RESUMO
γ-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the central nervous system (CNS). Its homeostasis is maintained by neuronal and glial GABA transporters (GATs). The four GATs identified in humans are GAT1 (SLC6A1), GAT2 (SLC6A13), GAT3 (SLC6A11), and betaine/GABA transporter-1 BGT-1 (SLC6A12) which are all members of the solute carrier 6 (SLC6) family of sodium-dependent transporters. While GAT1 has been investigated extensively, the other GABA transporters are less studied and their role in CNS is not clearly defined. Altered GABAergic neurotransmission is involved in different diseases, but the importance of the different transporters remained understudied and limits drug targeting. In this review, the well-studied GABA transporter GAT1 is compared with the less-studied BGT-1 with the aim to leverage the knowledge on GAT1 to shed new light on the open questions concerning BGT-1. The most recent knowledge on transporter structure, functions, expression, and localization is discussed along with their specific role as drug targets for neurological and neurodegenerative disorders. We review and discuss data on the binding sites for Na+, Cl-, substrates, and inhibitors by building on the recent cryo-EM structure of GAT1 to highlight specific molecular determinants of transporter functions. The role of the two proteins in GABA homeostasis is investigated by looking at the transport coupling mechanism, as well as structural and kinetic transport models. Furthermore, we review information on selective inhibitors together with the pharmacophore hypothesis of transporter substrates.
RESUMO
PURPOSE: This international survey recorded the opinions of multiple sclerosis (MS) nurses about their role in treatment decision making and about the importance of different attributes of autoinjectors used to deliver first-line parenteral therapy. METHODS: The survey involved 52 MS nurses in different practice settings in France, Germany, Italy, the UK, and the USA. Nurses described their role in patient education and in treatment decision making. They also rated the importance of nine prespecified attributes of autoinjectors and stated their preference, both overall and by attribute, for one of two autoinjectors used to deliver interferon ß-1b (ExtaviPro® 30G and Betacomfort®). Nurses' preferences were compared with those previously collected from patients using an identical questionnaire. RESULTS: There were pronounced differences between practice settings and between countries in the opinions of MS nurses about their influence on treatment decision making. Nurses considered themselves instrumental in helping patients decide between treatment options offered by neurologists. Of the nine autoinjector attributes, nurses rated "reliable to use" as most important, followed by attributes associated with convenience ("easy to operate," "ergonomic shape," "reach" [of injection sites], and "one-handed injection"). Nurses' and patients' rankings of attributes were closely aligned. For the nine attributes, 74%-98% of nurses preferred ExtaviPro® 30G to Betacomfort®, 94% preferring ExtaviPro® 30G overall. Nurses showed a greater preference than patients for ExtaviPro® 30G with respect to "easy to operate" (92% vs 78%), "intuitive to use" (98% vs 78%), and "attractive design" (98% vs 83%; P<0.05, all), but preference rates were otherwise similar across the two groups. The most common reasons in both groups for preferring ExtaviPro® 30G to Betacomfort® were "easy to use" and "ergonomic shape." CONCLUSION: MS nurses play a key role in patient guidance and education. Their preferences for ExtaviPro® 30G likely reflect their understanding of the challenges patients face when self-administering treatment.
RESUMO
BACKGROUND: The ExtaviPro™ 30G autoinjector has been developed for self-administration of interferon beta-1b (Extavia®), which is used as a first-line, parenteral, disease-modifying therapy in multiple sclerosis (MS). The aim of this survey was to investigate patients' perceptions of the importance of different general attributes of autoinjectors, and patient preferences when comparing the ExtaviPro™ 30G and Betacomfort® autoinjectors. METHOD: The survey was conducted in France, Germany, Italy, and the USA in patients with relapsing-remitting MS who had been using an autoinjector for at least 1 year. Participants examined the ExtaviPro™ 30G and Betacomfort® devices, viewed fact sheets, and watched a video of these autoinjectors in use, then scored nine prespecified attributes of autoinjectors in terms of importance on a scale of 1-7 (1 = not at all important; 7 = extremely important). They then indicated which device they preferred, both overall and by individual attribute. RESULTS: Among the 201 participants who completed the survey, being reliable to use was considered the most important general attribute of autoinjectors, followed by attributes associated with convenience (ease of operation, one-handed injection, ease of reach of injection sites, ergonomic shape). For each of the nine attributes, a significantly higher proportion of participants (74%-94% by attribute; P < 0.05 for each) preferred ExtaviPro™ 30G to the Betacomfort® autoinjector, and 173 (86%) participants indicated that they preferred ExtaviPro™ 30G overall (P < 0.05). CONCLUSION: The results of this survey suggest that patients with MS rate reliability and convenience as the most important general attributes of autoinjectors, and are more likely to prefer ExtaviPro™ 30G to the Betacomfort® autoinjector for routine self-administration of interferon beta-1b.
