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The effect on platelet aggregation of perezone, isoperezone, aminoperezone and isoaminoperezone has been determined in human platelets, using adenosinediphosphate (ADP), epinephrine and collagen as inducers. Perezone inhibited ADP- epinephrine- and collagen-induced platelet aggregation; isoperezone, aminoperezone and isoaminoperezone did not. The difference in biological responses could be the result of their structures. While isoperezone, aminoperezone and isoaminoperezone have carbonyl groups in the vicinity of other functional groups, this is not the case for perezone, in which one of the carbonyl groups has an adjacent free position.

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Bioassay-directed fractionation of the methanolic extract of seeds of Casimiroa edulis led to the isolation of seven constituents with cardiovascular activity, namely the new compound synephrine acetonide and the known compounds N-monomethylhistamine, N,N-dimethylhistamine, proline, N-methylproline, gamma-aminobutyric acid and casimiroedine. In anesthetized rats, both histamine derivatives produced transient hypotension mediated via H1-histaminergic receptors and in the case of N,N-dimethylhistamine, via nitric oxide release. Synephrine acetonide produced transient hypertension and tachycardia, mediated via alpha- and alpha- and beta-adrenergic receptores, respectively. The chromatographic zone containing N-methyproline, proline and gamma-aminobutyric acid elicited marked and prolonged hypotension. Finally, casimiroedine did not modify the blood pressure of anesthetized rats, but lowered it persistently in anesthetized guinea pigs. It was concluded that hypotension produced by C. edulis is due to several active components. The immediate effect can be attributed to the histamine derivatives acting on H1-receptors. More prolonged hypotension would be produced by the mixture of amino acids through an unknown mechanism, as well as by casimiroedine, possibly by activation of H3-receptors. Hypotension is partially offset by synephrine acetonide through adrenergic mechanisms.

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A germination bioassay with radish (Raphanus sativus L.) seeds was developed as a toxicological screening system for assessing the effects of new potential prodrugs of naproxen, as an alternative to animals and animal cell toxicity screens. Both enantiomers of naproxen (6-methoxy-α-methyl-2-naphthaleneacetic acid) and naproxol (6-methoxy-ß-2-naphthaleneethanol), and their racemic mixtures, inhibited the radicle growth of R. sativus at a concentration of 1mM, while only (R)-(+ )-naproxol and racemic naproxol inhibited the hypocotyl growth of R. sativus at the same concentration. Four novel combinatorial esters, naproxen naproxyl esters (6-methoxy-ß-methyl-2-naphthaleneethyl 6-methoxy-α-methyl-2-naphthaleneacetate), resulting from the combinatorial chemistry of the esterification reaction between naproxen and naproxol, were synthesised and then tested in the germination bioassay, at a concentration of 0.5mM. It was found that they did not inhibit either the radicle or the hypocotyl growth of R. sativus.

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The qualitative analytical detection of kaurenic compounds kauradienoic (kauradien-9(11),16-dienoic acid) (1), monoginoic (2), and kaurenoic acids (3) in the infusion of Montanoa tomentosa Cerv., was carried out using GC-MS and 2D-NMR methods to resolve contradictory HPLC results from previous reports.

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Ipomoea stans (IS) has long been used as an anticonvulsant. Although the use of HPLC and nuclear magnetic resonance techniques recently have allowed some of its compounds to be identified, the anticonvulsant properties of this Convolvulaceae remained to be tested. During the course of several weeks, mice (BALB/C) were given a normal infusion of the plant instead of clean water (IS-ad lib). They also were given total lyophilized powder (IS-T), and two mixtures of compounds (IS-A and IS-B) from the plant. Their convulsive thresholds were then tested with pentylenetetrazol (PTZ: 40, 60, 85 and 100mg/kg, s.c.) and electric shock (ECS: 0.1mAmp, 60 Hz). Results showed Ipomoea stans provides protection against ECS and a low dose of PTZ (40 mg/kg). However, some data from animals who died following ECS after receiving a high regimen of IS suggests they suffered mesenteric infarct. Similar results appeared after treatments with IS-T and IS-A. All IS preparations offered protection but IS-B in particular protected mice against seizures produced by a low dose of PTZ (40 mg/kg) and delayed the onset of seizures produced by ECS. In a second set of experiments, IS-ad lib and IS-T increased the threshold for amygdala discharges produced by the cortical electrical stimulation in Wistar rats. It is concluded that IS possesses some anticonvulsant properties similar to valproic acid, that are attributable to fraction B of the plant. Fraction A seems to possess a weaker anticonvulsant activity and some toxic properties.

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Three new tetrasaccharide glycosides, differing from one reported previously in the type of short-chain fatty acids ester-linked to the tetrasaccharide core, have been isolated and identified from an oligosaccharide fraction of Ipomea stans. Preliminary screening tests showed that the fraction containing these compounds had pronounced cytotoxicity towards three human tumor cell lines as well as specific antibiotic activity against two bacterial strains.

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The constituents of the volatile oils of MONTANOA TOMENTOSA and LIPPIA GRAVEOLENS, were investigated using capillary GC/MS. Borneol acetate, beta-cubebene, and beta-caryophyllene were found to be the major constituents of the volatile oil of M. TOMENTOSA, while P-cymene, 1,8-cineol, thymol, and carvacrol were the major volatile components of L. GRAVEOLENS. The possible correlation between the high concentration of monoterpenes and the alleged antifertility effect of the title plants is discussed.

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A collection of Montanoa (Cerv) specimens was conducted throughout Mexico. Twenty-one specimens were classified, some of them grown in the greenhouse and transplanted in an agricultural experimental field station in the Valley of Mexico. In vitro uterotonic potency was assayed and the results expressed as equivalents of oxytocine, by using estrogenized guinea pig uterine strips. A great variation of uterotonic potency was observed among the wild plants. A clear decrease and uniformity of uterotonic potency was found in plants grown in the experimental field. The study points out the importance of ecological variations in expression of the plant's biological activity.

PIP: 21 specimens of the zoapatle Montanoa (Cerv) plant were collected from sites throughout Mexico with a variety of climatic, humidity, soil composition, and altitude conditions to assess their uterotonic properties. Some plants were then grown in an agricultural experimental field station of the National Institute of Agricultural Research, where all the variables were known, allowing for a valid comparison between species and plants. In vitro uterotonic potency was assayed and the results expressed as equivalents of oxytocin. The wild plants were found to vary greatly in uterotonic potency, perhaps reflecting differences in ecological conditions. The most active uterotonic zoapatle aqueous crude extract was the Montanoa frutescens, and the least active was M. mollissima, the former having approximately 4 times the uterotonic potency of the latter. The plants grown in the agricultural field station showed a considerable decrease in uterotonic potency, but valid comparisons must await assay in winter to match the stage in the plant life when the wild samples were assayed. Plant age, the part of the plant from which the uterotonic principle is extracted, climate, altitude, and soil constituents are other possible influences on uterotonic potency. A sample of the zoapatle aqueous crude extract with the highest uterotonic potency will be assayed for its luteolytic activity in an animal model.

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Differences in uterotonic activity were observed between zoapatle Montanoa (Cerv.), plants growing in their natural habitat and plants growing in an experimental agricultural plot. Details of an in vitro analogic model for assaying uterotonic potency in guinea pig strips is described. Important species differences on the uterine response to zoapatle aqueous crude extract were noticed in rats, hamsters, guinea pigs, cats and Rhesus monkeys. The need for proper biological evaluation of chemical substances already isolated from zoapatle specimens, is mentioned, and the advantages of working with zoapatle specimens grown under controlled ecological conditions are pointed out.

PIP: An in vitro analogic method for comparing the uterotonic potency of dialysed zoapatle aqueous crude extract (DZ-ZACE) with oxytocin is described. Uterine strips from estrogenized guinea pigs were selected as the appropriate animal model after trials with estrogenized rats, hamsters, cats, and Rhesus monkeys. Results of the in vitro uterotonic effect produced by 21 different zoapatle Montanoa plants collected from different parts of Mexico and grown in an experimental agricultural field station indicate considerable difference, with less variation in uterotonic oxytocin/equivalents among the plants grown at the field station than in wild specimens. The general reduction in uterotonic potency of plants grown at the field station may be due to differences in the time of collection: wild specimens were collected in winter 1980, while field station specimens were collected just after flowering in early summer 1981. The findings clearly demonstrate the influence of the plant environment on the expression of biological response. Because of its lack of toxicity, abundance, ease of production, and the availability of an efficient analogic in vitro assay for the evaluation of relative uterotonic potency, ZACE may eventually be the source of a new agent to intercept pregnancy.

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The zoapatle aqueous crude extract has been used in Mexico for the last 5 centuries for the induction of labor, treatment of post-partum bleeding problems, and as a menses inducer. Today, it is sold in street markets, and its long documented history of use by humans could be taken as indirect evidence of a lack of toxicity. Rigorous pharmacological and clinical studies described here, fully confirm the empirical observations.

PIP: For the last 5 centuries in Mexico the zoapatle aqueous crude extract (ZACE) has been used for the induction of labor, treatment of postpartum bleeding problems, and as a menses inducer. Despite widespread and continuous use of ZACE on the part of the Mexican population and the absence of documented side effects or toxicological phenomenon associated with its use, it was decided to undertake acute and subacute toxicological studies prior to clinical studies in volunteer subjects in Mexico and Sweden. Plant specimens for the studies were collected in different batches at several locations near the National University of Mexico. The material was properly identified at the university's botanical herbarium. ZACE was prepared by boiling 100 g of dry leaves in 400 ml of distilled water for 20-30 minutes, filtered through gauze, and the final volume obtained by using a rotor evaporator 50-60 degrees Centigrade with light negative pressure, to 100 ml. The ZACE concentration was 1 g dry leaves/ml. The extract was tested in an "in vitro" guinea pig uterine strip assay. For the 1st series of studies in Mexico, 60 female Sprague-Dawley rats, 8 weeks old, and 6 mongrel female dogs, were used. 25 rats were used as control and 35 tested. All animals were maintained in a controlled laboratory condition with 12/12 hour light/darkness cycle. 2 dogs served as control, and 4 were treated. All experimental animals received, through a rubber cannula, 5 ml/KG of ZACE daily. Control animals received distilled water. Each animal was carefully observed for 30 minutes after fluid intake. At the end of the study, the rats were sacrificed with ether, and the dogs with phenobarbital. Complete anatomapathological examinations were performed. 6 control and 8 treated rats died during the study, and all deaths were associated with accidental placement of the rubber cannula. Behavioral changes were observed in neither rats nor dogs throughout the study. No changes were recorded in body weights. No macro nor microscopic alteration was found in either group of rats. Results of hematological examinations did not differ between the 2 groups. It was concluded that ZACE is devoid of acute and subacute toxicity. In addition to the clinical observations reported by Gallegos in Mexico, where 10 normally menstruating volunteer women received 15 or 30 gm/day of zoapatle dry leaves extract orally for 3-9 consecutive days without clinical evidence of any side effects, clinical investigations were conducted by Landgren et al. in Sweden. 6 women in early pregnancy were given zoapatle; 6 women in early pregnancy served as a control group. A significant dilation of the cervix was found in each of the subjects treated with zoapatle decocts. A menstrual like cramp was reported by all and bleeding occurred in 4 of 6 subjects. No gastrointestinal symptoms were observed. No pain or bleeding nor significant dilatation of the cervix was evident prior to surgery. Immediately prior to vacuum extraction, cervical dilatation was less than 5 mm in all subjects. In sum, ZACE was devoid of toxic complication or side effects.

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Kauradienoic acid was obtained from the hexanic extract of M. tomentosa (Cerv) leaves by chromatographic separation. This substance influenced the in vitro contractility of the rat, dog and guinea pig uterine strips. It also induced strong contractions of the guinea pig uterus in vivo when administered intravenously, without changes on arterial blood pressure. The effects produced by the plant infusion, the hexanic extract and pure species were compared. The hexanic of other utero-active compounds in M. tomentosa in addition to those already described is discussed.

PIP: The investigation of uterotonic effects of the hexanic extract (HE) of M. tomentosa leaves, as well as that (-)-kaura-9(11), 16-dien-19-oic acid, henceforth referred to as kauradienoic acid (KA) is described. Pregnant and nonpregnant female Wistar rats, guinea pigs, and dogs were used in this study. Strips obtained from 5 animals had spontaneous rhythmical contractions constant in amplitude and frequency. Muscular tone and frequency of contractions were notably increased by addition of 20 ul/ml of zoapatle aqueous crude extract (ZACE). The preparation returned to the original spontaneous contractility pattern after washing with a modified Ringer solution. Strips obtained from 5 gravid guinea pigs showed scarce spontaneous contractility which was strongly augmented by addition of ZACE. Regular spontaneous contractions were observed in over 30 assays of uterine strips obtained from 5 nongravid rats. The addition of ZACE drastically inhibited the spontaneous contractility. Constant and reproducible results were obtained in gravid rats by addition of ZACE. A gradual decrease in amplitude of contractions was observed. The addition of ZACE depressed the uterine contractility (UC) of 8 uterine strips from 2 animals. The addition of ZACE in gravid dogs in 8 uterine strips was accompanied by an increase of muscular tonus and frequency. A gradual decrease in the amplitude of the rat spontaneous UC was an effect produced by the HE. Addition of water suspension of HE elicited an immediate increase of guinea pig's uterine motility. Results were similar with those observed with ZACE. KA inhibited the "in vitro" rat UC and increased the "in vitro" guinea pig contractions of uterine musculature in a similar fashion as observed with ZACE and HE.

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From the bark of Tabebuia rosea, the iridoid 6-O-(p-coumaroyl)-catalpol (specioside) was isolated. Antimalarial properties have been attributed to the infusion prepared from this part of the plant, although the compound failed to exhibit antimicrobial activity. The structure was corroborated by comparison with reported data for specioside as well as some additional chemical and spectroscopic data described herein.