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Ilena Pochiero,1 Fabrizio Calisti,1 Alessandro Comandini,1 Alessandra Del Vecchio,1 Isabella Costamagna,1 Maria Teresa Rosignoli,1 Agnese Cattaneo,1 Sasikiran Nunna,2 Ilaria Peduto,3 Franca Heiman,3 Hsiu-Ching Chang,2 Chi-Chang Chen,2 Christoph Correll4– 6 1Angelini Regulatory, Research & Development, Angelini Pharma S.p.A., Rome, Italy; 2IQVIA, Plymouth Meeting, PA, USA; 3IQVIA Solutions Italy S.r.l., RWS, Milan, Italy; 4Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin, Berlin, Germany; 5Department of Psychiatry, The Zucker Hillside Hospital, Northwell Health, Glen Oaks, NY, USA; 6Department of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USACorrespondence: Ilena PochieroAngelini Pharma S.p.A., Viale Amelia 70, Rome, ItalyEmail ilena.pochiero@angelinipharma.comPurpose: The primary objectives were to describe weight changes following initiation of lurasidone versus other antipsychotics and estimate the risk of clinically relevant (≥ 7%) weight changes.Patients and Methods: This retrospective, longitudinal comparative cohort study was based on electronic medical records (EMRs) of United States (US) adult patients with schizophrenia who were prescribed lurasidone or other antipsychotics as monotherapy between 1 April 2013 and 30 June 2019.Results: Overall, the study included 15,323 patients with a diagnosis of schizophrenia; 6.1% of patients received lurasidone, 60.4% received antipsychotics associated with a medium-high risk of weight gain (clozapine, olanzapine, quetiapine, risperidone, paliperidone) and 33.5% received antipsychotics with a low risk of weight gain (aripiprazole, first-generation antipsychotics, ziprasidone). Lurasidone was associated with the smallest proportion of patients experiencing clinically relevant weight gain and the greatest proportion of patients with clinically relevant weight loss. The risk of clinically relevant weight gain was numerically higher with all antipsychotics versus lurasidone and was statistically significant for olanzapine (hazard ratio [HR]=1.541; 95% confidence interval [CI]=1.121; 2.119; p=0.0078) versus lurasidone. The likelihood of ≥ 7% weight loss was significantly greater with lurasidone versus all antipsychotics (p< 0.05), except ziprasidone.Conclusion: This real-world study suggests that lurasidone has a lower risk of clinically relevant weight gain and a higher likelihood of clinically relevant weight loss than other commonly used antipsychotics.Keywords: retrospective studies, weight gain, real world clinical trials

Background: The Mediterranean diet (MD) is recognized as a cultural heritage by UNESCO, thus, is a nutritional model widely spread in all Mediterranean countries. As already demonstrated by several studies, high adherence to MD is a protective factor against many chronic diseases. Conversely, poor adherence to the diet is correlated with an increased prevalence of these pathologies. The aim of the current study was to investigate the relationship between the adherence to MD and the prevalence of benign and malignant thyroid disease., Methods: We analyzed the health status of 60 patients, referred to total thyroidectomy and histological examination, due to nodular thyroid disease. Eating habits were evaluated according to the PREDIMED questionnaire, and patients' results were evaluated according to histological findings of benign or malignant disease., Results: PREDIMED Score was lower in patients with malignant thyroid disease (MTD) than those with benign thyroid disease (BTD) (5.27±0.87 vs. 7.00±1.23, respectively; P value <0.001). A significant correlation was found between poor adherence to MD and diagnosis of MTD (r=0.454; P<0.001). Excessive consumption of butter and sugary drinks, along with low consumption of pasta, white meat, and rice were found to be predictive factors of MTD., Conclusions: In our cohort, a PREDIMED Score ≤7 resulted significantly related to MTD diagnosis, while a good adherence to MD resulted associated with BTD. Moreover, high consumption of sweetened beverages seemed to predict MTD histologic diagnosis, while, conversely, low consumption resulted predictor of BTD. Nevertheless, more studies are needed to evaluate the effective impact of MD on MTD incidence on larger cohorts.

Introduction: Up to 50% of diabetic patients with neuropathy suffer from chronic pain, namely painful diabetic neuropathy (PDN), an unmet medical need with significant impact on quality of life. Gabapentin is widely used for PDN, albeit with frequent dose-limiting effects. Trazodone, an antidepressant with multi-modal action, has shown promising results when given at low doses as an add-on to gabapentin. Upon previous clinical trials and experimental evidence, a fixed-dose combination (FDC) of both compounds, at low doses, was developed for neuropathic pain., Methods: This was a phase II, randomized, double-blind, placebo and reference controlled, dose-finding, multicenter, international, prospective study. Male and female diabetic patients aged 18-75 years and affected by PDN were eligible for enrolment. Patients were randomized (1:1:1:1:2 ratio) to trazodone and gabapentin (Trazo/Gaba) 2.5/25 mg t.i.d. for 8 weeks, Trazo/Gaba 5/50 mg t.i.d. for 8 weeks, Trazo/Gaba 10/100 mg t.i.d. for 8 weeks, gabapentin (Gaba), or placebo (PLB). The aim of the study was to collect preliminary information on the effect of the 3 different FDCs of Trazo/Gaba on pain intensity based on the 11-point numeric rating score (NRS) after 8 weeks of treatment. The secondary objectives were the evaluation of the percentage of responders, neuropathic pain symptoms, anxiety, sleep, quality of life, safety, and tolerability. The primary efficacy endpoint was evaluated with last observation carried out forward (LOCF), using an analysis of covariance (ANCOVA), including treatment and centers as factors and baseline as covariate and applying linear contrast test, excluding the active treatment. Only if the linear contrast test was significant (p < 0.05), the step-down Dunnett test would be used to determine the minimum effective dose significantly different from PLB. If linearity was not verified, an adjusted ANCOVA model and comparisons with Dunnett test were performed. Before the application of the ANCOVA model, the non-significance of interaction treatment per baseline was verified., Results: A total of 240 patients were included in the modified intention-to-treat (m-ITT) population: 39 in Trazo/Gaba 2.5/25 mg, 38 in Trazo/Gaba 5/50 mg, 37 in Trazo/Gaba 10/100 mg, 83 in PLB, and 43 in Gaba. After 8 weeks of treatment, changes of the average daily pain score based on the 11-point NRS from baseline were - 2.52 ± 2.31 in Trazo/Gaba 2.5/25 mg group, - 2.24 ± 1.96 in Trazo/Gaba 5/50 mg group, - 2.46 ± 2.12 in Trazo/Gaba 10/100 mg group, - 1.92 ± 2.21 in Gaba group, and - 2.02 ± 1.95 in the PLB group. The linear contrast test did not result in significant differences (p > 0.05) among treatment groups. Consequently, the minimum effective dose against PLB was not determined. The multiple comparison with Dunnett adjustment did not show any statistically significant differences vs. PLB after 8 weeks of treatment: Trazo/Gaba 2.5/25 mg (95% confidence interval (CI) - 1.2739, 0.2026; p = 0.1539); Trazo/Gaba 5/50 mg (95% CI - 0.9401, 0.5390; p = 0.5931); Trazo/Gaba 10/100 mg (95% CI - 1.0342, 0.4582; p = 0.4471). However, patients receiving the lowest dose of Trazo/Gaba 2.5/25 mg showed a statistically significant difference to PLB after 6 weeks of treatment (95% CI - 1.6648, - 0.2126; p = 0.0116). Positive results were also found for responder patients, other items related to the pain, anxiety, depression, sleep, and quality of life, consistently in favor to the lowest Trazo/Gaba FDC. Two serious adverse events (SAEs) occurred but were judged unrelated to the study treatment. Treatment-emergent adverse events (TEAEs) were mainly mild-to-moderate in intensity and involved primarily nervous system, gastrointestinal disorders, and investigations., Conclusions: The primary end point of the study was the change from baseline of the average daily pain score based on the 11-point NRS after 8 weeks of treatment. While the primary endpoint was not reached, patients treated with Trazo/Gaba 2.5/25 mg t.i.d. showed statistically significant improvement of pain and other scores after 6 weeks and reported consistent better results in comparison to PLB on primary and secondary endpoints for the overall study duration. According to these results, the lowest dose of Trazo/Gaba FDC may be the best candidate for further clinical development to confirm the potential benefits of the FDC drug for this condition., Clinical Trial Registration: NCT03749642., (© 2024. The Author(s).)

Background and Objectives: The aim of this analysis was to evaluate the long-term safety and effectiveness of lurasidone in the treatment of schizophrenia in adolescents and young adults (13-25)., Methods: The 2 pooled studies used similar designs and outcome measures. Patients (13-25) with schizophrenia completed an initial double-blind 6-week trial of lurasidone (40 and 80 mg/day) in the adolescent trial and (80 and 160 mg/day) in the young adult trial. In open-label long-term trials, adolescent patients were treated with 20-80 mg/day lurasidone, and adults were treated with 40-160 mg/day lurasidone. Efficacy was evaluated based on the Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression-Severity Scale (CGI-S)., Results: The safety population consisted of 306 patients (mean age, 16.2 years; 208 patients (68.0%) who completed 12 months of treatment; 8.2% who discontinued treatment by 12 months due to an adverse event). The mean (SD) changes in the PANSS total score from the extension baseline to months 6 and 12 were - 11.8 (13.9) and - 15.3 (15.0), respectively (OC), and the mean (SD) changes in the CGI-S score were - 0.8 (1.0) and - 1.0 (1.1), respectively (OC). The most frequent adverse events were headache (17.6%), anxiety (11.4%), schizophrenia (9.8%), and nausea (9.8%). No clinically meaningful changes were observed in weight, metabolic parameters, or prolactin., Conclusions: In adolescents and young adults with schizophrenia, treatment with lurasidone was generally well tolerated and effective. Long-term treatment was associated with a continued reduction in symptoms of schizophrenia. Long-term treatment was associated with minimal effects on weight, metabolic parameters, and prolactin., Clinicaltrials: gov identifiers D1050234, D1050302., (© 2024. The Author(s).)

Background: Bleeding is one of the most fearsome and life-threatening complications after thyroid surgery. Several medical devices and haemostatic agents have been proposed to improve haemostasis during total and hemi-thyroidectomy. Resorbable polysaccharide powder (HaemoCer™) is a plant-based polymer that is helpful in terms of the coagulation cascade becoming a gel and forming a barrier to prevent further bleeding, having tested for haemostasis in different districts. The aim of the current study was the evaluation of drain output, the presence of significant postoperative blood loss and complications in patients treated with or without resorbable polysaccharide powder during thyroid surgery., Methods: From January to December 2022, postoperative bleeding, drainage output and the postoperative wound events of patients undergoing thyroid surgery, in a tertiary centre, with haemostasis completion with resorbable polysaccharide powder (Group A) or not (Group B), were retrospectively analysed., Results: Eighty-one patients in Group A received a haemostasis improvement with the use of reabsorbable polysaccharide powder, and 96 patients in Group B received thyroid surgery alone. Patients in Group A presented lower drainage output (0.005), lower incidence of neck haematoma (0.005) and seroma (0.021), confirmed also by multivariate analysis., Conclusions: The resorbable polysaccharide powder, in the current series, appeared to be an effective agent in achieving haemostasis in thyroidectomies, reducing the postoperative drainage output, and also neck events such as neck haematoma and seroma, improving the postoperative comfort of the patients. Further larger comparative studies are needed to address this issue.

The objective of this study is to confirm the efficacy and safety of lurasidone in the acute treatment of schizophrenia in European patients. Data were pooled from three studies of patients randomized to 6 weeks of double-blind, placebo-controlled, fixed-dose (40/80 mg and 120/160 mg) lurasidone. The primary efficacy endpoint was a week 6 change in the Positive and Negative Syndrome Scale (PANSS) total score and secondary endpoints included the Clinical Global Impression, Severity scale (CGI-S). In total 328 safety patients were enrolled; 72.6% were completers. Endpoint change was significantly greater in patients treated with 40-80 mg/d and 120-160 mg/d compared to placebo on the PANSS total score ( P  < 0.001) and the CGI-Severity score ( P  < 0.001) for all comparisons. For PANSS total scores, endpoint effect sizes for lurasidone 40-80 mg/d and 120-160 mg/d were 0.68 to 0.77, respectively. Adverse events with a frequency ≥5% (and were greater than for combined lurasidone) were insomnia (11.7%), akathisia (11.3%), headache (7.4%), Parkinsonism (6.5%) and nausea (5.7%). Median changes (in mg/dL) at endpoint were minimal for total cholesterol (-8.0); triglycerides (-8.5) and glucose (-2.0) and in mean weight (-0.2 kg). In European patients with schizophrenia, short-term treatment with lurasidone in doses of 40-160 mg/d was generally safe, well-tolerated and effective with minimal effects on weight and metabolic parameters., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: Acute bacterial skin and skin structure infections (ABSSSIs) are associated with considerable morbidity and a heavy healthcare burden. The primary objectives of this two-phase study were to determine the incidence of skin infections and ABSSSIs in hospitalized patients (Phase A), and to describe the characteristics and treatment of hospitalized patients with ABSSSIs (Phase B)., Methods: This non-interventional, retrospective study was based on data collected from adult patients hospitalized for skin infections in six European countries (Czech Republic, Greece, Italy, Portugal, Russia and Spain) between January 2014 and June 2016., Results: In Phase A, the total hospital incidence of skin infections and ABSSSIs was 2.4 and 1.8 per 1000 patient-days, respectively. Overall, 73.6% of 50,469 hospitalizations for skin infections were for ABSSSIs. Among the 750 patients with ABSSSIs included in Phase B, Gram-positive bacteria were isolated in 24.9%, most commonly methicillin-susceptible Staphylococcus aureus (11.5%). Empirical therapy was administered to 98.1% of patients, most often with a penicillin, with or without a β-lactamase inhibitor (42.1%). Complete cure was achieved in 46.5% and 34.5% of patients after initial treatment and treatment modification, respectively. Overall, 22.7% of patients had at least one additional ABSSSI-related hospitalization, 47.1% of patients visited the emergency room, 19.3% of patients visited primary care clinics, and 34.8% of patients visited a specialist., Conclusion: Treatment of ABSSSIs in Europe is associated with a heavy healthcare burden, highlighting the need for optimized management strategies that may reduce healthcare utilization., (Copyright © 2022 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)

Purpose: This study sought to describe patient characteristics and treatment patterns among patients with insomnia prescribed trazodone in the United States., Methods: This real-world, retrospective, descriptive cohort study used US commercial insurance claims from July 1, 2009, through June 30, 2019. The index date was the first prescription for trazodone between January 1, 2010, and December 31, 2018, with 6 months for the preindex period and ≥6 months for the postindex period., Findings: Among 5.8 million patients with insomnia, 17.7% were prescribed trazodone, and 357,380 adults (6.2%) and 7564 children (0.1%) met the study eligibility criteria. The mean (SD) age was 48.8 (15.8) years for adults and 14.8 (2.7) years for pediatrics. Most patients were female (229,280 adults [64.2%] and 4481 children [59.2%]). Insomnia due to mental disorder was the most common specific diagnosis. The most common (>25%) comorbid conditions were anxiety, depression, and hypertensive disease, and 1 of 10 had a history of substance abuse. Zolpidem was previously prescribed (73,342 adults [20.5%] and 233 children [3.1%]) and continued to be prescribed. Concomitant antidepressants were most common (216,893 adults [60.7%] and 5414 children [71.6%]), but benzodiazepines (132,740 adults [37.1%] and 1188 children [15.7%]), antiepileptics (115,064 adults [32.2%] and 2103 children [27.8%]), nonbenzodiazepines (90,946 adults [25.4%] and 542 children [7.2%]), and antipsychotics (40,490 adults [11.3%] and 2063 children [27.3%]) were also prescribed., Implications: This study provides current evidence that trazodone use is widespread among patients with insomnia and is often associated with other specific comorbidities, such as psychiatric conditions. A deeper knowledge of the real-world management of patients with insomnia may facilitate steps toward improving sleep quality, daytime functioning, and clinical outcomes for patients., Competing Interests: Declaration of Competing Interest All authors have seen and approved the manuscript. This study was sponsored by Angelini Pharma S.p.A., of which I. Pochiero, M. Gorini, A. Comandini, F. Calisti, G. Di Loreto, and A. Cattaneo are employees. The study was conducted by Labcorp Drug Development, of which T. Knight, K.P. Anastassopoulos, R. Patel, and R. Baik are employees. O. Bruni is a consultant for Fidia Pharma., (Copyright © 2022. Published by Elsevier Inc.)

Real-world evidence regarding the effectiveness of prulifloxacin in the treatment of acute exacerbations of chronic bronchitis (AECB) is limited. Therefore, this study aimed to assess the rates and time to symptom improvement and resolution in patients with moderate-to-severe AECB who were given prulifloxacin in the routine care in Greece. This observational, prospective study, conducted in 15 hospital-based clinics across Greece, enrolled outpatients >40 years old, with moderate-to-severe AECB, for whom the physician had decided to initiate treatment with prulifloxacin. Data were collected at prulifloxacin onset (baseline), 7-10 days after baseline, and at least 28 days after therapy completion. Between 23 November 2015 and 27 January 2018, 305 patients (males: 76.4%; mean (standard deviation) (SD) age: 69.7 (9.8) years; Anthonisen type I/II: 94.8%; chronic bronchitis duration >10 years: 24.9%) were consecutively enrolled. At baseline, >80% had increased sputum volume, cough, dyspnoea, and sputum purulence. Prulifloxacin improved symptoms in 99.7% of the patients after a mean (SD) of 5.47 (3.57) days, while symptoms fully recovered after a mean (SD) of 10.22 (5.00) days in 95.4%. The rate of adverse events related to prulifloxacin was 1.3% (serious: 0.7%). In the routine care in Greece, prulifloxacin was highly effective in moderate-to-severe AECB, while displaying a predictable safety profile., Competing Interests: Alessandro Ruggieri, Alessandra del Vecchio, Fabrizio Calisti, Alessandro Comandini, Giovanna Esposito, and Giorgio Di Loreto are full-time employees of Angelini S.p.A., the study sponsor., (Copyright © 2021 Konstantinos Gourgoulianis et al.)

Background: The aim of this pooled analysis was to evaluate the efficacy and safety of lurasidone in the treatment of an acute exacerbation of schizophrenia in adolescents and young adults., Methods: The six pooled studies in this analysis used similar study designs and outcome measures. Patients (aged 13-25 years) were randomized to 6 weeks of double-blind, placebo-controlled treatment with lurasidone in fixed doses of 40, 80, 120, or 160 mg. The primary efficacy endpoint was Week 6 change in the Positive and Negative Syndrome Scale (PANSS) total score; secondary efficacy endpoints included Week 6 change in the Clinical Global Impression-Severity scale., Results: The safety population consisted of 537 patients (mean age: 18.1 years); 82.6% of patients completed the studies. Treatment with lurasidone was significantly better than placebo at all doses (p < 0.001) for change in the PANSS total score at Week 6. Placebo-adjusted PANSS scores ranged from -9.4 to -16.1 (effect sizes: 0.53-0.90), with effect sizes increasing at higher doses. For lurasidone (combined doses), three adverse events occurred with a frequency of ≥5% (nausea: 13.5%; somnolence: 12.1%; akathisia: 10.1%). At last observation carried forward (LOCF)-endpoint weight gain of ≥7% was similar for lurasidone versus placebo (3.6 vs. 4.7%). Minimal median changes were observed at endpoint in cholesterol, -2.0 mg/dL; triglycerides, 0.0 mg/dL; and glucose, 0.0 mg/dL., Conclusions: In adolescents and young adults with schizophrenia, treatment with lurasidone in doses of 40-160 mg/d was a safe, well-tolerated, and effective treatment. Short-term treatment with lurasidone was associated with minimal effects on weight and metabolic parameters.

Our aim was to assess the efficacy and safety of intravenous (i.v.) paracetamol vs. i.v. ibuprofen for the treatment of hemodynamically significant patent ductus arteriosus (hsPDA) in preterm infants. This is a multicenter randomized controlled study. Infants with a gestational age of 25 +0 -31 +6  weeks were randomized to receive i.v. paracetamol (15 mg/kg/6 h for 3 days) or i.v. ibuprofen (10-5-5 mg/kg/day). The primary outcome was the closure rate of hsPDA after the first treatment course with paracetamol or ibuprofen. Secondary outcomes included the constriction rate of hsPDA, the re-opening rate, and the need for surgical closure. Fifty-two and 49 infants received paracetamol or ibuprofen, respectively. Paracetamol was less effective in closing hsPDA than ibuprofen (52 vs. 78%; P = 0.026), but the constriction rate of the ductus was similar (81 vs. 90%; P = 0.202), as confirmed by logistic regression analysis. The re-opening rate, the need for surgical closure, and the occurrence of adverse effects were also similar.Conclusions: Intravenous paracetamol was less effective in closing hsPDA than ibuprofen, but due to a similar constriction effect, its use was associated with the same hsPDA outcome. These results can support the use of i.v. paracetamol as a first-choice drug for the treatment of hsPDA.Trial registration: Clinicaltrials.gov : NCT02422966, Date of registration: 04/09/2015; EudraCT no: 2013-003883-30. What is Known: • The successful closure of patent ductus arteriosus with oral paracetamol has been recently reported in several preterm infants, but only one randomized controlled study investigated the efficacy of intravenous paracetamol. What is New: • Intravenous paracetamol is less effective in closing hsPDA than ibuprofen, but have a similar constriction effect. • These results can support the use of i.v. paracetamol as a first-choice drug for the treatment of hsPDA.

Objectives: To establish dose proportionality for trazodone and gabapentin at fixed ratios of trazodone/gabapentin 2.5/25, 10/100, and 30/300 and investigation of potential drug-drug interaction at a dose of 10/100., Materials and Methods: 29 out of 30 healthy subjects completed this single-center, open-label, randomized, 5-period cross-over trial with single-dose fasted administrations. Administrations were separated by a washout period of at least 6 days. Blood samples were drawn until 48 hours post dose. A validated liquid chromatography-tandem mass spectrometry method (LC-MS/MS) was applied for determination of trazodone and gabapentin in plasma. The lower limits of quantitation (LLOQ) were 1.00 ng/mL and 5.00 ng/mL for trazodone and gabapentin, respectively. Adverse events (AEs) were analyzed in the study population descriptively., Results: Plasma concentrations were characterized thoroughly. For trazodone, assessment of proportionality (power model/pairwise-comparison by ANOVA) showed proportionality for AUC over all doses and for C max between the middle and high dose. For gabapentin, a less than proportional increase in both metrices was present with a likely proportional increase from 25 to 100 mg only. Considering common bioequivalence criteria, absence of pharmacokinetic interaction was confirmed comparing the combination and individual agents. 23 subjects experienced 53 AEs during the trial, the most frequent being fatigue (20 cases/15 subjects) and dizziness (14 cases/11 subjects). No serious AEs were reported., Conclusion: To our knowledge, for the first time, proportionality for trazodone at doses of 2.5 to 30 mg and for gabapentin at doses of 25 to 300 mg was investigated. Absence of a pharmacokinetic interaction was shown.

Background: Painful diabetic neuropathy is an important therapeutic challenge as the efficacy of analgesic drugs in this setting is still unsatisfactory. Monotherapy with available treatments is often not sufficient and a combination of drugs is necessary. Trazodone (TRZ) is a compound with a multi-modal mechanism of action, being a serotonin-2 antagonist/reuptake inhibitor developed and approved for the treatment of depression in several countries. Previous clinical trials suggest a possible beneficial effect of low doses of trazodone for the treatment of patients affected by painful diabetic neuropathy., Objective: This phase II study was designed to collect data on the efficacy and safety of low doses of TRZ combined with gabapentin after 8 weeks of treatment in patients affected by painful diabetic neuropathy., Methods: This was a randomized, double-blind, placebo-controlled, multi-center, international, prospective study. Male and female diabetic patients aged 18-75 years and affected by painful diabetic neuropathy were eligible for enrollment. Subjects were randomized (1:1:1 ratio) to TRZ30 (10 mg three times daily for 8 weeks) or TRZ60 (20 mg three times daily for 8 weeks) or placebo. Gabapentin as background therapy was administered in open-label conditions to all patients. The primary endpoint was the change from baseline of the Brief Pain Inventory Short Form item 5 to week 8. Secondary endpoints included the other Brief Pain Inventory Short Form items, and the assessment of anxiety, sleep, quality of life, patient's improvement, and safety., Results: One hundred and forty-one patients were included in the intention-to-treat population: 43 allocated to the TRZ30 group, 50 to the TRZ60 group, and 48 to the placebo group. After 8 weeks, the mean changes of Brief Pain Inventory Short Form item 5 from baseline were - 3.1, - 2.6, and - 2.5 in the TRZ30, TRZ60, and placebo groups, respectively. No statistically significant differences between groups were seen. Nevertheless, a better trend was observed for TRZ30 vs placebo (95% confidence interval - 1.30, 0.15; p = 0.1179), on top of the background effect of gabapentin administered to all study groups. 62.8% of patients achieved a ≥ 50% reduction in the TRZ30 group, 54% in the TRZ60 group, and 45.8% in the placebo group. At the same time, a statistically significant improvement was observed in Brief Pain Inventory Short Form item 6 for TRZ30 vs placebo (95% confidence interval - 1.54, - 0.07; p = 0.0314). No serious adverse event occurred during the trial and the most frequent treatment-emergent adverse events involved nervous system, QT prolongation, and gastrointestinal disorders., Conclusions: All treatment groups showed a clinically meaningful pain improvement; nevertheless, patients in the TRZ30 treatment group reported better efficacy outcomes. This finding suggests that low doses of TRZ could be useful for treating painful diabetic neuropathy, and support further adequately powered confirmatory trials investigating the efficacy of TRZ., Clinical Trial Registration: NCT03202979, date of registration: 29/06/2017.

This study evaluated the effect of 3 doses of a trazodone hydrochloride 6% oral drops solution on the QT interval of healthy volunteers. Subjects were randomly assigned to receive a single dose of trazodone 20 mg, 60 mg, and 140 mg, moxifloxacin 400 mg, and trazodone-matched placebo in 5 periods separated by 7-day washouts, according to a double-blind, crossover study design. Subjects were monitored continuously, and triplicate ECGs were extracted from baseline (predose) until 24 hours postdose. Blood samples for trazodone and moxifloxacin analyses were collected at the same time points. The concentration-QTc relationship assessed on placebo-adjusted change from baseline for Fridericia-corrected QT (ΔΔQTcF) was the primary end point. ΔΔQTcF values of 4.5, 12.3, and 19.8 ms for the 20-, 60-, and 140-mg doses were observed at the corresponding trazodone peak plasma concentrations. The upper bound of the 90%CI exceeded 10 ms for the 60- and the 140-mg doses. Time-matched analysis results were in line with these findings. No significant trazodone effect on heart rate or PR or QRS intervals and no clinically significant new morphological changes were present. In this moxifloxacin-validated ECG trial, trazodone had a modest, dose-dependent effect on cardiac repolarization, with no QTc prolongation observed with the 20-mg dose and an effect exceeding the values set in E14 guideline with the 60- and 140-mg doses. The effect on cardiac repolarization is unlikely to represent a clinical risk for ventricular proarrhythmia, but caution should be used with concomitant use of other medications that prolong QT or increase trazodone exposure., (© 2020 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Objectives: To establish the relative bioavailability between a newly developed oral gel and a marketed oral lyophilisate-containing rizatriptan benzoate., Materials and Methods: A total of 47 out of 48 healthy subjects, aged 34 ± 10 (SD) years and body mass index 24.7 ± 3.3 (SD) kg/m 2 completed this single-center, open-label, randomized, 2-period cross-over trial with single-dose fasted administrations. Intake of both investigational products was separated by a washout period of at least 6 days. For pharmacokinetic evaluation, blood samples were withdrawn until 24 hours post dose. A validated liquid chromatography-tandem mass spectrometry method (LC-MS/MS) was applied for the determination of rizatriptan in plasma. The lower limit of quantitation (LLOQ) was 0.100 ng/mL. Adverse events (AEs) were descriptively analyzed in the study population. Palatability of the new product was investigated based on a questionnaire., Results: The geometric means of the parameters related with the extent of total exposure, i.e., AUC 0-tlast and AUC 0-∞ , were 60.285 ng × h/mL and 60.865 ng × h/mL for test and 62.729 ng × h/mL and 63.312 ng × h/mL for reference, respectively. The geometric means of the peak exposure, i.e., C max , were 21.262 ng/mL for test and 21.447 ng/mL for reference. The point estimates (PEs) of the test/reference (T/R) adjusted geometric mean ratios of AUC 0-tlast , C max , and AUC 0-∞ (secondary parameter) were 96.11%, 99.12%, and 96.15%, respectively, and all of them showed 90% confidence intervals (CIs) within the range of 80.00 - 125.00% as suggested by regulatory requirements for bioequivalence assessment. In total, 13 subjects experienced 20 AEs during the trial; the most frequently reported AEs were headache (5 cases) and dizziness (3 cases). No AEs of severe intensity were reported. Palatability assessment of the new product provided sufficient data to discuss its acceptability., Conclusion: Bioequivalence was demonstrated in terms of rate and extent of absorption after administration of test and reference products. Concerning the safety evaluation, no negative implications on the possible use of the test formulation could be determined. Based on ratings by the subjects no relevant problem concerning acceptability of the new formulation in particular regarding taste and smell is to be expected.

There is a paucity of clinical trials for the treatment of pediatric insomnia. This study was designed to predict the doses of trazodone to guide dosing in a clinical trial for pediatric insomnia using physiologically-based pharmacokinetic (PBPK) modeling. Data on the pharmacokinetics of trazodone in children are currently lacking. The interaction potential between trazodone and atomoxetine was also predicted. Doses predicted in the following age groups, with exposures corresponding to adult dosages of 30, 75, and 150 mg once a day (q.d.), respectively, were: (i) 2- to 6-year-old group, doses of 0.35, 0.8, and 1.6 mg/kg q.d.; (ii) >6- to 12-year-old group, doses of 0.4, 1.0, and 1.9 mg/kg q.d.; (iii) >12- to 17-year-old group, doses of 0.4, 1.1, and 2.1 mg/kg q.d. An interaction between trazodone and atomoxetine was predicted to be unlikely. Clinical trials based on the aforementioned predicted dosing are currently in progress, and pharmacokinetic data obtained will enable further refinement of the PBPK models., (© 2019 ANGELINI S.p.A. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Background: Sleep disturbances, in particular insomnia, represent a common problem in children with neurodevelopmental disabilities (NDDs). Currently, there are no approved medications for insomnia in children by the US Food and Drug Administration or European Medicines Agency and therefore they are prescribed off-label. We critically reviewed pediatric literature on drugs as well as nonpharmacological (behavioral) interventions used for sleep disturbances in children with NDDs., Methods: PubMed, Ovid (including PsycINFO, Ovid MEDLINE ® , and Embase), and Web of Knowledge databases were searched through February 12, 2017, with no language restrictions. Two authors independently and blindly performed the screening., Results: Good sleep practices and behavioral interventions, supported by moderate-to-low level evidence, are the first recommended treatments for pediatric insomnia but they are often challenging to implement. Antihistamine agents, such as hydroxyzine or diphenhydramine, are the most widely prescribed sedatives in the pediatric practice but evidence supporting their use is still limited. An increasing body of evidence supports melatonin as the safest choice for children with NDDs. Benzodiazepines are not recommended in children and should only be used for transient insomnia, especially if daytime anxiety is present. Only few studies have been carried out in children's and adolescents' zolpidem, zaleplon, and eszopiclone, with contrasting results. Limited evidence supports the use of alpha-agonists such as clonidine to improve sleep onset latency, especially in attention deficit/hyperactivity disorder subjects. Tricyclic antidepressants, used in adults with insomnia, are not recommended in children because of their safety profile. Trazodone and mirtazapine hold promise but require further studies., Conclusions: Here, we provided a tentative guide for the use of drugs for insomnia in children with NDDs. Well-controlled studies employing both objective polysomnography and subjective sleep measures are needed to determine the efficacy, effectiveness, and safety of the currently prescribed pediatric sleep medicines in children with NDDs., (© 2017 Association for Child and Adolescent Mental Health.)

This work evaluated the structure of dreams in people affected by schizophrenia. The verbal reports of 123 schizophrenic patients were compared with 123 dream reports from a control group. In accordance with the Jungian conceptualization of, dreams as texts, dream reports were assessed using textual analysis processing techniques. Significant differences were found in textual parameters, showing that the dreams reports of schizophrenic patients differ from those of the control group. It is thus possible that schizophrenia probably underlies changes in the oneiric production and dream reports. This work confirms the value of textual analysis in the study of oneiric material., (Copyright © 2010 Elsevier Inc. All rights reserved.)