Overview of results from the WaterTox intercalibration and environmental testing phase II program: Part 1, statistical analysis of blind sample testing.

There is an urgent need to evaluate the presence of toxicants in waters used for human consumption and to develop strategies to reduce and prevent their contamination. The International Development Research Centre undertook an intercalibration project to develop and validate a battery of bioassays for toxicity testing of water samples. The project was carried out in two phases by research institutions from eight countries that formed the WaterTox network. Results for the first phase were reported in the special September 2000 issue of Environmental Toxicology. Phase II involved toxicity screening tests of environmental and blind samples (chemical solutions of unknown composition to participating laboratories) using the following battery: Daphnia magna, Hydra attenuata, seed root inhibition with Lactuca sativa, and Selenastrum capricornutum. This battery was also used to assess potential toxicity in concentrated (10x) water samples. Results are presented for a set of six blind samples sent to the participating laboratories over a 1-year period. Analyses were performed for each bioassay to evaluate variations among laboratories of responses to negative controls, violations of test quality control criteria, false positive responses induced by sample concentration, and variability within and between labs of responses to toxic samples. Analyses of the data from all bioassays and labs provided comparisons of false positive rates (based on blind negative samples), test sensitivities to a metal or organic toxicant, and interlaboratory test variability. Results indicate that the battery was reliable in detecting toxicity when present. However, some false positives were identified with a concentrated soft-water sample and with the Lactuca and Hydra (sublethal end-point) tests. Probabilities of detecting false positives for individual and combined toxic responses of the four bioassays are presented. Overall, interlaboratory comparisons indicate a good reliability of the battery.

Overview of results from the WaterTox intercalibration and environmental testing phase II program: part 2, ecotoxicological evaluation of drinking water supplies.

Because of rapid population growth, industrial development, and intensified agricultural production increasing amounts of chemicals are being released into the environment, polluting receiving water bodies around the world. Given the potential health risk associated with the presence of toxicants in water sources used for drinking yet the scarcity of available data, there is a need to evaluate these waters and develop strategies to reduce and prevent their contamination. The present study examined the applicability of a battery of simple, inexpensive bioassays in environmental management and the relevance of the test results in establishing the toxicological quality of water sources and drinking water within the framework of the eight-country WaterTox Network, sponsored by the International Development Research Centre, Ottawa, Canada. Seventy-six samples were collected from surface and groundwater sources and seven samples from drinking water treatment plants. Each sample was tested with a core battery of bioassays (Daphnia magna, Hydra attenuata, and Lactuca sativa root inhibition tests) and a limited set of physical and chemical parameters. In addition, three labs included the Selenastrum capricornutum test. When no toxic effects were found with the battery, samples were concentrated 10x using a solid-phase extraction (SPE) procedure. Nonconcentrated natural water samples produced a toxic response in 24% of cases with all three core bioassays. When all bioassays are considered, the percentage of raw samples showing toxicity with at least one bioassay increased to 60%. Of seven treated drinkingwater samples, four showed toxicity with at least one bioassay, raising the possibility that treatment processes in these instances were unable to remove toxic contaminants. The Daphnia magna and Hydra attenuata tests indicated a high level of sensitivity overall. Although only three of the eight countries used S. capricornutum, it proved to be an efficient and reliable bioassay for toxicity assessment.

Microwave assisted synthesis of N-arylphthalamic acids with hyperlipidemic activity.

A series of substituted N-arylphthalamic acids 3a-i has been synthesized by the reaction of phthalic anhydride 1 and aryl- or heterocyclic amines 2a-i, in the absence of solvents, in a domestic microwave oven. The formation of nine N-arylphthalamic acids was accomplished in 1-3 min giving excellent yields for compounds 3a-g, but moderate yield of compounds 3h and 3i, respectively. Compounds 3h and 3i are new. Interestingly, N-arylphthalamic acids 3a-i induced hyperlipidemia in Swiss white mice and also increased animals' body weight.

Synthesis and hypolipidemic activity of N-phthalimidomethyl tetra-O-acyl-alpha-D-mannopyranosides.

A facile synthesis of anomerically pure phthalimidomethyl 2,3,4,6-tetra-O-acetyl- and phthalimidomethyl 2,3-di-O-acetyl-4,6-di-O-benzoyl-alpha-D-mannopyranosides (6 and 9b) starting from N-hydroxymethylphthalimide and tri-O-acetyl-D-glucal is described. Compounds 3, 6, 8, 9a and 9b have been tested for their hypolipidemic activity in mice. All these compound showed significant reduction of plasma cholesterol and triglyceride levels. Compound 9b has been found to possess the highest activity.

Synthesis, anti-inflammatory and antimicrobial activities of new 1,2,4-oxadiazoles peptidomimetics.

A new series of 1,2,4-oxadizoles 6a-g have been synthesised in good yields using the peptide synthesis strategy. The prepared compounds were tested for anti-inflammatory and antimicrobial activities. The anti-inflammatory activities were determined in the rat paw oedema induced by carrageenin. Compounds 6a, c, f and g (i.v.) significantly inhibited the rat paw oedema induced by carrageenin depending upon the dose employed. The compounds were also evaluated for their in vitro antimicrobial activity. Some compounds were found to have significant activity against Gram positive and Gram negative microorganisms.

New phthalimide derivatives with potent analgesic activity: II.

Seven new phthalimide derivatives (9a-g) with 1,2,4-oxadiazol-5-yl methyl group attached to nitrogen have been synthesized from N-phthaloylglycine 6 and arylamidoximes 7a-g. All of these showed potent analgesic effect with acetic acid induced "writhing" test in mice. One of the better compounds (ID50 = 2.2 mg/Kg i.p.) has been found to be 9a which also demonstrates analgesic activity against inflammatory pain.

Paediatric nephrology in countries with limited resources.

This paper summarises a symposium concerned with the provision of care for children with kidney disease in developing countries. Better organisation of services is required to prevent waste of resources, with the emphasis on team work between professionals, shared care with local health care personnel remote from the paediatric nephrology unit and good communications. Families need to be educated and provided with appropriate information so that they can care for their child at home. Technology should be simple and robust and the staff using it should be fully trained to maintain it in use. Therapies should be definitive where possible, because long-term supervision of treatment is often difficult. Effective but inexpensive medications should be used where possible. Twinning of developing and richer countries is valuable to transfer technology, help with training and assist in care through the development of personal contacts.

Analgesic and anti-inflammatory effects of 3-[3-(phenyl)-1,2,4-oxadiazol-5-yl] propionic acid.

Significant local analgesic and anti-inflammatory activity has been observed after oral administration of 3-[3-(phenyl)-1,2,4-oxadiazol-5-yl] propionic acid (POPA). Doses of 150 and 300 mg/kg body weight administered orally by gavage to adult (25-35 g) albino mice of both sexes can inhibit acetic acid-induced writhing by 31.0% and 49.5%, respectively (mean +/- SEM writhing numbers during 20 min were 52.0 +/- 6.0 and 38.3 +/- 7.2 vs 75.8 +/- 6.6 for control group which received saline; N = 6). Carrageenin-induced inflammation in the female Wistar rat (200-250 g) can be reduced by 43.3% and 42.2% 3 h after oral administration (gavage) of 75 and 150 mg/kg of POPA (mean +/- SEM, 30.0 +/- 1.3% and 30.6 +/- 2.4% vs 52.9 +/- 3.7% for control group which received saline; N = 5). In the hot plate test on adult albino mice (25-35 g) of both sexes, POPA (150 and 300 mg/kg, po) was totally ineffective (N = 10). Our results indicate that POPA appears to offer potential safety and efficacy as a local analgesic and anti-inflammatory agent with no central nervous system involvement

Analgesic and anti-inflammatory effects of 3-3-(phenyl)-1, 2, 4-oxadiazol-5-yl propionic acid

Significant local analgesic and anti-inflammatory activity has been observed after oral administration of 3-[3-(phenyl)-1,2,4-oxadiazol-5-yl] propionic acid (POPA). Doses of 150 and 300 mg/kg body weight administered orally by gavage to adult (25-35 g) albino mice of both sexes can inhibit acetic acid-induced writhing by 31.0 and 49.5, respectively (mean +/- SEM writhing numbers during 20 min were 52.0 +/- 6.0 and 38.3 +/- 7.2 vs 75.8 +/- 6.6 for control group which received saline; N = 6). Carrageenin-induced inflammation in the female Wistar rat (200-250 g) can be reduced by 43.3 and 42.2 3 h after oral administration (gavage) of 75 and 150 mg/kg of POPA (mean +/- SEM, 30.0 +/- 1.3 and 30.6 +/- 2.4 vs 52.9 +/- 3.7 for control group which received saline; N = 5). In the hot plate test on adult albino mice (25-35 g) of both sexes, POPA (150 and 300 mg/kg, po) was totally ineffective (N = 10). Our results indicate that POPA appears to offer potential safety and efficacy as a local analgesic and anti-inflammatory agent with no central nervous system involvement

Late resistance to corticosteroids in nephrotic syndrome.

Corticosteroid resistance appeared late in the course of relapsing nephrotic syndrome in 12 patients who previously had steroid-sensitive relapses for 0.8 to 13 years. In 11 patients, renal histology performed earlier in the course of the disease showed minimal change in eight, mesangial proliferative glomerulonephritis (MesPGN) in two, and focal segmental glomerulosclerosis (FSGS) in one. Renal biopsy in another patient and a repeat procedure in four of eight patients who initially showed minimal change was done after they had developed steroid resistance, and showed FSGS. Cyclophosphamide was given to 11 patients after they became steroid resistant, and induced remission in eight that continued for 1 to 2 years in two patients. The other six had relapses that were steroid sensitive, but three of them (two with FSGS and one with MesPGN) later became resistant to steroids as well as to cyclophosphamide. Of six patients with FSGS, four with initial or subsequent resistance to cyclophosphamide eventually developed renal insufficiency. The other two have remained in remission for 12 to 16 years; one of these did not receive cyclophosphamide. Our observations suggest that patients with late steroid resistance comprise a heterogeneous group; those with FSGS and resistance to cyclophosphamide therapy may have a poor outcome.