Abstract:
AIM:To develop a semi-mechanistic model, based on glutathione depletion and predict a previously identified intra-individual reduction in busulfan clearance to aid in more precise dosing. METHODS:Busulfan concentration data, measured as part of regular care for allogeneic hematopoietic cell transplantation (HCT) patients, were used to develop a semi-mechanistic model and compare it to a previously developed empirical model. The latter included an empirically estimated time effect, where the semi-mechanistic model included theoretical glutathione depletion. As older age has been related to lower glutathione levels, this was tested as a covariate in the semi-mechanistic model. Lastly, a therapeutic drug monitoring (TDM) simulation was performed comparing the two models in target attainment. RESULTS:In both models, a similar clearance decrease of 7% (range -82% to 44%), with a proportionality to busulfan metabolism, was found. After 40 years of age, the time effect increased with 4% per year of age (0.6-8%, P = 0.009), causing the effect to increase more than a 2-fold over the observed age-range (0-73 years). Compared to the empirical model, the final semi-mechanistic model increased target attainment from 74% to 76%, mainly through better predictions for adult patients. CONCLUSION:These results suggest that the time-dependent decrease in busulfan clearance may be related to gluthathione depletion. This effect increased with older age (>40 years) and was proportional to busulfan metabolism. The newly constructed semi-mechanistic model could be used to further improve TDM-guided exposure target attainment of busulfan in patients undergoing HCT.
journal_name
Br J Clin Pharmacoljournal_title
British journal of clinical pharmacologyauthors
Langenhorst JB,Boss J,van Kesteren C,Lalmohamed A,Kuball J,Egberts ACG,Boelens JJ,Huitema ADR,van Maarseveen EMdoi
10.1111/bcp.14256subject
Has Abstractpub_date
2020-08-01 00:00:00pages
1499-1509issue
8eissn
0306-5251issn
1365-2125journal_volume
86pub_type
杂志文章abstract::Ten healthy normal volunteers received an intravenous infusion of erythromycin lactobionate over 60 min to a total dose of 800 mg (n = 9), and 524 mg (n = 1). Blood samples were collected at 10 min intervals for 100 min and gastric contents aspirated, via a nasogastric tube, from pre-dose to 105 min after start of inf...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.1986.tb05193.x
更新日期:1986-03-01 00:00:00
abstract::1. The effect of icatibant (D-Arg-[Hyp3, Thi5, D-Tic7, Oic8] bradykinin) a potent B2-kinin receptor antagonist, was studied on bradykinin-induced vasodilation in the human forearm. 2. Eight healthy normotensive men were studied in a rising dose random-placebo controlled study. Placebo and icatibant (20, 50 and 100 mic...
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.1365-2125.1994.tb04360.x
更新日期:1994-10-01 00:00:00
abstract:AIMS:This double-blind, randomized, four-period, two-way crossover study was conducted to evaluate the acute effects of oral sildenafil (100-mg single dose) on sperm motility, count, density, morphology and vitality as well as ejaculate volume and viscosity in healthy male subjects. The concentrations of sildenafil and...
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.0306-5251.2001.00033.x
更新日期:2002-01-01 00:00:00
abstract::In a dog model of partial myocardial ischaemia, superimposed ST segment elevations in epicardial ECGs were inhibited by nicardipine over a cumulative i.v. dose range of 1-20 micrograms kg-1. Over the cumulative i.v. dose range of 0.5-166.5 micrograms kg-1, nicardipine had little overall effect on gross cardiac conduct...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.1985.tb05142.x
更新日期:1985-01-01 00:00:00
abstract::1. Changes in undergraduate medical education will involve the development of a core curriculum of material of essential knowledge and of the skills for self directed learning both as a student and a postgraduate. A survey of departments or individuals teaching clinical pharmacology and therapeutics was conducted to c...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.1994.tb04253.x
更新日期:1994-02-01 00:00:00
abstract:AIMS:To examine the effects of salbutamol and L-arginine, two compounds acting largely on the endothelium, and the endothelium-independent agent nitroglycerin on blood pressure, arterial compliance, cardiac function and vascular resistance. METHODS:Continuous radial pulse wave analysis, whole-body impedance cardiograp...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
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更新日期:2009-07-01 00:00:00
abstract::The effects of locally administered physostigmine and di-isopropylphosphorofluoridate (DFP) were compared on the secretory response of sweat glands to intradermally injected acetylcholine and carbachol in healthy male volunteers (physostigmine: six subjects; DFP: one subject). The response to acetylcholine reached its...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.1986.tb05166.x
更新日期:1986-02-01 00:00:00
abstract::This is the second of two papers which review issues concerning complementary medicines. The first reviewed the extent of use of complementary medicines, and issues related to the regulation and pharmaceutical quality of these products; the second considers evidence for the efficacy of several well-known complementary...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章,评审
doi:10.1046/j.1365-2125.2003.01811.x
更新日期:2003-04-01 00:00:00
abstract::The effect of metronidazole, at a dose of 1.2 g daily, on theophylline disposition was studied in 10 healthy adult volunteers. Neither theophylline half-life, volume of distribution nor total body clearance was altered by the anti-microbial. It is concluded that metronidazole does not impair theophylline metabolism de...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.1987.tb03146.x
更新日期:1987-07-01 00:00:00
abstract::In a double-blind, placebo-controlled, randomised, cross-over study of six healthy male subjects, the effect of nicardipine (5 mg h-1 for 3 h) on basal and stimulated pituitary hormone release was examined. Statistically significant differences between nicardipine and placebo were seen occasionally for follicle-stimul...
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.1365-2125.1985.tb05147.x
更新日期:1985-01-01 00:00:00
abstract::Medroxalol, a new drug which has been reported to possess both alpha- and beta-adrenoceptor antagonist properties, was compared with labetalol in single dose studies in normotensive males. Oral doses of 400 mg of each drug significantly reduced blood pressure, both supine and erect, without significant changes in hear...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.1984.tb02391.x
更新日期:1984-05-01 00:00:00
abstract:AIMS:To characterize the pharmacokinetics (PK) of moxetumomab pasudotox, an anti-CD22 recombinant immunotoxin, in adults with relapsed or refractory hairy cell leukaemia, we examined data from a phase 1 study (Study 1001; n = 49) and from the pivotal clinical study (Study 1053; n = 74). METHODS:Data from both studies ...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/bcp.14250
更新日期:2020-07-01 00:00:00
abstract::The pharmacokinetic behaviour and the bioavailability of midazolam were investigated in six volunteers after intravenous (0.15 mg/kg) and oral administration (10, 20 and 40 mg). Following rapid intravenous injection of midazolam, the plasma concentration of the substance decreased to approximately 10% within 2 h owing...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.1983.tb02270.x
更新日期:1983-01-01 00:00:00
abstract::Caffeine (5 mg kg-1) was administered orally to two healthy, non-smoking subjects on three separate occasions--before, and during therapy with the xanthine oxidase inhibitor allopurinol at doses of either 300 or 600 mg daily. Plasma and urinary levels of methylxanthines, endogenous oxypurines and allopurinol and its m...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.1986.tb05222.x
更新日期:1986-04-01 00:00:00
abstract::1. Lisinopril and enalapril were administered as 2.5 mg single doses and as eight single daily 2.5 mg doses to separate groups of six patients with chronic renal failure. Patients were receiving regular haemodialysis. 2. In the absence of haemodialysis, the decline in plasma concentrations of lisinopril and enalaprila...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.1988.tb05319.x
更新日期:1988-12-01 00:00:00
abstract:AIMS:It has been shown that the cellular uptake and cytotoxicity of anthracyclines decrease with increasing cell density in vitro, an event termed 'the inocculum effect'. It is not known whether such an effect occurs in vivo. In this study the relationships between white blood cell (WBC) count, plasma and cellular conc...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.2010.03894.x
更新日期:2011-04-01 00:00:00
abstract::Three calcium antagonists, diltiazem, flunarizine and verapamil stimulated human sperm motility in vitro. Among them, diltiazem induced the largest amplitude of motility increase. The concentration-response curve of diltiazem was similar in shape to those of calcium chelators. EGTA, a calcium chelator, potentiated the...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.1985.tb02611.x
更新日期:1985-01-01 00:00:00
abstract::1 Six healthy male volunteers received a total of 2500 mg of a new cephalosporin antibiotic Ro13-9904 by intramuscular injection in five divided doses at intervals of 12 h. 2 No significant systemic side-effects were observed and this was confirmed haematologically and biochemically. 3 The drug was distributed followi...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.1981.tb01188.x
更新日期:1981-08-01 00:00:00
abstract::Vertigo is associated with a wide range of vestibular pathologies. It increasingly affects the elderly, with a high cost to society. Solutions include vestibular suppressants and vestibular rehabilitation, which form the mainstay of therapy. Antihistamines represent the largest class of agents used to combat vestibula...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章,评审
doi:10.1111/bcp.14046
更新日期:2019-10-01 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:To investigate the impact of the specific red blood cell binding on the pharmacokinetics and pharmacodynamics of the nucleoside transport inhibitor draflazine after i.v. administration at various infusion rates. It was also aimed to relate the red blood cell (RBC) occupancy of draflazine to the ex vivo measured ad...
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.1365-2125.1997.00593.x
更新日期:1997-06-01 00:00:00
abstract:AIMS:Medication-related osteonecrosis of the jaw (MRONJ) is an uncommon but potentially debilitating condition, characterised by nonhealing jawbone, with or without mucosal exposure, in the presence of certain drugs. Those already strongly associated with MRONJ include antiresorptives denosumab and bisphosphonates; how...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/bcp.14681
更新日期:2020-11-27 00:00:00
abstract:AIMS:Antidepressant use has increased in the last decade. Several studies have suggested a possible association between maternal antidepressant use and teratogenic effects. METHODS:The pharmacy prescription database IADB.nl was used for a cohort study in which laxative and antidiarrhoeal medication use in children aft...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章,评审
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更新日期:2012-01-01 00:00:00
abstract::The dose-response effects of oral nicardipine on the systemic blood pressure were examined in 54 patients with uncomplicated essential hypertension (DBP greater than or equal to 100 mm Hg). The study was designed in four sequential stages. A 2 week single-blind placebo run-in period was followed by dose titration with...
journal_title:British journal of clinical pharmacology
pub_type: 临床试验,杂志文章
doi:10.1111/j.1365-2125.1985.tb05156.x
更新日期:1985-01-01 00:00:00
abstract::Aims We investigated whether venoconstriction by α-adrenoceptor stimulation, and venodilation by β-adrenoceptor stimulation and nitroglycerin are altered in patients with diabetes mellitus (DM). Methods Eight male patients with non insulin-dependent DM and eight age-matched control subjects were included. The patients...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1046/j.1365-2125.1999.00915.x
更新日期:1999-04-01 00:00:00
abstract::1. The relationship between the metabolism of the antiarrhythmic drug mexiletine and the debrisoquine/sparteine-type polymorphism was studied in vitro, using microsomes from six human livers, and in vivo, in nine healthy drug-free volunteers with wide variation in their ability to hydroxylate debrisoquine. 2. There wa...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.1991.tb03931.x
更新日期:1991-10-01 00:00:00
abstract::1. Using human mononuclear leucocytes as target cells, we have investigated the bioactivation of dapsone (DDS) to a cytotoxic metabolite in the presence of microsomes from nine human livers. Values for NADPH dependent toxicity ranged from 8.8-27% (15.8 +/- 5.9%) and were similar to those for microsomes from control mi...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.1989.tb03517.x
更新日期:1989-10-01 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::1. The antitussive properties of bronchodilators were evaluated in a total of 47 normal volunteers. 2. Cough was induced by inhalation of ultrasonically nebulized solutions of distilled water and hypotonic saline. 3. Inhaled fenoterol hydrobromide (360 micrograms; 20 volunteers) and inhaled ipratropium bromide (72 mic...
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.1365-2125.1987.tb03204.x
更新日期:1987-10-01 00:00:00
abstract::1. Apomorphine (1 and 5 micrograms kg-1) and placebo were given to nine normal volunteers, using a Latin-square design and double-blind procedures. The visual perception of static and moving patterns (static and motion contrast sensitivity) was evaluated before and 15 min after the dose administration. 2. Apomorphine ...
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.1365-2125.1991.tb03950.x
更新日期:1991-11-01 00:00:00