Methods for protection of a human from SVFS comprise the administration of a flavonoid compound of the basic structures 2-phenyl-4H-1-benzopyran or 2-phenyl-4-keto-1-benzopyran or glycosides thereof, alone or, optionally, together with one or more of an olive kernel extract, a non-bovine sulfated proteoglycan, bitter willow extract, a D-hexosamine sulfate, S-adenosylmethionine, folic acid, vitamin B12 and a serotonin inhibitor. Such treatment prevents, reduces or eliminates SVFS in patients receiving as much as 300-3000 mg/day of niacin therapeutically, whether administered prior to, or along with, an anti-SVFS composition.

Description of the Invention

SUBJECT OF THE INVENTION

The invention is generally related to the treatment of the flush syndrome. More specifically, the invention is related to the use of particular dietary supplements, medical foods, prescription products or other adjuvants to conventional approved medications for protection against superficial vasodilator flush syndrome ("SVFS") in humans.

SVFS is present in a related group of human conditions that includes carcinoid-induced flush, niacin-induced flush, mesenteric traction-induced flush, serotonin-induced flush, postmenopause-induced flush, alcohol-induced flush and monosodium glutamate ("MSG")-induced flush.

Niacin is the most potent agent for reversing the trend to increased serum levels of cholesterol and triglycerides and increasing levels of serum LDL, while also increasing levels of serum HDL. Unfortunately, compliance with the niacin treatment regimen is often compromised by the development of a feeling of cutaneous warmth and itching, especially in the face (flush), even with the use of slow or extended release niacin preparations. In about 75% of patients taking niacin, acetylsalicylic acid ("ASA") reduces the flush effects, but only about 30%.

Certain plant flavonoids that belong to the class of polypherols, found in citrus fruit pulp, seeds, sea weed) are now recognized as having anti-allergic, anti-inflammatory, anti-oxidant and cytoprotective properties. Only some flavonoids, e.g. flavonols such as quercetin and the flavones such as luteolin, inhibit mast cell activation.

Quercetin inhibits secretion from human activated mast and macrophages. However, other flavonoids may have opposite effects. Use of the term "bioflavonoids", "citrus flavonoids" or "soy flavonoids" in certain commercial products, therefore, provides little information, and may, indeed, include molecules that have detrimental effects; for example, soy contains isoflavones that have estrogen-like activity that worsens inflammatory conditions. As will be detailed below, quercetin and luteolin are the most potent anti-SVFS biochemicals in patients receiving niacin.

An important need, therefore, exists for compositions for administration to human patients being treated for cardiovascular conditions with niacin and/or other other compounds, who present with SVFS. This need has been fulfilled by the present inventor by the finding that certain biochemicals, known to inhibit mast cell-induced inflammatory diseases, can be used clinically to inhibit SVFS. Such methods have been discovered, and are described below.

SUMMARY OF THE INVENTION

The invention comprises a method for treating humans to avoid or lessen SVFS. The method involves the timely administration of compositions that contain a flavonoid compound having the basic structure of 2-phenyl-4H-1-benzopyran or its 4-keto counterpart, and, optionally, a sulfated proteoglycan, olive kernel extract ("OKE"), sulfated glucosamine, a serotonin antagonist, bitter willow extract, S-adenosylmethionine ("SAM"), vitamin B12, histamine-1 receptor antagonists, histamine-3 receptor agonists, folic acid, and long-chain polyunsaturated fatty acids, together with appropriate excipients and carriers, said compositions having improved absorption from the gastrointestinal tract, skin surface, and nasal and pulmonary surfaces, and anti-SVFS effects, wherein the SVFS effects are caused by treatment with niacin or by other similarly acting conditions said compositions to be administered as separate formulations administered along with, prior to or subsequent to administration of niacin or other SVFS-causing chemicals.

In preferred embodiments, the flavonoid compound used in the method of treatment is quercetin, luteolin, genistein, myricetin, kaempferol and/or their respective glycosides, the sulfated glucosamine is D-glucosamine sulfate, and the proteoglycan is non-bovine chondroitin sulfate.

In still other embodiments, serotonin inhibitors are used in anti-SVFS treatment formulations, which include prochlorperazine, cyproheptadine and azatadine.

In yet another embodiment, the inventive method of treatment uses compositions that protect humans against a variety of SVFSs, the compositions including a flavonoid compound, and, optionally, one or more of a non-bovine chondroitin sulfate, D-glucosamine sulfate, bitter willow extract, folic acid, vitamin B12 and a serotonin inhibitor.

In another embodiment, the composition used in the inventive method of treatment also contains OKE that improves the absorption of drugs across membrane barriers in the body, such as those of the intestine, skin and pulmonary alveoli, and also contributes its own content of useful polyphenols, slows the release of niacin, and has independent protective action on the cardiovasacular system.

DETAILED DESCRIPTION OF THE INVENTION

It has been discovered that SVFS due to a variety of etiologies, e.g., niacin administration, can be successfully treated or prevented in humans by the judicious administration of a composition containing a flavonoid compound or its glycoside counterpart, and, optionally, one or more of the group consisting of a sulfated proteoglycan, OKE, a sulfated D-hexosamine, a serotonin antagonist, bitter willow extract, a histamine-1 receptor antagonist, a histamine-3 receptor agonist, long chain polyunsaturated fatty acids, S-adenosylmethionine, folic acid and vitamin B12, wherein said compositions may, at least in the case of niacin-induced SVFS, be administered before, with, or subsequent to a dose of niacin.

The anti-SVFS compositions of the invention may be used together with serum cholesterol- and LDL-lowering statins, such as simvastatin, lavastatin, atorvastatin, rosuvastatin, fluvastatin, and provastatin in the treatment of patients also being treated with niacin

OKE improves the transmembrane transport of difficultly-absorbable molecules, such as therapeutic doses of lipophilic flavonoids and niacin, in the intestine, bladder, mouth, skin and pulmonary alveoli, and the release of water soluble molecules.

The highly preferred flavonoids are luteolin and quercetin, which inhibit secretion of inflammatory molecules from mast cells, macrophages and blood platelets by affecting moesin, a unique 78 kDa mast cell protein [Theoharides e al. J Pharm Exp Therap 294:810 (2000)]. In addition to luteolin and quercetin, other flavonoids suitable in carrying out the invention include the quercetin glycoside rutin, myricetin, genistein, kaempferol, the kaempferol glycoside astragaline or the isoflavone phenoxodiol.

In the method of treating SVFS in human It is preferred that the sulfated proteoglycan is non-bovine chondroitin sulfate, which blocks mast cell activation, degranulation and consequent secretion of inflammatory biochemicals from the mast cells. Other natural sulfated proteoglycans suitable for practicing this invention include keratan sulfate, dermatan sulfate and hyaluronic acid sodium salt, as well as polysaccharides, glycoproteins or proteoglycans containing plant extracts such as aloe vera. The preferred biological source of the chondroitin sulfate is shark cartilage which is more-highly sulfated than the common commercial chondroitin sulfate isolated from cow trachea, and which also avoids the potential dangers associated with bovine sources, such as "mad cow disease."

The OKE component of the compositions used in the inventive method is preferably an unrefined (first pressing, filtered, oleic acid-related acidity <3%, water content <1%) extract product produced, for one source, on the island of Crete in Greece. This kernel extract product is especially prepared by applicant's process consisting essentially of: (1) harvesting first collection ripe olives, preferably in December; (2) compressing the oil from the flesh of the ripe olives; (3) washing the kernels remaining after step (2) with water to remove debris; (4) drying the washed kernels with a stream of hot air; (5) crushing the dried kernels to produce an extract; (6) extracting the extract from step (5) with an organic solvent (e.g., hexane, heptane, octane) plus steam; (7) removing particulate matter from the organic extract by centrifugation or microfiltering through 1-2 micron pore size filters; (8) evaporating the organic solvent and water from the clarified extract of step (7) by maintaining the extract at 86-100.degree. C. while percolating helium (to avoid oxidation) through the fluid, which process reduces the water content to <1%, the acidity (as oleic acid) to <3%; and, the organic solvent to <1%; and (9) storing the final kernel extract product in the absence of air.

The applicant has found that the novel OKE surprisingly has the unique property of increasing absorption of the other components of the anti-SVFS treatment compositions through the oral, alveolar, bladder, intestinal mucosa or skin, and also adds its own content of important anti-oxidants, such as omega fatty acids (e.g., eicosapentanoic acid) and alpha tocopherol. The polyphenols found in such OKE also have anti-inflammatory effects in, for example, arthritis [Martinez-Dominguez et al., Inflamm. Res. 50:102 (2001)]. Sources of OKE were E.B.E.K., Inc., Commercial, Industrial Enterprises of Crete, 118 Ethnikis Antistasos, Heraklion, Crete, 71306, Greece, and Minerva Edible Oil Enterprises, 65 Tatoiou St., Oddideos, Attica,

n addition to its usefulness in increasing the absorption of the compositions across, for example, the intestinal wall and the skin, OKE is useful in aiding the dissolution of other drugs prior to administration to a patient, and is useful in promoting the absorption of other difficultly-absorbable molecules, e.g., the HDL-increasing drug torcetrapib (DeNinno et al. U.S. Pat. No. 6,586,448), across intestinal mucosa, oral mucosa, nasal mucosa, bladder mucosa, and skin of patients.

Inhibitors of mast cell activation and consequent secretion of SVFS-inducing molecules such as PGD2 and serotonin in SVFS processes, such as in niacin-induced SVFS, and also in carcinoid, postmenopausal, mesenteric tfraction, serotonin, alcohol and MSG-induced SVFS (see Example 12, below). Applicant has discovered that certain flavonoid compounds of the basic structures 2-phenyl-4H-1-benzoyran and its 4-keto counterpart (described in the legend and figure of FIG. 1 (see Original Patent).), particularly, quercetin, luteolin, rutin, myricetin, genistein, inhibit niacin-induced flush syndromes in humans (Example 4) and in rat models (Example 5).

In experiments with rat models of the SVFS syndrome, applicant has surprisingly discovered that serotonin released from platelets, macrophages and mast cells, moderates the flush syndrome induced by niacin administration. This discovery has opened up a new therapeutic approach for niacin SVFS. Applicant has discovered that serotonin inhibitors/antagonists such as prochlorperazine, cyproheptadine, azatadine and ketanserin, when used alone or in combination with the basic compositions, inhibit the niacin-induced SVFS (Example 5, below).

Optional supplementation of the compositions described above with the methylation reagent S-adenosylmethionine ("SAM") adds antioxidant, anti-inflammatory and cytoprotective properties. Addition of SAM also accelerates metabolism of homocysteine, which amino acid has been implicated in coronary disease, to cysteine, which is harmless. Folic acid and vitamin B12 may be added to certain of the present formulations for similar reasons.

Another optional supplement to the basic compositions described above is a histamine-1 receptor antagonist, such as hydroxyzine, misolastine, azelastine, azatadine, ruputadine and cyproheptadine. Other histamine-1 receptor antagonists are described in Table 25-1 in Goodman and Gilman's The Pharmaceutical Basis of Therapeutics, 9th ed., New York, 1996.

The inventor has also found that flavonoid compounds alone or with the other components described below can neutralize the flush effects of as much as 300-3000 mg of niacin given concurrently. A highly preferred composition for preventing niacin-induced SVFS in human patients consists of 300-3000 niacin plus 300-3000 mg of luteolin, 10-150 mg folic acid, polyunsaturated fatty acids (300 mg in total), S-adenosyl methionine 50-400 mg, and white willow extract 200-2000 mg.

The preferred concentration range of the proteoglycan, hexosamine sulfate and flavonoid components of the oral formulations are 10-3,000 mg per tablet or capsule. The preferred concentration range for SAM is 30-1,000 mg per capsule or tablet. Generally, where present, the amounts of OKE are about equal to those of the total other active ingredients, preferably 300-1200 mg/capsule. The number of capsules or tablets to be taken per day is determined by the nature and severity of the medical condition, and is readily determinable by the patient's health provider. Other representative formulations are described in the examples below.

The compositions of the invention may be formulated in any standard means of introducing pharmaceuticals into a patient, e.g., by means of tablets or capsules. Standard excipients and carriers for the active ingredients of the inventive compositions are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa.
 

Claim 1 of 10 Claims

1. A method for treating niacin-induced flush comprising administering to a patient in need thereof, a composition comprising an effective dose of a flavonoid compound, a non-bovine sulfated proteoglycan and olive kernel oil, wherein said flavonoid is selected from quercetin and luteolin.

 

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