Correspondence
EPP masquerading as angioedema To the Editor: A 9-yr-old girl was seen at Colorado General Hospital for recurrent episodes of swelling of the face which had occurred intermittently over the past five years. The child’s mother noted that the episodes occurred whenever the child went outdoors. Her local allergist evaluated her for the possibility of airborne allergens and, indeed, this youngster had one or two positive scratch tests. Repeated testing, however, failed to confirm the positive scratch testing. She was treated for a period of time with hyposensitization with no apparent influence on the course of her illness. When first seen at the University of Colorado Medical Center following an episode outdoors, she had edema of the upper eyelids, forehead, and cheeks with some crusting over her nose. She complained of “burning sensation” of her skin. Sun sensitivity was suspected and her red cells were fluoresced. Indeed, greater than 80% of her red cells fluoresced coral red, suggesting protoporphyria. Quantitative protoporphyrins in her peripheral red blood cells were elevated seven times above normal. Treatment with oral p-carotene at 30 mglday allowed her considerable sun tolerance and complete clearing of her angioedema. She is now able to be outdoors for 4 to 6 hr at a time without symptoms. When considering symptomatology related to outdoor exposure, one should always recall that ultraviolet light sensitivity should be considered as well as airborne environmental factors as we see in this child with erythmpoietic protoporphyria who was thought to have an airborne allergy.
William L. Weston, M.D. University of Colorado Medical Center Denver, Cola. 80220
Discrepancy of the conversion factor between theophylline and aminophylline To the Editor: Theophylline is a widely used potent bmnchodilating agent. Plasma level monitoring of this drug in patients has been strongly recommended. Recently Ellis and Eddy’ have correctly pointed out the potential clinical implications of the problem of the anhydrous theophylline equivalence of many commercial theophylline formulations. One of the compounds mentioned is aminophylline, which is a salt of two molecules of theophylline and one molecule of ethylenediamine. According to these authors, 100 mg of aminophylline should contain 85 mg of anhydmus theophylline. Vol. 61, No. 6. pp. 408-409
In other words, the conversion factor of aminophylline to theophylline is 0.85. A limited survey of the recent literature regarding the clinical pharmacokinetics and dosage regimens of theophylline, however, reveals some discrepancy in the conversion factor between these two compounds among various workers. The purposes of this communication are to point out the existence of such a discrepancy and its possible underlying causes, and also to propose a method for the solution. In this survey the conversion factor of 0.85 was found to be also used in a number of publications.2-5 In at least three publications+a a factor of 0.8 was used. The exact cause of such a discrepancy is not known. It probably resulted from the different interpretation of the official Pharmacopeia.g According to the Pharmacopeia, the pure arninophylline, available as anhydrous or dihydrate form, should contain not less than 98% and not more than 100.3% of (anhydrous) theophylline calculated on the anhydrous basis. Based on the molecular weights of theophylline (180.17) and anhydrous aminophylline (420.43), a conversion factor of 0.85 (180.17 x 2 x (0.98 + 1.003)/420.43 x 2) can be obtained. Indeed, such a factor is clearly used in some commercial dosage forms such as Mudraner” and Somophyllin rectal solution. lo On the other hand, the Pharmacopeiag specifies that aminophylline injection contains, in each milliliter, not less than 23.25 mg and not more than 26.75 mg of aminophylline dihydrate which has a molecular weight of 456.46. Based on this, the conversion factor should be 0.7894 (180.17 x 2/456.46). In other words, the correct conversion factor for the official intravenous aminophylline injection dosage form should be 0.7894. The factor of 0.8 used by others is probably an approximation of 0.7894 which should be clinically acceptable. It is of interest to note that the official specifications9 for the tablet, suppository, and enema dosage forms of aminophylline ate all based on the labeled contents of the dihydrate which should result in a conversion factor of 0.7894. Although the above discrepancies in the conversion factor may not be clinically significant, nevertheless, the difference of 7.5%, resulting from the use of 0.85 and 0.80 factors, will produce the same degree of error in the calculation of the apparent volume of distribution and total body clearance of theophylline. Ideally, such a source of error should be avoided. In light of the above discrepancy and confusion existing regarding ‘the aminophylline conversion factor, it’ is pmposed that the same single conversion factor be established for all of the official and nonofficial products containing aminophylline. If the dihydrate form is most widely avail-
EPP masquerading as angioedema To the Editor: A 9-yr-old girl was seen at Colorado General Hospital for recurrent episodes of swelling of the face which had occurred intermittently over the past five years. The child’s mother noted that the episodes occurred whenever the child went outdoors. Her local allergist evaluated her for the possibility of airborne allergens and, indeed, this youngster had one or two positive scratch tests. Repeated testing, however, failed to confirm the positive scratch testing. She was treated for a period of time with hyposensitization with no apparent influence on the course of her illness. When first seen at the University of Colorado Medical Center following an episode outdoors, she had edema of the upper eyelids, forehead, and cheeks with some crusting over her nose. She complained of “burning sensation” of her skin. Sun sensitivity was suspected and her red cells were fluoresced. Indeed, greater than 80% of her red cells fluoresced coral red, suggesting protoporphyria. Quantitative protoporphyrins in her peripheral red blood cells were elevated seven times above normal. Treatment with oral p-carotene at 30 mglday allowed her considerable sun tolerance and complete clearing of her angioedema. She is now able to be outdoors for 4 to 6 hr at a time without symptoms. When considering symptomatology related to outdoor exposure, one should always recall that ultraviolet light sensitivity should be considered as well as airborne environmental factors as we see in this child with erythmpoietic protoporphyria who was thought to have an airborne allergy.
William L. Weston, M.D. University of Colorado Medical Center Denver, Cola. 80220
Discrepancy of the conversion factor between theophylline and aminophylline To the Editor: Theophylline is a widely used potent bmnchodilating agent. Plasma level monitoring of this drug in patients has been strongly recommended. Recently Ellis and Eddy’ have correctly pointed out the potential clinical implications of the problem of the anhydrous theophylline equivalence of many commercial theophylline formulations. One of the compounds mentioned is aminophylline, which is a salt of two molecules of theophylline and one molecule of ethylenediamine. According to these authors, 100 mg of aminophylline should contain 85 mg of anhydmus theophylline. Vol. 61, No. 6. pp. 408-409
In other words, the conversion factor of aminophylline to theophylline is 0.85. A limited survey of the recent literature regarding the clinical pharmacokinetics and dosage regimens of theophylline, however, reveals some discrepancy in the conversion factor between these two compounds among various workers. The purposes of this communication are to point out the existence of such a discrepancy and its possible underlying causes, and also to propose a method for the solution. In this survey the conversion factor of 0.85 was found to be also used in a number of publications.2-5 In at least three publications+a a factor of 0.8 was used. The exact cause of such a discrepancy is not known. It probably resulted from the different interpretation of the official Pharmacopeia.g According to the Pharmacopeia, the pure arninophylline, available as anhydrous or dihydrate form, should contain not less than 98% and not more than 100.3% of (anhydrous) theophylline calculated on the anhydrous basis. Based on the molecular weights of theophylline (180.17) and anhydrous aminophylline (420.43), a conversion factor of 0.85 (180.17 x 2 x (0.98 + 1.003)/420.43 x 2) can be obtained. Indeed, such a factor is clearly used in some commercial dosage forms such as Mudraner” and Somophyllin rectal solution. lo On the other hand, the Pharmacopeiag specifies that aminophylline injection contains, in each milliliter, not less than 23.25 mg and not more than 26.75 mg of aminophylline dihydrate which has a molecular weight of 456.46. Based on this, the conversion factor should be 0.7894 (180.17 x 2/456.46). In other words, the correct conversion factor for the official intravenous aminophylline injection dosage form should be 0.7894. The factor of 0.8 used by others is probably an approximation of 0.7894 which should be clinically acceptable. It is of interest to note that the official specifications9 for the tablet, suppository, and enema dosage forms of aminophylline ate all based on the labeled contents of the dihydrate which should result in a conversion factor of 0.7894. Although the above discrepancies in the conversion factor may not be clinically significant, nevertheless, the difference of 7.5%, resulting from the use of 0.85 and 0.80 factors, will produce the same degree of error in the calculation of the apparent volume of distribution and total body clearance of theophylline. Ideally, such a source of error should be avoided. In light of the above discrepancy and confusion existing regarding ‘the aminophylline conversion factor, it’ is pmposed that the same single conversion factor be established for all of the official and nonofficial products containing aminophylline. If the dihydrate form is most widely avail-
