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The amphibian Xenopus laevis embryo (tadpole) provides a satisfactory alternative to mammalian screening for structural teratogens. Testing was undertaken to extend the usefulness of this species for behavioral teratogenicity testing. One simple and eight operant conditioning paradigms were examined: none elicited learning in Xenopus embryos. Adaptation to the conditioning stimulus (light) and freezing in response to the unconditioned stimulus (shock) were responses incompatible with conditioned learning.

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Short-term (96-h) tests on Xenopus laevis embryos are advocated for rapid screening of teratogens, as an alternative to the use of mammals. The objective of the present investigation was to determine whether extending the short-term tests beyond 96 h would detect the teratogenicity of chemicals that would otherwise be missed by the short-term tests. Lead teratogenicity was examined in Xenopus, using lead concentrations of 0.02, 0.05, 0.1, 0.5, 1.0, and 3.0 mg/L, which bracket the U.S. Environmental Protection Agency (EPA) maximum allowable concentration of 0.05 mg/L in water. Short-term exposure times were 72 or 96 h, starting on d 1, 2, or 3 postfertilization, while long-term exposure covered d 1 through metamorphosis. Short-term exposure resulted in neural tube defects (when exposure included d 1 and/or d 2) and tail curvatures, but only at the higher lead concentrations (1 and 3 mg/L). Lower lead concentrations produced no malformations upon short-term exposure, and this corresponded with the absence of tissue lead uptake. On the other hand, long-term exposure to lead (> 3 wk) resulted in the delayed appearance of lordoscoliosis at low lead concentrations (0.02-0.1 mg/L). The delayed appearance of lordoscoliosis corresponded roughly with the attainment of stable lead tissue levels, and this malformation persisted after metamorphosis. Thus, short-term observation tests alone may fail to detect the teratogenicity of low concentrations of environmental chemicals, and may result in the setting of inappropriately liberal exposure standards.

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1. Propyl-methylenedioxyindene (pr-MDI) is an intracellular calcium antagonist which inhibits cold-restraint stress ulceration at subcardiovascular doses (less than or equal to 30 mg/kg). It also inhibits gastric acid secretion evoked by RX77368 (a stable analog of thyrotropin-releasing hormone, the putative mediator of cold-restraint stress ulcers). 2. The objective of this investigation was to localize the site of the inhibitory effect of pr-MDI on gastric acid secretion stimulated by intracisternal (i.c.) administration of RX77368 (100 ng) in rats. 3. Peripheral administration of pr-MDI (30 mg/kg i.p. or i.v.) inhibited the elevated basal and the RX 77368-induced acid secretion in conscious 2-hr pylorus-ligated rats. This effect was completely blocked in anesthetized (urethane or pentobarbital) acute gastric fistula rats. 4. Intracisternal administration of pr-MDI (0.1-1 mumol) produced a dose-related inhibition of acid secretion in conscious pylorus-ligated rats. However, urethane anesthesia completely blocked the inhibitory effect of i.c.-administered pr-MDI (1 mumol) on RX77368-induced acid secretion. 5. Since previous studies indicate that anesthesia does not inhibit peripheral actions of pr-MDI (e.g. the antiarrhythmic effect), the convergent evidence suggests that the inhibitory effect of pr-MDI on gastric acid secretion is mediated primarily via the central nervous system.

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1. Propyl-methylenedioxyindene (pr-MDI) is an intracellularly acting calcium antagonist with H2-receptor blocking properties. Stimulus-secretion coupling is inhibited by much lower concentrations of pr-MDI than is excitation-contraction coupling. 2. Since the processes leading to gastric ulceration are calcium-dependent, the aim of this study was to determine if pr-MDI could provide useful antiulcer activity at doses below those required to produce cardiovascular effects. 3. The antiulcer activity of pr-MDI (10-30 mg/kg) was examined in the cold (4 degree C)/restraint (3 hr) stress-induced ulcer model in male rats, and compared with the effects of the H2-blocker cimetidine (10-30 mg/kg) and the calcium channel blocker verapamil (11-32 mg/kg). The drugs were administered intraperitoneally 10 min prior to the cold/restraint stress. 4. All three drugs significantly reduced the number of ulcers and the cumulative length of ulcerated stomach surface in a roughly dose-dependent and equivalent manner. However, whereas the antiulcer doses of verapamil were extremely high, those of pr-MDI were one-sixth to one-half of its antiarrhythmic ED50 in rodents.

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1. Propyl-methylenedioxyindene (pr-MDI) is an intracellularly acting calcium antagonist which protects against cold/restraint-induced stress ulcers in rats. The doses of pr-MDI which produce antiulcer activity (10-30 mg/kg i.p.) are significantly lower than those which exhibit cardiovascular effects. 2. Two potential mechanisms for the antiulcer action of pr-MDI were investigated in this study: the effects on hydrochloric acid secretion and on gastric motility (gastric emptying). 3. Bethanechol-induced hydrochloric acid secretion in acutely pylorus-ligated rats was significantly obtunded by pr-MDI (30 mg/kg i.p.), but the effect was significantly weaker than that produced by verapamil (16 mg/kg i.p.) or cimetidine (10 mg/kg i.p.). Since 30 mg/kg pr-MDI produces greater antiulcer activity than the very high dose of 16 mg/kg verapamil, it is unlikely that inhibition of acid secretion plays more than a contributory role in the antiulcer mechanism of action of pr-MDI. 4. pr-MDI (10-30 mg/kg i.p.) produced a dose-dependent slowing of gastric emptying in rats fed a methylcellulose/Phenol Red test meal, and this effect correlated well with the antiulcer action. Verapamil (16 mg/kg i.p.) did not affect gastric emptying. 5. The results indicate that a reduction of gastric motility plays a major role in the mechanism of the antiulcer action of pr-MDI.

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Propyl-methylenedioxyindene (pr-MDI; 30 mg/kg, i.p.), an intracellular calcium antagonist, significantly reduced the number and size of erosions per stomach induced by cold-restraint stress by 69% and 86%, respectively. Our previous findings indicate that the antiulcer activity of pr-MDI is highly correlated with its inhibitory effect on gastric motor activity. Since central TRH is suggested as the brain mediator responsible for cold-restraint stress gastric ulcers in rats, the inhibitory action of pr-MDI was evaluated in the TRH-induced gastric lesion model. Pr-MDI (30 mg/kg) did not reduce the gastric erosions induced by intracisternal administration of 100ng RX77368, a stable thyrotropin-releasing hormone (TRH) analogue, even though it abolished the RX77368-induced stimulation of gastric emptying, gastric acidity, and acid output. Since pr-MDI (30 mg/kg, i.p.) significantly inhibited the stimulation of gastric motility by both cold-restraint stress and TRH, but only cold-restraint stress-induced gastric erosions were effectively reduced by the drug, the present findings suggest a possible dissociation between the ulcerogenic mechanisms of cold-restraint stress and intracisternal administration of TRH.

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Since propyl-methylenedioxyindene (pr-MDI) exhibits significant protective effects against stress-induced ulcers in rats at subcardiovascular doses (10-30 mg/kg, i.p.), the aim of the present study was to explore the effect of this intracellular calcium antagonist on cysteamine-induced duodenal ulcers at the same low doses. Duodenal ulcers were induced in rats with a single dose of cysteamine (425 mg/kg, s.c.), which produced an 80% ulcer incidence within 24 h without affecting gastric acid concentration. Administration of pr-MDI (10 and 30 mg/kg, i.p.) at 0, 6 and 12 h post-cysteamine did not afford protection against ulceration. On the other hand, atropine (10 mg/kg, s.c., administered at 0, 6 and 12 h post-cysteamine) resulted in a 69% inhibition of ulceration, and the antacid Maalox (2 ml, administered p.o. at 0, 2, 4, 6 and 12 h post-cysteamine) completely prevented ulceration. The failure of pr-MDI to protect against duodenal ulceration is discussed in relation to its pharmacological mechanism of action and the pathogenetic mechanism of action of cysteamine.

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1. Calcium is proposed to play a role in the genesis of epileptic seizures, and a number of established antiepileptic drugs limit the transport of extracellular calcium into neuronal cells. 2. The aim of the present study was to explore the potential antiepileptic activity of three calcium antagonists: nifedipine (20 mg/kg i.p.), which blocks the calcium channel at its outer mouth; verapamil (30 mg/kg i.p.), which blocks the calcium channel at its inner mouth; and propyl-methylenedioxyindene (pr-MDI; 68, 100 and 120 mg/kg i.p.), which acts intracellularly to inhibit calcium mobilization from the endoplasmic reticulum. 3. In the maximal electroshock test, none of the calcium antagonists provided protection against tonic seizures in mice. Phenytoin (20 mg/kg i.p.), on the other hand, afforded complete protection. 4. In the pentylenetetrazol-induced seizure test, the order of effectiveness of the three calcium antagonists in attenuating the severity of the clonic and tonic seizures in mice was: nifedipine greater than verapamil greater than pr-MDI. All three calcium antagonists were less effective than ethosuximide (200 mg/kg i.p.). 5. These findings indicate that the calcium antagonists would be of no value in the treatment of grand mal epilepsy, while only those agents acting at the outer side of the membrane would have limited usefulness at best against petit mal seizures.

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Previous studies provided strong evidence that propyl-methylenedioxyindene (pr-MDI) interfered with calcium at an intracellular site. To further characterize the mechanism of action of pr-MDI, its pharmacological actions on chemically skinned vascular smooth muscle were examined. Rat caudal artery strips were chemically skinned with saponin (0.15 mg/mL for 1 h). The efficiency of the skinning was evidenced by a loss of contractile response to 74 mM K+. The intactness of the regulatory and contractile proteins was ascertained by the ability of the skinned tissue to contract in response to Ca2+ (free Ca2+ concentration of 10(-4) or 10(-6)M). Caffeine (25 mM) induced contraction was used as an index of the functional integrity of the sarcoplasmic reticulum in the skinned preparations. Contraction of the skinned artery with a free Ca2+ concentration of 10(-6)M was significantly obtunded by 1 X 10(-4)M trifluoperazine (a calmodulin antagonist) but not by 1 X 10(-4)M pr-MDI. Contraction of the skinned artery evoked by 25 mM caffeine in the absence of extracellular calcium was significantly obtunded by 1 X 10(-4)M pr-MDI but not by 1 X 10(-6)M nifedipine (a calcium channel blocker). The results indicate that pr-MDI acts intracellular to block calcium mobilization from the sarcoplasmic reticulum without directly interfering with the regulatory and contractile proteins.

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The actions of many vasoactive drugs are mediated through, or modified by, the endothelium-derived relaxing (EDRF) and constricting (EDCF) factors. While EDRF appears to be nitric oxide, EDCF is a peptide or cyclooxygenase product. Using verapamil (a calcium channel blocker), propyl methylenedioxyindene (pr-MDI; an intracellular calcium antagonist), and sodium nitroprusside (which liberates nitric oxide from its molecular structure) as EDRF-independent pharmacological probes in rat aortic rings with and without endothelium, we attempted to provide additional insight into the role of extracellular [( Ca]o) and intracellular [( Ca]i) calcium in EDRF and EDCF release and action, and to explain some mechanisms underlying the modulatory effects of these endothelial factors on the actions of vasoactive drugs. The findings suggest that (1) the [Ca]o required for evoked EDRF release does not enter endothelial cells through verapamil-sensitive calcium channels; (2) mobilization of endoplasmic reticular [Ca]i by [Ca]o entering the endothelial cell may be the trigger for evoked EDRF release; (3) spontaneous release of EDRF appears to depend more on mobilization of [Ca]i than on influx of [Ca]o; (4) the action of EDRF on smooth muscle either does not require Ca or does not involve the mobilization of [Ca]i by [Ca]o; (5) Both EDRF and EDCF can modulate the actions of vasoactive drugs; (6) the EDCF of the rat aorta is not a cyclooxygenase product, and (7) the action of EDCF on vascular smooth muscle, and possibly its release from endothelial cells, are Ca-dependent.

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This study was undertaken to determine the relative age-dependent responsiveness of the rat aorta to depolarizing (potassium) and receptor-activating (norepinephrine) contractile stimulants, and to the calcium antagonists propyl-methylenedioxyindene (pr-MDI) and nifedipine. Pr-MDI exhibits intracellular calcium antagonistic and calcium channel blocking properties in this tissue, while nifedipine acts principally as a calcium channel blocker. Thoracic strips from young (4-6 months old) and senescent (22-23 months old) Fischer F344 rats were contracted with KCl (10-60 mmol/l) or norepinephrine (10(-9)-5 X 10(-6) mol/l). Aortae from old rats were significantly more sensitive to norepinephrine than aortae from young rats, while the reverse was observed for KCl. Pr-MDI (10(-5)-10(-4) mol/l) significantly relaxed the aortic contractions induced by norepinephrine (10(-7) mol/l, a nondepolarizing concentration producing 88% of maximum response in young and old aortae) and by KCl (50 mmol/l, a depolarizing concentration producing 96% of maximum response in young and old aortae). However, there were no age-related differences in sensitivity to the relaxant effects of pr-MDI against either stimulant. Pr-MDI was more effective in relaxing KCl-induced contractions than those induced by norepinephrine. Similar results were obtained with nifedipine (10(-10)-10(-6) mol/l). These results indicate that senescence of the rat aorta is accompanied by an enhanced responsiveness of adrenergic alpha-receptor-mediated contraction, a reduced responsiveness to depolarizing stimuli, and no change in sensitivity to calcium antagonism.

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Epidemiological studies demonstrate the possible increased risk of Reye's syndrome after aspirin ingestion in children suffering from viral influenza or chicken pox. This study was conducted to determine whether the possible association between aspirin and Reye's syndrome in viral influenza and chicken pox deterred pediatricians and pharmacists in a large American city (Columbus, Ohio) from prescribing or recommending aspirin to their pediatric patients suffering from other causes of fever or pain. The results indicate that 90.6 percent of pediatricians and 97.8 percent of pharmacists no longer recommend aspirin to their pediatric patients, and an almost identical percentage recommend acetaminophen instead of aspirin. This change in prescribing habits of health professionals is reflected in a drop in sales of pediatric aspirin products with a simultaneous rise in sales of pediatric acetaminophen products reported by 93.3 percent of pharmacies. However, only 69.8 percent of pediatricians and 86.7 percent of pharmacists noted that their abstention from prescribing or recommending aspirin to children was rooted in a belief in a possible association between aspirin and Reye's syndrome.

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Calcium channel blockers have been advocated as potential therapeutic agents in the management of premature labor. In the present study, the class of intracellular calcium antagonistic methylenedioxyindenes (MDIs) was investigated for potential antiabortifacient activity in mice. Pretreatment of pregnant mice from day 15 of gestation with the MDIs did not afford protection against the abortifacient effect of prostaglandin F2alpha administered from day 17 of gestation. The MDIs demonstrated embryotoxic and fetotoxic activity as shown by a significant increase in the incidence of resorptions and stillbirths. Similar embryotoxicity was previously reported for the calcium channel blockers. It appears doubtful that any of the calcium antagonists so far examined will be clinically useful in the management of premature labor.

PIP: 2 intracellular calcium antagonists with weak membrane calcium channel blocking activity were tested for antiabortifacient and embryotoxic effects in mice. The compounds were 2-n-propyl-3-dimethylamino-5,6-methylenedioxyindene (pr-MDI) and cis-2-n-butyl-3-dimethylamino-5,6-methylenedioxindan (cis-H-bu-MDI). Charles River CD-1 mice treated intramuscularly with saline (controls), or Pgf2alpha twice daily to induce premature abortion starting on day 17 of gestation, with 15 or 25 mg/kg cis-H-bu-MDI. or 70 mg/kg/pr-MDI. the LD50 for cis-H-bu-MDI was 75 mg/kg (single intramuscular dose). The compounds had no effect on premature delivery. They significantly decreased numbers of live-born pups, however, counted as the difference between implantation sites and recovered live or stillborn pups. There were no malformations, maternal toxicity or detrimental effects of survival or term-born progeny. These calcium antagonists appear to be of no value in the management of premature labor.

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The antifibrillatory and electrophysiologic actions of bepridil and butyl-methylenedioxyindene (BU-MDI), two intracellular calcium antagonists, were examined in anesthetized dogs. The administration of bepridil (1.0-10.0 mg/kg i.v.) significantly increased the electrical threshold for ventricular fibrillation determined during unobstructed coronary flow, and was associated with a significant decrease in ventricular excitability and a progressive depression in ventricular myocardial conduction. BU-MDI (3.0-30.0 mg/kg i.v.) did not significantly alter ventricular fibrillation thresholds during unobstructed coronary flow, nor did it significantly alter electrophysiologic properties such as ventricular excitability, conduction or refractoriness. The administration of either bepridil (10 mg/kg i.v.) or BU-MDI (30 mg/kg i.v.), however, resulted in significant increases in the ventricular fibrillation thresholds determined during transient myocardial ischemia, restoring the threshold values to corresponding non-ischemic levels. These results suggest that an inhibition of the action and/or availability of intracellular calcium may play a role in the antifibrillatory actions of BU-MDI and bepridil during transient ischemia.

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The PGF2 alpha antagonist 5,6-bis(benzyloxy)-1-oxo-2-propyl-2-indanpropionic acid (1) had previously been shown to provide significant protection against the abortifacient actions of PGF2 alpha in mice. To explore further structural concepts in drug design employed for the development of 1, several mono(benzyloxy) ketones (3-10) and alcohols (11-15) as well as a diacid (22) were prepared. None of these structural modifications resulted in compounds of greater superiority to 1 as uterine relaxants and 22 was void of any antagonistic properties, suggesting that the original rationale requiring one carboxyl group and two benzyloxy functions appropriately placed for maximum PGF2 alpha antagonism in this series was a good assumption. A carbonyl rather than hydroxyl group at position C-1 of the indan is most beneficial for reversible antagonism. Reduction of the ketone to the alcohol is of synthetic interest and discussed in some detail.

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Dibenzyloxyindanpropionic acid (DIPA) is an antiabortifacient prostaglandin F2 alpha antagonist. Significant protection against prostaglandin F2 alpha-induced abortion in Charles River CD-1 mice is afforded by 50 mg/kg DIPA, administered intramuscularly twice daily from day-15 of gestation, two days prior to prostaglandin F2 alpha challenge. Furthermore, treatment of CD-1 mice with 50 mg/kg DIPA intramuscularly daily throughout gestation or with 50 or 200 mg/kg twice daily only on day-15 of pregnancy, revealed no structural teratological effects nor histopathological anomalies in the offspring. The present behavioral teratological investigation demonstrates that prenatal treatment of CD-1 mice with 50 mg/kg DIPA intramuscularly daily throughout gestation does not adversely affect postnatal morphological development (offspring viability; weight gain; timing of bilateral pinna detachment, eye opening, eruption of mandibular and maxillary incisors, appearance of mamillary ridges, vaginal opening, testicular descent, and appearance of downy fur), postnatal behavioral development (vocalization; auditory startle reflex; corneal reflex; righting reflex and subsequent air righting; cliff avoidance; limb placing response and grip strength; motor coordination; olfactory orientation; locomotion; motor activity; homing instinct; and acquisition and retention of an active avoidance task), or fertility of the progeny. It is concluded that DIPA is an effective and safe antiabortifacient in mice at the doses tested.

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Dibenzyloxyindanpropionic acid (DIPA) is an anti-abortifacient prostaglandin F2 alpha(PGF2 alpha) antagonist. Significant protection against PGF2 alpha-induced abortion in Charles River CD-1 mice is afforded by 50 mg/kg DIPA, administered i.m. twice daily from day-15 of gestation; two days prior to PGF2 alpha challenge. In the present teratological evaluation, CD-1 mice were treated either daily throughout gestation with 50 mg/kg DIPA i.m., or only on day-15 of gestation with two doses each of 50 or 200 mg/kg DIPA i.m. Controls received saline injections. Some dams were delivered by cesarian section on day-19 of gestation, while others were allowed to deliver spontaneously at term. Parameters monitored in the offspring were litter sizes, body weights, sex ratios, viability of progeny, external malformations, cleft palate, skeletal anomalies, patency (prenatal) and closure (postnatal) of the ductus arteriosus, gross anatomy of organs, and histopathological examination of tissues. Consistent with a PGF2 alpha antagonistic mechanism of action, DIPA treatment throughout gestation prolonged pregnancy to the upper normal limit. Prenatal administration of DIPA increased the pseudopregnancy rate, but none of the treatment schedules produced any recognizable teratogenic effects.

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