Urbina J A
Biological Chemistry Laboratory, Center for Biochemistry and Biophysics, Venezuelan Institute for Scientific Research, Caracas, Venezuela.
Curr Opin Infect Dis. 2001 Dec;14(6):733-41. doi: 10.1097/00001432-200112000-00012.
The current situation regarding specific chemotherapy for Chagas disease (American trypanosomiasis), and new developments in this field, are reviewed. Despite previous controversy on the autoimmune origin of Chagas disease pathology, available knowledge supports the notion that this condition should be treated as a parasitic, not an autoimmune, disease. Currently available drugs (nitrofurans and nitroimidazoles) are active in acute or short-term chronic infections, but have very low antiparasitic activity against the prevalent chronic form of the disease, and toxic side-effects are frequently encountered. The nitroimidazole benznidazole has also shown significant activity in the treatment of reactivated Trypanosoma cruzi infections in patients with acquired immune deficiency syndrome and in other immunosuppressed patients with underlying chronic Chagas disease. Although the etiological agent, T. (Schizotrypanum) cruzi, requires specific endogenous sterols for cell viability and proliferation, the currently available antifungal sterol biosynthesis inhibitors are not powerful enough to induce parasitological cures of human or experimental infections. However, new triazole antifungal compounds, which are potent inhibitors of the sterol C14alpha demethylase of the parasite and have special pharmacokinetic properties, are capable of inducing parasitological cures in murine models of both acute and chronic Chagas disease. They are currently the most advanced candidates for clinical trials in patients with Chagas disease. Other potential chemotherapeutic agents against T. cruzi currently in development include antiproliferative lysophospholipid analogs (already in clinical trials as the first oral treatment for visceral leishmaniasis), cysteine proteinase (cruzipain) inhibitors, and compounds that interfere with purine salvage and inositol metabolism.
本文综述了恰加斯病（美洲锥虫病）特异性化疗的现状以及该领域的新进展。尽管此前对于恰加斯病病理的自身免疫起源存在争议，但现有知识支持应将这种疾病视为寄生虫病而非自身免疫性疾病的观点。目前可用的药物（硝基呋喃类和硝基咪唑类）对急性或短期慢性感染有效，但对该疾病常见的慢性形式的抗寄生虫活性非常低，且经常出现毒副作用。硝基咪唑类药物苯并硝唑在治疗获得性免疫缺陷综合征患者以及其他患有潜在慢性恰加斯病的免疫抑制患者中重新激活的克氏锥虫感染方面也显示出显著活性。尽管病原体克氏锥虫（裂殖锥虫属）需要特定的内源性固醇来维持细胞活力和增殖，但目前可用的抗真菌固醇生物合成抑制剂不足以诱导人类或实验性感染的寄生虫学治愈。然而，新型三唑类抗真菌化合物是寄生虫固醇C14α脱甲基酶的有效抑制剂，具有特殊的药代动力学特性，能够在急性和慢性恰加斯病的小鼠模型中诱导寄生虫学治愈。它们目前是恰加斯病患者临床试验中最先进的候选药物。目前正在研发的其他针对克氏锥虫的潜在化疗药物包括抗增殖溶血磷脂类似物（已作为内脏利什曼病的首个口服治疗药物进行临床试验）、半胱氨酸蛋白酶（克氏锥虫蛋白酶）抑制剂以及干扰嘌呤补救和肌醇代谢的化合物。
