Voh,me 93 Number 1
evidence that persistent hypertension in the young deserves continued observation. David Goldring, M.D. Professor of Pediatrics Director of Pediatric Cardiology Sol Londe, M.D. Associate Clinical Professor of Pediatrics, Emeritus IVashington University School of Medicine Antonio Hernandez, M.D. Associate Professor of Pediatrics IVashington Universit), School of Medicine St. Louis Children's Hospital St. Louis, MO 63110
REFERENCES I.
2.
3.
4.
5.
6. 7.
Goldring D, Londe S, Sivakoff M, Hernandez A, Britton C, and Choi S: Blood pressure in a high school population, J PFDZATR91:884, 1978. Kirby RR Kemmerer WT and Morgan JL: TranscutaI ' neous:Doppler measurement of blood pressure, Anesthesiology 31:86, 1964. Zinner SH, Levy PS, and Kass EH: Familial aggregation of bloodpressure in childhood, N Engl J Med 284:401, 1971. Holland J, Kutchen T, and Dinuar B: Hypertension in children with chronic pyelonephritis, Kidney lnt 8:243, 1975. Londe S, Bourgoigne JJ, Robson AM, and Goldring D: Hypertension in apparently normal children, J PEO~ATR 78:569, 1971. Perera GA: The course of primary hypertension in the young, Ann Intern Med 49:1348, 1958. Heyden J, Bartel AG, Hames CG, et al: Elevated blood pressure levels in adolescents. Evans County, Georgia, JAMA 209:1683, 1969.
Editorial correspondence
15 7
methods, which should not be used for assessing the risk of kernicterus in the presence of elevated "direct" bilirubin levels) If this limitation is ignored, many unnecessary exchange transfusions will be performed both in neonates and in older patients, as the case under discussion demonstrates. The only Conclusion that should be drawn from this case is that "direct" bilirubin does not contribute to kernicterus, a fact already established for the newborn period. +. 7 Timos Valaes, M.D. Director of Neonatolog)' New England Medical Center Hospital 171 Harrison A re. Boston, MA 02111 REFERENCES 1. Buchanan N, Cane RD, and Kalk F: Free bilirubin without basal ganglion staining, J PEDXA'rR92:158, 1978. 2. Athanassiades S, Chopra D, Fisher MA, and McKenna J: An electrophoretic method for detection of unbound bilirubin and reserve bilirubin binding capacity in serum of newborn, J Lab Clin Med 83:968, 1974. 3. Kapitulnik J, Valaes T, Kaufmann NA, and Blondheim StI: Clinical evaluation of sephadex gel filtration in estimation of bilirubin binding in serum in neonatal jaundice, Arch Dis Child 49:886, 1974. 4. Jacobsen J, and Wennberg RP: Determination of unbound bilirubin in the serum of newborns, Clin Chem 20:783, 1974. 5. Valses T, Kapitulnik J, Kaufmann NA, and Blondheim StI: Experience with sephadex gel filtration in assessing the risk of bilirubin encephalopathy in neonatal jaundice (and discussion of), Birth Defects 12:215, 1976. 6. Opp6 TE, and Valaes T: Obstructive jaundice and haemolytic disease of the newborn, Lancet 1:536, 1959. 7. Polacek K" Risk of kernicterus in newborn infants with a high level of conjugated bilirubin, Acta Paediatr Scand 55:401, 1966.
Effect of "'direct'" bilirttbin on "'free" bilirubin measttrements
Dosage fornls for theophylline
To the E~fitor: The interesting case described by Buchanan et al I raises important questions regarding the interpretation of tests assessing the bilirubin binding to albumin. In the case described the "direct reacting" fraction of bilirubin ,,,,'as extremely elevated (total bilirubin 59.6 mg/dl, "direct" 34.4 mg/dl). Of the currently used methods for assessing the bilirubin binding to albumin, the electrophoretic method used by the authors, z the sephadex gel filtration) the peroxidase,' and probably all of the remaining are affected by the presence of "direct reacting" bilirubin. In the presence of"direct" bilirubin values of > 2 to 3 mg/dl and irrespective of the total bilirubin level, which can be low enough to exclude the possibility of saturation of the albumin binding sites, the above methods give positive results. This phenomenon has been recognized as a limitation of the
To the Editor: "Theophylline for treatment of asthma TM clearly summarizes the evidence for efficacy of this bronchodilator and, although not explicitly stated, supports the emerging concept that this substance is now the initial medical therapy of choice for childhood asthma, llowever, we do not understand Dr. Weinberger's reluctance to recommend USP aminophylline tablets as a useful theophylline preparation. The bioavailability of theophylline in aminophylline tablets is excellent, and in a recent study did not differ substantially for three generic products.-" Aminophylline tablets are well tolerated and in our experience can be given after crushing to many small children. The wholesale cost per 100 mg theophylline equivalent is approximately one-fourth that of the least expensive anhydrous theophylline preparation recommended by Dr. Weinberg-
!58
Editorial correspondence
er? He does mention that aminophylline syrup (Somophyllin) is a potentially useful theophylline preparation, and we agree, although at a cost about 20 times greater than that for USP aminophylline tablets. As Dr. Weinberger points out, it is important to calculate a dosage for any theophylline preparation based on its actual theophylline content. Potential minor variations in theophylline content (78 to 86 mg theophylline/100 mg aminophylline tablet) ~ of the various generic aminophylline preparations are of little consequence if therapy is based on maintenance of adequate theophylline levels in blood. We feel that many children with asthma can be treated optimally, and at considerable costsavings, by prescribing USP am~inophylline tablets. Thomas F. Boat, M.D. Robert C. Stern, 2I[.D. David M. Orenstein, 3I.D. 9 Robert E. I Vood, M.D. Department of Pediatrics Case IVestern Reserve University 9 Rainbow Babies and Children's Hospital Cleveland, OH 44106 REFERENCES I.
Weinberger M: Theophylline for treatment of asthma, J PEOIATR 92:1, 1978. 2. Loren M, Miklich DR, Chai II, and Barwise G: Aminophylline bioavailability and the across time stability of plasma theophylline levels, J PEDZATR90:473, 1977. 3. Facts and Comparisons, Facts and Comparisons Inc., St. Louis, June-August, 1977, pp 178-179.
Reply To the Editor: The only. therapeutic ingredient in a formulation identified as aminophylline USP is the drug theophylline. There is no evidence that the other moiety, ethylenediamine, contributes to therapeutic effect, and toxicity has been suggested from this chemical agent.' The lower cost of aminophylline tablets must therefore be balanced against the small risk of toxicity from the ethylenediamine and the high cost of professional time required to instruct rotating students and house officers as to the theophylline content of these antiquated formulations. An additional issue relates to the question of bioavailability. Recent reviews have emphasized the potential lack of bioequivalence among products with similar generic content. : 3 The reference' referred to by Boat et al examined only the relative and not the absolute bioavailability of three generic aminophylline products. Even if we accept that those three products were completely and reliably absorbed, can we assume that other generic preparations will all be equally so? Although it appears that plain uncoated theophylline tablets (with or without ethylenediamine) are generall)' rapidly and completely absorbed if the tablet is properly made? 1 am not sure we can assume without testing that ever)" small generic house will manufacture their product with similar consistency. The prescribing physician
The Journal of Pediatrics July 1978
will be more assured of a uniform product by selecting a source of the drug with known bioavailability and utilizing it on a consistent basis. In summary,' the lower cost of ordering USP aminophylline tablets does not outweigh the variable sources of the material, inadequate labeling, and the inclusion of an ingredient that is at best unnecessary and occasionally harmful. Miles II'einberger, 3f.D. Associate Professor of Pediatrics and Pharmacology Chairman of the Pediatric Allergy and Puhnonary Division University of Iowa Hospitals and Clinics The University of Iowa Iowa Ot), 1.4 52242 REFERENCES 1. Petrozzi JE, and Shore RN: Generalized exfoliative dermatitis from ethylenediamine, Arch Dermatol 112:525, 1976. 2. Levy G, and Barr WH: The basis for selection of the dosage form and source of a drug, Ration Drug Ther 6:1, 1972. 3. Koch-Weser J: Bioavailability of drugs, N Engl J Med 291:503, 1974. 4. Loren M, Miklich DR, Chai H, et al: Aminophylline bioavailability and the across time stability of plasma theophylline levels, J PEDIATR 90:473, 1977. 5. Hendeles L, Weinberger M, and Bighley L: Absolute bioavailability of oral theophylline,.Am J Hosp Pharm 34:525, 1977.
Danger of iodine skin absorption in the neonate To the Editor: The article of Pyati and associates, in the November, 1977, issue of THE Jougr~^t, focuses attention upon the great permeability ofskin in the early period oflife, and danger of iodine itself as a toxic agent (acidosis). The application of 1% Polyvidone solution was very small: from one to a total of nine applications to the umbilical cord. The authors found very high levels of plasma and urine iodine, but no abnormality in the thyroid hormonal values. We have recently made a control study in an intensive care unit where numerous procedures such as umbilical catheterizations, collections of capillary blood in the heel, scalp-vein infusions, and blood cultures are performed repeatedly. Their number may reach 20 to 40 daily, from two to eight days, 1% iodine alcohol is used and carefully washed off each time. Studying 30 newborn infants in this condition, we found five instances with a small but definite acquired goiter (confirmed by 99m technetium scan), considerable ioduria (I to 3 mg/24 hours; normal: 10 to 40 #g), and high TStl and low T, values ('I"3 in normal range). After thyroid treatment, complete recession, both clinical and biological, was observed. The prediction of the authors that "prolonged use of providone
evidence that persistent hypertension in the young deserves continued observation. David Goldring, M.D. Professor of Pediatrics Director of Pediatric Cardiology Sol Londe, M.D. Associate Clinical Professor of Pediatrics, Emeritus IVashington University School of Medicine Antonio Hernandez, M.D. Associate Professor of Pediatrics IVashington Universit), School of Medicine St. Louis Children's Hospital St. Louis, MO 63110
REFERENCES I.
2.
3.
4.
5.
6. 7.
Goldring D, Londe S, Sivakoff M, Hernandez A, Britton C, and Choi S: Blood pressure in a high school population, J PFDZATR91:884, 1978. Kirby RR Kemmerer WT and Morgan JL: TranscutaI ' neous:Doppler measurement of blood pressure, Anesthesiology 31:86, 1964. Zinner SH, Levy PS, and Kass EH: Familial aggregation of bloodpressure in childhood, N Engl J Med 284:401, 1971. Holland J, Kutchen T, and Dinuar B: Hypertension in children with chronic pyelonephritis, Kidney lnt 8:243, 1975. Londe S, Bourgoigne JJ, Robson AM, and Goldring D: Hypertension in apparently normal children, J PEO~ATR 78:569, 1971. Perera GA: The course of primary hypertension in the young, Ann Intern Med 49:1348, 1958. Heyden J, Bartel AG, Hames CG, et al: Elevated blood pressure levels in adolescents. Evans County, Georgia, JAMA 209:1683, 1969.
Editorial correspondence
15 7
methods, which should not be used for assessing the risk of kernicterus in the presence of elevated "direct" bilirubin levels) If this limitation is ignored, many unnecessary exchange transfusions will be performed both in neonates and in older patients, as the case under discussion demonstrates. The only Conclusion that should be drawn from this case is that "direct" bilirubin does not contribute to kernicterus, a fact already established for the newborn period. +. 7 Timos Valaes, M.D. Director of Neonatolog)' New England Medical Center Hospital 171 Harrison A re. Boston, MA 02111 REFERENCES 1. Buchanan N, Cane RD, and Kalk F: Free bilirubin without basal ganglion staining, J PEDXA'rR92:158, 1978. 2. Athanassiades S, Chopra D, Fisher MA, and McKenna J: An electrophoretic method for detection of unbound bilirubin and reserve bilirubin binding capacity in serum of newborn, J Lab Clin Med 83:968, 1974. 3. Kapitulnik J, Valaes T, Kaufmann NA, and Blondheim StI: Clinical evaluation of sephadex gel filtration in estimation of bilirubin binding in serum in neonatal jaundice, Arch Dis Child 49:886, 1974. 4. Jacobsen J, and Wennberg RP: Determination of unbound bilirubin in the serum of newborns, Clin Chem 20:783, 1974. 5. Valses T, Kapitulnik J, Kaufmann NA, and Blondheim StI: Experience with sephadex gel filtration in assessing the risk of bilirubin encephalopathy in neonatal jaundice (and discussion of), Birth Defects 12:215, 1976. 6. Opp6 TE, and Valaes T: Obstructive jaundice and haemolytic disease of the newborn, Lancet 1:536, 1959. 7. Polacek K" Risk of kernicterus in newborn infants with a high level of conjugated bilirubin, Acta Paediatr Scand 55:401, 1966.
Effect of "'direct'" bilirttbin on "'free" bilirubin measttrements
Dosage fornls for theophylline
To the E~fitor: The interesting case described by Buchanan et al I raises important questions regarding the interpretation of tests assessing the bilirubin binding to albumin. In the case described the "direct reacting" fraction of bilirubin ,,,,'as extremely elevated (total bilirubin 59.6 mg/dl, "direct" 34.4 mg/dl). Of the currently used methods for assessing the bilirubin binding to albumin, the electrophoretic method used by the authors, z the sephadex gel filtration) the peroxidase,' and probably all of the remaining are affected by the presence of "direct reacting" bilirubin. In the presence of"direct" bilirubin values of > 2 to 3 mg/dl and irrespective of the total bilirubin level, which can be low enough to exclude the possibility of saturation of the albumin binding sites, the above methods give positive results. This phenomenon has been recognized as a limitation of the
To the Editor: "Theophylline for treatment of asthma TM clearly summarizes the evidence for efficacy of this bronchodilator and, although not explicitly stated, supports the emerging concept that this substance is now the initial medical therapy of choice for childhood asthma, llowever, we do not understand Dr. Weinberger's reluctance to recommend USP aminophylline tablets as a useful theophylline preparation. The bioavailability of theophylline in aminophylline tablets is excellent, and in a recent study did not differ substantially for three generic products.-" Aminophylline tablets are well tolerated and in our experience can be given after crushing to many small children. The wholesale cost per 100 mg theophylline equivalent is approximately one-fourth that of the least expensive anhydrous theophylline preparation recommended by Dr. Weinberg-
!58
Editorial correspondence
er? He does mention that aminophylline syrup (Somophyllin) is a potentially useful theophylline preparation, and we agree, although at a cost about 20 times greater than that for USP aminophylline tablets. As Dr. Weinberger points out, it is important to calculate a dosage for any theophylline preparation based on its actual theophylline content. Potential minor variations in theophylline content (78 to 86 mg theophylline/100 mg aminophylline tablet) ~ of the various generic aminophylline preparations are of little consequence if therapy is based on maintenance of adequate theophylline levels in blood. We feel that many children with asthma can be treated optimally, and at considerable costsavings, by prescribing USP am~inophylline tablets. Thomas F. Boat, M.D. Robert C. Stern, 2I[.D. David M. Orenstein, 3I.D. 9 Robert E. I Vood, M.D. Department of Pediatrics Case IVestern Reserve University 9 Rainbow Babies and Children's Hospital Cleveland, OH 44106 REFERENCES I.
Weinberger M: Theophylline for treatment of asthma, J PEOIATR 92:1, 1978. 2. Loren M, Miklich DR, Chai II, and Barwise G: Aminophylline bioavailability and the across time stability of plasma theophylline levels, J PEDZATR90:473, 1977. 3. Facts and Comparisons, Facts and Comparisons Inc., St. Louis, June-August, 1977, pp 178-179.
Reply To the Editor: The only. therapeutic ingredient in a formulation identified as aminophylline USP is the drug theophylline. There is no evidence that the other moiety, ethylenediamine, contributes to therapeutic effect, and toxicity has been suggested from this chemical agent.' The lower cost of aminophylline tablets must therefore be balanced against the small risk of toxicity from the ethylenediamine and the high cost of professional time required to instruct rotating students and house officers as to the theophylline content of these antiquated formulations. An additional issue relates to the question of bioavailability. Recent reviews have emphasized the potential lack of bioequivalence among products with similar generic content. : 3 The reference' referred to by Boat et al examined only the relative and not the absolute bioavailability of three generic aminophylline products. Even if we accept that those three products were completely and reliably absorbed, can we assume that other generic preparations will all be equally so? Although it appears that plain uncoated theophylline tablets (with or without ethylenediamine) are generall)' rapidly and completely absorbed if the tablet is properly made? 1 am not sure we can assume without testing that ever)" small generic house will manufacture their product with similar consistency. The prescribing physician
The Journal of Pediatrics July 1978
will be more assured of a uniform product by selecting a source of the drug with known bioavailability and utilizing it on a consistent basis. In summary,' the lower cost of ordering USP aminophylline tablets does not outweigh the variable sources of the material, inadequate labeling, and the inclusion of an ingredient that is at best unnecessary and occasionally harmful. Miles II'einberger, 3f.D. Associate Professor of Pediatrics and Pharmacology Chairman of the Pediatric Allergy and Puhnonary Division University of Iowa Hospitals and Clinics The University of Iowa Iowa Ot), 1.4 52242 REFERENCES 1. Petrozzi JE, and Shore RN: Generalized exfoliative dermatitis from ethylenediamine, Arch Dermatol 112:525, 1976. 2. Levy G, and Barr WH: The basis for selection of the dosage form and source of a drug, Ration Drug Ther 6:1, 1972. 3. Koch-Weser J: Bioavailability of drugs, N Engl J Med 291:503, 1974. 4. Loren M, Miklich DR, Chai H, et al: Aminophylline bioavailability and the across time stability of plasma theophylline levels, J PEDIATR 90:473, 1977. 5. Hendeles L, Weinberger M, and Bighley L: Absolute bioavailability of oral theophylline,.Am J Hosp Pharm 34:525, 1977.
Danger of iodine skin absorption in the neonate To the Editor: The article of Pyati and associates, in the November, 1977, issue of THE Jougr~^t, focuses attention upon the great permeability ofskin in the early period oflife, and danger of iodine itself as a toxic agent (acidosis). The application of 1% Polyvidone solution was very small: from one to a total of nine applications to the umbilical cord. The authors found very high levels of plasma and urine iodine, but no abnormality in the thyroid hormonal values. We have recently made a control study in an intensive care unit where numerous procedures such as umbilical catheterizations, collections of capillary blood in the heel, scalp-vein infusions, and blood cultures are performed repeatedly. Their number may reach 20 to 40 daily, from two to eight days, 1% iodine alcohol is used and carefully washed off each time. Studying 30 newborn infants in this condition, we found five instances with a small but definite acquired goiter (confirmed by 99m technetium scan), considerable ioduria (I to 3 mg/24 hours; normal: 10 to 40 #g), and high TStl and low T, values ('I"3 in normal range). After thyroid treatment, complete recession, both clinical and biological, was observed. The prediction of the authors that "prolonged use of providone
