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Drug-Induced Phospholipidosis Services

Drug-Induced Phospholipidosis Services 薬剤誘発性リン脂質症サービス
Drug induced phospholipidosis (DIPL) is a phospholipid storage disorder characterized by an excessive accumulation of multi-lamellar bodies (myeloid bodies) in cells and tissues. Currently more than 350 drug candidates and marketed drugs have been reported to cause DIPL[1]. DIPL has been considered an adverse finding from a regulatory perspective whether justified or not[2]. Since DIPL may be linked to unwanted toxicities, it is important for pharmaceutical researchers and physicians to better understand, track, and manage this drug side effect.
  • Di-docosahexaenoyl (22:6)-BMP
    Bis(mono)acylglycerol phosphate (BMP) is a lysosomal phospholipid that is increased in the tissues of animals and humans with DIPL and NPC disease. A specific species of BMP, di-docosahexaenoyl (22:6)-BMP (di-22:6-BMP), is a biomarker of DIPL in humans and animals that can be monitored in the plasma/serum, urine and tissues[3-6].
  • In vitro Drug-Induced Phospholipidosis Screening
    The in vitro analysis of di-22:6-BMP provides a sensitive and specific high throughput screening assay to rapidly identify compounds with the potential to induce DIPL early in the drug discovery process.
  • Nonclinical & Clinical Studies
    Nextcea uses validated high sensitivity LC-MS/MS methods to measure the concentrations of di-22:6-BMP in biological samples from nonclinical and clinical studies.
    ◄ Case Study: Amiodarone and Chloroquine
    Levels of di-22:6-BMP in the urine of rats treated with 150 mg/kg/day of amiodarone and 120 mg/kg/day of chloroquine (Liu et al. Toxicology and Applied Pharmacology 2014; 279:467-476) Download the abstract

薬剤誘発性リン脂質症(DIPL)は、細胞や組織中に多層版構造物(ミエロイド小体)の過度の蓄積を特徴とするリン脂質の貯蔵障害です。現在350以上の薬剤候補や上市された薬剤で、DIPLが発現することが報告されています[1]。まだ解明されていませんが、規制当局の見解ではDIPLを有害な所見とみなしています [2]。 DIPLは望まれていない毒性とリンクしている可能性があるので、製薬研究者や臨床医にとってこの副作用をよりよく理解し、監視し、管理することが重要です。
  • Di-docosahexaenoyl (22:6)-BMP
    Bis(mono)acylglycerol phosphate (BMP)は、DIPL及びニューマンピック病C型(NPC disease)を患う動物やヒトの組織中に増加するリソソームリン脂質です。BMPの中で特定の物質、di-docosahexaenoyl (22:6)-BMP (di-22:6-BMP) は、ヒト及び動物の血漿/血清、尿、組織中でモニター可能なDIPLのバイオマーカーです[3-6]。
  • In vitro薬剤誘発性リン脂質症スクリーニング
    Di-22:6-BMPのin vitroでの分析は、探索研究フェーズでDIPLを引き起こす可能性のある化合物を迅速に特定できる、精度が高く特異的なハイスループットスクリーニングアッセイを提供します。
  • 非臨床及び臨床試験
    ◄ ケーススタディ:アミオダロン & クロロキン
    アミオダロン(150 mg/kg/day)またはクロロキン(120 mg/kg/day)を投与されたラットの尿中di-22:6-BMP量 (Liu et al. Toxicology and Applied Pharmacology 2014; 279:467-476) Download the abstract

  1. Willard J. FDA phospholipidosis working group preliminary results and developing opinions. Presented at the Society of Toxicology Pathology (STP) Continuing Education Course on Drug-Induced Phospholipidosis June 2008.
  2. Reasor M.J., Hastings K.L., and Ulrich, R.G., Drug-induced phospholipidosis: issues and future directions. Expert Opinion in Drug Safety 2006;5(4), 567-583
  3. Liu N., Tengstrand E., Chourb L., and Hsieh F. Di-22:6-bis(monoacylglycerol)phosphate: A clinical biomarker of drug-induced phospholipidosis for drug development and safety assessment. Toxicology and Applied Pharmacology 2014;279(3):467-476.
  4. Hsieh F., Tengstrand E. Detecting Phospholipidosis and Diagnosing Lysosomal Storage Disorders. US Patent 8,313,949 and Japanese patent (granted).
  5. Tengstrand E., Miwa G., and Hsieh F. Bis(monoacylglycerol)phosphate as a non-invasive biomarker to monitor the onset and time-course of phospholipidosis with drug induced toxicities. Expert Opinion in Drug Metabolism and Toxicology. 2010 6(5):555-570.
  6. Tengstrand-Baronas E., Lee J.W., Alden C., and Hsieh F. Biomarkers to monitor drug-induced phospholipidosis. Toxicology and Applied Pharmacology 2007;218:72-78.