EP1180058A1 - Combinations of gaba analogs and tricyclic compounds to treat depression - Google Patents

Combinations of gaba analogs and tricyclic compounds to treat depression

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Publication number
EP1180058A1
EP1180058A1 EP00913490A EP00913490A EP1180058A1 EP 1180058 A1 EP1180058 A1 EP 1180058A1 EP 00913490 A EP00913490 A EP 00913490A EP 00913490 A EP00913490 A EP 00913490A EP 1180058 A1 EP1180058 A1 EP 1180058A1
Authority
EP
European Patent Office
Prior art keywords
formula
gabapentin
hydrogen
composition
gaba analog
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Withdrawn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
EP00913490A
Other languages
German (de)
French (fr)
Inventor
Leslie Magnus
Douglas A. Saltel
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.)
Warner Lambert Co LLC
Original Assignee
Warner Lambert Co LLC
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 Warner Lambert Co LLC filed Critical Warner Lambert Co LLC
Publication of EP1180058A1 publication Critical patent/EP1180058A1/en
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • 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
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • 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
    • 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

Definitions

  • the invention includes treating depression with a compound of Formula II.
  • R ⁇ is a straight or branched alkyl of from 1 to 6 carbon atoms, phenyl, or

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

Abstract

The instant invention is a method of using certain analogs of glutamic acid and gamma-aminobutyric acid in combination with tricyclic compounds to relieve depression.

Description

COMBINATIONS OF GABA ANALOGS AND TRICYCLIC COMPOUNDS TO TREAT DEPRESSION
BACKGROUND OF THE INVENTION
Field Of The Invention The present invention relates to the use of analogs of glutamic acid and gamma-aminobutyric acid (GABA) in combination with tricyclic compounds for the treatment of depression.
2. Description of Related Art
The GABA analogs of the present invention are known agents useful in antiseizure therapy for central nervous system disorders such as epilepsy,
Huntington's chorea, cerebral ischemia, Parkinson's disease, tardive dyskinesia, and spasticity. It has also been suggested that the compounds can be used as antidepressants, anxiolytics, and antipsychotics. See WO 92/09560 (United States Serial Number 618,692 filed November 27, 1990) and WP 93/23383 (United States Serial Number 886,080 filed May 20, 1992).
WO 97/33858 teaches that compounds related to gabapentin are useful or treating epilespy, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, depression, anxiety, panic, pain, and neuropathological disorders. WO 97/33858 does not specify what forms of pain are treated. Additionally, the compounds of the invention are known for treatment of neuropathic pain. For example, see Rosner H; Rubin L; Kestenbaum A., Gabapentin adjunctive therapy in neuropathic pain states. Clin J Pain, 1996 Mar, 12:1, 56-8; Segal AZ; Rordorf G., Gabapentin as a novel treatment for postherpetic neuralgia. Neurology, 1996 Apr, 46:4, 1175-6; Wetzel CH; Connelly JF., Use of gabapentin in pain management. Ann Pharmacother, 1997 Sep, 31:9, 1082-3; Zapp JJ., Postpoliomyelitis pain treated with gabapentin [letter]. Am Fam Physician, 1996 Jun, 53:8, 2442, 2445; Cheville A, et al., Neuropathic pain in radiation myelopathy:a case report. Program book, American Pain Society (14th
Annual Scientific Meeting). Abstract #95823, p. A-115; Sist T; Filadora V; Miner M; Lema M., Gabapentin for idiopathic trigeminal neuralgia: report of two cases. Neurology, 1997 May, 48:5, 1467; Waldman SD, Tutorial 28: Evaluation and Treatment of Trigeminal Neuralgia. Pain Digest (1997) 7:21-24; Mellick LB; Mellick GA., Successful treatment of reflex sympathetic dystrophy with gabapentin [letter]. Am J Emerg Med, 1995 Jan, 13:1, 96; Mellick GA; Seng MI., The use of gabapentin in the treatment of reflex sympathetic dystrophy and a phobic disorder. Am J Pain Manage 1995; 5:7-9; Mellick GA; Mellicy LB; Mellick LB., Gabapentin in the management of reflex sympathetic dystrophy [letter]. J Pain Symptom Manage, 1995 May, 10:4, 265-6; Mellick GA; Mellick
LB., Reflex sympathetic dystrophy treated with gabapentin. Arch Phys Med Rehabil, 1997 Jan, 78:1, 98-105 and Mackin GA., Medical and phaimacologic management of upper extremity neuropathic pain syndromes. J Hand Ther, 1997 Tricyclic antidepressants are prescribed for endogenous depression, a condition thought to be caused by a defect in the uptake of amine neurotransmitters at the presynaptic junctions. The tricyclic antidepressants benefit from a controlled delivery formulation for a number of reasons. Depressed patients are at a higher risk for suicide, and thus more likely to hoard the drug and then attempt to take an overdose. Furthermore, tricyclic antidepressants have a long induction period, sometimes taking several weeks before patients obtain
relief from the drug. As a result of the long induction period, patients often stop using the medication after a short period of time because they think it is not working. A controlled delivery form of the drug solves these problems by providing continuous release of the drug for the time period necessary to provide relief.
Additionally, many patients who respond to tricyclic antidepressants are much more likely to avoid a relapse if they are maintained on the drug. However, patient compliance to long-term drug regimens is generally very poor. This problem is also eliminated with controlled release drug formulations. Representative examples of tricyclic antidepressants are shown below.
CH(CH2hN(CH3)2 imitriptyime
R * (CHzhNCCHsfc inupramtne
R (CH2)3NHCH3 desipramine
R = CH2CH(CH3)CH2N(CH3)2 trimtpramine
R m (CH2)3NHCH3 prouiptyline Tricyclic antidepressant drugs such as imipramine. 2 -chloroimipramine and amitriptyline; penfluridol; haloperidol; pimozide; clozapine; calmidazolin: and, mixtures and pharmaceutically acceptable salts of any of the foregoing are useful in the present invention
SUMMARY OF THE INNENΗON
The invention related to methods and compositions for treating patients suffering from depression. In methods according to the invention, compositions comprising a gaba analog and a tricyclic antidepressant in a pharmaceutically-
acceptable vehicle are administered to a patient suffering from depression. Compositions according to the invention comprise at least one gaba analog and at least one tricyclic antidepressant both in amounts effective to alleviate symptoms of depression.
This invention provides a method for treating depression comprising administering to a subject suffering from depression an effective amount of a GABA analog in combination with an effective amount of a tricyclic compounds. A preferred embodiment utilizes a cyclic amino acid compound of Formula I
wherein R\ is hydrogen or lower alkyl and n is an integer of from 4 to 6, and the
phaimaceutically acceptable salts thereof. An especially preferred embodiment utilizes a compound of Formula I where Ri is hydrogen and n is 4, which
compound is l-(aminomethyl)-cyclohexane acetic acid, known generically as gabapentin.
In another embodiment, the invention includes treating depression with a compound of Formula II. Formula II
H2NCHCCH2COOH II
I Rι
or a pharmaceutically acceptable salt thereof wherein
R\ is a straight or branched alkyl of from 1 to 6 carbon atoms, phenyl, or
cycloalkyl of from 3 to 6 carbon atoms; R2 is hydrogen or methyl; and
R3 is hydrogen, methyl, or carboxyl; and tricyclic compounds.
Preferred compounds of the invention are those wherein R3 and R2 are
hydrogen, and R is -(CH2)o-2"i C4H9 as an (R), (S), or (R,S) isomer. The more preferred compounds of Formula II invention are (S)-3-
(aminomethyl)-5-methylhexanoic acid and 3-aminomethyl-5-methyl-hexanoic acid, now known generically as pregabalin.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The method of this invention utilizes any GABA analog. A GABA analog is any compound derived from or based upon gamma-aminobutyric acid. The compounds are readily available, either commercially, or by synthetic methodology well-known to those skilled in the art of organic chemistry. The preferred GABA analogs to be utilized in the method of this invention are cyclic amino acids of Formula I. These are described in U.S. Patent 4,024,175, which is incorporated herein by reference. Another preferred method utilizes the GABA analogs of Formula II, and these are described in U.S. Patent 5,563,175, which is incorporated herein by reference.
All that is required to practice the method of this invention is to administer a GABA analog in combination with tricyclic compounds. The amount of GABA analog in the composition will generally be from about 1 to about 300 mg per kg of subject body weight. Typical doses will be from about 10 to about 5000 mg per day for an adult subject of normal weight. It is expected that common doses that might be administered could be from 100 mg three times a day up to 600 mg four times a day. Commercially available capsules of 100 mg, 300 mg, and 400 mg of gabapentin can be administered. Alternate forms include liquids and film-coated tablets.
If a compound of Formula II , such as pregabalin is used, the dosage level is one sixth that of gabapentin. The dosage range for pregabalin is from about 0.15 mg to about 50 mg per kg per day of subject body weight Typical dosages for pregabalin will be from about 1.6 mg to about 840 mg per day with individual dosages ranging from abut 0.15 mg to about 65 mg per dose.
The dosage range for the tricyclic antidepressant can be determined by one skilled in the art. Amitriptyline is available in 10, 25, 50, 75 and 150 mg tablets.
Daily dosages can range from between 75 to 350 mg.
A benefit of the claimed compositions is to lessen the chance of overdose. Overdoses of antidepressants are common reports to poison control centers. As a result, physicians and pharmacists are encouraged to provide small prescriptions
(2 to 4 weeks) at a time to avoid providing a potential suicide victim with the tools to do it. Antidepressant are therefore potential lethal as the dose is increased and patients have to be titrated up to an effective dose.
This invention would allow for a synergistic improvement in mood with lower doses (therefore) safer and potentially faster. The different mechanism of action of the two drugs would offer greater benefit to patients.
The compounds of the present invention may form pharmaceutically
acceptable salts with both organic and inorganic acids or bases. For example, the acid addition salts of the basic compoxmds are prepared either by dissolving the free base in aqueous or aqueous alcohol solution or other suitable solvents containing the appropriate acid and isolating the salt by evaporating the solution.
Examples of pharmaceutically acceptable salts are hydrochlorides, hydrobromides, hydrosulfates, etc. as well as sodium, potassium, and magnesium, etc. salts.
The compounds of the Formula II can contain one or several asymmetric carbon atoms. The invention includes the individual diastereomers or enantiomers, and the mixtures thereof. The individual diastereomers or enantiomers may be prepared or isolated by methods already well-known in the art.
Formulating the active compound in dosage unit form with a pharmaceutical carrier produces pharmaceutical compositions of the compound of the present invention or its salts. Some examples of dosage unit forms are tablets, capsules, pills, powders, aqueous and nonaqueous oral solutions and suspensions, and parenteral solutions packaged in containers containing either one or some larger number of dosage units and capable of being subdivided into individual doses.
Some examples of suitable pharmaceutical carriers, including pharmaceutical diluents, are gelatin capsules; sugars such as lactose and sucrose; starches such as com starch and potato starch, cellulose derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose, and cellulose acetate phthalate; gelatin; talc; stearic acid; magnesium stearate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, com oil, and oil of theobroma; propylene glycol, glycerin; sorbitol; polyethylene glycol; water; agar; alginic acid; isotonic saline, and phosphate buffer solutions; as well as other compatible substances normally used in pharmaceutical formulations. The compositions of the invention can also contain other components such as coloring agents, flavoring agents, and/or preservatives. These materials, if present, are usually used in relatively small amounts. The compositions can, if desired, also contain other therapeutic agents.
The percentage of the active ingredients in the foregoing compositions can be varied within wide limits, but for practical purposes it is preferably present in a concentration of at least 10% in a solid composition and at least 2% in a primary liquid composition. The most satisfactory compositions are those in which a much higher proportion of the active ingredient is present.
Routes of administration of the subject compound or its salts are oral or parenteral. For example, a useful intravenous dose is between 5 and 50 mg and a useful oral dosage is between 20 and 800 mg. The dosage is within the dosing range used in treatment of pain or as would be with the needs of the patient as described by the physician.
The advantages of using the compounds of Formula I and II, especially gabapentin and pregabalin, in the instant invention include the relatively nontoxic nature of the compounds, the ease of preparation, the fact that the compounds are well-tolerated, and the ease of IN administration of the drugs. Gabapentin has few interactions with major classes of drugs since it is not metabolized in the liver, but rather excreted unchanged from the body. Further, the drugs are not metabolized in the body. The subjects treated with the method of the present invention are mammals, including humans.
While the invention has been described in detail and with reference to specific examples thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.

Claims

What is claimed is:
1. A method for treating a patient having depression comprising administering a pharmaceutical composition comprising:
(a) a therapeutically effective amount of a GABA analog; and (b) a therapeutically effective amount of a tricyclic compounds.
2. The method according to claim 1, wherein the GABA analog is the compound according to Formula I:
wherein R\ is hydrogen or lower alkyl and n is an integer of from 4 to 6, and the
pharmaceutically acceptable salts thereof.
3. The method according to claim 2, wherein Formula I comprises gabapentin.
4. The method according to claim 2, comprising from about 10 mg to about 400 mg of Formula I.
5. The method according to claim 3, comprising from about 10 mg to about 400 mg of gabapentin.
6. The method according to claim 3, comprising from about 10 mg to about 400 mg of gabapentin and from about 25 mg to about 350 mg of tricyclic antidepressant
7. The method according to claim 1, wherein the GABA analog is a compound according to Formula II:
R3 *2
I I
H2NCHCCH2COOH II
I Ri
or a pharmaceutically acceptable salt thereof wherein
R\ is a straight or branched alkyl of from 1 to 6 carbon atoms, phenyl, or
cycloalkyl of from 3 to 6 carbon atoms; R2 is hydrogen or methyl; and
R3 is hydrogen, methyl, or carboxyl.
8. The method according to claim 7, wherein Formula II comprises pregabalin.
9. The method according to claim 7, comprising from about .15 mg to about 65 mg of Formula II.
10. The method according to claim 8, comprising from about .15 mg to about 65 mg of pregabalin.
11. A composition for treating depression in a human comprising:
(a) a therapeutically effective amount of a GABA analog; and
(b) a therapeutically effective amount of a tricyclic compounds.
12. The composition according to claim 11, wherein the GABA analog the compound according to Formula I:
wherein R\ is hydrogen or lower alkyl and n is an integer of from 4 to 6, and the
pharmaceutically acceptable salts thereof.
13. The composition method according to claim 12, wherein Formula I comprises gabapentin.
14. The composition according to claim 12, comprising from about 10 mg to about 400 mg of Formula I.
15. The composition according to claim 13, comprising from about 10 mg to about 400 mg of gabapentin.
16. The composition according to claim 11, wherein the GABA analog is a compound according to Formula II:
I I H NCHCCH2COOH II
I Rι
or a pharmaceutically acceptable salt thereof wherein
Rl is a straight or branched alkyl of from 1 to 6 carbon atoms, phenyl, or
cycloalkyl of from 3 to 6 carbon atoms;
R2 is hydrogen or methyl; and
R3 is hydrogen, methyl, or carboxyl.
17. The composition according to claim 16, wherein Formula II comprises pregabalin.
18. The composition according to claim 16, comprising from about .15 mg to about 65 mg of Formula II.
19. The composition according to claim 18, comprising from about .15 mg to about 65 mg of pregabalin.
EP00913490A 1999-04-09 2000-02-16 Combinations of gaba analogs and tricyclic compounds to treat depression Withdrawn EP1180058A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US12857199P 1999-04-09 1999-04-09
US128571P 1999-04-09
PCT/US2000/003983 WO2000061234A1 (en) 1999-04-09 2000-02-16 Combinations of gaba analogs and tricyclic compounds to treat depression

Publications (1)

Publication Number Publication Date
EP1180058A1 true EP1180058A1 (en) 2002-02-20

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Country Link
EP (1) EP1180058A1 (en)
JP (1) JP2002541224A (en)
KR (1) KR20010108466A (en)
AU (1) AU3492900A (en)
CA (1) CA2367494A1 (en)
HU (1) HUP0200733A3 (en)
IL (1) IL145736A0 (en)
NZ (1) NZ514401A (en)
TR (1) TR200102850T2 (en)
WO (1) WO2000061234A1 (en)
ZA (1) ZA200108259B (en)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6001876A (en) 1996-07-24 1999-12-14 Warner-Lambert Company Isobutylgaba and its derivatives for the treatment of pain
WO2003061656A1 (en) * 2002-01-16 2003-07-31 Endo Pharmaceuticals Inc. Pharmaceutical composition and method for treating disorders of the central nervous system
EP2156863A3 (en) * 2003-09-12 2011-01-12 Pfizer Limited Combinations comprising alpha-2-delta ligands and serotonin / noradrenaline reuptake inhibitors
WO2005025563A1 (en) * 2003-09-12 2005-03-24 Warner-Lambert Company Llc Combination comprising an alpha-2-delta ligand and an ssri and/or snri for treatment of depression and anxiety disorders

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2410821A1 (en) * 1974-03-07 1975-09-18 Hoechst Ag PHARMACEUTICAL COMBINATION PREPARATIONS WITH PSYCHOTROPIC EFFECT AND METHOD FOR THEIR PRODUCTION
FR2453643A2 (en) * 1977-06-24 1980-11-07 Synthelabo PHARMACEUTICAL COMPOSITIONS ACTIVE ON THE CENTRAL NERVOUS SYSTEM
US5025035A (en) * 1990-10-12 1991-06-18 Warner-Lambert Company Method of treating depression
AU9137091A (en) * 1990-11-27 1992-06-25 Northwestern University Gaba and l-glutamic acid analogs for antiseizure treatment
EP0726073A3 (en) * 1995-02-10 1998-07-08 Eduardo Samuel Bleiweiss Pharmaceutical compositions containing at least one of haloperidol, imipramine or trifluoroperazine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0061234A1 *

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TR200102850T2 (en) 2002-03-21
NZ514401A (en) 2003-10-31
KR20010108466A (en) 2001-12-07
IL145736A0 (en) 2002-07-25
WO2000061234A1 (en) 2000-10-19
AU3492900A (en) 2000-11-14
CA2367494A1 (en) 2000-10-19
HUP0200733A2 (en) 2002-07-29
JP2002541224A (en) 2002-12-03
HUP0200733A3 (en) 2003-04-28
ZA200108259B (en) 2003-03-26

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