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Cascara

Botanical Name: Rhamnus purshiana DC.
Pharmacopoeial Name: Cortex rhamni purshianae.
Synonym: Frangula purshiana (DC) A. Gray ex J.C. Cooper.
Common Names: Cascara, cascara sagrada.

herb description

Family

Rhamnaceae.

Related Species

Alder buckthorn, Rhamnus frangula L. (syn. Frangula alnus , Miller.), buckthorn, Rhamnus catharticus L.

Parts Used

Dried bark (aged at least 1 year, stored in dark).

Common Forms

  • Dried bark:   Powdered or cut for decoction.

  • Fluid Extract:   1:1 25% alcohol. 1

Other liquid and solid preparations.

interactions review

Strategic Considerations

Cascara bark is a major representative of the anthraquinone-containing herbs that are principally used for short-term relief of constipation. The anthraquinone-containing laxative group of botanicals traditionally includes related Rhamnaceae species such as the buckthorns ( Rhamnus frangula L. and R. catharticus L.), senna leaf and fruits ( Cassia senna L.), rhubarb root ( Rheum palmatum L.), and aloe latex ( Aloe ferox , Miller). The different crude drugs in this group have a large medical and commercial application as stimulant laxatives for the preparation of patients for radiological or colonoscopic procedures, softening of stool before anorectal surgical procedures, and treatment of constipation linked to drug-induced or lifestyle causes. In traditional botanical medicine, cascara and its relatives have long been used for short-term treatment of constipation, with a more recent history of folk use in herbal cancer treatments (e.g., the Hoxsey formula).

The widespread availability of both over-the-counter (OTC) and dietary supplement preparations containing stimulant laxatives has emphasized the problem of adverse effects from laxative abuse, with public education through cautionary product labeling suggesting restrictions for duration of use and contraindications for consumers. 2 Most of the professional literature echoes this concern. Cascara bark was approved for constipation by the German Commission E 3 and is the subject of monographs by the British Herbal Medical Association (BHMA), 1 World Health Organization (WHO), 4 and most comprehensively by the European Scientific Cooperative on Phytotherapy (ESCOP). 5

A distinction should be made between appropriate therapeutic use of cascara and related botanicals and the uncontrolled, self-prescribed consumption of these agents by certain individuals. These latter, for psychological reasons, either consider normal bowel movement frequency to be unhealthy or compulsively exhibit behaviors classified in the eating disorder group of diagnoses (i.e., bulimia, anorexia, binge eating) and use purgation (and/or vomiting) as a self-imposed means of eliminating ingested food. Although such abuse exists, preoccupation with the purgative aspects of these herbs and their anthraquinone constituents is only one concern to integrative practitioners. A broader consideration of the activity of these botanicals in light of recent research suggests therapeutic applications in other fields, such as cancer chemotherapy.

Recent findings have revealed that the earlier concept of all stimulant laxatives acting through gut motility mechanisms is oversimplistic. Multiple mechanisms are involved, including almost every aspect of active and passive electrolyte transport, such as sodium/potassium-adenosinetriphosphatase (Na+, K+-ATPase), cyclic nucleotides, protein kinase C, calcium (Ca++) dependence, autocoids or neurotransmitter release, increased mucosal permeability, and histological damage. 6-11Furthermore, it has become clear that significant differences exist between the mechanism of action of the different agents; for example, senna does not stimulate platelet-activating factor (PAF) or inducible nitric oxide synthase (iNOS), as occurs with cascara. 6,8

In the field of cancer biology, hydroxyanthraquinone agents such as emodin, once considered to be potentially carcinogenic, have more recently been studied for a variety of antiproliferative effects, mediated by inhibition of both nuclear factor kappa B (NF-κB) and tyrosine kinase. 12,13These results have particular impact on HER-2/neu overexpression, as discussed later in the context of cascara's possible therapeutic combination with herceptin. Parenthetically, it should be noted that a significant number of conventional chemotherapeutic agents, notably doxorubicin, idarubicin, epirubicin, and mitoxantrone, are all anthraquinone derivatives. Interestingly, drug resistance to these agents may be reduced by plant-based polyphenols, including aloe-emodin, probably by inhibition of NF-κB. 14 Experimental studies with whole-herb extracts are rare, and most available data derive from studies using isolated anthraquinone ingredients such as emodin and aloe-emodin, and extrapolations to whole-plant effects must be qualified.

Pharmacokinetic interactions involving modification of drug absorption resulting from decreased transit times induced by cascara administration should not be overlooked. Stockley 15 reports only one such interaction between quinidine and a senna preparation in which quinidine AUC (area under curve) levels were reduced to 25% of baseline 12 hours after administration of a dose of Liquedepur. This is in contrast to the German Commission E, who proposed potential for interactions between all laxative herbs and antiarrhythmic drugs because of electrolyte disturbances (hypokalemia) rather than drug depletion from reduced bioavailability. The onset of enhanced bowel motility and the formation of soft or semisolid stool after administration of anthraquinone laxatives are known to lag 6 to 8 hours after ingestion, a result of the bowel flora hydrolysis of anthrone conjugates into the active aglycone drug form. 16 The extended delay should be taken into account if pharmaceuticals with a therapeutically narrow range are already being administered to the patient before cascara administration. As always, clinical context and goals of coadministration are relevant for evaluating the significance of a potential interaction, and the cautions persistently repeated in relation to these drugs in the botanical literature (possible hypokalemia) are only discussed here in the section Theoretical, Speculative, and Preliminary Interactions Research.

Effects on Drug Metabolism and Bioavailability

Some evidence suggests that the naturally occurring anthraquinones such as emodin and chrysophanol are substrates that may undergo bioactivation into carcinogenic (mutagenic/genotoxic) intermediates through cytochrome P450 1A1 and 1A2. 17 However, in vitro data suggest that they may inhibit the same enzymes. 18,19Extrahepatic cytochromes, such as CYP1B1 (which is often overexpressed in certain reproductive malignancies), have been experimentally induced by emodin in a human lung cancer cell line. 20 Similar experimental models also suggest inhibitory effects on phase 2 enzymes, including glutathione- S-transferase P1 and N-acetyltransferase. 21,22These effects may be due to inhibition or downregulation of transcription factors NF-κB and activating protein 1 (AP-1). 22,23At present, the pharmacokinetic effects of anthraquinone herbs on drug metabolism are not well characterized, but the possibility of clinically significant effects cannot be ruled out.

herb-drug interactions
Trastuzumab
theoretical, speculative, and preliminary interactions research, including overstated interactions claims
Digoxin and Related Cardiac Glycosides and Antiarrhythmic Drugs

Amiodarone (Cordarone, Pacerone), deslanoside (cedilanin-D), digitoxin (Cystodigin), digoxin (purgoxin; Digitek, Lanoxin, Lanoxicaps), disopyramide (Norpace), dofetilide (Tikosyn), flecainide (Tambocor), ibutilide (Corvert), ouabain (g-strophanthin), procainamide (Procan-SR, Pronestyl), quinidine (Quinaglute, Quinidex, Quinora), sotalol (Betapace, Betapace AF, Sorine).

Potential electrolyte and acid-base disturbances resulting from chronic diarrhea caused by inappropriately prolonged use (or abuse) of cascara extracts was considered by the German Commission E. In their 1984 monograph on cascara, the Commission included a warning about the possibility of adverse interactions with cardiac glycosides, as well as other antiarrhythmic drugs, caused by hypokalemia. This was extended to a possible additive adverse interaction with known potassium-depleting drugs, such as thiazide diuretics and corticosteroids, as well as licorice root. 3 Over time, through force of repetition, this has now become a consensus interactions concern associated with all the stimulant laxative botanicals.

There are no actual clinical reports of this speculative interaction occurring. Therapeutic context should be acknowledged before general warnings about interactions are given. Laxative abuse is a possible context to consider.

Estimates of the incidence of laxative abuse are scarce. A review of 73 published studies suggested an incidence of approximately 4.0% in the general population, but 14% among bulimic patients. 40 The diagnosis of bulimia predominantly affects females and is rare in older populations likely to be taking antiarrhythmic medication. Also, hypokalemia is a rarely reported adverse effect of laxative use, although decades ago the issue was sporadically noted. 41 A single case report from the psychiatric literature does suggest that two severe episodes of torsades de pointes in a mentally ill woman were the result of electrolyte disturbance from the stimulant laxative bisacodyl. 42 No antiarrhythmics were being used by this patient; however, a preclinical study that examined the effect of coadministered bisacodyl on digoxin serum levels found a significant reduction in serum cardiac glycoside levels compared with controls, which the authors considered a result of absorption losses caused by the laxative. 43

Beyond the situation of overt or covert laxative abuse, the dangers of a hypokalemia-induced interaction seem remote. Stockley' s Drug Interactions 15 does not report drug-induced hypokalemia cases from any cause, including stimulant laxatives interacting with cardiac glycosides. As suggested by at least one commentator, these adverse effects are overstated and unlikely to be the basis of a clinically relevant interaction. 44,45 Unless a patient is borderline hypokalemic from potassium-wasting diuretic therapy without potassium supplementation, diarrhea-induced hypokalemia would require at least five voluminous liquid stools per day for several days, which is an improbable consequence of normal therapeutic administration of cascara.

Citations
  • 1.BHMA. Cascara bark. In: Bradley P, ed. British Herbal Compendium. 1 vol. Bournemouth, UK: British Herbal Medical Association; 1992.
  • 2.McGuffin M, Hobbs C, Upton R, Goldberg A. American Herbal Products Association’s Botanical Safety Handbook. Boca Raton, Fla: CRC Press; 1997.
  • 3.Blumenthal M, Busse W, Goldberg A et al. The Complete German Commission E Monographs. Austin, Texas: American Botanical Council: Integrative Medicine Communications; 1998.
  • 4.WHO. Cortex rhamni purshianae. WHO Monographs on Selected Medicinal Plants. 2 vol. Geneva: World Health Organization; 2002:259-268.
  • 5.ESCOP. Rhamni purshiani cortex. ESCOP Monographs: The Scientific Foundation for Herbal Medicinal Products. 2nd ed. Exeter, UK: European Scientific Cooperative on Phytotherapy and Thieme; 2003:413-418.
  • 6.Izzo AA, Gaginella TS, Mascolo N, Capasso F. Recent findings on the mode of action of laxatives: the role of platelet activating factor and nitric oxide. Trends Pharmacol Sci 1998;19:403-406.View Abstract
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