Sodium channel inactivation is vital for the proper cessation of action potentials. The decreased inactivation caused by these mutations, then, is expected to cause prolonged action potentials and repetitive firing. Such altered firing will cause increased pain sensation and increased sympathetic nervous system activity, producing the phenotype observed in patients with PEPD. Pathophysiology
There are a total of 8 mutations that account for the disorder in 8 of 14 studied families. These mutations are clustered in four regions throughout the channel: the linker between domains 2 and 3 (D2-3), the intracellular segment linking segments 4 and 5 in domain 3 (D3S4-5), the linker between domains 3 and 4 (D3-4) and the intracellular segment linking segments 4 and 5 in domain 4 (D4S4-5). The mutations in the D3S4-5 region (I1461T, F1462V and T1461I) are located in or next to an IFM motif that is conserved across all voltage-gated sodium channels. Mutagenesis studies of this region have shown that it acts as part of the inactivation gate, pivoting to block the central pore. Not surprisingly then, the two of these mutations that have received further study show incomplete inactivation. When the IFM motif pivots to block the central pore it interacts with residues in the D3S4-5 region. There are three mutations in this region (V1298F, F1298D and V1299F) that are believed to alter the interaction with the inactivation gate. While this region has been studied by mutagenesis these specific mutations have not all received attention, though they are expected to produce changes similar to the aforementioned IFM region mutations.
Salsalate is a medication that belongs to the salicylate and nonsteroidal anti-inflammatory drug (NSAID) classes. Salsalate is the generic name of a prescription drug marketed under the brandnames Mono-Gesic, Salflex, Disalcid, and Salsitab. Other generic and brand name formulations may be available. Mechanism of action
Relative to other NSAIDs, salsalate has a weak inhibitory effect on the cyclooxygenase enzyme and decreases the production of several proinflammatory chemical signals such as interleukin-6, TNF-alpha, and C-reactive protein.The mechanism through which salsalate is thought to reduce the production of these inflammatory chemical signals is through the inhibition of IκB kinase resulting in decreased action of NF-κB genes. This mechanism is thought to be responsible for salsalates insulin-sensitizing and blood sugar lowering properties. Medical uses
Salsalate may be used for inflammatory disorders such as rheumatoid arthritis or noninflammatory disorders such as osteoarthritis. Safety
The risk of bleeding is a common concern with use of the NSAID class of medications. However, the bleeding risk associated with salsalate is lower than that associated with aspirin use. Research
Salsalate has been proposed for the prevention and treatment of type 2 diabetes mellitus due to its ability to lower insulin resistance associated with inflammation and may be useful in prediabetes. However, the use of salsalate to prevent the progression from prediabetes to type 2 diabetes mellitus has received limited study. History
Salsalate had been suggested as possible treatment for diabetes as early as 1876. Synthesis


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