Cyp2j2 antagonists in the treatment of pain

Abstract

The present invention pertains to novel treatments of neuropathic pain; in particular chemotherapy induced peripheral neuropathic pain (CIPNP). The invention provides antagonists cytochrome P450 epoxygenases (CYP), and more specifically antagonists of CYP2J2, as therapeutics for use in the treatment of neuropathic pain such as CIPNP. CYP2J2 antagonists were identified to alleviate CIPNP in-vivo, and therefore are provided additionally in combination with chemotherapeutics for the treatment of diseases such as cancer or other proliferative disorders. The CYP2J2 antagonists reduce chemotherapeutic induced pain and therefore allow for a higher dosing of the chemotherapeutic during cancer treatment. In addition the invention relates to the use of CYP2J2 agonists, or metabolites of CYP2J2, for sensitizing TRPV1. In this context the invention proposes to use combinations of CYP2J2 agonist or metabolites and transient receptor potential vanilloid 1 (TRPV1) agonists to treat disorders that respond to TRPV1 agonists, such as neuropathic pain.

1 . A cytochrome P450 epoxygenase (CYP)-antagonist for use in the prevention or treatment of neuropathic pain in a subject, wherein said CYP antagonist is a CYP2J-antagonist. 
     
     
         2 . The CYP antagonist for use according to  claim 1 , wherein said neuropathic pain is selected from the group consisting of post-herpetic neuralgia, trigeminal neuralgia, focal peripheral nerve injury, and anesthesia dolorosa, central pain due to stroke or mass lesion, spinal cord injury, or multiple sclerosis, and peripheral neuropathy due to diabetes, HIV, or chemotherapy. 
     
     
         3 . The CYP antagonist for use according to  claim 1 , wherein said pain is chemotherapy-induced peripheral neuropathic pain (CIPNP). 
     
     
         4 . The CYP antagonist for use according to  claim 1 , wherein said CYP antagonist is a CYP2J2 antagonist selected from the group consisting of estradiol, phenoxybenzamine-HCl, loratadine, clobetasol propionate, doxazosin mesylate, fenofibrate, levonorgestrel, aripiprazole, halcinonide, telmisartan, clofazimine, levothyroxine-Na, alosetron-HCl, fluocinonide, liothyronine-Na, meclizine dihydrochloride and terfenadine. 
     
     
         5 . A 9,10-epoxy-12Z-octadecenoic acid (9,10-EpOME)-antagonist for use in the prevention or treatment of neuropathic pain in a subject. 
     
     
         6 . The 9,10-EpOME-antagonist according to  claim 5 , wherein said pain is chemotherapy-induced peripheral neuropathic pain (CIPNP). 
     
     
         7 . A combination comprising (i) a CYP antagonist or an 9,10-EpOME-antagonist and (ii) a chemotherapeutic agent for concomitant or sequential use in the prevention or treatment of a disease, wherein the disease is selected from a proliferative disorder, such as cancer, or pain, such as CIPNP. 
     
     
         8 . The combination for use according to  claim 7 , wherein (i) and (ii) are combined by sequential or concomitant administration to a subject during said prevention or treatment, preferably wherein the antagonists are concomitantly administered during said prevention or treatment. 
     
     
         9 . The CYP-antagonist for use according to  claim 1 , the 9,10-EpOME-antagonist for use in the prevention or treatment of neuropathic pain in a subject or the combination, comprising (i) a CYP antagonist or an 9,10-EpOME-antagonist and (ii) a chemotherapeutic agent for concomitant or sequential use in the prevention or treatment of a disease, wherein the disease is selected from a proliferative disorder, such as cancer, or pain, such as CIPNP, wherein said antagonists are selected from the group of compounds consisting of inhibitory RNA, inhibitory antibody, and/or small molecule. 
     
     
         10 . The CYP-antagonist for use according to  claim 1 , wherein at least one additional therapeutic effective against pain is administered to said subject. 
     
     
         11 . A 9,10-EpOME or a CYP2J-agonist, for use in the treatment of a disease in a subject. 
     
     
         12 . The 9,10-EpOME or the CYP2J-agonist for use according to  claim 11 , wherein said subject received, receives or will receive a therapy with a transient receptor potential vanilloid 1 (TRPV1)-agonist. 
     
     
         13 . A combination comprising (i) 9,10-EpOME or of an CYP2J-agonists, and (ii) an TRPV1-agonist, for use in medicine, 
     
     
         14 . The 9,10-EpOME or the CYP2J-agonist for use according to  claim 11 , or the combination comprising (i) 9,10-EpOME or of an CYP2J-agonists, and (ii) an TRPV1-agonist, wherein said disease is selected from neuropathic pain (including pain associated with diabetic neuropathy, postherpetic neuralgia, HIV/AIDS, traumatic injury, complex regional pain syndrome, trigeminal neuralgia, erythromelalgia and phantom pain), pain produced by mixed nociceptive and/or neuropathic mixed etiologies (e.g., cancer), osteoarthritis, fibromyalgia, lower back pain, inflammatory hyperalgesia, vulvar vestibulitis or vulvodynia, sinus polyps interstitial cystitis, neurogenic or overactive bladder, prostatic hyperplasia, rhinitis, surgery, trauma, rectal hypersensitivity, burning mouth syndrome, oral mucositis, herpes (or other viral infections), prostatic hypertrophy, dermatitis, pruritis, itch, tinnitus, psoriasis, warts, cancers (especially skin cancers), headaches, and wrinkles. 
     
     
         15 . The 9,10-EpOME or the CYP2J-agonist for use according to  claim 11 , or the combination comprising (i) 9,10-EpOME or of an CYP2J-agonists, and (ii) an TRPV1-agonist, wherein said TRPV1 agonist is selected from the group consisting of capsaicin, piperine, 6-gingerol, 6-shogaol, α-sanshool, β-sanshool, γ-sanshool, δ-sanshool, hydroxyl α-sanshool, and hydroxyl β-sanshool. 
     
     
         16 . The 9,10-EpOME-antagonist for use according to  claim 5  wherein at least one additional therapeutic effective against pain is administered to said subject. 
     
     
         17 . The combination for use according to  claim 7 , wherein at least one additional therapeutic effective against pain is administered to said subject.