Efficacy of low dose nitisinone in the management of alkaptonuria

Sloboda, Natacha; Wiedemann, Arnaud; Merten, Marc; Alqahtani, Amerh; Jeannesson, Élise; Blum, Alain; Henn-Menetre, S.; Guéant, Jean‐Louis; Renard, E.; Feillet, François

doi:10.1016/j.ymgme.2019.06.006

Cited by 21 publications

(19 citation statements)

References 23 publications

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“…Similar extremely positive outcomes in the SONIA-1 (Suitability of Nitisinone in Alkaptonuria) study with promising clinical results in demonstrating a 98.8% reduction in urinary excretion of HGA over 24 hours, when patients are administered 8mg/day [57]. In other work, low doses of nitisinone have also demonstrated efficacy in patients in the paediatric age group [57,58].…”

Section: Effectiveness Of Nitisinone In Akumentioning

confidence: 60%

The potential of nitisinone for the treatment of alkaptonuria

Taylor

Shepherd

2019

Expert Opinion on Orphan Drugs

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Introduction: Alkaptonuria is an iconic disease, dating back to the Egyptians and has continued to prove a valuable teaching tool to many medics as an example of an inborn error of metabolism. In recent years, much progress has been made on understanding the condition and its symptoms; the single defective gene has been identified and cloned. In humans novel phenotypic presentations of the condition have been documented, and in vitro models developed to understand the disease. Furthermore, a mouse model has studied and most recently clinical trials into the effectiveness of nitisinone have been undertaken. Nitisinone has been on a miraculous journey from its discovery as a weed killer to its effective treatment in hereditary tyrosinaemia type-1. Areas covered: The authors describe research into nitisinone and its application in model and human systems in both hereditary tyrosinaemia type 1 (HTT-1) and Alkaptonuria. The published literature was searched for outputs relating to "Alkaptonuria", "ochronosis", "nitisinone", "hereditary tyrosinaemia type 1". Any paper not in English or had no translation were excluded. Expert opinion: Now nitisinone is being studied for use in Alkaptonuria and this paper documents the journey of AKU and the promising potential of nitisinone in the treatment of Alkaptonuria.

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Section: Effectiveness Of Nitisinone In Akumentioning

confidence: 60%

The potential of nitisinone for the treatment of alkaptonuria

Taylor

Shepherd

2019

Expert Opinion on Orphan Drugs

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“…The effect of treatment on clinical symptoms was limited due to the fact that most of the participants had already significant AKU-related tissue damage [ 8 ]. In a more recent paper, doses of 0.2 mg per day were reported to lower HGA by > 90% in three AKU patients while plasma tyrosine levels were maintained below 500 µmol/l [ 16 ].…”

Section: Aiming For Which Hga Reduction?mentioning

confidence: 99%

“…In a more recent paper, doses of 0.2 mg per day were reported to lower HGA by > 90% in three AKU patients while plasma tyrosine levels were maintained below 500 µmol/l [ 16 ].…”

Section: Aiming For Which Hga Reduction?mentioning

confidence: 99%

“…in the second or third decade. Contra-indications for the use of nitisinone are limited: any treatment with nitisinone should be interrupted in women intending to become pregnant or who are breastfeeding, although uneventful pregnancy with a low dose of nitisinone has been reported [ 16 ]. Yearly costs of treatment in The Netherlands are approximately € 2000 for the prescription of 2 mg nitisinone on alternate days, and € 14,300 for the 10 mg daily dose.…”

Section: Unresolved Questions and Future Studiesmentioning

confidence: 99%

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Preventive use of nitisinone in alkaptonuria

Wolffenbuttel

Heiner‐Fokkema

Spronsen

2021

Orphanet J Rare Dis

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Alkaptonuria (AKU, OMIM 203500) is a rare congenital disorder caused by a deficiency of the enzyme homogentisate-1,2,-dioxygenase. The long-term consequences of AKU are joint problems, cardiac valve abnormalities and renal problems. Landmark intervention studies with nitisinone 10 mg daily, suppressing an upstream enzyme activity, demonstrated its beneficial effects in AKU patients with established complications, which usually start to develop in the fourth decade. Lower dose of nitisinone in the range of 0.2–2 mg daily will already reduce urinary homogentisic acid (uHGA) excretion by > 90%, which may prevent AKU-related complications earlier in the course of the disease while limiting the possibility of side-effects related to the increase of plasma tyrosine levels caused by nitisinone. Future preventive studies should establish the lowest possible dose for an individual patient, the best age to start treatment and also collect evidence to which level uHGA excretion should be reduced to prevent complications.

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“…The application of NTBC reduces the production of toxic metabolites by effectively blocking the tyrosine metabolic pathway [ 4 , 5 , 6 , 7 ]. NTBC can be also used in the treatment of alkaptonuria [ 8 , 9 ] or neuroblastoma [ 4 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

β-Cyclodextrin Derivative Grafted on Silica Gel Represents a New Polymeric Sorbent for Extracting Nitisinone from Model Physiological Fluids

2021

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Nitisinone (NTBC) is used in the treatment of disorders affecting the tyrosine pathway, including hereditary tyrosinemia type I, alkaptonuria, and neuroblastoma. An inappropriate dosage of this therapeutic drug causes side effects; therefore, it is necessary to develop a rapid and sensitive method to monitor the content of NTBC in patients’ blood. This study aimed to develop anew polymeric sorbent containing β-cyclodextrin (β-CD) derivatives grafted on silica gel to effectively extract NTBC from model physiological fluids. The inclusion complex formed between β-CD and NTBC was examined by proton nuclear magnetic resonance spectroscopy. The novel sorbents with derivatives of β-CD were prepared on modified silica gel using styrene as a comonomer, ethylene glycol dimethacrylate as a crosslinking agent, and 2,2′-azo-bis-isobutyronitrile as a polymerization initiator. The obtained products were characterized via Fourier transform infrared spectroscopy and then used as sorbents as part of a solid phase extraction technique. High NTBC recovery (70%indicated that the developed polymeric sorbent may be suitable for extracting this compound from patients’ blood samples.

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Efficacy of low dose nitisinone in the management of alkaptonuria

Cited by 21 publications

References 23 publications

The potential of nitisinone for the treatment of alkaptonuria

The potential of nitisinone for the treatment of alkaptonuria

Preventive use of nitisinone in alkaptonuria

β-Cyclodextrin Derivative Grafted on Silica Gel Represents a New Polymeric Sorbent for Extracting Nitisinone from Model Physiological Fluids

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