Association between the number of coadministered P-glycoprotein inhibitors and serum digoxin levels in patients on therapeutic drug monitoring

BACKGROUND: The ABC transporter P-glycoprotein (P-gp) is recognized as a site for drug-drug interactions and provides a mechanistic explanation for clinically relevant pharmacokinetic interactions with digoxin. The question of whether several P-gp inhibitors may have additive effects has not yet been addressed. METHODS: We evaluated the effects on serum concentrations of digoxin (S-digoxin) in 618 patients undergoing therapeutic drug monitoring. P-gp inhibitors were classified as Class I, with a known effect on digoxin kinetics, or Class II, showing inhibition in vitro but no documented effect on digoxin kinetics in humans. Mean S-digoxin values were compared between groups of patients with different numbers of coadministered P-gp inhibitors by a univariate and a multivariate model, including the potential covariates age, sex, digoxin dose and total number of prescribed drugs. RESULTS: A large proportion (47%) of the digoxin patients undergoing therapeutic drug monitoring had one or more P-gp inhibitor prescribed. In both univariate and multivariate analysis, S-digoxin increased in a stepwise fashion according to the number of coadministered P-gp inhibitors (all P values < 0.01 compared with no P-gp inhibitor). In multivariate analysis, S-digoxin levels were 1.26 ± 0.04, 1.51 ± 0.05, 1.59 ± 0.08 and 2.00 ± 0.25 nmol/L for zero, one, two and three P-gp inhibitors, respectively. The results were even more pronounced when we analyzed only Class I P-gp inhibitors (1.65 ± 0.07 for one and 1.83 ± 0.07 nmol/L for two). CONCLUSIONS: Polypharmacy may lead to multiple drug-drug interactions at the same site, in this case P-gp. The S-digoxin levels increased in a stepwise fashion with an increasing number of coadministered P-gp inhibitors in patients taking P-gp inhibitors and digoxin concomitantly. As coadministration of digoxin and P-gp inhibitors is common, it is important to increase awareness about P-gp interactions among prescribing clinicians

The role of antifungals in the management of patients with severe asthma

In patients with asthma, the inhalation of elevated amounts of fungal spores and hyphae may precipitate the onset of asthma or worsen control to the extent of being life-threatening. Sensitisation to fungi, especially Aspergillus fumigatus, is found in 15% to 48% of asthmatics in secondary care and is linked to worse asthma control, hospitalisation, bronchiectasis and fixed airflow obstruction, irrespective of whether allergic bronchopulmonary aspergillosis (ABPA) is diagnosed. ABPA represents a florid response to the presence of Aspergillus spp. but up to 70% of patients with severe asthma exhibit sensitisation to different fungi without meeting the diagnostic criteria for ABPA. The presence of persistent endobronchial colonisation with fungi, especially A. fumigatus, is linked to significantly higher rates of radiological abnormalities, lower post-bronchodilator FEV1 and significantly less reversibility to short acting bronchodilators. The therapeutic benefit for antifungal intervention in severe asthma is based on the assumption that reductions in airway fungal burden may result in improvements in asthma control, lung function and symptoms (especially cough). This contention is supported by several prospective studies which demonstrate the effectiveness of antifungals for the treatment of ABPA. Significantly, these studies confirm lower toxicity of treatment with azoles versus high dose oral corticosteroid dosing regimens for ABPA. Here we review recent evidence for the role of fungi in the progression of severe asthma and provide recommendations for the use of antifungal agents in patients with severe asthma, airways fungal infection (mycosis) and fungal colonisation. Documenting fungal airways colonisation and sensitisation in those with severe asthma opens up alternative therapy options of antifungal therapy, which may be particularly valuable in low resource settings

Changes in Circulating Androgens During Short-Term Carbamazepine Therapy

Serum concentrations of testosterone, androstenedione, dehydroepiandrosterone sulphate (DHAS), sex hormone binding globulin (SHBG) and luteinising hormone (LH) were measured before, during and after 21 days treatment with carbamazepine (CBZ)400 mg daily in six healthy male subjects. Induction of hepatic microsomal enzyme activity was confirmed by an increase in antipyrine clearance (P less than 0.02) and a fall in circulating CBZ concentrations from the seventh to the fourteenth CBZ dose (P less than 0.05). Within 7 days of starting CBZ there was a rise in SHBG (P less than 0.05) and a fall in testosterone, free testosterone fraction, DHAS and androstenedione (P less than 0.05). Testosterone, free testosterone fraction and androstenedione levels rose towards baseline by the end of the treatment period while DHAS concentration remained low (P less than 0.05). The rise in SHBG and increased androgen catabolism is most likely to be secondary to induction of hepatic monooxygenase activity by CBZ. These changes may be implicated in the production of sexual dysfunction encountered in some epileptic patients on chronic anticonvulsant therapy

Cognitive effects of adjunctive perampanel for partial-onset seizures: A randomized trial

Objective Assess cognitive effects of adjunctive perampanel in adolescents. Methods In this double-blind study (ClinicalTrials.gov identifier: NCT01161524), patients aged 12 to <18 years with partial-onset seizures despite receiving 1–3 antiepileptic drugs were randomized (2:1) to perampanel or placebo. Perampanel was increased weekly in 2-mg increments to 8–12 mg/day (6-week titration; 13-week maintenance). Changes in neuropsychological outcomes were assessed at end of maintenance: Cognitive Drug Research (CDR) System Global Cognition Score (primary end point), five CDR System domain T-scores (secondary end points), letter fluency, category fluency, and Lafayette Grooved Pegboard Test (LGPT). Results One hundred thirty-three patients were randomized. In the full analysis set, there were no differences of perampanel (n = 79) vs. placebo (n = 44) in CDR System Global Cognition Score (least squares mean change, −0.6 vs. 1.6; p = 0.145), Quality of Working Memory (1.1 vs. 2.0; p = 0.579), or Power of Attention (−6.9 vs. −2.7; p = 0.219). There were small differences with perampanel vs. placebo in other CDR System domains: improvements in Quality of Episodic Memory (3.0 vs. −1.2; p = 0.012), and worsening in Continuity of Attention (−3.3 vs. 1.6; p = 0.013) and Speed of Memory (0.3 vs. 7.0; p = 0.032). Letter fluency, category fluency, and LGPT were not significantly different between groups. The most frequent adverse events with perampanel were dizziness (30.6%) and somnolence (15.3%). Significance Perampanel did not differ from placebo in the global cognitive score, two of five subdomains, and four other cognitive measures. Perampanel was worse on two and better on one subdomain