Toxicological in vitro and subchronic evaluation of LASSBio-596.

LASSBio-596, 2-[4-(1,4-tiazinan-4-ylsulfonyl) phenylcarbamoyl] benzoic acid, is an achiral compound containing a subunit carboxylic amide, was capable of preventing induced mechanical and morphological changes in the lungs that commonly caused the onset of asthma. Previous studies to determine the acute toxicity of oral LASSBio-596 at dose of 2000mg/kg caused no deaths in any of the tested animals. To further evaluate the safety of LASSBio-596, in vitro and in vivo tests were carried out. Regarding to in vitro test were used renal, hepatic, pulmonary, cardiac, neurologic and intestinal cell lines. They were evaluated using neutral red (NR) and [3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] (MTT) assays. Micronuclei also was performed. Concerning to in vivo was performed subchronic on Wistar rats at doses of 10, 50, and 250mg/kg and zebrafish test. The in vitro tests results showed the safety of LASSBio-596. However, subchronic toxicity study results revealed changes in the blood parameters of amylase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), glucose and creatine kinase (CK) which is used for cardiotoxicity evaluation, although, did not identify any histopathological alterations. However, zebrafish test demonstrated cardiac damage. It was impossible to estimate the no-observed-adverse-effect-levels and lowest observed-adverse-effect level due to the presence of cardiotoxicity in all tested doses.

Toxicological, toxicokinetic and gastroprotective evaluation of the benzaldehyde semicarbazone.

Benzaldehyde semicarbazone (BS) has presented positive results in several pharmacological models, including anticonvulsivant and anti-inflammatory models. The present study evaluated the preclinical toxicity (acute and subchronic), as well as the toxicokinetic and gastroprotective effects of BS against ethanol lesions. Oral doses of 300 and 2000mg/kg were used in the preclinical acute toxicity study; 100, 200, and 300mg/kg were used in both the subchronic toxicity evaluation and the gastric study; and 300mg/kg was used in the toxicokinetic study. No impact from the dose of 300mg/kg could be identified; while, one animal died at 2000mg/kg in the acute toxicity test. In the subchronic toxicity test, changes in the biochemical parameters of the liver, as well as in the histopatological evaluation, demonstrated that BS is a hepatotoxic drug. BS proved to be effective for moderate and severe gastric lesions. In the toxicokinetics study, BS presented a low concentration and rapid plasma disappearance. Several results also indicate that BS is likely to be mostly eliminated from the liver and may well undergo a first-pass effect after oral absorption. It was impossible to estimate the noobserved-adverse-effect-levels (NOAEL) and lowest-observed-adverse-effect-levels (LOAEL) due to the presence of hepatotoxicity in all tested doses.

Campomanesia lineatifolia Ruiz & Pav. as a gastroprotective agent.

ETHNOPHARMACOLOGICAL RELEVANCE: Campomanesia lineatifolia Ruiz and Pav. (Myrtaceae) is a native edible species found in the Amazon Rainforest, commonly known as gabiroba. In Brazil, Campomanesia species are frequently used in traditional medicine for gastrointestinal disorders. MATERIALS AND METHODS: The present study performed phytochemical analyses and determined both the in vitro antioxidant activity of the ethanolic extract of Campomanesia lineatifolia leaves (EEC) as well as its ethyl acetate fraction (EAFC). In this analysis, quercetin was used as a positive control. Gastroprotective activity was also investigated at different oral doses in two experimental models in rats - gastric lesion induced by ethanol and gastric lesion induced by indomethacin. In this analysis, cimetidine and sucralfate were used as positive controls. The area of gastric lesion underwent macroscopic and histomorphometric evaluations, while the mucus content was estimated by applying the periodic acid-Schiff stain. Oral acute toxicity was also assessed. RESULTS: Phytochemical studies revealed the presence of flavonoids and tannins. Catechin and quercitrin were isolated by bioguided chromatographic fractionation of EAFC. EEC and EAFC presented in vitro antioxidant activity. The oral administration of EEC and EAFC at doses 100-400 mg/kg (ethanol model) and at doses of 400-1200 mg/kg (indomethacin model) proved to be effective in preventing gastric ulcerations in rats. Pretreatment with EAFC (400mg/kg) significantly increased the gastric mucus content in the ethanol model. No animals died during the acute oral toxicology test. CONCLUSIONS: Results confirm the Brazilian ethnopharmacological use of Campomanesia lineatifolia as a gastroprotective agent and indicate that the anti-ulcer effect is most likely mediated by scavenging free radicals due to the polyphenol content and, at least in part, by increasing the mucus secretion and the mucosal defense. In addition, EEC and EAFC were found to be safe when applied to a 2000 mg/kg single oral dose.