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1.
Muscle Nerve ; 70(2): 204-209, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38828849

RESUMO

INTRODUCTION/AIMS: Sodium phenylbutyrate-taurursodiol (PB-TURSO) was recently approved for treating amyotrophic lateral sclerosis (ALS). Third-party payors' coverage policies are evolving, and adverse events are just being fully assessed. The goals of this study were to evaluate patients' experiences in obtaining and continuing PB-TURSO and assess adverse events and medication adherence. METHODS: Medical records of 109 ALS patients who were considered PB-TURSO candidates by the treating physician at a tertiary ALS clinic from October 2022 to May 2023 were reviewed. Data was recorded for demographics, clinical, and insurance information. A survey was e-mailed to patients asking about out-of-pocket expenses for PB-TURSO, financial assistance, medication start and (if applicable) stop dates, and reasons for discontinuation. RESULTS: Insurance information was available for 91 patients [57 males (62%); mean age 64.8 years (range 25.7-88)]. Of 79 who applied for insurance approval, 71 (90%) were approved; however, 19 required 1-3 appeals. Among 73 patients with available data about medication status, 54 started PB-TURSO and 19 did not, most commonly due to personal choice or out-of-pocket expenses. About 44% of patients (24/54) stopped taking PB-TURSO, primarily due to adverse events. Monthly out-of-pocket expenses varied from $0 to $3500 and 36 patients qualified for financial assistance. Administrative and nursing staff devoted 7.2 hours/week to the insurance authorization process. DISCUSSION: Most patients received insurance approval for PB-TURSO, but one-fourth required appeals. Some out-of-pocket costs were very high. Investment of staff time was substantial. These findings have implications for insurance coverage of, and adherence to, future ALS treatments.


Assuntos
Esclerose Lateral Amiotrófica , Adesão à Medicação , Humanos , Esclerose Lateral Amiotrófica/tratamento farmacológico , Esclerose Lateral Amiotrófica/economia , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Adulto , Estados Unidos , Idoso de 80 Anos ou mais , Fenilbutiratos/uso terapêutico , Fenilbutiratos/economia , Gastos em Saúde , Estudos Retrospectivos
2.
Synapse ; 78(4): e22301, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38819491

RESUMO

Neurological disorders (NDs) are diseases of the central and peripheral nervous systems that affect more than one billion people worldwide. The risk of developing an ND increases with age due to the vulnerability of the different organs and systems to genetic, environmental, and social changes that consequently cause motor and cognitive deficits that disable the person from their daily activities and individual and social productivity. Intrinsic factors (genetic factors, age, gender) and extrinsic factors (addictions, infections, or lifestyle) favor the persistence of systemic inflammatory processes that contribute to the evolution of NDs. Neuroinflammation is recognized as a common etiopathogenic factor of ND. The study of new pharmacological options for the treatment of ND should focus on improving the characteristic symptoms and attacking specific molecular targets that allow the delay of damage processes such as neuroinflammation, oxidative stress, cellular metabolic dysfunction, and deregulation of transcriptional processes. In this review, we describe the possible role of sodium phenylbutyrate (NaPB) in the pathogenesis of Alzheimer's disease, hepatic encephalopathy, aging, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis; in addition, we describe the mechanism of action of NaPB and its beneficial effects that have been shown in various in vivo and in vitro studies to delay the evolution of any ND.


Assuntos
Doenças do Sistema Nervoso , Fenilbutiratos , Humanos , Fenilbutiratos/uso terapêutico , Fenilbutiratos/farmacologia , Animais , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças do Sistema Nervoso/metabolismo
3.
Mol Genet Metab ; 142(3): 108495, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38772223

RESUMO

PURPOSE: To identify therapies for combined D, L-2-hydroxyglutaric aciduria (C-2HGA), a rare genetic disorder caused by recessive variants in the SLC25A1 gene. METHODS: Patients C-2HGA were identified and diagnosed by whole exome sequencing and biochemical genetic testing. Patient derived fibroblasts were then treated with phenylbutyrate and the functional effects assessed by metabolomics and RNA-sequencing. RESULTS: In this study, we demonstrated that C-2HGA patient derived fibroblasts exhibited impaired cellular bioenergetics. Moreover, Fibroblasts form one patient exhibited worsened cellular bioenergetics when supplemented with citrate. We hypothesized that treating patient cells with phenylbutyrate (PB), an FDA approved pharmaceutical drug that conjugates glutamine for renal excretion, would reduce mitochondrial 2-ketoglutarate, thereby leading to improved cellular bioenergetics. Metabolomic and RNA-seq analyses of PB-treated fibroblasts demonstrated a significant decrease in intracellular 2-ketoglutarate, 2-hydroxyglutarate, and in levels of mRNA coding for citrate synthase and isocitrate dehydrogenase. Consistent with the known action of PB, an increased level of phenylacetylglutamine in patient cells was consistent with the drug acting as 2-ketoglutarate sink. CONCLUSION: Our pre-clinical studies suggest that citrate supplementation has the possibility exacerbating energy metabolism in this condition. However, improvement in cellular bioenergetics suggests phenylbutyrate might have interventional utility for this rare disease.


Assuntos
Fibroblastos , Glutaratos , Fenilbutiratos , Humanos , Fenilbutiratos/farmacologia , Fenilbutiratos/uso terapêutico , Fibroblastos/metabolismo , Fibroblastos/efeitos dos fármacos , Glutaratos/metabolismo , Ácidos Cetoglutáricos/metabolismo , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/genética , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/genética , Metabolômica , Sequenciamento do Exoma , Citrato (si)-Sintase/metabolismo , Citrato (si)-Sintase/genética , Encefalopatias Metabólicas Congênitas/tratamento farmacológico , Encefalopatias Metabólicas Congênitas/genética , Encefalopatias Metabólicas Congênitas/metabolismo , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , Encefalopatias Metabólicas/tratamento farmacológico , Encefalopatias Metabólicas/genética , Encefalopatias Metabólicas/metabolismo , Encefalopatias Metabólicas/patologia , Multiômica , Proteínas Mitocondriais , Transportadores de Ânions Orgânicos
4.
Zhongguo Dang Dai Er Ke Za Zhi ; 26(5): 512-517, 2024 May 15.
Artigo em Chinês | MEDLINE | ID: mdl-38802913

RESUMO

Glyceryl phenylbutyrate (GPB) serves as a long-term management medication for Ornithine transcarbamylase deficiency (OTCD), effectively controlling hyperammonemia, but there is a lack of experience in using this medicine in China. This article retrospectively analyzes the case of a child diagnosed with OTCD at Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, including a review of related literature. After diagnosis, the patient was treated with GPB, followed by efficacy follow-up and pharmacological monitoring. The 6-year and 6-month-old male patient exhibited poor speech development, disobedience, temper tantrums, and aggressive behavior. Blood ammonia levels peaked at 327 µmol/L; urine organic acid analysis indicated elevated uracil levels; cranial MRI showed extensive abnormal signals in both cerebral hemispheres. Genetic testing revealed de novo mutation in the OTC gene (c.241T>C, p.S81P). Blood ammonia levels were approximately 43, 80, and 56 µmol/L at 1, 2, and 3 months after starting GPB treatment, respectively. During treatment, blood ammonia was well-controlled without drug-related adverse effects. The patient showed improvement in developmental delays, obedience, temperament, and absence of aggressive behavior.


Assuntos
Doença da Deficiência de Ornitina Carbomoiltransferase , Fenilbutiratos , Humanos , Masculino , Doença da Deficiência de Ornitina Carbomoiltransferase/tratamento farmacológico , Doença da Deficiência de Ornitina Carbomoiltransferase/genética , Fenilbutiratos/uso terapêutico , Criança , Glicerol/análogos & derivados
5.
Muscle Nerve ; 70(1): 148-151, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38670927

RESUMO

INTRODUCTION/AIMS: The aim of this study was to examine clinical utilization and discontinuation rates of sodium phenylbutyrate-taurursodiol (PB-TURSO) in a single Amyotrophic Lateral Sclerosis (ALS) center. PB-TURSO was approved by the United States Food and Drug Administration (FDA) in September 2022. Prior experience has been limited to clinical trials or expanded access protocols. In this manuscript, we discuss insurance approval rates, patient uptake, and discontinuation of PB-TURSO in a large academic center. METHODS: Records of patients seen for clinical visits between January 2022 and May 2023 were reviewed. Demographic and clinical characteristics of our clinic population and those initiating PB-TURSO were obtained from our clinical database. RESULTS: A total of 228 patients were seen during the observation period and 122 requested PB-TURSO prescriptions. 77% (94) were approved by insurance. 66% (65) of those who were approved or received free drug chose to start medication. 51% (34) of those who initiated PB-TURSO continued to take it through the end of the observation period. Four patients discontinued due to death during the observation period. Of the 29 patients who survived and discontinued, the main reasons for discontinuation were GI symptoms (17, 58.6%) and taste (8, 29.6%). DISCUSSION: PB-TURSO was approved by insurance for most patients. The discontinuation rate was high and was driven largely by GI side effects and taste. Future considerations would include deeper examination of demographic trends, patient costs, side effects, and potential benefits in clinical practice.


Assuntos
Esclerose Lateral Amiotrófica , Humanos , Masculino , Feminino , Esclerose Lateral Amiotrófica/tratamento farmacológico , Pessoa de Meia-Idade , Idoso , Fenilbutiratos/uso terapêutico , Adulto , Estudos Retrospectivos , Combinação de Medicamentos
6.
Metabolomics ; 20(3): 46, 2024 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-38641695

RESUMO

INTRODUCTION: Cardiac dysfunction after sepsis the most common and severe sepsis-related organ failure. The severity of cardiac damage in sepsis patients was positively associated to mortality. It is important to look for drugs targeting sepsis-induced cardiac damage. Our previous studies found that 4-phenylbutyric acid (PBA) was beneficial to septic shock by improving cardiovascular function and survival, while the specific mechanism is unclear. OBJECTIVES: We aimed to explore the specific mechanism and PBA for protecting cardiac function in sepsis. METHODS: The cecal ligation and puncture-induced septic shock models were used to observe the therapeutic effects of PBA on myocardial contractility and the serum levels of cardiac troponin-T. The mechanisms of PBA against sepsis were explored by metabolomics and network pharmacology. RESULTS: The results showed that PBA alleviated the sepsis-induced cardiac damage. The metabolomics results showed that there were 28 metabolites involving in the therapeutic effects of PBA against sepsis. According to network pharmacology, 11 hub genes were found that were involved in lipid metabolism and amino acid transport following PBA treatment. The further integrated analysis focused on 7 key targets, including Comt, Slc6a4, Maoa, Ppara, Pparg, Ptgs2 and Trpv1, as well as their core metabolites and pathways. In an in vitro assay, PBA effectively inhibited sepsis-induced reductions in Comt, Ptgs2 and Ppara after sepsis. CONCLUSIONS: PBA protects sepsis-induced cardiac injury by targeting Comt/Ptgs2/Ppara, which regulates amino acid metabolism and lipid metabolism. The study reveals the complicated mechanisms of PBA against sepsis.


Assuntos
Cardiopatias , Fenilbutiratos , Sepse , Choque Séptico , Aminoácidos/metabolismo , Ciclo-Oxigenase 2/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Cardiopatias/tratamento farmacológico , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolômica , Fenilbutiratos/farmacologia , Fenilbutiratos/uso terapêutico , Sepse/complicações , Sepse/tratamento farmacológico , Sepse/metabolismo , Choque Séptico/complicações , Choque Séptico/tratamento farmacológico , Animais , Camundongos , Modelos Animais de Doenças , Catecol O-Metiltransferase/efeitos dos fármacos , Catecol O-Metiltransferase/metabolismo , PPAR alfa/efeitos dos fármacos , PPAR alfa/metabolismo
7.
Ann Clin Transl Neurol ; 10(12): 2297-2304, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37807839

RESUMO

OBJECTIVE: Sodium phenylbutyrate and taurursodiol (PB and TURSO) was evaluated in amyotrophic lateral sclerosis (ALS) in the CENTAUR trial encompassing randomized placebo-controlled and open-label extension phases. On intent-to-treat (ITT) survival analysis, median overall survival (OS) was 4.8 months longer and risk of death 36% lower in those originally randomized to an initial 6-month double-blind period of PB and TURSO versus placebo. To estimate PB and TURSO treatment effect without placebo-to-active crossover, we performed a post hoc survival analysis comparing PB and TURSO-randomized participants from CENTAUR and a propensity score-matched, PB and TURSO-naïve external control cohort from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database. METHODS: Clinical trial control participants from the PRO-ACT database who met prespecified eligibility criteria were propensity score matched 1:1 with PB and TURSO-randomized CENTAUR participants using prognostically significant covariates in ALS. RESULTS: Baseline characteristics including propensity score-matched covariates were generally well balanced between CENTAUR PB and TURSO (n = 89) and PRO-ACT external control (n = 85) groups. Estimated median (IQR) OS was 23.54 (14.56-39.32) months in the CENTAUR PB and TURSO group and 13.15 (9.83-19.20) months in the PRO-ACT external control group; hazard of death was 52% lower in the former group (hazard ratio, 0.48; 95% CI, 0.31-0.72; p = 0.00048). INTERPRETATION: This analysis suggests potentially greater survival benefit with PB and TURSO in ALS without placebo-to-active crossover than seen on ITT analysis in CENTAUR. Analyses using well-matched external controls may provide additional context for evaluating survival effects in future ALS trials.


Assuntos
Esclerose Lateral Amiotrófica , Humanos , Esclerose Lateral Amiotrófica/tratamento farmacológico , Fenilbutiratos/farmacologia , Fenilbutiratos/uso terapêutico , Análise de Sobrevida , Modelos de Riscos Proporcionais
8.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 40(9): 1107-1112, 2023 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-37643956

RESUMO

OBJECTIVE: To evaluate the efficacy and safety of glyceryl phenylbutyrate (GPB) therapy for patients with Ornithine transcarbamylase deficiency (OTCD). METHODS: Two children with OTCD were selected as the study subjects, and their clinical manifestations, blood ammonia, liver enzymes, growth and development information following the treatment with GPB were retrospectively analyzed. A literature review was also carried out by searching the PubMed database for studies on the GPB treatment for urea cycle disorders. RESULTS: With the GPB treatment, the blood ammonia and liver enzyme level in both patients have decreased to the normal range within 3 months. Motor development in child 2 has improved. No adverse reaction was noted, except for transient palmar greasy smell and loss of appetite in child 1. Analysis of the literature showed that patients had lower ammonia exposure, lower annual incidence of hyperammonemic crisis, more actual protein intake and fewer adverse events during GPB treatment. CONCLUSION: GPB is safe and effective for the treatment of OTCD.


Assuntos
Doença da Deficiência de Ornitina Carbomoiltransferase , Criança , Humanos , Doença da Deficiência de Ornitina Carbomoiltransferase/tratamento farmacológico , Fenilbutiratos/uso terapêutico , Amônia , Estudos Retrospectivos
9.
Mol Genet Metab ; 139(3): 107627, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37327713

RESUMO

Hyperammonemia has been reported following asparaginase administration, consistent with the mechanisms of asparaginase, which catabolizes asparagine to aspartic acid and ammonia, and secondarily converts glutamine to glutamate and ammonia. However, there are only a few reports on the treatment of these patients, which varies widely from watchful waiting to treatment with lactulose, protein restriction, sodium benzoate, and phenylbutyrate to dialysis. While many patients with reported asparaginase-induced hyperammonemia (AIH) are asymptomatic, some have severe complications and even fatal outcomes despite medical intervention. Here, we present a cohort of five pediatric patients with symptomatic AIH, which occurred after switching patients from polyethylene glycolated (PEG)- asparaginase to recombinant Crisantaspase Pseudomonas fluorescens (4 patients) or Erwinia (1 patient) asparaginase, and discuss their subsequent management, metabolic workup, and genetic testing. We developed an institutional management plan, which gradually evolved based on our local experience and previous treatment modalities. Because of the significant reduction in glutamine levels after asparaginase administration, sodium benzoate should be used as a first-line ammonia scavenger for symptomatic AIH instead of sodium phenylacetate or phenylbutyrate. This approach facilitated continuation of asparaginase doses, which is known to improve cancer outcomes. We also discuss the potential contribution of genetic modifiers to AIH. Our data highlights the need for increased awareness of symptomatic AIH, especially when an asparaginase with higher glutaminase activity is used, and its prompt management. The utility and efficacy of this management approach should be systematically investigated in a larger cohort of patients.


Assuntos
Antineoplásicos , Hiperamonemia , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Criança , Asparaginase/efeitos adversos , Fenilbutiratos/uso terapêutico , Hiperamonemia/induzido quimicamente , Hiperamonemia/tratamento farmacológico , Benzoato de Sódio/efeitos adversos , Glutamina/efeitos adversos , Amônia , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/induzido quimicamente , Resultado do Tratamento , Antineoplásicos/efeitos adversos
10.
Brasília; CONITEC; maio 2023.
Não convencional em Português | BRISA/RedTESA | ID: biblio-1443166

RESUMO

CONDIÇÃO CLÍNICA: A Esclerose Lateral Amiotrófica (ELA) é uma doença que acomete os neurônios motores do sistema nervoso central, incluindo o tronco cerebral e a medula espinhal, causando, progressivamente, fraqueza e atrofia da musculatura esquelética. Os mecanismos patogenéticos da doença envolvem múltiplas alterações no microambiente do neurônio motor, incluindo o acúmulo de agregados de proteína, disfunção no processamento de RNA, estresse oxidativo, inflamação neural, apoptose, disfunções mitocondriais e fragmentação do complexo de Golg. Essas alterações podem ser causadas por diferentes fatores, que são divididos em: Genéticos: envolvidos principalmente nos casos hereditários de ELA, com mutações nos genes SOD1, TARDBP e FUS, C9orf72; Ambientais: exposição a chumbo, alumínio, fertilizantes, inseticidas, herbicidas e tabaco; Epigenéticos: metilação de DNA, edição de RNA e silenciamento pós-transcricional de RNA. TRATAMENTO: A ELA é uma doença para a qual não existe cura. O objetivo do tratamento é diminuir a velocidade de progressão da doença, melhorar da qualidade de vida (preservação de funcionalidade, diminuição da dor e manutenção da independência) e potencialmente aumentar a sobrevida livre de doença. Até o início da década de 1990, o riluzol era o único medicamento aprovado pelo United States Food and Drug Administration (FDA) para o tratamento de pacientes com ELA. No Brasil, o riluzol é o único medicamento aprovado pela Agência Nacional de Vigilância Sanitária (Anvisa) para o tratamento específico da ELA. ESTRATÉGIA DE BUSCA: Foi realizada uma busca na base de registros de ensaios clínicos ClinicalTrials.gov no dia 28 de outubro de 2022. O termo empregado para a busca foi "Amyotrophic Lateral Sclerosis". Foram considerados como critérios de inclusão medicamentos em fase 2/3 ou 3 de pesquisa clínica para avaliação da eficácia e segurança no tratamento da ELA. Foi levado em conta que, apesar de ser uma doença rara, o volume de tecnologias em desenvolvimento para o tratamento da ELA é grande e, portanto, considerou-se mais pertinente abordar apenas aquelas em fase mais avançada da pesquisa. MEDICAMENTOS: Tecnologias aprovadas em agências regulatórias Taurursodiol + fenilbutirato de sódio. A associação de dose fixa composta por taurursodiol e fenilbutirato de sódio (Relyvrio) é um medicamento desenvolvido para reduzir a morte neuronal em pacientes com ELA, a partir de mitigação do estresse do retículo endoplasmático e da disfunção mitocondrial. O taurursodiol atua sobre receptores de membrana (TGR5, S1PR2 e α5ß1-integrina) envolvidos na atividade mitocondrial e responsáveis pela apoptose de células neurais. Já o fenilbutirato de sódio age como um inibidor da histona desacetilase, envolvida em mecanismos epigenéticos de remodelamento na estrutura da cromatina e no controle da expressão gênica. Portanto, taurursodiol e fenilbutirato de sódio atuam contornando, simultaneamente, disfunções do retículo endoplasmático e mitocondrial, o que reduz a morte neuronal. Edaravone: O edaravone é uma tecnologia sequestradora de radicais livres de peroxil e peroxinitrito, com potencial capacidade de reduzir a morte neuronal por meio de diminuição do estresse oxidativo. Esse medicamento está formulado tanto em apresentação para administração intravenosa quanto oral. Tecnologias em avaliação para registro: Tofersen Tofersen é um oligonucleotideo sintético antissentido de RNA, inibidor do gene da superóxido dismutase 1 (SOD1), que está em desenvolvimento para o tratamento da ELA com mutações SOD1. No FDA, a tecnologia está em processo de avaliação e sua fabricante, Biogen Inc., foi solicitada a fornecer mais informações sobre o medicamento - a decisão está prevista para abril de 2023. No EMA, o Tofersen recebeu designação de droga órfã em agosto de 2016. Foram encontrados dois estudos: VALOR (NCT03070119) e ATLAS (NCT04856982). Tecnologias emergentes. Foram identificadas 16 tecnologias emergentes para ELA. CONSIDERAÇÕES FINAIS: A ELA é uma doença rara, progressiva e com alto impacto na vida das pessoas acometidas, sendo associada à paralisia motora progressiva e à ventilação mecânica permanente. Atualmente, há poucas opções terapêuticas com potencial de modificar o curso da doença, que pode ser fatal. Duas tecnologias identificadas neste documento para o tratamento da ELA estão aprovadas no FDA: formulação de dose fixa de taurursodiol/fenilbutirato de sódio e edaravone. Apesar das limitações dos estudos, a agência justificou a aprovação das tecnologias devido ao pequeno número de opções terapêuticas disponíveis para pacientes com ELA. Além dessas duas tecnologias, o FDA avalia atualmente o medicamento torfersen, cuja decisão está prevista para a primeira metade do ano 2023. Nenhuma das três tecnologias está aprovada pela EMA e pela Anvisa. Apesar dos estudos recentes relacionados ao edaravone e taurursodiol/ fenilbutirato de sódio apresentarem alguns resultados positivos em desfechospesquisados, esses estudos também apresentam limitações, como pequeno tamanho amostral, curta duração e potenciais eventos adversos graves relacionados à via de administração do medicamento (como é o caso do tofersen). Cita-se, também, a baixa correlação entre o ALSFRS-R, principal ferramenta utilizada para mensuração de desfecho clínico, com o prognóstico. Foram encontradas outras 16 tecnologias emergentes. Dessas, apenas três possuem ensaios clínicos de fase 3 com resultados publicados: levosimendan, metilcobalamina e debamestrocel. As conclusões acerca da efetividade e segurança dessas tecnologias devem ser interpretadas com cautela, pois há poucas publicações de artigos científicos e de resultados no ClinicalTrials.gov. A despeito das evidências aqui apresentadas, para que ocorra a oferta desses medicamentos no SUS, é necessária a análise pela Comissão Nacional de Incorporação de Tecnologias no SUS (Conitec), conforme disposto na Lei nº 12.401/2011, que alterou a Lei nº 8.080/1990. Os relatórios de recomendação da Conitec levam em consideração as evidências científicas sobre eficácia, acurácia, efetividade e segurança do medicamento, assim como a avaliação econômica comparativa dos benefícios e dos custos em relação às tecnologias já incorporadas e o impacto da incorporação da tecnologia no SUS.


Assuntos
Humanos , Fenilbutiratos/uso terapêutico , Integrina alfa5beta1/uso terapêutico , Edaravone/uso terapêutico , Esclerose Lateral Amiotrófica/tratamento farmacológico , Brasil , Eficácia , Análise Custo-Benefício/economia , Projetos de Desenvolvimento Tecnológico e Inovação
11.
Artigo em Chinês | WPRIM (Pacífico Ocidental) | ID: wpr-1009259

RESUMO

OBJECTIVE@#To evaluate the efficacy and safety of glyceryl phenylbutyrate (GPB) therapy for patients with Ornithine transcarbamylase deficiency (OTCD).@*METHODS@#Two children with OTCD were selected as the study subjects, and their clinical manifestations, blood ammonia, liver enzymes, growth and development information following the treatment with GPB were retrospectively analyzed. A literature review was also carried out by searching the PubMed database for studies on the GPB treatment for urea cycle disorders.@*RESULTS@#With the GPB treatment, the blood ammonia and liver enzyme level in both patients have decreased to the normal range within 3 months. Motor development in child 2 has improved. No adverse reaction was noted, except for transient palmar greasy smell and loss of appetite in child 1. Analysis of the literature showed that patients had lower ammonia exposure, lower annual incidence of hyperammonemic crisis, more actual protein intake and fewer adverse events during GPB treatment.@*CONCLUSION@#GPB is safe and effective for the treatment of OTCD.


Assuntos
Criança , Humanos , Doença da Deficiência de Ornitina Carbomoiltransferase/tratamento farmacológico , Fenilbutiratos/uso terapêutico , Amônia , Estudos Retrospectivos
12.
Br J Biomed Sci ; 79: 10382, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35996497

RESUMO

Pyruvate dehydrogenase (PDH) deficiency is caused by a number of pathogenic variants and the most common are found in the PDHA1 gene. The PDHA1 gene encodes one of the subunits of the PDH enzyme found in a carbohydrate metabolism pathway involved in energy production. Pathogenic variants of PDHA1 gene usually impact the α-subunit of PDH causing energy reduction. It potentially leads to increased mortality in sufferers. Potential treatments for this disease include dichloroacetate and phenylbutyrate, previously used for other diseases such as cancer and maple syrup urine disease. However, not much is known about their efficacy in treating PDH deficiency. Effective treatment for PDH deficiency is crucial as carbohydrate is needed in a healthy diet and rice is the staple food for a large portion of the Asian population. This review analysed the efficacy of dichloroacetate and phenylbutyrate as potential treatments for PDH deficiency caused by PDHA1 pathogenic variants. Based on the findings of this review, dichloroacetate will have an effect on most PDHA1 pathogenic variant and can act as a temporary treatment to reduce the lactic acidosis, a common symptom of PDH deficiency. Phenylbutyrate can only be used on patients with certain pathogenic variants (p.P221L, p.R234G, p.G249R, p.R349C, p.R349H) on the PDH protein. It is hoped that the review would provide an insight into these treatments and improve the quality of lives for patients with PDH deficiency.


Assuntos
Doença da Deficiência do Complexo de Piruvato Desidrogenase , Humanos , Fenilbutiratos/uso terapêutico , Piruvato Desidrogenase (Lipoamida)/genética , Piruvato Desidrogenase (Lipoamida)/metabolismo , Doença da Deficiência do Complexo de Piruvato Desidrogenase/diagnóstico , Doença da Deficiência do Complexo de Piruvato Desidrogenase/tratamento farmacológico , Doença da Deficiência do Complexo de Piruvato Desidrogenase/genética
13.
CNS Drugs ; 36(9): 1007-1013, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35907175

RESUMO

An oral, fixed-dose coformulation of sodium phenylbutyrate and ursodoxicoltaurine (ALBRIOZA™; hereafter denoted sodium phenylbutyrate/ursodoxicoltaurine) is being developed by Amylyx Pharmaceuticals for the treatment of neurodegenerative diseases. In June 2022, the coformulation received its first approval with conditions in Canada for the treatment of amyotrophic lateral sclerosis (ALS) in adults. The approval was based on results from the multicentre, phase II CENTAUR trial, in which slowing of ALS progression was demonstrated with sodium phenylbutyrate/ursodoxicoltaurine relative to placebo. This article summarizes the milestones in the development of sodium phenylbutyrate/ursodoxicoltaurine leading to this first approval.


Assuntos
Esclerose Lateral Amiotrófica , Adulto , Esclerose Lateral Amiotrófica/tratamento farmacológico , Humanos , Preparações Farmacêuticas , Fenilbutiratos/farmacologia , Fenilbutiratos/uso terapêutico , Ácido Tauroquenodesoxicólico
14.
Eur J Pharmacol ; 919: 174810, 2022 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-35151644

RESUMO

5-Fluorouracil (5-FU)-induced oral mucositis has a severe negative impact on the patient's quality of life. This study aimed to investigate the role of endoplasmic reticulum stress (ERS) in the occurrence of 5-FU-induced oral mucositis in vivo and in the clinic. In vivo, 5-FU-induced oral mucositis model mice showed a higher level of glucose-regulated protein 78 kD (GRP78, a marker of ERS) than control mice. The inhibition of ERS could effectively reduce 5-FU-induced oxidative stress, inflammatory factor mRNA and cell apoptosis. Moreover, inhibition of ERS significantly decreased the activation of nuclear factor kappa-B (NF-κB) in 5-FU-induced oral mucositis model mice following tissue damage reduction. In the clinic, 5-FU could increase cell apoptosis and cause oral mucosa damage while increasing the expression of the ERS marker genes GRP78 and C/EBP-homologous protein (CHOP). Our study found that 5-FU could induce severe ERS, upregulate the expression of GRP78 and CHOP, raise oxidative stress and increase the expression of inflammatory factors by activating the NF-κB pathway, thus causing cell apoptosis and finally leading to oral mucosal injury.


Assuntos
Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fenilbutiratos/farmacologia , Estomatite/prevenção & controle , Animais , Antineoplásicos/efeitos adversos , Modelos Animais de Doenças , Fluoruracila/efeitos adversos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Fenilbutiratos/administração & dosagem , Fenilbutiratos/uso terapêutico , Estomatite/induzido quimicamente
15.
J Neuroinflammation ; 18(1): 238, 2021 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-34656124

RESUMO

BACKGROUND: Epigenetic regulation by histone deacetylases (HDACs) in Schwann cells (SCs) after injury facilitates them to undergo de- and redifferentiation processes necessary to support various stages of nerve repair. Although de-differentiation activates the synthesis and secretion of inflammatory cytokines by SCs to initiate an immune response during nerve repair, changes in either the timing or duration of prolonged inflammation mediated by SCs can affect later processes associated with repair and regeneration. Limited studies have investigated the regulatory processes through which HDACs in SCs control inflammatory cytokines to provide a favorable environment for peripheral nerve regeneration. METHODS: We employed the HDAC inhibitor (HDACi) sodium phenylbutyrate (PBA) to address this question in an in vitro RT4 SC inflammation model and an in vivo sciatic nerve transection injury model to examine the effects of HDAC inhibition on the expression of pro-inflammatory cytokines. Furthermore, we assessed the outcomes of suppression of extended inflammation on the regenerative potential of nerves by assessing axonal regeneration, remyelination, and reinnervation. RESULTS: Significant reductions in lipopolysaccharide (LPS)-induced pro-inflammatory cytokine (tumor necrosis factor-α [TNFα]) expression and secretion were observed in vitro following PBA treatment. PBA treatment also affected the transient changes in nuclear factor κB (NFκB)-p65 phosphorylation and translocation in response to LPS induction in RT4 SCs. Similarly, PBA mediated long-term suppressive effects on HDAC3 expression and activity. PBA administration resulted in marked inhibition of pro-inflammatory cytokine secretion at the site of transection injury when compared with that in the hydrogel control group at 6-week post-injury. A conducive microenvironment for axonal regrowth and remyelination was generated by increasing expression levels of protein gene product 9.5 (PGP9.5) and myelin basic protein (MBP) in regenerating nerve tissues. PBA administration increased the relative gastrocnemius muscle weight percentage and maintained the intactness of muscle bundles when compared with those in the hydrogel control group. CONCLUSIONS: Suppressing the lengthened state of inflammation using PBA treatment favors axonal regrowth and remyelination following nerve transection injury. PBA treatment also regulates pro-inflammatory cytokine expression by inhibiting the transcriptional activation of NFκB-p65 and HDAC3 in SCs in vitro.


Assuntos
Axônios/metabolismo , Histona Desacetilases/metabolismo , NF-kappa B/metabolismo , Regeneração Nervosa/fisiologia , Fenilbutiratos/farmacologia , Remielinização/fisiologia , Animais , Axônios/efeitos dos fármacos , Axônios/patologia , Linhagem Celular , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Inflamação/metabolismo , Inflamação/patologia , Inflamação/prevenção & controle , Masculino , NF-kappa B/antagonistas & inibidores , Regeneração Nervosa/efeitos dos fármacos , Fenilbutiratos/uso terapêutico , Ratos , Ratos Sprague-Dawley , Remielinização/efeitos dos fármacos , Células de Schwann/efeitos dos fármacos , Células de Schwann/metabolismo , Células de Schwann/patologia , Neuropatia Ciática , Células THP-1
16.
Psychopharmacology (Berl) ; 238(7): 1833-1845, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33723660

RESUMO

Autism spectrum disorder (ASD) is a neurodevelopment disorder characterized by deficits in social interaction and restrictive, repetitive, and stereotypical patterns of behavior. However, there is no pharmacological drug that is currently used to target these core ASD symptoms. Sodium phenylbutyrate (NaPB) is a well-known long-term treatment of urea cycle disorders in children. In this study, we assessed the therapeutic effects of NaPB, which is a chemical chaperone as well as histone deacetylase inhibitor on a BTBR T + Itpr3tf/J (BTBR) mice model of ASD. We found that acute and chronic treatment of NaPB remarkably improved, not only core ASD symptoms, including repetitive behaviors and sociability deficit, but also cognitive impairment in the BTBR mice. NaPB substantially induced histone acetylation in the brain of the BTBR mice. Intriguingly, the therapeutic effects of NaPB on autistic-like behaviors, such as repetitive behaviors, impaired sociability, and cognitive deficit also showed in the valproic acid (VPA)-induced mouse model of autism. In addition, pentylenetetrazole (PTZ)-induced seizure was significantly attenuated by NaPB treatment in C57BL/6J and BTBR mice. These findings suggest that NaPB may provide a novel therapeutic approach for the treatment of patients with ASD.


Assuntos
Transtorno do Espectro Autista/tratamento farmacológico , Disfunção Cognitiva/tratamento farmacológico , Asseio Animal/efeitos dos fármacos , Fenilbutiratos/uso terapêutico , Comportamento Social , Comportamento Estereotipado/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Transtorno do Espectro Autista/induzido quimicamente , Transtorno do Espectro Autista/psicologia , Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Disfunção Cognitiva/psicologia , Modelos Animais de Doenças , Feminino , Asseio Animal/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Camundongos Transgênicos , Fenilbutiratos/farmacologia , Comportamento Estereotipado/fisiologia , Ácido Valproico/toxicidade
17.
J Pediatr Endocrinol Metab ; 34(3): 407-410, 2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33675205

RESUMO

OBJECTIVES: The efficacy of sodium phenylbutyrate (SPB) for hyperammonemia associated with congenital portosystemic shunt (CPSS) remains unknown. We show the effectiveness of oral SPB. CASE PRESENTATION: Our patient had CPSS with severe hypoplasia of extrahepatic portal veins. At 9 months of age, to assess the efficacy of oral SPB, we evaluated the 24 h fluctuations of venous ammonia levels. In the first two days without SPB, ammonia levels were above 80 µmol/L for half a day. On the third and fourth days, administration of oral SPB three times a day decreased ammonia to acceptable levels, except at midnight. On the fifth day, another oral SPB administration at 8 pm decreased ammonia at midnight. Low levels of branched-chain amino acids, as well as coagulation disturbances, were observed without apparent symptoms. At 12 months of age, he showed normal psychomotor development. CONCLUSIONS: Oral SPB may be effective for hyperammonemia associated with CPSS.


Assuntos
Hiperamonemia/tratamento farmacológico , Fenilbutiratos/uso terapêutico , Sistema Porta/anormalidades , Administração Oral , Aminoácidos de Cadeia Ramificada/sangue , Amônia/sangue , Humanos , Hiperamonemia/sangue , Lactente , Masculino , Veia Porta/anormalidades
18.
Clin Cancer Res ; 27(8): 2352-2366, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33542077

RESUMO

PURPOSE: Nicotinamide phosphoribosyltransferase (NAMPT) inhibitors (NAMPTi) are currently in development, but may be limited as single-agent therapy due to compound-specific toxicity and cancer metabolic plasticity allowing resistance development. To potentially lower the doses of NAMPTis required for therapeutic benefit against acute myeloid leukemia (AML), we performed a genome-wide CRISPRi screen to identify rational disease-specific partners for a novel NAMPTi, KPT-9274. EXPERIMENTAL DESIGN: Cell lines and primary cells were analyzed for cell viability, self-renewal, and responses at RNA and protein levels with loss-of-function approaches and pharmacologic treatments. In vivo efficacy of combination therapy was evaluated with a xenograft model. RESULTS: We identified two histone deacetylases (HDAC), HDAC8 and SIRT6, whose knockout conferred synthetic lethality with KPT-9274 in AML. Furthermore, HDAC8-specific inhibitor, PCI-34051, or clinical class I HDAC inhibitor, AR-42, in combination with KPT-9274, synergistically decreased the survival of AML cells in a dose-dependent manner. AR-42/KPT-9274 cotreatment attenuated colony-forming potentials of patient cells while sparing healthy hematopoietic cells. Importantly, combined therapy demonstrated promising in vivo efficacy compared with KPT-9274 or AR-42 monotherapy. Mechanistically, genetic inhibition of SIRT6 potentiated the effect of KPT-9274 on PARP-1 suppression by abolishing mono-ADP ribosylation. AR-42/KPT-9274 cotreatment resulted in synergistic attenuation of homologous recombination and nonhomologous end joining pathways in cell lines and leukemia-initiating cells. CONCLUSIONS: Our findings provide evidence that HDAC8 inhibition- or shSIRT6-induced DNA repair deficiencies are potently synergistic with NAMPT targeting, with minimal toxicity toward normal cells, providing a rationale for a novel-novel combination-based treatment for AML.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Citocinas/antagonistas & inibidores , Leucemia Mieloide Aguda/tratamento farmacológico , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Proteínas Repressoras/antagonistas & inibidores , Sirtuínas/antagonistas & inibidores , Acrilamidas/farmacologia , Acrilamidas/uso terapêutico , Aminopiridinas/farmacologia , Aminopiridinas/uso terapêutico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linhagem Celular Tumoral , Dano ao DNA , Reparo do DNA por Junção de Extremidades/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Técnicas de Inativação de Genes , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Humanos , Ácidos Hidroxâmicos/farmacologia , Ácidos Hidroxâmicos/uso terapêutico , Indóis/farmacologia , Indóis/uso terapêutico , Leucemia Mieloide Aguda/patologia , Masculino , Camundongos , Fenilbutiratos/farmacologia , Fenilbutiratos/uso terapêutico , Reparo de DNA por Recombinação/efeitos dos fármacos , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Sirtuínas/genética , Sirtuínas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Res Vet Sci ; 136: 39-50, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33582313

RESUMO

Adipose-derived mesenchymal stem cells have been used to treat acute kidney injury (AKI). The role of endoplasmic reticulum (ER) stress in AKI treatment with canine adipose-derived mesenchymal stem cells (cADSCs) remains unknown. This study intended to investigate the therapeutic effects of cADSCs cultured in different media on AKI in mice and dogs and reveal the role of ER stress in this process. The mice were divided into two branches: a control group and a gentamicin induced group (this group treated with low-serum ADSC or high-serum ADSC or 4-phenylbutyric acid (4-PBA)). The dogs were divided into control, model, and cell-injected groups. To suppress ER stress, mice were simultaneously treated with 4-PBA. The results showed there were improvements in renal function and tissue damage and a corresponding decrease in ER stress in the kidneys of the mice that received cell injection. However, the cells cultured with 2% FBS showed a better growth state and resulted in lower ER stress levels in treated kidneys. In the 4-PBA-treated group, ER stress was suppressed, and there was corresponding kidney injury recovery. Similarly, both kidney damage and ER stress were alleviated after AKI dogs were injected with the cells. Our findings reveal that both allogeneic and xenogeneic cADSCs were effective treatments for AKI by inhibiting ER stress. These results also provide evidence for a new clinical therapy for acute renal disease in pets.


Assuntos
Injúria Renal Aguda/veterinária , Doenças do Cão/terapia , Estresse do Retículo Endoplasmático , Transplante de Células-Tronco Mesenquimais/veterinária , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/terapia , Animais , Apoptose/efeitos dos fármacos , Butilaminas/uso terapêutico , Células Cultivadas , Meios de Cultura , Cães , Gentamicinas , Rim/efeitos dos fármacos , Masculino , Células-Tronco Mesenquimais , Camundongos , Fenilbutiratos/uso terapêutico
20.
Cancer Chemother Pharmacol ; 87(5): 599-611, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33492438

RESUMO

PURPOSE: Given clinical activity of AR-42, an oral histone deacetylase inhibitor, in hematologic malignancies and preclinical activity in solid tumors, this phase 1 trial investigated the safety and tolerability of AR-42 in patients with advanced solid tumors, including neurofibromatosis type 2-associated meningiomas and schwannomas (NF2). The primary objective was to define the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs). Secondary objectives included determining pharmacokinetics and clinical activity. METHODS: This phase I trial was an open-label, single-center, dose-escalation study of single-agent AR-42 in primary central nervous system and advanced solid tumors. The study followed a 3 + 3 design with an expansion cohort at the MTD. RESULTS: Seventeen patients were enrolled with NF2 (n = 5), urothelial carcinoma (n = 3), breast cancer (n = 2), non-NF2-related meningioma (n = 2), carcinoma of unknown primary (n = 2), small cell lung cancer (n = 1), Sertoli cell carcinoma (n = 1), and uveal melanoma (n = 1). The recommended phase II dose is 60 mg three times weekly, for 3 weeks of a 28-day cycle. DLTs included grade 3 thrombocytopenia and grade 4 psychosis. The most common treatment-related adverse events were cytopenias, fatigue, and nausea. The best response was stable disease in 53% of patients (95% CI 26.6-78.7). Median progression-free survival (PFS) was 3.6 months (95% CI 1.2-9.1). Among evaluable patients with NF2 or meningioma (n = 5), median PFS was 9.1 months (95% CI 1.9-not reached). CONCLUSION: Single-agent AR-42 is safe and well tolerated. Further studies may consider AR-42 in a larger cohort of patients with NF2 or in combination with other agents in advanced solid tumors. TRIAL REGISTRATION: NCT01129193, registered 5/24/2010.


Assuntos
Inibidores de Histona Desacetilases/uso terapêutico , Neoplasias/tratamento farmacológico , Neurofibromatose 2/tratamento farmacológico , Fenilbutiratos/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/mortalidade , Neurofibromatose 2/mortalidade , Fenilbutiratos/efeitos adversos , Fenilbutiratos/farmacocinética , Adulto Jovem
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