CA2341855A1 - Method for treating schizophrenia, and means for use in this method - Google Patents
Method for treating schizophrenia, and means for use in this method Download PDFInfo
- Publication number
- CA2341855A1 CA2341855A1 CA002341855A CA2341855A CA2341855A1 CA 2341855 A1 CA2341855 A1 CA 2341855A1 CA 002341855 A CA002341855 A CA 002341855A CA 2341855 A CA2341855 A CA 2341855A CA 2341855 A1 CA2341855 A1 CA 2341855A1
- Authority
- CA
- Canada
- Prior art keywords
- nicotine
- pharmaceutically acceptable
- acceptable salt
- medical device
- hours
- 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.)
- Abandoned
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
-
- 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
- A61K31/465—Nicotine; Derivatives thereof
-
- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Psychiatry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Organic Chemistry (AREA)
- Dermatology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to transdermal administration of nicotine or a nicotine salt or a mixture of nicotine and nicotine salt for the treatment of schizophrenia. Disclosed are a method and a corresponding medical device.
Description
Method for treating schizophrenia, and means for use in this method The invention is directed at a method and a device for treating schizophrenia.
Schizophrenia is a psychological disorder which was first described as a disease by E. Kraepelin by summarizing individual features, for example of paranoid and catatonic states. The main deficit on which this illness is based is a splitting of psychological functions. However, the appearance of schizophrenia varies, and the diverse symptoms vary in the intensity and combination in which they occur.
Typical forms are paranoid hallucinatory schizophrenia, catatonic schizophrenia, schizophrenia simplex and hebephrenia. Symptoms of schizophrenia are, inter alia, disturbances of the thought process, disturbances of thought contents, hallucinations, so-called "ego disturbances", emotional disturbances (disturbances of affect) and disturbances of movement and drive.
Schizoaffective psychoses occupy a middle position between schizophrenias and cyclothymias.
In cases of schizophrenia a distinction is made between basic symptoms and accessory symptoms. The basic symptoms include disturbances of thought (incoherence of thought, interruption of thought, alterations in the chain of thought), affective disturbances (apathy, hypersensitivity, irritability, loss of contact, ambivalence of feelings) and disturbances of the perception of self (depersonalization, experiences of alienation and of being influenced, splitting of personality). The accessory symptoms (positive symptoms) include hallucinations (auditory, visual, - olfactory and gustatory hallucinations), mania (persecution mania, toxicomania, sex mania inter alia), disturbances of motor responses and of drive (immobility, mutism, athymia) and speech changes (mannerisms, bizarre modes of expression, neologisms, continual repetition).
A more detailed description of the pathological states is to be found in B. Bondy: "Was ist Schizophrenie".
Verlag C.H. Beck, Munich (-1994), the complete contents of~which are incorporated herein by reference.
For the distinction from other diseases, reference is made to the diagnostic criteria listed in the International Classification of Diseases and in the Diagnostic and Statistical Manual of Mental Disorders.
Schizophrenia is regarded as incurable, i.e. a causative treatment is regarded as impossible - as is the case, moreover, for many organic disorders such as, for example, diabetes. However, palliative treatment is possible, so that the symptoms in most of the patients can be suppressed at least to such- an extent that hospitalization is unnecessary and the patient is made capable of a controlled everyday life.
Before the second world war, medical treatment mainly consisted of administration of hypnotics and other substances for sedation. In addition, physical measures had the aim of calming the patient through physical exhaustion. The patients were for this purpose mainly confined in psychiatric establishments.
Medical treatment was extended by use of chlorpromazine, and this substance became a starting point for the development of substances with antipsychotic activity, called neuroleptics. However, these substances have a number o~f unwanted side effects.
Recently, methods for treating schizophrenia by use of nicotine-containing chewing-gum (L. E. Adler et al., Biol. Psychiatry, 32 (1992) 607-616) and by intestinal absorption (Rhodes et al., WO 98/02188) have been disclosed.
The invention is thus based on the object of providing a method and a medicinal product which makes symptom-minimizing treatment possible for patients with schizophrenia and is suitable for use in addition to or within the framework of psychotherapy and/or sociotherapy, by which means it is possible to reduce or avoid the disadvantages of treatment with neuroleptics or other substances with psychological activity. It is also intended to avoid the weaknesses of intermittent nicotine uptake by use of nicotine chewing-gum and the disadvantages the irritant effect of nicotine on the mucous membranes on oral administration.
The object is achieved by a method and a medicinal product which is suitable for continuous administration of nicotine, preferably onto and through the skin over a prolonged, for example over a 16- or 24-hour, and preferably over a more than 1 day, for example 3-day, period.
Medicinal products of this type are known, for example from European patents EP 261 402, EP 289 342, EP 387 694, EP 400 078, EP 427 741 and EP 708 627.
These are transdermal therapeutic systems (TTS), which deliver the active ingredient nicotine over a 16-hour (EP 400 078) or a 24-hour period. According to the teaching of these patents, the full contents of which are incorporated herein by reference, it is possible to produce TTSs which are also able to deliver the active ingredient nicotine over a longer period, for example 3 days. For this purpose it is merely necessary to suit .the active ingredient content and the thickness of the active ingredient-containing matrix, and the skin _-contact area of the TTS type used, to the required time of use .
The release characteristics of various commercially available nicotine TTSs are described in H. Ho et al., Drug Development and Industrial Pharmacy, 19 (3), 295-313 (1993).
The active ingredient nicotine means the naturally occurring (-)-nicotine. Nicotine has two nitrogen atoms. The pharmaceutically acceptable salts of nicotine include the monosalts of salicylic acid, of phenylpropionic acid or of dodecanoic acid. Also preferred as active ingredient are nicotine monoacetate, nicotine sulfate, nicotine hydrochloride, nicotine valerate, nicotine pivalate, nicotine lactate etc. This list cannot, of course, be complete.
It is also suitable to mix nicotine (as free base) with a nicotine salt as active ingredient. This may be the case if the planned duration of use is relatively long.
This is because free nicotine base permeates more quickly through the skin than do many nicotine salts.
After a certain time, this leads to exhaustion of the nicotine in the active ingredient reservoir of the TTS.
The nicotine salt content in the active ingredient reservoir is exhausted more slowly than is the free base in the active ingredient reservoir. The salt then plays a greater part in the delivery of nicotine and the maintenance of the nicotine level in the blood plasma at a later time in the use of the TTS.
The constructional elements of the TTS are a backing layer, an active ingredient-containing layer and a layer which brings about adhesion to the skin. It is moreover possible for the TTS to have a structure such .that the functions of "active ingredient-containing layer" and "layer bringing about adhesion to the skin"
are achieved in a single layer.
A further possibility is for the TTS to have a control membrane located between the active ingredient reservoir and the layer bringing about the adhesion to the skin. The control membrane has. the function of controlling the rate of release of the active ingredient from the TTS.
The active ingredient may also be present in micro-encapsulated form in the active ingredient-containing layer. In this case, the capsule material enveloping the active ingredient would then take over this release-controlling function.
The backing layer is impermeable to the active ingredient and is preferably impermeable to light and oxygen, in order to prevent chemical decomposition of the active ingredient by substances penetrating in from the outside.
The TTS may also have separate active ingredient reservoirs in a surrounding matrix.
The TTS is able to reach a nicotine level in the blood plasma above 2 ng/ml within a period of 4 hours after application.
A TTS is also suitable for reaching an essentially constant nicotine level in the blood plasma of between 2 and 20 ng/ml after completion of a period of 4 hours after application. A preferred TTS is one suitable for reaching an essentially constant nicotine level in the blood plasma of between 2 and 10 ng/ml after completion of a period of 4 hours after application.
The method for treating schizophrenia consists of . sticking a TTS according to the invention onto the patient's skin and removing it again after the intended duration of use. This duration of use of a single TTS
may be 16 hours or 24 hours. TTS for more than one day, for example for three days of use, are also suitable.
Long-term therapy is worthwhile, i.e. use of such nicotine TTS according to the invention designed to last months or years where appropriate.
This type of medical long-term therapy by use of transdermally supplied nicotine can be applied at the same time as psychotherapy and/or sociotherapy and/or medical therapy, in particular with medicines which specifically block dopamine receptors (olanzapine, risperidone etc.).
Schizophrenia is a psychological disorder which was first described as a disease by E. Kraepelin by summarizing individual features, for example of paranoid and catatonic states. The main deficit on which this illness is based is a splitting of psychological functions. However, the appearance of schizophrenia varies, and the diverse symptoms vary in the intensity and combination in which they occur.
Typical forms are paranoid hallucinatory schizophrenia, catatonic schizophrenia, schizophrenia simplex and hebephrenia. Symptoms of schizophrenia are, inter alia, disturbances of the thought process, disturbances of thought contents, hallucinations, so-called "ego disturbances", emotional disturbances (disturbances of affect) and disturbances of movement and drive.
Schizoaffective psychoses occupy a middle position between schizophrenias and cyclothymias.
In cases of schizophrenia a distinction is made between basic symptoms and accessory symptoms. The basic symptoms include disturbances of thought (incoherence of thought, interruption of thought, alterations in the chain of thought), affective disturbances (apathy, hypersensitivity, irritability, loss of contact, ambivalence of feelings) and disturbances of the perception of self (depersonalization, experiences of alienation and of being influenced, splitting of personality). The accessory symptoms (positive symptoms) include hallucinations (auditory, visual, - olfactory and gustatory hallucinations), mania (persecution mania, toxicomania, sex mania inter alia), disturbances of motor responses and of drive (immobility, mutism, athymia) and speech changes (mannerisms, bizarre modes of expression, neologisms, continual repetition).
A more detailed description of the pathological states is to be found in B. Bondy: "Was ist Schizophrenie".
Verlag C.H. Beck, Munich (-1994), the complete contents of~which are incorporated herein by reference.
For the distinction from other diseases, reference is made to the diagnostic criteria listed in the International Classification of Diseases and in the Diagnostic and Statistical Manual of Mental Disorders.
Schizophrenia is regarded as incurable, i.e. a causative treatment is regarded as impossible - as is the case, moreover, for many organic disorders such as, for example, diabetes. However, palliative treatment is possible, so that the symptoms in most of the patients can be suppressed at least to such- an extent that hospitalization is unnecessary and the patient is made capable of a controlled everyday life.
Before the second world war, medical treatment mainly consisted of administration of hypnotics and other substances for sedation. In addition, physical measures had the aim of calming the patient through physical exhaustion. The patients were for this purpose mainly confined in psychiatric establishments.
Medical treatment was extended by use of chlorpromazine, and this substance became a starting point for the development of substances with antipsychotic activity, called neuroleptics. However, these substances have a number o~f unwanted side effects.
Recently, methods for treating schizophrenia by use of nicotine-containing chewing-gum (L. E. Adler et al., Biol. Psychiatry, 32 (1992) 607-616) and by intestinal absorption (Rhodes et al., WO 98/02188) have been disclosed.
The invention is thus based on the object of providing a method and a medicinal product which makes symptom-minimizing treatment possible for patients with schizophrenia and is suitable for use in addition to or within the framework of psychotherapy and/or sociotherapy, by which means it is possible to reduce or avoid the disadvantages of treatment with neuroleptics or other substances with psychological activity. It is also intended to avoid the weaknesses of intermittent nicotine uptake by use of nicotine chewing-gum and the disadvantages the irritant effect of nicotine on the mucous membranes on oral administration.
The object is achieved by a method and a medicinal product which is suitable for continuous administration of nicotine, preferably onto and through the skin over a prolonged, for example over a 16- or 24-hour, and preferably over a more than 1 day, for example 3-day, period.
Medicinal products of this type are known, for example from European patents EP 261 402, EP 289 342, EP 387 694, EP 400 078, EP 427 741 and EP 708 627.
These are transdermal therapeutic systems (TTS), which deliver the active ingredient nicotine over a 16-hour (EP 400 078) or a 24-hour period. According to the teaching of these patents, the full contents of which are incorporated herein by reference, it is possible to produce TTSs which are also able to deliver the active ingredient nicotine over a longer period, for example 3 days. For this purpose it is merely necessary to suit .the active ingredient content and the thickness of the active ingredient-containing matrix, and the skin _-contact area of the TTS type used, to the required time of use .
The release characteristics of various commercially available nicotine TTSs are described in H. Ho et al., Drug Development and Industrial Pharmacy, 19 (3), 295-313 (1993).
The active ingredient nicotine means the naturally occurring (-)-nicotine. Nicotine has two nitrogen atoms. The pharmaceutically acceptable salts of nicotine include the monosalts of salicylic acid, of phenylpropionic acid or of dodecanoic acid. Also preferred as active ingredient are nicotine monoacetate, nicotine sulfate, nicotine hydrochloride, nicotine valerate, nicotine pivalate, nicotine lactate etc. This list cannot, of course, be complete.
It is also suitable to mix nicotine (as free base) with a nicotine salt as active ingredient. This may be the case if the planned duration of use is relatively long.
This is because free nicotine base permeates more quickly through the skin than do many nicotine salts.
After a certain time, this leads to exhaustion of the nicotine in the active ingredient reservoir of the TTS.
The nicotine salt content in the active ingredient reservoir is exhausted more slowly than is the free base in the active ingredient reservoir. The salt then plays a greater part in the delivery of nicotine and the maintenance of the nicotine level in the blood plasma at a later time in the use of the TTS.
The constructional elements of the TTS are a backing layer, an active ingredient-containing layer and a layer which brings about adhesion to the skin. It is moreover possible for the TTS to have a structure such .that the functions of "active ingredient-containing layer" and "layer bringing about adhesion to the skin"
are achieved in a single layer.
A further possibility is for the TTS to have a control membrane located between the active ingredient reservoir and the layer bringing about the adhesion to the skin. The control membrane has. the function of controlling the rate of release of the active ingredient from the TTS.
The active ingredient may also be present in micro-encapsulated form in the active ingredient-containing layer. In this case, the capsule material enveloping the active ingredient would then take over this release-controlling function.
The backing layer is impermeable to the active ingredient and is preferably impermeable to light and oxygen, in order to prevent chemical decomposition of the active ingredient by substances penetrating in from the outside.
The TTS may also have separate active ingredient reservoirs in a surrounding matrix.
The TTS is able to reach a nicotine level in the blood plasma above 2 ng/ml within a period of 4 hours after application.
A TTS is also suitable for reaching an essentially constant nicotine level in the blood plasma of between 2 and 20 ng/ml after completion of a period of 4 hours after application. A preferred TTS is one suitable for reaching an essentially constant nicotine level in the blood plasma of between 2 and 10 ng/ml after completion of a period of 4 hours after application.
The method for treating schizophrenia consists of . sticking a TTS according to the invention onto the patient's skin and removing it again after the intended duration of use. This duration of use of a single TTS
may be 16 hours or 24 hours. TTS for more than one day, for example for three days of use, are also suitable.
Long-term therapy is worthwhile, i.e. use of such nicotine TTS according to the invention designed to last months or years where appropriate.
This type of medical long-term therapy by use of transdermally supplied nicotine can be applied at the same time as psychotherapy and/or sociotherapy and/or medical therapy, in particular with medicines which specifically block dopamine receptors (olanzapine, risperidone etc.).
Claims (19)
1. Use of nicotine and/or a pharmaceutically acceptable salt of nicotine for producing a medicinal product for transdermal administration of nicotine and/or a pharmaceutically acceptable salt of nicotine for treating schizophrenia.
2. Medical device for the transdermal administration of nicotine and/or a pharmaceutically acceptable salt of nicotine for use for treating schizophrenia.
3. Medical device according to Claim 2, characterized in that the nicotine and/or a pharmaceutically acceptable salt of nicotine is delivered continuously over a period of at least 16 hours.
4. Medical device according to Claim 2, characterized in that the nicotine and/or a pharmaceutically acceptable salt of nicotine is delivered continuously over a period of at least 24 hours.
5. Medical device according to Claim 2, characterized in that the nicotine and/or a pharmaceutically acceptable salt of nicotine is delivered continuously over a period of at least 3 days.
6. Medical device according to Claim 2, characterized in that it is suitable for reaching a nicotine level in the blood plasma above 2 ng/ml within a period of 4 hours after application.
7. Medical device according to Claim 2, characterized in that it is suitable for reaching an essentially constant nicotine level in the blood plasma of between 2 and 20 ng/ml after completion of a period of 4 hours after application.
8. Medical device according to Claim 2, characterized in that it comprises a backing layer which is impermeable to nicotine and/or a pharmaceutically acceptable salt of nicotine, and a layer comprising nicotine and/or a pharmaceutically acceptable salt of nicotine.
9. Medical device according to Claim 2, characterized in that it comprises a layer which brings about adhesion of the device to the patient's skin.
10. Method for treating schizophrenia, characterized in that nicotine and/or a pharmaceutically acceptable salt of nicotine is administered transdermally.
11. Method according to Claim 10, characterized in that nicotine and/or a pharmaceutically acceptable salt of nicotine is administered continuously over a period of at least 16 hours.
12. Method according to Claim 10, characterized in that nicotine and/or a pharmaceutically acceptable salt is administered continuously over a period of at least 24 hours.
13. Method according to Claim 10, characterized in that nicotine and/or a pharmaceutically acceptable salt is administered continuously over a period of at least 3 days.
14. Method for treating schizophrenia, characterized in that a medical device according to Claim 2 is applied to the patient's skin and detached again after a wearing time of 16 hours.
15. Method for treating schizophrenia, characterized in that a medical device according to Claim 2 for transdermal or transmucosal administration of nicotine and/or a pharmaceutically acceptable salt of nicotine is applied to the patient's skin and detached again after a wearing time of 24 hours.
16. Method for treating schizophrenia, characterized in that a medical device according to Claim 2 is applied to the patient's skin and detached again after a wearing time of 3 days.
17. Method for treating schizophrenia, characterized in that a medical device according to Claim 6 is applied.
18. Method for treating schizophrenia, characterized in that a medical device according to Claim 7 is applied.
19. Method according to Claim 10, characterized in that it is applied at the same time as psychotherapy and/or sociotherapy and/or medical therapy.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19847715A DE19847715A1 (en) | 1998-10-16 | 1998-10-16 | Treatment of schizophrenia symptoms without side effects, by transdermal administration of nicotine or its salt |
| DE19847715.5 | 1998-10-16 | ||
| PCT/EP1999/007320 WO2000023077A1 (en) | 1998-10-16 | 1999-10-02 | Method for treating schizophrenia and means used in said method |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2341855A1 true CA2341855A1 (en) | 2000-04-27 |
Family
ID=7884666
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002341855A Abandoned CA2341855A1 (en) | 1998-10-16 | 1999-10-02 | Method for treating schizophrenia, and means for use in this method |
Country Status (10)
| Country | Link |
|---|---|
| EP (1) | EP1121126A1 (en) |
| JP (1) | JP2002527478A (en) |
| KR (1) | KR20010080135A (en) |
| CN (1) | CN1323210A (en) |
| AR (1) | AR020815A1 (en) |
| AU (1) | AU6199299A (en) |
| BR (1) | BR9914570A (en) |
| CA (1) | CA2341855A1 (en) |
| DE (1) | DE19847715A1 (en) |
| WO (1) | WO2000023077A1 (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10110953A1 (en) * | 2001-03-07 | 2002-09-19 | Lohmann Therapie Syst Lts | Transdermal therapeutic system for the administration of partial dopamine D2 agonists |
| KR20060120156A (en) * | 2003-10-28 | 2006-11-24 | 알자 코포레이션 | Method and apparatus for reducing the incidence of tobacco use |
| IL177071A0 (en) * | 2005-08-01 | 2006-12-10 | Nitto Denko Corp | Method of preparing a nicotine transdermal preparation |
| WO2012154710A1 (en) * | 2011-05-09 | 2012-11-15 | Envivo Pharmaceuticals, Inc. | Treatment of cognitive disorders with certain alpha-7 nicotinic acid receptor agonists in combination with nicotine |
| CZ309812B6 (en) * | 2021-05-25 | 2023-11-01 | Consumer Brands International s.r.o | A mixture for the production of nicotine pouches and a method of its production |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4680172A (en) * | 1985-03-05 | 1987-07-14 | Ciba-Geigy Corporation | Devices and methods for treating memory impairment |
| US4915950A (en) * | 1988-02-12 | 1990-04-10 | Cygnus Research Corporation | Printed transdermal drug delivery device |
| GB9614902D0 (en) * | 1996-07-16 | 1996-09-04 | Rhodes John | Sustained release composition |
| US5776956A (en) * | 1996-07-30 | 1998-07-07 | Lectec Corporation | Use of cotinine in treating psychiatric disorders |
| US5776957A (en) * | 1996-11-15 | 1998-07-07 | The University Of Kentucky Research Foundation | Nornicotine enantiomers for use as a treatment for dopamine related conditions and disease states |
-
1998
- 1998-10-16 DE DE19847715A patent/DE19847715A1/en not_active Withdrawn
-
1999
- 1999-10-02 CA CA002341855A patent/CA2341855A1/en not_active Abandoned
- 1999-10-02 AU AU61992/99A patent/AU6199299A/en not_active Abandoned
- 1999-10-02 EP EP99948923A patent/EP1121126A1/en not_active Ceased
- 1999-10-02 BR BR9914570-7A patent/BR9914570A/en not_active IP Right Cessation
- 1999-10-02 KR KR1020017004649A patent/KR20010080135A/en not_active Application Discontinuation
- 1999-10-02 WO PCT/EP1999/007320 patent/WO2000023077A1/en not_active Application Discontinuation
- 1999-10-02 JP JP2000576851A patent/JP2002527478A/en active Pending
- 1999-10-02 CN CN99812210A patent/CN1323210A/en active Pending
- 1999-10-14 AR ARP990105204A patent/AR020815A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AR020815A1 (en) | 2002-05-29 |
| KR20010080135A (en) | 2001-08-22 |
| BR9914570A (en) | 2001-07-03 |
| EP1121126A1 (en) | 2001-08-08 |
| CN1323210A (en) | 2001-11-21 |
| AU6199299A (en) | 2000-05-08 |
| WO2000023077A1 (en) | 2000-04-27 |
| DE19847715A1 (en) | 2000-04-20 |
| JP2002527478A (en) | 2002-08-27 |
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| FZDE | Dead |