Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/04—Drugs for disorders of the urinary system for urolithiasis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/06—Antipsoriatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P39/00—General protective or antinoxious agents
  • A61P39/02—Antidotes
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives

Definitions

• the invention generally relates to compounds, compositions and methods for reducing uric acid levels in a subject.
• the invention relates to the treatment of hyperuricemia and diseases associated with high uric acid levels in mammals using scyllo- inositol.
• Uric acid (7 ? 9-dihydro-l/f-purine-2,6,8(3/i)-trione; UA) has been implicated as a risk factor for several diseases or disease states. Kutzing, M.K. et al., JPET Vol. 324, No. 1, 1-7 (2008) (doi: 10.1124/jpet.107.129031).
• Abnormally high UA levels (i.e., hyperuricemic levels) in the blood contribute to a number of disease states, for example, gout, renal disease (Johnson, R.J., et al., Hypertension. 2003 Jun;41(6):l 183-90), atheroscleropathy (Hayden, M.R., Nutr Metab (Lond).
• Hyperuricemia for men can be a UA concentration greater than 386 ⁇ M (which is micromoles per liter or micromolar) in serum in one study (Klemp P. et al., Ann Rheum Dis. 56:22-26(1997)) and greater than 420 ⁇ M in a separate study (Johnson, RJ. et al., Hypertension 41:1183-1190(2003)).
• hyperuricemia For women, most studies define hyperuricemia as a concentration greater than approximately 360 ⁇ M (Klemp 1997 and Johnson 2003). The normal range of UA concentrations falls somewhere between about 120 ⁇ M and about 380 ⁇ M, varying slightly depending on gender (Kutzing 2008). In some instances uric acid concentration in blood or serum is expressed in milligrams per deciliter (mg/dL); to convert a uric acid value from micromoles per liter to mg/dL, divide the value by 59.48. After modification of diet, alcohol intake, and exercise levels for afflicted individuals, currently favored treatments for hyperuricemia include two types of drags: xanthine oxidase inhibitors and uricosuric drugs.
• Xanthine oxidase inhibitors such as allopurinol, inhibit the production of UA by blocking the final two steps of urate synthesis.
• Xanthine oxidase inhibitors are primarily used in patients who have an increased urate production compared to the norm.
• uricosuric drugs such as probenecid, sulfinpyrazone, and benzpromarone are used to reduce the serum UA concentration through the inhibition of a renal transporter that reabsorbs UA from the tubules which results in an increase in UA excretion (Emmerson, 1996; Choi et al., 2005).
• treatment of gout with some uricosuric drugs can lead to uric acid nephrolithiasis (kidney stones).
• Another older, less used treatment for gout is administration of colchicine. Side effects have been reported for these existing treatments, and there is still an unmet need for safe and effective treatments for hyperuricemia and for diseases associated with hyperuricemia.
• Scyllo-inositol has been found to lower uric acid levels in patients, and in particular it has been found that scyllo-inositol lowers the amount of uric acid in the blood in a dose dependent manner. Therefore, scyllo-inositol is useful in lowering uric acid levels in tissues or organs, blood, serum, urine, or combinations thereof, and has utility in treating conditions associated with aberrant levels of uric acid, such as conditions characterized by elevated levels of uric acid. Conditions associated with aberrant levels of uric acid may involve overproduction of uric acid, low excretion of uric acid, tumor lysis, a blood disorder, or a combination thereof.
• Scyllo-inositol has particular utility in lowering abnormally high levels of uric acid in the blood (hyperuricemia) and has utility in treating diseases associated with hyperuricemia or having hyperuricemia as a risk factor, or diseases, which are exacerbated by the presence of hyperuricemia.
• diseases include, but are not limited to, gout, atheroscleropathy, renal disease, cardiovascular disease, metabolic syndrome, urate lithiasis, and hypertension.
• the present invention relates to a method of decreasing uric acid levels in one or more tissues or organs, blood, serum, urine, or combinations thereof of an individual in need of decreased uric acid levels comprising administering to the individual a therapeutically effective amount of scyllo-inositol.
• the invention relates to a method of decreasing uric acid levels or maintaining uric acid levels in one or more tissues or organs, blood, serum, urine, or combinations thereof of an individual in need of decreased uric acid levels or maintaining uric acid levels, comprising administering to the individual a uric acid level lowering amount of scyllo-inositol.
• the invention also provides a method of decreasing uric acid production, increasing uric acid excretion, or both, or maintaining uric acid levels in an individual comprising administering a therapeutically effective amount of scyllo-inositol.
• the invention also relates to a method of treating an individual suffering from a condition associated with aberrant levels of uric acid comprising administering to the individual a therapeutically effective amount of scyllo-inositol.
• the condition is chosen or selected from the group consisting of gout; a recurrent gout attack; gouty tophus; gouty arthritis; gouty nephropathy; eclampsia; metabolic syndrome; diseases that involve accelerated formation and destruction of blood cells; hyperuricaemia; secondary hyperuricemia; drug related hyperuricaemia; secondary chronic hyperuricemia of polycythemia vera, of myeloid metaplasia, or of blood dyscrasia; atheroscleropathy; hyperuricaemia related to medical conditions such as nephropathies, myeloproliferative disorders; conditions associated with insulin resistance; conditions associated with transplantations; hypertension; cardiovascular disease; coronary heart disease; Lesch-Nyhan syndrome, Kelley-Seegm ⁇ ler
• the invention further relates to a method of treating a condition associated with aberrant levels of uric acid in an individual at increased risk of developing the condition comprising administering to the individual a therapeutically effective amount of scyllo- inositol.
• the invention relates to a method of reducing serum uric acid levels and/or increasing renal clearance of uric acid in an individual comprising administering a therapeutically effective amount of scyllo-inositol.
• the invention relates to a method of reducing serum uric acid levels in an individual in need thereof by administering a serum uric acid level lowering amount of scyllo-inositol.
• the individual to be treated has serum uric acid levels before treatment equal to or greater than 7 mg/dL (420 ⁇ moI/L).
• At least one condition treated using a method of the invention is gout or any condition brought about by high levels of uric acid in the joints or kidneys or a serum uric acid level over 9 mg/dL (530 ⁇ mol/L).
• the invention in another aspect, relates to a method of preventing or reducing the formation of tophi/tophus in an individual comprising administering to the individual a therapeutically effective amount of scyllo-inositol.
• the invention relates to a method of lowering hyperuricemia in a hyperuricemic patient comprising administering scyllo-inositol to the patient in an amount effective to lower the uric acid level in the blood.
• the invention relates to a method for treating or preventing hyperuricemia in an individual comprising administering a blood uric acid level lowering amount of scyllo- inositol to the individual.
• the invention in another aspect, relates to a method of treating a disease mediated at least in part by hyperuricemia by administering a therapeutically effective amount of scyllo- inositol to a patient having hyperuricemia and such a disease state or states.
• the invention provides a method of lowering hyperuricemia in a hyperuricemic patient comprising administering scyllo-inositol to the patient in an amount effective to lower the uric acid level in the blood, wherein the uric acid in the blood prior to administering scyllo-inositol is greater than or equal to about 360 ⁇ M as measured in blood serum.
• the amount of scyllo-inositol administered to the hyperuricemic patient ranges from about 100 mg/day to 7000 mg/day, 150 mg/day to 6000 mg/day 5 and within that range from about 200 mg/day to 6000 mg/day, from 400 mg/day to 6000 mg/day, from 150 mg/day to about 4000 mg/day s or from 200 mg/day to 3000 mg/day.
• the scyllo-inositol is administered to an individual, such as a hyperuricemic patient, in a unit dosage form.
• the unit dosage form is an immediate release dosage form.
• the unit dosage form is an extended release dosage form.
• the unit dosage form is a gastric retentive dosage form.
• the unit dosage form comprises 150 mg, 250 mg, 500 mg, 750 mg, 800 mg, 1000 mg or 2000 mg of scyllo-inositol.
• a method of preventing or treating gout in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of scyllo-inositol.
• the invention provides a method of treating or preventing gout, wherein the amount of scyllo-inositol administered to the patient ranges from about 100 mg/day to about 7000 mg/day, in particular about 150 rag/day to about 6000 mg/day, and more particularly about 150 mg/day to about 4000 mg/day.
• scyllo-inositol is administered to the patient in the treatment or prevention of gout in a unit dosage form.
• the unit dosage form is an immediate release dosage form. In another aspect, the unit dosage form is an extended release dosage form In another aspect, the unit dosage form is a gastric retentive dosage form. In an aspect of the invention the prevention or treatment of gout is performed with a unit dosage form comprising 150 mg, 250 mg, 500 mg, 750 mg, 800 mg, or 1000 mg of scyllo-inositol.
• Another aspect of the invention provides a method of treating a disease state in which hyperuricemia is a risk factor in a patient in need of such treatment comprising administering a uric acid level lowering amount or uric acid level maintaining amount of scyllo-inositol to the patient
• the disease state in which hyperuricemia is a risk factor being treated is chosen or selected from the group consisting of atheroscleropathy, renal disease, cardiovascular disease, metabolic syndrome, urate lithiasis, and hypertension.
• the patient having a disease state wherein hyperuricemia is a risk factor is administered an amount of scyllo-inositol from about 100 mg/day to about 7000 mg/day, in particular 150 mg/day to about 6000 mg/day, more particularly 150 mg/day to about 4000 mg/day.
• scyllo-inositol is administered in a unit dosage form.
• the unit dosage form is an immediate release dosage form.
• the unit dosage form is art extended release dosage form
• the unit dosage form is a gastric retentive dosage form.
• the unit dosage form may comprise 150 mg, 250 mg, 500 mg, 750 mg, 800 mg ? or 1000 mg of scyllo-inositol.
• the invention also relates to a method of treating a condition associated with aberrant levels of uric acid in an individual comprising determining the individual's average serum uric acid level and administering to the individual scyllo-inosito! according to a regimen effective to maintain the individual's serum uric acid level at or below 5 mg/dL or 6 mg/dL.
• the average serum uric acid level is generally the average of two or more uric acid readings obtained from the individual. The readings may be taken within hours, days, or weeks of each other. In an aspect of the invention, the two or more readings are obtained at least a week apart.
• a method of the invention may also comprise administering in combination with scyllo-inositol, a second treatment, such as a second therapeutic agent, effective for the treatment or prevention of a condition associated with aberrant levels of uric acid, such as a disease mediated in part by hyperuricemia. Therefore, the invention relates to a combination treatment for a condition associated with aberrant levels of uric acid comprising administering therapeutically effective amounts of scyllo-inositol and a second therapeutic agent.
• the second therapeutic agent is a uric acid lowering agent, such as a xanthine oxidase inhibitor.
• the invention also relates to a method for decreasing uric acid production, increasing uric acid excretion, or bothor maintaining uric acid levels comprising administering therapeutically effective amounts of scyllo-inositol and a uric acid lowering agent.
• the uric acid lowering agent is allopurinol, febuxostat, 4-(5-pyridin-4-yl-l/f-[l,2,4Jtriazol-3-yl)pyridine-2-carbonitrile (FYX- 051), or combinations thereof.
• the invention provides a method for treating edema and hypertension in a subject comprising administering an antihypertensive agent and a uric acid level maintaining amount or uric acid level lowering amount of a scyllo-inositol.
• the invention provides a method for treating cancer in a subject comprising administering an anticancer agent and a uric acid level maintaining amount or uric acid level lowering amount of a scyllo-inositol.
• the invention provides a method for reducing the side effects of chemotherapy in a cancer individual comprising administering a uric acid level maintaining amount or uric acid level lowering amount of a scyllo-inositol, wherein said side effects are related to elevated uric acid levels.
• the invention also relates to a pharmaceutical composition for treating a condition associated with aberrant levels of uric acid comprising therapeutically effective amounts of scyllo-inositol and a pharmaceutically acceptable carrier, excipient, or vehicle.
• the pharmaceutical compositions comprise uric acid level lowering amounts of scyllo-inositol.
• the pharmaceutical compositions of the invention contain adjuvants, excipients, vehicles, preservatives, agents for delaying absorption, fillers, binders, adsorbents, buffers, disintegrating agents, solubilizmg agents, other carriers, other inert ingredients, or combinations thereof.
• the pharmaceutical composition is in a form suitable for oral administration.
• the pharmaceutical composition is in the form of a tablet, capsule, pill, powder, sustained release formulation, solution, suspension, for parenteral injections as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository.
• the invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising an amount of scyllo-inositol effective to lower the uric acid level in a mammal's blood compared to a baseline level and at least one pharmaceutically acceptable component chosen from a carrier, an excipient, and a vehicle.
• the pharmaceutical compositions of the invention are useful for treating or preventing gout. In additional embodiments, the pharmaceutical compositions are useful for reducing hypertension or cardiovascular events. In additional embodiments, the pharmaceutical compositions are used as a medicament for use in the amelioration of symptoms related to a high level of uric acid, or as a dietary supplement.
• a pharmaceutical composition of the invention can be in a unit dosage form suitable for single administration of precise dosages.
• the amount of scyllo-inositol present in the unit dosage form ranges from about 150 mg to 2000 mg and in particular within that range from about 150 mg to 1500 mg, from about 100 mg to 2000 mg, from about 100 mg to 1500 mg, or from about 100 mg to 1000 mg.
• scyllo-inositol is administered in a single dose, once daily.
• scyllo-inositol is administered twice daily.
• scyllo-inositol is administered three times per day.
• scyllo-inositol is administered four times per day.
• a pharmaceutical composition of the invention may also comprise a second therapeutic agent, such as a uric acid lowering agent.
• a second therapeutic agent such as a uric acid lowering agent.
• Combinations of a scyllo-inositol and a second therapeutic agent, such as a uric acid lowering agent, in compositions of the invention may be selected to provide additive effects or greater than additive effects, for example, synergistic effects.
• the invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising a scyllo-inositol and a second therapeutic agent, such as a uric acid lowering agent, in combination with at least one pharmaceutically acceptable component chosen from a carrier, an exc ⁇ pient, and a vehicle, wherein the amounts of scyllo-inositol and second therapeutic agent are selected to provide an additive or synergistic effect in treating or preventing a condition disclosed herein.
• the invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising scyllo-inositol and a second therapeutic agent in combination with at least one pharmaceutically acceptable component chosen from a carrier, an excipient, and a vehicle, wherein the scyllo-inositol and second therapeutic agent are selected to provide a synergistic effect, as a combined preparation for simultaneous, separate, or sequential use in treatment of a condition associated with aberrant levels of uric acids.
• the invention relates to a pharmaceutical composition comprising scyllo-inositol and a second therapeutic agent, wherein said composition achieves a synergistic effect for treating a disease state in which hyperuricemia is a risk factor in a mammal in need thereof.
• the invention also relates to a pharmaceutical composition in separate containers and intended for simultaneous or sequential administration to a subject, comprising a scyllo- inositol and a second therapeutic agent, such as a uric acid lowering agent, both optionally together with pharmaceutically acceptable carriers, excipients, or vehicles.
• the scyllo-inositol is in a unit dosage form.
• the unit dosage from comprises a suboptimal dose of scyllo-inositol and optionally a suboptimal dose of the second therapeutic agent.
• a pharmaceutical composition of the invention comprises: (i) a scyllo-inositol; (ii) allopurinol, febuxostat, 4-(5-pyridin-4-yl-l/f-[l,2,4]triazol-3- yl)pyridine-2-carbomtrile (FYX-051), or combinations thereof; and (iii) optionally one or more pharmaceutically acceptable carriers, excipients, or vehicle.
• a pharmaceutical composition of the invention comprises: (i) a scyllo-inositol; (U) allopurinol; and (iii) optionally one or more pharmaceutically acceptable carriers, excipients, or vehicle.
• the amount of scyllo-inositol is in the range of about 100-2000 mg and in particular within that range about 100-1500 mg or 100-1000 mg
• the amount of allopurinol is in the range of about 50-500 mg and in particular within that range about 50-400 mg, 200-500 mg, 200-400 mg, or 100-300 mg.
• a pharmaceutical composition of the invention comprises: (i) a scyllo-inositol; (ii) febuxostat; and (iii) optionally one or more pharmaceutically acceptable carriers, excipients, or vehicle.
• the amount of scyllo-inositol is in the range of about 100-2000 mg and in particular within that range about 100-1500 mg or 100-1000 mg
• the amount of febuxostat is in the range of about 40-200 mg and in particular within that range about 40-150 mg, 40-120 mg, 40-80 mg, or 80-120 mg.
• the invention provides a pharmaceutical composition useful in the treatment of gout comprising: (i) a uric acid lowering agent; (ii) a uric acid level maintaining amount or lowering amount of a scyllo-inositol; and (iii) optionally one or more pharmaceutically acceptable carriers, excipients, or vehicle.
• the uric acid lowering agent is allopurinol or febuxostat.
• the invention provides a pharmaceutical composition useful in the treatment of edema and hypertension which also maintains uric acid levels at pretreatment levels or causes a decrease in uric acid levels comprising: (i) an antihypertensive agent; (ii) a uric acid level maintaining amount or lowering amount of a scyllo-inositol; and (iii) optionally one or more pharmaceutically acceptable carriers, excipients, or vehicle.
• the invention provides a pharmaceutical composition useful in the treatment of cancer which also maintains uric acid levels at pretreatment levels or causes a decrease in uric acid levels comprising: (i) an anticancer agent; (ii) a uric acid level maintaining amount or lowering amount of a scyllo-inositol; and (iii) optionally one or more pharmaceutically acceptable carriers, excipients, or vehicle.
• the invention provides a pharmaceutical composition useful for reducing the side effects of chemotherapy in a cancer individual comprising: (i) a uric acid level maintaining amount or lowering amount of a scyllo-inositol; and (iii) optionally one or more pharmaceutically acceptable carriers, excipients, or vehicle, wherein said side effects are related to elevated uric acid levels.
• the invention relates to the use of scyllo-inositol in the preparation of a medicament for decreasing uric acid levels in one or more tissues or organs, blood, serum, urine, or combinations thereof.
• the invention also relates to the use of scyllo-inositol in the preparation of a medicament for decreasing uric acid production, increasing uric acid excretion, or both.
• the invention further relates to the use of scyUo-inositol in the preparation of a medicament for treating or preventing a condition associated with aberrant levels of uric acid.
• the invention still further relates to the use of scyllo-inositol in the preparation of a medicament for treating a condition chosen or selected from the group consisting of gout; a recurrent gout attack; gouty tophus; gouty arthritis; gouty nephropathy; eclampsia; metabolic syndrome; diseases that involve accelerated formation and destruction of blood cells; hyperaricaemia; secondary hyperuricemia; drug related hyperuricaemia; secondary chronic hyperuricemia of polycythemia vera, of myeloid metaplasia, or of blood dyscrasia; atheroscleropathy; arterioloscleropathy; hyperuricaemia related to medical conditions such as nephropathies, myeloproliferative disorders; conditions associated with insulin resistance; conditions associated with transplantations; hypertension; cardiovascular disease; coronary heart disease; Lesch-Nyhan syndrome, Kelley-Seegmiller syndrome, renal disease, kidney stones ⁇ renal failure; acute renal failure; joint inflammation; arthritis; art
• the invention also relates to the use of a scyllo-inositol and at least one second therapeutic agent, composition, or combination treatment of the present disclosure for ameliorating disease severity, disease symptoms, and/or periodicity of recurrence of a condition disclosed herein. Further, the invention relates to the use of a scyllo-inositol and a second therapeutic agent as a medicament.
• the medicament may be suitable for use in treating a condition disclosed herein or is suitable for use in patients who are at risk of developing a condition disclosed herein.
• the invention contemplates pharmaceutical packs or kits comprising scyllo-inositol or a pharmaceutical composition disclosed herein, and optionally a second therapeutic agent.
• the invention is directed to a kit comprising a first container comprising a pharmaceutical composition comprising an amount of scyllo-inositol effective to lower a mammal's uric acid level in blood compared to a baseline level and at least one pharmaceutically acceptable component chosen from a carrier, an excipient, and a vehicle scyllo-inositol.
• the kit may further comprise a second container comprising a second therapeutic agent.
• Figure 1 shows a plot of serum levels of UA vs. time under administration of different dosages of scyllo-inositol to healthy human subjects.
• the legend shows doses that were 0 mg (control), 200 mg, 700 mg, 1500 mg, and 3000mg per day. Measurements were taken at days 0 (baseline), 4, 7, and 12.
• Figure 2 shows the change in serum uric acid levels in subjects in the same study as summarized in Figure 1 , DETAILED DESCRIPTION QF THE INVENTION
• Numerical ranges recited herein by endpoints include all numbers and fractions subsumed within that range (for example, from 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.90, 4, and 5). It is also to be understood that all numbers and fractions thereof are presumed to be modified by the term “about.” The term “about” means plus or minus 0.1 to 50%, 5-50%, or 10-40%, preferably 10-20%, more preferably 10% or 15%, of the number to which reference is being made. Further, it is to be understood that "a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. Aspects of the present disclosure requiring a particular value in a subject are substantially supported herein by population data in which the relevant value is assessed to be a meaningful delimitation of the subject population.
• a “condition(s) associated with aberrant levels of uric acid” may be characterized by levels of uric acid which are greater than or below normal levels in at least one tissue or organ, blood, serum, urine, or combinations thereof.
• Normal levels of uric acid generally range from between about 120 ⁇ M and about 380 ⁇ M or from about 2.0 and 8.0 mg/dL, varying slightly depending on gender.
• the condition is characterized by elevated levels of uric acid, that is, levels greater than normal, for example, levels greater than 5.0, 6.0, 7.0 or 8.0 mg/dL.
• the aberrant levels may result from overproduction of uric acid, low excretion of uric acid, tumor lysis, a blood disorder, or a combination thereof.
• conditions associated with aberrant levels of uric acid include without limitation gout; a recurrent gout attack; gouty tophus; gouty arthritis; gouty nephropathy; eclampsia; metabolic syndrome; diseases that involve accelerated formation and destruction of blood cells; hyperuricaemia; secondary hyperuricemia; drug related hyperuricaemia; secondary chronic hyperuricemia of polycythemia vera, of myeloid metaplasia, or of blood dyscrasia; atheroscleropathy; hyperuricaemia related to medical conditions such as nephropathies, myeloproliferative disorders; conditions associated with insulin resistance; conditions associated with transplantations; hypertension; cardiovascular disease; coronary heart disease; Lesch-Nyhan syndrome, Kelley-Seegmiller syndrome, renal disease, kidney stones, renal failure; acute renal failure; joint inflammation; arthritis; artherosclerosis; arterioloscleropathy; diabetes; diabetes related disorders; urolithiasis; urate Hthiasis; plumbis
• the condition is chosen or selected from the group consisting of gout, a recurrent gout attack, gouty arthritis, gouty nephritis, eclampsia, secondary hyperuricemia, and secondary chronic hyperuricemia of polycythermia vera, of myeloid metaplasia, or of blood dyscrasia.
• the condition is a drug related hyperuricaemia
• the drug may be one or more of nucleic acid metabolic antagonists, hypotensive diuretics, anti-tuberculosis drugs, anti-inflammatory analgesic drugs, hyperlipidemic drugs, therapeutic drugs for asthma, immunosuppressants, cytotoxic drugs, salicylic acid, pyrazinamide, ethambutol, nicotinic acid, ethanol, cyclosporine and the like.
• the condition is a disease state in which hyperuricemia is a risk factor
• a risk factor is a characteristic that has been implicated or demonstrated to be associated with (although not necessarily the direct cause of) a particular disease or syndrome.
• Risk factors can be used for targeting treatment and preventive efforts of individuals who may be particularly in danger of the disease or syndrome based on having a particular risk factor or combination of risk factors.
• Disease states in which hyperuricemia is a risk factor include without limitation atheroscleropathy, renal disease, cardiovascular disease, metabolic syndrome, urate Hthiasis, and hypertension.
• renal disease, atheroscleropathy, cardiovascular disease, metabolic syndrome, and hypertension are complex disease states in which there are more than one risk factor and an array of pathological processes. Treatment of those disease states by administration of scyllo-inositol is intended to treat that portion of the disease state that is mediated or affected by hyperuricemia.
• the condition is gout and related symptoms.
• the condition is hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency.
• HPRT hypoxanthine-guanine phosphoribosyltransferase
• the condition is hypertension or edema.
• the condition is acute renal failure.
• treating refers to reversing, alleviating, or inhibiting the progress of a condition, or one or more symptoms of such condition, to which such term applies.
• the term in some aspects of the invention may refer to preventing a condition, and includes preventing the onset, or preventing the symptoms associated with a condition.
• the term also includes maintaining the condition and/or symptom such that the condition and/or symptom does not progress in severity.
• a treatment may be either performed in an acute or chronic way.
• the term also refers to reducing the severity of a condition or symptoms associated with such condition prior to affliction with the disease.
• Such prevention or reduction of the severity of a condition prior to affliction refers to administration of scyllo-inositol, or composition, or combination of the present invention to a subject that is not at the time of administration afflicted with the condition.
• Preventing also refers to preventing the recurrence of a condition, or of one or more symptoms associated with such condition.
• treatment and “therapeutically,” refer to the act of treating, as “treating 11 is defined above.
• the purpose of intervention is to combat the condition and includes the administration of an active compound to prevent or delay the onset of the symptoms or complications, or alleviating the symptoms or complications, or eliminating the condition.
• a compound, composition, or combination disclosed herein may be used to ameliorate symptoms associated with elevated levels of uric acid such as muscle spasm, localized swelling, inflammation, joint pains, muscle fatigue, stress feelings, or myocardial infarction.
• administering refers to the process by which scyllo- inositol, compositions, and/or combinations disclosed herein are delivered to a subject for treatment or prophylactic purposes. Scyllo-inositol, compositions, and/or combinations are administered in accordance with good medical practices taking into account the subject's clinical condition, the site and method of administration, dosage, subject age, sex, body weight, and other factors known to the physician.
• administering refers to (1) providing, giving, dosing and/or prescribing by either a health practitioner or his authorized agent or under his direction scyllo-inositol, and (2) putting into, taking or consuming by the patient or person himself or herself, scyllo- inositol.
• a “combination treatment,” “administering in combination” or “administered in combination” means use of multiple pharmaceutical agents in combination as active ingredients administered concurrently to a patient being treated.
• the terms include use as a combination drug, use as a kit, and use in a combination characterized by independent administration of each by the same or different administration routes and the like.
• each component may be administered at the same time, or sequentially in any order at different points in time. Therefore, each component may be administered separately, but sufficiently close in time to provide a desired effect, such as an additive or synergistic effect.
• the first compound may be administered in a regimen that additionally comprises treatment with a second therapeutic agent.
• the terms refer to the administration of scyllo-inositol and a second therapeutic agent including separate administration of medicaments each containing one of the compounds, as well as simultaneous administration whether or not the compounds are combined in one formulation or whether they are in separate formulations.
• an “additive effect” of a scyllo-inositol and a second therapeutic agent refers to an effect that is equal to the sum of the effects of the two individual agents.
• a “synergistic effect” of a scyllo-inositol and a second therapeutic agent refers to an effect that is greater than the additive effect that results from the sum of the effects of the two individual agents.
• a "uric acid lowering agent” refers to an agent effective in reducing uric acid levels in tissues or organs, blood, serum, urine, or combinations thereof and in particular refers to an agent known to reduce blood or serum uric acid levels.
• Uric acid lowering agents include without limitation, NSAIDs, colchicine, cinchophan, bucolome,corticosteroids, adenocorticotropic hormones (ACTH), sulfinpyrazone, ArcalystTM (rilonacept), XOMA 052, xanthine oxidoreductase inhibitors such as 4 ⁇ (5-pyridin-4-yl-l/f-[l,2,4]triazo3-3-yl)pyridine-2- carbonitrile (FYX-051), xanthine oxidase inhibitors such as allopurinol, tisopurine, hydroxyakalone, TEI-6720, febuxostat (AdenuricTM
• subject refers to an animal including a warmblooded animal, such as a mammal.
• Mammal includes without limitation any members of the kingdom Mammalia.
• Mammal includes humans, but the term also includes domestic animals bred for food or as pets, such as horses, cows, sheep, poultry, fish, pigs, cats, dogs, and zoo animals, goats, apes (e.g. gorilla or chimpanzee), and rodents such as rats and mice.
• Subjects for treatment include mammals, such as humans, susceptible to, suffering from, suspected of having, being pre-disposed or that have suffered a condition disclosed herein.
• phrases "at least one pharmaceutically acceptable component chosen from a carrier, an excipient, and a vehicle” refers to a medium which is useful for preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable. It is generally selected so that it does not interfere with the effectiveness or activity of an active ingredient and is not toxic to the hosts to which it is administered.
• the phrase as used in the specification and claims include both one and more than one such carrier, excipient, or vehicle. Acceptable carriers, excipients, or vehicles may be chosen or selected from any of those commercially used in the art.
• a carrier, excipient, or vehicle includes diluents, binders, adhesives, lubricants, disintegrates, bulking agents, wetting or emulsifying agents, pH buffering agents, and miscellaneous materials such as absorbants that may be needed in order to prepare a particular composition.
• carriers, excipients, and vehicles include but are not limited to saline, buffered saline, dextrose, water, glycerol, ethanol, and combinations thereof. The use of such media and agents for an active substance is well known in the art.
• “Therapeutically effective amount” refers to the amount or dose of active compound(s) or a composition of the invention that will lead to one or more desired effects, in particular therapeutic effects.
• a therapeutically effective amount of a substance can vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the substance to elicit a desired response in the individual.
• a dosage regimen may be adjusted to provide the optimum therapeutic response (such as sustained therapeutic or beneficial effects). For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
• a therapeutically effective amount is a "uric acid level maintaining amount".
• the uric acid level maintaining amount maintains the uric acid levels in the individual at about normal levels, more preferably uric acid levels at or below 5 mg/dL 5 6 mg/dL, 7 mg/dL or 8 mg/dL.
• a therapeutically effective amount is a "uric acid level lowering amount".
• the uric acid level lowering amount may decrease the serum levels of uric acid to achieve normal serum uric acid levels.
• a uric acid lowering amount may decrease the uric acid level in an individual compared to the individual's uric acid level before administration.
• a uric acid level lowering amount can decrease uric acid levels by at least about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 75%, 80%, 85%, 90%, or 95%, preferably at least 10%, or any percentage in between.
• the uric acid lowering amount decreases uric acid from about 5% to 50%, 5% to 95% and in particular within that range about 5% to 50%, 10% to 50%, 10% to 20%, 10% to 30%, 10% to 40%, 10% to 50%, 10% to 60%, 10% to 70%, 10% to 95%, 15-% to 50%, 15% to 95%, 20-40%, or 20-60%.
• a uric acid level lowering amount can decrease serum uric acid levels by at least about 0.5 mg/dL (about 30 ⁇ M), 1 mg/dL (about 60 ⁇ M), 2 mg/dL (about 119 ⁇ M), 2.5 mg/dL (about 149 ⁇ M) or 3 mg/dL (about 178 ⁇ M).
• the uric acid level lowering amount can decrease blood uric acid levels from about 0.5 mg/dL (about 30 ⁇ M ) to 3 mg/dL (about 178 ⁇ M), from 1 mg/dL (about 60 ⁇ M ) to 3 mg/dL (about 178 ⁇ M), or from 2mg/dL (about 119 ⁇ M ) to 3 mg/dL (about 178 ⁇ M).
• “Suboptimal dose” refers to a dose of an active compound which is less than the optimal dose for that compound when used in monotherapy.
• Scyllo-inositol is a cyclohexane polyol, isomeric with myo-inositol, but differing in the orientation of the six hydroxyl groups around the ring.
• the structural formula of scyllo- inositol is depicted below in both 3-dimensional and planar drawings.
• Scyllitol is also known as scyllitol s quercinitol, and 1,2,3,4,5,6-cyclohexanehexol, (lalpha,2beta,3alpha,4beta,5alpha,6beta), Scyllo-inositol is commercially available in the SigmaAldrich catalog under CAS no. 488-59-5 or may be made by oxidation of myoinositol to scyllo-inosose and stereospec ⁇ fic reduction using a metal catalyst and hydrogen following known procedures. Scyllo-inositol may alternatively be produced using process steps described by Saraiah M.
• the scyllo-inositol is the compound designated
• the methods, compositions, and combinations disclosed herein may comprise an analog or derivative of scyllo-inositol, for example, an analog or derivative as disclosed in International Published Applications WO 2007/041855 and WO 2007/119108.
• Uric acid is denoted by the following systematic nomenclature: 7,9-dihydro-lH- ⁇ urine-2,6,8(3//)-trione.
• Urate is the anion of uric acid and may be found physiologically as the ammonium, calcium, or sodium salt, among other possible physiological counterions.
• Uric acid exists along with the ionized urate form physiologically. Unless otherwise constrained by the context in which it is used, uric acid includes urate salts.
• Scyllo-inositol may be administered by any of the accepted modes of systemic administration including oral, subdermal, intramuscular, parenteral, and other systemic routes of administration.
• Any pharmaceutically acceptable mode of administration can be used, including solid, semi-solid, or liquid dosage forms, such as for example, tablets, pills, capsules, powders, liquids, suspensions, or the like.
• Those dosage forms may be in a unit dosage form suitable for administration of precise dosages, or in sustained or controlled, such as extended, release forms for the prolonged administration of the compound at a predetermined rate.
• Sustained or continuous release compositions containing scyllo-inositol are described, for example, in WO 2007/101353.
• compositions of scyllo-inositol may be formulated as sterile, substantially isotonic and in full compliance with all Good Manufacturing Practice (GMP) regulations of appropriate regulatory authorities such as the US Food and Drag Administration.
• the compositions will typically include at least one pharmaceutically acceptable component chosen from a carrier, an excipient, and a vehicle and the active compound and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, and the like.
• Carriers, excipients, and vehicles are generally selected based on the intended form of administration, and consistent with conventional pharmaceutical practices. Suitable pharmaceutical carriers, excipients, and vehicles are described in the standard text, Remington: The Science and Practice of Pharmacy (21st Edition, Popovich, N (eds), Advanced Concepts Institute, University of the Sciences in Philadelphia, Philadelphia, PA. 2005).
• Parenteral administration is generally characterized by injection, whether subcutaneously or intramuscularly.
• Injectables can be prepared in conventional forms, either as liquid solutions or suspension, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions.
• Suitable excipients include, for example, water, saline, aqueous dextrose, glycerol, ethanol or the like.
• the pharmaceutical compositions may also contain minor amounts of non-toxic substances such as wetting or emulsifying agents, auxiliary pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate, and the like.
• Scyllo-inositol may be admixed, encapsulated, conjugated or otherwise associated with molecules to facilitate uptake, distribution and/or absorption of the compound.
• Various known delivery systems can be used to administer a medicament of the invention, e.g. encapsulation in liposomes, rnicroparticles, microcapsules, and the like.
• Medicaments can also be formulated as pharmaceutically acceptable salts.
• scyllo-inositol may be included in a pharmaceutical composition formulated for slow release, such as in microcapsules formed with biocompatible polymers, polymer coated multiparticulates or in liposomal carrier systems according to methods known in the art.
• the compositions may also be advantageously administered as bi-layer tablets containing an immediate release component and a delayed release component.
• the scyllo-inositol may be covalently conjugated to a water soluble polymer s such as a polylactide or biodegradable hydrogel derived from an amphipathic block copolymer, as described in U.S. Pat. No. 5,320,840.
• a water soluble polymer s such as a polylactide or biodegradable hydrogel derived from an amphipathic block copolymer, as described in U.S. Pat. No. 5,320,840.
• the scyllo-inositol may also be incorporated into a polymer or multi-polymer matrix having properties that release the active compound through diffusion from the matrix, erosion of the matrix or a combination of diffusion and erosion.
• Scyllo-inositol may be administered in substantially pure form as a powder or a powder contained in, for example, a gelatin capsule. It may also be administered in solid compositions with conventional non-toxic carriers, for example, mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like may be used. Liquid pharmaceutically admimstrable compositions can, for example, be prepared by dissolving, dispersing, etc.
• scyllo-inositol as defined above and optional pharmaceutical adjuvants in a sterile carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, mineral or vegetable oils and the like to thereby form a solution or suspension.
• a sterile carrier such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, mineral or vegetable oils and the like to thereby form a solution or suspension.
• the pharmaceutical composition to be administered may also contain minor amounts of non-toxic auxiliary pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate, etc.
• auxiliary pH buffering agents for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate, etc.
• compositions are advantageously compounded into unit dosage forms containing a predetermined, standard amount of the active compound, to make dosing and patient compliance simpler.
• capsules, tablets or controlled release delivery forms may be formulated and manufactured to contain, for example, 200 mg, 250 mg, 350 mg, 500 mg, 750 mg, 800 mg, 1000 mg, or 2000 mg of scyllo-inositol.
• Such tablets or controlled release delivery forms may be used for administration of one unit dosage form or any combination of unit dosage forms, that is more than one unit dosage form, to achieve the total dosage required as determined by the prescribing physician.
• the amount of active compound administered will be dependent on the subject being treated, the amount or severity of the condition (e.g.
• an effective dosage is in the range of about 100 mg/day to about 7000 mg/day, and in particular within that range, about 150 mg/day to about 6000 mg/day, about 150 mg/day to about 4000 mg/day, about 150 mg/day to about 3000 mg/day, 150 mg/day to about 2000 mg/day, 200 mg/day to about 3000 mg/day, 150 mg/day to about 4000 mg/day, 200 mg/day to about 4000 mg/day, or 500 mg/day to about 3000 mg/day.
• Daily dosages may be achieved by once a day, twice a day or three times daily administration.
• the duration of treatment can be adapted to the conditions of the patient, preferably with the aim to obtain long term normal uric acid levels.
• Dosage forms or compositions containing scyllo-inositol in the range of 0.25 to 100%, with the balance when less than 100% made up from non-toxic excipients and carriers may be prepared.
• a pharmaceutically acceptable non-toxic composition is formed, optionally with the incorporation of any of the normally employed pharmaceutical excipients, and may contain l% ⁇ 100% active ingredient, preferably 25%-75%.
• Percentages recited in the compositions in the specification and claims are weight percentages or w/w.
• Scyllo-inositol may be administered in combination with other medications (such as second therapeutic agents) or other medical procedures to treat the same or other aspects of the disease state being treated.
• a second therapeutic agent may either be within the same pharmaceutical composition (combination compositions), or the two agents may be administered in separate compositions at substantially the same time or at different times as required in the judgment of the prescribing physician.
• the second therapeutic agent can be an agent for the prophylaxis and/or treatment of hyperuricemia; gout arthritis; gouty kidney; urolithiasis; hypertension or hypertensive complications; hyperlipidemia or hyperlipidemic complications, diabetes or diabetes complications, obesity or obesity complications,; kidney failure; cardiovascular disorder; cancer; or a cerebrovascular disorder.
• the second therapeutic agent can be an agent that increases uric acid levels in a subject.
• the second therapeutic agent is chosen or selected from the group consisting of a diuretic (e.g. hydrochlorothiazide, furosemide), loop diuretics, angiotension-convertase inhibitors, angiotensin II receptor antagonists, renin angiotensin systems inhibitor (e.g.
• captopril cilazapril, enalapril, fosinopril, Hsinopril, quinapril, ramapr ⁇ l, zofenopril, candesartan cilexetil, eprosartan, irbesartan, losartan, tasosartan, telmisartan, and valsartan), CA antagonists, ⁇ -blockers, o ⁇ -blockers, ⁇ -blockers, statins, anion exchange resins, probucol, fibrate agents, eicosapentaenoic acid preparations, thromboxane synthetase inhibitor, thromboxane receptor antagonist, alkalinizing urine agents such as citric acid preparations, and sodium bicarbonate, cation exchange resins, aluminum hydroxide, alfacalcidol, ACE inhibitors, salicylate, pyrazinamide, ethambutol, NSAID (e.
• the second therapeutic agent is an agent for treatment of hyperlipidemia or hyperlipidemic complications including without limitation lovastatin, simvastatin, pravastatin, fiuvastatin, atorvastatin, cerivastatin, colestimide, colestyramine, niceritrol, nicomol, fenofibrate, bezafibrate, clinofibrate, clofibrate, ethyl icosapentate and the like.
• the second therapeutic agent is an agent for treatment of diabetes and diabetes complications including without limitation, insulin preparations, sulfonylureas, insulin secretagogues, sulfonamides, biguanides, ⁇ glucosidase inhibitors, insulin sensitizers, angiotensin-convertase inhibitors, aldose reductase inhibitors, antiarrhythmic drugs and the like, in particular, insulin, chlorpropamide, gUbenclamide, glipizide, tolbutamide, glyclopyramide, acetohexamide, glimepiride, tolazamide, gliclazide, nateglinide, glybuzole, metformin hydrochloride, buformin hydrochloride, voglibose, acarbose, pioglitazone hydrochloride, mexiletine and the like.
• insulin preparations sulfonylureas, insulin secretagogues, sulfon
• the second therapeutic agent is an agent for treatment of kidney failure, cardiovascular disorder, cerebrovascular disorder caused by hyperuricemia including without limitation loop diuretics (e.g., furosemide), citric acid preparations, sodium bicarbonate, cation exchange resins, aluminum hydroxide, alfacalcidol, ⁇ -blockers (e.g., propranolol hydrochloride), ACE inhibitors (e.g., captopril), cardiac stimulants (e.g., digoxin), angina pectoris therapeutic agents (e.g., isosorbide nitrate), Ca antagonists (e.g., diltiazem hydrochloride), uric acid production suppressants (e.g., allopurinol), amino acid preparations, hyperammonemia improvers, therapeutic agents for antiarrhythmia (e.g., mexiletine) and therapeutic agents for anemia (e.g., mepitiostane, erythropoietin
• the dose of the second therapeutic agent can be determined according to the dose employed clinically, and having regard to the age and body weight of the subject of administration, condition, administration time, dosage form, administration method, combination and the like.
• the mode of administration of the second therapeutic agent is not particularly limited.
• Medical procedures which may be used in combination with scyllo-inositol include, without limitation, surgical procedures which are likely to lead to post-operative elevation in serum uric acid levels such as cardiovascular surgery, prolonged orthopedic surgeries, organ transplantation, abdominal/GI-related surgery, gynecological-related surgery, among others, and procedures such as administration of contrast agents or nephrotoxins which can increase the risk for acute renal failure.
• a kit comprising a scyllo-inositol or pharmaceutical composition disclosed herein, and optionally one or more second therapeutic agent.
• the kit can be a package which houses a container which contains a scyllo-inositol or pharmaceutical composition disclosed herein, and also houses instructions for administering the scyllo-inositol or pharmaceutical composition disclosed herein.
• the invention further relates to a commercial package comprising a scyllo-inositol or pharmaceutical composition disclosed herein together with instructions for simultaneous, separate or sequential use.
• a label may include amount, frequency, and method of administration.
• a kit comprising a first container comprising a pharmaceutical composition comprising an amount of scyllo-inositol effective to lower a mammal's uric acid level in blood compared to a baseline level and at least one pharmaceutically acceptable component chosen from a carrier, an excipient, and a vehicle scyllo-inositol.
• the kit further comprises a second container comprising a second therapeutic agent.
• a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of a composition disclosed herein, optionally with a second therapeutic agent.
• Associated with such container(s) can be various written materials such as instructions for use, or a notice in the form prescribed by a governmental agency regulating the labeling, manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use, or sale for human administration.
• the invention also relates to articles of manufacture and kits containing materials useful for treating a condition associated with aberrant levels of uric acid.
• An article of manufacture may comprise a container with a label. Examples of suitable containers include bottles, vials, and test tubes which may be formed from a variety of materials including glass and plastic.
• a container holds a medicament or formulation of the invention comprising a scyllo-inositol or pharmaceutical composition disclosed herein, and optionally a second therapeutic agent which is effective for treating a condition associated with aberrant levels of uric acid.
• the label on the container indicates that the medicament or formulation is used for treating a condition associated with aberrant levels of uric acid, and may also indicate directions for use.
• a medicament or formulation in a container may comprise any of the medicaments or formulations disclosed herein.
• kits comprising scyllo-inositol and optionally one or more second therapeutic agent for treating a condition associated with aberrant levels of uric acid.
• a kit of the invention comprises a container described herein.
• a kit of the invention comprises a container described herein and a second container comprising a buffer.
• a kit may additionally include other materials desirable from a commercial and user standpoint, including, without limitation, buffers, diluents, filters, needles, syringes, and package inserts with instructions for performing any methods disclosed herein (e.g., methods for treating a polyglutamine disease).
• a medicament or formulation in a kit of the invention may comprise any of the formulations or compositions disclosed herein.
• a Phase 1 single site, open-label multiple dosing study evaluating a scyllo-inositol formulation was conducted in healthy adult subjects. Approximately 8 healthy male subjects received 2000 mg of scyllo-inositol twice daily (4 - 500 mg tablets orally administered twice a day) for 10 days. Blood samples were collected 12 hours prior to the first dose (day 0) and on days 6, 14, and 21.
• Scyllo-inositol 500 mg capsules were BSE/TSE-free soft gelatin, white, opaque capsules and no excipients were used in the finished product.
• Capsules were supplied in 60- niL, oblong, white pharmaceutical highdensity polyethylene (HDPE) bottles with white caps. Each 60-mL bottle contained 30 capsules of 500 mg strength scyllo-inositol.
• HDPE highdensity polyethylene
• uric acid decreased between Day 0 and Day 6; this decrease ranged from approximately 12 to 175 ⁇ mol/L, then returned to Day 0 values by Day 21, the last follow-up visit.
• Serum uric acid levels decreased in all subjects following the start of treatment, although mean uric acid levels remained within the normal range during the study. Maximal decreases were seen at Day 6, and ranged from approximately 12 to approximately 172 ⁇ mol/L between Day 0 and Day 6, and returned towards baseline by Day 21.
• Table 1 Summary of uric acid values in micromole per liter.
• Baseline is defined as the evaluation performed on Day 0; and Change from Baseline equals value at indicated time point - value at Baseline.
• Example 2 Multiple Ascending Dose Study of Orally Administered scyllo inositol Every Twelve Hours for Seven Days in Healthy Elderly Subjects
• a single-center, randomized, placebo-controlled, multiple ascending dose study evaluating a scyllo-inositol formulation was conducted in healthy elderly subjects. Approximately 32 healthy subjects (men and women) participated in one or four cohorts consisting of 8 subjects each (i.e., 6 on active drug and 2 on placebo). Subjects received drug twice daily (BID) (every 12 hours) for 7 days.
• BID drug twice daily
• the dosage levels of the scyllo-inositol were 200 mg BID (400 mg/d total), 700 mg BID (1400 mg/d total), 1500 mg BID (3000 mg/d total) and 3000 mg BID (6000 mg/d total) given every 12 hours. Blood samples were collected from each subject on days 0, 4, 7, and 12. Uric acid levels were measured in the blood samples and the results are shown in Figures 1 and 2.
• Scyllo-inositol 200 and 500 mg capsules were bovine spongiform encephalopathy (BSE)/transmissible spongiform encephalopathy (TSE)-free soft gelatin, white, opaque capsules and no excipient was used in the finished product
• BSE bovine spongiform encephalopathy
• TSE transmissible spongiform encephalopathy
• Capsules were supplied in 60- mL, oblong, white pharmaceutical high density polyethylene (HDPE) bottles with white caps. Each 60-mL bottle contained 30 capsules of 200 or 500 mg scy ⁇ lo-inositol.
• a dose-related decrease in mean uric acid levels was observed at Days 4 and 7, which partially resolved by Day 12.
• the baseline mean uric acid for all subjects treated with scyllo- inositol was 297.2 ⁇ mol/L-5mg/dL (normal range: 269.6 to 316.2 ⁇ mol/L) and for placebo subjects was 270.3 ⁇ mol/L.
• Table 2 Summary of uric acid results at Baseline in micromole per liter.
• Table 3 Summary of uric acid results at Day 4 in micromole per liter.
• Table 4 Summary of uric acid results at Day 7 in mlcromole per liter.
• Table 5 Summary of uric acid results at Day 12 in micromole per liter.
• the mean change from baseline to day 7 versus placebo was used to determine statistical significance.
• the ANCOVA model and a simple t-test resulted in p ⁇ 0.003 for both, 95% confidence interval (CI) for mean difference (PLC-TRT) was (0.34, 1.37), with point estimate of 0.85.
• the ANCOVA looked at the change of uric acid levels in controls from starting levels of uric acid; the software used was SAS 9.1.3.
• the confidence interval did not include 0 and the 95% CI difference between treatment and placebo demonstrated statistical significance.
• the point estimate of 0.85 is a population parameter in dosed subjects.
• the simple t-test did not control for variables.

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