Patent Application
20080058922
By “mammal” is meant any member of the class Mammalia including, without limitation, humans and nonhuman primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, sheep, pigs, goats and horses; domestic mammals such as dogs and cats; laboratory animals including rodents such as mice, rats, rabbits and guinea pigs, and the like. An “animal” includes vertebrates such as mammals, avians, amphibians, reptiles and aquatic organisms including fish.
As used herein, “adhesion molecules” include but are not limited to selectins, e.g., L-selectin, E-selectin and P-selectin, mucines, integrins, e.g., LFA-1 and ICAM-1, Ig superfamily members, VAP-1, retina-specific amine oxidase (AOC2), ectoenzymes, and ligands thereof. For instance, VLA-4 (an integrin) binds VCAM (CD106), LFA-1 (an integrin, CD11/18) binds ICAM (CD54), L-selectin (CD62) binds CD34, and CD44 binds hyaluronan (HA).
The terms “effective amount” or “amount effective to” or “therapeutically effective amount” refers to an amount sufficient to induce a detectable therapeutic response in the subject. Assays for determining therapeutic responses are well known in the art. For example repair (i.e., healing) of injured myocardium can be detected using magnetic resonance imaging (MRI) to detect changes in the myocardium that are indicative of tissue regrowth and reformation.
As used herein, “treating” or “treat” includes (i) preventing a pathologic condition from occurring (e.g. prophylaxis); (ii) inhibiting the pathologic condition or arresting its development; (iii) relieving the pathologic condition; and/or diminishing symptoms associated with the pathologic condition.
The terms, “patient”, “subject” or “animal” are used interchangeably and refer to a mammalian subject to be treated, with human patients being preferred In some cases, the methods of the invention find use in experimental animals, in veterinary application, and in the development of animal models for disease, including, but not limited to, rodents including mice, rats, and hamsters; and primates.
As used herein, “pharmaceutically acceptable salts” refer to derivatives of compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of compounds useful in the present invention can be synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, (1985), the disclosure of which is hereby incorporated by reference.
The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.
“Therapeutically effective amount” is intended to include an amount of a compound useful in the present invention or an amount of the combination of compounds claimed, e.g., to treat or prevent the disease or disorder, or to treat the symptoms of the disease or disorder, in a host. The combination of compounds is preferably a synergistic combination. Synergy, as described for example by Chou et al. (1984), occurs when the effect of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased activity, or some other beneficial effect of the combination compared with the individual components.
A compound can be administered as the parent compound, a pro-drug of the parent compound, or an active metabolite of the parent compound.
“Pro-drugs” are intended to include any covalently bonded substances which release the active parent drug or other formulas or compounds of the present invention in vivo when such pro-drug is administered to a mammalian subject. Pro-drugs of a compound of the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation in vivo, to the parent compound. Pro-drugs include compounds of the present invention wherein carbonyl, carboxylic acid, hydroxy or amino groups are bonded to any group that, when the pro-drug is administered to a mammalian subject, cleaves to form a free carbonyl, carboxylic acid, hydroxy or amino group. Examples of pro-drugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention, and the like.
“Metabolite” refers to any substance resulting from biochemical processes by which living cells interact with the active parent drug or other formulas or compounds of the present invention in vivo, when such active parent drug or other formulas or compounds of the present are administered to a mammalian subject. Metabolites include products or intermediates from any metabolic pathway.
This document describes, among other things compositions, methods and devices to inhibit or treat restenosis, inflammation, oxidative stress, or a combination thereof, and/or inhibit endogenous cell implantation at a selected physiological site. In one embodiment, an agent that inhibits expression, activation or activity of the adhesion molecule VAP-1 may be employed. The agent may be administered systemically or locally (e.g., via injection, stent or catheter delivery).
The invention thus provides methods to inhibit homing and/or extravasation of endogenous cells by administering an agent that blocks or inhibits binding of the adhesion molecules to a target tissue. For example, small molecule inhibitors or antibodies to adhesion molecules such as antibodies to VAP-1, selecting, or integrins, may be applied to a tissue, e.g., locally, to prevent or inhibit unwanted endogenous stem cell homing. In one embodiment, an agent that blocks or inhibits adhesion molecules may be incorporated into a stent to prevent or reduce restenosis, e.g., to block or inhibit smooth muscle cells derived from circulating stem cells. For instance, a sustained release form of one or more VAP-1 inhibitors is applied to or incorporated in a stent, e.g., a metal or biodegradable stent, in an amount effective to prevent or reduce restenosis. In another embodiment, an adhesion inhibiting agent may be injected into a tumor (e.g., to prevent or inhibit angiogenesis). In yet another embodiment, an adhesion inhibiting agent may be injected into a heart (e.g., to prevent or inhibit cardiomyopathy or scarring). Thus, the invention may be useful to inhibit or treat many conditions including but not limited to myocardial infarction, heart failure, cardiomyopathy, restenosis, cancer and other diseases.
The agents of the invention may be coated on and/or embedded in a biocompatible material which in turn may be coated on and/or embedded in a device. Biocompatible materials include polyacetic or polyglycolic acid and derivatives combinations thereof.
Additionally, it is possible to construct biocompatible materials from natural materials such as proteins or materials which may be crosslinked using a crosslinking agent such as 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride. Such natural materials include albumin, collagen, fibrin, alginate, extracellular matrix (ECM), e.g., xenogeneic ECM, hyaluronan, chitosan, gelatin, keratin, potato starch hydrolyzed for use in electrophoresis, and agar-agar (agarose), or polymers having pendant zwitterionic groups, specifically phosphorylcholine (PC) groups, generally described in WO 93/01221, or those described in WO 98/30615. Polymers may have pendant crosslinkable groups which are subsequently crosslinked by exposure to suitable conditions, generally heat and/or moisture.
In one embodiment, the material may include liposomes, a hydrogel, cyclodextrins, nanocapsules or microspheres. Thus, a biocompatible material includes synthetic polymers in the form of hydrogels or other porous materials, e.g., permeable configurations or morphologies, such as polyvinyl alcohol, polyvinylpyrrolidone and polyacrylamide, polyethylene oxide, poly(2-hydroxyethyl methacrylate); natural polymers such as gums and starches; synthetic elastomers such as silicone rubber, polyurethane rubber; and natural rubbers, and include poly[α(4-aminobutyl)]-1-glycolic acid, polyethylene oxide (Roy et al., Mol. Ther., 7:401 (2003)), poly orthoesters (Heller et al., Adv. Drug Delivery Rev., 54:1015 (2002)), silk-elastin-like polymers (Megeld et al., Pharma. Res., 19:954 (2002)), alginate (Wee et al., Adv. Drug Deliv. Rev., 31:267 (1998)), EVAc (poly(ethylene-co-vinyl acetate), microspheres such as poly (D,L-lactide-co-glycolide) copolymer and poly (L-lactide), poly(N-isopropylacrylamide)-b-poly(D,L-lactide), a soy matrix such as one cross-linked with glyoxal and reinforced with a bioactive filler, e.g., hydroxylapatite, poly(epsilon-caprolactone)-poly(ethylene glycol) copolymers, poly(acryloyl hydroxyethyl) starch, polylysine-polyethylene glycol, an agarose hydrogel, or a lipid microtubule-hydrogel.
In one embodiment, the biocompatible material includes but is not limited to hydrogels of poloxamers, polyacrylamide, poly(2-hydroxyethyl methacrylate), carboxyvinyl-polymers (e.g., Carbopol 934, Goodrich Chemical Co.), cellulose derivatives, e.g., methylcellulose, cellulose acetate and hydroxypropyl cellulose, polyvinyl pyrrolidone or polyvinyl alcohols.
In some embodiments, the biocompatible polymeric material is a biodegradable polymeric such as collagen, fibrin, polylactic-polyglycolic acid, or a polyanhydride. Other examples include, without limitation, any biocompatible polymer, whether hydrophilic, hydrophobic, or amphiphilic, such as ethylene vinyl acetate copolymer (EVA), polymethyl methacrylate, polyamides, polycarbonates, polyesters, polyethylene, polypropylenes, polystyrenes, polyvinyl chloride, polytetrafluoroethylene, N-isopropylacrylamide copolymers, poly(ethylene oxide)/poly(propylene oxide) block copolymers, poly(ethylene glycol)/poly(D,L-lactide-co-glycolide) block copolymers, polyglycolide, polylactides (PLLA or PDLA), poly(caprolactone) (PCL), poly(dioxanone) (PPS) or cellulose derivatives such as cellulose acetate. In an alternative embodiment, a biologically derived polymer, such as protein, collagen, e.g., hydroxylated collagen, or fibrin, or polylactic-polyglycolic acid or a polyanhydride, is a suitable polymeric matrix material.
In another embodiment, the biocompatible material includes polyethyleneterephalate, polytetrafluoroethylene, copolymer of polyethylene oxide and polypropylene oxide, a combination of polyglycolic acid and polyhydroxyalkanoate, or gelatin, alginate, collagen, hydrogels, poly-3-hydroxybutyrate, poly-4-hydroxybutyrate, and polyhydroxyoctanoate, and polyacrylonitrilepolyvinylchlorides.
Other biocompatible materials include natural polymers such as starch, chitin, glycosaminoglycans, e.g., hyaluronic acid, dermatan sulfate and chrondrotin sulfate, collagen, and microbial polyesters, e.g., hydroxyalkanoates such as hydroxyvalerate and hydroxybutyrate copolymers, and synthetic polymers, e.g., poly(orthoesters) and polyanhydrides, and including homo and copolymers of glycolide and lactides (e.g., poly(L-lactide, poly(L-lactide-co-D,L-lactide), poly(L-lactide-co-glycolide, polyglycolide and poly(D,L-lactide), pol(D,L-lactide-coglycolide), poly(lactic acid colysine) and polycaprolactone. The incorporation of molecules such as tricalciumphosphate, hydroxyapetite and basic salts into a polymer matrix can alter the degradation and resorption kinetics of the matrix. Moreover, the properties of polymers can be modified using cross-linking agents.
In one embodiment, the biocompatible material is isolated ECM. ECM may be isolated from endothelial layers of various cell populations, tissues and/or organs, e.g., any organ or tissue source including the dermis of the skin, liver, alimentary, respiratory, intestinal, urinary or genital tracks of a warm blooded vertebrate. ECM employed in the invention may be from a combination of sources. Isolated ECM may be prepared as a sheet, in particulate form, gel form and the like. The preparation and use of isolated ECM in vivo is described in co-pending, commonly assigned U.S. patent application Ser. No. 11/017,237, entitled “USE OF EXTRACELLULAR MATRIX AND ELECTRICAL THERAPY,” filed on Dec. 20, 2004, which is hereby incorporated by reference in its entirety.
In one embodiment, the agent may be encapsulated in a sustained delivery vehicle such as, but not limited to, a liposome or an absorbable polymeric particle. The preparation and use of such sustained delivery vehicles are well known to those of ordinary skill in the art. The sustained delivery vehicle containing the agent is then suspended in the composition.
Bioerodible microspheres can be prepared using any of the methods developed for making microspheres for drug delivery, for example, as described by Mathiowitz and Langer, J. Controlled Release, 5:13 (1987); Mathiowitz et al., Reactive Polymers, 6:275 (1987); and Mathiowitz et al., J. Appl. Polymer Sci., 35:755 (1988), the teachings of which are hereby incorporated by reference. The selection of the method depends on the polymer selection, the size, external morphology, and crystallinity that is desired, as described, for example, by Mathiowitz et al., Scanning Microscopy, 4:329 (1990); Mathiowitz et al., J. Appl. Polymer Sci., 45:125 (1992); and Benita et al., J. Pharm. Sci., 73:1721 (1984), the teachings of which are incorporated herein
The present invention also relates to a pharmaceutical composition including one or more agents that inhibit expression, activation or activity of adhesion molecules in endogenous tissue, in a pharmaceutically acceptable carrier. In one embodiment, the pharmaceutical composition includes agents that inhibit or block expression, activation or activity of adhesion molecules in endogenous tissue. In some therapeutic applications, compositions are administered to a patient suffering from a disease (e.g., cardiovascular disease), in an amount sufficient to cure or at least partially arrest the disease and its complications, e.g., by repairing injured myocardium or reducing occlusion in vessels. An amount adequate to accomplish this is defined as a therapeutically effective dose. Amounts effective for this use depend on the severity of the cardiovascular disease and the general state of the patient's health.
The amount of the agent, or an active salt or derivative thereof, required for use alone or with other compounds will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician. In general, however, a suitable dose may be in the range of from about 0.5 to about 100 mg/kg, e.g., from about 10 to about 75 mg/kg of body weight per day, such as 3 to about 50 mg per kilogram body weight of the recipient per day, preferably in the range of 6 to 90 mg/kg/day, most preferably in the range of 15 to 60 mg/kg/day.
The pharmaceutical compositions of the present invention may be administered by any means known in the art. Preferably, the compositions are suitable for parenteral administration (e.g., intravenous, intraperitoneal). The compositions of the invention may also be administered subcutaneously, into vascular spaces, or into joints, e.g., intraarticular injection.
Single or multiple administrations of the compositions may be administered depending on the dosage and frequency as required and tolerated by the patient. In any event, the composition should provide a sufficient quantity of the agent to effectively treat the patient, e.g., to repair or augment repair of injured myocardium.
Preferably, the compositions for administration include a solution of the composition and a pharmaceutically acceptable carrier, preferably an aqueous carrier. A variety of aqueous carriers can be used, e.g., buffered saline and the like. These solutions are sterile and generally free of undesirable matter. These compositions may be sterilized by conventional, sterilization techniques known in the art. The compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents and the like, for example, sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like. The composition having an agent that inhibits expression, activation or activity of adhesion molecules may also formulated in microspheres, liposomes or other microparticulate delivery systems. The concentration of composition having an agent that inhibits expression, activation or activity of adhesion molecules in these formulations can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight and the like in accordance with the particular mode of administration selected and the patient's needs.
The pharmaceutical compositions having an agent that inhibits expression, activation or activity of adhesion molecules may be administered in a therapeutically effective dose over either a single day or several days by daily intravenous infusion. The dose will be dependent upon the properties of the composition having an agent that inhibits expression, activation or activity of adhesion molecules employed, e.g., its activity and biological half-life, the concentration of the composition having an agent that inhibits expression, activation or activity of adhesion molecules in the formulation, the site and rate of dosage, the clinical tolerance of the patient involved, the extent of disease afflicting the patient and the like as is well within the skill of the physician.
The compositions may be administered in solution. The pH of the solution should be in the range of pH 5 to 9.5, preferably pH 6.5 to 7.5. The compositions thereof should be in a solution having a suitable pharmaceutically acceptable buffer such as phosphate, tris (hydroxymethyl) aminomethane-HCl or citrate and the like. Buffer concentrations should be in the range of 1 to 100 mM. The solution of the compositions may also contain a salt, such as sodium chloride or potassium chloride in a concentration of 50 to 150 mM. An effective amount of a stabilizing agent such as albumin, a globulin, a detergent, a gelatin, a protamine or a salt of protamine may also be included and may be added to a solution containing the agent or to the composition from which the solution is prepared. In some embodiments, systemic administration of the composition is typically made every two to three days or once a week. Alternatively, daily administration is useful.
The compositions described herein can be administered to a patient in conjunction with other therapies, e.g., therapies for cardiovascular disease. For example, the compositions may be administered in conjunction with angioplasty to promote repair of injured cardiac tissue. The compositions may be administered prior to the angioplasty, contemporaneous with the angioplasty, or subsequent to the angioplasty. In one embodiment, the composition is delivered via a stent, e.g., from a sustained released formulation coating and/or embedded in the stent. In another embodiment, VAP-1 inhibitors may be administered at the time of stenting, e.g., via oral, IV or catheter administration.
For example, a VAP-1 inhibitor may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet. For oral administration, the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form. The amount of active compound in such useful compositions is such that an effective dosage level will be obtained.
The tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations and devices.
The active compound may also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
The pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. In all cases, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like. Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use.
Agents and treatments useful in the methods of the invention include those which inhibit cell surface molecule expression, activation or activity of adhesion molecules or their ligands (see Table 1) on target tissue or cells, e.g., ex vivo, at a particular physiological site, or both, and including neutralizing and antagonistic antibodies of adhesion molecules or their ligands.
Agents useful to inhibit localization of endogenous circulating stem cells, or to inhibit or treat inflammation, restenosis or oxidative stress, include inhibitors of VAP-1 or SSAO, e.g., hydrazine derivatives, e.g., aryl(alkyl)hydrazines, arylalkylamines, propenyl- and proparyl-amines, oxazolidinones and haloalkylamines, including but not limited to 3-halo-2-phenylallylamines, semicarbazide, hydroxylamine, propargylamine, pyridoxamine, (+)mexiletine, B-24 (3,5-diethoxy-4-aminomethylpyridine), amiflamine (FLA 336(+)), FLA336(−), FLA788(+), FLA668(+), MDL-72145 ((E)-2-(3,4-dimethyloxyphenyl)-3-fluoroallyamine, MDL-72974A ((E)-2-(4-fluorophenethyl)-3-fluoroallylamine hydrochloride), iproniazid, phenelzine, procarbazine (N-isopropyl-alpha-(2-methylhydrazino)-p-toluamide hydrochloride), hydralazine, carbidopa, benserazide, aminoguanidine (pimagedine), 2 bromoethylamine, and carbocyclic hydrazino compounds, or a pharmaceutically acceptable salt thereof.
In one embodiment, inhibitors of VAP-1 or other copper containing amine oxidases such as SSAO useful in the devices and methods of the invention include but are not limited to those disclosed in U.S. Pat. Nos. 6,982,286, 6,624,202, and 6,066,321; U.S. published application 20060128770 (thiazole derivatives), 20060025438, 20050096360, 20040259923, 20040236108 (carbocyclic hydrazine), 20040106654, 20030125360, 20020173521, and 20020198189; Koskinen et al. (Blood, 103:3388 (2004)), Lazar et al. (Acta Pharma. Hungarica, 74:11 (2004), peptide inhibitors in Yegutkin et al. (Eur. J. Immunol., 34:2276 (2004)), Wang et al. (J. Med. Chem., 49:2166 (2006)), e.g., compounds 4a and 4c therein, esterified pectins such as those disclosed in Hou et al. (J. Ag. Food Chem., 51:6362 (2003)), e.g., DE65T4, DE94T18, DE25T4, and DE94T4, and includes anti-VAP antibodies such as those described in U.S. Pat. Nos. 5,580,780 and 5,512,442, and Koskinen et al. (Blood, 103:3388 (2004)), Arvilommi et al. (Eur. J. Immunol., 26:825 (1996)), Salmi et al. (J. Exp. Med., 178:2255 (1993)), and Kirten et al. (Eur. J. Immunol., 35:3119 (2005)). Other inhibitors of VAP-1 include, but are not limited to, phenylhydrazine, 5-hydroxytryptamine, 3-bromopropylamine, N-(phenyl-allyl)-hydrazine HCl (LJP-1207), 2-hydrazinopyridine, TNF-α, MDL-72274 ((E)-2-phenyl-3-chloroallylamine hydrochloride), MDL-72214 (2-phenylallylamine), mexiletine, isoniazid, an endogeneous molecule, e.g., see Lizcano et al., J. Neurol. Trans., 32:323 (1990) including one about 500 to 700 MW (see Obata et al., Neurosci. Lett., 296:58 (2000)), imipramine, maprotiline, zimeldine, nomifensine, azoprocarbazine, monomethylhydrazine, d1-alpha methyltryptamine, dl-alpha methylbenzylamine, MD780236 (Dostert et al., J. Pharmacy & Pharmacol., 36:782 (2984)), 2-(dimethyl(2-phenylethyl)silyl) methanamine, cuprozine, alkylamino derivatives of 4-amniomethylpyridine (Bertini et al., J. Med. Chem., 48:664 (2005)), and kynuramine. Preferred inhibitors are selective SSAO inhibitors, e.g., agents that inhibit SSAOs at least 2-fold more than MAOs. Inhibitors may be reversible, competitive, noncompetitive or irreversible inhibitors.
Devices useful for administering agents to an organ or body part, include a lumen, and may be, but are not limited to, a catheter, needle, stent, e.g., be made of stainless steel, Nitinol (NiTi), or chromium alloy and biodegradable materials, a stent graft, a synthetic vascular graft, e.g., one made of a cross-linked PVA hydrogel, polytetrafluoroethylene (PTFE), expanded polytetrafluoroethylene (ePTFE), porous high density polyethylene (HDPE), polyurethane, and polyethylene terephthalate, or biodegradable materials, a pacemaker, lead, e.g., pacemaker lead, defibrillator, a hemodialysis catheter, or a drug delivery port. The medical device can be made of numerous materials depending on the device. In one embodiment, the device is coated with one or more agents. For example, adhesion molecules or peptides thereof may be coated on the inside lumen of a catheter via a linker, e.g., polyethylene glycol (PEG) based linker. Thus, as cells are delivered to a mammal, they are activated by interaction with the adhesion molecules or peptides thereof that are coated on the lumen of the catheter.
Surface portion 114 is the portion of the device including a surface on which agent 112 is coated or otherwise formed. In one embodiment, the device is a percutaneous injection device that allows for injection of agent 112, such as a delivery catheter, a syringe, or a needle. In another embodiment, the device is an implantable device such as a bead, a transvascular lead, an intravascular stent, an implantable sensor, an implantable pulse generator (such as a pacemaker, a defibrillator, and a neurostimulator), and any other implantable device that delivers electrical, drug, and/or biologic therapies. The implantable device includes a portion that is a surface portion 114.
In one embodiment, intraluminal device 260 is an intravascular device including at least a portion coated with one or more inhibitory agents 212. Examples of the intravascular device include a stent and a transvenous lead. In a specific embodiment, the intravascular device is a coronary stent. In other specific embodiments, the intravascular device is a device for one or more peripheral vascular applications including, but not limited to, aortic aneurysm repair, carotid artery stenting, iliac artery stenting, femoropopliteal stenting, infrapopliteal stenting, renal artery stenting, and transjugular intrahepatic portosystemic shunting. In another embodiment, the intravascular device is a transvenous pacing and/or defibrillation lead. In another embodiment, intraluminal device 260 includes a non-vascular device, such as a non-vascular stent, including at least a portion coated with one or more inhibitory agents 212. The non-vascular device is configured to be placed in a body lumen that is external to the vascular system. In various specific embodiments, the non-vascular device is configured to be placed in a non-vascular lumen such as biliary, tracheobronchial, oesophagus, upper gastrointestinal tract, the small bowel, large bowel, or dacryocystic duct.
With reference to
As illustrated in
With reference to
The elongate body 432 forms an insulating sheath covering around conductor 434. Conductor 434 is coupled to a ring or ring-like electrode 436 at or near distal end portion 318 of the elongate body 42. The conductor 434 is coupled to a connector 438 at or near the proximal end 316 of elongate body 432. Device 304 includes a receptacle for receiving connector 438, thereby obtaining electrical continuity between electrode 436 and device 304.
Electrode 436, or at least a portion thereof, is not covered by the insulating sheath of elongate body 432. Electrode 436 provides an exposed electrically conductive surface around all, or at least part of, the circumference of lead 310. In one example, electrode 436 is a coiled wire electrode that is wound around the circumferential outer surface of lead 310. Lead 310 also includes other configurations, shapes, and structures of electrode 436.
As illustrated in
With reference to
Catheter assembly 552 as illustrated in
In
In an exemplary procedure to implant stent 550, guide wire 572 is advanced through the patient's vascular system by well known methods so that the distal end of the guide wire is advanced past the plaque or diseased area 578. Prior to implanting stent 550, the cardiologist may wish to perform an angioplasty procedure or other procedure, i.e., atherectomy, in order to open the vessel and remodel the diseased area. Thereafter, stent delivery catheter assembly 552 is advanced over guide wire 572 so that stent 550 is positioned in the target area. The expandable member or balloon 574 is inflated so that it expands radially outwardly and in turn expands stent 550 radially outwardly until stent 550 is apposed to the vessel wall. Expandable member 574 is then deflated and the catheter withdrawn from the patient's vascular system. Guide wire 572 is left in the lumen for post-dilatation procedures, if any, and subsequently is withdrawn from the patient's vascular system. As illustrated in
Stent 550 serves to hold open the artery after the catheter is withdrawn, as illustrated by
In one embodiment, the entire surface of stent 550 is coated to carry and deliver one or more inhibitory agents 212. In another embodiment, portions of the surfaces of the stent 550, e.g., the tissue contacting portions, are coated to carry the one or more inhibitory agents 212.
All publications, patents and patent applications are incorporated herein by reference. While in the foregoing specification, this invention has been described in relation to certain preferred embodiments thereof, and many details have been set forth for purposes of illustration, it will be apparent to those skilled in the art that the invention is susceptible to additional embodiments and that certain of the details herein may be varied considerably without departing from the basic principles of the invention.
