RESUMO
OBJECTIVE: To investigate the pharmacokinetics (PK) of tecovirimat in subjects with Mpox. METHODS: This monocentric, prospective, observational study enrolled subjects with Mpox who received standard treatment with oral tecovirimat. Plasma samples for PK assessment were collected at steady state (5-8 days after initiation of antiviral therapy), before and 3, 5, 7 and 12 h after tecovirimat administration. Drug concentrations were determined by validated liquid chromatography coupled with tandem mass spectrometry. PK parameters were calculated using Phoenix 8.1. RESULTS: Overall, 14 male patients hospitalized for severe Mpox with ongoing tecovirimat treatment were enrolled in this study. Six of the 14 patients were living with human immunodeficiency virus (HIV), all of whom were on antiretroviral therapy (ART) and virologically suppressed at the time of hospitalization. Significant differences in tecovirimat PK were observed in subjects without HIV compared with subjects with HIV. In subjects with HIV, the maximum tecovirimat plasma concentration (39%, P≤0.0001), minimum tecovirimat plasma concentration (42%, P=0.0079) and area under the curve from zero to the last measured time-point (40%, P≤0.0001) were significantly lower compared with subjects without HIV, but all concentrations remained above the in-vitro calculated 90% inhibitory concentration. No significant associations were found between demographic/clinical data and tecovirimat PK. All patients recovered completely within 14 (range 6-36) days of treatment initiation. CONCLUSIONS: This study found a significant decrease in plasma exposure of tecovirimat in Mpox patients with HIV on effective ART compared with those without HIV, with no evident impact on clinical outcomes. Although these results need to be confirmed in larger studies, they may provide useful information on the PK of tecovirimat.
Assuntos
Infecções por HIV , Mpox , Humanos , Masculino , Estudos Prospectivos , Infecções por HIV/tratamento farmacológico , HIVRESUMO
BACKGROUND: Remdesivir is the first antiviral drug against SARS-CoV-2 approved for use in COVID-19 patients. OBJECTIVES: To study the pharmacokinetic inter-individual variability of remdesivir and its main metabolite GS-441524 in a real-world setting of COVID-19 inpatients and to identify possible associations with different demographic/biochemical variables. METHODS: Inpatients affected by SARS-CoV-2 infections, undergoing standard-dose remdesivir treatment, were prospectively enrolled. Blood samples were collected on day 4, immediately after (C0) and at 1â h (C1) and 24â h (C24) after infusion. Remdesivir and GS-441524 concentrations were measured using a validated UHPLC-MS/MS method and the AUC0-24 was calculated. At baseline, COVID-19 severity (ICU or no ICU), sex, age, BMI and renal and liver functions were assessed. Transaminases and estimated glomerular filtration rate (e-GFR) were also evaluated during treatment. Linear regression, logistic regression and multiple linear regression tests were used for statistical comparisons of pharmacokinetic parameters and variables. RESULTS: Eighty-five patients were included. The mean (CV%) values of remdesivir were: C0 2091 (99.1%) ng/mL, C1 139.7 (272.4%) ng/mL and AUC0-24 2791 (175.7%) ng·h/mL. The mean (CV%) values of GS-441524 were: C0 90.2 (49.5%) ng/mL, C1 104.9 (46.6%) ng/mL, C24 58.4 (66.9) ng/mL and AUC0-24 1976 (52.6%) ng·h/mL. The multiple regression analysis showed that age (Pâ<â0.05) and e-GFR (Pâ<â0.01) were independent predictors of GS-441524 plasma exposure. CONCLUSIONS: Our results showed a high interpatient variability of remdesivir and GS-441524 likely due to both age and renal function in COVID-19 inpatients. Further research is required to understand whether the pharmacokinetics of remdesivir and its metabolites may influence drug-related efficacy or toxic effect.
Assuntos
Tratamento Farmacológico da COVID-19 , Adenosina/análogos & derivados , Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/efeitos adversos , Humanos , Pirróis , SARS-CoV-2 , Espectrometria de Massas em Tandem/métodos , Transaminases , TriazinasAssuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/sangue , Antivirais/metabolismo , Tratamento Farmacológico da COVID-19 , Monofosfato de Adenosina/sangue , Monofosfato de Adenosina/metabolismo , Monofosfato de Adenosina/uso terapêutico , Alanina/sangue , Alanina/metabolismo , Alanina/uso terapêutico , Antivirais/uso terapêutico , Terapia de Substituição Renal Contínua , Feminino , Humanos , Pessoa de Meia-IdadeRESUMO
The immunological mechanisms underlying the clinical presentation of SARS-CoV-2 infection and those influencing the disease outcome remain to be defined. Myeloid-derived suppressor cells (MDSC) have been described to be highly increased during COVID-19, however, their role remains elusive. We performed an in depth analysis of MDSC in 128 SARS-CoV-2 infected patients. Polymorphonuclear (PMN)-MDSC expanded during COVID-19, in particular in patients who required intensive care treatments, and correlated with IL-1ß, IL-6, IL-8, and TNF-α plasma levels. PMN-MDSC inhibited T-cells IFN-γ production upon SARS-CoV-2 peptides stimulation, through TGF-ß- and iNOS-mediated mechanisms, possibly contrasting virus elimination. Accordingly, a multivariate regression analysis found a strong association between PMN-MDSC percentage and fatal outcome of the disease. The PMN-MDSC frequency was higher in non-survivors than survivors at the admission time, followed by a decreasing trend. Interestingly, this trend was associated with IL-6 increase in non-survivors but not in survivors. In conclusion, this study indicates PMN-MDSC as a novel factor in the pathogenesis of SARS-CoV2 infection, and open up to new therapeutic options.
Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/patologia , Células Supressoras Mieloides/imunologia , Pneumonia Viral/patologia , Linfócitos T/imunologia , Idoso , Área Sob a Curva , Betacoronavirus/isolamento & purificação , Betacoronavirus/metabolismo , COVID-19 , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/virologia , Feminino , Humanos , Interferon gama/metabolismo , Interleucina-1beta/sangue , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Células Supressoras Mieloides/citologia , Neutrófilos/citologia , Neutrófilos/imunologia , Neutrófilos/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Pandemias , Peptídeos/imunologia , Peptídeos/metabolismo , Pneumonia Viral/imunologia , Pneumonia Viral/mortalidade , Pneumonia Viral/virologia , Modelos de Riscos Proporcionais , Curva ROC , SARS-CoV-2 , Taxa de Sobrevida , Linfócitos T/citologia , Linfócitos T/metabolismo , Fator de Crescimento Transformador beta/sangue , Fator de Crescimento Transformador beta/metabolismoRESUMO
BACKGROUND: Remdesivir is a prodrug of the nucleoside analogue GS-441524 and is under evaluation for treatment of SARS-CoV-2-infected patients. OBJECTIVES: To evaluate the pharmacokinetics of remdesivir and GS-441524 in plasma, bronchoalveolar aspirate (BAS) and CSF in two critically ill COVID-19 patients. METHODS: Remdesivir was administered at 200 mg loading dose on the first day followed by 12 days of 100 mg in two critically ill patients. Blood samples were collected immediately after (C0) and at 1 (C1) and 24 h (C24) after intravenous administration on day 3 until day 9. BAS samples were collected on Days 4, 7 and 9 from both patients while one CSF on Day 7 was obtained in one patient. Remdesivir and GS-441524 concentrations were measured in these samples using a validated UHPLC-MS/MS method. RESULTS: We observed higher concentrations of remdesivir at C0 (6- to 7-fold higher than EC50 from in vitro studies) and a notable decay at C1. GS-441524 plasma concentrations reached a peak at C1 and persisted until the next administration. Higher concentrations of GS-441524 were observed in the patient with mild renal dysfunction. Mean BAS/plasma concentration ratios of GS-441524 were 2.3% and 6.4% in Patient 1 and Patient 2, respectively. The CSF concentration found in Patient 2 was 25.7% with respect to plasma. GS-441524 levels in lung and CNS suggest compartmental differences in drug exposure. CONCLUSIONS: We report the first pharmacokinetic evaluation of remdesivir and GS-441524 in recovered COVID-19 patients. Further study of the pharmacokinetic profile of remdesivir, GS-441524 and the intracellular triphosphate form are required.
Assuntos
Monofosfato de Adenosina/análogos & derivados , Trifosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/farmacocinética , Betacoronavirus , Infecções por Coronavirus/metabolismo , Estado Terminal/terapia , Pneumonia Viral/metabolismo , Monofosfato de Adenosina/farmacocinética , Monofosfato de Adenosina/uso terapêutico , Trifosfato de Adenosina/farmacocinética , Trifosfato de Adenosina/uso terapêutico , Idoso , Alanina/farmacocinética , Alanina/uso terapêutico , Antivirais/uso terapêutico , COVID-19 , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/tratamento farmacológico , Feminino , Humanos , Masculino , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/tratamento farmacológico , Recuperação de Função Fisiológica/efeitos dos fármacos , Recuperação de Função Fisiológica/fisiologia , SARS-CoV-2Assuntos
Fármacos Anti-HIV/uso terapêutico , Disfunção Cognitiva/complicações , Disfunção Cognitiva/epidemiologia , Combinação Efavirenz, Emtricitabina, Fumarato de Tenofovir Desoproxila/uso terapêutico , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Adulto , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/sangue , Terapia Antirretroviral de Alta Atividade , Combinação Efavirenz, Emtricitabina, Fumarato de Tenofovir Desoproxila/efeitos adversos , Combinação Efavirenz, Emtricitabina, Fumarato de Tenofovir Desoproxila/sangue , Feminino , HIV , Infecções por HIV/psicologia , Humanos , Masculino , Adesão à Medicação , Testes de Estado Mental e Demência , Pessoa de Meia-Idade , Prevalência , Fatores de RiscoRESUMO
No data are available on the long-term immunovirological outcome of HIV-positive pregnant women experiencing sub-therapeutic antiretroviral drug (ARV) concentrations during pregnancy. The objective of our study was to assess the long-term virological outcome in pregnant women treated with HAART. A prospective, multi-center study enrolled 60 HIV-infected pregnant women stratified into 3 groups according to the response to HAART. Group A, women successfully treated with HAART; Group B, women with confirmed virological failure during HAART; Group C, women successfully treated with HAART during pregnancy for prevention of vertical transmission only. Smoking, alcohol use, low adherence to therapy, and increased viral load at delivery were significantly associated to virological failure at univariate analysis. At multivariate regression analysis, only adherence to therapy was reported as an independent variable related to the virological response (p < 0.001). Virological failure during follow-up was reported in 2 (25.0%) of the 8 women with sub therapeutic Ctrough and in 4 of the 33 (12.1%) women with therapeutic Ctrough (p=0.33). In group C, the viro-immunological set points during follow-up did not differ from those observed before HAART initiation. No significantly increased rate of virological failure after delivery was reported in women with sub-therapeutic ARV concentrations during pregnancy and long-term follow-up. The long-term virological outcome was independently associated to reduced adherence to therapy. Evaluation of the clinical impact of the low plasma ARV concentrations during pregnancy on the long-term virological outcome deserves further larger studies.
Assuntos
Fármacos Anti-HIV/farmacologia , Terapia Antirretroviral de Alta Atividade , Monitoramento de Medicamentos , Soropositividade para HIV/imunologia , HIV-1/imunologia , Complicações Infecciosas na Gravidez/imunologia , Complicações Infecciosas na Gravidez/virologia , Adulto , Contagem de Linfócito CD4 , Feminino , Seguimentos , Soropositividade para HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Humanos , Lactente , Recém-Nascido , Estudos Longitudinais , Masculino , Gravidez , Complicações Infecciosas na Gravidez/tratamento farmacológico , Resultado da Gravidez , Estudos Prospectivos , Resultado do Tratamento , Carga ViralRESUMO
The case of a 32-year-old Caucasian female with multi-drug resistant HIV-1 subtype B infection treated with a salvage regimen including maraviroc, raltegravir, etravirine and unboosted saquinavir who started atovaquone/proguanil prophylaxis, is reported. The potential interactions between atovaquone/proguanil and these anti-retroviral drugs are investigated. Pharmacokinetic analyses documented a marked increase in etravirine and saquinavir plasma concentrations (+55% and +274%, respectively), but not in raltegravir and maraviroc plasma concentrations. The evidence that atovaquone/proguanil significantly interacts with etravirine and saquinavir, but not with raltegravir and maraviroc, suggests that the mechanism of interaction is related to cytochrome P450.
Assuntos
Fármacos Anti-HIV/farmacocinética , Antimaláricos/administração & dosagem , Atovaquona/administração & dosagem , Interações Medicamentosas , Plasma/química , Proguanil/administração & dosagem , Piridazinas/farmacocinética , Saquinavir/farmacocinética , Adulto , Quimioprevenção/métodos , Combinação de Medicamentos , Feminino , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Humanos , Malária/prevenção & controle , Nitrilas , PirimidinasRESUMO
Multicompartment nanoscopic carriers can be easily assembled by inducing the aggregation of anionic "hybrid" niosomes by means of cationic biocompatible polyelectrolytes. The resulting vesicle clusters, whose size and overall net charge can be easily controlled by varying the polyelectrolyte-to-particle charge ratio, show an interesting potential for multidrug delivery. In this article we provide strong evidence for their effective use in vitro as multicompartment vectors selectively directed toward monocyte/macrophage cells, showing that the monocyte/macrophage-mediated activation of Tγδ lymphocytes induced by zoledronic acid is enhanced by a factor 10(3) when the zoledronic acid is intracellularly delivered through these carriers. Furthermore, the multicompartment É-polylysine niosome clusters, with their intrinsic selectivity toward macrophages, appear particularly suitable for implementing therapeutic strategies against chronically infected macrophages. FROM THE CLINICAL EDITOR: É-polylysine niosome clusters, with their intrinsic selectivity toward macrophages, offer the potential for multidrug delivery. The effectiveness of aminobisphosphonate zoledronate is demonstrated to enhance the recruitment of Tγδ lymphocytes by macrophages by 2 orders of magnitude, suggesting a new therapeutic strategy for addressing pathologies featuring chronically infected macrophages.
Assuntos
Conservadores da Densidade Óssea/administração & dosagem , Difosfonatos/administração & dosagem , Imidazóis/administração & dosagem , Ativação Linfocitária/efeitos dos fármacos , Linfócitos T/metabolismo , Conservadores da Densidade Óssea/metabolismo , Difosfonatos/metabolismo , Humanos , Imidazóis/metabolismo , Leucócitos/metabolismo , Lipossomos , Macrófagos/metabolismo , Nanomedicina , Polilisina/química , Polilisina/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Ácido ZoledrônicoRESUMO
OBJECTIVE: gammadelta T cells bearing the Vgamma9Vdelta2 T-cell receptor exert many antiviral effector functions in humans, including release of anti-HIV factors and direct cytotoxicity against virus-infected cells. Moreover, they are known to activate dendritic cells, improving antigen presentation function. After HIV infection, Vgamma9Vdelta2 T-cell number and reactivity are rapidly affected and they decrease upon disease progression. Bisphosphonate drugs such as zoledronic acid (Zol), used to treat bone diseases, have been shown to induce in vivo, in combination with interleukin-2, Vgamma9Vdelta2 T-cells' activation. The aim of this work was to verify whether the administration of Zol in combination with interleukin-2 in HIV-infected patients might improve Vgamma9Vdelta2 T-cell function, including immune adjuvancy mediated by gammadelta-dendritic cell cross-talk. DESIGN AND METHODS: In HIV patients naive to antiretroviral therapy, we analyzed the effect of combined Zol and interleukin-2 treatment, in comparison to Zol alone, on Vgamma9Vdelta2 T-cell number, maturation and function, on dendritic cell activation and on HIV-specific CD8 T-cell response. RESULTS: Zol and interleukin-2-combined treatment induced in-vivo Vgamma9Vdelta2 T-cell expansion and maturation. Paralleling Vgamma9Vdelta2 T-cell activation, increased dendritic cell maturation and HIV-specific CD8 T-cell responses were found. CONCLUSION: The specific modulation of Vgamma9Vdelta2 T-cell number and responsiveness after HIV infection may be at least transiently restored in vivo by Zol and interleukin-2 treatment. In this way, the immune effector mechanisms, secondary to Vgamma9Vdelta2 T-cell activation, were improved, suggesting a possible adjuvancy role of Zol and interleukin-2 treatment in restoring innate and specific competence in HIV-infected persons.
Assuntos
Difosfonatos/farmacologia , Infecções por HIV/imunologia , HIV-1 , Imidazóis/farmacologia , Interleucina-2/farmacologia , Receptores de Antígenos de Linfócitos T gama-delta/análise , Linfócitos T Citotóxicos/efeitos dos fármacos , Adjuvantes Imunológicos/farmacologia , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Citotoxicidade Imunológica , Células Dendríticas/efeitos dos fármacos , Quimioterapia Combinada , Infecções por HIV/tratamento farmacológico , Humanos , Imunocompetência/efeitos dos fármacos , Memória Imunológica , Imunofenotipagem , Ativação Linfocitária/efeitos dos fármacos , Contagem de Linfócitos , Proteínas Recombinantes/farmacologia , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Linfócitos T Citotóxicos/imunologia , Ácido ZoledrônicoRESUMO
BACKGROUND/AIMS: Hepatitis C virus (HCV) causes a chronic infection that can lead to fibrosis and carcinoma. Immune responses mediated by cytotoxic T lymphocytes (CTLs) could be involved in viral clearance or persistence, and therefore in determining the course of the disease. METHODS: Intrahepatic and peripheral blood CD8+T cells were obtained from 32 HCV-chronically infected patients and analysed by flow-cytometry for surface markers of differentiation, IFNgamma and TNFalpha production, degranulation capacity and perforin content, after CD3 triggering. Results were compared with those obtained from 13 patients with a non-viral liver disease. RESULTS: Intrahepatic CD8+T cells of HCV-infected patients, despite their phenotype of pre-terminally and terminally differentiated effectors (CCR7-CD45RA-/+), are poorly responsive to T cell receptor (TCR)-mediated stimulation compared with those obtained from uninfected subjects. This defect correlates with the severity of fibrosis, is more pronounced in patients with ALT<1.5xN than with ALT>1.5xNU/ml, and is not evident after mitogen stimulation. CONCLUSIONS: The present study describes the accumulation of hypo-responsive CD8+T cells in the liver of patients with chronic HCV infection. Understanding the mechanisms underlying this impairment may be helpful in the design of innovative strategies for HCV treatment.