Letters

Reference
Oral Montelukast versus Inhaled Salmeterol To Prevent 1. Edelman JM, Turpin JA, Bronsky EA, Grossman J, Kemp JP, Ghannam AF, et al.
Exercise-Induced Bronchoconstriction Oral montelukast compared with inhaled salmeterol to prevent exercise-induced bron-
choconstriction. A randomized, double-blind trial. Exercise Study Group. Ann Intern
TO THE EDITOR: The report (1) of efficacy of a leukotriene receptor Med. 2000;132:97-104.
antagonist for asthma prompts our report of zafirlukast-associated
hepatitis. A 68-year-old woman had had asthma for 25 years. She TO THE EDITOR: I would like to express my concerns about the
required intermittent corticosteroid therapy and had never been hos- study comparing montelukast with salmeterol in the long-term treat-
pitalized for asthma; her condition was generally controlled with ment of exercise-induced bronchoconstriction (1). Several questions
albuterol and inhaled corticosteroids. The patient experienced in- come to mind.
creased asthma severity, and zafirlukast was added. Her asthma im- First, why do such a study? Most people do not exercise more
proved, and she received maintenance therapy with zafirlukast until than once daily, and one or two inhalations of a short-acting ␤-
jaundice developed. After 4 months of zafirlukast therapy, she devel- agonist is effective at a fraction of the cost of salmeterol and monte-
oped weakness and anorexia, followed by jaundice, dark urine and lukast. My second concern is the requirement that anti-inflammatory
light-colored stools, and nausea and right upper quadrant abdominal medications (corticosteroids) be withdrawn. According to the au-
pain. thors, their patients met the criteria for moderate asthma; the rec-
The patient drank one glass of wine daily, reported no use of ommendation of the National Heart, Lung, and Blood Institute is
tobacco or other drugs, and had received a blood transfusion during that such patients receive anti-inflammatory medication. Two pa-
a cesarean section 35 years previously. For several years, she took a tients withdrew from the study because of worsening asthma, and
thiazide as prophylaxis against Ménière disease and was receiving one died!
estrogen replacement. She had no history of recent foreign travel, My last concern is that a journal that is held to high standards
raw shellfish ingestion, or contact with jaundiced persons. by its subscribers should print an article that raises such questionable
In addition to jaundice, the patient had a temperature of ethical concerns, especially when the benefit from the knowledge
36.4 °C, pulse of 58 beats/min, respiratory rate of 16 breaths/min, gained from the study is negligible. When issues such as these get
and blood pressure of 132/80 mm Hg. The liver breadth was 11 cm, past institutional review boards, peer-reviewed publications are obli-
and the liver was tender. No splenomegaly or ascites was present. gated to weigh the risks versus the benefits of medical research.
Other than ecchymosis on the patient’s right tibia, the rest of the
physical examination was normal. The aspartate aminotransferase Eric P. Brestel, MD
level was 8883 nkat/L, alanine aminotransferase level was 20 283 Greenville, NC 27858
nkat/L, alkaline phosphatase level was 3.76 ␮kat/L, bilirubin levels
Reference
were 232.6 ␮mol/L (13.6 mg/dL) (direct) and 360.8 ␮mol/L (21.1 1. Edelman JM, Turpin JA, Bronsky EA, Grossman J, Kemp JP, Ghannam AF, et al.
mg/dL) (total), ␥-glutamyltransferase level was 9.77 ␮kat/L, lactate Oral montelukast compared with inhaled salmeterol to prevent exercise-induced bron-
dehydrogenase level was 14.9 ␮kat/L, and albumin level was 24.0 choconstriction. A randomized, double-blind trial. Exercise Study Group. Ann Intern
g/L. The patient was negative for hepatitis B surface antigen, nega- Med. 2000;132:97-104.
tive for hepatitis-associated antigen, negative for anti– hepatitis C
antibody, negative on polymerase chain reaction for hepatitis C virus IN RESPONSE: The case of hepatitis reported by Dr. Grieco and Ms.
RNA, and positive for hepatitis B surface antibody (previously Burstein-Stein concerns a patient who was receiving zafirlukast, a
known). She was also negative for Lyme disease, Epstein–Barr virus, cysteinyl leukotriene receptor antagonist. The clinical history and
herpes simplex virus, and antimitochondrial antibodies. Findings on course indicate only that the patient’s hepatitis appeared after the
abdominal ultrasonography were normal. patient had been receiving zafirlukast for 4 months and resolved after
Zafirlukast therapy was discontinued, and liver function gradu- zafirlukast therapy was discontinued. This temporal association falls
ally returned to normal over the next several weeks. The serum al- far short of the evidence needed to conclude that the patient’s hep-
bumin level remained low for a few months but ultimately returned atitis was drug-induced. Furthermore, because montelukast is chem-
to normal. Wheezing recurred several weeks after zafirlukast therapy ically distinct from zafirlukast, it is incorrect to generalize from this
was discontinued but was controlled by inhaled albuterol. In view of single case to all antileukotriene drugs unless a mechanism-related
our patient’s zafirlukast-associated acute hepatitis, physicians should cause has been identified. Clearly, this case report does not support
be aware of this potential complication of leukotriene receptor an- such a cause.
tagonists. We carefully monitored the effects of montelukast on liver func-
tion during development of the drug in more than 2600 adolescent
Anthony J. Grieco, MD and adult patients, 320 pediatric patients between the ages of 6 and
Jessica Burstein-Stein, BS 14 years, and 314 patients between the ages of 2 and 5 years, as well
New York University School of Medicine as in postmarketing surveillance (1). We found no evidence of hep-
New York, NY 10016 atotoxic effects associated with the use of montelukast.

392 5 September 2000 Annals of Internal Medicine Volume 133 • Number 5

We respectfully disagree with Dr. Brestel’s comments on the hepatotoxicity similar to that associated with troglitazone (5) is still
ethical issues and scientific importance of our research question. The open to question.
study was conducted at 17 centers, each of which received approval
from their institutional review board before conducting the study.
Exercise-induced bronchoconstriction is a common condition, with a William L. Isley, MD
prevalence exceeding 5% in the adult population, and even higher in Julie C. Oki, PharmD
children (2). Salmeterol is widely used for the prevention of exercise- University of Missouri
induced asthma and is approved by the U.S. Food and Drug Ad- Kansas City, MO 64111
ministration for this use (3). Montelukast is a new therapy that has
also demonstrated inhibition of exercise-induced asthma (4). Rigor-
ously conducted randomized clinical trials represent the basis of the
evidence on which treatment decisions are made. Our study, which References
directly compared these two therapies, provided important new in- 1. Forman LM, Simmons DA, Diamond RH. Hepatic failure in a patient taking
formation about the differences between them. rosiglitazone. Ann Intern Med. 2000;132:118-21.
2. Al-Salman J, Arjomand H, Kemp DG, Mittal M. Hepatocellular injury in a patient
receiving rosiglitazone. A case report. Ann Intern Med. 2000;132:121-4.
Jonathan M. Edelman, MD
3. Naranjo CA, Busto U, Sellers M, Sandor P, Ruiz I, Roberts EA, et al. A method for
Merck & Co.
estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239-45.
West Point, PA 19486-0004
4. Freid J, Everitt D, Boscia J. Rosiglitazone and hepatic failure [Letter]. Ann Intern
Med. 2000;132:164.
5. Neuschwander-Tetri BA, Isley WL, Oki JC, Ramrakhiani S, Quiason SG, Phillips
References
1. Singulair (montelukast sodium). Product circular. 1998. NJ, et al. Troglitazone-induced hepatic failure leading to liver transplantation. A case
2. Cypcar D, Lemanske RF Jr. Asthma and exercise. Clin Chest Med. 1994;15:351-68. report. Ann Intern Med. 1998;129:38-41.
3. Serevent (salmeterol xinafoate). Product circular. 1994.
4. Leff JA, Busse WW, Pearlman D, Bronsky EA, Kemp J, Hendeles L, et al. Monte-
lukast, a leukotriene-receptor antagonist, for the treatment of mild asthma and exercise- IN RESPONSE: We appreciate Isley and Oki’s comments. The writers
induced bronchoconstriction. N Engl J Med. 1998;339:147-52. point out that our patient’s liver dysfunction may be related to hy-
potension. A similar point was made by Freid and colleagues from
SmithKline Beecham in a letter appearing in the same issue as our
report (1). The SmithKline Beecham group describes the patient’s
Rosiglitazone and Liver Failure hypotension and requirement of intensive support in detail. How-
ever, it is important to note that the patient’s profound liver function
TO THE EDITOR: We read with interest the recent reports of hepatic abnormalities were documented as being present before the hypoten-
dysfunction associated with the use of rosiglitazone (1, 2). According sion developed. At the time initial blood studies were obtained, the
to the classification scheme of Naranjo and colleagues (3), both re- patient was normotensive and had no physical examination or chest
ports would at most suggest a possible association with the adminis- radiograph findings of congestive heart failure. In addition, our pa-
tration of rosiglitazone because of other confounding factors. The tient had experienced several weeks of hepatitis-like symptoms before
liver abnormalities in the case presented by Forman and colleagues
presentation. Liver failure–induced metabolic acidosis may have
(1) may be related to hypotension, as hypothesized by Freid and
caused his subsequent cardiac decompensation. We believe that the
coworkers in an accompanying letter (4). The case presented by
patient’s temporal course is more consistent with the primary devel-
Al-Salman and associates (2) is clouded by a history of alcohol abuse,
opment of liver dysfunction, which, in the absence of another cause,
acetaminophen use, and concomitant administration of zafirlukast.
may be due to rosiglitazone. Without a rechallenge, it is impossible
Zafirlukast has been associated with hepatotoxicity and inhibits one
of the metabolic pathways for the clearance of rosiglitazone, the to be certain that any drug is responsible for a particular adverse
cytochrome P4502C9 pathway. Contrary to what Al-Salman and effect on the basis of a single case report. Our case is not perfectly
colleagues suggest, rosiglitazone-associated injury may not be similar “clean”—the patient is an elderly man with heart disease taking other
to the liver injury proposed by Neuschwander-Tetri and colleagues medications— but this is precisely the kind of patient who is likely to
(5) because rosiglitazone metabolism does not produce a quinone, be treated with this drug. Our goal in publishing this case was not to
nor does it have a vitamin E moiety as a side chain. If this idiosyn- indict the drug but to make other physicians aware that hepatotox-
cratic hepatotoxicity is a class effect, it is more likely to be related to icity may be a class effect of thiazolidenediones and not solely a
the basic thiazolidinedione structure. characteristic of troglitazone. Only with time will we see whether
We believe that liver monitoring is indicated when the newer other cases of rosiglitazone-associated hepatotoxicity occur and will
thiazolidinediones are used in therapy, but whether these agents have we be able to determine whether this drug is conclusively linked to

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