WO2011061743A1 - Metadoxine and derivatives thereof for use in the treatment of inflammation and immune-related disorders - Google Patents
Metadoxine and derivatives thereof for use in the treatment of inflammation and immune-related disorders Download PDFInfo
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- WO2011061743A1 WO2011061743A1 PCT/IL2010/000969 IL2010000969W WO2011061743A1 WO 2011061743 A1 WO2011061743 A1 WO 2011061743A1 IL 2010000969 W IL2010000969 W IL 2010000969W WO 2011061743 A1 WO2011061743 A1 WO 2011061743A1
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/45—Non condensed piperidines, e.g. piperocaine having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide
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- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4425—Pyridinium derivatives, e.g. pralidoxime, pyridostigmine
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- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- 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]
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- 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
- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- 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
Definitions
- the present invention relates to the use of metadoxine and derivatives thereof in the treatment of inflammatory and immune-related disorders.
- the present invention provides the use of metadoxine and derivatives thereof, as an antiinflammatory agents and/or as an immune-modulators, when comprised in sustained-, controlled-or delayed-release formulations, which may be combined with immediate- release treatment.
- Metadoxine (pyridoxol L-2-pyrrolidone-5-carboxylate) is an ion-pair salt of pyridoxine (vitamin B6) and pyrrolidone carboxylate (PCA). It has been used in the treatment of acute alcohol intoxication and in the treatment of alcohol withdrawal syndrome. Over 40 years of clinical use have shown metadoxine to be safe and effective as a blood alcohol reducing agent, and in the treatment of alcoholic steatosis [see e.g., Sung Hwan Ki et al. (2007) Chem-Biol. Interac. 169:80-90; WO 08/066353; Calabrese et al. (1995) Int. J. Tiss. Reac. XVII(3): 101-108; Arosio et al. (1993) Pharmacol. Toxicol. 73: 301304; Annoni et al. (1992) Pharmacol. Res. 25(l):87-93].
- NASH Non-alcoholic Steatohepatitis
- Concanavalin A (Con A), a plant lectin and T cell mitogen, rapidly induces severe immune-mediated hepatitis in mice, which is associated with increased TNFa, IFNy, IL-12, IL-18, and IL-4 expression, and in which NKT lymphocytes, CD4+ T cells and Kupffer cells have a contributory role. It is manifested by a robust increase of cytokines and liver damage. Together with TNFa, IFNy is considered to have a key role in the pathogenesis of the immune-mediated damage in this model.
- IFNy-inducing cytokines such as IL-12 and IL-18, and macrophage inflammatory protein-2 (MIP-2) contribute to the liver injury in this model
- IL-6, IL-11 and IL-10 may have a protective role
- Both CD4 and CD8 lymphocytes can be typed as either Thl cells that produce IL-2 and IFNy, or Th2 cells that produce IL-4, and IL-10.
- the way the immune system responds to foreign and self antigens is the result of a balance between the two subtypes of responses [Weiner, H.L., et al., Immunol. Today 18: 335-343 (1997); Adorini, L., et al., Immunol. Today 18:209-211 (1997)].
- a Thl type response is involved in the pathogenesis of several autoimmune and chronic inflammatory disorders [Adorini, L., et al., (1997) ibid.; Mizoguchi, A., et al., J. Exp.
- Thl -type and anti-inflammatory Th2-type cytokines can be perceived as an imbalance between proinflammatory Thl -type and anti-inflammatory Th2-type cytokines.
- anti-inflammatory cytokines such as IL10 can down regulate the pro-inflammatory effects of Thl -mediated cytokines, thereby alleviating immune-mediated disorders [Mizoguchi, A., et al., (1996) ibid.; Madsen, K.L., et al., Gastroenterology 113:151-159 (1997); Van Deventer Sander, J., et al., Gastroenterology 113:383-389 (1997)].
- the Con A treated mouse can serve as a murine model for immunemediated, T cell-or cytokine-mediated disorders, and has been previously described, e.g., in WO 02/051986.
- the present inventors employed the Con A mouse model to study the antiinflammatory and immune modulating effect of metadoxine, particularly when contained in special formulations and dosage forms.
- the present invention provides the use of metadoxine in the preparation of a pharmaceutical composition for the treatment of an immune-related disease, wherein said composition is formulated in a sustained-, delayed- or controlled- release dosage form.
- the invention provides a use of a salt adduct comprising:
- Ri is straight or branched CpC alkyl
- R 2 is selected from -OH, straight or branched Ci-C 6 alkoxy, and straight or branched Ci-C 6 alkoxy carbonyl;
- R.3 and R4 are each independently selected from formyl, straight or branched Cj-Q alkyl optionally substituted by at least one halogen, amine, hydroxyl, Cj-C 6 alkoxy, thiol, C]-C alkoxycarbonyl; and
- R is selected from H, straight or branched C C 6 alkyl optionally substituted by at least one halogen, straight or branched C 2 -C 6 alkenyl, straight or branched C 2 -C alkynyl, cycloalkyl, aryl and heteroaryl optionally substituted by a C!-C 6 alkyl;
- R 7 , R 8 , R 9 , R 10 Rn, Ri2, Rn and R 14 are each independently selected from H, straight or branched C[-C alkyl, C 2 -C 6 alkenyl, C 2 -C alkynyl, cycloalkyl, aryl and heteroaryl optionally substituted by at least one group selected from C ⁇ -C alkyl, halogen, amino, cyano, nitro, thiol, Cj- C 6 alkoxy, aminocarbonyl, C C alkoxycarbonyl, Ci-C 6 carboxyalkyl, Q-Q alkoxycarbonylalkyl and amidino;
- said carboxylated lactam ring is a compound of formula
- said positively charged moiety is compound (2): In am ring is compound (1):
- said positively charged moiety is a compound of formula (I):
- R ⁇ is a C C 6 alkyl and R 2 , R 3 and R4 are as defined above.
- R 2 is selected from-OH and C ⁇ -C alkoxy; and R l5 R 3 and R4 are as defined hereinabove.
- R 3 is -CH 2 R 15 , wherein R 15 is selected from -C ⁇ -Ce alkoxy, -OH and -NH 3 + ; and R l5 R 2 and R4 are as defined hereinabove.
- R4 is selected from formyl and -CH 2 R 16 , wherein R 16 is selected from -Ci-Ce alkoxy and -OH; and Ri, R 2 and R 3 are as defined hereinabove.
- said carboxylated lactam ring is a compound of formula (II):
- said carboxylated lactam ring is a compound of formula (II)
- Re is Cj-C 6 alkyl.
- R 9 is CrC 6 alkyl.
- said carboxylated lactam ring is a compound of formula (III):
- said carboxylated lactam ring is a compound of formula (IV):
- said positively charged moiety is a compound of formula (I):
- said positively charged moiety is compound (2):
- said salt adduct is selected from following group:
- said composition is formulated in a sustained-, delayed- or controlled-release dosage form combined with an immediate or burst effect dosage form.
- said composition is formulated to deliver metadoxine or salt adduct defined herein above, up to 0.1-1000 mg/kg body weight/day, preferably 1-400 mg/kg body weight, in a single dose administration or portion thereof, wherein said composition is formulated for enteral or parenteral administration.
- Said enteral administration may be oral or rectal administration.
- said parenteral administration may be by intramuscular, intraperitoneal, intratechal or intravenous, or sublingual, buccal, nasal, transdermal, transmucosal, or subcutaneous mode.
- said pharmaceutical composition may further comprise at least one additional pharmaceutically active agent.
- said immune-related disease is an autoimmune disease, graft rejection pathology, inflammatory disease, non-alcoholic fatty liver disease, hyperlipidemia, atherosclerosis, or Metabolic Syndrome or any of the conditions comprising the same.
- said immune-related disease is an autoimmune disease, graft rejection pathology, inflammatory disease, hyperlipidemia, atherosclerosis, or Metabolic Syndrome or any of the conditions comprising the same.
- the present invention provides a method of treating an immune-related disease in a subject in need thereof, said method comprising the step of administering a therapeutically effective dosage of metadoxine, or a composition comprising thereof, to said subject.
- the invention provides a method of treating an immune- related disease in a subject in need, said method comprising administering a therapeutically effective dosage of a salt adduct or a composition comprising thereof, to said subject, wherein said salt adduct comprises: a positively charged moiety of formula (I), as defined herein above; and a negatively charged carboxylated lactam ring selected from the group consisting of: compounds of formulae (II), (III) and (IV), as defined herein above.
- said metadoxine or salt adduct defined herein above, or composition comprising the same is formulated in a sustained-, delayed- or controlled-release dosage form, which may optionally be combined with an immediate or burst effect dosage form.
- said metadoxine or salt adduct defined herein above, or composition comprising the same is formulated in a dosage form to deliver 0.1-1000 mg/kg body weight/day, preferably 1-400 mg/kg body weight metadoxine or salt adduct defined herein above,, in a single dose administration or portion thereof.
- said composition is formulated for enteral or parenteral administration, wherein said enteral administration is oral or rectal administration, whereas said parenteral administration is by intramuscular, intraperitoneal, intratechal or intravenous, or sublingual, buccal, nasal, transdermal, transmucosal, or subcutaneous mode.
- said pharmaceutical composition further comprises at least one additional pharmaceutically active agent.
- said immune-related disease is selected from the group consisting of an autoimmune disease, graft rejection pathology, inflammatory disease, non-alcoholic fatty liver disease, hyperlipidemia, atherosclerosis, Metabolic Syndrome and any conditions, syndromes, disorders or diseases comprising the same.
- said immune-related disease is selected from the group consisting of an autoimmune disease, graft rejection pathology, inflammatory disease, hyperlipidemia, atherosclerosis, Metabolic Syndrome and any conditions, syndromes, disorders or diseases comprising the same.
- the present invention further provides a kit for use in treating an immune- related disease in a subject in need thereof, said kit comprising: (a) metadoxine or a composition comprising the same; (b) means for administering said metadoxine or composition comprising the same; and (c) instructions for use.
- the invention further encompasses a kit for treating an immune-related disease in a subject in need, said kit comprising: (a) salt adduct or a composition comprising the same; (b) means for administering said salt adduct or composition comprising the same; and (c) instructions for use; wherein said salt adduct comprises: a positively charged moiety of formula (I), as defined herein above; and a negatively charged carboxylated lactam ring selected from the group consisting of: compounds of formulae (II), (III) and (IV), as defined herein above.
- said metadoxine or salt adduct defined herein above, or composition comprising thereof is provided in a sustained-, delayed- or controlled-release dosage form.
- said composition is formulated in a sustained-, delayed or controlled-release dosage form combined with an immediate or burst effect dosage form.
- said immune-related disease is an autoimmune disease, graft rejection pathology, inflammatory disease, non-alcoholic fatty liver disease, hyperlipidemia, atherosclerosis, Metabolic Syndrome or any conditions, syndromes, disorders or diseases comprising the same.
- said immune-related disease is an autoimmune disease, graft rejection pathology, inflammatory disease, hyperlipidemia, atherosclerosis, Metabolic Syndrome or any conditions, syndromes, disorders or diseases comprising the same.
- the present invention provides a use of metadoxine in the preparation of a pharmaceutical composition for the treatment of a disorder or condition associated with or related to an imbalance in Thl and Th2 cells response.
- the treatment shifts the balance to favor Th2 cells response.
- the invention provides a use of a salt adduct comprising: a positively charged moiety of formula (I), as defined herein above; and a negatively charged carboxylated lactam ring selected from the group consisting of: compounds of formulae (II), (III) and (IV), as defined herein above; in the preparation of a pharmaceutical composition for the treatment of an imbalance in Thl and Th2 cells
- the present invention provides a method of treating a disorder or condition associated with or related to an imbalance in Thl and Th2 cells response in a subject in need thereof, said method comprising administering a therapeutically effective dosage of metadoxine, or a composition comprising thereof, to said subject.
- the treatment shifts the balance to favor Th2 cells response.
- the invention provides a method of treating an immune disorder associated with an imbalance in Thl and Th2 cells response in a subject in need, said method comprising administering a therapeutically effective dosage of a salt adduct, or a composition comprising thereof, to said subject, wherein said salt adduct comprises a positively charged moiety of formula (I), as defined herein above; and a negatively charged carboxylated lactam ring selected from the group consisting of: compounds of formulae (II), (III) and (IV), as defined herein above.
- salt adduct is meant to encompass a salt product of a direct addition of two or more distinct ions, wherein the overall charge of the salt adduct is zero.
- the salt adduct comprises one positively charged moiety having a single positive charge functional group (i.e., the positively charged moiety is charged with +1 net charge) and one negatively charged moiety having a single negative charge functional group (i.e., the negatively charged moiety is charged with -1 net charge).
- the salt adduct comprises one positively charged moiety having two positively charged functional groups, which may be the same or different (i.e., the positively charged moiety is charged with +2 net charge) and two negatively charged moieties, which may be the same or different, and each having a single negative charged functional group (i.e., each negatively charged moiety is charged with -1 net charge).
- the salt adduct comprises two positively charged moieties, which may be the same or different, having each one positively charged functional group (i.e., each positively charged moiety is charged with +1 net charge) and one negatively charged moiety, having two negatively charged functional groups, being the same or different (i.e., the negatively charged moiety is charged with -2 net charge).
- the salt adduct comprises a positively charged moiety charged with +n net charge (originating from one or more positively charged functional groups, which may be the same or different), and a negatively charge moiety having -n (originating from one or more negatively charged functional groups, which may be the same or different) net charge, wherein n is an integer which may be equal to 1, 2, 3, 4, 5 or 6.
- a "positively charged moiety of a salt adduct" of the invention is the corresponding acid of pyridoxine, or any derivative thereof.
- the positive charge of the positively charged moiety stems from the protonated basic nitrogen atom of pyridoxine (as for example in compound (2)) or any derivative thereof (such as for example compounds of formula (I)).
- the positively charged pyridoxine derivative is substituted with a positively charged functional group such as for example -NH3+, -CH2NH3+, -NH2R+, -NHR2+ (wherein each R is independently a C1-C6 alkyl), which may, in some embodiments, be present in addition to the positively charged protonated basic aromatic nitrogen atom in the pyridine ring.
- a positively charged functional group such as for example -NH3+, -CH2NH3+, -NH2R+, -NHR2+ (wherein each R is independently a C1-C6 alkyl), which may, in some embodiments, be present in addition to the positively charged protonated basic aromatic nitrogen atom in the pyridine ring.
- a "carboxylated 5- to 7-membered lactam ring" of a salt adduct of the invention is meant to encompass a ⁇ -lactam, ⁇ -lactam or ⁇ -lactam rings, having a negatively charged carboxylate group (-COO-) substituted thereto.
- said carboxylate group is substituted at the lactam ring carbon atom adjacent to the amide nitrogen.
- said carboxylated lactam ring is a L-2-pyrrolidone-5-carboxylate (compound (1)).
- said carboxylate group is substituted on any position of the lactam ring.
- said carboxylated 5- to 7-membered lactam ring may be substituted by another substituent at any position on the lactam ring.
- halogen as used herein means F, CI, Br or I.
- C1-C6 alkyl represents a saturated, branched or straight hydrocarbon chain having 1, 2, 3, 4, 5 or 6 carbon atoms.
- Typical Cl-6 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl and the like.
- C2-C6 alkenyl represents a branched or straight hydrocarbon chain having 2, 3, 4, 5 or 6 carbon atoms and at least one double bond positioned between any two carbons of the chain.
- groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, isopropenyl, 1,3-butadienyl, 1- butenyl, 2-butenyl, 1-pentenyl, 2-pentenyl, 1-hexenyl, 2-hexenyl and the like.
- C2-C6 alkynyl represents a branched or straight hydrocarbon chain having 2, 3, 4, 5 or 6 carbon atoms and at least one triple bond positioned between any two carbons of the chain.
- Examples of such groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2- pentynyl, 1-hexynyl, 2-hexynyl and the like.
- CI- C6 alkoxy refers to the radical -O-Cl-6 alkyl, wherein CI -6 alkyl is as defined above. Representative examples are methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like.
- CI- C6 alkylthio refers to the radical -S-Cl-6 alkyl, wherein CI -6 alkyl is as defined above. Representative examples are methylthio, ethylthio, isopropylthio, n-propylthio, butylthio, pentylthio and the like.
- cycloalkyl represents a monocyclic, carbocyclic group having 3, 4, 5, 6, 7 or 8 carbon atoms, but may also include heteroatoms such as N, O and/or S.
- Representative examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
- aryl as used herein is intended to include carbocyclic aromatic ring systems such as phenyl, biphenylyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, pentalenyl, azulenyl and the like.
- Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 1,2,3,4-tetrahydronaphthyl, 1,4- dihydronaphthyl and the like.
- heteroaryl refers to ring systems in which at least one ring is an aromatic ring in which at least one atom is a non-carbon atom, either substituted or non-substituted, where the non-carbon atom may be, for example, a nitrogen, sulfur or oxygen atom.
- C1-C6 alkoxycarbonyl refers to the radical -C(0)0- Cl-6 alkyl, wherein CI -6 alkyl is as defined above.
- C1-C6 alkoxy and C1-C6 alkylthio refers to the radicals CI -6-0- and C1-6-S-, respectively, wherein CI -6 alkyl is as defined above.
- hydroxyl refers to the radical -OH.
- thiol refers to the radical -SH.
- formyl refers to the radical -COH.
- cyano refers to the radical -CN.
- nitro refers to the radical -N02.
- amine refers to -NH3 or any primary (-NH2R), secondary (-NHR2), tertiary (-NR3) or quarternary amines (-NR4+), wherein each R may be the same or different and independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl as defined herein above.
- C1-C6 carboxyalkyl refers to the radical -CO-(Cl-C6 alkyl), wherein CI -6 alkyl is as defined above.
- aminocarbonyl refers to the radical -CONR2, wherein each of groups R is independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl as defined herein above.
- alkoxycarbonylalkyl refers to the radical -OCO-(Cl- C6alkyl), wherein CI -6 alkyl is as defined above.
- Such substituents can include, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, an alkylthio, an acyloxy, a phosphoryl, a phosphate, a phosphonate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aryl or heteroaryl moiety.
- moieties of a salt adduct of the invention may contain each at least one chiral center, and thus may exist in, and be isolated as, any stereoisomer thereof including, enantiomers, diastereomers or any mixtures thereod including, but not limited to racemic mixtures.
- the present invention includes any possible stereoisomer (e.g. enantiomers, diastereomers), any mixtures thereof including, but not limited to, racemic mixtures, of any of the individual moieties of a salt adduct of the invention.
- each of the moieties of a salt adduct of the invention may be separated by conventional techniques, such as preparative chromatography.
- the moieties of a salt adduct of the invention may be each prepared in any mixture of possible stereoisomers thereof, including but not limited to racemic mixtures thereof, or individual stereoisomers (e.g. enantiomers, diastereomers) may be prepared either by enantiospecific synthesis or by chiral chromatographic separation of a racemate.
- the invention should be understood to encompass natural and non-natural amino acids or any derivative thereof.
- non-natural amino acid refers herein to amino acids, or any derivative thereof, that are not among the amino acids which are the building blocks of proteins having L as well as D-configurations, while “natural amino acids”, refer to amino acids or any derivative thereof, which are the building blocks of proteins, having L as well as D-configurations.
- Carboxylated 5- to 7-membered lactam rings which may be optionally substituted as defined hereinabove, may be synthetically prepared by any method known to a person skilled in the art or by methods described herein.
- said carboxylated lactam may be prepared from the corresponding amino acids, such as by methods described herein.
- Figure 1 Histogram showing the level of liver enzymes (AST and ALT) in ConA-treated mice following the administration of metadoxine versus control.
- Figure 2 Histogram showing the level of IFNy in the serum of ConA-treated mice following the administration of metadoxine versus control.
- the present inventors found, as shown in the following examples, that treatment of Con A model mice with metadoxine induced a decrease in liver enzymes such as AST and ALT, as well as a decrease in the levels of IFNy in the serum, strongly suggesting that metadoxine may be used as a therapeutic agent in the treatment of immune-related disorders, and as a modulator of the Thl-Th2 cell balance.
- metadoxine may be used as a modulator of Thl/Th2 balance.
- High IFNy levels induce the differentiation of naive CD4 cells into Thl cells, and inhibit the proliferation of Th2 cells.
- the inhibition of IFNy by metadoxine may thus shift the Thl-Th2 balance in the opposite direction, favoring Th2 cells. In specific conditions, it may be desirable to shift the balance towards Thl cells.
- the invention provides a method for treating an imbalance between pro-inflammatory Thl -type and anti-inflammatory Th2type cytokines in a subject in need thereof.
- the invention relates to a process for the modulation of the Thl/Th2 cell balance, toward anti-inflammatory or pro-inflammatory cytokine producing cells, in a subject suffering from an inflammatory or immune-related disorder, said modulation being effected by administering to said subject an effective amount of metadoxine or a salt adduct defined herein above,, optionally in combination with another pharmaceutically active agent.
- the invention relates to a method for the treatment of immune-related disorders in a mammalian subject, this method involving manipulation of NK T cell population by ex vivo education of the said NK T cells, such that the educated NK T cells have the capability to modulate the ThllTh2 balance toward anti-inflammatory or pro-inflammatory cytokine producing cells.
- This method comprises the steps of: (a) obtaining NK T cells from said subject; (b) ex vivo educating the NK T cells obtained in step (a) such that the resulting educated NK T cells have the capability of modulating the ThllTh2 cell balance toward anti-inflammatory or proinflammatory cytokine producing cells; and (c) re-introducing to the subject the educated NK T cells that were obtained in step (b).
- step (b) is effected in culture, bringing the NK T cells into contact with metadoxine or a salt adduct defined herein above,, for any suitable time effective to confer unto said cells the capability of modulating the Thl-Th2 cell balance toward anti-inflammatory or pro-inflammatory cytokine producing cells.
- the cells are considered "educated”.
- the "education" toward antiinflammatory or pro-inflammatory cytokine producing cells will depend on the point of origin of the (to be) treated cells. Naturally, this is dependent on the immune system of the subject from whom the cells were obtained.
- Modulation of the Thl-Th2 cell balance toward anti-inflammatory cytokine producing cells results in an increase of the quantitative ratio between at least one of IL- 4 and IL-10 to IFNy.
- modulation of the ThllTh2 cell balance toward proinflammatory cytokine producing cells results in a decrease of the quantitative ratio between at least one of IL-4 and IL-10 to IFNy (i.e., an increase in the pro-inflammatory cytokines IL-2 and IFNy).
- the above-described method may optionally further comprise the step of eliciting in the subject up or down regulation of the immune response to the immune- related disorder.
- said regulation of the immune response is by oral tolerization.
- ex vivo educated NK T cells according to the method of the invention are re-introduced by adoptive transfer to the treated subject.
- the present invention also provides a therapeutic composition for the treatment of an immune-related disorder in a mammalian subject, which composition comprises as an effective ingredient ex vivo educated autologous NK T cells capable of modulating the Thl-Th2 cell balance toward anti-or pro-inflammatory cytokine producing cells.
- ex vivo educated autologous NK T cells capable of modulating the Thl-Th2 cell balance toward anti- or pro-inflammatory cytokine producing cells are produced by being in contact with metadoxine or salt adduct defined herein above, or a composition comprising same.
- composition may optionally further comprise one or more pharmaceutically acceptable carrier, diluent, excipient or additive.
- the invention relates to the use of metadoxine or salt adduct defined herein above, in the treatment of inflammatory and immune-related disorders.
- metadoxine or salt adduct defined herein above when comprised in sustained-, controlled- or delayed-release compositions, as detailed below.
- metadoxine refers to the currently known and available form of metadoxine, which is an ion-pair between pyrrolidone carboxylate (PCA) and pyridoxine (vitamin B6) with the two compounds linked in a single product by salification.
- PCA pyrrolidone carboxylate
- vitamin B6 pyridoxine
- Stable association between the PCA and pyridoxine may be non-covalent, such as through a salt link, or other hydrostatic or electrostatic forces.
- Stable association in other cases, may be accomplished by covalent bonding, e.g., by means of a linker or other chemical bond between the peA and pyridoxine in which metadoxine activity is retained.
- linker or other chemical bond between the peA and pyridoxine in which metadoxine activity is retained.
- the skilled artisan will be able to test the biological activity of any such complexes in standard metadoxine assays.
- acceptable derivative refers to any salt, conjugate, ester, complex or other chemical derivative of metadoxine or a salt adduct as defined herein above, or any of the moieties comprising the same, which, upon administration to a subject, is capable of providing (directly or indirectly) metadoxine or a salt adduct as defined herein above, or a metabolite or functional residue thereof, or measurable metadoxine activity.
- physiologically compatible metadoxine derivative may be used interchangeably herein with the term “acceptable derivative” and refers to a functional, active, pharmaceutically acceptable derivative of metadoxine or a salt adduct as defined herein above.
- excipient refers to an inactive substance used as a carrier for the active ingredient in a formulation.
- the present invention provides for the use of metadoxine or a salt adduct as defined herein above, in the preparation of a pharmaceutical composition for the treatment of an inflammatory or an immune-related disease.
- compositions are well known in the art and has been described in many articles and textbooks, see e.g., Remington's Pharmaceutical Sciences, Gennaro A. R. ed., Mack Publishing Company, Easton, Pennsylvania, 1990, and especially pages 1521-1712 therein.
- said composition is formulated III a sustained- or controlled-release dosage form, or such form combined with immediate release form.
- controlled release refers to any formulation which delivers an agent at a controlled rate for an extended time and is designed to achieve a desired agent level profile.
- sustained release is used in its conventional sense to refer to a formulation that provides for gradual release of an active material over an extended period of time, which in certain embodiments may also further result in substantially constant blood levels over an extended time period, i.e., controlled release.
- immediate release is used in its conventional sense to refer to a formulation that provides for non delayed or controlled release of an active material upon administration.
- the treatment regimen selected may be chronic or non-chronic.
- Optimal dosing schedules may be calculated from measurements of drug accumulation in the body of the patient. Persons of ordinary skill can easily determine optimum dosages, dosing methodologies and repetition rates. In general, dosage is calculated according to body weight, and may be given once or more daily, weekly, monthly or yearly, or even once every 2 to 20 years. Persons of ordinary skill in the art can easily estimate repetition rates for dosing based on measured residence times and concentrations of the combined composition of the invention in bodily fluids or tissues. Following successful treatment, it may be desirable to have the patient undergo maintenance therapy to prevent the recurrence of the disease state, wherein the composition of the invention is administered in maintenance doses, once or more daily.
- Administration of metadoxine or a salt adduct as defined herein above may be via enteral (via the digestive tract) and/or parenteral (other than digestive tract) routes, depending on the delivery systems of choice, which will also define the selection of the carrier, e.g. appropriate surfactants/co-surfactants composition or micro/nano particles (such as liposomes or nano-liposomes) entrapping the active ingredients, or other additives or excipients, for the delivery system of interest.
- the carrier e.g. appropriate surfactants/co-surfactants composition or micro/nano particles (such as liposomes or nano-liposomes) entrapping the active ingredients, or other additives or excipients, for the delivery system of interest.
- enteral delivery systems may be designed for oral administration (tablets, sachets, lozenges, capsules, gelcaps, drops, or other palatable form, drop solutions, syrups) or rectal administration (suppository or (mini) enema form).
- compositions of the invention are not administered by invasive modes of treatment (i.e., are non-invasive).
- the metadoxine or salt adduct as defined herein above, or compositions comprising thereof may be administered by intravenous, intraperitoneal or intramuscular injection.
- metadoxine or a salt adduct as defined herein above, or the composition comprising thereof is delivered as a microcrystalline powder or a solution suitable for nebulization; for intravaginal or intrarectal administration, pessaries, suppositories, creams or foams.
- the composition may be formulated for oral administration.
- the composition may be formulated for topical administration.
- the composition may be formulated for transmucosal administration, sublingual, buccal (absorbed through cheek near gumline) administration, administration by inhalation or ocular administration, e.g., in eye drops.
- the composition may be formulated for injection.
- the present invention can provide delivery systems for safe delivery of the active ingredient metadoxine or a salt adduct as defined herein above, due to their special physico-chemical features, particularly direct absorption, by non-invasive means, and consequent avoidance of side effects.
- the delivery systems significantly enhance efficiency and quality of metadoxine or a salt adduct as defined herein above absorption based on their unique physicochemical features, which enable lower concentrations or amounts of the active substance to be delivered to a subject in a biologically active form.
- the delivery systems of the invention provide for the direct access of the active substance to the tissues and thus provide immediate or near- immediate effects of metadoxine or a salt adduct as defined herein above to the subject in need thereof.
- the drug delivery systems comprising the metadoxine or a salt adduct as defined herein above, may be designed for oral, nasal, ocular, rectal, subcutaneous, transdermal, transmucosal, sublingual, buccal or inhalation administration.
- the drug delivery systems may provide the active substance in a controlled release mode.
- the drug delivery systems of the invention may further comprise at least one additional pharmaceutically active agent.
- the delivery systems used in the invention may generally comprise a buffering agent, an agent which adjusts the osmolarity thereof, and optionally, one or more pharmaceutically acceptable carriers, excipients and/or additives as known in the art.
- Supplementary pharmaceutically acceptable active ingredients can also be incorporated into the compositions.
- the carrier can be solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
- the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
- pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, preservatives and the like.
- the use of such media and agents for pharmaceutical active substances is well known in the art. Except when any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic composition is contemplated. It is contemplated that the active agent can be delivered by any pharmaceutically acceptable route and in any pharmaceutically acceptable dosage form.
- Oral forms include, but are not limited to, tablets, capsules, pills, sachets, lozenges, drops, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. Also included are oral rapid-release, time controlled-release, and delayed- release pharmaceutical dosage forms.
- the active drug components can be administered in a mixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier”), materials suitably selected with respect to the intended form of administration.
- the active drug components can be combined with a non-toxic pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, glucose, modified sugars, modified starches, methylcellulose and its derivatives, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, and other reducing and non-reducing sugars, magnesium stearate, stearic acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate and the like.
- a non-toxic pharmaceutically acceptable inert carriers such as ethanol, glycerol, water and the like.
- suitable binders, lubricants, disintegrating agents and coloring and flavoring agents can also be incorporated into the mixture.
- Stabilizing agents such as antioxidants, propyl gallate, sodium ascorbate, citric acid, calcium metabisulphite, hydroquinone, and 7- hydroxycoumarin can also be added to stabilize the dosage forms.
- Other suitable compounds can include gelatin, sweeteners, natural and synthetic gums such as acacia, tragacanth, or alginates, carboxymethylcellulose, polyethylene, glycol, waxes and the like.
- Additional suitable pharmaceutically acceptable carriers that may be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, magnesium stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and wool fat.
- the pharmaceutically acceptable carrier is magnesium stearate. Additional pharmaceutical excipients commonly accepted and used are found in, for example, Remington's Pharmaceutical Sciences (Gennar), serum
- solutions in suitable oil such as sesame or peanut oil or in aqueous propylene glycol can be employed, as well as sterile aqueous solutions of the corresponding water-soluble salts.
- aqueous solutions may be suitably buffered, if necessary, and the liquid diluent first rendered isotonic with sufficient saline or glucose.
- aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal injection purposes.
- the sterile aqueous media employed are all readily obtainable by standard techniques well-known to those skilled in the art. Methods of preparing various pharmaceutical compositions with a certain amount of active ingredient are known, or will be apparent in light of this disclosure, to those skilled in this art.
- metadoxine in human serum is very short. Lu Yuan et al. (Chin. Med. J. 2007 120(2) 160-168) shows a mean half life of about 0.8 hour.
- One way of prolonging serum levels of active moiety is by administering the material in a sustained- release formulation. Because metadoxine is freely soluble in water and in various biological fluids, it is difficult to sustain its release and prolong its absorption time. Therefore, a controlled release dosage form of metadoxine, which may be based on a predetermined gradual release of the active ingredient in the biological fluids, resulting in a sustained action with small fluctuations of the plasma level over a prolonged period of time, may be significantly advantageous in the treatment of diseases.
- the method of administration will be determined by the attending physician or other person skilled in the art after an evaluation of the subject's condition and requirements.
- An embodiment of the method of the present invention is to administer the therapeutic compound described herein in a sustained release form. Any controlled or sustained release method known to those of ordinary skill in the art may be used with the compositions and methods of the invention such as those described in Langer, Science 249(4976): 1527-33 (1990). Such method comprises administering a sustained-release composition, a suppository, or a coated implantable medical device so that a therapeutically effective dose of the composition of the invention is continuously delivered to a subject of such a method. Sustained release may also be achieved using a patch designed and formulated for the purpose.
- composition of the invention may be delivered via a capsule which allows sustained-release of the agent over a period of time.
- Controlled or sustained-release compositions include formulation in lipophilic depots (e.g., fatty acids, waxes, oils).
- particulate compositions coated with polymers e.g., poloxamers or poloxamines.
- Sustained release formulae or devices, or any topical formulations may additionally contain compositions to stabilize the composition or permeate physiological barrier such as skin or mucous membrane.
- Exemplary additional components may include any physiologically acceptable detergent, or solvent such as, for example, dimethylsulfoxide (DMSO).
- Sustained blood levels sustained release formulations slower the rate of absorption of drug and allow less blood concentrations fluctuations within a dosing interval.
- sustained release formulations slower the rate of absorption of drug and allow less blood concentrations fluctuations within a dosing interval.
- drugs with short half-lives like metadoxine, the use of extended-release formulation may maintain therapeutic concentrations over prolonged periods of time.
- the metadoxine or a salt adduct as defined herein above, in compositions to be used in the invention may be in immediate, fast or burst release form.
- the metadoxine or a salt adduct as defined herein above, in compositions to be used in the invention may be in a combination of sustained or slow release and immediate or fast release forms.
- the relative proportion of sustained or slow release metadoxine to immediate or fast release metadoxine or a salt adduct as defined herein above is, e.g., 1 to 99, 5 to 95, 10 to 90, 15 to 85, 20 to 80, 25 to 75, 30 to 70, 35 to 65, 40 to 60, 45 to 55, 50 to 50, 55 to 45, 60 to 40, 65 to 35, 70 to 30, 75 to 25, 80 to 20, 85 to 15, 90 to 10, 95 to 5, or 99 to 1.
- a polymeric material is used to sustain or control release of metadoxine or a salt adduct as defined herein above.
- the type of polymeric material and the amount of which is used have a strong influence on the rate of release of metadoxine or a salt adduct as defined herein above, from the product of the present invention.
- polymers include both hydrophobic and hydrophilic polymers.
- hydrophobic polymers include, but are not limited to, ethyl cellulose and other cellulose derivatives, fats such as glycerol palmito-stereate, beeswax, glycowax, castorwax, carnaubawax, glycerol monostereate or stearyl alcohol, hydrophobic polyacrylamide derivatives and hydrophobic methacrylic acid derivatives, as well as mixtures of these polymers.
- Hydrophilic polymers include, but are not limited to, hydrophilic cellulose derivatives such as methyl cellulose, hydroxypropylmethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethylcellulose and hydroxyethyl methylcellulose polyvinyl alcohol, polyethylene, polypropylene, polystyrene, polyacrylamide, ethylene vinyl acetate copolymer, polyacrylate, polyurethane, polyvinylpyrrolidone, polymethylmethacrylate, polyvinyl acetate, polyhydroxyethyl methacrylate, as well as mixtures of these polymers. Furthermore, any mixture of one or more hydrophobic polymer and one or more hydrophilic polymer could optionally be used.
- a polymeric material to be used in compositions of the invention is e.g., but not limited to, microcrystalline cellulose such as "Avicel PH 101" manufactured by FMC BioPolymer's, Hydroxypropyl Methylcellulose such as “Metholose” produced by Shin-Etsu Chemical Co., Ethyl cellulose such as “EthocelTM” manufactured by The Dow Chemical Company, an acrylic polymer such as “Eudragit RSTM” produced by Rohm GmbH, a colloidal silicone dioxide such as "AerosilTM” manufactured by Degussa, a Poly (Vinyl Acetate) such as "Kollicoat SR" manufactured by BASF, or an Ethyl Acetate and Vinyl Acetate solution such as "Duro-Tak” manufactured by Delasco Dermatologic Lab & Supply, Inc.
- microcrystalline cellulose such as "Avicel PH 101” manufactured by FMC BioPolymer's, Hydroxypropyl Methylcellulose such as “Metholose
- delivery systems of the invention comprise delivery devices.
- the compositions of the invention are delivered by an osmotic process at a controlled rate such as by an osmotic pump.
- the system may be constructed by coating an osmotically active agent with a rate controlling semipermeable membrane. This membrane may contain an orifice of critical size through which agent is delivered.
- the dosage form after coming into contact with aqueous fluids, imbibes water at a rate determined by the fluid permeability of the membrane and osmotic pressure of the core formulation. This osmotic imbibitions of water result in formation of a saturated solution of active material within the core, which is dispensed at controlled rate from the delivery orifice in the membrane.
- the compositions of the invention are delivered using biodegradable microparticles.
- the system to prepare microparticles consists of an organic phase comprised of a volatile solvent with dissolved polymer and the material to be encapsulated, emulsified in an aqueous phase.
- the biodegradable polymers that can be used for the microparticle matrix comprises polylactic acid (PLA) or the copolymer of lactic and glycolic acid (PLAGA).
- PLAGA polylactic acid
- PLAGA copolymer of lactic and glycolic acid
- the preparation may also contain an absorption enhancer and other optional components.
- absorption enhancers include, but are not limited to, cyclodextrins, phospholipids, chitosan, DMSO, Tween, Brij, glycocholate, saponin, fusidate and energy based enhancing absorption equipment.
- Optional components present in the dosage forms include, but are not limited to, diluents, binders, lubricants, surfactants, coloring agents, flavors, buffering agents, preservatives, stabilizing agents and the like.
- Diluents also termed “fillers” include, for example, dicalcium phosphate dihydrate, calcium sulfate, lactose, cellulose, kaolin, mannitol, sodium chloride, dry starch, hydrolyzed starches, silicon dioxide, colloidal silica, titanium oxide, alumina, talc, microcrystalline cellulose, and powdered sugar.
- the diluents include, for example, ethanol, sorbitol, glycerol, water and the like.
- Binders are used to impart cohesive qualities to the formulation.
- Suitable binder materials include, but are not limited to, starch (including corn starch and pregelatinzed starch), gelatin, sugars (including sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycol, waxes, natural and synthetic gums, e.g., acacia, tragacanth, sodium alginate, celluloses, and Veegum, and synthetic polymers such as polymethacrylates and polyvinylpyrrolidone .
- Lubricants are used to facilitate manufacture; examples of suitable lubricants include, for example, magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, and polyethylene glycol.
- Surfactants may be anionic, cationic, amphoteric or nonionic surface active agents.
- the surfactants are anionic.
- Suitable anionic surfactants include, but are not limited to, those containing carboxylate, sulfonate and sulfate ions, associated with cations such as sodium, potassium and ammonium ions.
- the surfactants include, but are not limited to: long alkyl chain sulfonates and alkyl aryl sulfonates such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium bis-(2-ethylhexyl)-sulfosuccinate; and alkyl sulfates such as sodium lauryl sulfate.
- Stabilizing agents such as antioxidants, include, but are not limited to, propyl gallate, sodium ascorbate, citric acid, calcium metabisulphite, hydroquinone, and 7- hydroxycoumarin.
- compositions may also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, preservatives, and the like.
- compositions of the invention may be used alone or in combination with one or more additional therapeutic agents, for the treatment of inflammatory conditions and/or immune-related disorders.
- Optional additional therapeutic agents of the composition may be selected from the group consisting of analgesics, antibiotics, anti-inflammatory agents, anti-neoplastic agents, glucocorticoids, hematopoietic agents, glycolipids, and immunosuppressants, but are not limited thereto.
- compositions of this invention may be formulated so that a dosage of between 0.1-1000 mg/kg body weight/day can be administered. In certain embodiments, the compositions of this invention may be formulated so that a dosage of between 1-400 mg/kg body weight can be administered.
- the dose of the compound depends on the condition and the illness of the patient, and the desired daily dose. In human therapy, the oral daily dose may be 50-3000 mg. These doses are administered in unit dosage forms, which may be divided into 2-3 smaller doses for each day in certain cases, especially in oral treatment.
- compositions of the present invention may act synergistically in combination with each other and may further act synergistically in the presence of an additional therapeutic agent. Therefore, the amount of compound(s) and additional therapeutic agent(s) in such compositions will be less than that required in a mono-therapy utilizing only that therapeutic agent. In such compositions a dosage of between 1-400 mg/kg bodyweight/day of the additional therapeutic agent can be administered.
- therapeutic effect refers to a local or systemic effect in animals, particularly mammals, and more particularly humans, caused by a pharmacologically active substance or substances.
- the term thus means any substance intended for use in diagnosis, cure, mitigation, treatment or prevention of disease or in the enhancement of desirable physical or mental development and conditions In an animal or human.
- therapeutically effective amount means that amount of such a substance that produces some desired local or systemic effect at a reasonable benefit/risk ratio applicable to any treatment.
- a therapeutically-effective amount of a compound or composition will depend on its therapeutic index, solubility, and the like.
- certain metadoxine formulations of the present invention may be administered in a sufficient amount to produce a reasonable benefit/risk ratio applicable to a selected treatment, as may be determined by the skilled artisan.
- the present invention provides a method of treating an immune-related disease in a subject in need, said method consisting of administering a therapeutically effective dosage of metadoxine or a salt adduct as defined herein above, or a composition comprising thereof, to said subject.
- dosage unit forms used by the methods of the invention may be either for a single or for repeated administration. Administration of said dosage unit form may be repeated, for example, everyone to five, ten or twenty- four hours, for a therapeutically sufficient period of time.
- the dosage unit form may be a sustained-released dosage unit form which provides continued pH-independent drug release for a considerable period of time after administration.
- an effective amount refers to the amount of a therapeutic reagent that when administered to a subject in an appropriate dose and regimen produces at least one desired result.
- a "subject” or “patient” to be treated by a method of the invention may mean either a human, or non-human animal, preferably a mammal.
- treating refers to mitigating or alleviating at least one symptom of a condition, disease or disorder in a mammal, such as a human, or the improvement of an ascertainable measurement associated with a condition, disease or disorder.
- metadoxine can serve for the treatment of any inflammatory disorder in which the immune system plays a role and which is either cytokine-mediated or cell mediated.
- cytokine-mediated or cell mediated include but not limited: any Thl- or Th2-mediated disorder, and T cell or B cell, or dendritic cells, or any other cell of the immune system-mediated disease.
- Modulation of the Thl/Th2 balance towards an anti-inflammatory Th2 response may be particularly applicable in immune related disorders having an undesired unbalanced pro-inflammatory Thl reaction.
- immune-related disorders may be an autoimmune disease, graft rejection pathology, inflammatory disease, non-alcoholic fatty liver disease, hyperlipidemia, atherosclerosis, Metabolic Syndrome or any of the conditions comprising the same.
- This metadoxine may be administered to a subject to treat or prevent disorders associated with an abnormal or unwanted immune response associated with cell, tissue or organ transplantation, e.g., renal, hepatic, and cardiac transplantation, e.g., graft versus host disease (GVHD), or to prevent allograft rejection.
- disorders associated with an abnormal or unwanted immune response associated with cell, tissue or organ transplantation e.g., renal, hepatic, and cardiac transplantation, e.g., graft versus host disease (GVHD), or to prevent allograft rejection.
- GVHD graft versus host disease
- immune-related disorders to be treated with metadoxine in accordance with the invention may be autoimmune disease, graft rejection pathology, inflammatory disease, non-alcoholic fatty liver disease, hyperlipidemia, atherosclerosis, Metabolic Syndrome or any of the conditions comprising the same.
- autoimmune disorders to be treated with metadoxine in accordance with the invention include, but are not limited to, Alopecia Areata, Lupus Erythematosus, Ankylosing Spondylitis, Meniere's Disease, Antiphospholipid Syndrome, Mixed Connective Tissue Disease, Autoimmune Addison's Disease, Multiple Sclerosis, Autoimmune Hemolytic Anemia, Myasthenia Gravis, Autoimmune Hepatitis, Pemphigus Vulgaris, Behcet's Disease, Pernicious Anemia, Bullous Pemphigoid, Polyarteritis Nodosa, Cardiomyopathy, Polychondritis, Celiac Sprue- Dermatitis, Polyglandular Syndromes, Chronic Fatigue Syndrome (CFIDS), Polymyalgia Rheumatica, Chronic Inflammatory Demyelinating, Polymyositis and Dermatomyositis, Chronic Inflammatory Polyneuropathy, Primary Agammaglobulinemia, Churg-Straus
- the present invention provides a kit for treating an immunerelated disease III a subject in need thereof, said kit compnsmg: (a) metadoxine or a composition comprising metadoxine; (b) means for administering said metadoxine or composition; and (c) instructions for use.
- mice Ten weeks old, male C57B1/6 mice were obtained from Jackson Harlan Laboratories, Jerusalem, Israel (http://www.harlanisrael.com) and maintained in the Animal Core of the Hadassah-Hebrew University Medical School. Mice were administered standard laboratory chow and water ad libitum, and kept in 12-hour light/dark cycles. Animal experiments were carried out according to the guidelines of the Hebrew University-Hadassah Institutional Committee for Care and Use of Laboratory Animals, and with the committee's approval.
- Concanavalin A (MP Biomedicals, USA) was dissolved in 50mM Tris pH 7, 150mM NaCl, 4mM CaCl 2 and injected into the tail vein at a dose of 500 ⁇ g/mouse (20mg/kg).
- the first group (A) was treated with PBS served as controls and the second (B) with Metadoxine
- Serum AST and ALT levels were measured by an automatic analyzer.
- Serum IFN- ⁇ levels were measured in each animal by "sandwich” ELISA, using commercial kits (Quantikine, R&D Systems, MN, USA).
- Group A DDW
- Group B Metadoxine
- Metadoxine had a profound anti-inflammatory effect in the immune-mediated Con A hepatitis model.
- Example 2 Effect of Pyridoxal L-2-pyrrolidone-5-carboxylate on Nitric Oxide and cytokine IL-l-beta secretion following LPS induction in mouse macrophage cells
- pyridoxal L-2-pyrrolidone-5-carboxylate referred to as "pyridoxal”
- RW 264.7 macrophage murine cellular system
- LPS Lipopolysaccharide
- IL-lbeta is a pro-inflammatory cytokine and is expressed by many cells including macrophage, NK cells, monocytes, and neutrophils. Inflammatory hypersensitivity has been found to be the result of IL- ⁇ activation of cyclooxygenase-2 (PTGS2/COX2). IL-lbeta has also been associated with septic shock, and wound healing. IL-l-beta levels were assessed using a commercial ELISA kit.
- Nitric oxide is generated by phagocytes (monocytes, macrophages, and neutrophils) as part of the human immune response. Phagocytes are armed with inducible nitric oxide synthase (iNOS), which is activated by IFN- ⁇ as a single signal or by tumor necrosis factor along with a second signal. NO production was measured by Griess reagent which detects the nitrite (N02) production. The minimum dose (0.003 mg/ml) of pyridoxal was calculated according to the following calculation:
- Human dose/amount of fluid in average human body amount of compound per ml of fluid.
- the average human body contains 6 liters, or 6000 ml of fluid.
- the dose given to humans in clinical trials (for treatment of alcohol intoxication) was 20 mg/kg, the therapeutic dose per ml is 0.003 mg/ml. Since this was an exploratory study, this dose was determined as the minimum concentration, with higher concentrations being 10 and 100 fold this minimum dose.
- EAE Experimental Autoimmune Encephalomyelitis
- the rodent species is the CB57/BLJ female mouse. Healthy adult animals (10 weeks old) are employed, with a total of 36 mice, divided into 3 groups. All three groups are immunized with an emulsion containing 300 ⁇ g of Myelin Oligodendrocyte Glycoprotein and an equal amount of Freund's adjuvant, with one group being treated with Metadoxine, the second one is treated with Pyridoxal and the third one is treated with the vehicle (the control group).
- mice are treated with their respective compound from day 1 (in conjunction with the CNS protein injection) until the study is terminated due to morbidity or until the last day of the study (day 42).
- the study endpoints are mortality and mobility observations as well as measurements of neurological scores (tail tonicity, hind leg weakness/paralysis).
- BSA Body Surface Area
- mice would be the equivalent of the dose given in humans to treat alcohol intoxication, however, since this is the first in vivo experiment carried out for treatment of inflammation with these compounds, a twofold dose of 500 mg/kg/day per mouse will be used in order to obtain an effect if one is indeed present. Higher doses are not recommended in order to avoid potential toxicity issues which may affect study outcome.
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WO2019102341A1 (en) * | 2017-11-21 | 2019-05-31 | Laboratori Baldacci S.P.A. | Use of metadoxine as hepatoprotector in the treatment of hepatic toxicity induced in patients treated with methotrexate |
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