Rejoinder To the Editor.\p=m-\Ishould like to
discovered more than 100 years ago. The choice of this as a cause célèbre would have been anachronis¬ tic if it had occurred in the previous decade. Today it is simply embarrass¬ ing. One wonders whether the sub¬ committee believed in March 1974 that propranolol was ineffective in angina pectoris. Does it still hold the same view? Does the FDA Advisory Committee doubt its efficacy today? Clearly, the top-level FDA staff has no such doubts. One can argue whether it is "not le¬ gally permissible" to include informa¬ tion about nonapproved labeling for drugs in the package insert, or whether this is rather a matter of regulation or de facto practice. The "law" seems not to prohibit inclusion of adverse effects relevant to the drug in question simply because they have not been proved beyond a shadow of a doubt. The toxicity data in a drug's package insert are often anecdotal, uncontrolled, and of unsubstantiated causality. The law is quite clear in re¬ gard to the kind of data required for marketing a drug, but I suspect that exactly what goes into a package in¬ sert is subject to a significant amount of regulatory discretion and flexibil¬ ity in language. (Indeed, the FDA is currently revising its entire approach were
re-
spond to Goldberg's rebuttal (232:143, 1975) to our commentary, "The FDA, Politics, and the Public" (232:141, 1975). To begin with, Wardell and I are certainly not arguing that the Food and Drug Administration (FDA) should approve labeling for uses of new drugs as soon as these uses gain acceptance in current medical practice and in the literature. As Goldberg recognizes in some of the quotations attributed to me, I do not
believe that there is a necessary relabetween actual and optimal clinical usage. Where Goldberg and I disagree, however, is in regard to what is "substantial evidence," who is to decide what is substantial evidence, and whether such substantial evidence exists for the use of propranolol in anginal patients. Distinguished and experienced clinicians all over the world have been impressed not only by the available literature on the use of propranolol in angina, but with its clinical utility. Like these men (and Dr. Crout), we do not believe that the question of propranolol's merit is a debatable one any more. In other words, anyone who says that propranolol is not ef¬ fective in angina is swimming against the tide not only of drug us¬ age, but of scientific evidence. I be¬ lieve that any FDA Advisory Com¬ mittee member who took an opposite point of view was ill-advised, either through not having access to the available world literature, or being incompetent to evaluate it. (Some, for example, appear to have gotten hung up on the concept of "the totally sat¬ isfactory paper." The only "totally satisfactory papers" to be found are usually those that are fraudulent. Ev¬ ery experiment has deficiencies, and the problem is to decide whether the deficiencies are so great as to render the experiment totally useless.) But in concentrating on these de¬ tails, Goldberg misses a key pointthat propranolol is the most impor¬ tant therapeutic agent to be devel¬ oped for angina since the nitrates
tionship
Edited by John D. Archer, MD, Senior Editor.
to
package inserts.)
is, in fact, the culprit, as Goldberg implies, then perhaps the law needs changing. The package in¬ sert could help keep potential prescribers up to date with both good and bad usage of the drug. For ex¬ ample, physicians should be warned away from prescribing practices that seem totally unwarranted. Goldberg's point about Dr. Crout's If the law
identification of 13 studies in March, months after the approval of the drug, is misleading. As is un¬ equivocally clear on page 222 of the hearing record that Goldberg cites, Dr. Crout reviewed all the studies prior to the drug's approval; he iden¬ tified certain studies some months later in March 1974 because the sub¬ committee had asked him to do so the previous week. I agree that it would be in the pub¬ lic interest for FDA to make avail¬ able to interested persons all of the some seven
Downloaded From: http://jama.jamanetwork.com/ by a New York University User on 05/18/2015
basic records for a new drug approval that are presently available to the Congress. We should also have avail¬ able corresponding data on drugs for which approval is denied. I do not, however, see why "the FDA's regu¬ latory performance can be evaluated by Congress only on the basis of the agency's official records." Is not evi¬ dence provided at hearings used by Congress to judge regulatory per¬ formance? Is not this evidence often absent from the agency's official records? Finally, I agree that no individual federal agency stands above the law. By the same token, no one individual, agency, or congressional committee should confuse itself, or its inter¬ pretations, with the law. Louis Lasagna, MD The University of Rochester School of Medicine and Dentistry Rochester, NY
Methanol Poisoning To the Editor.\p=m-\Inreading the editorial on methanol intoxication (229: 1335,1974), I recalled an endemic outbreak we faced at the Children's Hospital of Buenos Aires, Argentina, back in 1967. All patients were infants, averaging 2 to 8 months in age, who, due to a common illness (diarrhea, fever, etc), were rubbed with methanol-contaminated rubbing alcohol. After alcohol was applied, those infants were wrapped in diapers and plastic or rubber pants. Before diagnosis was made, there were a few patients who died of uncontrollable metabolic acidosis and coma, despite large amounts of bicarbonate. Peritoneal dialysis was started as methanol poisoning was susAn extra dose of sodium bicarbonate was added to the dialysate. Most of these patients were saved, especially when this procedure was started early in the course of the intoxication. In only a few did visual disturbances or acute renal failure desoon as
pected.
velop.
There is little in the literature about intoxication at this age. There is no doubt that alkalination is one of the major aspects of treatment. Stinebaugh (Arch Intern Med 105:613, 1960) reported in 1960 the use of peri¬ toneal dialysis in three adult patients, with good results. Keyvan-Larijarni and Tannenberg (Arch Intern Med 134:293, 1974) compared the benefits of hemodialysis against peritoneal di¬ alysis. However, their work cannot exclude the usefulness of peritoneal
dialysis
in the three
patients
started
it, since the first patient was started too late, as compared with the on
on hemodialysis. The second patient recovered and the third had visual damage but lived. In conclusion, early use of peri¬ toneal dialysis with high concentra¬
group
tions of bicarbonate can be lifesaving, and becomes especially important in infants, when hemodial¬ ysis is technically more difficult.
the speed of methanol removal that is of utmost importance in preventing irreversible damage. This is why he¬ modialysis, when available, is the method of choice. A. M. Tannenberg, MD H. Keyvan-Larijarni, MD
New York 1. Leaf G, Zatman LJ: A study on the conditions under which methanol may exert a toxic hazard in industry. Br J Indust Med 9:19-31, 1952. 2. Treon JF, in Patty FA: Industrial Hygiene and Toxicology, ed 2. New York, John Wiley & Sons, Inc, 1963, vol 2, pp 1416-1421.
A. Jose Wenger, MD University of Miami School of Medicine
Miami, Fla
In
Unusual
Reply.\p=m-\Dr.Wenger's observations
on an outbreak that was
of diarrhea in infants
thought, but not proved, to be complicated by methanol poisoning, are of interest from the dual standpoints of the effects of peritoneal dialysis on severe diarrhea of infancy as well as of its role in methanol poisoning. Metabolic acidosis, coma, and acute renal failure
are
not
sequelae of severe diarrhea of infancy. In such cases, peritoneal dialysis easily corrects the acidosis. If the infant is very dehydrated, the osmotic gradient between serum and dialysate will favor a shift of water from the dialysate to the systemic circulation. In addition, the glucose in the dialysate is a source of nutrition for the infant. Lastly, the efficiency of peritoneal dialysis is greater in infants than in adults because of the greater ratio of peritoneal surface area to body surface in infants. With respect to methanol poisoning in these infants, the following points are pertinent. As in the cases noted by Stinebaugh, specific determination of methanol in the blood was not obtained, making methanol poisoning just an assumption. Acute renal fail¬ ure is not a manifestation of meth¬ anol intoxication. In man, toxic amounts of methanol can only be at¬ tained through inhalation or by gas¬ trointestinal absorption.' Absorption through the skin has not been re¬ ported in man, and only under excep¬ tional experimental conditions has it been demonstrated in animals.We would like to emphasize two points that should be considered when methanol poisoning is suspected or proved. First, the acidosis of meth¬ anol poisoning can be easily and quickly treated without dialytic tech¬ uncommon
niques. Second, although peritoneal dialysis also removes methanol, it is
Nystagmus After Ethchlorvynol Use To the Editor.\p=m-\A27-year-old woman who had cine-esophagraphically confirmed aerophagia was electively admitted to the hospital for further evaluation of her long-standing problems of regurgitation and abdominal pain. She was extremely lethargic on arrival at the hospital, but roused in
response to her name. She was disoriented as to time and place, her gait was ataxic, and her attention span was short. Her pulse and blood pres-
normal, respirations were 12/min, and her temperature was 36.5 C (97.8 F). sure were
Concern
upon her
was immediately focused depressed mentation. She her aerophagic symptoms
said that had caused her great embarrassment, and she had been taking large amounts of a sedative, the name of which she could not recall, for an unknown period of time. She had fallen the day before, and she may have struck her forehead. She denied head-
ache, seizure, syncope, inappropriate affect, or ingestion of other medica-
tions. On initial examination, she had frontal cranial tenderness. The cra¬ nial nerves were intact. There was coarse nystagmus during right lateral and upward gaze when supine, but nystagmus was only barely noticeable at the extreme of left lateral.gaze; when the patient was sitting erect,
however,
coarse
nystagmus appeared
during left lateral gaze and none dur¬ ing right lateral gaze. The pattern was confirmed by several observers.
power, and sensation were in¬ tact. The right knee jerk reflex was 2 + , the left was 1 + , and the toes
Tone,
downgoing. Skull
x-ray films normal. An elec¬ troencephalogram showed occipital slowing, somewhat greater on the left. Lumbar puncture yielded normal fluid. The probability of a brain-stem were
and brain
scan were
Downloaded From: http://jama.jamanetwork.com/ by a New York University User on 05/18/2015
lesion was discussed with neurologi¬ cal consultants the next morning. Twenty-four hours after admission, ethchlorvynol was identified in her urine; the serum level was 1.7 mg/100 ml.1 Thirty-six hours after admission, vertical nystagmus during upward gaze had disappeared and her mental status was improving, but the posi-
tionally changing nystagmus
re¬
mained. Three
days after admission, higher integrative function was normal, and the concentration of ethchlorvynol in serum was down to 0.4 mg/100 ml. An
EEG at this time was normal. Neuro¬ logical examination five days after admission revealed subtle kneejerk asymmetry but otherwise normal results. The nystagmus had dis¬
appeared.
Horizontal
coarse
nystagmus,
usu¬
ally predominant in one direction, has been seen in patients who have in¬ gested large amounts of ethchlorvy¬ nol.24 However, to our knowledge, the pattern of gaze nystagmus predomi¬ nantly in opposite directions with dif¬ fering body positions has not been re¬ ported previously except in cases of anatomic lesions of the central ner¬ vous system. We believe this to be the first case of positional central "ves¬ tibular" nystagmus associated with
drug ingestion.5
Allan H. Ropper, MD School of Medicine University of California
San Francisco 1. Wallace
specific
rapid and determining ethchlorvynol. J Foren-
JE, Wilson WJ Jr, Dahl EV: A
method for
sic Med 9:342-352, 1964. 2. Westervelt FB Jr: Ethchlorvynol (Placidyl) intoxication: Experience with five patients, including treatment with hemodialysis. Ann Intern Med 64:1229-1236, 1966. 3. Kuenssberg EV: Side-effects of ethchlorvynol. Br Med J 2:1610, 1962. 4. Millhouse J, Davies DM, Wraith SR: Chronic ethchlorvynol intoxication. Lancet 2:1251-1252, 1966. 5. Huber A: Eye Symptoms in Brain Tumors, ed 2. FC Blodi (trans-ed), St Louis, CV Mosby Co, 1971, pp 54-55.
Convention Date and Time
Allergy Symposium Wrong. \p=m-\Inthe AN-
UNIT, published in 28 issue (232:417-452, 1975), errors occurred in the Section on Allergy program as listed on page 433. The "Symposium on the Troublesome Nose: What Causes It and What To Do About It" will be held Wednesday, June 18 at 9 AM (not Wednesday, June 16 at 2 PM), and the "Symposium on Differential Diagnosis of Bronchospastic Disease" will be held Wednesday, June 18 at 2 PM (not Wednesday, June 16 at 2 PM). NUAL CONVENTION
the
April
discovered more than 100 years ago. The choice of this as a cause célèbre would have been anachronis¬ tic if it had occurred in the previous decade. Today it is simply embarrass¬ ing. One wonders whether the sub¬ committee believed in March 1974 that propranolol was ineffective in angina pectoris. Does it still hold the same view? Does the FDA Advisory Committee doubt its efficacy today? Clearly, the top-level FDA staff has no such doubts. One can argue whether it is "not le¬ gally permissible" to include informa¬ tion about nonapproved labeling for drugs in the package insert, or whether this is rather a matter of regulation or de facto practice. The "law" seems not to prohibit inclusion of adverse effects relevant to the drug in question simply because they have not been proved beyond a shadow of a doubt. The toxicity data in a drug's package insert are often anecdotal, uncontrolled, and of unsubstantiated causality. The law is quite clear in re¬ gard to the kind of data required for marketing a drug, but I suspect that exactly what goes into a package in¬ sert is subject to a significant amount of regulatory discretion and flexibil¬ ity in language. (Indeed, the FDA is currently revising its entire approach were
re-
spond to Goldberg's rebuttal (232:143, 1975) to our commentary, "The FDA, Politics, and the Public" (232:141, 1975). To begin with, Wardell and I are certainly not arguing that the Food and Drug Administration (FDA) should approve labeling for uses of new drugs as soon as these uses gain acceptance in current medical practice and in the literature. As Goldberg recognizes in some of the quotations attributed to me, I do not
believe that there is a necessary relabetween actual and optimal clinical usage. Where Goldberg and I disagree, however, is in regard to what is "substantial evidence," who is to decide what is substantial evidence, and whether such substantial evidence exists for the use of propranolol in anginal patients. Distinguished and experienced clinicians all over the world have been impressed not only by the available literature on the use of propranolol in angina, but with its clinical utility. Like these men (and Dr. Crout), we do not believe that the question of propranolol's merit is a debatable one any more. In other words, anyone who says that propranolol is not ef¬ fective in angina is swimming against the tide not only of drug us¬ age, but of scientific evidence. I be¬ lieve that any FDA Advisory Com¬ mittee member who took an opposite point of view was ill-advised, either through not having access to the available world literature, or being incompetent to evaluate it. (Some, for example, appear to have gotten hung up on the concept of "the totally sat¬ isfactory paper." The only "totally satisfactory papers" to be found are usually those that are fraudulent. Ev¬ ery experiment has deficiencies, and the problem is to decide whether the deficiencies are so great as to render the experiment totally useless.) But in concentrating on these de¬ tails, Goldberg misses a key pointthat propranolol is the most impor¬ tant therapeutic agent to be devel¬ oped for angina since the nitrates
tionship
Edited by John D. Archer, MD, Senior Editor.
to
package inserts.)
is, in fact, the culprit, as Goldberg implies, then perhaps the law needs changing. The package in¬ sert could help keep potential prescribers up to date with both good and bad usage of the drug. For ex¬ ample, physicians should be warned away from prescribing practices that seem totally unwarranted. Goldberg's point about Dr. Crout's If the law
identification of 13 studies in March, months after the approval of the drug, is misleading. As is un¬ equivocally clear on page 222 of the hearing record that Goldberg cites, Dr. Crout reviewed all the studies prior to the drug's approval; he iden¬ tified certain studies some months later in March 1974 because the sub¬ committee had asked him to do so the previous week. I agree that it would be in the pub¬ lic interest for FDA to make avail¬ able to interested persons all of the some seven
Downloaded From: http://jama.jamanetwork.com/ by a New York University User on 05/18/2015
basic records for a new drug approval that are presently available to the Congress. We should also have avail¬ able corresponding data on drugs for which approval is denied. I do not, however, see why "the FDA's regu¬ latory performance can be evaluated by Congress only on the basis of the agency's official records." Is not evi¬ dence provided at hearings used by Congress to judge regulatory per¬ formance? Is not this evidence often absent from the agency's official records? Finally, I agree that no individual federal agency stands above the law. By the same token, no one individual, agency, or congressional committee should confuse itself, or its inter¬ pretations, with the law. Louis Lasagna, MD The University of Rochester School of Medicine and Dentistry Rochester, NY
Methanol Poisoning To the Editor.\p=m-\Inreading the editorial on methanol intoxication (229: 1335,1974), I recalled an endemic outbreak we faced at the Children's Hospital of Buenos Aires, Argentina, back in 1967. All patients were infants, averaging 2 to 8 months in age, who, due to a common illness (diarrhea, fever, etc), were rubbed with methanol-contaminated rubbing alcohol. After alcohol was applied, those infants were wrapped in diapers and plastic or rubber pants. Before diagnosis was made, there were a few patients who died of uncontrollable metabolic acidosis and coma, despite large amounts of bicarbonate. Peritoneal dialysis was started as methanol poisoning was susAn extra dose of sodium bicarbonate was added to the dialysate. Most of these patients were saved, especially when this procedure was started early in the course of the intoxication. In only a few did visual disturbances or acute renal failure desoon as
pected.
velop.
There is little in the literature about intoxication at this age. There is no doubt that alkalination is one of the major aspects of treatment. Stinebaugh (Arch Intern Med 105:613, 1960) reported in 1960 the use of peri¬ toneal dialysis in three adult patients, with good results. Keyvan-Larijarni and Tannenberg (Arch Intern Med 134:293, 1974) compared the benefits of hemodialysis against peritoneal di¬ alysis. However, their work cannot exclude the usefulness of peritoneal
dialysis
in the three
patients
started
it, since the first patient was started too late, as compared with the on
on hemodialysis. The second patient recovered and the third had visual damage but lived. In conclusion, early use of peri¬ toneal dialysis with high concentra¬
group
tions of bicarbonate can be lifesaving, and becomes especially important in infants, when hemodial¬ ysis is technically more difficult.
the speed of methanol removal that is of utmost importance in preventing irreversible damage. This is why he¬ modialysis, when available, is the method of choice. A. M. Tannenberg, MD H. Keyvan-Larijarni, MD
New York 1. Leaf G, Zatman LJ: A study on the conditions under which methanol may exert a toxic hazard in industry. Br J Indust Med 9:19-31, 1952. 2. Treon JF, in Patty FA: Industrial Hygiene and Toxicology, ed 2. New York, John Wiley & Sons, Inc, 1963, vol 2, pp 1416-1421.
A. Jose Wenger, MD University of Miami School of Medicine
Miami, Fla
In
Unusual
Reply.\p=m-\Dr.Wenger's observations
on an outbreak that was
of diarrhea in infants
thought, but not proved, to be complicated by methanol poisoning, are of interest from the dual standpoints of the effects of peritoneal dialysis on severe diarrhea of infancy as well as of its role in methanol poisoning. Metabolic acidosis, coma, and acute renal failure
are
not
sequelae of severe diarrhea of infancy. In such cases, peritoneal dialysis easily corrects the acidosis. If the infant is very dehydrated, the osmotic gradient between serum and dialysate will favor a shift of water from the dialysate to the systemic circulation. In addition, the glucose in the dialysate is a source of nutrition for the infant. Lastly, the efficiency of peritoneal dialysis is greater in infants than in adults because of the greater ratio of peritoneal surface area to body surface in infants. With respect to methanol poisoning in these infants, the following points are pertinent. As in the cases noted by Stinebaugh, specific determination of methanol in the blood was not obtained, making methanol poisoning just an assumption. Acute renal fail¬ ure is not a manifestation of meth¬ anol intoxication. In man, toxic amounts of methanol can only be at¬ tained through inhalation or by gas¬ trointestinal absorption.' Absorption through the skin has not been re¬ ported in man, and only under excep¬ tional experimental conditions has it been demonstrated in animals.We would like to emphasize two points that should be considered when methanol poisoning is suspected or proved. First, the acidosis of meth¬ anol poisoning can be easily and quickly treated without dialytic tech¬ uncommon
niques. Second, although peritoneal dialysis also removes methanol, it is
Nystagmus After Ethchlorvynol Use To the Editor.\p=m-\A27-year-old woman who had cine-esophagraphically confirmed aerophagia was electively admitted to the hospital for further evaluation of her long-standing problems of regurgitation and abdominal pain. She was extremely lethargic on arrival at the hospital, but roused in
response to her name. She was disoriented as to time and place, her gait was ataxic, and her attention span was short. Her pulse and blood pres-
normal, respirations were 12/min, and her temperature was 36.5 C (97.8 F). sure were
Concern
upon her
was immediately focused depressed mentation. She her aerophagic symptoms
said that had caused her great embarrassment, and she had been taking large amounts of a sedative, the name of which she could not recall, for an unknown period of time. She had fallen the day before, and she may have struck her forehead. She denied head-
ache, seizure, syncope, inappropriate affect, or ingestion of other medica-
tions. On initial examination, she had frontal cranial tenderness. The cra¬ nial nerves were intact. There was coarse nystagmus during right lateral and upward gaze when supine, but nystagmus was only barely noticeable at the extreme of left lateral.gaze; when the patient was sitting erect,
however,
coarse
nystagmus appeared
during left lateral gaze and none dur¬ ing right lateral gaze. The pattern was confirmed by several observers.
power, and sensation were in¬ tact. The right knee jerk reflex was 2 + , the left was 1 + , and the toes
Tone,
downgoing. Skull
x-ray films normal. An elec¬ troencephalogram showed occipital slowing, somewhat greater on the left. Lumbar puncture yielded normal fluid. The probability of a brain-stem were
and brain
scan were
Downloaded From: http://jama.jamanetwork.com/ by a New York University User on 05/18/2015
lesion was discussed with neurologi¬ cal consultants the next morning. Twenty-four hours after admission, ethchlorvynol was identified in her urine; the serum level was 1.7 mg/100 ml.1 Thirty-six hours after admission, vertical nystagmus during upward gaze had disappeared and her mental status was improving, but the posi-
tionally changing nystagmus
re¬
mained. Three
days after admission, higher integrative function was normal, and the concentration of ethchlorvynol in serum was down to 0.4 mg/100 ml. An
EEG at this time was normal. Neuro¬ logical examination five days after admission revealed subtle kneejerk asymmetry but otherwise normal results. The nystagmus had dis¬
appeared.
Horizontal
coarse
nystagmus,
usu¬
ally predominant in one direction, has been seen in patients who have in¬ gested large amounts of ethchlorvy¬ nol.24 However, to our knowledge, the pattern of gaze nystagmus predomi¬ nantly in opposite directions with dif¬ fering body positions has not been re¬ ported previously except in cases of anatomic lesions of the central ner¬ vous system. We believe this to be the first case of positional central "ves¬ tibular" nystagmus associated with
drug ingestion.5
Allan H. Ropper, MD School of Medicine University of California
San Francisco 1. Wallace
specific
rapid and determining ethchlorvynol. J Foren-
JE, Wilson WJ Jr, Dahl EV: A
method for
sic Med 9:342-352, 1964. 2. Westervelt FB Jr: Ethchlorvynol (Placidyl) intoxication: Experience with five patients, including treatment with hemodialysis. Ann Intern Med 64:1229-1236, 1966. 3. Kuenssberg EV: Side-effects of ethchlorvynol. Br Med J 2:1610, 1962. 4. Millhouse J, Davies DM, Wraith SR: Chronic ethchlorvynol intoxication. Lancet 2:1251-1252, 1966. 5. Huber A: Eye Symptoms in Brain Tumors, ed 2. FC Blodi (trans-ed), St Louis, CV Mosby Co, 1971, pp 54-55.
Convention Date and Time
Allergy Symposium Wrong. \p=m-\Inthe AN-
UNIT, published in 28 issue (232:417-452, 1975), errors occurred in the Section on Allergy program as listed on page 433. The "Symposium on the Troublesome Nose: What Causes It and What To Do About It" will be held Wednesday, June 18 at 9 AM (not Wednesday, June 16 at 2 PM), and the "Symposium on Differential Diagnosis of Bronchospastic Disease" will be held Wednesday, June 18 at 2 PM (not Wednesday, June 16 at 2 PM). NUAL CONVENTION
the
April
