WO2023040716A1 - Utilisation de nicotinamide adénine dinucléotide dans le traitement de la cardiotoxicité induite par la doxorubicine - Google Patents
Utilisation de nicotinamide adénine dinucléotide dans le traitement de la cardiotoxicité induite par la doxorubicine Download PDFInfo
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- WO2023040716A1 WO2023040716A1 PCT/CN2022/117468 CN2022117468W WO2023040716A1 WO 2023040716 A1 WO2023040716 A1 WO 2023040716A1 CN 2022117468 W CN2022117468 W CN 2022117468W WO 2023040716 A1 WO2023040716 A1 WO 2023040716A1
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- dox
- doxorubicin
- nad
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- adenine dinucleotide
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- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 title claims abstract description 87
- 229960004679 doxorubicin Drugs 0.000 title claims abstract description 31
- 229950006238 nadide Drugs 0.000 title claims abstract description 19
- 206010048610 Cardiotoxicity Diseases 0.000 title claims abstract description 15
- 231100000259 cardiotoxicity Toxicity 0.000 title claims abstract description 15
- BAWFJGJZGIEFAR-NNYOXOHSSA-N NAD zwitterion Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 BAWFJGJZGIEFAR-NNYOXOHSSA-N 0.000 title claims abstract description 14
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 title claims abstract description 11
- 239000004480 active ingredient Substances 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 2
- 230000004217 heart function Effects 0.000 abstract description 6
- 230000034994 death Effects 0.000 abstract description 5
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- BAWFJGJZGIEFAR-NNYOXOHSSA-O NAD(+) Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 BAWFJGJZGIEFAR-NNYOXOHSSA-O 0.000 description 22
- 241000699670 Mus sp. Species 0.000 description 9
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- 208000037891 myocardial injury Diseases 0.000 description 3
- 238000011740 C57BL/6 mouse Methods 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
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- 238000010172 mouse model Methods 0.000 description 2
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- DEGAKNSWVGKMLS-UHFFFAOYSA-N calcein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC(CN(CC(O)=O)CC(O)=O)=C(O)C=C1OC1=C2C=C(CN(CC(O)=O)CC(=O)O)C(O)=C1 DEGAKNSWVGKMLS-UHFFFAOYSA-N 0.000 description 1
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Images
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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
- A61K31/70—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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
Definitions
- the invention relates to the application of nicotinamide adenine dinucleotide in treating cardiotoxicity induced by doxorubicin, and belongs to the technical field of biomedicine.
- Doxorubicin is one of the most widely used anti-tumor drugs in clinical practice, and its main mechanism is to kill tumor cells by inhibiting DNA and RNA synthesis.
- cardiotoxicity caused by doxorubicin often limits its clinical application.
- great progress has been made in reducing cardiotoxicity by encapsulating doxorubicin in liposomes, it is still impossible to completely prevent myocardial injury caused by doxorubicin. Therefore, it is urgent to discover new targets for the treatment of cardiotoxicity caused by doxorubicin from a new perspective.
- doxorubicin Abnormal myocardial energy metabolism is an important pathological basis of doxorubicin-induced myocardial injury, and mitochondria, as the main place to provide ATP, play a key role in it. It has been reported that doxorubicin can lead to increased apoptosis of the mitochondrial pathway in cardiomyocytes, dysregulation of mitophagy homeostasis, and metabolic dysfunction such as the tricarboxylic acid cycle. Therefore, improving mitochondrial function could serve as a potential target to prevent doxorubicin-induced myocardial injury.
- Nicotinamide adenine dinucleotide is an essential coenzyme to maintain mitochondrial metabolism and function.
- NAD+ can act as an electron acceptor to transfer energy in different metabolic pathways such as fatty acid oxidation and tricarboxylic acid cycle.
- NAD+ is also required for mitochondrial oxidative phosphorylation, and NAD+ deficiency will result in the inability of mitochondria to produce ATP.
- the therapeutic advantage of targeting NAD+ against doxorubicin-induced cardiotoxicity has not yet been explored.
- the technical problem to be solved by the present invention is: how to improve the cardiotoxicity induced by doxorubicin.
- the present invention provides the application of nicotinamide adenine dinucleotide in the preparation of drugs for treating doxorubicin-induced cardiotoxicity.
- the medicament includes a medically acceptable carrier and an effective amount of an active ingredient, and the active ingredient is nicotinamide adenine dinucleotide.
- the present invention proves that the heart function of the DOX+NAD group is significantly improved compared with the DOX+Control group through animal experiments; the present invention proves that the proportion of dead cells in the DOX+NAD group is significantly lower than that of the DOX+PBS group through cell experiments;
- the present invention proposes the application of nicotinamide adenine dinucleotide in the treatment of doxorubicin-induced cardiotoxicity for the first time.
- the use of NAD can reduce the death of cardiomyocytes caused by doxorubicin and relieve the cardiotoxicity caused by doxorubicin.
- To combat the side effects of doxorubicin expand the scope of use of doxorubicin, and improve the prognosis of tumor patients who are clinically treated with doxorubicin.
- Fig. 1 is the left ventricular ejection fraction (LVEF) result of detection mouse model
- Fig. 2 is the left ventricular fractional contraction rate (LVFS) result of detecting mouse model
- Fig. 3 is the death and life staining result of cardiomyocytes; Wherein, green represents living cells (shown by dots in the figure), red represents dead cells (shown by circles in the figure);
- Figure 4 is the proportion of dead cells in each group
- N means not significant (no statistical difference); *: means p ⁇ 0.05; **: means p ⁇ 0.01; ***: means p ⁇ 0.001.
- the DOX+Control group and the DOX+NAD group were intraperitoneally injected with DOX (15mg/kg, Sigma, D1515), and then the Sham+NAD group and the DOX+NAD group continued to NAD (50mg/kg/d, Selleck, S2518) was injected intraperitoneally, and the same amount of normal saline was injected into the Sham+Control group and DOX+Control group, and the cardiac function of the mice was checked 7 days later.
- Echocardiography was detected at 4 weeks, and the frequency of the probe was 30 MHz. Specifically, after isoflurane gas anesthesia, the M-mode images were recorded when the heart rate of the mouse was maintained at 450-500 beats/min. B-Mode images of parasternal long-axis view and apical four-chamber view were collected. The parasternal left ventricular short axis was taken, and 2D ultrasound was used to show the left ventricular short axis view. M-mode ultrasound was used to record the left ventricular motion at the papillary muscle level. Functional indicators include: left ventricular ejection fraction (LVEF), left ventricular fractional contraction rate (LVFS).
- LVEF left ventricular ejection fraction
- LVFS left ventricular fractional contraction rate
- Cardiomyocyte life-and-death staining SPF-grade male C57BL/6 mice (purchased from Shanghai Jiesijie Experimental Animal Co., Ltd.), aged 8-10 weeks, weighing 20-25g, were used to extract primary cardiomyocytes from adult mice , divided into 4 groups (PBS group; NAD group; DOX+PBS group; DOX+NAD group), the intervention conditions are as follows: DOX+NAD group (DOX 1uM+NAD 500uM), DOX+PBS group (DOX 1uM+equivalent PBS) , NAD group (NAD 500uM), PBS group (equal amount of PBS), after 24 hours of intervention, use Calcein/PI Cell Viability and Cytotoxicity Detection Kit (beyotime, C2015S) to stain the cells for life and death, and you can see dead cells after DOX intervention The proportion increased significantly (P ⁇ 0.001), the proportion of dead cells in the DOX+NAD group was less than that in the DOX+PBS group (P ⁇
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- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Molecular Biology (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
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Abstract
Est divulguée, l'utilisation de nicotinamide adénine dinucléotide dans le traitement de la cardiotoxicité induite par la doxorubicine, qui relève du domaine technique des biomédicaments. Il a été démontré par des expériences sur des animaux, dans la présente invention, que la fonction cardiaque du groupe DOX + NAD est considérablement améliorée par comparaison avec le groupe témoin DOX +. Il a été démontré par des expériences cellulaires, dans la présente invention, que la proportion de cellules mortes du groupe DOX + NAD est considérablement réduite par comparaison avec le groupe DOX + PBS. Selon la présente invention, l'utilisation de nicotinamide adénine dinucléotide dans le traitement de la cardiotoxicité induite par la doxorubicine est proposée pour la première fois, la mort des cellules myocardiques provoquée par la doxorubicine peut être réduite au moyen de NAD, la cardiotoxicité provoquée par cette dernière est atténuée, les effets secondaires provoqués par son utilisation peuvent être contrariés, sa plage d'application est élargie, et le pronostic de patients atteints de tumeur l'utilisant est cliniquement amélioré.
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| CN202111085332.0A CN113662955A (zh) | 2021-09-16 | 2021-09-16 | 烟酰胺腺嘌呤二核苷酸在治疗阿霉素诱导的心脏毒性中的应用 |
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| CN114306366B (zh) * | 2021-11-30 | 2023-01-06 | 合肥康诺生物制药有限公司 | 含nad和cd38抑制剂的药物组合物及其用途 |
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| CN113143946A (zh) * | 2021-05-13 | 2021-07-23 | 清华大学 | 烟酰胺单核苷酸及其在抗肿瘤药物心肌损伤中的保护应用 |
| CN113662955A (zh) * | 2021-09-16 | 2021-11-19 | 复旦大学附属中山医院 | 烟酰胺腺嘌呤二核苷酸在治疗阿霉素诱导的心脏毒性中的应用 |
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| CN111789822B (zh) * | 2020-08-13 | 2022-05-13 | 宝利化（南京）制药有限公司 | 一种β-烟酰胺单核苷酸胶囊 |
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| CN113143946A (zh) * | 2021-05-13 | 2021-07-23 | 清华大学 | 烟酰胺单核苷酸及其在抗肿瘤药物心肌损伤中的保护应用 |
| CN113662955A (zh) * | 2021-09-16 | 2021-11-19 | 复旦大学附属中山医院 | 烟酰胺腺嘌呤二核苷酸在治疗阿霉素诱导的心脏毒性中的应用 |
Non-Patent Citations (3)
| Title |
|---|
| "Master's' Thesis", 1 April 2018, TIANJIN POLYTECHNIC UNIVERSITY , CN , article YI ZHANG: "Nicotinamide Riboside Protects Against Doxorubicin-Induced Cardiotoxicity by Improving Autophagic Flux", pages: 1 - 81, XP093003182 * |
| DONG ZHENG; YI ZHANG; MING ZHENG; TING CAO; GRACE WANG; LULU ZHANG; RUI NI; JOSEPH BROCKMAN; HUITING ZHONG; GUO-CHANG FAN; TIANQIN: "Nicotinamide riboside promotes autolysosome clearance in preventing doxorubicin-induced cardiotoxicity.", CLINICAL SCIENCE, LONDON, vol. 133, no. 13, 1 July 2019 (2019-07-01), London , pages 1505 - 1521, XP009544631, ISSN: 1470-8736, DOI: 10.1042/CS20181022 * |
| MENG XU, ZHANG JIREN, SARAH SC HUI.: "THE MECHANISM UNDERLYING THE ANTAGONISTIC EFFECT OF REDUCED FORM COENZYME I (NADH) AGAINST TOXIC EFFECT OF DOXORUBICIN ON MYOCARDIAL MITOCHONDRIA", MEDICAL JOURNAL OF CHINESE PEOPLE'S LIBERATION ARMY, BEIJING : RENMIN JUNYI CHUBANSHE, CN, vol. 27, no. 3, 1 March 2002 (2002-03-01), CN , pages 197 - 199, XP093049405, ISSN: 0577-7402 * |
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