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• Sulfasalazine is well known for its role in inhibiting the absorption of dietary folicin, most likely acting as a competitive inhibitor of Folate absorption. There has been some controversy as to whether folic acid by itself can cause clinically significant deficiencies of folic acid. Sulfasalazine also inhibits folate-dependent enzymes. The mechanisms by which sulphasalazine antagonizes folate metabolism are dose-dependent and, consequently, higher doses might precipitate folate deficiency. However, a strong proportion of the literature indicates a multifactorial causality for folate depletion in the affected populations with the side effects of sulfasalazine being an important but not necessarily adequate stress. The conditions for which the drug is usually prescribed are often associated with malabsorption, poor diet and chronic inflammation. For example, patients with ulcerative colitis commonly have decreased folate levels. Furthermore, any sulfasalazine-induced folic acid deficiency could contribute to higher levels of homocysteine and increased risk of cardiovascular disease.1
• Although maintenance sulfasalazine use may not commonly cause clinically significant folate deficiency states, sulphasalazine inherently impairs folate absorption and subclinical tissue depletion usually occurs as a dose-related effect. Folic acid is an especially important nutrient for those individuals who typically use sulfasalazine because they usually suffer from conditions for which folic acid can have therapeutic value. Folate is well known for its role in reducing the risks for some forms of cancer. A significant aspect of this benefit may be attributable to its key role in the healthy replication of cells. In particular, folate supplementation has been associated with a reduced risk of colon cancer in patients with ulcerative colitis while folate deficiency has been associated with an increased risk for colon cancer. For example, in a study of patients with chronic ulcerative colitis Lashner et al found a 62% lower risk of colon cancer with folate supplementation, compared to ulcerative colitis patients who did not supplement with folate . In a later study Lasher and a different team found that individuals who have ulcerative colitis and who supplement folic acid had a 55% lower risk of developing colon cancer. Although these findings were not statistically significant, they concluded that daily folate supplementation may protect against the development of neoplasia in ulcerative colitis. While many factors contribute to the occurrence of colon cancer many researchers have suggested that folic acid deficiency may increase susceptibility and that supplementation may have a preventive effect.2
• Most researchers have concluded that folate supplementation during sulfasalazine administration is recommended, especially to prevent the complication of dysplasia or cancer in ulcerative colitis. supplementation with folic acid would be appropriate for individuals taking sulfasalazine. Folate has no known risks at the suggested levels and can potentially provide a number of benefits to those taking sulfasalazine or even those simply suffering from, or predisposed to, some of the conditions it is most commonly prescribed for. Many commonly available multivitamin or B-complex formulations provide folic acid at daily doses of approximately 800 mcg. Individuals using sulfasalazine might benefit from higher doses, in the range of 1000-1200 mcg per day but should consult with their prescribing physician, pharmacist, and/or nutritionally trained healthcare professional before adopting such a regimen.3
• Iron and sulfasalazine have a tendency to bind to each other in the digestive tract. As a result, the simultaneous ingestion of both substances can lead to decreased sulfasalazine absorption, decreased iron absorption, or bothIron and sulfasalazine have a tendency to bind to each other in the digestive tract. As a result, the simultaneous ingestion of both substances can lead to decreased sulfasalazine absorption, decreased iron absorption, or both.) Since sulfasalazine may reduce the absorption of iron from dietary sources supplementation may be appropriate. However, individuals taking sulfasalazine should not begin supplementation with iron before consulting with their prescribing physician, pharmacist, and/or nutritionally trained healthcare professional. In any event, if iron supplementation is undertaken, no iron-containing products should be taken two hours before or after sulfasalazine. so as to minimize the potential interaction.4
• Sulfasalazine is usually prescribed to be taken after meals for best effect. Further, physicians and pharmacists generally advise patients to swallow the tablets whole in order to avoid inactivation by stomach acid.5
• PABA-containing compounds, as well as local anesthetics derived from PABA such as procaine, may directly inhibit the activity of sulfonamides, the class of drugs of which sulfasalazine is a member.6
• Common herbs containing cardiac glycosides: Asclepias tuberosa (Pleurisy Root ) Convallaria majalis (Lily of the Valley) Scrophularia nodosa (Figwort) Urginea maritima (Squill bulb) Note: These herbs contain therapeutically insignificant quantities of glycosides. Restricted or unusual herbs containing cardiac glycosides: Adonis vernalis (Pheasants Eye) Apocynum cannabinum (Canadian Hemp Root) toxic Digitalis spp. (Foxglove) toxic Helleborus niger (Black Hellebore) toxic Helleborus viride (Christmas Rose) toxic Nerium oleander (Rose Laurel) toxic Strophanthus spp. (Ouabain, Kombe) toxic Thevetia neriifolia (Yellow Oleander) toxic7
• SASP, the drug most widely used for the treatment of Crohn's disease and ulcerative colitis, is a competitive inhibitor of intestinal folate metabolism and transport. Some of the therapeutic effects of the drug could be related to antifolate actions on lymphocytes, which predominate in the inflammatory reaction in inflammatory bowel diseases. Experiments were designed to examine the effect of SASP on folate-dependent systems in cultured lymphocytes. In rat spleen lymphocytes, THF-dependent conversion of glycine to serine was inhibited by SASP, with 50% inhibition occurring at 0.1 mM. Further evidence of folate antagonism was obtained with the dU suppression test, which depends on the function of a folate-dependent pathway in the de novo synthesis of DNA. Folate antagonists like methotrexate or folate depletion reduces the incorporation of dU into DNA and thus favors incorporation of [3H]thymidine into DNA by an alternate pathway. SASP inhibited the folate-dependent pathway in proliferating virally transformed human lymphocytes (Raji cells). To confirm that SASP acts as a folate antagonist in this system, THF was demonstrated to partly reverse the action of SASP. The significance of this antifolate action by SASP in intact lymphocytes deserves further study in relation to the actions of SASP in patients with inflammatory bowel disease.8
• potential interaction: Digitalis (Foxglove) and other plants containing cardiac glycosides. In looking at drug-drug interactions researchers have found that sulfasalazine may cause reduced absorption of digoxin. While this research has focussed on pharmaceutical digoxin the findings could reasonably be extrapolated to the use of herbs containing digoxin and other cardiac glycosides.9
• In the unlikely event that an individual has been prescribed cardioactive herbs by a qualified medical herbalist or a physician trained in herbal prescribing the concurrent use of sulfasalazine might create results other than expected due to a potential interaction. The use of herbs based on the action of their cardiac glycosides is a potentially dangerous practice to be undertaken only under close observation by a highly trained and experienced herbal prescriber. Naturally occurring cardiac glycosides have a limited distribution confined to a few dozen species scattered across several genera, principally the Asclepiadaceae and Apocyanaceae. Concentrations of glycosides are generally well below 1%. Three genera contain sufficient concentrations of glycosides for commercial extraction: Digitalis spp.- Foxgloves - (Scrophulariaceae), Urginia spp - Squills - (Liliaceae) and Strophanthus (Apocynaceae). These plants are described as cardioactive by herbalists, as opposed to the milder cardiotonic herbs such as Hawthorn. Due to their toxicity, these herbs are not available to the public. Neither Digitalis or Strophanthus are commonly used in herbal therapeutics and in many countries their use is legally restricted. Convallaria majalis and Urginia maritima are listed in the British Herbal Pharmacopoeia. Their cardenolides have low cumulative toxicity compared to Digitalis, and these plants are used by professional herbalists101 Baum CL, et al. J Lab Clin Med 1981 Jun;97(6):779-784; Selhub J, et al. J Clin Invest 1978 Jan;61(1):221-224;4(3):114; Pironi L, et al. Minerva Dietol Gastroenterol 1987 Oct-Dec;33(4):307-313; Halsted CH, et al. N Engl J Med 1981;305:1513-1517; Swinson CM, et al. Gut 1981;22:456-61; Longstreth GF, Green R. N Engl J Med 1982;306:1488; Nutr Rev. 1988 Sep;46(9):320-323; Baggott JE, et al. Clin Exp Rheumatol 1993 Mar-Apr;11 Suppl 8:S101-105; Das KM, Dubin R. Clinical Pharmacokinetics 1976 Nov-Dec;1(6):406-425; Grindulis KA, McConkey B. Scand J Rheumatol 1985;14(3):265-270; Haagsma CJ, et al. Ann Rheum Dis 1999 Feb;58(2):79-84; Krogh Jensen M, et al. Scand J Clin Lab Invest 1996 Aug;56(5):421-429; Elsborg L.Dan Med Bull 1982; 29:362-365
2 Longstreth GF, Green R. Arch Intern Med 1983 May;143(5):902-904; Lashner BA, et al. Gastroenterology 1989 Aug;97(2):255-259; Gastroenterol 1988; 94(5 part 2): A252; Ma J, et al. Cancer Res 1997 Mar 15;57(6):1098-1102; Mason JB. J Nutr Biochem 1994;5:170-175; Cravo ML, et al. Am J Gastroenterol. 1998 Nov;93(11):2060-2064; Mouzas IA, et al. Ital J Gastroenterol Hepatol. 1998 Aug;30(4):421-425
3 Lashner BA, et al. Gastroenterology 1989 Aug;97(2):255-259; Ma J, et al. Cancer Res 1997;57:1098-102; Lashner BA, et al. Gastroenterol 1997;112:29-32; Elsborg L.Dan Med Bull 1982; 29:362-365
4 Not Available.
5 Threlkeld DS, ed. Sep 1997
6 Drug Evaluation Subscription. Vol II, Section 13, Chapter 7, Spring 1993
7 Weiss, RF. Herbal Medicine. Beaconsfield, England: Beaconsfield Publishers Ltd., 1988.
8 Baum CL, Selhub J, Rosenberg IH. Antifolate actions of sulfasalazine on intact lymphocytes. J Lab Clin Med 1981 Jun;97(6):779-784.
8 Brinker F. Herb Contraindications and Drug Interactions. Sandy, OR: Eclectic Institute, 1997.
9 Juhl RP, et al. Clin Pharmacol Ther. 1976 Oct;20(4):387-394
10 Weiss, RF. Herbal Medicine. Beaconsfield, England: Beaconsfield Publishers Ltd., 1988.
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