Cramer D V, Chapman F A, Makowka L
Department of Surgery, Cedars-Sinai Research Institute, Cedars-Sinai Medical Center, Los Angeles, California.
Transplant Proc. 1993 Jun;25(3 Suppl 2):23-8.
The data that has been obtained from preclinical studies in rodents demonstrate that BQR is an effective primary immunosuppressive agent with important advantages for use in transplantation immunotherapy. The drug is highly effective when used as a single agent to prevent the rejection of a variety of vascularized allografts and xenografts. BQR is easily administered orally, the drug displays a high level of bioavailability, and drug plasma levels and immunosuppressive activity can be directly measured. The adverse side effects seen with the drug are those normally associated with antiproliferative drugs and are predictable and easily reversed by treatment withdrawal. Most importantly, perhaps, is the broad range of synergistic activity when used in combination with new immunosuppressive drugs. We believe that the combination of these attributes separate BQR from many of the new drugs now under study. Some, for example, do not exhibit synergism (CsA and FK 506), others have may have problems with inadequate oral bioavailability (MPM and rapamycin), and some exhibit the potential for substantial toxicity (15-DSG, myzorbine). The data derived from the use of BQR in combination with other immunosuppressive drugs, such as the studies described above, are important. They provide direct evidence to support the concept that the next important advances in immunosuppressive therapy will involve the use of an effective multidrug approach to preventing organ graft rejection. Combination therapies with immunosuppressive drugs that exhibit different modes of action improve graft survival, widen therapeutic windows, and reduce the risk of toxic side effects. The experimental evidence that several of these combinations are potentially useful is solid, consistent, and exciting. It is our expectation from the rodent experiments described in this symposium that the treatment of allograft (and perhaps xenograft) rejection will consist of the use of CsA (or FK 506), BQR, and a third drug such as rapamycin or mycophenolate mofetil, the choice of which will be heavily influenced by the development of either analogues of these drugs or perhaps new compounds with improved bioavailability and effective monitoring techniques.
从啮齿动物的临床前研究中获得的数据表明，BQR是一种有效的原发性免疫抑制剂，在移植免疫治疗中具有重要优势。当作为单一药物用于预防多种血管化同种异体移植物和异种移植物的排斥反应时，该药物非常有效。BQR易于口服给药，药物具有很高的生物利用度，并且可以直接测量药物血浆水平和免疫抑制活性。该药物出现的不良副作用是通常与抗增殖药物相关的副作用，是可预测的，并且通过停药治疗很容易逆转。也许最重要的是，当与新型免疫抑制剂联合使用时，BQR具有广泛的协同活性。我们认为，这些特性使BQR有别于目前正在研究的许多新药。例如，有些药物不表现出协同作用（环孢素A和FK 506），其他药物可能存在口服生物利用度不足的问题（霉酚酸酯和雷帕霉素），还有一些药物表现出潜在的严重毒性（15-去氧精胍菌素、咪唑立宾）。从BQR与其他免疫抑制剂联合使用中获得的数据，如上述研究，很重要。它们提供了直接证据来支持这样一个概念，即免疫抑制治疗的下一个重要进展将涉及使用有效的多药方法来预防器官移植排斥反应。与具有不同作用模式的免疫抑制剂联合治疗可提高移植物存活率，拓宽治疗窗口，并降低毒副作用风险。这些联合治疗中有几种可能有用的实验证据是确凿、一致且令人兴奋的。从本次研讨会中描述的啮齿动物实验我们预期，同种异体移植物（也许还有异种移植物）排斥反应的治疗将包括使用环孢素A（或FK 506）、BQR和第三种药物，如雷帕霉素或霉酚酸酯，其选择将在很大程度上受到这些药物类似物或可能具有改善生物利用度的新化合物以及有效监测技术发展的影响。
