Abstract：
AIMS:Although genetic, clinical and demographic factors have been shown to explain approximately half of the inter-individual variability in warfarin dose requirement in adults, less is known about causes of dose variability in children. This study aimed to identify and quantify major genetic, clinical and demographic sources of warfarin dose variability in children using modelling and simulation. METHODS:Clinical, demographic and genetic data from 163 children with a median age of 6.3 years (range 0.06-18.9 years), covering over 183 years of warfarin therapy and 6445 INR observations were used to update and optimize a published adult pharmacometric warfarin model for use in children. RESULTS:Genotype effects in children were found to be comparable with what has been reported for adults, with CYP2C9 explaining up to a four-fold difference in dose (CYP2C9 *1/*1 vs. *3/*3) and VKORC1 explaining up to a two-fold difference in dose (VKORC1 G/G vs. A/A), respectively. The relationship between bodyweight and warfarin dose was non-linear, with a three-fold difference in dose for a four-fold difference in bodyweight. In addition, age, baseline and target INR, and time since initiation of therapy, but not CYP4F2 genotype, had a significant impact on typical warfarin dose requirements in children. CONCLUSIONS:The updated model provides quantitative estimates of major clinical, demographic and genetic factors impacting on warfarin dose variability in children. With this new knowledge more individualized dosing regimens can be developed and prospectively evaluated in the pursuit of improving both efficacy and safety of warfarin therapy in children.
journal_name
Br J Clin Pharmacoljournal_title
British journal of clinical pharmacologyauthors
Hamberg AK,Wadelius M,Friberg LE,Biss TT,Kamali F,Jonsson ENdoi
10.1111/bcp.12308subject
Has Abstractpub_date
2014-07-01 00:00:00pages
158-69issue
1eissn
0306-5251issn
1365-2125journal_volume
78pub_type
杂志文章abstract：:Pharmacogenetic research dedicated to the investigation of inherited factors that influence drug response has produced exciting results over the past decade. Adding to the knowledge that genetic variation in metabolic enzymes may cause drug-related adverse reactions, recent studies indicate that variation in neurotran...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章,评审
doi：10.1046/j.1365-2125.2002.01679.x
更新日期：2002-10-01 00:00:00
abstract：AIMS:The inhaled allergen challenge model has been used previously to investigate the effects of novel anti-inflammatory drugs in inhaled corticosteroid (ICS)-naïve asthmatics. The aim of this study was to characterize high- and low-dose allergen challenges in asthmatic patients using ICS. METHODS:Twenty-eight asthmat...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/bcp.12508
更新日期：2015-03-01 00:00:00
abstract：AIMS:Mycophenolic acid (MPA) suppresses lymphocyte proliferation through inosine monophosphate dehydrogenase (IMPDH) inhibition. Two formulations have been approved: mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS). Pantoprazole (PAN) inhibits gastric acid secretion, which may alter MPA expo...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章,随机对照试验
doi：10.1111/bcp.12664
更新日期：2015-11-01 00:00:00
abstract：:1. Effects of 3 h infusions of adrenaline (0.4 nmol kg-1 min-1) or placebo and of mental stress evoked by a colour word test (CWT) on adrenergic receptor function were investigated in healthy men. Responses of heart rate, blood pressure, plasma catecholamines, plasma cyclic AMP and plasma free fatty acids (FFA) were e...
journal_title：British journal of clinical pharmacology
pub_type： 临床试验,杂志文章
doi：10.1111/j.1365-2125.1989.tb03559.x
更新日期：1989-12-01 00:00:00
abstract：AIMS:(i) To model the effects of the monoclonal antibody ATM-027 on the number of target cells and on the receptor density on the cell surface as measured by Fluorescence Activated Cell Sorter analysis, (ii) to investigate the effects of categorizing a continuous scale, and (iii) to simulate a phase II trial from phase...
journal_title：British journal of clinical pharmacology
pub_type： 临床试验,杂志文章,多中心研究,随机对照试验
doi：10.1111/j.1365-2125.2004.02177.x
更新日期：2004-10-01 00:00:00
abstract：:1 Seventeen men, aged 45-57 yr, with essential hypertension showed obvious and, in the standing position, dose-related reductions in blood pressure during treatment with oral labetalol with weekly dose increments. 2 Pulse rate changes were not related to dose but reduced compared with pre-treatment values. 3 No postur...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：
更新日期：1976-08-01 00:00:00
abstract：AIM:To investigate the effect of sepsis upon the volume of distribution (Vd) of gentamicin in neonates. METHODS:A retrospective chart review was conducted of neonates admitted to Dunedin Hospital who had gentamicin concentrations performed between 1st January 2000 and 30th October 2003. Data from 277 neonates, includi...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/j.1365-2125.2005.02260.x
更新日期：2005-01-01 00:00:00
abstract：:1. Metoprolol (ME), pindolol (PI) and propranolol (PR) were studied in nine subjects at different doses and at 'maximum beta-adrenoceptor blockade' at a defined exercise load. Exercise tests were performed after each dosing period; isoprenaline stimulation was studied at the highest dose level. 2. ME and PR reduced he...
journal_title：British journal of clinical pharmacology
pub_type： 临床试验,杂志文章,随机对照试验
doi：10.1111/j.1365-2125.1980.tb01769.x
更新日期：1980-10-01 00:00:00
abstract：:1. We report a method for measuring the concentrations of haloperidol (HL) and its major active metabolite, reduced haloperidol (RHL), in human scalp hair. 2. Hair samples were obtained from 59 patients who had been taking HL at fixed daily doses for more than 4 months and whose compliance was good. A morning pre-dose...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/j.1365-2125.1990.tb03618.x
更新日期：1990-02-01 00:00:00
abstract：AIMS:The cytochrome P450 enzyme CYP2C9 catalyses the 4'-hydroxylation of the nonsteroidal analgesic drug diclofenac in humans. We studied the influences of the known amino acid variants, CYP2C9*2 (Arg144Cys) and CYP2C9*3 (Ile359Leu), on diclofenac pharmacokinetics after a 50-mg oral dose of diclofenac in healthy volunt...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1046/j.1365-2125.2003.01712.x
更新日期：2003-01-01 00:00:00
abstract：AIMS:We performed a prospective cohort study to gain more insight into risk factors for neuropsychiatric effects of mefloquine among tourists travelling to tropical areas. METHODS:We enrolled all patients who consulted the Travel Clinic of the Havenziekenhuis & Institute for Tropical Diseases Rotterdam for mefloquine ...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1046/j.1365-2125.2003.02035.x
更新日期：2004-04-01 00:00:00
abstract：:WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Reflux oesophagitis is a common clinical disorder associated with significant morbidity. Proton pump inhibitors are the current pharmacotherapy of choice, but not all treated patients achieve symptom relief. Little is known about the efficacy of mosapride, a prokinetic agent wh...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章,随机对照试验
doi：10.1111/j.1365-2125.2010.03696.x
更新日期：2010-08-01 00:00:00
abstract：AIMS:To determine whether a medicine review and education programme influences the compliance and knowledge of older people in general practice. METHODS:Older people taking at least three medicines were randomly allocated to a control or intervention group. Both groups received three visits from a clinical pharmacist:...
journal_title：British journal of clinical pharmacology
pub_type： 临床试验,杂志文章
doi：10.1046/j.1365-2125.2000.00247.x
更新日期：2000-08-01 00:00:00
abstract：:1. Codeine was administered rectally to thirteen infants and young children undergoing elective surgery. Nine infants (6-10 months old) received a 4 mg suppository and four children (3-4 years old) an 8 mg suppository. Codeine and its metabolite morphine were measured in plasma by GC/MS. 2. The mean concentrations of ...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/j.1365-2125.1992.tb03999.x
更新日期：1992-01-01 00:00:00
abstract：:1. The pharmacokinetics of butorphanol were evaluated in 18 female volunteers with varying degrees of renal function following a single, 1 mg transnasal dose of butorphanol tartrate. The creatinine clearance (CLCR) values for subjects in the normal (NOR), moderately impaired (MI), and severely impaired (SI) groups wer...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1046/j.1365-2125.1996.03327.x
更新日期：1996-05-01 00:00:00
abstract：AIMS:To study reporting of hypoglycaemia in angiotensin receptor blocker (ARB) users, and to investigate the possibility of confounding. METHODS:The French pharmacovigilance database was examined for an association between hypoglycaemia and ARBs or other drugs using reports notified between 1996 and 2005. This associa...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/j.1365-2125.2008.03176.x
更新日期：2008-07-01 00:00:00
abstract：AIM:Propylene glycol (PG) is often applied as an excipient in drug formulations. As these formulations may also be used in neonates, the aim of this study was to characterize the pharmacokinetics of propylene glycol, co-administered intravenously with paracetamol (800 mg PG/1000 mg paracetamol) or phenobarbital (700 mg...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/j.1365-2125.2012.04312.x
更新日期：2013-01-01 00:00:00
abstract：AIMS:To evaluate the effect of a 3-day regimen of ibuprofen 600 mg x 4 on acute postoperative swelling and pain and other inflammatory events after third molar surgery compared with a traditional regimen of paracetamol 1000 mg x 4. METHODS:A controlled, randomized, double-blind, cross-over study where 36 patients (26 ...
journal_title：British journal of clinical pharmacology
pub_type： 临床试验,杂志文章,随机对照试验
doi：10.1046/j.1365-2125.2003.01779.x
更新日期：2003-04-01 00:00:00
abstract：:1. The kinetics and effects of ebastine 10 and 50 mg were studied after oral dosing in healthy subjects. 2. The parent drug was extensively metabolised during the first pass to its carboxylic acid derivative, carebastine. 3. The pharmacokinetics of carebastine were linear over the dose range studied and the terminal e...
journal_title：British journal of clinical pharmacology
pub_type： 临床试验,杂志文章,随机对照试验
doi：10.1111/j.1365-2125.1988.tb05288.x
更新日期：1988-11-01 00:00:00
abstract：:1 The anticholinergic effects of atropine and two antihistamines (terfenadine and mequitazine) were investigated vs placebo in a double-blind study. 2 Salivary secretion, basal pupil diameter, pilocarpine (0.25%) induced miosis and heart rate were determined in eight healthy volunteers, seven male and one female, aged...
journal_title：British journal of clinical pharmacology
pub_type： 临床试验,杂志文章
doi：10.1111/j.1365-2125.1988.tb03278.x
更新日期：1988-01-01 00:00:00
abstract：:1 The pharmacokinetics of single oral doses of nortriptyline were studied in twenty patients with chronic renal failure, eight of whom were receiving treatment with haemodialysis. 2 The median nortriptyline half-life was 25.2 h (range 14.5-140.0 h) and the median nortriptyline clearance was 32.3 l/h (range 8.1-122.0 l...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/j.1365-2125.1981.tb01852.x
更新日期：1981-07-01 00:00:00
abstract：AIM:To review the literature on adverse drug reactions (ADRs) in children with respect to occurrence, seriousness, type, therapeutic group, age and gender of the child and category of reporter. METHODS:Medline and Embase databases were searched from origin and updated until February 2010. We included empirically based...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章,评审
doi：10.1111/j.1365-2125.2010.03682.x
更新日期：2010-10-01 00:00:00
abstract：:1 Measurements have been made of steady state serum phenytoin concentration, serum half-life of (14)C-labelled phenytoin, and the urinary ratio of the major metabolite of phenytoin to the unchanged drug (p-HPPH: DPH ratio) in epileptic patients on and off sulthiame therapy. 2 Starting sulthiame treatment produced an i...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/j.1365-2125.1974.tb00207.x
更新日期：1974-02-01 00:00:00
abstract：AIM:To evaluate the resistance to oxidation of human lipoproteins after hypolipidaemic therapy. METHODS:VLDL and LDL samples were obtained from patients with Familial Combined Hyperlipidaemia included in a randomized, double-blind, cross-over study, with 8 weeks of active treatment (gemfibrozil, 600 mg twice daily, or...
journal_title：British journal of clinical pharmacology
pub_type： 临床试验,杂志文章,随机对照试验
doi：10.1046/j.1365-2125.1998.00672.x
更新日期：1998-03-01 00:00:00
abstract：:Serum creatinine and drug concentrations were measured at 0, 1, 2, 3, 6, 9 and 12 months in 30 consecutive patients started on amiodarone. In 28 of these patients with no obvious cause for altered renal function, mean serum creatinine increased to 11% above baseline (P < 0.005). Rising creatinine concentrations correl...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/j.1365-2125.1993.tb04207.x
更新日期：1993-08-01 00:00:00
abstract：AIMS:To assess whether frequency of placebo administration is associated with duodenal ulcer healing. METHODS:A systematic literature review of randomized clinical trials was undertaken. 79 of 80 trials that met the inclusion criteria. The pooled 4 week placebo healing rate of all duodenal ulcer trials that employed a...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章,meta分析
doi：10.1046/j.1365-2125.1999.00094.x
更新日期：1999-12-01 00:00:00
abstract：AIMS:5-HT1B-receptor mediated vasoconstriction of cranial arteries is a potential mechanism by which 5-HT1B/1D-receptor agonists such as sumatriptan produce their antimigraine effects. 5-HT1B-receptors exist in other blood vessels which may give rise to unwanted vascular effects. Therefore we examined the distribution ...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1046/j.0306-5251.2001.01536.x
更新日期：2002-03-01 00:00:00
abstract：ADVERSE EVENT:A drug interaction leading to higher exposure to cyclosporine. DRUGS IMPLICATED:Cyclosporine and ticagrelor. THE PATIENT:A 49-year-old man with a stable renal graft, managed with cyclosporine with stable trough blood concentrations for several years, was treated with ticagrelor for unstable angina pecto...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/bcp.13433
更新日期：2018-01-01 00:00:00
abstract：AIMS:The effects of a single dose of oxymetazoline nasal spray on nasal patency have been compared with placebo using three separate measuring systems in normal subjects. METHODS:The study was a placebo-controlled, randomised double-blind crossover trial. Subjects without ear, nose or throat disease and with resting n...
journal_title：British journal of clinical pharmacology
pub_type： 临床试验,杂志文章,随机对照试验
doi：10.1046/j.1365-2125.1999.00972.x
更新日期：1999-07-01 00:00:00
abstract：:1. Mono(ADP-ribosyl)transferase activity has been identified on the external surface of human polymorphonuclear neutrophil leucocytes (PMNs). The enzyme is released from the plasma membrane by phosphoinositide-specific phospholipase C, suggesting a glycosylphosphatidylinositol (GPI) linkage of the enzyme to the plasma...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1046/j.1365-2125.1996.37014.x
更新日期：1996-07-01 00:00:00
