iopanoic acid 40 to 42 hours before roentgenography and a second dose Letters, if clearly marked "For Publication," will be published as space permits and at the discretion of the editor. They should be typewritten triple-spaced, with five or fewer references, should not exceed two pages in length, and will be subject to editing. Letters are
not
acknowledged.
Delayed Idiosyncratic Psychosis
With Phenytoin To the Editor.\p=m-\The clinical note by McDanal and Bolman (231:1063, 1975) raises some interesting points. It is
always tempting to postulate a cause and effect relationship between medi-
cation and symptom if the symptom disappears when the medication is withdrawn. However, this explanation, ie, that a paranoid psychosis was produced by an idiosyncratic reaction to phenytoin, must be evaluated in the context of the patient's disease state. The authors reported their patient to have had long-standing epileptic seizures, and the patient's husband is quoted as reporting the patient to have had symptoms of violent behavior even when the florid psychosis had disappeared. This makes one suspect that the patient's epileptic process involves her limbic
system.
The literature is replete with references to various forms of epileptic disease associated with abnormal behavior. The classic monograph of Slater et al1 in 1963 described certain forms of epilepsy that seemed to predispose to chronic paranoid and hallucinatory psychoses resembling schizo¬ phrenia. They concluded that the emergence of psychosis was related to the duration of the epilepsy and to brain damage but was independent of the severity of the epilepsy although related to temporal lobe seizures. More recently, this subject has been reviewed by Pincus and Tucker.2 It may be that the relationship re¬ ported by McDanal and Bolman is valid and extremely important. How¬ ever, since this case is an isolated case anermust be compared with an entire literature that relates epilepsy to various forms of abnormal behavior; further information and evidence must be obtained by these authors to substantiate their conclusion. Vernon H. Mark, MD Harvard Medical School Boston
Edited
by John D. Archer, MD, Senior Editor.
1. Slater E, Beard AW, Glithero E: The schizophrenialike psychoses of epilepsy. Br J Psychiatry 109:95-150, 1963. 2. Pincus JH, Tucker G: Behavioral Neurology. New York, Oxford University Press, 1974, chap 1 and 2.
In Reply.\p=m-\DrMark referred to the association of epilepsy and abnormal behavior documented by references supporting this clinical finding. We also knew that this phenomenon existed but had the complicated clinical problem of finding which factors influenced our patient's condition and what treatment would be best for her. The most significant clinical change resulted after discontinuing the use of phenytoin, even though the phenytoin blood levels were much below toxic range and the patient had no other signs of phenytoin toxicity. We were not certain as to the cause of this abnormal behavior and psychosis, but the phenytoin clearly had an in-
fluence. Since
we have reported this isolated occurrence, perhaps other physicians will find patients with a similar response to phenytoin or other anticonvulsants. Clarence E. McDanal Jr, MD University of Hawaii Honolulu
Cholecystographic Modifications Improve Initial Study
to
Opacification
To the Editor.\p=m-\An
editorial in The Journal (232:642, 1975) discussed the problem of nonopacification of the gallbladder with a single 3-gm dose of iopanoic acid (Telepaque). It pointed out that an estimated 15 million Americans are afflicted with gallbladder disease, and hence, are potential candidates for cholecystography. Nonopacified gallbladders occur in 25% of patients with a single 3-gm dose, but the second dose of 3 gm of iopanoic acid causes opacification in 70%. Eighty percent of patients in whom opacification is obtained with reinforcement have normal gallbladders. A recommendation for the sake of economy was therefore made that all patients routinely receive 3 gm of
Downloaded From: http://jama.jamanetwork.com/ by a Simon Fraser University User on 06/02/2015
of 3 gm at 14 to 16 hours before. 15 million cholecystograms are to be done, this recommendation means that 11,250,000 patients receive the double dose unnecessarily and suffer the inconvenience and morbidity of the greater dosage and longer period of preparation. Fur¬ thermore, 180 million iopanoic-acid tablets (approximately $30 million) are required instead of 111 million ($18 million). There is no economy in this recommendation.
Assuming that
Nevertheless, attempts to reduce insufficient opacification of the gall¬ bladder on the first study are worthy because any repeated examinations cause additional radiation exposure and waste time and money. There are ways of modifying the present pro¬ cedure of cholecystography to make good first-dose visualization more consistent and to reduce the necessity for repeated examinations. Bile salts enhance the intestinal absorption and hepatic excretion of iopanoic acid.1 Traditional precholecystographic fast¬ ing and low-fat diet cause gallbladder sequestration and impaired liver ex¬ cretion of bile salts.2 It appears that poor first-dose opacification of the gallbladder in normal patients may be the result of lack of circulating bile salts when the iopanoic acid is in¬ gested. Consequently, the iopanoic acid is incompletely absorbed from the intestine and poorly excreted by the liver. For these reasons, gallblad¬ der opacification can be improved by giving fat in the meal immediately before the ingestion of iopanoic acid or by combining the contrast tablets with a cholecystagogue such as corn oil.
Gallbladder opacification is also im¬ if the iopanoic acid is given over a six-hour period rather than over a 10- to 20-minute period. The improvement may result from a greater absorption of the contrast material because of the increased enterohepatic recirculation of bile salts during the six-hour interval.3 Optimal opacification of the gall¬ bladder occurs 14 to 17 hours after the administration of iopanoic acid. The conventional 12-hour interval be¬ tween the ingestion of contrast mate¬ rial and the x-ray films is too short to permit adequate concentration of the iopanoic acid in the gallbladder of
proved
some
patients.4
These modifications make it pos¬ sible to reduce the nonopacifiednor-
mal out
gallbladder resorting
to a minimum with¬ to the inefficient recommendation of subjecting all pa¬ tients to the expense, inconvenience,
and
morbidity of a double dose of panoic acid over a 40-hour period.
io¬
Charles E. Shopfner, MD Mobile, Ala
1. Berk RN, Loeb PM,
lecystography
with
210, 1974. 2.
Goldberger LE, et al: Oral choiopanoic acid. N Engl J Med 290:204\x=req-\
Goldberger LE, Berk RN, Lang JH, et al: Biopharinfluencing the intestinal absorption
maceutical factors
iopanoic acid. Invest Radiol 9:16-23, 1974. 3. Koehler PR, Kyaw MM: Effect of fractionated administration of Telepaque on gallbladder visualization. Radiology 108:517-519, 1973. 4. Whalen JP, Rizzuiti RJ, Evans JA: Time of optimal of
gallbladder opacification with Telepaque (iopanoic acid). Radiology 105:523-524, 1972.
Stamp for Charting
measurement, irregularity, dimpling,
Breast Lesions To the
The stamp and design are illustrated in the Figure. The nipple and areola are centrally placed. Concentric circles are made; each intervening space represents a finger's breadth or, if desired, a metric measurement. Straight lines, corresponding to the numbers on a clock, are made from the edge of the areola to the outer edge of the circle. With this as a chart, masses, thickening, and other findings are accurately recorded in exact position, ie, two fingers' breadth from the areola at the 9 o'clock position. Solid masses may be designated by a solid mark, cysts with a plain circle, and thickening with a cross-hatched symbol. The or other pertinent facts recorded in the margins. This stamped diagram allows pre¬ cision in record keeping by showing on a patient's chart the exact loca¬ tion, size, and type of all lesions. Sub¬ sequent changes are easily noted by providing a visual method for recall and comparison. The method is rapid and timesaving and is stamped on the office examination sheet. It elimi¬ nates the need for lengthy word de¬
retraction, is
Editor.\p=m-\There increasing public awareness of the importance of
breast examination. When the patient is examined by the physician, the findings are recorded and should become a permanent part of the patient's file. They are recorded by brief or lengthy word descriptions or by the use of printed forms, drawn diagrams, or rubber stamp. A stamp diagram was designed that permits specific, precise, and accurate location and description of all breast lesions.
are
scriptions, rough drawings, or printed
charts and is also valuable in the follow-up of multiple aspirated cysts. The stamp is inexpensive and is read¬ ily available for use by physicians (Printing Place of Kensington, Ken¬ sington, MD 20795). In addition, at the discretion of the examiner, the patient can be provided with copies of stamped imprints for recording find¬ ings on self-examination. Daniel J. Abramson, MD
Army Medical Center Washington, DC Walter Reed
Breast stamp and
diagram.
New Drugs for Hypertension: An FDA Reply To the Editor.\p=m-\In an editorial (229:689, 1974), Dr Edward D. Freis charged the Food and Drug Administration (FDA) with depriving American physicians and their patients of a number of useful antihypertensive drugs. Such "drug lag" editorials have appeared in various journals in the past, and we are not able to respond to all of them. This particular editorial, however, has generated numerous inquiries to the FDA, undoubtedly because of the importance of hypertension and the prominence of Dr Freis. I would therefore like to comment on some of the points he raises and correct several inaccuracies. A more complete discussion of
Downloaded From: http://jama.jamanetwork.com/ by a Simon Fraser University User on 06/02/2015
the drug lag issue by the FDA can be found in our testimony before subcommittees of the senate committees on labor and public welfare and on the judiciary on Aug 16 and Sept 27, 1974. Dr Freis cited the absence from the United States of three antihypertensive drugs popular in the United
Kingdom: bethanidine, debrisoquin, propranolol (available here but not labeled for treatment of hyper¬ tension). He stated that applications for these drugs were submitted to and
the FDA many years ago and that debrisoquin was disapproved while the others "have not been acted on as yet." The basic problem was attrib¬ uted to "endless delay and procrasti¬ nation" resulting from the "individ¬ ual reviewing officer who is unable or unwilling to arrive at a fair judgment of the benefit-risk ratio of a new drug." Unfortunately, these allega¬ tions are incorrect and serve only to perpetuate misconceptions about FDA review procedures. New drug applications (NDAs) for debrisoquin and bethanidine were submitted to the FDA in 1964 and 1966, respectively. Both applications were disapproved because of the lack of controlled studies providing ade¬ quate evidence of safety and effec¬ tiveness, and neither NDA sponsor has ever submitted a subsequent ap¬ plication. Dr Freis' concerns thus re¬ late to his disagreement with judg¬ ments and regulatory decisions made a number of years ago, rather than to untimely review procedures or pro¬ crastination. Marketing rights to bethanidine have been transferred to a different manufacturer, who has ac¬ tively supported clinical studies; an NDA for bethanidine is now under review. Clinical studies of debrisoquin were discontinued several years ago, and we are not aware of plans to mar¬ ket the drug in the United States. Propranolol also has not been sub¬ ject to a prolonged review by the FDA. Ayerst Laboratories first sub¬ mitted an application for propranolol for the treatment of hypertension in late December 1974. Such a submis¬ sion had been requested by FDA for about two years prior to that time. A supplemental application was sub¬ mitted in April 1975. Those appli¬ cations are currently under review. Whether medical practice in the United States is seriously impaired by the nonavailability of bethanidine and debrisoquin is difficult to de¬ termine. Guanethidine, a drug long
not
acknowledged.
Delayed Idiosyncratic Psychosis
With Phenytoin To the Editor.\p=m-\The clinical note by McDanal and Bolman (231:1063, 1975) raises some interesting points. It is
always tempting to postulate a cause and effect relationship between medi-
cation and symptom if the symptom disappears when the medication is withdrawn. However, this explanation, ie, that a paranoid psychosis was produced by an idiosyncratic reaction to phenytoin, must be evaluated in the context of the patient's disease state. The authors reported their patient to have had long-standing epileptic seizures, and the patient's husband is quoted as reporting the patient to have had symptoms of violent behavior even when the florid psychosis had disappeared. This makes one suspect that the patient's epileptic process involves her limbic
system.
The literature is replete with references to various forms of epileptic disease associated with abnormal behavior. The classic monograph of Slater et al1 in 1963 described certain forms of epilepsy that seemed to predispose to chronic paranoid and hallucinatory psychoses resembling schizo¬ phrenia. They concluded that the emergence of psychosis was related to the duration of the epilepsy and to brain damage but was independent of the severity of the epilepsy although related to temporal lobe seizures. More recently, this subject has been reviewed by Pincus and Tucker.2 It may be that the relationship re¬ ported by McDanal and Bolman is valid and extremely important. How¬ ever, since this case is an isolated case anermust be compared with an entire literature that relates epilepsy to various forms of abnormal behavior; further information and evidence must be obtained by these authors to substantiate their conclusion. Vernon H. Mark, MD Harvard Medical School Boston
Edited
by John D. Archer, MD, Senior Editor.
1. Slater E, Beard AW, Glithero E: The schizophrenialike psychoses of epilepsy. Br J Psychiatry 109:95-150, 1963. 2. Pincus JH, Tucker G: Behavioral Neurology. New York, Oxford University Press, 1974, chap 1 and 2.
In Reply.\p=m-\DrMark referred to the association of epilepsy and abnormal behavior documented by references supporting this clinical finding. We also knew that this phenomenon existed but had the complicated clinical problem of finding which factors influenced our patient's condition and what treatment would be best for her. The most significant clinical change resulted after discontinuing the use of phenytoin, even though the phenytoin blood levels were much below toxic range and the patient had no other signs of phenytoin toxicity. We were not certain as to the cause of this abnormal behavior and psychosis, but the phenytoin clearly had an in-
fluence. Since
we have reported this isolated occurrence, perhaps other physicians will find patients with a similar response to phenytoin or other anticonvulsants. Clarence E. McDanal Jr, MD University of Hawaii Honolulu
Cholecystographic Modifications Improve Initial Study
to
Opacification
To the Editor.\p=m-\An
editorial in The Journal (232:642, 1975) discussed the problem of nonopacification of the gallbladder with a single 3-gm dose of iopanoic acid (Telepaque). It pointed out that an estimated 15 million Americans are afflicted with gallbladder disease, and hence, are potential candidates for cholecystography. Nonopacified gallbladders occur in 25% of patients with a single 3-gm dose, but the second dose of 3 gm of iopanoic acid causes opacification in 70%. Eighty percent of patients in whom opacification is obtained with reinforcement have normal gallbladders. A recommendation for the sake of economy was therefore made that all patients routinely receive 3 gm of
Downloaded From: http://jama.jamanetwork.com/ by a Simon Fraser University User on 06/02/2015
of 3 gm at 14 to 16 hours before. 15 million cholecystograms are to be done, this recommendation means that 11,250,000 patients receive the double dose unnecessarily and suffer the inconvenience and morbidity of the greater dosage and longer period of preparation. Fur¬ thermore, 180 million iopanoic-acid tablets (approximately $30 million) are required instead of 111 million ($18 million). There is no economy in this recommendation.
Assuming that
Nevertheless, attempts to reduce insufficient opacification of the gall¬ bladder on the first study are worthy because any repeated examinations cause additional radiation exposure and waste time and money. There are ways of modifying the present pro¬ cedure of cholecystography to make good first-dose visualization more consistent and to reduce the necessity for repeated examinations. Bile salts enhance the intestinal absorption and hepatic excretion of iopanoic acid.1 Traditional precholecystographic fast¬ ing and low-fat diet cause gallbladder sequestration and impaired liver ex¬ cretion of bile salts.2 It appears that poor first-dose opacification of the gallbladder in normal patients may be the result of lack of circulating bile salts when the iopanoic acid is in¬ gested. Consequently, the iopanoic acid is incompletely absorbed from the intestine and poorly excreted by the liver. For these reasons, gallblad¬ der opacification can be improved by giving fat in the meal immediately before the ingestion of iopanoic acid or by combining the contrast tablets with a cholecystagogue such as corn oil.
Gallbladder opacification is also im¬ if the iopanoic acid is given over a six-hour period rather than over a 10- to 20-minute period. The improvement may result from a greater absorption of the contrast material because of the increased enterohepatic recirculation of bile salts during the six-hour interval.3 Optimal opacification of the gall¬ bladder occurs 14 to 17 hours after the administration of iopanoic acid. The conventional 12-hour interval be¬ tween the ingestion of contrast mate¬ rial and the x-ray films is too short to permit adequate concentration of the iopanoic acid in the gallbladder of
proved
some
patients.4
These modifications make it pos¬ sible to reduce the nonopacifiednor-
mal out
gallbladder resorting
to a minimum with¬ to the inefficient recommendation of subjecting all pa¬ tients to the expense, inconvenience,
and
morbidity of a double dose of panoic acid over a 40-hour period.
io¬
Charles E. Shopfner, MD Mobile, Ala
1. Berk RN, Loeb PM,
lecystography
with
210, 1974. 2.
Goldberger LE, et al: Oral choiopanoic acid. N Engl J Med 290:204\x=req-\
Goldberger LE, Berk RN, Lang JH, et al: Biopharinfluencing the intestinal absorption
maceutical factors
iopanoic acid. Invest Radiol 9:16-23, 1974. 3. Koehler PR, Kyaw MM: Effect of fractionated administration of Telepaque on gallbladder visualization. Radiology 108:517-519, 1973. 4. Whalen JP, Rizzuiti RJ, Evans JA: Time of optimal of
gallbladder opacification with Telepaque (iopanoic acid). Radiology 105:523-524, 1972.
Stamp for Charting
measurement, irregularity, dimpling,
Breast Lesions To the
The stamp and design are illustrated in the Figure. The nipple and areola are centrally placed. Concentric circles are made; each intervening space represents a finger's breadth or, if desired, a metric measurement. Straight lines, corresponding to the numbers on a clock, are made from the edge of the areola to the outer edge of the circle. With this as a chart, masses, thickening, and other findings are accurately recorded in exact position, ie, two fingers' breadth from the areola at the 9 o'clock position. Solid masses may be designated by a solid mark, cysts with a plain circle, and thickening with a cross-hatched symbol. The or other pertinent facts recorded in the margins. This stamped diagram allows pre¬ cision in record keeping by showing on a patient's chart the exact loca¬ tion, size, and type of all lesions. Sub¬ sequent changes are easily noted by providing a visual method for recall and comparison. The method is rapid and timesaving and is stamped on the office examination sheet. It elimi¬ nates the need for lengthy word de¬
retraction, is
Editor.\p=m-\There increasing public awareness of the importance of
breast examination. When the patient is examined by the physician, the findings are recorded and should become a permanent part of the patient's file. They are recorded by brief or lengthy word descriptions or by the use of printed forms, drawn diagrams, or rubber stamp. A stamp diagram was designed that permits specific, precise, and accurate location and description of all breast lesions.
are
scriptions, rough drawings, or printed
charts and is also valuable in the follow-up of multiple aspirated cysts. The stamp is inexpensive and is read¬ ily available for use by physicians (Printing Place of Kensington, Ken¬ sington, MD 20795). In addition, at the discretion of the examiner, the patient can be provided with copies of stamped imprints for recording find¬ ings on self-examination. Daniel J. Abramson, MD
Army Medical Center Washington, DC Walter Reed
Breast stamp and
diagram.
New Drugs for Hypertension: An FDA Reply To the Editor.\p=m-\In an editorial (229:689, 1974), Dr Edward D. Freis charged the Food and Drug Administration (FDA) with depriving American physicians and their patients of a number of useful antihypertensive drugs. Such "drug lag" editorials have appeared in various journals in the past, and we are not able to respond to all of them. This particular editorial, however, has generated numerous inquiries to the FDA, undoubtedly because of the importance of hypertension and the prominence of Dr Freis. I would therefore like to comment on some of the points he raises and correct several inaccuracies. A more complete discussion of
Downloaded From: http://jama.jamanetwork.com/ by a Simon Fraser University User on 06/02/2015
the drug lag issue by the FDA can be found in our testimony before subcommittees of the senate committees on labor and public welfare and on the judiciary on Aug 16 and Sept 27, 1974. Dr Freis cited the absence from the United States of three antihypertensive drugs popular in the United
Kingdom: bethanidine, debrisoquin, propranolol (available here but not labeled for treatment of hyper¬ tension). He stated that applications for these drugs were submitted to and
the FDA many years ago and that debrisoquin was disapproved while the others "have not been acted on as yet." The basic problem was attrib¬ uted to "endless delay and procrasti¬ nation" resulting from the "individ¬ ual reviewing officer who is unable or unwilling to arrive at a fair judgment of the benefit-risk ratio of a new drug." Unfortunately, these allega¬ tions are incorrect and serve only to perpetuate misconceptions about FDA review procedures. New drug applications (NDAs) for debrisoquin and bethanidine were submitted to the FDA in 1964 and 1966, respectively. Both applications were disapproved because of the lack of controlled studies providing ade¬ quate evidence of safety and effec¬ tiveness, and neither NDA sponsor has ever submitted a subsequent ap¬ plication. Dr Freis' concerns thus re¬ late to his disagreement with judg¬ ments and regulatory decisions made a number of years ago, rather than to untimely review procedures or pro¬ crastination. Marketing rights to bethanidine have been transferred to a different manufacturer, who has ac¬ tively supported clinical studies; an NDA for bethanidine is now under review. Clinical studies of debrisoquin were discontinued several years ago, and we are not aware of plans to mar¬ ket the drug in the United States. Propranolol also has not been sub¬ ject to a prolonged review by the FDA. Ayerst Laboratories first sub¬ mitted an application for propranolol for the treatment of hypertension in late December 1974. Such a submis¬ sion had been requested by FDA for about two years prior to that time. A supplemental application was sub¬ mitted in April 1975. Those appli¬ cations are currently under review. Whether medical practice in the United States is seriously impaired by the nonavailability of bethanidine and debrisoquin is difficult to de¬ termine. Guanethidine, a drug long
