Controlled administration of chemodenervating pharmaceuticals

• US 5,401,243 A
• Filed: 04/12/1993
• Issued: 03/28/1995
• Est. Priority Date: 08/21/1990
• Status: Expired due to Term

• Current Assignee: Revance Therapeutics, Inc.
• Original Assignee: Associated Synapse Biologics
• Inventors: Borodic, Gary E.
• Primary Examiner(s): Passaniti, Sebastiano
• Application Number:
  US08/046,097
• Time in Patent Office: 715 Days
• Field of Search: 604/49-53, 604/28, 128/749, 128/898, 128/632, 128/635, 128/774, 128/782, 128/741, 128/DIG. 13
• US Class Current: 604/511
• CPC Class Codes: A61K 38/4886 Metalloendopeptidases (3.4.24), e.g. collagenase
• CPC Class Codes: A61K 8/64 Proteins; Peptides; Derivatives or degradation products thereof
• CPC Class Codes: A61K 8/99 from microorganisms other than algae or fungi, e.g. protozoa or bacteria
• CPC Class Codes: A61Q 19/08 Anti-ageing preparations

Abstract

The activity of chemodenervating agents can be ascertained by injecting locally a known quantity of the agent and determining the extent of inhibition of acetylcholine release about the locus resulting therefrom. Inhibition of acetylcholine release is indicative of denervation in a muscle, therefore the extent of inhibition of acetylcholine release is coextensive with the zone of denervation induced by the quantity of the agent.

Claims

1. A method of measuring the denervating activity of a chemodenervating preparation comprising

injecting a quantity of said preparation into a muscle or muscle group of an animal;

permitting said preparation to diffuse within said muscle or muscle group thereby establishing a denervation field; and

determining the extent of the denervation field induced by said quantity of the preparation within said muscle or muscle group.

2. The method of claim 1 wherein the step of determining the extent of the denervation field is performed by measuring inhibition of acetylcholine release about the site of injection.

3. The method of claim 2 comprising determining the local concentration of acetylcholinesterase in regions of said muscle spaced apart from said site of injection.

4. The method of claim 3 wherein the local concentration is determined by histochemical estimation of acetylcholinesterase enzyme activity.

5. The method of claim 1 wherein the step of determining the extent of the denervation field is performed by determining the extent of inhibition of muscle stimulation in regions of said muscle spaced apart from said site of injection by electrophysiologic testing.

6. The method of claim 5 comprising determining the extent of effective muscular stimulation by single fiber electromyography.

7. The method of claim 1 wherein the step of determining the extent of the denervation field is performed by determining the density of acetylcholine receptors or acetylcholinesterase in regions of said muscle spaced apart from said site of injection.

8. The method of claim 7 wherein the density of said acetylcholine receptors or acetylcholinesterase is determined by binding labeled antibodies to said receptors or acetylcholinesterase.

9. The method of claim 1 wherein the step of determining the extent of the dernervation field is performed by measuring the change in muscle fiber diameter.

10. The method of claim 9 wherein the variation in muscle fiber diameter is determined by obtaining a biopsy of the treated muscle or muscle group at various distances from the site of injection and determining the mean muscle fiber diameter and diameter variation thereof.

11. The method of claim 1 wherein the muscle or muscle group comprises an eye muscle or muscle group, and wherein the step of determining the extent of the dernervation field is performed by observing the degree of ptosis or globe prolapse resulting from said injection.

12. The method of claim 1 wherein said preparation is a botulinum toxin-derived preparation.

13. A method of rapidly determining the extent of denervation induced by a unit quantity of a chemodenervating preparation comprising the steps of:

injecting said unit quantity of said chemodenervating preparation into a muscle or muscle group which controls eyelid movement of an animal; and

ascertaining the degree of ptosis or globe prolapse resulting from said injection, wherein said degree of ptosis or globe prolapse is indicative of the spatial extent of denervation induced by said unit quantity.

14. The method of claim 13 wherein the preparation is injected into the levator palpebral superioris muscle.

15. The method of claim 13 wherein said chemodenervating preparation comprises a botulinum toxin preparation.

16. The method of claim 13 wherein said ascertaining step further comprises determining the diffusion capability of said chemodenervating preparation.