Antiretroviral neurotoxicity.
Antiretroviral neurotoxicity.
复制标题
DOI：
10.1007/s13365-012-0120-3
复制
发表时间：
2012-10
影响因子：
3.2
通讯作者：
Meeker, Rick B.
中科院分区：
文献类型：
--
作者：
Robertson, Kevin;Liner, Jeff;Meeker, Rick B.
联合抗逆转录病毒疗法 (CART) 已被证明可以有效抑制全身 HIV 负担，但对中枢神经系统 (CNS) 的渗透性较差，无法提供完整的保护。尽管 HIV 相关神经认知障碍 (HAND) 的严重程度已有所降低，但随着 HIV 感染者寿命的延长，神经系统疾病预计将带来越来越大的负担。增强抗逆转录病毒化合物渗透到中枢神经系统的策略可能有助于控制艾滋病毒在该储存库中的复制，但也会增加神经毒性的风险。将抗逆转录病毒化合物靶向中枢神经系统的努力必须平衡这些风险与潜在收益。不幸的是，关于抗逆转录病毒化合物在中枢神经系统中的作用的信息很少，特别是在提供有效病毒抑制的浓度下。目前的研究评估了 15 种抗逆转录病毒化合物对神经元的直接影响，开始提供基本的神经毒性数据，为制定剂量和药物选择指南奠定基础。利用神经损伤的敏感指数，我们发现了多种毒性，中位毒性浓度范围为 2 至 10,000 ng/ml。一些毒性浓度与目前在脑脊液中观察到的浓度重叠，但在临床相关浓度下毒性水平通常较低。神经毒性最高的是阿巴卡韦、依伐伦、依曲韦林、奈伐平和阿扎那韦，而最低的是达芦那韦、恩曲他滨、替诺福韦和马拉韦罗。临床上使用的组合没有看到附加效应。这些数据为制定可能降低抗逆转录病毒神经毒性风险的治疗策略提供了有用的初步证据。
Combination antiretroviral therapy (CART) has proven to effectively suppress systemic HIV burden, however, poor penetration into the central nervous system (CNS) provides incomplete protection. Although the severity of HIV-associated neurocognitive disorders (HAND) has been reduced, neurological disease is expected to exert an increasing burden as HIV-infected patients live longer. Strategies to enhance penetration of antiretroviral compounds into the CNS could help to control HIV replication in this reservoir but also carries an increased risk of neurotoxicity. Efforts to target antiretroviral compounds to the CNS will have to balance these risks against the potential gain. Unfortunately, little information is available on the actions of antiretroviral compounds in the CNS, particularly at concentrations that provide effective virus suppression. The current studies evaluated the direct effects of 15 anti-retroviral compounds on neurons to begin to provide basic neurotoxicity data that will serve as a foundation for the development of dosing and drug selection guidelines. Using sensitive indices of neural damage, we found a wide range of toxicities, with median toxic concentrations ranging from 2 to 10,000 ng/ml. Some toxic concentrations overlapped concentrations currently seen in the CSF but the level of toxicity was generally modest at clinically relevant concentrations. Highest neurotoxicities were associated with abacavir, efavarenz, etravirine, nevaripine, and atazanavir, while the lowest were with darunavir, emtracitabine, tenofovir, and maraviroc. No additive effects were seen with combinations used clinically. These data provide initial evidence useful for the development of treatment strategies that might reduce the risk of antiretroviral neurotoxicity.
登录
查看更多内容
影响因子：
5
作者：
Bressani RF;Nowacek AS;Singh S;Balkundi S;Rabinow B;McMillan J;Gendelman HE;Kanmogne GD
通讯作者：
Kanmogne GD
影响因子：
25
作者：
Kim, Jin Young;Shen, Siming;Dietz, Karen;He, Ye;Howell, Owain;Reynolds, Richard;Casaccia, Patrizia
通讯作者：
Casaccia, Patrizia
影响因子：
3.2
作者：
Heaton, Robert K.;Franklin, Donald R.;Ellis, Ronald J.;McCutchan, J. Allen;Letendre, Scott L.;LeBlanc, Shannon;Corkran, Stephanie H.;Duarte, Nichole A.;Clifford, David B.;Woods, Steven P.;Collier, Ann C.;Marra, Christina M.;Morgello, Susan;Mindt, Monica Rivera;Taylor, Michael J.;Marcotte, Thomas D.;Atkinson, J. Hampton;Wolfson, Tanya;Gelman, Benjamin B.;McArthur, Justin C.;Simpson, David M.;Abramson, Ian;Gamst, Anthony;Fennema-Notestine, Christine;Jernigan, Terry L.;Wong, Joseph;Grant, Igor
通讯作者：
Grant, Igor
影响因子：
9.9
作者：
Robertson, K. R.;Su, Z.;Skiest, D. J.
通讯作者：
Skiest, D. J.
影响因子：
3.8
作者：
Robertson, Kevin R.;Smurzynski, Marlene;Ellis, Ron J.
通讯作者：
Ellis, Ron J.