RESUMO
Current guidelines recommend that individuals with moderate COVID-19 disease isolate for 5 days after the first appearance of symptoms or a positive SARS-CoV-2 test. It would be useful to understand the time course of infectious virus production and its correlation with virus detection using a rapid antigen test (RAT) or quantitative reverse transcriptase (qRT)-PCR. In a phase 2 study, 242 vaccinated patients with COVID-19 and at low risk for progression to severe disease initiated 5 days of treatment with pomotrelvir (PBI-0451, a SARS-CoV-2 main protease inhibitor) or placebo within 5 days after symptom onset. The primary endpoint, the proportion of subjects with SARS-CoV-2 viral titers below the limit of detection on Day 3 of treatment in the pomotrelvir versus placebo groups, was not met. No between-group differences in SARS-CoV-2 clearance or symptom resolution or alleviation were observed. Additional analyses evaluated the dynamics of SARS-CoV-2 replication in mid-turbinate nasal swabs and saliva samples using infectious virus assay (IVA), RAT, and qRT-PCR. SARS-CoV-2 cleared rapidly, with negative results first determined by IVA (TCID50 below the limit of detection), followed by the RAT (negative for SARS-CoV-2 N antigen), and qRT-PCR (RNA below the limit of detection), which suggests that delayed initiation of treatment (up to 5 days after symptom onset) may have contributed to the lack of treatment response. Symptom resolution lagged behind viral clearance assessed by IVA and RAT. These data support reliance on a negative RAT to determine when an individual is no longer producing infectious virus and may end isolation.IMPORTANCEA phase 2 double-blind, placebo-controlled study was performed evaluating pomotrelvir, a SARS-CoV-2 Mpro inhibitor, compared with placebo in 242 non-hospitalized, vaccinated, symptomatic adults with COVID-19 (Omicron). No improvement in the decrease of viral replication or relief of symptoms was observed between the two groups when treatment was initiated ≥3 days after symptom onset. These results suggest that future COVID-19 antiviral studies using a similar patient population may need to initiate treatment earlier, like influenza studies. This is the first study to prospectively evaluate SARS-CoV-2 viral dynamics and the time to viral clearance in a significant number of patients using concurrently obtained results from an infectious virus assay, a rapid antigen test (RAT), and a qRT-PCR assay over a 15-day time course. These results suggest that a negative RAT assay is a good indicator of loss of infectious virus and the ability to return to normal activities.
Assuntos
COVID-19 , SARS-CoV-2 , Adulto , Humanos , Método Duplo-Cego , Fatores de TempoRESUMO
Pomotrelvir is an orally bioavailable, target antiviral inhibitor of the main protease (Mpro) of coronaviruses, including severe acute respiratory syndrome coronavirus 2, the etiological agent of Coronavirus Disease 2019. The pharmacokinetics, metabolism and elimination of two [14C]-labeled microtracers of 5 µCi/700 mg pomotrelvir with separate labeling positions (isotopomers), [lactam carbonyl-14C-pomotelvir] and [benzene ring-U-14C-pomotrelvir], following a single oral dose in healthy adult males was evaluated in two separate cohorts. Pomotrelvir was rapidly absorbed and eliminated primarily through metabolism and subsequently excreted via urine and feces. There were no differences in pomotrelvir pharmacokinetics between the two cohorts. The mean total radioactive dose recovered was 93.8% (n = 8) in the lactam cohort (58% in urine and 36% in feces) and 94.2% (n = 8) in the benzene cohort (75% in urine and 19% in feces), with ≥80% of [14C] recovered within 96 hours after dosing. About 5% and 3% of the intact pomotrelvir was recovered in feces and urine, respectively. Eleven major metabolites were detected and characterized using liquid chromatography-accelerator mass spectrometry and liquid chromatography tandem mass spectrometry methods, with three and six different metabolites elucidated in the samples collected from lactam and benzene cohorts, respectively, and two metabolites observed in both cohorts. The major metabolism pathway of pomotrelvir is through hydrolysis of its peptide bonds followed by phase II conjugations. These results support that the application of two radiolabeled isotopomers provided a comprehensive metabolite profiling analysis and was a successful approach in identifying the major disposition pathways of pomotrelvir that has complex routes of metabolism. SIGNIFICANCE STATEMENT: An unconventional approach using two differentially labeled [14C] microtracers, [lactam carbonyl-14C-pomotrelvir] and [benzene ring-U-14C-pomotrelvir] evaluated the mass balance of orally administered pomotrelvir in healthy adult males in two separate cohorts. The radioactive dose recovered in excreta was about 94% for both cohorts. While the two isotopomers of the radiolabeled-pomotrelvir showed no major differences in pharmacokinetics overall, they allowed for differential detection of their radiolabeled metabolites and appropriate characterization of their plasma exposure and excretion in urine and feces.
Assuntos
Benzeno , Lactamas , Adulto , Humanos , Masculino , Cromatografia Líquida de Alta Pressão/métodos , Benzeno/análise , Cromatografia Líquida , Biotransformação , Fezes/química , Lactamas/análise , Administração Oral , Radioisótopos de Carbono/análiseRESUMO
Pomotrelvir is a new chemical entity and potent direct-acting antiviral inhibitor of the main protease of coronaviruses. Here the cytochrome P450 (CYP)-mediated drug-drug interaction (DDI) potential of pomotrelvir was evaluated for major CYP isoforms, starting with in vitro assays followed by the basic static model assessment. The identified CYP3A4-mediated potential DDIs were evaluated clinically at a supratherapeutic dose of 1050 mg twice daily (b.i.d.) of pomotrelvir, including pomotrelvir coadministration with ritonavir (strong inhibitor of CYP3A4) or midazolam (sensitive substrate of CYP3A4). Furthermore, a physiologically-based pharmacokinetic (PBPK) model was developed within the Simcyp Population-based Simulator using in vitro and in vivo information and validated with available human pharmacokinetic (PK) data. The PBPK model was simulated to assess the DDI potential for CYP isoforms that pomotrelvir has shown a weak to moderate DDI in vitro and for CYP3A4 at the therapeutic dose of 700 mg b.i.d. To support the use of pomotrelvir in women of childbearing potential, the impact of pomotrelvir on the exposure of the representative oral hormonal contraceptive drugs ethinyl estradiol and levonorgestrel was assessed using the PBPK model. The overall assessment suggested weak inhibition of pomotrelvir on CYP3A4 and minimal impact of a strong CYP3A4 inducer or inhibitor on pomotrelvir PK. Therefore, pomotrelvir is not anticipated to have clinically meaningful DDIs at the clinical dose. These comprehensive in vitro, in clinic, and in silico efforts indicate that the DDI potential of pomotrelvir is minimal, so excluding patients on concomitant medicines in clinical studies would not be required.
Assuntos
Citocromo P-450 CYP3A , Hepatite C Crônica , Humanos , Feminino , Antivirais/farmacologia , Sistema Enzimático do Citocromo P-450 , Interações Medicamentosas , Isoformas de Proteínas , Modelos Biológicos , Inibidores do Citocromo P-450 CYP3A/farmacologia , Simulação por ComputadorRESUMO
BACKGROUND: Necrotizing soft tissue infections (NSTIs) are an acute surgical condition with high morbidity and mortality. Timely identification, resuscitation, and aggressive surgical management have significantly decreased inpatient mortality. However, reduced inpatient mortality has shifted the burden of disease to long-term mortality associated with persistent organ dysfunction. METHODS: We performed a combined analysis of NSTI patients from the AB103 Clinical Composite Endpoint Study in Necrotizing Soft Tissue Infections randomized-controlled interventional trial (ATB-202) and comprehensive administrative database (ATB-204) to determine the association of persistent organ dysfunction on inpatient and long-term outcomes. Persistent organ dysfunction was defined as a modified Sequential Organ Failure Assessment (mSOFA) score of 2 or greater at Day 14 (D14) after NSTI diagnosis, and resolution of organ dysfunction defined as mSOFA score of 1 or less. RESULTS: The analysis included 506 hospitalized NSTI patients requiring surgical debridement, including 247 from ATB-202, and 259 from ATB-204. In both study cohorts, age and comorbidity burden were higher in the D14 mSOFA ≥2 group. Patients with D14 mSOFA score of 1 or less had significantly lower 90-day mortality than those with mSOFA score of 2 or higher in both ATB-202 (2.4% vs. 21.5%; p < 0.001) and ATB-204 (6% vs. 16%: p = 0.008) studies. In addition, in an adjusted covariate analysis of the combined study data sets D14 mSOFA score of 1 or lesss was an independent predictor of lower 90-day mortality (odds ratio, 0.26; 95% confidence interval, 0.13-0.53; p = 0.001). In both studies, D14 mSOFA score of 1 or less was associated with more favorable discharge status and decreased resource utilization. CONCLUSION: For patients with NSTI undergoing surgical management, persistent organ dysfunction at 14 days, strongly predicts higher resource utilization, poor discharge disposition, and higher long-term mortality. Promoting the resolution of acute organ dysfunction after NSTI should be considered as a target for investigational therapies to improve long-term outcomes after NSTI. LEVEL OF EVIDENCE: Prognostic/epidemiology study, level III.
Assuntos
Antígenos CD28/administração & dosagem , Desbridamento/métodos , Fasciite Necrosante/complicações , Insuficiência de Múltiplos Órgãos/epidemiologia , Infecções dos Tecidos Moles/complicações , Adulto , Idoso , Bases de Dados Factuais , Método Duplo-Cego , Fasciite Necrosante/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência de Múltiplos Órgãos/mortalidade , Escores de Disfunção Orgânica , Prognóstico , Estudos Retrospectivos , Análise de SobrevidaRESUMO
Background: Previous estimates of the incidence of necrotizing soft tissue infections (NSTI) in the United States have substantial limitations and underestimate its occurrence. Improvements in hospital mortality after NSTI have increased the number of survivors at risk for long-term sequelae. This study estimates the incidence of NSTI and the burden of re-admission and associated healthcare spending in patients who survived admission for NSTI. Methods: Index admissions for NSTI were identified using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes combined with either Current Procedural Technology (CPT) or diagnosis-related group codes to increase specificity. Two separate datasets were used to provide primary and secondary estimates of the annual incidence of NSTIs in the United States: the National Inpatient Sample (NIS) for the years 2012-2016 and the Watson Health dataset for 2009-2013, respectively, and extrapolated to estimate the incidence for 2018. The Nationwide Readmissions Database (NRD) from 2013-2015 was used to estimate of the risk for re-admission, cost of re-admissions, and to compare 90-day re-admission rates for NSTI to common medical conditions. Results: National Inpatient Sample and Watson Health datasets demonstrated an increasing annual incidence and estimated 33,600 and 28,500 cases in 2018, respectively. The estimated annual incidences in the United States in 2018 were 10.3 and 8.7 per 100,000 persons, respectively. Risk of 90-day re-admission ranged from 24%-29% over the 3 years, 89% of which were unplanned. Of those re-admitted, 90% had one or more comorbidities, the most common diagnoses associated with re-admission were infection in 65%, acute kidney injury in 22%, and shock in 10%. The median re-admission length of stay was seven days (interquartile range [IQR]: 4-13 days) with a median cost of re-admission of $13,590 (IQR: $7186-$27440). Conclusion: The incidence of NSTI is more common than generally reported. Re-admission within 90 days is common, occurring in more than one in four survivors resulting in high healthcare costs.
Assuntos
Fasciite Necrosante , Infecções dos Tecidos Moles , Hospitalização , Humanos , Incidência , Estudos Retrospectivos , Infecções dos Tecidos Moles/epidemiologia , Estados Unidos/epidemiologiaRESUMO
BACKGROUND AND OBJECTIVE: Reltecimod, a CD 28 T-lymphocyte receptor mimetic, inhibits T-cell stimulation by an array of bacterial pathogens. A previous phase 2 trial demonstrated improved resolution of organ dysfunction after NSTI. We hypothesized that early administration of reltecimod would improve outcome in severe NSTI. METHODS: Randomized, double-blind, placebo-controlled trial of single dose reltecimod (0.5âmg/kg) administered within 6âhours of NSTI diagnosis at 65 of 93 study sites. Inclusion: surgical confirmation of NSTI and organ dysfunction [modified Sequential Organ Failure Assessment Score (mSOFA) score ≥3]. Primary analysis was modified Intent-to-Treat (mITT), responder analysis using a previously validated composite endpoint, necrotizing infection clinical composite endpoint, defined as: alive at day 28, ≤3 debridements, no amputation beyond first operation, and day 14 mSOFA ≤1 with ≥3 point reduction (organ dysfunction resolution). A prespecified, per protocol (PP) analysis excluded 17 patients with major protocol violations before unblinding. RESULTS: Two hundred ninety patients were enrolled, mITT (Reltecimod 142, Placebo 148): mean age 55â±â15 years, 60% male, 42.4% diabetic, 28.6% perineal infection, screening mSOFA mean 5.5â±â2.4. Twenty-eight-day mortality was 15% in both groups. mITT necrotizing infection clinical composite endpoint success was 48.6% reltecimod versus 39.9% placebo, P = 0.135 and PP was 54.3% reltecimod versus 40.3% placebo, P = 0.021. Resolution of organ dysfunction was 65.1% reltecimod versus 52.6% placebo, P = 0.041, mITT and 70.9% versus 53.4%, P = 0.005, PP. CONCLUSION: Early administration of reltecimod in severe NSTI resulted in a significant improvement in the primary composite endpoint in the PP population but not in the mITT population. Reltecimod was associated with improved resolution of organ dysfunction and hospital discharge status.
Assuntos
Antígenos CD28/administração & dosagem , Desbridamento/métodos , Fasciite Necrosante/terapia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Fatores Imunológicos/administração & dosagem , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
BACKGROUND: In 2009, a retrospective study reported the detection of xenotropic murine leukemia virus-related virus (XMRV) in clinical isolates derived from individuals with chronic fatigue syndrome or myalgic encephalomyelitis (CFS). While many efforts to confirm this observation failed, one report detected polytropic murine leukemia virus (pMLV), instead of XMRV. In both studies, Polymerase Chain Reaction (PCR)-based methods were employed which could provide the basis for the development of a practical diagnostic tool. To confirm these studies, we hypothesized that the ability to detect these viruses will not only depend upon the technical details of the methods employed but also on the criteria used to diagnose CFS and the availability of well characterized clinical isolates. METHODS: A repository of clinical isolates from geographically distinct sites was generated by the collection of fresh blood samples from well characterized CFS and healthy subjects. Molecular techniques were used to generate assay positive controls and to determine the lower limit of detection (LLOD) for murine retroviral and Intracisternal A particle (Cell 12(4):963-72, 1977) detection methods. RESULTS: We report the establishment of a repository of well-defined, clinical isolates from five, geographically distinct regions of the US, the comparative determination of the LLODs and validation efforts for the previously reported detection methods and the results of an effort to confirm the association of these retroviral signatures in isolates from individuals with CFS in a blinded, multi-site, prospective study. We detected various, murine retroviral DNA signatures but were unable to resolve a difference in the incidence of their detection between isolates from CFS (5/72; 6.7%) and healthy (2/37; 5.4%) subjects (Fisher's Exact Test, p-value = 1). The observed sequences appeared to reflect the detection of endogenous murine retroviral DNA, which was not identical to either XMRV or pMLV. CONCLUSIONS: We were unable to confirm a previously reported association between the detection of XMRV or pMLV sequences and CFS in a prospective, multi-site study. Murine retroviral sequences were detected at a low frequency that did not differ between CFS and control subjects. The nature of these sequences appeared to reflect the detection of pre-existing, endogenous, murine retroviral DNA in the PCR reagents employed.
Assuntos
Bancos de Espécimes Biológicos , Síndrome de Fadiga Crônica/virologia , Vírus da Leucemia Murina/isolamento & purificação , Vírus Relacionado ao Vírus Xenotrópico da Leucemia Murina/isolamento & purificação , Adulto , Animais , Sequência de Bases , Estudos de Casos e Controles , DNA Viral/genética , DNA Viral/isolamento & purificação , Demografia , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Filogenia , Reação em Cadeia da Polimerase , Estudos Prospectivos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Proteínas Virais/metabolismoRESUMO
BACKGROUND: GSK1265744 (744) is an HIV-1 integrase inhibitor in clinical development as a long-acting (LA) injectable formulation. This study evaluated plasma and tissue pharmacokinetics after single-dose administration of 744 LA administered by intramuscular (IM) or subcutaneous injections. METHODS: This was a phase I, open-label, 9-cohort, parallel study of 744 in healthy subjects. 744 was administered as a 200 mg/mL nanosuspension at doses of 100-800 mg IM and 100-400 mg subcutaneous. RESULTS: Eight (6 active and 2 placebo) male and female subjects participated in each of the first 7 cohorts. All 8 subjects, 4 males and 4 females, received active 744 LA in cohorts 8 and 9 and underwent rectal and cervicovaginal tissue sampling, respectively. Plasma pharmacokinetic sampling was performed for a minimum of 12 weeks or until 744 concentrations were ≤0.1 µg/mL. Rectal and cervicovaginal tissue biopsies were performed at weeks 2 and 8 (cohort 8) and weeks 4 and 12 (cohort 9). 744 LA was generally safe and well tolerated after single injections. A majority of subjects reported injection site reactions, all graded as mild in intensity. Plasma concentration-time profiles were prolonged with measureable concentrations up to 52 weeks after dosing. 744 LA 800 mg IM achieved mean concentrations above protein adjusted-IC90 for approximately 16 weeks. Rectal and cervicovaginal tissue concentrations ranged from <8% to 28% of corresponding plasma concentrations. CONCLUSIONS: These data suggest 744 LA injection has potential application as a monthly or less frequent HIV treatment or prevention agent.
Assuntos
Fármacos Anti-HIV/farmacocinética , Preparações de Ação Retardada/farmacocinética , Plasma/química , Piridonas/farmacocinética , Adolescente , Adulto , Fármacos Anti-HIV/administração & dosagem , Estudos de Coortes , Preparações de Ação Retardada/administração & dosagem , Feminino , Voluntários Saudáveis , Humanos , Injeções , Injeções Intramusculares , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Piridonas/administração & dosagem , Adulto JovemRESUMO
PURPOSE: Dolutegravir (DTG) is an unboosted, integrase inhibitor for the treatment of HIV infection. Two studies evaluated the effects of efavirenz (EFV) and tipranavir/ritonavir (TPV/r) on DTG pharmacokinetics (PK) in healthy subjects. METHODS: The first study was an open-label crossover where 12 subjects received DTG 50 mg every 24 hours (q24h) for 5 days, followed by DTG 50 mg and EFV 600 mg q24h for 14 days. The second study was an open-label crossover where 18 subjects received DTG 50 mg q24h for 5 days followed by TPV/r 500/200 mg every 12 hours (q12h) for 7 days and then DTG 50 mg q24h and TPV/r 500/200 mg q12h for a further 5 days. Safety assessments and serial PK samples were collected. Non-compartmental PK analysis and geometric mean ratios and 90% confidence intervals were generated. RESULTS: The combination of DTG with EFV or TPV/r was generally well tolerated. Four subjects discontinued the TPV/r study due to increases in alanine aminotransferase that were considered related to TPV/r. Co-administration with EFV resulted in decreases of 57, 39 and 75% in DTG AUC(0-τ), Cmax and Cτ, respectively. Co-administration with TPV/r resulted in decreases of 59, 46 and 76% in DTG AUC(0-τ), Cmax and Cτ, respectively. CONCLUSIONS: Given the reductions in exposure and PK/pharmacodynamic relationships in phase II/III trials, DTG should be given at an increased dose of 50 mg twice daily when co-administered with EFV or TPV/r, and alternative regimens without inducers should be considered in integrase inhibitor-resistant patients.
Assuntos
Benzoxazinas/farmacologia , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Piridinas/farmacologia , Pironas/farmacologia , Ritonavir/farmacologia , Adulto , Idoso , Alcinos , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/farmacologia , Área Sob a Curva , Benzoxazinas/efeitos adversos , Estudos Cross-Over , Ciclopropanos , Combinação de Medicamentos , Interações Medicamentosas , Feminino , Inibidores de Integrase de HIV/efeitos adversos , Inibidores de Integrase de HIV/farmacocinética , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Oxazinas , Piperazinas , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Piridonas , Pironas/administração & dosagem , Pironas/efeitos adversos , Ritonavir/administração & dosagem , Ritonavir/efeitos adversos , Sulfonamidas , Adulto JovemRESUMO
This Phase I, randomized, open-label study evaluated the gastric pH-altering effects of omeprazole, a proton pump inhibitor, and the CYP3A enzyme/P-glycoprotein (Pgp)-inhibitory effects of ritonavir, an HIV protease inhibitor, on the pharmacokinetics and safety of the hepatitis C virus (HCV) non-structural protein 5A (NS5A) inhibitor GSK2336805 in healthy male and female subjects. Co-administration of GSK2336805 60 mg with omeprazole decreased GSK2336805 plasma AUC(0-∞) by 10% and Cmax by 18%; no marked effect was observed on t½ . Co-administration of GSK2336805 30 mg with ritonavir increased GSK2336805 plasma AUC(0-∞) by 52%, Cmax by 43%, and t½ by 40%; CL/F was decreased by 34%. All adverse events were minor in intensity. The gastric acid-suppressive effect of omeprazole had minimal impact on the extent and rate of GSK2336805 absorption in vivo; therefore, GSK2336805 may be co-administered with omeprazole without concern about lower GSK2336805 exposures and compromised antiviral efficacy. The modest increases in AUC and Cmax following co-administration of GSK2336805 plus ritonavir suggest that GSK2336805 when given concomitantly with a single CYP3A/Pgp inhibiting drug will not likely require dose adjustment. Final dose recommendation will be based on GSK2336805 efficacy and safety profiles from Phase III trials in HCV-infected patients.
Assuntos
Antivirais/farmacocinética , Carbamatos/farmacocinética , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Citocromo P-450 CYP3A/metabolismo , Absorção Gastrointestinal , Hepacivirus/efeitos dos fármacos , Omeprazol/administração & dosagem , Inibidores de Proteases/farmacocinética , Inibidores da Bomba de Prótons/administração & dosagem , Ritonavir/administração & dosagem , Valina/análogos & derivados , Proteínas não Estruturais Virais/antagonistas & inibidores , Adolescente , Adulto , Idoso , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Antivirais/sangue , Área Sob a Curva , Biotransformação , Carbamatos/administração & dosagem , Carbamatos/efeitos adversos , Carbamatos/sangue , Inibidores do Citocromo P-450 CYP3A/efeitos adversos , Interações Medicamentosas , Feminino , Meia-Vida , Voluntários Saudáveis , Hepacivirus/enzimologia , Humanos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , New York , Omeprazol/efeitos adversos , Inibidores de Proteases/administração & dosagem , Inibidores de Proteases/efeitos adversos , Inibidores de Proteases/sangue , Inibidores da Bomba de Prótons/efeitos adversos , Ritonavir/efeitos adversos , Valina/administração & dosagem , Valina/efeitos adversos , Valina/sangue , Valina/farmacocinética , Proteínas não Estruturais Virais/metabolismo , Adulto JovemRESUMO
This first-time-in-human, randomized, double-blind, placebo-controlled, dose-escalation study assessed the safety, tolerability, pharmacokinetics, and antiviral activity of GSK2485852, a hepatitis C virus (HCV) NS5B inhibitor, in 27 chronically infected HCV genotype-1 subjects. Subjects received GSK2485852 70, 420, and 70 mg with a moderate fat/caloric meal. Safety, pharmacokinetics, antiviral activity, HCV genotype/phenotype, and interleukin 28B genotype were evaluated. A statistically significant reduction in HCV ribonucleic acid (RNA) was observed after a single dose of 420 mg GSK2485852 (-1.33 log10 IU/mL) compared with placebo (-0.09 log10 IU/mL) at 24 hours post-dose. Subjects receiving 70 mg GSK2485852 were exposed to concentrations above the protein-adjusted 90% effective concentration for a short time; none experienced a significant decline in HCV RNA (-0.47 log10 copies/mL). GSK2485852 was readily absorbed; however, the observed geometric mean maximum plasma concentration (Cmax ) and area under the curve (AUC) values were significantly lower than expected due to a higher-than-predicted-oral clearance. Co-administration with food reduced the AUC and Cmax of GSK2485852 by 40% and 70%, respectively. Two metabolites were detected in human blood with one having approximately 50% higher concentrations than those of the parent. GSK2485852 was well-tolerated and exhibited antiviral activity after a single 420 mg dose in HCV subjects.
Assuntos
Antivirais/administração & dosagem , Antivirais/farmacocinética , Ácidos Borônicos/administração & dosagem , Ácidos Borônicos/farmacocinética , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Inibidores de Proteases/administração & dosagem , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacocinética , Proteínas não Estruturais Virais/antagonistas & inibidores , Adolescente , Adulto , Idoso , Antivirais/efeitos adversos , Ácidos Borônicos/efeitos adversos , Método Duplo-Cego , Feminino , Interações Alimento-Droga , Genótipo , Hepacivirus/enzimologia , Hepacivirus/genética , Hepatite C Crônica/sangue , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/genética , Humanos , Interferons , Interleucinas/genética , Masculino , Pessoa de Meia-Idade , Fenótipo , Inibidores de Proteases/efeitos adversos , Inibidores de Proteases/farmacocinética , RNA Viral/sangue , Sulfonamidas/efeitos adversos , Resultado do Tratamento , Estados Unidos , Carga Viral , Proteínas não Estruturais Virais/metabolismo , Adulto JovemRESUMO
Rapid, accurate diagnosis of community-acquired pneumonia (CAP) due to Mycoplasma pneumoniae is compromised by low sensitivity of culture and serology. Polymerase chain reaction (PCR) has emerged as a sensitive method to detect M. pneumoniae DNA in clinical specimens. However, conventional real-time PCR is not cost-effective for routine or outpatient implementation. Here, we evaluate a novel microfluidic real-time PCR platform (Advanced Liquid Logic, Research Triangle Park, NC) that is rapid, portable, and fully automated. We enrolled patients with CAP and extracted DNA from nasopharyngeal wash (NPW) specimens using a biotinylated capture probe and streptavidin-coupled magnetic beads. Each extract was tested for M. pneumoniae-specific DNA by real-time PCR on both conventional and microfluidic platforms using Taqman probe and primers. Three of 59 (5.0%) NPWs were positive, and agreement between the methods was 98%. The microfluidic platform was equally sensitive but 3 times faster and offers an inexpensive and convenient diagnostic test for microbial DNA.
Assuntos
Técnicas Bacteriológicas/métodos , Microfluídica/métodos , Técnicas de Diagnóstico Molecular/métodos , Mycoplasma pneumoniae/isolamento & purificação , Pneumonia por Mycoplasma/diagnóstico , Reação em Cadeia da Polimerase/métodos , Automação , Infecções Comunitárias Adquiridas/microbiologia , Humanos , Mycoplasma pneumoniae/genética , Nasofaringe/microbiologia , Pneumonia por Mycoplasma/microbiologia , Sistemas Automatizados de Assistência Junto ao Leito , Sensibilidade e Especificidade , Fatores de TempoRESUMO
BACKGROUND: The Centers for Disease Control and Prevention (CDC) monitors the occurrence of respiratory syncytial virus (RSV) in the United States and has historically reported on activity at the regional level. Prior to the 2007-2008 RSVseason, the CDC did not report seasonal RSV data for cities within North Carolina or for the state. The purpose of the present study is to characterize RSV seasonal activity within North Carolina and to determine the appropriate months in which at-risk children should receive prophylaxis. METHODS: We prospectively collected RSV test data monthly over three seasons (fall through spring), from September 2003 through July 2006, from a diverse group of hospitals and a community pediatric practice located within five regions throughout North Carolina. RESULTS: Approximately 14,000 laboratory tests, including 23.7% that were RSV positive, were evaluated over the three seasons, and RSV was detected within the state during all but three months of the study. Seasonal variation in the onset (October-November) of RSV activity and duration (six to seven months) of the RSV season according to the specified definition of seasonality was noted yearly within individual regions and among regions. On average over the study period, the greatest percentage of positive tests (33.8%) statewide occurred during January. CONCLUSIONS: Our data suggest the RSV season in North Carolina is longer than the national average, and RSV epidemics persist during months that fall outside of those in which RSV prophylaxis is given to high-risk children. Guidelines on the administration of RSV prophylaxis should ideally be based on results of local RSV test data.