Mactutus C F, Booze R M, Dowell R T
Division of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 40546, Lexington, KY, USA.
Neurotoxicol Teratol. 2000 May-Jun;22(3):357-68. doi: 10.1016/s0892-0362(99)00084-7.
The intravenous route of administration, accessed via a subcutaneous vascular access port, has been recently suggested as an animal model for studying the developmental effects of maternal cocaine abuse in the pregnant and/or group-housed rat. The present study (1) assessed the cardiovascular effects of intravenous (IV) cocaine, delivered via bolus injection, in chronically catheterized near-term pregnant rats, and (2) compared the IV cardiovascular responses to those following cocaine delivered via the commonly employed subcutaneous (SC) and intragastric (IG) routes of administration. Pregnant gestation day 15 (GD15) young adult female Sprague-Dawley rats (n = 21) were anesthetized and catheters surgically implanted into the carotid artery, jugular vein, fundus of the stomach, and a subcutaneous pouch. On GD17-19, heart rate (HR) and mean arterial pressure (MAP) were assessed, using a within-subjects design, prior and subsequent to IV (3 mg/kg), IG (60 mg/kg), and SC (40 mg/kg) cocaine. An interval of 6 h separated IV and IG cocaine administration and an interval of 18 h separated IG and SC cocaine administration. The peak responses of HR (23% downward arrow) and MAP (37% upward arrow) following IV cocaine were noted within 0.5 min. In contrast, the peak responses of HR (4% downward arrow, 6% downward arrow) and MAP (2% upward arrow, 15% downward arrow) after IG (23 min) or SC (26 min) cocaine, respectively, were significantly smaller and markedly delayed. No significant change in aortic blood flow velocity was detected following cocaine via any route of administration, although phasic flow velocities (PFV) were differentially sensitive to route of administration (PFV(dias) not PFV(sys)); IV cocaine increased (55% upward arrow) whereas IG or SC cocaine decreased approximately 35% downward arrow) PFV(dias). The pressor effects of an equimolar dose of IV cocaine methiodide (3.9 mg/kg) were indistinguishable from those of IV cocaine (38% upward arrow vs. 37% upward arrow), as were the effects on PFV(dias) (83% upward arrow vs. 55% upward arrow). The lack of an effect of cocaine methiodide on HR was consistent with the bradycardia effect of cocaine attributable to central mediation of the baroreflex. Finally, the pressor effects of IV cocaine paralleled the rapidly peaking arterial plasma levels of cocaine noted within 30 s after the initiation of drug injection. In sum, prominent effects of IV cocaine on maternal cardiovascular physiology are noted; as such, the recent reports of a lack of maternal/fetal toxicity following daily (3-6mg/kg) IV cocaine during GD8-21 are not due to use of an ineffective drug dose. It was equally clear that the SC and IG routes of exposure did not reproduce the cardiovascular component(s) of the expected physiological response to cocaine.
最近有人提出，通过皮下血管通路端口进行静脉给药，可作为一种动物模型，用于研究孕期和/或群居大鼠母体滥用可卡因的发育影响。本研究：（1）评估通过推注方式静脉注射可卡因对长期插管的近足月妊娠大鼠的心血管影响；（2）比较静脉注射可卡因与常用的皮下（SC）和胃内（IG）给药途径后可卡因的心血管反应。怀孕第15天（GD15）的成年雌性Sprague-Dawley大鼠（n = 21）进行麻醉，通过手术将导管植入颈动脉、颈静脉、胃底和皮下囊袋。在GD17 - 19期间，采用自身对照设计，在静脉注射（3 mg/kg）、胃内注射（60 mg/kg）和皮下注射（40 mg/kg）可卡因之前和之后评估心率（HR）和平均动脉压（MAP）。静脉注射和胃内注射可卡因的间隔为6小时，胃内注射和皮下注射可卡因的间隔为18小时。静脉注射可卡因后，HR（下降23%）和MAP（上升37%）的峰值反应在0.5分钟内出现。相比之下，胃内注射（23分钟）或皮下注射（26分钟）可卡因后，HR（分别下降4%、6%）和MAP（分别上升2%、下降15%）的峰值反应明显较小且明显延迟。尽管相流速（PFV）对给药途径有不同的敏感性（PFV（舒张期）而非PFV（收缩期）），但通过任何给药途径注射可卡因后，未检测到主动脉血流速度有显著变化；静脉注射可卡因使PFV（舒张期）增加（上升55%），而胃内或皮下注射可卡因使PFV（舒张期）下降约35%。等摩尔剂量的静脉注射可卡因甲碘化物（3.9 mg/kg）的升压作用与静脉注射可卡因（上升38%对上升37%）以及对PFV（舒张期）的作用（上升83%对上升55%）无差异。可卡因甲碘化物对HR无影响，这与可卡因通过压力反射中枢介导引起的心动过缓效应一致。最后，静脉注射可卡因的升压作用与药物注射开始后30秒内迅速达到峰值的动脉血浆可卡因水平平行。总之，静脉注射可卡因对母体心血管生理有显著影响；因此，最近关于在GD8 - 21期间每日静脉注射可卡因（3 - 6mg/kg）后未出现母体/胎儿毒性的报道，并非由于使用了无效的药物剂量。同样明显的是，皮下和胃内给药途径并未重现对可卡因预期生理反应的心血管成分。
