TY - JOUR T1 - Pharmacologic properties of high-dose ambroxol in four patients with Gaucher disease and myoclonic epilepsy JF - Journal of Medical Genetics JO - J Med Genet DO - 10.1136/jmedgenet-2019-106132 SP - jmedgenet-2019-106132 AU - Yoon-Myung Kim AU - Mi-Sun Yum AU - Sun Hee Heo AU - Taeho Kim AU - Hee Kyung Jin AU - Jae-sung Bae AU - Go Hun Seo AU - Arum Oh AU - Hee Mang Yoon AU - Hyun Taek Lim AU - Hyo-Won Kim AU - Tae-Sung Ko AU - Hyeong‐Seok Lim AU - Mark J Osborn AU - Jakub Tolar AU - Claudia Cozma AU - Arndt Rolfs AU - Ari Zimran AU - Beom Hee Lee AU - Han-Wook Yoo Y1 - 2019/10/24 UR - http://jmg.bmj.com/content/early/2019/10/23/jmedgenet-2019-106132.abstract N2 - Background Ambroxol (ABX) has been suggested as an augmentative pharmacological agent for neuronopathic Gaucher disease (nGD). This study assessed the long-term safety and efficacy of combined therapy with high-dose ABX and enzyme replacement therapy (ERT) in nGD.Methods ABX+ERT therapy was administered for 4.5 years in four patients with nGD. ABX was initiated at a dose of 1.5 mg/kg/day, and the dose was escalated up to 27 mg/kg/day. The target plasma level was 10 µmol/L or less. The changes in glucocerebrosidase activity, biochemical, safety and neurocognitive findings were assessed.Results Enhanced residual GCcase activity was observed in all patients, as evidenced in both in vitro and in vivo studies. During the first 2 years of study with ABX (up to 21 mg/kg/day), mean seizure frequencies and neurocognitive function worsened. After ABX dosage was increased up to 27 mg/kg/day of ABX, its trough plasma concentration was 3.2–8.8 µmol/L. Drug-to-drug interaction, especially with antiepileptic drug significantly affected the pharmacokinetic parameters of ABX. Importantly, at 27 mg/kg/day of ABX, the seizure frequencies markedly decreased from the baseline, and the neurocognitive function was improved. In addition, Lyso-Gb1, a biomarker for the severity and progression of GD, was normalised in all patients. High-dose ABX was well-tolerated with no severe adverse events.Conclusions Long-term treatment with high-dose ABX+ERT was safe and might help to arrest the progression of the neurological manifestations in GD. ER -