502 . ‘, Letiers to the Editor

marijuana, cirrhosis, congestive heart failure, obesity, oral con- traceptives, benzodiazepines, barbiturates, and ethanol. J Pharm

in plain uncoated and sustained-release dosage in relation to

Sci. 1979;68:1358. smoking habit: I. Single. dose study. Eur J Clin Pharmacol. 1983;24:79.

45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

Gardner MJ, Tomatore KM, Jusko WJ, Kanarkowski R. Effects of tobacco smoking and oral contraceptive use on theophylline disposition. Br J Clin Pharmacol. 1983;16:271. Pfiefer HF, Greenblatt DJ. Clinical toxicity of theophylline in relation to cigarette smoking. Chest. 1978;73:455. Powell JR, Thiercelin, JF, Vozeh S, Sandom L, Riegelman S. The influence of cigarette smoking and the sex on theophylline disposition. Am Rev Respir Dis. 1977;116:17. Hunt SN, Jusko WJ, Yurchak AM. Effect of smoking on theo- phylline disposition. Clin Pharmacol Ther. 1979;19:546. Jusko WF. Influence of cigarette smoking on drug metabolism in man. Drug Metab Rev. 1979;9:221. Jusko WF. Role of tobacco in pharmacokinetics. J Pharmacokinet Biopharm. 1979;6:7. Cusack B, Kelly JG, Lavan J, Noel J, O’Malley K. Theophylline kinetics in relation to age: the importance of smoking. Br J Clin Pharmacol. 1980;10:109. Grygiel JJ, Birkett DJ. Cigarette smoking and theophylline clear- ance and metabolism. Clin Pharmacol Ther. 1981;30:491. Ogilivie RI. Smoking and theophylline dose schedules. Ann Intern Med. 1978;88:263. Jenne J, Nagasawa H, McHugh R, MacDonald F, Wyse E. Decreased theophylline half-life in cigarette smokers. Life Sci. 1975;17:195.

55. Talseth T, Boye NP, Kongerud J, Bredesen JE. Aging, cigarette smoking, and oral theophylline requirements. Eur J Clin Pharma- col. 1981;21:33.

56. Horai Y, Ishizaki T, Sasaki T, Chiba K, Suganuma T, Echizen H, Ohnishi A. Bioavailability and pharmacokinetics of theophylline

0 Drug Interactions with Theophylline: Response to Drs. Zucchero and Hogan

I thank Zucchero and Hogan for taking the time to comment and for providing a rather extensive bibliogra- phy. Cimetidine was inadvertently omitted from the table; an error for which I accept full responsibility. I am grateful to the correspondents for pointing out its exclu- sion, however, it is my feeling that the data for the remaining drugs on this list are contentious. I shall first deal with those that I designated as having an unknown clinical significance and then the omissions. To avoid duplication, the citation numbers refer to Zucchero and Hogan’s reference list.

The two cited isoniazid studies directly contradict each other. Thompson et al (66) demonstrated increased theophylline clearance while Hoglund et al (67) showed the opposite. Interestingly, neither showed a significant change in theophylline half-life. At the very least the clinical significance of this interaction is unknown. One could even take the position that such an interaction does not exist.

The furosemide data merit analysis. Toback and Gilman (62) provide us with anecdotal data of decreased serum theophylline concentrations in four neonates who were treated with furosemide. Carpentiere et al (63), in a letter to the editor, briefly describe a study in eight

57.

58.

59.

60.

61.

62.

63.

64.

65.

66.

67.

Gardner MJ, Tomatore KM, Jusko WJ, Kanarkowski R. Effects of tobacco smoking and oral contraceptive use on theophylline disposition. Br J Clin Pharmacol. 1983;16:271. Cusack BJ. Cigarette smoking and theophylline metabolism: effects of cimetidine. Clin Pharmacol Ther. 1987;37:330. Vestal RE, Cusack BJ, Mercer GD, Dawson GW, Park BK. Aging and drug interactions: I. Effect of cimetidine and smoking on the oxidation of theophylline and cortisol in healthy man. J Pharmacol Exp Ther. 1987;241:488. Crowley JJ, Cusack BJ, Jue SG, Koup JR, Vestal RE. Cigarette smoking and theophylline metabolism: effects of phenytoin. Clin Pharmacol Ther. 1987;42:334. Trembath PW, Thorsbome-Palmer DD, Jarrott B, Hammond JJ, Prinsley DM. Theophylline pharmacokinetics in patients from a geriatric hospital: influence of cigarette smoking. Hum Toxicol. 1985;5:265. Toback JW, Gilman ME. Theophylline-furosemide inactivation. Pediatrics. 1983;71:140. Carpentiem G, Marino S, Caste110 F. Furosemide and theophylline [letter]. Ann Intern Med. 1985;103:957. Nakagawa RS. Theophylline-furosemide interaction. Am J Hosp Pharm. 1982;39:242. Gisclon LG. Ayres JW, Ewing GH. Pharmacokinetics of orally administered dyphylline. Am J Hosp Pharm. 1979;36:1179. Thompson JR, Buckart GJ, Self TH, Brown RE, Straughn AB. Isoniazid-induced alterations in theophylline pharmacokinetics. Curr Ther Res. 1982;32:921. Hoglund P, Nilsson LG, Paulsen 0. Interaction between isoniazid and theophylline. Eur J Respir Dis. 1987;70:110.

patients that also showed a decrease in serum theophyl- line concentration during furosemide administration. However, there was no statistical analysis of their results, thus the possibility of this being a chance finding was not excluded. Nakagawa (64) in his letter to the editor provides no data; he is merely sharing his hypoth- esis that such an interaction could occur. The inclusion of the work of Gisclon et al (65) is especially puzzling. It describes the pharmacokinetics of the renally excreted dyphilline, not the hepatic metabolized theophylline, and there is no mention at all of furosemide. These data (62,63) are contrasted with the work of Conlon et al (Am J Hosp Pharm. 1981;38:1345-1347), who demonstrated the opposite result, increases in theophylline serum concentration (P < 0.005). I would suggest that my conclusions for isoniazid are also appropriate for furo- semide .

The oral contraceptive literature is interesting. Four studies found decreases in theophylline clearance asso- ciated with coadministration of birth control pills (41,42, 44,45), one of them only in smokers (44). As well as a decreased theophylline clearance, there was an increased half-life in three of these studies (41,42,45). However, the results of Koren et al (43) directly conflict. They showed no change in theophylline clearance and half-life and discussed methodologic shortcomings of the above studies. These conflicting data, coupled with the fact that

The Journal of Emergency Medicine 503

there are obviously many women treated with both theophylline and oral contraceptives without any reports of theophylline toxicity, cast doubt upon the significance of this alleged drug interaction.

Tobacco was excluded because unlike prescription drugs, the physician has no control over this agent. A strong case for ciprofloxacin-theophylline interaction has been made (35-39), and it probably should have been included as a drug that may elevate serum theo- phylline concentrations. However, in the case of this new antimicrobial agent, I’m not sure whether there is enough evidence to judge the clinical significance of such an interaction.

The case for thiabendazole is unconvincing (3). It consists of an isolated report of a 71-year-old male who is treated with 5 drugs including theophylline. On one occasion, while suffering from an acute respiratory illness, the addition of thiabendazole resulted in theo- phylline toxicity (clinical and laboratory criteria). Three months earlier, while well, the same combination did not produce clinical toxicity. Since the authors described this as a “possible thiabendazole-induced theophylline tox- icity, ” I question Zucchero and Hogan including this drug and determining that the interaction is “moderately clinically significant. ’ ’

The support for pyrantel pamoate is equally conten- tious (40). It is a letter to the editor describing an isolated case of an g-year-old boy with an elevated serum theophylline concentration during therapy with this an- tihelminthic. However, his serum theophylline concen- tration was not at steady state when the pyrantel pamoate was given, which was during a time of switchover from

IJ The QBC2 Analyzer in the Emergency Depart- ment

In their article on clinical evaluation of the QBC2 centrifugal hematology analyzer in the emergency de- partment, Spivey et al noted (1) a significant time savings by performing CBCs using this analyzer. It is their opinion that use of this device may limit long waiting times, which are a major cause of patient dissatisfaction. Rosen, in an editorial response (2), has raised certain issues concerning their study. He questions the appropriateness of average turn-around times of 48 minutes for a CBC. In addition, he felt equipment maintenance and quality control are central concerns and best accomplished with main laboratory supervision. In our department, we were faced with a similar dilemma of very prolonged turn-around times for various laboratory studies, including CBCs. In the not too distant past, the laboratory averaged 70 minutes to report a CBC, 75

parenteral to oral theophylline therapy. Since the authors state that “the amount of information from this case is inconclusive as to a definite drug interaction,” I wonder at Zucchero and Hogan’s position that it occurs and that it is “moderately clinically significant. ”

It seems that Zucchero and Hogan are raising two issues, that “several recognized and significant” drug interactions were omitted, and that the significance of others was understated. They offer their rating system that scores the clinical importance from 1 to 3; highly, moderately, and minimally clinically significant. One could question the logic of their argument. At the outset they state that significant interactions were omitted, yet only one of the list was scored as “highly clinically significant.” One could also question the validity of their scoring system. The data for thiabendazole and pyrantel pamoate each consisted of an isolated case report whose authors were uncertain as to whether an interaction had occurred. The data for isoniazid, furo- semide, and oral contraceptives are conflicting, which at the very least cast doubt upon the significance of the hypothesized interactions. In the case of the latter, there must be countless women treated with both theophylline and birth control pills, yet there are no reports of resultant theophylline toxicity. We ought to have sound data before authoritative statements are made.

Milton Tenenbein, MD, FRCPC, FAAP, FAACT

Departments of Pediatrics and Pharmacology University of Manitoba

Winnipeg Children’s Hospital Manitoba Poison Control Centre, Winnipeg

minutes for electrolytes, BUN and glucose, and over 90 minutes for special studies such as CPK, dilantin, theophylline, etc. We found that these prolonged tum- around times not only impacted on patient satisfaction, but also created a gridlock situation with all stretchers filled with patients awaiting disposition.

As an alternative approach to the STAT lab concept, we had a series of meetings with the central laboratory personnel and came to agreement upon reasonable pa- rameters for turn-around times for the various laboratory studies. The central laboratory reorganized in such a way that they could meet these parameters without adding any new personnel to their staff. We are now averaging 25 minutes for CBCs, 40 minutes for electrolytes, BUN and glucose, and 50 minutes for special studies.

In addition, we reviewed the phlebotomy and trans- port processes, which often play a significant role in slow laboratory turn-around times. As a final step in the process, we began carefully monitoring through our