WO2001030352A1 - Acide folique a dose elevee aux fins du traitement de l'hyperhomocysteinemie - Google Patents

Acide folique a dose elevee aux fins du traitement de l'hyperhomocysteinemie Download PDF

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WO2001030352A1
WO2001030352A1 PCT/US2000/029788 US0029788W WO0130352A1 WO 2001030352 A1 WO2001030352 A1 WO 2001030352A1 US 0029788 W US0029788 W US 0029788W WO 0130352 A1 WO0130352 A1 WO 0130352A1
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folate
vitamin
folic acid
tetrahydrofolate
pharmaceutical composition
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PCT/US2000/029788
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English (en)
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Christopher S. Wilcox
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Cary Pharmaceuticals Inc.
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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines

Definitions

  • This invention relates to compositions and methods for treating hyperhomocysteinemia in patients with compromised renal function, especially end stage renal disease (ESRD) patients receiving hemodialysis.
  • ESRD end stage renal disease
  • ESRD ESRD
  • risk factors for cardiovascular disease in the general population include hypertension, dyslipidemia, obesity and smoking. These risk factors have not, however, proven to be reliable predictors of cardiovascular disease in patients with chronic renal insufficiency.
  • Non-traditional cardiovascular risk factors currently considered responsible for ESRP mortality include lipoprotein (a), oxidative stress, elevated plasma levels of dimethylarginine and homocysteine (Gris et al. , 1994 Kidnev Int. 46: 807; Cressman et al, 1992 Cjrc. 86: 475; and Paul et al, 1993 Nephron. 64: 106) (2-7).
  • Homocysteine is a non-protein amino acid that is the transmethylation product of methionine. Homocysteine may be re-methylated to methionine with the aid of tetrahydrofolate (THF) or, alternatively t-Hcy may participate in a transsulfuration sequence to produce cysteine (Barshop, "Homocystinuria," in CECIL'S TEXTBOOK OF MEDICINE 1112 (Bennett et al, editors; W.B.
  • Homocysteine may be detected and its levels may be quantitated by various techniques and assays known in the art, including, for example, the IMx homocysteine assay marketed by Abbott Laboratories, Inc. Moreover, plasma homocysteine has been shown to rise in proportion to the fall in the glomular filtration rate (Arnadottir et al, Scand. J. Clin. Lab. 56:41-46). Overproduction of homocysteine leads to a condition known as hyperhomocysteinemia.
  • Hyperhomocysteinemia can arise as a result of a genetic defect in the metabolism of homocysteine (t-Hcy) (e.g., congenital homocystinuria) (Monnerat et al, 1997 Sau Med. Klischr. 127: 1489), due to drug or diet induced folic acid deficiency or other vitamin deficiencies, and as a consequence of hemodialysis treatment for end stage renal disease (Quinn et al, 1997 J. Clin. Oncol. 15: 2800). Elevated homocysteine levels have also been associated with histologically confirmed Alzheimer's disease and vascular dementia.
  • t-Hcy homocysteine
  • subjects in the top homocysteine tertile were 4.5 times more likely to have Alzheimer's than those in the bottom tertile (less than 11 micromoles/L).
  • Subjects in the lowest tertiles for folate and vitamin B12 were 3.3 times and 4.3 times, respectively, more likely to have Alzheimer's disease than those in the top tertiles. (American Medical Association annual Science Reporters Conference on October 19, 1998 at Ourham, North Carolina).
  • ESRD patients Although hyperhomocysteinemia is not confined to ESRP patients, ESRD patients generally have greater elevations in plasma of total homocysteine (263-448% increase in t- Hey) than patients with renal failure (166-290% t-Hcy) or in other forms of hyperhomocysteinemia. Data from patients studied indicate that approximately 40% of an oral dose of folate is eliminated in a single dialysis treatment (Foley et al, 1998 J. Am. Soc. Nephrol. 9: 267; Gris et al, 1994; Cressman et al, 1992; and Paul et al, 1993).
  • Each hemodialysis session removes 50-75 ⁇ g of folic acid, or about 80% of the normal dietary intake (Foley et al, 1998; Gris et al, 1994; and Cressman et al, 1992).
  • the quantity removed increases with the rise in plasma folate levels (Foley et al, 1998).
  • Dialyzer clearance of folate results in a fall of plasma folate from 46.4 ⁇ 73.3 nmol/L to 25.9 ⁇ 30.7 nmol/L (44% decline) (Paul et al, 1993).
  • hemodialysis patients have a special requirement for very high levels of folate intake merely to maintain a given folate blood plasma level because of hemodialysis-induced loss of folic acid.
  • Folic acid also known as folate
  • Folic acid is used to treat hyperhomocysteinemia to reduce homocysteine levels, because folate is a co factor in the transformation of homocysteine to methionine.
  • Both folic acid (1-5 mg/day) alone and folic acid (1-5 mg/day) in combination with vitamins B 6 and B 12 (also known as cyanocobalamin) have been shown to reduce homocysteine concentrations in plasma (Welch et al. , 1998 N. Engl. J. Med. 338: 1042).
  • folic acid is a powerful homocysteine lowering agent in subjects with normal kidney function, it is much less powerful in those with kidney failure and ESRD. Folic acid and vitamins B 6 and B I2 are indicated for optimal homocysteine metabolism
  • Plasma t-Hcy concentrations normally correlate negatively with plasma concentrations of these vitamins (Robinson et al, 1996 Circ. 94: 2743; Robinson et al, 1995 Circ. 92: 2825).
  • t-Hcy levels can be elevated to those levels found in renal failure in normal subjects who are severely deficient in these vitamins (Guttormsen et al, 1996 J. Clin. Invest. 98: 2174, Stabler et al, 1998 J. Clin. Invest. 81 : 466).
  • t-Hcy levels in those with normal renal function and vitamin deficiency can be easily corrected by modest replacement of folic acid, vitamin B 6 and vitamin B ]2 (Guttormsen et al, 1996).
  • Nephrologists have recognized that patients with renal failure are at risk for folic acid and B vitamin deficiency.
  • One widely used B vitamin supplement contains 1 mg folic acid, 10 mg pyridoxine, and 6 ⁇ g cyanocobalamin. This multi-vitamin is recommended to be taken once daily.
  • a daily folic acid supplement of 0.65 mg/day is sufficient to normalize mild to moderate hyperhomocysteinemia in most individuals with normal renal function. In patients with severe renal failure, somewhat higher folate dosages have been used (1-5 mg).
  • supplements of folic acid were given to patients with normal renal function and hyperhomocysteinemia due to folate deficiency. In these patients, 0.2 mg of folic acid increased the plasma folate concentrations 2.1 -fold, whereas 5 mg daily elevated plasma folate levels above the limit of measurement. Indeed, in another study (Guttormsen et al., 1996 Am J. Clin. Nutri.
  • Folic acid supplementation has also been used to treat drug-induced hyperhomocysteinemia.
  • rheumatoid arthritis patients treated with methotrexate, both 5.0 mg or 27.5 mg of folic acid were shown to inhibit hyperhomocysteinemia induced by methotrexate (Morgan et al, 1998 J. Rheumatol. 25: 441).
  • differences in plasma homocysteine levels as between the 5 mg and 27.5 mg dosages of folic acid were negligible (Morgan et al, 1998).
  • methotrexate induced hyperhomocysteinemia impacts only one step in homocysteine metabolism, whereas ESRD induced hyperhomocysteinemia impacts homocysteine metabolism at many points, many of which remain to be fully elucidated.
  • Vitamin B 6 and folic acid have effectively treated young patients with arterial occlusive disease (van den Berg et al, 1994 J. Vase. Surg. 20: 933).
  • the effects of long-term homocysteine-lowering treatment on endothelial function has been of interest to researchers because of its potential role in athero- and thrombogenesis. Accordingly, studies have been conducted in which patients have been treated with 1, 5, and 15 mg of folic acid.
  • Some investigators recommend 10-15 mg of folic acid for patients receiving chronic hemodialysis, although in practice patients rarely receive more than 1 mg (Helbig et al, 1977 Folia Haematol. Int. Mag. Klin. Morphol. Blutforsch. 104: 242).
  • total normalization of plasma homocysteine levels is seldom achieved even with the higher rates of folate administration (van Guldener et al, 1998 Nephrol. Dial. Transplant 13: 106).
  • the invention relates to methods and compositions for treating diseases that are characterized by folate resistance in a significant patient population, such as end stage renal disease (ESRD) and Alzheimer's disease. More specifically, the invention provides for a method for treating hyperhomocysteinemia in a subject with compromised renal function, comprising administering a folate in an amount that is effective to normalize plasma homocysteine levels in the subject.
  • ESRD end stage renal disease
  • the invention provides for a method for treating hyperhomocysteinemia in a subject with compromised renal function, comprising administering a folate in an amount that is effective to normalize plasma homocysteine levels in the subject.
  • the invention also relates to a pharmaceutical composition for treating hyperhomocysteinemia , comprising at least about 30 mg to about 500 mg of a folate and one or more of the following: (A) about 1.0 mg to about 150 mg thiamin; (B) about 1.0 mg to about 150 mg riboflavin; (C) about 10 mg to about 500 mg niacin; (D) about 5.0 mg to about 100 mg pantothenic acid; (E) about 100 meg to about 200 meg biotin; (F) about 250 meg to about 2,000 meg vitamin B 12 ; (G) about 10 mg to about 100 mg vitamin B 6 ; (H) about 30 LU. to about 5,000 LU. vitamin E; (I) about 100 mg to about 2,000 mg vitamin C; (J) about 20 mg to about 200 mg zinc; (K) about 50 mg to about 500 mg iron; and (L) about 300 mg to about 2,000 mg calcium.
  • A about 1.0 mg to about 150 mg thiamin
  • B about 1.0 mg to about
  • the invention further relates to a pharmaceutical composition about 10 mg to about 100 mg of a folate derivative or a folate analog, in combination with at least one of vitamin B 6 , vitamin B ]2 , vitamin C, vitamin E, iron, zinc, calcium, pantothenic acid, niacin, riboflavin, thiamine, biotin, a methioninase, a nitrosating agent, Tempol, TEMPO, a thetin and serine.
  • folic acid or “folate” or “pteroylglutamic acid” is meant the chemical with the structure of:
  • a folate includes folic acid, its derivatives, analogs, metabolites, optical isomers, and pharmaceutically acceptable salts.
  • folate derivative or “folate metabolite” is meant the intermediate or active products of a folate, such as would be involved in conversion of homocysteine. These include, for example, 5-methyltetrahydrofolate (also known as 5-methyl-5,6,7,8-tetrahydropteroyl-L-glutamic acid), and 5- formyltetrahydrofolate (also known as folinic acid) and their pharmaceutically acceptable salts, such as magnesium, calcium and disodium salts, and their optical isomers.
  • 5-methyltetrahydrofolate also known as 5-methyl-5,6,7,8-tetrahydropteroyl-L-glutamic acid
  • 5- formyltetrahydrofolate also known as folinic acid
  • pharmaceutically acceptable salts such as magnesium, calcium and disodium salts, and their optical isomers.
  • “folate analog” and “folic acid analog” include compounds with the formula of folic acid and additional substituted groups, such as dihydrofolate, tetrahydrofolate, formiminoglutamate, 5 , 10-methylenetetrahydrofolate, 10-formyltetrahydrofolate, 5 , 10-methenyltetrahydrofolate, 5,10-rnethylenetetrahydrofolate, formiminotetrahydrofolate, hydroxymethyltetrahydrofolate, their pharmaceutically acceptable salts and optical isomers. See Goodman & Gilman's The
  • plasma homocysteine is meant the total plasma homocysteine ("t-Hcy”) measured, whether fasting or not fasting, before or after dialysis. This also refers to an increase in oxidized or reduced forms of protein-bound or free-form homocysteine.
  • hypohomocysteinemia denotes any level of total plasma homocysteine above normal in patients with end stage renal disease ("ESRD”) or in patients suffering from other renal disorders that result in elevated homocysteine levels.
  • ESRD end stage renal disease
  • frolate resistant or “folate resistance” or “folic acid resistant” or “folic acid resistance” is that population of ESRD patients receiving hemodialysis whose plasma homocysteine level cannot be normalized by administering up to 15 mg of folic acid per day.
  • vitamin B 12 is meant to include “cobalamin.”
  • vitamin B 6 is meant to include “pyridoxine.”
  • dialysis includes hemodialysis as well as other forms of dialysis and similar types of therapy.
  • Compromised renal function includes renal disorders resulting in elevated plasma homocysteine levels. Renal disorders can include, among others, ESRD and renal failure in a patient not yet receiving dialysis treatment.
  • the invention provides for a method for treating hyperhomocysteinemia in a subject with compromised renal function, comprising administering a folate in an amount that is effective to normalize plasma homocysteine levels in the subject.
  • Patients who are folate resistant may fall into the category of severe hyperhomocysteinemia or may have minimal to negligible renal function as compared to ESRD patients who respond to ⁇ 15 mg of folic acid.
  • Normal total plasma homocysteine concentrations range from 5-15 ⁇ mol/L in the fasting state (Welch et al. , 1998).
  • Mean values for plasma total homocysteine concentration depend upon plasma creatinine (Dennis et al, 1996 Kidney Int. 50: SI 1).
  • the preferred patients are those with end stage renal disease and who are receiving dialysis.
  • the folate to be administered for treating hyperhomocysteinemia may be folic acid, a folate derivative, a folate analog, their pharmaceutically acceptable salts and their optical isomers.
  • Folate derivatives and folate analogs contemplated include 5- methyltetrahydrofolate, 5-formyltetrahydrofolate (also known as folinic acid or Leucovorin), dihydro folate, tetrahydrofolate, formiminoglutamate, 5,10-methylene-tetrahydrofolate, 10- formyltetrahydrofolate, 5, 10-methyltetrahydro folate, and their pharmaceutically acceptable salts and optical isomers.
  • the most preferred folate derivative is 5-formyltetrahydrofolate, which is a biologically active metabolite of folate.
  • Leucovorin a commercially available source of folinic acid, is a mixture of the diastereoisomers of 5-formyltetrahydrofolate.
  • the biologically active compound is the L-isomer. It does not require reduction by the enzyme dihydrofolate reductase in order to participate in reactions utilizing folate as a source of one- carbon moieties. In plasma, it is rapidly converted to 5 -methyl-tetrahydro folate, another biologically active folate metabolite.
  • L-leucovorin While the half-life of L-leucovorin is very short, its biological affect is of longer duration because of the production of active metabolites. Following an oral dose, the peak concentration of reduced folate is seen at 2.3 hours with a terminal half-life of 5.7 hours.
  • Folic acid is preferably administered in an amount of from about 30 mg/day to about
  • More preferred ranges of folic acid for treating hyperhomocysteinemia in patients with ESRD or compromised renal function include: about 40 mg/day to about 400 mg/day; about 50 mg/day to about 200 mg/day; about 30 mg/day to about 100 mg/day; and about 60 mg/day to about 100 mg/day.
  • Folate derivatives and folate analogs are preferably administered in amounts of about 10 mg/day to about 100 mg/day. A more preferred range is from about 10 mg/day to about 50 mg/day.
  • compositions containing a folate for treating hyperhomocysteinemia.
  • the pharmaceutical compositions described may be formulated to provide immediate or sustained release.
  • Pharmaceutical compositions that may be used to treat hyperhomocysteinemia in a subject with compromised renal function include compositions comprising at least about 30 mg to about 500 mg of a folate and one or more of the following: (A) about 1.0 mg to about 150 mg thiamin; (B) about 1.0 mg to about 150 mg riboflavin; (C) about 10 mg to about 500 mg niacin; (D) about 5.0 mg to about 100 mg pantothenic acid; (E) about 100 meg to about 200 meg biotin; (F) about 250 meg to about 2000 meg vitamin B 12 ; (G) about 20 mg to about 100 mg vitamin B 6 ; (H) about 30 LU.
  • vitamin E about 100 mg to about 2,000 mg vitamin C; (J) about 20 mg to about 200 mg zinc; (K) about 50 mg to about 1,000 mg iron; and (L) about 200 mg to about 2,000 mg calcium (e.g., calcium carbonate).
  • the invention also provides pharmaceutical compositions that comprise about 10 mg to about 100 mg of a folate derivative or a folate analog, in combination with at least one of vitamin B 6 , vitamin B 12 , vitamin C, vitamin E, iron, zinc, calcium, pantothenic acid, niacin, riboflavin, thiamine, biotin, a methioninase, a nitrosating agent, Tempol, TEMPO, a thetin and serine.
  • the invention is related to the discovery that patients with hyperhomocysteinemia induced by ESRD, dialysis or other renal disorders, may be treated with dosages of a folate by itself, or in combination with other vitamins, minerals, amino acids, and/or homocysteine regulating agents.
  • a folate resistant patients when folic acid is administered in amounts of ⁇ 15 mg, either alone or in combination with vitamins B 6 and/or B 12 , the patient's plasma homocysteine level cannot be normalized.
  • the substantially higher dosages of folic acid in any of the proposed compositions described below, are therapeutically effective and are of sufficient concentration to be considered a prescription formulation in the United States.
  • This invention provides methods and pharmaceutical compositions for reducing elevated plasma homocysteine levels.
  • the pharmaceutical compositions and methods can also be used to reduce the incidence and complications arising from hyperhomocysteinemia, such as vascular and cardiovascular disease (e.g., coronary artery disease, carotid artery disease, peripheral vascular disease, atherosclerosis and occurrences of clotting of the arterio- venous grafts, fistulae, catheters or other devises used to gain blood access for hemodialysis).
  • vascular and cardiovascular disease e.g., coronary artery disease, carotid artery disease, peripheral vascular disease, atherosclerosis and occurrences of clotting of the arterio- venous grafts, fistulae, catheters or other devises used to gain blood access for hemodialysis.
  • compositions comprise a therapeutically effective, dosage of folic acid, its analogs, derivatives, pharmaceutically acceptable salts and optical isomers, which either alone or in combination with other vitamins, minerals, amino acids, and/or antioxidants, can normalize plasma homocysteine levels in folate resistant ESRD patients.
  • ESRD end stage renal disease
  • appropriate individuals with "end stage renal disease” or “ESRD” should preferably receive hemodialysis and be folate resistant, as defined above. It is this category of ESRD patient that would be both appropriately and safely treated with the proposed folate therapy.
  • folate resistant patients with other renal disorders can also be administered this therapy to treat elevated plasma homocysteine levels.
  • This folate therapy is preferably in conjunction with other antioxidants, vitamins, minerals, amino acids and/or homocysteine regulating agents.
  • compositions for treating folate resistant ESRD patients include folic acid, its analogs, derivatives, pharmaceutically acceptable salts and optical isomers.
  • the pharmaceutical compositions may contain more than one type of folate, for example, a methyltetrahydrofolate and folic acid.
  • Another preferred pharmaceutical composition used for treating this category of ESRD patient contains one or more folates (e.g., tetrahydrofolate), and other B vitamins, especially either or both vitamin B 6 or vitamin B 12 .
  • the vitamin B 6 dosage disclosed in this invention to be used in any pharmaceutical composition containing a folate for treatment of hyperhomocysteinemia and/or hyperdimethylargininemia is in the range of about 2 mg to about 500 mg.
  • the vitamin B 12 dosage range contemplated is about 1 meg to about 500 meg. More preferred ranges to be administered to patients fall in the range of about 5 mg to about 50 mg for B 6 and from about 10 meg to about 100 meg for B 12 .
  • the present invention further comprises other homocysteine-modulating agents.
  • Additional homocysteine modulating agents which may preferably be co-administered include nitrosating compounds such as those discussed in Stamler et al , 1995 U.S. Patent No. 5,385,937 (e.g.
  • nitroglycerin nitric oxide, S-nitrosothiol, S-nitroso-protein, nitroprusside, sydnonimines, furoxans, nitrosonium salts and related compounds
  • Tempol 4-hydroxy-2,2,6,6-tetramethyl-l- piperidine-1-oxyl
  • TEMPO Tempol (4-hydroxy-2,2,6,6-tetramethyl-l- piperidine-1-oxyl) and TEMPO
  • methioninase compositions such as those described in Lishko et al, 1998 U.S. Patent No. 5,715,835 (e.g., L-methioninase).
  • Another class of agents which can be administered in combination with a folate include thetins.
  • a folate and a thetin also can be administered in combination with betaine and choline.
  • Preferred thetins include: dimethylacetothetin and dimethylpropiothetin. Amounts of thetin administered in combination with a folate are likely to be lower than that needed if the thetin was administered alone. Amounts of other homocysteine modulating drugs administered to patients in combination with a folate also would likely be less than the other homocysteine regulating agent alone. In the case of thetins, a thetin and a folate could be additionally combined with choline and betaine, as well as other vitamins and minerals. The thetins used for controlling homocysteine and methods of administration are discussed generally in Garrow, 1997 U.S. Patent No. 5,668,173.
  • the patient class suffering from a renal disorder, such as ESRD, which may be treated with a folate include those who are folate resistant.
  • One embodiment of the invention is to treat these patients with a folate only.
  • ESRD is a multi-factor disease and is not caused by the interference of only one enzyme involved with homocysteine metabolism
  • additional active agents are considered for coadministration to a patient with ESRD or compromised renal function; these patients may or may not be receiving hemodialysis.
  • Other agents include vitamins, as well as other plasma homocysteine regulating agents.
  • the vitamins which may preferably be co-administered with a folate include thiamin (also known as vitamin B,), riboflavin, niacin, pantothenic acid, biotin, cyanocobalamin, pyridoxine, vitamin E, vitamin C, other anti-oxidants and other water and fat-soluble vitamins, as may be needed to meet the needs of a specific patient, as determined by the physician.
  • thiamin also known as vitamin B,
  • riboflavin also known as vitamin B, riboflavin, niacin, pantothenic acid, biotin, cyanocobalamin, pyridoxine, vitamin E, vitamin C, other anti-oxidants and other water and fat-soluble vitamins, as may be needed to meet the needs of a specific patient, as determined by the physician.
  • thiamin also known as vitamin B,
  • riboflavin also known as vitamin B, riboflavin, niacin, pantothenic acid
  • biotin
  • the minerals which may be used in admixture with a folate preferably include iron, calcium and zinc.
  • the nonessential amino acid serine may also be used in combination with a folate.
  • Serine may be present in an amount sufficient to provide about 1-500 mg/kg/day.
  • the preferred routes for administering compounds of this invention include oral and intravenous.
  • Intravenous administration of the contemplated compounds preferably occurs immediately after a patient has received hemodialysis or other dialysis-like treatment. Tablets, capsules, and liquids can be taken orally, typically during or immediately after hemodialysis. Other methods of administering a folate can also be utilized.
  • compositions discussed above may also be for parenteral, rectal or buccal administration, or in a form suitable for administration by inhalation or insufflation.
  • the pharmaceutical compositions may further be formulated using one or more pharmaceutically acceptable carriers and excipients.
  • the compositions can be administered in a single unit (e.g., one tablet), intravenously, in separate units, in a time release formulation, or orally in separate administrations during the course of a day.
  • the pharmaceutical compositions may be, for example, tablets or capsules prepared by conventional means, in admixture with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); wetting agents (e.g., sodium lauryl sulphate); glidants; artificial and natural flavors and sweeteners; artificial or natural colors and dyes; and solubilizers.
  • binding agents e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g., lactose, microcrystalline cellulose or calcium phosphate
  • lubricants e.g
  • the pharmaceutical compositions may additionally be formulated to release the active agents in a time-release manner as discussed in U.S. Patent Nos. 4,690,825 and 5,055,300.
  • the tablets may be coated by methods well known in the art.
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups, suspensions, or slurries (such as the liquid nutritional supplements described in Mulchandani et al, 1992 U.S. Patent No. 5,108,767), or they may be presented as a dry product for reconstitution with water or other suitable vehicles before use.
  • Liquid preparations of folic acid, and other vitamins and minerals may come in the form of a liquid nutritional supplement specifically designed for ESRD patients.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid); and artificial or natural colors and/or sweeteners.
  • suspending agents e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats
  • emulsifying agents e.g., lecithin or acacia
  • non-aqueous vehicles e.g., almond oil, oily esters or ethyl alcohol
  • preservatives e.g., methyl or propyl p-hydroxybenzoates or sorbic acid
  • the composition may be in the form of tablets or lozenges.
  • the active compounds may be formulated for parenteral administration by injection, which includes conventional catheterization techniques or infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampules or in multi-dose containers, with an added preservative.
  • the compositions may be in the form of suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredients may be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • the active compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • the active compounds are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient, or as an aerosol spray presentation from a pressurized container or nebulizer, with the use of a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas).
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the pressurized container or nebulizer may contain a solution or suspension of the active compound.
  • Capsules and cartridges for use in an inhaler or insufflator may be formulated containing a powder mix of an active compound and a suitable powder base such as lactose or starch.
  • a powder mix of an active compound such as lactose or starch.
  • folate for intravenous administration, folate, its analogs, derivatives, as well as other vitamins, minerals homocysteine-modulating agents and antioxidants may be administered as an IV admixture in a suitable isotonic vehicle.
  • intravenous administration of pharmaceutical compositions containing a folate occurs after hemodialysis.
  • compositions comprising a folate can be used in conjunction with antioxidants, minerals, other vitamins, amino acids, and other agents that modulate plasma homocysteine levels.
  • the following working examples which disclose compositions containing a folate in combination with minerals, antioxidants, amino acids, and other vitamins, therefore, specifically point out preferred embodiments of the present invention. These examples are not to be construed as limiting the scope of the invention. Other examples involving folic acid, its derivatives and its analogs suitable for reducing plasma homocysteine levels will be apparent to one skilled in the art.
  • folic acid dosages can be varied from about 30 to about 500 mg per tablet, more preferred dosages include from about 30 to about 100 mg in each tablet, capsule or sterile injectable solution.
  • the dosages of folate analogs or folate derivatives can be varied from 10-100 mg in each tablet, capsule or sterile solution for injection.
  • Vitamin E 30 LU Vitamin E 30 LU
  • Vitamin E 30 LU Vitamin E 30 LU
  • Vitamin E 30 LU Vitamin E 30 LU
  • Vitamin E 30 LU Vitamin E 30 LU
  • Vitamin E 100 LU Vitamin E 100 LU.
  • Vitamin C 250 mg Example 8 Treating a Patient with Folate Resistance with Folate Administered Intravenously If a patient is not receptive to treatment with folate compositions containing ⁇ 15 mg folate either by itself or in combination with other vitamins, minerals and/or antioxidants, then the patient is to be treated as follows. Shortly after concluding hemodialysis, the patient is administered a 60 mg folic acid or 10-100 mg of Leucovorin intravenously in a saline solution, together with, for example, 50 mg vitamin B 6 , 25 mg zinc, 500 meg vitamin B, 2 , 5 mg pantothenic acid, 20 mg niacin, 2.0 mg riboflavin and 1.5 mg thiamin. The patient receives this intravenous administration of folic acid after each hemodialysis session. On days when the patient is not receiving hemodialysis, the patient may be administered a tablet containing the same vitamins and minerals as described above.
  • the intravenous administration of vitamins and minerals are the same except for folic acid which is increased to 100 mg.
  • the folate composition may be administered orally.
  • Example 9 If a patient with a renal disorder not receiving dialysis, has elevated homocysteine levels which cannot be normalized with 15 mg folic acid, then this patient may be treated with any of the compositions discussed in Examples 1-7. If the patient is receiving hemodialysis or a dialysis-like therapy (which compensates for kidney dysfunction by cleansing the blood of accumulating toxins and impurities), then the regimen in Example 8 may be administered to the patient.

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Abstract

Cette invention a trait à des méthodes de traitement de patients atteints d'hyperhomocystéinémie provoquée, par exemple, par une maladie rénale au stade final. Elle porte également sur des compositions pharmaceutiques en rapport, contenant un folate, des vitamines et d'autres agents modulant l'homocystéine, qui traitent l'hyperhomocystéinémie grave. L'invention concerne, de surcroît, des combinaisons spécifiques et des dosages de l'acide folique et d'autres vitamines. Ces compositions visent également à atténuer l'incidence et à réduire les complications de maladies cardio-vasculaires et vasculaires ainsi que celles de problèmes de coagulation sanguine associés à ce type de patients.
PCT/US2000/029788 1999-10-28 2000-10-30 Acide folique a dose elevee aux fins du traitement de l'hyperhomocysteinemie WO2001030352A1 (fr)

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AU12431/01A AU1243101A (en) 1999-10-28 2000-10-30 High dose folic acid for the treatment of hyperhomocysteinemia

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US60/161,908 1999-10-28

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2851920A1 (fr) * 2003-03-06 2004-09-10 Larena Sa Produit destine a reduire le syndrome metabolique, et utilisation dudit produit pour la preparation d'une composition alimentaire ou dietetique destinee a la prevention ou au traitement du syndrome metabolique
WO2005053715A1 (fr) * 2003-12-05 2005-06-16 Phyt-Immun Gmbh Moyens permettant d'ameliorer l'absorption du fer
WO2005058300A1 (fr) * 2003-12-18 2005-06-30 London Health Sciences Centre Research Inc. Procede permettant de traiter les niveaux plasmiques eleves d'homocysteine chez des patients souffrant d'irsu
WO2006099233A2 (fr) * 2005-03-10 2006-09-21 Sciele Pharma, Inc. Compositions et methodes pour le traitement de l'osteoporose et des maladies articulaires inflammatoires
US20120164162A1 (en) * 2009-08-14 2012-06-28 Basf Se Methods in cell cultures, and related inventions, employing certain additives
WO2020092616A1 (fr) * 2018-10-31 2020-05-07 Rejuvenation Therapeutics Compositions servant au traitement de l'hyperhomocystéinémie
EP3003308B1 (fr) * 2013-05-30 2020-09-30 Sorbonne Université Nouveau médicament pour le traitement et/ou la prévention des troubles dépressifs

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EP0595005A1 (fr) * 1992-09-14 1994-05-04 Vesta Medicines (Proprietary) Limited Compositions pharmaceutiques pour diminuer des taux de homocystéine contenant de la vitamine B6, de l'acide folique et de la vitamine B12
WO1998019690A1 (fr) * 1996-11-06 1998-05-14 Bristol-Myers Squibb Company Methode de traitement de la maladie d'alzheimer
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EP0595005A1 (fr) * 1992-09-14 1994-05-04 Vesta Medicines (Proprietary) Limited Compositions pharmaceutiques pour diminuer des taux de homocystéine contenant de la vitamine B6, de l'acide folique et de la vitamine B12
WO1998019690A1 (fr) * 1996-11-06 1998-05-14 Bristol-Myers Squibb Company Methode de traitement de la maladie d'alzheimer
US6054128A (en) * 1997-09-29 2000-04-25 Wakat; Diane Dietary supplements for the cardiovascular system

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DATABASE CAPLUS [online] CHAUVEAU ET AL.: "Long-term folic acid (but not pyridoxine) supplementation lowers elevated plasma homocysteine level in chronic renal failure", XP002937727, accession no. STN Database accession no. 1995:967908 *
GIRGIS ET AL.: "5-Formyltetrahydrofolate regulates homocysteine remethylation in human neuroblastoma", THE JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 272, no. 8, 21 February 1997 (1997-02-21), pages 4729 - 4734, XP002937729 *
MINER. ELECTROLYTE METAB., vol. 22, no. 1-3, 1996, pages 106 - 109 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2851920A1 (fr) * 2003-03-06 2004-09-10 Larena Sa Produit destine a reduire le syndrome metabolique, et utilisation dudit produit pour la preparation d'une composition alimentaire ou dietetique destinee a la prevention ou au traitement du syndrome metabolique
WO2005053715A1 (fr) * 2003-12-05 2005-06-16 Phyt-Immun Gmbh Moyens permettant d'ameliorer l'absorption du fer
WO2005058300A1 (fr) * 2003-12-18 2005-06-30 London Health Sciences Centre Research Inc. Procede permettant de traiter les niveaux plasmiques eleves d'homocysteine chez des patients souffrant d'irsu
WO2006099233A2 (fr) * 2005-03-10 2006-09-21 Sciele Pharma, Inc. Compositions et methodes pour le traitement de l'osteoporose et des maladies articulaires inflammatoires
WO2006099233A3 (fr) * 2005-03-10 2007-04-26 First Horizon Pharmaceutical C Compositions et methodes pour le traitement de l'osteoporose et des maladies articulaires inflammatoires
US20120164162A1 (en) * 2009-08-14 2012-06-28 Basf Se Methods in cell cultures, and related inventions, employing certain additives
EP3003308B1 (fr) * 2013-05-30 2020-09-30 Sorbonne Université Nouveau médicament pour le traitement et/ou la prévention des troubles dépressifs
WO2020092616A1 (fr) * 2018-10-31 2020-05-07 Rejuvenation Therapeutics Compositions servant au traitement de l'hyperhomocystéinémie

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