Genotoxic effect of Phenanthrene on Chironomus sancticaroli (Diptera: Chironomidae)

Phenanthrene, a Polycyclic Aromatic Hydrocarbon, remains adsorbed to sedimentary particles in aquatic environments. It affects mainly benthic organisms, and is considered potentially genotoxic. In ecotoxicology, species of Chironomus Meigen, 1803 are widely known as bioindicators of the effects of chemicals on aquatic organisms. This study investigates the effects of phenanthrene on the size of the head capsule of Chironomus sancticaroli Strixino & Strixino, 1981 larvae after chronic (eight days) exposure, and DNA damage after acute (96 hours) and chronic exposure (eight days), under laboratory conditions. DNA damage, evaluated using the alkaline comet assay, detected effects for both exposure periods, indicating that phenanthrene is toxic for C. sancticaroli. For the acute exposure, we analyzed five concentrations of phenanthrene, between 0.16 mg.l-1 and 1.60 mg.l-1, detecting significant differences (Kruskall-Wallis test with p 0.05) in the degree of DNA damage in all groups. These effects were not dose-dependent. For the chronic exposure, two concentrations (0.16 mg.l-1, 0.83 mg.l-1) were analyzed, and DNA damage was observed in both. Again, the effects were not dose-dependent. This indicates that phenanthrene is genotoxic to larvae of C. sancticaroli even at low concentrations. The size of the head capsule was evaluated after chronic exposure to concentrations of 0.16 mg.l-1 and 0.83 mg.l-1. Significant differences (ANOVA test with p 0.05) were detected in the two concentrations, and a reduction in the size of the larval head capsule was observed. This suggests that phenanthrene causes delay in larval development. These results indicate that phenanthrene affects the development of and causes DNA damage in C. sancticaroli larvae. Therefore, we suggest that C. sancticaroli can be used as a biological indicator for environmental contamination with phenanthrene.

Genotoxic effect of Phenanthrene on Chironomus sancticaroli (Diptera: Chironomidae)

Phenanthrene, a Polycyclic Aromatic Hydrocarbon, remains adsorbed to sedimentary particles in aquatic environments. It affects mainly benthic organisms, and is considered potentially genotoxic. In ecotoxicology, species of Chironomus Meigen, 1803 are widely known as bioindicators of the effects of chemicals on aquatic organisms. This study investigates the effects of phenanthrene on the size of the head capsule of Chironomus sancticaroli Strixino & Strixino, 1981 larvae after chronic (eight days) exposure, and DNA damage after acute (96 hours) and chronic exposure (eight days), under laboratory conditions. DNA damage, evaluated using the alkaline comet assay, detected effects for both exposure periods, indicating that phenanthrene is toxic for C. sancticaroli. For the acute exposure, we analyzed five concentrations of phenanthrene, between 0.16 mg.l-1 and 1.60 mg.l-1, detecting significant differences (Kruskall-Wallis test with p 0.05) in the degree of DNA damage in all groups. These effects were not dose-dependent. For the chronic exposure, two concentrations (0.16 mg.l-1, 0.83 mg.l-1) were analyzed, and DNA damage was observed in both. Again, the effects were not dose-dependent. This indicates that phenanthrene is genotoxic to larvae of C. sancticaroli even at low concentrations. The size of the head capsule was evaluated after chronic exposure to concentrations of 0.16 mg.l-1 and 0.83 mg.l-1. Significant differences (ANOVA test with p 0.05) were detected in the two concentrations, and a reduction in the size of the larval head capsule was observed. This suggests that phenanthrene causes delay in larval development. These results indicate that phenanthrene affects the development of and causes DNA damage in C. sancticaroli larvae. Therefore, we suggest that C. sancticaroli can be used as a biological indicator for environmental contamination with phenanthrene.(AU)

Cardiotoxicity reduction induced by halofantrine entrapped in nanocapsule devices.

The main objective of the present study was to evaluate the reduction in halofantrine (Hf) toxicity, an antimalarial drug frequently associated with QT interval prolongation in electrocardiogram, by its entrapment in poly-epsilon-caprolactone nanocapsules (NC). The acute lethal dose (LD(100)) of Hf.HCl experimentally observed was 200 mg/kg whereas the calculated LD(50) was 154 mg/kg. In contrast, the LD(100) for Hf-NC was 300 mg/kg with a longer mean time to death than Hf.HCl. The calculated LD(50) was 249 mg/kg for Hf-NC. The Hf entrapped in PCL NC presented a greater efficacy than PLA-PEG NC and than Hf solution in P. berghei-infected mice at 1 mg/kg. The cardiovascular parameters, ECG and arterial blood pressure, were evaluated in anaesthetized Wistar rats after the IV administration of a single, especially high dose (100 and 150 mg/kg) of halofantrine base loaded-nanocapsules (Hf-NC) or halofantrine chlorhydrate (Hf.HCl) solution. It was observed that Hf solution caused prolongation of the QT and PR intervals of the ECG; however, this effect was significantly (P<0.001) reduced when Hf was administered entrapped in nanocapsules. The treatment with Hf.HCl induced a pronounced bradycardia and severe hypotension leading to death. The effect of Hf-NC upon heart rate was reduced from 58 to 75% for 100 and 150 mg/kg, respectively, when compared with Hf.HCl solution. These findings show that the encapsulation of halofantrine reduces the QT interval prolongation of ECG in rats and suggest that a modification of drug distribution was possible by using nanocapsules. Hf encapsulation was the main factor responsible for the significant reduction in cardiac toxicity observed.

Discovery of anticonvulsant activity of abietic acid through application of linear discriminant analysis.

Linear discriminant analysis was performed to derive discriminant functions based on 2D descriptors and capable of classifying anticonvulsant from non-anticonvulsant compounds. Through application in virtual screening of the discriminant function which performed best in the validation steps, abietic acid was identified as a potential new anticonvulsant agent. The anticonvulsant activity of abietic acid at 30 and 100mg/kg was confirmed in the Maximal Electroshock Test, both orally and intraperitoneally.

Two new protopines argemexicaines A and B and the anti-HIV alkaloid 6-acetonyldihydrochelerythrine from formosan Argemone mexicana.

Two new protopine-type alkaloids, argemexicaine A (1) and argemexicaine B (2), along with thirteen known alkaloids, were isolated from MeOH extracts of Formosan Argemone mexicana L. (Papaveraceae). Physical and spectral analyses, particularly IR and thermo-modulated 1D and 2D NMR, were used to determine the transannular conformations of the isolated protopine-type alkaloids. The known benzo[ c]phenanthridine (+/-)-6-acetonyldihydrochelerythrine (5) exhibited significant anti-HIV activity in H9 lymphocytes with EC50 and TI (Therapeutic Index) values of 1.77 microg/mL and 14.6, respectively.

Antimalarial drug susceptibility testing of Plasmodium falciparum in Brazil using a radioisotope method

From March 1996 to August 1997, a study was carried out in a malaria endemic area of the Brazilian Amazon region. In vivo sensitivity evaluation to antimalarial drugs was performed in 129 patients. Blood samples (0.5 ml) were drawn from each patient and cryopreserved to proceed to in vitro studies. In vitro sensitivity evaluation performed using a radioisotope method was carried out with the cryopreserved samples from September to December 1997. Thirty-one samples were tested for chloroquine, mefloquine, halofantrine, quinine, arteether and atovaquone. Resistance was evidenced in 96.6 percent (29/30) of the samples tested for chloroquine, 3.3 percent (1/30) for quinine, none (0/30) for mefloquine and none for halofantrine (0/30). Overall low sensitivity was evidenced in 10 percent of the samples tested for quinine, 22.5 percent tested for halofantrine and in 20 percent tested for mefloquine. Means of IC 50 values were 132.2 (SD: 46.5) ng/ml for chloroquine, 130.6 (SD: 49.6) ng/ml for quinine, 3.4 (SD: 1.3) ng/ml for mefloquine, 0.7 (SD: 0.3) ng/ml for halofantrine, 1 (SD: 0.6) ng/ml for arteether and 0.4 (SD: 0.2) ng/ml for atovaquone. Means of chloroquine IC 50 of the tested samples were comparable to that of the chloroquine-resistant strain W2 (137.57 ng/ml) and nearly nine times higher than that of the chloroquine-sensitive strain D6 (15.09 ng/ml). Means of quinine IC 50 of the tested samples were 1.7 times higher than that of the low sensitivity strain W2 (74.84 ng/ml) and nearly five times higher than that of the quinine-sensitive strain D6 (27.53 ng/ml). These results disclose in vitro high resistance levels to chloroquine, low sensitivity to quinine and evidence of decreasing sensitivity to mefloquine and halofantrine in the area under evaluation

A clinical trial with halofantrine on patients with falciparum malaria in Colombia.

A total of 120 semi-immune adult male malaria patients from an area of multidrug-resistant Plasmodium falciparum malaria were hospitalized for 42 days in Medellin, Colombia (an area of no malaria transmission), and treated with halofantrine in a double-blind, randomized, prospective clinical trial according to five different treatment schedules. Each patient was assigned to one of the following halofantrine schedules: I, one dose of 1000 mg; II, three doses of 500 mg; III, two doses of 500 mg; IV, three doses of 250 mg; and V, one dose of 750 mg. Best results (75% cure rate) were obtained with schedule II, although there was no statistically significant difference compared with the other schedules. A total of 46 patients experienced recrudescent malaria. Drug levels in plasma 72 hours after beginning treatment showed no statistically significant difference between relapsing and cured patients. Side-effects (mainly gastrointestinal) were uncommon and mild. Cardiotoxicity was studied by electrocardiogram. A mean prolongation of 28.5 ms (6.6 +/- 6.3% increase from baseline) was observed in the Q-Tc interval on day 1 of the trial.

Halofantrine uma nova opçäo terapêutica na malária / Halofantrine: a new therapeutic option in malaria

Os AA. referem o resultado do tratamento da malária falciparum, da malária vivax e da malária mista com o uso do halofantrine em esquema de dois dias de administraçäo da droga, com intervalo de cinco a sete dias entre cada um dos esquemas. Controles parasitológicos negativos foram observados em 96,6 por cento dos casos entre o 5§ e o 7§ dias pós-tratamento inicial, em 100 por cento dos casos no 14§ dia e em 84,5 por cento dos casos no 30§ dia de observaçäo. A droga mostrou-se de excelente tolerabilidade, alta praticidade de administraçäo, näo tendo sido observados efeitos colaterais no grupo controle

The treatment of falciparum malaria in children with halofantrine suspension.

Malaria treatment of children is particularly difficult because of the absence of palatable suspensions for young children. Halofantrine hydrochloride is available as a suspension which is both palatable and simple to administer, and has been studied in a number of trials in the past 5 years. Children (331) ranging from 4 months to 17 years of age (mean 4.7 years) were treated with the 5% suspension using various dose regimens and 364 children ranging from 4 months to 14 years of age (mean 5.7 years) were treated with the 2% suspension 6 hourly for 3 doses. Using the 3-dose regimen there were only 2/462 (0.4%) who failed to clear the initial parasitaemia. Recrudescence occurred in 28/367 (7.6%) children with evaluable follow up data. The mean parasite clearance time in this group was 57.1 h (n = 417) and the mean fever clearance time was 50.9 h (n = 325). Symptoms related to malaria cleared rapidly following treatment generally by 24-48 h post treatment. Side effects possibly related to treatment were uncommon but were similar to those reported in adults. The frequency of diarrhoea and abdominal pain was lower than that seen in adults and was also less frequent following multiple doses and the use of the more dilute suspension. Since there was evidence that the majority of recrudescences were seen in younger children or those living in areas with low or seasonal transmission it is recommended that a further course of treatment 7 days later is given to these patients to prevent recrudescence.(ABSTRACT TRUNCATED AT 250 WORDS)