RESUMO
Silymarin is proclaimed to be a blend of flavonolignans or phytochemicals. An era of new generation of direct-acting antivirals (DAAs) has commenced to have facet effect in swaying of the hepatitis C virus (HCV). Nonetheless, this therapy has serious side effects that jeopardize its efficacy. This study is aimed at probing the effects of ribavirin (RBV) and sofosbuvir (SOF) along with silymarin as an adjunct therapy on hematological parameters and markers of obscured oxidative stress. The effect of DAAs along with silymarin was also examined on variable sex hormone level and liver function markers such as alanine aminotransferase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), and bilirubin. The study was followed to determine viral load and viral genotypes. A total of 30 patients were randomly divided into two equal groups comprising the control group (n = 15) and treatment group (n = 15). The control group was solely administered with DAAs (SOF and RBV; 400 mg/800 mg each/day). Conversely, the treatment group was dispensed with DAAs, but with adjunct therapy of silymarin (400 mg/day) along with DAAs (400/800 mg/day) over period of 8 weeks. Sampling of blood was performed at pre- and posttreatment levels for the evaluation of different propound parameters. Our data showed that silymarin adjunct therapy enhances the efficiency of DAAs. A decrease in menace level of liver markers such as ALT, ALP, AST, and bilirubin was observed (p > 0.05). The adjunct therapy concurrently also demonstrated an ameliorative effect on hematological indices and oxidative markers, for instance, SOD, TAS, GSH, GSSG, and MDA (p < 0.05), diminishing latent viral load. The silymarin administration was also found to revamp the fluster level of sex hormones. Our outcomes provide evidence that systematic administration of silymarin effectively remits deviant levels of hematological, serological, hormonal, and antioxidant markers. This demonstrates a possibly unique role of silymarin in mitigating hepatitis C.
Assuntos
Antioxidantes/administração & dosagem , Antivirais/administração & dosagem , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Compostos Fitoquímicos/administração & dosagem , Fitoterapia/métodos , Ribavirina/administração & dosagem , Silimarina/administração & dosagem , Sofosbuvir/administração & dosagem , Adolescente , Adulto , Estudos de Casos e Controles , Quimioterapia Combinada/métodos , Feminino , Genótipo , Hepatite C Crônica/metabolismo , Hepatite C Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo/efeitos dos fármacos , Resultado do Tratamento , Carga Viral , Adulto JovemRESUMO
This trial compared the rate and time of viral clearance in subjects receiving a combination of nitazoxanide, ribavirin, and ivermectin plus Zinc versus those receiving supportive treatment. This non-randomized controlled trial included 62 patients on the triple combination treatment versus 51 age- and sex-matched patients on routine supportive treatment. all of them confirmed cases by positive reverse-transcription polymerase chain reaction of a nasopharyngeal swab. Trial results showed that the clearance rates were 0% and 58.1% on the 7th day and 13.7% and 73.1% on the 15th day in the supportive treatment and combined antiviral groups, respectively. The cumulative clearance rates on the 15th day are 13.7% and 88.7% in the supportive treatment and combined antiviral groups, respectively. This trial concluded by stating that the combined use of nitazoxanide, ribavirin, and ivermectin plus zinc supplement effectively cleared the SARS-COV2 from the nasopharynx in a shorter time than symptomatic therapy.
Assuntos
Tratamento Farmacológico da COVID-19 , Ivermectina/uso terapêutico , Nitrocompostos/uso terapêutico , Ribavirina/uso terapêutico , SARS-CoV-2 , Tiazóis/uso terapêutico , Zinco/uso terapêutico , Adulto , Antimetabólitos/administração & dosagem , Antimetabólitos/uso terapêutico , Antiparasitários/administração & dosagem , Antiparasitários/uso terapêutico , Feminino , Humanos , Ivermectina/administração & dosagem , Masculino , Nitrocompostos/administração & dosagem , Ribavirina/administração & dosagem , Tiazóis/administração & dosagem , Oligoelementos/administração & dosagem , Oligoelementos/uso terapêutico , Zinco/administração & dosagemRESUMO
OBJECTIVE: To investigate synergistic effect of Reduning (RDN) injection plus ribavirin against severe pneumonia induced by H1N1 influenza A virus in mice. METHODS: We established a mouse model of severe pneumonia induced by influenza A virus by infecting Balb/c mice with CA07 virus. We randomly assigned the infected mice into four groups, and treated them with normal saline (NS group), RDN (injection, 86.6 mg/kg), ribavirin (injection, 66.6 mg/kg) or double Ribavirin plus RDN group, the same dosage as used in the single treatments) for 5 d. Lung index and lung pathology were recorded or calculated in terms of the curative effective. Cytokines, NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome related protein including caspase-associated recruitment domain (CARD) domain Apoptosis-associated speck-like protein containing a caspase recruitment domain(ASC), caspase-1 and NOD-like receptor family, pyrin domain containing 3 (NLRP3), and reactive oxygen species were simultaneously investigated. RESULTS: RDN plus ribavirin treatment, not RDN or ribavirin alone, provided a significant survival benefit to the influenza A virus-infected mice. The combination treatment protected the mice against severe influenza infection by attenuating the severe lung injury. The combined treatment also reduced the viral titers in mouse lungs and lung index, downregulated their immunocytokine levels, including IL-1ß and IL-18, and down regulated the NLRP3, especially the transcription and translation of caspase-1. Meanwhile NS group had significantly higher reactive oxygen species (ROS) expression which could was dramatically reduced by the treatment of RDN plus ribavirin. CONCLUSION: Our study showed that RDN combined with ribavirin could protect the mice, and reduce the lung immunopathologic damage caused by severe influenza pneumonia. The mechanism could be that it reduced ROS produce and inhibited NLRP3 inflammasome activation so that mainly lower the downstream inflammatory cytokines IL-1ß and IL-18.
Assuntos
Medicamentos de Ervas Chinesas/administração & dosagem , Vírus da Influenza A Subtipo H1N1/fisiologia , Pneumonia/tratamento farmacológico , Ribavirina/administração & dosagem , Animais , Sinergismo Farmacológico , Quimioterapia Combinada , Feminino , Humanos , Vírus da Influenza A Subtipo H1N1/genética , Influenza Humana/complicações , Influenza Humana/virologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Interleucina-8/genética , Interleucina-8/imunologia , Pulmão/imunologia , Pulmão/virologia , Camundongos , Camundongos Endogâmicos BALB C , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Pneumonia/etiologia , Pneumonia/genética , Pneumonia/imunologiaRESUMO
BACKGROUND: At present, coronavirus disease 2019 (COVID-19) has spread in many countries. We conducted this study to help pediatricians understand the conditions of COVID-19 in children. METHODS: We retrospectively summarized the characteristics, treatment and outcomes of pediatric cases in Wuhan Children's Hospital which was the only designated hospital for children with COVID-19 in Hubei Province. A Cox proportional hazards regression analysis was used to evaluate factors associated with clinical outcomes. RESULTS: As of February 29, 75 children had been discharged, of which only one was has severe pneumonia and one was critical cases. Children younger than 2 years were more susceptible to COVID-19. All patients have received interferon-α nebulization, and eight cases including the severe and critical cases were co-administrated ribavirin. Five patients with mild pneumonia were given arbidol. Twenty-three patients were given traditional Chinese medicine (TCM). The average length of stay (LOS) and the time of SARS-CoV-2 clearance were 10.57 and 6.39 days, respectively. None of the factors was associated with LOS or time of SARS-CoV-2 clearance. CONCLUSIONS: The severity of COVID-19 in pediatric cases were milder than adults. The efficacy of the antiviral therapy in children with COVID-19 remains to be evaluated.
Assuntos
Antivirais/uso terapêutico , Betacoronavirus/fisiologia , Infecções por Coronavirus/tratamento farmacológico , Suscetibilidade a Doenças , Pneumonia Viral/tratamento farmacológico , Adolescente , COVID-19 , Criança , Pré-Escolar , China , Infecções por Coronavirus/virologia , Feminino , Hospitais Pediátricos , Humanos , Lactente , Interferon-alfa/administração & dosagem , Tempo de Internação , Masculino , Pandemias , Pediatras , Pneumonia Viral/virologia , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Ribavirina/administração & dosagem , SARS-CoV-2 , Índice de Gravidade de DoençaRESUMO
BACKGROUND & OBJECTIVES: The effect of vitamin D supplementation on response to antiviral therapy in hepatitis C virus (HCV) genotype 1 and 4 infection still remains unclear, with studies yielding inconsistent results. The aim of the present study was to assess the effect of vitamin D supplementation on treatment outcome in patients with genotype 1/4 chronic hepatitis C (CHC) infection. METHODS: Sixty consecutive, treatment-naïve, genotype 1 and 4 chronic HCV patients were included in the study. The patients were randomized into two groups: Vitamin D supplemented group received pegylated (PEG)-interferon α-2a 180 µg per week plus ribavirin (RBV) (1000-1200 mg/d) together with vitamin D3 (2000 IU/d) and control group received identical therapy without vitamin D (32 patients). RESULTS: There were no significant differences between the two groups in terms of age, sex, body mass index and baseline laboratory values. Lower vitamin D levels were associated with higher grades of fibrosis in liver histology (vitamin D >20 ng/ml - 70% vs vitamin D <20 ng/ml - 37%, P<0.05). Vitamin D supplemented group had similar rapid viral response (40 vs 28%, P=0.36), complete early viral response (53.2 vs 40%, P=0.34), end of treatment response (64 vs 46%, P=0.17) and sustained virological response (SVR) (60 vs 44%, P=0.19) as compared to control group. Interleukin 28B polymorphism [odds ratio (OR)-15.37, 95% confidence interval (CI)-2.32-101.76, P=0.04] and baseline serum vitamin D levels (OR-6.36, 95% CI-1.36-29.61 P=0.02) were independent predictors of SVR in genotype 1/4 CHC. Vitamin D supplementation was not found to be predictor of response in genotype 1/4 CHC on multivariate analysis (OR-2.79, 95% CI- 0.63-12.34, P=0.74). INTERPRETATION & CONCLUSIONS: The present study showed that addition of vitamin D to PEG/RBV combination therapy in treatment-naïve patients who were infected with HCV genotype 1/4 had no effect on the rates of rapid, early and sustained viral responses.
Assuntos
Suplementos Nutricionais , Hepatite C Crônica/dietoterapia , Fígado/efeitos dos fármacos , Vitamina D/administração & dosagem , Adulto , Feminino , Genótipo , Hepacivirus/efeitos dos fármacos , Hepacivirus/patogenicidade , Hepatite C Crônica/genética , Hepatite C Crônica/patologia , Hepatite C Crônica/virologia , Humanos , Índia/epidemiologia , Interferon-alfa/administração & dosagem , Fígado/patologia , Fígado/virologia , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/administração & dosagem , RNA Viral/genética , Proteínas Recombinantes/administração & dosagem , Ribavirina/administração & dosagem , Resposta Viral Sustentada , Resultado do Tratamento , Carga Viral/genéticaRESUMO
In many countries, vaccines are used for the prevention of foot-and-mouth disease (FMD). However, because there is no protection against FMD immediately after vaccination, research and development on antiviral agents is being conducted to induce protection until immunological competence is produced. This study tested whether well-known chemicals used as RNA virus treatment agents had inhibitory effects on FMD viruses (FMDVs) and demonstrated that ribavirin showed antiviral effects against FMDV in vitro/in vivo. In addition, it was observed that combining the administration of the antiviral agents orally and complementary therapy with vaccines synergistically enhanced antiviral activity and preserved the survival rate and body weight in the experimental animals. Antiviral agents mixed with an adjuvant were inoculated intramuscularly along with the vaccines, thereby inhibiting virus replication after injection and verifying that it was possible to induce early protection against viral infection prior to immunity being achieved through the vaccine. Finally, pigs treated with antiviral agents and vaccines showed no clinical signs and had low virus excretion. Based on these results, it is expected that this combined approach could be a therapeutic and preventive treatment for early protection against FMD.
Assuntos
Antivirais/uso terapêutico , Vírus da Febre Aftosa , Febre Aftosa/prevenção & controle , Ribavirina/uso terapêutico , Vacinas Virais/uso terapêutico , Animais , Antivirais/administração & dosagem , Linhagem Celular , Sinergismo Farmacológico , Febre Aftosa/tratamento farmacológico , Injeções Intramusculares , Injeções Intraperitoneais , Camundongos , Camundongos Endogâmicos C57BL , Ribavirina/administração & dosagem , Suínos , Porco Miniatura , Vacinas Virais/administração & dosagemRESUMO
Elbasvir (EBR; HCV NS5A inhibitor) and grazoprevir (GZR; HCV NS3/4A protease inhibitor) are approved as a fixed-dose combination to treat patients chronically infected with HCV genotypes 1 and 4. During the development programme and supported by in vitro potency, the efficacy of EBR+GZR was assessed in HCV GT3-infected patients. This study's aim was to determine the efficacy and tolerability of 12 or 18 weeks of EBR+GZR with ribavirin (RBV) in treatment-naïve, noncirrhotic HCV GT3-infected patients. Randomized patients received open-label EBR (50 mg once daily) + GZR (100 mg once daily) + RBV. The primary efficacy objective was to evaluate the sustained virologic response rates 12 weeks after the end of all study therapy (SVR12). SVR12 rates (95% confidence interval) were 45.0% (23.1, 68.5) and 57.1% (34.0, 78.2) after treatment with EBR+GZR+RBV for 12 weeks or 18 weeks, respectively. On-treatment virologic failure was observed in 41% (17 of 41) of patients. At virologic failure, resistance-associated substitutions (RASs) with a >five-fold shift in potency occurred in the NS3 region in six (35%) patients and in the NS5A region in 16 (94%) patients. The most common RAS at virologic failure was Y93H in NS5A which was identified in 13 of 17 (76%) patients. The efficacy of EBR+GZR+RBV was suboptimal in HCV GT3-infected patients due to a high rate of on-treatment virologic failure and treatment-emergent RASs which demonstrates an inadequate barrier to the development of GT3 resistance. However, rapid viral clearance demonstrated the antiviral activity of EBR+GZR+RBV in GT3-infected patients.clinicaltrials.gov: NCT01717326.
Assuntos
Antivirais/uso terapêutico , Benzofuranos/uso terapêutico , Genótipo , Hepacivirus/genética , Hepatite C/tratamento farmacológico , Hepatite C/virologia , Imidazóis/uso terapêutico , Quinoxalinas/uso terapêutico , Ribavirina/uso terapêutico , Adulto , Idoso , Amidas , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Benzofuranos/administração & dosagem , Benzofuranos/efeitos adversos , Carbamatos , Ciclopropanos , Farmacorresistência Viral , Quimioterapia Combinada , Feminino , Hepacivirus/efeitos dos fármacos , Humanos , Imidazóis/administração & dosagem , Imidazóis/efeitos adversos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Mutação , Quinoxalinas/administração & dosagem , Quinoxalinas/efeitos adversos , RNA Viral , Ribavirina/administração & dosagem , Ribavirina/efeitos adversos , Sulfonamidas , Fatores de Tempo , Falha de Tratamento , Resultado do Tratamento , Carga ViralRESUMO
AIM: To quantify drug-drug-interactions (DDIs) encountered in patients prescribed hepatitis C virus (HCV) treatment, the interventions made, and the time spent in this process. METHODS: As standard of care, a clinical pharmacist screened for DDIs in patients prescribed direct acting antiviral (DAA) HCV treatment between November 2013 and July 2015 at the University of Colorado Hepatology Clinic. HCV regimens prescribed included ledipasvir/sofosbuvir (LDV/SOF), paritaprevir/ritonavir/ombitasvir/dasabuvir (OBV/PTV/r + DSV), simeprevir/sofosbuvir (SIM/SOF), and sofosbuvir/ribavirin (SOF/RBV). This retrospective analysis reviewed the work completed by the clinical pharmacist in order to measure the aims identified for the study. The number and type of DDIs identified were summarized with descriptive statistics. RESULTS: Six hundred and sixty four patients (83.4% Caucasian, 57% male, average 56.7 years old) were identified; 369 for LDV/SOF, 48 for OBV/PTV/r + DSV, 114 for SIM/SOF, and 133 for SOF/RBV. Fifty-one point five per cent of patients were cirrhotic. Overall, 5217 medications were reviewed (7.86 medications per patient) and 781 interactions identified (1.18 interactions per patient). The number of interactions were fewest for SOF/RBV (0.17 interactions per patient) and highest for OBV/PTV/r + DSV (2.48 interactions per patient). LDV/SOF and SIM/SOF had similar number of interactions (1.28 and 1.48 interactions per patient, respectively). Gastric acid modifiers and vitamin/herbal supplements commonly caused interactions with LDV/SOF. Hypertensive agents, analgesics, and psychiatric medications frequently caused interactions with OBV/PTV/r + DSV and SIM/SOF. To manage these interactions, the pharmacists most often recommended discontinuing the medication (28.9%), increasing monitoring for toxicities (24.1%), or separating administration times (18.2%). The pharmacist chart review for each patient usually took approximately 30 min, with additional time for more complex patients. CONCLUSION: DDIs are common with HCV medications and management can require medication adjustments and increased monitoring. An interdisciplinary team including a clinical pharmacist can optimize patient care.
Assuntos
Antivirais/uso terapêutico , Interações Medicamentosas , Hepatite C Crônica/tratamento farmacológico , Analgésicos , Quimioterapia Combinada , Feminino , Hepacivirus/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Farmacêuticos , Farmácia/métodos , Estudos Retrospectivos , Ribavirina/administração & dosagem , Simeprevir/administração & dosagem , Sofosbuvir/administração & dosagem , Resultado do TratamentoRESUMO
BACKGROUND: Hepatitis C virus infection and interferon treatment are often associated with anxiety, depressive symptoms and poor health-related quality of life. To evaluate the Silybin-vitamin E-phospholipids complex effect on work ability and whether health related factors (anxiety and depression) were associated with work ability in subjects with chronic hepatitis C treated with Pegylated-Interferon-α2b (Peg-IFN) and Ribavirin (RBV). METHODS: Thirty-one patients (Group A) with chronic hepatitis and other 31 subjects in Group B were recruited in a randomized, prospective, placebo controlled, double blind clinical trial. Group A received 1.5 mg/kg per week of Peg-IFN plus RBV and placebo, while Group B received the same dosage of Peg-IFN plus RBV plus association of Silybin 94 mg + vitamin E 30 mg + phospholipids 194 mg in pills for 12 months. All subjects underwent to laboratory exams and questionnaires to evaluate depression (Beck Depression Inventory - BDI), anxiety (State-trait anxiety inventory - STAI) and work ability (Work ability Index - WAI). RESULTS: The comparison between group A and group B showed significant differences after 6 months in ALT (P < 0.001), and viremia (P < 0.05), after 12 months in ALT (P < 0.001), and AST (P < 0.001), at follow up in AST (P < 0.05), and ALT (P < 0.001). Significant difference were observed after 1 month in WAI (p < 0.001) and BDI (P < 0.05), after 6 months in WAI (P < 0.05) and STAI (P < 0.05), after 12 months and at follow up in WAI, STAI and BDI (p < 0.01). CONCLUSIONS: The supplementation with Silybin-vitamin E -phospholipids complex increased work ability and reduced depression and anxiety in patients treated with Peg-IFN and RBV. TRIAL REGISTRATION: NCT01957319 , First received: September 25, 2013. Last updated: September 30, 2013 (retrospectively registered).
Assuntos
Ansiedade , Depressão , Hepatite C Crônica , Interferon-alfa/administração & dosagem , Ribavirina/administração & dosagem , Silimarina/administração & dosagem , Adulto , Antioxidantes/administração & dosagem , Antivirais/administração & dosagem , Ansiedade/complicações , Ansiedade/diagnóstico , Ansiedade/fisiopatologia , Depressão/complicações , Depressão/diagnóstico , Depressão/fisiopatologia , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/psicologia , Humanos , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Silibina , Resultado do Tratamento , Desempenho ProfissionalRESUMO
This study aimed to evaluate the clinical efficacy and safety of using the traditional Chinese herbal medicine Scutellaria baicalensis for the treatment of severe HFMD in 725 patients aged >1 year in a multicenter, retrospective analysis. The patients were divided into the S. baicalensis and ribavirin groups, and the temperatures, presence or absence of skin rashes and oral lesions, nervous system (NS) involvement, and viral loads of the patients, as well as the safety of the treatments, were evaluated. The median duration of fever, median time to NS involvement, and the number of patients with oral ulcers and/or vesicles, as well as skin rashes, were decreased in the S. baicalensis group compared with the ribavirin group. In addition, the EV71 viral loads were decreased in the S. baicalensis group, suggesting that S. baicalensis exerted more potent antiviral effects compared with ribavirin. The present study demonstrated that S. baicalensis was suitable for the treatment of severe HFMD in patients aged >1 year, since it was shown to rapidly relieve fever, attenuate oral lesions and rashes, and improve NS involvement. Furthermore, it was demonstrated to be relatively safe for topical application.
Assuntos
Encefalite Viral/tratamento farmacológico , Enterovirus Humano A , Infecções por Enterovirus/tratamento farmacológico , Doença de Mão, Pé e Boca/tratamento farmacológico , Doença de Mão, Pé e Boca/virologia , Extratos Vegetais/administração & dosagem , Antivirais/administração & dosagem , China , Medicamentos de Ervas Chinesas/administração & dosagem , Encefalite Viral/diagnóstico , Encefalite Viral/virologia , Infecções por Enterovirus/diagnóstico , Infecções por Enterovirus/virologia , Feminino , Doença de Mão, Pé e Boca/diagnóstico , Humanos , Lactente , Masculino , Estudos Retrospectivos , Ribavirina/administração & dosagem , Scutellaria baicalensis/química , Resultado do TratamentoRESUMO
OBJECTIVE: To investigate the effects of ribavirin administration combined with Reduning in a mouse model of influenza A (H1N1)-induced severe pneumonia. METHODS: Influenza A/Beijing/501/2009 (H1N1)-infected C57BL/6 mice were randomly divided into four experimental groups treated with either a mock injection of phosphate-buffered saline (PBS), ribavirin (66.6 mg/kg daily) or Reduning (86.6 mg/ kg daily), or a combination of both, for 7 days. Mice were monitored for clinical signs and survival, and body weight was measured daily for 14 days. Virus titer, lung wet-to-dry ratios, pathology and cytokines including interleukin (IL)-6, IL-10, and interferon (IFN)-γ were assayed on different days. RESULTS: In the untreated group injected with phosphate buffer saline, all the mice died of the infection. The survival rate of mice treated with Reduning was only 10%, whereas 100% of the ribavirin- and the combination-treated mice survived. Low lung viral loads indicated that ribavirin significantly inhibited virus replication, whereas Reduning did not. Lung wet-to-dry ratios demonstrated that both ribavirin and Reduning, administered together or separately, reduced acute lung edema compared with results in the untreated group. Pathology analyses also showed that treatment with a combination of both drugs relieved pathological lesions, whereas the single drug treatment did not. Levels of IL-6, IL-10 and IFN-γ in mice treated with ribavirin or the combination of both ribavirin and Reduning were all significantly lower than in the untreated group, especially in the combination-treated group. In addition, Reduning administration significantly decreased both IL-6 and IL-10 production but had no effect on IFN-γ. CONCLUSION: Due to the synergistic effect of antiviral and antiinflammation, the combination of ribavirin and Reduning could be an effective treatment for severe H1N1 which was considered to be significant to delayed antiviral and drug resistant.
Assuntos
Antivirais/administração & dosagem , Medicamentos de Ervas Chinesas/administração & dosagem , Vírus da Influenza A Subtipo H1N1/fisiologia , Influenza Humana/tratamento farmacológico , Pneumonia/tratamento farmacológico , Ribavirina/administração & dosagem , Animais , Sinergismo Farmacológico , Quimioterapia Combinada , Feminino , Humanos , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Influenza Humana/genética , Influenza Humana/imunologia , Influenza Humana/virologia , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Pneumonia/genética , Pneumonia/imunologia , Pneumonia/virologiaRESUMO
The herb-derived compounds silymarin, glycyrrhizin, and oxymatrine are widely used to treat chronic hepatitis C virus infections in China. They are often prescribed in combination with ribavirin, which has a narrow therapeutic index. We investigated the influence of these compounds on ribavirin pharmacokinetics following concurrent administration at the human dose in rats. Pharmacokinetic parameters were determined in rats following oral (p.o.) administration of ribavirin (30 mg/kg) with or without silymarin (40 mg/kg, p.o.), glycyrrhizin (15 mg/kg, intraperitoneal [i.p.]), or oxymatrine (60 mg/kg, p.o.). Compared with the animals in ribavirin group, silymarin significantly decreased the area under the plasma concentration-time curve (AUC0-t ) and the peak plasma concentration (Cmax ) of ribavirin and ribavirin base by 31.2-44.5% and 48.9-50.0%, respectively. Glycyrrhizin significantly decreased the Cmax and AUC0-t of both ribavirin and its metabolite by 35.3-37.6% and 38.6-39.8%, respectively. However, silymarin or glycyrrhizin did not change the ribavirin metabolite/parent ratios of the AUC and Cmax . Oxymatrine did not induce significant changes in ribavirin concentration, but it significantly decreased the Cmax (26.6%) and AUC (21.8%) of the metabolite. This study indicates that the therapeutic efficacy of ribavirin may be compromised by the concurrent administration of herbal medicines/dietary supplements containing silymarin, glycyrrhizin, or oxymatrine.
Assuntos
Alcaloides/farmacologia , Ácido Glicirrízico/farmacologia , Quinolizinas/farmacologia , Ribavirina/farmacocinética , Silimarina/farmacologia , Alcaloides/administração & dosagem , Animais , Área Sob a Curva , Interações Medicamentosas , Ácido Glicirrízico/administração & dosagem , Interações Ervas-Drogas , Masculino , Quinolizinas/administração & dosagem , Ratos , Ratos Sprague-Dawley , Ribavirina/administração & dosagem , Silimarina/administração & dosagemRESUMO
Although measles is usually considered a benign viral disease of childhood, adults may be affected at any age and may experience severe respiratory or neurologic consequences. We present three adult cases (one of whom was pregnant) admitted to our University Hospital who were diagnosed to have measles and who had uncommon clinical features such as hepatitis and hyponatremia. All patients were markedly hypoxic; one required mechanical ventilation. Two patients received therapy with intravenous ribavirin and all patients received high-dose vitamin A for 3 days. Therapy with intravenous ribavirin and vitamin A were well tolerated by our patients except one patient who developed acute renal failure and were associated with reversal of respiratory compromise. Life-threatening measles pneumonitis in adults may be more common than previously appreciated, regardless of the patient's immune status, and ribavirin and high-dose vitamin A might be a treatment option.
Assuntos
Sarampo/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Insuficiência Respiratória/tratamento farmacológico , Ribavirina/administração & dosagem , Vitamina A/administração & dosagem , Administração Intravenosa , Adulto , Feminino , Humanos , Masculino , Sarampo/diagnóstico por imagem , Sarampo/terapia , Pneumonia Viral/diagnóstico por imagem , Pneumonia Viral/terapia , Respiração Artificial , Insuficiência Respiratória/diagnóstico por imagem , Insuficiência Respiratória/terapia , Insuficiência Respiratória/virologia , Resultado do TratamentoRESUMO
UNLABELLED: Ebola virus (EBOV) is an RNA virus that can cause hemorrhagic fever with high fatality rates, and there are no approved vaccines or therapies. Typically, RNA viruses have high spontaneous mutation rates, which permit rapid adaptation to selection pressures and have other important biological consequences. However, it is unknown if filoviruses exhibit high mutation frequencies. Ultradeep sequencing and a recombinant EBOV that carries the gene encoding green fluorescent protein were used to determine the spontaneous mutation frequency of EBOV. The effects of the guanosine analogue ribavirin during EBOV infections were also assessed. Ultradeep sequencing revealed that the mutation frequency for EBOV was high and similar to those of other RNA viruses. Interestingly, significant genetic diversity was not observed in viable viruses, implying that changes were not well tolerated. We hypothesized that this could be exploited therapeutically. In vitro, the presence of ribavirin increased the error rate, and the 50% inhibitory concentration (IC50) was 27 µM. In a mouse model of ribavirin therapy given pre-EBOV exposure, ribavirin treatment corresponded with a significant delay in time to death and up to 75% survival. In mouse and monkey models of therapy given post-EBOV exposure, ribavirin treatment also delayed the time to death and increased survival. These results demonstrate that EBOV has a spontaneous mutation frequency similar to those of other RNA viruses. These data also suggest a potential for therapeutic use of ribavirin for human EBOV infections. IMPORTANCE: Ebola virus (EBOV) causes a severe hemorrhagic disease with high case fatality rates; there are no approved vaccines or therapies. We determined the spontaneous mutation frequency of EBOV, which is relevant to understanding the potential for the virus to adapt. The frequency was similar to those of other RNA viruses. Significant genetic diversity was not observed in viable viruses, implying that changes were not well tolerated. We hypothesized that this could be exploited therapeutically. Ribavirin is a viral mutagen approved for treatment of several virus infections; it is also cheap and readily available. In cell culture, we showed that ribavirin was effective at reducing production of infectious EBOV. In mouse and monkey models of therapy given post-EBOV exposure, ribavirin treatment delayed the time to death and increased survival. These data provide a better understanding of EBOV spontaneous mutation and suggest that ribavirin may have great value in the context of human disease.
Assuntos
Ebolavirus/genética , Variação Genética , Taxa de Mutação , Animais , Antivirais/administração & dosagem , Antivirais/farmacologia , Modelos Animais de Doenças , Feminino , Genes Reporter , Proteínas de Fluorescência Verde/genética , Doença pelo Vírus Ebola/tratamento farmacológico , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Concentração Inibidora 50 , Macaca fascicularis , Masculino , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , RNA Viral/genética , Ribavirina/administração & dosagem , Ribavirina/farmacologia , Análise de Sequência de DNA , Análise de Sobrevida , Resultado do TratamentoRESUMO
Human respiratory syncytial virus (hRSV) is the most common cause of respiratory tract infection among young children because of immature T cell immunity of them against hRSV. CD8 T cells play a pivotal role in clearing hRSV and preventing subsequent infection. We examined the effects of dietary bovine colostrum on virus infection and CD8 T cell responses following hRSV infection in the mouse model. Mice received bovine colostrum for 14 days prior to hRSV challenge, and lung indexes (severity of symptom) and lung virus titers were analyzed. In addition, the activation of CD8 T cells in the bronchoalveolar lavage fluids (BALFs) of mice receiving bovine colostrum were compared with those in the BALFs of mice receiving phosphate-buffered saline (PBS) or ribavirin, post virus challenge. The severity of infection and lung virus titers were reduced in the mice receiving bovine colostrum, compared to those receiving PBS. Moreover CD8 T cell responses were selectively enhanced in the former. Our results suggest that dietary bovine colostrum exerts the effects to inhibit hRSV and ameliorate the symptom by hRSV infection, and enhances the CD8 T cell response during the hRSV infection.
Assuntos
Colostro , Infecções por Vírus Respiratório Sincicial/dietoterapia , Infecções por Vírus Respiratório Sincicial/imunologia , Vírus Sincicial Respiratório Humano/imunologia , Animais , Anticorpos Antivirais/sangue , Linfócitos T CD8-Positivos/imunologia , Bovinos , Dieta , Modelos Animais de Doenças , Feminino , Humanos , Pulmão/virologia , Camundongos Endogâmicos BALB C , Gravidez , Vírus Sincicial Respiratório Humano/patogenicidade , Ribavirina/administração & dosagem , Carga Viral/imunologiaRESUMO
BACKGROUND AND AIM: An intention-to-treat prospective randomized study was carried out to compare the potentiation of antiviral efficacies between cholecalciferol, non-activated vitamin D3 supplement, and alfacalcidol, activated 1α-Hydroxyvitamin D3 [1α (OH)-vitamin D3]. METHODS: Chronic hepatitis patients with genotype 1b hepatitis C virus (HCV) infection showing serum HCV-RNA levels greater than 5 Log IU/mL received oral administration of cholecalciferol (2000 IU/day) or alfacalcidol (0.5 µg/day) for 4 weeks, and then they were given pegylated interferon (Peg-IFN)-α2a plus ribavirin therapy in combination with either vitamin D3 for 48 or 72 weeks according to the response-guided manner. RESULTS: A total of 36 patients were evaluated. Serum 25-hydroxyvitamin D3 [25(OH)-D3] levels were increased only in patients in the cholecalciferol group during the lead-in vitamin D administration, and the levels at 4 weeks were higher in these patients than in those in the alfacalcidol group (P < 0.001), while serum 1α,25-dihydroxyvitamin D3 [1α,25(OH)2 -D3] levels were not different between both groups. Rapid virological response was obtained in six (33%) patients in the cholecalciferol group; the ratio was higher than that in the alfacalcidol group (one patient; 6%, P < 0.05). Serum HCV-RNA level decline at 4 weeks of combined Peg-IFN-α2a plus ribavirin therapy compared with the baseline levels were greater in the cholecalciferol group (4.6 Log IU/mL) than in the alfacalcidol group (3.5 Log IU/mL) (P < 0.05), when four patients showing null response to the therapy was excluded. However, both complete early virological response and sustained viral response rates were not different between both groups. CONCLUSION: Cholecalciferol produced superior potentiation of the antiviral activity than alfacalcidol only during the initial periods of combined Peg-IFN-α2a plus ribavirin therapy through upregulation of serum 25(OH)-D3 levels.
Assuntos
Antivirais/administração & dosagem , Colecalciferol/administração & dosagem , Hepatite C Crônica/tratamento farmacológico , Hidroxicolecalciferóis/administração & dosagem , Interferon-alfa/administração & dosagem , Polietilenoglicóis/administração & dosagem , Ribavirina/administração & dosagem , Administração Oftálmica , Idoso , Biomarcadores/sangue , Calcifediol/sangue , Colecalciferol/farmacologia , Sinergismo Farmacológico , Quimioterapia Combinada , Feminino , Hepacivirus/genética , Hepatite C Crônica/virologia , Humanos , Hidroxicolecalciferóis/farmacologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , RNA Viral/sangue , Proteínas Recombinantes/administração & dosagem , Resultado do Tratamento , Regulação para Cima/efeitos dos fármacosRESUMO
BACKGROUND & AIMS: Intravenous silibinin (SIL) is a potent antiviral agent against hepatitis C virus (HCV) genotype-1. In this proof of concept case-study we tested: (i) whether interferon-alfa (IFN)-free treatment with SIL plus ribavirin (RBV) can achieve sustained virological response (SVR); (ii) whether SIL is safe and feasible for prolonged duration of treatment and (iii) whether mathematical modelling of early on-treatment HCV kinetics can guide duration of therapy to achieve SVR. METHODS: A 44 year-old female HCV-(genotype-1)-infected patient who developed severe psychiatric adverse events to a previous course of pegIFN+RBV, initiated combination treatment with 1200 mg/day of SIL, 1200 mg/day of RBV and 6000 u/day vitamin D. Blood samples were collected frequently till week 4, thereafter every 1-12 weeks until the end of therapy. The standard biphasic mathematical model with time-varying SIL effectiveness was used to predict the duration of therapy to achieve SVR. RESULTS: Based on modelling the observed viral kinetics during the first 3 weeks of treatment, SVR was predicted to be achieved within 34 weeks of therapy. Provided with this information, the patient agreed to complete 34 weeks of treatment. IFN-free treatment with SIL+RBV was feasible, safe and achieved SVR (week-33). CONCLUSIONS: We report, for the first time, the use of real-time mathematical modelling of HCV kinetics to individualize duration of IFN-free therapy and to empower a patient to participate in shared decision making regarding length of treatment. SIL-based individualized therapy provides a treatment option for patients who do not respond to or cannot receive other HCV agents and should be further validated.
Assuntos
Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Medicina de Precisão/métodos , RNA Viral/sangue , Silimarina/farmacologia , Adulto , Antivirais/administração & dosagem , Quimioterapia Combinada/métodos , Feminino , Humanos , Injeções Intravenosas , Cinética , Modelos Biológicos , Ribavirina/administração & dosagem , Ribavirina/farmacologia , Silibina , Silimarina/administração & dosagem , Fatores de TempoRESUMO
Simeprevir is a second-wave hepatitis C virus NS3/4A protease inhibitor that was designed to optimize its antiviral activity, safety, drug-drug interactions, and pharmacokinetic profile. When used to treat patients with hepatitis C virus genotype 1, simeprevir is coadministered with peginterferon and ribavirin for 12 weeks, followed by double therapy with Peg-IFN and ribavirin for an additional 12 or 36 weeks. Phase III studies achieved a sustained virologic response in 80-90% of treatment-naïve patients (International Phase III studies QUEST-1/2: 80/81%; Japanese Phase III trial CONCERTO-1: 89%). Unlike with the first protease inhibitors, telaprevir or boceprevir, used in triple therapy, when using simeprevir the frequency of clinically problematic adverse events such as anemia, rash, and digestive symptoms is almost comparable to that of double therapy. The advent of simeprevir has enabled interferon therapy, which started as monotherapy in early 1990s, to reach its maximum efficacy and arrive at what can be considered its final form at least in genotype 1b.
Assuntos
Antivirais/uso terapêutico , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Sulfonamidas/uso terapêutico , Antivirais/administração & dosagem , Antivirais/química , Ensaios Clínicos como Assunto , Esquema de Medicação , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Quimioterapia Combinada , Genótipo , Hepacivirus/genética , Hepatite C Crônica/virologia , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/química , Humanos , Interferon alfa-2 , Interferon-alfa/administração & dosagem , Interferon-alfa/uso terapêutico , Estrutura Molecular , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/uso terapêutico , RNA Viral/sangue , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico , Ribavirina/administração & dosagem , Ribavirina/uso terapêutico , Simeprevir , Sulfonamidas/administração & dosagem , Sulfonamidas/química , Resultado do TratamentoRESUMO
BACKGROUND: Daclatasvir (DCV; BMS-790052) is a picomolar inhibitor of HCV non-structural protein 5A (NS5A) and has demonstrated efficacy in patients chronically infected with HCV. METHODS: In the double-blind, randomized studies AI444021 and AI444022, 71 Japanese patients chronically infected with HCV genotype 1 (predominantly genotype 1b) received DCV (10 mg or 60 mg) plus peginterferon alfa-2b or alfa-2a and ribavirin. Virological failure occurred in 14% (5/36) of treatment-naive patients and 54% (19/35) of prior alfa/ribavirin non-responders. Resistance testing was performed on baseline samples and samples with HCV RNA≥1,000 IU/ml at week 1 through post-treatment week 24. RESULTS: Baseline NS5A resistance-associated polymorphisms had less impact on virological response rates than IL28B genotype. All patients with virological failure had NS5A DCV-resistant variants at the time of failure. The predominant NS5A variants were L31V/M/I plus Y93H; this combination was detected in 100% (5/5) of treatment-naive patients and 74% (14/19) of non-responders with failure. Emergent resistance variants in prior non-responders (four viral breakthroughs, one relapse) were more varied with novel combinations such as L31F-ΔP32 and L28M-R30Q-A92K detected. Significant loss in DCV antiviral activity was generally only seen with ≥ two resistance-associated NS5A substitutions. All DCV-resistant variants were still detected at end of study. CONCLUSIONS: Virological failure in HCV genotype 1b treatment-naive Japanese patients receiving DCV plus alfa-2a/ribavirin or alfa-2b/ribavirin was associated with enrichment of NS5A resistance variants L31V/M-Y93H. In prior non-responders, emergent variants associated with failure also included NS5A-A92K or NS5A-ΔP32. As with L31-Y93 variants, these variants persisted.
Assuntos
Antivirais/uso terapêutico , Genótipo , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Imidazóis/uso terapêutico , Interferon-alfa/uso terapêutico , Polietilenoglicóis/uso terapêutico , Ribavirina/uso terapêutico , Adulto , Idoso , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Carbamatos , Farmacorresistência Viral , Quimioterapia Combinada , Feminino , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/genética , Hepatite C Crônica/virologia , Humanos , Imidazóis/administração & dosagem , Imidazóis/efeitos adversos , Interferon alfa-2 , Interferon-alfa/administração & dosagem , Interferon-alfa/efeitos adversos , Interferons , Interleucinas/genética , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Mutação , Fenótipo , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/efeitos adversos , Pirrolidinas , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Ribavirina/administração & dosagem , Ribavirina/efeitos adversos , Resultado do Tratamento , Valina/análogos & derivados , Carga Viral , Adulto JovemRESUMO
The purpose of this study is to investigate the applicability of a natural swelling matrix derived from boat-fruited sterculia seed (SMS) as the propellant of osmotic pump tablets. The sugar components, static swelling, water uptake and viscosity of SMS were determined and compared with that of polythylene oxide (WSR-N10 and WSR-303). Both ribavirin and glipizide were used as water-soluble and water-insoluble model drugs. Then, the monolayer osmotic pump tablets of ribavirin and the bilayer osmotic pump tablets of glipizide were prepared using SMS as the osmotically active substance and propellant. SMS was mainly composed of rhamnose, arabinose, xylose and galactose and exhibited relatively high swelling ability. The area of the disintegrated matrix tablet was 20.1 times as that at initial after swelling for 600 s. SMS swelled rapidly and was fully swelled (0.5%) in aqueous solution with relative low viscosity (3.66 +/- 0.03) mPa x s at 25 degrees C. The monolayer osmotic pump tablets of ribavirin and the bilayer osmotic pump tablets of glipizide using SMS as propellant exhibited typical drug release features of osmotic pumps. In conclusion, the swelling matrix derived from boat-fruited sterculia seed, with low viscosity and high swelling, is a potential propellant in the application of osmotic pump tablets.