Repurpose terbutaline sulfate for amyotrophic lateral sclerosis using electronic medical records.
Prediction of new disease indications for approved drugs by computational methods has been based largely on the genomics signatures of drugs and diseases. We propose a method for drug repositioning that uses the clinical signatures extracted from over 13 years of electronic medical records from a tertiary hospital, including >9.4 M laboratory tests from >530,000 patients, in addition to diverse genomics signatures. Cross-validation using over 17,000 known drug-disease associations shows this approach outperforms various predictive models based on genomics signatures and a well-known "guilt-by-association" method. Interestingly, the prediction suggests that terbutaline sulfate, which is widely used for asthma, is a promising candidate for amyotrophic lateral sclerosis for which there are few therapeutic options. In vivo tests using zebrafish models found that terbutaline sulfate prevents defects in axons and neuromuscular junction degeneration in a dose-dependent manner. A therapeutic potential of terbutaline sulfate was also observed when axonal and neuromuscular junction degeneration have already occurred in zebrafish model. Cotreatment with a β2-adrenergic receptor antagonist, butoxamine, suggests that the effect of terbutaline is mediated by activation of β2-adrenergic receptors.
1] Department of Biomedical Informatics, Ajou University School of Medicine, Suwon, Gyeonggido, Korea [2] Division of Systems Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, and Lucile Packard Children's Hospital, Palo Alto, CA, USA.
Hyojung
H
Paik
Graduate School of Medicine, Korea University, Ansan, Gyeonggido, Korea.
Ah-Young
AY
Chung
Graduate School of Medicine, Korea University, Ansan, Gyeonggido, Korea.
Hae-Chul
HC
Park
Department of Biomedical Informatics, Ajou University School of Medicine, Suwon, Gyeonggido, Korea.
Rae Woong
RW
Park
Department of Pharmacology, Brain Science &Engineering Institute, Kyungpook National University, Daegu, Korea.
Kyoungho
K
Suk
Department of Biomedical Informatics, Ajou University School of Medicine, Suwon, Gyeonggido, Korea.
Jihyun
J
Kim
Department of Biomedical Informatics, Ajou University School of Medicine, Suwon, Gyeonggido, Korea.
Hyosil
H
Kim
Department of Biomedical Informatics, Ajou University School of Medicine, Suwon, Gyeonggido, Korea.
KiYoung
K
Lee
Division of Systems Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, and Lucile Packard Children's Hospital, Palo Alto, CA, USA.
Atul J
AJ
Butte
D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000235:genetics; D057225:Data Mining; D016208:Databases, Factual; D066264:Datasets as Topic; D058492:Drug Repositioning; D057286:Electronic Health Records; D023281:Genomics / Q000379:methods; D006801:Humans; D008490:Medical Informatics / Q000379:methods*; D015203:Reproducibility of Results; D013726:Terbutaline / Q000494:pharmacology / Q000627:therapeutic use*
D013726:Terbutaline