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1.
Ann Hematol ; 99(9): 2193-2195, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32621180
2.
J Med Chem ; 63(13): 6834-6846, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32511917

RESUMO

Tankyrases 1 and 2 are central biotargets in the WNT/ß-catenin signaling and Hippo signaling pathways. We have previously developed tankyrase inhibitors bearing a 1,2,4-triazole moiety and binding predominantly to the adenosine binding site of the tankyrase catalytic domain. Here we describe a systematic structure-guided lead optimization approach of these tankyrase inhibitors. The central 1,2,4-triazole template and trans-cyclobutyl linker of the lead compound 1 were left unchanged, while side-group East, West, and South moieties were altered by introducing different building blocks defined as point mutations. The systematic study provided a novel series of compounds reaching picomolar IC50 inhibition in WNT/ß-catenin signaling cellular reporter assay. The novel optimized lead 13 resolves previous atropisomerism, solubility, and Caco-2 efflux liabilities. 13 shows a favorable ADME profile, including improved Caco-2 permeability and oral bioavailability in mice, and exhibits antiproliferative efficacy in the colon cancer cell line COLO 320DM in vitro.


Assuntos
Desenho de Fármacos , Inibidores de Poli(ADP-Ribose) Polimerases/química , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Tanquirases/antagonistas & inibidores , Triazóis/química , Triazóis/farmacologia , Animais , Disponibilidade Biológica , Células CACO-2 , Proliferação de Células/efeitos dos fármacos , Humanos , Camundongos , Inibidores de Poli(ADP-Ribose) Polimerases/farmacocinética , Solubilidade , Triazóis/farmacocinética
3.
J Med Chem ; 63(9): 4496-4505, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32302130

RESUMO

The insertion of single 1,4-disubstituted 1,2,3-triazoles as metabolically stable bioisosteres of trans-amide bonds (triazole scan) was recently applied to the 177Lu-labeled tumor-targeting analog of minigastrin, [Nle15]MG11. The reported novel mono-triazolo-peptidomimetics of [Nle15]MG11 showed either improved resistance against enzymatic degradation or a significantly increased affinity toward the target receptor but never both. To enhance further the tumor-targeting properties of the minigastrin analogs, we studied conjugates with multiple amide-to-triazole substitutions for additive or synergistic effects. Promising candidates were identified by modification of two or three amide bonds, which yielded both improved stability and increased receptor affinity of the peptidomimetics in vitro. Biodistribution studies of radiolabeled multi-triazolo-peptidomimetics in mice bearing receptor-positive tumor xenografts revealed up to 4-fold increased tumor uptake in comparison to the all-amide reference compound [Nle15]MG11. In addition, we report here for the first time a linear peptidomimetic with three triazole insertions in its backbone and maintained biological activity.


Assuntos
Antineoplásicos/farmacologia , Gastrinas/farmacologia , Peptidomiméticos/farmacologia , Compostos Radiofarmacêuticos/farmacologia , Triazóis/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Desenho de Fármacos , Gastrinas/síntese química , Gastrinas/metabolismo , Gastrinas/farmacocinética , Humanos , Lutécio/química , Camundongos , Neoplasias/metabolismo , Peptidomiméticos/síntese química , Peptidomiméticos/metabolismo , Peptidomiméticos/farmacocinética , Ligação Proteica , Radioisótopos/química , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/metabolismo , Compostos Radiofarmacêuticos/farmacocinética , Receptor de Colecistocinina B/metabolismo , Triazóis/síntese química , Triazóis/metabolismo , Triazóis/farmacocinética
4.
J Med Chem ; 63(9): 4484-4495, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32302139

RESUMO

MG11 is a truncated analog of minigastrin, a peptide with high affinity and specificity toward the cholecystokinin-2 receptor (CCK2R), which is overexpressed by different tumors. Thus, radiolabeled MG11 derivatives have great potential for use in cancer diagnosis and therapy. A drawback of MG11 is its fast degradation by proteases, leading to moderate tumor uptake in vivo. We introduced 1,4-disubstituted 1,2,3-triazoles as metabolically stable bioisosteres to replace labile amide bonds of the peptide. The "triazole scan" yielded peptidomimetics with improved resistance to enzymatic degradation and/or enhanced affinity toward the CCK2R. Remarkably, our lead compound achieved a 10-fold increase in receptor affinity, resulting in a 2.6-fold improved tumor uptake in vivo. Modeling of the ligand-CCK2R complex suggests that an additional cation-π interaction of the aromatic triazole moiety with the Arg356 residue of the receptor is accountable for these observations. We show for the first time that the amide-to-triazole substitution strategy offers new opportunities in drug development that go beyond the metabolic stabilization of bioactive peptides.


Assuntos
Antineoplásicos/farmacologia , Gastrinas/farmacologia , Peptidomiméticos/farmacologia , Compostos Radiofarmacêuticos/farmacologia , Triazóis/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Feminino , Gastrinas/síntese química , Gastrinas/metabolismo , Gastrinas/farmacocinética , Humanos , Lutécio/química , Camundongos , Neoplasias/metabolismo , Peptidomiméticos/síntese química , Peptidomiméticos/metabolismo , Peptidomiméticos/farmacocinética , Ligação Proteica , Conformação Proteica , Radioisótopos/química , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/metabolismo , Compostos Radiofarmacêuticos/farmacocinética , Receptor de Colecistocinina B/metabolismo , Triazóis/síntese química , Triazóis/metabolismo , Triazóis/farmacocinética
5.
AAPS PharmSciTech ; 21(3): 91, 2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32060665

RESUMO

Doravirine is a non-nucleoside reverse transcriptase inhibitor indicated for the treatment of human immunodeficiency virus-1 infection, available as a single tablet in combination with other antiretroviral agents or as a fixed-dose regimen with lamivudine and tenofovir disoproxil fumarate (TDF). Alternative formulations of these drugs are being developed for individuals who have difficulty swallowing tablets. Two phase 1 trials were conducted, both in 24 healthy adults, to assess the pharmacokinetics of uncoated and coated oral granule formulations of doravirine, lamivudine, and TDF administered alone and with vanilla pudding or apple sauce. The pharmacokinetics for all uncoated granules, and of coated lamivudine and TDF granules, were similar to those of currently marketed tablets (geometric mean ratios [GMRs] 0.92-1.04). Coated doravirine granules had decreased AUC0-∞ (11%) and Cmax (23%) values versus the tablet. The pharmacokinetics were similar for uncoated and coated doravirine granules administered with or without pudding (GMRs 0.96-1.10); administration with apple sauce increased doravirine AUC0-∞ (26-29%), Cmax (56-59%), and C24 (20-21%) versus administration of granules alone. Lamivudine granules administered with pudding or apple sauce decreased AUC0-∞ and Cmax (14-25%) versus granules alone. Tenofovir AUC0-∞, Cmax, and C24 increased for TDF granules administered with pudding or apple sauce versus alone (11-23%). Pharmacokinetic differences when administering doravirine, lamivudine, or TDF as uncoated or coated granules versus tablets, or when granules were administered with (versus without) pudding or apple sauce, are not considered clinically meaningful, supporting further development of these granule formulations.


Assuntos
Fármacos Anti-HIV/farmacocinética , Antirretrovirais/farmacocinética , Lamivudina/farmacocinética , Piridonas/farmacocinética , Inibidores da Transcriptase Reversa/farmacocinética , Tenofovir/farmacocinética , Triazóis/farmacocinética , Adulto , Fármacos Anti-HIV/administração & dosagem , Antirretrovirais/administração & dosagem , Disponibilidade Biológica , Estudos Cross-Over , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , Humanos , Lamivudina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Piridonas/administração & dosagem , Inibidores da Transcriptase Reversa/administração & dosagem , Comprimidos , Tenofovir/administração & dosagem , Triazóis/administração & dosagem , Adulto Jovem
6.
J Med Chem ; 63(4): 1511-1525, 2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-31951127

RESUMO

We recently reported the discovery of a potent, selective, and brain-penetrant V1a receptor antagonist, which was not suitable for full development. Nevertheless, this compound was found to improve surrogates of social behavior in adults with autism spectrum disorder in an exploratory proof-of-mechanism study. Here we describe scaffold hopping that gave rise to triazolobenzodiazepines with improved pharmacokinetic properties. The key to balancing potency and selectivity while minimizing P-gp mediated efflux was fine-tuning of hydrogen bond acceptor basicity. Ascertaining a V1a antagonist specific brain activity pattern by pharmacological magnetic resonance imaging in the rat played a seminal role in guiding optimization efforts, culminating in the discovery of balovaptan (RG7314, RO5285119) 1. In a 12-week clinical phase 2 study in adults with autism spectrum disorder balovaptan demonstrated improvements in Vineland-II Adaptive Behavior Scales, a secondary end point comprising communication, socialization, and daily living skills. Balovaptan entered phase 3 clinical development in August 2018.


Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos/uso terapêutico , Transtorno do Espectro Autista/tratamento farmacológico , Benzodiazepinas/uso terapêutico , Piridinas/uso terapêutico , Receptores de Vasopressinas/metabolismo , Triazóis/uso terapêutico , Adolescente , Adulto , Animais , Antagonistas dos Receptores de Hormônios Antidiuréticos/síntese química , Antagonistas dos Receptores de Hormônios Antidiuréticos/farmacocinética , Transtorno do Espectro Autista/metabolismo , Benzodiazepinas/síntese química , Benzodiazepinas/farmacocinética , Encéfalo/metabolismo , Criança , Ensaios Clínicos como Assunto , Descoberta de Drogas , Feminino , Humanos , Masculino , Mamíferos , Piridinas/síntese química , Piridinas/farmacocinética , Triazóis/síntese química , Triazóis/farmacocinética
7.
Eur J Clin Pharmacol ; 76(2): 185-197, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31919558

RESUMO

PURPOSE: The present studies assessed the drug-drug interaction of molidustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, with iron and calcium supplements, which are common medications in patients with anaemia due to chronic kidney disease (CKD). METHODS: Forty-two healthy men received molidustat alone (fasted or fed) or combined with oral iron(II) or calcium(II), given immediately before or between 4 h before and 1 h after molidustat in three randomized, open-label, crossover studies (12-15 participants per study). Molidustat AUC and Cmax were assessed as the main pharmacokinetic parameters, and endogenous erythropoietin (EPO) was measured to evaluate pharmacodynamics. RESULTS: Depending on prandial state, concomitant intake of iron(II) reduced molidustat AUC and Cmax by 50-75% and 46-84%, respectively, and EPO AUC(0-24) and Cmax by 31-44% and 36-48%, respectively. The influence of iron(II) declined with increasing the time interval to the intake of molidustat, with reductions in molidustat AUC and Cmax of 9% and 10%, respectively, when iron(II) intake occurred 4 h before molidustat. Accordingly, effects on endogenous EPO were less pronounced with increased time separation between oral iron(II) and molidustat intake. Calcium(II) reduced molidustat AUC and Cmax by 15% and 47%, respectively, without influence on EPO response. All treatments were well tolerated. CONCLUSIONS: In contrast to concomitant oral intake of calcium, the effect of oral iron supplements on molidustat pharmacokinetics and pharmacodynamics should be considered, and the two agents should be administered with an appropriate time separation.


Assuntos
Cálcio/administração & dosagem , Ferro/administração & dosagem , Pirazóis/administração & dosagem , Triazóis/administração & dosagem , Administração Oral , Adulto , Anemia/tratamento farmacológico , Área Sob a Curva , Cálcio/farmacologia , Estudos Cross-Over , Suplementos Nutricionais , Esquema de Medicação , Interações Medicamentosas , Eritropoetina/metabolismo , Humanos , Prolina Dioxigenases do Fator Induzível por Hipóxia/antagonistas & inibidores , Ferro/farmacologia , Masculino , Pessoa de Meia-Idade , Pirazóis/farmacocinética , Pirazóis/farmacologia , Fatores de Tempo , Triazóis/farmacocinética , Triazóis/farmacologia , Adulto Jovem
8.
Expert Opin Pharmacother ; 21(4): 399-408, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31957504

RESUMO

Introduction: Despite unprecedented advances in the treatment of multiple myeloma (MM), almost all patients develop a disease that is resistant to the five most commonly used and active anti-MM agents. The prognosis for this patient population is particularly poor resulting in an unmet need for additional therapeutic options. Exportin-1 (XPO-1) is a major nuclear export protein of macromolecular cargo frequently overexpressed in MM. Selinexor is a first-in-class, oral Selective-Inhibitor-of-Nuclear-Export (SINE) compound that impedes XPO-1. Based on results of the STORM-trial, selinexor in combination with dexamethasone was granted accelerated FDA approval for patients with penta-refractory MM in July 2019.Areas covered: This article summarizes our up-to-date knowledge on the pathophysiologic role of XPO-1 in MM. Furthermore, it reviews the most recent clinical data on selinexor in combination with dexamethasone and other anti-MM agents; and discusses its safety profile, management strategies; and potential future developments.Expert opinion: Selinexor represents a next-generation-novel agent with an innovative mechanism of action that marks a significant advance in the treatment of heavily pretreated MM patients. Ongoing studies investigate its therapeutic potential also in earlier lines of therapy. Additional data is needed to confirm that selinexor and other SINE compounds are a valuable addition to our current therapeutic armamentarium.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Hidrazinas/uso terapêutico , Carioferinas/antagonistas & inibidores , Mieloma Múltiplo/tratamento farmacológico , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Triazóis/uso terapêutico , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Linhagem Celular Tumoral , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Ensaios Clínicos como Assunto , Dexametasona/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Humanos , Hidrazinas/administração & dosagem , Hidrazinas/efeitos adversos , Hidrazinas/farmacocinética , Carioferinas/genética , Mieloma Múltiplo/metabolismo , Prognóstico , Receptores Citoplasmáticos e Nucleares/genética , Triazóis/administração & dosagem , Triazóis/efeitos adversos , Triazóis/farmacocinética
9.
Biomed Chromatogr ; 34(4): e4802, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31998982

RESUMO

Filgotinib is a selective JAK1 (Janus kinase) inhibitor, filed in Japan for the treatment of rheumatoid arthritis. In this paper, we report a validated liquid chromatography coupled with tandem mass spectrometry for the quantification of filgotinib in rat plasma using tofacitinib as an internal standard (IS) as per the Food and Drug Administration regulatory guidelines. Filgotinib and the IS were extracted from rat plasma using ethyl acetate as an extraction solvent and chromatographed using an isocratic mobile phase (0.2% formic acid:acetonitrile; 20:80, v/v) at a flow rate of 0.9 mL/min on a Gemini C18 column. Filgotinib and the IS were eluted at ~1.31 and 0.89 min, respectively. The MS/MS ion transitions monitored were m/z 426.3 → 291.3 and m/z 313.2 → 149.2 for filgotinib and the IS, respectively. The calibration range was 0.78-1924 ng/mL. No matrix effect and carryover were observed. Intra- and inter-day accuracies and precisions were within the acceptance range. Filgotinib was stable for three freeze-thaw cycles: on bench-top up to 6 h, in an autosampler up to 21 h, and at -80°C for 1 month. This novel method has been applied to a pharmacokinetic study in rats.


Assuntos
Cromatografia Líquida/métodos , Piridinas/sangue , Piridinas/farmacocinética , Espectrometria de Massas em Tandem/métodos , Triazóis/sangue , Triazóis/farmacocinética , Animais , Estabilidade de Medicamentos , Modelos Lineares , Masculino , Piridinas/química , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Triazóis/química
10.
J Environ Sci Health B ; 55(3): 175-183, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31631749

RESUMO

The purpose of this study was to study the excretion stereoselectivity of triticonazole enantiomers in rat urine and faeces. Six male Sprague-Dawley (SD) rats were administrated 50 mg/kg rac-triticonazole. Rats urine and faeces were separately and quantitatively collected at the following intervals: 0-3, 3-6, 6-9, 9-12, 12-24, 24-36 and 36-48 h. The faeces samples were homogenized in an aqueous solution containing 0.2% DMSO at the ratio of 1 g: 40 mL. An aliquot of 100 µL rats urine or faeces homogenate was spiked and mixed with 6.0 µL of 1.00 µg/mL flusilazole as an internal standard. The triticonazole enantiomers in urine and faeces were determined by using an HPLC/MS-MS after samples preparation. The excreted amounts of enantiomers in the urine showed a significant difference (P < 0.05) except for 3-6 h. The cumulative excretion rate (Xu0→24) in urine was 26.43 ± 0.08% and 37.58 ± 0.11% for R-(-)- and S-(+)-triticonazole, respectively, indicating high enantioselectivity (P < 0.001). The cumulative excretion rate (Xu0→72) in faeces was 6.93 ± 0.03% and 6.77 ± 0.03% for R-(-)- and S-(+)-triticonazole, respectively, without a difference. The results showed that the total cumulative percentage of triticonazole enantiomers accounted for in urine and faeces was 64.00 ± 0.13% and 13.70 ± 0.32%, the urinary excretion of R-(-)- and S-(+)-triticonazole were significantly different and S-(+)-triticonazole was preferentially excreted. However, the faecal excretion of the enantiomers showed no difference.


Assuntos
Ciclopentanos/química , Ciclopentanos/farmacocinética , Fezes/química , Triazóis/química , Triazóis/farmacocinética , Administração Oral , Animais , Cromatografia Líquida de Alta Pressão/métodos , Ciclopentanos/urina , Fungicidas Industriais/química , Fungicidas Industriais/farmacocinética , Fungicidas Industriais/urina , Masculino , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Silanos/urina , Estereoisomerismo , Espectrometria de Massas em Tandem , Triazóis/urina
11.
J Med Chem ; 63(7): 3461-3471, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-31851518

RESUMO

DNA-PK is a key component within the DNA damage response, as it is responsible for recognizing and repairing double-strand DNA breaks (DSBs) via non-homologous end joining. Historically it has been challenging to identify inhibitors of the DNA-PK catalytic subunit (DNA-PKcs) with good selectivity versus the structurally related PI3 (lipid) and PI3K-related protein kinases. We screened our corporate collection for DNA-PKcs inhibitors with good PI3 kinase selectivity, identifying compound 1. Optimization focused on further improving selectivity while improving physical and pharmacokinetic properties, notably co-optimization of permeability and metabolic stability, to identify compound 16 (AZD7648). Compound 16 had no significant off-target activity in the protein kinome and only weak activity versus PI3Kα/γ lipid kinases. Monotherapy activity in murine xenograft models was observed, and regressions were observed when combined with inducers of DSBs (doxorubicin or irradiation) or PARP inhibition (olaparib). These data support progression into clinical studies (NCT03907969).


Assuntos
Proteína Quinase Ativada por DNA/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Purinas/uso terapêutico , Piranos/uso terapêutico , Triazóis/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Classe Ib de Fosfatidilinositol 3-Quinase/metabolismo , Cães , Descoberta de Drogas , Humanos , Camundongos , Estrutura Molecular , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Purinas/síntese química , Purinas/farmacocinética , Piranos/síntese química , Piranos/farmacocinética , Ratos , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/farmacocinética , Ensaios Antitumorais Modelo de Xenoenxerto
12.
J Med Chem ; 63(2): 569-590, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31855426

RESUMO

The prostanoid EP4 receptor is one of the key receptors associated with inflammatory mediator PGE2-elicited immunosuppression in the tumor microenvironment. Blockade of EP4 signaling to enhance immunity-mediated tumor elimination has recently emerged as a promising strategy for cancer immunotherapy. In our efforts to discover novel subtype-selective EP4 antagonists, we designed and synthesized a class of 1H-1,2,3-triazole-based ligands that display low nanomolar antagonism activity toward the human EP4 receptor and excellent subtype selectivity. The most promising compound 59 exhibits single-digit nanomolar potency in the EP4 calcium flux and cAMP-response element reporter assays and effectively suppresses the expression of multiple immunosuppression-related genes in macrophage cells. On the basis of its favorable ADMET properties, compound 59 was chosen for further in vivo biological evaluation. Oral administration of compound 59 significantly inhibited tumor growth in the mouse CT26 colon carcinoma model accompanied by enhanced infiltration of cytotoxic T lymphocytes in the tumor tissue.


Assuntos
Imunoterapia/métodos , Neoplasias/terapia , Receptores de Prostaglandina E Subtipo EP4/antagonistas & inibidores , Triazóis/farmacologia , Triazóis/uso terapêutico , Animais , Cálcio/metabolismo , Linhagem Celular Tumoral , Neoplasias do Colo/terapia , Inibidores das Enzimas do Citocromo P-450/farmacologia , Descoberta de Drogas , Feminino , Células HEK293 , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Microssomos Hepáticos/metabolismo , Neoplasias/imunologia , Neoplasias/patologia , Células RAW 264.7 , Relação Estrutura-Atividade , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Triazóis/farmacocinética , Microambiente Tumoral/efeitos dos fármacos
13.
J Oncol Pharm Pract ; 26(1): 5-12, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30854922

RESUMO

BACKGROUND: Posaconazole reduces the risk of invasive Aspergillus in transplant patients, but significantly inhibits tacrolimus metabolism. One study demonstrated that a three-fold dose reduction of tacrolimus was required to obtain therapeutic concentrations when used with posaconazole. However, with empiric dose reduction, there is a risk of subtherapeutic tacrolimus levels and subsequent graft failure or graft-versus-host disease. Overall, the existing data on the impact of posaconazole on tacrolimus pharmacokinetics is limited. OBJECTIVE: The purpose of this study is to determine whether tacrolimus doses should be decreased upon initiation of posaconazole in patients receiving an allogeneic stem cell transplant. METHODS: This is a retrospective chart review at an academic medical center. All allogeneic stem cell transplant adults who received concomitant posaconazole and tacrolimus from February 2016 through December 2017 were included. RESULTS: Seventy-nine patients identified using an internal electronic database were analyzed. The median time to therapeutic tacrolimus concentration was significantly longer in patients who did not receive an empiric dose reduction (0% DR, 10d; 1-30% DR, 4d; 31-65% DR, 5d; >65% DR, 4d; p = 0.0395). The rate of supratherapeutic levels was highest amongst patients who did not receive an empiric DR, and was noted to be significant compared to the group that had 31-65% DR (p < 0.001). CONCLUSION: This study validates our current practice of instituting an empiric 50% dose reduction of oral tacrolimus to 0.03 mg/kg/day when used concomitantly with posaconazole to achieve therapeutic levels in allogeneic stem cell transplant patients.


Assuntos
Antifúngicos/farmacocinética , Transplante de Células-Tronco Hematopoéticas/tendências , Imunossupressores/farmacocinética , Transplante de Células-Tronco/tendências , Tacrolimo/farmacocinética , Triazóis/farmacocinética , Adulto , Antifúngicos/administração & dosagem , Esquema de Medicação , Interações Medicamentosas/fisiologia , Feminino , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Humanos , Imunossupressores/administração & dosagem , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tacrolimo/administração & dosagem , Triazóis/administração & dosagem
14.
Drug Deliv ; 26(1): 1167-1177, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31738083

RESUMO

Onychomycosis is a progressive fungal infection of the nails that involves the deeper nail layer and nail bed. It is important to maintain sufficient drug concentration in the diseased tissues after topical application. In this study, a stable topical delivery system for efinaconazole (EFN) was designed to enhance absorption potential through the skin and nail plate by incorporating ethanol, diethylene glycol monoethyl ether (Transcutol P) and isopropyl myristate, and cyclomethicone into the topical solution as a delivery vehicle, permeation enhancers, and a wetting agent, respectively. In addition, the stability of EFN in the formulation was significantly improved by adding butylated hydroxytoluene, diethylenetriamine pentaacetic acid, and citric acid as an antioxidant, chelating agent, and pH-adjusting agent, respectively, without discoloration. The optimum EFN formulation (EFN-K) showed 1.46-fold greater human skin permeation than that of the reference control (commercial 10% EFN topical solution). Furthermore, after a 24-hour incubation, the amount of infiltrated EFN from EFN-K in the human nail plate was 4.11-fold greater than that of the reference control, resulting in an 89.7% increase in nail flux at 7 days after treatment. EFN-K significantly accelerated structural recovery of the keratin layer in a Trichophyton mentagrophytes-infected guinea pig onychomycosis model, decreasing the mean viable fungal cell count by 54.3% compared to the vehicle-treated group after once-daily treatment for 4 weeks. Thus, the accelerated skin and nail penetration effect of EFN-K is expected to achieve good patient compliance, and improve the complete cure rate of onychomycosis.


Assuntos
Antifúngicos/uso terapêutico , Unhas/efeitos dos fármacos , Onicomicose/tratamento farmacológico , Pele/efeitos dos fármacos , Tinha/tratamento farmacológico , Triazóis/uso terapêutico , Administração Tópica , Animais , Antifúngicos/administração & dosagem , Antifúngicos/farmacocinética , Modelos Animais de Doenças , Cobaias , Humanos , Técnicas In Vitro , Masculino , Membranas Artificiais , Unhas/metabolismo , Onicomicose/metabolismo , Onicomicose/microbiologia , Permeabilidade , Pele/metabolismo , Absorção Cutânea/efeitos dos fármacos , Tinha/metabolismo , Triazóis/administração & dosagem , Triazóis/farmacocinética , Trichophyton/efeitos dos fármacos
15.
Drug Metab Lett ; 13(2): 111-122, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31613735

RESUMO

BACKGROUND: Clinical development of lesinurad, a selective uric acid reabsorption inhibitor, required analysis of lesinurad in plasma from special patient populations. METHODS: EMA and FDA bioanalytical method validation guidance have recommended studying matrix effects on quantitation if samples from special patient populations are to be analyzed. In addition to lesinurad (plasma protein binding 98.2%), the matrix effects from special population plasma on the quantitation of verapamil (PPB 89.6%), allopurinol and oxypurinol (PPB negligible) were also investigated. RESULTS: The plasma from special population patients had no matrix effects on the three quantification methods with stable isotope labeled internal standard, protein precipitation extraction, and LC-MS/MS detection. The validated lesinurad plasma quantification method was successfully applied for the pharmacokinetic evaluations to support the clinical studies in renal impaired patients. CONCLUSION: Special population plasma did not affect quantitation of drugs with a wide range of plasma protein binding levels in human plasma. With the confirmation that there is no impact on quantification from the matrix, the bioanalytical method can be used to support the pharmacokinetic evaluations for clinical studies in special populations.


Assuntos
Insuficiência Hepática/metabolismo , Insuficiência Renal/metabolismo , Tioglicolatos/sangue , Triazóis/sangue , Uricosúricos/sangue , Alopurinol/farmacocinética , Calibragem , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida de Alta Pressão/normas , Ensaios Clínicos como Assunto , Insuficiência Hepática/sangue , Insuficiência Hepática/fisiopatologia , Humanos , Rim/metabolismo , Rim/fisiopatologia , Fígado/metabolismo , Fígado/fisiopatologia , Oxipurinol/sangue , Oxipurinol/farmacocinética , Padrões de Referência , Insuficiência Renal/sangue , Insuficiência Renal/fisiopatologia , Reabsorção Renal , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos , Espectrometria de Massas em Tandem/normas , Tioglicolatos/farmacocinética , Triazóis/farmacocinética , Uricosúricos/farmacocinética , Verapamil/sangue , Verapamil/farmacocinética
16.
Int J Pharm ; 571: 118702, 2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31593810

RESUMO

Rizatriptan produces antimigraine activity by acting as selective agonist of 5-HT1B and 5-HT1D receptors present on intracranial and extracerebral blood vessels. Absorption from oral tablet is slow with Tmax of approximately 1-1.5 h. A few attempts have been made to promote rapid absorption such as oral or sublingual films with limited success. The aim of our study was to develop intranasal spray formulation of rizatriptan with quick onset of action. Solubility was enhanced by a co-solvent system where we studied solubility of rizatriptan benzoate in pure solvents, binary and ternary mixtures. Binary and ternary co-solvents using ethanol, water, propylene glycol and polyethylene glycol resulted rizatriptan equivalent base solubility more than 60 mg/mL. Same co-solvents were used at different level to make nasal spray formulations and evaluated pharmacokinetics using beagle dog animal model. Nasal spray formulation containing 20% w/w ethanol exhibited highest exposure, where Cmax (312 ng/mL) reached in 5 min and maintained higher concentration than oral dose for more than 30 min.


Assuntos
Composição de Medicamentos/métodos , Transtornos de Enxaqueca/tratamento farmacológico , Solventes/química , Triazóis/administração & dosagem , Triptaminas/administração & dosagem , Administração Intranasal , Administração Oral , Animais , Área Sob a Curva , Cápsulas , Cães , Etanol/química , Humanos , Modelos Animais , Polietilenoglicóis/química , Propilenoglicol/química , Solubilidade , Fatores de Tempo , Triazóis/química , Triazóis/farmacocinética , Triptaminas/química , Triptaminas/farmacocinética , Água/química
17.
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
18.
Clin Drug Investig ; 39(11): 1109-1116, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31432392

RESUMO

BACKGROUND AND OBJECTIVES: New intravenous and solid oral formulations of the antifungal agent posaconazole have been developed. This randomized, open-label, crossover study in 18 healthy adult Chinese male and female subjects evaluated the pharmacokinetics of single-dose posaconazole (oral 300-mg posaconazole tablet fasted, intravenous 300-mg posaconazole solution fasted, and oral 300-mg posaconazole tablet with standard high-fat breakfast). Primary objectives were to determine the single-dose pharmacokinetics of posaconazole in healthy Chinese subjects when administered as an intravenous solution and as an oral tablet under fasted conditions and the effect of food on the absorption of posaconazole. METHODS: The three treatments consisted of the following: a single oral dose of posaconazole 300 mg (fasted), a single oral dose of posaconazole 300 mg (high-fat breakfast), and a single intravenous dose of posaconazole 300 mg (fasted). Blood samples for pharmacokinetic analysis were collected before dosing and at regular intervals after dosing. Adverse events were monitored throughout. The pharmacokinetic population included the per-protocol population. The safety population included all subjects who received one or more doses of the study drug. RESULTS: Time to maximum plasma concentration of intravenous posaconazole coincided with the end of infusion; the half-life (t½) was 25.76 h. Geometric mean (% coefficient of variation) values of area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC0-∞) and maximum plasma concentration (Cmax) were 59,925 (36.2%) h·ng/mL and 3999 (28.5%) ng/mL, respectively. The posaconazole tablet had a time to maximum plasma concentration of 4 h and a t½ of 25.21 h after fasting. Geometric mean (coefficient of variation) values of AUC0-∞ and Cmax were 25,263 (39.9%) h·ng/mL and 674.5 (29.6%) ng/mL, respectively. Standard high-fat breakfast increased the exposure of posaconazole approximately twofold with geometric mean ratios (high-fat breakfast/fasted) for AUC0-∞ and Cmax of 2.06 (90% confidence interval 1.86-2.30) and 1.95 (90% confidence interval 1.65-2.31), respectively. The geometric mean absolute bioavailability of the tablet formulation was 42.2% in the fasted state and 87.1% under high-fat breakfast conditions. The most commonly reported adverse events were nausea, vomiting, dizziness, and first-degree atrioventricular block for intravenous posaconazole 300 mg and nausea for oral posaconazole 300 mg (high-fat breakfast). All adverse events were mild and resolved without sequelae. CONCLUSIONS: Posaconazole was generally well tolerated in healthy Chinese male and female subjects. The safety and the high-fat breakfast and fasted pharmacokinetics of posaconazole in healthy Chinese subjects are within exposures demonstrated to be generally well tolerated and efficacious and compare reasonably well with the overall posaconazole data across Western countries.


Assuntos
Antifúngicos/efeitos adversos , Antifúngicos/farmacocinética , Jejum/fisiologia , Interações Alimento-Droga/fisiologia , Triazóis/efeitos adversos , Triazóis/farmacocinética , Administração Intravenosa , Administração Oral , Adulto , Antifúngicos/administração & dosagem , Estudos Cross-Over , Dieta Hiperlipídica , Feminino , Voluntários Saudáveis , Humanos , Masculino , Náusea/induzido quimicamente , Náusea/diagnóstico , Comprimidos , Triazóis/administração & dosagem , Adulto Jovem
19.
Cancer Chemother Pharmacol ; 84(4): 759-770, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31367790

RESUMO

PURPOSE: Seviteronel is an orally-administered selective cytochrome P450c17a 17,20-lyase and androgen receptor inhibitor with anti-tumor activity in vitro and in vivo, and clinical activity in men with advanced castration-resistant prostate cancer (CRPC) and men and women with advanced breast cancer. The purpose of this study was to assess the pharmacokinetics (PK) of seviteronel across the aforementioned populations. METHODS: This report describes the PK of seviteronel (50-750 mg, QD or BID) using noncompartmental and population approaches from 243 patients with advanced breast or prostate cancer pooled across 4 clinical studies. First dose and steady-state PK were examined, as well as covariates including prandial status, sex and concomitant dexamethasone. RESULTS: Seviteronel PK can be characterized by transit absorption and a bi-phasic first-order elimination while accounting for covariance between random effects. Prandial status did not significantly affect any parameters to a clinically-relevant extent. Both sex and body weight were significant covariates on clearance, explaining 37% of the interindividual variability on that parameter. There were no significant effects from the race or the presence of a corticosteroid (either dexamethasone or prednisone). CONCLUSIONS: Seviteronel demonstrates linear PK over the dose range of 50-750 mg given either BID or QD in men with advanced CRPC or men and women with breast cancer. The disposition of seviteronel following oral administration is well described by this population PK model and can be used for accurate simulations for future studies with body weight and sex affecting clearance, but not to a clinically-meaningful degree requiring a change in the current dosing scheme.


Assuntos
Neoplasias da Mama , Dexametasona/farmacocinética , Naftalenos/farmacocinética , Neoplasias de Próstata Resistentes à Castração , Triazóis/farmacocinética , Antagonistas de Receptores de Andrógenos/farmacocinética , Antineoplásicos/farmacocinética , Disponibilidade Biológica , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Ensaios Clínicos Fase II como Assunto , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos/métodos , Quimioterapia Combinada/métodos , Feminino , Humanos , Masculino , Estadiamento de Neoplasias , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores
20.
Eur J Med Chem ; 181: 111576, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31400709

RESUMO

The enzyme nicotinamide phosphoribosyltransferase is both a key intracellular enzyme for NAD biosynthesis (iNAMPT) and an extracellular cytokine (eNAMPT). The relationship between this latter role and the catalytic activity of the enzyme is at present unknown. With the intent of discovering inhibitors specifically able to target eNAMPT, we increased the polarity of MV78 (EC50 = 5.8 nM; IC50 = 3.1 nM), a NAMPT inhibitor previously discovered by us. The replacement of a phenyl ring with a 1,2,3-triazole bearing a protonable N,N-dialkyl methanamine group gave a series of molecules which maintained the inhibition of the enzymatic activity but were unable to cross the plasma membrane and affect cell viability in vitro. Compounds 30b and 30f can therefore be considered as the first experimental/pharmacological tools for scientists that wish to understand the role of the catalytic activity of eNAMPT. Serendipitously, we also discovered a compound (25) which, notwithstanding its high polarity, was able to cross the plasma membrane being cytotoxic, a potent NAMPT inhibitor and effective in reducing growth of triple negative mammary carcinoma in mice. In our hands, 25 lacked retinal and cardiac toxicity, although we observed a lesser toxicity of NAMPT inhibitors in general compared to other reports.


Assuntos
Citocinas/antagonistas & inibidores , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Triazóis/química , Triazóis/farmacologia , Animais , Linhagem Celular Tumoral , Química Click , Citocinas/metabolismo , Inibidores Enzimáticos/farmacocinética , Humanos , Camundongos , Neoplasias/tratamento farmacológico , Nicotinamida Fosforribosiltransferase/metabolismo , Triazóis/farmacocinética
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