Dose-dependent uricosuric effect of ambroxol

Oosterhuis, B.; Storm, Gerrit; Cornelissen, P. J. G.; Su, C. A. P. F.; Sollie, Frans A. E.; Jonkman, J. H. G.

doi:10.1007/bf00271364

Cited by 9 publications

(6 citation statements)

References 1 publication

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“…The ABX concentrations that produced the highest GCase enhancements in cell culture, 30 and 60 M (12.4 and 24.8 g/ml), are ϳ15-150 times the human plasma concentrations (0.15-0.8 g/ml) derived from previous clinical pharmacokinetics studies (67,68). However, ABX produced enhancement of GCase activity in cells between 5 and 60 M (Fig.…”

Section: Discussionmentioning

confidence: 73%

Identification and Characterization of Ambroxol as an Enzyme Enhancement Agent for Gaucher Disease

Maegawa

Tropak

Buttner

et al. 2009

Journal of Biological Chemistry

291

297

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Gaucher disease (GD), the most prevalent lysosomal storage disease, is caused by a deficiency of glucocerebrosidase (GCase). The identification of small molecules acting as agents for enzyme enhancement therapy is an attractive approach for treating different forms of GD. A thermal denaturation assay utilizing wild type GCase was developed to screen a library of 1,040 Food and Drug Administration-approved drugs. Ambroxol (ABX), a drug used to treat airway mucus hypersecretion and hyaline membrane disease in newborns, was identified and found to be a pH-dependent, mixed-type inhibitor of GCase. Its inhibitory activity was maximal at neutral pH, found in the endoplasmic reticulum, and undetectable at the acidic pH of lysosomes. The pH dependence of ABX to bind and stabilize the enzyme was confirmed by monitoring the rate of hydrogen/deuterium exchange at increasing guanidine hydrochloride concentrations. ABX treatment significantly increased N370S and F213I mutant GCase activity and protein levels in GD fibroblasts. These increases were primarily confined to the lysosome-enriched fraction of treated cells, a finding confirmed by confocal immunofluorescence microscopy. Additionally, enhancement of GCase activity and a reduction in glucosylceramide storage was verified in ABX-treated GD lymphoblasts (N370S/N370S). Hydrogen/deuterium exchange mass spectrometry revealed that upon binding of ABX, amino acid segments 243-249, 310 -312, and 386 -400 near the active site of GCase are stabilized. Consistent with its mixedtype inhibition of GCase, modeling studies indicated that ABX interacts with both active and non-active site residues. Thus, ABX has the biochemical characteristics of a safe and effective enzyme enhancement therapy agent for the treatment of patients with the most common GD genotypes.

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Section: Discussionmentioning

confidence: 73%

Identification and Characterization of Ambroxol as an Enzyme Enhancement Agent for Gaucher Disease

Maegawa

Tropak

Buttner

et al. 2009

Journal of Biological Chemistry

291

297

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“…Previous studies had suggested that high doses of ambroxol reduced the plasma uric acid concentration by increasing its clearance. It was shown that plasma hypoxanthine levels were not affected by ambroxol 7 …”

Section: Discussionmentioning

confidence: 99%

“…It was shown that plasma hypoxanthine levels were not affected by ambroxol. 7 It was proved that partial deficiency of hypoxanthine-guanine phosphorybosyltransferase (HPRT) leads to hypoxanthine and serum uric acid accumulation. Hypoxanthine and guanine have accumulated in the culture medium in the case of HPRT deficiency in the in vitro model.…”

Section: Discussionmentioning

confidence: 99%

Parenteral ambroxol treatment causes xanthine and calcium oxalate stones in rats

Drewa

Misterek²,

Pachnowska³

et al. 2007

Int J of Urology

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Introduction: Ambroxol (ABX) is known to promote bronchial secretion and is used as an expectorant. This study was undertaken to document the connection between ambroxol parenteral treatment and bladder stones in rats. Material and Methods: Forty-five wild rats (Rattus sp.) were divided into three equal groups. Rats from the first and second groups received ABX s.c. during 2 weeks in total doses of 30 mg/kg per 24 h and 60 mg/kg per 24 h, respectively. Rats from the control group received 1 mL of injection solution s.c. One month after the treatment termination, animals were sacrificed and urinary tracts without urethra were dissected. Stones found in the bladders were measured , weighed and chemically analysed. Voiding cystography was performed to exclude pathology of the lower urinary tract. Photo documentation was produced. Results: From the first and second groups, 33% and 47% of rats, respectively, had solitary stones in the bladder. In one case from the second group, there was a huge stone in the bladder and urethra. There were no stones in rats from the control group. The mean length of stones was 1.38 Ϯ 0.23 mm and 1.41 Ϯ 0.60 mm in the first and second groups, respectively. Mean stone weight was 1.2 Ϯ 0.2 ¥ 10 -3 g and 1.44 Ϯ 0.54 ¥ 10 -3 g. Stones were composed of 67% of xanthine and 33% of calcium oxalate. Conclusions: Ambroxol parenteral treatment caused xanthine and oxalate stone formation. Attention should be paid to the possibility of urinary stone formation after long-term ABX treatment.

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“…Several newer uricosuric drugs are undergoing clinical studies, but their usefulness in the long-term treatment of hyperuricemia in allopurinol-intolerant patients with gout and renal insufficiency has not been evaluated [40][41][42].…”

Section: Benzbromaronementioning

confidence: 99%

Difficult gout and new approaches for control of hyperuricemia in the allopurinol-allergic patient

Fam

2001

Curr Rheumatol Rep

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A major obstacle to the treatment of hyperuricemia in patients allergic to allopurinol is the limited availability of suitable, equally effective, alternative, urate-lowering drugs. Conventional uricosuric drugs, including probenecid and sulfinpyrazone, are recommended for allopurinol- intolerant patients with gout and "underexcretion" hyperuricemia who have normal renal function and no history of nephrolithiasis. Therapeutic options in those in whom traditional uricosuric drugs are contraindicated, ineffective, or poorly tolerated include slow oral desensitization to allopurinol and cautious administration of oxipurinol. Allopurinol desensitization is useful particularly in those who have failed other treatment modalities. If available (as in Europe, South Africa, and Japan), benzbromarone may be tried in patients with gout and mild-to-moderate renal insufficiency. Recombinant urate oxidase can be used in the short-term prophylaxis and treatment of chemotherapy- associated hyperuricemia in patients with lymphoproliferative and myeloproliferative disorders. Hyperuricemia and gout occur with increased frequency in cyclosporine-treated allograft transplant recipients. The management of gout in these patients is complicated by two main factors: cyclosporine-induced renal impairment, and interactions with medications used to preserve the allograft.

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Dose-dependent uricosuric effect of ambroxol

Cited by 9 publications

References 1 publication

Identification and Characterization of Ambroxol as an Enzyme Enhancement Agent for Gaucher Disease

Identification and Characterization of Ambroxol as an Enzyme Enhancement Agent for Gaucher Disease

Parenteral ambroxol treatment causes xanthine and calcium oxalate stones in rats

Difficult gout and new approaches for control of hyperuricemia in the allopurinol-allergic patient

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