Hoy J B, Cornell J A, Karlix J L, Schmidt C J, Tebbett I R, van Haaren F
Department of Psychology, University of Florida, Gainesville 32611, USA.
Vet Hum Toxicol. 2000 Apr;42(2):65-71.
Drug interactions have been suggested as a cause of Gulf War Syndrome. Pyridostigmine bromide (PB), a prophylactic treatment against potential nerve gas attack, the insect repellent DEET, and permethrin (PERM) impregnated in soldiers' uniforms may have interacted and caused greater than expected toxicity. We tested those 3 drugs singly and in combinations on male and female Sprague-Dawley rats in open field arenas to find the effects on rate of locomotion and thigmotaxis. Administration rates were 10 mg PB/kg; 50, 200, or 500 mg DEET/kg; 15, 30, or 60 mg PERM/kg; 5 mg PB/kg + 100 mg DEET/kg; 5 mg PB/kg + 15 mg PERM/kg; 100 mg DEET/kg + 15 mg PERM/kg; or vehicle by gavage and i.p. injection. Locomotor behavior was quantified by video-computer analysis for 2 h post-treatment. Female rats were tested in either pro- or metestrus. Drug interactions were determined by the isobolographic method. Blood serum drug concentrations were estimated by high performance liquid chromatography or gas chromatography-mass spectrometry. Single drug effects were very limited within the ranges tested. Double-drug administrations at half the single-drug rates resulted in statistically significant interactions in male rats for both locomotion rate and thigmotaxis. Combination of PB + PERM and DEET + PERM significantly affected speed, whereas only the combination of DEET + PERM significantly affected thigmotaxis. Female rats did not show significant interactions. Our data suggest that serum concentrations of PB and DEET may have been higher in females than males. Administration of PB + DEET may have reduced the serum concentration of DEET, and administration of PB + PERM may have increased the serum concentration of PERM.
药物相互作用被认为是海湾战争综合征的一个病因。溴化吡啶斯的明（PB）是一种针对潜在神经毒气攻击的预防性治疗药物，驱虫剂避蚊胺（DEET）以及浸渍在士兵制服中的氯菊酯（PERM）可能发生了相互作用，导致了超出预期的毒性。我们在旷场实验中对雄性和雌性斯普拉格-道利大鼠单独及联合使用这三种药物，以研究其对运动速度和趋触性的影响。给药剂量分别为：10毫克PB/千克；50、200或500毫克DEET/千克；15、30或60毫克PERM/千克；5毫克PB/千克 + 100毫克DEET/千克；5毫克PB/千克 + 15毫克PERM/千克；100毫克DEET/千克 + 15毫克PERM/千克；或通过灌胃和腹腔注射给予溶剂。治疗后2小时通过视频计算机分析对运动行为进行量化。雌性大鼠在动情前期或动情期进行测试。通过等效应线图法确定药物相互作用。采用高效液相色谱法或气相色谱-质谱法估算血清药物浓度。在所测试的剂量范围内，单一药物的作用非常有限。以单一药物剂量的一半进行双药给药时，雄性大鼠在运动速度和趋触性方面均出现了具有统计学意义的相互作用。PB + PERM和DEET + PERM的组合对速度有显著影响，而只有DEET + PERM的组合对趋触性有显著影响。雌性大鼠未表现出显著的相互作用。我们的数据表明，雌性大鼠血清中PB和DEET的浓度可能高于雄性。PB + DEET的给药可能降低了DEET的血清浓度，而PB + PERM的给药可能提高了PERM的血清浓度。
