British Journal of Clinical Pharmacology - Accepted Articles

1. The Risk of Adverse Outcomes in Association with Use of Testosterone Products: A Cohort Study using the UK‐based General Practice Research Database

Date: May 11, 2012

Structured Summary AIMS: To study the relative safety of the intramuscular injection formulation of testosterone with oral testosterone undecanoate in relation to the risks for hypertension, polycythemia, prostate cancer, benign prostatic hypertrophy (BPH), and prostatism. METHODS: We conducted a cohort study of men in the UK based General Practice Research Database who were users of the oral undecanoate and...

2. Dose‐Independent Kinetics with Low Level Exposure to Nicotine and Cotinine

Date: May 11, 2012

abstract In studying the effects of exposure to secondhand smoke (SHS) levels of cotinine (the proximate metabolite of nicotine), measured in plasma, urine or saliva, are widely used as indicators of nicotine exposure [1]. In interpreting the levels of cotinine in non‐smokers relative to levels in smokers, the assumption is made that the pharmacokinetics of nicotine and cotinine are independent of level of nicotine exposure. ...

3. Pioglitazone and bladder cancer: A propensity score matched cohort study

Date: May 11, 2012

Summary AIM: To examine whether exposure to pioglitazone use is associated with increased incidence of bladder cancer in patients with type 2 diabetes mellitus. METHODS: A cohort study was done in the General Practice Research Database (GPRD) between 2001 and 2010. 207,714 patients aged ≥40 years with type 2 diabetes were studied (23,548 exposed to pioglitazone and 184,166 exposed to other antidiabetic...

4. Apple Juice Greatly Reduces Systemic Exposure to Atenolol

Date: May 11, 2012

Abstract Aim: Fruit juice reduces the plasma concentrations of several beta‐blockers, likely by inhibiting OATP2B1‐mediated intestinal absorption. The aim of this study was to investigate the effects of apple juice on the pharmacokinetics of atenolol. Methods: Twelve healthy Korean volunteers with genotypes of SLCO2B1 c.1457C> T (*1/*1 (n=6) and *3/*3 (n=6)) were enrolled in this study. In a three‐phase, one‐sequence...

5. Generics, Chemisimilars and Biosimilars: is clinical testing fit for purpose?

Date: May 11, 2012

Summary The effectiveness and safety of generic drugs is backed by sound physicochemical control and regulatory bioequivalence acceptance criteria. Statistical testing of bioequivalence, comparing the pharmacokinetic profiles of the test and reference products, was made possible by modern drug assays. When the pharmacokinetic profile correlates with the dose, such comparisons show assay sensitivity and readily detect differences in...

6. Pharmacokinetic and Pharmacodynamic profiling of P2X7 receptor allosteric modulator GSK1482160 in Healthy Human subjects

Date: May 08, 2012

Summary Aims: This paper describes findings from the first‐in‐human study for GSK1482160, an orally available allosteric P2X7 receptor modulator. The study aimed to assess the pharmacokinetics (PK), pharmacodynamics (PD), safety and tolerability of the compound in healthy subjects. Methods: Escalating single doses of up to one gram were administered to healthy subjects in a single‐blind and placebo‐controlled ...

7. RE: Darren G N Craig, Caroline M Bates, Janice S Davidson, Kirsty G Martin, Peter C Hayes, Kenneth J Simpson 
Staggered overdose pattern and delay to hospital presentation are associated with adverse outcomes following paracetamol‐induced hepatoto

Date: May 08, 2012

abstract This article had a strong following in German pharmaceutical, medical and life style media, which aroused my interest in this publication. Unfortunately, the authors failed to mention their previous evaluation of the same data set published in Br. J Clin Pharmacol. in the spring of 2011. In this paper the investigated categories were Intentional Overdose, Unintentional Overdose and Intention ...

8. Roger Finch, Peter Davey, Mark Wilcox, William Irving Antimicrobial Chemotherapy 6 ^th edition, OUP 2012

Date: May 08, 2012

abstract As junior registrars learning the ropes of medical microbiology back in the early 80s (when the first edition of Antimicrobial Chemotherapy was published), we decided that advising on antibiotics was probably the easiest part of the job‐at least, compared with learning infectious diseases, trying to think of some decent research, and dealing with consultant surgeons. In those days the problem of multi‐resistant Klebsiella was more or...

9. “Response to Dr Reiter”

Date: May 08, 2012

Abstract We are very grateful to the editors for allowing us the opportunity to respond to the issues raised by Dr Reiter following his analysis of our data from our two recent publications in the British Journal of Clinical Pharmacology (BJCP).[1,2] We fully acknowledge the seriousness of our omission in not citing our earlier paper.[1] This highly regrettable oversight stemmed from the close temporal nature of the drafting and...

10. Inhaled and Systemic Corticosteroid Response in Severe Asthma Assessed by Alveolar Nitric Oxide: a randomised crossover pilot study of add‐on therapy

Date: May 08, 2012

ABSTRACT Aims: Alveolar nitric oxide (CANO) is a potential biomarker of small airway inflammation. We investigated effects on CANO of the addition of coarse and fine particle inhaled corticosteroids to standard therapy in severe asthma. Methods: Severe asthmatics taking ≥1600µg/day budesonide or equivalent performed a randomised open‐label crossover study. Subjects with FEV1<80%, gas trapping and CANO≥2ppb entered a...

11. Effects of clopidogrel and itraconazole on the disposition of efavirenz and its hydroxyl‐metabolites: exploration of a novel CYP2B6 phenotyping index

Date: May 03, 2012

Summary AIMS: To evaluate the effects of clopidogrel and itraconazole on the disposition of efavirenz and its hydroxyl‐metabolites in relation to the CYP2B6*6 genotype and explore potential phenotyping indices for CYP2B6 activity in vivo using a low dose of oral efavirenz. METHODS: We conducted a randomized 3‐phase crossover study in 17 healthy Korean subjects pre‐genotyped for the CYP2B6*6 allele (CYP2B6*1/*1, n= 6; *1/*6,...

12. Monitoring Medicines Use and Reducing Medication errors: The role of the Clinical Pharmacologist

Date: May 03, 2012

Abstract Appreciation of the potential of newly marketed medicines to produce both benefit and harm has increased the role of the clinical pharmacologist. Pharmacoepidemiology applies epidemiological reasoning, methods and knowledge to the study of the uses and effects of drugs in human populations. Pharmacovigilence, identifies and then responds to safety issues about marketed drugs. Whilst adverse drug reaction (ADR) reporting...

13. Piecing together the puzzle of progression and mortality in Parkinson's disease

Date: May 03, 2012

Summary Parkinson's disease is a chronic, progressive disease that affects motor, autonomic, cognitive and emotional function and reduces lifespan. The rate of progression and survival in patients with Parkinson's disease is highly variable. The reasons for this are unknown, although some associations have been established. Vu et al. have undertaken a complex modeling analysis of a clinical trial dataset to investigate predictors...

14. Prescribing errors in hospital practice

Date: May 03, 2012

Summary Prescribing errors that occur in hospitals have been a source of concern for decades. This narrative review describes some of the recent work in this field. There is considerable heterogeneity in definitions and methods used in research on prescribing errors. There are three definitions that are used most frequently (one for prescribing errors specifically and two for the broader arena of medication errors), although many...

15. Differences between opioids Pharmacological, experimental, clinical and economical perspectives

Date: May 03, 2012

Abstract Clinical studies comparing the response and side effects of various opioids have not been able to show robust differences between drugs. Hence, recommendations of the regulatory authorities have been driven by costs with a general tendency in many countries to restrict physician's use of opioids to morphine. Although this approach is recognised as cost‐effective in most cases there is solid evidence that, on an individual...

16. Developmental pharmacokinetics of propylene glycol in preterm and term neonates

Date: Apr 27, 2012

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 (800mgPG/1000mg paracetamol) or phenobarbital (700mgPG/200mg phenobarbital) in preterm and term neonates. Methods: A population...

17. Sex differences in cardiovascular drug induced adverse reactions causing hospital admissions.

Date: Apr 26, 2012

Abstract Aim: Cardiovascular disease in women is often underestimated. Drug effects of cardiovascular drugs differ between the sexes because of pharmacokinetic and pharmacodynamic differences. Adverse drug reactions (ADRs) within these drug classes may have serious consequences, leading to hospital admission. We aimed to study differences between men and women in hospital admissions for adverse drug reactions due to cardiovascular...

18. Regional differences in symptomatic fever management among pediatricians in Switzerland: The results of a cross‐sectional Web‐based survey

Date: Apr 26, 2012

Structured Summary Aims: In symptomatic fever management, there is often a gap between everyday clinical practice and current evidence. We were interested to see whether the 3 linguistic regions of Switzerland differ in the management of fever. Methods: A close‐ended questionnaire, sent to 900 Swiss pediatricians, was answered by 322 pediatricians. 214 respondents were active in the German‐speaking, 78 in the...

19. Disease Progression Model in MCI Subjects from Alzheimer's Disease Neuroimaging Initiative: CSF Biomarkers Predict Population Subtypes

Date: Apr 25, 2012

ABSTRACT AIMS:  The objective is to develop a semi‐mechanistic disease progression model for mild cognitive impairment (MCI) subjects. The model aims to describe the longitudinal progression of ADAS‐cog scores from the Alzheimer's disease neuroimaging initiative trial that had data from 198 MCI subjects with cerebrospinal fluid (CSF) information who were followed for three years. METHODS:  Various covariates...

20. Birth weight and cytochrome P4503A4/5 activity in obese women.

Date: Apr 25, 2012

21. Serum and Urine Bone Resorption Markers and Pharmacokinetics of Cathepsin K Inhibitor ONO‐5334 after Ascending Single Doses in Post‐menopausal Women

Date: Apr 25, 2012

Structured summary Aims:  To investigate the safety, pharmacokinetics and pharmacodynamics of the new cathepsin K inhibitor, ONO‐5334. Methods:  A double‐blind, placebo‐controlled, randomised study in 52 healthy post‐menopausal females. Single ascending doses of ONO‐5334 (3‐600mg) were evaluated in 6 cohorts. Effect of food was studied at ONO‐5334 100mg. Results:  Across the doses tested,...

22. Rapid Clinical Induction of Bupropion Hydroxylation by Metamizole in Healthy Chinese Men

Date: Apr 23, 2012

ABSTRACT Aims: This study was aimed to investigate the effect of metamizole on bupropion hydroxylation related to different CYP2B6 genotype groups in healthy volunteers. Methods: Sixteen healthy male volunteers (6 CYP2B6*1/*1, 6 CYP2B6*1/*6 and 4 CYP2B6*6/*6) received orally administered bupropion alone and during daily treatment with metamizole 1500 mg day‐1 (500‐mg tablet taken three times daily) for four days. Serial...

23. Paediatric use of Mycophenolate Mofetil

Date: Apr 23, 2012

Abstract A number of medications do not have a license, or label, for use in the paediatric age group nor for the specific indication being treated for in children. Over recent years mycophenolate mofetil has increasingly been used off‐label (i.e. off‐license) in adults for a number of indications including autoimmune conditions: progressively this wider use has been extended to children. This review summarises current use of...

24. Efficacy and safety of venous thromboembolism prophylaxis with fondaparinux or low‐molecular weight heparin in a large cohort of consecutive patients undergoing major orthopaedic surgery – findings from the ORTHO‐TEP registry.

Date: Apr 20, 2012

Summary Objectives:  In large randomized trials, thromboprophylaxis with fondaparinux in major orthopaedic surgery (MOS) has been shown superior over low molecular weight heparin (LMWH) prophylaxis with comparable safety. However, patient treated under trial conditions are different from unselected patients and efficacy and safety outcomes may be different in unselected patients in daily practice. We performed a retrospective cohort...

25. Acute hemodynamic response in relation to plasma vardenafil levels in patients with pulmonary hypertension

Date: Apr 20, 2012

Structured summary Aims:  To evaluate the acute hemodynamic effects of a single oral dose of vardenafil, and study the drug concentration in relation to hemodynamic effects in patients with pulmonary hypertension (PH). Methods:  Sixteen patients with PH (aged 29‐85 years), received one single oral dose of vardenafil (5, 10, or 20 mg). The hemodynamic effect was assessed over a 60‐min period. Vardenafil plasma...

26. Integrated pharmacokinetics and pharmacodynamics of epoprostenol in healthy subjects

Date: Apr 20, 2012

Summary AIMS: Report the first thorough characterization of the pharmacokinetics (PK) and pharmacodynamics (PD) of epoprostenol in an integrated manner. METHODS: Twenty healthy male subjects received two formulations of intravenous epoprostenol, in a cross‐over design, in sequential infusions of 2, 4, 6, and 8 ng/kg/min for 2 h each. A sensitive assay was developed which allowed accurate PK characterisation ...

27. Severe efavirenz‐induced vacuolar axonopathy complicated by fatal aspiration pneumonia

Date: Apr 18, 2012

28. e‐Learning initiatives to support prescribing

Date: Apr 18, 2012

Summary Preparing medical students to prescribe is a major challenge of undergraduate education. They must develop an understanding of clinical pharmacology, and acquire knowledge about drugs and therapeutics, as well as the skills to prescribe for individual patients in the face of multiple variables. The task of delivering the learning required to achieve these attributes relies upon limited numbers of teachers, who have...

29. How biologics targeting the IL‐1 system are being considered for the treatment of type 2 diabetes

Date: Apr 17, 2012

Abstract Metabolic diseases are associated with activation of the innate immune system in various tissues and characterised by elevated inflammatory factors and the presence of immune cells. Type 2 diabetes develops when islet beta‐cells are deficient in producing sufficient insulin to overcome peripheral insulin resistance. Intra‐islet IL‐1β activity diminishes beta‐cell function and survival and governs islet inflammation....

30. Androgens and doping tests: Genetic variation and pit‐falls

Date: Apr 17, 2012

ABSTRACT The large variation in disposition known for most drugs is also true for anabolic androgenic steroids. Genetic factors are probably the single most important cause of this variation. Further, there are reasons to believe that there is a corresponding variation in efficacy of doping agents. Doped individuals employ a large variety of doping strategies in respect of choice of substance, dose, dose interval, duration of...

31. CANNABIDIOL AS POTENTIAL ANTICANCER DRUG

Date: Apr 17, 2012

Summary Over the past years, several lines of evidence support an antitumorigenic effect of cannabinoids including Δ9‐tetrahydrocannabinol (Δ9‐THC), synthetic agonists, endocannabinoids and endocannabinoid transport or degradation inhibitors. Indeed, cannabinoids possess anti‐proliferative and pro‐apoptotic effects and they are known to interfere with tumour neovascularization, cancer cell migration, adhesion, invasion and metastasization....

32. Human Microdose Evaluation of the Novel EP1 Receptor Antagonist GSK269984A

Date: Apr 13, 2012

Summary AIMS:  The primary objective was to evaluate the pharmacokinetics (PK) of the novel EP1 antagonist GSK269984A in human volunteers after a single oral and intravenous (i.v.) microdose (100 . METHODS:  GSK269984A was administered to two groups of healthy human volunteers as a single oral (n=5) or i.v. (n=5) microdose (100 . Blood samples were collected for up to 24 hours and the parent drug concentrations were...

33. The effect of omeprazole and esomeprazole on the maintenance dose of phenprocoumon

Date: Apr 12, 2012

© 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society

34. Retrospective Commentary: The Clofibrate Saga

Date: Apr 05, 2012

abstract After many years of study clofibrate, the first of the fibrates, seemed in the 1960s, to be an effective means of lowering raised plasma cholesterol. It provided an opportunity for examining the key question of whether reduction of plasma cholesterol might lead to reduction in the incidence of coronary heart disease (CHD). While small secondary prevention trials looked promising, a large primary prevention trial (the WHO...

35. QRisk or Framingham?

Date: Apr 05, 2012

36. Intravitreal pegaptanib sodium (Macugen ^® ) for treatment of diabetic macular ooedema: a morphologic and functional study.

Date: Apr 05, 2012

ABSTRACT AIMS: To study whether morphologic (foveal thickness, FT) variations of clinical significant macular oedema (CMO) in patients suffering from diabetes following intravitreal pegaptanib sodium (IVP) injection were associated to functional (macular sensitivity‐MS‐ and color discrimination, CD) changes. METHODS: A longitudinal, interventional, non randomized study was performed. FT was assessed by optical...

37. Population Pharmacokinetics of Clindamycin orally and intravenously administrated in osteomyelitis patients.

Date: Apr 05, 2012

Abstract Aims: This study was performed to describe clindamycin concentration‐time courses administrated either orally or intravenously to osteomyelitis patients, to study the effects of different covariates on clindamycin pharmacokinetics and to simulate an optimized administration scheme. Methods: Clindamycin concentrations were measured in 50 patients. A total of 122 plasma concentrations were available (58...

38. Pharmacogenetic Markers of CYP2B6 Associated with Efavirenz Plasma Concentrations in HIV‐1 infected Thai Adults

Date: Apr 04, 2012

Abstract AIMS: To investigate the frequency of CYP2B6 polymorphisms and the influence of haplotype structure on plasma efavirenz concentration in Thai adults with HIV‐1 infection. METHODS: Genotyping of 9 single nucleotide polymorphisms (SNPs; c.64C > T, c.499C > G, c.516G > T, c.785A > G, c.1375A > G, c.1459C > T, g.3003T > C, g.18492C > T, and g.21563C > T) of CYP2B6 were performed using...

39. Meta‐analysis on the association between non‐steroidal anti‐inflammatory drug use and ovarian cancer

Date: Apr 03, 2012

Abstract Aim: Animal and in vitro studies suggest that the use of non‐steroidal anti‐inflammatory drugs (NSAIDs) may be associated with reduced risk for ovarian cancer; however, results from these studies have been inconsistent. The aim of our study is to review and summarize the evidence provided by longitudinal studies on the association between NSAID use and ovarian cancer risk. Methods: A comprehensive...

40. Inhaled LPS challenges in smokers: a study of pulmonary and systemic effects

Date: Mar 30, 2012

Abstract Aims: Lipopolysaccharide (LPS) is a TLR4 agonist which activates NFkB dependent cytokine production. We investigated LPS inhalation in healthy smokers as a model of COPD bacterial exacerbations. We studied safety, reproducibility, the translocation of the NFκB subunit p65 in sputum cells and changes in systemic biomarkers of inflammation. Methods: 12 smokers inhaled 5 and 30 µg LPS; safety was monitored...