Relationship Between Serum Concentrations of Nitisinone and Its Effect on Homogentisic Acid and Tyrosine in Patients with Alkaptonuria (original) (raw)
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Annals of the rheumatic diseases, 2014
Alkaptonuria (AKU) is a serious genetic disease characterised by premature spondyloarthropathy. Homogentisate-lowering therapy is being investigated for AKU. Nitisinone decreases homogentisic acid (HGA) in AKU but the dose-response relationship has not been previously studied. Suitability Of Nitisinone In Alkaptonuria 1 (SONIA 1) was an international, multicentre, randomised, open-label, no-treatment controlled, parallel-group, dose-response study. The primary objective was to investigate the effect of different doses of nitisinone once daily on 24-h urinary HGA excretion (u-HGA24) in patients with AKU after 4 weeks of treatment. Forty patients were randomised into five groups of eight patients each, with groups receiving no treatment or 1 mg, 2 mg, 4 mg and 8 mg of nitisinone. A clear dose-response relationship was observed between nitisinone and the urinary excretion of HGA. At 4 weeks, the adjusted geometric mean u-HGA24 was 31.53 mmol, 3.26 mmol, 1.44 mmol, 0.57 mmol and 0.15 mm...
Annals of clinical biochemistry, 2017
Background Alkaptonuria (AKU) is a rare, debilitating autosomal recessive disorder affecting tyrosine metabolism. Deficiency of homogentisate 1,2-dioxygenase leads to increased homogentisic acid (HGA) which is deposited as ochronotic pigment. Clinical sequelae include severe early onset osteoarthritis, increased renal and prostate stone formation and cardiac complications. Treatment has been largely based on analgaesia and arthroplasty. The National AKU Centre in Liverpool has been using 2mg nitisinone (NTBC) off-license for all patients in the United Kingdom with AKU and monitoring the tyrosine metabolite profiles. Methods Patients with confirmed AKU are commenced on 2mg dose (alternative days) of NTBC for three months with daily dose thereafter. Metabolite measurement by LC-MS/MS is performed at baseline, day 4, three-months, six-months and one-year post-commencing nitisinone. Thereafter, monitoring and clinical assessments are performed annually. Results Urine HGA concentration d...
2015
Lakshminarayan R Ranganath, FRCP(Edin), FRCPath1, Anna M Milan PhD, FRCPath1, Andrew T Hughes MPhil1, John J Dutton FIBMS1, Richard Fitzgerald MRCP2, Michael C Briggs FRCS3, Helen Bygott BSc1, Eftychia E Psarelli MSc4, Trevor F Cox PhD4, James A Gallagher PhD5, Jonathan C Jarvis PhD6, Christa van Kan7, Anthony K Hall MBBS, BSc, AKC8, Dinny Laan MSc7, Birgitta Olsson MSc9, Johan Szamosi MSc9, Mattias Rudebeck MSc, BMedSc9, Torbjörn Kullenberg MD9, Arvid Cronlund MSc9, Lennart Svensson PhD9, Carin Junestrand DDS9, Hana Ayoob BA10, Oliver G Timmis BA10, Nicolas Sireau PhD10, Kim-Hanh Le Quan Sang11, Federica Genovese PhD12, Daniela Braconi PhD13, Annalisa Santucci PhD13, Martina Nemethova MSc14, Andrea Zatkova PhD14, Judith McCaffrey MSc, Peter Christensen PhD, Gordon Ross PhD, Richard Imrich MD, PhD17, Jozef Rovensky17.
Annals of clinical biochemistry, 2015
Alkaptonuria is a rare debilitating autosomal recessive disorder of tyrosine metabolism, where deficiency of homogentisate 1,2-dioxygenase results in increased homogentisic acid. Homogentisic acid is deposited as an ochronotic pigment in connective tissues, especially cartilage, leading to a severe early onset form of osteoarthritis, increased renal and prostatic stone formation and hardening of heart vessels. Treatment with the orphan drug, nitisinone, an inhibitor of 4-hydroxyphenylpyruvate dioxygenase has been shown to reduce urinary excretion of homogentisic acid. A reverse phase liquid chromatography tandem mass spectrometry method has been developed to simultaneously analyse serum homogentisic acid, tyrosine and nitisinone. Using matrix-matched calibration standards, two product ion transitions were identified for each compound (homogentisic acid, tyrosine, nitisinone) and their respective isotopically labelled internal standards ((13)C6-homogentisic acid, d2-tyrosine, (13)C6-...