Misoprostol prevents nonsteroidal antiinflammatory drug-induced gastric ulcers—Has pandora's box been opened?

October 1989

illness,

SELECTED

but in whom

identified,

only

tients

with

acute,

non-B

hepatitis,

least

6 mo after

58%

no source had

resolving only

15%

the onset

antibody.

of infection Among

transfusion-associated had antibodies

could

Japanese

when

be pa-

non-A, assayed

at

of illness.

Comment.

These long-awaited reports strongly suggest that some of the dilemmas presented by blood-borne non-A, non-B hepatitis will be resolved shortly. Assuming that these studies can be confirmed and replicated so that the specificity and sensitivity of the antibody test can be more fully characterized, it should become possible to more fully characterize the responsible agent and to define with some degree of precision the periods of antigenemia and viremia in acute and chronic infection, and to correlate these with periods of infectivity. It also should be possible to determine the carrier rate in various populations, to estimate the prevalence and incidence of acute and chronic infection in diverse geographic areas, and to utilize this testing in the screening of blood donors to eliminate viremic carriers of the non-A, non-B agent. Whether there is but one non-A, non-B agent or multiple agents remains uncertain. Should the described assay prove to be even more highly sensitive than reported here, the failure to identify antibody in epidemiologically bona fide cases of non-A. non-B heuatitis would orovide more convincina suooort for the existence bf more than one non-A, non-B agent.hoieiheless, the high frequency with which this antibody has been detected in transfusion-associated non-A, non-B hepatitis, as described in this report, strongly suggests that the responsible agent is the major, if not the sole, etiologic player in non-A, non-B hepatitis, perhaps worthy of the “hepatitis C virus” designation. It will also be important to more clearly identify the time-course of the development of antibody in infected individuals or chimpanzees. One wonders about the observation that the latent period between infection and the development of antibody appears to be several months long. Will this phenomenon be confirmed if a more sensitive assay can be developed and more frequent sampling attempted? Are there other antigen-antibody systems associated with this non-A, non-B hepatitis agent? If so, is the time-course of the development of these other antigens or antibodies similar to that reported here? Is the antibody assayed here a neutralizing, protective antibody? Is this antibody present in current preparations of immune globulin? Was it present in any of the materials used in the studies of immune globulin prophylaxis for transfusion-associated hepatitis undertaken in the 197Os? Further questions about the nature of the blood-borne non-A, non-B agent(s) are now amenable to study. The size and morphology of the blood-borne agent(s) remain unknown. Filtration experiments in which one strain of virus was passed through variably sized polycarbonate membranes indicated that the virus is between 30 and 60 nm in diameter (J Infect Dis 1987;156: 63640). Confirmation of the morphology and physicochemical characteristics should now be readily achieved. Clinically important questions concerning methods for inactivating the agent or removing it from biological products may now begin to be answered. The currently controversial relationship of one non-A, non-B agent to retroviruses may now be examined. A relationship was postulated when particle-associated reverse transcriptase activity, characteristic of retroviruses, was detected in human serum specimens and in plasma-derived products that had been shown to transmit non-A, non-B viral hepatitis to human beings or chimpanzees (Lancet 1984;ii:941-3). However, others failed to detect reverse transcriptase activity in well-defined and wellcharacterized serum samples shown to contain infective quantities of the non-A, non-B hepatitis agent(s) (J Gen Virol 1966; 67:777-g, Lancet 1985;ii:665).

SUMMARIES

1053

Similarly the role of human hepatitis B virus-related variants, which have been postulated to be responsible for some human non-A, non-B hepatitis infections, can now be more critically assessed (Gastroenterology 1986;91:1357-63, Proc Nat1 Acad Sci USA 1986;83:6608-12, J Med Virol 1985;15:343-50). The development of methods to identify infected individuals should also permit the appropriate use of antiviral treatment in patients with chronic non-A, non-B infection, and should initiate the process likely to lead to the development of a safe and effective vaccine. All in all, these reports indicate that a new phase in the history of the conquest of viral hepatitis has begun. It is an altogether extraordinary story. R. S. K0FF.M.D.

MISOPROSTOL PREVENTS NONSTEROIDAL ANTIINFLAMMATORY DRUG-INDUCED GASTRIC ULCERS-HAS PANDORA’S BOX BEEN OPENED?

Graham DY, Agrawal NM, Roth SH (Veterans tion

Medical

Center,

Houston,

Tulane Center

New Orleans,

Louisiana;

and Arthritis

nix, Arizona)

Prevention

of NSAID-induced

with

misoprostol:

trolled

trial.

multicentre,

Lancet

Administra-

Texas;

University, Ltd.,

Phoe-

gastric ulcer

double-blind,

placebo-con-

1988;ii:1277-80.

A large multicenter trial was conducted to determine whether administration of misoprostol, a synthetic E prostaglandin with both antisecretory and cytoprotective properties, would prevent gastric ulceration in patients taking one of several nonsteroidal antiinflammatory drugs (NSAIDs). Patients with osteoarthritis were included if they were receiving ibuprofen, piroxicam, or naproxen; had abdominal pain; and had no gastric ulcer at the initial endoscopic examination. After randomization either to placebo, misoprostol (100 pg), or misoprostol(200 pg) four times daily, patients underwent repeat endoscopy at 1, 2, and 3 mo of therapy. failures

and removed

cm in diameter) The severity

were

considered

from the study

Patients

if a gastric

was noted

of abdominal

at any of these

rate.

according

Of the

patients

420

were

patients

race,

smoking

ulcers

were

at the

patients,

dose misoprostol,

At the

cebo-treated

patients

3 patients

were

found

prostol.

to have misoprostol

Thus,

l-mo

an ulcer and

the cumulative

receiving

receiving another

6 (4%)

the low

Finally,

7 (5%) placebo-treated compared

with

taking

3-mo

at the patients

2 (1%)

high-dose

prevalence

pla-

compared

receiving

respectively.

none

low-

high-dose

an ulcer

(0.7%)

in age, Gastric

in 17 (12.3%)

patients

(0.7%)

139

misopros-

taken.

endoscopy

developed

another

study,

comparable

NSAIDs

endoscopy

had

of misoprostol,

3-mo examination, low-dose

and

(2%) and 1 patient

and high doses

the

and 138 patients

were

3 (2%)

2-mo

completed compliance

to high-dose

misoprostol,

and 1 patient

misoprostol.

completed

groups

history,

noted

placebo-treated

with

who

to low-dose

The treatment

enrolled

a remarkable

assigned

to placebo. sex,

originally

to protocol,

randomly

tol, 143 patients

(~0.3

examinations.

pain was also rated at each visit.

All but one of the patients the study

treatment ulcer

taking miso-

of gastric

1054 SELECTED SUMMARIES

ulcer was 22% for placebo, 6% for 100 pg of misoprostol, and 1% for 200 pg of misoprostol. Both doses of misoprosto1 were significantly superior to placebo, but no different from each other, in preventing gastric ulceration. If only gastric ulcers 20.5 cm in diameter were considered, the cumulative 3-mo prevalence was 12% 4%, and 1% for placebo and low- and high-dose misoprostol, respectively. At the end of the 3-mo period, ~70% of patients in each of the misoprostol groups were free of pain compared with 57% of the placebo-treated patients. This impressive symptom response in the placebo group accounted for the lack of a statistically significant difference between the misoprostol and placebo groups. Diarrhea was noted significantly more often in misoprostol-treated patients than the placebo-treated patients, occurring in 13% of placebotreated patients, 25% of patients taking 100 pg of misoprostol, and 39% of those taking 200 pg of misoprostol. Diarrhea resulted in withdrawal from the study of 0.7%, 2.8%, and 5.7%, of patients taking placebo, low-dose misoprostol, and high-dose misoprostol, respectively. Comment. Almost a fourth of the placebo-treated subjects in this large study were found to have a gastric ulcer at one of three endoscopic examinations performed during a 3-mo period. This figure might be somewhat inflated, as about 40% of these lesions were 3-4 mm in diameter, lesions that can be difficult to distinguish from erosions. Nevertheless, even if one uses a size of ~5 mm, this study still confirms the frequent occurrence of gastric ulcer in patients taking NSAIDs. More important is the potential for NSAID-induced ulcers to bleed or perforate. Although the relative risk per prescription of a major complication from an NSAID-induced ulcer is relatively small (Arch Intern Med 1987;147:85-8, Arch Intern Med 1987; 147:1821-3, Alim Pharm Ther 1988;25:9-26), even a small increase in risk becomes a concern when one considers that more than 70 million prescriptions are written for NSAIDs in this country each year (Ann Intern Med 1988:109:353-l). Patients with complicated gastric or duodenal ulcer are about three times more likely to have taken NSAIDs than controls (Gut 1985; 26:359-63, Lancet 1986;i:462+ Br Med J [Clin Res] 1988;297: 1311-3, Gut 1988;29:70-4). Indeed, recognition of the ulcer complications associated with NSAIDs recently prompted the U.S. Food and Drug Administration to request manufacturers to include appropriate warnings on package labels. With concern over NSAID-induced complications prominent in their minds, and with the results of Graham’s well-designed, well-executed, and well-presented study before them, the Food and Drug Administration recently approved misoprostol (Cytotec) in a dose of 200 pg four times daily for the “prevention of NSAID-induced gastric ulcers in patients at high risk of complications from a gastric ulcer.” The package insert suggests that such patients include the elderly, patients with concomitant debilitating illnesses, and patients with a history of ulcer. This seems like a rather broad indication if its primary support came from the Graham study, a study with an intentionally narrower perspective. Only symptomatic patients, with osteoarthritis, taking one of three NSAIDs were included. We do not know if similar results would be obtained with misoprostol if other subjects, without symptoms, taking other NSAIDs were studied. Several other questions, not addressed by the Graham study, also remain unanswered: 1. What patients are really at “high risk” to develop a complicated gastric ulcer? Epidemiologic surveys suggest that patients with prior ulcer disease and the elderly are at some

GASTROENTEROLOGY Vol. 97. No. 4

increased risk. Langman [Stand J Gastroenterol 1988;23(Suppl 146):185-901 has suggested that the risk of bleeding ulcer attributable to NSAIDs is 1 in 3000 prescriptions for those 160 yr old but much less for younger individuals. However, prospective studies with enough patients to provide a reliable answer to this question are not available to guide physicians. For example, are patients who have taken NSAIDs safely for many years at the same risk as someone just starting therapy? Will misoprostol (or HZ-receptor antagonists) prevent complications of gastric ulcer? Can we assume that, as misoprostol reduced the prevalence of NSAID-associated gastric ulcer over a 3-mo period, it will prevent bleeding gastric ulcers over many years of NSAID use? Only with a properly designed controlled trial involving thousands of patients can we know for sure. Will misoprostol prevent NSAID-induced duodenal ulcer? This is important, as a substantial proportion of NSAIDassociated complicated ulcers are duodenal. In Graham’s study, duodenal ulcer occurred in only 3.6% of patients taking placebo and 2.5% taking misoprostol. The placebo rate is lower than has been found in other studies and may reflect exclusion of patients with prior ulcers. Nevertheless, if true, it suggests that it would be very difficult to prove any drug superior to placebo. Would HZ-receptor antagonists work as well to prevent ulcers as misoprostol? This is important to know for several reasons. First, if HZ-receptor antagonists (which act just by suppressing acid secretion) were not effective, it would suggest that the main mode of action misoprostol (which suppresses acid secretion about as well as HZ-receptor antagonists) was through cytoprotection. Second, many patients taking NSAIDs are already being cotreated with HZ-blockers and we need to know if they should be switched to misoprostol. Third, in some locales, Hz-blockers may be less expensive than misoprostol. Fourth, misoprostol causes diarrhea in some patients. Fifth, misoprostol should not be used in any woman who is, or may become, pregnant. Unfortunately, the answer to this question is not known. Most previous studies of HZ-receptor antagonists suffer either from small sample sizes or the use for an end-point of “lesion scores” from which the incidence of frank ulceration cannot always be gleaned. Lesions other than true ulcers may be clinically meaningless. Two studies suggest that 150 mg of ranitidine twice daily, when compared with placebo, significantly reduces the prevalence of NSAID-associated duodenal ulcer but not gastric ulcer (Br Med J [Clin Res] 1988;297: 1017-21, Dig Dis Sci 1989;34:424-8). However, the cumulative 4- and 8-wk prevalences of gastric ulcer in the placebo group of the first of these studies was only 5% and 6%, lower than that found in the Graham study. What is needed is a large, headto-head comparison of misoprostol and an HZ-blocker using true ulcer as the endpoint. So what should be recommended? Certainly we can call for additional studies to answer these questions, but that begs the very important practical issue of the prophylactic use today of misoprostol to prevent gastric ulcers in patients taking NSAIDs. My suggestions are as follows: 1. Reassess

the need for, and dose of, NSAIDs. Large doses of NSAIDs should not be used for simple analgesia where lower doses of NSAIDs or acetaminophen would work as effectively. 2. Treat prophylactically patients with a prior complication of gastric ulcer or patients in whom the development of a complicated gastric ulcer would be devastating. Such patients include those who have other important illnesses that would severely limit their tolerance to a complication.

SELECTED

October 1989

Patients

with prior uncomplicated

gastric

ulcer

are another

group in whom misoprostol should be considered. However, until we know the risk of complications in patients with prior uncomplicated gastric ulcers, this indication should be considered relative. The risk of gastric ulcer in patients with prior duodenal ulcer is unclear. This leaves a large group of patients-“elderly” patients in general-that the package insert of misoprostol suggests are at risk of a complicated gastric ulcer. On the one hand, administration of misoprostol may prevent some complications, and some deaths, from NSAID-induced ulcers. On the other hand, can we justify the cost? The average cost for a l-mo prescription of misoprostol (in Dallas) is $64 [range $55-$76). If Langman is correct and the risk of an NSAID-induced bleeding ulcer in patients over 60 is 1 in 3000, and if, say, 50 million prescriptions a year are filled for such patients, we would at best prevent about 17,000 bleeds a year at a cost of 3 billion dollars. Of course, there are costs of caring for patients with complicated ulcers that would be saved, but such costs must be an order of magnitude lower than the cost of prophylaxis. Although consideration of “cost-effectiveness” is difficult when sitting face-to-face with individual patients, these dollar figures should at least give us pause in our deliberations. Personally, until more data are available, I would not use misoprostol (or Hz-receptor antagonists] prophylactically to prevent NSAID-induced complications in healthy elderly patients. W. L. PETERSON, M.D.

SALMONELLA BACTERIAL ADHERENCE AND PENETRATION OF MUCOSAL CELLS: INDUCING ROLE OF THE EPITHELIUM Finlay BB, Heffron F, Falkow S (Department of Medical Microbiology, Stanford University School of Medicine and Department of Molecular Biology, The Research Institute of Scripps Clinic) Epithelial cell surfaces induce salmonella proteins required for bacterial adherence and invasion. Science 1989;243:940-3. This study examines the key issue of how Salmonella bacteria adhere to and invade eukaryote cells, two essential events for penetrating the intestinal mucosal barrier. Previous studies from this group had demonstrated that S. choleraesuis, a highly invasive Salmonella species, can enter, multiply, and proceed through viable Madin Darby canine kidney (MDCK) epithelial cells grown on permeable filters (J Cell Biol 1988;107:221). As these events can be blocked by inhibitors of bacterial RNA or protein synthesis, these investigators hypothesized that certain epithelial cells might induce bacterial synthesis of de novo proteins essential for these processes. The kinetics of adherence and invasion of S. choleraesuis in MDCK cells were determined. Binding of organisms to MDCK monolayers occurred only after 2 h, but proceeded exponentially thereafter, reaching a maximum value at 6 h. However, if bacteria were preincubated with MDCK cells for 3 h, removed, and added to another monolayer preparation, stable binding occurred within 1 h. Treatment of bacteria with inhibitors of protein or RNA (but not DNA) synthesis completely blocked adherence and invasion. These data, therefore, were consistent

SUMMARIES

1055

with the idea that an induction event requiring protein synthesis by the bacteria is essential for adherence and subsequent invasion into host cells. Attempts were made to identify MDCK-induced bacterial protein by pulse-labeling bacteria with [?S]methionine in the presence and absence of MDCK monolayers. At least six new proteins were made by MDCK-bound S. choleraesuis, whereas a minimum of seven proteins were no longer produced when compared with nonadherent bacteria. The time-course of appearance of the inducible proteins closely correlated with the kinetics of adherence properties. Further studies demonstrated that the regulation and synthesis of these proteins were not dependent on heat shock or the presence of a large plasmid essential for Salmonella bacteria virulence (but not penetration). By using several mutants of Salmonella bacteria with defects in adherence, invasion, or penetration, these investigators corroborated that Salmonella organisms must synthesize these proteins to stably adhere and invade epithelial cells. Induction of these proteins by epithelial cells appeared to be quite specific. The same proteins could be induced by the presence of epithelial cells such as Hep-2 cells as well as MDCK cells, but not by Chinese hamster ovary cells, indicating that specific epithelial surface receptors were required. Altering the surface of epithelial cells with trypsin or neuramidase treatment inhibited bacterial binding to epithelial cells and also blocked the induction of synthesis of these proteins. Thus, it is likely that glycoproteinlike structures are required for these properties. In summary, these studies indicate that stable adherence to and invasion of epithelial cells by Salmonella bacteria require de novo synthesis of several new bacterial proteins. Their induction is dependent on the presence of specific epithelial glycoproteinlike surface receptors. Salmonella are a group of motile gram-negative bacilli that in humans frequently cause a self-limiting gastroenteritis, but on occasion cause life-threatening septicemia. To produce disease, Salmonella, as well as other facultative intracellular parasites such as Yersinia, Chlamydia, Shigella, Neisseria, and Brucellae, must penetrate through the epithelial cell barrier (J Clin Invest 1973;52:441-53). The underlying mechanisms for bacterial invasion have not been well understood and, by and large, most of what is known remains descriptive. In 1967 a comprehensive study of Salmonella tissue penetration was reported by Takeuchi (Am J Path01 1967;50:109-361, who, using standard transmission electron microscopy, determined the events of Salmonella penetration across the intestinal epithelium of guinea pigs. Some bacteria appear to penetrate through intercellular tight junctions. Others come in close proximity to the brush border, attach to the microvillus membrane, and induce degeneration of epithelial microvilli and the terminal web. After penetrating the luminal membrane, bacteria can be seen within membrane-bound cavities, presumably as a consequence of endocytosis. Later studies suggested that these vacuoles reach the basal lateral membrane where they exit (J Cell Biol 1988;107:221-30), a process similar to the transcytosis or the transport of immunoglobulins such as immunoglobulin A and immunglobulin M across epithelia. Bacterial adherence is essential to bacterial invasion and penetration of the epithelial cell barrier. Thus, a great deal of attention has been focused on the dynamics of bacterial adherence to the luminal plasma membrane. The process consists of two major stages. The first appears to be a reversible stage where bacteria can

Comment.