D,L
EVA
D,L
EVA
a
b
c
d
e
f
poly-1-lactic acid/Polyglycolic acid polyanhydride
a f a f
a d
e
a d
g body passageway duct
expandable intraluminal graft
expandable vascular graft
h
g h
i The tetracyclines can be administered alone or in combination with, either before,
simultaneously, or subsequently to treatment using conventional chemotherapeutic or radiation therapy.A preferred embodiment is the systemic administration, either by injection or implantation of polymericencapsulated drug, of minocycline in combination with a chemotherapeutic such as - cyclodextrin, in
a ratio of between 0.5 and 2.0 to 1, -cyclodextrin to minocycline.Other chemotherapeutics includecarmustine BCNU , 5-fluorouracil, - cyclodextrin, vinca allcaloids such as vincristin, taxol andvinblastin, immunotoxins
Pharmaceutical compositions are prepared using the antibiotic as the active agent to inhibitangiogenesis based on the specific application. Application is either topical, localized, or systemic. Anyof these compositions may also include preservatives, antioxidants, antibiotics, immunosuppressants,and other biologically or pharmaceutically effective agents which do not exert a detrimental effect onthe antibiotic or cells. For treatment of tumors, the composition may include a cytotoxic agent whichselectively kills the faster replicating tumor cells, many of which areknown and clinically in use.
j In a preferred form, the composition is administered in combination with a biocompatiblepolymeric implant which releases the antibiotic over a controlled period of time at a selected site.Examples of preferred biodegradable polymeric materials include polyanhydrides, polyorthoesters,polyglycolic acid, polylactic acid, polyethylene vinyl acetate, and copolymers and blends thereof.Examples of preferred non-biodegradable polymeric materials include ethylene vinyl acetatecopolymers.
i j
k Drugs that prevent or reduce the proliferation of pathological cell types are essential to thetreatment and control of various diseases involving undesirable or uncontrolled cell proliferation. Butantiproliferatives, by definition, must be toxic to certain cell types. It is often not feasible to administerthese drugs systemically, because the amounts needed to control the diseased cell types may be toxic ordeadly to the patient's normal cells. This difficulty could be circumvented by administeringantiproliferative agents directly to the site of the undesired cell proliferation. A mechanism is alsoneeded for retaining antiproliferative agents at the disease site, so that they may effectively control theproliferation of undesired cells, while being restrained from migrating and damaging normal cell types.Specific diseases and conditions for which site-specific delivery and retention of antiproliferativeswould be particularly effective are briefly described below. Each of these conditions involves theproliferation of a particular undesirable cell type, and systemic administration of drug therapy for theirtreatment has not yielded optimal results.
1. Post-Angioplasty Reocclusion and Restenosis
2. Rheumatoid Arthritis
3. Ovarian Cancer
4. Psoriasis
l In accordance with the present invention, the above-described compounds are used forsiteselective delivery of therapeutic agents, and retention thereof at the selected site. According to apreferred aspect of the invention, the therapeutic agent has an anti-proliferative action, useful for thetreatment of diseases or other pathological conditions involving cell proliferation.
Such chemotherapeutic substances may be selected, for example, from the group consisting ofcolchicine, vinca alkaloids, taxol and derivatives thereof, which exhibit their bio-effect only uponrelease from the compounds.
k l 1 2
1 2
2 1
m
n
o
m o
p Abstract
A mechanical support or stent containing pharmaceutical agents. The stent can be placed in the wallof a blood vessel where it releases pharmaceutical agents to prevent arterial thromboses, plateletaggregation and/or excessive endothelial cell proliferation at the placement site. The stent may also beplaced in a blood vessel, bile duct, ureter, or fallopian tube or other duct or vessel, so that it deliversdrugs to specific body sites or organs.
q Detailed Description of The Invention
The mechanical support or stent of this invention may be formed from any of the materialsemployed in the prior art that are non-toxic to the blood and body tissue and otherwise biocompatable.The stent may be in the form of any structure that successfully preserves the luminal diameter of avessel or duct, and may operate by any mechanism known in the art.
The pharmaceutical agents suitable to be employed in this invention are too numerous to list. Theagents may be anticoagulants, antiplatelet substances, antispasmodics or drugs that inhibit excessiveendothelial cell growth, or they may be antimicrobial agents, hormones or anticancer drugs, or anycombination of these agents, or any others to accomplish any other localized purpose. The precisecoating or impregnating of the stent with the pharmaceutical agent will vary depending on the form andmaterial of the stent, and upon the pharmaceutical agent employed.
p q
a d
k
b p q
k
a d k i
p q
c
c
"CAM"
angiogenesis
angiogenesis
angiogenesis
CAM
d
i The tetracyclines can be
administered alone or in combination with, either before, simultaneously, or subsequentlyto treatment using conventional chemotherapeutic or radiation therapy.
Other chemotherapeutics include carmustine BCNU , 5-fluorouracil, - cyclodextrin,
vinca allcaloids such as vincristin, taxol and vinblastin, immunotoxins.
BCNU
k l
1 1
k l
1 2
k
q
1 2
American Heart Journal
Walter R. M. Hermans Prevention of restenosis after percutaneous
transluminal coronary angioplasty: The search for a "magic bullet"
Drugs Jean-Paul R. Herrman
Pharmacological Approaches to the Prevention of Restenosis Following
Angioplasty The Search for the Holy Grail? Part 1
Currier
Prevention of restenosis after percutaneous
transluminal coronary angioplasty: The search for a "magic bullet"
Barath
i j
j
1 2
1 2
k
l
HeLa
1 2
p q
MDAY-D2
BIOTECHNOLOGY Marsha
A. Moses INHIBITORS OF ANGIOGENESIS
Angiogenesis
TABLE 1
J.
Stenesh angiogenesis
angiogenesis
THE ANGIOGENIC PROCESS AND IN VIVO
ASSAYS FOR ANGIOGENESIS INHIBITORS
The two most commonly used in vivo assays are the rabbit corneal pocket
model and the CAM assay.
in vivo
"CAM"
d
SMC
J Am Coll Cardiol
Austin GE Intimal Proliferation of smooth muscle cells as an explanation
for recurrent coronary artery stenosis after percutaneous transluminal coronary
angioplasty.
JACC Peter Barath
LOW DOSE OF ANTITUMOR AGENTS PREVENTS SMOOTH MUSCLE
CELL PROLIFERATION AFTER ENDOTHELIAL INJURY
0.075mg/kg D 0.015mg/kg
Supplement Circulation Jesse V. Currier
Colchicine Inhibits Restenosis After Iliac Angioplasty in the Atherosclerotic
Rabbit
American Heart Journal Walter R. M.
Hermans Prevention of restenosis after percutaneous transluminal coronary
angioplasty: The search for a "magic bullet"
Table
Barath
0.075mg/kg D 0.015mg/kg
Drugs Jean-Paul R. Herrman Pharmacological
Approaches to the Prevention of Restenosis Following Angioplasty The Search for the
Holy Grail? Part 1
Colchicum autumnale
d
CANCER
RESEARCH Peter H. Wiernik Phase I Clinical and
Pharmacokinetic Study of Taxol
Annals of Internal
Medicine William P. McGuire Taxol: A Unique
Antineoplastic Agent with Signficant Activity in Advanced Ovarian Epithelial NeoplasmsJournal of Clinical
Oncology Raymond B. Weiss Hypersensitivity Reactions
from Taxol
HSR
HSR
Journal of the National
Cancer Institute Eric k. Rowinsky Taxol: A Novel
Investigational Antimicrotubule Agent
Journal of Clinical
Oncology Eric k. Rowinsky Cardiac Disturbances
During the Administration of Taxol
Seminars in Oncollogy
Eric k. Rowinsky Taxol: The First of the Taxanes, an
Important New Class of Antitumor Agents
H1- H2-
II 29
AV
Cremophor EL
Taxotere RP 56976
Clinical Pharmacy
R. Elizabeth Gregory Paclitaxel: A New Antineoplastic Agent for
Refractory Ovarian Cancer Paclitaxel
Journal of Clinical
Oncology Victoria Seewaldt Bowel Complications with
Taxol Therapy
e
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