WO1997007807A1 - New use of pregnane-diones as analgesic agents - Google Patents

New use of pregnane-diones as analgesic agents Download PDF

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Publication number
WO1997007807A1
WO1997007807A1 PCT/AU1996/000531 AU9600531W WO9707807A1 WO 1997007807 A1 WO1997007807 A1 WO 1997007807A1 AU 9600531 W AU9600531 W AU 9600531W WO 9707807 A1 WO9707807 A1 WO 9707807A1
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Prior art keywords
analgesic
compound
formula
composition according
new use
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Application number
PCT/AU1996/000531
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French (fr)
Inventor
Colin Stanley Goodchild
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Colin Stanley Goodchild
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Colin Stanley Goodchild filed Critical Colin Stanley Goodchild
Priority to EP96927448A priority Critical patent/EP0845990A4/en
Priority to AU67267/96A priority patent/AU6726796A/en
Publication of WO1997007807A1 publication Critical patent/WO1997007807A1/en
Priority to US09/026,520 priority patent/US6048848A/en
Priority to US09/197,161 priority patent/US6787530B1/en

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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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • 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

Definitions

  • TITLE New Use of Pregnane-diones as analgesic agents
  • This invention relates to compounds and compositions.
  • the present invention relates to analgesia, methods of analgesia and analgesic compositions.
  • the present invention provides:-
  • R 1 is H or Me, preferably H; R 2 is OH, preferably in alpha conformation; R 3 is H; or R 2 and R 3 , taken together, are O; R* is H or Me, preferably Me and preferably in alpha conformation; R 5 is H; R 6 is H; or R 5 and R 6 , taken together, are O; R 7 is H or Me, preferably H; R ⁇ is H, Me or -CH 2 0 CO CH 3 .
  • R 1 is H or Me, preferably H
  • R 2 is OH, preferably in alpha conformation
  • R 3 is H; or R 2 and R 3 , taken together, are 0;
  • R 4 is H or Me, preferably Me and preferably in alpha conformation
  • R 5 is H
  • R 6 is H; or R 5 and R 6 , taken together, are 0;
  • R 7 is H or Me, preferably H
  • R ⁇ is H, Me or -CH 2 0 CO CH 3 .
  • the present invention also provides an analgesic composition
  • an analgesic composition comprising a compound of Formula II wherein
  • R 1 is H or Me, preferably H;
  • R 2 is OH, preferably in alpha conformation;
  • R 3 is H; or R 2 and R 3 , taken together, are 0;
  • R* is H or Me, preferably Me and preferably in alpha conformation;
  • R 5 is H;
  • R 6 is H; or
  • R 5 and R 6 taken together, are 0;
  • R 7 is H or Me, preferably H;
  • R ⁇ is H, Me or -CH 2 0 CO CH 3 together with a pharmaceutically acceptable diluent.
  • the compounds of the invention are related to pregnane-dione which is shown in Formula I.
  • German Patent Specification No. 2,162,554 (filed 29th June, 1972, based on British Application No. 60,068/70 filed 17th December, 1970) to GLAXO;
  • a preferred compound for use is
  • the compounds may be used individually or in mixtures with other compounds of Formula II.
  • compounds of Formula II may be used concurrently with other analgesic drugs such as opioids to potentiate or increase the analgesic effects of those drugs.
  • opioids for this use include morphine.
  • the compounds for use in this invention may be provided in free acid form or as a salt. It is preferred that the compounds are provided as either sulphate or methane sulphonate salts.
  • compositions of this invention may be prepared for administration by various routes including intravenous. intramuscular, peritoneal and any other convenient route.
  • the present invention provides a composition in a form suitable for oral administration.
  • That form may include tablet, capsule or lozenge or a liquid form.
  • composition contains a surfactant and/or a solubility improver.
  • a solubility improver is water-soluble polyoxyethylated castor oil.
  • a suitable surfactant is Cremophor EL.
  • a suitable dosage in a 70kg human would be about a maximum of 2.00 grams of the compound of Formula II every 6 hours.
  • Figure 1 is a graph showing results obtained.
  • Figure 2 is a graph showing results obtained
  • figure 2 is a time response curve showing the mean of the responses in all five rats to the drug with vehicle and vehicle (Cremophor) alone. In all cases alphadolone caused rises in ECT pain thresholds in the neck and tail whereas the vehicle alone had no effect.
  • bicuculline 10 pmol was given intrathecally 30 minutes after the intragastric drug or vehicle.
  • Bicuculline is a selective GABA A receptor antagonist. In confining bicuculline to the part of the spinal cord responsible for tail innervation we would expect tail GABA-mediated responses to be reversed but those responsible for neck sensations to be unaffected. That is the result shown in Figure 2.
  • alphadolone causes analgesia by acting on GABA ⁇ receptors in the spinal cord even when the drug is given into the stomach.
  • the vehicle had no effect the rats were not sedated or exhibited any disturbances in consciousness in any way.

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

Abstract

The present invention provides: the new use of compounds of formula (II) wherein R1 is H or Me, preferably H; R2 is OH, preferably in alpha conformation; R3 is H, or R?2 and R3¿, taken together, are O; R4 is H or Me, preferably Me, and preferably in alpha conformation; R5 is H; R6 is H; or R5 and R¿6?, taken together, are O; R?7¿ is H or Me, preferably H; R8 is H, Me or -CH¿2? O CO CH3. The present invention also provides a method of analgesia comprising administering an effective amount of a compound of formula (II) wherein R?1¿ est H or Me, preferably H; R2 is OH, preferably in alpha conformation; R3 is H, or R?2 and R3¿, taken together, are O; R4 is H or Me, preferably Me, and preferably in alpha conformation; R5 is H; R6 is H; or R?5 and R6¿, taken together, are O; R7 is H or Me, preferably H; R8 is H, Me or -CH¿2? O CO CH3. The present invention also provides an analgesic composition comprising a compound of formula (II) wherein R?1¿ is H or Me, preferably H; R2 is OH, preferably in alpha conformation; R3 is H, or R?2 and R3¿, taken together, are O; R4 is H or Me, preferably Me, and preferably in alpha conformation; R5 is H; R6 is H; or R?5 and R6¿, taken together, are O; R7 is H or Me, preferably H; R8 is H, Me or -CH¿2? O CO CH3 together with a pharmaceutically acceptable diluent.

Description

TITLE : New Use of Pregnane-diones as analgesic agents
FIELD OF THE INVENTION
This invention relates to compounds and compositions.
In a particular instance, the present invention relates to analgesia, methods of analgesia and analgesic compositions.
SUMMARY OF THE INVENTION
The present invention provides:-
the new use of compounds of Formula II as shown in the accompanying drawings wherein R1 is H or Me, preferably H; R2 is OH, preferably in alpha conformation; R3 is H; or R2 and R3, taken together, are O; R* is H or Me, preferably Me and preferably in alpha conformation; R5 is H; R6 is H; or R5 and R6, taken together, are O; R7 is H or Me, preferably H; Rβ is H, Me or -CH20 CO CH3.
The present invention also provides a method of analgesia comprising administering an effective amount of a compound of Formula II wherein
R1 is H or Me, preferably H;
R2 is OH, preferably in alpha conformation;
R3 is H; or R2 and R3, taken together, are 0;
R4 is H or Me, preferably Me and preferably in alpha conformation;
R5 is H;
R6 is H; or R5 and R6, taken together, are 0;
R7 is H or Me, preferably H;
Rβ is H, Me or -CH20 CO CH3.
The present invention also provides an analgesic composition comprising a compound of Formula II wherein
R1 is H or Me, preferably H; R2 is OH, preferably in alpha conformation; R3 is H; or R2 and R3, taken together, are 0;
R* is H or Me, preferably Me and preferably in alpha conformation; R5 is H; R6 is H; or R5 and R6, taken together, are 0; R7 is H or Me, preferably H; Rβ is H, Me or -CH20 CO CH3 together with a pharmaceutically acceptable diluent.
PREFERRED ASPECTS OF THE INVENTION
The compounds of the invention are related to pregnane-dione which is shown in Formula I.
The following Patent Specifications describe some of the compounds and their method of preparation:-
British Patent Specification No. 1,317,185 (Application No. 33162/72 filed 16th May, 1973) to GLAXO;
German Patent Specification No. 2,255,108 (based on British Application No. 52465/71 filed 11th November, 1971) to GLAXO;
USA Patent Specification No. 3,558,608 (granted 27th January, 1971, filed 30th December, 1968) to SEARLE;
South African Patent Specification 70/03861 (filed 15th January, 1971 based on British Application filed 20th June, 1969) to GLAXO;
German Patent Specification No. 2,162,554 (filed 29th June, 1972, based on British Application No. 60,068/70 filed 17th December, 1970) to GLAXO;
French Patent Specification No. 2,118,121 (filed 1st September, 1972, based on British Application 60,068/70 filed 17th December, 1970) to GLAXO; and German Patent Specification No. 2,162,593 (filed 6th July, 1972, based on British Application No. 60,067/70 filed 17th December, 1970) to GLAXO.
The whole of the subject matter of those specifications together with items 105627c and 9285v of Chemical Abstracts, Vol. 77, 1972; 64113v, 64114w, 20793n of Chemical Abstract 5, Vol. 75, 1971; 115783f and 66672h of Chemical Abstracts Vol 79, 1973; and 1020345 of Chemical Abstracts Vol 78, 1973 is to be considered included and imported hereinto.
A preferred compound for use is
21-acetoxy-3alpha-hydroxy-5alpha-pregnane-ll,20-dione which is of Formula III and which is commonly referred to as alphadolone.
Other compounds which may be suitable for use include: 3alpha-hydroxy-5alpha-pregnan-20-one and 3alpha-hydroxy-5beta-pregnan-20-one which are of Formula IV.
The compounds may be used individually or in mixtures with other compounds of Formula II.
In addition, compounds of Formula II may be used concurrently with other analgesic drugs such as opioids to potentiate or increase the analgesic effects of those drugs. Suitable opioids for this use include morphine.
The compounds for use in this invention may be provided in free acid form or as a salt. It is preferred that the compounds are provided as either sulphate or methane sulphonate salts.
The compositions of this invention may be prepared for administration by various routes including intravenous. intramuscular, peritoneal and any other convenient route.
However, the applicant has found that effective results are obtained when a compound of Formula II is administered into the intestines particularly intragastrically, and in a particular instance via an oral route.
Accordingly, in a preferred aspect, the present invention provides a composition in a form suitable for oral administration.
That form may include tablet, capsule or lozenge or a liquid form.
It is preferred that the composition contains a surfactant and/or a solubility improver. One solubility improver is water-soluble polyoxyethylated castor oil.
A suitable surfactant is Cremophor EL.
A suitable dosage in a 70kg human would be about a maximum of 2.00 grams of the compound of Formula II every 6 hours.
BRIEF DESCRIPTION OF THE VIEW OF THE DRAWINGS
Figure 1 is a graph showing results obtained.
Figure 2 is a graph showing results obtained, and
Figure 3 is formula drawings.
Examples
Example 1
We performed a pilot experiment on one drug naive male Wistar rat that weighed approximately 200g. We measured the nociceptive (pain) threshold in the tail using electrical current as the noxious stimulus. We measured the electrical current threshold for pain (ECT) in the tail every five minutes until the readings stabilised. We then gave 150 mg alphadolone suspended in 1% Cremophor EL, 99% saline, intragastrically. Subsequent ECT measurements as shown in Figure 1 showed a significant rise in tail pain thresholds which lasted a long time after drug administration.
Example 2
We performed a more controlled series of experiments with intragastric alphadolone (150 mg dissolved in 1.0 ml 20% Cremophor EL to 200g male wistar rats). We measured ECT in the neck and the tail every 5 minutes for 15 minutes before and for some time after drug administration. Five rats received on two successive days at random either alphadolone in Cremophor EL followed by Cremophor alone on the next day or vice versa. These experiments were also performed double blind. By that we mean that, at the time of the experiment the person making the measurements did not know what the rat received, drug plus Cremophor or just Cremophor alone.
These results are shown in figure 2 which is a time response curve showing the mean of the responses in all five rats to the drug with vehicle and vehicle (Cremophor) alone. In all cases alphadolone caused rises in ECT pain thresholds in the neck and tail whereas the vehicle alone had no effect.
In all of these experiments bicuculline 10 pmol was given intrathecally 30 minutes after the intragastric drug or vehicle. By giving bicuculline intrathecally to the lumbrosacral spinal cord we were able to test the theory that the antinociception or pain relief following intragastric alphadolone was due to an action of that drug on spinal cord GABAA receptors. Bicuculline is a selective GABAA receptor antagonist. In confining bicuculline to the part of the spinal cord responsible for tail innervation we would expect tail GABA-mediated responses to be reversed but those responsible for neck sensations to be unaffected. That is the result shown in Figure 2. Thus the conclusion from this is that alphadolone causes analgesia by acting on GABAλ receptors in the spinal cord even when the drug is given into the stomach. The vehicle had no effect the rats were not sedated or exhibited any disturbances in consciousness in any way.
The claims and drawings form part of the disclosure of this specification as does the description, claims, illustrations, photographs and drawings of any associated provisional or parent specification or of any priority document, if any, all of which are imported herelnto as part of the record hereof.
Finally it is to be understood that various alterations, modifications and/or additions may be incorporated into the various constructions and arrangements or parts without departing from the spirit and ambit of the invention.

Claims

THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:-
1. An analgesic composition comprising a compound of Formula II wherein
R1 is H or Me,
R2 is OH,
R3 is H; or R2 and R3, taken together, are 0; R4 is H or Me,
Rs is H;
R6 is H; or R5 and R6, taken together, are O;
R7 is H or Me, Rβ is H, Me or -CH20 CO CH3 together with a pharmaceutically acceptable diluent.
2. An analgesic composition according to Claim 1, wherein R1 is H; R2 is OH in alpha conformation, R4 is Me and R7 is H.
3. An analgesic composition according to Claim 2 wherein R4 is Me in alpha conformation.
4. An analgesic composition according to Claim 1 comprising alphadolone.
5. An analgesic composition according to Claim 1 comprising 3alpha-hydroxy-5alpha-pregnan-20-one.
6. An analgesic composition according to Claim 1 comprising 3alpha-hydroxy-5beta-pregnan-20-one.
7. An analgesic composition according to Claim 1 comprising more than one compound according to Formula
II.
8. An analgesic composition according to Claim 1 comprising an additional analgesic drug.
9. An analgesic composition according to Claim 8 comprising an opioid drug.
10. An analgesic composition according to Claim 9 comprising morphine.
11. An analgesic composition according to Claim 1 in a form suitable for oral administration.
12. An analgesic composition according to Claim 11 in a liquid form.
13. An analgesic composition according to Claim 11 in the form of a tablet, capsule or lozenge.
14. An analgesic composition according to Claim 1 comprising a surfactant and/or a solubility improver.
15. An analgesic composition according to claim 14 in which the surfactant is Cremophor EL.
16. An analgesic composition according to Claim 14 in which the solubility improver is water-soluble polyoxyethylated castor oil.
17. A method of analgesia comprising administering an effective amount of a compound of Formula II wherein:
R1 is H or Me, R2 is OH, R3 is H; or R2 and R3, taken together, are 0; R4 is H or Me, R5 is H; R6 is H; or R5 and R6, taken together, are 0; R7 is H or Me,
Rβ is H, Me or -CH2 0 CO CH3
18. A method according to Claim 17 wherein R1 is H; R2 is OH in alpha conformation, R4 is Me and R7 is H.
19. A method according to Claim 18 wherein R4 is Me in alpha conformation.
20. A method according to Claim 17 wherein the compound of Formula II is alphadolone.
21. A method according to Claim 17 wherein the compound of Formula II is 3alpha-hydroxy-5alpha-pregnan-20-one.
22. A method according to Claim 17 wherein the compound of Formula II is 3alpha-hydroxy-5beta-pregnan-20-one.
23. A method according to Claim 17 comprising administering effective amounts of more than one compound according to Formula II.
24. A method according to Claim 17 comprising an additional analgesic drug.
25. A method according to Claim 24 wherein the additional analgesic drug is an opioid drug.
26. A method according to Claim 25 wherein the opioid drug is morphine.
27. A method according to Claim 17 in which the compound is administered by the intravenous, intramuscular or peritoneal route.
28. A method according to Claim 17 in which the compound is administered into the intestines.
29. A method according to Claim 28 in which the compound is administered intragastrically.
30. A method according to Claim 29 in which the compound is administered via an oral route.
31. A method according to Claim 17 in which the compound of Formula II is administered up to a maximum dose of 2.00 grams/70kg human every 6 hours.
32. The new use as an analgesic agent of a compound of Formula II wherein
R1 is H or Me,
R2 is OH,
R3 is H; or R2 and R3, taken together, are 0;
R4 is H or Me,
R5 is H;
R6 is H; or R5 and R6, taken together, are 0; R7 is H or Me,
R8 is H, Me or -CH2 0 CO CH3
33. The new use as an analgesic agent of a compound according to Claim 32 wherein R1 is H; R2 is OH in alpha conformation, R4 is Me and R7 is H.
34. The new use as an analgesic agent of a compound according to Claim 33 wherein R4 is Me in alpha conformation.
35. The new use as an analgesic agent of alphdolone.
36. The new use as an analgesic agent of 3alρha-hydroxy- 5alpha-pregnan-20-one.
37. The new use as an analgesic agent of 3alpha-hydroxy- 5beta-pregnan-20-one.
38. The new use as an analgesic agent of a mixture of more than one compound according to Claim 32.
39. The new use of a compound of Formula II wherein
R1 is H or Me,
R2 is OH,
R3 is H; or R2 and R3, taken together, are 0; R4 is H or Me,
R5 is H;
R6 is H; or R5 and R6, taken together, are 0;
R7 is H or Me, R8 is H, Me, or -CH2 0 CO CH3 to potentiate the effect of an analgesic drug.
40. The new use of a compound of Formula II according to Claim 39 to potentiate the analgesic effect of an opioid drug.
41. The new use of a compound of Formula II according to Claim 40 to potentiate the analgesic effect of morphine.
42. An analgesic composition substantially as hereinbefore described with reference to the examples.
43. A method of analgesia substantially as hereinbefore described with reference to the examples.
44. The new use as an analgesic agent of a compound of Formula II substantially as hereinbefore described with reference to the examples.
45. The steps, features, compositions and compounds referred to or indicated in the specification and/or claims of this application, individually or collectively, and any and all combinations or any two or more of said steps or features.
PCT/AU1996/000531 1995-08-23 1996-08-23 New use of pregnane-diones as analgesic agents WO1997007807A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP96927448A EP0845990A4 (en) 1995-08-23 1996-08-23 New use of pregnane-diones as analgesic agents
AU67267/96A AU6726796A (en) 1995-08-23 1996-08-23 New use of pregnane-diones as analgesic agents
US09/026,520 US6048848A (en) 1996-08-23 1998-02-20 Use of pregnane-diones as analgesic agents
US09/197,161 US6787530B1 (en) 1996-08-23 1998-11-20 Use of pregnane-diones as analgesic agents

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AUPN4980A AUPN498095A0 (en) 1995-08-23 1995-08-23 Compounds and compositions
AUPN4980 1995-08-23

Related Child Applications (1)

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US09/026,520 Continuation-In-Part US6048848A (en) 1996-08-23 1998-02-20 Use of pregnane-diones as analgesic agents

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Cited By (2)

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WO2003018027A1 (en) * 2001-08-28 2003-03-06 Monash University Use of pregnane-diones or diols as neuropathic analgesic agents
WO2005037289A1 (en) * 2003-10-18 2005-04-28 Vernalis (Cambridge) Limited Analgesia method

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KAVALIERS M, WIEBE J P: "ANALGESIC EFFECTS OF THE PROGESTERONE METABOLITE, 3ALPHA-HYDROXY-5ALPHA-PREGNAN-20-ONE, AND POSSIBLE MODES OF ACTION IN MICE", BRAIN RESEARCH, ELSEVIER, AMSTERDAM, NL, vol. 415, 1 January 1987 (1987-01-01), NL, pages 393 - 398, XP001011432, ISSN: 0006-8993, DOI: 10.1016/0006-8993(87)90228-9 *
See also references of EP0845990A4 *
WINFREE C J, ET AL.: "ANALGESIC EFFECTS OF INTRATHECALLY-ADMINISTERED 3ALPHA-HYDROXY-5ALPHA-PREGNAN-20-ONE IN A RAT MECHANICAL VISCERAL PAIN MODEL", LIFE SCIENCES., PERGAMON PRESS, OXFORD, GB, vol. 50, 1 January 1992 (1992-01-01), GB, pages 1007 - 1012, XP001011429, ISSN: 0024-3205, DOI: 10.1016/0024-3205(92)90095-7 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003018027A1 (en) * 2001-08-28 2003-03-06 Monash University Use of pregnane-diones or diols as neuropathic analgesic agents
JP2005504776A (en) * 2001-08-28 2005-02-17 モナシュ　ユニバーシティ Use of pregnane-diones or diols as neuropathic analgesics
WO2005037289A1 (en) * 2003-10-18 2005-04-28 Vernalis (Cambridge) Limited Analgesia method

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AUPN498095A0 (en) 1995-09-14
EP0845990A4 (en) 2001-02-14

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