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Background: Depressive symptoms are common in patients seeking medication treatment for opioid use disorder (MOUD treatment) and decrease quality of life but have been inconsistently related to opioid treatment outcomes. Here, we explore whether depressive symptoms may only be related to adverse treatment outcomes among individuals reporting high opioid use-related coping motives (i.e., use of opioids to change affective states) and high trait impulsivity, two common treatment targets., Methods: Patients seeking MOUD treatment (N = 118) completed several questionnaires within two weeks of their treatment intake. Treatment outcomes (opioid-positive urine screens and days retained in treatment) were extracted from treatment records. Moderation analyses controlling for demographic characteristics and main effects were conducted to explore interaction effects between depressive symptoms and two distinct moderators., Results: Depressive symptoms were only related to opioid use during early treatment among patients reporting high opioid use-related coping motives (B = 2.67, p =.004) and patients reporting high trait impulsivity (B = 2.01, p =.039). Further, depressive symptoms were only inversely related to days retained among individuals with high opioid use-related coping motives (B = -10.12, p =.003)., Conclusions: Individuals presenting to treatment with opioid-related coping motives and/or impulsivity in the context of depressive symptoms may confer unique risk for adverse treatment outcomes. Clinicians may wish to consider these additive risk factors when developing their treatment plan., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

We investigated whether latent trajectories of anxiety and depressive symptoms were associated with clinically relevant variables including treatment attrition among individuals seeking treatment for alcohol use. Participants were drawn from 78 addiction treatment centers and included individuals in treatment for alcohol use, had in-treatment data, and screened positive for anxiety (n = 6147) or depressive symptoms (n = 6197) at intake. Anxiety and depressive symptoms were measured weekly during the first month of treatment. Three trajectories of anxiety symptoms (i.e., Persistent Moderate Anxiety Symptoms, Remitting Moderate Anxiety Symptoms, and Remitting Mild Anxiety Symptoms) and depressive symptoms (i.e., Increasing Moderate Depressive Symptoms, Persistent Moderate Depressive Symptoms, and Remitting Mild Depressive Symptoms) were identified. Women, younger individuals, and individuals who endorsed greater past month benzodiazepine use and depressive symptoms at intake were more likely to be in the Persistent Moderate Anxiety Symptoms trajectory relative to the Remitting Mild Anxiety Symptoms subgroup. Women, individuals who screened positive for anxiety at intake, and individuals reporting past month heroin use were more likely to be in the Increasing Moderate Depressive Symptoms trajectory relative to the Remitting Mild Depressive Symptom trajectory. Trajectories characterized by persistent moderate anxiety and depressive symptoms during the first month of treatment were more likely to drop out of treatment compared to individuals who reported low symptom levels. Findings indicate heterogeneity in the clinical course of anxiety and depressive symptoms among individuals in treatment for alcohol use and highlight that persistently high anxiety and depressive symptoms may pose an impediment to successful treatment completion. Results also demonstrate the importance of considering demographic and clinical characteristics at treatment intake as they may have significant implications for the unfolding of anxiety and depressive symptoms during treatment and subsequent outcomes., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Contingency management (CM) interventions involve providing reinforcement for engaging in a desired behavior, and have been shown to increase treatment adherence and promote abstinence in the treatment of substance use disorders. This review was conducted to systematically review the literature on the effectiveness of CM when applied to a range of medical conditions outside of substance use disorders., Method: The authors identified a total of 24 randomized studies examining the effects of CM on four outcomes: weight change, physical activity, medication/device adherence, and viral load that were included in the qualitative summary, and 20 studies included in the meta-analysis., Results: CM was associated with positive outcomes for physical activity and medication/device adherence compared to control conditions. Findings with weight loss and viral load were more mixed, and evidence for publication bias was found for both outcomes. The effects of CM tend to dissipate when the contingency is removed. Heterogeneity was observed across most outcomes., Limitations and Conclusions: This review provides preliminary support for the use of CM in increasing physical activity and improving adherence to medication for chronic health conditions while reinforcement is ongoing. Future studies should examine potential moderators and identify strategies to maintain these changes over time., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Individuals with gambling disorder are at an elevated risk for engaging in gambling-related illegal behaviors. The present study examined client (N = 88) and clinician ratings (N = 30) of client characteristics associated with a history of gambling-related illegal behaviors. We also examined client characteristics associated with history of arrest for a gambling-related crime. Gambling-related illegal behaviors and arrest were common (57.3% and 23.9%, respectively) in the present sample. Clients of younger age, and those with greater gambling-related financial consequences, lifetime alcohol problems, impulsivity, mood symptoms, and daily living role difficulties were more likely to report gambling-related illegal behaviors. Clients who had been arrested for a gambling-related crime were more likely to report daily living and role functioning difficulties and lifetime alcohol problems. Clinicians rated clients with a history of gambling-related illegal behaviors and/or gambling-related arrests as more impulsive, and clinicians also endorsed higher rates of treatment failure among these clients. Both client and clinician report suggested that clients with a history of illegal behaviors may have a variety of comorbid problems that may be a focus of clinical intervention., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

We previously reported that interferon (IFN)-free direct-acting antiviral combination treatment succeeded in eradicating genotype 1b hepatitis C virus (HCV) in human hepatocyte chimeric mice. In this study, we examined the effect of vaniprevir (MK7009, NS3/4A protease inhibitor) and BMS-788329 (NS5A inhibitor) combination treatment on HCV genotype 1b and the expression of IFN-stimulated genes (ISGs) using a subgenomic replicon system and the same animal model. Combination treatment with vaniprevir and BMS-788329 significantly reduced HCV replication compared to vaniprevir monotherapy in HCV replicon cells (Huh7/Rep-Feo cells). HCV genotype 1b-infected human hepatocyte chimeric mice were treated with vaniprevir alone or in combination with BMS-788329 for four weeks. Vaniprevir monotherapy reduced serum HCV RNA titers in mice, but viral breakthrough was observed in mice with high HCV titers. Ultra-deep sequence analysis revealed a predominant replacement by drug-resistant substitutions at 168 in HCV NS3 region in these mice. Conversely, in mice with low HCV titers, HCV was eradicated by vaniprevir monotherapy without viral breakthrough. In contrast to monotherapy, combination treatment with vaniprevir and BMS-788329 succeeded in completely eradicating HCV regardless of serum viral titer. IFN-alpha treatment significantly increased ISG expression; however, vaniprevir and BMS-788329 combination treatment caused no increase in ISG expression both in cultured cells and in mouse livers. Therefore, combination treatment with vaniprevir and BMS-788329 eliminated HCV via a non-ISG-mediated mechanism. This oral treatment might offer an alternative DAA combination therapy for patients with chronic hepatitis C., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Brain penetration of drugs which are subject to P-glycoprotein (Pgp)-mediated efflux is attenuated, as manifested by the fact that the cerebrospinal fluid concentration (C(CSF)), a good surrogate of the unbound brain concentration (C(ub)), is lower than the unbound plasma concentration (C(up)) for Pgp substrates. In rodents, the attenuation magnitude of brain penetration by Pgp-mediated efflux has been estimated by correlating the ratio of CSF to plasma exposures (C(CSF)/C(p)) with the unbound fraction in plasma (f(u)) upon the incorporation of the in vivo or in vitro Pgp-mediated efflux ratios (ERs). In the present work, we investigated the impact of Pgp-mediated efflux on C(CSF) in monkeys. Following intravenous administration to cisterna magna ported rhesus monkeys, the CSF and plasma concentrations were determined for 25 compounds from three discovery programs. We also evaluated their f(u) in rhesus plasma and ER in human and African green monkey MDR-transfected LLC-PK1 cells. These compounds varied significantly in the f(u) (0.025-0.73), and 24 out of 25 are considered Pgp substrates based on their appreciable directional transport (ER>2). The C(CSF)/C(p) was significantly lower than the corresponding f(u) (>or=3-fold) for 16 compounds regardless of a significant correlation (R(2)=0.59, p=4 x 10(-5)) when the C(CSF)/C(p) was plotted against the f(u). When the f(u) was normalized to the ER (f(u)/ER) the correlation was improved (R(2)=0.75, p=8 x 10(-8)). More importantly, only one compound showed the C(CSF)/C(p) that exceeded 3-fold of the normalized f(u). The results suggest that the impact of Pgp-mediated efflux in monkeys, similar to the case in rodents, is reasonably reflected by the gradient between the free concentrations in plasma and in CSF. Therefore, f(u) and Pgp ER may serve as useful measurements in estimating in vivo C(CSF)/C(p) ratios in monkeys, and potentially in humans.

A method based on LC-MS/MS was developed for the determination of the fibrinogen-receptor antagonist Aggrastat in human plasma. The drug is isolated from plasma by liquid extraction and converted into its N-trifluoroacetyl derivative prior to analysis by HPLC with atmospheric pressure negative chemical ionization MS/MS detection. A structural analog is used as the internal standard and the lower quantifiable limit of the assay is 0.4 ng ml-1 with a relative standard deviation of 7%. This assay was used to cross-validate the existing immunoassay by analysis of plasma from patients receiving the drug. The specificity of the immunoassay was thereby confirmed.

An analytical method based on radioimmunoassay (RIA) has been developed for the determination of the antiarrhythmic agent, MK-0499, in plasma and urine. Owing to the potency of the drug, the specificity of this assay in human plasma could not be adequately determined using conventional RIA procedures. A highly specific procedure, based on LC/MS-MS, was developed to cross-validate the RIA. The lower quantifiable limits of the RIA and LC/MS-MS-based methods were 0.05 and 0.013 ng ml-1, respectively. Cross-validation data, compared using paired student's t-test regression analysis, showed excellent correlation between methods. The mass spectrometric assay was also used to simultaneously measure plasma concentrations of unlabeled and 14C-labeled MK-0499 following administration of the drug at high specific activity to volunteers.