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At least 19 recordsLinked to original sources
PubMed1997

The synergistic purgative action of aloe-emodin anthrone and rhein anthrone in mice: synergism in large intestinal propulsion and water secretion.

This study aimed to explore the mechanism involved in the synergistic purgative action of aloe-emodin anthrone and rhein anthrone, the active metabolites of sennoside C. Aloe-emodin anthrone and rhein anthrone, and their equimolar mixture, induced excretion of an approximately equal number of faeces by intracaecal administration at a dose of 23.2 mumol kg-1 in mice (= 1.0 standard dose). The number of wet faeces induced by aloe-emodin anthrone was less than those of rhein anthrone and the mixture. At the same dose, rhein anthrone and the mixture significantly stimulated large intestinal propulsion, though aloe-emodin anthrone had little stimulatory effect. Aloe-emodin anthrone and rhein anthrone decreased net water absorption but could not reverse it to the net secretion at 1/2 dose. The mixture significantly decreased net water absorption and reversed it to the net secretion at this dose. These anthrones did not stimulate mucus secretion in the colon at 1/2 dose. We concluded that the synergistic purgative effect of aloe-emodin anthrone and rhein anthrone in mice results from synergistic stimulation of large intestinal transit and large intestinal water secretion.

Animals↗
PubMedDate not supplied

Detection and characterization of 9-anthron-10-yl radicals formed by antipsoriatic and tumor-promoting 9-anthrones in aqueous buffers.

Certain 1,8-dihydroxy-9-anthrones have been used for the topical treatment of psoriasis for over seventy-five years. The therapeutic usefulness of these compounds is limited, however, by side effects including severe skin inflammation and staining. Antipsoriatic 9-anthrones are also tumor promoters in mouse skin. The chemical mechanisms underlying the biological properties of 9-anthrones are believed to involve the generation of free radical products such as 9-anthron-10-yl radicals or secondary oxygen radicals such as O2.- or OH.. However, the specific role that 9-anthron-10-yl radicals may play in mediating the biological effects of 9-anthrones is uncertain because these species have not been detected in biological systems. In the present study we have used the EPR spin trapping technique to demonstrate for the first time the formation of the 1,8-dihydroxy-9-anthron-10-yl radical in aqueous buffers. Additionally, in order to gain information concerning the role of 9-anthron-10-yl radicals in tumor promotion and antipsoriatic activities, we have used this technique to investigate the formation of these radical species by a series of 9-anthrones of known tumor-promoting and antipsoriatic activities. All of the 9-anthrones studied formed spin adducts with 3,5-dibromo-4-nitrosobenzenesulfonic acid in aqueous buffers. The formation of these adducts was pH-dependent, being favored at alkaline pH.(ABSTRACT TRUNCATED AT 250 WORDS)

Anthracenes↗
PubMed1994

Structure-activity relationships for the formation of secondary radicals and inhibition of keratinocyte proliferation by 9-anthrones.

The biological properties of tumor-promoting and antipsoriatic 9-anthrones have been hypothesized to be mediated by free radical products such as the corresponding 9-anthron-10-yl radicals or by O2-, OH, and other persistent secondary radicals that are formed in the skin after topical treatment with 9-anthrones. To gain additional insights into the possible role of reactive oxygen or secondary radicals in mediating the biological effects of 9-anthrones, we have used EPR spectroscopy to investigate the formation of these species by a series of 9-anthrones or 9-anthrone dimers with known tumor-promoting and antipsoriatic activities. The effect of the 9-anthrones on keratinocyte proliferation in vitro was also investigated. 5,5-Dimethyl-1-pyrroline N-oxide was used as a spin trap to detect reactive oxygen-centered radicals in aqueous buffer/dimethylsulfoxide solutions. Super-radicals in aqueous buffer/dimethylsulfoxide solutions. Superoxide was trapped during the autoxidation of most of the 9-anthrones. For 9-anthrones that generated no detectable superoxide, evidence of anthronyl-peroxyl radical formation was found instead. In the presence of Fe3+ complexed to EDTA, but not diethylenetriaminepentaacetic acid, the hydroxyl radical was produced by all of the 9-anthrones. 9-Anthrone dimers produced oxygen-centered radicals only weakly or not at all. Direct EPR was used to detect 9-anthrone-derived secondary radicals in keratinocyte suspensions or in dimethysulfoxide solutions. These radicals were similar to those previously reported to occur in skin after topical treatment with the antipsoriatic drug anthralin (1,8-dihydroxy-9-anthrone). In contrast to the ubiquitous ability of the 9-anthrones to generate reactive oxygen radicals, only the hydroxy-substituted 9-anthrones or their dimers possessed significant secondary radical-forming ability. The ability of the 9-anthrones or dimers to form secondary radicals in keratinocytes was found to correlate with their in vitro inhibition of keratinocyte proliferation. The data suggest the possible importance of reactive dimeric intermediates in mediating the biological effects of the 9-anthrones.

Animals↗
PubMed1992

Metabolic activation of sennoside C in mice: synergistic action of anthrones.

Sennosides A and C directly injected into the caecum of mice showed equal purgative activity. Intracaecal administration reduced time to onset of diarrhoea induced by sennoside C from about 3 h after oral administration to about 24 min. At 2.3 h after oral administration of sennoside C, nearly equimolar amounts of aloe-emodin anthrone and rhein anthrone were detected in the large intestine of mice. The purgative effect of oral sennoside C could be reduced by pretreating mice with chloramphenicol. This was observed as a decreased formation of total anthrones in the large intestine. Both anthrones and an equimolar mixture of both anthrones directly injected into the caecum exerted a purgative effect, although the activity was lower for aloe-emodin anthrone. The intracaecal ED50 values were 54.5 (24.1-89.6), 11.4 (5.0-15.7) and 11.2 (6.1-14.6) mumol kg-1 for aloe-emodin anthrone, rhein anthrone and an equimolar mixture of both anthrones, respectively. We concluded that aloe-emodin anthrone and rhein anthrone, formed mainly by intraluminal bacterial action, are the true active metabolites of sennoside C in mice and that both anthrones synergistically exert their purgative effects on mice.

Animals↗
PubMed1999

Synergistic effects of anthraquinones on the purgative activity of rhein anthrone in mice.

This study was performed to determine whether intracaecally administered rhein anthrone and anthraquinones such as aloe-emodin, chrysophanol, emodin or rhein synergistically enhance the purgative action as has been observed for rhein anthrone and aloe-emodin anthrone. These anthraquinones were less potent than rhein anthrone. An equimolar mixture of aloe-emodin and rhein anthrone had synergistic potentiating effects because the ED50 value (50% purgative dose) of the combination was smaller than that calculated additively from the ED50 values of aloe-emodin and rhein anthrone. An equimolar mixture of other anthraquinones and rhein anthrone tended to potentiate the purgative action. These results confirmed that rhein anthrone and aloe-emodin synergistically exert a purgative action as has been observed for rhein anthrone and aloe-emodin anthrone.

Animals↗
PubMed1978

Structure and tumor-promoting activity of analogues of anthralin (1,8-dihydroxy-9-anthrone).

Seventeen analogues of the tumor-promoting agent anthralin were tested for the same biological property by repeated skin application on mouse skin using female ICR/Ha Swiss mice, after a single application of a subcarcinogenic dose of 7,12-dimethylbenz[a]anthracene. Seven of the compounds tested are new compounds. They are 1,8-diacetoxy-9-anthrone, 1,8-dimyristoyloxy-9-anthrone, 1,8-dihydroxy-10-acetyl-9-anthrone, 1,8-dihydroxy-10-myristoyl-9-anthrone, 1,8,10-trihydroxy-9-anthrone, 1,8-dihydroxy-9,10-dihydroanthracene, and myristoyljuglone. All compounds were used in pure form for the bioassays. Of the 17 test compounds four showed notable tumor-promoting activity. They are 1,8-dihydroxy-10-acetyl-9-anthrone, 1,8-dihydroxy-10-myristoyl-9-anthrone, 1-hydroxy-9-anthrone, and juglone. In order to determine whether there is any relationship between tumor-promoting activity and metal chelation in this series, the chelating abilities of anthralin and of its inactive analogue 1,8-dihydroxyanthraquinone were examined using the bivalent metal ions Cu(II), Zn(II), Mn(II), Mg(II), and Ca(II). No relationship between chelation and tumor-promoting ability was found.

Animals↗
PubMedDate not supplied

Direct and indirect evidence for the involvement of prostaglandins in the secretagogue action of rhein anthrone in the small intestine.

The present study was undertaken to investigate the involvement of prostaglandins in the secretagogue action, observed after intraduodenal administration of rhein anthrone and rhein in rats. After intraduodenal administration of rhein anthrone (50 mg/kg), the active metabolite of sennosides, a very marked increase of secretion was observed compared to control. The amount of secretion was calculated by dividing the total weight of the small intestine, obtained 30 minutes after administration of the drug, by the total length. The effect seen with rhein (50 mg/kg) is far less pronounced than that with rhein anthrone and is not significant when compared with control. Pretreating the animals with indomethacin (15 mg/kg, p.o., 1 hour in advance) or with ibuprofen (15 mg/kg, p.o., 1 hour in advance) largely prevents the secretagogue effect of rhein anthrone, suggesting that prostaglandins play an important role in the observed pharmacological action. This idea is reinforced by the observation that pretreatment with hydrocortisone (50 mg/kg, p.o., 6 hours in advance) is also able to counteract the effect of rhein anthrone. After administration of rhein anthrone, an almost tenfold increase of the tissue content of prostaglandin E2 was observed. Here again, the results with rhein were far less pronounced. It is concluded that prostaglandins play an important role in the secretagogue action of rhein anthrone.

Animals↗
PubMed1988

Structure-activity relationships for epidermal ornithine decarboxylase induction and skin tumor promotion by anthrones.

The present study was designed to compare the skin tumor promoting and epidermal ornithine decarboxylase (ODC) inducing activities of various structural analogs of anthralin (1,8-dihydroxy-9-anthrone) and chrysarobin (1,8-dihydroxy-3-methyl-9-anthrone). Groups of 30 SENCAR mice each were initiated with 7,12-dimethylbenz[a]anthracene and 2 weeks later promoted with once- or twice-weekly applications of various doses of these anthrone derivatives. Carbon-10 (C10)-acyl derivatives of anthralin were active skin tumor promoters in the range of 25-440 nmol per mouse. 10-Acetylanthralin was significantly more active than 10-myristoyl-anthralin at low doses (e.g. 25 and 50 nmol per mouse) and nearly as potent as the unsubstituted compound. Higher doses (greater than or equal to 100 nmol per mouse) of this derivative were toxic, hence, reducing the final papilloma response. On a relative activity scale where anthralin is 1.0, these derivatives had activities that were approximately 0.7 and 0.2, respectively. 10,10-Dipropylanthralin was totally inactive at the doses tested. C6-Substituted derivatives of chrysarobin demonstrated diverse tumor promoting activities when tested in the range of 25-440 nmol per mouse. On a relative activity scale where chrysarobin is 1.0, 6-methoxychrysarobin (physcion anthrone) was approximately 0.9, whereas 6-hydroxychrysarobin (emodin anthrone) had no activity. Chrysophanic acid (1,8-dihydroxy-3-methyl-9,10-anthraquinone) was also inactive as a tumor promoter at the doses tested. In general, the tumor promoting activities of these anthrone derivatives correlated very well with their ability to induce epidermal ODC after a single topical application indicating an important role for this enzyme in skin tumor promotion by anthones. The ability of C10-substituted derivatives of anthralin to undergo base catalyzed oxidation in vitro correlated with both ODC inducing and tumor promoting activities. In addition, copper(II)bis(diisopropylsalicylate) was found to inhibit both ODC induction and skin tumor promotion by chrysarobin. These latter data, when taken together, suggest a role for oxidation at C10 in skin tumor promotion by anthrone derivatives.

Animals↗
PubMed1981

Structure specificity of the antipsoriatic anthrones.

In the investigations of Krebs and Schaltegger between 1964 and 1972 on the structure specificity of the antipsoriatic anthrones it could be shown that at least a 1-hydroxy-9-anthrone is necessary for their efficacy. This structure was then called "minimum structure of the antipsoriatic anthrones'. Since even very minor changes of this structure in most cases lead to inactive compounds, only a few antipsoriatic anthrones have been found so far. Their most important representative chrysarobin, anthralin and I-hydroxy-9-anthrone have been known for more than 60 years. The later discovered antipsoriatic anthralin derivatives, triacetoxy-anthracene and 10-acyl-anthralin, are probably hydrolysed in the skin and thus act as their parent compound anthralin. The strong structure-activity dependence of the antipsoriatic anthrones seems to include a highly specific and complex mechanism of action.

Anthracenes↗
PubMed1993

Influence of rhein anthrone on peristaltic reflex of guinea-pig isolated ileum: involvement of prostaglandins.

1 The influence of rhein anthrone on the peristaltic reflex was studied with a modified Trendelenburg technique in a range from 10(-8) M to 4 x 10(-5) M, on a normal and reversed guinea-pig ileum segment. Rhein anthrone had no significant effects on longitudinal muscle tension, intraluminal pressure or volume displacement when tested on the normal segment in doses up to 10(-5) M. When applied to the mucosal side (reversed segment), rhein anthrone produced a dose-dependent increase of longitudinal muscle tension (significant from 10(-7) M), of intraluminal pressure (significant from 3 x 10(-6) M) and of volume displacement (significant from 10(-7) M). The data show that rhein anthrone possesses in vitro activity which is dependent on contact with the mucosa. 2 The action of rhein anthrone on the reversed segment was inhibited by BW755C (a dual inhibitor of cyclo-oxygenase and lipoxygenase), by indomethacin and by SC19220 (an antagonist of prostaglandin E2 (PGE2) and PGF2 alpha). The effects remaining on longitudinal muscle tension, intraluminal pressure and volume displacement, calculated as percentage (mean +/- s.e.mean) of the initial value, were respectively: 13 +/- 8; 23 +/- 13; 112 +/- 5 for BW755C; 66 +/- 19; 51 +/- 8; 53 +/- 8 for indomethacin and 27 +/- 12; 13 +/- 7; 50 +/- 5 for SC19220. It is concluded that arachidonic acid metabolites, especially PGE2 and PGF2 alpha are involved in the effects of rhein anthrone on the reversed segment.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1990

Prostaglandin E2-mediated stimulation of mucus synthesis and secretion by rhein anthrone, the active metabolite of sennosides A and B, in the mouse colon.

Rhein anthrone, the active metabolite of sennosides A and B, stimulated PGE2 release into the mouse colonic lumen. At 6.24 mg kg-1, it decreased net water and Na+ absorption significantly in the case of water, but could not reverse the net absorption in mouse ligated colon, although it enhanced net K+ secretion. Pretreatment with indomethacin diminished the effects of rhein anthrone except on K+ net secretion. Rhein anthrone or PGE2 markedly stimulated mucus secretion and synthesis in mouse ligated colon. The enhanced mucus secretion and synthesis induced by rhein anthrone were significantly suppressed by pretreatment with indomethacin. Our results have shown that the colonic secretion of water and electrolytes mediated by PGE2 is partly involved in the rhein anthrone-induced diarrhoea but that in mice, the mucoid diarrhoea induced by rhein anthrone results mainly from PGE2-mediated mucus synthesis and secretion in the colon.

Animals↗
PubMed1993

In vitro demonstration of a positive effect of rhein anthrone on peristaltic reflex of guinea pig ileum.

The influence of rhein anthrone on the peristaltic reflex was studied with a modified Trendelenburg technique in the range from 10(-8) to 4 x 10(-5) mol/l, using a normal and reversed guinea pig ileum segment. Rhein anthrone had no significant effects on longitudinal muscle tension, intraluminal pressure or volume displacement when tested on the normal segment in doses up to 10(-5) mol/l. When applied to the mucosal side (reversed segment), rhein anthrone produced a dose-dependent increase of longitudinal muscle tension, of intraluminal pressure and of volume displacement. The data show that rhein anthrone possesses in vitro activity which is dependent on contact with the mucosa. The action of rhein anthrone on the reversed segment was inhibited by BW755C (a dual inhibitor of cyclo-oxygenase and lipoxygenase), by indomethacin and by SC19220 (an antagonist of PGE2 and PGF2 alpha). It is concluded that arachidonic acid metabolites, especially PGE2 and PGF2 alpha are involved in the effects of rhein anthrone on the reversed segment.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMedDate not supplied

An EPR study of free radicals formed by antipsoriatic and tumor-promoting 9-anthrones in nonpolar solvents.

Certain 9-anthrone derivatives are useful in treating psoriasis and are also known to be tumor promoters in mouse skin. Their therapeutic use is accompanied by side effects of severe skin inflammation, irritation, and staining. The precise biochemical mechanisms of therapeutic action, tumor promotion, and side effects are presently uncertain, although the corresponding 9-anthron-10-yl radicals have been proposed as important intermediates. In order to gain insight into the possible role of anthrone-derived radicals in mediating the biological effects of these compounds, in the present study free radicals from a number of anthrone derivatives were generated by thermolysis in nonpolar solvents. Hyperfine splitting constants (hfsc) of the radicals were determined by electron paramagnetic resonance (EPR) spectroscopy. The experimentally determined hfsc's were also compared with spin densities obtained by molecular calculations (MOPAC 6.0). The experimental and theoretical data were found to be consistent in all cases. The formation of 9-anthron-10-yl radicals appears to be a general phenomenon among 9-anthrones regardless of therapeutic or tumor-promoting effectiveness, although there is a trend toward easier radical formation for the more active compounds.

Administration, Topical↗
PubMed1979

[Metabolism of antipsoriatic anthrone derivatives].

The metabolisation of the antipsoriatically active molecules 1,8,9-triacetoxy-anthracene und 1,8-diacetoxy-9-anthrone by serum is described. Under these conditions 1,8-dihydroxy-9-anthrone, 1-hydroxy-8-acetoxy-9-anthrone, 1,8,1',8'-tetrahydroxy-bisanthrone, 1,8-dihyroxy-anthraquinone, 1,8-diacetoxy-anthraquinone and 1-hydroxy-8-acetoxy-anthraquinone arise from both educts. Quantitative determinations of these metabolites indicate that hydrolytic reactions occur prior to oxidation. Contrary to 1,8-dihydroxy-9-anthrone, 1,8,9-triacetoxyanthracene and 1,8-diacetoxy-9-anthrone are effective against psoriatic lesions without accompanying inflammations of the skin. 1,8,9-Trimethoxy-anthracene, however, is ineffective, also indicating that at least 1,8,9-triacetoxy-anthracene is a prodrug.--In agreement with Krebs' hypothesis 10,10-dialkylated 1,8-dihydroxy-9-anthrones described in this paper are ineffective against psoriasis.

Anthracenes↗
PubMed1992

Influence of rhein anthrone and rhein on small intestine transit rate in rats: evidence of prostaglandin mediation.

The present study was undertaken to investigate the role of prostaglandins in the shortening of transit time observed after intraduodenal administration of rhein anthrone and rhein. After intraduodenal administration of rhein anthrone (0.5-10 mg/rat), a dose-dependent acceleration of small intestinal transit was observed. The effect for rhein (1-10 mg/rat) was far less pronounced. In the same test conditions, analysis of small intestinal tissue revealed a significant increase of prostaglandin E2 (PGE2), reaching its maximum value 30 min after administration of rhein anthrone. The increase in PGE2 found 30 min after administration of rhein was not significant. The effects provoked by rhein anthrone could be largely prevented by pretreatment of the animals with indomethacin (1-3 mg rat) or cortisol (10 mg/rat). It is concluded that prostaglandins play an important role in the acceleration of the transit provoked in rats by rhein anthrone.

Animals↗
PubMed1991

Suppression of the purgative action of rhein anthrone, the active metabolite of sennosides A and B, by indomethacin in rats.

Rhein anthrone (12.48 mg kg-1) produces watery and mucoid diarrhoea approximately 20 min after intracaecal administration to rats. Pretreatment with the prostaglandin (PG) biosynthesis inhibitor indomethacin (10 mg kg-1, i.p.) only delayed and did not completely block the onset of the induced diarrhoea. Rhein anthrone stimulated PGE2 release into the rat colonic lumen and the increased release was depressed by indomethacin. Rhein anthrone also accelerated large intestinal transit and this acceleration could be partly inhibited by indomethacin, which was probably responsible for the delay in the onset of diarrhoea. Indomethacin prevented the enhanced water, K+ and mucus secretion and the reduced Na+ absorption in the colon which were induced by rhein anthrone. The net water secretion could not be reversed to net absorption and the mucus secretion was only slightly depressed by indomethacin. Thus, our findings suggest that other mechanisms, together with the PG-dependent mechanism, are involved in the purgative action of rhein anthrone in rats.

Animals↗
PubMed1988

Instability of rhein-9-anthrone as a problem in pharmacological and analytical use.

The stability of rhein-9-anthrone, one of the main and most active metabolites of the sennosides A + B, was studied under physiological conditions. A high-pressure liquid chromatographic method for the determination of rhein-9-anthrone and its oxidation products, rhein and sennidins A + B, was developed. Rhein-9-anthrone, dissolved in Tyrode buffer at pH 6.5 or 7.5 at a concentration of 10(-4) mol/l, completely disappeared from a solution warmed to 37 degrees C within 30 min. More than 90% were transformed into rhein and sennidins A + B. Pharmacological experiments in rats showed that net water absorption in the small intestine was reversed to net secretion by rhein-9-anthrone, whereas rhein and sennidins in corresponding concentrations were ineffective. As at least rhein is known to stimulate secretion under different experimental conditions, all pharmacological results with rhein-9-anthrone must be interpreted with caution and should be checked whether they essentially differ from those of its main oxidation products.

Animals↗