Chemical constituents and antifilarial activity of Lantana camara against human lymphatic filariid Brugia malayi and rodent filariid Acanthocheilonema viteae maintained in rodent hosts.

Lymphatic filariasis continues to be a major health problem in tropical and subtropical countries. A macrofilaricidal agent capable of eliminating adult filarial parasites is urgently needed. In the present study, we report the antifilarial activity in the extract of stem portion of the plant Lantana camara. The crude extract at 1 g/kg for 5 days by oral route killed 43.05% of the adult Brugia malayi parasites and sterilized 76% of surviving female worms in the rodent model Mastomys coucha. A 34.5% adulticidal activity along with sterilization of 66% of female worms could be demonstrated in the chloroform fraction. Remarkable antifilarial activity was observed in the adult B. malayi transplanted gerbil model where up to 80% of the adult worms could be killed at the same dose and all the surviving female parasites were found sterilized. The extract was also found effective against a subcutaneous rodent filariid Acanthocheilonema viteae maintained in Mastomys coucha, where it exerted strong microfilaricidal (95.04%) and sterilization (60.66%) efficacy with mild macrofilaricidal action. Two compounds, oleanonic acid and oleanolic acid, isolated from hexane and chloroform fractions showed LC100 at 31.25 and 62.5 mug/ml, respectively, on B. malayi in vitro. This is the first ever report on the antifilarial efficacy of Lantana camara.

Effects of Bay 44-4400, a new cyclodepsipeptide, on developing stages of filariae (Acanthocheilonema viteae, Brugia malayi, Litomosoides sigmodontis) in the rodent Mastomys coucha.

Bay 44-4400 was used as a spot on formulation and administered in single doses of 25 and 100 mg/kg to Acanthocheilonema viteae, Brugia malayi, and Litomosoides sigmodontis infected Mastomys coucha on various dates during prepatency, aiming to affect third stage larvae, fourth stage larvae or preadult worms. Microfilaraemia levels were controlled in comparison to untreated controls until necropsies were performed 100 days p.i. (A. viteae, L. sigmodontis) and 150 days p.i. (B. malayi) to determine the numbers of surviving worms and the condition of intrauterine developing stages. A significant proportion (86-100%) of larval and preadult stages of A. viteae were killed by Bay 44-4400 at a dose of 100 mg/kg. A dose of 25 mg/kg had only insignificant effects on the developing parasites, however, it strongly reduced microfilaraemia levels caused by surviving worms in the early phase of patency. Larval and preadult B. malayi and L. sigmodontis were not killed by Bay 44-4400 to a significant degree. Microfilaraemia developing by surviving parasites was generally and significantly reduced throughout the observation period when treatment was performed to affect the preadult parasites. In the other cases variable results were obtained. Intrauterine early embryonic stages were found to be pathologically altered in worms which had been treated at a preadult stage.

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.

Anticancer agents suppressive for adult parasites of filariasis in Mongolian jirds.

Eight chemical structures not previously reported to possess antifilarial activity have been identified. A total of 79 compounds with anticancer properties were evaluated for possible macrofilaricidal activity against Brugia pahangi and Acanthocheilonema viteae transplanted into male Mongolian jirds (Meriones unguiculatus). All eight active compounds were suppressive for the onchocerciasis type (Acanthocheilonema viteae) of the disease. None was macrofilaricidal for the lymphatic form (Brugia pahangi). These new structures may represent a nucleus around which effective drugs can be synthesized.

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.

The potential of mice as animal models for antifilarial screening.

Transplanted infections of Brugia pahangi and Dipetalonema viteae in male BALB/c and CDI mice were investigated as models for evaluating potential antifilarial compounds. The physiology and genetics of the above mouse strains are better defined than any of the rodent species currently used for primary in vivo screening, facilitating a more reproducible means for predicting the filaricidal activity of compounds. The recoveries of B. pahangi macrofilariae, implanted intraperitoneally were greater than or equal to 50% up to six weeks after implant in both CDI and BALB/c mice. The recoveries of D. viteae macrofilariae, implanted subcutaneously, were greater than 50% up to four weeks post implant but had fallen to less than 30% by six weeks. The survival of B. pahangi and D. viteae macrofilariae simultaneously implanted into mice mimicked that seen with the mono-infections, but significantly better recoveries were obtained from dual implanted CDI mice compared to the BALB/c mice when the numbers of macrofilariae implanted were varied. Standard antifilarials were evaluated against D. viteae and B. pahangi dual implanted into either CDI mice or gerbils. The mouse dual implant detected significant worm reductions against D. viteae, B. pahangi or both with all antifilarials tested except CGP 6140. Similarly under the test conditions CGP 6140 was not detected in the gerbil assay, but there were marked differences in the results obtained with the mice and gerbil models. The reasons for these differences are discussed.

[Preliminary results of the use of a new rodent filaria, Dipetalonema dessetae (Bain, 1973), in the evaluation of filaricides]. / Résultats préliminaires sur l'utilisation d'une nouvelle filaire de rongeur Dipetalonema dessetae (Bain, 1973) dans l'évaluation des antifilariens

The sensitivity of this filarial worm living in his natural host has been identified with respect to 2 well known filaricidal compounds. With diethylcarbamazine the microfilaremia drops rapidly but not completely and a long term treatment destroys the adults. Suramin is toxic to the adults and to the microfilariae. This experimental model is therefore more sensitive than anything presently available.