Cascara

Scientific Name(s): Rhamnus pushiana DC. Family: Rhamnaceae. Synonym: Frangula purshiana (D.C.) A. Gray ex J.C. Cooper.

Common Name(s): Bitter bark , buckthorn , cascararinde , cascara sagrada , chittem bark , Cortex rhamni purshianae , purshiana bark , Rhamnus , sacred bark

Uses

Limited clinical studies exist for cascara aside from those of its laxative effects. Attention has shifted to studying the effects of its constituent emodin, particularly with regard to possible therapeutic applications in the treatment of cancer.

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Dosing

Cascara sagrada over-the-counter (OTC) laxative products were declared no longer safe and effective by the US Food and Drug Administration (FDA) in 2002. Typical doses of cascara are 1 g of bark, 2 to 6 mL of fluid extract or 325 mg of dried extract.

Contraindications

Cascara is contraindicated in ileus of any origin and in inflammatory diseases of the colon, including ulcerative colitis, irritable bowel syndrome (IBS), and Crohn disease.

Pregnancy/Lactation

Documented emmenagogue and abortifacient effects. Avoid use. Anthranoid metabolites may be excreted in breast milk.

Interactions

None well documented.

Adverse Reactions

Extended use may cause chronic diarrhea and consequent electrolyte imbalance.

Toxicology

Overdose of anthraquinone laxatives results in intestinal pain and severe diarrhea with consequent electrolyte imbalance and dehydration. No causal relationship between long-term use of cascara and colorectal cancer has been established. The carcinogenicity of emodin has been studied with equivocal results.

Botany

The official cascara sagrada is the dried bark of R. pushiana collected from small- to medium-sized wild deciduous trees. They usually range from 6 to 12 m and possess thin, elliptical to ovate-oblong, acutely pointed leaves. The greenish flowers are arranged in umbellate cymes, and the fruit is purplish-black and broadly obovoid (8 mm long). Commercial bark is flattened or transversely curved, longitudinally ridged with a brownish to red-brown color. It has gray or white lichen patches and occasional moss attachments. Cascara trees are found in North America in California, Oregon, Washington, Idaho, and Montana, and as far north as Southeast British Columbia. 1 , 2 , 3 , 4

History

Cascara is a folkloric medicine used by indigenous American people and immigrants as a natural laxative. R. purshiana itself was not described officially until 1805, and the bark was not brought into common medicinal use until 1877. The berries of the European counterpart (European buckthorn, Rhamnus frangula ) were described in the London Pharmacopoeia of 1650. In 2002, the FDA banned the use of cascara sagrada as an OTC laxative ingredient. 2 , 5 , 6

Chemistry

The active laxative principles of cascara include at least 6% to 9% anthracene derivatives, which exist as normal O-glycosides and C-glycosides. The 4 primary glycosides or cascarosides A, B, C, and D, contain both O- and C-glycosidin linkages that are chemically designated as the C-10 isomers of the 8-O-beta-D-glucopyranosides of aloin and chrysophanol. A number of dianthrones are also present and include emodin, chrysophanol, and the heterodianthrones, as well as palmidin A, B, and C.

The free anthraquinones are likely formed in the leaves and stored in the bark mostly as C-glycosides, with older bark containing the largest concentration. Although not a commercially viable source, R. purshiana cell suspension cultures produce anthracene derivatives.

Cascara juice also contains other nonlaxative compounds such as rhamnol (cinchol, cupreol, quebrachol); linoleic, myristic, and syringic acids; resins, fat, starch, and glucose; and malic and tannic acid. The dried seeds contain 7% to 25% protein, 13% to 57% oil, and 1% to 2% ash.

A variety of extraction methods have been examined for cascara. Boiling water prevents the losses and changes to the compound that occur in cold water extraction. Analysis and quantification of cascara's chemical constituents have been reported, and techniques for the production of emodin derivatives have been published. 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14

Uses and Pharmacology

Laxative

On November 5, 2002, the FDA ruled that cascara sagrada OTC laxative products were no longer considered safe and effective. 6 A systematic review has been published on the use of cascara and other laxatives. 15 Studies conducted in elderly populations show that the majority of patients using long-term laxative preparations, including cascara, were able to discontinue laxative use when a fiber supplement was added. 15 , 16 , 17

As in other stimulant laxatives (eg, aloe, senna), anthraglycosides are responsible for the cathartic properties of cascara. Cascarosides A and B are the major active principles that act on the large intestine to induce peristalsis and evacuation. More specifically, anthraglycosides produce an active secretion of water and electrolytes within the lumen of the small intestine and inhibit their absorption from the large intestine, causing an increase in the bowel content volume and strengthening intestinal dilatation pressure to stimulate peristalsis. 2 , 4 , 5 The emodin glycoside also causes laxative action, first requiring metabolism to the active aglycone by intestinal flora, and possibly increasing the excitability of the smooth muscles of the intestinal wall. 18 , 19

Other uses

Aside from laxative effects, limited clinical studies exist for cascara. Attention has shifted to studying the effects of its constituent emodin, particularly with regard to possible therapeutic applications in the treatment of cancer.

Antimicrobial action

In vitro studies of cell cultures have shown that emodin possesses antibacterial ( Helicobacter pylori , Escherichia coli , Pseudomonas aeruginosa , and some Staphylococcus aureus strains), virucidal (herpes simplex), and antifungal ( Candida ) action. 18 , 20 , 21

Antifibrotic effects

Emodin demonstrated protective action in animal models for hepatic injury, pancreatitis, renal failure, and pulmonary fibrosis, 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 as well as fibrinolytic action via activation of plasminogen activator. 30

Anti-inflammatory/immune system effects

Experimental models of inflammation, including rat paw edema and ocular surface inflammation, have been used to demonstrate the action of emodin. The mechanism of action is unclear, but may involve influence on cytokines or transcription factor. 18 , 28 , 31 , 32

Cancer

The potential applications of emodin as a constituent of cascara in the management of cancer have been reviewed. 18 Cell cycle inhibition of many human cancer lines has been reported in vitro. 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 A definitive mechanism of action, however, is unclear. 18 Apoptosis, as well as antitumor action, has been demonstrated, and a role as an adjunct to chemotherapy has been suggested for emodin. 42 , 43 Antiangiogenic action has also been revealed. 37 , 46 Direct cytotoxicity is not thought to be responsible for apoptosis, with some researchers suggesting the involvement of signaling pathways, inhibition of kinases, and microsomal enzyme activation. 36 , 37 , 47 Few animal experiments have been conducted, 43 and clinical studies are lacking. 18

Cardiac and smooth muscle effects

In animal models of acute myocardial infarction and reperfusion injury, emodin appears to have a protective role on the cardiac tissue by unclear mechanisms. 49 , 50 Anti- and pro-oxidant effects have been described for emodin. 18 , 51 , 52 In smooth muscle tissue, calcium and potassium efflux mechanisms are affected by emodin. 53 , 54 , 55

CNS effects

In vitro and animal studies suggest emodin exerts action on receptor signaling mechanisms in models of schizophrenia, and may also possess serotonin or muscarinic activity by protecting against induced amnesia in animals. 56 , 57

Lipids

Hypolipidemic and hypoglycemic effects have been demonstrated in animal models. 58 , 59

Dosage

On November 5, 2002, the FDA ruled that OTC cascara sagrada products were no longer generally recognized as safe and effective. 6 Use in children younger than 10 years of age is not recommended. 2 Cascara has mainly been used as a liquid extract, elixir, or tablet made from a standardized dry extract. Typical doses of cascara are 1 g of bark, 2 to 6 mL of fluid extract, or 325 mg of dried extract. 60 Laxative action is seen within 6 to 8 hours after administration. 2 Due to the risk of electrolyte imbalance, use should be limited to less than 2 weeks. 2 , 60

Pregnancy/Lactation

Documented emmenagogue and abortifacient effects. Avoid use. 61 , 62 , 63 Anthranoid metabolites may be excreted in breast milk. 2

Interactions

Case reports are lacking. Long-term cascara use may lead to a potassium deficiency that can potentiate the effects of cardiac glycosides, antiarrhythmics, and corticosteroids. 64 , 65 Interference with the absorption of other drugs is possible with anthranoid-containing plants, including senna and cascara. 2 , 66

Adverse Reactions

Extended or habitual use of cascara can cause chronic diarrhea and weakness due to excessive potassium loss and should be avoided. Long-term use can cause melanin pigmentation of the colon mucous membranes. 7 , 8 Discoloration of the urine may occur. 60

Cascara is contraindicated in ileus of any origin and in inflammatory diseases of the colon (ulcerative colitis, IBS, Crohn disease). Laxative products should not be used when abdominal pain, nausea, and/or vomiting are present unless directed by a health care provider. 17 , 60

A case report exists of intrahepatic cholestasis, and consequent portal hypertension, related to cascara use. It is unclear if the event was due to the cascara preparation or to adulterants. 67 Freshly prepared cascara product contains anthrones; severe vomiting and intestinal cramping can result from its consumption. Therefore, the bark should be stored for at least 1 year before use or processed by heating in air to eliminate the presence of anthrones. 68

Toxicology

Overdose of anthraquinone laxatives results in intestinal pain and severe diarrhea with consequent electrolyte imbalance and dehydration. Treatment is symptomatic, with special attention to potassium and other electrolyte levels, especially in elderly patients and children. 2

No causal relationship between long-term use of cascara and colorectal cancer has been established. 2 In a rat colon carcinogenesis model study, cascara did not increase the incidence of aberrant crypt foci or tumors. 69 Samples of herbal preparations were evaluated for heavy metal contamination (cadmium, mercury, and lead), with low levels reported for cascara. 70 The carcinogenicity of emodin has been studied with equivocal results. 18 Emodin paradoxically exhibits an antioxidant action as well as pro-oxidant activity, 48 and has shown protective and toxic effects in rat glioma cells. 45 No consensus on the mutagenicity of emodin has been achieved: a 2-year study conducted by the National Cancer Institute found equivocal evidence of carcinogenicity in rats. 71

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