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In this work, we studied the effects of kaurenoic acid, a diterpene isolated from the oleo-resin of Copaifera langsdorffii in developing sea urchin (Lytechinus variegatus) embryos, on tumor cell growth in microculture tetrazolium (MTT) test and on mouse and human erythrocytes in hemolysis assay. Continuous exposure of embryos to kaurenoic acid starting immediately after fertilization inhibited the first cleavage (IC(50): 84.2 microM) and progressively induced embryo destruction (IC(50): 44.7 microM and < 10 microM for blastulae and larvae stages, respectively). In MTT assay, kaurenoic acid at a concentration of 78 microM produced growth inhibition of CEM leukemic cells by 95%, MCF-7 breast and HCT-8 colon cancer cells by 45% each. Further, kaurenoic acid induced a dose-dependent hemolysis of mouse and human erythrocytes with an EC(50) of 74.0 and 56.4 microM, respectively. The destruction of sea urchin embryos, the inhibition of tumor cell growth and the hemolysis of mouse and human erythrocytes indicate the potential cytotoxicity of kaurenoic acid.

The red sap obtained by slashing the bark of Croton urucurana Baill. (Euphorbiaceae), also known as dragon's blood, was screened for a possible antidiarrhoeal activity on castor oil-induced diarrhoea in rats, cholera toxin-induced intestinal secretion in mice and on small intestinal transit in mice. Dragon's blood at an oral dose of 600 mg/kg caused in marked inhibition of the diarrhoeal response following castor oil administration as well as the intestinal fluid accumulation promoted by cholera toxin. At a similar dose the red sap significantly inhibited the small intestinal transit which was, however, found to be independent of the opioid mechanism. These results suggest a potential usefulness of the red sap from Croton urucurana Baill. in the control of secretory diarrhoea associated pathologies., (Copyright 2001 John Wiley & Sons, Ltd.)

This study aims to evaluate the in vitro and in vivo leishmanicidal activity of lapachol, a naphthoquinone found in the seeds and heartwood of certain tropical plants, and to compare its efficacy with a reference drug, sodium stibogluconate (Pentostam(R)). These compounds (0.0125-4.0 mg/mL) were evaluated in vitro against intracellular amastigotes of Leishmania (Viannia) braziliensis (LVb), then tested in an animal model (hamster) to try to reproduce the leishmanicidal activity. In vitro, lapachol exhibited an anti-amastigote effect, whereas in vivo it did not prevent the development of LVb-induced lesions at an oral dose of 300 mg/kg/day for 42 days. Pentostam(R) demonstrated a significant anti-amastigote effect in vitro for LVb and apparent clinical cure in vivo (60 mg/kg/day). However, it could not completely eradicate parasites from the tissues of infected animals. The observation that lapachol exerts leishmanicidal activity in vitro without offering significant protection against LVb-infected lesions in hamsters suggests that lapachol in vivo might possibly inhibit the microbicidal functioning of macrophages. Alternatively, it might be transformed into an inactive metabolite(s) or neutralized, losing its leishmanicidal activity. It is also possible that an optimal and sustained plasma level of the drug could not be achieved at the dose used in this study., (Copyright 2001 John Wiley & Sons, Ltd.)

Phytochemical and pharmacological studies of Croton cajucara were oriented by traditional medicine. The stem bark of the mature plant is a rich source of clerodane-type diterpenes: trans-dehydrocrotonin (DCTN), trans-crotonin (CTN), cis-cajucarin B, cajucarin A, cajucarinolide and two novel clerodanes, trans-cajucarin B and sacacarin. In young (18-month-old) plants, the triterpene acetyl aleuritolic acid (AAA) was the major stem bark component and in these the diterpene DCTN was not present. The highest concentration of DCTN (1.4% of dry bark) was detected in 4-6 year-old plants, while 3-year-old plants contained only 0.26% of this diterpene. Three steroids (beta-sitosterol, stigmasterol and sitosterol-3-O-beta-glucoside), two flavonoids (kaempferol 3,4', 7-trimethyl ether and 3,7-dimethyl ether) and one diterpene (cajucarinolide) were isolated from the leaves of this Croton. The main pharmacological activity was correlated with DCTN. This clerodane produced anti-inflammatory and antinociceptive effects and a significant hypoglycemia in alloxan-induced diabetic rats. The compound also reduced the index of gastric lesions induced by restraint-in-cold. Dose-related DCTN and CTN inhibited in vivo the basal acid secretion in pylorus-ligature rats and oxyntic glands isolated from rabbit gastric mucosa, DCTN, CTN or AAA decreased in vitro uptake basal acid secretion induced by histamine and measured with the 14C-aminopyrine uptake method. Uniquely DCTN inhibited 14C-AP uptake induced by bethanechol. The terpenoids, DCTN and AAA, and the chloroform extract of 6-month-old plants reduced gastrointestinal transit in mice. The effects of DCTN and CTN on the survival of mice bearing Sarcoma 180 and Ehrlich carcinoma ascitic tumors, on the proliferation of cultured cells and TNFalpha were determined. DCTN was also evaluated for a possible antioestrogenic activity using the immature rat as a model system for bioassay of oestrogen and for an anti-implantation effect in regularly cycling rats. The biological experiments, using the plant extracts and the terpenoids DCTN, CTN and AAA, are herein discussed.

This study examined trans-dehydrocrotonin (t-DCTN), a nor-clerodane diterpene isolated from the Brazilian medicinal plant Croton cajucara Benth., for a possible antioestrogenic activity using immature rats as a model system for bioassay of oestrogen, and for an antiimplantation effect in regularly cycling rats of proven fertility. In the antioestrogen test, t-DCTN (25 and 50 mg/kg) effectively prevented oestrogen-induced increases of uterine wet weights. In addition, the vaginal openings provoked by oestrogen were completely prevented by t-DCTN. However, blastocyst-implantation was only insignificantly affected in t-DCTN pretreated animals. These results suggest that t-DCTN may be an antioestrogen and warrants further studies with regard to its mechanism of action., (Copyright 1999 John Wiley & Sons, Ltd.)

The effects of oleo-resin obtained from the stem bark of Copaifera langsdorffii on ethanol, indomethacin and hypothermic restraint-stress induced gastric lesions were studied in rats. Oral administration of oleo-resin at doses of 200 and 400 mg/kg provided dose-dependent significant protection against gastric damage caused by ethanol and restraint stress, and at a dose of 400 mg/kg it also prevented the gastric ulceration induced by indomethacin. Further, in the 4 h pylorus ligated rats, the accumulation of gastric juice volume and the mucus secretion was significantly enhanced by oleo-resin whereas the total acidity was inhibited. These results highlight the gastroprotective potential of C. langsdorffii oleo-resin and the need for a systematic study on this traditional remedy.

The present studies tested the ability of 1,8-cineole to produce inflammatory oedema in the hind paw of the rat and verified the possible involvement of mast cells in the response. Subplantar injection of 1,8-cineole (10, 15 and 20 microl/paw) induced a dose-dependent paw oedema which was apparent within 30 min. At higher doses the oedema effect was persistent, peaked at 2 h, and then decreased gradually but was still pronounced at 24 h post injection. In contrast, the oedema produced by mast cell degranulator compound 48/80 (10 microg/paw) had a rapid onset with a peak effect at the first hour, followed by a gradual decrease thereafter and at 24 h post injection it was almost absent. The oedema response to 20 microl 1,8-cineole was significantly inhibited throughout its time-course in rats pretreated with antihistaminic and antiserotonergic drugs such as diphenhydramine, methysergide and cyproheptadine or with ketotifen, a mast cell stabilizer. A more effective blockade of the oedema response was, however, observed in rats depleted of mast cell granules by systemic treatment with compound 48/80. Furthermore, 1,8-cineole was able to cause rat peritoneal mast cell degranulation (94%) in vitro, in a concentration as low as 0.3 microl/ml, which was almost comparable to that produced by 0.1 microg/ml of compound 48/80. The data provide evidence of a key role for the mast cell in 1,8-cineole-induced hind paw oedema in the rat.

The essential oil obtained from the leaves of Psidium guyanensis Pers. (Myrtaceae) was studied against lethal seizures induced by intraperitoneal injection of pentylenetetrazole (80 mg/kg), picroptoxin (6 mg/kg), and strychnine (2 mg/kg) in mice. At oral doses of 100, 200, and 400 mg/kg, the essential oil attenuated the severity of pentylenetetrazole-induced seizures and offered a dose-related protection but it was found to be ineffective against convulsions induced by picrotoxin and strychnine. The blockade of its protective effect on pentylenetetrazole lethal seizures by caffeine (10 and 50 mg/kg, i.p.) suggests a probable participation of endogenous adenosine in its mechanism. Furthermore, a peripheral mechanism also appears to be involved as the essential oil (5-20 micrograms/ml) was able to block selectively the acetylcholine (1.65 x 10(-6) M) induced contractions but not those evoked by high potassium (80 mM) or caffeine (2 x 10(-3) M) on isolated toad rectus abdominis muscle.

The study was designed to verify the gastroprotective and antidiarrhoeal effects of ternatin, tetramethoxyflavone isolated from Egletes viscosa Less. The gastroprotective function of ternatin was evaluated in rats against gastric mucosal damage induced by hypothermic restraint stress, absolute ethanol, and indomethacin, whereas the antidiarrhoeal activity was investigated by studying its influence on gastrointestinal transit as measured by a charcoal marker and on castor oil-induced accumulation of intestinal fluid in mice and also on contractile responses evoked by acetylcholine, histamine, serotonin, and barium chloride in isolated guinea-pig ileum. The results demonstrate that pretreatment of animals with the plant flavonoid (25 and 50 mg/kg, i.p.) produces a significant inhibition of gastric lesions induced by ethanol but not those induced by restraint stress or indomethacin and suggest a probable involvement of a prostaglandins-independent mechanism of gastroprotection. At similar doses, both the intestinal transit as well as the accumulation of intestinal fluids induced by castor oil in mice were significantly inhibited by ternatin. Furthermore, the flavonoid antagonised the contractile responses evoked by different agonists on guinea-pig ileum in vitro and its inhibitory potential for the drugs are in the order of acetylcholine > histamine > serotonin > barium chloride. Taken together, these results point out a possible antidiarrhoeal effect of ternatin since inhibition of intestinal motility and secretion can greatly control clinical diarrhoea.

The effect of ternatin, a tetramethoxyflavone from Egletes viscosa Less., on liver injury induced by carbon tetrachloride (CCl4) was investigated in rats. Twenty-four hours following CCl4 insult (2.5 ml/kg s.c.), changes in the serum enzymes, alanine aminotransferase, aspartate aminotransferase and gamma-glutamyltransferase, as well as liver cell histology were used as indices of hepatic dysfunction. The results show that ternatin (30 mg/kg i.p. daily for 5 consecutive days) causes marked inhibition of CCl4-induced serum enzymes and morbid histologic changes. The observation suggests that ternatin possesses antihepatotoxic activity.

Ternatin, a tetramethoxy flavone isolated from Egletes viscosa Less (Compositae), was tested for its efficacy in modulating mouse passive cutaneous anaphylaxis (PCA) and rat carrageenan-induced pleurisy. Ternatin (12.5, 25 and 50 mg/kg, ip) caused a dose-dependent inhibition of IgG antibody-mediated 1.5-h homologous PCA as well as IgE antibody-mediated 48-h homologous PCA in 2-month old mice (N = 5 per group). The inhibitory activity of ternatin was more potent on IgE-mediated PCA (47-79%) than on IgG (45-59%). In the rat carrageenan pleurisy test, ternatin (25 and 50 mg/kg, ip) reduced the response to carrageenan at 5 h both by decreasing exudate volume (33-40%) and leukocyte number (60%) in 5-6-month old rats (N = 6 per group). In contrast, indomethacin (2 mg/kg, po), a known cyclooxygenase inhibitor, showed greater potency in the inhibition of exudate volume (57%) and leukocyte number (77%). These results show that ternatin has both anti-inflammatory and anti-anaphylactic properties and suggest that it may be a useful alternative to anti-allergic drugs of the disodium cromoglycate (DSCG) type for use in bronchial asthma.

Alpinia speciosa Schum or A. nutans is a plant of the Zingiberaceae family, known popularly as "colony" (colônia) and used as a diuretic and to control hypertension. We have determined the concentration of Na+ and K+ found in the alcoholic extract and in the tea concoction. They contained 51.0 mEq Na+, and 132 mEq K+ in the extract, and 0.0 mEq of Na+ and 26 mEq K+ in the tea. Phytochemical analysis of the leaves demonstrated the presence of catecquic tanins, phenols and alkaloids, and also some essential oils. When injected intra-peritoneally the hydroalcoholic extract, in a dose range of 100 to 1400 mg/kg, (or 2500-18000 mg/kg orally) produced in mice: writhing, psychomotor excitation, hypokinesis and pruritus. The LD50 by ip was 0.760 +/- 0.126 g/kg and 10.0 +/- 2.5 g/kg by oral administration for the hydroalcoholic extract. Subacute toxicity made by injecting daily for 30 days the LD10 in rats caused an increase in transaminases and lactate dehydrogenase, whereas other parameters such as blood glucose, urea and creatinine were normal. A histopathological analysis of liver, spleen, gut, lung and heart showed no alterations. The drug also produced a prolongation of the sleeping time. The hydroalcoholic extract induced in the rat and in the dog a dose-dependent fall in blood pressure in doses of 10 to 30 mg/kg. In isolated atria the extract induced a reduction of the frequency and in the inotropic responses. Neither the extract nor the tea had an effect on the diuresis of the rat.

In order to assess the use of Astronium urundeuva in folk medicine for treatment of diarrheal conditions, the alcoholic extract of its bark was tested on gastrointestinal transit in mice. The extract at oral doses of 100 and 200 mg/kg significantly inhibited physostigmine-induced gastrointestinal propulsion. Considering these data together with an in-vitro anti-acetylcholine effect reported earlier from this laboratory, we suggest that anti-cholinergic effects of the plant may account in part for its anti-diarrheal activity.

The effects of the aqueous extract of Astronium urundeuva Engl. on aspirin and restraint plus histamine-induced ulceration in rats are described. The extract significantly inhibited aspirin-induced gastric lesions as well as restraint plus histamine-induced ulceration in rats.