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Once daily doses of phenobarbital in children
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
304
Brief clinical and laboratory observations
The Journal of Pediatrics August 1980
Table. Subject characteristics and dose/level relationships are presented
Mean serum levels
Dosc
Subject 1
2 3 4 5 6 (a) (b) 7 8 9 10 11 12
Age (vr) 1.3
6.9 6.0* 7.0 7.5 4.0* 4.2* 5.0 2.3 2.8 3.9 1.0 8.8
,o1 ,oloo
(mg/kg/day) 4.0 2.7 1.3 4.0 4.2 4.4 4.1 3.2 3.6 4.4 5.6 3.8 3.4
Mean salivarv levels T1D
BID
[ QD
-
5.5 7.0 3.7 3.4 3.7 7.5 6.0 6.2 7.2 4.9 2.0 5.5
5.4 7.3 4.3 3.4 4.0 6.9 10.8 6.1 6.6 4.9 5.5 2.3 -
--
17.5
17.1
--
21.9
19.6
-
12.0
13.3
-
13.8
15.0
-
15.1 24.6
15.9 23.5
23.1
19.0 25.4 20.5 -
19.5 23.4 16.6 24.7
5.7
17.6
17.9
--
6.8
-
--
-
-
Saliva~serum TID
-
] BID ] QD 0.31 0.32 0.31 0.25 0.25 0.30
0.32 0.37 0.32 0.23 0.25 0.29
0.33 0.28 0.24 -0.31
0.31 0.28 0.30 0.23 -
--
0.25 0.39
*Subjects 3 and 6 were receivinga fixed phenytoin dose during the study.
subjects had samples collected just prior to a dose. At each visit the parent's log was checked; then mixed unstimulated saliva samples (1 to 2 ml) were collected. Saliva w a s aspirated from the mouth of the two youngest children using a plastic syringe; all other children voluntarily expectorated into test tubes. On Wednesday, Thursday, and Friday visits, we attempted to obtain blood samples immediately after saliva collection. If this sampling frequency was not tolerated, we abandoned further attempts rather than risk losing all data. Therefore, Subjects 6 and 7 had only four, and Subject 8 had only two matched serum and salivary samples (2 and 1 per regimen, respectively). Subjects 9 and 10 had two matched pairs for Q D but three matched pairs for their other regimen. Salivary levels were measured in all samples even when doses were erroneously given prior to clinic arrival. However, the concentrations in these samples were invariably very high and were disregarded when calculating the averages. This error caused the loss of all data from one patient, and single specimens in two subjects of the study group. Subjects 6 through 12 were studied at the University of Miami. Samples from these patients were collected, frozen for shipment, then shipped packed in dry ice to Tucson for batch analysis. Serum and salivary phenobarbital levels were measured using a Waters High Pressure Liquid Chromatograph with a prepacked Waters #C~ reverse phase column and 254 nm UV detector. The method was a modified version of that reported by Kabra et al' and is similar to other reported methods except for the use of pentobarbital as the internal standard. Concentrations were calculated by peak height ratios. Standard curves for peak height ratios were rerun before and after each day's analyses. Mean serum levels were the simple arithmetic means of
serum levels measured on either regimen. Mean salivary levels were the simple arithmetic means of saliva samples with matched (same day) serum specimens even though unused salivary levels (Mondays and Tuesdays) did not differ significantly from those in matched samples. Ratios of saliva to serum levels were the arithmetic means of all available matched samples. As noted, for most subjects this was three matched pairs per dosing regimen, but for two subjects (6 and 7) it was two, and for one (8) it was only one pair per regimen. Two subjects (9 and 10) had three pairs for one but only two for the alternate regimen. Two salivary levels were considered spurious and discarded: One was collected 30 to 60 minutes after the parents erroneously administered a dose prior to clinic arrival (Subject 4). Another level was significantly lower than all nine other salivary levels; therefore, it was discarded, causing the loss of one matched serum level (Subject 9). This sample was small and required dilution prior to determination; no specimen remained for a repeat determination. RESULTS Serum and salivary levels. There were no statistically significant differences in mean serum or salivary levels on either regimen (Table). The ratio of mean serum levels after Q D administration to those after BID or T I D administration averaged 0.98 with a range 0.81 to 1.11. Excluding the second Q D saliva level from Subject 6b (Table), the ratio of mean saliva levels after Q D administration to those after BID or TID dosing also average 0.98 with a range of 0.82 to 1.16. Dose/level relationships. Mean serum levels (in mg/1) averaged 5.6 times the daily dose (in mg/kg) but there was a wide range of values. In Subject 4 this was as low as 3.5
Volume 97 Number 2
whereas in Subject 3 the serum levels were as high as 10.2 times the dose. Saliva to serum ratio. There was a consistent relationship between salivary and serum phenobarbital levels on both regimens for each subject, but there was a significant variation in this relationship among subjects (see Table). Except in Patient 12, all ratios were ___20% of each other, but the individual ratios varied from 0.21 to 0.39. The mean ratios for BID and Q D doses were both 0.29. Seizures and symptoms. No patient had increased seizure frequency during the study. However, the parents of Subject 3 reported increased "hyperactive behavior," nervousness, and some irritability about two to six hours after his once daily dose. This patient was also receiving phenytoin and had the highest dose to serum level ratio found. DISCUSSION These data are consistent with the hypothesis that most children with seizures can be safely and effectively treated with once daily doses of phenobarbital. Although therapeutic efficiency was only indirectly assessed, in no case did the change in dosing frequency significantly alter steady-state serum or saliva phenobarbital concentrations. This result is predictable in view of the studies on phenobarbital kinetics in children.:! .~ It also appears that although a wide range of doses is necessary to achieve therapeutic levels, most children achieve therapeutic levels on less than 5 m g / k g / d a y . The data also suggest that salivary levels can be used to determine an approximate value for simultaneous serum levels, Salivary levels can be used to predict simultaneous serum levels more reliably in a given patient if saliva to serum ratios are measured previously, since the intraindividual variation was much smaller than the intersubject variability. The use o f once daily dosage regimens should maximize compliance and minimize the risk of missed or delayed
B r i e f clinical and laboratory observations
305
doses. Once daily administration of phenobarbital can be r e c o m m e n d e d in children provided that at least one trough blood level is obtained at or near steady state (two or more weeks after initiating therapy). The ability to reliably predict simultaneous serum levels from measured salivary concentrations, TM and the premise ~ that salivary pH and phenobarbital concentrations can be used to reliably measure active (free) serum concentrations, are potentially useful advantages of phenobarbital therapy. Thanks are due to the staff of the University of Arizona Clinical Research Center, to Mr. David Nyman for technical assistance, and to the subjects and their parents. REFERENCES 1. Rane A: Clinical pharmacokinetics ofantieplileptic drugs in children, Pharmacol Ther C 2:251, 1978. 2. Garrettson LK, and Dayton PG: Disappearance of phenobarbital and diphenylhydantoin from serum of children, Clin Pharmacol Ther 11:674, 1970. 3. Jailing B: Plasma and cerebrospinal fluid concentrations of phenobarbital in infants given single doses, Dev Med Child Neurol 16:781, 1976. 4. Neimann G, and Gladtke E: Pharmacokinetics of phenobarbital in childhood, Eur J Clin Pharmacol 12:305, 1977. 5. Schmidt D, and Kupferberg H J: Dipheny/hydantoin, phenobarbital and primidone in saliva, plasma, and cerebrospinal fluid. Epilepsia 16:735, 1975. 6. Cook CE, Arnerson E, Poole WK, Lesser P, and O'Tuama L: Phenytoin and phenobarbital concentrations in saliva and plasma measured by radioimmunoassay, Clin Pharmacol Ther 18:742, 1975. 7. Homing ME, Brown L, Nowlin J, Lertratanang K. Kellaway P, and Zion TE: Use of saliva in therapeutic drug monitoring, Clin Chem 23:157, 1977. 8, Nishihara K, Uchino K, Saitoh Y, Honda Y, Nakagawa F, and Tamura Z: Estimation of plasma unbound phenobarbital concentration by using mixed saliva, Epilepsia 20:37, 1979. 9. Kabra AM, Koo HY, and Marton LJ: Simultaneous liquid-chromatographic determination of 12 common sedatives in serum, Clin Chem 24:657, 1978. 10. Danhof M, and Breimer DD: Therapeutic drug monitoring in saliva, Clin Pharmacokinet 3:39, 1978.
High titer multiple dose therapy with HBIG in newborn infants of HBsA g positive mothers Ramesh Jhaveri, M.D.,* Warren Rosenfeid, M.D., J. Delfor Salazar, M.D., Harvey Dosik, M.D., Chau-Chie Cheng, M.D., and Hugh E. Evans, M.D., Brooklyn, N.Y. From the Departments of Pediatrics, Obstetrics, and Medicine, The Jewish Hospital and Medical Center of Brooklyn, SUN Y-Downstate Medical Center. *Reprint address: Division of Newborn Service, Department of Pediatrics, The Jewish Hospital and Medical Center of Brooklyn. 555 Prospect Place, Brooklyn, NY 11238.
0022-3476/80/080305 +04500.40/0 9 1980 The C. V. Mosby Co.
HEPATITIS B INFECTION can be serious, even fatal, in infancy, and may result from either the HB~Ag carrier state or from acute infection in the mother or other household members. The HB,Ag carrier state, characterized by the persistence of HB~Ag in the blood, develops in
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
304
Brief clinical and laboratory observations
The Journal of Pediatrics August 1980
Table. Subject characteristics and dose/level relationships are presented
Mean serum levels
Dosc
Subject 1
2 3 4 5 6 (a) (b) 7 8 9 10 11 12
Age (vr) 1.3
6.9 6.0* 7.0 7.5 4.0* 4.2* 5.0 2.3 2.8 3.9 1.0 8.8
,o1 ,oloo
(mg/kg/day) 4.0 2.7 1.3 4.0 4.2 4.4 4.1 3.2 3.6 4.4 5.6 3.8 3.4
Mean salivarv levels T1D
BID
[ QD
-
5.5 7.0 3.7 3.4 3.7 7.5 6.0 6.2 7.2 4.9 2.0 5.5
5.4 7.3 4.3 3.4 4.0 6.9 10.8 6.1 6.6 4.9 5.5 2.3 -
--
17.5
17.1
--
21.9
19.6
-
12.0
13.3
-
13.8
15.0
-
15.1 24.6
15.9 23.5
23.1
19.0 25.4 20.5 -
19.5 23.4 16.6 24.7
5.7
17.6
17.9
--
6.8
-
--
-
-
Saliva~serum TID
-
] BID ] QD 0.31 0.32 0.31 0.25 0.25 0.30
0.32 0.37 0.32 0.23 0.25 0.29
0.33 0.28 0.24 -0.31
0.31 0.28 0.30 0.23 -
--
0.25 0.39
*Subjects 3 and 6 were receivinga fixed phenytoin dose during the study.
subjects had samples collected just prior to a dose. At each visit the parent's log was checked; then mixed unstimulated saliva samples (1 to 2 ml) were collected. Saliva w a s aspirated from the mouth of the two youngest children using a plastic syringe; all other children voluntarily expectorated into test tubes. On Wednesday, Thursday, and Friday visits, we attempted to obtain blood samples immediately after saliva collection. If this sampling frequency was not tolerated, we abandoned further attempts rather than risk losing all data. Therefore, Subjects 6 and 7 had only four, and Subject 8 had only two matched serum and salivary samples (2 and 1 per regimen, respectively). Subjects 9 and 10 had two matched pairs for Q D but three matched pairs for their other regimen. Salivary levels were measured in all samples even when doses were erroneously given prior to clinic arrival. However, the concentrations in these samples were invariably very high and were disregarded when calculating the averages. This error caused the loss of all data from one patient, and single specimens in two subjects of the study group. Subjects 6 through 12 were studied at the University of Miami. Samples from these patients were collected, frozen for shipment, then shipped packed in dry ice to Tucson for batch analysis. Serum and salivary phenobarbital levels were measured using a Waters High Pressure Liquid Chromatograph with a prepacked Waters #C~ reverse phase column and 254 nm UV detector. The method was a modified version of that reported by Kabra et al' and is similar to other reported methods except for the use of pentobarbital as the internal standard. Concentrations were calculated by peak height ratios. Standard curves for peak height ratios were rerun before and after each day's analyses. Mean serum levels were the simple arithmetic means of
serum levels measured on either regimen. Mean salivary levels were the simple arithmetic means of saliva samples with matched (same day) serum specimens even though unused salivary levels (Mondays and Tuesdays) did not differ significantly from those in matched samples. Ratios of saliva to serum levels were the arithmetic means of all available matched samples. As noted, for most subjects this was three matched pairs per dosing regimen, but for two subjects (6 and 7) it was two, and for one (8) it was only one pair per regimen. Two subjects (9 and 10) had three pairs for one but only two for the alternate regimen. Two salivary levels were considered spurious and discarded: One was collected 30 to 60 minutes after the parents erroneously administered a dose prior to clinic arrival (Subject 4). Another level was significantly lower than all nine other salivary levels; therefore, it was discarded, causing the loss of one matched serum level (Subject 9). This sample was small and required dilution prior to determination; no specimen remained for a repeat determination. RESULTS Serum and salivary levels. There were no statistically significant differences in mean serum or salivary levels on either regimen (Table). The ratio of mean serum levels after Q D administration to those after BID or T I D administration averaged 0.98 with a range 0.81 to 1.11. Excluding the second Q D saliva level from Subject 6b (Table), the ratio of mean saliva levels after Q D administration to those after BID or TID dosing also average 0.98 with a range of 0.82 to 1.16. Dose/level relationships. Mean serum levels (in mg/1) averaged 5.6 times the daily dose (in mg/kg) but there was a wide range of values. In Subject 4 this was as low as 3.5
Volume 97 Number 2
whereas in Subject 3 the serum levels were as high as 10.2 times the dose. Saliva to serum ratio. There was a consistent relationship between salivary and serum phenobarbital levels on both regimens for each subject, but there was a significant variation in this relationship among subjects (see Table). Except in Patient 12, all ratios were ___20% of each other, but the individual ratios varied from 0.21 to 0.39. The mean ratios for BID and Q D doses were both 0.29. Seizures and symptoms. No patient had increased seizure frequency during the study. However, the parents of Subject 3 reported increased "hyperactive behavior," nervousness, and some irritability about two to six hours after his once daily dose. This patient was also receiving phenytoin and had the highest dose to serum level ratio found. DISCUSSION These data are consistent with the hypothesis that most children with seizures can be safely and effectively treated with once daily doses of phenobarbital. Although therapeutic efficiency was only indirectly assessed, in no case did the change in dosing frequency significantly alter steady-state serum or saliva phenobarbital concentrations. This result is predictable in view of the studies on phenobarbital kinetics in children.:! .~ It also appears that although a wide range of doses is necessary to achieve therapeutic levels, most children achieve therapeutic levels on less than 5 m g / k g / d a y . The data also suggest that salivary levels can be used to determine an approximate value for simultaneous serum levels, Salivary levels can be used to predict simultaneous serum levels more reliably in a given patient if saliva to serum ratios are measured previously, since the intraindividual variation was much smaller than the intersubject variability. The use o f once daily dosage regimens should maximize compliance and minimize the risk of missed or delayed
B r i e f clinical and laboratory observations
305
doses. Once daily administration of phenobarbital can be r e c o m m e n d e d in children provided that at least one trough blood level is obtained at or near steady state (two or more weeks after initiating therapy). The ability to reliably predict simultaneous serum levels from measured salivary concentrations, TM and the premise ~ that salivary pH and phenobarbital concentrations can be used to reliably measure active (free) serum concentrations, are potentially useful advantages of phenobarbital therapy. Thanks are due to the staff of the University of Arizona Clinical Research Center, to Mr. David Nyman for technical assistance, and to the subjects and their parents. REFERENCES 1. Rane A: Clinical pharmacokinetics ofantieplileptic drugs in children, Pharmacol Ther C 2:251, 1978. 2. Garrettson LK, and Dayton PG: Disappearance of phenobarbital and diphenylhydantoin from serum of children, Clin Pharmacol Ther 11:674, 1970. 3. Jailing B: Plasma and cerebrospinal fluid concentrations of phenobarbital in infants given single doses, Dev Med Child Neurol 16:781, 1976. 4. Neimann G, and Gladtke E: Pharmacokinetics of phenobarbital in childhood, Eur J Clin Pharmacol 12:305, 1977. 5. Schmidt D, and Kupferberg H J: Dipheny/hydantoin, phenobarbital and primidone in saliva, plasma, and cerebrospinal fluid. Epilepsia 16:735, 1975. 6. Cook CE, Arnerson E, Poole WK, Lesser P, and O'Tuama L: Phenytoin and phenobarbital concentrations in saliva and plasma measured by radioimmunoassay, Clin Pharmacol Ther 18:742, 1975. 7. Homing ME, Brown L, Nowlin J, Lertratanang K. Kellaway P, and Zion TE: Use of saliva in therapeutic drug monitoring, Clin Chem 23:157, 1977. 8, Nishihara K, Uchino K, Saitoh Y, Honda Y, Nakagawa F, and Tamura Z: Estimation of plasma unbound phenobarbital concentration by using mixed saliva, Epilepsia 20:37, 1979. 9. Kabra AM, Koo HY, and Marton LJ: Simultaneous liquid-chromatographic determination of 12 common sedatives in serum, Clin Chem 24:657, 1978. 10. Danhof M, and Breimer DD: Therapeutic drug monitoring in saliva, Clin Pharmacokinet 3:39, 1978.
High titer multiple dose therapy with HBIG in newborn infants of HBsA g positive mothers Ramesh Jhaveri, M.D.,* Warren Rosenfeid, M.D., J. Delfor Salazar, M.D., Harvey Dosik, M.D., Chau-Chie Cheng, M.D., and Hugh E. Evans, M.D., Brooklyn, N.Y. From the Departments of Pediatrics, Obstetrics, and Medicine, The Jewish Hospital and Medical Center of Brooklyn, SUN Y-Downstate Medical Center. *Reprint address: Division of Newborn Service, Department of Pediatrics, The Jewish Hospital and Medical Center of Brooklyn. 555 Prospect Place, Brooklyn, NY 11238.
0022-3476/80/080305 +04500.40/0 9 1980 The C. V. Mosby Co.
HEPATITIS B INFECTION can be serious, even fatal, in infancy, and may result from either the HB~Ag carrier state or from acute infection in the mother or other household members. The HB,Ag carrier state, characterized by the persistence of HB~Ag in the blood, develops in