本文選題：三苯雙脒 + 華支睪吸蟲��； 參考：《中國疾病預(yù)防控制中心》2013年博士論文

【摘要】：根據(jù)第二次全國人體寄生蟲病分布調(diào)查的估算,我國的華支睪吸蟲感染人數(shù)已達1249萬。由于缺乏預(yù)防食源性吸蟲病的疫苗和人們的飲食方式難以改變,藥物化療仍然是控制該類疾病的主要手段。目前用于治療華支睪吸蟲感染的藥物主要是吡喹酮,根據(jù)世界衛(wèi)生組織的推薦,吡喹酮用于治療華支睪吸蟲感染的適宜劑量療程是每次口服25mg/kg,3次/d,連給2d。該療法雖有較好的療效,但應(yīng)用于大規(guī)模群體治療具有一定的難度,因此,繼續(xù)尋求新的抗華支睪吸蟲病藥物仍是十分必要的。近年來動物試驗發(fā)現(xiàn)頓服單劑三苯雙脒對華支睪吸蟲和麝貓后睪吸蟲有很好的殺滅效果,且其對麝貓后睪吸蟲的療效在臨床試驗中得到了驗證。本論文先通過實驗室研究確定三苯雙脒對華支睪吸蟲的療效,并初步探討其抗蟲機制及在膽汁中的代謝動力學(xué),然后嘗試通過三苯雙脒治療腸道線蟲和華支睪吸蟲混合感染的病人,評價三苯雙脒對感染華支睪吸蟲的療效及安全性,為華支睪吸蟲病的現(xiàn)場群體化療提供參考。 在實驗室研究中,我們首先通過觀察不同劑量的三苯雙脒對體外培養(yǎng)的華支睪吸蟲和對感染華支睪吸蟲囊蚴的倉鼠的療效,評價其對體外和體內(nèi)的華支睪吸蟲的作用。該研究明確了三苯雙脒對體外培養(yǎng)的華支睪吸蟲具有很強的殺滅作用,且對其最低致死劑量僅為吡喹酮的一半；對倉鼠體內(nèi)的華支睪吸蟲童蟲和成蟲均有好的療效,其中100mg/kg三苯雙脒治療華支睪吸蟲成蟲可有高于90%的減蟲率,即使劑量低至12.5mg/kg仍可有50%的減蟲率,效價強度顯著高于吡喹酮。 其次,我們通過觀察三苯雙脒對華支睪吸蟲超微結(jié)構(gòu)的影響,對其抗蟲機制進行了初步探討。大鼠經(jīng)胃灌服三苯雙脒300mg/kg后4h、8h、24h、48h和72h分別剖殺取蟲,經(jīng)預(yù)處理后置于透射電鏡下觀察。結(jié)果顯示三苯雙脒能引起華支睪吸蟲皮層乳突的腫脹、破潰和溶解,層皮內(nèi)桿狀顆粒、盤狀顆粒和膜樣小泡的減少,線粒體和內(nèi)質(zhì)網(wǎng)的減少,線粒體形成空泡以及皮層細胞核膜損傷。 再次,本論文對三苯雙脒代謝物氨脒在大鼠體內(nèi)的藥物代謝動力學(xué)進行了研究。首先建立了大鼠血漿和膽汁中氨脒濃度的測定方法,然后用200mg/kg三苯雙脒治療大鼠后于不同時間點取血樣及收集膽汁,同樣時間點收集未經(jīng)治療的空白大鼠的血樣和膽汁,經(jīng)處理后進樣測定,繪制血藥濃度—時間曲線、膽汁藥物濃度—時間曲線以及膽汁排泄速率和累計排泄量曲線。結(jié)果發(fā)現(xiàn)氨脒在血漿中的達峰時間Tmax為0.90±0.22h,峰濃度Cmax為8.12±2.05mg/L.而氨脒在膽汁中的達峰時間Tmax為1.15±0.42h,峰濃度Cmax為11.16±2.07mg/L,11h內(nèi)氨脒的膽汁累積排泄量為40.12±12.00μ g,累積排泄率0.38‰,給藥后0.5～3h的膽汁排泄速率最大。 最后,本論文還通過觀察三苯雙脒治療腸道線蟲和華支睪吸蟲混合感染的病人的治愈率、蟲卵減少率和不良反應(yīng),評價三苯雙脒抗華支睪吸蟲療效和安全性。通過倫理審查后,在試驗地區(qū)采用Kato-Katz法進行基線調(diào)查,根據(jù)入選標準和排除標準確定擬服藥人員,隨機分為3組,簽訂知情同意書及經(jīng)過臨床醫(yī)生體檢后,分別口服吡喹酮(總劑量為75mg/kg)、三苯雙脒(400mg,頓服)、三苯雙脒(200mg*2次)。部分接受三苯雙脒治療的病人在治療前和治療后24h檢測血尿常規(guī)、心電圖和肝腎功能(空腹抽血)。研究人員對服藥人員治療后48h內(nèi)進行隨訪,詢問有無不良反應(yīng)并記錄具體情況。治療后3w,收集病人糞樣,用Kato-Katz法檢測并計數(shù)糞樣的華支睪吸蟲、鉤蟲、蛔蟲、鞭蟲和絳蟲的蟲卵數(shù),計算華支睪吸蟲的治愈率和蟲卵減少率。然后根據(jù)第一次試驗結(jié)果,邀請未治愈病人,按照同樣的操作標準進行第二次相同藥物治療,并評價療效與安全性。最后所有未治愈的受試者,采用吡喹酮標準療法進行治療。本研究發(fā)現(xiàn)頓服400mg的三苯雙脒組的治愈率和蟲卵減少率與吡喹酮組無顯著性差異,但不良反應(yīng)較吡喹酮組少,且吡喹酮組更易出現(xiàn)眩暈的不良反應(yīng)。 綜合以上各部分的研究結(jié)果,我們認為三苯雙脒對華支睪吸蟲具有良好的治療作用,但是還需開展大規(guī)模多中心的臨床試驗以進一步驗證其療效和評價安全性,為華支睪吸蟲病現(xiàn)場群體化療提供依據(jù)。
[Abstract]:According to the second national survey of the distribution of human parasitology, the number of Clonorchis sinensis infection in China has reached 12 million 490 thousand. Due to the lack of vaccines to prevent foodborne parasitition and the difficult change of people's diet, drug and chemotherapy is still the main means to control the disease. If praziquantel, according to the recommendation of the WHO, the suitable dose of praziquantel for the treatment of Clonorchis sinensis infection is 25mg/kg every time, 3 times /d, even to 2D., although it has a good effect, but it is difficult to apply to mass group therapy, because of this, continuing to seek new anticlonorchiasis drugs is still ten. In recent years, the animal test found that the single dose of three benzamine had a good killing effect on Clonorchis sinensis and the posterior testosterone of the cat cat, and its effect on the posterior testosterone of the cat was verified in clinical trials. First, the effect of three benzamid on Clonorchis sinensis was determined by laboratory study, and its resistance was preliminarily discussed. The mechanism of the insect and the metabolic kinetics in the bile, and then try to evaluate the efficacy and safety of the three benzamid in the infection of Clonorchis sinensis through the treatment of the mixed infection of intestinal nematodes and Clonorchis sinensis by three benzamines, and provide reference for the field group chemotherapy of Clonorchis sinensis.
In laboratory studies, we first evaluated the effect of different doses of three benzamid on Clonorchis sinensis in vitro and hamsters infected with cysts of Clonorchis sinensis in vitro, and evaluated its effect on Clonorchis sinensis in vitro and in vivo. The study clearly showed that three benzamiprid was strongly killed in vitro culture of Clonorchis sinensis. The minimum lethal dose was only half of the praziquantel, which had a good effect on the adults and adults of Clonorchis sinensis in the hamster, and 100mg/kg three benzamiprid could have a higher than 90% worm reduction rate in the treatment of Clonorchis sinensis adults. Even if the dose was low to 12.5mg/kg, the rate of insect reduction was 50%, and the titer intensity was significantly higher than that of praziquantel.
Secondly, by observing the ultrastructure of three benzamidin on the ultrastructure of Clonorchis sinensis, the mechanism of its insect resistance was preliminarily discussed. The rats were killed by 4h, 8h, 24h, 48h and 72h after the gastric perfusion of 300mg/kg, and then observed under transmission electron microscope after preprocessing. The results showed that three benzamidamidin could cause the clonorchis sinensis cortical mastoid process. Swelling, ulceration and dissolution, rod like particles in the skin, disc and membrane like vesicles decreased, mitochondria and endoplasmic reticulum decreased, mitochondria formed vacuoles, and cortical cell nuclear membrane damage.
In this paper, the pharmacokinetics of amamamid, a three benzamid metabolite, was studied in rats. First, the determination of amamamid concentration in rat plasma and bile was established, and then 200mg/kg three benzamiprid was used to collect blood samples at different time points and collect bile juice at different time points, and the untreated blank was collected at the same time. The blood samples and bile of rats were measured after treatment. The concentration of blood drug concentration time curve, the concentration time curve of bile drugs and the curve of bile excretion rate and cumulative excretion were drawn. The results showed that the peak time of amamamid in plasma was Tmax 0.90 + 0.22h, the peak concentration Cmax was 8.12 + 2.05mg/L. and the peak time of amamiamid in the bile was Tm The ax was 1.15 + 0.42h, the peak concentration Cmax was 11.16 + 2.07mg/L, the accumulated excretion of bile in 11h was 40.12 + 12 mu g, and the cumulative excretion rate was 0.38 per thousand. The rate of bile excretion in 0.5 ~ 3H after administration was the largest.
Finally, the efficacy and safety of three benzamid in the treatment of mixed infection of intestinal nematodes and Clonorchis sinensis, the rate of egg reduction and adverse reactions, and the efficacy and safety of the three benzamid in the anti Clonorchis Clonorchis were also evaluated. After the ethical review, the Kato-Katz method was used in the baseline survey in the experimental area. The people were divided into 3 groups randomly, including 3 groups. After signing informed consent and after medical examination, they were taken oral praziquantel (total dose of 75mg/kg), three benzendine (400mg, meal), and three benzenamiprid (200mg*2 times). The patients receiving three benzendine treated and treated with three benzamines were tested for hematuria routine, electrocardiogram and liver and kidney before and after treatment. Function (fasting blood). The researchers were followed up in 48h after treatment, asked for adverse reactions and recorded specific conditions. After treatment, 3W, collected patient feces, detected and counted feces of Clonorchis sinensis, hookworm, Ascaris, flagellate and tapeworm eggs, and calculated the cure rate of Clonorchis sinensis and the decrease of eggs by Kato-Katz. Rate. Then according to the results of the first trial, the uncured patients were treated with the same medication for second times of the same drug treatment, and the efficacy and safety were evaluated. Finally, all uncured subjects were treated with praziquantel standard therapy. This study found the cure rate and the rate of egg reduction in the three benzamid group of 400mg. There was no significant difference between the praziquantel group and the praziquantel group, but the adverse reaction was less than that in the praziquantel group, and the praziquantel group was more likely to have adverse reactions to vertigo.
We think that three benzamiprid has a good therapeutic effect on Clonorchis sinensis, but we need to carry out large-scale multicenter clinical trials to further verify its efficacy and evaluate safety, and provide a basis for the field group chemotherapy of Clonorchis sinensis.

【學(xué)位授予單位】：中國疾病預(yù)防控制中心
【學(xué)位級別】：博士
【學(xué)位授予年份】：2013
【分類號】：R532.23;R969

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