WO2023098416A1 - 含nad和cd38抑制剂的药物组合物及其用途 - Google Patents

含nad和cd38抑制剂的药物组合物及其用途 Download PDF

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WO2023098416A1
WO2023098416A1 PCT/CN2022/130472 CN2022130472W WO2023098416A1 WO 2023098416 A1 WO2023098416 A1 WO 2023098416A1 CN 2022130472 W CN2022130472 W CN 2022130472W WO 2023098416 A1 WO2023098416 A1 WO 2023098416A1
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nad
inhibitor
pharmaceutical composition
mice
pharmaceutical
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葛均波
孙爱军
罗伟
王伟
王康林
王磊
张倍健
董正
翁鑫宇
赵永超
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合肥康诺生物制药有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7084—Compounds having two nucleosides or nucleotides, e.g. nicotinamide-adenine dinucleotide, flavine-adenine dinucleotide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/02—Antidotes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

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  • the invention belongs to the field of pharmaceutical compositions, and in particular relates to NAD-containing pharmaceutical compositions and applications thereof.
  • Anthracyclines represented by doxorubicin
  • doxorubicin are an important class of chemotherapy drugs, which are widely used in the treatment of solid and hematological malignancies, such as breast cancer, acute leukemia, and lymphoma.
  • DIC doxorubicin-induced cardiotoxicity
  • the new liposomal doxorubicin has improved the targeting of tumors, its cardiotoxicity has not been completely eliminated.
  • congestive heart failure caused by doxorubicin occurs, the fatality rate is as high as 50%.
  • Dextropropanimine is the only drug approved by the FDA for the prevention of DIC.
  • its poor effect and side effects force people to constantly look for new and effective prevention and treatment drugs.
  • Nicotinamide adenine dinucleotide (Nicotinamide adenine dinucleotide, NAD) is an important coenzyme in the process of cell metabolism, participates in the mitochondrial mitochondrial electron transporter, is the coenzyme of many dehydrogenases in the body, and plays an important role in maintaining mitochondrial homeostasis and cell nucleus damage important role in the restoration process.
  • NAD intracellular neurodegenerative diseases
  • diabetes for example, diabetes, ischemic heart disease, heart failure, etc.
  • Exogenous supplementation of NAD or endogenous stimulation of NAD synthesis can effectively delay aging and prevent and treat various diseases.
  • the latest research has found that the imbalance of NAD homeostasis promotes the occurrence of DIC, and increasing the level of NAD in the heart can reduce DIC. Therefore, NAD is expected to become an important target for the prevention and treatment of DIC and other diseases.
  • the invention provides a composition containing NAD (nicotinamide adenine dinucleotide) and a CD38 inhibitor to reduce cardiotoxicity caused by cancer chemotherapy drugs.
  • NAD nicotinamide adenine dinucleotide
  • the present invention provides a pharmaceutical composition in one embodiment, the pharmaceutical composition comprising nicotinamide adenine dinucleotide and a CD38 inhibitor.
  • the pharmaceutical composition comprising nicotinamide adenine dinucleotide and a CD38 inhibitor.
  • nicotinamide adenine dinucleotide can be administered in an oxidized state or a reduced state.
  • the CD38 inhibitor is selected from compound 78c.
  • compound 78c also known as CD38-IN-78c, MDK-7553, CAS No. 1700637-55-3.
  • the mass ratio of nicotinamide adenine dinucleotide to CD38 inhibitor in the composition is 1:20 to 20:1.
  • the mass ratio of nicotinamide adenine dinucleotide to CD38 inhibitor in the composition is 1:10 to 10:1.
  • the mass ratio of nicotinamide adenine dinucleotide to CD38 inhibitor in the composition is 1:5 to 5:1.
  • the present invention provides a pharmaceutical preparation comprising the pharmaceutical composition described in any one of the above.
  • the formulation is selected from a liquid dosage form, a solid dosage form, a semi-solid dosage form or a gaseous dosage form.
  • the liquid dosage forms include solutions, injections, infusions or oral liquids;
  • the solid dosage forms include tablets, capsules, powders or granules;
  • the semisolid dosage forms include ointments or gels;
  • Gaseous dosage forms include aerosols or sprays.
  • the present invention provides an application of the pharmaceutical composition or the pharmaceutical preparation in the preparation of cardiotoxicity drugs for the prevention and/or treatment of cancer chemotherapy drugs.
  • the use is selected from doxorubicin-induced cardiotoxicity.
  • compound 78c also known as CD38-IN-78c, MDK-7553, CAS No. 1700637-55-3.
  • the invention provides a pharmaceutical composition containing NAD (nicotinamide adenine dinucleotide), which enhances the effect of NAD on the prevention and/or treatment of cardiotoxicity caused by cancer chemotherapy drugs, and expands the therapeutic range of NAD.
  • NAD nicotinamide adenine dinucleotide
  • Figure 1 The expression of CD38 in endothelial cells was significantly increased after doxorubicin treatment
  • mice involved in the examples were purchased from Changzhou Calvin Experimental Animal Center; NAD and 78c drugs were from Kaifeng Kangnuo Pharmaceutical Co., Ltd. and Selleck Chemicals respectively; Adriamycin was provided by Sigma Company of the United States; NAD detection kit was purchased from Bi Yuntian Biological Co., Ltd. Animal experiments were approved by the Ethics Committee of Zhongshan Hospital affiliated to Fudan University.
  • mice Eight-week-old C57BL/6 male mice were injected with 5 mg/kg doxorubicin or normal saline into the tail vein, once a week for four consecutive weeks. Four weeks after the last administration, the mice were subjected to echocardiography to detect the cardiac function of the mice, and the myocardial tissue of the mice was taken to detect the NAD content.
  • mice were intraperitoneally injected with the same volume of normal saline as that of the experimental group, the administration frequency was once a day, and the duration period was the same as that of the DIC model administration period. After the administration, echocardiography was performed on the mice to detect the heart function of the mice, and the myocardial tissue of the mice was taken to detect the NAD + content.
  • NAD synthase Nampt agonist group NAD synthase Nampt agonist P7C3 was dissolved in DMSO, and 20 mg/kg NAD synthase Nampt agonist P7C3 was injected intraperitoneally into mice. same. After the administration, the myocardial tissue of the mice was taken to detect the NAD + content.
  • NAD-depleting enzyme PARP inhibitor group NAD-depleting enzyme PARP inhibitor Olaparib was dissolved in DMSO, and mice were injected intraperitoneally with 10 mg/kg NAD-consuming enzyme PARP inhibitor Olaparib. The frequency of Olaparib was once a day, and the continuous period was the same as that of the DIC model. same. After the administration, the myocardial tissue of the mice was taken to detect the NAD + content.
  • CD38 inhibitor group CD38 inhibitor 78c was dissolved in DMSO, and 10 mg/kg of CD38 inhibitor 78c was injected intraperitoneally into mice. The frequency of 78c administration was once a day, and the duration was the same as that of the DIC model. After the administration, the myocardial tissue of the mice was taken to detect the NAD + content.
  • NAD synthase Nampt agonist+DOX group NAD synthase Nampt agonist P7C3 was dissolved in DMSO, and in the DIC model 3 hours before doxorubicin injection, 20 mg/kg NAD synthase Nampt agonist P7C3, P7C3 was intraperitoneally injected into mice The frequency of medication was once a day and continued until the end of the DIC model. After the end of the model, the myocardial tissue of the mice was taken to detect the NAD + content.
  • NAD-depleting enzyme PARP inhibitor Olaparib NAD-consuming enzyme PARP inhibitor Olaparib was dissolved in DMSO, and in the DIC model 3 hours before doxorubicin injection, 10 mg/kg NAD-consuming enzyme PARP inhibitor Olaparib, Olaparib was injected intraperitoneally into mice The frequency of medication was once a day and continued until the end of the DIC model. After the end of the model, the myocardial tissue of the mice was taken to detect the NAD + content.
  • CD38 inhibitor + DOX group CD38 inhibitor 78c was dissolved in DMSO, and 10 mg/kg of CD38 inhibitor 78c was injected intraperitoneally into mice 3 hours before doxorubicin injection in the DIC model, and the frequency of 78c administration was once a day until DIC Model endpoint. After the model ended, echocardiography was performed on the mice to detect the heart function of the mice, and the myocardial tissue of the mice was taken to detect the NAD + content.
  • NAD+DOX group NAD was dissolved in normal saline, and 50 mg/kg NAD was intraperitoneally injected into the mice 3 hours before doxorubicin injection in the DIC model, and the frequency of NAD administration was once a day until the end of the DIC model. After the model ended, echocardiography was performed on the mice to detect the heart function of the mice, and the myocardial tissue of the mice was taken to detect the NAD content.
  • NAD synthase Nampt agonist+NAD+DOX group NAD synthase Nampt agonist P7C3 was dissolved in DMSO, and 50 mg/kg NAD and 20 mg/kg NAD synthesis were injected intraperitoneally into mice 3 hours before doxorubicin injection in the DIC model Enzyme Nampt agonist P7C3, the frequency of P7C3 administration was once a day, and continued until the end of the DIC model. After the end of the model, the myocardial tissue of the mice was taken to detect the NAD + content.
  • NAD-depleting enzyme PARP inhibitor+NAD+DOX group NAD-depleting enzyme PARP inhibitor Olaparib was dissolved in DMSO, and 50 mg/kg NAD and 10 mg/kg NAD were injected intraperitoneally into mice 3 hours before doxorubicin injection in the DIC model Enzyme PARP inhibitor Olaparib, the frequency of Olaparib is once a day, continuing to the end of the DIC model. After the end of the model, the myocardial tissue of the mice was taken to detect the NAD + content.
  • CD38 inhibitor+NAD+DOX group CD38 inhibitor 78c was dissolved in DMSO, and 50mg/kg NAD and 10mg/kg CD38 inhibitor 78c were intraperitoneally injected into mice 3 hours before doxorubicin injection in the DIC model, and the frequency of 78c medication Once a day, continued until the end of the DIC model. After the model ended, echocardiography was performed on the mice to detect the heart function of the mice, and the myocardial tissue of the mice was taken to detect the NAD + content.
  • mice of the present invention are treated with doxorubicin, and at the same time given NAD synthetase Nampt agonist P7C3, NAD consuming enzyme PARP inhibitor Olaparib, NAD consuming enzyme CD38 inhibitor 78c and NAD.
  • NAD synthetase Nampt agonist P7C3 NAD synthetase Nampt agonist
  • PARP inhibitor Olaparib NAD consuming enzyme CD38 inhibitor 78c
  • NAD NAD consuming enzyme
  • NAD or 78c alone can moderately increase the NAD level of the heart, but the combination of NAD and 78c can significantly increase the NAD content of the heart tissue, and the combination group of NAD and the NAD-consuming enzyme PARP inhibitor Olaparib has no significant difference compared with the NAD alone group.
  • the combination group of NAD and Nampt agonist P7C3 was also significantly weaker than the combination group of NAD and 78c in increasing NAD content.

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Abstract

一种含烟酰胺腺嘌呤二核苷酸和CD38抑制剂的药物组合物及其用途，CD38抑制剂优选化合物78c。药物组合物用于制备预防和/或治疗抗肿瘤药物引发的心脏毒性药物中的应用，所述应用选自阿霉素引发的心脏毒性。

Description

含NAD和CD38抑制剂的药物组合物及其用途 技术领域
本发明属于药物组合物领域，具体涉及含NAD的药物组合物及其用途。
背景技术
以阿霉素为代表的蒽环类药物，是一类重要的化疗药物，被广泛的应用于实体和血液系统恶性肿瘤的治疗，如乳腺癌、急性白血病、淋巴瘤等。然而，阿霉素引起的心脏毒性(Doxorubicin-induced cardiotoxicity，DIC)严重限制了它的临床应用。尽管新型脂质体阿霉素提高了对肿瘤的靶向性，但是仍然没有彻底消除其引起的心脏毒性。阿霉素引起的充血性心力衰竭一旦发生，致死率高达50％。目前DIC目前没有效的治疗措施，右丙亚胺是现在FDA唯一批准的用于预防DIC的药物，但是其欠佳的效果和产生的副作用迫使人们不断寻找新型有效的防治药物。
阿霉素引起的心脏毒性机制主要包括，线粒体损伤，细胞核DNA损伤，活性氧大量产生等。烟酰胺腺嘌呤二核苷酸(Nicotinamide adenine dinucleotide，NAD)是细胞代谢过程中的重要辅酶，参与线粒体粒体电子转递体，是体内很多脱氢酶的辅酶，在维持线粒体稳态和细胞核损伤修复的过程中发挥重要作用。
大量临床前研究表明，细胞内NAD水平的降低促进了衰老以及多种疾病的进展，例如，神经退行性疾病，糖尿病，缺血性心脏病，心力衰竭等。通过外源补充NAD或者内源性激动NAD合成，可以有效延缓衰老，防治多种疾病。尤其，最新研究发现，NAD稳态失衡促进了DIC发生，提高心脏NAD水平可以减少DIC，因此，NAD被寄予厚望，有望成为防治DIC以及其他疾病的重要靶点。尽管大量动物研究证实了通过外源补充NAD提高组织NAD水平的可行性，但近期临床 研究发现，人体补充外源NAD并没有显著提高组织的NAD水平。NAD补充效率过低，大大削弱了NAD在防治疾病中的作用以及限制了其广泛的临床应用。
发明内容
(一)解决的技术问题
本发明提供了一种含NAD(烟酰胺腺嘌呤二核苷酸)和CD38抑制剂的组合物，减少癌症化疗药物引起的心脏毒性。
(二)技术方案
为实现以上目的，本发明在一个实施例中提供了一种药物组合物，所述药物组合物包含烟酰胺腺嘌呤二核苷酸和CD38抑制剂。其中，烟酰胺腺嘌呤二核苷酸可以以氧化态或还原态用药。
优选地，所述CD38抑制剂选自化合物78c。其中，化合物78c，又名CD38-IN-78c，MDK-7553，CAS No.1700637-55-3。
优选地，所述组合物中烟酰胺腺嘌呤二核苷酸与CD38抑制剂的质量比为1:20至20:1。
优选地，所述组合物中烟酰胺腺嘌呤二核苷酸与CD38抑制剂的质量比为1:10至10:1。
优选地，所述组合物中烟酰胺腺嘌呤二核苷酸与CD38抑制剂的质量比为1:5至5:1。
在一个实施例中，本发明提供一种药物制剂，所述药物制剂包含上述任一项所述的药物组合物。
优选地，所述制剂选自液体剂型、固体剂型、半固体剂型或气体剂型。
优选地，所述液体剂型包括溶液剂、注射剂、输液剂或口服液；所述固体剂型包括片剂、胶囊剂、散剂或颗粒剂；所述半固体剂型包括软膏剂或凝胶剂；所述气体剂型包括气雾剂或喷雾剂。
在另一个实施例中，本发明提供了一种所述药物组合物或所述药 物制剂在制备预防和/或治疗癌症化疗药物引发的心脏毒性药物中的应用。
优选地，所述应用选自阿霉素引发的心脏毒性。
其中，化合物78c，又名CD38-IN-78c，MDK-7553，CAS No.1700637-55-3。
(三)有益效果
本发明提供了一种含NAD(烟酰胺腺嘌呤二核苷酸)的药物组合物，增强了NAD对癌症化疗药物引发的心脏毒性预防和/或治疗的效果，扩大了NAD的治疗范围。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案，下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本发明的一些实施例，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他的附图。
图1阿霉素处理后显著增加内皮细胞表达CD38；
图2NAD联合78c显著增加心脏组织NAD含量；
图3NAD联合78c显著改善心功能；
注：图中*p<0.05，**p<0.01,***p<0.001。
具体实施方式
为使本发明实施例的目的、技术方案和优点更加清楚，下面将结合本发明实施例中的附图，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
下面通过具体的实施例进行详细的说明。
实施例中涉及的小鼠购自常州卡文实验动物中心；NAD和78c药 物分别来自开封康诺药业有限公司和Selleck Chemicals公司；阿霉素由美国Sigma公司提供；NAD检测试剂盒购自碧云天生物有限公司。动物实验已通过复旦大学附属中山医院伦理委员会批准。
心脏毒性(Doxorubicin-induced cardiotoxicity，DIC)模型可参见文献:“Doxorubicin Blocks Cardiomyocyte Autophagic Flux by Inhibiting Lysosome Acidification.Circulation.2016；133:1668–1687.”；
78c抑制CD38活性可参考文献“A Potent and Specific CD38 Inhibitor Ameliorates Age-Related Metabolic Dysfunction by Reversing Tissue NAD+Decline.Cell Metabolism.2018.03.016”。
实施例1 阿霉素心脏毒性模型构建方法
对8周大的C57BL/6雄性小鼠尾静脉注射5mg/kg的阿霉素或者生理盐水，给药频率为每周一次，连续四周。最后一次给药后4周，对小鼠行超声心动图检测小鼠心脏功能，并取小鼠心肌组织，检测NAD含量。
实施例2
空白对照组：给小鼠腹腔注射与实验组同等体积含量的生理盐水，给药频率为每天一次，持续周期与DIC模型给药周期相同。给药结束后，对小鼠行超声心动图检测小鼠心脏功能，并取小鼠心肌组织，检测NAD +含量。
NAD合成酶Nampt激动剂组：NAD合成酶Nampt激动剂P7C3用DMSO溶解，给小鼠腹腔注射20mg/kg NAD合成酶Nampt激动剂P7C3，P7C3用药频率为每天一次，持续周期与DIC模型给药周期相同。给药结束后，取小鼠心肌组织，检测NAD +含量。
NAD消耗酶PARP抑制剂组：NAD消耗酶PARP抑制剂Olaparib用DMSO溶解，给小鼠腹腔注射10mg/kg NAD消耗酶PARP抑制剂Olaparib，Olaparib用药频率为每天一次，持续周期与DIC模型给药周期相同。给药结束后，取小鼠心肌组织，检测NAD +含量。
CD38抑制剂组：CD38抑制剂78c用DMSO溶解，给小鼠腹腔注 射10mg/kg CD38抑制剂78c，78c用药频率为每天一次，持续周期与DIC模型给药周期相同。给药结束后，取小鼠心肌组织，检测NAD +含量。
NAD合成酶Nampt激动剂+DOX组：NAD合成酶Nampt激动剂P7C3用DMSO溶解，在DIC模型中阿霉素注射前3小时，给小鼠腹腔注射20mg/kg NAD合成酶Nampt激动剂P7C3，P7C3用药频率为每天一次，持续到DIC模型终点。模型结束后，取小鼠心肌组织，检测NAD +含量。
NAD消耗酶PARP抑制剂+DOX组：NAD消耗酶PARP抑制剂Olaparib用DMSO溶解，在DIC模型中阿霉素注射前3小时，给小鼠腹腔注射10mg/kg NAD消耗酶PARP抑制剂Olaparib，Olaparib用药频率为每天一次，持续到DIC模型终点。模型结束后，取小鼠心肌组织，检测NAD +含量。
CD38抑制剂+DOX组：CD38抑制剂78c用DMSO溶解，在DIC模型中阿霉素注射前3小时，给小鼠腹腔注射10mg/kg CD38抑制剂78c，78c用药频率为每天一次，持续到DIC模型终点。模型结束后，对小鼠行超声心动图检测小鼠心脏功能，并取小鼠心肌组织，检测NAD +含量。
NAD+DOX组：NAD用生理盐水溶解，在DIC模型中阿霉素注射前3小时，给小鼠腹腔注射50mg/kg NAD，NAD用药频率为每天一次，持续到DIC模型终点。模型结束后，对小鼠行超声心动图检测小鼠心脏功能，并取小鼠心肌组织，检测NAD含量。
NAD合成酶Nampt激动剂+NAD+DOX组：NAD合成酶Nampt激动剂P7C3用DMSO溶解，在DIC模型中阿霉素注射前3小时，给小鼠腹腔注射50mg/kg NAD以及20mg/kg NAD合成酶Nampt激动剂P7C3，P7C3用药频率为每天一次，持续到DIC模型终点。模型结束后，取小鼠心肌组织，检测NAD +含量。
NAD消耗酶PARP抑制剂+NAD+DOX组：NAD消耗酶PARP抑 制剂Olaparib用DMSO溶解，在DIC模型中阿霉素注射前3小时，给小鼠腹腔注射50mg/kg NAD以及10mg/kg NAD消耗酶PARP抑制剂Olaparib，Olaparib用药频率为每天一次，持续到DIC模型终点。模型结束后，取小鼠心肌组织，检测NAD +含量。
CD38抑制剂+NAD+DOX组：CD38抑制剂78c用DMSO溶解，在DIC模型中阿霉素注射前3小时，给小鼠腹腔注射50mg/kg NAD以及10mg/kg CD38抑制剂78c，78c用药频率为每天一次，持续到DIC模型终点。模型结束后，对小鼠行超声心动图检测小鼠心脏功能，并取小鼠心肌组织，检测NAD +含量。
研究结果表明：阿霉素处理后，小鼠心脏组织CD38表达明显升高，并且主要表达在内皮细胞标志物CD31阳性的区域(如图1所示)。
另外，人体内主要有三个消耗NAD +的途径，分别是sirtuins信号通路、PARP信号通路以及CD38途径。本发明小鼠接受阿霉素处理，同时给予NAD合成酶Nampt激动剂P7C3，NAD消耗酶PARP抑制剂Olaparib，NAD消耗酶CD38抑制剂78c和NAD。如图2所示，阿霉素处理后，与对照组相比，小鼠心脏组织NAD含量明显下降。NAD或78c单独使用能够适量提高心脏NAD水平，但是NAD与78c联合应用却可以显著提高心脏组织NAD含量，其中NAD和NAD消耗酶PARP抑制剂Olaparib的联合组与NAD单独使用组相比却无显著性差异；NAD和Nampt激动剂P7C3的联合组在提高NAD含量方面也明显弱于NAD与78c的联合组。
模型终点对小鼠心功能进行评价，结果如图3显示，阿霉素处理显著降低了小鼠心脏射血分数和缩短分数，NAD或78c单独使用可以改善心功能，然而NAD联合78c却可以显著改善心功能。
需要说明的是，在本文中，诸如第一和第二等之类的关系术语仅仅用来将一个实体或者操作与另一个实体或操作区分开来，而不一定要求或者暗示这些实体或操作之间存在任何这种实际的关系或者顺序。 而且，术语“包括”、“包含”或者其任何其他变体意在涵盖非排他性的包含，从而使得包括一系列要素的过程、方法、物品或者设备不仅包括那些要素，而且还包括没有明确列出的其他要素，或者是还包括为这种过程、方法、物品或者设备所固有的要素。在没有更多限制的情况下，由语句“包括一个……”限定的要素，并不排除在包括所述要素的过程、方法、物品或者设备中还存在另外的相同要素。
以上实施例仅用以说明本发明的技术方案，而非对其限制；尽管参照前述实施例对本发明进行了详细的说明，本领域的普通技术人员应当理解：其依然可以对前述各实施例所记载的技术方案进行修改，或者对其中部分技术特征进行等同替换；而这些修改或者替换，并不使相应技术方案的本质脱离本发明各实施例技术方案的精神和范围。

Claims (10)

  1. 一种药物组合物，其特征在于，所述药物组合物包含烟酰胺腺嘌呤二核苷酸和CD38抑制剂。
  2. 根据权利要求1所述的药物组合物，其特征在于，所述CD38抑制剂选自化合物78c。
  3. 根据权利要求1-2任一项所述的药物组合物，其特征在于，所述组合物中烟酰胺腺嘌呤二核苷酸与CD38抑制剂的质量比为1:20至20:1。
  4. 根据权利要求3所述的药物组合物，其特征在于，所述组合物中烟酰胺腺嘌呤二核苷酸与CD38抑制剂的质量比为1:10至10:1。
  5. 根据权利要求4所述的药物组合物，其特征在于，所述组合物中烟酰胺腺嘌呤二核苷酸与CD38抑制剂的质量比为1:5至5:1。
  6. 一种药物制剂，其特征在于，所述药物制剂包含权利要求1-5任一项所述的药物组合物。
  7. 如权利要求6所述的药物制剂，其特征在于，所述制剂选自液体剂型、固体剂型、半固体剂型或气体剂型。
  8. 如权利要求7所述的药物制剂，其特征在于，所述液体剂型包括溶液剂、注射剂、输液剂或口服液；所述固体剂型包括片剂、胶囊剂、散剂或颗粒剂；所述半固体剂型包括软膏剂或凝胶剂；所述气体剂型包括气雾剂或喷雾剂。
  9. 如权利要求1-5所述的任一项药物组合物或权利要求6-8所述的任一项药物制剂在制备预防和/或治疗抗肿瘤药物引发的心脏毒性药物中的应用。
  10. 如权利要求9所述的应用，其特征在于，所述应用选自阿霉素 引发的心脏毒性。
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