Standardizing dose in dosimetric bronchial challenge tests

Recent technical recommendations on bronchial challenge testing aim at standardized assessment of provocative dose of causing 20% decrease in FEV1 (PD20). The aim of this study was to investigate the effect of mode of nebulization on the output of a computerized dosimeter (APS) and to compare PD20 obtained by two different dosimetric systems in vivo. The output of the APS system was tested during continuous nebulization, and using simulated breaths, for intermittent actuations with four different durations. Using output data, a modified methacholine challenge protocol was applied for APS and compared with a standard set‐up using Spira dosimeter in 14 asthmatic patients attending duplicate methacholine challenges using both systems, within median (range) 3 (1–6) days apart. The calculated output (mg min^?1) with all the intermittent mode settings was significantly higher (P<0·001) than in the continuous mode, and in the intermittent mode, the output was dependent of the pulse duration. The PD20 values assessed with the APS and Spira systems were significantly correlated (r = 0·69; P<0·007), without systematic difference in the geometric means (P = 0·10). A moderate to good agreement was found for assessment of significant hyperresponsiveness. The results suggest that in dosimetric systems for bronchial challenge tests, the output of the nebulizer is dependent on the mode of nebulization, and this should be considered when standardizing the dose between devices and protocols. As long as the delivered dose is determined for the specified nebulization mode of the protocol, it may be possible to obtain comparable results between different devices.     

Effects of terbinafine and itraconazole on the pharmacokinetics of orally administered tramadol

Background

Tramadol is widely used for acute, chronic, and neuropathic pain. Its primary active metabolite is O-desmethyltramadol (M1), which is mainly accountable for the μ-opioid receptor-related analgesic effect. Tramadol is metabolized to M1 mainly by cytochrome P450 (CYP)2D6 enzyme and to other metabolites by CYP3A4 and CYP2B6. We investigated the possible interaction of tramadol with the antifungal agents terbinafine (CYP2D6 inhibitor) and itraconazole (CYP3A4 inhibitor).

Methods

We used a randomized placebo-controlled crossover study design with 12 healthy subjects, of which 8 were extensive and 4 were ultrarapid CYP2D6 metabolizers. On the pretreatment day 4 with terbinafine (250 mg once daily), itraconazole (200 mg once daily) or placebo, subjects were given tramadol 50 mg orally. Plasma concentrations of tramadol and M1 were determined over 48 h and some pharmacodynamic effects over 12 h. Pharmacokinetic variables were calculated using standard non-compartmental methods.

Results

Terbinafine increased the area under plasma concentration–time curve (AUC_0-∞) of tramadol by 115 % and decreased the AUC_0-∞ of M1 by 64 % (P?<?0.001). Terbinafine increased the peak concentration (C _max) of tramadol by 53 % (P?<?0.001) and decreased the C _max of M1 by 79 % (P?<?0.001). After terbinafine pretreatment the elimination half-life of tramadol and M1 were increased by 48 and 50 %, respectively (P?<?0.001). Terbinafine reduced subjective drug effect of tramadol (P?<?0.001). Itraconazole had minor effects on tramadol pharmacokinetics.

Conclusions

Terbinafine may reduce the opioid effect of tramadol and increase the risk of its monoaminergic adverse effects. Itraconazole has no meaningful interaction with tramadol in subjects who have functional CYP2D6 enzyme.

     

Potentiation of Glibenclamide Hypoglycaemia in Mice by MK‐467, a Peripherally Acting Alpha2‐Adrenoceptor Antagonist

Pharmacological antagonism and genetic depletion of pancreatic α_2A‐adrenoceptors increase insulin secretion in mice and enhance the insulinotropic action of glibenclamide, a representative of the sulphonylurea class of insulin secretagogues used in the therapy of type 2 diabetes. Antagonism of α₂‐adrenoceptors in the central nervous system (CNS) causes tachycardia and hypertension, making generalized α₂‐adrenoceptor blockade unfavourable for clinical use despite its potential to decrease blood glucose levels. The purpose of this study was to test the acute effects of the peripherally acting α₂‐adrenoceptor antagonist MK‐467 alone and in combination with glibenclamide in non‐diabetic C57BL/6N mice. Cardiovascular safety was assessed in freely moving mice with radiotelemetry. Dose‐dependent decreases in blood glucose and increases in plasma insulin concentrations were seen with the combination of MK‐467 and glibenclamide; the combinations were much more potent than glibenclamide or MK‐467 alone. Furthermore, MK‐467 had no effect on mean arterial pressure or heart rate in freely moving mice and did not prevent the centrally mediated hypotensive effect of the α₂‐adrenoceptor agonist medetomidine. Thus, peripheral blockade of α₂‐adrenoceptors does not evoke the same cardiovascular adverse effects as antagonism of CNS α₂‐adrenoceptors. The current results indicate that the combined use of small doses of a peripherally acting α₂‐adrenoceptor antagonist with a sulphonylurea drug could provide a novel option for the treatment of type 2 diabetes, especially in patients with increased tonic α₂‐adrenoceptor‐mediated inhibition of insulin secretion.     

Demographic Characteristics and Psychiatric Comorbidity of Children and Adolescents Diagnosed with ADHD in Specialized Healthcare

Recent studies have shown an increasing incidence of attention-deficit/hyperactivity disorder (ADHD) among children diagnosed in specialized services. This study aims to describe children with ADHD in Finnish specialized healthcare by reporting the demographic characteristics, time trends in diagnosis, psychiatric comorbidity, and the validity of register-based diagnoses. All the singletons born in Finland between 1991 and 2005 and diagnosed with ADHD by 2011 were identified and their psychiatric comorbidity data was obtained from the Finnish Hospital Discharge Register (FHDR). Parents of 69 patients were interviewed via telephone for a diagnostic validation. A total of 10,409 children were identified with ADHD, with a male: female ratio of 5.3:1 and a psychiatric comorbidity rate of 76.7 %. Of the validation sample 88 % met the diagnostic criteria of ADHD for DSM-IV. There is an increasing trend of ADHD diagnosis among both males and females. Psychiatric comorbidity is common and includes a wide range of disorders among children with ADHD. There was an increase of ADHD diagnoses especially among boys. More attention is needed to detect ADHD among girls in health services. Diagnoses in the FHDR show diagnostic validity and their sociodemographic patterns are in line with previous studies.     

Subjective visual awareness emerges prior to P3

Studies on the neural basis of visual awareness, the subjective experience of seeing, have found several potential neural correlates of visual awareness. Some of them may not directly correlate with awareness but with post‐perceptual processes, such as reporting one's awareness of the stimulus. We dissociated potential electrophysiological correlates of visual awareness from those occurring during response selection and thus co‐occurring with post‐perceptual processing. The participants performed two GO‐NOGO conditions. In the aware‐GO condition they responded with a key press when they were aware of the stimulus and withheld responding when they were unaware of it. In the unaware‐GO condition they withheld responding when they were aware and responded when they were not aware of the stimulus. Thus, event‐related potentials could be measured to aware and unaware trials when responding was required and when not required. The results revealed that the N200 amplitude (180–280 ms) over the occipital and posterior temporal cortex was enhanced in aware trials as compared with trials without awareness. This effect (visual awareness negativity, VAN) did not depend on responding. The amplitude of P3 (350–450 ms) also was enhanced in aware trials as compared with unaware trials. In addition, the amplitudes in the P3 time window depended on responding: they were greater when awareness was mapped to GO‐response than when not, suggesting that P3 reflects post‐perceptual processing, that is, it occurs after awareness has emerged. These findings support theories of visual awareness that assume a relatively early onset of visual awareness before P3.