[CANCER RESEARCH 43, 925-929, February 1983]
0008-5472/83/O043-0000502.00
Disposition of Bisantrene in Humans and Rabbits: E v i d e n c e for
Intravascular Deposition of Drug as a C a u s e of Phlebitis 1
Garth Powis 2 and John S. Kovach
Division of Oncology Research, Mayo Clinic/Foundation, Rochester, Minnesota 55905
ABSTRACT
The investigational antitumor agent bisantrene ( 9 , 1 0 - a n t h r a cenedicarboxaldehyde
bis[(4,5-dihydro-1H-imidazol-2-yl)hydrazone] d i h y d r o c h l o r i d e ) causes frequent local complications
of phlebitis and t h r o m b o s e s in patients receiving the drug by
peripheral venous infusion. Bisantrene p h a r m a c o k i n e t i c s was
studied in five patients. Plasma elimination was biphasic with
t~/2 o~ of 65 min and tl/2 [~ of 1142 min; the mean apparent
volumes of distribution of the central c o m p a r t m e n t and peripheral c o m p a r t m e n t s were 185 and 1 662 l i t e r s / s q m, suggesting
extensive uptake, binding, or deposition of drug. Total body
clearance was 735 m l / m i n / s q m, and 1 1 . 3 % of drug was
excreted in urine. One hr after bisantrene ( 2 6 0 m g / s q m) at 1
m g / m l in 5% dextrose was infused into the marginal ear vein
of a rabbit, the vein was congested with blood and contained
2.1 mg precipitated bisantrene. After 24 hr, the vein was
clotted and contained 1.1 8 mg precipitated drug. Precipitation
of bisantrene appears to be related to the low solubility of the
drug at physiological pH. M a x i m u m solubility of bisantrene in
human and rabbit serum was 1 2.7 ffg/ml. Intravascular precipitation of bisantrene may be responsible for phlebitis and
thromboses in humans receiving the drug by i.v. infusion.
INTRODUCTION
Bisantrene ( 9 , 1 0 - a n t h r a c e n e d i c a r b o x y a l d e h y d e
bis[(4,5d i h y d r o - 1 H - i m i d a z o l - 2 - y l ) h y d r a z o n e ] d i h y d r o c h l o r i d e ) is an anthracene b i s h y d r a z o n e derivative undergoing clinical evaluation for activity against a wide spectrum of human cancers. The
drug was initially placed in clinical trials because of activity
against many model murine tumor systems (3). Special clinical
interest in bisantrene has been generated by reports of responses in patients with advanced cancers including renal
carcinoma and melanoma (1, 7, 8).
M y e l o s u p p r e s s i o n was the major toxicity noted in large-animal studies (3) and has been reported as the dose-limiting
toxicity in 3 Phase I studies (1, 7, 8). More t r o u b l e s o m e than
reversible leukopenia have been local complications of phlebitis and t h r o m b o s e s in up to two-thirds of patients given
bisantrene by infusion into a peripheral vein. These toxicities
occurred on 3 different schedules, 1 day every 4 weeks,
weekly for 3 weeks, and daily for 5 days every 4 w e e k s (1, 7,
8). As little as 8 0 mg bisantrene per sq m in 5 0 0 ml 5 %
dextrose in water, which is about one-third of the dose rec1This work was supported in part by Grant CH143 from the American Cancer
Society, by USPHS Grant CA 31967 from the National Cancer Institute, and by
Contract CM97273 from the Division of Cancer Treatment, National Cancer
Institute.
2 To whom requests for reprints should be addressed, at Division of Oncology
Research, Guggenheim Building, Room 428, Mayo Clinic, Rochester, Minn.
55905.
Received May 26, 1982; accepted October 21, 1982.
o m m e n d e d for Phase II trials on the single-day schedule,
produced immediate local toxicity in some patients (7). Local
complications of bisantrene t h e r a p y prompted Speigel et al. (7)
to speculate that the drug may exert a direct effect on vascular
endothelium leading to loss of integrity of the vein and local
inflammation.
We became interested in the mechanism by which bisantrene
produces local toxicity because of our difficulties in administering the drug without producing pain, venospasm, and redness over the infused vein in some patients. Dilution of bisantrene at 2 6 0 m g / s q m in volumes up to 1 5 0 0 ml 5 % dextrose
in w a t e r and administration over 3 hr in as large a peripheral
vein as possible d e c r e a s e d the f r e q u e n c y and severity of signs
of acute local irritation but did not prevent the o c c u r r e n c e of
thrombosis in several patients 7 to 10 days later (6). Because
bisantrene a p p e a r e d to be exerting a toxic effect locally, we
reexamined some physicochemical characteristics of the drug
in vitro and in vivo in animal models, in addition to studying the
p h a r m a c o k i n e t i c s of the drugs in humans as part of a recently
completed Phase II trial in advanced colorectal c a r c i n o m a (6).
MATERIALS AND METHODS
Bisantrene was obtained from Division of Drug Treatment, National
Cancer Institute, Bethesda, Md. Human studies on the pharmacokinetics of bisantrene were conducted in patients with colorectal or
bladder cancer receiving the drug in Phase II clinical trial. All patients
had no direct-reacting serum bilirubin and a serum creatinine less than
1.5 mg/dl. Patients were hospitalized in a clinical studies unit for 36 hr
for the pharmacokinetic study. Bisantrene was dissolved in 500 ml 5%
dextrose and water (approximately 1 mg/ml), and 260 mg/sq m were
administered over 90 rain into a peripheral vein. Blood samples were
collected in heparinized tubes from the opposite arm used for infusion
before and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4.5, 5.5, 8, 10, 12, 18, and 24
hr after starting infusion. Plasma was stored frozen at - 7 0 ~ Urine was
collected before and for 24 hr after administration of drug. Male New
Zealand White rabbits, weighing 1.75 to 3.0 kg, were infused through
a 23-gauge needle (Miniset Infusion Set; Travenol, Deerfield, II1.) with
bisantrene at a dose of 260 mg/sq m into a peripheral ear vein over 1,
24, or 72 hr with a solution of bisantrene in 5% dextrose in water at 1
mg/ml, 50 ffg/ml, and 15 ffg/ml, respectively. The flow rate for each
infusion was approximately 0.5 ml/min. After administration of bisantrene, the ear vein was infused with 5 ml 0.9% NaCI solution at the
same flow rate, the infusion needle was removed, and the animal was
sacrificed 1 or 24 hr later. Both ears were removed, and a 0.5-cmwide strip of skin overlying the peripheral ear vein was peeled back to
expose approximately 6 cm of vein from just above the point of infusion
to the base of the ear. The vein was examined under low-power light
microscopy and cut into 1-cm lengths. Each 1-cm segment was extracted for 1 hr with 0.1 N HCI with vigorous shaking, and the extracts
were assayed for bisantrene. Bisantrene was assayed by a reversedphase high-pressure liquid chromatographic procedure described previously (5).
Solubility studies were conducted using bisantrene supplied as the
dihydrochloride salt and bisantrene base prepared by adjusting a
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925
G. P o w i s e t al.
solution of bisantrene dihydrochloride to pH 7.0, collecting the precipitated base by filtration, washing extensively with water, and drying
under vacuum. Fresh human serum, phosphate-buffered saline (Dulbecco's), and 10% crystalline human serum albumin (Sigma Chemical
Co., St. Louis, Mo.) in phosphate-buffered saline were each mixed with
a solution of bisantrene dihydrochloride (10 mg/ml water; 25 #l/ml
serum or 0.9% NaCI solution) and gently agitated for 30 min at room
temperature. The pH was adjusted to 7.3 with 0.1 N NaOH. The sample
was centrifuged twice at 15,000 rpm for 15 rain, and aliquots were
taken for determination of bisantrene. Fresh human serum and phosphate-buffered saline were shaken with an excess of bisantrene base
(1 mg/ml) for 2 hr at 37 ~ in the dark. The pH was adjusted at intervals
to 7.3. Serum samples were also filtered through a O.45-/zm filter
(Millex-HA Filter Unit; Millipore, Bedford, Mass.). Results were corrected for 16.6% binding of bisantrene to the filter determined in
separate experiments with saturated solutions of bisantrene in serum.
Ultrafiltrates were prepared from solutions of bisantrene in serum and
albumin using Amicon ultrafilter cones (Amicon, Lexington, Mass.). To
determine the extent of binding or uptake of bisantrene by blood cells,
washed cells from 1.5 ml heparinized homologous blood were mixed
with 1.5 ml bisantrene-saturated serum and incubated with gentle
shaking at 37 ~ for 30 min or at room temperature for 60 min. Cells
were removed by centrifugation, and the amount of bisantrene in the
serum was determined.
Analysis of pharmacokinetic data for short-term infusions were conducted using the NONLIN least-squares regression analysis program
(2) on a CDC Cyber 170-720 computer with interactive graphic analysis. Pharmacokinetic parameters were calculated with allowance for
a 90-rain infusion. The biexponential decline in the plasma concentrations of bisantrene was fitted to the equation
C = Ae -''t + Be /st
with a weighing factor of 1 l y e , where C is the plasma concentration of
bisantrene at time t after completion of infusion, A and B are intercepts
at this time, and ~xand ,8 are the fast and slow disposition constants.
RESULTS
Pharmacokinetic Studies in Humans. Plasma c o n c e n t r a tions of bisantrene in 5 patients receiving a 90-min infusion of
bisantrene at 2 6 0 m g / s q m declined in a biphasic manner after
cessation of the infusion (Chart 1 ) with a mean initial half-life of
65 +_ 15 (S.E.) min and a mean terminal half-life of 1 1 4 2 _+
2 2 6 min. The peak plasma concentration during infusion was
a p p r o x i m a t e l y 5 f f g / m l (Table 1). The mean apparent volume
5
c~
c
1
Eo
0.5
U]
0.2
~o
O.O5
Time(hr)
Chart 1. Plasma concentration of bisantrene in humans. Five patients were
given bisantrene (260 mg/sq m) as a peripheral i.v. infusion over 90 rain (heavy
arrow). Each point is the mean of five patients. Bars, S.E. Continuous line is a
computer fit to the data.
926
of distribution of the central c o m p a r t m e n t (V~) was 1 85 _+ 46
l i t e r s / s q m, and the mean a p p a r e n t volume of distribution of
the peripheral c o m p a r t m e n t (V2) was 1 6 6 2 +__ 4 8 6 l i t e r s / s q m.
Mean total body plasma clearance (C/) was 7 3 5 +_ 125 m l /
m i n / s q m, and 11.3 +_ 1.8% of the total dose was excreted
unchanged in the urine in 24 hr.
S o l u b i l i t y of B i s a n t r e n e in Human Serum. A study of the
solubility of bisantrene in human plasma was p r o m p t e d by our
observation that some bisantrene precipitated and remained as
a precipitate in the peritoneal cavity of mice 24 hr after i.p.
injection of 2 6 0 m g / s q m (0.1 ml of a 2 3 - m g / m l solution in
water). We found that a solution of bisantrene d i h y d r o c h l o r i d e
as prepared for administration to patients, 1 m g / m l in 5%
dextrose in water, has a pH of 4.2. As the pH of this solution is
increased with 0.1 M NaOH, bisantrene precipitates as a bright
yellow a m o r p h o u s material. When a 1 - m g / m l solution of bisantrene d i h y d r o c h l o r i d e in 5% dextrose in w a t e r was mixed
with heparinized human plasma in ratios of 1:1 or 1:4, plasma
cloudiness developed after a few min and a m o r p h o u s yellow
material could be sedimented by centrifugation. We determined
the maximum solubility of bisantrene in human serum by adding
an excess of bisantrene d i h y d r o c h l o r i d e in solution (1 m g / m l
in 5% dextrose in water) and an excess of bisantrene base as
a solid to fresh human serum at 37 ~ The maximum concentration of bisantrene in human serum after addition of the drug in
solution and after addition of the drug as a solid was 13 f f g / m l
(Table 2). We assumed that most of the drug in serum was
bound to protein because an ultrafiltrate of serum had no
detectable drug ( < 1 0 m g / m l ) .
The solubility of bisantrene in phosphate-buffered saline, pH
7.3, was no more than 0 . 4 3 + 0 . 0 5 / ~ g / m l (n = 3). This may
be an overestimate since most of the drug was removed by a
0.45-#m filter. The solubility of bisantrene in a 1 0 % solution of
crystalline human serum albumin in phosphate-buffered saline,
pH 7.3, was 77 /zg/ml. Little bisantrene ( < 1 0 n g / m l ) was
present in an ultrafiltrate of this solution. Incubation of RBC
with an equal volume of a saturated solution of bisantrene in
serum reduced the concentration of drug in serum. The ratio of
the concentration of bisantrene in RBC to the concentration in
serum was 3:1.
I n t r a v a s c u l a r D e p o s i t i o n of B i s a n t r e n e in Rabbit. We studied the effect of bisantrene on the ear veins of rabbits after
infusing the drug at the dose used in our clinical studies, 2 6 0
m g / s q m (about 4 0 m g / r a b b i t ) . The concentration of bisantrene in rabbit plasma at the end of infusion of 2 6 0 m g / s q m
over 1 hr was 10.7 _+ 2.2 # g / m l (n = 3), and at the end of
infusion of 2 6 0 m g / s q m over 24 hr it was 0 . 2 6 +_ 0 . 0 2 ffg/ml.
The ear vein of a rabbit 1 hr after infusion of bisantrene ( 2 6 0
m g / s q m over 1 hr) contained deposits of bright yellow material
along its length. A vein from the opposite ear contained no
yellow deposits and was indistinguishable in a p p e a r a n c e from
an ear vein of an untreated rabbit (Fig. 1 ). T w e n t y - f o u r hr after
a 1-hr i.v. infusion of bisantrene dihydrochloride, the infused
ear vein was distended with liquid and clotted blood and
contained deposits of yellow material. To establish that the
deposits w e r e precipitated bisantrene, 1-cm segments of infused veins w e r e extracted with 0.1 N HCI and assayed for
bisantrene. Infused ear veins contained bisantrene along their
entire lengths (Chart 2). One hr after administration of 40 mg
of bisantrene by 60-min infusion, 6-cm lengths of infused vein
contained a total nf 9 0 9 +_ 0 . 6 3 mg (n = 3) bisantrene.
CANCER RESEARCH VOL. 43
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Intravascular
Deposition
of Bisantrene
Table 1
Pharmacokinetic parameters of bisantrene in humans
Peak
plasma
Patient
ml)
(min)
t,/2/~ (min)
sq m)
V2 (liters/sq
m)
sq m)
Urinary excretion (%
24 hr)
4.6
4.4
2.6
7.7
5.7
76
91
37
23
100
665
1870
1006
735
1435
320
206
146
35
218
1414
1415
1533
488
3460
1200
451
836
348
842
7.7
10.4
8.5
13.1
16.8
5.0 ___0.7
65 _+ 15
1142 _+ 226
185 4- 46
1662 4- 486
735 4- 125
11.3 _+ 1.8
concentrat i o n (/~g/
t J/2 ~x
Sex
1
F
2
3
4
5
F
M
M
F
Mean +_ S.E.
Vl (liters/
Table 2
s t o p p i n g the i n f u s i o n , a 6 - c m s e g m e n t of i n f u s e d v e i n c o n t a i n e d
o n l y 7 . 2 #g of drug.
Solubifity of bisantrene
Maximum solubility was determined by mixing an excess of bisantrene dihydrochloride in solution with serum and allowing it to stand at room temperature
for 30 min or shaking an excess of bisantrene base with serum for 2 hr at 37 ~
In both cases, pH was adjusted to 7.3. Serum was centrifuged twice at 15,000
rpm for 15 min to remove undissolved drug.
NO.
Preparation
Bisantrene dihydrochloride
Bisantrene base
of
preparations
Maximum solubility in serum
(tLg/ml)
Ultrafiltrate
(#g/ml)
4
12.6 + 1.9 a
0.6 + 0.3
3
12.8 + 1.1 c
0.0
Blood
cell:serum concentration ratio
3.0
4- 0.6 b
2.15 4- 0.8 d
Mean _ S.E.
Homologous blood cells incubated with saturated serum for 1 hr at room
temperature.
c Filtered through a O.45-tLm filter, corrected for 16.6% binding to filter.
d Homologous blood cells incubated with saturated serum for 30 min at 37 ~
a
b
OL,
02
O(
-~o.4
B1
2
c 02
s
s
s
6
I
o
ca
0c
Cl(ml/min/
1
2
3
4,
5
6
o = ~
2
3
L
5
6
C
Length (cm]
Chart 2. Bisantrene in rabbit peripheral ear vein. Rabbits were infused with
bisantrene (260 mg/sq m) for 1 hr and killed 1 hr later (A); for 1 hr and killed 24
hr later (B); and for 24 hr and killed 1 hr later (C). Veins from the infused ear
were removed, cut into 1-cm segments, extracted, and assayed for bisantrene.
Arrow, position of the tip of the infusion needle. Left to right, distal to proximal.
There were 3 rabbits in each group; bars, S.E. No bisantrene could be detected
in any of the noninfused ear veins (results are not shown).
T w e n t y - f o u r hr after i n f u s i o n of b i s a n t r e n e , v e i n s c o n t a i n e d
1 . 1 8 +_ 0 . 2 8 mg b i s a n t r e n e (n = 3) p e r 6 - c m s e g m e n t . No
b i s a n t r e n e w a s d e t e c t e d in v e i n s from u n i n f u s e d ears. W h e n
b i s a n t r e n e d i h y d r o c h l o r i d e w a s i n f u s e d at 2 6 0 m g / s q m o v e r
24 hr, i n f u s e d v e i n s w e r e c o n g e s t e d a n d c o n t a i n e d s o m e
c l o t t e d blood but a p p e a r e d to c o n t a i n less p r e c i p i t a t e d d r u g
than did v e i n s i n f u s e d w i t h the s a m e d o s e o v e r 1 hr. A c i d
e x t r a c t s of 6 - c m s e g m e n t s of v e i n s i n f u s e d o v e r 24 hr c o n t a i n e d 0 . 1 3 +_ 0 . 0 2 mg of b i s a n t r e n e (n = 3). O n e r a b b i t w a s
g i v e n b i s a n t r e n e , 2 6 0 m g / s q m o v e r 72 hr. O n e hr after
DISCUSSION
O u r s t u d i e s of b i s a n t r e n e d i s s o l v e d in v a r i o u s m e d i a d e m o n s t r a t e t h a t it is v e r y i n s o l u b l e at a pH g r e a t e r t h a n a p p r o x i m a t e l y 4 . 5 and is v i r t u a l l y i n s o l u b l e at pH 7 . 4 . T h e m a x i m u m
s o l u b i l i t y of b i s a n t r e n e h y d r o c h l o r i d e in r a b b i t a n d in h u m a n
s e r u m is a p p r o x i m a t e l y 13 # g / m l . M o s t of the d r u g in s e r u m
a p p e a r s to be b o u n d to p r o t e i n b e c a u s e u l t r a f i l t r a t i o n of p l a s m a
s a t u r a t e d w i t h b i s a n t r e n e r e m o v e d all d e t e c t a b l e d r u g . T h e low
s o l u b i l i t y of b i s a n t r e n e at p h y s i o l o g i c a l pH m a k e s it likely that,
w h e n the d r u g is a d m i n i s t e r e d at c o n c e n t r a t i o n s in the i n f u s a t e
w h i c h p r o d u c e i.v. c o n c e n t r a t i o n s g r e a t e r t h a n 13 f f g / m l , p r e c i p i t a t i o n of the d r u g o c c u r s i n t r a v a s c u l a r l y .
In o u r P h a s e II s t u d y of b i s a n t r e n e in p a t i e n t s w i t h a d v a n c e d
c o l o r e c t a l c a r c i n o m a , the d r u g w a s g i v e n at 2 6 0 m g / s q m, t h e
total d o s e b e i n g d i s s o l v e d in a m a x i m u m of 1 5 0 0 ml of 5 %
d e x t r o s e in w a t e r and i n f u s e d o v e r 1.5 to 3 hr (6). P e a k p l a s m a
c o n c e n t r a t i o n s of b i s a n t r e n e after 2 6 0 m g / s q m g i v e n o v e r 9 0
min r a n g e d from 4 to 8 f f g / m l . The m a g n i t u d e of t h e s e v a l u e s
is c o m p a r a b l e to t h a t r e p o r t e d by P e n g e t al. (4), 6 f f g / m l , at
the end of a 3 0 - m i n i n f u s i o n of 1 10 m g / s q m. T h e s e c o n d a r y
p h a s e of p l a s m a e l i m i n a t i o n of b i s a n t r e n e r a n g e d from 7 to 3 0
hr w i t h a m e a n of 1 7 hr. T h e v a l u e of t h e t e r m i n a l half-life is an
e s t i m a t e b a s e d u p o n b l o o d s a m p l e s c o l l e c t e d for o n l y 2 4 hr.
A l t h o u g h t h e r e w e r e c o n s i d e r a b l e d i f f e r e n c e s in the v o l u m e s
of d i s t r i b u t i o n a m o n g the 5 p a t i e n t s s t u d i e d , all v o l u m e s of
d i s t r i b u t i o n w e r e e x t r e m e l y large. T h e y reflect, w e b e l i e v e ,
p r e c i p i t a t i o n of d r u g in v i v o r a t h e r than e n t r y of s o l u b l e d r u g
into s o m e large c o m p a r t m e n t s u c h as d r u g b i n d i n g to t i s s u e
and/or plasma macromolecules. When bisantrene was admini s t e r e d to r a b b i t s via an ear v e i n at a total d o s e , c o n c e n t r a t i o n ,
and rate u s e d for a d m i n i s t r a t i o n of the d r u g to h u m a n s ( 2 6 0
m g / s q m as a 1 - m g / m l s o l u t i o n o v e r 6 0 min), the d r u g p r e c i p itated in t h e i n f u s e d v e s s e l and a d h e r e d to t h e v e s s e l walls.
We b e l i e v e t h a t the s a m e p h e n o m e n a o c c u r in h u m a n s and are
r e s p o n s i b l e for at least the local t o x i c i t y r e p o r t e d in h u m a n s .
The fate of the p r e c i p i t a t e d b i s a n t r e n e in h u m a n s is not k n o w n .
We b e l i e v e t h a t it is u n l i k e l y t h a t large a m o u n t s of d r u g are
r e l e a s e d from p o t e n t i a l d e p o t sites of p r e c i p i t a t e d material
b e c a u s e of the virtual i n s o l u b i l i t y of the d r u g at pH 7 . 4 . T h i s
s p e c u l a t i o n is s u p p o r t e d by the f a c t t h a t in no clinical s t u d y in
w h i c h c o u r s e s of d r u g w e r e r e p e a t e d e v e r y 3 to 4 w e e k s has
t h e r e b e e n u n e q u i v o c a l e v i d e n c e of c u m u l a t i v e t o x i c i t y of bisa n t r e n e or has l e u k o p e n i a b e e n p r o l o n g e d (7, 8).
Reducing
the c o n c e n t r a t i o n
of b i s a n t r e n e
in t h e i n f u s i o n
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927
G. P o w i s e t al.
vehicle and increasing
the duration
of i n f u s i o n i n t o t h e e a r
v e i n s of r a b b i t s d e c r e a s e d t h e a m o u n t of d r u g r e c o v e r a b l e
from the infused vessels. The mean amounts of drug extracta b l e f r o m a 6 - c m s e g m e n t o f v e i n i m m e d i a t e l y p r o x i m a l to t h e
s i t e of i n f u s i o n 1 h r a f t e r 2 6 0 m g / s q m i n f u s e d o v e r 1 h r (1
mg/ml), 24 hr (0.05 mg/ml), and 72 hr (0.015 mg/ml) were
2091,
134,
and
7 /~g. T h e s e
data
suggest
t h a t it m a y
be
a d v a n t a g e o u s to a d m i n i s t e r b i s a n t r e n e a s a d i l u t e s o l u t i o n s o
a s n o t to e x c e e d its s o l u b i l i t y in b l o o d . P r o l o n g e d i n f u s i o n m a y
allow cytotoxic effects of bisantrene upon tumor and upon
b o n e m a r r o w to be a c h i e v e d w i t h little l o c a l t o x i c i t y b y m i n i m i z ing local precipitation and maximizing bioavailability. We are
n o w s t u d y i n g t h e d r u g b y 7 2 - h r i n f u s i o n in a P h a s e I s t u d y .
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CANCER RESEARCH VOL. 43
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Research.
Intravascular Deposition of Bisantrene
Fig. 1. Top, peripheral ear vein from a control rabbit.
The vein is collapsed and contains little blood. Bottom,
peripheral ear vein from a rabbit infused with bisantrene
(260 mg/sq m) over 60 rain. The animal was killed 1 hr
after completion of infusion. The vein is congested with
blood and contains bright yellow deposits of drug on the
wall.
FEBRUARY
1983
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Research.
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Disposition of Bisantrene in Humans and Rabbits: Evidence
for Intravascular Deposition of Drug as a Cause of Phlebitis
Garth Powis and John S. Kovach
Cancer Res 1983;43:925-929.
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