WO1994012184A1 - Use of mycophenolic acid, mycophenolate mofetil or derivate thereof to inhibit stenosis - Google Patents
Use of mycophenolic acid, mycophenolate mofetil or derivate thereof to inhibit stenosis Download PDFInfo
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- WO1994012184A1 WO1994012184A1 PCT/US1992/009932 US9209932W WO9412184A1 WO 1994012184 A1 WO1994012184 A1 WO 1994012184A1 US 9209932 W US9209932 W US 9209932W WO 9412184 A1 WO9412184 A1 WO 9412184A1
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- pharmaceutically acceptable
- mycophenolate mofetil
- mycophenolic acid
- acceptable salt
- derivative
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- 0 CC1OC(*)(*)OC1 Chemical compound CC1OC(*)(*)OC1 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
Definitions
- the present invention relates to methods of preventing stenosis following surgical treatment, particularly the prevention of restenosis following angioplasty through the administration of mycophenolic acid or a related compound, particularly mycophenolate mofetil.
- Mycophenolic acid is a weakly-active antibiotic found in the fermentation broth of Penn ⁇ cilli m brevicompactum.
- Compounds relating to mycophenolic acid, and their uses in the treatment of inflammatory diseases, autoimmune diseases, viral diseases, cancer, and/or for the prevention of allograft rejection, are disclosed in U.S. Patents Nos. 4,686,234; 4,725,622 4,727,069; 4,748,173; 4,753,935; 4,786,637; 4,808,592; 4,861,776; 4,868,153; 4,948,793; 4,952,579; 4,959,387; and 4,922,467, all incorporated herein by reference.
- Mycophenolic acid, mycophenolate mofetil, or a pharmaceuticaly acceptable salt or derivative thereof have the one of the following general structures.
- R is H or lower alkyl having 1 to 6 carbon atoms
- R j is H, lower alkyl having 1 to 6 carbon atoms or -phenyl-4-CO-R 3 , in which R 3 is H, lower alkyl having 1 to 6 carbon atoms or a pharmaceutically acceptable cation;
- R 4 and R 5 are each independently H or lower alkyl having 1 to 6 carbon atoms
- X, and Y are each independently O or S; and q is an integer of 1-6.
- A is oxygen or sulfur
- R is selected from the group consisting of: h. O Q H
- A is oxygen or sulfur; q is an integer from 0-6;
- Rj is alkyl, haloalkyl or -NR 4 R 5 , where:
- R 4 and Rj are independently H, alkyl, haloalkyl, cycloalkyl, phenyl optionally monosubstituted with halogen, hydroxy, carboxy, chlorocarbonyl, sulfonylamino, nitro, cyano, phenyl, alkyl, acyl, alkoxycarbonyl, acylamino, dialkylami or dialkylaminoethoxycarbonyl, phenyl optionally disubstituted with hydroxy, carboxy, nitro or alkyl, or benzyl optionally substituted with dialkylamino;
- R 3 is H, alkyl or a pharmaceutically acceptable cation
- Q and Q are independently H or -CO J J ;
- Z_ is selected from the group consisting of: IH-tetrazolyl, -CH-OH, -CH
- Aj is oxygen or sulfur
- R is H, alkyl, alkenyl, cycloalkyl, optionally substituted phenyl, optionally substituted benzyl or a pharmaceutically acceptable cation;
- R 7 and g are independently H, alkyl or cycloalkyl, or R 7 and Rg taken together are -(CH 2 ) 2 0(CH 2 ) 2 -, -(CH 2 ) 4 , or -(CH 2 )j-; with the proviso that R, and are oxygen.
- Z is hydrogen or -C(0)R, where R is lower alkyl or aryl, and the pharmaceutically acceptable salts thereof.
- a compound of Formula I wherein: m is an integer from two to four;
- Z is selected from Formulae (a), (b), (c), or (d), as follows: (a)
- R 1 is hydrogen, alkyl having seven or more carbon atoms including cycloalkyl such as adamantyl, or -NR 2 R 3 , where R 2 is hydrogen or lower alkyl, and R 3 is hydrogen, lower alkyl, -phenyl-4-C0 2 R 2 or a pharmaceutically acceptable cation; (b) S
- R 4 is hydrogen, alkyl, aryl or -NR 2 R 3 ;
- n is an integer from zero to six
- R 5 is hydrogen, lower alkyl, or a pharmaceutically acceptable cation
- R 6 and R 7 are independently hydrogen or -CO ⁇ R 5 ;
- Y is lower alkylene of four to six carbon atoms, or lower alkylene of three to five carbon atoms and one member that is -O-, -S- or where R 8 is hydrogen or alkyl of one to five carbon atoms.
- a compound of Formula II wherein: m is an integer from two to four;
- Z is hydrogen or -C(0)R 9 , where R 9 is lower alkyl or aryl; and Y 1 is lower alkylene of four to si carbon atoms, or lower alkylene of three to five carbon atoms and one member that is -O-, -S-, or N-R B where R 8 is hydrogen or alkyl of one to five carbon atoms; and the pharmaceutically acceptable salts thereof; except that when m is two, Y 1 does not include -(CH 2 ) 2 -0-(CH 2 ) 2 -.
- Mycophenolate mofetil the morpholinoethyl ester of mycophenolic acid, is described in U.S. Patent No. 4,753,935 (previously incorporated by reference), and has the chemical name morpholinoethyl E-6-(l,3-dihydro-4- hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoate. I has been shown effective in preventing allograft rejection, including chroni allograft rejection.
- Stenosis is a narrowing of the lumen of a blood vessel caused by the thickening of a blood vessel wall, involving complex interactions between th cells of the vessel wall (connective tissue cells, especially smooth muscle cells) and circulating blood elements, with consequent restriction of blood flow.
- Stenosis has been associated with insult to the endothelial lining or underlying layers of the vessel " wall, typically during a surgical procedure
- Angioplasty involves the removal of obstructions (e.g., plaque) and results in the widening of constricted blood vessels, i.e., a treatment for stenosis; the procedure often entails an insult to the endothelial lining or underlying layers, which triggers an early vascular cell proliferation, especially of smooth muscle cells (one of the cell types responding to the insult) and oth connective tissue cells, and causes a thickening of the vessel wall with a corresponding narrowing of the lumen, called restenosis.
- obstructions e.g., plaque
- smooth muscle cells one of the cell types responding to the insult
- oth connective tissue cells oth connective tissue cells
- One aspect of the present invention concerns use of a therapeutically effective amount of mycophenolic acid or mycophenolate mofetil, or a pharmaceutically acceptable salt or derivative thereof for the treatment of stenosis.
- Another aspect of the present invention concerns use of a therapeutically effective amount of mycophenolic acid or mycophenolate mofetil, or a pharmaceutically acceptable salt or derivative thereof for performing angioplasty or by-pass surgery including prophylactic administration.
- Still another aspect of the present invention concerns inhibiting intimal vascular proliferation, especially of smooth muscle cells following insult to a blood vessel wall, by administering a proliferation inhibitory amount of mycophenolic acid or mycophenolate mofetil, or a pharmaceutically acceptable salt or derivative thereof.
- Still another aspect of the present invention is a pharmaceutical composition for the treatment of stenosis comprising a pharmaceutically acceptable non-toxic excipient and a therapeutically effective amount of mycophenolic acid, mycophenolate mofetil, or a pharmaceutically acceptable salt or derivative thereof.
- mycophenolate mofetil or a pharmaceutically acceptable salt thereof, is orally administered to prevent stenosis or restenosis following angioplasty or a cardiac by-pass surgical procedure.
- alkyl refers to a fully saturated monovalen radical containing only carbon and hydrogen, and which may be a cyclic, branched or straight chain radical. This term is further exemplified by radicals such as methyl, ethyl, t-butyl, pentyl, heptyl, pivalyl, cyclopenty and cyclohexyl.
- lower alkyl refers to a monovalent alkyl radical of one to six carbon atoms. This term is further exemplified by such radicals as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, i-butyl (or 2- methylpropyl) , isoamyl, pentyl and isopentyl.
- alkylene refers to a fully saturated divalent radical containing only carbon and hydrogen, and which may be a branched or straight chain radical.
- alkoxy refers to the group -OR wherein R is lower alkyl as herein defined.
- aryl refers to a substituted or unsubstituted monovalent unsaturated aromatic carbocyclic radical having a single ring (e.g., phenyl) or two condensed rings (e.g «, naphthyl).
- acyl refers to a radical based on an organic acid, e.g., -C(0)R' where R 1 is alkyl or aryl.
- halo refers to fluoro, bromo, chloro and iodo.
- Isolation and purification of the compounds and intermediates describe herein can be effected, if desired, by any suitable separation or purificati procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography or thick-layer chromatography, or a combination of these procedures.
- a “pharmaceutically acceptable salt” may be any salt derived fro an inorganic or organic acid.
- pharmaceutically acceptable anion refers to the anion of such salts. The salt and the anion are chosen not to be biologically or otherwise undesirable.
- salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid (giving the sulfate and bisulfate salts), nitric acid, phosphoric acid and t like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
- inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid (giving the sulfate and bisulfate salts), nitric acid, phosphoric acid and t like
- organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic
- treatment means any treatment of a disease in a mammal, including: (i) preventing the disease, that is, causing the clinical symptoms of the disease not to develop;
- the terms “effective amount” or “therapeutically effective amount” means a dosage sufficient to provide treatment for the disease state being treated. This will vary depending on the patient, the disease and the treatment being effected. As used herein, the term “stenosis” should be read to include
- the term "derivative" means a compound based upon the structure of mycophenolic acid bearing a substituent for -OH on the 4-positi of the bicyclic ring and/or on the carboxylic acid of the side chain, as described in U.S. Patents Nos. 4,686,234; 4,725,622; 4,727,069; 4,748,173; 4,753,935; 4,786,637; 4,808,592; 4,861,776; 4,868,153; 4,948,793; 4,952,579; 4,959,387; and 4,922,467, all previously incorporated herein by reference
- Mycophenolic acid is available, for example, from Sigma Chemical Company, of St. Louis, Missouri.
- Mycophenolate mofetil, or morpholinoethyl E-6-(l,3-dihydro-4-hydroxy-6 methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoate can be made, formulated and administered as described in U.S. Patent No. 4,753,935, previously incorporated herein by reference.
- the pharmaceutically acceptable salts or derivatives of mycophenolic acid and mycophenolate mofetil can be made, formulated and administered as described in U.S. Patents Nos. 4,686,234; 4,725,622; 4,727,069; 4,748,173;
- the compounds used in the methods of the present invention inhibit proliferating cells, including smooth muscle cells, acting through the inhibition of inosine monophosphate dehydrogenase and the consequential depletion of deoxyguanosine triphosphate, which is required for DNA synthesi and cell proliferation.
- the compounds are useful for preventing proliferati responses to vascular injury, e.g., stenosis following an insult to a blood vessel wall.
- mycophenolic acid, mycophenolate mofetil, or a pharmaceutically acceptable salt or derivative thereof is administered to a patient prophylactically and/or following a surgical procedure associated wi injury to the endothelium or underlying layers of a blood vessel wall (e.g., procedure involving removal of, or damage to, endothelial cells).
- a surgical procedure associated wi injury to the endothelium or underlying layers of a blood vessel wall e.g., procedure involving removal of, or damage to, endothelial cells.
- the compounds used in the methods of the present invention do not require the co administration of another active agent for efficacy, although such additiona active agents may be employed.
- I vitro activity for treating stenosis is demonstrated by inhibiting the proliferation of smooth muscle cells.
- This is established by the human arterial smooth muscle cell proliferation assay. Human smooth muscle cells are grown in culture. A test group is treated with the test compound added selected concentrations in fresh media. Both groups receive 2 ⁇ Ci tritiated thymidine ( ⁇ TdR) , a radioisotope label. After 24 hours, the cells are harvested and the amount of label incorporated into DNA is counted by scintillation; this is compared for the test and control groups, the amount being proportional to cell proliferation. Inhibition of smooth muscle proliferation is established when the test group has a lower radioisotope count than the control group. The concentrations of test compound required inhibit proliferation by 50% (the IC ⁇ ) , and to inhibit proliferation by more than 95% are determined.
- In vivo activity for treating stenosis is demonstrated in a rat model for arterial stenosis.
- a test group is treated with the test compound, starting 6 days before and continuing for 14 days after injury to the left carotid artery; the test group is compared to a control group receiving vehicle without the test compound.
- Injury is achieved by a gentle perfusio of air through a 10 mm long section of the left artery.
- the right artery i left intact.
- Arterial cross-sections (10 ⁇ m) are taken from both the left right arteries of each subject, and the area of the vessel wall (endotheliu intima, media) is measured.
- the amount of vascular proliferation is calculated by subtracting the mean area of the intact, right carotid artery from the mean area of the injured, left carotid artery. Reduction in vascu proliferation is established when the test group shows less proliferation t the control group.
- Mycophenolic acid, mycophenolate mofetil, and the pharmaceutically acceptable salts and derivatives thereof can be administered via any of th accepted modes and formulations for agents serving similar utilities, e.g., described in U.S. Patents Nos. 4,753,935 and 4,922,467, previously incorporated herein by reference.
- Administration can be, for example, orally, nasally, parenterally or topically, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as for example, tablets, suppositories, pills, capsules, powders, solutions, suspensions, emulsions, creams, lotions, aerosols, ointments, gels, or the like, preferably in unit dosage forms suitable for simple administration of precise dosages.
- the compositions will include a conventional pharmaceutical carrier or excipient and an active compound (mycophenolic acid, mycophenolate mofetil, or a pharmaceutically acceptable salt or derivative thereof) and; in addition, may include other medicinal agents, pharmaceutical agents carriers, adjuvants, etc.
- the compounds are administered in a therapeutically effect amount, i.e., a dosage sufficient to effect treatment, which will vary depending on the individual and condition being treated.
- the therapeutically effective amount inhibits cellular proliferative response to vascular injury.
- a plasma concentrat of about 0.3 ⁇ M to 10.0 ⁇ M, most preferably about 1.0 ⁇ M is therapeutically effective; this is a proliferation inhibitory amount.
- a pharmaceutically acceptable, non-toxic composition is formed by the incorporation of any of the normally employed excipients, such as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, glucose, gelatin, sucrose, magnesium carbonate and the like.
- excipients such as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, glucose, gelatin, sucrose, magnesium carbonate and the like.
- Such compositions take the form of solutions, suspensions, tablets, pills, capsules, powders, sustained release formulations and the like.
- compositions will take the form of a pill or tablet and thus the composition will contain, along with the active ingredient, a dilue such as lactose, sucrose, dicalcium phosphate, and the like; a disintegrant such as starch or derivatives thereof; a lubricant such as magnesium stearat and the like; and a binder such as starch, gum acacia, polyvinylpyrrolidone, gelatin, cellulose and derivatives thereof, and the like.
- a dilue such as lactose, sucrose, dicalcium phosphate, and the like
- a disintegrant such as starch or derivatives thereof
- a lubricant such as magnesium stearat and the like
- binder such as starch, gum acacia, polyvinylpyrrolidone, gelatin, cellulose and derivatives thereof, and the like.
- Liquid pharmaceutically administerable compositions can, for example, prepared by dissolving, dispersing, etc. an active compound (about 0.5% to about 20%), as described above, and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like, to thereby form a solution or suspension.
- a carrier such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like, to thereby form a solution or suspension.
- the pharmaceutical composition to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate, etc.
- non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate, etc.
- composition to be administered will, in any event, contain a quantity of the active compound(s) in a pharmaceutically effective amount for relief of the particular condition being treated when administere in accordance with the teachings of this invention.
- a therapeutically effective daily oral dose is from as low as 0.02 mg/ to about 100 mg/kg of body weight, preferably from about 25 mg/kg to about 60 mg/kg.
- Intravenous doses are comparable.
- Mycophenolate mofetil is administered for preventing allograft rejection in oral dosages of 2.0, 3.0, 3.5 and 4.0 grams per day, corresponding to a daily dosage from about 25 mg/ to about 60 mg/kg, depending upon the patient and the allograft being treate Similar dosing regimens are effective in the methods of treatment of the present invention.
- This example illustrates the preparation of a representative pharmaceutical formulation for oral administration containing an active compound, e.g., mycophenolic acid, mychophenolate mofetil, or a pharmaceutically acceptable salt or derivative thereof, e.g., morpholinoethyl E-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4- methyl-4-hexenoate hydrochloride.
- an active compound e.g., mycophenolic acid, mychophenolate mofetil
- a pharmaceutically acceptable salt or derivative thereof e.g., morpholinoethyl E-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4- methyl-4-hexenoate hydrochloride.
- Active compound 200 lactose, spray-dried 148 magnesium ⁇ tearate 2
- the above ingredients are mixed and introduced into a hard-shell gela capsule.
- EXAMPLE 2 This example illustrates the preparation of another representative pharmaceutical formulation for oral administration containing an active compound, e.g., mycophenolic acid, mychophenolate mofetil, or a pharmaceutically acceptable salt or derivative thereof, e.g., morpholinoeth
- Active compound 400 cornstarch 50 lactose 145 magnesium stearate 5
- This example illustrates the preparation of a representative pharmaceutical formulation containing an active compound, e.g., mycophenoli acid, mychophenolate mofetil, or a pharmaceutically acceptable salt or derivative thereof, e.g., morpholinoethyl E-6-(l,3-dihydro-4-hydroxy-6- methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoate hydrochlorid Ingredients
- an active compound e.g., mycophenoli acid, mychophenolate mofetil
- a pharmaceutically acceptable salt or derivative thereof e.g., morpholinoethyl E-6-(l,3-dihydro-4-hydroxy-6- methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoate hydrochlorid
- Active compound 1.0 g. fumaric acid 0.5 g. sodium chloride 2.0 g. methyl paraben 0.1 g. granulated sugar 25.5 g. sorbitol (70% solution) 12.85 g.
- Veegum K (Vanderbilt Co.) 1.0 g. flavoring 0.035 ml colorings 0.5 mg distilled water q.s. to 100 ml EXAMPLE 4
- Human smooth muscle cells AG11545 (obtained from Coriell Cell Repository) were plated at low concentration (2.5 x 10 4 cells/ml) in 24-well plates (Dulbecco's modified Eagle's medium containing 10% fetal calf serum). The cells were allowed to grow for 48 hours. Fresh media containing mycophenolic acid (0.01 ⁇ M, 0.1 ⁇ M, 1.0 ⁇ M and 10 ⁇ M) was then added (except to the control wells). A label of 2 ⁇ Ci ⁇ HTdR/well was also added. The cells were allowed to grow for 24 hours, and then harvested using TCA precipitatio The amount of label incorporated into DNA was counted by scintillation, and compared for test and control wells. From the results, the in vitro concentration of mycophenolic acid effective for reducing smooth muscle cell proliferation by 50% (IC,), and by more than 95%, were determined.
- mycophenolic acid When tested by this method, mycophenolic acid had an IC*, of about 0.3 ⁇ M. Concentrations of 1.0 ⁇ M inhibited smooth muscle cell proliferation by more than 95%. This is predictive that mycophenolic acid is useful for inhibiting stenosis or restenosis in human patients undergoing surgical procedures.
- Mycophenolic acid concentrations of 0.3 to 10 ⁇ M are readily attainabl in humans treated with daily oral doses of about 25 to about 60 mg/kg of mycophenolate mofetil. This is predictive that mycophenolate mofetil, its pharmaceutically acceptable salts and the ester derivatives of mycophenolic acid are useful for inhibiting stenosis or restenosis in human patients undergoing surgical procedures.
- Mycophenolate mofetil is suspended in SSV, a vehicle consisting of 0.5 sodium carboxymethylcellulose, 0.9% NaCl, 0.4% Tween 80, and 0.9% benzyl alcohol in water.
- the left carotid artery of each rat was injured using the technique described by Fishman, JA, et al., "Endothelial regeneration in the rat caro artery and the significance of endothelial denudation in the pathogenesis o myointimal thickening," Lab Invest. , 1975, 32:339-351.
- Each animal was anesthetized by administering ip a mixture of 58% ketamine (Fort Dodge Laboratories, Iowa) 60 mg/kg, and 42% xylazine (Lloyd Laboratories, Iowa) 10 mg/kg.
- a 10 mm long section of the distal left comm carotid artery was then exposed.
- Silk ties were positioned and loosely ligated at each end of the exposed artery.
- a puncture site was created nea each ligature, using a 30-gauge needle attached to a syringe containing Tyrode's solution (Sigma). Next, Tyrode's solution was perfused through th orifices to rinse blood from the isolated vessel.
- the puncture sites were allowed to clot, the ligatures were removed, and the wound was closed. This procedure produced endothelia denudation as well as some disruption to the underlying intima and media of the vessel wall.
- the stained arterial cross-sectio were projected through a microscope onto a digitizing board connected to a computer programmed with SigmaScan (Jandel Scientific, Corte Madera, CA) .
- SigmaScan Jandel Scientific, Corte Madera, CA
- the mean cross-sectional area of both the left (injured) and right (control) arteries were computed electronically from sections 1, 4, 7, 10, 13 of the 15 arterial cross-sections.
- the final area of smooth muscle proliferation for each rat was calculated by subtracting the mean area of t control artery from that of the injured artery. All scoring was done blind with the investigator unaware of whether the cross-section came from a test control rat, or from an injured or intact artery.
- Mycophenolate mofetil inhibits neointimal proliferation by 51% follow vascular injury in vivo. This is predictive that mycophenolate mofetil is useful for inhibiting stenosis or restenosis in human patients undergoing surgical procedures.
- mycophenolic acid or a pharmaceutically acceptable salt or derivative thereof, or a pharmaceuticall acceptable salt or derivative of mycophenolate mofetil By repeating the procedure and substituting mycophenolic acid or a pharmaceutically acceptable salt or derivative thereof, or a pharmaceuticall acceptable salt or derivative of mycophenolate mofetil, for mycophenolate mofetil, similar inhibition of neointimal proliferation is observed.
- Mycophenolic acid and the pharmaceutically acceptable salts and derivatives thereof, and the pharmaceutically acceptable salts and derivatives of mycophenolate mofetil are useful for inhibiting stenosis or restenosis in human patients undergoing surgical procedures.
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Abstract
Description
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Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/US1992/009932 WO1994012184A1 (en) | 1992-11-24 | 1992-11-24 | Use of mycophenolic acid, mycophenolate mofetil or derivate thereof to inhibit stenosis |
JP6513067A JPH08503487A (en) | 1992-11-24 | 1992-11-24 | Use of mycophenolic acid, mycophenolate mofetil or their derivatives to control stenosis |
AU31782/93A AU3178293A (en) | 1992-11-24 | 1992-11-24 | Use of mycophenolic acid, mycophenolate mofetil or derivate thereof to inhibit stenosis |
EP93900534A EP0670724A1 (en) | 1992-11-24 | 1992-11-24 | Use of mycophenolic acid, mycophenolate mofetil or derivate thereof to inhibit stenosis |
KR1019950702066A KR950703966A (en) | 1992-11-24 | 1992-11-24 | Use of mycophenolic acid, mycophenolate mofetil or derivate according to inhibit stenosis |
CA002144189A CA2144189A1 (en) | 1992-11-24 | 1992-11-24 | Prevention of stenosis |
NO951966A NO951966L (en) | 1992-11-24 | 1995-05-18 | |
FI952479A FI952479A0 (en) | 1992-11-24 | 1995-05-22 | Prevention of stenosis |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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PCT/US1992/009932 WO1994012184A1 (en) | 1992-11-24 | 1992-11-24 | Use of mycophenolic acid, mycophenolate mofetil or derivate thereof to inhibit stenosis |
CA002144189A CA2144189A1 (en) | 1992-11-24 | 1992-11-24 | Prevention of stenosis |
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WO1994012184A1 true WO1994012184A1 (en) | 1994-06-09 |
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Cited By (25)
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EP0746314A1 (en) * | 1992-07-10 | 1996-12-11 | The Board Of Trustees Of The Leland Stanford Junior University | Method of treating hyperproliferative vascular disease |
US5807876A (en) * | 1996-04-23 | 1998-09-15 | Vertex Pharmaceuticals Incorporated | Inhibitors of IMPDH enzyme |
US5932600A (en) * | 1997-03-14 | 1999-08-03 | Vertex Pharmaceuticals Incorporated | Inhibitors of IMPDH enzyme |
US6054472A (en) * | 1996-04-23 | 2000-04-25 | Vertex Pharmaceuticals, Incorporated | Inhibitors of IMPDH enzyme |
US6107052A (en) * | 1999-06-09 | 2000-08-22 | Roche Diagnostics Corporation | Enzymatic measurement of mycophenolic acid |
US6128582A (en) * | 1996-04-30 | 2000-10-03 | Vertex Pharmaceuticals Incorporated | Molecules comprising an IMPDH-like binding pocket and encoded data storage medium capable of graphically displaying them |
US6399773B1 (en) | 1998-10-29 | 2002-06-04 | Bristol-Myers Squibb Co. | Compounds derived from an amine nucleus that are inhibitors of IMPDH enzyme |
US6420403B1 (en) | 1998-10-29 | 2002-07-16 | Edwin J. Iwanowicz | Inhibitors of IMPDH enzyme |
US6514979B1 (en) | 1999-03-03 | 2003-02-04 | University Of Maryland Biotechnology Institute | Synergistic combinations of guanosine analog reverse transcriptase inhibitors and inosine monophosphate dehydrogenese inhibitors and uses therefor |
US6518291B1 (en) | 1997-03-14 | 2003-02-11 | Vertex Pharmaceuticals, Incorporated | Inhibitors of IMPDH enzyme |
US6541496B1 (en) | 1996-04-23 | 2003-04-01 | Vertex Pharmaceuticals Incorporated | Inhibitors of IMPDH enzyme |
WO2003032978A1 (en) * | 2001-10-17 | 2003-04-24 | Novartis Ag | Pharmaceutical compositions comprising mycophenolic acid or mycophenolate salt |
US6596747B2 (en) | 1998-10-29 | 2003-07-22 | Bristol-Myers Squibb Company | Compounds derived from an amine nucleus and pharmaceutical compositions comprising same |
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US6919335B2 (en) | 2000-04-24 | 2005-07-19 | Bristol-Myers Squibb Co. | Heterocycles that are inhibitors of IMPDH enzyme |
EP1559779A1 (en) | 2004-01-30 | 2005-08-03 | Boehringer Mannheim Gmbh | Modified inosine monophosphate dehydrogenases |
WO2007093346A1 (en) * | 2006-02-13 | 2007-08-23 | Novartis Ag | High dosage of mycophenolic acid (mpa) |
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WO2013041205A1 (en) * | 2011-09-19 | 2013-03-28 | Pyxirion Pharma Gmbh | Novel therapeutic concepts for treating vascular diseases |
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4686234A (en) * | 1985-11-27 | 1987-08-11 | Syntex (U.S.A) Inc. | Mycophenolic acid derivatives in the treatment of inflammatory diseases, in particular rheumatoid arthritis |
US4725622A (en) * | 1986-01-23 | 1988-02-16 | Syntex (U.S.A.) Inc. | Mycophenolic acid derivatives in the treatment of rheumatoid arthritis |
US4727069A (en) * | 1987-01-30 | 1988-02-23 | Syntex (U.S.A.) Inc. | Heterocyclic aminoalkyl esters of mycophenolic acid, derivatives thereof and pharmaceutical compositions |
EP0281713A1 (en) * | 1987-01-30 | 1988-09-14 | Syntex (U.S.A.) Inc. | Morpholinoethylester of mycophenolic acid and derivatives thereof, their preparation and use in pharmaceutical compositions |
-
1992
- 1992-11-24 WO PCT/US1992/009932 patent/WO1994012184A1/en not_active Application Discontinuation
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4686234A (en) * | 1985-11-27 | 1987-08-11 | Syntex (U.S.A) Inc. | Mycophenolic acid derivatives in the treatment of inflammatory diseases, in particular rheumatoid arthritis |
US4725622A (en) * | 1986-01-23 | 1988-02-16 | Syntex (U.S.A.) Inc. | Mycophenolic acid derivatives in the treatment of rheumatoid arthritis |
US4727069A (en) * | 1987-01-30 | 1988-02-23 | Syntex (U.S.A.) Inc. | Heterocyclic aminoalkyl esters of mycophenolic acid, derivatives thereof and pharmaceutical compositions |
EP0281713A1 (en) * | 1987-01-30 | 1988-09-14 | Syntex (U.S.A.) Inc. | Morpholinoethylester of mycophenolic acid and derivatives thereof, their preparation and use in pharmaceutical compositions |
Non-Patent Citations (4)
Title |
---|
FASEB vol. J6, no. 4, April 1992, page A940 C. GREGORY ET AL. 'USE OF ANTIPROLIFERATIVE AGENTS FOR THE TREATMENT OF OCCLUSIVE VASCULAR DISEASE' * |
SURGICAL FORUM vol. 43, October 1992, pages 383 - 385 D.M. STEELE ET AL. 'RS-61443 INHIBITS INTIMAL HYPERPLASIA IN AORTIC ALLOGRAFTS' * |
'THE MERCK MANUAL' 1987 , MERCK SHARP & DOHME RESEARCH LABORATORIES , RAHWAY, N.J. CORONARY ARTERIAL BYPASS SURGERY AND ANGIOPLASTY * |
TRANSPLANTATION PROCEEDINGS vol. 25, no. 1, 1993, pages 770 - 771 C.R. GREGORY ET AL. 'EFFECTS OF TREATMENT WITH CYCLOSPORINE, FK 506, RAPAMYCIN, MYCOPHENOLIC ACID, OR DEOXYSPERGUALIN ON VASCULAR MUSCLE PROLIFERATION IN VITRO AND IN VIVO' * |
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