作者投稿
专家审稿
编辑办公
主编办公
Exploring the Accessibility by Using the Hydroxycobalamin Preparations of High Concentration in Treating Methylmalonic Acidemia
-
摘要: 甲基丙二酸血症(MMA)是中国有机酸代谢病较常见的疾病之一，需长期使用维生素B12进行治疗。用于治疗的维生素B12形式多样，目前中国境内现有的甲钴胺、腺苷钴胺无法达到MMA患儿的治疗需求。肌内注射高浓度羟钴胺治疗MMA相比其他维生素B12具有显著优势，但目前中国高浓度羟钴胺制剂的可及性较差，因此，急需研发、引进或自主配制高浓度的羟钴胺，以满足国内大量MMA患者的鉴别诊断和治疗需求。通过对现有羟钴胺制剂的监测和调整，可探索出适宜的用药方案，同时考虑开发口服羟钴胺制剂作为补充治疗。解决羟钴胺制剂相关问题有助于满足MMA患者的治疗需求，也为罕见病用药路径的探索提供了新的可能性。优化相关政策和监管措施，可促进羟钴胺制剂的研发、引进和生产，提高患者获得适当治疗的机会。Abstract: Methylmalonic acidemia(MMA) is one of the common diseases in hereditary organic acid metabolism disorder. The disorder is mainly treated by using vitamin B12 which comes in various forms.The use of the methylcobalamin and adenosylcobalamin in China cannot meet the needs of children with MMA. Parenteral use of hydroxocobalamin of high concentration has significant advantages in the treatment of MMA. But, the accessibility to hydroxocobalamin is challenging now.Through the supervision and adjustment of hydroxocobalamin, we explored the strategy of using the drugs. Meanwhile, we are considering the oral use of the hydroxocobalamin as supplement to treatment. Solving the challenges of the hydrococobalamin is helpful to meet the treatment of MMA and to provide a new possibility for the use of medication for rare diseases. The improvement in policy and supervision measures will facilitate the development, involvement, and production of hydroxocobalamin, so that the patients will have a good chance of access to the treatment.
-
Key words:
- hydroxocobalamin /
- methylmalonic acidemia /
- orphan drugs /
- vitamin B12
-
图 1 钴胺素的化学结构
R=5′-deoxyadenosyl，-CH3, -OH, -CN
Figure 1. The chemical structure of cobalamin
表 1 不同钴胺类药物相关药学特性及适应证比较
Table 1. Comparison of pharmaceutical characteristics and indications of different cobalt amine drugs
项目 羟钴胺 氰钴胺 甲钴胺 腺苷钴胺 通用名 羟钴胺 维生素B12 甲钴胺 腺苷钴胺 英文名 hydroxocobalamine vitamin B12 mecobalamin cobamamide 理化性质 暗红色结晶或结晶性粉末，微溶于水和乙醇 红色，性质相对稳定，遇光不易降解 暗红色结晶或结晶性粉末，微溶于水和乙醇，见光不稳定，易分解成羟钴胺，需避光贮存 暗红色结晶或粉末溶于水、乙醇、苯酚，见光不稳定，易分解成羟钴胺，需避光贮存 给药途径 im、iv、po po、im、ih po、im、iv po、im 注射剂型 注射剂、冻干粉针剂 注射剂 注射剂、冻干粉针剂 冻干粉针剂 药物代谢动力学 注射后迅速吸收，im注射后60 min达峰值，90%贮存于肝细胞并代谢，t1/2约6 d 口服8~12 h血药浓度达峰值；im后吸收迅速且完全，约1 h达血药浓度峰值；肝脏为主要贮存部位；大部分在8 h内经肾排泄 口服后3 h血药浓度达峰值，im后约1 h达到血药浓度峰值，t1/2约为29 h 注射后1 h达血药浓度峰值，吸收后77%可在肝脏中贮存，排泄较慢，大部分在8 h内排空 适应证(美国FDA批准) 氰化物解毒剂(大剂量iv)、恶性贫血、由于胃结构或功能损伤、胃黏膜病变等原因导致的VB12缺乏 巨幼红细胞贫血、肠道病变恶心肿瘤、叶酸缺乏等由于VB12吸收不良引起的缺陷 - 巨幼红细胞贫血、营养不良性贫血等；神经性疾病；放射或药物所致白细胞减少 适应证(美国批准) 恶性贫血、巨幼红细胞性贫血、神经痛、肝实质损害与接触性皮炎等，氰化物解毒剂 巨幼红细胞性贫血，亚急性联合变性神经系统病变 周围神经病、巨红细胞性贫血 巨幼细胞贫血，营养不良性贫血、妊娠期贫血、多发性神经炎、神经根炎、三叉神经痛、坐骨神经痛、神经麻痹，也可用于营养性神经疾病及放射线、药物引起的白细胞减少症 不良反应 常见尿液红色、血压升高、光敏反应；少见过敏反应 胃肠道反应; 少见过敏反应 偶有食欲不振、胃肠道反应；少见过敏反应 胃肠道反应、过敏反应 注意事项 粉针剂复溶后若6 h内未用完应丢弃 不可iv，痛风患者使用可能发生高尿酸血症 从事汞及其化合物的工作人员，不宜长期大量服用 遇光易分解，溶解后应尽快使用 体内代谢过程 还原羟基 脱氰基 脱烷基 脱烷基 是否具有直接生物活性 无 无 有 有 im：肌内注射；iv：静脉注射；po：口服；ih：皮下注射；t1/2：半衰期；NMPA：国家药品监督管理局；-指美国FDA未批准此药物 
下载: 导出CSV
表 2 羟钴胺境内外市售情况
Table 2. Sales of hydroxocobalamin in China and abroad
通用名(英文名) 上市地区 商品名 规格 储藏条件 羟钴胺
(hydroxocobalamin)美国、加拿大、法国、德国 Cyanokit 5 GM/VIAL(GM/KTT) 8 ℃~15 ℃密闭容器避光保存 法国 VIBALGAN 0.5 mg 法国 DODECAVIT 0.5 mg/mL 醋酸羟钴胺
(hydroxocobalamin acetate)日本 スブロン/フレスミンS注射液 1 mg/mL 2 ℃~8 ℃密闭容器避光保存 英国 - 1 mg/mL 中国台湾地区 爱康宝 10 mg/2 mL；2.5 mg/mL 中国台湾地区 “优良”优乐命注射液 1.25 mg/mL 中国台湾地区 “大丰”持续性维生素B12注射液 1 mg/mL 日本 FRESMIN 1 mg/mL 德国 Depogamma 1 mg/mL 盐酸羟钴胺
(hydroxocobalamine hydrochloride)中国 盐酸羟钴胺注射液 0.25 mg/mL 密封，避光保存
下载: 导出CSV
-
[1] Lerner-Ellis JP, Tirone JC, Pawelek PD, et al. Identifica-tion of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type[J]. Nat Genet, 2006, 38(1): 93-100. doi: 10.1038/ng1683 [2] Oberholzer VG, Levin B, Burgess EA, et al. Methylmalonic aciduria. An inborn error of metabolism leading to chronic metabolic acidosis[J]. Arch Dis Child, 1967, 42(225): 492-504. doi: 10.1136/adc.42.225.492 [3] 杨艳玲, 莫若, 陈哲晖. 甲基丙二酸血症的多学科综合治疗与防控[J]. 中华实用儿科临床杂志, 2020, 35(9): 647-652. doi: 10.3760/cma.j.cn101070-20200324-00493 [4] 杨艳玲, 张月华, 姜玉武. 甲基丙二酸尿症一例[J]. 中华儿科杂志, 2000, 38(7): 450. doi: 10.3760/j.issn:0578-1310.2000.07.030 [5] 刘怡, 刘玉鹏, 张尧, 等. 中国1003例甲基丙二酸血症的复杂临床表型、基因型及防治情况分析[J]. 中华儿科杂志, 2018, 56(6): 414-420. doi: 10.3760/cma.j.issn.0578-1310.2018.06.003 [6] Kang L, Liu Y, Shen M, et al. A study on a cohort of 301 Chinese patients with isolated methylmalonic acidemia[J]. J Inherit Metab Dis, 2020, 43(3): 409-423. doi: 10.1002/jimd.12183 [7] Jiang YZ, Shi Y, Shi Y, et al. Methylmalonic and propionic acidemia among hospitalized pediatric patients: a nationwide report[J]. Orphanet J Rare Dis, 2019, 14(1): 292. doi: 10.1186/s13023-019-1268-1 [8] Shigematsu Y, Hirano S, Hata I, et al. Newborn mass screening and selective screening using electrospray tandem mass spectrometry in Japan[J]. J Chromatogr B Analyt Technol Biomed Life Sci, 2002, 776(1): 39-48. doi: 10.1016/S1570-0232(02)00077-6 [9] Melo DR, Kowaltowski AJ, Wajner M, et al. Mitochondrial energy metabolism in neurodegeneration associated with methylmalonic acidemia[J]. J Bioenerg Biomembr, 2011, 43(1): 39-46. doi: 10.1007/s10863-011-9330-2 [10] Cheng KH, Liu MY, Kao CH, et al. Newborn screening for methylmalonic aciduria by tandem mass spectrometry: 7 years' experience from two centers in Taiwan[J]. J Chin Med Assoc, 2010, 73(6): 314-318. doi: 10.1016/S1726-4901(10)70067-8 [11] 黄新文, 杨建滨, 童凡, 等. 串联质谱技术对新生儿遗传代谢病的筛查及随访研究[J]. 中华儿科杂志, 2011, 49(10): 765-770. doi: 10.3760/cma.j.issn.0578-1310.2011.10.013 [12] Zhou W, Li H, Wang C, et al. Newborn screening for methylmalonic acidemia in a Chinese population: molecular genetic confirmation and genotype phenotype correlations[J]. Front Genet, 2018, 9: 726. [13] Tu WJ, Chen H, He J. Methylmalonic aciduria: newborn screening in mainland China?[J]. J Pediatr Endocrinol Metab, 2013, 26(3-4): 399-400. [14] Shibata N, Hasegawa Y, Yamada K, et al. Diversity in the incidence and spectrum of organic acidemias, fatty acid oxidation disorders, and amino acid disorders in Asian countries: selective screening vs. expanded newborn screening[J]. Mol Genet Metab Rep, 2018, 16: 5-10. doi: 10.1016/j.ymgmr.2018.05.003 [15] 杨艳玲, 韩连书. 单纯型甲基丙二酸尿症饮食治疗与营养管理专家共识[J]. 中国实用儿科杂志, 2018, 33(7): 481-486. doi: 10.19538/j.ek2018070601 [16] 刘玉鹏. 160例新生儿期发病的甲基丙二酸尿症患儿的临床与实验室研究[C]. 长沙: 第五届全国新生儿疾病筛查技术与管理新进展学术研讨会论文集, 2012: 65. [17] 杨艳玲, 山口清次, 田上泰子, 等. 有机酸尿症71例临床分析[J]. 北京大学学报(医学版), 2002, 34(3): 214-248. doi: 10.3321/j.issn:1671-167X.2002.03.005 [18] Wang F, Han L, Yang Y, et al. Clinical, biochemical, and molecular analysis of combined methylmalonic acidemia and hyperhomocysteinemia (cblC type) in China[J]. J Inherit Metab Dis, 2010, 33 Suppl 3: S435-S442. [19] Liu Y, Wang Q, Li X, et al. First Chinese case of successful pregnancy with combined methylmalonic aciduria and homocystinuria, cblC type[J]. Brain Dev, 2015, 37(3): 286-291. doi: 10.1016/j.braindev.2014.06.007 [20] Baumgartner MR, Hörster F, Dionisi-Vici C, et al. Propo-sed guidelines for the diagnosis and management of methylmalonic and propionic acidemia[J]. Orphanet J Rare Dis, 2014, 9: 130. doi: 10.1186/s13023-014-0130-8 [21] 黄倬, 韩连书, 叶军, 等. 甲基丙二酸血症合并同型半胱氨酸尿症患者治疗效果分析[J]. 中华儿科杂志, 2013, 51(3): 194-198. doi: 10.3760/cma.j.issn.0578-1310.2013.03.009 [22] Hodgkin DC, Kamper J, Mackay M, et al. Structure of vitamin B12[J]. Nature, 1956, 178(4524): 64-66. doi: 10.1038/178064a0 [23] Lenhert PG, Hodgkin DC. Structure of the 5, 6-dimethyl-benzimidazolylcobamide coenzyme[J]. Nature, 1961, 192: 937-938. doi: 10.1038/192937a0 [24] Richard E, Jorge-Finnigan A, Garcia-Villoria J, et al. Genetic and cellular studies of oxidative stress in methylmalonic aciduria (MMA) cobalamin deficiency type C (cblC) with homocystinuria (MMACHC)[J]. Hum Mutat, 2009, 30(11): 1558-1566. doi: 10.1002/humu.21107 [25] Okada K, Tanaka H, Temporin K, et al. Akt/mammalian target of rapamycin signaling pathway regulates neurite outgrowth in cerebellar granule neurons stimulated by methylcobalamin[J]. Neurosci Lett, 2011, 495(3): 201-204. doi: 10.1016/j.neulet.2011.03.065 [26] Richard E, Alvarez-Barrientos A, Pérez B, et al. Methylma-lonic acidaemia leads to increased production of reactive oxygen species and induction of apoptosis through the mitochondrial/caspase pathway[J]. J Pathol, 2007, 213(4): 453-461. doi: 10.1002/path.2248 [27] Huemer M, Diodato D, Schwahn B, et al. Guidelines for diagnosis and management of the cobalamin-related remethylation disorders cblC, cblD, cblE, cblF, cblG, cblJ and MTHFR deficiency[J]. J Inherit Metab Dis, 2017, 40(1): 21-48. doi: 10.1007/s10545-016-9991-4 [28] The National Organization for Rare Disorders. Acidemia, Methylmalonic[EB/OL]. (2007-08-10)[2022-12-05]. https://rarediseases.org/rare-diseases/acidemia-methylmalonic/ .[29] 中国国家罕见病注册系统. 甲基丙二酸血症[EB/OL ]. (2019-11-01)[2022-12-05]. https://www.nrdrs.org.cn/app/rare/disease-list-article.html?index=71 .[30] Zwickler T, Lindner M, Aydin HI, et al. Diagnostic work-up and management of patients with isolated methylmalonic acidurias in European metabolic centres[J]. J Inherit Metab Dis, 2008, 31(3): 361-367. doi: 10.1007/s10545-008-0804-2 [31] Hertz H, Kristensen HP, Hoff-Jorgensen E. Studies on vitamin b12 retention. comparison of retention following intramuscular injection of cyanocobalamin and hydroxocobalamin[J]. Scand J Haematol, 1964, 1: 5-15. [32] Heinrich HC, Gabbe EE. Metabolism of the vitamin b12 coenzyme in rats and man[J]. Ann NY Acad Sci, 1964, 112: 871-903. [33] Waggoner DJ, Ueda K, Mantia C, et al. Methylmalonic aciduria (cblF): case report and response to therapy[J]. Am J Med Genet, 1998, 79(5): 373-375. doi: 10.1002/(SICI)1096-8628(19981012)79:5<373::AID-AJMG8>3.0.CO;2-K [34] Chu RC, Begley JA, Colligan PD, et al. The methylcobalamin metabolism of cultured human fibroblasts[J]. Metabolism, 1993, 42(3): 315-319. doi: 10.1016/0026-0495(93)90080-8 [35] Mellman I, Willard HF, Youngdahl-Turner P, et al. Cobalamin coenzyme synthesis in normal and mutant human fibroblasts. Evidence for a processing enzyme activity deficient in cblC cells[J]. J Biol Chem, 1979, 254(23): 11847-11853. doi: 10.1016/S0021-9258(19)86394-9 [36] Andersson HC, Shapira E. Biochemical and clinical response to hydroxocobalamin versus cyanocobalamin treatment in patients with methylmalonic acidemia and homocystinuria (cblC)[J]. J Pediatr, 1998, 132(1): 121-124. doi: 10.1016/S0022-3476(98)70496-2 [37] Pezacka E, Green R, Jacobsen DW. Glutathionylcobalamin as an intermediate in the formation of cobalamin coenzymes[J]. Biochem Biophys Res Commun, 1990, 169(2): 443-450. doi: 10.1016/0006-291X(90)90351-M [38] 国家卫生健康委员会, 科学技术部, 工业和信息化部, 等. 关于公布第一批罕见病目录的通知[EB/OL ]. (2018-05-11)[2022-09-26]. http://www.gov.cn/zhengce/zhengceku/2018-12/31/content_5435167.htm .[39] 国家药品监督管理局. 国产药品——"国药准字H41024838"基本信息[EB/OL]. (2019-03-15)[2022-09-26 ]. https://www.nmpa.gov.cn/datasearch/search-info.html?nmpa=aWQ9NjQwMTImaXRlbUlkPWZmODA4MDgxN2M4MzEyYzQwMTdjOWJiZmM4ZGUwMzYw .[40] 原国家食品药品监督管理总局. 《关于解决药品注册申请积压实行优先审评审批的意见》)[EB/OL ]. (2016-02-26)[2022-12-27]. https://www.nmpa.gov.cn/xxgk/fgwj/gzwj/gzwjyp/20160226085101295.html .[41] 王雪, 赵聪, 许淑红, 等. 我国罕见病用药可及性现状分析[J]. 中国临床药理学杂志, 2021, 37(8): 1026-1032. doi: 10.13699/j.cnki.1001-6821.2021.08.024 [42] Elian KM, Hoffer LJ. Hydroxocobalamin reduces hyperhomocysteinemia in end-stage renal disease[J]. Metabolism, 2002, 51(7): 881-886. doi: 10.1053/meta.2002.32800 [43] Tsao CS, Miyashita K, Young M. Cytotoxic activity of cobalamin in cultured malignant and nonmalignant cells[J]. Pathobiology, 1990, 58(5): 292-296. doi: 10.1159/000163599 [44] Pery-Man N, Houeto P, Coirault C, et al. Hydroxoco-balamin vs cobalt toxicity on rat cardiac and diaphragmatic muscles[J]. Intensive Care Med, 1996, 22(2): 108-115. doi: 10.1007/BF01720716 [45] 那姝美, 杨悦. 我国罕见病医疗保障用药体系的研究[J]. 中国执业药师, 2016, 13(4): 33-37. doi: 10.3969/j.issn.1672-5433.2016.04.007 [46] 美国药典委员会. 美国药典(2019年版)[M]. 42版. 美国: 美国药典委员会, 2019. [47] 日本药局方编辑委员会. 日本药典(2018年版)[M]. 18版. 日本: 日本厚生省出版社, 2018. [48] 英国药品委员会. 英国药典(2022年版)[M]. 英国: 英国药品委员会, 2022. [49] 国家药典委员会. 中华人民共和国药典(2020年版)[M]. 北京: 中国中医药科技出版社, 2020. [50] 李敏, 陈超阳, 陈哲晖, 等. 钴胺素代谢及其不同形式的临床应用[J]. 中华实用儿科临床杂志, 2020, 35(9): 716-720. doi: 10.3760/cma.j.cn101070-20200407-00596 [51] 中华人民共和国中央人民政府. 两部门发布氯巴占临时进口方案50家医院可使用[EB/OL]. (2022-06-30)[2022-12-20]. http://www.gov.cn/xinwen/2022-06/30/content_5698577.htm .[52] 刘鑫, 唐彦, 张波, 等. 超说明书用药在罕见病治疗领域的应用现状[J]. 国际药学研究杂志, 2019, 46(9): 685-690. doi: 10.13220/j.cnki.jipr.2019.09.007 -
点击扫码阅读文章
图(1) / 表(2)
计量
- 文章访问数: 3
- HTML全文浏览量: 1
- PDF下载量: 0
- 被引次数: 0
