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PubMed1986

Gastric antisecretory and antiulcer properties of enprostil, (+/-)-11 alpha, 15 alpha-dihydroxy-16-phenoxy-17,18,19,20-tetranor-9-oxoprosta- 4,5,13(t)-trienoic acid methyl ester.

Prostaglandins of the E series have been shown, both in animals and humans to produce gastrointestinal antisecretory and antiulcer effects. Enprostil, a modified allenic prostaglandin E was found to be a highly potent inhibitor of gastric HCl secretion in a variety of species. In rats, in which both the pylorus and esophagus were ligated, p.o. ED50 values and 95% CL for inhibiting acid secretion evoked by histamine, pentagastrin and carbachol were 9.9 (6.7-15), 40 (11-145) and 0.83 (0.78-0.89) micrograms/kg, respectively. In inhibiting histamine-evoked acid secretion, enprostil was more potent when administered p.o. than when injected into the duodenum or s.c. When enprostil was injected directly into the pouch of Heidenhein dogs, intense antisecretory activity occurred, ED50 = 0.9 (0.7-1.1) micrograms/kg, whereas, when given p.o. to the main stomach the ED50 was 6.6 (3.2-13.6) micrograms/kg. Administration of cimetidine either p.o. or to the pouch resulted in virtually identical ED50 values, viz., 2.9 and 3.1 mg/kg. Enprostil also inhibited dimaprit- and pentagastrin-induced acid secretion in cats with permanent gastric fistulae. The oral ED50 values for inhibiting acid secretion evoked by these two secretagogues were 2.5 (1.4-4.3) and 0.8 (0.5-1.5) micrograms/kg, respectively. Enprostil was extremely potent in preventing indomethacin plus "cold stress" ulcers in rats. When given orally the ED50 was 0.61 (0.31-1.22) and s.c. it was 22 (9.0-52) micrograms/kg. It was also highly potent in preventing cysteamine-induced duodenal ulcers when given p.o., ED50 = 20 (17-23) micrograms/kg. Thus, enprostil is a highly potent antisecretory and antiulcer agent. It appears to act topically; directly at gastric mucosal sites.

Animals↗
PubMed1986

Effects of scavengers of reactive oxygen and radical species on cell survival following photodynamic treatment in vitro: comparison to ionizing radiation.

The effects of various scavengers of reactive oxygen and/or radical species on cell survival in vitro of EMT6 and CHO cells following photodynamic therapy (PDT) or gamma irradiation were compared. None of the agents used exhibited major direct cytotoxicity. Likewise, none interfered with cellular porphyrin uptake, and none except tryptophan altered singlet oxygen production during porphyrin illumination. The radioprotector cysteamine (MEA) was equally effective in reducing cell damage in both modalities. In part, this protection seems to have been induced by oxygen consumption in the system due to MEA autoxidation under formation of H2O2. The addition of catalase, which prevents H2O2 buildup, reduced the effect of MEA to the same extent in both treatments. Whether the remaining protection was due to MEA's radical-reducing action or some remaining oxygen limitation is unclear. The protective action of MEA was not mediated by a doubling of cellular glutathione levels, since addition of buthionine sulfoximine, which prevented glutathione increase, did not diminish the observed MEA protection. The hydroxyl radical scavenger mannitol also afforded protection in both kinds of treatment, but it was approximately twice as effective in gamma irradiation as in PDT. This is consistent with the predominant role of OH radicals in ionizing radiation damage and their presumed minor involvement in PDT damage. Superoxide dismutase, a scavenger of O2, acted as a radiation protector but was not significantly effective in PDT. Catalase, which scavenges H2O2, was ineffective in both modalities. Tryptophan, an efficient singlet oxygen scavenger, reduced cell death through PDT by several orders of magnitude while being totally ineffective in gamma irradiation. These data reaffirm the predominant role of 1O2 in the photodynamic cell killing but also indicate some involvement of free radical species.

Animals↗
PubMed1988

Radioprotection of DNA by thiols: relationship between the net charge on a thiol and its ability to protect DNA.

Release of free bases from calf thymus DNA upon irradiation in aerated 0.1 mol dm-3NaClO4 at pH 7 has been measured by HPLC and shown to be markedly influenced by the presence of thiols during irradiation. The ability of thiols to protect DNA was shown to depend upon the net charge (Z) at pH 7 in the order WR 1065 (Z = +2) greater than cysteamine (Z = +1) greater than 2-mercaptoethanol (Z = 0) approximately equal to dithiothreitol (Z = 0) greater than GSH (Z = -1) approximately equal to 2-mercaptoethanesulfonic acid (Z = -1) approximately equal to 2-mercaptosuccinate (Z = -2). A similar dependence of protection upon net charge was found for disulfides: cystamine (Z = +2) greater than 2-mercaptoethyl disulfide (Z = 0) greater than GSSG (Z = -2). Protection by WR 1065, but not by 2-mercaptoethanol or GSH, was found to decrease significantly with increasing ionic strength. Protection by WR 1065 and GSH was not markedly dependent upon pH between pH 6 and 8. The results are explained in terms of electrostatic interaction of the thiols with DNA, leading to high concentrations of cations near DNA, which allow them to scavenge hydroxyl radicals and repair DNA radicals effectively and to low concentrations of anionic thiols near DNA, which limit their effectiveness as protectors. Poly(dG,dC) and calf thymus DNA exhibited comparable release of G and C upon changing from 0.1 to 0.7 mol dm-3 MgSO4. Since this change causes poly(dG,dC), but not calf thymus DNA, to undergo a change from the B-form to the Z-form of DNA, both forms must have a comparable susceptibility to radiation-induced base release.

Anions↗
PubMedDate not supplied

MFO activity changes in single living 3T3 fibroblasts treated with adriamycin.

The effects of Adriamycin on 3T3 fibroblasts has been followed by microspectrofluorimetry. MFO activity was monitored by BaP metabolism and three points were studied: long-term ADR treatment, reversibility of this treatment and cysteamine effect on ADR treatment. The appearance of a sub-population that does not accumulate BaP suggests either a greater efflux of BaP or no penetration of the compound after ADR treatment. Moreover drastic morphological changes were observed.

Animals↗
PubMed1978

Molecular properties of the adrenergic alpha-receptor. III - Origin of topographical dualism in the reaction of a receptor thiol with symmetrical and unsymmetrical polyamine disulfides.

Structure activity relationship studies previously led to the discovery of two distinct classes of tetramine-disulfides [(I) and (II)] each exhibiting optimum adrenergic alpha-blocking activity. The more potent one (I) was shown to uniquely discriminate between noradrenaline (NA) and adrenaline (A) binding sites. The unusual receptor topographical dualism toward (I) and (II) led to an investigation of the role of structural symmetry in their interaction with the receptor. To this end, a series of unsymmetrical disulfide analogs (x-z) where half of (I) was retained and the other half was made of unsubstituted N-(omega-aminoalkyl)cysteamines [as present in (II) and its homologs] were synthesized and evaluated as alpha-blockers. In addition, the role of the number of basic nitrogens on activity was also examined. It was found that the presence of four nitrogens is necessary for optimum activity. Moreover, it was discovered that optimum alpha-blocking potency is obtained when the respective halves of the two best prototypes (I) and (II) of symmetrical structures are fused [compound (XVI)]. This new unsymmetrical tetramine disulfide has a potency approaching that of (I) and its receptor saturation mechanism is similar. Moreover, it also shares with (I) the ability to discriminate between NA and A elicited responses. The effect of methylation of a single inner nitrogen on potency allowed the conclusion that each half of the unsymmetrical disulfide (XVI) respectively occupy half of the sites for (I) and half of those for (II). Accordingly, the previously observed topographical dualism toward (I) and (II) can best be accommodated by a model where two distinct sets of sites crossing each other over the same receptor thiol are involved. The possible significance of the anionic site multiplicity of the alpha-receptor is briefly discussed.

Adrenergic alpha-Antagonists↗
PubMed1978

Inhibitory effect of reducing agents on N-acetoxy- and N-hydroxy-2-acetylaminofluorene-induced mutagenesis.

The effect of cysteine (alpha-amino-beta-mercaptopropionic acid) on the mutagenic activities of the proximate carcinogen, N-hydroxy-2-acetylaminofluorene, and the ultimate carcinogen, N-acetoxy-2-acetylaminofluorene, was examined by estimating the frequency of his+ revertants of Salmonella typhimurium. Nontoxic concentrations of cysteine significantly reduced the formation of revertants when it was applied concurrently with the two carcinogens. Cysteine showed no detectable effect on mutagenesis when added to bacteria before or after exposure to carcinogens. The magnitude of inhibition of mutagenesis depended on the dose of cysteine and the concentration of the carcinogens. Cysteine at equimolar concentrations inhibited to a larger degree the mutagenesis induced by N-hydroxy-2-acetylaminofluorene than it inhibited that elicited by N-acetoxy-2-acetylaminofluorene. The inhibitory action of cysteamine and glutathione was comparable to that of cysteine. The results appear to be consistent with the assumption that cysteine traps electrophiles prior to their action on DNA.

Acetoxyacetylaminofluorene↗
PubMed1987

Gastric mucosal protection by agents altering gastric mucosal sulfhydryls. Role of endogenous prostaglandins.

Intragastric administration of sulfhydryl-containing cysteamine or sulfhydryl-oxidizing diethylmaleate caused a dose-dependent reduction in the mean area of gastric lesions induced by absolute ethanol. The protective effects of these agents are abolished by the sulfhydryl blocker N-ethylmaleimide, while indomethacin, a potent inhibitor of cyclooxygenase, caused only about 50% reduction in this protection. This study indicates that mucosal generation of prostaglandins contributes to the gastric cytoprotection by these agents administered intragastrically, but endogenous sulfhydryls are also involved in the gastric mucosal protection by sulfhydryl-containing or sulfhydryl-oxidizing compounds.

Animals↗
PubMed1986

Evidence for the involvement of dopamine agonists and antagonists in duodenal ulcer disease.

In experimental duodenal ulceration, dopamine levels, turnover, and binding sites are influenced. Dopamine agonists and antagonists exert anti- and proulcerogenic effect, respectively, probably by influencing duodenal hyper- or hypomotility, rather than effecting gastric secretion. The duodenal ulcerogenic effect of the dopamine neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) given to rats in multiple daily doses (p.o. or s.c.) also induced in a dose-dependent manner duodenal ulcers. Duodenal ulcers were prevented by pretreatment with dopamine agonists (e.g. bromocriptine, lergotrile) or monoamine oxidase inhibitors (e.g. pargyline or 1-deprenyl). Our hypothesis suggests that duodenal ulcerogens may interfere with the action of dopamine resulting in loss of the inhibitory function of dopamine, and producing tissue damage from the accumulated auto-oxidation products of dopamine. Alternatively a motility disorder induced by cysteamine, propionitrile or MPTP may contribute to the pathogenesis probably by involving localized hyperacidity in the duodenal bulb because of decreased neutralization and impaired duodenal emptying of acid.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1986

[Effect of testosterone, its 5 alpha-reduced metabolites, estradiol and progesterone on the formation of an experimental duodenal ulcer in male rats].

The influence of different doses (0.01, 0.1, 1.0, 10.0, 100.0, 250.0, 1,000.0, 2,500.0 gamma/kg body weight) of testosterone, dihydrotestosterone, 5 alpha-androstane-3 alpha, 17 beta-diol, 5 alpha-androstane-3 beta, 17 beta-diall, 4-androsterone-3,17-dione, estradiol and progesterone on the formation of cysteamine-induced duodenal ulcer was studied in mature male rats. It has been shown that all the steroids, but for progesterone, bring down the ulcer index after six days of i/p administration, the effect depending on the nature and dose of a steroid. Estradiol and 4-androstene-3,17-dione proved to be the most effective in the given dose range. The results do not only confirm the role of androgens and estradiol in the pathogenesis of duodenal ulcer, but also indicate the participation of their precursors and metabolites in the ulcer induction. The prospects of using steroids in the treatment of ulcer are discussed.

Androstane-3,17-diol↗
PubMed1986

Cooperative behavior in the thiol oxidation of rabbit muscle glycogen phosphorylase in cysteamine/cystamine redox buffers.

Glycogen phosphorylase a and b are irreversibly inactivated by oxidation with the disulfide cystamine. The mechanism is complex and involves oxidation of at least two classes of sulfhydryl groups. The oxidation of one or more of the first class of 4 +/- 1 sulfhydryl groups is reversible, but the equilibrium constant for the oxidation is so unfavorable (1 X 10(-4)) that the micromolar concentrations of cysteamine released stoichiometrically with enzyme oxidation are sufficient to prevent complete oxidation even in the presence of 100 mM cystamine. The rapid phase of inactivation of phosphorylase b, which is first order in cystamine (k = 2.9 +/- 0.3 M-1 min-1), is followed by the oxidation of 5 +/- 1 groups in an irreversible process that is second order in cystamine concentration (k = 3.9 +/- M-2 min-1). Similar behavior is observed for phosphorylase a, although the behavior is complicated by association/dissociation equilibrium. The second-order dependence of the rate of irreversible inactivation on cystamine concentration is interpreted in terms of a "cooperative" model in which a rapidly reversible thermodynamically unfavorable equilibrium oxidation of one or more sulfhydryl groups must precede the irreversible oxidation of one or more additional sulfhydryl groups. The thiol/disulfide oxidation equilibrium constant for the initial reversible reaction is estimated to be at least 10(4) less favorable than that for the reversible oxidation of phosphofructokinase.

Adenosine Monophosphate↗
PubMed1987

Evaluation of a tetrazolium-based semiautomated colorimetric assay: assessment of radiosensitivity.

Radiation survival curves were generated for V79 Chinese hamster and two human lung cancer cell lines (NCI-H460 and NCI-H249) with doubling times of 10, 20, and 85 h, respectively, using a standard clonogenic assay, a dye exclusion assay, and a semiautomated colorimetric assay utilizing a tetrazolium salt, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenylformazan bromide. Comparable results for D0 and extrapolation number (n) were observed for all assays in the lines with doubling times of 10 and 20 h. In these instances the tumor cell lines had undergone seven or more doublings after radiation. For the tumor line (H249) with an 80-h doubling time the D0S were comparable between the assays while the extrapolation number was increased in the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenylformazan bromide assay, a result probably related to the lower number of doublings (less than 4) after radiation. We then tested the ability of the assays to detect radiation protection and sensitization using known agents. We found that cysteamine treatment resulted in radioprotection (by a factor of 8 at 8 Gy) while 5-bromo-2-deoxyuridine incorporation caused enhancement of radiation sensitivity in all three assays. We conclude that, while optimal conditions for each cell line (cell number plated and doubling time) must be established, using characterized tumor cell lines, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenylformazan bromide assay could be automated and thus be of great value in screening large numbers of potential radiosensitizers or protectors.

Animals↗
PubMed1987

[Effect of the hexapeptide dalargin on ornithine decarboxylase activity in the duodenal mucosa of rats in experimental duodenal ulcer].

The effect of an opioid antiulcerogenic hexapeptide dalargin on ornithine decarboxylase activity of duodenal mucosa has been studied in rats with experimental duodenal ulcers induced by cysteamine. The intraperitoneal injection of 12.5 micrograms/kg of dalargin inhibited ulcerogenesis and activated the enzyme. The effect of the peptide was antagonized by an opiate antagonist naloxone. 5000 micrograms/kg of dalargin failed to inhibit the ulcer formation or to activate ornithine decarboxylase. Since ornithine decarboxylase activation is a marker of intensified cell proliferation and tissue regeneration, our results suggest that the antiulcerogenic effect of dalargin is due to the enhancement of duodenal mucosa regeneration.

Animals↗
PubMed1985

Effects of AET and MEA treatment of mice on the first day of pregnancy.

Porton female mice were injected intraperitoneally with 2-aminoethylisothiouronium bromide hydrobromide (AET) or cysteamine hydrochloride (MEA) in a dose of 40 mg/kg of body weight on the first day of pregnancy. On the last, nineteenth, day of gestation, taking into consideration females in whose uterus live fetuses were observed, the increase in their body weight throughout pregnancy, the number of fetuses in the uterus, the body weight of fetuses, and placental weight were found smaller in mice treated with AET or MEA, than in control ones. Among the injected compounds, AET appeared to be less toxic than MEA.

Animals↗
PubMedDate not supplied

Oxidative deamination of thialysine by snake venom L-aminoacid oxidase.

Thialysine is oxidatively deaminated by snake venom L-aminoacid oxidase at alkaline pH. The oxygen consumption curves show a characteristic diphasic course: the quick uptake of half a mole of oxygen per mole of substrate, in aggreement with a typical oxidative deamination, is followed by a slow extra oxygen consumption. The first product of the reaction is the corresponding alpha-oxo-epsilon-amino acid, which spontaneously cyclizes to the internal Schiff base 5-6-dihydro-delta 3,1,4-thiazin-3-carboxylic acid (TZCA). This latter has been identified by its UV absorption spectrum, by some chemical reactions, by paper chromatography, and by the production of cystamine and glyoxylic acid after prolonged oxidation of thialysine followed by acid hydrolysis. The possibility of an alpha-beta elimination reaction giving rise to cysteamine from thialysine, coupled to the oxidative deamination, has been excluded.

Amino Acid Oxidoreductases↗
PubMed1985

Embryonic survival in mice treated with AET, MEA or 5-HT on the first day of pregnancy.

The embryotoxicity of AET, MEA, and 5-HT was investigated in Porton mice. Female mice on the first day of gestation were injected intraperitoneally with 2-amino-ethylisothiouronium bromide hydrobromide (AET), cysteamine hydrochloride (MEA) or serotonin-creatinine sulphate (5-HT) in a dose of 40 mg/kg body weight. Uterine contents were examined on the nineteenth day of pregnancy. As compared with controls, in mice treated with AET, MEA or 5-HT, a smaller number of live fetuses and a greater number of non-implanted embryos, resorptions, and dead fetuses were found. Not all females which were injected with these compounds had live fetuses. Among the compounds, MEA appeared to be more toxic than AET and 5-HT.

Animals↗
PubMed1985

Quantity of DNA in the organs of 19-day-old foetuses after AET, MEA, or 5-HT treatment of mice on the first day of gestation.

On the first day of gestation, Porton mice were injected intraperitoneally with AET (2-aminoethylisothiouronium bromide hydrobromide), MEA (cysteamine hydrochloride,) or 5-HT (serotonin-creatinine sulphate), in a dose of 40 mg/kg of bodyweight. On the nineteenth day of pregnancy, the fresh weight of both heart and kidneys of foetuses, as well as DNA content in 25 mg of fresh tissue and in these whole organs were analysed. DNA was extracted from the foetal organs by means of Burton's method, which is based on the estimation of deoxiribose content in the colour reaction with diphenylamine. As compared to controls, in the remaining groups of mice lower fresh weight of both heart and kidneys of foetuses, greater DNA content in 25 mg of fresh tissue and smaller total amounts of DNA in the whole organs were found. Among the experimental groups of mice, statistically significant differences in the analysed values were observed between the group of animals treated with 5-HT and the remaining groups, with the exception of statistically non-significant difference in the DNA content of the whole kidneys between those injected with 5-HT and MEA.

Animals↗
PubMed1985

Quantitative measurement of DNA strand breaks and repair in gamma-irradiated human leukocytes from normal and ataxia telangiectasia donors.

Fluorimetric analysis of DNA unwinding, which allows measurement of DNA strand breaks in human leukocytes, has been optimized by reducing the amount of cells required for the test and by modifying the DNA alkali unwinding conditions. This permitted measurement of DNA strand-break induction in cells irradiated with low (0.5-7 Gy) or high doses (5-20 Gy) of gamma rays. Linear dose-response curves were obtained for both dose ranges. Presence of cysteamine during irradiation caused a decrease in the extent of DNA strand breaks. The kinetics of the DNA strand-break rejoining process appeared to be biphasic over the dose range of 2-20 Gy when plotted on a linear vs linear axis (percentage of damage as a function of time). Since the rate of disappearance of damaged DNA was similar for any given dose and for all postirradiation incubation times tested, we have expressed the extent of repair after a given postirradiation incubation as the ratio of the slopes of the regression lines obtained from incubated and nonincubated cells. Leukocytes from 25 healthy donors were analyzed to determine an average value for controls. No difference in the level of DNA strand breaks and the rate of repair of these breaks was observed between leukocytes from three ataxia telangiectasia patients and those from normal donors.

Ataxia Telangiectasia↗