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WHO Monographs on Selected Medicinal Plants - Volume 2
(2004; 358 pages) View the PDF document
Table of Contents
View the documentIntroduction
View the documentGeneral technical notices
View the documentRadix Althaeae
View the documentHerba Andrographidis
View the documentRadix Angelicae Sinensis
View the documentFlos Calendulae
View the documentFlos Caryophylli
View the documentRhizoma Cimicifugae Racemosae
View the documentFolium cum Flore Crataegi
View the documentRadix Eleutherococci
View the documentAetheroleum Eucalypti
View the documentFolium Eucalypti
View the documentCortex Frangulae
View the documentFolium et Cortex Hamamelidis
View the documentSemen Hippocastani
View the documentHerba Hyperici
View the documentAetheroleum Melaleucae Alternifoliae
View the documentFolium Melissae
View the documentAetheroleum Menthae Piperitae
View the documentFolium Menthae Piperitae
View the documentFolium Ocimi Sancti
View the documentOleum Oenotherae Biennis
View the documentRhizoma Piperis Methystici
View the documentCortex Pruni Africanae
View the documentCortex Rhamni Purshianae
View the documentFlos Sambuci
View the documentRadix Senegae
View the documentFructus Serenoae Repentis
View the documentFructus Silybi Mariae
View the documentHerba Tanaceti Parthenii
View the documentRadix Urticae
View the documentFolium Uvae Ursi
View the documentAnnex: Participants in the Second WHO Consultation on Selected Medicinal Plants
 

Cortex Frangulae

Definition

Cortex Frangulae consists of the dried bark of the stem and branches of Rhamnus frangula L. (Rhamnaceae) (1-3).

Synonyms

Frangula alnus Mill., F. frangula (L.) Karst., F. vulgaris Borgh., Rhamnus alnus Mill., R. korolkowii Hort. Rehd., R. nemoralis Salisb., R. pentapetala Gilib. Ortega (1, 2, 4).

Selected vernacular names

Alder buck, alder buckthorn, alder dogwood, alno nero, alqueshra almoqadassa, amieiro preto, Amselbaum, arrow-wood, awsag aswad, bird cherry, black alder, black alder bark, black dog wood, bois à poudre, bois noir, bourdaine, Brechwegdorn, buckthorn, buckthorn bark, casca de amiero, corteccia di frangola, cortex frangulae, Cortex rhamni frangulae, corteza de arraclau, corteza de frangula, dog wood, écorce d’aune noir, écorce de bourdaine, écorce de frangule, Faulbaum, frangola, frangula, Gelbholzrinde, Glatter Wegdorn, glossy buckthorn, Grindholz, krusinnik, kulit frangula, kutyabengekéreg, Pulverholz, Pulverholzrinde, purging buckthorn, quishrul awsagel aswad, rhamnusbast, Schwarzholz, seyah-tusseh, shagrat hhabb esh shung, siâhtouseh, Spillbaum, sporkenhoutbast, vuilboombast, Zapfenholz, Zweckenholz (1, 4-7).

Geographical distribution

Indigenous to Mediterranean countries and temperate regions of Africa, western Asia and Europe (1, 8).

Description

A shrub, 3-5m high with non-thorny stalks and dark-red to purplishblue young branches spotted with greenish lenticels. Leaves alternate and ovate, entire or slightly sinuate along the margin, and have parallel secondary veins which curve as they meet the edge of the blade. Flowers small, greenish-white, hermaphrodite, pentamerous, arranged in axillary clusters of 2-3. Fruit a drupe, red at first, then black at maturity, with 2 or 3 seeds (1, 9, 10).

Plant material of interest: dried bark

The fresh bark contains free anthrones and must be stored for at least 1 year or artificially aged by heat or aeration before therapeutic use (1, 11, 12).

General appearance

Single or double quills, rarely in channelled pieces; usually 15 cm long, 0.5-2 cm wide and extremely thin (not more than 2 mm thick). Outer surface greyish-brown or purplish-black, wrinkled, with numerous transversely elongated whitish lenticels; sometimes bearing patches of foliaceous lichen, with small black apothecia; when gently scratched, crimson colour of inner layers of cork becomes evident. Inner surface reddish-yellow to dark brown; fine longitudinal striations, becoming red when moistened with dilute solutions of alkali (Bornträger’s test). Fracture, short in the outer part and slightly fibrous in the inner part (1, 2).

Organoleptic properties

Odour: characteristic; taste: sweetish then slightly bitter and astringent; mucilaginous (1, 8).

Microscopic characteristics

Cortex yellowish-brown, consisting of thin-walled parenchyma, containing scattered cluster crystals of calcium oxalate and few small starch grains, and showing large cells filled with mucilage and few groups of slightly lignified fibres, each up to 40µm wide. Phloem yellowish-brown, traversed by numerous, somewhat wavy medullary rays, 1-3 cells wide and 10-25 cells high, and showing numerous tangential groups of strongly lignified bast fibres, accompanied by prismatic crystals of calcium oxalate, forming a crystal sheath around each group; individual fibres 12-24 µm in diameter (1).

Powdered plant material

Yellowish-brown. Fragments of reddish-brown cork; fragments of groups of lignified bast fibres, accompanied by a calcium oxalate crystal sheath; occasional fragments of slightly lignified fibres; fragments showing cells of medullary rays, with yellow contents which turn red with solutions of alkali or with sodium hypochlorite solution; cluster crystals of calcium oxalate, 10-25µm in diameter; prismatic crystals of calcium oxalate, 7-15µm long; few starch grains 3-10µm in diameter; sclereid cells absent (1, 2).

General identity tests

Macroscopic, microscopic and microchemical (Bornträger’s test) examinations and thin-layer chromatography for characteristic hydroxyanthracene glycosides (1, 2).

Purity tests

Microbiological

Tests for specific microorganisms and microbial contamination limits are as described in the WHO guidelines on quality control methods for medicinal plants (13).

Foreign matter

Not more than 1% (2).

Total ash

Not more than 6% (2).

Acid-insoluble ash

Not more than 2% (1).

Loss on drying

Not more than 10% (2).

Pesticide residues

The recommended maximum limit of aldrin and dieldrin is not more than 0.05 mg/kg (14). For other pesticides, see the European pharmacopoeia (14), and the WHO guidelines on quality control methods for medicinal plants (13) and pesticide residues (15).

Heavy metals

For maximum limits and analysis of heavy metals, consult the WHO guidelines on quality control methods for medicinal plants (13).

Radioactive residues

Where applicable, consult the WHO guidelines on quality control methods for medicinal plants (13) for the analysis of radioactive isotopes.

Other purity tests

Chemical, sulfated ash, water-soluble extractive and alcohol-soluble extractive tests to be established in accordance with national requirements.

Chemical assays

Contains not less than 7.0% of glucofrangulins, calculated as glucofrangulin A, determined by spectrophotometry at 515 nm (2). The high-performance liquid chromatography method reported for quantitative analysis of cascarosides (16) can also be considered.

Major chemical constituents

The active constituents are hydroxyanthraquinone glycosides (3-8%) consisting of monoglycosides and diglycosides of frangula emodin, with the diglycosides, glucofrangulins A and B, being the major compounds. The major monoglucosides are frangulins A and B (17). Other anthranoid derivatives present include emodin anthrone-6-O-rhamnoside (franguloside), as well as physcion and chrysophanol in glycosidic and aglycone forms (17, 18). In the fresh bark, anthraquinones are not present, but exist as their reduced anthrone and dianthrone glycosides, which are converted by oxidation during drying and storage, or by accelerated heat and air treatment (4, 6, 8, 9, 17). The structures of the major anthraquinone glycosides, free anthraquinones and frangula emodin anthrone are presented below.

 

R1

R2

frangula emodin

H

H

frangulin A

H

Rha

glucofrangulin A

Glc

Rha

frangulin B

H

Api

glucofrangulin B

Glc

Api


D-apio-β-D-furanosyl


β-D-glucopyranosyl


6-deoxy-α-L-mannopyranosyl


frangula emodin anthrone

Medicinal uses

Uses supported by clinical data

Short-term treatment of occasional constipation (1, 9-11). As a single dose, for total intestinal evacuation before X-rays and other diagnostic examinations when electrolyte solutions alone are insufficient for adequate evacuation or the use of electrolyte solutions is not possible (11).

Uses described in pharmacopoeias and in traditional systems of medicine

As a cathartic (1).

Uses described in folk medicine, not supported by experimental or clinical data

Internally for treatment of diabetes and externally for skin irritations (6).

Experimental pharmacology

Laxative effects

The pharmacological effects of Cortex Frangulae are associated with the hydroxyanthraquinone glycosides, glucofrangulins A and B, and frangulins A and B (17). After oral administration of Cortex Frangulae, the hydroxyanthracene glycosides are not absorbed in the upper intestine, but are hydrolysed in the colon by intestinal bacteria to form the pharmacologically active metabolites. These metabolites are partially absorbed in the colon and act as a stimulant and irritant to the gastrointestinal tract, as does senna (11, 18, 19, 20). The mechanism of action, similar to that of senna, is twofold. Firstly, there is stimulation of colonic motility, resulting in augmented propulsion, and accelerated colonic transit (which reduces fluid absorption from the faecal mass). Secondly, there is an increase in paracellular permeability across the colonic mucosa, probably due to inhibition of sodium/potassium-transporting adenosine triphosphatase or inhibition of chloride channels (18, 21). The increased permeability results in increased water content in the colon (11, 21).

The laxative effect of Cortex Frangulae is not generally observed until 6-8 hours after oral administration. Hydroxyanthracene glycosides are excreted predominantly in the faeces but are also excreted to some extent in urine, producing an orange colour; anthrones and anthranols will also pass into breast milk (18).

Toxicity and overdose

As with other anthraquinone laxatives, the major symptoms of overdose are gripes and severe diarrhoea with consequent loss of fluid and electrolytes (22). Treatment of overdose should be supportive with generous amounts of fluid. Electrolyte levels should be monitored, particularly those of potassium. This is especially important in children and the elderly (22).

Clinical pharmacology

None.

Contraindications

Cortex Frangulae should not be administered to patients with intestinal obstruction and stenosis, atony, inflammatory diseases of the colon (such as ulcerative colitis, irritable bowel syndrome, Crohn disease), appendicitis, severe dehydration with water and electrolyte depletion, or chronic constipation (9, 19, 23). As with other stimulant laxatives, Cortex Frangulae is contraindicated in patients with cramps, colic, haemorrhoids, nephritis, or any undiagnosed abdominal symptoms such as abdominal pain, nausea or vomiting (22). Cortex Frangulae and other anthranoid laxatives are contraindicated during pregnancy because of their pronounced action on the large intestine and the lack of data on their toxicology (24, 25). As anthranoid metabolites may appear in breast milk, Cortex Frangulae should not be used during lactation, since there are insufficient data to assess the potential for pharmacological effects in the breastfed infant (25). Use of Cortex Frangulae for children under the age of 12 years is contraindicated (11).

Warnings

Cortex Frangulae should only be used if no effect can be obtained through a change of diet or by the use of bulk-forming laxatives. Patients should also be warned that certain constituents of the bark are excreted by the kidney and may colour the urine orange, which is harmless. Cortex Frangulae and other stimulant laxatives should not be used by patients with abdominal pain, nausea or vomiting. The use of stimulant laxatives for longer than 2 weeks requires medical supervision. Rectal bleeding or failure to have a bowel movement after taking a laxative may indicate a serious condition. Chronic use may result in aggravation of constipation with laxative dependence and need for increased dosages, and disturbances of water and electrolyte balance (e.g. hypokalaemia). Chronic use may also lead to colonic dysfunction (atonicity) and melanotic pigmentation of the colonic mucosa (pseudomelanosis coli), which is harmless (22). Laxative abuse resulting in diarrhoea and consequent fluid and electrolyte losses (mainly of potassium) may cause albuminuria, haematuria, and cardiac and neuromuscular dysfunction. Neuromuscular dysfunction may arise particularly in the case of concomitant use of cardiotonic glycosides (e.g. digoxin, digitalis and strophanthin), diuretics, corticosteroids or liquorice root (22).

Precautions

General

Cortex Frangulae and other laxatives containing anthraquinone glycosides should not be used continuously for longer than 1-2 weeks, because of the possibility of electrolyte imbalance (22).

Drug interactions

Increased intestinal transit time may result in reduced absorption of orally administered drugs (26). Electrolyte imbalances, such as hypokalaemia, may potentiate the effects of cardiotonic glycosides (e.g. digoxin, digitalis and strophanthus). Hypokalaemia resulting from long-term laxative abuse can also potentiate the effects of antiarrhythmic drugs (e.g. quinidine) that change sinus rhythm by affecting potassium channels. Hypokalaemia caused by drugs such as thiazide diuretics, adrenocorticosteroids or liquorice root may be exacerbated, and imbalance of other electrolytes may be aggravated (11).

Drug and laboratory test interactions

Anthranoid metabolites may not be detectable in faeces or urine by standard methods. Thus faecal excretion measurements may not be reliable (26). Urinary excretion of certain anthranoid metabolites may cause discoloration of the urine which is not clinically relevant, but may cause false positives in urinary urobilinogen tests and in estrogen measurements using the Kober procedure (27).

Carcinogenesis, mutagenesis, impairment of fertility

Although chronic use of anthranoid-containing laxatives has been hypothesized to play a role in colorectal cancer, no causal relationship has been demonstrated (28-31).

Various Cortex Frangulae extracts have been shown to be genotoxic in several in vitro systems, resulting in bacterial mutation, and chromosomal aberration and DNA-repair defects in mammalian cells. However, no mutagenicity was observed in a gene mutation assay in mammalian cells (23). Frangula emodin was mutagenic in the Salmonella/microsome assay with S. typhimurium strain TA1537 only, but gave inconsistent results in gene mutation assays in mammalian cells. Frangula emodin was also a strong inducer of unscheduled DNA synthesis in primary rat hepatocytes, but gave negative results in the sister chromatid exchange assay (18, 23, 32, 33).

Pregnancy: teratogenic effects

The teratogenic effects of Cortex Frangulae have not been evaluated. (See also Contraindications.)

Pregnancy: non-teratogenic effects

See Contraindications.

Nursing mothers

See Contraindications.

Paediatric use

See Contraindications.

Adverse reactions

Single doses of Cortex Frangulae may result in cramp-like discomfort of the gastrointestinal tract, which may require a reduction of dosage (11). Overdose can lead to colicky abdominal spasms and pain, as well as the formation of thin, watery stools.

Long-term laxative abuse may lead to electrolyte imbalance (hypokalaemia and hypocalcaemia being the most important), metabolic acidosis, malabsorption of nutrients, weight loss, albuminuria and haematuria (34, 35). Weakness and orthostatic hypotension may be exacerbated in elderly patients when stimulant laxatives are repeatedly used. Secondary aldosteronism may occur due to renal tubular damage after prolonged use. Steatorrhoea and protein-losing gastroenteropathy with hypoalbuminaemia have also been reported in laxative abuse (36). Pseudomelanosis coli has been observed in individuals taking anthraquinone laxatives for extended time periods (22, 35). The pigmentation is harmless and usually reversible within 4-12 months after the drug is discontinued (35). Conflicting data exist on other toxic effects after long-term use such as damage to the autonomous nervous system of the colon (35, 37). In incontinent patients using anthranoid laxatives, prolonged exposure of the skin to faeces may cause skin damage (38).

Use of the fresh bark of Rhamnus frangula may cause severe vomiting, with possible abdominal spasms (18).

Dosage forms

Finely cut and powdered crude drug, powder, dried extract, liquid and solid preparations (8). Store in a tightly closed, light-resistant container for a maximum of 3 years (1, 2).

Posology

(Unless otherwise indicated)
The correct dosage for the treatment of occasional constipation is the smallest dosage necessary to maintain a soft stool. Daily dosage: 0.5-2.5g crude drug taken directly or in a decoction; 0.5-2.5 ml 25% ethanol extract (18); all preparations standardized to contain 20-30 mg hydroxyanthracene derivatives calculated as glucofrangulin A (11); taken at bedtime, or in two divided doses, one in the morning and one at bedtime.

References

1. African pharmacopoeia. Vol. 1, 1st ed. Lagos, Organization of African Unity, Scientific Technical & Research Commission, 1985.

2. European pharmacopoeia, 3rd ed., Suppl. 2000. Strasbourg, Council of Europe, 1999.

3. Pharmacopoeia Hungarica, 7th ed. Budapest, Hungarian Pharmacopoeia Commission, Medicina Konyvkiado, 1986.

4. Blaschek W et al., eds. Hagers Handbuch der pharmazeutischen Praxis. Folgeband 2: Drogen A-K, 5th ed. Berlin, Springer-Verlag, 1998.

5. Bedevian AK. Illustrated polyglottic dictionary of plant names in Latin, Arabic, Armenian, English, French, German, Italian and Turkish languages. Cairo, Argus & Papazian Press, 1936.

6. Farnsworth NR, ed. NAPRALERT database. Chicago, University of Illinois at Chicago, IL, July 8, 1998 production (an online database available directly through the University of Illinois at Chicago or through the Scientific and Technical Network [STN] of Chemical Abstracts Services).

7. Leung AY, Foster S. Encyclopedia of common natural ingredients used in food, drugs, and cosmetics, 2nd ed. New York, NY, John Wiley & Sons, 1996.

8. Bisset NG. Herbal drugs and phytopharmaceuticals. Boca Raton, FL, CRC Press, 1994:463-469.

9. Bruneton J. Pharmacognosy, phytochemistry, medicinal plants. Paris, Lavoisier, 1995.

10. Youngken HW. Textbook of pharmacognosy, 6th ed. Philadelphia, PA, Blakiston, 1950.

11. Blumenthal M et al., eds. The complete German Commission E monographs. Austin, TX, American Botanical Council, 1998.

12. Tyler VE, Bradley LR, Robbers JE, eds. Pharmacognosy, 9th ed. Philadelphia, PA, Lea and Febiger, 1988:62-63.

13. Quality control methods for medicinal plant materials. Geneva, World Health Organization, 1998.

14. European pharmacopoeia, 3rd ed. Strasbourg, Council of Europe, 1996.

15. Guidelines for predicting dietary intake of pesticide residues, 2nd rev. ed. Geneva, World Health Organization, 1997 (document WHO/FSF/FOS/97.7).

16. De Witte P, Cuveele J, Lemli J. Determination of bicascarosides in cascara fluid extract by high-performance liquid chromatography. Journal of Liquid Chromatography, 1991, 14:2201-2206.

17. Westendorf J. Anthranoid derivatives - Rhamnus species. In: De Smet PAGM et al., eds. Adverse effects of herbal drugs. Vol. 2. Heidelberg, Springer-Verlag, 1993:129-131.

18. Bradley PR, ed. British herbal compendium. Vol. 1. Bournemouth, British Herbal Medicine Association, 1992.

19. Reynolds JEF, ed. Martindale, the extra pharmacopoeia, 30th ed. London, The Pharmaceutical Press, 1996.

20. WHO monographs on selected medicinal plants. Vol. I. Geneva, World Health Organization, 1999.

21. De Witte P. Metabolism and pharmacokinetics of the anthranoids. Pharmacology, 1993, 47 (Suppl. 1):86-97.

22. Hardman JG, Limbird LE, eds. Goodman and Gilman’s The pharmacological basis of therapeutics, 9th ed. New York, McGraw-Hill, 1996.

23. ESCOP monographs on the medicinal uses of plant drugs. Fascicule 5. Devon, European Scientific Cooperative on Phytotherapy, 1997.

24. Lewis JH, Weingold AB. The use of gastrointestinal drugs during pregnancy and lactation. American Journal of Gastroenterology, 1985, 80:912-923.

25. Physician’s Desk Reference. Montvale, NJ, Medical Economics, 1998.

26. American Hospital Formulary Service. Bethesda, MD, American Society of Hospital Pharmacists, 1990.

27. The United States pharmacopeia: dispensing information. Rockville, MD, The United States Pharmacopeia Convention, 1992.

28. Loew D. Pseudomelanosis coli durch Anthranoide. Zeitschrift für Phytotherapie, 1994, 16:312-318.

29. Patel PM et al. Anthraquinone laxatives and human cancer. Postgraduate Medical Journal, 1989, 65:216-217.

30. Siegers CP. Anthranoid laxatives and colorectal cancer. Trends in Pharmaceutical Sciences, 1992, 13:229-231.

31. Siegers CP et al. Anthranoid laxative abuse - a risk for colorectal cancer? Gut, 1993, 34:1099-1101.

32. Westendorf J et al. Possible carcinogenicity of anthraquinone-containing medical plants. Planta Medica, 1988, 54:562.

33. Westendorf J et al. Genotoxicity of naturally occurring hydroxyanthraquinones. Mutation Research, 1990, 240:1-12.

34. Godding EW. Therapeutics of laxative agents with special reference to the anthraquinones. Pharmacology, 1976, 14 (Suppl. 1):78-101.

35. Muller-Lissner SA. Adverse effects of laxatives: facts and fiction. Pharmacology, 1993, 47 (Suppl. 1):138-145.

36. Heizer WD et al. Protein-losing gastroenteropathy and malabsorption associated with factitious diarrhoea. Annals of Internal Medicine, 1968, 68:839-852.

37. Kune GA. Laxative use not a risk for colorectal cancer: data from the Melbourne colorectal cancer study. Zeitschrift für Gastroenterologie, 1993, 31:140-143.

38. Helwig H, Mund P. Akute Hautschädigung durch “X-Prep”. Monatsschrift Kinderheilkunde, 1986, 134:164.

 

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