Rationale and evidence for the use of oxcarbazepine in neuropathic pain.

Oxcarbazepine is a second-generation antiepileptic drug (AED) with proven efficacy in managing partial epileptic seizures, with or without secondary generalization, in adults and children. The overlap between the underlying pathophysiologic mechanisms of some epilepsy models and neuropathic pain models supports the rationale for using certain AEDs in the treatment of neuropathic pain. Several AEDs have reportedly produced analgesia in a range of neuropathic pains, including painful diabetic neuropathy (PDN) and post-herpetic neuralgia. Increasing evidence suggests that oxcarbazepine can provide significant analgesia in several neuropathic pain conditions, including trigeminal neuralgia and PDN, and is also may be effective in treating neuropathic pain refractory to other AEDs, such as carbamazepine and gabapentin. The analgesic effects of oxcarbazepine, and its generally improved safety and tolerability profile compared with other standard AEDs, suggests that oxcarbazepine will be an important addition to the neuropathic pain armamentarium. The rationale and evidence to support the efficacy of oxcarbazepine are presented here.

First human dose-escalation study with remogliflozin etabonate, a selective inhibitor of the sodium-glucose transporter 2 (SGLT2), in healthy subjects and in subjects with type 2 diabetes mellitus.

BACKGROUND: Remogliflozin etabonate (RE) is the prodrug of remogliflozin, a selective inhibitor of the renal sodium-dependent glucose transporter 2 (SGLT2), which could increase urine glucose excretion (UGE) and lower plasma glucose in humans. METHODS: This double-blind, randomized, placebo-controlled, single-dose, dose-escalation, crossover study is the first human trial designed to evaluate safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of RE. All subjects received single oral doses of either RE or placebo separated by approximately 2 week intervals. In Part A, 10 healthy subjects participated in 5 dosing periods where they received RE (20 mg, 50 mg, 150 mg, 500 mg, or 1000 mg) or placebo (4:1 active to placebo ratio per treatment period). In Part B, 6 subjects with type 2 diabetes mellitus (T2DM) participated in 3 dose periods where they received RE (50 mg and 500 mg) or placebo (2:1 active to placebo per treatment period). The study protocol was registered with the NIH clinical trials data base with identifier NCT01571661. RESULTS: RE was generally well-tolerated; there were no serious adverse events. In both populations, RE was rapidly absorbed and converted to remogliflozin (time to maximum plasma concentration [Cmax;Tmax] approximately 1 h). Generally, exposure to remogliflozin was proportional to the administered dose. RE was rapidly eliminated (mean T½ of ~25 min; mean plasma T½ for remogliflozin was 120 min) and was independent of dose. All subjects showed dose-dependent increases in 24-hour UGE, which plateaued at approximately 200 to 250 mmol glucose with RE doses ≥150 mg. In T2DM subjects, increased plasma glucose following OGTT was attenuated by RE in a drug-dependent fashion, but there were no clear trends in plasma insulin. There were no apparent effects of treatment on plasma or urine electrolytes. CONCLUSIONS: The results support progression of RE as a potential treatment for T2DM. TRIAL REGISTRATION: ClinicalTrials.gov NCT01571661.