JP-2022514014-A5 -

Dates

Publication Date

20221227

Application Date

20191220

Description

In conclusion, nerve block injections of RTX as a single dose to rats at doses of 0 μg, 0.625 μg, 2.5 μg, or 10 μg did not result in any substance-related mortality, organ weight differences, or macroscopic findings. RTX ≥ 2.5 μg resulted in non-adverse microscopic changes (single-cell necrosis) in the mammary gland, and 10 μg of RTX resulted in microscopic changes (muscle fiber degeneration/necrosis) in the skeletal muscle, all of which resolved completely after a 14-day recovery period. Microscopic changes related to control substance 2 were observed at the injection site (mixed cell inflammation with or without muscle fiber degeneration/necrosis). All of these findings resolved completely after a 14-day recovery period. In certain embodiments, for example, the following items are provided: (Item 1) A method for treating maladaptive pain, comprising the step of administering resiniferatoxin (RTX) periperineurally to a subject requiring treatment for maladaptive pain. (Item 2) A composition comprising resiniferatoxin (RTX) for use in a method for treating maladaptive pain, wherein the method comprises the step of administering RTX periperineurally to a subject requiring treatment of maladaptive pain. (Item 3) The method or composition for use according to item 1 or 2, wherein the method comprises the step of administering RTX in a dose of 0.1 μg to 100 μg. (Item 4) The method or composition for use according to item 3, wherein the dose of RTX is in the range of 0.1 to 1 μg, 1 to 2 μg, 2 to 5 μg, 5 to 10 μg, 10 to 20 μg, 20 to 30 μg, 30 to 40 μg, 40 to 50 μg, 50 to 60 μg, 60 to 70 μg, 70 to 80 μg, 80 to 90 μg, or 90 to 100 μg. (Item 5) A method or composition for use according to any one of the above items, wherein the RTX is administered perineurally to a single site, multiple sites, the sciatic nerve, saphenous nerve, femoral nerve, radial nerve, ulnar nerve, median nerve, musculocutaneous nerve, and/or palmar digital nerve. (Item 6) A method or composition for use according to any one of the above items, wherein the RTX is administered perineurally to multiple sites that collectively correspond to sensory input from one or more fingers, feet or hands, forelimbs, limbs, and/or joints. (Item 7) A method or composition for use as described in any one of the above items, wherein the subject is a person who has undergone amputation surgery. (Item 8) A method or composition for use according to any one of the preceding items, wherein the perineurial administration targets one or more nerve fibers downstream of the transection site. (Item 9) A method or composition for use according to any one of the above items, wherein the subject is suffering from phantom limb pain or stump pain. (Item 10) A method or composition for use according to any one of items 7 to 9, wherein the perineurial administration targets at least two, three, four, or five nerve fibers downstream of the transection site. (Item 11) A method or composition for use according to any one of the above items, wherein the subject has abnormal nerve growth at the nerve terminal. (Item 12) A method or composition for use according to item 11, wherein the perineurial administration targets one or more nerve fibers downstream of a nerve that has abnormal growth at its peripheral end. (Item 13) A method or composition for use according to any one of the preceding items, wherein the perineurial administration targets one or more nerve fibers downstream of the neuroma. (Item 14) A method or composition for use according to any one of the preceding items, comprising the step of administering a pharmaceutical formulation comprising the RTX and a pharmaceutically acceptable carrier. (Item 15) The pharmaceutically acceptable carrier comprises water, the method or composition for use described in item 14. (Item 16) A method or composition for use according to item 14 or 15, wherein the pharmaceutically acceptable carrier comprises polysorbate® 80. (Item 17) A method or composition for use according to any one of items 14 to 16, wherein the pharmaceutically acceptable carrier comprises polyethylene glycol. (Item 18) A method or composition for use according to any one of items 14 to 17, wherein the pharmaceutically acceptable carrier comprises a sugar or a sugar alcohol. (Item 19) The pharmaceutically acceptable carrier comprises mannitol, the method or composition for use described in item 18. (Item 20) A method or composition for use according to item 18 or 19, wherein the pharmaceutically acceptable carrier comprises dextrose. (Item 21) A method or composition for use according to any one of items 14 to 20, wherein the pharmaceutically acceptable carrier comprises a pharmaceutically acceptable buffer. (Item 22) The method or composition for use according to item 21, wherein the pharmaceutically acceptable carrier comprises a phosphate buffer. (Item 23) The method or composition for use according to any one of items 14 to 22, wherein the pharmaceutical preparat