Theophylline: Its rise, demise, and resurrection

Theophylline: ItsRise, Demis and Resurrection By MichaelShannon,MD, MPH BOSTON, MASSACHUSETTS

I

N A 1991 ARTICLE entitled Methylxanthines in the Treatment of Asthma: The Rise, the Fall, and the Possible Rise Again, McFadden1 predicted that theophylline, a drug relegated to the third tier of asthma treatment after decades of use, seemed destined to make a comeback. Based on data rapidly appearing at that time, there was a belief that this drug would return to the forefront of management of severe asthma as well as take on new indications.* Now, with interest in this drug remaining alive, theophylline use is on the rise. Outside the United States, theophylline has never lost its popularity in part because of the relative absence of more effective asthma therapies, eg, /3-adrenergic agonists, mast cell stabilizers, and leukotriene inhibitors. Therefore, a need remains to understand this drug’s actions and toxicity. Emergency physicians must be particularly knowledgeable about theophylline to (1) recognize the broad range of drugs and diseases that interact significantly with theophylline, carrying the risk of iatrogenic intoxication; (2) recognize theophylline toxicity in its early, inapparent phases; and (3) understand current management principles and their underlying basis. In this report, a pharmacological and toxicological profile of theophylline is provided.

Pharmacology Theophylline has important structural relationships with many other agents. It is a congener of both caffeine and theobromine (an ingredient of chocolate). Classified as a xanthine (ie, a dioxypurine), it also is structurally similar to the ubiquitous cellular messenger, adenosine. These structural relationships have important clinical implications: the toxicity of caffeine reTHEOPHYLLINE: ITS RISE, DEMISE, AND RESURRECTIONI MICHAEL SHANNON

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THEOPHYLlINE: ITS RISE, DEMISE, AND RESURRECTION/ MICHAEL SHANNON

TABLEI. CommonPharmacological AgentsAssociated with Alterationsin Theophylline Clearance Agent (Common

Proprietary

Name and Manufacturer)

Effect on Clearance

Mechanism

Barbiturates

Increased

Induces CYP3A3

Increased

Induces CYP3A3

Decreased

Inhibits CYP3A3

Decreased

Inhibits CYPIA2

Decreased

Inhibits CYPIAZ & CYP3A3

Decreased

Inhibits CYPIA2

Decreased

Inhibits CYP3A3*

Decreased

Inhibits CYP3A3

Decreased or increased

Unclear

Increased

Induces CYP3A3

Decreased

Inhibits CYPIA2

Oral contraceptives

Increased

Induces CYP3A3*

Phenytoin (Dilantin; Parke-Davis, Morris Plain, NJ)

Increased or decreased

Unclear

Primidone (Mysoline; Elan Pharmaceuticals, South San Francisco, CA)

Increased

Induces CYP3A3*

Rifampin

Increased

Induces CYP3A3

Thiabendazole

Decreased

Unclear

Tobacco smoke

Increased

Induces CYP IA2 activity

Verapamil (Calan [GD Searle, Chicago, IL], lsoptin [Knoll Pharmaceutical Co, Mt Olive, NJ])

Decreased

Inhibits CYP3A3

Decreased

Inhibits CYPIA2*

Carbamazepine (Tegretol; Dorval, PQ) Cimetidine

Novartis

Pharmaceuticals

Canada Inc,

(Tagamet; Baxter Healthcare Corp, Deer-field, IL)

Ciprofloxacin

(Cipro; Bayer Corp, West Haven, CT)

Clarithromycin

(Biaxin; Abbott

Laboratories,

North

Chicago, IL)

Erythromycin Famotidine

(Pepcid; Merck & Co, West Point, PA)

Fluvoxamine

(Luvox; Solvay Pharmaceuticals

Inc, Marietta, GA)

Fosphenytoin (Cerebyx; Parkdale Pharmaceuticals Rochester, Ml)

Inc,

lsoniazid (INH) Norfloxacin

Zafirlukast

(Noroxin;

Merck & Co)

(Accolate; Zeneca Pharmaceuticals,

& CYP3A3

Wilmington,

DE)

* Suspected mechanism.

sembles that of theophylline. Also, many of the actions of theophylline are attributed to its antagonism of adenosine receptors. Theophylline is produced in many forms. Its intravenous form, aminophylline, is an ethylene diamine salt that is 80% theophylline. Oral preparations of theophylline include liquid and both standard-release and sustained-release tablets or capsules. Sustained-release preparations are the most common form in use, offering the convenience of once- or twice-daily dosing.3,* Sustainedrelease theophylline products have proven to be particularly valuable in those with nocturnal asthma.2,4,5 After ingestion, the peak absorption of theophylline may be highly variable. Liquid preparations are

absorbed rapidly and completely within 2 to 4 hours. Standard-release tablets similarly have rapid absorption. However, sustained-release preparations may have markedly delayed absorption. This has important implications in the management of those who take an overdose of sustained-release theophylline products, because it is unclear when absorption will be complete. Once absorbed, theophylline undergoes extensive hepatic metabolism. The pathways of theophylline metabolism have been well elucidated. The two cytochrome isoenzymes that are largely responsible for theophylline metabolism are CYPlA2 and CYP3A3.25 Characterization of these enzymes has begun to explain why and how certain drugs affect theophylline metabolism. As Table 1 indi-

THEOPHYLLINE: ITS RISE, DEMISE, AND RESURRECTIONI MICHAEL SHANNON

cates, there is a list of drugs that have been associated with significant alterations in theophylline metabolism.z,r,s The most important of the agents listed are those that reduce the rate of theophylline metabolism and, therefore, have the potential to produce unintentional poisoning. Table 1 also indicates that drugs of a similar class, such as quinolone antibiotics (ciprofloxacin, norfloxacin), macrolide antibiotics (eg, erythromycin, clarithromycin) and Ha-antagonists (eg, cimetidine, famotidine) may alter theophylline metabolism. However, this effect is not universal; the macrolide azithromycin (Zithromax; Pfizer, New York, NY) and the Hz-antagonist ranitidine (Zantac; Glaxo Wellcome, Research Triangle Park, NC) do not significantly affect theophylline metabolism.4 Disease states also may produce changes in theophylline metabolism.7 Hyperthyroidism may lead to increased theophylline metabolism, whereas cardiac and hepatic disease may significantly reduce its metabolism. In children, febrile illnesses often reduce theophylline clearance.’ Renal disease has no significant effect on theophylline kinetics. Theophylline has a relatively unique pattern of elimination, commonly referred to as MichaelisMenten kinetics.* In this pattern of “saturable” elimination, theophylline metabolism is consistent and predictable across a narrow range of drug dose. However, when dose exceeds a threshold, drug elimination becomes prolonged, inconsistent, and unpredictable. One of the most common causes of chronic theophylline poisoning is a dose increase that exceeds the clearance threshold, resulting in a disproportionate increase in serum theophylline concentration. Theophylline metabolites, which are clinically inactive, are excreted in the urine. There is no significant urinary excretion of unchanged theophylline; therefore, diuresis has no value in the treatment of theophylline intoxication. Caffeine is metabolized, in part, to theophylline; those taking caffeine have measurable serum theophylline concentrations. Theophylline’s greatest therapeutic value has been in conditions of reversible bronchospasm, particularly asthma and chronic obstructive pulmonary disease.*,9 It also is the primary pharmacological agent for treatment of apnea of prematurity. In the treatment of bronchoconstriction, theophylline, until recently, played a pivotal role.2 Having the ideal properties of ease of administration, consistent bronchodilation, and easily measured and interpreted serum concentrations, it was part of the treatment foundation in asthma for 60 years.2 However, theophylline efficacy was questioned because

215

evidence accumulated to suggest it produces only modest benefit in the treatment of acute asthma exacerbations.10 Theophylline was ultimately removed from the list of agents recommended for treatment of acute asthma. Despite that action, it has maintained its role as a medication for chronic treatment of moderate-to-severe asthma. Recent data, which seem to signal renewed popularity of theophylline, have shown it possesses potent anti-inflammatory actions. Theophylline can significantly reduce the requirement for corticosteroids in those with severe asthma,liJ2 attributed to its inhibitory effects on the cytokines that mediate the inflammatory cascade, eg, interleukin4 13,14 Theophylline’s neurostimulatory actions have been exploited for the treatment of neonatal apnea.15 Although the exact mechanism of this disorder remains unestablished, theophylline has been shown to be an effective respiratory stimulant.i6J7 In a recent commentary, however, Schmidt suggested that theophylline currently is overprescribed for neonatal apnea and bradycardia.ls

Toxicity Theophylline has an extremely narrow therapeutic index. Manifestations of toxicity may occur in those with therapeutic serum drug concentrations (10 to 20 pg/mL).2 Theophylline intoxication generally is defined as a serum theophylline concentration of 20 &/mL or greater. The incidence of theophylline overdose has fallen dramatically over the last decade. In a loyear prospective study of consecutive patients with theophylline overdose, the Massachusetts Poison Control System managed 58 cases in 1987, but only 10 in 1994.i9 There are 3 typical causes of theophylline intoxication with 3 concomitant syndromes of overdose.20Ji Acute theophylline intoxication is the ingestion or intravenous administration of greater than 10 mg/kg of theophylline in an individual not taking the drug regularly. Acute theophylline intoxication most commonly results from ingestion by toddlers; attempted suicide by adolescents or adults; or a lo-fold error in intravenous administration by a physician, nurse, or pharmacist. Acuteon-therapeutic theophylline intoxication occurs when an individual who has been taking theophylline regularly ingests or receives 10 mg/kg or more. Acute-on-therapeutic intoxication typically results from a suicide gesture or a medication error by a health care provider (usually a lo-fold error).

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THEOPHYLLINE: ITS RISE, DEMISE, AND RESURRECTION/ MICHAEL SHANNON

TABLE2. MajorClinicalManifestations of Theophylline Intoxication,PresumedMechanism and Recommended Pharmacotherapy Manifestation

Presumed Mechanism

Recommended

Therapy

Cardiac Supraventricular

tachyarrhythmias

Hypotension

Adenosine antagonism, adrenergic hyperstimulation

Adenosine,

P-mediated

Fluids, vasopressors

vasodilation

P-blocking

agents

Neurological Vomiting

Vomiting

center stimulation

Ondansetron

Seizures

Adenosine antagonism, GABA receptor antagonism

CNS GABA agonists (benzodiazepines)

Decreased lower esophageal sphincter pressure, gastric acid hypersecretion

Metoclopramide,

Hypokalemia

Adrenergic

hyperstimulation

None

Hyperglycemia

Adrenergic

hyperstimulation

None

Metabolic acidosis

Adrenergic

hyperstimulation

Sodium bicarbonate

Gastrointestinal Vomiting

Ranitidine

Metabolic

Chronic theophylline overmedication occurs in those taking theophylline regularly but who, over an extended period, take the drug at a rate that exceeds its clearance, leading to a gradual rise in serum theophylline concentration. Common causes of chronic overmedication include erratic dosing by the patient; inappropriate dose increases by the patient, parent, or physician; cardiac disease; or administration of a drug that lowers theophylline clearance.19Ji Theophylline poisoning produces multiple physiological disturbances, many of which have a welldefined mechanism (Table 2). The mechanisms of toxicity best characterized are adrenergic hyperstimulation and adenosine receptor antagonism. Five prominent abnormalities appear after theophylline poisoning: cardiac, neurological, gastrointestinal, metabolic, and musculoskeletal.19,22,23 Cardiotoxicity consists of both rhythm and vascular disturbances. Sinus tachycardia appears in most patients who have significant intoxication. With more severe poisoning, supraventricular tachycardia may appear (unlike adults, children with theophylline poisoning rarely have atria1 flutter or fibrillation). Supraventricular tachyarrhythmias are likely to be a result of theophylline’s antagonism of

adenosine receptors (both err and (~a). In the most severely intoxicated patients, life-threatening ventricular rhythms (ventricular fibrillation, ventricular tachycardia) occur; recalcitrant ventricular arrhythmias are the most common cause of death after theophylline intoxication. Ventricular disturbances may result from adrenergic hyperstimulation in the face of metabolic acidosis. Adrenergic excess is universal in those with theophylline intoxication, predominantly producing &-receptor stimulation. The result is a blood pressure fall with a widened pulse pressure. Hypertension does not occur after theophylline poisoning24-2’ Theophylline has neurostimulatory effects that are used therapeutically in infants, but it also has notorious central nervous system toxicity. Neurotoxicity manifests as vomiting, agitation, hyperventilation, and convulsions. Seizures, when they occur, may be single or multiple. They may begin focally, although they typically progress to generalized convulsions.2s Theophylline-induced seizures are considered the gravest sign of toxicity, because survivors of seizures may be left with permanent, disabling neurological impairment.29-31 Elegant experiments by Eldridge et al32 and others have firmly established that a major mechanism of these sei-

THEOPHYLLINE: ITS RISE, DEMISE, AND RESURRECTION/ MICHAEL SHANNON

zures is theophylline antagonism of central nervous system adenosine receptors, leading to cerebral vasoconstriction and unmodulated electrical discharge.J2-36 Studies in the author’s laboratory using a rodent model of theophylline intoxication have shown that adenosine administration significantly delays seizure onset.33 These seizures may be resistant to conventional anticonvulsant therapy. In victims of chronic overmedication, seizures are often the first manifestation of theophylline intoxication.21 Gastrointestinal effects of theophylline include lowering of lower esophageal sphincter pressure and stimulation of gastric acid secretion. With severe, particularly acute intoxication, vomiting may lead to a Mallory-Weiss syndrome.37 Theophylline produces extensive metabolic disturbances including hypokalemia, hyperglycemia, metabolic acidosis, and hypercalcemia. Hypokalemia may be profound, with serum potassium falling to as low as 2.2 mEq/L.-?s This fall represents increased cellular uptake of potassium with preservation of total body potassium stores, an effect mediated by &adrenergic stimulation.39-“1 Interestingly, other &agonists (eg, albuterol and terbutaline) also produce hypokalemia and hyperglycemia after overdose. Hypercalcemia likewise is thought to follow &-receptor agonism.42 None of these abnormalities has clinical significance; even hypokalemia produces no important effect. Victims of theophylline overdose, particularly those with acute intoxication, have coarse muscle tremor.19 This tremor, which correlates closely with serum potassium concentration, is likely a result of &-mediated disturbances in skeletal muscle potassium homeostasis.39,4° Theophylline is one of a few drugs in which manifestations of toxicity are dependent on how intoxication occurred (salicylates and lithum are two other such examples). After acute intoxication, severe vomiting, profound hyperglycemia, hypokalemia, and metabolic acidosis develop.20,3s,43-45 However, victims do not generally have seizures or life-threatening arrhythmias until their serum theophylline concentration exceeds SO to 100 pg/mL. In such patients, the clinical course may be predicted largely on the basis of serum theophylline concentration.21 In contrast, victims of chronic overmedication have a lower rate of vomiting, hypokalemia, hyperglycemia, and metabolic acidosis.20,38 However, life-threatening cardiac arrhythmias and seizures may appear at serum concentrations as low as 20 &/mL. There is no correlation between serum concentration and risk of major toxicity in victims of chronic theophylline over-

217

medication.zOxQj Studies from the author’s center have shown that patient age is a greater predictor of toxicity than serum theophylline concentration after chronic overmedication. Victims at extremes of age, ie, the very young and the very old, are at highest risk.i9,21,47 In the pediatric population, it is young infants, particularly premature neonates, who are at risk for seizures and arrhythmias after chronic theophylline overmedication. Older children have a much lower risk of such events.20

Management Understanding of the spectrum of theophylline intoxication and its mechanisms has provided the ability to create a treatment algorithm that is highly specific (Table 3). Routine stabilization measures are vital in initial treatment. Airway and breathing should be assessed, although in the absence of seizures or ventricular arrhythmias these should be stable. Because of the risk of cardiovascular instability or seizures, intravenous access should be established immediately. Major toxicity should be anticipated in those with acute overdose and serum concentrations 280 &/mL and in young children with chronic theophylline overmedication. Supraventricular tachycardia, if it appears, should be treated with a bolus of intravenous adenosine. Beta blocking agents such as propranolol are also effective. However, P-blocking agents may produce bronchospasm; they should not be given to those with a history of asthma. Ventricular tachyarrhythmias should be treated according to advanced cardiac life support algorithms, including cardioversion or defibrillation along with lidocaine administration, when appropriate. Should seizures occur, a benzodiazepine (eg, diazepam or lorazepam) should be administered. Phenytoin has been shown in animal models to increase the incidence of theophylline-induced seizures and should not be administered.8 Skeletal muscle paralysis effectively ends muscular seizure activity. However, electrical seizure activity may continue, requiring that intubated patients receive electroencephalogram monitoring. Gastrointestinal decontamination is appropriate in those with recent (within 6 hours) acute theophylline overdose. This consists of administration of 1 g/kg (maximum 50 g) activated charcoal. Cathartics should not be administered. For those with chronic overmedication, even those who have taken only a therapeutic or supratherapeutic dose of theophylline, activated charcoal should also be provided to initiate elimination enhancement.

218

THEOPHYLLINE: ITS RISE, DEMISE, AND RESURRECTION/ MICHAEL SHANNON

TABLE3. PracticeGuidelinefor Treatmentof Theophylline Intoxication I

,

Stabilization Assess airway, breathing Establish intravenous Treat hypotension Treatment

line with fluid, o-dominant

of Life-Threatening

Adenosine

Events

for supraventricular

Lidocaine for ventricular Cardioversion

vasopressors

tachycardia

arrhythmias

or defibrillation

if necessary

Benzodiazepines (diazepam or lorazepam) for seizures. Avoid phenytoin and fosphenytoin. Paralysis if necessary. Treatment

of Metabolic Disturbances

Do not treat hypokalemia unless severe (serum K+ < 3.0 mEq/L) Sodium bicarbonate No treatment Gastrointestinal Activated

for metabolic acidosis

necessary for hyperglycemia,

hypercalcemia

Decontamination

charcoal in all cases

Aggressive antiemetic therapy with ranitidine metoclopramide or ondansetron

and

Enhanced Elimination Multiple-dose Administer

activated charcoal in all cases. Provide antiemetic therapy

Hemodialysis Follow recommended

criteria

Hemoperfusion Rarely needed Exchange transfusion For acute, severe neonatal cases in which activated charcoal cannot be administered

Laboratory evaluation should consist of a serum theophylline concentration, electrolytes (including calcium), serum pH, and blood sugar. In those with acute intoxication, a serum concentration of greater than 80 to 100 &/mL is associated with the greatest risk of life-threatening events; if serum theophylline concentration is less than 70 to 80 &/ mL, major toxicity is unlikely as long as other aspects of management are fully provided. In children with chronic overmedication, serum theophylline

concentration has no predictive value; patient age and physical findings should guide further management. Hypokalemia, unless severe (serum Kt < 3.0 mEq/L), does not require treatment. Inadvertent hyperkalemia may occur if potassium supplements are provided at the same time that serum theophylline concentration is falling.48 If potassium is administered, there should be very close attention to serum potassium concentration. Sodium bicarbonate should be administered if there is significant metabolic acidosis. There are 4 potential means of enhancing the elimination of theophylline after overdose: multiple dose activated charcoal, hemoperfusion, hemodialysis, and exchange transfusion. Because of its pharmacokinetic characteristics (low protein binding, small volume of distribution), theophylline is rapidly cleared from the body if activated charcoal is administered repetitively (“gastrointestinal dialysis”). This method of elimination enhancement is effective even if theophylline intoxication occurred though excess intravenous administration.49 The rate of theophylline clearance induced by multipledose activated charcoal has been compared with that of hemodialysis. 5o Therefore, all patients with theophylline intoxication should receive multipledose charcoal, 0.5 g/kg every 2 hours. Multiple-dose activated charcoal may be administered safely to neonates.“i Cathartic should be administered with every 2 to 3 charcoal doses to prevent its inspissation. Because of the severe vomiting that accompanies theophylline intoxication, aggressive antiemetic therapy must be provided, consisting of administration of metoclopramide, 0.5 to 1.0 @/kg per dose, or ondansetron, 0.15 mg/kg per dose (maximum 8 mg).37,52 Intravenous ranitidine also is effective in reducing the rate of emesis and should be given.j3,54 Hemoperfusion and hemodialysis are both highly effective but technically demanding, particularly in small children. Historically, hemoperfusion was associated with the most rapid rates of theophylline clearance and was considered the treatment of choice for severe theophylline intoxicationss-“7 However, hemoperfusion is associated with a significant rate of complications. Also, it is a technique of limited availability, found only in centers with a large clinical nephrology service. Because of these factors, hemodialysis has been used increasingly as an alternative to hemoperfusion. Hemodialysis is associated with a lower rate of complications. More recent data suggest that hemodialysis, although less efficient than hemoperfusion in its rate of theophylline removal, is as effective as hemoperfusion in preventing the appearance of life-threatening tox-

THEOPHYLLINE: ITS RISE, DEMISE, AND RESURRECTIONI MICHAEL SHANNON

icity after theophylline overdose.“” Consequently, the role of hemoperfusion for this poisoning has begun to vanish with hemodialysis becoming the preferred treatment. Because hemodialysis and hemoperfusion have been shown persuasively to prevent the life-threatening events of theophylline intoxication, the most important aspect of management is early identification of those patients at highest risk for major toxicity.j6-58 Current recommendations are that hemodialysis be performed in patients with acute intoxication who have a peak serum theophylline concentration of greater than 80 to 100 &/mL or those with a concentration greater than 60 to 80 &/mL and intractable vomiting.2r In victims of chronic overmedication, hemodialysis is recommended for those less than 6 months of age with a peak serum theophylline concentration of greater than 30 to 40 &/mL.21 Patients also should be considered candidates for hemodialysis or hemoperfusion if they already have major toxicity such as seizures or cardiac arrhythmias with hemodynamic compromise, regardless of serum theophylline concentration (although existing data suggest that hemodialysis and hemoperfusion do not prevent major toxicity from continuing once it has begun) .19,21,58 In neonates with acute, severe theophylline intoxication, exchange transfusion has been used successfully to accelerate theophylline elimination, averting serious toxicity.59,60 This procedure should be reserved for neonates who are unable to receive activated charcoal and in whom hemodialysis or hemoperfusion cannot be performed. Children with severe theophylline intoxication are best treated in the intensive care unit of a tertiary care facility because seizures and arrhythmias may appear abruptly and often are resistant to conventional therapy. Moreover, severe vomiting is likely to prevent successful administration of activated charcoal unless there is an intensivist present to closely supervise care. If a patient requires hospital transfer, the greatest challenge is to assure that the patient is stable for transfer. Advanced life support personnel with protocols for management of status epilepticus and cardiac arrhythmias should provide such transport.

Conclusion Theophylline has ridden a course of popularity, then of relative abandonment, and now of therapeutic resurrection. Its newly discovered pharma-

219

cological benefits portend increasing use over the next few years. Unfortunately, the growing use of theophylline in the pediatric population undoubtedly will be associated with episodes of theophylline intoxication. Emergency physicians must remain aware of this drug, its mechanisms of toxicity, as well as specific management strategies for treatment of this poisoning. Moreover, it is essential that the emergency physician, whenever prescribing medications to patients taking theophylline, first determine whether any potential drug-drug interaction exists. The greatest clinical challenge remains the treatment of patients who have chronic overmedication in whom life-threatening toxicity may appear without warning. It is also these patients who have the greatest risk of permanent neurological injury.19 Early identification of high-risk patients and aggressive, appropriate intervention may prevent the appearance of major toxicity.

References 1. McFadden ER: Methylxanthines in the treatment of asthma: The rise, the fall, and the possible rise again. Ann Intern Med 115:323-324, 1991. 2. Weinberger M, Hendeles L: Theophylline in asthma. N Engl J Med 334:1380-1388, 1996. 3. Weinberger M, Hendeles L: Slow-release theophylline-Rationale and basis for product selection. N Engl J Med 308:?60-764, 1988. 4. Butts JD, Secrest B, Berger R: Nonlinear theophylline pharmacokinetics-A preventable cause of iatrogenie theophylline toxic reactions. Arch Intern Med 151: 2073-2077, 1991.

5. Martin R: Nocturnal asthma and the use of theophylline.

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6. Shannon M: Drug-drug interactions and the cytochrome P4.50 system: An update. Pediatr Emerg Care 13:350-353, 1997. 7. American Academy of Pediatrics, Committee on Drugs: Precautions concerning the use of theophylline. Pediatrics 89:781-782, 1992. 8. Hendeles L, Jenkins J, Temple R: Revised FDA labeling guidelines for theophylline oral dosage forms. Pharmacotherapy 15409-427, 1995.

9. Murciano D, Auclair M-I-I, Pariente R, et al: A randomized, with severe N Engl J Med 10. Wrenn line therapy

controlled trial of theophylline in patients chronic obstructive pulmonary disease. 320:1521-1525, 1989. K, Slovis CM, Murphy F, et al: Aminophylfor acute bronchospastic disease in the

emergency room. Ann Intern Med 115:241-247, 1991. 11. Evans D, Taylor D, Zetterstrom 0, et al: A comparison of low-dose inhaled budesonide plus theophylline and high-dose inhaled budesonide for moderate asthma. N Engl J Med 337:1412-1418, 1997. 12. Epstein PE: Hemlock or healer? The mercurial

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THEOPHYLLINE:

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RISE,

DEMISE,

AND

RESURRECTION

reputation of theophylline. Ann Intern Med 119:12161217, 1993. 13. Tohda Y, Nakahara H, Kubo H, et al: Theophylline suppresses the release of interleukin-4 by peripheral blood mononuclear cells. Int Arch Allergy Immunol 115: 42-46, 1998. 14. Page C: Recent advances in our understanding of the use of theophylline in the treatment of asthma. J Clin Pharmacol39:237-240, 1999. 15. Myers T, Milsap R, Krauss A, et al: Low-dose theophylline therapy in idiopathic apnea of prematurity. J Pediatr 96:99-103, 1980. 16. Serafin WE: Drugs used in the treatment of asthma, in Hardman J, Limbird L, Molinoff P, et al (eds): Goodman and Gilman’s The Pharmacological Basis of Therapeutics. New York, NY, McGraw-Hill, 1996, pp 659682. 17. Davi 111,Sankaran K, Simons K, et al: Physiologic changes induced by theophylline in the treatment of apnea in preterm infants. J Pediatr 92:91-95, 1978. 18. Schmidt B: Methylxanthine therapy in premature infants: Sound practice, disaster, or fruitless byway. J Pediatr 135:526-528, 1999. 19. Shannon M: Life-threatening events after theophylline overdose-A IO-year prospective analysis. Arch Intern Med 159:989-994, 1999. 20. Shannon M, Lovejoy F: Effect of acute versus chronic intoxication on clinical features of theophylline poisoning in children. J Pediatr 121:125-130, 1992. 21. Shannon M: Predictors of major toxicity after theophylline overdose. Ann Intern Med 119:1161-1167, 1993.

22. Baker MD: Theophylline toxicity in children. J Pediatr 109:538-542, 1986. 23. Skinner MH: Adverse reactions and interactions with theophylline. Drug Safety 5:275-285, 1990. 24. Curry SC, Vance MV, Requa R, et al: Cardiovascular effects of toxic concentrations of theophylline in the dog. Arm Emerg Med 14:547-553, 1985. 25. Kearney TE, Manoguerra AS, Curtis GP, et al: Theophylline toxicity and the beta-adrenergic system. Ann Intern Med 102:766-769, 1985. 26. Higbee MD, Kumar M, Galant SP: Stimulation of endogenous catecholamine release by theophylline: A proposed additional mechanism of action for theophylline effects. J Allergy Clin Immunol 70:377-382, 1982. 27. Vestal RE, Eiriksson CE, Musser B, et al: Effect of intravenous aminophylline on plasma levels of catecholamines and related cardiovascular and metabolic responses in man. Circulation 67:162-171, 1983. 28. Nakada T, Keww IL, Lerner AM, et al: Theophylline-induced seizures: Clinical and pathophysiologic aspects. West J Med 138:371-374, 1983. 29. Bahls F, Ma KK, Bird TD: Theophyline-associated seizures with “therapeutic” or low toxic serum concentrations: Risk factors for serious outcome in adults. Neurology 41:1309-1312, 1991. 30. Richards W, Church JA, Brent DK: Theophyllineassociated seizures in children. Ann Allergy 54:276-279, 1985.

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31. Woody RC, Laney M: A second case of infantile intracranial hemorrhage and severe neurological sequelae following theophylline overdose. Dev Med Child Neurol 28:120-121, 1986. 32. Eldridge F, Paydarfar D, Scott S, et al: Role of endogenous adenosine in recurrent generalized seizures. Exp Neurol 103:179-185, 1989. 33. Shannon M, Maher T: Anticonvulsant effects of intracerebroventricular Adenocard in theophylline-induced seizures. Ann Emerg Med 26:65-68, 1995. 34. Dragunow M: Adenosine receptor antagonism accounts for the seizure-prolonging effects of. aminophylline. Pharmacol Biochem Behav 36:751-755, 1990. 35. Cavelheiro EA, Filho LSC, Bortolotto ZA, et al: Anticonvulsant role of adenosine. Pol J Pharmacol Pharm 39:537-544, 1987. 36. Pinard E, Riche D, Puiroud S, et al: Theophylline reduces cerebral hyperaemia and enhances brain damage induced by seizures. Brain Res 511:303-309, 1990. 37. Sessler CN: Poor tolerance of oral activated charcoal with theophylline overdose. Am J Emerg Med 5:492495, 1987. 38. Shannon M, Lovejoy F: Hypokalemia after theophylline intoxication-The effects of acute vs. chronic poisoning. Arch Intern Med 149:2725-2729, 1989. 39. Clausen T: Adrenergic control of Na-K-homeostasis. Acta Med Stand 672:111-115, 1983 (suppl). 40. Clausen T, Flatman JA: Beta-2 adrenoceptors mediate the stimulating effect of adrenaline on active electrogenic Na-K-transport in rat soleus muscle. Br J Pharmacol 68:749-755, 1980. 41. Shannon M: Hypokalemia, hyperglycemia and plasma catecholamine activity after severe theophylline intoxication. J Toxic01 Clin Toxic01 32:41-47, 1994. 42. McPherson ML, Prince SR, Atamer ER, et al: Theophylline-induced hypercalcemia. Ann Intern Med 105: 52-54, 1986. 43. Amitai Y, Lovejoy FH: Hypokalemia in acute theophylline poisoning. Am J Emerg Med 6:214-218, 1988. 44. Sawyer WT, Caravati EM, Ellison MJ, et al: Hypokalemia, hyperglycemia, and acidosis after intentional theophylline overdose. Am J Emerg Med 3:408-411, 1985. 45. Olson KR, Benowitz NL, Woo OF, et al: Theophylline overdose: Acute single ingestion versus chronic repeated overmedication. Am J Emerg Med 3:386-394, 1985. 46. Bertino JS, Walker Jw: Reassessment of theophylline toxicity-serum concentrations, clinical course, and treatment. Arch Intern Med 147:757-760, 1987. 47. Shannon M, Lovejoy F: The influence of age vs. peak serum concentration of life-threatening events after chronic theophylline intoxication. Arch Intern Med 150: 20452048, 1990. 48. D’Angio R, Sabatelli F: Management considerations in treating metabolic abnormalities associated with theophylline overdose. Arch Intern Med 147:18371838, 1987. 49. Kulig KW, Bar-Or D, Rumack BH: Intravenous

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