Response of pre-adult and adult stages of Trichuris muris to common anthelmintics in mice.

The common anthelmintics, oxantel, mebendazole, albendazole and pyrantel were assessed for their comparative activity against Trichuris muris in mice. Mice were infected with T. muris and the infection was maintained by a brief cortisone administration during the second week of infection. Mice carrying the infection with different life cycle stages, viz. fourth stage larvae (L4), pre-adult and adult stages were dosed with anthelminitics. The worm burdens in control infection groups varied although infection dose and other conditions were uniformly followed. With various dose regimens tested, oxantel was highly potent; it eliminated completely pre-adult and adult stages, respectively at 25 and 12.5 mg kg-1 dose levels with significant activity also against adult worms at a 1.56 mg kg-1 dose level and against pre-adults at a 6.25 mg kg-1 level. Pre-adults required twice the dose given to that of adults for complete (100%) activity. Mebendazole was the next most active; a dosage of 37.5 mg kg-1 was completely active against pre-adults whereas a dosage of 2 x 50 mg kg-1 was required for complete elimination of adult worms. In addition, about 90% of the worms were eliminated with a single dose of 150 mg kg-1. However, a significant activity was seen against adults at a 25 mg kg-1 level and pre-adults at 37.5 mg kg-1, the lowest level tested. In comparison, albendazole did not induce complete clearance of pre-adult and adult stages even when tested at dose levels as high as 150 and 2 x 75 mg kg-1, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Response of adult Necator americanus to some known anthelminthics in hamsters.

Adult Necator americanus infection in laboratory hamsters (the hamster-hookworm model) was examined as an anthelminthic screening system. Three reference anthelminthics--pyrantel (PYTL), mebendazole (MBZ) and ivermectin (IVRN)--were used to assess the sensitivity of adult N. americanus and also to investigate the value of the hamster-hookworm model for predicting clinical results. Serial drug dosages were used, and the ED50 was determined from the resulting cure rates. In addition, percentage worm reductions were calculated by reference to the worm burdens in control groups. The results showed that the hamster-hookworm model was able to differentiate anthelminthics on their efficacy. Absolute activity (100% worm reduction) followed treatment with 8 mg kg-1 MBZ, 38-40 mg kg-1 PYTL and 18 mg kg-1 IVRN. Based on ED50 data of PYTL and MBZ, adult N. americanus appeared to be two to five times more sensitive than pre-adult stages. However, with IVRN the reverse appeared true. MBZ appeared to be most active and PYTL least active in terms of curing infected animals, but there were no obvious differences between the rates of worm reductions following single or multiple doses of anthelminthics. It is considered that the hamster-hookworm model will prove of value in identifying and characterizing possible new anthelminthics.

Response of laboratory-adapted human hookworm and other nematodes to ivermectin.

The activity of ivermectin was examined in Necator americanus, a human hookworm, adapted to the laboratory hamster. A dose of 30 mg kg-1 X 1 or 10 mg kg-1 X 2 was required for complete clearance of pre-adult N. americanus; however, hamsters carrying adult N. americanus were completely cured of infection by doses of 15 mg kg-1 or 7.5 mg kg-1 X 2. The doses of ivermectin required for complete elimination of N. americanus were much higher than those reported for other intestinal nematodes. The probable reasons for these higher doses are discussed. Tests were also carried out with other rodent parasites, namely Nematospiroides dubius, Strongyloides ratti and Trichuris muris. Doses as low as 0.3 mg kg-1 X 1 completely eliminated adult N. dubius from mice, whereas++ S. ratti needed a repeated dose (0.3 mg kg-1 X 2). None of the mice was cured of T. muris infection even at doses of 10 mg kg-1 X 2, although some degree of cure was apparent at the toxic dose. It thus appears that ivermectin is in no way superior in its activity against N. americanus and T. muris than the existing anthelmintics.

Response of preadult Necator americanus to some known anthelmintics in hamsters.

Hamsters infected with laboratory-adapted preadult Necator americanus were dosed with 6 reference anthelmintics. Their efficacy was measured in terms of percentage cure of infected animals as well as percentage worm reduction following treatment. Mebendazole and pyrantel were equally effective in this system. Other anthelmintics, including anti-hookworm compound, bephenium hydroxynaphthoate, were less effective. The comparative results revealed that the N. americanus model is sensitive and reliable for identifying and characterizing new anti-parasite preparations.

Site of resistance to Necator americanus in hamsters.

Resistance to the development of human hookworm, Necator americanus was examined in 3- to 6-week-old young adult hamsters. Only 3% of N. americanus infective third stage larvae (NaL3) reached maturity in the intestines of young adults as opposed to as many as 60% in 2-day-old baby hamsters. This seemingly effective resistance prevailing in young adults was investigated in some detail. The skin, the first site of contact for the invading NaL3, was bypassed during the infection process. Completely in vitro exsheathed NaL3 (ExNaL3) were used, and young adult hamsters were infected parenterally, by-passing the skin. Even after exsheathing the larvae artificially before infection and by-passing the skin, no improvement was seen in the development of N. americanus in the intestines of young adults. Higher infection doses also did not increase the worm burden. Some of the factors limiting the development of parasites in young adults were examined. N. americanus were monitored in lungs and intestines during various intervals after infection. Similar parasite burdens were apparent in lungs of baby as well as young adult hamsters. In the intestines, a significantly lower burden of N. americanus was seen during various intervals in young adults compared to the baby hamsters. Moreover, N. americanus were expelled soon after reaching the intestine. This comparative monitoring revealed the intestine as the seat of resistance against the establishment of N. americanus in young adult hamsters.

Necator americanus and Ancylostoma ceylanicum: development of protocols for dual infection in hamsters.

Two-day-old baby hamsters were infected initially with the infective larvae of hamster-adapted human hookworm, Necator americanus (NaL3). After a specified period they were again infected orally with infective larvae of Ancylostoma ceylanicum (AcL3). Three weeks after the second infection they were killed and the establishment of N. americanus and A. ceylanicum was assessed. The effect of different infection levels and exposure period of N. americanus on the concurrent establishment of A. ceylanicum was also examined. An infection with 50 NaL3 percutaneously, and 3 weeks later, a second infection with 50 AcL3 orally has produced reasonably equal number of hookworms (no statistical difference in the burden of N. americanus and A. ceylanicum) in the intestine of hamsters. Thus this protocol of dual infection was found suitable to develop two species of hookworms in hamsters for anthelmintic screening.

Anthelmintic efficacy of amoscanate (C 9333-Go/CGP 4540) against various infections in rodents, dogs and monkeys.

The anthelmintic activity of Amoscanate (C 9333-GO/CGP 4540) has been studied in experimental infections with the human hookworm, Necator americanus, in hamsters; Nematospiroides dubius, Hymenolepsis nana and natural infections with Syphacia obvelata in mice; Ancylostoma caninum, A. ceylanicum in mongrel dogs; Oesophagostomum apiostumum and Strongyloides fuelleborni in rhesus monkeys. Single oral doses of 30-60 mg/kg eliminated 94 to 99% of the total Necator parasites in 37-day-old non-patent infection, while single oral doses of 25 mg/kg expelled the entire worm burden in patient infection in hamsters. When incorporated in feed at the 0.01% level and administered ad lib. to hamsters at 20, 27 and 34 days postexposure for 5 days, the worm burdens were reduced 88 to 94%. N. dubius was completely eradicated by a single oral dose of 200 mg/kg while S. obvelata and H. nana were expelled at doses of 12.6 mg/kg and 50 mg/kg, respectively. A dose of 25 mg/kg in dogs produced 100% fecal egg reduction in hookworm and 99% in ascarid infections. The drug at 3 x 2.5 mg/kg administered at 4-hour intervals produced similar effects in mixed A. caninum and A. ceylanicum infections. Against natural infections of S. fulleborni and Oe. apiostumum in rhesus monkeys the drug showed 100% efficacy at a dosage of 60 mg/kg administered thrice at 12-hour intervals.