Co-administration of morphine and oxycodone vaccines reduces the distribution of 6-monoacetylmorphine and oxycodone to brain in rats.
Co-administration of morphine and oxycodone vaccines reduces the distribution of 6-monoacetylmorphine and oxycodone to brain in rats.
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DOI：
10.1016/j.vaccine.2012.04.101
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发表时间：
2012-06-29
期刊：
影响因子：
5.5
通讯作者：
Pentel, P. R.
中科院分区：
文献类型：
--
作者：
Pravetoni, M.;Raleigh, M. D.;Le Naour, M.;Tucker, A. M.;Harmon, T. M.;Jones, J. M.;Birnbaum, A. K.;Portoghese, P. S.;Pentel, P. R.
阿片结合疫苗在动物模型中显示出作为治疗阿片成瘾的潜在疗法的前景。个别疫苗非常具体，每种疫苗只针对有限数量的结构相似的阿片类药物。由于阿片使用者可以在阿片类药物之间切换或转换，我们研究了一种二价免疫策略，将两种疫苗结合起来，可以针对几种最常见的滥用阿片类药物：海洛因、羟考酮及其活性代谢物。将吗啡(M)和羟考酮(Oxy)半抗原通过C6位的四甘氨酸(Gly)4接头连接到锁孔帽状血蓝蛋白(KLH)上。单独用M-KLH免疫大鼠产生了针对海洛因、6-乙酰吗啡(6-MAM)和吗啡的高滴度抗体。用Oxy-KLH免疫产生了高滴度的抗羟考酮和羟吗啡酮抗体。用双价疫苗免疫后，针对这两种免疫原的抗体效价一直很高。针对单个免疫原的双价疫苗抗体效价高于单价疫苗，至少部分原因是抗体的交叉反应。双价疫苗免疫大鼠同时单次静脉注射6-MAM和羟考酮可增加6-MAM、吗啡和羟考酮在血清中的滞留，减少6-MAM和羟考酮在脑中的分布。两种单价疫苗单独或联合使用时，疫苗效力与血清抗体效价相关。单独接种疫苗的效果不会因它们的联合使用而受到影响。与双价疫苗组的效价升高一致，观察到双价疫苗的药代动力学效率有增强的趋势。这些数据支持同时联合注射两种或两种以上阿片疫苗的可能性，以靶向多种可滥用的阿片类药物，而不损害个别成分的免疫原性或疗效。
Opioid conjugate vaccines have shown promise in animal models as a potential treatment for opioid addiction. Individual vaccines are quite specific and each targets only a limited number of structurally similar opioids. Since opioid users can switch or transition between opioids, we studied a bivalent immunization strategy of combining 2 vaccines that could target several of the most commonly abused opioids; heroin, oxycodone and their active metabolites. Morphine (M) and oxycodone (OXY) haptens were conjugated to keyhole limpet hemocyanin (KLH) through tetraglycine (Gly)4 linkers at the C6 position. Immunization of rats with M-KLH alone produced high titers of antibodies directed against heroin, 6-monoacetylmorphine (6-MAM) and morphine. Immunization with OXY-KLH produced high titers of antibodies against oxycodone and oxymorphone. Immunization with the bivalent vaccine produced consistently high antibody titers against both immunogens. Bivalent vaccine antibody titers against the individual immunogens were higher than with the monovalent vaccines alone owing, at least in part, to cross-reactivity of the antibodies. Administration of a single concurrent intravenous dose of 6-MAM and oxycodone to rats immunized with the bivalent vaccine increased 6-MAM, morphine and oxycodone retention in serum and reduced the distribution of 6-MAM and oxycodone to brain. Vaccine efficacy correlated with serum antibody titers for both monovalent vaccines, alone or in combination. Efficacy of the individual vaccines was not compromised by their combined use. Consistent with the enhanced titers in the bivalent group, a trend toward enhanced pharmacokinetic efficacy with the bivalent vaccine was observed. These data support the possibility of co-administering two or more opioid vaccines concurrently to target multiple abusable opioids without compromising the immunogenicity or efficacy of the individual components.
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