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1.
Biomolecules ; 11(7)2021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202146

RESUMO

Liver malignant tumors (LMTs) represent a serious adverse drug event associated with drug-induced liver injury. Increases in endocrine-disrupting chemicals (EDCs) have attracted attention in recent years, due to their liver function-inhibiting abilities. Exposure to EDCs can induce nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, which are major etiologies of LMTs, through interaction with nuclear receptors (NR) and stress response pathways (SRs). Therefore, exposure to potential EDC drugs could be associated with drug-induced LMTs. However, the drug classes associated with LMTs and the molecular initiating events (MIEs) that are specific to these drugs are not well understood. In this study, using the Food and Drug Administration Adverse Event Reporting System, we detected LMT-inducing drug signals based on adjusted odds ratios. Furthermore, based on the hypothesis that drug-induced LMTs are triggered by NR and SR modulation of potential EDCs, we used the quantitative structure-activity relationship platform for toxicity prediction to identify potential MIEs that are specific to LMT-inducing drug classes. Events related to cell proliferation and apoptosis, DNA damage, and lipid accumulation were identified as potential MIEs, and their relevance to LMTs was supported by the literature. The findings of this study may contribute to drug development and research, as well as regulatory decision making.


Assuntos
Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Bases de Dados Factuais/estatística & dados numéricos , Neoplasias Hepáticas/epidemiologia , United States Food and Drug Administration/estatística & dados numéricos , Carbamatos/efeitos adversos , Carbamatos/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/genética , Previsões , Humanos , Imidazóis/efeitos adversos , Imidazóis/toxicidade , Isoquinolinas/efeitos adversos , Isoquinolinas/toxicidade , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/genética , Inibidores de Proteases/efeitos adversos , Inibidores de Proteases/toxicidade , Pirrolidinas/efeitos adversos , Pirrolidinas/toxicidade , Receptores de Calcitriol/genética , Receptores de Estrogênio/genética , Sulfonamidas/efeitos adversos , Sulfonamidas/toxicidade , Estados Unidos/epidemiologia , Valina/efeitos adversos , Valina/análogos & derivados , Valina/toxicidade
2.
Lancet Gastroenterol Hepatol ; 6(6): 448-458, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33865507

RESUMO

BACKGROUND: In low-income and middle-income countries, affordable direct-acting antivirals are urgently needed to treat hepatitis C virus (HCV) infection. The combination of ravidasvir, a pangenotypic non-structural protein 5A (NS5A) inhibitor, and sofosbuvir has shown efficacy and safety in patients with chronic HCV genotype 4 infection. STORM-C-1 trial aimed to assess the efficacy and safety of ravidasvir plus sofosbuvir in a diverse population of adults chronically infected with HCV. METHODS: STORM-C-1 is a two-stage, open-label, phase 2/3 single-arm clinical trial in six public academic and non-academic centres in Malaysia and four public academic and non-academic centres in Thailand. Patients with HCV with compensated cirrhosis (Metavir F4 and Child-Turcotte-Pugh class A) or without cirrhosis (Metavir F0-3) aged 18-69 years were eligible to participate, regardless of HCV genotype, HIV infection status, previous interferon-based HCV treatment, or source of HCV infection. Once daily ravidasvir (200 mg) and sofosbuvir (400 mg) were prescribed for 12 weeks for patients without cirrhosis and for 24 weeks for those with cirrhosis. The primary endpoint was sustained virological response at 12 weeks after treatment (SVR12; defined as HCV RNA <12 IU/mL in Thailand and HCV RNA <15 IU/mL in Malaysia at 12 weeks after the end of treatment). This trial is registered with ClinicalTrials.gov, number NCT02961426, and the National Medical Research Register of Malaysia, NMRR-16-747-29183. FINDINGS: Between Sept 14, 2016, and June 5, 2017, 301 patients were enrolled in stage one of STORM-C-1. 98 (33%) patients had genotype 1a infection, 27 (9%) had genotype 1b infection, two (1%) had genotype 2 infection, 158 (52%) had genotype 3 infection, and 16 (5%) had genotype 6 infection. 81 (27%) patients had compensated cirrhosis, 90 (30%) had HIV co-infection, and 99 (33%) had received previous interferon-based treatment. The most common treatment-emergent adverse events were pyrexia (35 [12%]), cough (26 [9%]), upper respiratory tract infection (23 [8%]), and headache (20 [7%]). There were no deaths or treatment discontinuations due to serious adverse events related to study drugs. Of the 300 patients included in the full analysis set, 291 (97%; 95% CI 94-99) had SVR12. Of note, SVR12 was reported in 78 (96%) of 81 patients with cirrhosis and 153 (97%) of 158 patients with genotype 3 infection, including 51 (96%) of 53 patients with cirrhosis. There was no difference in SVR12 rates by HIV co-infection or previous interferon treatment. INTERPRETATION: In this first stage, ravidasvir plus sofosbuvir was effective and well tolerated in this diverse adult population of patients with chronic HCV infection. Ravidasvir plus sofosbuvir has the potential to provide an additional affordable, simple, and efficacious public health tool for large-scale implementation to eliminate HCV as a cause of morbidity and mortality. FUNDING: National Science and Technology Development Agency, Thailand; Department of Disease Control, Ministry of Public Health, Thailand; Ministry of Health, Malaysia; UK Aid; Médecins Sans Frontières (MSF); MSF Transformational Investment Capacity; FIND; Pharmaniaga; Starr International Foundation; Foundation for Art, Research, Partnership and Education; and the Swiss Agency for Development and Cooperation.


Assuntos
Benzimidazóis/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Sofosbuvir/uso terapêutico , Valina/análogos & derivados , Proteínas não Estruturais Virais/antagonistas & inibidores , Adulto , Idoso , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Antivirais/uso terapêutico , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Coinfecção/epidemiologia , Quimioterapia Combinada , Feminino , Genótipo , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Hepacivirus/efeitos dos fármacos , Hepacivirus/genética , Hepatite C Crônica/complicações , Hepatite C Crônica/virologia , Humanos , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/epidemiologia , Cirrose Hepática/etiologia , Malásia/epidemiologia , Masculino , Pessoa de Meia-Idade , RNA Viral/efeitos dos fármacos , Segurança , Sofosbuvir/administração & dosagem , Sofosbuvir/efeitos adversos , Resposta Viral Sustentada , Tailândia/epidemiologia , Resultado do Tratamento , Valina/administração & dosagem , Valina/efeitos adversos , Valina/uso terapêutico
4.
Kaohsiung J Med Sci ; 36(11): 920-928, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32643842

RESUMO

Hepatitis C virus (HCV) eradication deteriorates lipid profiles. Although HCV eradication may reduce the risk of vascular events as a whole, whether deteriorated lipid profiles increases the risk of cardio-cerebral disease in certain patients is elusive. Serial lipid profiles were measured before, during, at and 3 months after the end of direct-acting antivirals (DAAs) therapy, and annually thereafter in chronic hepatitis C patients who achieved a sustained virological response (SVR, undetectable HCV RNA at posttreatment week 12). The primary end-point was the occurrence of the events. A total of 617 patients were included, with a mean follow-up period of 26.8 months (range: 1-65 months). The total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels increased significantly from treatment week 4 to 2 years after treatment. Logistic regression analysis revealed that the factors independently associated with a significant cholesterol increase included age (odds ratio [OR]/95% confidence intervals [CIs]:1.02/1.006-1.039, P = .007) and smoking (OR/CI:3.21/1.14-9.02, P = .027). Five patients developed cardio-cerebral diseases during 1376 person-years follow-up period. Compared to patients without vascular events, a significantly higher proportion of those with vascular events experienced an LDL-C surge >40% (80% vs 19.9%, P = .001). Cox-regression analysis revealed that an LDL-C surge >40% was the only factor predictive of vascular events (HR/CI: 15.44/1.73-138.20, P = .014). Dyslipidemia occurred after HCV eradication, and it was associated with the risk of cardio-cerebrovascular diseases. Attention should also be paid to the extrahepatic consequence beyond liver-related complications in the post-SVR era.


Assuntos
Antivirais/efeitos adversos , Doença da Artéria Coronariana/sangue , Dislipidemias/sangue , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Resposta Viral Sustentada , Idoso , Antivirais/administração & dosagem , Carbamatos/administração & dosagem , Carbamatos/efeitos adversos , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Doença da Artéria Coronariana/induzido quimicamente , Doença da Artéria Coronariana/virologia , Dislipidemias/induzido quimicamente , Dislipidemias/virologia , Feminino , Seguimentos , Hepacivirus/genética , Hepacivirus/crescimento & desenvolvimento , Hepatite C Crônica/sangue , Hepatite C Crônica/patologia , Hepatite C Crônica/virologia , Humanos , Imidazóis/administração & dosagem , Imidazóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Pirrolidinas/administração & dosagem , Pirrolidinas/efeitos adversos , RNA Viral/sangue , RNA Viral/genética , Ribavirina/administração & dosagem , Ribavirina/efeitos adversos , Risco , Sofosbuvir/administração & dosagem , Sofosbuvir/efeitos adversos , Triglicerídeos/sangue , Valina/administração & dosagem , Valina/efeitos adversos , Valina/análogos & derivados
5.
J Viral Hepat ; 27(9): 886-895, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32358826

RESUMO

Safe and efficacious pan-genotypic direct-acting antiviral (DAA) regimens, such as sofosbuvir and daclatasvir (SOF + DCV), facilitate simplified models of care for hepatitis C virus (HCV). However, in Cambodia access to HCV testing and treatment has typically been low. In response, Médecins Sans Frontières (MSF) implemented a HCV testing and treatment pilot project in Phnom Penh, Cambodia in 2016. This project provides the first real-world evidence of SOF + DCV effectiveness across a large patient cohort using a simplified care model in Cambodia. Patients treated with SOF + DCV from September 2016 to June 2019 were included in the analysis. Medical standard operational procedures (SOPs) were simplified significantly across the study period. Treatment effectiveness was assessed by sustained viral response at 12 weeks post-treatment (SVR12) according to a modified intention-to-treat methodology. Treatment safety was assessed by clinical outcome and occurrence of serious and nonserious adverse events (S/AE). Of 9158 patients, median age was 57 years and 39.6% were male. At baseline assessment, 27.2% of patients had compensated cirrhosis and 2.9% had decompensated cirrhosis. Genotype 6 was predominant (53.0%). Among patients analysed according to modified intention to treat (n = 8525), treatment effectiveness was high, with 97.2% of patients achieving SVR12. Occurrence of SAE was low (0.7%). Treatment effectiveness and safety was not affected by the iterative simplification to treatment modality. In conclusion, in this large treatment cohort in Phnom Penh, Cambodia, the SOF + DCV regimen showed high rates of treatment effectiveness and safety across patient sub-groups and during progressive simplification.


Assuntos
Antivirais , Carbamatos , Hepatite C , Imidazóis , Pirrolidinas , Sofosbuvir , Resposta Viral Sustentada , Valina/análogos & derivados , Antivirais/efeitos adversos , Antivirais/uso terapêutico , Camboja , Carbamatos/efeitos adversos , Carbamatos/uso terapêutico , Quimioterapia Combinada , Hepacivirus , Hepatite C/tratamento farmacológico , Humanos , Imidazóis/efeitos adversos , Imidazóis/uso terapêutico , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Pirrolidinas/efeitos adversos , Pirrolidinas/uso terapêutico , Ribavirina/uso terapêutico , Sofosbuvir/efeitos adversos , Sofosbuvir/uso terapêutico , Resultado do Tratamento , Valina/efeitos adversos , Valina/uso terapêutico
6.
Pharmacol Res Perspect ; 8(2): e00568, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32162844

RESUMO

We report a phase I pharmacological study of an oral formulation of CKD-516, a vascular-disrupting agent, in patients with refractory solid tumors. Twenty-seven patients (16 in the dose-escalation cohort and 11 in the expansion cohort) received a single daily dose (5-25 mg) of CKD-516 five days per week. Nausea (67%) and diarrhea (63%) were the most common treatment-related adverse events. The recommended phase II dose of oral CKD-516 was 20 mg/d (15 mg/d with a body surface area (BSA) <1.65 m2 ). Notably, S-516 half-lives in patients receiving 15-20 mg CKD-516/d significantly differed between patients with and without splenomegaly that is suggestive of portal hypertension associated with liver cirrhosis (6.1 vs 4.6 hours, respectively). Of 11 patients without splenomegaly who completed at least one cycle of a daily CKD-516 dose of either 15 or 20 mg, only one patient (9.1%) suffered from any dose-limiting toxicity. We conclude that a daily oral dose of 15 or 20 mg CKD-516 five days per week could be tolerable in patients without liver cirrhosis.


Assuntos
Antineoplásicos/farmacocinética , Benzofenonas/farmacocinética , Neoplasias/metabolismo , Valina/análogos & derivados , Administração Oral , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/sangue , Benzofenonas/efeitos adversos , Benzofenonas/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/tratamento farmacológico , Resultado do Tratamento , Valina/efeitos adversos , Valina/sangue , Valina/farmacocinética , Adulto Jovem
7.
Can J Gastroenterol Hepatol ; 2020: 1632959, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32083035

RESUMO

Background: Direct-acting antivirals (DAAs) made a drastic change in the management of HCV infection. Sofosbuvir is one of the highly potent DAAs, eliminated mainly through the kidney. But concerns about renal safety during treatment may limit its use. Neutrophil gelatinase-associated lipocalin (NGAL) has been proven as a predictor of renal tubular injury. Hence, the aim of this work was to assess serum neutrophil gelatinase-associated lipocalin (NGAL) in HCV-positive patients before and after treatment with the sofosbuvir-based antiviral regimen. Methods: This prospective study included 87 Egyptian patients with chronic HCV infection treated with sofosbuvir plus daclatasvir with or without ribavirin for 12 weeks. Serum NGAL was measured before and at the end of treatment (EOT). Analysis of NGAL and estimated glomerular filtration rate (eGFR) evolution was done. Results: Our results showed a statistically significant decrease in serum NGAL (P=0.02) with a nonsignificant reduction in eGFR (P=0.02) with a nonsignificant reduction in eGFR (P=0.02) with a nonsignificant reduction in eGFR (P=0.02) with a nonsignificant reduction in eGFR (P=0.02) with a nonsignificant reduction in eGFR (. Conclusions: Sofosbuvir appears to have no nephrotoxic effects and is safe to treat patients with chronic HCV infection.


Assuntos
Injúria Renal Aguda/diagnóstico , Antivirais/efeitos adversos , Hepatite C Crônica/sangue , Lipocalina-2/sangue , Sofosbuvir/efeitos adversos , Injúria Renal Aguda/induzido quimicamente , Adulto , Carbamatos/efeitos adversos , Quimioterapia Combinada , Egito , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Humanos , Imidazóis/efeitos adversos , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Pirrolidinas/efeitos adversos , Ribavirina/efeitos adversos , Valina/efeitos adversos , Valina/análogos & derivados
8.
J Clin Psychiatry ; 81(2)2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31995679

RESUMO

Valbenazine and deutetrabenazine are FDA-approved as treatment for tardive dyskinesia (TD). Both medications are vesicular monoamine transporter type 2 (VMAT2) inhibitors, and both are effective for reducing TD symptoms. Clinicians need to be aware of the adverse effects of valbenazine and deutetrabenazine, as well as other key differences between the two, in order to individualize treatment. Using the Abnormal Involuntary Movement Scale assists clinicians in assessing progress for each patient. Treating TD effectively with these new medications will reduce the burden of the condition for patients.


Assuntos
Exame Neurológico/métodos , Discinesia Tardia , Tetrabenazina/análogos & derivados , Valina/análogos & derivados , Proteínas Vesiculares de Transporte de Monoamina/antagonistas & inibidores , Monitoramento de Medicamentos/métodos , Humanos , Conduta do Tratamento Medicamentoso , Moduladores de Transporte de Membrana/administração & dosagem , Moduladores de Transporte de Membrana/efeitos adversos , Administração dos Cuidados ao Paciente/métodos , Administração dos Cuidados ao Paciente/normas , Psiquiatria/educação , Discinesia Tardia/induzido quimicamente , Discinesia Tardia/diagnóstico , Discinesia Tardia/tratamento farmacológico , Tetrabenazina/administração & dosagem , Tetrabenazina/efeitos adversos , Resultado do Tratamento , Valina/administração & dosagem , Valina/efeitos adversos
9.
Am J Health Syst Pharm ; 77(3): 167-174, 2020 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-31974564

RESUMO

PURPOSE: The purpose of this review is to summarize the current evidence for valbenazine and deutetrabenazine use for the treatment of tardive dyskinesia (TD). SUMMARY: A literature search was conducted to gather relevant data regarding the use of valbenazine and deutetrabenazine for TD management. PubMed, MEDLINE, and ClinicalTrials.gov were searched using the following keywords and MeSH terms: valbenazine, deutetrabenazine, tardive dyskinesia, VMAT2 inhibitors, and vesicular monoamine transporter 2 inhibitors. Randomized, double-blind, placebo-controlled trials and meta-analyses published in English from April 2015 to August 2019 were included. Valbenazine 40-80 mg and deutetrabenazine 12-36 mg per day have been evaluated for the treatment of TD. Abnormal Involuntary Movement Scale (AIMS) scores decline similarly (by 2-5 points) with use of either agent. AIMS response rates, defined by a 50% decline in symptoms, range from 33% to 50%. Both agents are well tolerated, with somnolence and akathisia reported most frequently (at low rates). Agent selection may be guided by manufacturer labeling recommendations for special populations and cost considerations. CONCLUSIONS: Valbenazine and deutetrabenazine were demonstrated to be effective in decreasing AIMS scores and were well tolerated in randomized controlled trials. These treatments may be considered as a next-line option when traditional strategies are not feasible or are ineffective. Head-to-head studies are warranted to decipher if either agent is preferable in terms of efficacy or tolerability.


Assuntos
Discinesia Tardia/tratamento farmacológico , Tetrabenazina/análogos & derivados , Valina/análogos & derivados , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Discinesia Tardia/fisiopatologia , Tetrabenazina/administração & dosagem , Tetrabenazina/efeitos adversos , Tetrabenazina/farmacologia , Resultado do Tratamento , Valina/administração & dosagem , Valina/efeitos adversos , Valina/farmacologia , Proteínas Vesiculares de Transporte de Monoamina/antagonistas & inibidores
10.
Clin Res Hepatol Gastroenterol ; 44(3): 329-339, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31523019

RESUMO

BACKGROUND: The World Health Organization estimates that 1% of the world population (71 million) is infected with hepatitis C virus (HCV). In 2015, three direct-acting antivirals (DAAs), simeprevir (SMV), sofosbuvir (SOF) and daclatasvir (DCV) were included in the Brazilian protocol for the treatment of chronic hepatitis C. Despite the fact that the use of these drugs is associated with higher treatment response rates and with lower incidence of side effects, studies have shown the association between the presence of viral resistance mutations and the failure of pharmacological treatment. AIM: This way, this study aimed to evaluate the safety and effectiveness of treatment for HCV genotypes 1a and 1b infected patients with these DAAs, also analyzing the occurrence and prevalence of baseline resistance associated substitutions (RAS), observing the impact of these mutations into the treatment success. METHODS: Clinical data were collected from all the 262 HCV infected patients included for comparative analysis, while serum samples collected from 144 of these individuals, before treatment, were submitted to molecular biology approaches for mutation analysis into NS3, NS5A and NS5B regions. RESULTS: Regarding the treatment regimens, 49.6% of the patients received SOF+DCV±ribavirin and 50.4% used SOF+SMV±ribavirin. The sustained virological response at 12 weeks post-treatment (SVR12) rate was 92.7% (93.9% for SOF plus DCV and 91.7% for SOF plus SMV). No clinical or laboratorial factor was statistically associated with SVR. The most common adverse reactions were haematological events, nausea/vomiting, headache and asthenia. Out of 144 blood samples, 70 (48.6%) had detected RAS, 34.8% treated with SOF+DCV±ribavirin and 61.3% SOF+SMV±ribavirin. The resistance mutations against SMV were detected into NS3: substitutions G122S (28%), I170V (22.7%), Y56F (17.3%) and V132I (14.7%). The mutations against DCV R30Q (9.1%), P58H (6.1%) and Q62E (6.1%) were observed into NS5A, and for SOF the mutations A421V (10.6%), L159F (6.4%) and C316N (6.4%) were present inside NS5B viral protein. Four patients did not reach SVR, three of them presented viruses carrying RAS (1 treated with SOF+DCV and 2 with SOF+SMV). Some of these mutations, like R30Q (present in relapsing samples) and L159F, are well known by their influence on antiviral resistance, while others, like C316N, have a compensatory effect on viral fitness, maintaining these baseline RAS. CONCLUSION: The use of treatment regimens composed of SOF and DCV or SOF and SMV showed a high SVR rate, despite of a high rate of RAS, and a good tolerability profile in patients with HCV genotype 1. However, the high occurrence of baseline RAS observed in this casuistic is still a concern and studies like this show the necessity to understand how they are maintained in the population and to direct more efficiently the use of DAAs.


Assuntos
Antivirais/uso terapêutico , Farmacorresistência Viral/genética , Genótipo , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Antivirais/efeitos adversos , Brasil , Carbamatos/efeitos adversos , Carbamatos/uso terapêutico , Estudos de Coortes , Feminino , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/sangue , Humanos , Imidazóis/efeitos adversos , Imidazóis/uso terapêutico , Masculino , Pessoa de Meia-Idade , Mutação , Estudos Prospectivos , Pirrolidinas/efeitos adversos , Pirrolidinas/uso terapêutico , Ribavirina/uso terapêutico , Simeprevir/efeitos adversos , Simeprevir/uso terapêutico , Sofosbuvir/efeitos adversos , Sofosbuvir/uso terapêutico , Resultado do Tratamento , Valina/efeitos adversos , Valina/análogos & derivados , Valina/uso terapêutico
12.
J Clin Psychopharmacol ; 39(6): 620-627, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31688452

RESUMO

PURPOSE/BACKGROUND: Valbenazine is approved to treat tardive dyskinesia (TD) in adults. KINECT 4 (NCT02405091) was conducted to explore the long-term effects of once-daily valbenazine in patients with TD. METHODS/PROCEDURES: The study included a 48-week, open-label treatment period and 4-week washout. Dosing was initiated at 40 mg/d, with escalation to 80 mg/d at week 4 based on efficacy and tolerability. Standard safety methods were applied, including treatment-emergent adverse event (TEAE) reporting. Valbenazine effects on TD were assessed using the Abnormal Involuntary Movement Scale (AIMS), Clinical Global Impression of Change-TD, and Patient Global Impression of Change. FINDINGS/RESULTS: After week 4, <15% of all participants had a serious TEAE (13.7%) or TEAE leading to discontinuation (11.8%). Participants experienced TD improvements during long-term treatment as indicated by mean change from baseline to week 48 in AIMS total score (sum of items 1-7, evaluated by site raters) with valbenazine 40 mg/d (-10.2 [n = 45]) or 80 mg/d (-11.0 [n = 107]). At week 48, most participants had ≥50% improvement from baseline in AIMS total score (40 mg/d, 90.0%; 80 mg/d, 89.2%), Clinical Global Impression of Change-TD rating of much or very much improved (40 mg/d, 90.0%; 80 mg/d, 95.9%), and Patient Global Impression of Change rating of much or very much improved (40 mg/d, 90.0%; 80 mg/d, 89.2%). No dose effects were apparent by week 36. Week 52 results indicated some loss of effect after washout. IMPLICATIONS/CONCLUSIONS: Valbenazine was generally well tolerated, and no new safety concerns were detected. Substantial clinician- and patient-reported improvements were observed in adults with TD who received once-daily valbenazine for up to 48 weeks.


Assuntos
Antipsicóticos/efeitos adversos , Transtornos do Humor/tratamento farmacológico , Avaliação de Resultados em Cuidados de Saúde , Transtornos Psicóticos/tratamento farmacológico , Esquizofrenia/tratamento farmacológico , Discinesia Tardia/tratamento farmacológico , Tetrabenazina/análogos & derivados , Valina/análogos & derivados , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Pessoa de Meia-Idade , Discinesia Tardia/etiologia , Tetrabenazina/administração & dosagem , Tetrabenazina/efeitos adversos , Tetrabenazina/sangue , Tetrabenazina/farmacologia , Valina/administração & dosagem , Valina/efeitos adversos , Valina/sangue , Valina/farmacologia , Adulto Jovem
13.
J Comp Eff Res ; 8(13): 1077-1088, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31464152

RESUMO

Aim: Utilize the Bucher indirect treatment comparison (ITC) method to compare valbenazine and deutetrabenazine efficacy using clinical trial data. Methods: Outcomes included mean change from baseline in Abnormal Involuntary Movement Scale (AIMS) total score, AIMS response (≥50% improvement), clinical global impression of change response (score ≤2) and safety outcomes. Data were pooled by trial and dose; outcomes were analyzed at multiple time points. Results: ITC of AIMS score improvement significantly favored valbenazine 80 mg/day at 6 weeks versus deutetrabenazine 36 mg/day at 8 weeks, while valbenazine 40 mg/day was statistically similar to all doses of deutetrabenazine at all time points. No significant differences between drugs were found in AIMS and clinical global impression of change responses and safety outcomes. Conclusion: In this ITC of pooled trial data, valbenazine was generally favorable over deutetrabenazine, although dose titration and equivalency should be considered when interpreting results.


Assuntos
Discinesia Tardia/tratamento farmacológico , Tetrabenazina/análogos & derivados , Valina/análogos & derivados , Relação Dose-Resposta a Droga , Método Duplo-Cego , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Tetrabenazina/administração & dosagem , Tetrabenazina/efeitos adversos , Tetrabenazina/uso terapêutico , Valina/administração & dosagem , Valina/efeitos adversos , Valina/uso terapêutico
14.
Arch Iran Med ; 22(4): 182-188, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31126176

RESUMO

BACKGROUND: Dietary amino acids have been associated with blood pressure (BP) in previous studies; we conducted this study to examine the association between dietary branched chain amino acids (BCAAs) and the incidence of hypertension among participants of the Tehran Lipid and Glucose Study (TLGS). METHODS: Analyses were conducted on 4,288 participants aged 20-70 years, who were free of hypertension at baseline (2008- 2011) and were followed for 3 years (2011-2014) to ascertain incident hypertension. Dietary intakes of BCAAs including, valine, leucine, and isoleucine were collected at baseline using the food frequency questionnaire (FFQ). Odds ratio (OR) of hypertension were determined by logistic regression across quartiles of BCAAs, adjusted for sex, age, smoking status, physical activity, body mass index (BMI), diabetes, and some dietary factors. RESULTS: The mean ± standard deviation for age and BMI of participants (41.9% men) were 39.7 ± 12.8 years and 26.9 ± 4.6 kg/ m2 , respectively. The median intakes of total BCAAs, valine, leucine, and isoleucine was 17.9, 5.5, 7.8, and 4.5 percentage of total amino acids intake, respectively. We documented 429 (10%) hypertension incident cases. The multivariable adjusted OR for the highest vs lowest quartiles of BCAAs was 1.54 (95% confidence interval (CI):1.03-2.32; P for trend = 0.05); furthermore, the OR (95% CI) of hypertension for the highest vs the lowest quartile of valine was 1.61 (1.10-2.36; P for trend = 0.009) in the fully adjusted model. However, we found no significant association between leucine and isoleucine with incidence of hypertension. CONCLUSION: Findings indicated that higher BCAA intake, in particular valine, is associated with higher risk of incident hypertension.


Assuntos
Aminoácidos de Cadeia Ramificada/efeitos adversos , Dieta Rica em Proteínas/efeitos adversos , Hipertensão/epidemiologia , Valina/efeitos adversos , Adulto , Idoso , Aminoácidos de Cadeia Ramificada/sangue , Feminino , Humanos , Hipertensão/sangue , Incidência , Irã (Geográfico)/epidemiologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Valina/sangue , Adulto Jovem
15.
Forensic Sci Int ; 297: 372-377, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30850157

RESUMO

Synthetic cannabinoids (SCs) belong to the group of new psychoactive substances (NPS) which appear sprayed on herbal mixtures on the "street" drug market and are intended for smoking like marijuana. In the present report we discuss a fatal case of 18-years-old boy, who had smoked SCs since several months and an overuse of SCs during last 48 h of his life has been apprised. The autopsy findings revealed acute respiratory distress syndrome (ARDS). Both toxicological analysis of deceased blood and urine samples and chemical analysis of the herbal mixture seized revealed presence of two SCs - 5F-ADB and FUB-AMB. The amount of 5F-ADB in blood was found to be 3.7 ng/mL by standard addition method. Severe and irreversible morphology changes in lung specimen, leading to ischemic damage of all internal organs and tissues, were observed during histological examination. The present case can be discussed as an example of both drug-induced and drug-related death resulting from acute intoxication with 5F-ADB and FUB-AMB as well as from systematic use of both synthetic cannabinoids.


Assuntos
Canabinoides/efeitos adversos , Drogas Desenhadas/efeitos adversos , Indazóis/efeitos adversos , Insuficiência Respiratória/induzido quimicamente , Valina/análogos & derivados , Adolescente , Canabinoides/sangue , Canabinoides/urina , Drogas Desenhadas/análise , Overdose de Drogas , Humanos , Indazóis/sangue , Indazóis/urina , Extração Líquido-Líquido , Pulmão/patologia , Masculino , Transtornos Relacionados ao Uso de Substâncias/complicações , Valina/efeitos adversos , Valina/sangue , Valina/urina
16.
J Affect Disord ; 246: 217-223, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30583148

RESUMO

BACKGROUND: Few studies have assessed the treatment of tardive dyskinesia (TD) in patients with primary mood disorders who are managed with antipsychotics. The effects of once-daily valbenazine on TD were evaluated in adults with a bipolar or depressive disorder. METHODS: Data were pooled from two 6-week double-blind placebo-controlled trials (KINECT 2 and KINECT 3; 114 mood participants) and a long-term blinded extension study (KINECT 3 extension; 77 mood participants) of valbenazine in adults with TD. Efficacy assessments included Abnormal Involuntary Movement Scale (AIMS) total score (sum of items 1-7), Clinical Global Impression of Change-Tardive Dyskinesia (CGI-TD), and Patient Global Impression of Change (PGIC). Safety assessments included treatment-emergent adverse events (TEAEs), Young Mania Rating Scale, and Montgomery-Åsberg Depression Rating Scale. RESULTS: At Week 6, mean improvements in AIMS total score were significantly greater with valbenazine versus placebo (40 mg/day, -3.1 [P < 0.01]; 80 mg/day, -3.5 [P < 0.001]; placebo, -0.9). Significant differences between valbenazine (80 mg/day) and placebo were also found for Week 6 AIMS response (≥50% total score improvement) and CGI-TD response ("much improved" or "very much improved"), but not PGIC response. Sustained improvements in AIMS, CGI-TD, and PGIC were found through 48 weeks. Valbenazine was generally well tolerated, with no unexpected TEAEs, worsening in psychiatric symptoms, or emergence of suicidality. LIMITATIONS: Pooled analyses were conducted post hoc, and neither study was designed to focus solely on mood disorder patients. CONCLUSIONS: In participants with primary mood disorders, once-daily treatment with valbenazine was generally well tolerated and resulted in 6-week and sustained TD improvements.


Assuntos
Transtornos do Humor/tratamento farmacológico , Discinesia Tardia/tratamento farmacológico , Tetrabenazina/análogos & derivados , Valina/análogos & derivados , Antipsicóticos/efeitos adversos , Antipsicóticos/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos do Humor/complicações , Discinesia Tardia/induzido quimicamente , Discinesia Tardia/complicações , Tetrabenazina/efeitos adversos , Tetrabenazina/uso terapêutico , Valina/efeitos adversos , Valina/uso terapêutico
18.
Consult Pharm ; 33(4): 201-209, 2018 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-29609698

RESUMO

OBJECTIVE: To provide a review of tardive dyskinesia (TD) symptoms, etiology, pathophysiology, and treatments. DATA SOURCES: PubMed, Web of Science, ClinicalTrials. gov, and Google Scholar were searched for relevant literature using a combination of the following terms: tardive dyskinesia, treatment, management, guidelines, tetrabenazine, deutetrabenazine, and valbenazine. Sources were limited to human data. STUDY SELECTION/DATA EXTRACTION: Articles were reviewed for relevance to TD therapy. Reference lists were manually searched for other relevant articles. Selected literature was published between 1968 and 2017. DATA SYNTHESIS: This article reviews treatment options available for patients with TD. Many agents have been tried off-label to manage symptoms, with limited evidence of benefit. The Food and Drug Administration approved the first drug to treat TD valbenazine on April 11, 2017. CONCLUSION: TD is largely iatrogenic. Valbenazine's approval by the Food and Drug Administration was followed by the approval of deutetrabenazine, a drug with similar mechanism of action. Further data from postmarketing studies will be needed to verify that valbenazine's adverse effect profile is different from the profiles of tetrabenazine and deutetrabenazine.


Assuntos
Aprovação de Drogas , Discinesia Tardia/tratamento farmacológico , Proteínas Vesiculares de Transporte de Monoamina/antagonistas & inibidores , Humanos , Guias de Prática Clínica como Assunto , Discinesia Tardia/fisiopatologia , Tetrabenazina/efeitos adversos , Tetrabenazina/análogos & derivados , Tetrabenazina/farmacologia , Tetrabenazina/uso terapêutico , Estados Unidos , United States Food and Drug Administration , Valina/efeitos adversos , Valina/análogos & derivados , Valina/farmacologia , Valina/uso terapêutico
19.
Exp Hematol ; 63: 12-16.e1, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29705267

RESUMO

Hematopoietic stem cells (HSCs) are used clinically in bone marrow (BM) transplantation due to their unique ability to reform the entire hematopoietic system. Recently, we reported that HSCs are highly sensitive to valine, one of the three branched-chain amino acids (BCAAs) in addition to isoleucine and leucine. Dietary depletion of valine could even be used as a conditioning regimen for HSC transplantation. Here, we report that HSCs are highly sensitive to the balance of BCAAs, with both proliferation and survival reduced by BCAA imbalance. However, low but balanced BCAA levels failed to rescue HSC maintenance. Importantly, in vivo depletion of all three BCAAs was significantly less toxic than depletion of valine only. We demonstrate that BCAA depletion can replace valine depletion as a safer alternative to BM conditioning. In summary, by determining HSC metabolic requirements, we can improve metabolic approaches to BM conditioning.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Isoleucina/administração & dosagem , Leucina/administração & dosagem , Condicionamento Pré-Transplante/métodos , Valina/administração & dosagem , Anemia/etiologia , Animais , Medula Óssea/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Meios de Cultura/química , Meios de Cultura/farmacologia , Meios de Cultura/toxicidade , Dieta , Contagem de Eritrócitos , Sangue Fetal/citologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , Isoleucina/efeitos adversos , Isoleucina/farmacologia , Leucina/efeitos adversos , Leucina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Quimera por Radiação , Condicionamento Pré-Transplante/efeitos adversos , Valina/efeitos adversos , Valina/farmacologia
20.
Drugs ; 78(5): 525-541, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29484607

RESUMO

Tardive dyskinesia (TD) encompasses the spectrum of iatrogenic hyperkinetic movement disorders following exposure to dopamine receptor-blocking agents (DRBAs). Despite the advent of atypical or second- and third-generation antipsychotics with a presumably lower risk of complications, TD remains a persistent and challenging problem. Prevention is the first step in mitigating the risk of TD, but early recognition, gradual withdrawal of offending medications, and appropriate treatment are also critical. As TD is often a persistent and troublesome disorder, specific antidyskinetic therapies are often needed for symptomatic relief. The vesicular monoamine transporter 2 (VMAT2) inhibitors, which include tetrabenazine, deutetrabenazine, and valbenazine, are considered the treatment of choice for most patients with TD. Deutetrabenazine-a deuterated version of tetrabenazine-and valbenazine, the purified parent product of one of the main tetrabenazine metabolites, are novel VMAT2 inhibitors and the only drugs to receive approval from the US FDA for the treatment of TD. VMAT2 inhibitors deplete presynaptic dopamine and reduce involuntary movements in many hyperkinetic movement disorders, particularly TD, Huntington disease, and Tourette syndrome. The active metabolites of the VMAT2 inhibitors have high affinity for VMAT2 and minimal off-target binding. Compared with tetrabenazine, deutetrabenazine and valbenazine have pharmacokinetic advantages that translate into less frequent dosing and better tolerability. However, no head-to-head studies have compared the various VMAT2 inhibitors. One of the major advantages of VMAT2 inhibitors over DRBAs, which are still being used by some clinicians in the treatment of some hyperkinetic disorders, including TD, is that they are not associated with the development of TD. We also briefly discuss other treatment options for TD, including amantadine, clonazepam, Gingko biloba, zolpidem, botulinum toxin, and deep brain stimulation. Treatment of TD and other drug-induced movement disorders must be individualized and based on the severity, phenomenology, potential side effects, and other factors discussed in this review.


Assuntos
Antipsicóticos/uso terapêutico , Discinesia Tardia/tratamento farmacológico , Proteínas Vesiculares de Transporte de Monoamina/antagonistas & inibidores , Antipsicóticos/administração & dosagem , Antipsicóticos/efeitos adversos , Antipsicóticos/química , Aprovação de Drogas , Humanos , Doença de Huntington/tratamento farmacológico , Tetrabenazina/administração & dosagem , Tetrabenazina/efeitos adversos , Tetrabenazina/análogos & derivados , Tetrabenazina/química , Tetrabenazina/uso terapêutico , Síndrome de Tourette/tratamento farmacológico , Estados Unidos , United States Food and Drug Administration , Valina/administração & dosagem , Valina/efeitos adversos , Valina/análogos & derivados , Valina/química , Valina/uso terapêutico
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