Taylor Olivia, Van Laeken Nick, Polis Ingeborgh, Dockx Robrecht, Vlerick Lise, Dobbeleir Andre, Goethals Ingeborg, Saunders Jimmy, Sadones Nele, Baeken Chris, De Vos Filip, Peremans Kathelijne
Department of Veterinary Medicine, Ghent University, Ghent, Belgium.
Laboratory of Radiopharmacy, Ghent University, Ghent, Belgium.
PLoS One. 2017 Jun 23;12(6):e0179927. doi: 10.1371/journal.pone.0179927. eCollection 2017.
Although the favourable characteristics of escitalopram as being the most selective serotonin reuptake inhibitor and having an increased therapeutic efficacy via binding on an additional allosteric binding site of the serotonin transporter, its dosing regimen has not yet been optimized for its use in dogs. This study aimed to estimate the optimal dosing frequency and the required dose for achieving 80% occupancy of the serotonin transporters in the basal ganglia. The dosing frequency was investigated by determining the elimination half-life after a four day oral pre-treatment period with 0.83 mg/kg escitalopram (3 administrations/day) and a subsequent i.v. injection 0.83 mg/kg. Blood samples were taken up to 12 hours after i.v. injection and the concentration of escitalopram in plasma was analysed via LC-MSMS. The dose-occupancy relationship was then determined by performing two PET scans in five adult beagles: a baseline PET scan and a second scan after steady state conditions were achieved following oral treatment with a specific dose of escitalopram ranging from 0.5 to 2.5 mg/kg/day. As the elimination half-life was determined to be 6.7 hours a dosing frequency of three administrations a day was proposed for the second part of the study. Further it was opted for a treatment period of four days, which well exceeded the minimum period to achieve steady state conditions. The optimal dosing regimen to achieve 80% occupancy in the basal ganglia and elicit a therapeutic effect, was calculated to be 1.85 mg/kg/day, divided over three administrations. Under several circumstances, such as insufficient response to other SSRIs, concurrent drug intake or in research studies focused on SERT, the use of escitalopram can be preferred over the use of the already for veterinary use registered fluoxetine, however, in case of long-term treatment with escitalopram, regularly cardiac screening is recommended.
尽管艾司西酞普兰具有诸多有利特性，如作为最具选择性的5-羟色胺再摄取抑制剂，且通过与5-羟色胺转运体的另一个变构结合位点结合而具有更高的治疗效果，但其给药方案在犬类中的应用尚未得到优化。本研究旨在估算实现基底神经节中5-羟色胺转运体80%占有率所需的最佳给药频率和剂量。通过在为期四天的口服预处理期给予0.83mg/kg艾司西酞普兰（每日给药3次），随后静脉注射0.83mg/kg，测定消除半衰期来研究给药频率。静脉注射后12小时内采集血样，通过液相色谱-串联质谱法分析血浆中艾司西酞普兰的浓度。然后通过对五只成年比格犬进行两次正电子发射断层扫描（PET）来确定剂量-占有率关系：一次基线PET扫描，以及在用0.5至2.5mg/kg/天的特定剂量艾司西酞普兰口服治疗达到稳态条件后的第二次扫描。由于确定消除半衰期为6.7小时，因此在研究的第二部分建议每日给药三次。此外，选择了四天的治疗期，这远远超过了达到稳态条件的最短时间。计算得出，在基底神经节中实现80%占有率并产生治疗效果的最佳给药方案为1.85mg/kg/天，分三次给药。在几种情况下，如对其他选择性5-羟色胺再摄取抑制剂（SSRI）反应不足、同时服用药物或在专注于5-羟色胺转运体（SERT）的研究中，使用艾司西酞普兰可能比使用已获兽医使用许可的氟西汀更可取，然而，在长期使用艾司西酞普兰治疗的情况下，建议定期进行心脏检查。
