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Background: We aimed to examine the efficacy of selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) for anxiety disorders examining overall symptom improvement, likelihood of treatment response, time course of treatment response, individual pharmacological agent, diagnostic indication dose, and tolerability., Methods: We searched PubMed and Cochrane Central Register of Controlled Trials. We included randomized placebo-controlled clinical trials of SSRIs/SNRIs in adult patients with anxiety disorders that provided data at three or more time points. Extracted data included trial duration, weekly/biweekly anxiety scores for 12 weeks., Results: Meta-analysis included 57 trials (N = 16,056). A linear mixed model analysis based on weekly outcome data suggested that for SNRI a logarithmic model offered the best fit compared to placebo (indicating the greatest incremental improvement from baseline occurred early in treatment); whereas for SSRI a linear model provided the best fit (indicating a similar improvement over the duration of the acute treatment phase). There were no significant differences in efficacy between pharmacological agents within each class or when comparing SSRIs to SNRIs. The greatest treatment benefits were observed for social anxiety disorder for both medication classes. Higher doses of SSRIs, but not SNRIs, were associated with significantly greater symptom improvement and likelihood of treatment response. For both medical classes, higher doses were associated with an increased likelihood of dropout due to side effects., Conclusions: SSRIs and SNRIs are effective in treating anxiety disorders. Higher doses of SSRIs within the therapeutic range are associated with greater treatment benefit, whereas higher doses of SNRIs are not., (© 2018 Wiley Periodicals, Inc.)

We evaluated blinatumomab pharmacokinetics, pharmacodynamics (CD3+ T-cell, CD19+ B-cell, and cytokine levels), and their associations with efficacy or safety in relapsed/refractory acute lymphoblastic leukemia. Blinatumomab pharmacokinetics (continuous intravenous infusion) from a phase 2 study (n = 189; NCT01466179) were assessed noncompartmentally. Associations between steady-state concentration (C ss ) and efficacy (complete remission [CR] or CR with partial hematologic recovery [CRh]) or safety (cytokine release syndrome [CRS] and neurologic events [NEs]) were evaluated with statistical models. Blinatumomab mean ± SD C ss was 621 ± 502 pg/mL (28 μg/day dose). Cytokines were transiently elevated in >50% of patients; B-cell levels decreased in most patients. Lower B-cell and bone marrow (BM) blast percentages and higher T-cell percentages were associated with higher CR/CRh (P < .001) in univariate analysis. Higher C ss (OR, 1.90; 95%CI, 1.12-3.21), higher peak IL-10 level (1.59; 1.13-2.22), and lower BM blast percentage (0.78; 0.69-0.89) were associated with higher CR/CRh in multivariate analysis. Higher C ss (HR, 1.40; 1.01-1.94) and lower B-cell level (0.90; 0.84-0.97) were associated with shorter time to NEs. Cytokine peaks were not associated with NEs or CRS. In conclusion, blinatumomab led to T cell-mediated depletion of target B cells in blood and blasts in the bone marrow. Immune system effectiveness was important for treatment responses., (© 2017, The American College of Clinical Pharmacology.)

Background: Our goal was to quantify the risk of hyperhidrosis associated with commonly used antidepressant agents and examine the impact of medication class, pharmacodynamics, and dose on risk of hyperhidrosis., Methods: We conducted a PubMed search to identify all double-blind, randomized, placebo-controlled trials examining the efficacy of second-generation antidepressant medications in the treatment of adults with a depressive disorder, anxiety disorders, or obsessive-compulsive disorder. We used a random-effects meta-analysis to examine the pooled risk ratio of hyperhidrosis reported as a side effect in adults treated with second-generation antidepressants compared to placebo. We used stratified subgroup analysis and metaregression to examine the effects of medication type, class, dosage, indication, and receptor affinity profile on the measured risk of hyperhidrosis., Results: We identified 76 trials involving 28,544 subjects. There was no significant difference in the risk of hyperhidrosis between serotonin-norepinephrine reuptake inhibitors (SNRI) [risk ratio (RR) = 3.17, 95% CI: 2.63-3.82] and selective serotonin reuptake inhibitors (SSRI) (RR = 2.93, 95% CI: 2.46-3.47) medications compared to placebo. All antidepressant medications were associated with a significantly increased risk of hyperhidrosis except fluvoxamine (RR = 0.56, 95% CI: 0.12-2.53), bupropion (RR = 1.23, 95% CI: 0.57-2.67), and vortioxetine (RR = 1.35, 95% CI: 0.79-2.33). The dose of SSRI/SNRI medications was not significantly associated with the risk of hyperhidrosis. Increased risk of hyperhidrosis was associated with increased affinity of SSRI/SNRI medications to the dopamine transporter., Conclusion: Risk of hyperhidrosis was significantly increased with most antidepressant medications but was associated with dopamine transporter affinity., (© 2017 Wiley Periodicals, Inc.)

Objective: Current practice guidelines do not recommend benzodiazepines for acute management of anxiety disorders in pediatric patients. However, in procedural settings, benzodiazepines are commonly used to relieve acute preprocedural stress. This meta-analysis examines the efficacy and tolerability of benzodiazepines as short-term anxiolytics in children., Method: PubMed was searched for randomized controlled trials assessing the efficacy of benzodiazepines as short-term anxiolytics in pediatric patients. Twenty-one trials involving 1,416 participants were included. A fixed effects model was used to examine the standardized mean difference of improvement in anxiety levels compared to control conditions. In stratified subgroup and meta-regression, the effect of the specific agent, dose, timing, and setting of benzodiazepine treatment was examined., Results: A significant benefit was seen for benzodiazepines compared to control (standardized mean difference = 0.71 [95% confidence interval, 0.60-0.82], k = 24, z = 12.7, P < .001). There was also funnel plot asymmetry in this meta-analysis, suggesting some evidence of publication bias. Moderator analyses found that when benzodiazepines were used in dental or nonoperating room procedures, they were more effective than when they were used in operating room procedures (test for subgroup differences Q 2 = 6.34, P = .04). Tolerability analysis revealed there was no significant difference in the risk of developing irritability or behavioral changes between benzodiazepine and control groups., Conclusions: Benzodiazepines are effective and well-tolerated when used as short-term anxiolytics in procedural settings for pediatric patients. Further research is needed to determine whether benzodiazepines are effective in pediatric anxiety disorders., (© 2017 Wiley Periodicals, Inc.)

Evolocumab binds PCSK9, increasing low-density lipoprotein cholesterol (LDL-C) receptors and lowering LDL-C. Target-mediated evolocumab elimination is attributable to PCSK9 binding. As circulating PCSK9 and LDL-C levels are primarily regulated by the liver, we compared evolocumab pharmacokinetics, pharmacodynamics, and safety in individuals with and without hepatic impairment. An open-label, parallel-group study evaluated the pharmacokinetics of evolocumab in hepatic-impaired (Child-Pugh Class A or B) or healthy adults. Participants were classified as having no, mild, or moderate hepatic impairment (n = 8/group) and received a single 140-mg evolocumab dose. Assessments of unbound evolocumab and PCSK9 were made predose and postdose. Adverse events were monitored throughout the study. No significant association was observed between baseline PCSK9 and increasing level of hepatic impairment. No difference in extent and time course of PCSK9 or LDL-C reduction was observed despite an apparent decrease in mean unbound evolocumab exposure with increasing hepatic impairment (Jonckheere-Terpstra trend test; maximum serum concentration P = .18; area under the curve P = .09). Maximum reductions were observed in moderately impaired subjects vs healthy individuals: mean maximum serum concentration -34%; mean area under the concentration-time curve (AUC) -47%. On average, unbound PCSK9 serum concentrations fell by >80% at 4 hours after a single evolocumab dose. Mean (95% confidence interval) maximum LDL-C reductions in the healthy, mild, and moderate groups were -57% (-64% to -48%), -70% (-75% to -63%), and -53% (-61% to -43%), respectively. No safety risks were identified. These results support evolocumab use without dose adjustment in patients with active liver disease and mild or moderate hepatic impairment., (© 2016, The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.)

Background: The purpose of the current study was to determine the incidence of late recurrences, which were defined as those occurring >or=5 years after initial therapy, among patients treated for salivary gland cancer., Methods: Between 1960 and 2000, 145 patients underwent definitive therapy for localized carcinomas of the salivary glands and were clinically without evidence of disease at 5 years of follow-up. Cumulative probabilities for developing a subsequent late recurrence were estimated using the Kaplan-Meier method., Results: The 10-year and 15-year cumulative probabilities of late recurrence in patients who were free of disease at 5 years were 13% and 18%, respectively. The crude rates of late recurrence by histologic subtype were adenoid cystic carcinoma (26%), mixed malignant tumor (25%), mucoepidermoid carcinoma (17%), adenocarcinoma (10%), and acinic cell carcinoma (8%). Sites of late recurrence included distant metastasis (17 patients), local recurrence (8 patients), and regional recurrence (2 patients). The median time to late recurrence was 7.1 years (range, 5.2-23.1 years) from the date of initial surgery. Salvage treatment varied according to location of disease recurrence and initial treatment characteristics. The 15-year estimate of overall survival was 39% for patients who experienced a late recurrence compared with 71% for those who remained free of disease (P= .001)., Conclusions: A significant proportion of patients who are presumed to be cured of their disease at 5 years after initial treatment for salivary gland cancer will be found to develop late disease recurrence with additional follow-up.