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OBJECTIVE: To review the safety and efficacy of sodium phenylbutyrate and taurursodiol (SP + T) in slowing progression of amyotrophic lateral sclerosis (ALS) compared with pre-existing therapies. DATA SOURCES: A PubMed (from January 1, 2009, to April 13, 2023) and ClinicalTrials.gov search conducted using sodium phenylbutyrate, taurursodiol, AMX0035, riluzole, and edaravone. Additional articles were identified by hand from references. DATA SELECTION AND DATA EXTRACTION: This included English-language articles evaluating SP + T efficacy or safety in humans for decreasing neuronal death and slowing the progression of ALS. DATA SYNTHESIS: In one phase II clinical trial that encompassed an open-label extension phase, disease severity, assessed by the rate of decline in overall score on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised with higher scores indicating more functional ability, was -1.24 points per month with active drug and -1.66 points per month with placebo (difference, 0.42 points per month; 95% CI, 0.03-0.81; P = 0.03). Post hoc analysis found survival benefit of median 4.8 months with active medication compared with placebo. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE IN COMPARISON WITH EXISTING DRUGS: SP + T is a new US Food and Drug Administration-approved oral suspension for the treatment of ALS. Patients who received active medication through the phase II trial showed decreased rates of disease progression. Overall, SP + T could be considered a potential agent for the treatment of ALS which has a high unmet need. CONCLUSION: SP + T is an option for the treatment of ALS; however, additional data regarding efficacy in phase III trials with long-term safety profile considerations, as well as trials to compare current therapy with SP + T, are needed.
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Esclerose Lateral Amiotrófica , Estados Unidos , Humanos , Esclerose Lateral Amiotrófica/tratamento farmacológico , Fenilbutiratos/efeitos adversosRESUMO
Indole-3-acetic acid is a common naturally occurring auxin in plants. A synthesized derivative of this compound, 4-(2,4-difluorophenyl)-2-(1H-indol-3-yl)-4-oxobutanoic acid also called mitochonic acid 5 (MA-5), has shown to increase the survival ratio of fibroblasts from patients with mitochondrial disease under stress-induced conditions. Further studies verified its efficacy in pathological models, such as an ischemia-reperfusion model, possibly by increasing ATP production. However, the efficacy of MA-5 in mental disorders, such as anxiety, schizophrenia, and autism spectrum disorders (ASD), has not been investigated. Our study focused on examining the effect of MA-5 in a mouse model of ASD induced by prenatal exposure to valproic acid (VPA). VPA exposure significantly deteriorated the level of anxiety and exploratory behavior in an open field test. We fed mice an MA-5-containing diet for 5 weeks and observed an improvement in the above behavior in the MA-5-fed groups. The efficacy of MA-5 was also observed in the elevated plus maze and three-chambered tests. These findings suggest that MA-5 could potentially be used to treat ASD, especially in patients with mitochondrial dysfunction.
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Transtorno do Espectro Autista , Transtorno Autístico , Efeitos Tardios da Exposição Pré-Natal , Humanos , Gravidez , Feminino , Camundongos , Animais , Ácido Valproico/efeitos adversos , Transtorno Autístico/tratamento farmacológico , Transtorno Autístico/induzido quimicamente , Ácidos Indolacéticos/efeitos adversos , Fenilbutiratos/efeitos adversos , Transtorno do Espectro Autista/tratamento farmacológico , Modelos Animais de Doenças , Comportamento Animal , Comportamento SocialRESUMO
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.
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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 JovemRESUMO
BACKGROUND: Sodium phenylbutyrate and taurursodiol have been found to reduce neuronal death in experimental models. The efficacy and safety of a combination of the two compounds in persons with amyotrophic lateral sclerosis (ALS) are not known. METHODS: In this multicenter, randomized, double-blind trial, we enrolled participants with definite ALS who had had an onset of symptoms within the previous 18 months. Participants were randomly assigned in a 2:1 ratio to receive sodium phenylbutyrate-taurursodiol (3 g of sodium phenylbutyrate and 1 g of taurursodiol, administered once a day for 3 weeks and then twice a day) or placebo. The primary outcome was the rate of decline in the total score on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R; range, 0 to 48, with higher scores indicating better function) through 24 weeks. Secondary outcomes were the rates of decline in isometric muscle strength, plasma phosphorylated axonal neurofilament H subunit levels, and the slow vital capacity; the time to death, tracheostomy, or permanent ventilation; and the time to death, tracheostomy, permanent ventilation, or hospitalization. RESULTS: A total of 177 persons with ALS were screened for eligibility, and 137 were randomly assigned to receive sodium phenylbutyrate-taurursodiol (89 participants) or placebo (48 participants). In a modified intention-to-treat analysis, the mean rate of change in the ALSFRS-R score was -1.24 points per month with the active drug and -1.66 points per month with placebo (difference, 0.42 points per month; 95% confidence interval, 0.03 to 0.81; P = 0.03). Secondary outcomes did not differ significantly between the two groups. Adverse events with the active drug were mainly gastrointestinal. CONCLUSIONS: Sodium phenylbutyrate-taurursodiol resulted in slower functional decline than placebo as measured by the ALSFRS-R score over a period of 24 weeks. Secondary outcomes were not significantly different between the two groups. Longer and larger trials are necessary to evaluate the efficacy and safety of sodium phenylbutyrate-taurursodiol in persons with ALS. (Funded by Amylyx Pharmaceuticals and others; CENTAUR ClinicalTrials.gov number, NCT03127514.).
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Esclerose Lateral Amiotrófica/tratamento farmacológico , Fenilbutiratos/uso terapêutico , Ácido Tauroquenodesoxicólico/uso terapêutico , Idoso , Progressão da Doença , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Humanos , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Fenilbutiratos/efeitos adversos , Índice de Gravidade de Doença , Ácido Tauroquenodesoxicólico/administração & dosagem , Resultado do TratamentoRESUMO
INTRODUCTION: Glycerol phenylbutyrate (GPB) is currently approved for use in the US and Europe for patients of all ages with urea cycle disorders (UCD) who cannot be managed with protein restriction and/or amino acid supplementation alone. Currently available data on GPB is limited to 12â¯months exposure. Here, we present long-term experience with GPB. METHODS: This was an open-label, long-term safety study of GPB conducted in the US (17 sites) and Canada (1 site) monitoring the use of GPB in UCD patients who had previously completed 12 months of treatment in the previous safety extension studies. Ninety patients completed the previous studies with 88 of these continuing into the long-term evaluation. The duration of therapy was open ended until GPB was commercially available. The primary endpoint was the rate of adverse events (AEs). Secondary endpoints were venous ammonia levels, number and causes of hyperammonemic crises (HACs) and neuropsychological testing. RESULTS: A total of 45 pediatric patients between the ages of 1 to 17â¯years (median 7â¯years) and 43 adult patients between the ages of 19 and 61 years (median 30â¯years) were enrolled. The treatment emergent adverse events (TEAE) reported in ≥10% of adult or pediatric patients were consistent with the TEAEs reported in the previous safety extension studies with no increase in the overall incidence of TEAEs and no new TEAEs that indicated a new safety signal. Mean ammonia levels remained stable and below the adult upper limit of normal (<35⯵mol/L) through 24â¯months of treatment in both the pediatric and adult population. Over time, glutamine levels decreased in the overall population. The mean annualized rate of HACs (0.29) established in the previously reported 12-month follow-up study was maintained with continued GPB exposure. CONCLUSION: Following the completion of 12-month follow-up studies with GPB treatment, UCD patients were followed for an additional median of 1.85 (range 0 to 5.86) years in the present study with continued maintenance of ammonia control, similar rates of adverse events, and no new adverse events identified.
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Glicerol/análogos & derivados , Fenilbutiratos/uso terapêutico , Distúrbios Congênitos do Ciclo da Ureia/tratamento farmacológico , Adolescente , Adulto , Canadá , Criança , Pré-Escolar , Gerenciamento Clínico , Feminino , Seguimentos , Glicerol/efeitos adversos , Glicerol/uso terapêutico , Humanos , Hiperamonemia/induzido quimicamente , Lactente , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Fenilbutiratos/efeitos adversos , Estados Unidos , Adulto JovemRESUMO
BACKGROUND: Hepatic encephalopathy is a common complication of cirrhosis, with high related morbidity and mortality. Its presence is associated with a wide spectrum of change ranging from clinically obvious neuropsychiatric features, known as 'overt' hepatic encephalopathy, to abnormalities manifest only on psychometric or electrophysiological testing, 'minimal' hepatic encephalopathy. The exact pathogenesis of the syndrome is unknown but ammonia plays a key role. Drugs that specifically target ammonia include sodium benzoate, glycerol phenylbutyrate, ornithine phenylacetate, AST-120 (spherical carbon adsorbent), and polyethylene glycol. OBJECTIVES: To evaluate the beneficial and harmful effects of pharmacotherapies that specifically target ammonia versus placebo, no intervention, or other active interventions, for the prevention and treatment of hepatic encephalopathy in people with cirrhosis. SEARCH METHODS: We searched the Cochrane Hepato-Biliary Controlled Trials Register, CENTRAL, MEDLINE, Embase, and three other databases to March 2019. We also searched online trials registries such as ClinicalTrials.gov, European Medicines Agency, WHO International Clinical Trial Registry Platform, and the Food and Drug Administration for ongoing or unpublished trials. In addition, we searched conference proceedings, checked bibliographies, and corresponded with investigators. SELECTION CRITERIA: We included randomised clinical trials comparing sodium benzoate, glycerol phenylbutyrate, ornithine phenylacetate, AST-120, and polyethylene glycol versus placebo or non-absorbable disaccharides, irrespective of blinding, language, or publication status. We included participants with minimal or overt hepatic encephalopathy or participants who were at risk of developing hepatic encephalopathy. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from the included reports. The primary outcomes were mortality, hepatic encephalopathy, and serious adverse events. We undertook meta-analyses and presented results using risk ratios (RR) or mean differences (MD), both with 95% confidence intervals (CIs), and I2 statistic values as a marker of heterogeneity. We assessed bias control using the Cochrane Hepato-Biliary domains and the certainty of the evidence using GRADE. MAIN RESULTS: We identified 11 randomised clinical trials that fulfilled our inclusion criteria. Two trials evaluated the prevention of hepatic encephalopathy while nine evaluated the treatment of hepatic encephalopathy. The trials assessed sodium benzoate (three trials), glycerol phenylbutyrate (one trial), ornithine phenylacetate (two trials), AST-120 (two trials), and polyethylene glycol (three trials). Overall, 499 participants received these pharmacotherapies while 444 participants received a placebo preparation or a non-absorbable disaccharide. We classified eight of the 11 trials as at 'high risk of bias' and downgraded the certainty of the evidence to very low for all outcomes.Eleven trials, involving 943 participants, reported mortality data, although there were no events in five trials. Our analyses found no beneficial or harmful effects of sodium benzoate versus non-absorbable disaccharides (RR 1.26, 95% CI 0.49 to 3.28; 101 participants; 2 trials; I2 = 0%), glycerol phenylbutyrate versus placebo (RR 0.65, 95% CI 0.11 to 3.81; 178 participants; 1 trial), ornithine phenylacetate versus placebo (RR 0.73, 95% CI 0.35 to 1.51; 269 participants; 2 trials; I2 = 0%), AST-120 versus lactulose (RR 1.05, 95% CI 0.59 to 1.85; 41 participants; 1 trial), or polyethylene glycol versus lactulose (RR 0.50, 95% CI 0.09 to 2.64; 190 participants; 3 trials; I2 = 0%).Seven trials involving 521 participants reported data on hepatic encephalopathy. Our analyses showed a beneficial effect of glycerol phenylbutyrate versus placebo (RR 0.57, 95% CI 0.36 to 0.90; 178 participants; 1 trial; number needed to treat for an additional beneficial outcome (NNTB) 6), and of polyethylene glycol versus lactulose (RR 0.19, 95% CI 0.08 to 0.44; 190 participants; 3 trials; NNTB 4). We did not observe beneficial effects in the remaining three trials with extractable data: sodium benzoate versus non-absorbable disaccharides (RR 1.22, 95% CI 0.51 to 2.93; 74 participants; 1 trial); ornithine phenylacetate versus placebo (RR 2.71, 95% CI 0.12 to 62.70; 38 participants; 1 trial); or AST-120 versus lactulose (RR 1.05, 95% CI 0.59 to 1.85; 41 participants; 1 trial).Ten trials, involving 790 participants, reported a total of 130 serious adverse events. Our analyses found no evidence of beneficial or harmful effects of sodium benzoate versus non-absorbable disaccharides (RR 1.08, 95% CI 0.44 to 2.68; 101 participants; 2 trials), glycerol phenylbutyrate versus placebo (RR 1.63, 95% CI 0.85 to 3.13; 178 participants; 1 trial), ornithine phenylacetate versus placebo (RR 0.92, 95% CI 0.62 to 1.36; 264 participants; 2 trials; I2 = 0%), or polyethylene glycol versus lactulose (RR 0.57, 95% CI 0.18 to 1.82; 190 participants; 3 trials; I2 = 0%). Likewise, eight trials, involving 782 participants, reported a total of 374 non-serious adverse events and again our analyses found no beneficial or harmful effects of the pharmacotherapies under review when compared to placebo or to lactulose/lactitol.Nine trials, involving 733 participants, reported data on blood ammonia. We observed significant reductions in blood ammonia in placebo-controlled trials evaluating sodium benzoate (MD -32.00, 95% CI -46.85 to -17.15; 16 participants; 1 trial), glycerol phenylbutyrate (MD -12.00, 95% CI -23.37 to -0.63; 178 participants; 1 trial), ornithine phenylacetate (MD -27.10, 95% CI -48.55 to -5.65; 231 participants; 1 trial), and AST-120 (MD -22.00, 95% CI -26.75 to -17.25; 98 participants; 1 trial). However, there were no significant differences in blood ammonia concentrations in comparison with lactulose/lactitol with sodium benzoate (MD 9.00, 95% CI -1.10 to 19.11; 85 participants; 2 trials; I2 = 0%), AST-120 (MD 5.20, 95% CI -2.75 to 13.15; 35 participants; 1 trial), and polyethylene glycol (MD -29.28, 95% CI -95.96 to 37.39; 90 participants; 2 trials; I2 = 88%). FUNDING: Five trials received support from pharmaceutical companies while four did not; two did not provide this information. AUTHORS' CONCLUSIONS: There is insufficient evidence to determine the effects of these pharmacotherapies on the prevention and treatment of hepatic encephalopathy in adults with cirrhosis. They have the potential to reduce blood ammonia concentrations when compared to placebo, but their overall effects on clinical outcomes of interest and the potential harms associated with their use remain uncertain. Further evidence is needed to evaluate the potential beneficial and harmful effects of these pharmacotherapies in this clinical setting.
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Amônia/antagonistas & inibidores , Encefalopatia Hepática/tratamento farmacológico , Encefalopatia Hepática/prevenção & controle , Cirrose Hepática/complicações , Adulto , Carbono/uso terapêutico , Causas de Morte , Feminino , Glicerol/efeitos adversos , Glicerol/análogos & derivados , Glicerol/uso terapêutico , Humanos , Lactulose/uso terapêutico , Masculino , Pessoa de Meia-Idade , Ornitina/efeitos adversos , Ornitina/análogos & derivados , Ornitina/uso terapêutico , Óxidos/uso terapêutico , Fenilbutiratos/efeitos adversos , Fenilbutiratos/uso terapêutico , Placebos/uso terapêutico , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Benzoato de Sódio/efeitos adversos , Benzoato de Sódio/uso terapêuticoRESUMO
BACKGROUND: Hyperammonemia can result in hepatic encephalopathy, which in severe cases eventually can lead to coma and death. In dogs, congenital portosystemic shunts (CPSS) are the most common cause for hyperammonemia. Conservative treatment consists of a protein modified diet, nonabsorbable disaccharides, antibiotics, or some combinations of these. Sodium benzoate (SB) and sodium phenylbutyrate (SPB) both are used in the acute and long-term treatment of humans with hyperammonemia caused by urea cycle enzyme deficiencies. Both treatments are believed to lower blood ammonia concentrations by promoting excretion of excess nitrogen via alternative pathways. OBJECTIVES: To evaluate the efficacy and safety of PO treatment with SB and SPB on hyperammonemia and clinical signs in CPSS dogs. METHODS: Randomized, double-blind, placebo-controlled crossover trial. Concentrations of blood ammonia and bile acids were measured in CPSS dogs before and after a 5-day treatment with SB, SPB, and placebo. A wash-out period of 3 days was used between treatments. A standard questionnaire was developed and distributed to owners to evaluate clinical signs before and after each treatment. RESULTS: Blood ammonia concentrations were not influenced by any of the treatments and were comparable to those observed during placebo treatment. In addition, SB and SPB treatment did not result in improvement of clinical signs. Adverse effects during treatment included anorexia, vomiting, and lethargy. CONCLUSIONS AND CLINICAL IMPORTANCE: Based on our results, we conclude that SB or SPB are not useful in the conservative treatment of hyperammonemia in dogs with CPSS.
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Hiperamonemia/veterinária , Fenilbutiratos/farmacologia , Benzoato de Sódio/farmacologia , Amônia/sangue , Animais , Ácidos e Sais Biliares/sangue , Estudos Cross-Over , Cães , Método Duplo-Cego , Feminino , Hiperamonemia/tratamento farmacológico , Masculino , Fenilbutiratos/administração & dosagem , Fenilbutiratos/efeitos adversos , Veia Porta/anormalidades , Distribuição Aleatória , Benzoato de Sódio/administração & dosagem , Benzoato de Sódio/efeitos adversos , Malformações Vasculares/veterináriaRESUMO
Hepatic encephalopathy (HE) influences short-term and long-term prognoses. Recently, glycerol phenylbutyrate (PB), that lowers ammonia by providing an alternate pathway to urea for waste nitrogen excretion, has shown that it was effective in preventing the occurrence of HE in RCT. The aim was to assess the benefits of sodium PB in cirrhotic patients admitted to ICU for overt HE, in terms of ammonia levels decrease, neurological improvement, and survival. Cirrhotic patients who presented with overt HE, ammonia levels >100 µmol/L, and did not display any contra-indication were included. Sodium PB was administered at 200 mg/kg/day. Control group included historical controls treated by standard therapy, matched for age, sex, MELD score, and severity of HE. Eighteen patients were included and treated with sodium PB (age: 59 [45-68], male gender: 15 [83%], Child-Pugh B: 8 [44%], Child-Pugh C: 10 [56%], and MELD score: 16 [13-23]). Ammonia levels significantly decreased in the PB as compared to the control group from inclusion to 12 h and from inclusion to 48 h (P = 0.0201 and P = 0.0230, respectively). The proportion of patients displaying neurological improvement was only higher in the PB-treated group as compared to controls at ICU discharge (15 [83%] vs. 9 [50%], P = 0.0339). ICU discharge survival was significantly higher in patients treated with PB (17 [94%] vs. 9 [50%], P = 0.0017). In cirrhotic patients with overt HE, sodium PB could be effective in reducing ammonia levels and might be effective in improving neurological status and ICU discharge survival. More extensive data, especially a RCT, are mandatory.
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Encefalopatia Hepática/tratamento farmacológico , Hiperamonemia/tratamento farmacológico , Unidades de Terapia Intensiva , Cirrose Hepática/complicações , Admissão do Paciente , Fenilbutiratos/uso terapêutico , Idoso , Amônia/sangue , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Encefalopatia Hepática/sangue , Encefalopatia Hepática/etiologia , Encefalopatia Hepática/mortalidade , Mortalidade Hospitalar , Humanos , Hiperamonemia/sangue , Hiperamonemia/etiologia , Hiperamonemia/mortalidade , Cirrose Hepática/sangue , Cirrose Hepática/mortalidade , Masculino , Pessoa de Meia-Idade , Alta do Paciente , Fenilbutiratos/efeitos adversos , Dados Preliminares , Estudos Prospectivos , Fatores de Tempo , Resultado do TratamentoRESUMO
Cough is the reflex defense response of the respiratory tract to the present secretions in the throat, trachea and bronchi, and ongoing inflammation in the mucous membranes of the upper and lower respiratory tract. From a practical point of view, cough is dry (unproductive) and productive cough with expulsion of significant amounts of secretion. Drugs used to treat cough differ in both mechanism of action and pharmacokinetic activity. Butamirate citrate belongs to a new class of cough suppressants acting centrally through the receptors in the brainstem. In addition, it has a very beneficial effect, because it reduces the resistance in the airways by inhibiting bronchospasm and anti-inflammatory effect. It is rapidly absorbed after oral administration and its therapeutic plasma concentration is determined after 5-10 minutes of administration, irrespective of the dose. Possible side effects are rarely seen in 0.5-1% of patients, mainly in the form of skin rash, nausea, diarrhea, dizziness, which usually resolves during treatment. The cough effect of most cough suppressants is good, but their mechanisms are different and for that reason they should be individually selected. An important asset of this group of drugs is peripheral activity and effects on bronchodilator muscles, such as in the case of butamirate. Inclusion of this feature is particularly beneficial in chronic inflammatory bronchial diseases.
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Antitussígenos/uso terapêutico , Tosse/tratamento farmacológico , Fenilbutiratos/uso terapêutico , Administração Oral , Antitussígenos/administração & dosagem , Antitussígenos/efeitos adversos , Antitussígenos/farmacologia , Humanos , Inflamação/tratamento farmacológico , Fenilbutiratos/administração & dosagem , Fenilbutiratos/efeitos adversos , Fenilbutiratos/farmacologia , Doenças Respiratórias/tratamento farmacológicoRESUMO
INTRODUCTION: Glycerol phenylbutyrate (GPB) is approved in the US for the management of patients 2months of age and older with urea cycle disorders (UCDs) that cannot be managed with protein restriction and/or amino acid supplementation alone. Limited data exist on the use of nitrogen conjugation agents in very young patients. METHODS: Seventeen patients (15 previously on other nitrogen scavengers) with all types of UCDs aged 2months to 2years were switched to, or started, GPB. Retrospective data up to 12months pre-switch and prospective data during initiation of therapy were used as baseline measures. The primary efficacy endpoint of the integrated analysis was the successful transition to GPB with controlled ammonia (<100µmol/L and no clinical symptoms). Secondary endpoints included glutamine and levels of other amino acids. Safety endpoints included adverse events, hyperammonemic crises (HACs), and growth and development. RESULTS: 82% and 53% of patients completed 3 and 6months of therapy, respectively (mean 8.85months, range 6days-18.4months). Patients transitioned to GPB maintained excellent control of ammonia and glutamine levels. There were 36 HACs in 11 patients before GPB and 11 in 7 patients while on GPB, with a reduction from 2.98 to 0.88 episodes per year. Adverse events occurring in at least 10% of patients while on GPB were neutropenia, vomiting, diarrhea, pyrexia, hypophagia, cough, nasal congestion, rhinorrhea, rash/papule. CONCLUSION: GPB was safe and effective in UCD patients aged 2months to 2years. GPB use was associated with good short- and long-term control of ammonia and glutamine levels, and the annualized frequency of hyperammonemic crises was lower during the study than before the study. There was no evidence for any previously unknown toxicity of GPB.
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Amônia/metabolismo , Glutamina/metabolismo , Glicerol/análogos & derivados , Fenilbutiratos/efeitos adversos , Fenilbutiratos/uso terapêutico , Distúrbios Congênitos do Ciclo da Ureia/tratamento farmacológico , Pré-Escolar , Tosse , Gerenciamento Clínico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Febre , Glutamina/efeitos dos fármacos , Glicerol/efeitos adversos , Glicerol/sangue , Glicerol/uso terapêutico , Glicerol/toxicidade , Humanos , Lactente , Masculino , Neutropenia , Fenilbutiratos/sangue , Fenilbutiratos/toxicidade , Estudos Prospectivos , Estudos RetrospectivosRESUMO
PURPOSE: Phenylbutyrate (PB), a histone deacetylase inhibitor (HDACi) has demonstrated radiation protection in both in vitro and in vivo models. Studies previously demonstrated that PB and other HDAC inhibitors could inhibit radiation lethality in vivo by subcutaneous (s.c) injection. The objective of this study was to test the ability of oral PB treatment to protect against or to mitigate acute gamma radiation-induced lethality in vivo. MATERIALS AND METHODS: Human osteoblasts cells were used to evaluate radiation survival when PB was delivered pre- or post-radiation. A 30-day radiation lethality study was used to assess the radioprotective (pre-radiation) and radiomitigative (post-radiation) capability of PB. Possible mechanisms evaluated were antioxidant activity effects, HDAC inhibition, DNA damage, and hematological recovery. RESULTS: Treatment of HOS cells with PB 50 µM either before or after radiation increased radiation resistance as assessed by clonogenic survival. Western blot studies showed that PB treatment acetylated histones in vivo and ameliorated the radiation-induced reduction in acetylated histone-4 (H4). Pre-radiation oral administration of PB (10 mg/kg) provided radioprotection against gamma radiation (7-11.5 Gy) with a dose reduction factor of 1.25 (p = 0.001). PB oral administration post-radiation provided moderate radiation mitigation against gamma radiation (7-11.5 Gy) and demonstrated a dose reduction factor of 1.18 (p = 0.05). PB pre-radiation and post-radiation treatment was associated with significant elevations in neutrophils and platelets and attenuation of DNA damage. CONCLUSIONS: These results indicate that oral PB has potential as a radiation protector and a radiation mitigator and that potential mechanisms of action include attenuation of DNA damage, antioxidant activity, and bone marrow protection.
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Dano ao DNA/efeitos dos fármacos , Raios gama , Osteoblastos/efeitos dos fármacos , Osteoblastos/efeitos da radiação , Fenilbutiratos/farmacologia , Lesões por Radiação/prevenção & controle , Espécies Reativas de Oxigênio/metabolismo , Administração Oral , Animais , Linhagem Celular , Relação Dose-Resposta a Droga , Estudos de Viabilidade , Humanos , Dose Letal Mediana , Masculino , Camundongos , Camundongos Endogâmicos DBA , Osteoblastos/citologia , Osteoblastos/fisiologia , Fenilbutiratos/efeitos adversos , Doses de Radiação , Lesões por Radiação/diagnóstico , Protetores contra Radiação/efeitos adversos , Protetores contra Radiação/farmacologia , Taxa de Sobrevida , Resultado do TratamentoRESUMO
Histone deacetylase inhibitors (HDACi) have proven activity in hematologic malignancies, and their FDA approval in multiple myeloma (MM) and T-cell lymphoma highlights the need for further development of this drug class. We investigated AR-42, an oral pan-HDACi, in a first-in-man phase 1 dose escalation clinical trial. Overall, treatment was well tolerated, no DLTs were evident, and the MTD was defined as 40 mg dosed three times weekly for three weeks of a 28-day cycle. One patient each with MM and mantle cell lymphoma demonstrated disease control for 19 and 27 months (ongoing), respectively. Treatment was associated with reduction of serum CD44, a transmembrane glycoprotein associated with steroid and immunomodulatory drug resistance in MM. Our findings indicate that AR-42 is safe and that further investigation of AR-42 in combination regimens for the treatment of patients with lymphoma and MM is warranted. TRIAL REGISTRATION: http://clinicaltrials.gov/ct2/show/NCT01129193.
Assuntos
Inibidores de Histona Desacetilases , Linfoma de Células B , Mieloma Múltiplo , Fenilbutiratos , Inibidores de Histona Desacetilases/efeitos adversos , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Linfoma de Células B/tratamento farmacológico , Mieloma Múltiplo/tratamento farmacológico , Fenilbutiratos/efeitos adversos , Fenilbutiratos/uso terapêuticoRESUMO
Phenylbutyrate is recommended in urea cycle disorders and liver injury to enhance nitrogen disposal by the urine. However, hypothetically there may be adverse responses to the use of phenylbutyrate in the treatment of liver disease because of its role as a histone deacetylase inhibitor and its stimulatory effect on branched-chain alpha-keto acid dehydrogenase, the rate-limiting enzyme in the catabolism of branched-chain amino acids (BCAA; valine, leucine and isoleucine). We report the effects of phenylbutyrate on liver regeneration and amino acid levels in plasma of partially hepatectomized (PH) rats. Phenylbutyrate or saline was administered at 12-h intervals to PH or laparotomized rats. Phenylbutyrate delayed the onset of liver regeneration compared to the saline-treated controls, as indicated by lower hepatic DNA specific activities 18 and 24( ) h post-PH, decreased hepatic fractional protein synthesis rates 24 h post-PH and lowered the increases in liver weights and hepatic protein and DNA contents 48 h after PH. Hepatic DNA fragmentation (a hallmark of apoptosis) was higher in the phenylbutyrate-treated animals than in controls. Phenylbutyrate decreased the glutamine and BCAA concentrations and the ratio of the BCAA to aromatic amino acids (phenylalanine and tyrosine) in the blood plasma in both hepatectomized and laparotomized animals. In conclusion, the delayed onset of liver regeneration and the decrease in BCAA/AAA ratio in blood suggest that phenylbutyrate administration may be disastrous in subjects with acute hepatic injury and BCAA supplementation is needed when phenylbutyrate is used therapeutically.
Assuntos
Aminoácidos de Cadeia Ramificada/efeitos dos fármacos , Aminoácidos/metabolismo , Regeneração Hepática/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fenilbutiratos/efeitos adversos , Amônia/metabolismo , Animais , Glutamina/metabolismo , Hepatectomia/métodos , Fígado/metabolismo , Masculino , Ratos WistarRESUMO
BACKGROUND: Health care outcomes have been increasingly assessed through health-related quality of life (HRQoL) measures. While the introduction of nitrogen-scavenging medications has improved survival in patients with urea cycle disorders (UCDs), they are often associated with side effects that may affect patient compliance and outcomes. METHODS: Symptoms commonly associated with nitrogen-scavenging medications were evaluated in 100 adult and pediatric participants using a non-validated UCD-specific questionnaire. Patients or their caregivers responded to a pre-defined list of symptoms known to be associated with the use of these medications. Responses were collected at baseline (while patients were receiving sodium phenylbutyrate [NaPBA]) and during treatment with glycerol phenylbutyrate (GPB). RESULTS: After 3 months of GPB dosing, there were significant reductions in the proportion of patients with treatment-associated symptoms (69% vs. 46%; p<0.0001), the number of symptoms per patient (2.5 vs. 1.1; p<0.0001), and frequency of the more commonly reported individual symptoms such as body odor, abdominal pain, nausea, burning sensation in mouth, vomiting, and heartburn (p<0.05). The reduction in symptoms was observed in both pediatric and adult patients. The presence or absence of symptoms or change in severity did not correlate with plasma ammonia levels or NaPBA dose. CONCLUSIONS: The reduction in symptoms following 3 months of open-label GPB dosing was similar in pediatric and adult patients and may be related to chemical structure and intrinsic characteristics of the product rather than its effect on ammonia control.
Assuntos
Glicerol/análogos & derivados , Fenilbutiratos/efeitos adversos , Qualidade de Vida , Autorrelato , Distúrbios Congênitos do Ciclo da Ureia/tratamento farmacológico , Adolescente , Adulto , Idoso , Amônia/sangue , Antineoplásicos/uso terapêutico , Criança , Pré-Escolar , Feminino , Glicerol/efeitos adversos , Glicerol/química , Glicerol/uso terapêutico , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Fenilbutiratos/química , Fenilbutiratos/uso terapêutico , Inquéritos e Questionários , Distúrbios Congênitos do Ciclo da Ureia/sangue , Distúrbios Congênitos do Ciclo da Ureia/psicologia , Adulto JovemRESUMO
Compared with Ammonaps granules, Pheburane coated granules mask the unpleasant taste of sodium phenylbutyrate. A more precise dosing device is provided with the coated granules than with the uncoated granules (Ammonaps).
Assuntos
Fenilbutiratos/administração & dosagem , Distúrbios Congênitos do Ciclo da Ureia/tratamento farmacológico , Administração Oral , Química Farmacêutica , Cálculos da Dosagem de Medicamento , Humanos , Fenilbutiratos/efeitos adversos , Fenilbutiratos/química , Fenilbutiratos/farmacocinética , Pós , Paladar/efeitos dos fármacos , Equivalência Terapêutica , Distúrbios Congênitos do Ciclo da Ureia/enzimologiaRESUMO
Sodium phenylbutyrate (NaPBA) is a commonly used medication for the treatment of patients with urea cycle disorders (UCDs). Previous reports involving small numbers of patients with UCDs have shown that NaPBA treatment can result in lower plasma levels of the branched-chain amino acids (BCAA) but this has not been studied systematically. From a large cohort of patients (n=553) with UCDs enrolled in the Longitudinal Study of Urea Cycle Disorders, a collaborative multicenter study of the Urea Cycle Disorders Consortium, we evaluated whether treatment with NaPBA leads to a decrease in plasma BCAA levels. Our analysis shows that NaPBA use independently affects the plasma BCAA levels even after accounting for multiple confounding covariates. Moreover, NaPBA use increases the risk for BCAA deficiency. This effect of NaPBA seems specific to plasma BCAA levels, as levels of other essential amino acids are not altered by its use. Our study, in an unselected population of UCD subjects, is the largest to analyze the effects of NaPBA on BCAA metabolism and potentially has significant clinical implications. Our results indicate that plasma BCAA levels should to be monitored in patients treated with NaPBA since patients taking the medication are at increased risk for BCAA deficiency. On a broader scale, these findings could open avenues to explore NaPBA as a therapy in maple syrup urine disease and other common complex disorders with dysregulation of BCAA metabolism.
Assuntos
Aminoácidos de Cadeia Ramificada/sangue , Fenilbutiratos/uso terapêutico , Distúrbios Congênitos do Ciclo da Ureia/sangue , Distúrbios Congênitos do Ciclo da Ureia/tratamento farmacológico , Adolescente , Adulto , Idoso , Aminoácidos de Cadeia Ramificada/deficiência , Aminoácidos Essenciais/sangue , Criança , Pré-Escolar , Feminino , Humanos , Hiperamonemia/etiologia , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Fenilbutiratos/administração & dosagem , Fenilbutiratos/efeitos adversos , Distúrbios Congênitos do Ciclo da Ureia/diagnóstico , Adulto JovemRESUMO
OBJECTIVE: To evaluate glycerol phenylbutyrate (GPB) in the treatment of pediatric patients with urea cycle disorders (UCDs). STUDY DESIGN: UCD patients (n=26) ages 2months through 17years were treated with GPB and sodium phenylbutyrate (NaPBA) in two short-term, open-label crossover studies, which compared 24-hour ammonia exposure (AUC0-24) and glutamine levels during equivalent steady-state dosing of GPB and sodium phenylbutyrate (NaPBA). These 26 patients plus an additional 23 patients also received GPB in one of three 12-month, open label extension studies, which assessed long-term ammonia control, hyperammonemic (HA) crises, amino acid levels, and patient growth. RESULTS: Mean ammonia exposure on GPB was non-inferior to NaPBA in each of the individual crossover studies. In the pooled analyses, it was significantly lower on GPB vs. NaPBA (mean [SD] AUC0-24: 627 [302] vs. 872 [516] µmol/L; p=0.008) with significantly fewer abnormal values (15% on GPB vs. 35% on NaPBA; p=0.02). Mean ammonia levels remained within the normal range during 12months of GPB dosing and, when compared with the 12months preceding enrollment, a smaller percentage of patients (24.5% vs. 42.9%) experienced fewer (17 vs. 38) HA crises. Glutamine levels tended to be lower with GPB than with NaPBA during short-term dosing (mean [SD]: 660.8 [164.4] vs. 710.0 [158.7] µmol/L; p=0.114) and mean glutamine and branched chain amino acid levels, as well as other essential amino acids, remained within the normal range during 12months of GPB dosing. Mean height and weight Z-scores were within normal range at baseline and did not change significantly during 12months of GPB treatment. CONCLUSIONS: Dosing with GPB was associated with 24-hour ammonia exposure that was non-inferior to that during dosing with NaPBA in individual studies and significantly lower in the pooled analysis. Long-term GPB dosing was associated with normal levels of glutamine and essential amino acids, including branched chain amino acids, age-appropriate growth and fewer HA crises as compared with the 12month period preceding enrollment.
Assuntos
Fenilbutiratos/administração & dosagem , Fenilbutiratos/efeitos adversos , Distúrbios Congênitos do Ciclo da Ureia/tratamento farmacológico , Adolescente , Amônia/sangue , Criança , Pré-Escolar , Estudos Cross-Over , Feminino , Glutamina/urina , Humanos , Lactente , Recém-Nascido , Masculino , Fenilbutiratos/uso terapêutico , Distúrbios Congênitos do Ciclo da Ureia/dietoterapia , Distúrbios Congênitos do Ciclo da Ureia/fisiopatologiaRESUMO
There is substantial clinical and experimental evidence that ammonia is a major factor in the pathogenesis of hepatic encephalopathy. In the article is demonstrated that in hepatocellular dysfunction, ammonia detoxification to glutamine (GLN) in skeletal muscle, brain, and likely the lungs, is activated. In addition to ammonia detoxification, enhanced GLN production may exert beneficial effects on the immune system and gut barrier function. However, enhanced GLN synthesis may exert adverse effects in the brain (swelling of astrocytes or altered neurotransmission) and stimulate catabolism of branched-chain amino acids (BCAA; valine, leucine, and isoleucine) in skeletal muscle. Furthermore, the majority of GLN produced is released to the blood and catabolized in enterocytes and the kidneys to ammonia, which due to liver injury escapes detoxification to urea and appears in peripheral blood. As only one molecule of ammonia is detoxified in GLN synthesis whereas two molecules may appear in GLN breakdown, these events can be seen as a vicious cycle in which enhanced ammonia concentration activates synthesis of GLN leading to its subsequent catabolism and increase in ammonia levels in the blood. These alterations may explain why therapies targeted to intestinal bacteria have only a limited effect on ammonia levels in patients with liver failure and indicate the needs of new therapeutic strategies focused on GLN metabolism. It is demonstrated that each of the various treatment options targeting only one the of the ammonia-lowering mechanisms that affect GLN metabolism, such as enhancing GLN synthesis (BCAA), suppressing ammonia production from GLN breakdown (glutaminase inhibitors and alpha-ketoglutarate), and promoting GLN elimination (phenylbutyrate) exerts substantial adverse effects that can be avoided if their combination is tailored to the specific needs of each patient.
Assuntos
Glutamina/metabolismo , Encefalopatia Hepática/metabolismo , Aminoácidos de Cadeia Ramificada/metabolismo , Aminoácidos de Cadeia Ramificada/uso terapêutico , Amônia/metabolismo , Encéfalo/metabolismo , Estado Terminal , Interações Medicamentosas , Enterócitos/metabolismo , Ácido Glutâmico/metabolismo , Ácido Glutâmico/farmacologia , Ácido Glutâmico/uso terapêutico , Glutaminase/antagonistas & inibidores , Encefalopatia Hepática/dietoterapia , Encefalopatia Hepática/tratamento farmacológico , Humanos , Hiperamonemia/tratamento farmacológico , Hiperamonemia/etiologia , Hiperamonemia/metabolismo , Intestinos/microbiologia , Ácidos Cetoglutáricos/efeitos adversos , Ácidos Cetoglutáricos/farmacologia , Ácidos Cetoglutáricos/uso terapêutico , Rim/metabolismo , Fígado/metabolismo , Microbiota , Músculo Esquelético/metabolismo , Especificidade de Órgãos , Fenilbutiratos/efeitos adversos , Fenilbutiratos/farmacologia , Fenilbutiratos/uso terapêuticoAssuntos
Aprovação de Drogas , Distúrbios Congênitos do Ciclo da Ureia/tratamento farmacológico , Adulto , Ensaios Clínicos como Assunto , Aprovação de Drogas/economia , Indústria Farmacêutica/economia , Glicerol/análogos & derivados , Glicerol/economia , Glicerol/uso terapêutico , Humanos , Cooperação do Paciente , Fenilbutiratos/efeitos adversos , Fenilbutiratos/economia , Fenilbutiratos/uso terapêutico , Distúrbios Congênitos do Ciclo da Ureia/economiaRESUMO
OBJECTIVES: To examine ammonia levels, pharmacokinetics, and safety of glycerol phenylbutyrate (GPB; also referred to as HPN-100) and sodium phenylbutyrate (NaPBA) in young children with urea cycle disorders (UCDs). STUDY DESIGN: This open label switch-over study enrolled patients ages 29 days to under 6 years taking NaPBA. Patients underwent 24-hour blood and urine sampling on NaPBA and again on a phenylbutyric acid-equimolar dose of GPB and completed questionnaires regarding signs and symptoms associated with NaPBA and/or their UCD. RESULTS: Fifteen patients (8 argininosuccinate lyase deficiency, 3 argininosuccinic acid synthetase deficiency, 3 ornithine transcarbamylase deficiency, 1 arginase deficiency) ages 2 months through 5 years enrolled in and completed the study. Daily ammonia exposure (24-hour area under the curve) was lower on GPB and met predefined noninferiority criteria (ratio of means 0.79; 95% CI 0.593-1.055; P=.03 Wilcoxon; 0.07 t test). Six patients experienced mild adverse events on GPB; there were no serious adverse events or significant laboratory changes. Liver tests and argininosuccinic acid levels among patients with argininosuccinate lyase deficiency were unchanged or improved on GPB. Eleven of 15 patients reported 35 symptoms on day 1; 23 of these 35 symptoms improved or resolved on GPB. Mean systemic exposure to phenylbutyric acid, phenylacetic acid, and phenylacetylglutamine (PAGN) were similar and phenylacetic acid exposure tended to be higher in the youngest children on both drugs. Urinary PAGN concentration was greater on morning voids and varied less over 24 hours on GPB versus NaPBA. CONCLUSIONS: GPB results in more evenly distributed urinary output of PAGN over 24 hours were associated with fewer symptoms and offers ammonia control comparable with that observed with NaPBA in young children with UCDs.