EP1019041A1 - Procede d'amelioration de comportements perturbes et de stimulation de l'humeur chez des humains - Google Patents

Procede d'amelioration de comportements perturbes et de stimulation de l'humeur chez des humains

Info

Publication number
EP1019041A1
EP1019041A1 EP98920311A EP98920311A EP1019041A1 EP 1019041 A1 EP1019041 A1 EP 1019041A1 EP 98920311 A EP98920311 A EP 98920311A EP 98920311 A EP98920311 A EP 98920311A EP 1019041 A1 EP1019041 A1 EP 1019041A1
Authority
EP
European Patent Office
Prior art keywords
dronabinol
dementia
patients
administered
humans
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Withdrawn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
EP98920311A
Other languages
German (de)
English (en)
Other versions
EP1019041A4 (fr
Inventor
Ladislav Volicer
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.)
Unimed Pharmaceuticals LLC
Original Assignee
Unimed Pharmaceuticals 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
Priority claimed from US08/866,511 external-priority patent/US5804592A/en
Application filed by Unimed Pharmaceuticals LLC filed Critical Unimed Pharmaceuticals LLC
Publication of EP1019041A1 publication Critical patent/EP1019041A1/fr
Publication of EP1019041A4 publication Critical patent/EP1019041A4/fr
Withdrawn legal-status Critical Current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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates generally to methods for improving disturbed behavior and negative mood in animals, and more specifically to methods for improving disturbed behavior and negative mood in humans suffering from dementia, particularly of the Alzheimer type.
  • Dementia usually denotes a clinical syndrome composed of failing memory and loss of other intellectual functions due to chronic progressive degenerative disease of the brain. Dementia is generally characterized by the gradual loss of intellectual capacities. However, certain behavioral abnormalities and changes in personality are also associated with dementia.
  • ADCT Alzheimer's disease
  • DAT Alzheimer's disease
  • DAT Alzheimer's disease
  • the disease is extremely uncommon in the young (except for those with Down's syndrome) and rare in those of middle age, it is the most common cause of dementia in the elderly and is associated with distress to the patients and their families and economic loss resulting from costs due to long-term care of patients disabled by the disease.
  • Alzheimer's disease is often associated with a lack of initiative, irritability, loss of interest in things, forgetfulness, change in mood often taking the form of apathy, and excessive lability of mood (i.e., easy fluctuation between laughter and tears on slight provocation) .
  • Dementia of the Alzheimer type also leads to progressive loss of learned behaviors, such as the ability to feed oneself, speech and language disturbances, and lack of coordination of voluntary movement.
  • Dronabinol is a cannabinoid having the chemical designation (6aR- trans) -6a, 7, 8, 10a-tetrahydro-6 , 6, 9-trimethyl-3-pentyl-6H- dibenzo [b, d] pyran-1-ol and is also referred to as delta- 9-tetrahydrocannabinol (delta-9-THC) . It is naturally occurring and has been extracted from Cannabis sativa L. (marijuana) . It can also be chemically synthesized.
  • Dronabinol is currently marketed in a formulation having the trademark Marinol ® for the treatment of anorexia associated with weight loss in patients with AIDS, and for the treatment of nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments. Physicians ' Desk Reference , 1997.
  • dronabinol has not been used or suggested for use in dementia patients, Alzheimer's patients in particular, to improve disturbed behavior or elevate the mood of these patients.
  • an object of the present invention to provide a method for improving disturbed behavior and elevating mood in patients suffering from dementia, particularly of the Alzheimer's type.
  • the present invention is directed to a method for improving disturbed behavior in humans suffering from dementia comprising administering an effective amount of dronabinol.
  • the present invention also provides a method for improving negative mood in humans suffering from dementia comprising administering an effective amount of dronabinol.
  • the methods of the present invention are particularly beneficial when applied to patients suffering from dementia of the Alzheimer's type.
  • dronabinol may be administered alone or in combination with a pharmaceutically effective carrier or other pharmaceutically acceptable additives.
  • the methods of the present invention may be administered in any suitable manner, including orally, buccally, sublingually, subcutaneously, intramuscularly, intravenously, transdermally, and rectally, as well as others.
  • the quantity of dronabinol administered may vary widely.
  • the amount may be from about 0.01 to 35 mg/kg of body weight administered one to five times per day.
  • dronabinol may be administered concurrently or in succession with other medications, i.e. psychoactive medications .
  • Figure 1 is a graphical representation identifying changes in the Cohen-Mansfield Agitation Inventory score during the placebo treatment period and the dronabinol treatment period.
  • Figure 2 is a graphical representation identifying changes in the Negative Affect score during the placebo treatment period and the dronabinol treatment period.
  • the present invention is directed to a method for improving disturbed behavior in humans suffering from dementia by administering an effective amount of dronabinol.
  • the present invention is also directed to a method for elevating negative mood in humans suffering from dementia by administering an effective amount of dronabinol .
  • the method of the present invention may be used to treat any type of disturbed behavior or negative mood, but most preferably is used to treat disturbed behavior and negative mood associated with dementia in humans.
  • diseases and medical conditions associated with human dementia for which dronabinol may be useful including Alzheimer's disease, Pick's disease, Huntington's chorea, leukodystrophies, lipid storage diseases such as lipofuscinosis, Creutzfeltd-Jakob disease, multi-infarct dementia, normal pressure hydrocephalus , intracranial masses and posttraumatic dementia.
  • the method of the present invention improves disturbed behavior and elevates mood in those patients suffering from Alzheimer type dementia.
  • dronabinol may improve any of the numerous disturbed behaviors found in dementia patients, including but not limited to, aimless or wandering pace, inappropriate dress, spitting, cursing or verbal aggression, constant unwarranted request for attention or help, repetitive sentences or questions, hitting, kicking, grabbing onto people, pushing, throwing things, strange noises, screaming, biting, scratching, trying to get to a different place, intentional falling, complaining, negativism, eating/drinking inappropriate substances, hurting themselves or others, handling things inappropriately, hiding things, hoarding things, tearing things or destroying property, performing repetitious mannerisms, making verbal sexual advances, general restlessness, and strange movements or making faces .
  • the method of the present invention may elevate the mood of patients suffering from any of the following moods, including but not limited to, anger, anxiety or fear, and depression or sadness .
  • Dronabinol may also be administered to a dementia patient regardless of the length of time the patient has been suffering from dementia, be it one day or many years. Further, dronabinol may be administered to a dementia patient for as long as the disturbed behavior improves or the patient's mood is elevated. Dronabinol is a cannabinoid which has complex effects on the central nervous system (CNS) , including central sympathomimetic activity. Cannabinoid receptors have been discovered in neural tissues. It is believed that these receptors may play a role in mediating the effects of dronabinol on the CNS.
  • CNS central nervous system
  • Alzheimer's disease and other progressive dementias lead to nerve cell death. This deprives the brain of substances, such as neurotransmitters, which are necessary for normal brain function. These substances stimulate specific receptors and coordinate function of brain cells. Although the endogenous transmitter which stimulates cannabinoid receptors is not known, it is believed that it does exist. Therefore, it is postulated that some symptoms seen in Alzheimer's disease are due to the lack of this endogenous transmitter. Administration of dronabinol may be substituting for the lack of this endogenous transmitter. It is theorized that administration of dronabinol may substitute for the lack of this endogenous transmitter and improve brain function affected by cell loss. It is further believed that dronabinol may have a prolonged effect on disturbed behavior and mood.
  • Dronabinol pharmacokinetics can be described by a four compartment model, with an initial half-life of four hours and a terminal half-life of 25-36 hours. (Agurell et al . , Pharmacol . Rev. , 38:21-43 (1986)).
  • dronabinol may be administered in the form of a composition, including a pharmaceutical composition, comprising dronabinol.
  • the composition additionally comprises a pharmaceutically acceptable carrier.
  • dronabinol compositions of the invention are available, and, although more than one route can be used to administer a particular composition, a particular route can provide a more immediate and more effective reaction than another route.
  • compositions of the present invention are also well-known to those who are skilled in the art.
  • choice of carrier will be determined, in part, both by the particular composition and by the particular method used to administer the composition. Accordingly, there is a wide variety of suitable formulations of the pharmaceutical compositions of the present invention.
  • Suitable specific forms of administration include the forms for the oral route, buccal and sublingual forms of administration, subcutaneous, transdermal, intramuscular or intravenous forms of administration and rectal forms of administration, as well as forms for inhalation.
  • the compounds according to the invention may be used in creams, ointments or lotions.
  • compositions of the present invention for oral, buccal, nasal, sublingual, subcutaneous, intramuscular, intravenous, topical, transdermal or rectal administration, dronabinol may be administered in sustained or controlled release forms or in dosage unit forms of administration mixed with standard pharmaceutical vehicles to animals or humans.
  • the formulations may conveniently be prepared by any of the methods well known in the art.
  • Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of dronabinol dissolved in diluents, such as water, oil, or saline, (b) capsules, sachets or tablets, each containing a predetermined amount of the active ingredient, as solids or granules, (c) suspensions in an appropriate liquid, and (d) suitable emulsions.
  • liquid solutions such as an effective amount of dronabinol dissolved in diluents, such as water, oil, or saline
  • diluents such as water, oil, or saline
  • capsules, sachets or tablets each containing a predetermined amount of the active ingredient, as solids or granules
  • suspensions in an appropriate liquid and (d) suitable emulsions.
  • Tablet forms can include one or more of lactose, mannitol, corn starch, potato starch, microcrystalline cellulose, acacia, gelatin, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, stearic acid, and other excipients, colorants, diluents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible carriers.
  • Lozenge forms can comprise the active ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin or sucrose and acacia emulsions, gels, and the like containing, in addition to the active ingredient, such carriers as are known in the art .
  • Dronabinol alone or in combination with other suitable components, can be made into aerosol formulations to be administered via inhalation. These aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like.
  • Formulations suitable for parenteral administration include aqueous and non-aqueous solutions, isotonic sterile injection solutions, which can contain antioxidants, buffers such as acetate and phosphate, toxicity adjusting agents, such as sodium chloride, pH adjusting agents, such as hydrochloric and phosphoric acid, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • the formulations can be presented in unit-dose or multi-dose sealed containers, such as ampules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water, for injections, immediately prior to use.
  • sterile liquid carrier for example, water
  • Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.
  • dronabinol is administered as an oral capsule composition containing 2.5 mg, 5 mg or 10 mg dronabinol, sesame oil, gelatin, glycerin, methylparaben, propylparaben, and titanium dioxide.
  • the dose administered to an animal, particularly a human, in the context of the present invention should be sufficient to effect a therapeutic response over a reasonable time frame.
  • the dose will be determined by the strength of the particular compositions employed and the condition of the person, as well - li ⁇
  • a suitable dosage for internal administration is 0.01 to 100 mg/kg per day.
  • a preferred dosage is 0.01 to 35 mg/kg per day.
  • a more preferred dosage is 0.05 to 5 mg/kg per day.
  • a suitable concentration of dronabinol in pharmaceutical compositions for oral administration is 0.05 to 15% (by weight) .
  • a preferred concentration is from 0.02 to 5%.
  • a more preferred concentration is from 0.1 to 4%. More preferably, 0.03 to 0.06 mg/kg body weight per day is administered orally, and most preferably, a 2.5 mg oral dosage form is administered two times per day.
  • the most preferred dosage for extracorporeal administration is in the range from about 0.1 mg/kg to 5 mg/kg of body weight per day.
  • topical (including buccal and sublingual) or transdermal route of administration the preferred dosage thereof (estimated as the base) is in the 0.05 mg/kg to 20 mg/kg of body weight per day.
  • dronabinol may be administered as needed, preferably, dronabinol is administered one to five times per day.
  • Dronabinol may be administered concurrently with other necessary medications.
  • one or more psychoactive medications may be administered before, concurrently and after treatment with dronabinol.
  • psychoactive medications include, but are not limited to, antidepressants, neuroleptics, and benzodiazepines.
  • Specific neuroleptic medications include, but are not limited to, perphenazine, thiothixene, haloperidol, and thioridazine .
  • Specific benzodiazepines include, but are not limited to, lorazepam and alprazolam.
  • Specific antidepressants include, but are not limited to, sertraline, trazodone and desipramine.
  • the preferred embodiment of the present invention is the treatment of dementia, particularly of the Alzheimer type, in humans
  • the methods of the present invention may be used to treat disturbed behavior and elevate mood in animals of any kind.
  • suitable animals include but are not limited to dogs, pigs, sheep, horses, cows, and cats. All publications cited to or referenced herein are incorporated by reference in their entirety.
  • Each patient in the this example was diagnosed with "probable" DAT by a neurologist according to DSM III-R and NINCDS-ARDDA criteria. These generally accepted criteria include deficits in two or more areas of cognition, progressive worsening of memory and other cognitive functions, no disturbances of consciousness, and absence of systemic disorders or other brain disease that in and of themselves could account for the progressive deficits in memory and cognition. (McKhann et al . , Neurology, 34:939-944 (1984). Each patient received physical examination and laboratory examination including complete blood count with differential, liver function tests, thyroid function tests including TSH, iron binding capacity, BUN, creatinine, and electrolytes.
  • MMSE Mini-mental Status Examination
  • MMSE is generally known in the art and is generally described in Folstein et al., J “ . Psychiatr. Res . , 12:189-198 (1975), Katz Activity of Daily Living scale (Katz ADL) (Katz et al . , JAMA, 185:914-19 (1963) , and Bedford Alzheimer Nursing Scale-Severity (BANS-S) (Volicer et al . , J. Gerontol . , 49:M223-26 (1994). This data is reported in Table 1.
  • the patients included in the analysis were all 65 years old or older and all but one were males. Duration of DAT varied from 2 to 16 years and most patients had been in institutional long-term care for many months before the onset of the study. Most also suffered from severe dementia; the MMSE score was 0 in 8 subjects. Patients also were severely impaired in activities of daily living; 9 were dependent in all 6 activities. BANS-S score, which detects progression of the disease even in the severe stage indicated moderate to severe impairment .
  • Antidepressant treatment was initiated at least 4 weeks before the start of the study and the mean duration of antidepressant treatment before study initiation was 7 months. Eleven patients had orders for psychoactive medications as needed (PRN) . These included lorazepam in 4 patients and alprazolam, trazodone, doxepin, haloperidol, perphenazine and thioridazine in one patient each. The patients received these medications very rarely, on the average 9.7 doses / 6 weeks during the placebo administration and 7.2 doses / 6 weeks during dronabinol treatment .
  • *n refers to the number of patients experiencing the listed effect and % identifies the percentage of total patients experiencing the effect.
  • CMAI Cohen-Mansfield Agitation Inventory
  • F order x treatment
  • Affect Scale includes two items (anger and anxiety/fear) which are commonly present in patients during agitated behaviors.
  • the third item, depression/sadness was rarely observed as can be seen from Table 2.
  • both scales measured similar disruptive behaviors. It is possible that this effect was partly due to somnolence, which was twice as common in patients treated with dronabinol than in patients on placebo.
  • Dronabinol treatment did not change the Positive Affect, although euphoria as an adverse reaction was reported more frequently and in more patients during the dronabinol treatment than during placebo periods. It is possible that the Positive Affect items represent more a degree of patient's engagement than patient's mood (Lawton et al . , Psychol . Aging, 3:469-477 (1995) ) . While this invention has been described with an emphasis upon preferred embodiments, it will be obvious to those of ordinary skill in the art that variations in the preferred methods of the present invention may be used and that it is intended that the invention may be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications encompassed within the spirit and scope of the invention as defined by the following claims .

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

Abstract

Cette invention se rapporte à un procédé d'amélioration des comportements perturbés et de stimulation de la bonne humeur chez des sujets atteints de démence, notamment chez des humains atteints de démence telle que celle liée à la maladie d'Alzheimer, ledit procédé consistant en l'administration de dronabinol.
EP98920311A 1997-05-07 1998-05-06 Procede d'amelioration de comportements perturbes et de stimulation de l'humeur chez des humains Withdrawn EP1019041A4 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US4581397P 1997-05-07 1997-05-07
US45813P 1997-05-07
US08/866,511 US5804592A (en) 1997-05-30 1997-05-30 Method for improving disturbed behavior and elevating mood in humans
US866511 1997-05-30
PCT/US1998/009269 WO1998050027A1 (fr) 1997-05-07 1998-05-06 Procede d'amelioration de comportements perturbes et de stimulation de l'humeur chez des humains

Publications (2)

Publication Number Publication Date
EP1019041A1 true EP1019041A1 (fr) 2000-07-19
EP1019041A4 EP1019041A4 (fr) 2002-04-17

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Family Applications (1)

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EP98920311A Withdrawn EP1019041A4 (fr) 1997-05-07 1998-05-06 Procede d'amelioration de comportements perturbes et de stimulation de l'humeur chez des humains

Country Status (6)

Country Link
EP (1) EP1019041A4 (fr)
JP (1) JP2002501510A (fr)
AU (1) AU743788B2 (fr)
CA (1) CA2288693A1 (fr)
IL (1) IL132784A (fr)
WO (1) WO1998050027A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2571696B (en) 2017-10-09 2020-05-27 Compass Pathways Ltd Large scale method for the preparation of Psilocybin and formulations of Psilocybin so produced
KR20220009954A (ko) 2019-04-17 2022-01-25 컴퍼스 패쓰파인더 리미티드 신경인지 장애, 만성 통증을 치료하고 염증을 감소시키는 방법

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0427518A1 (fr) * 1989-11-07 1991-05-15 Yissum Research Development Company Of The Hebrew University Of Jerusalem Composés de NMDA-blocage, compositions pharmaceutiques, leur préparation et leur usage
WO1995020958A1 (fr) * 1994-02-07 1995-08-10 Ramot University Authority For Applied Research And Industrial Development Ltd. Derives de dexanabinol et leur emploi en tant que compositions pharmaceutiques neuroprotectrices

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5596106A (en) * 1994-07-15 1997-01-21 Eli Lilly And Company Cannabinoid receptor antagonists

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0427518A1 (fr) * 1989-11-07 1991-05-15 Yissum Research Development Company Of The Hebrew University Of Jerusalem Composés de NMDA-blocage, compositions pharmaceutiques, leur préparation et leur usage
WO1995020958A1 (fr) * 1994-02-07 1995-08-10 Ramot University Authority For Applied Research And Industrial Development Ltd. Derives de dexanabinol et leur emploi en tant que compositions pharmaceutiques neuroprotectrices

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
"Study finds Dronabinol promising in Alzheimer disease" JOURNAL OF PHARMACY TECHNOLOGY, CINCINNATI, OH, US, vol. 12, no. 6, November 1996 (1996-11), page 294 XP002114257 ISSN: 8755-1225 *
RUPNIAK ET AL.: "Induction of cognitive impairment by scopolamine and noncholinergic agents in Rhesus monkeys" LIFE SCIENCES, vol. 48, no. 9, 1991, pages 893-899, XP008000795 *
See also references of WO9850027A1 *
VOLICER ET AL.: "Effects of dronabinol on anorexia and disturbed behavior in patients with Alzheimer's disease" INT. J. GERIATRIC PSY., vol. 12, no. 9, September 1997 (1997-09), pages 913-919, XP008000789 *
VOLICER ET AL.: "Effects of dronabinol on anorexia and disturbed behavior in patients with Alzheimer's disease" NEUROBIOLOGY OF AGING, vol. 17, no. 4supl., 1996, pages s73-s74, XP008000790 *
VOLICER L: "Dronabinol may help behavior problems in Alzheimer's disease" AMERICAN FAMILY PHYSICIAN, AMERICAN ACADEMY OF FAMILY PHYSICIANS, US, vol. 55, no. 4, March 1997 (1997-03), page 1338 XP002114258 *

Also Published As

Publication number Publication date
IL132784A0 (en) 2001-03-19
JP2002501510A (ja) 2002-01-15
AU7291698A (en) 1998-11-27
AU743788B2 (en) 2002-02-07
WO1998050027A1 (fr) 1998-11-12
IL132784A (en) 2004-07-25
EP1019041A4 (fr) 2002-04-17
CA2288693A1 (fr) 1998-11-12

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