我国血吸虫对吡喹酮抗药性研究之概要

血吸虫病是一种严重危害人类健康、影响社会经济发展的重大传染病,为全球公共卫生负担和危害最严重的被忽视的热带病之一。吡喹酮是20世纪70年代研制出的一种高效、低毒、价廉的广谱抗蠕虫口服药,为世界卫生组织（WHO）推荐的抗血吸虫的首选药物。吡喹酮在血吸虫病流行区现场大规模反复使用已超过40年,血吸虫是否会对吡喹酮产生抗药性引起国际社会极大担忧,为学术界关注的热点科学问题。针对血吸虫病防治中这一重大需求,自1996年起, 在国家科技支撑计划、国家自然科学基金、江苏省自然科学基金等项目基金资助下,我们在血吸虫病流行区现场和实验室,对血吸虫在吡喹酮药物的压力是否会产生抗药性、抗性虫株的生物学特性、抗性的检测、吡喹酮抗性的交叉抗药性及抗药性的预防和控制等科学问题进行较为系统的研究,本文就其研究及其意义作一概述。     

1—氰基—2—苯甲酰—1,2—二氢异喹啉的合成

采用1,1,2-三氯乙烷作溶剂,三乙胺作相转移催化剂合成了吡喹酮的重要中间体1-氰基-2-苯甲酰-1,2-二氢异喹啉。本法单耗低,产物质量好。Reissert 反应收率由文献报道的82%提高至90%。     

吡喹酮治疗56例华枝睾吸虫病患者的纵向观察

目的 探讨采用低剂量吡喹酮（７５ｍｇ／ｋｇ×１ｄ）反复治疗华枝睾吸虫重流行区人群的效果。方法 采用Ｋａｌｏ－Ｋａｔｚ法对人群进行普查。结果 人群肠道寄生虫感染率为７３．１％,其中华枝睾吸虫感染率为３７．３％。通过两年四查三治,５６例被观察者的虫卵阴转率为７６．８％,虫卵减少率达９１．６％。结论 在华枝睾吸虫轻、中度流行区,采用该剂量组治疗人群,安全易行,效果满意。     

吡喹酮杂质的研究

用LC-MS和HPLC法以对照品对照,确定吡喹酮合成过程中产生的主要杂质是(1,11b)-位不饱和的吡喹酮,利用催化氢化法可把含该杂质过量的吡喹酮粗品转化为合格品.     

Comparison of the in vitro Effects of One-day Exposure to Amodiaquine and Praziquantel on Schistosoma mansoni Adult Worm Pairs

It has been demonstrated that continuous exposure to amodiaquine (AQ) alone elicits in vitro antischistosomal activities at concentrations of 1–10 μg/ml. However, orally administered drugs reach a peak blood concentration within one or two hours and then gradually decrease. The blood concentration does not remain at a constant level over several days as in vitro concentration of continuous drug exposure. In vitro activities by one day exposure to AQ better reflect the actual antischistosomal activities after oral administration than those elicited by continuous exposure.The objective of the present study is to compare the antischistosomal potential of one-day exposure to AQ with that to praziquantel (PZQ), a current antischistosomal drug. Schistosoma mansoni adult worm pairs were incubated with 0 (control), 1, 2, 5 and 10 μg/ml AQ as well as 0.01, 0.02, 0.05 and 0.1 μg/ml PZQ for the first day, and were subsequently incubated in drug-free media for a period of 14 days. The one-day exposure to AQ significantly reduced the daily egg output of the worm pairs at 1–10 μg/ml. The inhibitory effect on egg production continued at 5 and 10 μg/ml but proved temporary at 1 and 2 μg/ml. Furthermore, AQ-induced specific morphological alterations (severe swelling and/or localization of hemozoin) were observed in the worms at 5 and 10 μg/ml. The AQ-specific appearance of the male worms gradually faded during subsequent incubation in drug-free media, although the female worms showed elongation. Meanwhile, PZQ inhibited the egg output of adult worm pairs at concentrations of 0.01–0.1 μg/ml during exposure. The inhibitory effect on egg production continued at 0.05 and 0.1 μg/ml but proved temporary at 0.01 and 0.02 μg/ml. Furthermore, PZQ induced a visible contraction and shortening of the male and female worms at 0.05 and 0.1 μg/ml during exposure, but the PZQ-specific alterations quickly disappeared during subsequent incubation in drug-free media. To our knowledge, this is the first report showing that one-day exposure to AQ inhibits the egg production of adult worm pairs at 1–10 μg/ml and induces specific morphological alterations in the worms at 5 and 10 μg/ml. The present findings have important implications for the evaluation of the therapeutic effects of both AQ monotherapy and combination therapy with artesunate on schistosomiasis in clinical field trials.     

9例脑裂头蚴病的临床与影像学特点分析

目的:分析脑裂头蚴病的临床表现、影像特点。方法:回顾性分析9例脑裂头蚴患者的临床资料及动态影像学改变,并结合既往文献进行回顾性分析。结果:9例患者中男性5例,女性4例;临床表现主要包括癫痫发作8例,轻瘫3例,头痛2例,记忆下降2例、头晕1例。9例均行MRI检查,病灶多位于额颞叶,呈环状或线样强化。7例患者的血清学及脑脊液裂头蚴抗体均为阳性,2例患者仅血清学抗体阳性。8例患者行吡喹酮驱虫治疗,1例因伴随艾滋病,未行驱虫治疗。4例因误诊或确诊行手术治疗。5例治疗后复发。结论:脑裂头蚴病临床症状主要为癫痫、轻瘫、头痛。头颅MRI增强呈环状或线样强化,脑裂头蚴治疗可行长程大剂量规律口服吡喹酮药物治疗及手术治疗,治疗效果可,但复发率高。     

吡喹酮与甲苯达唑药盐治疗福建棘隙吸虫病的疗效比较

目的：探讨用吡喹酮与甲苯达唑药盐治疗福建棘隙吸虫病的效果。方法：对１０９例粪检福建棘隙吸虫卵阳性者随机分为４组，分别用吡喹酮（Ａ）５ｍｇ／ｋｇ；（Ｂ）２．５ｍｇ／ｋｇ顿服与甲苯达唑（Ｃ）总剂量８００ｍｇ，８０ｍｇ／ｄ，连服１０ｄ；（Ｄ）总剂量４００ｍｇ，４０ｍｇ／ｄ，连服１０ｄ（药盐）治疗，于治后１ｗｋ和４ｗｋ复查，以虫卵阴转率和减少率为评价疗效。结果：４ｗｋ后上述４组阴转率依次为１００％、９２．３％、８５．２％和７１．４％；虫卵减少率为８４．８％—１００％，Ａ、Ｂ组疗效显著优于Ｄ组。结论：吡喹酮（２．５—５ｍｇ／ｋｇ）疗效高，疗程短，服药简便，为治疗本病的首选药物；甲苯达唑疗效尚可，在伴有肠道线虫感染时可用５００ｍｇ治疗。     

Integrated community-directed treatment for the control of onchocerciasis, schistosomiasis and intestinal helminths infections in Uganda: advantages and disadvantages

Onchocerciasis is co-endemic with schistosomiasis and intestinal helminths infections, which are all diseases of the rural and the poorest communities in Africa. Community-directed treatment (ComDT) for the control of onchocerciasis is the only functional health approach in most of these communities and the strategy has proven to be effective for onchocerciasis control. This study was conducted to assess the feasibility of integrating ComDT with ivermectin for the control of onchocerciasis, and with praziquantel (PZQ) and mebendazole (MBD) for the control of schistosomiasis and intestinal helminths infections in children aged 5-14 years, and to assess advantages and disadvantages of the integrated ComDT over the routine ComDT and the school-based treatment approach. Integrated ComDT achieved higher treatment coverage (85%) for PZQ and MBD than the school-based treatment approach (79%) among children aged 5-14 years (P = 0.03). There were more reported adverse reactions after treatment with a combination of PZQ and MBD in the school-based treatment approach (33%) than for the combination of ivermectin and MBD on day 1 and PZQ on day 2 in the integrated ComDT (18%). However, all adverse reactions were mild (headache, nausea/vomiting and abdominal pain). The integrated ComDT also achieved higher ivermectin treatment coverage for all ages (81.3%) than routine ComDT (77.2%) (P = 0.0003). To achieve even better coverage for PZQ and MBD among the targeted high risk groups, integrated ComDT should treat all age groups in areas where the prevalence of schistosomiasis and intestinal helminths infections is >50%. This would minimize the shortage of the drugs targeted to treat the high risk groups, as the non-targeted groups, will inevitably demand and receive the treatment from the distributors. The results of this study show that PZQ and MBD treatment for the control of schistosomiasis and intestinal helminths, respectively, can be integrated with ivermectin treatment for the control of onchocerciasis without negatively affecting ivermectin treatment coverage.     

血吸虫病小鼠肝纤维化肝组织中Fas/FasL的表达

目的 探讨Fas／FasL在血吸虫病肝纤维化肝组织中的表达及意义。 方法 采用免疫组化技术检测血吸虫病小鼠肝纤维化肝组织中Fas／FasL的表达,并对照经吡喹酮、已酮可可碱治疗前后其表达的变化,分析其意义。 结果Fas以肝细胞浆表达为主,FasL主要在浸润淋巴细胞浆、肝细胞核表达。经吡喹酮及高剂量已酮可可碱治疗后其肝组织Fas／FasL表达明显减少(P<0.01)。 结论 血吸虫感染可诱导肝细胞Fas／FasL的表达,增强Fas／FasL途径介导的肝细胞凋亡,这一机制在血吸虫病肝纤维化的发病中可能起重要作用。吡喹酮及高剂量已酮可可碱可明显下调Fas／FasL的表达,抑制肝细胞凋亡,改善肝功能。     

肝泡状棘球蚴病52例临床治疗经验

本文报道由于多房棘球绦虫所致的肝泡状棘球蚴病52例:男35例,女17例,年龄14～52岁,多来自牧区。主要体征为上腹部包块,有黄疸者12例,免疫试验均显阳性,辅助检查如B超、同位素扫描、PTC等提示肝内占位性病变,X片显示特殊钙化点。病例均经手术及病理证实。根治手术5例,术后预后好,8～21年随访无复发。姑息性手术7例亦获改善症状等疗效。13例经长达1～16个月的甲苯咪唑化疗无明显副作用,病情改善,包块缩小,药物剂量较大,疗程较长,治疗效果较好。本文就诊断和治疗方面作简要讨论。