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1
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Radu AF, Bungau SG, Corb Aron RA, Tarce AG, Bodog R, Bodog TM, Radu A. Deciphering the Intricate Interplay in the Framework of Antibiotic-Drug Interactions: A Narrative Review. Antibiotics (Basel) 2024; 13:938. [PMID: 39452205 PMCID: PMC11505481 DOI: 10.3390/antibiotics13100938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 09/20/2024] [Accepted: 10/04/2024] [Indexed: 10/26/2024] Open
Abstract
Drug interactions are a significant and integral part of the concept of medication-related adverse events, whether referring to potential interactions or those currently observed in real-world conditions. The high global consumption of antibiotics and their pharmacokinetic and pharmacodynamic mechanisms make antibiotic-drug interactions a key element that requires continuous study due to their clinical relevance. In the present work, the current state of knowledge on antibiotic-drug interactions, which are less studied than other drug-drug interactions despite their frequent use in acute settings, has been consolidated and updated. The focus was on the interactions of the commonly used antibiotics in clinical practice, on the characteristics of the geriatric population susceptible to interactions, and on the impact of online drug interaction checkers. Additionally, strategies for optimizing the management of these interactions, including spacing out administrations, monitoring, or avoiding certain combinations, are suggested. Sustained research and careful monitoring are critical for improving antibiotic safety and efficacy, especially in susceptible populations, to enhance precision in managing antibiotic-drug interactions.
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Affiliation(s)
- Andrei-Flavius Radu
- Doctoral School of Biological and Biomedical Sciences, University of Oradea, 410087 Oradea, Romania; (A.-F.R.); (R.B.); (T.M.B.)
- Department of Preclinical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania;
| | - Simona Gabriela Bungau
- Doctoral School of Biological and Biomedical Sciences, University of Oradea, 410087 Oradea, Romania; (A.-F.R.); (R.B.); (T.M.B.)
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 410028 Oradea, Romania
| | - Raluca Anca Corb Aron
- Department of Preclinical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania;
| | - Alexandra Georgiana Tarce
- Medicine Program of Study, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania;
| | - Ruxandra Bodog
- Doctoral School of Biological and Biomedical Sciences, University of Oradea, 410087 Oradea, Romania; (A.-F.R.); (R.B.); (T.M.B.)
| | - Teodora Maria Bodog
- Doctoral School of Biological and Biomedical Sciences, University of Oradea, 410087 Oradea, Romania; (A.-F.R.); (R.B.); (T.M.B.)
| | - Ada Radu
- Doctoral School of Biological and Biomedical Sciences, University of Oradea, 410087 Oradea, Romania; (A.-F.R.); (R.B.); (T.M.B.)
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 410028 Oradea, Romania
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Prasad P, Sharma S, Mohanasundaram S, Agarwal A, Verma H. Tuberculosis in kidney transplant candidates and recipients. World J Transplant 2024; 14:96225. [PMID: 39295970 PMCID: PMC11317863 DOI: 10.5500/wjt.v14.i3.96225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 06/06/2024] [Accepted: 07/04/2024] [Indexed: 07/31/2024] Open
Abstract
Tuberculosis (TB) is the leading cause of infectious mortality and morbidity in the world, second only to coronavirus disease 2019. Patients with chronic kidney disease and kidney transplant recipients are at a higher risk of developing TB than the general population. Active TB is difficult to diagnose in this population due to close mimics. All transplant candidates should be screened for latent TB infection and given TB prophylaxis. Patients who develop active TB pre- or post-transplantation should receive multidrug combination therapy of antitubercular therapy for the recommended duration with optimal dose modification as per glomerular filtration rate.
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Affiliation(s)
- Pallavi Prasad
- Department of Nephrology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi 110029, Delhi, India
| | - Sourabh Sharma
- Department of Nephrology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi 110029, Delhi, India
| | | | - Anupam Agarwal
- Department of Nephrology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi 110029, Delhi, India
| | - Himanshu Verma
- Department of Nephrology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi 110029, Delhi, India
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3
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Mohamed ME, Saqr A, Staley C, Onyeaghala G, Teigen L, Dorr CR, Remmel RP, Guan W, Oetting WS, Matas AJ, Israni AK, Jacobson PA. Pharmacomicrobiomics: Immunosuppressive Drugs and Microbiome Interactions in Transplantation. Transplantation 2024; 108:1895-1910. [PMID: 38361239 PMCID: PMC11327386 DOI: 10.1097/tp.0000000000004926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/17/2024]
Abstract
The human microbiome is associated with human health and disease. Exogenous compounds, including pharmaceutical products, are also known to be affected by the microbiome, and this discovery has led to the field of pharmacomicobiomics. The microbiome can also alter drug pharmacokinetics and pharmacodynamics, possibly resulting in side effects, toxicities, and unanticipated disease response. Microbiome-mediated effects are referred to as drug-microbiome interactions (DMI). Rapid advances in the field of pharmacomicrobiomics have been driven by the availability of efficient bacterial genome sequencing methods and new computational and bioinformatics tools. The success of fecal microbiota transplantation for recurrent Clostridioides difficile has fueled enthusiasm and research in the field. This review focuses on the pharmacomicrobiome in transplantation. Alterations in the microbiome in transplant recipients are well documented, largely because of prophylactic antibiotic use, and the potential for DMI is high. There is evidence that the gut microbiome may alter the pharmacokinetic disposition of tacrolimus and result in microbiome-specific tacrolimus metabolites. The gut microbiome also impacts the enterohepatic recirculation of mycophenolate, resulting in substantial changes in pharmacokinetic disposition and systemic exposure. The mechanisms of these DMI and the specific bacteria or communities of bacteria are under investigation. There are little or no human DMI data for cyclosporine A, corticosteroids, and sirolimus. The available evidence in transplantation is limited and driven by small studies of heterogeneous designs. Larger clinical studies are needed, but the potential for future clinical application of the pharmacomicrobiome in avoiding poor outcomes is high.
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Affiliation(s)
- Moataz E Mohamed
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN
| | - Abdelrahman Saqr
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN
| | | | - Guillaume Onyeaghala
- Hennepin Healthcare Research Institute, Minneapolis, MN
- Department of Medicine, University of Minnesota, Minneapolis, MN
| | - Levi Teigen
- Department of Food Science and Nutrition, University of Minnesota, St Paul, MN
| | - Casey R Dorr
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN
- Hennepin Healthcare Research Institute, Minneapolis, MN
- Department of Medicine, University of Minnesota, Minneapolis, MN
- Department of Medicine, Hennepin Healthcare, Minneapolis, MN
| | - Rory P Remmel
- Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN
| | - Weihua Guan
- Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN
| | - William S Oetting
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN
| | - Arthur J Matas
- Department of Surgery, University of Minnesota, Minneapolis, MN
| | - Ajay K Israni
- Hennepin Healthcare Research Institute, Minneapolis, MN
- Department of Medicine, Hennepin Healthcare, Minneapolis, MN
- Department of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN
| | - Pamala A Jacobson
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN
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4
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McAteer J, Tamma PD. Diagnosing and Managing Urinary Tract Infections in Kidney Transplant Recipients. Infect Dis Clin North Am 2024; 38:361-380. [PMID: 38729666 PMCID: PMC11090456 DOI: 10.1016/j.idc.2024.03.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/12/2024]
Abstract
In the article, the authors review antibiotic treatment options for both acute uncomplicated UTI and complicated UTI. In addition, they review alternative regimens which are needed in the setting of drug-resistant pathogens including vancomycin-resistant Enterococcus, -extended-spectrum beta-lactamase-producing Enterobacterales (ESBL-E), carbapenem-resistant Enterobacterales, and carbapenem-resistant Pseudomonas, which are encountered with more frequency.
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Affiliation(s)
- John McAteer
- Division of Pediatric Nephrology, Johns Hopkins University School of Medicine; Division of Pediatric Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Pranita D Tamma
- Division of Pediatric Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
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5
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Yudhawati R, Wicaksono NF. Immunomodulatory Effects of Fluoroquinolones in Community-Acquired Pneumonia-Associated Acute Respiratory Distress Syndrome. Biomedicines 2024; 12:761. [PMID: 38672119 PMCID: PMC11048665 DOI: 10.3390/biomedicines12040761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 03/18/2024] [Accepted: 03/26/2024] [Indexed: 04/28/2024] Open
Abstract
Community-acquired pneumonia is reported as one of the infectious diseases that leads to the development of acute respiratory distress syndrome. The innate immune system is the first line of defence against microbial invasion; however, its dysregulation during infection, resulting in an increased pathogen load, stimulates the over-secretion of chemokines and pro-inflammatory cytokines. This phenomenon causes damage to the epithelial-endothelial barrier of the pulmonary alveoli and the leakage of the intravascular protein into the alveolar lumen. Fluoroquinolones are synthetic antimicrobial agents with immunomodulatory properties that can inhibit bacterial proliferation as well as exhibit anti-inflammatory activities. It has been demonstrated that the structure of fluoroquinolones, particularly those with a cyclopropyl group, exerts immunomodulatory effects. Its capability to inhibit phosphodiesterase activity leads to the accumulation of intracellular cAMP, which subsequently enhances PKA activity, resulting in the inhibition of transcriptional factor NF-κB and the activation of CREB. Another mechanism reported is the inhibition of TLR and ERK signalling pathways. Although the sequence of events has not been completely understood, significant progress has been made in comprehending the specific mechanisms underlying the immunomodulatory effects of fluoroquinolones. Here, we review the indirect immunomodulatory effects of FQs as an alternative to empirical therapy in patients diagnosed with community-acquired pneumonia.
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Affiliation(s)
- Resti Yudhawati
- Department of Pulmonology and Respiratory Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya 60132, Indonesia
- Department of Pulmonology and Respiratory Medicine, Universitas Airlangga Teaching Hospital, Surabaya 60015, Indonesia
- Department of Pulmonology and Respiratory Medicine, Dr. Soetomo General Hospital, Surabaya 60286, Indonesia
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Mathew JS, Philips CA. Drug Interactions and Safe Prescription Writing for Liver Transplant Recipients. J Clin Exp Hepatol 2023; 13:869-877. [PMID: 37693257 PMCID: PMC10483006 DOI: 10.1016/j.jceh.2023.03.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 03/28/2023] [Indexed: 09/12/2023] Open
Abstract
Immunosuppression optimization is central to graft function in liver transplant recipients. Post-transplantation patients develop new onset or worsening metabolic syndrome, are prone to atypical infections, and are at higher risk of developing cardiac and brain-related clinical events. In this context, liver transplant recipients are at risk of using multiple comedications alongside immunosuppressants. It is imperative for the transplant physician to understand the various drug-drug interactions that potentially reduce or promote toxicity of immunosuppression, as well as associated synergistic or antagonistic effects on extrahepatic organ systems. This comprehensive review discusses drug-drug interactions in liver transplant recipients and the impact and role of complementary and alternative medicines among individuals on immunosuppression.
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Affiliation(s)
- Johns S. Mathew
- Gastrointestinal, Hepatobiliary and Multi-organ Transplant Surgery, Center of Excellence in Gastrointestinal Sciences, Rajagiri Hospital, Aluva, Kerala 683112, India
| | - Cyriac A. Philips
- Clinical and Translational Hepatology & Monarch Liver Laboratory, The Liver Institute, Center for Excellence in Gastrointestinal Sciences, Rajagiri Hospital, Aluva, Kerala 683112, India
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7
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Chen J, Cai S, Li R, Xie J, Yang F, Liu T. Blockade of Cycloxygenase-2 ameliorates sepsis induced immune-suppression by regulating myeloid-derived suppressor cells. Int Immunopharmacol 2022; 104:108506. [PMID: 35008007 DOI: 10.1016/j.intimp.2021.108506] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 12/27/2021] [Accepted: 12/27/2021] [Indexed: 12/17/2022]
Abstract
BACKGROUND Myeloid-derived suppressor cells (MDSCs) and cyclooxy-genase-2 (COX-2)/Prostaglandin E2 (PGE2) axis are important contributors to sepsis-induced immune-suppression. The purpose of present study is to explore whether COX-2 inhibitor can improve immunological disorder after sepsis via regulating MDSCs. METHODS A ''two-hit'' model reflecting clinical sepsis development was performed. Cecal ligation and puncture (CLP) and Legionella pneumophila infection were used as the first and the second hit, respectively. NS398, a selective COX-2 inhibitor, was utilized to treat septic mice. The motality, bacterial counts in the lung, systematic inflammatory reaction and CD4 + T cells response after sepsis were assessed, so as the frequency and function of MDSCs. In some experiments, the number of MDSCs was manipulated by adoptive transfer or neutralizing antibody before induction of secondary infection. RESULTS Mice surviving CLP showed a marked expansion and activation of MDSCs in spleen, accompanied by suppressed proliferating capability, impaired secreting functionand increased apoptosis of CD4 + T cells. Majority of CLP survivors became succumbed to L. pneumophila invasion, associated with defective bacteria elimination ability. NS398 treatment was found to ameliorate these adverse outcomes significantly. CONCLUSION MDSCs contribute greatly to the sepsis-induced immune dysfunction. Inhibiting COX-2 may become a promising therapy that targets MDSCs-induced immunosuppression.
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Affiliation(s)
- Jiajun Chen
- Department of Trauma Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan, Hubei, PR China
| | - Shiqi Cai
- Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan, Hubei, PR China
| | - Renjie Li
- Department of Emergency Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan, Hubei, PR China
| | - Jie Xie
- Department of Trauma Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan, Hubei, PR China
| | - Fan Yang
- Department of Trauma Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan, Hubei, PR China
| | - Tao Liu
- Department of Trauma Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan, Hubei, PR China.
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8
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Salvadori M, Tsalouchos A. Microbiota, renal disease and renal transplantation. World J Transplant 2021; 11:16-36. [PMID: 33816144 PMCID: PMC8009061 DOI: 10.5500/wjt.v11.i3.16] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 01/06/2021] [Accepted: 02/12/2021] [Indexed: 02/06/2023] Open
Abstract
Aim of this frontier review has been to highlight the role of microbiota in healthy subjects and in patients affected by renal diseases with particular reference to renal transplantation. The microbiota has a relevant role in conditioning the healthy status and the diseases. In particular gut microbiota is essential in the metabolism of food and has a relevant role for its relationship with the immune system. The indigenous microbiota in patients with chronic renal failure is completely different than that of the healthy subjects and pathobionts appear. This abnormality in microbiota composition is called dysbiosis and may cause a rapid deterioration of the renal function both for activating the immune system and producing large quantity of uremic toxins. Similarly, after renal trans-plantation the microbiota changes with the appearance of pathobionts, principally in the first period because of the assumption of immunosuppressive drugs and antibiotics. These changes may deeply interfere with the graft outcome causing acute rejection, renal infections, diarrhea, and renal interstitial fibrosis. In addition, change in the microbiota may modify the metabolism of immuno-suppressive drugs causing in some patients the need of modifying the immunosuppressant dosing. The restoration of the indigenous microbiota after transplantation is important, either to avoiding the complications that impair the normal renal graft, and because recent studies have documented the role of an indigenous microbiota in inducing tolerance towards the graft. The use of prebiotics, probiotics, smart bacteria and diet modification may restore the indigenous microbiota, but these studies are just at their beginning and more data are needed to draw definitive conclusions.
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Affiliation(s)
- Maurizio Salvadori
- Department of Transplantation Renal Unit, Careggi University Hospital, Florence 50139, Italy
| | - Aris Tsalouchos
- Nephrology and Dialysis Unit, Saints Cosmas and Damian Hospital, Pescia 51017, Italy
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Degraeve AL, Moudio S, Haufroid V, Chaib Eddour D, Mourad M, Bindels LB, Elens L. Predictors of tacrolimus pharmacokinetic variability: current evidences and future perspectives. Expert Opin Drug Metab Toxicol 2020; 16:769-782. [PMID: 32721175 DOI: 10.1080/17425255.2020.1803277] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
INTRODUCTION In kidney transplantation, tacrolimus (TAC) is at the cornerstone of current immunosuppressive strategies. Though because of its narrow therapeutic index, it is critical to ensure that TAC levels are maintained within this sharp window through reactive adjustments. This would allow maximizing efficiency while limiting drug-associated toxicity. However, TAC high intra- and inter-patient pharmacokinetic (PK) variability makes it more laborious to accurately predict the appropriate dosage required for a given patient. AREAS COVERED This review summarizes the state-of-the-art knowledge regarding drug interactions, demographic and pharmacogenetics factors as predictors of TAC PK. We provide a scoring index for each association to grade its relevance and we present practical recommendations, when possible for clinical practice. EXPERT OPINION The management of TAC concentration in transplanted kidney patients is as critical as it is challenging. Recommendations based on rigorous scientific evidences are lacking as knowledge of potential predictors remains limited outside of DDIs. Awareness of these limitations should pave the way for studies looking at demographic and pharmacogenetic factors as well as gut microbiota composition in order to promote tailored treatment plans. Therapeutic approaches considering patients' clinical singularities may help allowing to maintain appropriate concentration of TAC.
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Affiliation(s)
- Alexandra L Degraeve
- Integrated Pharmacometrics, Pharmacogenomics and Pharmacokinetics (PMGK), Louvain Drug Research Institute (LDRI), Université Catholique De Louvain , Brussels, Belgium.,Metabolism and Nutrition Research Group (Mnut), Louvain Drug Research Institute (LDRI), Université Catholique De Louvain , Brussels, Belgium
| | - Serge Moudio
- Integrated Pharmacometrics, Pharmacogenomics and Pharmacokinetics (PMGK), Louvain Drug Research Institute (LDRI), Université Catholique De Louvain , Brussels, Belgium.,Louvain Centre for Toxicology and Applied Pharmacology (LTAP), Institut De Recherche Expérimentale Et Clinique (IREC), Université Catholique De Louvain , Brussels, Belgium
| | - Vincent Haufroid
- Louvain Centre for Toxicology and Applied Pharmacology (LTAP), Institut De Recherche Expérimentale Et Clinique (IREC), Université Catholique De Louvain , Brussels, Belgium.,Department of Clinical Chemistry, Cliniques Universitaires Saint-Luc , Brussels, Belgium
| | - Djamila Chaib Eddour
- Kidney and Pancreas Transplantation Unit, Cliniques Universitaires Saint-Luc , Brussels, Belgium
| | - Michel Mourad
- Kidney and Pancreas Transplantation Unit, Cliniques Universitaires Saint-Luc , Brussels, Belgium
| | - Laure B Bindels
- Metabolism and Nutrition Research Group (Mnut), Louvain Drug Research Institute (LDRI), Université Catholique De Louvain , Brussels, Belgium
| | - Laure Elens
- Integrated Pharmacometrics, Pharmacogenomics and Pharmacokinetics (PMGK), Louvain Drug Research Institute (LDRI), Université Catholique De Louvain , Brussels, Belgium.,Louvain Centre for Toxicology and Applied Pharmacology (LTAP), Institut De Recherche Expérimentale Et Clinique (IREC), Université Catholique De Louvain , Brussels, Belgium
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10
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Wang Y, Bahar MA, Jansen AME, Kocks JWH, Alffenaar JWC, Hak E, Wilffert B, Borgsteede SD. Improving antibacterial prescribing safety in the management of COPD exacerbations: systematic review of observational and clinical studies on potential drug interactions associated with frequently prescribed antibacterials among COPD patients. J Antimicrob Chemother 2020; 74:2848-2864. [PMID: 31127283 PMCID: PMC6814093 DOI: 10.1093/jac/dkz221] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Revised: 04/13/2019] [Accepted: 04/26/2019] [Indexed: 02/07/2023] Open
Abstract
Background Guidelines advise the use of antibacterials (ABs) in the management of COPD exacerbations. COPD patients often have multiple comorbidities, such as diabetes mellitus and cardiac diseases, leading to polypharmacy. Consequently, drug–drug interactions (DDIs) may frequently occur, and may cause serious adverse events and treatment failure. Objectives (i) To review DDIs related to frequently prescribed ABs among COPD patients from observational and clinical studies. (ii) To improve AB prescribing safety in clinical practice by structuring DDIs according to comorbidities of COPD. Methods We conducted a systematic review by searching PubMed and Embase up to 8 February 2018 for clinical trials, cohort and case–control studies reporting DDIs of ABs used for COPD. Study design, subjects, sample size, pharmacological mechanism of DDI and effect of interaction were extracted. We evaluated levels of DDIs and quality of evidence according to established criteria and structured the data by possible comorbidities. Results In all, 318 articles were eligible for review, describing a wide range of drugs used for comorbidities and their potential DDIs with ABs. DDIs between ABs and co-administered drugs could be subdivided into: (i) co-administered drugs altering the pharmacokinetics of ABs; and (ii) ABs interfering with the pharmacokinetics of co-administered drugs. The DDIs could lead to therapeutic failures or toxicities. Conclusions DDIs related to ABs with clinical significance may involve a wide range of indicated drugs to treat comorbidities in COPD. The evidence presented can support (computer-supported) decision-making by health practitioners when prescribing ABs during COPD exacerbations in the case of co-medication.
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Affiliation(s)
- Yuanyuan Wang
- Department of PharmacoTherapy, -Epidemiology & -Economics, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands
| | - Muh Akbar Bahar
- Department of PharmacoTherapy, -Epidemiology & -Economics, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands.,Faculty of Pharmacy, Hasanuddin University, Makassar, Indonesia
| | - Anouk M E Jansen
- Department of PharmacoTherapy, -Epidemiology & -Economics, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands
| | - Janwillem W H Kocks
- Department of General Practice and Elderly Care Medicine, Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Jan-Willem C Alffenaar
- Department of Clinical Pharmacy & Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.,Faculty of Medicine and Health, School of Pharmacy and Westmead Hospital, University of Sydney, Sydney, Australia
| | - Eelko Hak
- Department of PharmacoTherapy, -Epidemiology & -Economics, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands
| | - Bob Wilffert
- Department of PharmacoTherapy, -Epidemiology & -Economics, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands.,Department of Clinical Pharmacy & Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Sander D Borgsteede
- Department of Clinical Decision Support, Health Base Foundation, Houten, The Netherlands.,Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, The Netherlands
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11
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Guo Y, Lee H, Jeong H. Gut microbiota in reductive drug metabolism. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2020; 171:61-93. [PMID: 32475528 DOI: 10.1016/bs.pmbts.2020.04.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Gut bacteria are predominant microorganisms in the gut microbiota and have been recognized to mediate a variety of biotransformations of xenobiotic compounds in the gut. This review is focused on one of the gut bacterial xenobiotic metabolisms, reduction. Xenobiotics undergo different types of reductive metabolisms depending on chemically distinct groups: azo (-NN-), nitro (-NO2), alkene (-CC-), ketone (-CO), N-oxide (-NO), and sulfoxide (-SO). In this review, we have provided select examples of drugs in six chemically distinct groups that are known or suspected to be subjected to the reduction by gut bacteria. For some drugs, responsible enzymes in specific gut bacteria have been identified and characterized, but for many drugs, only circumstantial evidence is available that indicates gut bacteria-mediated reductive metabolism. The physiological roles of even known gut bacterial enzymes have not been well defined.
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Affiliation(s)
- Yukuang Guo
- Department of Pharmaceutical Sciences, Center for Biomolecular Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, United States
| | - Hyunwoo Lee
- Department of Pharmaceutical Sciences, Center for Biomolecular Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, United States.
| | - Hyunyoung Jeong
- Department of Pharmaceutical Sciences, Center for Biomolecular Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, United States.
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12
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Generics in transplantation medicine: Randomized comparison of innovator and substitution products containing mycophenolate mofetil
. Int J Clin Pharmacol Ther 2019; 57:506-519. [PMID: 31397274 PMCID: PMC6751510 DOI: 10.5414/cp203487] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/20/2019] [Indexed: 12/05/2022] Open
Abstract
Objective: Mycophenolate mofetil (MMF) is widely used as an immunosuppressant for the prophylaxis of acute organ rejection in recipients of solid organ transplants. Materials and methods: We have compared, in healthy subjects, the pharmacokinetics of mycophenolic acid when MMF was administered in the form of the innovator product CellCept (F. Hoffmann-La Roche Ltd.) or one of three commercially available generics, Renodapt (Biocon Ltd.), Mycept (Panacea Biotec), or Cellmune (Cipla Ltd.). The study was powered to detect a 20% difference in mean formulation performance measures, but not to formally evaluate bioequivalence. Geometric mean ratios of maximum concentrations (Cmax) and areas under plasma concentration-time curves were calculated. Results: Comparing generics against each other, the differences in point estimates of the geometric mean ratios of Cmax of two of the comparisons were either borderline within (Renodapt/Cellmune) or clearly outside (Mycept/Cellmune) a region of 80 – 125% around the reference mean, indicating that bioequivalence between these generics may be difficult to show. Conclusion: Physicians in the field of transplantation should be aware of the potential risk of altering the therapeutic outcome when switching from one preparation of MMF to another. ClinicalTrials.gov identifier: NCT02981290.
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Identification of Antibiotic Administration as a Potentially Novel Factor Associated With Tacrolimus Trough Variability in Kidney Transplant Recipients: A Preliminary Study. Transplant Direct 2019; 5:e485. [PMID: 31579813 PMCID: PMC6739039 DOI: 10.1097/txd.0000000000000930] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2019] [Revised: 07/18/2019] [Accepted: 07/19/2019] [Indexed: 01/06/2023] Open
Abstract
Supplemental Digital Content is available in the text. Tacrolimus trough variability is an important risk factor for kidney allograft outcomes. Recent evidence suggests that the gut microbiota is associated with tacrolimus dosing requirements and direct metabolism of tacrolimus. We hypothesize that administration of antibiotics, which are known to alter the gut microbiota, is associated with tacrolimus trough variability.
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Li X, Wang R, Liu Y, Liu Y, Zheng H, Feng Y, Zhao N, Geng H, Zhang W, Wen A. Pharmacokinetic study of single- and multiple-dosing with metolazone tablets in healthy Chinese population. BMC Pharmacol Toxicol 2017; 18:73. [PMID: 29145890 PMCID: PMC5689141 DOI: 10.1186/s40360-017-0178-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2016] [Accepted: 10/30/2017] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Metolazone is a diuretic, saluretic and antihypertensive chemical compound from the quinazoline category that possesses medicinal features similar to those of other thiazide diuretic drugs. However, the pharmacokinetics of metolazone in the Chinese population has rarely been studied. This study aimed to examine the pharmacokinetic characteristics, safety characteristic, and tolerability of metolazone in healthy Chinese subjects after single and multiple doses taken orally as well as the effects that food and gender have on oral metolazone pharmacokinetic parameters. METHODS An open-label, randomized, and single- and multiple-dosing investigation was performed in healthy Chinese subjects. The investigation included 3 study groups: the 0.5 mg, 1 mg and 2 mg dose groups were the single-dose study groups in the first stage. Eligible volunteers were randomly and orally administered a single 0.5 mg, 1 mg, or 2 mg metolazone tablet. The 0.5 mg dose group was also part of the multiple-dose study group, and the 1 mg dose group was the food-effect study group in the second stage. Human plasma samples were gathered pre-dosing and up to 48 h after dosing. The human plasma sample concentration of metolazone was quantified using a validated liquid chromatography tandem mass spectrometry method. Pharmacokinetic data were calculated by a noncompartmental analysis method using WinNonlin version 6.4. Tolerability was evaluated based on adverse events, medical examination, 12-lead ECG, and other clinical laboratory exams. RESULTS Thirty eligible subjects (15 men and 15 women) were registered in our investigation and completed all of the study stages. The AUC and Cmax showed dose proportionality after a single dose based on the linear-regression analysis. A comparison of the pharmacokinetic data revealed that the differences between the male and female groups were not statistically significant. The tmax of metolazone was increased by approximately 100% in the fed condition. Metolazone was well tolerated at the tested dose, and no adverse effects were observed. CONCLUSIONS Single dosing with 0.5 mg, 1 mg, or 2 mg metolazone yielded linear plasma pharmacokinetic properties in healthy Chinese subjects. Multiple oral doses of metolazone did not display significantly different distributions or elimination characteristics from those observed for a single dose. Gender factors did not appear to influence the pharmacokinetic parameter variation of metolazone. The tmax of metolazone increased in the fed condition. Metolazone was well tolerated at the tested dose in this study. TRIAL REGISTRATION This investigation is retrospectively registered at chictr.org.cn (ChiCTR-IIR-17012929, October 09 2017).
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Affiliation(s)
- Xueqing Li
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
| | - Rutao Wang
- Xi'an Libang Zhaoxin Biological Technology Co., Ltd, Xi'an, China
| | - Yang Liu
- Eliving Pharmaceutical Co., Ltd, Shenyang, China
| | - Yun Liu
- Xi'an Libang Zhaoxin Biological Technology Co., Ltd, Xi'an, China
| | - Heng Zheng
- Department of Pharmacy, Tongji Hospital, Wuhan, China
| | - Yabo Feng
- Eliving Pharmaceutical Co., Ltd, Shenyang, China
| | - Na Zhao
- Eliving Pharmaceutical Co., Ltd, Shenyang, China
| | - Hongbin Geng
- Xi'an Libang Zhaoxin Biological Technology Co., Ltd, Xi'an, China
| | - Wanzhi Zhang
- Xi'an Libang Zhaoxin Biological Technology Co., Ltd, Xi'an, China
| | - Aidong Wen
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, China
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A Retrospective Study on Mycophenolic Acid Drug Interactions: Effect of Prednisone, Sirolimus, and Tacrolimus With MPA. Ther Drug Monit 2017; 39:220-228. [DOI: 10.1097/ftd.0000000000000403] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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16
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Andersen LPH, Werner MU, Rosenkilde MM, Harpsøe NG, Fuglsang H, Rosenberg J, Gögenur I. Pharmacokinetics of oral and intravenous melatonin in healthy volunteers. BMC Pharmacol Toxicol 2016; 17:8. [PMID: 26893170 PMCID: PMC4759723 DOI: 10.1186/s40360-016-0052-2] [Citation(s) in RCA: 121] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2015] [Accepted: 02/12/2016] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The aim was to investigate the pharmacokinetics of oral and iv melatonin in healthy volunteers. METHODS The study was performed as a cohort crossover study. The volunteers received either 10 mg oral melatonin or 10 mg intravenous melatonin on two separate study days. Blood samples were collected at different time points following oral administration and short iv infusion, respectively. Plasma melatonin concentrations were determined by RIA technique. Pharmacokinetic analyses were performed by "the method of residuals" and compartmental analysis. The pharmacokinetic variables: k a, t 1/2 absorption, t max, C max, t 1/2 elimination, AUC 0-∞, and bioavailability were determined for oral melatonin. C max, t 1/2 elimination, V d, CL and AUC 0-∞ were determined for intravenous melatonin. RESULTS Twelve male volunteers completed the study. Baseline melatonin plasma levels did not differ significantly between the study days (P = 0.067). Mean (SD) t 1/2 absorption of oral melatonin was 6.0 (3.1) min. Mean t max was 40.8 (17.8) min with a median (IQR) C max of 3550.5 (2500.5-8057.5) pg ml(-1). Mean t 1/2 elimination was 53.7 (7.0) min. Median absolute bioavailability was 2.5 (1.7-4.7) %. Median C max after short iv infusion of melatonin was 389,875.0 (174,775.0-440,362.5) pg ml(-1). Mean t 1/2 elimination was 39.4 (3.6) min, mean V d 1.2 (0.6) l kg(-1) and mean CL 0.0218 (0.0102) l min(-1) kg(-1). CONCLUSIONS This cohort crossover study estimated pharmacokinetics of oral and iv melatonin, respectively in healthy volunteers. Bioavailability of oral melatonin was only 3 %. TRIAL REGISTRATION Eudra-CT number: 2013-000205-23 (initial registration 27.03.2013). Clinicaltrials.gov Identifier: NCT01923974 (initial registration 08.08.2013).
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Affiliation(s)
- Lars P H Andersen
- Department of Surgery D, Herlev Hospital, University of Copenhagen, Herlev, DK-2730, Denmark.
| | - Mads U Werner
- Multidisciplinary Pain Center 7612, Neuroscience Center, Rigshospitalet, Copenhagen, DK-2100, Denmark.
| | - Mette M Rosenkilde
- Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, DK-2100, Denmark.
| | - Nathja G Harpsøe
- Department of Surgery D, Herlev Hospital, University of Copenhagen, Herlev, DK-2730, Denmark.
| | - Hanne Fuglsang
- Department of Surgery D, Herlev Hospital, University of Copenhagen, Herlev, DK-2730, Denmark.
| | - Jacob Rosenberg
- Department of Surgery D, Herlev Hospital, University of Copenhagen, Herlev, DK-2730, Denmark.
| | - Ismail Gögenur
- Department of Surgery, Roskilde and Køge Hospital, University of Copenhagen, Roskilde, DK-4000, Denmark.
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17
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Lee JR, Muthukumar T, Dadhania D, Taur Y, Jenq RR, Toussaint NC, Ling L, Pamer E, Suthanthiran M. Gut microbiota and tacrolimus dosing in kidney transplantation. PLoS One 2015; 10:e0122399. [PMID: 25815766 PMCID: PMC4376942 DOI: 10.1371/journal.pone.0122399] [Citation(s) in RCA: 128] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2014] [Accepted: 01/13/2015] [Indexed: 12/14/2022] Open
Abstract
Tacrolimus dosing to establish therapeutic levels in recipients of organ transplants is a challenging task because of much interpatient and intrapatient variability in drug absorption, metabolism, and disposition. In view of the reported impact of gut microbial species on drug metabolism, we investigated the relationship between the gut microbiota and tacrolimus dosing requirements in this pilot study of adult kidney transplant recipients. Serial fecal specimens were collected during the first month of transplantation from 19 kidney transplant recipients who either required a 50% increase from initial tacrolimus dosing during the first month of transplantation (Dose Escalation Group, n=5) or did not require such an increase (Dose Stable Group, n=14). We characterized bacterial composition in the fecal specimens by deep sequencing of the PCR amplified 16S rRNA V4-V5 region and we investigated the hypothesis that gut microbial composition is associated with tacrolimus dosing requirements. Initial tacrolimus dosing was similar in the Dose Escalation Group and in the Stable Group (4.2±1.1 mg/day vs. 3.8±0.8 mg/day, respectively, P=0.61, two-way between-group ANOVA using contrasts) but became higher in the Dose Escalation Group than in the Dose Stable Group by the end of the first transplantation month (9.6±2.4 mg/day vs. 3.3±1.5 mg/day, respectively, P<0.001). Our systematic characterization of the gut microbial composition identified that fecal Faecalibacterium prausnitzii abundance in the first week of transplantation was 11.8% in the Dose Escalation Group and 0.8% in the Dose Stable Group (P=0.002, Wilcoxon Rank Sum test, P<0.05 after Benjamini-Hochberg correction for multiple hypotheses). Fecal Faecalibacterium prausnitzii abundance in the first week of transplantation was positively correlated with future tacrolimus dosing at 1 month (R=0.57, P=0.01) and had a coefficient±standard error of 1.0±0.6 (P=0.08) after multivariable linear regression. Our novel observations may help further explain inter-individual differences in tacrolimus dosing to achieve therapeutic levels.
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Affiliation(s)
- John R. Lee
- Department of Medicine, Division of Nephrology and Hypertension, Weill Cornell Medical College, New York, New York, United States of America
- Department of Transplantation Medicine, New York Presbyterian Hospital—Weill Cornell Medical Center, New York, New York, United States of America
- * E-mail:
| | - Thangamani Muthukumar
- Department of Medicine, Division of Nephrology and Hypertension, Weill Cornell Medical College, New York, New York, United States of America
- Department of Transplantation Medicine, New York Presbyterian Hospital—Weill Cornell Medical Center, New York, New York, United States of America
| | - Darshana Dadhania
- Department of Medicine, Division of Nephrology and Hypertension, Weill Cornell Medical College, New York, New York, United States of America
- Department of Transplantation Medicine, New York Presbyterian Hospital—Weill Cornell Medical Center, New York, New York, United States of America
| | - Ying Taur
- Department of Medicine, Infectious Diseases Services, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
- Lucille Castori Center for Microbes, Inflammation and Cancer, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
- Weill Cornell Medical College, New York, New York, United States of America
| | - Robert R. Jenq
- Lucille Castori Center for Microbes, Inflammation and Cancer, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
- Weill Cornell Medical College, New York, New York, United States of America
- Department of Medicine, Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
| | - Nora C. Toussaint
- Department of Medicine, Infectious Diseases Services, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
| | - Lilan Ling
- Lucille Castori Center for Microbes, Inflammation and Cancer, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
| | - Eric Pamer
- Department of Medicine, Infectious Diseases Services, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
- Lucille Castori Center for Microbes, Inflammation and Cancer, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
- Weill Cornell Medical College, New York, New York, United States of America
| | - Manikkam Suthanthiran
- Department of Medicine, Division of Nephrology and Hypertension, Weill Cornell Medical College, New York, New York, United States of America
- Department of Transplantation Medicine, New York Presbyterian Hospital—Weill Cornell Medical Center, New York, New York, United States of America
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Gao CH, Yu LS, Zeng S, Huang YW, Zhou Q. Personalized therapeutics for levofloxacin: a focus on pharmacokinetic concerns. Ther Clin Risk Manag 2014; 10:217-27. [PMID: 24707182 PMCID: PMC3972025 DOI: 10.2147/tcrm.s59079] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background Personalized medicine should be encouraged because patients are complex, and this complexity results from biological, medical (eg, demographics, genetics, polypharmacy, and multimorbidities), socioeconomic, and cultural factors. Levofloxacin (LVX) is a broad-spectrum fluoroquinolone antibiotic. Awareness of personalized therapeutics for LVX seems to be poor in clinical practice, and is reflected in prescribing patterns. Pharmacokinetic–pharmacodynamic studies have raised concerns about suboptimal patient outcomes with the use of LVX for some Gram-negative infections. Meanwhile, new findings in LVX therapeutics have only been sporadically reported in recent years. Therefore, an updated review on personalized LVX treatment with a focus on pharmacokinetic concerns is necessary. Methods Relevant literature was identified by performing a PubMed search covering the period from January 1993 to December 2013. We included studies describing dosage adjustment and factors determining LVX pharmacokinetics, or pharmacokinetic–pharmacodynamic studies exploring how best to prevent the emergence of resistance to LVX. The full text of each included article was critically reviewed, and data interpretation was performed. Results In addition to limiting the use of fluoroquinolones, measures such as reducing the breakpoints for antimicrobial susceptibility testing, choice of high-dose short-course of once-daily LVX regimen, and tailoring LVX dose in special patient populations help to achieve the validated pharmacokinetic–pharmacodynamic target and combat the increasing LVX resistance. Obese individuals with normal renal function cleared LVX more efficiently than normal-weight individuals. Compared with the scenario in healthy subjects, standard 2-hour spacing of calcium formulations and oral LVX was insufficient to prevent a chelation interaction in cystic fibrosis patients. Inconsistent conclusions were derived from studies of the influence of sex on the pharmacokinetics of LVX, which might be associated with sample size and administration route. Children younger than 5 years cleared LVX nearly twice as fast as adults. Patients in intensive care receiving LVX therapy showed significant pharmacokinetic differences compared with healthy subjects. Creatinine clearance explained most of the population variance in the plasma clearance of LVX. Switching from intravenous to oral delivery of LVX had economic benefits. Addition of tamsulosin to the LVX regimen was beneficial for patients with bacterial prostatitis because tamsulosin could increase the maximal concentration of LVX in prostatic tissue. Coadministration of multivalent cation-containing drugs and LVX should be avoided. For patients receiving warfarin and LVX concomitantly, caution is needed regarding potential changes in the international normalized ratio; however, it is unnecessary to seek alternatives to LVX for the sake of avoiding drug interaction with warfarin. It is unnecessary to proactively reduce the dose of cyclosporin or tacrolimus when comedicated with LVX. Transporters such as organic anion-transporting polypeptide 1A2, P-glycoprotein, human organic cation transporter 1, and multidrug and toxin extrusion protein 1 are involved in the pharmacokinetics of LVX. Conclusion Personalized LVX therapeutics are necessary for the sake of better safety, clinical success, and avoidance of resistance. New findings regarding individual dosing of LVX in special patient populations and active transport mechanisms in vivo are opening up new horizons in clinical practice.
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Affiliation(s)
- Chu-Han Gao
- Department of Pharmacy, the Second Affiliated Hospital, School of Medicine, Hangzhou, Zhejiang Province, People's Republic of China
| | - Lu-Shan Yu
- Department of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang Province, People's Republic of China
| | - Su Zeng
- Department of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang Province, People's Republic of China
| | - Yu-Wen Huang
- Department of Pharmacy, the Second Affiliated Hospital, School of Medicine, Hangzhou, Zhejiang Province, People's Republic of China
| | - Quan Zhou
- Department of Pharmacy, the Second Affiliated Hospital, School of Medicine, Hangzhou, Zhejiang Province, People's Republic of China
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Yuan S. Drugs to cure avian influenza infection--multiple ways to prevent cell death. Cell Death Dis 2013; 4:e835. [PMID: 24091678 PMCID: PMC3824676 DOI: 10.1038/cddis.2013.367] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2013] [Revised: 08/15/2013] [Accepted: 08/16/2013] [Indexed: 12/31/2022]
Abstract
New treatments and new drugs for avian influenza virus (AIV) infection are developed continually, but there are still high mortality rates. The main reason may be that not all cell death pathways induced by AIV were blocked by the current therapies. In this review, drugs for AIV and associated acute respiratory distress syndrome (ARDS) are summarized. The roles of antioxidant (vitamin C) and multiple immunomodulators (such as Celecoxib, Mesalazine and Eritoran) are discussed. The clinical care of ARDS may result in ischemia reperfusion injury to poorly ventilated alveolar cells. Cyclosporin A should effectively inhibit this kind of damages and, therefore, may be the key drug for the survival of patients with virus-induced ARDS. Treatment with protease inhibitor Ulinastatin could also protect lysosome integrity after the infection. Through these analyses, a large drug combination is proposed, which may hypothetically greatly reduce the mortality rate.
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Affiliation(s)
- S Yuan
- College of Resources and Environmental Sciences, Sichuan Agricultural University, Chengdu, China
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20
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Humar A, Gill J, Johnston O, Fergusson D, House AA, Lebel L, Cockfield S, Kim SJ, Zaltzman J, Cantarovich M, Karpinski M, Ramsay T, Knoll GA. Quinolone prophylaxis for the prevention of BK virus infection in kidney transplantation: study protocol for a randomized controlled trial. Trials 2013; 14:185. [PMID: 23800312 PMCID: PMC3691619 DOI: 10.1186/1745-6215-14-185] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2013] [Accepted: 06/06/2013] [Indexed: 12/01/2022] Open
Abstract
BACKGROUND BK virus infection has emerged as a major complication in kidney transplantation leading to a significant reduction in graft survival. There are currently no proven strategies to prevent or treat BK virus infection. Quinolone antibiotics, such as levofloxacin, have demonstrated activity against BK virus. We hypothesize that administration of a quinolone antibiotic, when given early post-transplantation, will prevent the establishment of BK viral replication in the urine and thus prevent systemic BK virus infection. METHODS/DESIGN The aim of this pilot trial is to assess the efficacy, safety and feasibility of a 3-month course of levofloxacin in the kidney transplant population. This is a multicenter, randomized, double-blind, placebo-controlled trial with two parallel arms conducted in 11 Canadian kidney transplant centers. A total of 154 patients with end-stage renal disease undergoing kidney transplantation will be randomized to receive a 3-month course of levofloxacin or placebo starting in the early post-transplant period. Levofloxacin will be administered at 500 mg po daily with dose adjustments based on kidney function. The primary outcome will be the time to occurrence of BK viruria within the first year post-transplantation. Secondary outcomes include BK viremia, measures of safety (adverse events, resistant infections,Clostridium difficile-associated diarrhea), measures of feasibility (proportion of transplanted patients recruited into the trial), proportion of patients adherent to the protocol, patient drop-out and loss to follow-up,and use of quinolone antibiotics outside of the trial protocol. DISCUSSION Results from this pilot study will provide vital information to design and conduct a large, multicenter trial to determine if quinolone therapy decreases clinically meaningful outcomes in kidney transplantation. If levofloxacin significantly reduces BK viruria and urine viral loads in kidney transplantation, it will provide important justification to progress to the larger trial. If the full trial shows that levofloxacin significantly reduces BK infection and improves outcomes, its use in kidney transplantation will be strongly endorsed given the lack of proven therapies for this condition. TRIAL REGISTRATION This trial was funded by the Canadian Institutes of Health Research (grant number:222493) and is registered at ClinicalTrials.gov (NCT01353339).
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Affiliation(s)
- Atul Humar
- Department of Medicine, Faculty of Medicine & Dentistry, 2J2.00 WC Mackenzie Health Sciences Centre, University of Alberta, Edmonton, AB T6G 2R7, Canada
| | - John Gill
- Department of Medicine, St Paul’s Hospital, 1081 Burrard Street, Vancouver, BC V6Z 1Y6, Canada
| | - Olwyn Johnston
- Department of Medicine, Vancouver General Hospital, 855 West 12th Avenue, Vancouver, BC V5Z 1M9, Canada
| | - Dean Fergusson
- Clinical Epidemiology Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada
| | - Andrew A House
- Department of Medicine, Western University and London Health Sciences Centre, 339 Windermere Road, London, ON N6A 5A5, Canada
| | - Louise Lebel
- Clinical Epidemiology Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada
| | - Sandra Cockfield
- Department of Medicine, Faculty of Medicine & Dentistry, 2J2.00 WC Mackenzie Health Sciences Centre, University of Alberta, Edmonton, AB T6G 2R7, Canada
| | - S Joseph Kim
- Department of Medicine, Toronto General Hospital, 200 Elizabeth Street, Toronto, ON M5G 2C4, Canada
| | - Jeff Zaltzman
- Department of Medicine, St Michael’s Hospital, 30 Bond Street, Toronto, ON M5B 1W8, Canada
| | - Marcelo Cantarovich
- Department of Medicine, McGill University Health Center, 687 Pine Avenue West, Montreal, QC H3A 1A1, Canada
| | - Martin Karpinski
- Department of Medicine, University of Manitoba, 820 Sherbrook Street, Winnipeg, MB R3T 2N2, Canada
| | - Tim Ramsay
- Clinical Epidemiology Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada
| | - Greg A Knoll
- Department of Medicine, Ottawa Hospital Research Institute, University of Ottawa, 1967 Riverside Drive, Ottawa, ON K1H 7W9, Canada
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Einollahi B. Two-hour postdose level of cyclosporine monitoring of solid-organ transplant patients. EXP CLIN TRANSPLANT 2012; 10:416-7. [PMID: 22537141 DOI: 10.6002/ect.2011.0191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Nelson CA, Zunt JR. Tuberculosis of the central nervous system in immunocompromised patients: HIV infection and solid organ transplant recipients. Clin Infect Dis 2011; 53:915-26. [PMID: 21960714 DOI: 10.1093/cid/cir508] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Central nervous system (CNS) tuberculosis (TB) is a devastating infection with high rates of morbidity and mortality worldwide and may manifest as meningitis, tuberculoma, abscess, or other forms of disease. Immunosuppression, due to either human immunodeficiency virus infection or solid organ transplantation, increases susceptibility for acquiring or reactivating TB and complicates the management of underlying immunosuppression and CNS TB infection. This article reviews how immunosuppression alters the clinical presentation, diagnosis, treatment, and outcome of TB infections of the CNS.
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Affiliation(s)
- Christina A Nelson
- Department of Neurology, Global Health, Medicine, and Epidemiology, University of Washington School of Medicine, Seattle, Washington, USA
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23
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Kim JH, Kim SR, Song IS, Shin HJ, Kim HS, Lee JH, Ko SG, Shin YC. Different Transport Activity of Human Triallelic MDR1
893Ala/Ser/Thr Variant and its Association with Herb Extracts. Phytother Res 2011; 25:1141-7. [DOI: 10.1002/ptr.3405] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2010] [Revised: 12/09/2010] [Accepted: 12/20/2010] [Indexed: 11/11/2022]
Affiliation(s)
- Jeong-Hyun Kim
- Department of Preventive Medicine; College of Oriental Medicine; Kyung Hee University; Seoul Republic of Korea
| | - Soon Re Kim
- Department of Preventive Medicine; College of Oriental Medicine; Kyung Hee University; Seoul Republic of Korea
| | - Im-Sook Song
- Department of Pharmacology and Pharmacogenomics Research Center; Inje University College of Medicine; Busan Republic of Korea
| | - Ho-Jung Shin
- Department of Pharmacology and Pharmacogenomics Research Center; Inje University College of Medicine; Busan Republic of Korea
| | - Han-Seop Kim
- Department of Life Science and Basic Science Institute for Cell Damage Control; Sogang University; Seoul Republic of Korea
| | - Jung-Ha Lee
- Department of Life Science and Basic Science Institute for Cell Damage Control; Sogang University; Seoul Republic of Korea
| | - Seong-Gyu Ko
- Department of Preventive Medicine; College of Oriental Medicine; Kyung Hee University; Seoul Republic of Korea
| | - Yong-Cheol Shin
- Department of Preventive Medicine; College of Oriental Medicine; Kyung Hee University; Seoul Republic of Korea
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Capone D, Tarantino G, Polichetti G, Kadilli I, Sabbatini M, Basile V, Carrano R, Nappi R, Federico S. Absence of pharmacokinetic interference of moxifloxacin on cyclosporine and tacrolimus in kidney transplant recipients. J Clin Pharmacol 2010; 50:576-80. [PMID: 20089827 DOI: 10.1177/0091270009347869] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
This study investigates the potential pharmacokinetic interactions between an antimicrobial agent, moxifloxacin, and 2 immunosuppressant drugs, cyclosporine and tacrolimus, in kidney transplant recipients. Twenty-two kidney transplant patients needing antibiotic therapy for urinary tract infections are enrolled. Eleven patients are under cyclosporine treatment and the other 11 patients are under tacrolimus treatment. Because the urinary tract infections are caused by gram-negative aerobes sensitive to moxifloxacin, this antibiotic is administered by oral route at a dose of 400 mg/d for 1 week; in each patient pharmacokinetic studies are carried out before and at the seventh day of therapy. For both immunosuppressors, none of the pharmacokinetic parameters investigated show statistically significant differences between values obtained before and during treatment with moxifloxacin. In fact, the concentration-time profiles of monoclonal cyclosporine, polyclonal cyclosporine, and tacrolimus are not significantly different before and during the antimicrobial therapy. The results of the present study rule out interference of moxifloxacin with both cyclosporine and tacrolimus kinetics and indicate that the concomitant administration of the fluoroquinolone and cyclosporine or tacrolimus does not require modifications of the dosages of 2 immunosuppressant drugs.
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Affiliation(s)
- Domenico Capone
- Department of Neurosciences, Unit of Clinical Pharmacology. School of Medicine, Federico II University, Via S. Pansini 5, 80131 Naples, Italy.
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Garrison A, Morris M, Doblecki Lewis S, Smith L, Cleary T, Procop G, Vincek V, Rosa-Cunha I, Alfonso B, Burke G, Tzakis A, Hartstein A. Mycobacterium abscessusinfection in solid organ transplant recipients: report of three cases and review of the literature. Transpl Infect Dis 2009; 11:541-8. [DOI: 10.1111/j.1399-3062.2009.00434.x] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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Kuypers DRJ. Immunotherapy in elderly transplant recipients: a guide to clinically significant drug interactions. Drugs Aging 2009; 26:715-37. [PMID: 19728747 DOI: 10.2165/11316480-000000000-00000] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Currently, >50% of candidates for solid organ transplantation in Europe and the US are aged >50 years while approximately 15% of potential recipients are aged >or=65 years. Elderly transplant candidates are characterized by specific co-morbidity profiles that compromise graft and patient outcome after transplantation. The presence of coronary artery or peripheral vascular disease, cerebrovascular disease, history of malignancy, chronic obstructive lung disease or diabetes mellitus further increases the early post-transplant mortality risk in elderly recipients, with infections and cardiovascular complications as the leading causes of death. Not only are elderly patients more prone to developing drug-related adverse effects, but they are also more susceptible to pharmacokinetic and pharmacodynamic drug interactions because of polypharmacy. The majority of currently used immunosuppressant drugs in organ transplantation are metabolized by cytochrome P450 (CYP) or uridine diphosphate-glucuronosyltransferases and are substrates of the multidrug resistance (MDR)-1 transporter P-glycoprotein, the MDR-associated protein 2 or the canalicular multispecific organic anion transporter, which predisposes these immunosuppressant compounds to specific interactions with commonly prescribed drugs. In addition, important drug interactions between immunosuppressant drugs have been identified and require attention when choosing an appropriate immunosuppressant drug regimen for the frail elderly organ recipient. An age-related 34% decrease in total body clearance of the calcineurin inhibitor ciclosporin was observed in elderly renal recipients (aged >65 years) compared with younger patients, while older recipients also had 44% higher intracellular lymphocyte ciclosporin concentrations. Similarly, using a Bayesian approach, an inverse relationship was noted between sirolimus clearance and age in stable kidney recipients. Ciclosporin and tacrolimus have distinct pharmacokinetics, but both are metabolized by intestinal and hepatic CYP3A4/3A5 and transported across the cell membrane by P-glycoprotein. The most common drug interactions with ciclosporin are therefore also observed with tacrolimus, but the two drugs do not interact identically when administered with CYP3A inhibitors or inducers. The strongest effects on calcineurin-inhibitor disposition are observed with azole antifungals, macrolide antibacterials, rifampicin, calcium channel antagonists, grapefruit juice, St John's wort and protease inhibitors. Drug interactions with mycophenolic acids occur mainly through inhibition of their enterohepatic recirculation, either by interference with the intestinal flora (antibacterials) or by limiting drug absorption (resins and binders). Rifampicin causes a reduction in mycophenolic acid exposure probably through induction of uridine diphosphate-glucuronosyltransferases. Proliferation signal inhibitors (PSIs) such as sirolimus and everolimus are substrates of CYP3A4 and P-glycoprotein and have a macrolide structure very similar to tacrolimus, which explains why common drug interactions with PSIs are comparable to those with calcineurin inhibitors. Ciclosporin, in contrast to tacrolimus, inhibits the enterohepatic recirculation of mycophenolic acids, resulting in significantly lower concentrations and hence risk of underexposure. Therefore, when switching from tacrolimus to ciclosporin and vice versa or when reducing or withdrawing ciclosporin, this interaction needs to be taken into account. The combination of ciclosporin with PSIs requires dose reductions of both drugs because of a synergistic interaction that causes nephrotoxicity when left uncorrected. Conversely, when switching between calcineurin inhibitors, intensified monitoring of PSI concentrations is mandatory. Increasing age is associated with structural and functional changes in body compartments and tissues that alter absorptive capacity, volume of distribution, hepatic metabolic function and renal function and ultimately drug disposition. While these age-related changes are well-known, few specific effects of the latter on immunosuppressant drug metabolism have been reported. Therefore, more clinical data from elderly organ recipients are urgently required.
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Affiliation(s)
- Dirk R J Kuypers
- Department of Nephrology and Renal Transplantation, University Hospitals of Leuven, Leuven, Belgium.
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Abstract
Adverse drug reactions (ADRs) occur frequently in modern medical practice, increasing morbidity and mortality and inflating the cost of care. Patients with cardiovascular disease are particularly vulnerable to ADRs due to their advanced age, polypharmacy, and the influence of heart disease on drug metabolism. The ADR potential for a particular cardiovascular drug varies with the individual, the disease being treated, and the extent of exposure to other drugs. Knowledge of this complex interplay between patient, drug, and disease is a critical component of safe and effective cardiovascular disease management. The majority of significant ADRs involving cardiovascular drugs are predictable and therefore preventable. Better patient education, avoidance of polypharmacy, and clear communication between physicians, pharmacists, and patients, particularly during the transition between the inpatient to outpatient settings, can substantially reduce ADR risk.
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Flieger D, Klassert C, Hainke S, Keller R, Kleinschmidt R, Fischbach W. Phase II Clinical Trial for Prevention of Delayed Diarrhea with Cholestyramine/Levofloxacin in the Second-Line Treatment with Irinotecan Biweekly in Patients with Metastatic Colorectal Carcinoma. Oncology 2007; 72:10-6. [DOI: 10.1159/000111083] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2007] [Accepted: 06/21/2007] [Indexed: 11/19/2022]
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Borrows R, Chusney G, Loucaidou M, James A, Goel S, Borrows S, Van Tromp J, Cairns T, Griffith M, Hakim N, McLean A, Palmer A, Papalois V, Taube D. Analysis of factors influencing tacrolimus levels and immunoassay bias in renal transplantation. J Clin Pharmacol 2007; 47:1035-42. [PMID: 17660485 DOI: 10.1177/0091270007303765] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Affiliation(s)
- Richard Borrows
- West London Renal and Transplant Centre, Hammersmith Hospital, London, United Kingdom
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