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.
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.
View Article and Find Full Text PDFThe voltage gated sodium channel Na1.8 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 Na1.
View Article and Find Full Text PDFHormones 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.
View Article and Find Full Text PDFTropomyosin 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.
View Article and Find Full Text PDFBackground: 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.
The neurotrophin family of growth factors, comprised of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4), is implicated in the physiology of chronic pain. Given the clinical efficacy of anti-NGF monoclonal antibody (mAb) therapies, there is significant interest in the development of small molecule modulators of neurotrophin activity. Neurotrophins signal through the tropomyosin related kinase (Trk) family of tyrosine kinase receptors, hence Trk kinase inhibition represents a potentially "druggable" point of intervention.
View Article and Find Full Text PDFVoltage-gated sodium channels, in particular Nav1.8, can be targeted for the treatment of neuropathic and inflammatory pain. Herein, we described the optimization of Nav1.
View Article and Find Full Text PDFBackground And Purpose: NaV 1.8 ion channels have been highlighted as important molecular targets for the design of low MW blockers for the treatment of chronic pain. Here, we describe the effects of PF-01247324, a new generation, selective, orally bioavailable Nav 1.
View Article and Find Full Text PDFDrug Discov Today Technol
June 2014
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 blood–brain 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.
View Article and Find Full Text PDFA series of 4-substituted pyrimido[4,5-d]azepines that are potent, selective 5-HT2C receptor partial agonists is described. A rational medicinal chemistry design strategy to deliver CNS penetration coupled with SAR-based optimization of selectivity and agonist potency provided compounds with the desired balance of preclinical properties. Lead compounds 17 (PF-4479745) and 18 (PF-4522654) displayed robust pharmacology in a preclinical canine model of stress urinary incontinence (SUI) and no measurable functional agonism at the key selectivity targets 5-HT2A and 5-HT2B in relevant tissue-based assay systems.
View Article and Find Full Text PDFACS Med Chem Lett
December 2012
Pseudoaneurysms arising from the visceral arteries are rare. We present 2 patients who developed pseudoaneurysms arising from branches of the superior mesenteric artery (SMA) following laparoscopic appendicectomy. Both cases were successfully treated by endovascular embolization.
View Article and Find Full Text PDFEarly 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.
View Article and Find Full Text PDFObjectives: 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.
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.
View Article and Find Full Text PDFThe 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.
View Article and Find Full Text PDFWhat 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.
J Pharm Biomed Anal
April 2011
A unifying approach is presented for developing mathematical models of microdialysis that are applicable to both in vitro and in vivo situations. Previous models for cylindrical probes have been limited by accommodating analyte diffusion through the surrounding medium in the radial direction only, i.e.
View Article and Find Full Text PDFNew 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.
View Article and Find Full Text PDFCardiovasc Intervent Radiol
February 2011
Drug Metab Dispos
September 2010
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.
View Article and Find Full Text PDFMicrodialysis 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.
View Article and Find Full Text PDF