European journal of clinical pharmacology
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Eur. J. Clin. Pharmacol. · Apr 2013
Clinical TrialAcetaminophen protein adduct formation following low-dose acetaminophen exposure: comparison of immediate-release vs extended-release formulations.
Acetaminophen (APAP) protein adducts are a biomarker of APAP metabolism, reflecting oxidation of APAP and generation of the reactive metabolite N-acetyl-p-benzoquinone imine. High levels of adducts correspond to liver toxicity in patients with APAP-related acute liver failure. Adduct formation following low-dose exposure to APAP has not been well studied. APAP protein adducts were measured in blood samples collected from fasted individuals who participated in a crossover study of APAP (80 mg/kg) comparing extended release (ER) and immediate release (IR) formulations. ⋯ APAP protein adducts are rapidly formed following nontoxic ingestion of APAP at levels significantly lower than those associated with acute liver failure.
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Eur. J. Clin. Pharmacol. · Apr 2013
Randomized Controlled TrialTiclopidine inhibits both O-demethylation and renal clearance of tramadol, increasing the exposure to it, but itraconazole has no marked effect on the ticlopidine-tramadol interaction.
We assessed possible drug interactions of tramadol given concomitantly with the potent CYP2B6 inhibitor ticlopidine, alone or together with the potent CYP3A4 and P-glycoprotein inhibitor itraconazole. ⋯ Ticlopidine increased exposure to tramadol, reduced its renal clearance and inhibited the formation of M1, most likely via inhibition of CYP2B6 and/or CYP2D6. The addition of itraconazole to ticlopidine did not modify the outcome of the drug interaction. Concomitant clinical use of ticlopidine and tramadol may enhance the risk of serotonergic effects, especially when higher doses of tramadol are used.
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Eur. J. Clin. Pharmacol. · Apr 2013
Orphan drugs, orphan diseases. The first decade of orphan drug legislation in the EU.
To assess the methodological quality of Orphan Medicinal Product (OMP) dossiers and discuss possible reasons for the small number of products licensed. ⋯ Although there may have been some small improvements over time in the methods for developing OMPs, in our opinion, the number of patients studied, the use of placebo as control, the type of outcome measure and the follow-up have often been inadequate. The present system should be changed to find better ways of fostering the development of effective and sustainable treatments for patients with orphan diseases. Public funds supporting independent clinical research on OMPs could bridge the gap between designation and approval. More stringent criteria to assess OMPs' efficacy and cost/effectiveness would improve the clinical value and the affordability of products allowed onto the market.
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Eur. J. Clin. Pharmacol. · Apr 2013
Contribution of prolonged-release melatonin and anti-benzodiazepine campaigns to the reduction of benzodiazepine and Z-drugs consumption in nine European countries.
Benzodiazepines (BZD) and benzodiazepine receptor agonists (zolpidem, zaleplon, zopiclone, altogether Z-drugs) are most commonly prescribed for the treatment of insomnia. However, long-term use of BZD/Z-drugs is associated with major adverse events including, but not limited to, falls and fractures, domestic and traffic accidents, confusion, cognitive impairment, Alzheimer's disease and cancer. The prolonged use of these drugs is thought to be related to severe withdrawal symptoms and potential dependency. The chronic and extensive use of BZD/Z drugs has become a public health issue and has led to multiple campaigns to reduce both prescription and consumption of BZD/Z-drugs. Prolonged-release (PR) melatonin is the first of a new class of melatonin receptor agonist drugs that has demonstrated clinically relevant efficacy on improving quality of sleep and morning alertness, with a good safety profile. ⋯ Campaigns aiming to reduce the use of BZD/Z-drugs failed when they were not associated with the availability and market uptake of PR-melatonin. The reimbursement of PR-melatonin supports better penetration rates and a higher reduction in sales for BZD/Z-drugs.
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While some people remain fit and active as they grow older, others experience complex problems: disease, dependency and disability. Frailty is a term used to describe this latter group, capturing differences in health status among older people. Many frail older people have multiple chronic co-morbidities and functional impairments and, according to guidelines for the management of individual conditions, should be prescribed long lists of medications. However, older people (particularly those who are frail) are often excluded from drug trials, and treatment decisions are therefore based on evidence extrapolated from more robust patient groups with fewer physiological deficits. The risk of adverse drug reactions (ADRs) increases with increasing patient frailty, and polypharmacy has negative consequences above and beyond the risks of individual drugs. Increasing numbers of medications are associated with a higher likelihood of non-adherence and a significantly greater risk of ADRs. Older people taking five or more medications are at higher risk of delirium and falls, independent of medication indications. ⋯ Since all physicians are likely to provide care for this group of vulnerable patients, understanding the concept of frailty may help to optimise medication prescribing for older people. The incorporation of frailty measures into future clinical studies of drug effects and pharmacokinetics is important if we are to improve medication use and guide drug doses for fit and frail older people.