Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 546
Filtrar
1.
J Chromatogr B Analyt Technol Biomed Life Sci ; 1134-1135: 121877, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31785533

RESUMO

PH-797804 is a selective p38 MAPK inhibitor currently evaluated in clinical trials. This study described a validated UPLC-MS/MS combined with one-step protein precipitation extraction method for determination of PH-797804 in rat plasma. After protein precipitation with acetonitrile, the plasma sample was analyzed by a Waters Acquity UPLC BEH C18 column, with acetonitrile/0.1% formic acid (70:30) as the mobile phase. Mass spectrometric detection was conducted with a Waters TQ-S mass spectrometer via electrospray, positive-mode ionization, with target quantitative ion pairs of m/z 476.895 → 126.860 for PH-797804, and 482.726 → 269.707 for regorafenib (internal standard). The assay showed a good linearity over the range of 1.0-1600 ng/mL, with acceptable accuracy (RE from -7.8% to 8.5%) and precision (RSD within 8.4%) values. Recovery from plasma was 81.4-90.2% and matrix effect was negligible (93.3-95.4%). The validated method presented a quantification method of PH-797804 in detail for the first time and utilized for a pharmacokinetic study at three dose concentrations after oral administration in Wistar rats. The pharmacokinetic profiles of PH-797804 showed a linear relationship between drug concentration and dose, which provided dosage and safety information on further clinical studies.


Assuntos
Benzamidas/sangue , Benzamidas/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Piridonas/sangue , Piridonas/farmacocinética , Espectrometria de Massas em Tandem/métodos , Animais , Benzamidas/química , Modelos Lineares , Masculino , Piridonas/química , Ratos , Ratos Wistar , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores
2.
Pharm Res ; 37(1): 3, 2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31823096

RESUMO

PURPOSE: Inhaled delivery of pirfenidone to the lungs of patients with idiopathic pulmonary fibrosis holds promise to eliminate oral-observed side effects while enhancing efficacy. This study aimed to comprehensively describe the pulmonary pharmacokinetics of inhaled aerosol pirfenidone in healthy adult sheep. METHODS: Pirfenidone concentrations were evaluated in plasma, lung-derived lymph and epithelial lining fluid (ELF) with data subjected to non-compartmental pharmacokinetic analysis. RESULTS: Compartmental pharmacokinetic evaluation indicated that a 49 mg lung-deposited dose delivered an ELF Cmax of 62 ± 23 mg/L, and plasma Cmax of 3.1 ± 1.7 mg/L. Further analysis revealed that plasma pirfenidone reached Tmax faster and at higher concentrations than in lymph. These results suggested inhaled pirfenidone was cleared from the alveolar interstitium via blood faster than the drug could equilibrate between the lung interstitial fluid and lung lymphatics. However, the data also suggested that a 'reservoir' of pirfenidone feeds into lung lymph at later time points (after it has largely been cleared from plasma), prolonging lung lymphatic exposure. CONCLUSIONS: This study indicates inhaled pirfenidone efficiently deposits in ELF and is cleared from the lungs by initial absorption into plasma, followed by later equilibrium with lung interstitial and lymph fluid.


Assuntos
Anti-Inflamatórios não Esteroides/farmacocinética , Pulmão/metabolismo , Piridonas/farmacocinética , Administração por Inalação , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Feminino , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/metabolismo , Linfa/metabolismo , Piridonas/administração & dosagem , Ovinos
3.
Bioanalysis ; 11(16): 1495-1508, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31502859

RESUMO

Aim: A method to quantitate doravirine (MK-1439) in human plasma has been developed to support human clinical trials designed to evaluate the safety, pharmacokinetics and efficacy of the compound. Methodology & results: The analyte was extracted using liquid-liquid extraction, separated on a reverse phase HPLC column, and detected on an API-4000 mass spectrometer using a Turbo-Ion spray source in positive ionization mode coupled with multiple reaction monitoring mode was used for quantification. The dynamic range for the assay was 0.02-10 ng/ml using 100 µl of human plasma. Conclusion: The assay was found to be sensitive, selective and reproducible and applied to support the doravirine clinical development program.


Assuntos
Análise Química do Sangue/métodos , Cromatografia Líquida de Alta Pressão/métodos , Extração Líquido-Líquido/métodos , Piridonas/sangue , Piridonas/isolamento & purificação , Espectrometria de Massas em Tandem/métodos , Triazóis/sangue , Triazóis/isolamento & purificação , Humanos , Limite de Detecção , Masculino , Piridonas/farmacocinética , Reprodutibilidade dos Testes , Triazóis/farmacocinética
4.
BMC Pharmacol Toxicol ; 20(1): 53, 2019 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-31464657

RESUMO

BACKGROUND: Apixaban effectively lowers the risk of ischemic stroke and systemic embolism in patients with non-valvular atrial fibrillation. Systemic exposure to a given apixaban dose depends on multiple clearance pathways. Though routine quantification of direct oral anticoagulants (DOACs) in neurological emergency situations has not been widely established, suspected associations of DOAC peak concentrations with bleeding events and DOAC trough concentrations with efficacy and safety suggest that such information might support clinical decision making. CASE PRESENTATION: We describe the case of a 75 year-old woman with atrial fibrillation maintained on apixaban who was admitted due to suspected acute stroke. Clinical work-up did not confirm ischemic or hemorrhagic stroke but routine quantification of apixaban revealed an excessively high apixaban plasma concentration (~ 3 h after the last drug intake: 1100 ng/ml (expected range: 91-321 ng/ml); ~ 12 h after drug intake: 900 ng/ml (expected range: 41-230 ng/ml)) and a substantially prolonged elimination half-life (~ 31 h). The corresponding apixaban concentration-to-dose ratio was 9900 (ng/ml)/(mg/kg/d) and 8100 (ng/ml)/(mg/kg/d), respectively (expected range: 249-463 (ng/ml)/(mg/kg/d)). Renal function was only moderately impaired (creatinine 1.36 mg/dl (0.5-1.1 mg/dl), creatinine clearance 40 ml/min). Genotype analyses revealed that the patient was a CYP3A5*3/*3 non-expressor, a heterozygous carrier of the ABCG2 c.421C/A alleles, and a homozygous carrier of ABCB1 c.2677 T/T and ABCB1 c.3435 T/T. In the absence of known drug interactions explaining apixaban clearance impairment, excessive apixaban concentrations were most probably caused by moderate renal impairment combined with multiple functional polymorphisms of apixaban clearance pathways. CONCLUSIONS: This case suggests that concurrent genetic polymorphisms can impair multiple apixaban elimination pathways and thus substantially increase its exposure.


Assuntos
Anticoagulantes/farmacocinética , Polimorfismo Genético , Pirazóis/farmacocinética , Piridonas/farmacocinética , Idoso , Anticoagulantes/sangue , Anticoagulantes/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Feminino , Humanos , Pirazóis/sangue , Pirazóis/uso terapêutico , Piridonas/sangue , Piridonas/uso terapêutico
5.
Am J Health Syst Pharm ; 76(8): 505-511, 2019 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-31361865

RESUMO

PURPOSE: This case series presents 3 patients with acute kidney injury taking apixaban or rivaroxaban and transitioning to a heparin infusion. SUMMARY: Case 1 was a 78-year-old man admitted with respiratory failure, acute decompensated heart failure, and acute kidney injury. He was taking apixaban for atrial flutter. He was transitioned to an i.v. heparin infusion and had 2 consecutive heparin antifactor-Xa levels greater than 2 units/mL. Heparin was held and resumed about 36 hours later when the apixaban anti-Xa level was less than 50 ng/mL. Case 2 was a 55-year-old man admitted with acute kidney injury, taking apixaban for a recent deep vein thrombosis. Apixaban anti-Xa levels were monitored and i.v. heparin was initiated when the level was less than 100 ng/mL, about 56 hours after the last apixaban dose. Case 3 was a 64-year-old woman admitted with sepsis and acute kidney injury taking rivaroxaban for pulmonary embolism, which occurred 2 weeks prior to admission. Rivaroxaban anti-Xa levels were monitored and i.v. heparin was initiated about 36 hours after the last dose when the level was less than 100 ng/mL. The management strategy did not lead to any thrombotic outcomes; however, 1 patient experienced bleeding. CONCLUSION: Specific anti-Xa levels for rivaroxaban and apixaban appeared to be helpful in the transition of 3 patients to unfractionated heparin infusions in the setting of acute kidney injury. These levels provided enhanced, individualized care and likely helped avoid over and under anticoagulation.


Assuntos
Lesão Renal Aguda/fisiopatologia , Monitoramento de Medicamentos , Inibidores do Fator Xa/análise , Heparina/análise , Pirazóis/análise , Piridonas/análise , Administração Oral , Idoso , Flutter Atrial/tratamento farmacológico , Substituição de Medicamentos , Inibidores do Fator Xa/administração & dosagem , Inibidores do Fator Xa/farmacocinética , Feminino , Heparina/administração & dosagem , Humanos , Infusões Intravenosas , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Embolia Pulmonar/tratamento farmacológico , Pirazóis/administração & dosagem , Pirazóis/farmacocinética , Piridonas/administração & dosagem , Piridonas/farmacocinética , Eliminação Renal , Rivaroxabana/administração & dosagem , Rivaroxabana/análise , Rivaroxabana/farmacocinética , Trombose Venosa/tratamento farmacológico
6.
Expert Opin Pharmacother ; 20(14): 1755-1765, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31264486

RESUMO

Introduction: Antiseizure drugs (ASDs) play a central and crucial role in the treatment of epilepsy patients, as the majority require anticonvulsant treatment for an extended period of time. Since up to 30% of patients are refractory to medical treatment, new therapeutic options are necessary. Perampanel (PER) and brivaracetam (BRV) are the latest approved ASDs that may be considered in a variety of epilepsy syndromes. PER has a distinct and selective mode of action on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and is licensed for use in focal and generalized epilepsies. BRV is a derivative of levetiracetam but exhibits a 20-fold higher affinity and a faster brain entry time as a synaptic vesicle glycoprotein 2A (SV2A) ligand. Areas covered: This article reviews the advances in the epileptic treatment and provides a comparison of PER and BRV. Both drugs have shown comparable results in randomized controlled trials, and both are well tolerated. Expert opinion: PER and BRV have the potential to perform as important, broad-spectrum ASDs with significant market shares. BRV's intravenous formulation and fast penetration into the brain and PER's unique mode of action will result in the more frequent use of both drugs in status epilepticus.


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Piridonas/uso terapêutico , Pirrolidinonas/uso terapêutico , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/farmacocinética , Ensaios Clínicos como Assunto , Epilepsia/patologia , Meia-Vida , Humanos , Piridonas/efeitos adversos , Piridonas/farmacocinética , Pirrolidinonas/efeitos adversos , Pirrolidinonas/farmacocinética , Receptores de AMPA/química , Receptores de AMPA/metabolismo , Estado Epiléptico/tratamento farmacológico , Resultado do Tratamento
7.
Biomed Chromatogr ; 33(10): e4620, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31215048

RESUMO

A simple, highly sensitive and rapid method for quantification of olprinone (phosphodiesterase 3 inhibitor) in rabbit plasma using liquid chromatography-tandem mass spectrometry with electrospray was developed. An aliquot of 50 µL of plasma sample was cleaned up and extracted using Ostro™ 96-well plate followed by dilution. Chromatographic separation of olprinone and olprinone-d3 was carried out on a CORTECS® T3 column within 3 min. Detection was achieved using a triple quadrupole mass spectrometer employing electrospray ionization operated in positive ion multiple reaction monitoring mode using the transitions m/z 251.07 → m/z 155.06 and m/z 254.21 → m/z 158.10 for olprinone and olprinone-d3, respectively. The method was validated according to US Food and Drug Administration guideline for bioanalytical methods, and showed excellent linearity in the range 10.0-2000.0 ng/mL with coefficient of determination >0.99. The intra- and inter-day precisions (CV) were <5.1% and the accuracies were within the range 99.7-103.2% at all quality control concentrations. Furthermore, olprinone was stable under various stability conditions. The developed method was used for quantification of olprinone in rabbit plasma after its intravenous administration at the dose of 1 mg/kg in order to better understand the metabolism of olprinone in a rabbit model of lung injury.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Imidazóis/sangue , Piridonas/sangue , Espectrometria de Massas em Tandem/métodos , Animais , Estabilidade de Medicamentos , Imidazóis/química , Imidazóis/farmacocinética , Limite de Detecção , Modelos Lineares , Piridonas/química , Piridonas/farmacocinética , Coelhos , Reprodutibilidade dos Testes
8.
Int J Pharm ; 568: 118466, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31254623

RESUMO

Some recent studies have shown that pirfenidone (PFD) has favorable results in the healing process of the cornea. However, PFD in solution exhibits short half-life after topical application, and in this context, a liquid crystal nanoparticle system containing PFD (PFD-LCNPs) was developed. The nanoparticles were characterized by transmission electron microscopy, atomic force microscopy, small angle X-ray diffraction and polarized light microscopy. The PFD-LCNPs had particle size and zeta potential of 247.3 nm and -33.60 mV (stores at 4 °C), respectively, and 257.5 nm and -46.00 mV (stored at 25 °C), respectively. The pH of the formulation was 6.9 and the encapsulation efficiency was 35.9%. The in vitro release profiles indicated that PFD sustained release from PFD-LCNPs for up to 12 h. In vitro study of ocular irritation (HET-CAM test) concluded that components of the formulation are well tolerated for ocular administration. Corneal re-epithelialization time after chemical burning was significantly reduced in rabbits treated with PFD-loaded LCNPs when compared to the group treated with a vehicle. In addition, the anti-inflammatory action of pirfenidone was observed by reducing myeloperoxidase activity (MPO) and inflammatory cells in the histology of the tissues of animals treated with PFD-LCNPs. These findings indicated that the PFD-LCNPs might have the potential for effective ocular drug delivery.


Assuntos
Analgésicos/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Queimaduras Químicas/tratamento farmacológico , Queimaduras Oculares/tratamento farmacológico , Cristais Líquidos , Nanopartículas/administração & dosagem , Piridonas/administração & dosagem , Administração Oftálmica , Analgésicos/farmacocinética , Animais , Anti-Inflamatórios/farmacocinética , Queimaduras Químicas/metabolismo , Queimaduras Químicas/patologia , Embrião de Galinha , Membrana Corioalantoide/efeitos dos fármacos , Córnea/efeitos dos fármacos , Córnea/metabolismo , Córnea/patologia , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Queimaduras Oculares/induzido quimicamente , Queimaduras Oculares/metabolismo , Queimaduras Oculares/patologia , Feminino , Tamanho da Partícula , Peroxidase/metabolismo , Piridonas/farmacocinética , Coelhos
9.
Clin Appl Thromb Hemost ; 25: 1076029619847524, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31088146

RESUMO

The currently available oral anti-Xa agents are claimed to produce their anticoagulant and antithrombotic effects solely by the inhibition of factor Xa. This study profiled various anti-Xa drugs in routinely used laboratory assays to demonstrate that their effects are not solely related to the anti-Xa activities. Apixaban, betrixaban, edoxaban, and rivaroxaban were obtained commercially. Native and citrated whole blood was used for the activated clotting time (ACT) and thromboelastography (TEG). Citrated plasma was used for monitoring the prothrombin time (PT), activated partial thromboplastin time (aPTT), Heptest, and prothrombinase-induced clotting time (PiCT) tests. An amidolytic method was used for the determination of anti-Xa effects. Thrombin-induced fibrinokinetics was monitored optically. Thrombin generation studies were carried out using the calibrated automated thrombogram. All of the anti-Xa agents produced concentration- and assay-dependent effects. In the ACT at 2.5 µg/mL and TEG at 1.0 µg/mL, edoxaban exhibited the strongest anticoagulation effect. In the PiCT, PT, and aPTT assay at 1 µg/mL, edoxaban showed stronger effects than other agents. The half maximal inhibitory concentration of these agents for the inhibition of factor Xa ranged from 340 to >1000 ng/mL. In the thrombin generation inhibition assay, apixaban showed the strongest activity. In the fibrinokinetics, different anti-Xa agents produced varying degrees of inhibition. These results demonstrate that the measured anti-Xa activity alone does not fully reflect the overall biologic spectrum of these agents.


Assuntos
Benzamidas , Inibidores do Fator Xa , Fator Xa/metabolismo , Tempo de Protrombina , Pirazóis , Piridinas , Piridonas , Rivaroxabana , Benzamidas/farmacocinética , Benzamidas/farmacologia , Inibidores do Fator Xa/farmacocinética , Inibidores do Fator Xa/farmacologia , Humanos , Tempo de Tromboplastina Parcial , Pirazóis/farmacocinética , Pirazóis/farmacologia , Piridinas/farmacocinética , Piridinas/farmacologia , Piridonas/farmacocinética , Piridonas/farmacologia , Rivaroxabana/farmacocinética , Rivaroxabana/farmacologia , Tiazóis/farmacocinética , Tiazóis/farmacologia , Tromboelastografia
10.
Dalton Trans ; 48(13): 4299-4313, 2019 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-30860215

RESUMO

The prototype tris(1,6-dimethyl-3-hydroxypyridin-4-one) chelator for gallium-68, THPMe, has shown great promise for rapid and efficient kit-based 68Ga labelling of PET radiopharmaceuticals. Peptide derivatives of THPMe have been used to image expression of their target receptors in vivo in preclinical and clinical studies. Herein we describe new synthetic routes to the THP platform including replacing the 1,6-dimethyl-3-hydroxypyridin-4-one N1-CH3 group of THPMe with O (tris(6-methyl-3-hydroxypyran-4-one, THPO) and N1-H (tris(6-methyl-3-hydroxypyridin-4-one), THPH) groups. The effect of these structural modifications on lipophilicity, gallium binding and metal ion selectivity was investigated. THPH was able to bind 68Ga in extremely mild conditions (5 min, room temperature, pH 6, 1 µM ligand concentration) and, notably, in vivo, when administered to a mouse previously injected with 68Ga acetate. The 67Ga radiolabelled complex was stable in serum for more than 7 days. [68Ga(THPH)] displayed a log P value of -2.40 ± 0.02, less negative than the log P = -3.33 ± 0.02 measured for [68Ga(THPMe)], potentially due to an increase in intramolecular hydrogen bonding attributable to the N1-H pyridinone units. Spectrophotometric determination of the Ga3+/Fe3+ complex formation constants for both THPMe and THPH revealed their preference for binding Ga3+ over Fe3+, which enabled selective labelling with 68Ga3+ in the presence of a large excess of Fe3+ in both cases. Compared to THPMe, THPH showed significantly reduced affinity for Fe3+, increased affinity for Ga3+ and improved radiolabelling efficiency. THPO was inferior to both THPH and THPMe in terms of labelling efficiency, but its benzylated precursor Bn-THPO (tris(6-methyl-3-benzyloxypyran-4-one)) provides a potential platform for the synthesis of a library of THP compounds with tunable chemical properties and metal preferences.


Assuntos
Quelantes/síntese química , Meios de Contraste/síntese química , Complexos de Coordenação/síntese química , Radioisótopos de Gálio/química , Piridonas/síntese química , Compostos Radiofarmacêuticos/síntese química , Animais , Quelantes/química , Meios de Contraste/farmacocinética , Complexos de Coordenação/farmacocinética , Ligantes , Masculino , Camundongos SCID , Tomografia por Emissão de Pósitrons/métodos , Piridonas/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética , Relação Estrutura-Atividade , Termodinâmica , Distribuição Tecidual
11.
Artigo em Inglês | MEDLINE | ID: mdl-30745394

RESUMO

Doravirine is a novel nonnucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus 1 (HIV-1) infection. A population pharmacokinetic (PK) model was developed for doravirine using pooled data from densely sampled phase 1 trials and from sparsely sampled phase 2b and phase 3 trials evaluating doravirine administered orally as a single entity or as part of a fixed-dose combination of doravirine-lamivudine-tenofovir disoproxil fumarate. A one-compartment model with linear clearance from the central compartment adequately described the clinical PK of doravirine. While weight, age, and healthy versus HIV-1 status were identified as statistically significant covariates affecting doravirine PK, the magnitude of their effects was not clinically meaningful. Other intrinsic factors (gender, body mass index, race, ethnicity, and renal function) did not have statistically significant or clinically meaningful effects on doravirine PK. Individual exposure estimates for individuals in the phase 2b and 3 trials obtained from the final model were used for subsequent exposure-response analyses for virologic response (proportion of individuals achieving <50 copies/ml) and virologic failure. The exposure-response relationships between these efficacy endpoints and doravirine PK were generally flat over the range of exposures achieved for the 100 mg once-daily regimen in the phase 3 trials, with a minimal decrease in efficacy in individuals in the lowest 10th percentile of steady-state doravirine concentration at 24 h values. These findings support 100 mg once daily as the selected dose of doravirine, with no dose adjustment warranted for the studied intrinsic factors.


Assuntos
Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Piridonas/farmacocinética , Piridonas/uso terapêutico , Triazóis/farmacocinética , Triazóis/uso terapêutico , Adulto , Idoso , Área Sob a Curva , Feminino , Infecções por HIV/metabolismo , Infecções por HIV/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Transcriptase Reversa , Adulto Jovem
13.
Drugs Aging ; 36(1): 65-71, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30411284

RESUMO

BACKGROUND: Use of direct-acting oral anticoagulants (DOACs) is increasing, but knowledge about pharmacokinetics and safety in frail patients is lacking. OBJECTIVE: The aim was to determine serum concentrations and elimination rates of DOACs in older hip fracture patients hospitalized for surgery. METHODS: The study included patients ≥ 65 years of age hospitalized for acute hip fracture surgery over a period of 6 months. Use of antithrombotic drugs was registered and serum samples collected for analysis of DOACs (apixaban, dabigatran and rivaroxaban) at admission and surgery. Measured concentrations were assessed in relation to reference (therapeutic) ranges of the respective drugs and applied for half-life calculations. Furthermore, waiting time for surgery was compared between DOAC and warfarin users. RESULTS: Of 167 patients included (median age 84 years), 11 and 14 used DOACs and warfarin, respectively. Seven of the DOAC-treated patients had concentrations above the upper reference range (> 300 nM) at admission, and concentrations were still in the reference range for five of these at surgery. Elimination half-lives could be estimated in eight patients and ranged between 14.6 and 59.7 h (median 21.6). The observed waiting time for surgery was longer for patients using DOACs than warfarin (median 44 vs. 25 h). CONCLUSION: This pilot study indicates that older patients prone to hip fracture are at risk of being exposed to therapeutic serum concentrations of DOACs during surgery due to reduced drug elimination rates. The observation that almost 50% of the patients had therapeutic concentrations at surgery should be investigated further regarding safety of DOAC use in this frail elderly population.


Assuntos
Anticoagulantes/uso terapêutico , Fraturas do Quadril/cirurgia , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/farmacocinética , Dabigatrana/farmacocinética , Dabigatrana/uso terapêutico , Feminino , Fraturas do Quadril/tratamento farmacológico , Humanos , Masculino , Projetos Piloto , Estudos Prospectivos , Pirazóis/farmacocinética , Pirazóis/uso terapêutico , Piridonas/farmacocinética , Piridonas/uso terapêutico , Rivaroxabana/farmacocinética , Rivaroxabana/uso terapêutico , Varfarina/farmacocinética , Varfarina/uso terapêutico
14.
Eur J Drug Metab Pharmacokinet ; 44(3): 319-327, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30387005

RESUMO

Available antiretroviral drugs have demonstrated effectiveness in both pre-exposure prophylaxis and treatment of HIV infection. However, some concerns still persist regarding these therapies, mainly related to patient adherence, drug toxicity and dosing convenience. Cabotegravir is a potent integrase strand transfer inhibitor with a chemical structure similar to dolutegravir that is under clinical evaluation both as oral and long-acting injectable (LAI) formulations for both the prevention or treatment of HIV infection. Indeed, preclinical and clinical studies have consistently shown that LAI cabotegravir is readily absorbed following intramuscular and subcutaneous administration, with an elimination half-life of approximately 40 days, permitting infrequent dosing, possibly once every 1 or 2 months (eventually combined with rilpivirine). Here, we reviewed the existing literature on the preclinical and clinical pharmacokinetics and pharmacodynamics of LAI cabotegravir, with emphasis on the actual pharmacokinetic challenges of this novel formulation, as well as its potential to act as a victim or perpetrator of drug-drug interactions.


Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/farmacologia , Inibidores de Integrase de HIV/farmacocinética , Piridonas/farmacologia , Piridonas/farmacocinética , Animais , Ensaios Clínicos como Assunto , Relação Dose-Resposta a Droga , Esquema de Medicação , Avaliação Pré-Clínica de Medicamentos , Interações Medicamentosas , Infecções por HIV/enzimologia , Inibidores de Integrase de HIV/uso terapêutico , Humanos , Injeções Intramusculares , Injeções Subcutâneas , Piridonas/uso terapêutico , Fatores de Tempo
15.
Eur J Anaesthesiol ; 36(6): 449-456, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30308522

RESUMO

BACKGROUND: Rapid detection of the anticoagulant effect of oral factor Xa (FXa) inhibitors may be essential in several emergency clinical situations. Specific assays quantifying the drugs are performed in plasma and require a turnaround time that is too long to be useful in emergency situations. Rotational thromboelastometry (ROTEM) is a whole blood coagulation assay of blood viscoelasticity and could be of interest for FXa inhibitor detection in emergency. However, conventional ROTEM reagents only detect high amounts of inhibitors. OBJECTIVE: The aim of this study was first to assess the effect of whole blood components on the viscoelastic measurement of the effects of FXa inhibitors, and second to evaluate whether a modified ROTEM, triggered with a low amount of tissue factor and a saturating amount of phospholipid vesicles, can reliably detect low levels of FXa inhibitor activity in whole blood. DESIGN: Diagnostic test study. SETTINGS: A university research laboratory. From November 2014 to April 2016. PATIENTS: Sixty-six patients: 30 treated with rivaroxaban, 17 with apixaban and 19 without treatment. INTERVENTION: ROTEM was triggered with 2.5 pmol l of tissue factor and 10 µmol l of phospholipid vesicles. MAIN OUTCOME MEASURES: Modified ROTEM parameters were measured in different experimental conditions: platelet-poor plasma (PPP), platelet-rich plasma, PPP supplemented with fibrinogen and reconstituted whole blood with various haematocrit levels adjusted between 30 and 60%. Modified ROTEM was further validated using whole blood from patients who were either treated or not treated with FXa inhibitors. RESULTS: Modified ROTEM allowed detection of as little as 25 ng ml FXa inhibitors in PPP, with at least a 1.4-fold increase of the clotting time (P ≤ 0.02). Neither changes of fibrinogen concentration nor variations of platelet count or haematocrit precluded FXa inhibitor detection. A lengthened modified ROTEM clotting time of more than 197 s allowed detection of FXa inhibitor concentrations above 30 ng ml in whole blood with 90% sensitivity and 85% specificity. CONCLUSION: Modified ROTEM may be applicable in emergency situations for the detection of FXa inhibitors in whole blood.


Assuntos
Inibidores do Fator Xa/sangue , Tromboelastografia/métodos , Administração Oral , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Coagulação Sanguínea/efeitos dos fármacos , Cuidados Críticos/métodos , Inibidores do Fator Xa/administração & dosagem , Inibidores do Fator Xa/farmacocinética , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pirazóis/administração & dosagem , Pirazóis/sangue , Pirazóis/farmacocinética , Piridonas/administração & dosagem , Piridonas/sangue , Piridonas/farmacocinética , Rivaroxabana/administração & dosagem , Rivaroxabana/sangue , Rivaroxabana/farmacocinética , Sensibilidade e Especificidade , Fatores de Tempo , Adulto Jovem
17.
Xenobiotica ; 49(9): 1001-1006, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30216091

RESUMO

Steady-state plasma concentrations of anticoagulants and the time since the previous administration in mainly outpatients with atrial fibrillation administered standard or reduced doses were analyzed for 110 elderly Japanese subjects (mean age, 76 years) treated with apixaban (2.5 or 5.0 mg twice daily), dabigatran etexilate (110 or 150 mg twice daily), edoxaban (30 or 60 mg once daily) or rivaroxaban (10 or 15 mg once daily) at one general hospital. The pharmacokinetics in patients treated with standard and reduced doses of the four anticoagulants using liquid chromatography-tandem mass spectrometry was compared with the concentration ranges estimated using physiologically based pharmacokinetic modeling. Reduced doses of anticoagulants resulted in relatively small pharmacokinetic variations compared with the standard dose. Statistical analyses revealed that renal impairment is likely not the sole determinant factor for high plasma concentrations of apixaban, dabigatran, edoxaban and rivaroxaban. Patients with atrial fibrillation should be treated with the correct doses of oral anticoagulants as specified in the package inserts (e.g. reduced doses for elderly patients, patients with low body weights and in combination with P-glycoprotein inhibitor drugs) to avoid excessive or insufficient doses of direct oral anticoagulants.


Assuntos
Anticoagulantes/sangue , Anticoagulantes/farmacocinética , Fibrilação Atrial/tratamento farmacológico , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Dabigatrana/administração & dosagem , Dabigatrana/efeitos adversos , Dabigatrana/sangue , Dabigatrana/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Humanos , Nefropatias/induzido quimicamente , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Pirazóis/sangue , Pirazóis/farmacocinética , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Piridinas/sangue , Piridinas/farmacocinética , Piridonas/administração & dosagem , Piridonas/efeitos adversos , Piridonas/sangue , Piridonas/farmacocinética , Rivaroxabana/administração & dosagem , Rivaroxabana/efeitos adversos , Rivaroxabana/sangue , Rivaroxabana/farmacocinética , Tiazóis/administração & dosagem , Tiazóis/efeitos adversos , Tiazóis/sangue , Tiazóis/farmacocinética
18.
Br J Clin Pharmacol ; 85(1): 270-272, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30421528

RESUMO

A 67-year-old man was admitted to the emergency department about 5 h after deliberate self-poisoning with 300 mg of Apixaban. The clinical examination did not show any organ dysfunctions or haemorrhagic signs, and the patient's life was not in danger. The first analysis, upon admission, showed a concentration of 2655 µg l-1 of Apixaban. The Cmax was observed 17 h after the intake (3654 µg l-1 ), about four times the classical Tmax value (median [range]: 4 h [2-4]). The Apixaban was then eliminated following a first order elimination with a calculated half-life of 10.8 h. The anti-Xa activity seems to be linearly related to concentration up to 4000 µg l-1 . This report suggests that the use of activated charcoal should be effective up to 17 h after a massive intake.


Assuntos
Depressão/complicações , Overdose de Drogas/sangue , Inibidores do Fator Xa/farmacocinética , Pirazóis/farmacocinética , Piridonas/farmacocinética , Idoso , Depressão/psicologia , Overdose de Drogas/etiologia , Overdose de Drogas/psicologia , Inibidores do Fator Xa/envenenamento , Meia-Vida , Humanos , Masculino , Pirazóis/envenenamento , Piridonas/envenenamento , Comprimidos
19.
Med Chem ; 15(5): 561-570, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30398119

RESUMO

BACKGROUND: Natural products have shown potent anti-HIV activity, but some of these also possess toxicity. The pharmacophoric fragments of these natural products have scope of combination with other pharmacophoric fragment and derivatization to reduce toxicity and increase the potency. Combination of natural product fragments from different classes of anti-HIV compounds may lead to a new class of potent anti-HIV agents. OBJECTIVE: Design, in silico prediction of drug-likeness, ADMET properties and synthesis of pyrazol- pyridones. Evaluation of the anti-HIV-1 activity of synthesized pyrazol-pyridones. METHODS: Pyrazol-pyridones were designed by combining reported anti-HIV pharmacophoric fragments. Designed molecules were synthesized after in silico prediction of drug-likeness and ADMET properties. Compounds were evaluated for activity against HIV-1VB59 and HIV-1UG070. RESULTS: QED value of designed pyrazol-pyridones was greater than the known drug zidovudine. The designed compounds were predicted to be noncarcinogenic and nonmutagenic in nature. Seventeen novel pyrazol-pyridones were synthesized with good yield. Compound 6q and 6l showed activity with IC50 values 6.14 µM and 15.34 µM against HIV-1VB59 and 16.21 µM and 18.21 µM against HIV-1UG070, respectively. CONCLUSION: Compound 6q was found to be most potent among the synthesized compounds with a therapeutic index of 54.31against HIV-1VB59. This is the first report of anti-HIV-1 activity of pyrazol-pyridone class of compounds. Although the anti-HIV-1 activity of these compounds is moderate, this study opens up a new class for exploration of chemical space for anti-HIV-1 activity.


Assuntos
Fármacos Anti-HIV/farmacologia , HIV-1/efeitos dos fármacos , Pirazóis/farmacologia , Piridonas/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/toxicidade , Desenho de Fármacos , Células HeLa , Humanos , Pirazóis/síntese química , Pirazóis/farmacocinética , Pirazóis/toxicidade , Piridonas/síntese química , Piridonas/farmacocinética , Piridonas/toxicidade
20.
Xenobiotica ; 49(4): 422-432, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29557716

RESUMO

Absorption, distribution, metabolism and elimination of doravirine (MK-1439), a novel non-nucleoside reverse transcriptase inhibitor, were investigated. Two clinical trials were conducted in healthy subjects: an oral single dose [14 C]doravirine (350 mg, ∼200 µCi) trial (n = 6) and an intravenous (IV) single-dose doravirine (100 µg) trial (n = 12). In vitro metabolism, protein binding, apparent permeability and P-glycoprotein (P-gp) transport studies were conducted to complement the clinical trials. Following oral [14 C]doravirine administration, all of the administered dose was recovered. The absorbed dose was eliminated primarily via metabolism. An oxidative metabolite (M9) was the predominant metabolite in excreta and was the primary circulating metabolite (12.9% of circulating radioactivity). Following IV administration, doravirine clearance and volume of distribution were 3.73 L/h (95% confidence intervals (CI) 3.09, 4.49) and 60.5 L (95% CI 53.7, 68.4), respectively. In vitro, doravirine is not highly bound to plasma proteins (unbound fraction 0.24) and has good passive permeability. The metabolite M9 was generated by cytochrome P450 3A (CYP3A)4/5-mediated oxidation. Doravirine was a P-gp substrate but P-gp efflux is not expected to play a significant role in limiting doravirine absorption or to be involved in the elimination of doravirine. In conclusion, doravirine is a low clearance drug, primarily eliminated by CYP3A-mediated metabolism.


Assuntos
Absorção Fisiológica , Piridonas/farmacocinética , Inibidores da Transcriptase Reversa/farmacocinética , Triazóis/farmacocinética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Administração Intravenosa , Adulto , Humanos , Masculino , Metaboloma/efeitos dos fármacos , Pessoa de Meia-Idade , Piridonas/sangue , Piridonas/química , Piridonas/urina , Inibidores da Transcriptase Reversa/sangue , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/urina , Distribuição Tecidual , Triazóis/sangue , Triazóis/química , Triazóis/urina , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA