 |
| About Bioline | All Journals | Testimonials | Membership | News |
|
||||||
|
||||||
Activity of 9-acridanone-hydrazone Drugs Detected at the pre-postural Phase, in the Experimental Schistosomiasis Mansoni Leogenes Horacio Pereira+ Paulo Marcos Zech Coelho, Jose Oswaldo Costa*, Romulo Teixeira de Departamento de parasitologia, ICB, Universidade Federal de Minas Gerais, Caixa Postal 486, 30161-970 Belo Horizonte, MG, Brasil ,Departamento de Medicina Veterinaria Preventiva, Escola de Veterinaria, UFMG, Belo Horizonte **Departamento de Analises Clinicas e Toxicol6gicas, Faculdade de Fannacia, UFMG, Belo Horizonte, MG, Brasil
The compound Ro-15.5458/000, derivative in the class of 9-acridanone-hydrazones, was found to be effective against Schistosoma mansoni in mice, killing almost all the skin schistosomules (24 hr after infection), when administered at the dose of 100mg/kg. In experintents carried out with Cebus monkeys, the drug was shown to be fully effective at 25mg/kg, 7 days after infection- These data, associated with the good results obtained earlier at the post-postural phase of schistosomiasis, allow the inference that this promising compound may be important in the set of antischistosomal drugs, depending on further toxicological and clinical tests. Key words: acndanone-hydrazones - Schistosotna mansoni - experimental schistosomiasis Derivatives in the chemical group of 9-acridanone-hydrazones showed high schistosomicidal activity at the post-postural phase of experimental schistosomiasis in primates (Sturrock et al. 1987, Coelho & Pereira 1991, Coelho et al. 1994 in press). Some compounds of this group, as Ro-lS.5458/000, were found to be highly active against adult worms, at doses of 12.5mg/kg body weight, in Cebus monkeys infected with well defined Brazilian geographical strains of Schistosoma mansoni (Coelho & Pereira 1991, Coelho et al. 1994 in press). In this study, undertaken to investigate the activity of the compound Ro-15.5458/000 at the pre-postural phase of infection, the authors used albino mice and Cebus monkeys as models. MATERIALS AND METHODS The chemical structure of compound Ro15.5458/000, which was developed at the laboratories of F. Hoffmann - La Roche & Co. Ltd. (Basel, Switzerland), is shown in the Figure. Test with mice - Eighty adult albino mice (Mus musculus), all outbred females, reared at the Schistosomiasis Research Unit - Laboratory Prof. Jose Pellegrino - Federal University of Minas Gerais (Brazil), were used.
The animals were transcutaneously infected with about 100 S. mansoni cercafiae (LE strain), as described by Barbosa et al. (1978). The LE strain of S. mansoni has been maintained at the laboratories of the Schistosomiasis Research Unit for more than 30 years, through Biomphalaria glabrata passages, and using miracidia from the liver of hamsters (Cricetus auratus). Twenty infected animals were kept as controls, and the other 60 were treated 24hr after infection. The compound Ro-15.5458/000 was given at a dose of 100mg/kg bodyweight, by oral route. Thirty-five days after infection, the animals were killed by cervical fracture and their portal system was perfused for worms, in general terms, according to the technique described by Pellegrino and Siqueira (1956). Test with Cebus monkeys - Five adult animals were transcutaneously infected with about 200 S. mansoni cercariae (LE strain). Two monkeys (M-16 and H-17) were maintained as controls, and three others (H-15, H-18 and M-19) received specific treatment (25mg/kg Ro15.5458/000) by oral route, one day after infection (monkey H-15), 7 days after infection (monkey H-18), and 28 days after infection (monkey M-19). Rectal biopsies were carried out at 79 days after treatment, for collection of rectal snips, which were weighed and examined under optical microscope for counting and classification of S. mansoni eggs (quantitative oogram, as outlined by Katz et al. 1966). At 183 days after infection, the monkeys H-15, M-16 and H-18 were sacririced by means of a lethal dose of pentobarbital sodium, and perfused for worms, as described by Pellegrino and Siqueira (1956). Fragments of the liver and intestinal mucosa were examined by using the quantitative oogram method (Katz et al. 1966). Statistical analysis - The Student's t-test for unpaired samples was used for comparison of the mean numbers of worms recovered from mice. RESULTS
As can be seen in Table I, a marked difference
(p
At 183 days following infection, the monkeys H-18,
H-15 and M-16 were sacrificed and peffused for worms.
Monkey H-18 (treated at 7 days after infection) presented
no worms at perfusion. The absence of eggs in both hepatic
tissue and rectal mucosa confirms the parasitological cure.
At perfusion, monkey H-15 (treated at 24hr after
infection) showed the presence of 63 worms (26 females and 37
males), as well as viable eggs in the hepatic tissue and
rectal mucosa.
Monkey M-16 (untreated, kept as control) showed a total of
135 worms (86 males and 49 females) at perfusion. This worm
recovery, clearly higher than that obtained from monkey H15,
suggests a partial activity of the drug, which was able to
eliminate some but not all schistosomules at skin level.
DISCUSSION
The results from the present study indicate the efficacy
of Ro-15.5458/000 against S. mansoni, at the skin
phase, in mice treated with 100mgJkg bodyweight. However, the
results obtained from Cebus monkeys treated with this
drug, at the dose of 25mg/kg, 24hr after infection (skin
phase), were not as satisfactory as those seen in mice, due to
the survival of a significant number of worms. On the other
hand, at the pulmonary phase of the parasites cycle (7 days
after infection), a complete erradication of the parasitism
was achieved in Cebus monkeys. These latest results
showed the full effectiveness of the drug Ro-15.5458/000 given
at a relatively lower dose (25mgJkg), at the pulmonary phase.
Possibly, using higher doses in Cebus monkeys, the
parasite's population could be markedly reduced at the skin
phase (24hf after infection).
TABLE I
Recovery of worms from mice, by means of peffusion of the
portal system, 35 days after trapscutaneous infection with
about 200 Schistosoma mansoni cercanae, from the group
treated with Ro-15.5458/000 (100mg/kg), at 24hr after
infection, and the respective control group
The Student's t-test showed highly significant differences for
all the values from the treated group in relation to the
respective values from the control group (p<0.001).
TABLE II
Activity of Ro-15.5458/000 (25mg/kg, per os, single
dose) in prepostural periods of infection by Schistosoma
mansoni (LE strain) in Cebus monkeys. Each primate
was previously exposed to about 200 cercariae
Earlier results obtained with 9-acridanonehydrazones
showed the efficacy of these drugs at the post-postural phase
of schistosomiasis mansoni (Stunock et al. 1987, Coelho &
Pereira 1991, Coelho et al. 1994 in press). The results re-
corded so far, added to the ones presented in this compounds
may be considered as an impotlant reserve in the set of
schistosomicide drugs. The 9-acridanone-hydrazone compounds,
if approved by means of toxicological and clinical tests, may
play an important role in the treatment for human
schistosomiasis.
ACKNOWLEDGMENTS
To Dr HR Stohler (F Hoffmann-La Roche & Co. Ltd, Basel,
Switzedand) for providing compounds used in work, as well as
for financial support and advice; to Dr Faical Simon and Dr
Adayr Mafuz Saliba (Fundacao Parque Zoologico de Sao Paulo)
for the supply de Paula Ribeiro for translating the
manuscript; to Mr Alberto G Santos, Mrs Alice Neni F
Balzuweit, Miss Zenir de Souza, and in memoriam: Mr Adelino
Ferreim and Mr Mauncio V Costa, for technical assistance.
REFERENCES
Barbosa MA, Pellegrino J, Codho PMZ, Sampaio IBM 1978.
Quantitative aspects of the migration and evolutive
asynchronism of Schistosoma mansoni in mice. Rev Inst Med
Trop S Paulo 20: 121-132.
Codho PMZ, Pereira LH 1991. Schistosoma mansoni:
Preclinical studies with 9-Acridanone-hydrazones in
Cebus monkeys experimentally infected. Rev Inst Med
Trop S Paulo 33: 50-5Z
Coelho PMZ, Pereira LH 1994. Antischistosomal activity of
9-Acridanone-hydrazones in Cebus monkeys experimentally
infected with the SJ strain of Schistosoma mansoni. Rev
Inst Med Trop S Paulo (in press).
Katz N, Pellegrino J, Pompeu-Memoria JIM 1966.
Quantitative oogram method in Cebus monkeys ex-
perimentally infected with Schistosoma mansoni. J Parasitol
52: 917-919.
Pellegrino J, Siqueira AF 1956. Tecnica de peffusao pain
colbeita de Schistosoma mansoni em cobaias
experimentalmente infestadas. Rev Bras Malariol 8:
589-597.
Sturrock RF, Bain J, Webbe G, Doenhoff MJ, Stohler H 1987.
Parasitological evaluation of curative and subeumtive doses of
9-Acndanone-hydrazone drugs against Schistosoma mansoni in
baboons, and observations in senan levels of anti-egg
antibodies detected by ELISA. Trans R Soc Trop Med Hyg 81:
188-192.
Copyright 1995 Fundacao Oswaldo Cruz
|
| |||||||||
