Note: Descriptions are shown in the official language in which they were submitted.
21 8q9~7
WO 9SI31219 PCTIEP9S/01762
The use of porphyr~n-~omplex or expanded porphyr~n-complex compounds aslocal1satlon d1agnost~cum for lnfarct~on or necros~s
.
The present invention relates to the use of porphyrin-
complex and P~ ntlP~ porphyrin-complex compounds for use as a
diagnosticum, in particular for use as a diagnosticum for the
detection, locali2ation, and monitoring of an infarction, and
5 of a necrosis.
Suitable porphyrin-complex compounds are subject of
DE-A-4,232,925, DE-A-4,305,523, EP-A-336,879, and
EP-A-355,041. The subject matter of these applications are
inrll~lPr. by cross reference.
These porphyrin-complex compounds are used as a
pharmaceutical preparation for the diagnosis and therapy of
tumours .
Other suitable porphyrin-complex compounds are ~;3n
prophyrin - c omp 1 ex c omp ounds ( 17 ) .
The present invention is based on the inside that these
porphyrin-complex compounds can be used for the detection,
lor~li7~tio~, and monitoring of an infarction, and of a
necrosis, such as ischemic, alcohol, and biliary obstruction, ~-~
induced necrosis, and further laser lnduced hepatic, renal
20 and muscular necrosis.
EIereafter the use as an infarction localization
diagnosticum is primarily exemplified for a myocardial
infarction and for a renal infarction, but it will be obvious
for a skilled person that due to similar pathophysiological
25 situations the same experimental findings apply to other
infarction such as those of the intestines, lung, brain and
the like .
Myocardial infarction is not a stable
pathophysiological situation, but instead progresses to its
30 definite form over several weeks to months. This process can
be subdivided, although overlapping, in at least three ~
periods. The first 24 hours after the start of ischemia - --
CONFIRMATION COPY
,
21 89967
WO 95131219 PCr/EP95/01762
(acute evolving myocardial infarction~ damage progresses as a
wavefront phPnnTn~nnn from the subendocardium to include the
myocardium transmurally. During the second phase (established
myocardial infarction~ this area stabilizes and fibrosis is
S formed as a healing process. The third phase (healed
infarction~ starts after all the damaged tissue is repl~ced
by a fibrotic scar. During this phase, considerable
remodelling takes place. So far no accurate and reliable
t~-hni ~10 exists that can determine the evolution phase of
lO the myocaraial infarction antemortem.
The most important long-term prognostic factor after a
myocardial in~arction is the amount of myocardial tissue lost
during this process. So far, no accurate and reliable
technique exists to demonstrate the end-point, the amount of
15 irreversibly damaged tissue antemortem.
In the three phases described above, it is of extreme
importance to have an accurate status about the amount and
lor~l;7zltinn o~ the affected myocardial tissue. During an
evolving myocardial infarction, it is important to assess the
20 amount of tissue at risk, the amount already lost, and from
th~se parameters the amount of tissue that can be salvaged by
reperfusion by thrombolysis or emergency surgical
revascularisation, according to the hemodynamic status of the
patient. In a--patient with unstable angina, it is often
25 impossible to discriminate between reversibly injured
(akinetic, stunned) myocardium and irreversibly damaged
tissue. This would nevertheless have a profound impact on the
therapeutic strategy. In the case o~ compli--~t;nnc in the
phase of est~hl i ~hPd infarction, requiring surgical
30 intervention, it is known that mortality is highest when dead
tissue is revascularized, causing hemorrhagic infarctions. An
operative strategy of repair of the ventricular septum defect
or mitral insuf f iciency with selective revascularisation of
non-necrotic tissue could save lifes.
Up to now, a satisfactory in vivo method for localizing
and defining an infarction and the size of an infarction has
not yet been available, which impedes the progress of both
the basic rese rch and clinical practice (l~ . For instance,
current imaging techniques such as echocardiography ( 2 ~,
_ _ _ . _ _ _ _ _ _
~ 89~67
Wo 9~31219 3 pCr/EP95/01762
nuclear scintigraphy with perfusion and infarct avid tracers
(3-5) and magnetic resonance imaging ~MRI) without and with
different contrast media (6-9) are still far from optimal in
terr3s of sensitivity, specificity, spatial resolution,
5 contrast and rPl;~hility (l).
Slmilar cnntomr~A~ions apply for infarctions of the
kidney intestines, lung and brain
Necrosis is a status of local tissue death, and results
from the effects of ~iiCP;~RP¢ rP,q~ in~ in an adverse and
lO detrimental effect on body tissue. Necrosis may be caused by
radiation, injury, chemicals, local oxygen deficiency,
infections, cancer, and the like. Monitoring, localization
and detection of necrosis allowes the follow up and
ef~ectiveness determination of all kinds of diagnostic and
15 therapeutic therapies and tro~tmpnt
The present invention relates to the use of these :~
porphyrin-complex compounds or metalloporphyrins, for the
lnc~li7a~ion, visualization of an infarction and of a
necrosis. This invention is based on expprimpnr~l results
20 with myocardial and renal infarctions, and with hepatic,
renal and muscle necrosis demonstrating an extraordinary
effect with one-to-one correlation between ~.agnetic resonance
images (MRI) and histochemical preparations. This preclinical ~
result open new horizons for especially the cardiac and F
25 necrotic imaging.
The porphyrin-complex compounds comprise a ligand
having the general formula I
CH
, 1 3
H~C ~
~NH Nl -
~N HN~ -
H C ~ CH~
.2 3
R (I)
WO 95131219 PCr/LP95/01762
and at least one metal ion suitable ~or e corporal
determination. Suitable metal ions have an atomic number of
21-32, 37-39, :~L2-51 and 57=33 . ..
In this general ~ormula:
R1 represents a hydrogen atom, a stralght or branched
C1-C6 alkyl group, a C-C~2 aralkyl group Qr a OR' group
wherein R ' is a hydrogen atom or a C1 - C1 alkyl group,
R' and R3 represent a group CO~- ~ or a group
(NH) O- ~A) q-NH~D, wherein Z is a group OL with L is an
l0 inorganic Qr organic cation or a C1-C~ alkyl group, A is a
phenylenoxy group, a C,-C1, alkylene group possibly interrupted
by one or more oxygen atoms, or a C,-C13 aralkylene group, o
and o~ independently represent an integer 0 or l, and D
represents an hydrogen atom or a group CO-A (COOL)o= (H) = with
15 m e~uals 0 or l under the provisio that the sum of m and o
e~uals l;
R' represents a group (C=M) (NR~)o~ (A) - (NRs) -K, wherein M
represents an oxygen atom or two hydrogen atoms;
R~ represents a group (A)q-H; and
K represents a complex former having the general
formula IIa or :IIb, and
Rs when K is formula Ira has the same meaning as ~ and
when K has the formula IIb has the same meaning as D, under
the proviso that a direct oxygen-nitroyen bond is not
25 allowedr
wherein L1 has the meaning of a C1-C~ alkyl group or an
inorganic or oryanic cation and wherein
L~ ~ L3 and Li independently have the same meaniny as L1 or are
an hydrogen atom, under the proviso that the co~nplex former
3 0 comprises at least two f ree carbon acid groups, and
optionally ~or charge mutuali ation of the metalloporphyrin
other anions, and pharmaceutically acceptable addition salts
and carrierE and diIuants.
~ Wo95/31219 2~ 8~7 P~ l7~l,62
O~ ~ ~ rCOOL
N N N
5 COOH COOH COOL (lla)
.
~COOL
0 ~LA--N N--
OH ~N~,>
COOL (llb)
For MR localization the pc,L~1-yLin-complex compounds
comprises at least one paramagnetic metal ion, preferably di-
or trivalent ions of the metal elements having the atomic
nU~mber 21-29, 42, 44 and 57-70. Suitable metal ions are for
instance chromium (III), m~nJ~nr~ce (II), r~nrg~nP~e (III),
iron (III), cobalt (II), cobalt (III), nickel (II), copper =~
( I I ), praseodymium ( I I ), neodymium ( I I I ), samarium ( I I I ) and
ytterbium (III) . Pre~ered are ~J~ l ;nium (III), terbium
(III), dysprosium (III), holmium (III), eroium (III) and iron
(III) .
For radioscintigraphic determination radioisotopes of
the elements having the atomic num.ber 27, 29-32, 37-39,
42-51, 62, 64, 70, 75, 77, 82 or 83 are preferred
It is noted that when the complex rr~mrQ~ln~l~ comprises
various metal ions these metal ions may originate f rom the
group for MR visualization and radioscintigraphic
Visll~l; 7 t i on .
Futhermore the metal ion may be crmrl ~rcl in the
35 porphyrin skeleton, in the so called P~r~nr~r~ porhyrin
skeleton, and/or in the complex forme~.
Examples of the porphyrin-complex compounds are the
disodium salt of the digadolinium complex of N,N'-Bis[9-
SUBSTITUTE S~iEET (RULE 26)
., . , . .. , . _ _ _ _ . _ . .
W095~31219 ~ 8996~7 r ~ )62 ~
carboxylato - 2 r 5, 8 - tris ( carboxylatomethyl ) - 2, 5, 8 - triazanonyl -
carbamoyl~ -mesoporphyrin-IX-13, 17-diamides (Gd-MP) .
The disodium salt of the di~ l ;n;um complex of manganese
~III) - N,N' -Bis [ll-carboxylato-2-oxo-4, 7-
5 bis(carboxylatomethyl)-10-(ethoxycarbonylmethyl)-1,4,7,1Q-
tetr~7~lln~1Pcyl] -3,a-bis~l-propyl) -porphyrin-IX-13,17-
diamides -acetates, and the di~ l In;llm complex of manganese
(III) - N,N' -Bis [ll-carboxylato-2-oxo-~, 7-
bi s ( carboxyl atomethyl ) -10 - ( e thoxycarbonylmethyl ) -1, 4, 7, 10 -
10 tetr~il7~lln~ecyl]-3,8-bis(l-propyl)-porphyrin-IX-13,17-
diamides -acetates (Mn-TPP) .
The diagnosticum has the form of a pharmaceutical
formulation suitable for intra-veneous or intra-arterial
injection in the form of a solution or suspension. The
15 diagnosticum m--ay comprise suitable additives, such as a
buffer (tromet~amine), complex formers such as
diethylenetriaminpenta-acetic acid, electrolyte such as
sodium chloride, antioxydantia such as ascorbinic acid.
FurthP ~ additives, tencides and the like may be
2 0 added ~ :. .
WO 95/31219 2 ~ g 9 9 b 7 PCT/EP95/01762
Gd-MP
Bis-Gd-DTPA-{Mesoporphyrin-lX-l 3, 1 7-bis[2-oxo-4, 7,1 0,1 0-tetra-(carboxyla-
tomethyl)-1, 4, 7, 10-tetraazadecyl]-13, 17-diamide}, bis sodium salt
~'
r~ = NH-NHJ~ ~ Gd3~ ~COO
CO-R CO-R l`coo
Mn-TPP:
Manganese-(lll)-{Tetrakis-[3]-(carboxylatomethoxy-phenyl)-porphyrin}-acetate,
tetra sodium salt
¢~o~CO2'Na-
Na~O~C~
~ MnOA,~
~ O~CO2-Na'
Na~02C~O
Cl II~CTITI ITI: CL~CT 1^~
WO 95131219 2 1 8 q ~ ~ 7 PCT/EP9~/0176~ --
The diagnosticum may comprise the porphyrin or expanded
porphyrin complex compound in an amount of 0 . 0001 - 10 . 0
mmol/kg body weight . Preferred is an amount of 0 . 005 - 2
mmol/kg body weight, more preferred 0.01 - 1.0 mmol/kg body
5 weight. The actual dose is also dependent on the infarction
to be localized, on the patient and on the localization
technique to be~ used.
Hereafter the use of a diagnosticum comprising these
specific metalloporphyrins, for the localization of an
10 infarction and of necrosis, according to the invention will
be shown for the visualization of an acute myocardial
infarction and renal infarction, and of necrosis. The result
obtained so far did not Pncollntpr neither false positive nor
false negative findings. Striking is the almost perfect
15 matching of the ex corporal localization and the
histochemical confirmation.
In the experlments two paramagnetic metalloporphyrins
have been used which were originally developped as potential
tumour specific MRI contrast agents (10-14) . GA~lnl inium
20 mesoporphyrin (Gd-MP) and m~ln~nPCe tetraphenylporphyrin
(Mn-TPP) have been used.
Rl~mrl e 1
The model of myocardial infarction was produced in rats
25 by ligation of=the left coronary artery according to an
est~hl i chP~ technique (15) . Two groups of rats (12 in each~
with myocardial infarction aging 2 to 24 hours received
intravenously either Gd-MP (IDF Gm.bH, Berlin) or Mn-TPP
(IDF ~m.~bH, Berlin) at dosefi of 0.1, 0.05 and 0.01 m.mol/kg
30 (4 rats each) . After an interval of 3 to 24 hours
postinj ection, axial and coronal Tl weighted spin echo MR
images were obt=ained i ~i~tely before and after sacrificing
the animals The excised heart was incubated with triphenyl
tetrazolium chloride (TTC), which is a reliable histochemical
35 staining to distinguish the infarcted from the non-infarcted
myocardium (16). In addition, two groups of rats (6 in each)
were used as controls and underwent the same imaging and
histochemical procedures, i . e . one group with infarction but
without contrast agent injection, the other group with
2 ~ 89961
Wo 95/31219 PCT/EP95~01762
injection (3 with Gd-MP, 3 with Mn-TPP) but without
inf arction . The dif f erence between the inf arcted and non-
infarcted myocardium seen on MR images was quantified by
measuring the signal intensities (SI) with a monitor defined =~
5 region of interest and expresse_ as contrast ration
(CR) :CR = SI infarct / SI noninfarct (mean i SD) . The metal
content of the tissue was measured by ICP-AES. Finally the MR
images were carefully compared with the corresponding macro-
and microscopic tissue preparations and correlated with the
lO results of local metal content measurement.
The infarct of the 6 control rats could not be
discerned by MRI without contrast media. E~owever, 3 to 24
hours after injection of either Gd-MP or Mn-TPP, all 24 rats
with myocardial infarction exhibited on MR imag~s a clear
15 flPl in~Ation of the infarcted areas of the heart, which
precisely matched the areas of negative staining on the
histochemical samples (Fig. l) . The CRs between the infarcted
and nnninfArcted regions were 3 40 i 0.26 at 3 hours and 1.92
i 0.17 at 24 hours after contrast agent injection. Even the
20 small dose of O.Ol mmol/kg worked well (CR = 1.84 ~ 0.13 at
lO hours postinjection). Neither false positive findings
(i.e. contrast ~nhAnn~mPnt in noninfarcted area) nor false
negative findings (i.e. infarcted myocardium not ~nhAnnPfl
with the agents) were obtained. The Gd content was as much as
25 9 fold higher in the infarcted myocardium (Table l),
suggesting that the MRI signal ~nhAn~ t is mainly due to a
preferential accumulation of metalloporphyrins in infarcted -~
tissue .
3 0 Exam~l e 2 ` -
Using the same model of myocardial infarction, in two
rats minor necrotic lesions were found at the ligation sides.
The MRI was per_ormed lO hours after Mn-TPP (0.05
mmol/kg body weight) intervenous injection. The technique is
35 so sensitive that even lesions between l to ' mm in size were
easily detectable (Fig.2) .
21 ~9~7
Wo 95131219 PCTIEP95/01762
ExamQle 3
A rat with partial renal infarction of the rlght kidney
was injected with Gd-MP (O.l mmol/kg body weiyht by
intervenous inj ection) .
24 Bours after Gd-MP injection, the Gd-content
(measured with ICP-AES technir,~ue) of the infarcted and non
infarcted kidney were similar but the signal intensities was
at least two fQld higher for the infarcted kidney (Table 2).
Presumably the mprhAn; ~m for metalloporphyrin induced
lO specific Pnh~nrPmPnt seems not only related to an
~rr~lm~ tion of the porphyrin-complex compound in the
infarcted tissue. An increased relaxivity of the
metalloporphyrins induced by a change in local molecular
environment plays also a role in the observed increased
15 signal intens~ty (Fig . 3 ) .
ExamQle 4
In order to evaluate the potential of these agents for
the detection and monitoring of other types of necrosis
20 following experiments were performed.
.Srnnt~ner,l-~ liver necrosis was induced by ligation of
the common bile duct in rats. 72 ~ours after surgery both
types of metalloporphyrins (Gd-MP and Mn-TPP) were
intravenously injected at a dose of 0 05 mmol/kg. Already lO
25 minutes after injection areas of strong PnhAnrPmPnt could be
observed in the liver. This ~nh~nrPm.~nt lasted for about one
week. Macroscopic Plr~m1n~tlrr~ confirmed that the Pnh~nrinq
areas corresponded to cholestatically related liver necrosis.
A second exper~ment consisted in the induction of local
30 necrosis ln liver, kidney and muscle in rats by local
inj ection of absolute alcohol . Imaging 8 to 24 hours af ter
alcoholisation of both metalloporphyrins caused a concentric
Pnhilnr~ t of the induced lesions. Those remained enhanced
for several days. Macroscopy and microscopy after sacrifice
35 confirmed the necrotic nature of the lesions (Fig. 4A, 4B,
4C)
Wo 95/31219 2 1 ~ 9 q 6 7 PcrlEP95/01762
mnl e 5
Infarcted myocàrdium induced the model of example l and
laser induced necrosis using standard laser model techniques
were studied in rats.
Before injection of the contrast agents, the induced
necrosis were not visible on MR images. However, positive
Pnh;~nr~ t appeared in these lesions after contrast agent
injection and persisted for more than 24 hours.
The contrast agents used were Mn-~PPS4 ~Mn-meso-tetra-
~4-sulfonato-phenyl)-porphyrine (available from Porphyrin
Products Inc., Logan, Utah, USA), in an amount of
0.05 mmol/kg, and Gd-Mn-porphyrin (Mn(III) -{N-Bis- [ll-
carboxylato-2-oxo-4, 7, lO-tris- (carboxylatomethyl) -l, 4, 7, lO-
tetr~7~-ln~1Pcyl~-methylpyrroporphyrin-XXI-amide}-acetate, Gd-
15 complex, sodium salt can be prepared according to example
l/14 in W084/07894).
Methylpyrroporphyrinethylester (Aldrich Chemicals) jis
reacted with hydrazine in pyridine and subsequently with
~-nr~nPce acetate in acetic acid. The obtained intPrmP~i ~te
20 i5 reacted with DTPA-monoanhydride-monoethyleSter in absolute
N,N-dimethylf~ ~1P and addition of triethylamine. After
hydrolysis and neutralisation complexation is carried out
with the use of ra~ 1 inivm acetate in an amount of
0 . 05 mmol/kg .
The experimental results are summarized in tables 3 and
4.
The fact that necrosis of different origine, vascular
and biliary infarction and alcoholisation, all show similar
degreEs of enhancement opens new prospectives f or the
30 monitoring of therapies that ultimately cause tissue
necrosis, such as radiot_erapy, chemotherapy, thermotherapy,
laser therapy, ultrasound and radiofrequency ablation,
alrnhnl i ~tion, etc. ...
~***~
WO 95l312lg 2 ~ ~ 9 q 6 7 PCT/EP9~/01762
Table
Gd content and MRI signal intensity in rats with myocardial
infarction measured 24 hours after Gd-MP (0.05 mmol/kg)
Myocardium Gd (llmol/g) Signal Intensity
ICP -AES ( ROI )
infarcted ~ 0 . 065 i O 006 422 :~ 31
non infarcted 0.007 i 0.002 193 i 17
ratio7 9 . 29 2 .19
Note: iinfarcted/non infarcted
.
Ta~l~ 2
Gd content and signal intensity in a rat ~ith partial renal
infarction measured 24 hours after Gd-MP (0.1 mmol/kg).
Tissue . Gd (~mol/g) Signal intensity
ICP-AES (24 h)
inf~rcted kidney 0 . 75 1340
40 non-infarcted kidney 0.79 63
2 1 89967
WO 9~/31219 l3 PCT/EP95101762
Table 3
MRI Findings af ter myocardial in~arction*
Signal Intensity CR
Normal Infarcted
Myocardium Myocardium Infarct/Normal
Mn-TPPS4 343 583 1.7
Gd-Mn-porphyrin 320 669 2 . l
* The agents were inj ected 12 hours be~ore MR imaging in rats
with myocardial infarction (MI) aging 24 hours.
Tal~le 4
MR Imaging in Laser Induced Necrosis~
Signal Intensity CR
Precontrast 24 h post-contrast Lesion/
Liver tissue Necrosis Normal
Mn-TPPS4 518 ~ 21 625 + 34 1063 + 52 1. 7
Gd-Mn-porphyrin 501 t 30 593 + 27 1126 + 18 1.9
* The signal intensities of the liver and necrotic lesions were
derived from pre- and 24 hours postcontrast MR images.
21 899b7
WO 95/31219 14 P~ /62
Legends for figures-
Fig. 1 (A-C). MRI and macroscopic photographs of a rodent heart with
myocardial infarction. The MRI was p~. [Ol ..led 24 hours after Gd-MP
(0.lmmol/kg) illL~r-.~-uu~ injection and imm~flia~r-~y after sacrificing the
animal.
A, B: Coronal (A) and axial (B) T1 weighted spin echo images (TR/TE =
300/15 msec, slice thickness = 2 mm, FOV = 100 mm, matrix size = 256 x 256,
NEX = 6) display a strongly signal ~nhanrm~n~ in almost all left ventrical
wall including part of the ventricular septum (arrows) but not some
papillary .ll~u..l-dial structures (arrowheads). The graduation near the
frame on the right side represents I cm.
C: Axial section of the heart on a similar piane to the axial MR image (B),
incubated with 1 % triphenyl t~L.~uliull. chloride (TTC) for 15 minutes and
fixed overnight with 10 % formalin, shows the left Yentricai wall including
part of the septum as unstained, (pale) infarcted area. Arrowheads indicate
the intact myocardial papillae shown in B.
Fig. 2 (A-C). MF;I and macroscopic ~IluLù~ ,uhs of a rodent heart with lûcal
injury caused by ligation. Such minute necrotic Icsions werc found at the
ligation sites in two rats who failed to form real infarction and were
exduded as successful models from the study. The MRI was performed 10
hours after Mn-TPP (0.05 mmol/kg) intravenous injection and immP~iia~ly
after sacrificing the animal.
A, B: On both the coronai (A) and axial (B) MR images (the same p~
as in fig. 1), an }Iy~c:l;llL~ -~e lesion(arrow) of a~u~u;dl~aL~:ly I mm in size. can be clearly seen in the left ventricular wall, despite a parhal volume effect
(i.e. the diameter of the lesion is smaller than the thickness of the MR slice;
otherwise the lesion would appear brighter). The graduation near the frame
on the right side represents I cm.
2 ~ 9 b7
WO 95/31219 PCT/EP95/01762
1 5
C.: TIC stained axiai section of the heart on a simiiar plane to the MR image
(B) displays the ligature and adjacent minutc unstain~d n~crotic l~sion
(arrow).
Fig. 3 ~A - D~. MRI and ~la~us~ulJic phulu~ s of a rat with parhal r~nal
infarction in the right kidney.
A - C: ~xial T1 weighted spin echo images (Ti~/TE = 600/15 msec, the rest
iJA~ rl ~ are the same as in Fig. I A and B.
A: On i~leLul~Lld~l plain scan in the right kidney, infarcted and nu...l~f.l.~Le.
parts cannot be discerned.
B: Ten minutes after Gd-MP 0.1 mmol/kg) intravenous injection, the
nulul.rdl~led pdl~ yllla (lower part) is strongly enhanced in contrast with
the lln~nh~nr~l infarcted ~dle~ a (upper part), which is gradually filled
up with time by the agent (images not shown).
C: Forty-eight hours postcontrast, when the signal intensity of the
nu.ul,rdl.~d kidney (lower part) has almost normalized, the infarcted upper
part of the kidney is still strikingly enhanced.
D: Macroscopic view of the right kidney on a similar section as in C. Note
how well the areas of the infarcted and noninfarcted parenchyma seen on
the speomwr~ m~ch with the con~ it e h~nc~ MR im~e (C).
WO9S/31219 2 1 899 67 P~ . I/OZ
Legends for Fig. 4 A-D: Axial Tl W SE MR images and macroscopic
pllulu~l~ s of rat liver with alcohol induced l-oA~ nn necrosis.
A. On ~ u~ aal image, the 10 hours old necrotic lesion (arrow) is
isointerl3e and therefore can not be detected.
B. Ten minutes after illlla~_~.vuS injection of ~e ~ .._3u~lplly~
(Gd-MP, 0.05 mmol/kg), the lesion (arrow) appear3 ~y~uill~ Se with some
central bright spots (blood vessels). The lesion .. ~i ;. Ally enhances with
time whereas the liver intensity l~.ù~ Iy decreases (images not shown).
C 24 houls later when the liver intensity has largely decreased, the bright
'i Iesion appears bright (arrow~ with some central dark spots. This
suggests a specific retention and a strong affinity of the mehlloporphyrin for
the necrosis.
D. Macroscopic phu~u;~;~apl~ of the liver section in the plane similar to MR
images, The alcohol induced .u~bul~liull necrosis (arrow) has the same
J..VI~' ' 6Y with some in~ mAI blood vessels, as shown on the contrast
enhanced MR images.
WO g5/31219 17 . ~ t. . 1762
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18
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