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1.
Medicina (B Aires) ; 79 Suppl 3: 2-5, 2019.
Artigo em Espanhol | MEDLINE | ID: mdl-31603834

RESUMO

Phenylketonuria, also known as PKU, is the most frequent congenital inborn error of metabolism. The severe form or classic PKU untreated causes intellectual disability, although with the early detection programs in the neonatal period, diagnosis and treatment prevent the appearance of the symptoms. Despite early diagnosis and treatment we have observed some neurotoxicity in treated PKU patients. We analyzed the factors involved apart from the toxicity due to the high cerebral concentrations of phenylalanine (Phe), the defects of synthesis of neurotransmitters, the alteration of cerebral myelination, the effect of the elevation of Phe in the processes of transport and distribution of neutral amino acids with an abnormal synthesis of brain proteins, plasma and cerebral tyrosine deficiency, the neurotoxicity of Phe metabolites, the defect of cholesterol biosynthesis or the increase of oxidative stress. White matter alterations in early treated PKU patients have an important role in neurological manifestations. The treatment of PKU is for life and is based on the reduction of foods containing Phe combined with the administration of a special formula or tetrahydrobiopterin (BH4) treatment. New therapeutic options will be analyzed.


Assuntos
Neurônios/patologia , Fenilalanina/efeitos adversos , Fenilcetonúrias/diagnóstico , Fenilcetonúrias/terapia , Tirosina/metabolismo , Biopterina/análogos & derivados , Dietoterapia , Diagnóstico Precoce , Humanos , Fenilcetonúrias/fisiopatologia
2.
BMJ Case Rep ; 12(8)2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31466958

RESUMO

Eluxadoline is a novel medication that was approved in the USA in 2015 for the treatment of diarrhoea-predominant irritable bowel syndrome. Due to its unique mechanism of action as both an opioid agonist and antagonist, it has been placed as a schedule IV controlled substance. Since its approval, there have been several cases of eluxadoline-induced pancreatitis reported in the literature. The majority of patients who presented with eluxadoline-induced pancreatitis were reported to have had a prior cholecystectomy. Due to this, the Food and Drug Administration released a warning in 2017 that eluxadoline should no longer be used in patients who do not have a gall bladder. We present a rare case of an adult man without prior cholecystectomy who presented with severe mid-epigastric pain and was found to have eluxadoline-induced pancreatitis.


Assuntos
Imidazóis/efeitos adversos , Pancreatite/diagnóstico , Fenilalanina/análogos & derivados , Dor Abdominal/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Pancreatite/induzido quimicamente , Fenilalanina/efeitos adversos
3.
Eur J Ophthalmol ; 29(4): 394-401, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30112930

RESUMO

PURPOSE: Characterize the safety and tolerability of lifitegrast ophthalmic solution 5.0% for the treatment of dry eye disease. METHODS: Pooled data from five randomized controlled trials were analyzed. Key inclusion criteria were adults with dry eye disease (Schirmer tear test score ⩾1 and ⩽10 mm, eye dryness score ⩾40 (visual analog scale 0-100), corneal staining score ⩾2.0 (0-4 scale)). Participants were randomized to lifitegrast ophthalmic solution 5.0% or placebo twice daily for 84 or 360 days. Treatment-emergent adverse events and drop comfort scores were assessed. RESULTS: Overall, 2464 participants (lifitegrast, n = 1287; placebo, n = 1177) were included. Ocular treatment-emergent adverse events occurring in >5% in either group were instillation site irritation (lifitegrast, 15.2%; placebo, 2.8%), instillation site reaction (lifitegrast, 12.3%; placebo, 2.3%), and instillation site pain (lifitegrast, 9.8%; placebo, 2.1%); the most common (> 5%) nonocular treatment-emergent adverse event was dysgeusia (lifitegrast, 14.5%; placebo, 0.3%). The majority of treatment-emergent adverse events were mild to moderate in severity. Discontinuation due to treatment-emergent adverse events occurred in 7.0% (lifitegrast) versus 2.6% (placebo) of participants (ocular: 5.5% vs 1.5%; nonocular: 1.9% vs 1.1%). Drop comfort scores with lifitegrast improved within 3 min of instillation and the score at 3 min improved across visits (12-week trials (both eyes, day 84 vs 0): 2.0 vs 3.3; SONATA (day 360 vs 0): right eye, 1.2 vs 1.7; left eye, 1.2 vs 1.8). CONCLUSION: Lifitegrast ophthalmic solution 5.0% appeared to be safe and well tolerated for the treatment of dry eye disease. Drop comfort with lifitegrast improved within 3 min of instillation.


Assuntos
Síndromes do Olho Seco/tratamento farmacológico , Soluções Oftálmicas/uso terapêutico , Fenilalanina/análogos & derivados , Sulfonas/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Método Duplo-Cego , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Soluções Oftálmicas/efeitos adversos , Fenilalanina/efeitos adversos , Fenilalanina/uso terapêutico , Estudos Prospectivos , Sulfonas/efeitos adversos , Resultado do Tratamento , Escala Visual Analógica
5.
Drugs Today (Barc) ; 54(7): 423-432, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30090879

RESUMO

Telotristat ethyl (Xermelo), developed by Lexicon Pharmaceuticals, is an oral tryptophan hydroxylase inhibitor blocking peripheral conversion of tryptophan to serotonin (5-hydroxytryptamine [5-HT]). It was approved by the U.S. Food and Drug Administration (FDA) in February 2017 and by the European Commission in September 2017 for patients with carcinoid syndrome in whom diarrhea is not adequately controlled by somatostatin analogues (SSAs). Diarrhea, secondary to the release of serotonin, is the predominant gastrointestinal symptom in patients with carcinoid syndrome and has a significant impact on patients' quality of life. Telotristat is not meant for all patients with diarrhea and carcinoid syndrome. Prescribing of telotristat for patients with diarrhea refractory to SSAs requires careful consideration and an approach that involves identifying and ruling out other common causes of diarrhea in patients with carcinoid syndrome. Delineating the timing of diarrhea and whether it occurs in patients with stable disease versus cancer progression can help identify the right drug candidates for therapy.


Assuntos
Diarreia/tratamento farmacológico , Síndrome do Carcinoide Maligno/tratamento farmacológico , Fenilalanina/análogos & derivados , Pirimidinas/uso terapêutico , Somatostatina/análogos & derivados , Ensaios Clínicos como Assunto , Humanos , Tumores Neuroendócrinos/tratamento farmacológico , Fenilalanina/efeitos adversos , Fenilalanina/farmacologia , Fenilalanina/uso terapêutico , Pirimidinas/efeitos adversos , Pirimidinas/farmacologia
6.
Drugs ; 78(9): 941-950, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29931594

RESUMO

Telotristat ethyl (Xermelo®), a first-in-class peripheral tryptophan hydroxylase (TPH) inhibitor, is approved to treat carcinoid syndrome diarrhoea in combination with somatostatin analogue (SSA) therapy in adults inadequately controlled by SSA therapy alone. Some neuroendocrine tumours secrete serotonin (5-HT) into the blood, resulting in frequent bowel movements (BMs) and other symptoms. Telotristat ethyl inhibits TPH, thereby reducing the production of 5-HT and improving carcinoid syndrome diarrhoea. In the 12-week placebo-controlled phase of randomized trials in patients with carcinoid syndrome diarrhoea (most of whom were receiving SSA therapy), the addition of oral telotristat ethyl 250 three times daily provided significant reductions in the frequency of BMs and levels of urinary 5-hydroxyindolacetic acid (u5-HIAA; a metabolite of 5-HT) relative to placebo. Telotristat ethyl 250 mg three times daily was well tolerated, with the proportion of patients reporting at least one treatment-emergent adverse event being similar to that with placebo. With regard to adverse events of special interest, relative to placebo, telotristat ethyl had a comparable incidence of depression-related symptoms, a somewhat higher incidence of gastrointestinal (GI) disorders and a higher incidence of elevated hepatic enzyme levels.


Assuntos
Diarreia/tratamento farmacológico , Síndrome do Carcinoide Maligno/tratamento farmacológico , Fenilalanina/análogos & derivados , Pirimidinas/uso terapêutico , Triptofano Hidroxilase/antagonistas & inibidores , Interações de Medicamentos , Quimioterapia Combinada , Humanos , Fenilalanina/administração & dosagem , Fenilalanina/efeitos adversos , Fenilalanina/farmacologia , Fenilalanina/uso terapêutico , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Pirimidinas/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Transdução de Sinais , Somatostatina/análogos & derivados , Somatostatina/uso terapêutico , Resultado do Tratamento
7.
Expert Opin Investig Drugs ; 27(3): 251-263, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29451407

RESUMO

INTRODUCTION: Diarrhea-predominant irritable bowel syndrome (IBS-D) is a common disorder characterized by a complex pathophysiology hampering optimal targeted drug development. Recent advances in our understanding of key underlying mechanisms prompted novel therapeutics including novel pharmacological approaches. AREAS COVERED: This review summarizes the latest advancements in the pipeline of IBS-D drugs focusing on new pharmacological targets, efficacy and safety of medicinal products considering the recent harmonization of regulatory requirements by the FDA and the EMA. EXPERT OPINION: The new 5-HT3 receptor antagonist ramosetron appears a promising therapeutic approach devoid of significant adverse events, although it is presently unavailable in Western countries, most likely because of the precautionary approach taken by regulatory agencies with this drug class. New pharmacological concepts on full agonists/antagonists, mixed-receptor activity and novel drug targets may streamline the present drug pipeline along with the adherence on new regulatory guidelines on outcome measures. Eluxadoline can be taken as an example of this paradigm shift. It has now been granted marketing authorization for IBS-D on both sides of the Atlantic, but it is still considered as a second-line agent by the NICE. There is still much work to be done to fully cover clinical needs of patients with IBS-D.


Assuntos
Diarreia/tratamento farmacológico , Fármacos Gastrointestinais/uso terapêutico , Síndrome do Intestino Irritável/tratamento farmacológico , Animais , Benzimidazóis/efeitos adversos , Benzimidazóis/farmacologia , Benzimidazóis/uso terapêutico , Diarreia/etiologia , Desenho de Drogas , Controle de Medicamentos e Entorpecentes , Fármacos Gastrointestinais/efeitos adversos , Fármacos Gastrointestinais/farmacologia , Humanos , Imidazóis/efeitos adversos , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Internacionalidade , Síndrome do Intestino Irritável/fisiopatologia , Fenilalanina/efeitos adversos , Fenilalanina/análogos & derivados , Fenilalanina/farmacologia , Fenilalanina/uso terapêutico
8.
Aliment Pharmacol Ther ; 47(6): 809-815, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29349789

RESUMO

BACKGROUND: Cases of pancreatitis were identified in the eluxadoline clinical development program, reflected in initial product labelling, and the subject of postmarketing reports. AIM: To analyse postmarketing cases of eluxadoline-associated pancreatitis. METHODS: We retrospectively analysed all US adverse event reports of pancreatitis associated with eluxadoline reported to the FDA Adverse Event Reporting System (FAERS) database from May 27, 2015 through February 15, 2017. RESULTS: The analysis included 119 cases of pancreatitis associated with eluxadoline; one resulted in death and 75 in hospitalisation. Sixty-seven cases reported the presence (n = 12) or absence (n = 55) of the patient's gallbladder. The eluxadoline dose received in the 55 cases of patients without gallbladders was 75 mg (n = 43), 100 mg (n = 5), or not reported (n = 7). Of the 119 cases, 37 reported the patient did not abuse alcohol and 82 did not report the alcohol abuse status. The single fatal case occurred in a patient without a gallbladder who received eluxadoline 75 mg and did not abuse alcohol. Forty-seven cases reported development of pancreatitis within the first or second dose of eluxadoline initiation. The median time to onset for the development of pancreatitis (n = 83) was 1 day, ranging from 1 to 56 days of continued use of eluxadoline. CONCLUSION: The FAERS cases suggest that patients with or without a gallbladder receiving eluxadoline are at risk for the development of pancreatitis. However, patients without a gallbladder, despite receiving the recommended lower dose of eluxadoline 75 mg and screening for alcohol abuse, appear to be overrepresented among patients who developed eluxadoline-associated pancreatitis.


Assuntos
Doenças da Vesícula Biliar/cirurgia , Imidazóis/efeitos adversos , Pancreatite/induzido quimicamente , Pancreatite/epidemiologia , Fenilalanina/análogos & derivados , Adolescente , Adulto , Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Idoso , Idoso de 80 Anos ou mais , Bases de Dados Factuais , Feminino , Vesícula Biliar/patologia , Vesícula Biliar/cirurgia , Doenças da Vesícula Biliar/complicações , Doenças da Vesícula Biliar/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Pancreatite/complicações , Fenilalanina/efeitos adversos , Vigilância de Produtos Comercializados/estatística & dados numéricos , Estudos Retrospectivos , Estados Unidos/epidemiologia , United States Food and Drug Administration , Adulto Jovem
9.
Toxicol In Vitro ; 47: 26-37, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29107685

RESUMO

A library of N-protected dehydroamino acids, namely dehydroalanine, dehydroaminobutyric acid and dehydrophenylalanine derivatives, was screened in three human cancer cell lines [(lung (A549), gastric (AGS) and neuroblastoma (SH-SY5Y)] in order to characterize their toxicological profile and identify new molecules with potential anticancer activity. Results showed N-protected dehydrophenylalanine and dehydroaminobutyric acid derivatives have no or low toxicity for all tested cell lines. The N-protected dehydroalanines exhibit significant toxic effects and the AGS and SH-SY5Y cells were significantly more vulnerable than A549 cells. Four α,ß-dehydroalanine derivatives, with IC50<62.5µM, were selected to investigate the pathways by which these compounds promote cell death. All compounds, at their IC50 concentrations, were able to induce apoptosis in both AGS and SH-SY5Y cell lines. In both cell lines, loss of mitochondrial membrane potential (ΔΨm) was found and caspase activity was increased, namely endoplasmic reticulum-resident caspase-4 in AGS cells and caspase-3/7 in SH-SY5Y cells. When evaluated in a non-cancer cell line, the molecules displayed no to low toxicity, thus suggesting some degree of selectivity for cancer cells. The results indicate that α,ß-dehydroalanine derivatives can be considered a future resource of compounds able to work as anticancer drugs.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Neuroblastoma/tratamento farmacológico , Neoplasias Gástricas/tratamento farmacológico , Ácido gama-Aminobutírico/análogos & derivados , Alanina/efeitos adversos , Alanina/análogos & derivados , Alanina/química , Alanina/farmacologia , Antineoplásicos/efeitos adversos , Antineoplásicos/química , Caspases/química , Caspases/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Forma Celular/efeitos dos fármacos , Descoberta de Drogas , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/enzimologia , Humanos , Interações Hidrofóbicas e Hidrofílicas , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Estrutura Molecular , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Fenilalanina/efeitos adversos , Fenilalanina/análogos & derivados , Fenilalanina/química , Fenilalanina/farmacologia , Bibliotecas de Moléculas Pequenas , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Relação Estrutura-Atividade , Ácido gama-Aminobutírico/efeitos adversos , Ácido gama-Aminobutírico/química , Ácido gama-Aminobutírico/farmacologia
10.
Clin Gastroenterol Hepatol ; 16(3): 378-384.e2, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28804032

RESUMO

BACKGROUND & AIMS: The Food and Drug Administration approved eluxadoline for the treatment of diarrhea-predominant irritable bowel syndrome despite cases of pancreatitis in early stage trials. We investigated the frequency of pancreatitis attributed to eluxadoline in postmarketing surveillance. METHODS: We extracted reports on eluxadoline submitted to the Federal Adverse Event Reporting System from January through September 2016. We collected data on patient age and sex, event date, reporting entity (consumer, physician, pharmacist, legal worker, or other), medications, dosages, presumed role in the event (coinciding, primary, or secondary suspect), treatment indication, and outcome (death, life threatening, hospitalization, disability, or other).We compared data for eluxadoline with data from antidiarrheals, oxycodone, and rifaximin using the κ2 test, Kruskal-Wallis rank test, and analysis of variance; findings with P < .05 were considered statistically significant. RESULTS: Pancreatitis accounted for 16.4% of the 597 reports of adverse events linked to eluxadoline; 53 cases required hospitalization. Pancreatitis was listed as treatment complication of other agents in significantly lower proportions of cases (loperamide, 0.3%; diphenoxylate, 0.4%; oxycodone, 0.2%; rifaximin, 0.5%), with 75% of these submissions not considering the agent as causal. CONCLUSIONS: In an analysis of reports on eluxadoline submitted to the Federal Adverse Event Reporting System, we confirmed a previously reported risk of pancreatitis associated with eluxadoline. The need for hospitalization in at least half of these instances and a recent report of 2 fatalities should prompt reassessments of the agent's risk-benefit ratio.


Assuntos
Fármacos Gastrointestinais/efeitos adversos , Fármacos Gastrointestinais/uso terapêutico , Imidazóis/efeitos adversos , Imidazóis/uso terapêutico , Síndrome do Intestino Irritável/tratamento farmacológico , Pancreatite/induzido quimicamente , Pancreatite/epidemiologia , Fenilalanina/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Humanos , Incidência , Síndrome do Intestino Irritável/complicações , Masculino , Pessoa de Meia-Idade , Fenilalanina/efeitos adversos , Fenilalanina/uso terapêutico , Vigilância de Produtos Comercializados , Medição de Risco
11.
J Inherit Metab Dis ; 41(4): 679-687, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29230603

RESUMO

Phenylketonuria (PKU), one of the most prevalent autosomal recessive disorders of amino acid metabolism, is characterized by abnormal accumulation of phenylalanine, which can lead to intellectual disability. The main pathologic changes in the central nervous system of untreated phenylketonuric patients are reductions in the number of axons, dendrites, and synapses in the brain. Such alterations are thought to be mainly associated with the toxic effects caused by phenylalanine. However, the underlying molecular mechanisms have not been fully elucidated. The present study shows that a high concentration of phenylalanine remarkably inhibited neuronal neurite formation in vitro. Interestingly, AMP-activated protein kinase (AMPK), the energy status sensor, was activated in cultured cerebral cortical neurons upon phenylalanine treatment. Pretreatment with an AMPK inhibitor ameliorated the reduction of neurite formation caused by phenylalanine. In addition, the levels of the phosphorylated AMPK, the active form of AMPK, were significantly higher in the cerebral cortices of PKU mice with elevated phenylalanine levels in this brain region compared to those in wild-type control mice, whereas the density of dendritic spines on basal secondary dendrites of pyramidal neurons in prefrontal cortices of PKU mice was significantly decreased. Collectively, these findings indicate that AMPK activation is a key event in impaired neuronal dendritic development in PKU and consequently, a potential therapeutic target for developing neuroprotective strategies against phenylalanine-evoked brain injury in PKU.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Fenilcetonúrias/metabolismo , Animais , Córtex Cerebral/metabolismo , Feminino , Masculino , Camundongos , Modelos Teóricos , Neurônios/efeitos dos fármacos , Fenilalanina/efeitos adversos , Fenilalanina/farmacologia , Fosforilação , Cultura Primária de Células , Ratos , Ratos Sprague-Dawley
13.
Drug Des Devel Ther ; 11: 2827-2840, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29033544

RESUMO

Eluxadoline is a novel drug approved for the management of diarrhea predominant irritable bowel syndrome (IBS-D). It has unique pharmacology and works on three different opioid receptors. Several Phase II and III clinical trials have demonstrated eluxadoline's efficacy in reducing symptoms related to IBS-D. Clinical trial results and postmarketing reports show a risk of pancreatitis in patients without a gallbladder or those abusing alcohol. This review article will include information on clinical trial results related to IBS-D management as well as eluxadoline's limitations.


Assuntos
Diarreia/tratamento farmacológico , Fármacos Gastrointestinais/uso terapêutico , Imidazóis/uso terapêutico , Síndrome do Intestino Irritável/tratamento farmacológico , Fenilalanina/análogos & derivados , Ensaios Clínicos como Assunto , Humanos , Imidazóis/efeitos adversos , Imidazóis/farmacocinética , Imidazóis/farmacologia , Fenilalanina/efeitos adversos , Fenilalanina/farmacocinética , Fenilalanina/farmacologia , Fenilalanina/uso terapêutico
14.
Expert Opin Pharmacother ; 18(14): 1517-1524, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28841079

RESUMO

INTRODUCTION: Dry eye disease (DED) is a common ocular disorder that can have a substantial burden on quality of life and daily activities. Lifitegrast ophthalmic solution 5.0% is the first medication approved in the US for the treatment of the signs and symptoms of DED. The aim of this article is to summarize the preclinical and clinical data on lifitegrast and discuss how lifitegrast may fit into the current treatment landscape for DED. Areas covered: A literature search of published preclinical and clinical data was conducted to review the chemistry, pharmacodynamics, pharmacokinetics, and clinical efficacy/safety of lifitegrast. The impact that lifitegrast may have on DED treatment practices is also discussed. Expert opinion: The introduction of lifitegrast provides a potentially important additional option for eye care professionals treating DED. In clinical trials conducted in adults with DED, lifitegrast ophthalmic solution 5.0% improved both signs and symptoms of DED. Of note, in 2 phase 3 trials, symptom improvements were observed as early as 2 weeks, which may be explained by lifitegrast's unique mechanism of action of blocking a specific signaling pathway in inflammation. Future research should include evaluation of whether lifitegrast can be used in combination with other DED treatments.


Assuntos
Síndromes do Olho Seco/tratamento farmacológico , Fenilalanina/análogos & derivados , Sulfonas/uso terapêutico , Adulto , Ensaios Clínicos como Assunto , Síndromes do Olho Seco/imunologia , Humanos , Antígeno-1 Associado à Função Linfocitária/imunologia , Soluções Oftálmicas/uso terapêutico , Fenilalanina/administração & dosagem , Fenilalanina/efeitos adversos , Fenilalanina/farmacocinética , Fenilalanina/uso terapêutico , Qualidade de Vida , Sulfonas/administração & dosagem , Sulfonas/efeitos adversos , Sulfonas/farmacocinética , Resultado do Tratamento
15.
Drug Ther Bull ; 55(8): 90-93, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28808081

RESUMO

Irritable bowel syndrome (IBS) is a chronic relapsing gastrointestinal problem characterised by intestinal pain and associated alterations of defecation and/or bowel habit (constipation: IBS-C or diarrhoea: IBS-D).1,2 Opioid receptors in the gut have a role in gastrointestinal motility, secretion and sensation.3 Τ Eluxadoline (Truberzi-Allergan) is a locally acting, mixed opioid receptor agonist/antagonist licensed for the treatment of IBS-D in adults.4 Here, we consider the evidence for eluxadoline and how it fts with current management strategies for IBS-D.


Assuntos
Fármacos Gastrointestinais/uso terapêutico , Imidazóis/uso terapêutico , Síndrome do Intestino Irritável/tratamento farmacológico , Fenilalanina/análogos & derivados , Ensaios Clínicos Fase III como Assunto , Dieta , Fármacos Gastrointestinais/administração & dosagem , Fármacos Gastrointestinais/efeitos adversos , Fármacos Gastrointestinais/farmacologia , Humanos , Imidazóis/administração & dosagem , Imidazóis/efeitos adversos , Síndrome do Intestino Irritável/terapia , Estilo de Vida , Fenilalanina/administração & dosagem , Fenilalanina/efeitos adversos , Fenilalanina/uso terapêutico , Receptores Opioides/efeitos dos fármacos
19.
Sleep Med ; 35: 12-16, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28619176

RESUMO

OBJECTIVE: To evaluate the effects of JZP-110 on the Maintenance of Wakefulness Test (MWT) with data censored to include only the first 20 min of a 40-min MWT. METHODS: In a 4-week, placebo-controlled crossover design (Study 201; N = 33) and a 12-week parallel-group design (Study 202; N = 93), JZP-110 was evaluated in narcolepsy patients using changes from baseline in the 40-min MWT as the primary endpoint. Effect sizes based on the change from baseline in mean MWT sleep latency were calculated using 20-min censored MWT data and compared to 40-min MWT data. RESULTS: In Study 201, mean (standard deviation) changes in MWT sleep latency were 12.7 (10.6) min with JZP-110 versus 0.9 (6.0) min with placebo (P = 0.0002) for 40-min data, and 8.9 (6.3) versus 0.4 (4.6) min for 20-min censored data (P < 0.0001). In Study 202, mean changes in MWT sleep latency were 12.8 (10.3) min with JZP-110 versus 2.1 (7.9) min with placebo (P < 0.0001) for 40-min data, and 8.9 (5.5) versus 1.1 (5.6) min for 20-min censored data (P < 0.0001). In Studies 201 and 202, respectively, Cohen's d effect sizes were large and numerically greater for 20-min censored data (1.54 and 1.41) versus 40-min data (1.37 and 1.17). CONCLUSIONS: In patients with narcolepsy, JZP-110 significantly improved the ability to stay awake compared with placebo, with large effect sizes using both the 40-min and 20-min censored MWT data.


Assuntos
Carbamatos/uso terapêutico , Narcolepsia/tratamento farmacológico , Fenilalanina/análogos & derivados , Promotores da Vigília/uso terapêutico , Adulto , Carbamatos/efeitos adversos , Estudos Cross-Over , Feminino , Humanos , Masculino , Narcolepsia/diagnóstico , Fenilalanina/efeitos adversos , Fenilalanina/uso terapêutico , Sono/efeitos dos fármacos , Fatores de Tempo , Resultado do Tratamento , Vigília/efeitos dos fármacos , Promotores da Vigília/efeitos adversos
20.
Drugs ; 77(9): 1009-1016, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28493170

RESUMO

Eluxadoline (Truberzi®) is an orally administered, minimally absorbed agent that acts locally in the gastrointestinal tract as a mixed µ-opioid receptor agonist and δ-opioid receptor antagonist. The randomized, double-blind, placebo-controlled, multinational, phase 3 IBS-3001 and IBS-3002 trials examined the efficacy of eluxadoline in patients with diarrhoea-predominant irritable bowel syndrome (IBS-D). The composite response rate (i.e. the proportion of patients with improvement in both worst abdominal pain and stool consistency on ≥50% of days; primary endpoint), was significantly higher in patients receiving eluxadoline 100 mg twice daily than in those receiving placebo after 12 and 26 weeks' therapy. Other abdominal and bowel symptoms (e.g. bloating, urgency, frequency of bowel movement) and health-related quality of life scores were also improved with eluxadoline. Eluxadoline was generally well tolerated in patients with IBS-D. Constipation was the most commonly occurring adverse event, although no serious constipation events were reported. Pancreatitis and adverse events consistent with sphincter of Oddi spasm were uncommon. In conclusion, eluxadoline is a new option to consider in the treatment of adult patients with IBS-D.


Assuntos
Diarreia/tratamento farmacológico , Fármacos Gastrointestinais/uso terapêutico , Imidazóis/uso terapêutico , Síndrome do Intestino Irritável/tratamento farmacológico , Fenilalanina/análogos & derivados , Adulto , Constipação Intestinal/induzido quimicamente , Método Duplo-Cego , Feminino , Fármacos Gastrointestinais/administração & dosagem , Fármacos Gastrointestinais/efeitos adversos , Fármacos Gastrointestinais/farmacologia , Humanos , Imidazóis/administração & dosagem , Imidazóis/efeitos adversos , Imidazóis/farmacologia , Síndrome do Intestino Irritável/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fenilalanina/administração & dosagem , Fenilalanina/efeitos adversos , Fenilalanina/farmacologia , Fenilalanina/uso terapêutico , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores Opioides delta/antagonistas & inibidores
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