Yanez A M, Wallace M, Ho R, Shen D, Yaksh T L
Department of Anesthesiology, University of California, San Diego 92093-0818, USA.
Anesthesiology. 1995 May;82(5):1189-98. doi: 10.1097/00000542-199505000-00014.
Phospholipid-based liposomes can alter the kinetics of spinally administered agents. We have observed that spinal delivery of these preparations results in an unexpected touch-evoked agitation, a state in which light touch evokes vocalization by the rat. In the current study we characterized this agitated state induced by various liposome preparations.
Rats prepared with lumbar intrathecal catheters received a variety of phospholipids delivered spinally as emulsions or as liposomes. Before and after injection, the animal's hot-plate latency (52.5 degrees C surface), spontaneous mobility, and spontaneous and evoked pain behavior were assessed.
Spinal delivery of L-alpha-phosphatidylcholine of egg yolk (L-EPC) and the phospholipase hydrolysis product (lyso-L-alpha-phosphatidylcholine [lyso-L-EPC]) produced dose-dependent touch-evoked agitation; the order of potency and rapidity of onset was lyso-L-EPC > L-EPC, with no difference in activity whether administered as an emulsion or as a liposome preparation. Examination of the activity of a series of pure phospholipids revealed the ordering of touch-evoked agitation potency (where PC = phosphatidylcholine) to be L-monopalmitoyl-PC (lyso product of L-dipalmitoyl-PC) > L-dipalmitoyl-PC > L-distearoyl-PC, L-dioleoyl-PC >> L-dilauroyl-PC > L-dimyristoyl-PC; D-dipalmitoyl-PC = 0. The effect of unsaturation on touch-evoked agitation cannot be predicted because dioleoyl-PC and dioleoyl phosphatidylglycerol produced touch-evoked agitation but dipalmitoleoyl-PC did not. Substitution of glycerol for choline as the head group had no influence on touch-evoked agitation. Spinal treatment with an inhibitor of phospholipase (mepacrine) or a cyclooxygenase (ketorolac) blocked the touch-evoked agitation of L-EPC but not that of lyso-L-EPC.
These results emphasize that certain L-isomeric phospholipids with their gel-transition temperatures near body temperature can produce prominent touch-evoked agitation after spinal delivery, an effect likely mediated by a phospholipase hydrolysis product. This touch-evoked agitation, which is consistent with neurotoxicity reported in the early literature on lysophospholipids, suggests that the choice of lipids for the formulation of liposomes intended for spinal drug delivery should be carefully considered.
基于磷脂的脂质体可改变经脊髓给药药物的动力学。我们观察到，这些制剂经脊髓给药会导致一种意外的触觉诱发激惹状态，即轻微触摸会诱发大鼠发声。在本研究中，我们对各种脂质体制剂诱导的这种激惹状态进行了特征描述。
通过腰段鞘内导管制备的大鼠接受了多种以乳剂或脂质体形式经脊髓递送的磷脂。注射前后，评估动物的热板潜伏期（表面温度52.5℃）、自发活动能力以及自发和诱发的疼痛行为。
经脊髓递送蛋黄卵磷脂（L-EPC）及其磷脂酶水解产物（溶血卵磷脂[lyso-L-EPC]）会产生剂量依赖性的触觉诱发激惹；效力和起效速度顺序为lyso-L-EPC > L-EPC，以乳剂或脂质体制剂给药时活性无差异。对一系列纯磷脂活性的检测显示，触觉诱发激惹效力的顺序（其中PC = 磷脂酰胆碱）为L-单棕榈酰磷脂酰胆碱（L-二棕榈酰磷脂酰胆碱的溶血产物）> L-二棕榈酰磷脂酰胆碱 > L-二硬脂酰磷脂酰胆碱、L-二油酰磷脂酰胆碱 >> L-二月桂酰磷脂酰胆碱 > L-二肉豆蔻酰磷脂酰胆碱；D-二棕榈酰磷脂酰胆碱 = 0。不饱和键对触觉诱发激惹的影响无法预测，因为二油酰磷脂酰胆碱和二油酰磷脂酰甘油会产生触觉诱发激惹，而二棕榈油酰磷脂酰胆碱则不会。用甘油取代胆碱作为头部基团对触觉诱发激惹没有影响。用磷脂酶抑制剂（米帕林）或环氧化酶抑制剂（酮咯酸）进行脊髓治疗可阻断L-EPC的触觉诱发激惹，但不能阻断lyso-L-EPC的触觉诱发激惹。
这些结果强调，某些凝胶转变温度接近体温的L-异构体磷脂在经脊髓给药后可产生显著的触觉诱发激惹，这种效应可能由磷脂酶水解产物介导。这种触觉诱发激惹与早期关于溶血磷脂的文献中报道的神经毒性一致，提示在为脊髓药物递送设计脂质体时，脂质的选择应谨慎考虑。
