Northwick Park Institute for Medical Research

Harrow on the Hill, United Kingdom

Northwick Park Institute for Medical Research

Harrow on the Hill, United Kingdom
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Motterlini R.,French Institute of Health and Medical Research | Sawle P.,Northwick Park Institute for Medical Research | Hammad J.,Northwick Park Institute for Medical Research | Mann B.E.,University of Sheffield | And 3 more authors.
Pharmacological Research | Year: 2013

Carbon monoxide-releasing molecules (CO-RMs) are a class of organometallo carbonyl complexes capable of delivering controlled quantities of CO gas to cells and tissues thus exerting a broad spectrum of pharmacological effects. Here we report on the chemical synthesis, CO releasing properties, cytotoxicity profile and pharmacological activities of four novel structurally related iron-allyl carbonyls. The major difference among the new CO-RMs tested was that three compounds (CORM-307, CORM-308 and CORM-314) were soluble in dimethylsulfoxide (DMSO), whereas a fourth one (CORM-319) was rendered water-soluble by reacting the iron-carbonyl with hydrogen tetrafluoroborate. We found that despite the fact all compounds liberated CO, CO-RMs soluble in DMSO caused a more pronounced toxic effect both in vascular and inflammatory cells as well as in isolated vessels. More specifically, iron carbonyls soluble in DMSO released CO with a fast kinetic and displayed a marked cytotoxic effect in smooth muscle cells and RAW 247.6 macrophages despite exerting a rapid and pronounced vasorelaxation ex vivo. In contrast, CORM-319 that is soluble in water and liberated CO with a slower rate, preserved smooth muscle cell viability, relaxed aortic tissue and exerted a significant anti-inflammatory effect in macrophages challenged with endotoxin. These data suggest that iron carbonyls can be used as scaffolds for the design and synthesis of pharmacologically active CO-RMs and indicate that increasing water solubility and controlling the rate of CO release are important parameters for limiting their potential toxic effects. © 2012 Elsevier Ltd.

Hoerauf A.,University of Bonn | Townson S.,Northwick Park Institute for Medical Research | Slatko B.E.,New England Biolabs
Parasitology | Year: 2014

SUMMARY Anti-Wolbachia therapy delivers safe macrofilaricidal activity with superior therapeutic outcomes compared to all standard anti-filarial treatments, with the added benefit of substantial improvements in clinical pathology. These outcomes can be achieved, in principle, with existing registered drugs, e.g. doxycycline, that are affordable, available to endemic communities and have well known, albeit population-limiting, safety profiles. The key barriers to using doxycycline as an mass drug administration (MDA) strategy for widespread community-based control are the logistics of a relatively lengthy course of treatment (4-6 weeks) and contraindications in children under eight years and pregnancy. Therefore, the primary goal of the anti-Wolbachia (A·WOL) consortium is to find drugs and regimens that reduce the period of treatment from weeks to days (7 days or less), and to find drugs which would be safe in excluded target populations (pregnancy and children). A secondary goal is to refine regimens of existing antibiotics suitable for a more restricted use, prior to the availability of a regimen that is compatible with MDA usage. For example, for use in the event of the emergence of drug-resistance, in individuals with high loiasis co-infection and at risk of severe adverse events (SAE) to ivermectin, or in post-MDA 'endgame scenarios', where test and treat strategies become more cost effective and deliverable. © Cambridge University Press 2013.

Tayem Y.,Northwick Park Institute for Medical Research | Green C.J.,Northwick Park Institute for Medical Research | Motterlini R.,University Paris Est Creteil | Motterlini R.,French Institute of Health and Medical Research | And 2 more authors.
Pharmacological Research | Year: 2014

Heme oxygenase-1 (HO-1) is a redox sensitive inducible enzyme endowed with important antioxidant and cytoprotective activities. Here we report that two water-soluble isothiocyanate-cysteine conjugates, S-[N-benzyl(thiocarbamoyl)]-l- cysteine (BTTC) and S-[N-(3-phenylpropyl)(thiocarbamoyl)]-l-cysteine (PTTC), potently increase HO-1 protein expression and heme oxygenase activity in renal tubular epithelial cells at 5 and 10 μM, while higher concentrations are themselves cytotoxic and pro-apoptotic. Inhibitors of the pro-survival pathways ERK, MAPK and PI3K almost completely abolished the increase in HO-1 induction and heme oxygenase activity, while the JNK pathway appeared to be mainly involved in the apoptosis triggered by the isothiocyanates. We also found that renal cells exposed to 50 μM cisplatin (CDDP), a chemotherapeutic agent known for its nephrotoxic actions, displayed a marked increase in caspase-3 activity and the number of apoptotic cells. These effects were abolished by pre-incubation of cells with concentrations of BTCC or PTCC that maximize HO-1 induction and were reversed by the inhibitor of heme oxygenase activity tin protoporphyrin IX (SnPPIX). Moreover, in a model of CDDP-induced nephrotoxicity in vivo, pre-treatment of rats with a daily dose of BTCC or PTCC (25 mg/kg, i.p.) completely abolished the increase in serum creatinine and urea levels and markedly reduced the severity of renal tissue apoptosis caused by CDDP. The renoprotective effects of BTCC and PTCC in vivo were markedly attenuated by administration of rats with SnPPIX. These findings indicate that water-soluble isothiocyanates counteract renal dysfunction and apoptosis by up-regulating the HO-1 system and could be used as a supplementary treatment to mitigate CDDP-induced nephrotoxic effects. © 2014 Elsevier Ltd. All rights reserved.

Prabhu I.S.,University of Manchester | Homer-Vanniasinkam S.,Northwick Park Institute for Medical Research
Journal of Cranio-Maxillofacial Surgery | Year: 2013

The aim of this proof-of-principle study was to assess an intraluminal expandable stent design using an existing cardiac stent. Intraluminal stents minimise the amount of suturing necessary when performing an end-to-end anastomosis. The stent is passed halfway through the lumen on each end of the vessel to be anastomosed and is expanded using a retrievable balloon. An adequately expanded stent holds the blood vessel ends in contact without the need for sutures. This method was tested on an end-to-end anastomosis performed on the carotid vessels of two New Zealand male rabbits. The vessels were patent with good blood flow at the end of 16 days. This method has a potential use in vascular, microvascular and luminal anastomoses within various sub-specialities of surgery. © 2012 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.

Crook S.H.,University of Sheffield | Mann B.E.,University of Sheffield | Meijer A.J.H.M.,University of Sheffield | Adams H.,University of Sheffield | And 3 more authors.
Dalton Transactions | Year: 2011

[Mn(CO)4{S2CNMe(CH2CO2H)}], 1, is shown to be a CO releasing molecule providing at least three moles CO per mole of compound. The mechanism of CO loss is dissociative and reversible and was investigated using Gaussian 09 calculations. The reversible binding of CO results in a relatively stable solution of the compound, while in the presence of a CO receptor or a ligand to prevent the rebinding of CO, the CO is lost rapidly. The X-ray structure was determined. © 2011 The Royal Society of Chemistry.

Atkin A.J.,University of York | Lynam J.M.,University of York | Moulton B.E.,University of York | Sawle P.,Northwick Park Institute for Medical Research | And 5 more authors.
Dalton Transactions | Year: 2011

The deoxy-myoglobin (deoxy-Mb)/carbonmonoxy-myoglobin (Mb-CO) UV-vis assay is the principal method used for quantifying the rates of CO release from CO-releasing molecules (CO-RMs) that might possess therapeutic benefits. Some issues emerge when the Mb-CO assay is utilized for testing CO-RMs with novel structures, which are comprehensively discussed here for the first time. Two methods for processing raw UV-vis spectroscopic data generated from the assay are presented in this paper. © The Royal Society of Chemistry 2011.

Yabluchanskiy A.,Northwick Park Institute for Medical Research | Sawle P.,Northwick Park Institute for Medical Research | Homer-Vanniasinkam S.,Northwick Park Institute for Medical Research | Green C.J.,Northwick Park Institute for Medical Research | And 4 more authors.
Critical Care Medicine | Year: 2012

Objective: Intracerebral hemorrhage is accompanied by a pronounced inflammatory response that mediates brain damage but is also essential for the tissue reparative process. We assessed the effect of CORM-3, a water-soluble carbon monoxide-releasing molecule possessing anti-inflammatory properties, on inflammation and brain injury after intracerebral hemorrhage. Design: In vivo and in vitro laboratory study. Setting: Research laboratory. Subjects: Male Sprague-Dawley rats, 250-350 g. Interventions: A model of collagenase injection (2 μL) in the brain was established to induce intracerebral hemorrhage. CORM-3 (4 or 8 mg/kg) was administered intravenously at different times as follows: 1) 5 mins before collagenase; 2) 3 hrs after collagenase; and 3) 3 days after collagenase challenge. Measurements and Main Results; Saline was used as a negative control. Brain damage, brain water content, and behavioral assessment were evaluated. The inflammatory response was determined at set intervals after intracerebral hemorrhage by counting peripheral neutrophils and lymphocytes, neutrophils, and activated microglia/macrophages in the intracerebral hemorrhage area and measuring plasma tumor necrosis factor-á levels. BV2 microglia and DI-TNC1 astrocytes were exposed to triton (1%) or CORM-3 (10-100 ìM) and cytotoxicity (lactic dehydrogenase assay) measured at 24 hrs. A challenge with collagenase to induce intracerebral hemorrhage caused marked brain damage and modified the levels of inflammatory markers. Pretreatment with CORM-3 significantly prevented injury, modulated inflammation, and reduced plasma tumor necrosis factor-α. CORM-3 given 3 hrs after collagenase significantly increased brain injury and tumor necrosis factor-α production. In contrast, CORM-3 given 3 days after collagenase afforded partial protection, modulated inflammation, and decreased tumor necrosis factor-α starting from the day of application. No dose-dependent effects were observed. Conclusions: CORM-3 promotes neuroprotection or neurotoxicity after intracerebral hemorrhage depending on the time of administration. Beneficial effects are achieved when CORM-3 is given either before or 3 days after intracerebral hemorrhage, namely, as a prophylactic agent or during the postacute inflammatory phase. Copyright © 2012 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins.

De Castro Bras L.E.,Northwick Park Institute for Medical Research | Shurey S.,Northwick Park Institute for Medical Research | Sibbons P.D.,Northwick Park Institute for Medical Research
Hernia | Year: 2012

Introduction Abdominal wall defects and incisional hernias represent a challenging problem. Currently, several commercially available biologic prostheses are used clinically for hernia repair. We compared the performance and efficacy of two non-crosslinked meshes in ventral hernia repair to two crosslinked prostheses in a rodent model. Methods Animals were divided into 12 groups (4 matrix types and 3 termination time-points per matrix). A ventral defect was carefully created and overlapped with the biologic prosthesis. Results Major complications were seroma induction (3 mesh types), implant extrusion (1 mesh type), severe inflammatory and immune responses (non-crosslinked mesh), fibrosis and mineralisation (3 mesh types). After inflammation resolution, 3 of the matrices tested supported hernia healing but with marked tissue and temporal differences. AlloDerm®* and Surgisis Gold TM showed tissue reactivity with the host and a rapid rate of matrix remodelling. Bard CollaMend TM* Implant proved to be inept for hernia repair under the conditions tested. Permacol TM biological implant integration with host tissue increased over time, supporting hernia healing with strength of tissue, and appears to be a safe prosthetic material for ventral hernia repair based on the results of this rodent study. © Springer-Verlag 2011.

Northwick Park Institute For Medical Research | Date: 2010-02-05

Methods for the detection or diagnosis of a bacterial infection or colonisation utilising mass spectrometric analysis are provided. The methods involve short-term enrichment of samples followed by mass spectrometric analysis of biomarker profiles. Also provided are methods for preparing short-term enrichment cultures.

Agency: GTR | Branch: Innovate UK | Program: | Phase: Smart - Proof of Concept | Award Amount: 76.08K | Year: 2016

Airway obstructions cause breathlessness and difficulty swallowing. They occur in up to 30% of lung cancer patients, where prognosis is often poor and palliative treatment the only option. Additionally, there were over 2,000 patients suffering from tracheomalacia (collapsed airway) and stenosis (abnormal narrowing of the airway) in the UK last year. The current gold standard treatment for airway obstruction is surgical resection. However, surgery is an invasive, time consuming procedure and complications such as infection may arise during recovery. An alternative is to use Airway stents, hollow cylindrical prostheses that provide support. They can be deployed without surgery and provide significant relief from the discomfort associated with an obstructed airway, a marked increase in quality of life, and in many cases a prolonged lifespan. There are a number of Airway stents on the market, including silicone, metal and hybrid stents. Each of these have significant shortcomings. Silicone stents tend to migrate and require re positioning. Metal stents have a risk of airway perforation and are very difficult to remove or reposition. Hybrid stents are significantly more expensive than either silicone or metal stents. There is a growing, unmet need for the perfect Airway stent. We propose to create NuAIR, an Airway stent customised for patients that possesses all the characteristics of the perfect stent. It will be made using biocompatible collagen and a synthetic polymer to meet the physiological demands of the trachea. The design will be inspired by structural architecture found in nature. This will result in a stent that is strong yet flexible, using the minimal amount of material. NuAIR will be made by 3D-printing, a fast and cost effective method. Most importantly, this will allow customisation of stents based on computerised-tomography (CT) scans of individual patients. This will reduce unwanted movement and increase comfort – key components of the ideal stent.

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