Brexpiprazole toxicity in a paediatric patient.

Brexpiprazole is a relatively new drug that has no published research or applications within the paediatric population. Brexpiprazole targets multiple receptors and can manifest as multisystem symptoms when ingested in supratherapeutic quantities. In this report, we discuss the case of a child in early childhood who presented with delayed neurological and cardiac symptoms 24 hours after accidental ingestion of brexpiprazole. Due to delayed onset, this case highlights that a high index of suspicion and prolonged observation are necessary to appropriately manage brexpiprazole overdose or accidental ingestion.

Adjunctive Brexpiprazole for Patient Life Engagement in Major Depressive Disorder: A Canadian, Phase 4, Open-Label, Interventional Study: Brexpiprazole d'appoint pour l'engagement dans la vie des patients souffrant de trouble dépressif majeur: une étude interventionnelle canadienne ouverte de phase 4.

OBJECTIVES: To characterize the effects of adjunctive brexpiprazole on patient life engagement and depressive symptoms in patients with major depressive disorder (MDD) using patient-reported outcomes. METHODS: An 8-week, Phase 4, open-label, interventional study was conducted at 15 Canadian trial sites between April 2021 and May 2022. Adult outpatients with MDD (at least moderately severe) and inadequate response to 1-2 antidepressants continued their current antidepressant and received oral adjunctive brexpiprazole 0.5-2 mg/day. Co-primary endpoints were change from baseline to Week 8 in Inventory of Depressive Symptomatology Self-Report (IDS-SR) 10-item Life Engagement subscale score, and IDS-SR 30-item total score. Safety was assessed by standard variables. RESULTS: Of 122 enrolled patients, 120 (98.4%) were treated (mean [SD] dose: 1.2 [0.4] mg/day) and analyzed, and 111 (91.0%) completed the study. Statistically significant least squares mean improvements to Week 8 were observed on IDS-SR10 Life Engagement subscale score (baseline mean [SD]: 16.1 [4.7]; change [95% confidence interval]: -8.11 [-9.34, -6.88]; p < 0.001) and IDS-SR total score (baseline mean [SD]: 41.3 [9.8]; change [95% confidence interval]: -17.38 [-20.08, -14.68]; p < 0.001). Improvements were observed from Week 2, onwards. Treatment-emergent adverse events with incidence ≥5% were fatigue (n = 13, 10.8%), headache (n = 13, 10.8%), insomnia (n = 12, 10.0%), nausea (n = 9, 7.5%), tremor (n = 8, 6.7%), and weight increase (n = 7, 5.8%). Six patients (5.0%) discontinued due to adverse events. Mean (SD) change in body weight from baseline to last visit was +1.9 (3.4) kg. CONCLUSIONS: Using an exploratory patient-reported outcome measure, patients with MDD and inadequate response to antidepressants who received open-label adjunctive brexpiprazole showed early and clinically meaningful improvement in patient life engagement, which should be further assessed in a prospective randomized controlled trial. Patient-rated depressive symptoms (on the validated 30-item IDS-SR) also improved. Adjunctive brexpiprazole was well tolerated, and no new safety signals were observed. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04830215.

Efficacy, safety, and side effects of oliceridine in acute postoperative pain, a protocol for a systematic review and meta-analysis.

This will be the first meta-analysis on the efficacy, safety, and side effects of oliceridine on postoperative pain. Our aim with this work is to evaluate the clinical utility of this relatively new substance in a broad postoperative context. Oliceridine is a new so-called bias opioid that is approved for severe pain requiring an opioid. Due to its biased agonism, it is said to have fewer side effects than conventional opioids. This systematic review and meta-analysis will analyze the efficacy, safety, and side effects of oliceridine compared to placebo or morphine in acute postoperative pain for up to 72 hours. In January 2024, an extensive search in various databases will be performed without restrictions for randomized controlled trials with at least single blinding. After data extraction, data will be pooled and meta-analytic calculations performed. A random-effects model will be used. Dichotomous data will be presented as risk ratio and continuous data as standardized mean difference. Dose-dependent side effects will be evaluated with meta-regression. Heterogeneity will be assessed via the Q statistic and prediction interval in case of a sufficient number of included studies. Publication bias will be examined using funnel plot and Duval and Tweedie's trim and fill method.

Duloxetine for fibromyalgia syndrome: a systematic review and meta-analysis.

INTRODUCTION: The optimal dose of duloxetine in the management of fibromyalgia remains still controversial. Therefore, a systematic review and meta-analysis to investigate efficacy and safety of duloxetine was conducted. The outcomes of interests were to assess changes in Fibromyalgia Impact Questionnaire (FIQ), Brief Pain Inventory (BPI), and Clinical Global Impression (CGI). The rate of of adverse events and those leading to therapy discontinuation were also investigated. MATERIAL AND METHODS: This study followed the 2020 PRISMA guidelines. The literature search started in December 2022 accessing PubMed, Google scholar, Embase, and Scopus databases. All the RCTs investigating the efficacy and safety of daily administration of duloxetine for fibromyalgia were accessed. Studies reporting quantitative data under the outcomes of interest, and including a minimum of 10 patients who completed a minimum of 4 weeks follow-up, were included. Studies on combined pharmacological and non-pharmacological managements for fibromyalgia were not considered. RESULTS: Data from 3432 patients (11 RCTs) were included. The mean age of the patients was 46.4 ± 10.7 years old, and the mean BMI 25.3 ± 3.2 kg/m2. 90% (3089 of 3432 patients) were women. The 60 mg/daily cohort reported the higher FIQ, followed by the 30, 30-60, 120 mg/daily, and placebo groups, while the 60-120 mg /daily group performed the worst results. Concerning the CGI severity scale, placebo resulted in the lowest improvement, and no differences were found in the other groups. Concerning the BPI interference and severity pain scores, the 30-60 mg/daily group reported the worst result, along with the placebo group. The rate of adverse events leading to study discontinuation were lower in the 60-120 group, followed by the 30-60 and 30 mag/daily groups. Duloxetine was superior in all the comparisons to placebo, irrespective of the doses, in all endpoints analysed. CONCLUSIONS: Duloxetine could help in improving symptoms of fibromyalgia. The dose of duloxetine should be customised according to individual patients. Irrespective of the doses, duloxetine was more effective than placebo in the management of fibromyalgia. The dose of duloxetine must be customised according to individual patients. Level of evidence I Meta-analysis of double-blind RCTs.

A meta-analysis evaluating effects of the rotigotine in Parkinson's disease, focusing on sleep disturbances and activities of daily living.

BACKGROUND: Rotigotine transdermal patch (TP) is a useful dopaminergic medication for Parkinson's disease (PD). This meta-analysis attempted to evaluate the effects of rotigotine TP on motor performance, activities of daily living (ADL) limitations, and sleep disturbances in patients with PD. METHODS: Only randomized controlled clinical trials (RCTs) with placebo design were included in this study. The clinical outcomes, evaluated using the Unified Parkinson's Disease Rating Scale (UPDRS III), UPDRS-II, UPDRS Part II + III, Parkinson's Disease Sleep Scale (PDSS)-2, and adverse events (AEs) were evaluated. The Jadad scale was used to evaluate study quality. RESULTS: A total of 16 RCTs with 4682 patients with PD were enrolled in this study. We found that rotigotine TP significantly reduced the UPDRS-III, UPDRS-II, and UPDRS Part II + III scores, indicating that rotigotine TP led to a significant amelioration of movement symptoms and ADL limitations. Moreover, we found that rotigotine TP significantly reduced PDSS-2 scores, suggesting that rotigotine TP led to a remarkable improvement in sleep quality. Meanwhile, compared with the placebo group, patients taking rotigotine TP did not have added incidence of AEs. CONCLUSION: This study verified the efficacy and safety of rotigotine TP in treating PD. The findings of the present study provide compelling evidence concerning and insight into clinical usage of rotigotine TP. Future studies will focus on more non-motor symptoms affected by rotigotine TP.

Effects of Brexpiprazole on Functioning in Patients With Schizophrenia: Post Hoc Analysis of Short- and Long-Term Studies.

Objective: To evaluate the short- and long-term effects of brexpiprazole on patient functioning in schizophrenia.Methods: Data were included from three 6-week, randomized, double-blind, placebo-controlled studies (hospitalized patients); a 52-week, randomized, double-blind, placebo-controlled maintenance treatment study (terminated early by the study sponsor based on the positive result of an interim analysis); and two 52-week, open-label extension studies-all in patients with schizophrenia (DSM-IV-TR criteria) and conducted from July 2011-February 2016. Patients allocated to oral brexpiprazole received 2-4 mg/d (short-term studies) or 1-4 mg/d (long-term studies). Functioning was measured using the Personal and Social Performance (PSP) and Global Assessment of Functioning (GAF) scales, with response defined as a PSP/GAF increase of ≥ 10 points and remission as PSP score ≥ 71 or GAF score ≥ 61.Results: Patients receiving brexpiprazole (n = 831) showed greater improvement than those receiving placebo (n = 490) from baseline to week 6 in PSP score (least squares mean difference, 3.20; 95% confidence interval, 1.82-4.58; P < .0001; Cohen d = 0.31) and in all 4 PSP domains. At week 52 of the maintenance study (which had a low completion rate primarily due to the early termination), GAF functional remission was achieved by 65.3% (62/95) of stabilized patients randomized to brexpiprazole and 47.1% (48/102) of stabilized patients randomized to placebo, with a number needed to treat of 6 (95% confidence interval, 4-22; P = .0076). At week 52 of the open-label studies (n = 177), PSP functional response and remission were achieved by 84.2% and 41.8% of patients receiving brexpiprazole, respectively.Conclusions: Although limited by the lack of an active comparator, analyses of this large dataset demonstrate that brexpiprazole treatment is associated with clinically relevant improvement in functioning among patients with schizophrenia, in the short term and long term.Trial Registration: Data used in this post hoc analysis were from studies with ClinicalTrials.gov identifiers: NCT01396421, NCT01393613, NCT01810380, NCT01668797, NCT01397786, and NCT01810783.

Comparative risk of acute myocardial infarction for anti-osteoporosis drugs in primary care: a meta-analysis of propensity-matched cohort findings from the UK Clinical Practice Research Database and the Catalan SIDIAP Database.

The aim of this study was to evaluate the risk of acute myocardial infarction in patients taking osteoporosis medication. Patients were taken from the SIDIAP or CPRD database and were matched using propensity scores. Patients with diabetes and chronic kidney disease taking SERMs were at an increased risk. The results favour the cardiovascular safety of alendronate as a first-line choice for osteoporosis treatment. INTRODUCTION: This study aims to evaluate the comparative safety of anti-osteoporosis drugs based on the observed risk of acute myocardial infarction while on treatment in a primary care setting. METHODS: This is a propensity-matched cohort study and meta-analysis. This study was conducted in two primary care record databases covering UK NHS (CPRD) and Catalan healthcare (SIDIAP) patients during 1995-2014 and 2006-2014, respectively. The outcome was acute myocardial infarction while on treatment. Users of alendronate (reference group) were compared to those of (1) other oral bisphosphonates (OBP), (2) strontium ranelate (SR), and (3) selective oestrogen receptor modulator (SERM), after matching on baseline characteristics (socio-demographics, fracture risk factors, comorbidities, and concomitant drug use) using propensity scores. Multiple imputation was used to handle missing data on confounders and competing risk modelling for the calculation of relative risk (sub-distribution hazard ratios (SHR)) according to therapy. Country-specific data were analysed individually and meta-analysed. RESULTS: A 10% increased risk of acute myocardial infarction was found in users of other bisphosphonates as compared to alendronate users within CPRD. The meta-analysis of CPRD and SIDIAP results showed a 9% increased risk in users of other bisphosphonate as compared to alendronate users. Sensitivity analysis showed SERMS users with diabetes and chronic kidney disease were at an elevated risk. CONCLUSIONS: This study provides additional data on the risk of acute myocardial infarction in patients receiving osteoporosis treatment. The results favour the cardiovascular safety of alendronate as a first-line choice for osteoporosis treatment.

The sodium-glucose cotransporter 2 inhibitor ipragliflozin improves liver function and insulin resistance in Japanese patients with type 2 diabetes.

Sodium-glucose cotransporter 2 inhibitor (SGLT2i) treatment is a therapeutic approach for type 2 diabetes mellitus (T2DM). Some reports have shown that SGLT2i treatment improves insulin resistance; however, few studies have evaluated insulin resistance by the glucose clamp method. Hepatic insulin clearance (HIC) is a new pathophysiological mechanism of T2DM. The effect of SGLT2i treatment on hepatic insulin clearance and insulin resistance is not well known. We investigated the effect of SGLT2i treatment on insulin resistance, insulin secretion, incretin levels, body composition, and hepatic insulin clearance. We conducted a meal tolerance test (MTT) and a hyperinsulinemic-euglycemic clamp test in 9 T2DM patients. Ipragliflozin (50 mg/day) was administered, and the MTT and clamp test were performed after 4 months. We calculated HIC as the postprandial C-peptide AUC-to-insulin AUC ratio. We also measured GLP-1, GIP, and glucagon levels during the MTT. Body weight and HbA1c were decreased, although not significantly, after 4 months of treatment. Postprandial glucose, fasting insulin and postprandial insulin were significantly decreased. Insulin resistance with the glucose clamp was not changed, but the HOMA-IR and insulin sensitivity indices were significantly improved. Incretin and glucagon levels were not changed. Hepatic insulin clearance was significantly increased, but whole-body insulin clearance was not changed. The FIB-4 index and fatty liver index were significantly reduced. The HOMA-beta and insulinogenic indices were not changed, but the C-peptide index was significantly increased. Although the number of patients was small, these results suggested that SGLT2i treatment improved liver function, decreased hepatic insulin resistance, and increased hepatic insulin clearance, despite the small weight reduction.

Comparing the effects and safety of dorzolamide hydrochloride + timolol maleate versus brimonidine after neodymium-doped yttrium aluminium garnet laser capsulotomy posterior capsule opacification.

AIM: Posterior capsular opacification is treated using neodymium-doped yttrium aluminium garnet laser capsulotomy that leads to increased intraocular pressure. Here, we compare the effects of dorzolamide hydrochloride + timolol maleate versus brimonidine on intraocular pressure. We also investigate their side effects after neodymium-doped yttrium aluminium garnet laser capsulotomy. In these patients, there are no prior studies comparing the results of these two drugs. MATERIALS: Ninety patients with posterior capsule opacification contributed to the study. They received yttrium aluminium garnet laser capsulotomy. After yttrium aluminium garnet laser capsulotomy, they were randomized into three groups. Group 1 received dorzolamide hydrochloride + timolol maleate; Group 2 took brimonidine; and Group 3, the control group, took no drug. Group 1 took dorzolamide hydrochloride + timolol maleate eye drops 1 h before the procedure and on the third hour of the first day and two times per day between the second and the seventh days. Group 2 took brimonidine eye drops 1 h before the procedure and on the third hour of the first day, two times per day between the second and the seventh days. RESULTS: Brimonidine had a similar side effect profile to the fix combination. Intraocular pressure on the first (p = 0.87) and third days (p = 0.124) were similar in Group 1 (dorzolamide hydrochloride + timolol maleate), Group 2 (brimonidine) and the control group. The mean intraocular pressure value of the control group was significantly higher than Groups 1 and 2 because the anti-glaucomatous effects of the drugs become prominent on the seventh day (p = 0.041). In Group 1 and Group 2, intraocular pressure was significantly lower than the control group on the seventh day (p = 0.041). Stinging, itching, hyperemia and Tyndall rates were similar in Group 1, Group 2 and the control group. Watery eyes were less common in the brimonidine group than in the dorzolamide hydrochloride-timolol maleate and the control groups on the seventh day (p = 0.02). Brimonidine also significantly lowered the chemosis rate on the third (p = 0.04) and seventh (p = 0.03) days. CONCLUSION: We suggest that brimonidine and a combination of dorzolamide + timolol are similarly effective at reducing eye pressure for routine cases. In cases where intraocular pressure attacks might be at higher risk, using the dorzolamide + timolol combination would be more appropriate.

Preclinical discovery and development of oliceridine (Olinvyk®) for the treatment of post-operative pain.

INTRODUCTION: Opioids acting at the MOP (mu:µ) receptor produce analgesia but also side effects. There is debate suggesting opioid receptors produce analgesia via G-protein and side-effects via ß-arrestin-2 pathways. Opioids targeting G-proteins over the arrestins (bias) offer potential therapeutic advantages. Oliceridine is a putative MOP, G-protein biased agonist. AREAS COVERED: Oliceridine is selective for MOP receptors with greater activity at G-proteins over arrestins. A substantial body of evidence now points to a simpler pharmacological descriptor of partial agonist. Preclinical in vivo data indicates a robust antinociceptive response of shorter duration than morphine. Apollo trials (Phase-III RCT-bunionectomy/abdominoplasty) describe good analgesic efficacy that was non-inferior to morphine with good tolerability and side-effect profile. There is evidence for an improved respiratory safety profile. Oliceridine is approved by the FDA. EXPERT OPINION: Oliceridine will be an important addition to the clinical armamentarium for use for the management of acute pain severe enough to require an intravenous opioid analgesic and for whom alternative treatments are inadequate. Respiratory advantage and the possibility of reduced abuse potential are possible advantages over the use of traditional opioids. Based on a number of excellent, highly detailed studies, oliceridine should be described as a partial agonist; this 'label' does not matter.

The structure, function, and clinical use of the thrombopoietin receptor agonist avatrombopag.

Thrombopoietin regulates platelet production through activation of the thrombopoietin receptor (TPO-R). TPO-R agonists (TPO-RAs) are available to treat thrombocytopenia in chronic immune thrombocytopenia (ITP), chronic liver disease (CLD) patients who are undergoing a procedure, severe aplastic anemia (SAA), and hepatitis C virus (HCV) infection. There are four TPO-RAs approved in the US and Europe: romiplostim (ITP), eltrombopag (ITP, SAA, HCV), avatrombopag (ITP, CLD), and lusutrombopag (CLD). It is important to understand pharmacological characteristics of these agents when evaluating treatment options. Avatrombopag interacts with the transmembrane domain of the TPO-RA and does not compete with endogenous thrombopoietin for TPO-R binding. Structural differences between avatrombopag and other TPO-RAs may impart differential downstream effects on cell signaling pathways, potentially resulting in clinically relevant differences in outcome. Avatrombopag has a favorable pharmacological profile with similar exposure in Japanese, Chinese, or Caucasian patients and no drug-drug interactions, food interactions, or potential for chelation.

Avatrombopag: A Review in Thrombocytopenia.

Avatrombopag (Doptelet®) is an orally administered second generation thrombopoietin receptor agonist (TPO-RA) approved for the treatment of primary chronic immune thrombocytopenia (ITP) in adult patients who are refractory or have an unsatisfactory response to other treatments, as well as for the treatment of thrombocytopenia in adult patients with chronic liver disease (CLD) scheduled to undergo an invasive procedure. In phase III studies, avatrombopag was associated with a significantly greater platelet response than placebo in patients with chronic ITP, and was superior to placebo in reducing the requirement for platelet transfusion or rescue procedures for bleeding caused by surgery in patients with CLD with a platelet count < 50 × 109/L at baseline. Longer term data indicate that avatrombopag is associated with high durable response rates in ITP and may have corticosteroid-sparing effects. The drug was generally well tolerated in both indications. Avatrombopag thus represents a convenient and effective second-line treatment for patients with chronic ITP and can prevent bleeding events in patients with CLD scheduled to undergo a procedure, offering a useful alternative to other available treatments in both indications.

Avatrombopag (Doptelet^®) is an orally administered drug that mimics the natural compound (thrombopoietin) responsible for stimulating the production of platelets, an essential component of the clotting process that prevents excessive bleeding. Several conditions can cause reduced platelet levels (thrombocytopenia) to the point that intervention is needed to prevent excessive blood loss. Avatrombopag is approved for the treatment of primary chronic immune thrombocytopenia (ITP) and to prevent bleeding caused by surgery in patients with low platelet levels caused by chronic liver disease (CLD). Clinical trials in patients with ITP show that avatrombopag quickly increases platelet levels and that this increase is maintained in the longer term in many patients. Similarly, clinical trials in patients with low platelet levels because of CLD showed that giving avatrombopag prior to surgery reduced the need for platelet transfusions or rescue procedures for bleeding. Avatrombopag is thus a convenient and effective treatment for patients with chronic ITP and can prevent bleeding events in patients with CLD scheduled to undergo a procedure. In both indications avatrombopag offers a useful alternative to other available treatments.