"PANTOPAQUE"
Early Development
(In) approximately
1918, following a proposal by Dandy, visualization of the spinal
cord radiographically was done by injection of air into the spinal
column to enhance anatomic structure imaging.(7)
In 1922, iodinized
poppy seed oil, which had been commercially available since 1901
for injection into the epidural space, began to be used for intrathecal
injection for enhanced imaging of the spinal cord. Usually less
than 5 cc of poppy seed oil was introduced into the intrathecal
space and it was recommended that it be removed following imaging.
A 1932 opinion
statement of the American Medical Association had discouraged
the introduction of any foreign oily material, such as iodinized
poppy seed oil, into the spinal cord unless the potential benefit
of the procedure could justify the potential long-term risk to
the patient.
The investigation
of the use of the medical imaging agent ethyl iodophenylundecylate,
which would eventually be called Pantopaque, began in 1936 at
the University of Rochester, School of Medicine and Dentistry,
Rochester, NY with initial animal work done by William Strain,
Ph.D. and Stafford Warren, MD.
The investigators
were reportedly seeking a more effective and safer medical imaging
agent for imaging the spinal cord then iodinized poppy seed oil.
They also wanted to develop a radiopaque substance that would
be nontoxic when injected into the spinal canal, that would disappear
from the body within several weeks, more rapidly than the iodinized
poppy seed oil, and also improve the overall quality of radiological
imaging of the spinal cord.
They began working
with several different oily iodinated compounds. During animal
studies in 1937-1938, Warren and Strain began referring to one
of their new oily iodinized non water-soluble medical imaging
agents as ethyl iodophenylundecylate, iophendylate, or "Pantopaque".
Their animal
studies indicated that the oily imaging compound was not absorbed
by the body and, just as with the already available oily non water
soluble iodinized poppy seed oil, would remain permanently encysted
within the spinal column as a foreign body capable of triggering
a moderate inflammatory reaction with production of fibrosis.
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The June 1941
doctoral thesis of T.B. Steinhausen, also at the University of
Rochester and who was working with Strain and Warren, a study
funded for the Radiopaque Group by Eastman Kodak Company, was
entitled "An Experimental Study of Iodinated Compounds for
Intrathecal Use". His work involved the use of rat and dog
animal studies and a series of iodinated imaging compounds. The
potential contrast media of his thesis, Pantopaque, had been a
product synthesized by Plati in 1940.
Steinhausen began
his thesis work by looking at the intrathecal injection effects
of the already available iodinized poppy seed oil (or Lipiodol)
in animal systems. It was his opinion that since there had been
no histological tissue information available, with very little
experimental studies done regarding the nature of the foreign
body reaction stimulated by the material, when injected into the
human’s subarachnoid space, that it (iodinized poppy seed
oil – Lipiodol) should not be considered as a suitable product
for human use.
He reviewed cat
studies that demonstrated there was no absorption of the iodinized
poppy seed oil over time and that one of the cats had died following
injection. He commented that those researchers appeared to have
used too much oil in that cat and that there was no way that iodinized
poppy seed oil should ever be considered as safe for human injection.
Steinhausen cited
an earlier 1925 rabbit study using 17 rabbits with intrathecal
Lipiodol injection that had a 47% mortality with pathological
changes seen at autopsy.
He referred to
a 1938 study by Mettier and Leake that had reported numerous untoward
reactions secondary to the (8) introduction of iodinized poppy
seed oil into the intrathecal space. For this reason, Steinhausen
stated that those authors had recommended that the oily iodinized
poppy seed agent be used very carefully and that every effort
should be made to remove as much of the substance as possible
immediately from the intrathecal space following an imaging procedure.
He cited that
in 1939, Brison had developed a technique that would aid in removal
of iodinized poppy seed oil from the subarachnoid space in order
to help decrease the potential meningeal irritation. This was
a procedure that was similar to a procedure used at the Mayo Clinic.
A 1941 study
by Brown and Carr, following a 6 month instillation of retained
intrathecal injection of poppy seed oil, had found the oil emeshed
or encysted within fibrous adhesions in the spinal column amongst
a thickened dura with chronic inflammation. The authors also had
indicated that there was a significant danger in injection of
iodinated poppy seed oil within the spinal canal for imaging.
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One of the new
iodinated compounds that was studied by Steinhausen in his thesis
included ethyl iophenylundecylate ("Plati’s iophendylate"
or "Pantopaque"). This compound was reportedly chosen
by Steinhausen because it would break down more slowly than the
other iodinized agents that he examined. That property was one
that he thought would help facilitate better radiographic imaging.
In a series using
3 dogs, Steinhausen’s Pantopaque produced meningeal irritation
symptoms that ranged from slight to severe. In another series
of 15 dogs all injected intrathecally with 4 cc Pantopaque:
· 27%
were clinically free of meningeal irritation symptoms,
· 46%
had symptoms of slight meningeal irritation at 2-9 days,
· 20%
had moderate symptoms at 3-9 days,
· 7% had
severe meningeal irritation symptoms beginning at day 4 and lasting
12 days, with
· 1 dog
dying on the 24th day post-injection from a gangrenous terminal
ileum.
In the dog studies,
despite a lack of overt acute clinical symptoms, at time of termination
of the study and autopsy, the histological and gross meningeal
changes were more severe in nature then had been clinically suggested.
Such significant
changes included:
· granulomatous
foreign body reactions with acute inflammation, polymorphonucleocytes
(PMNs),
· phagocytes,
· and
fibroblasts with fibrous adhesions involving the nerve roots.
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The typical meningeal
histological changes seen at dog sacrifice at 1½ months
post intrathecal injection included clear cystic areas, dispersed
throughout the spinal column, consistent with the presence of
pockets of retained oily injected material, surrounded by fibrosis,
scattered macrophages and acute inflammation.
One of Steinhausen’s
15 Pantopaque dogs following injection had a persistent generalized
weakness of the legs with an inability to walk. This was the first
time that this type of generalized neurological reaction with
lower limb paralysis had been reported by Steinhausen associated
with the use of any of the oily imaging compounds that he was
testing.
For the purpose
of comparison and using his model, Steinhausen injected a series
of 9 dogs with iodinized poppy seed oil. One dog died 24 hours
after injection, with symptoms of moderate meningeal irritation
and subarachnoid hemorrhage.
80% of the dogs
appeared to recover clinically without remaining neurological
symptoms. However, histologically, at time of termination and
autopsy, the histological and gross changes were similar to the
changes that had been seen with injections of ethyl iophenylundecyalate
(Pantopaque) and the findings were more severe than would have
been suggested clinically. (9)
"The primary
difference for the iodinized poppy seed oil, when compared to
Pantopaque in the dog model, was that the iodinized poppy seed
oil appeared to produce greater number of clinical symptoms referable
to the immediate mechanical trauma of the injection. Histologically,
the iodinized poppy seed oil resembled the changes produced by
Pantopaque, including moderate meningeal irritation with areas
of oil floating within the cord as encysted clusters, acute inflammation,
fibroblasts, fibrous adhesions and nerve root involvement."
Steinhausen’s
research in dogs foreshadowed both the significant acute and long-term
adverse events that were reported in human patients following
the intrathecal injection of Pantopaque for myelography.
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In terms of the
body of Steinhausen’s research, it is unclear why, in lieu
of the significant and severe animal safety findings produced
by intrathecal administration of Pantopaque, and the similarity
to the harmful effects of iodinized poppy seed oil, that he would
have made the following 4 thesis conclusions regarding the apparent
imaging "utility" of Pantopaque for injection into humans
for myelography:
1. Of the 26
ethyl esters of various iodinated organic acids, only ethyl iodophenylundecylate
seemed suitable for myelography.
2. Ethyl iodophenylundecylate
appeared to be absorbed and as long as any of the ester was present
there was some pathological reaction about the compound.
3. Comparative
tests with the standard iodized poppy seed oil showed a definite
but different pathological response which persisted indefinitely,
since the compound was very slowly absorbed.
4. Ethyl-w-(4-iodophenyl)-o-valerate,
although not suitable for myelography, had found clinical application
as a contrast medium."
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(This last statement
is a direct contradiction of itself! But for real shock horror
read the next paragraph which I have split up for easy reading.
M.F.)
Despite the documentation
by Steinhausen of the similarities and risks of Pantopaque when
compared to Lipiodol in animal studies,
despite the 1932
warning of the AMA regarding the permanent long-term risks for
introduction of foreign oily compounds into the spinal cord for
imaging, and
despite the FDCA’s
1938 requirements for obtaining FDA’s premarketing approval
through demonstration of "safety" to the FDA before
introducing an imaging agent for use in U.S. patients,
Dr. Warren took
it upon himself to begin sending Pantopaque to U.S. physicians
to obtain their clinical input from imaging their own patients.
The 1938 FDCA,
as seen with the later distribution in the U.S. of two million
of investigational tablets of thalidomide in the early 1960s,
did not address the legal responsibility of a manufacturer to
control the distribution of "investigational drugs",
nor did it require obtaining informed patient consent or obtaining
an Investigational New Drug (IND) exemption from FDA.
On June 26, 1942,
Dr. Rigler, University of Minnesota Hospitals, Minneapolis, MN,
wrote to Dr. Warren reporting his facility’s negative clinical
experience with Pantopaque for imaging their patients. Dr. Rigler
did not provide "favorable" information to Dr. Warren
regarding the performance of Pantopaque in human patients.
Dr. Rigler indicated
that it was his opinion, as well as his staff’s opinion,
that the material mixed too readily with the spinal fluid and
did not improve imaging quality. He also indicated that he felt
that the material was extremely difficult to remove. (10)
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Dr. Rigler wrote
to Dr. Warren of the experiences of his staff with Pantopaque:
"We have
completed some myelographies with your Pantopaque which you were
so kind to send me, but for our purposes we have found it somewhat
unsatisfactory.
Doctor Peterson,
who has been doing this work here for some time and has had a
considerable experience with both air and lipiodol, feels that
the material mixes much too readily with the spinal fluid so that
a clear cut picture cannot be obtained.
Obviously, in
a case of a block of any degree, it would be entirely satisfactory,
but if you are trying to demonstrate herniated disc or tumor without
complete block or arachnoiditis, the normal miscibility of the
material would be most confusing."
Furthermore,
he found it extremely difficult to remove.
"Large quantities
of spinal fluid were removed by the usual methods that we use
in removing lipiodol, but he(sic) was quite unsuccessful.
I am sending
you illustrations of two cases, one done with lipiodol and the
other with Pantopaque, to give you some idea of the contrast,
both the original films and the amount of opaque material left
after attempts at removal.
You will note
that in the case of lipiodol, using the maneuver of Kubik and
Hampton, all except a very few droplets were successfully removed
whereas in the case of the Pantopaque most of it all remained."
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From other documentation,
Dr. Warren had also sent Pantopaque to physicians based at military
hospitals to encourage their use of the product for imaging military
patients.
Major R.G. Spurling,
Walter Reed Hospital, Washington, D.C., September 5, 1942, wrote
to Dr. Warren in 1942 indicating that Pantopaque produced, "as
many irritative symptoms as lipiodol (poppy seed oil) but it was
absorbed more rapidly."
When removed
immediately post procedure, there had been no more evidence of
meningeal irritation than after a plain lumbar puncture. Major
Spurling felt 90-95% of the Pantopaque could be removed, with
the remainder absorbed in two to four weeks.
Major Spurling
had observed a patient of his that he had injected a 5cc dose
of Dr. Warren’s Pantopaque material intrathecally and concluded
that approximately 50% (*2.5cc) had been absorbed at the end of
7 months by serial x-ray. He also wrote:
When Pantopaque
is removed immediately following the myelogram, there is no more
evidence of meningeal reaction than after plain lumbar puncture
studies.
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Furthermore,
with ordinary care, it is possible in all cases to remove 90 to
95% of the Pantopaque from the subarachnoid space. A few drops
remaining cause no demonstrable clinical signs and these droplets
are absorbed within two to four weeks.
I have used Pantopaque
in approximately one hundred clinical cases and I consider it
to be the most nearly ideal myelographic medium yet available.”
September 16,
1942, eleven days after Dr. Spurling’s letter had been written
to Dr. Warren, (the) FDA responded to an earlier (September 4,
1942) letter received from Mr. J.T.Fuess of Chemical Sales Division,
Eastman Kodak Company, Rochester, NY, regarding the issue of Eastman
Kodak’s reported interstate deliveries of Pantopaque. (11)
The letter was written by the Assistant Commissioner of the FDA,
P.B. Dunbar.
This refers again
to your letter of September 4 in reference to Pantopaque. With
the understanding that deliveries of this drug will be restricted
exclusively to the military forces, this Administration will not
insist on compliance with the requirements of section 505 of the
Act dealing with new drugs.
Should you contemplate
at any time entering into the ordinary commercial distribution
of Pantopaque, it will be expected that the precise requirements
of section 505 of the Act will be met. This will require the filing
of a formal application with proof of the safety of the drug.
If in lieu of
filing of a formal application you elect to take advantage of
section 505(i) and distribute the drug solely for investigational
use by qualified civilian experts, it will be expected that the
requirements of section 505(i), together with the regulations
thereunder, will be met, including the labeling of the product
with the statement:
"Caution:
New drug - Limited by Federal law to investigational use.
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Up to the present
time we have had inquiries regarding the use of Pantopaque only
from the Office of the Surgeon General of the War Department.
Should a similar request be received from medical authorities
of the Navy our decision would be identical.
However, in apparent
violation of the "military-only restrictions" stated
in the FDA’s letter for legal distribution of the drug to
military facilities, of December 1st 1942, Dr’s; Steinhausen,
Plati, Furst, Dungan, Smith, Strain and Warren presented the results
of their:
"Experimental
and Clinical Myeolography with Ethyl Iodophenylundecylate (Pantopaque)"
at the 28th Meeting
of the Radiological Society of North America, a "civilian
medical association".
The data began
with a presentation of results of intrathecal injection of 3-5cc
in dogs. However, the presentation concluded with an open "off
label clinical discussion" of the use of their "unapproved"
contrast agent in three unusual clinical cases, with no mention
of FDA’s restriction to military-only use.
There was no
mention within the written abstract that product availability
had been "restricted" by FDA to military medical facilities,
nor was there a discussion that the "safety" for human
use had never been submitted, nor demonstrated, to the FDA for
support of marketing the product for use in a US human population.
In terms of the
sponsors’ Pantopaque presentation, in the abstract, it also
appeared that the authors did not wish to accurately reflect the
earlier Steinhausen dog data, nor actual clinical experience described
in the 1942 letter from Dr. Rigler in terms of his facility’s
"unfavorable" clinical experience.
There appears
to have been a conscious decision in 1942 by the authors
· to disregard
Dr. Rigler’s clinical findings,
· an intentional
disregard of the requirements that had been detailed by the FDA,
· an intentional
disregard of clinical ethical conduct, and
· failure
to provide physicians with complete and accurate, and truthful
outcomes documented for Pantopaque through both human and animal
experience.
The abstract
misrepresents the scientific facts for Pantopaque as known by
the authors in 1942 by containing "misleading" statements
about the long-term effects of Pantopaque in the dog studies (as
follows):-
· The
new medium is more fluid than the iodinized oils and may be injected
with ease. With dogs intrathecal injection of 3-5 cc causes a
transitory pleocytosis with cell counts of 200 to 700 (mostly
polys).
· Histological sections taken during or after this transient
reaction period show collection of the medium under the meninges
with a localized foreign body response around the small droplets.
· Consecutive
radiographs demonstrate that the preparation is rapidly absorbed
at first, but more slowly as the medium becomes fixed in position.
· Nevertheless,
amounts of 3-5 cc are absorbed nearly completely in the course
of a year with little or no evidence of residual reaction.
· Parallel
experiments with iodized poppy seed oil in dogs show somewhat
more extensive pathology with little evidence of absorption.
· Clinically,
the new medium has been found to facilitate greatly myelographic
examination.
· In addition to ease of injection, the preparation flows
readily immediately after injection and may be removed without
difficulty
· The
entire examination, including injection and removal, can be completed
in fifteen minutes."
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