复化疗周期而降低(Morrow et al.，Cancer76：343-357，1995)。
因此，对于增进预防与治疗恶心与呕吐的方法有所需求。
当胃肠道暴露于化疗和/或放射治疗，反应于细胞损伤(粘膜炎)，衬在胃肠道的肠嗜铬细胞会释放神经传导物质以传达讯息至中枢神经系统的VC/CTZ，造成化疗与放射治疗所引发的恶心与呕吐。然而，仅阻断胃肠道与中枢神经系统的神经传导物质作用并无法治疗所有类型的化疗与放射治疗所引发的恶心与呕吐。因此，除了标的胃肠道与中枢神经系统中活化的神经传导物质与其受体，可预防细胞损伤(粘膜炎)的方法或药剂能维持胃肠道上皮完整性，以减低胃肠道释放神经传导物质至中枢神经系统的呕吐中枢，将有用于预防与治疗化疗与放射治疗所引发的恶心与呕吐。
B.化疗与放射治疗所引发的粘膜炎
口部粘膜炎与胃肠道粘膜炎被认为是属需求各异的不同区域的消化道粘膜炎(alimentary mucositis)(Keefe，DMK.SupportiveCare Cancer.12：6-9，2004)。粘膜炎不仅为单纯地由化疗和/或放射治疗直接引起基底上皮干细胞的反应，也为由粘膜下层的结缔组织(内皮与间充质细胞)开始并标定到上皮细胞的一连串生物反应的结果(Sonis ST et al.，J.Supp.Oncol.2：21-31，2004)。由化疗和/或放射治疗所引起的粘膜炎，其病理机制可分为以下五个阶段：
第I期-起始期。化疗及放射治疗引发细胞损伤特征为活性氧(reactive oxygen species，简称ROS)的产生会破坏双链DNA，同时活化ROS依存性讯息传递路径，如蛋白质激酶c(proteinkinasec，简称PKC)。
第II期-损伤讯号产生期。损伤讯号产生期特征为转录因子如NF-κB的活化会启动前炎症细胞活素表现，如TNF-α，IL-1β，及IL-6。
第III期-损伤讯号扩增期。损伤讯号扩增是由NF-κB与TNF-α间的正向回馈环进一步增加前炎症细胞活素的数目与程度；TNF-α不仅进一步增加NF-κB的活性，也诱发外在细胞凋亡路径，造成上皮细胞死亡。
第IV期-溃疡与感染期。溃疡与感染期(中度至重度粘膜炎)特征为初步上皮细胞损失以及继发细菌移生(造成疼痛、发炎及失去功能)。
第V期-恢复期。上皮恢复(re-epithelium)的恢复过程是由暴露的细胞外基质的讯号及由粘膜下层纤维母细胞分泌的生长因子所激发。
虽然可能从第I期至第III期会有一点粘膜发红的现象，组织通常仍很完整且病患仅有轻微症状，除非进展到第IV期，发生上皮细胞死亡而发生溃疡性粘膜炎。由起始期(第I期)至恢复期(第V期)的组织损伤的进程可能在放射治疗的每个阶段或整个疗程的每个化疗周期中于胃肠道粘膜层的不同部位复发。因此，前述五个阶段皆可能成为预防、减缓、和/或增进恢复由化疗和/或放射治疗所引发细胞损伤或粘膜炎的潜在标的。然而，虽然病原学下的机制已提供治疗标的的范围，但发展治疗法的主要挑战还是在于缓和放射治疗或化疗相关毒性，以确保其可有效地标的正常组织，但不会减低放射治疗与化疗的抗肿瘤效果。
为了防止溃疡性粘膜炎的发生，最好能在进展到第IV期之前阻止病程发展。然而，若在第I期就阻断作用，可能放射治疗与化疗的杀肿瘤效果也会受到波及，因产生活性氧破坏双链DNA就是放射治疗与化疗杀肿瘤的主要机制。因此，似乎仅有第II期(如NF-κB)与第III期(如TNF-α)是预防粘膜炎且不会影响肿瘤控制效果的较佳标的。
在化疗与放射治疗造成损伤后，如TNF-α的细胞活素与如TGF-β的生长因子会在受治疗的组织产生，使炎症反应持续与扩大，并促进纤维母细胞的补充与增殖，抑制上皮细胞生长(Hill，RP.，et al.，Int.J.Radiat.Oncol.Biol.Phys.，49：353-365，2001)。对于化疗与放射治疗的损伤反应可经由持续地由上皮、内皮、与结缔组织分泌TNF-α与TGF-β而扩增，并可能是由遗传预定的细胞分化与增殖的改变所造成，导致特征为粘膜炎的组织变化(Zhou，D.，et al.，Int.J.Radiat.Biol.，77：763-772，2001)。因此，化疗与放射治疗所引发的细胞损伤可视为创伤修复过程的遗传失调。
C.组蛋白脱乙酰基酶(Histone deacetylase，简称HDAC)抑制剂为一种基因调控物
HDAC抑制剂是一群具有多基因调控能力的化合物，其能调控特定组基因的表现，是经由增加组蛋白乙酰化，由此调控染色质结构与标的基因进行转录的路径，而治疗疾病(Marks，PA.，etal.，J.Natl.Cancer Inst.，92：1210-6，2000)。HDAC抑制剂可选择性作用基因表现，改变培养的肿瘤细胞仅约2％的基因表现。经由调控相关于细胞周期抑制子、肿瘤抑制子及促肿瘤基因等特定基因，HDAC抑制剂显示，在体外与体内，对转形细胞的生长休止、分化、和/或细胞凋亡为强效诱发物。HDAC抑制剂会诱发肿瘤细胞中大量组蛋白乙酰化，造成细胞凋亡、末期分化、及生长休止，却不会毒害正常细胞(Richon，VM.，et al.，Proc.Natl.Acad.Sci.USA.，97：10014-10019，2000；Van Lint，C.，et al.，Gene Expr.，5：245-243，1996)。此外，HDAC抑制剂对染色质形态的调控可进一步使对放射处理敏感的肿瘤细胞转变放射抗性(Ferrandina，G.，et al.，Oncol.Res.，12：429-440，2001；Miller，AC.，et al.，Int.J.Radiat.Biol.，72：211-218，1997；Biade，S.，et al.，Int.J.Radiat.Biol.，77：1033-1042，2001)。实验性胚胎的染色质结构变化也暗示着HDAC抑制剂不仅为癌症治疗的候选药物，也可能治疗遗传失调症(Jaenisch，R.，et al.，Nat.Genet.，33：245-254，2003；Garber，K.，et al，J.Natl.Cancer Inst.，94：793-795，2002)。另一方面，HDAC抑制剂也可引发非组蛋白的蛋白过乙酰化。非组蛋白的蛋白如核糖体S3或NF-κB的Rel-A次单位的过乙酰化会抑制NF-κB活性并抑制前炎症细胞活素生产(TNF-α，Il-1β，Il-6，IL-8，TGF-β)(Chen，L.，et al.，Science，293：1653-1657，2001)。HDAC抑制剂在许多炎症疾病如溃疡性结肠炎及自体免疫疾病等也具有抗炎症效果(Segain，JP.，et al.，Gut，47：397-403，2000；Mishra，N.，et al.，Proc.Natl.Acad.Sci.USA.，98：2628-2633，2001；Leoni，F.，et al.，Proc.Natl.Acad.Sci.USA，99：2995-3000，2002；Chung，YL.，et al.，Mol.Ther.8：707-717，2003)。
本发明人之前的研究(Chung，YL，et al.，Mol.Cancer Ther.3：317-325，2004)发现除了抑制肿瘤生长，HDAC抑制剂还对于预防与治疗放射治疗所引发的皮肤炎与促进创伤修复有效，其经由向下调节TNF-α与TGF-β的表现。
另一项研究(Reddy P，et al.，Proc.Natl.Acad.Sci.USA.101：3921-6，2004)也显示HDAC抑制剂作为抗肿瘤剂使用可减低前炎症细胞活素如TNF-α的生产，而预防骨髓移植后的急性移殖物-抗-宿主病(graft-versus-host disease)。
HDAC抑制剂也对于适当肠上皮细胞调节很重要，其是抑制NF-κB活化与IL-8生产而调控，而有用于治疗溃疡性结肠炎(YinL，et al.，J.Biol.Chem.276：44641-6，2001；Huang N，et al.，Cytokine 9：27-36，1997)。
发明内容
因此，本发明提供一种治疗或预防免疫缺陷或接受化疗和/或放射治疗的个体的急性与慢性胃肠不适(gastrointestinaldistress)，包括恶心、呕吐、乳糖不耐症、阻塞症状、下痢、粘膜炎、出血、体重减轻及营养不良的医药组合物和方法。上述医药组合物，包括一组蛋白脱乙酰基酶抑制剂(histone deacetylaseinhibitor)或其药学上可接受盐，及一药学上可接受载体。上述医药组合物还包括一第二药剂。上述方法包括投与有效治疗剂量的HDAC抑制剂或与一第二药剂组合以及其药学上可接受的载体或其药学上可接受的盐至上述个体的口部、咽部、食道、或胃肠道组织，以治疗或预防细胞损伤，维持胃肠道上皮细胞完整性，以及减低胃肠道传入迷走神经传到中枢神经系统呕吐中枢的讯息。同时提供一种保护正常组织免受化疗和/或放射治疗所引发损伤、且不造成癌症治疗时肿瘤保护危险性的组合物与方法。更提供一种治疗或预防恶病质、癌症相关疲劳或慢性疲劳症的医药组合物与方法，因细胞活素的释放、胃肠不适、及肿瘤生长皆可采用HDAC抑制剂而抑制。
HDAC抑制剂可向上调节肿瘤抑制子，向下调节促肿瘤基因及抑制前炎症细胞活素，以抑制肿瘤生长及炎症反应。这些化合物制备成可以经口，腹腔内，椎管内，动脉内，鼻内，实质内(intraparenchymally)，皮下，肌肉内，静脉内，真皮，直肠内，及局部投与的剂型。投与剂量根据体外与体内研究观察的有效浓度而定。上述化合物的各种有效的应用可更进一步地与第二HDAC抑制剂，5-羟色胺(5-hydroxytryptamine 3，简称5-HT3)受体拮抗剂，多巴胺受体拮抗剂，多巴-5-羟色胺(DOPA-5-HT3)受体拮抗剂，神经激肽(neurokinin，简称NK)-1受体拮抗剂，抗组胺，抗胆碱剂(anticholinergics)，非类固醇抗炎症药(non-steroidanti-inflammation drug，简称NSAID)，类固醇，生长因子，细胞活素，抗氧化剂，三环抗忧郁剂，镇静剂，大麻碱(cannabinoids)，维生素，或抗生素同时或组合投与。
曾用于控制化疗及放射治疗所引发胃肠不适的药物包括抗胆碱剂，抗组胺，吩噻嗪类(phenothiazines)，丁酰苯类(butyrophenones)，大麻碱(cannabinoids)，苯甲酰胺(benzamides)，糖皮质激素(glucocorticoids)，苯二氮平(benzodiazepines)，5-HT3受体拮抗剂，及三环抗忧郁剂。上述皆无法有效抑制所有种类的化疗及放射治疗所引发的胃肠不适。寻找可保护正常组织且不损及化疗及放射治疗的抗肿瘤作用的药物是癌症治疗长久以来的目标。然而，从没有人暗示或揭露可使用HDAC抑制剂或与上述或其它药剂组合以预防粘膜炎，维持胃肠道完整性，并减低胃肠道传入迷走神经传到中枢神经的VC/CTZ的讯息，而治疗或预防化疗及放射治疗所引发的急性及慢性胃肠不适。且从没有人暗示或揭露可使用HDAC抑制剂保护正常组织而不损及化疗和/或放射治疗的肿瘤治疗效果。此外，由于细胞活素释放，胃肠不适及肿瘤生长皆可采用HDAC抑制剂抑制，更提供一种治疗或预防接受化疗和/或放射治疗疗程的个体的恶病质，癌症相关疲劳或慢性疲劳症的方法。
附图说明
图1显示载体组与空白对照组在放射处理后，会在预期粘膜炎高峰期(第14至18天)表现出预期的临床严重放射处理引发的粘膜炎评分，以及相对于载体组与空白对照组，不论在放射处理引发粘膜炎的发生率，严重度，及持续时间各方面，ASN-02(丁酸苯酯)口胶可减低平均临床粘膜炎评分。
图2A至图2F为大体照片，显示放射处理后第14天，空白与载体对照组以及ASN-02(丁酸苯酯)处理组有极大的差异。溃疡性粘膜炎发生在空白与载体对照组；相反地，ASN-02(丁酸苯酯)处理组的颊囊粘膜仍完整。图2A与图2B为ASN-02处理组；图2C与图2D为空白对照组；图2E与图2F为载体对照组。图2A，图2C，及图2E为第6天；图2B，图2D，及图2F为第14天。
图3显示放射处理粘膜后TNF-αmRNA程度的暂时变化，经内源性对照GAPDH(3-磷酸甘油醛脱氢酶)标准化，并表现为与未受放射处理粘膜样品程度的比率。每个点代表同样族群(空白组，载体组，或ASN-02(丁酸苯酯)组)的5个样品的平均mRNA程度。TNF-α向上调节的高峰期时间点与粘膜炎的发展完全相关。与空白与载体对照组相比，HDAC抑制剂可长期有效抑制异常的TNF-α表现。
具体实施方式
本发明提供一种治疗或预防有需要的个体的急性与慢性胃肠不适，包括恶心、呕吐、乳糖不耐症、阻塞症状、下痢、粘膜炎、出血、体重减轻及营养不良的方法。
上述个体有免疫缺陷(immunocompromised)或接受化疗和/或放射治疗的疗程。上述放射治疗为离子化放射治疗(ionizingradiation)，外部放射线照射治疗(external beam radiation)，近距离照射治疗(brachytherapy)，放射性药剂(radiopharmaceuticalagent)，放射性结合剂(radioactive conjugate agent)，或放射标定抗体(radiolabeled antibody)。上述方法包括投与有效治疗剂量的HDAC抑制剂或与一第二药剂组合至上述个体的口部、咽部、食道、或胃肠道组织。上述医药组合物包括一有效治疗剂量的HDAC抑制剂，或与一第二药剂组合以预防细胞损伤，维持胃肠道完整性，以及减低胃肠道传入迷走神经传到中枢神经系统VC/CTZ的讯息，结果预防与治疗急性及慢性胃肠不适。同时提供一种采用HDAC抑制剂的医药组合物与方法，以保护正常组织免受化疗及放射治疗所引发的损伤，而不会对癌症治疗发生保护肿瘤的危险性。基于抑制细胞活素释放、胃肠不适、与肿瘤生长可采用HDAC抑制剂的发现，同时提供一种治疗或预防恶病质，癌症相关疲劳或慢性疲劳症的方法。
化疗剂及放射治疗所造成的急性组织损伤被认为与自由基形成而造成氧化损伤有关。因此，化疗及放射治疗所引发急性胃肠不适的病理机制被认为直接牵涉细胞损伤或胃肠道粘膜炎，释放活化神经传导物质，造成由胃肠道传入迷走神经传到中枢神经系统的呕吐中枢的增加，而引发恶心与呕吐。急性胃肠不适的程度或强度及持续时间与化疗剂，放射来源，累积剂量，剂量强度，受影响小肠范围，及病患特征，即女性，年纪较轻，晕动症(motionsickness)病史，及少量酒精消耗密切相关。
另一方面，由化疗及放射治疗所引发的慢性胃肠道粘膜炎为癌症治疗的后期并发症，最常发生于口腔，食道，胃，胰脏，肝脏，胆管，直肠，前列腺，及骨盆恶性病。常为进行性，且会导致多种临床后果，包括乳糖不耐症，阻塞症状，慢性下痢，胃肠道出血，体重减轻，及营养不良，依损伤广度而定。通常在治疗后六或更多个月发生(平均约5年，范围由两个月至30年之久)(Waddell BE.，et al.，J.Am.Coll.Surg.189(6)：611-624，1999)。不同于急性胃肠道粘膜炎(其特征为恶心，呕吐，水样下痢，及腹痛)的发生时点，其通常在治疗中或治疗后很短的时间内发作，且会在二至六周内恢复。
化疗及放射治疗所引发的慢性粘膜炎较显著的组织病理特征为闭塞性脉管炎(occlusive vasculitis)与散布性胶原蛋白沈积与纤维化(Hasleton PS.；et al.，Histopathology 9(5)：517-534，1985)。动脉管壁显示玻璃样环状增厚，且血管内膜下有大型泡状细胞(foams cells)。可能会有毛细血管扩张(telangiectasias)。肠段与其相关浆膜在大体上可见到增厚。粘膜溃疡，坏死，及穿孔也可能随着病程而发生。进行性纤维化会导致狭窄与近端肠段扩张。生理后果可包括改变肠道运输，减低胆汁酸(bile acid)吸收，增加小肠通透性，细菌过度增生与乳糖不吸收(Yeoh E.；et al.，Am.J.Med.95(4)：397-406，1993)。
因此，由化疗及放射治疗所引发的急性与慢性胃肠不适所造成的临床表现可包括恶心，呕吐，乳糖不耐症，阻塞症状，下痢，体重减轻，营养不良，及出血。
前人研究已证实如何由起始粘膜损伤演变成后期并发症(Dorr W.；et al.，Radiothe.r Oncol.61(3)：223-231，2001)。化疗和/或放射治疗引发组织损伤如粘膜炎后，在受影响组织释放前炎症细胞活素(TNF-α和TGF-β)会延续与扩大炎症反应，促进纤维母细胞补充与增殖，但抑制上皮细胞生长。特别是，扩大损伤反应于上皮、内皮、及结缔组织细胞持续分泌TNF-α与TGF-β，这可能是由遗传预定细胞分化与增殖的改变所致。慢性活化TGF-β路径也刺激后期肿瘤生长。因此，由于异常细胞活素基因大量表现造成化疗及放射治疗所引发细胞损伤或粘膜炎可视为遗传失调，且会导致较差的创伤复原，进行性纤维化，与后期肿瘤生长。
基因调控物的一群，HDAC抑制剂，会活化与抑制一次群基因，是经由改变组蛋白乙酰化状态而重塑染色质结构(Marks et al，J.Natl.Cancer Inst.，92：1210-6，2000；Kramer et al，TrendsEndocrinol.Metab.，12：294-300，2001)。组蛋白过乙酰化会造成向上调节细胞周期抑制子(p21Cip1，p27Kip1，及p16INK4)，向下调节促肿瘤基因(Myc及Bcl-2)，抑制炎症细胞活素(介白素(IL)-1，IL-8，TNF-α，及TGF-β)，或不改变(GAPDH与γ-肌动蛋白)(Lagger et al，EMBO J.，21：2672-81，2002；Richon et al，Clin.Cancer Res.，8：662-667，2002；Richon et al，Proc.Natl.Acad.Sci.USA.，97：10014-9，2000；Van Lint et al，GeneExpr.，5：245-3，1996；Huang et al，Cytokine，9：27-36，1997；Mishra et al，Proc.Natl.Acad.Sci.USA.，98：2628-33，2001；Stockhammer et al，J.Neurosurg.，83：672-81，1995；Segainet al，Gut，47：397-403，2000；Leoni et al，Proc.Natl.Acad.Sci.USA，99：2995-3000，2002)。除了诱发组蛋白过乙酰化，HDAC抑制剂也诱发非组蛋白的蛋白的过乙酰化，如核糖体S3，p53或NF-κB的Rel-A次单位，调控蛋白激酶C(PKC)的活性，抑制蛋白的异戊二烯化(isoprenylatio n)修饰，降低DNA的甲基化，及结合至核受体(Webb et al，J.Biol.Chem.，274：14280-7，1999；Chen et al，Science，293：1653-7，2001)。更多不同机制也指出以HDAC抑制剂处理会抑制F-κB转录活性。HDAC抑制剂也显示诱发肿瘤细胞的细胞周期休止，细胞分化，及细胞凋亡，并减低炎症疾病的发炎与纤维化情形(Warrell et al，J.Natl.Cancer Inst.，90：1621-5，1998；Vigushin et al，Clin.CancerRes.，7：971-6，2001；Saunders et al，Cancer Res.，59：399-404，1999；Gottlicher et al，EMBO J.，20：6969-78，2001；Romboutset al，Acta Gastroenterol.Belg.，64：239-46，2001)。HDAC抑制剂诱发大量组蛋白乙酰化，造成肿瘤细胞的细胞凋亡，末期分化，及生长休止，然而，这些现象并不发生于正常细胞，因对于HDAC抑制剂诱发细胞凋亡的敏感性是基于细胞分化的原始状态及乙酰化组蛋白的状态(Garber et al，J.Natl.Cancer Inst.，94：793-5，2002)。此外，HDAC抑制剂调控染色质形态也进一步使本质上为放射抗性的肿瘤细胞转变为放射敏感性，亦可使肿瘤细胞对化疗更敏感(Ferrandina et al，Oncol.Res.，12：429-40，2001；Miller et al，Int.J.Radiat.Biol.，72：211-8，1997；Biadeet al，Int.J.Radiat.Biol.，77：1033-42，2001)。
基于同时地，同等地，选择性地，与实验胚胎地经由差别重塑正常与肿瘤细胞的染色质与抑制NF-κB活性而操作肿瘤细胞的抑制子、促肿瘤基因、及前炎症细胞活素(TNF-α，IL-1，IL-6)与纤维原性生长因子(TGF-β)表现的潜在可能性，可能HDAC抑制剂可经由干扰化疗与放射治疗所引发的粘膜炎的第II期(NF-κB活化)/第III期(TNF-α产生)病理机制而达成减轻胃肠道细胞损伤或粘膜炎的效果(Sonis ST et al.，J.S upp.Oncol.2：21-31，2004)，且仍可显现出癌症治疗的抗肿瘤效果与肿瘤的放射性敏感性。
媒介细胞-至-细胞的联络的炎症细胞活素与神经传导物在具有癌症或接受化疗或放射治疗的病患会大量释放。癌症、化疗或放射治疗所引发的细胞活素释放会促进疲劳发生，其经由内泌系统与神经传导物而执行其效果(Anisman H.，et al.，Can.Med.Assoc.J.155：1075-1082，1996)，例如慢性疲劳症(Moss RB.，etal.，J.Clin.Immunol.19：314-316，1999)。癌症、化疗或放射治疗所引发高浓度的TNF-α，IL-1，及IL-6已发现会促进发烧，体重减轻，流汗，与贫血，及疲劳(Kurzrock R.Cancer 92：1684-1688，2001；Wetzler M.et al.，Blood 84：3142-3147，1994)。因此，HDAC抑制剂在抑制炎症细胞活素释放，预防胃肠不适，及抑制肿瘤生长的效果可进一步降低恶病质，癌症相关疲劳，或慢性疲劳症的发生。
用于实施本发明的活性化合物通常为组蛋白过乙酰化药剂(histone hyperacetylating agents)，如HDAC抑制剂。已知有多种这类药物。参见如P.Dulski的国际专利申请案“HistoneDeacetylase as Target for Antiprotozoal Agents”，第WO97/11366号(1997年3月27日申请)。上述化合物的例子包括，但不限于以下：
A.曲古柳菌素A(Trichostatin A)及其类似物，如曲古柳菌素A(简称TSA)；及曲古柳菌素C(Koghe et al.1998.Biochem.Pharmacol.56：1359-1364)(曲古柳菌素B已经分离，但未显示具有HDAC抑制剂的活性)。
B.胜肽，如澳杉弗利廷(音译oxamflatin)([(2E)-5-[3-[(phenylsufonyl)aminophenyl]-pent-2-en-4-ynohydroxamic acid](Kim et al.Oncogene，18：2461-2470(1999))；穿普克辛A(音译trapoxin A ，简称TPX)-环四肽(cyclo-(L-phenylalanyl-L-phenylalanyl-D-pipecolinyl-L-2-amino-8-oxo-9，10-epoxy-decanoyl))(Kijima et al.，J.Biol.Chem.268，22429-22435(1993))；FR901228，缩酚酸肽(Depsipeptide)(Nakajima et al.，Ex.Cell Res.241，126-133(1998))；FR225497，环四肽(H.Mori et al.，PCT申请第WO00/08048(Feb.17，2000))；阿匹西定(音译apicidin)，环四肽([cyclo(N-O-methyl-L-tryptophanyl-L-isoleucinyl-D-pipecolinyl-L-2-amino-8-oxodecanoyl)](Darkin-Rattray et al.，Proc.Natl.Acad.Sci.USA 93，13143-13147(1996))；阿匹西定1a，阿匹西定Ib，阿匹西定Ic，阿匹西定IIa，及阿匹西定IIb(P.Dulski etal.，国际专利申请案第WO 97/11366号)；HC-毒素，环四肽(Boschet al.，Plant Cell 7，1941-1950(1995))；WF27082，环四肽(国际专利申请案第WO 98/48825号)；及克来米多辛(音译chlamydocin)(Bosch et al.，supra)。
C.氧肟酸为基的杂合极性化合物(Hydroxamic Acid-BasedHybrid Polar Compounds，简称HPCs)，如：柳酸基氧肟酸(salicylihydroxamic acid，简称SBHA)(Andrews et al.，International J.Parasitology 30，761-8(2000))；辛二酸酰基苯胺氧肟酸(suberoylanilide hydroxamic acid，简称SAHA)(Richon et al.，Proc.Natl.Acad.Sci.USA 95，3003-7(1998))；壬二酸二氧肟酸(azelaic bishydroxamic acid，简称AB HA)(Andrews et al.，supra)；壬二酸-1-氧肟酸-9-酰基苯胺(azelaic-1-hydroxamate-9-anilide，简称AAHA)(Qiu et al.，Mol.Biol Cell 11，2069-83(2000))；M-羧基肉桂酸二氧肟酰胺(M-carboxycinnamic acid bishydroxamide，简称CBHA)(Riconet al.，supra)；6-(3-氯化苯脲基)己酸氧肟酸(6-(3-chlorophenylureido)caproic hydroxamic acid，简称3-Cl-UCHA)(Richon et al.，supra)；MW2796(Andrews et al.，supra)；及MW2996(Andrews et al.，supra)；皮罗酰胺(部分音译pyroxamide)；史贵坦(音译scriptaid)；含环氧肟酸胜肽(cyclichydroxamic acid-containing peptide，简称CHAP)；A-161906(7-[4-(4-cyanophenyl)phenoxy]-heptanohydroxamicacid，Abbott制造)；PXD-101(Prolifix制造)；及LAQ-824(Novartis制造)。附注，无HDAC抑制剂效果的类似物为六亚甲基二乙酰胺(hexamethylene bisacetamide，简称HBMA)(Richon et al.1998，PNAS，95：3003-7)；及二乙基二(戊甲叉-N，N-二甲羧酰胺)丙二酸酯(diethyl bix(pentamethylene-N，N-dimethylcarboxamide)malonate，简称EMBA)(Richon et al.1998，PNAS，95：3003-7)。
D.脂肪酸化合物，如：丁酸钠(sodium butyrate)(Cousens etal.，J.Biol.Chem.254，1716-23(1979))；异戊酸酯(isovalerate)(McBain et al.，Biochem.Pharm.53：1357-68(1997))；丙戊酸(valproic acid)；戊酸酯(valerate)(McBain et al.，supra)；4-丁酸苯酯(4-phenylbutyrate，简称4-PBA)(Lea and Tulsyan，Anticancer Research，15，879-3(1995))；丁酸苯酯(phenylbutyrate，简称PB)(Wang et al.，Cancer Research，59，2766-99(1999))；丙酸酯(propionate)(McBain et al.，supra)；丁酰胺(butrymide)(Lea and Tulsyan，supra)；异丁酰胺(isobutyramide)(Lea and Tulsyan，supra)；乙酸苯酯(phenylacetate)(Lea and Tulsyan，supra)；3-溴丙酸酯(3-bromopropionate)(Lea and Tulsyan，supra)；三丁酸甘油酯(tributyrin)(Guan et al.，Cancer Research，60，749-55(2000))；丁酸精氨酸酯(arginine butyrate)；及丙戊酸酯(valproate)。
E.苯甲酰胺衍生物(Benzamide derivatives)，如：MS-27-275([N-(2-aminophenyl)-4-[N-(pyridin-3-yl-methoxycarbonyl)aminomethyl]benzamide])(Saito et al.，Proc.Natl.Acad.Sci.USA 96，4592-7(1999))；MS-27-275的3’-胺基衍生物(Saitoet al.，supra)；及CI-994(N-acetyldinaline，Pfizer制造)。
F.其它抑制剂，如：低朴第辛(音译depudecin)[其类似物(单-MTM-低朴第辛及低朴第辛-二乙醚)不会抑制HDAC](Kwon etal.1998.PNAS 95：3356-61；及史贵坦(音译scriptaid)(Su et al.2000 Cancer Research，60：3137-42)。
此处所述的组蛋白脱乙酰基酶(histone deacetylases，简称HDACs)是催化染色质体核心组蛋白的胺基端离胺酸残基除去乙酰基团。如此，HDAC与组蛋白乙酰转移酶(histone acetyltransferases，简称HATs)可调控组蛋白的乙酰化状态。组蛋白乙酰化会影响基因表现，且HDAC抑制剂，如氧肟酸为基的杂合极性化合物辛二酸酰基苯胺氧肟酸(suberoylanilide hydroxamicacid，简称SAHA)会在体外诱发转形细胞的生长休止，分化和/或细胞凋亡，与在体内抑制肿瘤生长。HDAC可依照构造相似性分成三群。第I群HDAC(即HDACs 1，2，3及8)类似于酵母菌RPD3蛋白质，位于细胞核，且可在转录共抑制子相关复合物中发现。第II群HDAC(即HDACs 4，5，6，7及9)类似于酵母菌HDA1蛋白质，位在细胞核与细胞质次细胞单位。第I群与第II群HDAC皆受到氧肟酸为基的HDAC抑制剂所抑制，如SAHA。第III群HDAC形成一构造大异于烟酰胺(nicotinamide，简称NAD)依存性酵素的族群，与酵母菌SIR2蛋白质相关，且不受氧肟酸为基的HDAC抑制剂所抑制。
此处所述的HDAC抑制剂为能在体内与在体外抑制组蛋白脱乙酰化的化合物。如此，HDAC抑制剂抑制了至少一种组蛋白脱乙酰基酶的活性。结果使乙酰化的组蛋白增加，而累积的乙酰化组蛋白是评估HDAC抑制剂活性的适当生物标记。因此，评估累积的乙酰化组蛋白的方法可以用于确认感兴趣的HDAC抑制剂活性。抑制组蛋白脱乙酰基酶活性的化合物也可以结合至其它受质，并抑制其它生物活性分子，如酵素或非组蛋白的蛋白质。
HDAC抑制剂可以药学上可接受盐形式使用。可使用的药学上可接受盐是不影响该化合物所欲医药效果者。其选择与生产可以本技术领域所熟知的方法进行。药学上可接受盐的例子包括碱金属盐，如钠盐或钾盐，碱土金属盐，如钙盐或镁盐，带有机基团的盐如铵盐，或带有机基团的盐如三乙基胺盐或乙醇胺盐。
HDAC抑制剂可以经口服或非口服投与。口服投与时，可以软或硬的胶囊，锭剂，丸剂，颗粒，粉末，溶液，悬浮液，漱口水等形式投与。非口服投与时，可以软膏，油膏，凝胶，糊剂，乳液，贴片，栓剂，纳米颗粒，微脂粒形式，注射溶液，点滴输液配方，灌肠剂，或借助可维持持续性膜吸收的固态，黏液，生物附着性物质或悬浮液的形式投与。配方制备方法与载体或载剂，分散剂或悬浮剂的选择可由熟于本技术领域者为之。HDAC抑制剂可包括第二药剂以及药学上可接受载体或其药学上可接受盐。
此处所述的药学上可接受载体包括，但不限于，具有反向热胶化(reverse-thermal gelation)特性的生物兼容性聚合物，聚合树脂，粘性聚合物凝胶，水凝胶，或生物可附着性物质。
如熟于本技术领域者所可辨认，有效剂量是依照投与途径，赋形剂的使用，及同时使用的其它治疗方法而异，上述其它治疗方法为如使用第二药剂，如第二HDAC抑制剂，5-羟色胺(5-hydroxytryptamine 3，简称5-HT3)受体拮抗剂，多巴胺受体拮抗剂，DOPA-5-HT3受体拮抗剂，神经激肽(neurokinin，简称NK)-1受体拮抗剂，抗组胺，抗胆碱剂(anticholinergics)，非类固醇抗炎症药(non-steroid anti-inflammation drug，简称NSAID)，类固醇，生长因子，细胞活素，抗氧化剂，三环抗忧郁剂，镇静剂，大麻碱(cannabinoids)，维生素，或抗生素。
多巴胺受体拮抗剂可为吩噻嗪类(phenothiazines)或丁酰苯类(butyrophenones)。5-HT3受体拮抗剂的例子为多拉司琼(dolasetron)，格拉司琼(granisetron)，恩丹西酮(ondansetron)，帕洛诺司琼(palonosetron)，或妥比司琼(音译tropistron)。DOPA-5-HT3受体拮抗剂可为甲氧氯普胺(metoclopramide)。NK-1受体拮抗剂为沃弗吡坦(音译vofopitant)；CP-122，721((+)-(2S，3S)-3-(2-methoxy-5-trifluoromethoxybenzyl)amino-2-phenylpiperidine，Pfizer制造)；CJ-11，794(Milos Dokmanovic，Paul A.Marks，Journal of Celluar Biochemistry，96：293-304，2005)；L-758，298(Merck制造)；或阿瑞吡坦(apre pitant)。此外，抗生素包括，但不限于，更昔洛韦(ganciclovir)，阿昔洛韦(acyclovir)，泛昔洛韦(famciclovir)，或四环素(tetracycline)。生长因子可为角质细胞生长因子(keratinocyte growth factor，简称KGF)，或粒细胞巨噬细胞-集落刺激因子(granulocytemacrophage-colony stimulating factor，简称GM-CSF)。抗氧化剂可为阿米福汀(amifostine)，苄达明(benzydamine)，或N-乙酰半胱氨酸(N-acetylcysteine)。维生素包括，但不限于，烟酰胺(nicotinamide)，维生素B复合物，维生素C，或维生素E。
任何特定个体(如人，狗，或猫)的有效剂量与治疗法也根据多种其它因子而异，包括所使用特定化合物的活性，个体年龄，体重，一般健康状况，性别，饮食，投与时间，排泄速率，疾病严重程度或病程，及病患染患疾病的倾向，然通常为不论投与方法为何，剂量占该组合物重量百分比的0.001％至100％。活性化合物可选择性地与第二药剂组合，以有用于对免疫缺陷或接受化疗和/或放射治疗疗程的个体预防细胞损失或粘膜炎，维持胃肠道完整性，与减低传入迷走神经由胃肠道传到中枢神经的VC/CTZ，以预防及治疗急性及慢性胃肠不适，包括恶心，呕吐，乳糖不耐症，阻塞症状，下痢，粘膜炎，出血，体重减轻，及营养不良。上述第二药剂可经口服，腹腔内，椎管内，动脉内，鼻内，实质内(intraparenchymally)，皮下，肌肉内，静脉内，真皮，直肠内，及局部投与。此外，第二药剂可配方为乳膏，胶体，油膏，糊剂，漱口水，粉末，锭剂，丸剂，颗粒，胶囊，乳液，悬浮液，微脂粒配方，纳米颗粒，贴片，栓剂，灌肠剂，点滴输液剂，或注射溶液。第二药剂可选择性地并存或连续投与。如此处所述，“并存(concurrently)”是指足够接近的时间点以产生组合效果(也就是说，并存投与可为同时，或可为二或以上次数投与间仅隔很短时间间隔)。如此处所述，“并存(concurrently)”或“组合(incombination)”投与二或多个化合物是指该二化合物投与时间足够接近，使其一的存在可改变另一的生物效果。上述二化合物可同时或连续投与。同时投与可经由在投与前混合化合物，或在同一时间点、但在不同解剖位置或采用不同途径投与二者。
为使本发明更令人了解，以下提供数个实施例。需了解以下实施例仅是用于说明本发明，并非用以限制本发明的范畴。此处所举所有参考文献的整体皆并入本案作为参考。
[实施例]
实施例1：用以治疗及预防化疗及放射治疗所引发的粘膜炎的含有HDAC抑制剂的组合物
选择性减低粘膜发病，而不损及化疗及放射治疗的杀肿瘤效果的方法是癌症治疗的长期目标。本实施例揭露一生物为基，局部施用的粘膜炎治疗法。粘膜对于载体的可接受性与医疗处置接触时间对于治疗粘膜炎药剂的效果是很重要的。然而，此方法仅有少数可用的载体或载剂。
将一HDAC抑制剂，丁酸苯酯，配方为水溶树脂中的口胶，并带有食物等级的甜味剂。水溶树脂的骨架是非离子性聚乙烯氧化物的聚合物，以用于结合，润滑，黏着，及软化特性，可符合美国药典(the United States Pharmacopoeia-National Formulary)所述。水溶树脂是使用于如控制释放固态剂量基质系统，经皮药物递送系统，及粘膜生物黏着剂。此特征允许口胶经历相转移，由口服投与的液态并在达到体温时成为胶体。此相转移作用为增加活性化合物丁酸苯酯经由接触表面的厚包覆层接触粘膜的时间。选择口胶配方是因其容易使用，粘膜较广的包覆，且病患接受度高(熟悉度高)。
例如，每毫升口胶含有50mg苯丁酸钠盐(sodiumphenylbutyrate)，1.0％水溶树脂作为生物附着物质，对羟基苯甲酸甲酯(methylparaben)作为防腐剂，糖精钠(sodium saccharin)作为甜味剂，香料及纯水。此产品为透明无色胶状粘稠液，带有香味。
实施例2：采用HDAC抑制剂治疗放射治疗所引发的粘膜炎及预防营养不良与疲劳
为评估配方于水溶树脂中含有5％丁酸苯酯的口胶(命名为ASN-02)对于治疗放射所引发的粘膜炎的效力，使用Steve Sonis博士所建立的仓鼠动物模式(Harvard School of DentalMedicine，Brigham and Women′s Hospital，Boston，Mass.)。
在研究开始时，将5至6周龄，体重约90g的雄性黄金叙利亚仓鼠以戊巴比妥钠(sodium pentobarbital)(80mg/kg)腹腔注射而麻醉。以铅罩(lead shield)使左颊囊外翻，固定并分离。并以标准化急性放射疗程引发粘膜炎。施以单一剂量的放射(40Gy/剂量)至每只实验动物的左颊囊，订为第0天。放射线是由线性加速器产生，于100公分的SSD(源皮距)下传输6MeV的电子束，速率为300cGy/分钟。此放射疗程产生口腔粘膜炎的高峰期在放射疗程后第14至18天。由第1天至第28天，每天三次，对实验动物局部施用50μl的ASN-02或载体至其左(经放射处理的)颊囊。由第6天至第28天每天评估实验动物的临床粘膜炎，体重，食欲，及活动力。粘膜炎以视觉评分系统评估。在进行视觉评分系统评估后，对每只动物的粘膜照相以便比较。
临床粘膜炎评分的说明：1-2分代表轻微粘膜炎，3-5分代表中度至重度粘膜炎。
| 评分 | 说明 |
| 0 | 颊囊完全健康。没有发红或血管扩张的现象。 |
| 1 | 轻微至重度发红与血管扩张。没有粘膜糜烂。 |
| 2 | 严重发红与血管扩张。粘膜表层糜烂，留下裸露的区域。粘膜彩斑减少。 |
| 3 | 于一或多个部位形成灰(黄)白溃疡。溃疡为黄/灰色是因有伪膜。溃疡累积大小约有颊囊的1/4。严重发红与血管扩张。 |
| 4 | 溃疡累积大小约有颊囊的1/2。失去柔软度。严重发红与血管扩张。 |
| 5 | 实际上整个颊囊皆溃疡。失去柔软度(颊囊仅有部份能由口腔翻出)。 |
粘膜炎的视觉评分数据与显示粘膜炎高峰期发展的代表性照片分别如图1与图2A-2F所示。粘膜炎严重程度随着评分数而增加。1-2分代表轻微粘膜炎，3-5分代表中度至重度粘膜炎。所显示的数值为每个配方处理或对照组(空白对照组为N＝9仓鼠，载体组为N＝9仓鼠，以及ASN-02处理组为N＝11仓鼠)的平均临床粘膜炎评分±SEM。载体与空白对照组显示在预期粘膜炎高峰期(即放射照射后第14至18天)产生预期的临床粘膜炎评分(即3至4分)。ASN-02组的11只仓鼠有5只在高峰期(第18天)有2.0与3.0之间的粘膜评分，且没有一只ASN-02组的仓鼠在整个实验过程有大于3.0分的粘膜炎。所有空白对照组中实验动物(n＝9)在高峰期(第18天)皆为＞3.0分的粘膜炎，其中有6只具有＞＝4.0的粘膜炎。所有载体组动物(n＝9)在高峰期(第18天)具有＞3.0的粘膜炎，其中有5只具有＞＝4.0的粘膜炎。ASN-02组的平均高峰期粘膜炎评分为2.3分，相对于此，载体组与空白对照组为3.75分。除了预防中度至重度粘膜炎，ASN-02还能在2天内使轻微粘膜炎由高峰期回到正常状态。每组的体重减轻、活动力下降及食欲下降皆与粘膜炎严重程度相关连。总结上述，相对于载体组与空白对照组受放射线引发口腔粘膜炎的发生率，严重度与持续时间，ASN-02(即丁酸苯酯)口胶可减低平均临床粘膜炎评分，并预防临床上疲劳症状与营养不良的情形。
实施例3：HDAC抑制剂可长期抑制放射处理所引发的异常前炎症细胞活素
放射处理引发粘膜炎的发展被认为是由于放射处理所引发持续性前炎症细胞活素如TNF-α的向上调节。因此采用多种细胞活素的RNase保护试验套组(Riboquant；Pharmingen，San Diego，CA)测量主要前炎症细胞活素TNF-α的mRNA程度，上述套组包括一模板组以产生32P-标记的反义RNA探针组，其可与标的TNF-αmRNA与内源性对照GAPDH杂交。在标记探针与标的RNA杂交后，未受保护的RNA会经核糖核酸酶(RNase)处理，而受保护的RNA片段可经6％的聚丙烯酰胺胶体解析并以磷影像(phosphorimaging，Molecular Dynamics Corp.，Sunnyvale，CA)纪录。使用密度测定法(Densitometry)定量每种mRNA的数量，并以内源性对照GAPDH标准化数据。取出受放射处理的粘膜(左颊)与未受放射处理的粘膜(右颊)并于特定时间点进行测试。
由放射处理引发TNF-α向上调节的高峰期时间点在所有族群皆与粘膜炎发展相关，请参见图3。于ASN-02(丁酸苯酯)组，TNF-α最高量是在放射处理后第1天，但在14天后随之受抑制。抑制可持续到第12个月。于空白与载体对照组，TNF-α的mRNA量于放射处理的粘膜会增加，且波动高于未受放射处理的粘膜可持续1年的期间，并在放射处理后第1天达到第一次高峰，为未受放射处理粘膜的2-3倍程度，约在放射处理后第14-28天达到第二次高峰，为10.5-16倍，且在放射处理后第9个月达到第三次高峰，为13-14倍；放射处理后第12个月时会降低到正常的2-3倍。
此结果显示HDAC抑制剂可长期抑制TNF-α的向上调节，而可减低放射处理造成的急性与慢性副作用。
[其它实施方式]
由上述说明，熟于本技术领域人士可容易地确定本发明的主要特征，且在不脱离本发明的精神与范畴之内，可对本发明作种种的变化与修饰，以适应各种应用与状况。例如，结构与功能上类似于上述HDAC抑制剂的化合物也可以用于实施本发明。因此，其它实施方式也包括在本发明申请专利范围之内。
Claims (14)
1.一种丁酸苯酯或其药学上可接受盐类在制备治疗和/或预防化疗和/或放射治疗所引起的粘膜炎及其症状的药物中的用途，上述症状包括体重减轻、活动力下降、食欲下降或营养不良，所述药物包括一丁酸苯酯或其药学上可接受盐，及一药学上可接受载体，
该药物还包括一第二药剂，其选自由一第二组蛋白脱乙酰基酶抑制剂，5-羟色胺受体拮抗剂，多巴胺受体拮抗剂，多巴-5-羟色胺受体拮抗剂，神经激肽-1受体拮抗剂，抗组胺，抗胆碱剂，非类固醇抗炎症药，抗氧化剂，三环抗忧郁剂，镇静剂，大麻碱及维生素所组成的群。
2.根据权利要求1所述的用途，其中该药物制备成适于免疫缺陷或接受化疗和/或放射治疗的个体的口腔，咽部，食道，或胃肠道组织投与的剂型。
3.根据权利要求1所述的用途，其中该药学上可接受的载体选自由一具有反向热胶化特性的生物兼容性聚合物，聚合树脂，粘性聚合物凝胶，水凝胶，以及生物可附着性物质所组成的群。
4.根据权利要求1所述的用途，其中该第二药剂是同时投与的。
5.根据权利要求1所述的用途，其中该第二药剂是连续投与的。
6.根据权利要求1所述的用途，其中该第二药剂制备成适于与丁酸苯酯或其药学上可接受盐类于不同路径投与的剂型。
7.根据权利要求1所述的用途，其中该多巴胺受体拮抗剂选自由吩噻嗪类，及丁酰苯类所组成的群。
8.根据权利要求1所述的用途，其中该5-羟色胺受体拮抗剂选自由多拉司琼，格拉司琼，恩丹西酮，帕洛诺司琼，及妥比司琼所组成的群。
9.根据权利要求1所述的用途，其中该多巴-5-羟色胺受体拮抗剂为甲氧氯普胺。
10.根据权利要求1所述的用途，其中该神经激肽-1受体拮抗剂选自由沃弗吡坦，(+)-(2S，3S)-3-(2-甲氧基-5-三氟甲氧基苯基)氨基-2-苯基哌啶及阿瑞吡坦所组成的群。
11.根据权利要求1所述的用途，其中该抗氧化剂选自由阿米福汀，苄达明，及N-乙酰半胱氨酸所组成的群。
12.根据权利要求1所述的用途，其中该维生素选自由烟酰胺，维生素B复合物，维生素C，及维生素E所组成的群。
13.一种丁酸苯酯或其药学上可接受盐类在制备治疗和/或预防癌症相关疲劳或慢性疲劳症候群的药物中的用途，所述药物包括丁酸苯酯或其药学上可接受的盐，以及一药学上可接受的载体。
14.根据权利要求13所述的用途，其中该药物制备成适于免疫缺陷或接受化疗和/或放射治疗的个体的口腔，咽部，食道，或胃肠道组织投与的剂型。
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| US20190192458A1 (en) * | 2016-04-05 | 2019-06-27 | Keio University | Therapeutic/prophylactic agent for graft-versus-host disease, fibrocyte invasion inhibitor, and inhibitor against tear reduction and reduction in goblet cells |
| CN107362362B (zh) * | 2017-07-20 | 2019-01-01 | 复旦大学 | Sirt1抑制剂在预防和治疗放射引起的肠道疾病中的应用 |
| WO2019055687A1 (en) | 2017-09-13 | 2019-03-21 | Ohio State Innovation Foundation | METHODS AND COMPOSITIONS FOR THE TREATMENT OF CANCER CACHEXIA |
| WO2019104936A1 (zh) * | 2017-11-28 | 2019-06-06 | 上海交通大学医学院附属新华医院 | 含丁酸类化合物的组合物及其应用 |
| CN108126201B (zh) * | 2018-01-29 | 2020-09-01 | 南京大学 | 肠道菌抗生素在制备防治化疗并发症药物中的应用 |
| CN109745563B (zh) * | 2019-01-09 | 2021-04-16 | 复旦大学 | Sirt1抑制剂用于预防和治疗放射引起的口腔损伤 |
| CN113694202B (zh) * | 2020-06-29 | 2023-03-31 | 江苏省中医院 | Ass1或bckdk抑制剂在制备治疗溃疡性结肠炎的药物中的应用 |
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| CN115737616A (zh) * | 2021-11-29 | 2023-03-07 | 南方医科大学南方医院 | Lmk-235在医学中的新应用 |
| CN117017967A (zh) * | 2023-08-31 | 2023-11-10 | 中山大学附属第六医院 | 三丁酸甘油酯及其衍生物在制备预防和/或治疗放疗引起的消化道并发症药物中的应用 |
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2005
- 2005-04-07 US US11/100,788 patent/US20060229237A1/en not_active Abandoned
- 2005-07-28 JP JP2005218682A patent/JP2006290863A/ja active Pending
- 2005-08-25 TW TW094129073A patent/TWI283572B/zh not_active IP Right Cessation
- 2005-10-09 CN CN200510108030A patent/CN100574804C/zh not_active Expired - Fee Related
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Also Published As
| Publication number | Publication date |
|---|---|
| CN1843508A (zh) | 2006-10-11 |
| TWI283572B (en) | 2007-07-11 |
| JP2006290863A (ja) | 2006-10-26 |
| US20060229237A1 (en) | 2006-10-12 |
| TW200635573A (en) | 2006-10-16 |
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