EP1112067A2 - Use of acetylcholinesterase inhibitors for the preparation of pharmaceutical compositions for the treatment of functional and/or organic pain syndromes - Google Patents

Use of acetylcholinesterase inhibitors for the preparation of pharmaceutical compositions for the treatment of functional and/or organic pain syndromes

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Publication number
EP1112067A2
EP1112067A2 EP99946150A EP99946150A EP1112067A2 EP 1112067 A2 EP1112067 A2 EP 1112067A2 EP 99946150 A EP99946150 A EP 99946150A EP 99946150 A EP99946150 A EP 99946150A EP 1112067 A2 EP1112067 A2 EP 1112067A2
Authority
EP
European Patent Office
Prior art keywords
treatment
functional
acetylcholinesterase
organic
pain syndromes
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.)
Granted
Application number
EP99946150A
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German (de)
French (fr)
Other versions
EP1112067B1 (en
Inventor
Maria Nicolodi
Federigo Sicuteri
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.)
Eisai R&D Management Co Ltd
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Eisai Co Ltd
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Publication date
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Publication of EP1112067A2 publication Critical patent/EP1112067A2/en
Application granted granted Critical
Publication of EP1112067B1 publication Critical patent/EP1112067B1/en
Anticipated expiration legal-status Critical
Expired - Lifetime 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
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • 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
    • A61K31/325—Carbamic acids; Thiocarbamic acids; Anhydrides or salts thereof
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P25/06—Antimigraine agents

Definitions

  • the present invention refers to the use of acetylcholinesterase inhibitors with high specificity and selectivity for centrally active acetylcholinesterase (resulting in an increased concentration and duration of acetylcholine in brain) for preparing pharmaceutical compositions for the treatment of functional (migraine and primary fibromyalgia) and/or organic ("phantom limb" caused by tumoral or traumatic denervation or autoimmune mechanism) central pain syndromes.
  • functional miraine and primary fibromyalgia
  • organic phantom limb
  • migraine has been the object of deep interest and studies in view of the importance of this pathology both for the extremely large number of patients involved and because it causes (during its more serious episodes) important or total limitations to otherwise healthy subjects.
  • Fig. 1 shows the number of hours with pain before and after 60 days chronic treatment with Donepezil hydrochloride.
  • Fig. 2 shows the number of migraine attacks before and after chronic Donepezil hydrochloride treatment.
  • Fig. 3 shows the number of hours with pain before and after chronic treatment with
  • Fig. 4 shows the number of migraine attacks before and after Donepezil hydrochloride treatment.
  • Fig. 5 shows the results of prophylaxis of migraine with Donepezil hydrochloride.
  • Fig. 6 shows the results of prophylaxis of migraine with Donepezil hydrochloride.
  • acetylcholinesterase inhibiting compounds with high specificity and selectivity for centrally active acetylcholinesterase can be used with excellent results in the acute, abortive or preventive, prophylactic treatment of migraine and also of other related disorders which are commonly defined as functional and/or organic neurogenic central pain syndromes.
  • the acetylcholinesterase inhibiting compounds with high specificity and selectivity for centrally active acetylcholinesterase in the present invention is defined as follows: the acetylcholinesterase inhibiting compounds having clinical indication of use such as central -progressive memory deterioration in Alzheimer disease or senile dementia and which can cross the blood-brain barrier and_can enter the brain in large amounts.
  • Other anticholinesterase agents can not be useful for treating CNS cholinergic disturbances due to acting peripheral tissues including sympathetic ganglia.
  • migraine migraine
  • primary fibromyalgia pain syndromes from organic deafferentation caused by amputation
  • denervation or autoimmune mechanism multiple sclerosis
  • infections zosteric postherpetic nevralgia
  • acetylcholinesterase inhibitors according to the invention as above defined do not present the undesired side effects as miosis and block of accomodation reflex with resultant focusing problems in near vision, changes in the function of all the secretory glands, including lacrimal, bronchial, sweat, salivary, antral, intestinal, and acinar pancreatic glands, nausea, vomit, gastric acid hyper-secretion, abdominal pains, diarrhoea, fainting or pre-fainting sensation, disturbances of cardio-vascular functions.
  • the administration is well tolerated by patients and allows to obtain the desired results even with a single oral administration daily.
  • the present invention obviously refers to pharmaceutical compositions containing as active principle an acetylcholinesterase inhibitor having central activity possibly in combination with the usual excipient used for preparing pharmaceutical composition for oral administration for the treatment of the above said pathologies.
  • compositions according to the invention will contain the active principle in quantities comprised between 1.5 - 12 mg, more preferably 5 - 10 mg.
  • the treatment can be symptomatic or chronic.
  • the symptomatic, acute treatment is normally performed by administering orally to the patient a single dosage containing from 0.1 to 50 mg daily, preferably 0.5 to 40 mg daily, more preferably 1 to 30 mg daily of active principle ; while for the chronic treatment the same administration can be repeated once a day for 40 - 80 days.
  • Rivastigmine or a pharmacologically acceptable salt thereof and Metrifonate Rivastigmine or a pharmacologically acceptable salt thereof and Metrifonate.
  • the term "pharmacologically acceptable salt thereof include the salts of inorganic acids, such as hydrochloride, hydrobromide, sulfate, nitrate and phosphate, and those of organic acids, such as formate, acetate, oxalate, succinate, maleate, fumarate, methanesulfonate, benzenesulfonate and toluenesulfonate.
  • inorganic acids such as hydrochloride, hydrobromide, sulfate, nitrate and phosphate
  • organic acids such as formate, acetate, oxalate, succinate, maleate, fumarate, methanesulfonate, benzenesulfonate and toluenesulfonate.
  • hydrochloride is more preferable.
  • the acetylcholinesterase inhibitor compounds of the present invention may be orally or parentally administered.
  • the dose will vary depending upon the symptom, age, sex, body weight, sensitivity of patients, method of administration, time and interval of administration and property, dispensing, and kind of pharmaceutical preparations, kind of effective ingredients, etc..
  • Pharmaceutical preparations in the form of, e.g., tablet, granule, capsule, syrup, injections are prepared according to the usual manner.
  • Experimental data Migraines Various groups of patients suffering from different kind of migraine were treated with 5 mg of Donepezil hydrochloride daily.
  • Fig. 1 - Shows the number of hours with pain before and after 60 days chronic treatment with Donepezil hydrochloride (5 mg/die) measured in tests on 17 patients suffering from chronic migraine, otherwise known as "transformed migraine” (International Headache Society criteria).
  • Fig. 2 Shows the number of migraine attacks before and after chronic Donepezil hydrochloride treatment (5 mg/die) for the above said group of patients.
  • Fig. 3 Shows the number of hours with pain before and after chronic treatment with Donepezil hydrochloride (5 mg/die) measured in tests on 18 patients suffering from migraine without aura.
  • Fig. 4 Shows the number of migraine attacks before and after Donepezil hydrochloride treatment (5 mg/die) for the same group of patients as in Fig. 3.
  • Fig. 5 - Shows the results of prophylaxis of migraine with Donepezil hydrochloride reporting the number of migraine attacks following 60 days run-in and 60 days treatment in 35 patients suffering from severe migraine without aura.
  • Fig. 6 - Shows the results of prophylaxis of migraine with Donepezil hydrochloride reporting the hour with pain following 60 days run-in and 60 days treatment for the same group of patients as in Fig. 5.

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

Abstract

The application refers to the use of acetylcholinesterase inhibitors having central action for the treatment of functional (migraine and primary fibromyalgia) and/or organic (amputation, 'phantom limb', tumoral or traumatic denervation or autoimmune mechanism) central pain syndromes.

Description

USE OF ACETYLCHOLINESTERASE INHIBITORS FOR THE PREPARATION OF PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF FUNCTIONAL AND/OR ORGANIC PAIN SYNDROMES Field of the invention The present invention refers to the use of acetylcholinesterase inhibitors with high specificity and selectivity for centrally active acetylcholinesterase (resulting in an increased concentration and duration of acetylcholine in brain) for preparing pharmaceutical compositions for the treatment of functional (migraine and primary fibromyalgia) and/or organic ("phantom limb" caused by tumoral or traumatic denervation or autoimmune mechanism) central pain syndromes. State of the art
Along the years migraine has been the object of deep interest and studies in view of the importance of this pathology both for the extremely large number of patients involved and because it causes (during its more serious episodes) important or total limitations to otherwise healthy subjects.
Various theories were formulated in order to find an explanation to the origin of migraine. Among these theories we can remember the "dry theory" (according to which the pain is due to the pulsing distension of cephalic vessels), the "wet theory" (which implies the sterile inflammation of the arterial vessels which became dilated and bloated), the "serotonin-theory" according to which the pathology is caused by a disorder of the serotoninergic system in the central nervous system.
This last theory was very successful and allowed the preparation of active principles having a serotonino-mimetic activity capable of relieving a migraine attack.
About thirty years ago an interesting article [Stoyan Iv. IKONOMOFF - Archives Suisses de Neurologie, Neurochirurgie et de Psychiatrie - Vol. 102, fascicule p. 299-312 (1968)] referred to the possibility of treating migraine by using pharmaceutical products, such as Nivaiine, an alkaloid, and Syntostigmine, which were known for their acetylcholinesterase inhibiting effect .
The article proposed the use of the two above said compounds (or more generally of acetylcholinesterase inhibiting medicaments) as a possible new way for resolving migraine disorders. Unfortunately the use of the medicaments suggested in the above said work, as also of other similar compounds having the same effect, required very high dosages, the administration should be performed by injection and was responsible of various side effects which made their use difficult; therefore this way was abandoned and no indication was thereafter reported in the literature about the use of acetylcholinesterase inhibitors as medicament for the treatment of migraine. In fact even the most recent editions of fundamental text-books in Neurology and Pharmacology [see for example .Victor and Adams, McGraw-Hill, New York (last edition) and Goodman and Gilman,
McGraw-Hill, New York (1996) respectively] do not report these drugs as employed or useful for treating pain, whatever its origin and mechanism.
Moreover in various studies [see for example C. Ghelardini et al. - Presynaptic auto- and hetero-receptors in the cholinergic regulation of pain - Trends in Receptor Research (Elsevier Science Publishers B.V. ) (1992)] it is reported that peripherically active acetylcholinesterase inhibiting compounds are not suitable for analgesic use in man.
Brief description of the drawings
Fig. 1 shows the number of hours with pain before and after 60 days chronic treatment with Donepezil hydrochloride.
Fig. 2 shows the number of migraine attacks before and after chronic Donepezil hydrochloride treatment.
Fig. 3 shows the number of hours with pain before and after chronic treatment with
Donepezil hydrochloride. Fig. 4 shows the number of migraine attacks before and after Donepezil hydrochloride treatment.
Fig. 5 shows the results of prophylaxis of migraine with Donepezil hydrochloride.
Fig. 6 shows the results of prophylaxis of migraine with Donepezil hydrochloride.
Detailed description of the invention It was now surprisingly found that acetylcholinesterase inhibiting compounds with high specificity and selectivity for centrally active acetylcholinesterase can be used with excellent results in the acute, abortive or preventive, prophylactic treatment of migraine and also of other related disorders which are commonly defined as functional and/or organic neurogenic central pain syndromes. Furthermore, the acetylcholinesterase inhibiting compounds with high specificity and selectivity for centrally active acetylcholinesterase in the present invention is defined as follows: the acetylcholinesterase inhibiting compounds having clinical indication of use such as central -progressive memory deterioration in Alzheimer disease or senile dementia and which can cross the blood-brain barrier and_can enter the brain in large amounts. Other anticholinesterase agents can not be useful for treating CNS cholinergic disturbances due to acting peripheral tissues including sympathetic ganglia. Among the above said pathologies we can remember : migraine, primary fibromyalgia, pain syndromes from organic deafferentation caused by amputation ("phantom limb"), denervation or autoimmune mechanism (multiple sclerosis) or infections (zosteric postherpetic nevralgia).
The acetylcholinesterase inhibitors according to the invention as above defined do not present the undesired side effects as miosis and block of accomodation reflex with resultant focusing problems in near vision, changes in the function of all the secretory glands, including lacrimal, bronchial, sweat, salivary, antral, intestinal, and acinar pancreatic glands, nausea, vomit, gastric acid hyper-secretion, abdominal pains, diarrhoea, fainting or pre-fainting sensation, disturbances of cardio-vascular functions. The administration is well tolerated by patients and allows to obtain the desired results even with a single oral administration daily.
The present invention obviously refers to pharmaceutical compositions containing as active principle an acetylcholinesterase inhibitor having central activity possibly in combination with the usual excipient used for preparing pharmaceutical composition for oral administration for the treatment of the above said pathologies.
In particular the compositions according to the invention will contain the active principle in quantities comprised between 1.5 - 12 mg, more preferably 5 - 10 mg. The treatment can be symptomatic or chronic.
The symptomatic, acute treatment is normally performed by administering orally to the patient a single dosage containing from 0.1 to 50 mg daily, preferably 0.5 to 40 mg daily, more preferably 1 to 30 mg daily of active principle ; while for the chronic treatment the same administration can be repeated once a day for 40 - 80 days.
Among the compounds useful according to the present invention particularly preferable are : Donepezil or a pharmacologically acceptable salt thereof,
Rivastigmine or a pharmacologically acceptable salt thereof and Metrifonate.
These compounds are shown hereinafter:
Donepezil
1 H-lnden-1-one, 2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4- piperidinyljmethyl]-, hydrochloride
[Hydrochloride: CAS Registry No. 120011-70-3]
(2) Rivastigmine
Carbamic acid, ethylmethyl-, 3-[1-(dimethylamino)ethyl]phenyl ester
[CAS Registry No. 123441-03-2]
(3) Metrifonate
Phosphoric acid, (2,2,2-trichloro-1-hydroxyethyl)-, dimethyl ester
[CAS Registry No. 52-68-6]
In the present invention, the term "pharmacologically acceptable salt thereof include the salts of inorganic acids, such as hydrochloride, hydrobromide, sulfate, nitrate and phosphate, and those of organic acids, such as formate, acetate, oxalate, succinate, maleate, fumarate, methanesulfonate, benzenesulfonate and toluenesulfonate. Among these, hydrochloride is more preferable.
In practising the present invention, the acetylcholinesterase inhibitor compounds of the present invention may be orally or parentally administered. In general, the are administered in the form of tablet, granule, capsule and syrup, and in the form of injection, such as intravenous, subcutaneous and intramuscular injection, suppositories or sublingual tablets.
The dose will vary depending upon the symptom, age, sex, body weight, sensitivity of patients, method of administration, time and interval of administration and property, dispensing, and kind of pharmaceutical preparations, kind of effective ingredients, etc.. Pharmaceutical preparations in the form of, e.g., tablet, granule, capsule, syrup, injections are prepared according to the usual manner. Experimental data Migraines Various groups of patients suffering from different kind of migraine were treated with 5 mg of Donepezil hydrochloride daily.
The results are reported in the following histograms 1 to 6 (see Figure 1 - 6).
Fig. 1 - Shows the number of hours with pain before and after 60 days chronic treatment with Donepezil hydrochloride (5 mg/die) measured in tests on 17 patients suffering from chronic migraine, otherwise known as "transformed migraine" (International Headache Society criteria).
Fig. 2 - Shows the number of migraine attacks before and after chronic Donepezil hydrochloride treatment (5 mg/die) for the above said group of patients. Fig. 3 - Shows the number of hours with pain before and after chronic treatment with Donepezil hydrochloride (5 mg/die) measured in tests on 18 patients suffering from migraine without aura.
Fig. 4 - Shows the number of migraine attacks before and after Donepezil hydrochloride treatment (5 mg/die) for the same group of patients as in Fig. 3. Fig. 5 - Shows the results of prophylaxis of migraine with Donepezil hydrochloride reporting the number of migraine attacks following 60 days run-in and 60 days treatment in 35 patients suffering from severe migraine without aura.
Fig. 6 - Shows the results of prophylaxis of migraine with Donepezil hydrochloride reporting the hour with pain following 60 days run-in and 60 days treatment for the same group of patients as in Fig. 5.
Moreover, 8 patients suffering from migraine attacks longer than 72 h were treated with 20 mg of Donepezil hydrochloride acutely given, also in this case the results were highly satisfactory.
Primary fibromyalgia Systemic pain of muscles, tendons, viscera (oesophagus, stomach, colon) ; these syndromes are considered particularly difficult to hale.
Tests performed on 16 patents (same conditions as those described for the migraine tests) showed an improvement of the patient's conditions in 60% of the cases treated and total disappearance of the pain in 10% of the cases. Pain syndromes caused by denervation
In the pain syndromes caused by denervation or amputation pain develops on the limb or body part which is denervated and therefore is insensible to nociceptive stimuli ("painful anaesthesia").
Nine patients who had no advantages after treatment with antiinflammatory analgesica or opioids were tested in the same conditions as above described.
Five patients showed an improvement of their conditions of 50 - 80%. All patients showed an high tolerance to the treatment, with side effects much lower then those observed in the case of administration of the commonly available acute and prophylactic therapies for curing migraine and central neurogenic pain.

Claims

CLAIMS 1. A use of an acetylcholinesterase inhibitor with high specificity and selectivity for centrally active acetylcholinesterase for preparing pharmaceutical composition useful for the treatment of functional and/or organic pain syndromes.
2. The use according to Claim 1 wherein such functional and/or organic neurogenic pain syndromes are : migraine, primary fibromyalgia, pain syndromes due to amputation ("phantom limb"), tumoral or traumatic denervation or autoimmune mechanism.
1 3. The use according to Claim 1 or 2 wherein the active principle is Donepezil or a pharmacologically acceptable salt thereof.
1 4. The use according to Claim 1 or 2 wherein the active principle is Rivastigmine or a pharmacologically acceptable salt thereof. l
5. The use according to Claim 1 or 2 wherein the active principle is Metrifonate.
1 6. A Pharmaceutical composition for the treatment of functional and/or organic
2 pain syndromes containing an active principle according to Claim 1 in combination
3 with the pharmaceutically acceptable excipients for the preparation of formulation
4 for oral use.
1 7. The pharmaceutical compositions according to Claim 6 wherein the active
2 principle is present in quantities comprised between 1 to 30 mg.
1 8. A method for the treatment of functional or organic pain syndromes
2 characterised in that 1 to 30 mg of the active principle are administered to the
3 patient orally, daily. l
9. The method according to Claim 8 wherein the treatment is relief from pain.
1 10. The method according to Claim 8 wherein the treatment is prevention of pain
2 attack.
1 11. The method according to Claim 8 wherein the treatment is chronic and
2 prolonged for 40 - 80 days.
1 12. A method for the treatment of functional and/or organic pain syndromes in
2 human in need of such treatment which comprises administering a therapeutically
3 amount of acetylcholinesterase inhibitors with high specificity and selectivity for
4 centrally active acetylcholinesterase.
13. The method claimed in claim 12, wherein acetylcholinesterase inhibitor is Donepezil or pharmacologically acceptable salt thereof.
14. The method claimed in either of claim 12 or 13, wherein acetylcholinesterase inhibitor administered in a daily dose of from 0.1 to 50 mg.
15. The method claimed in either of claim 12 to 14, wherein acetylcholinesterase inhibitor administered in a daily dose of from 1 to 30 mg.
16. A use of acetylcholinesterase inhibitor with high specificity and selectivity for centrally active acetylcholinesterase for the treatment of functional and/or organic pain syndrome.
EP99946150A 1998-09-11 1999-09-09 Use of acetylcholinesterase inhibitors for the preparation of pharmaceutical compositions for the treatment of functional and/or organic pain syndromes Expired - Lifetime EP1112067B1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
IT1998FI000208A IT1304904B1 (en) 1998-09-11 1998-09-11 ANTICOLINESTERASIC DERIVATIVES FOR THE TREATMENT OF FUNCTIONAL AND / OR ORGANIC SYNDROME
ITFI980208 1998-09-11
PCT/EP1999/006648 WO2000015205A2 (en) 1998-09-11 1999-09-09 Use of acetylcholinesterase inhibitors for the preparation of pharmaceutical compositions for the treatment of functional and/or organic pain syndromes

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EP1112067A2 true EP1112067A2 (en) 2001-07-04
EP1112067B1 EP1112067B1 (en) 2006-05-31

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US (1) US6608088B1 (en)
EP (1) EP1112067B1 (en)
JP (1) JP3984787B2 (en)
AT (1) ATE327740T1 (en)
AU (1) AU5861799A (en)
CY (1) CY1105125T1 (en)
DE (1) DE69931640T2 (en)
DK (1) DK1112067T3 (en)
ES (1) ES2265691T3 (en)
IT (1) IT1304904B1 (en)
PT (1) PT1112067E (en)
WO (1) WO2000015205A2 (en)

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US6608088B1 (en) 2003-08-19
WO2000015205A2 (en) 2000-03-23
WO2000015205A3 (en) 2000-08-24
JP3984787B2 (en) 2007-10-03
AU5861799A (en) 2000-04-03
CY1105125T1 (en) 2009-11-04
DE69931640D1 (en) 2006-07-06
ES2265691T3 (en) 2007-02-16
PT1112067E (en) 2006-09-29
ITFI980208A1 (en) 2000-03-11
IT1304904B1 (en) 2001-04-05
ITFI980208A0 (en) 1998-09-11
EP1112067B1 (en) 2006-05-31
JP2002524498A (en) 2002-08-06

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