Abstract:
AIM:To evaluate safety, tolerability and pharmacokinetics of oral PF-05190457, an oral ghrelin receptor inverse agonist, in healthy adults. METHODS:Single (SAD) and multiple ascending dose (MAD) studies were randomised, placebo-controlled, double-blind studies. Thirty-five healthy men (age 38.2 ± 10.4 years; body mass index 24.8 ± 3.1 kg m-2 [mean ± standard deviation]) received ≥1 dose (2, 10, 40 [divided], 50, 100, 150, and 300 [single or divided] mg) of PF-05190457 and/or placebo in the SAD. In the MAD study, 35 healthy men (age 39.7 ± 10.1 years; body mass index 25.9 ± 3.3 kg m-2 ) received ≥1 dose (2, 10, 40 and 100 mg twice daily) of PF-05190457 and/or placebo daily for 2 weeks. RESULTS:PF-05190457 absorption was rapid with a Tmax of 0.5-3 hours and a half-life between 8.2-9.8 hours. PF-05190457 dose-dependently blocked ghrelin (1 pmol kg-1 min-1 )-induced growth hormone (GH) release with (mean [90% confidence interval]) 77% [63-85%] inhibition at 100 mg. PF-05190457 (150 mg) delayed gastric emptying lag time by 30% [7-58%] and half emptying time by 20% [7-35%] with a corresponding decrease in postprandial glucose by 9 mg dL-1 . The most frequent adverse event reported by 30 subjects at doses ≥50 mg was somnolence. PF-05190457 plasma concentrations also increased heart rate up to 13.4 [4.8-58.2] beats min-1 and, similar to the effect on glucose and ghrelin-induced GH, was lost within 2 weeks. CONCLUSIONS:PF-05190457 is a well-tolerated first-in-class ghrelin receptor inverse agonist with acceptable pharmacokinetics for oral daily dosing. Blocking ghrelin receptors inhibits ghrelin-induced GH, and increases heart rate, effects that underwent tachyphylaxis with chronic dosing. PF-051940457 has the potential to treat centrally-acting disorders such as insomnia.
journal_name
Br J Clin Pharmacoljournal_title
British journal of clinical pharmacologyauthors
Denney WS,Sonnenberg GE,Carvajal-Gonzalez S,Tuthill T,Jackson VMdoi
10.1111/bcp.13127subject
Has Abstractpub_date
2017-02-01 00:00:00pages
326-338issue
2eissn
0306-5251issn
1365-2125journal_volume
83pub_type
杂志文章,随机对照试验abstract:AIMS:To investigate the effect of multiple dosing with montelukast, a selective leukotriene-receptor antagonist, on the pharmacokinetics of rosiglitazone, a CYP2C8 substrate, in humans. METHODS:A two-period, randomized crossover study was conducted in 10 healthy subjects. After administration of oral doses of placebo ...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章,随机对照试验
doi:10.1111/j.1365-2125.2006.02764.x
更新日期:2007-03-01 00:00:00
abstract::Mirabegron is used for the treatment of symptoms associated with overactive bladder syndrome. It selectively stimulates the β3 -adrenoreceptor, which relaxes the detrusor muscle. This improves urine storage by distension of the bladder body. ...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/bcp.12647
更新日期:2015-10-01 00:00:00
abstract:AIMS:To obtain in vivo evidence for the involvement of cytochrome P450 (CYP) 3A4 in the metabolism of brotizolam. METHODS:Fourteen healthy male volunteers received erythromycin 1200 mg day(-1) or placebo for 7 days in a double-blind randomized crossover manner. On the 6th day they received a single oral 0.5-mg dose of...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章,随机对照试验
doi:10.1111/j.1365-2125.2005.02380.x
更新日期:2005-08-01 00:00:00
abstract::1 The effect of labetalol has been assessed in an open clinical trial in 19 patients with sub-optimal control of blood pressure on other therapy, and in a placebo-controlled cross-over study. Most patients were taking a diuretic before the trial and they continued to do so during the trial. 2 In the open trial, labeta...
journal_title:British journal of clinical pharmacology
pub_type: 临床试验,杂志文章,随机对照试验
doi:
更新日期:1976-08-01 00:00:00
abstract::The effects of single doses of anhydrous caffeine (250 mg and 500 mg) and placebo on physiological, psychological measures and subjective feelings were studied in a double-blind, cross-over study in nine healthy subjects who had abstained from caffeine-containing beverages for 24 h before each occasion. Caffeine and c...
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.1365-2125.1986.tb02883.x
更新日期:1986-07-01 00:00:00
abstract::In a randomised crossover study in volunteers plasma midazolam levels were estimated for 24 h following 15 mg by mouth, either preceded by no medication or following 24 h therapy with ranitidine. Administration of the H2-receptor blocker significantly increased bioavailability of the benzodiazepine and resulted in hig...
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.1365-2125.1983.tb01559.x
更新日期:1983-06-01 00:00:00
abstract::1 The plasma levels of disopyramide and mono-N-dealkyldisopyramide were measured from 118 patients, and the protein binding of both drugs from 50 patients during chronic oral disopyramide therapy. 2 No significant correlation was seen between the daily dose of disopyramide and the achieved plasma drug concentration. 3...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.1981.tb01134.x
更新日期:1981-04-01 00:00:00
abstract::Calcium subserves a ubiquitous role in the organisation of cell function. Ca2+ channels which control influx may be modified in disease states. Animal models of cerebral ischaemia do present some problems when investigating potential therapies involving Ca2+ channels. However, it is important not to be too rigid in se...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章,评审
doi:10.1111/j.1365-2125.1992.tb04125.x
更新日期:1992-09-01 00:00:00
abstract::We have introduced to the course in pharmacology for medical students a simple human experiment that demonstrates the efficacy of activated charcoal in gastrointestinal drug binding. Sixty-one students were given 40 mg frusemide with water, water only, or 40 mg frusemide and 8 g activated charcoal with water either im...
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.1365-2125.1990.tb03805.x
更新日期:1990-09-01 00:00:00
abstract::This study investigated the effects of placebo, 1 mg, 3 mg, 10 mg and 30 mg ritanserin and 10 mg diazepam on human sleep. Twelve normal volunteers participated in this randomized, double-blind, placebo-controlled cross-over sleep study. A clear dose-response relationship was found for ritanserin with higher doses evok...
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.tb05514.x
更新日期:1991-02-01 00:00:00
abstract::Methods of expressing the effects of beta-adrenoceptor blocking drugs on exercise heart rate have been evaluated using a standardised exercise test. In six normal subjects given atropine (0.04 mg/kg) on two separate occasions, the mean +/- s.e. mean exercise heart rate rose by 10.3 +/- 1.8 beats/min and by 11.0 +/- 1....
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.1976.tb00348.x
更新日期:1976-12-01 00:00:00
abstract::Individual and population differences in polymorphic cytochrome P450 enzyme function have been known for decades. The biological significance of these differences has now been deciphered with regard to drug metabolism, action and toxicity as well as disposition of endogenous substrates, including neuroactive compounds...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章,评审
doi:10.1111/bcp.12227
更新日期:2014-04-01 00:00:00
abstract::A double-blind, placebo-controlled, cross-over trial of quinine in leg cramps occurring at rest was conducted in 22 elderly cramp sufferers. Despite demonstration of impaired quinine elimination in the elderly, prescription of the traditional dose of 300 mg quinine bisulphate at night failed to produce a significant (...
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.tb03076.x
更新日期:1987-04-01 00:00:00
abstract:AIMS:To study the potential drug interaction between cimetidine and caffeine in a group of children who received cimetidine for gastritis. METHODS:The caffeine breath test was carried out prior to the administration of cimetidine and after 2-3 weeks therapy. The children (n = 1) received 300-800 mg cimetidine daily (1...
journal_title:British journal of clinical pharmacology
pub_type: 临床试验,杂志文章
doi:10.1046/j.1365-2125.1997.00589.x
更新日期:1997-05-01 00:00:00
abstract:AIMS:The CYP3A metric 4β-hydroxycholesterol (4βOHC) has been shown to correlate with tacrolimus steady-state apparent oral clearance (CL/F). Recently, pretransplant 4βOHC was shown not to predict tacrolimus CL/F after transplantation in a cohort of renal recipients (n = 79). The goal of the current study was determine ...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/bcp.13343
更新日期:2017-11-01 00:00:00
abstract::The effects of intravenous boluses of adenosine on respiration and heart rate were compared in young and elderly individuals. Respiratory stimulation and biphasic changes in heart rate were confirmed. The dose-response relationship for the effects of adenosine on respiration and heart-rate did not differ significantly...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.1989.tb05360.x
更新日期:1989-02-01 00:00:00
abstract::1. The antihypertensive efficacy and tolerability of a low dose combination of the angiotensin converting enzyme inhibitor ramipril (2.5 mg) and the extended release formulation of the dihydropyridine calcium channel antagonist felodipine (5 mg) were assessed in a double-blind, double dummy placebo controlled, randomi...
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.1365-2125.1993.tb00371.x
更新日期:1993-10-01 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:AIMS:To discover whether patients have the same expectations of benefit from taking the first and any additional drugs for the treatment of hypertension and to investigate any patient characteristics which predict willingness to take treatment. METHODS:This was an anonymous questionnaire survey carried out in a single...
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.0306-5251.2001.01505.x
更新日期:2002-01-01 00:00:00
abstract:AIMS:Since suspicion has been raised that administration of an oral live attenuated rotavirus vaccine may increase the risk of intussusception in young children, there has been concern about the possible effects of oral polio vaccine. The aim of the study was to evaluate the relationship between oral attenuated polio v...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1046/j.1365-2125.2001.00090.x
更新日期:2001-10-01 00:00:00
abstract:AIM:To compare gentamicin dose estimates from four predictive methods. METHODS:A retrospective study was conducted, comprising patients at Fremantle Hospital who received gentamicin therapy and had at least one gentamicin serum concentration reported. A manual calculation method, the Australian 'Therapeutic Guidelines...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.2004.02201.x
更新日期:2004-11-01 00:00:00
abstract:AIMS:To evaluate if rivaroxaban, an oral factor Xa (FXa) inhibitor, could modify the expression in vitro of inflammatory and oxidative stress biomarkers in abdominal aortic aneurysmal (AAA) sites showing intraluminal thrombus. METHODS:AAA sites with intraluminal mural thrombus were obtained from six patients undergoin...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/bcp.13383
更新日期:2017-12-01 00:00:00
abstract:AIMS:The pharmacokinetics (PK) of fluconazole and micafungin differ in neonates compared with children and adults. Dosing instructions in product labels appear to be inconsistent with the emerging scientific evidence. Limited information is available on the safety profile of these agents in neonates. Our objective was ...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章,多中心研究,随机对照试验
doi:10.1111/bcp.13628
更新日期:2018-09-01 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:AIMS:Data regarding the cardiac toxicity of cabozantinib lacks. The aim of our study was to assess the risk of cabozantinib-related cardiotoxicity in mRCC patients. METHODS:We performed a multicentre prospective study on mRCC patients treated with cabozantinib between October 2016 and November 2017. Transthoracic echo...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章,多中心研究
doi:10.1111/bcp.13895
更新日期:2019-06-01 00:00:00
abstract:AIMS:Nicotine nasal spray and transdermal nicotine are effective aids to smoking cessation, and are being evaluated for treatment of other medical diseases. Wide variation in levels of nicotine and its metabolite, cotinine, have been observed with such therapies. This study aimed primarily to assess sources of individu...
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.1365-2125.1997.00566.x
更新日期:1997-03-01 00:00:00
abstract:AIMS:Increased exposure to fondaparinux, as observed in patients with renal impairment, may increase bleeding risk. This study aims to determine the time course of major bleeding after major orthopaedic surgery, identify predictors of bleeding and simulate the effect of a reduced dose of fondaparinux on bleeding for pa...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章,多中心研究
doi:10.1111/bcp.13663
更新日期:2018-10-01 00:00:00
abstract::Since platelet activation has been incriminated in the pathogenesis of asthma, we have investigated the effect of one of its major granule-derived mediators, 5-hydroxytryptamine (5-HT, serotonin) on airway calibre in normal (12), atopic non-asthmatic (12) and atopic asthmatic subjects (16). On separate days subjects i...
journal_title:British journal of clinical pharmacology
pub_type: 临床试验,杂志文章
doi:10.1111/j.1365-2125.1986.tb02923.x
更新日期:1986-10-01 00:00:00
abstract:AIMS:This study investigates paediatric drug dosage guidelines with the aim of investigating their agreement with body surface area (BSA) scaling principles. METHODS:A total of 454 drug dosage guidelines listed in the AMH-CDC 2015 were examined. Data extracted included the administration, frequency and dose per age br...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/bcp.13511
更新日期:2018-05-01 00:00:00
abstract:AIM:Omalizumab, a humanized IgG monoclonal antibody that binds to human immunoglobulin E (IgE), interrupts the allergic cascade in asthmatic patients. The aim was to compare simultaneously drug exposure and IgE biomarker responses in Japanese and White patient populations. METHODS:An instantaneous equilibrium drug-lig...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章,多中心研究
doi:10.1111/j.1365-2125.2006.02803.x
更新日期:2007-05-01 00:00:00