Pilot study using ambroxol as a pharmacological chaperone in type 1 Gaucher disease

被引:113
作者
Zimran, Ari [1 ]
Altarescu, Gheona [2 ]
Elstein, Deborah [1 ]
机构
[1] Hebrew Univ Jerusalem, Hadassah Med Sch, Shaare Zedek Med Ctr, Gaucher Clin, IL-91031 Jerusalem, Israel
[2] Hebrew Univ Jerusalem, Hadassah Med Sch, Shaare Zedek Med Ctr, Genet Unit, IL-91031 Jerusalem, Israel
关键词
Gaucher disease; Glucocerebrosidase activity; Ambroxol; Pharmacological chaperones; Enzyme replacement therapy; BETA-GLUCOCEREBROSIDASE; ENZYME REPLACEMENT; DOUBLE-BLIND; IDENTIFICATION; MUTANT;
D O I
10.1016/j.bcmd.2012.09.006
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The purpose of this pilot was to assess the tolerability and efficacy of ambroxol as a pharmacological chaperone in patients with symptomatic, type 1 Gaucher disease who present with measurable disease parameters but are not receiving enzyme replacement therapy (ERT) in order to provide proof of concept and/or ascertain the suitability of ambroxol for a larger clinical trial. The Israeli Ministry of Health Form 29c was employed to prescribe ambroxol for off-label use. Twelve patients were dispensed 2 capsules of 75 mg of ambroxol daily for 6 months. There were 8 females (66.7%). Mean age at entry was 41.1 (range: 24-63) years. Mean body weight at entry was 66.4 (range: 46.5-100) kg. One patient withdrew because of a hypersensitivity reaction, one because of elective splenectomy. No patient experienced clinically relevant deterioration in disease parameters measured. One patient achieved a robust response relative to baseline: +16.2% hemoglobin; +32.9% platelets; -2.8% liver volume; and -14.4% spleen volume. Three patients, including the above one, elected to continue on ambroxol for a further 6 months: hemoglobin levels and liver volumes were relatively stable, but platelet counts further increased in the above patient (+52.6% from baseline) and spleen volumes decreased further in all three patients (-6.4%, -18.6%, and -23.4% from baseline). Thus, ambroxol may be a safe option for Gaucher disease patients with potential disease-specific efficacy and should be expanded into a clinical trial using higher doses and placebo-controlled design. (C) 2012 Elsevier Inc. All rights reserved.
引用
收藏
页码:134 / 137
页数:4
相关论文
共 35 条
[1]   Bicyclic (galacto)nojirimycin analogues as glycosidase inhibitors: Effect of structural modifications in their pharmacological chaperone potential towards β-glucocerebrosidase [J].
Aguilar-Moncayo, Matilde ;
Isabel Garcia-Moreno, M. ;
Trapero, Ana ;
Egido-Gabas, Meritxell ;
Llebaria, Amadeu ;
Garcia Fernandez, Jose M. ;
Ortiz Mellet, Carmen .
ORGANIC & BIOMOLECULAR CHEMISTRY, 2011, 9 (10) :3698-3713
[2]   Pharmacological chaperones facilitate the post-ER transport of recombinant N370S mutant β-glucocerebrosidase in plant cells: Evidence that N370S is a folding mutant [J].
Babajani, Gholamreza ;
Tropak, Michael B. ;
Mahuran, Don J. ;
Kermode, Allison R. .
MOLECULAR GENETICS AND METABOLISM, 2012, 106 (03) :323-329
[3]  
Beeh KM, 2008, EUR J MED RES, V13, P557
[4]   Characterization of the ERAD process of the L444P mutant glucocerebrosidase variant [J].
Bendikov-Bar, Inna ;
Ron, Idit ;
Filocamo, Mirella ;
Horowitz, Mia .
BLOOD CELLS MOLECULES AND DISEASES, 2011, 46 (01) :4-10
[5]   Neurologic improvement in a type 3 Gaucher disease patient treated with imiglucerase/miglustat combination [J].
Capablo, Jose L. ;
Franco, Rafael ;
de Cabezon, Alicia Saenz ;
Alfonso, Pilar ;
Pocovi, Miguel ;
Giraldo, Pilar .
EPILEPSIA, 2007, 48 (07) :1406-1408
[6]   Hydrophilic iminosugar active-site-specific chaperones increase residual glucocerebrosidase activity in fibroblasts from Gaucher patients [J].
Chang, Hui-Hwa ;
Asano, Naoki ;
Ishii, Satoshi ;
Ichikawa, Yoshitaka ;
Fan, Jian-Qiang .
FEBS JOURNAL, 2006, 273 (17) :4082-4092
[7]   Novel oral treatment of Gaucher's disease with N-butyldeoxynojirimycin (OGT 918) to decrease substrate biosynthesis [J].
Cox, T ;
Lachmann, R ;
Hollak, C ;
Aerts, J ;
van Weely, S ;
Hrebícek, M ;
Platt, F ;
Butters, T ;
Dwek, R ;
Moyses, C ;
Gow, I ;
Elstein, D ;
Zimran, A .
LANCET, 2000, 355 (9214) :1481-1485
[8]   Parenteral ambroxol treatment causes xanthine and calcium oxalate stones in rats [J].
Drewa, Tomasz ;
Misterek, Bartosz ;
Pachnowska, Hanna ;
Wolski, Zbigniew ;
Mikulska-Jovanovic, Magdalena ;
Drewa, Joanna .
INTERNATIONAL JOURNAL OF UROLOGY, 2007, 14 (05) :463-465
[9]   Computerized cognitive testing in patients with type I Gaucher disease: Effects of enzyme replacement and substrate reduction [J].
Elstein, D ;
Guedalia, J ;
Doniger, GM ;
Simon, ES ;
Antebi, V ;
Arnon, Y ;
Zimran, A .
GENETICS IN MEDICINE, 2005, 7 (02) :124-130
[10]   Low-dose low-frequency imiglucerase as a starting regimen of enzyme replacement therapy for patients with type I Gaucher disease [J].
Elstein, D ;
Abrahamov, A ;
Hadas-Halpern, I ;
Meyer, A ;
Zimran, A .
QJM-MONTHLY JOURNAL OF THE ASSOCIATION OF PHYSICIANS, 1998, 91 (07) :483-488