Antifilarial activity of Caesalpinia bonducella against experimental filarial infections.

BACKGROUND & OBJECTIVE: Lymphatic filariasis is a disabling disease that continues to cripple population in tropical countries. Currently available antifilarial drugs are not able to control the disease. Therefore, a better antifilarial is urgently required for proper management of the disease. We undertook this study to assess the antifilarial activity of Caesalpinia bonducella-seed kernel against rodent filarial parasite in experimental model. METHODS: Microfilaraemic cotton rats and Mastomys coucha harbouring Litomosoides sigmodontis and Brugia malayi respectively, were treated with crude extract or fractions of the seed kernel C. bonducella through oral route for 5 consecutive days. Microfilaricidal, macrofilaricidal and female worm sterilizing efficacy was assessed. RESULTS: Crude extract showed gradual fall in microfilariae (mf) count in L. sigmodontis-cotton rat model from day 8 post-treatment attaining more than 95 per cent fall by the end of observation period. It also exhibited 96 per cent macrofilaricidal and 100 per cent female sterilizing efficacy. The butanol fraction F018 caused 73.7 per cent reduction in mf count and 82.5 per cent mortality in adult worms with 100 per cent female sterilization. The aqueous fraction F019 exerted more than 90 per cent microfilaricidal activity and 100 per cent worm sterilization. Two chromatographic fractions, F024 and F025 of hexane soluble fraction exhibited 64 and 95 per cent macrofilaricidal activity, respectively. Both the fractions caused gradual fall in microfilaraemia and 100 per cent worm sterilization. In B. malayi-M. coucha model F025 showed gradual reduction in microfilaraemia and caused 80 per cent sterilization of female parasites INTERPRETATION & CONCLUSION: In conclusion, C. bonducella- seed kernel extract and fractions showed microfilaricidal, macrofilaricidal and female-sterilizing efficacy against L. sigmodontis and microfilaricidal and female-sterilizing efficacy against B. malayi in animal models, indicating the potential of this plant in providing a lead for new antifilarial drug development.

Effects of 2-deoxy-D-glucose on Acanthocheilonema viteae: rodent filariids as studied by multinuclear NMR spectroscopyt.

A well known glucose antimetabolite, 2-deoxy glucose (2DG) widely used in chemotherapy of cancer along with radiation, was evaluated as an antifilarial agent by nuclear magnetic resonance. The uptake and metabolism of 2DG in the experimental filarial infection Acanthocheilonema viteae was studied by in vivo multinuclear NMR. An unusually long retention time of 2DG6P within these parasites was observed on continuous 31P NMR monitoring, along with a decrease in ATP levels. These results led to therapeutic investigation in A. viteae infected host Mastomys coucha. 2DG showed a remarkable adulticidal activity (73.6%) with 50% sterilization of surviving female worms at a dose of 250 mg/kg x 5, p.o. NMR observations and activity profile substantiate the findings of one another, directed towards the hitting of bioenergetic machinery of A. viteae by macrofilaricidal agent (2DG).

Syntheses and antifilarial profile of 7-chloro-4-(substituted amino) quinolines: a new class of antifilarial agents.

The syntheses of 7-chloro-4-(substituted amino) quinolines (2-22) and their antifilarial activities are delineated. Some of the screened compounds have shown promising filarial response and sterilization effect on female Acanthocheilonema viteae in rodents.

Antifilarial activity of a synthetic marine alkaloid, aplysinopsin (CDRI Compound 92/138).

CDRI Compound 92/138, a synthetic analogue of aplysinopsin, was evaluated in experimental filarial infections, Litomosoides carinii in cotton rats (Sigmodon hispidus) and Acanthocheilonema viteae in Mastomys coucha. The compound killed 63.8 and 90% of adult L. carinii and A. viteae at doses of 30 and 50 mg/kg (i.p.) respectively given for 5 days. By the oral route, at 100 mg/kg for 5 days the compound caused 50.9 and 57% mortality of adult L. carinii and A. viteae, respectively. At 200 mg/kg administered orally on days 0, 10 and 25 post-infection, it reduced establishment of adult A. viteae by 68.5%. We also found 43.7 and 37.8% effect in vivo respectively on L3 and L4 stages of A. viteae at a single dose of 250 mg/kg, p.o. The compound was active in vitro at 100 micrograms/ml concentration and caused a significant decline in MTT reduction and 14C-glucose uptake by adult filariids. Thus synthetic marine aplysinopsin could provide a new pharmacophore for the development of antifilarial agents.

1H magnetic resonance imaging and 31P magnetic resonance spectroscopy in experimental filariasis.

1H Magnetic resonance imaging and 31P magnetic resonance spectroscopy (MRS) have been carried out in experimental rodent filariasis, i.e., Acanthocheilonema viteae infection in the rodent host, Mastomys coucha. The T2-weighted image of the infected host shows fine hyperintense thread like structures of adult filariid nests in the cervical region. 31P MRS of normal and infected hosts, localized over the same region of interest, show seven major peaks corresponding to phosphomonoesters (including glucose-6-phosphate, fructose-6-phosphate, fructose-1-6-diphosphate, phosphorylcholine, and adenine monophosphate or AMP), inorganic phosphate, glycerophosphorylcholine, phosphoenolpyruvate, phosphocreatine and nucleoside di- and tri-phosphates. Concentrations of phosphomonoesters (PMEs) are higher in the normal rodent compared with the infected ones. In vivo 31P MRS provides a non-invasive assessment of tissue bioenergetics and phospholipid metabolism.

Chemotherapy of experimental filariasis: enhancement of activity profile of ivermectin with immunomodulators.

The effect of certain immunopotentiators (Freund's complete adjuvant, picroliv, tuftsin and CDRI Compound 86/448) was evaluated on exertion of antifilarial activity of ivermectin at different dose levels in cotton rats experimentally infected with Litomosoides carinii. Ivermectin alone (up to 250 micrograms/kg p.o. x 5 days) caused sterilization of most of the surviving female parasites, but had no lethal effect on adult worms. In combination with immunomodulators, ivermectin brought about significant lethal effect on adult parasites even at a dose of 1 microgram/kg x 5 days. Nevertheless, in animals receiving FCA alone, sterility was caused in > 50% of female parasites. Other immunomodulators used alone had a suppressive effect on microfilaraemia only. Immunomodulators alone or in combination with ivermectin also caused enhanced filaria-specific antibody response.

Activity of alpha-anilinobenzyl cyanides and 2-methoxycarbonylamino-1-phenylimidazoles, a new class of antifilarial agents.

The activity of alpha-anilinobenzyl cyanides (2a-f), 5-aryl-4,5-dihydro-2-methoxycarbonylamino-1-phenylimidazoles (5a-d) and 2-methoxycarbonylamino-1-phenyl-1,3-diazaspiro[4:5]dec-2-ene (5f) have been tested for their micro- and macrofilaricidal activity against Litomosoides carinii and Acanthocheilonema viteae in rodents. In this test alpha-anilinobenzyl cyanides (2a-b), 5-(4-methoxyphenyl)-4,5-dihydro-2-methoxy-carbonylamino-1-phenylim idazole (5b) and 2-methoxycarbonylamino-1-phenyl-1,3-diazaspiro[4:5]dec-2-ene (5f) were found to possess marked filaricidal activity at doses ranging from 3-100 mg/kg given parenterally or orally for 5 days.

Evaluation of vanillic acid analogues as a new class of antifilarial agents.

A number of vanillic acid analogues (1-14) have been synthesised and evaluated against experimental filarial infections using cotton rats (Sigmodon hispidus) infected with Litomosoides carinii, a primary screening model, at a dose of 30 mg/kg, ip for 5 days. Of the 8 compounds tested, 4 (5,7, 11 and 12) exhibited high micro- and macro-filaricidal activity with sterilization of surviving female worms. Compounds 5, 7, 12 showed remarkable adulticidal action (> 80%). Sterilization of the female worms by compounds 11 and 12 was highly significant (80-100%).

A new technique of in vitro assay of antifilarials using different life-forms of Acanthocheilonema viteae.

An approach has been made to develop an in vitro screening system to evaluate antifilarial efficacy of compounds and an effort has been made to establish correlation between in vivo and in vitro screening technique. The in vitro experiments were conducted simultaneously using three life-forms (adult, microfilaria and infective larva) of Acanthocheilonema viteae using five antifilarial agents representing four chemical groups. All the selected antifilarials were known to be active against one or more life-stages of human lymphatic or animal filariids. Diethylcarbamazine and Centperazine showed 100% microfilaricidal and infective larvicidal actions at concentrations of 0.5 and 0.25 mg/ml and 0.5 and 0.0313 mg/ml respectively with no effect on adult worms even at 1 mg/ml. Levamisole was effective against all the three life-stages killing 100% adult worms at 1 mg/ml, infective larvae at 0.0625 mg/ml and microfilariae at 0.0125 mg/ml, while mebendazole exhibited activity only against adult worms (100% at 0.5 mg/ml). Ivermectin killed adult females and microfilariae at 0.063 and 0.5 mg/ml respectively but did not affect infective larvae even up to 1 mg/ml concentration. The study indicated that in vitro screening system can be used for primary screening of potential antifilarial agents provided three life-forms of A. viteae are used simultaneously to avoid false negative results. It would however be more appropriate if a few compounds of a particular chemical class are initially assessed both in vivo and in vitro for validity of subsequent test results in vitro.

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.