A new class of compounds that induce apoptosis by targeting Akt and ERK2 signaling pathways in human prostate cancer cells can be synthesized by modifying existing COX-2 inhibitors.

Objective Neonatal abstinence syndrome (NAS)—a clinical entity of infants from in utero exposure to psychoactive xenobiotic and buprenorphine—has been successfully used to treat NAS. However, nothing is known about the pharmacokinetics (PK) of buprenorphine in neonates with NAS. To our knowledge, this is the first study to investigate the population pharmacokinetic of sublingual buprenorphine in neonates with NAS. Design A retrospective population PK analysis of: (1) neonates with NAS treated with sublingual buprenorphine in randomized, double blinded clinical study and (2) data from healthy adults from a previously published pharmacokinetic study. Setting Neonatal intensive care unit and general clinical research unit. Patients Twenty-four neonates with NAS and five healthy adults. Interventions All participants received sublingual buprenorphine per study protocol. Measurements and Main Results A total of 303 PK data from 29 neonates and adults were used for model development. A population pharmacokinetic analysis was conducted using a first order conditional estimation with interaction in the NONMEM software program. A two-compartment linear PK model with first-order absorption process best described the pharmacokinetics of sublingual buprenorphine in neonates. The apparent clearance (CL) of buprenorphine was linearly related to body weight and matured with increasing age via two distinct saturated pathways. A typical neonate with NAS (body weight, 2.9 kg; postnatal age; 5.4 days) had a CL of 3.5 L/kg/hour and elimination half-life of 11 hours. Phenobarbital did not affect the clearance of buprenorphine compared to neonates of similar age and weight. Conclusions This is the first study to investigate the population PK of sublingual buprenorphine in neonatal NAS. To our knowledge, this is also the first report to describe the age-dependent changes of buprenorphine PK in this patient population. No buprenorphine dose adjustment is needed for neonates with NAS treated with buprenorphine and concurrent phenobarbital.

Interaction of the Alzheimer's Aβ peptides with the plasma membrane of cells in culture results in chronic increases in cytosolic [Ca(2+)]. Such increases can cause a variety of secondary effects leading to impaired cell growth or cell degeneration. In this investigation, we made a comprehensive study of the changes in cytosolic [Ca(2+)] in single PC12 cells and human neurons stressed by continuous exposure to a medium containing Aβ42 for several days. The differential timing and magnitude of the Aβ42-induced increase in [Ca(2+)] reveal subpopulations of cells with differential sensitivity to Aβ42. These results suggest that the effect produced by Aβ on the level of cytosolic [Ca(2+)] depends on the type of cell being monitored. Moreover, the results obtained of using potent inhibitors of Aβ cation channels such as Zn(2+) and the small peptide NA7 add further proof to the suggestion that the long-term increases in cytosolic [Ca(2+)] in cells stressed by continuous exposure to Aβ is the result of Aβ ion channel activity.

Human islet amyloid polypeptide (hIAPP), co-secreted with insulin from pancreatic b cells, is linked to the pathogenesis of type II diabetes mellitus. While the mechanism of hIAPP-membrane interaction at aggregating concentrations of the peptide is well established, the same is not true for monomeric hIAPP. We used imaging total internal reflection-Fluorescence Correlation Spectroscopy (ITIR-FCS) to monitor the effect of monomeric hIAPP on live cell membrane dynamics. The complex interaction of hIAPP with the plasma membrane operates via formation of domains. After hIAPP addition, overall membrane diffusion first increases and then decreases along with concomitant formation and enlargement of the domains which encompass the entire membrane in a time dependent manner. However, the current limitation of ITIR-FCS data analysis does not allow the complete characterization of the temporal evolution of the domains. We implemented Bayesian inference tests which were previously applied to confocal FCS. This allowed us to observe three phases in the evolution of hIAPP-membrane interaction -i) Pre-nucleation phase (1-10 min) where diffusion is single component at most of the pixels and the diffusion coefficient increases monotonically. ii) Propagation phase (15-40 min) where the two-component model fits better for the pixels within the domains. The components exhibit distinct but constant diffusion coefficients but their molecular fraction change with the slow diffusing fraction increasing in time. iii) Saturation phase (40-60 min) where pixels within the domain fit better with single-component model. Therefore, we conclude that hIAPP instantaneous increases membrane diffusion. This is followed by the formation of diffusion-restricted domains that eventually slows down overall membrane dynamics. The novel Bayesian inference analysis of imaging FCS successfully resolved hIAPP-induced domain formation and concomitant modulation of plasma membrane dynamics, which was not explained by the conventional fitting routine.

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