Efficacy and tolerability of twice-daily pregabalin for treating pain and related sleep interference in postherpetic neuralgia: a 13-week, randomized trial.

OBJECTIVE: This trial evaluated the efficacy and safety of pregabalin dosed twice daily (BID) for relief of neuro-pathic pain associated with postherpetic neuralgia (PHN). RESEARCH DESIGN AND METHODS: The 13-week, double-blind, placebo-controlled study randomized 370 patients with PHN to pregabalin (150, 300, or 600 mg/day BID) or placebo. MAIN OUTCOME MEASURES: Primary efficacy measure was endpoint mean pain score from daily pain diaries. Secondary efficacy measures included endpoint mean sleep-interference score from daily sleep diaries and Patient Global Impression of Change (PGIC). Safety evaluations included adverse events (AEs), physical and neurologic examinations, 12-lead ECG, vital signs, and laboratory testing. RESULTS: Pregabalin provided significant, dose-proportional pain relief at endpoint: difference from placebo in mean pain score, 150 mg/day, -0.88, p = 0.0077; 300 mg/day, -1.07, p = 0.0016; 600 mg/day, -1.79, p = 0.0003. Weekly mean pain scores significantly improved as early as week 1. Sleep interference in all pregabalin groups was also significantly improved at endpoint, compared with placebo (p < 0.001), beginning at week 1 (p < 0.01). At study termination, patients in the 150 (p = 0.02) and 600 mg/day (p = 0.003) groups were more likely to report global improvement than were those in the placebo group. Most AEs were mild or moderate. Among pregabalin-treated patients, 13.5% withdrew due to AEs, most commonly for dizziness (16 patients, 5.8%), somnolence (8, 2.9%), or ataxia (7, 2.5%). CONCLUSIONS: Pregabalin, dosed BID, reduced neuropathic pain associated with PHN and was well tolerated. It also reduced the extent to which pain interfered with sleep. Pregabalin's effects were seen as early as week 1 and were sustained throughout the 13-week study.

Identification of an IL-6 response element in the human LCAT promoter.

LCAT is a key enzyme of reverse cholesterol transport that is essential to maintain HDL-mediated lipid transport and cholesterol homeostasis. Alterations in LCAT expression have a profound effect on plasma HDL cholesterol concentrations. Previously LCAT mRNA and activity were shown to be regulated by several inflammatory cytokines, including the pleiotrophic cytokine interleukin-6 (IL-6). A series of full-length and sequential deletion LCAT promoter constructs were used to determine whether inflammatory stimuli affect LCAT transcription and to further identify functional, cytokine-responsive promoter regions that mediate this response. Using transfected HepG2 cells, results indicate that treatment with IL-6 induced a 2.5-fold activation of full-length LCAT promoter activity. A minimal (-1514 bp to -1508 bp) IL-6 response element with high sequence homology to the signal transducer and activator of transcription (STAT) family member, STAT3, was mapped within the distal promoter and shown to be sufficient to mediate the IL-6 response. Further, overexpression of STAT3 significantly enhanced the effect of IL-6 on LCAT promoter activity. These data suggest that the IL-6 responsive transcription factor, STAT3, contributes to LCAT transcriptional regulation. The elucidation of distinct biochemical signaling pathways associated with inflammation may provide new insight into transcriptional regulation of genes involved in lipid metabolism.