吡喹酮制剂的发展和应用

吡喹酮是临床有效治疗血吸虫病的首选药物, 然而其生物利用度低、 剂型单一、 对童虫作用不明显等缺点, 限制了其发挥最大效用。本文针对吡喹酮性质及药代动力学特点, 并结合现有吡喹酮新型制剂的研究进展做一综述, 为充分发挥吡喹酮的抗血吸虫作用以及吡喹酮新制剂的研究开发提供参考及借鉴。     

国内外吡喹酮研究进展

20世纪70年代中期,吡喹酮的问世开启了血吸虫病化疗的新篇章[1,2].吡喹酮不仅对感染人体的5种血吸虫,即日本血吸虫、埃及血吸虫、曼氏血吸虫、间插血吸虫和湄公血吸虫均有效,而且疗程短(1～2d)、疗效高、不良反应少[ 3].尽管吡喹酮用于治疗血吸虫病长达30余年,但其确切杀虫机制迄今尚未阐明14,5].随着吡喹酮在世界许多国家血吸虫病流行区的长期大量反复使用,虫体是否会在药物选择压力下下产生抗药性引发了广泛关注[6-10].本文从吡喹酮的理化性质、测定方法、抗寄生虫作用、抗血吸虫作用机制、抗药性以及不良反应等方面对2010年吡喹酮的研究进展作一综述.     

血吸虫病化学治疗进展(综述)

近年,随着安全有效的抗血吸虫药物的出现,越来越多的人认识到,化学治疗是防治血吸虫病最简单有效的方法之一。现将近年来的主要进展综述如下: 1 吡喹酮吡喹酮是目前公认的治疗血吸虫病的首选药物。近年研究进展主要有: 1.1 左旋吡喹酮吡喹酮是一种外消旋化合物,由左旋和右旋光学异构体各半组成。国外虽有部分学者报告其抗日本血吸虫作用集中在左旋异构体,但至今未见临床报告。而国内学者则作了大量研究。刘约翰等报告将合成吡喹酮的中间体拆分,得到左旋与右旋二种光学异构体,小白鼠急性测毒,左旋吡喹     

近年来发展抗血吸虫新药的进展

全球有2亿人感染血吸虫,其治疗仅依赖吡喹酮一种药物是很不相适应的。吡喹酮虽有很好的治疗效果,但无预防作用,故发展抗血吸虫新药倍受关注。本文综述近年来报道的恶二唑-2-氧化物和甲氟喹等抗血吸虫新药的实验研究,阐述这些药物的发展过程,及其抗血吸虫特点。     

蛋白激酶C及其亚型对钙通道的调节功能

吡喹酮是目前治疗血吸虫的惟一特效药,但其作用靶点及机制仍未完全阐明,研究表明吡喹酮的作用靶点町能为钙通道.钙通道可受多种因素的调控,该文综述了蛋白激酶C及其亚型对钙通道的调控作用,为阐明吡喹酮的药物作用机制以及进一步研发抗血吸虫新药提供了思路.     

云南省洱源县抗血吸虫药物应用历史分析

分析抗血吸虫药物在云南省洱源县的应用历史;洱源县抗血吸虫药物的应用和全国的药物研发进展一样,经历了中医中药中草药治疗,锑剂,呋南丙胺,血防-846锑-273片,硝硫氰胺,吡喹酮等几个阶段。仍在使用的吡喹酮是高效低毒安全有效的抗血吸虫药物。     

血吸虫电压门控性钙通道(VGCCs)亚单位与吡喹酮药物靶点的关系

吡喹酮作为当前治疗血吸虫病的首选药物,临床应用已达30余年,但其作用机制至今尚未完全阐明.电压门控性钙通道(voltage-gated calcium channels,VGCCs)为Ca2+的内流提供通道,同时也是多种药物与毒素的作用靶点.该文围绕"血吸虫钙通道亚单位-吡喹酮药物靶点"假说,讨论血吸虫VGCCs亚单位的结构与功能,尤其是变异的β亚单位(Cavβvar),及β亚单位作为吡喹酮抗血吸虫药物靶点的研究进展.     

血吸虫对吡喹酮的抗药性研究进展

吡喹酮是高效、低毒的口服抗血吸虫首选药物,自1970年代研制出至今,已被大规模反复用于现场30余年。血吸虫是否会在药物选择压力下对吡喹酮产生抗药性已引起了高度关注。该文对血吸虫抗药性的定义、吡喹酮抗药性的实验和现场研究近况、抗药性产生机制、血吸虫对吡喹酮敏感性的检测、抗药性产生的相关因素及控制措施等作一综述。     

血吸虫病联合用药的研究进展

目前治疗血吸虫病仍然依赖于吡喹酮单一疗法,尽管吡喹酮可有效杀灭血吸虫成虫,但对幼虫作用弱,且单独使用吡喹酮不能逆转与感染相关的不良病理损害。由于吡喹酮耐药株的出现,亟需寻求可替代的抗血吸虫病药物。当前抗血吸虫病新药研发进展缓慢,但临床前研究和临床试验发现吡喹酮与多种抗疟药物联合应用显示出良好的杀虫效果,与其他辅助药物的联合应用也发挥了协同治疗作用。本文就此方面研究进行综述。     

吡喹酮抗血吸虫作用机制研究进展

血吸虫病是一种人畜共患寄生虫病。目前,化学治疗控制血吸虫病仍然是主要手段之一。现阶段的治疗血吸虫病药物中,吡喹酮以其疗效高、疗程短、不良反应少等优点,成为治疗血吸虫病等寄生虫病的首选药物。随着吡喹酮在流行区的大量长期使用,血吸虫抗药性问题越来越引起人们的重视,但是虽然吡喹酮治疗血吸虫病已30余年,但其作用机制仍未充分阐明,这极大地阻碍了抗血吸虫新药的发展。     

甲氟喹抗血吸虫及其他蠕虫作用的研究进展

近年来抗疟药甲氟喹,一种氨基乙醇化合物,被发现具有很强的抗血吸虫作用,其特点是对不同发育期的血吸虫童虫和成虫的杀灭作用相仿。本文对近3年有关甲氟喹抗血吸虫和其他蠕虫的实验研究进展进行综述。     

吡喹酮抗血吸虫作用机理的奥秘

本文简要综述吡喹酮抗血吸虫作用的机理,指出吡喹酮对血吸虫发育不同阶段有不同的作用,且呈现间隔变化的模式,并对这一奇特现象提出开展研究的建议。     

蒿甲醚对血吸虫超微结构的影响

蒿甲醚是青蒿素的一个衍生物,不仅是有效的抗疟药,而且对血吸虫特别是血吸虫童虫亦有效,并已在20世纪末被发展为预防血吸虫病的药物.为了了解蒿甲醚的抗血吸虫作用,除观察其对血吸虫生化代谢的影响外,还用扫描电镜和透射电镜观察了蒿甲醚对感染人体的主要3种血吸虫,即日本血吸虫、曼氏血吸虫和埃及血吸虫超微结构的影响,结果表明蒿甲醚不仅损害血吸虫的皮层、感觉器和皮层结节,而且对虫的肌层、实质组织、肠上皮细胞和卵黄细胞等亦引起广泛的损害.该文综述了蒿甲醚对这3种血吸虫超微结构损害的观察结果,并进行了讨论.     

钙通道β亚单位相关作用蛋白ahnak的研究进展

吡喹酮作为当前治疗血吸虫病的首选药物,对所有种类的血吸虫均有疗效且副作用甚微,临床应用已达30余年,但其作用机制至今尚未完全阐明.研究表明吡喹酮抗血吸虫作用与Ca~(2+)内稳态的破坏有直接关系.电压门控性钙通道(voltage-gated calcium channels,VGCC)为Ca~(2+)的内流提供通道,并已有研究者提出了"血吸虫钙通道-吡喹酮作用靶点"假说.研究显示ahnak蛋白与钙通道β亚单位结合能增加Ca~(2+)内流,该文围绕ahnak蛋白的基本结构、功能以及ahnak/β亚单位之间的相互作用及功能等方面的研究进展作一综述,为探讨吡喹酮抗血吸虫的机制提供一定的参考价值.     

Genetic analysis of hycanthone resistance in Schistosoma mansoni

Interbreeding between hycanthone-resistant and hycanthone-sensitive schistosomes was achieved using a worm transfer technique which considerably reduced the length and the complexity of the operations generally involved in performing schistosome genetic crosses. A mouse was considered to harbor resistant schistosomes if, three weeks or more after a single intrasmuscular injection of 80 mg/kg hycanthone schistosome eggs were still excreted in the feces, at least one normal worm pair was obtained by perfusion, or miracidia could be seen hatching from the liver. The F1 hybrid progeny from crosses between sensitive and resistant schistosomes proved to be sensitive to hycanthone, irrespective of whether the resistant parent was the male or the female. The resistant phenotype reappeared in back-crosses and in the F2 progeny. These results could be confirmed using the traditional technique of single sex infections. It can thus be concluded that hycanthone resistance behaves like an autosomal recessive trait. These results suggest that hycanthone-resistant schistosomes are deficient in some factor, possibly an enzymatic activity which transforms hycanthone into a biologically active molecule, as suggested in a recent hypothesis on the mode of action of hycanthone.     

Yeast genome-wide drug-induced haploinsufficiency screen to determine drug mode of action

Methods to systematically test drugs against all possible proteins in a cell are needed to identify the targets underlying their therapeutic action and unwanted effects. Here, we show that a genome-wide drug-induced haploinsufficiency screen by using yeast can reveal drug mode of action in yeast and can be used to predict drug mode of action in human cells. We demonstrate that dihydromotuporamine C, a compound in preclinical development that inhibits angiogenesis and metastasis by an unknown mechanism, targets sphingolipid metabolism. The systematic, unbiased and genome-wide nature of this technique makes it attractive as a general approach to identify cellular pathways affected by drugs.     

Genetic analysis of decreased praziquantel sensitivity in a laboratory strain of Schistosoma mansoni

A laboratory strain of Schistosoma mansoni subjected to repeated in vivo praziquantel (PZQ) treatments for several generations has been previously found to have lesser sensitivity to the drug than the original unselected strain. In this study we have collected evidence on the mode of inheritance of the partial insensitivity exhibited by the PZQ-selected schistosomes. A single male and a single female worm of the two strains, assorted in the four possible combinations, were introduced into the mesenteric veins of mice and the eggs produced by each pair were used as the source of the F₁ progeny. PZQ sensitivity was assessed using both in vivo and in vitro methods. In the first approach, the PZQ ED₅₀ was determined by infecting mice with cercariae of the strains to be tested, treating at seven weeks with different drug doses and counting the number of surviving worms three weeks later. For the in vitro approach, adult schistosomes kept in culture were exposed overnight to different PZQ concentrations and their survival was monitored during the subsequent 7 days. Results from both approaches lead to the conclusion that hybrid schistosomes of the F₁ generation have a drug sensitivity intermediate between those of the two parental strains and are thus suggestive of a pattern of partial dominance for the trait under study.     

Efficacy of alternating therapy with oxamniquine and praziquantel to treat Schistosoma mansoni in children following failure of first treatment

Two hundred children infected with Schistosoma mansoni were treated with either 20 mg/kg oxamniquine or 60 mg/kg praziquantel. Cure rates (about 85%) were similar as was the percentage reduction (80%) in egg counts in uncured children. Treatment with the alternative drug of children not cured with the first treatment resulted in negative stools in 11 of 12 cases examined one month after the second round of therapy. In order to minimize the risk of the development of drug resistance, our data suggest that infected patients be treated with one drug, and therapeutic failures with another. Evidence from experiments in mice with isolates obtained after failures of one treatment in children suggests that therapeutic failure does not necessarily indicate the presence of drug-resistant schistosomes. The value of using mice to assess drug resistance in schistosomes is questioned.     

Artemether, an effective new agent for chemoprophylaxis against shistosomiasis in China: its in vivo effect on the biochemical metabolism of the Asian schistosome.

Conventional drug chemotherapy against human schistosomiasis currently relies on treatment with praziquantel to eliminate adult schistosome worm pairs. The use of praziquantel for control purposes is limited, however, by high rates of post-treatment re-infection with subsequent parasite egg deposition and host end-organ damage. Artemether, a methyl ether derivative of the anti-malarial drug quinghaosu, was discovered recently to also have anti-schistosomal properties. Because artemether selectively targets the larval migratory stages of the parasite, known as schistosomulae, it blocks the development of ovipositing adult schistosome worm pairs in the vasculature. On this basis, we have since shown in clinical trials conducted in China that artemether has proven benefit as an agent for chemoprophylaxis. In vivo studies using laboratory animals suggest that artemether causes damage to the tegument and musculature of schistosomulae. Artemether may exert its helminthotoxic effect through synergy with hemin or related heme-containing compounds. Schistosomes recovered from artemether treated laboratory animals have increased glycogen phosphorylase activity, but decreased glucose uptake. These findings may account for their decreased glycogen content, relative to schistosomes recovered from untreated laboratory animals. The artemether-damaged schistosomes also have decreased activities of a number of enzymes and enzyme systems, including glycolysis. This might suggest common pathways by which artemether may target human parasites that live in the bloodstream.