WO1994012166A1 - Therapeutic agents for the treatment of cachexia - Google Patents
Therapeutic agents for the treatment of cachexia Download PDFInfo
- Publication number
- WO1994012166A1 WO1994012166A1 PCT/GB1993/002423 GB9302423W WO9412166A1 WO 1994012166 A1 WO1994012166 A1 WO 1994012166A1 GB 9302423 W GB9302423 W GB 9302423W WO 9412166 A1 WO9412166 A1 WO 9412166A1
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- WIPO (PCT)
- Prior art keywords
- compound
- formula
- pharmaceutically acceptable
- medicament
- acceptable salt
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-
- 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
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
Definitions
- the present invention relates to 4- [2- [ (2-hydroxy-3- phenoxypropyl)amino] ethoxy] -N- (2-methoxyethyl)phenoxyacetamide, depicted herei below as formula (I) wherein R is -NHCH CH OCH , and the acid metabolite thereof wherein R is -OH.
- the present invention relates to these compounds and in particular to their use in the therapeutic treatment of animals including humans.
- the compounds of the formula (I) have been shown to be selective ⁇ -adrenoceptor agonists in animals [Holloway et al., British Journal of Pharmacology , (1991) , 104, 97-104] . That is they stimulate thermogenesis.
- the administration of the compound of the formula (I) wherein R is methoxyethylamino selectively increased oxygen consumption and brown adipose tissue activity in rats. Oxygen consumption was potently stimulated during tests on dogs and cats.
- thermogenesis Maximal effects on thermogenesis were achieved at doses that had only minimal effects on the heart rate and on tremor, that is the compound was selective as a ⁇ -adrenoceptor agonist with little or no effects on ⁇ - and ⁇ -adrenoceptors.
- the administration of the compounds was therefore predicted to be of use in the treatment of obesity and related conditions such as non-insulin dependent diabetes associated with obesity.
- the compounds have also been predicted to be beneficial in lowering triglyceride and cholesterol levels and in stimulating 'atypical' ⁇ -receptors in the gastro-intestinal tract and therefore inhibiting gastrointestinal motility.
- the compounds of the formula (I) have also been suggested to be of value m the modification of carcass composition, for example, by increased catabolism of fat in meat producing animals sucn as cattle, pigs, sheep, goats and/or rabbits.
- the compounds increase lean cody mass although they decrease fat content and body weight leading to an overall loss of weight.
- the compounds are therefore of use in combatting medical conditions wherein such control of whole body protein turnover is thought to be beneficial especially wherein metabolic rate increase is not desirable.
- These compounds may be used in the treatment of cachexia.
- Cachexia is the loss of weight and condition associated with many forms of severe illness. Progressive weight loss is a characteristic feature of cancer.
- the compounds of the formula (I) will be of particular value n treating cancer cachexia.
- the compounds of the formula (I) will also be of value in treating related conditions such as cachexia associated with trauma, burns, AIDS, anorexia nervosa and surgery and in treating negative nitrogen balance m intensive care patients and the elderly Furthermore, the compounds of the formula (I) have little or no effect on the ⁇ and ⁇ -adrenoceptors so that the treatment of cachexia patients, who are often very ill, has minimal undesirable side-effects .
- the present invention provides a method of treating cachexia whch comprises administering, to an animal in need thereof, a therapeutically effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof.
- the present invention provides the use of the compound of the formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating cachexia.
- the present invention provides the use of the compound of the formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for lowering protein turnover.
- the present invention provides a method of lowering protein turnover which comprises administering, to an animal in need thereof, an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof.
- R is 2-methoxyethylamino
- the compounds of the formula (I) contain an asymmetric carbon atom and can exist as an optically active enantiomer (R or S according to the Cahn-Ingold-Prelog convention) or as an optically inactive racemate.
- the compounds for use in the present invention contain at least some of the laevorotatory optically active form (-) which corresponds to (S) absolute configuration.
- the compounds for use in the present invention are provided as the racemate but preferably are provided as the laevorotatory optically active form (- ⁇ .
- the compounds of formula (I) are basic and may be isolated and used either m the form of a free base or of a pharmaceutically acceptable acid-addition salt thereof.
- the compound of the formula (I) wherein R is hydroxy is ampnoteric and may be isolated and used in the zwitterionic form, or as a pharmaceutically acceptable acid-addition salt, or as a salt with a base affording a pharmaceutically acceptable cation.
- Particular examples of pharmaceutically acceptable acid-addition salts include, for example, salts with inorganic acids such as hydrohalides (especially hydrochlorides or hydrobromides) , sulphates and phosphates, and salts with organic acids such as the free acid form of sulphonated polystyrene.
- salts with bases affording a pharmaceutically acceptable cation include, for example, alkali metal and alkaline earth metal salts, such as sodium, potassium, calcium and magnesium salts, and ammonium salts and salts with suitable organic bases, such as triethanolamme.
- a preferred compound for use in the methods of the present invention is :
- the compound of the formula (I) and pharmaceutically acceptable salts thereof wherein R is hydroxy are known from, and/or can be prepared by, the methods of European Patent Application Publication No 210849.
- the compounds of the formula (I) and pharmaceutically acceptable salts thereof wherein R s 2-methoxyethylam ⁇ no are known from, and/or can be prepared by, the methods of European Patent Application Publication No 254532.
- the pnarmaceutical compositions of this invention may be administered in standard manner for example by oral or parenteral administration.
- they may be formulated by means known to the art into the form of, for example, tablets, capsules, pills, powders, aqueous or oily solutions or suspensions, emulsions, and sterile m * jectable aqueous or oily solutions or suspensions.
- compositions for oral administration are preferred.
- compositions may be obtained using standard excip ents and procedures well known in the art.
- a unit dose form such as a tablet or capsule will usually contain 0.1-250mg of active ingredient, suitably 10-100 mg and typically 25 mg or 50 mg.
- the compositions may be administered m conjunction with parenteral nutrition feeding fluids, for example Intralipid (Kabi Pharmacia) or appetite stimulants for example cyproheptadme.
- parenteral nutrition feeding fluids for example Intralipid (Kabi Pharmacia) or appetite stimulants for example cyproheptadme.
- the compounds of the formula (I) may also be used in combination with a low calorie diet in order to adjust protein metabolism to prevent loss of protem/lean-body mass whilst allowing weight loss through mobilisation of fat stores.
- a compound of the formula (I) or a pharmaceutically acceptable salt When used to lower protein turnover in warm-blooded animals including humans, a compound of the formula (I) or a pharmaceutically acceptable salt will be administered so that a dose in the general range 0.002-20mg/kg, and preferably m the range 0.02-10mg/kg, is administered daily, given in a single dose or divided doses as necessary.
- a dose in the general range 0.002-20mg/kg, and preferably m the range 0.02-10mg/kg is administered daily, given in a single dose or divided doses as necessary.
- the dosage will necessarily be varied as appropriate, depending on the severity of the condition under treatment and on the age and sex of the patient and according to known medical principles
- Volunteers receiving the compound experienced a mean decrease n weight of 0.57 kg. Volunteers treated with placebo experienced a mean decrease in body weight of 0.94 kg over the 14 day period.
- Leucine oxidation was measured in accordance with the methodology of Nair et al. , Journal of Clinical Investigations 8_2, 198-205, 1988. The compound therefore had a statistically significant (p ⁇ .02) effect on leucme oxidation. This shows that the compound conserves or spares an essential amino-acid (leucine) and will have a beneficial effect on the maintenance of whole body protein.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The use of 4-[2-[(2-hydroxy-3-phenoxypropyl)amino]ethoxy]-N-(2-methoxyethyl)phenoxy acetamide or its acid metabolite in the treatment of cachexia and in particular cancer cachexia.
Description
Therapeutic agents for the treatment of cachexia.
The present invention relates to 4- [2- [ (2-hydroxy-3- phenoxypropyl)amino] ethoxy] -N- (2-methoxyethyl)phenoxyacetamide, depicted herei below as formula (I) wherein R is -NHCH CH OCH , and the acid metabolite thereof wherein R is -OH.
Ph-OCH CH(OH)CH NHCH CH 0-( )-OCH COR (I)
The present invention relates to these compounds and in particular to their use in the therapeutic treatment of animals including humans.
The compounds of the formula (I) have been shown to be selective β -adrenoceptor agonists in animals [Holloway et al., British Journal of Pharmacology , (1991) , 104, 97-104] . That is they stimulate thermogenesis. The administration of the compound of the formula (I) wherein R is methoxyethylamino selectively increased oxygen consumption and brown adipose tissue activity in rats. Oxygen consumption was potently stimulated during tests on dogs and cats. Maximal effects on thermogenesis were achieved at doses that had only minimal effects on the heart rate and on tremor, that is the compound was selective as a β -adrenoceptor agonist with little or no effects on β - and β -adrenoceptors.
The administration of the compounds was therefore predicted to be of use in the treatment of obesity and related conditions such as non-insulin dependent diabetes associated with obesity. The compounds have also been predicted to be beneficial in lowering triglyceride and cholesterol levels and in stimulating 'atypical' β-receptors in the gastro-intestinal tract and therefore inhibiting gastrointestinal motility.
The compounds of the formula (I) have also been suggested to
be of value m the modification of carcass composition, for example, by increased catabolism of fat in meat producing animals sucn as cattle, pigs, sheep, goats and/or rabbits. The compounds increase lean cody mass although they decrease fat content and body weight leading to an overall loss of weight.
The compound of the formula (I) wherein R is methoxyethylammo was introduced into human volunteer patients. Disappointingly there was insufficient effect on metabolic rate in the clinical situation. This, in effect, pointed to insufficient efficacy of the carboxylic acid, wherein R is hydroxy, at the β -adrenoceptor m the human patient.
We have now discovered that, although β -adrenoceptor agonist activity has not been expressed in man, the compounds of the formula (I) influence the control of whole body protein turnover.
More particularly the compounds of the formula (I) have been found to conserve leucme (based on observations of leucme oxidation), without increasing metabolic rate. A reduction in leucme oxidation has been shown to correlate with an increase m protein synthesis and a consequent maintenance of lean body mass.
The compounds are therefore of use in combatting medical conditions wherein such control of whole body protein turnover is thought to be beneficial especially wherein metabolic rate increase is not desirable. These compounds may be used in the treatment of cachexia. Cachexia is the loss of weight and condition associated with many forms of severe illness. Progressive weight loss is a characteristic feature of cancer. Thus the compounds of the formula (I) will be of particular value n treating cancer cachexia. The compounds of the formula (I) will also be of value in treating related conditions such as cachexia associated with trauma, burns, AIDS, anorexia nervosa and surgery and in treating negative nitrogen balance m intensive care patients and the elderly
Furthermore, the compounds of the formula (I) have little or no effect on the β and β -adrenoceptors so that the treatment of cachexia patients, who are often very ill, has minimal undesirable side-effects .
Accordingly the present invention provides a method of treating cachexia whch comprises administering, to an animal in need thereof, a therapeutically effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof.
In another aspect the present invention provides the use of the compound of the formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating cachexia.
In a further aspect the present invention provides the use of the compound of the formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for lowering protein turnover.
In yet a further aspect the present invention provides a method of lowering protein turnover which comprises administering, to an animal in need thereof, an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof.
Preferably in the compounds of the formula (I) R is 2-methoxyethylamino.
The compounds of the formula (I) contain an asymmetric carbon atom and can exist as an optically active enantiomer (R or S according to the Cahn-Ingold-Prelog convention) or as an optically inactive racemate. The compounds for use in the present invention contain at least some of the laevorotatory optically active form (-) which corresponds to (S) absolute configuration. Conveniently the compounds for use in the present invention are provided as the racemate but preferably are provided as the laevorotatory optically active form (-} .
The compounds of formula (I) are basic and may be isolated and used either m the form of a free base or of a pharmaceutically acceptable acid-addition salt thereof. In addition, the compound of the formula (I) wherein R is hydroxy is ampnoteric and may be isolated and used in the zwitterionic form, or as a pharmaceutically acceptable acid-addition salt, or as a salt with a base affording a pharmaceutically acceptable cation.
Particular examples of pharmaceutically acceptable acid-addition salts include, for example, salts with inorganic acids such as hydrohalides (especially hydrochlorides or hydrobromides) , sulphates and phosphates, and salts with organic acids such as the free acid form of sulphonated polystyrene.
Particular examples of salts with bases affording a pharmaceutically acceptable cation include, for example, alkali metal and alkaline earth metal salts, such as sodium, potassium, calcium and magnesium salts, and ammonium salts and salts with suitable organic bases, such as triethanolamme.
A preferred compound for use in the methods of the present invention is :
(S) -4- [2- (2-hydroxy-3-phenoxypropylamιno)ethoxy] -N- (2-methoxyethyl) - phenoxyacetamide hydrochloπde.
The compound of the formula (I) and pharmaceutically acceptable salts thereof wherein R is hydroxy are known from, and/or can be prepared by, the methods of European Patent Application Publication No 210849. The compounds of the formula (I) and pharmaceutically acceptable salts thereof wherein R s 2-methoxyethylamιno are known from, and/or can be prepared by, the methods of European Patent Application Publication No 254532.
In order to use the compounds of the formula (I) and pnarmaceutically acceptaole salts thereof for the lowering of proteir. tumover thev are normalIv formulated in accorαance with standarα
pharmaceutical practice as a pharmaceutical composition.
The pnarmaceutical compositions of this invention may be administered in standard manner for example by oral or parenteral administration. For these purposes they may be formulated by means known to the art into the form of, for example, tablets, capsules, pills, powders, aqueous or oily solutions or suspensions, emulsions, and sterile m*jectable aqueous or oily solutions or suspensions.
In general compositions for oral administration are preferred.
The compositions may be obtained using standard excip ents and procedures well known in the art. A unit dose form such as a tablet or capsule will usually contain 0.1-250mg of active ingredient, suitably 10-100 mg and typically 25 mg or 50 mg. The compositions may be administered m conjunction with parenteral nutrition feeding fluids, for example Intralipid (Kabi Pharmacia) or appetite stimulants for example cyproheptadme.
The compounds of the formula (I) may also be used in combination with a low calorie diet in order to adjust protein metabolism to prevent loss of protem/lean-body mass whilst allowing weight loss through mobilisation of fat stores.
When used to lower protein turnover in warm-blooded animals including humans, a compound of the formula (I) or a pharmaceutically acceptable salt will be administered so that a dose in the general range 0.002-20mg/kg, and preferably m the range 0.02-10mg/kg, is administered daily, given in a single dose or divided doses as necessary. However, t will be appreciated by those skilled in the art that the dosage will necessarily be varied as appropriate, depending on the severity of the condition under treatment and on the age and sex of the patient and according to known medical principles
The effects of a representative compound for use m a raetnoα accorαmσ to this invention are describeα in the following Example
Example 1
In a double-Dlmd, randomised, parallel, placeoo-controlled study over 14 days, (S) -4- [2- (2-hydroxy-3- henoxypropylamino) - ethoxy] -N- (2-methoxyethyl)pnenoxyacetamιde hydrocnloride ("the compound") was dosed orally to adult volunteers.
Eighteen healthy obese volunteers were studied over two periods n a 14 day single-blind placebo baseline period and a 14 day double-blind, randomised, placebo-controlled period. A one day treatment with placebo preceded both periods m order to stabilise the volunteer's hydration status and carbohydrate metabolism. Both periods were concluded with a one day placebo 'washout' .
The volunteers received a standardised weight-maintaining diet throughout the study beginning on the first day. The effects of the compound on body weight and components of energy balance were measured throughout the study. Energy expenditure was measured by indirect caloπmetry and by the application of the doubly labelled turnover was measured using
Results
Body weight
Volunteers receiving the compound experienced a mean decrease n weight of 0.57 kg. Volunteers treated with placebo experienced a mean decrease in body weight of 0.94 kg over the 14 day period.
Energy Expenditure
Measured by the doubly labelled water method (Schoeller et al., American Journal of Physiology 250 -R823-R830, 1986) , the volunteers treated with compound and placebo decreased energy expenditure by 257.78 Kcal/24 hour (8.24%) and 231.11 Kcal/24 hour (8.56%) respectively. There was no significant effect due to treatment with compound.
Measured by the indirect calorimetry method (Wong et al. , American Journal of Clinical Nutrition 45:1543-1548, 1987) , for 3 nours after tne morning αose, energy expenditure decreased by 136 35
Kcal/24 hour (5.76%) for the volunteers treated with compound and by 45.70 Kcal/24 hour (1.66%) for volunteers receiving placebo. Again there was no increase in energy expenditure due to the compound.
Leucine Oxidation
In contrast, leucine oxidation decreased relative to baseline by 19% in the volunteers treated with the compound whereas in those volunteers receiving placebo, oxidation increased by 1.6%.
Leucine oxidation was measured in accordance with the methodology of Nair et al. , Journal of Clinical Investigations 8_2, 198-205, 1988. The compound therefore had a statistically significant (p<.02) effect on leucme oxidation. This shows that the compound conserves or spares an essential amino-acid (leucine) and will have a beneficial effect on the maintenance of whole body protein.
This study has shown that, whereas the effects of the compound on protein synthesis and lean body mass as predicted by the pharmacology of the compound in animals have been retained in man, the effects on energy expenditure have been lost.
Claims
1. The use of a compound of the formula (I) :
Ph-OCH CH(OH) (I) 
wherein R is hydroxy or 2-methoxyethylamino, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating cachexia.
2. The use of a compound of the formula (I) or a pharmaceutically acceptable salt thereof as defined in claim 1 for the manufacture of a medicament for treating cachexia associated with cancer, trauma, burns, AIDS, anorexia nervosa and surgery.
3. The use of a compound of the formula (I) or a pharmaceutically accepable salt thereof as defined in claim 1 for the manufacture of a medicament for lowering protein turnover.
4. The use of a compound of the formula (I) or a pharmaceutically acceptable salt thereof as defined in claim 1 for the manufacture of a medicament for conserving or sparing protein.
5. The use of a compound of the formula (I) or a pharmaceutically acceptable salt thereof as defined in claim 1 for the manufacture of a medicament for reducing or preventing leucine oxidation.
6. The use of a compound of the formula (I) or a pharmaceutically acceptable salt thereof as defined in claim 1 for the manufacture of a medicament for conserving or sparing leucine.
7. The use of a compound of the formula (I) or a pharmaceutically acceptable salt thereof as defined in claim 1 for the manufacture of a medicament for reducing the irreversible loss of essential amino acids.
8. The use according to any one of claims 1-7 wherein the compound of the formula (I) or pharmaceutically acceptable salt thereof, as defined in claim 1, is in the laevorotatory optically active form (-) .
9. The use according to claim 8 wherein R is 2-methoxyethyla ino.
10. The use according to claim 9 wherein the compound of the formula (I) is (S) -4- [2- (2-hydroxy-3-phenoxypropyl amino)ethoxy] - N- (2-methoxyethyl)phenoxyacetamide hydrochloride.
11. The use according to any one of claim 1-10 wherein the medicament is suitable for oral administration.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU55320/94A AU5532094A (en) | 1992-11-26 | 1993-11-25 | Therapeutic agents for the treatment of cachexia |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB929224740A GB9224740D0 (en) | 1992-11-26 | 1992-11-26 | Therapeutic agents |
| GB9224740.2 | 1992-11-26 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1994012166A1 true WO1994012166A1 (en) | 1994-06-09 |
Family
ID=10725688
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/GB1993/002423 Ceased WO1994012166A1 (en) | 1992-11-26 | 1993-11-25 | Therapeutic agents for the treatment of cachexia |
Country Status (5)
| Country | Link |
|---|---|
| AU (1) | AU5532094A (en) |
| GB (2) | GB9224740D0 (en) |
| IL (1) | IL107767A0 (en) |
| WO (1) | WO1994012166A1 (en) |
| ZA (1) | ZA938803B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001035947A3 (en) * | 1999-11-15 | 2001-11-22 | Lilly Co Eli | Treating wasting syndromes with aryloxy propanolamines |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0210849A1 (en) * | 1985-07-30 | 1987-02-04 | Imperial Chemical Industries Plc | 2-Hydroxy-3-phenoxypropyl amines |
| EP0254532A1 (en) * | 1986-07-23 | 1988-01-27 | Imperial Chemical Industries Plc | Amide derivatives |
| EP0431763A2 (en) * | 1989-11-17 | 1991-06-12 | Imperial Chemical Industries Plc | Therapeutic agents for lowering triglyceride and/or cholesterol levels and/or increasing HDL levels |
-
1992
- 1992-11-26 GB GB929224740A patent/GB9224740D0/en active Pending
-
1993
- 1993-11-24 ZA ZA938803A patent/ZA938803B/en unknown
- 1993-11-25 AU AU55320/94A patent/AU5532094A/en not_active Abandoned
- 1993-11-25 GB GB939324241A patent/GB9324241D0/en active Pending
- 1993-11-25 WO PCT/GB1993/002423 patent/WO1994012166A1/en not_active Ceased
- 1993-11-26 IL IL10776793A patent/IL107767A0/en unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0210849A1 (en) * | 1985-07-30 | 1987-02-04 | Imperial Chemical Industries Plc | 2-Hydroxy-3-phenoxypropyl amines |
| EP0254532A1 (en) * | 1986-07-23 | 1988-01-27 | Imperial Chemical Industries Plc | Amide derivatives |
| EP0431763A2 (en) * | 1989-11-17 | 1991-06-12 | Imperial Chemical Industries Plc | Therapeutic agents for lowering triglyceride and/or cholesterol levels and/or increasing HDL levels |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001035947A3 (en) * | 1999-11-15 | 2001-11-22 | Lilly Co Eli | Treating wasting syndromes with aryloxy propanolamines |
Also Published As
| Publication number | Publication date |
|---|---|
| AU5532094A (en) | 1994-06-22 |
| GB9224740D0 (en) | 1993-01-13 |
| ZA938803B (en) | 1994-05-26 |
| GB9324241D0 (en) | 1994-01-12 |
| IL107767A0 (en) | 1994-05-30 |
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