Abstract：
AIM:To investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of the highly selective oral p38alpha/beta mitogen-activated protein (MAP) kinase inhibitor Org 48,775-0 in a first-in-human study. METHODS:In the single ascending dosing (SAD) study, an oral dose of Org 48,775-0 (0.3-600 mg) was evaluated in healthy males. In the multiple ascending dosing (MAD) study, levels of 30, 70 and 150 mg were dosed for six consecutive days, twice daily. Both studies were performed in a double-blind, randomized, placebo-controlled, cross-over fashion and evaluated pharmacokinetics, pharmacodynamics (ex vivo inhibition of lipopolysaccharide [LPS]-induced tumor necrosis factor (TNFα) release) and routine clinical and laboratory data. Pharmacokinetic and pharmacodynamic parameters of Org 48,775-0 were compared between healthy males and postmenopausal females, and the effect of a standardized fat meal was evaluated. RESULTS:All adverse events observed in the SAD (16; dizziness and headache, diarrhoea and catheter-related phlebitis) and MAD (43; mainly somnolence, dizziness, headache and nasopharyngitis) cohorts were mild, transient and completely reversible. Pharmacokinetics were linear up to single doses of 400 mg. Median Tmax ranged from 0.5 to 1.8 hours, geometric mean for T1/2 from 7.0 to 14.4 hours. Org 48,775-0 doses equal to and greater than 30 mg significantly inhibited LPS-induced TNFα release (42.3%; 95% CI = -65.2, -4.3) compared to placebo. In the MAD study, Org 48,775-0 treatment inhibited LPS-induced TNFα release during the entire steady-state period. Levels of inhibition amounted 30-75% for 30 mg, 53-80% for 70 mg and 77-92% for 150 mg Org 48,775-0. CONCLUSION:Org 48,775-0 has the capacity to significantly inhibit MAP kinase activity in humans without safety concerns.
journal_name
Br J Clin Pharmacoljournal_title
British journal of clinical pharmacologyauthors
Moerland M,Kales AJ,Broekhuizen K,Nässander U,Nelissen R,de Kam ML,Peeters PAM,Burggraaf Jdoi
10.1111/bcp.14655subject
Has Abstractpub_date
2020-11-17 00:00:00eissn
0306-5251issn
1365-2125pub_type
杂志文章abstract：AIMS:Brentuximab vedotin, an antibody-drug conjugate (ADC), selectively delivers the microtubule-disrupting agent monomethyl auristatin E (MMAE) into CD30-expressing cells. The pharmacokinetics of brentuximab vedotin have been characterized in patients with CD30-positive haematologic malignancies. The primary objective...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章,多中心研究
doi：10.1111/bcp.12988
更新日期：2016-09-01 00:00:00
abstract：AIMS:AT9283 is used to treat patients with solid tumours and patients with leukaemia. However, the maximum tolerated dose (MTD) for children with leukaemia remains unknown due to early termination of the Phase I trial. The aim of this study was to develop a population model of AT9283 to describe the pharmacokinetics in...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/bcp.13260
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abstract：AIMS:This study was conducted to determine whether atenolol was able to decrease BP level and mitigate BP increase during dynamic resistance exercise performed at three different intensities in hypertensives. METHODS:Ten essential hypertensives (systolic/diastolic BP between 140/90 and 160/105mmHg) were blindly studie...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/j.1365-2125.2010.03742.x
更新日期：2010-11-01 00:00:00
abstract：:The effect of anticonvulsant therapy on early morning concentration of cortisol in saliva and plasma was assessed in a group of epileptic patients receiving regular phenytoin medication and the results compared with those obtained from a group of normal subjects not receiving drug therapy. Values of cortisol in matche...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/j.1365-2125.1985.tb05042.x
更新日期：1985-08-01 00:00:00
abstract：:1. The study was performed to determine the sensitivity and short-term and day-to-day variability of a novel technique based on laser interferometry of ocular fundus pulsations and of non-invasive methods for the quantification of haemodynamic drug effects. An additional aim was to assess sex differences in haemodynam...
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.1365-2125.1995.tb04462.x
更新日期：1995-04-01 00:00:00
abstract：AIMS:To investigate the extent of concomitant use of analgesic and psychotropic medicines among home-dwelling elderly people aged at least 75 years in Finland. METHODS:This was a population-based study in Finland, performed as part of Kuopio 75 + study focusing on the clinical epidemiology of diseases, medication and ...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章,随机对照试验
doi：10.1111/j.1365-2125.2005.02417.x
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abstract：:1 The relationship between serum quinidine levels and rate-corrected QT (QTc) interval after administration of single identical doses of quinidine was assessed. Quinidine concentrations were determined by a modification of Hamfelt & Malers' (1963) method. The significance and clinical application of our findings is di...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/j.1365-2125.1974.tb01694.x
更新日期：1974-12-01 00:00:00
abstract：:1. The relative bioavailability of cyclosporin was studied in 11 healthy volunteers after single oral capsule doses of cyclosporin on three separate occasions; fasting, with breakfast and with breakfast together with bile acid tablets (400 mg of cholic acid and 100 mg of dehydrocholic acid). 2. There was a significant...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/j.1365-2125.1990.tb03677.x
更新日期：1990-05-01 00:00:00
abstract：:1. The effect of nomifensine on the uptake of 5-hydroxytryptamine (5-HT) and dopamine (DA) into human platelet-rich plasma has been studied. 2. A significant inhibition of DA uptake was observed at nomifensine 10(-6) M. 3. 5-HT uptake was significantly inhibited only at nomifensine 10(-4) M or more. 4. These results a...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/j.1365-2125.1977.tb05745.x
更新日期：1977-01-01 00:00:00
abstract：:1. The efficacy of a metered dose inhaler (MDI) is highly dependent on the mode of inhalation. The relatively high built-in resistance in the Turbohaler (TBH), a new dry powder inhaler device for inhalation of terbutaline sulphate and budesonide, reduces the flow during inhalation. We compared five different modes of ...
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.1365-2125.1992.tb04064.x
更新日期：1992-04-01 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
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abstract：:1 The effect of pregnancy on the binding of phenytoin and phenobarbitone to serum proteins was studied in normal women and in drug treated epileptic women. 2 The binding of both drugs was reduced during pregnancy. The reduction correlated positively with the gestational age and negatively with the serum albumin concen...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/j.1365-2125.1982.tb01420.x
更新日期：1982-04-01 00:00:00
abstract：:Essential hypertension is an escalating problem for industrialized populations. It is currently seen as a 'complex' genetic trait caused by multiple susceptibility genes the effects of which are modulated by gene-environment and gene-gene interactions. Nevertheless, the success to date in identifying these susceptibil...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章,评审
doi：10.1046/j.1365-2125.2001.01254.x
更新日期：2001-01-01 00:00:00
abstract：AIMS:To characterize potential mechanism-based inactivation (MBI) of major human drug-metabolizing cytochromes P450 (CYP) by monoamine oxidase (MAO) inhibitors, including the antitubercular drug isoniazid. METHODS:Human liver microsomal CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A activities were investigated following c...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/j.1365-2125.2006.02627.x
更新日期：2006-05-01 00:00:00
abstract：AIMS:To investigate the relationships between pretreatment folate concentrations, MTX pharmacokinetics and acute toxicities following high dose methotrexate (HD MTX) therapy. METHODS:MTX and its major extracellular metabolite 7-OH-MTX were measured in eight serum samples per HD MTX cycle in 65 consecutive osteosarcoma...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/j.1365-2125.2011.04054.x
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abstract：:Although blood pressure measured at the brachial artery plays a central role in our understanding and management of cardiovascular risk, in recent years great emphasis has been placed on the importance of central blood pressure. It seems straightforward that knowledge of the blood pressure directly affecting the major...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章,评审
doi：10.1111/j.1365-2125.2012.04203.x
更新日期：2012-08-01 00:00:00
abstract：AIMS:Roux-en-Y gastric bypass (RYGB) alters the anatomical structure of the gastrointestinal tract, which can result in alterations in drug disposition. The aim of the present study was to evaluate the oral disposition of two compounds belonging to the Biopharmaceutical Classification System Class II - fenofibrate (bil...
journal_title：British journal of clinical pharmacology
pub_type： 临床试验,杂志文章
doi：10.1111/bcp.13054
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journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1046/j.1365-2125.2001.01336.x
更新日期：2001-04-01 00:00:00
abstract：:Studies were done to examine the influence of the menstrual cycle on the elimination kinetics of paracetamol. Salivary concentrations of paracetamol were determined after oral administration of 1 g of paracetamol on day 3, 10, 14, 20 and 25 of the menstrual cycle in normal healthy women volunteers with regular menstru...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/j.1365-2125.1987.tb03056.x
更新日期：1987-03-01 00:00:00
abstract：AIM:To assess the effect of Schisandra sphenanthera extract (SchE) on the pharmacokinetics of tacrolimus in healthy volunteers. METHODS:Twelve healthy male volunteers were orally treated with SchE, three capsules twice daily for 13 days. Pharmacokinetic investigations of oral tacrolimus administration at 2 mg were per...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/j.1365-2125.2007.02922.x
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abstract：:1. We investigated the effect of the haemostatic agent ethamsylate on aspirin-induced gastric mucosal bleeding. 2. Eighteen healthy subjects were studied three times: at the end of 48 h periods of treatment with (a) placebo, (b) aspirin 600 mg four times daily, (9 doses) and (c) aspirin 600 mg four times daily with ea...
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.1365-2125.1989.tb03512.x
更新日期：1989-07-01 00:00:00
abstract：AIMS:Venlafaxine may increase the risk of arrhythmia in certain patients. We sought to characterize the cardiovascular effects of venlafaxine overdose in adults. METHODS:A retrospective casenote review of patients admitted to the Royal Infirmary of Edinburgh between January 2000 and June 2006. Haemodynamic and electro...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章,评审
doi：10.1111/j.1365-2125.2007.02849.x
更新日期：2007-08-01 00:00:00
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：:1 Roth et al. (1972) have proposed that within the affective disorders there are two distinct syndromes--anxiety and depression--differentiated by the relative predominance of these symptoms, the presence or absence of premorbid maladaptive traits, and the natural outcome of the disorder. 2 Goldberg (1982) on the othe...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/j.1365-2125.1983.tb05859.x
更新日期：1983-01-01 00:00:00
abstract：:Three hypothalamic regulatory hormones, thyrotrophin-releasing hormone (TRH), luteinizing hormone/follicle-stimulating hormone-releasing hormone (LH/FSH-RH) and growth hormone-release inhibiting hormone (GH-RIH) given intravenously had no effect on the electroencephalographic response known as the contingent negative ...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/j.1365-2125.1976.tb04871.x
更新日期：1976-08-01 00:00:00
abstract：AIMS:To examine the feasibility of using the human iris in vivo for the assessment of the interaction between tyramine and monoamine oxidase (MAO) inhibitors. To examine the relative roles of the two forms of MAO in terminating the response to sympathomimetic amines in the iris, by comparing the effects of single oral ...
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.1365-2125.1998.00729.x
更新日期：1998-06-01 00:00:00
abstract：:1 The pharmacokinetics of diazepam following intravenous administration have been investigated in six normal volunteers and nine epileptic patients receiving chronic antiepileptic drug therapy. 2 After intravenous administration, serum diazepam levels declined biexponentially in all subjects. The elimination half-life...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/j.1365-2125.1981.tb01317.x
更新日期：1981-12-01 00:00:00
abstract：:Activation of mu opioid receptors on sensory nerves in the lung represents an attractive mechanism for reducing cough and reflex bronchoconstriction. We have examined the effect of the peptide 443C81, a peripherally acting mu opioid agonist, on the cough and reflex increase in respiratory resistance (Rrs) produced by ...
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.tb03966.x
更新日期：1991-11-01 00:00:00
abstract：AIMS:Surgical site infections contribute to morbidity and mortality after surgery. The authors hypothesized that higher antibiotic tissue concentrations can be reached for a prolonged time span by continuous administration of prophylactic cefuroxime compared to bolus administration. METHODS:Twelve patients undergoing ...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/bcp.13865
更新日期：2019-04-01 00:00:00
