Central Middlesex Hospital
Central Middlesex Hospital
Waldmeier F.,Novartis |
Bruin G.J.,Novartis |
Glaenzel U.,Novartis |
Hazell K.,Novartis |
And 3 more authors.
Drug Metabolism and Disposition | Year: 2010
Deferasirox (ICL670) is a novel once-daily, orally administered iron chelator to treat chronic iron overload in patients with transfusiondependent anemias. Absorption, distribution, metabolism, and excretion of [ 14C]deferasirox at pharmacokinetic steady state was investigated in five adult β-thalassemic patients. Deferasirox (1000 mg) was given orally once daily for 6 days to achieve steady state. On day 7, patients received a single oral 1000-mg dose (∼20 mg/kg) of [ 14C]deferasirox (2.5 MBq). Blood, plasma, feces, and urine samples collected over 7 days were analyzed for radioactivity, deferasirox, its iron complex Fe-[deferasirox] 2, and metabolites. Deferasirox was well absorbed. Deferasirox and its iron complex accounted for 87 and 10%, respectively, of the radioactivity in plasma (area under the curve at steady state). Excretion occurred largely in the feces (84% of dose), and 60% of the radioactivity in the feces was identified as deferasirox. Apparently unchanged deferasirox in feces was partly attributable to incomplete intestinal absorption and partly to hepatobiliary elimination of deferasirox (including first-pass elimination) and of its glucuronide. Renal excretion was only 8% of the dose and included mainly the glucuronide M6. Oxidative metabolism by cytochrome 450 enzymes to M1 [5-hydroxy (OH) deferasirox, presumably by CYP1A] and M4 (5′-OH deferasirox, by CYP2D6) was minor (6 and 2% of the dose, respectively). Direct and indirect evidence indicates that the main pathway of deferasirox metabolism is via glucuronidation to metabolites M3 (acyl glucuronide) and M6 (2-O-glucuronide). Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics.
Warrington S.,Central Middlesex Hospital |
Nagakawa S.,Kowa Company Ltd |
Hounslow N.,Kowa Research Europe
Clinical Drug Investigation | Year: 2011
Background and Objectives: Pitavastatin is a highly effective lipid-lowering drug (approved dose range 1-4mg/day) with a distinctive metabolic pathway that has a low potential for drug interactions. The efficacy and safety of pitavastatin have been characterized in a broad clinical development programme conducted initially in Japanese patients. The objectives of the present study were to evaluate the pharmacokinetic bioequivalence of the European (EU) and Japanese (JP) formulations of pitavastatin 2mg in healthy Japanese and Caucasian men, and to assess whether the bioavailability of each formulation was similar in the two ethnic groups. Methods: In this open-label, single-dose, two-way crossover pharmacokinetic study, healthy men aged 18-45 years were randomized to receive: the JP formulation of pitavastatin 2mg followed by the EU formulation; or the EU formulation of pitavastatin 2mg followed by the JP formulation. The main outcome measures were maximum plasma concentration (C max), area under the plasma concentration-time curve (AUC) during a dosage interval (τ) [AUC τ] and AUC from time zero to infinity (AUC ∞) for pitavastatin and its main (inactive) metabolite pitavastatin lactone. Plasma concentrations of pitavastatin and pitavastatin lactone were determined using a validated liquid chromatography-tandem mass spectrometry method. Results: Forty-eight Caucasian and 12 Japanese men completed the study. Compared with the Japanese men, the Caucasian men were of greater mean body weight (76.1 vs 58.9 kg), height (180.8 vs 170.8 cm) and body mass index (23.2 vs 20.2 kg/m 2). Geometric mean ratios (GMRs) of the pharmacokinetic parameters of pitavastatin demonstrated bioequivalence of the EU and JP formulations: GMRs and 90% confidence intervals (CIs) fell within the range 80-125% in Caucasian men and in Caucasian and Japanese groups combined for pitavastatin C max (combined analysis: GMR 103.1% [90% CI 96.0, 110.6]), AUC τ (GMR 99.6%[90%CI 95.5, 104.0]), and AUC ∞ (GMR 104.2% [90% CI 96.2, 112.8]). After adjusting for age and body weight in the pooled formulation analysis, bioequivalence between the Caucasian and Japanese groups was similarly demonstrated for pitavastatin C max (GMR 96.8% [90% CI 90.2, 103.8]), AUC τ (GMR 98.3% [90%CI 94.2, 102.7]) and AUC ∞ (GMR 85.9% [90% CI 81.1, 91.0]). Conclusion: The EU and JP formulations of pitavastatin showed pharmacokinetic bioequivalence, and there were no clinically relevant differences in exposure to pitavastatin between Caucasian and Japanese participants when differences in body weight were taken into account. © 2011 Adis Data Information BV. All rights reserved.
Ong H.S.,Central Middlesex Hospital |
Levin S.,Central Middlesex Hospital |
Vafidis G.,Central Middlesex Hospital
Journal of Glaucoma | Year: 2013
PURPOSE: We performed this study to determine the positive predictive value of a Diabetic Retinopathy Screening Program (DRSP) in detecting early glaucoma using diabetic retinopathy screening images. PATIENTS AND METHODS: The study was carried out on patients referred to the glaucoma clinic from the local DRSP. Retinal images considered by DRSP graders to show possible glaucomatous optic discs were referred to the final referral grader, a medical retina specialist (MR). The same images were independently graded by a glaucoma specialist (GS). GS-positive patients were referred to the glaucoma clinic. Possible outcomes at 1 year were true cases (patients found to have glaucoma or glaucoma suspects) or false cases (patients for whom a diagnosis of glaucoma was excluded). RESULTS: Of 11,565 diabetic patients screened, 216 were suspected to have glaucoma after DRSP grading (1.87%). A total of 170 were graded glaucoma positive and referred to a clinic. At 1 year, 113 were true cases (98 per 10,000 screened with previously undiagnosed glaucoma or glaucoma suspect) and 22 were false cases and discharged from clinic (19 false positives per 10,000 screened). Of the 113 true cases, 89 were given a positive grade by the MR and 24 were given a negative grade, giving the DRSP a positive predictive value of 78.8% in detecting glaucoma in the population. Comparison of the MR and GS grading showed an agreement of 76.4%. The κ-coefficient was 0.404 (95% confidence interval, 0.272-0.536). CONCLUSIONS: We conclude that optic discs imaging in DRSP can be useful as part of a glaucoma screening strategy to identify new disease within a diabetic population. Copyright © 2013 by Lippincott Williams & Wilkins.
Negretti G.S.,Central Middlesex Hospital
Eye (London, England) | Year: 2014
PURPOSE: To investigate the distribution of new vessels (NV) in patients treated with pan-retinal photocoagulation for proliferative diabetic retinopathy (PDR). To assess whether it is safe to discharge treated PDR patients to the NHS Diabetic Eye Screening Programme (DESP) which uses two mydriatic 45° fields of each eye.METHODS: Consecutive treated PDR patients undergoing fundus fluorescein angiography between July 2010 and October 2011 for the purpose of looking for NV were included. The distribution of NV was mapped. In particular it was noted whether NV occurred in the area covered by the DESP standard screening images.RESULTS: A total of 76 patients (108 eyes) met the inclusion criteria for the study. Leaking NV were found inside the DESP fields in 89% of study patients. In 108 eyes with leaking NV, there were a total of 35 NVD and 336 NVE. NV were found within DESP fields in 83% of eyes. Of the 336 NVE, 54% occurred within and 46% outside DESP standard fields. There was no statistically significant difference in the retinal quadrant distribution of NVE.CONCLUSIONS: If these findings apply to the whole treated PDR population, NVE would be identified in 89% of patients undergoing DESP screening. This would support stable treated PDR patients being monitored within the DESP. We found no preferential clustering of NV within quadrants or between posterior and less posterior retina suggesting that there would be no benefit to the DESP of taking an additional field or graders concentrating on one particular quadrant more than another.
Boyce M.,Central Middlesex Hospital |
Warrington S.,Central Middlesex Hospital
British Journal of Clinical Pharmacology | Year: 2013
Aim: To administer repeated oral doses of netazepide to healthy subjects for the first time, to assess safety, tolerability, pharmacokinetics and effect on 24h gastric pH and plasma gastrin. Method: We did two randomized, double-blind, parallel group studies. The first compared netazepide 25 and 100mg 12hourly, omeprazole 20mg once daily and placebo for 7 days. On day 7 only, we measured pH and assayed plasma gastrin. The second study compared netazepide 5, 10 and 25mg and placebo once daily for 14 days. We measured pH on days 1, 7 and 14 and assayed plasma gastrin on days 1 and 14. We compared treatments by time gastric pH ≥ 4 during 0-4, 4-9, 9-13 and 13-24h after the morning dose, and by plasma gastrin. P < 0.05 was significant. Results: Netazepide was well tolerated. On day 7 of the first study, netazepide increased pH significantly only during 9-13h after the 100mg dose, whereas omeprazole raised pH significantly during all periods. Both netazepide and omeprazole increased plasma gastrin significantly. Netazepide had linear pharmacokinetics. In the second study, netazepide caused dose-dependent, sustained increases in pH on day 1, but as in the first study, netazepide had little effect on pH on days 7 and 14. Again, netazepide increased plasma gastrin significantly. Conclusion: Although repeated doses of netazepide led to tolerance to its effect on pH, the accompanying increase in plasma gastrin is consistent with continued inhibition of acid secretion, via gastrin receptor antagonism and gene up-regulation. © 2013 The British Pharmacological Society.
Boyce M.,Central Middlesex Hospital |
Warrington S.,Central Middlesex Hospital |
Black J.,James Black Foundation
British Journal of Clinical Pharmacology | Year: 2013
Aims: To confirm by means of pentagastrin, a synthetic gastrin agonist, that netazepide is a gastrin/CCK2 receptor antagonist in healthy subjects, and that antagonism persists during repeated dosing. Methods: We did two studies in which we infused pentagastrin (0.6μgkg-1h-1 intravenously), aspirated gastric secretion and measured the volume, pH and H+ secretion rate of the gastric aspirate. First, we did a double-blind, five-way crossover study (n = 10) to assess the effect of single oral doses of netazepide (1, 5, 25 and 100mg) and placebo on the response to pentagastrin. Then, we did a single-blind, placebo-controlled study (n = 8) to assess the effect of the first and last oral doses of netazepide (100mg) twice daily for 13 doses on the response to pentagastrin. Results: Netazepide was well tolerated. After placebo, pentagastrin increased the volume and H+ secretion rate and reduced the pH of gastric aspirate. Compared with placebo, single doses of netazepide caused dose-dependent inhibition of the pentagastrin response (P < 0.02); netazepide (100mg) abolished the response. After 13 doses, the reduction in volume and H+ secretion rate persisted (P < 0.001), but the pH effect was mostly lost. Conclusions: Netazepide is an orally active, potent, competitive antagonist of human gastrin/CCK2 receptors. Antagonism is dose dependent and persists during repeated dosing, despite tolerance to the effect on pH. Further studies are required to explain that tolerance. Netazepide is a tool to study the physiology and pharmacology of gastrin, and merits studies in patients to assess its potential to treat gastric acid-related conditions and the trophic effects of hypergastrinaemia. © 2013 The British Pharmacological Society.
Hui E.,Imperial College London |
Devendra D.,Imperial College London |
Devendra D.,Central Middlesex Hospital
Diabetes/Metabolism Research and Reviews | Year: 2010
Abstinence from food and liquid during daylight hours is observed by Muslim individuals during the month of Ramadan. Even though the Koran exempts the sick from fasting, many people with diabetes still fast during this religious period. It is essential for patients, family and healthcare professionals to be aware of the religious attitude to and health implications of fasting. Major changes in dietary habits, daily physical activities and sleeping patterns during Ramadan have significant impact on the glycaemic control, lipid profile, weight and dietary intake. Hence, the patient is encouraged to have appropriate pre-Ramadan assessment and education in order to stratify and modify his or her risk with fasting. Dose and timing adjustments to insulin and to some oral hypoglycaemic agents, especially sulphonylureas, may well be necessary during Ramadan. © 2010 John Wiley & Sons, Ltd.
Bourkiza R.,Central Middlesex Hospital |
Lee V.,Central Middlesex Hospital
Orbit | Year: 2012
Punctal and canalicular plugs are widely used for both temporary and permanent occlusion of the lacrimal puncta in dry eyes. There are many designs and materials available on the market. While their efficacy in improving dry eye symptoms is widely proven, the gamut of complications associated with these devices have never been subject to a general review, although there are numerous case series in the literature associated with one particular device. This review aims to examine the track record of a variety of plugs currently in use, to review the management of complications, and propose strategies for both the prevention of these complications and their treatment. © 2012 Informa Healthcare USA, Inc.
Burton J.,Central Middlesex Hospital |
Brook G.,Central Middlesex Hospital |
McSorley J.,Central Middlesex Hospital |
Murphy S.,Central Middlesex Hospital
Sexually Transmitted Infections | Year: 2014
Background: Patients attending for sexually transmitted infection (STI)/HIV testing may be at continuing risk of infection and advised to return for retesting at a later date. Objectives:: To measure the impact of short message service (SMS) text reminders on the reattendance rates of patients who require repeat STI testing. Methods: Reattendance rates were measured for two groups of higher risk patients: those listed for routine SMS text reminders in 2012 and a control group of patients from 2011 with the same risk profile who had not received any active recall. Reattendance was counted if it was within 4 months of the end of the episode of care. Results: Reattendance rates were not statistically different between the text group 32% (89/274) and the control group 35% (92/266). Reattendance also was not statistically different between the text and control groups respectively in patients with the following risks: recent chlamydia 43/121 (36%) versus 41/123 (33%), recent gonorrhoea 4/21 (19%) versus 7/21 (33%), recent emergency contraception 27/60 (45%) versus 25/56 (45%) and other risks 7/27 (26%) versus 9/26 (35%). High rates of STIs were found in patients who reattended in both the text group (13/90, 14%) and control group (15/91, 17%) and at even higher rates at reattendance if the reason for recall was chlamydia infection at the initial visit: 9/43 (21%) in the text group and 10/41 (24%) in the control group. Conclusions: SMS texts sent as reminders to patients at higher risk of STIs and HIV did not increase the reattendance rate, when compared with standard advice, in this service which already has a high reattendance rate. STI rates were high in those patients who reattended.
Anie K.A.,Central Middlesex Hospital |
Green J.,Central Middlesex Hospital
The Cochrane database of systematic reviews | Year: 2015
BACKGROUND: Sickle cell disease comprises a group of genetic blood disorders. It occurs when the sickle haemoglobin gene is inherited from both parents. The effects of the condition are: varying degrees of anaemia which, if severe, can reduce mobility; a tendency for small blood capillaries to become blocked causing pain in muscle and bone commonly known as 'crises'; damage to major organs such as the spleen, liver, kidneys, and lungs; and increased vulnerability to severe infections. There are both medical and non-medical complications, and treatment is usually symptomatic and palliative in nature. Psychological interventions for individuals with sickle cell disease might complement current medical treatment, and studies of their efficacy have yielded encouraging results. This is an update of a previously published Cochrane Review.OBJECTIVES: To examine the evidence that psychological interventions improve the ability of people with sickle cell disease to cope with their condition.SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register, which comprises references identified from comprehensive electronic database searches and the Internet, handsearches of relevant journals and abstract books of conference proceedings.Date of the most recent search of the Group's Haemoglobinopathies Trials Register: 17 February 2015.SELECTION CRITERIA: All randomised or quasi-randomised controlled trials comparing psychological interventions with no (psychological) intervention in people with sickle cell disease.DATA COLLECTION AND ANALYSIS: Both authors independently extracted data and assessed the risk of bias of the included studies.MAIN RESULTS: Twelve studies were identified in the searches and seven of these were eligible for inclusion in the review. Five studies, involving 260 participants, provided data for analysis. One study showed that cognitive behaviour therapy significantly reduced the affective component of pain (feelings about pain), mean difference -0.99 (95% confidence interval -1.62 to -0.36), but not the sensory component (pain intensity), mean difference 0.00 (95% confidence interval -9.39 to 9.39). One study of family psycho-education was not associated with a reduction in depression. Another study evaluating cognitive behavioural therapy had inconclusive results for the assessment of coping strategies, and showed no difference between groups assessed on health service utilisation. In addition, family home-based cognitive behavioural therapy did not show any difference compared to disease education. One study of patient education on health beliefs showed a significant improvement in attitudes towards health workers, mean difference -4.39 (95% CI -6.45 to -2.33) and medication, mean difference -1.74 (95% CI -2.98 to -0.50). Nonetheless, these results may not apply across all ages, severity of sickle cell disease, types of pain (acute or chronic), or setting.AUTHORS' CONCLUSIONS: Evidence for the efficacy of psychological therapies in sickle cell disease is currently limited. This systematic review has clearly identified the need for well-designed, adequately-powered, multicentre randomised controlled trials assessing the effectiveness of specific interventions in sickle cell disease.