RESUMO
Sepsis is an organ dysfunction caused by a host's unregulated response to infection, causing long-term brain dysfunction with microglial activation, the release of inflammatory components, and mitochondrial changes. Neuroinflammation can increase the expression of the 18-kD translocator protein (TSPO) in the mitochondria, leading to the activation of the microglia and the release of inflammatory components. The antagonist PK-11195 can modulate TSPO and reduce microglial activation and cognitive damage presented in an animal model of sepsis. The aim of this was to evaluate the effects of PK-11195 on long-term brain inflammation and cognitive impairment in an animal model of sepsis. Wistar rats, 60 days old, were submitted to cecal ligation and puncture (CLP) surgery, divided into groups control/saline, control/PK-11195, sepsis/saline, and sepsis/PK-11195. Immediately after surgery, the antagonist PK-11195 was administered at a dose of 3 mg/kg. Ten days after CLP surgery, the animals were submitted to behavioral tests and determination of brain inflammatory parameters. The sepsis/saline group presented cognitive damage. However, there was damage prevention in animals that received PK-11195. Besides, the sepsis increased the levels of cytokines and M1 microglia markers and caused oxidative damage. However, PK-11195 had the potential to decrease inflammation. These events show that the modulation of neuroinflammation during sepsis by PK-11195, possibly related to changes in TSPO, improves mitochondrial function in the animals' brains. In conclusion, the antagonist PK-11195 attenuated brain inflammation and prevented cognitive impairment in animals subjected to sepsis.
Assuntos
Disfunção Cognitiva/tratamento farmacológico , Isoquinolinas/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Sepse/tratamento farmacológico , Sepse/microbiologia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Citocinas/metabolismo , Isoquinolinas/farmacologia , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Ratos WistarRESUMO
Curine is a bisbenzylisoquinoline alkaloid (BBA) with anti-allergic, analgesic, and anti-inflammatory properties. Previous studies have demonstrated that this alkaloid is orally active at non-toxic doses. However, the mechanisms underlying its anti-inflammatory effects remain to be elucidated. This work aimed to investigate the effects of curine on macrophage activation and neutrophil recruitment. Using a murine model of lipopolysaccharide (LPS)-induced pleurisy, we demonstrated that curine significantly inhibited the recruitment of neutrophils in association with the inhibition of cytokines tumor necrosis factor (TNF-α), interleukin (IL)-1ß, IL-6, monocyte chemotactic protein (CCL2/MCP-1) as well as leukotriene B4 in the pleural lavage of mice. Curine treatment reduced cytokine levels and the expression of iNOS in in vitro cultures of macrophages stimulated with LPS. Treatment with a calcium channel blocker resulted in comparable inhibition of TNF-α and IL-1ß production, as well as iNOS expression by macrophages, suggesting that the anti-inflammatory effects of curine may be related to the inhibition of calcium-dependent mechanisms involved in macrophage activation. In conclusion, curine presented anti-inflammatory effects that are associated with inhibition of macrophage activation and neutrophil recruitment by inhibiting the production of inflammatory cytokines, LTB4 and nitric oxide (NO), and possibly by negatively modulating Ca2+ influx.
Assuntos
Anti-Inflamatórios/uso terapêutico , Inflamação/tratamento farmacológico , Isoquinolinas/uso terapêutico , Ativação de Macrófagos/efeitos dos fármacos , Infiltração de Neutrófilos/efeitos dos fármacos , Animais , Anti-Inflamatórios/farmacologia , Cálcio/metabolismo , Citocinas/imunologia , Modelos Animais de Doenças , Inflamação/induzido quimicamente , Inflamação/imunologia , Isoquinolinas/farmacologia , Lipopolissacarídeos , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismoRESUMO
Wobbler mice are experimental models for amyotrophic lateral sclerosis. As such they show motoneuron degeneration, motor deficits, and astrogliosis and microgliosis of the spinal cord. Additionally, Wobbler mice show increased plasma, spinal cord and brain corticosterone levels and focal adrenocortical hyperplasia, suggesting a pathogenic role for glucocorticoids in this disorder. Considering this endocrine background, we examined whether the glucocorticoid receptor (GR) modulator CORT 113176 prevents spinal cord neuropathology of Wobblers. CORT 113176 shows high affinity for the GR, with low or null affinity for other steroid receptors. We employed five-month-old genotyped Wobbler mice that received s.c. vehicle or 30â¯mg/kg/day for 4â¯days of CORT 113176 dissolved in sesame oil. The mice were used on the 4th day, 2â¯h after the last dose of CORT 113176. Vehicle-treated Wobbler mice presented vacuolated motoneurons, increased glial fibrillary acidic protein (GFAP)+ astrocytes and decreased glutamine synthase (GS)+ cells. There was strong neuroinflammation, shown by increased staining for IBA1+ microglia and CD11b mRNA, enhanced expression of tumor necrosis factor-α, its cognate receptor TNFR1, toll-like receptor 4, the inducible nitric oxide synthase, NFkB and the high-mobility group box 1 protein (HMGB1). Treatment of Wobbler mice with CORT 113176 reversed the abnormalities of motoneurons and down-regulated proinflammatory mediators and glial reactivity. Expression of glutamate transporters GLT1 and GLAST mRNAs and GLT1 protein was significantly enhanced over untreated Wobblers. In summary, antagonism of GR with CORT 113176 prevented neuropathology and showed anti-inflammatory and anti-glutamatergic effects in the spinal cord of Wobbler mice.
Assuntos
Esclerose Lateral Amiotrófica/patologia , Inflamação/tratamento farmacológico , Isoquinolinas/uso terapêutico , Degeneração Neural/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Pirazóis/uso terapêutico , Receptores de Glucocorticoides/antagonistas & inibidores , Medula Espinal/efeitos dos fármacos , Esclerose Lateral Amiotrófica/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Astrócitos/patologia , Modelos Animais de Doenças , Proteína Glial Fibrilar Ácida/metabolismo , Inflamação/metabolismo , Inflamação/patologia , Isoquinolinas/farmacologia , Camundongos , Camundongos Mutantes Neurológicos , Degeneração Neural/metabolismo , Degeneração Neural/patologia , Fármacos Neuroprotetores/farmacologia , Pirazóis/farmacologia , Medula Espinal/metabolismo , Medula Espinal/patologia , Resultado do TratamentoRESUMO
BACKGROUND: The efficacy and safety of asunaprevir + daclatasvir combination therapy for treatment of hepatitis C virus (HCV) in compensated cirrhotic patients was not fully evaluated in real-world. Outcomes were assessed in cirrhotic patients with sustained viral response (SVR). MATERIAL AND METHODS: A total of 145 patients without resistance-associated substitutions (RASs) at L31 and Y93 in the nonstructural protein 5A of HCV genotype 1b, consisting of 49 hepatic cirrhotic and 96 non-cirrhotic patients, were enrolled to the therapy. The patients were treated with 100 mg asunaprevir twice daily plus 60 mg daclatasvir once daily for 24 weeks. The primary endpoint was SVR 24 weeks after completing treatment. In addition, we evaluated the improvement of liver function and development of HCC for 1 year from the end of treatment (EOT). RESULTS: The SVR24 rate was 96% (47/49) in the cirrhotic group and 96% (91/95) in the non-cirrhotic group (p = 0.69). During treatment, grade III/IV adverse events occurred more frequently in cirrhotic patients (10/49; 20.4%) than in non-cirrhotic patients (10/96; 10.4%) (p = 0.099). After EOT, alanine aminotransferase and AFP levels were significantly decreased in cirrhotic patients with SVR. In addition, serum levels of albumin and platelet counts were significantly increased. On the other hand, the rates of HCC recurrence (43%) and development (7.4%) were higher in cirrhotic patients than in the non-cirrhotic patients (12.5% and 1.1%, respectively). CONCLUSION: RAS-oriented asunaprevir/daclatasvir therapy has a strong anti-HCV effect in patients with HCV genotype 1b. However, careful management is necessary in patients with cirrhosis.
Assuntos
Antivirais/uso terapêutico , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Imidazóis/uso terapêutico , Isoquinolinas/uso terapêutico , Cirrose Hepática/tratamento farmacológico , Sulfonamidas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antivirais/efeitos adversos , Carbamatos , Carcinoma Hepatocelular/virologia , Farmacorresistência Viral/genética , Quimioterapia Combinada , Feminino , Genótipo , Hepacivirus/genética , Hepatite C Crônica/complicações , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/virologia , Humanos , Imidazóis/efeitos adversos , Isoquinolinas/efeitos adversos , Japão , Cirrose Hepática/diagnóstico , Cirrose Hepática/virologia , Testes de Função Hepática , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Pirrolidinas , Recuperação de Função Fisiológica , Fatores de Risco , Sulfonamidas/efeitos adversos , Resposta Viral Sustentada , Fatores de Tempo , Resultado do Tratamento , Valina/análogos & derivados , Proteínas não Estruturais Virais/genéticaRESUMO
Abstract: Background. Daclatasvir and asunaprevir dual therapy is approved for the treatment of HCV genotype 1b infection in several countries. Aim. To evaluate the efficacy and safety of daclatasvir and asunaprevir dual therapy in Turkish patients. Material and methods. Sixty-one patients with HCV genotype 1b were enrolled in the Turkish early access program. Most of the patients were in difficult-to-treat category. Patients were visited at each 4 week throughout the follow-up period. Laboratory findings and adverse events were recorded at each visit. Results. Fifty-seven of 61 enrolled patients completed 24 weeks of treatment. Two patients died as a result of underlying diseases at 12-14th weeks of treatment. Two patients stopped the treatment early as a consequence of virological breakthrough, and 2 patients had viral relapse at the post-treatment follow-up. Overall SVR12 rates were 90% (55/61) and 93.2% (55/59) according to intention-to-treat (ITT) and per protocol (PP) analysis respectively. In ITT analysis, SVR12 was achieved by 93% (13/14) in relapsers, 80% (12/15) in interferon-ineligible patients and 91% (20/22) in previous nonresponder patients. SVR12 rates were 86.5% and 91.4% in patients with cirrhosis according to ITT and PP analysis respectively. SVR12 was 95.8% in non-cirrhosis group in both analysis. Patients with previous protease inhibitor experience had an SVR12 of 87.5%. Common adverse events developed in 28.8% of patients. There were no treatment related severe adverse event or grade-4 laboratory abnormality. Conclusions. Daclatasvir and asunaprevir dual therapy is found to be effective and safe in difficult-to-treat Turkish patients with HCV genotype 1b infection.
Assuntos
Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Antivirais/uso terapêutico , Sulfonamidas/uso terapêutico , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Acessibilidade aos Serviços de Saúde , Imidazóis/uso terapêutico , Isoquinolinas/uso terapêutico , Antivirais/economia , Antivirais/efeitos adversos , Sulfonamidas/economia , Sulfonamidas/efeitos adversos , Fatores de Tempo , Turquia , RNA Viral/genética , Avaliação de Programas e Projetos de Saúde , Resultado do Tratamento , Custos de Medicamentos , Análise Custo-Benefício , Hepacivirus/genética , Carga Viral , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/economia , Hepatite C Crônica/virologia , Quimioterapia Combinada , Genótipo , Acessibilidade aos Serviços de Saúde/economia , Imidazóis/economia , Imidazóis/efeitos adversos , Isoquinolinas/economia , Isoquinolinas/efeitos adversosRESUMO
Background. Daclatasvir and asunaprevir dual therapy is approved for the treatment of HCV genotype 1b infection in several countries. AIM: To evaluate the efficacy and safety of daclatasvir and asunaprevir dual therapy in Turkish patients. MATERIAL AND METHODS: Sixty-one patients with HCV genotype 1b were enrolled in the Turkish early access program. Most of the patients were in difficult-to-treat category. Patients were visited at each 4 week throughout the follow-up period. Laboratory findings and adverse events were recorded at each visit. RESULTS: Fifty-seven of 61 enrolled patients completed 24 weeks of treatment. Two patients died as a result of underlying diseases at 12-14th weeks of treatment. Two patients stopped the treatment early as a consequence of virological breakthrough, and 2 patients had viral relapse at the post-treatment follow-up. Overall SVR12 rates were 90% (55/61) and 93.2% (55/59) according to intention-to-treat (ITT) and per protocol (PP) analysis respectively. In ITT analysis, SVR12 was achieved by 93% (13/14) in relapsers, 80% (12/15) in interferon-ineligible patients and 91% (20/22) in previous nonresponder patients. SVR12 rates were 86.5% and 91.4% in patients with cirrhosis according to ITT and PP analysis respectively. SVR12 was 95.8% in non-cirrhosis group in both analysis. Patients with previous protease inhibitor experience had an SVR12 of 87.5%. Common adverse events developed in 28.8% of patients. There were no treatment related severe adverse event or grade-4 laboratory abnormality. CONCLUSIONS: Daclatasvir and asunaprevir dual therapy is found to be effective and safe in difficult-to-treat Turkish patients with HCV genotype 1b infection.
Assuntos
Antivirais/uso terapêutico , Acessibilidade aos Serviços de Saúde , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Imidazóis/uso terapêutico , Isoquinolinas/uso terapêutico , Sulfonamidas/uso terapêutico , Idoso , Antivirais/efeitos adversos , Antivirais/economia , Carbamatos , Análise Custo-Benefício , Custos de Medicamentos , Quimioterapia Combinada , Feminino , Genótipo , Acessibilidade aos Serviços de Saúde/economia , Hepacivirus/genética , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/economia , Hepatite C Crônica/virologia , Humanos , Imidazóis/efeitos adversos , Imidazóis/economia , Isoquinolinas/efeitos adversos , Isoquinolinas/economia , Masculino , Pessoa de Meia-Idade , Avaliação de Programas e Projetos de Saúde , Pirrolidinas , RNA Viral/genética , Sulfonamidas/efeitos adversos , Sulfonamidas/economia , Fatores de Tempo , Resultado do Tratamento , Turquia , Valina/análogos & derivados , Carga ViralRESUMO
INTRODUCTION: Daclatasvir and Asunaprevir (DCV/ASV) have recently been approved for the treatment of chronic hepatitis C virus infection. In association, they are more effective and safer than previous available treatments, but more expensive. It is unclear if paying for the additional costs is an efficient strategy considering limited resources. METHODS: A Markov model was built to estimate the expected costs in Chilean pesos (CL$) and converted to US dollars (US$) and benefits in quality adjusted life years (QALYs) in a hypothetic cohort of naive patients receiving DCV/ASV compared to protease inhibitors (PIs) and Peginterferon plus Ribavirin (PR). Efficacy was obtained from a mixed-treatment comparison study and costs were estimated from local sources. Utilities were obtained applying the EQ-5D survey to local patients and then valued with the Chilean tariff. A time horizon of 46 years and a discount rate of 3% for costs and outcomes was considered. The ICERs were estimated for a range of DCV/ASV prices. Deterministic and probabilistic sensitivity analyses were performed. RESULTS: PIs were extendedly dominated by DCV/ASV. The ICER of DCV/ASV compared to PR was US$ 16,635/QALY at a total treatment price of US$ 77,419; US$11,581 /QALY at a price of US$ 58,065; US$ 6,375/QALY at a price of US$ 38,710; and US$ 1,364 /QALY at a price of US$ 19,355. The probability of cost-effectiveness at a price of US$ 38,710 was 91.6% while there is a 21.43% probability that DCV/ASV dominates PR if the total treatment price was US$ 19,355. Although the results are sensitive to certain parameters, the ICER did not increase above the suggested threshold of 1 GDP per capita. CONCLUSIONS: DCV/ASV can be considered cost-effective at any price of the range studied. These results provide decision makers useful information about the value of incorporating these drugs into the public Chilean healthcare system.
Assuntos
Antivirais/uso terapêutico , Análise Custo-Benefício , Genótipo , Hepacivirus/genética , Hepacivirus/fisiologia , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/economia , Carbamatos , Chile , Quimioterapia Combinada , Humanos , Imidazóis/uso terapêutico , Interferon-alfa/uso terapêutico , Isoquinolinas/uso terapêutico , Polietilenoglicóis/uso terapêutico , Probabilidade , Inibidores de Proteases/uso terapêutico , Pirrolidinas , Qualidade de Vida , Proteínas Recombinantes/uso terapêutico , Ribavirina/uso terapêutico , Sulfonamidas/uso terapêutico , Valina/análogos & derivadosAssuntos
Aprovação de Drogas , Tratamento Farmacológico/enfermagem , Ácidos Carbocíclicos , Benzoxazinas/uso terapêutico , Compostos de Boro/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Cefalosporinas/uso terapêutico , Ciclopentanos/uso terapêutico , Combinação de Medicamentos , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Guanidinas/uso terapêutico , Humanos , Imidazóis/uso terapêutico , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Interferon beta/uso terapêutico , Isoquinolinas/uso terapêutico , Ácido Penicilânico/análogos & derivados , Ácido Penicilânico/uso terapêutico , Polietilenoglicóis/uso terapêutico , Piridinas/uso terapêutico , Quinuclidinas/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Tazobactam , Triazóis/uso terapêutico , Estados Unidos , United States Food and Drug AdministrationRESUMO
RATIONALE: Systemic treatment with NMDA receptor (NMDAR) antagonists, inhibitors of neuronal nitric oxide synthase (nNOS) or of soluble guanylyl cyclase (sGC), induce antidepressant-like effects in rats. Increased levels of glutamate and nitric oxide (NO) in the medial prefrontal cortex (MPFC) of stressed animals have been described in the literature. However, the role of the NMDAR-nNOS-sGC pathway of the MPFC in the mediation of forced swim-induced behaviors remains unclear. OBJECTIVE: The aim of this work was to test the hypothesis that the inhibition of the NMDAR-nNOS-sGC pathway in the ventral MPFC (infralimbic (IL) or prelimbic (PL)) would elicit antidepressant-like effects in the forced swim test (FST). METHODS: Rats implanted with cannulae aimed at the PL or the IL were exposed to the FST and injected with LY235959 (NMDAR antagonist), NPA (nNOS inhibitor), ODQ (sGC inhibitor), or carboxy-PTIO (NO scavenger). Additional groups received the AMPA antagonist, NBQX, before the effective doses of LY235959 or NPA. RESULTS: LY235959 administration into PL or IL before the FS pretest produced no effects. Administration of LY235959 (3 and 10 nmol/0.2 µL) after pretest was effective only when administered into the PL. However, the administration of NPA (0.01 nmol/0.2 µL), c-PTIO (1.0 nmol/0.2 µL), and ODQ (1.0 nmol/0.2 µL) into the PL or IL before the FST produced antidepressant-like effects. NBQX blocked the antidepressant-like effect of LY235959 but not of NPA. CONCLUSION: Blocking NMDAR or NO signaling in the vMPFC, either in the IL or the PL, induces antidepressant-like effects in the rat FST. These effects seemingly occur through independent mechanisms, since NBQX blocked the former effect but not the latter.
Assuntos
Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Óxido Nítrico Sintase Tipo I/antagonistas & inibidores , Córtex Pré-Frontal/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Natação , Animais , Antidepressivos/farmacologia , Depressão/metabolismo , Depressão/psicologia , Relação Dose-Resposta a Droga , Isoquinolinas/farmacologia , Isoquinolinas/uso terapêutico , Masculino , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo I/metabolismo , Córtex Pré-Frontal/metabolismo , Quinoxalinas/farmacologia , Quinoxalinas/uso terapêutico , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/metabolismo , Natação/psicologiaRESUMO
Curine is a natural alkaloid isolated from Chondrodendron platyphyllum and it has been reported that this alkaloid has vasodilatory and anti-inflammatory effects. The aim of this study is to analyze the cytotoxic effects of curine in cancer cell lines HL-60, K562, and HT-29, and in primary cultures of peripheral blood mononuclear cells (PBMC). Cells were treated with curine (from 3 to 15 µM) for 24 and 48 h. Cell viability was analyzed by the 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test and flow cytometry with propidium iodide (PI) assay. To assess the type of cell death induced in HL-60, the cell cycle, morphological, and biochemical alterations were analyzed, which were determined by differential staining with acridine orange/ethidium bromide, and annexin V/PI double-labeling and change in mitochondrial membrane potential assays. Curine demonstrated a potent cytotoxic effect on leukemic cell lines (HL-60 and K562). Its cytotoxic effects in HL-60 cells was related to plasma membrane damage and cell cycle arrest at the G1 phase from 43.4 ± 1.0 to 56.7 ± 1.4 % (p < 0.05). Curine (15 µM) also increased the apoptotic cells number by around 60 % in HL-60 cells and caused phosphatidylserine externalization, inducing about 57 % of apoptosis. Moreover, this alkaloid provoked 20 % of mitochondrial membrane depolarization. We conclude that curine presented a cytotoxic effect and induced apoptosis in HL-60 cells. Thus, it can be considered a promising pharmacological drug.