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Intravenous administration of aminophylline in asthmatic children taking theophylline orally
PEDIATRIC PHARMACOLOGY AND THERAPEUTICS P..l s. Lietman, Editor
Brief clinical and laboratory observations Intravenous administration of aminophylline in asthmatic children taking theophylline orally J. William Canavan, M.D., Norman S. Ellerstein, M.D.,* and T. Dennis Sullivan, M.D., Buffalo, N. Y.
INTRAVENOUS AMINOPHYLLINE is commonly recommended for the treatment of children with acute exacerbations of asthma. 1:~ However, enthusiasm for this agent is tempered by concern for its relatively narrow therapeutic margin? In spite of advances in understanding the pharmacokinetics of theophylline, serious toxic effects continue to occur?" ~ Some authors explicitly caution that the usual dose must be adjusted downward if the patient has received a recent oral dose of theophylline?" :~ particularly if given within six hours. It was the purpose of this study to assess the safety of intravenous administration of aminophylline in the child who recently has received theophylline orally.
mg of anhydrous theophylline per kg) was infused intravenously over a period of ten minutes. For 80 minutes following the infusion, each patient was clinically monitored for emesis, tremors, seizures, and palpable cardiac arrhythmia. One hour after completion of the aminophylline infusion blood was collected for a serum theophylline "peak" level. The time elapsed from the last oral theophylline dose to "time zero" was calculated. The anhydrous theophylline equivalent per kilogram of the last oral theophylline dose was computed. Serum theophylline levels were determined with high pressure liquid chromatography by the method described by .Jusko and Poliszczuk. ~
METHODS Forty children with asthma were studied in the emergency room at The Children's Hospital of Buffalo. The patients ranged in age from 0.5 to 20.9 years (mean 6.6 years). Each patient received beta adrenergic bronchodilators in the emergency room and continued to have signs of bronchoconstriction and respiratory distress, necessitating intravenous use of aminophylline. Each child had received a theophylline preparation orally at home and had taken a dose within six hours of coming to the hospital. Nine children were taking sustained release preparations. Oral doses ranged from 2.7 to 9.6 mg/kg of anhydrous theophylline equivalent (mean -- 5.4 mg/kg). Prior to the intravenous administration of aminophylline, blood was drawn for determination of serum theophylline level ("time zero" level). An aminophylline dose of 6.0 mg/kg of the patient's total body weight (equivalent to 5.1 From the Division of Ambulatory Pediatrics, Department of Pediatrics, State University of New York at Buffalo, School of Medicine, and The Children's Hospital of Buffalo. *Reprint address: The Children's Hospital of Buffalo, 219 Bryant St., Buffalo, NY 14222.
0022-3476/80/080301+03500.30/0 9 1980 The C. V. Mosby Co.
Abbreviations used iv: intravenous TBW: total body weight IBW: ideal body weight RESULTS Time zero theophylline levels ranged from 0 to 24.0 #g/ml (mean = 6.7/~g/ml). Thirty-two patients (80%) had levels below 10 /tg/ml; six patients (15%) had levels between 10.0 and 20.0/xg/ml; two patients (5%) had levels above 20.0 #g/ml. Peak theophylline levels ranged from 8.1 to 35.2 #g/ml (mean = 15.2/.tg/ml). The change in the theophylline level achieved by iv aminophylline infusion ranged from 3.9 to 17.0 /tg/ml (mean change = 8.3 /~g/ml). During the observation period no serious side effects (protracted emesis, seizures, cardiac arrhythmias) were noted. However, 14 of 40 patients experienced mild side effects; 12 had vomiting and two became tremulous. Peak theophylline levels among these 14 patients ranged from 8.3 to 35.2 #g/ml, with a mean of 15.9/tg/ml. Among the 26 patients with no adverse effects, peak theophylline levels ranged from 8.1 to 26.8 ~g/ml, with a mean of 14.4 /tg/ml.
The Journal of P E D I A T R I C S
301
302
Brief clinical and laboratory observations
The relationship between side effects and peak levels was not a consistent one. For example, one patient had a peak level of 26.8/~g/ml and had no side effects. On the other hand, 11 patients had side effects at peak levels below 20/~g/ml; three of these patients had levels below 10/Lg/ml. The two children with peak levels greater than 30/Lg/ml had only minor side effects. DISCUSSION The potential toxicity of theophylline should be readily appreciated, but the margin of safety is somewhat greater than is usually recognized. Even though some effect is noted at serum levels below 10/~g/ml, 4 most agree that levels between 10 and 20/~g/ml are optimally therapeutic. At levels above 20 ~g/ml the possibility of toxic effects may be greater than the beneficial effect. In our patients, adverse effects were observed in patients with peak levels ranging from 8.3 to 35.2/~g/ml; most with adverse effects had peak theophylline levels below 20/~g/ml. It is unknown whether the time zero theophylline level in our patients represented the steady state, because a history of theophylline administration prior to the last oral dose was not obtained. The preponderance of subtherapeutic time zero serum theophylline concentrations supports those who emphasize poor compliance as a major problem in treating children with asthma. ~ ~ In addition, the metabolism of theophylline may be affected by various disease states, 1~ " the ingestion of certain drugs, ~' " and diet/-' One patient is representative of two groups at increased risk for higher baseline theophylline levels. This patient was 20 years of age and markedly obese. She took 3.5 mg/kg of a sustained release theophylline preparation 4.2 hours before the iv aminophylline; her time zero level was 14.0 #g/ml, her peak level was 31.0 t~g/ml, and she manifested tremors. Adults and adolescents are known to have a longer theophylline half-life than do children.~ This patient received an intravenous dose based on her total body weight. Her oral doses had been less but exceeded a dose based on her ideal body weight. Others have found no satisfaction in dose6 based on either TBW or IBW. 13 Gal et al TM suggest that the initial dose in an obese patient be based on TBW since that represents the theophylline volume of distribution. They suggest that subsequent doses be based on IBW since that more readily reflects clearance of theophylline by the liver. The oral theophylline preparations taken by nine of our study patients were in a sustained release form. For these patients, the blood sample at one hour after aminophylline infusion may not represent the highest serum theophylline concentration. The true peak level in these patients may have occurred after the one hour period
The Journal of Pediatrics August 1980
because of the delayed absorption of the sustained released products. Furthermore, toxic side effects may have been missed because the children were monitored for only the first 80 minutes after the iv infusion. In addition, the delayed absorption of these preparations may account for some of the low time zero levels. Drugs other than theophylline can cause the type of adverse effects observed in our patients. These drugs may be in a preparation combined with theophylline or may be taken in addition to the theophylline product. None of our patients was taking any combination products, but ten were taking drugs other than theophylline which are known to cause similar side effects (terbutaline, isoproterenol, or metaproterenol). Two of these patients had side effects which may have been caused by the theophylline, by one of the aforementioned drugs, or by the additive toxic effect of both drugs. If theophylline levels were available to the physician moments after the blood was obtained, then the intravenous aminophylline dose could be individualized more readily. However, in lieu of an instantly available theophylline level, this study has demonstrated that a full iv dose of aminophylline can be administered to most patients without serious side effects. We conclude that children experiencing respiratory distress from asthma can be treated safely with aminophylline intravenously, even if the child received oral theophylline within six hours of the iv dose. The risk of deterioration of the respiratory status may be greater than the risk of serious theophylline toxicity. We thank Drs. Elliot F. Ellis, Danny D. Shen, and Stanley J. Szefler for their critical review of our manuscript. REFERENCES
1. Frick OL: Bronchial asthma, in Rudolph AM, editor: Pediatrics, ed 16, New York, 1977, Appleton-CenturyCrofts, pp 346-354. 2. Gallant SP: Status asthmaticus, in Pasco DJ, and Grossman M, editors: Quick reference to pediatric emergencies, Philadelphia, 1973, WB Saunders Company, pp 105-108. 3. PiconeF: Asthma, in Reece RM, editor: Manual of emergency pediatrics, ed 2, Philadelphia, 1978, WB Saunders Company, pp 22-28. 4. Weinberger M: Theophylline for treatment of asthma, J PEDIATR92:1, 1978. 5. ZwillichCW, Sutton FD, Neff TA, Cohn WM, Matthay RA, and Weinberger MM: Theophylline-induced seizures in adults, Ann Intern Med 82"784, 1975. 6. Hendeles L, Bighley L, Richardson RH, Hepler CD, and Carmichael J: Frequent toxicity from IV aminophylline infusion in critically ill patients, Drug Intelligence Clin Pharmacy 11:12, 1977. 7. Jusko WJ, and PoliszczukA: High-pressure liquid chromatographic anal spectrophotometric assays for theophylline in biological fluids, Am J Hosp Pharm 33:1193, 1976.
Volume 97 Number 2
8. Ellis EF, Koysooko R, and Levy G: Pharmacokinetics of theophylline in children with asthma, Pediatrics 58:542, 1976. 9. Eney RD, and Goldstein EO: Compliance of chronic asthmatics with oral administration of theophylline as measured by serum and salivary levels, Pediatrics 57:513, 1976. 10. Jenne JW, Wyze E, Rood FS, and MacDonald FM: Pharmacokinetics of theophylline, Clin Pharmacol Ther 13:349, 1972. I I. Powell JR, Vozeh S, Hopewell P, Costellow J, Sheiner LB, and Riegelman S: Theophylline disposition in acutely ill
B r i e f clinical and laboratory observations
3 03
hospitalized patients, Am Rev Respir Dis 118:229, 1978. 12. Kappas A, Anderson KE, Conney AH, and Alvares AP: Influence of dietary protein and carbohydrate on antipyrine and theophylline metabolism in man, Clin Pharmacol Ther 20:643, 1976. 13. Kordash TR, VanDellan RG, and McCall JT: Theophylline concentrations in asthmatic patients, JAMA 238:139, 1977~ 14. Gal P, Jusko WJ, Yurchak AM, and Franklin BA: Theophylline disposition in obesity, Clin Pharmacol Ther 23:438, 1978.
Once daily doses of phenobarbital in children P. D. Walson, M.D.,* T. Mimaki, M.D., R. Curless, M.D., M. Mayersohn, Ph.D., and D. Perrier, Ph.D., Tucson, Ariz., and Miami, Fla.
ALTHOUGH RELATIVELY FEW STUDIES haveinvestigated the disposition and elimination of phenobarbital in pediatric patients,' three studies have reported long serum half-lives (21 to 133 hours). 2-4 These half-lives indicate that once daily administration should provide adequate, minimally fluctuating levels in all children. Despite these studies, many physicians continue to use two or more daily doses. In addition, several studies (mostly in adults) indicate that salivary levels may be useful to reliably predict simultaneous serum levels, and that a combination of salivary phenobarbital concentration and pH may be useful to predict active or free serum concentration. :'-~ This study was designed to test the hypothesis that single daily doses of phenobarbital would provide seizure control with reliable serum (and salivary) levels in pediatric patients in an outpatient setting, without producing undesirable peak effects. From the University of Arizona, Health Sciences Center, Departments o f Pediatrics and Pharmaceutical Sciences, and University o f Miami School of Medicine, Departments of Neurology and Pediatrics. Supported in part by U.S. Public Health Service Grant No. 5T32 GM07533," The University of Arizona Clinical Research Center U.S. Public Health Service Grant No. SRR 00714; and the University of Miami Pediatric Neurology Research F,md. Presented in part at the International Congress of Pharmacology, Paris, France, 1978; and the 11th International Epilepsy Symposium, Florence, Italy, 1979. *Reprint address: Department of Pediatrics. Arizona Health Sciences Center, Tucson, AZ 85724.
0022-3476/80/080303 + 03500.30/0 9 1980 The C. V. Mosby Co.
MATERIALS
AND METHODS
The 12 subjects had been receiving phenobarbital for at least three months for control of a seizure disorder. Patients with infrequent seizures (less than 3/year) were preferentially selected to decrease the likelihood of being dropped from the study because of increasing seizure frequency. Abbreviations used TID: three times daily BID: two times daily QD: once daily All parents signed a consent form approved by the Human Subjects Committees of the universities. The subjects ranged from 1 to 8.8 years of age (mean 4.7 years). There were seven boys. Phenobarbital doses being given prior to the study ranged from 1.3 to 5.6 m g / k g / d a y (mean 3.7). On entry into the study, one patient had been receiving TID doses, nine BID doses, and two subjects had already been receiving one dose per day (Table). The study was conducted over a four-week period. For the first two weeks the subjects continued on their usual regimen. For the second two weeks the subjects were treated with an alternate regimen, QD for all except Subject 12 and the two subjects who were already being given single daily doses (Patients 7 and 9). Subject 12, originally on BID doses, was given TID doses during the study. During the entire study period the parents kept a log of doses given, seizure frequency, and any behavior changes. Subjects came to the clinic on Monday through Friday during the second and fourth weeks of the study. All
Brief clinical and laboratory observations Intravenous administration of aminophylline in asthmatic children taking theophylline orally J. William Canavan, M.D., Norman S. Ellerstein, M.D.,* and T. Dennis Sullivan, M.D., Buffalo, N. Y.
INTRAVENOUS AMINOPHYLLINE is commonly recommended for the treatment of children with acute exacerbations of asthma. 1:~ However, enthusiasm for this agent is tempered by concern for its relatively narrow therapeutic margin? In spite of advances in understanding the pharmacokinetics of theophylline, serious toxic effects continue to occur?" ~ Some authors explicitly caution that the usual dose must be adjusted downward if the patient has received a recent oral dose of theophylline?" :~ particularly if given within six hours. It was the purpose of this study to assess the safety of intravenous administration of aminophylline in the child who recently has received theophylline orally.
mg of anhydrous theophylline per kg) was infused intravenously over a period of ten minutes. For 80 minutes following the infusion, each patient was clinically monitored for emesis, tremors, seizures, and palpable cardiac arrhythmia. One hour after completion of the aminophylline infusion blood was collected for a serum theophylline "peak" level. The time elapsed from the last oral theophylline dose to "time zero" was calculated. The anhydrous theophylline equivalent per kilogram of the last oral theophylline dose was computed. Serum theophylline levels were determined with high pressure liquid chromatography by the method described by .Jusko and Poliszczuk. ~
METHODS Forty children with asthma were studied in the emergency room at The Children's Hospital of Buffalo. The patients ranged in age from 0.5 to 20.9 years (mean 6.6 years). Each patient received beta adrenergic bronchodilators in the emergency room and continued to have signs of bronchoconstriction and respiratory distress, necessitating intravenous use of aminophylline. Each child had received a theophylline preparation orally at home and had taken a dose within six hours of coming to the hospital. Nine children were taking sustained release preparations. Oral doses ranged from 2.7 to 9.6 mg/kg of anhydrous theophylline equivalent (mean -- 5.4 mg/kg). Prior to the intravenous administration of aminophylline, blood was drawn for determination of serum theophylline level ("time zero" level). An aminophylline dose of 6.0 mg/kg of the patient's total body weight (equivalent to 5.1 From the Division of Ambulatory Pediatrics, Department of Pediatrics, State University of New York at Buffalo, School of Medicine, and The Children's Hospital of Buffalo. *Reprint address: The Children's Hospital of Buffalo, 219 Bryant St., Buffalo, NY 14222.
0022-3476/80/080301+03500.30/0 9 1980 The C. V. Mosby Co.
Abbreviations used iv: intravenous TBW: total body weight IBW: ideal body weight RESULTS Time zero theophylline levels ranged from 0 to 24.0 #g/ml (mean = 6.7/~g/ml). Thirty-two patients (80%) had levels below 10 /tg/ml; six patients (15%) had levels between 10.0 and 20.0/xg/ml; two patients (5%) had levels above 20.0 #g/ml. Peak theophylline levels ranged from 8.1 to 35.2 #g/ml (mean = 15.2/.tg/ml). The change in the theophylline level achieved by iv aminophylline infusion ranged from 3.9 to 17.0 /tg/ml (mean change = 8.3 /~g/ml). During the observation period no serious side effects (protracted emesis, seizures, cardiac arrhythmias) were noted. However, 14 of 40 patients experienced mild side effects; 12 had vomiting and two became tremulous. Peak theophylline levels among these 14 patients ranged from 8.3 to 35.2 #g/ml, with a mean of 15.9/tg/ml. Among the 26 patients with no adverse effects, peak theophylline levels ranged from 8.1 to 26.8 ~g/ml, with a mean of 14.4 /tg/ml.
The Journal of P E D I A T R I C S
301
302
Brief clinical and laboratory observations
The relationship between side effects and peak levels was not a consistent one. For example, one patient had a peak level of 26.8/~g/ml and had no side effects. On the other hand, 11 patients had side effects at peak levels below 20/~g/ml; three of these patients had levels below 10/Lg/ml. The two children with peak levels greater than 30/Lg/ml had only minor side effects. DISCUSSION The potential toxicity of theophylline should be readily appreciated, but the margin of safety is somewhat greater than is usually recognized. Even though some effect is noted at serum levels below 10/~g/ml, 4 most agree that levels between 10 and 20/~g/ml are optimally therapeutic. At levels above 20 ~g/ml the possibility of toxic effects may be greater than the beneficial effect. In our patients, adverse effects were observed in patients with peak levels ranging from 8.3 to 35.2/~g/ml; most with adverse effects had peak theophylline levels below 20/~g/ml. It is unknown whether the time zero theophylline level in our patients represented the steady state, because a history of theophylline administration prior to the last oral dose was not obtained. The preponderance of subtherapeutic time zero serum theophylline concentrations supports those who emphasize poor compliance as a major problem in treating children with asthma. ~ ~ In addition, the metabolism of theophylline may be affected by various disease states, 1~ " the ingestion of certain drugs, ~' " and diet/-' One patient is representative of two groups at increased risk for higher baseline theophylline levels. This patient was 20 years of age and markedly obese. She took 3.5 mg/kg of a sustained release theophylline preparation 4.2 hours before the iv aminophylline; her time zero level was 14.0 #g/ml, her peak level was 31.0 t~g/ml, and she manifested tremors. Adults and adolescents are known to have a longer theophylline half-life than do children.~ This patient received an intravenous dose based on her total body weight. Her oral doses had been less but exceeded a dose based on her ideal body weight. Others have found no satisfaction in dose6 based on either TBW or IBW. 13 Gal et al TM suggest that the initial dose in an obese patient be based on TBW since that represents the theophylline volume of distribution. They suggest that subsequent doses be based on IBW since that more readily reflects clearance of theophylline by the liver. The oral theophylline preparations taken by nine of our study patients were in a sustained release form. For these patients, the blood sample at one hour after aminophylline infusion may not represent the highest serum theophylline concentration. The true peak level in these patients may have occurred after the one hour period
The Journal of Pediatrics August 1980
because of the delayed absorption of the sustained released products. Furthermore, toxic side effects may have been missed because the children were monitored for only the first 80 minutes after the iv infusion. In addition, the delayed absorption of these preparations may account for some of the low time zero levels. Drugs other than theophylline can cause the type of adverse effects observed in our patients. These drugs may be in a preparation combined with theophylline or may be taken in addition to the theophylline product. None of our patients was taking any combination products, but ten were taking drugs other than theophylline which are known to cause similar side effects (terbutaline, isoproterenol, or metaproterenol). Two of these patients had side effects which may have been caused by the theophylline, by one of the aforementioned drugs, or by the additive toxic effect of both drugs. If theophylline levels were available to the physician moments after the blood was obtained, then the intravenous aminophylline dose could be individualized more readily. However, in lieu of an instantly available theophylline level, this study has demonstrated that a full iv dose of aminophylline can be administered to most patients without serious side effects. We conclude that children experiencing respiratory distress from asthma can be treated safely with aminophylline intravenously, even if the child received oral theophylline within six hours of the iv dose. The risk of deterioration of the respiratory status may be greater than the risk of serious theophylline toxicity. We thank Drs. Elliot F. Ellis, Danny D. Shen, and Stanley J. Szefler for their critical review of our manuscript. REFERENCES
1. Frick OL: Bronchial asthma, in Rudolph AM, editor: Pediatrics, ed 16, New York, 1977, Appleton-CenturyCrofts, pp 346-354. 2. Gallant SP: Status asthmaticus, in Pasco DJ, and Grossman M, editors: Quick reference to pediatric emergencies, Philadelphia, 1973, WB Saunders Company, pp 105-108. 3. PiconeF: Asthma, in Reece RM, editor: Manual of emergency pediatrics, ed 2, Philadelphia, 1978, WB Saunders Company, pp 22-28. 4. Weinberger M: Theophylline for treatment of asthma, J PEDIATR92:1, 1978. 5. ZwillichCW, Sutton FD, Neff TA, Cohn WM, Matthay RA, and Weinberger MM: Theophylline-induced seizures in adults, Ann Intern Med 82"784, 1975. 6. Hendeles L, Bighley L, Richardson RH, Hepler CD, and Carmichael J: Frequent toxicity from IV aminophylline infusion in critically ill patients, Drug Intelligence Clin Pharmacy 11:12, 1977. 7. Jusko WJ, and PoliszczukA: High-pressure liquid chromatographic anal spectrophotometric assays for theophylline in biological fluids, Am J Hosp Pharm 33:1193, 1976.
Volume 97 Number 2
8. Ellis EF, Koysooko R, and Levy G: Pharmacokinetics of theophylline in children with asthma, Pediatrics 58:542, 1976. 9. Eney RD, and Goldstein EO: Compliance of chronic asthmatics with oral administration of theophylline as measured by serum and salivary levels, Pediatrics 57:513, 1976. 10. Jenne JW, Wyze E, Rood FS, and MacDonald FM: Pharmacokinetics of theophylline, Clin Pharmacol Ther 13:349, 1972. I I. Powell JR, Vozeh S, Hopewell P, Costellow J, Sheiner LB, and Riegelman S: Theophylline disposition in acutely ill
B r i e f clinical and laboratory observations
3 03
hospitalized patients, Am Rev Respir Dis 118:229, 1978. 12. Kappas A, Anderson KE, Conney AH, and Alvares AP: Influence of dietary protein and carbohydrate on antipyrine and theophylline metabolism in man, Clin Pharmacol Ther 20:643, 1976. 13. Kordash TR, VanDellan RG, and McCall JT: Theophylline concentrations in asthmatic patients, JAMA 238:139, 1977~ 14. Gal P, Jusko WJ, Yurchak AM, and Franklin BA: Theophylline disposition in obesity, Clin Pharmacol Ther 23:438, 1978.
Once daily doses of phenobarbital in children P. D. Walson, M.D.,* T. Mimaki, M.D., R. Curless, M.D., M. Mayersohn, Ph.D., and D. Perrier, Ph.D., Tucson, Ariz., and Miami, Fla.
ALTHOUGH RELATIVELY FEW STUDIES haveinvestigated the disposition and elimination of phenobarbital in pediatric patients,' three studies have reported long serum half-lives (21 to 133 hours). 2-4 These half-lives indicate that once daily administration should provide adequate, minimally fluctuating levels in all children. Despite these studies, many physicians continue to use two or more daily doses. In addition, several studies (mostly in adults) indicate that salivary levels may be useful to reliably predict simultaneous serum levels, and that a combination of salivary phenobarbital concentration and pH may be useful to predict active or free serum concentration. :'-~ This study was designed to test the hypothesis that single daily doses of phenobarbital would provide seizure control with reliable serum (and salivary) levels in pediatric patients in an outpatient setting, without producing undesirable peak effects. From the University of Arizona, Health Sciences Center, Departments o f Pediatrics and Pharmaceutical Sciences, and University o f Miami School of Medicine, Departments of Neurology and Pediatrics. Supported in part by U.S. Public Health Service Grant No. 5T32 GM07533," The University of Arizona Clinical Research Center U.S. Public Health Service Grant No. SRR 00714; and the University of Miami Pediatric Neurology Research F,md. Presented in part at the International Congress of Pharmacology, Paris, France, 1978; and the 11th International Epilepsy Symposium, Florence, Italy, 1979. *Reprint address: Department of Pediatrics. Arizona Health Sciences Center, Tucson, AZ 85724.
0022-3476/80/080303 + 03500.30/0 9 1980 The C. V. Mosby Co.
MATERIALS
AND METHODS
The 12 subjects had been receiving phenobarbital for at least three months for control of a seizure disorder. Patients with infrequent seizures (less than 3/year) were preferentially selected to decrease the likelihood of being dropped from the study because of increasing seizure frequency. Abbreviations used TID: three times daily BID: two times daily QD: once daily All parents signed a consent form approved by the Human Subjects Committees of the universities. The subjects ranged from 1 to 8.8 years of age (mean 4.7 years). There were seven boys. Phenobarbital doses being given prior to the study ranged from 1.3 to 5.6 m g / k g / d a y (mean 3.7). On entry into the study, one patient had been receiving TID doses, nine BID doses, and two subjects had already been receiving one dose per day (Table). The study was conducted over a four-week period. For the first two weeks the subjects continued on their usual regimen. For the second two weeks the subjects were treated with an alternate regimen, QD for all except Subject 12 and the two subjects who were already being given single daily doses (Patients 7 and 9). Subject 12, originally on BID doses, was given TID doses during the study. During the entire study period the parents kept a log of doses given, seizure frequency, and any behavior changes. Subjects came to the clinic on Monday through Friday during the second and fourth weeks of the study. All