- Email: [email protected]
Controlled Release Theophylline
In their survey of the training undergone by echocardiographic technicians, the Study Group has found that only about one-third of respondent technicians indicated that they had attended any formal course in echocardiography. The technician, in profile, emerges as a high school graduate who has generally attended (but not necessarily completed) college and has received on-the-job training of at least two months' duration. It is the conclusion of the Study Group that the lack of formal training for echocardiographic technicians makes it highly desirable that technicians be encouraged, or perhaps required, to attend formal courses. Such training programs should (1) provide familiarity with cardiac anatomy, physiology, and pathology; (2) foster a thorough understanding of the principles of diagnostic ultrasound; and (3) provide technical experience in performing the echocardiographic examination. The recommendations of the Study Group are consistent with those made by the InterSociety Commission for Heart Disease Resources in
1975.2 In reviewing the procedures prevalent in the various echocardiographic laboratories, the Study Group noted that the responding echocardiographic facilities were all under the direction of cardiologists or internist-cardiologists. It was further noted that in only 43 percent of teaching hospitals with cardiology fellowship training programs did cardiology fellows actually perform echocardiograms. This lack of experience by the fellow in the actual performance of echocardiograms contradicts the goal set forth for physician training by the American Society of Echocardiography that the physician should have the "ability to perform standard echocardiograms.''3 The most important projected equipment change noted in the study is the anticipated availability of two-dimensional ( cross-sectional) echocardiographic instruments in 85 percent of respondent institutions by the end of 1980. This widespread availability of two-dimensional echocardiography should improve the reliability of noninvasive cardiac diagnosis, but also will require more intensive echocardiographic training of technicians and physicians and possibly result in increased hospital costs. The Study Group did not assess objectively either the quality of echocardiographic recordings or the knowledge and capabilities of the echocardiographic technicians and physicians. This type of evaluation, of course, would have been a significant undertaking: a degree of subjectivity and perhaps some resistance on the part of the participants would have been involved. Studies like this one are important because they
250 EDITORIALS
provide objective peer-review of the status of a segment of medical practice. It is axiomatic that medical practitioners must scrutinize their own practice lest outside agencies perform this function for them. Julius M. Gardin, M.D., F.C.C.P.·
Orange, CA
James V. Talano, M.D., F.C.C.P.t
Chicago
• Assistant Professor of Medicine and Director, Noninvasive Cardiology Laboratory, University of California-Irvine Medical Center. tAssociate Professor of Medicine and Director, Cardiology Graphics Laboratory, Northwestern University Medical School. Reprint requests: Dr. Talano, Wesley Pavilion, Room 587, 250 East Superior, Chicago 60611
REFERENCES 1 Gardin JM, Talano J, Battle W, et ale The status of echocardiographic practice in a large metropolitan area: Report of the Echocardiography Study Group, Diagnostics Committee, Chicago Heart Association. Arch Intern Med 1980; 140:923-26 2 Gramiak R, Fortuin M], King DL, et ale Report of the Inter-Society Commission for Heart Resources: Optimal resources for ultrasonic examination of the heart. J Clin Ultrasound 1975; 3:145-151 3 Physician training in adult M-mode echocardiography. Suggested guidelines of the American Society of Echocardiography, 1979
Controlled Release Theophylline
I t is generally accepted that the therapeutic ac-
tivity of theophylline in patients with reversible airway disease can be maximized by maintaining the plasma concentration above 10 /Lg/ ml. The dosage form of theophylline can influence rate and extent of drug delivery and therefore can influence the plasma level. In this issue of Chest (see page 300) Meyer and co-workers reported on the bioavailability of three different theophylline or aminophylline dosage forms manufactured by one pharmaceutical company. A prior study by another research group! using a different batch of aminophylline (Aminodur Dura-tabs) controlled-release tablets reported only 65 percent bioavailability relative to a reference solution. However, this earlier report was justifiably challenged by the present authors on the basis of inadequate experimental design. In their study, Meyer et al used 12 healthy, nonsmoking male subjects in a cross-over design, administering each drug on an eight-hour dosing schedule and measuring the concentration-time course during the ninth dosing interval. Their results clearly indicate no difference in the mean bioavailability among the three dosage forms with the batches selected for testing. However, one can abstract some additional comparative information from their study. The authors
CHEST, 78: 2, AUGUST, 1980
include the SDs about the mean values. Examina-
tion of the relative ~D CftIl lend to informRtion in
the variability of the sustained-release preparation when compared with the elixir. The relative SD of the elixir was 26 percent. Since this solution dosage fonn is virtually 100 percent bioavailable.v" this variation is due to variation in elimination clearance of the drug within the population tested In contrast, the sustained-release capsules showed a 34 percent relative SD, and the tablets 30 percent. Any significant increases in variation are in all likelihood due to dose-to-dose variability in drug absorption from the preparation. These variations
may be of minimal clinical significance, yet their
effect would be amplified in patients with high elimination clearance (short half-life); those who can best benefit from administration of controlledrelease dosage forms. One can calculate the parameters controlling the elimination characteristics of theophylline from the results obtained by Meyer et al (mean clearance = 37+6 mI/kg/hr; volume of distribution=490 mIl kg; half-life, 8.7 hr). These values ·are virtually identical to the results of earlier studies of Powell et al3 for healthy nonsmokers. Elimination half-lives ranging from 2.4 to more than 20 hours (mean half-life = 5.5 hr) have been measured in asthmatics free from other pathologic conditions known to affect theophylline kinetics. 2,. Subjects with shorter half-lives will show larger peak-trough differences. Presuming a dose of the elixir is administered to achieve a peak therapeutic concentration, serum levels in subjects with a halflife less than 5.5 hr will fall below the therapeutic level before their next dose, even on a six-hour schdule and will decline far below therapeutic levels overnight. Drug monitoring and dosage adjusbnent are more difficult. The use of the sustained-release dosage forms such as reported in this issue is extremely useful in the treatment of patients with high rates of clearance of theophylline (eg, half-lives of less than six hours). Such subjects can be much more effectively controlled using one of the sustained-action
CHEST, 78: 2, AUGUST, 1980
dosage forms. The study of Meyers et al used an
@ipt.Bnup 80liBft ieh@8uI@. It illii@}V ~l~ AIftlftft.
dur Dura-tabs can be used on a 12-hour dosing sehedule.s but additional testing is required to validate whether the sustained release capsule can maintain control on a 12-hour dosing schedule, particularly owing to the apparent higher dose-to-dose variability shown with the capsules. Subjects with a long half-life (slow clearance) can be treated with less expensive aminophylline tablets. However, side effects have been noted to be reduced by administration of sustained-release dosage forms, even in this special population.
Sustained-release preparations are most clearly
indicated in asthmatic subjects, many of whom have great fluctuations in airway caliber. Those with a pattern of severe nocturnal bronchospasm are, in fact, at risk of sudden asthmatic death. Ii The ensurance of therapeutic levels during these hours and the entire 24-hour day is comforting to patient and physician. Sidney Riegelman, Ph.D.,·
San Francisco, and
John w. Jenne, M.D.,t Hines, Ill.
°Department of Pharmacy and Pharmaceutical Chemistry, University of California, and tPulmonary Disease Section, Edward Hines, Jr. Veterans Administration Hospital. Reprint requesta: DI. Jenne, VA HoaplttJl, Hina, ID. 60141
REFERENCES 1 Weinberger M, Hendeles L, Bighley L. The relation of product formulation to absorption of oral theophylline. N Engl J Med 1978; 299:852 2 Upton RA, Sanson L, Guentert TW, et ale The evaluation of absorption from 15 commercial products indicating deficiencies in currently applied bioavailability criteria. J Pharmacokin Biopharm 1980. In press 3 Powell JR, Bozeh S, Hopewell P, et at Theophylline disposition in acutely ill hospitalized patients: affect of smoking, heart failure, severe airway obstruction and pneumonia. Am Rev Resp Dis 1978; 118:229 4 Ogilvie RI. Clinical pharmacokinetics of theophylline. Coo Pharmacokin 1978; 3:267 5 Hetzel MR, Clark TJH, Braithwaite MA. Asthma: analysis of sudden death and ventilatory arrests in hospital Br Moo J 1978; 1:808
EDITORIALS 251
1975.2 In reviewing the procedures prevalent in the various echocardiographic laboratories, the Study Group noted that the responding echocardiographic facilities were all under the direction of cardiologists or internist-cardiologists. It was further noted that in only 43 percent of teaching hospitals with cardiology fellowship training programs did cardiology fellows actually perform echocardiograms. This lack of experience by the fellow in the actual performance of echocardiograms contradicts the goal set forth for physician training by the American Society of Echocardiography that the physician should have the "ability to perform standard echocardiograms.''3 The most important projected equipment change noted in the study is the anticipated availability of two-dimensional ( cross-sectional) echocardiographic instruments in 85 percent of respondent institutions by the end of 1980. This widespread availability of two-dimensional echocardiography should improve the reliability of noninvasive cardiac diagnosis, but also will require more intensive echocardiographic training of technicians and physicians and possibly result in increased hospital costs. The Study Group did not assess objectively either the quality of echocardiographic recordings or the knowledge and capabilities of the echocardiographic technicians and physicians. This type of evaluation, of course, would have been a significant undertaking: a degree of subjectivity and perhaps some resistance on the part of the participants would have been involved. Studies like this one are important because they
250 EDITORIALS
provide objective peer-review of the status of a segment of medical practice. It is axiomatic that medical practitioners must scrutinize their own practice lest outside agencies perform this function for them. Julius M. Gardin, M.D., F.C.C.P.·
Orange, CA
James V. Talano, M.D., F.C.C.P.t
Chicago
• Assistant Professor of Medicine and Director, Noninvasive Cardiology Laboratory, University of California-Irvine Medical Center. tAssociate Professor of Medicine and Director, Cardiology Graphics Laboratory, Northwestern University Medical School. Reprint requests: Dr. Talano, Wesley Pavilion, Room 587, 250 East Superior, Chicago 60611
REFERENCES 1 Gardin JM, Talano J, Battle W, et ale The status of echocardiographic practice in a large metropolitan area: Report of the Echocardiography Study Group, Diagnostics Committee, Chicago Heart Association. Arch Intern Med 1980; 140:923-26 2 Gramiak R, Fortuin M], King DL, et ale Report of the Inter-Society Commission for Heart Resources: Optimal resources for ultrasonic examination of the heart. J Clin Ultrasound 1975; 3:145-151 3 Physician training in adult M-mode echocardiography. Suggested guidelines of the American Society of Echocardiography, 1979
Controlled Release Theophylline
I t is generally accepted that the therapeutic ac-
tivity of theophylline in patients with reversible airway disease can be maximized by maintaining the plasma concentration above 10 /Lg/ ml. The dosage form of theophylline can influence rate and extent of drug delivery and therefore can influence the plasma level. In this issue of Chest (see page 300) Meyer and co-workers reported on the bioavailability of three different theophylline or aminophylline dosage forms manufactured by one pharmaceutical company. A prior study by another research group! using a different batch of aminophylline (Aminodur Dura-tabs) controlled-release tablets reported only 65 percent bioavailability relative to a reference solution. However, this earlier report was justifiably challenged by the present authors on the basis of inadequate experimental design. In their study, Meyer et al used 12 healthy, nonsmoking male subjects in a cross-over design, administering each drug on an eight-hour dosing schedule and measuring the concentration-time course during the ninth dosing interval. Their results clearly indicate no difference in the mean bioavailability among the three dosage forms with the batches selected for testing. However, one can abstract some additional comparative information from their study. The authors
CHEST, 78: 2, AUGUST, 1980
include the SDs about the mean values. Examina-
tion of the relative ~D CftIl lend to informRtion in
the variability of the sustained-release preparation when compared with the elixir. The relative SD of the elixir was 26 percent. Since this solution dosage fonn is virtually 100 percent bioavailable.v" this variation is due to variation in elimination clearance of the drug within the population tested In contrast, the sustained-release capsules showed a 34 percent relative SD, and the tablets 30 percent. Any significant increases in variation are in all likelihood due to dose-to-dose variability in drug absorption from the preparation. These variations
may be of minimal clinical significance, yet their
effect would be amplified in patients with high elimination clearance (short half-life); those who can best benefit from administration of controlledrelease dosage forms. One can calculate the parameters controlling the elimination characteristics of theophylline from the results obtained by Meyer et al (mean clearance = 37+6 mI/kg/hr; volume of distribution=490 mIl kg; half-life, 8.7 hr). These values ·are virtually identical to the results of earlier studies of Powell et al3 for healthy nonsmokers. Elimination half-lives ranging from 2.4 to more than 20 hours (mean half-life = 5.5 hr) have been measured in asthmatics free from other pathologic conditions known to affect theophylline kinetics. 2,. Subjects with shorter half-lives will show larger peak-trough differences. Presuming a dose of the elixir is administered to achieve a peak therapeutic concentration, serum levels in subjects with a halflife less than 5.5 hr will fall below the therapeutic level before their next dose, even on a six-hour schdule and will decline far below therapeutic levels overnight. Drug monitoring and dosage adjusbnent are more difficult. The use of the sustained-release dosage forms such as reported in this issue is extremely useful in the treatment of patients with high rates of clearance of theophylline (eg, half-lives of less than six hours). Such subjects can be much more effectively controlled using one of the sustained-action
CHEST, 78: 2, AUGUST, 1980
dosage forms. The study of Meyers et al used an
@ipt.Bnup 80liBft ieh@8uI@. It illii@}V ~l~ AIftlftft.
dur Dura-tabs can be used on a 12-hour dosing sehedule.s but additional testing is required to validate whether the sustained release capsule can maintain control on a 12-hour dosing schedule, particularly owing to the apparent higher dose-to-dose variability shown with the capsules. Subjects with a long half-life (slow clearance) can be treated with less expensive aminophylline tablets. However, side effects have been noted to be reduced by administration of sustained-release dosage forms, even in this special population.
Sustained-release preparations are most clearly
indicated in asthmatic subjects, many of whom have great fluctuations in airway caliber. Those with a pattern of severe nocturnal bronchospasm are, in fact, at risk of sudden asthmatic death. Ii The ensurance of therapeutic levels during these hours and the entire 24-hour day is comforting to patient and physician. Sidney Riegelman, Ph.D.,·
San Francisco, and
John w. Jenne, M.D.,t Hines, Ill.
°Department of Pharmacy and Pharmaceutical Chemistry, University of California, and tPulmonary Disease Section, Edward Hines, Jr. Veterans Administration Hospital. Reprint requesta: DI. Jenne, VA HoaplttJl, Hina, ID. 60141
REFERENCES 1 Weinberger M, Hendeles L, Bighley L. The relation of product formulation to absorption of oral theophylline. N Engl J Med 1978; 299:852 2 Upton RA, Sanson L, Guentert TW, et ale The evaluation of absorption from 15 commercial products indicating deficiencies in currently applied bioavailability criteria. J Pharmacokin Biopharm 1980. In press 3 Powell JR, Bozeh S, Hopewell P, et at Theophylline disposition in acutely ill hospitalized patients: affect of smoking, heart failure, severe airway obstruction and pneumonia. Am Rev Resp Dis 1978; 118:229 4 Ogilvie RI. Clinical pharmacokinetics of theophylline. Coo Pharmacokin 1978; 3:267 5 Hetzel MR, Clark TJH, Braithwaite MA. Asthma: analysis of sudden death and ventilatory arrests in hospital Br Moo J 1978; 1:808
EDITORIALS 251