~(14)C—呋喃嘧酮的合成

呋喃嘧酮(Furapyrimidone,代号 M-170)化学名为:1-〔(5-硝基-呋喃-2-)甲叉胺基〕-四氢嘧啶-2-酮〔Tetrahydro-1-〔(5-nitro-furfurylidene)-amino〕-2(1H)-pyrimidone〕。是一个有希望的治疗丝虫病新药。药理试验表明,对棉鼠体内的棉鼠丝虫成虫和微丝蚴及长爪沙鼠体内的马来丝虫成虫、血液和腹腔内的微丝蚴均有明显的杀灭作用,其中对棉鼠丝虫成虫作用尤为显著。     

冷冻保存马来丝虫成虫

近年来,国内外学者对微丝蚴及感染期蚴的低温冷冻保存已有不少报道。经冷冻后的幼虫仍具有原有的生物学特性。成虫的低温冷冻保存,国内尚未见公开报道;国外,Townson等(1986)首次报道了牛盘尾丝虫(Onchocerca gutturosa)成虫雄虫在液氮中保存36天,仍具有活力。本实验用液氮冷冻保存马来丝虫成虫获得成功,冷冻后的虫体能在体外培养液中存活并继续产出微丝蚴。材料与方法一、虫源:周期型马来丝虫(Brugia malayi)雌性成虫,取自本实验室动物模型,长爪沙鼠腹腔,生理盐水洗涤后备用。     

伊维菌素降低马来丝虫感染东乡伊蚊和长爪沙鼠传播能力的效果观察

作者用伊维菌素(IVM)0.05ug/ml、0.1 ug/ml和海群生(DEC)150ug/ml浓度在体外与兔血混合马来丝虫微丝蚴实验感染东乡伊蚊。12天后全部蚊虫进行个体解剖:伊维菌素组蚊体内未发现马来丝虫三期幼虫,而海群生组东乡伊蚊感染率为30.5％、对照组为36.0％。单剂量的伊维菌素以400ug/kg体重,对照组用无菌生理盐水,经皮下或腹腔液内注入微丝蚴阳性的长爪沙鼠。治疗组和对照组分別于治疗后间隔1、7、30和75天喂饲东乡伊蚊。实验组于治疗后1—15天蚊体内未发现幼虫,对照组东乡伊蚊自然感染率为13.6％—14.6％。在治疗后75天蚊体内检获L_3数目,仍低于对照组。本研究提示伊维菌素能降低马来丝虫在蚊媒中的传播作用。其作用方式将进一步探讨。     

N~1-(4-取代氨基-6-三氟甲基-2-嘧啶基)-N~3-(卤苯基)胍的合成及其抗丝虫作用

报道了N~1-[4＇-[3-(二烷胺基)甲基和3, 5-双[(二烷胺基)甲基]-4-羟基苯胺基]-6-三氟甲基-2-嘧啶基]-N~3-(4-卤苯基)胍的合成。合成了24个化合物,经药理初筛表明,该类型化合物对感染沙鼠的棉鼠丝虫微丝蚴或成虫有一定的杀灭作用。     

周期型马来丝虫微丝蚴液氮内保存的初步观察

丝虫幼虫置液氮内冷冻保存国外已有报道,国内报道甚少。1985年我们参考国外有关文献,并改进一些方法,进行了周期型马来丝虫微丝蚴液氮内冷冻保存的试验,取得初步结果,现报告如下。材料和方法一.微丝蚴(mf)的收集及冷冻保护液用腹腔内灌洗法从马来丝虫感染的长爪沙鼠腹腔液中收集微丝蚴。实验前用灭菌的37℃Earle 氏液冲洗微丝蚴,并于1500rpm 离心10分钟,弃去上清液,反复三次。     

N~1-(4-取代氨基-6-甲基-2-嘧啶基)-N~3-(对氯苯基)胍类的合成及其抗丝虫作用

报道了 N~1-[4-[3-(二烷胺基)甲基-和3,5-双[(二烷胺基)甲基]-4-羟基苯基]氨基]-6-甲基-2-嘧啶基]-N~3-(4-氯苯基)胍的合成。所合成的10个化合物进行了药理初筛,其中8个对感染沙鼠的棉鼠丝虫微丝蚴或成虫显示一定的杀灭作用。     

棉鼠丝虫动物模型应用于药物筛选

为了寻找新的口服抗丝虫药物,1972年从国外引进棉鼠、棉鼠丝虫和柏氏禽剌螨后在我所建立了棉鼠丝虫动物模型,并开展了药物筛选工作。几年来筛选已知的和新合成的化合物共150个以及中草药7个。有14个化合物对棉鼠丝虫微丝蚴和/或成虫具有明显的杀死作用。其中硝硫氰胺、氨硝喹唑啉、呋喃西林、6-对氨基苯基-2,3,5,6-四氢咪唑并(2,1-6)噻唑-盐酸盐、2-(4-蜜胺2-基苯基)-4-羟甲基-1,3-二噻砷环戊烷和5个2-[2-(5-硝基呋喃-2)乙烯-1]-1,3,4-(口恶)二唑-5-酮的衍生物的作用较显著,尤其是对成虫。 本文也报道了用棉鼠丝虫动物模型进行药物筛选的有关实验方法以及棉鼠体内的微丝蚴和成虫的消长。     

棉鼠丝虫动物模型应用于药物筛选

为了寻找新的口服抗丝虫药物,1972年从国外引进棉鼠、棉鼠丝虫和柏氏禽剌螨后在我所建立了棉鼠丝虫动物模型,并开展了药物筛选工作。几年来筛选已知的和新合成的化合物共150个以及中草药7个。有14个化合物对棉鼠丝虫微丝蚴和/或成虫具有明显的杀死作用。其中硝硫氰胺、氨硝喹唑啉、呋喃西林、6-对氨基苯基-2,3,5,6-四氢咪唑并(2,1-6)噻唑-盐酸盐、2-(4-蜜胺2-基苯基)-4-羟甲基-1,3-二噻砷环戊烷和5个2-[2-(5-硝基呋喃-2)乙烯-1]-1,3,4-(口恶)二唑-5-酮的衍生物的作用较显著,尤其是对成虫。本文也报道了用棉鼠丝虫动物模型进行药物筛选的有关实验方法以及棉鼠体内的微丝蚴和成虫的消长。     

马来丝虫感染期蚴低温保存

丝虫感染期蚴(L_3)的低温保存,国内外已有一些报道。冷冻后的L_3仍能保持原有的生物学特性,在易感宿主体内能继续发育至成虫;亦能在体外继续培养,蜕皮发育至童虫(L_4)。鉴于L_3的来源和虫种的不同,所采用的冷冻方法也各异,目前尚无标准化的方法。本实验采用不同冷冻方法,对马来丝虫L_3进行低温保存研究,以探索长时间冷冻保存L_3的实验方法。材料与方法一、虫源周期型马来丝虫(Brugia malayi)感染期蚴,从本实验室马来丝虫长爪沙鼠动物模     

氯喹、呋喃嘧酮、痢特灵和海群生对体外培养的周期型马来丝虫成虫、感染期幼虫和微丝幼作用的观察

1987年4月,我们用抗疟药氯喹作了体外抗周期型马来丝虫成虫、感染期幼虫和微丝蚴的效果观察,并与呋喃嘧酮、痢特灵和海群生比较,结果报道如下。材料与方法一.虫源(一)周期型马来丝虫成虫和微丝蚴(Mf)的收集:分别用腹腔灌洗法和解剖法从感染马来丝虫沙鼠腹腔内收集 mf 和成虫于消毒离心管,盛 Mf 管加入10倍灭菌 RPMI—1640液(加青、链霉素各500u/ml),1500rpm 离心10分钟,弃去上清液,如此反复3     

Synthesis and anthelmintic activity of 5(6)-(benzimidazol-2-ylcarbamoyl) and (4-substituted piperazin-1-yl)benzimidazoles

The synthesis of alkyl 5(6)-(benzimidazol-2-ylcarbamoyl)benzimidazole-2-carbamates (6, 7), and alkyl 5(6)-(4-substituted piperazin-1-yl)benzimidazole-2-carbamates (31-40) has been carried out. When the compounds were tested for their anthelmintic activity against Ancylostoma ceylanicum in hamsters, Hymenolepis nana in rats, Litomosoides carinii in cotton rats, and Dipetalonema viteae in Mastomys natalensis, methyl 5(6)-(4-benzoylpiperazin-1-yl)benzimidazole-2-carbamate (31), methyl 5(6)-[4-(2-furoyl)piperazin-1-yl]benzimidazole-2-carbamate and methyl 5(6)-[4-[(diethylamino)carbonyl]piperazin-1-yl]benzimidazole- -2-carbamate (36) showed 100% elimination of tapeworms H. nana at three oral doses of 100-250 mg/kg. Compounds 34 and 36 also killed the microfilariae and adult worms of L. carinii in cotton rats at an intraperitoneal dose of 30 mg/kg given for 5 days.     

Studies in potential filaricides. 18. Synthesis of 2,2'-disubstituted 5,5'-dibenzimidazolyl ketones and related compounds as potential anthelmintics

A series of 2,2'-disubstituted 5,5'-dibenzimidazolyl ketones and related compounds have been synthesized of which 2,2'-bis(carbomethoxyamino)-5,5'-dibenzimidazolyl ketone exhibited a broad spectrum of anthelmintic activity in experimental animals. At doses of 10-50 mg/kg given intraperitoneally, 5 killed 100% of the adult worms of Litomosoides carinii, Dipetalonema viteae, and Brugia malayi. By the oral route the macrofilaricidal efficacy of 5 was 97-100% at 100-200 mg/kg X 5 days. The treated animals showed gradual disappearance of microfilariae and before autopsy they became amicrofilariaemic. Some of the compounds also showed 100% efficacy against the human hookworms and tapeworm, Ancylostoma ceylanicum in hamsters, and Hymenolepis nana in rats at a single oral dose of 50-250 mg/kg. Compound 5 was also effective against Syphacia obvelata in mice at a single oral dose of 100 mg/kg and was found to be well tolerated by mice up to an oral dose of 2500 mg/kg.     

In vitro effects of 2-tert-butyl-benzothiazole derivatives on microfilariae of Litomosoides carinii, Brugia malayi and Acanthocheilonema viteae.

Six 2-tert-butyl-benzothiazole derivatives (2-tert-butyl-6-iso-thiocyanato-5-methyl-benzothiazole CGP 21306); 3-[(2-tert-butyl-5-methyl-benzothiazole-6-yl) aminothiocarbonylthiol] propionic acid (CGP 21835); 2-tert-butyl-5-methyl-6-(N-methyl-piperazinyl-thiocarbonylamino)-b enzothiazole (CGP 21833); 2-tert-butyl-5-methyl-6-(4-dimethylamino-piperid-1-yl-thiocarbo nylamino)- benzothiazole (CGP 26702); CGP 20376, the 5-methoxy analogue to CGP 21835 and CGP 20309, the 5-methoxy analogue to CGP 21833) with known, high filaricidal activity in vivo were tested for in vitro efficacy against microfilariae of L. carinii (Lc), B. malayi (Bm) and A. viteae (Av) in order to study intrinsic antifilarial activities. All drugs affected the motility of the microfilariae of the three species in a species, dose and time dependent fashion. Lc was the most sensitive, Av the most resistant species. CGP 20376 and 21835 were the most effective compounds followed by CGP 21306. Complete immobilization of microfilariae was observed after 20 h in protein-free medium RPMI 1640 at drug concentrations of 0.1 to 10 nmol/ml. Effects were still marked 2 when graded on a 4 (full motility) to 0 (immobile) scale at concentrations of 0.01-0.1 nmol/ml. In the case of the thiourea derivatives CGP 21833, 26702 and 20309 concentrations had to be increased 10-100 fold to obtain similar effects. When proteins were present in the incubation medium (10% foetal calf serum, 100% normal serum) the efficacy of the compounds was reduced, i.e. drug concentrations had to be increased up to 100 fold to produce similar effects as in protein-free medium.(ABSTRACT TRUNCATED AT 250 WORDS)     

OLTIPRAZ对小鼠日本血吸虫病的初步治疗

Oltipraz is a new drug against Schistosomiasis mansoni and was used to treat mice Schistosorniasis japonica in our laboratory. The results showed that 48 h after oral administraction of oltipraz at a single dose of 900 mg/kg, 97% Schistosomes in mice infected with Schistosomiasis japonica schifted to the liver of the host. About half of these worms returned to the mesenteric veins in 96 h. Infected mice was given oltipraz orally at the dose of 900 mg/kg.d for 3～5 days, and killed in 28 days after the last dose. Over 95% total worm reduction rate was found.Schistosomes in infected mice treated with oltipraz were collected for histological observation. The results showed that the tegument of schistosomes were damaged and host cells invaded into the worm body; and granuloma formation of dead worm was observed.During the treatment, food uptake and body weight of the infected mice were decreased, but regained soon after the cessation of the treatment.     

Chemotherapeutic reactions of Chandlerella hawkingi, the filarial parasite of the Indian jungle crow, Corvus macrorhynchos (Wagler)

1. A high percentage of Indian jungle crows (Corvus macrorhynchos Wagler), found in and around Lucknow, harbour a natural filarial infection Chandlerella hawkingi. The microfilariae of this species are sheathed and show nocturnal periodicity.2. Fourteen compounds active against other kinds of filariae, especially against Litomosoides carinii, were tested against Ch. hawkingi in jungle crows to find whether this infection would be suitable for routine filarial chemotherapy. This is apparently the first report of systematic screening of antifilarial compounds against an avian filariasis.3. Tartar emetic (10 mg/kg intravenously, daily for 6 days) and arsenamide (5 mg/kg intraperitoneally, daily for 6 days) proved to be effective in killing adult worms. Trivalent tryparsamide, though effective, was toxic in the doses tried. Diethylcarbamazine and other compounds tested were ineffective.4. The chemotherapeutic susceptibilities of Ch. hawkingi differ considerably from those of L. carinii and Wuchereria bancrofti.     

Immunomodulator tuftsin augments antifilarial activity of diethylcarbamazine against experimental brugian filariasis

In the present study, we evaluated the potential of an immunomodulator tuftsin in increasing the efficacy of liposomised diethylcarbamazine (DEC) against experimental filarial infection of Brugia malayi. The liposomised form of DEC, when used at sub-optimal dose of 25 mg/kg body weight, successfully eliminated filarial parasite from systemic circulation in animals inflicted with B. malayi infection. However, the formulation was effective upto 60 days post infection only, followed by recurrence of the infection. In contrast, the co-administration of liposomal formulation of DEC along with an immunomodulator tuftsin was found to be competent enough to suppress microfilarial stage of parasite till 90 days post treatment. Interestingly, tuftsin bearing DEC liposomes were found to be effective against adult parasite as well.     

青蒿酯对动物血吸虫病的治疗实验

青蒿酯是还原青蒿素的琥珀酸单酯,代号为804(图1)。初筛证明,该化合物及其钠盐对小鼠体内血吸虫有明显的杀死作用,故用以对小鼠和家兔日本血吸虫病作进一步的动物实验     

Anticestodal Efficacy of Lasia spinosa. Extract Against Experimental Hymenolepis diminuta. Infections in Rats

Abstract

The use of Lasia spinosa. (L.) Thwaites (Araceae) leaves in the treatment of intestinal worm infections is a common ethnobotanical practice in the Naga tribes of India. In the current study, the anticestodal efficacy of L. spinosa. leaf extract was investigated against a tapeworm using Hymenolepis diminuta.–rat animal model. The anticestodal effects of L. spinosa. leaf extract was determined by monitoring the eggs per gram of feces (EPG) counts and percentage worm recovery rates after treatment with leaf extract in single and double doses of 200, 400, 800, and 1600 mg/kg that were given orally for 5 days to the rats harboring immature and mature worms. The effect of plant extract was found to be dose-dependent, and double doses showed better efficacy as compared with single doses. In the case of infections with immature worms, 1600 mg/kg double dose of L. spinosa. leaf extract reduced the fecal egg counts of H. dimunta. by 80.8% and worm recovery rate by 16.7%, respectively. Praziquantel, the standard anticestodal drug given in 5 mg/kg single dose, reduced the fecal egg count by 83.2% and worm recovery rate by 16.7%. In the case of efficacy against mature worms, 1600 mg/kg double dose of leaf extract reduced the fecal egg counts of H. diminuta. by 94.9% and worm recovery rate by 8.5%, respectively. Praziquantel (5 mg/kg, single dose) reduced the fecal egg counts by 95.1% and worm recovery rate by 16.7%. The study suggests that the leaf extract of L. spinosa. possesses significant anticestodal efficacy and supports its use in folk medicine.     

吡喹酮治疗动物华支睾吸虫病和肺吸虫病的实验观察

吡喹酮(Praziquantel)对人、畜体内大多数绦虫的成虫和幼虫均有驱杀作用,对治疗人体的三种血吸虫病亦有效。Davis又引述吡喹酮对动物华支睾吸虫病和肺吸虫病有效。     

Potent 1,3-disubstituted-9H-pyrido[3,4-b]indoles as new lead compounds in antifilarial chemotherapy

Substituted 9H-pyrido[3,4-b]indoles (beta-carbolines), identified in our laboratory as potential pharmacophores for designing macrofilaricidal agents, have been explored further for identifying the pharmacophore responsible for the high order of adulticidal activity. This has led to syntheses and macrofilaricidal evaluations of a number of 1-aryl-9H-pyrido[3,4-b]indole-3-carboxylate derivatives (3-7). The macrofilaricidal activity was initially evaluated in vivo against Acanthoeilonema viteae. Among all the synthesized compounds, only 12 compounds, namely 3a, 3c, 3d, 3f, 4c, 4d, 4f, 5a, 6f, 6h, 6i, and 7h, have exhibited either >90% micro- or macrofilaricidal activity or sterlization of female worms. These compounds have also been screened against Litomosoides carinii, and of these only 3f and 5a have also been found to be active. Finally these two compounds have been evaluated against Brugia malayi. The structure-activity relationship (SAR) associated with position 1 and 3 substituents in beta-carbolines has been discussed. It has been observed that the presence of a carbomethoxy at position 3 and an aryl substituent at position 1 in beta-carbolines effectively enhances antifilarial activity particularly against A. viteae. Among the various compounds screened, methyl 1-(4-methylphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate (4c) has shown the highest adulticidal activity and methyl 1-(4-chlorophenyl)-1,2,3,4-tetrahydro-9H-pyrido[3, 4-b]indole-3-carboxylate (3a) has shown the highest microfilaricidal action against A. viteae at 50 mg/kg x 5 days (ip). Another derivative of this compound, namely 1-(4-chlorophenyl)-3-(hydroxymethyl)-9H-pyrido[3,4-b]indole (5a), exhibited the highest activity against L. carinii at 30 mg/kg x 5 days (ip) and against B. malayiat 50 mg/kg x 5 days (ip) or at 200 mg/kg x 5 days (po).