The invention relates to compounds of formula I or pharmaceutically acceptable salts thereof, useful as inhibitors of sodium channels: (I). The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders, including pain. ##STR00001##

In part, the present disclosure relates methods for treating, preventing, or reducing the severity of a myeloproliferative disorder (e.g., polycythemia vera, essential thrombocythemia, and myelofibrosis) or one or more complications of a myeloproliferative disorder. The present disclosure further relates methods for treating, preventing, or reducing the severity of a Janus kinase-associated disorder or one or more complications of a Janus kinase-associated disorder. In certain aspects the disclosure provides TβRII antagonists for treating, preventing, or reducing the severity of a myeloproliferative disorder (e.g., polycythemia vera, essential thrombocythemia, and myelofibrosis) or a Janus kinase-associated disorder or one or more complications of a myeloproliferative disorder or a Janus kinase-associated disorder.

The present invention relates to compositions providing improved preservative efficacy. The present invention further relates to polyquaternium compound containing compositions having improved the antifungal activity. In certain embodiments, the present invention relates to ophthalmic compositions comprising a polyquaternium compound, a polyol or combination of polyols, borate compound, and an antimicrobial mixture comprising electrolytes and nutrients.

The present invention provides compounds useful as inhibitors of PAD4, compositions thereof, and methods of treating PAD4-related disorders.

A topical composition includes a cannabinoid, a terpenoid, and a skin penetration system that includes dimethyl sulfoxide (DMSO) and at least one compatibilizer. The composition may be in the form of an emulsion that further contains water and at least one fatty component. The composition can be used to reduce or eliminate pain by topical application to an affected region of the body. The composition provides localized pain relief by providing a focused quantity of cannabinoid in the region of the pain instead of distributing the cannabinoid systemically and/or delivering it to the brain or central nervous system.

A topical composition includes a cannabinoid, a terpenoid, and a skin penetration system that includes dimethyl sulfoxide (DMSO) and at least one compatibilizer. The composition may be in the form of an emulsion that further contains water and at least one fatty component. The composition can be used to reduce or eliminate pain by topical application to an affected region of the body. The composition provides localized pain relief by providing a focused quantity of cannabinoid in the region of the pain instead of distributing the cannabinoid systemically and/or delivering it to the brain or central nervous system.

A medicinal agent for the prevention and/or treatment of diseases caused by EP.sub.4 receptor activation is disclosed. A compound having antagonistic activity against the EP.sub.4 receptor is contained as an active ingredient in the medicinal agent. The compound represented by the following general formula (I) as defined in the specification, a salt, an N-oxide, or a solvate thereof, or a prodrug of these is useful as a medicinal component having antagonistic activity against the EP.sub.4 receptor for the prevention and/or treatment of diseases caused by EP.sub.4 receptor activation. ##STR00001##

The invention concerns a method for relieving idiopathic ocular pain by administering an effective amount of a fluid composition comprising hyaluronic acid, a hyaluronic acid analogue, or a combination thereof, to the eye of a human or non-human animal subject, wherein the fluid composition is administered after onset of the idiopathic ocular pain and in the absence of detectable signs known to cause ocular pain.

An increasing body of evidence suggests that Nav1.7 encoded by SCN9A gene may play a key role in various pain states, including acute, inflammatory and/or neuropathic pain. The inventors now report an efficient treatment for severe cases of primary erythromelagia linked to a specific SCN9A mutation. In particular the inventors demonstrated that the inhibition of JAK2 produces a rightward shift in the voltage dependent activation of mutant Nav1.7 channels, thereby normalizing the function of mutant Nav1.7 channels. On this basis, the inventors treated a patient suffering from PE with very severe refractory pain with a JAK2 inhibitor (ruxolitinib) and showed the therapy leads to considerable reduction of pain. Accordingly, the present invention relates to the use of JAK inhibitors for the treatment of painful conditions involving Nav1.7 channels.

An increasing body of evidence suggests that Nav1.7 encoded by SCN9A gene may play a key role in various pain states, including acute, inflammatory and/or neuropathic pain. The inventors now report an efficient treatment for severe cases of primary erythromelagia linked to a specific SCN9A mutation. In particular the inventors demonstrated that the inhibition of JAK2 produces a rightward shift in the voltage dependent activation of mutant Nav1.7 channels, thereby normalizing the function of mutant Nav1.7 channels. On this basis, the inventors treated a patient suffering from PE with very severe refractory pain with a JAK2 inhibitor (ruxolitinib) and showed the therapy leads to considerable reduction of pain. Accordingly, the present invention relates to the use of JAK inhibitors for the treatment of painful conditions involving Nav1.7 channels.