18 results on '"Saich R"'
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2. Toxic molecules in liver failure plasma
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Saich, R.
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616.3 - Abstract
Liver failure remains a disease with a high mortality and with the exception of transplantation therapeutic options are limited. The liver however has regenerative potential, and strategies based not only at supporting the failing liver, but promoting its recovery would be a significant evolution. Plasma from patients with liver failure contains toxic molecules that have many effects on the liver including loss of cell viability. These factors represent a significant barrier to stem cell transplantation, bioreactor function and autologous liver recovery, suggesting removal or antagonism of these factors may be appropriate therapeutic strategies. Since apoptosis has been implicated in the pathogenesis of a number of liver diseases including liver failure we proposed that it may be one of the mechanisms by which plasma is toxic to hepatocytes. We developed and validated a model using primary human hepatocytes to investigate if plasma from patients with acute and acute-on-chronic liver disease was pro-apoptotic. Compared with normal plasma, acute liver failure plasma induced apoptosis whereas plasma from patients with acutely-decompensated chronic liver disease did not. Having identified that acute-liver failure plasma was pro-apoptotic we investigated the pathway via which the apoptosis was mediated by using specific inhibitors of caspases, key components of the death receptor and mitochondrial pathways. We found that apoptosis was induced via a pathway involving caspase 8 and caspase 3, suggesting involvement of the death-receptor pathway. We investigated the effects of Caspase inhibition as a therapeutic option in acute liver failure by using an established animal model but did not find an improved outcome in treated animals. We also investigated the effects of treatment with molecular adsorbent dialysis (MARS) on the pro-apoptotic effects of plasma and found MARS dialysis improved biochemical parameters, indicating effective removal of albumin-bound molecules, but the apoptotic effects of the patients' plasma were unchanged.
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- 2012
3. Association of Genetic Variants in NUDT15 With Thiopurine-Induced Myelosuppression in Patients With Inflammatory Bowel Disease
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Walker, GJ, Harrison, JW, Heap, GA, Voskuil, MD, Andersen, V, Anderson, CA, Ananthakrishnan, AN, Barrett, JC, Beaugerie, L, Bewshea, CM, Cole, AT, Cummings, FR, Daly, MJ, Ellul, P, Fedorak, RN, Festen, EAM, Florin, TH, Gaya, DR, Halfvarson, J, Hart, AL, Heerasing, NM, Hendy, P, Irving, PM, Jones, SE, Koskela, J, Lindsay, JO, Mansfield, JC, McGovern, D, Parkes, M, Pollok, RCG, Ramakrishnan, S, Rampton, DS, Rivas, MA, Russell, RK, Schultz, M, Sebastian, S, Seksik, P, Singh, A, So, K, Sokol, H, Subramaniam, K, Todd, A, Annese, V, Weersma, RK, Xavier, R, Ward, R, Weedon, MN, Goodhand, JR, Kennedy, NA, Ahmad, T, Holden, AL, Andrews, J, Auth, M, Babu, S, Bampton, P, Banim, P, Barnes, T, Basude, D, Beckly, J, Bell, A, Bell, S, Bhandari, P, Bloom, S, Border, D, Bredin, F, Brookes, MJ, Brown, M, Calvert, C, Campbell, D, Chanchlani, N, Chaudhary, B, Chaudhary, R, Chung-Faye, G, Colleypriest, B, Connor, S, Cooney, R, Cooper, S, Creed, TJ, Croft, N, Cullen, S, D'Amato, M, Dalal, H, Daneshmend, TK, Das, D, Delaney, M, Desilva, S, Dhar, A, Dharmasiri, S, Direkze, N, Dunckley, P, Elphick, D, Everett, SM, Feeney, M, Fell, J, Foley, S, Franke, A, Gavin, D, Gee, I, Ghosh, D, Goldsmith, C, Gorard, D, Gordon, JN, Gore, S, Green, J, Grimes, D, Hamill, G, Harbord, M, Hart, J, Hawkey, C, Iqbal, T, Ireland, A, Johnson, M, Jones, C, Kanegasundaram, S, Karban, A, Katsanos, KH, Kiparissi, F, Kirkham, S, Lal, S, Langlands, S, Lawrance, IC, Lees, CW, Lev-Tzion, R, Levison, S, Lewis, SJ, Li, A, Limdi, J, Lin, S, Lobo, A, Lockett, M, Loehry, J, MacDonald, C, MacFaul, G, Mahmood, T, Mann, S, Mawdsley, J, Mazhar, Z, McGovern, JF, McNair, A, Modi, A, Monahan, K, Moran, A, Morris, M-A, Mortimore, M, Mowat, C, Muhammed, R, Murray, CDR, Olivier, H, Orchard, TR, Panter, S, Patel, V, Phillips, R, Prasad, N, Preston, C, Radford-Smith, G, Rajasekhar, P, Roy, D, Saich, R, Satsangi, J, Schreiber, S, Sen, S, Shah, N, Shenderay, R, Shenoy, A, Shutt, J, Silverberg, M, Simmons, A, Simmons, J, Singh, S, Smith, M, Snook, JA, Sonwalker, S, Stevens, CR, Sturniolo, G, Subramanian, S, Thomas, A, Tighe, M, Torrente, F, Tremelling, M, Tsianos, E, Vani, D, Walsh, A, Watermeyer, G, Watts, D, Watts, G, Weaver, S, Wesley, E, Willmott, A, Yearsley, K, Zambar, V, Zeissig, S, University of Helsinki, Broad Institute, University of Helsinki, Complex Disease Genetics, Institute for Molecular Medicine Finland, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), and Simmons, A
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Male ,PREDICTOR ,AZATHIOPRINE ,Azathioprine ,Genome-wide association study ,CHILDREN ,S-METHYLTRANSFERASE ,SUSCEPTIBILITY ,Gastroenterology ,THERAPY ,Leukocyte Count ,0302 clinical medicine ,Crohn Disease ,Interquartile range ,Medicine ,Exome ,Pyrophosphatases ,11 Medical and Health Sciences ,0303 health sciences ,Thiopurine methyltransferase ,biology ,IBD Pharmacogenetics Study Group ,General Medicine ,3. Good health ,Editorial Commentary ,Cohort ,030211 gastroenterology & hepatology ,Female ,Life Sciences & Biomedicine ,medicine.drug ,Adult ,medicine.medical_specialty ,Adolescent ,MERCAPTOPURINE INTOLERANCE ,European Continental Ancestry Group ,3121 Internal medicine ,Polymorphism, Single Nucleotide ,White People ,03 medical and health sciences ,Young Adult ,Medicine, General & Internal ,Internal medicine ,General & Internal Medicine ,MANAGEMENT ,Humans ,POLYMORPHISMS ,030304 developmental biology ,ACUTE LYMPHOBLASTIC-LEUKEMIA ,Science & Technology ,business.industry ,Case-control study ,Odds ratio ,Methyltransferases ,Sequence Analysis, DNA ,Haplotypes ,3121 General medicine, internal medicine and other clinical medicine ,Case-Control Studies ,biology.protein ,Colitis, Ulcerative ,business ,Pharmacogenetics ,Genome-Wide Association Study - Abstract
Funding Information: reported serving as a consultant for AbbVie UK; receiving honoraria from Falk and AbbVie UK; receiving grants from Crohn’s & Colitis UK and Tillott’s Pharmaceuticals; having a fellowship from the UK National Institute for Health Research; and receiving travel reimbursement from Merck Sharp & Dohme and Norgine. Dr Heap reported receiving travel reimbursement from AbbVie; and being a current employee of AbbVie and owning stock in the company. Dr Andersen reported receiving personal fees from Merck Sharp & Dohme and Janssen. Dr Ananthakrishnan reported receiving a grant from Pfizer; and receiving personal fees from Takeda. Dr Beaugerie reported receiving advisory board fees from Allergan, Janssen, and Pfizer; receiving a grant from Hospira; and receiving grants and honoraria from AbbVie, Merck Sharp & Dohme, Ferring, Takeda, and Tillott’s Pharmaceuticals. Dr Cummings reported receiving personal fees from AbbVie, Takeda, Biogen, Janssen, Merck Sharp & Dohme, Amgen, Hakim Pharmaceuticals, and Pfizer/Hospira; and receiving grants from Takeda, Biogen, AstraZeneca, and Pfizer/Hospira. Dr Halfvarson reported receiving personal fees from AbbVie, Hospira, Janssen, Medivir, Merck Sharp & Dohme, Pfizer, RenapharmaVifor, Takeda, Tillott’s Pharmaceuticals, Celgene, Sandoz, and Shire; and receiving grants from Janssen, Merck Sharp & Dohme, and Takeda. Dr Hart reported receiving advisory board fees from AbbVie, Atlantic, Bristol-Myers Squibb, Celltrion, Janssen, Merck Sharp & Dohme, Pfizer, Shire, and Takeda; receiving honoraria from Falk and Ferring; and receiving a grant from Takeda. Dr Irving reported receiving personal fees from Janssen, AbbVie, Takeda, Ferring, Pfizer, Lilly, Merck Sharp & Dohme, Samsung, and Sandoz; and receiving grants from Takeda and Merck Sharp & Dohme. Dr Lindsay reported receiving advisory board fees from Atlantic Health, AbbVie UK/global, Merck Sharp & Dohme, Shire UK, Vifor Pharma, Ferring International, Celltrion, Takeda, Napp, Pfizer, and Janssen; serving as a consultant for AbbVie UK/global, Takeda, and Pfizer; receiving grants from Shire UK, AbbVie UK/global, Warner Chilcott, Funding Information: Takeda, Hospira, Ferring International, and Merck Sharp & Dohme; receiving honoraria from Takeda, Cornerstones US, Tillott’s Pharmaceuticals, Napp, Shire International, Janssen, AbbVie, and Pfizer; and receiving travel reimbursement from AbbVie UK, Merck Sharp & Dohme, Warner Chilcott, Takeda, and Shire International. Dr McGovern reported receiving grants from the National Institutes of Health, Helmsley Charitable Trust, and Janssen; and serving as a consultant for Pfizer, Q Biologics, Cidara, Gilead, and Janssen. Dr Seksik reported receiving advisory board fees from Astellas; receiving honoraria from Takeda, AbbVie, and Ferring; and receiving grants from Merck Sharp & Dohme and Biocodex. Dr Sokol reported receiving grants from Biocodex, Danone, and BiomX; serving as a consultant for Enterome, Takeda, AbbVie, Roche, Amgen, Danone, BiomX, Ferring, Bristol-Myers Squibb, Astellas, Merck Sharp & Dohme, Novartis, Tillott’s Pharmaceuticals, and Biose; and being the co-founder of Nextbiotix. Dr Annese reported receiving advisory board fees from Takeda, AbbVie, and Medtronic; and receiving honoraria from Janssen, Takeda, AbbVie, and Medtronic. Dr Weersma reported receiving grants from Takeda, Ferring, and Tramedico; and receiving personal fees from AbbVie. Dr Goodhand reported receiving honoraria from Falk, AbbVie, and Shield Therapeutics. Dr Kennedy reported serving as a consultant for Falk; receiving honoraria from Falk, Allergan, Pharmacosmos, and Takeda; and being a deputy editor of Alimentary Pharmacology & Therapeutics. Dr Ahmad reported receiving unrestricted grants, advisory board fees, speaker honoraria, and support to attend international meetings from AbbVie, Merck Sharp & Dohme, Janssen, Takeda, Ferring, Tillott’s Pharmaceuticals, Ferring, Pfizer, Napp, Celltrion, and Hospira. No other disclosures were reported. Funding Information: Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California), Alistair McNair, PhD (Queen Elizabeth Hospital, London, UK), Anita Modi, MD (Luton and Dunstable University Hospital, Luton, UK), Kevin Monahan, PhD (West Middlesex University Hospital, Middlesex, UK), Alex Moran, MD (Northern Devon Healthcare Trust, Barnstaple, UK), Mary-Anne Morris, MD (Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich, UK), Marianne Mortimore, MBBS (Mater Research Institute, University of Queensland, South Brisbane, Australia), Craig Mowat, MD (Ninewells Hospital, NHS Tayside, Dundee, UK), Rafeeq Muhammed, MD (Birmingham Children's Hospital, Birmingham, UK), Charles D. R. Murray, PhD (Royal Free Hospital, Royal Free London NHS Foundation Trust, London, UK), Hanlie Olivier (IBD Pharmacogenetics Group, University of Exeter, Exeter, UK), Timothy R. Orchard, DM (Imperial College Healthcare NHS Trust, London, UK), Simon Panter, MD (South Tyneside District Hospital, South Tyneside, UK), Vinod Patel, MBBS (Tameside and Glossop Integrated Care NHS Foundation Trust, Ashton-under-Lyne, UK), Rosemary Phillips, MD (Princess Alexandra Hospital, Essex, UK), Neeraj Prasad, MSc (Wrightington Hospital, Wrightington, UK), Cathryn Preston, MBChB (Bradford Royal Infirmary, Bradford, UK), Graham Radford-Smith, PhD (Royal Brisbane and Women’s Hospital, Brisbane, Australia), Praveen Rajasekhar, MD (Northumbria NHS Trust, Tyne and Wear, UK), Dipak Roy, PhD (Tameside and Glossop Integrated Care NHS Foundation Trust, Ashton-under-Lyne, UK), Rebecca Saich, PhD (Basingstoke and North Hampshire Hospital, Basingstoke, UK), Jack Satsangi, PhD (Western General Hospital, NHS Lothian, Edinburgh, UK), Stefan Schreiber, PhD (Kiel University, Kiel, Germany), Sandip Sen, MD (Royal Stoke University Hospital, Stoke-on-Trent, UK), Neil Shah, MD (Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK), Richard Shenderay, MBBS (Airedale NHS Foundation Trust, Keighley, UK), Acuth Shenoy, MD (Colchester Hospital University NHS Foundation Trust, Colchester, UK), James Shutt, DM (Dorset County Hospital NHS Foundation Trust, Dorchester, UK), Mark Silverberg, PhD (Mount Sinai Hospital, Toronto, Ontario, Canada), Alison Simmons, PhD (Oxford University Hospitals, Oxford, UK), Jonathan Simmons, DM (Royal Berkshire Hospital, Royal Berkshire NHS Foundation Trust, Reading, UK), Salil Singh, PhD (Bolton NHS Foundation Trust, Bolton, UK), Malcolm Smith, MBChB (Aberdeen Royal Infirmary, Aberdeen, UK), Mark Smith, MD (Shrewsbury and Telford Hospital NHS Trust, Shrewsbury, UK), Melissa Smith, MB (Royal Sussex County Hospital, Brighton, UK), Jonathon A. Snook, DPhil (Poole Hospital NHS Foundation Trust, Poole, UK), Sunil Sonwalker, MD (Calderdale Royal Hospital, Halifax, UK), Christine R. Stevens, PhD (Broad Institute, Harvard University, Cambridge, Massachusetts), Giacomo Sturniolo, PhD (Univerita di Padova, Padova, Italy), Sreedhar Subramanian, MD (Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK), Amanda Thomas, MBBS (Department of Gastroenterology, Royal Devon and Exeter Hospital NHS Foundation Trust, Exeter, UK), Mark Tighe, BM (Poole Hospital NHS Foundation Trust, Poole, UK), Franco Torrente, MD (Department of Gastroenterology, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK), Mark Tremelling, MD (Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich, UK), Epameinondas Tsianos, PhD (University Hospital of Ioannina, Ioannina, Greece), Deven Vani, MD (Mid Yorkshire Hospitals NHS Trust, Wakefield, UK), Alissa Walsh, MBBS (St Vincent’s Hospital, Sydney, Australia), Gillian Watermeyer, MBChB (Groote Schuur Hospital, Cape Town, South Africa), David Watts, MBChB (Forth Valley Royal Hospital, Larbert, UK), Gill Watts, MD (Wythenshawe Hospital, South Manchester, UK), Sean Weaver, PhD (Royal Bournemouth General Hospital, Bournemouth, UK), Emma Wesley, MBBS (Musgrove Park Hospital, Taunton and Somerset NHS Hospitals, Taunton, UK), Anne Willmott, MBChB (Leicester Royal Infirmary-Paediatric, Leicester, UK), Karen Yearsley, BM (Nevill Hall Hospital, Abergavenny, UK), Veena Zambar, MBBS (Leeds General Infirmary, Leeds, UK), and Sebastian Zeissig, MD (University Medical Center Schleswig-Hostein, Kiel, Germany). These individuals identified and recruited patient s to the study and provided comments on a draft of the manuscript. Funding Information: Adverse Events Consortium funded the sample collection and genotyping at the Broad Institute. The UK National Institute for Health Research provided research nurse support to facilitate recruitment at all UK research sites. Crohn’s & Colitis UK and forCrohns provided funding support and publicized this study to their members. The Exeter National Institute for Health Research Clinical Research Facility provided DNA storage and management. Institutional strategic support award WT097835MF from Wellcome Trust supported the management of the study. Samples from Cedars-Sinai were collected and processed through the MIRIAD biobank that was funded by grant P01DK046763 from the National Institutes of Health. Publisher Copyright: © 2019 American Medical Association. All rights reserved. IMPORTANCE Use of thiopurines may be limited by myelosuppression. TPMT pharmacogenetic testing identifies only 25% of at-risk patients of European ancestry. Among patients of East Asian ancestry, NUDT15 variants are associated with thiopurine-induced myelosuppression (TIM). OBJECTIVE To identify genetic variants associated with TIM among patients of European ancestry with inflammatory bowel disease (IBD). DESIGN, SETTING, AND PARTICIPANTS Case-control study of 491 patients affected by TIM and 679 thiopurine-tolerant unaffected patients who were recruited from 89 international sites between March 2012 and November 2015. Genome-wide association studies (GWAS) and exome-wide association studies (EWAS) were conducted in patients of European ancestry. The replication cohort comprised 73 patients affected by TIM and 840 thiopurine-tolerant unaffected patients. EXPOSURES Genetic variants associated with TIM. MAIN OUTCOMES AND MEASURES Thiopurine-induced myelosuppression, defined as a decline in absolute white blood cell count to 2.5 x 10(9)/L or less or a decline in absolute neutrophil cell count to 1.0 x 10(9)/L or less leading to a dose reduction or drug withdrawal. RESULTS Among 1077 patients (398 affected and 679 unaffected; median age at IBD diagnosis, 31.0 years [interquartile range, 21.2 to 44.1 years]; 540 [50%] women; 602 [56%] diagnosed as having Crohn disease), 919 (311 affected and 608 unaffected) were included in the GWAS analysis and 961 (328 affected and 633 unaffected) in the EWAS analysis. The GWAS analysis confirmed association of TPMT (chromosome 6, rs11969064) with TIM (30.5% [95/311] affected vs 16.4% [100/608] unaffected patients; odds ratio [OR], 2.3 [95% CI, 1.7 to 3.1], P = 5.2 x 10(-9)). The EWAS analysis demonstrated an association with an in-frame deletion in NUDT15 (chromosome 13, rs746071566) and TIM (5.8% [19/328] affected vs 0.2% [1/633] unaffected patients; OR, 38.2 [95% CI, 5.1 to 286.1], P = 1.3 x 10(-8)), which was replicated in a different cohort (2.7% [2/73] affected vs 0.2% [2/840] unaffected patients; OR, 11.8 [95% CI, 1.6 to 85.0], P = .03). Carriage of any of 3 coding NUDT15 variants was associated with an increased risk (OR, 27.3 [95% CI, 9.3 to 116.7], P = 1.1 x 10(-7)) of TIM, independent of TPMT genotype and thiopurine dose. CONCLUSIONS AND RELEVANCE Among patients of European ancestry with IBD, variants in NUDT15 were associated with increased risk of TIM. These findings suggest that NUDT15 genotyping may be considered prior to initiation of thiopurine therapy; however, further study including additional validation in independent cohorts is required.
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- 2019
4. PTH-157 The Introduction of Biosimilar Infliximab (CT-P13) through A Managed Switching Programme Generates Significant Cost Savings with High Levels of Patient Satisfaction
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Rahmany, S, primary, Cotton, S, additional, Garnish, S, additional, McCabe, L, additional, Brown, M, additional, Saich, R, additional, Lloyd, D, additional, and Gordon, JN, additional
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- 2016
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5. PTU-073 In Patients with IBD Switching from Originator Infliximab (Remicade) to Biosimilar Infliximab (CT-P13) Is Safe and Effective
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Rahmany, S, primary, Cotton, S, additional, Garnish, S, additional, Brown, M, additional, Saich, R, additional, Lloyd, D, additional, and Gordon, JN, additional
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- 2016
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6. PMO-068 Timing of parenteral nutrition administration set changes: impact on incidence of catheter associated infections
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Driver, R, primary, Mistry, P, additional, Swain, D, additional, Colinese, E, additional, and Saich, R, additional
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- 2012
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7. What's new in ... The neurochemistry of schizophrenia
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Saich, R., Chapman, R., and Reynolds, G.P.
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The new millennium has already proved to be an exciting time in hepatobiliary disease. In the developed world, the epidemic of obesity leading to metabolic syndrome has aroused academic and commercial interest in non-alcoholic fatty liver disease (NAFLD). This update covers some of the most recent developments in hepatology.
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- 2004
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8. What's new in ... Gastroenterology
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Saich, R., Chapman, R., Chaudhary, R., and Ghosh, S.
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The new millennium has already proved to be an exciting time in hepatobiliary disease. In the developed world, the epidemic of obesity leading to metabolic syndrome has aroused academic and commercial interest in non-alcoholic fatty liver disease (NAFLD). This update covers some of the most recent developments in hepatology.
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- 2003
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9. What's new in ... Liver disorders
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Saich, R. and Chapman, R.
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The new millennium has already proved to be an exciting time in hepatobiliary disease. In the developed world, the epidemic of obesity leading to metabolic syndrome has aroused academic and commercial interest in non-alcoholic fatty liver disease (NAFLD). This update covers some of the most recent developments in hepatology. Author Biography Rebecca Saich MRCP, Centre for Hepatology, Royal Free and University College Hospital Medical School, London, UK. Roger Chapman MD FRCP, John Radcliffe Hospital and the University of Oxford, UK.
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- 2002
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10. PTU-062 Investment in a dedicated biosimilar ibd nurse and pharmacist facilitates provision of a high quality infliximab infusion service and reduces infusion-related costs
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Cotton, S, Garnish, S, Brown, M, Saich, R, Gordon, J, and Lloyd, D
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IntroductionWe instituted a biosimilar switch programme in September 2015 in adult IBD patients. Predicted cost savings were used to recruit a dedicated IBD nurse and pharmacist who supervised the switch and reviewed and updated pathways for administration of biologicals. Their appointments allowed completion of point of care assessments, standardised monitoring of drug levels and facilitated a switch from on site vial reconstitution of infliximab to pre-ordering of pre-filled bags.The aim of this study was to assess the impact of the IBD nurse and pharmacist on patient management, patient satisfaction and pharmacy costs.MethodData were reviewed over a 16 month period from the start of the biosimilar switch programme to the end of December 2016. As part of the programme, enhanced monitoring of patients including completion of disease activity scores (HBAI and SCCAI) and Patient Recorded Outcome (PRO) was performed at each infusion. Data were contemporaneously recorded. Patients were asked to complete a satisfaction questionnaire 6 months after they switched to biosimilar infliximab. Pharmacy records were interrogated and cost savings estimated using standard NHS salary and procurement costs.ResultsOver the review period 235 patients received infliximab. A total of 1182 HBAI and SCCAI assessments and 1115 PROs were completed and infliximab levels and dosing were monitored prior to each infusion. 74/235 (31%) of patients had their treatment altered as a direct result of these assessments with 60 patients having their infliximab dose or dose interval altered and 14 patients switching to an alternative biological.71 patients completed the satisfaction questionnaire. All were pleased (11%) or very pleased (89%) with their overall standard of care. Patients thought that their standard of management was the same (60%), better (20%) or much better (20%). They reported that their disease activity was the same (68%), better (26%) or much better (6%).Estimated cost savings from switching from on site vial reconstitution of infliximab to ordering pre-filled bags totalled £4280 over the review period as a result of staff time saved and reduced consumable costs. Additional review of pharmacy records identified incorrect drug charging with a subsequent refund of £12 000 to the Trust.ConclusionIntegration of a dedicated IBD nurse and pharmacist into the infliximab infusion service as part of a switch to biosimilar infliximab has helped achieve a responsive service with excellent patient satisfaction measures. It also achieved cost savings over and above those expected from the switch from originator to biosimilar infliximab.Disclosure of InterestNone Declared
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- 2017
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11. A biomarker-stratified comparison of top-down versus accelerated step-up treatment strategies for patients with newly diagnosed Crohn's disease (PROFILE): a multicentre, open-label randomised controlled trial.
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Noor NM, Lee JC, Bond S, Dowling F, Brezina B, Patel KV, Ahmad T, Banim PJ, Berrill JW, Cooney R, De La Revilla Negro J, de Silva S, Din S, Durai D, Gordon JN, Irving PM, Johnson M, Kent AJ, Kok KB, Moran GW, Mowat C, Patel P, Probert CS, Raine T, Saich R, Seward A, Sharpstone D, Smith MA, Subramanian S, Upponi SS, Wiles A, Williams HRT, van den Brink GR, Vermeire S, Jairath V, D'Haens GR, McKinney EF, Lyons PA, Lindsay JO, Kennedy NA, Smith KGC, and Parkes M
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- Adult, Humans, Male, Female, Infliximab therapeutic use, Azathioprine therapeutic use, Biomarkers, Immunologic Factors therapeutic use, Inflammation, Leukocyte L1 Antigen Complex, Crohn Disease diagnosis, Crohn Disease drug therapy, Crohn Disease complications
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Background: Management strategies and clinical outcomes vary substantially in patients newly diagnosed with Crohn's disease. We evaluated the use of a putative prognostic biomarker to guide therapy by assessing outcomes in patients randomised to either top-down (ie, early combined immunosuppression with infliximab and immunomodulator) or accelerated step-up (conventional) treatment strategies., Methods: PROFILE (PRedicting Outcomes For Crohn's disease using a moLecular biomarker) was a multicentre, open-label, biomarker-stratified, randomised controlled trial that enrolled adults with newly diagnosed active Crohn's disease (Harvey-Bradshaw Index ≥7, either elevated C-reactive protein or faecal calprotectin or both, and endoscopic evidence of active inflammation). Potential participants had blood drawn to be tested for a prognostic biomarker derived from T-cell transcriptional signatures (PredictSURE-IBD assay). Following testing, patients were randomly assigned, via a secure online platform, to top-down or accelerated step-up treatment stratified by biomarker subgroup (IBDhi or IBDlo), endoscopic inflammation (mild, moderate, or severe), and extent (colonic or other). Blinding to biomarker status was maintained throughout the trial. The primary endpoint was sustained steroid-free and surgery-free remission to week 48. Remission was defined by a composite of symptoms and inflammatory markers at all visits. Flare required active symptoms (HBI ≥5) plus raised inflammatory markers (CRP >upper limit of normal or faecal calprotectin ≥200 μg/g, or both), while remission was the converse-ie, quiescent symptoms (HBI <5) or resolved inflammatory markers (both CRP ≤ the upper limit of normal and calprotectin <200 μg/g) or both. Analyses were done in the full analysis (intention-to-treat) population. The trial has completed and is registered (ISRCTN11808228)., Findings: Between Dec 29, 2017, and Jan 5, 2022, 386 patients (mean age 33·6 years [SD 13·2]; 179 [46%] female, 207 [54%] male) were randomised: 193 to the top-down group and 193 to the accelerated step-up group. Median time from diagnosis to trial enrolment was 12 days (range 0-191). Primary outcome data were available for 379 participants (189 in the top-down group; 190 in the accelerated step-up group). There was no biomarker-treatment interaction effect (absolute difference 1 percentage points, 95% CI -15 to 15; p=0·944). Sustained steroid-free and surgery-free remission was significantly more frequent in the top-down group than in the accelerated step-up group (149 [79%] of 189 patients vs 29 [15%] of 190 patients, absolute difference 64 percentage points, 95% CI 57 to 72; p<0·0001). There were fewer adverse events (including disease flares) and serious adverse events in the top-down group than in the accelerated step-up group (adverse events: 168 vs 315; serious adverse events: 15 vs 42), with fewer complications requiring abdominal surgery (one vs ten) and no difference in serious infections (three vs eight)., Interpretation: Top-down treatment with combination infliximab plus immunomodulator achieved substantially better outcomes at 1 year than accelerated step-up treatment. The biomarker did not show clinical utility. Top-down treatment should be considered standard of care for patients with newly diagnosed active Crohn's disease., Funding: Wellcome and PredictImmune Ltd., Competing Interests: Declaration of interests NMN reports personal fees from Galapagos, Janssen, Lilly, SBK Healthcare, and Takeda outside the submitted work; and grants from Dr Falk, Pfizer, Pharmacosmos, and Tillotts Pharma outside the submitted work. JCL reports consultancy fees from AbbVie, AgPlus Diagnostics, PredictImmune, and C4X Discover outside the submitted work; and grants from GSK outside the submitted work. KVP reports personal fees from AbbVie, DrFalk, Galapagos, Janssen, PredictImmune, Pfizer, and Takeda outside the submitted work; grants from AbbVie, Celltrion, Dr Falk, Ferring, Janssen, Takeda, and Tillotts Pharma outside the submitted work; and fees from advisory board membership of AbbVie, Galapagos, Janssen, and Pfizer outside the submitted work. TA reports personal fees from Amgen, Celltrion, Janssen, Lilly, Pfizer, and Tillotts Pharma; and grants from Biogen, Celltrion, Galapagos, Nova Pharmaceuticals, Pfizer, Roche, and Takeda outside the submitted work. JWB reports personal fees from Janssen outside the submitted work. RC reports personal fees from AbbVie, Galapagos, and Lilly outside the submitted work, grants from Celltrion, Ferring, and Tillotts Pharma outside the submitted work; and fees from advisory board membership of AbbVie and Bristol Myers Squibb outside the submitted work. SD reports personal fees from AbbVie, Ferring, Janssen, and Takeda outside the submitted work; grants from AbbVie, Dr Falk, and Janssen, outside the submitted work; and fees from advisory board membership of AbbVie outside the submitted work. DD reports personal fees from Takeda outside the submitted work; and grants from AbbVie and Janssen outside the submitted work. PMI reports personal fees from AbbVie, Arena, Boehringer-Ingelheim, BMS, Celgene, Celltrion, Dr Falk, Galapagos, Genentech, Gilead, Hospira, Janssen, Lilly, MSD, Pfizer, Prometheus, Sandoz, Samsung Bioepis, Sapphire Medical, Takeda, Topivert, VH2, Vifor Pharma, and Warner Chilcott outside the submitted work; and grants from AbbVie and Takeda outside the submitted work. AJK reports personal fees from AbbVie, Galapagos, and Takeda outside the submitted work; grants from AbbVie, Janssen, and Tillotts Pharma outside the submitted work; and fees from advisory board membership of AbbVie and Janssen outside the submitted work. CM reports grants from Janssen outside the submitted work. CSP reports personal fees from Dr Falk outside the submitted work. TR reports personal fees from AbbVie, Arena, Aslan, AstraZeneca, Boehringer-Ingelheim, BMS, Eli Lilly, Ferring, Galapagos, Gilead, GSK, Heptares, LabGenius, Novartis, Numab, Janssen, Pfizer, Roche, Takeda, UCB, and XAP therapeutics outside the submitted work; grants from AbbVie outside the submitted work; and fees from data monitoring board membership of UCB outside the submitted work. SS reports personal fees from AbbVie, Celltrion, Dr Falk, Ipsen, Janssen, and Takeda outside the submitted work. HRTW reports fees from advisory board membership of Pfizer outside the submitted work. SV reports personal fees from AbbVie, Abivax, AbolerISPharma, AgomAb, Alimentiv (formerly Robarts Clinical Trials), Arena Pharmaceuticals, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Cytoki Pharma, Dr Falk Pharma, Ferring, Galapagos, Genentech-Roche, Gilead, GSK, Hospira, Imidomics, Janssen, J&J, Lilly, Materia Prima, Mestag Therapeutics, MiroBio, Morphic, MrMHealth, MSD, Mundipharma, Pfizer, Prodigest, Progenity, Prometheus, Surrozen, Takeda, Theravance, Tillotts Pharma, VectivBio, Ventyx, and Zealand Pharma outside the submitted work; and grants from AbbVie, Galapagos, J&J, Pfizer, and Takeda outside the submitted work. VJ reports personal fees from AbbVie, Alimentiv (formerly Robarts Clinical Trials), Arena Pharmaceuticals, Asahi Kasei Pharma, Asieris, AstraZeneca, Avoro Capital, BMS, Celltrion, Endpoint Health, Enthera, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, Gilde Healthcare, GSK, Genentech, Gilead, Innomar, JAMP, Janssen, Lilly, Merck, Metacrine, Mylan, Pandion, Pendopharm, Pfizer, Protagonist, Prometheus, Reistone Biopharma, Roche, Roivant, Sandoz, SCOPE, Second Genome, Sorriso Pharmaceuticals, Takeda, Teva, Topivert, Ventyx, and Vividion outside the submitted work; and fees from advisory board membership of AbbVie, Alimentiv (formerly Robarts Clinical Trials), Arena Pharmaceuticals, Asahi Kasei Pharma, Asieris, AstraZeneca, BMS, Celltrion, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, Gilde Healthcare, GSK, Genentech, Gilead, Innomar, JAMP, Janssen, Lilly, Merck, Metacran, Mylan, Pandion, Pendopharm, Pfizer, Protagonist, Prometheus, Reistone Biopharma, Roche, Sandoz, SCOPE, Second Genome, Sorriso Pharmaceuticals, Takeda, Teva, Topivert, Ventyx, and Vividion outside the submitted work. GRDH reports personal fees from AbbVie, Alimentiv, AstraZeneca, Immunic, J&J, Lilly, Pfizer, Takeda, Tillotts, and Ventyx outside the submitted work; grants from AbbVie, BMS, Lilly, Pfizer, and Takeda outside the submitted work; and fees from advisory board membership of AstraZeneca, Galapagos, and Seres Health outside the submitted work. EFM reports being a co-founder and receiving consultancy fees from PredictImmune; and holds PredictImmune stock or stock options. PAL reports being a co-founder and receiving consultancy fees from PredictImmune; and holds PredictImmune stock or stock options. JOL reports personal fees from AbbVie, Atlantic Healthcare, Bristol Meyer Squibb, Celgene, Celltrion, Engytix, Eli Lilly, Ferring, Galapagos, Gilead, GSK, Janssen, MSD, Norgine, Pfizer, Shire, and Takeda outside the submitted work; and grants from AbbVie, Ferring, Gilead, Takeda, and Shire outside the submitted work. NAK reports personal fees from Amgen, Bristol Myers Squibb, Celltrion, Falk, Galapagos, Janssen, Pfizer, Pharmacosmos, Takeda, and Tillotts Pharma outside the submitted work; and reports data monitoring board membership for the BEACON study outside the submitted work. KGCS reports being a co-founder and receiving consultancy fees from Predictimmune; consultancy fees from GSK outside the submitted work; and holds PredictImmune stock or stock options. MP reports personal fees from Janssen and Takeda outside the submitted work; and grants from AstraZeneca, Galapagos, Gilead, and Pfizer outside the submitted work. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2024
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12. Is Newborn Screening the Ultimate Strategy to Reduce Diagnostic Delays in Pompe Disease? The Parent and Patient Perspective.
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Saich R, Brown R, Collicoat M, Jenner C, Primmer J, Clancy B, Holland T, and Krinks S
- Abstract
Pompe disease (PD) is a rare, autosomal-recessively inherited deficiency in the enzyme acid α-glucosidase. It is a spectrum disorder; age at symptom onset and rate of deterioration can vary considerably. In affected infants prognosis is poor, such that without treatment most infants die within the first year of life. To lose a baby in their first year of life to a rare disease causes much regret, guilt, and loneliness to parents, family, and friends. To lose a baby needlessly when there is an effective treatment amplifies this sadness. With so little experience of rare disease in the community, once a baby transfers to their home they are subject to a very uncertain and unyielding diagnostic journey while their symptomology progresses and their health deteriorates. With a rare disease like PD, the best opportunity to diagnose a baby is at birth. PD is not yet included in the current newborn screening (NBS) panel in Australia. Should it be? In late 2018 the Australian Pompe Association applied to the Australian Standing committee on Newborn Screening to have PD included. The application was not upheld. Here we provide an overview of the rationale for NBS, drawing on the scientific literature and perspectives from The Australian Pompe Association, its patients and their families. In doing so, we hope to bring a new voice to this very important debate., Competing Interests: Conflicts of InterestThe authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results., (© 2020 by the authors.)
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- 2020
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13. The role of patient advocacy organizations in shaping medical research: the Pompe model.
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House T, O'Donnell K, Saich R, Di Pietro F, Broekgaarden R, Muir A, and Schaller T
- Abstract
The Pompe model is the term used by the Pompe community to describe the relationship that exists between the patient community, the medical/scientific community, and industry. The development of the Pompe model represented a new paradigm for the involvement of patients in new treatments-and also for scientists and pharmaceutical companies. It saw patients developing a sense of agency, of involvement in the process of treatment development rather than powerless recipients or (if lucky) occasional spectators. At the same time, as described below, it benefited the other partners in the process with the result that the different components of the model added up to more than the sum of their parts. However, in order for this to happen, each part had to undergo a transformation in mindset. The development of enzyme replacement therapy (ERT) for Pompe disease represented a unique set of circumstances and individuals that helped to bring about this change and, in doing so, created a model that has had far wider applications., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.
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- 2019
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14. Primary sclerosing cholangitis, autoimmune hepatitis and overlap syndromes in inflammatory bowel disease.
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Saich R and Chapman R
- Subjects
- Comorbidity, Haplotypes, Humans, Risk Factors, Syndrome, Cholangitis, Sclerosing genetics, Cholangitis, Sclerosing immunology, Cholangitis, Sclerosing physiopathology, Cholangitis, Sclerosing therapy, Hepatitis, Autoimmune genetics, Hepatitis, Autoimmune immunology, Hepatitis, Autoimmune physiopathology, Hepatitis, Autoimmune therapy, Inflammatory Bowel Diseases genetics, Inflammatory Bowel Diseases immunology, Inflammatory Bowel Diseases physiopathology, Inflammatory Bowel Diseases therapy
- Abstract
Primary sclerosing cholangitis (PSC) is a chronic progressive disorder of unknown aetiology characterised by chronic inflammation and stricture formation of the biliary tree. Symptoms include itch and lethargy and in advanced cases cholangitis and end-stage liver disease, however increasing numbers of asymptomatic individuals are being identified. The disease is rare in the general population but is strongly associated with inflammatory bowel disease (IBD) affecting up to 5% of patients with ulcerative colitis, with a slightly lower prevalence (up to 3.6%) in Crohn's disease. The strength of this association means that the vast majority (> 90%) of patients with PSC also have IBD, although many may have only mild gastro-intestinal symptoms. Usually IBD presents before PSC, although vice-versa can occur and the onset of both conditions can be separated in some cases by many years. Mean age of diagnosis of PSC is in the fifth decade of life with a strong male predominance. Risk is increased in those with a family history of PSC, suggesting a genetic predisposition and the disease is almost exclusive to non-smokers. The ulcerative colitis associated with PSC is characteristically mild, runs a quiescent course, is associated with rectal sparing, more severe right sided disease, backwash ileitis and has a high risk of pouchitis post-colectomy. Most worrisome is the high risk of colorectal malignancy which necessitates routine colonoscopic surveillance. Cholangiocarcinoma is also a frequent complication of PSC with a 10%-15% lifetime risk of developing this condition. Treatment with high dose ursodeoxycholic acid offers some chemoprotective effects against colorectal malignancy and may decrease symptoms, biochemical and histological progression of liver disease. Small duct PSC patients characteristically have normal cholangiography, and liver biopsy is required for diagnosis, it appears to have a more favourable prognosis. Autoimmune Hepatitis (AIH) is also more prevalent in patients with IBD, with up to 16% of patients with AIH also having ulcerative colitis. A small subgroup of patients have a AIH-PSC overlap syndrome and the management of these patients depends on liver histology, serum IgM levels, autoantibodies, degree of biochemical cholestasis and cholangiography as some of these patients may respond to immunosuppression.
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- 2008
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15. Characterization of pro-apoptotic effect of liver failure plasma on primary human hepatocytes and its modulation by molecular adsorbent recirculation system therapy.
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Saich R, Selden C, Rees M, and Hodgson H
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- Adult, Aged, Apoptosis Regulatory Proteins blood, Caspase 3 metabolism, Caspase 8 metabolism, Caspase Inhibitors, Cells, Cultured, Chronic Disease, Cysteine Proteinase Inhibitors pharmacology, Female, Hepatocytes drug effects, Hepatocytes enzymology, Hepatocytes pathology, Humans, Liver Failure blood, Liver Failure metabolism, Liver Failure pathology, Liver Failure, Acute blood, Liver Failure, Acute metabolism, Liver Failure, Acute pathology, Male, Middle Aged, Apoptosis drug effects, Apoptosis Regulatory Proteins metabolism, Hepatocytes metabolism, Liver Failure therapy, Liver Failure, Acute therapy, Sorption Detoxification methods
- Abstract
Plasma from patients with liver failure may contain toxic molecules that cause hepatocyte apoptosis and worsen liver disease, suggesting that removal of pro-apoptotic factors is an appropriate therapeutic strategy. We investigated the apoptosis of human hepatocytes induced by plasma from patients with both acute and acute-on-chronic liver disease, and the effect of molecular adsorbent dialysis (molecular adsorbent recirculation system [MARS] dialysis) on this. Apoptotic effects of acute and acute-on-chronic liver failure plasmas from 46 patients were assessed on cultured primary human hepatocytes using terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) labeling and caspase 3 activation. In 11 patients undergoing MARS dialysis, the pro-apoptotic effect of their plasma was analyzed before and after therapy. Acute liver failure plasma induced more apoptosis than normal plasma (within 4-6 h of culture, a 2.5-fold increase by TUNEL labeling, 1.8-fold by caspase 3 activation), via a pathway involving caspase 8, suggesting involvement of the death-receptor pathway. However, not all acute liver failure plasmas were significantly more pro-apoptotic than normal plasma. Plasma from patients with acutely decompensated chronic liver disease induced apoptosis at the same rate as normal plasma. MARS dialysis improved biochemical parameters indicating effective removal of albumin-bound molecules, but the apoptotic effects of the plasma were unchanged. Thus, plasma of patients with acute liver failure, compared to normal plasma, induced increased apoptosis of primary human hepatocytes by a caspase-8- and caspase-3-dependent pathway. The apoptosis induced in the presence of liver failure plasma was not reduced by MARS dialysis.
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- 2007
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16. 13C-methacetin breath test shortened: 2-point-measurements after 15 minutes reliably indicate the presence of liver cirrhosis.
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Schneider A, Caspary WF, Saich R, Dietrich CF, Sarrazin C, Kuker W, and Braden B
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- Adult, Aged, Biopsy, Breath Tests methods, Carbon Isotopes, Cytochrome P-450 Enzyme System metabolism, Female, Follow-Up Studies, Humans, Liver enzymology, Liver pathology, Liver Cirrhosis enzymology, Male, Middle Aged, Sensitivity and Specificity, Severity of Illness Index, Spectroscopy, Near-Infrared, Time Factors, Acetamides, Liver Cirrhosis diagnosis
- Abstract
Background and Goals: The 13C-methacetin breath test (MBT) measures the activity of the cytochrome P450 dependent enzyme system and has been developed to assess the functional hepatic mass. We evaluated simple modifications of the 13C-MBT to further increase its practicability and therefore clinical acceptance., Study: One hundred and four patients with different chronic liver diseases (including 35 patients with histologically proven cirrhosis) and 65 healthy controls underwent the 13C-MBT. Breath test results of 2-point measurements were compared with conventional breath test results (cumulative recovery after 30 min) and liver histology., Results: The 2-point-measurement at 0 and 15 minutes (with a cut-off <14.6 per thousand delta over baseline) had 92.6% sensitivity and 94.1% specificity in identifying the presence of cirrhosis compared with liver histology. The 2-point-measurements at 5 and 10 minutes also provided good discrimination between cirrhotic and noncirrhotic patients., Conclusions: The 13C-MBT using 2-point-measurement of breath samples at baseline and after 15 minutes reliably indicates decreased liver function in liver cirrhosis. This simplification of the 13C-MBT will increase practicability and cost efficiency, thus facilitating its clinical acceptability.
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- 2007
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17. During thioacetamide-induced acute liver failure, the proliferative response of hepatocytes to thyroid hormone is maintained, indicating a potential therapeutic approach to toxin-induced liver disease.
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Malik R, Saich R, Rahman T, and Hodgson H
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- Animals, Dose-Response Relationship, Drug, Hepatocytes pathology, Liver Failure, Acute chemically induced, Liver Regeneration drug effects, Male, Mitogens pharmacology, Random Allocation, Rats, Thioacetamide, Cell Proliferation drug effects, Hepatocytes drug effects, Liver Failure, Acute pathology, Triiodothyronine pharmacology
- Abstract
In toxic liver injury, proliferation of preexisting hepatocytes helps restore liver mass and function. While loss of liver mass per se stimulates hepatocyte proliferation, exogenous mitogens have a potential role in enhancing liver regeneration. The aim of this study was to characterize the effects of the mitogen, tri-iodothyonine, on the regenerative capacity of hepatocytes during thioacetamide-induced liver failure. Rats received (two) thioacetamide injections and, 12 hr later, either tri-iodothyonine or vehicle-only control. Liver cell proliferation was assessed and comparison made with other control groups receiving tri-iodothyonine or vehicle only. In rats with thioacetamide-induced hepatitis the proportion of hepatocytes in S-phase was greater in the tri-iodothyonine group (27+/-3.5%) compared to the vehicle-only group (20+/-2.5%; P < 0.05), with, notably, a greater number of midzonal (BrdU) positive hepatocytes in the tri-iodothyonine group. We conclude that the ability of hepatocytes in the midzonal areas of rat liver to proliferate in response to tri-iodothyonine is maintained during severe acute toxic injury.
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- 2006
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18. Benign recurrent intrahepatic cholestasis with secondary renal impairment treated with extracorporeal albumin dialysis.
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Saich R, Collins P, Ala A, Standish R, and Hodgson H
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- Adult, Cholestasis, Intrahepatic complications, Humans, Male, Recurrence, Serum Albumin metabolism, Acute Kidney Injury etiology, Cholestasis, Intrahepatic therapy, Sorption Detoxification methods
- Abstract
Benign recurrent intrahepatic cholestasis (BRIC) is a rare autosomal recessive condition characterized by intermittent episodes of pruritus and jaundice that may last days to months. Treatment is often ineffective and symptoms, particularly pruritus, can be severe. Extracorporeal albumin dialysis (molecular adsorbent recycling system, MARS) is a novel treatment which removes albumin bound toxins including bilirubin and bile salts. We describe a case of a 34-year-old man with BRIC and secondary renal impairment who, having failed standard medical therapy, was treated with MARS. The treatment immediately improved his symptoms, renal and liver function tests and appeared to terminate the episode of cholestasis. We conclude that MARS is a safe and effective treatment for BRIC with associated renal impairment.
- Published
- 2005
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