Frontiers in pharmacology
-
Frontiers in pharmacology · Jan 2013
A thermosensitive mutation alters the effects of lacosamide on slow inactivation in neuronal voltage-gated sodium channels, NaV1.2.
Epilepsy is a disorder characterized by seizures and convulsions. The basis of epilepsy is an increase in neuronal excitability that, in some cases, may be caused by functional defects in neuronal voltage gated sodium channels (NaVs). The C121W mutation of the β1 subunit, in particular, gives rise to the thermosensitive generalized epilepsy with febrile seizures plus (GEFS+) phenotype. ⋯ Lacosamide was more effective in NaV1.2 associated with the WT-β1 than with C121W-β1 at either temperature. There is also a more potent effect by lacosamide on slow inactivation at elevated temperatures. Our data suggest a modulatory role is imparted by the β1 subunit in the interaction between the drug and the channel.
-
Frontiers in pharmacology · Jan 2013
Dabigatran - a case history demonstrating the need for comprehensive approaches to optimize the use of new drugs.
There are potential conflicts between authorities and companies to fund new premium priced drugs especially where there are safety and/or budget concerns. Dabigatran, a new oral anticoagulant for the prevention of stroke in patients with non-valvular atrial fibrillation (AF), exemplifies this issue. Whilst new effective treatments are needed, there are issues in the elderly with dabigatran due to variable drug concentrations, no known antidote and dependence on renal elimination. Published studies have shown dabigatran to be cost-effective but there are budget concerns given the prevalence of AF. There are also issues with potentially re-designing anticoagulant services. This has resulted in activities across countries to better manage its use. ⋯ Models for introducing new drugs are essential to optimize their prescribing especially where there are concerns. Without such models, new drugs may be withdrawn prematurely and/or struggle for funding.
-
Frontiers in pharmacology · Jan 2013
Determinants of patient adherence: a review of systematic reviews.
A number of potential determinants of medication non-adherence have been described so far. However, the heterogenic quality of existing publications poses the need for the use of a rigorous methodology in building a list of such determinants. The purpose of this study was a systematic review of current research on determinants of patient adherence on the basis of a recently agreed European consensus taxonomy and terminology. ⋯ This study provides clear evidence that medication non-adherence is affected by multiple determinants. Therefore, the prediction of non-adherence of individual patients is difficult, and suitable measurement and multifaceted interventions may be the most effective answer toward unsatisfactory adherence. The limited number of publications assessing determinants of persistence with medication, and lack of those providing determinants of adherence to short-term treatment identify areas for future research.
-
Frontiers in pharmacology · Jan 2013
ReviewOrexin receptor antagonists as therapeutic agents for insomnia.
Insomnia is a common clinical condition characterized by difficulty initiating or maintaining sleep, or non-restorative sleep with impairment of daytime functioning. Currently, treatment for insomnia involves a combination of cognitive behavioral therapy (CBTi) and pharmacological therapy. Among pharmacological interventions, the most evidence exists for benzodiazepine (BZD) receptor agonist drugs (GABAA receptor), although concerns persist regarding their safety and their limited efficacy. ⋯ The development of these agents may lead to novel therapies for insomnia without the side effect profile of hypnotics (e.g., impaired cognition, disturbed arousal, and motor balance difficulties). However, antagonizing a system that regulates the sleep-wake cycle may create an entirely different side effect profile. In this review, we discuss the role of orexin and its receptors on the sleep-wake cycle and that of orexin antagonists in the treatment of insomnia.
-
Frontiers in pharmacology · Jan 2013
2-Aminoethoxydiphenyl borate activates the mechanically gated human KCNK channels KCNK 2 (TREK-1), KCNK 4 (TRAAK), and KCNK 10 (TREK-2).
Two-pore domain K(+) (KCNK, K2P) channels underlie the "leak" (background) potassium conductance in many types of excitable cells. They oppose membrane depolarization and cell excitability. These channels have been reported to be modulated by several physical and chemical stimuli. ⋯ TREK channels are widely expressed in the central nervous system and peripheral tissues, where they play roles in several key processes. However, little is known regarding their pharmacology; therefore, the identification of a common, stable and inexpensive agonist should aid further investigations of these channels. Additionally, 2-APB has been used to study native receptors in cell systems that endogenously express members of the TREK subfamily (e.g., rat dorsal root ganglia); our results thus warn against the use of 2-APB at high concentrations in these systems.