Tolmetin-Warfarin interaction

LETTERS TO THE EDITOR

INTERFERON INACTlVATOR(S) AlDS AND AIDS-UNRELATED

J. L. AMBRUS, M.D., Ph.D., F.A.C.P. K. C. CHADHA, Ph.D. M. A. LILLIE, M.D., Ph.D. Roswell Park Memorial Institute and State University of New York at Buffalo Buffalo, New York 14263

IN PATIENTS WITH KAPOSI’S SARCOMA

To the Editor: The report of Ikossi-O’Connor et al (Am J Med 1986; 81: 783-785) describing alpha interferon inhibitory activity in the serum of patients with the acquired immune deficiency syndrome (AIDS) is a most interesting one. The interferon assay that the authors described measured a protective effect afforded human foreskin cells by test serum, when challenged by vesicular stomatitis virus. As the serum from the evaluated patients with AIDS was not treated to remove or inactivate human immunodeficiency virus (HIV, formerly termed HTLV-III/LAV) particles, it would seem possible that the cytotoxic activity of HIV could account for the interferon inactivation observed. Perhaps it has already been shown that the HIV does not affect human foreskin cells. Whether or not interferon inactivator exist independent of the presence of HIV, it is interesting to note that of the 14 patients with AIDS who were studied, interferon inhibitory activity was found in the 11 patients with Kaposi’s sarcoma, but not in the three patients who had only opportunistic infections. Should this observation be borne out in further study, it might suggest a pathophysiologic correlate to the varied clinical expressions of AIDS. DAVID

M. MARGOLIS,

1.

2.

TOLMETtN-WARFARIN

December

9, 1986, and accepted

March

M.D.

13, 1987

The Reply: The points raised by Dr. Margolis are well taken. It is true that no attempts were made to remove the HIV particles from the serum of patients with AIDS prior to use in the interferon inactivator assays. However, we are certain that dilutions of the serum used routinely in our tests did not produce any cytopathic effects on human foreskin cells, at least for the duration of our assays. Cytopathic effects were seen after cells were challenged with vesicular stomatitis virus. Similar interferon inactivators have been identified in patients with advanced cancer [ 1] who possibly had no HIV infection. The question remains unresolved whether inactivators found in patients with cancer and those found in patients with AIDS are identical or different. Our studies were based on a total of 18 patients. Since that time, we have collected more than 100 samples. These are currently under study. The results appear to support the hypothesis that significant levels of serum interferons are present in early phases of HIV infection. As the disease progresses, the serum interferon level decreases and interferon inhibitor(s) appear. We hope to isolate and identify the interferon inhibitors and eventually develop inhibitor inactivators, which may be of therapeutic value. We have recently published results [2] showing that indomethacin/pentoxifylline combinations may increase interferon-producing activity. The possible preventive value of this finding is to be explored.

1279

June

1987

The

American

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of Medicine

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INTERACTlON

To the Editor: Bleeding diathesis is a dreaded complication of warfarin treatment. A recent study revealed a linear increase in the risk of major hemorrhage, with a five-year probability of 41 percent (Am J Med 1986; 81: 255-259). Drug interactions with warfarin are well documented [I] and can increase the risk of bleeding. We report the first documented case of an interaction between tolmetin and warfarin, causing a marked prolongation of the prothrombin time. A GCyear-old white male resident of a long-term care nursing facility who had a history of insulin-dependent diabetes mellitus, diabetic peripheral neuropathy, diabetic nephropathy with renal insufficiency (calculated creatinine clearance, 28 ml/minute), ischemic heart disease, and deep vein thrombosis documented in May 1986 was being treated with warfarin 2.5 mg daily. The patient’s prothrombin time was stabilized between 15 and 22 seconds. Because of complaints of right shoulder pain, the patient began to receive tolmetin (400 mg) twice daily on September 3, 1986. No other change was made in the patient’s medication regimen, which included long-term digoxin (0.125 mg daily), 10 units of NPH insulin subcutaneously every morning, theophylline (200 mg three times a day), ferrous sulfate (325 mg three times a day), furosemide (20 mg daily), and sodium polystyrene sulfonate (45 ml every other day). The following day, after receiving three doses of tolmetin, the patient was noted to look pale and observed to have a nosebleed. Results of Hemoccult test of the stool were positive. The prothrombin time at this point was found to be 70.2 seconds. Tolmetin was discontinued, and the patient was given 15 mg of vitamin K1 (Aqua-Mephyton) intramuscularly. The prothrombin time was measured again approximately five hours later and found to be 75 seconds. At this point, the patient was transferred to the medical service and given one unit of fresh frozen plasma along with another 15 mg of vitamin K, intravenously. Two and one half hours after the plasma and second dose of vitamin KI were given, the prothrombin time had dropped to 19 seconds. Findings on liver function studies in May 1986 were within normal limits, with the exception of an elevated alkaline phosphatase value of 210 units/liter (normal, 15 to

New England Medical Center Boston, Massachusetts 02 111 Submitted

Ikossi-O’Connor MG, Chadha KG: The effect of malignant epithelial tumors, surgical therapy and bacterial sepsis upon various parameters of interferon system. J Surg Oncol 1984; 26: 27-34. lkossi MG, Ambrus JL, Chadha KC: Regulation of in vitro human leukocyte interferon production. Effect of prostaglandin synthetase and phosphodiesterase inhibition. Pies Commun Chem Pathol Pharmacol 1986: 54: 379-393.

82

LETTERS

TO THE EDITOR

F. KOREN, Pharm.D. L. COCHRAN, D.O. Veterans Administration Medical Center Salisbury, North Carolina 28144 JAMES

I 15 units/liter). Repeated liver function studies on September 5, 1986, revealed no change except for a greater elevation of the patient’s alkaline phosphatase value to 324 units/liter. Of note is the patient’s serum albumin level, which was low (3.1 g/dl; normal, 3.2 to 5.09 g/dl) in May 1986 and even lower (2.7 g/dl) on September 5, 1986. A MEDLINE search of the literature failed to reveal any case reports of a tolmetin-warfarin interaction; however, personal communication with the manufacturer of tolmetin (A. Santopolo, M.D.; McNeil Pharmaceuticals, Spring House, Pennsylvania) did disclose IO cases that have been reported in the last 10 years. The patients were generally older, with most being between 45 and 80 years of age, and tolmetin had been taken anywhere from two or three days to two weeks prior to observation of changes in prothrombin time. Although the mechanism of this interaction is unknown, it most likely involves either inhibition of warfarin metabolism or displacement of warfarin from protein binding sites [I]. The former is unlikely, since warfarin undergoes hydroxylation within the liver to 6- and 7-hydroxywarfarin [I], whereas tolmetin’s major metabolic transformation involves oxidation of the para-methyl group to a carboxylic acid [2]. Displacement from protein binding sites would seem a more plausible explanation, since both drugs are highly bound (99 percent) to plasma albumin [ 1,2]. The product monograph for tolmetin sodium in the 1988 (40th) edition of the Physicians’ Desk Reference states, “The in vitro binding of warfarin to human plasma proteins is unaffected by tolmetin, and tolmetin does not alter the prothrombin time of normal volunteers” [3]. Indeed, a study of 15 healthy volunteers given either warfarin and placebo or warfarin and tolmetin (400 mg three times a day) for 14 days showed no difference in prothrombin time, partial thromboplastin time, bleeding time, or platelet aggregation There was no difference in the warfarin dosage necessary to maintain a prothrombin time of one and one half to two times the control, and no difference in warfarin requirements following withdrawal of tolmetin [4]. Although the fact that warfarin dose could be varied invalidates the significance of some of these results, the fact that there was no difference in warfarin requirements would suggest the absence of a clinical interaction. However, an in vitro model utilizing fluorescence spectroscopy to determine displacement of warfarin from human serum albumin binding sites revealed a potentially clinically significant displacement of warfarin, even at lower concentrations of tolmetin 1.51. A recent in vivo study performed in rats used single doses of warfarin and several other nonsteroidal antiinflammatory agents to evaluate the effects of the latter on warfarin’s influence on the prothrombin time. Tolmetin was shown to increase the prothrombin time 34.4 percent above the baseline control value in rats receiving warfarin alone [6]. Because tolmetin (like most other nonsteroidal anti-inflammatory agents) can affect platelet adhesion and aggregation and prolong the bleeding time [7], it should be used with caution in patients receiving warfarin. The fact that tolmetin can displace warfarin from protein binding sites and thus prolong the prothrombin time makes this a potentially dangerous drug combination.

DAVID

REX L. JANES,

Veterans

1. 2.

3. 4.

5.

6.

7.

M.D.

Administration Medical Center Murfreesboro, Tennessee 37 130

Serlin MJ, Ereckenridge AM: Drug interactions with warfarin. Drugs 1983; 25: 610-620. Flower RJ, Moncada S, Vane JR: Analgesic-antipyretics and antiinflammatory agents: drugs employed in the treatment of gout. In: Gilman AG, Goodman LS, Rall TW, Murad F, eds. Goodman and Gilman’s the pharmacological basis of therapeutics. New York: Macmillan, 1985; 699-700. Physicians’ Desk Reference, 40th ed. Oradell, New Jersey: Medical Economics Company, 1986; 1095. Whitsett TL, Barry JP, Czerwinski AW, et al: Tolmetin and warfarin: a clinical investigation to determine if interaction exists. Excerpta Medica Int Cong Ser 1975; 372: 160-167. Otagiri M, Otagiri Y, Perrin JH: Some fluorescent investigations of the interaction between the enantiomers of warfarin and human serum albumin. Int J Pharm 1979; 2: 283-294. Sancilio LF, Taylor MA, Mathur PP, Crowe JT: Interaction between warfarin and nonsteroidal anti-inflammatory drugs (NSAIDs) in rats. Life Sci 1985; 36: 1041-1050. Mielke CH, Heiden D, Amadio P: Tolmetin: hematological effects in normal subjects. Excerpta Medica Int Cong Ser 1975; 372: 200-210. Submitted

December

29, 1986, and accepted

March

13, 1987

The Reply: It has long been established that many exogenous factors, including concomitant administration of a number of drugs, can contribute to prolonged prothrombin time and increased bleeding in patients receiving warfarin therapy (O’Reilly RA: Anticoagulant, antithrombotic and thrombolytic drugs. In: Gilman AG, Goodman LS, Rail TW, Murad F, eds. Goodman and Gilman’s the pharmacological basis of therapeutics, 7th ed. New York: Macmillan, 1985; 1338-1359). These findings are reflected in the prescribing information for warfarin, as well as in the prescribing information for many nonsteroidal anti-inflammatory drugs, including tolmetin. We agree with Koren et al that nonsteroidal anti-inflammatory drugs in general, including tolmetin, should be used with caution in patients receiving concomitant warfarin therapy. To our knowledge, however, there are no preclinical or clinical data that indicate any unique risk of a tolmetin-warfarin interaction. Koren et al reported that tolmetin increased prothrombin time by 34.4 percent in rats following warfarin pretreatment. The study included six other nonsteroidal anti-inflammatory drugs tested under identical conditions. Tolmetin ranked sixth of the seven tested anti-inflammatory agents in propensity to elevate prothrombin time in warfarin-pretreated rats. The prescribing information for nonsteroidal anti-inflammatory drugs marketed in this country includes a statement that patients receiving concomitant warfarin therapy should be monitored for increased prothrombin time or signs of

June

1987

The American

Journal

of Medicine

Volume

82

1279