α2-Adrenergic Agonists or Stimulants for Preschool-Age Children With Attention-Deficit/Hyperactivity Disorder.

Importance: Attention-deficit/hyperactivity disorder (ADHD) is diagnosed in approximately 2.4% of preschool-age children. Stimulants are recommended as first-line medication treatment. However, up to 25% of preschool-age children with ADHD are treated with α2-adrenergic agonist medications, despite minimal evidence about their efficacy or adverse effects in this age range. Objective: To determine the frequency of reported improvement in ADHD symptoms and adverse effects associated with α2-adrenergic agonists and stimulant medication for initial ADHD medication treatment in preschool-age children. Design, Setting, and Participants: Retrospective electronic health record review. Data were obtained from health records of children seen at 7 outpatient developmental-behavioral pediatric practices in the Developmental Behavioral Pediatrics Research Network in the US. Data were abstracted for 497 consecutive children who were younger than 72 months when treatment with an α2-adrenergic agonist or stimulant medication was initiated by a developmental-behavioral pediatrician for ADHD and were treated between January 1, 2013, and July 1, 2017. Follow-up was complete on February 27, 2019. Exposures: α2-Adrenergic agonist vs stimulant medication as initial ADHD medication treatment. Main Outcomes and Measures: Reported improvement in ADHD symptoms and adverse effects. Results: Data were abstracted from electronic health records of 497 preschool-age children with ADHD receiving α2-adrenergic agonists or stimulants. Median child age was 62 months at ADHD medication initiation, and 409 children (82%) were males. For initial ADHD medication treatment, α2-adrenergic agonists were prescribed to 175 children (35%; median length of α2-adrenergic agonist use, 136 days) and stimulants were prescribed to 322 children (65%; median length of stimulant use, 133 days). Improvement was reported in 66% (95% CI, 57.5%-73.9%) of children who initiated α2-adrenergic agonists and 78% (95% CI, 72.4%-83.4%) of children who initiated stimulants. Only daytime sleepiness was more common for those receiving α2-adrenergic agonists vs stimulants (38% vs 3%); several adverse effects were reported more commonly for those receiving stimulants vs α2-adrenergic agonists, including moodiness/irritability (50% vs 29%), appetite suppression (38% vs 7%), and difficulty sleeping (21% vs 11%). Conclusions and Relevance: In this retrospective review of health records of preschool-age children with ADHD treated in developmental-behavioral pediatric practices, improvement was noted in the majority of children who received α2-adrenergic agonists or stimulants, with differing adverse effect profiles between medication classes. Further research, including from randomized clinical trials, is needed to assess comparative effectiveness of α2-adrenergic agonists vs stimulants.

Phase 1 study of telisotuzumab vedotin in Japanese patients with advanced solid tumors.

Telisotuzumab vedotin (formerly ABBV-399) is an antibody-drug conjugate targeting c-Met-overexpressing tumor cells, irrespective of MET gene amplification status. Safety, pharmacokinetics, and preliminary efficacy of telisotuzumab vedotin were evaluated outside of Japan. This phase 1 open-label study evaluated the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of telisotuzumab vedotin in Japanese patients with advanced solid tumors. Telisotuzumab vedotin was administered intravenously at either 2.4 mg/kg (n = 3) or 2.7 mg/kg (n = 6) every 3 weeks, following a 3 + 3 design. Maximum tolerated dose was not reached on the basis of the study design; no dose-limiting toxicity events were observed. The most common treatment-emergent adverse events related to telisotuzumab vedotin were peripheral sensory neuropathy (44%), and nausea, decreased appetite, and decreased white blood cell count (33% each). Most frequent grade ≥3 treatment-emergent adverse events, irrespective of relationship to telisotuzumab vedotin, were decreased neutrophil count and hypoalbuminemia, reported in two patients (22%) each. Systemic exposure of telisotuzumab vedotin at both dose levels was approximately dose proportional. Pharmacokinetic profile in Japanese patients was similar to that previously reported in non-Japanese patients. Two (22%) patients achieved a partial response, six (67%) had stable disease, one (11%) had progressive disease. Overall disease control rate was 89% (eight of nine patients; 95% confidence interval: 51.8%-99.7%]). Median progression-free survival was 7.1 months (95% confidence interval: 1.2-10.4). In conclusion, telisotuzumab vedotin demonstrated a manageable safety profile, with antitumor activity in Japanese patients with advanced solid tumors; the recommended phase 2 dose was confirmed as 2.7 mg/kg every 3 weeks. ClinicalTrials.gov registration number: NCT03311477.

Anlotinib for previously treated advanced or metastatic esophageal squamous cell carcinoma: A double-blind randomized phase 2 trial.

BACKGROUND: Currently, there are no randomized trials on the effect of antiangiogenic therapy in patients with esophageal squamous cell carcinoma (ESCC). The following study investigated the efficacy and safety of anlotinib in patients with advanced ESCC who were previously treated with chemotherapy. METHODS: This randomized, placebo-controlled, double-blind phase 2 trial (NCT02649361) was conducted in 13 Chinese hospitals. Eligible patients were adults with histologically confirmed recurrent or metastatic ESCC who were previously treated with chemotherapy, and were randomly assigned (2:1) to receive oral anlotinib 12 mg or placebo on days 1-14 (repeated every 21 days). The primary endpoint was progression-free survival (PFS). RESULTS: One hundred and sixty-five patients were randomly assigned to the anlotinib (n = 110) or the placebo (n = 55) arm. Median PFS was 3.02 months (95% CI 2.63-3.65) in the anlotinib group and 1.41 months (95% CI 1.38-1.41) in the placebo group (hazard ratio 0.46 [95% CI 0.32-0.66]; p < 0.001). The most common treatment-related adverse events of grade 3 or 4 were hypertension (17 [16%] patients), decreased appetite (6 [6%] patients), and hyponatremia (4 [4%] patients) in the anlotinib group and decreased appetite (2 [4%] patients) in the placebo group. Three (3%) deaths in the anlotinib group were considered as drug related, while there were no treatment-related deaths in the placebo group. CONCLUSIONS: The use of anlotinib in previously treated, recurrent, or metastatic ESCC patients significantly improved PFS compared with placebo. Our findings suggest that antiangiogenesis might be an important therapeutic target in advanced ESCC. CLINICAL TRIALS REGISTRATION: Study of Anlotinib in Patients With Esophageal Squamous Cell Carcinoma (ALTER1102), NCT02649361.

Acute patient-reported outcomes in B-cell malignancies treated with axicabtagene ciloleucel.

Chimeric antigen receptor T-cell therapy with axicabtagene ciloleucel (axi-cel) has considerably improved survival in adults with relapsed/refractory large B-cell lymphoma. This study reports patient-reported outcomes (PROs) such as quality of life (QOL) and toxicity in the first 90 days after treatment. Hematologic cancer patients treated with axi-cel (N = 103, mean age = 61, 39% female) completed SF-36 or PROMIS-29 QOL questionnaires prior to treatment and 90 days after. PRO-Common Terminology Criteria for Adverse Events toxicity items were completed by patients at baseline and 14, 30, 60, and 90 days after treatment. Mixed models examined change in PROs over time. From preinfusion to 90 days later, patients reported improvements in physical functioning, pain, and fatigue (ps < 0.01), but worsening of anxiety (p = 0.02). Patient-reported toxicities worsened by day 14 with improvement thereafter. The five most severe symptoms at day 14 included fatigue, decreased appetite, dry mouth, diarrhea frequency, and problems with concentration. Results indicate improvement in some domains of QOL over time with transient patient-reported toxicities.

Unhealthy life habits associated with self-induced vomiting and laxative misuse in Brazilian adolescents.

Adolescence is a stage in life characterized by important social, cognitive, and physical changes. Adolescents are vulnerable to various psychosocial disorders, including eating disorders. We aimed to investigate the association between unhealthy habits, sociodemographic characteristics, and the practice of self-induced vomiting or laxative misuse in a representative sample of Brazilian adolescent girls and boys. Data from 102,072 students who participated in the National Adolescent School-based Health Survey were analyzed using the dependent variable: presence or absence of self-induced vomiting and/or laxative misuse; independent variables: consumption of unhealthy and high-calorie food items, age during first sexual intercourse, and the use of tobacco, alcohol, and/or illicit drugs. Associations between exposure and outcome were estimated using Poisson's regression models stratified by sex, and including region, school, age group, and mother's educational history as adjustment variables. Eating ultra-processed foods and age during first sexual intercourse were associated with self-induced vomiting and laxative misuse only for girls; all other variables (consuming unhealthy foods and using legal or illicit substances) were associated with these behaviors for both sexes after applying adjustment variables. Early interventions focusing on changing unhealthy behaviors may prevent development of eating disorders in adolescents. Our findings demonstrate a strong association of many unhealthy habits with laxative misuse and self-induced vomiting practices in Brazilian adolescents.

Phase 1 dose escalation trial of volasertib in combination with decitabine in patients with acute myeloid leukemia.

Polo-like kinase 1 (PLK1) regulates mitotic checkpoints and cell division. PLK1 overexpression is reported in numerous cancers, including acute myeloid leukemia (AML), and is associated with poor prognosis. Volasertib is a selective, potent cell-cycle kinase inhibitor that targets PLK to induce mitotic arrest and apoptosis. This phase 1 trial investigated the maximum tolerated dose (MTD), safety, pharmacokinetics, and anti-leukemic activity of volasertib in combination with decitabine in AML patients aged ≥ 65 years. Thirteen patients were treated with escalating volasertib doses (3 + 3 design; 300 mg, 350 mg, and 400 mg) plus standard-dose decitabine. Dose-limiting toxicity was reported in one patient in cycle 1; the MTD of volasertib in combination with decitabine was determined as 400 mg. The most common treatment-emergent adverse events were febrile neutropenia, pneumonia, and decreased appetite. Objective response rate was 23%. The combination was well tolerated, and the adverse event profile was in line with previous findings.

Longitudinal association between dopamine agonists and weight in Parkinson's disease.

OBJECTIVE: To examine the longitudinal relation of dopamine agonists (DA) use with body mass index (BMI) change and weight gain in Parkinson's disease (PD). METHODS: In a cohort of 356 patients with PD annually followed up to 6 years, BMI, antiparkinsonian drugs use, and impulse control disorders (ICDs) were assessed at each visit. DA dose trajectories were estimated using latent class mixed models. The association of DA use with BMI change and weight gain was examined using latent-process mixed models and time-dependent Cox models respectively, while adjusting for disease severity and levodopa (LD) use. RESULTS: In the mixed model, BMI (kg/m2) increased over the follow-up in DA users (betaDA×time = 0.13, 95% CI = 0.02, 0.24) compared to non-users, while it decreased in LD users (betaLD×time = -0.26, 95% CI = -0.38, -0.13). We identified three trajectories of average daily DA dose over the follow-up. Patients in the high trajectory gained more weight than patients who never used DA (P = .001) and in the low (P = .02) or moderate (P = .04) trajectories. The incidence of weight gain of ≥6 kg was 2.10-fold (95% CI = 1.03, 4.28) higher in DA users compared to non-users, while LD users were less likely to gain weight (HR = 0.60, 95% CI = 0.33, 1.11). Associations decreased in analyses adjusted for compulsive eating or ICDs. CONCLUSION: Weight increased in DA users over 6 years, and DA use was associated with increased incidence of weight gain. These associations were partially explained by compulsive eating. Alternatively, weight decreased in LD users. These findings warrant careful monitoring of compulsive eating and weight in PD patients.

Unexpected effect of Zolpidem in a patient with attention deficit hyperactivity disorder.

Sleep-related eating disorder (SRED) is characterized by recurrent episodes of eating during the night, accompanied by partial consciousness and followed by limited recall. Zolpidem is a sedative-hypnotic drug commonly used to treat sleep disorders. Zolpidem reduces sleep latency and increases the total time of sleep. Here, we described a case of a patient with attention-deficit/hyperactivity disorder (ADHD) who suffered from zolpidem-induced SRED. The symptoms disappeared when the use of zolpidem as discontinuation. To the best of our knowledge, this is the first documented case of SRED induced by the use of zolpidem in a patient with ADHD.

Cannabinoids: the lows and the highs of chemotherapy-induced nausea and vomiting.

Despite remaining one of the most widely abused drugs worldwide, Cannabis sativa exhibits remarkable medicinal properties. The phytocannabinoids, cannabidiol and Δ-9-tetrahydrocannabinol, reduce nausea and vomiting, particularly during chemotherapy. This is attributed to their ability to reduce the release of serotonin from enterochromaffin cells in the small intestine, which would otherwise orchestrate the vomiting reflex. Although there are many preclinical and clinical studies on the effects of Δ-9-tetrahydrocannabinol during nausea and vomiting, little is known about the role that cannabidiol plays in this scenario. Since cannabidiol does not induce psychotropic effects, in contrast to other cannabinoids, its use as an anti-emetic is of great interest. This review aims to summarize the available literature on cannabinoid use, with a specific focus on the nonpsychotropic drug cannabidiol, as well as the roles that cannabinoids play in preventing several other adverse side effects of chemotherapy including organ toxicity, pain and loss of appetite.

Preventive effect of cyproheptadine on sleep and appetite disorders induced by methylphenidate: an exploratory randomised, double-blinded, placebo-controlled clinical trial.

OBJECTIVES: Insomnia and loss of appetite are the most common side effects of methylphenidate in patients with attention deficit/hyperactivity disorder (ADHD). The adverse effects may limit optimal dosing and patients' compliance with treatment leading to the discontinuation of treatment. This research evaluates the preventive effects of cyproheptadine on sleeping and appetite disorders induced by methylphenidate in ADHD children. METHODS: During this exploratory, randomised, double-blinded, placebo-controlled clinical trial, forty patients with ADHD diagnosis who had received methylphenidate randomly were assigned to participate in the cyproheptadine or the placebo group. Patients' weight and Pittsburgh Sleep Quality Index (PSQI) score were recorded at baseline, after four, six and eight weeks of treatment. The ADHD Parent Rating Scale-V score was also defined at the beginning and the end of study for each patient. RESULTS: There was no significant difference between the cyproheptadine and the placebo groups regarding their weight, rate of growth and PSQI score in the monthly assessment. In addition, there was no significant difference in response to the therapy between the two groups. CONCLUSIONS: Based on our findings, cyproheptadine does not have any considerable preventive effect on sleeping and appetite disorders induced by methylphenidate in ADHD children.

Sleep-related eating disorder with mirtazapine.

Sleep-related eating disorder (SRED) is classified within parasomnia and is characterised by recurrent episodes of abnormal, dysfunctional eating during sleep. This report describes a case of SRED in a 19-year-old woman admitted to the psychiatric ward with worsening anxiety, low mood and suicidal ideation. She was started on low-dose mirtazapine for mood stabilisation and, following an incremental increase to 30 mg, she developed nocturnal binge eating of which she retained only partial memory on waking. She developed adverse health consequences as a result of these recurrent episodes. The subject's symptoms were relieved rapidly following reduction of the dose of mirtazapine back to 15 mg.

Corticotrophin-releasing factor mediates vasoactive intestinal peptide-induced hypophagia and changes in plasma parameters.

Vasoactive intestinal peptide (VIP) and corticotrophin-releasing factor (CRF) are anorexigenic neuropeptides that act in the hypothalamus to regulate food intake. Intracerebroventricular (ICV) microinjection of VIP promotes increased plasma adrenocorticotrophic hormone (ACTH) and corticosterone, indicating that VIP activates hypothalamic-pituitary-adrenal axis. The aim of this study was to evaluate the interaction between VIP and CRF, by verifying the effects of ICV administration of VIP on the activity of neurons and CRF mRNA expression in paraventricular nucleus of hypothalamus (PVN). In addition, it was evaluated the effects of pretreatment with CRF type 1 receptor (CRFR1) antagonist (Antalarmin, ANT) or CRF type 2 receptor (CRFR2) antagonist (Antisauvagine-30, AS30) on VIP-induced changes on food intake and plasma parameters of male rats. Compared to Saline group, VIP increased not only the number of Fos-related antigens (FRA)-immunoreactive neurons in the PVN but also CRF mRNA levels in this nucleus. Both ANT and AS30 treatment attenuated the inhibition of food intake promoted by VIP, ANT showing a more pronounced effect. Both antagonists also attenuated VIP-induced reduction and enhancement of free fatty acids and corticosterone plasma levels, respectively, and only AS30 was able to attenuate the hyperglycemia. These results suggest that CRF is an important mediador of VIP effects on energy balance, and CRFR1 and CRFR2 are involved in these responses.

Sleep-Related Eating Disorder (SRED): Paradoxical Effect of Clonazepam.

ABSTRACT: A 9-year-old boy with primary myoclonus dystonia with comorbid severe attention deficit hyperactive disorder (ADHD) also had sleep onset and maintenance insomnia. Polysomnography showed features of non-rapid eye movement parasomnia. Daily bedtime clonidine helped sleep and hyperactivity. ADHD symptoms improved with 40 mg daily lisdexamphetamine mesylate. As the myoclonus and dystonia symptoms progressed, clonazepam was initiated at a dose of 0.5 mg daily at bedtime. It was anticipated that clonazepam would also improve parasomnia. Concomitant with the initiation of clonazepam, he developed a sleep-related eating disorder (SRED) continuing almost throughout the night. The symptoms went away upon stopping clonazepam. This is the first description of clonazepam producing SRED though it is the treatment of choice for this disorder.

Early Empiric Antibiotic Use Is Associated With Delayed Feeding Tolerance in Preterm Infants: A Retrospective Analysis.

The causative factors of neonatal feeding intolerance are poorly understood, but potentially related to clinical practices such as empiric antibiotic usage. The objective of this study was to evaluate whether early empiric antibiotic exposure negatively affects preterm infants' enteral feeding tolerance. Data from infants without risk factors for sepsis, 500 to 1499 g birth weight and 24 to 34 weeks gestational age were analyzed. The primary outcomes were the empiric antibiotic exposure effects on the infants' total parenteral nutrition usage duration and prevalence of necrotizing enterocolitis (NEC). Among the 901 infants included, 67 were exposed to early empiric antibiotic. A 50% increase in parenteral nutrition usage duration and a 4-fold greater prevalence of NEC was seen in the early empiric antibiotic-exposed neonates, when compared with control infants (P < 0.01). Early empiric antibiotic exposure appears to negatively influence preterm infant feeding tolerance and possibly contributes to NEC.

S-1 versus placebo in patients with sorafenib-refractory advanced hepatocellular carcinoma (S-CUBE): a randomised, double-blind, multicentre, phase 3 trial.

BACKGROUND: Unresectable advanced hepatocellular carcinoma is a heterogeneous disease, for which sorafenib is the first targeted agent approved for first-line therapy, and treatment options for patients with sorafenib-refractory advanced hepatocellular carcinoma are limited. We assessed the efficacy and safety of S-1, a chemotherapeutic agent based on fluorouracil, in patients with sorafenib-refractory advanced hepatocellular carcinoma. METHODS: We did a randomised, double-blind, placebo-controlled, phase 3 study done at 57 sites in Japan. Patients with advanced hepatocellular carcinoma who were ineligible for surgical or local-regional therapy and judged refractory to sorafenib (ie, had progressed on sorafenib or had discontinued sorafenib because of adverse events) were randomly assigned (2:1) to receive oral S-1 (weight-banded 80 mg/m2 [80-120 mg per day]), or placebo, twice per day for 28 days consecutively, followed by a minimum 14 day drug-free period. This cycle was repeated until disease progression or the patient became intolerant to the study treatment. Patients were stratified by site and presence or absence of extrahepatic metastasis or vascular invasion. The primary endpoint was overall survival, assessed in the full analysis set (ie, all patients who were treated with study drug except any individuals who were found not to have hepatocellular carcinoma or who were found to have active double cancer). Patients, medical staff, investigators, and the sponsor were masked to treatment assignment. Blinding was maintained even after study treatment concluded. This study is registered with JapicCTI, number JapicCTI-090920, and has been completed. FINDINGS: Between Oct 26, 2009, and Aug 22, 2012, we screened 399 patients. 65 patients were excluded due to not meeting criteria (n=61), declining to participate (n=3), or other reasons (n=1). 334 patients were randomly assigned to receive either S-1 (n=223) or placebo (n=111). One patient in the S-1 group did not receive treatment, and was thus excluded from analyses. At data cutoff, median follow-up was 32·4 months (IQR 24·0-34·7) in the S-1 group and 32·9 months (23·7-39·5) in the placebo group. Median overall survival was 11·1 months (95% CI 9·7-13·1) in the S-1 group and 11·2 months (9·2-12·8) in the placebo group (hazard ratio 0·86, 95% CI 0·67-1·10; p=0·220). The most frequently reported adverse events were skin hyperpigmentation (123 [55%] of 222 patients in the S-1 group vs nine [8%] of 111 patients in the placebo group), decreased appetite (104 [47%] vs 21 [19%]), fatigue (102 [46%] vs 20 [18%]), diarrhoea (77 [35%] vs 14 [13%]), and increased blood bilirubin (77 [35%] vs 14 [13%]). Serious adverse events were reported in 90 (41%) of 222 patients in the S-1 group and 24 (22%) of 111 patients in the placebo group. Five treatment-related deaths were reported in the S-1 group. INTERPRETATION: S-1 did not prolong overall survival in patients with sorafenib-refractory advanced hepatocellular carcinoma. Further research is needed to identify subgroups of patients who might benefit from S-1. FUNDING: Taiho Pharmaceuticals.

Difference in toxicity reporting between patients and clinicians during systemic chemotherapy in patients with urothelial carcinoma.

OBJECTIVES: To compare toxicity reporting between patients and clinicians in the case of systemic chemotherapy for urothelial carcinoma. METHODS: Between June 2013 and March 2016, 100 urothelial carcinoma patients received two courses of chemotherapy of gemcitabine plus cisplatin or gemcitabine plus carboplatin, and they were prospectively enrolled in the present study. During chemotherapy, patients answered European Organization for the Research and Treatment of Cancer Quality-of-Life Questionnaire C30 quality-of-life questionnaires, including four toxicity-related symptoms (appetite loss, nausea, constipation and diarrhea). Clinicians evaluated adverse events using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Differences of toxicity reporting were compared between patients and clinicians. Logistic regression analyses were carried out to investigate potential factors for underreporting by clinicians. RESULTS: Toxicity underreporting was most frequently for diarrhea (44%), followed by appetite loss (39%), constipation (33%) and nausea (22%). In total, toxicity underreporting was observed in 72% of patients. Background-adjusted logistic regression analyses showed pretreatment quality-of-life items of global, symptomatic scores to be predictors for toxicity underreporting by clinicians. The limitations of the present study included its retrospective nature and small sample size. CONCLUSIONS: Toxicity underreporting by clinicians is frequent in urothelial carcinoma patients receiving systemic chemotherapy. Pretreatment quality-of-life evaluation is essential not only for quality-of-life evaluation, but also to identify potential individuals at risk for toxicity underreporting.

Appetite Loss as an Adverse Effect During Treatment with EGFR-TKIs in Elderly Patients with Non-small Cell Lung Cancer.

AIM: We conducted a retrospective study to investigate the frequency of appetite loss during treatment with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) in elderly patients, aged 75 years or older, with non-small cell lung cancer harboring EGFR gene mutations. PATIENTS AND METHODS: Data of a total of 64 patients, including 39 relatively young (hereinafter, younger) patients and 25 elderly patients were analyzed. RESULTS: Appetite loss of all grades (p=0.074) and of grade 3 or greater (p=0.030) was more frequently observed in elderly patients. Diarrhea and oral mucositis were also more frequent in elderly patients, although they did not reach statistical significance. No apparent differences were observed in the frequency of aspartate aminotransferase/ alanine aminotransferase elevation, skin rash or fatigue between the two patient groups. The median (95% confidence interval) progression-free survival times were 10.8 (6.6-16.4) months and 11.8 (4.4-20.3) months in the younger and elderly patient groups, respectively. CONCLUSION: Our findings suggest that appetite loss is a major adverse effect in elderly patients with non-small cell lung cancer receiving treatment with EGFR-TKIs.