Pharmacokinetics, safety, and tolerability of a depot formulation of naltrexone in alcoholics: an open-label trial

BACKGROUND: Naltrexone is an effective medication for treatment of alcohol dependence, but its efficacy is limited by lack of adherence to the oral dosage form. A long-acting depot formulation of naltrexone may increase adherence. METHODS: A single site, 6-week open label study was conducted with 16 alcohol dependent subjects each receiving 300 mg of Naltrexone Depot by intramuscular injection. The main outcomes were safety and tolerability of the Naltrexone Depot formulation, blood levels of naltrexone and its main metabolite 6-beta naltrexol, and self-reported alcohol use. All subjects received weekly individual counseling sessions. RESULTS: The medication was well tolerated with 88% of subjects completing the 6-week trial. The most common side effect experienced was injection site complications. There were no serious adverse events. Subjects had naltrexone and 6-beta-naltrexol concentrations throughout the trial with mean values ranging from 0.58 ng/mL to 2.04 ng/mL and 1.51 ng/mL to 5.52 ng/mL, respectively, at each sampling time following administration. Compared to baseline, subjects had significantly reduced number of drinks per day, heavy drinking days and proportion of drinking days. CONCLUSION: Naltrexone Depot is safe and well tolerated in alcoholics and these findings support the further investigation of its utility in larger double-blind placebo controlled trials

Longitudinal Associations Between Perceived Parent-Adolescent Attachment Relationship Quality and Generalized Anxiety Disorder Symptoms in Adolescence

This longitudinal study examined the direction of effects between adolescents’ generalized anxiety disorder (GAD) symptoms and perceived parent-adolescent attachment relationship quality, as well as the moderating role of gender and age. 1,313 Dutch adolescents (48.5% boys) from two age cohorts of early (n = 923, Mage = 12 at W1) and middle (n = 390, Mage = 16 at W1) adolescents completed questionnaires regarding their attachment relationship to parents and GAD symptoms in four waves. Cross-lagged path analyses demonstrated that adolescents’ GAD symptoms and perceived father-adolescent attachment relationship quality bidirectionally negatively affected each other over time. For mothers, adolescents’ GAD symptoms negatively predicted perceived mother-adolescent attachment relationship quality over time. The within-wave correlated residuals between perceived attachment relationship quality with fathers and GAD symptoms were stronger for boys than for girls and stronger for the cohort of middle adolescents than for the cohort of early adolescents. This study demonstrates that both the parents’ and the adolescents’ gender as well as the adolescents’ age affects the relation between adolescents’ GAD symptoms and perceived parent-adolescent attachment relationship quality

Systematic Conservation Planning in the Face of Climate Change: Bet-Hedging on the Columbia Plateau

Systematic conservation planning efforts typically focus on protecting current patterns of biodiversity. Climate change is poised to shift species distributions, reshuffle communities, and alter ecosystem functioning. In such a dynamic environment, lands selected to protect today's biodiversity may fail to do so in the future. One proposed approach to designing reserve networks that are robust to climate change involves protecting the diversity of abiotic conditions that in part determine species distributions and ecological processes. A set of abiotically diverse areas will likely support a diversity of ecological systems both today and into the future, although those two sets of systems might be dramatically different. Here, we demonstrate a conservation planning approach based on representing unique combinations of abiotic factors. We prioritize sites that represent the diversity of soils, topographies, and current climates of the Columbia Plateau. We then compare these sites to sites prioritized to protect current biodiversity. This comparison highlights places that are important for protecting both today's biodiversity and the diversity of abiotic factors that will likely determine biodiversity patterns in the future. It also highlights places where a reserve network designed solely to protect today's biodiversity would fail to capture the diversity of abiotic conditions and where such a network could be augmented to be more robust to climate-change impacts

C-Type inactivation involves a significant decrease in the intracellular aqueous pore volume of Kv1.4 K+ channels expressed in Xenopus oocytes

Channels are water-filled membrane-spanning proteins, which undergo conformational changes as they gate, i.e. open or close. These conformational changes affect both the shape of the channel and the volume of the water-filled pore. We measured the changes in pore volume associated with activation, deactivation, C-type inactivation and recovery in an N-terminal-deleted mutant of the Kv1.4 K+ channel (Kv1.4ΔN) expressed in Xenopus oocytes. We used giant-patch and cut-open oocyte voltage clamp techniques and applied solutes which are too large to enter the pore mouth to exert osmotic pressure and thus favour smaller pore volume conformations. Applied intracellular osmotic pressure (300 mm sucrose) sped inactivation (time constants (τinactivation): control, 0.66 ± 0.09 s; hyperosmotic solution, 0.29 ± 0.04 s; n = 5, P < 0.01), sped deactivation (τdeactivation: control, 18.8 ± 0.94 ms; hyperosmotic solution, 8.01 ± 1.92 ms; n = 5, P < 0.01), and slowed activation (τactivation: control, 1.04 ± 0.05 ms; hyperosmotic solution, 1.96 ± 0.31 ms; n = 5, P < 0.01). These effects were reversible and solute independent. We estimated the pore volume change on inactivation to be about 4500 Å3. Osmotic pressure had no effect when applied extracellularly. These data suggest that the intracellular side of the pore closes during C-type inactivation and the volume change is similar to that associated with activation or deactivation. This is also similar to the pore volume estimated from the crystal structure of KcsA and MthK K+ channels. Intracellular osmotic pressure also strongly inhibited re-opening currents associated with recovery from inactivation, which is consistent with a physical similarity between the C-type inactivated and resting closed state

KV4.3 N-terminal deletion mutant Δ2–39: Effects on inactivation and recovery characteristics in both the absence and presence of KChIP2b

Gating transitions in the KV4.3 N-terminal deletion mutant Δ2–39 were characterized in the absence and presence of KChIP2b. We particularly focused on gating characteristics of macroscopic (open state) versus closed state inactivation (CSI) and recovery. In the absence of KChIP2b Δ2–39 did not significantly alter the steady-state activation “a4” relationship or general CSI characteristics, but it did slow the kinetics of deactivation, macroscopic inactivation and macroscopic recovery. Recovery kinetics (for both WT KV4.3 and Δ2–39) were complicated and displayed sigmoidicity, a process which was enhanced by Δ2–39. Deletion of the proximal N-terminal domain therefore appeared to specifically slow mechanisms involved in regulating gating transitions occurring after the channel open state(s) had been reached. In the presence of KChIP2b Δ2–39 recovery kinetics (from both macroscopic and CSI) were accelerated, with an apparent reduction in initial sigmoidicity. Hyperpolarizing shifts in both “a4” and isochronal inactivation “i” were also produced. KChIP2b-mediated remodeling of KV4.3 gating transitions was therefore not obligatorily dependent upon an intact N-terminus. To account for these effects we propose that KChIP2 regulatory domains exist in KV4.3 α subunit regions outside of the proximal N-terminal. In addition to regulating macroscopic inactivation, we also propose that the KV4.3 N-terminus may act as a novel regulator of deactivation-recovery coupling

Can a preoperative bevacizumab injection prevent recurrent postvitrectomy diabetic vitreous haemorrhage?

Aims: To evaluate the recurrence rate of vitreous haemorrhage (VH) in patients treated with one intravitreal bevacizumab (IVB) injection (2.5 mg/0.1 ml) before planned pars plana vitrectomy for treatment of diabetic non-clearing VH. Methods: Prospective pilot study of 32 eyes of 31 consecutive diabetic patients who underwent IVB injection within 1 week before surgery for persistent VH in the presence of active proliferative diabetic retinopathy. Three masked retinal specialists graded the amount of VH from grade 0 to grade 3 with slit-lamp biomicroscopy. Main outcome measures were the rate of recurrence of the VH, improvement in visual acuity, incidence of cataract formation, and postoperative complications through a follow-up of 6 months. Results: The percentage of severe recurrent VH with no fundus details (grade 3) was 3% at 1 week follow-up and 3, 6, and 6% respectively at 1-, 3-, and 6-month follow-up. The mean best-corrected visual acuity (BCVA) improved from 1.6 (1/60) to 0.40 (6/15) logMAR (P=0.02) in 29 out of 32 eyes (91%). In all, 12 out of 22 (54%) phakic eyes developed cataract during the follow-up period, and 10 (31%) of them underwent cataract surgery. Conclusions: Our study suggests that IVB injection few days before planned surgery seems to be efficacious and safe as an adjuvant treatment to prevent rebleeding in eyes undergoing pars plana vitrectomy for treatment of diabetic vitreous haemorrhage. IVB facilitates the surgery and reduces the need for extensive delamination and segmentation, decreasing the possibility of significant early active postoperative VH. © 2009 Macmillan Publishers Limited All rights reserved.link_to_subscribed_fulltex

Kv1.4 channel block by quinidine: evidence for a drug-induced allosteric effect

We studied quinidine block of Kv1.4ΔN, a K+ channel lacking N-type inactivation, expressed in Xenopus ooctyes. Initially, quinidine intracellularly blocked the open channel so rapidly it overlapped with activation. This rapid open channel block was reduced (non-additively) by interventions that slow C-type inactivation: [K+]o elevation and an extracellular lysine to tyrosine mutation (K532Y). These manipulations reduced the affinity of rapid open channel block ≈10-fold, but left the effective electrical distance unchanged at ≈0.15. Following rapid open channel block, there were time-dependent quinidine effects: the rate of inactivation during a single depolarisation was increased, and repetitive pulsing showed use dependence. The rate of recovery from the time-dependent aspect of quinidine block was similar to recovery from normal C-type inactivation. Manipulations that prevented the channel from entering the C-type inactivated state (i.e. high [K+]o or the K532Y mutation) prevented the development of the time-dependent quinidine-induced inactivation. The concentration dependence of the rapid block and the time-dependent quinidine-induced inactivation were similar, but the time-dependent component was strongly voltage sensitive, with an effective electrical distance of 2. Clearly, this cannot reflect the permeation of quinidine through the electric field, but must be the result of some other voltage-sensitive change in the channel. We propose that quinidine promotes the entry of the channel into a C-type inactivated state in a time- and voltage-dependent manner. We developed a mathematical model based on these results to test the hypothesis that, following rapid open channel block, quinidine promotes development of the C-type inactivated state through a voltage-dependent conformational change