Search

Bianthraquinone glycosides are formed during the preparation and conservation of fluid extracts of cascara. Analysis of these preparations has shown that up to 20% of total amount of anthracene glycosides can be dimerized. These dimers are devoid of laxative activity. They are absorbed in the intestine and very slowly excreted.

A quantitative determination of bicascarosides by HPLC in pharmaceutical preparations is described. These compounds are transformed by oxidative hydrolysis into their aglycones which can be separated on a RP-18 column. Concentrations as low as 0.05% can be determined without interference from monomeric aglycones.

A sensitive spectrofluorimetric method is described to determine small quantities of rhein anthrone in complex biological systems as caecum content and faeces. The method is based on the stability and fluorescent properties of anthrone molecules in borax solution and combines the sensitivity of spectrofluorimetric methods with the resolution power of liquid chromatography. After extraction of the faeces with a solution of sodium tetraborate and ascorbic acid in water and centrifugation, an aliquot of the supernatant is injected on a Sephadex-G25 precolumn. After rejection of the first fractions (fluorophors present in caecal content), rhein anthrone is collected on an RP-C18 column and eluted with an acetonitrile-borax buffer gradient. The anthrone is quantified using a fluorescence HPLC monitor.

The effect of rhein and rhein anthrone on the transit and the transport of water and electrolytes in the large intestine was investigated in germ-free rats. After intracaecal administration, neither of the two compounds was found to accelerate the transit of a colour marker through the large intestine. Both drugs reduced the net absorption of sodium and chloride in the colon and enhanced net potassium secretion. Net water absorption was decreased by rhein and even reversed into net secretion by rhein anthrone. Our results show that the secretagogue activity of the compounds is not sufficient to induce laxation in germ-free rats. Furthermore rhein and rhein anthrone had no laxative properties under our experimental conditions.

A review of the recent progress in the study of the mode of action of the sennosides, the active constituents of the senna drug, is presented. An interaction between rhein anthrone, the active metabolite of the sennosides, and the immune cells of the colon is suggested as a base for laxative activity.

The 12th of July 1635, Jan van Beverwyck wrote a letter from Dordrecht to his esteemed friend Luis Nunez, in Antwerp. He asked him for indications about the cure of kidney stones of which he was suffering. He had just passed two calculi very painfully. Nunez answered on July 31. His letter summarized his own experience with this disease. In such cases, temperate diuretics and emollients are well indicated: ingestion of light decoctions of Malva and Viola, Caerefolium and Parieteria as well as Marshmallow syrup. No purge and no 'chemicals'. However, the best remedy was drinking Spa water. Usually the best way to absorb it is to come to the springs, in the Ardennes, part of the independent Principality of Liège. However, considering the horrors of the war (the Thirty Years War) endangering the country, van Beverwyck would be wise to drink imported water during 40 or 50 days, while staying home quietly, in Dordrecht. The letter points out the importance of provoked diuresis in the treatment of kidney stones. On the other hand the letter is an illustration of the continuing contacts between the United Provinces and the Spanish territories and of the commercial traffic between Antwerp, Dordrecht and Spa. The exported water was bottled from many 'pouhons'. It was acid, ferruginous, sulfurous and saturated with carbon dioxide; no pathogen germs, at least at the spring. Nunez quoted the large number of his patients cured with Spa water in Antwerp. This is an illustration of its commercial expansion even during this critical period.

A review of the recent progress in the study of the mode of action of the sennosides, the active constituents of the senna drug, is presented. An interaction between rhein anthrone, the active metabolite of the sennosides, and the immune cells of the colon is suggested as a base for laxative activity.

The influence of the intestinal microbial reduction of rhein anthraquinone on the formation of deterioration products was studied. Therefore [14C]rhein and [14C]rhein anthrone were mixed with sterilized or non-sterilized cecal mass of rats and incubated for 20 hours at 37 degrees C. Extractions with a methanol-water (50:50) mixture or 4-nitroso-N,N-dimethylaniline (0.1%) in pyridine revealed several radioactive derivatives after TLC and autoradiography, except in the case where the anthraquinone was mixed with sterilized cecal content. Gel permeation on a styrene-divinylbenzene copolymer column of an methanol/water extract of non-sterilized cecal content incubated with [14C]rhein, showed radioactive deterioration products with a molecular weight higher than rhein anthraquinone. The high molecular weight of some deterioration products was confirmed by an ultrafiltration study where the methanol/water extract was centrifuged on a Centricon-3 microconcentrator (nominal cutoff: 3000 MW). Aqueous extracts of non-sterilized cecal content incubated with rhein were extracted with chloroform to remove rhein anthraquinone, rhein anthrone and sennidins before being intracecally injected in rats. No laxative activity was found. Furthermore it was shown that the deterioration products which are probably formed through radical reactions, no longer develop a color with a solution of KOH. Therefore it is concluded that the reduction process of dihydroxy-anthraquinones in the gut microflora followed by an extraction, accounts for the loss of anthranoid equivalents in in vivo circumstances, as several times reported in the past.

A sensitive spectrofluorimetric method is described to determine small quantities of prostaglandin E 2 in complex biological systems as intestinal tissues. The method is based on a solid phase extraction combined with a coupling with a fluorescent marker and measuring the derivatization product by fluorescence densitometry. After mixing the tissue with an ice-cold perchloric acid solution, adjusting the pH, centrifugation and filtration steps, the prostaglandins are retained on a solid phase extraction C18 disposable column. They are eluted with diethylether, derivatized with 4-bromomethyl-7-methoxy-coumarin using potassium carbonate as condensating agent and finally analysed using fluorescence densitometry on silica gel TLC plates. Applying this method, amounts down to 5 ng (per gram wet tissue) could be measured in intestinal tissues, the s.e.m. for replicated total analysis being less than 15%. The foregoing method is applied for the determination of PGE 2 released in the intestinal wall under the influence of laxatives.

Bianthraquinone glycosides are formed during the preparation and conservation of fluid extracts of cascara. Analysis of these preparations has shown that up to 20% of total amount of anthracene glycosides can be dimerized. These dimers are devoid of laxative activity. They are absorbed in the intestine and very slowly excreted.

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.

We can distinguish four periods in the iconography of the cocaplant, namely the prehispanic period in South-America, the early period in Europe, from 1749 until 1860, the period of confusion (1860-1906) and finally the period of modern iconography. The iconography of the cocaplant before the arrival of the Spanish invaders was limited to the drawing of cocaleaves. In Europe, the first people who showed any interest for the cocaplant were the botanists. In the second half of the XVIIIth century, the botanists made especially good drawings of Erythroxylum coca. From the second half of the XIXth century, the industry became interested in coca and, consequently, a very intensive research arose, coming from several directions. This led to the discovery of new species, at that time often described by non botanists. This resulted in discussions and in serious confusion as to the nomenclature. Excellent pictures were however produced in this period. During the XXth century fundamental botanical research resulted in the final classification of the different coca species. The quality of the pictures was however not better.

The secretagogue activity of 30 different anthracene and diphenylmethane derivatives was investigated by determining their influence on water, sodium and potassium absorption in the gastrointestinal tract of the rat by direct administration into the rat colon. To obtain an effect two phenolic groups are necessary. However the distance between these groups seems to be a major factor for secretagogue activity. In the case of the anthranoids an intact anthraquinone or anthrone structure is a prerequisite.

Rhein (1,8-dihydroxy-3-carboxyanthraquinone), in a concentration of 6 × 10−4 M, inhibits water absorption from the colon and causes a net transfer of fluid and electrolyte into the intestinal lumen. Morphine (4 × 10−4 M) counteracted the water and electrolyte secretion. Prior perfusion with morphine protected the large intestine from the laxative effect of a rhein perfusion. Differences in absorption rate of 99mTc-EDTA, a poorly absorbable marker, were found, as morphine caused nearly all radioactive compound to be retained in the colon, while rhein significantly facilitated the transfer of marker from colon through mucosal barrier to blood. The route followed by the 99mTc-EDTA complex was not the same as that followed by water, suggesting that 99mTc-EDTA travels by a paracellular route. Morphine counteracted the inhibition of Na+ absorption caused by rhein and antagonized the massive loss of K+ incurred by the presence of rhein in the colon. Cl− absorption is reversed to secretion in the presence of rhein while normal values were restored by morphine. Neither the HCO−3 content nor the pH were affected by either drug. Active absorption of glucose was completely blocked in the presence of rhein; the block could be antagonized by morphine.

After single intracaecal administration of [14C]rhein (25 mg kg−1) and [14C]rhein anthrone (20 mg kg−1) to rats, the summated recovery rates of 14C after five days were in urine 37(±8.3)% and 2.8(±0.4)% and in faeces 53(±9.5)% and 95 (±10.1)%, respectively. The clearance of radioactivity from the organs and tissues was almost complete within three days, with the exception of the kidney which exhibited pronounced retention of radioactivity even after five days (

The two radioactive compounds were administered intracaecally to rats, and the recovery rates amounted to 89.9% for 14C-rhein and to 97.4% for 14C-rhein anthrone after 5 days. All organs and tissues showed for both compounds a significant clearance of radioactivity with exception of the kidneys where high levels persisted even after 5 days. Different metabolites could be detected in urine as well as in faeces where also nonanthraquinone fractions could be found.

The synthesis of C-9-14C-rhein is reported, 14CO2 is used as a 14C-source. After preparing 14C-1,8-dimethoxy-3-methylanthraquinone by a condensation reaction, the product is demethylated and the 3-methyl group converted to the corresponding 3-carboxy group. The radio-active yield of the total synthesis, starting with 1 Ci 14CO2 is 6,9% (6,9 mCi); 352 mg 14rhein is produced with a specific activity of 55,7 mCi/mmol.

Senna was introduced in therapy in the 9th century by the Arabs. In the second half of the 19th century chemical investigation of the drug was undertaken, but only a century later the sennosides were isolated. Pharmacological research on senna started at the beginning of this century. During the last 25 years interest in the pharmacology of synthetic and natural laxatives steadily increased. Senna, containing only dianthrones as active substances, is still in the center of scientific research and merits this special attention.

The two radioactive compounds were administered intracaecally to rats, and the recovery rates amounted to 89.9% for 14C-rhein and to 97.4% for 14C-rhein anthrone after 5 days. All organs and tissues showed for both compounds a significant clearance of radioactivity with exception of the kidneys where high levels persisted even after 5 days. Different metabolites could be detected in urine as well as in faeces where also nonanthraquinone fractions could be found.

Administration of 1,8-dihydroxyanthraquinone (DHA) markedly increases the permeability of guinea-pig colonic mucosa. In 1 h 25% of the administered dose of99m Tc-EDTA complex leaks through the mucosa. Orally administered loperamide blocks the99m Tc-EDTA transfer after DHA administration. Loperamide injected in situ in the ligated colon segment shows the same blocking properties of the transfer rate of the complex. These findings suggest that the opposing action on fluid transport of the laxative DHA and the antidiarrhoeal loperamide could be due to these drugs affecting the permeability of the colonic mucosa. The minimal dose of loperamide, able to restore normal permeability, was as low as 0·01 mg kg−1.

A rapid and simple colorimetric method is presented for the estimation of organic bases in pharmaceutical preparations. Solid cobalt thiocyanate reagent is used. Many bases form blue coloured ion pairs soluble in dichloromethane.

The anthranoid composition in roots of Rheum officinale has been followed during a one year cycle. No statistical correlation could be found between total anthranoid content and time of sampling. The mean total anthranoid content was found to be 3.17%, calculated on freeze dried plant material. On the other hand the ratio anthrone/total anthranoid varied with the season. It was concluded that all anthranoids were present under oxidized form, the anthraquinone, in summer months. They were in the reduced form, the anthrone, in winter. The conversion occured in a time lapse of three weeks. Also cyclic variations between the relative amounts of anthrone aglycones, anthronemono- and diglycosides could be observed. Just before the conversion anthrone --> anthraquinone and vice versa, the anthrone diglycoside content increased markedly. To find out if ambient temperature decrease is one of the factors influencing the anthraquinone --> anthrone conversion, analyses were carried out on plants submitted to a cooling treatment. After comparison with reference plants, it was clear that the composition was similar to that of plants harvested in winter time. This experiment confirms that the conversion anthraquinone --> anthrone could be induced artificially by decreasing ambient temperature.

The metabolism of sennosides is discussed in view of the results obtained during the last years. Rhein anthrone is to be considered as the ultimate active form produced by microorganisms in the colon. Several contributions of this senna symposium bring complementary information of utmost interest.