竇勤,閆明,李柯翱,李治建,熱比姑麗·伊斯拉木,艾西木江·熱甫卡提,季志紅

(1.新疆維吾爾自治區(qū)維吾爾醫(yī)藥研究所,烏魯木齊 830049;2.新疆維吾爾醫(yī)方劑學(xué)實(shí)驗(yàn)室,烏魯木齊 830049;3.新疆奇康哈博維藥有限公司,烏魯木齊 830001)

祖卡木顆粒大鼠灌胃長期毒性研究

竇勤1,2,閆明1,2,李柯翱3,李治建1,2,熱比姑麗·伊斯拉木1,2,艾西木江·熱甫卡提1,2,季志紅3

(1.新疆維吾爾自治區(qū)維吾爾醫(yī)藥研究所,烏魯木齊 830049;2.新疆維吾爾醫(yī)方劑學(xué)實(shí)驗(yàn)室,烏魯木齊 830049;3.新疆奇康哈博維藥有限公司,烏魯木齊 830001)

目的 觀察SD大鼠反復(fù)灌胃給予祖卡木顆粒的長期毒性反應(yīng)。方法SD大鼠120只,雌雄各半,按體質(zhì)量隨機(jī)分為對(duì)照組及低、中、高劑量組。對(duì)照組給予羧甲基纖維素鈉,低、中、高劑量組分別給予祖卡木顆粒0.72,1.43, 2.86 g·kg-1·d-1,po,qd,連續(xù)1個(gè)月;停藥后恢復(fù)期2周。結(jié)果高劑量組3只動(dòng)物僅給藥期間出現(xiàn)1 d稀便、腹瀉。給藥末期,與對(duì)照組比較,高劑量組白細(xì)胞計(jì)數(shù)、紅細(xì)胞計(jì)數(shù)、血紅蛋白、血細(xì)胞比容及氯水平升高,低、中、高劑量組凝血酶原時(shí)間縮短;低、中、高劑量組血尿素氮、丙氨酸氨基轉(zhuǎn)移酶、總膽固醇、天冬氨酸氨基轉(zhuǎn)移酶降低,組織病理學(xué)檢查無明顯變化。結(jié)論祖卡木顆粒連續(xù)灌胃1個(gè)月,對(duì)大鼠無明顯毒性,未見明顯毒性反應(yīng)劑量為1.4 g·kg-1·d-1(相當(dāng)于生藥20.8 g·kg-1·d-1)。

祖卡木顆粒;大鼠;毒性;長期

祖卡木顆粒是維吾爾醫(yī)臨床常用、具有代表性的特色經(jīng)典方劑,由山奈、睡蓮花、薄荷、大棗、洋甘菊、破布木果、甘草、蜀葵子、大黃、罌粟殼10味藥材組成,具有調(diào)節(jié)異常氣質(zhì)、清熱、發(fā)汗、通竅功能,用于治療感冒咳嗽、發(fā)熱無汗、咽喉腫痛、鼻塞流涕。為對(duì)其臨床應(yīng)用安全性進(jìn)行再評(píng)價(jià),本研究通過大鼠長期毒性實(shí)驗(yàn),探討其毒性表現(xiàn)和毒性靶器官。

1 材料與方法

1.1 動(dòng)物 SD大鼠,SPF級(jí),雌雄各半,體質(zhì)量180～220 g,由新疆實(shí)驗(yàn)動(dòng)物研究中心提供,實(shí)驗(yàn)動(dòng)物生產(chǎn)許可證號(hào):SCXK(新)2011-0001,動(dòng)物合格證號(hào): SCXK-LAC2013-4-3,實(shí)驗(yàn)動(dòng)物使用許可證號(hào):SYXK (新)2011-0006。動(dòng)物于GCP中心SPF級(jí)動(dòng)物房飼養(yǎng),每籠飼養(yǎng)同性動(dòng)物≤5只,自由攝食、飲水,室溫20～26℃,相對(duì)濕度40%～70%,光照12 h,黑暗12 h。

1.2 藥品與試劑 祖卡木顆粒干浸膏由新疆奇康哈博維藥有限公司提供,批號(hào):130103,1 g干浸膏相當(dāng)于生藥14.88 g;羧甲基纖維素鈉(sodiumcarboxymethy cellulose,CMC-Na)對(duì)照品,天津市光復(fù)精細(xì)化工研究所提供,批號(hào):100409。血液生化試劑由深圳邁瑞生物醫(yī)療電子股份有限公司提供,具體包括:丙氨酸氨基轉(zhuǎn)移酶(alanine aminotransferase,ALT,批號(hào):140113002),天冬氨酸氨基轉(zhuǎn)移酶(aspartate aminotransferase,AST,批號(hào):140213002),堿性磷酸酶(alkaline phosphatase, ALP,批號(hào):140313001),血尿素氮(blood urea nitrogen, BUN,批號(hào):141313002),肌酐(creatinine,Cr,批號(hào):14102028),總蛋白(totalprotein,TP,批號(hào): 140813002),清蛋白(albumin,ALB,批號(hào): 140913002),總膽固醇(total cholesterol,CHO,批號(hào): 141613001),血糖(glucose,Glu,批號(hào):141513001),總膽紅素(total bilirubin,TBiL,批號(hào):140613002),肌酸磷酸激酶(creatine kinase,CK,批號(hào):142512018),三酰甘油(triglycerides,TG,批號(hào):1141712030)。血液學(xué)試劑由希森美康醫(yī)用電子(上海)有限公司提供(批號(hào): 105198);血凝試劑由上海太陽生物技術(shù)有限公司提供,白細(xì)胞FFS-801分類染色液,批號(hào):A2007;白細(xì)胞分類溶血素,批號(hào):A2008;網(wǎng)紅細(xì)胞RED-800染色液,批號(hào):ZA2042;網(wǎng)紅細(xì)胞RED-300染色液稀釋液,批號(hào):ZA2042;血色素SLS-220A檢測液,批號(hào):A2026;嗜堿通道FBA-200A溶血素,批號(hào):A2022。電解質(zhì)試劑由鄭州市希萊恒醫(yī)用電子有限公司提供(A標(biāo),批號(hào): 20130314;B標(biāo),批號(hào):20130320)。

1.3 儀器 7100型全自動(dòng)生化分析儀,日立公司。XT-2000iv全自動(dòng)血液分析儀,sysmex corporation。KOBE,JAPAN;S22血凝儀,深圳市鵬瑞佳電子有限公司。XR2000電解質(zhì)儀,深圳市鵬瑞佳電子有限公司。DM2500生物顯微鏡,德國萊卡公司。RM2235切片機(jī),德國萊卡公司。KD-BM生物組織自動(dòng)包埋機(jī),浙江金華科迪儀器設(shè)備有限公司。生物組織自動(dòng)脫水機(jī):KD-TS3D,浙江金華科迪儀器設(shè)備有限公司。攤片烤片機(jī):KZPG-1A,天津天利航空機(jī)電有限公司。

1.4 實(shí)驗(yàn)方法[1-3]

1.4.1 動(dòng)物分組 120只SD大鼠檢疫1周后,按體質(zhì)量隨機(jī)分為4組,每組30只,雌雄各半,分別為對(duì)照組和低、中、高劑量組。

1.4.2 劑量設(shè)計(jì) 祖卡木顆粒以供試品計(jì)算,成人用量為2.862 g·d-1,成人體質(zhì)量按60 kg計(jì)算,即成人每日用供試品的量為2.862g/60kg= 0.047 7 g·kg-1。低、中、高劑量組分別為臨床成人每日每千克體質(zhì)量用量的15,30,60倍,分別為0.72 (生藥10.4 g)、1.43(生藥20.8 g)、2.86(生藥41.6 g)g·kg-1。

1.4.3 給藥方法與觀察指標(biāo) 將供試品灌胃給予大鼠,1 mL·(100 g)-1,每天1次,連續(xù)1個(gè)月,對(duì)照組給予等量CMC-Na。每天觀察并記錄動(dòng)物的外觀體征、行為活動(dòng)、飲食、大便、體質(zhì)量等情況,出現(xiàn)中毒反應(yīng)應(yīng)重點(diǎn)觀察。每4 d稱體質(zhì)量1次,并根據(jù)體質(zhì)量情況調(diào)整給藥量,于停藥后24 h,各組分別處死大鼠20只,進(jìn)行全面、細(xì)致的系統(tǒng)尸檢,取腦、心、肝、脾、肺、腎、腎上腺、胸腺、睪丸、附睪、子宮、卵巢等稱定質(zhì)量,計(jì)算臟器器官系數(shù);對(duì)大腦、小腦、腦干、脊髓、垂體、胸腺、甲狀腺與甲狀旁腺、食管、唾液腺、胃、小腸、結(jié)腸、肝臟、膽囊、腎臟、腎上腺、脾、胰腺、氣管、肺、主動(dòng)脈、心臟、附睪、睪丸、卵巢、子宮、前列腺、膀胱、視神經(jīng)、腸系膜淋巴結(jié)、胸骨骨髓等臟器,用15%中性甲醛固定,首先對(duì)高劑量組和對(duì)照組動(dòng)物標(biāo)本進(jìn)行常規(guī)石蠟包埋、切片,蘇木精-伊紅(hematoxylin-eosin,HE)染色,光鏡檢查,觀察臟器組織病理變化。分別測定血液學(xué):紅細(xì)胞計(jì)數(shù)(red blood cell count,RBC)、血細(xì)胞比容(hematocrit,HCT)、平均紅細(xì)胞血紅蛋白含量(mean corpuscularhemoglobin,MCH)、網(wǎng)織紅細(xì)胞(reticulocyte,RET)、血小板計(jì)數(shù)(platelet count,PLT)、血紅蛋白(hemoglobin,HGB)、平均紅細(xì)胞體積(meancorpuscular volume,MCV)、平均紅細(xì)胞血紅蛋白濃度(meancorpuscularhemoglobinconcentration, MCHC)、白細(xì)胞計(jì)數(shù)(white blood cell count,WBCCD)、淋巴細(xì)胞數(shù)目(lymphocytes,LYMPH)、單核細(xì)胞計(jì)數(shù)(monocyte count,MC)、粒細(xì)胞計(jì)數(shù)(granulocyte count,GRAN)、凝血酶原時(shí)間(prothromvin time,PT)和血液生化學(xué)指標(biāo):ALT、AST、ALP、BUN、Cr、TP、ALB、CHO、Glu、T-BiL、CK、TG、鉀(kalium,K+)、鈉(natrium, Na+)、氯(chlorin,Cl-)。剩余大鼠繼續(xù)飼養(yǎng)2周,同樣進(jìn)行上述觀察和檢測。通過上述觀察和檢測,了解大鼠在給藥期間的毒性反應(yīng)及停藥后一段時(shí)間內(nèi)的恢復(fù)情況。

2 結(jié)果

2.1 一般狀況 高劑量組3只動(dòng)物給藥第10,25,37天出現(xiàn)稀便、腹瀉,其他組動(dòng)物無明顯異常,各給藥組進(jìn)食量和體質(zhì)量與對(duì)照組比較差異無統(tǒng)計(jì)學(xué)意義。

2.2 臟器質(zhì)量和臟器系數(shù) 祖卡木顆粒給藥1個(gè)月和恢復(fù)期,各給藥組臟器質(zhì)量和臟器系數(shù)與對(duì)照組比較,差異無統(tǒng)計(jì)學(xué)意義。

2.3 血液學(xué)檢查 給藥末期:♂高劑量組RBC、HGB、HCT較對(duì)照組升高(P＜0.01),♂低劑量組的HGB,中、高劑量組HCT較對(duì)照組升高(P＜0.05),♂低、中、高劑量組PT較對(duì)照組縮短(P＜0.01);♀中劑量組WBC比較對(duì)照組顯著升高(P＜0.01)。除上述指標(biāo)外,其余血液學(xué)指標(biāo)與對(duì)照組比較差異無統(tǒng)計(jì)學(xué)意義;恢復(fù)期結(jié)束,♂高劑量組NEUT較對(duì)照組升高(P＜0.05),LYMPH較對(duì)照組降低(P＜0.05)。其余血常規(guī)指標(biāo)與對(duì)照組比較差異無統(tǒng)計(jì)學(xué)意義,見表1,2。

表1 4組大鼠灌胃長期毒性實(shí)驗(yàn)給藥30 d血液學(xué)指標(biāo)檢測結(jié)果Tab.1 Hematological indexes of four groups of rats after 30-day oral treatment in long termtoxicity test ±s,n=10

表1 4組大鼠灌胃長期毒性實(shí)驗(yàn)給藥30 d血液學(xué)指標(biāo)檢測結(jié)果Tab.1 Hematological indexes of four groups of rats after 30-day oral treatment in long termtoxicity test ±s,n=10

與對(duì)照組比較,*1P＜0.05,*2P＜0.01Compared with control group,*1P＜0.05,*2P＜0.01

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表2 4組大鼠停藥2周血液學(xué)指標(biāo)檢測結(jié)果Tab.2 Hematological indexes of four groups of rats two weeks after drug withdrawal ±s,n=5

表2 4組大鼠停藥2周血液學(xué)指標(biāo)檢測結(jié)果Tab.2 Hematological indexes of four groups of rats two weeks after drug withdrawal ±s,n=5

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續(xù)表2Tab.2 ±s,n=5

續(xù)表2Tab.2 ±s,n=5

與對(duì)照組比較,*1P＜0.05Compared with control group,*1P＜0.05

性別與組別WBCPLT (×109·L-1) RBC/ (×1012·L-1) HGB/ (g·L-1) HCT/ % MCV/ fL MCH/ pg♀對(duì)照組335.00±5.0914.04±1.4380.78±1.923.86±0.951.32±0.583.57±0.136.86±0.52低劑量組335.60±3.3612.68±3.1282.14±3.983.92±1.401.26±0.443.70±0.446.62±0.48中劑量組336.40±2.8817.84±2.8675.94±3.064.56±0.841.66±0.533.52±0.767.66±1.62高劑量組338.00±3.8017.38±5.4876.36±7.174.24±1.292.02±0.763.32±0.667.02±0.44

2.4 血液生化指標(biāo)和電解質(zhì)檢查結(jié)果 給藥末期:♂高劑量組BUN、ALT較對(duì)照組降低(P＜0.01),♂低、中劑量組CHO,低、高劑量組AST較對(duì)照組降低(P＜0.05),除上述指標(biāo)外,其余生化學(xué)指標(biāo)與對(duì)照組比較差異無統(tǒng)計(jì)學(xué)意義;恢復(fù)期:♂高劑量組Cl-較對(duì)照組升高(P＜0.05),除上述指標(biāo)外,其余生化學(xué)指標(biāo)與對(duì)照組比較差異無統(tǒng)計(jì)學(xué)意義,見表3,4。

2.5 解剖檢查 給藥結(jié)束和恢復(fù)期結(jié)束對(duì)大鼠進(jìn)行解剖,各組動(dòng)物大體解剖檢查肉眼未見臟器異常。

2.6 組織病理學(xué)檢查 給藥結(jié)束、恢復(fù)期結(jié)束組織病理學(xué)檢查,高劑量組肺間質(zhì)淋巴細(xì)胞及單核細(xì)胞浸潤,大腸黏膜下淋巴細(xì)胞浸潤,肝細(xì)胞點(diǎn)狀壞死,這些病理改變?cè)趯?duì)照組動(dòng)物中也有發(fā)現(xiàn),與給藥組比較病變數(shù)量及程度未見明顯差異,病變范圍小、程度輕,符合SD大鼠常見自發(fā)性病變,故考慮與藥物作用無關(guān)。本實(shí)驗(yàn)條件下,未發(fā)現(xiàn)明顯藥物相關(guān)性病理改變,亦無明顯靶器官。

表3 4組大鼠給藥30 d血生化指標(biāo)檢測結(jié)果Tab.3 Hematological biochemical indexes of four groups of rats after 30-day treatment ±s,n=10

表3 4組大鼠給藥30 d血生化指標(biāo)檢測結(jié)果Tab.3 Hematological biochemical indexes of four groups of rats after 30-day treatment ±s,n=10

與對(duì)照組比較,*1P＜0.05,*2P＜0.01Compared with control group,*1P＜0.05,*2P＜0.01

性別與組別CRE/ (μmol·L-1) BUNCHOTGGlu (mmol·L-1) ALBTP (g·L-1) AST/ (U·L-1)♂對(duì)照組26.30±6.588.23±1.441.17±0.090.54±0.206.85±0.5832.59±0.8654.39±1.96108.70±14.24低劑量組26.58±10.667.07±1.201.42±0.18*10.56±0.286.58±1.2632.67±1.1853.14±1.7791.00±13.58*1中劑量組32.75±10.427.50±1.001.39±0.26*10.64±0.286.79±0.7232.26±0.9254.27±1.6195.20±13.79高劑量組36.28±4.786.32±0.90*21.28±0.130.47±0.147.11±1.2033.19±1.2755.52±2.5995.90±11.99*1♀對(duì)照組34.89±6.227.72±1.021.36±0.210.39±0.196.76±0.8334.41±2.1857.46±3.3692.40±19.83低劑量組39.68±5.928.33±2.041.55±0.280.28±0.067.01±0.7133.59±1.3656.31±2.48103.20±24.14中劑量組32.41±5.626.75±1.461.56±0.220.32±0.116.81±0.7334.08±1.3556.40±2.9293.70±17.80高劑量組37.23±6.196.78±1.241.55±0.210.41±0.177.39±0.7433.37±1.3555.71±1.8387.00±14.73性別與組別ALTALPCK (U·L-1) T-BiL/ (μmol·L-1) K+Na+Cl-(mmol·L-1)♂對(duì)照組43.00±6.94177.90±43.62606.10±197.761.19±1.484.24±0.24139.03±0.66104.27±1.59低劑量組39.20±6.94136.30±30.08427.20±186.590.99±0.964.43±0.28138.91±1.28104.19±1.29中劑量組42.20±4.46134.90±43.50486.00±211.890.82±0.524.33±0.32139.54±1.03104.71±0.72高劑量組33.30±4.22*2136.50±38.34506.60±274.580.69±0.484.61±0.33139.17±1.18104.51±1.57♀對(duì)照組41.20±13.7773.60±26.48441.70±177.260.64±0.444.14±0.28138.28±0.68105.28±0.78低劑量組40.20±12.3487.30±25.75427.30±170.741.10±0.864.07±0.26138.81±1.44105.10±1.26中劑量組33.50±7.3283.80±24.96319.70±112.060.65±0.564.40±0.42138.76±2.64104.56±3.59高劑量組30.90±8.0276.00±15.79313.40±116.620.43±0.314.20±0.19138.25±0.92104.48±1.32

表4 4組大鼠停藥2周血生化指標(biāo)檢測結(jié)果Tab.4 Hematological biochemical indexes of four groups of rats after 30-day treatment ±s,n=5

表4 4組大鼠停藥2周血生化指標(biāo)檢測結(jié)果Tab.4 Hematological biochemical indexes of four groups of rats after 30-day treatment ±s,n=5

與對(duì)照組比較,*1P＜0.05Compared with control group,*1P＜0.05

性別與組別CRE/ (μmol·L-1) BUNCHOTGGlu (mmol·L-1) ALBTP (g·L-1)♂對(duì)照組33.44±6.745.74±1.021.48±0.251.14±0.328.64±1.6631.66±1.6958.38±2.36低劑量組34.82±5.626.94±1.501.34±0.221.02±0.187.71±1.8233.10±2.0660.00±3.24中劑量組34.66±7.027.74±1.501.48±0.140.82±0.246.86±2.6231.16±1.6658.20±2.32高劑量組29.32±4.166.10±0.641.48±0.380.67±0.486.83±0.7231.84±2.0958.88±2.86♀對(duì)照組37.12±3.757.00±0.701.36±0.190.52±0.267.68±0.1934.06±2.3661.88±3.62低劑量組31.86±3.516.94±1.261.59±0.300.92±0.387.40±0.5435.26±1.3163.70±1.36中劑量組29.32±4.166.10±0.641.48±0.380.67±0.486.83±0.7231.84±2.0958.88±2.86高劑量組33.30±8.586.12±1.911.68±0.320.61±0.157.14±0.7833.36±2.6761.02±4.06性別與組別ASTALTALPCK (U·L-1) T-BiL/ (μmol·L-1) K+Na+Cl-(mmol·L-1)♂對(duì)照組93.60±14.1440.60±4.8290.80±15.12305.20±178.201.66±1.224.04±0.12139.12±0.71103.62±0.39低劑量組120.60±18.2443.20±6.61119.60±27.96503.40±171.841.18±0.824.47±0.41139.68±1.26103.88±0.86中劑量組113.20±26.7244.60±5.94100.80±26.64472.40±326.800.46±0.314.25±0.16140.38±0.42104.08±1.26高劑量組95.80±32.8734.40±8.3877.60±34.52384.00±287.041.02±0.304.24±0.36140.98±1.44105.28±0.85*1♀對(duì)照組87.00±16.2428.20±4.0859.00±20.77231.00±122.590.60±0.603.90±0.13140.06±0.34105.72±0.99低劑量組87.60±26.2734.20±8.7693.40±19.38223.60±86.890.76±0.644.00±0.19140.64±1.42104.72±1.56中劑量組95.80±32.8734.40±8.3877.60±34.52384.00±287.041.02±0.303.86±0.30140.24±1.37105.30±1.09高劑量組81.00±8.0034.20±8.4959.20±15.08260.20±11.650.92±0.294.10±0.38140.14±1.23105.60±0.82

3 討論

祖卡木顆粒不同劑量連續(xù)灌胃1個(gè)月,大鼠一般癥狀表現(xiàn)為給藥組隨著劑量的增加,高劑量組給藥期間出現(xiàn)稀便、腹瀉,但僅1 d,各給藥組動(dòng)物體質(zhì)量、進(jìn)食量與對(duì)照組比較差異無統(tǒng)計(jì)學(xué)意義,表明祖卡木顆粒對(duì)大鼠的體質(zhì)量和進(jìn)食量基本無影響。

血液學(xué)檢查表明,給藥末期RBC、HGB、HCT、PT指標(biāo)雖然與對(duì)照組比較有所增減,偶有統(tǒng)計(jì)學(xué)意義,但絕對(duì)值差別較小,多為一個(gè)劑量所致,無明顯劑量相關(guān)性。血生化指標(biāo)和電解質(zhì)檢查表明,給藥末期BUN與對(duì)照組比較偶有差異,是數(shù)值降低而非升高,但變化無劑量規(guī)律性,腎臟組織病理學(xué)光鏡檢查未見明顯病變,認(rèn)為本品無腎臟毒性;給藥末期AST、ALT與對(duì)照組比較偶有差異,變化無劑量規(guī)律性,且數(shù)值下降,無明顯病理意義,肝臟組織病理學(xué)光鏡檢查未見明顯病變,認(rèn)為本供試品無肝毒性。給藥末期CHO與對(duì)照組比較偶有差異,但變化差值很小,無劑量規(guī)律性,認(rèn)為本供試品無升高CHO作用。恢復(fù)期Cl-電解質(zhì)指標(biāo)與對(duì)照組比較,雖有統(tǒng)計(jì)學(xué)差異,但考慮與標(biāo)準(zhǔn)差過小有關(guān),變化無劑量規(guī)律性,且變化絕對(duì)值差別較小,認(rèn)為供試品無升高Cl-的作用。

組織病理學(xué)檢查:各組間臟器病變例數(shù)差異不大,考慮為動(dòng)物自身病變,而非藥物毒性所致,其余臟器未見明顯病理變化。綜上所述,在本實(shí)驗(yàn)條件下,祖卡木顆粒對(duì)SD大鼠無明顯藥物關(guān)聯(lián)性毒性靶器官,祖卡木顆粒對(duì)大鼠的未見明顯毒性反應(yīng)劑量為1.4 g·kg-1·d-1(相當(dāng)于生藥20.8 g·kg-1·d-1)[4]。

[1] 袁伯俊,繆明陽,李波.藥物毒理學(xué)實(shí)驗(yàn)方法與技術(shù)[M].北京:化學(xué)工業(yè)出版社,2007:200-210.

[2] 徐叔云,卞如濂,陳修.藥理實(shí)驗(yàn)方法學(xué)[M].3版.北京:人民衛(wèi)生出版社,2003:226-229.

[3] 熱比姑麗·伊斯拉木.新疆曼陀羅子及其代表制劑艾比西帕丸的大鼠長期毒性實(shí)驗(yàn)[J].中國藥理學(xué)通報(bào),2011, 27(10):1479-1480.

[4] 易沙克江·馬合穆德.中國醫(yī)學(xué)百科全書-維吾爾醫(yī)學(xué)[M].上海:上?？茖W(xué)技術(shù)出版社,2005:302-303.

DOI 10.3870/yydb.2014.07.008

Studies on the Chronic Toxicity of Zukamu Granules in Rats

DOU Qin1,2,YAN Ming1,2,LI Ke-ao3,LI Zhi-Jian1,2,RABIGUL·Islam1,2,HAXIMJAN Rapkat1,2,JI Zhi-hong3
(1.Institute of Xinjiang Traditional Uyghur Medicine,Urumqi 830049,China;2.Laboratory of Traditional Uyghur Medicine Prescription of Xinjiang,Urumqi 830049,China;3.Xinjiang Ciconhabo Uygur Medicine Co., Ltd,Urumqi 830001,China)

ObjectiveTo study the chronic toxicology ofZukamugranules in rats.MethodsA total of 120 healthy SD rats(male∶female=1∶1)were randomly divided into the control,low(0.72 g·kg-1·d-1),middle (1.43 g·kg-1·d-1),and high(2.86 g·kg-1·d-1)doses ofZukamugranules.The drug was given orally,once daily for a month,and the controls were given with sodiumcarboxymethyl cellulose.A 2-week recovery period was allowed after the drug withdrawal.ResultsThree rats in the high dose group developed diarrhea and loose stools for one day.Compared with the control group,the white blood cells(WBC),red blood cells(RBC),hemoglobin(HGB),hematocrit(HCT)and chlorine(Cl-) in the high dose group increased.Prothrombin time(PT),blood urea nitrogen(BUN),alanine aminotransferase(ALT), cholesterol(CHO),and aspartate aminotransferase(AST)decreased markededly in the low,middle and high dose group.No obvious change was found in histopathological examination.ConclusionNo obvious toxicity was observed in SD rats treated withZukamugranules at 1.4g·kg-1·d-1(equivalently to crude drug of 20.8 g·kg-1·d-1)given orally for one month.

Zukamugranula;Rat;Toxicity,chronic

R286;R965

A

1004-0781(2014)07-0869-05

2013-08-22

2013-09-25

竇勤(1977-),女,新疆奇臺(tái)人,助理研究員,碩士,主要從事藥理毒理學(xué)研究。E-mail:douqin123@sina.com。

季志紅(1961-),女,副主任藥師,研究方向:項(xiàng)目管理。E-mail:jizhihongdyy@163.com。