[METHODS OF RESEARCH ON SCHISTOSOMICIDES AND STUDY ON THE SCHISTOSOMICIDAL EFFECT OF VARIOUS PREPARATIONS].
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Animals↗
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METHODS FOR THE STUDY OF SCHISTOSOMICIDES AND OF INVESTIGATION INTO THE SCHISTOSOMICIDAL ACTION OF A FEW COMPOUNDS.
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Antiprotozoal Agents↗
The association of steroids and schistosomicides in the treatment of experimental schistosomiasis.
The best therapeutic approach to acute schistosomiasis (Katayama fever) is still unsettled. In this paper we report a synergistic effect between schistosomicides and steroids in the treatment of the early stages of Schistosoma mansoni infection in the mouse. CBA mice infected with 150 S. mansoni cercariae were treated with oxamniquine or praziquantel and dexamethasone or prednisolone. The rate of parasite egg excretion by treated mice and appropriate controls was monitored, and the mice were perfused 43 d after infection for estimation of worm burdens and tissue egg densities. Mice treated with schistosomicides alone or with schistosomicides plus steroids had worm burdens of similar size. Significant reductions in egg counts were, however, recorded in faeces, and in the intestines and livers (with consequent reduction in liver pathology), of mice treated with schistosomicide and steroid, when compared to mice treated with schistosomicide alone or steroid alone. The apparent inhibition of fecundity of S. mansoni by combining these drugs has clear implications for treatment of the Katayama syndrome.
Animals↗
Toxicological profile of praziquantel, a new drug against cestode and schistosome infections, as compared to some other schistosomicides.
2-Cyclohexylcarbonyl-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a] isoquinolin-4-one (praziquantel, EMBAY 8440, Biltricide), a new anthelminthic drug with activity against all species of schistosomes pathogenic to man, and against a wide range of cestodes, did not reveal any undesired pharmacodynamic effects. After oral administration praziquantel is quantitatively and rapidly absorbed, metabolized and excreted as a variety of metabolites predominantly via the kidneys by all species tested, including man. Its acute toxicity tested in rats, mice, rabbits and dogs is very low as compared with other schistosomicidal drugs. After repeated oral administration rats tolerated daily doses of up to 1000 mg/kg for four weeks, and dogs up to 180 mg/kg for thirteen weeks without any organ damage. In contrast to some other schistosomicidal drugs praziquantel did not disturb the whole reproductive process (up to F2-generation) in rats, nor did it reveal teratogenic effects in mice, rats and rabbits. In extensive mutagenicity trials performed in different European laboratories in a variety of test systems no induction of point mutations, nor of gene conversion, nor of DNA-repair, nor of sister chromatid exchanges (SCEs), nor of X-linked recessive lethals was detected. Besides, Salmonella tests with urines of praziquantel-treated mice, rats, healthy and Schistosoma-infected persons gave no indication of a mutagenic effect. In different in vivo mammalian assays praziquantel was not mutagenic either. In contrast to these findings other schistosomicidal drugs demonstrated mutagenic potential, in bacterial tests at least. According to the results available so far from carcinogenicity studies with oral doses of 100 and 250 mg praziquantel/kg, given once weekly to Syrian hamsters for 80 weeks and to rats for 104 weeks, there is no hint of a carcinogenic potential of praziquantel in small rodents, while hycanthone had cancerogenic effects in mice and niridazole was carcinogenic in mice, rats and Syrian hamsters.
Animals↗
Modification of cytochrome P-450, NADPH-cytochrome c reductase and aryl hydrocarbon hydroxylase activities by schistosomicidal drugs.
This study was planned to investigate the modification of the mouse microsomal monooxygenase enzymes using various schistosomicidal drugs. Enzymes investigated were cytochrome P-450, NADPH-cytochrome c reductase and aryl hydrocarbon hydroxylase (AHH). Administration of oxamniquine and niridazole increased, whereas praziquantel and hycanthone lowered the cytochrome P-450 content. An apparent increase in the activity of NADPH-cytochrome c reductase was only observed with oxamniquine. The in vivo and in vitro effects of schistosomicidal drugs on the activity of AHH were investigated using benzo(a)pyrene (BP) as substrate. Oxamniquine and niridazole significantly increased the AHH activity in vivo and in vitro, while the antimonial drugs enhanced the enzyme activity only in vivo. On the other hand, praziquantel and hycanthone lowered the AHH activity only in vivo. Metrifonate did not show any effect either in vivo or in vitro. The mechanisms by which these drugs modify the AHH activity are discussed in the text.
Animals↗
Relationship between schistosomicidal drug efficacy, gonadal steroid hormonal changes and state of disease immunopathology in murine schistosomiasis mansoni.
The schistosomicidal efficacy of praziquantel (2 x 500 mg/kg), oxamniquine (1 x 100 mg/kg) and combined one-third the curative dose of each of them (333 mg/kg praziquantel + 33 mg/kg oxamniquine), were correlated to gonadal steroid hormonal changes and state of disease immunopathology, in mice infected with 100 Schistosoma mansoni (S. mansoni) cercariae. Maximum efficacy recorded with combination regimen particularly 4 weeks after treatment, was accompanied by maximum reduction in granuloma volume (65%), least fall in testosterone level (-56.2 and -60.2% in male and female mice respectively) and increased progesterone level (+33.9 and +81.5% in male and female mice respectively). These findings revealed a potentiated effect of combination therapy on mature infection and the possible involvement of gonadal steroid hormones in affecting the efficacy of schistosomicidal drugs and state of disease immunopathology.
Animals↗
In vitro effect of schistosomicidal drugs on hepatic arylsulfatase B from the schistosoma-infected mouse.
Arylsulfatase B (ASB) hydrolyzes the desulfation of N-acetylgalactosamine-4-sulfate at the non-reducing terminal of glycosaminoglycans. This enzyme activity was found to be elevated in mice schistosomiasis. In the present study, the catalytic and immunological properties of purified ASB from the liver of Schistosoma-infected mouse was investigated in the presence and absence of the schistosomicidal drugs praziquantel and Commiphora extract. The in vitro effect of praziquantel was found to be inhibitory with a Ki value of 5.5 x 10(-4) M while that of commiphora extract was as an activator. Furthermore, these drugs did not have an observed effect on the immunological properties of ASB with regard to its binding to its polyclonal rabbit antibody. These results indicate that some schistosomicidal drugs may reverse the alteration of the catalytic properties of the enzyme in schistosomiasis.
Animals↗
Dissociation of mutagenic and other toxic properties from schistosomicides.
Structural alterations of two schistosomicides (hycanthone and niridazole) can bring about very marked reductions in mutagenic activity without decreasing antischistosomal potency. Therefore, these two effects are not necessarily associated with each other, providing opportunities for the design and development of safer schistosomicidal drugs.
Animals↗
Praziquantel: a new schistosomicide against Schistosoma haematobium.
The effectiveness of the new schistosomicide praziquantel was assessed in African schoolchildren infected with Schistosoma haematobium. They were stratified according to the severity of their infection and were then randomly allocated to treatment with two single-dose regimens (30 and 40 mg/kg) and a split regimen of two doses of 20 mg/kg given four hours apart. All three regimens were highly effective and produced few side effects. Children who initially had very high pretreatment egg loads showed a poorer therapeutic response at all dose levels, and further investigations are necessary to find the optimum dose. Because of its effectiveness in a single dose and lack of toxicity, praziquantel may prove to be the ideal schistosomicide.
Adolescent↗
Studies on the mode of action of oxamniquine and related schistosomicidal drugs.
Adult Schistosoma mansoni were incubated for 1 hour in vitro with various drugs and then returned into the mesenteric veins of permissive animal hosts. Survival of schistosomes was assessed 3-4 weeks later by portal perfusion. Under these conditions, oxamniquine and hycanthone proved effective in killing S. mansoni, whereas UK-3883, lucanthone and lucanthone-4-desmethyl had no lethal activity. The same drugs which were schistosomicidal in vitro also persistently inhibited DNA, RNA, and protein synthesis in S. mansoni, whereas they were only transiently inhibitory against Schistosoma japonicum, against hycanthone-resistant S. mansoni and against immature worms. When drugs were administered in vivo to infected mice and the synthesis of macromolecules was assayed in vitro on worms obtained 1 or 3 days after treatment, not only oxamniquine and hycanthone, but also UK-3883 and lucanthone, proved effective in inhibiting the synthesis of macromolecules in sensitive--but not in resistant--S. mansoni. It is suggested that oxamniquine, like hycanthone, may exert its schistosomicidal activity by inhibiting nucleic acid synthesis in the parasite.
Animals↗
[Efficacy of schistosomicide derivatives, appreciation with electronic microscopy experimental model (author's transl)].
The activity of some schistosomicidal drugs have been studied by electron microscopy on the tegument of Schistosoma mansoni. Results are different and depend of the compound which is tested. Two new compounds: RO 11 3128 and RO 13 3978 are specially active and act in different ways on the tegument. On of them, a benzodiazepine, have been tested in association with an "antibenzodiazepine" compound in order to avoid the sedative action without decrease of the schistosomicidal activity.
Animals↗
Use of praziquantel in patients with schistosomiasis mansoni previously treated with oxamniquine and/or hycanthone: resistance of Schistosoma mansoni to schistosomicidal agents.
Fourteen patients with active schistosomiasis mansoni in spite of previous treatment with oxamniquine and/or hycanthone were treated with praziquantel, single oral dose of 45 to 50 mg/kg body-weight. All underwent clinical, laboratory and electrocardiographic examination before and after treatment. Untoward effects (dizziness, drowziness, nausea and abdominal pain) were observed in ten. Laboratory findings disclosed no significant alteration and the electrocardiograms showed no abnormalities. Monthly follow-up examinations of 13 patients for six consecutive months showed parasitological cure in all. Before praziquantel treatment strains of Schistosoma mansoni were isolated from two patients, one treated three times with oxamniquine and the other with hycanthone once and oxamniquine twice. Progenies of these strains were maintained in Biomphalaria glabrata and mice. Groups of these infected mice were then treated with oxamniquine, hycanthone, niridazole and praziquantel and results compared with the BH strain maintained in our laboratory for many years. Schistosomicidal activity was assessed by the localization of worms in the portal vein system and oogram changes. Progenies from the strains isolated in this study were resistant to oxamniquine and hycanthone but sensitive to niridazole and praziquantel. The BH strain was sensitive to all four drugs. The serial runs of S. mansoni strains through intermediate and definitive hosts have not influenced their reactions to these schistosomicides.
Adolescent↗
Lack of correlation between schistosomicidal and anticholinergic properties of hycanthone and related drugs.
Visual observation of the motor activity of Schistosoma mansoni kept in vitro showed an increase of activity in the presence of hycanthone (HC). In addition, HC caused a delay in the paralytic effects of carbachol. Similar results were observed in the presence of oxamniquine (OXA). The same pattern of motor activity, however, was shown by HC-resistant worms, by Schistosoma japonicum, and by worms exposed to drug precursors (lucanthone and UK-3883), which are not schistosomicidal in vitro. Other analogs with in vitro killing activity (IA-4 and IA-4 N-oxide) showed minimal anticholinergic effects. The anticholinergic effects of HC and OXA were quickly reversible in vitro and in vivo, whereas their antischistosomal effects are irreversible and delayed. Incubation of schistosomes with high concentrations of carbachol or with anticholinergic drugs failed to compete with the schistosomicidal effects of HC. These results are viewed as contradictory to the hypothesis that HC kills schistosomes by blocking their acetylcholine receptors.
Animals↗
[Thienyl acrylamides and thienyl pyrazolines as potential schistosomicidal agents].
Alpha-Thienyl-N-substituted acrylamides that possess analogous structures to known schistosomicidal agents were synthesized. Two chalcones were prepared by condensing alpha-thiophenealdehyde and acetophenone or its o-hydroxy derivative. Cyclization of the chalcones with hydrazine hydrate or monosubstituted hydrazines afforded 1.3.5 trisubstituted 2-pyrazoline
Acrylamides↗
Synthesis of benzo-benzothiopyranoquinolines (pyridobenzothioxanthones) as possible schistosomicidal and antitumor agents.
The synthesis of a new class of compounds structurally related to cyclohexenothiaxanthones and benzothiaxanthones including a pyridine ring is described in an attempt to find compounds that may have schistosomicidal and carcinostatic activity. Synthesis was achieved through the condensation of amino-cyclohexenothiaxanthones and amino-benzothiaxanthones with ethyl acetoacetate by the Knorr and Conrad-Limpach methods.
Animals↗
5-(Hydroxyimino)-4-methoxy-2-(pivaloylimino)thiazolidine-3 -acetamide, a reduced nitroheterocyclic derivative with potent schistosomicidal properties.
The synthesis and antischistosome properties of 5-(hydroxyimino)-4-methoxy-2-(pivaloylimino)thiazolidine-3- acetamide (1) are described. The compound was prepared by reduction of the nitrothiazoline (2) with stannous chloride in methanol, and represents the first example of a reduced nitroheterocyclic compound showing potent schistosomicidal properties. The possible relationship of compounds such as 1 to the as yet unidentified reduced active but toxic entities formed in vivo from nitroheterocyclics like metronidazole is discussed.
Animals↗
Drug resistance to schistosomicides and other anthelmintics of medical significance.
It is usual for people to be infected for some period in life with parasitic worms, which may cause morbidity or even kill. Anthelmintics are used for the treatment and control of the human helminthiases, since no vaccines are yet available. Despite the widespread use of these compounds, drug resistance has become apparent only with antischistosomal chemotherapy, in contrast to the situation with other anti-infective agents in human medicine and with veterinary anthelmintics, where resistance is widespread. This paper reviews research on drug resistance in human helminthiasis with emphasis on schistosomicidal drugs.
Animals↗
Enhanced schistosomicidal efficacy of tartar emetic encapsulated in pegylated liposomes.
The aim of the present study was to evaluate the ability of liposomes to improve the efficacy of tartar emetic (TA) against established Schistosoma mansoni infection. TA was used as a schistosomicidal drug model and both conventional liposomes (CL) and long-circulating pegylated liposomes (LCL) were evaluated. In the first experiment, TA, either free or encapsulated within CL or LCL, was given intraperitoneally (i.p.) as a single dose of 11 mg Sb/kg to mice experimentally infected with S. mansoni. Only the group treated with LCL showed a significant (55%) reduction in the worm burden, compared to the control groups (untreated or treated with empty LCL). In the second experiment, the efficacy of TA-containing LCL was evaluated at a higher dose (27 mg Sb/kg) by both subcutaneous (s.c.) and i.p. routes. Reduction levels of 67 and 82% were achieved by s.c. and i.p. routes, respectively. Strikingly, all mice survived to this high dose of antimony. This is in contrast with free TA that was lethal in 100% of mice at the same dose. The present work demonstrates that LCL reduce the acute toxicity of TA and effectively deliver this drug to S. mansoni during the late stages of parasite infection.
Animals↗