US20050153993A1 - Treatment of statin side effects using uridine derivatives - Google Patents

Treatment of statin side effects using uridine derivatives Download PDF

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US20050153993A1
US20050153993A1 US10/499,078 US49907805A US2005153993A1 US 20050153993 A1 US20050153993 A1 US 20050153993A1 US 49907805 A US49907805 A US 49907805A US 2005153993 A1 US2005153993 A1 US 2005153993A1
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uridine
statin
salt
treatment
precursor
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Anthony Linnane
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Centre for Molecular Biology and Medicine
Magral Ltd
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Assigned to CENTRE FOR MOLECULAR BIOLOGY AND MEDICINE reassignment CENTRE FOR MOLECULAR BIOLOGY AND MEDICINE ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: LINNANE, ANTHONY W.
Assigned to MAGRAL PTY LTD. reassignment MAGRAL PTY LTD. CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: CENTRE FOR MOLECULAR BIOLOGY AND MEDICINE
Publication of US20050153993A1 publication Critical patent/US20050153993A1/en
Priority to US12/692,045 priority Critical patent/US8293755B2/en
Abandoned legal-status Critical Current

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/70Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A61K31/7072Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/21Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • A61P11/02Nasal agents, e.g. decongestants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00Drugs for disorders of the muscular or neuromuscular system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/20Hypnotics; Sedatives
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00Drugs for disorders of the senses
    • A61P27/16Otologicals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/06Antihyperlipidemics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/04Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/10Drugs 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

Definitions

  • the present invention relates generally to treatment of muscle pain and/or fatigue and to methods for treatment of side effects of statin therapy.
  • the invention relates to the use of uridine, biological precursors or derivatives of uridine or salts, esters, tautomers or analogues thereof (“uridine related compounds”).
  • uridine related compounds biological precursors or derivatives of uridine or salts, esters, tautomers or analogues thereof.
  • the invention is also directed to compositions, uses and combination packs or kits related to the treatment methods.
  • Cardiovascular disease is a term that encompasses a broad range of diseases and syndromes relating to the impairment of function of the heart and its associated network of blood vessels within the body. In spite of decades of declining death rate in the developed world cardiovascular disease is still the single most common cause of death, accounting for about one third of all deaths in the United States in 1997. Cardiovascular disease has many causes and is characterised by complex interactions between the heart, blood vessels, peripheral organs and the tissues. Some types of cardiovascular disease such as coronary heart disease or stroke can occur acutely and without warning, often with severe consequences, including death. Medically these are managed with aggressive treatment (drugs and surgery) followed by chronic treatment to prevent recurrence. Other types of cardiovascular disease such as hypertension (high blood pressure) and hyperlipidemia (high cholesterol) progress slowly, often without overt symptoms, and must be managed by diet and long-term chronic drug therapy.
  • hypertension high blood pressure
  • hyperlipidemia high cholesterol
  • cholesterol is an essential component of a healthy functioning body, being required, amongst other things, for the formation of functional membranes, steroid hormones and bile acids, excessive levels, particularly when associated with low density lipoproteins (LDLs), constitute a health risk.
  • LDLs low density lipoproteins
  • Arteriosclerosis is a generalized disease of the arteries that develops in a symptom free manner over many years.
  • the most common form of arteriosclerosis is atherosclerosis which often gives rise to coronary heart disease, stroke, kidney disease and peripheral vascular disease. Elevated blood cholesterol concentration is a major contributing factor in the development of atherosclerosis.
  • cholesterol is gradually deposited on the artery walls together with other fats, resulting in build up which disrupts the free flow of blood, with potentially severe results.
  • statins drugs
  • statins examples of which include atorvastatin, simvastatin, pravastatin, lovastatin, cerivastatin, fluvastatin and crestor, are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCoA reductase).
  • HMGCoA reductase 3-hydroxy-3-methylglutaryl coenzyme A reductase
  • statins have also recently been reported to have potential utility in the treatment of a wide range of conditions including, but not limited to, dementia ( The Lancet, 2000: 356; 1627-1631), various cancers, eg. prostate, skin, lung colon, bladder, uterus and kidney ( Arch. Intern. Med. 2000, 160: 2363-2368), immune disorders, blood clotting disorders, osteoporosis, autoimmune diseases and cell cycle abnormalities.
  • statin therapy there are a number of potentially serious side effects associated with statin therapy, including rhabdomyolysis, headache, joint pain, fever, muscle pain, back pain, abdominal cramping, sleep disorder, rhinitis, sinusitis, dizziness, myopathy and fatigue.
  • myalgia fatigue and/or muscle pain
  • these symptoms may lead to the undesirable cessation of the vital therapy.
  • severe muscle wastage rhabdomyolysis
  • the risk of adverse side effects during treatment with the statins is increased with concurrent administration of certain other drugs, such as cyclosporin, fibric acid derivatives (eg. gemfibrozil), erthyromycin, niacin and antifungals.
  • cyclosporin fibric acid derivatives
  • erthyromycin erthyromycin
  • niacin niacin and antifungals.
  • Similar symptoms to those experienced by patients undergoing statin therapy may also be experienced by patients undergoing therapy with other drugs, or may be experienced as a
  • Uridine related compounds can usefully be administered in treating muscle pain and fatigue and for treating adverse side effects associated with some drug therapies. Uridine related compounds can therefore provide a useful adjunctive therapy to certain drug therapies.
  • a method of treatment of one or more side effects of statin therapy comprising administering to a subject in need of such treatment an effective amount of uridine, a biological precursor or derivative of uridine or a salt, ester, tautomer or analogue thereof.
  • a method of treatment of one or more side effects of statin therapy comprising administering to a subject in need of such treatment an effective amount of magnesium orotate, optionally in association with one or more pharmaceutically acceptable additives.
  • uridine a biological precursor or derivative of uridine or a salt, ester, tautomer or analogue thereof in preparation of a medicament for treatment of one or more side effects of statin therapy.
  • magnesium orotate and optionally one or more pharmaceutically acceptable additives in preparation of a medicament for treatment of one or more side effects of statin therapy.
  • composition comprising uridine, a biological precursor or derivative of uridine or a salt, ester, tautomer or analogue thereof in association with one or more pharmaceutically acceptable additives.
  • composition comprising magnesium orotate and one or more pharmaceutically acceptable additives.
  • composition comprising uridine, one of its biological precursors or a salt, ester, tautomer or analogue thereof and at least one statin.
  • a combination pack or kit comprising at least one statin and uridine, a biological precursor or derivative of uridine or a salt, ester, tautomer or analogue thereof wherein said pack or kit is adapted for the simultaneous, sequential or separate administration of the statin and uridine, its biological precursor or derivative or a salt, ester, tautomer or analogue thereof.
  • a combination pack or kit comprising at least one statin and magnesium orotate wherein said pack or kit is adapted for the simultaneous, sequential or separate administration of the statin and magnesium orotate.
  • a method of treatment of muscle pain and/or fatigue comprising administering to a subject in need of such treatment an effective amount of uridine, a biological precursor or derivative of uridine or a salt, ester, tautomer or analogue thereof.
  • a method of treatment of a side effect of a drug therapy comprising administering to a subject in need of such treatment an effective amount of uridine, a biological precursor or derivative of uridine or a salt, ester, tautomer or analogue thereof.
  • the drug therapy may be a therapy for hypercholesterolemia, a therapy for hyperlipidemia, a corticosteroid therapy, a therapy for chronic fatigue syndrome (CFS), a therapy for a central nervous system (CNS) disorder or a cancer chemotherapy, for example.
  • uridine a biological precursor or derivative of uridine or a salt, ester, tautomer or analogue thereof
  • uridine a biological precursor or derivative of uridine or a salt, ester, tautomer or analogue thereof
  • biological precursor is intended to define compounds that would be converted over one or more steps to uridine within a human or animal system.
  • derivative defines compounds that in one or more steps could be derived from uridine. Preferably the conversion will be over one to four steps, preferably one or two steps.
  • Some examples of biological precursors and derivatives of uridine include orotidine monophosphate, uridine monophosphate, uridine diphosphate, uridine triphosphate, uridine diphosphoglucose, uridine diphosphogalactose, uridine diphospoglucosamine, orotic acid, dihydroorotate, triacetyl uridine and N-carbamoylaspartate.
  • Salts of such compounds with biologically acceptable cations such as for example ions of magnesium, sodium, calcium or potassium, as well as tautomers, such as keto-enol tautomers and esters of such compounds are also embraced by the invention.
  • a particularly preferred salt of orotic acid is magnesium orotate.
  • uridine related compounds For convenience, throughout this specification the class of compounds including uridine itself and precursors or derivatives thereof or their salts, esters or tautomers will be referred to as “uridine related compounds”.
  • uridine related compounds can have an asymmetric centre and therefore can exist in more than one stereoisomeric form.
  • the invention extends to each of these forms individually and to mixtures thereof, including racemates.
  • Uridine or related compounds may be commercially available (eg magnesium orotate) or may be synthesised using methods known in organic chemistry, may be obtained by microbiological means or may be derived from compounds obtained by any one or more of these means.
  • the methods and compositions of the invention may be used to treat humans, mammals or other animal subjects.
  • the invention is considered to be particularly suitable for the treatment of human subjects.
  • Non-human subjects may include primates, livestock animals, domestic companion animals and laboratory test animals.
  • the uridine or related compounds are administered in a treatment effective amount.
  • Reference herein to a treatment effective amount is intended to include an amount which, when administered according to a desired dosing regimen, will at least partially attain the desired therapeutic effect or will inhibit, halt or otherwise delay the onset of fatigue, muscle pain or a side effect of the drug treatment concerned.
  • treatment therefore embraces prophylactic treatments.
  • Dosing may occur at intervals of hours, days or weeks and may be continued for as long as the desired therapeutic effect is maintained or required. Suitable dosages and dosing regimens can be determined by an appropriate health professional and may depend on the particular cause of the side effect, the severity of the condition as well as the general health, age and weight of the subject.
  • Suitable dosages of uridine related compounds lie within the range of 10 mg to 10 g per day, such as 500 mg to 5 g per day. Particularly suitable dosages lie in the range of 1000 to 4000 mg per day. Preferably the uridine related compounds are administered from once to four times per day. Some exemplary administration regimes are as follows: 1 ⁇ 800 mg, 1 ⁇ 1200 mg, 1 ⁇ 1600 mg or 1 ⁇ 2000 mg per day, or twice a day, eg 2 ⁇ 400 mg, 2 ⁇ 600 mg, 2 ⁇ 800 mg or 2 ⁇ 1000 mg. Dosage forms may be of any suitable size (eg 200 mg, 400 mg or 1000 mg). In one preferred embodiment of the invention magnesium orotate is administered twice a day as two doses each of 800 mg (which could for example comprise 2 ⁇ 400 mg tablets) to give a total administration of 1600 mg per day.
  • magnesium orotate is administered twice a day as two doses each of 800 mg (which could for example comprise 2 ⁇ 400 mg tablets) to give a total administration of 1600 mg per day.
  • the methods of the invention may be used to treat any type of muscle fatigue or pain arising from certain conditions or diseases, surgery, injury or as a side effect of certain drug therapies.
  • Muscle pain and/or fatigue associated with conditions or diseases such as chronic fatigue syndrome (CFS), fibromyalgia, myofascial pain syndrome, viral infections, myolysis, rhabdomyolysis, central nervous system (CNS) disorders such as Parkinson's disease, Alzheimer's disease, Huntington's chorea and dementia and neuromuscular diseases may also be treated by administration of uridine or related compounds.
  • statins One example of a group of therapeutic drugs characterised by side effects treatable by the present invention is the statins, of which some notable examples are atorvastatin, simvastatin, pravastatin, lovastatin, cerivastatin, crestor and fluvastatin.
  • statins include rhabdomyolysis, headache, joint pain, fever, muscle pain, back pain, abdominal cramping, sleep disorder, rhinitis, sinusitis, dizziness, myopathy, abnormal liver function and fatigue.
  • therapeutic drugs for which muscle fatigue and/or pain or other symptoms treatable by the inventive methods may be a side effect are AZT, hypercholesterolemia therapy drugs (apart from the statins, such as bile acid binding agents such as cholestyramine and colestipol or others such as niacin, probucol), hyperlipidemia therapy drugs such as fibric acid drugs, corticosteroids and cancer chemotherapy drugs.
  • statins such as bile acid binding agents such as cholestyramine and colestipol or others such as niacin, probucol
  • hyperlipidemia therapy drugs such as fibric acid drugs, corticosteroids and cancer chemotherapy drugs.
  • uridine related compounds may be a useful adjunctive treatment where drugs such as the statins, or others are used to treat, for example, AIDS, hypercholesterolemia, hyperlipidemia, CFS, CNS disorders or cancers such as prostate, skin, lung, breast, colon, bladder, uterus and kidney cancers.
  • the uridine related compounds may be administered in conjunction (either separately, simultaneously or sequentially) with other active agents and in particular with one or more further anti-oxidant compound or compounds, such as Vitamin C or E, carotenoids or carnitine, or their derivatives or analogues.
  • further anti-oxidant compound or compounds such as Vitamin C or E, carotenoids or carnitine, or their derivatives or analogues.
  • Uridine related compounds can be administered alone or in combination with the therapeutic drug (eg a statin compound) and optionally with a further active agent or anti-oxidant.
  • the combination of components constituting the treatment may be administered either simultaneously (as discrete dosage forms or as a single composition), sequentially, or separated by a suitable time interval.
  • each component may be administered in the same form or a different form, eg oral, nasal, parenteral, rectal, vaginal or dermal.
  • the components may be provided as discrete dosage forms.
  • the components of the combination may be provided in a kit form wherein the kit is preferably in compartmentalised form adapted for the discrete administration of the components.
  • the components of the combination when administered simultaneously, they may be provided as a single composition containing the two or more components or may be provided in a kit form, wherein the kit is for example compartmentalised for the simultaneous administration of the components.
  • compositions may be formulated together with one or more pharmaceutically acceptable additives to form compositions.
  • the composition may also optionally comprise one or more pharmaceutically acceptable additives.
  • compositions may contain any suitable additives such as carriers, diluents or excipients, which are pharmaceutically acceptable in the sense of being compatible with the other ingredients of the composition and not injurious to the subject.
  • suitable additives include all conventional solvents, oils, dispersion media, fillers, solid carriers, coatings, antifungal and antibacterial agents, dermal penetration agents (where appropriate), surfactants, isotonic and absorption agents and the like. It will be understood that the compositions of the invention may also include other supplementary physiologically active agents. Further details of pharmaceutically acceptable additives may be found in Remington's Pharmaceutical Sciences, 18 th Edition, Mack Publishing Co., Easton, Pa., USA, the disclosure of which is included herein in its entirety by way of reference.
  • compositions may conveniently be presented in unit dosage form and may be prepared by methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier, which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
  • compositions of the invention may be presented for oral administration (although other forms such as parenteral, rectal, vaginal and dermal, may, under appropriate circumstances also be contemplated) and may be presented as discrete units such as capsules, sachets of powders or granules or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; oils; paste; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g inert diluent, preservative disintegrant (e.g. sodium starch glycolate, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose) surface-active or dispersing agent.
  • a binder e.g inert diluent, preservative disintegrant (e.g. sodium starch glycolate, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose) surface-active or dispersing agent.
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
  • the compounds may also be presented in the form of hard or soft gelatin capsules
  • compositions of this invention may include other agents or additives conventional in the art having regard to the type of composition in question, for example, those suitable for oral administration may include such further agents as binders, sweeteners, thickeners, flavouring agents disintegrating agents, coating agents, preservatives, lubricants and/or time delay agents.
  • suitable sweeteners include sucrose, lactose, glucose, aspartame or saccharine.
  • Suitable disintegrating agents include corn starch, methylcellulose, polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid or agar.
  • Suitable flavouring agents include peppermint oil, oil of wintergreen, cherry, orange or raspberry flavouring.
  • Suitable coating agents include polymers or copolymers of acrylic acid and/or methacrylic acid and/or their esters, waxes, fatty alcohols, zein, shellac or gluten.
  • Suitable preservatives include sodium benzoate, vitamin E, alpha-tocopherol, ascorbic acid, methyl paraben, propyl paraben or sodium bisulphite.
  • Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride or talc.
  • Suitable time delay agents include glyceryl monostearate or glyceryl distearate.
  • compositions may also be presented for use in veterinary compositions. These may be prepared by any suitable means known in the art. Examples of such compositions include those adapted for:
  • Table 1 outlines data for seventeen patients (numbered #i-#xvii) undergoing statin therapy for treatment of hypercholesterolemia and who had reported suffering from varying levels of muscular pain and fatigue. This study is ongoing but the results below follow the study in relation to these patients for varying periods, from day 0 (T 0d ) up to a maximum of 56 days (T 56d ).
  • the design of the clinical trial involves a blood sample being taken from the patients prior to commencing medication administration and then on four further occasions during the 13 week trial, at around days 13-16, days 26-30, days 35-60 and finally at days 80-90. Patients were also required to submit answers to a questionnaire on approximately a weekly basis to enable patients to be scored for pain using the McGill Pain Questionnaire (Melzack, R., 1975 “The McGill Pain Questionnaire: Major Properties and Scoring Methods”. Pain 1:277-299, the disclosure of which is included herein in its entirety by way of reference) scales for Pain Rating Index (PRI) and Present Pain Intensity (PPI). In the PRI index, which comprises two scores, higher scores indicate increasing levels of pain.
  • PRI index Pain Rating Index
  • PPI Pain Intensity
  • Blood samples were taken prior to commencement of trial medication (T 0d ) and after approximately 14 (T 14d ), 28 (T 28d ), 42 (T 42d ) and 56 (T 56d ) days to determine individual baseline levels of uridine ( ⁇ g/ml) arising from magnesium orotate (MgOr) administration, to thereby monitor patient compliance.
  • CK creatine kinase concentration
  • GTT gamma glutaryl transferase
  • AST aspartate amino transferase
  • ALT alanine aminotransferase concentration
  • serum lipid levels including total cholesterol concentration, high density lipoprotein (HDL-CHOL) concentration, low density lipoprotein (LDL-CHOL) concentration, tryglyceride (TRIG) concentration and levels of other serum components routinely tested for including magnesium ion concentration.
  • Table 1 shows the normal parameters of blood serum components that are routinely monitored, for both males and females.
  • GGT gamma glutaryl transferase
  • ALT alanine amino transferase
  • AST aspartate amino transferase
  • the GGT serum concentration dropped from 96 U/L at day 0 to 83 U/L at day 43
  • ALT serum concentration dropped from 105 U/L at commencement to 74 U/L at day 43
  • AST serum concentration dropped from 56 U/L at commencement to 42 U/L at day 43.
  • CK creatine kinase concentration

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JP5426918B2 (ja) * 2009-04-20 2014-02-26 株式会社 伊藤園 ウリジンを含有する抗疲労剤又は体力向上剤
TR2022013331A2 (tr) * 2022-08-24 2022-09-21 Bursa Uludag Ueniversitesi Üridinin Akut Ağrıdaki Doz Bağımlı Analjezik Etkisi

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EP1465616A4 (en) 2005-04-06
EP1465616B1 (en) 2010-06-30
AU2002349186B2 (en) 2008-01-17
US8293755B2 (en) 2012-10-23
JP2005516912A (ja) 2005-06-09
US20100184717A1 (en) 2010-07-22
AUPR951101A0 (en) 2002-01-24
JP4781629B2 (ja) 2011-09-28
EP1465616A1 (en) 2004-10-13
CA2469612C (en) 2011-11-15
CA2469612A1 (en) 2003-06-19
AU2002349186A1 (en) 2003-06-23
NZ533382A (en) 2007-03-30
ATE472323T1 (de) 2010-07-15
DE60236894D1 (de) 2010-08-12
WO2003049730A1 (en) 2003-06-19

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