U.S. patent application number 09/157979 was filed with the patent office on 2002-01-10 for process for therapeutic treatment of proliferative diseases.
Invention is credited to BLUME, FRIEDHELM, DINKELBORG, LUDGER, HELDMANN, DIETER, HILGER, STEPHAN.
Application Number | 20020004031 09/157979 |
Document ID | / |
Family ID | 27217783 |
Filed Date | 2002-01-10 |
United States Patent
Application |
20020004031 |
Kind Code |
A1 |
DINKELBORG, LUDGER ; et
al. |
January 10, 2002 |
PROCESS FOR THERAPEUTIC TREATMENT OF PROLIFERATIVE DISEASES
Abstract
The invention relates to a process for therapeutic treatment of
proliferative diseases, which is characterized in that first an
administration catheter is placed on the site of the lesion, and a
radioactive substance is administered topically via the catheter,
then the catheter is again removed, and the radioactive substance
remains on the site of the lesion.
Inventors: |
DINKELBORG, LUDGER; (BERLIN,
DE) ; HILGER, STEPHAN; (BERLIN, DE) ;
HELDMANN, DIETER; (BERLIN, DE) ; BLUME,
FRIEDHELM; (BERLIN, DE) |
Correspondence
Address: |
MILLEN, WHITE, ZELANO & BRANIGAN, P.C.
2200 CLARENDON BLVD.
SUITE 1400
ARLINGTON
VA
22201
US
|
Family ID: |
27217783 |
Appl. No.: |
09/157979 |
Filed: |
September 22, 1998 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60062261 |
Oct 17, 1997 |
|
|
|
Current U.S.
Class: |
424/1.69 ;
424/1.11; 424/1.65; 424/9.1 |
Current CPC
Class: |
C07B 59/004 20130101;
C07F 13/005 20130101; A61K 51/1282 20130101 |
Class at
Publication: |
424/1.69 ;
424/1.65; 424/1.11; 424/9.1 |
International
Class: |
A61M 036/14; A61K
051/00; A61K 049/00 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 23, 1997 |
DE |
197 42 880.0 |
Claims
1. Process for therapeutic treatment of proliferative diseases,
characterized in that first an administration catheter is placed on
the site of the lesion and a radioactive substance is administered
topically via the catheter, then the catheter is removed, and the
radioactive substance remains on the site of the lesion.
2. Process for therapeutic treatment of arteriosclerotic diseases,
wherein first an administration catheter is placed on the site of
the lesion and a radioactive substance is administered topically
via the catheter, then the catheter is removed, and the radioactive
substance remains on the site of the lesion.
3. Process according to claim 1 or 2, wherein the radioactive
substance is a metal complex.
4. Process according to claim 1 or 2, wherein the radioactive
substance is a metal complex, whose ligand is a bis-amine-oxime
derivative of general formula I, 4in which n=0-3, and radicals
R.sup.1 to R.sup.8 are the same or different and in each case stand
for a hydrogen atom and/or for an unbranched, branched, cyclic or
polycyclic C.sub.1-C.sub.100 alkyl, C.sub.1-C.sub.100 alkenyl,
C.sub.1-C.sub.100 alkinyl, C.sub.1-C.sub.100 aryl,
C.sub.1-C.sub.100 alkylaryl and/or C.sub.1-C.sub.100 arylalkyl
radical, which optionally is substituted with fluorine, chlorine,
bromine and/or iodine atoms, and/or hydroxy, oxo, carboxy,
aminocarbonyl, alkoxycarbonyl, amino, aldehyde or alkoxy groups
with up to 30 carbon atoms and/or optionally is interrupted and/or
substituted by one or more heteroatoms from the series N, P, As, O,
S, Se, and whereby radicals R.sup.2 and R.sup.3, R.sup.4 and
R.sup.5 as well as R.sup.6 and R.sup.7 together optionally can
stand for an oxygen atom, and whose central atom is a radionuclide
of the elements of atomic numbers 27, 29-32, 37-39, 42-51, 62, 64,
70, 75, 77, 82 or 83.
5. Process according to claim 1 or 2, wherein the radioactive
substance is a metal complex, whose ligand is an N.sub.2S.sub.2
derivative of general formula II, 5whereby R.sup.9 to R.sup.20 are
the same or different and in each case stand for a hydrogen atom
and/or for an unbranched, branched, cyclic or polycyclic
C.sub.1-C.sub.100 alkyl, C.sub.1-C.sub.100 alkenyl,
C.sub.1-C.sub.100 alkinyl, C.sub.1-C.sub.100 aryl,
C.sub.1-C.sub.100 alkylaryl and/or C.sub.1-C.sub.100 arylalkyl
radical, which optionally is substituted with fluorine, chlorine,
bromine and/or iodine atoms and/or hydroxy, oxo, carboxy,
aminocarbonyl, alkoxycarbonyl, amino, aldehyde or alkoxy groups
with up to 30 carbon atoms, and/or optionally is interrupted and/or
substituted by one or more heteroatoms from the series N, P, As, O,
S, Se, and whereby radicals R.sup.11 and R.sup.12, R.sup.13 and
R.sup.14, R.sup.15 and R.sup.16 as well as R.sup.17 and R.sup.18
together optionally can stand for an oxygen atom, and n, m and p,
independently of one another, mean 1 or 2, and whose central atom
is a radionuclide of the elements of atomic numbers 27, 29-32,
37-39, 42-51, 62, 64, 70, 75, 77, 82 or 83.
6. Process according to claim 1 or 2, wherein the radioactive
substance is a metal complex, whose ligand is an N.sub.2S.sub.2
derivative of general formula III, 6whereby R.sup.21 to R.sup.32
are the same or different and in each case stand for a hydrogen
atom and/or for an unbranched, branched, cyclic or polycyclic
C.sub.1-C.sub.100 alkyl, C.sub.1-C.sub.100 alkenyl,
C.sub.1-C.sub.100 alkinyl, C.sub.1-C.sub.100 aryl,
C.sub.1-C.sub.100 alkylaryl and/or C.sub.1-C.sub.100 arylalkyl
radical, which optionally is substituted with fluorine, chlorine,
bromine and/or iodine atoms and/or hydroxy, oxo, carboxy,
aminocarbonyl, alkoxycarbonyl, amino, aldehyde or alkoxy groups
with up to 30 carbon atoms, and/or optionally is interrupted and/or
substituted by one or more heteroatoms from the series N, P, As, O,
S, Se, and whose central atom is a radionuclide of the elements of
atomic numbers 27, 29-32, 37-39, 42-51, 62, 64, 70, 75, 77, 82 or
83.
7. Process according to claim 4, 5, or 6, wherein a central atom,
which is selected from the group .sup.99mTc, .sup.186Re,
.sup.188Re, .sup.67Cu, .sup.90Y and .sup.107Ag, contains the metal
complex that is used.
8. Process according to claim 1 or 2, wherein the radioactive
substance is a metal complex, whose ligand is a porphyrin
derivative.
9. Process according to claim 1 or 2, wherein the radioactive
substance is a thallium compound of isotopes .sup.201Tl .sup.207Tl,
.sup.209Tl and .sup.210Tl.
10. Process according to claim 1 or 2, wherein the radioactive
substance is .sup.201TlCl.
11. Process according to claim 1 or 2, wherein the radioactive
substance is a tetrofosmin derivative.
12. Process according to claim 1 or 2, wherein the radioactive
substance is a sestamibi derivative.
13. Process according to claim 1 or 2, wherein the radioactive
substance is a furifosmin derivative.
14. Process according to claim 1 or 2, wherein the radioactive
substance is a colloidal solution with particle sizes of between 5
and 1000 nm.
15. Process according to claim 1 or 2, wherein the radioactive
substance is .sup.99mTc-tin colloid or .sup.186Re-tin colloid.
16. Process according to claim 1 or 2, wherein the catheter that is
used is a microporous balloon catheter.
17. Process according to claim 1 or 2, wherein the catheter that is
used is a multichamber balloon catheter.
Description
[0001] The invention pertains to the field of treatment of
proliferative diseases and especially the treatment of vascular
diseases such as, for example, arteriosclerosis.
[0002] It is known that ionizing radiation inhibits the
proliferation of cells. A considerable number of neoplastic and
non-neoplastic diseases have already been treated in this way
(Fletcher, Textbook of Radiotherapy, Philadelphia, Pa.: Lea and
Febiger, 1980, Hall, Radiobiology for the Radiologist,
Philadelphia, Pa.: Lippincott, 1988).
[0003] An attempt has also already been made to treat
arteriosclerotic diseases using this process. Arteriosclerosis is
an inflammatory, fibroproliferative disease that is responsible for
50% of all deaths in the USA, Europe, and Japan (Ross 1993, Nature
362: 801-809). In its peripheral manifestation, it threatens the
upkeep of the extremities; with its coronary manifestation, the
risk of fatal myocardial infarction exists; and with supra-aortic
infection, there is the threat of stroke.
[0004] At this time, arteriosclerosis is treated in various ways.
In addition to conservative measures (e.g., lowering the
cholesterol level in the blood) and the bypass operation,
mechanical dilatation (angioplasty), as well as the intravascular
removal of atheromatous tissue (atherectomy) of stenotic segments
in peripheral arteries and the coronaries have been established as
alternatives in regular clinical practice.
[0005] As stated below, the above-mentioned methods are associated
with a considerable number of drawbacks, however.
[0006] The value of mechanical recanalization processes is greatly
diminished by vascular occlusions as a result of vascular tears and
dissections, as well as acute thromboses (Sigwart et al. 1987, N.
Engl. J. Med. 316: 701-706). Long-term success is jeopardized by
the reoccurrence of constrictions (restenosis). The CAVEAT study
thus revealed that of 1012 patients, the restenosis rate six months
after intervention in coronary atherectomy was 50% and in coronary
angioplasty even 57% (Topol et al. 1993, N. Engl. J. Med. 329:
221-227). In addition, abrupt vascular occlusion occurred in this
study in 7% of the atherectomy patients and in 3% of the
angioplasty patients. Nicolini and Pepine (1992, Endovascular
Surgery 72: 919-940) report a restenosis rate of between 35 and 40%
and an acute occlusion rate of 4% after angioplastic
intervention.
[0007] To combat these complications, various techniques have been
developed. These include the implantation of metal endoprostheses
(stents), (Sigwart et al. 1987, N. Engl. J. Med. 316: 701-706;
Strecker et al., 1990, Radiology 175: 97-102). The implantation of
stents in large-caliber arteries, e.g., in occlusions in the axis
in the pelvis, has already become a treatment modality that is to
be applied primarily. The use of stents in femoral arteries has
shown disappointing results, however, with a primary openness rate
of 49% and a reocclusion frequency of 43% (Sapoval et al., 1992,
Radiology 184: 833-839). Similar unsatisfactory results have been
achieved with currently available stents in coronary arteries
(Kavas et al. 1992, J. Am. Coll. Cardiol. 20: 467-474).
[0008] Up until now, no pharmacological or mechanical interventions
have been able to prevent restenosis (Muller et al. 1992, J. Am.
Coll. Cardiol. 19: 418-432, Popma et al. 1991, Circulation 84:
14226-1436).
[0009] The reason for the restenoses frequently occurring after
mechanical intervention is assumed to be that interventions induce
a proliferation and migration of unstriped muscle cells in the
vascular wall. The latter result in a neointimal hyperplasia and
the observed restenoses in the treated vessel sections (Cascells
1992, Circulation 86, 723-729, Hanke et al. 1990, Circ. Res. 67,
651-659, Ross 1986, Nature 362, 801-809, Ross 1993, Nature 362,
801-809).
[0010] An alternative process for treating arteriosclerotic
diseases uses ionizing radiation. The use of ionizing radiation of
external origin on restenosis is associated with the drawback,
however, that upon administration the radiation dose is not limited
just to the desired spot; rather, the surrounding (healthy) tissue
is also undesirably exposed to the radiation. Thus, to date,
various studies have come up with little to increase the chances of
success (Gellmann et al. 1991, Circulation 84 Suppl. II: 46A-59A,
Schwartz et al. 1992, J. Am. Coll. Cardiol. 19: 1106-1113).
[0011] These drawbacks, which occur when external radiation sources
are used, can be overcome if gamma radiation is directly used with
restenosis via, e.g., a catheter in the vascular area. With this
form of administration with iridium-192, a high radiation dose of
20 Gy is applied to the restenosis foci. Some works report on the
almost complete prevention of restenosis after this intervention
(Wiedermann et al. 1994, Am. J. Physiol. 267: H125-H132, Bottcher
et al. 1994, Int. J. Radiation Oncology Biol. Phys. 29: 183-186,
Wiedermann et al. 1994 , J. Am. Coll. Cardiol. 23: 1491-1498,
Liermann et al. 1994, Cardiovasc. Intervent. Radiol. 17: 12-16). A
drawback to this method is, however, that the radiation dose of 20
Gy that is applied in this case is very high. Since the lesions are
dispersed irregularly on the vascular wall, uniform administration
of a defined dose is not possible using this technique. Moreover,
treatment of large-caliber vessels is not possible since, because
of the dose reduction from the iridium source, the dose that can be
administered is not adequate.
[0012] Another possible way of inhibiting restenosis is the
implantation of P-32-doped stents (Fischell et al. Stents III,
Entwicklung, Indikationen und Zukunft, Konstanz [Development,
Indications, and the Future: Constancy]: Kollath and Liermann,
1995). In this work, an activity of 0.2 kBq P-32 per centimeter of
stent length was enough (corresponding to a radiation dose of 0.25
Gy) to achieve maximum inhibition of unstriped vascular muscle
cells in vitro. It was thus possible to show that not only
.gamma.-emitters but also .beta.-emitters prevent the proliferation
of unstriped muscle cells. An advantage of this Method is that the
radiation dose administered is considerably lower than in all
previously mentioned interventions. At this low dose, the
endothelial cells that line the vascular bed are not damaged
(Fischell et al. Stents III, Entwicklung, Indikationen und Zukunft,
Konstanz: Kollath and Liermann, 1995). This form of intervention
can be used only once, however, namely when the stent is
positioned. In addition, it is limited only to those interventions
in which stents are used. The restenoses that occur in the far more
common types of interventions, such as atherectomies and
angioplasties, cannot be treated with this method. Because of the
small range of action of the .beta.-radiation, it is not possible
to administer a uniform dose of energy to the entire lesion.
[0013] In addition to radiation therapy, a number of other
therapeutic strategies are used for inhibiting neointimal
hyperplasias (restenoses). The latter comprise standard medicines
for suppression of restenoses such as antithrombotic agents,
platelet aggregation inhibitors, calcium antagonists,
anti-inflammatory and antiproliferative substances, but also
gene-therapy approaches. In this case, the inhibition of growth
stimulators, e.g., by antisense oligonucleotides or the enhancement
of inhibiting factors by expression-vector-plasmids and the
virus-mediated gene integration, is possible. Also, Aptamer
oligonucleotides can be used for inhibiting a wide variety of
receptor-mediated processes, which play a decisive role in
restenosis.
[0014] With great energy and care, substances have been studied
over the years that were administered under strictly controlled
conditions as a long-term treatment since the desired purpose was
theoretically to reduce the restenosis rate (Herrmann et al., 1993,
Drugs 46: 18-52).
[0015] More than 50 controlled studies with different substance
groups were performed, without yielding definite proof that the
substances examined could seriously reduce the restenosis rate.
[0016] This also applies for topical administration, in which the
substances are brought via a special balloon catheter to the site
of action that is desired in each case. It has been shown, however,
that the previously used substances are washed too quickly from the
vascular wall to be able to be therapeutically effective. Moreover,
additional vascular wall alterations, which even act to promote
restenosis, are induced by these pressure-mediated liquid
injections.
[0017] The object of this invention was therefore to develop a
process for the treatment of proliferative diseases that overcomes
the drawbacks of previously known treatment processes.
[0018] This object is achieved by this invention.
[0019] A process for therapeutic treatment of proliferative
diseases was developed that is characterized in that first an
administration catheter is placed at the site of the lesion, a
radioactive substance is topically administered via the catheter,
then the catheter is removed, and the radioactive substance remains
at the site of the lesion.
[0020] Since radioactive substances are transported via an
administration catheter right to the wall of a blood vessel and
remain there, the concentration of the radionuclide lasts long
enough to inhibit the proliferation of the cells and thus a
restenosis.
[0021] The process according to the invention has some important
advantages over known treatment processes. In comparison to a
considerable number of studied compounds from a wide variety of
classes, the topical administration of certain substances and with
certain catheters results in a surprisingly high radioactive dose
at the desired, pathologically altered spot. This procedure results
in a highly effective radiation dose with a low systemic load. The
radioactive substances have a long dwell time at the administration
site, which results in a highly effective dose on the spot. They
are dispersed in particular and uniformly in the pathological
regions. The unbonded radioactive substances are quickly
eliminated.
[0022] Since certain radioactive substances, which are described in
more detail below, pass into the wall of the arteriosclerotically
altered vessels, not only the cells of the intima that face the
lumen, but also those of the media and adventitia are kept from
proliferating. The portion of the administered dose that passes
through the cell membrane results in a high radiation dose, which
is effective close to the cell core.
[0023] Owing to the sensitivity of proliferating cells to ionizing
radiation, the process according to the invention is suitable not
only for treatment of arteriosclerotic diseases, but also for the
treatment of other proliferative diseases, such as, e.g., tumor
diseases.
[0024] Suitable radioactive substances are those that have
sufficiently high lipophilia to remain adhered to the plaque. For
example, radiolabeled metal complexes are suitable, such as, e.g.,
metal complexes of bis-amine-oxime derivatives of general formula I
1
[0025] in which n=0-3, and radicals R.sup.1 to R.sup.8 are the same
or different and in each case stand for a hydrogen atom and/or for
an unbranched, branched, cyclic or polycyclic C.sub.1-C.sub.100
alkyl, C.sub.1-C.sub.100 alkenyl, C.sub.1-C.sub.100 alkinyl,
C.sub.1-C.sub.100 aryl, C.sub.1-C.sub.100 alkylaryl and/or
C.sub.1-C.sub.100 arylalkyl radical, which optionally is
substituted with fluorine, chlorine, bromine and/or iodine atoms,
and/or hydroxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl, amino,
aldehyde or alkoxy groups with up to 30 carbon atoms and/or
optionally is interrupted and/or substituted by one or more
heteroatoms from the series N, P, As, O, S, Se, and whereby
radicals R.sup.2 and R.sup.3, R.sup.4 and R.sup.5 as well as
R.sup.6 and R.sup.7 together optionally can stand for an oxygen
atom. These compounds, together with a radionuclide, form a metal
complex, which is then used for topical administration in the
treatment of proliferative diseases.
[0026] Also suitable are the metal complexes of the N.sub.2S.sub.2
derivatives of general formulas II and III 2
[0027] whereby R.sup.9 to R.sup.32 are the same or different and in
each case stand for a hydrogen atom or for an unbranched, branched,
cyclic or polycyclic C.sub.1-C.sub.100 alkyl, C.sub.1-C.sub.100
alkenyl, C.sub.1-C.sub.100 alkinyl, C.sub.1-C.sub.100 aryl,
C.sub.1-C.sub.100 alkylaryl and/or C.sub.1-C.sub.100 arylalkyl
radical, which is optionally substituted with fluorine, chlorine,
bromine, and/or iodine atoms and/or hydroxy, oxo, carboxy,
aminocarbonyl, alkoxycarbonyl, amino, aldehyde, or alkoxy groups
with up to 30 carbon atoms, and/or optionally is interrupted and/or
substituted by one or more heteroatoms from the series N, P, As, O,
S, Se, and whereby radicals R.sup.11 and R.sup.12, R.sup.13 and
R.sup.14, R.sup.15 and R.sup.16, as well as R.sup.17 and R.sup.18
together optionally can stand for an oxygen atom, and n, m and p,
independently of one another, mean 1 or 2.
[0028] Other suitable compounds, which are suitable for topical
treatment after complexing with suitable radioisotopes, are
tetrofosmin, sestamibi and furifosmin derivatives.
.sup.99mTc-tetrofosmin can be obtained under the trade name
Myoview.TM. from the Amersham Company; .sup.99m Tc-sestamibi is
marketed under the trade name Cardiolite.RTM. by the DuPont
Company; and .sup.99mTc-furifosmin can be purchased under the trade
name TechneScan Q-12 from the Mallinckrodt Medical Company.
[0029] Together with a radionuclide, all these compounds form a
metal complex that can then be used for topical administration in
the treatment of proliferative diseases.
[0030] To form a metal complex, radionuclides can be introduced
that are alpha-, beta- and/or gamma-radiators, positron-radiators,
Auger electron-radiators, and fluorescence radiators, whereby
.beta.- as well as combined .beta./.gamma.-radiators are preferred
for therapeutic purposes.
[0031] Corresponding radionuclides are known to one skilled in the
art. By way of example, the radionuclides of the elements of atomic
numbers 27, 29-32, 37-39, 42-51, 62, 64, 70, 75, 77, 82, or 83 can
be mentioned.
[0032] Preferred are the nuclides .sup.99mTc, .sup.186Re,
.sup.188Re, .sup.67Cu, .sup.90Y and .sup.107Ag; especially
preferred are nuclides .sup.186Re, .sup.188Re and .sup.67Cu.
[0033] The production of bis-amine-oxime derivatives is described
in U.S. Pat. Nos. 5,506,345 and 5,387,692; the production of
N.sub.2S.sub.2 derivatives is described in U.S. Pat. No.
5,279,811.
[0034] The production of tetrofosmin derivatives is described in
European Patent Application EP 303 374; the production of
furifosmin derivatives is described in U.S. Pat. No. 5,112,595.
Sestamibi derivatives and their production are described in
International Patent Application WO 89/02433.
[0035] Other suitable metal complexes have ligands that are derived
from ethylenediaminetetraacetic acid (EDTA),
diethylenetriaminepentaacetic acid (DTPA), or a macrocyclic
compound, such as, e.g., tetraazacyclododecane. The production of
these compounds is known to one skilled in the art and is,
moreover, described in detail in the examples below.
[0036] Other suitable ligands are, e.g., porphyrin derivatives, as
they are described in, e.g., DE 42 32 925 A1 and DE 43 05 523 A1.
Metal complexes that are suitable for the process according to the
invention can also be produced with radionuclides from these
ligands.
[0037] Also suitable are radioactive thallium compounds of isotopes
.sup.201Tl, .sup.207Tl, .sup.209Tl, and .sup.210Tl; especially
suitable is .sup.201TlCl.
[0038] Radiolabeled colloidal solutions are also extremely well
suited for the treatment of proliferative diseases and especially
for topical administration.
[0039] Suitable colloidal solutions are the tin colloids that are
described in the examples; especially suitable are the tin colloids
that can be produced with the aid of a kit from the Amersham
Company ("Amerscan Zinnkolloid (.sup.99mTc)--Markierungskit fur die
Leberszintigraphie [Amerscan Tin Colloid (.sup.99mTc)--Labeling Kit
for Liver Scintigraphy])." Other suitable colloids are, e.g.,
radioactive gold sol (.sup.198Au colloid) and radiolabeled sulfur
colloids as well as other physiologically compatible, radioactive
colloidal solutions.
[0040] Suitable radionuclides for radioactive labeling of colloidal
solutions are known to one skilled in the art. By way of example,
the radionuclides of elements Ag, As, At, Au, Ba, Bi, Br, C, Co,
Cr, Cu, F, Fe, Ga, Gd, Hg, Ho, I, In, Ir, Lu, Mn, N, O, P, Pb, Pd,
Pm, Re, Rh, Ru, Sb, Sc, Se, Sm, Sn, Tb, Tc, or Y can be
mentioned.
[0041] Preferred are the nuclides .sup.99mTc, .sup.186Re,
.sup.188Re, .sup.67Cu, .sup.90Y, .sup.153Sm, .sup.160Tb,
.sup.162Tb, .sup.198Au, and .sup.107Ag.
[0042] The production of the colloidal solutions is generally done
with a redox reaction or the alteration of pH in an aqueous or
alcoholic solution in the presence of a radioactive salt. The
colloid can be formed in the presence of a stabilizer or
subsequently mixed with a surfactant or another stabilizing
amphiphilic substance. Other production methods for suitable
colloidal solutions are electrochemical methods, such as are
described by, e.g., M. T. Reetz et al. in Angew. Chem. [Applied
Chemistry] 1995, Vol. 107, p. 2461 ff. The production of the tin
colloids is described in the examples below, as well as in the
instructions of the labeling kit of the Amersham Company. The
production of a gold colloid for diagnostic purposes is described
in Patent DE 24 20 531 C3.
[0043] The size of the particles formed is in the range between 5
and 1000 nm, and in the case of the tin colloid it is between 300
and 600 nm.
[0044] As catheters that are suitable for topical administration of
the substances according to the invention, the catheters that are
sketched in FIG. 3 can be used. Especially suitable are
multichamber balloon catheters (such as, e.g., Dispatch.TM.,
SciMed) and microperforated balloon catheters.
[0045] In the examples below, the process in the animal experiment
is described. In addition, the production of some compounds that
are suitable for use in this treatment process is described. In
Examples 1 to 5, the process is implemented with .sup.99mTc-labeled
HMPAO, whereby the ligand HMPAO has the following structure: 3
[0046] (see also Radiopharmaceuticals, Chemistry and Pharmacology,
edited by Adrian D. Nunn, 1992, page 53).
EXAMPLE 1
Topical Administration of .sup.99mTc-HMPAO
[0047] The test animal, a white New Zealand rabbit (internal animal
identification no.: 1708, male, 3.7 kg of body weight), was
prepared 4 weeks before the actual administration experiment:
[0048] Under anesthesia (Rompun/Ketavet 1:2, 1 ml/kg of body
weight, i.m. administration), the endothelium was damaged with a 2F
Fogarthy balloon catheter in the arteria carotis dextra (balloon
denudation). Then, the animal received a special diet with an
addition of 0.2% cholesterol. The test animal developed an
arteriosclerotic lesion on the balloon-denuded spot created by this
pretreatment.
[0049] Topical administration of HMPAO that was labeled with
technetium 99m was carried out on the anesthetized test animal
(anesthesia type s.o.) via a coronary perfusion/infusion catheter
(dispatch 3.0, Xtra slippery coating, manufacturer: Boston
Scientific Corporation, Ratingen) directly on the lesion in the
carotid artery. The radioactive dose of 0.48 mCi (=17.76 MBq) was
administered in a volume of 0.85 ml.
[0050] During the entire experiment, the test animal was under a
gamma camera (Elscint SP4 HR) to measure the dispersion of
radioactivity in the body. The activity at the lesion was set as a
proportion of the total activity (measured at this time in the
animal). In the case of this test animal, there was found:
[0051] 5 minutes post administration 55.38% of the dose at the
lesion
[0052] 4 hours post administration 46.78% of the dose at the
lesion
[0053] 24 hours post administration 21.45% of the dose at the
lesion
EXAMPLE 2
Topical Administration of .sup.99mTc-HMPAO
[0054] The test animal, a white New Zealand rabbit (internal animal
identification no.: 1856, male, 3.3 kg of body weight), was
prepared 4 weeks before the actual administration experiment as
follows:
[0055] Under anesthesia (Rompun/Ketavet 1:2, 1 ml/kg of body
weight, i.m. administration), the endothelium was damaged with a 2F
Fogarthy balloon catheter in the arteria carotis dextra (balloon
denudation). Then, the animal received a special diet with an
addition of 0.2% cholesterol. The test animal developed an
arteriosclerotic lesion on the balloon-denuded spot created by this
pretreatment.
[0056] The topical administration of the HMPAO that was labeled
with technetium 99m was carried out on the anesthetized test animal
(anesthesia type s.o.) via a coronary perfusion/infusion catheter
(dispatch 3.0, Xtra slippery coating, manufacturer: Boston
Scientific Corporation, Ratingen) directly on the lesion in the
carotid artery. The radioactive dose of 1.91 mCi (=70.67 MBq) was
administered in a volume of 1.0 ml (flushing with 0.3 ml of
physiological saline solution).
[0057] During the entire experiment, the test animal was under a
gamma camera (Elscint SP4 HR) to measure the dispersion of
radioactivity in the body. The activity in the lesion was set as a
proportion of the total activity (measured at this time in the
animal). In the case of this test animal, there was found:
[0058] 5 minutes post administration 40.74% of the dose at the
lesion
[0059] 4 hours post administration 35.13% of the dose at the
lesion
[0060] 24 hours post administration 23.69% of the dose at the
lesion
EXAMPLE 3
Topical Administration of .sup.99mTc-HMPAO
[0061] The test animal was a white New Zealand rabbit (internal
animal identification no.: 1584, male, 3.4 kg of body weight).
[0062] Under anesthesia (Rompun/Ketavet 1:2, 1 ml/kg of body
weight, i.m. administration), the endothelium was damaged with a
balloon catheter in the infraranal aorta (balloon denudation).
Then, over a period of 5 minutes, technetium 99m-labeled HMPAO was
administered to the test animal via a microperforated balloon
catheter (4 mm Match-35 PTA, Schneider Company, FRG). The
radioactive dose of 0.64 mCi (=23.68 MBq) was administered in a
volume of 1 ml.
[0063] During the entire experiment, the test animal was under a
gamma camera (Elscint SP4 HR) to measure the dispersion of
radioactivity in the body. The activity in the lesion was set as a
proportion of the total activity (measured at this time in the
animal). In the case of this test animal, there was found:
[0064] 5 minutes post administration 38.45% of the dose at the
lesion
[0065] 4 hours post administration 35.64% of the dose at the
lesion
[0066] 24 hours post administration 16.63% of the dose at the
lesion
EXAMPLE 4
Topical Administration of .sup.99mTc-HMPAO
[0067] The test animal was a white New Zealand rabbit (internal
animal identification no.: 1587, male, 3.5 kg of body weight).
[0068] Under anesthesia (Rompun/Ketavet 1:2, 1 ml/kg of body
weight, i.m. administration), the endothelium was damaged with a
balloon catheter in the infraranal aorta (balloon denudation).
Then, over a period of 5 minutes, technetium 99m-labeled HMPAO was
administered to the test animal via a microperforated balloon
catheter (4 mm Match-35 PTA, Schneider Company, FRG). The
radioactive dose of 1.18 mCi (=43.66 MBq) was administered in a
volume of 1 ml.
[0069] During the entire experiment, the test animal was under a
gamma camera (Elscint SP4 HR) to measure the dispersion of
radioactivity in the body. The activity in the lesion was set as a
proportion of the total activity (measured at this time in the
animal). In the case of this test animal, there was found:
[0070] 5 minutes post administration 37.06% of the dose at the
lesion
[0071] 4 hours post administration 32.03% of the dose at the
lesion
[0072] 24 hours post administration 20.01% of the dose at the
lesion
EXAMPLE 5
Topical Administration of .sup.99mTC-HMPAO
[0073] The test animal was a white New Zealand rabbit (internal
animal identification no.: 1586, male, 3.3 kg of body weight).
[0074] Under anesthesia (Rompun/Ketavet 1:2, 1 ml/kg of body
weight, i.m. administration), the endothelium was damaged with a
balloon catheter in the infraranal aorta (balloon denudation).
Then, over a period of 5 minutes, technetium 99m-labeled HMPAO was
administered to the test animal via a microperforated balloon
catheter (4 mm Match-35 PTA, Schneider Company, FRG). The
radioactive dose of 0.45 mCi (=16.65 MBq) was administered in a
volume of 1 ml.
[0075] During the entire experiment, the test animal was under a
gamma camera (Elscint SP4 HR) to measure the dispersion of
radioactivity in the body. The activity in the lesion was set as a
proportion of the total activity (measured at this time in the
animal). In the case of this test animal, there was found:
[0076] 5 minutes post administration 45.56% of the dose at the
lesion
[0077] 4 hours post administration 36.39% of the dose at the
lesion
[0078] 24 hours post administration 15.24% of the dose at the
lesion
EXAMPLE 6
Production of
1-{3-[N-(2-Methoxyethyl)-octadecylsulfamoyl]-2-hydroxy-propy-
l}-4,7,10-tetraaza-cyclododecane, Yttrium-90 Complex
[0079] 5 mg of
1-{3-[N-(2-methoxyethyl)-octadecylsulfamoyl]-2-hydroxypropy-
l}-4,7,10-tetraazacyclododecane (produced according to DE
4340809.5) is dissolved in 500 .mu.l of dimethyl sulfoxide and 50
.mu.l of 0.1M sodium acetate buffer (pH=4.0). After 37 MBq of
yttrium-90-trichloride solution is added, the reaction mixture is
heated for 10 minutes to 100.degree. C. The Y-90 complex solution
that is thus prepared can be used without additional
purification.
EXAMPLE 7
[0080] a) Production of
N,N'-Bisundecyl-diethylene-triamine-pentaacetic acid Diamide
[0081] 3.57 g (10 mmol) of diethylene-triamine-pentaacetic acid
bisanhydride is suspended together with 4.05 g (40 mmol) of
triethylamine in 100 ml of absolute dimethylformamide. Then, a
solution of 3.42 g (20 mmol) of undecylamine, dissolved in 50 ml of
absolute dichloromethane, is added in drops to the reaction mixture
at room temperature. The reaction batch is stirred for 6 hours at
room temperature, filtered and concentrated by evaporation in a
medium-high vacuum. The residue is dissolved three times in 100 ml
of dimethylformamide and concentrated by evaporation in a
medium-high vacuum in each case. 50 ml of absolute diethyl ether is
poured over the foamy reaction product, and it is stirred
overnight. It is filtered and dried in a medium-high vacuum.
[0082] Yield: 6.3 g (90%), white powder.
[0083] Elementary analysis:
[0084] Cld: C 61.77 H 9.94 N 10.01 O 18.86
[0085] Fnd: C 61.52 H 9.63 N 9.91 O
[0086] b) Production of
N,N'-bisundecyl-diethylenetriamine-pentaacetic acid diamide,
yttrium-90 complex
[0087] 5 mg of N,N'-bisundecyl-diethylenetriamine-pentaacetic acid
diamide (Example 7a) is dissolved in 500 .mu.l of dimethyl
sulfoxide and 50 .mu.l of 0.1 M sodium acetate buffer (pH=4.0).
After 37 MBq of yttrium-90 trichloride solution is added, the
reaction mixture is allowed to stand for 10 minutes at room
temperature. The Y-90 complex solution that is thus prepared can be
used without additional purification.
EXAMPLE 8
[0088] a) Production of
N-Benzyloxycarbonyl-glycyl-N'-undecyl-glycinamide
[0089] 3.63 g (10 mmol) of
N-benzyloxycarbonyl-glycyl-glycine-N-hydroxysuc- cinimide ester and
1.71 g (10 mmol) of undecylamine are dissolved in 100 ml of
absolute dichloromethane. The reaction mixture is stirred for 6
hours at room temperature. Then, it is diluted with 100 ml of
dichloromethane, the organic phase is washed twice with 50 ml of
saturated sodium bicarbonate solution and once with 50 ml of water.
It is dried on magnesium sulfate, and the solvent is evaporated in
a vacuum. The crude product is purified by chromatography on silica
gel (eluent: dichloromethane/methanol 95:5).
[0090] Yield: 3.8 g (90.6%), white powder.
[0091] Elementary analysis:
[0092] Cld: C 65.84 H 8.89 N 10.01 O 15.25
[0093] Fnd: C 65.71 H 9.02 N 10.10 O
[0094] b) Production of Glycyl-N'-undecyl-glycinamide
[0095] 3 g (7.15 mmol) of
N-benzyloxycarbonyl-glycyl-N'-undecyl-glycinamid- e (Example 8a) is
dissolved in 100 ml of absolute ethanol. After 300 mg of palladium
is added to carbon (10%), it is hydrogenated for 2 hours at room
temperature (1 atmosphere of hydrogen). It is filtered and
concentrated by evaporation in a vacuum. The resulting amine is
used for subsequent reaction without additional purification.
[0096] Yield: 1.92 g (94.1%), white foam.
[0097] Elementary analysis:
[0098] Cld: C 63.12 H 10.95 N 14.72 O 11.21
[0099] Fnd: C 63.03 H 11.04 N 14.57 O
[0100] c) Production of
N-(S-Acetyl-mercaptoacetyl)-glycyl-N'-undecyl-glyc- inamide
[0101] 285.4 mg (1 mmol) of glycyl-N'-undecyl-glycinamide (Example
8b) and 231.2 mg (1 mmol) of S-acetyl-mercapto-acetic
acid-N-hydroxy-succinimide ester are dissolved together in 20 ml of
absolute dichloromethane. The reaction mixture is stirred for 6
hours at room temperature. Then, it is diluted with 20 ml of
dichloromethane, and the organic phase is washed twice with 5 ml of
semi-saturated sodium bicarbonate solution and once with 5 ml of
water. It is dried on magnesium sulfate, and the solvent is
evaporated in a vacuum. The crude product is purified by
chromatography on silica gel (eluent: dichloromethane/methanol
93:7).
[0102] Yield: 362 mg (90.1%), white powder
[0103] Elementary analysis:
[0104] Cld: C 56.83 H 8.79 N 10.46 O 15.94 S 7.98
[0105] Fnd: C 56.67 H 8.93 N 10.18 O S 7.72
[0106] d) Production of
N-(Mercaptoacetyl)-glycyl-N'-undecyl-glycinamide
[0107] 201 mg (0.5 mmol) of
N-(S-acetyl-mercaptoacetyl-glycyl-N'-undecyl-g- lycinamide (Example
8c) is dissolved in 15 ml of absolute ethanol. It is saturated with
argon, and an ammonia stream is directed through the solution for
30 minutes. Then, it is concentrated by evaporation, and the
residue is taken up in 20 ml of dichloromethane. The organic phase
is shaken once with 2% aqueous citric acid and dried on sodium
sulfate. The solvent is evaporated in a vacuum, and the residue is
chromatographed on silica gel (eluent: dichloromethane/methanol
9:1).
[0108] Yield: 153 mg (85.1%), white powder
[0109] Elementary analysis:
[0110] Cld: C 56.79 H 9.25 N 11.69 O 13.35 S 8.92
[0111] Fnd: C 56.67 H 9.43 N 11.48 O S 8.71
[0112] e) Production of
N-(Mercaptoacetyl)-glycyl-N'-undecyl-glycinamide, Re-186
Complex
[0113] 5 mg of N-(mercaptoacetyl)-glycyl-N'-undecyl-glycinamide
(Example 8d) is dissolved in 800 .mu.l of ethanol. After 5 mg of
disodium-L-tartrate and 50 .mu.l of 0.1 M sodium hydrogen phosphate
buffer (pH=8.5) are added, 37 MBq of perrhenate and 10 .mu.l of tin
dichloride-dihydrate solution (5 mg of SnCl.sub.2.times.2H.sub.2O/1
ml of 0.1 M HCl) are added. The reaction mixture is heated for 5
minutes to 60.degree. C. The thus prepared solution of the Re-186
complex of N-(mercaptoacetyl)-glycyl-N'-undecyl-glycinamide can be
used without additional purification.
EXAMPLE 9
Production of
N,N'-Bis[3,6,9,9-tetra(hydroxycarboxymethyl)-1-oxo-3,6,9-tri-
aza-non-1-yl]-mesoporphyrin-IX-13,17-dihydrazide, Y-90 Complex
[0114] 5 mg of
N,N'-bis[3,6,9-tri(hydroxycarboxymethyl)-9-(ethoxycarboxyme-
thyl)-1-oxo-3,6,9-triaza-non-1-yl]-mesoporphyrin-IX-13,17-dihydrazide
(produced according to DE 42 32 925 A1, Example 1a) is stirred in 5
ml of 0.1 M NaOH under argon atmosphere for 3 hours at room
temperature. After saponification of the bis-ethyl ester (TLC
monitoring) has been completed, it is set at pH=6 with glacial
acetic acid, and 37 MBq of yttrium-90-trichloride solution is added
to the batch. It is stirred for 15 minutes at room temperature.
HPLC analysis indicates 95% incorporation of the radioisotope.
EXAMPLE 10
Production of
5,10,15,20-Tetrakis-[3-(carboxymethoxy)-phenyl]-porphyrin,
Yttrium-90 Complex
[0115] 2.0 mg of
5,10,15,20-tetrakis-[3-(carboxymethoxy)-phenyl]-porphyrin (produced
according to DE 43 05 523 A1, Example 13a) is dissolved in 5 ml of
acetic acid and mixed with a hydrochloric acid solution of 1.0 mCi
yttrium-90-chloride. The reaction mixture is autoclaved for one
hour at 140.degree. C., the solvent is evaporated in a vacuum, and
the residue is taken up in 5 ml of water. By adding aqueous sodium
bicarbonate solution in drops, it is set at pH 7.3, and the red
solution that is produced is filtered with a membrane filter. HPLC
monitoring of the filtrate indicates an incorporation rate of
>95% of the activity used in the porphyrin ligands.
EXAMPLE 11
Production of
5,10,15,20-Tetrakis-[3-(carboxymethoxy)-phenyl]-porphyrin,
Copper-67 Complex
[0116] The production of the complex is described in DE 43 05 523
A1, Example 14.
EXAMPLE 12
Production of a Technetium-99m-tin Colloid
[0117] 555 MBq of sodium pertechnetate-99m in 2 ml of 0.9% sodium
chloride solution is mixed at room temperature with 20 .mu.l of
tin(II) chloride solution (5 mg of tin(II) chloride-dihydrate/1 ml
of 0.01 M HCl). After 10 minutes, it is diluted with 1 ml of PBS
buffer. The solution that is obtained is slightly opalescent.
EXAMPLE 13
Production of a Rhenium-186-tin Colloid
[0118] 37 MBq of sodium perrhenate-186 in 2 ml of 0.9% sodium
chloride solution is mixed at room temperature with 40 .mu.l of
tin(II) chloride solution (5 mg of tin(II) chloride dihydrate/1 ml
of 0.01 M HCl). After 10 minutes, it is diluted with 1 ml of PBS
buffer. The solution that is obtained is slightly opalescent.
EXAMPLE 14
Topical Administration of a Tin Colloid
[0119] The test animal is a white New Zealand rabbit (internal
animal identification no.: 1852, male, 3.5 kg of body weight).
[0120] Under anesthesia (Rompun/Ketavet 1:2, 1 ml/kg of body
weight, i.m. administration), the endothelium was damaged with a
balloon catheter in the infraranal aorta (balloon denudation).
Then, over a period of 5 minutes, tin colloid, which was produced
according to the kit of the Amersham Company ("Amerscan Zinnkolloid
(.sup.99mTc)--Markierungskit fur die Leberszintigraphie [Amerscan
Tin Colloid (.sup.99mTc)--Labeling Kit for Liver Scintigraphy]"),
was administered to the test animal with a microperforated Match
catheter (balloon catheter with a 5 mm diameter; manufacturer:
Schneider Company, Dusseldorf). The radioactive dose of 0.4 mCi
(=14.8 MBq) was administered in a volume of 0.1 ml.
[0121] During the entire experiment, the test animal was under a
gamma camera (Elscint SP4 HR) to display the dispersion of
radioactivity in the body. In FIG. 1, the situation before
administration is depicted in the upper part. The catheter that
contains the tin colloid can be seen clearly. The arrow shows the
balloon of the catheter, which is at the desired administration
spot. In the lower part of the image, the same site is shown 1.5
hours after administration and removal of the catheter. The amount
of tin colloid that remains at the administration spot is clearly
visible.
EXAMPLE 15
Topical Administration of a Tin Colloid
[0122] The test animal is a white New Zealand rabbit (internal
animal identification no.: 1839, male, 3.7 kg of body weight).
[0123] Under anesthesia (Rompun/Ketavet 1:2, 1 ml/kg of body
weight, i.m. administration), the endothelium was damaged with a
balloon catheter in the infraranal aorta (balloon denudation).
Then, over a period of 5 minutes, tin colloid, which was produced
according to the kit of the Amersham Company ("Amerscan Zinnkolloid
(.sup.99mTc)--Markierungskit fur die Leberszintigraphie") was
administered to the test animal with a microperforated Match
catheter (balloon catheter with a 5 mm diameter; manufacturer:
Schneider Company, Dusseldorf). The radioactive dose of 0.47 mCi
(=17.39 MBq) was administered in a volume of 0.1 ml.
[0124] During the entire experiment, the test animal was under a
gamma camera (Elscint SP4 HR) to display the dispersion of
radioactivity in the body. In FIG. 2, the situation before
administration is depicted in the upper part. The catheter that
contains the tin colloid can be seen clearly. The arrow shows the
balloon of the catheter, which is at the desired administration
spot. In the lower part of the image, the same site is shown 1.5
hours after administration and removal of the catheter. The amount
of tin colloid that remains at the administration spot is clearly
visible.
* * * * *