Lavergne Sidonie N, Volkman Erin M, Maki Jennifer E, Yoder Andrea R, Trepanier Lauren A
Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, 2015 Linden Drive, Madison, WI 53706-1102, USA.
Toxicology. 2005 Mar 1;208(1):63-72. doi: 10.1016/j.tox.2004.11.009.
Sulfonamide antimicrobials such as sulfamethoxazole (SMX) have been associated in humans with hypersensitivity reactions, to include fever, skin eruptions, hepatotoxicity, and blood dyscrasias. These reactions also occur in dogs, the only non-human species known to develop a similar spectrum of sulfonamide hypersensitivity. Sulfonamide hypersensitivity is not well understood, but has been hypothesized to be due to the generation of the reactive oxidative metabolite, nitroso sulfamethoxazole (SMX-NO). SMX-NO, unlike the parent sulfonamide, is cytotoxic in vitro, haptenizes tissue proteins, and is immunogenic in rodents. The purpose of this pilot study was to determine whether SMX-NO, when administered to dogs, would lead to drug-tissue adducts, anti-drug antibodies, antioxidant depletion, or clinical evidence of drug hypersensitivity. Four dogs were randomized to one of four treatments: SMX-NO 1 mg/kg; SMX-NO 3 mg/kg; SMX-NO 10 mg/kg; or vehicle control. Dosing was by the intraperitoneal route, once daily for four consecutive days per week, for 2 weeks total, followed by a third week of observation. Following this, all dogs were challenged with trimethoprim-sulfamethoxazole, 25 mg/kg for 12 h for 2 weeks. No dog developed clinical or biochemical evidence of drug hypersensitivity. Plasma cysteine and leukocyte reduced glutathione were not depleted during dosing; however, ascorbate was significantly depleted by week 2 following SMX-NO at 10 mg/kg. Anti-SMX antibodies (IgG or IgM by ELISA) were not detected in any dogs at any time points. SMX-hemoglobin adducts were detected in the spleen in SMX-NO dosed dogs; however, these adducts were not accompanied by an immunologic or systemic response. The results of this pilot study indicate that SMX-NO dosing in dogs, using a dosing protocol shown to be immunogenic in other species, produces modest ascorbate depletion and hemoglobin adduct formation, but is insufficient to produce an immunologic response or a clinical syndrome of sulfonamide hypersensitivity in this susceptible species.
磺胺类抗菌药物如磺胺甲恶唑（SMX）在人类中与超敏反应有关，包括发热、皮疹、肝毒性和血液系统异常。这些反应在犬类中也会发生，犬类是已知唯一会出现类似磺胺类超敏反应谱的非人类物种。磺胺类超敏反应尚未完全明确，但据推测是由于活性氧化代谢产物亚硝基磺胺甲恶唑（SMX-NO）的产生所致。与母体磺胺不同，SMX-NO在体外具有细胞毒性，能使组织蛋白半抗原化，并且在啮齿动物中具有免疫原性。本初步研究的目的是确定给犬类施用SMX-NO后是否会导致药物-组织加合物、抗药物抗体、抗氧化剂耗竭或药物超敏反应的临床证据。四只犬被随机分为四种治疗组之一：1毫克/千克的SMX-NO；3毫克/千克的SMX-NO；10毫克/千克的SMX-NO；或溶剂对照组。给药途径为腹腔注射，每周连续四天每天一次，共2周，随后观察第三周。在此之后，所有犬均接受甲氧苄啶-磺胺甲恶唑挑战，剂量为25毫克/千克，持续12小时，共2周。没有犬出现药物超敏反应的临床或生化证据。给药期间血浆半胱氨酸和白细胞还原型谷胱甘肽未耗竭；然而，在10毫克/千克的SMX-NO给药后第2周，抗坏血酸显著耗竭。在任何时间点，任何犬均未检测到抗SMX抗体（通过ELISA检测的IgG或IgM）。在接受SMX-NO给药的犬的脾脏中检测到SMX-血红蛋白加合物；然而，这些加合物并未伴随免疫或全身反应。本初步研究结果表明，采用在其他物种中显示具有免疫原性的给药方案给犬类施用SMX-NO，会导致适度的抗坏血酸耗竭和血红蛋白加合物形成，但不足以在这个易感物种中产生免疫反应或磺胺类超敏反应的临床综合征。
