Suitability Of Nitisinone In Alkaptonuria 1 (SONIA 1): an international, multicentre, randomised, open-label, no-treatment controlled, parallel-group, dose-response study to investigate the effect of once daily nitisinone on 24-h urinary homogentisic acid excretion in patients with alkaptonuria after 4 weeks of treatment

Ranganath, L.; Milan, Anna M.; Hughes, Andrew T.; Dutton, John; Fitzgerald, Richard J.; Briggs, Michael; Bygott, Helen; Psarelli, Eftychia Eirini; Cox, Trevor F.; Gallagher, James A.; Jarvis, Jonathan C.; Kan, Christa van; Hall, Anthony K; Laan, Dinny; Olsson, Birgitta; Szamosi, Johan; Rudebeck, Mattias; Kullenberg, Torbjörn; Cronlund, Arvid; Svensson, Lennart; Junestrand, Carin; Ayoob, Hana; Timmis, Oliver; Sireau, Nicolas; Sang, Kim-Hanh Le Quan; Genovese, Federica; Braconi, Daniela; Santucci, Annalisa; Nemethova, Martina; Zaťková, Andrea; McCaffrey, Judith C.; Christensen, Peter; Ross, Gordon; Imrich, Richard; Rovenský, Jozef

doi:10.1136/annrheumdis-2014-206033

Cited by 137 publications

(219 citation statements)

References 17 publications

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“…Ranganath and colleagues recently showed a similar dose-response effect of nitisinone when analysing urinary HGA excretion over a 24 h period in AKU patients. Furthermore, they found that nitisinone was well tolerated within the studied dose range (Ranganath et al 2014), which is consistent with our observations in mice. Both our data and that of Ranganath et al highlight the efficacy of nitisinone in reducing the levels of circulating HGA.…”

Section: Discussionsupporting

confidence: 81%

Nitisinone Arrests but Does Not Reverse Ochronosis in Alkaptonuric Mice

et al. 2015

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Alkaptonuria (AKU) is an ultrarare autosomal recessive disorder resulting from a deficiency of homogentisate 1,2 dioxygenase (HGD), an enzyme involved in the catabolism of phenylalanine and tyrosine. Loss of HGD function prevents metabolism of homogentisic acid (HGA), leading to increased levels of plasma HGA and urinary excretion. Excess HGA becomes deposited in collagenous tissues and subsequently undergoes polymerisation, principally in the cartilages of loaded joints, in a process known as ochronosis. This results in an early-onset, devastating osteoarthropathy for which there is currently no effective treatment. We recently described the natural history of ochronosis in a murine model of AKU, demonstrating that deposition of ochronotic pigment begins very early in life and accumulates with age. Using this model, we were able to show that lifetime treatment with nitisinone, a potential therapy for AKU, was able to completely prevent deposition of ochronotic pigment. However, although nitisinone has been shown to inhibit ochronotic deposition, whether it can also facilitate removal of existing pigment has not yet been examined. We describe here that midlife administration of nitisinone to AKU mice arrests further deposition of ochronotic pigment in the tibiofemoral joint, but does not result in the clearance of existing pigment. We also demonstrate the dose-dependent response of plasma HGA to nitisinone, highlighting its efficacy for personalised medicine, where dosage can be tailored to the individual AKU patient.

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Section: Discussionsupporting

confidence: 81%

Nitisinone Arrests but Does Not Reverse Ochronosis in Alkaptonuric Mice

et al. 2015

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“…Reproducibility test was repeated after 2 week storage of DUS, with no appreciable loss compared to fresh spots (recovery 93.7-105.6%; CV ¼ 8.7%). These data and values expressed as mmol/mol creatinine (1,741 AE 541) or mmol/24 h (17.0 AE 7.4) were in agreement with those reported in the literature (Bory et al 1989;Mannoni et al 2004;Hughes et al 2014;Ranganath et al 2016). No appreciable HGA could be detected in DUS or urine samples from controls.…”

Section: Hplc Analysis Of Urines and Dus (Methods 2)supporting

confidence: 81%

“…The deposition of an "ochronotic" pigment produced after circulating HGA oxidation within the articular connective tissues causes ochronotic arthritis, a degenerative joint disease (Ranganath et al 2013;Millucci et al 2015); deposition may also occur in cardiac valves, leading to cardiovascular pathologies. Currently, there is no therapy for AKU, but a clinical trial with nitisinone is in progress (Ranganath et al 2016).…”

Section: Introductionmentioning

confidence: 99%

Quick Diagnosis of Alkaptonuria by Homogentisic Acid Determination in Urine Paper Spots

et al. 2016

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Objectives: Two methods are described for homogentisic acid (HGA) determination in dried urine spots (DUS) on paper from Alkaptonuria (AKU) patients, devised for quick early diagnosis. AKU is a rare autosomal recessive disorder caused by deficiency of homogentisate 1,2-dioxygenase, yielding in accumulation of HGA. Its massive excretion causes urine darkening by exposure to air or alkalinization, and is a diagnostic marker. The deposition of polymers produced after HGA oxidation within the connective tissues causes ochronotic arthritis, a degenerative joint disease manifesting in adulthood and only rarely in childhood. No early diagnosis is usually accomplished, awareness following symptom development.Design and methods: Two methods were designed for HGA determination in DUS: (1) a rapid semi-quantitative reliable method based on colour development in alkali and quantification by comparison with dried paper spots from HGA solutions of known concentration and (2) a quantitative and sensitive HPLC-linked method, previously devised for purine and pyrimidine analysis in urine and plasma.Results: Colour intensity developed by DUS after alkali addition was proportional to HGA concentration, and calculated amounts were in good agreement with quantitative analysis performed by RP-HPLC on DUS and on urines as such.Conclusions: DUS, often used for different diagnostic purpose, are easily prepared and safely delivered. The simple and quick colour method proposed provides reliable HGA assessment and is fit for large screening. HGA concentration determined in 10 AKU patient DUS by both methods 1 and 2 was in agreement with direct urine assay and in the range reported by literature.A reliable HGA quantification based on colour development in paper urine spots is validated by HPLC-linked HGA quantification, and proposed as a quick diagnostic tool for AKU patients.

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“…A current ongoing trial looking at the suitability of nitisinone in AKU patients is looking to be very promising for reducing HGA. However, the major risk in these patients is an increase in plasma tyrosine, leading to corneal opacities and other more severe complications (Ranganath et al 2016). An absence of detectable tyrosine from the spectra in our study suggests that patients who have established ochronosis will likely not have to worry about the polymerisation of tyrosine and it binding to the already established ochronotic pigment in their tissues.…”

Section: Discussionmentioning

confidence: 99%

Analysis of Melanin-like Pigment Synthesized from Homogentisic Acid, with or without Tyrosine, and Its Implications in Alkaptonuria

Taylor

Vercruysse

2016

JIMD Reports

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Alkaptonuria is an iconic disease used by Archibald Garrod to demonstrate the theory of "inborn errors of metabolism". AKU knowledge has advanced in recent years: development of an in vitro model, discovery of murine models and advances in understanding bone and cartilage phenotypes and arthropathy in AKU. These discoveries have aided in a new clinical trial into nitisinone. However, there are still knowledge gaps surrounding the pigment in AKU and the pigmentation process. We demonstrate an advance in the understanding in the kinetics and chemistry of the polymerisation of homogentisic acid (HGA) into its pigment using size-exclusion chromatography and IR spectroscopy. We compared the properties of HGA-based pigments that were freshly prepared to those stored in solution for 2 years. Our results demonstrate the importance of pH in the polymerisation process and that colour change seen in solution (analogous to AKU patient urine) is not initially due to presence of ochronotic pigment but the quinone intermediary. In addition, we observed that pigment formation from HGA can occur in the presence of tyrosine, without the inclusion of this tyrosine into the pigment. These observations have positive implications for patients with alkaptonuria; an increased understanding of the pigment polymer chemistry, the presence of an intermediary and their kinetics present more therapeutic opportunities for treating the condition, including preventing the pigment from forming, binding or reversing established pigmentation. AKU patients treated with nitisinone show elevated tyrosine levels causing side effects such as corneal opacities; our data demonstrates that elevated tyrosine levels should not contribute or add to the ochronotic pigment burden in these patients.

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Abstract: Background

Cited by 137 publications

References 17 publications

Nitisinone Arrests but Does Not Reverse Ochronosis in Alkaptonuric Mice

Nitisinone Arrests but Does Not Reverse Ochronosis in Alkaptonuric Mice

Quick Diagnosis of Alkaptonuria by Homogentisic Acid Determination in Urine Paper Spots

Analysis of Melanin-like Pigment Synthesized from Homogentisic Acid, with or without Tyrosine, and Its Implications in Alkaptonuria

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