Method of inducing opioid analgesia and anesthesia without respiratory suppression

• US 20030092701A1
• Filed: 11/09/2001
• Published: 05/15/2003
• Est. Priority Date: 11/09/2001
• Status: Active Grant

• Current Assignee: Wisconsin Alumni Research Foundation (University of Wisconsin System)
• Original Assignee: Wisconsin Alumni Research Foundation (University of Wisconsin System)
• Inventors: Lalley, Peter M.
• Granted Patent: US 6,706,704 B2
• Time in Patent Office: Days
• US Class Current: 514/217.02
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole

Abstract

The invention is directed to a pharmaceutical composition and a corresponding method for inducing analgesia or anesthesia in a mammalian subject, while simultaneously inhibiting respiratory depression in the subject. The composition contains in combination, an opiate or opioid analgesic or anesthetic and a D₁-dopamine receptor agonist in an amount sufficient to inhibit respiratory depression caused by the opiate or opioid.

Claims

1. A method of eliminating or inhibiting respiratory depression in mammals during treatment with opiates or opioids, the method comprising:

administering to a mammalian subject being treated with opiates or opioids, an amount of a D₁-dopamine receptor agonist, the amount being sufficient to inhibit respiratory depression.

2. The method of claim 1, wherein the mammalian subject is a human.

3. The method of claim 1, wherein there is administered to the subject a D₁-dopamine receptor agonist selected from the group consisting of:

(±

)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol;

(−

)-(6aR,12bR)-4,6,6a,7,8,12b-hexahydro-7-methylindolo{4,3-a}phenanthridine;

(±

)-trans-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo-{a}phenanthridine;

(±

)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine;

(±

)-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine;

ABT 431;

enriched or pure enantiomers or diastereomers thereof, racemic mixtures thereof, and pharmaceutically-suitable salts thereof.

4. The method of claim 3, wherein the mammalian subject is a human.

5. The method of claim 4, wherein (±

)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol is administered to the subject.

6. The method of claim 4, wherein (−

)-(6aR,12bR)-4,6,6a,7,8,12b-hexahydro-7-methylindolo{4,3-a}phenanthridine is administered to the subject.

7. The method of claim 4, wherein (±

)-trans-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo-{a}phenanthridine is administered to the subject.

8. The method of claim 4, wherein (±

)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine is administered to the subject.

9. The method of claim 4, wherein (±

)-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine is administered to the subject.

10. The method of claim 4, wherein ABT 431 is administered to the subject.

11. The method of claim 1, wherein the D₁-dopamine receptor agonist is administered systemically.

13. The method of claim 1, wherein the D₁-dopamine receptor agonist is administered to the subject in an amount ranging from about 0.01 to about 50 mg/kg body weight per day,

14. The method of claim 1, wherein the D₁-dopamine receptor agonist is administered to the subject in an amount ranging from about 0.1 to about 10 mg/kg body weight per day.

12. The method of claim 111, wherein the D₁-dopamine receptor agonist is administered intravenously.

15. A pharmaceutical composition for inducing analgesia or anasthesia in a mammalian subject, while simultaneously inhibiting respiratory depression in the subject, the composition comprising, in combination, an opiate or opioid analgesic or anesthetic, a D₁-dopamine receptor agonist, and a pharmaceutically-suitable carrier therefor.

16. The pharmaceutical composition of claim 15, wherein the opiate or opioid is selected from the group consisting of alfentanil, buprenorphine, carfentanil, codeine, dihydrocodeine, diprenorphine, etorphine, fentanyl, heroin, hydrocodone, hydromorphone, LAAM, levorphanol, meperidine, methadone, morphine, naloxone, naltrexone, beta-hydroxy-3-methylfentanyl, oxycodone, oxymorphone, propoxyphene, remifentanil, sufentanil, tilidine, tramadol, enriched or pure enantiomers or diastereomers thereof;

racemic mixtures thereof; and

pharmaceutically-suitable salts thereof.

17. The pharmaceutical composition of claim 15, wherein the D₁-dopamine receptor agonist is selected from the group consisting of

(±

)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol;

(−

)-(6aR, 12bR)-4,6,6a,7,8,12b-hexahydro-7-methylindolo{4,3-a}phenanthridine;

(±

)-trans-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo-{a}phenanthridine;

(±

)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine;

(±

)-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine;

ABT 431;

enriched or pure enantiomers or diastereomers thereof;

racemic mixtures thereof, and pharmaceutically-suitable salts thereof.

18. The pharmaceutical composition of claim 15, wherein the D₁-dopamine receptor agonist is (±

)-11-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol.

19. The pharmaceutical composition of claim 15, wherein the D₁-dopamine receptor agonist is (−

)-(6aR, 12bR)-4,6,6a,7,8, 12b-hexahydro-7-methylindolo{4,3-a}phenanthridine.

20. The pharmaceutical composition of claim 15, wherein the D₁-dopamine receptor agonist is (±

)-trans-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo-{a}phenanthridine.

21. The pharmaceutical composition of claim 15, wherein the D₁-dopamine receptor agonist is (±

)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine.

22. The pharmaceutical composition of claim 15, wherein the D₁-dopamine receptor agonist is (±

)-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine.

23. The pharmaceutical composition of claim 15, wherein the D₁-dopamine receptor agonist is ABT 431.