RU2441653C2 - Compositions containing nebivolol - Google Patents

Abstract

FIELD: chemistry; medicine.

SUBSTANCE: invention refers to medical products, and related to the use of therapeutically safe and effective amount of combination of nebivolol or its pharmaceutical salt and ramiprilat or elanapril or their pharmaceutical salt to get a medical product that improves NO release in black patient and results in decreased mortality related to cardiovascular diseases.

EFFECT: proposed combination has synergy effect on endothelium dependent NO release from the cells of black donors.

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Description

This application is a partial continuation of application with registration number 11/141235, filed May 31, 2005, which is based on and which claims the priority of provisional patent application US registration number 60/577423 in the name of Eric Davis, John O'Donnell, Peter Bottini filed June 4, 2004.

Technical field

The present invention relates to compositions containing nebivolol and one or more other active agents. More specifically, the present invention relates to compositions containing nebivolol and one or more cardiovascular agents for the treatment and / or prevention of cardiovascular diseases.

BACKGROUND OF THE INVENTION

Hypertension is a major US health problem. Approximately 50 million Americans have high blood pressure, defined as systolic blood pressure (SKD) ≥140 mmHg. Art. or diastolic blood pressure (DCD) ≥90 mmHg. Art. In addition, individuals with a blood pressure of 120/80 mmHg. Art. or higher have an increased risk of developing hypertension and are considered to be in a “prehypertensive” state. The severity of hypertension is currently classified into stages, with stage 1 covering blood pressure limits from 140/90 to 159/99 mmHg. Art., and stage 2, including blood pressure ≥160 / 100 mm RT. Art.

The onset of hypertension (only diastolic or in combination with systolic) usually occurs from 25 to 55 years. The risk of developing hypertension increases more dramatically with age. According to the CDC in the United States, 68.3% of men aged 65 to 74 years old suffer from hypertension (Health United States, 2003, CDC / National Center for Health Statistics) and 70.7% of men over 75 years old suffer from hypertension in the United States. (Health United States, 2003, CDC / National Center for Health Statistics). In addition, in the United States, 73.4% of women aged 64 to 74 years old suffer from hypertension (Health United States, 2003, CDC / National Center for Health Statistics) and 84.9% of women over 75 years old suffer from hypertension (Health United States, 2003, CDC / National Center for Health Statistics).

There is a need for pharmaceutical compositions that stimulate, enhance or potentiate the formation of endothelial nitric oxide, especially compositions that produce increased levels of nitric oxide in black Americans.

Disclosure of invention

In one aspect, the present invention includes a pharmaceutical composition comprising nebivolol and at least one active agent. In a further embodiment of the invention, at least one of the active agents is a cardiovascular agent. In a further embodiment of the invention, at least one cardiovascular agent is selected from the group consisting of ACE inhibitors (angiotensin II-converting enzyme inhibitors), ARB (angiotensin II receptor antagonists (blockers), adrenergic blockers, adrenergic agonists, anti-pheochromocytoma agents , antiarrhythmic agents, antiplatelet agents, anticoagulants, antihypertensive agents, anti-lipid agents, anti-diabetes agents, anti-inflammatory agents, blocking agents calcium channels, CETP inhibitors, COX-2 inhibitors, direct thrombin inhibitors, diuretics, endothelin receptor antagonists, HMG Co-A reductase inhibitors, inotropic agents, renin inhibitors, vasodilators, vasopressors, AGE cross-linking substances (substances - crosslinking of extended glycosylation end products, such as alabebrium, see USP 6458819), and AGE formation inhibitors (inhibitors of the formation of extended glycosylation end products, such as pimagedin) and mixtures thereof. In one embodiment, the other cardiovascular agent is an ACE or ARB inhibitor. In a further embodiment, another cardiovascular agent includes an ACE and ARB inhibitor. In a further embodiment, the ACE inhibitor is selected from the group consisting of alacepril, benazepril, captopril, ceronapril, cilazapril, delapril, enalapril, enalapril, fosinopril, imidapril, lisinopril, perindopril, quinapril, ramipril, ramiprilapril, ramiprilapril. In a further embodiment, the ACE inhibitor is enalapril, ramipril or ramiprilat. In a further embodiment, the other cardiovascular agent is ARB selected from the group consisting of candesartan, eprosartan, irbesartan, losartan, valsartan.

In a further embodiment, the pharmaceutical composition comprises an amount of nebivolol ranging from about 0.125 mg to about 40 mg. In a further embodiment, the amount of ACE inhibitor may be in the range of about 0.5 mg to about 80 mg, and / or the amount of ARB may be in the range of about 1 mg to about 1200 mg.

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 (angiotensin II receptor antagonists (blockers), adrenergic blockers, adrenergic agonists, anti-pheochromocytoma agents, anti-angina agents , antiarrhythmic agents, antiplatelet agents, anticoagulants, antihypertensive agents, anti-lipid agents, anti-diabetes agents, anti-inflammatory agents, bl calcium channel agents, CETP inhibitors, COX-2 inhibitors, direct thrombin inhibitors, diuretics, endothelin receptor antagonists, HMG Co-A reductase inhibitors, inotropic agents, renin inhibitors, vasodilators, vasopressors, substances that break down AGE cross-linking ( cross-linking extended glycosylation end products such as alabrium, see USP 6458819), and AGE formation inhibitors (extended glycosylation end product formation inhibitors such as pimagedin). In a further embodiment of the invention, the other cardiovascular agent is an ACE or ARB inhibitor.

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

In another aspect, the present invention includes a method for the prevention of cardiovascular disease, comprising administering to the subject an effective amount of nebivolol in combination with at least one cardiovascular agent. In a further embodiment of the invention, the cardiovascular disease is selected from the group consisting of congestive heart failure, hypertension, pulmonary hypertension, myocardial and cerebral infarction, atherosclerosis, atherogenesis, thrombosis, coronary heart disease, restenosis after angioplasty, coronary artery disease, renal failure, stable, unstable and variant (prinzmetal) angina pectoris, cardiac edema, renal failure, nephrotic edema, hepatic edema, stroke, transient x ischemic attacks, cerebrovascular events, restenosis, controlling blood pressure in hypertension, platelet adhesion, platelet aggregation, smooth muscle cell proliferation, pulmonary edema, and vascular complications in the use of medical devices.

In another aspect, the present invention includes a kit comprising an effective amount of nebivolol in combination with an effective amount of another cardiovascular agent.

Even though nebivolol has β-blocking properties, nebivolol differs from other classical β-blockers in that it is highly selective for β1-adrenergic receptors and also has vasodilating effects associated with its action on endothelial nitric oxide. It is believed that nebivolol increases the levels of nitric oxide in the vascular endothelium via the L-arginine-nitric oxide biochemical pathway, and it has been shown to improve endothelial function and improve blood vessel ductility. It has also been shown that nebivolol has antioxidant characteristics that are favorable for the normal functioning of the vascular endothelium. Such characteristics make nebivolol an effective antihypertensive agent with a beneficial effect on the vascular endothelium and the cardiovascular system. Nebivolol has been shown to be useful in the treatment of cardiovascular diseases such as hypertension, congestive heart failure, arterial stiffness and endothelial dysfunction. In part, the present invention includes a composition comprising nebivolol and at least one other cardiovascular agent, which is believed to act by a different mechanism and is useful for the treatment and / or prevention of vascular diseases characterized by nitric oxide deficiency. The present invention also describes a method for reducing mortality associated with cardiovascular disease in black patients, comprising administering to a black patient a therapeutically effective amount of nebivolol or a pharmaceutical salt thereof and at least one other cardiovascular agent. The invention also relates to a method for improving NO release in black patients in need thereof, comprising administering to black patients a therapeutically safe and effective amount of nebivolol or a pharmaceutically acceptable salt thereof and at least one other cardiovascular agent sufficient to improve NO release. The present invention further describes a method for improving exercise tolerance or improving quality of life for black patients in need thereof, comprising administering to black patients a therapeutically effective amount of nebivolol or a pharmaceutical salt thereof and at least one cardiovascular agent.

The above embodiments of the present invention, other options and their properties and characteristics will be apparent from the following description, drawings and claims.

Brief Description of the Drawings

Figure 1 shows a comparison of the release of NO from endothelial cells of black and white donors after prolonged treatment with ramiprilat followed by treatment with nebivolol (1 μM).

Figure 2 shows a comparison of the increase in the release of NO from endothelial cells of black and white donors after prolonged treatment with ramprilat followed by treatment with nebivolol (1 μM).

Figure 3 shows a comparison of the release of NO from endothelial cells of black and white donors after prolonged treatment with enalapril followed by treatment with nebivolol (1 μM).

Figure 4 shows a comparison of the increase in the release of NO from endothelial cells of black and white donors after prolonged treatment with enalapril followed by treatment with nebivolol (1 μM).

DETAILED DESCRIPTION OF THE INVENTION

Definitions

For convenience, before further description of the present invention, certain terms used in the description, examples and the attached formula are collected in this description. These definitions should be read taking into account the remainder of the disclosure and should be understood as understood by a person skilled in the art. Unless otherwise specified, all technical and scientific terms used in this description have the same meaning, which is usually understood by a person skilled in the art.

The singular number of indefinite nouns used in this description refers to one or more than one (i.e., at least one) of the grammatical objects in the singular. By way of example, “element” means one element or more than one element.

“At about the same time” means that the other active compound (s) is administered to the patient within about thirty minutes from the administration of one compound (nebivolol) to the patient. “Around the same time” also includes the simultaneous administration of the compounds.

The phrase “angiotensin converting enzyme inhibitor” or “ACE inhibitor” as used herein refers to a compound that inhibits any enzyme from converting angiotensin to any other form.

The phrase “angiotensin II receptor antagonist” or “ARB” refers to a compound that binds a receptor site in angiotensin II but does not cause any physiological changes while another receptor is present.

The term “antagonist” is recognized in the art and refers to a compound that binds to the receptor site but does not cause any physiological changes while another ligand of the receptor is present.

The term "bioavailable" is recognized in this field and refers to the form of the object of the invention, which allows it to adsorb or to be included or part of the administered amount or otherwise physiologically accessible to the subject or patient to whom they are administered.

“Black” refers to a person of African descent or an African American, but is not necessarily limited to only people of African descent (for example, people of descent from the Caribbean).

A “therapeutically effective amount” refers to an amount of a compound and / or a compound that is effective in achieving its intended purpose.

The phrase “cardiovascular agent” or “cardiovascular drug” refers to a therapeutic compound that is useful for treating or preventing a cardiovascular disease. Non-limiting examples of cardiovascular agents include ACE inhibitors (angiotensin II-converting enzyme inhibitors), ARB (angiotensin II receptor antagonists), adrenergic blockers, adrenergic agonists, anti-pheochromocytoma agents, anti-angina agents, anti-arrhythmia, anti-platelets, anti-platelets , lipid-lowering agents, anti-diabetes agents, anti-inflammatory agents, calcium channel blockers, CETP inhibitors, COX-2 inhibitors, etc. thrombin inhibitors, diuretics, endothelin receptor antagonists, HMG Co-A reductase inhibitors, inotropic agents, renin inhibitors, vasodilators, vasopressors, AGE cross-linking substances (substances that cross-crosslink extended end products such as glycosylation, see USP 6458819), and AGE formation inhibitors (extended glycosylation end-product formation inhibitors such as pimagedin), and combinations thereof.

Cardiovascular disease or disorder refers to any cardiovascular disease or disorder known in medicine, including, but not limited to, cardiovascular diseases that are selected from the group consisting of congestive heart failure, hypertension, pulmonary hypertension, myocardial infarction and brain, atherosclerosis, atherogenesis, thrombosis, coronary heart disease, restenosis after angioplasty, coronary artery disease, renal failure, stable, unstable and option angina pectoris, cardiac edema, renal failure, nephrotic edema, liver edema, stroke, transient ischemic attacks, cerebrovascular events, restenosis, blood pressure control for hypertension, platelet adhesion, platelet aggregation, pulmonary proliferation and smooth cell proliferation complications when using medical devices.

The term “combination” refers to two or more different active agents that are administered at about the same time (for example, where the active agents are in the same pharmaceutical preparation) or at different times (for example, one agent is administered to the subject before the other).

The terms “drug”, “pharmaceutically active agent”, “biologically active agent”, “therapeutic agent” or “active agent” can be used interchangeably and refer to a substance, such as a chemical compound or complex, that has a measurable physiological effect on the body, such as a therapeutic effect in the treatment of a disease or disorder when administered in an effective amount. Additionally, when these terms are used or when a specific active agent is precisely defined by name or category, it becomes clear that such a statement is intended to include the active agent in itself, as well as in the form of its pharmaceutically acceptable, pharmacologically active derivatives or compounds closely related to him, including, but without limitation, salts, pharmaceutically acceptable salts, N-oxides, prodrugs, active metabolites, isomers, fragments, analogues, solvates, hydrates, radioisotopes, etc.

The phrase "effective amount" refers to the amount of a substance that produces some desired local or systemic effect with a reasonable benefit / risk ratio applicable to any treatment. The effective amount of such a substance will vary depending on the object and condition of the disease being treated, the weight and age of the subject, the severity of the condition of the disease, method of administration, etc., which can easily be determined by a person skilled in the art.

"Endothelial dysfunction" refers to impaired ability in any physiological process carried out by the endothelium, in particular, nitric oxide production, regardless of cause. It can be evaluated by, for example, invasive techniques, such as, for example, the reactivity of coronary arteries to acetylcholine or methacholine, etc., or by non-invasive techniques, such as, for example, blood flow measurement, flow mediated brachial artery dilatation using a cuff on arm above or below the elbow, ultrasonography of the brachial artery, imaging techniques, measurement of circulating biomarkers such as asymmetric dimethylarginine (ADMA), etc. For the final measurement, endothelial-dependent flow-mediated dilatation will be lower in patients diagnosed with endothelial dysfunction.

The phrase “endothelial nitric oxide synthetase” or “eNOS” refers to enzymes that produce nitric oxide.

The phrase “nebivolol composition” refers to a composition containing nebivolol, and these two concepts can be used interchangeably. Nebivolol is a mixture of the d and l isomers of α, α ′ - [iminobismethylene] bis [6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol]. The composition may include at least one other cardiovascular agent or at least one pharmaceutically acceptable carrier, or both.

The term "pharmaceutically acceptable salts" is recognized in this field and refers to the relatively non-toxic additive salts of inorganic and organic acids of the compounds, including, for example, salts that are contained in the present invention.

The term "pharmaceutically acceptable carrier" is recognized in this field and refers to a pharmaceutically acceptable material, composition or delivery medium, such as lipids or solid excipients, diluents, excipients, solvents or encapsulating materials involved in the storage or transportation of any target composition or component thereof from one organ or part of an organism to another organ or part of an organism. Each carrier must be acceptable in terms of compatibility with the target composition and its components and not harm the patient. Some examples of materials that can serve as pharmaceutically acceptable excipients include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as polyethylene glycol; (11) polyalcohols such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic solution; (18) intravenous fluids, including, but not limited to, Ringer's solution, 5% dextrose in water, and semi-normal saline; (19) ethyl alcohol; (20) phosphate buffers; and (21) other non-toxic compatible substances used in pharmaceutical formulations.

"Patient" refers to animals, preferably mammals, most preferably to humans, and includes both male and female.

“Quality of life” refers to one or more abilities of a person to walk, climb stairs, do housework, actively relax and / or not need rest during the day, and / or lack of sleep problems or shortness of breath.

The term “prophylactic” or “therapeutic” treatment is recognized in the art and refers to the administration of one or more target compositions to a host. If they are administered before the clinical manifestations of an undesirable condition (for example, a disease or other undesirable condition of the host animal), then the treatment is prophylactic, i.e. it protects the host from the development of an undesirable state, whereas when administered after the manifestation of an undesirable state, the treatment is therapeutic (i.e., aimed at reducing, alleviating, or maintaining an existing undesirable state or side effects caused by it).

The term “relationship of structure and activity” or “SAR” is recognized in this field and refers to a method in which changing the molecular structure of a drug or other compound changes its interaction with a receptor, enzyme, nucleic acid or other target, etc.

It will be understood that “substitution” or “substituted” includes the implied condition that such a substitution is in accordance with the permissible valency of the substituted atom and substitution and that the substitution leads to a stable compound, for example, which does not undergo spontaneous transformations, such as rearrangement reactions, cyclization elimination or other reactions.

The term "substituted" also includes the inclusion of all valid substituents of organic compounds. In a broad aspect, acceptable substituents include acyclic and cyclic, branched and unbranched, carbon cyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. Illustrative substituents include, for example, those described above. Permissible substituents may be single or multiple, the same or different for the corresponding organic compounds. For the purposes of the invention, heteroatoms, such as nitrogen, may have hydrogen substituents and / or any permissible substituents of the organic compounds described herein that satisfy the valency of the heteroatoms. The present invention should not be limited in any way to only valid substituents of organic compounds.

The term “synthetic” is recognized in the art and refers to in vitro production by chemical or enzymatic synthesis.

The phrase “therapeutic effect” is recognized in the art and refers to a local or systemic effect in animals, especially mammals, and more particularly in humans, caused by a pharmacologically active substance. This term therefore means any substance intended for use in the diagnosis, treatment, mitigation, treatment or prevention of disease or in enhancing the desired physical or mental development and / or condition in an animal or human. The phrase “therapeutically effective amount” means that the amount of such a substance, giving some desired local or systemic effect with an acceptable benefit / risk ratio, is useful in any treatment. A therapeutically effective amount of such a substance will vary depending on the subject and the condition of the disease to be treated, the weight and age of the subject, the severity of the condition of the disease, route of administration, etc., which can be easily determined by a person skilled in the art.

The term "treatment" is recognized in this field and refers to the course of treatment, as well as to alleviate at least one symptom of any condition or disease.

Nebivolol

Nebivolol is a β-receptor blocking drug, which is a mixture of d - and l- enantiomers, of which d- nebivolol is a highly selective β ₁ receptor antagonist.

d- nebivolol

l- nebivolol

In addition to β-receptor blocking properties, nebivolol has been shown to cause endothelial-dependent vasodilation in subjects with both normal and elevated blood pressure. Cockcroft JR, Chowienczyk PJ, Brett SE, Chen CP, Dupont AG, Nueten LV, Wooding SJ, Ritter JM., Journal of Pharmacology and Experimental Therapeutics . 1995; 274: 1067-1071; Tzemos N, Lim PO, MacDonaldTM., Circulation , 2001; 104: 511-514; Breeders MA, Doevendans PA, Bekkers BC, Bronsaer R, van Gorsel E, Heemskerk JW, Egbrink MG, van Breda E, Reneman RS, van Der Zee R., Circulation 2000; 102: 677-684. Bowman, AJ, CPL-H Chen, GA Ford. Br. J. Clin. Pharmac. 1994; 38: 199-204. In experimental models, it was shown that nebivolol stimulates the release of NO via the β ₂ -adrenergic receptor-mediated NO production and / or ATP outflow followed by stimulation of the P2Y-purine-mediated NO release. Broeders MA, Doevendans PA, Bekkers BC, Bronsaer R, van Gorsel E, Heemskerk JW, Egbrink MG, van Breda E, Reneman RS, van Der Zee R., Circulation , 2000; 102: 677-684; Kalinowski L, Dobrucki LW, Szczepanska-Konkel M, Jankowski M, Martyniec L, Angielski S, Malinski T., Circulation , 2003; 107: 2747-2752. It has also been reported that nebivolol inhibits the separation of NO synthetase and gives a systemic antioxidant effect. Mollnau H, Schulz E, Daiber A, Baldus S, Oelze M, August M, Wendt M, Walter U, Geiger C, Agrawal R, Kleschyov AL, Meinertz T, Thomas Munzel T., Arteriosclerosis, Thrombosis, and Vascular Biology . 2003; 23: 615-621; Troost R, Schwedhelm E, Rojczyk S, Tsikas D, Frolich JC., British Journal of Clinical Pharmacology , 2000; 50: 377-379.

Compositions containing nebivolol

In part, the present invention includes 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 composition may vary depending on the number of variables, such as age, weight, gender, and health status. In general, the dosage of cardiovascular agents will typically range from about 0.01 ng to about 10 g per kg body weight, specifically from about 1 ng to about 0.1 g per kg, and more specifically, in the range of about 100 ng to about 10 mg per kg. In another embodiment, the amount of nebivolol in the compositions of the present invention may be any from about 0.125 mg to about 40 mg. In one example, when the other cardiovascular agent is an ACE inhibitor, the amount of ACE inhibitor can be any one from 0.5 mg to about 80 mg. When the other cardiovascular agent is ARB, the amount of ARB may be any from about 1 mg to about 1200 mg. The amount of the other cardiovascular agent will depend in part on what specific cardiovascular agent is used.

In addition to ACE and ARB inhibitors, additional cardiovascular agents include, but are not limited to, adrenergic blockers, adrenergic agonists, anti-pheochromocytoma agents, anti-angina agents, anti-arrhythmic agents, antiplatelet agents, anticoagulants, antihypertensive drugs, anti-lipid agents , anti-inflammatory agents, calcium channel blockers, CETP inhibitors, COX-2 inhibitors, direct thrombin inhibitors, diuretics, end receptor antagonists hotels, HMG Co-A reductase inhibitors, inotropic agents, renin inhibitors, vasodilators, vasopressors, AGE crosslinkers (crosslinking agents of extended glycosylation end products such as alabrium, see USP 6458819), and inhibitors AGE formation (inhibitors of the formation of extended end glycosylation end products such as pimagedin). Cardiovascular agents falling into these general categories are described in the examples below:

“Angiotensin II-converting enzyme (ACE) antagonists and angiotensin II receptor antagonists (ARB)”

"Angiotensin II receptor antagonists" (ARB) are compounds that adversely affect angiotensin II activity by binding to angiotensin II receptors and adversely affect its activity. Angiotensin I and angiotensin II are synthesized by the renin-angiotensin biochemical pathway. The synthesis process is initiated when the renin enzyme acts on an angiotensinogen, pseudoglobulin in blood plasma, producing angiotensin I decapeptide. Angiotensin is converted (converted) by angiotensin-converting enzyme (ACE) into angiotensin II (angiotensin-octapeptide [1-8]). The latter is an active precursor substance, which is the root cause in several forms of hypertension in various species of mammals, for example in humans.

Angiotensin II receptor antagonists (ARBs) are well known and include peptide compounds and non-peptide compounds. Most angiotensin II receptor antagonists are slightly modified compounds belonging to the same class in which the agonistic effect is weakened by replacing phenylalanine at position 8 with some other amino acids; stability can be enhanced by other substitutions that reduce in vivo degradation.

Examples of angiotensin II receptor antagonists include: peptide compounds (eg, saralazine and related analogues); N-substituted imidazol-2-one (US patent No. 5087634); imidazole acetate derivatives including 2-N-butyl-4-chloro-1- (2-chlorodibenzyl) imidazole-5-acetic acid (see, Long et al., J. Pharmacol. Exp. Ther. 247 (1), 1 -7 (1988)); 4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridine-6-carboxylic acid and its derivatives analogs (US patent No. 4816463); analogues of N2-tetrazole beta-glucuronide (US patent No. 5085992); substituted pyrroles, pyrazoles and triazoles (US patent No. 5081127); phenol and heterocyclic derivatives, such as 1,3-imidazoles (US patent No. 5073566); imidazocondensed 7-membered ring heterocycles (US patent No. 5064825); peptides (for example, US patent No. 4772684); antibodies to angiotensin II (for example, US patent No. 4302386) and aralkylimidazole compounds, such diphenylmethyl substituted imidazoles (for example, EP 253310, January 20, 1988); ES8891 (N-morpholinoacetyl - (- 1-naphthyl) -L-alanyl- (4, thiazolyl) -L-alanyl (35.45) -4-amino-3-hydroxy-5-cyclohexapentanoyl-N-hexylamide, Sankyo Company , Ltd., Tokyo, Japan); SKF108566 (E-alpha-2- [2-butyl-l- (carboxyphenyl) methyl] -1H-imidazol-5-yl [methylane] -2-thiophenpropanoic acid, Smith Kline Beecham Pharmaceuticals, Pa.); losartan (DUP753 / MK954, DuPont Merck Pharmaceutical Company); remikirin (RO42-5892, F. Hoffman LaRoche AG); A ₂ agonists (Marion Merrill Dow) and certain non-peptide heterocycles (GD Searle and Company). Other non-limiting examples of ARB include candesartan, eprosartan, losartan, and valsartan. Other ARBs can be identified using standard assay methods known to one skilled in the art.

An “angiotensin converting enzyme” (ACE) is an enzyme that catalyzes the conversion of angiotensin I to angiotensin II. ACE inhibitors include amino acids and their derivatives, peptides, including di- and tripeptides, and antibodies to ACE, which interfere with the renin-angiotensin system by inhibiting ACE activity, thereby reducing or eliminating the formation of the angiotensin II precursor substance.

ACE inhibitors are used in medicine to treat hypertension, congestive heart failure, myocardial infarction, and kidney disease. Classes of compounds known to be useful as ACE inhibitors include acylmercapto and mercaptoalkanoylproline, such as captopril (US patent No. 4105776) and zofenopril (US patent No. 4316906), carboxyalkyl dipeptides, such as enalapril (US patent No. 4374829) US No. 4374829), quinapril (US patent No. 4344949), ramipril (US patent No. 4587258) and perindopril (US patent No. 4508729), carboxyalkyl dipeptide mimetics, such as cilazapril (US patent No. 4512924) and benzazapril (US patent No. 4410520) , phosphinylalkanoylproline, such as fosinopril (patent US No. 4337201) and trandolapril. Other non-limiting examples of ACE inhibitors include, but are not limited to, alazepril, benazepril, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, perindopril, quinapril, ramiprilpril, ramiprilat, ramiprilat,

Adrenergic blockers

Non-limiting examples of adrenergic blockers of both α- and β-adrenergic blockers that can be used in the compositions of the present invention include beta-adrenergic blockers, including, but not limited to, atenolol, acebutolol, alprenolol, befunolol, betaxolol, bunitrolol, cartolol, celiprolol, gedroxalol, indenolol, labetalol, levobunolol, mepindolol, metipranol, methindol, metoprolol, metrizoranolol, oxprenolol, pindolol, propranolol, praktolol, sotalolnadolol, tiprenolol, tolamolol, timolol lol, penbutolol, trimepranol, yohimbine, 2- (3- (1,1-dimethylethyl) amino-2-hydroxypropoxy) -3-pyridinecarbonitrile-HCl, 1-butylamino-3- (2,5-dichlorophenoxy) -2-propanol , 1-isopropylamino-3- (4- (2-cyclopropylmethoxyethyl) phenoxy) -2-propanol, 3-isopropylamino-1- (7-methylindan-4-yloxy) -2-butanol, 2- (3-tert-butylamino -2-hydroxypropylthio) -4- (5-carbamoyl-2-thienyl) thiazole, 7- (2-hydroxy-3-tert-butylamine propoxy) phthalide. The compounds defined above can be used as isomeric mixtures or in their respective levorotatory and dextrorotatory forms.

Adrenergic agonists

Non-limiting examples of adrenergic agonists, both α- and β-adrenergic agonists, which can be used in the compositions of the present invention include adrafinyl, adrenalone, albuterol, amidephrine, apraclonidine, bitolterol, budralazine, carbuterol, clenbuterol, clonidine, clorpine cyclin, , denopamine, detomidine, dimethofrin, dioxetedrine, dipivefrin, dopexamine, ephedrine, epinephrine, ethhedrine, ethylnorepinephrine, fenoterol, phenoxazoline, formoterol, guanabenz, guanfacin, hexoprenaline, hydroxyamphetamine, because Pamina, indanazolin, isoetharine, isometheptene, isoproterenol, mabuterol, mephentermine, metaproterenol, metaraminol, metizolin, methoxamine, methylhexaneamine, methoxyphenamine, midodrine, modafinil, moxonidine, naphazoline, norepinephrine, norfenefrine, oktodrin, octopamine, oxyfedrine, oxymetazoline, phenylephrine hydrochloride, phenylpropanolamine hydrochloride, phenylpropylmethylamine, foledrin, pirbuterol prenalterol, prouterol, propylhexedrine, protokyolol, pseudoephedrine, reproterol, rilmenedin, rimeterol, ritodrin, salmeterol, solterinol, synephrine, talip Xolo, terbutaline, tetrahydrozoline, tiamenidine, tramazolin, tretohinol, tuaminoheptane, tulobuterol, timazolin, tyramine, xamoterol, xylometazoline, and mixtures thereof.

Agents Against Pheochromocytoma

Chemotherapeutic agents include, but are not limited to.

Remedies for angina pectoris

Includes, but is not limited to, amlodipine besylate, amlodipine maleate, betaxolol hydrochloride, bevantolol hydrochloride, butoprozin hydrochloride, carvedilol, cinipazeta maleate, metoprolol succinate, molsidomine, monatepil maleate, nitrates (including, but not limited to, nitrite, not limited to , nitro-bid), isosorbide-5-mononitrate (5-ISMN, ismo), amyl nitrate and nicorandil (ikorel)), primidolol, ranolazine hydrochloride, tosifen, verapamil hydrochloride).

Antiarrhythmic drugs

Non-limiting examples of antiarrhythmic drugs that can be used in the compositions of the present invention include acebutolol, acecainide, adenosine, aymalin, alprenolol, amiodarone, amoproxan, aprindine, aprotinolol, atenolol, azimilide, bevantolol, bidisomolol, butenoltene, butenolitene, butenoltol, butenolol, butene bunitrolol, bupranolol, butidrine hydrochloride, butobendin, capobenic acid, karazolol, cartolol, cifenlin, cloranolol, disopyramide, dofetilide, encainide, esmolol, flecainide, hydroquinidine, ibutilide, indecainide, ind enolol, ipratropium bromide, lidocaine, loraimine, lorcainide, meobentin, mexiletine, moricisin, nadoxolol, nifenaolol, oxprenolol, penbutolol, pentisomide, pilsikainolid, propindolinol, propindolindolindolindolindolind, propindolindolindolind, propindolindolindolind, propindolindolind, propolindolind sematilide, sotalol, talinolol, tilizolol, timolol, tocainide, verapamil, vikhidil, xibenolol and mixtures thereof.

Antiplatelet agents

Non-limiting examples of antiplatelet agents that may be used in the present invention include clopidogrel, dipyridamole, abciximab, and ticlopidine.

Anticoagulants

Anticoagulants are agents that inhibit the biochemical pathway of blood coagulation by negatively affecting the production, precipitation, cleavage and / or activation of factors necessary for the formation of a blood clot. Non-limiting examples of anticoagulants (i.e., coagulation-related therapeutic agents) that can be used in the compositions of the present invention include aggrenox, agrilin, amikar, anturan, arikstra, coumadin, fragmentin, heparin sodium, lovenox, mefiton, miradon, persantin , plavix, weaved, tiklid, trental, warfarin. Other “anticoagulants” and / or “fibrinolytics” include plasminogen (degraded to plasmin when reacted with prekallikrein, kininogens, Factors XII, XIIIa, plasminogen proactivator and tissue plasminogen activator [TPA]); streptokinase; urokinase; anisoylated plasminogen-streptokinase activator complex; prourokinase (Pro-UK); rTPA (alteplase or activase; r stands for recombinant); rPro-UK; abbokinase; eminase; streptase + anagrelide hydrochloride; bivalirudin; dalteparin sodium; sodium danaparoid; dazoxyben hydrochloride; ephegatran sulfate; enoxaparin sodium; ifetroban; ifetroban sodium; tinzaparin sodium; reteplase; triphenagrel; warfarin; dextrans.

Other anticoagulants include, but are not limited to, ancrod; anticoagulant solution citrate + dextrose; anticoagulant solution citrate + phosphate + dextrose + adenine; anticoagulant solution citrate + phosphate + dextrose; heparin anticoagulant solution; sodium citrate anticoagulant solution; ardeparin sodium; bivalirudin; bromindione; dalteparin sodium; desirudin; dicumarol; calcium heparin; heparin sodium; sodium diapolate; nafamostat mesylate; fenprocoumone; tinzaparin sodium.

Platelet function inhibitors are agents that disrupt the ability of mature platelets to fulfill their normal physiological role (i.e., their normal functions). Platelets are normally involved in a number of physiological processes, such as adhesion to cellular or non-cellular subjects, aggregation, for example, to form a blood clot, and the release of factors such as growth factors (e.g., platelet-derived growth factor (PDGF)) and platelet granular components. One subcategory of platelet function inhibitors is platelet aggregation inhibitors, which are compounds that reduce or stop the ability of platelets to physically bind to each other or to other cellular and non-cellular components, thereby preventing the ability of platelets to form a blood clot.

Examples of suitable platelet function inhibitors include, but are not limited to, acadezin, anagrelide (if given in a dosage exceeding 10 mg / day), anipamil, argatroban, aspirin, clopidogrel, cyclooxygenase inhibitors such as non-steroidal anti-inflammatory drugs, and the synthetic compound -122047, sodium danaparoid, dazoxyben hydrochloride, 5 ', 5''' diadenosine analogs - P1, P4 tetraphosphate (Ap4A), diphibrotide, dilazep hydrochloride, 1,2- and 1,3-glyceryl dinitrate, dipyridamole, dopamine and 3 -methoxytiramine, ephegatran sulfate, enoxaparin sodium, glucagon, IIb / IIIa glycoprotein antagonists such as Ro-43-8857 and L-700462, ifetroban, sodium ifetroban, iloprost, integrilin (eptifibatide), isocarbacilin methyl ester, isosorbide-5-mononitrate, itazerigrel -13.177, lamifiban, lifarisine, molsidomine, nifedipine, oxagrelate, PGE, platelet activating factor antagonists such as lexipaphant, prostacyclin (PGI ₂ ), pyrazines, pyridinol carbamate, ReoPro (i.e. abciximab), sulfinpyrazone, synthetic compounds BN-50727, BN-52021, CV-4151, E-5510, FK-409, GU-7, KB-2796, KBT-3022, KC-404, KF-4939, OP-41483 , TRK-100, TA-3090, TFC-612 and ZK-36374, 2,4,5,7-tetratiaoctane, 2,4,5,7-tetratiaoctane 2,2-dioxide, 2,4,5-trithihexane, theophylline, pentoxifylline, thromboxane and thromboxane synthetase inhibitors such as picotamide and sulotroban, ticlopidine, tirofiban, trapidil and ticlopidine, triphenagrel, trilinolein, 3-substituted 5,6-bis (4-methoxyphenyl) -1,2,4-triazines and antibodies against glycoprotein IIb / IIIa, as well as disclosed in US patent No. 5440020, and antiserotonin drugs, lopidogrel; sulfinpyrazone; aspirin; dipyridamole; clofibrate; pyridinol carbamate; PGE; glucagon; antiserotonin drugs; caffeine; theophylline; pentoxifylline; ticlopidine.

Antihypertensive drugs

Non-limiting examples of antihypertensive agents that can be used in the compositions of the present invention include amlodipine, benidipine, benazepril, candesartan, captopril, darodipine, diltiazem HCl, diazoxide, doxazosin HCl, enalapril, eprosartan, losartan mesylate, felopinoldefinoldefoldefoldefoldefoldefoldefoldefoldefoldefoldefoldefoldefoldefoldefoldefoldefoldefelopinolandfelopinoldefinoplefelopinolanfelodolanfeloplozeneplodenophenolphenolfelopodinolfelopolynfelopinoldeneplozeneplodenophenolfoldeplodenophenolphenolfoldefoldefelopinoldeneplozenophenolfelopinoldeneplozenolfelopinoldeneplozenolfelopinolden programs methods , irbesartan, isradipine, lisinopril, mecamylamine, minoxidil, nicardipine HCl, nifedipine, nimodipine, nizoldipine, phenoxybenzamine HCl, prazosin HCl, hinapril, reserpine, terazosin HCl, telmisartan and valsartan.

The present invention also provides combinations of fixed doses of nebivolol with hydrochlorothiazide and at least one other additional active agent.

Lipid-lowering agents

Non-limiting examples of anti-lipid agents that can be used in the compositions of the present invention include acipimox, aluminum nicotinate, atorvastatin, cholestyramine resin, colestipol, polydexide, beclobrate, fluvastatin, gemfibrozil, lovastatin, lysosomal acid lipase, niacofibrate; PRARα agonists such as fibrates, which include, but are not limited to, fenofibrate, clofibrate, pyrifibrate, ciprofibrate, benzofibrate, clinofibrate, ronifibrate, theofibrate, clofibric acid, etofibrate and gemfibrozil; pravastatin sodium, simfibrate, simvastatin, niceritrol, nicoclonate, nicomoloxyniacinic acid, ethyroxate, thyropropic acid, thyroxine, acifran, azacosterol, benfluorex, beta-benzalbutyramide, carnitine, chondrostromaton sulfate 5, sodium chondrostromaton sulfate, 1, chondrostromatin sulfate, 1 14,17-eicosapentaenoic acid, erythadenine, furazabol, meglutol, melinamide, mitatrienediol, ornithine, gamma-oryzanol, pantetine, pentaerythritol tetraacetate, alpha-phenylbutyramide, pyrozadyl, probucol, beta-sulfuitrosuitrosuiterositeroate adenol, tryparanol, xenbucin and mixtures thereof.

Diabetes Remedies

Non-limiting examples of anti-diabetes agents that can be used in the compositions of the present invention include biguanides such as buformin, metformin and phenformin; hormones such as insulin; sulfonylurea derivatives such as acetohexamide, 1-butyl-3-methanylylurea, carbutamide, chlorpropamide, glibornuride, glyclazide, glimepiride, glipizide, glycvidone, glyxoxepide, glyburide, glybutiazide, glybimidamide, glybideamide, tolbimide ; HDL agonists; PRARγ agonists such as thiazolidinediones such as pioglitazone, rosiglitazone and troglitazone; and others, including acarbose, calcium mesoxalate, miglitol, and repaglinide.

Anti-inflammatory agents

Non-limiting examples of anti-inflammatory agents that can be used in the compositions of the present invention include alklofenac; alkomethasone dipropionate; algestone acetonide; alpha amylase; amcinafal; amcinafide; amfenac sodium; amiprilose hydrochloride; anakinru; anilolac; anitrazafen; azone; balsalazide disodium; bendazak; benoxaprofen; benzidamine hydrochloride; bromelain; broperamol; budesonide; caprofen; cycloprofen; cytazone; cliprofen; clobetasol propionate; clobetasone butyrate; clopirac; clotikazone propionate; cormetasone acetate; cortodoxone; deflazacort; desonide; deoxymethasone; dexamethasone dipropionate; diclofenac potassium; diclofenac sodium; diflorazone diacetate; diphlumidone sodium; diflunisal; difluprednat; diphthalon; dimethyl sulfoxide; drocinonide; endrizone; Enlimomab; enolikam sodium; epirizole; etodolac; etofenamate; felbinak; phenamol; fenbufen; fenclofenac; fenclorec; fendozal; fenpipalon; fentiazac; flazalon; fluazacort; flufenamic acid; flumizole; flunisolide acetate; flunixin; flunixin meglumin; fluocortin butyl; fluorometholone acetate; fluquazone; flurbiprofen; fluuretophen; fluticasone propionate; furaprofen; furobufen; halcinonide; halobetazole propionate; halopredone acetate; ibufenac; ibuprofen; ibuprofen aluminum; ibuprofen piconol; ilonidap; indomethacin; indomethacin sodium; indoprofen; indoxol; intrazole; isoflupredone acetate; isoxepack; isoxicam; ketoprofen; lofemisole hydrochloride; lornoxicam; loteprednol etabonate; meclofenamate sodium; meclofenamic acid; meclarizone dibutyrate; mefenamic acid; mesalamine; mezeclasone; methylprednisolone suleptanate; morniflumat; nabumeton; naproxen; naproxen sodium; naproxol; nimazon; olsalazine sodium; orgotein; orpanoxin; oxaprozin; oxyphenbutazone; paraniline hydrochloride; pentosan sodium polysulfate; fenbutazone sodium glycerate; pirphenidone; piroxicam; piroxicam cinnamate; piroxicam olamine; pirprofen; prednazat; prifelon; longitudinal acid; proquasone; proxazole; proxazole citrate; Rimexolone; romazarite; salcolex; salnazedin; salsalate; salicylates; sanguinarium chloride; seclason; sermethacin; Sudoxicam sulindac; suprofen; talmetacin; tanniflumat; talosalate; tebufelon; tenadap; tenadap sodium; tenoxicam; tezikam; tesimide; tetridamine; thiopinac; thixocortol pivalate; tolmetin; tolmetin sodium; triclonide; trifumidate; zidomethacin; glucocorticoids; zomepirac sodium. One preferred anti-inflammatory drug is aspirin.

Calcium channel blockers

Calcium channel blockers are a chemically heterogeneous class of compounds that are important in therapy to control many diseases, including several cardiovascular diseases such as hypertension, angina pectoris and cardiac arrhythmias (Fleckenstein, Cir. Res. V. 52, (suppl. 1) , p. 13-16 (1983); Fleckenstein, Experimental Facts and Therapeutic Prospects, John Wiley, New York (1983); McCaIl, D., Curr Pract Cardiol, v. 10, p. 1-11 (1985)). Calcium channel blockers are a heterogeneous group of drugs that prevent or slow the entry of calcium into the cell by regulating cellular calcium channels. (Remington, The Science and Practice of Pharmacy, Nineteenth Edition, Mack Publishing Company, Eaton, Pa., P. 963 (1995)). Most currently available calcium channel blockers and useful in the present invention belong to one of the three main chemical groups of drugs, dihydropyridines, such as nifedipine, phenylalkylamines, such as verapamil, and benzothiazepines, such as diltiazem. Non-limiting examples of calcium channel blockers that can be used in the compositions of the present invention include bepridil, klentiazem, diltiazem, fendilin, gallopamil, mibefradil, prenylamine, semotiadil, therodilin, verapamil, amlodipine, aranidipine, barnidipine, elipidipine, bilidipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nizoldipine, nitrendipine, cinnarizine, flunarizine, lidoflazin, lomerizine, bencyclan, ethaphenone, phantofaron xylin and mixtures thereof.

CETP inhibitors

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

SOX-2 inhibitors

Non-limiting examples of COX-2 inhibitors that can be used in the compositions of the present invention include compounds corresponding to the following: all compounds and substances described starting on page 8 of Winokur WO99 / 20110 as members of three different structural classes of selective COX-2 inhibitors ; compounds and substances that are selective COX-2 inhibitors described in Nichtberger, US Pat. No. 6,136,804 of October 24, 2000, entitled “Combination Therapy for the Treatment, Prevention or Reduction of Risks Associated with Acute Coronary Coronary Syndrome and Related Disorders”; compounds and substances that are selective COX-2 inhibitors described by Isakson et al, in PCT application WO / 09641645, published December 27, 1996, filed as PCT / US 9509905 June 12, 1995, entitled "Combination of cyclooxygenase-2 inhibitor and antagonist B4 leukotriene receptor for the treatment of inflammatory processes. " The values "COX-2 inhibitor" in this invention should include compounds and substances that are referenced and which are included in Winokur WO99 / 20110 through the references therein to this field; compounds and materials referenced and included in Nichtberger, US patent No. 6136804 of October 24, 2000, through the references therein to this area; COX-2 inhibitor compounds and substances referred to and included in Isakson et al, PCT Application WO / 09641645, published December 27, 1996, filed as PCT / US 9509905 June 12, 1995, entitled “Combination of Cyclooxygenase Inhibitor” -2 and an antagonist of the leukotriene receptor B4 for the treatment of inflammatory processes. " The values “COX-2 inhibitor” in this invention also include rofecoxib and celecoxib sold as VIOXX and CELEBREX manufactured by Merck and Searle / Pfizer, respectively. Rofecoxib is discussed in Winokur WO99 / 20110, as compound 3 on page 9. Celecoxib is discussed as SC-58635 in the same reference and in T. Penning, Synthesis and biological evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors: identification of 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrozol-1-yl] benzenesulfonami de (SC-58635, celecoxib) ", J. Med. Chem. Apr. 25, 1997: 40 (9): 1347-56. SC299, also referred to as fluorescent diaryloxazole, is also included in the meaning of “COX-2 inhibitor.” C. Lanzo et al, “Fluorescence quenching analysis of the association and dissociation of a diarylheterocycle to cyclooxygenasel-1 and cyclooxygenase-2: dynamic basis of cycloxygenase-2 selectivity ", Biochemistry May 23, 2000, vol. 39 (20): 6228-34, and J. Talley et al," 4,5-Diaryloxaz ole inhibitors of cyclooxygenase-2 (COX-2) ", Med. Res. Rev. May 1999; 19 (3): 199-208. Valdecoxib is also included in the meaning of COX-2 inhibitor in this invention, see" 4 - [5-Methyl-3-phenylisoxazol-l-yl] benzenesulfonamide, Valdecoxib: A Potent and Selective Inhibitor of COX-2 ", J. Med. Chem. 2000, Vol. 43: 775-777, and parecoxib sodium salt or parecoxib sodium, see N - [[(5-methyl-3-phenylixoxazol-4yl) -phenyl] sulfonyl] propanimide, Sodium Salt, Parecoxib Sodium: A Potent and Selective Inhibitor of COX-2 for Parenteral Administration ", J. Med. Chem. 2000, Vol. 43: 1661-1663. The term" COX-2 inhibitor "in this invention also includes the substitution of the sulfamide moiety as a suitable substitute for the methylsulfonyl moiety. See , J. Carter et al, Synthesis and activity of sulfonamide-substituted 4,5-diaryl thiazoles as selective cyclooxygenase-2 inhibitors. " Bioorg. Med. Chem. Lett Apr. 19, 1999: Vol. 9 (8): 1171-74, and compounds referenced in the article "Design and synthesis of sulfonyl-substituted 4,5-diarylthiazoles as selective cyclooxygenase-2 inhibitors", Bioorg. Med. Chem. Lett Apr. 19, 1999: Vol. 9 (8): 1167-70. The content of this invention includes a COX-2 inhibitor, NS398, referenced in two articles: Attiga et al, "Inhibitors of Prostaglandin Synthesis Inhibit Human Prostate Tumor Cell Invasiveness and Reduce the Release of Matrix Metalloproteinases", 60 Cancer Research 4629-4637, Aug . 15, 2000, and in "The cyclooxygenase-2 inhibitor celecoxib induces apoptosis by blocking Akt activation in human prostate cancer cells independently of Bcl-2," Hsu et al, 275 (15) J. Biol. Chem. 11397-11403 (2000). The term “COX-2 inhibitor” in this invention includes cyclooxygenase-2 selective compounds referenced by Mitchell et al in Cyclo-oxygenase-2: pharmacology, physiology, biochemistry and relevance to NSAID therapy, Brit. J. of Pharmacology (1999) vol. 128: 1121-1132, see especially page 1126. The so-called NO-NSAIDs or nitric oxide-releasing NSAIDs given by L. Jackson are included in the meaning of “COX-2 inhibitor” in this invention. et al., in "COX-2 Selective Nonsteroidal Anti-Inflammatory Drugs: Do They Really Offer Any Advantages?", Drugs, June, 2000 vol. 59 (6): 1207-1216 and the articles under references 27 and 28. Also included in the meaning of the COX-2 inhibitor in this invention is any substance that selectively inhibits the COX-2 isoenzyme, and not the COX-1 isoenzyme, in a ratio of more than 10 to 1, and preferably in a ratio of at least 40 to 1, as mentioned in Winokur WO 99/20110, and has one substituent having both free-electron atoms located on a closed ring according to the traditional theory of repulsion of valence electron pairs (as in the sulfylamine portion of celecoxib), and a second substituent, located on another ring far enough from the specified first Deputy, so as not to have significant electronic interaction with the first Deputy. The second substituent must have an electronegativity in such a substituent of more than 0.5, or the second substituent must be an atom located on the edge of the compound selected from the group of halogens F, Cl, Br or I, or from elements of group IV, S or O. Therefore, for practical For the purposes of the last included value of the COX-2 inhibitor, one part of the COX-2 inhibitor should be hydrophilic and the other part lipophilic. Also included as an COX-2 inhibitor are the compounds listed on page 553 in the Pharmacotherapy: A Pathophysiologic Approach, Depiro et al (McGraw Hill 1999), including nabumetone and etodolac. Given that there is an overlap between the selective COX-2 inhibitors presented in this section, the meaning of the term COX-2 inhibitor is the comprehensive inclusion of all selective COX-2 inhibitors that are selective for COX-2 inhibition, not COX-1. The inventors added to the class of COX-2 inhibitors useful in this invention a drug called etoricoxib, referred to in the Wall Street Journal on December 13, 2000, manufactured by Merck. See also Chauret et al., "In vitro metabolism considerations, including activity testing of metabolites, in the discovery and selection of the COX-2 inhibitor etoricoxib (MK-0663)," Bioorg. Med. Chem. Lett. 11 (8): 1059-62 (Apr. 23, 2001). Another selective COX-2 inhibitor is the DFU [5,5-dimethyl-3- (3-fluorophenyl) -4- (4-methylsulfonyl) phenyl-2 (5H) furanone] described by Yergey et al, Drug Metab. Dispos. 29 (5): 638-44 (May 2001). The inventors also include, as a selective inhibitor of COX-2, the flavonoid antioxidant silymarin and the active ingredient in silymarin, silibinin, which has shown significant inhibition of COX-2 relative to the inhibition of COX-1. Silymarin also showed a protective effect against glutathione peroxidase depletion. Zhao et al., "Significant Inhibition by the Flavonoid Antioxidant Silymarin against 12-O-tetracecanoylphorbol 13-acetate-caused modulation of antioxidant and inflammatory enzymes, and cyclooxygenase 2 and interleukin-1 alpha expression in SENCAR mouse epidermis: implications in the prevention of stage I tumor promotion, "MoI. Carcinog. December 1999, VoI 26 (4): 321-33 PMID 10569809. Silymarin has also been used to treat liver diseases in Europe.

A number of COX-2 inhibitors as defined above are drug precursors of selective COX-2 inhibitors and exert their effect by in vivo conversion to active and selective COX-2 inhibitors. Active and selective COX-2 inhibitors obtained from prodrugs of the above COX-2 inhibitors are described in detail in WO 95/00501 published January 5, 1995, WO 95/18799 published July 13, 1995, and in US patent No. 5474995, issued December 12, 1995. Based on the data of US patent No. 5543297, entitled: "Human cyclooxygenase-2 and analysis methods for assessing the activity of cyclooxygenase-2", a person skilled in the art will be able to determine whether the agent is a selective COX-2 inhibitor or a precursor of a COX-2 inhibitor, and thus, part of the present invention.

"Direct thrombin inhibitors"

Non-limiting examples of direct thrombin inhibitors include hirudin, hirugen, hirulog, argatroban, PPAC and thrombin aptamers.

Diuretics

Non-limiting examples of diuretics that can be used in the compositions of the present invention include Altiazide, Bendroflumethiazide, Benzthiazide, Butiazide, Chlortalidone, Cyclopentiazide, Cyclothiazide, Epithiazide, Ethiazide, Fenchisone, Indapamide, Hydroflumethiazide, Methicraniazidazide, Methicraniazidazide, Methicraniazidazide, Methicraniazidazide, Methicraniazidazide, Methicraniazidazide, Methicraniazide, teclothiazide, trichloromethiazide, chlormerodrin, meraluride, mercamfamide, mercaptomerin sodium, mercurmatilin sodium, monovalent mercury chloride, mercalyl, acefillin, 7-morpholinomethylteophylline, pambrom, p rototeobromine, theobromine, canrenone, oleandrin, spironolactone, acetazolamide, ambuside, azosemide, bumetanide, butazolamide, clopamide, clorexolone, disulfamide, ethoxolamide, furosemide, amide amide amide, pyrethanamide, pyrethanamide amide arbutin, chlorazanyl, ethacrylic acid, etosoline, hydracarbazine, isosorbide, mannitol, methochalcon, muzolimin, perhexiline, ticrinafen, triamterene, urea, and mixtures thereof. Depending on the diuretic used, potassium may also be administered to the patient to optimize fluid balance, as well as to avoid hypokalemic alkalosis. Administration of potassium can take place in the form of potassium chloride or by daily intake of foods high in potassium, such as, for example, bananas or orange juice.

Endothelin Receptor Antagonists

Non-limiting examples of endothelin receptor antagonists that can be used in the compositions of the present invention include bosentan, sulfamide endothelin antagonists, BQ-123, SQ 28608, and the like. and mixtures thereof.

HMG-CoA reductase inhibitors (Statins)

The reductase HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) is a microsomal enzyme that catalyzes a rate-limiting reaction in cholesterol biosynthesis (HMG-CoA6-Mevalonate). An HMG-CoA reductase inhibitor inhibits HMG-CoA reductase and, as a result, inhibits cholesterol synthesis. A number of HMG-CoA reductase inhibitors have been used to treat patients with hypercholesterolemia. Recently, it has been shown that HMG-CoA reductase inhibitors may be useful in the treatment of stroke (Endres M, et al., Proc Natl Acad Sci US A, 1998, 95: 8880-5).

HMG-CoA reductase inhibitors suitable for co-administration with the agents of the invention include, but are not limited to, simvastatin (US patent No. 4444784), lovastatin (US patent No. 4231938), pravastatin sodium (US patent No. 4346227), fluvastatin (US patent No. 4739073), atorvastatin (US patent No. 5273995), cerivastatin and many others described in US patent No. 5622985; 5,135,935; 5356896; 4,920109; 5,286,895; 5,262,435; 5,260,332; 5,371,031; 5,282,356; 5,256,689; 5,182,298; 5,369,125; 5,302,604; 5,166,171; 5,202,327; 5,267,021; 5,196,440; 5,091,386; 5,091,378; 4,904,646; 5,385,932; 5,250,435; 5,132,312; 5,130,306; 5116870; 5,112,857; 5,102,911; 5,098,931; 5081136; 5,025,000; 5,021,453; 5017716; 5001144; 5,001,128; 4,997,837; 4,996,234; 4,994,494; 4,992,429; 4,970,231; 4,968,693; 4,963,538; 4,957,940; 4,950,675; 4,946,864; 4,946,860; 4,940,800; 4,940,727; 4,939,143; 4,929,620; 4,923,861; 4,906,657; 4906624 and 4897402, the contents of which are incorporated into this description by reference.

Other non-limiting examples of HMG-CoA reductase inhibitors that can be used in the compositions of the present invention include mevastatin, pitavastatin, rosuvastatin, gemcaben and probucol.

Inotropic Agents

Non-limiting examples of inotropic agents that can be used in the compositions of the present invention include acephillin, acetyldigitoxins, 2-amino-4-picoline, amrinone, benfurodil hemisuccinate, bucladesine, camphotamide, convallatoxin, cymarin, denopamine, deslanoside, digitalitalin, digitalitalin, digitalin digoxin, dobutamine, docarpamine, dopamine, dopexamine, enoximon, erythroplein, phenolsomin, gitalin, gitoksin, glycociamine, heptaminol, hydrastitin, ibopamine, lanatosides, loprinin, milrinone, nerifolin, oleandrin, ouabain, oxyfed imobendan, prenalterol, proscillaridin, rezibufogenin, stsillaren, stsillarenin, strophanthin, sulmazol, theobromine, vesnarinone, xamoterol, and mixtures thereof.

"Renin inhibitors"

Renin inhibitors are compounds that interfere with renin activity. Renin inhibitors include amino acids and their derivatives, peptides and their derivatives and antibodies to renin. Examples of renin inhibitors, which are the subject of US patents, are the following compounds: urea derivatives of peptides (US patent No. 5116835); amino acids connected by non-peptide bonds (US patent No. 5114937); di - and tripeptide derivatives (US patent No. 5106835); amino acids and their derivatives (US patent No. 5104869 and 5095119); diol sulfamides and sulfenyls (US patent No. 5098924); modified peptides (US patent No. 5095006); peptidyl beta-aminoacylaminodiol carbamates (US Pat. No. 5,089,471); pyrolimidazolones (U.S. Pat. No. 5075451); peptides containing fluorine or chloride statin or staton (US patent No. 5066643); peptidylaminodiols (US patent No. 5063208 and 4845079); N-morpholine derivatives (US Pat. No. 5,055,466); pepstatin derivatives (US Pat. No. 4,980,283); N-heterocyclic alcohols (US patent No. 4885292); monoclonal antibodies to renin (US patent No. 4780401); and a number of other peptides and their analogues (US patent No. 5071837, 5064965, 5063207, 5036054, 5036053, 5034512 and 4894437).

Vasodilators

Non-limiting examples of vasodilators that can be used in the compositions of the present invention include bencyclan, cinnarizine, citicoline, cyclandelate, cyclonicate, diisopropylamine dichloroacetate, eburnamonin, fazudil, phenoxedil, flunarizin, ibudilast, ifenprodilin isolithidorithonitrosulfate, isoformid, isolithide, isorosulfonitrate, isorosulfonitrate, isorosulfonitrate, isonorithide, isorosulfonitrate, isonorbitonitrosulfonitrate, isonorbitonitrate, isonorbitonitrate, isonorithide, isitoridate, isonorbide, isitoridate, isonorbide , nicergoline, nimodipine, papaverine, pentifillin, tinofedrin, vancamine, vinprocetin, vikhidil, amotrifen, bendazole, benfurodil, hemisuccinate, benziodarone, chlorazizin, chromonar, clobenfuro , clonitrate, cloricromene, dislazep, dipyridamole, droprenylamine, efloxate, erythrityl tetranitrate, ethaphenone, fendilin, floredil, ganglefens, cardiac muscle extract, hexestrol bis (alpha-diethylaminoethyl ether, lidobeninolitin, itlindinitelin, hydrolazinitin, hydrolazinitin, hydrolazinitin, hydrolazinelin, hydrolazinelin, hydrolazine, hydrolazinitin, hydrolazinitin hexanitrate, medibazine, nitroglycerin, isosorbide mononitrate and other nitrates, pentaerythritol tetranitrate, pentrinitrol, perhexylin, pimefillin, prenylamine, propatyl nitrate, pyridophylline, trapidyl, tricromyl, trimetazidine, trinit at, visnadine, aluminum nicotinate, bametan, bencyclan, betahistine, bradykinin, brovinkamine, bufeniod, buflomedil, butalamine, cetiedil, cyclonicate, cinazazide, cinnarizine, cyclandelate, diisopropylamine, hephenyldinodinolin, hephenyldinodinolin, hephenyldinodinolin, hephenyldinodinolin, hephenyldinodinodinolin , isoxuprine, kallidine, kallikrein, moxysilite, nafronil, nikametata nicergoline, nicofuranose, nicotinic alcohol, nilidrin, pentifillin, pentoxifylline, pyribedil, prostaglandin E1, suloctidyl, tolazoline, xanthanol niñinolum.

It should be noted that “hydralazine compound” refers to a compound having the formula:

where a, b and c, each independently, is a single or double bond; R ₁ and R ₂ each independently is hydrogen, alkyl, ester or heterocyclic ring; R ₃ and R ₄ each independently is a lone electron pair or hydrogen, provided that at least one of R ₁ , R ₂ , R ₃ and R _{4 is} not hydrogen. Examples of hydralazine compounds include, but are not limited to, budralazine, cadralazine, dihydralazine, endralazine, hydralazine, pildralazine, todralazine, and the like.

Vasopressors

Non-limiting examples of vasopressors that may be used in the compositions of the present invention include amesinia methyl sulfate, angiotensinamide, dimethofrin, dopamine, ethifelmin, hepefrin, metaraminol, methoxamine, midodrin, norepinephrine, foledrin, synephrine and mixtures thereof.

AGE crosslinkers (crosslinkers of branched glycosylation end products)

Non-limiting examples of AGE crosslinkers that can be used in the compositions of the present invention include aAlabrium.

AGE Formation Inhibitors (Branched Glycosylation End Product Formation Inhibitors)

Non-limiting examples of AGE formation inhibitors that can be used in the compositions of the present invention include pimagedin.

Other active substances:

Non-limiting examples of other active ingredients that can be combined with 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 aloksiprin, auranofin, azapropazone, benorilat, 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;

antihelminthic agents such as albedanzole, befenia hydroxy naphthoate, cambendazole, dichlorophen, ivermectin, mebendazole, oxamnihin, oxfendazole, oxantela embonate, praziquantel, pyrantel embonate and thiabendazole;

anti-asthma agents such as zileuton, zafirlukast, terbutaline sulfate, montelukast and albuterol;

antibacterial agents , such as alatrofloxacin, azithromycin, baclofen, benzathine penicillin, cinoxacin, ciprofloxacin HCl, clarithromycin, clofazimine, cloxacillin, demeclocycline, dirithromycinfiloxinofilofenofidefilofidefilofidefilofideflonidone nitrofurantoin, norfloxacin, ofloxacin, rifampicin, rifabutin, rifapentin, sparfloxacin, spiramycin, sulfabenzamide, sulfadoxine, sulfamerazine, ulfacetamide, sulfadiazine, sulfafurazole, su lfamethoxazole, sulfapyridine, tetracycline, trimethoprim, trovafloxacin and vancomycin;

antiviral agents such as abacavir, amprenavir, delaviridine, efavirenz, indinavir, lamivudine, nelfinavir, nevirapine, ritonavir, saquinavir and stavudine;

antidepressants such as amoxapine, bupropion, citalopram, clomipramine, fluoxetine HCl, maprotiline HCl, mianserin HCl, nortriptyline HCl, paroxetine HCl, sertraline HCl, trazodone HCl, trimipramine maleate and venlafaxine HCl;

antiepileptic drugs such as beclamide, carbamazepine, clonazepam, etotoin, felbamate, sodium fosphenytoin, lamotrigine, methoin, metsuximide, methylphenobarbitone, oxcarbazepine, parametadione, phenacemide, phenobenone, fenucamide, fenucamide, tensecion, phenacemone vigabatrin;

antifungal agents , such as amphotericin, butenafine HCl, butoconazole nitrate, clotrimazole, econazole nitrate, fluconazole, flucytosine, griseofulfine, itraconazole, ketoconazole, miconazole, natamycin, nystatin azolazonazole nitrate, sulfonazonazole nitrate

anti-gout agents such as allopurinol, probenecid, and sulfinpyrazone;

antimalarials such as amodiaquine, chloroquine, chlorproguanil HCl, halofantrine HCl, mefloquine HCl, proguanil HCl, pyrimethamine and quinine sulfate;

anti-migraine agents such as dihydroergotamine mesylate, ergotamine tartrate; frovatriptan, methysergide maleate, naratriptan HCl, pisotifen maleate, risatriptan benzoate, sumatriptan succinate and zolmitriptan;

anti- muscarinic agents such as atropine, benzhexol HCl, biperiden, etopropazine HCl, hyoscyamine, mepenzolate bromide, oxyphencyclimine HCl and tropicamide;

antineoplastic agents and immunosuppressants , such as aminoglutethimide, amsacrine, azathioprine, bicalutamide, bisanthrene, busulfan, camptothecin, capecitabine, chlorambucil, cyclosporine, dacarbazine, ellipticin, methromanthrin metromanthrin metromanthrin metromanthrin metromancitromancitromancitromancitromancanth, erythromanthrin metromanthrin metrinotrin metrinthrin metrinthrin metrinthrin metrinthrin metrinthrin metrinthrin metrinthrin metrinthrin metrincomin , mycophenolate mofetil, nilutamide, paclitaxel, procarbazine HCl, sirolimus, tacrolimus, tamoxifen citrate, teniposide, testolactone, topotecan HCl and toremifene citrate;

antiprotozoal agents such as atovaquone, benznidazole, clioquinol, decohinate, diiodohydroxyquinoline, diloxanide furoate, dinitolmide, furazolidone, metronidazole, nimrazole, nitrofurazone, ornidazole and tinidazole;

antipsychotics , such as aripiprazole, clozapine, ziprasidone, haloperidol, molindone, loxapine, thioridazine, molindone, thiotixen, pimozide, flufenazine, risperidone mesoridazine, quetiapine, trifluoperazin, chlorpromazinpropin, trinazazinpropin, prinazazin,

antithyroid agents such as carbimazole, paricalcitol and propylthiouracil;

antitussive agents such as benzonate;

anxiolytics, sedatives, sleeping pills and antipsychotics , such as alprazolam, amylobarbitone, barbitone, bentazepam, bromazepam, bromperidol, brotizolam, butobarbitone, carbromal, chlordiazepoxide, chlormethiazamazone, clpromazepamazazone, chlorpromazepazamazone, chlorpromazepazamazone, chlorpromazepamazole, , fluanisone, flunitrazepam, triflupromazine, flupentixol decanoate, flufentixol decanoate, flurazepam, gabapentin, haloperidol, lorazepam, lormetazepam, medazepam, meprobamate, mesoridazine, methaqualone, methylphenid am, molindone, nitrazepam, olanzapine, oxazepam, pentobarbitone, perphenazine pimozide, prochlorperazine, pseudoephedrine, quetiapine, risperidone, sertindole, sulpiride, temazepam, thioridazine, triazolam, zolpidem and zopiklon;

corticosteroids such as beclomethasone, betamethasone, budesonide, cortisone acetate, deoxymethasone, dexamethasone, fludrocortisone acetate, flunisolide, fluocortolone, fluticasone propionate, hydrocortisone, methylprednisolone, prednisolone, prednisone and triamine;

antiparkinsonian agents such as apomorphine, bromocriptine mesylate, lisuride maleate, pramipexole, ropinirole HCl and tolcapone;

gastrointestinal agents such as bisacodyl, cimetidine, cisapride, diphenoxylate HCl, domperidone, famotidine, lansoprazole, loperamide, mesalazine, nizatidine, omeprazole, ondansetron HCl, rabeprazole sodium, ranitidine HCl and sulfasalase;

keratolytics such as acitretin, calcipotriene, calciphediol, calcitriol, cholecalciferol, ergocalciferol, etretinate, retinoids, targretin and tazarotene;

lipid regulating agents such as atorvastatin, bezafibrate, cerivastatin, ciprofibrate, clofibrate, fenofibrate, fluvastatin, gemfibrozil, pravastatin, probucol and simvastatin;

muscle relaxants such as dantrolene sodium and tizanidine HCl;

nutrients such as calcitriol, carotenes, dihydrotachysterol, essential fatty acids, minor fatty acids, phytonadiol, vitamin A, vitamin B ₂ , vitamin D, vitamin E and vitamin K;

opioid analgesics such as codeine, dextropropoxyphene, diamorphine, dihydrocodeine, fentanyl, meptazinol, methadone, morphine, nalbuphine and pentazocine;

sex hormones such as clomiphene citrate, cortisone acetate, danazole, dehydroepiandrosterone, ethinyl estradiol, finasteride, fludrocortisone, fluoxymesterone, medroxyprogesterone acetate, megestrol acetate, mestranolone, testosterone styrene, romesterolone congestone tibolone;

stimulants such as amphetamine, dexamphetamine, dexfenfluramine, fenfluramine and mazindol;

anti-rheumatoid arthritis drugs such as methotrexate, auranofin, aurothioglucose and sodium gold thiomalate;

anti-osteoporosis drugs such as alendronate and raloxifene;

local anesthetics;

antiherpetic drugs such as acyclovir, valaciclovir and famciclovir;

antiemetics such as ondansetron and granisetron;

Flavonoids and isoflavonoids include anthocyanidins and anthocyanins; proanthocyanidins; flavan-3-ols; flavonols; flavones; flavanones; isoflavanones; their salts and esters. This development, however, is not limited to flavonoid compounds isolated from a plant, part of a plant or extracts of Astragalus Membranaceus , but encompasses any suitable flavonoid compound isolated from various sources or chemically synthesized. In addition, any suitable known or not yet discovered flavonoid compound and isoflavonoid compound are within the scope of the present procedure. A number of flavonoids and isoflavonoids are described in the USDA-Iowa State University Database on the Isoflavone Content of Foods, Release 1.3-2002 database and the 2003 flavonoid content in selected food products USDA Database for the Flavonoid Content of Selected Foods-2003 (http: //www.nal.usda. Gov / fhic / foodcomp / Data / isoflav / isoflav.html) and (http://www.nal.usda.gov/fnic/foodcomp/Data /Flav/flav.html) (both incorporated herein by reference). It will be apparent to any person skilled in the art how to select a suitable flavonoid and / or isoflavonoid compound for the purposes of this development. For example, flavonoid compounds for the purposes of this development can be, but are not limited to, (-) - epictechin, (+) - catechin, procyanidin B2, quercetin dehydrate, taxifolin, resveratrol, etc.

Carotenoids are usually tetraterpenes, which are derivatives of the biosynthesis of mevalonate and deoxyxylulose phosphate (old sources cite the source of carotenoids as an “isoprenoid” pathway). Two molecules of compound C _{20 of} geranyl geranyl diphosphate (GGDP) condense to form a symmetrical carotenoid skeleton.

Carotenoids are divided into two subclasses, namely, more polar compounds called xanthophylls or oxycarotenoids, and non-polar hydrocarbon carotenes.

Terms such as a carotenoid analog and a carotenoid derivative may generally refer, in some embodiments, to chemical compounds or compositions derived from a naturally occurring carotenoid or simply synthetic carotenoids. In some embodiments, terms such as a carotenoid analog or a carotenoid derivative may generally refer to chemical compounds or compositions that are synthetically prepared from non-carotenoid starting compounds; however, which ultimately are very similar to the analogue obtained from the carotenoid. In certain embodiments, terms such as a carotenoid analog or a carotenoid derivative may generally refer to a synthetic derivative or a naturally occurring carotenoid. Examples of carotenoids are provided in the book "Carotenoids Handbook," edited by G. Britton et al , 2004, which is incorporated herein by reference.

One skilled in the art will appreciate how to select the appropriate carotenoid compound for the purposes of this development.

Examples of carotenoids include astaxanthin, zeaxanthin, lutein, lycopene, beta-carotene.

Other non-limiting examples of naturally occurring carotenoids include: aptopurpurin; actinioerythrin; actinioerythrol; adonirubin; adonixanthin; A.g. 470; A.g. 471; agelaxanthin C; aleuriaxanthin; alloxanthin; amaruciaxanthin A; amaruciaxanthin B; anhovixanthin; 3 ', 4'-anhydrodiatoxanthin; anhydrodeoxyflexixanthin; anhydroeschsholtzxanthin; anhydrolutein; anhydroperidinine; anhydrogen rovibrin; anhydrosaproxanthin; anhydrovirmingol; anhydrovirmingon; anteraxanthin; afanicin; afanikol; Athenan; afanol; afanisophyll; 8'-apo-beta-carotene-8'-al; 10'-apo-beta-carotene-10'-al; 12'-apo-beta-carotene-12'-al; 14'-apo-beta-carotene-14'-al; 6'-apo-psi-carotene-6'-al; 8'-apo-psi-carotene-8'-al; beta apo-2-carotinal; beta apo-3-carotinal; beta apo-4-carotinal; beta apo-2'-carotinal; beta apo-8'-carotinal; beta apo-10'-carotinal; beta apo-12'-carotinal; beta apo-14'-carotinal; apo-8.8'-carotindial; 8'-apo-beta-carotene-3,8'-diol; 4'-apo-beta-carotene-4'-oic acid; 8'-apo-beta-carotene-8'-oic acid; 10'-apo-beta-carotene-10'-oic acid; 12'-apo-beta-carotene-12'-oic acid; beta-apo-2'-carotinic acid; beta-apo-2'-carotinic acid methyl ester; beta-apo-8'-carotinic acid; beta-apo-10'-carotinic acid; beta-apo-12'-carotinic acid; 8'-apo-beta-carotin-3-ol; beta-apo-2'-carotinol; apo-7-fucoxanthinol; apo-2-lycopinal; apo-3-lycopinal; apo-6'-lycopinal; apo-8'-lycopinal; apo-10'-violaxanthal; apo-12'-violaxanthal; apoviolaxanthinal; apo-2-zeaxanthinal; apo-3-zeaxanthinal; apo-4-zeaxanthinal; astacein; astacin; astacin dipalmitate; astaxanthin; asteric acid; asteroidone; asymmetric zeta-carotene; aurochrome; auroxanthin; azafrine; azafrinaldehyde;

bacterial phytoin; bacterioerythrin alpha; bacterioerythrin beta; bacteriopurpurine alpha; bacterioruberin; alpha bacterioruberin; bacterioruberin diglycoside; bacterioruberin monoglycoside; alpha bacterioruberin monomethyl ether; bisanhydrobacterioruberin; 3,4,3 ', 4'-bisdehydro-beta-carotene; bisdehydrolikopin; 2,2'-bis (4-hydroxy-3-methyl-2-butenyl) beta, beta-carotene; 2,2'-bis [3- (glucosyloxy) -3-methylbutyl] -3,4,3 ', 4'-tetrahydro-1,2,1'2'-tetrahydro-psi-psi-carotene-1,1 '-diol; 2,2'-bis [4- (beta, D-glucopyranosyloxy) -3-methyl-2-butenyl] -gamma, gamma-carotene; 2,2'-bis (4-hydroxy-3-methyl-2-butenyl) -gamma, gamma-carotene; 2,2'-bis (4-hydroxy-3-methyl-2-butenyl) - [epsi], [epsi] -carotene; 2,2'-bis (3-hydroxy-3-methylbutyl-3,4,3 ', 4'-tetradehydro-psi, psi-carotene-1,2,1', 2'-tetrahydro-psi, psi-carotene -1,1'-diol; 2,2'-bis (3-methyl-2-butenyl) - [epsi], [epsi] -carotene; 2,2'-bis (3-methyl-2-butenyl) - 3,4,3 ', 4'-tetradehydro-1,2-dihydro-psi, psi-carotin-1-ol; 2,2'-bis (3-methyl-2-butenyl) -3,4,3' , 4'-tetradehydro-1,2,1'2'-tetrahydro-psi-psi-carotene-1,1'-diol; 2,2'-bis (3-methyl-2-butenyl) -1,2, 1'2'-tetrahydro-psi-psi-carotene-1,1'-diol; 2,2'-bis (O-methyl-5-C-methylpentosyloxy) -3,4,3 ', 4'-tetrahydrohydro 1,2,1'2'-tetrahydro-psi-psi-carotene-1,1'-diol; 3,3'-bis (rhamnosyloxy) beta, beta-carotene; 2,2'-bis (rhamnosyloxy) - 3,4,3 ', 4'-tetradehydro-1,2, 1 ', 2'-tetrahydro-psi, psi-carotene-1,1'-diol; biksin;

caloxanthin; kaltaxanthin; canthaxanthin; capsanthin; capsanthin epoxide; capsantinone; capsanton; capsochrome; capsorubin; capsorubindion; capsorubon; Karangoxanthin; 16'-carboxyl-3 ', 4'-dehydro-gamma-carotene;carcinoxanthin;caricaxanthin; beta carotinal; psi, psi-carotene-20-al; carotene; carotene X; alpha carotene; beta carotene; beta, beta-carotene; beta, gamma carotene; beta, [epsi] -carotene; beta, [fi] -carotene; beta, psi-carotene; gamma carotene; gamma, gamma carotene; gamma, psi-carotene; [delta] carotene; [epsi] -carotene; [epsi] (1) -carotene; [epsi], [epsi] -carotene; [epsi], psi-carotene; zeta carotene; zeta-carotene, asim; eta-carotene; [theta] carotene; xi-carotene; [fi] -carotene; [fi], [fi] -carotene; [fi] X-carotene; [fi] psi carotene; X, X-carotene; psi carotene; psi, alpha-carotene; psi, psi-carotene; [theta] carotene; beta-carotene-5,6,5 ', 6'-diepoxide; beta-carotene-5.8.5 ', 8'-diepoxide; beta, beta-carotene-2,2'-diol; beta, beta-carotene-2,3-diol; beta, beta-carotene-3,4-diol; beta, beta-carotene-3,3'-diol; beta, beta-carotene-4,4'-diol; beta, [epsi] -carotene-3,2'-diol; beta, [epsi] -carotene-3,3'-diol; beta, psi-carotene-2,3-diol; beta, psi-carotene-3,3'-diol; [epsi], [epsi] -carotene-3,3'-diol; [phi], [phi] -carotene-3,3'-diol; psi, psi-carotene-16.16'-diol; beta, beta-carotene-3,3'-diol dipalmitate; beta, [epsi] -carotene-3,3'-diol dipalmitate; beta, beta-carotene-2,2'-dione; beta, beta-carotene-3,4-dione; beta, beta-carotene-4,4'-dione; beta, psi-carotene-3,4-dione; [epsi], [epsi] -carotene-3,3'-dione; beta, chi-carotene-3 ', 6'-dione; beta, X-carotene-3,4-dione; beta, psi-carotene-4,4'-dione; beta, [phi] -carotene-3,4-dione; psi, psi-carotene-4,4'-dione;alpha-carotene-5,6-epoxide;beta-carotene-5,6-epoxide; zeta-carotene epoxide; carotene oxide; beta, beta-carotene-3,4,3 ', 4'-tetraol; beta, beta-carotene-2,3,2 ', 3'-tetraol; beta, beta-carotene-3,4,3 ', 4'-tetraone; chi, chi-carotene-3,6,3 ', 6'-tetraone; beta, beta-carotene-2,3,2'-triol; beta, beta-carotene-2,3,3'-triol; beta, beta-carotene-3,4,3'-triol; beta, beta-carotene-3,4,4'-triol; beta, [epsi] -carotene-3,4,3'-triol; beta, [epsi] -carotene-3,19,3'-triol; beta, [epsi] -carotene-3,20,3'-triol; beta, beta-carotene-3,4,4'-trion; beta, beta-carotene-2-ol; beta, beta-carotene-3-ol; beta, beta-carotene-4-ol; beta, [epsi] -carotin-2-ol; beta, [epsi] -carotin-3-ol; beta, [epsi] -carotin-3'-ol; beta, [epsi] -carotin-4-ol; beta, [phi] -carotin-3-ol; beta, X-carotin-3-ol; beta, psi-carotin-3-ol; beta, psi-carotene-4'-ol; [epsi], psi-carotin-3-ol; [phi], [phi] -carotin-3-ol; [phi], [phi] -carotin-16-ol; [phi], [phi] -carotin-20-ol; carotinonaldehyde; beta carotinone; beta, beta-carotene-2-one; beta, beta-carotene-4-one; beta, [epsi] -carotin-2-one; beta, [epsi] -carotin-4-one; beta, psi-carotene-4-one; gamma-carotene-4-one; alpha carotone, celaxanthin; chiriquixanthin A; Hiriquixanthin B; chlorellaxanthin; chlorobactin; chloroxanthin; chrysantemaxanthin; citranaxanthin; alpha citraurin; beta citraurin; beta-citraurinine; beta-citraurinol; citroxanthin; compound X; S.p .: Corynebacterium poinsettiae ; Corinexanthin; Corinexanthin Glucoside; S.R .; S.R .; S.R .; crocetin; gamma crocetin; crocetindial (dehydrate); crocetin diglycosyl ether; crocetin dimethyl ether; crocetin gentiobiosyl glucosyl diester; crocetin glucose methyl ether; crocetin monogentiobiosyl ether; crocetinsemialdehyde; crocin; croxanthine; crustaxanthin; cryptocapsin; cryptocapsone; cryptochrome alpha cryptoeitreptiellanone; beta cryptoetreptiellanone; cryptoflavin; cryptomonaxanthin; cryptoxanthin; cryptoxanthin; alpha cryptoxanthin; beta cryptoxanthin; cryptoxanthin-5,6,5 ', 6'-diepoxide; cryptoxanthin-5,6,5 ', 8'-diepoxide; cryptoxanthin-5.8.5 ', 8'-diepoxide;cryptoxanthin-5,6-epoxide;cryptoxanthin-5.8-epoxide;cryptoxanthol;cucurbitaxanthin; cyclic zeta-carotene; cintiaxanthin; decahydro-beta-carotene; 1,2,7,8,11,12,7 ', 8', 11 ', 12'-decahydro-psi, psi-carotene; 7,8,11,12,15,7 ', 8', 11 ', 12', 15'-decahydro-psi, psi-carotene; 1,2,7,8,11,12,7 ', 8', 11 ', 12'-decahydro-psi, psi-carotin-1-ol; decahydrolikopin; decaprenoxanthin; decaprenoxanthin diglucoside; decaprenoxanthin monoglucoside; deepoxineoxanthin; dehydro-, see also bisdehydro-, didehydro-, monodehydro dehydroadonirubin; dehydroadonixanthin; dehydrocarotene II; dehydrocarotene III; dehydro-beta-carotene; 3,4-dehydro-beta-carotene; 3 ', 4'-dehydro-gamma-carotene; 3 ', 4'-dehydrocryptoxanthin;dehydrogenans-P;dehydrogenans-P;dehydrogenans-P;dehydrogenans-P; dehydrogenans-P 439 mono-OH; dehydrogenans-phytoin; dehydrogenans-phytofluin; dehydrohydroxyecinenone; 3'-dehydrolutein;3,4-dehydrolikopin-16-al;dehydrolikopin;3,4-dehydrolikopin;15,15'-dehydrolycopersin; 7 ', 8', 11 ', 12'-dehydrononaprenoxanthin; 11 ', 12'-dehydrononaprenoxanthin; 3 ', 4'-dehydro-17' (or 18 ') - oxo-gamma-carotene; dehydropapylioerythrin; 11,12-dehydrophytoin; 11 ', 12'-dehydrophytoin;2'-dehydropletanyaxanthin;dehydrorethrocarotene;3,4-dehydrorodopin; dehydrogen rovibrin; 3 ', 4'-dehydrorubixanthin;dehydrosqualene; 7.8,7 ', 8'-dehydrozeaxanthin;7,8-dehydrozeinoxanthin; demethylated spheroidin; deoxyflexixanthin; deoxylutein I; dehydroxydecaprenoxanthin; diadinochrome; diadinoxanthin; dianhydroeschsholtzxanthin; 4,4'-diapo-zeta-carotene;4,4'-diapocarotin-4-al;4,4'-diapocarotin-4,4'-dial;8.8'-diapocarotin-8.8'-dial;6,6'-diapocarotin-6,6'-dionicacid;8.8'-diapocarotin-8.8'-dionicacid;4,4'-diapocarotin-4-acid;4,4'-diaponeurosporin;4,4'-diaponeurosporin-4-oicacid;4,4'-diapophytoin;4,4'-diapophytofluin;4,4'-diapo-7,8,11,12-tetrahydrolikopin;diatoxanthin; didehydro, see also dehydro, monohydro-3 ', 4'-didehydro-2'-apo-beta-carotene-2'-al; 3 ', 4'-didehydro-2'-apo-beta-carotin-2'-ol;7,8-didehydroastaxanthin; 3 ', 4'-didehydro-beta, psi-carotene-16'-al; 3,4-didehydro-psi, psi-carotene-16-al; 3,4-didehydro-beta, beta-carotene; 4,4'-didehydro-beta-carotene; 3,4-didehydro-beta, [epsi] -carotene; 3,4-didehydro-beta, [phi] -carotene; 3,4-didehydro-beta, X-carotene; 3 ', 4'-didehydro-beta, psi-carotene; 3 ', 4'-didehydro-gamma, psi-carotene; 7,8-didehydro- [phi], [phi] -carotene; 7,8-didehydro [phi], X-carotene; 3,4-didehydro-psi, psi-carotene; 7,8-didehydro-beta, beta-carotene-3,3'-diol; 7,8-didehydro-beta, [epsi] -carotene-3,3'-diol; 3,4-didehydro-beta, beta-carotene-2,2'-dione; 3 ', 4'-didehydro-beta, psi-carotene-16'-oic acid; 3 ', 4'-didehydro-beta, beta-carotin-3-ol; 3 ', 4'-didehydro-beta, beta-caroten-4-ol; 7,8-didehydro-beta, [epsi] -carotin-3-ol; 7,8-didehydro-beta, [phi] -carotin-3-ol; 7,8-didehydro-beta, X-carotin-3-ol; 3 ', 4'-didehydro-beta, psi-carotin-3-ol; 3 ', 4'-didehydro-beta, psi-carotin-16'-ol; 3 ', 4'-didehydro-beta, psi-carotene-18'-ol; 3 ', 4'-didehydro-beta, beta-carotene-4-one; 3 ', 4'-didehydro-beta, psi-carotin-4-one; 7 ', 8'-didehydro-beta, beta-carotene-3,4,3'-triol; 3,4-didehydro-1,2-dihydro-psi, psi-carotene; 3,4-didehydro-1,2-dihydro-psi, psi-carotin-20-al; 6,7-didehydro-5,6-dihydro-beta, beta-carotene-3,3'-diol; 3 ', 4'-didehydro-1', 2'-dihydro-beta, psi-carotene-3,1'-diol; 3 ', 4'-didehydro-1', 2'-dihydro-beta, psi-carotene-1,2'-diol; 3 ', 4'-didehydro-1', 2'-dihydro-beta, psi-carotene-4,2'-dione; 3,4-didehydro-1,2-dihydro-psi, psi-carotene-1,2-diol; 7 ', 8'-didehydro-5,6-dihydro-beta, beta-carotene-3,5,6,3'-tetraol; 6,7-didehydro-5,6-dihydro-beta, beta-carotene-3,5,3'-triol;7'8'-didehydro-5,6-dihydro-beta,beta-carotene-3,5,3'-triol; 3 ', 4'-didehydro-1', 2'-dihydro-beta, psi-carotene-2.1 ', 2'-triol; 1 ', 16'-didehydro-1', 2'-dihydro-beta, psi-carotin-2'-ol;3'4'-didehydro-1',2'-dihydro-beta,psi-carotin-1'-ol; 3 ', 4'-didehydro-1', 2'-dihydro-beta, psi-carotin-2'-ol; 3,4-didehydro-1,2-dihydro-psi, psi-carotin-1-ol; 3 ', 4'-didehydro-18'-hydroxy-gamma-carotene;7,8-didehydroisorenieratin; 3 ', 4'-didehydro-4-keto-gamma-carotene;7,8-didehydro-rhenieratin; 4 ', 5'-didehydro-4,5'-retro-beta, beta-carotene; 4 ', 5'-didehydro-4,5'-retro-beta, psi-carotene; didehydroretro-gamma-carotene; 4 ', 5'-didehydro-4,5'-retro-beta, beta-carotene-3,3'-diol; 4 ', 5'-didehydro-4,5'-retro-beta, beta-carotene-3,3'-dione; 10 ', 11'-didehydro-5.8,11', 12'-tetrahydro-10'-apo-beta-carotene-3,5,8-triol; 6 ', 7'-didehydro-5,6,5', 6'-tetrahydro-beta, beta-carotene-3,5,6,3 ', 5'-pentol; 6,7-didehydro-5,6,5 ', 6'-tetrahydro-beta, beta-carotene-3,5,3', 5'-tetraol; 3,4-didehydro-1,2,7 ', 8'-tetrahydro-psi, psi-carotin-1-ol; didehydrotricentriorodine; 7,8-didehydroseaxanthin; didemethylated spirilloxanthin; 1,2,1 ', 2'-diepoxy-2,2'-b is (3-hydroxy-3-methylbutyl) 3,4-didehydro-1,2,1', 2'-tetrahydro-psi, psi carotene; diepoxy beta carotene; 5,8,5 ', 8'-diepoxycryptoxanthin; 5,6,5 ', 6'-diepoxy-5,6,5', 6'-tetrahydro-beta, beta-carotene; 5,6,5 ', 8'-diepoxy-5,6,5', 8'-tetrahydro-beta, beta-carotene; 5.8.5 ', 8'-diepoxy-5.8.5', 8'-tetrahydro-beta, beta-carotene; 5,6,5 ', 6'-diepoxy-5,6,5', 6'-tetrahydro-beta, beta-carotene-3,3'-diol; 5,6,5 ', 8'-diepoxy-5,6,5', 8'-tetrahydro-beta, beta-carotene-3,3'-diol; 5.8.5 ', 8'-diepoxy-5.8.5', 8'-tetrahydro-beta, beta-carotene-3,3'-diol; 5,6,5 ', 6'-diepoxy-5,6,5', 6'-tetrahydro-beta, beta-carotin-3-ol; 5,6,5 ', 8'-diepoxy-5,6,5', 8'-tetrahydro-beta, beta-carotin-3-ol; 5.8.5 ', 8'-diepoxy-5.8.5', 8'-tetrahydro-beta, beta-carotin-3-ol; 5,6,5 ', 8 '-diepoxyseaxanthin; 5.8.5 ', 8 '-diepoxyseaxanthin; digentiobiosyl 8.8'-diapocarotin-8.8'-dioate; di- (beta, D-glucopyranosyl) -4,4'-diapocarotin-4,4'-dioate; diglucosyl 8.8'-diapocarotin-8.8'-dioate;dihydroanhydrodovibrin; 9 ', 10'-dihydro-9'-apo-beta-carotene-3,9'-dione; 9 ', 10'-dihydro-9'-apo [epsi] carotene-3,9'-dione; 7 ', 8'-dihydro-7'-apo-beta-carotene-8'-one; 5 ', 6'-dihydro-5'-apo-18'-nor-beta-carotene-6'-one;7,8-dihydroastaxanthin; beta dihydrocarotene; 1,1'-dihydro-beta-carotene;3,4-dihydro-beta-carotene;7,7'-dihydro-beta-carotene; 7 ', 8'-dihydro-beta, psi-carotene; 7 ', 8'-dihydro-gamma-carotene; 7 ', 8'-dihydro-gamma, psi-carotene; 7 ', 8'-dihydro [delta] carotene; 7 ', 8'-dihydro- [epsi], psi-carotene; 1,2-dihydro-zeta-carotene; 1,2-dihydro-psi, psi-carotene; 7,8-dihydro-psi, psi-carotene; 7,8-dihydro-beta, beta-carotene-3,3'-diol; 7 ', 8'-dihydro-beta, psi-carotene 3.17'-diol; 9 ', 10'-dihydro-beta, psi-carotene-3,17'-diol; 7 ', 8'-dihydro- [epsi], psi-carotene-3,17'-diol; 1,2-dihydro-psi, psi-carotene-1,20-diol; 5,6-dihydro-beta, beta-carotene-3,5,6,3'-tetraol; 5,6-dihydro-beta, beta-carotene-3,5,3'-triol; 1 ', 2'-dihydro-beta, psi-carotin-1'-ol; 7 ', 8'-dihydro-beta, psi-carotin-3-ol; 1 ', 2'-dihydro [phi], psi-carotin-1'-ol; 1,2-dihydro-psi, psi-carotin-1-ol; 5,6-dihydro-beta, beta-carotene-3,5,6,3'-tetraol; 5,6-dihydro-beta, [epsi] -carotene-3,5,6,3'-tetraol; 7.8 (or 7 ', 8) -dihydrodecaprenoxanthin monoglucoside; 1 ', 2'-dihydro-3', 4'-dehydro-3,1'-dihydroxy-gamma-carotene;1,2-dihydro-3,4-dehydrolikopin;1,2-dihydro-3,4-dehydro-1-OH-lycopene;7,8-dihydro-4,4'-diapocarotene; 7 ', 8'-dihydro-4,4'-diapocarotin-4-al; 7 ', 8'-dihydro-4,4'-diapocarotin-4-oic acid; 1 ', 2'-dihydro-3', 4'-didehydro-3,1'-dihydroxy-gamma-carotene-2'yl rhamnoside; 1 ', 2'-dihydro-1', 2'-dihydroxy-4-ketotorulin; 1 ', 2'-dihydro-3,1'-dihydroxytorulin glucoside; 1 ', 2'-dihydro-3,1'-dihydroxytorulin rhamnoside; 1 ', 2'-dihydro-4,2'-diketotorulin;3'-dihydro [boxH] doradecin; 1 ', 2'-dihydro-1'-glucosyl-3,4-dehydrotorulin; 1 ', 2'-dihydro-1'-glucosyl-4-ketotorulin; 1 ', 2'-dihydro-1'-hydroxy-gamma-carotene; 1 ', 2'-dihydro-1'-hydroxychiorobactin; 1 ', 2'-dihydro-2'-hydroxy-3', 4'-dehydro-4-keto-gamma-carotene; 1 ', 2'-dihydro-1'-hydroxy-3,4-dehydrotorulin glucoside; 1 ', 2'-dihydro-1'-hydroxy-4-keto-gamma-carotene; 1 ', 2'-dihydro-1'-hydroxy-4-ketotorulin; 1 ', 2'-dihydro-1'-hydroxy-4-ketotorulin glucoside; 1 ', 2'-dihydro-1'-hydroxysferoidinone; 1 ', 2'-dihydro-1'-hydroxytorulin glucoside; 1 ', 2'-dihydro-1'-hydroxytorulin rhamnoside; 1,2-dihydrolikopin; 1 ', 2'-dihydrolycopene;7,8-dihydrolikopin;1,2-dihydro-1-methoxy-lycopin-20-al;dihydromethoxylikopin;5,6-dihydro-4-methoxy-lycopin-6-one;1,2-dihydroneurosporin; 1 ', 2'-dihydroneurosporin;1,2-dihydro-1-OH-lycopene; 1 ', 2'-dihydro-1'-OH-torulin;2'-dihydrophyllipsiaxanthine;dihydrophytoin;1,2-dihydrophytoin; 1 ', 2'-dihydrophytoin;1,2-dihydrophytoluin; 1 ', 2'-dihydrophytoluin;7.8-dihydro-8.7'-retro beta, beta-carotene; 7 ', 8'-dihydrogen rovibrin; 7.8 (or 7 ', 8') - dihydrosarcinaxanthin; 3,4-dihydrospheroidine; 11 ', 12'-dihydrospheroidine;3,4-dihydrospirilloxanthin;3,3'-dihydroxycanthaxanthin;3,3'-dihydroxy-alpha-carotene;3,4-dihydroxy-beta-carotene; 2,3-dihydroxy-beta, beta-carotene-4,4'-dione;3,3'-dihydroxy- [epsi] carotene; 2,3'-dihydroxy-beta, beta-carotene-4,4'-dione;3,3'-dihydroxy-beta,beta-carotene-4,4'-dione;3,3'-dihydroxy-beta, [epsi] -carotene-4,2'-dione;3,3'-dihydroxy-beta,chi-carotene-4,6'-dione;3,3'-dihydroxy-chi;chi-carotene-6,6'-dione; 2,3-dihydroxy-beta, beta-carotin-4-one; 3,3'-dihydroxy-beta, beta-carotene-4-one; 3,2'-dihydroxy-beta, [epsi] -carotin-4-one; 3,3'-dihydroxy-beta, [epsi] -carotin-4-one; 3,3'-dihydroxy-beta, chi-carotin-6'-one; 3,8-dihydroxy-chi, X-carotin-6-one; 3,3'-dihydroxydehydro-beta-carotene;3,3'-dihydroxy-7,8-dehydro-beta-carotene;3,3'-dihydroxy-7,8,7',8'-dehydro-beta-carotene;3,3'-dihydroxy-7,8-dehydro-beta-carotene-5',6'-epoxide;3,3'-dihydroxy-2,3-didehydro-beta,beta-carotene-4,4'-dione;3,3'-dihydroxy-7,8-didehydro-beta,beta-carotene-4,4'-dione; 3 ', 8'-dihydroxy-7,8-didehydro-beta, chi-carotene-3', 6'-dione;3,3'-dihydroxy-2,3-didehydro-beta,beta-carotin-4-one;3,3'-dihydroxy-7',8'-didehydro-beta,beta-carotin-4-one;3,4'-dihydroxy-2,3-didehydro-beta,beta-carotin-4-one;3,3'-dihydroxy-2,3-didehydro-beta, [epsi] -carotin-4-one; 3,8-dihydroxy-7 ', 8'-didehydro-chi, X-carotene-6-one; 3,6'-dihydroxy-7,8-didehydro-6 ', 7'-dihydro-beta, [epsi] -carotene-3', 8'-dione;3,3'-dihydroxy-7,8-didehydro-7',8'-dihydro-beta,chi-carotene-6',8'-dione;3,1'-dihydroxy-3',4'-didehydro-1',2'-dihydro-beta,psi-carotin-4-one; 1 ', 2'-dihydroxy-3', 4'-didehydro-1 ', 2'-dihydro-beta, psi-carotin-4-one; 3,5-dihydroxy-6,7-didehydro-5,6,7 ', 8'-tetrahydro-7'-apo-beta-carotin-8'-one;6,3'-dihydroxy-7',8'-didehydro-5,6,7,8-tetrahydro-beta,beta-carotene-3,8-dione;3,3'-dihydroxy-5,8,5',8'-diepoxy-beta-carotene;5,6-dihydroxy-5,6-dihydro-10'-apo-beta-carotene-10'-al;5,6-dihydroxy-5,6-dihydro-10'-apo-beta-carotene-10'-oicacid;5,6-dihydroxy-5,6-dihydro-12'-apo-beta-carotene-12'-oicacid;3,3'-dihydroxy-7,8-dihydro-beta,beta-carotene-4,4'-dione;3,1'-dihydroxy-1',2'-dihydrotorulin; 1 ', 2'-dihydroxy-1', 2'-dihydrotorulin;3,3'-dihydroxy-4,4'-diketo-beta-carotene;3,3'-dihydroxy-2,2'-dinor-beta,beta-carotene-4,4'-dione-3,3'-diacylate; 3,19-dihydroxy-3 ', 6'-dioxo-7,8-didehydro-beta, chi-carotene-17-al; 1,1'-dihydroxy-2,2'-diramnosyl-1,2,1 ', 2'-tetrahydro-3,4,3', 4'-tetrahydrolikopin;3,3'-dihydroxyecininone;3,3'-dihydroxy-5,6-epoxy-alpha-carotene;3,3'-dihydroxy-5,8-epoxy-alpha-carotene;3,3'-dihydroxy-5,6-epoxy-beta-carotene;3,3'-dihydroxy-5,8-epoxy-beta-carotene; 2- (dihydroxyisopentenyl) -2'-isopentenyl-beta-carotene;3,3'-dihydroxyisorenieratin;3,3'-dihydroxy-4-keto-gamma-carotene;3,3'-dihydroxyluteochrome; dihydroxy silikopin; 3,1'-dihydroxy-2 '- (5-C-methylpentosyloxy) -3', 4'-didehydro-1 ', 2'-dihydro-beta, psi-carotin-4-one; dihydroxyneurosporin; 2 ', 3'-dihydroxy-2-nor-beta, beta-carotene-3,4-dione; 3,3'-dihydroxy-2-nor-13-beta, beta-carotene-4,4'-dion-3-acylate;3,3'-dihydroxy-2-nor-13-beta,beta-carotene-4,4'-dione-3,3'-diacylate;1,2-dihydroxyphytoluene;dihydroxypyrardixanthin;3,3'-dihydroxyretro-beta-carotene;3,3'-dihydroxy-2,3,2'3'-tetradehydro-beta,beta-carotene-4,4'-dione;3,3'-dihydroxy-7,8,7',8'-tetradehydro-beta,beta-carotene-4,4'-dione;3,3'-dihydroxy-2,3,2',3'-tetradehydro-beta,beta-carotene-4,4'-dionedipalmitate;3,3'-dihydroxy-7,8,7',8'-tetradehydro-beta,beta-carotin-4-one;1,1'-dihydroxy-3,4,3',4'-tetrahydro-1,2,1',2'-tetrahydro-psi,psi-carotene-2,2'-dione;3,8'-dihydroxy-5',6', 7 ', 8'-tetrahydro-5'-apo-18'-nor-beta-carotin-6'-one;1,1'-dihydroxy-1,2,1'2'-tetrahydro-zeta-carotene;5,5'-dihydroxy-5,6,5',6'-tetrahydro-beta,beta-carotene-3,3'-dione;3,3'-dihydroxy-7,8,7',8'-tetrahydro-chi,chi-carotene-6,6'-dione; 9 ', 10'-dihydro-beta-zeacarotin-3,17'-diol; diketo-, see also dioxo- or -dione 2,2'-diketobacterioruberin;3,4-diketo-beta-carotene;4,4'-diketo-beta-carotene;4,4'-diketo-gamma-carotene;4,4'-diketocintiaxanthin;3,3'-diketodehydro-beta-carotene;4,4'-diketolikopin;diketopyrardixanthin;3,3'-diketoretro-beta-carotene;3,3'-diketoretrodehydro-beta-carotene;2,2'-diketospirilloxanthin;4,4'-diketo-7,8,7',8'-tetradehydrozeaxanthin;3,3'-dimethoxy-beta,beta-carotene;3,3'-dimethoxy-beta, [epsi] -carotene; 3,3'-dimethoxy-gamma-carotene;3,3'-dimethoxy-3',4'-dehydro-gamma-carotene;1,1'-dimethoxy-3,4-didehydro-1,2,1',2', 7 ', 8'-hexahydro-psi, psi-carotene; 1,1'-dimethoxy-3,4-didehydro-1,2,1 ', 2', 7 ', 8'-hexahydro-psi, psi-carotin-2-one; 1,1'-dimethoxy-3,4-didehydro-1,2,1 ', 2'-tetrahydro-psi, psi-carotene; 1,1'-dimethoxy-3 ', 4'-didehydro-1,2,1', 2'-tetrahydro-psi, psi-carotin-4-one; 1,1'-dimethoxy-1,2,7,8,1 ', 2'-hexahydro-psi, psi-carotene; 1,1'-dimethoxy-1,2,7,8,11,12,1 ', 2'-octahydro-psi, psi-carotene; 1,1'-dimethoxy-3,4,3 ', 4'-tetrahydro-1,2,1', 2'-tetrahydro-psi, psi-carotene; 1,1'-dimethoxy-3,4,3 ', 4'-tetrahydro-1,2,1', 2'-tetrahydro-psi, psi-carotene-2,2'-dione;1,1'-dimethoxy-1,2,1',2'-tetrahydro-psi,psi-carotene-20-al;1,1'-dimethoxy-1,2,1',2'-tetrahydro-psi,psi-carotene;1,1'-dimethoxy-1,2,1',2'-tetrahydro-psi,psi-carotene-4,4'-dione;1,1'-dimethoxy-1,2,1',2'-tetrahydrolikopin;1,1'-dimethoxy-1,1',2,2'-tetrahydroneirosporin; dimethyl crocetin; dimethyl-6,6'-diapocarotin-6,6'-dioate;dimethyl-8.81-diapocarotin-8.8'-dioate;dineapolitanosyl-8.8'-diapocarotin-8.8'-dioate; 2,2-dinor-beta, beta-carotene-3,4,3 ', 4'-tetraone;dinoxanthin;3,3'-dioxo-4-oxo-beta-carotene; dioxo, see also diketo- or-dione 5,6-dioxo-10'-apo-5,6-seco-beta-carotene-10'-al; 5,6,5 ', 6'-disco-beta, beta-carotene-5,6,5', 6'-tetraone; 7,8,11,12,13,14,15,7 ', 8', 11 ', 12', 15'-dodecahydro-13.15 ', 14.15'-biscyclo-15.15'-sec psi, psi-carotene-15-ol; dodecahydrolikopin; alpha doradecin; beta doradecin; alpha doradexanthin; beta doradexanthin;

echinenone; echininone; eloxanthin; 6-epicaproxanthin; 3'-epilutein; 5,6-epoxy-alpha-carotene; 5,8-epoxy alpha carotene; 5,8-epoxy beta carotene; 1,2-epoxy-1,2,7,8,11,12,7 ', 8', 11 ', 12'-decahydro-psi, psi-carotene; 5,6-epoxy-7 ', 8'-didehydro-5,6-dihydro-beta, beta-carotene-3,3'-diol; 5,8-epoxy-7 ', 8'-didehydro-5,8-dihydro-beta, beta-carotene-3,3'-diol; 1 ', 2'-epoxy-3', 4'-didehydro-1,2'-dihydro-beta, psi-carotin-2-ol; 5'6'-epoxy-6,7-didehydro-5,6,5'6'-tetrahydro-beta, beta-carotene-3,5,19 (or 19 ') - 3'-tetraol; 5'6'-epoxy-6,7-didehydro-5,6,5'6'-tetrahydro-beta, beta-carotene-3,5,3'-triol; 5 ', 6'-epoxy-6,7-didehydro-5,6,5', 6'-tetrahydro-beta, beta-carotene-3,5,3'-triol 3-acetate; 5 ', 8'-epoxy-6,7-didehydro-5,6,5', 8'-tetrahydro-beta, beta-carotene-3,5,3'-triol; 5,6-epoxy-5,6-dihydro-12'-apo-beta-carotene-3,12'-diol; 5,8-epoxy-5,8-dihydro-10'-apo-beta-carotene-3,10'-diol; 5,8-epoxy-5,8-dihydro-12'-apo-beta-carotene-3,12'-diol; 5,6-epoxy-5,6-dihydro-beta, beta-carotene; 5.8-epoxy-5.8-dihydro-beta, beta-carotene; 5,6-epoxy-5,6-dihydro-beta, [epsi] -E-carotene; 5.8-epoxy-5.8-dihydro-beta, [epsi] -carotene; 1 ', 2'-epoxy-1', 2'-dihydro-beta, psi-carotene; 1 ', 2'-epoxy-1', 2'-dihydro- [epsi], psi-carotene; 1,2-epoxy-1,2-dihydro-psi, psi-carotene; 5,6-epoxy-5,6-dihydro-psi, psi-carotene; 5,6-epoxy-5,6-dihydro-beta, beta-carotene-3,3'-diol; 5.8-epoxy-5.8-dihydro-beta, beta-carotene-3,3'-diol; 5,6-epoxy-5,6-dihydro-beta, [epsi] -carotin-3, 3'-diol; 5,6-epoxy-5,6-dihydro-beta, [epsi] -carotene-3,3'-diol dipalmitate; 5,8-epoxy-5,8-dihydro-beta, [epsi] -carotene-3,3'-diol; 5,6-epoxy-5,6-dihydro-beta, [epsi] -carotene-3,3 ', 6'-triol; 5,8-epoxy-5,8-dihydro-beta, [epsi] -carotene-3,3 ', 6'-triol; 5,6-epoxy-5,6-dihydro-beta, beta-carotin-2-ol; 5,6-epoxy-5,6-dihydro-beta, beta-carotin-3-ol; 5 ', 8'-epoxy-5', 8'-dihydro-beta, beta-carotin-3-ol; 5,6-epoxy-5,6-dihydro-beta, [epsi] -carotin-2-ol; 5,6-epoxy-5,6-dihydro-beta, psi-carotin-3-ol; 5.8-epoxy-5.8-dihydro-beta, psi-carotin-3-ol; 5,8-epoxy-3,3'-dihydroxy-alpha-carotene; 5,6-epoxy-3,3'-dihydroxy-7 ', 8'-didehydro-5,6,7,8-tetrahydro-beta, beta-carotin-8-one; 5 ', 6'-epoxy-3,3'-dihydroxy-7,8-didehydro-5', 6'-dihydro-10,11,20-trinor-beta, beta-carotene-19 ', 11'-olide ; 5 ', 6'-epoxy-3,3'-dihydroxy-4,7-didehydro-5', 6'-dihydro-10,11,20-trinor-beta, beta-carotene-19 ', 11'-olide 3-acetate; 5 ', 6'-epoxy-3,3'-dihydroxy-7,8-didehydro-5', 6'-dihydro-10,11,2O-trinor-beta, beta-carotene-19 ', 11'-olide 3-acetate; 5,6-epoxy-3,3'-dihydroxy-5,6-dihydro-beta, chi-carotin-6'-one; 5,8-epoxy-3,3'-dihydroxy-5,8-dihydro-beta, chi-carotin-6'-one; 5,6-epoxy-3,3'-dihydroxy-5,6,7 ', 8'-tetrahydro-beta, [epsi] -carotene-11', 19'-olide; 1 ', 2'-epoxy-2' - (2,3-epoxy-3-methylbutyl) -2- (3-hydroxy-3-methylbutyl) -3 ', 4'-didehydro-1,2,1', 2'-tetrahydro-psi, psi-carotin-1-ol; 1,2-epoxy-1,2,7,8,7 ', 8'-hexahydro-psi, psi-carotene; 5,6-epoxy-3-hydroxy-8'-apo-beta-carotene-8'-al; 5,6-epoxy-5,6-dihydro-10'-apo-beta-carotene-3,10'-diol; 5,8-epoxy-3-hydroxy-gamma-carotene; 5,8-epoxy-3-hydroxy-5,8-dihydro-8'-apo-beta-carotene-8'-al; 5,6-epoxy-3-hydroxy-5,6-dihydro-10'-apo-beta-carotene-10'-al 502; 5,6-epoxy-3-hydroxy-5,6-dihydro-12'-apo-beta-carotene-12'-al; 5,6-epoxy-3-hydroxy-5,6,7 ', 8'-tetrahydro-7'-apo-beta-carotin-8'-one; 5,8-epoxylutein; 1,2-epoxy-1,2,7,8,11,12,7 ', 8'-octahydro-psi, psi-carotene; 1,2-epoxy-1,2,7,8,7 ', 8', 11 ', 12'-octahydro-psi, psi-carotene; 1 ', 2'-epoxy-7,8,11,12,1', 2 ', 7', 8'-octahydro-beta, psi-carotin-2-ol; 1,2-epoxyphytoin; 5,8-epoxirubixanthin; 5 ', 8'-epoxy-5,6,5', 8'-tetrahydro-beta, beta-carotene-3,5,6,3'-tetraol; 5 ', 6'-epoxy-5,6,5', 6'-tetrahydro-beta, beta-carotene-3,5,6,3'-tetraol; 5,6-epoxy-3 ', 4', 7 ', 8'-tetradehydro-5,6-dihydro-beta, beta-carotin-4-one; 5,6-epoxy-3,3 ', 5', 19'-tetrahydroxy-6 ', 7'-didehydro-5,6,7,8,5', 6'-hexahydro-beta, beta-carotene-8 -one 3'-acetate 19'-hexanoate; 5,6-epoxy-3,3 ', 5'-trihydroxy-6', 7'-didehydro-5,6,7,8,5 ', 6'-hexahydro-beta, beta-carotin-8-one; 5,6-epoxy-3,3 ', 5'-trihydroxy-6', 7'-didehydro-5,6,7,8,5 ', 6'-hexahydro-beta, beta-carotene-8-one 3 '-acetate; 5 ', 6'-epoxy-3,5,3'-trihydroxy-6,7-didehydro-5,6,5', 6'-tetrahydro-10,11,12-trinor-beta, beta-carotene-19 ', 11'-olide; 5 ', 6'-epoxy-3,5,3'-trihydroxy-6,7-didehydro-5,6,5', 6'-tetrahydro-10,11,20-trinor-beta, beta-carotene-19 ', 11'-olide 3-acetate; 4 ', 5'-epoxy-3,6,3'-trihydroxy-7,8,4', 5 ', 7', 8'-hexahydro-gamma, [epsi] -carotin-8-one; 5,6-epoxyseaxanthin; 5,8-epoxyseaxanthin; eskhsholtzksantin; eskhsholtzksanton; 4'-ethoxy-beta, beta-caroten-4-one; 4'-ethoxy-4-keto-beta-carotene; euglenanone; euglenarodon; eutreptiellanone;

flavacin; flavochrome; flavorodine; flavoxanthin; flexixanthin; foliachrome; foliaxanthin; fritshiellaxanthin; fucochrome; fucoxanthin; fucoxanthinol; fucoxanthol;

gazaniaxanthin; beta, D-gentiobiosyl beta, D-glucosyl-8.8'-diapocarotin-8.8'-dioate; gentiobiosyl hydro-8.8'-dioate; gentiobiosyl neapolitanosyl 8.8'-diapocarotin-8.8'-dioate; beta, D-glucosyl hydro-4,4'-diapocarotin-4,4'-dioate; 4'-beta, D-glucosyl 4-hydro-7 ', 8'-dihydro-4,4'-diapocarotin-4,4'-dioate; beta, D-glucosyl hydro-8.8'-diapocarotin-8.8'-dioate; beta, D-glucosyl methyl 8,8'-diapocarotin-8,8'-dioate; glucopyranosyloxy (see glucosyloxy); 4-glucosyloxy-4,4'-diaponeurosporin; 1'-glucosyloxy-3 ', 4'-didehydro-1', 2'-dihydro-beta, psi-carotene; 1-glucosyloxy-3,4-didehydro-1,2-dihydro-psi, psi-carotene; 2'-glucosyloxy-3 ', 4'-didehydro-1', 2'-dihydro-beta, psi-carotene-3,1'-diol; 1'-glucosyloxy-3 ', 4'-didehydro-1', 2'-dihydro-beta, psi-carotin-3-ol; 1'-glucosyloxy-3 ', 4'-didehydro-1', 2'-dihydro-beta, psi-carotin-2'-ol; 1'-glucosyloxy-3 ', 4'-didehydro-1', 2'-dihydro-beta, psi-carotin-4-one; 1-glucosyloxy-3,4-didehydro-1,2,7 ', 8'-tetrahydro-psi, psi-carotene; 1-glucosyloxy-1,2-dihydro-psi, psi-carotin-20-al; 1-glucosyloxy-1 ', 2'-dihydro-beta, psi-carotene; 1'-glucosyloxy-1 ', 2'-dihydro [phi], psi-carotene; 1-glucosyloxy-1,2-dihydro-psi, psi-carotene; 4-glucosyloxy-7 ', 8'-dihydro-4,4'-diapocarotene; 1'-glucosyloxy-2-hydroxy-3 ', 4'-didehydro-1', 2'-dihydro-beta, psi-carotin-4-one; 2- (4-glucosyloxy-3-methyl-2-butenyl) -2 '- (4-hydroxy-3-methyl-2-butenyl) -gamma, gamma-carotene; 2- (4-glucosyloxy-3-methyl-2-butenyl) -2 '- (4-hydroxy-3-methyl-2-butenyl) - [epsi], [epsi] -carotene; 2- (4-glucosyloxy-3-methyl-2-butenyl) -2 '- (4-hydroxy-3-methyl-2-butenyl) -7,8-dihydro- [epsi], [epsi] -carotene; 2 '- (4-glucosyloxy-3-methyl-2-butenyl) -2- (3-methyl-2-butenyl) - [epsi], [epsi] -carotin-18-ol; 2- [3- (glucosyloxy) -3-methylbutyl] -2 '- (3-hydroxy-3-methylbutyl) -3,4,3', 4'-tetrahydro-1,2,1 ', 2'-tetrahydro psi, psi-carotene-1,1'-diol; 1'-glucosyloxy-3,4,3 ', 4'-tetradehydro-1', 2'-dihydro-beta, psi-carotene; glycymerin; guaraxanthin;

halocinthiaxanthin; gelenium; heteroxanthin; hexadecahydrolikopin; 2,3,2 ', 3', 45'-hexadehydro-4,5'-retro-beta, beta-carotene; 1,2,7,8,11,12-hexahydro-psi, psi-carotene; 1,2,7,8,1 ', 2'-hexahydro-psi, psi-carotene; 1,2,7,8,7 ', 8'-hexahydro-psi, psi-carotene; 7,8,11,12,7 ', 8'-hexahydro-psi, psi-carotene; 7,8,11,12,7 ', 8'-hexahydro-beta, psi-carotin-2-ol; 15.7 ', 8', 11 ', 12', 15'-hexahydro-beta, psi-carotin-2-ol; 1,2,7 ', 8', 11 ', 12'-hexahydro-psi, psi-carotin-1-ol; 7,8,11,12,7 ', 8'-hexahydro-psi, psi-carotin-16-ol; 7,8,11,12,7 ', 8'-hexahydro-4,4'-diapocarotene; 1,2,7,8,11,12-hexahydrolikopin; 1 ', 2', 7 ', 8'11', 12'-hexahydrolikopin; 7,8,11,12,7,8'-hexahydrolikopin; 7,8,1 ', 2', 7 ', 8'-hexahydrolikopin; 3,4,3 ', 4', 7 ', 8'-hexahydro-spirilloxanthin; 19'-hexanoyloxyfucoxanthin; 19-hexanoyloxy paracentron; 1-hexosyl-1,2-dihydro-3,4-didehydro-apo-8'-lycopinol; O-hexosyl-1'-hydroxy-1 ', 2'-dihydro-gamma-carotene; O-hexosyl-4-keto-1'-hydroxy-1 ', 2'-dihydro-3', 4'-didehydro-gamma-carotene; hopkinsiaxanthin; hydroxy, see also monohydroxy, OH or -ol 3-hydroxy-beta-apo-2-carotinal; 3-hydroxy-8'-apo-beta-carotene-8'-al; 3-hydroxy-10'-apo-beta-carotene-10'-al: 3-hydroxy-12'-apo-beta-carotene-12'-al; 3-hydroxy-8'-apo [epsi] carotene-8'-al; 3-hydroxy-8'-apo-beta-carotene-8'-oic acid; 9'-hydroxy-9'-apo-beta-carotin-3-one; 9'-hydroxy-9'-apo [epsi] -carotin-3-one; hydroxyasteroidone; 3-hydroxycanthaxanthin; 3-hydroxy-beta, psi-carotene-18'-al; 3-hydroxy alpha-carotene; 3'-hydroxy-alpha-carotene; 4-hydroxy alpha-carotene; 2-hydroxy-beta-carotene; 3-hydroxy-beta-carotene; 4-hydroxy-beta-carotene; 3-hydroxy-gamma-carotene; 4'-hydroxy-gamma-carotene; 3-hydroxy- [delta] carotene; 2-hydroxy-beta, beta-carotene-4,4'-dione; 3-hydroxy-beta, beta-carotene-4,4'-dione; 3'-hydroxy-beta, beta-carotene-3,4-dione; 4'-hydroxy-beta, beta-carotene-3,4-dione; 3-hydroxy-beta, [epsi] -carotene-4,3'-dione; 3'-hydroxy-beta, [epsi] -carotene-3,4-dione; 3-hydroxy-beta, chi-carotene-3 ', 6'-dione; 3'-hydroxy-beta, beta-carotene-3,4,4'-trion; 2'-hydroxy-beta, beta-carotin-2-one; 2-hydroxy-beta, beta-carotin-4-one; 3-hydroxy-beta, beta-carotin-4-one; 3'-hydroxy-beta, beta-carotin-4-one; 4'-hydroxy-beta, beta-carotin-4-one; 3-hydroxy-beta, [epsi] -carotin-4-one; 3-hydroxy-beta, [epsi] -carotin-3'-one; 3'-hydroxy-beta, chi-carotene-6'-one; 3-hydroxy-beta, psi-carotene-4'-one; 3-hydroxy-beta, psi-carotin-4-one; 3-hydroxy- [epsi], [epsi] -carotin-3'-one; 3'-hydroxy-psi, psi-carotin-4-one; 3-hydroxycytranaxanthin; 3-hydroxy-7,8-dehydro-alpha-carotene; 3'-hydroxy-3,4-dehydro-beta-carotene; 3-hydroxy-3 ', 4'-dehydro-gamma-carotene; 4-hydroxy-4,4'-diaponeurosporin; 3-hydroxy-2,3-didehydro-beta, beta-carotene-4,4'-dione; 2'-hydroxy-3,4-didehydro-beta, beta-carotin-2-one; 3-hydroxy-2,3-didehydro-beta, beta-carotin-4-one; 3-hydroxy-2,3-didehydro-beta, [epsi] -carotin-4-one; 3-hydroxy-2,3-didehydro-beta, X-carotin-4-one; 3-hydroxy-2,3-didehydro-beta, [phi] -carotin-4-one; 3-hydroxy-3 ', 4'-didehydro-beta, psi-carotin-4-one; 3-hydroxy-7,8-didehydro-7 ', 8'-dihydro-7'-apo-beta-carotene-4,8'-dione; 3-hydroxy-7,8-didehydro-7 ', 8'-dihydro-7'-apo-beta-carotene-8'-one; 3-hydroxy-7 ', 8'-didehydro-7.8-dihydro-chi, X-carotene-6.8-dione; 1'-hydroxy-3 ', 4'-didehydro-1', 2'-dihydro-beta, psi-carotin-4-one; 1'-hydroxy-3 ', 4'-didehydro-1', 2'-dihydro-beta, psi-carotin-2'-one; 2'-hydroxy-3 ', 4'-didehydro-1', 2'-dihydro-beta, psi-carotin-4-one; 5-hydroxy-4 ', 5'-didehydro-4,5-dihydro-4,5'-retro-beta, beta-carotene-3,3'-dione; 3'-hydroxy-2 ', 3'-didehydro-2-nor-beta, beta-carotene-3,4,4'-trion; 3'-hydroxy-4 ', 5'-didehydro-4,5'-retro-beta, beta-carotin-3-one; 3-hydroxy-5,8,5 ', 8'-diepoxy-beta-carotene; 3-hydroxy-7 ', 8'-dihydro-7'-apo-beta-carotene-8'-one; 3-hydroxy-5 ', 6'-dihydro-5'-apo-18'-nor-beta-carotin-6'-one; 1-hydroxy-1,2-dihydro-psi, psi-carotene-20-al; 1'-hydroxy-1 ', 2'-dihydro-gamma-carotene; 3-hydroxy-7.8-dihydro-chi, X-carotene-6.8-dione; 4'-hydroxy-5 ', 6'-dihydro-beta, beta-carotin-4-one; 1'-hydroxy-1 ', 2'-dihydro-beta, psi-carotin-4-one; 8'-hydroxy-7 ', 8'-dihydrocytranaxanthin; 4-hydroxy-7 ', 8'-dihydro-4,4'-diapocarotene; 4'-hydroxy-5 ', 6'-dihydroequinenone; 1'-hydroxy-1 ', 2'-dihydro-2-isopentenyl-2' - (hydroxyisopentenyl) torulin; 1-hydroxy-1,2-dihydrolikopin; 1-hydroxy-1,2-dihydroneurosporin; 1'-hydroxy-1 ', 2'-dihydroneurosporin; 1-hydroxy-1,2-dihydrophytoin; 1 (or 1 ') - hydroxy-1,2 (or 1'2') - dihydrophytofluin; 8'-hydroxy-7 ', 8'-dihydroreticulataxanthin; 1'-hydroxy-1 ', 2'-dihydrospheroidine; 2'-hydroxy-1 ', 2'-dihydrotorulin; 2-hydroxy-1 ', 2'-dihydrotorulin-1', 2'-oxide; 5-hydroxy-5,6-dihydrozeaxanthin; 3-hydroxy-3 ', 4'-diketo-alpha-carotene; 3-hydroxy-4,4'-diketo-beta-carotene; 3'-hydroxy-3,4-diketo-beta-carotene; 2'-hydroxy-3,1'-dimethoxy-3 ', 4'-didehydro-1', 2'-dihydro-beta, psi-carotin-4-one; 4-hydroxy-3 ', 4'-dioxo-beta-carotene; 2-hydroxyechinenone; 3-hydroxyechinenone; 3'-hydroxyecinenone; 4'-hydroxyecinenone; 3-hydroxy-5,8-epoxy-beta-carotene; 3'-hydroxy-3,6-epoxy-5,6-dihydro-beta, [epsi] -carotin-4-one; 3'-hydroxy-3,6-epoxy-7 ', 8'-didehydro-5,6-dihydro-beta, beta-carotin-4-one; 3'-hydroxyevglenanone; 2'-hydroxyflexixanthin; 1-hydroxy-1,2,7 ', 8', 11 ', 12'-hexahydrolikopin; 1'-hydroxy-3,4,1 ', 2', 11 ', 12'-hexahydrospheroidine; 2- (4-hydroxy-3-hydroxymethyl-2-butenyl) -2 '- (3-methyl-2-butenyl) beta, beta-carotene; 3-hydroxyisorenieratin; 3-hydroxy-4-keto-alpha-carotene; 3-hydroxy-3'-keto-alpha-carotene; 3-hydroxy-4-keto-beta-carotene; 3-hydroxy-4'-keto-beta-carotene; 4-hydroxy-4'-keto-beta-carotene; 1'-hydroxy-2'-keto-1 ', 2'-dihydrotorulin; 3-hydroxy-3'-keto-retrodehydrocarotene; 19-hydroxylutein; 16-hydroxylicopin; 3-hydroxy-3'-methoxy-beta-carotene; 1'-hydroxy-1-methoxy-3,4-didehydro-1,2,1 ', 2', 7 ', 8'-hexahydro-psi, psi-carotin-2-one; 1'-hydroxy-1-methoxy-1,2,1 ', 2', 7 ', 8'-hexahydro-psi, psi-carotin-4-one; 1'-hydroxy-1-methoxy-3,4,3 ', 4'-tetrahydro-1,2,1', 2'-tetrahydro-psi, psi-carotin-2-one; 1'-hydroxy-1-methoxy-1,2,1 ', 2'-tetrahydro-psi, psi-carotin-4-one; 2- (4-hydroxy-3-methyl-2-butenyl) beta, beta-carotene; 2- (4-hydroxy-3-methyl-2-butenyl) - [epsi], psi-carotene; 2- (3-hydroxymethyl-but-2-enyl) -7 ', 8'-dihydro [delta] carotene; 2- (4-hydroxy-3-methyl-2-butenyl) -7 ', 8'-dihydro- [epsi], psi-carotene; 2- (4-hydroxy-3-methyl-2-butenyl) -2 '- (3-methyl-2-butenyl) - [epsi], [epsi] -carotene; 2- (4-hydroxy-3-methyl-2-butenyl) -2 '- (3-methyl-2-butenyl) - [epsi], [epsi] -carotin-18-ol; 2 '- (4-hydroxy-3-methyl-2-butenyl) -2- (3-methyl-2-butenyl) -3', 4'-didehydro-1 ', 2'-dihydro-beta, psi-carotene -1'-ol; 2 (or 2 ') - (4-hydroxy-3-methyl-2-butenyl) -2' (or 2) - (3-methyl-2-butenyl) -3 ', 4'-didehydro-1', 2 '-dihydro- [epsi], psi-carotin-1'-ol; 2 '- (4-hydroxy-3-methyl-2-butenyl) -2- (3-methyl-2-butenyl) -7.8 (or 7', 8 ') - dihydro- [epsi], [epsi] -carotin-18-ol; 2- (4-hydroxy-3-methyl-2-butenyl) -7,8,7 ', 8'-tetrahydro- [epsi], psi-carotene; 2- (4-hydroxy-3-methyl-2-butenyl) -7 ', 8', 11 ', 12'-tetrahydro- [epsi], psi-carotene; 16- (3-hydroxy-3-methylbutyl) -16 '- (3-methyl-2-butenyl) -7,8,11,12,15,7', 8 ', 11', 12 ', 15'- decahydro-psi, psi-carotene; 2- (3-hydroxy-3-methylbutyl) -2 '- (3-methyl-2-butenyl) -3,4,3', 4'-tetrahydro-1,2,1 ', 2'-tetrahydro-psi psi-carotene-1,1'-diol; 2-hydroxy-monocyclic-phytofluin; 4-hydroxymyxoxanthophyll; Hydroxyneurosporin; 15-hydroxy-7 ', 8', 9 ', 10', 11 ', 12', 13 ', 14'-octahydro-6'-apo-beta-carotin-7'-one; 1'-hydroxy-3,4,7,8,1 ', 2', 11 ', 12'-octahydrospheroidine; 3'-hydroxy-4-oxo-beta-carotene; 3-hydroxy-4-oxo-2,3-dehydro-beta-carotene; 4'-hydroxy-3-oxoechinenone; hydroxyphytoin; hydroxyphytofluin; 4'-hydroxy-4-oxo-pyrardixanthin; 2-hydroxypletanyaxanthin; 3-hydroxy-4,5'-retro-5'-apo-beta-carotene-5'-one; 3-hydroxy-4 ', 12'-retro-beta, beta-carotene-3', 12'-dione; 3'-hydroxyrubixanthin; 3'-hydroxy-5,6-seco-beta, beta-carotene-5,6-dione; 3-hydroxysemi-beta-carotinone; 3-hydroxysyntaxanthin; hydroxysferoidin; hydroxysferoidinone; hydroxyspiryloxanthin; 8'-hydroxy-5 ', 6', 7 ', 8'-tetrahydro-5'-apo-18'-nor-beta-carotene-6'-one; 4'-hydroxy-5,6,5 ', 6'-tetrahydro-beta, beta-carotin-4-one; 1-hydroxy-3,4,3 ', 4'-tetradehydro-1,2-dihydro-psi, psi-carotin-2-one; 1-hydroxy-1,2,7 ', 8'-tetrahydrolikopin; 1'-hydroxy-3,4,1 ', 2'-tetrahydrospheroidine; 3-hydroxytorulin; 16'-hydroxytorulin; 18'-hydroxytorulin; 3-hydroxy-3 ', 4'-triketo-beta-carotene; 3-hydroxy-beta-zeacarotene; 5-hydroxyseaxanthin;

idoxanthin; isoagelaxanthin A; isobixin; isocarotene; iso-zeta-carotene; iso-zeta-carotene; isocrocetin; isocryptoxanthin; isofucoxanthin; isofucoxanthinol; Isolutein; isomethylbixin; isomethyloxanthin; 2-isopentenyl-3,4-dehydrorodopine; isorenieratin; beta-isorenieratin; 3,3'-isorenieratinediol; 3-isorenieratinol; isotedaniaxanthin; isotedanine; isoseaxanthin;

carpoxanthin; keto; see also oxo or -one ketocapsanthin; 4-ketocapsanthin; 4-keto-alpha-carotene; 4-keto-beta-carotene; 4-keto-gamma-carotene; 4-ketocintiaxanthin: 4-keto-3 ', 4'-dehydro-beta-carotene; 4-keto-1 ', 2'-dihydro-1'-hydroxytorulin; 2-keto-7 ', 8'-dihydrogen rovibrin; 4-keto-3,3'-dihydroxy-alpha-carotene; 4'-keto-3-hydroxy-gamma-carotene; 4-keto-3'-hydroxylicopin; 4-ketolutein 332 4-ketomyixol 2 '- (methylpentoside); 4-ketomyxoxanthophyll; 2-keto-OH-spirilloxanthin; 4-ketofleiksantofill; 2-ketorodovibrin; 4'-ketorubixanthin; 2-ketospirilloxanthin; 4-ketotorulin; 4-ketoseaxanthin;

lactucaxanthin; latochrom; latoxanthin; leprotin; lilixanthin; loniceraxanthin; loroxanthin; lusomycin; lutein; lutein dimethyl ether; lutein dipalmitate; lutein epoxide; luteochrom; luteol; luteoxanthin; lycopinal; lycopene-20-al; lycopene; lycopene-16.16'-diol; lycopene 1,2-epoxide; lycopene 5,6-epoxide; lycopin-16-ol; lycopin-20-ol; lycopersin; lycophyll; lycoxanthin;

Mactraxanthin; manixanthin; 1-mannosyloxy-3,4-didehydro-1,2-dihydro-8'-apo-psi-carotin-8'-ol; 3'-methoxy-beta, beta-carotin-3-ol; 3-methoxy beta, X-carotene; 1-methoxy-1,2,7,8,1,12,7 ', 8', 11 ', 12'-decahydro-psi, psi-carotene; 1'-methoxy-1,2,7,8,11,12,1 ', 2', 7 ', 8'-decahydro-psi, psi-carotin-1-ol; 1-methoxy-3,4-didehydro-1,2-dihydro-psi, psi-carotin-20-al; 1'-methoxy-3 ', 4'-didehydro-1', 2'-dihydro-beta, psi-carotene; 1-methoxy-3,4-didehydro-1,2-dihydro-psi, psi-carotene; 1-methoxy-3,4-didehydro-1,2,7 ', 8', 11 ', 12'-hexahydro-psi, psi-carotene; 1'-methoxy-3 ', 4'-didehydro-1,2,7,8,1', 2'-hexahydro-psi, psi-carotin-1-ol; 1-methoxy-3,4-didehydro-1,2,7 ', 8'-tetrahydro-psi, psi-carotene; 1'-methoxy-3 ', 4'-didehydro-1,2,1', 2'-tetrahydro-psi, psi-carotin-1-ol; 1-methoxy-3,4-didehydro-1,2,7 ', 8'-tetrahydro-psi, psi-carotin-2-one; 1-methoxy-1,2-dihydro-psi, psi-carotene-20-al; 1-methoxy-1,2-dihydro-psi, psi-carotene; 1'-methoxy-1 ', 2'-dihydro-beta, psi-carotin-4'-one; 1'-methoxy-1 ', 2'-dihydro-X, psi-carotin-4'-one; 1-methoxy-1,2-dihydro-psi, psi-carotin-4-one; 1'-methoxy-1 ', 2'-dihydro-3', 4'-dehydro-gamma-carotene; 1-methoxy-1,2-dihydro-3, A-dehydrolycopene; 1-methoxy-1,2-dihydro-3,4-didehydrolikopin-20-al; 1-methoxy-1,2-dihydrolikopin; 4-methoxy-5,6-dihydrolikopin; 1-methoxy-1,2-dihydroneurosporin; 1-methoxy-1,2-dihydrophytoin; 1-methoxy-1,2-dihydrophytofluin; 1'-methoxy-1 ', 2'-dihydrospheroidine; 3-methoxy-19,3'-dihydroxy-7,8-didehydro-beta, chi-carotene-6 ', 8'-dione; 1-methoxy-1,2,7 ', 8', 11 ', 12'-hexahydro-psi, psi-carotene; 1'-methoxy-1,2,7,8,1 ', 2'-hexahydro-psi, psi-carotin-1-ol; 1-methoxy-1,2,7 ', 8'11', 12'-hexahydro-psi, psi-carotin-4-one; 1-methoxy-1'-hydroxy-1,2,1 ', 2'-tetrahydrophytofluin; 1-methoxy-2-keto-7 ', 8'-dihydro-3,4-dehydrolycopene; methoxy silicate; 1-methoxy-1,2,7,8,7 ', 8', 11 ', 12'-octahydro-psi, psi-carotene; 1'-methoxy-1,2,7,8,11,12,1 ', 2'-octahydro-psi, psi-carotin-1-ol; 1-methoxy-4-oxo-1,2-dihydro-8'-apo-psi-carotene-8'-al; 1-methoxy-4-oxo-1,2-dihydro-12'-apo-psi-carotene-12'-al; methoxyphytoin; methoxyphytofluin; methoxysferoidin; 1'-methoxy-3,4,3 ', 4'-tetrahydro-1,2,1', 2'-tetrahydro-psi, psi-carotin-1-ol; 1-methoxy-1,2,7 ', 8'-tetrahydro-psi, psi-carotene; 1-methoxy-1,2,7 ', 8'-tetrahydro-psi, psi-carotin-4-one; 1-methoxy-1,2,7 ', 8'-tetrahydro-3,4-dehydrolycopene; 3-methoxy-19,3 ', 8'-trihydroxy-7,8-didehydro-beta, chi-carotin-6'-one; methyl 4'-apo-beta-carotene-4'-oat; methyl 8'-apo-beta-carotene-8'-oat; methyl 6'-apo-psi-carotene-6'-oat; methyl apo-6'-lycopinoate; methyl bixin; 2- (3-methyl-2-butenyl) beta, beta-carotene-18 (or 18 ') - ol; 2- (3-methyl-2-butenyl) -3,4-didehydro-1,2-dihydro-psi, psi-carotin-1-ol; 2- (3-methyl-2-butenyl) -7,8,7 ', 8'-tetrahydro [epsi], psi-carotin-18-ol; methyl 3 ', 4'-didehydro-beta, psi-carotene-16'-oat; methyl 1-hexosyl-1,2-dihydro-3,4-didehydro-apo-8'-lycopinoate; methyl hydro-6,6'-diapocarotin-dioate; methyl 1-mannosyloxy-3,4-didehydro-1,2-dihydro-8'-apo-psi-carotene-8'-oat; methyl 1'-methoxy-4'-oxo-1 ', 2'-dihydro-X, psi-carotene-16 (or 17 or 18) -oat; 2 '- (O-methyl-5-C-methylpentosyloxy) -3', 4'-didehydro-1 ', 2'-dihydro-beta, psi-carotene-3,1'-diol; metridine; mimulaxanthin; monadoxanthin; monoanhydrobacterioruberin; monodehydro-beta-carotene; monodehydrolikopin; monodemethylated spirilloxanthin; monoepoxy-, see Epoxy-monohydroxy cyclophytoin; monohydroxy cyclophitofluin; mutatochrome; mutatoxanthin; mityloxanthin; mityloxanthinone; myxobactin; mixobactone; mixola 2'-glucoside; mixola 2'-O-methylmethylpentoside; mixol-2'-rhamnoside; mixoxanthin; mixoxanthol; mixoxanthophyll;

neocarotene; neochrom; neo-beta-carotene B; neo-beta-cryptoxanthin A; neoxanthin; neoxanthin 3-acetate; neurosporaxanthin; neurosporaxanthin methyl ester; neurosporin; nonaprenoxanthin; 2'-nor-astaxanthin diester; norbixin; nostaxanthin;

octahydro-beta-carotene; 1,2,7,8,11,12,7 ', 8'-octahydro-psi, psi-carotene; 7,8,11,12,7 ', 8', 11 ', 12'-octahydro-psi, psi-carotene; 1,2,7,8,11,12,7 ', 8'-octahydro-psi, psi-carotene-1,2-diol; 1,27,8,1 ', 2', 7 ', 8'-octahydro-psi, psi-carotene-1,1'-diol; 1,2,7,8,11,12,7 ', 8'-octahydro-psi, psi-carotin-1-ol; 7,8,11,12,7 ', 8', 11 ', 12'-octahydro-beta, psi-carotin-2-ol; 1,2,7,8,7 ', 8', 11 ', 12'-octahydro-psi, psi-carotin-1-ol; 7,8,11,12,7 ', 8', 11 ', 12'-octahydro-4,4'-diapocarotene; octahydrolikopin; 5,6,7,8,5 ', 6', 7 ', 8'-octahydrolikopin; 7,8,11,12,7 ', 8', 11 ', 12'-octahydrolikopin; 3,4,3 ', 4', 7 ', 8', 11 ', 12'-octahydro-spirilloxanthin; OH, see also hydroxy- or -ol OH-chlorobactin; OH-chlorobactin glucoside; OH-lycopene; 2-OH-monocyclophytoin; 2-OH-monocyclophitofluin; OH-neurosporin; OH-Okenone; OH-P 481; OH-P 482; OH-P 511; OH-R; OH-rhodofin; OH syntaxanthin 5,6-epoxide; OH-spheroidin; OH-spheroidenone; OH-7,8,11,12-tetrahydrolikopin; OH-Y; okenone; opioxanthin; oscillaxanthin; Oscillol 2,2'-di (O-methyl-methylpentoside); oscillol 2,2'-diramnoside; ovoester; oxo-, see also keto or -one 3-oxocanthaxanthin; 4'-oxo-4,4'-diapocarotin-4-oic acid; 8'-oxo-8,8'-diapocarotinic acid; 3-oxoechinenone; 4-oxosaproxanthin; 16'-oxotorulin; 6'-hydroxychrysanthemaxanthin; P 412; P 444; P 450; P 452; P 481; P 500; P 518; 1 '- [(chi-O-palmitoyl-beta, D-glucosyl) oxy] -3', 4'-didehydro-1 ', 2'-dihydro-beta, psi-carotin-2'-ol; papillioerythrin; papillioerythrinone; paracentron; parasiloxanthin; pectenol; pectenolone; pectenoxanthin; pentaxanthin; peridinine; peridininol; peachachrome; peachaxanthin; phillipsiaxanthin; phylosamiaxanthin; fleiksantofill; fleixanthophyll palmitate; pheniconone; phenicopteron; phenicoxanthin; fisalien; physoxanthin; phytoin; C (30) phytoin; phytoin 1,2- (ep) oxide; finoinol; phytofluin; phytofluin epoxide; phytofluinol; pigment R; pigment X; pigment Y; pectanyaxanthin; poly-cis-gamma-carotene; poly-cis-psi-carotene; poly-cis-lycopene; prazinoxanthin; prelicopersin pyrophosphate; prefitoin pyrophosphate; pro-gamma carotene; prolicopin; proneurosporin; protetrahydrolikopin; pseudo-alpha-carotene; pyrenoxanthin; pyroxanthin; pyroxanthinol;

7-cis: rhenieracistin; rhenirapurpurin; rhenyratin; reticulaxanthin; retinylidiglate acid; retrobisdehydro (β-beta) carotene; retrodehydro (β-beta) carotene; retrodehydro-gamma-carotene; retrodehyderoseaxanthin; rhamnopyranosyloxy, see ramnosyloxy-2'-O-rhamnosyl-4-ketomyixol; 2'-O-rhamnosylmixol; 3'-rhamnosyloxy-beta, beta-carotin-3-ol; 1-rhamnosyloxy-3 ', 4'-didehydro-1', 2'-dihydro-beta, psi-carotene; 2'-rhamnosyloxy-3 ', 4'-didehydro-1', 2'-dihydro-beta, psi-carotene-3,1'-diol; 2'-rhamnosyloxy-3 ', 4'-didehydro-1', 2'-dihydro-beta, psi-carotene-3,4,1'-triol; 1'-rhamnosyloxy-3 ', 4'-didehydro-1', 2'-dihydro-beta, psi-carotin-3-ol; rhodoauranxanthin; rhodopin; rhodopin (-20-) al; rhodopinal glucoside; rhodopine glucoside; rhodopinol; rhodopurpurine; rhodotorulin; rhodovibrin; rhodoviolastcin; rhodoxanthin; roserythrin; rubichrome; rubixanthin; rubixanthin 5,6-epoxide; rubiksanton;

salmon acid; salmoxanthin; saproxanthin; sarcinaxanthin; sarcinaxanthin diglucoside; sarcinaxanthin monoglucoside; sarcinin; 5,6-seco-beta, beta-carotene-5,6-dione; 5,6-seco-beta, [epsi] -carotene-5,6-dione; semi-alpha carotinone; seven beta carotinone; Sydniaxanthin; syntaxanthin; siphonaxanthin; syphonein; sodium-3,19-dihydroxy-7,8-didehydro-beta, chi-carotene-3 ', 6'-dione 3-sulfate; sodium 3,19-dihydroxy-3 ', 6'-dioxo-7,8-didehydro-beta, chi-carotene-17'-al 3-sulfate; sodium-3,19,3'-trihydroxy-7,8-didehydro-6'-oxo-beta, chi-carotene-17'-oat 3-sulfate; sodium-3,19,17'-trihydroxy-7,8-didehydro-beta, chi-carotene-3 ', 6'-dione 3-sulfate; sphaerobolin; spheroidin; spheroidenone; spirilloxanthin; sulcatoxanthin;

Tangeraxanthin; taraxanthin; taraxanthin dipalmitate; taraxien; tareoxanthin; tedanyaxanthin; tedanine; ternstroemyaxanthin; tetiatin; 7.8,7 ', 8'-tetradehydroastaxanthin; 3,4,3 ', 4'-tetradehydro-beta, beta-carotene; 3,4,3 ', 4'-tetradehydro-psi, psi-carotene; 7.8,7 ', 8'-tetradehydro-beta, beta-carotene-3,3'-diol; 3,4,3 ', 4'-tetradehydro-beta, beta-carotene-2,2'-dione; 3 ', 4', 7 ', 8'-tetradehydro-beta, beta-carotin-3-ol; 3,4,3 ', 4'-tetradehydrolikopin; 6,7,6 ', 7'-tetrahydro-5,6,5', 6'-tetrahydro-beta, beta-carotene-3,3'-diol; 6,7,6 ', 7'-tetrahydro-5,6,5', 6'-tetrahydro-beta, beta-carotene-3,5,3 ', 5'-tetraol; 7.8.7 ', 8 '-tetradehydrozeaxanthin; 3,4,3 ', 4'-tetradehydrobisanhydrobacterioruberin; 5,6,5 ', 6'-tetrahydrocanthaxanthin; 7.8.7 ', 8'-tetrahydrocapsorubin; tetrahydro-beta-carotene; 7.8.7 ', 8'-tetrahydro-beta, beta-carotene; 7 ', 8', 11 ', 12'-tetrahydro-beta, psi-carotene; 7 ', 8', 11 ', 12'-tetrahydro-gamma-carotene; 7 ', 8', 11 ', 12'-tetrahydro-gamma, psi-carotene; 1,2,7,8-tetrahydro-psi, psi-carotene; 1,2,1 ', 2'-tetrahydro-psi, psi-carotene; 7,8,11,12-tetrahydro-psi, psi-carotene; 7.8.7 ', 8'-tetrahydro-psi, psi-carotene; 5,6,5 ', 6'-tetrahydro-beta, beta-carotene-4,4'-diol; 7.8,7 ', 8'-tetrahydro-beta, beta-carotene-3,3'-diol; 7 ', 8', 9 ', 10'-tetrahydro-beta, psi-carotene-3.17'-diol; 1,2,1 ', 2'-tetrahydro-psi, psi-carotene-1,1'-diol; 5,6,5 ', 6'-tetrahydro-beta, beta-carotene-4,4'-dione; 5,6,5 ', 6'-tetrahydro-beta, beta-carotene-3,5,6,3', 5 ', 6'-hexol; 1,2,7,8-tetrahydro-psi, psi-carotin-1-ol; 1,2,7 ', 8'-tetrahydro-psi, psi-carotin-1-ol; 7,8,11,12-tetrahydro-4,4'-diapocarotene; 7.8,7 ', 8'-tetrahydro-4,4'-diapocarotene; tetrahydrolikopin; 1,2,1 ', 2'-tetrahydrolikopin; 5,6,5 ', 6'-tetrahydrolikopin; 7,8,11,12-tetrahydrolikopin; 7.8.7 ', 8'-tetrahydrolikopin; 7 ', 8', 11 ', 12'-tetrahydrolikopin; 1,2,1 ', 2'-tetrahydrolikopin-1,1'-diol; 1,2,1 ', 2'-tetrahydroneurosporin; 3,4,11 ', 12'-tetrahydrospheroidine; 3,4,7,8-tetrahydrospirilloxanthin; 3,4,3 ', 4'-tetrahydrospiryloxanthine; 3,4,3 ', 4'-tetrahydrospyryloxanthin-20-al; 5,6,5 ', 6'-tetrahydro-3,4,3', 4'-tetraol 4,4'-disulfate; 2,3,2 ', 3'-tetrahydroxy-beta, beta-carotene-4,4'-dione; 2,3,2 ', 3'-tetrahydroxy-beta, beta-carotin-4-one; 3.19.3 ', 17'-tetrahydroxy-beta, chi-carotin-6'-one 3-sulfate; 3,5,3 ', 5'-tetrahydroxy-6', 7'-didehydro-5,8,5 ', 6'-tetrahydro-beta, beta-carotin-8-one; 3.3 ', 5.5'-tetrahydroxy-6'-hydro-7-dehydro-beta-carotene; 3,4,3 ', 4'-tetrahydroxypyrardixanthin; 3,4,3 ', 4'-tetrahydroxy-5,6,5', 6'-tetrahydro-beta, beta-carotene; (3,4,3'4 ') - tetraketo-beta-carotene; 4,5,4 ', 5'-tetraketo-beta-carotene; thiotic-425; thiotic-460; thiotic-474; thiotic-478; thiotic-484; thiotic-OH-484; tilefishxanthin I; tilefishxanthin II; tilefishxanthin III; tilefishxanthin IV; torularodin; torularodinaldehyde; torularodin methyl ether; torulinal; torulin; torulin carboxylic acid; 2,3,2'-trihydroxy-beta, beta-carotene-4-one; 3.3 ', 4'-trihydroxy-beta, beta-carotene-4-one; 3,4,3'-trihydroxy-beta, chi-carotin-6'-one; 3.3 ', 5'-trihydroxy-6', 7'-dehydro-alpha-carotene; 3.3 ', 8'-trihydroxy-7,8-didehydro-beta, chi-carotene-4,6'-dione; 3,3 ', 8'-trihydroxy-7,8-didehydro-beta, chi-carotin-6'-one; 3,19,3'-trihydroxy-7,8-didehydro-beta, chi-carotin-6'-one 3-sulfate; 3,1 ', 2'-trihydroxy-3', 4'-didehydro-1 ', 2'-dihydro-beta, psi-carotin-4-one; 3,5,19-trihydroxy-6,7-didehydro-5,6,7 ', 8'-tetrahydro-7'-apo-beta-carotin-8'-one 3-acetate 19-hexanoate; 3,5,6'-trihydroxy-6,7-didehydro-5,6,7 ', 8'-tetrahydro-beta, [epsi] -carotene-3', 8'-dione; 3,5,3'-trihydroxy-5,6-dihydro-beta-carotene; 3,3 ', 5'-trihydroxy-5', 6'-dihydro-beta-carotene 5 ', 6'-epoxide; 3,19,3'-trihydroxy-7,8-dihydro-beta, [epsi] -carotin-8-one; 3,19,3'-trihydroxy-7,8-dihydro-beta, beta-carotene-8-one 19-laurate; 3,6,3'-trihydroxy-7,8-dihydro-gamma, [epsi] -carotin-8-one; 3.3 ', 19-trihydroxy-7,8-dihydro-8-oxo-alpha-carotene; 3.3 ', 6'-trihydroxy-5,8-epoxy-alpha-carotene; 3,4,4'-trihydroxypyrardixanthin; 1,1 ', 2'-trihydroxy-3,4,3', 4'-tetrahydro-1,2,1 ', 2'-tetrahydro-psi, psi-carotin-2-one; 3,4,4'-trihydroxy-5,6,5 ', 6'-tetrahydro-beta, beta-carotene; tricentriorodine; 3,4,4'-triketo-beta-carotene; 3,1 ', 2'-trimethoxy-3', 4'-didehydro-1 ', 2'-dihydro-beta, psi-carotin-4-one; triofaxanthin; triphasiaxanthin; trisanhydrobacterioruberin; trollin; trolichrome; trolliflavin; trolliflor; trollyxanthin; tunaxanthin; uriolide; vauheriaxanthin; violaxanthin; violeoxanthin; violaerythrin; warmingol; warmingon; web biaxanthin; xanthophyll; xanthophyll K (1); xanthophyll K (1) S; xanthophyll dipalmitate; xanthophyllum epoxide; alpha zeacarotin; beta zeacarotin; beta (1) -zeacarotene; alpha zeacarotin-3,17'-diol; beta zeacarotin-3,17'-diol; beta-zeacarotin-3-ol; zeaxanthin; zeaxanthin; zeaxanthin diepoxide; zeaxanthin dimethyl ether; zeaxanthin diramnoside; zeaxanthin dipalmitate; zeaxanthin 5,6-epoxide; zeaxanthin 5.8-epoxide; zeaxanthin furanoxide; zeaxanthin monomethyl ether; zeaxanthin monoramnoside; zeaxanthol; and zeynoxanthin.

The above list of naturally occurring carotenoids is intended to be a non-limiting example of naturally occurring carotenoids. This list is not exhaustive, since more naturally occurring molecules will be discovered that fall into the category of carotenoids.

Sulfonylureas

Non-limiting examples of sulfonylureas include, but are not limited to, acetohexamide, DiaBeta, glibenclamide, glyclazide, glipizide (glucotrol), glyclopyramide, chlorpropamide, tolazamide, tolbutamide, glimepiride (amaryl), tolbutamide and meglithinidinide, e.g. meglitinidinide, e.g. (KAD-1229)), etc.

Niacin and related derivatives

The term niacin is a generic description for nicotinic acid (pyridine-3-carboxylic acid) and its derivatives. Non-limiting examples of nicotinic acid derivatives include nicofuranose, acipimox (5-methylpyrazine-2-carboxylic acid 4-oxide), niceritrol, probucol, isonicotinic acid, cholexamine, oxiniacin acid, nicoclonate, nicomol, NIASPAN, nicericotene and nicotinol.

Other examples of other active agents which may be suitable for this invention, include but without limitations: abecarnial acamprostat Akavir acebutolol aceclofenac acemetacin acetaminophen, acetaminosalol, acetanilide acetohexamide acetophenazine maleate, acetophenazine acetoxolone acetoxypregnenolone, acetretin acrizorcin, acrivastin acyclovir adinazolam adiphenine hydrochloride, adrafinyl adrenolone agatroban anitrine Akatinol alatrofloxacin, albendazole Albuterol aldioxa alendronate alfentanil, alibendol, aletretinoin, allopurinol, allylamines, allylestrenol, alminoprofen, almotriptan alosetron aloxiprine alprazolam alprenolol, amantadine ambucetamide amidephrine amidinomycin, amiloride aminoarylcarboxylic acid derivatives, aminoglutethimide, aminoglycosides, aminopentamide aminopromazine Aminorex amiodarone amiphenazole amiprilose amisulpride amitriptyline, amlexanox, amlodipine amodiaquine amosulalol, Amotrifen amoxapine amoxicillin amphekloral amphetamine, amphomycin amphotericin ampicillin empyroxicam amprenavir amrinone amsacrine amyl nitrate, amylobarbitone anagestone acetate, anastrozole, andinocillin, androstenediol, androstenediol-17-acetate, androstenediol-17-benzoate, androstindiol-3-acetate, androstindiol-3-acetate-17-benzoate, androstenedione, androsterone acetate, androsterone benzoate, androsterone propionate, androsterone angiotensin anidulatungin, Aniracetam azone apicycline apoatropin, apomorphine apraclonidine aprepitant Aprotinin arbaprostil ardeparin, aripiprazole, arnicacin arotinolol, arstinol aryl acetic acid derivatives, arylalkylamines, derivatives of arylbutic acid, arylcarboxylic acids arylpiperazines, derivatives of arylpropionic acid, aspirin, astemizole atenolol atomoxetine atorvastatin, atowachone atropine, auranofin, azapropazone azathioprine, azelastine azetazolamide azithromycin baclofen bambuterol, bametan barbiton barnidipine basalazide beclamide becoblorate befimolol bemegrid benazepril bicyclan bendazak bendazole bendroflumethiazide, benetamine penicillin, benexate hydrochloride, benfurodil hemisuccinate, benidipine benorilate bentazepam benzhexol benziodarone benznidazole, benzoctamine benzodiazepine derivatives, benzodiazepine, benzonate benzfetamine benzylmorphine, biperiden, befenia hydroxynaphthoate, bepridil betahistine betamethasone betaxolol Bevantolol bevonia methyl sulfate, bexarotene detoxification, bezafibrat, bialamicol, biapenem bicalutamide, bietamiverin, bifonazole binedalin, binifibrate Birikodar bisacodyl bisanthrene bisoprolol bitolterol, bopindolol, boswellic acid bradykinin brazil Bromazepam bromocriptine bromperidol brotizolam brovinkamkin, bicyclate buccloic acid bucumolol, budralazine buy iodine bufetolol buffered bufuralol bumetanide bunitrolol bupranolol, buprenorphine, bupropion Buspirone busulfan, butalamine, butorphanol, butaverine butenatm butidrine hydrochloride, butobarbitone, butoconazole nitrate, butoconazole, butophylol, butropium bromide, cabergoline calciphediol, calcipotriene calcitriol caldibine cambendazole camioxirol, camostat campesterol camptothecin, candesartan Candoxatryl capecitabine caprat capsaicin captopril Karazolol carbacephemes carbamates carbamazepine carbapinems carbarzone carbatrol carbenoxolone carbimazole carbromal carbuterol carisoprodol, carotenes caroverine cartolol, carvedilol cefaclor cefazolin cefbuperazone cefepime cefozelis ceftibutene celecoxib celiprolol cefaelin cephalosporin C, cephalosporins cefamycins cerivastatin, certoparin, cetamolol chain cetirizine cetraxate chloracisin, chlorambucil, chlorobetamide chlordantoin chlordiazepoxide, chlormadinone acetate, chloromethiazole, chloroquine chlorothiazide, chlorpheniramine, chlorphenoxamide, chlorfentermine, chlorproguanil, chlorpromazine chlorpropamide chlorprotixen, chlortetracycline, chlortalidone colecalciferol, chromonar cyclonazide cyclonic cidofovir, ciglitazone, cilansetron cilostazol, cimetidine cymetropia bromide, cinipazeta maleate, cinnamedrine cinnarizine, cinolazepam cinoxacin, ciprofibrate ciprofloxacin, cisapride cisplatin, citalopram, citicoline clarithromycin, kleboprid clemastine, Clenbuterol Klidanak clinofibrate clioquinol, clobazam clobenfurol, clobenzorex, clofazimine, clofibrate clofibric acid cloforex, clomipramine, clonazepam clonidine clonitrate clopidogrel clopirac indomethacin, cloranolol, cloricrome clorprenaline clortermine clotiazepam clotrimazole cloxacillin, clozapine cmepazide codeine methyl bromide, codeine phosphate, codeine sulfate, codeine, bismuth colloidal subcitrate, cromafiban cromolyn, cropropamide crotetamide curcumin cyclandelate cyclamide, cyclazocine cyclexedrine cyclizine cyclobenzaprine, cyclodrine cyclonium iodide, cyclopentamine, cyclosporin cypionate cyproheptadine, cyproterone acetate, cytarabine dacarbazine, dalphopristine Dantrolene sodium dapiprazole, Darodipine decanoate decitabine decochinate dehydroemethine, delavirdine delaviridine demeclocycline, denopamine deramcyclone descitalopram, desipramine, desloratadine 3-ketodesogesquel, desomorphine deoxymethasone detomidine dexamphetamine dexanabinol dexchlorpheniramine, dexfenfluramine, dexmethylphenidate dexrazoxane dextroamphetamine sulfate, dextroamphetamine dextropropoxyphene, DHEA diacetate diamorphine diazemin diazepam diaziquinone diazoxide dibromopropamidine, dichlorophen, diclofenac dicumarol didanosine, dideoxyadenosine, diethylpropion diphemerin diphenamisole, diflunisal digitoxin digoxin, dihydroergotamine, dihydrocodeine, dihydrocodeinone enolate acetate, dihydroergotamine mesylate, dihydroergotamine, dihydrogesterone dihydromorphine, dihydropyridine derivatives, dihydrostreptomycin, dihydrotachysterol, dihydroxyaluminium acetylsalicylate, diiodohydroxyquinoline, diisopromine, Delazep Divevalol diltiazem diloxanide furoate, Diloxanide diltiazem Dimeflin dimenhydrinate, dimethisterone dimetotrin dimorpholamine, dinitolmide, dioxafetil butyrate, dioxetedrine diphemethoxidine, diphenhydramine, diphenoxylate, diphitarson, dipivefrin, dipony bromide, dipyridamole dirithromycin, disopyramids divalproex sodium, dofetilide domperidone donepezil dopexamine extradite dosmalfat, doxapram doxazosin doxasefazepam doxepin doxycycline drofenin dromostanolone propionate, dromostanolone, dronabinol droperidol dropenylamine, d-threo-methylphenidate, duloxetine ebrotidine, eburnamonin, Ecobet esenofloxacin, econazole nitrate, edavaron edoxudine efavirenz, Effivarenz efloxate eledoisin eletriptan Elgodipine ellipticin, emepronium bromide, emetine, enalapril enanthate encainide enlopitate Enoximon enprostil entacapone epanolol ephedrine, epinastine epinephrine epirubicin, eplerenone eprosartan ergocalciferol, ergoloid mesylates, ergotamine, ertapenem erythromycin erythritol tetranitrate, esaprazole escitalopram esmolol esomeprazole esonarimod estazolam estradiol benzoate, estramustine esquiola succinate, estrone acetate, estrone sulfate, etafedrine, etaphenone ethacrylic acid etamivan ethinamate, ethinillescadiol 3-acetate, ethinillescadiol 3-benzoate, ethinyl estradiol, ethionamide ethisterone (17a-ethinyltestosterone), etopropazine etotoin, ethoxyphenamine Ethylestrenol ethyl morphine, Ethylnorepinephrine ethinodiol diacetate, etodolac this is fibrate etoposide etoricoxib etretinate Everolimus exalamide examiner examorelin ezemetib falecalcitriol, famciclovir famotidine Phantofaron Faropenum Farglitazar fazudil felbamate, felodipine phenalamide fenbulin, fenbutrazate fendilin fenfluramine, fenoldopam, phenoprofen, fenoterol, fenoverin, phenoxazoline, phenoxedil fenpipran fenproporex, fenspiride fentanyl fexofenadine flavoxate flecainide flopropion floredil phloxuridine fluconazole flucytosine, fludarabine fludiazepam fludrocortisone flulenamic acid flunanison, flunarizine, flunisolid, flunitrazepam fluocortolone fluoxetine flupentixol decanoate, fluphenazine decanoate, fluphenazine enanthate, fluphenazine fluproquasone, flurazepam flurbiprofen, flurogestone acetate, fluticasone propionate, fluvastatin fluvoxamine fominoben formoterol foscarnet fosinopril, fosphenytoin, frovatriptan fudostein, fumagillin furazolidone furazolidone furfurylmethyl amphetamine, furosemide gabapentin gabexat gaboxadol, galantamine, gallopamil gammaparin ganciclovir ganglefen hepharnatus gemcitabine gemfibrozil gepirone gestadine ghrelin glatiramer glaucarubin, glibenclamide, gliclazide glimepiride glipizide gluconic acid glutamic acid glyburide glyceryl trinitrate, glimepiride granisetron grefafloxacin, griseofulfin, guaiazulen guanabentz guanfacine, halofankin haloperidol decanoate, haloperidol, haloxazolam, hepatronate heptanoate hexobendin hexoprenaline hydramitrazine hydrazides hydrocodone hydrocortisone hydromorphone hydroxyamphetamine hydroxymethylprogesterone acetate, hydroxymethylprogesterone hydroxyprogesterone acetate, hydroxyprogesterone caproate, hydroxyprogesterone gimekromon, hyoscyamine, ibopamine ibudilast ibutenac ibuprofen ibutilide idoxuridine ifenprodil Igmesin iloprost, imatinib imidapril imidazoles imipenem imipramine imolamine, incadronic acid pergolide, indanazoline, indenolol indinavir indomethacin Indoramine inosine pranobex, inositol niacin, iodoquinol ipidracin, iproniazide, irbesartan irinotecan irsogladin, isobutyrate esters of isocaprate, isoetharin, isomeptene isoproterenol, isosorbide dinitrate, isosorbide mononitrate, isosorbide dinitrate, isoxuprin isradipine itetetron, itraconazole, itramine tosylate, ivermectin callidine kallikrein, kanamycin ketamine ketoconazole, ketoprofen Ketorolac ketotifen, labetalol lafutidin lamifiban lamivudine lamotrigine, lanatoside c lansoprazole lazofoksifen, leflunomide leminoprazole, lercanidipine, lezopitron letrozole leucovorin levabuterol, Levallorfan levetiracetam levetriacetam levobunolol, levodopa, levofloxacin, levofacetoperan, levorphanol lidocaine lidoflazin liffrol limaprost linezolid lintitript lyranaftate, lisinopril, lisuride lobelin lobucavir lodoxamide lomefloxacin, lomerizin lomustine loperamide lopinavir loprazolam loracarbef loratadine lorazepam lorefloxacin, lormetazepam losartan lovastatin lovastatin loxapine succinate, loxapine l-threomethylphenidate, lumiracoxib, lysine acetylsalicylate, lysozyme lisuride mabuterol mafenide magnesium acetylsalicylate, malgramostin mannitol hexanitrate, maprotiline, mazindol, mebendazole, Meclizine meclofenamic acid, mecloxamine pentapiperide, medazepam medbaza medigoxin medrogeston medroxyprogesterone acetate, mefenamic acid mefenorex, Mefloquine Mefloquine megestrol acetate, melengestrol acetate, melphalan memantine mepenzolate bromide, meperidine mefenoxalon, mefentermin, mepindolol, mepixanox, meprobamate meptazinol, mercaptopurine, meropenum mesalamine mesalazine mesoridazine besylate, mesoridazine metaclazepam methamphepramone metampicillin metaproterenol, metaraminol metacycline methadone hydrochloride, methadone methamphetamine methaqualone metharnetamine, Metoin methotrexate methoxamine Metsuximide methylhexanamine methylphenidate d-threo-methylphenidate, methylphenidate methylphenobarbitone, methylprednisolone metisergide, methiazinic acid methizoline metoclopramide, metolazone metoprolol methoxalon metripranolol, metronidazole, mexiletine metaxalon, mianserin mibefradil miconazole midazolam midodrin miglitol milnacipran milrinon minoxidil mirtazapine misoprostol, mitomycin, mitotan mitoxantrone misolastine modafinil mofebutazone mofetil molindone hydrochloride, molindone molsidomine, monatepil, montelukast Monteplazu moprolol moricizin morphine hydrochloride, morphine sulfate, morphine morpholine salicylate, mozapramine moxifloxacin, moxysilitis moxonidine mycophenolates nabumeton pinned nadoxolol, nadroparin nafamostat, nafronil, naftopidyl nalbuphine nalidixic acid nalmefen nalorphine naloxone naltrexone nandrolone benzoate, nandrolone cyclohexanecarboxylate, nandrolone cyclohexane propionate, nandrolone decanoate, nandrolone furyl propionate, nandrolone fenpropionate, naphazoline, naproxen naratriptan natamycin nateglinide undercame nefazodone nefopam nelfinavir nemonaprid neomycin undecylenate, neomycin neocofin neziridid n-ethylamphetamine, nevirapine nikametat nicardipine nicergoline nicofibrate nicofuranose nicomorphine Nicorandil nicotine alcohol, Nikumalon nifedipine nifenalol niketamide nilutamide nilvadipine, nimodipine nimorazol nipradilol nizoldipin, nitizonone nitrazepam nitrofurantoin, nitrofurazone nitroglycerine, nizatidine norastemizole, norepinephrine, norethinodrel, norfenephrine norfloxacin, norgestimate, norgeskel norgestrienone normetadone normetisterone normorphin norpsevdoephedrine, nortriptyline, novantron nilidrin nystatin octamylamine octodrine octopamine, ofloxacin olanzapine olapatadine olmesartan Olapatadine, olsalazine omapatrilate, omeprazole ondansetron, opium, oprevelkin, orlistat ornidazole ornoprostil oseltamivir oxaliplatin, oxamnihin oxandrolone oxantela embonate, oxaprozin, pemirolast oxatomide, oxatomide oxazepam oxcarbazepine, oxfendazole oxyconazole oxiracetam oxolinic acid oxprenolol oxycodone oxyfedrine oxymetazoline, oxymorphone, oxyphenbutazone, oxyphencyclimine, ozagrel, paclitaxel palonosetron pantoprazole papaverine, paricalcitol, Paramethione, parecoxib, pariprazole paromomycin, paroxetine parsalmide pazin slope pemoline penbutolol, penciclovir penicillin G benzatine, penicillin G procaine, penicillin V, penicillins pentaerythritol tetranitrate, pentaerythritol tetranitrate, pentapiperide pentazocine pentifillin pentigetide pentobarbitone pentorex, pentoxifylline pentrinitrol, pirbuterol, pirenzepine, pergolide perhexiline, perindopril erbumin, perospon perphenazine pimozide, perphenazine fanquinone phenazemide phenacetin phenazopyridine fencarbamide fendimethrazine phenelzine, fenindion, phenmetrazine phenobarbitone phenoperidine phenothiazines, phenoxybenzamine, fensuximide phentermine phentolamine, phenyl salicylate, phenyl acetate phenylbutazone phenylephrine hydrochloride, phenylpropanolamine hydrochloride, phenylpropanolamine hydrochloride, phenylpropyl methylamine, phenytoin phloroglucinol, Foledrin physostigmine salicylate, physostigmine phytonadiol, phytosterols, piapenum Pitsilorex piclamast picrotoxin picumast pytharnine, Pilsikainide pimagedin pimeclone pimecrolimus Pimefillin pimozide pinaveria bromide, pindolol, pioglitazone piperacillin piperazine estrone sulfate, piperazine derivatives, piperylate, piracetam pyribedil pyrifibrate, piroxicam pitavastatin pisotilin plunotol, half rubber, polybenzarsol, polyestrol phosphate, praktolol pralnakasan pramipexole pranlukast pravastatin prazepam praziquantel prazosin pregabalin prenalterol prenylamine pinned affinity bromide, primidon primipramine probenecid probucol procainamide procarbazine carterol, prochlorperazine, proguanil pronetalol propafenone propamidine propatyl nitrate propentoffilin propionate propira propoxyphene propranolol propylhexedrine propylthiouracil, protokyolol protriptyline, proxazole pseudoephedrine purines pyrantela embonate, pyrazoles pyrazolones pyridophylline, pyrimethamine, pyrimidines pyrrolidones, quasepam quetiapine quetuapine quinagolide, hinapril hinestrol hinfamide, quinidine quinine sulfate, quinolones quinupritin, rabalzotan rabeprazole sodium rabeprazole racefimin ramahroban ramipril ranitidine ranolazine Ransoprazole razagilin rebamipide refludan Repaglinide Repinotan repirinist reproterol reserpine, retinoids ribavirin rifabutin rifampicin rifapentin rilmenidine Riluzole rimantadine rmiterol rioprostil risperidone Ritanovir Ritapentin ritipenem ritodrin ritonavir rivastigrnin, risatriptan rociverin rofecoxib, Rohypnol rolipram remoxipride ronifibrate ropinirole ropivacaine, rosaprostol, rosiglitazone rosuvastatin, rotinolol rotraxate roxatidine acetate, roxindole rubitecan salacetamide salicin, salicylamide derivatives of salicylic acid, salmeterol saquinavir scopolamine secnidazole selegiline semothiadyl sertindole, sertraline sibutramine, sildenafil simvastatin siramezin, sirolimus, sitaxentan Sofalkon somotiadil sorivudine sotalol soterenol, sparfloxacin, spasmolitol, spectinomycin, spiramycin, spizofuron, stavudine streptomycin, succinylsulfathiazole, Sucralfate sufentanil sulfonazole nitrate, sulfacetamide, sulfadiazine, sulfaloxic acid, sulfarside sulfmalol, sulindac suloctidyl, sulfabenzamide, sulfacetamide, sulfadiazine, sulfadoxine, sulfafurazole, sulfamerazine sulfamethoxazole, sulfapyridine sulfasalazine sulfinpyrazone sulpiride, sultiam suloprid, sulbroponium, Somanirol sumacriptan Sunepihon superoxide dismutase, Suplatast suramin sodium synephrine tacrine tacrolimus tadalafil talinolol, Talipexole tamoxifen tamsulosin, Targretin tazanolastic tazarotene tazobactam tecastemizole teclosan tedizamil tegaserod, telenzepine telmisartan temazepam teniposide teprenone terazosin terbinafine terbutaline sulfate, terbutaline terconazole terfenadine Therodyline Therophenamate tertatolol, testolactone 4-dihydrotestosterone, tetracyclic compounds tetracycline tetrahydrocannabinol, tetrahydrozoline, thalidomide, theofibrate thiabendazole, thiazinecarboxamides, thiocarbamates, thiocarbamisine, thiocarbarzone, thioridazine, thiotriksen, tiagabin, thiamenidine tianeptine thiaprofenic acid, tiaramide ticlopidine, tigloidin tilizolol timolol tinidazole tinofedrine tinzaparin, thioconazole, tipranavir tirapazamine, Tirofiban tyropramide titanicene tizanadine tizanidine tizinadine tizanidine tokinide, tolazamide tolazoline tolbutamide tolkapon tolcyclate tolfenamic acid toliprolol tolteridine tolterodine tonaberstat topiramate, topotecan torsemid toremifene cybrate, toremifene tosufloxacin, tramadol tramazoline trandolapril, Tranilast tranylcypromine, trapidil traxanox trazodone tretoquinol triacetin triamcinolone, triamterin, triamteren triazolam trifluoperazine hydrochloride, trifluoperazin, triflupromazine, trihexyphenidyl trimazosin trimebutin, trimetazidine, trimethoprim, Trimgeston trimipramine trimoprostil tritiosin troglitazone trolnibrate phosphate, tromethamine tropicamide trovafloxacin, troxipid tuaminoheptane tulobuterol, thymazoline tyramine undecanoate, undecenoic acid urinastatin valaciclovir valdecoxib, valerate valganciclovir, valproic acid valsartan vancomycin vardenafil venlafaxine venorelbine verapamil vidarabine vigabakin winkamine vinpocetine, viomycin, I saw visnadine Vitamin A derivatives vitamin A, vitamin b ₂ , vitamin D, vitamin E, vitamin K, voglibose, voriconazole, xaliproden, xamoterol, xanthinol niacin, xenitropium bromide, xibenolol, ximelagatran, xylomethazoline, yohimbine, zakoprid, zafirlucin zadone, zalbitabin zalbitabin zalbitabin zalbitabin zalbitabin zalbitabine zimeldin, zinc propionate, ziprasidone, zolimidine, zolmitriptan, zolpidem, zonisamide, zopiclone and mixtures thereof.

Dosage Forms

The nebivolol compositions of the present invention can be administered in various ways, depending on their intended use, well known in the art. For example, if the compositions of the present invention are administered by mouth, they can be formulated as tablets, capsules, granules, powders, suspensions or syrups. Alternatively, the dosage forms of the present invention can be administered parenterally in the form of injections (intravenous, intramuscular or subcutaneous), drip preparations or suppositories. For use through the mucous membrane of the eye, the compositions of the present invention can be formulated as dosage forms, such as eye drops or eye ointments. Such dosage forms can be prepared by conventional methods and, if desired, the compositions can be mixed with any well-known additive, such as an excipient, a binder, a disintegrating agent, a lubricant, a flavoring agent, a solvent, a resuspending agent, an emulsifier or an enveloping agent.

In the dosage forms of this invention, moisturizers, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as colorants, drug release agents, coating agents, sweeteners, flavoring and flavoring agents, preservatives and antioxidants may be present among the substances included in the recipe.

These compositions may be suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, aerosol and / or parenteral administration. Dosage forms can accordingly be presented in unit dosage forms and can be obtained by any means well known in the pharmaceutical art. The amount of composition that can be mixed with a carrier substance to produce a unit dose varies depending on the subject of treatment and the particular route of administration.

Methods for preparing these dosage forms include the step of combining the composition of the present invention with a carrier and, optionally, one or more accessory ingredients. Typically, dosage forms are obtained by uniformly and directly combining agents with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product.

Dosage forms suitable for oral administration can be in the form of capsules, sachets, pills, tablets, caramel (using a flavored base, usually sucrose and gum or tragacanth), powders, granules, or as a solution or suspension in water or another liquid, or as an oil in water or water in oil emulsion, or as an elixir or syrup, or as a lozenge (using an inert base such as gelatin and glycerin, or sucrose and gum), each containing a predetermined amount this composition as an active ingredient. The compositions of the present invention may also be administered as a bolus, electuary or paste.

In solid dosage forms for oral administration (capsules, pills, tablets, dragees, powders, granules, etc.), the target composition is mixed with one or more pharmaceutically acceptable carriers such as sodium citrate or calcium phosphate and / or any of the following: (1) fillers or dry diluents, such as starch, lactose, sucrose, glucose, mannitol and / or silicic acid; (2) binders, such as, for example, carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and / or gum; (3) water-retaining substances, such as glycerin; (4) disintegrants such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, individual silicates and sodium carbonate; (5) solution holding agents, such as paraffin; (6) adsorption accelerators, such as quaternary ammonium compounds; (7) humectants, such as, for example, acetyl alcohol or glycerol monostearate; (8) adsorbents such as kaolin or bentonite clay; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) dyes. In the case of capsules, tablets and pills, the compositions may also contain buffering agents. Solid compositions of a similar type can also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be made using a binder (e.g. gelatin or hydroxypropyl methyl cellulose), a lubricant, an inert diluent, preservative, a de-disintegrating agent (e.g. sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), a surfactant or dispersant. Molded tablets may be made by molding in a suitable machine a mixture of the desired composition moistened with an inert liquid diluent. Tablets and other solid dosage forms, such as dragees, capsules, pills and granules, may optionally be notched or coated with a shell or capsule, such as enteric coatings and other coatings well known in the pharmaceutical art.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the intended composition, liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water and 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, peanut, corn, from germ (grain), olive, castor and sesame oils), glycerin, tetrahydrofuryl alcohol, polyethylene glycols and fats. Suspensions in addition to the desired composition may contain suspending agents, such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitan and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar agar and tragacanth and mixtures thereof.

Dosage forms for rectal or vaginal administration can be presented in the form of suppositories, which can be made by mixing the target composition with one or more suitable non-irritant excipients or carriers containing, for example, cocoa butter, polyethylene glycol, suppository wax or salicylate, and which are solid at room temperature, but become liquid at body temperature and therefore will melt in body cavities and release the active substance. Dosage forms that are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or sprays containing such carriers that are known in the pharmaceutical field as suitable.

Dosage forms for administration through the skin of the target composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, plasters and inhalers. The active ingredient may be mixed under sterile conditions with a pharmaceutically acceptable carrier and with any preservatives, buffers or propellants that may be required.

Ointments, pastes, creams and gels may contain, in addition to the target 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 aerosols may contain, in addition to the target composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder or mixtures of these substances. Sprays may additionally contain consumer propellants, such as chlorofluorocarbons, and volatile unsubstituted hydrocarbons, such as butane and propane.

The compositions of the present invention can alternatively be administered by aerosol. This is achieved by obtaining an aqueous aerosol, liposome preparation, or solid particles containing compound (s). Non-aqueous (e.g., fluorocarbon propellants) suspensions may be used. Ultrasonic nebulizers can be used because they minimize the mechanical damage of the agent, which can lead to the destruction of the compositions contained in the target composition.

Typically, an aqueous aerosol is prepared by administering to a dosage form an aqueous solution or suspension of a desired composition together with conventional pharmaceutically acceptable carriers or stabilizers. Carriers and stabilizers vary according to the requirements of the specific target composition, but usually include nonionic surfactants (Tweens, Pluronics or polyethylene glycols), harmless proteins such as serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols are usually prepared from isotonic solutions.

Pharmaceutical compositions of the present invention suitable for parenteral administration contain the desired composition in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted into sterile injectable or dispersible solutions directly before use, which may contain antioxidants, buffers, bacteriostatics, salts that make the pharmaceutical composition and otonichnoy blood of the intended recipient or suspending agents or thickening agents.

Examples of suitable aqueous and non-aqueous vehicles that can be used in the pharmaceutical composition of the present invention include water, ethanol, polyalcohols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil and suitable injectable organic esters such as ethyl oleate. Proper fluidity can 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.

The pharmaceutical compositions may also be dosage forms with sustained or delayed release of the active principle, where the active agents are released over an extended period of time.

Dosage

The compositions of the present invention will be administered in an amount sufficient to achieve a therapeutic effect as determined by a person skilled in the art.

The dosage of any compositions of the present invention will vary depending on the symptoms, age and weight of the patient, the nature and severity of the disease to be treated or prevented, the route of administration and the form of the target composition. Any of the desired dosage forms can be administered in a single dose or in divided doses. Dosages of the compositions of the present invention can be easily determined using methods known to specialists in this field, or as described in this description.

Dosage limits for nebivolol range from about 0.1 mg to about 100 mg per day. In another embodiment, the dosage limits may be from about 0.75 mg to about 50 mg per day. In yet another embodiment, the dosage ranges may be from about 1.25 mg to about 10 mg per day.

In certain embodiments of the invention, dosages of concomitant active compounds will generally range from about 0.01 ng to about 1 g per kg of body weight, especially from about 1 ng to about 0.1 g per kg, and more specifically , in the range of about 100 ng to about 10 mg per kg body weight.

For any particular composition of the present invention, it may be necessary to determine the effective dose or amount and any possible negative effects on the time of administration of the dosage form. This can be accomplished using the routine experimentation described herein using one or more groups of animals (preferably at least 5 animals per group) or, if possible, in clinical trials in humans. The effectiveness of any target composition and method of treatment or prevention can be assessed by administering the composition and assessing the effect of administration by measuring one or more parameters used and comparing the values of these parameters after treatment with the values of the same parameters before treatment.

The exact time of administration and the amount of any particular target composition that may lead to the most effective treatment for a given patient will depend on the activity, pharmacokinetics and bioavailability of the target composition, the physiological state of the patient (including age, gender, type of disease and stage, general physical condition, response for a given dosage and type of drug), route of administration, etc. The guidelines presented in this description can be used to optimize treatment, for example, determining the optimal time and / or amount for administration, which will require no more than routine experimentation consisting of observing the treatment subject and adjusting the dosage and / or time.

During the treatment of a patient, his health can be monitored by measuring one or more important parameters at specific time points during treatment. Treatment, including compositions, amounts, time of administration and dosage form, can be optimized based on the results of these observations. The patient's condition can be re-evaluated to determine the degree of improvement by measuring the same parameters. A fit of the amount of the target composition to be administered and optionally the time of administration can be made based on these repeated evaluations.

Treatment can be started with small doses that are less than the optimal dose of the compound. After this, the dosage can be gradually increased until an optimal therapeutic effect is achieved.

The use of the desired compositions can reduce the required dosage for any single agent contained in the compositions (for example, a steroidal anti-inflammatory drug), since the onset and duration of action of various agents can complement each other.

The toxicity and therapeutic effect of the target compositions can be determined using standard pharmacobiological methods in cell cultures or experimental animals, for example, to determine LD ₅₀ and ED ₅₀ .

Data obtained using methods on cell cultures and animal studies can be used to determine dosage limits for use in humans. The dose of any desired composition is preferably within the range of circulating concentrations that include ED ₅₀ with low or no toxicity. Dosage may vary within these limits depending on the dosage form used and the route of administration used. For the compositions of the present invention, a therapeutically effective dose can be calculated based on cell culture assay methods.

Typically, doses of the active agent can be selected by the therapist based on age, physical condition, weight, and other factors known in medicine.

Treatment effectiveness

The effectiveness of the treatment for the target compositions can be determined using a number of methods known to specialists in this field.

In one example method, the median rate of reduction of inflammation for treatment with a target composition can be compared with other treatments with a specific cardiovascular agent contained in the target composition or other cardiovascular agents. Reducing inflammation in the treatment using the target composition compared to treatment in another way can be 10, 25, 50, 75, 100, 150, 200, 300, 400% more effective or even more. The time period for observing such a decrease may be about 1, 3, 5, 10, 15, 30, 60, or 90, or more hours. Comparison can be made against treatment with a specific cardiovascular agent contained in the target composition, or other cardiovascular agents, or the introduction of the same or different agents in a different way, or administration based on a different drug delivery device than the target composition. Comparison can be made against the same or different effective dosage of different agents.

Alternatively, a comparison of the various treatment regimens described above may be based on the effectiveness of the treatment using standard indicators known to those skilled in the art. One treatment method can be 10%, 20%, 30%, 50%, 75%, 100%, 150%, 200%, 300% more effective than the other method.

Alternatively, different treatment regimens can be studied by comparing the therapeutic indices for each of them in the treatment with the target composition compared to another regimen having therapeutic indices two, three, five or seven times or even one, two, three or more orders of magnitude higher than treatment in another way using the same or a different cardiovascular agent.

Sets

The invention also provides kits for conveniently and effectively implementing the methods of the invention. Such kits contain any desired composition and means to facilitate compliance with the methods of the present invention. Such kits provide convenient and effective means to ensure that the subject receives the appropriate active substance in the right dosage in the right way. Means of compliance from such kits include any means that facilitate the administration of active substances in accordance with the method of the present invention. Such compliance means include instructions, packaging and dispensers, and combinations thereof. The components of the kits can be packaged either for manual, or partially or fully automated use of the above methods. In other embodiments of the invention, including kits, this invention provides a kit comprising the compositions of the present invention and, optionally, instructions for their use.

Explanatory examples

Example 1

Measurement of NO release from the human endothelium

All presented measurements were carried out in vitro using a sensitive porphyrin sample, as described previously. Malinski T, Taha Z., Nature . 1992; 358: 676-678; Malinski T, Czuchajowski L., Methods in Nitric Oxide Research . 1996: 319-339. NO release was measured directly from HUVEC cells. HUVEC cells from black and white donors were grown on Ham F12K medium with 2 mM L-glutamine, adjusted to contain 1.5 g / L sodium bicarbonate, and added 0.1 mg / ml heparin and 0.03-0.05 mg / ml nutrition for growth of endothelial cells (ECGS) + 10% fetal bovine serum. HUVEC cells were kept in an atmosphere with a high content of CO ₂ (5%). Nebivolol was obtained from Mylan Laboratories (Morgantown, WV).

All measurements on the release of endothelial NO were performed in a balanced Hank's solution (Hank's solution) at 37 ° C. Cell wells were transferred to a Faraday cage and a porphyrin sensor (with a diameter of 0.5 mm) was placed at a distance of 5 ± 2 mm from the surface of the endothelial cells using an inverted microscope (Leica Microsystems, Wetzlar, Germany) and a computer-controlled micromanipulator. The sensor was driven using a three-electrode system: a nanosensor (working electrode), a saturated calomel electrode (reference electrode), and a platinum wire (read electrode with a diameter of 0.5 mm). Three electrodes were connected to a PAR273 potentiostat / galvanostat. The baseline stabilized after approximately 20 seconds. Test compounds were sprayed with a nanoinjector onto the cell surface after solubilization in buffer. Cells were incubated with test compounds for a 24-hour period. The system was then washed from the compounds before being reintroduced immediately in order to evaluate the effects of prolonged treatment on the release of NO from cells. For further experiments, cells were incubated with AGE inhibitors for 24 hours, the system was washed from the inhibitor, nebivolol was added and NO release was measured. A current proportional to the NO concentration was measured using a sensor that operated in a current measuring mode at a constant voltage of 0.63 V. Data were collected using an IBM computer with special software and amperograms (current-time curves) were recorded with Guniry FASl Femtostat (Warminster, PA). The maximum release of NO was obtained using a calcium agonist (1 μM). With increasing levels of cytoplasmic calcium, ion can bind calmodulin. The Ca ²⁺ -calmodulin complex is a cofactor of NO synthetase along with FAD, FMN, heme and BH4.

Nanosensors were made from carbon fibers. The size and tip of the carbon fiber was reduced from 6 μm to less than 1 μm by annealing at a controlled temperature. Sensors were sensitized to NO by applying an electrically conductive polymer porphyrin and coated with a thin layer of Nafion. The porphyrin microsensor has a response time of 0.1 ms at micromolar concentrations of NO and 10 ms at a detection limit of 1 nM.

The nanosensor for NO was calibrated using a saturated solution (concentration of 1.82 mm, checked by colorimetric method). Linear calibration curves were constructed for each sensor from 5 × 10 ^-9 to 3 × 10 ^-6 M NO before and after measuring cellular activity. The concentration-dependent effect of nebivolol and individual AGE inhibitors on the ability to release NO were tested using calcium ionophore (A23187), which stimulates the release of NO regardless of G-protein receptors. Data were presented as mean ± SOS (standard error of the mean) for each of the triplicate measurements. Data (calculations and graphics) was transferred to Microcal Origin Software (OriginLab Corp., Northampton, MA).

HUVEC cell preparations are stable throughout the course of these experiments with cells that remain alive in culture for more than 24 hours. In the absence of stimulation, the basal levels of NO release were very low (<30 nM). Measurement of NO release as a function of treatment was performed on individual endothelial cells. Multiple measurements of NO release can be performed on single cells after a brief period of time without excitation. For robust statistical analysis, individual cells were used for each concentration and type of drug used in these analyzes.

1, the degree of NO release from black and white donors was measured after prolonged treatment with an AGE inhibitor, ramiprilat, followed by treatment with nebivolol (1 μM). At concentrations of 1, 5, and 10 μM ramiprilat, small but significant effects of the ability of nebivolol to increase the release of NO from endothelial cells from black and white donors were observed. The magnitude of the increase was greater in endothelial cells from black donors.

In Fig. 3, the degree of NO release from black and white donors was measured in the presence of nebivolol (1 μM) after prolonged treatment with an AGE inhibitor, enalapril. Like ramiprilat (above), enalapril significantly increased the ability of nebivolol to increase the release of NO at concentrations of 5 and 10 μM and 1.5 and 10 μM in black and white donors, respectively. The magnitude of the increase was greater for endothelial cells from black donors than from white ones (Fig. 4).

Significant concentration-dependent effects were observed on the ability of nebivolol to increase the release of NO from endothelial cells from black and white donors, which were long-term treated with AGE inhibitors. Additionally, this property of the drug seems to work independently of the blockade of β1-adrenergic receptors. By stimulating a more normal vascular physiology via an NO-dependent biochemical pathway, treatment with nebivolol can be more effective and have less side effects compared with agents that inhibit only the sympathetic nervous system. These data further support the hypothesis that nebivolol may have long-term pharmacological positive effects through modulation of endothelial functions and NO metabolism.

Link inclusion

All patents and publications cited herein are hereby incorporated by reference.

Equivalents

It will be apparent to those skilled in the art or they will be able to establish, using no more than routine experimentation, the many equivalents of the specific embodiments of the invention described herein.

Claims (1)

The use of a therapeutically safe and effective amount of a combination of nebivolol or a pharmaceutical salt thereof and ramiprilat or enalapril or a pharmaceutical salt thereof for the manufacture of a medicament for improving NO release in black patients, resulting in a reduction in mortality associated with cardiovascular disease.

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