Letters
The Editors welcome submissions for possible publication in the Letters section. Authors of letters should: • Include no more than 400 words of text, three authors, and five references • Type with double-spacing • Send three copies of the letter and a transfer-of copyright form (see Table of Contents for location) signed by all authors • Provide a self-addressed envelope if they want to be notified that the letter was received Letters commenting on an Annals article will be considered if they are received within 6 weeks of the time the article was published. Only some of the letters received can be published. Published letters are edited and may be shortened; tables and figures are included only selectively. Authors will be notified that the letter has been received. If the letter is selected for publication, the author will be notified about 3 weeks before the publication date. Unpublished letters cannot be returned.
New Macrolide Antibiotics To the Editors: Recently, Biaxin (Abbott Laboratories, North Chicago, Illinois), a brand of clarithromycin, has been heavily promoted for common respiratory infections because it covers Haemophilus influenzae as well as Streptococcus pneumoniae and Mycoplasma pneumoniae. Abbott's efficacy claim is supported almost entirely by data either on file with the company or published in company-sponsored symposia. Unfortunately, Dr. Neu (1), in his editorial on the new macrolides, never evaluates their efficacy relative to currently available (and much cheaper) treatments for H. influenzae. Instead, he limits his discussion to a brief comparison of azithromycin and clarithromycin with erythromycin, an agent known to be unreliable against H. influenzae. In the editorial (1), the new macrolides appear superior to erythromycin against H. influenzae, but important data to the contrary are missing. For example, in vitro, clarithromycin is only half as effective as erythromycin against H. influenzae (2). Although azithromycin may be four to eight times more effective than erythromycin against H. influenzae, in vivo, azithromycin attains high intracellular but low serum concentrations. Thus, it may not be effective against an organism like H. influenzae that acts at extracellular sites. Dr. Neu concludes that the new macrolides are "a suitable alternative to many of the currently available therapies for common outpatient respiratory infections." He does not mention studies which have shown clarithromycin to be less effective than amoxicillin in the treatment of H. influenzae sinusitis (3) or than ampicillin in the treatment of H. influenzae bronchitis (4). He does not discuss the activity of the new macrolides (if any) in pneumonia caused by H. influenzae. The example of ciprofloxacin suggests that patients can be endangered by an advertising campaign that contains inflated claims of antibiotic efficacy (5). In omitting critical questions about the effectiveness of the new macrolides, Dr. Neu misses an important opportunity to prevent a repetition of this problem. Jaime B. Friedman, MD Sand Point Internists Seattle, WA 98105
References 1. Neu HC. New macrolide antibiotics: azithromycin and clarithromycin [Editorial]. Ann Intern Med. 1992;116:517-9. 2. Neu HC. The development of macrolides: clarithromycin in perspective. J Antimicrob Chemother. 1991;27(Suppl A): 1-9. 3. Karma P, Pukander J, Penttila M, Ylikoski J, Savolainen S, Olen L, et al. The comparative efficacy and safety of clarithromycin and amoxycillin in the treatment of outpatients with acute maxillary sinusitis. J Antimicrob Chemother. 1991 ;27(Suppl A):83-90. 4. Bachand RT Jr. Comparative study of clarithromycin and ampicillin in the treatment of patients with acute bacterial exacerbations of chronic bronchitis. J Antimicrob Chemother. 1991;27(Suppl A):91100. 5. Frieden TR, Mangi RJ. Inappropriate use of oral Ciprofloxacin. JAMA. 1990;264:1438-40.
To the Editors: Clarithromycin has been widely promoted for community-acquired pneumonia. Some respiratory pathogens such as Streptococcus pneumoniae, however, may be only moderately sensitive. Few patients with life-threatening Haemophilus influenzae or Moraxella catarrhalis pneumonia have been treated with the drug, and its success in patients with bacteremic pneumonia is not established. Resistance to these respiratory pathogens may develop over time. For all these reasons, rigorous susceptibility monitoring is of utmost importance, as noted by Dr. Neu (1). Once an antibiotic is marketed, easy access to the compound for susceptibility testing is mandatory. This issue may represent another example of the physician's patient advocacy role in relations with the pharmaceutical industry. Steven L. Berk, MD East Tennessee State University Johnson City, TN 37614-0622 Reference 1. Neu HC. New macrolide antibiotics: azithromycin and clarithromycin [Editorial]. Ann Intern Med. 1992;116:517-9.
To the Editors: The new macrolide antibiotics, azithromycin and clarithromycin, may be beneficial in the control of cryptosporidiosis, one cause of severe intractable diarrhea in immunocompromised patients such as those with AIDS (1). We recently saw a 22-year-old human immunodeficiency virus (HIV)-l seropositive patient with hemophilia, who in October 1991 was diagnosed by modified acid-fast stain of stool and duodenal aspirate as having cryptosporidiosis. At that time he was having 15 to 20 watery bowel movements a day. He was treated with octreotide, up to 400 fig, given subcutaneously every 8 hours, paromomycin, 500 mg, given orally three times a day, and paregoric. The frequency of bowel movements decreased to approximately 4 to 6 per day, but his medications were eventually stopped because of nausea. In February 1992, he was admitted to the hospital with the symptoms of shortness of breath and fever, at which time he was having 5 to 10 loose stools per day. A modified acid-fast stain of the stool was still positive for Cryptosporidium oocysts, and octreotide in titrated doses from 50 fig to 500 fig, given subcutaneously every 8 hours for 1 week, and paromomycin, 500 mg, given orally three times a day, were reinstituted. Clarithromycin, 1000 mg, given orally every 12 hours, was also started. Within 10 days, the diarrhea was totally resolved. The patient subsequently died from respiratory failure; postmortem examination showed no evidence of cryptosporidiosis. No satisfactory therapy for cryptosporidiosis currently exists (1). Clarithromycin and azithromycin may be effective in treat-
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ing enteric cryptosporidiosis in immunosuppressed rodents (2, 3). These agents appear to be superior to spiramycin, another macrolide antibiotic (1, 2). Our patient had complete improvement in the frequency of loose stools when treated with octreotide, paromomycin, and clarithromycin, whereas he previously had only partial improvement when treated with the first two agents. The new macrolides warrant further study in the management of cryptosporidiosis. Steven J. Sperber, MD Nancy Gornish, MD University of Medicine & Dentistry of New Jersey New Brunswick, NJ 08903-0019 References 1. Current WL, Garcia LS. Cryptosporidiosis. Clin Microbiol Rev. 1991;4:325-58. 2. Rehg JE. Activity of azithromycin against Cryptosporidia in immunosuppressed rats. J Infect Dis. 1991;163:1293-6. 3. Cama VA, Marshall MM, Sterling CR. Evaluation of clarithromycin for the treatment of enteric cryptosporidiosis. Presented at the First International Conference on the Macrolides, Azalides, and Streptogramins. Santa Fe, New Mexico: January 1992. In response: Dr. Friedman addresses an important point. I was asked to address primarily the possible new uses of these interesting agents with only slight mention of other uses (1). We have shown that clarithromycin, 500 mg twice daily, yields protective serum bactericidal activity against H. influenzae (2). In addition, researchers at Abbott Laboratories (3) and in our own group (4) have shown that, at serum levels comparable to those in humans, H. influenzae is eradicated from the ears of infected guinea pigs. Azithromycin has very high tissue and phagocytic concentrations and lower serum levels, but the tissue levels in the bronchi, where the H. influenzae organisms are located, and in the alveoli are well above that needed to inhibit the organisms (5). Furthermore, animal models of ear and lung infections with H. influenzae have shown azithromycin to be effective. I did not address the problem of H. influenzae pneumonia, which, I believe, is uncommon, and when it does occur is caused by type b H. influenzae. There is inadequate data on macrolides as treatment of well-verified H. influenzae pneumonia. Dr. Berk's comment that Streptococcus pneumoniae are only moderately susceptible is incorrect. In the United States, 5. pneumoniae are extremely susceptible, and in the serum bactericidal studies, I had a serum bactericidal titer against S. pneumoniae of greater than 1:32 that was measured 12 hours after administration of 500 mg of clarithromycin. Data on file at Pfizer indicate the efficacy of azithromycin for treatment of pneumococcal pneumonia (S. Hopkins. Personal communication). Readers should not consider using an oral macrolide once or twice dairy to treat life-threatening H. influenzae pneumonia. Finally, I would be cautious in accepting that either clarithromycin or azithromycin is highly effective in treating cryptosporidiosis, as indicated by Drs. Sperber and Gornish. I recall the claims for spiramycin, which could not be substantiated in double-blind trials. It is also important when using azithromycin to use the lactose-free preparation and a dose of 1 g daily. This preparation can be obtained on a compassionate basis from Dr. Deborah Wilson at Pfizer, Inc. A recent review of the published data on the use of macrolides for gastrointestinal infections discouraged me about their efficacy. I await the results of trials of clarithromycin for Helicobacter pylori gastritis and of azithromycin for typhoid. I believe that both of these new macrolides are useful agents. These antibiotics are appropriate to use in therapy for selected respiratory infections. My editorial clearly emphasized cost aspects, which must be considered in treating all nonlifethreatening infections. Harold C. Neu, MD Columbia University New York, NY 10032 534
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References 1. Neu HC. New macrolide antibiotics:azithromycin and clarithromycin [Editorial]. Ann Intern Med. 1992;116:517-9. 2. Gu JW, Scully BE, Neu HC. Bactericidal activity of clarithromycin and its 14-hydroxy metabolite against Haemophilus influenzae and streptococcal pathogens. J Clin Pharmacol. 1991;31:1146-50. 3. Hardy DJ, Swanson RN, Rode RA, Marsh K, Shipkowitz NL, Clement JJ. Enhancement of the in vitro and in vivo activities of clarithromycin against Haemophilus influenzae by 14-hydroxy-clarithromycin, its major metabolite in humans. Antimicrob Agents Chemother. 1992; 34:1407-13. 4. Chin NX, Yan SD, Gu JW, Neu HC. Evaluation of clarithromycin and its 14-hydroxy metabolite in treatment of Haemophilus influenzae otitis media in a gerbil model. Abstract 190. 17th International Congress on Chemotherapy. Berlin: 23-28 June 1991. 5. Drew RH, Gallis HA. Azithromycin, spectrum of activity, pharmacokinetics and clinical applications. Pharmacotherapy. 1992; 12:16173.
Paradoxic Paradoxes To the Editors: Brown and colleagues (1) described a "policy makers' paradox" with respect to preventive health strategies and alluded to divergent recommendations made by the National Cholesterol Education Program in the United States and the Toronto Working Group on Cholesterol Policy in Canada. Although we thank Brown and colleagues for their interest in our work, their speculation about the reasons for our "different resolution" of the "policy makers' paradox" was unnecessary. If Brown and colleagues had read the primary sources rather than an editorial by Garber (2), they would have found discussion of the various issues in preventive policy making (3). They would also have found careful acknowledgment of the British epidemiologist, Geoffrey Rose, who outlined and named the "prevention paradox" a decade ago (4, 5). Rose's conceptualization for the case of cholesterol and coronary disease can be summarized as follows: Those persons with high serum levels are candidates for treatment in a clinical setting because they have a reasonable probability of benefit. The greatest proportion of incident coronary disease occurs in persons who are at comparatively low absolute risk in terms of cholesterol levels. Although they are not included in standard treatment trials, they are assumed to benefit from cholesterol lowering, given the graded relation between cholesterol and coronary events in observational studies. Hence, treating highrisk persons is epidemiologically insufficient, and treating the lower risk persons is clinically inefficient. A key to resolving the "prevention paradox" is to recognize the inherent difficulties in implementing clinical interventions directed at lower risk groups and to consider a role for public health strategies or community-wide interventions. The distinction between clinical prevention and public health approaches arises, as Rose put it, from appreciating the difference between "sick individuals and sick populations" (5). Our conclusions were therefore affected by analysis of the roles of clinical prevention compared with public health measures—a key preventive policy issue that Brown and colleagues do not address. It seems somewhat paradoxic that Rose's antecedent work on preventive policy paradoxes went uncited by Brown and colleagues, while our views were taken as an epiphenomenon of a similar paradox proposed by them (1). C. David Naylor, MD, DPhil John W. Frank, MD, MSc University of Toronto North York, Ontario M4N 3M5 References 1. Brown EY, Viscoli CM, Horwitz RI. Preventive health strategies and the policy makers' paradox. Ann Intern Med. 1992;116:593-7. 2. Garber AM. Where to draw the line against cholesterol. Ann Intern Med. 1989;111:625-7. 3. Toronto Working Group on Cholesterol Policy. Asymptomatic hypercholesterolemia: a clinical policy review. J Clin Epidemiol. 1990;43: 1021-22.
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4. Rose G. Strategy for prevention: lesson from cardiovascular disease. Br Med J. 1981;282:1847-51. 5. Rose G. Sick individuals and sick populations. Int J Epidemiol. 1985;14:32-8. In response: Our pleasure at Drs. Naylor and Frank's vigorous response to our recent article (1) is tempered by their apparent misunderstanding of the issues underlying our analysis. The policy makers' paradox occurs when evidence to support a strategy designed to prevent disease by lowering levels of a risk factor is obtained in persons with high levels of the risk factor, whereas persons with moderately elevated or normal levels of the risk factor account for most cases of the disease. Choosing this population made the study easier to do but may affect its relevance. Policy makers must try to resolve this paradox in deciding whether available evidence and the characteristics of their society support a particular strategy to prevent the disease and, if so, whether to apply interventions through individual or population-based strategies. It is to this issue that Geoffrey Rose applied the prevention paradox, when "a measure that brings large benefits to the community offers little to each participating individual (2). Although the policy makers' paradox describes a problem in interpreting and applying evidence for the effectiveness of interventions, the prevention paradox describes the potential inefficiencies of different strategies used to apply these interventions. Because the policy makers' paradox is concerned with efficiency and effectiveness of interventions, an intellectual precedent is found in the work of A. Cochrane (3). With all due respect to Rose, we chose to refer to the earlier work of Cochrane because efficiency and effectiveness are directly relevant to external validity and resolution of the policy makers' paradox. In contrast, the prevention paradox relates to the distinction between clinical and public health interventions. Drs. Naylor and Frank also concluded that our article is based on the reading of editorials rather than primary sources. In fact, our paper required the review of hundreds of primary sources (including those so prized by Drs. Naylor and Frank). As a courtesy to our readers, we did not reference those primary sources, which were neither fundamental to our discussion nor likely to be of direct use to readers. Eric Y. Brown, MD Catherine M. Viscoli, PhD Ralph I. Horwitz, MD Yale University School of Medicine New Haven, CT 06510-8056 References 1. Brown EY, Viscoli CM, Horwitz RI. Preventive health strategies and the policy makers' paradox. Ann Intern Med. 1992;116:593-7. 2. Rose G. Strategy of prevention: lessons from cardiovascular disease. Br Med J. 1981;282:1847-51. 3. Cochrane AL. Effectiveness and Efficiency. Abingdon: Burgess and Son; 1972.
Ovarian Insulin-like Growth Factors To the Editors: LeRoith and colleagues (1) could have added to their discussion of insulin-like growth factors (IGFs) in health and disease yet another organ in which the physiologic, pathophysiologic, and therapeutic importance of IGFs has been shown. Physiologically, ovaries produce various growth factors, including IGFs, that are important for normal follicular development (2). Ovaries also possess receptors for IGFs (3). Pathologically, IGF-I receptors are the likely mediators of insulin-induced hyperandrogenism, which is commonly observed in insulin-resistant patients (3). In addition to stimulating androgen production, hyperinsulinemia appears to upregulate ovarian IGF-I receptors, which further enhances this "alternate" pathway for insulin action (3). High levels of circulating insulin, acting, at least in part, through IGF-I receptors, also appear to contribute to abnormal ovarian growth and cyst formation observed in polycystic ovary syndrome (4). Finally, the therapeutic importance of IGFs in the ovary has been shown by successful use of growth hormone in certain
ovulation induction regimens (5). The effect of growth hormone on fertility in such cases is mediated, at least in part, by IGF-I. Leonid Poretsky, MD Cabrini Medical Center New York, NY 10010 References 1. LeRoith D, Clemmons D, Nissley P, Rechler M. Insulin-like growth factors in health and disease. Ann Intern Med. 1992;116:854-62. 2. Adashi EY, Resnick CE, D'Ercole AJ, Svoboda ME, Van Wykk JJ. Insulin-like growth factors as intraovarian regulators of granulosa cell growth and function. Endocr Rev. 1985;6:400-20. 3. Poretsky L. On the paradox of insulin-induced hyperandrogenism in insulin-resistant states. Endocr Rev. 1991;12:3-13. 4. Poretsky L, demons J, Bogovich K. Hyperinsulinemia and human chorionic gonadotrophin promote the growth of ovarian follicular cysts in rats. Metabolism. 1992;41:903-10. 5. Homburg R, West C, Torresani T, Jacobs HS. Cotreatment with human growth hormone and gonadotropins for induction of ovulation: a controlled clinical trial. Fertil Steril. 1992;53:254-60. In response: Dr. Poretsky's comments are quite appropriate. The reason for not including the ovary and a number of other excellent examples was space limitation. Derek LeRoith, MD, PhD National Institutes of Health Bethesda, MD 20892 Fish Oil Supplementation and Ulcerative Colitis To the Editors: I read with interest the article by Stenson and colleagues (1). The authors chose to use Max-EPA (R. P. Scherer, Clearwater, Florida), eicosapentaenoic acid, as their source of omega-3 unsaturated fatty acids. Because each capsule may contain 5 mg of cholesterol, giving patients 18 capsules per day would provide them with 90 mg of cholesterol each day. It would be interesting to know whether lipoprotein measurements were done before and after treatment with MaxEPA. The American Heart Association and the National Cholesterol Education Program have recommended that all persons reduce their cholesterol consumption from the current 400 to 450 mg/d to 300 mg/d. For patients with an elevated lowdensity lipoprotein (LDL)-cholesterol level, reducing dietary cholesterol intake to 200 mg per day may be necessary (2). Future trials of omega-3 fatty acid supplements in the treatment of ulcerative colitis should include fish oil capsules containing 0 mg of cholesterol per capsule. Examples of such products include the cholesterol-free variety of Max-EPA and Cardi-Omega 3 (Thomson Medical Company, New York, New York). David M. Gorson, MD University of Miami School of Medicine Aventura, FL 33180 References 1. Stenson WF, Cord D, Rodgers J, Burakoff R, DeSchryver-Kecskemeti K, Gramlich TL, et al. Dietary supplementation with Ash oil in ulcerative colitis. Ann Intern Med. 1992;116:609-14. 2. Carlton RA, Dwyer J, Finberg L, Flora J, Goodman DS, Grundy S, et al. National Cholesterol Education Program: report of the Expert Panel on Population Strategies for Blood Cholesterol Reduction: executive summary. Arch Intern Med. 1991;151:1071-84. To the Editors: Before assigning fish oil supplements a minor role in treatment of ulcerative colitis (1), a few points bear consideration. The double-blind, crossover study design, although elegant, imposes certain conditions. The disease studied should return to prestudy baseline before the crossover to the second treatment. To subtract placebo effect from active treatment, there must be no carry-over effect from the first treatment period. In the common relapsing and remitting form of ulcerative colitis, 4 months of successful treatment of active disease may well induce a sustained improvement through a 1-month washout and subsequently such a carry-over effect
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would underestimate the therapeutic effect of the first treatment. Aside from the nature of the disease itself, it is not unreasonable to expect a carry-over effect based on previous work using fish oil. In several studies of fish or fish oil supplements, a slowly evolving therapeutic effect has been reported, which persisted for several weeks after treatment ended, and which correlated poorly with changes in cellular fatty acid composition and eicosanoid profiles (2, 3). As Stenson and colleagues (1) acknowledge, maintaining blinding is difficult in trials using fish oil because of its characteristic odor and taste. A recent study reported that 85% of the participants randomized to fish oil capsules correctly identified their supplement. In the same study, 14% of the group randomized to no treatment self supplemented with fish or fish oil (4). Because most patients with chronic inflammatory disease are aware of the current interest in fish oil, self supplementation may be common and may obscure any differences between treatment periods. The baseline intake of n-6 polyunsaturated fatty acids and other fats in patients' diets before commencing fish oil supplementation may be important. Animal trials suggest that the effect of n-3 fatty acid supplementation is greatly influenced by total fat content and the proportion of n-6 fatty acids in the diet. If we postulate that the efficacy of fish oil reflects the capacity of the constituent n-3 fatty acids to compete with arachidonic acid in the eicosanoid pathway, combining fish oil with an overall reduction of fat intake (especially n-6 fatty acids) may favor the production of noninflammatory eicosanoid analogues. Finally, fish oil supplements contain, in addition to eicosapentaenoic acid (EPA), significant quantities of docosahexaenoic acid, a longer chain n-3 fatty acid with poorly understood biologic effects, which are distinct from those of EPA. MaxEPA also contains vitamins A and E, which may be therapeutic in protecting against free radical damage, cited as a mechanism of tissue injury in both ulcerative colitis and radiation enteritis. Although fish oil will never supplant sulfasalazine and steroids in the management of ulcerative colitis, further study is needed to define the circumstances where it will be most beneficial. Anne Tobin, MB Fred Hutchinson Cancer Research Center Seattle, WA 98104 References 1. Stenson WF, Cort D, Rodgers J, Burakoff R, DeSchryver-Kecskemeti K, Gramlich TL, et al. Dietary supplementation with fish oil in ulcerative colitis. Ann Intern Med. 1992;116:609-14. 2. Thorngren M, Shan S, Born GV. Delay in primary haemostasis produced by a fish diet without change in local thromboxane A2. Br J Haematol. 1984;58:567-78. 3. Kremer JM, Jubiz W, Michalek A, et al. Fish oil fatty acid supplementation in active rheumatoid arthritis, a double-blind, controlled, crossover study. Ann Intern Med. 1987;106:497-503. 4. Olsen SF, Sorensen JD, Secher NJ, et al. Randomised controlled trial of effect of fish-oil supplementation on pregnancy duration. Lancet. 1992;339:1003-7.
In response: We thank Drs. Gorson and Tobin for their comments. Dr. Gorson correctly notes that, in the Max-EPA capsules, our patients received approximately 90 mg of cholesterol per day from the fish oil supplement (1). Max-EPA capsules were the most convenient and available form of fish oil. More recently, as Dr. Gorson notes, cholesterol-free fish oil supplements have become available and seem to be reasonable substitutes. We did not measure lipoproteins in our study. Dr. Tobin questions our crossover study design. We had a 1-month placebo washout period between the two treatment arms. The number of patients in this study was small enough and the clinical course in ulcerative colitis was variable enough that it is not possible to say whether a beneficial effect of the initial fish oil treatment was carried over beyond the 1-month washout. In possible support of this carry-over effect, the patients randomized to receive fish oil supplementation first required a lower average dose of prednisone at the beginning 536
of the placebo period than either group at the beginning of the study. As Dr. Tobin points out, any carry-over effect would diminish the therapeutic effect seen with fish oil and would raise the possibility that fish oil supplementation may be even more effective than we demonstrated. We did a careful history to make sure that the baseline intake of n-3 polyunsaturated fatty acids was low and instructed patients to maintain their baseline diet during the entire 9 months of the study. Finally, Dr. Tobin raises the possibility that other components of fish oil may have contributed to its therapeutic effects. We are confident that the beneficial effects were caused by a reduction in leukotriene B4 production brought on by competition of eicosapentaenoic acid for 5-lipoxygenase. Four weeks of treatment with a selective 5-lipoxygenase inhibitor, zileuton, induced similar degrees of reduction in dialysate leukotriene B4 levels and similar levels of clinical and histologic improvement as fish oil supplementation (2). The amount of vitamin E in Max-EPA capsules is fairly modest, and it is unlikely that enough vitamin E would reach the colon to have significant effects as a free radical scavenger. William F. Stenson, MD Washington University Medical Center St. Louis, MO 63178 References 1. Stenson WF, Cort D, Rodgers J, Burakoff R, DeSchryver-Kecskemeti K, Gramlich TL, et al. Dietary supplementation with fish oil in ulcerative colitis. Ann Intern Med. 1992;116:609-14. 2. Stenson WF, Lauritsen K, Laursen LS, Rask-Madsen J, Jacobsen O, Naesdal J, et al. A clinical trial of zileuton, a specific inhibitor of 5lipoxygenase, in ulcerative colitis. Gastroenterology. 1991; 100:A253.
Overtreating Hypertension To the Editors: Kaplan (1) failed to address in his recent review of the overtreatment of hypertension whether merely treating rather than controlling hypertension is adequate for the prevention of morbid events. In the Systolic Hypertension in the Elderly Program (SHEP) (2) and the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension) study (3), a relatively fixed dosage schedule was used and a number of elderly patients who were treated did not reach their target blood pressure level (28% in the case of the SHEP study). The authors did not do subgroup analysis to determine whether patients who did not reach their blood pressure goal had more end point events. In short, should we merely follow the protocol of the studies in treating systolic and diastolic hypertension in the elderly rather than increase drug dose if the target blood pressure goal is not met? William Zinn, MD Harvard Medical School Cambridge, MA 02139 References 1. Kaplan NM. The appropriate goals of antihypertensive therapy: neither too much nor too little. Ann Intern Med. 1992;116:686-90. 2. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: Final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA. 1991;265:3255-64. 3. Dahlof B, Lindholm LH, Hansson L, Schersten B, Ekbom T, Wester PO. Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension). Lancet. 1991;23;338: 1281-5.
In response: Dr. Zinn makes a valid point: Antihypertensive treatment that does not lower the blood pressure will probably not benefit the patient. This point relates to the discussion of resistance to therapy as a mechanism for undertreatment of a number of patients. Yet another issue, this one involved in overtreatments, was not addressed in my review (1). The recommended drug dosages are derived from clinical studies, wherein a sizable number of patients almost certainly were noncompliant with their assigned regimen. Neither pill counts nor measurements of
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drug levels can accurately assess long-term compliance (2). Despite close surveillance, patients in these trials may not take from 20% to 50% of their prescribed doses (3). Thus, when phase 3 preapproval study data are examined, the estimated average dose providing the desired 10 to 15 mm Hg fall in blood pressure may be 20% to 50% higher than the actual optimal dose. Of course, patients given the recommended doses will also often be noncompliant. If the patient is fully compliant, however, and takes 100% of a dose, up to 2-fold more than needed to provide the optimal response, the potential for overtreatment is obvious. The best advice for practitioners remains as follows: Start low, go slow, but push on until the desired effect (or a bothersome side effect) occurs. Norman M. Kaplan, MD Southwestern Medical Center at Dallas Dallas, TX 75235-8899 References 1. Kaplan NM. The appropriate goals of antihypertensive therapy: neither too much nor too little. Ann Intern Med. 1992;116:686-90. 2. Rudd P, Byyny RL, Zachary V, et al. Pill count measures of compliance in a drug trial: variability and suitability. Am J Hypertens. 1988;1:309-12. 3. Cramer JA, Scheyer RD, Mattson RH. Compliance declines between visits. Arch Intern Med. 1990;150:1509-10.
Arthritis after Bacillus Calmette-Guerin Therapy To the Editors: A 49-year-old male had transurethral resection and intravesical and intramuscular bacillus Calmette-Guerin (BCG) therapy in 1988 for transitional cell carcinoma of the bladder. From October to December 1991, he again received intravesicular BCG for tumor recurrence. Within 2 weeks of the last instillation, he developed metatarsophalangeal joint and hip pain. Physical examination showed dactylitis of the left fourth toe, pain with motion of his right hip, and stress of both sacroiliac joints. Erythrocyte sedimentation rate was 61 mm/h, and rheumatoid factor was absent. Indomethacin, 50 mg three times a day, isoniazid, 300 mg/d, and rifampin, 600 mg/d, were given for 2 weeks, and the arthritis resolved in 4 weeks. The iliac margin of the right sacroiliac joint was indistinct on subsequent radiograms. Human leukocyte antigen (HLA) typing included A(ll,32), B(27,55), and DR(1,6). Intravesical BCG is currently the most effective treatment for superficial transitional cell carcinoma of the bladder. Early studies reported arthralgias and polyarthritis in up to 6% of treated patients (1). Previously reported patients who developed polyarthritis after BCG therapy have had HLA-DR4 (2, 3), suggesting these cases may have been the human equivalent of the animal adjuvant arthritis model, a major histocompatibility complex (MHC)-II-restricted response where CD4+ T lymphocytes recognize segments of mycobacterial 65 kDa heat-shock protein (4). Similar reactivity to this 65 kDa heatshock protein has been shown for lymphocytes from synovial fluid of patients with recent onset rheumatoid arthritis (5). We believe this patient to be the first reported definite case of spondyloarthropathy after BCG therapy. Reactive arthritis occurs predominately in people bearing HLA-B27 and is felt to be caused by a class I MHC-restricted response. Recent work has investigated the endogenous protein fragments contained in the cleft of the class I MHC receptor as potential epitopes for immune responses. In the normal human host, HLA-B27 is now known to express nonamer self-peptides that are derived from abundant cytosolic and nuclear proteins, including fragments from heat-shock protein 83 (6) for which sequence homology between prokaryotic heat-shock protein 83 and human heat-shock protein 83 has been reported (7). In this particular patient, an immune response initiated by the intracellular organism BCG may have been perpetuated by cross-reactivity with host proteins that were being presented by the class I MHC receptor. Differences in processing and presentation of antigens by available MHC class I or II molecules may determine the
nature of arthritis affecting susceptible hosts exposed to potential immunostimulatory pathogens. David W. Puett, MD Howard A. Fuchs, MD Vanderbilt University School of Medicine Nashville, TN 37232-2681 References 1. Orihuela E, Herr HW, Pinsky CM, Whitmore WF. Toxicity of intravesical BCG and its management in patients with superficial bladder tumors. Cancer. 1987;60:326-33. 2. Hughes RA, Allard SA, Maini RN. Arthritis associated with adjuvant mycobacterial treatment for carcinoma of the bladder. Ann Rheum Dis. 1989;48:432-4. 3. Ochsenkuhn T, Weber MM, Caselmann WH. Arthritis after Mycobacterium bovis immunotherapy for bladder cancer. Ann Intern Med. 1990; 112:882. 4. Hogervorst EJ, Boog CJ, Wagenaar JP, Wauben MH, van der Zee R, van Eden W. T cell reactivity to an epitope of the mycobacterial 65 kDa heat-shock protein (hsp 65) corresponds with arthritis susceptibility in rats and is regulated by hsp 65-specific cellular responses. Eur J Immunol. 1991;21:1289-96. 5. Res PC, Schaar CG, Breed veld FC, van Eden W, van Embden JD, Cohen IR, et al. Synovial fluid T cell reactivity against 65 kD heat shock protein of mycobacteria in early chronic arthritis. Lancet. 1988;2:478-80. 6. Jardetzky TS, Lane WS, Robinson RA, Madden DR, Wiley DC. Identification of self peptides bound to purified HLA-B27. Nature. 1991;353:321-5. 7. Bardwell JC, Craig EA. Eukaryotic Mr 83,000 heat shock protein has a homologue in Escherichia coli. Proc Natl Acad Sci USA. 1987;84: 5177-81.
Common Prescribing Errors To the Editors: From 1 April 1991 to 31 March 1992, we detected 118 instances of the prescribing of an inappropriate dosage form of a drug available as both a "standard" and a "controlled" release product. This number compares with only 19 such errors in 1987 (1). All errors were averted before drug dispensing from the pharmacy. The drugs involved were diltiazem (32 errors), nifedipine (27), verapamil (23), theophylline (14), propranolol (5), morphine (4), procainamide (4), isosorbide (3), albuterol (3), divalproex (2), and disopyramide (1). The most common type of error was prescribing the standard-release dosage form (or not specifying the controlled-release form) at a frequency or dose inappropriate for the standard-release form (for example, theophylline, 300 mg every 12 hours, instead of TheoDur [Key Pharmaceuticals, Kenilworth, New Jersey] or Slo-bid [Rorer Pharmaceuticals, Fort Washington, Pennsylvania], or Procardia, 90 mg every morning instead of Procardia XL [Pfizer Inc., New York, New York]). Other errors included prescribing the controlled-release form to be given per tube (for example, Calan SR [Searle Laboratories, Chicago, Illinois], 240 mg every 24 hours per tube, or TheoDur, 300 mg every 12 hours per tube), which required crushing of the dosage form and thereby destroyed the controlled-release mechanisms, and prescribing sustained-release forms when they were not appropriate (for example, sustained-release morphine, MS Contin, [Purdue Frederick Company, Norwalk, Connecticut] on an as-needed basis for pain, or Procardia XL, 30 mg given sublingually, as needed for blood pressure control). One advantage of controlled dosage forms is the avoidance of dose-to-dose variations in drug concentrations, which reduces post-dose "peak" side effects and inadequate therapeutic effects at the end of the dosing interval. Another advantage is improved patient convenience and compliance. Most agents became available after 1987 and were originally marketed as standard-release products, then as controlled-release products such as Procardia XL, Cardizem SR (Marion Laboratories, Kansas City, Missouri), and Calan SR. The technique of adding a suffix to an established brand name is understandable from a marketing standpoint but appears to contribute to the increase in errors (2). Pharmaceutical companies should con-
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sider using brand names that more clearly differentiate controlled- from standard-release dosage forms.
Correction: Hepatitis B Virus and Bone Marrow Transplantation
Timothy S. Lesar, PharmD Albany Medical Center Hospital Albany, NY 12208
A recent letter (1) appearing in Annals incorrectly stated that hepatitis B infection had developed in the reported patient after bone marrow transplantation. The occurrence of the virus was before transplantation. Also, the correct author address is: University of Hong Kong, Hong Kong.
References 1. Lesar TS, Briceland LL, Delcoure K, Crilly-Parmalee J, Masta-Gornick V, Pohl H. Medication prescribing errors in a teaching hospital. JAMA. 1990;263:2329-34. 2. Vitillo J, Lesar T. Preventing medication prescribing errors. DICP Ann Pharmacother. 1991;25:1388-94.
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Reference 1. Lok AS, Liang RH, Chung HT. Recovery from chronic hepatitis B. Ann Intern Med. 1992; 116:957.
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The Editors welcome submissions for possible publication in the Letters section. Authors of letters should: • Include no more than 400 words of text, three authors, and five references • Type with double-spacing • Send three copies of the letter and a transfer-of copyright form (see Table of Contents for location) signed by all authors • Provide a self-addressed envelope if they want to be notified that the letter was received Letters commenting on an Annals article will be considered if they are received within 6 weeks of the time the article was published. Only some of the letters received can be published. Published letters are edited and may be shortened; tables and figures are included only selectively. Authors will be notified that the letter has been received. If the letter is selected for publication, the author will be notified about 3 weeks before the publication date. Unpublished letters cannot be returned.
New Macrolide Antibiotics To the Editors: Recently, Biaxin (Abbott Laboratories, North Chicago, Illinois), a brand of clarithromycin, has been heavily promoted for common respiratory infections because it covers Haemophilus influenzae as well as Streptococcus pneumoniae and Mycoplasma pneumoniae. Abbott's efficacy claim is supported almost entirely by data either on file with the company or published in company-sponsored symposia. Unfortunately, Dr. Neu (1), in his editorial on the new macrolides, never evaluates their efficacy relative to currently available (and much cheaper) treatments for H. influenzae. Instead, he limits his discussion to a brief comparison of azithromycin and clarithromycin with erythromycin, an agent known to be unreliable against H. influenzae. In the editorial (1), the new macrolides appear superior to erythromycin against H. influenzae, but important data to the contrary are missing. For example, in vitro, clarithromycin is only half as effective as erythromycin against H. influenzae (2). Although azithromycin may be four to eight times more effective than erythromycin against H. influenzae, in vivo, azithromycin attains high intracellular but low serum concentrations. Thus, it may not be effective against an organism like H. influenzae that acts at extracellular sites. Dr. Neu concludes that the new macrolides are "a suitable alternative to many of the currently available therapies for common outpatient respiratory infections." He does not mention studies which have shown clarithromycin to be less effective than amoxicillin in the treatment of H. influenzae sinusitis (3) or than ampicillin in the treatment of H. influenzae bronchitis (4). He does not discuss the activity of the new macrolides (if any) in pneumonia caused by H. influenzae. The example of ciprofloxacin suggests that patients can be endangered by an advertising campaign that contains inflated claims of antibiotic efficacy (5). In omitting critical questions about the effectiveness of the new macrolides, Dr. Neu misses an important opportunity to prevent a repetition of this problem. Jaime B. Friedman, MD Sand Point Internists Seattle, WA 98105
References 1. Neu HC. New macrolide antibiotics: azithromycin and clarithromycin [Editorial]. Ann Intern Med. 1992;116:517-9. 2. Neu HC. The development of macrolides: clarithromycin in perspective. J Antimicrob Chemother. 1991;27(Suppl A): 1-9. 3. Karma P, Pukander J, Penttila M, Ylikoski J, Savolainen S, Olen L, et al. The comparative efficacy and safety of clarithromycin and amoxycillin in the treatment of outpatients with acute maxillary sinusitis. J Antimicrob Chemother. 1991 ;27(Suppl A):83-90. 4. Bachand RT Jr. Comparative study of clarithromycin and ampicillin in the treatment of patients with acute bacterial exacerbations of chronic bronchitis. J Antimicrob Chemother. 1991;27(Suppl A):91100. 5. Frieden TR, Mangi RJ. Inappropriate use of oral Ciprofloxacin. JAMA. 1990;264:1438-40.
To the Editors: Clarithromycin has been widely promoted for community-acquired pneumonia. Some respiratory pathogens such as Streptococcus pneumoniae, however, may be only moderately sensitive. Few patients with life-threatening Haemophilus influenzae or Moraxella catarrhalis pneumonia have been treated with the drug, and its success in patients with bacteremic pneumonia is not established. Resistance to these respiratory pathogens may develop over time. For all these reasons, rigorous susceptibility monitoring is of utmost importance, as noted by Dr. Neu (1). Once an antibiotic is marketed, easy access to the compound for susceptibility testing is mandatory. This issue may represent another example of the physician's patient advocacy role in relations with the pharmaceutical industry. Steven L. Berk, MD East Tennessee State University Johnson City, TN 37614-0622 Reference 1. Neu HC. New macrolide antibiotics: azithromycin and clarithromycin [Editorial]. Ann Intern Med. 1992;116:517-9.
To the Editors: The new macrolide antibiotics, azithromycin and clarithromycin, may be beneficial in the control of cryptosporidiosis, one cause of severe intractable diarrhea in immunocompromised patients such as those with AIDS (1). We recently saw a 22-year-old human immunodeficiency virus (HIV)-l seropositive patient with hemophilia, who in October 1991 was diagnosed by modified acid-fast stain of stool and duodenal aspirate as having cryptosporidiosis. At that time he was having 15 to 20 watery bowel movements a day. He was treated with octreotide, up to 400 fig, given subcutaneously every 8 hours, paromomycin, 500 mg, given orally three times a day, and paregoric. The frequency of bowel movements decreased to approximately 4 to 6 per day, but his medications were eventually stopped because of nausea. In February 1992, he was admitted to the hospital with the symptoms of shortness of breath and fever, at which time he was having 5 to 10 loose stools per day. A modified acid-fast stain of the stool was still positive for Cryptosporidium oocysts, and octreotide in titrated doses from 50 fig to 500 fig, given subcutaneously every 8 hours for 1 week, and paromomycin, 500 mg, given orally three times a day, were reinstituted. Clarithromycin, 1000 mg, given orally every 12 hours, was also started. Within 10 days, the diarrhea was totally resolved. The patient subsequently died from respiratory failure; postmortem examination showed no evidence of cryptosporidiosis. No satisfactory therapy for cryptosporidiosis currently exists (1). Clarithromycin and azithromycin may be effective in treat-
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ing enteric cryptosporidiosis in immunosuppressed rodents (2, 3). These agents appear to be superior to spiramycin, another macrolide antibiotic (1, 2). Our patient had complete improvement in the frequency of loose stools when treated with octreotide, paromomycin, and clarithromycin, whereas he previously had only partial improvement when treated with the first two agents. The new macrolides warrant further study in the management of cryptosporidiosis. Steven J. Sperber, MD Nancy Gornish, MD University of Medicine & Dentistry of New Jersey New Brunswick, NJ 08903-0019 References 1. Current WL, Garcia LS. Cryptosporidiosis. Clin Microbiol Rev. 1991;4:325-58. 2. Rehg JE. Activity of azithromycin against Cryptosporidia in immunosuppressed rats. J Infect Dis. 1991;163:1293-6. 3. Cama VA, Marshall MM, Sterling CR. Evaluation of clarithromycin for the treatment of enteric cryptosporidiosis. Presented at the First International Conference on the Macrolides, Azalides, and Streptogramins. Santa Fe, New Mexico: January 1992. In response: Dr. Friedman addresses an important point. I was asked to address primarily the possible new uses of these interesting agents with only slight mention of other uses (1). We have shown that clarithromycin, 500 mg twice daily, yields protective serum bactericidal activity against H. influenzae (2). In addition, researchers at Abbott Laboratories (3) and in our own group (4) have shown that, at serum levels comparable to those in humans, H. influenzae is eradicated from the ears of infected guinea pigs. Azithromycin has very high tissue and phagocytic concentrations and lower serum levels, but the tissue levels in the bronchi, where the H. influenzae organisms are located, and in the alveoli are well above that needed to inhibit the organisms (5). Furthermore, animal models of ear and lung infections with H. influenzae have shown azithromycin to be effective. I did not address the problem of H. influenzae pneumonia, which, I believe, is uncommon, and when it does occur is caused by type b H. influenzae. There is inadequate data on macrolides as treatment of well-verified H. influenzae pneumonia. Dr. Berk's comment that Streptococcus pneumoniae are only moderately susceptible is incorrect. In the United States, 5. pneumoniae are extremely susceptible, and in the serum bactericidal studies, I had a serum bactericidal titer against S. pneumoniae of greater than 1:32 that was measured 12 hours after administration of 500 mg of clarithromycin. Data on file at Pfizer indicate the efficacy of azithromycin for treatment of pneumococcal pneumonia (S. Hopkins. Personal communication). Readers should not consider using an oral macrolide once or twice dairy to treat life-threatening H. influenzae pneumonia. Finally, I would be cautious in accepting that either clarithromycin or azithromycin is highly effective in treating cryptosporidiosis, as indicated by Drs. Sperber and Gornish. I recall the claims for spiramycin, which could not be substantiated in double-blind trials. It is also important when using azithromycin to use the lactose-free preparation and a dose of 1 g daily. This preparation can be obtained on a compassionate basis from Dr. Deborah Wilson at Pfizer, Inc. A recent review of the published data on the use of macrolides for gastrointestinal infections discouraged me about their efficacy. I await the results of trials of clarithromycin for Helicobacter pylori gastritis and of azithromycin for typhoid. I believe that both of these new macrolides are useful agents. These antibiotics are appropriate to use in therapy for selected respiratory infections. My editorial clearly emphasized cost aspects, which must be considered in treating all nonlifethreatening infections. Harold C. Neu, MD Columbia University New York, NY 10032 534
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References 1. Neu HC. New macrolide antibiotics:azithromycin and clarithromycin [Editorial]. Ann Intern Med. 1992;116:517-9. 2. Gu JW, Scully BE, Neu HC. Bactericidal activity of clarithromycin and its 14-hydroxy metabolite against Haemophilus influenzae and streptococcal pathogens. J Clin Pharmacol. 1991;31:1146-50. 3. Hardy DJ, Swanson RN, Rode RA, Marsh K, Shipkowitz NL, Clement JJ. Enhancement of the in vitro and in vivo activities of clarithromycin against Haemophilus influenzae by 14-hydroxy-clarithromycin, its major metabolite in humans. Antimicrob Agents Chemother. 1992; 34:1407-13. 4. Chin NX, Yan SD, Gu JW, Neu HC. Evaluation of clarithromycin and its 14-hydroxy metabolite in treatment of Haemophilus influenzae otitis media in a gerbil model. Abstract 190. 17th International Congress on Chemotherapy. Berlin: 23-28 June 1991. 5. Drew RH, Gallis HA. Azithromycin, spectrum of activity, pharmacokinetics and clinical applications. Pharmacotherapy. 1992; 12:16173.
Paradoxic Paradoxes To the Editors: Brown and colleagues (1) described a "policy makers' paradox" with respect to preventive health strategies and alluded to divergent recommendations made by the National Cholesterol Education Program in the United States and the Toronto Working Group on Cholesterol Policy in Canada. Although we thank Brown and colleagues for their interest in our work, their speculation about the reasons for our "different resolution" of the "policy makers' paradox" was unnecessary. If Brown and colleagues had read the primary sources rather than an editorial by Garber (2), they would have found discussion of the various issues in preventive policy making (3). They would also have found careful acknowledgment of the British epidemiologist, Geoffrey Rose, who outlined and named the "prevention paradox" a decade ago (4, 5). Rose's conceptualization for the case of cholesterol and coronary disease can be summarized as follows: Those persons with high serum levels are candidates for treatment in a clinical setting because they have a reasonable probability of benefit. The greatest proportion of incident coronary disease occurs in persons who are at comparatively low absolute risk in terms of cholesterol levels. Although they are not included in standard treatment trials, they are assumed to benefit from cholesterol lowering, given the graded relation between cholesterol and coronary events in observational studies. Hence, treating highrisk persons is epidemiologically insufficient, and treating the lower risk persons is clinically inefficient. A key to resolving the "prevention paradox" is to recognize the inherent difficulties in implementing clinical interventions directed at lower risk groups and to consider a role for public health strategies or community-wide interventions. The distinction between clinical prevention and public health approaches arises, as Rose put it, from appreciating the difference between "sick individuals and sick populations" (5). Our conclusions were therefore affected by analysis of the roles of clinical prevention compared with public health measures—a key preventive policy issue that Brown and colleagues do not address. It seems somewhat paradoxic that Rose's antecedent work on preventive policy paradoxes went uncited by Brown and colleagues, while our views were taken as an epiphenomenon of a similar paradox proposed by them (1). C. David Naylor, MD, DPhil John W. Frank, MD, MSc University of Toronto North York, Ontario M4N 3M5 References 1. Brown EY, Viscoli CM, Horwitz RI. Preventive health strategies and the policy makers' paradox. Ann Intern Med. 1992;116:593-7. 2. Garber AM. Where to draw the line against cholesterol. Ann Intern Med. 1989;111:625-7. 3. Toronto Working Group on Cholesterol Policy. Asymptomatic hypercholesterolemia: a clinical policy review. J Clin Epidemiol. 1990;43: 1021-22.
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4. Rose G. Strategy for prevention: lesson from cardiovascular disease. Br Med J. 1981;282:1847-51. 5. Rose G. Sick individuals and sick populations. Int J Epidemiol. 1985;14:32-8. In response: Our pleasure at Drs. Naylor and Frank's vigorous response to our recent article (1) is tempered by their apparent misunderstanding of the issues underlying our analysis. The policy makers' paradox occurs when evidence to support a strategy designed to prevent disease by lowering levels of a risk factor is obtained in persons with high levels of the risk factor, whereas persons with moderately elevated or normal levels of the risk factor account for most cases of the disease. Choosing this population made the study easier to do but may affect its relevance. Policy makers must try to resolve this paradox in deciding whether available evidence and the characteristics of their society support a particular strategy to prevent the disease and, if so, whether to apply interventions through individual or population-based strategies. It is to this issue that Geoffrey Rose applied the prevention paradox, when "a measure that brings large benefits to the community offers little to each participating individual (2). Although the policy makers' paradox describes a problem in interpreting and applying evidence for the effectiveness of interventions, the prevention paradox describes the potential inefficiencies of different strategies used to apply these interventions. Because the policy makers' paradox is concerned with efficiency and effectiveness of interventions, an intellectual precedent is found in the work of A. Cochrane (3). With all due respect to Rose, we chose to refer to the earlier work of Cochrane because efficiency and effectiveness are directly relevant to external validity and resolution of the policy makers' paradox. In contrast, the prevention paradox relates to the distinction between clinical and public health interventions. Drs. Naylor and Frank also concluded that our article is based on the reading of editorials rather than primary sources. In fact, our paper required the review of hundreds of primary sources (including those so prized by Drs. Naylor and Frank). As a courtesy to our readers, we did not reference those primary sources, which were neither fundamental to our discussion nor likely to be of direct use to readers. Eric Y. Brown, MD Catherine M. Viscoli, PhD Ralph I. Horwitz, MD Yale University School of Medicine New Haven, CT 06510-8056 References 1. Brown EY, Viscoli CM, Horwitz RI. Preventive health strategies and the policy makers' paradox. Ann Intern Med. 1992;116:593-7. 2. Rose G. Strategy of prevention: lessons from cardiovascular disease. Br Med J. 1981;282:1847-51. 3. Cochrane AL. Effectiveness and Efficiency. Abingdon: Burgess and Son; 1972.
Ovarian Insulin-like Growth Factors To the Editors: LeRoith and colleagues (1) could have added to their discussion of insulin-like growth factors (IGFs) in health and disease yet another organ in which the physiologic, pathophysiologic, and therapeutic importance of IGFs has been shown. Physiologically, ovaries produce various growth factors, including IGFs, that are important for normal follicular development (2). Ovaries also possess receptors for IGFs (3). Pathologically, IGF-I receptors are the likely mediators of insulin-induced hyperandrogenism, which is commonly observed in insulin-resistant patients (3). In addition to stimulating androgen production, hyperinsulinemia appears to upregulate ovarian IGF-I receptors, which further enhances this "alternate" pathway for insulin action (3). High levels of circulating insulin, acting, at least in part, through IGF-I receptors, also appear to contribute to abnormal ovarian growth and cyst formation observed in polycystic ovary syndrome (4). Finally, the therapeutic importance of IGFs in the ovary has been shown by successful use of growth hormone in certain
ovulation induction regimens (5). The effect of growth hormone on fertility in such cases is mediated, at least in part, by IGF-I. Leonid Poretsky, MD Cabrini Medical Center New York, NY 10010 References 1. LeRoith D, Clemmons D, Nissley P, Rechler M. Insulin-like growth factors in health and disease. Ann Intern Med. 1992;116:854-62. 2. Adashi EY, Resnick CE, D'Ercole AJ, Svoboda ME, Van Wykk JJ. Insulin-like growth factors as intraovarian regulators of granulosa cell growth and function. Endocr Rev. 1985;6:400-20. 3. Poretsky L. On the paradox of insulin-induced hyperandrogenism in insulin-resistant states. Endocr Rev. 1991;12:3-13. 4. Poretsky L, demons J, Bogovich K. Hyperinsulinemia and human chorionic gonadotrophin promote the growth of ovarian follicular cysts in rats. Metabolism. 1992;41:903-10. 5. Homburg R, West C, Torresani T, Jacobs HS. Cotreatment with human growth hormone and gonadotropins for induction of ovulation: a controlled clinical trial. Fertil Steril. 1992;53:254-60. In response: Dr. Poretsky's comments are quite appropriate. The reason for not including the ovary and a number of other excellent examples was space limitation. Derek LeRoith, MD, PhD National Institutes of Health Bethesda, MD 20892 Fish Oil Supplementation and Ulcerative Colitis To the Editors: I read with interest the article by Stenson and colleagues (1). The authors chose to use Max-EPA (R. P. Scherer, Clearwater, Florida), eicosapentaenoic acid, as their source of omega-3 unsaturated fatty acids. Because each capsule may contain 5 mg of cholesterol, giving patients 18 capsules per day would provide them with 90 mg of cholesterol each day. It would be interesting to know whether lipoprotein measurements were done before and after treatment with MaxEPA. The American Heart Association and the National Cholesterol Education Program have recommended that all persons reduce their cholesterol consumption from the current 400 to 450 mg/d to 300 mg/d. For patients with an elevated lowdensity lipoprotein (LDL)-cholesterol level, reducing dietary cholesterol intake to 200 mg per day may be necessary (2). Future trials of omega-3 fatty acid supplements in the treatment of ulcerative colitis should include fish oil capsules containing 0 mg of cholesterol per capsule. Examples of such products include the cholesterol-free variety of Max-EPA and Cardi-Omega 3 (Thomson Medical Company, New York, New York). David M. Gorson, MD University of Miami School of Medicine Aventura, FL 33180 References 1. Stenson WF, Cord D, Rodgers J, Burakoff R, DeSchryver-Kecskemeti K, Gramlich TL, et al. Dietary supplementation with Ash oil in ulcerative colitis. Ann Intern Med. 1992;116:609-14. 2. Carlton RA, Dwyer J, Finberg L, Flora J, Goodman DS, Grundy S, et al. National Cholesterol Education Program: report of the Expert Panel on Population Strategies for Blood Cholesterol Reduction: executive summary. Arch Intern Med. 1991;151:1071-84. To the Editors: Before assigning fish oil supplements a minor role in treatment of ulcerative colitis (1), a few points bear consideration. The double-blind, crossover study design, although elegant, imposes certain conditions. The disease studied should return to prestudy baseline before the crossover to the second treatment. To subtract placebo effect from active treatment, there must be no carry-over effect from the first treatment period. In the common relapsing and remitting form of ulcerative colitis, 4 months of successful treatment of active disease may well induce a sustained improvement through a 1-month washout and subsequently such a carry-over effect
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would underestimate the therapeutic effect of the first treatment. Aside from the nature of the disease itself, it is not unreasonable to expect a carry-over effect based on previous work using fish oil. In several studies of fish or fish oil supplements, a slowly evolving therapeutic effect has been reported, which persisted for several weeks after treatment ended, and which correlated poorly with changes in cellular fatty acid composition and eicosanoid profiles (2, 3). As Stenson and colleagues (1) acknowledge, maintaining blinding is difficult in trials using fish oil because of its characteristic odor and taste. A recent study reported that 85% of the participants randomized to fish oil capsules correctly identified their supplement. In the same study, 14% of the group randomized to no treatment self supplemented with fish or fish oil (4). Because most patients with chronic inflammatory disease are aware of the current interest in fish oil, self supplementation may be common and may obscure any differences between treatment periods. The baseline intake of n-6 polyunsaturated fatty acids and other fats in patients' diets before commencing fish oil supplementation may be important. Animal trials suggest that the effect of n-3 fatty acid supplementation is greatly influenced by total fat content and the proportion of n-6 fatty acids in the diet. If we postulate that the efficacy of fish oil reflects the capacity of the constituent n-3 fatty acids to compete with arachidonic acid in the eicosanoid pathway, combining fish oil with an overall reduction of fat intake (especially n-6 fatty acids) may favor the production of noninflammatory eicosanoid analogues. Finally, fish oil supplements contain, in addition to eicosapentaenoic acid (EPA), significant quantities of docosahexaenoic acid, a longer chain n-3 fatty acid with poorly understood biologic effects, which are distinct from those of EPA. MaxEPA also contains vitamins A and E, which may be therapeutic in protecting against free radical damage, cited as a mechanism of tissue injury in both ulcerative colitis and radiation enteritis. Although fish oil will never supplant sulfasalazine and steroids in the management of ulcerative colitis, further study is needed to define the circumstances where it will be most beneficial. Anne Tobin, MB Fred Hutchinson Cancer Research Center Seattle, WA 98104 References 1. Stenson WF, Cort D, Rodgers J, Burakoff R, DeSchryver-Kecskemeti K, Gramlich TL, et al. Dietary supplementation with fish oil in ulcerative colitis. Ann Intern Med. 1992;116:609-14. 2. Thorngren M, Shan S, Born GV. Delay in primary haemostasis produced by a fish diet without change in local thromboxane A2. Br J Haematol. 1984;58:567-78. 3. Kremer JM, Jubiz W, Michalek A, et al. Fish oil fatty acid supplementation in active rheumatoid arthritis, a double-blind, controlled, crossover study. Ann Intern Med. 1987;106:497-503. 4. Olsen SF, Sorensen JD, Secher NJ, et al. Randomised controlled trial of effect of fish-oil supplementation on pregnancy duration. Lancet. 1992;339:1003-7.
In response: We thank Drs. Gorson and Tobin for their comments. Dr. Gorson correctly notes that, in the Max-EPA capsules, our patients received approximately 90 mg of cholesterol per day from the fish oil supplement (1). Max-EPA capsules were the most convenient and available form of fish oil. More recently, as Dr. Gorson notes, cholesterol-free fish oil supplements have become available and seem to be reasonable substitutes. We did not measure lipoproteins in our study. Dr. Tobin questions our crossover study design. We had a 1-month placebo washout period between the two treatment arms. The number of patients in this study was small enough and the clinical course in ulcerative colitis was variable enough that it is not possible to say whether a beneficial effect of the initial fish oil treatment was carried over beyond the 1-month washout. In possible support of this carry-over effect, the patients randomized to receive fish oil supplementation first required a lower average dose of prednisone at the beginning 536
of the placebo period than either group at the beginning of the study. As Dr. Tobin points out, any carry-over effect would diminish the therapeutic effect seen with fish oil and would raise the possibility that fish oil supplementation may be even more effective than we demonstrated. We did a careful history to make sure that the baseline intake of n-3 polyunsaturated fatty acids was low and instructed patients to maintain their baseline diet during the entire 9 months of the study. Finally, Dr. Tobin raises the possibility that other components of fish oil may have contributed to its therapeutic effects. We are confident that the beneficial effects were caused by a reduction in leukotriene B4 production brought on by competition of eicosapentaenoic acid for 5-lipoxygenase. Four weeks of treatment with a selective 5-lipoxygenase inhibitor, zileuton, induced similar degrees of reduction in dialysate leukotriene B4 levels and similar levels of clinical and histologic improvement as fish oil supplementation (2). The amount of vitamin E in Max-EPA capsules is fairly modest, and it is unlikely that enough vitamin E would reach the colon to have significant effects as a free radical scavenger. William F. Stenson, MD Washington University Medical Center St. Louis, MO 63178 References 1. Stenson WF, Cort D, Rodgers J, Burakoff R, DeSchryver-Kecskemeti K, Gramlich TL, et al. Dietary supplementation with fish oil in ulcerative colitis. Ann Intern Med. 1992;116:609-14. 2. Stenson WF, Lauritsen K, Laursen LS, Rask-Madsen J, Jacobsen O, Naesdal J, et al. A clinical trial of zileuton, a specific inhibitor of 5lipoxygenase, in ulcerative colitis. Gastroenterology. 1991; 100:A253.
Overtreating Hypertension To the Editors: Kaplan (1) failed to address in his recent review of the overtreatment of hypertension whether merely treating rather than controlling hypertension is adequate for the prevention of morbid events. In the Systolic Hypertension in the Elderly Program (SHEP) (2) and the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension) study (3), a relatively fixed dosage schedule was used and a number of elderly patients who were treated did not reach their target blood pressure level (28% in the case of the SHEP study). The authors did not do subgroup analysis to determine whether patients who did not reach their blood pressure goal had more end point events. In short, should we merely follow the protocol of the studies in treating systolic and diastolic hypertension in the elderly rather than increase drug dose if the target blood pressure goal is not met? William Zinn, MD Harvard Medical School Cambridge, MA 02139 References 1. Kaplan NM. The appropriate goals of antihypertensive therapy: neither too much nor too little. Ann Intern Med. 1992;116:686-90. 2. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: Final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA. 1991;265:3255-64. 3. Dahlof B, Lindholm LH, Hansson L, Schersten B, Ekbom T, Wester PO. Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension). Lancet. 1991;23;338: 1281-5.
In response: Dr. Zinn makes a valid point: Antihypertensive treatment that does not lower the blood pressure will probably not benefit the patient. This point relates to the discussion of resistance to therapy as a mechanism for undertreatment of a number of patients. Yet another issue, this one involved in overtreatments, was not addressed in my review (1). The recommended drug dosages are derived from clinical studies, wherein a sizable number of patients almost certainly were noncompliant with their assigned regimen. Neither pill counts nor measurements of
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drug levels can accurately assess long-term compliance (2). Despite close surveillance, patients in these trials may not take from 20% to 50% of their prescribed doses (3). Thus, when phase 3 preapproval study data are examined, the estimated average dose providing the desired 10 to 15 mm Hg fall in blood pressure may be 20% to 50% higher than the actual optimal dose. Of course, patients given the recommended doses will also often be noncompliant. If the patient is fully compliant, however, and takes 100% of a dose, up to 2-fold more than needed to provide the optimal response, the potential for overtreatment is obvious. The best advice for practitioners remains as follows: Start low, go slow, but push on until the desired effect (or a bothersome side effect) occurs. Norman M. Kaplan, MD Southwestern Medical Center at Dallas Dallas, TX 75235-8899 References 1. Kaplan NM. The appropriate goals of antihypertensive therapy: neither too much nor too little. Ann Intern Med. 1992;116:686-90. 2. Rudd P, Byyny RL, Zachary V, et al. Pill count measures of compliance in a drug trial: variability and suitability. Am J Hypertens. 1988;1:309-12. 3. Cramer JA, Scheyer RD, Mattson RH. Compliance declines between visits. Arch Intern Med. 1990;150:1509-10.
Arthritis after Bacillus Calmette-Guerin Therapy To the Editors: A 49-year-old male had transurethral resection and intravesical and intramuscular bacillus Calmette-Guerin (BCG) therapy in 1988 for transitional cell carcinoma of the bladder. From October to December 1991, he again received intravesicular BCG for tumor recurrence. Within 2 weeks of the last instillation, he developed metatarsophalangeal joint and hip pain. Physical examination showed dactylitis of the left fourth toe, pain with motion of his right hip, and stress of both sacroiliac joints. Erythrocyte sedimentation rate was 61 mm/h, and rheumatoid factor was absent. Indomethacin, 50 mg three times a day, isoniazid, 300 mg/d, and rifampin, 600 mg/d, were given for 2 weeks, and the arthritis resolved in 4 weeks. The iliac margin of the right sacroiliac joint was indistinct on subsequent radiograms. Human leukocyte antigen (HLA) typing included A(ll,32), B(27,55), and DR(1,6). Intravesical BCG is currently the most effective treatment for superficial transitional cell carcinoma of the bladder. Early studies reported arthralgias and polyarthritis in up to 6% of treated patients (1). Previously reported patients who developed polyarthritis after BCG therapy have had HLA-DR4 (2, 3), suggesting these cases may have been the human equivalent of the animal adjuvant arthritis model, a major histocompatibility complex (MHC)-II-restricted response where CD4+ T lymphocytes recognize segments of mycobacterial 65 kDa heat-shock protein (4). Similar reactivity to this 65 kDa heatshock protein has been shown for lymphocytes from synovial fluid of patients with recent onset rheumatoid arthritis (5). We believe this patient to be the first reported definite case of spondyloarthropathy after BCG therapy. Reactive arthritis occurs predominately in people bearing HLA-B27 and is felt to be caused by a class I MHC-restricted response. Recent work has investigated the endogenous protein fragments contained in the cleft of the class I MHC receptor as potential epitopes for immune responses. In the normal human host, HLA-B27 is now known to express nonamer self-peptides that are derived from abundant cytosolic and nuclear proteins, including fragments from heat-shock protein 83 (6) for which sequence homology between prokaryotic heat-shock protein 83 and human heat-shock protein 83 has been reported (7). In this particular patient, an immune response initiated by the intracellular organism BCG may have been perpetuated by cross-reactivity with host proteins that were being presented by the class I MHC receptor. Differences in processing and presentation of antigens by available MHC class I or II molecules may determine the
nature of arthritis affecting susceptible hosts exposed to potential immunostimulatory pathogens. David W. Puett, MD Howard A. Fuchs, MD Vanderbilt University School of Medicine Nashville, TN 37232-2681 References 1. Orihuela E, Herr HW, Pinsky CM, Whitmore WF. Toxicity of intravesical BCG and its management in patients with superficial bladder tumors. Cancer. 1987;60:326-33. 2. Hughes RA, Allard SA, Maini RN. Arthritis associated with adjuvant mycobacterial treatment for carcinoma of the bladder. Ann Rheum Dis. 1989;48:432-4. 3. Ochsenkuhn T, Weber MM, Caselmann WH. Arthritis after Mycobacterium bovis immunotherapy for bladder cancer. Ann Intern Med. 1990; 112:882. 4. Hogervorst EJ, Boog CJ, Wagenaar JP, Wauben MH, van der Zee R, van Eden W. T cell reactivity to an epitope of the mycobacterial 65 kDa heat-shock protein (hsp 65) corresponds with arthritis susceptibility in rats and is regulated by hsp 65-specific cellular responses. Eur J Immunol. 1991;21:1289-96. 5. Res PC, Schaar CG, Breed veld FC, van Eden W, van Embden JD, Cohen IR, et al. Synovial fluid T cell reactivity against 65 kD heat shock protein of mycobacteria in early chronic arthritis. Lancet. 1988;2:478-80. 6. Jardetzky TS, Lane WS, Robinson RA, Madden DR, Wiley DC. Identification of self peptides bound to purified HLA-B27. Nature. 1991;353:321-5. 7. Bardwell JC, Craig EA. Eukaryotic Mr 83,000 heat shock protein has a homologue in Escherichia coli. Proc Natl Acad Sci USA. 1987;84: 5177-81.
Common Prescribing Errors To the Editors: From 1 April 1991 to 31 March 1992, we detected 118 instances of the prescribing of an inappropriate dosage form of a drug available as both a "standard" and a "controlled" release product. This number compares with only 19 such errors in 1987 (1). All errors were averted before drug dispensing from the pharmacy. The drugs involved were diltiazem (32 errors), nifedipine (27), verapamil (23), theophylline (14), propranolol (5), morphine (4), procainamide (4), isosorbide (3), albuterol (3), divalproex (2), and disopyramide (1). The most common type of error was prescribing the standard-release dosage form (or not specifying the controlled-release form) at a frequency or dose inappropriate for the standard-release form (for example, theophylline, 300 mg every 12 hours, instead of TheoDur [Key Pharmaceuticals, Kenilworth, New Jersey] or Slo-bid [Rorer Pharmaceuticals, Fort Washington, Pennsylvania], or Procardia, 90 mg every morning instead of Procardia XL [Pfizer Inc., New York, New York]). Other errors included prescribing the controlled-release form to be given per tube (for example, Calan SR [Searle Laboratories, Chicago, Illinois], 240 mg every 24 hours per tube, or TheoDur, 300 mg every 12 hours per tube), which required crushing of the dosage form and thereby destroyed the controlled-release mechanisms, and prescribing sustained-release forms when they were not appropriate (for example, sustained-release morphine, MS Contin, [Purdue Frederick Company, Norwalk, Connecticut] on an as-needed basis for pain, or Procardia XL, 30 mg given sublingually, as needed for blood pressure control). One advantage of controlled dosage forms is the avoidance of dose-to-dose variations in drug concentrations, which reduces post-dose "peak" side effects and inadequate therapeutic effects at the end of the dosing interval. Another advantage is improved patient convenience and compliance. Most agents became available after 1987 and were originally marketed as standard-release products, then as controlled-release products such as Procardia XL, Cardizem SR (Marion Laboratories, Kansas City, Missouri), and Calan SR. The technique of adding a suffix to an established brand name is understandable from a marketing standpoint but appears to contribute to the increase in errors (2). Pharmaceutical companies should con-
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sider using brand names that more clearly differentiate controlled- from standard-release dosage forms.
Correction: Hepatitis B Virus and Bone Marrow Transplantation
Timothy S. Lesar, PharmD Albany Medical Center Hospital Albany, NY 12208
A recent letter (1) appearing in Annals incorrectly stated that hepatitis B infection had developed in the reported patient after bone marrow transplantation. The occurrence of the virus was before transplantation. Also, the correct author address is: University of Hong Kong, Hong Kong.
References 1. Lesar TS, Briceland LL, Delcoure K, Crilly-Parmalee J, Masta-Gornick V, Pohl H. Medication prescribing errors in a teaching hospital. JAMA. 1990;263:2329-34. 2. Vitillo J, Lesar T. Preventing medication prescribing errors. DICP Ann Pharmacother. 1991;25:1388-94.
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Reference 1. Lok AS, Liang RH, Chung HT. Recovery from chronic hepatitis B. Ann Intern Med. 1992; 116:957.
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