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1.
Biomed Chromatogr ; 34(3): e4791, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31899538

RESUMO

The aim of the present study was to develop a liquid chromatography/electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) method for the determination of olaparib in rat plasma. The plasma samples were processed using one-step protein precipitation with acetonitrile and then separated on Waters Acquity BEH C18 column (50 × 2.1 mm, particle size 1.7 µm) using water containing 0.1% formic acid and acetonitrile as mobile phase with optimized gradient elution. Mass spectrometric detection was carried out by selective reaction monitoring mode via positive ESI mode with precursor-to-product transitions of m/z 435.3 > 367.1 and m/z 443.1 > 375.2 for olaparib and 2 H8 -olaparib (internal standard). The method was linear over the concentration range 0.1-2000 ng/ml with correlation coefficient >0.9987. The lower limit of quantitation was 0.1 ng/ml. The method showed excellent accuracy and precision, negligible matrix effect and high extraction recovery. The validated method was subsequently utilized to determine the concentration of olaparib in rat plasma and further applied to the pharmacokinetic study of olaparib in rat plasma. Our results demonstrated that olaparib showed gender-dependent pharmacokinetics in rats. Compared with that in males, olaparib showed high plasma exposure, long half-life, low clearance and high bioavailability in females.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Ftalazinas/sangue , Ftalazinas/farmacocinética , Piperazinas/sangue , Piperazinas/farmacocinética , Espectrometria de Massas por Ionização por Electrospray/métodos , Animais , Feminino , Modelos Lineares , Masculino , Ftalazinas/química , Piperazinas/química , Ratos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Fatores Sexuais , Espectrometria de Massas em Tandem/métodos
2.
Leuk Res ; 88: 106286, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31865062

RESUMO

Diffuse large B-cell lymphoma (DLBCL), the most common type of B-cell non-Hodgkin lymphoma (NHL), is categorized into two major subtypes, activated B-cell-like (ABC) and germinal center B-cell-like (GCB). The ABC subtype is associated with worse prognosis than the GCB subtype using currently available therapies such as combination treatment with rituximab plus standard cytotoxic chemotherapy. The B-cell receptor (BCR) pathway is activated in ABC DLBCL, suggesting that inhibition of this pathway could provide an alternative strategy for treatment. Naquotinib is an irreversible tyrosine kinase inhibitor (TKI) originally designed to target the epidermal growth factor receptor (EGFR). As sequence alignment analysis indicates that irreversible EGFR-TKIs also inhibit Bruton's tyrosine kinase (BTK), here, we characterized the inhibitory effects of naquotinib against BTK in comparison to ibrutinib, acalabrutinib, tirabrutinib and spebrutinib. Naquotinib inhibited BTK kinase activity with similar potency to that for EGFR activating mutations. In vivo, naquotinib induced tumor regression and suppressed tumor recurrence in TMD8 and OCI-Ly10, ABC DLBCL cell line xenograft models, at a lower dose than the clinically relevant dose. Compared to other BTK inhibitors, naquotinib showed faster onset and comparable inhibition of BTK following incubation with cell lines for 3 and 20 h. In addition, naquotinib showed longer continuous inhibition of BTK following removal of the compound, lasting for at least 26 h after removal. Pharmacokinetics studies in the TMD8 xenograft model showed higher concentration and slower elimination of naquotinib in tumors than other BTK inhibitors. These data suggest that naquotinib may have therapeutic potential in ABC DLBCL patients.


Assuntos
Linfócitos B/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/patologia , Piperazinas/uso terapêutico , Piperidinas/uso terapêutico , Pirazinas/uso terapêutico , Pirrolidinas/uso terapêutico , Receptores de Antígenos de Linfócitos B/efeitos dos fármacos , Tirosina Quinase da Agamaglobulinemia/genética , Tirosina Quinase da Agamaglobulinemia/metabolismo , Animais , Linfócitos B/imunologia , Linfócitos B/patologia , Células Cultivadas , Feminino , Humanos , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Piperazinas/farmacocinética , Piperidinas/farmacocinética , Pirazinas/farmacocinética , Pirrolidinas/farmacocinética , Receptores de Antígenos de Linfócitos B/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
3.
AAPS PharmSciTech ; 21(1): 27, 2019 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-31858315

RESUMO

The purpose of this study was to develop and evaluate a new formulation of ziprasidone (ZIP) for improved fasted state absorption and sustained drug release. ZIP solid dispersions were produced via spray drying using Soluplus®, an amphiphilic polymer, as the solubility enhancer. Physicochemical analysis proved that ZIP presented at amorphous state in the spray-dried microparticles and the dissolution rate of ZIP from the Soluplus®-ZIP composite microparticles was significantly increased compared with that of the physical mixtures. Commonly used encapsulation materials including Eudragit® RL, Eudragit® S100 and Ethyl Cellulose were incorporated into the solid dispersions to regulate the drug release kinetics. The formulation containing ethyl cellulose provided the most sustained release behaviors. Pharmacokinetic studies in beagle dogs confirmed that there was no significant difference in oral bioavailability of the microparticles under fasted and fed states, and a prolonged Tmax value was simultaneously achieved compared with the commercial ZIP capsules.


Assuntos
Antipsicóticos/administração & dosagem , Celulose/análogos & derivados , Interações Alimento-Droga , Piperazinas/administração & dosagem , Polietilenoglicóis/química , Polivinil/química , Tiazóis/administração & dosagem , Animais , Antipsicóticos/farmacocinética , Disponibilidade Biológica , Celulose/química , Preparações de Ação Retardada , Cães , Piperazinas/farmacocinética , Solubilidade , Tiazóis/farmacocinética
4.
Expert Opin Pharmacother ; 20(17): 2063-2072, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31644326

RESUMO

Introduction: Cariprazine, a D3-preferring, dopamine D2/D3 partial agonist, has efficacy in treating both acute phases of bipolar I disorder (BD-I). It has been approved by the FDA for treatment of acute manic, mixed and depressive episodes associated with BD-I.Areas covered: In this review, the authors discuss the unique pharmacological properties and clinical efficacy profile of cariprazine, and their relevance in the context of routine clinical decision-making for BD-I. For the purpose of this review, the authors searched for clinical trials in BD published in the PubMed, Web of Science, Embase and PsychInfo databases as well as for studies registered in the ClinicalTrials.gov database.Expert opinion: Based on evidence from RCTs in manic and mixed episodes, cariprazine in a dose-range of 3-12 mg is effective for treating acute mania and mixed states associated with BD-I. Importantly, evidence from placebo-controlled trials in bipolar depression suggests that cariprazine is also effective as a monotherapy in treating acute bipolar depression in doses of 1.5-3 mg/day. It is overall well tolerated; however, clinicians need to monitor patients for akathisia.


Assuntos
Antipsicóticos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Piperazinas/uso terapêutico , Antipsicóticos/efeitos adversos , Antipsicóticos/farmacocinética , Ensaios Clínicos como Assunto , Bases de Dados Factuais , Agonistas de Dopamina/efeitos adversos , Meia-Vida , Humanos , Piperazinas/efeitos adversos , Piperazinas/farmacocinética , Resultado do Tratamento
5.
Drug Des Devel Ther ; 13: 3229-3248, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31571826

RESUMO

Introduction : Cariprazine, a dopamine D3-preferring D3/D2 receptor partial agonist and serotonin 5-HT1A receptor partial agonist, has two major human metabolites, desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR). The metabolite pharmacology was profiled to understand the contribution to cariprazine efficacy. Methods: In vitro receptor binding and functional assays, electrophysiology, animal models, microdialysis, and kinetic-metabolism approaches were used to characterize the pharmacology of DCAR and DDCAR. Results: Similar to cariprazine, both metabolites showed high affinity for human D3, D2L, 5-HT1A, 5-HT2A, and 5-HT2B receptors, albeit with higher selectivity than cariprazine for D3 versus D2 receptors. In [35S]GTPγS binding assays, cariprazine and DDCAR were antagonists in membranes from rat striatum and from cells expressing human D2 and D3 receptors, and were partial agonists in membranes from rat hippocampus. In cAMP signaling assays, cariprazine, DCAR, and DDCAR acted as partial agonists at D2 and D3 receptors; cariprazine and DDCAR were full agonists, whereas DCAR was a partial agonist at 5-HT1A receptors. Cariprazine, DCAR, and DDCAR were pure antagonists at human 5-HT2B receptors. Cariprazine and DDCAR increased rat striatal dopamine and reduced cortical serotonin turnover. Cariprazine and DDCAR showed similar in vivo D3 receptor occupancy in rat brain; however, cariprazine was more potent for D2 receptor occupancy. Both cariprazine and DDCAR dose-dependently but partially suppressed the spontaneous activity of midbrain dopaminergic neurons in rats, with the parent compound being more potent but shorter acting than its metabolite. Consistent with the D2 receptor occupancy profile, DDCAR was 3- to 10-fold less potent than cariprazine in rodent models of antipsychotic-like activity. Following acute cariprazine administration, DDCAR was detected in the rodent brain but at much lower levels than cariprazine. Conclusion: Overall, in vitro and in vivo pharmacological profiles of DCAR and DDCAR demonstrated high similarity with cariprazine, suggesting that the major metabolites of cariprazine contribute significantly to its clinical efficacy.


Assuntos
Piperazinas/farmacologia , Animais , Antipsicóticos/farmacologia , Encéfalo/metabolismo , Células CHO , Cricetulus , AMP Cíclico/metabolismo , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Células HEK293 , Humanos , Masculino , Camundongos , Piperazinas/metabolismo , Piperazinas/farmacocinética , Ratos , Ratos Wistar , Receptor 5-HT1A de Serotonina , Receptor 5-HT2B de Serotonina , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D3/agonistas , Receptores de Dopamina D3/antagonistas & inibidores , Serotonina/metabolismo , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Transdução de Sinais
6.
Eur J Med Chem ; 183: 111707, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31561043

RESUMO

The diverse nature of Alzheimer's disease (AD) has prompted researchers to develop multi-functional agents. Herein, we have designed and synthesized molecular hybrids of 2-pyridylpiperazine and 5-phenyl-1,3,4-oxadiazoles. Biological activities of synthesized compounds suggested significant and balanced inhibitory potential against target enzymes. In particular, compound 49 containing 2,4-difluoro substitution at terminal phenyl ring considered as most potential lead with inhibition of acetylcholinesterase (hAChE, IC50 = 0.054 µM), butyrylcholinesterase (hBChE, IC50 = 0.787 µM) and beta-secretase-1 (hBACE-1, IC50 = 0.098 µM). The enzyme kinetics study of 49 against hAChE suggested a mixed type of inhibition (Ki = 0.030 µM). Also, 48 and 49 showed significant displacement of propidium iodide from the peripheral anionic site (PAS) of hAChE, excellent blood-brain barrier (BBB) permeability in parallel artificial membrane permeation assay (PAMPA), and neuroprotective ability against SH-SY5Y neuroblastoma cell lines. Further, 49 also exhibited anti-Aß aggregation activity in self- and AChE-induced thioflavin T assay, which was ascertained by morphological characterization by atomic force microscopy (AFM). Moreover, in vivo behavioral studies signified learning and memory improvement by compound 49 in scopolamine- and Aß-induced cognitive dysfunctions performed on Y-maze and Morris water maze. The ex vivo studies suggested decreased AChE activity and antioxidant potential of compound 49, with good oral absorption characteristics ascertained by pharmacokinetic studies.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Fármacos Neuroprotetores/química , Oxidiazóis/química , Piperazinas/química , Piridinas/química , Acetilcolinesterase/metabolismo , Doença de Alzheimer/psicologia , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Barreira Hematoencefálica/metabolismo , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacocinética , Disfunção Cognitiva/tratamento farmacológico , Feminino , Humanos , Cinética , Simulação de Acoplamento Molecular , Fármacos Neuroprotetores/farmacocinética , Oxidiazóis/farmacocinética , Piperazinas/farmacocinética , Agregados Proteicos , Piridinas/farmacocinética , Ratos Wistar , Relação Estrutura-Atividade
7.
AAPS PharmSciTech ; 20(7): 276, 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31388783

RESUMO

Olaparib (OLA) is a poly ADP ribose polymerase (PARP) inhibitor approved for germline BRCA-mutated (gBRCAm) advanced ovarian cancer and breast cancer. Low oral bioavailability of this drug requires increase in the dose and frequency causing haematological toxicity in the patients. The purpose of this study is to prepare different nano-formulations of OLA lipospheres (LP) by melt dispersion and nano-suspensions (NSP) by solvent evaporation (SE) and wet milling (WM) techniques and compare oral bioavailability of these formulations. Size of the nano-formulations OLA-LP, OLA-NSPSE and OLA-NSPWM were found to be 126.71 ± 4.54, 128.6 ± 2.34 and 531.1 ± 5.34 nm with polydispersity index below 0.3. In vitro release studies were performed by dialysis bag method where the sustained drug release was observed from nano-formulations until 9 h with Higuchi for OLA suspended in 2.5% w/v sodium carboxy methyl cellulose (OLA-SP), OLA-LP and OLA-NSPWM and Peppas for OLA-NSPSE-based drug release kinetics. In vivo pharmacokinetic studies, haematological toxicity and distribution studies were performed on rats. Results showed that there was an improvement in Cmax, AUCtotal, t1/2 and MRT by OLA nano-formulations when compared with OLA-SP. OLA-SP has shown reduction in WBC, platelets and lymphocytes at 12 and 36 h time points; however, no reduction in cell count was observed with OLA nano-formulations. Distribution studies proved FITC nano-formulations were most rapidly absorbed and distributed when compared with FITC-loaded suspension. From the above results, it was concluded that OLA nano-formulations can be an alternative to enhance the oral bioavailability and to reduce the haematological toxicity of OLA.


Assuntos
Ftalazinas/uso terapêutico , Piperazinas/uso terapêutico , Administração Oral , Animais , Disponibilidade Biológica , Neoplasias da Mama , Composição de Medicamentos , Liberação Controlada de Fármacos , Humanos , Ftalazinas/administração & dosagem , Ftalazinas/farmacocinética , Piperazinas/administração & dosagem , Piperazinas/farmacocinética , Ratos
8.
J Pharmacol Exp Ther ; 371(1): 202-207, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31371481

RESUMO

Fenebrutinib (GDC-0853) is an orally administered small molecule inhibitor of Bruton's tyrosine kinase being investigated for treatment of rheumatoid arthritis in patients with inadequate responses to methotrexate (MTX). This study interrogated the potential for pharmacokinetic drug interactions between fenebrutinib and MTX. Eighteen healthy male subjects were enrolled in the study. They received a single oral dose of MTX (7.5 mg) on day 1 followed by a 13-day washout period. Subsequently, on days 15-20 the participants received 200 mg of fenebrutinib twice daily. On day 21, they received a 7.5 mg dose of MTX and a 200 mg dose of fenebrutinib under fasting conditions. The geometric mean ratios of MTX area under the plasma concentration-time curve (AUC) and C max on day 21 relative to day 1 (90% confidence interval [CI]) were 0.96 (0.88-1.04) and 1.05 (0.94-1.18), respectively. The geometric mean ratios of fenebrutinib AUC and C max for day 21 relative to day 20 (90% CI) were 1.03 (0.95-1.11) and 1.02 (0.90-1.15), respectively. The combination treatment was well tolerated, with an adverse event profile similar to that reported in other MTX trials. These results indicate that there is no clinically significant pharmacokinetic interaction between fenebrutinib and MTX.


Assuntos
Antirreumáticos/farmacocinética , Metotrexato/farmacocinética , Piperazinas/farmacocinética , Inibidores de Proteínas Quinases/farmacocinética , Piridonas/farmacocinética , Adulto , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Antirreumáticos/administração & dosagem , Antirreumáticos/efeitos adversos , Interações Medicamentosas , Humanos , Masculino , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Piridonas/administração & dosagem , Piridonas/efeitos adversos
9.
Curr Top Med Chem ; 19(19): 1679-1693, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31258088

RESUMO

The medicinal chemist plays the most important role in drug design, discovery and development. The primary goal is to discover leads and optimize them to develop clinically useful drug candidates. This process requires the medicinal chemist to deal with large sets of data containing chemical descriptors, pharmacological data, pharmacokinetics parameters, and in silico predictions. The modern medicinal chemist has a large number of tools and technologies to aid him in creating strategies and supporting decision-making. Alongside with these tools, human cognition, experience and creativity are fundamental to drug research and are important for the chemical intuition of medicinal chemists. Therefore, fine-tuning of data processing and in-house experience are essential to reach clinical trials. In this article, we will provide an expert opinion on how chemical intuition contributes to the discovery of drugs, discuss where it is involved in the modern drug discovery process, and demonstrate how multidisciplinary teams can create the optimal environment for drug design, discovery, and development.


Assuntos
Descoberta de Drogas , Piperazinas/química , Química Farmacêutica , Estrutura Molecular , Piperazinas/síntese química , Piperazinas/farmacocinética
10.
Artigo em Inglês | MEDLINE | ID: mdl-31200246

RESUMO

Reversed-phase thin-layer chromatography and micellar thin-layer chromatography were used in order to investigate retention behaviour and to determine lipophilicity of series of 2-(methoxy)phenylpiperazine dopamine D2 ligands with different size, shape and rigidity. The retention mechanism was discussed. The lipophilicity parameters obtained in conventional reversed-phase systems expressed as RM0 and C0, as well as RM values determined in microemulsion reversed-phase systems were correlated with in silico determined lipophilicity values. In silico pharmacokinetic properties of 2-(methoxy)phenylpiperazine dopamine D2 ligands revealed the importance of experimentally determined lipophilicity values besides the molecular weight, on the blood-brain barrier permeability process. Also, the experimentally determined lipophilicity was found as a very important factor in plasma protein binding process of 2-(methoxy)phenylpiperazine dopamine D2 ligands. Besides, the Lipinski's rule of five indicates that examined ligands satisfy the criterion of drug-like molecules. The principal component analysis was performed on the experimentally determined and calculated lipophilicity values as well on the molecular descriptors which describe the pharmacokinetic properties in order to provide basic insights into similarities among the studied ligands.


Assuntos
Cromatografia em Camada Delgada/métodos , Dopamina/química , Piperazinas/química , Receptores de Dopamina D2/agonistas , Simulação por Computador , Dopamina/farmacocinética , Humanos , Ligantes , Piperazinas/farmacocinética , Análise de Componente Principal
11.
Nutr Metab Cardiovasc Dis ; 29(7): 751-760, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31133498

RESUMO

BACKGROUND AND AIMS: Metabolic syndrome associated with insulin resistance and hypertension is often caused by excessive fructose consumption. Treatment of hypertension in patients with metabolic syndrome is a difficult task as many antihypertensive drugs have adverse effects on the metabolic profile. We investigated if MH-76 and MH-79, non-quinazoline α1-adrenoceptor antagonists with an additional ability to stimulate NO/cGMP/K+ pathway, ameliorates metabolic syndrome in fructose-fed rats. As reference compound prazosin was used. METHODS AND RESULTS: Male rats were divided into 5 groups (n = 8) and studied for 18 weeks: group control: standard diet and drinking water; group Fructose: high-fructose diet (20% fructose in drinking water); groups Fructose + MH-76, Fructose + MH-79, Fructose + prazosin: high-fructose diet with subsequent MH-76, MH-79 (5 mg/kg/day ip) or prazosin (0.2 mg/kg/day ip) treatment 12 weeks later. In addition to their antihypertensive effect, the studied compounds reversed endothelial dysfunction, decreased hyperglycemia and hypertriglyceridemia, as well as prevented abdominal adiposity. Moreover, MH-76 reduced insulin resistance and decreased TNF-α concentration and lipid peroxidation in adipose tissue. Prazosin treatment exerted an antihypertensive effect, reduced hyperglycemia but did not improve endothelial dysfunction, insulin resistance, and abdominal adiposity. The lower efficacy of prazosin may be the result of its short half-time and the lack of described pleiotropic effects. CONCLUSIONS: α1-adrenoceptor blockade, endothelial protection, TNF-α suppressing and antioxidant activity together with favorable pharmacokinetic parameters determines high efficacy of MH-76, leading to the effective improvement of hemodynamic and metabolic disturbances in metabolic syndrome. The use of non-quinazoline, multiple-targeted α1-blockers may be an interesting option for treatment of hypertension with metabolic complications.


Assuntos
Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Frutose , Hipertensão/tratamento farmacológico , Síndrome Metabólica/tratamento farmacológico , Piperazinas/farmacologia , Prazosina/farmacologia , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Antagonistas de Receptores Adrenérgicos alfa 1/farmacocinética , Animais , Anti-Hipertensivos/farmacocinética , Biomarcadores/sangue , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Modelos Animais de Doenças , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Hipertensão/etiologia , Hipertensão/fisiopatologia , Peroxidação de Lipídeos/efeitos dos fármacos , Lipídeos/sangue , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/etiologia , Piperazinas/farmacocinética , Ratos Wistar , Fator de Necrose Tumoral alfa/sangue
12.
Basic Clin Pharmacol Toxicol ; 125(4): 370-381, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31125491

RESUMO

The main objective of this phase I trial was to investigate pharmacokinetics (PKs) of olmutinib in three racial subjects. We also evaluate safety/tolerability and a population PK and pharmacogenomic analysis were performed for explorative purposes. A dose escalation study was conducted in 56 Korean, Japanese and Caucasian subjects. The food effect was assessed in the 300 mg Korean group. Individual PK parameters were calculated by non-compartmental methods and presented by dose and race. Genotype analysis was performed using DMET® plus to identify genotypes which affect PK characteristics. A population PK model was developed to explore inter-individual variability and to evaluate the influence of possible covariates using NONMEM® . Tmax was 2-3 hour, regardless of race. The mean terminal half-life ranged from 4.8 to 7.4 hour, with no significant differences between dose or racial groups. Dose-normalized Cmax and AUClast were not significantly different between race groups. PK parameters were similar between the fasting and fed conditions. A single-nucleotide polymorphism in the GSTM3 gene (rs4783) and a copy number variation in the GSTM1 gene were significantly related to AUC. A one-compartment model with first-order absorption adequately described the observed olmutinib data. Thirty adverse events were observed in 15 subjects, of which 26 events, all mild, were possibly related to olmutinib. A single oral dose of olmutinib 100-300 mg was safe and well tolerated. PK parameters were dose-proportional and did not differ by race. Food intake did not affect olmutinib absorption. Pharmacogenomic analysis indicated that glutathione S-transferase might be involved in olmutinib metabolism.


Assuntos
Glutationa Transferase/genética , Piperazinas/farmacocinética , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/farmacocinética , Administração Oral , Adulto , Área Sob a Curva , Grupo com Ancestrais do Continente Asiático , Variações do Número de Cópias de DNA , Relação Dose-Resposta a Droga , Receptores ErbB , Grupo com Ancestrais do Continente Europeu , Interações Alimento-Droga , Glutationa Transferase/metabolismo , Meia-Vida , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Polimorfismo de Nucleotídeo Único , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Adulto Jovem
13.
Clin Ther ; 41(6): 1214-1220, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31076203

RESUMO

PURPOSE: Nemiralisib, a phosphoinositide 3-kinase δ inhibitor, is being investigated as an immunomodulatory agent with anti-inflammatory properties in chronic obstructive pulmonary disease. This study evaluated the pharmacokinetic (PK) properties and safety of a new formulation of nemiralisib that contains 0.4% magnesium stearate. METHODS: In this randomized, double-blind, parallel-group study, healthy individuals received a single dose of 500 or 750 µg of nemiralisib administered via the Ellipta dry powder inhaler (DPI) (n = 6 in each treatment group). Aerodynamic particle size distribution (APSD) data comparing previous and new formulations were available before the study. Serial PK analyses for plasma exposure and safety assessments were performed during the first 24 h after dosing, with follow-up measurements on days 3 and 6 in clinic. FINDINGS: APSD had increases of approximately 6-fold and 2-fold in very fine particle mass and fine particle mass over the previous (Diskus) formulation. In humans, systemic exposure (AUC) was greater after inhalation of 750 versus 500 µg of nemiralisib (AUC0-t: 17,200 h∙pg/mL; 95% CI, 10,900-27,200 h∙pg/mL and 13,100; 95% CI, 8130-21,000 h∙pg/mL, respectively). A low frequency of individual adverse events and no serious adverse events were reported after both doses. IMPLICATIONS: After single-dose inhalation of 500 and 750 µg of nemiralisib from the Ellipta DPI in healthy individuals, plasma PK data were well defined, and as predicted based on previous PK and APSD data, exposure was increased with the new formulation. Nemiralisib was well tolerated with no new safety issues identified. These data supported progression of nemiralisib to a Phase IIb study in patients with chronic obstructive pulmonary disease. ClinicalTrials.gov identifier: NCT03189589.


Assuntos
Inaladores de Pó Seco , Indazóis , Indóis , Oxazóis , Piperazinas , Administração por Inalação , Método Duplo-Cego , Humanos , Indazóis/administração & dosagem , Indazóis/efeitos adversos , Indazóis/sangue , Indazóis/farmacocinética , Indóis/administração & dosagem , Indóis/efeitos adversos , Indóis/sangue , Indóis/farmacocinética , Oxazóis/administração & dosagem , Oxazóis/efeitos adversos , Oxazóis/sangue , Oxazóis/farmacocinética , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Piperazinas/sangue , Piperazinas/farmacocinética
14.
J Labelled Comp Radiopharm ; 62(8): 425-437, 2019 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-30991462

RESUMO

We report the design, synthesis, and evaluation of a new series of benzylpiperazine derivatives as selective σ1 receptor ligands. All seven ligands possessed low nanomolar affinity for σ1 receptors (Ki (σ1 ) = 0.31-4.19 nM) and high subtype selectivity (Ki (σ2 )/Ki (σ1 ) = 50-2448). The fluoroethoxy analogues also exhibited high selectivity toward the vesicular acetylcholine transporter (Ki (VAChT)/Ki (σ1 ) = 99-18252). The corresponding radiotracers [18 F]13, [18 F]14, and [18 F]16 with high selectivity (Ki (σ2 )/Ki (σ1 ) > 100, Ki (VAChT)/Ki (σ1 ) > 1000) were prepared in 42% to 55% radiochemical yields (corrected for decay), greater than 99% radiochemical purity (RCP), and molar activity of about 120 GBq/µmol at the end of synthesis (EOS). All three radiotracers showed high initial brain uptake in mouse (8.37-11.48% ID/g at 2 min), which was not affected by pretreatment with cyclosporine A, suggesting that they are not substrates for permeability-glycoprotein (P-gp). Pretreatment with SA4503 or haloperidol resulted in significantly reduced brain uptake (35%-62% decrease at 30 min). In particular, [18 F]16 displayed high brain-to-blood ratios and high in vivo metabolic stability. Although it may not be an optimal neuroimaging agent because of its slow kinetics in the mouse brain, [18 F]16 can serve as a lead compound for further structural modifications to explore new potential radiotracers for σ1 receptors.


Assuntos
Radioisótopos de Flúor/química , Piperazinas/química , Piperazinas/metabolismo , Tomografia por Emissão de Pósitrons , Receptores sigma/metabolismo , Animais , Transporte Biológico , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Estabilidade de Medicamentos , Marcação por Isótopo , Ligantes , Masculino , Camundongos , Camundongos Endogâmicos ICR , Piperazinas/farmacocinética , Radioquímica , Especificidade por Substrato , Distribuição Tecidual
15.
ChemMedChem ; 14(13): 1238-1247, 2019 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-30957954

RESUMO

Histamine H3 receptor (H3R) inverse agonists that have been in clinical trials for the treatment of excessive sleep disorders, have been plagued with insomnia as a mechanism-based side effect. We focused on the identification of compounds that achieve high receptor occupancy within a short time, followed by rapid disengagement from the receptor, a target profile that could provide therapeutic benefits without the undesired side effect of insomnia. This article describes the optimization work that led to the discovery of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate (18 b, LML134).


Assuntos
Agonistas dos Receptores Histamínicos/uso terapêutico , Piperazina/química , Piperazinas/química , Receptores Histamínicos H3/metabolismo , Transtornos do Sono-Vigília/tratamento farmacológico , Animais , Avaliação Pré-Clínica de Medicamentos , Agonismo Inverso de Drogas , Meia-Vida , Agonistas dos Receptores Histamínicos/química , Agonistas dos Receptores Histamínicos/farmacocinética , Humanos , Masculino , Microssomos Hepáticos/metabolismo , Piperazina/farmacocinética , Piperazina/uso terapêutico , Piperazinas/farmacocinética , Piperazinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Receptores Histamínicos H3/química , Relação Estrutura-Atividade
16.
Eur J Pharm Sci ; 139: 104899, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30953752

RESUMO

CCT241736 is a dual fms-like tyrosine kinase 3 (FLT3)/Aurora kinase inhibitor in development for the treatment of acute myeloid leukaemia. The successful development of any new drug relies on adequate safety testing including preclinical toxicology studies. Selection of an appropriate preclinical species requires a thorough understanding of the compound's metabolic clearance and pathways, as well as other pharmacokinetic and pharmacodynamic considerations. In addition, elucidation of the metabolising enzymes in human facilitates improved clinical prediction based on population pharmacokinetics and can inform drug-drug interaction studies. Intrinsic clearance (CLint) determination and metabolite profiling of CCT241736 in human and four preclinical species (dog, minipig, rat and mouse) was undertaken in cryopreserved hepatocytes and liver microsomes. Recombinant human cytochrome P450 bactosomes (rCYP) were utilised to provide reaction phenotyping data and support prediction of metabolic pathways. CCT241736 exhibited low CLint in both hepatocytes and liver microsomes of human, dog, minipig and rat, but considerably higher CLint in mouse. CYP3A4 and CYP3A5 were identified as the major enzymes responsible for biotransformation of CCT241736 in human, exclusively forming five out of seven metabolites. Minipig showed greatest similarity to human with regard to both overall metabolic profile and abundance of specific metabolites relative to parent compound, and is therefore proposed as the most appropriate toxicological species. The greatest disparity was observed between human and dog. Based on metabolic profile, either mouse or rat is a suitable rodent species for toxicology studies.


Assuntos
Aurora Quinases/antagonistas & inibidores , Piperazinas/farmacocinética , Inibidores de Proteínas Quinases/farmacocinética , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Animais , Sistema Enzimático do Citocromo P-450/metabolismo , Cães , Avaliação Pré-Clínica de Medicamentos , Feminino , Hepatócitos/metabolismo , Humanos , Masculino , Camundongos Endogâmicos ICR , Microssomos Hepáticos/metabolismo , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Ratos Sprague-Dawley , Especificidade da Espécie , Suínos , Porco Miniatura , Testes de Toxicidade
17.
Biomed Chromatogr ; 33(7): e4525, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30822365

RESUMO

A rapid, sensitive and selective liquid chromatography-tandem mass spectrometry method for the detection of tandospirone (TDS) and its active metabolite 1-[2-pyrimidyl]-piperazine (1-PP) in Sprague-Dawley rat plasma is described. It was employed in a pharmacokinetic study. These analytes and the internal standards were extracted from plasma using protein precipitation with acetonitrile, then separated on a CAPCELL PAK ADME C18 column using a mobile phase of acetonitrile and 5 mm ammonium formate acidified with formic acid (0.1%, v/v) at a total flow rate of 0.4 mL/min. The detection was performed with a tandem mass spectrometer equipped with an electrospray ionization source. The method was validated to quantify the concentration ranges of 1.000-500.0 ng/mL for TDS and 10.00-500.0 ng/mL for 1-PP. Total time for each chromatograph was 3.0 min. The intra-day precision was between 1.42 and 6.69% and the accuracy ranged from 95.74 to 110.18% for all analytes. Inter-day precision and accuracy ranged from 2.47 to 6.02% and from 98.37 to 105.62%, respectively. The lower limits of quantification were 1.000 ng/mL for TDS and 10.00 ng/mL for 1-PP. This method provided a fast, sensitive and selective analytical tool for quantification of tandospirone and its metabolite 1-PP in plasma necessary for the pharmacokinetic investigation.


Assuntos
Buspirona/análogos & derivados , Cromatografia Líquida de Alta Pressão/métodos , Isoindóis/sangue , Piperazinas/sangue , Pirimidinas/sangue , Espectrometria de Massas em Tandem/métodos , Animais , Buspirona/sangue , Buspirona/química , Buspirona/farmacocinética , Estabilidade de Medicamentos , Feminino , Isoindóis/química , Isoindóis/farmacocinética , Limite de Detecção , Modelos Lineares , Masculino , Piperazinas/química , Piperazinas/farmacocinética , Pirimidinas/química , Pirimidinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes
18.
Science ; 363(6431)2019 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-30846569

RESUMO

Recent characterization of broadly neutralizing antibodies (bnAbs) against influenza virus identified the conserved hemagglutinin (HA) stem as a target for development of universal vaccines and therapeutics. Although several stem bnAbs are being evaluated in clinical trials, antibodies are generally unsuited for oral delivery. Guided by structural knowledge of the interactions and mechanism of anti-stem bnAb CR6261, we selected and optimized small molecules that mimic the bnAb functionality. Our lead compound neutralizes influenza A group 1 viruses by inhibiting HA-mediated fusion in vitro, protects mice against lethal and sublethal influenza challenge after oral administration, and effectively neutralizes virus infection in reconstituted three-dimensional cell culture of fully differentiated human bronchial epithelial cells. Cocrystal structures with H1 and H5 HAs reveal that the lead compound recapitulates the bnAb hotspot interactions.


Assuntos
Anticorpos Neutralizantes/química , Materiais Biomiméticos/farmacologia , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Influenza Humana/prevenção & controle , Piperazinas/farmacologia , Inibidores de Proteínas Virais de Fusão/farmacologia , Internalização do Vírus/efeitos dos fármacos , Administração Oral , Animais , Materiais Biomiméticos/administração & dosagem , Materiais Biomiméticos/farmacocinética , Brônquios/virologia , Células Cultivadas , Cães , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Glicoproteínas de Hemaglutininação de Vírus da Influenza/metabolismo , Humanos , Células Madin Darby de Rim Canino , Camundongos , Piperazinas/administração & dosagem , Piperazinas/farmacocinética , Mucosa Respiratória/virologia , Inibidores de Proteínas Virais de Fusão/administração & dosagem , Inibidores de Proteínas Virais de Fusão/farmacocinética
19.
Molecules ; 24(5)2019 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-30862103

RESUMO

Olaparib, an orally active inhibitor of poly(ADP-ribose)polymerase(PARP), is the drug of choice in the treatment of gBRCA1/2+ metastatic breast cancers. Unfortunately, Olaparib is poorly soluble with low bioavailability and tumor accumulation; nano-delivery could be a good choice to overcome these disadvantages. Here, a rapid and robust HPLC-ESI⁻MS/MS method for the quantification of Olaparib in ferritin nano-carriers led to the development of cells compartments, different tissues, plasma and urines and were validated to assess the effects of nano-delivery on cell compartment distribution of the drug. This method allows the quantification of Olaparib within the linear range of 0.1⁻10ng/mL in cells culture medium and cell cytoplasm, of 0.5⁻10ng/mL in nuclei, of 0.5⁻100ng/mL in plasma and urine and of 10⁻500ng/mL in tissue samples (kidney and liver). The limit of quantification was found to be 1.54 ng/mL for liver, 2.87 ng/mL for kidney, and lower than 0.48 ng/mL for all matrices. The method has been applied to quantify Ola encapsulated in ferritin-nano-carriers during the nano-drug development. The application of the method to human BRCA-mutated cell model to quantify the Olaparib distribution after incubation of free or ferritin-encapsulated Olaparib is also reported. This sensitive method allows the quantification of low concentrations of Olaparib released from nano-carriers in different cell compartments, leading to the determination of the drug release and kinetic profile of an essential parameter to validate nano-carriers.


Assuntos
Cromatografia Líquida , Sistemas de Liberação de Medicamentos , Nanotecnologia , Ftalazinas/administração & dosagem , Ftalazinas/farmacocinética , Piperazinas/administração & dosagem , Piperazinas/farmacocinética , Espectrometria de Massas em Tandem , Linhagem Celular , Estabilidade de Medicamentos , Humanos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Fluxo de Trabalho
20.
J Pharmacol Exp Ther ; 369(3): 337-344, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30886125

RESUMO

Nemiralisib (GSK2269557), a potent inhaled inhibitor of phosphoinositide 3-kinase δ (PI3Kδ), is being developed for the treatment of respiratory disorders including chronic obstructive pulmonary disease. Determining the pharmacokinetic (PK) and pharmacodynamic (PD) responses of inhaled drugs early during drug development is key to informing the appropriate dose and preferred dose regimen in patients. We set out to measure PD changes in induced sputum in combination with drug concentrations in plasma and bronchoalveolar lavage (BAL) taken from healthy smokers (n = 56) treated for up to 14 days with increasing doses of inhaled nemiralisib (0.1-6.4 mg). Induced sputum analysis demonstrated a dose-dependent reduction in phosphatidylinositol-(4,5)-trisphosphate (PIP3, the product of PI3K activation), with a maximum placebo-corrected reduction of 23% (90% confidence interval [CI], 11%-34%) and 36% (90% CI, 11%-64%) after a single dose or after 14 days of treatment with nemiralisib, respectively (2 mg, once daily). Plasma analysis suggested a linear PK relationship with an observed accumulation of ∼3- to 4.5-fold (peak vs. trough) in plasma exposure after 14 days of nemiralisib treatment. The BAL analysis at trough confirmed higher levels of the drug in the lungs versus plasma (32-fold in the BAL fluid component, and 214-fold in the BAL cellular fraction). A comparison of the drug levels in plasma and the reductions in sputum PIP3 showed a direct relationship between exposure and PIP3 reduction. These results demonstrated target engagement upon treatment with inhaled nemiralisib and provide confidence for a once-daily dosing regimen.


Assuntos
Voluntários Saudáveis , Indazóis/farmacologia , Indazóis/farmacocinética , Indóis/farmacologia , Indóis/farmacocinética , Oxazóis/farmacologia , Oxazóis/farmacocinética , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/farmacocinética , Piperazinas/farmacologia , Piperazinas/farmacocinética , Fumantes , Adulto , Líquido da Lavagem Broncoalveolar/química , Relação Dose-Resposta a Droga , Feminino , Humanos , Indazóis/sangue , Indóis/sangue , Masculino , Pessoa de Meia-Idade , Oxazóis/sangue , Fosfatidilinositóis/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/sangue , Piperazinas/sangue , Escarro/efeitos dos fármacos , Escarro/metabolismo
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