The Search for the Ideal_video on diagnostic imaging_Visipaque

The Search for the Ideal
Contrast agents and the quest to
image human physiology
Written and co-produced by
Michael Cala for Sanofi Winthrop
An exploration into the discovery and use of injected contrast media for medical diagnosis

VIDEO AUDIO
1. FADE IN: ECU: Male “patient”
about 50 years old
SOUND UP
AMBIENT NOISES: carts being rolled...female and male
voices UNDER...other SOUNDS as appropriate to a
cardiac catheterization laboratory.
2. ANGLE ON: Patient -- he looks
anxious
VOICE (O.S.)
How we doing, Mr. Rizzo? (PATIENT NODS)
Okay...you’re going to feel real warm...
3. PULL BACK TO REVEAL:
Clinical setting
ANNOUNCER
Each year, despite great strides in safety, as many as
one-and-one-half million patients undergoing
contrast-enhanced radiography in the U.S. may
experience adverse reactions. These can range from
mild to moderate discomfort upon injection, to life-
threatening allergic, cardiovascular or neurological
“events.”
4. DOCTOR (off-screen) DOCTOR (O.S.)
Okay...
5. CUT TO: Patient as we hear
the SOUND of the power injector
and the cardiology unit; the
patient has his eyes closed
tightly
NARRATOR
While serious adverse reactions constitute a
relatively small percentage of the more than 18
million procedures performed in the United States
each year,1
contrast-related reactions still account for
significant morbidity and mortality.2
Even patients
who do not experience adverse reactions of any kind
frequently report pain and discomfort from contrast
injection.
1
2

VIDEO AUDIO
6. NO SCENE 6
7. Nurse preparing setup for next
patient (laying out catheters,
hanging contrast or saline, etc.)
NARRATOR
The desire to eliminate adverse reactions and pain
has been the driving force behind continued
refinement of contrast media since they were first
developed in the 1890s.
8. DISSOLVE THROUGH: BRING
UP GRAPHIC: MOLECULES
REPRESENTATIVE OF HOCM
-THEN IONIC LOCM; NEXT,
NONIONIC LOCM; NEXT
ISOSMOLAR IODIXANOL
NARRATOR
From early high-osmolar ionic contrast agents, to the
development of the newest class of nonionic
isosmolar contrast media, the quest has been to
balance radiopacity with biocompatibility, especially
for high-risk patients. These include those with a
variety of chronic medical conditions as well as those
who have demonstrated previous reactions to
contrast media.
9. MONTAGE: Diagnostic Images
suggesting all major indications
for iodixanol.
§ Cardioangiography
§ Visceral angiography
§ Peripheral angiography
§ Cerebral angiography
§ CT
NARRATOR
This is the story of the search for what some have
called, the ideal contrast agent.
10. TITLE GRAPHIC [MUSIC UP AND UNDER]
11. NO SCENE 11. NO SCENE 11

VIDEO AUDIO
12. DOCTOR HILL ON CAMERA
CHYRON OVER:
James Hill, M.D.
[Title]
University of Florida at
Gainesville School of Medicine
DR. HILL (O.C.)
“The contrast agent is something to enhance an
image. Something to enable you to make a
diagnostic image of some organ system or some
intravascular structure ... Anything else that
compound does is an adverse event.”
13. MONTAGE: Archival images to
cover track. Film is preferred, if
available.
NARRATOR
Over the years, thousands of researchers have
attempted to create an ideal contrast agent. How well
they have succeeded is a fascinating story of
ingenuity, perseverance ... and genius.
14.Photo: Roentgen NARRATOR
Our story begins on November 8, 1895, when
German physicist Wilhelm Roentgen discovered that
he could visualize human skeletal anatomy by
passing X-rays through living tissue and recording
the results on film.
15. C.U.: EARLY X-RAY STUDY NARRATOR
Researchers immediately began hunting for an
injectable, radiopaque, plasma-soluble substance
that could isolate vasculature from surrounding
structures.
16. C.U.: EARLY VASCULAR X-
RAY STUDY
NARRATOR
The first experiment by Harshak and Lindenthal only
weeks after Roentgen’s discovery employed a thick
chalk emulsion to image vessels in an amputated
hand.

VIDEO AUDIO
17. GRAPHIC: Build Selectan
neutral molecule
NARRATOR
In 1925, Binz and Rath in Germany successfully
detoxified iodine by adding a heteropyridine ring, an
organic acid chain, to a single iodine atom to create
“Selectan Neutral,” a somewhat radiopaque but toxic
compound with limited water solubility.
18. MODIFY Selectan neutral to
Uroselectan-B molecule
NARRATOR
In 1930, a second iodine atom was added to increase
radiopacity, the organic acid chain was altered, and a
carboxyl or acetic acid group added to provide better
water solubility. This compound was used for
intravenous urography well into the 1950s.
19. HOLD LAST GRAPHIC:
highlight IODINE atoms
NARRATOR
These experiments showed that iodine was the safest
radiopaque element to inject in the volumes required
for vascular imaging.
20. DR. SIEGEL ON CAMERA
CHYRON OVER:
Edward L. Siegel, M.D.
TITLE
Department of Radiology
University of Kansas Medical
Center
DR SIEGEL (O.C.)
“You know, many non-radiological clinicians think of
contrast agents as being rather toxic substances. But
all of them are among the safest drugs in existence.
And we give huge quantities. What other
pharmaceutical product can you give 60 grams to a
patient over the course of an hour or over the course
of a bolus?

VIDEO AUDIO
21. ANIMATION: Build on Benzene
ring; 2nd iodine at position 4;
third iodine at position 6.
Organic side chain fly in at
position 3, 5. (COOH) attached
at position 1.
NARRATOR
By the 1950s, the heteropyridine ring had been
replaced by a benzene ring, and a third iodine atom
was added. Amino acid side chains were bonded at
positions 3 and 5, and an electrically-charged
carboxyl or acetic acid group at position one. These
changes improved radiopacity and solubility, and led
to the development of sodium diatrizoate. By the
mid-1960s, all contrast media were ionized salts of
iodinated benzoic acid compounds.
22. HOLD GRAPHIC: Sodium
diatrizoate; HIGHLIGHT iodine;
NEXT, COOH; ANIMATE
IONIZATION IN SOLUTION
NARRATOR
All these ionic compounds dissociate or “ionize” in
solution into two charged particles: a positively
charged anion, [AN-eye-on] and a negatively charged
cation. [KAT-eye-on]
23. HIGHLIGHT (+) showing
proportions of particles, charges
NARRATOR
However, only the anion is radiopaque. The cation
simply doubles osmolality and may cause
hemodynamic changes. The carboxyl side chain was
also neurotoxic ... and therefore totally unsuitable for
myelography.

VIDEO AUDIO
24. DR. MORRIS ON CAMERA;
CHYRON OVER:
Thomas Morris, PhD.
University of Rochester
Strong Memorial Hospital
Department of Radiology
DR. MORRIS (O.C.)
“Those early agents were a tri-iodinated benzoic acid
ring molecule. The osmolalities could go as high as
two thousand milliosmoles, which is a very hypertonic
solution. It was clear early on that this high
hypertonicity was a problem. It would cause lots of
pain. It causes a lot of vasodilation in arterial vessels.
Probably some in venous vessels. It also caused
changes in cardiac function.
25. CHYRON BUILD:
Properties Causing Adverse
Reactions:
§Osmotoxicity
§Chemotoxicity
§Ionic toxicity
NARRATOR
At this point, the issues had crystallized. The most
common adverse reactions from high-osmolar ionic
media were based on three distinctly negative
properties: osmotoxicity, chemotoxicity, and ionic
toxicity.
26. GRAPHIC CONTRASTING
OSMOLALITIES OF BLOOD
AND HYPEROSMOLAR
COMPOUNDS
Mike: Find a 3000 m/Osmol
compound: Selectan?
NARRATOR
Osmotoxicity refers to the high number of particles in
solution relative to blood. Depending on iodine
concentrations, osmolality of these early agents could
reach three thousand milliosmoles per liter. This is
approximately ten times the osmolality of human
blood, which is approximately 285 to 295
milliosmoles. Because fluids are always drawn
across a semi-permeable membrane from low
osmolality to high, a contrast agent that is not
isosmolar draws additional cellular fluid into
circulation, and may cause hemodynamic and cardiac
disturbances -- a critical concern for high-risk
patients.

VIDEO AUDIO
27. GRAPHIC/Generic HOCM
molecule (per Almen);
CHYRON OVER:
High Osmolar Compounds
§ Damage endothelium
§ Release vasoactive
substances
§ Cause severe pain
NARRATOR
High-osmolar contrast media, with a ratio of three
iodine atoms to two ionized particles, are sometimes
known as “ratio one-point-five” compounds. These
hyperosmolar ionic contrast media damage vascular
endothelium, induce release of vasoactive
substances, and cause severe pain upon injection.
28. GRAPHIC/w CHYRON
CHEMOTOXICITY
§ Chemical composition
§ Exposure
§ Dosage
§ Ionicity (+ or -)
§ Osmolality
NARRATOR
Chemotoxicity may be caused by one or more of the
following: the chemical composition of the agent,
duration of exposure, dosage, electric charge, or
osmolality, and is blamed for the adverse effects of
contrast media on cellular activity, protein binding,
enzymes, and electrolyte balance.
29. GRAPHIC. PU (+/-) in solution NARRATOR
Ionic toxicity refers to the release of ionized
particles... the anion and cation.
30.B-Roll: RADIOLOGY SUITE
PU: Graphic in Scene 27: Modify to
reflect reduction of osmolality
and elimination of carboxyl chain
.
NARRATOR
The problems of pain and adverse reactions
associated with high-osmolar contrast media raised
the question: How to create a contrast medium with a
better side effect profile while maintaining
radiopacity? To accomplish this objective, osmolality
had to be significantly reduced, and toxicity had to be
neutralized.

VIDEO AUDIO
31. GRAPHIC: IOXAGLATE
molecule. ANIMATE: Take first
tri-I benzene ring; FLY IN
second; attach; highlight iodine
atoms; attach amino acid/COOH
chain; NEXT, highlight charged
particles; bring up Ioxaglate
molecule
NARRATOR
Pharmacologically, there were at least two choices:
To improve tolerability of ionic compounds, two tri-
iodinated benzene rings could be combined into a
molecule with six iodine atoms for each pair of ions
increasing the ratio of iodine to charged particles to
3:1, and reducing osmolality by half. Creating a “ratio
three” compound led to the development of ionic low-
osmolar contrast media such as ioxaglic acid, or
ioxaglate.
32. TAKE LAST; KEEP IODINE;
FLY OUT charges; REMOVE
carboxyl; FLY IN hydroxyls;
amino chains
NARRATOR
Meanwhile another, potentially superior, approach
was already in motion: to create a totally new class of
contrast media.
33. DR. MORRIS ON CAMERA DR. MORRIS (O.C.)
“After many years of experience with these ionic
monomer agents, people realized ... particularly
Torsten Almén realized that there was an option.
That we could go to a nonionic agent and get
something akin to a glucose or sucrose molecule,
which doesn't have any ions to it at all.”
34. PHOTO: Torsten Almén
.
NARRATOR
In 1968, Swedish radiologist Torsten Almén [TOR-
stin -- all-MAIN] created a new class of contrast
media, which was both nonionic and low osmolar.
Almén had long theorized that hyperosmolality was
primarily responsible for adverse reactions and pain.

VIDEO AUDIO
35. PHOTO: Saito NARRATOR:
He recalled earlier studies by the Japanese
physiologist Saito [“sah-YEE-toh”] in 1930, in which
subjects injected with an iodinated oil equal in
osmolality to human blood experienced no pain at all
during carotid arterial injection.
36. ECU: Myelogram; PAN for
movement .
NARRATOR
Almén also knew that the osmotoxicity of high
osmolar ionic contrast media could damage the
blood-brain barrier, exposing delicate nerve cells to
toxic carboxyl molecules.
37. BUILD metrizamide compound NARRATOR
Almén replaced the neurotoxic carboxyl group with
more benign and water-soluble hydroxyl side chains.
This new formulation had no charge, and maintained
radiopacity equal to that of the ionic compounds.
This led to the first “ratio-3” nonionic contrast agent
metrizamide [meh-TRIZ-a-mide] in the 1970s.
Marketed in the U.S. as Amipaque, it was the first
nonionic, water-soluble contrast medium safe for
myelography. Its use expanded to include other
contrast-enhanced vascular procedures, even though
it was very expensive to produce..
38. NO SCENE 38 NO SCENE 58

VIDEO AUDIO
39. [59.] B-ROLL Patient(s) in
Interventional Radiology Suite,
or
MONTAGE:
§ Myelogram (per St. Vincent)
§ CT
§ IVP
§ Visceral/Peripheral, etc.
§ Cardiac angiogram
NARRATOR
Other nonionic low-osmolar contrast media such as
iohexol would follow. Their greatly improved safety
profile led to their ready acceptance for myelography,
as well as other vascular imaging procedures. As
of 1994, it is estimated that nearly seventy percent of
all enhanced procedures are using nonionic, low
osmolar contrast media.
40. [59A.] Tech setting up
catheters, etc.
NARRATOR:
Though not nearly as expensive as metrizamide, the
new, second generation nonionic media were still
more costly to produce than ionics. The “savings,”
however, in increased patient comfort and safety,
were substantial.
41. [18.] DR. SIEGEL ON
CAMERA:
DOCTOR SIEGEL (O.C.)
“When I work out my equation of how to give a
contrast agent, I have to factor in not only the cost of
an adverse event but the potential for an adverse
event. And the ability to get the study completed.”
“It certainly appears that we are going in the right
direction; that, as we move from the hypertonic ionic
contrast media to the nonionic monomer contrast
media, and now to the nonionic dimers, we see a real
improvement in reaction rates and tolerance.”

VIDEO AUDIO
WE WILL INSERT VISUAL
TRANSITION HERE...
VISIPAQUE - NEW SECTION
43. DR.SIEGEL ON CAMERA DR. SIEGEL (O.C.)
“I think there is abundant evidence that there is a
substantial safety benefit using nonionics, as
compared to conventional agents. I think Katayama
showed that, as a matter of fact, the single most
important parameter in predicting a contrast reaction
is the type of agent being used. It is more important
than previous drug reactions. More important than
allergy history. More important than medical
condition. So it's hard to justify using an agent which
is six times as likely to produce an adverse reaction,
when you have a better agent available.”
44. NO SCENE 44
45. NO SCENE 45
46. NO SCENE 46
47. B-ROLL: Chem. lab.
BUILD IODIXANOL MOLECULE;
LABEL
NARRATOR
The drive to synthesize a truly biocompatible ratio-6
nonionic compound has led to the development of
Visipaque, which represents the first and only one of
a new class: nonionic, dimeric, isosmolar contrast
media. Visipaque, or iodixanol, is marketed in the
U.S. by Nycomed, a leader in iodinated contrast
media development for more than fifty years.

VIDEO AUDIO
48. CHYRON OVER:
Visipaque biocompatibility:
§ Isosmolar
§ Electrolyte balanced
(Na+, Ca-)
§ Similar to human serum
NARRATOR
Visipaque has come closest so far to total
biocompatibility. In addition to being isosmolar, it is
also balanced with the key electrolytes sodium and
calcium, added in proportions nearly identical to
those found in human serum.
“Recently, we've done a study in animals of the
effects of the new formulation of iodixanol, what I
would call the optimized formulation, with the right
amount of sodium and calcium present. And in that
study, we found that there was minimal effect of
iodixanol, the nonionic dimer, on cardiac functions,
when we did selective injections into the left coronary
artery. In fact, we found no difference from baseline,
basically. There was really no change that we could
detect. That was not true with the nonionic monomer
agents. They did cause a different difference from
baseline, a decrease in function.”
50. PUSH/SLIDE-IN clinical
papers;
TABLE GRAPHIC(s) comparing
iodixanol to Hexabrix and
nonionic LOCM (to be discussed
with client)
NARRATOR
Recent Phase Three clinical trials have shown that
Visipaque causes limited changes in cardiac function
and hemodynamics and virtually no fluid shifts.

VIDEO AUDIO
51. GRAPHIC: Renal anatomy
CHYRON OVER:
VISIPAQUE
§ Selective renal excretion
§ Limited protein binding
and enzymuria
§ Benefits to renal patients
NARRATOR
The selective renal excretion of Visipaque, with
limited protein binding and enzymuria, is believed to
benefit patients with renal dysfunction or disease.
Reports show minimal change in tubular function, and
clinically insignificant changes in glomerular function.
52. Technician hanging IV’s NARRATOR
Because Visipaque has been specifically formulated
to limit adverse reactions and hemodynamic changes,
its side effect profile has elicited positive responses
from the clinical community, especially in relation to
high-risk patients.
53. DOCTOR ON CAMERA; DR. SIEGEL (O.C.)
“Iodixanol may be better tolerated by very high-risk
patients, because it's a lower osmolar load. Patients
who are subject to going into congestive heart failure
may do better having such a low osmolar load.”
54. NO SCENE 54
55. NO SCENE 55

VIDEO AUDIO
56. GRAPHIC/Chart
AGENT OSMOLALITY
Blood 285 - 290
mOsm.
Iodixanol 320 290
Ioxaglate 320 460
Ioversol 320 702
Iopromide 370 770
Iopamidol 370 796
Iopentol 350 811
Iohexol 350 844
Hypaque [need data]
Renographin[need data]
NARRATOR
Low-osmolar contrast media, though relatively
benign, still possess osmolalities that range from
approximately two to three times that of iodixanol.
57. [71]. GRAPHIC/Heart NARRATOR
The isosmolality of iodixanol has been shown to limit
the intensity of adverse reactions and pain overall.
And its favorable electrolyte balance has contributed
to minimal reports of arrhythmias and alterations in
cardiac contractility and conductivity.
58. DR. SIEGEL ON CAMERA DR. SIEGEL (O.C.)
“When we compared Hexabrix to iodixanol, in a
hundred patients undergoing angiographic
procedures ... this was a randomized, prospective,
double blind study, and it was conducted here at the
University of Kansas, and at the University of
Chicago...

VIDEO AUDIO
“Conclusions that we drew from the study were that,
number one, Iodixanol was a safe and effective agent
for peripheral and visceral angiography. And, two,
that it was better tolerated than Hexabrix, both in
terms of adverse events, and in terms of patient
discomfort. “
60. GRAPHIC/Elements to include
a graphical comparison based
on osmolality and ionicity.
or
B-Roll per audio
NARRATOR
Because of its superior biocompatibility, especially
when compared to other agents, iodixanol appears to
offer greater margins of safety to high-risk patients in
both the cardiac catheterization laboratory and the
radiology suite.
61. CU: Dr. Hill ON CAMERA DR. HILL (O.C.)
“The issue is one of easing the patient through the
procedure. You don't have to slow down the
procedure, and wait for the blood pressure to come
back. You don't have to wait for the EKG changes to
go away... the heart rate to come back up.

VIDEO AUDIO
62. GRAPHIC: Relative risk (see
Mike)
NARRATOR
Some patients undergoing contrast-enhanced
procedures may be at risk because of a previous
history of idiosyncratic or anaphylactoid reactions to
contrast media. Such patients are at five or six times
greater risk for a subsequent reaction with ionic
media when compared to normal-risk patients. With
nonionic low osmolar contrast media, the relative risk
factor is approximately tripled, while risks associated
with the new isosmolar nonionic contrast medium,
Visipaque, are no greater than those occurring in the
general population.
“Overall, we felt that the incidence of adverse
reactions, given previous adverse reactions, given a
history of allergy, was significantly lower with
iodixanol....
64. ECU: Patient undergoing
procedure
NARRATOR
Because contrast reactions may appear on first
exposure, it is clear that additional precautions must
be taken with high-risk patients, some of whom may
have a propensity for contrast-related allergic
reactions.

VIDEO AUDIO
65. CONTINUE LAST; HOLD;
CHRYON BUILD OVER:
High Risk/Compromised Patients
§ Previous Reactors
§ Congestive Heart Failure
§ Renal disease
§ Diabetes
§ Asthma
§ Allergy
§ Vascular disease
§ Hypertension
NARRATOR
Also at risk for contrast- or procedure-related adverse
events are patients who may be compromised by
chronic medical conditions such as congestive heart
failure, renal insufficiency or disease, diabetes
mellitus, asthma, allergy, vascular disease or
hypertension. Their ability to withstand any
hemodyamic, cardiovascular or other changes is
significantly weaker than that of normal-risk patients.
66. CHRYON BUILD:
High Risk/Compromised Patients
§ history of vessel disease
§ invasive nature of procedure
NARRATOR:
Many patients undergoing invasive therapeutic
procedures like PTA are also at greater risk because
of existing vessel disease. There are also risks
related to the invasive nature of the procedure such
as endothelial cell disruption, which may in turn
induce thrombosis.
67. DR. HILL ON CAMERA DR. HILL (O.C.)
“I think that the other issue, in terms of angioplasty, is
that, when you're intermittently occluding coronary
arteries, and causing ischemia and reperfusion, it's
my bias that if you're in a situation like that, the last
thing you want to do is give a contrast agent that
enhances bradycardia, enhances arrhythmias,
enhances hemodynamic compromise or causes
more hemodynamic effects.”

VIDEO AUDIO
68. CU: Dr. Hill setting up 3-way
manifold, catheter/tubing in lab.
NARRATOR
While nonionic contrast media are generally more
biocompatible than ionic compounds, it has been
suggested that ionic media may have an advantage
in certain patients because they possess
anticoagulant properties. Some clinicians have even
suggested that nonionic media may be procoagulant.
69. Dr. Siegel ON CAMERA DOCTOR SIEGEL (O.C.)
“I think it is a misconception among many radiologists
that nonionic contrast agents are pro-coagulant.
They're not -- they do not cause blood clots to form.
What they are is less anticoagulant than ionic agents
because they are more biocompatible.”
70. NEW SCENE 70
BEAUTY: PUSH IN
GRABOWSKI STUDIES
(include graphics/photos)
NARRATOR
Once this issue was raised, in the mid-1980s,
researchers worldwide, including Dr. Eric Grabowski,
investigated the matter. While some evidence of
platelet aggregation has been confirmed in the
artificial environment of in vitro flow cytometry
studies, aggregation has been noted in both ionic and
nonionic media. However, to date, no one has been
able to demonstrate that these in vitro experiments
translate in vivo to an increased thrombotic risk from
contrast media.
71. CUT TO: Video Microscopy:
aggregation
DR. GRABOWSKI (O.C. or V.O.)
“Dr. Marjorie Zucker showed that the apparent red
cell ‘clotting’ wasn't clotting at all, but rather an
agglutination of red cells, which was completely
reversible.”

VIDEO AUDIO
71A. DR. GRABOWSKI ON
CAMERA.
DR. GRABOWSKI (O.C.):
“These little red cell aggregates did not contain
fibrin... And that's one of the paramount features of a
true clot.”
72. NEW SCENE 72
CU: LAB STUDIES
NARRATOR
Recent investigations by Dr. Grabowski using the
new technique known as flowing whole blood flow
aggregometry utilize a substrate of cultivated
vascular endothelial cells over which whole blood
flows under normal physiologic flow conditions. This
closely simulates in vivo physiology. The results
demonstrate that, while degranulation is observed for
certain media under the unnatural conditions of flow
cytometry, flowing whole blood aggregometry
demonstrates conclusively that platelet adhesion or
aggregation observed in artificial cytometric settings
is not reflected in true flow states.
NEW SCENE 73.
GRAPHIC/VIDEO
per Dr. Grabowski
NARRATOR
According to the work of Dr. Grabowski and
colleagues at Massachusetts General Hospital and
elsewhere, a platelet marker known as GPII BIIIA
(GP2,B3,A), which is responsible for platelet
aggregation, is not activated at all by Visipaque.

VIDEO AUDIO
74. Dr. Grabowski ON CAMERA
DR. GRABOWSKI
“One of the major issues in PTCA ... and, I might
also add, in neuroradiologic interventions ... is
adequacy of anticoagulation. It may be that some of
the reports of increased thrombosis and clotting seen
with nonionics, is not so much an effect of the
nonionics directly, but an unmasking of an underlying
inadequate anticoagulation in the first place.”
74A. BEAUTY: Journal article NARRATOR
While the issue of platelet aggregation has been laid
to rest, a related issue -- Do certain contrast media
actually cause platelet activation? -- has also been
raised.
75. NO SCENE 75.
76. DR. GRABOWSKI ON
CAMERA
DR. GRABOWSKI (O.C.)
What we have found, with respect to activation
markers, is that iohexol and diatrizoate both
degranulate platelets... both with respect to P-
selectin, and CD 63. But neither iodixanol nor
ioxaglate degranulate platelets at all. [TRANSCRIPT
10-20]
76A. DR. GRABOWSKI O.C. DR. GRABOWSKI
On a scientific level we have found no clear evidence
that the [in vitro] degranulation issue.. translates into
anywhere near a comparable thrombotic risk.”

VIDEO AUDIO
76B. DR. GRABOWSKI O.C. DR. GRABOWSKI
And we would hypothesize that the degranulation is a
consequence, in the case of iohexol, of the absence
of trace salts in the formulation. In the case of
diatrizoate, we speculate that degranulation is
present because of its osmolality, its high osmolality,
in addition to charge.
77. BUILD PER AUDIO NARRATOR
Visipaque currently has the highest LD50 of all
injectable contrast media. Effects on cardiac
contractility and conductivity are minimal, due to its
key electrolyte formulation. In 17 U.S. clinical
studies, it was found that patients with a previous
history of contrast reaction, congestive heart failure,
or renal disease, were at no greater risk following
administration of Visipaque than the general
population.
78. CHARTS NARRATOR
In controlled prospective randomized clinical trials,
Visipaque has demonstrated significantly less intense
heat and pain upon injection.
“...I would hear things like, oh, it's like lying out in the
sun, on a hot day ... or it's like drinking a warm glass
of milk.”

VIDEO AUDIO
80. GRAPHIC. NARRATOR
Generally, reports of adverse events have been
minimal. Of these, nausea and vomiting have been
most common, though to a significantly lesser degree
than with existing low osmolar agents.
81. CU: Arterial study
DISSOLVE THROUGH
CU: Venous image
NARRATOR
In addition to its excellent side effect profile,
especially for high-risk patients, the arterial imaging
quality of Visipaque is optimal, thanks to its dimeric
structure containing six iodine atoms per molecule.
Moreover, its venous imaging potential may be
extraordinary, due in large measure to its
isosmolality.
“We expect to see some sort of difference in the
opacification of the renal vein with these agents. It
would seem very reasonable to expect that the
opacification of the veins would be much greater, or
at least noticeably greater, than it would with either
the monomeric nonionic agents or the ionic monomer
agents.” [TRANSCRIPT 3-2]
83. DR. SIEGEL ON CAMERA
CUT TO:
“Superb” venogram per Dr. Siegel
DR. SIEGEL (O.C.)
I certainly had the impression, as we were doing the
study, that there were a number of patients that just
had superb splenic vein opacification. We'd hang up
the films, and I'd say, ‘Gee, look at that splenic vein.
That's beautiful.’ ” [TRANSCRIPT 4-18 ]

VIDEO AUDIO
84. CHYRON BUILD NARRATOR
The indications for iodixanol by intra-arterial injection
include angiocardiography, peripheral, visceral and
cerebral arteriography.
85. CHYRON BUILD NARRATOR
Indications for intravenous injection include excretory
urography, enhanced CT of the head and body, and
venography. Current research seeks to support
extension of the indications of Visipaque.
86. CU: Digitized images (from
University of Rochester, NY,
shot on 5/23/94)
NARRATOR
Visipaque may also be used for digital subtraction
angiography.
87. CU: Archival photos;
DISSOLVE THROUGH.
NARRATOR
For many reasons, especially regarding safety in
higher-risk patients, including previous reactors, the
new nonionic dimeric isosmolar contrast medium,
Visipaque, appears to be fulfilling the promise of
biocompatibility first envisioned by early
experimenters.
88. PU: patient being wheeled to
Recovery
NARRATOR
There is little doubt that many more patients will
require the injection of contrast media in coming
years, as invasive diagnostic and therapeutic
procedures become more routine. While clinicians
have long been clear in their demand for minimal
adverse events from contrast media, patients, too,
have become concerned with these issues,
particularly those of pain and discomfort.

VIDEO AUDIO
89. [DELETED]
90. MONTAGE OF IMAGES MUSIC UP AND UNDER
91. MONTAGE builds into “Eye”
Graphic
NARRATOR
The long road from Wilhelm Roentgen’s laboratory in
1895 has led today to the creation of Visipaque/
iodixanol... a truly advanced compound that is highly
radiopaque and yet biocompatible... just as early
researchers had hoped.
With its lower potential for causing adverse allergic,
cardiovascular, or neurological reactions, especially
in high-risk patients, Visipaque/iodixanol offers
significant assurance to physicians and patients
alike, with regard to efficacy, tolerance, comfort
and...most important...safety.
92. “Eye” Graphic builds to
Visipaque Logo.
MUSIC UP
93. SCROLL CREDITS: MUSIC UP AND OUT.

VIDEO AUDIO
The producers wish to thank:
Eric F. Grabowski, MD, ScD
James A. Hill, MD
Orlando Manfredi, MD
Ronald Manfredi, MD
Thomas Morris, PhD
Edward L. Siegel, MD
The Cath Lab Staff of the University
of Florida at Gainesville
The Radiology Staff of the
University of Kansas Medical
Center
The Interventional Radiology and
Public Relations Staffs of St.
Vincent’s Medical Center of
Richmond (NYC)
The New York Academy of
Medicine
Torsten Almén, MD
This program was sponsored by
SANOFI WINTHROP
PHARMACEUTICALS,
Hospital Products Division,
© Sanofi Winthrop
Pharmaceuticals
Produced by:
SHELTER ROCK
COMMUNICATIONS,
New York.
Writer/Producer: Michael Cala
Director: John Leinung
Production Assistants:
Robert Levy
Sandra Vasquez

Pursuing The Ideal/Visipaque
Sanofi Winthrop Pharmaceuticals pg. R-1
REFERENCES:
(Please Note: References on this and following pages are provided for review ONLY.)
Almén T. Contrast media: the relation of chemical structure, animal toxicity, and adverse clinical effects,
Am. J. Cardiol 1990;66: 2F-8F
Almén T. Relations between chemical structure, animal toxicity and clinical adverse effects of contrast
media. Visipaque Reprint Binder #10, 1989.
Bentley A, Piper K; Organic radiopaques (2), Pharm J.,March 14, 1987, 338-342)
Chronos N Goodall A Wilson D et al. Profound platelet degranulation is an important side effect of some
types of contrast media used in interventional cardiology. Circulation 1993; 88:5:1, 2035-2044
Dawson P, Howell M. The nonionic dimers: a new class of contrast agents. Br J Radiol 1986:59;987-991
Dundore R Silver P Ezrin A, et al. The effects of iodixanol and iopamidol on hemodynamic and cardiac
electrophysiologic parameters in vitro and in vivo. Invest Radiol 1991;26: 715-721. [720]
Georgsen J The effect of radiographic contrast media on the chemotaxis of granulocytes. Investigative
Radiology 23, August 1988: 150-155, [150]
Grabowski E, Rodriguez M, McDonnell, S; Platelet adhesion/aggregation and endothelial cell function in
flowing blood: Effects of contrast media, Seminars in Hematology 28:4: Supp. 7; 7October, 1991; 60-65.
Grabowski EF, Kaplan K, Halpern E. Anticoagulant effects of nonionic versus ionic contrast media in
angiography syringes. Inv Radiol, 1991;26:417-421
Grabowski, EF, Contrast media which activate platelets by flow cytometry do not do so by flowing blood
aggregometry. Abstract, submitted 5/1/94 to RSNA.
Harnish P Fountaine H. Iodixanol. U.S. experience in 1259 patients., Visipaque clinical reprint binder,
#18.
Hellmans A., and Bunch, B., Timetables of History, Simon and Schuster, pub., 1988, pp. 387, 399.
Higgins, C. B. Coronary angiography: A decade of advances. Am. J. Cardiol. 62:7K-10K, 1988.
Katayama H. Adverse reactions to contrast media: what are the risk factors? Invest Radiol 1990;25:S16-
17.
Morris T, X-ray contrast media: Where are we now, where are we going? Radiology, Vol.188; July, 1993;
No.1, 11-16.
McClennan B, Stolberg H, Intravascular contrast media: Ionic versus nonionic - current status; Contemp
Uroradiology, May 1991;29: 437-453.

Pursuing The Ideal/Visipaque
Sanofi Winthrop Pharmaceuticals pg. R-2
Michelet, AA. Effects of intravascular contrast media on blood-brain barrier. Acta Radiol:1987:28;329-
333.
Raininko R, Ylinen SL. Effect of ionic and nonionic contrast media on aggregation of red cells in vitro.
Acta Radiol 1987;28:97-92.
Redmond, P. L., Kilcoyne, R. F. and Rose, J. S. Principles of Angiography. In: Vascular Surgery, 3rd
edition, edited by R. B. Rutherford. W. B. Saunders Co., 1989.
Robertson HJF. Blood clot formation in angiographic syringes containing nonionic contrast media.
Radiology 1987;162:621-622.
Saito M, Kamilkawa K, Yanagizawa,H: A new method for blood vessel visualization (arteriography,
venography, angiography) in vivo. Am J Surg 10:225, 1930
Speck U, Mutzel W, Mannessmann G, et al, Pharmacology of nonionic dimers; Inv Radiol. 15:S317-322,
Nov-Dec., 1980.
Visipaque Clinical Investigator’s Brochure, sections on Clinical Pharmacology and Clinical
Considerations, courtesy Sanofi Winthrop Pharmaceuticals.
Additional References (History):
Sanofi Winthrop Medical Research Division, 1994.
Benotti J. R., The comparative effects of ionic versus nonionic agents in cardiac catheterization.
Investigative Radiology, 23: Suppl 2, 1988.
Kern MJ, Ed. Cardiac Catheterization Handbook. New York. Mosby Year Book. 1991. Chapter 7,
“High Risk Cardioac Catheterization,” pp. 373-381.
Higgins CB. Coronary Angiography: A Decade of Advances. Am J. Cardiol. 62: 1988.
Highlights in the Development of Radiocontrast Media: Life Shadows. Winthrop Pharmaceuticals:
Diagnostic Imaging Division.
Physicians' Desk Reference, ed. 45. Oradell, NJ, Medical Economics Company, Inc. 1991, p 2482.
OMNIPAQUE 140 180 240 300 350 INJECTION (IOHEXOL)
Redmond PL, Kilcoyne RF, and Rose JS. Principles of Angiography. in: Rutherford RB,ed. Vascular
Surgery. 3rd ed. WB Saunders Co; 1989.

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Sanofi Winthrop Pharmaceuticals
“Pursuing The Ideal”
The Search for the Ideal Contrast Agent

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