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2.
Science ; 368(6489): 409-412, 2020 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-32198291

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is a global health emergency. An attractive drug target among coronaviruses is the main protease (Mpro, also called 3CLpro) because of its essential role in processing the polyproteins that are translated from the viral RNA. We report the x-ray structures of the unliganded SARS-CoV-2 Mpro and its complex with an α-ketoamide inhibitor. This was derived from a previously designed inhibitor but with the P3-P2 amide bond incorporated into a pyridone ring to enhance the half-life of the compound in plasma. On the basis of the unliganded structure, we developed the lead compound into a potent inhibitor of the SARS-CoV-2 Mpro The pharmacokinetic characterization of the optimized inhibitor reveals a pronounced lung tropism and suitability for administration by the inhalative route.


Assuntos
Amidas/química , Amidas/farmacologia , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/enzimologia , Cisteína Endopeptidases/química , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Proteínas não Estruturais Virais/química , Amidas/metabolismo , Animais , Antivirais/química , Antivirais/metabolismo , Antivirais/farmacocinética , Antivirais/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Cristalografia por Raios X , Cisteína Endopeptidases/metabolismo , Desenho de Fármacos , Meia-Vida , Humanos , Pulmão/metabolismo , Camundongos , Modelos Moleculares , Inibidores de Proteases/metabolismo , Inibidores de Proteases/farmacocinética , Domínios Proteicos , Multimerização Proteica , Piridonas/química , Proteínas não Estruturais Virais/metabolismo , Replicação Viral/efeitos dos fármacos
3.
Expert Opin Drug Metab Toxicol ; 16(2): 97-101, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32003256

RESUMO

Introduction: Despite the high rate of response, the treatment of special populations, the management of patients with previous failure to direct-acting antiviral (DAA) regimens, and the development of drug resistance are still a challenge. Moreover, the FDA suggested stopping research on new DAA because of the high efficacy of those already available.Areas covered: Understanding pharmacokinetic/pharmacodynamic parameters could be a simple and effective way to improve the management of anti-hepatitis C virus (HCV) treatment. The aim of this review is to provide an overview of this aspect in order to offer a new insight into treatment choice.Expert opinion: Clinicians should offer an adequate strategy for HCV treatment taking into consideration patient-related factors and by improving their knowledge of the antiviral activity and pharmaceutical 'forgiveness' of each DAA.


Assuntos
Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Antivirais/farmacocinética , Farmacorresistência Viral , Hepatite C/virologia , Humanos
4.
PLoS One ; 15(1): e0227104, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31914458

RESUMO

Despite the availability of highly effective direct-acting antiviral (DAA) regimens for the treatment of hepatitis C virus (HCV) infections, sustained viral response (SVR) rates remain suboptimal for difficult-to-treat patient populations such as those with HCV genotype 3, cirrhosis or prior treatment experience, warranting development of more potent HCV replication antivirals. AT-527 is the hemi-sulfate salt of AT-511, a novel phosphoramidate prodrug of 2'-fluoro-2'-C-methylguanosine-5'-monophosphate that has potent in vitro activity against HCV. The EC50 of AT-511, determined using HCV laboratory strains and clinical isolates with genotypes 1-5, ranged from 5-28 nM. The active 5'-triphosphate metabolite, AT-9010, specifically inhibited the HCV RNA-dependent RNA polymerase. AT-511 did not inhibit the replication of other selected RNA or DNA viruses in vitro. AT-511 was approximately 10-fold more active than sofosbuvir (SOF) against a panel of laboratory strains and clinical isolates of HCV genotypes 1-5 and remained fully active against S282T resistance-associated variants, with up to 58-fold more potency than SOF. In vitro, AT-511 did not inhibit human DNA polymerases or elicit cytotoxicity or mitochondrial toxicity at concentrations up to 100 µM. Unlike the other potent guanosine analogs PSI-938 and PSI-661, no mutagenic O6-alkylguanine bases were formed when incubated with cytochrome P450 (CYP) 3A4, and AT-511 had IC50 values ≥25 µM against a panel of CYP enzymes. In hepatocytes from multiple species, the active triphosphate was the predominant metabolite produced from the prodrug, with a half-life of 10 h in human hepatocytes. When given orally to rats and monkeys, AT-527 preferentially delivered high levels of AT-9010 in the liver in vivo. These favorable preclinical attributes support the ongoing clinical development of AT-527 and suggest that, when used in combination with an HCV DAA from a different class, AT-527 may increase SVR rates, especially for difficult-to-treat patient populations, and could potentially shorten treatment duration for all patients.


Assuntos
Antivirais/farmacologia , Guanosina/farmacologia , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Pró-Fármacos/farmacologia , Animais , Antivirais/química , Antivirais/metabolismo , Antivirais/farmacocinética , Linhagem Celular , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Feminino , Guanosina/análogos & derivados , Guanosina/metabolismo , Guanosina/farmacocinética , Haplorrinos , Hepacivirus/genética , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/virologia , Humanos , Masculino , Camundongos , Pró-Fármacos/química , Pró-Fármacos/metabolismo , Pró-Fármacos/farmacocinética , Ratos
6.
PLoS Negl Trop Dis ; 13(11): e0007890, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31751347

RESUMO

Recent outbreaks of the Ebola virus (EBOV) have focused attention on the dire need for antivirals to treat these patients. We identified pyronaridine tetraphosphate as a potential candidate as it is an approved drug in the European Union which is currently used in combination with artesunate as a treatment for malaria (EC50 between 420 nM-1.14 µM against EBOV in HeLa cells). Range-finding studies in mice directed us to a single 75 mg/kg i.p. dose 1 hr after infection which resulted in 100% survival and statistically significantly reduced viremia at study day 3 from a lethal challenge with mouse-adapted EBOV (maEBOV). Further, an EBOV window study suggested we could dose pyronaridine 2 or 24 hrs post-exposure to result in similar efficacy. Analysis of cytokine and chemokine panels suggests that pyronaridine may act as an immunomodulator during an EBOV infection. Our studies with pyronaridine clearly demonstrate potential utility for its repurposing as an antiviral against EBOV and merits further study in larger animal models with the added benefit of already being used as a treatment against malaria.


Assuntos
Antimaláricos/administração & dosagem , Antivirais/administração & dosagem , Doença pelo Vírus Ebola/prevenção & controle , Naftiridinas/administração & dosagem , Animais , Antimaláricos/efeitos adversos , Antimaláricos/farmacocinética , Antivirais/efeitos adversos , Antivirais/farmacocinética , Citocinas/imunologia , Reposicionamento de Medicamentos , Ebolavirus/efeitos dos fármacos , Ebolavirus/genética , Ebolavirus/fisiologia , Feminino , Doença pelo Vírus Ebola/imunologia , Doença pelo Vírus Ebola/virologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Naftiridinas/efeitos adversos , Naftiridinas/farmacocinética
7.
Pharm Res ; 36(12): 180, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31728737

RESUMO

PURPOSE: To examine the potential of stratum corneum (SC) sampling via tape-stripping in humans to assess bioequivalence of topical acyclovir drug products, and to explore the potential value of alternative metrics of local skin bioavailability calculable from SC sampling experiments. METHODS: Three acyclovir creams were considered in two separate studies in which drug amounts in the SC after uptake and clearance periods were measured and used to assess bioequivalence. In each study, a "reference" formulation (evaluated twice) was compared to the "test" in 10 subjects. Each application site was replicated to achieve greater statistical power with fewer volunteers. RESULTS: SC sampling revealed similarities and differences between products consistent with results from other surrogate bioequivalence measures, including dermal open-flow microperfusion experiments. Further analysis of the tape-stripping data permitted acyclovir flux into the viable skin to be deduced and drug concentration in that 'compartment' to be estimated. CONCLUSIONS: Acyclovir quantities determined in the SC, following a single-time point uptake and clearance protocol, can be judiciously used both to objectively compare product performance in vivo and to assess delivery of the active into skin tissue below the barrier, thereby permitting local concentrations at or near to the site of action to be determined.


Assuntos
Aciclovir/farmacocinética , Antivirais/farmacocinética , Creme para a Pele/farmacocinética , Aciclovir/administração & dosagem , Administração Tópica , Adulto , Antivirais/administração & dosagem , Disponibilidade Biológica , Transporte Biológico , Liberação Controlada de Fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Permeabilidade , Pele/metabolismo , Absorção Cutânea , Creme para a Pele/administração & dosagem , Equivalência Terapêutica
8.
Expert Opin Drug Metab Toxicol ; 15(10): 779-785, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31593639

RESUMO

Introduction: Interferon (IFN) had both antiviral and immunomodulatory effects, and was one of the approved treatments for hepatitis B virus (HBV). Herein, we reviewed the pharmacokinetics and pharmacodynamics of pegylated IFN-α (PegIFN-α) for the treatment of HBV. Areas covered: The steady-state serum levels of PegIFN-α were reached within 5 to 8 weeks, and the week 48 mean trough concentrations were approximately 2-fold higher than week 1. There was also no difference of the pharmacokinetics in male or female, healthy volunteers or patients with hepatitis B or C infection. PegIFN-α did not affect the metabolism of the cytochrome P450 (CYP) isozymes, except inhibition of CYP1A2. There was also no pharmacokinetic interaction between PegIFN-α and HBV nucleot(s)ide analogues (NUCs). Forty-eight weeks of PegIFN-α achieved 32% of HBeAg seroconversion, 32-43% of HBV DNA suppression, 41-59% of ALT normalization, and 3% of HBsAg seroconversion rate with a post-treatment durable response up to 80% in the initial responders. Expert opinion: On-treatment HBsAg titer guided the treatment of HBV with PegIFN-α. The recommendation of PegIFN-α and NUC combination or switch remained controversial. New immunotherapeutic agents are now in development. Although, PegIFN-α should continue to play a role in the treatment of HBV.


Assuntos
Hepatite B Crônica/tratamento farmacológico , Interferon alfa-2/administração & dosagem , Interferon-alfa/administração & dosagem , Polietilenoglicóis/administração & dosagem , Animais , Antivirais/administração & dosagem , Antivirais/farmacocinética , Antivirais/farmacologia , DNA Viral/efeitos dos fármacos , Interações Medicamentosas , Feminino , Antígenos E da Hepatite B/sangue , Humanos , Interferon alfa-2/farmacocinética , Interferon alfa-2/farmacologia , Interferon-alfa/farmacocinética , Interferon-alfa/farmacologia , Masculino , Polietilenoglicóis/farmacocinética , Polietilenoglicóis/farmacologia , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/farmacologia
9.
Int J Pharm ; 569: 118586, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31377407

RESUMO

The main objective of this study was to develop a novel self-assembled micelle system to improve the oral bioavailability of the water-insoluble and thermal instable germacrone (GEM). Micelles were prepared with an improved supercritical reverse phase evaporation (ISCRPE) method, and the thin-film hydration (TFH) method was used for comparison. Physicochemical characterization confirmed the nanospherical morphology of the micelles prepared by the ISCRPE method (GEM@SDL-SCF Micelles) had smaller particle size and greater encapsulation efficiency than that of the micelles prepared by the TFH method (GEM@SDL-THF Micelles). Dilution resistance and stability experiments were performed to assess the structural integrity. In vitro GEM release was analyzed by the dialysis diffusion method, and the micelle system showed sustained and cumulative release. Furthermore, the fluorescence results from the cellular uptake study revealed improved drug absorption of GEM since the green fluorescence intensity of C6@SDL-SCF Micelles were stronger than that of C6@SDL-TFH Micelles. The transcellular transport study showed a distinct increase in the apparent permeability coefficient (AP → BL) in a Caco-2 cell transport model, and free GEM solution, GEM@SDL-TFH Micelles and GEM@SDL-SCF Micelles had permeability coefficients of 7.30 × 10-6, 8.01 × 10-6, and 10.57 × 10-6 cm·s-1, respectively. The pharmacokinetics study in Sprague-Dawley rats showed that the oral absorption capacity of the GEM@SDL-SCF Micelles was obviously enhanced, with a relative oral bioavailability of 298% and 147% compared with that of free GEM solution and GEM@SDL-TFH Micelles, respectively. The gastrointestinal safety assessment demonstrated that the micelles used in the experiment did not cause gastrointestinal toxicity. These results indicated that self-assembled micelles are promising nanocarriers aimed at enhancing the oral absorption of drugs with thermal sensitivity and low aqueous solubility, and micelles prepared by supercritical fluid (SCF) technology showed better performance than those prepared by the TFH method.


Assuntos
Antivirais/administração & dosagem , Micelas , Sesquiterpenos de Germacrano/administração & dosagem , Administração Oral , Animais , Antivirais/química , Antivirais/farmacocinética , Disponibilidade Biológica , Células CACO-2 , Sistemas de Liberação de Medicamentos , Humanos , Masculino , Ratos Sprague-Dawley , Sesquiterpenos de Germacrano/química , Sesquiterpenos de Germacrano/farmacocinética
10.
Biomed Pharmacother ; 118: 109226, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31377471

RESUMO

The effects of Reduning injection and nebulized inhalation for treating upper respiratory tract infections were compared, including anti-bacterial, anti-viral, anti-inflammatory, anti-pyretic, anti-tussive, and anti-phlegm. Using chlorogenic acid, cryptochlorogenic acid, neochlorogenic acid, and geniposide as the index components, the pharmacokinetics and tissue distributions were compared. Influenza virus PR8-infected mice in the Reduning groups showed significantly reduced mortality and prolonged survival time. The white blood cell count was significantly reduced in the 20- and 10-min groups. Inhalation significantly decreased the temperature from 2 h in the 20- and 10-min groups. Inhalation significantly reduced the cough rate but not cough latency. Phenol red excretion was significantly increased in all Reduning groups. The elimination half-life of geniposide after inhalation in male and female rats was 2.05-5.28 and 4.03-10.4 h, respectively, which was much greater than after injection. Regarding tissue distribution, the injection dose (2 mL/kg) was 50 times the inhalation dose, and maximum serum concentration (Cmax) and AUCINF_obs of the four components in the trachea and lung were 0.95-11.1 and 0.59-4.36 times the inhalation values, respectively. Plasma Cmax and AUCINF_obs were 160-637 and 22.7-180 times the inhalation values, respectively. Atomized Reduning dose was equivalent to 1/90 of the mouse injection dose, and the effects of inhalation were similar or superior to those of injections. Atomization inhalation is targeted to the lungs, so systemic drug exposure was greatly reduced and lung concentration was high, which may increase the efficacy and reduce the safety risks associated with injections.


Assuntos
Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/farmacocinética , Injeções , Nebulizadores e Vaporizadores , Administração por Inalação , Animais , Antibacterianos/farmacologia , Antivirais/administração & dosagem , Antivirais/farmacocinética , Antivirais/farmacologia , Antivirais/uso terapêutico , Tosse/tratamento farmacológico , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/uso terapêutico , Feminino , Contagem de Leucócitos , Masculino , Pneumonia/sangue , Pneumonia/tratamento farmacológico , Pneumonia/patologia , Substâncias Protetoras/farmacologia , Substâncias Protetoras/uso terapêutico , Ratos Sprague-Dawley , Ratos Wistar , Temperatura , Distribuição Tecidual , Resultado do Tratamento
11.
J Ethnopharmacol ; 243: 112097, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31325600

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: According to Traditional Chinese Medicine theory, influenza is categorized as a warm disease or Wen Bing. The Wen Bing formulas, such as Yin-Qiao-San and Sang-Ju-Yin, are still first-line herbal therapies in combating variant influenza virus. To continue our study on the pharmacokinetic and pharmacodynamic interactions between Wen Bing formulas and oseltamivir (OS), the first-line western drug for the treatment of influenza, further interactions between OS and the eight single herbs and their relevant marker components from Wen Bing formulas were investigated in the current study. AIM OF STUDY: To establish an in-vitro screening platform for investigation of the potential anti-influenza herbs/herbal components that may have pharmacokinetic and pharmacodynamic interactions with OS. MATERIALS AND METHODS: To screen potential inhibition on OS hydrolysis, 1 µg/mL of OS is incubated with herbs/herbal components in diluted rat plasma, microsomes and human recombinant carboxylesterase 1(hCE1) under optimized conditions. MDCK-WT and MDCK-MDR1 cell lines are utilized to identify potential modification on P-gp mediated transport of OS by herbs/herbal components. Caco-2 cells with and without Gly-Sar inhibition are performed to study the uptake of OS via PEPT1 transporters. Modification on OAT3 mediated transport is verified by the uptake of OS on HEK293-MOCK/HEK293-OAT3 cells. Anti-virus effects were evaluated using plaque reduction assay on H1N1 and H3N2 viruses. Potential pharmacokinetic and pharmacodynamic interaction between OS (30 mg/kg) and the selected herb, Radix Scutellariae (RS), at 300-600 mg/kg were carried out on rats. All samples are analyzed by an LC/MS/MS method for the contents of OS and OSA. A mechanistic PK model was developed to interpret the HDI between OS and RS in rats. RESULTS: Our developed platform was successfully applied to screen the eight herbal extracts and their ten marker components on metabolic inhibition of OS and modification of OS transport mediated by P-gp, OAT3 and PEPT1. Results from six in-vitro experiments were analyzed after converting raw data from each experiment to corresponding fold-change (FC) values, based on which Radix Scutellariae (RS) were selected to have the most HDI potential with OS. By analyzing the plasma and urine pharmacokinetic data after co-administration of OS with a standardized RS extract in rats using an integrated population pharmacokinetics model, it is suggested that RS could inhibit OS hydrolysis during absorption and increase the absorbed fraction of OS, which leads to the increased ratio of OS concentration versus that of OSA in both rat plasma and urine. Never the less, the anti-virus effects of 2.5 h post-dose rat plasma were not influenced by co-administration of OS with RS. CONCLUSION: A six-dimension in-vitro screening platform has been developed and successfully applied to find RS as a potential herb that would influence the co-administrated OS in rats. Although co-administered RS could inhibit OS hydrolysis during absorption and increase the absorbed fraction of OS, which lead to the increased ratio of OS concentration versus that of OSA in both rat plasma and urine, the anti-virus effect of OS was not influenced by co-administered RS.


Assuntos
Antivirais/farmacocinética , Medicamentos de Ervas Chinesas/farmacologia , Interações Ervas-Drogas , Oseltamivir/farmacocinética , Scutellaria baicalensis , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Animais , Antivirais/farmacologia , Células CACO-2 , Cães , Células HEK293 , Humanos , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus da Influenza A Subtipo H3N2/efeitos dos fármacos , Células Madin Darby de Rim Canino , Masculino , Medicina Tradicional Chinesa , Microssomos Hepáticos/metabolismo , Transportadores de Ânions Orgânicos Sódio-Independentes/genética , Oseltamivir/farmacologia , Ratos Sprague-Dawley
12.
Pak J Pharm Sci ; 32(3 (Supplementary)): 1269-1274, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31303600

RESUMO

Sofosbuvir along with ribavirin is being widely used for treatment of HCV in Pakistan but it may show delayed response and reoccurrence of disease in some cases. The aim of the study was to investigate pharmacokinetics and concentration effect analysis of sofosbuvir. HCV patients (n=100) received 400 mg sofosbuvir along with low dose or weight based ribavirin (400 mg). Nonlinear mixed effects modeling (NONMEM) and unpaired t-test were used for the association of concentrations and treatment outcomes. Average day 10 sofosbuvir metabolite BM 331007 concentration was higher in patients having haemoglobin nadir value <10 g/dl compared to the patients having heamoglobin nadir value >10 g/dl (5.34 versus 4.87 pmol/106 cells; p=0.03). The average concentration trends of GS331007 at day 10 was towards being higher in the patients achieved sustained virologic response (SVR) as compare to the patients relapsed (5.19 versus 4.86 pmol/106 cells; p=0.05). Sofosbuvir (GS331007) thresholds concentration (suggested at day 10 through receiver operating characteristic curve) was 5.4 pmol/106 cells for SVR (p=0.05) and haemoglobin nadir cells was 6.3 pmol/106 with sensitivity and specificity of >60%. Dosing simulations shows that 400 mg sofosbuvir twice daily produce day 10 concentration range of 5.4 to 6.7 pmol/106 cells. The range of therapeutic values was identified for HCV patients receiving sofosbuvir in combination with ribavirin for 24 weeks, suggesting a potential pharmaceutical basis for individualized therapeutic dosing.


Assuntos
Antivirais/farmacocinética , Hepatite C/tratamento farmacológico , Ribavirina/farmacologia , Sofosbuvir/farmacocinética , Adulto , Idoso , Antivirais/administração & dosagem , Antivirais/sangue , Quimioterapia Combinada , Feminino , Meia-Vida , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC , Ribavirina/administração & dosagem , Sofosbuvir/administração & dosagem , Sofosbuvir/sangue , Resposta Viral Sustentada
13.
Expert Opin Pharmacother ; 20(14): 1711-1718, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31169040

RESUMO

Introduction: Influenza represents a major public health threat worldwide. Implementation of good personal health and hygiene habits, together with vaccination, is the most effective tools to reduce influenza burden both in community and in healthcare setting. However, achieving adequate vaccination rates is challenging, and vaccination does not always guarantee complete protection. Neuraminidase inhibitors represent an important measure to reduce the risk of influenza-related complications among high-risk patients developing influenza infection. Areas covered: Neuraminidase inhibitors have been proven to be safe and effective in reducing influenza severity, duration of symptoms, hospitalizations, and influenza-related-mortality. Here the authors review the available data on neuraminidase inhibitors, including the mechanism of action, pharmacokinetics, efficacy, safety and current indications for their use in clinical practice. Expert opinion: Although vaccination is the most effective tool to reduce influenza-associated morbidity and mortality, neuraminidase inhibitors represent an important option for the treatment of patients with influenza infection, particularly in high-risk categories. Moreover, antivirals play an important role in influenza prevention and prophylaxis in selected settings.


Assuntos
Antivirais/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Influenza Humana/tratamento farmacológico , Neuraminidase/antagonistas & inibidores , Antivirais/farmacocinética , Farmacorresistência Viral/efeitos dos fármacos , Inibidores Enzimáticos/farmacocinética , Meia-Vida , Humanos , Oseltamivir/farmacocinética , Oseltamivir/uso terapêutico , Zanamivir/farmacocinética , Zanamivir/uso terapêutico
14.
Life Sci ; 231: 116540, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31176778

RESUMO

MRP4 is an ABC membrane transporter involved in clinical outcomes as it is located in many tissues that manages the transport and the elimination of many drugs. This review explores the implication of MRP4 in clinical pharmacology and the importance of its genetic variability. Although there is no specific recommendation regarding the study of MRP4 in drug development, it should be considered when drugs are eliminated by the kidney or liver or when drug-drug interactions are expected.


Assuntos
Antineoplásicos/farmacologia , Antivirais/farmacologia , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Animais , Antineoplásicos/farmacocinética , Antivirais/farmacocinética , Interações Medicamentosas , Humanos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Farmacogenética , Farmacocinética , Farmacologia
15.
PLoS One ; 14(5): e0217229, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31107913

RESUMO

Recent data support that the vaginal microbiota may alter mucosal pharmacokinetics (PK) of topically delivered microbicides. Our team developed an intravaginal ring (IVR) that delivers tenofovir (TFV) (8-10 mg/day) alone or with levonorgestrel (LNG) (20 ug/day). We evaluated the effect of IVRs on the vaginal microbiota, and describe how the vaginal microbiota impacts mucosal PK of TFV. CONRAD A13-128 was a randomized, placebo controlled phase I study. We randomized 51 women to TFV, TFV/LNG or placebo IVR. We assessed the vaginal microbiota by sequencing the V3-V4 regions of 16S rRNA genes prior to IVR insertion and after approximately 15 days of use. We measured the concentration of TFV in the cervicovaginal (CV) aspirate, and TFV and TFV-diphosphate (TFV-DP) in vaginal tissue at the end of IVR use. The change in relative or absolute abundance of vaginal bacterial phylotypes was similar among active and placebo IVR users (all q values >0.13). TFV concentrations in CV aspirate and vaginal tissue, and TFV-DP concentrations in vaginal tissue were not significantly different among users with community state type (CST) 4 versus those with Lactobacillus dominated microbiota (all p values >0.07). The proportions of participants with CV aspirate concentrations of TFV >200,000 ng/mL and those with tissue TFV-DP concentrations >1,000 fmol/mg were similar among women with anaerobe versus Lactobacillus dominated microbiota (p = 0.43, 0.95 respectively). There were no significant correlations between the CV aspirate concentration of TFV and the relative abundances of Gardnerella vaginalis or Prevotella species. Tissue concentrations of TFV-DP did not correlate with any the relative abundances of any species, including Gardnerella vaginalis. In conclusion, active IVRs did not differ from the placebo IVR on the effect on the vaginal microbiota. Local TFV and TFV-DP concentrations were high and similar among IVR users with Lactobacillus dominated microbiota versus CST IV vaginal microbiota. Trial registration: ClinicalTrials.gov NCT02235662.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/farmacocinética , Dispositivos Anticoncepcionais Femininos , Levanogestrel/administração & dosagem , Microbiota/efeitos dos fármacos , Tenofovir/administração & dosagem , Tenofovir/farmacocinética , Vagina/metabolismo , Vagina/microbiologia , Adenina/análogos & derivados , Adenina/farmacocinética , Adulto , Antivirais/administração & dosagem , Antivirais/farmacocinética , Remoção de Dispositivo , Feminino , Infecções por HIV/prevenção & controle , Herpes Genital/prevenção & controle , Humanos , Microbiota/genética , Pessoa de Meia-Idade , Membrana Mucosa/efeitos dos fármacos , Membrana Mucosa/metabolismo , Organofosfatos/farmacocinética , Vagina/efeitos dos fármacos , Adulto Jovem
16.
PLoS One ; 14(5): e0216384, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31048874

RESUMO

Drug performance in the gastrointestinal tract (GIT) plays a crucial role in determining release and absorption. In the present work, we assessed the in vitro digestion of two synthetic N1-aryl-2-arylthioacetamidobenzimidazoles (NAABs), NAAB-496 and NAAB-503, using bio-relevant models of the human stomach and small intestine. The activity of NAAB-496 and NAAB-503 against herpes simplex virus (HSV-1) replication was also investigated. NAAB-496 was resistant to pepsin in the gastric environment, with a virtual 100% recovery, which decreased to 43.2% in the small intestine. NAAB-503 was sensitive to pepsin, with 65.7% degradation after 120 min gastric phase. 1H Nuclear magnetic resonance (NMR) post in vitro digestion highlighted an alteration of NAAB-496 after the gastric phase, whereas NAAB-503 appeared comparable to the original spectral data. Both NAAB-496 and NAAB-503 revealed some antiviral activity anti-HSV-1. The 50% effective concentration (EC50) of the compounds was 0.058 mg/mL for NAAB-496 and 0.066 for NAAB-503. Future studies will evaluate the behavior of NAAB-496 within pharmaceutical formulations.


Assuntos
Antivirais , Suco Gástrico , Herpesvirus Humano 1/crescimento & desenvolvimento , Secreções Intestinais , Modelos Biológicos , Inativação de Vírus/efeitos dos fármacos , Antivirais/química , Antivirais/farmacocinética , Antivirais/farmacologia , Suco Gástrico/metabolismo , Suco Gástrico/virologia , Humanos , Secreções Intestinais/metabolismo , Secreções Intestinais/virologia , Intestino Delgado/metabolismo , Intestino Delgado/virologia , Estômago/virologia
17.
Clin Drug Investig ; 39(7): 671-681, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31079356

RESUMO

BACKGROUND AND OBJECTIVES: Yimitasvir is a novel oral hepatitis C virus non-structural protein 5A (NS5A) inhibitor. The aims of this first-in-human study were to evaluate the safety, tolerability and pharmacokinetics of single and multiple doses of yimitasvir in healthy adult Chinese volunteers and to assess the effect of food on yimitasvir pharmacokinetics. METHODS: Randomized, double-blind, placebo-controlled, single-ascending-dose (30, 100, 200 and 400 mg) and multiple-ascending-dose (100 and 200 mg once daily for 7 days) studies were performed in 32 and 24 subjects, respectively, in male and female adults. Additionally, the effect of food on yimitasvir pharmacokinetics was assessed with a crossover study in 15 male subjects. RESULTS: Yimitasvir was absorbed slowly after oral administration with a median time to maximum plasma concentration (Tmax) of 3.5-4.0 h. Increases in the maximum plasma concentration (Cmax) and area under the concentration-time curve from 0 to the last measurable time point (AUC0-t) were proportional to the dose of yimitasvir over a dose range of 30-100 mg, while increases were less than dose proportional over a dose range of 200-400 mg in part 1, indicating that absorption at the 200-mg dose was nearly saturated. The geometric mean terminal half-life of yimitasvir was 13.4-19.7 h in each cohort, supporting once-daily dosing. Faecal excretion of parent yimitasvir was the major route of elimination. Steady state was achieved following 5 days of dosing with minimal accumulation. A standardized high-fat meal decreased the rate and extent of absorption. All doses of yimitasvir were well tolerated. CONCLUSIONS: Yimitasvir, at single doses of 30-400 mg and multiple doses of 100-200 mg for 7 days, was well tolerated in healthy Chinese subjects. The results of this study formed the basis for the dosing schemes evaluated in a phase Ib study and subsequent phase II and phase III clinical studies. CLINICAL TRIAL REGISTRATION: This study was registered at the China Food and Drug Administration (Registration numbers: 2014L02064 and 2014L02065) and at http://www.chictr.org.cn (Nos. CTR20140854, CTR20150048 and CTR20150123).


Assuntos
Antivirais/uso terapêutico , Hepatite C/tratamento farmacológico , Compostos Orgânicos/uso terapêutico , Administração Oral , Adolescente , Adulto , Antivirais/efeitos adversos , Antivirais/farmacocinética , Estudos Cross-Over , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Compostos Orgânicos/efeitos adversos , Compostos Orgânicos/farmacocinética , Adulto Jovem
18.
Ann Biol Clin (Paris) ; 77(3): 295-305, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30977732

RESUMO

Liquid wastes from clinical biology automated systems are currently evacuated in the urban network after chemical treatment to eliminate a possible risk of infection. Since these wastes are ecotoxic because of the presence of numerous chemical reagents, we studied their intrinsic microbicidal power towards a selection of infectious agents widely found in clinical specimens. The objective was to determine if an additional anti-infectious treatment before elimination is necessary. Thus, we evaluated the bactericidal effect of liquid wastes of several automated systems towards four bacterial species (Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa and Enterococcus faecalis) and their virucidal activity against a non-enveloped virus, resistant in the environment (adenovirus). This effect was determined for different exposure times. Our results showed that the antibacterial activity was highly variable depending on the waste-bacteria pair considered (varying from no activity to complete sterilization of a strong bacterial inoculum). The liquid wastes were on the other hand globally inactive towards adenovirus.


Assuntos
Anti-Infecciosos/isolamento & purificação , Técnicas de Laboratório Clínico , Resíduos de Serviços de Saúde , Esgotos/análise , Esterilização , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Anti-Infecciosos/farmacologia , Antivirais/isolamento & purificação , Antivirais/farmacocinética , Automação Laboratorial/instrumentação , Automação Laboratorial/métodos , Biodegradação Ambiental , Líquidos Corporais/microbiologia , Líquidos Corporais/virologia , Técnicas de Laboratório Clínico/instrumentação , Técnicas de Laboratório Clínico/métodos , França , Humanos , Laboratórios/normas , Testes de Sensibilidade Microbiana , Esgotos/microbiologia , Esterilização/métodos , Esterilização/normas , Purificação da Água/métodos , Purificação da Água/normas
19.
Pol J Vet Sci ; 22(1): 75-82, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30997764

RESUMO

In the current study, twenty lambs, aged 4 months, half male and half female, were classified into four groups, with five in each group. The experimental three groups of lambs were given intravenous (IV), intramuscular (IM) and subcutaneous (SC) administrations of recombinant ovine interferon-τ (roIFN-τ). The fourth group (normal control) of lambs was given normal saline injections in the same way. After administrations, blood samples were collected from the tested animals at different time points post injection, and the serum titers of roIFN-τ were measured using cytopathic effect (CPE) inhibition bioassay. The results of calculating pharmacokinetic (PK) parameters using DAS software showed that the PK characteristics of roIFN-τ through IV injection conformed to the two-compartment open model, whose half-life of distribution phases (T1/2α) was 0.33±0.034 h and the elimination half-life(T1/2ß) was 5.01±0.24 h. However, the PK features of IM injection and SC injection of roIFN-τ conformed to the one compartment open model, whose Tmax were 3.11±0.26 h and 4.83±0.43 h, respectively, together with an elimination half life(T1/2ß) of 9.11±0.76 h and 7. 43±0.58 h, and an absorption half-life (T1/2k(a)) of 1.13±0.31 h and 1.85±0.40 h, respectively. The bioavailability of roIFN-τ after IM administration reaches 73.57%, which is greater than that of SC administration (53.43%). These results indicate that the drug administration effect can be preferably obtained following a single dose IM administration of the roIFN-τ aqueous preparation. This study will facilitate the clinical application of roIFN-τ as a potential antiviral agent in future work.


Assuntos
Antivirais/farmacocinética , Interferon Tipo I/farmacocinética , Proteínas da Gravidez/farmacocinética , Ovinos/sangue , Animais , Antivirais/sangue , Área Sob a Curva , Feminino , Meia-Vida , Injeções Intravenosas , Interferon Tipo I/administração & dosagem , Masculino , Proteínas da Gravidez/administração & dosagem , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacocinética , Ovinos/metabolismo
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