British Journal of Clinical Pharmacology - Volume 73 Issue 3 (March 2012)

1. Cardiac safety, drug‐induced QT prolongation and torsade de pointes (TdP)

Date: Feb 13, 2012, Pages: 331-334

2. A unified pharmacokinetic approach to individualized drug dosing

Date: Feb 13, 2012, Pages: 335-339

3. The pharmacogenetics of the response to warfarin in Chinese

Date: Feb 13, 2012, Pages: 340-347

Warfarin is a commonly used oral anticoagulant with a narrow therapeutic range and large interindividual variability in daily dose. Compared with Caucasians, Chinese are known to require lower doses of warfarin. Differences between Caucasians and Chinese in the allelic frequencies of two genes, CYP2C9 and VKORC1, largely explain the difference in dose requirement. There are other genetic polymorphisms that may further explain the response ...

4. Alcoholic neuropathy: possible mechanisms and future treatment possibilities

Date: Feb 13, 2012, Pages: 348-362

Chronic alcohol consumption produces painful peripheral neuropathy for which there is no reliable successful therapy, mainly due to lack of understanding of its pathobiology. Alcoholic neuropathy involves coasting caused by damage to nerves that results from long term excessive drinking of alcohol and is characterized by spontaneous burning pain, hyperalgesia and allodynia. The mechanism behind alcoholic neuropathy is not well understood,...

5. The analgesic effect of pregabalin in patients with chronic pain is reflected by changes in pharmaco‐EEG spectral indices

Date: Feb 13, 2012, Pages: 363-372

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Pregabalin is an anticonvulsive agent prescribed as a secondary analgesic for patients when standard pain treatment is insufficient. • The analgesic effect resides in the central nervous system. • The central analgesic effect can be evaluated by electroencephalography. WHAT THIS STUDY ADDS • The analgesic effect of...

6. Mechanism‐based population modelling of the effects of vildagliptin on GLP‐1, glucose and insulin in patients with type 2 diabetes

Date: Feb 13, 2012, Pages: 373-390

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Vildagliptin is a potent and selective inhibitor of dipeptidylpeptidase‐IV (DPP‐4). • DPP‐4 inhibition leads to increased active glucagon‐like peptide 1 (GLP‐1) concentrations and decreased plasma glucose in patients with type 2 diabetes. WHAT THIS STUDY ADDS • No mechanism‐based population PD modelling has been...

7. Mechanism‐based population pharmacokinetic modelling in diabetes: vildagliptin as a tight binding inhibitor and substrate of dipeptidyl peptidase IV

Date: Feb 13, 2012, Pages: 391-401

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Vildagliptin is a novel antidiabetic agent that acts by inhibiting dipeptidyl peptidase IV (DPP‐4). • DPP‐4 inhibition results in higher active concentrations of incretin hormone, glucagon‐like peptide 1 (GLP‐1), leading to reduced glucose concentrations. • Mechanism‐based modelling of the pharmacokinetics (PK) of vildagliptin and its DPP‐4...

8. Population pharmacokinetics and pharmacodynamics of escitalopram in overdose and the effect of activated charcoal

Date: Feb 13, 2012, Pages: 402-410

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Escitalopram is a selective serotonin re‐uptake inhibitor and the S‐enantiomer of racemic citalopram. Previous studies have shown that the most clinically important effect of escitalopram overdose is QT prolongation with the associated risk of torsade de pointes. It remains unclear at what dose the risk of QT prolongation is important and whether decontamination will reduce ...

9. Pharmacokinetic interaction between domperidone and ketoconazole leads to QT prolongation in healthy volunteers: a randomized, placebo‐controlled, double‐blind, crossover study

Date: Feb 13, 2012, Pages: 411-421

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Domperidone, a dopamine antagonist metabolized mainly by CYP3A, has been used as an anti‐emetic and prokinetic agent by mouth for over 30 years. • Domperidone has a good safety record. However, early studies of high dose intravenous domperidone were associated with QTc prolongation and arrhythmias, including torsade de pointes. ...

10. The effect of staggered administration of zinc sulfate on the pharmacokinetics of oral cephalexin

Date: Feb 13, 2012, Pages: 422-427

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Zinc supplementation is an important intervention against mortality from infectious disease. • Many patients using zinc supplementation will also be prescribed antimicrobials at some time. • Recently, an inhibitory effect of zinc on the absorption of β‐lactam antibiotics has been demonstrated in animal studies, but there has been no clinical assessment...

11. Impact of genetic factors ( VKORC1, CYP2C9, CYP4F2 and EPHX1 ) on the anticoagulation response to fluindione

Date: Feb 13, 2012, Pages: 428-436

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • CYP2C9 and VKORC1 genetic variants contribute to differences in patients' responses to anticoagulant coumarin derivatives. Patients carrying the VKORC1 1173TT genotype have a decreased time to the first INR within the therapeutic range and to the first INR >4, and also require lower warfarin maintenance doses. Patients carrying the *2 or *3 CYP2C9 allele have lower maintenance...

12. Reported paediatric adverse drug reactions in the UK 2000–2009

Date: Feb 13, 2012, Pages: 437-446

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Use of off‐label and unlicensed medicines in children is associated with a higher risk of adverse drug reactions (ADRs). • Spontaneous reporting systems such as the UK Yellow Card Scheme run by the Medicines and Healthcare Products Regulatory Agency (MHRA) are important in identifying signals of ADRs. • Up to 95% of all ADRs are not reported,...

13. The safety and tolerability of spironolactone in patients with mild to moderate chronic kidney disease

Date: Feb 13, 2012, Pages: 447-454

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Spironolactone has recently been shown to exert beneficial effects on the cardiovascular and renal systems. To date, its use in patients with chronic kidney disease has been limited due to potential risks of hyperkalaemia and declining renal dysfunction. WHAT THIS STUDY ADDS • Non‐diabetic patients with early stage chronic kidney disease...

14. Comparison of the effects of levofloxacin on QT/QTc interval assessed in both healthy Japanese and Caucasian subjects

Date: Feb 13, 2012, Pages: 455-459

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Although the ICH guidelines state that it is not expected that the results of a ‘thorough QT interval/corrected QT interval (QT/QTc)’ study would be affected by ethnic factors and would consequently be independent of the race of the study population, there is little documented evidence to support or refute this. • Since 2010, the ICH E14 guidelines have...

15. Is a positive history of non‐anaesthetic drug allergy a predictive factor for positive allergy tests to anaesthetics?

Date: Feb 13, 2012, Pages: 460-466

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • International recommendations stipulate not to perform skin tests to a drug in the absence of a clinical history consistent with drug allergy. • In 2006, two publications showed that a positive history of non‐anaesthetic drug allergy was the only predictive factor for allergy to anaesthetic drugs when the screening was done in a general surgical...