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Great Efficacy of Sulfachloropyrazine-Sodium Against Acute Murine

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Great Efficacy of Sulfachloropyrazine-Sodium Against Acute Murine Asian Pac J Trop Biomed 2012; 2(1): 70-75 70 Contents lists available at ScienceDirect Asian Pacific Journal of Tropical Biomedicine journal homepage:www.elsevier.com/locate/apjtb Document heading doi:10.1016/S2221-1691(11)60193-7 襃 2012 by the Asian Pacific Journal of Tropical Biomedicine. All rights reserved. Great efficacy of sulfachloropyrazine-sodium against acute murine toxoplasmosis Yan-Bo Zeng, Shun-Hai Zhu, Hui Dong, Hong-Yu Han, Lian-Lian Jiang, Quan Wang, Jun Cheng, Qi-Ping Zhao, Wei-Jiao Ma, Bing Huang* Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Science, Key Laboratory for Animal Parasitology of Ministry of Agriculture, Shanghai 200241 ARTICLE INFO ABSTRACT Article history: Objective: To identify more effective and less toxic drugs to treat animal toxoplasmosis. 15 2011 Methods: Toxoplasma gondii T. gondii Received May Efficacy of seven kinds of sulfonamides against ( ) in 27 2011 Received in revised form June an acute murine model was evaluated. The mice used throughout the study were randomly Accepted 15 July 2011 assigned to many groups (10 mice each), which either remained uninfected or were infected A 28 J 2012 T. gondii vailable online anuary intraperitoneally with tachyzoites of (strains RH and CN). All groups were then treated with different sulfonamides and the optimal treatmenResults:t protoco l was determined candidates. Keywords: Sulfadiazine-sodium (SD) was used for comparison. The optimal therapy involved 250 ( ) Toxoplasmosis gavaging mice twice per day with mg/kg bw of sulfachloropyrazine-sodium SPZ for five days. 50% Sulfonamides Using this protocol, the average survival time and the time-point of fatalities were prolonged 40% Sulfachloropyrazine-sodium significantly compared with SD treatment. Treatment with SPZ protected of mice from death, Efficacy and the heart and kidney tissue of these animals was parasite-freT.e, gondiias determined by nested- PCR. SPZ showed excellent therapeutic effects in the treatment of in an acute murine TToxoplasmaherapy gondii T. gondii model and iConclusions:s therefore a p romising drug candidate for the treatment and prevention of Murine in animals. It can be concluded that the effective drug sulfachloropyrazine may be Therapeutic effect the new therapeutic options against animal toxoplasmosis. 1. Introduction Apicomplexa, as it is the most experimentally tractable Toxoplasma gondii T. gondii organism in thiPlasmodiums important groEimeriaup of intraCryptosporidiumcellular parasites ( ) has been identified as Neosporathat includes Theileria , , , a major oppoe.g.rtunistic pathogen in immunocompromised , and . Felids are the key animal species individuals ( , patients with AIDS or organ transplant in the life cycle of this parasite because they are the recipients) and neonates. Infection can result in definitive hosts that can excrete the environmentally- [6] encephalitis, chorioretinitis or congenital traT.ns mgondiiission if a resistant stage, the oocyst . According to the serological seronegative pregnant women is infected[1,2]. is an investigations, about 30% of the human population is obligate intracellular protozoan pathogen with worldwide infected with this parasite[5]. A recent serosurvey using distribution that can infect almost all warmed-blooded samples from the population-based National Health and animals. ExaminatioT.n Ngondiiutrition Study found a decrease in the age- Other members of the Plasmodiumsame phylum, ApicCryptosporidiumomplexa, include adjusted prevalence in USA-born persons, 12 49 14 1% 1988 1994 9% the human pathogens Eimeria and Sarcocystis T., of - years of age, from . in - to in [3-5] 1999 2004[6,7] gondiiand the animal pathogens and . - . InT. th egondii mainland of China, the rate of human has become a model organism for the study of the infection with has been reported to be 7.88% nationwide, as detected by ELISA[8]. *Corresponding author: Bing Huang, Professor, Key Laboratory for Animal At present, there are no non-infective commercial Parasitology of Ministry of Agriculture, Shanghai Veterinary Research Institute, Chinese vaccines to prevent clinical toxoplasmosis in humans and Academic of Agricultural Science. [9,10] R Tel: +86 21 3429 3464 animals . esearch into potential drug treatments have Fax: +86 21 5408 1818 excluded many antibiotics, synthetic drugs and traditionT.al E-mail: [email protected] Chinese medicines as being ineffective against the Foundation Project: Supported by a grant from The National Special Research Program gondii fi S for Non-Pro t Trades (Agriculture, China) ( grant No. 200803017). ulfonamides arT.e cgondiiurrently considered as the best therapeutic option for infection. Sulfonamides Yan-Bo Zeng et al./Asian Pac J Trop Biomed 2012; 2(1): 70-75 71 are a class of broad spectrum synthetic antibiotics that by Shanghai Baoshan Zhenzong Biochemistry Engineering are effective against many kinds of microorganisms Factory, Henan, China. 60 [10] and have been used clinically for over T. gondiiyears . The All agents were provided in the powder form of the sulfonamides that have been used against include pharmaceutical raw materials (containing minimum purity), the sulfonamides, sulfamethoxazole, sulfanilanilides, and were dissolved in physiological saline. Then the sulfathiazole, sulfisoxazine and sulfadiazine[11-13]. The mixtures were sonicated to produce a smooth dispersion synergistic combination of sulfadiazine-sodium (SD) and and the desired concentration was prepared daily in pyrimethamine is currently considered to be the most physiological saline and administered to’ mice at a dosage of effective first-line antitoxoplasma therapy, and is also used 250 mg/kg/day, according to the animal s body weight, for 5 as a standard control therapy. This type of therapy has been or 10 days, 24 h after infection. [2] used after the diagnosis of prenatal infection . However, 2.4. Evaluating the efficacy of sulfonamides these drugs are not always efficacious and often cannot be tolerated due to severe toxic side effects[14]. Therapy is hampered by hematologic toxicity and allergic reactions in Ninety mice were randomly allocated into nine groups (10 5%-15% of patients, and some patients require continuous mice each) designated G1-G9. Eight of these groups (G1-G8) treatment[15,16]. Furthermore, some patients are intolerant of were infected with RH strains, the other group (G9) remained one of these regimens and require alternative therapies[17]. uninfected. Each drug was dissolved in physiological Few medications are currently available to treat animal saline and prepared daily as a liquid suspension. 24 h after toxoplasmosis and those that are available are limited due intraperitoneal infection, the G1-G7 mice were administered to poor efficacy. There isT. t hgondiierefore an urgent need for new, each drug intragastrically daily for five days using a effective drugs to treat , particularly in livestock 16-gauge blunt feeding needle. Mice from the untreated and other warm-blooded animals. In this study, a variety group (G8) and the uninfected group (G9) were administered of candidate sulfonamides, some of which are widely useT.d physiological saline intragastrically daily. Over the course of [18] (30 ) agondiis human and animal antibiotics were used to treat the experiment days , mice were observed daily and the in an acute murine infection model and the potency mortality rate was recorded. and safety of these sulfonamides against infection were 2.5. Different methods of drug administration evaluated. ( ) 2. Materials and methods Ninety mice were randomized into nine groups G1-G9 . All mice were intraperitoneally infected with RH strains, except 5 8 2.1. Animals for group G and G mice who were infected with the CN strain as a control, and G9 mice remained uninfected. After 24 h, the mice were administered orally the specified drugs. Outbred, strain Kunming (KM), female mice (Slack G1-G5 mice were administered the SPZ at the same dosage Shanghai Laboratory Animal Co., Ltd., China), weighing via different methods: G1 mice received SPZ by drinking between 20 and 24 g, were used in each experiment. The water (100 mL) daily for five days, G2 mice by gavage once animals were acclimatized for two days, then maintained in per day for ten days, G3 mice by gavage twice a day (morning a suitable rearing environment with free access to water and and night) for five days, G4 mice by gavage once a day for rodent food throughout the experiment[19]. five days, G5 mice by gavage once a day for 10 days. G6 mice 10 2.2. Parasites received SD by gavage once a day for days as a control. G7 and G8 mice received physiological saline solution as 9 T. gondii infected untreated controls. G mice remained uninfected Tachyzoites of of the swine strain, Changning and received physiological saline solution. All mice were (CN), and the human strain RH, were propagated in our observed and their condition was recorded twice daily. The laboratory (Shanghai Veterinary Research Institute, CAAS, experiment continued for 65 days. ) China . Highly virulent tachyzoites were maintained in the 2.6. Nested-PCR detection peritoneal cavities by propagating every three or four days in KM mice, three times. The harvested tachyzoites were 65 resuspended in physiological saline and each ex3perimental At the end of the -day experiment described above, mouse was inoculated intraperitoneally with 5暳10 organisms live mice were euthanized and the viscera organs and brain (in 0.2 mL). tissue were excised. These tissues were then digested in trypsin
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