Efficacy of ivermectin against the bloodsucking insect, Rhodnius prolixus (Hemiptera, Triatominae)

Ivermectin (0.2 mg/kg body weight) caused a high mortality in nymphs and adults of Rhodnius prolixus following a single meal in mice sub-cutaneously injected with the drug. This effect was more evident in nymphs of 1st-and 2nd-instar than in older nymphs and adults. Third-instar nymphs presented a high mortality when fed on mice treated with ivermectin 24 and 48 hours previously, while mortality was significantly reduced in nymphs fed on mice treated 72 hours before. Surviving 3rd-instar nymphs did not molt. When adult females were fed once on mice treated for 24 hours with ivermectin there was a considerable reduction in egg production. This inhibition was not reversed by a second feeding on normal mice. We concluded that sub-lethal doses of ivermectin caused toxic effects interfering in the neuro-endocrine control of development and reproduction of this bloodsucking insect.

Thymulin: biochemistry, biology and therapeutical applications

Thymulin is a pharmacologically active metallononapeptide inducing the differentiation of T cells and enhancing several functions of the various T cell subsets in normal or partially thymus-deficient recipients. Its effect on suppressor T cells is, so far, the most remarkable and should be the first to find useful clinical applications. The peptide is a natural hormone, available in synthetic form. It is not toxic and one may foresee its clinical use as one of the major immunoregulatory agents in the near future.

Cell-matrix interactions in Schistosomal portal fibrosis: a dynamic event

In recent years, one of the most significant progress in the understanding of liver diseases was the demonstration that liver fibrosis is a dynamic process resulting from a balance between synthesis and degradation of several matrix components, collagen in particular. Thus, fibrosis has been found to be a very early event during liver diseases, be it of toxic, viral or parasitic origin, and to be spontaneously reversible, either partially or totally. In liver fibrosis cell matrix interactions are dependent on the existence of the many factors (sometimes acting in combination) which produce the same events at the cellular and molecular levels. These events are: (i) the recruitment of fiber-producing cells, (ii) their proliferation, (iii) the secretion of matrix constituents of the extracellular matrix, and (iv) the remodeling and degradation of the newly formed matrix. All these events represent, at least in principle, a target for a therapeutic intervention aimed at influencing the experimentally induced hepatic fibrosis. In this context, hepatosplenic schistosomiasis is of particular interest, being an immune cell-mediated granulomatous disease and a model of liver fibrosis allowing extensive studies in human and animals as well as providing original in vitro models.

Pharmacokinetic aspects of Tert-Butylaminoethyl disulfide, an experimental drug against schistosomiasis in mice

A preliminary study of the pharmacokinetic parameters of t-Butylaminoethyl disulfide was performed after administration of two different single doses (35 and 300 mg/kg) of either the cold or labelled drug. Plasma or blood samples were treated with dithiothreitol, perchloric acid, and, after filtration, submitted to further purification with anionic resein. In the final step, the drug was retained on a cationic resin column, eluted with NaCl 1M and detected according to the method of Ellman (1958). Alternatively, radioactive drug was detected by liquid scintillation counting. The results corresponding to the smaller dose of total drug suggested a pharmacokinetic behavior related to a one open compartment model with the following parameters: area under the intravenous curve (AUC i.v.):671 ± 14; AUC oral: 150 ± 40 µg.min. ml [raised to the power of -1]; elimination rate constant: 0.071 min [raised to the power of -1]; biological half life: 9.8 min; distribution volume: 0.74 ml/g. For the higher dose, the results seemed to obey a more complex undertermined model. Combining the results, the occurence of a dose-dependent pharmacokinetic behavior is suggested, the drug being rapidly absorbed and rapidly eliminated; the elimination process being related mainly to metabolization. The drug seems to be more toxic when administered I.V. because by this route it escapes first pass metabolism, while being quickly distributed to tissues. The maximum tolerated blood level seems to be around 16 µg/ml.

Bioactivity of neolignans from fructus Schizandrae

Fructus Schisandrae sinensis Baill, a traditional Chinese medicine, used as tonic and sedative, has been shown at the beginning of 70's to lower the elevated serum glutamic-pyruvic transaminase (SGPT) levels of patients suffering from chronic viral hepatitis. Durign past 20 years, a series of neolignans have been isolated and identified as effective principles. Pharmacological studies revealed that they increased liver protein and glicogen synthesis, antagonized liver injuries from CCl4 and thioacetamide. The mechanism of SGPT lowering was considered as a hepato-protective and membrane stabilize action, although inhibition of the activity of liver GPT may also be existed. It was found that some principles of Schisandrae have an inducing effect on hepatic microsomal drug-metabolizing enzynme system P-450, thus explained their anti-toxic, anti-carcinogenic and anti-mutagenic effects. A synthetic derivative compound of Schisandrin called DDB has most of the above mentioned actions now used widely in Chine as a hepato-protective drug with high effectiveness in normalizing liver functions and very low side effects. From Schisandrin to synthesized DDB, pointed out a successful way in the development of new drugs from natural products.

Toxicological and toxicogenetic effects of plants used in popular medicine and in cattle food

Toxicological and toxicogenetic effects of aqueous (tea) and hexanica fruit extract of Indigofera suffruticosa Mill, and hydroalcoholic root extract od Solanum agrarium Stendt. Were evaluated in Balb C male mice intraperitoneally exposed. A hepatotoxic effect was observed just for animals treated with aqueous fruit extract of I. suffruticosa. In relation to the toxicogenetic effect, just the group trreated with 12.5% of toxic dose of aqueous fruit extract of I. suffruticosa showed a statistically significant increase in the frequency of cells with chromosome aberrations (cytogenetic effect), although a slight increase was also observed for the highest dose (25% of LF50_ of hydroalcoholic root extract of S. agrarium. The results obtanied show that before S. agrarium is used as medicine and before the wide use of I. suffruticosa in cattle food, careful evaluation must be done.

Enterolobin induces rat paw oedema independently of PAF-acether

The potential participation of PAF-acether (PAF) on the paw oedema triggered by enterolobin was investigated. Intraplantar injections of enterolobin )5-20 µg/paw) yielded a dose response curve for edema which appeared after 30 min, peaked in the interval between 2-4 h and faded after 24h. The pre-treatment with BN 52021, but not with other PAF antagonists such as PCA 4248 or WEB 2086, significantly blocked enterolobin-induced oedema. To clarify better the discrepant results obtained with the PAF antagonists, desensitization to PAF was performed. The oedema triggered by enterolobin was not modified in paf desensitized animals. It was concluded that the paw inflammation induced by enterolobin does not require PAF mechanism.

Sulphate-reducing bacteria associated with biocorrosion: a review

Biocorrosion means any process of corrosion in wich microorganisms are somehow involved. As far as the petroleum industry is concerned, the anaerobic type is the more important, with Sulphate-Reducing Bacteria (SRB) accouting for half of the described processes. SRB are obligate anaerobs that use sulphur, sulphate or other oxidized sulphur compounds as oxidizing agents when decomposing organic material. A typical product of SRB metabolism, hydrogen sulphide -H2S-, is extremely toxic. In the present work we review the literature on mechanisms underlying biocorrosive process in wich SRB are involved and summarize some of the ultrastructural and eletrochemical work developed using SRB obtained from water injection flow in wells located on PETROBRAS offshore marine plataforms, sampled directly in the field over metallic probes, or cultured under laboratory conditions. Biofilms develop when SRB adhere to inert surfaces. A high diversity of morphological types is found inside these biofilms. Their extracellular matrix is highly hydrated and mainly anionic, as shown by its avid reaction with cationic compounds like ruthenium red. We have noted that variations in iron contet lead to interesting changes in the ultrastructure of the bacterial cell coat and also in the rate of corrosion induced in metallic test cupons. Since routine methods to prevent and treat SRB contamination and biodeterioration involve the use of biocides that are toxic and always have some environmental impact, an accurate diagnosis of biocorrosion is always required prior to a treatment decision. We developed a method that detects and semi-quantifies the presence of living or dead SRB by using free silver potentials as an indicator of corrosive action by SRB-associated sulphides. We found a correlation between sulphide levels (determined either by spectrophotometry, or using a silver electrode -E(Ag)- that measured changes in free potentials induced by the presence of exogeneously added sulphide) and SRB concentration (enumerated by a culturing method). E (Ag) was characterized under a variety of conditions andwas found to be relatively immune to possible interference resulting from aeration of media or from the psence of iron corrosion products. The method offers a simple, rapid, and effective means of diagnosing biocorrosive processes prior to their control.

Evaluation of some organic compounds on bloodstream forms of Trypanosoma cruzi

Accidental transmission of Chagas' disease to man by blood transfusion is a serious problem in Latin-America. This paper describes the testing of several synthetic, semi-synthetic, and natural compounds for their activity against blood trypomastigotes in vitro at 4-C. The compounds embody several types of chemical structures: benzoquinone, naphthoquinone, anthracenequinone, phenanthrenequinone, imidazole, piperazine, quinoline, xanthene, and simple benzenic and naphthalenic derivates. Some of them are for the first time tested against Trypanosoma cruzi. The toxic effect these compounds on this parasite was done by two quite distinct sets of experiments. In one set, the compounds were added to infected blood as ethanolic solution. In this situation the most active one was a furan-1, 2-naphthoquinone, in the same range as gentian violet, a new fact to be considered in the assessment of structure-activity relationships in this class of compounds. In other set, we tentatively evaluated the biological activity of water insoluble compounds by adding them in a pure form without solvent into infected blood. In this way some appear to be very active and it was postulated that the effectiveness of such compounds must result from interactions between them and specific blood components.

Partial isolation and some properties of enterotoxin produced by Bacillus cereus strains

Extracellular proteins produced by Bacillus cereus AL-42 and AL-15 were fractioned by chromatography on QAE-Sephadex and Sephadex G75. This last chromatographic process resulted in three peaks. The major peak showed vascular permeability activity to rabbits, lethality to mice, and cytotoxicity to Vero and Hela cells. The analysis by SDS-PAGE after ultrafiltration confirm recent findings that the enterotoxin is a compound with molecular mass > 30.000.

On the safe of pesticides in controlling the terrestrial mollusc pests

The preferred food items of the slugs Laevicaulis alte and the snails Achatina fulica were used to prepare 'poison baits'by injecting the pesticides 'Rogor'and 'Nuvan'to kill these mollusc pests. The 'poison baits'prepared with Thrichosanthes dioica and Lycopersicum esculentum were accepted by 100% individuals of both the species irrespective of the pesticides used. In all cases the slug and the snail individuals died within a considerable length of time following consuption of the bait. The importance of using 'poison bait'lies not only with the sure success in killing the pests but also with the 'safe use'of toxic materials in order to avoid environmental hazards.

Thevetia peruviana (Family: Apocynaceae) in the control of slug and snail pests

An aqueous extract prepared from Kernels of the fruit of Thevetia peruviana (Pers.) Schumann (Family : Apocynaceae) was found under experimental conditions, to be toxic ti the slug Laevicaulis alte (Férussac) and the snail Achatina fulica Bowdich, the important agrihorticultural pests of Indo-Pacific countries. Concentrations as low as 1% (w/v) killed all the slugs exposed in less than 981.00 (± SD 22.76) min, and 2% of the extract killed 100% of the slugs L. alte and 50%, 50% and 30% of the snail A. fulica in between 92.34 (± SD 6.63) - 321.33 (± SD 4.14) and 271.20 (± SD 17.54) - 298.26 (± SD 16.69) min respectively. The most effective concentration of the extract was 20%; it killed 100% of exposed slugs and snails within a short time (40-50 and 90-1440 min respectively) when the extract was exposed on the soil in experimental trays or when it was applied to potato slices offered as food to the gastropods.

Schistosomicidal activity of alkylaminooctanethiosulfuric acids

The schistosomicidal activity of a new series of alkylaminooctanethiosulfuric acids was studied in white Swiss mice infected with the L.E. strain of Schistosoma mansoni (Belo Horizonte, MG, Brazil). In a preliminary screening of six compounds, two derivatives - 2-[(1-methylpropyl)amino]-1-octanethiosulfuric acid and 2-[(1-methylethyl)-amino]-1-octanethiosulfuric acid - given orally in doses of 300 mg/kg/day for five consecutive days, caused interruption of the oviposition and the hepatic shift of more than 90 of the worms. Both compounds caused a significant reduction in worm burden and, interestingly, the female schistosomes were more susceptible. With the therapeutic schedule of two doses of 800 mg/kg over a 20 day interval, the death of almost all the females and about 50 of the males was observed. Female worms recovered from treated mice showed scattered vitteline glands. Results of in vitro experiments against different developmental stages of the parasite revealed the induction of paralysis and damage to the tegument membrane. The drugs presented no toxic effects on the animals.

Infected erythrocyte choline carrier inhibitors: exploring some potentialities inside Plasmodium phospholipid metabolism for eventual resistance acquisition

We have developed a model for designing antimalarial drugs based on interference with an essential metabolism developed by Plasmodium during its intraerythrocytic cycle, phospholipid (PL) metabolism. The most promising drug interference is choline transporter blockage, which provides Plasmodium with a supply of precursor for synthesis of phosphatidylcholine (PC), the major PL of infected erythrocytes. Choline entry is a limiting step in this metabolic pathway and occurs by a facilitated-diffusion system involving an asymmetric carrier operating according to a cyclic model. Choline transport in the erythrocytes is not sodium dependent nor stereospecific as demonstrated using stereoisomers of alpha and beta methylcholine. These last two characteristics along with distinct effects of nitrogen substitution on transport rate demonstrate that choline transport in the infected erythrocyte possesses characteristics quite distinct from that of the nervous system. This indicates a possible discrimination between the antimalarial activity (inhibition of choline transport in the infected erythrocyte) and a possible toxic effect through inhibition of choline entry in synaptosomes. Apart from the de novo pathway of choline, PC can be synthesized by N-methylation from phosphatidylethanolamine (PE). There is a de novo pathway for PE biosynthesis from ethanolamine in infected cells but phosphatidylserine (PS) decarboxylation also occurs. In addition, PE can be directly and abundantly synthesized from serine decarboxylation into ethanolamine, a pathway which is absent from the host. The variety of the pathways that exist for the biosynthesis of one given PL led us to investigate whether an equilibrium can occur between all PL metabolic pathways. Indeed, if alternative (compensative) pathway(s) can operate after blockage of the de novo PC biosynthesis pathway this would indicate a potential mechanism for resistance acquisition. Up until now, there is no evidence of such a compensative process occurring in Plasmodium-infected erythrocytes under physiological conditions. Besides, the discovery of a highly parasite-specific pathway (serine decarboxylation and the presence of PS synthase) constitutes a very attractive and promising target, which could be attacked if resistances are built up against choline analogs. Indeed, potential inhibitions of the serine decarboxylase pathway could be very useful in acting instead of, or in surgery with, choline analogs.

Biochemistry and mode of action of the Bacillus sphaericus toxins

Bacillus sphaericus produces at least two toxins which are highly toxic to mosquito larvae. The binary toxin, which is comprised of proteins of 51.4 and 41.9 kDa, is present in all highly insecticidal strains. The 100 kDa SSII-1 toxin is present in most highly insecticidal as well as the weakly insecticidal strains. The current status of studies on biochemistry and mode of action of these toxins is reviewed.