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Carotenoids are divided into two subclasses, i. Terms such as carotenoid analog and carotenoid derivative may generally refer to in some embodiments chemical compounds or compositions derived from a naturally occurring carotenoid or simply to synthetic carotenoids. In some embodiments, terms such as carotenoid analog and carotenoid derivative may generally refer to chemical compounds or compositions which are synthetically derived from non-carotenoid based parent compounds; however, which ultimately substantially resemble a carotenoid derived analog.

In certain embodiments, terms such as carotenoid analog and carotenoid derivative may generally refer to a synthetic derivative of a naturally occurring carotenoid. Britton et al, , which is herein incorporated by reference. It will be evident to any skilled person how to choose the suitable carotenoid compound for the purpose of the present development.

Examples of carotenoids include astaxanthin, zeaxanthin, lutein, lycopene, beta-carotene. Other non-limiting examples of naturally occurring carotenoids include: Corynebacterium poinsettiae ; Corynexanthin; Corynexanthin glucoside; C.

Karpoxanthin; Keto-, see also oxo or -one Ketocapsanthin; 4-Ketocapsanthin; 4-Keto-alpha-carotene; 4-Keto-beta-carotene; 4-Keto-gamma-carotene; 4-Ketocynthiaxanthin: The above list of naturally occurring carotenoids is meant to be a non-limiting example of naturally occurring carotenoids.

This list is not comprehensive as more naturally occurring molecules are being discovered which will fall within the category of carotenoids. Non-limiting examples of sulfonylureas include, but are not limited to acetohexamide, DiaBeta, glibenclamide, gliclazide, glipizide Glucotrol , glyclopyramide, chlorpropamide, tolazamide, tolbutamide, glimepiride Amaryl , tolbutamide and meglitinide analogues for example, repaglinide, nateglinide, meglitinide and mitiglinide KAD and the like.

The term niacin is the generic descriptor for nicotinic acid pyridinecarboxylic acid and its derivatives. Non-limiting examples of nicotinic acid derivatives include nicofuranose, Acipimox 5-methyl pyrazinecarboxylic acid 4-oxide , niceritrol, probucol, isonicotinic acid, Cholexamin, oxiniacic acid, nicoclonate, nicomol, NIASPAN, nicerikol and tocopherol nicotinate. Further examples of other active agents which may be suitable for this invention include, without limitation: The nebivolol compositions of the present invention may be administered by various means, depending on their intended use, as is well known in the art.

For example, if compositions of the present invention are to be administered orally, they may be formulated as tablets, capsules, granules, powders, suspensions or syrups.

Alternatively, formulations of the present invention may be administered parenterally as injections intravenous, intramuscular or subcutaneous , drop infusion preparations or suppositories. For application by the ophthalmic mucous membrane route, compositions of the present invention may be formulated as eyedrops or eye ointments. These formulations may be prepared by conventional means, and, if desired, the compositions may be mixed with any conventional additive, such as an excipient, a binder, a disintegrating agent, a lubricant, a corrigent, a solubilizing agent, a suspension aid, an emulsifying agent or a coating agent.

In formulations of the subject invention, wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants may be present in the formulated agents. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.

The amount of composition that may be combined with a carrier material to produce a single dose vary depending upon the subject being treated, and the particular mode of administration. Methods of preparing these formulations include the step of bringing into association compositions of the present invention with the carrier and, optionally, one or more accessory ingredients.

In general, the formulations are prepared by uniformly and intimately bringing into association agents with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

Formulations suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges using a flavored basis, usually sucrose and acacia or tragacanth , powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles using an inert base, such as gelatin and glycerin, or sucrose and acacia , each containing a predetermined amount of a subject composition thereof as an active ingredient.

Compositions of the present invention may also be administered as a bolus, electuary, or paste. In the case of capsules, tablets and pills, the compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like. A tablet may be made by compression or molding, optionally with one or more accessory ingredients.

Compressed tablets may be prepared using binder for example, gelatin or hydroxypropyl methyl cellulose , lubricant, inert diluent, preservative, disintegrant for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose , surface-active or dispersing agent.

Molded tablets may be made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsion, solutions, suspensions, syrups and elixirs. In addition to the subject composition, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils , glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty.

Suspensions, in addition to the subject composition, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.

Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate. Dosage forms for transdermal administration of a subject composition includes powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.

The active component may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required. The ointments, pastes, creams and gels may contain, in addition to a subject composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

Compositions of the present invention may alternatively be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound s. Sonic nebulizers may be used because they minimize exposing the agent to shear, which may result in degradation of the compounds contained in the subject compositions. Ordinarily, an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers.

The carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants Tweens, Pluronics, or polyethylene glycol , innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols generally are prepared from isotonic solutions.

Pharmaceutical compositions of this invention suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

Examples of suitable aqueous and non-aqueous carriers which may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols such as glycerol, propylene glycol, polyethylene glycol, and the like , and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.

Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

Pharmaceutical formulations may also be extended or delayed release formulations where the active agents are released over an extended period of time. Administration of the compositions of the present invention will be in an amount sufficient to achieve a therapeutic effect as recognized by one of ordinary skill in the art. The dosage of any compositions of the present invention will vary depending on the symptoms, age and body weight of the patient, the nature and severity of the disorder to be treated or prevented, the route of administration, and the form of the subject composition.

Any of the subject formulations may be administered in a single dose or in divided doses. Dosages for the compositions of the present invention may be readily determined by techniques known to those of skill in the art or as taught herein. The dosage range for nebivolol ranges from about 0. In another embodiment, the dosage range may be from about 0. In yet another embodiment, the dosage range may be from about 1.

In certain embodiments, the dosage of the co-active compounds will generally be in the range of about 0. An effective dose or amount, and any possible affects on the timing of administration of the formulation, may need to be identified for any particular composition of the present invention. This may be accomplished by routine experiment as described herein, using one or more groups of animals preferably at least 5 animals per group , or in human trials if appropriate.

The effectiveness of any subject composition and method of treatment or prevention may be assessed by administering the composition and assessing the effect of the administration by measuring one or more applicable indices, and comparing the post-treatment values of these indices to the values of the same indices prior to treatment.

The precise time of administration and amount of any particular subject composition that will yield the most effective treatment in a given patient will depend upon the activity, pharmacokinetics, and bioavailability of a subject composition, physiological condition of the patient including age, sex, disease type and stage, general physical condition, responsiveness to a given dosage and type of medication , route of administration, and the like.

The guidelines presented herein may be used to optimize the treatment, e. While the subject is being treated, the health of the patient may be monitored by measuring one or more of the relevant indices at predetermined times during the treatment period.

Treatment, including composition, amounts, times of administration and formulation, may be optimized according to the results of such monitoring. The patient may be periodically reevaluated to determine the extent of improvement by measuring the same parameters.

Adjustments to the amount s of subject composition administered and possibly to the time of administration may be made based on these reevaluations. Treatment may be initiated with smaller dosages which are less than the optimum dose of the compound.

Thereafter, the dosage may be increased by small increments until the optimum therapeutic effect is attained. The use of the subject compositions may reduce the required dosage for any individual agent contained in the compositions e.

Toxicity and therapeutic efficacy of subject compositions may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e. The data obtained from the cell culture assays and animal studies may be used in formulating a range of dosage for use in humans. The dosage of any subject composition lies preferably within a range of circulating concentrations that include the ED 50 with little or no toxicity.

The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For compositions of the present invention, the therapeutically effective dose may be estimated initially from cell culture assays.

In general, the doses of an active agent will be chosen by a physician based on the age, physical condition, weight and other factors known in the medical arts. The efficacy of treatment with the subject compositions may be determined in a number of fashions known to those of skill in the art. In one exemplary method, the median rate of decrease in inflammation for treatment with a subject composition may be compared to other forms of treatment with the particular cardiovascular agent contained in the subject composition, or with other cardiovascular agents.

The period of time for observing any such decrease may be about 1, 3, 5, 10, 15, 30, 60 or 90 or more hours. The comparison may be made against treatment with the particular cardiovascular agent contained in the subject composition, or with other cardiovascular agents, or administration of the same or different agents by a different method, or administration as part of a different drug delivery device than a subject composition. The comparison may be made against the same or a different effective dosage of the various agents.

Alternatively, a comparison of the different treatment regimens described above may be based on the effectiveness of the treatment, using standard indices known to those of skill in the art. Alternatively, the different treatment regimens may be analyzed by comparing the therapeutic index for each of them, with treatment with a subject composition as compared to another regimen having a therapeutic index two, three, five or seven times that of, or even one, two, three or more orders of magnitude greater than, treatment with another method using the same or different cardiovascular agents.

This invention also provides kits for conveniently and effectively implementing the methods of this invention. Such kits comprise any subject composition, and a means for facilitating compliance with methods of this invention. Such kits provide a convenient and effective means for assuring that the subject to be treated takes the appropriate active in the correct dosage in the correct manner.

The compliance means of such kits includes any means which facilitates administering the actives according to a method of this invention. Such compliance means include instructions, packaging, and dispensing means, and combinations thereof. Kit components may be packaged for either manual or partially or wholly automated practice of the foregoing methods. In other embodiments involving kits, this invention contemplates a kit including compositions of the present invention, and optionally instructions for their use.

All measurements presented were recorded in vitro using a sensitive porphyrinic probe, as previously described. Malinski T, Taha Z. Nebivolol was obtained from Mylan Laboratories Morgantown, W. Cell wells were transferred to a Faraday cage and a porphyrinic sensor diameter 0.

The sensor operated with a three-electrode system: The baseline was stabilized after about 20 seconds. The test compounds were injected with a nanoinjector onto the surface of the cells following solubilization in buffer.

Cells were incubated with the test compounds for a hour period. The compounds were then washed out of the system before being immediately reintroduced in order to evaluate the consequences of chronic treatment on NO release from the cells.

For additive experiments, cells were incubated with ACE inhibitor for 24 hours, the inhibitor was washed out of the system, nebivolol was added and the NO release measured.

The current proportional to the NO concentration was measured with the sensor, which operated in amperometric mode at a constant potential of 0. Data were acquired with the use of an IBM computer with custom software and amperograms current vs. By increasing cytoplasmic levels of calcium, the ion can bind to calmodulin. Nanosensors were prepared from carbon fibers.

The sensors were sensitized to NO by deposition of electrically conductive polymeric porphyrin and covered with a thin layer of Nafion. The porphyrinic microsensor has a response time of 0. The nanosensor for NO was calibrated using saturated solution concentration 1.

The concentration-dependent effects of nebivolol and certain ACE-inhibitors on NO releasing capacity were tested using a calcium ionophore A that stimulates NO release, independently of G-protein-coupled receptors. Measurement of NO release as a function of treatment was conducted in individual endothelial cells.

Multiple measurements of NO release can be conducted on single cells following a brief refractory period. For robust statistical analysis, separate cells were used for each concentration and type of drug used in these analyses. The magnitude of the increase is greater in endothelial cells from Black donors. There were significant concentration dependent effects on the ability of nebivolol to enhance NO release from Black and White donor endothelial cells that had been chronically treated with ACE inhibitors.

By promoting a more normal vascular physiology through an NO-dependent pathway, nebivolol treatment may have better efficacy and fewer side effects as compared to agents that only inhibit the sympathetic nervous system. These data further support the hypothesis that nebivolol may have distinct pharmacologic benefits through modulation of endothelial function and NO metabolism.

All of the patents and publications cited herein are hereby incorporated by reference. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Nebivolol has been shown to be beneficial in the treatment of cardiovascular diseases such hypertension, congestive heart failure, arterial stiffness and endothelial dysfunction.

The present invention features a pharmaceutical composition comprising nebivolol and at least one other active agent, wherein Compositions comprising nebivolol US B2. The present invention features a pharmaceutical composition comprising nebivolol and at least one other active agent, wherein the at least one other active agent is a cardiovascular agent.

A method of treating hypertension comprising administering to a subject in need thereof a composition comprising between about 0. A method of treating a hypertension comprising administering to a subject in need thereof a composition comprising between about 0. The method of claim 1 wherein the cardiovascular active agent is olmesartan or a pharmaceutically acceptable salt thereof. The method of claim 1 wherein the cardiovascular active agent is valsartan or a pharmaceutically acceptable salt thereof.

The method of claim 1 wherein the cardiovascular active agent is losartan or a pharmaceutically acceptable salt thereof.

The method of claim 2 wherein the ARB is olmesartan or a pharmaceutically acceptable salt thereof. The method of claim 2 wherein the ARB is valsartan or a pharmaceutically acceptable salt thereof. The method of claim 2 wherein the ARB is losartan or a pharmaceutically acceptable salt thereof.

The method of claim 9 wherein the cardiovascular active agent is olmesartan or a pharmaceutically acceptable salt thereof. The method of claim 9 wherein the cardiovascular active agent is valsartan or a pharmaceutically acceptable salt thereof.

The method of claim 9 wherein the cardiovascular active agent is losartan or a pharmaceutically acceptable salt thereof. Year of fee payment: Eric Davis , John P. Forest Laboratories Holdings Limited. Local administration of pharmacologically active agents to treat premature ejaculation. Methods of treating and preventing congestive heart failure with hydralazine compounds and isosorbide dinitrate or isosorbide mononitrate.

On demand administration of clomipramine and salts thereof to treat premature ejaculation. Method for treating fibrotic diseases with azolium chroman compounds. Methods of treating vascular diseases characterized by nitric oxide insufficiency. Method for treating fibrotic diseases or other indications utilizing thiazole, oxazole and imidazole compounds. Methods using hydralazine compounds and isosorbide dinitrate or isosorbide mononitrate. As-needed administration of tricyclic and other non-SRI antidepressant drugs to treat premature ejaculation.

Combinations of hormone replacement therapy composition s and sterol absorption inhibitor s and treatments for vascular conditions in post-menopausal women.

Nitrosated and nitrosylated nebivolol and its metabolites, compositions and methods of use. Administration of active agents, including 5-HT receptor agonists and antagonists, to treat premature ejaculation.

Semiconductor laser device which includes AlGaAs optical waveguide layer being formed over internal stripe groove and having controlled refractive index.

Epoxy steroidal aldosterone antagonist and beta-adrenergic antagonist combination therapy for treatment of congestive heart failure. Combinations of sterol absorption inhibitor s with blood modifier s for treating vascular conditions.

Combinations of peroxisome proliferator-activated receptor PPAR activator s and sterol absorption inhibitor s and treatments for vascular indications. Use of substituted azetidinone compounds for the treatment of sitosterolemia. Combinations of nicotinic acid and derivatives thereof and sterol absorption inhibitor s and treatments for vascular indications. Combinations of bile acid sequestrant s and sterol absorption inhibitor s and treatments for vascular indications.

Combinations of sterol absorption inhibitor s with cardiovascular agent s for the treatment of vascular conditions. Methods and therapeutic combinations for the treatment of obesity using sterol absorption inhibitors. Methods for treating or preventing vascular inflammation using sterol absorption inhibitor s. Methods of treating or preventing cardiovascular conditions while preventing or minimizing muscular degeneration side effects. Methods and therapeutic combinations for the treatment of xanthoma using sterol absorption inhibitors.

Methods of treating or preventing a cardiovascular condition using a cyclooxygenase-1 inhibitor. Method for treating fibrotic diseases or other indications with imidazolium agents.

Glucopyranosyloxypyrazole derivatives and use thereof in medicines. PH triggered targeted controlled release systems for the delivery of pharmaceutical active ingredients. Glucopyranosyloxypyrazole derivative medicinal composition containing the same medicinal use thereof and intermediate therefor. Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof. Coating precursor and method for coating a substrate with a refractory layer.

Methods and therapeutic combinations for the treatment of diabetes using sterol absorption inhibitors. Epoxy steroidal aldosterone antagonist and beta-adremergic antagonist combination therepy for treatment of congestive heart failure. In part, the present invention features a composition comprising nebivolol and another cardiovascular agent that is believed to work via a different mechanism. These embodiments of the present invention, other embodiments, and their features and characteristics, will be apparent from the description, drawings and claims that follow.

For convenience, before further description of the present invention, certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and understood as by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art.

Non-limiting examples of suitable cardiovascular agents include ACE inhibitors angiotensin II converting enzyme inhibitors , ARB's angiotensin II receptor antagonists , adrenergic blockers, adrenergic agonists, agents for pheochromocytoma, antianginal agents, antiarrhythmics, antiplatelet agents, anticoagulants, antihypertensives, antilipemic agents, antidiabetics, antiinflammatory agents, calcium channel blockers, CETP inhibitors, COX-2 inhibitors, direct thrombin inhibitors, diuretics, endothelin receptor antagonists, HMG Co-A reductase inhibitors, inotropic agents, rennin inhibitors, vasodialators, vasopressors, AGE crosslink breakers advanced glycosylation end-product crosslink breakers, such as alagebrium, see U.

Cardiovascular disease or disorder refers to any cardiovascular disease or disorder known in the art, including, but not limited to, wherein the cardiovascular disease is selected from the group consisting of congestive heart failure, hypertension, pulmonary hypertension, myocardial and cerebral infarctions, atherosclerosis, atherogenesis, thrombosis, ischemic heart disease, post-angioplasty restenosis, coronary artery diseases, renal failure, stable, unstable and variant Prinzmetal angina, cardiac edema, renal insufficiency, nephrotic edema, hepatic edema, stroke, transient ischemic attacks, cerebrovascular accidents, restenosis, controlling blood pressure in hypertension, platelet adhesion, platelet aggregation, smooth muscle cell proliferation, pulmonary edema, and vascular complications associated with the use of medical devices.

Further, when these terms are used, or when a particular active agent is specifically identified by name or category, it is understood that such recitation is intended to include the active agent per se, as well as pharmaceutically acceptable, pharmacologically active derivatives thereof, or compounds significantly related thereto, including without limitation, salts, pharmaceutically acceptable salts, N-oxides, prodrugs, active metabolites, isomers, fragments, analogs, solvates hydrates, radioisotopes, etc.

The effective amount of such substance will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.

It may be evaluated by, such as, for example, invasive techniques, such as, for example, coronary artery reactivity to acetylcholine or methacholine, and the like, or by noninvasive techniques, such as, for example, blood flow measurements, brachial artery flow dilation using cuff occlusion of the arm above or below the elbow, brachial artery ultrasonography, imaging techniques, measurement of circulating biomarkers, such as, asymmetric dimethylarginine ADMA , and the like. For the latter measurement the endothelial-dependent flow-mediated dialation will be lower in patients diagnosed with an endothelial dysfunction.

The composition may include at least one other cardiovascular agent or at least one pharmaceutically acceptable carrier or both. Each carrier must be acceptable in the sense of being compatible with the subject composition and its components and not injurious to the patient.

Some examples of materials which may serve as pharmaceutically acceptable excipients include: If it is administered prior to clinical manifestation of the unwanted condition e. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described herein above.

The permissible substituents may be one or more and the same or different for appropriate organic compounds. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds. The therapeutically effective amount of such substance will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.

It has also been reported that nebivolol inhibits NO synthase uncoupling and produces systemic antioxidant effects. In part, the present invention features compositions comprising nebivolol and at least one other active agent, wherein the at least one other active agent is a cardiovascular agent. The amount of each cardiovascular agent present in the compositions may vary depending on a number of variables such as age, weight, gender, and health related issues.

In general, the dosage of the cardiovascular agents will generally be in the range of about 0. In another embodiment, the amount of nebivolol in the compositions of the present invention may be anywhere from about 0. In one example, when the other cardiovascular agent is an ACE inhibitor, the amount of the ACE inhibitor may be anywhere from 0. The amount of the other cardiovascular agent will depend in part on the particular cardiovascular agent used.

In addition to ACE inhibitors and ARBs, additional cardiovascular agents include, but are not limited to adrenergic blockers, adrenergic agonists, agents for pheochromocytoma, antianginal agents, antiarrhythmics, antiplatelet agents, anticoagulants, antihypertensives, antilipemic agents, antidiabetics, antiinflammatory agents, calcium channel blockers, CETP inhibitors, COX-2 inhibitors, direct thrombin inhibitors, diuretics, endothelin receptor antagonists, HMG Co-A reductase inhibitors, inotropic agents, rennin inhibitors, vasodialators, vasopressors, AGE crosslink breakers advanced glycosylation end-product crosslink breakers, such as alagebrium, see U.

Cardiovascular agents falling within these general categories are exemplified by the following:. Angiotensin I and angiotensin II are synthesized by the enzymatic renin-angiotensin pathway. The synthetic process is initiated when the enzyme renin acts on angiotensinogen, a pseudoglobulin in blood plasma, to produce the decapeptide angiotensin I.

The latter is an active pressor substance which has been implicated as a causative agent in several forms of hypertension in various mammalian species, e. Angiotensin II receptor antagonists ARB's are well known and include peptide compounds and non-peptide compounds. Most angiotensin II receptor antagonists are slightly modified congeners in which agonist activity is attenuated by replacement of phenylalanine in position 8 with some other amino acid; stability can be enhanced by other replacements that slow degeneration in vivo.

Examples of angiotensin II receptor antagonists include: Other non-limiting examples of ARBs include candesartan, eprosartan, irbesartan, losartan, and valsartan. Other ARBs may be identified using standard assaying techniques known to one of ordinary skill in the art.

ACE inhibitors include amino acids and derivatives thereof, peptides, including di- and tri-peptides and antibodies to ACE which intervene in the renin-angiotensin system by inhibiting the activity of ACE thereby reducing or eliminating the formation of pressor substance angiotensin II. ACE inhibitors have been used medically to treat hypertension, congestive heart failure, myocardial infarction and renal disease. Classes of compounds known to be useful as ACE inhibitors include acylmercapto and mercaptoalkanoyl prolines such as captopril U.

Other non-limiting examples of ACE inhibitors include, but are not limited to, alacepril, benazepril, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, perindopril, quinapril, ramipril, ramiprilat, spirapril, temocapril, trandolapril. The above-identified compounds can be used as isomeric mixtures, or in their respective levorotating or dextrorotating form.

Include but are not limited to amlodipine besylate, amlodipine maleate, betaxolol hydrochloride, bevantolol hydrochloride, butoprozine hydrochloride, carvedilol, cinepazet maleate, metoprolol succinate, molsidomine, monatepil maleate, nitrates including but not limited to glyceryl trinitrate GTN, nitroglycerin, Nitro-Bid , isosorbide dinitrate ISDN, Isordil , isosorbidemononitrate 5-ISMN, Ismo , amyl nitrate and nicorandil Icorel , primidolol, ranolazine hydrochoride, tosifen, verapamil hydrochloride.

Non-limiting examples of antiarrhythmics that may be used in the compositions of the present invention include acebutolol, acecainide, adenosine, ajmaline, alprenolol, amiodarone, amoproxan, aprindine, aprotinolol, atenolol, azimilide, bevantolol, bidisomide, bretylium tosylate, bucumolol, butetolol, bunaftine, bunitrolol, bupranolol, butidrine hydrochloride, butobendine, capobenic acid, carazolol, carteolol, cifenline, cloranolol, disopyramide, dofetilide, encainide, esmolol, flecainide, hydroquinidine, ibutilide, indecainide, indenolol, ipratropium bromide, lidocaine, lorajmine, lorcainide, meobentine, mexiletine, moricizine, nadoxolol, nifenaolol, oxprenolol, penbutolol, pentisomide, pilsicainide, pindolol, pirmenol, practolol, prajmaline, procainamide hydrochloride, pronethalol, propafenone, propranolol, pyrinoline, quinidine, sematilide, sotalol, talinolol, tilisolol, timolol, tocainide, verapamil, viquidil, xibenolol, and mixtures thereof.

Non-limiting examples of antiplatelet agents that may be used in the compositions of the present invention include clopidogrel, dipyridamole, abcixamab, and ticlodipine. Non-limiting examples of anticoagulants i. Inhibitors of platelet function are agents that impair the ability of mature platelets to perform their normal physiological roles i.

Platelets are normally involved in a number of physiological processes such as adhesion, for example, to cellular and non-cellular entities, aggregation, for example, for the purpose of forming a blood clot, and release of factors such as growth factors e.

One subcategory of platelet function inhibitors are inhibitors of platelet aggregation which are compounds which reduce or halt the ability of platelets to associate physically with themselves or with other cellular and non-cellular components, thereby precluding the ability of a platelet to form a thrombus. Non-limiting examples of antihypertensives that may be used in the compositions of the present invention include amlodipine, benidipine, benezepril, candesartan, captopril, darodipine, dilitazem HCl, diazoxide, doxazosin HCl, enalapril, eposartan, losartan mesylate, felodipine, fenoldopam, fosenopril, guanabenz acetate, irbesartan, isradipine, lisinopril, mecamylamine, minoxidil, nicardipine HCl, nifedipine, nimodipine, nisoldipine, phenoxybenzamine HCl, prazosin HCl, quinapril, reserpine, terazosin HCl, telmisartan, and valsartan.

One preferred antiinflammatory agent is aspirin. Calcium channel blockers are a chemically diverse class of compounds having important therapeutic value in the control of a variety of diseases including several cardiovascular disorders, such as hypertension, angina, and cardiac arrhythmias Fleckenstein, Cir. Calcium channel blockers are a heterogeneous group of drugs that prevent or slow the entry of calcium into cells by regulating cellular calcium channels.

Most of the currently available calcium channel blockers, and useful according to the present invention, belong to one of three major chemical groups of drugs, the dihydropyridines, such as nifedipine, the phenyl alkyl amines, such as verapamil, and the benzothiazepines, such as diltiazem. Non-limiting examples of calcium channel blockers that may be used in the compositions of the present invention include bepridil, clentiazem, diltiazem, fendiline, gallopamil, mibefradil, prenylamine, semotiadil, terodiline, verapamil, amlodipine, aranidipine, barnidipine, benidipine, cilnidipine, efonidipine, elgodipine, felodipine, isradipine, lacidipine, lercanidpine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, cinnarizine, flunarizine, lidoflazine, lomerizine, bencyclane, etafenone, fantofarone, perhexiline, and mixtures thereof.

A non-limiting example of a CETP inhibitor that may be used in the compositions of the present invention includes torcetrapib. Non-limiting examples of COX-2 inhibitors that may be used in the compositions of the present invention include compounds according to the following: Celecoxib is discussed as SC in the same reference, and in T. Penning, Synthesis and biological evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors: The meaning of COX-2 inhibitor in this invention also includes SC referred to as a fluorescent diaryloxazole.

May ; 19 3: The meaning of COX-2 inhibitor in this invention also includes the substitution of the sulfonamide moiety as a suitable replacement for the methylsulfonyl moiety. Carter et al, Synthesis and activity of sulfonamide-substituted 4,5-diaryl thiazoles as selective cyclooxygenase-2 inhibitors. The second substituent should have an electronegativity within such substituent greater than 0. Thus for purposes of this last included meaning of a COX-2 inhibitor, one portion of the COX-2 inhibitor should be hydrophilic and the other portion lipophilic.

Also included as a COX-2 inhibitor are compounds listed at page in Pharmacotherapy: The inventors add to the class of COX-2 inhibitors useful in the invention the drug bearing the name etoricoxib referenced in the Wall Street Journal, Dec. See, also, Chauret et al. The inventors also include as a selective COX-2 inhibitor the flavonoid antioxidant silymarin, and an active ingredient in silymarin, silybinin, which demonstrated significant COX-2 inhibition relative to COX-1 inhibition.

The silymarin also showed protection against depletion of glutathione peroxidase. December , Vol 26 4: Silymarin has been used to treat liver diseases in Europe. A number of the above-identified COX-2 inhibitors are prodrugs of selective COX-2 inhibitors, and exert their action by conversion in vivo to the active and selective COX-2 inhibitors.

Given the teachings of U. Non limiting examples of direct thrombin inhibitors include hirudin, hirugen, hirulog, agatroban, PPACK, and thrombin aptamers. A non-limiting example of an endothelin receptor antagonist that may be used in the compositions of the present invention is bosentan.

A number of HMG-CoA reductase inhibitors has been used to treat individuals with hypercholesterolemia. HMG-CoA reductase inhibitors useful for co-administration with the agents of the invention include, but are not limited to, simvastatin U. Other non-limiting examples of HMG-CoA reductase inhibitors that may be used in the compositions of the present invention include mevastatin, pitavastatin, rosuvastatin, gemcabene, and probucol.

Non-limiting examples of inotropic agents that may be used in the compositions of the present invention include acefylline, acetyldigitoxins, 2-aminopicoline, amrinone, benfurodil hemisuccinate, bucladesine, camphotamide, convallatoxin, cymarin, denopamine, deslanoside, digitalin, digitalis, digitoxin, digoxin, dobutamine, docarpamine, dopamine, dopexamine, enoximone, erythrophleine, fenalsomine, gitalin, gitoxin, glycocyamine, heptaminol, hydrastinine, ibopamine, lanatosides, loprinine, milrinone, nerifolin, oleandrin, ouabain, oxyfedrine, pimobendan, prenalterol, proscillaridin, resibufogenin, scillaren, scillarenin, strophanthin, sulmazole, theobromine, vesnarinone, xamoterol, and mixtures thereof.

Renin inhibitors are compounds which interfere with the activity of renin. Renin inhibitors include amino acids and derivatives thereof, peptides and derivatives thereof, and antibodies to renin. Examples of renin inhibitors that are the subject of United States patents are as follows: Non-limiting examples of vasopressors that may be used in the compositions of the present invention include amezinium methyl sulfate, angiotensin amide, dimetofrine, dopamine, etifelmin, etilefrin, gepefrine, metaraminol, methoxamine, midodrine, norepinephrine, pholedrine, synephrine, and mixtures thereof.

Non-limiting examples of AGE crosslink breakers that may be used in the compositions of the present invention include Alagebrium. Non-limiting examples of AGE formation inhibitors that may be used in the compositions of the present invention include Pimagedine.

Non-limiting examples of other active ingredients that may be combined with these nebivolol compositions include, but are not limited to, the following representative classes of compounds, as well as their pharmaceutically acceptable salts, isomers, esters, ethers and other derivatives:. Further examples of other active agents which may be suitable for this invention include, without limitation: The nebivolol compositions of the present invention may be administered by various means, depending on their intended use, as is well known in the art.

For example, if compositions of the present invention are to be administered orally, they may be formulated as tablets, capsules, granules, powders, suspensions or syrups. Alternatively, formulations of the present invention may be administered parenterally as injections intravenous, intramuscular or subcutaneous , drop infusion preparations or suppositories.

For application by the ophthalmic mucous membrane route, compositions of the present invention may be formulated as eyedrops or eye ointments. These formulations may be prepared by conventional means, and, if desired, the compositions may be mixed with any conventional additive, such as an excipient, a binder, a disintegrating agent, a lubricant, a corrigent, a solubilizing agent, a suspension aid, an emulsifying agent or a coating agent.

In formulations of the subject invention, wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants may be present in the formulated agents.

The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of composition that may be combined with a carrier material to produce a single dose vary depending upon the subject being treated, and the particular mode of administration. Methods of preparing these formulations include the step of bringing into association compositions of the present invention with the carrier and, optionally, one or more accessory ingredients.

In general, the formulations are prepared by uniformly and intimately bringing into association agents with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product. Formulations suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges using a flavored basis, usually sucrose and acacia or tragacanth , powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles using an inert base, such as gelatin and glycerin, or sucrose and acacia , each containing a predetermined amount of a subject composition thereof as an active ingredient.

Compositions of the present invention may also be administered as a bolus, electuary, or paste. In the case of capsules, tablets and pills, the compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder for example, gelatin or hydroxypropylmethyl cellulose , lubricant, inert diluent, preservative, disintegrant for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose , surface-active or dispersing agent.

Molded tablets may be made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent. Tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the subject composition, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils , glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

Suspensions, in addition to the subject composition, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof. Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.

Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate. Dosage forms for transdermal administration of a subject composition includes powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active component may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.

The ointments, pastes, creams and gels may contain, in addition to a subject composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.

Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane. Compositions of the present invention may alternatively be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound s. Sonic nebulizers may be used because they minimize exposing the agent to shear, which may result in degradation of the compounds contained in the subject compositions.

Ordinarily, an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants Tweens, Pluronics, or polyethylene glycol , innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols.

Aerosols generally are prepared from isotonic solutions. Pharmaceutical compositions of this invention suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

Examples of suitable aqueous and non-aqueous carriers which may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols such as glycerol, propylene glycol, polyethylene glycol, and the like , and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.

Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Pharmaceutical formulations may also be extended or delayed release formulations where the active agents are released over an extended period of time. Administration of the compositions of the present invention will be in an amount sufficient to achieve a therapeutic effect as recognized by one of ordinary skill in the art.

The dosage of any compositions of the present invention will vary depending on the symptoms, age and body weight of the patient, the nature and severity of the disorder to be treated or prevented, the route of administration, and the form of the subject composition.

Any of the subject formulations may be administered in a single dose or in divided doses. Dosages for the compositions of the present invention may be readily determined by techniques known to those of skill in the art or as taught herein. In certain embodiments, the dosage of the subject compounds will generally be in the range of about 0.

An effective dose or amount, and any possible affects on the timing of administration of the formulation, may need to be identified for any particular composition of the present invention. This may be accomplished by routine experiment as described herein, using one or more groups of animals preferably at least 5 animals per group , or in human trials if appropriate.

The effectiveness of any subject composition and method of treatment or prevention may be assessed by administering the composition and assessing the effect of the administration by measuring one or more applicable indices, and comparing the post-treatment values of these indices to the values of the same indices prior to treatment. The precise time of administration and amount of any particular subject composition that will yield the most effective treatment in a given patient will depend upon the activity, pharmacokinetics, and bioavailability of a subject composition, physiological condition of the patient including age, sex, disease type and stage, general physical condition, responsiveness to a given dosage and type of medication , route of administration, and the like.

The guidelines presented herein may be used to optimize the treatment, e. While the subject is being treated, the health of the patient may be monitored by measuring one or more of the relevant indices at predetermined times during the treatment period.

Treatment, including composition, amounts, times of administration and formulation, may be optimized according to the results of such monitoring. The patient may be periodically reevaluated to determine the extent of improvement by measuring the same parameters. Adjustments to the amount s of subject composition administered and possibly to the time of administration may be made based on these reevaluations. Treatment may be initiated with smaller dosages which are less than the optimum dose of the compound.

Thereafter, the dosage may be increased by small increments until the optimum therapeutic effect is attained. The use of the subject compositions may reduce the required dosage for any individual agent contained in the compositions e. Toxicity and therapeutic efficacy of subject compositions may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e. The data obtained from the cell culture assays and animal studies may be used in formulating a range of dosage for use in humans.

The dosage of any subject composition lies preferably within a range of circulating concentrations that include the ED 50 with little or no toxicity.

The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For compositions of the present invention, the therapeutically effective dose may be estimated initially from cell culture assays. In general, the doses of an active agent will be chosen by a physician based on the age, physical condition, weight and other factors known in the medical arts.

The efficacy of treatment with the subject compositions may be determined in a number of fashions known to those of skill in the art. In one exemplary method, the median rate of decrease in inflammation for treatment with a subject composition may be compared to other forms of treatment with the particular cardiovascular agent contained in the subject composition, or with other cardiovascular agents.

The period of time for observing any such decrease may be about 1, 3, 5, 10, 15, 30, 60 or 90 or more hours. The comparison may be made against treatment with the particular cardiovascular agent contained in the subject composition, or with other cardiovascular agents, or administration of the same or different agents by a different method, or administration as part of a different drug delivery device than a subject composition. The comparison may be made against the same or a different effective dosage of the various agents.

Alternatively, a comparison of the different treatment regimens described above may be based on the effectiveness of the treatment, using standard indices known to those of skill in the art. Alternatively, the different treatment regimens may be analyzed by comparing the therapeutic index for each of them, with treatment with a subject composition as compared to another regimen having a therapeutic index two, three, five or seven times that of, or even one, two, three or more orders of magnitude greater than, treatment with another method using the same or different cardiovascular agents.

This invention also provides kits for conveniently and effectively implementing the methods of this invention. Such kits comprise any subject composition, and a means for facilitating compliance with methods of this invention. Such kits provide a convenient and effective means for assuring that the subject to be treated takes the appropriate active in the correct dosage in the correct manner. The compliance means of such kits includes any means which facilitates administering the actives according to a method of this invention.

Such compliance means include instructions, packaging, and dispensing means, and combinations thereof. Kit components may be packaged for either manual or partially or wholly automated practice of the foregoing methods. In other embodiments involving kits, this invention contemplates a kit including compositions of the present invention, and optionally instructions for their use.

All measurements presented were recorded in vitro using a sensitive porphyrinic probe, as previously described. Malinski T, Taha Z. Nebivolol was obtained from Mylan Laboratories Morgantown, W. Cell wells were transferred to a Faraday cage and a porphyrinic sensor diameter 0. The sensor operated with a three-electrode system: The baseline was stabilized after about 20 seconds. The test compounds were injected with a nanoinjector onto the surface of the cells following solubilization in buffer.

Cells were incubated with the test compounds for a hour period.

with

In a further embodiment, the pharmaceutical composition comprises an amount of nebivolol in the range of between about 0. In a further embodiment, the amount of an ACE inhibitor may be in the range of between about 0. In a further embodiment, the pharmaceutical composition comprises nebivolol and only one other active agent. In a further embodiment, the pharmaceutical composition comprises nebivolol and only one cardiovascular agent.

In a further embodiment, the cardiovascular agent is selected from the group consisting of ACE inhibitors angiotensin II converting enzyme inhibitors , ARB's angiotensin II receptor antagonists , adrenergic blockers, adrenergic agonists, agents for pheochromocytoma, anti-anginal agents, antiarrhythmics, antiplatelet agents, anticoagulants, antihypertensives, antilipemic agents, antidiabetics, antiinflammatory agents, calcium channel blockers, CETP inhibitors, COX-2 inhibitors, direct thrombin inhibitors, diuretics, endothelin receptor antagonists, HMG Co-A reductase inhibitors, inotropic agents, rennin inhibitors, vasodialators, vasopressors, AGE crosslink breakers advanced glycosylation end-product crosslink breakers, such as alagebrium, see U.

In another aspect, the present invention features a method of treating a subject for a cardiovascular disorder comprising administering to the subject an effective amount of nebivolol in combination with at least one other cardiovascular agent. In a further embodiment, the cardiovascular disorder is selected from the group consisting of atherosclerosis, hypertension, diabetes mellitus, hyperhomocysteinemia, heart failure, and renal failure.

In another aspect, the present invention features a method of preventing a cardiovascular disorder comprising administration to a subject an effective amount of nebivolol in combination with an effective amount of at least one other cardiovascular agent. In a further embodiment, the cardiovascular disorder is selected from the group consisting of congestive heart failure, hypertension, pulmonary hypertension, myocardial and cerebral infarctions, atherosclerosis, atherogenesis, thrombosis, ischemic heart disease, post-angioplasty restenosis, coronary artery diseases, renal failure, stable, unstable and variant Prinzmetal angina, cardiac edema, renal insufficiency, nephrotic edema, hepatic edema, stroke, transient ischemic attacks, cerebrovascular accidents, restenosis, controlling blood pressure in hypertension, platelet adhesion, platelet aggregation, smooth muscle cell proliferation, pulmonary edema, and vascular complications associated with the use of medical devices.

In another aspect, the present invention features a kit comprising an effective amount of nebivolol in combination with an effective amount of another cardiovascular agent. It is believed that nebivolol increases the levels of nitric oxide within the vascular endothelium through the L-arginine-nitric oxide pathway and has been shown to improve endothelial dysfunction and improve compliance of blood vessels. Nebivolol has also been shown to have antioxidant characteristics which are favorable to the normal functioning of the vascular endothelium.

These characteristics make nebivolol an effective antihypertensive agent with favorable effects on the vascular endothelium and cardiovascular system. Nebivolol has been shown to be beneficial in the treatment of cardiovascular diseases such as hypertension, congestive heart failure, arterial stiffness and endothelial dysfunction.

In part, the present invention features a composition comprising nebivolol and another cardiovascular agent that is believed to work via a different mechanism. These embodiments of the present invention, other embodiments, and their features and characteristics, will be apparent from the description, drawings and claims that follow. For convenience, before further description of the present invention, certain terms employed in the specification, examples and appended claims are collected here.

These definitions should be read in light of the remainder of the disclosure and understood as by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art. Non-limiting examples of suitable cardiovascular agents include ACE inhibitors angiotensin II converting enzyme inhibitors , ARB's angiotensin II receptor antagonists , adrenergic blockers, adrenergic agonists, agents for pheochromocytoma, antianginal agents, antiarrhythmics, antiplatelet agents, anticoagulants, antihypertensives, antilipemic agents, antidiabetics, antiinflammatory agents, calcium channel blockers, CETP inhibitors, COX-2 inhibitors, direct thrombin inhibitors, diuretics, endothelin receptor antagonists, HMG Co-A reductase inhibitors, inotropic agents, rennin inhibitors, vasodialators, vasopressors, AGE crosslink breakers advanced glycosylation end-product crosslink breakers, such as alagebrium, see U.

Cardiovascular disease or disorder refers to any cardiovascular disease or disorder known in the art, including, but not limited to, wherein the cardiovascular disease is selected from the group consisting of congestive heart failure, hypertension, pulmonary hypertension, myocardial and cerebral infarctions, atherosclerosis, atherogenesis, thrombosis, ischemic heart disease, post-angioplasty restenosis, coronary artery diseases, renal failure, stable, unstable and variant Prinzmetal angina, cardiac edema, renal insufficiency, nephrotic edema, hepatic edema, stroke, transient ischemic attacks, cerebrovascular accidents, restenosis, controlling blood pressure in hypertension, platelet adhesion, platelet aggregation, smooth muscle cell proliferation, pulmonary edema, and vascular complications associated with the use of medical devices.

Further, when these terms are used, or when a particular active agent is specifically identified by name or category, it is understood that such recitation is intended to include the active agent per se, as well as pharmaceutically acceptable, pharmacologically active derivatives thereof, or compounds significantly related thereto, including without limitation, salts, pharmaceutically acceptable salts, N-oxides, prodrugs, active metabolites, isomers, fragments, analogs, solvates hydrates, radioisotopes, etc.

The effective amount of such substance will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.

It may be evaluated by, such as, for example, invasive techniques, such as, for example, coronary artery reactivity to acetylcholine or methacholine, and the like, or by noninvasive techniques, such as, for example, blood flow measurements, brachial artery flow dilation using cuff occlusion of the arm above or below the elbow, brachial artery ultrasonography, imaging techniques, measurement of circulating biomarkers, such as, asymmetric dimethylarginine ADMA , and the like.

For the latter measurement the endothelial-dependent flow-mediated dialation will be lower in patients diagnosed with an endothelial dysfunction. The composition may include at least one other cardiovascular agent or at least one pharmaceutically acceptable carrier or both. Each carrier must be acceptable in the sense of being compatible with the subject composition and its components and not injurious to the patient. Some examples of materials which may serve as pharmaceutically acceptable excipients include: If it is administered prior to clinical manifestation of the unwanted condition e.

In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.

Illustrative substituents include, for example, those described herein above. The permissible substituents may be one or more and the same or different for appropriate organic compounds. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds. The therapeutically effective amount of such substance will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.

It has also been reported that nebivolol inhibits NO synthase uncoupling and produces systemic antioxidant effects. In part, the present invention features compositions comprising nebivolol and at least one other active agent, wherein the at least one other active agent is a cardiovascular agent. The amount of each cardiovascular agent present in the compositions may vary depending on a number of variables such as age, weight, gender, and health related issues.

In general, the dosage of the cardiovascular agents will generally be in the range of about 0. In another embodiment, the amount of nebivolol in the compositions of the present invention may be anywhere from about 0.

In one example, when the other cardiovascular agent is an ACE inhibitor, the amount of the ACE inhibitor may be anywhere from 0. The amount of the other cardiovascular agent will depend in part on the particular cardiovascular agent used. In addition to ACE inhibitors and ARBs, additional cardiovascular agents include, but are not limited to adrenergic blockers, adrenergic agonists, agents for pheochromocytoma, antianginal agents, antiarrhythmics, antiplatelet agents, anticoagulants, antihypertensives, antilipemic agents, antidiabetics, antiinflammatory agents, calcium channel blockers, CETP inhibitors, COX-2 inhibitors, direct thrombin inhibitors, diuretics, endothelin receptor antagonists, HMG Co-A reductase inhibitors, inotropic agents, rennin inhibitors, vasodialators, vasopressors, AGE crosslink breakers advanced glycosylation end-product crosslink breakers, such as alagebrium, see U.

Cardiovascular agents falling within these general categories are exemplified by the following:. Angiotensin I and angiotensin II are synthesized by the enzymatic renin-angiotensin pathway.

The synthetic process is initiated when the enzyme renin acts on angiotensinogen, a pseudoglobulin in blood plasma, to produce the decapeptide angiotensin I. The latter is an active pressor substance which has been implicated as a causative agent in several forms of hypertension in various mammalian species, e.

Angiotensin II receptor antagonists ARB's are well known and include peptide compounds and non-peptide compounds. Most angiotensin II receptor antagonists are slightly modified congeners in which agonist activity is attenuated by replacement of phenylalanine in position 8 with some other amino acid; stability can be enhanced by other replacements that slow degeneration in vivo. Examples of angiotensin II receptor antagonists include: Other non-limiting examples of ARBs include candesartan, eprosartan, irbesartan, losartan, and valsartan.

Other ARBs may be identified using standard assaying techniques known to one of ordinary skill in the art. ACE inhibitors include amino acids and derivatives thereof, peptides, including di- and tri-peptides and antibodies to ACE which intervene in the renin-angiotensin system by inhibiting the activity of ACE thereby reducing or eliminating the formation of pressor substance angiotensin II.

ACE inhibitors have been used medically to treat hypertension, congestive heart failure, myocardial infarction and renal disease. Classes of compounds known to be useful as ACE inhibitors include acylmercapto and mercaptoalkanoyl prolines such as captopril U. Other non-limiting examples of ACE inhibitors include, but are not limited to, alacepril, benazepril, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, perindopril, quinapril, ramipril, ramiprilat, spirapril, temocapril, trandolapril.

The above-identified compounds can be used as isomeric mixtures, or in their respective levorotating or dextrorotating form. Include but are not limited to amlodipine besylate, amlodipine maleate, betaxolol hydrochloride, bevantolol hydrochloride, butoprozine hydrochloride, carvedilol, cinepazet maleate, metoprolol succinate, molsidomine, monatepil maleate, nitrates including but not limited to glyceryl trinitrate GTN, nitroglycerin, Nitro-Bid , isosorbide dinitrate ISDN, Isordil , isosorbidemononitrate 5-ISMN, Ismo , amyl nitrate and nicorandil Icorel , primidolol, ranolazine hydrochoride, tosifen, verapamil hydrochloride.

Non-limiting examples of antiarrhythmics that may be used in the compositions of the present invention include acebutolol, acecainide, adenosine, ajmaline, alprenolol, amiodarone, amoproxan, aprindine, aprotinolol, atenolol, azimilide, bevantolol, bidisomide, bretylium tosylate, bucumolol, butetolol, bunaftine, bunitrolol, bupranolol, butidrine hydrochloride, butobendine, capobenic acid, carazolol, carteolol, cifenline, cloranolol, disopyramide, dofetilide, encainide, esmolol, flecainide, hydroquinidine, ibutilide, indecainide, indenolol, ipratropium bromide, lidocaine, lorajmine, lorcainide, meobentine, mexiletine, moricizine, nadoxolol, nifenaolol, oxprenolol, penbutolol, pentisomide, pilsicainide, pindolol, pirmenol, practolol, prajmaline, procainamide hydrochloride, pronethalol, propafenone, propranolol, pyrinoline, quinidine, sematilide, sotalol, talinolol, tilisolol, timolol, tocainide, verapamil, viquidil, xibenolol, and mixtures thereof.

Non-limiting examples of antiplatelet agents that may be used in the compositions of the present invention include clopidogrel, dipyridamole, abcixamab, and ticlodipine. Non-limiting examples of anticoagulants i. Inhibitors of platelet function are agents that impair the ability of mature platelets to perform their normal physiological roles i. Platelets are normally involved in a number of physiological processes such as adhesion, for example, to cellular and non-cellular entities, aggregation, for example, for the purpose of forming a blood clot, and release of factors such as growth factors e.

One subcategory of platelet function inhibitors are inhibitors of platelet aggregation which are compounds which reduce or halt the ability of platelets to associate physically with themselves or with other cellular and non-cellular components, thereby precluding the ability of a platelet to form a thrombus.

Non-limiting examples of antihypertensives that may be used in the compositions of the present invention include amlodipine, benidipine, benezepril, candesartan, captopril, darodipine, dilitazem HCl, diazoxide, doxazosin HCl, enalapril, eposartan, losartan mesylate, felodipine, fenoldopam, fosenopril, guanabenz acetate, irbesartan, isradipine, lisinopril, mecamylamine, minoxidil, nicardipine HCl, nifedipine, nimodipine, nisoldipine, phenoxybenzamine HCl, prazosin HCl, quinapril, reserpine, terazosin HCl, telmisartan, and valsartan.

One preferred antiinflammatory agent is aspirin. Calcium channel blockers are a chemically diverse class of compounds having important therapeutic value in the control of a variety of diseases including several cardiovascular disorders, such as hypertension, angina, and cardiac arrhythmias Fleckenstein, Cir. Calcium channel blockers are a heterogeneous group of drugs that prevent or slow the entry of calcium into cells by regulating cellular calcium channels.

Most of the currently available calcium channel blockers, and useful according to the present invention, belong to one of three major chemical groups of drugs, the dihydropyridines, such as nifedipine, the phenyl alkyl amines, such as verapamil, and the benzothiazepines, such as diltiazem. Non-limiting examples of calcium channel blockers that may be used in the compositions of the present invention include bepridil, clentiazem, diltiazem, fendiline, gallopamil, mibefradil, prenylamine, semotiadil, terodiline, verapamil, amlodipine, aranidipine, barnidipine, benidipine, cilnidipine, efonidipine, elgodipine, felodipine, isradipine, lacidipine, lercanidpine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, cinnarizine, flunarizine, lidoflazine, lomerizine, bencyclane, etafenone, fantofarone, perhexiline, and mixtures thereof.

A non-limiting example of a CETP inhibitor that may be used in the compositions of the present invention includes torcetrapib.

Non-limiting examples of COX-2 inhibitors that may be used in the compositions of the present invention include compounds according to the following: Celecoxib is discussed as SC in the same reference, and in T.

Penning, Synthesis and biological evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors: The meaning of COX-2 inhibitor in this invention also includes SC referred to as a fluorescent diaryloxazole.

May ; 19 3: The meaning of COX-2 inhibitor in this invention also includes the substitution of the sulfonamide moiety as a suitable replacement for the methylsulfonyl moiety. Carter et al, Synthesis and activity of sulfonamide-substituted 4,5-diaryl thiazoles as selective cyclooxygenase-2 inhibitors. The second substituent should have an electronegativity within such substituent greater than 0. Thus for purposes of this last included meaning of a COX-2 inhibitor, one portion of the COX-2 inhibitor should be hydrophilic and the other portion lipophilic.

Also included as a COX-2 inhibitor are compounds listed at page in Pharmacotherapy: The inventors add to the class of COX-2 inhibitors useful in the invention the drug bearing the name etoricoxib referenced in the Wall Street Journal, Dec.

See, also, Chauret et al. The inventors also include as a selective COX-2 inhibitor the flavonoid antioxidant silymarin, and an active ingredient in silymarin, silybinin, which demonstrated significant COX-2 inhibition relative to COX-1 inhibition. The silymarin also showed protection against depletion of glutathione peroxidase.

December , Vol 26 4: Silymarin has been used to treat liver diseases in Europe. A number of the above-identified COX-2 inhibitors are prodrugs of selective COX-2 inhibitors, and exert their action by conversion in vivo to the active and selective COX-2 inhibitors. Given the teachings of U. Non limiting examples of direct thrombin inhibitors include hirudin, hirugen, hirulog, agatroban, PPACK, and thrombin aptamers. A non-limiting example of an endothelin receptor antagonist that may be used in the compositions of the present invention is bosentan.

A number of HMG-CoA reductase inhibitors has been used to treat individuals with hypercholesterolemia. HMG-CoA reductase inhibitors useful for co-administration with the agents of the invention include, but are not limited to, simvastatin U. Other non-limiting examples of HMG-CoA reductase inhibitors that may be used in the compositions of the present invention include mevastatin, pitavastatin, rosuvastatin, gemcabene, and probucol.

Non-limiting examples of inotropic agents that may be used in the compositions of the present invention include acefylline, acetyldigitoxins, 2-aminopicoline, amrinone, benfurodil hemisuccinate, bucladesine, camphotamide, convallatoxin, cymarin, denopamine, deslanoside, digitalin, digitalis, digitoxin, digoxin, dobutamine, docarpamine, dopamine, dopexamine, enoximone, erythrophleine, fenalsomine, gitalin, gitoxin, glycocyamine, heptaminol, hydrastinine, ibopamine, lanatosides, loprinine, milrinone, nerifolin, oleandrin, ouabain, oxyfedrine, pimobendan, prenalterol, proscillaridin, resibufogenin, scillaren, scillarenin, strophanthin, sulmazole, theobromine, vesnarinone, xamoterol, and mixtures thereof.

Renin inhibitors are compounds which interfere with the activity of renin. Renin inhibitors include amino acids and derivatives thereof, peptides and derivatives thereof, and antibodies to renin. Examples of renin inhibitors that are the subject of United States patents are as follows: Non-limiting examples of vasopressors that may be used in the compositions of the present invention include amezinium methyl sulfate, angiotensin amide, dimetofrine, dopamine, etifelmin, etilefrin, gepefrine, metaraminol, methoxamine, midodrine, norepinephrine, pholedrine, synephrine, and mixtures thereof.

Non-limiting examples of AGE crosslink breakers that may be used in the compositions of the present invention include Alagebrium. Non-limiting examples of AGE formation inhibitors that may be used in the compositions of the present invention include Pimagedine. Non-limiting examples of other active ingredients that may be combined with these nebivolol compositions include, but are not limited to, the following representative classes of compounds, as well as their pharmaceutically acceptable salts, isomers, esters, ethers and other derivatives:.

Further examples of other active agents which may be suitable for this invention include, without limitation: The nebivolol compositions of the present invention may be administered by various means, depending on their intended use, as is well known in the art. For example, if compositions of the present invention are to be administered orally, they may be formulated as tablets, capsules, granules, powders, suspensions or syrups.

Alternatively, formulations of the present invention may be administered parenterally as injections intravenous, intramuscular or subcutaneous , drop infusion preparations or suppositories. For application by the ophthalmic mucous membrane route, compositions of the present invention may be formulated as eyedrops or eye ointments. These formulations may be prepared by conventional means, and, if desired, the compositions may be mixed with any conventional additive, such as an excipient, a binder, a disintegrating agent, a lubricant, a corrigent, a solubilizing agent, a suspension aid, an emulsifying agent or a coating agent.

In formulations of the subject invention, wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants may be present in the formulated agents.

The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of composition that may be combined with a carrier material to produce a single dose vary depending upon the subject being treated, and the particular mode of administration. Methods of preparing these formulations include the step of bringing into association compositions of the present invention with the carrier and, optionally, one or more accessory ingredients.

In general, the formulations are prepared by uniformly and intimately bringing into association agents with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

Formulations suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges using a flavored basis, usually sucrose and acacia or tragacanth , powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles using an inert base, such as gelatin and glycerin, or sucrose and acacia , each containing a predetermined amount of a subject composition thereof as an active ingredient.

Compositions of the present invention may also be administered as a bolus, electuary, or paste. In the case of capsules, tablets and pills, the compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder for example, gelatin or hydroxypropylmethyl cellulose , lubricant, inert diluent, preservative, disintegrant for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose , surface-active or dispersing agent.

Molded tablets may be made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent. Tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the subject composition, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils , glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

Suspensions, in addition to the subject composition, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.

Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate. Dosage forms for transdermal administration of a subject composition includes powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.

The active component may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required. The ointments, pastes, creams and gels may contain, in addition to a subject composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

Compositions of the present invention may alternatively be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound s. Sonic nebulizers may be used because they minimize exposing the agent to shear, which may result in degradation of the compounds contained in the subject compositions.

Ordinarily, an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers.

The carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants Tweens, Pluronics, or polyethylene glycol , innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols.

Aerosols generally are prepared from isotonic solutions. Pharmaceutical compositions of this invention suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

Examples of suitable aqueous and non-aqueous carriers which may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols such as glycerol, propylene glycol, polyethylene glycol, and the like , and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.

Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Pharmaceutical formulations may also be extended or delayed release formulations where the active agents are released over an extended period of time. Administration of the compositions of the present invention will be in an amount sufficient to achieve a therapeutic effect as recognized by one of ordinary skill in the art.

The dosage of any compositions of the present invention will vary depending on the symptoms, age and body weight of the patient, the nature and severity of the disorder to be treated or prevented, the route of administration, and the form of the subject composition.

Any of the subject formulations may be administered in a single dose or in divided doses. Dosages for the compositions of the present invention may be readily determined by techniques known to those of skill in the art or as taught herein.

In certain embodiments, the dosage of the subject compounds will generally be in the range of about 0. An effective dose or amount, and any possible affects on the timing of administration of the formulation, may need to be identified for any particular composition of the present invention. This may be accomplished by routine experiment as described herein, using one or more groups of animals preferably at least 5 animals per group , or in human trials if appropriate.

The effectiveness of any subject composition and method of treatment or prevention may be assessed by administering the composition and assessing the effect of the administration by measuring one or more applicable indices, and comparing the post-treatment values of these indices to the values of the same indices prior to treatment. The precise time of administration and amount of any particular subject composition that will yield the most effective treatment in a given patient will depend upon the activity, pharmacokinetics, and bioavailability of a subject composition, physiological condition of the patient including age, sex, disease type and stage, general physical condition, responsiveness to a given dosage and type of medication , route of administration, and the like.

The guidelines presented herein may be used to optimize the treatment, e. While the subject is being treated, the health of the patient may be monitored by measuring one or more of the relevant indices at predetermined times during the treatment period. Treatment, including composition, amounts, times of administration and formulation, may be optimized according to the results of such monitoring.

The patient may be periodically reevaluated to determine the extent of improvement by measuring the same parameters. Adjustments to the amount s of subject composition administered and possibly to the time of administration may be made based on these reevaluations.

Treatment may be initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage may be increased by small increments until the optimum therapeutic effect is attained.

The use of the subject compositions may reduce the required dosage for any individual agent contained in the compositions e. Toxicity and therapeutic efficacy of subject compositions may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e. The data obtained from the cell culture assays and animal studies may be used in formulating a range of dosage for use in humans.

The dosage of any subject composition lies preferably within a range of circulating concentrations that include the ED 50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For compositions of the present invention, the therapeutically effective dose may be estimated initially from cell culture assays.

In general, the doses of an active agent will be chosen by a physician based on the age, physical condition, weight and other factors known in the medical arts. The efficacy of treatment with the subject compositions may be determined in a number of fashions known to those of skill in the art. In one exemplary method, the median rate of decrease in inflammation for treatment with a subject composition may be compared to other forms of treatment with the particular cardiovascular agent contained in the subject composition, or with other cardiovascular agents.

The period of time for observing any such decrease may be about 1, 3, 5, 10, 15, 30, 60 or 90 or more hours. The comparison may be made against treatment with the particular cardiovascular agent contained in the subject composition, or with other cardiovascular agents, or administration of the same or different agents by a different method, or administration as part of a different drug delivery device than a subject composition.

The comparison may be made against the same or a different effective dosage of the various agents. Alternatively, a comparison of the different treatment regimens described above may be based on the effectiveness of the treatment, using standard indices known to those of skill in the art.

Alternatively, the different treatment regimens may be analyzed by comparing the therapeutic index for each of them, with treatment with a subject composition as compared to another regimen having a therapeutic index two, three, five or seven times that of, or even one, two, three or more orders of magnitude greater than, treatment with another method using the same or different cardiovascular agents. This invention also provides kits for conveniently and effectively implementing the methods of this invention.

Most of the currently available calcium channel blockers, and useful according to the present invention, belong to one of three major chemical groups of drugs, the dihydropyridines, such as nifedipine, the phenyl alkyl amines, such as verapamil, and the benzothiazepines, such as diltiazem.

Non-limiting examples of calcium channel blockers that may be used in the compositions of the present invention include bepridil, clentiazem, diltiazem, fendiline, gallopamil, mibefradil, prenylamine, semotiadil, terodiline, verapamil, amlodipine, aranidipine, barnidipine, benidipine, cilnidipine, efonidipine, elgodipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, cinnarizine, flunarizine, lidoflazine, lomerizine, bencyclane, etafenone, fantofarone, perhexiline, and mixtures thereof.

A non-limiting example of a CETP inhibitor that may be used in the compositions of the present invention includes torcetrapib. Non-limiting examples of COX-2 inhibitors that may be used in the compositions of the present invention include compounds according to the following: Celecoxib is discussed as SC in the same reference, and in T.

Penning, Synthesis and biological evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors: The meaning of COX-2 inhibitor in this invention also includes SC referred to as a fluorescent diaryloxazole. May ; 19 3: The meaning of COX-2 inhibitor in this invention also includes the substitution of the sulfonamide moiety as a suitable replacement for the methylsulfonyl moiety. Carter et al, Synthesis and activity of sulfonamide-substituted 4,5-diaryl thiazoles as selective cyclooxygenase-2 inhibitors.

The second substituent should have an electronegativity within such substituent greater than 0. Thus for purposes of this last included meaning of a COX-2 inhibitor, one portion of the COX-2 inhibitor should be hydrophilic and the other portion lipophilic.

Also included as a COX-2 inhibitor are compounds listed at page in Pharmacotherapy: The inventors add to the class of COX-2 inhibitors useful in the invention the drug bearing the name etoricoxib referenced in the Wall Street Journal, Dec. See, also, Chauret et al. The inventors also include as a selective COX-2 inhibitor the flavonoid antioxidant silymarin, and an active ingredient in silymarin, silybinin, which demonstrated significant COX-2 inhibition relative to COX-1 inhibition.

The silymarin also showed protection against depletion of glutathione peroxidase. December , Vol 26 4: Silymarin has been used to treat liver diseases in Europe. A number of the above-identified COX-2 inhibitors are prodrugs of selective COX-2 inhibitors, and exert their action by conversion in vivo to the active and selective COX-2 inhibitors. Given the teachings of U. Non limiting examples of direct thrombin inhibitors include hirudin, hirugen, Hirulog, argatroban, PPACK, and thrombin aptamers.

Depending on the diuretic employed, potassium may also be administered to the patient in order to optimize the fluid balance while avoiding hypokalemic alkalosis. The administration of potassium can be in the form of potassium chloride or by the daily ingestion of foods with high potassium content such as, for example, bananas or orange juice. Non-limiting examples of an endothelin receptor antagonist that may be used in the compositions of the present invention include bosentan, sulfonamide endothelin antagonists, BQ, SQ , and the like ; and mixtures thereof.

A number of HMG-CoA reductase inhibitors have been used to treat individuals with hypercholesterolemia. HMG-CoA reductase inhibitors useful for co-administration with the agents of the invention include, but are not limited to, simvastatin U.

Other non-limiting examples of HMG-CoA reductase inhibitors that may be used in the compositions of the present invention include mevastatin, pitavastatin, rosuvastatin, gemcabene, and probucol. Non-limiting examples of inotropic agents that may be used in the compositions of the present invention include acefylline, acetyldigitoxins, 2-aminopicoline, anrinone, benfurodil hemisuccinate, bucladesine, camphotamide, convallatoxin, cymarin, denopamine, deslanoside, digitalin, digitalis, digitoxin, digoxin, dobutamine, docarpamine, dopamine, dopexamine, enoximone, erythrophleine, fenalsomine, gitalin, gitoxin, glycocyamine, heptaminol, hydrastinine, ibopamine, lanatosides, loprinine, milrinone, nerifolin, oleandrin, ouabain, oxyfedrine, pimobendan, prenalterol, proscillaridin, resibufogenin, scillaren, scillarenin, strophanthin, sulmazole, theobromine, vesnarinone, xamoterol, and mixtures thereof.

Renin inhibitors are compounds which interfere with the activity of renin. Renin inhibitors include amino acids and derivatives thereof, peptides and derivatives thereof, and antibodies to renin. Examples of renin inhibitors that are the subject of United States patents are as follows: Examples of hydralazine compounds include, but are not limited to budralazine, cadralazine, dihydralazine, endralazine, hydralazine, pildralazine, todralazine and the like.

Non-limiting examples of vasopressors that may be used in the compositions of the present invention include amezinium methyl sulfate, angiotensin amide, dimetofrine, dopamine, etifelmin, etilefrin, gepefrine, metaraminol, methoxamine, midodrine, norepinephrine, pholedrine, synephrine, and mixtures thereof. Non-limiting examples of AGE crosslink breakers that may be used in the compositions of the present invention include Alagebrium. Non-limiting examples of AGE formation inhibitors that may be used in the compositions of the present invention include Pimagedine.

Non-limiting examples of other active ingredients that may be combined with these nebivolol compositions include, but are not limited to, the following representative classes of compounds, as well as their pharmaceutically acceptable salts, isomers, esters, ethers and other derivatives:. Analgesics and anti-inflammatory agents, such as aloxiprin, auranofin, azapropazone, benorylate, capsaicin, celecoxib, diclofenac, diflunisal, etodolac, fenbufen, fenoprofen calcium, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, leflunomide, meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxaprozin, oxyphenbutazone, phenylbutazone, piroxicam, rofecoxib, sulindac, tetrahydrocannabinol, tramadol and tromethamine;.

Flavonoids and Isoflavonoids include the anthocyanidins and anthocyanins; proanthocyanidins; flavanols; flavonols; flavones; flavanones; isoflavanones; salts and esters thereof. This development is however, not limited to flavonoid compounds isolated from plant, part of plant or extracts of Astragalus Membranaceus , but encompasses any suitable flavonoid compound isolated from different sources or chemically synthesized.

In addition, any suitable known or not yet discovered flavonoid compound, and isoflavonoid compound, is within the scope of the present technology. Two molecules of the C 20 compound geranylgeranyldiphosphate GGDP condense to form the symmetrical carotenoid skeleton. Carotenoids are divided into two subclasses, i.

Terms such as carotenoid analog and carotenoid derivative may generally refer to in some embodiments chemical compounds or compositions derived from a naturally occurring carotenoid or simply to synthetic carotenoids.

In some embodiments, terms such as carotenoid analog and carotenoid derivative may generally refer to chemical compounds or compositions which are synthetically derived from non-carotenoid based parent compounds; however, which ultimately substantially resemble a carotenoid derived analog. In certain embodiments, terms such as carotenoid analog and carotenoid derivative may generally refer to a synthetic derivative of a naturally occurring carotenoid. Britton et al, , which is herein incorporated by reference.

It will be evident to any skilled person how to choose the suitable carotenoid compound for the purpose of the present development. Examples of carotenoids include astaxanthin, zeaxanthin, lutein, lycopene, beta-carotene.

Other non-limiting examples of naturally occurring carotenoids include: Corynebacterium poinsettiae ; Corynexanthin; Corynexanthin glucoside; C. Karpoxanthin; Keto-, see also oxo or -one Ketocapsanthin; 4-Ketocapsanthin; 4-Keto-alpha-carotene; 4-Keto-beta-carotene; 4-Keto-gamma-carotene; 4-Ketocynthiaxanthin: The above list of naturally occurring carotenoids is meant to be a non-limiting example of naturally occurring carotenoids.

This list is not comprehensive as more naturally occurring molecules are being discovered which will fall within the category of carotenoids. Non-limiting examples of sulfonylureas include, but are not limited to acetohexamide, DiaBeta, glibenclamide, gliclazide, glipizide Glucotrol , glyclopyramide, chlorpropamide, tolazamide, tolbutamide, glimepiride Amaryl , tolbutamide and meglitinide analogues for example, repaglinide, nateglinide, meglitinide and mitiglinide KAD and the like.

The term niacin is the generic descriptor for nicotinic acid pyridinecarboxylic acid and its derivatives. Non-limiting examples of nicotinic acid derivatives include nicofuranose, Acipimox 5-methyl pyrazinecarboxylic acid 4-oxide , niceritrol, probucol, isonicotinic acid, Cholexamin, oxiniacic acid, nicoclonate, nicomol, NIASPAN, nicerikol and tocopherol nicotinate. Further examples of other active agents which may be suitable for this invention include, without limitation: The nebivolol compositions of the present invention may be administered by various means, depending on their intended use, as is well known in the art.

For example, if compositions of the present invention are to be administered orally, they may be formulated as tablets, capsules, granules, powders, suspensions or syrups. Alternatively, formulations of the present invention may be administered parenterally as injections intravenous, intramuscular or subcutaneous , drop infusion preparations or suppositories.

For application by the ophthalmic mucous membrane route, compositions of the present invention may be formulated as eyedrops or eye ointments. These formulations may be prepared by conventional means, and, if desired, the compositions may be mixed with any conventional additive, such as an excipient, a binder, a disintegrating agent, a lubricant, a corrigent, a solubilizing agent, a suspension aid, an emulsifying agent or a coating agent.

In formulations of the subject invention, wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants may be present in the formulated agents.

The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of composition that may be combined with a carrier material to produce a single dose vary depending upon the subject being treated, and the particular mode of administration. Methods of preparing these formulations include the step of bringing into association compositions of the present invention with the carrier and, optionally, one or more accessory ingredients.

In general, the formulations are prepared by uniformly and intimately bringing into association agents with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product. Formulations suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges using a flavored basis, usually sucrose and acacia or tragacanth , powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles using an inert base, such as gelatin and glycerin, or sucrose and acacia , each containing a predetermined amount of a subject composition thereof as an active ingredient.

Compositions of the present invention may also be administered as a bolus, electuary, or paste. In the case of capsules, tablets and pills, the compositions may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder for example, gelatin or hydroxypropyl methyl cellulose , lubricant, inert diluent, preservative, disintegrant for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose , surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsion, solutions, suspensions, syrups and elixirs. In addition to the subject composition, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils , glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty.

Suspensions, in addition to the subject composition, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof. Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.

Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate. Dosage forms for transdermal administration of a subject composition includes powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active component may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.

The ointments, pastes, creams and gels may contain, in addition to a subject composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.

Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane. Compositions of the present invention may alternatively be administered by aerosol.

This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound s. Sonic nebulizers may be used because they minimize exposing the agent to shear, which may result in degradation of the compounds contained in the subject compositions. Ordinarily, an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers.

The carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants Tweens, Pluronics, or polyethylene glycol , innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols.

Aerosols generally are prepared from isotonic solutions. Pharmaceutical compositions of this invention suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

Examples of suitable aqueous and non-aqueous carriers which may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols such as glycerol, propylene glycol, polyethylene glycol, and the like , and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.

Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

Pharmaceutical formulations may also be extended or delayed release formulations where the active agents are released over an extended period of time. Administration of the compositions of the present invention will be in an amount sufficient to achieve a therapeutic effect as recognized by one of ordinary skill in the art. The dosage of any compositions of the present invention will vary depending on the symptoms, age and body weight of the patient, the nature and severity of the disorder to be treated or prevented, the route of administration, and the form of the subject composition.

Any of the subject formulations may be administered in a single dose or in divided doses. Dosages for the compositions of the present invention may be readily determined by techniques known to those of skill in the art or as taught herein.

The dosage range for nebivolol ranges from about 0. In another embodiment, the dosage range may be from about 0. In yet another embodiment, the dosage range may be from about 1. In certain embodiments, the dosage of the co-active compounds will generally be in the range of about 0. An effective dose or amount, and any possible affects on the timing of administration of the formulation, may need to be identified for any particular composition of the present invention. This may be accomplished by routine experiment as described herein, using one or more groups of animals preferably at least 5 animals per group , or in human trials if appropriate.

The effectiveness of any subject composition and method of treatment or prevention may be assessed by administering the composition and assessing the effect of the administration by measuring one or more applicable indices, and comparing the post-treatment values of these indices to the values of the same indices prior to treatment.

The precise time of administration and amount of any particular subject composition that will yield the most effective treatment in a given patient will depend upon the activity, pharmacokinetics, and bioavailability of a subject composition, physiological condition of the patient including age, sex, disease type and stage, general physical condition, responsiveness to a given dosage and type of medication , route of administration, and the like.

The guidelines presented herein may be used to optimize the treatment, e. While the subject is being treated, the health of the patient may be monitored by measuring one or more of the relevant indices at predetermined times during the treatment period.

Treatment, including composition, amounts, times of administration and formulation, may be optimized according to the results of such monitoring.

The patient may be periodically reevaluated to determine the extent of improvement by measuring the same parameters. Adjustments to the amount s of subject composition administered and possibly to the time of administration may be made based on these reevaluations. Treatment may be initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage may be increased by small increments until the optimum therapeutic effect is attained.

The use of the subject compositions may reduce the required dosage for any individual agent contained in the compositions e. Toxicity and therapeutic efficacy of subject compositions may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e. The data obtained from the cell culture assays and animal studies may be used in formulating a range of dosage for use in humans.

The dosage of any subject composition lies preferably within a range of circulating concentrations that include the ED 50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For compositions of the present invention, the therapeutically effective dose may be estimated initially from cell culture assays.

In general, the doses of an active agent will be chosen by a physician based on the age, physical condition, weight and other factors known in the medical arts. The efficacy of treatment with the subject compositions may be determined in a number of fashions known to those of skill in the art. In one exemplary method, the median rate of decrease in inflammation for treatment with a subject composition may be compared to other forms of treatment with the particular cardiovascular agent contained in the subject composition, or with other cardiovascular agents.

The period of time for observing any such decrease may be about 1, 3, 5, 10, 15, 30, 60 or 90 or more hours. The comparison may be made against treatment with the particular cardiovascular agent contained in the subject composition, or with other cardiovascular agents, or administration of the same or different agents by a different method, or administration as part of a different drug delivery device than a subject composition.

The comparison may be made against the same or a different effective dosage of the various agents. Alternatively, a comparison of the different treatment regimens described above may be based on the effectiveness of the treatment, using standard indices known to those of skill in the art.

Alternatively, the different treatment regimens may be analyzed by comparing the therapeutic index for each of them, with treatment with a subject composition as compared to another regimen having a therapeutic index two, three, five or seven times that of, or even one, two, three or more orders of magnitude greater than, treatment with another method using the same or different cardiovascular agents. This invention also provides kits for conveniently and effectively implementing the methods of this invention.

Such kits comprise any subject composition, and a means for facilitating compliance with methods of this invention. Such kits provide a convenient and effective means for assuring that the subject to be treated takes the appropriate active in the correct dosage in the correct manner. The compliance means of such kits includes any means which facilitates administering the actives according to a method of this invention.

Such compliance means include instructions, packaging, and dispensing means, and combinations thereof. Kit components may be packaged for either manual or partially or wholly automated practice of the foregoing methods.

In other embodiments involving kits, this invention contemplates a kit including compositions of the present invention, and optionally instructions for their use.

All measurements presented were recorded in vitro using a sensitive porphyrinic probe, as previously described.

Malinski T, Taha Z. Nebivolol was obtained from Mylan Laboratories Morgantown, W. Cell wells were transferred to a Faraday cage and a porphyrinic sensor diameter 0. The sensor operated with a three-electrode system: The baseline was stabilized after about 20 seconds. The test compounds were injected with a nanoinjector onto the surface of the cells following solubilization in buffer. Cells were incubated with the test compounds for a hour period. The compounds were then washed out of the system before being immediately reintroduced in order to evaluate the consequences of chronic treatment on NO release from the cells.

For additive experiments, cells were incubated with ACE inhibitor for 24 hours, the inhibitor was washed out of the system, nebivolol was added and the NO release measured. The current proportional to the NO concentration was measured with the sensor, which operated in amperometric mode at a constant potential of 0. Data were acquired with the use of an IBM computer with custom software and amperograms current vs. By increasing cytoplasmic levels of calcium, the ion can bind to calmodulin.

Nanosensors were prepared from carbon fibers. The sensors were sensitized to NO by deposition of electrically conductive polymeric porphyrin and covered with a thin layer of Nafion. The porphyrinic microsensor has a response time of 0. The nanosensor for NO was calibrated using saturated solution concentration 1. The concentration-dependent effects of nebivolol and certain ACE-inhibitors on NO releasing capacity were tested using a calcium ionophore A that stimulates NO release, independently of G-protein-coupled receptors.

Measurement of NO release as a function of treatment was conducted in individual endothelial cells. Multiple measurements of NO release can be conducted on single cells following a brief refractory period. For robust statistical analysis, separate cells were used for each concentration and type of drug used in these analyses.

The magnitude of the increase is greater in endothelial cells from Black donors. There were significant concentration dependent effects on the ability of nebivolol to enhance NO release from Black and White donor endothelial cells that had been chronically treated with ACE inhibitors. By promoting a more normal vascular physiology through an NO-dependent pathway, nebivolol treatment may have better efficacy and fewer side effects as compared to agents that only inhibit the sympathetic nervous system.

These data further support the hypothesis that nebivolol may have distinct pharmacologic benefits through modulation of endothelial function and NO metabolism. All of the patents and publications cited herein are hereby incorporated by reference. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein.

Nebivolol has been shown to be beneficial in the treatment of cardiovascular diseases such hypertension, congestive heart failure, arterial stiffness and endothelial dysfunction. The present invention features a pharmaceutical composition comprising nebivolol and at least one other active agent, wherein Compositions comprising nebivolol US B2.

The present invention features a pharmaceutical composition comprising nebivolol and at least one other active agent, wherein the at least one other active agent is a cardiovascular agent.

A method of treating hypertension comprising administering to a subject in need thereof a composition comprising between about 0. A method of treating a hypertension comprising administering to a subject in need thereof a composition comprising between about 0. The method of claim 1 wherein the cardiovascular active agent is olmesartan or a pharmaceutically acceptable salt thereof. The method of claim 1 wherein the cardiovascular active agent is valsartan or a pharmaceutically acceptable salt thereof.

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The dosage of any subject composition lies preferably within a range of circulating concentrations that include the ED 50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.

For compositions of the present invention, the therapeutically effective dose may be estimated initially from cell culture assays. In general, the doses of an active agent will be chosen by a physician based on the age, physical condition, weight and other factors known in the medical arts. The efficacy of treatment with the subject compositions may be determined in a number of fashions known to those of skill in the art.

In one exemplary method, the median rate of decrease in inflammation for treatment with a subject composition may be compared to other forms of treatment with the particular cardiovascular agent contained in the subject composition, or with other cardiovascular agents. The period of time for observing any such decrease may be about 1, 3, 5, 10, 15, 30, 60 or 90 or more hours.

The comparison may be made against treatment with the particular cardiovascular agent contained in the subject composition, or with other cardiovascular agents, or administration of the same or different agents by a different method, or administration as part of a different drug delivery device than a subject composition.

The comparison may be made against the same or a different effective dosage of the various agents. Alternatively, a comparison of the different treatment regimens described above may be based on the effectiveness of the treatment, using standard indices known to those of skill in the art. Alternatively, the different treatment regimens may be analyzed by comparing the therapeutic index for each of them, with treatment with a subject composition as compared to another regimen having a therapeutic index two, three, five or seven times that of, or even one, two, three or more orders of magnitude greater than, treatment with another method using the same or different cardiovascular agents.

This invention also provides kits for conveniently and effectively implementing the methods of this invention. Such kits comprise any subject composition, and a means for facilitating compliance with methods of this invention. Such kits provide a convenient and effective means for assuring that the subject to be treated takes the appropriate active in the correct dosage in the correct manner.

The compliance means of such kits includes any means which facilitates administering the actives according to a method of this invention. Such compliance means include instructions, packaging, and dispensing means, and combinations thereof. Kit components may be packaged for either manual or partially or wholly automated practice of the foregoing methods. In other embodiments involving kits, this invention contemplates a kit including compositions of the present invention, and optionally instructions for their use.

All measurements presented were recorded in vitro using a sensitive porphyrinic probe, as previously described. Malinski T, Taha Z. Nebivolol was obtained from Mylan Laboratories Morgantown, W. Cell wells were transferred to a Faraday cage and a porphyrinic sensor diameter 0. The sensor operated with a three-electrode system: The baseline was stabilized after about 20 seconds. The test compounds were injected with a nanoinjector onto the surface of the cells following solubilization in buffer.

Cells were incubated with the test compounds for a hour period. The compounds were then washed out of the system before being immediately reintroduced in order to evaluate the consequences of chronic treatment on NO release from the cells. For additive experiments, cells were incubated with ACE inhibitor for 24 hours, the inhibitor was washed out of the system, nebivolol was added and the NO release measured.

The current proportional to the NO concentration was measured with the sensor, which operated in amperometric mode at a constant potential of 0. Data were acquired with the use of an IBM computer with custom software and amperograms current vs. By increasing cytoplasmic levels of calcium, the ion can bind to calmodulin. Nanosensors were prepared from carbon fibers. The sensors were sensitized to NO by deposition of electrically conductive polymeric porphyrin and covered with a thin layer of Nafion.

The porphyrinic microsensor has a response time of 0. The nanosensor for NO was calibrated using saturated solution concentration 1. The concentration-dependent effects of nebivolol and certain ACE-inhibitors on NO releasing capacity were tested using a calcium ionophore A that stimulates NO release, independently of G-protein-coupled receptors.

Measurement of NO release as a function of treatment was conducted in individual endothelial cells. Multiple measurements of NO release can be conducted on single cells following a brief refractory period.

For robust statistical analysis, separate cells were used for each concentration and type of drug used in these analyses. The magnitude of the increase is greater in endothelial cells from Black donors. There were significant concentration dependent effects on the ability of nebivolol to enhance NO release from Black and White donor endothelial cells that had been chronically treated with ACE inhibitors.

By promoting a more normal vascular physiology through an NO-dependent pathway, nebivolol treatment may have better efficacy and fewer side effects as compared to agents that only inhibit the sympathetic nervous system. These data further support the hypothesis that nebivolol may have distinct pharmacologic benefits through modulation of endothelial function and NO metabolism. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein.

A SumoBrain Solutions Company. Search Expert Search Quick Search. United States Patent Nebivolol has been shown to be beneficial in the treatment of cardiovascular diseases such hypertension, congestive heart failure, arterial stiffness and endothelial dysfunction. The present invention features a pharmaceutical composition comprising nebivolol and at least one other active agent, wherein the at least one other active agent is a cardiovascular agent.

Click for automatic bibliography generation. Nebivolol; Drugs of the Future, vol. Lacourciere, Yves, et al. Biology and Chemistry Abstracts; vol. Tzemos, Nikolaos, et al. European Search Report dated Jul. EP 08 00 Clin Pharmacol ; 43; pp. De Cree, et al. Hypertension 12 Suppl 3 p. Lacourciere, Yves, et aI.

Van Der Loo, et al. A comparison of [3H]CGP Izzo, Joseph et al. Van De Water, et al. Evdokimova, AG et al. De Groot, et al. Waring, W S, et al. Therapeutic Strategies, Elsevier, vol. This application is based on and claims priority from U. Provisional Patent Application Ser. What is claimed is: A composition comprising between about 0.

The composition of claim 1 wherein the ARB is olmesartan or a pharmaceutically acceptable salt thereof. The composition of claim 1 wherein the ARB is losartan or a pharmaceutically acceptable salt thereof. The composition of claim 1 wherein the ARB is valsartan or a pharmaceutically acceptable salt thereof.

The composition of claim 5 wherein the ARB is olmesartan or a pharmaceutically acceptable salt thereof. The composition of claim 5 wherein the ARB is losartan or a pharmaceutically acceptable salt thereof. The composition of claim 5 wherein the ARB is valsartan or a pharmaceutically acceptable salt thereof. The composition of claim 9 wherein the ARB is olmesartan or a pharmaceutically acceptable salt thereof. The composition of claim 9 wherein the ARB is losartan or a pharmaceutically acceptable salt thereof.

The composition of claim 9 wherein the ARB is valsartan or a pharmaceutically acceptable salt thereof. Compositions Comprising Nebivolol In part, the present invention features compositions comprising nebivolol and at least one other active agent, wherein the at least one other active agent is a cardiovascular agent.

Cardiovascular agents falling within these general categories are exemplified by the following: Agents for Pheochromocytoma Include but are not limited to chemotherapeutics. Antiangina Agents Include but are not limited to amlodipine besylate, amlodipine maleate, betaxolol hydrochloride, bevantolol hydrochloride, butoprozine hydrochloride, carvedilol, cinepazet maleate, metoprolol succinate, molsidomine, monatepil maleate, nitrates including but not limited to glyceryl trinitrate GTN, nitroglycerin, Nitro-Bid , isosorbide dinitrate ISDN, Isordil , isosorbidemononitrate 5-ISMN, Ismo , amyl nitrate and nicorandil Icorel , primidolol, ranolazine hydrochoride, tosifen, verapamil hydrochloride.

Antiarrhythmics Non-limiting examples of antiarrhythmics that may be used in the compositions of the present invention include acebutolol, acecainide, adenosine, ajmaline, alprenolol, amiodarone, amoproxan, aprindine, aprotinolol, atenolol, azimilide, bevantolol, bidisomide, bretylium tosylate, bucumolol, butetolol, bunaftine, bunitrolol, bupranolol, butidrine hydrochloride, butobendine, capobenic acid, carazolol, carteolol, cifenline, cloranolol, disopyramide, dofetilide, encainide, esmolol, flecainide, hydroquinidine, ibutilide, indecainide, indenolol, ipratropium bromide, lidocaine, lorajmine, lorcainide, meobentine, mexiletine, moricizine, nadoxolol, nifenaolol, oxprenolol, penbutolol, pentisomide, pilsicainide, pindolol, pirmenol, practolol, prajmaline, procainamide hydrochloride, pronethalol, propafenone, propranolol, pyrinoline, quinidine, sematilide, sotalol, talinolol, tilisolol, timolol, tocainide, verapamil, viquidil, xibenolol, and mixtures thereof.

Antiplatelet Agents Non-limiting examples of antiplatelet agents that may be used in the compositions of the present invention include clopidogrel, dipyridamole, abcixamab, and ticlodipine.

Antihypertensives Non-limiting examples of antihypertensives that may be used in the compositions of the present invention include amlodipine, benidipine, benezepril, candesartan, captopril, darodipine, dilitazem HCl, diazoxide, doxazosin HCl, enalapril, eposartan, losartan mesylate, felodipine, fenoldopam, fosenopril, guanabenz acetate, irbesartan, isradipine, lisinopril, mecamylamine, minoxidil, nicardipine HCl, nifedipine, nimodipine, nisoldipine, phenoxybenzamine HCl, prazosin HCl, quinapril, reserpine, terazosin HCl, telmisartan, and valsartan.

Calcium Channel Blockers Calcium channel blockers are a chemically diverse class of compounds having important therapeutic value in the control of a variety of diseases including several cardiovascular disorders, such as hypertension, angina, and cardiac arrhythmias Fleckenstein, Cir.

COX-2 Inhibitors Non-limiting examples of COX-2 inhibitors that may be used in the compositions of the present invention include compounds according to the following: Endothelin Receptor Antagonists A non-limiting example of an endothelin receptor antagonist that may be used in the compositions of the present invention is bosentan.

Inotropic Agents Non-limiting examples of inotropic agents that may be used in the compositions of the present invention include acefylline, acetyldigitoxins, 2-aminopicoline, amrinone, benfurodil hemisuccinate, bucladesine, camphotamide, convallatoxin, cymarin, denopamine, deslanoside, digitalin, digitalis, digitoxin, digoxin, dobutamine, docarpamine, dopamine, dopexamine, enoximone, erythrophleine, fenalsomine, gitalin, gitoxin, glycocyamine, heptaminol, hydrastinine, ibopamine, lanatosides, loprinine, milrinone, nerifolin, oleandrin, ouabain, oxyfedrine, pimobendan, prenalterol, proscillaridin, resibufogenin, scillaren, scillarenin, strophanthin, sulmazole, theobromine, vesnarinone, xamoterol, and mixtures thereof.

Vasopressors Non-limiting examples of vasopressors that may be used in the compositions of the present invention include amezinium methyl sulfate, angiotensin amide, dimetofrine, dopamine, etifelmin, etilefrin, gepefrine, metaraminol, methoxamine, midodrine, norepinephrine, pholedrine, synephrine, and mixtures thereof. Non-limiting examples of other active ingredients that may be combined with these nebivolol compositions include, but are not limited to, the following representative classes of compounds, as well as their pharmaceutically acceptable salts, isomers, esters, ethers and other derivatives: Formulation The nebivolol compositions of the present invention may be administered by various means, depending on their intended use, as is well known in the art.

Dosages Administration of the compositions of the present invention will be in an amount sufficient to achieve a therapeutic effect as recognized by one of ordinary skill in the art.

Efficacy of Treatment The efficacy of treatment with the subject compositions may be determined in a number of fashions known to those of skill in the art. Kits This invention also provides kits for conveniently and effectively implementing the methods of this invention.

Combination therapy for the treatment of dyslipidemia. Combinations of hormone replacement therapy composition s and sterol absorption inhibitor s and treatments for vascular conditions in post-menopausal women.

Combinations and methods for headaches. Glucopyranosyloxypyrazole derivatives and medicinal use thereof. Solid dosage form comprising a fibrate. Melanin-concentrating hormone receptor antagonists containing piperidine derivatives as the active ingredient. Pharmaceutical use of fused 1,2,4-triazoles. Pharmaceutical use of substituted 1,2,4-triazoles.

Combination therapy using an 11beta-hydroxysteroid dehydrogenase type 1 inhibitor and a glucocorticoid receptor agonist to minimize the side effects associated with glucocorticoid receptor agonist therapy. Pharmaceutical use of substituted amides.

Combination therapy using an 11beta-hydroxysteroid dehydrogenase type 1 inhibitor and an antihypertensive agent for the treatment of metabolic syndrome and related diseases and disorders.

Sterol absorption inhibitor compositions. Combinations of substituted azetidinones and CB1 antagonists. Glucopyranosyloxypyrazole derivatives and use thereof in medicines. Compositions and methods using proton pump inhibitors. Methods for reducing hospitalizations related to heart failure. Compositions and methods related to heart failure. Nebivolol and its metabolites in combination with nitric oxide donors, compositions and methods of use.

Methods and therapeutic combinations for the treatment of obesity using sterol absorption inhibitors. Pyrazole derivatives, medicinal composition containing the same, medicinal use thereof, and intermediate for production thereof.

Diphenylazetidinone derivatives for treating disorders of the lipid metabolism. Antagonists to melanin-concentrating hormone receptor comprising benzimidazole derivative as active ingredient. Epoxy-steroidal aldosterone antagonist and beta-adrenergic antagonist combination therapy for treatment of congestive heart failure. As-needed administration of tricyclic and other non-SRI antidepressant drugs to treat premature ejaculation. Methods for inhibiting sterol absorption.

Combinations of lipid modulating agents and substituted azetidinones and treatments for vascular conditions. Transdermal and topical administration of drugs using basic permeation enhancers.

Formulations and use of a beta-blocker and an ACE-inhibitor for the treatment of cardiovascular diseases. Method for treating fibrotic diseases or other indications utilizing thiazole, oxazole and imidazole compounds. Therapeutic formulations for the treatment of beta-amyloid related diseases. Dihydrothiazine prodrugs of thiazolium agents.

Method for treating fibrotic diseases or other indications IE. Epoxy steroidal aldosterone antagonist and beta-adremergic antagonist combination therepy for treatment of congestive heart failure.

Methods and therapeutic combinations for the treatment of diabetes using sterol absorption inhibitors. Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof. Coating precursor and method for coating a substrate with a refractory layer.

Novel method of treatment. Glucopyranosyloxypyrazole derivative medicinal composition containing the same medicinal use thereof and intermediate therefor. Methods using hydralazine compounds and isosorbide dinitrate or isosorbide mononitrate. Nitrosated and nitrosylated nebivolol and its metabolites, compositions and methods of use. PH triggered targeted controlled release systems for the delivery of pharmaceutical active ingredients. Methods of treating vascular diseases characterized by nitric oxide insufficiency.

Method for treating fibrotic diseases or other indications IIIC. Combinations of nicotinic acid and derivatives thereof and sterol absorption inhibitor s and treatments for vascular indications.

Solid dispersions of nitrate active principles. Methods of treating and preventing congestive heart failure with hydralazine compounds and isosorbide dinitrate or isosorbide mononitrate. Method for evaluating and treating hypertension. Method for treating fibrotic diseases or other indications with imidazolium agents.

Formulation for the prevention of cardiovascular disease. Methods of treating or preventing a cardiovascular condition using a cyclooxygenase-1 inhibitor. Method for treating fibrotic diseases with azolium chroman compounds. Method for treating fibrotic diseases or other indications IIC. Methods and therapeutic combinations for the treatment of xanthoma using sterol absorption inhibitors. Methods of treating or preventing cardiovascular conditions while preventing or minimizing muscular degeneration side effects.

Methods for treating or preventing vascular inflammation using sterol absorption inhibitor s. In vivo delivery methods and compositions. Methods for tissue protection using highly effective inhibition of the renin-angiotensin system. Combinations of sterol absorption inhibitor s with cardiovascular agent s for the treatment of vascular conditions. Method of lowering the blood pressure. Combinations of bile acid sequestrant s and sterol absorption inhibitor s and treatments for vascular indications.

Method for treating fibrotic diseases or other indications V. Method for treating fibrotic diseases or other indications VI. On demand administration of clomipramine and salts thereof to treat premature ejaculation. Method for treating fibrotic diseases or other indications ID. Use of substituted azetidinone compounds for the treatment of sitosterolemia.

Combinations of peroxisome proliferator-activated receptor PPAR activator s and sterol absorption inhibitor s and treatments for vascular indications. Combinations of sterol absorption inhibitor s with blood modifier s for treating vascular conditions. Epoxy steroidal aldosterone antagonist and beta-adrenergic antagonist combination therapy for treatment of congestive heart failure. Method for treating fibrotic diseases or other indications IVC. Method for treating fibrotic diseases or other indications IC.

Administration of active agents, including 5-HT receptor agonists and antagonists, to treat premature ejaculation. Use of nebivolol as an anti-atherogenic. Local administration of pharmacologically active agents to treat premature ejaculation. Given the teachings of U. Non limiting examples of direct thrombin inhibitors include hirudin, hirugen, Hirulog, argatroban, PPACK, and thrombin aptamers. Depending on the diuretic employed, potassium may also be administered to the patient in order to optimize the fluid balance while avoiding hypokalemic alkalosis.

The administration of potassium can be in the form of potassium chloride or by the daily ingestion of foods with high potassium content such as, for example, bananas or orange juice.

Non-limiting examples of an endothelin receptor antagonist that may be used in the compositions of the present invention include bosentan, sulfonamide endothelin antagonists, BQ, SQ , and the like ; and mixtures thereof.

A number of HMG-CoA reductase inhibitors have been used to treat individuals with hypercholesterolemia. HMG-CoA reductase inhibitors useful for co-administration with the agents of the invention include, but are not limited to, simvastatin U.

Other non-limiting examples of HMG-CoA reductase inhibitors that may be used in the compositions of the present invention include mevastatin, pitavastatin, rosuvastatin, gemcabene, and probucol. Non-limiting examples of inotropic agents that may be used in the compositions of the present invention include acefylline, acetyldigitoxins, 2-aminopicoline, anrinone, benfurodil hemisuccinate, bucladesine, camphotamide, convallatoxin, cymarin, denopamine, deslanoside, digitalin, digitalis, digitoxin, digoxin, dobutamine, docarpamine, dopamine, dopexamine, enoximone, erythrophleine, fenalsomine, gitalin, gitoxin, glycocyamine, heptaminol, hydrastinine, ibopamine, lanatosides, loprinine, milrinone, nerifolin, oleandrin, ouabain, oxyfedrine, pimobendan, prenalterol, proscillaridin, resibufogenin, scillaren, scillarenin, strophanthin, sulmazole, theobromine, vesnarinone, xamoterol, and mixtures thereof.

Renin inhibitors are compounds which interfere with the activity of renin. Renin inhibitors include amino acids and derivatives thereof, peptides and derivatives thereof, and antibodies to renin.

Examples of renin inhibitors that are the subject of United States patents are as follows: Examples of hydralazine compounds include, but are not limited to budralazine, cadralazine, dihydralazine, endralazine, hydralazine, pildralazine, todralazine and the like.

Non-limiting examples of vasopressors that may be used in the compositions of the present invention include amezinium methyl sulfate, angiotensin amide, dimetofrine, dopamine, etifelmin, etilefrin, gepefrine, metaraminol, methoxamine, midodrine, norepinephrine, pholedrine, synephrine, and mixtures thereof.

Non-limiting examples of AGE crosslink breakers that may be used in the compositions of the present invention include Alagebrium. Non-limiting examples of AGE formation inhibitors that may be used in the compositions of the present invention include Pimagedine. Non-limiting examples of other active ingredients that may be combined with these nebivolol compositions include, but are not limited to, the following representative classes of compounds, as well as their pharmaceutically acceptable salts, isomers, esters, ethers and other derivatives:.

Analgesics and anti-inflammatory agents, such as aloxiprin, auranofin, azapropazone, benorylate, capsaicin, celecoxib, diclofenac, diflunisal, etodolac, fenbufen, fenoprofen calcium, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, leflunomide, meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxaprozin, oxyphenbutazone, phenylbutazone, piroxicam, rofecoxib, sulindac, tetrahydrocannabinol, tramadol and tromethamine;.

Flavonoids and Isoflavonoids include the anthocyanidins and anthocyanins; proanthocyanidins; flavanols; flavonols; flavones; flavanones; isoflavanones; salts and esters thereof. This development is however, not limited to flavonoid compounds isolated from plant, part of plant or extracts of Astragalus Membranaceus , but encompasses any suitable flavonoid compound isolated from different sources or chemically synthesized.

In addition, any suitable known or not yet discovered flavonoid compound, and isoflavonoid compound, is within the scope of the present technology. Two molecules of the C 20 compound geranylgeranyldiphosphate GGDP condense to form the symmetrical carotenoid skeleton. Carotenoids are divided into two subclasses, i. Terms such as carotenoid analog and carotenoid derivative may generally refer to in some embodiments chemical compounds or compositions derived from a naturally occurring carotenoid or simply to synthetic carotenoids.

In some embodiments, terms such as carotenoid analog and carotenoid derivative may generally refer to chemical compounds or compositions which are synthetically derived from non-carotenoid based parent compounds; however, which ultimately substantially resemble a carotenoid derived analog.

In certain embodiments, terms such as carotenoid analog and carotenoid derivative may generally refer to a synthetic derivative of a naturally occurring carotenoid. Britton et al, , which is herein incorporated by reference. It will be evident to any skilled person how to choose the suitable carotenoid compound for the purpose of the present development.

Examples of carotenoids include astaxanthin, zeaxanthin, lutein, lycopene, beta-carotene. Other non-limiting examples of naturally occurring carotenoids include: Corynebacterium poinsettiae ; Corynexanthin; Corynexanthin glucoside; C. Karpoxanthin; Keto-, see also oxo or -one Ketocapsanthin; 4-Ketocapsanthin; 4-Keto-alpha-carotene; 4-Keto-beta-carotene; 4-Keto-gamma-carotene; 4-Ketocynthiaxanthin: The above list of naturally occurring carotenoids is meant to be a non-limiting example of naturally occurring carotenoids.

This list is not comprehensive as more naturally occurring molecules are being discovered which will fall within the category of carotenoids. Non-limiting examples of sulfonylureas include, but are not limited to acetohexamide, DiaBeta, glibenclamide, gliclazide, glipizide Glucotrol , glyclopyramide, chlorpropamide, tolazamide, tolbutamide, glimepiride Amaryl , tolbutamide and meglitinide analogues for example, repaglinide, nateglinide, meglitinide and mitiglinide KAD and the like.

The term niacin is the generic descriptor for nicotinic acid pyridinecarboxylic acid and its derivatives. Non-limiting examples of nicotinic acid derivatives include nicofuranose, Acipimox 5-methyl pyrazinecarboxylic acid 4-oxide , niceritrol, probucol, isonicotinic acid, Cholexamin, oxiniacic acid, nicoclonate, nicomol, NIASPAN, nicerikol and tocopherol nicotinate.

Further examples of other active agents which may be suitable for this invention include, without limitation: The nebivolol compositions of the present invention may be administered by various means, depending on their intended use, as is well known in the art. For example, if compositions of the present invention are to be administered orally, they may be formulated as tablets, capsules, granules, powders, suspensions or syrups.

Alternatively, formulations of the present invention may be administered parenterally as injections intravenous, intramuscular or subcutaneous , drop infusion preparations or suppositories. For application by the ophthalmic mucous membrane route, compositions of the present invention may be formulated as eyedrops or eye ointments. These formulations may be prepared by conventional means, and, if desired, the compositions may be mixed with any conventional additive, such as an excipient, a binder, a disintegrating agent, a lubricant, a corrigent, a solubilizing agent, a suspension aid, an emulsifying agent or a coating agent.

In formulations of the subject invention, wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants may be present in the formulated agents.

The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of composition that may be combined with a carrier material to produce a single dose vary depending upon the subject being treated, and the particular mode of administration.

Methods of preparing these formulations include the step of bringing into association compositions of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association agents with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

Formulations suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges using a flavored basis, usually sucrose and acacia or tragacanth , powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles using an inert base, such as gelatin and glycerin, or sucrose and acacia , each containing a predetermined amount of a subject composition thereof as an active ingredient.

Compositions of the present invention may also be administered as a bolus, electuary, or paste. In the case of capsules, tablets and pills, the compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder for example, gelatin or hydroxypropyl methyl cellulose , lubricant, inert diluent, preservative, disintegrant for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose , surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsion, solutions, suspensions, syrups and elixirs. In addition to the subject composition, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils , glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty.

Suspensions, in addition to the subject composition, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof. Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.

Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.

Dosage forms for transdermal administration of a subject composition includes powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active component may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required. The ointments, pastes, creams and gels may contain, in addition to a subject composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane. Compositions of the present invention may alternatively be administered by aerosol.

This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound s. Sonic nebulizers may be used because they minimize exposing the agent to shear, which may result in degradation of the compounds contained in the subject compositions. Ordinarily, an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants Tweens, Pluronics, or polyethylene glycol , innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols.

Aerosols generally are prepared from isotonic solutions. Pharmaceutical compositions of this invention suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

Examples of suitable aqueous and non-aqueous carriers which may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols such as glycerol, propylene glycol, polyethylene glycol, and the like , and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.

Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Pharmaceutical formulations may also be extended or delayed release formulations where the active agents are released over an extended period of time.

Administration of the compositions of the present invention will be in an amount sufficient to achieve a therapeutic effect as recognized by one of ordinary skill in the art. The dosage of any compositions of the present invention will vary depending on the symptoms, age and body weight of the patient, the nature and severity of the disorder to be treated or prevented, the route of administration, and the form of the subject composition.

Any of the subject formulations may be administered in a single dose or in divided doses. Dosages for the compositions of the present invention may be readily determined by techniques known to those of skill in the art or as taught herein.

The dosage range for nebivolol ranges from about 0. In another embodiment, the dosage range may be from about 0. In yet another embodiment, the dosage range may be from about 1. In certain embodiments, the dosage of the co-active compounds will generally be in the range of about 0. An effective dose or amount, and any possible affects on the timing of administration of the formulation, may need to be identified for any particular composition of the present invention. This may be accomplished by routine experiment as described herein, using one or more groups of animals preferably at least 5 animals per group , or in human trials if appropriate.

The effectiveness of any subject composition and method of treatment or prevention may be assessed by administering the composition and assessing the effect of the administration by measuring one or more applicable indices, and comparing the post-treatment values of these indices to the values of the same indices prior to treatment. The precise time of administration and amount of any particular subject composition that will yield the most effective treatment in a given patient will depend upon the activity, pharmacokinetics, and bioavailability of a subject composition, physiological condition of the patient including age, sex, disease type and stage, general physical condition, responsiveness to a given dosage and type of medication , route of administration, and the like.

The guidelines presented herein may be used to optimize the treatment, e. While the subject is being treated, the health of the patient may be monitored by measuring one or more of the relevant indices at predetermined times during the treatment period. Treatment, including composition, amounts, times of administration and formulation, may be optimized according to the results of such monitoring. The patient may be periodically reevaluated to determine the extent of improvement by measuring the same parameters.

Adjustments to the amount s of subject composition administered and possibly to the time of administration may be made based on these reevaluations. Treatment may be initiated with smaller dosages which are less than the optimum dose of the compound.

Thereafter, the dosage may be increased by small increments until the optimum therapeutic effect is attained. The use of the subject compositions may reduce the required dosage for any individual agent contained in the compositions e. Toxicity and therapeutic efficacy of subject compositions may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e. The data obtained from the cell culture assays and animal studies may be used in formulating a range of dosage for use in humans.

The dosage of any subject composition lies preferably within a range of circulating concentrations that include the ED 50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For compositions of the present invention, the therapeutically effective dose may be estimated initially from cell culture assays.

In general, the doses of an active agent will be chosen by a physician based on the age, physical condition, weight and other factors known in the medical arts. The efficacy of treatment with the subject compositions may be determined in a number of fashions known to those of skill in the art. In one exemplary method, the median rate of decrease in inflammation for treatment with a subject composition may be compared to other forms of treatment with the particular cardiovascular agent contained in the subject composition, or with other cardiovascular agents.

The period of time for observing any such decrease may be about 1, 3, 5, 10, 15, 30, 60 or 90 or more hours. The comparison may be made against treatment with the particular cardiovascular agent contained in the subject composition, or with other cardiovascular agents, or administration of the same or different agents by a different method, or administration as part of a different drug delivery device than a subject composition.

The comparison may be made against the same or a different effective dosage of the various agents. Alternatively, a comparison of the different treatment regimens described above may be based on the effectiveness of the treatment, using standard indices known to those of skill in the art. Alternatively, the different treatment regimens may be analyzed by comparing the therapeutic index for each of them, with treatment with a subject composition as compared to another regimen having a therapeutic index two, three, five or seven times that of, or even one, two, three or more orders of magnitude greater than, treatment with another method using the same or different cardiovascular agents.

This invention also provides kits for conveniently and effectively implementing the methods of this invention. Such kits comprise any subject composition, and a means for facilitating compliance with methods of this invention. Such kits provide a convenient and effective means for assuring that the subject to be treated takes the appropriate active in the correct dosage in the correct manner. The compliance means of such kits includes any means which facilitates administering the actives according to a method of this invention.

Such compliance means include instructions, packaging, and dispensing means, and combinations thereof. Kit components may be packaged for either manual or partially or wholly automated practice of the foregoing methods. In other embodiments involving kits, this invention contemplates a kit including compositions of the present invention, and optionally instructions for their use. All measurements presented were recorded in vitro using a sensitive porphyrinic probe, as previously described.

Malinski T, Taha Z. Nebivolol was obtained from Mylan Laboratories Morgantown, W. Cell wells were transferred to a Faraday cage and a porphyrinic sensor diameter 0.

The sensor operated with a three-electrode system: The baseline was stabilized after about 20 seconds. The test compounds were injected with a nanoinjector onto the surface of the cells following solubilization in buffer.

Cells were incubated with the test compounds for a hour period. The compounds were then washed out of the system before being immediately reintroduced in order to evaluate the consequences of chronic treatment on NO release from the cells. For additive experiments, cells were incubated with ACE inhibitor for 24 hours, the inhibitor was washed out of the system, nebivolol was added and the NO release measured.

The current proportional to the NO concentration was measured with the sensor, which operated in amperometric mode at a constant potential of 0. Data were acquired with the use of an IBM computer with custom software and amperograms current vs. By increasing cytoplasmic levels of calcium, the ion can bind to calmodulin. Nanosensors were prepared from carbon fibers. The sensors were sensitized to NO by deposition of electrically conductive polymeric porphyrin and covered with a thin layer of Nafion.

The porphyrinic microsensor has a response time of 0. The nanosensor for NO was calibrated using saturated solution concentration 1. The concentration-dependent effects of nebivolol and certain ACE-inhibitors on NO releasing capacity were tested using a calcium ionophore A that stimulates NO release, independently of G-protein-coupled receptors.

Measurement of NO release as a function of treatment was conducted in individual endothelial cells. Multiple measurements of NO release can be conducted on single cells following a brief refractory period.

For robust statistical analysis, separate cells were used for each concentration and type of drug used in these analyses. The magnitude of the increase is greater in endothelial cells from Black donors. There were significant concentration dependent effects on the ability of nebivolol to enhance NO release from Black and White donor endothelial cells that had been chronically treated with ACE inhibitors.

By promoting a more normal vascular physiology through an NO-dependent pathway, nebivolol treatment may have better efficacy and fewer side effects as compared to agents that only inhibit the sympathetic nervous system. These data further support the hypothesis that nebivolol may have distinct pharmacologic benefits through modulation of endothelial function and NO metabolism. All of the patents and publications cited herein are hereby incorporated by reference.

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Nebivolol has been shown to be beneficial in the treatment of cardiovascular diseases such hypertension, congestive heart failure, arterial stiffness and endothelial dysfunction.

The present invention features a pharmaceutical composition comprising nebivolol and at least one other active agent, wherein Compositions comprising nebivolol US B2. The present invention features a pharmaceutical composition comprising nebivolol and at least one other active agent, wherein the at least one other active agent is a cardiovascular agent.

A method of treating hypertension comprising administering to a subject in need thereof a composition comprising between about 0. A method of treating a hypertension comprising administering to a subject in need thereof a composition comprising between about 0. The method of claim 1 wherein the cardiovascular active agent is olmesartan or a pharmaceutically acceptable salt thereof. The method of claim 1 wherein the cardiovascular active agent is valsartan or a pharmaceutically acceptable salt thereof.

The method of claim 1 wherein the cardiovascular active agent is losartan or a pharmaceutically acceptable salt thereof. The method of claim 2 wherein the ARB is olmesartan or a pharmaceutically acceptable salt thereof. The method of claim 2 wherein the ARB is valsartan or a pharmaceutically acceptable salt thereof.

The method of claim 2 wherein the ARB is losartan or a pharmaceutically acceptable salt thereof. The method of claim 9 wherein the cardiovascular active agent is olmesartan or a pharmaceutically acceptable salt thereof. The method of claim 9 wherein the cardiovascular active agent is valsartan or a pharmaceutically acceptable salt thereof. The method of claim 9 wherein the cardiovascular active agent is losartan or a pharmaceutically acceptable salt thereof.

Year of fee payment: Eric Davis , John P. Forest Laboratories Holdings Limited. Local administration of pharmacologically active agents to treat premature ejaculation. Methods of treating and preventing congestive heart failure with hydralazine compounds and isosorbide dinitrate or isosorbide mononitrate.

On demand administration of clomipramine and salts thereof to treat premature ejaculation. Method for treating fibrotic diseases with azolium chroman compounds.

Methods of treating vascular diseases characterized by nitric oxide insufficiency. Method for treating fibrotic diseases or other indications utilizing thiazole, oxazole and imidazole compounds. Methods using hydralazine compounds and isosorbide dinitrate or isosorbide mononitrate.

As-needed administration of tricyclic and other non-SRI antidepressant drugs to treat premature ejaculation. Combinations of hormone replacement therapy composition s and sterol absorption inhibitor s and treatments for vascular conditions in post-menopausal women. Nitrosated and nitrosylated nebivolol and its metabolites, compositions and methods of use.

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