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[PMID]:29195145
[Au] Autor:Sundberg J; Wibrand F; Lund AM; Christensen M
[Ad] Endereço:Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100 Copenhagen, Denmark.
[Ti] Título:Simultaneous quantification of succinylacetone and nitisinone for therapeutic drug monitoring in the treatment of Tyrosinemia type 1.
[So] Source:J Chromatogr B Analyt Technol Biomed Life Sci;1072:259-266, 2018 Jan 01.
[Is] ISSN:1873-376X
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:We present a straightforward and robust method for simultaneous quantification of succinylacetone and nitisinone in plasma using LC-ESI-MS/MS. The method has been developed for routine therapeutic drug monitoring in hepatorenal tyrosinemia type 1 (HT1) patients undergoing nitisinone treatment. Previous methods are based on separate analyses of succinylacetone and nitisinone, often using the potentially harmful compound hydrazine for derivatization of the former. In the present procedure, succinylacetone is derivatized in a single-step using butanolic HCl. Analyte extraction and sample clean-up is carried out by simple protein precipitation. The linear range for both analytes is 0.1 up to 125µM, covering the vast majority of encountered levels in real-life samples. The sensitivity and limit of quantification allows measurement of succinylacetone in the therapeutical range for HT1 patients. Stability studies show that succinylacetone is highly sensitive to storage conditions, whereas nitisinone shows little to no degradation. Correct sample handling is therefore important for reliable results when monitoring succinylacetone concentrations.
[Mh] Termos MeSH primário: Cicloexanonas/sangue
Monitoramento de Medicamentos/métodos
Heptanoatos/sangue
Nitrobenzoatos/sangue
Tirosinemias/tratamento farmacológico
[Mh] Termos MeSH secundário: Cromatografia Líquida/métodos
Cicloexanonas/uso terapêutico
Seres Humanos
Modelos Lineares
Nitrobenzoatos/uso terapêutico
Reprodutibilidade dos Testes
Sensibilidade e Especificidade
Espectrometria de Massas em Tandem/métodos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cyclohexanones); 0 (Heptanoates); 0 (Nitrobenzoates); 51568-18-4 (succinylacetone); K5BN214699 (nitisinone)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180221
[Lr] Data última revisão:
180221
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171202
[St] Status:MEDLINE


  2 / 340 MEDLINE  
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[PMID]:28949985
[Au] Autor:van Ginkel WG; van Vliet D; Burgerhof JGM; de Blaauw P; Rubio Gozalbo ME; Heiner-Fokkema MR; van Spronsen FJ
[Ad] Endereço:Department of Metabolic Diseases, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
[Ti] Título:Presumptive brain influx of large neutral amino acids and the effect of phenylalanine supplementation in patients with Tyrosinemia type 1.
[So] Source:PLoS One;12(9):e0185342, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Hereditary Tyrosinemia type 1 (HT1) is a rare metabolic disease caused by a defect in the tyrosine degradation pathway. Current treatment consists of 2-(2-nitro-4-trifluoromethylbenoyl)-1,3-cyclohexanedione (NTBC) and a tyrosine and phenylalanine restricted diet. Recently, neuropsychological deficits have been seen in HT1 patients. These deficits are possibly associated with low blood phenylalanine concentrations and/or high blood tyrosine concentrations. Therefore, the aim of the present study was threefold. Firstly, we aimed to calculate how the plasma amino acid profile in HT1 patients may influence the presumptive brain influx of all large neutral amino acids (LNAA). Secondly, we aimed to investigate the effect of phenylalanine supplementation on presumptive brain phenylalanine and tyrosine influx. Thirdly, we aimed to theoretically determine minimal target plasma phenylalanine concentrations in HT1 patient to ensure adequate presumptive brain phenylalanine influx. METHODS: Data of plasma LNAA concentrations were obtained. In total, 239 samples of 9 HT1 children, treated with NTBC, diet, and partly with phenylalanine supplementation were collected together with 596 samples of independent control children. Presumptive brain influx of all LNAA was calculated, using Michaelis-Menten parameters (Km) and Vmax-values obtained from earlier articles. RESULTS: In HT1 patients, plasma concentrations and presumptive brain influx of tyrosine were higher. However, plasma and especially brain influx of phenylalanine were lower in HT1 patients. Phenylalanine supplementation did not only tend to increase plasma phenylalanine concentrations, but also presumptive brain phenylalanine influx, despite increased plasma tyrosine concentrations. However, to ensure sufficient brain phenylalanine influx in HT1 patients, minimal plasma phenylalanine concentrations may need to be higher than considered thus far. CONCLUSION: This study clearly suggests a role for disturbed brain LNAA biochemistry, which is not well reflected by plasma LNAA concentrations. This could play a role in the pathophysiology of the neuropsychological impairments in HT1 patients and may have therapeutic implications.
[Mh] Termos MeSH primário: Aminoácidos Neutros/metabolismo
Encéfalo/metabolismo
Fenilalanina/administração & dosagem
Tirosinemias/tratamento farmacológico
[Mh] Termos MeSH secundário: Adolescente
Criança
Pré-Escolar
Seres Humanos
Lactente
Recém-Nascido
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amino Acids, Neutral); 47E5O17Y3R (Phenylalanine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170927
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0185342


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[PMID]:28166616
[Au] Autor:Rossi LC; Santagada F; Besagni F; Cambiaghi S; Colombo E; Brena M; Tadini G
[Ad] Endereço:Pediatric Dermatology Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico di Milano, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.
[Ti] Título:Palmoplantar hyperkeratosis with a linear disposition along dermatoglyphics: a clue for an early diagnosis of tyrosinemia type II.
[So] Source:G Ital Dermatol Venereol;152(2):182-183, 2017 Apr.
[Is] ISSN:1827-1820
[Cp] País de publicação:Italy
[La] Idioma:eng
[Mh] Termos MeSH primário: Dermatoglifia
Ceratodermia Palmar e Plantar/diagnóstico
Tirosinemias/diagnóstico
[Mh] Termos MeSH secundário: Pré-Escolar
Diagnóstico Precoce
Seres Humanos
Ceratodermia Palmar e Plantar/patologia
Masculino
Tirosinemias/patologia
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170904
[Lr] Data última revisão:
170904
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170208
[St] Status:MEDLINE
[do] DOI:10.23736/S0392-0488.16.05070-7


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[PMID]:28128559
[Au] Autor:Santucci A; Bernardini G; Braconi D; Petricci E; Manetti F
[Ad] Endereço:Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena , via A. Moro 2, I-53100 Siena, Italy.
[Ti] Título:4-Hydroxyphenylpyruvate Dioxygenase and Its Inhibition in Plants and Animals: Small Molecules as Herbicides and Agents for the Treatment of Human Inherited Diseases.
[So] Source:J Med Chem;60(10):4101-4125, 2017 May 25.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:This review mainly focuses on the physiological function of 4-hydroxyphenylpyruvate dioxygenase (HPPD), as well as on the development and application of HPPD inhibitors of several structural classes. Among them, one illustrative example is represented by compounds belonging to the class of triketone compounds. They were discovered by serendipitous observations on weed growth and were developed as bleaching herbicides. Informed reasoning on nitisinone (NTBC, 14), a triketone that failed to reach the final steps of the herbicidal design and development process, allowed it to become a curative agent for type I tyrosinemia (T1T) and to enter clinical trials for alkaptonuria. These results boosted the research of new compounds able to interfere with HPPD activity to be used for the treatment of the tyrosine metabolism-related diseases.
[Mh] Termos MeSH primário: 4-Hidroxifenilpiruvato Dioxigenase/antagonistas & inibidores
Descoberta de Drogas
Inibidores Enzimáticos/química
Inibidores Enzimáticos/farmacologia
Herbicidas/química
Bibliotecas de Moléculas Pequenas/química
Bibliotecas de Moléculas Pequenas/farmacologia
Controle de Plantas Daninhas
[Mh] Termos MeSH secundário: 4-Hidroxifenilpiruvato Dioxigenase/metabolismo
Alcaptonúria/tratamento farmacológico
Alcaptonúria/enzimologia
Animais
Descoberta de Drogas/métodos
Inibidores Enzimáticos/farmacocinética
Inibidores Enzimáticos/uso terapêutico
Herbicidas/metabolismo
Seres Humanos
Modelos Moleculares
Plantas/efeitos dos fármacos
Plantas/enzimologia
Bibliotecas de Moléculas Pequenas/farmacocinética
Bibliotecas de Moléculas Pequenas/uso terapêutico
Tirosinemias/tratamento farmacológico
Tirosinemias/enzimologia
Controle de Plantas Daninhas/métodos
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Herbicides); 0 (Small Molecule Libraries); EC 1.13.11.27 (4-Hydroxyphenylpyruvate Dioxygenase)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170619
[Lr] Data última revisão:
170619
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170128
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.6b01395


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[PMID]:28053091
[Au] Autor:Li L; Zhang Q; Yang H; Zou Q; Lai C; Jiang F; Zhao P; Luo Z; Yang J; Chen Q; Wang Y; Newsome PN; Frampton J; Maxwell PH; Li W; Chen S; Wang D; Siu TS; Tam S; Tse HF; Qin B; Bao X; Esteban MA; Lai L
[Ad] Endereço:From the CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China, and Guangzhou Medical University, Guangzhou 511436, China.
[Ti] Título:Fumarylacetoacetate Hydrolase Knock-out Rabbit Model for Hereditary Tyrosinemia Type 1.
[So] Source:J Biol Chem;292(11):4755-4763, 2017 Mar 17.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Hereditary tyrosinemia type 1 (HT1) is a severe human autosomal recessive disorder caused by the deficiency of fumarylacetoacetate hydroxylase (FAH), an enzyme catalyzing the last step in the tyrosine degradation pathway. Lack of FAH causes accumulation of toxic metabolites (fumarylacetoacetate and succinylacetone) in blood and tissues, ultimately resulting in severe liver and kidney damage with onset that ranges from infancy to adolescence. This tissue damage is lethal but can be controlled by administration of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), which inhibits tyrosine catabolism upstream of the generation of fumarylacetoacetate and succinylacetone. Notably, in animals lacking FAH, transient withdrawal of NTBC can be used to induce liver damage and a concomitant regenerative response that stimulates the growth of healthy hepatocytes. Among other things, this model has raised tremendous interest for the expansion of human primary hepatocytes inside these animals and for exploring experimental gene therapy and cell-based therapies. Here, we report the generation of knock-out rabbits via pronuclear stage embryo microinjection of transcription activator-like effector nucleases. rabbits exhibit phenotypic features of HT1 including liver and kidney abnormalities but additionally develop frequent ocular manifestations likely caused by local accumulation of tyrosine upon NTBC administration. We also show that allogeneic transplantation of wild-type rabbit primary hepatocytes into rabbits enables highly efficient liver repopulation and prevents liver insufficiency and death. Because of significant advantages over rodents and their ease of breeding, maintenance, and manipulation compared with larger animals including pigs, rabbits are an attractive alternative for modeling the consequences of HT1.
[Mh] Termos MeSH primário: Hidrolases/genética
Tirosinemias/genética
[Mh] Termos MeSH secundário: Animais
Modelos Animais de Doenças
Feminino
Técnicas de Inativação de Genes
Hepatócitos/transplante
Seres Humanos
Hidrolases/metabolismo
Rim/metabolismo
Rim/patologia
Fígado/metabolismo
Fígado/patologia
Falência Hepática/etiologia
Falência Hepática/metabolismo
Falência Hepática/patologia
Falência Hepática/terapia
Masculino
Coelhos
Tirosinemias/complicações
Tirosinemias/metabolismo
Tirosinemias/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 3.- (Hydrolases); EC 3.7.1.2 (fumarylacetoacetase)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170106
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M116.764787


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[PMID]:27876694
[Au] Autor:Yang H; Al-Hertani W; Cyr D; Laframboise R; Parizeault G; Wang SP; Rossignol F; Berthier MT; Giguère Y; Waters PJ; Mitchell GA; Québec NTBC Study Group
[Ad] Endereço:Division of Medical Genetics, Department of Pediatrics, CHU Sainte-Justine and Université de Montréal, Montréal, Québec, Canada.
[Ti] Título:Hypersuccinylacetonaemia and normal liver function in maleylacetoacetate isomerase deficiency.
[So] Source:J Med Genet;54(4):241-247, 2017 Apr.
[Is] ISSN:1468-6244
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: A high level of succinylacetone (SA) in blood is a sensitive, specific newborn screening marker for hepatorenal tyrosinemia type 1 (HT1, MIM 276700) caused by deficiency of fumarylacetoacetate hydrolase (FAH). Newborns with HT1 are usually clinically asymptomatic but show liver dysfunction with coagulation abnormalities (prolonged prothrombin time and/or high international normalised ratio). Early treatment with nitisinone (NTBC) plus dietary restriction of tyrosine and phenylalanine prevents the complications of severe liver disease and neurological crises. METHODS AND RESULTS: Six newborns referred for hypersuccinylacetonaemia but who had normal coagulation testing on initial evaluation had sequence variants in the gene, encoding maleylacetoacetate isomerase (MAAI), the enzyme preceding FAH in tyrosine degradation. Initial plasma SA levels ranged from 233 to 1282 nmol/L, greater than normal (<24 nmol/L) but less than the initial values of patients with HT1 (16 944-74 377 nmol/L, n=15). Four individuals were homozygous for c.449C>T (p.Ala150Val). One was compound heterozygous for c.259C>T (p.Arg87Ter) and an intronic sequence variant. In one, a single heterozygous sequence variant was identified, c.295G>A (p.Val99Met). Bacterial expression of p.Ala150Val and p.Val99Met revealed low MAAI activity. The six individuals with mild hypersuccinylacetonaemia (MHSA) were not treated with diet or nitisinone. Their clinical course has been normal for up to 13 years. CONCLUSIONS: MHSA can be caused by sequence variants in . Such individuals have thus far remained asymptomatic despite receiving no specific treatment.
[Mh] Termos MeSH primário: Glutationa Transferase/genética
Hidrolases/genética
Fígado/enzimologia
Tirosinemias/genética
[Mh] Termos MeSH secundário: Adolescente
Criança
Pré-Escolar
Feminino
Variação Genética
Glutationa Transferase/deficiência
Heptanoatos/sangue
Sequenciamento de Nucleotídeos em Larga Escala
Seres Humanos
Hidrolases/sangue
Lactente
Recém-Nascido
Fígado/patologia
Masculino
Tirosina/sangue
Tirosinemias/sangue
Tirosinemias/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Heptanoates); 42HK56048U (Tyrosine); 51568-18-4 (succinylacetone); EC 2.5.1.- (GSTZ1 protein, human); EC 2.5.1.18 (Glutathione Transferase); EC 3.- (Hydrolases); EC 3.7.1.2 (fumarylacetoacetase)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171103
[Lr] Data última revisão:
171103
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161124
[St] Status:MEDLINE
[do] DOI:10.1136/jmedgenet-2016-104289


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[PMID]:27855279
[Au] Autor:Elgilani F; Mao SA; Glorioso JM; Yin M; Iankov ID; Singh A; Amiot B; Rinaldo P; Marler RJ; Ehman RL; Grompe M; Lillegard JB; Hickey RD; Nyberg SL
[Ad] Endereço:William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota.
[Ti] Título:Chronic Phenotype Characterization of a Large-Animal Model of Hereditary Tyrosinemia Type 1.
[So] Source:Am J Pathol;187(1):33-41, 2017 Jan.
[Is] ISSN:1525-2191
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Hereditary tyrosinemia type 1 (HT1) is an autosomal recessive disease caused by deficiency in fumarylacetoacetate hydrolase, the last enzyme in the tyrosine catabolic pathway. In this study, we investigated whether fumarylacetoacetate hydrolase deficient (FAH ) pigs, a novel large-animal model of HT1, develop fibrosis and cirrhosis characteristic of the human disease. FAH pigs were treated with the protective drug 2-(2-nitro-4-trifluoromethylbenzoyl)-1, 3 cyclohexandione (NTBC) at a dose of 1 mg/kg per day initially after birth. After 30 days, they were assigned to one of three groups based on dosing of NTBC. Group 1 received ≥0.2 mg/kg per day, group 2 cycled on/off NTBC (0.05 mg/kg per day × 1 week/0 mg/kg per day × 3 weeks), and group 3 received no NTBC thereafter. Pigs were monitored for features of liver disease. Animals in group 1 continued to have weight gain and biochemical analyses comparable to wild-type pigs. Animals in group 2 had significant cessation of weight gain, abnormal biochemical test results, and various grades of fibrosis and cirrhosis. No evidence of hepatocellular carcinoma was detected. Group 3 animals declined rapidly, with acute liver failure. In conclusion, the FAH pig is a large-animal model of HT1 with clinical characteristics that resemble the human phenotype. Under conditions of low-dose NTBC, FAH pigs developed liver fibrosis and portal hypertension, and thus may serve as a large-animal model of chronic liver disease.
[Mh] Termos MeSH primário: Tirosinemias/patologia
[Mh] Termos MeSH secundário: Animais
Doença Crônica
Modelos Animais de Doenças
Técnicas de Imagem por Elasticidade
Feminino
Heptanoatos/metabolismo
Seres Humanos
Hidrolases/deficiência
Hidrolases/metabolismo
Rim/metabolismo
Rim/patologia
Fígado/patologia
Fígado/fisiopatologia
Cirrose Hepática/patologia
Espectroscopia de Ressonância Magnética
Masculino
Redes e Vias Metabólicas
Fenótipo
Pressão na Veia Porta
Sus scrofa
Tirosina/metabolismo
Ganho de Peso
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Heptanoates); 42HK56048U (Tyrosine); 51568-18-4 (succinylacetone); EC 3.- (Hydrolases); EC 3.7.1.2 (fumarylacetoacetase)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170522
[Lr] Data última revisão:
170522
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:161118
[St] Status:MEDLINE


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[PMID]:27832414
[Au] Autor:Soares DC; Stroparo MN; Lian YC; Takakura CY; Wolf S; Betz R; Kim CA
[Ad] Endereço:Clinical Genetics Unit, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, Av. Dr. Eneas Carvalho de Aguiar, 647, São Paulo, 05403-000, SP, Brasil. diogo.soares@hc.fm.usp.br.
[Ti] Título:Herpetiform keratitis and palmoplantar hyperkeratosis: warning signs for Richner-Hanhart syndrome.
[So] Source:J Inherit Metab Dis;40(3):461-462, 2017 May.
[Is] ISSN:1573-2665
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Richner-Hanhart syndrome (RHS, tyrosinemia type II) is a rare, autosomal recessive inborn error of tyrosine metabolism caused by tyrosine aminotransferase deficiency. It is characterized by photophobia due to keratitis, painful palmoplantar hyperkeratosis, variable mental retardation, and elevated serum tyrosine levels. Patients are often misdiagnosed with herpes simplex keratitis. We report on a a boy from Brazil who presented with bilateral keratitis secondary to RHS, which had earlier been misdiagnosed as herpes simplex keratitis.
[Mh] Termos MeSH primário: Ceratite/diagnóstico
Ceratodermia Palmar e Plantar/diagnóstico
Tirosinemias/diagnóstico
[Mh] Termos MeSH secundário: Brasil
Pré-Escolar
Seres Humanos
Masculino
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171018
[Lr] Data última revisão:
171018
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161111
[St] Status:MEDLINE
[do] DOI:10.1007/s10545-016-9996-z


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[PMID]:27305933
[Au] Autor:Ward JP; Dunster JL; Derks G; Mistry P; Salazar JD
[Ad] Endereço:Department of Mathematical Sciences, Loughborough University, Loughborough LE11 3TU, UK.
[Ti] Título:Predicting tyrosinaemia: a mathematical model of 4-hydroxyphenylpyruvate dioxygenase inhibition by nitisinone in rats.
[So] Source:Math Med Biol;34(3):335-390, 2017 Sep 01.
[Is] ISSN:1477-8602
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Nitisinone or 2-(2-nitro-4-trifluoromethylbenzoyl)cyclohexane-1,3-dione is a reversible inhibitor of 4-hydroxyphenylpyruvate dioxygenase (HPPD), an enzyme important in tyrosine catabolism. Today, nitisinone is successfully used to treat Hereditary Tyrosinaemia type 1, although its original expected role was as a herbicide. In laboratory animals, treatment with nitisinone leads to the elevation of plasma tyrosine (tyrosinaemia). In rats and Beagle dogs, repeat low-dose exposure to nitisinone leads to corneal opacities whilst similar studies in the mouse and Rhesus monkey showed no comparable toxicities or other treatment related findings. The differences in toxicological sensitivities have been related to the upper limit of the concentration of tyrosine that accumulates in plasma, which is driven by the amount/activity of tyrosine aminotransferase. A physiologically based, pharmacodynamics ordinary differential equation model of HPPD inhibition to bolus exposure of nitisinone in vivo is presented. Going beyond traditional approaches, asymptotic analysis is used to separate the different timescales of events involved in HPPD inhibition and tyrosinaemia. This analysis elucidates, in terms of the model parameters, a critical inhibitor concentration (at which tyrosine concentration starts to rise) and highlights the contribution of in vitro measured parameters to events in an in vivo system. Furthermore, using parameter-fitting methods, a systematically derived reduced model is shown to fit well to rat data, making explicit how the parameters are informed by such data. This model in combination with in vitro descriptors has potential as a surrogate for animal experimentation to predict tyrosinaemia, and further development can extend its application to other related medical scenarios.
[Mh] Termos MeSH primário: 4-Hidroxifenilpiruvato Dioxigenase/antagonistas & inibidores
Cicloexanonas/efeitos adversos
Modelos Biológicos
Nitrobenzoatos/efeitos adversos
Tirosinemias/etiologia
[Mh] Termos MeSH secundário: 4-Hidroxifenilpiruvato Dioxigenase/metabolismo
Animais
Simulação por Computador
Cicloexanonas/administração & dosagem
Inibidores Enzimáticos/administração & dosagem
Inibidores Enzimáticos/efeitos adversos
Cinética
Fígado/efeitos dos fármacos
Fígado/metabolismo
Conceitos Matemáticos
Modelos Animais
Nitrobenzoatos/administração & dosagem
Ratos
Tirosina/metabolismo
Tirosinemias/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cyclohexanones); 0 (Enzyme Inhibitors); 0 (Nitrobenzoates); 42HK56048U (Tyrosine); EC 1.13.11.27 (4-Hydroxyphenylpyruvate Dioxygenase); K5BN214699 (nitisinone)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160617
[St] Status:MEDLINE
[do] DOI:10.1093/imammb/dqw006


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Fotocópia
[PMID]:27701365
[Ti] Título:In brief: Nitisinone (Orfadin) for hereditary tyrosinemia.
[So] Source:Med Lett Drugs Ther;58(1505):e132, 2016 Oct 10.
[Is] ISSN:1523-2859
[Cp] País de publicação:United States
[La] Idioma:eng
[Mh] Termos MeSH primário: 4-Hidroxifenilpiruvato Dioxigenase/antagonistas & inibidores
Cicloexanonas/uso terapêutico
Inibidores Enzimáticos/uso terapêutico
Nitrobenzoatos/uso terapêutico
Tirosinemias/tratamento farmacológico
[Mh] Termos MeSH secundário: 4-Hidroxifenilpiruvato Dioxigenase/metabolismo
Administração Oral
Cápsulas
Cicloexanonas/administração & dosagem
Cicloexanonas/efeitos adversos
Esquema de Medicação
Inibidores Enzimáticos/administração & dosagem
Inibidores Enzimáticos/efeitos adversos
Seres Humanos
Nitrobenzoatos/administração & dosagem
Nitrobenzoatos/efeitos adversos
Soluções Farmacêuticas
Resultado do Tratamento
Tirosinemias/diagnóstico
Tirosinemias/enzimologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Capsules); 0 (Cyclohexanones); 0 (Enzyme Inhibitors); 0 (Nitrobenzoates); 0 (Pharmaceutical Solutions); EC 1.13.11.27 (4-Hydroxyphenylpyruvate Dioxygenase); K5BN214699 (nitisinone)
[Em] Mês de entrada:1701
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:161005
[St] Status:MEDLINE



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