Ekstrand Carl, Michanek Peter, Gehring Ronette, Sundell Anna, Källse Annika, Hedeland Mikael, Ström Lena
Department of Biomedicine and Veterinary Public Health, Division of Pharmacology and Toxicology, Swedish University of Agricultural Sciences, Uppsala, Sweden.
Department of Population Health Sciences, Division of Veterinary and Comparative Pharmacology, Utrecht University, Utrecht, Netherlands.
Front Vet Sci. 2022 Sep 2;9:951300. doi: 10.3389/fvets.2022.951300. eCollection 2022.
Atropine is an essential part of the treatment protocol for equine uveitis. Topical atropine administration has been associated with decreased intestinal motility and abdominal pain in horses. Experimental studies have indicated that frequent dosing is associated with a higher risk than dosing every 6 h. Unfortunately, no quantitative pharmacodynamic data for inhibition of the equine gut are published.
Eight standardbred horses were assigned to receive either atropine or saline (control) to be infused over 30 min in a two-treatment cross-over design. Atropine concentrations in plasma were measured using ultra-high-performance liquid chromatography-tandem mass spectrometry. Intestinal motility was measured using borborygmi frequency and electrointestinography (EIG). Experimental data were analyzed using a non-linear mixed effects model. The model was then used to simulate different dosing regimens.
Atropine significantly decreased borborygmi response and EIG response. Six horses developed clinical signs of abdominal pain. The pharmacokinetic typical values were 0.31, 1.38, 0.69, and 1.95 L/kg·h for the volumes of the central, the highly perfused, the scarcely perfused compartments, and the total body clearance, respectively. The pharmacodynamic typical values were 0.31 μg/L and 0.6 and 207 nV7 cpm for the plasma concentration at 50% of the maximum response and the maximum response and the baseline of cecal EIG response, respectively. Six different dosing regimens of topical atropine sulfate to the eye (0.4 and 1 mg every hour, every 3 h, and every 6 h) were simulated.
The IV PK/PD data coupled with simulations predict that administration of 1 mg of topical atropine sulfate administered to the eye every hour or every 3 h will lead to atropine accumulation in plasma and decreased intestinal myoelectric activity. Administration every 6 h predicted a safe dosing regimen in full-sized horses. Clinical studies would be valuable to confirm the conclusions. For smaller equids and horses put at risk for colic due to othercauses, droplet bottles that deliver 40 μl of 1% atropine sulfate per drop or less may be used to lower the risk further.
阿托品是马葡萄膜炎治疗方案的重要组成部分。局部应用阿托品已被证实与马的肠道蠕动减慢和腹痛有关。实验研究表明，频繁给药比每6小时给药一次的风险更高。遗憾的是，目前尚未发表关于抑制马肠道的定量药效学数据。
采用两治疗交叉设计，将8匹标准赛马分为两组，分别接受阿托品或生理盐水（对照组），在30分钟内进行输注。使用超高效液相色谱 - 串联质谱法测定血浆中的阿托品浓度。通过肠鸣音频率和肠电图（EIG）测量肠道蠕动。使用非线性混合效应模型分析实验数据。然后使用该模型模拟不同的给药方案。
阿托品显著降低了肠鸣音反应和EIG反应。6匹马出现了腹痛的临床症状。药代动力学典型值分别为：中央室、高灌注室、低灌注室的容积以及全身清除率，分别为0.31、1.38、0.69和1.95 L/kg·h。药效学典型值分别为：最大反应的50%时的血浆浓度为0.31μg/L，最大反应为0.6，盲肠EIG反应的基线为207 nV7 cpm。模拟了局部应用硫酸阿托品滴眼液的六种不同给药方案（每小时、每3小时和每6小时分别给予0.4和1 mg）。
静脉药代动力学/药效学数据结合模拟预测，每小时或每3小时向眼局部应用1 mg硫酸阿托品将导致血浆中阿托品蓄积，并降低肠道肌电活动。每6小时给药一次预测在成年马中是一种安全的给药方案。临床研究对于证实这些结论将是有价值的。对于体型较小的马以及因其他原因有患绞痛风险的马，可使用每滴输送40μl或更少1%硫酸阿托品的滴瓶来进一步降低风险。
