QRS Morphology and Pacemakers

QRS Morphology and Pacemakers To the Editor: It has come to our attention, after the publication of our article, QRS Morphology Associated with Transvenous Pacemakers" (Chest 1985; 87:517-21), that similar observations and explanations were briefly described by Barold et al in a chapter entitled "Electrocardiographic analysis of normal and abnormal pacemaker function.~~l

ccu nusual

Herman O. Klein, M.D., Rambam Medical Center; H ai/a, Israel

curred at three times per day dosing, 50 percent with twice per day and 67 percent patient compliance with a once daily preparation. Data are available that adults' and some children7 can be switched from a twice-a-day to a once-a-day preparation, maintaining good clinical effectiveness with the expected increased convenience and improved compliance as an added benefit. Data are available that effective clinical benefit can be derived from theophylline blood levels in the 5 to 10 mcglml range. In summary, although the authors of this article have provided interesting information regarding the food effect ofone theophylline product given under very speci&c conditions, their concept should be placed in a more balanced light, especially in view of recent data regarding other theophylline products and the more generalized concept of food interacting with theophylline.

Sheldon L. Spector; M.D., RC.C.P.; Sheldon C. Siegel, M.D.; Roger M. Katz, M.D., RC.C.P.; Gary S. Rachelefs1cy, M.D.; Albert S. Rohr, M.D: Allergy Medical Clinic, Lo, Angele,

REFERENCE

1 Dreyfus LD, ed. Cardiovascular clinics. Pacemaker therapy. Philadelphia: F A Davis Company, 1983; 97-134

Theophylline Dose-dumplng To the Editor: Although the manuscript by Hendeles et al ("Food-induced cdosedumping~ from a one-a-day theophylline product as a cause of theophylline toxicity." Chest 1985; 87:758-65) brings to the attention of the reader an interaction between Theo-24 and foods. Aspects of the design ofthe study prevent the extrapolation ofthese findings to the general use of Theo-24. Most importantly, a single dose of theophylline ofl2OO to 1500 mg as used in these normal subjects, is a very unusual total daily dose of theophylline in our experience. It probably would represent that dose required by rapid metabolizers, a subgroup of patients who, in keeping with the current package insert for Theo-24, should not have received single dose theophylline in the first place. In other words, rapid metabolizers requiring 900 mg or more, such as commonly found in smoking adults and many young children, are not appropriate candidates for once-a-day theophylline. The breakfast utilized by these investigators consisting of 2 eggs, bacon, muffins, margarine, hash brown potatoes and 8 oz. of whole milk is not a usual breakfast for most Americans, but one with a very heavy fat content. Thus, the likelihood ofthese doses oftheophylline being combined with a big fatty breakfast becomes very small. In accordance with data presented at a recent symposium, 1 no food effect was seen with up to 900 mg ofTheo-24 when the breakfast has a low fat content, and even with a high fat breakfast, a fatty food effect is not substantial if Theo-24 is taken one hour before the meal. Of course, foods not only effect Theo-24 as reported by the authors, there are data that foods will affect many theophylline products. Not included in their discussion are our findings that the absorption of Theo-Dur tablets given once per day was significantly delayed with food. 2 The conditions ofour study were similar to those described by these authors but with a dose of900 mg or less. Additionally, TheoOur Sprinkles (Key Pharmaceuticals, Inc) and Theolair (S. R. Riker Labs, Inc) are markedly influenced by food intake. In fact, Pederson et al3 found that food taken with Theo-Our Sprinkles not only delayed absorption but reduced the bioavailability of Theo-Dur Sprinkles from 91 percent with fasting to 44 percent with food containing 20 percent of the calories derived from fats. The biggest advantage of a once-a-day theophylline is the expected improved compliance, as extrapolated from the literature. For example, in one studt patient compliance for a psychotropic drug improved from 40 percent with three times per day dosage to 70 percent at twice per day dosing and 93 percent with once per day administration. In an English study, 5 44 percent compliance oc-

REFERENCES

1 Authors? After 85 years: new criteria for theophylline therapy. J Respir Dis (in press) 2 Spector SL, Rohr, AS, Rachelefsky CS. The effect of food on once daily Theo-Dur in asthmatic subjects. J Clin Immun 1985; 75:105 3 Pederson S, Moller-Peterson J. Erratic absorption of a slowrelease theophylline sprinkle product caused by food. Pediatrics 1984; 74:534-38 4 Ayd F: Single daily dose ofantidepressants. JAMA 1974; 230:263 5 Gatley MS. To be taken as directed. JR ColI Cen Prac 1968; 16:39 6 Dockhom RJ, Creen AW. Comparing long-term effects of 12- and 24-hour theophyllines. J Respir Dis (in press) 7 Pierson WE. Clinical effects of once and twice daily theophylline dosing. J Respir Dis (in press)

To the Editor: Dr. Spector and his colleagues question the relevancy of our report on food-induced dose dumping of Theo-24 because of the "unusual" dose of theophylline that was not "in keeping with the current package insert;the "very heavy fat content" of the breakfast, and our failure to discuss "data that foods will affect many theophylline products;" they particularly note that we failed to discuss their unpublished report that "absorption ofTheo-Our tablets given once per day was significantly delayed with food." In point of fact, the limitation ofa 900 mg once daily dosage in the current package insert ofTheo-24 resulted from a meeting between FDA and Searle on February 16, 1984 that was initiated after FDA! evaluation of the data included in our published report in Cheat (1985; 87:758-65). Searle's argument that this was a generic problem was rejected, and they were directed by FDA to restrict dosing recommendations and draft: a "Dear Doctor" letter warning that "food may Significantly increase the absorption of 111eo-24". l An FDA evaluation of the fOrmulation also demonstrated that dissolution ofTheo-24 greatly increased at alkaline pH levels, an in vitro correlate to our clinical findings of dose dumping. I As a consultant to Searle at the June 20, 1983 meeting of the FDA's Pulmonary/Allergy Drugs Advisory Committee on once-a-day theophylline products, 3 Dr. Spector should also be aware that data submitted to the FDA reported by Searle showed mean steady state peak and trough concentrations of 10.1 and 5.5 ...~ml, respectively, after the fifth day of 900 mglday, compared to 17.7 and ll.1 ..,glml after 1500 m~day (Fig 1). 4 Furthermore, early advertisements for Theo-24 contained a graph of mean steady state serum concentrations 5 between 10 and 20 ...~ml at a dose of1200 to 1500 m~day. The low CHEST I 89 I 2 I FEBRUARY. 1986

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