Alcohol use disorder is a chronic, relapsing brain disorder causing substantial morbidity and mortality. Cholinergic interneurons (CIN) within the nucleus accumbens (nAc) have been suggested to exert a regulatory impact on dopamine (DA) neurotransmission locally, and defects in CIN have been implied in several psychiatric disorders. The aim of this study was to investigate the role of CIN in regulation of basal extracellular levels of DA and in modulation of nAc DA release following ethanol administration locally within the nAc of male Wistar rats. Using reversed in vivo microdialysis, the acetylcholinesterase inhibitor physostigmine was administered locally in the nAc followed by addition of either the muscarinic acetylcholine (ACh) receptor antagonist scopolamine or the nicotinic ACh receptor antagonist mecamylamine. Further, ethanol was locally perfused in the nAc following pretreatment with scopolamine and/or mecamylamine. Lastly, ethanol was administered locally into the nAc of animals with accumbal CIN-ablation induced by anticholine acetyl transferase-saporin. Physostigmine increased accumbal DA levels via activation of muscarinic ACh receptors. Neither scopolamine and/or mecamylamine nor CIN-ablation altered basal DA levels, suggesting that extracellular DA levels are not tonically controlled by ACh in the nAc. In contrast, ethanol-induced DA elevation was prevented following coadministration of scopolamine and mecamylamine and blunted in CIN-ablated animals, suggesting involvement of CIN-ACh in ethanol-mediated DA signaling. The data presented in this study suggest that basal extracellular levels of DA within the nAc are not sustained by ACh, whereas accumbal CIN-ACh is involved in mediating ethanol-induced DA release.
Given increasing concern in suicide in preadolescent children, this study aimed to characterize and identify potential indicators of risk for suicidal ideation (SI) and suicide attempts (SAs) in this population.
Data were drawn from two population-based samples of preadolescents the 2007 and 2010 Minnesota Student Survey and analyses were restricted to 11- and 12-year-olds. Sociodemographic characteristics, childhood maltreatment, parental relations, peer relations, and school climate were examined in relation to past-year SI and SA. To examine correlates of SI, unconfounded by risk for SA, individuals with a history of SA were excluded from SI analyses. Correlates of SA were examined among individuals with past-year SI. Logistic regression analyses were conducted with past-year SI and SA as criterion variables.
Results from the 2007 and 2010 data sets were highly consistent. The prevalence of past-year SI was 9.28% and 9.25% in 2007 and 2010, respectively. Of the total sample, 1.90% and 1.87% reported a past-year SA (17.00% and 16.78% of those with past-year SI). Overall, effect sizes were generally modest to medium. The strongest effects were observed for sexual and physical abuse, parental support, and perceived safety at school (ps < .001). In multivariate analyses of SI and SA, sexual and physical abuse had the largest effect sizes (OR
= 2.18 [95% CI = 1.90-2.51] to 2.96 [95% CI = 2.69-3.26]; OR
= 1.55 [95% CI = 1.29-1.86] to 2.26 [95% CI = 1.82-2.80]).
SI and SA occur at a concerning rate among preadolescent children. Screening for childhood sexual and physical abuse may be important for identifying those at risk for these clinical outcomes.
SI and SA occur at a concerning rate among preadolescent children. Screening for childhood sexual and physical abuse may be important for identifying those at risk for these clinical outcomes.
To evaluate the efficacy and safety of cabozantinib, through a bridging study to METEOR, in Japanese patients with advanced renal cell carcinoma who had progressed after prior tyrosine kinase inhibitor therapy.
This phaseII, open-label, single-arm study (ClinicalTrials.gov registration number NCT03339219) included adult Japanese patients with advanced renal cell carcinoma and measurable disease who had received one or more tyrosine kinase inhibitors. Patients received cabozantinib 60mg orally once daily while there was clinical benefit, or until unacceptable toxicity or disease progression. The primary end-point was objective response rate per Response Evaluation Criteria in Solid Tumors Version 1.1. Secondary end-points included clinical benefit rate (complete or partial response, or ≥8-week stable disease), progression-free survival, overall survival and safety.
Of the 35 patients enrolled, 68.6%, 22.9% and 8.6% had previously received one, two and three prior tyrosine kinase inhibitors, respectively.essed after prior tyrosine kinase inhibitor therapy.
Raltitrexed (RTX) is a thymidylate synthase inhibitor with large pharmacokinetics (PK) variability that can be administered in case of 5-fluorouracil (5FU) intolerance or dihydropyrimidine dehydrogenase deficiency. While it is a more potent thymidylate synthase inhibitor than 5FU, RTX failed to replace this drug for colorectal cancer patients, mainly due to its toxicity at the recommended dose of 3 mg/m
every 3 weeks. However, every 2 weeks administration at 2 mg/m
demonstrated a favourable toxicity profile.
We performed a randomized crossover comparative population PK study between every 2 weeks TOMOX (RTX 2 mg/m
) and every 3 weeks TOMOX (RTX 3 mg/m
).
A three-compartment model and a proportional error model best describe the data. Creatinine clearance and sex, but not body surface area (BSA), were covariates of RTX clearance leading to decrease of its interindividual variability of 28%. Weight and body surface area were covariates of central and peripheral volumes of distribution, respectively, leading to decreases of interindividual variability of 34.6% and 100%, respectively. Selleckchem MTX-531 In contrast to the dose, AUC was a good predictor of liver toxicity (P = 0.006, OR = 3.91, 95%CI = [1.48-10.34]). Using covariates to compute individual clearance and a threshold AUC (1.639, determined in this study), a covariates-based dose was calculated, leading to less variability in AUC than observed with the actual BSA-based or fixed doses.
These results advocate for the use of creatinine clearance and sex to determine the RTX dose instead of BSA.
These results advocate for the use of creatinine clearance and sex to determine the RTX dose instead of BSA.Selleckchem MTX-531
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