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At least 469 records · Page 26Linked to original sources
PubMed1991

[Evaluation of occupational exposure to aromatic polycyclic hydrocarbons in bituminous pulp plants].

A method was developed for isolation of aromatic polycyclic hydrocarbons (APH) from atmospheric air. Air samples were filtered through Whatman GF/C filter papers, subsequently extracted with benzene. Aromatic polycyclic hydrocarbons were isolated from the extract, purified by column chromatography on aluminium oxide and determined by gas chromatography. This method was applied to determine qualitatively and quantitatively: naphthalene, anthracene, pyrene, perilene, biphenyl, fluoranthene, phenanthrene, benzo(a)pyrene, dibenzo(a,c)anthracene, dibenzo(g,h)anthracene, 11H-benzo(a)fluorane, 11H-benzo(b)fliorene, benzo(g,h,i)perylene, benzo(a)anthracene, chrysene, indene and durene. Professional exposure in years 1977-1989 was comparatively assessed using the evaluation criterion for APH expressed as the benzene fraction (0.2 mg/m3--USA standard) and as benzo(a)pyrene (0.00015 mg/m3--USSR standard). According to the accepted standards, working conditions in the examined plants entail a risk for the employees. Comparison of the results obtained before and after reconditioning of the machinery suggests the need for further modernization aimed at application of new technical solutions allowing for limitation of pollutant emission to air.

Air Pollutants, Occupational↗
PubMedDate not supplied

Highly selective and specific antagonism of central and peripheral alpha 2-adrenoceptors by atipamezole.

The potency, selectivity and specificity of atipamezole [MPV-1248, 4-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole], as an alpha 2-adrenoceptor antagonist was studied. In receptor binding studies [( 3H]-clonidine and [3H]-prazosin displacement) an alpha 2/alpha 1 selectivity ratio of 8526 was obtained for atipamezole, while idazoxan and yohimbine showed ratios of 27 and 40, respectively. Atipamezole had also about a 100 times higher affinity on alpha 2-adrenoceptors than the reference compounds. In the electrically stimulated prostatic portion of rat vas deferens, atipamezole showed potent competitive antagonistic activity against clonidine (pA2 8.6) and medetomidine (pA2 8.7) at presynaptic alpha 2-adrenoceptors. In the epididymal portion of the rat vas deferens, atipamezole had only weak competitive antagonistic activity against phenylephrine (pA2 5.0). In binding studies and studies with isolated organs, atipamezole had no effect on beta 1-, beta 2-, H1-, H2-, 5-HT1-, 5-HT2-, muscarine, DA2-, tryptamine, GABA, opiate and benzodiazepine receptors. In the pithed rat, atipamezole, like idazoxan, had partial alpha 1-adrenoceptor-mediated vasoconstrictor effects in addition to potent alpha 2-adrenoceptor blocking activity. In mice, medetomidine-induced sedation was effectively antagonized by atipamezole. These results show that atipamezole is a potent, selective and specific antagonist of both centrally and peripherally located alpha 2-adrenoceptors.

Adrenergic alpha-Antagonists↗
PubMedDate not supplied

Alpha 2-adrenoceptor-mediated inhibition of gastric acid secretion by medetomidine is efficiently antagonized by atipamezole in rats.

The effect of a novel highly selective alpha 2-adrenoceptor agonist, medetomidine (4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole), was studied on gastric secretion in conscious and anaesthetized rats. Medetomidine (3-30 micrograms/kg s.c.) inhibited basal gastric acid and fluid output in conscious rats in a dose-dependent manner, while in anaesthetized rats no effect was observed when administered i.v. at the doses of 1-1000 micrograms/kg. Furthermore, medetomidine did not modify gastric acid output stimulated by infusion of histamine i.v. in anaesthetized rats, suggesting also that a medetomidine-induced change in gastric secretion does not involve any action on histamine H2-receptors. Furthermore, evidence was given indicating that alpha 2-adrenoceptors mediate the antisecretory action of medetomidine, since a low dose (0.1 mg/kg s.c., -30 min) of a selective alpha 2-adrenoceptor antagonist, atipamezole [MPV 1248, 4-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole] efficiently antagonized the effects of medetomidine (30 micrograms/kg s.c.) in conscious rats. In summary, medetomidine inhibits gastric secretion in the rat via alpha 2-adrenoceptor activation, the antisecretory action being blocked by atipamezole. Probably due to its high specificity for alpha 2-adrenoceptors, medetomidine did not show a stimulatory effect on gastric acid secretion in anaesthetized rats.

Adrenergic alpha-Agonists↗
PubMed1987

Protective effects of indeloxazine hydrochloride on cerebral ischemia in animals.

Effects of indeloxazine hydrochloride [(+/-)-2-[(inden-7-yloxy)methyl]morpholine hydrochloride, YM-08054] on cerebral ischemia were investigated in animals. Indeloxazine prolonged the gasping duration dose-dependently in decapitated mice. Bilateral occlusion of the carotid artery for 5 min shortened the latency of step-through in passive avoidance task 4 days following ischemia in mongolian gerbils. The i.p. administration of indeloxazine was started just after the surgical operation and repeated twice a day for 4 days. Indeloxazine (2 mg/kg) significantly prolonged the latency of step-through in this amnesic model, indicating a reversal effect on the ischemia-induced amnesia. In biochemical studies, decreases in brain ATP and total adenine nucleotide levels were inhibited by indeloxazine (2 mg/kg i.p., once a day for 7 days) in four-vessel occluded rats. These findings indicate that indeloxazine possesses protective effects on cerebral ischemia presumably due, in part, to improvement of the cerebral energy metabolism.

Animals↗
PubMed1987

Effects of indeloxazine hydrochloride (YM-08054) on anoxia.

Effects of indeloxazine hydrochloride [(+/-)-2-[(inden-7-yloxy)methyl]morpholine hydrochloride, YM-08054] on anoxia were examined. Indeloxazine significantly prolonged survival time of mice subjected to anoxia and improved anoxia-induced impairment of the passive and active avoidance learnings in rats. Indeloxazine at doses inducing anti-anoxic actions showed no effect on cerebral blood flow in cats and pentobarbital sleeping time in mice. Therefore, anti-anoxic actions of indeloxazine are not attributable to cerebral vasodilative or central depressant activities. Calcium hopantenate (cerebral metabolic enhancer) also showed anti-anoxic actions, whereas neither viloxazine, amitriptyline (antidepressant) nor dihydroergotoxine (cerebral vasodilator) showed any effect on anoxia. These results suggest that indeloxazine possesses anti-anoxic activities similar to calcium hopantenate. The mode of anti-anoxic actions of indeloxazine is also discussed.

Amitriptyline↗
PubMed1984

Molecular structures of metabolites and analogues of diethylstilbestrol and their relationship to receptor binding and biological activity.

A series of indanyl derivatives of diethylstilbestrol (DES) have recently been identified as inv vivo metabolites of DES. These compounds are of interest because they possess effective uterine estrogen receptor-binding affinity but poor biological activity. The X-ray crystal structures of three of these derivatives were determined and their conformations were compared with those of estradiol and DES. The more active derivatives, indenestrol A (I) and indenestrol B (II) have nearly identical conformations, in which the overall molecule is highly planar, the phenyl ring is twisted out of the plane of the indene rings by approximately 30 degrees, and the distance between the hydroxyl groups is 11.6 A. In the least active derivative, idanestrol (III), the methyl, ethyl, and phenyl substituents were found to be in the same side of the indane ring so that the molecule is constrained to an L-shape. The crystallographically observed conformations of I, II, III, DES, and estradiol, their competative binding affinities, and their in vivo biological activities are consistent with the proposal that the steroid A-ring plays a dominant role in initiating receptor binding while the D-ring orientation relative to the A-ring has a more decisive influence upon activity. The reduction in estrogen receptor-binding affinity and associated reduced activity of III is almost certainly due to its L-shape conformation. The extended conformation of I and II in which both phenolic rings are exposed permitting ready access to both surfaces of either ring probably accounts for the ability of these derivatives to compete so successfully with estradiol for estrogen receptor binding. There are eight different ways in which the molecules of the racemic mixtures of I and II could initiate receptor binding. The reduced biological activity of I and II is probably due to the fact that not all eight binding orientations are compatible with eliciting estrogenic response. Comparison of the observed conformations of I, II, DES, and estradiol suggests that it is the alpha-ring of I and II that minics the steroid A-ring in receptor binding, and that two of the four possible alpha-ring/A-ring matches are most conducive to eliciting hormone activity.

Animals↗
PubMed1980

Mechanism of oxygen transfer by prostaglandin hydroperoxidase.

The peroxidase associated with prostaglandin cyclooxygenase in ram seminal vesicle microsomes will utilize a wide variety of hydroperoxides and reducing substrates. One such reducing substrate, sulindac sulfide (cis-5-fluoro-2-methyl-1-[p-(methylthio)benzylidenyl]indene-3-acetic acid), inhibits the oxygenase, stimulates the peroxidase, and is oxidized to its analogous sulfoxide by the peroxidase. The peroxidase-catalyzed transfer of oxygen atoms from 15-hydroperoxyprostaglandin E2 (15-HPE2) to sulindac sulfide was examined using [18O]15-HPE2 which was prepared enzymatically and analyzed mass spectrometrically. The sulfoxide resulting from sulindac sulfide oxidation was also analyzed mass spectrometrically and found to possess an oxygen atom arising exclusively from the 15-HPE2. Since sulindac sulfide inhibits the oxygenase activity of this enzyme (ID50 approximately equal to 0.2 microM), it seemed possible that the oxygen atom was transferred while the sulfide was bound to this site. However, indomethacin, an inhibitor of the oxygenase with no effect on the peroxidase, did not alter the stoichiometry of sulindac sulfide oxidation, precluding this possibility. These findings are discussed in the context of identifying the nature of the actual oxidant and distinguishing between the oxidation mechanisms of various peroxidases and between sulindac sulfide and other reducing substrates for these enzymes.

Animals↗
PubMedDate not supplied

Anti-hypoxic and anti-ischemic actions of indeloxazine hydrochloride and its optical isomers: possible involvement of cerebral energy metabolism.

We evaluated the anti-hypoxic and anti-ischemic actions of indeloxazine hydrochloride ((+/-)-2-[(inden-7-yloxy)methyl]morpholine hydrochloride, YM-08054) in comparison with its optical isomers and several selective monoamine uptake inhibitors in mice. The effects of indeloxazine on both cerebral energy metabolism in normal mice and local cerebral glucose utilization in normal rats were also studied. Indeloxazine and its (-)-isomer, with both serotonin and norepinephrine uptake inhibitory actions, and its (+)-isomer, with a serotonin uptake inhibitory action, prolonged the survival time of mice subjected to nitrogen gas and the gasping duration in decapitated mice. Indeloxazine and its (+)-isomer were approximately 3-10 times more potent than the (-)-isomer with regard to their anti-hypoxic and anti-ischemic activities. Selective norepinephrine uptake inhibitors such as maprotiline and viloxazine, and selective serotonin uptake inhibitors such as citalopram, alaproclate and zimeldine, did not show anti-hypoxic properties. On the other hand, amantadine, a selective dopamine uptake inhibitor, and amitriptyline, a tricyclic antidepressant with anticholinergic properties, significantly shortened the survival time in hypoxic mice. In biochemical studies, increases in brain ATP and glucose levels without affecting lactate level in mice and an elevation in local cerebral glucose utilization in 10 brain regions involving the frontal cortex in rats were observed after administration of indeloxazine. These results suggest that indeloxazine and its optical isomers possess anti-hypoxic and anti-ischemic actions distinct from those of typical monoamine uptake inhibitors, and that these effects of indeloxazine may be due, at least in part, to a facilitation of cerebral energy metabolism.

Animals↗
PubMed1996

Observations with an S-adenosylmethionine decarboxylase inhibitor in rats with prostatic adenocarcinoma.

CGP 48664A (2-(4-aminoiminomethyl)-2,3-dihydro-1H-inden-1-ylidene dihydrochloride, CAS 149400-88-4) is a new potent inhibitor of S-adenosylmethionine decarboxylase with antitumor properties. In view of the eminent clinical problems in the treatment of non hormone dependent prostatic cancer, the antiproliferative potency of this compound was tested in Dunning MAT-LyLu rat prostatic adenocarcinoma. The compound proved inefficient in preventing the growth of this tumor, even at a near toxic dose. A reason for the lacking effect is presumably the inadequate accumulation of the drug in the tumor cells due to the excessive growth rate of the MAT-LyLu xenografts. Tumor growth seems not to be accompanied by a proportionally rapid vascularization of the tumor mass. CGP 48664A was found to be a potent inhibitor of polyamine oxidase. This property of the drug may have contributed to the activation of the phagocytic capacity of peritoneal macrophages from tumor-bearing rats.

Adenocarcinoma↗
PubMed1997

Chronic morphine treatment increases stimulatory beta-2 adrenoceptor signaling in A431 cells stably expressing the mu opioid receptor.

Chronic opioid regulation of stimulatory beta-2 adrenoceptor (beta-2 AR) signaling was investigated in human mammary epidermoid carcinoma A431 cells stably expressing the cloned rat mu opioid receptor. In the cell clone used (A431/mu 13; Bmax = 302.9 +/- 46 fmol/mg membrane protein), the addition of morphine acutely attenuated basal as well as (-)-isoproterenol-stimulated cAMP accumulation. Prolonged exposure of the cells to morphine (10 microM; 2 d) resulted in homologous desensitization of MOR function as well as heterologous sensitization of adenylate cyclase (AC). Up-regulation of AC in A431/mu 13 cells is characterized by an increased capacity rather than an increased sensitivity of beta-2 AR-stimulated AC. Moreover, opioid withdrawal falls to precipitate a cAMP overshoot in this cell system. Sensitization of stimulatory AC signaling by chronic morphine develops in a time- and dose-dependent manner and is blocked by both naloxone and pertussis toxin. Investigation into the mechanism leading to up-regulation of AC revealed a 40% increase in the number of beta-2 ARs as assessed by [125I]-cyanopindolol binding experiments. No additional quantitative changes were found for stimulatory G proteins and the effector enzyme itself. Sensitization of AC appears to be mediated solely by the increase in beta-2 AR numbers, because (+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3- [(1-methylethyl)amino]-2-butanol hydrochloride, which acts as an "inverse agonist" at the beta-2 AR, completely reversed elevated basal AC activities, and because the ratio between functional active beta-2 ARs and stimulatory G proteins remained unchanged. In conclusion, chronic exposure of clonal A431/ mu13 cells to morphine increases the capacity of stimulatory AC signaling by up-regulating beta-2 AR number. These results demonstrate participation of stimulatory receptor systems in the cellular mechanisms underlying opioid dependence.

Adenylyl Cyclases↗
PubMed1998

Stimulation of apoptosis by sulindac and piroxicam.

1.Sulindac, cis-5-fluoro-2-methyl-1-(p-methylsulphinylbenzylidene)indene-3-ace tic acid, inhibits growth of colon polyps and cancers. This effect has been attributed to inhibition of prostaglandin synthesis but more recent observations indicate that, in vitro, cells that do not have cyclo-oxygenase nor RNA for synthesis of such enzymes are affected by sulindac. Therefore the presumptive effect is probably not correct.2.It has also been found that sulindac stimulates apoptosis. It is herein postulated that in tumour cells such effects may be due to interaction of the anionic form of the drug with protons in the intermembrane space of mitochondria to disrupt the potential across the inner mitochondrial membrane and thereby initiate apoptosis. Normal cells are not affected.

Anti-Inflammatory Agents, Non-Steroidal↗