Early initiation of ambroxol treatment diminishes neurological manifestations of type 3 Gaucher disease: A long-term outcome of two siblings

Ramadža, Danijela Petković; Zekušić, Marija; Žigman, Tamara; Škaričić, Ana; Bogdanić, Ana; Mustać, Gordana; Bošnjak-Nađ, Katarina; Ozretić, David; Ohno, Kousaku; Fumić, Ksenija; Barić, Ivo

doi:10.1016/j.ejpn.2021.03.013

Cited by 12 publications

(18 citation statements)

References 26 publications

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“…Previous studies reported that ambroxol had a promising outcome when used with ERT or SRT for patients with GD . However, to our knowledge, there have been few reports on the clinical benefits of ambroxol alone for patients with GD .…”

Section: Discussionmentioning

confidence: 93%

“…Ambroxol has been shown to cross the BBB . Based on this evidence, in several countries where ambroxol is approved and available, it has been prescribed off label with ERT or SRT for patients with neuronopathic GD (nGD) . With no specific treatment for nGD and the aforementioned encouraging reports, off-label use of high-dose ambroxol has become a realistic option for managing nGD as an adjunct to ERT or for GD among patients without access to ERT or SRT.…”

Section: Introductionmentioning

confidence: 99%

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Use of Ambroxol as Therapy for Gaucher Disease

et al. 2023

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ImportanceAmbroxol was identified as an enhancer of stability and residual activity of several misfolded glucocerebrosidase variants in 2009.ObjectivesTo assess hematologic and visceral outcomes, biomarker changes, and safety of ambroxol therapy for patients with Gaucher disease (GD) without disease-specific treatment.Design, Setting, and ParticipantsPatients with GD who could not afford enzyme replacement therapy were enrolled and received oral ambroxol from May 6, 2015, to November 9, 2022, at Xinhua Hospital, affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, China. Thirty-two patients with GD (29 with GD type 1, 2 with GD type 3, and 1 with GD intermediate types 2-3) were enrolled. Of those, 28 patients were followed up for longer than 6 months; 4 were excluded due to loss of follow-up. Data analyses were performed from May 2015 to November 2022.InterventionAn escalating dose of oral ambroxol (mean [SD] dose, 12.7 [3.9] mg/kg/d).Main Outcomes and MeasuresPatients with GD receiving ambroxol were followed up in a genetic metabolism center. Biomarkers of chitotriosidase activity and glucosylsphingosine level, liver and spleen volumes, and hematologic parameters were measured at baseline and various time points throughout the ambroxol treatment.ResultsA total of 28 patients (mean [SD] age, 16.9 [15.3] years; 15 male patients [53.6%]) received ambroxol for a mean (SD) duration of 2.6 (1.7) years. Two patients with severe symptoms at baseline experienced deterioration of hematologic parameters and biomarkers and were deemed nonresponders; clinical response was observed in the other 26 patients. After 2.6 years of ambroxol treatment, the mean (SD) hemoglobin concentration improved from 10.4 (1.7) to 11.9 (1.7) g/dL (mean [SD], 1.6 [1.7] g/dL; 95% CI, 0.8-2.3 g/dL; P &lt; .001), and the mean (SD) platelet count improved from 69 (25) to 78 (30) × 103/µL (mean [SD], 9 [22] × 103/µL; 95% CI, −2 to 19 × 103/µL; P = .09). The mean (SD) spleen volume decreased from 17.47 (7.18) to 12.31 (4.71) multiples of normal (MN) (mean [SD], −5.16 [5.44] MN; 95% CI, −10.19 to −0.13; P = .04), and the mean (SD) liver volume decreased from 1.90 (0.44) to 1.50 (0.53) MN (mean [SD], −0.39 [0.42] MN; 95% CI, −0.75 to −0.04; P = .03). Biomarker median percentage changes from baseline were −43.1% for chitotriosidase activity (from 14 598 [range, 3849-29 628] to 8312 [range, 1831-16 842] nmol/mL/h; z = −3.413; P = .001) and −34.1% for glucosylsphingosine level (from 251.3 [range, 73.6-944.2] to 165.7 [range, 21.3-764.8] ng/mL; z = −2.756; P = .006). Patients were divided into subgroups according to age when initiating treatment; those who received treatment at a younger age (mean [SD] age, 6.3 [2.7] years) experienced more rapid improvements: hemoglobin concentration increased by 16.5% (from 10.3 [1.5] to 12.0 [1.5] g/dL; mean [SD] change, 1.6 [1.6] g/dL; 95% CI, 0.7-2.5 g/dL; P = .002), and platelet count increased by 12.0% (from 75 [24] to 84 [33] × 103/µL; mean [SD] change, 9 [26] × 103/µL; 95% CI, −5 to 24 × 103/µL; P = .17); whereas chitotriosidase activity decreased by 64.0% (from 15 710 [range, 4092-28 422] to 5658 [range, 1146-16 843] nmol/mL/h; z = −2.803; P = .005), and glucosylsphingosine level decreased by 47.3% (from 248.5 [range, 122.8-674.9] to 131.0 [range, 41.1-448.5] ng/mL; z = −2.385; P = .02). Three of the 28 patients experienced mild and transient adverse events.Conclusions and RelevanceIn this case series of ambroxol repurposing among patients with GD, long-term treatment with ambroxol was safe and associated with patient improvement. Improvements in hematologic parameters, visceral volumes, and plasma biomarkers were larger among patients with relatively mild symptoms of GD and patients who received initial treatment at younger ages.

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Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Use of Ambroxol as Therapy for Gaucher Disease

et al. 2023

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“…Ramadza i wsp. zaobserwowali pozytywny efekt leczenia ABX w dawce 25 mg/kg m.c./dobę u 2 pacjentów (rodzeństwa) będących złożonymi heterozygotami dla L444P oraz H225Q i D409H, przy czym leczenie ABX zostało wdrożone wcześnie -w wieku 5 lat i 7 tygodni (rozpoznanie GD w ramach skriningu rodzinnego) [33].…”

Section: Ambroksol Jako Farmakologiczny Chaperon W Chorobie Gaucheraunclassified

Stosowanie farmakologicznych chaperonów w leczeniu wrodzonych chorób metabolicznych

2022

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“…Numerous case reports have described satisfactory outcomes in patients with GD following treatment with Ambroxol [15][16][17][18][19][20]. However, no systematic reviews aimed at evaluating Ambroxol as a therapeutic alternative for the treatment of GD have been performed.…”

Section: Introductionmentioning

confidence: 99%

The use of Ambroxol for the treatment of Gaucher disease: A systematic review

Abelleyra Lastoria,

Grewal,

Hughes

2024

eJHaem

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Gaucher disease (GD) is a heterogeneous condition requiring tailored treatment approaches. The aim of this systematic review was to synthesise and evaluate current evidence pertaining to the use of Ambroxol for the treatment of GD. Published and unpublished literature databases, conference proceedings and the reference lists of included studies were searched until 23 November 2023. A narrative synthesis was performed. Database search and risk of bias assessment were performed independently by two reviewers.Twenty‐one studies (182 patients) were included. The evidence was low in quality. Variable responses to Ambroxol were observed. Response rates were 36% and 55% in two studies reporting on type 1 GD. One study found a 22% response rate in type 2 GD, whereas another study found 29% of patients with type 3 GD reported neurological improvements. No severe adverse events were reported in the literature, with mild and reversible side effects reported. Varying response rates are to be expected (29%–100%) when treating neurological manifestations. Varying degrees of symptomatic improvement for the treatment of GD were noted in the literature. Multidisciplinary team input and clinical judgement are advised to provide personalized treatment of this complex and multi‐faceted condition.

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Early initiation of ambroxol treatment diminishes neurological manifestations of type 3 Gaucher disease: A long-term outcome of two siblings

Cited by 12 publications

References 26 publications

Use of Ambroxol as Therapy for Gaucher Disease

Use of Ambroxol as Therapy for Gaucher Disease

Stosowanie farmakologicznych chaperonów w leczeniu wrodzonych chorób metabolicznych

The use of Ambroxol for the treatment of Gaucher disease: A systematic review

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