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1.
Molecules ; 26(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206357

RESUMO

In the current work, a simple, economical, accurate, and precise HPLC method with UV detection was developed to quantify Favipiravir (FVIR) in spiked human plasma using acyclovir (ACVR) as an internal standard in the COVID-19 pandemic time. Both FVIR and ACVR were well separated and resolved on the C18 column using the mobile phase blend of methanol:acetonitrile:20 mM phosphate buffer (pH 3.1) in an isocratic mode flow rate of 1 mL/min with a proportion of 30:10:60 %, v/v/v. The detector wavelength was set at 242 nm. Maximum recovery of FVIR and ACVR from plasma was obtained with dichloromethane (DCM) as extracting solvent. The calibration curve was found to be linear in the range of 3.1-60.0 µg/mL with regression coefficient (r2) = 0.9976. However, with acceptable r2, the calibration data's heteroscedasticity was observed, which was further reduced using weighted linear regression with weighting factor 1/x. Finally, the method was validated concerning sensitivity, accuracy (Inter and Intraday's % RE and RSD were 0.28, 0.65 and 1.00, 0.12 respectively), precision, recovery (89.99%, 89.09%, and 90.81% for LQC, MQC, and HQC, respectively), stability (% RSD for 30-day were 3.04 and 1.71 for LQC and HQC, respectively at -20 °C), and carry-over US-FDA guidance for Bioanalytical Method Validation for researchers in the COVID-19 pandemic crisis. Furthermore, there was no significant difference for selectivity when evaluated at LLOQ concentration of 3 µg/mL of FVIR and relative to the blank.


Assuntos
Amidas/análise , Amidas/sangue , Antivirais/análise , Antivirais/sangue , Bioensaio/métodos , COVID-19/tratamento farmacológico , Cromatografia Líquida de Alta Pressão/métodos , Extração Líquido-Líquido/métodos , Pirazinas/análise , Pirazinas/sangue , Aciclovir/análise , Aciclovir/sangue , COVID-19/sangue , Calibragem , Estabilidade de Medicamentos , Congelamento , Humanos , Padrões de Referência , Reprodutibilidade dos Testes , Solventes/química
2.
J Clin Pharmacol ; 60(2): 240-255, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31489678

RESUMO

Pregnancy is associated with physiological changes that may impact drug pharmacokinetics (PK). The goals of this study were to build maternal-fetal physiologically based pharmacokinetic (PBPK) models for acyclovir and emtricitabine, 2 anti(retro)viral drugs with active renal net secretion, and to (1) evaluate the predicted maternal PK at different stages of pregnancy; (2) predict the changes in PK target parameters following the current dosing regimen of these drugs throughout pregnancy; (3) evaluate the predicted concentrations of these drugs in the umbilical vein at delivery; (4) compare the model performance for predicting maternal PK of emtricitabine in the third trimester with that of previously published PBPK models; and (5) compare different previously published approaches for estimating the placental permeability of these 2 drugs. Results showed that the pregnancy PBPK model for acyclovir predicted all maternal concentrations within a 2-fold error range, whereas the model for emtricitabine predicted 79% of the maternal concentrations values within that range. Extrapolation of these models to earlier stages of pregnancy indicated that the change in the median PK target parameters remained well above the target threshold. Concentrations of acyclovir and emtricitabine in the umbilical vein were overall adequately predicted. The comparison of different emtricitabine PBPK models suggested an overall similar predictive performance in the third trimester, but the comparison of different approaches for estimating placental drug permeability revealed large differences. These models can enhance the understanding of the PK behavior of renally excreted drugs, which may ultimately inform pharmacotherapeutic decision making in pregnant women and their fetuses.


Assuntos
Aciclovir/farmacocinética , Fármacos Anti-HIV/farmacocinética , Antivirais/farmacocinética , Emtricitabina/farmacocinética , Complicações Infecciosas na Gravidez/metabolismo , Aciclovir/sangue , Adulto , Fármacos Anti-HIV/sangue , Antivirais/sangue , Ensaios Clínicos como Assunto , Simulação por Computador , Esquema de Medicação , Emtricitabina/sangue , Feminino , Feto/metabolismo , Humanos , Troca Materno-Fetal , Modelos Biológicos , Placenta/metabolismo , Gravidez/sangue , Complicações Infecciosas na Gravidez/tratamento farmacológico , Trimestres da Gravidez/metabolismo , Eliminação Renal , Veias Umbilicais/metabolismo
3.
Pharm Dev Technol ; 24(10): 1299-1307, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31507245

RESUMO

Acyclovir (ACV) is widely used in the treatment of herpes encephalitis. The present study was conducted to prepare chitosan-tween 80 coated solid lipid nanoparticles (SLNs) as a delivery system for brain targeting of ACV in rabbits. The SLNs were prepared and coated in one step by microemulsion method using a coating solution containing chitosan (0.1% w/v) and tween 80 (2% w/v) for loading sustained release ACV. In vitro characterization was performed for coated ACV-SLNs. Concerning in vivo experiments; a single intravenous bolus dose of coated ACV-SLNs was given versus free ACV solution to rabbits (62 mg/kg). Plasma pharmacokinetic parameters were calculated from the ACV concentration-time profiles in plasma using the two compartmental analysis. The values of AUC0-∞ and MRT of coated ACV-SLNs were higher than free drug by about twofold, 233.36 ± 41.56 µg.h/mL and 1.81 ± 0.36 h, respectively. The noncompartmental analysis was conducted to estimate the brain pharmacokinetic parameters. The AUC0-∞ brain/AUC0-∞ plasma ratio for coated ACV-SLNs and free ACV was 0.22 and 0.12, respectively. These results indicated the effectiveness of using coated ACV-SLNs for brain targeting.


Assuntos
Aciclovir/farmacocinética , Antivirais/farmacocinética , Encéfalo/metabolismo , Portadores de Fármacos/química , Lipídeos/química , Nanopartículas/química , Aciclovir/sangue , Aciclovir/química , Animais , Antivirais/sangue , Antivirais/química , Área Sob a Curva , Quitosana/química , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Polissorbatos/química , Coelhos
4.
Eur J Pharm Sci ; 123: 560-568, 2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-30081070

RESUMO

In this study, a physiologically based pharmacokinetic (PBPK) model was established for valacyclovir based on absolute expression quantity of hPEPT1 along the entire length of the human intestine and other reliable in vitro, in vivo observed data. The PBPK model-3 defined acyclovir as metabolite of valacyclovir and simulated the plasma concentration-time profiles of valacyclovir and acyclovir simultaneously. It was validated strictly by a series of observed plasma concentration-time profiles. The average fold error (AFE) and absolute average fold error (AAFE) values were all smaller than 2. Then, it was used to quantitatively evaluate the effect of hPEPT1, luminal degradation rate, drug release rate and gastric residence time on the oral absorption of valacyclovir and acyclovir. The PBPK model-3 suggests that mainly 75% of valacyclovir was absorbed by active transport of hPEPT1. The luminal degradation of valacyclovir in the upper intestinal lumen cannot be considered the only reason for its incomplete bioavailability. The plasma concentration-time profiles of valacyclovir and its metabolite acyclovir were not sensitive to dissolution rate faster than T85% = 120 min. Prolonged gastric residence time of sustained release tablet can improve the oral absorption of valacyclovir. All in all, the PBPK model-3 in this study is reliable and accurate. It is useful for the research of clinical application and dosage forms design of valacyclovir.


Assuntos
Aciclovir/farmacocinética , Antivirais/farmacocinética , Absorção Intestinal , Intestinos/enzimologia , Modelos Biológicos , Transportador 1 de Peptídeos/metabolismo , Pró-Fármacos/farmacocinética , Valaciclovir/farmacocinética , Aciclovir/administração & dosagem , Aciclovir/sangue , Administração Oral , Adulto , Animais , Antivirais/administração & dosagem , Antivirais/sangue , Disponibilidade Biológica , Biotransformação , Preparações de Ação Retardada , Liberação Controlada de Fármacos , Feminino , Humanos , Hidrólise , Masculino , Camundongos , Pró-Fármacos/administração & dosagem , Ratos , Reprodutibilidade dos Testes , Comprimidos , Valaciclovir/administração & dosagem , Valaciclovir/sangue
5.
Artigo em Inglês | MEDLINE | ID: mdl-29945109

RESUMO

It is challenging to conduct a pharmacokinetic (PK) study on mice due to the limited amount of plasma one can obtain, which is also true for some clinical studies. Here, we developed and validated a simple, sensitive and robust LC-MS/MS method for measuring the prodrug valacyclovir (VACV) and its metabolite acyclovir (ACV) in mouse and human plasma. This assay utilized an acetonitrile protein precipitation method with isotope-labeled internal standards (IS) and enabled precise and accurate quantification of VACV and ACV in 10 µL plasma samples with a nine-min gradient. The analytes were separated on a Waters Atlantis T3 C18 column. The precursor-product ion transitions for VACV (m/z 325.2 > 152.1), ACV (m/z 226.2 > 152.1), VACV-D4 (m/z 329.2 > 152.1, IS) and ACV-D4 (m/z 230.2 > 152.1, IS) were detected in a multiple reaction monitoring (MRM) positive ion mode using an API4000 LC-MS/MS system. The lower limit of quantification (LLOQ) was 2 nM for both VACV and ACV. The linear range was validated over the concentration ranges of 2-200 nM and 200-5000 nM for both compounds. The matrix effect and stability of VACV and ACV were also evaluated. This assay was successfully applied to a PK study in mice.


Assuntos
Aciclovir/análogos & derivados , Cromatografia Líquida/métodos , Espectrometria de Massas em Tandem/métodos , Valina/análogos & derivados , Aciclovir/sangue , Aciclovir/química , Aciclovir/farmacocinética , Animais , Estabilidade de Medicamentos , Humanos , Modelos Lineares , Camundongos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Valaciclovir , Valina/sangue , Valina/química , Valina/farmacocinética
6.
Eur J Drug Metab Pharmacokinet ; 43(6): 693-706, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29748821

RESUMO

BACKGROUND AND OBJECTIVES: The helicase-primase inhibitor amenamevir (ASP2151) is a novel therapeutic agent which has been approved for the treatment of herpes zoster. The present study examined the pharmacokinetic profile of amenamevir in rodents and compared it with data from the literature of past and current established therapies (acyclovir and valaciclovir) to provide additional data to facilitate drug discovery and proper drug use. METHODS: In situ absorption, blood and plasma radioactivity concentrations, tissue distribution, and excretion were determined using liquid scintillation counting. Plasma amenamevir concentrations were measured using a validated chromatographic method. Chemical structures of in vivo metabolites were investigated using liquid chromatography-mass spectrometry and nuclear magnetic resonance spectroscopy. RESULTS: Amenamevir, after single intravenous administration to mice, had an elimination half-life of 2 h. Bioavailability was 40% after single oral administration. In situ absorption data indicated that amenamevir is mainly absorbed in the small intestine. The main component in mouse plasma was amenamevir, accounting for 87.9% of amenamevir-derived components. Our results suggest that the main elimination pathway in mice is oxidative metabolism at a methyl group and a 1,2,3-trisubstituted benzene ring followed by biliary and fecal excretion. Following oral administration of 14C-amenamevir to mice, 100.63% of the dose (10.06% in urine and 90.46% in feces) was excreted by 96 h post-dose. CONCLUSIONS: The underlying mechanism of the improved pharmacokinetic profile of amenamevir was linked to an improved absorption ratio (not hepatic availability) compared to acyclovir, and qualitative differences in elimination (slow metabolism of amenamevir vs rapid urinary excretion of acyclovir/valaciclovir).


Assuntos
Aciclovir/farmacocinética , Oxidiazóis/farmacocinética , Valaciclovir/farmacocinética , Aciclovir/sangue , Animais , Disponibilidade Biológica , Radioisótopos de Carbono/farmacocinética , Masculino , Camundongos , Oxidiazóis/sangue , Ratos , Distribuição Tecidual , Valaciclovir/sangue
7.
Biomed Chromatogr ; 32(6): e4194, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29349796

RESUMO

Time-concentration curves for the topical anti-viral drug acyclovir can provide valuable information for drug development. Open flow microperfusion is used for continuous sampling of dermal interstitial fluid but it requires validated methods for subsequent sample analysis. Therefore, we developed a sensitive, selective and high-throughput ultra-high-performance liquid chromatography-high-resolution tandem mass spectrometry method to determine acyclovir in human dermal interstitial fluid and serum. We validated the method over a concentration range of 0.1-25 ng/mL for a sample volume of just 20 µL and employed cation-exchange solid-phase extraction in a fully automated sample treatment procedure. Short- and long-term sample stability data and the analysis of 5000 samples from a clinical trial demonstrate the successful application of our method.


Assuntos
Aciclovir/análise , Aciclovir/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Derme/citologia , Líquido Extracelular/química , Espectrometria de Massas em Tandem/métodos , Aciclovir/sangue , Derme/química , Derme/metabolismo , Líquido Extracelular/metabolismo , Humanos , Limite de Detecção , Modelos Lineares , Reprodutibilidade dos Testes , Extração em Fase Sólida , Equivalência Terapêutica
8.
Antiviral Res ; 146: 205-212, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28939476

RESUMO

Recurrent herpes simplex keratitis (HSK) is a leading infectious cause of blindness in industrialized countries. Antiviral prophylaxis (AVP) may fail to prevent recurrence of HSK due to viral resistance, inadequate dosing, or poor patient compliance. In this prospective multicenter study, we enrolled immunocompetent patients with recurrent HSK despite AVP. Ocular samples were tested by PCR for herpes simplex virus 1 (HSV-1). HSV-1 drug resistance was assessed with a genotypic assay based on UL23 and UL30 gene sequencing. After curative full dose valacyclovir (VACV) treatment was started, peak and trough acyclovir (ACV) plasma concentrations were measured, and patient compliance to AVP was assessed with a questionnaire. The study sample was comprised of 43 patients. Six (14%) patients were positive for HSV-1 using PCR, of whom 5 (83%) harbored genotypically ACV-resistant (ACVR) virus, due to mutations in UL23 (n = 4) or UL30 (n = 1). Disease duration was statistically significantly longer in patients with viral resistance compared to other HSK patients [35.5 ± 23.4 years (range, 6.8-68.4 years) versus 11.1 ± 12.3 years (range, 0.8-56.3 year) respectively; Mann-Whitney p = 0.01)]. While patients were treated with full dose VACV, trough ACV plasma concentrations were below the threshold for ACV sensitivity in 9.5% of cases, and compliance was poor in 5.3% of cases. To summarize, HSV-1 resistance to ACV seems to be a significant cause of failure of prophylaxis in patients with HSK and is associated with longer disease duration. Most PCR-positive samples contained genotypically ACVR virus and identification may aid in adapting treatment. Incomplete 24-h drug coverage may also explain some cases of failure of prophylaxis.


Assuntos
Antivirais/administração & dosagem , Antivirais/sangue , Herpesvirus Humano 1/efeitos dos fármacos , Ceratite Herpética/virologia , Aciclovir/administração & dosagem , Aciclovir/análogos & derivados , Aciclovir/sangue , Aciclovir/uso terapêutico , Adolescente , Adulto , Idoso , Antivirais/uso terapêutico , Criança , Pré-Escolar , Farmacorresistência Viral/genética , Feminino , Herpes Simples/tratamento farmacológico , Herpes Simples/virologia , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/isolamento & purificação , Humanos , Lactente , Ceratite Herpética/tratamento farmacológico , Ceratite Herpética/epidemiologia , Ceratite Herpética/etiologia , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Estudos Prospectivos , Recidiva , Lágrimas/virologia , Valaciclovir , Valina/administração & dosagem , Valina/análogos & derivados , Valina/uso terapêutico , Adulto Jovem
9.
Pharm Res ; 34(11): 2349-2361, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28770489

RESUMO

PURPOSE: We developed simulation and modeling methods to predict the in vivo pharmacokinetic profiles of acyclovir, following escalating oral doses of valacyclovir, in wildtype and Pept1 knockout mice. We also quantitated the contribution of specific intestinal segments in the absorption of valacyclovir in these mice. METHODS: Simulations were conducted using a mechanistic advanced compartmental absorption and transit (ACAT) model implemented in GastroPlus™. Simulations were performed for 3 h post-dose in wildtype and Pept1 knockout mice following single oral doses of 10, 25, 50 and 100 nmol/g valacyclovir, and compared to experimentally observed plasma concentration-time profiles of acyclovir. RESULTS: Good fits were obtained in wildtype and Pept1 knockout mice. Valacyclovir was primarily absorbed from duodenum (42%) and jejunum (24%) of wildtype mice, with reduced uptake from ileum (3%) and caecum/colon (1%), for a total of 70% absorption. In contrast, the absorption of valacyclovir in Pept1 knockout mice was slow and sustained throughout the entire intestinal tract in which duodenum (4%), jejunum (14%), ileum (10%) and caecum/colon (12%) accounted for a total of 40% absorption. CONCLUSION: The ACAT model bridged the gap between in situ and in vivo experimental findings, and facilitated our understanding of the complicated intestinal absorption processes of valacyclovir.


Assuntos
Aciclovir/análogos & derivados , Antivirais/farmacocinética , Simulação por Computador , Absorção Intestinal , Modelos Biológicos , Transportador 1 de Peptídeos/genética , Valina/análogos & derivados , Aciclovir/sangue , Aciclovir/farmacocinética , Administração Oral , Animais , Antivirais/sangue , Relação Dose-Resposta a Droga , Mucosa Intestinal/metabolismo , Camundongos , Camundongos Knockout , Permeabilidade , Valaciclovir , Valina/sangue , Valina/farmacocinética
11.
J Liposome Res ; 27(4): 283-292, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27558522

RESUMO

Niosomes suggest a versatile vesicle delivery system with possible transport of drugs via topical route for skin delivery. The aim of the present research was to optimize niosome gel formulation of acyclovir and to evaluate in both in vitro and in vivo rabbit model. Niosome formulations were formulated by coacervation phase separation technique with different ratios of nonionic surfactants, phospholipids and cholesterol using 32 factorial design. Altering the surfactant concentration has influenced the drug entrapment, but not vesicle size. At high surfactant combinations, the acyclovir release from niosomes was strongly influenced by cholesterol:lecithin ratio. Ex vivo drug permeation data indicate substantial difference in flux values and was influenced by the niosome composition. Ex vivo studies using formulation (B8) for drug deposition indicate greater amount of niosome being diffused into the skin layers and formed a depot, compared to commercial acyclovir cream (control). Two distinct dermatopharmacokinetic profiles were observed, in vivo, for niosome gel formulation (B8) and control, which were analog to the profiles observed with ex vivo deposition studies. In vivo plasma drug level suggests low systemic exposure of acyclovir (Cmax: 9.44 ± 2.27 ng/mL and 14.54 ± 3.11 ng/mL for niosome formulation and control, respectively). Comparison of kinetic data of acyclovir in the stratum corneum and plasma signifies that the niosome formulation forms a depot in the epidermis or dermis region. This study concludes that the niosome gel formulation (B8) could be a viable vesicular system for an impressive transdermal delivery of acyclovir by topical application.


Assuntos
Aciclovir/química , Aciclovir/farmacocinética , Lipossomos/química , Dermatopatias/tratamento farmacológico , Aciclovir/administração & dosagem , Aciclovir/sangue , Administração Cutânea , Animais , Química Farmacêutica/métodos , Colesterol/química , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Humanos , Lecitinas/química , Limite de Detecção , Nanopartículas/química , Tamanho da Partícula , Coelhos , Absorção Cutânea , Propriedades de Superfície
12.
Drug Metab Dispos ; 45(2): 137-144, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27895114

RESUMO

Despite peptide transporter 1 (PEPT1) being responsible for the bioavailability for a variety of drugs, there has been little study of its potential involvement in drug-drug interactions. Pomaglumetad methionil, a metabotropic glutamate 2/3 receptor agonist prodrug, utilizes PEPT1 to enhance absorption and bioavailability. In vitro studies were conducted to guide the decision to conduct a clinical drug interaction study and to inform the clinical study design. In vitro investigations determined the prodrug (LY2140023 monohydrate) is a substrate of PEPT1 with Km value of approximately 30 µM, whereas the active moiety (LY404039) is not a PEPT1 substrate. In addition, among the eight known PEPT1 substrates evaluated in vitro, valacyclovir was the most potent inhibitor (IC50 = 0.46 mM) of PEPT1-mediated uptake of the prodrug. Therefore, a clinical drug interaction study was conducted to evaluate the potential interaction between the prodrug and valacyclovir in healthy subjects. No effect of coadministration was observed on the pharmacokinetics of the prodrug, valacyclovir, or either of their active moieties. Although in vitro studies showed potential for the prodrug and valacyclovir interaction via PEPT1, an in vivo study showed no interaction between these two drugs. PEPT1 does not appear to easily saturate because of its high capacity and expression in the intestine. Thus, a clinical interaction at PEPT1 is unlikely even with a compound with high affinity for the transporter.


Assuntos
Aciclovir/análogos & derivados , Aminoácidos/metabolismo , Transportador 1 de Peptídeos/metabolismo , Pró-Fármacos/metabolismo , Receptores de Glutamato Metabotrópico/agonistas , Valina/análogos & derivados , Aciclovir/administração & dosagem , Aciclovir/sangue , Aciclovir/metabolismo , Aciclovir/urina , Adolescente , Adulto , Idoso , Aminoácidos/administração & dosagem , Aminoácidos/sangue , Aminoácidos/urina , Transporte Biológico , Compostos Bicíclicos Heterocíclicos com Pontes/sangue , Compostos Bicíclicos Heterocíclicos com Pontes/urina , Óxidos S-Cíclicos/sangue , Óxidos S-Cíclicos/urina , Interações Medicamentosas , Feminino , Células HeLa , Humanos , Masculino , Pessoa de Meia-Idade , Pró-Fármacos/administração & dosagem , Pró-Fármacos/farmacocinética , Especificidade por Substrato , Valaciclovir , Valina/administração & dosagem , Valina/sangue , Valina/metabolismo , Valina/urina , Adulto Jovem
13.
Am J Vet Res ; 77(8): 833-45, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27463546

RESUMO

OBJECTIVES To determine, following oral administration of famciclovir, pharmacokinetic (PK) parameters for 2 of its metabolites (penciclovir and BRL42359) in plasma and tears of healthy cats so that famciclovir dosage recommendations for the treatment of herpetic disease can be optimized. ANIMALS 7 male domestic shorthair cats. PROCEDURES In a crossover study, each of 3 doses of famciclovir (30, 40, or 90 mg/kg) was administered every 8 or 12 hours for 3 days. Six cats were randomly assigned to each dosage regimen. Plasma and tear samples were obtained at predetermined times after famciclovir administration. Pharmacokinetic parameters were determined for BRL42359 and penciclovir by compartmental and noncompartmental methods. Pharmacokinetic-pharmacodynamic (PK-PD) indices were determined for penciclovir and compared among all dosage regimens. RESULTS Compared with penciclovir concentrations, BRL42359 concentrations were 5- to 11-fold greater in plasma and 4- to 7-fold greater in tears. Pharmacokinetic parameters and PK-PD indices for the 90 mg/kg regimens were superior to those for the 30 and 40 mg/kg regimens, regardless of dosing frequency. Penciclovir concentrations in tears ranged from 18% to 25% of those in plasma. Administration of 30 or 40 mg/kg every 8 hours achieved penciclovir concentrations likely to be therapeutic in plasma but not in tears. Penciclovir concentrations likely to be therapeutic in tears were achieved only with the two 90 mg/kg regimens. CONCLUSIONS AND CLINICAL RELEVANCE In cats, famciclovir absorption is variable and its metabolism saturable. Conversion of BRL42359 to penciclovir is rate limiting. The recommended dosage of famciclovir is 90 mg/kg every 12 hours for cats infected with feline herpesvirus.


Assuntos
2-Aminopurina/análogos & derivados , Aciclovir/análogos & derivados , Antivirais/farmacocinética , Gatos/metabolismo , Lágrimas/metabolismo , 2-Aminopurina/administração & dosagem , 2-Aminopurina/sangue , 2-Aminopurina/farmacocinética , Aciclovir/administração & dosagem , Aciclovir/sangue , Aciclovir/farmacocinética , Administração Oral , Animais , Antivirais/administração & dosagem , Antivirais/sangue , Área Sob a Curva , Estudos Cross-Over , Relação Dose-Resposta a Droga , Famciclovir , Guanina , Masculino , Organismos Livres de Patógenos Específicos
14.
Mater Sci Eng C Mater Biol Appl ; 61: 858-64, 2016 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-26838917

RESUMO

An electrochemical sensor for the sensitive detection of acyclovir was developed by the electropolymerization of Eriochrome black T at a pretreated glassy carbon electrode. The surface morphology of the modified electrode was characterized by field emission scanning electron microscopy. Under the optimized conditions, a significant electrochemical improvement was observed toward the electrooxidation of acyclovir on the modified electrode surface relative to the unmodified electrode. The detection limit of 12 nM and two linear calibration ranges of 0.03-0.3 µM and 0.3-1.5 µM were obtained for acyclovir determination using a differential pulse voltammetric method in acetate buffer (0.1 M, pH 4.0). Real sample studies were carried out in human blood serum and pharmaceutical formulations, which offered good recovery (98-102%). The electrode showed excellent reproducibility, selectivity and antifouling effects.


Assuntos
Aciclovir/análise , Antivirais/análise , Técnicas Eletroquímicas , Polímeros/química , Aciclovir/sangue , Antivirais/sangue , Carbono/química , Eletrodos , Vidro/química , Humanos , Concentração de Íons de Hidrogênio , Limite de Detecção , Oxirredução , Reprodutibilidade dos Testes , Comprimidos/química
15.
Drug Deliv Transl Res ; 6(3): 299-307, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26902907

RESUMO

The purpose of this investigation was to prepare and characterize acyclovir loaded floating microspheres by emulsification solvent evaporation method. Piperine was added to investigate its effect on acyclovir bioavailability. The microspheres were characterized for size, shape, entrapment efficiency, in vitro drug release, and in vivo pharmacokinetic parameters. The morphological characterization of microspheres was done using a scanning electron microscope. The microspheres were spherical and had particle size in the range of 400 to 525 µm. The percent drug entrapment efficiency varied between 56.12 ± 1.32 % to 87.32 ± 5.28 %. The drug release was decreased at higher polymer concentrations. Nearly two times higher AUC0-24 value of acyclovir-loaded piperine containing microspheres (15614.13 ± 6953.13 ng h ml(-1)) was observed as compared to the drug solution (7552.33 ± 3219.09 ng h ml(-1)). Under the accelerated storage conditions, the best selected formulation was found to be stable for 90 days. The preliminary results of this study suggest that the developed microspheres containing acyclovir could enhance drug entrapment efficiency, reduce initial burst release, and prolong the drug release with enhanced bioavailability.


Assuntos
Aciclovir/farmacocinética , Alcaloides/farmacocinética , Benzodioxóis/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Microesferas , Piperidinas/farmacocinética , Alcamidas Poli-Insaturadas/farmacocinética , Trato Gastrointestinal Superior/metabolismo , Aciclovir/sangue , Aciclovir/química , Alcaloides/farmacologia , Animais , Benzodioxóis/farmacologia , Disponibilidade Biológica , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Microscopia Eletrônica de Varredura , Tamanho da Partícula , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Ratos , Solubilidade
16.
Antimicrob Agents Chemother ; 60(3): 1830-3, 2016 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-26824940

RESUMO

The current recommendations for intravenous (i.v.) acyclovir dosing in obese patients suggest using ideal body weight (IBW) rather than total body weight (TBW). To our knowledge, no pharmacokinetic analysis has validated this recommendation. This single-dose pharmacokinetic study was conducted in an inpatient oncology population. Enrollment was conducted by 1:1 matching of obese patients (>190% of IBW) to normal-weight patients (80 to 120% of IBW). All patients received a single dose of i.v. acyclovir, 5 mg/kg, infused over 60 min. Consistent with current recommendations, IBW was used for obese patients and TBW for normal-weight patients. Serial plasma concentrations were obtained and compared. Seven obese and seven normal-weight patients were enrolled, with mean body mass indexes of 45.0 and 22.5 kg/m(2), respectively. Systemic clearance was substantially higher in the obese than normal-weight patients (mean, 19.4 ± 5.3 versus 14.3 ± 5.4 liters/h; P = 0.047). Area under the concentration-time curve was lower in the obese patients (15.2 ± 2.9 versus 24.0 ± 9.4 mg · h/liter; P = 0.011), as was maximum concentration (5.8 ± 0.9 versus 8.2 ± 1.3 mg/liter; P = 0.031). Utilization of IBW for dose calculation of i.v. acyclovir in obese patients leads to lower systemic exposure than dosing by TBW in normal-weight patients. While not directly evaluated in this study, utilization of an adjusted body weight for dose determination appears to more closely approximate the exposure seen in normal-weight patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT01714180.).


Assuntos
Aciclovir/sangue , Aciclovir/farmacocinética , Cálculos da Dosagem de Medicamento , Obesidade/sangue , Índice de Massa Corporal , Feminino , Humanos , Peso Corporal Ideal , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
17.
Mater Sci Eng C Mater Biol Appl ; 53: 134-41, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26042700

RESUMO

A novel voltammetric sensor based on glassy carbon electrode (GCE) modified with a thin film of multi-walled carbon nanotubes (MWCNTs) coated with an electropolymerized layer of tiron-doped polypyrrole was developed and the resulting electrode was applied for the determination of acyclovir (ACV). The surface morphology and property of the modified electrode were characterized by field emission scanning electron microscopy and electrochemical impedance spectroscopy techniques. The electrochemical performance of the modified electrode was investigated by means of linear sweep voltammetry (LSV). The effect of several experimental variables, such as pH of the supporting electrolyte, drop size of the cast MWCNTssuspension, number of electropolymerization cycles and accumulation time was optimized by monitoring the LSV response of the modified electrode toward ACV. The best response was observed at pH7.0 after accumulation at open circuit for 160 s. Under the optimized conditions, a significant electrochemical improvement was observed toward the electrooxidation of ACV on the modified electrode surface relative to the bare GCE, resulting in a wide linear dynamic range (0.03-10.0µ M) and a low detection limit (10.0 nM) for ACV. Besides high sensitivity, the sensor represented high stability and good reproducibility for ACV analysis, and provided satisfactory results for the determination of this compound in pharmaceutical and clinical preparations.


Assuntos
Sal Dissódico do Ácido 1,2-Di-Hidroxibenzeno-3,5 Dissulfônico/química , Aciclovir/sangue , Vidro/química , Nanotubos de Carbono/química , Polímeros/química , Pirróis/química , Antivirais/sangue , Técnicas Eletroquímicas/instrumentação , Eletrodos , Humanos , Limite de Detecção , Modelos Lineares , Reprodutibilidade dos Testes
18.
Pharm Res ; 32(7): 2241-9, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25609011

RESUMO

PURPOSE: The effects of chitosan hydrochloride on the oral absorption of acyclovir in humans were studied to confirm the absorption enhancing effects reported for in vitro and rat studies, respectively. METHODS: A controlled, open-label, randomized, 3-phase study was conducted in 12 healthy human volunteers. Zovirax 200 mg dispersible tablets co-administered with doses of 400 and 1000 mg chitosan HCl were compared with Zovirax only. RESULTS: The expected increased absorption of acyclovir was not observed. On the contrary, mean area under the plasma concentration-time curve (AUC0-12 h) and maximal plasma concentration (Cmax) decreased following concomitant chitosan intake (1402 versus 1017 and 982.0 ng ∙ h/ml and 373 versus 208 and 235 ng/ml, respectively). In addition, Tmax increased significantly in presence of 1000 mg of chitosan from 1 to 2 h. CONCLUSIONS: The results of this study in human volunteers did not confirm an absorption enhancing effect of chitosan. Reference values were comparable to literature data, whereas addition of chitosan resulted in significant opposite effects on Cmax, Tmax and AUC. Additional studies are needed to investigate the cause of the discrepancy. The observed variability and complex potential interactions may complicate the use of chitosan HCl in oral pharmaceutical formulations.


Assuntos
Aciclovir/administração & dosagem , Aciclovir/farmacocinética , Antivirais/administração & dosagem , Antivirais/farmacocinética , Quitosana/química , Portadores de Fármacos/química , Aciclovir/sangue , Administração Oral , Adulto , Antivirais/sangue , Disponibilidade Biológica , Cromatografia Líquida de Alta Pressão , Interpretação Estatística de Dados , Feminino , Voluntários Saudáveis , Humanos , Masculino
19.
Pediatr Infect Dis J ; 33(1): 42-9, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24346595

RESUMO

BACKGROUND: Acyclovir is used to treat herpes infections in preterm and term infants; however, the influence of maturation on drug disposition and dosing requirements is poorly characterized in this population. METHODS: We administered intravenous acyclovir to preterm and term infants <31 days postnatal age and collected plasma samples. We performed a population pharmacokinetic analysis. The primary pharmacodynamic target was acyclovir concentration ≥3 mg/L for ≥50% of the dosing interval. The final model was simulated using infant data from a clinical database. RESULTS: The analysis included 28 infants (median 30 weeks gestation). Acyclovir pharmacokinetics was described by a 1-compartment model: clearance (L/h/kg) = 0.305 × [postmenstrual age (PMA)/31.3 weeks]. This equation predicts a 4.5-fold increase in clearance from 25 to 41 weeks PMA. With proposed dosing, the pharmacodynamic target was achieved in 91% of infants: 20 mg/kg every 12 hours in infants <30 weeks PMA; 20 mg/kg every 8 hours in infants 30 to <36 weeks PMA and 20 mg/kg every 6 hours in infants 36-41 weeks PMA. CONCLUSIONS: Acyclovir clearance increased with infant maturation. A dosing strategy based on PMA accounted for developmental changes in acyclovir disposition to achieve the surrogate pharmacodynamic target in many infants.


Assuntos
Aciclovir/farmacocinética , Antivirais/farmacocinética , Recém-Nascido Prematuro/metabolismo , Aciclovir/administração & dosagem , Aciclovir/sangue , Administração Intravenosa , Antivirais/administração & dosagem , Antivirais/sangue , Teorema de Bayes , Análise por Conglomerados , Feminino , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro/sangue , Masculino
20.
Ther Drug Monit ; 35(4): 417-9, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23851913

RESUMO

Acyclovir-induced neuropsychiatric symptoms (AINSs) may resemble several diseases of the central nervous system. Laboratory testing of acyclovir may be critical in supporting the diagnosis of AINSs when there is doubt. We present a case of suspected herpes encephalitis in which the diagnosis of AINSs was supported by therapeutic drug monitoring of plasma and cerebrospinal fluid concentrations of acyclovir and its main metabolite 9-carboxymethoxymethylguanine.


Assuntos
Aciclovir/efeitos adversos , Antivirais/efeitos adversos , Transtornos Mentais/induzido quimicamente , Transtornos Mentais/diagnóstico , Síndromes Neurotóxicas/diagnóstico , Síndromes Neurotóxicas/etiologia , Aciclovir/sangue , Aciclovir/uso terapêutico , Antivirais/sangue , Antivirais/uso terapêutico , Sistema Nervoso Central/efeitos dos fármacos , Diagnóstico Diferencial , Monitoramento de Medicamentos , Encefalite por Herpes Simples/tratamento farmacológico , Feminino , Humanos , Transtornos Mentais/sangue , Pessoa de Meia-Idade , Síndromes Neurotóxicas/sangue
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