Departments of Pharmacology (M.D.R., M.P.) and Medicine (M.P.), Center for Immunology (M.P.), Medical School, University of Minnesota, Minneapolis, Minnesota; Universita' degli Studi di Milano, Socrates Program, Milano, Italy (C.A.); and Hennepin Healthcare Research Institute, Minneapolis, Minnesota (M.P.).
Departments of Pharmacology (M.D.R., M.P.) and Medicine (M.P.), Center for Immunology (M.P.), Medical School, University of Minnesota, Minneapolis, Minnesota; Universita' degli Studi di Milano, Socrates Program, Milano, Italy (C.A.); and Hennepin Healthcare Research Institute, Minneapolis, Minnesota (M.P.)
J Pharmacol Exp Ther. 2020 Sep;374(3):392-403. doi: 10.1124/jpet.120.000014. Epub 2020 Jun 25.
Opioid use disorders (OUDs) and opioid-related fatal overdoses are a significant public health concern in the United States and worldwide. To offer more effective medical interventions to treat or prevent OUD, antiopioid vaccines are in development that reduce the distribution of the targeted opioids to brain and subsequently reduce the associated behavioral and toxic effects. It is of critical importance that antiopioid vaccines do not interfere with medications that treat OUD. Hence, this study tested the preclinical proof of concept of combining a candidate oxycodone vaccine [oxycodone-keyhole limpet hemocyanin (OXY-KLH)] with an FDA-approved extended-release naltrexone (XR-NTX) depot formulation in rats. The effects of XR-NTX on oxycodone-induced motor activity and antinociception were first assessed in nonvaccinated naïve rats to establish a baseline for subsequent studies. Next, OXY-KLH and XR-NTX were coadministered to determine whether the combination would affect the efficacy of each individual treatment, and it was found that the combination of OXY-KLH and XR-NTX offered greater efficacy in reducing oxycodone-induced motor activity, thigmotaxis, antinociception, and respiratory depression over a range of repeated or escalating oxycodone doses in rats. These data support the feasibility of combining antibody-based therapies with opioid receptor antagonists to provide greater or prolonged protection against opioid-related toxicity or overdose. Combining antiopioid vaccines with XR-NTX may provide prophylactic measures to subjects at risk of relapse and accidental or deliberate exposure. Combination therapy may extend to other biologics (e.g., monoclonal antibodies) and medications against substance use disorders. SIGNIFICANCE STATEMENT: Opioid use disorders (OUDs) remain a major problem worldwide, and new therapies are needed. This study reports on the combination of an oxycodone vaccine [oxycodone-keyhole limpet hemocyanin (OXY-KLH)] with a currently approved OUD therapy, extended-release naltrexone (XR-NTX). Results demonstrated that XR-NTX did not interfere with OXY-KLH efficacy, and combination of low doses of XR-NTX with vaccine was more effective than each individual treatment alone to reduce behavioral and toxic effects of oxycodone, suggesting that combining OXY-KLH with XR-NTX may improve OUD outcomes.
阿片类药物使用障碍（OUDs）和阿片类相关的致命过量是美国和全球的一个重大公共卫生问题。为了提供更有效的医学干预措施来治疗或预防 OUD，正在开发抗阿片类药物疫苗，以减少目标阿片类药物在大脑中的分布，从而减少相关的行为和毒性作用。至关重要的是，抗阿片类药物疫苗不应干扰治疗 OUD 的药物。因此，这项研究测试了将候选羟考酮疫苗[羟考酮-贻贝血蓝蛋白（OXY-KLH）]与 FDA 批准的延长释放纳曲酮（XR-NTX）储库制剂联合用于大鼠的临床前概念验证。首先，在未接种疫苗的大鼠中评估 XR-NTX 对羟考酮诱导的运动活动和镇痛作用的影响，以确定随后研究的基线。接下来，共给 OXY-KLH 和 XR-NTX，以确定组合是否会影响每种单独治疗的疗效，结果发现，OXY-KLH 和 XR-NTX 的组合在降低大鼠反复或递增羟考酮剂量引起的运动活动、触诱发应、镇痛和呼吸抑制方面更有效。这些数据支持将基于抗体的疗法与阿片受体拮抗剂联合用于提供对阿片类相关毒性或过量的更大或更持久保护的可行性。将抗阿片类药物疫苗与 XR-NTX 联合使用可能为有复发风险以及意外或故意暴露风险的受试者提供预防措施。联合疗法可能扩展到其他生物制剂（例如单克隆抗体）和药物滥用障碍药物。意义声明：阿片类药物使用障碍（OUDs）仍然是全球的一个主要问题，需要新的治疗方法。本研究报告了羟考酮疫苗[羟考酮-贻贝血蓝蛋白（OXY-KLH）]与目前批准的 OUD 治疗药物，即延长释放纳曲酮（XR-NTX）的联合使用。结果表明，XR-NTX 不干扰 OXY-KLH 的疗效，并且低剂量 XR-NTX 与疫苗联合使用比单独使用每种药物更有效，可降低羟考酮的行为和毒性作用，表明将 OXY-KLH 与 XR-NTX 联合使用可能改善 OUD 结局。
