EP2155181A1 - Polythérapie à base de 5-htp - Google Patents

Polythérapie à base de 5-htp

Info

Publication number
EP2155181A1
EP2155181A1 EP07776982A EP07776982A EP2155181A1 EP 2155181 A1 EP2155181 A1 EP 2155181A1 EP 07776982 A EP07776982 A EP 07776982A EP 07776982 A EP07776982 A EP 07776982A EP 2155181 A1 EP2155181 A1 EP 2155181A1
Authority
EP
European Patent Office
Prior art keywords
hydroxytryptophan
administered
composition
amount
htp
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07776982A
Other languages
German (de)
English (en)
Other versions
EP2155181A4 (fr
Inventor
Connie Sanchez Morillo
Toni D. Wolinsky
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
H Lundbeck AS
Original Assignee
H Lundbeck AS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by H Lundbeck AS filed Critical H Lundbeck AS
Publication of EP2155181A1 publication Critical patent/EP2155181A1/fr
Publication of EP2155181A4 publication Critical patent/EP2155181A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • 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
    • A61K31/403—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 condensed with carbocyclic rings, e.g. carbazole
    • 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
    • A61K31/403—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 condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to combination therapies and pharmaceutical compositions comprising a combination of 5-hydroxytryptophan and a serotonin reuptake inhibitor with improved efficacy.
  • 5-hydroxytryptophan is the direct precursor to serotonin (5- hydroxytryptamine; 5-HT). In vivo, 5-HTP is decarboxylated to produce 5- HT. 5-HT levels in the brain are dependent on levels of 5-HTP in the central nervous system (CNS). No transport molecules are necessary to transport 5-HTP across the blood-brain barrier. 5-HTP has been clinically shown to increase production of serotonin in the brain and therefore 5-HTP administration has been suggested as a treatment for patients with mild or moderate depression (for review, see Meyers, S., A/tern Med Rev. 2000 Feb. 5(1):64-71; and Birdsall, T.C., Altern Med Rev. 1998 Aug; 3(4):271- 80).
  • Serotonin reuptake inhibitors have become first choice therapeutics in the treatment of affective disorders, especially depression, because they are effective, well tolerated and have a favorable safety profile compared to the classic tricyclic antidepressants.
  • 5-HTP monotherapy has been associated with gastrointestinal (nausea, vomiting, diarrhea) and psychopathological (acute anxiety state, hypomania) side effects in open studies with human patients (Zmilacher, K., Battegay, R. and Gastpar, M., Neuropsychobiology. 1988, 20(1):28-35; Gijsman, H.J., et al., J Clin Psychopharmacot. 2002 Apr, 22(2): 183-9).
  • 5-HTP administration has been implicated as a possible cause of Eosinophilia-Myalgia Syndrome (for review, see Das, Y.T., et al., Toxicol Lett. 2004 Apr 15; 150(1):111-22.).
  • One approach to managing these risks of side effects may be to lower the dose of 5-HTP.
  • SRIs SRI-associated side effects to be balanced against the known benefits of SRIs and to be managed may include sexual dysfunction and sleep disturbances. Many patients experience delayed onset of a therapeutic effect during SRl monotherapy. Further clinical studies on depression and anxiety disorders indicate that more than 30% of patients treated with SRI monotherapy as a class are non-responsive.
  • patients may benefit from administration of a lower dose of 5-HTP.
  • Patients may also benefit from administration of a lower dose of an SRI.
  • patients that do not respond to SRIs may benefit from a combination therapy of an SRI and 5-HTP.
  • Such combination therapy includes lower doses of either SRI or 5-HTP, yet may achieve greater efficacy or earlier onset of therapeutic effect than with SRI or 5-HTP monotherapy.
  • An objective of the present invention is to provide a pharmaceutical composition comprising (i) 5-hydroxytryptophan in an amount ranging from about 1 mg to about 75 mg; and (ii) a serotonin reuptake inhibitor.
  • Another objective of the present invention also is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising (i) a subclinical dose of a serotonin reuptake inhibitor; and (ii) 5-hydroxytryptophan.
  • Another objective of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising (i) a serotonin reuptake inhibitor and (ii) 5- hydroxytrytophan.
  • FIG. 1 Effect of escitalopram and fluoxetine alone and in combination with 5-HTP on extra-cellular 5-HT in frontal cortex in freely moving rats.
  • 5- HTP 25 mg/kg, s.c.
  • escitalopram 0.5 mg/kg s.c.
  • fluoxetine 10 mg/kg, s.c.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising 5-hydroxytryptophan and a serotonin reuptake inhibitor.
  • subclinical dose shall mean a dose in an amount less than the lowest dose that is approved as a monotherapy for marketing by a governmental regulatory agency as of the priority filing date of this application.
  • allosteric modulator shall mean an SRI that has a Z- factor of greater than 0 (zero), which shall be determined by the method described herein.
  • serotonin dual action compound shall mean a compound that both 1) binds to the primary binding site of the serotonin transporter having an IC 50 value of less than about 50 nM, and 2) binds to an allosteric site of the serotonin transporter having a Z-factor greater than zero (0), as determined by the methods described herein.
  • the serotonin dual action compound further binds to the primary binding site of the serotonin transporter having an IC50 value of less than about 10 nM.
  • 5-hydroxytryptophan (5-HTP) is an aromatic amino acid naturally produced in the body from amino acid L-tryptophan. 5-HTP is the direct precursor to 5-HT. The formula of 5-HTP is shown below as Formula I.
  • 5-HTP is also known as 2-amino-3-(5-hydroxy-1 H-indol-3-yl)-propanoic acid (C 11 H 12 N 2 O 3 ).
  • 5-HTP 2-amino-3-(5-hydroxy-1 H-indol-3-yl)-propanoic acid
  • 5-HTP 2-amino-3-(5-hydroxy-1 H-indol-3-yl)-propanoic acid
  • such salts may be formed with pharmaceutically acceptable bases, particularly strong bases such as sodium potassium or ammonium hydroxide.
  • Such salts of 5-HTP may also be formed with pharmaceutically acceptable acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, maleic acid, oxalic acid, tartaric acid and the like.
  • 5-HTP may be used in the form of an acid addition salt, or in the form of a zwitter ion hydrate, zwitter ion monohydrate, or zwitter ion anhydrate.
  • 5-HTP may be in a racemic mixture or as the substantially pure D-enantiomer, D-5-hydroxytryptophan, or as the substantially pure L-enantiomer, L-5-hydroxytryptophan.
  • One aspect of the present invention relates to a pharmaceutical composition comprising 5-HTP for use in a combination therapy with an SRI.
  • Another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising (i) 5-hydroxytryptophan in an amount ranging from about 1 mg to about 75 mg; and (ii) a serotonin reuptake inhibitor.
  • 5-HTP may be used to augment and/or provide an earlier onset of the therapeutic effect of serotonin reuptake inhibitors. Further, as part of the present invention, lower doses of 5-HTP when used in combination therapy may augment and/or provide an earlier onset of the therapeutic effect of an SRI.
  • 5-HTP in an amount ranging from about 1 mg to about 75 mg is coadministered with an SRI. In another embodiment of the invention, 5-HTP in an amount ranging from about 3 mg to about 50 mg is coadministered with an SRI. In still another embodiment of the invention, 5-HTP in an amount ranging from about 10 mg to about 50 mg is coadministered with an SRI.
  • augmenting shall mean improving the therapeutic effect and/or potentiating the effect of an SRI.
  • Any pharmacologically active compound which primarily or partly exerts its therapeutic effect by binding to the primary ligand binding site of the serotonin transporter to inhibit serotonin reuptake in the central nervous system (CNS), may benefit from augmentation with 5-HTP.
  • the following list contains a number of serotonin reuptake inhibitors which may benefit from augmentation or combined administration with 5-HTP: citalopram, escitalopram, fluoxetine, R-fluoxetine, sertraline, paroxetine, fluvoxamine, venlafaxine, duloxetine, dapoxetine, nefazodone, imipramine, imipramine N-oxide, desipramine, pirandamine, dazepinil, nefopam, befuraline, fezolamine, femoxetine, clomipramine, cianoimipramine, litoxetine, cericlamine, seproxetine, WY 27587, WY 27866, imeldine, ifoxetine, tiflucarbine, viqualine, milnacipran, apelinaprine, YM 922, S 33005, F 98214-TA, OPC 14523, alaproclate, cyano
  • the serotonin reuptake inhibitor is selected from citalopram, escitalopram, fluoxetine, sertraline, paroxetine, fluvoxamine, venlafaxine, duloxetine, dapoxetine, nefazodone, imipramine, femoxetine and clomipramine or a pharmaceutically acceptable salt of any of these compounds.
  • SSRI selective serotonin reuptake inhibitor
  • the SRI may be an SSRI such as citalopram, escitalopram, fluoxetine, fluvoxamine, sertraline, or paroxetine.
  • citalopram is in the form of the racemate, or racemic mixture of the R-(-)-enantiomer (R-citalopram) and the S-(+)-enantiomer (S- citalopram).
  • S-citalopram also known as escitalopram
  • escitalopram is the pure enantiomer.
  • the IUPAC name for escitalopram is S-(+)-1-[3- (dimethylamino)propyl]-1-(p-fluorophenyl)-5-phthalancarbonitrileoxalate.
  • paroxetine is the pure enantiomer.
  • the IUPAC name for paroxetine is (3S 1 4ft)-3-( ⁇ 1,3-benzodioxol-5-yloxy)methyl)-4-(4- fluorophenyl)-piperidine.
  • the compounds mentioned above may be used in the form of the free base or in the form of a pharmaceutically acceptable salt, such as an acid addition salt, the latter being obtainable by a reaction of the base form with an appropriate acid.
  • a pharmaceutically acceptable salt such as an acid addition salt, the latter being obtainable by a reaction of the base form with an appropriate acid.
  • citalopram may be used in the form of the hydrobromide or the free base; escitalopram in the form of the oxalate, hydrobromide, or the free base; fluoxetine and sertraline in the form of the hydrochloride; paroxetine in the form of the hydrochloride or the mesylate; and fluvoxamine in the form of the maleate.
  • the SRI may be an allosteric modulator.
  • allosteric modulator shall mean an SRI that has a Z- factor of greater than 0 (zero), which shall be determined by the method described herein.
  • the allosteric modulator may be selected from escitalopram and paroxetine.
  • the SRI may be a serotonin dual action compound.
  • a "serotonin dual action compound” shall mean a compound that both 1) binds to the primary binding site of the serotonin transporter having an IC 50 value of less than about 50 nM, and 2) binds to an allosteric site of the serotonin transporter having a Z-factor greater than zero (0), as determined by the methods described herein.
  • the serotonin dual action compound further binds to the primary binding site of the serotonin transporter having an IC 5 0 value of less than about 10 nM.
  • the serotonin dual action compound may be selected from escitalopram and paroxetine.
  • the combination of 5-HTP with an SRI unexpectedly shows a synergistic effect on the central nervous system.
  • lower doses of 5-HTP than normally used in monotherapy may be used in combination with a dose of serotonin reuptake inhibitor normally used in monotherapy to augment the 5-HT output and thereby may provide an earlier onset of the therapeutic effect of serotonin reuptake inhibitors.
  • the amount of 5-HTP to be used in combination therapy may range from about 1 to about 75 mg per day, such as from about 3 to about 50 mg per day, or from about 10 to about 50 mg per day.
  • Pharmaceutical compositions of the present invention may therefore comprise from about 1 to about 75 mg, such as from about 3 to about 50 mg, or from about 10 to about 50 mg 5-HTP.
  • Serotonin reuptake inhibitors, and serotonin dual action compounds differ both in molecular weight and in activity.
  • the amount of serotonin reuptake inhibitor or serotonin dual action compound used in combination therapy depends on the nature of said serotonin reuptake inhibitor.
  • the serotonin reuptake inhibitor, serotonin dual action compound, SSRI or allosteric modulator is administered in a therapeutically effective amount.
  • the pharmaceutical composition contains a therapeutically effective amount of escitalopram. In a further embodiment of the invention, the pharmaceutical composition contains from 5 mg to 30 mg of escitalopram. Also included in the present invention is the administration of such pharmaceutical compositions to a patient in need thereof, so that the daily dose ranges of escitalopram are 5 mg to 30 mg per day.
  • the pharmaceutical composition contains a therapeutically effective amount of paroxetine. In a further embodiment of the invention, the pharmaceutical composition contains from 10 mg to 60 mg of paroxetine. Also included in the present invention is the administration of such pharmaceutical compositions to a patient in need thereof, so that the daily dose ranges of paroxetine are 10 mg to 60 mg per day.
  • combination therapy using 5-HTP with a subclinical dose of an SRI normally used in monotherapy may have the advantage that a beneficial central nervous system effect may be obtained in the large number of patients that do not respond to conventional monotherapy with SRIs.
  • subclinical doses of an SRI may be used in combination with 5-HTP to augment and/or provide an earlier onset of the therapeutic effect of the SRI.
  • combination therapy using 5-HTP with a subclinical dose of serotonin reuptake inhibitor may be used to augment the therapeutic effect and/or to reduce side-effects associated with larger amounts of SRI used in monotherapy.
  • one aspect of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising (i) a subclinical dose of a serotonin reuptake inhibitor; and (N) 5-hydroxytryptophan.
  • subclinical dose shall mean a dose in an amount less than the lowest dose that is approved as a monotherapy for marketing by a governmental regulatory agency as of the priority filing date of this patent application.
  • amount of 5-HTP to be used in combination therapy may range from about 1 mg to about 600 mg per day, such as from about 25 mg to about 300 mg per day, or from about 50 mg to about 200 mg per day.
  • Pharmaceutical compositions of the present invention may therefore comprise from about 1 mg to about 600 mg, such as from about 25 mg to about 300 mg, or from about 50 mg to about 200 mg 5-HTP.
  • the serotonin reuptake inhibitor is selected from citalopram, escitalopram, fluoxetine, sertraline, paroxetine, fluvoxamine, venlafaxine, duloxetine, dapoxetine, nefazodone, imipramine, femoxetine and clomipramine or a pharmaceutically acceptable salt of any of these compounds.
  • the SRI may be an SSRI, such as citalopram, escitalopram, fluoxetine, fluvoxamine, sertraline, or paroxetine.
  • the SRI may be an allosteric modulator.
  • the allosteric modulator may be selected from escitalopram and paroxetine.
  • the SRI may be a serotonin dual action compound.
  • the serotonin dual action compound may be selected from escitalopram and paroxetine.
  • one embodiment of the present invention includes a pharmaceutical composition comprising a subclinical dose of an allosteric modulator and 5-HTP, wherein the composition comprises 5-HTP in an amount ranging from about 1 mg to about 600 mg, from about 25 mg to about 300 mg, or from about 50 mg to about 200 mg.
  • Another embodiment includes a pharmaceutical composition comprising a subclinical dose of a serotonin dual action compound and 5-HTP, wherein the composition comprises 5-HTP in an amount ranging from about 1 mg to about 600 mg, from about 25 mg to about 300 mg, or from about 50 mg to about 200 mg. Also included in the present invention is the administration of such pharmaceutical compositions to a patient in need thereof, so that the daily dose ranges are from about 1 mg to about 600 mg per day, or about 25 mg to about 300 mg per day, or about 50 mg to 200 mg per day
  • the pharmaceutical composition comprises a subclinical dose of escitalopram.
  • the pharmaceutical composition may comprise escitalopram in an amount less than 5 mg.
  • the pharmaceutical composition comprises escitalopram in an amount less than 5 mg and 5-HTP in an amount ranging from about 1 mg to about 600 mg. In another embodiment of the invention, the pharmaceutical composition comprises escitalopram in an amount less than 5 mg and 5-HTP in an amount ranging from about 25 mg to about 300 mg. In still another embodiment of the invention, the pharmaceutical composition comprises escitalopram in an amount less than 5 mg and 5-HTP in an amount ranging from about 50 mg to about 200 mg. In a further embodiment of the invention, the pharmaceutical composition comprises escitalopram in an amount from about 0.1 mg to about 4.9 mg. In another embodiment, the pharmaceutical composition comprises escitalopram in an amount from about 0.5 mg to about 4.5 mg. In still another embodiment, the pharmaceutical composition comprises escitalopram in an amount from about 1 mg to about 4 mg.
  • the pharmaceutical composition comprises a subclinical dose of paroxetine. In one aspect of the invention, the pharmaceutical composition comprises paroxetine in an amount less than 10 mg.
  • the pharmaceutical composition comprises paroxetine in an amount less than 10 mg and 5-HTPin an amount ranging from about 1 mg to about 600 mg. In another embodiment of the invention, the pharmaceutical composition comprises paroxetine in an amount less than 10 mg and 5-HTPin an amount ranging from about 25 mg to about 300 mg. In still another embodiment of the invention, the pharmaceutical composition comprises paroxetine in an amount less than 10 mg and 5-HTP in an amount ranging from about 50 mg to about 200 mg.
  • the pharmaceutical composition comprises paroxetine in an amount from about 0.1 mg to about 9.9 mg. In another embodiment, the pharmaceutical composition comprises paroxetine in an amount from about 0.5 mg to about 9.5 mg. In still another embodiment, the pharmaceutical composition comprises paroxetine in an amount from about 1 mg to about 9 mg.
  • Another aspect of the present invention relates to a pharmaceutical composition comprising (i) a serotonin reuptake inhibitor; and (ii) 5- hydroxytryptophan.
  • the amount of 5-HTP to be used in combination therapy may range from about 1 mg to about 600 mg per day, such as from about 25 mg to about 300 mg per day, or from about 50 mg to about 200 mg per day.
  • Pharmaceutical compositions of the present invention may therefore comprise from about 1 mg to about 600 mg, such as from about 25 mg to about 300 mg, or from about 50 mg to about 200 mg 5-HTP.
  • the serotonin reuptake inhibitor is selected from citalopram, escitalopram, fluoxetine, sertraline, paroxetine, fluvoxamine, venlafaxine, duloxetine, dapoxetine, nefazodone, imipramine, femoxetine and clomipramine or a pharmaceutically acceptable salt of any of these compounds.
  • the SRI may be an SSRI, such as citalopram, escitalopram, fluoxetine, fluvoxamine, sertraline, or paroxetine.
  • the SRI may be an allosteric modulator.
  • the allosteric modulator may be selected from escitalopram and paroxetine.
  • the SRI may be a serotonin dual action compound.
  • the serotonin dual action compound may be selected from escitalopram and paroxetine.
  • one embodiment of the present invention includes a pharmaceutical composition comprising an allosteric modulator and 5-HTP, wherein the composition comprises 5-HTP in an amount ranging from about 1 mg to about 600 mg, from about 25 mg to about 300 mg, or from about 50 mg to about 200 mg. Also included in the present invention is the administration of such pharmaceutical compositions to a patient in need thereof, so that the daily dose ranges are from about 1 mg to about 600 mg per day, or about 25 mg to about 300 mg per day, or about 50 mg to 200 mg per day
  • the pharmaceutical composition comprises escitalopram.
  • the pharmaceutical composition may comprise escitalopram in an amount ranging from about 5 mg to about 30 mg.
  • the pharmaceutical composition comprises escitalopram in an amount from about 5 mg to about 30 mg and
  • the pharmaceutical composition comprises escitalopram in an amount from about 5 mg to about 30 mg and 5-HTP in an amount ranging from about 25 mg to about 300 mg. In still another embodiment of the invention, the pharmaceutical composition comprises escitalopram in an amount ranging from about 5 mg to about 30 mg and 5-HTP
  • the pharmaceutical composition comprises paroxetine. In one aspect of the invention, the pharmaceutical composition comprises paroxetine in an amount ranging from about 10 mg to about 60 mg.
  • the pharmaceutical composition comprises paroxetine in an amount from about 10 mg to about 60 mg and 5-HTP in an amount ranging from about 1 mg to about 600 mg. In another embodiment of the invention, the pharmaceutical composition comprises paroxetine in an amount from about 10 mg to about 60 mg and 5-HTP in an amount ranging from about 25 mg to about 300 mg. In still another embodiment of the invention, the pharmaceutical composition comprises paroxetine in an from about 10 mg to about 60 mg and 5-HTP in an amount ranging from about 50 mg tp about 200 mg.
  • Aromatic amino acid decarboxylases that degrade 5-HTP to serotonin are widely distributed throughout the body.
  • a peripheral decarboxylation inhibitor can be administered in combination with 5-HTP to prevent the degradation of 5-HTP to serotonin.
  • the pharmaceutical composition may further comprise a peripheral decarboxylation inhibitor.
  • Peripheral decarboxylation inhibitors include, but are not limited to, carbidopa, L- ⁇ -methyldopa, monofluoromethyldopa, difluoromethyldopa and benserazide.
  • compositions of the present invention may contain carbidopa in an amount ranging from about 100 mg to about 150 mg.
  • the pharmaceutical compositions described herein may be administered in any suitable way, e.g. orally or parentally, and it may be presented in any suitable form for such administration, e.g. in the form of tablets, capsules, powders, syrups or solutions or dispersions for injection.
  • the composition is administered in the form of a solid pharmaceutical entity, suitably as a tablet or a capsule or in the form of a suspension, solution or dispersion for injection.
  • tablets may thus be prepared by mixing the active ingredients with ordinary adjuvants and/or diluents and subsequently compressing the mixture in a convenient tabletting machine.
  • adjuvants or diluents comprise: com starch, lactose, talcum, magnesium stearate, gelatin, gums, and the like.
  • Other adjuvants or additives such as colorings, aroma, preservatives, etc. may also be used provided that they are compatible with the active ingredients.
  • the pharmaceutical compositions can be administered as part of the claimed invention as an oral dose form, such as a solid dose form, typically tablets or capsules, or as a liquid oral dose form.
  • the pharmaceutical compositions described herein are most conveniently administered in unit dosage forms such as tablets or capsules.
  • such tablets or capsules may contain 5-HTP in amounts ranging from about 1 to about 600 mg, or from about 25 mg to about 300 mg, or from about 10 to 50 mg.
  • a pharmaceutically acceptable carrier which can take a wide variety of forms depending on the form desired for administration.
  • Those pharmaceutical compositions may be in unitary dosage form suitable for administration orally, rectally, percutaneously, or by parenteral injection.
  • any of the usual pharmaceutical media such as water, glycols, oils, alcohols, and the like, may be incorporated in the form of oral liquid preparations.
  • Oral liquid preparations may be suspensions, syrups, elixirs, and solutions.
  • any of the usual pharmaceutical media such as starches, sugars, kaolin, lubricants, binders, disintegrating agents, and the like, may be incorporated in the form of solid carriers.
  • Oral solid preparations may be powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage form, in which case solid pharmaceutical carriers would be employed.
  • unitary dosage form means physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of 5-HTP and/or serotonin reuptake inhibitor calculated to produce the desired therapeutic effect, in association with the required pharmaceutical carrier.
  • unitary dosage forms are tablets (including scored coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, and the like, and combinations thereof.
  • 5-HTP may be administered before, during or after the administration of the SRI provided that the time between administration of 5-HTP and the administration of the SRI is such that ingredients are allowed to act synergistically on the central nervous system.
  • a single composition containing both an SRI and 5-HTP may be particularly convenient.
  • the serotonin reuptake inhibitor and 5-HTP may be administered separately in the form of suitable compositions.
  • Such pharmaceutical compositions may further comprise a peripheral decarboxylation inhibitor.
  • the compositions may be prepared as described hereinabove.
  • such compositions may comprise an SRI and a peripheral decarboxylation inhibitor, such as carbidopa.
  • compositions may comprise 5-HTP and a peripheral decarboxylation inhibitor, such as carbidopa.
  • a peripheral decarboxylation inhibitor such as carbidopa.
  • Such compositions may be administered simultaneously, such as in a single tablet, and the like, or may be administered separately, such as in separate compositions or tablets, and the like.
  • the present invention also comprises 5-HTP and an SRI as a combination preparation for simultaneous, separate or sequential use in psychiatric drug therapy.
  • Such compositions may comprise, for example, a kit comprising discrete unit dosage forms containing 5-HTP and discrete unit dosage forms of an SRI, all contained in the same container or pack, e.g. a blister pack.
  • Such pharmaceutical compositions may further comprise a peripheral decarboxylation inhibitor.
  • the invention relates to a kit comprising a subclinical dose of an SRI and 5-HTP. In some embodiments, the invention relates to a kit comprising a subclinical dose of serotonin reuptake inhibitor and 5-HTP in an amount ranging from about 1 mg to about 600 mg, in an amount ranging from about 25 mg to about 300 mg or in an amount ranging from about 50 mg to about 200 mg.
  • the invention relates to a kit comprising an SRI and 5-HTP in an amount ranging from about 1 mg to about 75 mg, in an amount ranging from about 3 mg to about 50 mg or in an amount ranging from about 10 mg to about 50 mg.
  • the invention relates to a kit comprising an SRI and 5-HTP.
  • the invention relates to a kit comprising an SRI and 5-HTP in an amount ranging from about 1 mg to about 600 mg, in an amount ranging from about 25 mg to about 300 mg or in an amount ranging from about 50 mg to about 200 mg.
  • the invention relates to the pharmaceutical compositions as described herein comprising 5-HTP and an SRI for use in combination therapy for the treatment of affective disorders.
  • the invention relates to the pharmaceutical compositions as described herein comprising 5-HTP and an SRI for use in combination therapy for the treatment of depression.
  • the present invention relates to the pharmaceutical compositions as described herein comprising 5-HTP and an SRI for use in combination therapy for the treatment of anxiety disorders.
  • Such pharmaceutical compositions may further comprise a peripheral decarboxylation inhibitor.
  • the invention relates to the use of 5-HTP for the preparation of a pharmaceutical composition to be used in combination with an SRI.
  • the invention relates to the use of 5-HTP for the preparation of a pharmaceutical composition useful for augmenting and/or providing an earlier onset of the therapeutic effect of an SRI.
  • the invention relates to a method of treatment of diseases or disorders responsive to an SRI, comprising administering 5- HTP and an SRI to a human patient in need thereof.
  • a further aspect of the invention relates to use of 5-HTP and an SRI for the preparation of a pharmaceutical composition for the treatment of diseases or disorders responsive to the therapeutic effect of an SRI.
  • the invention relates to use of 5-HTP for the preparation of a pharmaceutical composition for the treatment of an individual to be treated with or undergoing treatment with an SRI, wherein said individual suffers from diseases or disorders responsive to the therapeutic effect of an SRI.
  • the invention relates to use of 5-HTP for the preparation of a kit for the treatment of an individual to be treated with or undergoing treatment with an SRI, wherein said individual suffers from diseases or disorders responsive to the therapeutic effect of an SRI.
  • the invention relates to a method for augmenting and/or providing an earlier onset of the therapeutic effect of an SRI comprising administering 5-HTP to a human patient to be treated with or undergoing treatment with an SRI.
  • the pharmaceutical compositions as described herein are used in the treatment of depression, anxiety disorders and other affective disorders, eating disorders such as bulimia, anorexia and obesity, phobias, dysthymia, premenstrual syndrome, cognitive disorders, impulse control disorders, attention deficit hyperactivity disorder, and drug abuse, in particular depression.
  • the pharmaceutical compositions as described herein are used in the treatment of anxiety disorders includes general anxiety disorder, panic anxiety, obsessive compulsive disorder, acute stress disorder, post trauma stress disorder, or social anxiety disorder.
  • mice Male NMRI/BOM mice (18-25 g; Bomholtgaard, Denmark) were used. The mice were housed in plastic cages (35 x 30 x 12 cm), 10 in each and habituated to the animal facilities for at least a week before test. The room temperature (21 +/- 2° C), relative humidity (55 +/- 5%), and air exchange (16 times per h) were automatically controlled. The animals had free access to commercial food pellets and tap water before test.
  • a mouse that is forced to swim in a spatially constrained container will exert a characteristic immobile posture. Pretreatment with an antidepressant will counteract this effect.
  • the test was conducted as described in detail by Sanchez and Meier (Psychopharmacol. 129: 197- 205; 1997). Briefly, a fully automated test system with 6 swim units (2000 ml glass jars filled with 1200 ml soiled water (23 - 25° C) in which a mouse had been placed previously) was used. The assessment of immobility was performed by image analysis.
  • mice Thirty minutes after drug or vehicle treatment the mice were treated with 5- HTP and 20 min later the mice were placed into the glass jar and left in the water for a total of 6 min. The accumulated duration of immobility was measured during the last 3 min. A total of 9-18 mice were tested per dose.
  • Microdialysis in freely moving rats was performed as described in detail by M ⁇ rk, A., Kreilgaard, M. and Sanchez, C. ⁇ Neuropharmacology. 2003 Aug, 45(2): 167-73) to study the effect of escitalopram and fluoxetine alone, and in combination with 5-HTP (25 mg/kg, s.c.) on extracellular serotonin levels.
  • a microdialysis probe was inserted through the guide cannula.
  • Perfusion of the microdialysis probe with filtered Ringer solution 146 mM NaCI, 3 mM KCI, 1 mM MgCI 2 , 1.2 mM CaCI 2
  • test compound escitalopram 0.5 mg/kg, s.c. or fluoxetine 10 mg/kg s.c.
  • 5-HTP 25 mg/kg, s.c.
  • mice Male BALB/cByJ mice (Jackson labs, Bar Harbor, ME) were housed 5/cage upon arrival, at which time they were 7-8 weeks of age. Animals acclimated to the housing facility under standard laboratory conditions for a period of at least one week before testing (lights on at 6:00 AM).
  • mice Following a one hour period of acclimation to the test room, animals were dosed with either vehicle (saline) or escitalopram (0.0625, 0.125, or 0.25 mg/kg, i.p.) Thirty minutes later, animals received an injection of vehicle or 5-HTP (2.5 mg/kg, i.p.). Fifteen minutes after the second injection, animals were individually placed into novel cages in which a layer of Aspen Pine bedding on which two parallel rows of 10 marbles each (i.e. twenty total) were placed. After 30 minutes had elapsed, the mice were removed from their test cages and returned to their home cages. The number of fully visible marbles (less than 2/3 covered with bedding) were counted and subtracted from 20 to arrive at the number of marbles buried.
  • vehicle saline
  • 5-HTP 2.5 mg/kg, i.p.
  • the content of radioactivity is determined by liquid scintillation counting (cpm).
  • Uptake is obtained by subtracting the non-specific binding and passive transport measured in the presence of 10 ⁇ M test compound. The measured cpm is plotted against test compound concentration, and the best fitting s-shaped curve is drawn. The uptake inhibitory potencies are expressed as IC 5 O values in nM (logarithmic means). Two full concentration-response curves can be measured using five concentrations of test compound in triplicate. The IC 5 O value is determined as the concentration at which the uptake is 50% of the total uptake in control samples minus the non-specific binding and uptake in the presence of 10 ⁇ M test compound.
  • a serotonin reuptake inhibitor that binds with high affinity at the serotonin transporter primary binding site, i.e. has stronger uptake inhibitory potency, is determined by the above test as a compound having an ICso value less than about 50 nM.
  • SRIs that bind to the primary binding site of the serotonin transporter having an IC50 value of less than about 10 nM have even stronger uptake inhibitory potency. Allosteric Modulation Of The Serotonin Transporter
  • the allosteric site of a protein is an additional binding site, which is distinct from the primary ligand binding site.
  • Compounds that modulate, for instance increase and/or stabilize, binding between the ligand and the ligand binding site are generally considered to operate through an allosteric mechanism.
  • the serotonin transporter is considered to have at least two separate binding sites: a primary, high-affinity binding site that mediates the inhibition of serotonin reuptake, and one or more low-affinity binding sites that allosterically modulate the binding of ligands at the primary site (Plenge, P., and Mellerup, E.T. Eur J Pharmacol. 1985 Dec 10; 119(1-2):1-8; Wennogle, L.P. and Meyerson, L.R. Life ScL 1985 Apr 22; 36(16): 1541 -50).
  • escitalopram The binding of escitalopram to an allosteric binding site on the SERT has been demonstrated in several studies. Studies of the interaction of escitalopram with the human serotonin transporter expressed in COS-1 cell membranes demonstrated that escitalopram binds to a secondary low- affinity allosteric site and retards the dissociation rate of 3 H-escitalopram (used in a concentration that exclusively binds to the high-affinity primary site) from the transporter; that is, escitalopram appears to have a stabilizing / self-potentiating effect on the escitalopram:serotonin transporter complex. The effect of escitalopram is concentration-dependent (Chen, F., et al., Eur Neuropsychopharmacol. 2005 Mar; 15(2):193-8).
  • paroxetine In addition to escitalopram, the interaction of paroxetine, sertraline, fluoxetine, venlafaxine, duloxetine, and serotonin with high- and low-affinity binding sites on the human serotonin transporter expressed in COS-1 cell membranes has been investigated (Chen, F., et al., Eur Neuropsychopharmacol. 2005 Mar; 15(2): 193-8). The study suggested that paroxetine, although to a lesser extent than escitalopram, stabilized the 3 H-paroxetine:human serotonin transporter complex at the primary high- affinity site.
  • Sertraline, fluoxetine, venlafaxine, and duloxetine had little or no stabilizing effect on their binding to the primary binding site on the serotonin transporter (Chen, F., et al., Eur Neuropsychopharmacol. 2005 Mar; 15(2): 193-8).
  • Whether a compound operates through an allosteric mechanism can be determined by in vitro dissociation experiments.
  • Dissociation binding experiments measure the "off rate" (k O ff) for a radioligand of the protein. After radioligand and transporter protein are allowed to bind (i.e. form a complex), then iigand is added to block further binding of radioligand to the transporter so that the rate of dissociation can be measured. Binding (as measured by radioactivity of the radioligand transporter complex) is measured at various times to determine the rate at which the radioligand dissociates from the transporter. Dissociation rate constants can be used to determine the half-life of the bound complex. Half-life determinations can be used to ascertain whether a compound is an allosteric modulator of the human SERT.
  • a compound particularly an SRI 1 is an allosteric modulator of the human serotonin transporter (hSERT) as recited in the claims of this application, by determining the Z-factor for a compound by the method described in the following paragraphs.
  • hSERT human serotonin transporter
  • a radioligand/hSERT complex is formed during a 30-minute incubation of membrane preparations expressing hSERT and radioligand (radiolabeled-test compound) at 4 0 C in buffer (50 mM Tris, pH 7.4; 120 mM NaCI, 5mM KCI). Radioligand is present at a concentration approximately 10 times the Kd value for the radioligand. (Kd values are previously determined in the same buffer).
  • the radioligand/hSERT complex is diluted by 30-fold in the same buffer.
  • the radioligand/hSERT complex is diluted by 30-fold in the same buffer containing test compound (cold, non-radiolabeled).
  • Incubation of the radioligand/hSERT complex diluted in buffer with or without test compound continues for increasing time intervals at 20 0 C. At each time interval (e.g. 10 min., 20 min., 30 min., etc.), samples are removed from the incubation and the reaction is stopped by filtration through GF/C glass-fiber filters on a cell harvester. Accumulated radioactivity for each sample is determined by direct counting of plates using a Packard Bell microplate scintillation counter.
  • the radioactivity represents binding and is expressed as fmol complex/mg membranes. Binding for each sample is plotted against increasing time to determine dissociation rate.
  • the dissociation rate of the radioligand (k off ) is determined by non-linear regression using a GraphPad PRISM program (GraphPad Software, San Diego, CA). Dissociation half-life (ti /2 ) is calculated by 0.69302/k Off and is represented in units of time.
  • Dissociation half-life of radioligand/hSERT complex (expressed in minutes) is plotted against increasing concentration of test compound in dissociation buffer (e.g. 10 ⁇ M, 20 ⁇ M, 30 ⁇ M, 40 ⁇ M, and 50 ⁇ M of test compound).
  • the slope of this plot is termed a Z-factor.
  • the Z-factor is calculated from at least four independent determinations.
  • Z-factor is a measure of the degree of stabilization of the radioligand/hSERT complex.
  • a Z-factor greater than 0 (zero) is indicative of a positive allosteric modulator.
  • an allosteric modulator is defined as a compound that has a Z-factor greater than 0 (zero) as determined by the above test.
  • serotonin dual action compounds that 1) bind to the primary binding site of the serotonin transporter having an IC50 value of less than about 50 nM, and 2) bind to an allosteric site of the serotonin transporter having a Z-factor greater than zero (0), are considered to be serotonin dual action compounds. These compounds bind to the primary binding site of the serotonin transporter with high affinity, i.e. have stronger uptake inhibitory potency, and also bind to an allosteric site of the serotonin transporter to stabilize, or modulate the binding of ligands at the primary site to further enhance inhibition of 5-HT reuptake. Serotonin dual action compounds are also known as allosteric serotonin reuptake inhibitors, or ASRIs.
  • the serotonin dual action compound further binds to the primary binding site of the serotonin transporter having an IC50 value of less than about 10 nM.
  • IC50 value of less than about 10 nM.
  • /?-citalopram does not fall within the definition of serotonin dual action compound because f?-citalopram binds to the primary binding site of the serotonin transporter having a reported IC 5O value of greater than 50 nM. See, for example, Sanchez, C. et al. Psychopharmacology 2003; 167:353-362.
  • the minimal effective dose of 5-HTP in the mouse forced swim test was 10 mg/kg and the maximum potentiation effect was achieved at 50 mg/kg 5- HTP in combination with escitalopram at a dose that corresponds to a clinically effective concentration.
  • 5- HTP has been shown to be effective in ameliorating the symptoms of depression (for review, see Birdsall, T.C., Altem Med Rev. 1998 Aug; 3(4):271-80).
  • typical doses of 100 - 200 mg of 5-HTP result in plasma levels of 50-100 ng/ml (Gijsman, HJ., et al., J Clin Psychopharmacol. 2002 Apr, 22(2): 183-9).
  • significant potentiating effects of 5-HTP on the efficacy of escitalopram in the mouse forced swim test are achieved at plasma levels that are at least 3 times lower than those required to achieve clinical efficacy in humans.
  • 5-HTP doses of approximately 34 mg (30-35 mg) given to a human may achieve plasma levels of approximately 17 ng/ml and thus still potentiate escitalopram. Furthermore, 5-HTP doses even 2.5 times lower, or at doses of approximately 13 mg (10-15 mg) may still achieve a strong potentiating effect of escitalopram.
  • the larger 5-HTP potentiation effect of an allosteric modulator compared to a non-allosteric SRI is confirmed at the mechanistic level in the rat microdialysis model.
  • the 5-HTP potentiation effect measured as increase of extra-cellular 5-HT in the frontal cortex is dramatically higher with the allosteric modulator, escitalopram, than with fluoxetine (Figure 1), which is not considered to be an allosteric modulator.
  • the plasma levels achieved at the dose range of 0.0625 - 0.25 mg/kg escitalopram correspond to plasma levels and transporter occupancy well below those necessary to achieve clinical efficacy (Sanchez, C. and Kreilgaard, M., Pharmacol Biochem Behav. 2004 Feb; 77(2):391-8; Larsen, A. K. et al M Sr J Pharm. 2004, 141:1015-23).
  • the clinically used dose range for escitalopram which corresponds to approximately 70% receptor occupancy (Klein, N. et al, Eur Neunopsychopharmacol 2005, 15 (Suppl 3): S387), is 5- 20 mg escitalopram.
  • a significant synergistic effect is achieved between escitalopram and 5-HTP even at doses that are below clinically used doses of both compounds.

Landscapes

  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Emergency Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne des polythérapies et des compositions pharmaceutiques renfermant une combinaison de 5-hydroxytryptophane et d'un inhibiteur de la réabsorption de la sérotonine. La présente invention concerne une composition pharmaceutique renfermant (i) un inhibiteur de la réabsorption de la sérotonine et (ii) du 5-hydroxytryptophane. La présente invention concerne en outre une composition pharmaceutique renfermant (i) du 5-hydroxytryptophane dans une quantité située dans la plage d'environ 1 mg à environ 75 mg ; et (ii) un inhibiteur de la réabsorption de la sérotonine. La présente invention concerne également une composition pharmaceutique renfermant (i) une dose subclinique d'un inhibiteur de la réabsorption de la sérotonine ; et (ii) du 5-hydroxytryptophane.
EP07776982A 2007-05-11 2007-05-11 Polythérapie à base de 5-htp Withdrawn EP2155181A4 (fr)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US2007/011362 WO2008140448A1 (fr) 2007-05-11 2007-05-11 Polythérapie à base de 5-htp

Publications (2)

Publication Number Publication Date
EP2155181A1 true EP2155181A1 (fr) 2010-02-24
EP2155181A4 EP2155181A4 (fr) 2012-02-29

Family

ID=40002488

Family Applications (1)

Application Number Title Priority Date Filing Date
EP07776982A Withdrawn EP2155181A4 (fr) 2007-05-11 2007-05-11 Polythérapie à base de 5-htp

Country Status (11)

Country Link
EP (1) EP2155181A4 (fr)
JP (1) JP2010526804A (fr)
KR (1) KR20100014081A (fr)
CN (1) CN101472575A (fr)
AU (1) AU2007353453A1 (fr)
BR (1) BRPI0712195A2 (fr)
CA (1) CA2655846A1 (fr)
EA (1) EA200870554A1 (fr)
IL (1) IL196041A0 (fr)
NO (1) NO20085278L (fr)
WO (1) WO2008140448A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11464756B1 (en) 2017-05-19 2022-10-11 Jerry Darm Mecuna pruriens, L-DOPA and 5-HTP based dietary supplements, pharmaceutical formulations and uses thereof

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6579899B1 (en) * 1998-07-16 2003-06-17 Massachusetts Institute Of Technology Composition for treatment of stress

Also Published As

Publication number Publication date
JP2010526804A (ja) 2010-08-05
AU2007353453A1 (en) 2008-11-20
CA2655846A1 (fr) 2008-11-20
KR20100014081A (ko) 2010-02-10
EA200870554A1 (ru) 2009-04-28
BRPI0712195A2 (pt) 2012-01-10
NO20085278L (no) 2009-02-12
WO2008140448A1 (fr) 2008-11-20
CN101472575A (zh) 2009-07-01
EP2155181A4 (fr) 2012-02-29
IL196041A0 (en) 2009-09-01

Similar Documents

Publication Publication Date Title
US20120258984A1 (en) 5-htp combination therapy
US20100267772A1 (en) Combination of a Serotonin Reuptake Inhibitor and Agomelatine
US20020103249A1 (en) Combination of a serotonin reuptake inhibitor and irindalone
TW200843763A (en) 5-HTP combination therapy
EP2145620A2 (fr) Gaboxadole pour le traitement de la dépression et d'autres troubles affectifs
AU2003240434A1 (en) Combination therapy wherein a serotinin reuptake inhibitor is used
US20100286226A1 (en) Combination therapy related to serotonin dual action compounds
WO2008140448A1 (fr) Polythérapie à base de 5-htp
CA2537747A1 (fr) Combinaison d'un inhibiteur de recaptage de serotonine et de loxapine
US20070042014A1 (en) Combination of a serotonin reuptake inhibitor and loxapine
WO2005056056A2 (fr) Combinaison d'un inhibiteur de reabsorption de la serotonine et d'un antagoniste du recepteur de l'histamine 3, agoniste inverse ou partiel
MX2008016138A (es) Terapia de combinacion de 5-htp
CA2643922A1 (fr) Combinaison d'un inhibiteur de reabsorption de la serotonine et d'un antagoniste du recepteur de l'histamine 3, agoniste inverse ou partiel
HK1134241A (en) 5-htp combination therapy
US20080167290A1 (en) Combination of a Serotonin Reuptake Inhibitor and Amoxapine
CA2537757A1 (fr) Combinaison d'un inhibiteur de recaptage de la serotonine et d'amoxapine

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20091211

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL BA HR MK RS

RIC1 Information provided on ipc code assigned before grant

Ipc: A61P 25/22 20060101ALI20120118BHEP

Ipc: A61P 25/24 20060101ALI20120118BHEP

Ipc: A61K 31/445 20060101ALI20120118BHEP

Ipc: A61K 31/405 20060101ALI20120118BHEP

Ipc: A61K 31/403 20060101ALI20120118BHEP

Ipc: A61K 31/381 20060101ALI20120118BHEP

Ipc: A61K 31/343 20060101ALI20120118BHEP

Ipc: A61K 31/137 20060101AFI20120118BHEP

A4 Supplementary search report drawn up and despatched

Effective date: 20120130

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20120828