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Effects of cyclosporin A administered into the airways against antigen-induced airway inflammation and hyperreactivity in the rat.

https://arctichealth.org/en/permalink/ahliterature15481
Source
Eur J Pharmacol. 2001 May 25;420(2-3):165-73
Publication Type
Article
Date
May-25-2001
Author
S L Underwood
S. McMillan
R. Reeves
J. Hunt
C J Brealey
S. Webber
M. Foster
C A Sargent
Author Affiliation
Aventis Pharma, Pharmacology Department, Dagenham Research Centre, Rainham Road South, Essex RM10 7XS, Dagenham, UK. stephen.underwood@aventis.com
Source
Eur J Pharmacol. 2001 May 25;420(2-3):165-73
Date
May-25-2001
Language
English
Publication Type
Article
Keywords
Administration, Inhalation
Animals
Antigens - administration & dosage
Antigens, CD2 - analysis
Antigens, CD4 - analysis
Area Under Curve
Bronchial Hyperreactivity - chemically induced - genetics - prevention & control
Bronchitis - chemically induced - immunology - prevention & control
Cyclosporine - pharmacokinetics - pharmacology
Dose-Response Relationship, Drug
Eosinophils - pathology
Immunosuppressive Agents - pharmacokinetics - pharmacology
Interleukin-5 - genetics
Lung - drug effects - metabolism - pathology
Lymphocytes - drug effects - immunology - pathology
Male
RNA, Messenger - drug effects - genetics - metabolism
Rats
Rats, Inbred BN
Rats, Sprague-Dawley
Receptors, Interleukin-2 - analysis
Abstract
The immunosuppressant cyclosporin A given orally has anti-asthma properties but carries an undesirable risk of systemic effects. We administered cyclosporin A to Brown Norway rats either orally (p.o.) or topically by intratracheal (i.t.) instillation into the airways before inhaled antigen. Cyclosporin A suppressed the antigen-induced accumulation of activated (CD25+) CD4+ T lymphocytes and eosinophils in the lung, interleukin-5 mRNA expression in lung tissue and airway hyperreactivity. Intratracheal cyclosporin A suppressed cell accumulation at a 10-fold lower dose than that required orally. Minimum effective doses were 3 mg x kg(-1) i.t. and 30 mg x kg(-1) p.o. Intratracheal administration reduced the plasma concentration and systemic exposure compared with an equieffective oral dose, but the reduction (4-5-fold) was not as large as anticipated. Our data suggests that although topical administration to asthmatics would provide some potential for an improved safety margin, it may not offer any major advantage over existing oral therapy. However, the data clearly demonstrate that a novel immunosuppressant with similar anti-inflammatory properties but reduced potential for systemic effects would offer an attractive therapy for severe asthma.
PubMed ID
11408039 View in PubMed
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Genotyping should be considered the primary choice for pre-treatment evaluation of thiopurine methyltransferase function.

https://arctichealth.org/en/permalink/ahliterature126359
Source
J Crohns Colitis. 2012 Jul;6(6):655-9
Publication Type
Article
Date
Jul-2012
Author
Ulf Hindorf
Malin Lindqvist Appell
Author Affiliation
Department of Gastroenterology, Skåne University Hospital, Lund, Sweden. ulf.hindorf@skane.se
Source
J Crohns Colitis. 2012 Jul;6(6):655-9
Date
Jul-2012
Language
English
Publication Type
Article
Keywords
6-Mercaptopurine - pharmacokinetics - therapeutic use
Azathioprine - pharmacokinetics - therapeutic use
Biological Markers - blood
Cohort Studies
Genetic markers
Genotype
Genotyping Techniques
Humans
Immunosuppressive Agents - pharmacokinetics - therapeutic use
Inflammatory Bowel Diseases - drug therapy - genetics
Metabolic Detoxication, Drug - genetics
Methyltransferases - blood - genetics
Phenotype
Retrospective Studies
Sweden
Abstract
A pre-treatment determination of the thiopurine S-methyltransferase (TPMT) genotype or phenotype can identify patients at risk of developing severe adverse reactions from thiopurine treatment. The risk of misclassifying a patient might be dependent on the method used. The aim of this study was to investigate the concordance between TPMT genotyping and phenotyping.
The data consist of 7195 unselected and consecutive TPMT genotype and phenotype determinations sent to the division of Clinical Pharmacology, Linköping, Sweden. TPMT activity was measured in red blood cells (RBC) and the genotype determined by pyrosequencing for the three most common TPMT variants (TPMT *2, *3A, *3C).
TPMT genotyping identified 89% as TPMT wild type (*1/*1), 10% as TPMT heterozygous and 0.5% as TMPT defective. The overall concordance between genotyping and phenotyping was 95%, while it was 96% among IBD patients (n=4024). Genotyping would have misclassified 8% of the TPMT defectives as heterozygous as compared to 11% if only TPMT activity had been measured. 11% of the heterozygous patients had a normal TPMT activity (>8.9 U/ml RBC) and 3% of the TPMT wild-type patients had an intermediate TPMT activity (2.5-8.9 U/ml RBC).
There is a risk for TPMT misclassification when only genotyping or phenotyping is used, but it is not reasonable to check both in all patients. Since TPMT genotyping is the more reliable test, especially in TPMT heterozygotes, we suggest that genotyping should be considered the primary choice for the pre-treatment evaluation of TPMT function before initiation of thiopurine therapy.
Notes
Comment In: J Crohns Colitis. 2012 Aug;6(7):807; author reply 80822542920
PubMed ID
22398041 View in PubMed
Less detail

Pharmacogenetic impact of UDP-glucuronosyltransferase metabolic pathway and multidrug resistance-associated protein 2 transport pathway on mycophenolic acid in thoracic transplant recipients: an exploratory study.

https://arctichealth.org/en/permalink/ahliterature139833
Source
Pharmacotherapy. 2010 Nov;30(11):1097-108
Publication Type
Article
Date
Nov-2010
Author
Lillian S L Ting
Marie-Odile Benoit-Biancamano
Olivier Bernard
K Wayne Riggs
Chantal Guillemette
Mary H H Ensom
Author Affiliation
Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
Source
Pharmacotherapy. 2010 Nov;30(11):1097-108
Date
Nov-2010
Language
English
Publication Type
Article
Keywords
Adult
Aged
Area Under Curve
British Columbia
Cross-Sectional Studies
Female
Glucuronosyltransferase - genetics
Heart Transplantation - methods
Humans
Immunosuppressive Agents - pharmacokinetics - therapeutic use
Lung Transplantation - methods
Male
Middle Aged
Multidrug Resistance-Associated Proteins - genetics
Multivariate Analysis
Mycophenolic Acid - analogs & derivatives - pharmacokinetics - therapeutic use
Pharmacogenetics
Polymorphism, Genetic
Retrospective Studies
Treatment Outcome
Young Adult
Abstract
To assess the contribution of polymorphisms in the uridine diphosphate glucuronosyltransferase gene (UGT) and the multidrug resistance-associated protein 2 gene (ABCC2) to mycophenolic acid (MPA) pharmacokinetics and clinical outcomes in thoracic transplant recipients.
Open-label, cross-sectional study.
Transplant clinic in Vancouver, British Columbia, Canada.
Sixty-eight thoracic (36 lung, 32 heart) transplant recipients who were receiving steady-state oral mycophenolate mofetil.
Eleven blood samples were obtained from each patient over a 12-hour dosing period. Plasma concentrations of MPA (active metabolite of mycophenolate mofetil), the MPA metabolites 7-Omycophenolic acid glucuronide (MPAG) and acyl glucuronide (AcMPAG), and free MPA were measured, and dose-normalized conventional pharmacokinetic parameters were determined by noncompartmental methods. Genetic polymorphisms in UGT and ABCC2 were determined by sequencing, and their contributions to pharmacokinetic variability were investigated by using multivariate analysis. For both the lung and heart transplant groups, the UGT2B7 variant 802T (Tyr(268) or UGT2B7*2, rs7439366) and the UGT2B7 variant -138A modified AcMPAG exposure (2.5-3.7-fold and 9.3-12.3-fold higher AcMPAG area under the concentration-time curve [AUC] and AcMPAG:MPA ratio, respectively). In an exploratory analysis, occurrences of rejection, infection, anemia, and leukopenia were associated with an AcMPAG AUC greater than 50 µg·hour/ml and an AcMPAG:MPA ratio greater than 2.
UGT2B7 is a promising gene candidate that may influence MPA pharmacokinetics clinically; however, larger clinical pharmacogenetic studies in thoracic transplant subpopulations are warranted to corroborate the role of AcMPAG and UGT2B7 variants in optimizing mycophenolate mofetil therapy.
PubMed ID
20973683 View in PubMed
Less detail

Population pharmacokinetics of mycophenolic acid during the first week after renal transplantation.

https://arctichealth.org/en/permalink/ahliterature173599
Source
Eur J Clin Pharmacol. 2005 Aug;61(7):507-16
Publication Type
Article
Date
Aug-2005
Author
Christine E Staatz
Stephen B Duffull
Bryce Kiberd
Albert D Fraser
Susan E Tett
Author Affiliation
School of Pharmacy, University of Queensland, Brisbane, QLD, 4072, Australia. chris@pharmacy.uq.edu.au
Source
Eur J Clin Pharmacol. 2005 Aug;61(7):507-16
Date
Aug-2005
Language
English
Publication Type
Article
Keywords
Adult
Aged
Female
Humans
Immunosuppressive Agents - pharmacokinetics
Kidney Transplantation
Male
Middle Aged
Mycophenolic Acid - pharmacokinetics
Nova Scotia
Population Surveillance
Abstract
To investigate the population pharmacokinetics of mycophenolic acid (MPA) in adult kidney transplant recipients during the crucial first week after transplantation.
Data were collected from 117 patients. MPA plasma concentrations were determined at t=0, 1, 2, 3 and 4 h after mycophenolate mofetil dosing on days 3, 5 and 7. Population analysis was performed using NONMEM. Covariates screened were sex, age, body weight, serum creatinine, creatinine clearance, serum albumin, days of therapy, diabetes mellitus, organ source (live or cadaveric) and co-therapy (tacrolimus or cyclosporine). Final model validity was evaluated using 200 boot strapped samples from the original data. Bias and precision were determined through comparison of observed and predicted concentrations.
Individual concentration-time profiles showed evidence of an absorption lag time and enterohepatic recirculation of MPA in some patients on some occasions. The best base model had bi-exponential elimination with a typical population (SE%) apparent clearance (CL/F) of 29 l/h (5%) and apparent volume of the central compartment of 65 l (7%). CL/F decreased significantly with increasing serum albumin (1.42 l/h reduction in total plasma CL/F with each 1 g/l increase in albumin) and was 27% greater in patients receiving cyclosporine than in those receiving tacrolimus. Evaluation of the final model showed close agreement between pairs of boot strapped and final model parameter estimates (all differences
PubMed ID
16049701 View in PubMed
Less detail

Renal transplantation in Helsinki: influence on long-term survival of early posttransplant factors.

https://arctichealth.org/en/permalink/ahliterature196873
Source
Clin Transpl. 1999;:173-9
Publication Type
Article
Date
1999
Author
K. Salmela
L. Kyllönen
Author Affiliation
4th Department of Surgery, Helsinki University Central Hospital, Finland.
Source
Clin Transpl. 1999;:173-9
Date
1999
Language
English
Publication Type
Article
Keywords
Adult
Cadaver
Cyclosporine - pharmacokinetics - therapeutic use
Follow-Up Studies
Graft Rejection - epidemiology
Graft Survival
Histocompatibility testing
Humans
Immunosuppressive Agents - pharmacokinetics - therapeutic use
Kidney Transplantation - mortality - physiology - statistics & numerical data
Retrospective Studies
Survivors
Sweden
Time Factors
Tissue Donors
Abstract
1. The half-life of kidney grafts performed at Helsinki University Central Hospital has tripled from 6.5 years in 1980-84 to 17.1 years in the 1990's. 2. Delayed graft function constitutes a significant determinant of later kidney graft survival. Five-year graft survival was 81% for patients with early graft function and 71% for those with DGF. 3. High (> 350 mg/L) early (10 +/- 2 days after transplantation) cyclosporine trough levels were associated with inferior long-term graft survival. The 5-year graft survival rate was 74% compared with 86% for patients with trough levels between 250-349 mg/L. 4. Posttransplant conversion of the crossmatch test against the kidney donor, especially in association with DGF, indicates a group with significantly worse prognosis. Among 76 patients who developed antidonor antibody after transplantation, half experienced an acute rejection within 100 days and the 5-year graft survival rate was 68% compared with 83% for non-converters.
PubMed ID
11038635 View in PubMed
Less detail

Sirolimus experience at a Swedish transplantation center.

https://arctichealth.org/en/permalink/ahliterature185438
Source
Transplant Proc. 2003 May;35(3 Suppl):84S-88S
Publication Type
Article
Date
May-2003
Author
H E Wilczek
C. Brattström
Author Affiliation
Department of Transplantation Surgery, Huddinge University Hospital, Karolinska Institute, Stockholm, Sweden.
Source
Transplant Proc. 2003 May;35(3 Suppl):84S-88S
Date
May-2003
Language
English
Publication Type
Article
Keywords
Clinical Trials as Topic
Diltiazem - pharmacokinetics
Drug Therapy, Combination
Humans
Immunosuppressive Agents - pharmacokinetics - therapeutic use
Kidney Transplantation - immunology - physiology
Reference Values
Registries
Sirolimus - pharmacokinetics - therapeutic use
Sweden
Abstract
Sirolimus is an interesting drug due to its original mechanism of action and because it seems to lack the nephrotoxicity associated with calcineurin inhibitors. During the past 10 years, sirolimus has undergone several clinical trials. Beginning with phase I studies, our first patient given sirolimus was enrolled in 1993, after which we participated in sirolimus phase II trials and finally conducted the large phase III study that led to registration of sirolimus in the European Union (EU) in 2001. Altogether, 111 patients have been treated with sirolimus in our department. Initially, we participated in clinical trials evaluating sirolimus in combination with cyclosporine, but later we focused on studies using sirolimus as base therapy. We found sirolimus to be an effective immunosuppressant lacking several of the disturbing side effects associated with calcineurin inhibitors. It has a high antirejection efficacy and yields excellent survival results, with better renal function than that achieved by calcineurin inhibitors. The main side effects, hyperlipidemia and leukothrombocytopenia, are usually easily manageable. Sirolimus presents an alternative to prophylactic immunosuppression with calcineurin inhibitors and, in the field of transplantation, it represents a welcome addition to the immunosuppressive armamentarium.
PubMed ID
12742473 View in PubMed
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6 records – page 1 of 1.