- Email: [email protected]
Effect of chrysotherapy on the lower gastrointestinal tract: A review
Effect of Chrysotherapy
on the Lower Gastrointestinal A Review
Tract:
By Maria P. Rocha, Paul J. Burrichter, and Randolph C. Blodgett
T
HE RECENT introduction of auranofin, an oral gold compound that is primarily absorbed and eliminated through the gastrointestinal (GI) tract, has focused attention on the effect of gold on the lower GI tract. Auranofin is effective for the treatment of rheumatoid arthritis (RA) when received orally and is reported to have a lower incidence of serious adverse reactions than injectable gold.’ Approximately 25% of the oral dose is absorbed from the GI tract, and 85% of the total dose is eliminated in the feces (75% unabsorbed and 10% GI elimination).* This compares with the 30% fecal elimination of injectable gold products following intramuscular (IM) administration.3 This report reviews and analyzes recent reports of loose stools and diarrhea associated with gold therapy to determine the severity, incidence, and possible mechanism of this reaction, and to place in perspective the lower GI side effects of auranofin compared with injectable gold. REVIEW OF CLINICAL STUDIES
Eighteen clinical studies4-23 have been performed to compare the safety and efficacy of auranofin with injectable gold for the treatment of RA. Seven of the studies were double-blind in design; the remainder were single-blind or open trials. A mean prevalence of 44% (range, 0% to 73%)4-23 was reported for loose stools/diarrhea in
From the Department of Gastroenterology. Lisbon Military Hospital. Lisbon, Portugal; and the Medical Information Department and Department of Rheumatology, SK&F International, Philadelphia. Maria P.Rocha, MD: Specialist in Gastroenterology, Lisbon Military Hospital, Lisbon, Portugal. Group Director, Medical and Regulatory Affairs, SK & F, Portugal; Paul J. Burrichter, RPh: Assistant Manager Medical Information, SK&F International, Philadelphia: Randolph C. Blodgett, MD, FACP: Vice-President and Medical Director Rheumatology, SK&F International, Philadelphia. Address reprint requests to Maria P. Rocha. MD, Instiiuto Luso Farmaco. Rua Do Quelhas 8e18, 1296 Lisbon, Portugal. 8 1987 by Grune & Stratton, Inc. 0049-0172/87/l 604-0007$S.O0/0
294
these studies. The symptoms tended to be mild, occured early (Fig 1), and usually resolved spontaneously or with a reduction of auranofin dosage. In controlled studies, the withdrawal rates due to diarrhea were 3% to 5%.‘.” Virtually all the patients in these studies were also receiving non-steroidal antiinflammatory drugs (NSAIDs), some of which have been reported to cause diarrhea.25 In the overall comparison of seven double-blind studies, the reported incidence of diarrhea was 46% with auranofin and 20% with injectable gold. Diarrhea occurred with parenteral gold products about twice as frequently as placebo and occurred with auranofin about twice as often as parenteral gold (Table 1). In the 11 nondouble-blind studies, the prevalence of diarrhea was 4% with parenteral gold, but remained approximately the same (41%) with auranofin. The rates of withdrawal of patients due to diarrhea in the seven double-blind and 11 nondouble-blind studies were 4% and 2% for auranofin and 2% and 0.4% for injectable gold, respectively. 2’,22These low withdrawal rates reflect that the diarrhea was tolerated by most patients. In a more recent auranofin post-marketing study of 2,777 patients26 with side-effects being reported spontaneously, the reported incidence of altered stool pattern was 22%. MECHANISM
OF DIARRHEA
Recent evidence suggests that diarrhea from auranofin is due to a pharmacologic action in the gut and is not the result of an intestinal lesion or hypersensitivity reaction. A study by Higgens et a127*2*evaluated the effect of auranofin on the intestinal mucosa. Biopsies were taken from the distal duodenum of patients before and after 3 months of auranofin, 6 mg/d. No differences were found between the pre-and post-drug biopsy specimens by light or electron microscopy in 24 patients. Small bowel function tests were normal during auranofin treatment. Human jejunal biopsies were also reported by Martin et a12’ to be normal by light and electron microscopy, with no difference between patients administered auranofin or placebo for 3 months. In addition, serum
Seminars in Arthritis and Rheumatism, Vol 16, No
4
(May),
1987:
pp 294-299
EFFECT OF GOLD IN THE LOWER GI TRACT
295
Fig 1. Risk of developing diarrhea during auranofm therapy. The conditional probability of developing diarrhea is listed for each 3 month interval. Patients at risk are the number of patients who enter the interval without previously experiencing the adverse event.= (Reprinted with permission.‘.)
levels of gastrin and GI polypeptide following a test meal showed no difference between auranofin- and placebo-treated patients. Tests of upper GI function, including absorption of sugar and fat, were normal after 3 months of treatment with auranofin. Van Riel et a129reported finding no pathologic flora, steatorrhea, occult bleeding, or abnormality of plasma electrolytes, total protein, blood sugar, or serum cholesterol in 11 patients who had an auranofin associated diarrhea for more than 1 week. Three patients studied more extensively had normal D-Xylose, Schilling test, glucose breath test, total daily (wet) stool weight, and stool osmolality. Patients with loose stools had increased Na+ and decreased K+ content in their stools compared with patients who did not have loose stools. These values became normal after discontinuation of auranofin. There was no change in serum gold levels related to the occurrence of loose stools. The investigators theorize a direct effect of auranofin on the ion and water absorption in the intestine. Behrens et a13’evaluated the GI function of six Table 1. Comparison of Rates of Loose Stools/Diarrhea Reported in 7 Double-Blind and 11 Non-Double-Blind Studies*’ DoubkBlind+ Auranofin
46.5%
(N = 275)
Injectable gold
20.2%
(N = 277)
Placebo
12.6%(N
*Cumulative of seven studies tCumulative of 1 1 studies
= 111)
Single-Blind/Opent 40.5%
(N = 252)
4.0% (N = 249) 0.0% (N = 21)
RA patients who developed diarrhea during treatment with auranofin. The whole gut transit time was decreased by 50% or more in five of six patients. The mean concentration of sodium in fecal water increased threefold, while the concentrations of potassium and chloride were not significantly different from control values. Biopsy samples and colonoscopy were normal, with no evidence of inflammation or colitis. The absorption of vitamin B12 and the excretion of fecal fat were not significantly altered, although one patient developed mild steatorrhea. The investigators concluded that auranofin caused diarrhea in association with a reversible effect on intestinal permeability, but without significant change in the absorption of nutrients. The cause of gold-related diarrhea has been studied by two separate investigative groups, Fondacaro et a13’ and Hardcastle et a1.32q33 In addition, Chan34 performed in vitro experiments to determine the effect of auranofin and gold sodium thiomalate on membrane-bound and purified Na +/K+ adenosine triphosphatase (ATPase) activity. Both gold sodium thiomalate and auranofin significantly inhibited Na’/K+ ATPase activity in a dose-related manner. Gold sodium thiomalate was ten to 12 times more inhibitory than auranofin on fluid phase ATPase, although they had similar inhibitory effects on ouabain binding to membrane ATPase. Triethylphosphine and thiomalic acid (the ligands for auranofin and gold sodium thiomalate, respectively) showed no effect on the same enzyme systems. The results of this study are in agreement with results of a study by Nechay,35 who demonstrated the inhibitory effect of gold sodium thiomalate on ATPase activity in human and dog kidney homogenates. Fondacaro et a13’observed an increase in Na+ and water excretion and a decrease in K+ concentration in Thiry-Vella loops of the dog small intestine perfused with auranofin. Hardcastle also reported an inhibition of Na+-dependent glucose and glycine absorption in everted sacs of rat small intestine.32 Furthermore, they found that auranofin reversibly inhibits Na+/K+ ATPase in crude homogenates of rat intestine.31*32This would adversely affect the Na+ pump, which would dissipate the Na+ gradient and lead to an increase in fluid and osmotic load reaching the colon. Under normal physiologic
296
ROCHA. BURRICHTER, AND BLODGElT
conditions, the colon has a significant reserve capacity for absorbing fluids. However, the colon ion-transport mechanisms are also inhibited by auranofin so that the increased fluid load is presented to a colon that is less capable of handling it.33 These laboratory findings are compatible with the clinical reports of Van Riel et alz9 and Behrens et a13’ who observed an increase in sodium and fluid content in the stools of auranofin treated patients. These studies suggest that diarrhea early in the course of auranofin treatment should respond to temporary discontinuation or lowered dose of drug. These reports are supported by a chronic (7 years) dosing study in dogs in which auranofin, nine to 24 times the human dose on a mg/kg basis, was orally administered. There was a transient increase in stools early in the course of treatment which then resolved. After 7 years of daily auranofin treatment, no gross or histopathologic abnormalities of the GI tract were observed.36 GOLD-INDUCED
ENTEROCOLITIS
An important distinction must be made between the diarrhea observed with chrysotherapy and the more severe colitis occasionally reported with various gold products. Since 1935, a total of 27 cases of gold-induced colitis have been documented in the literature.37-6’ Colitis occurs early in the course of therapy, after as little as 140 mg, and usually before a total dose of 500 mg of gold compound. Symptoms of abdominal pain, vomiting, and profuse watery diarrhea with ten to 40 bowel movements per day,38*39 sometimes with blood and mucus, appear abruptly, often resembling ulcerative colitis. Varying degrees of inflammation, multiple ulcerations, and occasionally, perforation are seen endoscopitally. Biopsy specimens generally show chronic inflammation with some degree of change in villous architecture and eosinophilic, or mononuclear cell infiltration of the lamina propria. 42,45*48,50,52*54*55 The most important aspect of therapy is maintenance of fluid and electrolyte status, adequate nutrition, and treating opportunistic infections while the colitis runs its course. Various anti-diarrhea1 preparations are ineffective. It may take 1 to several months for symp-
toms to resolve completely after discontinuation of gold therapy. Before 1976, the mortality rate from this syndrome was 50% (6 of 12).37-45Since then, only one of 15 patients (7%) has died from gold-induced colitis.46-6’ This severe side effect has been reported with several gold products, including gold sodium thiomalate (19 cases), aurothioglucose (three cases), sodium aurothiosulphate (three cases), aurothiopropanolsulfonate (one case), and auranofin (one case). Because enterocolitis occurs with several different products, it is most likely associated with gold rather than a specific drug molecule. Since the reaction occurs early in therapy and at a relatively low dose, it has been speculated that it is a hypersensitivity reaction. This theory is supported by work done by Szpak et a14’ who demonstrated the ability of gold sodium thiosulfate to cause a positive in vitro lymphocyte transformation response in a patient with enterocolitis. Other patients have had eosinophilia or biopsy evidence of eosinophilic infiltration of the lamina propria. There is evidence of an association between the histocompatibility antigens HLA-DR and the occurrence of idiopathic inflammatory bowel disease. Smolen et al62 found that the frequency of HLA-B12 was significantly (P < .OOl) greater in patients with Crohn’s disease (52%) than in healthy controls (10%) and patients with ulcerative colitis, Only one of the 27 published cases of gold colitis had HLA antigens determined. In this report, HLA-B8 and HLA-DRw3 were present.52 Further research is needed to determine if there is a relationship between HLA antigens and gold colitis. DISCUSSION
The definition of diarrhea in clinical medicine implies an increase in the fluidness and frequency of bowel movements to more than three a day.63 This definition is not necessarily the standard used by most patients who may consider diarrhea any increase in looseness or frequency of stools. Historically, diarrhea has not been a major concern during parenteral gold administration unless severe colitis occurred. However, in recent double-blind studies, while the incidence of
EFFECT OF GOLD IN THE LOWER GI TRACT
diarrhea with parenteral gold salts was found to be less than that observed with auranofin, it was more than that seen with placebo. When the studies were conducted using a single-blind or open design, the reported incidence of diarrhea with parenteral gold (4) was lower than that reported in the double-blind studies (20.2%). The double-blind studies have probably provided a truer incidence of any stool alteration with gold therapy, while the open design trial results and the low incidence of patient withdrawal reflects the mild nature of the diarrhea. Loose stools or diarrhea has been reported in an average of 44% of patients treated with auranofin. The diarrhea is generally mild, dose related, and self-limiting. The symptoms can be treated with a reduction in dose or a temporary discontinuation of therapy. Treatment with antidiarrheals, bulk forming agents, iron compounds,29 and bran may also be useful. In order to better characterize the course of the diarrhea observed with auranofin, the investigators retrospectively reviewed the records of 100 patients reporting diarrhea. The 100 case report forms came from three different studies and were reviewed as to the severity, duration, and treatment of the large bowel side effects. Of these 100 case reports, 97 were evaluable for this information, and one additional patient was receiving placebo during the bout of diarrhea, making a total of 96 patients who were included in this tabulation. Four patterns emerged, which describe the varying severity and treatment of the diarrhea seen in these patients: (1) loose stools/diarrhea was transient, requiring no action (44 patients); (2) loose stools/diarrhea was transient, but required manipulation of the dose of auranofin (27 patients)*; (3) loose stools/ diarrhea was controlled by anti-diarrhea1 or bulk forming agents (22 patients)t; and (4) diarrhea required the withdrawal of the patient from the study (three patients). Because the largest group of patients fell into
*Auranofin dose either decreased or temporarily discontinued. tDrugs used included Kaopectate (The Upjohn Co, Kalamazoo, MI), Lomotil (Searle, Skokie, IL), Pepto-Bismol (Procter & Gamble, Cincinnati), dicyclomine, Metamucil, (Procter & Gamble, Cincinnati), cholestyramine, etc.
297
group 1, those patients not requiring dose alteration or other treatment, these 44 cases were further scrutinized to determine the duration and pattern of the diarrhea. The onset of the loose stools occurred during the initial 3 months of therapy in 66% of these patients (34% in month 1) and 23% during the remainder of their first year. Eleven percent occurred during the second year of therapy. The duration ranged from one day to 12 weeks in all but three patients, with 41% of them having GI symptoms for 1 week or less and 70% for 4 weeks or less. The average was 3.4 weeks, with a median of less than 2 weeks. The three cases with longest duration (21, 26, and 40 weeks) were recorded as mild and intermittent and did not interfere with their course of therapy. In a report of 134 patients receiving auranofin and observed for 5 years, the incidence of diarrhea was 33% during the first 3 months, 6% the second 3 months, and diminished throughout the study. These data suggest an absence of cumulative GI toxicity. Indeed, during the final 3 months of the study, no diarrhea was recorded in the 134 patients.64 To date, no GI morphologic abnormalities have been identified in either human biopsy or chronic dog studies that would explain or establish an etiology for the diarrhea. The lack of a lesion in these studies suggests a pharmacologic mechanism rather than a structural alteration of tissue. A major hypothesis, postulated by Fondacaro and Hardcastle, is interference with the Na+/K+ ATPase. Other mechanisms that should be explored include correlation with histocompatibility antigens, the possible influence of more bile salts in the colon (which are also reabsorbed by a Na+-dependent mechanism65), and their potential to alter gut transit time, transmucosal fluid transport, and bacterial flora. CONCLUSION
The occurrence of loose stools/diarrhea was recorded for both injectable gold and oral gold in patients in double-blind comparative studies. Auranohn treated patients experienced approximately twice the incidence of diarrhea as injectable gold. In the majority of cases, the incidence of diarrhea was mild and transient, and the highest incidence occurred within the first 3
ROCHA, 8URRICHTER. AND 8LODGET-T
298
months of therapy. It was generally controlled with dose adjustment and non-specific antidiarrhea1 therapy. Less than 5% of the patients treated with auranofin had to discontinue therapy for this reason. Recent studies strongly suggest Na’/K+ ATPase inhibition as a possible mechanism, but remaining questions include why the incidence is
highest during the first weeks of administration, and what is the mechanism of the adaptation resulting in the transient nature of this symptom. This “gold-associated diarrhea” is different from toxic gold enterocolitis based on postulated causes, clinical manifestations, and subsequent course.
REFERENCES I. Heuer MA, Pietrusko RD, Morris RW, et al: An analysis of worldwide safety experience with auranofin. J Rheumatol 12:695-699, 1985 2. Blocka K: Auranofin vs injectable gold: Comparison of pharmacokinetic properties. Am J Med 75:114-122, 1983 3. Gottlieb N, Smith P, Smith E: Gold excretion correlated with clinical course during chrysotherapy in rheumatoid arthritis. Arthritis Rheum 15:582-592, 1972 4. Barraclough D, Boyden K, Brooks P, et al: A comparative study of auranofin, gold sodium thiomalate and p-penicillamine in rheumatoid arthritis: A progress report, in Capell, HA (ed): Auranofin: Proceedings of the SK&F International Symposium, Amsterdam. Excerpta Medica, 1983, pp 240-248 5. Davies J, Bacon PA, Hall ND, et al: Placebo-controlled comparison of auranofin with Myocrisin in patients with rheumatoid arthritis, in Auranofin: Proceedings of the SK&F International Symposium, Amsterdam. Excerpta Medica, 1983, pp 194-200 6. Nissila M, Lehtinen K, Martio J, et al: Comparison of oral gold (auranofin) and intramuscular gold (Myocrisine) in the treatment of early rheumatoid arthritis. Presented at ILAR poster session, P205, Sydney, Australia, May 1985 7. Dequeker J, Verdickt W, Gevers G, et al: Long-term experience with oral gold in rheumatoid arthritis and psoriatic arthritis. Clin Rheumatol 3:67-73, 1984 (suppl I) 8. Kahn MF, Doury P, Delcambre B, et al: A multi-center double-blind comparative study of auranofin and intramuscular gold (Allochrysine), in Auranofin: Proceedings of the SK&F International Symposium, Amsterdam. Excerpta Medica, 1983, pp 165-180 9. Jarner P, Ammitzboll F, Sinding J, et al: Auranofin and Myocrisin (gold sodium thiomalate): A double-blind comparative study, in Auranofin: Proceedings of the SK&F lnternational Symposium, Amsterdam. Excerpta Medica, 1983, pp 358-365 10. Kaik B, Broil H, Muller-Fassbender H, et al: Auranofin and Tauredon in the treatment of chronic polyarthritis, in Auranofin: Proceedings of the SK&F International Symposium, Amsterdam. Excerpta Medica, 1983, pp 453-463 11. Keegan DAJ, Cole DS, Hodkinson E, et al: A comparative open study of the efficacy and safety of gold sodium thiomalate and auranofin treatment in patients with rheumatoid arthritis, in Auranofin: Proceedings of the SK&F International Symposium, Amsterdam. Excerpta Medica, 1983, pp 430-441 12. Lewis D, Cape11 HA: Oral gold: A comparison with placebo and with intramuscular sodium aurothiomalate. Clin Rheumatol 3:83-95, 1984 (suppl 1)
13. Menard HA, Beaudet F, Davis P, et al: Gold therapy in rheumatoid arthritis: Interim report of the Canadian multi-center prospective trial comparing sodium aurothiomalate and auranofin. J Rheumatol 9:179-183, 1982 (suppl 8) 14. Prouse PJ, Gumpel JM: Placebo-controlled comparison of auranolin with gold sodium thiomalate, in Auranofin: Proceedings of the SK&F International Symposium, Amsterdam. Excerpta Medica, 1983, pp 303-3 12 15. Schattenkirchner M, Kaik B, Muller-Fassbender H, et al: Auranofin and sodium aurothiomalate in the treatment in rheumatoid arthritis: A double-blind, comparative multicenter study. J Rheumatol9:184-189, I982 (suppl 8) 16. Smith PR, Brown GMM, Meyers OL: An open comparative study of auranofin vs. gold sodium thiomalate. J Rheumatol9:190-196, 1982 (suppl8) 17. Tvede N, Strandberg B: The effect of auranotin compared with Myocrisin in the treatment of rheumatoid arthritis, in Auranofin: Proceedings of the SK&F International Symposium, Amsterdam. Excerpta Medica, 1983. pp 442-452 18. Van Riel PLCM, Van De Putte LBA, Gribnau FWJ. et al: Comparison of auranofin and aurothioglucose in the treatment of rheumatoid arthritis: A single-blind study. Clin Rheumatol 3:51-56, 1984 (suppl 1) 19. Williams HJ, Ward JR, Egger MJ, et al: Auranofin. gold sodium thiomalate and placebo in the treatment of rheumatoid arthritis: Cooperative systematic studies of rheumatic diseases. Clin Rheumatol3:39-50, 1984 (suppl I) 20. Martin PS, Roberts SD, Buchanan KD: Results of a clinical study assessing the safety and efficacy of auranofin compared with sodium aurothiomalate and placebo. (in preparation) 21. Pietrusko R: Benefit to risk analysis of auranolin vs injectible gold in 1,053 patients. (in preparation) 22. SK&F: Data on file. 23. Foley JA, Mathews JA: A comparison of sodium aurothiomalate, auranofin and placebo in active rheumatoid arthritis. Presented at ILAR poster session, P206, Sydney, Australia, May 1985 24. Berkson J, Gage RP: Calculation of survival rates for cancer. Mayo Clin Proc 25:270-286, 1950 25. O’Brien WM, Bagby GF: Rare adverse reactions to non-steroidal antiinflammatory drugs. J Rheumatol 12:3. 562-567, 1985 26. Schattenkirchner M, Missler B, Mulz D: Post Marketing Surveillance Program (PMSP) ‘Ridaura’ in West Germany. Stand J Rheumatol63, 1986 (suppl) 27. Higgins CS, Moss J, Woodrow D, et al: Small intes-
EFFECT OF GOLD IN THE LOWER GI TRACT
tine ultrastructure changes and auranofin treatment in rheumatoid arthritis. Br J Rheumatol 25:227, 1986 28. Higgins CS, Moss J, Woodrow D, et al: Ultrastructure and function of the small bowel in rheumatoid arthritis with auranofin (oral gold) treatment. (in preparation) 29. Van Riel PL, Gribnau FW, Van De Putte LB, et al: Loose stools during auranotin treatment: Clinical study and some pathogenetic possibilities. J Rheumatol 10:222-226, 1983 30. Behrens R, Devereaux M, Hazelman B, et al: Investigation of auranofin-induced diarrhea. Gut 27: 59-65, 1986 3 I. Fondacaro JD, Hendersen LS, Hardcastle PT, et al: Effect of auranofin (SKF 39162) on water and electrolyte flux in canine small bowel: A possible diarrheogenic mechanism. J Rheumatol 13:288-293, 1986 32. Hardcastle J, Hardcastle PT, Kelleher DK, et al: Effect of auranotin on absorptive processes in the rat small bowel. J Rheumatol 13541-546, 1986 33. Hardcastle J, Hardcastle PT, Kelleher DK, et al: The effect of auranofm on the colonic transport of Na+ and fluid in the rat. J Pharm Pharmacol 38:466-468, 1986 34. Chan MK, Minta JO: Effects of anti-inflammatory and anti-rheumatic drugs on the activities of purified and membrane-bound Na+/K+ adenosine triphosphatase. Immunopharmacology 10:61-67, 1985 35. Nechay BR: Inhibition of adenosine triphosphatases by gold. Arthritis Rheum 23:464-470, 1980 36. Saunders L: Seven year study of auranofin in dogs. (unpublished report) 37. Goldhammer S: A fatal case of Solganal poisoning. Med Klin, 31:645-647, 1935 38. Perry MW: Gold injections and colitis. JAMA 113:965, 1939 39. Anderson NL, Palmer WL: Danger of gold salt therapy, report of a fatal case. JAMA 115:1627- 1630, 1940 40. Kandrac M, Pav J, Pechova I: Successful steroid therapy of severe enteritis caused by gold therapy. Cas Lek Cesk 100:361-367, 1961 41. Kaplinsky N, Pras M: Ulcerative colitis with gold treatment in rheumatoid arthritis. Harefuah 80:406-407, 1971 42. Roe M, Sears AD, Arndt JH: Gold reaction panenteritis: A case report with radiographic findings. Radiology 104:59-60,1972 43. Kaplinsky N, Pras M, Frank1 0: Sever enterocolitis complicating chrysotherapy. Ann Rheum Dis 32:574-577, 1973 44. Stein HB, Urowitz MB: Gold-induced enterocolitis. Case report and literature review. J Rheumatol 3:22-26, 1976 45. Siegman-Igra Y, Yaron M, Siletzki M, et al: Colitis and death following gold therapy. Rheumatol and Rehab 151245-247, 1976 46. Gerster JC, DeKalbermatten A, DePeyer R, et al: Reactions toxiques aux sels d’or avec enterocolite grave chez
299
un homme attenit d’une polyarthrite rhumatoi’de. Schweiz Med Wochenschr 106:1606-1608, 1976 47. Szpak MW, Johnson RC, Brady CE, et al: Gold (AU) induced enterocolitis. Gastroenterology, 76: 1257, I979 (abstr) 48. Sckolnick BR, Katz LA, Kozower M: Life-threatening enterocolitis after gold salt therapy. J Clin Gastroenterol 1:145-148, 1979 49. Fam AG, Paton TW, Shamess CJ, et al: Fulminant colitis complicating gold therapy. J Rheumatol 7:479-485, 1980 50. Huston GJ: Gold colitis, therapy and confirmation of mucosal recovery by measurement of rectal potential difference. Postgrade Med J 56:875-876, 1980 51. Martin DM, Goldman JA, Gilliam J, et al: Goldinduced eosinophilic enterocolitis: Response to oral cromolyn sodium. Gastrocnterology 80:1567-1570, 1981 52. Sukenik S, Hirsch M, Yanai-Inbar I, et al: Enterocolitis complicating chrysotherapy: Case report and review of the literature. Isr J Med Sci 18:1040-1043, 1982 53. Eaves R, Hansky J, Wallis I? Gold induced enterocolitis: Case report and a review of the literature. Aust NZ J Med 12:617-620, 1982 54. Reinhart WH, Kappeler M, Halter F: Severe pseudomembranous and ulcerative colitis during gold therapy. Endoscopy 15:70-72, 1983 55. Jarner D, Nielsen AM: Auranofin (SK&F 39162) induced enterocolitis in rheumatoid arthritis. Stand J Rheumatol 12:254-256, 1983 56. White RF, Major GAC: Gold colitis. Med J Aust 1:174-175, 1983 57. Nagler J, Paget SA: Nonexudative diarrhea after gold salt therapy: Case report and review of the literature. Am J Gastroenterol78:12-14, 1983 58. McCormick PA, O’Donoghue D, Lemass B: Gold induced colitis: Case report and literature review. Ir Med J 78:17-18, 1985 59. Wright A, Benfield FA, Felix-Davies D: Ischaemic colitis and immune complexes during gold therapy for rheumatoid arthritis. Ann Rheum Dis 43:495-497, 1984 60. Goebel KM: Basistherapie der rheumatoiden arthritis mit auranofin. Dtsch Med Wochenschr 110:64-65, 1985 61. Jackson CW, Haboubi NY, Whorwell PJ, et al: Gold induced enterocolitis. Gut 27:452-456, 1986 62. Smolen JS, Gang1 A, Polterauer P, et al: HLA antigens in inflammatory bowel disease. Gastroenterology 82:3438.1982 63. Krejs GJ, Fordtran JS: Diarrhea, in Sleisenger MH, Fordtran JS (eds): Gastrointestinal Disease. Philadelphia, Saunders, 1983, pp 257-280 64. Blodgett RC, Pietrusko RG: Five years of clinical experience with auranofin. Presented at ILAR poster session, P18 1, Sydney, Australia, May 1985 65. Holt PR: Intestinal absorption of bile salts in the rat. Am J Physiol 207: 1-7, 1964
on the Lower Gastrointestinal A Review
Tract:
By Maria P. Rocha, Paul J. Burrichter, and Randolph C. Blodgett
T
HE RECENT introduction of auranofin, an oral gold compound that is primarily absorbed and eliminated through the gastrointestinal (GI) tract, has focused attention on the effect of gold on the lower GI tract. Auranofin is effective for the treatment of rheumatoid arthritis (RA) when received orally and is reported to have a lower incidence of serious adverse reactions than injectable gold.’ Approximately 25% of the oral dose is absorbed from the GI tract, and 85% of the total dose is eliminated in the feces (75% unabsorbed and 10% GI elimination).* This compares with the 30% fecal elimination of injectable gold products following intramuscular (IM) administration.3 This report reviews and analyzes recent reports of loose stools and diarrhea associated with gold therapy to determine the severity, incidence, and possible mechanism of this reaction, and to place in perspective the lower GI side effects of auranofin compared with injectable gold. REVIEW OF CLINICAL STUDIES
Eighteen clinical studies4-23 have been performed to compare the safety and efficacy of auranofin with injectable gold for the treatment of RA. Seven of the studies were double-blind in design; the remainder were single-blind or open trials. A mean prevalence of 44% (range, 0% to 73%)4-23 was reported for loose stools/diarrhea in
From the Department of Gastroenterology. Lisbon Military Hospital. Lisbon, Portugal; and the Medical Information Department and Department of Rheumatology, SK&F International, Philadelphia. Maria P.Rocha, MD: Specialist in Gastroenterology, Lisbon Military Hospital, Lisbon, Portugal. Group Director, Medical and Regulatory Affairs, SK & F, Portugal; Paul J. Burrichter, RPh: Assistant Manager Medical Information, SK&F International, Philadelphia: Randolph C. Blodgett, MD, FACP: Vice-President and Medical Director Rheumatology, SK&F International, Philadelphia. Address reprint requests to Maria P. Rocha. MD, Instiiuto Luso Farmaco. Rua Do Quelhas 8e18, 1296 Lisbon, Portugal. 8 1987 by Grune & Stratton, Inc. 0049-0172/87/l 604-0007$S.O0/0
294
these studies. The symptoms tended to be mild, occured early (Fig 1), and usually resolved spontaneously or with a reduction of auranofin dosage. In controlled studies, the withdrawal rates due to diarrhea were 3% to 5%.‘.” Virtually all the patients in these studies were also receiving non-steroidal antiinflammatory drugs (NSAIDs), some of which have been reported to cause diarrhea.25 In the overall comparison of seven double-blind studies, the reported incidence of diarrhea was 46% with auranofin and 20% with injectable gold. Diarrhea occurred with parenteral gold products about twice as frequently as placebo and occurred with auranofin about twice as often as parenteral gold (Table 1). In the 11 nondouble-blind studies, the prevalence of diarrhea was 4% with parenteral gold, but remained approximately the same (41%) with auranofin. The rates of withdrawal of patients due to diarrhea in the seven double-blind and 11 nondouble-blind studies were 4% and 2% for auranofin and 2% and 0.4% for injectable gold, respectively. 2’,22These low withdrawal rates reflect that the diarrhea was tolerated by most patients. In a more recent auranofin post-marketing study of 2,777 patients26 with side-effects being reported spontaneously, the reported incidence of altered stool pattern was 22%. MECHANISM
OF DIARRHEA
Recent evidence suggests that diarrhea from auranofin is due to a pharmacologic action in the gut and is not the result of an intestinal lesion or hypersensitivity reaction. A study by Higgens et a127*2*evaluated the effect of auranofin on the intestinal mucosa. Biopsies were taken from the distal duodenum of patients before and after 3 months of auranofin, 6 mg/d. No differences were found between the pre-and post-drug biopsy specimens by light or electron microscopy in 24 patients. Small bowel function tests were normal during auranofin treatment. Human jejunal biopsies were also reported by Martin et a12’ to be normal by light and electron microscopy, with no difference between patients administered auranofin or placebo for 3 months. In addition, serum
Seminars in Arthritis and Rheumatism, Vol 16, No
4
(May),
1987:
pp 294-299
EFFECT OF GOLD IN THE LOWER GI TRACT
295
Fig 1. Risk of developing diarrhea during auranofm therapy. The conditional probability of developing diarrhea is listed for each 3 month interval. Patients at risk are the number of patients who enter the interval without previously experiencing the adverse event.= (Reprinted with permission.‘.)
levels of gastrin and GI polypeptide following a test meal showed no difference between auranofin- and placebo-treated patients. Tests of upper GI function, including absorption of sugar and fat, were normal after 3 months of treatment with auranofin. Van Riel et a129reported finding no pathologic flora, steatorrhea, occult bleeding, or abnormality of plasma electrolytes, total protein, blood sugar, or serum cholesterol in 11 patients who had an auranofin associated diarrhea for more than 1 week. Three patients studied more extensively had normal D-Xylose, Schilling test, glucose breath test, total daily (wet) stool weight, and stool osmolality. Patients with loose stools had increased Na+ and decreased K+ content in their stools compared with patients who did not have loose stools. These values became normal after discontinuation of auranofin. There was no change in serum gold levels related to the occurrence of loose stools. The investigators theorize a direct effect of auranofin on the ion and water absorption in the intestine. Behrens et a13’evaluated the GI function of six Table 1. Comparison of Rates of Loose Stools/Diarrhea Reported in 7 Double-Blind and 11 Non-Double-Blind Studies*’ DoubkBlind+ Auranofin
46.5%
(N = 275)
Injectable gold
20.2%
(N = 277)
Placebo
12.6%(N
*Cumulative of seven studies tCumulative of 1 1 studies
= 111)
Single-Blind/Opent 40.5%
(N = 252)
4.0% (N = 249) 0.0% (N = 21)
RA patients who developed diarrhea during treatment with auranofin. The whole gut transit time was decreased by 50% or more in five of six patients. The mean concentration of sodium in fecal water increased threefold, while the concentrations of potassium and chloride were not significantly different from control values. Biopsy samples and colonoscopy were normal, with no evidence of inflammation or colitis. The absorption of vitamin B12 and the excretion of fecal fat were not significantly altered, although one patient developed mild steatorrhea. The investigators concluded that auranofin caused diarrhea in association with a reversible effect on intestinal permeability, but without significant change in the absorption of nutrients. The cause of gold-related diarrhea has been studied by two separate investigative groups, Fondacaro et a13’ and Hardcastle et a1.32q33 In addition, Chan34 performed in vitro experiments to determine the effect of auranofin and gold sodium thiomalate on membrane-bound and purified Na +/K+ adenosine triphosphatase (ATPase) activity. Both gold sodium thiomalate and auranofin significantly inhibited Na’/K+ ATPase activity in a dose-related manner. Gold sodium thiomalate was ten to 12 times more inhibitory than auranofin on fluid phase ATPase, although they had similar inhibitory effects on ouabain binding to membrane ATPase. Triethylphosphine and thiomalic acid (the ligands for auranofin and gold sodium thiomalate, respectively) showed no effect on the same enzyme systems. The results of this study are in agreement with results of a study by Nechay,35 who demonstrated the inhibitory effect of gold sodium thiomalate on ATPase activity in human and dog kidney homogenates. Fondacaro et a13’observed an increase in Na+ and water excretion and a decrease in K+ concentration in Thiry-Vella loops of the dog small intestine perfused with auranofin. Hardcastle also reported an inhibition of Na+-dependent glucose and glycine absorption in everted sacs of rat small intestine.32 Furthermore, they found that auranofin reversibly inhibits Na+/K+ ATPase in crude homogenates of rat intestine.31*32This would adversely affect the Na+ pump, which would dissipate the Na+ gradient and lead to an increase in fluid and osmotic load reaching the colon. Under normal physiologic
296
ROCHA. BURRICHTER, AND BLODGElT
conditions, the colon has a significant reserve capacity for absorbing fluids. However, the colon ion-transport mechanisms are also inhibited by auranofin so that the increased fluid load is presented to a colon that is less capable of handling it.33 These laboratory findings are compatible with the clinical reports of Van Riel et alz9 and Behrens et a13’ who observed an increase in sodium and fluid content in the stools of auranofin treated patients. These studies suggest that diarrhea early in the course of auranofin treatment should respond to temporary discontinuation or lowered dose of drug. These reports are supported by a chronic (7 years) dosing study in dogs in which auranofin, nine to 24 times the human dose on a mg/kg basis, was orally administered. There was a transient increase in stools early in the course of treatment which then resolved. After 7 years of daily auranofin treatment, no gross or histopathologic abnormalities of the GI tract were observed.36 GOLD-INDUCED
ENTEROCOLITIS
An important distinction must be made between the diarrhea observed with chrysotherapy and the more severe colitis occasionally reported with various gold products. Since 1935, a total of 27 cases of gold-induced colitis have been documented in the literature.37-6’ Colitis occurs early in the course of therapy, after as little as 140 mg, and usually before a total dose of 500 mg of gold compound. Symptoms of abdominal pain, vomiting, and profuse watery diarrhea with ten to 40 bowel movements per day,38*39 sometimes with blood and mucus, appear abruptly, often resembling ulcerative colitis. Varying degrees of inflammation, multiple ulcerations, and occasionally, perforation are seen endoscopitally. Biopsy specimens generally show chronic inflammation with some degree of change in villous architecture and eosinophilic, or mononuclear cell infiltration of the lamina propria. 42,45*48,50,52*54*55 The most important aspect of therapy is maintenance of fluid and electrolyte status, adequate nutrition, and treating opportunistic infections while the colitis runs its course. Various anti-diarrhea1 preparations are ineffective. It may take 1 to several months for symp-
toms to resolve completely after discontinuation of gold therapy. Before 1976, the mortality rate from this syndrome was 50% (6 of 12).37-45Since then, only one of 15 patients (7%) has died from gold-induced colitis.46-6’ This severe side effect has been reported with several gold products, including gold sodium thiomalate (19 cases), aurothioglucose (three cases), sodium aurothiosulphate (three cases), aurothiopropanolsulfonate (one case), and auranofin (one case). Because enterocolitis occurs with several different products, it is most likely associated with gold rather than a specific drug molecule. Since the reaction occurs early in therapy and at a relatively low dose, it has been speculated that it is a hypersensitivity reaction. This theory is supported by work done by Szpak et a14’ who demonstrated the ability of gold sodium thiosulfate to cause a positive in vitro lymphocyte transformation response in a patient with enterocolitis. Other patients have had eosinophilia or biopsy evidence of eosinophilic infiltration of the lamina propria. There is evidence of an association between the histocompatibility antigens HLA-DR and the occurrence of idiopathic inflammatory bowel disease. Smolen et al62 found that the frequency of HLA-B12 was significantly (P < .OOl) greater in patients with Crohn’s disease (52%) than in healthy controls (10%) and patients with ulcerative colitis, Only one of the 27 published cases of gold colitis had HLA antigens determined. In this report, HLA-B8 and HLA-DRw3 were present.52 Further research is needed to determine if there is a relationship between HLA antigens and gold colitis. DISCUSSION
The definition of diarrhea in clinical medicine implies an increase in the fluidness and frequency of bowel movements to more than three a day.63 This definition is not necessarily the standard used by most patients who may consider diarrhea any increase in looseness or frequency of stools. Historically, diarrhea has not been a major concern during parenteral gold administration unless severe colitis occurred. However, in recent double-blind studies, while the incidence of
EFFECT OF GOLD IN THE LOWER GI TRACT
diarrhea with parenteral gold salts was found to be less than that observed with auranofin, it was more than that seen with placebo. When the studies were conducted using a single-blind or open design, the reported incidence of diarrhea with parenteral gold (4) was lower than that reported in the double-blind studies (20.2%). The double-blind studies have probably provided a truer incidence of any stool alteration with gold therapy, while the open design trial results and the low incidence of patient withdrawal reflects the mild nature of the diarrhea. Loose stools or diarrhea has been reported in an average of 44% of patients treated with auranofin. The diarrhea is generally mild, dose related, and self-limiting. The symptoms can be treated with a reduction in dose or a temporary discontinuation of therapy. Treatment with antidiarrheals, bulk forming agents, iron compounds,29 and bran may also be useful. In order to better characterize the course of the diarrhea observed with auranofin, the investigators retrospectively reviewed the records of 100 patients reporting diarrhea. The 100 case report forms came from three different studies and were reviewed as to the severity, duration, and treatment of the large bowel side effects. Of these 100 case reports, 97 were evaluable for this information, and one additional patient was receiving placebo during the bout of diarrhea, making a total of 96 patients who were included in this tabulation. Four patterns emerged, which describe the varying severity and treatment of the diarrhea seen in these patients: (1) loose stools/diarrhea was transient, requiring no action (44 patients); (2) loose stools/diarrhea was transient, but required manipulation of the dose of auranofin (27 patients)*; (3) loose stools/ diarrhea was controlled by anti-diarrhea1 or bulk forming agents (22 patients)t; and (4) diarrhea required the withdrawal of the patient from the study (three patients). Because the largest group of patients fell into
*Auranofin dose either decreased or temporarily discontinued. tDrugs used included Kaopectate (The Upjohn Co, Kalamazoo, MI), Lomotil (Searle, Skokie, IL), Pepto-Bismol (Procter & Gamble, Cincinnati), dicyclomine, Metamucil, (Procter & Gamble, Cincinnati), cholestyramine, etc.
297
group 1, those patients not requiring dose alteration or other treatment, these 44 cases were further scrutinized to determine the duration and pattern of the diarrhea. The onset of the loose stools occurred during the initial 3 months of therapy in 66% of these patients (34% in month 1) and 23% during the remainder of their first year. Eleven percent occurred during the second year of therapy. The duration ranged from one day to 12 weeks in all but three patients, with 41% of them having GI symptoms for 1 week or less and 70% for 4 weeks or less. The average was 3.4 weeks, with a median of less than 2 weeks. The three cases with longest duration (21, 26, and 40 weeks) were recorded as mild and intermittent and did not interfere with their course of therapy. In a report of 134 patients receiving auranofin and observed for 5 years, the incidence of diarrhea was 33% during the first 3 months, 6% the second 3 months, and diminished throughout the study. These data suggest an absence of cumulative GI toxicity. Indeed, during the final 3 months of the study, no diarrhea was recorded in the 134 patients.64 To date, no GI morphologic abnormalities have been identified in either human biopsy or chronic dog studies that would explain or establish an etiology for the diarrhea. The lack of a lesion in these studies suggests a pharmacologic mechanism rather than a structural alteration of tissue. A major hypothesis, postulated by Fondacaro and Hardcastle, is interference with the Na+/K+ ATPase. Other mechanisms that should be explored include correlation with histocompatibility antigens, the possible influence of more bile salts in the colon (which are also reabsorbed by a Na+-dependent mechanism65), and their potential to alter gut transit time, transmucosal fluid transport, and bacterial flora. CONCLUSION
The occurrence of loose stools/diarrhea was recorded for both injectable gold and oral gold in patients in double-blind comparative studies. Auranohn treated patients experienced approximately twice the incidence of diarrhea as injectable gold. In the majority of cases, the incidence of diarrhea was mild and transient, and the highest incidence occurred within the first 3
ROCHA, 8URRICHTER. AND 8LODGET-T
298
months of therapy. It was generally controlled with dose adjustment and non-specific antidiarrhea1 therapy. Less than 5% of the patients treated with auranofin had to discontinue therapy for this reason. Recent studies strongly suggest Na’/K+ ATPase inhibition as a possible mechanism, but remaining questions include why the incidence is
highest during the first weeks of administration, and what is the mechanism of the adaptation resulting in the transient nature of this symptom. This “gold-associated diarrhea” is different from toxic gold enterocolitis based on postulated causes, clinical manifestations, and subsequent course.
REFERENCES I. Heuer MA, Pietrusko RD, Morris RW, et al: An analysis of worldwide safety experience with auranofin. J Rheumatol 12:695-699, 1985 2. Blocka K: Auranofin vs injectable gold: Comparison of pharmacokinetic properties. Am J Med 75:114-122, 1983 3. Gottlieb N, Smith P, Smith E: Gold excretion correlated with clinical course during chrysotherapy in rheumatoid arthritis. Arthritis Rheum 15:582-592, 1972 4. Barraclough D, Boyden K, Brooks P, et al: A comparative study of auranofin, gold sodium thiomalate and p-penicillamine in rheumatoid arthritis: A progress report, in Capell, HA (ed): Auranofin: Proceedings of the SK&F International Symposium, Amsterdam. Excerpta Medica, 1983, pp 240-248 5. Davies J, Bacon PA, Hall ND, et al: Placebo-controlled comparison of auranofin with Myocrisin in patients with rheumatoid arthritis, in Auranofin: Proceedings of the SK&F International Symposium, Amsterdam. Excerpta Medica, 1983, pp 194-200 6. Nissila M, Lehtinen K, Martio J, et al: Comparison of oral gold (auranofin) and intramuscular gold (Myocrisine) in the treatment of early rheumatoid arthritis. Presented at ILAR poster session, P205, Sydney, Australia, May 1985 7. Dequeker J, Verdickt W, Gevers G, et al: Long-term experience with oral gold in rheumatoid arthritis and psoriatic arthritis. Clin Rheumatol 3:67-73, 1984 (suppl I) 8. Kahn MF, Doury P, Delcambre B, et al: A multi-center double-blind comparative study of auranofin and intramuscular gold (Allochrysine), in Auranofin: Proceedings of the SK&F International Symposium, Amsterdam. Excerpta Medica, 1983, pp 165-180 9. Jarner P, Ammitzboll F, Sinding J, et al: Auranofin and Myocrisin (gold sodium thiomalate): A double-blind comparative study, in Auranofin: Proceedings of the SK&F lnternational Symposium, Amsterdam. Excerpta Medica, 1983, pp 358-365 10. Kaik B, Broil H, Muller-Fassbender H, et al: Auranofin and Tauredon in the treatment of chronic polyarthritis, in Auranofin: Proceedings of the SK&F International Symposium, Amsterdam. Excerpta Medica, 1983, pp 453-463 11. Keegan DAJ, Cole DS, Hodkinson E, et al: A comparative open study of the efficacy and safety of gold sodium thiomalate and auranofin treatment in patients with rheumatoid arthritis, in Auranofin: Proceedings of the SK&F International Symposium, Amsterdam. Excerpta Medica, 1983, pp 430-441 12. Lewis D, Cape11 HA: Oral gold: A comparison with placebo and with intramuscular sodium aurothiomalate. Clin Rheumatol 3:83-95, 1984 (suppl 1)
13. Menard HA, Beaudet F, Davis P, et al: Gold therapy in rheumatoid arthritis: Interim report of the Canadian multi-center prospective trial comparing sodium aurothiomalate and auranofin. J Rheumatol 9:179-183, 1982 (suppl 8) 14. Prouse PJ, Gumpel JM: Placebo-controlled comparison of auranolin with gold sodium thiomalate, in Auranofin: Proceedings of the SK&F International Symposium, Amsterdam. Excerpta Medica, 1983, pp 303-3 12 15. Schattenkirchner M, Kaik B, Muller-Fassbender H, et al: Auranofin and sodium aurothiomalate in the treatment in rheumatoid arthritis: A double-blind, comparative multicenter study. J Rheumatol9:184-189, I982 (suppl 8) 16. Smith PR, Brown GMM, Meyers OL: An open comparative study of auranofin vs. gold sodium thiomalate. J Rheumatol9:190-196, 1982 (suppl8) 17. Tvede N, Strandberg B: The effect of auranotin compared with Myocrisin in the treatment of rheumatoid arthritis, in Auranofin: Proceedings of the SK&F International Symposium, Amsterdam. Excerpta Medica, 1983. pp 442-452 18. Van Riel PLCM, Van De Putte LBA, Gribnau FWJ. et al: Comparison of auranofin and aurothioglucose in the treatment of rheumatoid arthritis: A single-blind study. Clin Rheumatol 3:51-56, 1984 (suppl 1) 19. Williams HJ, Ward JR, Egger MJ, et al: Auranofin. gold sodium thiomalate and placebo in the treatment of rheumatoid arthritis: Cooperative systematic studies of rheumatic diseases. Clin Rheumatol3:39-50, 1984 (suppl I) 20. Martin PS, Roberts SD, Buchanan KD: Results of a clinical study assessing the safety and efficacy of auranofin compared with sodium aurothiomalate and placebo. (in preparation) 21. Pietrusko R: Benefit to risk analysis of auranolin vs injectible gold in 1,053 patients. (in preparation) 22. SK&F: Data on file. 23. Foley JA, Mathews JA: A comparison of sodium aurothiomalate, auranofin and placebo in active rheumatoid arthritis. Presented at ILAR poster session, P206, Sydney, Australia, May 1985 24. Berkson J, Gage RP: Calculation of survival rates for cancer. Mayo Clin Proc 25:270-286, 1950 25. O’Brien WM, Bagby GF: Rare adverse reactions to non-steroidal antiinflammatory drugs. J Rheumatol 12:3. 562-567, 1985 26. Schattenkirchner M, Missler B, Mulz D: Post Marketing Surveillance Program (PMSP) ‘Ridaura’ in West Germany. Stand J Rheumatol63, 1986 (suppl) 27. Higgins CS, Moss J, Woodrow D, et al: Small intes-
EFFECT OF GOLD IN THE LOWER GI TRACT
tine ultrastructure changes and auranofin treatment in rheumatoid arthritis. Br J Rheumatol 25:227, 1986 28. Higgins CS, Moss J, Woodrow D, et al: Ultrastructure and function of the small bowel in rheumatoid arthritis with auranofin (oral gold) treatment. (in preparation) 29. Van Riel PL, Gribnau FW, Van De Putte LB, et al: Loose stools during auranotin treatment: Clinical study and some pathogenetic possibilities. J Rheumatol 10:222-226, 1983 30. Behrens R, Devereaux M, Hazelman B, et al: Investigation of auranofin-induced diarrhea. Gut 27: 59-65, 1986 3 I. Fondacaro JD, Hendersen LS, Hardcastle PT, et al: Effect of auranofin (SKF 39162) on water and electrolyte flux in canine small bowel: A possible diarrheogenic mechanism. J Rheumatol 13:288-293, 1986 32. Hardcastle J, Hardcastle PT, Kelleher DK, et al: Effect of auranotin on absorptive processes in the rat small bowel. J Rheumatol 13541-546, 1986 33. Hardcastle J, Hardcastle PT, Kelleher DK, et al: The effect of auranofm on the colonic transport of Na+ and fluid in the rat. J Pharm Pharmacol 38:466-468, 1986 34. Chan MK, Minta JO: Effects of anti-inflammatory and anti-rheumatic drugs on the activities of purified and membrane-bound Na+/K+ adenosine triphosphatase. Immunopharmacology 10:61-67, 1985 35. Nechay BR: Inhibition of adenosine triphosphatases by gold. Arthritis Rheum 23:464-470, 1980 36. Saunders L: Seven year study of auranofin in dogs. (unpublished report) 37. Goldhammer S: A fatal case of Solganal poisoning. Med Klin, 31:645-647, 1935 38. Perry MW: Gold injections and colitis. JAMA 113:965, 1939 39. Anderson NL, Palmer WL: Danger of gold salt therapy, report of a fatal case. JAMA 115:1627- 1630, 1940 40. Kandrac M, Pav J, Pechova I: Successful steroid therapy of severe enteritis caused by gold therapy. Cas Lek Cesk 100:361-367, 1961 41. Kaplinsky N, Pras M: Ulcerative colitis with gold treatment in rheumatoid arthritis. Harefuah 80:406-407, 1971 42. Roe M, Sears AD, Arndt JH: Gold reaction panenteritis: A case report with radiographic findings. Radiology 104:59-60,1972 43. Kaplinsky N, Pras M, Frank1 0: Sever enterocolitis complicating chrysotherapy. Ann Rheum Dis 32:574-577, 1973 44. Stein HB, Urowitz MB: Gold-induced enterocolitis. Case report and literature review. J Rheumatol 3:22-26, 1976 45. Siegman-Igra Y, Yaron M, Siletzki M, et al: Colitis and death following gold therapy. Rheumatol and Rehab 151245-247, 1976 46. Gerster JC, DeKalbermatten A, DePeyer R, et al: Reactions toxiques aux sels d’or avec enterocolite grave chez
299
un homme attenit d’une polyarthrite rhumatoi’de. Schweiz Med Wochenschr 106:1606-1608, 1976 47. Szpak MW, Johnson RC, Brady CE, et al: Gold (AU) induced enterocolitis. Gastroenterology, 76: 1257, I979 (abstr) 48. Sckolnick BR, Katz LA, Kozower M: Life-threatening enterocolitis after gold salt therapy. J Clin Gastroenterol 1:145-148, 1979 49. Fam AG, Paton TW, Shamess CJ, et al: Fulminant colitis complicating gold therapy. J Rheumatol 7:479-485, 1980 50. Huston GJ: Gold colitis, therapy and confirmation of mucosal recovery by measurement of rectal potential difference. Postgrade Med J 56:875-876, 1980 51. Martin DM, Goldman JA, Gilliam J, et al: Goldinduced eosinophilic enterocolitis: Response to oral cromolyn sodium. Gastrocnterology 80:1567-1570, 1981 52. Sukenik S, Hirsch M, Yanai-Inbar I, et al: Enterocolitis complicating chrysotherapy: Case report and review of the literature. Isr J Med Sci 18:1040-1043, 1982 53. Eaves R, Hansky J, Wallis I? Gold induced enterocolitis: Case report and a review of the literature. Aust NZ J Med 12:617-620, 1982 54. Reinhart WH, Kappeler M, Halter F: Severe pseudomembranous and ulcerative colitis during gold therapy. Endoscopy 15:70-72, 1983 55. Jarner D, Nielsen AM: Auranofin (SK&F 39162) induced enterocolitis in rheumatoid arthritis. Stand J Rheumatol 12:254-256, 1983 56. White RF, Major GAC: Gold colitis. Med J Aust 1:174-175, 1983 57. Nagler J, Paget SA: Nonexudative diarrhea after gold salt therapy: Case report and review of the literature. Am J Gastroenterol78:12-14, 1983 58. McCormick PA, O’Donoghue D, Lemass B: Gold induced colitis: Case report and literature review. Ir Med J 78:17-18, 1985 59. Wright A, Benfield FA, Felix-Davies D: Ischaemic colitis and immune complexes during gold therapy for rheumatoid arthritis. Ann Rheum Dis 43:495-497, 1984 60. Goebel KM: Basistherapie der rheumatoiden arthritis mit auranofin. Dtsch Med Wochenschr 110:64-65, 1985 61. Jackson CW, Haboubi NY, Whorwell PJ, et al: Gold induced enterocolitis. Gut 27:452-456, 1986 62. Smolen JS, Gang1 A, Polterauer P, et al: HLA antigens in inflammatory bowel disease. Gastroenterology 82:3438.1982 63. Krejs GJ, Fordtran JS: Diarrhea, in Sleisenger MH, Fordtran JS (eds): Gastrointestinal Disease. Philadelphia, Saunders, 1983, pp 257-280 64. Blodgett RC, Pietrusko RG: Five years of clinical experience with auranofin. Presented at ILAR poster session, P18 1, Sydney, Australia, May 1985 65. Holt PR: Intestinal absorption of bile salts in the rat. Am J Physiol 207: 1-7, 1964