德拉马尼

德拉马尼
临床资料
商品名（英语：Drug nomenclature）	Deltyba
其他名称	OPC-67683
AHFS/Drugs.com	英国药物信息
给药途径	口服给药
ATC码	J04AK06 (WHO) ;
法律规范状态
法律规范	欧：Rx-only; 英：处方药（℞-only） (POM); 处方药（℞-only）;
药物动力学数据
血浆蛋白结合率	≥99.5%
药物代谢	与血浆中与白蛋白结合, 经肝脏分泌的; CYP3A4 代谢(较少程度)
生物半衰期	30–38小时
排泄途径	未经尿液排出人体
识别信息
	IUPAC命名法 (2R)-2-Methyl-6-nitro-2-[(4-{4-[4-(trifluoromethoxy)phenoxy]-1-piperidinyl}phenoxy)methyl]-2,3-dihydroimidazo[2,1-b] [1,3]oxazole; ;
CAS号	681492-22-8
PubChem CID	6480466;
DrugBank	DB11637;
ChemSpider	4981055;
UNII	8OOT6M1PC7;
KEGG	D09785;
ChEBI	CHEBI:134742;
ChEMBL	ChEMBL218650;
CompTox Dashboard（英语：CompTox Chemicals Dashboard） (EPA)	DTXSID60218326 ;
ECHA InfoCard	100.348.783
化学信息
化学式	C25H25F3N4O6
摩尔质量	534.49 g·mol−1
3D模型（JSmol（英语：JSmol））	交互式图像;
	SMILES FC(F)(F)Oc5ccc(OC4CCN(c3ccc(OC[C@@]2(Oc1nc(cn1C2)[N+]([O-])=O)C)cc3)CC4)cc5;
	InChI InChI=1S/C25H25F3N4O6/c1-24(15-31-14-22(32(33)34)29-23(31)38-24)16-35-18-4-2-17(3-5-18)30-12-10-20(11-13-30)36-19-6-8-21(9-7-19)37-25(26,27)28/h2-9,14,20H,10-13,15-16H2,1H3/t24-/m1/s1; Key:XDAOLTSRNUSPPH-XMMPIXPASA-N;

德拉马尼 （INN：delamanid）以Deltyba品牌在市面贩售，是一种用于治疗结核病的药物。^[2]基本上是它被用于与其他结核病管理（英语：Tuberculosis management）药物联合进行治疗活动性多重抗药性结核病（英语：multidrug-resistant tuberculosis）之用。^[2]此药物经口服方式给药。^[2]

使用后常见的副作用有头痛、头晕和恶心。^[3]其他副作用有药物引发QT间期延长（英语：Drug-induced QT prolongation）。^[2]德拉马尼的作用是阻断分枝菌酸（英语：mycolic acid）产生，进而破坏细菌细胞壁的稳定性。^[4]此药物属于5-硝基咪唑类药物。^[5]

德拉马尼于2014年在欧洲、日本和韩国被批准用于医疗用途。^[6]它已被列入世界卫生组织基本药物标准清单之中。^[7]截至2016年，位于瑞士大萨科内的非营利组织Stop TB Partnership（英语：Stop TB Partnership）已与日本大冢制药达成协议，在100多个国家以每六个月完整疗程的剂量，支付1,700美元的价格即可取得该药物。^[8]

医疗用途

德拉马尼与其他抗结核药物联合使用，用来治疗活动性多重抗药性结核病。^[2]

不良影响

常见的副作用有头痛、头晕和恶心。^[3]其他副作用有药物引发的QT间期延长。^[2]个体于怀孕期间使用对胎儿的影响尚未有广泛研究，但已有属于安全的报告，^[9]目前在南非被推荐作为治疗具有利福平抗药性结核病孕妇的标准方案中的一种。^[10]

与其他药物交互作用

德拉马尼有少量会被由肝脏酵素CYP3A4代谢，因此会强烈强诱导这种酵素分泌的药物将会降低其有效性。^[11]

作用机转

德拉马尼在分枝杆菌属中被脱氮黄素依赖性硝基还原酶 (Deazaflavin-dependent nitroreductase，Ddn) 激活，Ddn会利用还原形式的二氢F₄₂₀将德拉马尼转化为一氧化氮和另一种高活性代谢物，产生的代谢物会攻击合成酶DprE2。DprE2对于结核菌细胞壁阿拉伯半乳聚糖（英语：arabinogalactan）的合成很重要，分支菌酸无阿拉伯半乳聚糖可依附以形成细胞壁，导致分枝杆菌无法正常生长。德拉尼的杀菌机制与抗生素药物普瑞莫尼（英语：pretomanid）类似。对德拉尼产生抗药性之临床分离株，通常是其合成辅酶二氢F₄₂₀的生化途径中发生突变的结果。^[12]

历史

在此药物的II期临床试验中，将药物与标准治疗药物合并使用，例如乙胺丁醇、异烟肼、吡嗪酰胺、利福平、氨基糖苷类抗生素和喹诺酮类药物其中的四、五种。另外加上服用德拉马尼的患者，其治愈率（以痰培养转换率衡量）会明显较好。^[13]^[14]

欧洲药品管理局 (EMA) 建议对德拉马尼给予有条件行销授权，用于治疗因抗药性或耐受性而无其他治疗选择的多重抗药性肺结核成人患者。 EMA认为数据显示使用德拉马尼的益处大于风险，但认为需要对其长期有效性进行更多研究。^[15]

社会与文化

截至2015年，该药物尚未在全球各地上市。当初被认为售价将会与贝达喹啉（也是一种治疗活动性结核病的药物）类似（在低收入国家的六个月完整疗程剂量价格为近600美元）。截至2016年，制药厂已与Stop TB Partnership达成协议，透过后者的Global Drug Facility ，可以每六个月的完整疗程剂量以1,700美元的价格取得。^[8]

参见

^ Deltyba (delamanid): Summary of Product Characteristics. 5.2. Pharmacokinetic Properties (PDF). Otsuka Novel Products GmbH: 10. [2016-07-09]. （原始内容存档 (PDF)于2016-08-17）.
^ ^2.0 ^2.1 ^2.2 ^2.3 ^2.4 ^2.5 World Health Organization. The selection and use of essential medicines. Twentieth report of the WHO Expert Committee 2015 (including 19th WHO Model List of Essential Medicines and 5th WHO Model List of Essential Medicines for Children). Geneva: World Health Organization. 2015: 30–1. ISBN 9789241209946. ISSN 0512-3054. hdl:10665/189763 . WHO technical report series;994.
^ ^3.0 ^3.1 Smith MR, Accinelli A, Tejada FR, Kharel MK. Drugs Used in Tuberculosis and Leprosy. Ray SD (编). Side Effects of Drugs Annual: A Worldwide Yearly Survey of New Data in Adverse Drug Reactions. Elsevier. 2016: 284. ISBN 978-0-444-63889-2. （原始内容存档于2016-12-20）（英语）.
^ Blair HA, Scott LJ. Delamanid: a review of its use in patients with multidrug-resistant tuberculosis. Drugs. January 2015, 75 (1): 91–100. PMID 25404020. S2CID 34541500. doi:10.1007/s40265-014-0331-4.
^ Alves de Oliverira TS, da Sliva Rabello MC. Vaccines Against Tuberculosis. de Paiva Cavalcanti M, Pereira VR, Dessein AJ (编). Tropical Diseases: An Overview of Major Diseases Occurring in the Americas. Bentham Science Publishers. 2017: 461. ISBN 978-1-68108-587-6. doi:10.2174/9781681085876117010022 （英语）.
^ Fischer J. Successful Drug Discovery. John Wiley & Sons. 2016: 139. ISBN 978-3-527-34115-3. （原始内容存档于2016-12-20）（英语）.
^ World Health Organization. World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. 2019. hdl:10665/325771 . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
^ ^8.0 ^8.1 Stop TB Partnership's Global Drug Facility jumpstarts access to new drugs for MDR-TB with innovative public-private partnerships. TB Online. [2024-04-26]. （原始内容存档于2024-04-26）.
^ Acquah R, Mohr-Holland E, Daniels J, Furin J, Loveday M, Mudaly V, Reuter A. Outcomes of Children Born to Pregnant Women With Drug-resistant Tuberculosis Treated With Novel Drugs in Khayelitsha, South Africa: A Report of Five Patients. The Pediatric Infectious Disease Journal. May 2021, 40 (5): e191–e192. PMC 8043512 . PMID 33847295. doi:10.1097/INF.0000000000003069 .
^ Clinical Management of Rifampicin-Resistant Tuberculosis: Updated Clinical Reference Guide (PDF). Department of Health, Republic of South Africa. September 2023 [2024-05-04]. （原始内容存档 (PDF)于2024-06-21）.
^ Delamanid: Neuer Wirkstoff gegen multiresistente TB. Pharmazeutische Zeitung. 2014-05-09. （原始内容存档于2015-09-24）（德语）.
^ Abrahams KA, Batt SM, Gurcha SS, Veerapen N, Bashiri G, Besra GS. DprE2 is a molecular target of the anti-tubercular nitroimidazole compounds pretomanid and delamanid. Nature Communications. June 2023, 14 (1): 3828. Bibcode:2023NatCo..14.3828A. PMC 10307805 . PMID 37380634. doi:10.1038/s41467-023-39300-z .
^ Spreitzer H. Neue Wirkstoffe – Bedaquilin und Delamanid. Österreichische Apothekerzeitung. 18 February 2013, (4/2013): 22 （德语）.
^ Gler MT, Skripconoka V, Sanchez-Garavito E, Xiao H, Cabrera-Rivero JL, Vargas-Vasquez DE, Gao M, Awad M, Park SK, Shim TS, Suh GY, Danilovits M, Ogata H, Kurve A, Chang J, Suzuki K, Tupasi T, Koh WJ, Seaworth B, Geiter LJ, Wells CD. Delamanid for multidrug-resistant pulmonary tuberculosis. The New England Journal of Medicine. June 2012, 366 (23): 2151–2160. PMID 22670901. doi:10.1056/NEJMoa1112433 .
^ European Medicines Agency recommends two new treatment options for tuberculosis. European Medicines Agency. 2013-12-22. （原始内容存档于2013-12-03）.

[1] Deltyba (delamanid): Summary of Product Characteristics. 5.2. Pharmacokinetic Properties (PDF). Otsuka Novel Products GmbH: 10. [2016-07-09]. （原始内容存档 (PDF)于2016-08-17）.

[WHO2015Use-2] 2.0 ^2.1 ^2.2 ^2.3 ^2.4 ^2.5 World Health Organization. The selection and use of essential medicines. Twentieth report of the WHO Expert Committee 2015 (including 19th WHO Model List of Essential Medicines and 5th WHO Model List of Essential Medicines for Children). Geneva: World Health Organization. 2015: 30–1. ISBN 9789241209946. ISSN 0512-3054. hdl:10665/189763 . WHO technical report series;994.

[World2016-3] 3.0 ^3.1 Smith MR, Accinelli A, Tejada FR, Kharel MK. Drugs Used in Tuberculosis and Leprosy. Ray SD (编). Side Effects of Drugs Annual: A Worldwide Yearly Survey of New Data in Adverse Drug Reactions. Elsevier. 2016: 284. ISBN 978-0-444-63889-2. （原始内容存档于2016-12-20）（英语）.

[4] Blair HA, Scott LJ. Delamanid: a review of its use in patients with multidrug-resistant tuberculosis. Drugs. January 2015, 75 (1): 91–100. PMID 25404020. S2CID 34541500. doi:10.1007/s40265-014-0331-4.

[5] Alves de Oliverira TS, da Sliva Rabello MC. Vaccines Against Tuberculosis. de Paiva Cavalcanti M, Pereira VR, Dessein AJ (编). Tropical Diseases: An Overview of Major Diseases Occurring in the Americas. Bentham Science Publishers. 2017: 461. ISBN 978-1-68108-587-6. doi:10.2174/9781681085876117010022 （英语）.

[6] Fischer J. Successful Drug Discovery. John Wiley & Sons. 2016: 139. ISBN 978-3-527-34115-3. （原始内容存档于2016-12-20）（英语）.

[WHO21st-7] World Health Organization. World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. 2019. hdl:10665/325771 . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.

[TB2016-8] 8.0 ^8.1 Stop TB Partnership's Global Drug Facility jumpstarts access to new drugs for MDR-TB with innovative public-private partnerships. TB Online. [2024-04-26]. （原始内容存档于2024-04-26）.

[9] Acquah R, Mohr-Holland E, Daniels J, Furin J, Loveday M, Mudaly V, Reuter A. Outcomes of Children Born to Pregnant Women With Drug-resistant Tuberculosis Treated With Novel Drugs in Khayelitsha, South Africa: A Report of Five Patients. The Pediatric Infectious Disease Journal. May 2021, 40 (5): e191–e192. PMC 8043512 . PMID 33847295. doi:10.1097/INF.0000000000003069 .

[10] Clinical Management of Rifampicin-Resistant Tuberculosis: Updated Clinical Reference Guide (PDF). Department of Health, Republic of South Africa. September 2023 [2024-05-04]. （原始内容存档 (PDF)于2024-06-21）.

[PZ-11] Delamanid: Neuer Wirkstoff gegen multiresistente TB. Pharmazeutische Zeitung. 2014-05-09. （原始内容存档于2015-09-24）（德语）.

[12] Abrahams KA, Batt SM, Gurcha SS, Veerapen N, Bashiri G, Besra GS. DprE2 is a molecular target of the anti-tubercular nitroimidazole compounds pretomanid and delamanid. Nature Communications. June 2023, 14 (1): 3828. Bibcode:2023NatCo..14.3828A. PMC 10307805 . PMID 37380634. doi:10.1038/s41467-023-39300-z .

[Spreitzer-13] Spreitzer H. Neue Wirkstoffe – Bedaquilin und Delamanid. Österreichische Apothekerzeitung. 18 February 2013, (4/2013): 22 （德语）.

[14] Gler MT, Skripconoka V, Sanchez-Garavito E, Xiao H, Cabrera-Rivero JL, Vargas-Vasquez DE, Gao M, Awad M, Park SK, Shim TS, Suh GY, Danilovits M, Ogata H, Kurve A, Chang J, Suzuki K, Tupasi T, Koh WJ, Seaworth B, Geiter LJ, Wells CD. Delamanid for multidrug-resistant pulmonary tuberculosis. The New England Journal of Medicine. June 2012, 366 (23): 2151–2160. PMID 22670901. doi:10.1056/NEJMoa1112433 .

[15] European Medicines Agency recommends two new treatment options for tuberculosis. European Medicines Agency. 2013-12-22. （原始内容存档于2013-12-03）.

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