Effect of Disease States on Theophylline Serum Concentrations: Are We Still Vigilant?

Effect of Disease States on Theophyll ine Serum Concentrations: Are We Sti II Vigi lant? TIMOTHY H. SELF, PHARMD;

CAROL C. CHAFIN, PHARMD;

ABSTRACT: The use of theophylline has decreased over the past decade because of concerns over the risks of serious adverse effects as well as availability of more effective, safer drugs. Because of this decline in use, some clinicians may not be alert to the marked effect of some disease states on theophylline serum concentrations. The purpose of this review is to heighten awareness of the effect of decompensated heart failure, cor pulmonale, hepatic

D

uring the 1990s, the use of theophylline declined because of concerns over serious risks l- 5 and because of the availability of other more efficacious, safer therapies for asthma 6 and chronic obstructive pulmonary disease (COPD).7-9 Despite this decline in use, many patients continue to require maintenance therapy with this drug, including COPD patients as a "step 3" agent after ipratropium and (32 adrenoceptor agonists. 7- 9 In addition, some patients with asthma 6 require an evening dose of sustained release theophylline as adjunctive therapy for nocturnal symptoms when antiinflammatory agents do not eliminate symptoms and long-acting inhaled (32 adrenoceptor agonists are not selected by the clinician. Mild anti-inflammatory effects for theophylline have been reviewed along with its other pharmacologic effects.lo For long-term management of both COPD7-9 and asthma 6 ,lO patients, theophylline can be a helpful agent if dosing and monitoring are carefully done. Unfortunately, if theophylline is used without appropriate dosing and monitoring of serum concentrations, risk of life-threatening toxicity continues. I - 5 Reduced use of this once extremely popular agent may result in less awareness or vigilance concerning its risks and the numerous factors, including decompensated congestive heart failure (CHF) and liver disease, that increase its risk of From the Department of Clinical Pharmacy (THS, eee), and the Department of Medicine, Division of Cardiology (JES), University of Tennessee, Memphis, Tennesee, Submitted March 16, 1999; accepted in revised form June 24, 1999. Correspondence: Dr. Timothy H. Self, Department of Clinical Pharmacy, University of Tennessee, 26 S. Dunlap, Suite 202, Memphis, TN 38163 THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES

JUDITH E. SOBERMAN, MD

dysfunction, thyroid disease, and febrile illness on theophylline serum concentrations. Because many patients receive some benefit from this drug, safe use by clinicians requires closer monitoring of serum concentrations in patients with factors that alter theophylline clearance, including several disease states. KEY INDEXING TERMS: Theophylline; Disease states; Serum concentrations [Am J

Med Sci 2000;319(3):177-82.]

toxicity. Table 1 lists diseases documented to affect theophylline clearance. Much attention has been focused on other drugs that alter theophylline metabolism-indeed, there are many clinically relevant drug interactions with theophylline. 6 ,lo Because some patients with the disease states to be discussed may receive drugs that alter theophylline clearance, a few examples of these interactions are listed in Table 2. Furthermore, factors such as age-related changes in theophylline disposition are important; dietary factors and smoking history are also significant. 6 ,lO The purpose of this review is to remind clinicians of the necessity of careful monitoring of theophylline levels in patients with CHF, hepatic dysfunction, and other disease states. The impetus for this review was the recent admission of 2 patients with decompensated CHF to our university hospital. Both patients had concomitant COPD, and were receiving theophylline therapy before admission, with continuation of the same dose in the hospital. Unfortunately, theophylline serum concentrations were not ordered in the emergency department (ED), on admission, or within the first day of hospitalization. Only after the patients were presented to a senior faculty member were levels immediately requested. Both patients had theophylline levels above the accepted therapeutic range; fortunately, however, no serious toxicity was encountered. Obviously, the concern is that subsequent admissions for CHF could have very different outcomes. For both asthma6 ,lO,11 and COPD,8,9,12 use of theophylline for acute exacerbations is no longer recommended for routine initial treatment. Thus, simply continuing use of oral therapy being given before admission may perhaps lull the clinician into forgetting to monitor levels in the setting of, for example, 177

Disease States and Theophylline Serum Concentrations

Table 1. Effect of Disease States on Theophylline Serum Concentrations Disease states that may result in increased serum concentrations CHF 1 3--20 Cor pulmonale21 ,22 Liver diseases 16,23,26--28 Cirrhosis, decompensated 16,23,26,27 Cirrhosis, compensated23 ,26,27 Viral hepatitis 27 ,28 Febrile illness Pneumonia 15 Influenza33,34 Hypothyroidism4o ,41 Disease states that may result in decreased serum concentrations Hyperthyroidism38,4o Cystic Fibrosis41-43

CHF exacerbation. If decompensated CHF is the primary reason for admission to the hospital and COPD is stable, monitoring a COPD medication may easily be overlooked. CHF Exacerbation and Cor Pulmonale

A dramatic reduction in the elimination oftheophylline in patients with CHF was first reported in 1974 in an abstract by Piafsky et aP3 with a subsequent full report in 1977.14 Nine patients with acute cardiogenic pulmonary edema were given theophylline intravenously, and the kinetics of the drug were evaluated over the next 24 hours.1 4 Although there was a wide range of clearance values, the mean plasma clearance was 66% of the control subjects. The mean elimination half-life was 22.9 hours; one patient had a striking increase in elimination halflife to 82 hours (compared with average 8 hours in an otherwise healthy adult nonsmoker). Other studies that further documented the effect Table 2. Examples of Well-Documented Theophylline Drug Interactions 6 ,1o Drugs that may increase serum theophylline levelsa Cimetidine Ciprofloxacin, enoxacin, grepafloxacin, norfloxacin Erythromycin, clarithromycin Fluvoxamine Oral contraceptives Ticlopidine Zileuton Drugs that may decrease serum theophylline levelsb Barbiturates Carbamazepine Phenytoin Rifampin a A few examples only; there are many theophylline interactions; consult drug interaction texts or other literature for more complete information including onset and magnitude of effect b cigarette smoking (chemicals in smoke, NOT nicotine) also well documented to decrease theophylline levels

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of CHF on theophylline clearance quickly followed in the 1970s. 15,16 Powell et aP5 found that CHF patients had theophylline clearance decreased to 43% compared with control subjects. Jusko et aP6 also found theophylline clearance was markedly reduced in "moderate to severe" CHF. Clearance in "moderate to severe" CHF patients who were nonsmokers or light smokers was about 52% of that found in patients with either no CHF or "mild" CHF. Although cigarette smoking reduces the effect of CHF on theophylline clearance,15,16 the effect should be weighed against the severity of CHF exacerbation. In 1983, Kuntz et al 17 evaluated theophylline clearance in 50 patients with CHF versus 20 control subjects. Patients with hepatic congestion as part of CHF had theophylline clearance approximately 38% of the clearance found in control patients. Case reports have added to the body of evidence that CHF exacerbation results in reduced theophylline clearance and very high serum concentrations. 18 - 2o In a report focusing on theophylline-induced seizures, Zwillich et all described several patients with concurrent CHF and COPD and toxic theophylline levels. Similar to the effect of CHF exacerbation, cor pulmonale has also been demonstrated to signficantly decrease theophylline clearance. Vicuna et al 21 found that COPD patients with cor pulmonale had a theophylline clearance rate that was 60% of the rate in patients with COPD only. These findings were validated in a study of cor pulmonale patients by Dal Negro et a1. 22 Several reports 2- 5 in the early 1990s demonstrated the continuation of theophylline toxicity, despite widespread publication of appropriate dosing and monitoring guidelines. For example, in a study of inpatient theophylline toxicity, Schiff et al 2 found 17 patients with CHF who had excessive dosing of theophylline. One probable mechanism of decreased theophylline clearance in CHF is reduced capacity of the liver to metabolize the drug as a result of passive hepatic congestion. 14 That is, cytochrome P450 isozymes responsible for theophylline metabolism (CYP 1A2 , CYP2E1, CYP3A3) may not function as well with edema and hypoxemia. Hepatic dysfunction is well known to be associated with CHF. Patients with liver disease not related to CHF have marked decrease in theophylline clearance. 23 Change in hepatic blood flow is not a mechanism for reduced clearance because theophylline has low hepatic extraction. 14 After checking the serum theophylline concentration in the ED or on admission to the hospital, it is important to note that because CHF is treated acutely, theophylline clearance will be increasing. Thus, serial monitoring of serum concentrations is required if theophylline therapy is continued. To minimize risk and reduce costs of monitoring, a more prudent approach is to hold theophylline therMarch 2000 Volume 319 Number 3

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Table 3. Examples of Theophylline Toxicity: Chronic Overdosage 4 ,5 Nausea, vomiting, abdominal pain, diarrhea Hypokalemia, hyperglcemia Sinus tachycardia, other supraventricular tachycardias, premature ventricular contractions, moltifocal atrial tachycardia Ventricular arrhythmias Hypotension/shock Nervousness, tremors, disorientation Seizures Chronic overdosage defined as serum theophylline levels >30 pg/mL (major toxicity usually in patients >60 years of age 5 ). Seizures have been reported at levels <30 pg/mL in patients <60 years, 3

apy until the CHF exacerbation has resolved. Increased doses of short acting inhaled (32 adrenoceptor agonists or inhaled ipratropium can treat the COPD in the interim. If the clinician chooses to continue theophylline therapy in the setting of decompensated CHF, the initial maintenance intravenous dosing guideline in adults is 0.2 mg/kglhr (or equivalent dose of oral theophylline).24 Using this guideline for a 70-kg man (using ideal body weight to dose theophylline), the total daily intravenous dose would be 336 mg. If an oral dose of sustained release theophylline is used in this situation, it would be wise to round the dose down to 300 mg per day. However, serum levels must continue to be monitored. Based on NIH guidelines, 6 clinicians should aim for serum concentrations of 5 to 15 ILg/mL when using theophylline in asthma management, This is certainly a reasonable therapeutic range to aim for in COPD as well. Other recommendations in the 1990s for COPD management include aiming for 8 to 12 ILg/mU or 10 to 12 ILg/mL,8 The former accepted range of 10 to 20 ILg/mL is no longer considered state of the art. Serum theophylline levels> 15 ILg/mL offer no significant benefit.25 On the other hand, maintaining steady-state serum theophylline concentrations> 15 lLg/mL increases risk of toxicity for patients who have a CHF exacerbation or encounter other factors, including numerous drugs or other disease states that decrease theophylline clearance. 1o ,24 That is, even a small decrease in clearance can raise the theophylline level to the toxic range. Table 3 lists examples of theophylline toxicity in patients who are chronically overmedicated. Even in the therapeutic range, theophylline can cause "minor" adverse effects including anorexia, nausea, vomiting, nervousness, and insomnia. 3 Liver Disease

In the 1970s, cirrhosis was clearly demonstrated to result in a marked reduction in theophylline elimTHE AMERICAN JOURNAL OF THE MEDICAL SCIENCES

ination. 16 ,23 Piafsky et a12 3 found that in 9 patients with alcoholic cirrhosis, the clearance of theophylline was about 68% of that in control patients. In patients with decompensated cirrhosis, including ascites, the theophylline clearance was only 45% of that found in control subjects. Jusko et aP6 reported that in 15 patients with either heavy ethanol use or documented cirrhosis, theophylline clearance was approximately 45% of that found in control subjects. Two reports 26 ,27 in 1980 further documented the effect of cirrhosis in decreasing theophylline clearance. Mangione et al 26 found that in 8 patients with stable cirrhosis, theophylline clearance was 35% that of age-matched control subjects. Staib et a1. 27 reported that in 7 patients with decompensated cirrhosis, clearance oftheophylline was about 18% that of healthy subjects. Unlike other reports, Staib et a12 7 did not find reduced clearance in 5 patients with compensated cirrhosis. Because decompensated cirrhosis has such a marked effect on theophylline clearance, one would expect that other liver disease would also affect theophylline elimination. Staib et a12 7 found that in 4 patients with viral hepatitis, theophylline clearance was about 55% that of healthy subjects. The same group of investigators found that in 7 patients with cholestasis, there was no change in theophylline clearance, but an increase in theophylline elimination half-life accompanied by a larger volume of distribution. In a case report,28 acute viral hepatitis resulted in a 44% decrease in theophylline clearance, consistent with the findings of Staib et al.2 7 Further reports are needed to more clearly define the effect of hepatic dysfunction other than cirrhosis on the disposition of theophylline. As in CHF, patients with liver disease should have serum theophylline concentrations monitored carefully, especially when liver function is changing. For example, a patient with alcoholic cirrhosis who had been compensated but has now gone on a drinking binge with subsequent decompensation will probably have significant increases in serum concentrations of theophylline, and levels should be checked frequently. Preferably, the drug will be withheld until liver function is again stable, and other agents can be used to manage the concurrent COPD or asthma. Should the drug absolutely be required, after verifying the recent theophylline history and checking a blood level, a dose of 0.2 mg/kglh (intravenous or equivalent oral dose) is appropriate. 24 Febrile Illness

In 1978, while investigating factors such as CHF on theophylline clearance, Powell et aP5 discovered that pneumonia had a marked effect on the elimination of this drug. Although the observation was made in only 2 of 3 patients with pneumonia, their 179

Disease States and Theophylline Serum Concentrations

clearance was 65% that of nonsmoker control subjects. Antipyrine is a marker of hepatic drug disposition, and the clearance of this marker is also reduced in pneumonia. 29 Antipyrine clearance is also reduced in patients with hypoxemia,30 which is often associated with pneumonia. The same group of investigators who first reported pneumonia as a factor that decreases theophylline clearance have suggested that hypoxemia is one explanation. 31 In 1994, Shedlofsky et al32 reported the effect of Gram-negative endotoxin administration on the metabolism of theophylline and antipyrine. The inflammatory response that was evoked, including fever, reduced the mean clearance of theophylline by 22% and antipyrine by 35% at 24 hours after endotoxin administration. The authors suggested that inhibition of drug metabolism was caused by inflammatory cytokines. In 1978, Chang et al 33 reported that acute respiratory viral illness reduced theophylline elimination. Patients with influenza A and adenovirus infection had a mean elimination half-life of 7 hours (compared with 4.2 hours 1 month after the infection). An outbreak of influenza B in the Seattle area resulted in 11 children having evidence oftheophylline toxicity; 2 children had seizures. Over a period of 1 to 3 months after infection, theophylline elimination returned to norma1. 34 Respiratory viral illness that does not produce sustained fever does not seem to alter theophylline clearance. 35,36 Respiratory viral illness probably affects theophylline clearance by the induction of interferon, which has been demonstrated to inhibit the metabolism of antipyrine. 37 For both pneumonia and febrile respiratory viral illness, serum theophylline concentrations should be monitored carefully, with anticipation of changing dose requirements during the acute phase of infection and then as these episodes resolve. Thyroid Dysfunction

Hyperthyroidism causes increased theophylline clearance. 38 - 4o In 1984, Vozeh et al38 found that hyperthyroid patients had increased theophylline clearance, which correlated with serum thyroxine concentrations. Clearapce of theophylline decreased an average of 20% after patients were treated for hyperthyroidism. In that same year, Bauman et al 39 reported 1 patient who had increased theophylline clearance when hyperthyroid versus when the patient was euthyroid. The concern with hyperthyroidism and risk of theophylline toxicity is that clearance slows as the patient becomes euthyroid; failure to decrease the theophylline dose can result in toxicity. Furthermore, because some patients become hypothyroid after treatment for hyperthyroidism, risk is further increased. Pokrajac et al40 evaluated 15 patients with 180

COPD-5 with hyperthyroidism, 5 with hypothyroidism, and 5 who were euthyroid. Although the authors reported a wide range of variability in theophylline kinetics, elimination rates were higher in hyperthyroidism and lower in hypothyroidism compared with euthyroid patients. These changes correlated with thyroxine, triiodothyronine serum concentrations and total body clearance. One case has been reported of hypothyroidism associated with toxic theophylline serum concentrations, a seizure, and ventricular fibrillation. 41 However, the patient had concomitant mild CHF, which could have contributed to the accumulation of theophylline. Although further study is needed to clearly establish the effect of thyroid dysfunction on theophylline clearance and serum concentrations, it would be prudent to monitor theophylline levels during thyroid dysfunction. Because it may take weeks or months for a patient to become euthyroid, dosage titration will require serial theophylline levels. Additional vigilance is needed for patients who receive radioactive iodine and may subsequently become hypothyroid. Cystic Fibrosis

In 1983, Isles et al42 found that cystic fibrosis (CF) patients had more rapid elimination of theophylline than healthy volunteers. Healthy subjects had theophylline clearance that was roughly 50% of the clearance observed in CF patients. Other groups of investigators have also reported that CF patients eliminate theophylline more rapidly than healthy subjects. 43,44 Although the mechanism of increased clearance of theophylline in CF patients is not known, clinicians should be aware of the need for increased dose requirements, guided by serum concentrations. Other Disease States

For the sake of completeness, we include other conditions that have been evaluated regarding the potential to affect theophylline clearance. The effect of renal disease on theophylline clearance has been studied by Bauer et a1. 45 These investigators found that neither acute nor chronic renal disease affected theophylline clearance. However, consistent with other authors cited previously, they found that patients with concomitant CHF did have greatly reduced clearance. 4 Hypoxemia associated with COPD has been debated as a possible factor that reduces theophylline clearance, but the data are not conclusive. 46 In addition, the effect of arterial pH on theophylline kinetics has been studied, but the data are inconclusive. 47,48 March 2000 Volume 319 Number 3

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Conclusion

Several disease states have clinically important effects on theophylline clearance and serum concentrations ofthis drug. CHF, cor pulmonale, cirrhosis, viral hepatitis, pneumonia, febrile respiratory viral illness, and possibly hypothyroidism may result in greatly increased serum theophylline concentrations. Cystic fibrosis and hyperthyroidism are documented to increase theophylline clearance and lower serum concentrations. Although theophylline is still required in many patients, there has been an overall decline 8 ,lo in its use, with the possible result ofless awareness on the part of clinicians of the effect of disease states on theophylline clearance. Clinicians need to be vigilant when using theophylline in patients with these disease states. If the drug must be used when patients have these diseases, additional care in dosing and monitoring of serum concentrations is essential. References 1. Zwillich CW, Sutton FD, Neff TA, et al. Theophylline induced seizures in adults. Ann Intern Med 1975;82:784-7. 2. Schiff GD, Hegde HK, LaCloche L, et al. Inpatient theophylline toxicity: preventable factors. Ann Intern Med 1991; 114:748-53. 3. Tsiu SJ, Self TH, Burns R. Theophylline toxicity: update. Ann Allergy 1990;64:241-57. 4. Sessler CN. Theophylline toxicity: clinical features of 115 consecutive cases. AnI J Med 1990;88:567-76. 5. Shannon M. Predictors of major toxicity after theophylline overdose. Ann Intern Med 1993;119:1161-7. 6. Expert Panel Report 2. Guidelines for the diagnosis and management of asthma. NIH publication no. 97-4051. Bethesda (MD): National Institutes of Health; 1997. 7. Ferguson GT, Cherniack RM. Management of chronic obstructive pulmonary disease. N Engl J Med 1993;328:101722. 8. AnIerican Thoracic Society Statement. Standard for the diagnosis and care of patients with chronic obstructive pulmonary disease. AnI J Respir Crit Care Med 1995;152:S78-S121. 9. Siafakas NM, Vermeire P, Pride NB, et ai. Optimal assessment and management of chronic obstructive pulmonary disease (COPD). The European Respiratory Society Task Force. Eur Respir J 1995;8:1398-420. 10. Weinberger M, Hendeles L. Theophylline in asthma. N Engl J Med 1996;334:1380-8. 11. SelfTH, Abou-Shala N, Burns et al. Inhaled albuterol and oral prednisone therapy in hospitalized adult asthmatics: does aminophylline add any benefit? Chest 1990;98:1317-21. 12. Rice KL, Leatherman JW, Duane PG, et al. AnIinophylline for acute exacerbations of chronic obstructive pulmonary disease. Ann Intern Med 1987;107:305-9. 13. Piafsky KM, Sitar DS, Rangno RE, et al. Disposition of theophylline in acute pulmonary edema. Clin Res 1974;22: 726A. 14. Piafsky KM, Sitar DS, Rangno RE,et ai. Theophylline kinetics in acute pulmonary edema. Clin Pharmacol Ther 1977;21:310-6. 15. Powell JR, Vozeh S, Hopewell P, et al. Theophylline disposition in acutely ill hospitalized patients: the effect of smoking, heart failure, severe airway obstruction and pneumonia. AnI Rev Respir Dis 1978;118:229-38. THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES

16. Jusko WJ, Gardner MJ, Mangione A, et ai. Factors affecting theophylline clearances: age, tobacco, marijuana, cirrhosis, congestive heart failure, obesity, oral contraceptives, benzodiazepines, barbiturates, and ethanol. J Pharm Sci 1979;68:1358-65. 17. Kuntz HD, Straub H, May B. Theophylline elimination in congestive heart failure. Klin Wochenschr 1983;61:1105-6. 18. Jenne JW, Chick TW, Miller BA, et al. Apparent theophylline half-life fluctuations during treatment of acute left ventricular failure. AnI J Hosp Pharm 1977;34:408-9. 19. Matthay RA, Matthay MA, Weinberger MM. Grand mal seizure induced by oral theophylline. Thorax 1976;31:470-1. 20. LeGatt DF. Theophyllline toxicity-A consequence of congestive heart failure. Drug Intell Clin Pharm 1983;17:59-60. 21. Vicuna N, McNay JL, Ludden TM, et al. Impaired theophylline clearance in patients with cor pulmonale. Br J Clin Pharmacol 1979;7:33-7. 22. Dal Negro R, Turco P, Pomari C, et ai. Effect of various disease states on theophylline plasma levels and on pulmonary function in patients with chronic airway obstruction treated with a sustained release theophylline preparation. Int J Clin Pharmacol Ther Toxicol. 1987;25:401-5. 23. Piafsky KM, Sitar DS, Rangno RE. Theophylline disposition in patients with hepatic cirrhosis. N Engl J Med 1977; 296:1495-7. 24. Hendeles L, Weinberger M. Theophylline: a state of the art review. Pharmacotherapy 1983;3:2-44. 25. Self TH, Heilker GM, Alloway RR, et ai. Reassessing the therapeutic range for theophylline on laboratory report forms: the importance of 5-15 mcg/ml. Pharmacotherapy 1993;13:590-4. 26. Mangione A, Imhoff TE, Lee RV, et al. Pharmacokinetics of theophylline in hepatic disease. Chest 1978;73:616-22. 27. Staib AH, Schuppen D, Lissner R. Pharmacokinetics and metabolism of theophylline in patients with liver diseases. J Clin Pharmacol Ther ToxicoI1980;18:500-2. 28. Feinstein RA, Miles MV. The effects of acute viral hepatitis on theophylline clearance. Clin Ped 1985;24:357-8. 29. Sonne J, Dossing M, Loft M, et al. Antipyrine clearance in pneumonia. Clin Pharmacol Ther 1985;37:701-4. 30. Cumming JF. The effect of arterial oxygen tension on antipyrine half-time in plasma. Clin Pharmacol Ther 1976;19: 468-71. 31. Vozeh S, Powell JR, Riegelman S, et ai. Changes in theophylline clearance during acute illness. JAMA 1978;240: 1882-4. 32. Shedlofsky SI, Israel BC, McClain CJ, et ai. Endotoxin administration to humans inhibits hepatic cytochrome P450mediated drug metabolism. J Clin Invest 1994;94:2209-14. 33. Chang KC, Lauer BA, Bell TD, et al. Altered theophylline pharmacokinetics during acute respiratory viral illness. Lancet 1978;1:1132-3. 34. Kraemer MJ, Furukawa CT, Koup JR, et ai. Altered theophylline clearance during an influenza B outbreak. Pediatrics 1982;69:476-9. 35. Muslow HA, Bernard L, Brown RD, et al. Lack of effect of respiratory syncytial virus infection on theophylline disposition in children. J Pediatr 1992;121:466-71. 36. Bachmann K, Schwartz J, Martin M, et ai. Theophylline clearance during and after mild upper respiratory infection. Ther Drug Monit 1987;9:279-82. 37. Williams SJ, Farrell GC. Inhibition of antipyrine metabolism by interferon. Br J Clin Pharmacol 1986;22:610-2. 38. Vozeh S, Otten M, Staub JJ, et ai. Influence of thyroid dysfunction on theophylline kinetics. Clin Pharmacol Ther 1984;36:634-40. 39. Bauman JH, Teichman S, Wible DA. Increased theophylline clearance in a patient with hyperthyroidism. Ann Allergy 1984;52:94-6. 40. Pokrajac M, Simic D, Varagic VM. Phamacokinetics of

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41. 42. 43. 44.

theophylline in hyperthyroid and hypothyroid patients with chronic obstructive pulmonary disease. Eur J Clin Pharmacol 1987;33:483-6. Aderka D, Shavirtt G, Garfinkel D, et al. Life-threatening theophylline intoxication in a hypothyroid patient. Respiration 1983;44:77-80. Isles A, Spino M, Tachnik E, et al. Theophylline disposition in cystic fibrosis. Am Rev Respir Dis 1983;127:417-21. Georgitis JW, Eigen H, Warner R, et al. Oral theophylline disposition in cystic fibrosis. Ann Allergy 1982;48:175-7. Larsen GL, Barron RJ, Landay RA, et al. Intravenous aminophylline in patients with cystic fibrosis. Am J Dis Child 1980;134:1143-8.

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45. Bauer LA, Bauer SP, Blouin RA. The effect of acute and chronic renal failure on theophylline clearance. J Clin Pharmacol 1982;22:65-8. 46. Cusack BJ, Crowley JJ, Mercer GD, et al. Theophylline clearance in patients with severe chronic obstructive pulmonary disease receiving supplemental oxygen and the effect of acute hypoxemia. Am Rev Respir Dis 1986;133:1110-4. 47. Vallner JJ, Speir WA Jr, Kolbeck RC, et al. Effect of pH on the binding of theophylline to serum proteins. Am Rev Respir Dis 1979;120:83-6. 48. Resar RK, Walson PD, Fritz WL, et al. Kinetics oftheophylline: variability and effect of arterial pH in chronic obstructive lung disease. Chest 1979;76:11-6.

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