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1.
Ann Vasc Surg ; 96: 186-194, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37068625

RESUMO

BACKGROUND: The endovascular approach to treating ruptured or symptomatic abdominal aortic aneurysms (AAAs) with difficult neck anatomy still poses a major challenge. This study proposes and evaluates the outcomes of a novel technique, Transrenal Endovascular Aneurysm Repair (Tr-EVAR) which utilizes the top ring 'valley' and 'peak' configuration of the Anaconda stent graft to achieve proximal seal in AAAs with an unfavourable neck. METHODS: All patients treated with Tr-EVAR over a period of 10 years were identified retrospectively. Demographic, clinical and outcome data were collected, and survival analysis was performed. The time-to-event was analyzed using Kaplan-Meier curves for complication-free survival, reintervention-free survival, and overall survival. RESULTS: During the study period, 36 patients ruptured, symptomatic or large AAAs having unfavorable necks and not fit for open repair underwent Tr-EVAR. Two patients died in the first 30 days postprocedure (5.6%). The overall survival at 1 year, 3 years and 5 years were 86%, 72% and 54% respectively with a mean overall survival of 74.0 months (SE 7.8, 95% confidence interval 58.7-89.3) which was comparable to chimney endovascular aneurysm repair (EVAR). The complication-free survival and reintervention-free survival at 1 year, 3 years, and 5 years were 75%, 61%, 42%, 78%, 64%, and 45%, respectively. CONCLUSIONS: Tr-EVAR can be considered as an off-the-shelf solution for urgent cases not fit for open repair with unfavourable neck features for standard EVAR. Careful patient selection and planning have generated acceptable immediate, midterm and long-term results comparable to those presented by chimney EVAR in the literature.


Assuntos
Aneurisma da Aorta Abdominal , Implante de Prótese Vascular , Procedimentos Endovasculares , Humanos , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/cirurgia , Correção Endovascular de Aneurisma , Estudos Retrospectivos , Implante de Prótese Vascular/efeitos adversos , Procedimentos Endovasculares/efeitos adversos , Resultado do Tratamento
2.
Bioorg Med Chem ; 27(1): 230-239, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30538065

RESUMO

The voltage gated sodium channel NaV1.8 has been postulated to play a key role in the transmission of pain signals. Core hopping from our previously reported phenylimidazole leads has allowed the identification of a novel series of benzimidazole NaV1.8 blockers. Subsequent optimization allowed the identification of compound 9, PF-06305591, as a potent, highly selective blocker with an excellent preclinical in vitro ADME and safety profile.


Assuntos
Benzimidazóis/farmacologia , Canal de Sódio Disparado por Voltagem NAV1.8/metabolismo , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Benzimidazóis/síntese química , Benzimidazóis/química , Benzimidazóis/farmacocinética , Desenho de Fármacos , Células HEK293 , Humanos , Estrutura Molecular , Solubilidade , Relação Estrutura-Atividade , Bloqueadores do Canal de Sódio Disparado por Voltagem/síntese química , Bloqueadores do Canal de Sódio Disparado por Voltagem/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacocinética
4.
Ann Vasc Surg ; 46: 257-264, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28619356

RESUMO

BACKGROUND: Early and 1-year outcomes are presented for fenestrated endovascular aneurysm repair (FEVAR) of complex aortic aneurysmal disease with the custom-made Anaconda fenestrated stent graft in 101 patients. METHODS: Retrospective site-reported data from the first 101 elective cases (2010-2014) from 4 UK centers were studied to evaluate patient demographics, aneurysm morphology, clinical success, and 1-year outcomes in patients undergoing fenestrated aneurysm repair with the custom-made Anaconda device. RESULTS: 101 fenestrated grafts (median age 76, 85% male) were implanted with a total of 255 fenestrations (196 renal arteries, 48 superior mesenteric artery, and 11 celiac arteries) with 3% mortality, 98.4% target vessel patency (TVP) at 30 day follow-up. Although 15 type I or III endoleaks were demonstrated at completion angiography, all 10 type Ia endoleaks resolved spontaneously. Survival by Kaplan-Meier analysis was 97% and 91% at 1 month and 1 year, respectively; with 75.8% showing reduction in abdominal aortic aneurysm diameter and only 1 patient with sac expansion. Freedom from loss of TVP was 97.6%. CONCLUSIONS: Custom-made fenestrated Anaconda devices demonstrate low procedural mortality and a high rate of technical and clinical success at 30 days and 1 year.


Assuntos
Aneurisma da Aorta Abdominal/cirurgia , Implante de Prótese Vascular/instrumentação , Prótese Vascular , Procedimentos Endovasculares/instrumentação , Stents , Idoso , Idoso de 80 Anos ou mais , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/mortalidade , Aneurisma da Aorta Abdominal/fisiopatologia , Aortografia/métodos , Implante de Prótese Vascular/efeitos adversos , Implante de Prótese Vascular/mortalidade , Angiografia por Tomografia Computadorizada , Intervalo Livre de Doença , Endoleak/etiologia , Procedimentos Endovasculares/efeitos adversos , Procedimentos Endovasculares/mortalidade , Inglaterra , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada Multidetectores , Desenho de Prótese , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Grau de Desobstrução Vascular
5.
Drug Discov Today Technol ; 12: e79-85, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25027378

RESUMO

Some drug discovery approaches can benefit from restricting the access of compounds to the central nervous system (CNS) to minimise the risk of side-effects. Designing compounds that act as substrates for efflux transporters in the blood­brain barrier can achieve CNS restriction without significantly impairing absorption in the intestine. In vitro assays can be deployed to optimise a balance between passive permeability and active efflux via the ABC family transporters P-glycoprotein (P-gp, ABCB1) and Breast Cancer Resistance Protein (BCRP, ABCG2) whilst in vivo estimates of distribution of unbound concentrations of drug are needed to understand pharmacologically relevant exposure in peripheral and central compartments. This strategy can deliver significant CNS restriction whilst retaining good oral bioavailability, cell penetration and pharmacological activity. The possible risks of targeting P-gp and BCRP in orally delivered drugs are discussed.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Barreira Hematoencefálica/metabolismo , Descoberta de Drogas/métodos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Preparações Farmacêuticas , Transportadores de Cassetes de Ligação de ATP/genética , Administração Oral , Animais , Transporte Biológico , Permeabilidade Capilar , Endotélio Vascular/metabolismo , Humanos , Mucosa Intestinal/metabolismo , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/sangue , Preparações Farmacêuticas/química , Relação Estrutura-Atividade , Especificidade por Substrato
6.
Xenobiotica ; 42(1): 94-106, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22035569

RESUMO

Early prediction of human pharmacokinetics (PK) and drug-drug interactions (DDI) in drug discovery and development allows for more informed decision making. Physiologically based pharmacokinetic (PBPK) modelling can be used to answer a number of questions throughout the process of drug discovery and development and is thus becoming a very popular tool. PBPK models provide the opportunity to integrate key input parameters from different sources to not only estimate PK parameters and plasma concentration-time profiles, but also to gain mechanistic insight into compound properties. Using examples from the literature and our own company, we have shown how PBPK techniques can be utilized through the stages of drug discovery and development to increase efficiency, reduce the need for animal studies, replace clinical trials and to increase PK understanding. Given the mechanistic nature of these models, the future use of PBPK modelling in drug discovery and development is promising, however, some limitations need to be addressed to realize its application and utility more broadly.


Assuntos
Descoberta de Drogas/métodos , Modelos Biológicos , Preparações Farmacêuticas/metabolismo , Interações Medicamentosas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Cetoconazol/administração & dosagem , Cetoconazol/farmacocinética , Cetoconazol/farmacologia , Preparações Farmacêuticas/sangue , Farmacocinética , Pirazóis/administração & dosagem , Pirazóis/farmacocinética , Pirazóis/farmacologia , Sulfonas/administração & dosagem , Sulfonas/farmacocinética , Sulfonas/farmacologia
7.
JOP ; 13(6): 660-6, 2012 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-23183395

RESUMO

CONTEXT: Pseudoaneurysms associated with pancreatitis are rare, and bleeding pseudoaneurysms are associated with a high mortality. OBJECTIVE: The aim of this study was to report the outcomes of endovascular and percutaneous therapy in the management of pseudoaneurysms secondary to pancreatitis. PATIENTS: Patients who underwent angiography for pseudoaneurysms associated with pancreatitis from 2005 to 2011 were identified from the angiography database. MAIN OUTCOME MEASURES: Patient demographics, clinical presentation, radiological findings, treatment, and outcomes were retrospectively reviewed. RESULTS: Nineteen pseudoaneurysms associated with pancreatitis in 13 patients were identified. The diagnosis of a pseudoaneurysm was made by computerised tomography angiography in seven patients, followed by portal venous phase contrast enhanced CT (n=4), duplex ultrasound (n=1) and angiography (n=1). At angiography, coil embolisation was attempted in 11 patients with an initial success rate of 82% (n=9). One patient underwent successful embolisation with percutaneous thrombin injection. The recurrence rate following initial successful embolisation was 11% (n=1). There were no episodes of re-bleeding following embolisation but re-bleeding following thrombin injection was observed in one case. The morbidity and mortality rate in the 12 patients that were successfully treated was 25% (n=3) and 8% (n=1), respectively. All 12 patients that were successfully treated demonstrated radiological resolution of their pseudoaneurysms, with a median follow-up of 20 months. CONCLUSION: Endovascular embolisation is a suitable first-line management strategy associated with low recurrence rates. The role of percutaneous thrombin injection is yet to be defined.


Assuntos
Falso Aneurisma/terapia , Pancreatite/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Falso Aneurisma/diagnóstico por imagem , Falso Aneurisma/mortalidade , Angiografia , Embolização Terapêutica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pancreatite/diagnóstico , Recidiva , Estudos Retrospectivos , Tomografia Computadorizada por Raios X
8.
J Pharmacol Exp Ther ; 339(2): 642-53, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21849626

RESUMO

There is considerable ongoing investment in the research and development of selective progesterone receptor (PR) modulators for the treatment of gynecological conditions such as endometriosis. Here, we provide the first report on the clinical evaluation of a nonsteroidal progesterone receptor antagonist 4-[3-cyclopropyl-1-(mesylmethyl)-5-methyl-1H-pyrazol-4-yl]oxy,-2,6-dimethylbenzonitrile (PF-02413873) in healthy female subjects. In in vitro assays, PF-02413873 behaved as a selective and fully competitive PR antagonist, blocking progesterone binding and PR nuclear translocation. The pharmacological mode of action of PF-02413873 seems to differ from the founding member of the class of steroidal PR antagonists, 11ß-4-dimethylaminophenyl-17ß-hydroxy-17α-propinyl-4,9-estradiene-3-one (RU-486; mifepristone). Exposure-effect data from studies in the cynomolgus macaque, however, demonstrated that PF-02413873 reduced endometrial functionalis thickness to a comparable degree to RU-486 and this effect was accompanied by a decrease in proliferation rate (as measured by bromodeoxyuridine incorporation) for both RU-486 and high-dose PF-02413873. These data were used to underwrite a clinical assessment of PF-02413873 in a randomized, double-blinded, third-party open, placebo-controlled, dose-escalation study in healthy female volunteers with dosing for 14 days. PF-02413873 blocked the follicular phase increase in endometrial thickness, the midcycle lutenizing hormone surge, and elevation in estradiol in a dose-dependent fashion compared with placebo. This is the first report of translational efficacy data with a nonsteroidal PR antagonist in cynomolgus macaque and human subjects.


Assuntos
Endométrio/efeitos dos fármacos , Estrogênios não Esteroides/farmacologia , Fase Folicular/efeitos dos fármacos , Pirazóis/farmacologia , Receptores de Progesterona/antagonistas & inibidores , Sulfonas/farmacologia , Adulto , Animais , Relação Dose-Resposta a Droga , Método Duplo-Cego , Endometriose/tratamento farmacológico , Estradiol/sangue , Feminino , Antagonistas de Hormônios/farmacologia , Humanos , Hormônio Luteinizante/sangue , Macaca , Mifepristona/farmacologia , Terapia de Alvo Molecular , Pesquisa Translacional Biomédica , Adulto Jovem
9.
Drug Metab Dispos ; 39(8): 1396-405, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21543556

RESUMO

The recently discovered selective nonsteroidal progesterone receptor (PR) antagonist 4-[3-cyclopropyl-1-(methylsulfonylmethyl)-5-methyl-1H-pyrazol-4-yl]oxy-2,6-dimethylbenzonitrile (PF-02413873) was characterized in metabolism studies in vitro, in preclinical pharmacokinetics in rat and dog, and in an initial pharmacokinetic study in human volunteers. Clearance (CL) of PF-02413873 was found to be high in rat (84 ml · min(-1) · kg(-1)) and low in dog (3.8 ml · min(-1) · kg(-1)), consistent with metabolic stability determined in liver microsomes and hepatocytes in these species. In human, CL was low in relation to hepatic blood flow, consistent with metabolic stability in human in vitro systems, where identified metabolites suggested predominant cytochrome P450 (P450)-catalyzed oxidative metabolism. Prediction of CL using intrinsic CL determined in human liver microsomes (HLM), recombinant human P450 enzymes, and single species scaling (SSS) from pharmacokinetic studies showed that dog SSS and HLM scaling provided the closest estimates of CL of PF-02413873 in human. These CL estimates were combined with a physiologically based pharmacokinetic (PBPK) model to predict pharmacokinetic profiles after oral suspension administration of PF-02413873 in fasted and fed states in human. Predicted plasma concentration versus time profiles were found to be similar to those observed in human over the PF-02413873 dose range 50 to 500 mg and captured the enhanced exposure in fed subjects. This case study of a novel nonsteroidal PR antagonist underlines the utility of PBPK modeling techniques in guiding prediction confidence and design of early clinical trials of novel chemical agents.


Assuntos
Pirazóis/farmacocinética , Receptores de Progesterona/antagonistas & inibidores , Sulfonas/farmacocinética , Animais , Biotransformação , Células CACO-2 , Cromatografia Líquida de Alta Pressão , Cães , Relação Dose-Resposta a Droga , Método Duplo-Cego , Avaliação Pré-Clínica de Medicamentos , Hepatócitos/enzimologia , Hepatócitos/metabolismo , Humanos , Injeções Intravenosas , Secreções Intestinais/química , Masculino , Microssomos Hepáticos/enzimologia , Microssomos Hepáticos/metabolismo , Modelos Biológicos , Estrutura Molecular , Valor Preditivo dos Testes , Estudos Prospectivos , Ligação Proteica , Pirazóis/sangue , Pirazóis/química , Ratos , Ratos Sprague-Dawley , Solubilidade , Especificidade da Espécie , Sulfonas/sangue , Sulfonas/química , Espectrometria de Massas em Tandem
10.
J Vasc Surg ; 54(6): 1832-8, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21958563

RESUMO

OBJECTIVES: The Anaconda fenestrated stent graft (Vascutek, Inchinnan, United Kingdom) is a new device that can easily be repositioned during deployment. This study evaluated its feasibility for treating abdominal aortic aneurysms with inadequate infrarenal sealing zones. METHODS: Patients undergoing stent graft placement at two institutions in the United Kingdom were recruited. RESULTS: A total of 12 visceral vessels were accommodated with 8 fenestrations for renal arteries and 4 superior mesenteric artery valleys/scallops in 4 patients. One type Ib endoleak was identified at the 1-month follow-up and successfully treated. CONCLUSIONS: The Anaconda fenestrated stent graft device can be used for the repair of abdominal aortic aneurysms with hostile anatomy and has acceptable immediate and short-term results.


Assuntos
Aneurisma da Aorta Abdominal/cirurgia , Implante de Prótese Vascular , Prótese Vascular , Procedimentos Endovasculares , Desenho de Prótese , Stents , Idoso , Estudos de Coortes , Estudos de Viabilidade , Feminino , Humanos , Masculino , Resultado do Tratamento , Reino Unido
11.
Br J Clin Pharmacol ; 72(2): 235-46, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21392072

RESUMO

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: This study provides antimuscarinic agents for overactive bladder (OAB) display variable association with side effects mediated by the central nervous system (CNS), which may be of particular concern in the elderly. Adverse effects on CNS functioning are related to muscarinic receptor subtype selectivity and the ability of the agent to cross the blood-brain barrier, where P-gp plays a role in limiting permeability. WHAT THIS STUDY ADDS: This study provides a parallel investigation of CNS penetration of antimuscarinic OAB agents in vivo and assessment of physical properties and permeability in cell monolayers in vitro. It adds further understanding of the roles of passive transcellular permeability and P-gp in determining CNS penetration of antimuscarinic OAB agents. It also enables a comparison of CNS side-effect profiles of OAB agents with preclinical CNS penetration data. AIMS: To assess and compare the mechanisms of central nervous system (CNS) penetration of antimuscarinic overactive bladder (OAB) agents. METHODS: Physical properties were computed or compiled from the literature. Rats were administered 5-hydroxymethyl tolterodine (HMT), darifenacin, oxybutynin, solifenacin, tolterodine or trospium subcutaneously. At 1 h postdose, plasma, brain and cerebrospinal fluid (CSF) concentrations were determined using LC-MS/MS assays. Brain and plasma protein binding were determined in vitro. Permeability in the presence and absence of the efflux transporter P-glycoprotein (P-gp) was assessed in RRCK and MDCK-MDR1 transwell assays. RESULTS: Oxybutynin displayed extensive CNS penetration, with brain:plasma ratios (B:P), unbound brain:unbound plasma ratios (Kp,free) and CSF:free plasma ratios each >1. Tolterodine (B:P = 2.95, Kp,free = 0.23 and CSF:free plasma = 0.16) and solifenacin (B:P = 3.04, Kp,free = 0.28 and CSF:free plasma = 1.41) showed significant CNS penetration but with some restriction from CNS as indicated by Kp,free values significantly <1. 5-HMT, darifenacin and trospium displayed much lower B:P (0.03-0.16), Kp,free (0.01-0.04) and CSF:free plasma (0.004-0.06), consistent with poor CNS penetration. Permeability in RRCK cells was low for trospium (0.63 × 10(-6) cm s(-1) ), moderate for 5-HMT (11.7 × 10(-6) cm s(-1) ) and high for darifenacin, solifenacin, tolterodine and oxybutynin (21.5-38.2 × 10(-6) cm s(-1) ). In MDCK-MDR1 cells 5-HMT, darifenacin and trospium, were P-gp substrates, whereas oxybutynin, solifenacin and tolterodine were not P-gp substrates. CONCLUSIONS: Brain penetration was low for antimuscarinics that are P-gp substrates (5-HMT, darifenacin and trospium), and significant for those that are not P-gp substrates (oxybutynin, solifenacin and tolterodine). CNS adverse events reported in randomized controlled clinical trials show general alignment with the preclinical data described in this study.


Assuntos
Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Antagonistas Muscarínicos/farmacocinética , Bexiga Urinária Hiperativa/tratamento farmacológico , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Animais , Compostos Benzidrílicos/farmacocinética , Benzofuranos/farmacocinética , Linhagem Celular , Cromatografia Líquida de Alta Pressão , Cresóis/farmacocinética , Humanos , Masculino , Ácidos Mandélicos/farmacocinética , Fenilpropanolamina/farmacocinética , Pirrolidinas/farmacocinética , Quinuclidinas/farmacocinética , Ensaios Clínicos Controlados Aleatórios como Assunto , Ratos , Ratos Sprague-Dawley , Receptores Muscarínicos/metabolismo , Succinato de Solifenacina , Espectrometria de Massas em Tandem , Tetra-Hidroisoquinolinas/farmacocinética , Tartarato de Tolterodina
12.
Bioorg Med Chem Lett ; 21(9): 2715-20, 2011 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-21195614

RESUMO

New pyrimido[4,5-d]azepines 7 are disclosed as potent 5-HT(2C) receptor agonists. A preferred example, 7b had minimal activation at either the 5-HT(2A) or 5-HT(2B) receptors combined with robust efficacy in a preclinical canine model of stress urinary incontinence (SUI) and attractive pharmacokinetic and safety properties. Based on this profile, 7b (PF-3246799) was identified as a candidate for clinical development for the treatment of SUI. In addition, it proved to be critical to build an understanding of the translation between recombinant cell-based systems, native tissue preparations and in vivo preclinical models. This was a significant undertaking and proved to be crucial in compound selection.


Assuntos
Azepinas/síntese química , Pirimidinas/síntese química , Agonistas do Receptor 5-HT2 de Serotonina/síntese química , Animais , Azepinas/química , Azepinas/farmacologia , Azepinas/uso terapêutico , Modelos Animais de Doenças , Cães , Masculino , Estrutura Molecular , Pirimidinas/química , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Ratos , Agonistas do Receptor 5-HT2 de Serotonina/química , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Agonistas do Receptor 5-HT2 de Serotonina/uso terapêutico , Incontinência Urinária/tratamento farmacológico
13.
Drug Metab Dispos ; 38(9): 1471-9, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20516255

RESUMO

Bazedoxifene (BZA) acetate, a novel estrogen receptor modulator being developed for the prevention and treatment of postmenopausal osteoporosis, undergoes extensive metabolism in women after oral administration. In this study, the in vitro metabolism of [(14)C]BZA was determined in human hepatocytes and hepatic and intestinal microsomes, and the UDP glucuronosyltransferase (UGT) isozymes involved in the glucuronidation of BZA were identified. In addition, BZA was evaluated for its potential as a substrate of P-glycoprotein (P-gp) transporter in Caco-2 cell monolayers. BZA was metabolized to two monoglucuronides, BZA-4'-glucuronide and BZA-5-glucuronide, in hepatocytes and in liver and intestinal microsomes including jejunum, duodenum, and ileum. Both BZA-4'-glucuronide and BZA-5-glucuronide were major metabolites in the intestinal microsomes, whereas BZA-4'-glucuronide was the predominant metabolite in liver microsomes and hepatocytes. The kinetic parameters of BZA-4'-glucuronide formation were determined in liver, duodenum, and jejunum microsomes and with UGT1A1, 1A8, and 1A10, the most active UGT isoforms involved in the glucuronidation of BZA, whereas those of BZA-5-glucuronide were determined with all the enzyme systems except in liver microsomes and in UGT1A1 because the formation of the BZA-5-glucuronide was too low. K(m) values in liver, duodenum, and jejunum microsomes and UGT1A1, 1A8, and 1A10, were similar and ranged from 5.1 to 33.1 microM for BZA-4'-glucuronide formation and from 2.5 to 11.1 microM for BZA-5-glucuronide formation. V(max) values ranged from 0.8 to 2.9 nmol/(min . mg) protein for BZA-4'-glucuronide and from 0.1 to 1.2 nmol/(min . mg) protein for BZA-5-glucuronide. In Caco-2 cells, BZA appeared to be a P-gp substrate.


Assuntos
Moduladores de Receptor Estrogênico/farmacocinética , Indóis/farmacocinética , Disponibilidade Biológica , Células CACO-2 , Cromatografia Líquida de Alta Pressão , Moduladores de Receptor Estrogênico/metabolismo , Feminino , Humanos , Indóis/metabolismo , Espectrometria de Massas , Microssomos/metabolismo
14.
J Memb Sci ; 348(1-2): 131-149, 2010 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-20161534

RESUMO

Microdialysis is a well-developed membrane-based tool relying on diffusion to sample diffusible constituents of complex media, such as biological tissue. The objective of this research is to expand the utility of microdialysis by combining transmembrane convection with diffusion to enhance solute exchange between microdialysis probes and the surrounding medium. We have developed a mathematical model to describe probe performance and performed validation experiments utilizing tracer solutes and commercially available probes with 100-kDa molecular weight cutoff membranes. Diffusive and fluid permeabilities of the probe membranes are evaluated for probes immersed in well-stirred bathing media in vitro. Transmembrane convection alters the solute extraction fraction, i.e., the fractional loss of a solute from the probe perfusate during delivery and the fractional gain by the perfusate during sampling. The extraction fraction change depends upon the magnitude and direction (inward or outward) of fluid movement across the membrane. However, for solutes with zero reflection coefficients, equality is maintained between these delivery and sampling extraction fractions. This equality is a prerequisite for probe calibration approaches that rely on analyte delivery from the perfusate. Thus, we have provided the theoretical and experimental basis for exploiting convection in a quantitative manner to enhance solute delivery and sampling in microdialysis applications.

15.
ACS Pharmacol Transl Sci ; 3(4): 706-719, 2020 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-32832872

RESUMO

The hormone adrenomedullin has both physiological and pathological roles in biology. As a potent vasodilator, adrenomedullin is critically important in the regulation of blood pressure, but it also has several roles in disease, of which its actions in cancer are becoming recognized to have clinical importance. Reduced circulating adrenomedullin causes increased blood pressure but also reduces tumor progression, so drugs blocking all effects of adrenomedullin would be unacceptable clinically. However, there are two distinct receptors for adrenomedullin, each comprising the same G protein-coupled receptor (GPCR), the calcitonin receptor-like receptor (CLR), together with a different accessory protein known as a receptor activity-modifying protein (RAMP). The CLR with RAMP2 forms an adrenomedullin-1 receptor, and the CLR with RAMP3 forms an adrenomedullin-2 receptor. Recent research suggests that a selective blockade of adrenomedullin-2 receptors would be therapeutically valuable. Here we describe the design, synthesis, and characterization of potent small-molecule adrenomedullin-2 receptor antagonists with 1000-fold selectivity over the adrenomedullin-1 receptor, although retaining activity against the CGRP receptor. These molecules have clear effects on markers of pancreatic cancer progression in vitro, drug-like pharmacokinetic properties, and inhibit xenograft tumor growth and extend life in a mouse model of pancreatic cancer. Taken together, our data support the promise of a new class of anticancer therapeutics as well as improved understanding of the pharmacology of the adrenomedullin receptors and other GPCR/RAMP heteromers.

16.
J Med Chem ; 62(1): 247-265, 2019 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-29672039

RESUMO

Tropomyosin receptor kinases (TrkA, TrkB, TrkC) are activated by hormones of the neurotrophin family: nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4). Moreover, the NGF antibody tanezumab has provided clinical proof of concept for inhibition of the TrkA kinase pathway in pain leading to significant interest in the development of small molecule inhibitors of TrkA. However, achieving TrkA subtype selectivity over TrkB and TrkC via a Type I and Type II inhibitor binding mode has proven challenging and Type III or Type IV allosteric inhibitors may present a more promising selectivity design approach. Furthermore, TrkA inhibitors with minimal brain availability are required to deliver an appropriate safety profile. Herein, we describe the discovery of a highly potent, subtype selective, peripherally restricted, efficacious, and well-tolerated series of allosteric TrkA inhibitors that culminated in the delivery of candidate quality compound 23.


Assuntos
Inibidores de Proteínas Quinases/química , Receptor trkA/antagonistas & inibidores , Regulação Alostérica , Sequência de Aminoácidos , Animais , Sítios de Ligação , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Ensaios de Triagem em Larga Escala , Humanos , Ligantes , Microssomos Hepáticos/metabolismo , Simulação de Dinâmica Molecular , Ligação Proteica , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Estrutura Terciária de Proteína , Pirazóis/síntese química , Pirazóis/química , Pirazóis/farmacocinética , Ratos , Receptor trkA/metabolismo , Alinhamento de Sequência , Relação Estrutura-Atividade
17.
J Pharmacol Exp Ther ; 327(1): 78-87, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18593954

RESUMO

The progesterone receptor (PR) is an important regulator of endometrial function. Blockade of PR function has been recognized as the potential basis for preventing gynecological conditions such as endometriosis and uterine fibroids. In this study, we examine the in vitro and in vivo properties of a nonsteroidal PR antagonist, 2-[4-(4-cyano-phenoxy)-3,5-dicyclopropyl-1H-pyrazol-1-yl]-N-methylacetamide (PF-02367982) in comparison with the nonselective steroidal antagonist RU-486 (mifepristone). PF-02367982 was found to be a potent PR antagonist with far greater selectivity over the glucocorticoid receptor than RU-486. Both PF-02367982 and RU-486 blocked progesterone-induced arborization of the rabbit endometrium in a dose-dependent manner at unbound drug exposures that were commensurate with their potencies as PR antagonists in vitro. Translation of this pharmacology to a clinically relevant system was required to bridge the pharmacological gap between nonmenstruating rabbits and humans. Thus, the pharmacokinetic (PK) and pharmacodynamic (PD) data from the rabbit were combined to predict pharmacological effects on the naturally cycling cynomolgus macaque endometrium. PF-02367982 blocked the effect of progesterone on the cynomolgus macaque endometrium to the same degree as RU-486 and at exposures predicted by the rabbit PK-PD model. With such an efficacious and superior selectivity profile to the nonselective RU-486, PF-02367982 may have significant therapeutic value in the treatment of gynecological conditions such as endometriosis.


Assuntos
Acetamidas/farmacologia , Pirazóis/farmacologia , Receptores de Progesterona/antagonistas & inibidores , Animais , Células CHO , Cricetinae , Cricetulus , Endométrio/efeitos dos fármacos , Feminino , Humanos , Imuno-Histoquímica , Antígeno Ki-67/análise , Modelos Logísticos , Macaca fascicularis , Mifepristona/farmacologia , Coelhos , Receptores Androgênicos/análise , Receptores de Progesterona/análise
18.
J Med Chem ; 61(15): 6779-6800, 2018 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-29944371

RESUMO

Hormones of the neurotrophin family, nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4), are known to activate the family of Tropomyosin receptor kinases (TrkA, TrkB, and TrkC). Moreover, inhibition of the TrkA kinase pathway in pain has been clinically validated by the NGF antibody tanezumab, leading to significant interest in the development of small molecule inhibitors of TrkA. Furthermore, Trk inhibitors having an acceptable safety profile will require minimal brain availability. Herein, we discuss the discovery of two potent, selective, peripherally restricted, efficacious, and well-tolerated series of pan-Trk inhibitors which successfully delivered three candidate quality compounds 10b, 13b, and 19. All three compounds are predicted to possess low metabolic clearance in human that does not proceed via aldehyde oxidase-catalyzed reactions, thus addressing the potential clearance prediction liability associated with our current pan-Trk development candidate PF-06273340.


Assuntos
Descoberta de Drogas , Dor/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Animais , Humanos , Ligantes , Simulação de Acoplamento Molecular , Conformação Proteica , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/química , Piridinas/farmacocinética , Piridinas/farmacologia , Piridinas/uso terapêutico , Ratos , Receptores Proteína Tirosina Quinases/química , Receptores Proteína Tirosina Quinases/metabolismo , Solubilidade , Relação Estrutura-Atividade , Distribuição Tecidual
19.
Invest Ophthalmol Vis Sci ; 48(5): 2023-9, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17460256

RESUMO

PURPOSE: To determine the short and long-term pharmacokinetics and assess the toxicity of a cyclosporine (CsA) episcleral implant for the prevention of high-risk keratoplasty rejection. METHODS: CsA episcleral implants were made with a high (implant A) or low (implant B) release rate, and in vitro release rates were performed. Short-term pharmacokinetics were performed in rabbits using implant B, and the spatial and temporal spread of drug was observed by sampling from multiple corneal and conjunctival sites at 3 and 72 hours. Implant A was used in long-term pharmacokinetic studies in dogs aged more than 1 year. An ocular toxicity study was performed in dogs older than 1 year. RESULTS: A high release rate was observed with both implants over the initial 5 months followed by a steady state release. The cumulative release over the 400-day assay period from implants A and B was 3.8 +/- 0.3 and 2.3 +/- 0.3 mg, respectively. In the short-term pharmacokinetic studies, the cornea had CsA concentrations of 0.15 +/- 0.06, 0.07 +/- 0.02, and 0.05 +/- 0.02 microg/mg at sites centered 8, 13, and 18 mm away from the implant site, respectively. In the long-term pharmacokinetic studies, corneal CsA levels ranged from 0.18 +/- 0.06 to 0.009 +/- 0.004 microg/mg during the 1-year study. There were no signs of ocular toxicity at 1 year. CONCLUSIONS: Episcleral implants are safe and effective at delivering therapeutic CsA levels to the cornea to potentially prevent corneal allograft rejection. The implant can be surgically inserted at the time of penetrating keratoplasties, since the implant achieves therapeutic levels as early as 3 hours.


Assuntos
Córnea/metabolismo , Ciclosporina/farmacocinética , Rejeição de Enxerto/prevenção & controle , Imunossupressores/farmacocinética , Ceratoplastia Penetrante , Esclera/metabolismo , Animais , Humor Aquoso/metabolismo , Disponibilidade Biológica , Túnica Conjuntiva/metabolismo , Ciclosporina/toxicidade , Cães , Implantes de Medicamento , Pálpebras/metabolismo , Feminino , Imunossupressores/toxicidade , Linfonodos/metabolismo , Masculino , Coelhos
20.
J Neurosci Methods ; 155(2): 187-93, 2006 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-16466808

RESUMO

A number of investigators are using the quantitative no-net-flux microdialysis technique to monitor basal neurotransmitter dynamics in discrete brain regions of behaving animals. The predictive validity of the probe extraction fraction (Ed) for quantifying decreases in the rate of dopamine (DA) clearance from the extracellular space is well documented. It was recently suggested, however, that Ed may be insensitive to increases in DA clearance. Here we report that the Ed for DA in the nucleus accumbens (NAc) of the behaving mouse is increased following pharmacological inactivation of kappa-opioid receptors, a treatment previously shown to augment DA uptake. The Ed obtained in control mice and those that received the long-acting kappa-opioid receptor antagonist, nor-binaltorphimine (nor-BNI), satisfied the requirement that the mean values of each were lower than the mean value in vitro for the same probes immersed in well-stirred artificial cerebrospinal fluid. The Ed was increased in the NAc of nor-BNI-treated mice as compared to saline-treated control animals. The corresponding increase in the DA uptake rate was quantified by using the Ed values to calculate a change in the apparent clearance rate constant. Nor-BNI treatment did not alter the apparent extracellular dopamine concentration represented by the point of no-net-flux indicating that the rates of DA uptake and release were both increased.


Assuntos
Dopamina/metabolismo , Microdiálise/métodos , Núcleo Accumbens/metabolismo , Animais , Cromatografia Líquida de Alta Pressão/métodos , Eletroquímica/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Estatísticos , Naltrexona/análogos & derivados , Naltrexona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Valor Preditivo dos Testes , Receptores Opioides kappa/fisiologia
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