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Objectives: To demonstrate adequate skin adhesion of a new once-daily rotigotine transdermal patch (ROT-TDS) compared to the originator product (reference) in patients with Parkinson's disease (PD)., Materials and Methods: Pharmacokinetic bioequivalence (PK BE) was assessed with the 4 mg/24h patches in healthy adults in a single-/multiple-dose, crossover trial. The trial investigating skin adhesion in PD patients (stable dose ≥ 8 mg/day rotigotine) was performed with the 8 mg/24h patches as a multiple-dose, crossover trial (4 alternating once-daily patch applications). Skin status (seborrhea, sweating) was characterized at screening. Adhesion was assessed 5 minutes after application and 5 minutes before removal of each patch. Systemic safety and skin irritation/sensitization were monitored., Results: ROT-TDS was bioequivalent to the reference product in the PK BE trial in 48 randomized healthy subjects. In the skin adhesion trial in 43 randomized PD patients, the cumulative mean percentage of adhesion (90% CI) at the end-of-dosing interval was 92.948% (90.156 - 95.740%) for ROT-TDS and 90.471% (87.574 - 93.367%) for the reference. For ROT-TDS, 80.23% of patches were ≥ 90% adhered at the end-of-dosing interval, while this was the case for 67.44% of the reference patches. Safety and skin tolerability of both products were comparable; the most frequent treatment-related adverse event was application-site pruritus for both treatments at comparable extent., Conclusion: ROT-TDS - with shown BE to the originator reference product - displayed similar safety and local tolerability as the reference product in patients with PD. The results show a trend to improved skin adhesion of the new patch compared to the reference in the target population.

Purpose: This study evaluated the efficacy, safety, and tolerability of a single-dose, preservative-free (PF) Dorzolamide/Timolol combination (Twinzol-SDU)., Methods: A 3-month single-arm, multicenter, prospective cohort study was conducted in Egypt between January 2021 and October 2022 on previously diagnosed and controlled patients with ocular hypertension and/or glaucoma. Efficacy was assessed using the change in intraocular pressure (IOP) after 6 and 12 weeks. Safety was identified through the change in the incidence of ocular side effects, ocular surface disease index (OSDI) scores and grades, and Time Break-Up time (TBUT)., Results: A total of 382 patients were enrolled in the analysis. After the three-month period of therapy, a significant reduction in IOP was seen (mean change: -1.9, P < 0.001) after switching to PF Dorzolamide/Timolol combination. The rate of ocular abrasion decreased significantly from 30.6% to 1.3% (P < 0.001). The rate of normal aqueous tear production increased from 24.1% to reach 79.4% (P < 0.001). The OSDI scores decreased significantly throughout the study period, with a median score decreased from 41.7 (21.7) to 12.5 (12.5) (P < 0.001). Mild OSDI grades significantly increased from the baseline of 12.6% to reach 24.7%. Moderate OSDI grade decreased at the same rate, from 12.8% to 11.1%. The number of patients with severe OSDI grade substantially decreased from 64.4% to 4.5%, with a P < 0.001. TBUT increased from 9 (3.7) seconds to reach and 12.3 (4) seconds after 12 weeks of treatment (P < 0.001)., Conclusion: Generally, the PF dorzolamide/timolol combination was associated with a significant reduction in IOP and tolerability among glaucoma patients., Competing Interests: Declarations. Conflict of interest: This study and its investigators were fully sponsored and funded by Orchidia Pharmaceutical Industry. Ethical approval: The protocol and its amendments were submitted to independent ethics committees (IECs) of "Genuine Research Center (GRC)" under study code "GRC/ORCDT/EG/37/CT", protocol code number "ORC-001" for review and written approval. It complied with recommendations of the 18th World Health Congress (Helsinki, 1964), laws and regulations, and any applicable guidelines. Consent to participate: All patients signed written informed consent., (© 2025. The Author(s), under exclusive licence to Springer Nature B.V.)

Following the approval of elexacaftor/tezacaftor/ivacaftor (ETI), there have been post-marketing reports and published cases of papilledema and intracranial hypertension in children with cystic fibrosis (CF) taking ETI. In those reports, the patients often presented with marked symptoms and concomitant hypervitaminosis A. In this multicenter case series, we report eight cases of papilledema in children with CF taking ETI that were diagnosed via routine eye exam, the majority of whom presented with minimal to no symptoms and all had normal serum Vitamin A levels., (© 2024 Wiley Periodicals LLC.)

Xanomeline/trospium chloride (COBENFY™), formerly KarXT, is a first-in-class, oral, fixed-dose muscarinic agonist/antagonist combination being developed for use in schizophrenia and Alzheimer's disease psychosis. Xanomeline is thought to confer efficacy by acting as an agonist at M 1 and M 4 muscarinic acetylcholine receptors in the brain, and trospium chloride reduces the peripheral cholinergic adverse events associated with xanomeline. Xanomeline/trospium chloride received its first approval on 26 September 2024 in the USA for the treatment of schizophrenia in adults. This article summarizes the milestones in the development of xanomeline/trospium chloride leading to this first approval for schizophrenia., Competing Interests: Declarations. Funding: The preparation of this review was not supported by any external funding. Authorship and Conflict of interest: During the peer review process the manufacturer of the agent under review was offered an opportunity to comment on the article. Changes resulting from any comments received were made by the authors on the basis of scientific completeness and accuracy. Yahiya Y. Syed is a salaried employee of Adis International Ltd/Springer Nature, and declares no relevant conflicts of interest. All authors contributed to this article and are responsible for its content. Ethics approval, Consent to participate, Consent to publish, Availability of data and material, Code availability: Not applicable., (© 2024. Springer Nature Switzerland AG.)

Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a class of drugs used in the clinical management of patients with type 2 diabetes, and their prescriptions have been increasing in recent years. Herein, we performed a retrospective analysis of seasonal variation in SGLT2 inhibitor-associated adverse events recorded in the Japanese Adverse Drug Event Report (JADER) database, an adverse event reporting database which reflects real-world clinical practice. To this end, seasonal variations in SGLT2 inhibitor-related dehydration, cerebral infarction, urinary tract infection, and ketoacidosis were analyzed. Six SGLT2 inhibitors prescribed in Japan (ipragliflozin, empagliflozin, luseogliflozin, canagliflozin, dapagliflozin, and tofogliflozin) were included. The reporting ratio (RR) for SGLT2 inhibitor adverse events per month in the JADER database from April 2014 to December 2023 was determined. The RR for dehydration-related adverse events was highest in the summer months of July and August, as well as in the winter months of December, January, and February. The highest RR for cerebral infarction was in February. No association with seasonal variations in the occurrence of ketoacidosis related to dehydration was observed. Healthcare providers should take adequate precautions against dehydration caused by SGLT2 inhibitors, not only in summer but also in winter. These findings are instructive and informational for health care professionals involved in diabetes care., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethical approval: Ethical approval was not sought for this study because the study was a database-related observational study which did not directly involve any research subjects. All results were obtained from data openly available online from the PMDA website ( www.pmda.go.jp ). All data from the JADER database were fully anonymized by the relevant regulatory authority before we accessed them. Our research does not fall within the purview of any of the following laws and guidelines: “Clinical Trials Act (Act No. 16 of April 14, 2017),” “Act on Securing Quality, Efficacy and Safety of Products Including Pharmaceuticals and Medical Devices (Law number: Act No. 145 of 1960, Last Version: Amendment of Act No. 50 of 2015),” “Guideline for good clinical practice E6 (R1), https://www.pmda.go.jp/int-activities/int-harmony/ich/0076.html ,” “Ethical guidelines for human genome and gene analysis research, https://www.mhlw.go.jp/general/seido/kousei/i-kenkyu/genome/0504sisin.html ,” and “Ethical Guidelines for Medical and Health Research Involving Human Subjects, https://www.mhlw.go.jp/stf/seisakunitsuite/bunya/hokabunya/kenkyujigyou/i-kenkyu/index.html .” Therefore, it is not subject to ethical examination. The study was an observational study without any research subjects. No consent to participate was required due to the retrospective nature of this study., (© 2024. The Author(s).)

Background and Objective: Inadequate response to antidepressant monotherapy is common among patients with major depressive disorder (MDD). The efficacy and safety of adjunctive brexpiprazole 2 mg/day has recently been confirmed during the 6-week, randomized, placebo-controlled phase 2/3 (BLESS) study, which evaluated brexpiprazole at 1 mg/day and 2 mg/day versus placebo as adjunctive therapy to antidepressant therapies in 740 Japanese patients with MDD and an inadequate response to antidepressant monotherapy. This study evaluated the long-term safety and efficacy of adjunctive fixed-dose brexpiprazole 2 mg/day in Japanese patients with MDD., Methods: An open-label, 52-week study enrolled rollover patients who completed the 6-week, double-blind, randomized, placebo-controlled phase 2/3 BLESS study (NCT03697603), and de novo patients aged ≥ 65 years. Patients were titrated to fixed-dose brexpiprazole 2 mg/day from Week 1. Safety assessments included treatment-emergent adverse events (TEAEs; primary outcome) and clinical and laboratory variables. Efficacy was assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS), Clinical Global Impression-Improvement (CGI-I) scale, Hamilton Depression Rating Scale (HAM-D) 17-item total score, and Sheehan Disability Scale (SDS) score., Results: In total, 247 patients [rollover, n = 216; de novo (previously unexposed), n = 31] were included in the safety/efficacy populations, and 138 (rollover, n = 132; de novo, n = 6; 55.9%) completed the study. Common TEAEs (incidence ≥ 10%) were weight gain [33.2% (n = 82)], akathisia [23.5% (n = 58)], nasopharyngitis [21.1% (n = 52)], and somnolence [10.5% (n = 26)]. TEAEs leading to treatment discontinuation occurred in 26.7% of patients receiving brexpiprazole and 58.1% of de novo patients. The mean (SD) increase in body weight from baseline to Week 52 [observed cases (OC)] was 4.2 (6.5) kg (n = 138); 44.5% (n = 110) had weight gain ≥ 7% at any postbaseline visit. There were no cases of tardive dyskinesia and no AEs related to suicide/suicide attempts. One death occurred (unknown cause), which was unrelated to study treatment. Improvements in the MADRS total score were observed from baseline over the course of the 52-week study [mean (SD) change at Week 52 (OC): - 7.3 (8.7)] for all patients receiving brexpiprazole. The overall MADRS response rate and remission rate in patients receiving brexpiprazole was 41.3% (n = 57) and 34.8% (n = 48), respectively, at Week 52 (OC). Improvements in CGI-S, HAM-D 17 item total score, and SDS mean scores were also observed from baseline over the 52-week study, with a mean (SD) change from baseline at Week 52 (OC) of - 0.8 (1.0), - 5.9 (6.3), and - 1.0 (2.2), respectively, indicating a sustained improvement in symptoms with long-term brexpiprazole treatment., Conclusions: This is the first study to evaluate the safety profile of brexpiprazole 2 mg/day in Japanese patients with MDD, including older adults, which is similar to previous reports, with no new safety risks, and continued efficacy over 52 weeks., Study Registration: ClinicalTrials.gov (NCT03737474; registered on 29 July 2018)., (© 2024. The Author(s).)

We report a case of unilateral serous choroidal effusion in a patient without prior glaucoma surgeries that developed within 1 week of starting topical dorzolamide. A Caucasian female in her 60s with a history of severe primary open-angle glaucoma in the left eye without prior glaucoma surgeries developed irritation and subsequently blurry vision in her left eye within 1 week of starting topical dorzolamide 2% in the left eye only. Funduscopic exam and B-scan ultrasound demonstrated a serous choroidal effusion in the nasal and temporal periphery. After discontinuing dorzolamide and initiating prednisolone and cycloplegic agents, the choroidal effusions fully resolved after 2 weeks, and vision returned to baseline. Choroidal effusion can occur as a result of an idiosyncratic reaction to topical dorzolamide even in patients without prior glaucoma surgeries. Immediate cessation of dorzolamide and treatment with steroid and cycloplegic agents result in good vision recovery for dorzolamide-induced choroidal effusion., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Alzheimer's disease (AD) is a prevalent neurodegenerative disease characterized by progressive cognitive and functional decline. Nearly all patients with AD develop neuropsychiatric symptoms (NPSs). Agitation is one of the most distressing and challenging NPS. Brexpiprazole is an oral antipsychotic and is the first approved pharmacologic agent in the United States for the treatment of agitation associated with dementia due to AD. Its effect is thought to be from its partial serotonin 5-HT 1A and dopamine D 2 receptor agonist activity and serotonin 5-HT 2A receptor antagonism. Brexpiprazole is a maintenance medication, and it should not be used "as needed" or as a "PRN" treatment for breakthrough agitation. Brexpiprazole is a major substrate of CYP2D6 and CYP3A4. Dose adjustments may be required for drug interactions or impaired renal or hepatic function. Clinical trials found brexpiprazole 2 to 3 mg/d demonstrated significant improvements in agitation, with brexpiprazole showing an approximate 5-point greater reduction on change in the Cohen-Mansfield Agitation Inventory total score at week 12 from baseline compared with placebo. Brexpiprazole is generally well tolerated and safe, and common adverse reactions when used for this indication include dizziness, headaches, insomnia, nasopharyngitis, somnolence, and urinary tract infections. Like other antipsychotics used for agitation in AD, brexpiprazole is associated with higher mortality rates compared with placebo. In a long-term care setting, there are several considerations for its use. Benefits include an oral agent that is well tolerated and clinical data showing statistically significant effects on agitation. However, brexpiprazole has not been studied in head-to-head clinical trials against other antipsychotics, and there are differing opinions if the agitation score reductions translate to a clinically meaningful difference. The approval of brexpiprazole signals favorably for upcoming agents for this indication, including escitalopram and dextromethorphan-bupropion. Both escitalopram and dextromethorphan-bupropion are currently undergoing clinical trials., Competing Interests: Disclosures E.D.C. reports personal fees from Genomadix Inc and a grant to her institution from Alzheon. A.P.P. reports personal fees from Acadia Pharmaceuticals, Athira, BMS, Cognitive Research Corp, Eisai, IQVIA, Lundbeck, Novartis, ONO Pharmaceuticals, WCG, WebMD, and Xenon; and grants to his institution from Alector, Athira, Biogen, Cassava, Eisai, Eli Lilly, Genentech/Roche, Vaccinex, NIA, NIMH, and DOD. He is a member of the Scientific Advisory Board of Alzheon. D.L. and I.M.A. declare no conflicts of interest., (Copyright © 2024 Post-Acute and Long-Term Care Medical Association. Published by Elsevier Inc. All rights reserved.)

Recent randomized controlled trials (RCTs) have shown a benefit of brexpiprazole in managing agitation in patients with Alzheimer's disease (AD). However, its efficacy and safety remain unclear. We systematically searched PubMed, Embase, and Cochrane Library for RCTs comparing brexpiprazole with placebo in patients with agitation and AD. Three studies comprising 1,048 patients were included. In patients with agitation and AD, brexpiprazole significantly improved the Cohen-Mansfield Agitation Inventory total score (CMAI) at any dose (MD -3.05; 95% CI -5.12, -0.98; p < 0.01; I 2  = 19%) and at 2 mg (MD -4.36; 95% CI -7.02, -1.70; p < 0.01; I 2  = 0%) over 12 weeks. Brexpiprazole at any dose and 2 mg also showed benefit in the Clinical Global Impression - Severity of illness (CGI-S) score as related to agitation over 12 weeks (MD -0.20; 95% CI -0.36, -0.05; p < 0.01; I 2  = 35%). There is no significant difference between the groups in the incidence of at least one treatment-emergent adverse events (TEAEs; RR 1.14; 95% CI 0.95, 1.37; p = 0.16; I 2  = 45%) and all-cause mortality (RR 1.99; 95% CI 0.37, 10.84; p = 0.42; I 2  = 0%). Brexpiprazole at any dose significantly increased the Simpson-Angus Scale (SAS; MD 0.47; 95% CI 0.28, 0.66; p < 0.01). Our results suggest that brexpiprazole is more efficacious than placebo in the treatment of agitation in AD patients. Further studies are still necessary to confirm long-term effects of brexpiprazole.Prospero registry: CRD42023486694., (© 2024. Fondazione Società Italiana di Neurologia.)

Introduction: Eprosartan is an angiotensin receptor blocker (ARB) used for management of essential hypertension. With unique pharmacological characteristics, dual action mechanism, and clinical effectiveness, eprosartan offers additional advantages over other ARBs in specific patient populations., Areas Covered: A comprehensive review of the literature was performed across publicly available databases, with no time limitations, to ensure the inclusion of all relevant studies. The review focuses on presenting the efficacy and safety profile of eprosartan, alone or in combination with other agents. Additionally, it explores the etiology of hypertension concerning the structure and function of angiotensin II type 1 receptors. Further, the efficacy of eprosartan in special populations and its additional benefits are also discussed., Expert Opinion: Eprosartan effectively reduces blood pressure (BP), with a 24-hour BP-lowering effect at 600 mg/day. Eprosartan demonstrates similar or better efficacy than other ARBs, such as telmisartan and losartan, particularly in managing coagulation-related abnormalities and peripheral resistance. In combination therapy, eprosartan with hydrochlorothiazide significantly enhances BP reduction. Eprosartan is well-tolerated, with a low incidence of adverse events, making it a reliable choice for long-term hypertension management across various patient populations, such as those with comorbid diabetes and renal disease and older adults.

Background: Colorectal cancer is the third most common cancer and the second leading cause of cancer death. There are limited therapeutic options for the treatment of locally advanced or metastatic colorectal cancers which fail first-line chemotherapy. Phase I/II studies showed that the combined application of the raltitrexed and irinotecan has significant synergistic effect and acceptable toxicity. However, most of these previous studies have relatively small sample size., Methods: This is a prospective open-label, single-arm, multi-center, Phase II trial. Brief inclusion criteria: patients were aged 18 to 75 years with locally advanced or metastatic colorectal cancer after failure of 5-FU and oxaliplatin therapy. Enrolled patients received raltitrexed (3 mg/m 2 , d1) and irinotecan (180 mg/m 2 , d1) each 21-day cycle until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival, and the secondary endpoints were disease control rate, objective response rate, overall survival and safety., Results: A total of 108 patients were enrolled between September 2016 and May 2020. The median age was 61 years, ECOG 1 score accounts for 67.6%, the rest were ECOG 0. A total of 502 cycles were completed, with an average of 4.6 cycles and a median of 4 cycles. 108 patients were evaluated, with an objective response rate of 17.6%, and disease control rate of 76.9%. The median follow-up time was 27 months (range:3.1-61.0 m) at data cut-off on March 2023. Median progression-free survival was 4.9 months (95% CI 4.1-5.7) and median overall survival was 13.1 months (95% CI 12.2-15.5). The most common adverse events that were elevated are alanine aminotransferase increased, aspartate aminotransferase increased, fatigue, diarrhoea, neutrocytopenia, thrombocytopenia, hypohemoglobin, and leukocytopenia. Most of the adverse events were Grade I/II, which were relieved after symptomatic treatment, and there were no treatment-related cardiotoxicities and deaths., Conclusions: The combination of raltitrexed and irinotecan as second-line treatment for mCRC could be a reliable option after failure of standard 5-Fu-first-line chemotherapy in locally advanced or metastatic colorectal cancers, especially for patients with 5-FU intolerance (cardiac events or DPD deficiency patients)., Trial Registration: ClinicalTrials.gov identifier: NCT03053167, registration date was 14/2/2017., (© 2024. The Author(s).)

Obsessive-compulsive disorder (OCD) is a common and debilitating psychiatric disorder with an approximate incidence of 2.5% in the general population. Serotonin reuptake inhibitors (SRIs) are considered the first line of pharmacological treatment but up to 50% of patients fail to achieve clinical remission or response. Atypical antipsychotics are one of the most common augmentation strategies in OCD treatment resistant patients. Brexpiprazole, a novel atypical antipsychotic with dopamine partial agonism action, has never been studied in addition to SRIs treatment in OCD resistant patients. This study retrospectively investigated the safety and efficacy of a 12 week brexpiprazole augmentation trial in 34 OCD resistant patients. SRI treatment resistance was defined as failing to improve the YBOCS total score by more than 25% from the beginning of the SRI trial. Brexpiprazole augmentation response was defined as at least a 25% improvement in the YBOCS total score. At the end of the study, 17 patients (50.0%) met the response criteria of ≥25% improvement in YBOCS total score vs. baseline. No safety issues were raised throughout the observation period. A total of 19 patients (55.9%) reported adverse experiences, generally mild and not requiring medical intervention. This is the first study to examine the safety and efficacy of brexpiprazole augmentation in resistant OCD patients. Our findings show that brexpiprazole may be a promising and well-tolerated augmentation strategy for SRI-resistant OCD patients. However, further research in larger populations is needed to confirm these results and investigate the long-term safety and tolerability of brexpiprazole in OCD patients.

Competing Interests: Conflict of interest or source of funding: The authors declared no conflicts of interest.

Acute pain management requires balancing analgesia with adverse effects risk. The voltage-gated sodium channel NaV1.8 plays an important role in pain physiology, and its inhibition was shown to have analgesic effects. VX-548 is a new oral NaV1.8-specific inhibitor that received United States Food and Drug Administration Fast Track and Breakthrough Therapy designations. Its efficacy was demonstrated in two Phase II trials of patients who underwent abdominoplasty and bunionectomy. These showed that VX-548, when given as an oral loading dose of 100 mg followed by 50 mg 12-hly, significantly decreased pain scores compared with placebo. Similarly, two Phase III trials of patients who underwent abdominoplasty and bunionectomy comparing VX-548 with hydrocodone bitartrate-acetaminophen and placebo reported significantly reduced pain scores compared with placebo, but no improvement compared with hydrocodone bitartrate-acetaminophen. Evidence from Phase II and III trials suggest that VX-548 is well-tolerated, with headache, nausea, constipation and dizziness being the most common adverse effects. However, the safety of prolonged VX-548 administration is uncertain; a Phase II trial of patients with diabetic neuropathy who received high-dose VX-548 over 12 weeks reported decreased creatinine clearance. Data pertaining to VX-548 safety and efficacy within the context of multimodal analgesia and pregnancy are also needed.

Introduction: The onset of psychotic symptoms occurs prior to age 19 in 39% of the patients with schizophrenia. There are limited approved treatment options for adolescents with schizophrenia. Brexpiprazole was approved by the United States Food and Drug Administration (FDA) for treatment of schizophrenia in adolescents in 2022., Areas Covered: Extrapolation of adult data to youth and use of pharmacologic modeling coupled with open long-term safety data were used by the FDA to approve brexpiprazole for adolescent schizophrenia. They were all reviewed herein., Expert Opinion: D2 receptor partial agonist antipsychotic agents are preferred in the early phase of treatment of psychotic disorders. Approval of brexpiprazole in adolescent schizophrenia provides an additional option. Brexpiprazole was approved by the FDA on the basis of extrapolation of adult data without controlled trials in adolescents. This reduces placebo exposure in young people. Two previous agents (asenapine and ziprasidone) approved for adult schizophrenia failed to separate from placebo in adolescent schizophrenia studies; this partially undermines the process of extrapolation. For brexpiprazole, the paucity of data in adolescents relegates it to a second-line agent. More research on brexpiprazole is needed to delineate its relative role in the management of adolescent schizophrenia.

A pharmacokinetic (PK) bridging approach was successfully employed to support the dosing regimen and approval of brexpiprazole in pediatric patients aged 13-17 years with schizophrenia. Brexpiprazole was approved in 2015 for the treatment of schizophrenia and the adjunctive treatment of major depressive disorder in adults based on efficacy and safety data from clinical trials. On January 13, 2020, the US Food and Drug Administration issued a general advice letter to sponsors highlighting the acceptance of efficacy extrapolation of certain atypical antipsychotics from adult patients to pediatric patients considering the similarity in disease and exposure-response relationships. Brexpiprazole is the first atypical antipsychotic approved in pediatrics using this approach. The PK data available from pediatric patients aged 13-17 years have shown high variability due to the limited number of PK evaluable subjects, which limits a robust estimation of differences between adult and pediatric patients. The PK model-based approach was thus utilized to evaluate the appropriateness of the dosing regimen by comparing PK exposures in pediatric patients aged 13-17 years with exposures achieved in adults at the approved doses. In addition to exposure matching, safety data from a long-term open-label clinical study in pediatric patients informed the safety profile in pediatric patients. This report illustrates the potential of leveraging previously collected efficacy, safety, and PK data in adult patients to make a regulatory decision in pediatric patients for the indication of schizophrenia., (© 2024, The American College of Clinical Pharmacology.)

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-SR 10 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., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: FT is a full-time employee of Otsuka Canada Pharmaceutical Inc.; CW is a full-time employee of Otsuka Pharmaceutical Development & Commercialization Inc.; PC has served as speaker/received consultant fees from AbbVie, Lundbeck, Janssen, Otsuka, Purdue, and Takeda, and has received research/grant support from AbbVie, Lundbeck, Otsuka, Takeda, Janssen, Telus, and Mitacs; JH has served as a speaker/ad board participant or performed scientific planning committee work for Pfizer, Amgen, AbbVie, GSK, Bayer, Valeo, Boehringer, Eli-Lilly, Elvium, Takeda, Bausch, AstraZeneca, Novartis, Lundbeck, Novo Nordisk, Janssen, Eisai, HLS, Otsuka, Idorsia, MDBriefcase, Liv, MedPlan, Master Clinician Alliance, Academy, Bridge, PeerVoice, Seacourses, Thrombosis Canada, Meducom, CHRC, CTC, STA, CCRN, CPD Network, Telus Health, EOCI, AgenceUnik, Humber Hospital, ABPHE, and CSEM; ZI has received grant support from CIHR, NIH, Brain Canada, and Weston Foundation, and has served as a consultant for Eisai, Lundbeck, Novo Nordisk, Otsuka, and Roche. Additionally, his institution has received funds on his behalf from Biogen and Roche; RSM has received research grant support from CIHR/GACD/National Natural Science Foundation of China (NSFC) and the Milken Institute; speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Neurawell, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Viatris, Abbvie, and Atai Life Sciences. He is a CEO of Braxia Scientific Corp; EMM was a full-time employee of Lundbeck Canada Inc. at the time of this work.

Tegileridine () is a small molecule μ-opioid receptor biased agonist developed by Jiangsu Hengrui Pharmaceuticals Co., Ltd for the treatment of postoperative pain. Tegileridine selectively activates the G-protein-coupled pathway, which mediates strong central analgesic effects and only weakly activates the β-arrestin-2 pathway implicated in adverse events like respiratory depression and gastrointestinal dysfunction. In January 2024, tegileridine received its first approval in China for the treatment of moderate to severe pain after abdominal surgery. This article summarizes the milestones in the development of tegileridine leading to this first approval for the treatment of moderate to severe pain after abdominal surgery., (© 2024. Springer Nature Switzerland AG.)

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., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: In the absence of head-to-head comparative data from randomized controlled trials, indirect treatment comparisons (ITCs) may be used to compare the relative effects of treatments versus a common comparator (either placebo or active treatment). For acute pain management, the effects of oliceridine have been compared in clinical trials to morphine but not to fentanyl or hydromorphone. Aim: To assess the comparative safety (specifically differences in the incidence of nausea, vomiting and opioid-induced respiratory depression [OIRD]) between oliceridine and relevant comparators (fentanyl and hydromorphone) through ITC analysis. Methods: A systematic literature review identified randomized clinical trials with oliceridine versus morphine and morphine versus fentanyl or hydromorphone. The ITC utilized the common active comparator, morphine, for the analysis. Results: A total of six randomized controlled trials (oliceridine - 2; hydromorphone - 3; fentanyl - 1) were identified for data to be used in the ITC analyses. The oliceridine data were reported in two studies (plastic surgery and orthopedic surgery) and were also reported in a pooled analysis. The ITC focused on nausea and vomiting due to limited data for OIRD. When oliceridine was compared with hydromorphone in the ITC analysis, oliceridine significantly reduced the incidence of nausea and/or vomiting requiring antiemetics compared with hydromorphone (both orthopedic surgery and pooled data), while results in plastic surgery were not statistically significant. When oliceridine was compared with hydromorphone utilizing data from Hong, the ITC only showed a trend toward reduced risk of nausea and vomiting with oliceridine that was not statistically significant across all three comparisons (orthopedic surgery, plastic surgery and combined). An ITC comparing oliceridine with a study of fentanyl utilizing the oliceridine orthopedic surgery data and combined orthopedic and plastic surgery data showed a trend toward reduced risk that was not statistically significant. Conclusion: In ITC analyses, oliceridine significantly reduced the incidence of nausea and/or vomiting or the need for antiemetics in orthopedic surgery compared with hydromorphone and a non-significant trend toward reduced risk versus fentanyl.

Brexpiprazole is a new antipsychotic drug from the group of dopamine D2/D3 receptor partial agonists. It represents a development of the second-generation antipsychotics and is an important addition to the pharmacological treatment options for schizophrenia. The purpose of this article is to present, illustrated by the case of brexpiprazole, how advances in the pharmacological properties of new antipsychotics translate into improved results in the treatment of schizophrenia, not only in terms of symptom reduction, but also in terms of functional improvement. The ratio of activation to blocking of the D2/D3 receptor is lower for brexpiprazole than for aripiprazole and cariprazine, which may translate into a lower risk of akathisia. Brexpiprazole has also stronger antihistaminic activity, which is likely to be associated with a stronger sedative effect, a lower risk of akathisia, excessive agitation and insomnia. Brexpiprazole meets the traditional requirements for an antipsychotic drug's efficacy, i.e., compared to placebo, it brings a greater reduction in schizophrenia symptoms in short-term studies and prevents schizophrenia relapses in long-term follow-up. The highest antipsychotic efficacy was found with the highest registered dose (4 mg/day). In addition to reducing positive symptoms, brexpiprazole treatment also leads to a reduction in negative and depressive symptoms, as well as anxiety. It has also a positive effect on patients' social and personal functioning and quality of life. This action of the drug is in line with the expectations of patients and their families regarding effective treatment. It should not only reduce symptoms, but also enable a return to health, i.e., a state that, in addition to optimal health and a sense of psychological well-being, also makes it possible to maintain proper social relations.

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., Competing Interests: Dr. Alexander Wolf is a shareholder of Trevena, (Copyright: © 2024 Wolf et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Safe and effective glaucoma treatment remains a critical task in ophthalmology. Newly introduced medications, in addition to mandatory registration trials, are also evaluated in real-world clinical settings., Purpose: This study assesses the efficacy and safety of the fixed combination of dorzolamide/timolol (Dorzotimol) in patients with primary open-angle glaucoma (POAG) in real-world clinical settings., Material and Methods: The study included 55 patients aged 46 to 75 years with stage I and II POAG. The initial mean intraocular pressure (IOP) was 24.07±1.31 mm Hg. All patients were prescribed the fixed combination of dorzolamide/timolol., Results: The mean IOP after 1, 3, 6, and 12 weeks of therapy was 19.20±2.46, 18.48±2.04, 17.88±1.88, and 17.62±1.63 mm Hg, respectively. After 12 weeks of therapy, IOP reduction to 18 mm Hg was observed in 63.64% of patients, a reduction of 20% or more from baseline in 81.82% of patients, and a reduction of 30% or more in 14.55% of patients. No serious adverse events were recorded during the observation period., Conclusion: This study confirms the high hypotensive efficacy and safety of the fixed combination of dorzolamide/timolol (Dorzotimol).

Competing Interests: None declared

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/m 2 . 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., (© 2023. The Author(s).)

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., (© 2022. Fondazione Società Italiana di Neurologia.)

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.

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., (© 2022. International Osteoporosis Foundation and National Osteoporosis Foundation.)

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., (Copyright © 2021 The Author. Published by Elsevier Ltd.. All rights reserved.)

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., (© Copyright 2022 Physicians Postgraduate Press, Inc.)

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 β-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.

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., (© 2022. The Author(s).)

Introduction: Opioids for managing postoperative pain are associated with side effects including opioid-induced respiratory depression (OIRD) and gastrointestinal complications. Opioids induce analgesia via G-protein signaling, while adverse effects are mediated by the β-arrestin pathway. Oliceridine is a biased ligand that preferentially activates G-protein signaling over β-arrestin, theoretically reducing adverse effects. Oliceridine has been approved by the Food and Drug Administration to treat acute pain severe enough to require intravenous opioid analgesics., Areas Covered: Preclinical and clinical trials demonstrate the analgesic efficacy of oliceridine. Available evidence suggests that oliceridine may have a lower risk of OIRD and gastrointestinal complications compared to conventional opioids., Expert Opinion: The analgesic efficacy of oliceridine has been evaluated in several clinical trials. However, safety data were obtained from an open-label observational study and studies assessing adverse effects as secondary outcomes, as post-hoc analyses, or from retrospective studies. These may be affected by gaps in detecting adverse events, heterogeneity in the original studies, and the limitations of retrospective studies. Prospective trials examining the safety of oliceridine versus conventional opioids are needed. Studies are also needed to assess the safety and efficacy of oliceridine in obstetric and pediatric populations, and in the context of multimodal analgesia and Enhanced Recovery after Surgery protocols.

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 × 10 9 /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., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

This study assessed the clinical risk factors for periorbital dermatitis (PD) after using dorzolamide/timolol eye drops in a total of 1282 glaucoma patients. Both the PD(+) group and the PD(-) group were evaluated using clinical data such as age, sex, dosing duration, presence of benzalkonium chloride (BAK) in the formulation, ocular surgery history (e.g. cataract or glaucoma operations), height, weight, personal history of systemic hypertension, smoking, alcohol consumption, intraocular pressure, best-corrected visual acuity (BCVA), central corneal thickness, axial length, and visual field index (VFI). Univariate analyses showed that shorter dosing duration, higher rate of BAK-included cases, worse BCVA, worse VFI, more systemic hypertension history, and more ocular surgery history were more associated with the PD(+) group than the PD(-) group. The BAK(-) group showed a lower PD rate than the BAK-included group, which was supported by the Kaplan-Meier analysis (log-rank test, p = 0.0014). Multivariate analyses revealed that the probability of PD increased by 8 times if they had a history of ocular surgery and increased by 2.3% when the VFI decreased by 1% (Cox's hazard regression test, p < 0.001). Therefore, a preservative-free dorzolamide/timolol can benefit the subjects for those who had ocular surgery or who have worse VFI., (© 2021. The Author(s).)

Brexpiprazole (Bre) is a new multi-target antipsychotic drug (APD) approved by the US FDA in 2015, and shows good therapeutic potential. But it lacks assessments on the metabolic side effects, which obstructs the treatment of schizophrenia. Glucagon-like peptide 1 (GLP1), an incretin associated with insulin action and metabolism, is involved in the metabolic syndrome (MS) caused by most APDs. In this study, we examined the adverse effects of Bre on glycolipid metabolism in rats and determined whether GLP1 was involved in Bre-caused MS. In the first part of experiments, rats were orally administered Bre (0.5 mg· kg -1 · d -1 ) for 28 days with aripiprazole (1.0 mg· kg -1 · d -1 ) or olanzapine (1.0 mg· kg -1 · d -1 ) as the controls. Compared to vehicle, Bre administration significantly increased the weight gain, serum lipid (TG, TC, LDL, FFA), and blood glucose levels accompanied by the hormonal (insulin, glucagon, GLP1) imbalance, and the impaired glucose tolerance and insulin sensitivity. Moreover, we demonstrated that Bre administration significantly decreased the protein and mRNA levels of GLP1 in pancreas and small intestine by suppressing CaMKIIα, AMPK, and β-catenin; Bre administration also caused islet dysfunction with decreased GLP1R, PI3K, IRβ expression in pancreas, and the interference of IRS1, PI3K, p-AKT, and GLUT4 expression in the liver and skeletal muscle that represented the insulin resistance. In the second part of experiments, rats were orally administered Bre (0.5 mg· kg -1 · d -1 ) for 42 days. We showed that co-administration with the GLP1 receptor (GLP1R) agonist liraglutide (0.125 mg· kg -1 · d -1 , ip) could ameliorate Bre-caused metabolic abnormalities. Our results demonstrate that GLP1/GLP1R signaling is involved in Bre-induced glycolipid metabolic disorders and co-treatment with liraglutide is an effective intervention against those abnormal metabolisms., (© 2021. The Author(s), under exclusive licence to CPS and SIMM.)

Background: Brexpiprazole is a dopamine/serotonin receptor partial agonist (D 2 , 5-HT 1A ) and antagonist (5-HT 2A ) approved for treatment of schizophrenia and major depressive disorder (adjunct to antidepressants)., Aims: This study aimed to investigate brexpiprazole as monotherapy in acute mania (bipolar I disorder) in two short-term (ST) studies (study 080 and study 081) and one open-label (OL) extension (study 083)., Methods: ST studies were three-week randomized, double-blind, flexible dose (2-4 mg/day), placebo-controlled studies. The primary endpoint was mean change in Young Mania Rating Scale (YMRS) total score from baseline to day 21. The OL study was a 26-week flexible dose (2-4 mg/day) study for patients completing the ST studies., Results: A total of 164 and 158 (study 080) and 170 and 162 (study 081) inpatients with DSM-5 mania with/without mixed features were randomized to placebo or brexpiprazole, respectively. The primary analyses did not show a statistically significant difference between brexpiprazole and placebo: study 080: least squares mean difference (95% confidence limits): 0.14 (-1.74, 2.03), p  = 0.8797; study 081: -1.62 (-3.56, 0.32), p  = 0.1011. OL study patients ( n  = 381) demonstrated a gradual improvement in YMRS total score. Akathisia was the only adverse event, with an incidence of ⩾5% with brexpiprazole and more than placebo in the ST studies, or ⩾5% in the OL study. Brexpiprazole was more efficacious in patients with impaired or no insight (predominantly EU patients) than in patients with excellent insight (predominantly US patients)., Conclusions: Further studies are necessary to address the potential efficacy of brexpiprazole in acute mania, which should ensure that the study sample is severe enough (especially with regard to insight), and that the dose/titration schedule is not too modest.

Background: Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are a novel class of pharmacotherapeutics for type 2 diabetes management that work by reducing renal reabsorption of glucose. Ipragliflozin is a potent, selective SGLT-2 inhibitor used for the management of type 2 diabetes., Objective: The primary aim of this review is to summarize the available evidence on the efficacy and safety of ipragliflozin for the management of type 2 diabetes. We also review the discovery, pharmacokinetic, and pharmacodynamic profile of ipragliflozin., Methods: To inform our review, we searched MEDLINE, International Pharmaceutical Abstracts, and Embase to identify relevant papers to ipragliflozin use in type 2 diabetes. Clinical trial registries were also searched., Results: Findings from randomized clinical trials demonstrate that compared to placebo, ipragliflozin significantly reduces glucose as measured via Hemoglobin A1c and fasting plasma glucose levels. Ipragliflozin is also associated with weight reduction and an improvement in some, but not all, cardiovascular risk markers. Ipragliflozin has a favourable safety profile with a low risk of hypoglycemia and the rates of common adverse events are not significantly different than placebo. Limited data are available to assess rare and long-term adverse effects., Conclusion: Current evidence shows that ipragliflozin is an effective therapeutic option for the management of glucose control in type 2 diabetes. However, no cardiovascular outcome trials have been conducted to date. Real-world observational studies are still needed to accurately capture any possible rare or long-term adverse events., Competing Interests: The authors report no conflicts of interest in this work., (© 2021 Alkabbani and Gamble.)

Background: Chronic kidney disease (CKD) is an independent risk factor for osteoporosis and is more prevalent among people with CKD than among people who do not have CKD. Although several drugs have been used to effectively treat osteoporosis in the general population, it is unclear whether they are also effective and safe for people with CKD, who have altered systemic mineral and bone metabolism., Objectives: To assess the efficacy and safety of pharmacological interventions for osteoporosis in patients with CKD stages 3-5, and those undergoing dialysis (5D)., Search Methods: We searched the Cochrane Kidney and Transplant Register of Studies up to 25 January 2021 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov., Selection Criteria: Randomised controlled trials comparing any anti-osteoporotic drugs with a placebo, no treatment or usual care in patients with osteoporosis and CKD stages 3 to 5D were included., Data Collection and Analysis: Two review authors independently selected studies, assessed their quality using the risk of bias tool, and extracted data. The main outcomes were the incidence of fracture at any sites; mean change in the bone mineral density (BMD; measured using dual-energy radiographic absorptiometry (DXA)) of the femoral neck, total hip, lumbar spine, and distal radius; death from all causes; incidence of adverse events; and quality of life (QoL). Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach., Main Results: Seven studies involving 9164 randomised participants with osteoporosis and CKD stages 3 to 5D met the inclusion criteria; all participants were postmenopausal women. Five studies included patients with CKD stages 3-4, and two studies included patients with CKD stages 5 or 5D. Five pharmacological interventions were identified (abaloparatide, alendronate, denosumab, raloxifene, and teriparatide). All studies were judged to be at an overall high risk of bias. Among patients with CKD stages 3-4, anti-osteoporotic drugs may reduce the risk of vertebral fracture (RR 0.52, 95% CI 0.39 to 0.69; low certainty evidence). Anti-osteoporotic drugs probably makes little or no difference to the risk of clinical fracture (RR 0.91, 95% CI 0.79 to 1.05; moderate certainty evidence) and adverse events (RR 0.99, 95% CI 0.98 to 1.00; moderate certainty evidence). We were unable to incorporate studies into the meta-analyses for BMD at the femoral neck, lumbar spine and total hip as they only reported the percentage change in the BMD in the intervention group. Among patients with severe CKD stages 5 or 5D, it is uncertain whether anti-osteoporotic drug reduces the risk of clinical fracture (RR 0.33, 95% CI 0.01 to 7.87; very low certainty evidence). It is uncertain whether anti-osteoporotic drug improves the BMD at the femoral neck because the certainty of this evidence is very low (MD 0.01, 95% CI 0.00 to 0.02). Anti-osteoporotic drug may slightly improve the BMD at the lumbar spine (MD 0.03, 95% CI 0.03 to 0.04, low certainty evidence). No adverse events were reported in the included studies. It is uncertain whether anti-osteoporotic drug reduces the risk of death (RR 1.00, 95% CI 0.22 to 4.56; very low certainty evidence)., Authors' Conclusions: Among patients with CKD stages 3-4, anti-osteoporotic drugs may reduce the risk of vertebral fracture in low certainty evidence. Anti-osteoporotic drugs make little or no difference to the risk of clinical fracture and adverse events in moderate certainty evidence. Among patients with CKD stages 5 and 5D, it is uncertain whether anti-osteoporotic drug reduces the risk of clinical fracture and death because the certainty of this evidence is very low. Anti-osteoporotic drug may slightly improve the BMD at the lumbar spine in low certainty evidence. It is uncertain whether anti-osteoporotic drug improves the BMD at the femoral neck because the certainty of this evidence is very low. Larger studies including men, paediatric patients or individuals with unstable CKD-mineral and bone disorder are required to assess the effect of each anti-osteoporotic drug at each stage of CKD., (Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Use of fluoropyrimidine-based therapy in patients with metastatic colorectal cancer is associated with significant toxicities. This study aimed to assess the safety and efficacy of raltitrexed use in patients with metastatic colorectal cancer who developed significant toxicities after fluoropyrimidine-based treatment., Patients and Methods: We identified patients with metastatic colorectal cancer who were treated with raltitrexed-based systemic therapy after developing serious adverse events with fluoropyrimidine-based treatment in a large Canadian province from 2004 to 2018. Demographic, tumor, and treatment characteristics were retrieved from the electronic medical records. Progression-free and overall survival were assessed from the start of raltitrexed-based therapy., Results: A total of 86 patients were identified for the study. The median age was 66.5 years, and 58.1% of patients were men. The primary cancer site was right, left, and transverse colon in 38.4%, 27.9%, and 9.3%, respectively. The remaining 24.4% had rectal cancer. Among all patients, 43.0% had received more than 2 prior systemic therapies, and 37.6% had developed previous cardiotoxicity to fluoropyrimidine-based treatment. The median progression-free and overall survival were 8.5 and 10.2 months, respectively. On multivariable Cox regression model, patients with left-sided colon cancer (hazard ratio [HR], 0.33; 95% confidence interval [CI], 0.12-0.97; P = .044) and the Eastern Cooperative Oncology Group performance status of 0/1 (HR, 0.10; 95% CI, 0.01-0.82; P = .032) had a longer progression-free survival, whereas left-sidedness of colon cancer was the only factor that predicted overall survival (HR, 0.30; 95% CI, 0.10-0.88; P = .029). Raltitrexed was well-tolerated with common adverse events that included anemia in 41.7% of patients and chemotherapy-induced nausea and vomiting in 27.4%. Most toxicities were grade 1/2, but 16.7% of patients experienced grade 3. There were no cardiac events and treatment-related deaths., Conclusions: Raltitrexed in patients with colorectal cancer who were previously treated with fluoropyrimidine-based systemic therapy is effective and well-tolerated., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Cancer and normal cells use multiple antiapoptotic BCL2 proteins to prevent cell death. Therapeutic targeting of multiple BCL2 family proteins enhances tumor killing but is also associated with increased systemic toxicity. Here, we demonstrate that the dual targeting of MCL1 and BCL2 proteins using the small molecules S63845 and venetoclax induces durable remissions in mice that harbor human diffuse large B-cell lymphoma (DLBCL) tumors but is accompanied by hematologic toxicity and weight loss. To mitigate these toxicities, we encapsulated S63845 or venetoclax into nanoparticles that target P-selectin, which is enriched in tumor endothelial cells. In vivo and ex vivo imaging demonstrated preferential targeting of the nanoparticles to lymphoma tumors over vital organs. Mass spectrometry analyses after administration of nanoparticle drugs confirmed tumor enrichment of the drug while reducing plasma levels. Furthermore, nanoparticle encapsulation allowed 3.5- to 6.5-fold reduction in drug dose, induced sustained remissions, and minimized toxicity. Our results support the development of nanoparticles to deliver BH3 mimetic combinations in lymphoma and in general for toxic drugs in cancer therapy., (© 2021 by The American Society of Hematology.)

Alpha-Pyrrolidinopentiothiophenone (α-PVT) belongs to the drug class of pyrrolidinophenones, a subgroup of synthetic cathinones, which are among the most prevalent new psychoactive substances. The study describes a series of 44 authentic forensic cases with analytical confirmed intake of α-PVT. Plasma concentrations, determined by a validated LC-MS/MS method, ranged from ca. 0.9 to 306 µg/L (median 35.6; mean 66.6 µg/L). Comprehensive toxicological analysis proved excessive co-consumption in almost all cases, including other pyrovalerones and classic stimulants as well as central depressant drugs such as opiates/opioids, benzodiazepines, pregabalin and/or ethanol. Subjects were aged between 26 and 54 years (median 35 years, mean 36 years) and appeared to be mainly experienced intravenous drug consumers. A high incidence of aberrant behavior in terms of aggressive, combative behavior and psychotic changes could be observed, as also reflected in accused offences, which frequently presented violent crimes. In consideration of several confounding factors, the study suggests a relationship between frequency of such impairment and plasma concentrations of α-PVT, but individual cases without signs of behavioral changes and high plasma concentrations also occurred, which might be explained by developed tolerance and/or individual vulnerably for the psychotic effects of pyrovalerones., (Copyright © 2021 Elsevier B.V. All rights reserved.)