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The nor-clerodane diterpene trans-crotonin isolated from the bark of Croton cajucara BENTH. was investigated for its ability to prevent the formation of gastric-mucosa ulceration in different experimental models in mice. The results obtained from crotonin were compared with those obtained with another diterpene, DHC (trans-dehydrocrotonin) in the same models. When previously administered (p.o.) at the dose of 100 mg/kg, crotonin, as well as DHC, significantly reduced (p<0.05) gastric injury induced by stress (72, 67%), indomethacin/bethanechol (78, 29%) and pylorus ligature (35, 30%). In the HCl/ethanol-induced gastric ulcer model, at oral doses of 100 and 250 mg/kg, crotonin significantly prevented (p<0.05) the formation of gastric lesions by 51 and 56%, respectively, when compared to the control group. Gastric injury was also of significantly less magnitude in the DHC treatment group (p<0.05). In the pylorus-ligature model, crotonin (p.o.), like cimetidine, increased the volume of gastric juice when compared to the control group (p<0.05). No significant modifications where found in gastric parameters such as pH or total acid content after oral crotonin treatment. However, systemic alterations were observed when crotonin (100 mg/kg) was previously administered intraduodenally to mice. We observed significant changes (p<0.001) in gastric-juice parameters such as an increase in volume and a decrease in gastric acidity. Those pre-treated with crotonin as well as with DHC did not increase free mucus production (p>0.05). The results suggest that crotonin presents a significant anti-ulcer effect when assessed in these ulcer-induced models. As with DHC, the antiulcerogenic effects of crotonin are probably related to anti-secretory or/and gastroprotective properties of this substance. In light of results obtained with DHC and natural trans-crotonin in the present study, we concluded that the A-ring of both diterpenes is not directly involved in the antiulcerogenic activity.

Turnera ulmifolia is a plant belonging to the family Turneraceae, popularly known in Brazil as chanana. This species is distributed from Guyana to southern Brazil where it is considered a weed. The plant occurs in tropical rain forest, fields, and gardens. Chanana tea is used in Brazilian folk medicine for the treatment of diseases related mainly to gastric dysfunction including gastric and duodenal ulcers. In this study, the ability of a lyophilized infusion, as an aqueous fraction (AqF) of the aerial parts of T. ulmifolia, was investigated for its ability to prevent ulceration of the gastric and duodenal mucosa was examined in mice and rats, respectively. The AqF significantly reduced the formation of lesions associated with HCl/ethanol administration by 39% and 46%, respectively, at doses of 500 mg/kg and 1000 mg/kg, p.o. The AqF also significantly reduced the incidence of gastric lesions induced by a combination of indomethacin and bethanechol by 58% and 72% at doses of 500 mg/kg and 1000 mg/kg, respectively. In stress-induced gastric ulcer, the inhibition by the AqF was 48%, 57%, and 58% at doses of 250 mg/kg, 500 mg/kg, and 1000 mg/kg, respectively (p<0.05). A pyloric ligature experiment showed that the highest dose of the AqF significantly affected the gastric juice parameters by increasing the pH from 2.5 (control) to 5.3 and decreasing the acid output from 11.3 (control) to 3.7 mEq/ml/4 h. The AqF had no significant effect on duodenal ulcers induced by cysteamine. Preliminary phytochemical screening confirmed that flavonoids were the major constituents of the AqF of T. ulmifolia. These results indicate that this extract has a significant antiulcerogenic effect, as popularly believed.

Aparisthmium cordatum (Juss.) Bail. (Euphorbiaceae), known in the State of Pará, Brazil as "ariquena queimosa", is a medium-sized tree which is native to the North Brazilian coastal region. Previous phytochemical studies of the bark of A. cordatum yielded a furan diterpenoid with a clerodane skeleton, called aparisthman. Recently, we reported the antiulcerogenic activity of trans-dehydrocrotonin (DHC), a furan diterpene isolated from Croton cajucara bark, in different ulcerogenic models in mice and rats. The aim of the present study was to assess the possible antiulcerogenic activity of aparisthman. When previously administered (p.o.) at the dose of 100 mg/kg(-1), aparisthman reduced significantly (p < 0.01) gastric injury induced by the indomethacin/bethanechol (71%), ethanol (71%), pylorus ligature, (59%) and hypothermic restraint-stress models (50%), in mice and rats. In the HCl/ethanol-induced gastric ulcer model in mice, at oral doses of 100 and 250 mg/kg(-1), aparisthman from A. cordatum reduced significantly (p < 0.001) the formation of gastric lesions by 59% and 66%, respectively, as compared with control. In the pylorus-ligature model, aparisthman (p.o.) decreased the volume of gastric juice as compared with control (p < 0.001). When aparisthman (100 mg/kg(-1)) was administered intraduodenally to mice, significant modifications were found, such as a decrease in gastric acidity as compared with control. In the animals pre-treated with aparisthman, free mucus production increased by 19% in the gastric mucosa (p < 0.05). The results suggest that aparisthman from A. cordatum presents a significant anti-ulcer effect when assessed in these induced ulcer models. Although the mechanism underlying this antiulcerogenic effect remains unknown, it seems to be related to an increase of the defensive mechanisms of the stomach such as prostaglandin synthesis and mucus production. The good yield of aparisthman obtained from A. cordatum, as well as its antiulcerogenic activity, suggest that this compound should be submitted to pharmacological research as a potential new antiulcerogenic drug.

The decoction or juice of leaves of Boerhaavia diffusa L. (Nyctaginaceae) is used in Martinican folk medicine for its analgesic and anti-inflammatory properties. In the present investigation we studied the acute oral (p.o.) toxicity of a crude extract obtained from a lyophilized decoction (DE) and from the juice (JE) of fresh leaves. We observed no signs of toxicity up to the dose of 5000 mg/kg (p.o.) in mice. At the dose of 1000 mg/kg, neither extract altered sleeping time evoked by the administration of pentobarbital sodium (i.p.). The DE and JE of B. diffusa were assessed in standard rodent models of algesia and inflammation. We investigated the antinociceptive effect of DE and JE in chemical (acetic acid) and thermal (hot plate) models of hyperalgesia in mice. Dipyrone sodium (200 mg/kg), JE (1000 mg/kg) and DE at the same dose (p.o.), produced a significant inhibition of acetic acid-induced abdominal writhing in mice (100, 50 and 47% inhibition, respectively) when compared with the negative control (P<0.001). In the hot-plate test in mice, morphine and JE produced a significant increase in latency during the observation time. The DE, however, only raised the pain thresholds during the first period (30 min) of observation (P<0.05). The extracts of B. diffusa were also investigated for their anti-edematogenic effect on carrageenan-induced edema in mice. However, neither extract inhibited the paw edema induced in mice (P>0.05). In the acetic acid-induced abdominal writhing in mice, pre-treatment of the animals with naloxone (5 mg/kg, i.p.) significantly reversed the analgesic effect of morphine and JE but not that of DE. These data show that the active antinociceptive principle of B. diffusa is present mainly in the juice of fresh leaves and has a significant antinociceptive effect when assessed in these pain models. The mechanism underlying this analgesic effect of fresh leaves of B. diffusa remains unknown, but seems to be related to interaction with the opioid system.

Neurolaena lobata is a species used widely in Caribbean folk medicine to treat gastric pain and ulcers. The hexane (HxF), chloroform (ClF) and aqueous (H2OF) fractions of a hydroalcoholic extract (HE) of N. lobata aerial parts were investigated for their ability to prevent ulceration of the gastric mucosa. In the stress-induced gastric model the HE, HxF and ClF fractions produced a significant reduction of gastric lesion formation by 48, 70 and 52%, respectively. HE, HxF and ClF fractions (41, 57 and 51%, respectively) also reduced significantly the gastric lesions induced by the combination of indomethacin and bethanechol, and the ulcers induced by HCl/ethanol solution by 77, 86 and 83%, respectively (P < 0.05). The pylorus-ligature experiment demonstrated that the HE, HxF and ClF fractions changed significantly the gastric juice parameters, such as pH values (increases to 5.4, 4.9 and 4.8, respectively) and acid output (decreased by 4.6, 5.8 and 6.2 mEq mL(-1) 4h respectively) and gastric content (increased by 400, 410 and 390 mg, respectively) in animals. In the animals pre-treated orally with the HxF fraction, prostaglandin synthesis was increased significantly, by 104%, and free mucus production was increased by 54 % in the gastric mucosa (P < 0.001). The H2OF did not exhibit activity in any of the experimental models assayed. The data suggest that the HE and mainly the HxF of fractions from N. lobata present a significant anti-ulcer effect when assessed in these ulcer-induced models. Although the mechanism underlying this antiulcerogenic effect remains unknown, it seems to be related to an increased activity of the defensive mechanisms of the stomach, such as prostaglandin synthesis and mucus production.

The gastroprotective activity of the essential oil from the bark of Croton cajucara Benth (Euphorbiaceae) was assessed in three different models of experimentally induced gastric ulcer in mice. At oral dose of 100 mg/kg the essential oil reduced gastric lesions induced by hypothermic restraint stress and HCl/ethanol significantly. In the HCl/ethanol model a dose-dependent gastroprotective effect was found. Moreover, significant changes in gastric parameters such as pH, secretion rate and total gastric acid were found after intraduodenal administration of essential oil under ligated pylorus (Shay) conditions. The acute toxicity of essential oil was assessed in mice. The LD50 values were 9.3 and 680 mg/kg for oral and intraperitoneal administrations, respectively. The cytotoxicity of essential oil was studied also. A dose-dependent cell viability inhibition was found in V79 fibroblast cell cultures with an IC50 of 22.9 microg/ml. Our results support the pharmacological study of this essential oil.

The trypanocidal activities of cis-3-(4'-bromo[1,1'-biphenyl]-4-yl)- 3-(phenyl)-N,N-dimethyl-2-propen-1-amine (Vb) and cis-3-(4'-bromo[1,1'-biphenyl]-4-yl)-3-(4-bromophenyl)-N,N-dimethyl-2- propen-1-anine (Vg) appeared 6.3 and 3.5 fold more active than the trans-isomers, respectively. Multi-endpoints for toxicity were also applied. Neutral red uptake (NRU), tetrazolium salt reduction (MTT), DNA content on V79 fibroblast cell culture and acute toxicity von E. coli were measured. The IC50 through DNA contents was lower for the cis-isomers in both series of compounds 5b: 7.8 microM and 5g: 5.2 microM). NRU values for derivative 5b in isomeric mixture shows the same value as the isolated isomers however, in the case of 5g a more significant toxicity of the cis-isomer was found. MTT values show that 5g is more toxic than 5b. In both cases, the acute toxicity of the trans-isomers was higher than that of the cis-isomers.

The decoction of Dalbergia monetaria L. is popularly used in Brazil for the treatment of gastric ulcer and the lyophilized aqueous extract (LAE) of D. monetaria has significant anti-ulcerogenic activity and inhibits gastric ulcer lesions induced by pylorus-ligature, ethanol and hypothermic-restraint stress. This work was conducted to identify the antiulcerogenic mechanisms of action of the LAE of D. monetaria. We analysed the effect of the LAE on prostaglandin E2 (PGE2) synthesis and on the characteristics (pH, volume and total acid content) of gastric juice. The antagonism between the LAE and histamine or carbachol was also analysed. The LAE increased gastric mucosal PGE2 synthesis compared with control (89.7+/-21.5 and 52.6+/-11.8 pg mg(-1), respectively) as assayed by enzyme immunoassay in the rat stomach. The LAE reduced the total acid content of gastric juice, but did not modify pH or gastric volume significantly, in Shay rats. Dose-response curves to histamine were shifted to the right in guinea-pig isolated right atria (pD2 values were 5.77+/-0.2 and 5.42+/-0.3, respectively, in the absence and presence of the LAE), with a significant reduction in maximum response (140+/-15.1 and 98+/-13.0, respectively). The same effect was observed when the agonist was isoprenaline. The LAE had no effect on the dose-response curve to carbachol in rat fundus strips. Thus, the protective effect of the LAE on induced gastric lesions might be because of synergistic effects, e.g. increased PGE2 synthesis and antagonism of H2 histamine and beta-adrenergic receptors, reducing gastric acid secretion. Increased PGE2 synthesis results in increased protection, and antagonism of H2 histamine and beta-adrenergic receptors reduces aggressive factors against the gastric mucosa.

Diarylpropenamine derivatives are a class of compounds which have been evaluated as potential drug candidates. Here a specific and reproducible HPLC method for the determination of cis- and trans-isomers of the unsubstituted derivative, 3-(4'-bromo-[1,1'-biphenyl]-4-yl)-3-(4-X-phenyl-N,N-dimethyl-2-propen -1-amine (I, where X=H) in feces is described. The analyte I and internal standard, nitro derivative (II, where X=NO2), were isolated from the basified biological matrix using a liquid-liquid extraction with ethyl acetate followed by a solid-phase procedure performed on a silica cartridge. The organic phase was evaporated to dryness, the residue was reconstituted in mobile phase and injected into the HPLC system. The analytes were eluted with ethyl acetate-hexane-triethylamine (59:40:1) in HPLC column (silica) and detected by UV spectrophotometry at 272 nm. Linearity, precision and accuracy data for feces standards after extraction were acceptable. The method has been applied to analyses of feces samples from rats dosed with I, in which it could be anticipated that fecal excretion is quantitatively the major route for I elimination.

Croton cajucara Benth. (Euphorbiaceae) is widely used in Amazonian folk medicine for the treatment of a wide range of gastrointestinal symptoms. The essential oil from its bark was investigated for acute toxicity in mice and for its ability to prevent the formation of ulceration of the gastric mucosa in different models of experimentally induced gastric ulcer in mice and rats. When previously administered orally at a dose of 100 mg kg(-1), the essential oil significantly reduced (P < 0.01) the gastric injury induced by hypothermic restraint stress (48%), indomethacin (47%), ethanol (86%) and pylorus ligature models (87%) in rats. In the HCl/ethanol-induced gastric ulcer model in mice, at oral doses of 100 and 200 mg kg(-1), the essential oil from C. cajucara significantly reduced (P < 0.01) the formation of gastric lesions by 52% and 67%, respectively, when compared with the control group. In rats submitted to pylorus ligature, the essential oil given orally increased the volume of gastric juice when compared with the control group (P < 0.01). When the essential oil (100 mg kg(-1)) was administered intraduodenally to mice, significant modifications were found in gastric parameters such as pH and total acid content after oil treatment. We observed significant changes (P < 0.01) in gastric juice parameters such as an increase in volume and a decrease in gastric acidity (pH and total acid content). The acute toxicologic effects of the essential oil from C. cajucara were assessed in mice. The LD50 values were 9.3 g kg(-1) by the oral route and 680 mg kg(-1) by the intraperitoneal route. The good yield of essential oil obtained from dried C. cajucara bark (1%) as well as its anti-ulcerogenic activity and low toxicity suggest that pharmacological studies of this substance as a potential new anti-ulcerogenic drug are warranted.

In this study we have investigated the effects of Petiveria alliacea on the hematopoietic response of mice infected with Listeria monocytogenes. Our results demonstrate a protective effect of the crude extract of P. alliacea since the survival of the treated/infected was higher than that in the infected group. Moreover, the number of granulocyte/macrophage colonies (CFU-GM) and the serum colony stimulating activity levels were increased in the treated/infected mice in relation to the infected group. These results suggest an immunomodulation of Petiveria alliacea extract on hematopoiesis, which may be responsible, at least in part, for the increased resistance of mice to Listeria monocytogenes infection.

An infusion of the aerial parts of Neurolaena lobata (L.) R. Br. (Compositae-Asteraceae) is used in Caribbean folk medicine to treat several kinds of pain. In this investigation we studied the acute oral toxicity of the hydroalcoholic extract of the plant and the antinociceptive effect of the extract and of its hexane- and chloroform-partitioned fractions, given orally, in nociception and inflammatory models in mice. No signs of toxicity were observed for oral doses up to 5000 mg kg(-1) in mice. Morphine hydrochloride (100 mg kg(-1)), dipyrone sodium (200 mg kg(-1)), the hydroalcoholic extract (1000 mg kg(-1)), and its chloroform- and hexane-partitioned fractions (100 mg kg(-1)) significantly inhibited acetic acid-induced abdominal constriction in mice (100, 95, 47, 62 and 60% inhibition, respectively when compared with the negative control). In the hot-plate test in mice, morphine hydrochloride, the chloroform- and hexane-partitioned fractions, but not the hydroalcoholic extract, resulted in a significant latency increase in all observation times. In the acetic acid-induced abdominal constriction in mice, pretreatment of the animals with naloxone significantly reversed the analgesic effect of morphine, but not that of the hydroalcoholic extract or of its hexane- and chloroform-partitioned fractions. Finally, administration of the hexane- and chloroform-partitioned fractions (100 mg kg(-1)) had a significant anti-oedematogenic effect on carrageenan-induced oedema in mice. These data show that the hydroalcoholic extract of N. lobata and, in particular, its partitioned fractions have significant analgesic properties when assessed through these pain models. Their antinociceptive effect might be the result of interference with the inflammatory process.

Anti-inflammatory studies were conducted on rats or mice using a crude hydroalcoholic extract of the aerial parts of Turnera ulmifolia and it's partitioned fractions, i.e. the aqueous, ethyl acetate and ethanolic fractions. The hydroalcoholic extract and it's fractions (aqueous and ethanolic) inhibited carrageenan-induced edema. However, only the ethanolic fraction was used in the other experiments due to it's yield. The extract also inhibited the cotton pellet granuloma and the increase of vascular permeability induced by histamine, 5-hydroxytryptamine and prostaglandin E2, but not that produced by bradykinin. The extract or the fraction did not present analgesic activity in the writhing test using acetic acid and did not reduce croton oil-induced ear edema in mice. When the ethanolic fraction and LPS were administered i.p. to Balb/C mice 72 h before blood or peritoneal fluid collection, no changes were observed in the white or total blood cell counts in the peripheral blood. On the other hand, changes were observed in both total and differential cell counts in the peritoneal exudate since all doses of the fraction reduced the number of total leukocytes (mainly lymphocytes) obtained from the peritoneal exudate. In contrast to nonsteroidal anti-inflammatory drugs, the administration of the hydroalcoholic extract or the ethanolic fraction alone did not potentiate gastric mucosal lesions induced by aspirin. The extract and the fraction inhibited the appearance of gastric lesions induced by indomethacin, ethanol and pylorus ligature, but not those induced by stress. As also observed with carbenoxolone, the ethanolic fraction increased the wall mucus in hypothermical-restraint stress-induced gastric lesions. The anti-ulcerogenic effect of the extract and of the ethanolic fraction may be related to an increase of mucosal defensive factors, such as prostaglandin and mucus. The anti-inflammatory actions of the extract and the fraction may be due to an inhibitory effect on histamine and cyclooxygenase II, but not on cyclooxygenase I, because the extract and it's fraction present both anti-inflammatory and anti-ulcerogenic effects. The major substances present in the ethanolic fraction are flavonoids which will be isolated and identified.

1. SB-73, a magnesium ammonium phospholinoleate anhydride aggregate, exhibited antiviral action in vitro in the concentration range of 50 to 100 micrograms/ml against herpes simplex type 1, stomatitis vesicular virus, adenovirus type 5, and in vivo in the dose range of 0.7 to 1.3 mg/kg against canine parvovirus and distemper virus. 2. The lethal dose (LD50) was 2.71 +/- 1.55 g/kg body weight in mice inoculated intraperitoneally. Oral ingestion of the aggregate up to 30 g/kg body weight by mice had no lethal effects during the 14 days of observation. 3. In in vitro cytotoxicity experiments with fibroblasts (V-79 Chinese hamster cell line), no toxic effects were observed with SB-73 concentrations (120 micrograms/ml) having antiviral activity. 4. In a cellular proliferation experiment using hamster V-79 cells, we observed 72% proliferation after treatment of the cells with a high concentration (500 micrograms/ml) of SB-73. 5. Compound SB-73 showed no genotoxicity for human lymphocytes at concentrations of 100 micrograms/ml. 6. When the cytotoxicity and genotoxicity of SB-73 were compared with those of acyclovir, idoxuridine and AZT at 500 micrograms/ml concentrations the compound was found to have effects similar to those of acyclovir.