Synonyms: Ambrosan, Mucosolvan
Chemical Name: trans-4-(2-Amino-3,5-dibrombenzylamino)-cyclohexanol
Therapy Type: Small Molecule (timeline)
Target Type: alpha-synuclein, Other (timeline)
Condition(s): Parkinson's Disease, Parkinson's Disease Dementia, Dementia with Lewy Bodies
U.S. FDA Status: Parkinson's Disease (Phase 2), Parkinson's Disease Dementia (Phase 2), Dementia with Lewy Bodies (Phase 2)
Status in Select Countries: OTC for cough relief.
Ambroxol is a mucolytic compound and the main ingredient of over-the-counter cough medicines sold in many countries. Syrup, tablet, and other forms are used at doses of 30 to 120 mg per day to reduce or thin mucous secretions and ease sore throat pain. The most common side effects are gastrointestinal. Ambroxol is unavailable in North America.
Interest in repurposing ambroxol to treat Parkinson’s disease stems from its activity as a molecular chaperone for the lysosomal enzyme glucocerebrosidase (GCase) (Maegawa et al., 2009). Loss-of-function mutations in the GCase gene, GBA1, are the leading genetic risk factor for the synucleinopathies Parkinson’s disease and dementia with Lewy bodies (DLB).
GCase activity and α-synuclein are linked: GCase deficiency causes pathologic accumulation of α-synuclein (Cullen et al., 2011), while GCase overexpression in brain reduces pathology and memory deficits in a synucleinopathy mouse model (Sardi et al., 2011). GCase activity is also diminished in cases of idiopathic PD and DLB without GBA1 mutations, and lower GCase correlates with earlier disease onset and worse cognitive and non-motor symptoms (Gegg et al., 2012; Chiasserini et al., 2015). GBA1 mutations were originally identified as the cause of parkinsonism in Gaucher’s disease, a lysosomal storage disorder characterized by the buildup of sphingolipids, and, in some cases, α-synuclein pathology (Lwin et al, 2004; Mazzulli et al., 2011).
In cells derived from patients with Gaucher’s or PD, ambroxol stabilized mutant GCase and facilitated its movement from the endoplasmic reticulum to lysosomes, increasing protein levels, enzyme activity, and lysosome function (Bendikov-Bar et al., 2013; McNeill et al., 2014). In flies with GCH1 mutations, ambroxol increased GCase activity, decreased ER stress, and protected motor function (Sanchez-Martinez et al., 2016).
In wild-type and GCH1-mutation-bearing mice, ambroxol induced brain GCase activity, and in mice overexpressing human α-synuclein, it decreased total and phosphorylated α-synuclein (Migdalska-Richards et al., 2016). In a mouse model of amyotrophic lateral sclerosis, ambroxol improved motor function and extended survival (Bouscary et al., 2019).
In healthy, non-human primates, daily ambroxol increased brain GCase activity (Migdalska-Richards et al., 2017).
In December 2016, an open-label pilot study in Parkinson’s disease, called AIM-PD, began at University College London. It enrolled 23 patients, half with a GBA1 mutation and half without, to assess safety, tolerability, CNS penetration and target engagement of ambroxol. After a one-month dose escalation, participants received 1,260 mg per day for five months—a dose 10 times higher than used to treat cough. Primary endpoints were ambroxol levels and GCase activity in CSF. Secondary outcomes included safety, GCase protein and activity, α-synuclein and tau in CSF and blood, and measures of cognitive and motor function.
Results were presented at a 2018 AD/PD conference and later formally published (Apr 2018 conference news; Mullin et al., 2020). Eighteen patients completed the study, five withdrew due to problems related to lumbar-puncture, but no serious adverse events were reported. The study met its primary endpoints: Ambroxol crossed the blood-brain barrier and in the CSF achieved a concentration of 11 percent of blood levels. CSF GCase activity decreased by 19 percent, consistent with ambroxol’s ability to inhibit the enzyme at neutral pH. Other findings included a 35 percent increase in CSF GCase protein levels, and a significant increase in CSF α-synuclein, with no change in tau or glucosyl ceramide. Participants improved on the Unified Parkinson’s Disease Rating Scale, mainly due to gains in motor function. Drug effects were detected in patients with or without GBA mutations.
In November 2015, a Phase 2 trial at the Parkwood Institute, Ontario, Canada, began recruiting 75 people with Parkinson’s and mild to moderate dementia (Silveira et al., 2019). Participants were to receive 525 or 1,050 mg daily ambroxol or placebo for one year. Primary outcomes are changes on ADAS-Cog and ADCS-CGIC; secondary outcomes include additional cognitive measures, movement testing, CSF biomarkers of α-synuclein, tau, phospho-tau, and Aβ, MRI measures of ventricular volume and hippocampal atrophy. The trial also assesses GCase activity in lymphocytes and plasma ambroxol levels. As of July 2018, the trial had enrolled 25 patients, with 10 completing one year of treatment (see AAIC abstract). Blood levels of ambroxol were sufficient to increase GCase activity in peripheral lymphocytes. The drug was well tolerated. The trial is slated to end in December 2021. Sometime after this report, the lower-dose group was discontinued and the enrollment target reduced to 58. Enrollment is expected to be complete in the summer of 2021.
In May 2020, the same investigators registered an additional Phase 2 trial to test a higher dose of 1,350 mg/day. The study will treat 15 people with PDD for one year, with primary outcomes of MMSE, safety, pharmacokinetics, and GCase activity in blood and CSF.
In March 2019, an open-label Phase 2 began in Israel for 60 participants with Gaucher’s disease who responded poorly to enzyme replacement therapy.
Japanese researchers published a pilot study on five people with neurological symptoms due to Gaucher’s, in whom open-label ambroxol ameliorated muscle spasms (Narita et al., 2016). In September 2019, this group registered a larger, open-label trial in 25 patients in Japan.
In spring 2021, a Phase 2 trial will begin testing ambroxol in people with dementia or mild cognitive impairment with Lewy Bodies. The study, at seven centers in Norway, will enroll 172 participants for 18 months treatment with 1,320 mg daily or placebo. Treatment groups will be stratified based on ApoE4 and CSF Aβ42 concentrations. Primary outcomes are adverse events, treatment discontinuations, and other safety signs, plus measures of cognition, functional decline, and neuropsychiatric symptoms. Secondary outcomes will assess sleep, cognitive fluctuations, motor symptoms, and falls. The trial offers a one-year, open label extension.
In May 2020, an investigator-initiated global registry of ambroxol use in 300 patients with Gaucher's or GBA-Parkinson's disease was listed as an observational study of real-world evidence on clinicaltrials.gov. In March 2021, it published data from the first 41 participants, reporting no severe adverse effects related to ambroxol, and clinical benefit in 25 of them (Istaiti et al., 2021).
For details on ambroxol trials, see clinicaltrials.gov.
Last Updated: 22 Apr 2021
- Mullin S, Smith L, Lee K, D'Souza G, Woodgate P, Elflein J, Hällqvist J, Toffoli M, Streeter A, Hosking J, Heywood WE, Khengar R, Campbell P, Hehir J, Cable S, Mills K, Zetterberg H, Limousin P, Libri V, Foltynie T, Schapira AH. Ambroxol for the Treatment of Patients With Parkinson Disease With and Without Glucocerebrosidase Gene Mutations: A Nonrandomized, Noncontrolled Trial. JAMA Neurol. 2020 Apr 1;77(4):427-434. PubMed.
- Silveira CR, MacKinley J, Coleman K, Li Z, Finger E, Bartha R, Morrow SA, Wells J, Borrie M, Tirona RG, Rupar CA, Zou G, Hegele RA, Mahuran D, MacDonald P, Jenkins ME, Jog M, Pasternak SH. Ambroxol as a novel disease-modifying treatment for Parkinson's disease dementia: protocol for a single-centre, randomized, double-blind, placebo-controlled trial. BMC Neurol. 2019 Feb 9;19(1):20. PubMed.
- Narita A, Shirai K, Itamura S, Matsuda A, Ishihara A, Matsushita K, Fukuda C, Kubota N, Takayama R, Shigematsu H, Hayashi A, Kumada T, Yuge K, Watanabe Y, Kosugi S, Nishida H, Kimura Y, Endo Y, Higaki K, Nanba E, Nishimura Y, Tamasaki A, Togawa M, Saito Y, Maegaki Y, Ohno K, Suzuki Y. Ambroxol chaperone therapy for neuronopathic Gaucher disease: A pilot study. Ann Clin Transl Neurol. 2016 Mar;3(3):200-15. Epub 2016 Feb 2 PubMed.
- Istaiti M, Revel-Vilk S, Becker-Cohen M, Dinur T, Ramaswami U, Castillo-Garcia D, Ceron-Rodriguez M, Chan A, Rodic P, Tincheva RS, Al-Hertani W, Lee BH, Yang CF, Kiec-Wilk B, Fiumara A, Rubio B, Zimran A. Upgrading the evidence for the use of ambroxol in Gaucher disease and GBA related Parkinson: Investigator initiated registry based on real life data. Am J Hematol. 2021 May 1;96(5):545-551. Epub 2021 Mar 11 PubMed.
- Maegawa GH, Tropak MB, Buttner JD, Rigat BA, Fuller M, Pandit D, Tang L, Kornhaber GJ, Hamuro Y, Clarke JT, Mahuran DJ. Identification and characterization of ambroxol as an enzyme enhancement agent for Gaucher disease. J Biol Chem. 2009 Aug 28;284(35):23502-16. Epub 2009 Jul 3 PubMed.
- Cullen V, Sardi SP, Ng J, Xu YH, Sun Y, Tomlinson JJ, Kolodziej P, Kahn I, Saftig P, Woulfe J, Rochet JC, Glicksman MA, Cheng SH, Grabowski GA, Shihabuddin LS, Schlossmacher MG. Acid β-glucosidase mutants linked to Gaucher disease, Parkinson disease, and Lewy body dementia alter α-synuclein processing. Ann Neurol. 2011 Jun;69(6):940-53. PubMed.
- Sardi SP, Clarke J, Kinnecom C, Tamsett TJ, Li L, Stanek LM, Passini MA, Grabowski GA, Schlossmacher MG, Sidman RL, Cheng SH, Shihabuddin LS. CNS expression of glucocerebrosidase corrects alpha-synuclein pathology and memory in a mouse model of Gaucher-related synucleinopathy. Proc Natl Acad Sci U S A. 2011 Jul 19;108(29):12101-6. PubMed.
- Gegg ME, Burke D, Heales SJ, Cooper JM, Hardy J, Wood NW, Schapira AH. Glucocerebrosidase deficiency in substantia nigra of parkinson disease brains. Ann Neurol. 2012 Sep;72(3):455-63. PubMed.
- Chiasserini D, Paciotti S, Eusebi P, Persichetti E, Tasegian A, Kurzawa-Akanbi M, Chinnery PF, Morris CM, Calabresi P, Parnetti L, Beccari T. Selective loss of glucocerebrosidase activity in sporadic Parkinson's disease and dementia with Lewy bodies. Mol Neurodegener. 2015 Mar 27;10:15. PubMed.
- Lwin A, Orvisky E, Goker-Alpan O, LaMarca ME, Sidransky E. Glucocerebrosidase mutations in subjects with parkinsonism. Mol Genet Metab. 2004 Jan;81(1):70-3. PubMed.
- Mazzulli JR, Xu YH, Sun Y, Knight AL, McLean PJ, Caldwell GA, Sidransky E, Grabowski GA, Krainc D. Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell. 2011 Jul 8;146(1):37-52. Epub 2011 Jun 23 PubMed.
- Bendikov-Bar I, Maor G, Filocamo M, Horowitz M. Ambroxol as a pharmacological chaperone for mutant glucocerebrosidase. Blood Cells Mol Dis. 2013 Feb;50(2):141-5. Epub 2012 Nov 14 PubMed.
- McNeill A, Magalhaes J, Shen C, Chau KY, Hughes D, Mehta A, Foltynie T, Cooper JM, Abramov AY, Gegg M, Schapira AH. Ambroxol improves lysosomal biochemistry in glucocerebrosidase mutation-linked Parkinson disease cells. Brain. 2014 May;137(Pt 5):1481-95. Epub 2014 Feb 25 PubMed.
- Sanchez-Martinez A, Beavan M, Gegg ME, Chau KY, Whitworth AJ, Schapira AH. Parkinson disease-linked GBA mutation effects reversed by molecular chaperones in human cell and fly models. Sci Rep. 2016 Aug 19;6:31380. PubMed.
- Migdalska-Richards A, Daly L, Bezard E, Schapira AH. Ambroxol effects in glucocerebrosidase and α-synuclein transgenic mice. Ann Neurol. 2016 Nov;80(5):766-775. PubMed.
- Bouscary A, Quessada C, Mosbach A, Callizot N, Spedding M, Loeffler JP, Henriques A. Ambroxol Hydrochloride Improves Motor Functions and Extends Survival in a Mouse Model of Familial Amyotrophic Lateral Sclerosis. Front Pharmacol. 2019;10:883. Epub 2019 Aug 7 PubMed.
- Migdalska-Richards A, Ko WK, Li Q, Bezard E, Schapira AH. Oral ambroxol increases brain glucocerebrosidase activity in a nonhuman primate. Synapse. 2017 Jul;71(7) Epub 2017 Mar 17 PubMed.
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- Han TU, Sam R, Sidransky E. Small Molecule Chaperones for the Treatment of Gaucher Disease and GBA1-Associated Parkinson Disease. Front Cell Dev Biol. 2020;8:271. Epub 2020 May 19 PubMed.
- Kopytova AE, Rychkov GN, Nikolaev MA, Baydakova GV, Cheblokov AA, Senkevich KA, Bogdanova DA, Bolshakova OI, Miliukhina IV, Bezrukikh VA, Salogub GN, Sarantseva SV, Usenko TC, Zakharova EY, Emelyanov AK, Pchelina SN. Ambroxol increases glucocerebrosidase (GCase) activity and restores GCase translocation in primary patient-derived macrophages in Gaucher disease and Parkinsonism. Parkinsonism Relat Disord. 2021 Mar;84:112-121. Epub 2021 Feb 10 PubMed.
- Bouscary A, Quessada C, René F, Spedding M, Henriques A, Ngo S, Loeffler JP. Drug repositioning in neurodegeneration: An overview of the use of ambroxol in neurodegenerative diseases. Eur J Pharmacol. 2020 Oct 5;884:173446. Epub 2020 Jul 30 PubMed.
- Ramadža DP, Zekušić M, Žigman T, Škaričić A, Bogdanić A, Mustać G, Bošnjak-Nađ K, Ozretić D, Ohno K, Fumić K, Barić I. Early initiation of ambroxol treatment diminishes neurological manifestations of type 3 Gaucher disease: A long-term outcome of two siblings. Eur J Paediatr Neurol. 2021 Mar 31;32:66-72. PubMed.
- Ciana G, Dardis A, Pavan E, Da Riol RM, Biasizzo J, Ferino D, Zanatta M, Boni A, Antonini L, Crichiutti G, Bembi B. In vitro and in vivo effects of Ambroxol chaperone therapy in two Italian patients affected by neuronopathic Gaucher disease and epilepsy. Mol Genet Metab Rep. 2020 Dec;25:100678. Epub 2020 Nov 21 PubMed.
- Khoury T, Ishay Y, Rotnemer-Golinkin D, Zolotarovya L, Arkadir D, Zimran A, Ilan Y. A synergistic effect of Ambroxol and Beta-Glucosylceramide in alleviating immune-mediated hepatitis: A novel immunomodulatory non-immunosuppressive formulation for treatment of immune-mediated disorders. Biomed Pharmacother. 2020 Dec;132:110890. Epub 2020 Oct 17 PubMed.