Alice V. Araújo

Acute and subacute toxicity of the Carapa guianensis Aublet (Meliaceae) seed oil.

Carapa guianensis (Meliaceae), known as Andiroba in Brazil, has been used by Amazon Rainforest indigenous communities for treatment of coughs, convulsions, skin diseases, arthritis, rheumatism, ear infections, to heal wounds and bruises and as an insect repellent. Carapa guianensis seed oil (SO) was evaluated for its acute and subacute toxicity (30 days) by the oral route in Wistar rats. In the acute toxicity test, SO (0.625-5.0g/kg, n=5/sex) did not produce any hazardous symptoms or deaths. The subacute treatment with SO (0.375, 0.75 and 1.5g/kg, n=10/group) failed to change body weight gain, food and water consumption. Hematological analysis showed no significant differences in any of the parameters examined. However, in the biochemical parameters, there was an increase in the alanine aminotransferase (ALT) serum level (29%) in the group SO 1.5g/kg. In addition, absolute and relative liver weights were increased at the doses of 0.75g/kg (23.4 and 19.1%) and 1.5g/kg (18.7 and 33.1%). In conclusion, acute and subacute administration of Carapa guianensis seed oil did not produce toxic effects in male Wistar rats. However, the increase in the ALT serum level and in both absolute and relative liver weights may indicate a possible hepatic toxicity.

Gastroprotective Mechanisms of the Monoterpene 1,8-Cineole (Eucalyptol).

Recently, our research group identified and reported 1,8-cineole (CIN), a monoterpene that naturally occur in many aromatic plants, as one of the major constituent of the essential oil from leaves of Hyptis martiusii (EOHM), as well as characterized the gastroprotective action of this oil. The aim of this study was to investigate the mechanisms of action involved in the antiulcer and healing activity of CIN, in order to confirm its correlation with the gastroprotective effect of EOHM. Wistar rats were exposed to different protocols (acute ulceration, gastrointestinal motility and antisecretory activity). In addition, were determinated the involvement of nitric oxide and sulphydryl groups; the levels of gastric mucus, lipid peroxidation, sulphydryl groups and myeloperoxidase activity. The healing ability was evaluated by acetic acid-induced chronic ulcer and histological and immunohistochemical analysis (PCNA, Ki-67 and BrdU). The treatment with CIN inhibited ethanol-, ethanol/HCl- and indomethacin-induced gastric lesions. The highest doses of CIN inhibited gastric emptying, but did not affect intestinal transit. CIN (100 mg/kg) reduced the volume of basal but not stimulated acid secretion. CIN increased levels of mucus (89.3%), prevented depletion of –SH groups (62.6%) and reduced the level of lipid peroxidation (55.3%) and myeloperoxidase activity (59.4%) in the gastric mucosa. In chronic ulcer model, CIN reduced in 43.1% the gastric area lesion, promoted significant regeneration and restoration of the levels of mucus in glandular cells as confirmed by histological analysis; and promoted increase in cell proliferation as evidenced by reactivity for PCNA, Ki-67 and BrdU. This findings demonstrate the role of 1,8-cineole as an important ulcer healing agent and indicate the involvement of antioxidant and cytoprotective mechanisms in the gastroprotective effect of compound. This study also provides evidence that 1,8-cineole is related to the gastroprotective effect of the essential oil of Hyptis martiusii.

Gastroprotective and ulcer healing effects of essential oil of Hyptis martiusii Benth. (Lamiaceae).

Hyptis martiusii Benth. is an aromatic plant found in abundance in northeastern Brazil that is used in ethnomedicine to treat gastric disorders. The aim of this study was to elucidate the mechanisms of action involved in the gastroprotection of the essential oil of Hyptis martiusii (EOHM) and to evaluate its healing capacity. Wistar rats were exposed to different protocols and subsequently were treated with 1% Tween-80 aqueous solution (negative control), pantoprazole, carbenoxolone, N-acetylcysteine (depending on the specificity of each model) or EOHM. The antisecretory activity (basal or stimulated) was determined using the pyloric ligature method. The gastroprotective action of nitric oxide and sulphydryl groups (–SH groups), as well as the quantification of adherent mucus and the levels of malondialdehyde and –SH groups in gastric mucosa, were evaluated using ethanol-induced gastric ulcer model. The healing ability was evaluated using the acetic acid-induced gastric ulcer model and histological and immunohistochemical analysis (HE, PAS and PCNA). EOHM (400 mg/kg) reduced the volume and acidity of gastric secretion stimulated by histamine and pentagastrin. The gastroprotective effect of EOHM involves the participation of endogenous sulfhydryl groups. EOHM increased mucus production (54.8%), reduced levels of MDA (72.5%) and prevented the depletion of –SH groups (73.8%) in the gastric mucosa. The treatment with EOHM reduced in 70.3% the gastric lesion area, promoting significant regeneration of the gastric mucosa, as confirmed by histological analysis and analysis of proliferating cell nuclear antigen. The results show that gastroprotective effect of EOHM is mediated by cytoprotective and antioxidant mechanisms and by their antisecretory activity, and suggest that the essential oil of Hyptis martiusii is a promising candidate for the treatment of gastric ulcers.

Hepatoprotective Effect of the Aqueous Extract of Simarouba amara Aublet (Simaroubaceae) Stem Bark against Carbon Tetrachloride (CCl4)-Induced Hepatic Damage in Rats

Simarouba amara stem bark decoction has been traditionally used in Brazil to treat malaria, inflammation, fever, abdominal pain, diarrhea, wounds and as a tonic. In this study, we investigate the hepatoprotective effects of the aqueous extract of S. amara stem bark (SAAE) on CCl4-induced hepatic damage in rats. SAAE was evaluated by high performance liquid chromatography. The animals were divided into six groups (n = 6/group). Groups I (vehicle—corn oil), II (control-CCl4), III, IV, V and VI were pretreated during 10 consecutive days, once a day p.o, with Legalon® 50 mg/kg b.w, SAAE at doses 100, 250 and 500 mg/kg b.w, respectively. The hepatotoxicity was induced on 11th day with 2 mL/kg of 20% CCl4 solution. 24 h after injury, the blood samples were collected and their livers were removed to biochemical and immunohistochemical analyzes. The SAAE decreased the levels of liver markers and lipid peroxidation in all doses and increased the catalase levels at doses 250 and 500 mg/kg. Immunohistochemical results suggested hepatocyte proliferation in all doses. These results may be related to catechins present in SAAE. Thus, SAAE prevented the oxidative damage at the same time that increased regenerative and reparative capacities of the liver.

Acute toxicity and laxative activity of Aloe ferox resin

Aloe ferox Mill., Xanthorrhoeaceae, resin is the solid residue obtained by evaporating the latex that drains from the leaves transversally cut. Aloe ferox has been used in folk medicine as anti-inflammatory, immunostimulant, anti-bacterial, anti-fungal, antitumor, laxative and to heal wounds and burns. The effects of the oral administration of A. ferox resin (10, 25, 50, 100 and 200 mg/kg) were evaluated on intestinal transit in mice and its acute toxicity (5.0 g/kg) in Wistar rats. The hydroxyanthracene derivatives present in the resin were expressed as aloin, identified by thin layer chromatography and quantified by spectrophotometry. The aloin (Rf 0.35) was identified and the percentage of hydroxyanthracene derivates expressed as aloin was 33.5%. A. ferox resin extract (50, 100 and 200 mg/kg) increased the gastrointestinal motility at a 30 min interval at 93.5, 91.8 and 93.8%, respectively, when compared to control group (46.5%). A single oral dose of the A. ferox resin extract did not induce signs of toxicity or death. Thus, the results demonstrate that A. ferox has laxative activity and that it is nontoxic, since LD50 could not be estimated and it is possibly higher than 5.0 g/kg.

Repeated-Doses Toxicity Study of the Essential Oil of Hyptis martiusii Benth. (Lamiaceae) in Swiss Mice

Hyptis martiusii Benth. (Lamiaceae) is found in abundance in Northeastern Brazil where it is used in traditional medicine to treat gastric disorders. Since there are no studies reporting the toxicity and safety profile of this species, we investigated repeated-doses toxicity of the essential oil of Hyptis martiusii (EOHM). Swiss mice of both sexes were orally treated with EOHM (100 and 500 mg/kg) for 30 days, and biochemical, hematological, and morphological parameters were determined. No toxicity signs or deaths were recorded during the treatment with EOHM. The body weight gain was not affected, but there was an occasional variation in water and food consumption among mice of both sexes treated with both doses. The hematological and biochemical profiles did not show significant differences except for a decrease in the MCV and an increase in albumin, but these variations are within the limits described for the species. The microscopic analysis showed changes in liver, kidneys, lungs, and spleen; however, these changes do not have clinical relevance since they varied among the groups, including the control group. The results indicate that the treatment of repeated-doses with the essential oil of Hyptis martiusii showed low toxicity in mice.

Vasoactive Thiomethyl-Pyrimidines: Promising Drug Candidates with Vascular Activity

Pyrimidines and their derivatives are present in various biologically active molecules. Most of the synthetic methods employed to achieve the pyrimidinone ring consist of two stages: the synthesis of a Michael intermediate from an aldehyde and an “active methylene” containing compound; and the condensation of this intermediate with a molecule containing an uranium moiety. This may take one to two days of laboratory work. In this paper we describe a new methodology in which these derivatives are obtained via multicomponent synthesis mediated by ultrasound in only 2 hours. In order to obtain water-soluble pyrimidinone derivatives, our previous compounds were further converted into their sodium salts. In pharmacologic studies, these salts inhibited phenylephrineinduced contraction in isolated rat aorta, suggesting that they may act as alpha-1 antagonists and, therefore, are candidates for anti-hypertensive drugs.

The Effect of Schinus terebinthifolius Raddi (Anacardiaceae) Bark Extract on Histamine-Induced Paw Edema and Ileum Smooth Muscle Contraction

Schinus terebinthifolius Raddi (Anacardiaceae), popularly known as red aroeira, is used in traditional medicine to treat inflammatory, gastric, and respiratory disorders. The aim of this study was to evaluate the antihistaminic activity of S. terebinthifolius (St) bark extract by using in vivo and in vitro experimental models. The effects of St were investigated on contractions induced by histamine, carbachol, and potassium chloride in isolated guinea pig ileum. St was also studied in response to hind paw edema induced by histamine in rats. Experiments revealed that although St (250, 500, and 1,000 µg/mL) reduced the histamine-induced contractions by 9.1 ± 1.8, 50.2 ± 2.0, and 68.9 ± 2.0%, respectively, it did not inhibit contractions induced by carbachol or KCl. The association of St (250 and 500 µg/mL) with hydroxyzine, an H1-antihistamine (0.125 and 0.250 µM), increased the inhibitory effect to 67.0 ± 3.2 and 85.1 ± 2.1%, respectively. Moreover, St (100, 200, and 400 mg/kg) decreased paw edema from its peak by 33.9, 48.4, and 54.8%, respectively, whereas hydroxyzine (70 mg/kg) inhibited the peak edema by 56.5%. Altogether, the results suggest that the bark extract of S. terebinthifolius has an antihistaminic effect (H1).