RESUMEN
Cenobamate (CNB), ([(R)-1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethyl], is a novel tetrazole alkyl carbamate derivative. In November 2019, the Food and Drug Administration approved Xcopri®, marketed by SK Life Science Inc., (Paramus, NJ, USA) for adult focal seizures. The European Medicines Agency approved Ontozry® by Arvelle Therapeutics Netherlands B.V.(Amsterdam, The Neatherlands) in March 2021. Cenobamate is a medication that could potentially change the perspectives regarding the management and prognosis of refractory epilepsy. In this way, this study aims to review the literature on CNB's pharmacological properties, pharmacokinetics, efficacy, and safety. CNB is a highly effective drug in managing focal onset seizures, with more than twenty percent of individuals with drug-resistant epilepsy achieving seizure freedom. This finding is remarkable in the antiseizure medication literature. The mechanism of action of CNB is still poorly understood, but it is associated with transient and persistent sodium currents and GABAergic neurotransmission. In animal studies, CNB showed sustained efficacy and potency in the 6 Hz test regardless of the stimulus intensity. CNB was revealed to be the most cost-effective drug among different third-generation antiseizure medications. Also, CNB could have neuroprotective effects. However, there are still concerns regarding its potential for abuse and suicidality risk, which future studies should clearly assess, after which protocols should be changed. The major drawback of CNB therapy is the slow and complex titration and maintenance phases preventing the wide use of this new agent in clinical practice.
Asunto(s)
Clorofenoles , Epilepsia Refractaria , Estados Unidos , Animales , Epilepsia Refractaria/tratamiento farmacológico , Carbamatos/uso terapéutico , Tetrazoles/uso terapéutico , ConvulsionesRESUMEN
BACKGROUND AND AIMS: Treatment of hepatitis C with direct antiviral agents (DAA) is associated with almost 95% of sustained virological response. However, some patients need retreatment. In Brazil, it should be done according to the Ministry of Health guidelines, frequently updated to include newly available drugs. This study aimed to conduct a national survey about the characteristics and outcomes of retreatment of hepatitis C in previously non-responders to DAAs. PATIENTS AND METHODS: Institutions from all over the country were invited to participate in a national registry for retreatment, including information about clinical and epidemiological characteristics of the patients, type and outcomes of retreatment regimens. Only patients previously treated with interferon-free regimens were included. RESULTS: As previous treatments the distribution was: SOF/DCV (56%), SOF/SIM (22%), 3D (11%), SOF/LED (6%) and SOF/RBV (5%). For retreatment the most frequently used drugs were SOF/GP (46%), SOF/DCV (23%) and SOF/VEL (11%). From 159 patients retreated, 132/159 (83%) had complete information in the registry and among them only seven patients were non-responders (SVR of 94.6%). All retreatments were well tolerated, without any serious adverse events or interruptions. CONCLUSION: The retreatment of patients previously non-responders to DAAs was associated with high rate of SVR in this sample of Brazilian patients. This finding allows us to conclude that the retreatment options available in the public health system in Brazil are effective and safe and are an important component of the strategy of elimination of hepatitis C in our country.
Asunto(s)
Hepatitis C Crónica , Hepatitis C , Antivirales , Brasil , Carbamatos/farmacología , Carbamatos/uso terapéutico , Quimioterapia Combinada , Genotipo , Hepacivirus/genética , Hepatitis C/complicaciones , Hepatitis C/tratamiento farmacológico , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/tratamiento farmacológico , Humanos , Retratamiento , Ribavirina/farmacología , Sofosbuvir/uso terapéutico , Resultado del Tratamiento , ValinaRESUMEN
ABSTRACT: The second of a two-part series, this article describes eight recently approved drugs, including the first drug approved for the treatment of SARS-CoV-2, a first-in-class HIV attachment inhibitor, and a new intravenous injection indicated for the treatment of acute pain in adults for whom other treatments are ineffective.
Asunto(s)
Aprobación de Drogas , Adenosina Monofosfato/análogos & derivados , Adenosina Monofosfato/uso terapéutico , Alanina/análogos & derivados , Alanina/uso terapéutico , Amisulprida/uso terapéutico , Carbamatos/uso terapéutico , Cefalosporinas/uso terapéutico , Clorofenoles/uso terapéutico , Combinación de Medicamentos , Fumaratos/uso terapéutico , Humanos , Indanos/uso terapéutico , Organofosfatos/uso terapéutico , Oxadiazoles/uso terapéutico , Piperazinas/uso terapéutico , Compuestos de Espiro/uso terapéutico , Tetrazoles/uso terapéutico , Tiofenos/uso terapéutico , Trometamina/uso terapéutico , Estados Unidos , United States Food and Drug Administration , Tratamiento Farmacológico de COVID-19 , CefiderocolRESUMEN
Patients with hepatitis C virus (HCV) genotype 3 (GT3) infection are resistant to direct-acting antiviral (DAA) treatments. This study aimed to analyze the effectiveness of sofosbuvir (SOF)+daclatasvir (DCV) ± ribavirin (RBV); SOF+velpatasvir (VEL)±RBV; SOF+VEL+voxilaprevir (VOX); and glecaprevir (GLE)+pibrentasvir (PIB) in the treatment of HCV GT3-infected patients in real-world studies. Articles were identified by searching the PubMed, EMBASE, and Cochrane Library databases from January 1, 2016 to September 10, 2019. The meta-analysis was conducted to determine the sustained virologic response (SVR) rate, using R 3.6.2 software. Thirty-four studies, conducted on a total of 7328 patients from 22 countries, met the inclusion criteria. The pooled SVR rate after 12/24 weeks of treatment was 92.07% (95% CI: 90.39-93.61%) for the evaluated regimens. Also, the SVR rate was 91.17% (95% CI: 89.23-92.94%) in patients treated with SOF+DCV±RBV; 95.08% (95% CI: 90.88-98.13%) in patients treated with SOF+VEL±RBV; 84.97% (95% CI: 73.32-93.91%) in patients treated with SOF+VEL+VOX; and 98.54% (95% CI: 96.40-99.82%) in patients treated with GLE+PIB. The pooled SVR rate of the four regimens was 95.24% (95% CI: 93.50-96.75%) in non-cirrhotic patients and 89.39% (95% CI: 86.07-92.33%) in cirrhotic patients. The pooled SVR rate was 94.41% (95% CI: 92.02-96.42%) in treatment-naive patients and 87.98% (95% CI: 84.31-91.25%) in treatment-experienced patients. The SVR rate of GLE+PIB was higher than other regimens. SOF+VEL+VOX can be used as a treatment regimen following DAA treatment failure.
Asunto(s)
Antivirales/uso terapéutico , Bencimidazoles/uso terapéutico , Carbamatos/uso terapéutico , Hepatitis C/tratamiento farmacológico , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Imidazoles/uso terapéutico , Compuestos Macrocíclicos/uso terapéutico , Pirrolidinas/uso terapéutico , Quinoxalinas/uso terapéutico , Sofosbuvir/uso terapéutico , Sulfonamidas/uso terapéutico , Valina/análogos & derivados , Combinación de Medicamentos , Hepatitis C/virología , Humanos , Ribavirina/uso terapéutico , Valina/uso terapéuticoRESUMEN
Hepatitis C virus (HCV) genotype 3 presents a high level of both baseline and acquired resistance to direct-acting antivirals (DAAs), particularly those targeting the NS5A protein. To understand this resistance we studied a cohort of Brazilian patients treated with the NS5A DAA, daclatasvir and the nucleoside analogue, sofosbuvir. We observed a novel substitution at NS5A amino acid residue 98 [serine to glycine (S98G)] in patients who relapsed post-treatment. The effect of this substitution on both replication fitness and resistance to DAAs was evaluated using two genotype 3 subgenomic replicons. S98G had a modest effect on replication, but in combination with the previously characterized resistance-associated substitution (RAS), Y93H, resulted in a significant increase in daclatasvir resistance. This result suggests that combinations of substitutions may drive a high level of DAA resistance and provide some clues to the mechanism of action of the NS5A-targeting DAAs.
Asunto(s)
Antivirales/farmacología , Carbamatos/farmacología , Farmacorresistencia Viral/genética , Hepacivirus/efectos de los fármacos , Imidazoles/farmacología , Pirrolidinas/farmacología , Valina/análogos & derivados , Proteínas no Estructurales Virales/genética , Antivirales/uso terapéutico , Brasil , Carbamatos/uso terapéutico , Línea Celular Tumoral , Estudios de Cohortes , Farmacorresistencia Viral/efectos de los fármacos , Quimioterapia Combinada , Genotipo , Hepacivirus/genética , Hepacivirus/fisiología , Hepatitis C/tratamiento farmacológico , Hepatitis C/virología , Humanos , Imidazoles/uso terapéutico , Mutación , Pirrolidinas/uso terapéutico , Recurrencia , Sofosbuvir/farmacología , Sofosbuvir/uso terapéutico , Valina/farmacología , Valina/uso terapéutico , Proteínas no Estructurales Virales/antagonistas & inhibidores , Replicación Viral/genéticaRESUMEN
Chronic hepatitis C virus (HCV) infection and autoimmune disorders show a complex interplay, with HCV often being identified as the trigger of autoimmune phenomena or diseases. While there is evidence of successful HCV treatment with direct-acting antivirals (DAA) in patients with concomitant HCV and autoimmune hepatitis (AIH), there are also sparse reports of AIH developing during, or following, DAA treatment. Here we report a case of a patient with suspected concomitant HCV and AIH who underwent liver biopsy but showed no histological hallmarks of autoimmunity. The patient later developed a hepatitic flare following DAA-induced viral clearance, and a second liver biopsy showed features compatible with AIH. Response to corticosteroid and azathioprine treatment was seen. This reports demonstrates that patients with features of auto-reactivity and HCV after DAA-induced viral clearance require careful follow-up.
Asunto(s)
Hepatitis C Crónica/complicaciones , Hepatitis Autoinmune/complicaciones , Actinas/inmunología , Anciano , Anticuerpos Antinucleares/inmunología , Antivirales/uso terapéutico , Azatioprina/uso terapéutico , Biopsia , Carbamatos/uso terapéutico , Combinación de Medicamentos , Glucocorticoides/uso terapéutico , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/patología , Hepatitis Autoinmune/tratamiento farmacológico , Hepatitis Autoinmune/inmunología , Hepatitis Autoinmune/patología , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Humanos , Inmunosupresores/uso terapéutico , Masculino , Prednisolona/uso terapéutico , Sofosbuvir/uso terapéutico , Resultado del TratamientoRESUMEN
This article reviews seven drugs recently approved by the FDA, including indications, precautions, adverse reactions, and nursing considerations.
Asunto(s)
Aprobación de Drogas , Anticuerpos Monoclonales/uso terapéutico , Benzofuranos/uso terapéutico , Carbamatos/uso terapéutico , Humanos , Fenilalanina/análogos & derivados , Fenilalanina/uso terapéutico , Piperidinas/uso terapéutico , Purinas/uso terapéutico , Tetraciclinas/uso terapéutico , Estados Unidos , United States Food and Drug AdministrationRESUMEN
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.
Asunto(s)
Antivirales/uso terapéutico , Farmacorresistencia Viral/genética , Genotipo , Hepacivirus/genética , Hepatitis C Crónica/tratamiento farmacológico , Antivirales/efectos adversos , Brasil , Carbamatos/efectos adversos , Carbamatos/uso terapéutico , Estudios de Cohortes , Femenino , Hepacivirus/efectos de los fármacos , Hepatitis C Crónica/sangre , Humanos , Imidazoles/efectos adversos , Imidazoles/uso terapéutico , Masculino , Persona de Mediana Edad , Mutación , Estudios Prospectivos , Pirrolidinas/efectos adversos , Pirrolidinas/uso terapéutico , Ribavirina/uso terapéutico , Simeprevir/efectos adversos , Simeprevir/uso terapéutico , Sofosbuvir/efectos adversos , Sofosbuvir/uso terapéutico , Resultado del Tratamiento , Valina/efectos adversos , Valina/análogos & derivados , Valina/uso terapéuticoRESUMEN
SUMMARY OBJECTIVE The recent development of direct-acting antiviral agents (DAAs) has dramatically changed the treatment of chronic hepatitis C, and interferon-based regimes have become a poor treatment choice in clinical practice. Today DAAs offer shorter, well-tolerated, highly effective curative therapies. This study aimed to evaluate the effectiveness and safety of DAAs in patients with end-stage renal disease and HCV genotype 1 infection in real clinical practice. METHODS Thirty-six patients who attended our clinic, were diagnosed with chronic hepatitis C (CHC), undergoing hemodialysis, and fulfilled the criteria of age >18 years, genotype 1 infection, with a detectable HCV RNA level were considered for the study. Patients with GT1a infection received OBV/PTV/r plus DSV plus RBV for 12 weeks; GT1b infected patients received this regimen without RBV for 12 weeks. RESULTS The study was conducted on 33 patients. The mean age was 52.30 ±13.77 years, and 70 % of them were male. By the fourth week of treatment, HCV RNA levels decreased below 15 IU/ml in all patients. Sustained virologic response (SVR) 12 rate was 100%. Nine patients had side effects during treatment. Of the patients with side effects, 89.9% were in group 1a and 11.1% in group 1b. CONCLUSION In this study, treatment with OBV/PTV/r and DSV with or without RBV resulted in high rates of sustained virologic response in HCV GT1-infected patients with end-stage renal disease (ESRD). SVR was achieved in all patients with few side effects.
RESUMO O recente desenvolvimento de agentes antivirais de ação direta (DAAs) mudou drasticamente o tratamento da hepatite C crônica, e os regimes livres de interferon tornaram-se pobres escolhas para tratamento na prática clínica. Hoje os DAAs oferecem terapias curativas mais curtas, bem toleradas e altamente eficazes. O objetivo deste estudo foi avaliar a eficácia e segurança dos DAAs em pacientes com doença renal em estágio terminal e infecção pelo genótipo 1 do HCV na prática clínica real. MÉTODOS Trinta e seis pacientes, que se inscreveram em nossa clínica com diagnóstico de hepatite C crônica (CHC), inclusive no programa de hemodiálise, e preencheram os critérios de idade >18 anos, foram considerados para infecção pelo genótipo 1 com nível detectável de RNA do HCV. Os pacientes com infecção por GT1a receberam OBV/PTV/r mais DSV mais RBV por 12 semanas. Os pacientes infectados com GT1b receberam este regime sem RBV por 12 semanas. RESULTADOS O estudo foi realizado em 33 pacientes. A idade média foi de 52,30±13,77 anos e 70% deles eram do sexo masculino. Na semana 4 do tratamento, os níveis de ARN do VHC diminuíram para menos de 15 UI/ml em todos os pacientes. A taxa de resposta virológica sustentada (RVS) 12 foi de 100%. Nove pacientes apresentaram efeitos colaterais durante o tratamento. Dos pacientes com efeitos colaterais, 89,9% estavam no grupo 1a e 11,1% no grupo 1b. CONCLUSÃO Neste estudo, o tratamento com OBV/PTV/r e DSV com ou sem RBV resultou em altas taxas de resposta virológica sustentada em pacientes infectados pelo VGC GT1 com doença renal em estágio final (ESRD). A RVS foi alcançada em todos os pacientes com poucos efeitos colaterais.
Asunto(s)
Humanos , Masculino , Femenino , Adulto , Anciano , Adulto Joven , Antivirales/uso terapéutico , Hepatitis C Crónica/tratamiento farmacológico , Fallo Renal Crónico/virología , Ribavirina/uso terapéutico , Sulfonamidas/uso terapéutico , Factores de Tiempo , Uracilo/análogos & derivados , Uracilo/uso terapéutico , ARN Viral/sangre , Carbamatos/uso terapéutico , Resultado del Tratamiento , Hepacivirus/efectos de los fármacos , Hepacivirus/genética , Estadísticas no Paramétricas , Ritonavir/uso terapéutico , Hepatitis C Crónica/virología , Compuestos Macrocíclicos/uso terapéutico , Quimioterapia Combinada , Respuesta Virológica Sostenida , Genotipo , Anilidas/uso terapéutico , Persona de Mediana EdadRESUMEN
This article reviews seven drugs recently approved by the FDA, including indications, precautions, adverse reactions, and nursing considerations.
Asunto(s)
Aprobación de Drogas , Aminoquinolinas/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Benzamidas/uso terapéutico , Cannabidiol/uso terapéutico , Carbamatos/uso terapéutico , Dibenzotiepinas , Humanos , Morfolinas , Oxazinas/uso terapéutico , Piridinas/uso terapéutico , Piridonas , Tiepinas/uso terapéutico , Triazinas/uso terapéutico , Estados Unidos , United States Food and Drug AdministrationRESUMEN
INTRODUCTION AND AIM: Interferon-free regimen has been reported to be highly efficient in treatment of HCV infection, including patients with compensated cirrhosis. We compared the efficacy of Ombitasvir, Paritaprevir, Ritonavir, Dasabuvir and Ribavirin (OBT/PTV/r, with DSV and RBV) therapy in patients with chronic HCV genotype 1b infection and compensated cirrhosis with and without prior treatment experience with pegylated interferon and ribavirin (IFN/RBV). MATERIAL AND METHODS: A prospective two-center study was conducted in Mures County Hospital and Brasov County Hospital, Romania in period November 2015-July 2016. Both treatment naïve and PegIFN/RBV experienced patients with chronic HCV genotype 1b infection received 12 weeks of OBT/PTV/r, with DSV and RBV. Sustained virologic response 12 weeks after the treatment and eventual discontinuation of therapy due to adverse events were assessed in order to estimate safety and efficiency of therapeutic regimen. RESULTS: Fifty nine patients were included in study, 35 (59.3%) of them were previously treated with IFN/RBV. Forty four (74.5%) patients were previously diag-nosed with cirrhosis Child Pugh score 5, while 15 (25.4%) with Child Pugh score 6. All 59 patients achieved a SVR12 of 100% and one patient from treatment naïve cohort discontinued the therapy due to hyperbilirubinemia and encephalopathy. However viral load assessed at 12 weeks after discontinuation of therapy in this patient was undetectable. Conclusion An all-oral regimen of co-for-mulated OBT/PTV/r with DSV and RBV results in high rate of sustained virologic response at post-treatment week 12 among HCV GT1b infected patients associated with compensated cirrhosis, regardless of previous treatment experience with PegIFN/RBV.
Asunto(s)
Antivirales/uso terapéutico , Inhibidores del Citocromo P-450 CYP3A/uso terapéutico , ADN Viral/genética , Hepacivirus/genética , Hepatitis C Crónica/tratamiento farmacológico , 2-Naftilamina , Anilidas/uso terapéutico , Carbamatos/uso terapéutico , Ciclopropanos , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Genotipo , Hepatitis C Crónica/virología , Humanos , Interferones , Lactamas Macrocíclicas , Cirrosis Hepática , Compuestos Macrocíclicos/uso terapéutico , Masculino , Persona de Mediana Edad , Prolina/análogos & derivados , Estudios Prospectivos , Ribavirina/uso terapéutico , Ritonavir/uso terapéutico , Sulfonamidas/uso terapéutico , Resultado del Tratamiento , Uracilo/análogos & derivados , Uracilo/uso terapéutico , Valina , Carga Viral/efectos de los fármacosRESUMEN
OBJECTIVE: The recent development of direct-acting antiviral agents (DAAs) has dramatically changed the treatment of chronic hepatitis C, and interferon-based regimes have become a poor treatment choice in clinical practice. Today DAAs offer shorter, well-tolerated, highly effective curative therapies. This study aimed to evaluate the effectiveness and safety of DAAs in patients with end-stage renal disease and HCV genotype 1 infection in real clinical practice. METHODS: Thirty-six patients who attended our clinic, were diagnosed with chronic hepatitis C (CHC), undergoing hemodialysis, and fulfilled the criteria of age >18 years, genotype 1 infection, with a detectable HCV RNA level were considered for the study. Patients with GT1a infection received OBV/PTV/r plus DSV plus RBV for 12 weeks; GT1b infected patients received this regimen without RBV for 12 weeks. RESULTS: The study was conducted on 33 patients. The mean age was 52.30 ±13.77 years, and 70 % of them were male. By the fourth week of treatment, HCV RNA levels decreased below 15 IU/ml in all patients. Sustained virologic response (SVR) 12 rate was 100%. Nine patients had side effects during treatment. Of the patients with side effects, 89.9% were in group 1a and 11.1% in group 1b. CONCLUSION: In this study, treatment with OBV/PTV/r and DSV with or without RBV resulted in high rates of sustained virologic response in HCV GT1-infected patients with end-stage renal disease (ESRD). SVR was achieved in all patients with few side effects.
Asunto(s)
Antivirales/uso terapéutico , Hepatitis C Crónica/tratamiento farmacológico , Fallo Renal Crónico/virología , 2-Naftilamina , Adulto , Anciano , Anilidas/uso terapéutico , Carbamatos/uso terapéutico , Ciclopropanos , Quimioterapia Combinada , Femenino , Genotipo , Hepacivirus/efectos de los fármacos , Hepacivirus/genética , Hepatitis C Crónica/virología , Humanos , Lactamas Macrocíclicas , Compuestos Macrocíclicos/uso terapéutico , Masculino , Persona de Mediana Edad , Prolina/análogos & derivados , ARN Viral/sangre , Ribavirina/uso terapéutico , Ritonavir/uso terapéutico , Estadísticas no Paramétricas , Sulfonamidas/uso terapéutico , Respuesta Virológica Sostenida , Factores de Tiempo , Resultado del Tratamiento , Uracilo/análogos & derivados , Uracilo/uso terapéutico , Valina , Adulto JovenAsunto(s)
Humanos , Femenino , Anciano , Antivirales/uso terapéutico , Inhibidores de Proteasas/uso terapéutico , Carbamatos/uso terapéutico , Hepatitis C/tratamiento farmacológico , Sofosbuvir/uso terapéutico , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Esquema de Medicación , Carga Viral , Ciclopropanos , Quimioterapia Combinada , Ácidos AminoisobutíricosAsunto(s)
Aprobación de Drogas , Ácidos Aminoisobutíricos , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Neutralizantes/uso terapéutico , Antipirina/análogos & derivados , Antipirina/uso terapéutico , Benzamidas/uso terapéutico , Bencimidazoles/uso terapéutico , Anticuerpos ampliamente neutralizantes , Carbamatos/uso terapéutico , Ciclopropanos , Combinación de Medicamentos , Edaravona , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Humanos , Lactamas Macrocíclicas , Leucina/análogos & derivados , Compuestos Macrocíclicos/uso terapéutico , Naltrexona/análogos & derivados , Naltrexona/uso terapéutico , Péptidos Natriuréticos/uso terapéutico , Prolina/análogos & derivados , Piridinas/uso terapéutico , Pirrolidinas , Quinoxalinas/uso terapéutico , Sofosbuvir/uso terapéutico , Sulfonamidas/uso terapéutico , Estados Unidos , United States Food and Drug AdministrationAsunto(s)
Antivirales/uso terapéutico , Carbamatos/uso terapéutico , Hepatitis C/tratamiento farmacológico , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Inhibidores de Proteasas/uso terapéutico , Sofosbuvir/uso terapéutico , Viremia/tratamiento farmacológico , Anciano , Ácidos Aminoisobutíricos , Antivirales/administración & dosificación , Antivirales/economía , Bencimidazoles/administración & dosificación , Bencimidazoles/uso terapéutico , Carbamatos/administración & dosificación , Ciclopropanos , Esquema de Medicación , Quimioterapia Combinada , Femenino , Genotipo , Hepacivirus/efectos de los fármacos , Hepacivirus/genética , Compuestos Heterocíclicos de 4 o más Anillos/administración & dosificación , Humanos , Lactamas Macrocíclicas , Leucina/análogos & derivados , Compuestos Macrocíclicos/administración & dosificación , Compuestos Macrocíclicos/uso terapéutico , Prolina/análogos & derivados , Inhibidores de Proteasas/administración & dosificación , Salud Pública/economía , Pirrolidinas , Quinoxalinas/administración & dosificación , Quinoxalinas/uso terapéutico , Sofosbuvir/administración & dosificación , Sulfonamidas/administración & dosificación , Sulfonamidas/uso terapéutico , Carga ViralAsunto(s)
Aprobación de Drogas , United States Food and Drug Administration , Amidas , Anticuerpos Monoclonales Humanizados/uso terapéutico , Benzofuranos/uso terapéutico , Carbamatos/uso terapéutico , Ciclopropanos , Quimioterapia/enfermería , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Humanos , Imidazoles/uso terapéutico , Péptidos/uso terapéutico , Fenilalanina/análogos & derivados , Fenilalanina/uso terapéutico , Quinoxalinas/uso terapéutico , Sofosbuvir/uso terapéutico , Sugammadex , Sulfonamidas , Sulfonas/uso terapéutico , Tioglicolatos/uso terapéutico , Triazoles/uso terapéutico , Estados Unidos , gamma-Ciclodextrinas/uso terapéuticoRESUMEN
BACKGROUND: URB597 is a compound largely linked to the inhibition of fatty acid amide hydrolase (FAAH), an enzyme responsible for the metabolic degradation of the endocannabinoid anandamide (AEA). Despite this pharmacological property accounts for its modulatory profile demonstrated in some neurotoxic paradigms, the possible protective properties of this agent have been poorly investigated, and deserve exploration in different neurotoxic models. In this study, we explored the effects of URB597 on oxidative damage to lipids and other major endpoints of toxicity in two neurotoxic models in vivo in rats (the first one produced by the mitochondrial neurotoxin 3-nitropropionic acid [3-NP], and the other generated by the striatal injection of the pro-oxidant toxin 6-hydroxidopamine [6-OHDA]) in order to provide further supporting evidence of its modulatory profile. METHODS: Male Wistar adult rats were treated for 5 or 7 consecutive days with URB597 (0.3mg/kg, i.p.) and simultaneously exposed to three injections of 3-NP (30mg/kg, i.p.) or a single intrastriatal infusion of 6-OHDA (0.02mg/2µl), respectively. Twenty four hours after all treatments were administered, lipid peroxidation was measured in the striatum of 3-NP-treated rats, and in the midbrain of 6-OHDA-treated rats. Motor skills and histological assessment in the striatum were also evaluated in 3-NP-treated rats 6 and 7days after the last drug administration, respectively; whereas apomorphine-induced circling behavior and tyrosine hydroxylase immunolocalization in the striatum and substantia nigra were investigated 21 and 22days after the last drug infusion, respectively. RESULTS: URB597 prevented the oxidative damage to lipids induced by 3-NP in the striatum, and this effect could account for the attenuation of motor deficits in this model. Attenuation of motor disturbances induced by URB597 in both models was associated with the morphological preservation of the striatum in the 3-NP model and the partial preservation of tyrosine hydroxylase in the 6-OHDA model in the SNpc and striatum. CONCLUSION: The modulatory actions exerted by URB597 in both toxic models support its potential against toxic conditions implying motor and neurochemical alterations linked to energy depletion, excitotoxicity and oxidative stress. Although most of these effects could be attributable to its action on FAAH and further AEA accumulation, in light of our present findings other properties are suggested.
Asunto(s)
Benzamidas/uso terapéutico , Carbamatos/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Síndromes de Neurotoxicidad/tratamiento farmacológico , Amidohidrolasas/antagonistas & inhibidores , Animales , Apomorfina , Conducta Animal/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Inyecciones , Peroxidación de Lípido/efectos de los fármacos , Masculino , Destreza Motora/efectos de los fármacos , Neostriado , Síndromes de Neurotoxicidad/patología , Síndromes de Neurotoxicidad/psicología , Nitrocompuestos , Oxidopamina , Propionatos , Ratas , Ratas WistarRESUMEN
Selective stimulation of carotid chemoreceptors by intravenous infusion of low doses of potassium cyanide (KCN) produces short-lasting escape responses that have been proposed as a model of panic attack. In turn, preclinical studies suggest that facilitation of the endocannabinoid system attenuate panic-like responses. Here, we compared the effects of cannabinoid-related compounds to those of alprazolam, a clinically effective panicolytic, on the duration of the escape reaction induced by intravenous infusion of KCN (80µg) in rats. Alprazolam (1, 2, 4mg/kg) decreased escape duration at doses that did not alter basal locomotor activity. URB597 (0.1, 0.3, 1mg/kg; inhibitor of anandamide hydrolysis), WIN55,212-2 (0.1, 0.3, 1mg/kg; synthetic cannabinoid), arachidonoyl-serotonin (1, 2.5, 5mg/kg; dual TRPV1 and anandamide hydrolysis inhibitor), and cannabidiol (5, 10, 20, 40mg/kg; a phytocannabinoid) did not decrease escape duration. Alprazolam also prevented the increase in arterial pressure evoked by KCN, while bradycardia was unchanged. This study reinforces the validity of the KCN-evoked escape as a model of panic attack. However, it does not support a role for the endocannabinoid system in this behavioral response. These results might have implications for the screening of novel treatments for panic disorder.
Asunto(s)
Alprazolam/uso terapéutico , Cannabinoides/uso terapéutico , Hipnóticos y Sedantes/uso terapéutico , Trastorno de Pánico/tratamiento farmacológico , Analgésicos/uso terapéutico , Animales , Ácidos Araquidónicos/uso terapéutico , Benzamidas/uso terapéutico , Benzoxazinas/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Carbamatos/uso terapéutico , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/toxicidad , Reacción de Fuga/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Locomoción/efectos de los fármacos , Masculino , Ratones , Morfolinas/uso terapéutico , Naftalenos/uso terapéutico , Trastorno de Pánico/inducido químicamente , Cianuro de Potasio/toxicidad , Ratas Wistar , Serotonina/análogos & derivados , Serotonina/uso terapéuticoRESUMEN
BACKGROUND: A high-throughput bioanalytical method using 96-blade thin film microextraction (TFME) and LC-MS/MS for the analysis of repaglinide (RPG) and two of its main metabolites was developed and used for an in vitro metabolism study. RESULTS: The target analytes were extracted from human microsomal medium by a 96-blade-TFME system employing the low-cost prototype 'SPME multi-sampler' using C18 coating. Method validation showed recoveries around 90% for all analytes and was linear over the concentration range of 2-1000 ng ml(-1) for RPG and of 2-500 ng ml(-1) for each RPG metabolite. CONCLUSION: The method was applied to an in vitro metabolism study of RPG employing human liver microsomes and proved to be very useful for this purpose.
Asunto(s)
Carbamatos/uso terapéutico , Cromatografía Liquida/métodos , Hipoglucemiantes/uso terapéutico , Técnicas In Vitro/métodos , Piperidinas/uso terapéutico , Microextracción en Fase Sólida/métodos , Espectrometría de Masas en Tándem/métodos , Carbamatos/administración & dosificación , Humanos , Hipoglucemiantes/administración & dosificación , Piperidinas/administración & dosificaciónRESUMEN
Temporal Lobe Epilepsy (TLE) is a chronic condition characterized by epileptic seizures originating mainly in temporal lobe areas. Epileptogenesis is a process in which a central nervous system injury can lead surviving neuronal populations to generate abnormal, synchronous and recurrent epileptiform discharges producing focal or generalized seizures. Hipocampal sclerosis, a massive cell death in the hippocampal formation and in the other regions of temporal lobe, is considered as hallmark of TLE. Despite the numerous antiepileptic drugs (AEDs) commercially available, about 30-40% of patients remain with seizures refractory to pharmacological treatment. In addition, there is no drug with significant efficacy to modify the epileptogenesis process. In this review we present some data regarding the neuroprotective effect of some adenosinergic agents, erythropoietin and carisbamate regarding the disease- and epileptogenesis-modifying effect.