The combination of topiramate and diazepam is partially neuroprotective in the hippocampus but not antiepileptogenic in the lithium-pilocarpine model of temporal lobe epilepsy

Lithium-pilocarpine induces status epilepticus (SE), leading to extensive damage and spontaneous recurrent seizures (SRS). Neuroprotective and antiepileptogenic effects of topiramate (TPM) associated with diazepam (DZP) were investigated in this model. SE was induced by LiCl and pilocarpine. TPM (10, 30 or 60 mg/kg) was injected at the onset of SE and 10h later and DZP (2.5 and 1.25mg/kg) at 2 and 10h after SE. TPM treatment was continued twice daily for 6 days. Other rats received two injections of DZP on the day of SE. Cell counting was performed on thionine-stained sections 14 days after SE and after 2 months of epilepsy. Occurrence and frequency of SRS were video-recorded. The MRI T2-weighted signal was quantified in hippocampus and ventral cortices. DZP-TPM treatment induced partial neuroprotection in CA1 and hilus, and tended to increase the percentage of rats with protected neurons in layer III/IV of the ventral entorhinal cortex. The latency to and frequency of SRS were not modified by DZP-TPM. T2-weighted signal was decreased in hippocampus 3 days after SE at all TPM doses and in ventral hippocampus after epilepsy onset. In conclusion, although DZP-TPM treatment was able to partially protect two areas critical for epileptogenesis, the hippocampus and ventral entorhinal cortex, it was not sufficient to prevent epileptogenesis.     

Early-Emerging Nicotine Dependence Has Lasting and Time-Varying Effects on Adolescent Smoking Behavior

Novice and light adolescent smokers can develop symptoms of nicotine dependence, which predicts smoking behavior several years into the future. However, little is known about how the association between these early - emerging symptoms and later smoker behaviors may change across time from early adolescence into young adulthood. Data were drawn from a 7-year longitudinal study of experimental (<100 cigarettes/lifetime; N?=?594) and light (100+ cigarettes/lifetime, but ≤5 cigarettes/day; N?=?152) adolescent smokers. Time-varying effect models were used to examine the relationship between baseline nicotine dependence (assessed at age 15?±?2 years) and future smoking frequency through age 24, after controlling for concurrent smoking heaviness. Baseline smoking status, race, and sex were examined as potential moderators of this relationship. Nicotine dependence symptoms assessed at approximately age 15 significantly predicted smoking frequency through age 24, over and above concurrent smoking heaviness, though it showed declining trends at older ages. Predictive validity was weaker among experimenters at young ages (<16), but stronger at older ages (20–23), relative to light smokers. Additionally, nicotine dependence was a stronger predictor of smoking frequency for white smokers around baseline (ages 14.5–16), relative to nonwhite smokers. Nicotine dependence assessed in mid-adolescence predicts smoking frequency well into early adulthood, over and above concurrent smoking heaviness, especially among novice smokers and nonwhite smokers. Early-emerging nicotine dependence is a promising marker for screening and interventions aimed at preventing smoking progression.     

Cost-effectiveness of pembrolizumab with axitinib as first-line treatment for advanced renal cell carcinoma

Abstract

Objective

Pembrolizumab/axitinib significantly prolonged overall survival (OS) and progression-free survival (PFS), and increased objective response rate versus sunitinib in the phase III trial KEYNOTE-426 among previously untreated patients with advanced renal cell carcinoma (RCC). This study assessed the cost-effectiveness of pembrolizumab/axitinib versus other first-line treatments of advanced RCC from a US public healthcare payer perspective.