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The ability of antimony and antimony-containing parasiticidal agents to enhance the rate of heme degradation in liver and kidney was investigated. Trivalent antimony was shown to be an extremely potent inducer of heme oxygenase, the initial and rate-limiting enzyme in heme degradation, in both organs, whereas the pentavalent form was a weak inducer of this enzyme. The ability of antimony to induce heme oxygenase was dose-dependent, independent of the salt used, and not a result of a direct activation of the enzyme in vitro. Concomitant with heme oxygenase induction by antimony, microsomal heme and cytochrome P-450 contents decreased, the cyto-chrome P-450-dependent mixed function oxidase system was impaired, and delta-ami-nolevulinate synthase (ALAS), the rate-limiting enzyme of heme synthesis, underwent the sequential changes-initial inhibition followed by rebound induction-usually associated with the administration of transition elements such as cobalt. Antimony induction of heme oxygenase however, unlike the enzyme induction elicited by cobalt, was not prevented either by cysteine administered orally or as a cysteine metal complex, or by simultaneous zinc administration. Desferoxamine also did not block heme oxygenase induction by antimony, but this chelator did prevent the rebound increase in ALAS activity associated with antimony or cobalt treatment. Antimony-containing parasiticidal drugs were also potent inducers of heme oxygenase in liver and kidney. The heme degradative action of these drugs may be related in part to the jaundice commonly associated with the prolonged therapeutic use of these agents. The heme-oxygenase-inducing action of antimony-containing parasiticidal drugs is a newly defined biological property of these compounds. The relation between the parasiticidal and the heme-oxygenase-inducing actions of such drugs is unknown. However, certain parasites contain hemoproteins or require heme compounds during their life cycle. It may therefore be useful to explore the possibility that the heme-degrading and the parasiticidal actions of certain metals or metal-containing therapeutic agents are in some way related.
Infection with Toxoplasma gondii has become a major cause of morbidity in patients with AIDS. To investigate the mechanisms responsible for immune responses to toxoplasma Ag we used a highly purified membrane protein (P30) of T. gondii to stimulate an in vitro Ag-specific cytotoxic T cell response. P30 immune mouse splenocytes reduced extracellular T. gondii plaque-forming units by more than 50% when incubated at an E/T ratio of 10:1 or greater. By using a [3H]uracil radioisotope release assay, the effect of the immune splenocytes was determined to be a direct parasite lytic mechanism. The immune splenocytes were P30 Ag specific and of the Thy 1.2, Lyt2,3+ (CD4-, CD8+) phenotype, specific for mouse cytotoxic T cells. Opsonization of the parasites with monoclonal P30-reactive mAb did not enhance parasiticidal activity. Culture supernatants obtained during the 2-h cytotoxic assay were not parasiticidal, and anti-asialo-GM1 antibody plus C did not destroy the parasiticidal activity of the P30 responder cells. Accordingly, we have identified an Ag-specific subset of CD4-, CD8+, P30 responder T cells that are directly parasiticidal to extracellular T. gondii, and that exhibit cytotoxicity independent of antibody opsonization, lymphokine secretion, NK cell activity, and, apparently, MHC involvement as well.
The prevalence and number of naturally acquired gastrointestinal parasites were compiled for horses used in critical tests of activity of parasiticides over a 28-year period (1956-1983). Data are presented as follows: n = number of horses examined; % = mean prevalence; number in parentheses after % = aggregate mean number of parasites in infected horses. Parasites found were: bots (n = 513) - Gasterophilus intestinalis, 2nd instar, 61%(58); 3rd instar, 94%(168); G. nasalis, 2nd instar, 36%(28); 3rd instar, 81%(51); stomach worms (n = 200) - Habronema muscae, 65%(179); Draschia megastoma, 29%(95); Trichostrongylus axei, 46%(3000); ascarids (n = 513) - Parascaris equorum, mature, 50%(25); immature, 23%(33); tapeworms (n = 513), Anoplocephala perfoliata, 17%(15); A. magna, 14%(10); large strongyles (n = 487), Strongylus vulgaris, 84%(80); S. edentatus, 79%(101); S. equinus, 6%(14); small strongyles (n = 210), 100%(142,000); pinworms (Oxyuris equi), immature (n = 210), 78%(9000); mature (n = 506), 40%(62); Probstmayria vivipara (n = 210), 12%(10(7]; S. vulgaris in cranial mesenteric artery (n = 472), 89%(57). The majority of the horses examined were mixed lighthorse type but several Thoroughbreds were included. Ages varied from about 4 months to 20 years old, with most being approximately 1-3 years old. They probably had either no or infrequent previous treatment with parasiticides. Most of the horses were selected for presence of certain internal parasites, usually large strongyles, prior to usage in the critical tests.
The effect of parasiticide treatment on dynamics of antigen specific antibody responses to Hypoderma lineatum (De Villers) was investigated in naturally infested calves. Parasiticides were applied to cattle 1 month prior to, 1 week prior to, and coincident with the appearance of warbles in untreated calves from the same source herd. When cattle were treated approximately 1 month before warbles appeared in untreated control animals, antigen specific antibody levels increased for 25-34 days then declined to undetectable levels by approximately 75 days. Antigen specific antibody levels sharply declined in cattle treated 1 week prior to appearance of warbles in untreated controls. Treatment applied coincident with arrival of grubs on the back did not alter the antigen specific antibody profile, but reduced the relative magnitude of antigen specific antibodies present. Persistence of the antigen specific antibody following treatment will permit conduct of serological surveillance programmes.
When humans serve as inadvertent intermediate hosts for Echinococcus multilocularis, disease (alveolar echinococcosis [AE]) may result from the expanding parasite metacestode in visceral organs, mostly in the liver. Benzimidazole carbamate derivatives such as mebendazole and albendazole are used for chemotherapeutic treatment of AE. However, these treatments are, in most cases, parasitistatic rather than parasiticidal. As treatment is discontinued, a recurrence of parasite growth has been observed in many AE patients with nonradical resections. The only curative treatment for AE is radical surgical resection of the parasite tissue and support by chemotherapy. As there is a need for new treatment options for AE, the in vitro efficacy of nitazoxanide (NTZ), a broad-spectrum drug used against intestinal parasites and bacteria, was investigated. We showed that in vitro treatment of E. multilocularis metacestodes with NTZ induced high levels of alkaline phosphatase activity in the medium. Concurrently, distinct morphological and ultrastructural alterations were detected. Most significantly, two distinct types of alterations were observed as soon as after 3 h of NTZ treatment. At first, the drug induced a peripheral output of membranous vesicles from the tegumental membrane into the laminated layer. Simultaneously, germinal layer-associated undifferentiated cells produced large vacuoles filled with lipid-like and often electron-dense membranous segments. Other alterations were observed at later time points, including vacuolization of the germinal layer, accumulation of lipid droplets, and lastly, loss of microtriches and separation of the laminated and germinal layers. The pattern of damage induced by NTZ was different from the alterations earlier observed in albendazole sulfoxide-treated vesicles. The nonviability of NTZ-treated metacestodes was confirmed through bioassay, i.e., inoculation of treated and untreated parasites into mice. These experiments demonstrate the in vitro parasiticidal effect of NTZ on E. multilocularis metacestodes.
The administration of trivalent arsenic, either as sodium arsenite or as the trypanocidal drug melarsoprol, to rats produced a profound induction of microsomal heme oxygenase (EC 1.14.99.3) in both liver and kidney and a concomitant decrease in cytochrome P-450 content. In addition, perturbations of delta-aminolevulinate synthase were observed which showed an initial decline followed by a rebound increase in the activity of this enzyme with arsenical treatment. Pentavalent arsenic did not induce hepatic heme oxygenase but did induce the enzyme in kidney, although to a lesser extent (50%) than trivalent arsenic. Treatment of isolated chick embryo liver cells in vitro with sodium arsenite or the parasiticidal drug melarsoprol also showed a potent induction of heme oxygenase. These findings describe a new and potent ability of arsenic and parasiticidal arsenicals to induce heme oxygenase resulting in enhanced degradation of cellular heme.
Foals (79), born in 2004 on three thoroughbred horse farms (C, M, and S) in central Kentucky, were fed pyrantel tartrate daily, beginning at about 3 months of age. In addition, other parasiticides [fenbendazole (FBZ), ivermectin (IVM) alone or with praziquantel (PRAZ), oxibendazole (OBZ), pyrantel pamoate (PRT), and moxidectin (MOX)] were given periodically. All treatments were administered by farm personnel. Over a 14-month period, from May 2004 to July 2005, collections (n=989) of feces were made from the foals for determination of presence of internal parasite eggs/oocysts by qualitative and/or quantitative methods. Conclusions on drug activity are based necessarily on considering the combined effect of pyrantel tartrate and the other compounds. For small strongyles, this was related to which specific additional compound was given. Based on the percentage of foals with strongyle-egg-positive feces and/or the level of eggs per gram of feces (EPG) counts for the foals after treatment, drug activity on small strongyles was highest to lowest for MOX, IVM and IVM/PRAZ, FBZ, OBZ, PRT, and FBZ (2x for 5 days). The macrocyclic lactones (MOX and IVM) were highly superior to the other compounds. Some of the strongyle counts were high (over 2,000), especially on one farm (S), during periods when foals received only pyrantel tartrate, but a few days after administration of therapeutic dose rates of the drugs IVM or MOX, they were negative or very low. Ascarid eggs were present in feces of three foals after treatment with a combination of IVM and PRAZ. The qualitative method was more efficient than the quantitative method in detection of ascarid and strongyle eggs in the feces. Prevalence of eggs of ascarids (Parascaris equorum) was low (0, 4, and 31%), of strongyles high (80, 100, and 100%), of Strongyloides westeri very low (only one infected foal), and oocysts of Eimeria leuckarti medium to high (36, 41, and 85%) for the three farms, C, M, and S, respectively. It is uncertain whether the low ascarid prevalence was from activity of pyrantel tartrate and/or the other drugs or to a limited source of infective eggs.
These guidelines are intended to assist the planning and conduct of laboratory and clinical studies to assess the efficacy of ectoparasiticides applied to dogs or cats for the purpose of treating, preventing and controlling flea and tick infestations. The term ectoparasiticide includes insecticidal and acaricidal compounds, as well as insect growth regulators. The range of biological activities accruing from animal treatment that are considered include: repellency and anti-feeding effects, knockdown, speed of kill, immediate and persistent lethal effects, and interference with egg fertility and subsequent development of off-host life cycle stages. Information is provided on the selection of animals, dose determination, dose confirmation and field studies, record keeping, interpretation of results and animal welfare. These guidelines are also intended to assist registration authorities involved in the approval and registration of new parasiticides, and to facilitate the worldwide adoption of harmonized procedures.
We have synthesized a library of thiosemicarbazones and screened them against three parasitic cysteine proteases, cruzain, falcipain-2, and rhodesain, and against the respective parasite sources of these three proteases, Trypanosoma cruzi, Plasmodium falciparum, and Trypanosoma brucei. The screens identified compounds that were effective against the enzymes and the parasites but also some compounds that were parasiticidal despite a lack of activity against the proteases. Several compounds were effective in killing all tested parasites. These promising lead compounds were tested for general toxicity in mice, and only one produced observable toxicity after 62 h. Our results suggest that thiosemicarbazones represent validated drug leads that kill several species of protozoan parasites through the inhibition of cysteine proteases as well as other novel targets.
Clindamycin, which has been reported to have no significant in vitro activity against Toxoplasma gondii, actually markedly inhibits the growth of this parasite in infected human fibroblasts. When measured 3 days after treatment, the concentration required to reduce parasite growth by 50% is about 1 ng/ml. Some observers failed to note this inhibition because of its markedly delayed onset. At 6 ng/ml, clindamycin is parasiticidal, and the rate and extent of parasite killing increase with higher drug concentrations. With the aid of chemical mutagenesis, we isolated a parasite mutant that is approximately 100-fold more resistant to clindamycin than is the wild type. Lincomycin inhibits T. gondii at a higher 50% inhibitory concentration, about 100 ng/ml. The clindamycin-resistant mutant is partially cross-resistant to lincomycin.
Toxoplasma gondii is an obligatory intracellular parasitic protozoan transmitted via the ingestion of raw, infected meat that causes congenital infections. In a cell-free environment, virulent Toxoplasma was strikingly resistant to H2O2. The activity of H2O2 or H2O2 generated by glucose-glucose oxidase against the resistant tachyzoite stage of pathogenic T. gondii was enhanced by adding KI and bovine lactoperoxidase (bLPO), referred to here as the bLPO system. Replacing bLPO (heme content, 90%) with recombinant bLPO (heme content, 6%) did not enhance the parasiticidal activity with KI and H2O2. These results indicated that heme contributed to the enzyme activity and resulted in the killing of tachyzoites of T. gondii. Tachyzoites treated with the bLPO system also lost the ability to penetrate the mouse fibroblast cell line (NIH/3T3), and could be killed intracellularly after exposure by bLPO to a mouse macrophage cell line (J774A.1). These findings suggested that toxicity was mediated through small amounts of H2O2 generated by phagocytic events in naive macrophages, and by the peroxidative activity of bLPO. Our observations suggest that the bLPO system could help prevent the development of Toxoplasmosis in humans after ingesting raw, infected meat.
Residues of veterinary parasiticides in dung of treated livestock have nontarget effects on dung-breeding insects and dung degradation. Here, we review the nature and extent of these effects, examine the potential risks associated with different classes of chemicals, and describe how greater awareness of these nontarget effects has resulted in regulatory changes in the registration of veterinary products.
The present review is restricted to the collation and evaluation of information describing the excretion profile and ecotoxicity of veterinary medicines developed specifically for the control of either internal or external parasites of livestock. It identifies numerous gaps in our knowledge and highlights our poor understanding of the environmental fate of many of these chemicals, especially those developed for the control of ticks, lice, and/or biting flies. Residues of most anthelmintics are largely harmless to dung-feeding arthropods, but those of many ectoparasiticides, especially the synthetic pyrethroids, are highly toxic to fly larvae and adult dung beetles. Organophosphates, because they are metabolized extensively and eliminated mostly in urine, are considered to be unlikely to have a major impact on the development or survival of dung-dwelling organisms. The present review stresses the need for better information regarding spatial and temporal usage patterns of veterinary parasiticides, and it examines the role of ecotoxicological models for evaluating their impact on populations of dung-dependent arthropods.
Schistosomula were recovered from the skin of mice following primary infections. On the surface of such "infecting schistosomula", mouse C3 could not be detected by immunofluorescence. Subsequent incubation in vitro with fresh mouse serum led to the effective deposition of mouse C3 on schistosomula only when they were recovered within a few hours but not after one or two days following infection. In vitro deposited murine C3c was lost from i.v. injected schistosomula in the mouse circulation within one day as was human C3c. Infecting schistosomula exhibited a close to complete resistance to the lytic in vitro activity of human complement. This resistance was complete in older parasites. It existed in spite of the presence of parasite-bound human C9, which was detectable on all developmental stages of schistosomes following incubation in fresh, but not inactivated human serum. Lung schistosomula, 3-week and 6-week-old schistosomes were resistant to cellular cytotoxicity upon incubation with fresh human serum and rat peritoneal exudate cells although cell adherence mediated by human C3b was demonstrated with lung worms. The data suggest that schistosomula may evade in vivo the lytic activity of complement and also complement-mediated cellular cytotoxicity. Depending on the species of serum, this can be demonstrated in vitro by lack of opsonization or by resistance to lytic and cellular attack mechanisms.
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In vitro and in vivo efficacy data indicate that chemical activity is optimized at the 2 carbon chain length and that these compounds have injectable potency and spectrum of activity against major animal external parasite species.
To evaluate whether pregnancy has a synergetic effect on the host's immune response against Trichinella spiralis infection, immunological and parasitological parameters relating to the infection were assessed in pregnant rats and compared to those observed in virgin infected rats. The muscle parasite load was lower in pregnant infected rats but no differences were found in the intestinal worm burdens or the fecundity of female worms. The ability of sera to mediate death in newborn larvae (NBL) in an antibody-dependent cell cytotoxicity assay was higher for pregnant rats, even in the absence of specific anti-NBL antibodies. High levels of total and anti-NBL IgE were found in both groups, however, these levels were higher in the group of pregnant infected animals. No differences were found in anti-NBL IgGAM titers, nevertheless in some pregnant infected rats these antibodies were found earlier. No differences were found in peritoneal or blood eosinophil counts. Offspring born to infected dams were found to be infected. The results obtained in this model demonstrate that during pregnancy there is an enhanced helminthotoxic effect towards the NBL. Despite this immunoactivation, vertical transmission of the parasite is possible.