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.

Efficacy and safety of quinolones as potential first line therapy in pulmonary tuberculosis: a meta-analysis.

INTRODUCTION: Tuberculosis is an infectious disease that continues to plague the world today, causing concerns due to its high mortality rate. The therapy regimens used for the treatment of tuberculosis today have demonstrated high efficacy and safety, potentially reducing the disease's burden, but the use of some standardized medications has caused many resistances to emerge. Over the last decade, researchers have been looking for suitable alternatives, with quinolones emerging as the most promising candidate due to their efficacy, safety, and availability. However, their efficacy as a first-line treatment remains debatable.

Treatment challenges in the management of difficult-to-treat gram-positive infections: A consensus view apropos therapeutic role of novel anti-MRSA antibiotics, levonadifloxacin (IV) and alalevonadifloxacin (oral).

PURPOSE: Treatment of antibiotic-resistant Gram-positive infections (GPIs), including methicillin-resistant Staphylococcus aureus (MRSA) is becoming increasingly difficult, particularly in patients with multiple co-morbidities who require antibiotics with greater safety and a consistent pharmacokinetic/pharmacodynamic (PK/PD) profile. Such difficult-to-treat GPIs are often associated with poor outcomes, extended hospital stay and increased expenditure. This can be partly attributed to the limited safety and aberrant PK/PD profile of existing anti-MRSA antibiotics. In this context, intravenous levonadifloxacin and its oral prodrug alalevonadifloxacin are novel anti-MRSA antibiotics that have significant advantages over conventional anti-Gram-positive antibiotics. The purpose of this paper was to generate a consensus on the optimal use of levonadifloxacin and alalevonadifloxacin for tackling resistant Gram-positive infections in patients with multiple co-morbidities. METHOD: Using a modified Delphi approach that combines critical appraisal of evidence and expert opinion, therapeutic use of levonadifloxacin and alalevonadifloxacin in various clinical scenarios and specific unmet conditions was deliberated. Fifteen expert members from medicine, critical-care, emergency, microbiology, and intensive-care disciplines participated and voted on 11 pre-conceived statements. When there was at least 70 % agreement, a consensus was reached. RESULTS: Following the voting, agreements were reached on 10 out of the 11 statements. Broadly, a consensus was reached in defining the therapeutic role of levonadifloxacin and alalevonadifloxacin in the treatment of various clinical indications involving resistant Gram-positive pathogens, including MRSA, in patients with co-morbidities, such as co-existing or increased risk for kidney dysfunction or hepatic disease and/or immunosuppression; also, in therapeutically challenging conditions caused by Gram-positive bacteria such as bacteraemia, bone and joint infection, diabetic foot infection, febrile neutropenia, and hospital-acquired pneumonia. CONCLUSIONS: This consensus supports the therapeutic use of levonadifloxacin and alalevonadifloxacin in the treatment of antibiotic-resistant GPIs, including those caused by MRSA and certain polymicrobial infections, in patients with multiple co-morbidities requiring drug with adequate safety and consistent efficacy.

Population Pharmacokinetic Analysis of Brexpiprazole to Support its Indication and Dose Selection in Adolescents With Schizophrenia.

Due to the customary delay between medication approvals in adult and adolescent populations, adolescents with schizophrenia may receive off-label antipsychotic treatment, without empirically justified dosing recommendations. In order to accelerate pediatric drug development, the US Food and Drug Administration (FDA) released a general advice letter to sponsors permitting the effectiveness of atypical antipsychotics for the treatment of schizophrenia in adults to be extrapolated to adolescents based on a pharmacokinetic (PK) analysis to support dose selection, plus a safety study. The aim of the present article is to describe the population PK analysis that was submitted to the FDA to inform brexpiprazole dose selection in adolescents with schizophrenia. Using a population PK model with brexpiprazole clearance and volume of distribution allometrically scaled by body weight, PK simulations showed comparable brexpiprazole dose-exposure between adults and adolescents aged 13-17 years following oral daily doses of brexpiprazole 1-4 mg, indicating that the target brexpiprazole dose of 2-4 mg/day in adults with schizophrenia is also suitable for adolescents. Based on this population PK analysis, together with a safety study in adolescents, the FDA approved brexpiprazole for the treatment of schizophrenia in adolescents aged 13-17 years, via extrapolation of the efficacy of brexpiprazole from adults to adolescents.

Cytotoxicity of Tetracyclines in Human Tympanic Membrane Fibroblasts.

HYPOTHESIS: Tetracyclines are less cytotoxic to tympanic membrane (TM) fibroblasts than quinolones. BACKGROUND: Use of quinolone ear drops after tympanostomy tube placement and for acute otitis externa has been linked to an increased risk of TM perforation. This has been verified in animal models. Cell culture studies have shown quinolones to be highly toxic to TM fibroblasts. Tetracyclines are a potential alternative to quinolones as they have been used to treat acute otitis externa and are thought to be nontoxic to the inner ear. We aimed to determine if tetracyclines are cytotoxic to TM fibroblasts. METHODS: Human TM fibroblasts were treated with 1:10 dilutions of ofloxacin 0.3%, ciprofloxacin 0.3%, doxycycline 0.3 and 0.5%, minocycline 0.3 and 0.5%, tetracycline 0.3 and 0.5%, or dilute HCl (control), twice within 24 hours or four times within 48 hours. After 2 hours of treatment, cells were returned to growth media. Cells were observed with phase-contrast microscopy until cytotoxicity was measured. RESULTS: Fibroblasts had lower survival with ciprofloxacin 0.3% and doxycycline 0.5% treatment compared with the control after 24 and 48 hours (all p < 0.0001). Fibroblasts treated with minocycline 0.5% had increased cell survival after 24 hours. Minocycline 0.3 and 0.5% showed increased TM fibroblast survival after 48 hours (all p < 0.0001). Phase-contrast images mirrored the cytotoxicity findings. CONCLUSIONS: Tetracyclines are less toxic to cultured TM fibroblasts than ciprofloxacin. Fibroblast tetracycline toxicity is drug and dose specific. Minocycline shows the most promise for possible otic applications in which fibroblast toxicity is a concern.

Relapse in patients with schizophrenia and amisulpride-induced hyperprolactinemia or olanzapine-induced metabolic disturbance after switching to other antipsychotics.

Hyperprolactinemia and metabolic disturbance are common side effects of antipsychotics that cause intolerance. Despite its potential influence on relapse, there are no established guidelines for antipsychotic switching. This naturalistic study explored the association between antipsychotic switching, baseline clinical status, metabolic changes, and relapse in patients with schizophrenia. In total, 177 patients with amisulpride-induced hyperprolactinemia and 274 with olanzapine-induced metabolic disturbance were enrolled. Relapse was determined by assessing changes in Positive and Negative Syndrome Scale (PANSS) total scores from baseline to 6 months (increased over 20% or 10% reaching 70). Metabolic indices were measured at baseline and 3 months. Patients with baseline PANSS >60 were more likely to relapse. Further, patients switching to aripiprazole had a higher risk of relapse regardless of their original medication. Participants who originally used amisulpride had reduced prolactin levels following medication change, while switching to olanzapine caused increased weight and blood glucose levels. In patients originally using olanzapine, only switching to aripiprazole reduced insulin resistance. Adverse effects on weight and lipid metabolism were observed in patients who switched to risperidone, while amisulpride improved lipid profiles. Changing schizophrenia treatment requires careful consideration of multiple variables, particularly the choice of substituted drug and the patient's baseline symptoms.

Efficacy of aripiprazole as adjunctive therapy in major depressive disorder with somatic symptoms: A randomized, double-blind, placebo-controlled trial with clinical and electroencephalography evidence.

BACKGROUND: Somatic symptoms, which are common in major depressive disorder (MDD), are associated with a worse prognosis and increased health costs. AIMS: This randomized, double-blind, placebo-controlled study evaluated the efficacy of aripiprazole augmentation in MDD patients with somatic symptoms. METHODS: In all, 41 MDD patients with somatic symptoms completed the study. Participants who had been on a stable dose of antidepressants for at least 1 month were randomly assigned to receive an 8-week adjunctive treatment with either aripiprazole or placebo. The initiation dose of aripiprazole was 2 mg/day, which was later adjusted to 1-10 mg/day. The primary endpoint was the change in the Symptom Checklist-90-Revised-Somatization (SCL-90-R-SOM) score. We collected quantitative electroencephalogram data and performed spectral analyses to obtain the absolute power of frequency bands. RESULTS/OUTCOMES: The aripiprazole group (n = 20; 2.98 ± 1.75 mg/day) showed a significant improvement in SCL-90-R-SOM scores compared to the placebo group (n = 21; F = 8.56, p = 0.006), without significant differences in changes in depression and anxiety symptoms. Compared to the control, the aripiprazole group showed a greater decrease in total alpha power (F = 7.03, p = 0.01). Changes in frontal alpha power were positively correlated with changes in SCL-90-R-SOM scores in the aripiprazole group (r = 0.53, p = 0.014). CONCLUSIONS/INTERPRETATION: Aripiprazole adjunctive to antidepressants in patients with MDD and somatic symptoms improved somatic symptom severity without significant safety concerns, and this improvement correlated with a decrease in total and frontal alpha power.Trial Registration: https://cris.nih.go.kr; identifier: KCT0004607.

Quinolone Ear Drops and Achilles Tendon Rupture.

BACKGROUND: Delayed eardrum healing has been observed in the ear opposite to the ear treated with otic quinolones (OQ) in rats. Case reports describe tendinopathies after OQ treatment, suggesting adverse systemic effects. METHODS: We studied patients aged 19 to 64 years with diagnosis of otitis externa or media in private insurance between 2005 and 2015. We compared OQ treatment against otic neomycin, oral amoxicillin, or azithromycin. Outcomes included Achilles tendon rupture (ATR), Achilles tendinitis (AT), and all-type tendon rupture (ATTR). We applied an active comparator, new-user design with 1-year look-back and ceased follow-up at initiation of systemic steroids or oral quinolones, external injury, hospitalization, and after 35 days. We used trimmed stabilized inverse probability of treatment weights to balance comparison groups in a survival framework. Negative outcomes (clavicle fractures or sports injuries) were examined to rule out differences from varied physical activity (unmeasured confounding). RESULTS: We examined 1 501 009 treated otitis episodes. Hazard ratios (HR) for OQ exposure associated with ATR were 4.49 (95% confidence interval [CI], 1.83-11.02), AT 1.04 (95% CI, 0.73-1.50), and ATTR 1.71 (95% CI, 1.21-2.41). Weighted risk differences (RD) per 100 000 episodes for OQ exposure were ATR 7.80 (95% CI, 0.72-14.89), AT 1.01 (95% CI, -12.80 to 14.81), and ATTR 18.57 (95% CI, 3.60-33.53). Corresponding HRs for clavicle fractures and sports injuries were HR,1.71 (95% CI, 0.55-5.27) and HR,1.45 (95% CI, 0.64-3.30), suggesting limited residual confounding. CONCLUSIONS: OQ exposure may lead to systemic consequences. Clinicians should consider this potential risk and counsel patients accordingly. Risk factors and mechanisms for this rare, adverse effect deserve further evaluation. Mechanistic and other clinical studies are warranted to corroborate this finding.

Dolutegravir in Pregnancy as Compared with Current HIV Regimens in the United States.

BACKGROUND: Data on the effectiveness and safety of dolutegravir-based antiretroviral therapy (ART) for human immunodeficiency virus type 1 (HIV-1) infection in pregnancy as compared with other ART regimens commonly used in the United States and Europe, particularly when initiated before conception, are limited. METHODS: We conducted a study involving pregnancies in persons with HIV-1 infection in the Pediatric HIV/AIDS Cohort Study whose initial ART in pregnancy included dolutegravir, atazanavir-ritonavir, darunavir-ritonavir, oral rilpivirine, raltegravir, or elvitegravir-cobicistat. Viral suppression at delivery and the risks of infants being born preterm, having low birth weight, and being small for gestational age were compared between each non-dolutegravir-based ART regimen and dolutegravir-based ART. Supplementary analyses that included participants in the Swiss Mother and Child HIV Cohort Study were conducted to improve the precision of our results. RESULTS: Of the pregnancies in the study, 120 were in participants who received dolutegravir, 464 in those who received atazanavir-ritonavir, 185 in those who received darunavir-ritonavir, 243 in those who received rilpivirine, 86 in those who received raltegravir, and 159 in those who received elvitegravir-cobicistat. The median age at conception was 29 years; 51% of the pregnancies were in participants who started ART before conception. Viral suppression was present at delivery in 96.7% of the pregnancies in participants who received dolutegravir; corresponding percentages were 84.0% for atazanavir-ritonavir, 89.2% for raltegravir, and 89.8% for elvitegravir-cobicistat (adjusted risk differences vs. dolutegravir, -13.0 percentage points [95% confidence interval {CI}, -17.0 to -6.1], -17.0 percentage points [95% CI, -27.0 to -2.4], and -7.0 percentage points [95% CI, -13.3 to -0.0], respectively). The observed risks of preterm birth were 13.6 to 17.6%. Adjusted risks of infants being born preterm, having low birth weight, or being small for gestational age did not differ substantially between non-dolutegravir-based ART and dolutegravir. Results of supplementary analyses were similar. CONCLUSIONS: Atazanavir-ritonavir and raltegravir were associated with less frequent viral suppression at delivery than dolutegravir. No clear differences in adverse birth outcomes were observed with dolutegravir-based ART as compared with non-dolutegravir-based ART, although samples were small. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others.).

Safety of Quinolones in Children: A Systematic Review and Meta-Analysis.

BACKGROUND: The results of animal experiments show that quinolone antibacterial drugs may permanently damage the soft tissues of the weight-bearing joints of young animals. Out of safety concerns, using quinolones in children has always been controversial. OBJECTIVE: The aim of this study was to assess the risk of using quinolones in children and provide evidence for clinicians to support decision making. DATA SOURCES: The MEDLINE (Ovid), EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), International Pharmaceutical Abstracts (Ovid), CINAHL, CNKI, VIP, and WanFang Data databases were searched from inception to 8 September 2021. STUDY SELECTION: All types of studies that reported the safety data of quinolones in children, including clinical trials and observational studies. DATA EXTRACTION: Data extraction and cross-checking were completed by two independent reviewers using a pilot-tested standardized data extraction form. RESULTS: The overall incidence rate of adverse drug events (ADEs) in children using systemic quinolones was 5.39% and the most common ADEs were gastrointestinal reactions (incidence rate, 2.02%). Quinolone-induced musculoskeletal ADEs in children were uncommon (0.76%). Meta-analysis results showed that the risk of musculoskeletal ADEs in children using quinolones was higher than children in the control group (51 studies; rate ratio [RR] 2.03, 95% confidence interval [CI] 1.82-2.26; p < 0.001; I2 = 18.6%; moderate-quality evidence). However, the subgroup analysis results showed that differences might only be observed in children who were followed up for 2 months to 1 year (2-6 months: RR 2.56, 95% CI 2.26-2.89; 7 months to 1 year: RR 1.35, 95% CI 0.98-1.86). Moreover, children (adolescents) aged between 13 and 18 years might be sensitive to the musculoskeletal toxicity of quinolones (RR 2.69, 95% CI 2.37-3.05; moderate-quality evidence) and the risk of levofloxacin-induced musculoskeletal ADEs might be higher (RR 1.33, 95% CI 1.00-1.77; low-quality evidence). CONCLUSIONS: Although the existing evidence shows that quinolone-induced musculoskeletal ADEs seem to be only short-term and reversible, and no serious skeletal and muscular system damage cases have been reported in children, quinolones should be avoided unless necessary in children because the incidence rate of quinolone-related ADEs is not low and they are broad-spectrum antibiotics that will induce the emergence of resistant strains if used frequently.

Brexpiprazole-Associated Pisa Syndrome (Pleurothotonus) in a Patient With Dementia.

OBJECTIVES: The aims of the study were to report brexpiprazole-induced Pisa syndrome (PS) in a patient with Alzheimer disease and to discuss the pathophysiology and the treatment of PS. METHODS: We report a 71-year-old female patient with Alzheimer disease. After 2 months medication of brexpiprazole, she presented PS. By switching to quetiapine, the symptom was ameliorated; however, transient acute dystonia was occurred. CONCLUSIONS: Drug-induced PS may be associated with dopamine-acetylcholine imbalance. This imbalance causes the dysfunction of the cortex and basal ganglia and the dysfunction of sensory and somatosensory system. Stopping the offending drugs is a choice for the treatment of PS. This is the first report of PS-induced brexpiprazole.

At-home compounding preparation of slow desensitization of elexacaftor/tezacaftor/ivacaftor for delayed hypersensitivity rash.

As elexacaftor/tezacaftor/ivacaftor has proven to have robust clinical efficacy for eligible persons with cystic fibrosis, desensitization should be offered to those with maculopapular eruption hypersensitivity reactions to achieve tolerance. As presented in this case, if provided with tools for crushing and mixing the medication, a successful escalation protocol can be completed at home without coordinating the help of a compound pharmacy.

Systemic quinolones and risk of retinal detachment III: a nested case-control study using a US electronic health records database.

BACKGROUND: Quinolones are popular antibiotics that are known for their potency, broad coverage, and reasonable safety. Concerns have been raised about a possible association between quinolones and retinal detachment (RD). METHODS: We conducted a nested case-control study using electronic health records (EHR) from the Health Facts® Database. The initial cohort included all patients who were admitted between 2000 and 2016, with no history of eye disease, and had a minimum medical history of one year. Eligible cases comprised inpatients who were first admitted with a primary diagnosis of RD between 2010 and 2015. Each eligible case was matched without replacement to five unique controls by sex, race, age, and period-at-risk. We used conditional logistic regression to calculate RD risk, adjusting for exposure to other medications, and major risk factors. RESULTS: We identified 772 cases and 3860 controls. Whereas our primary analysis of all subjects revealed no quinolone-associated RD risk, elevated but non-significant risks were noted in African Americans (ciprofloxacin and levofloxacin), those aged 56-70 years old (moxifloxacin), and women (ciprofloxacin). CONCLUSION: Our study did not identify an elevated RD risk within 30 days following systemic administration of quinolone antibiotics. Suggestions of increased risk observed in some population subgroups warrant further investigation.

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.

Comparing the efficacy of aripiprazole as an add-on to valproate with other second-generation antipsychotics in acute mania symptoms in manic patients in Iran.

BACKGROUND: Given the great importance of treating patients with bipolar disorder, the aim of this study was to compare the efficacy of aripiprazole with other second-generation antipsychotics in relieving acute symptoms of mania. MATERIALS AND METHODS: In this study, 50 patients with bipolar I disorder, manic episode, were divided into two groups receiving aripiprazole (n = 25) and other second-generation antipsychotics (risperidone, olanzapine, and quetiapine) (n = 25) for 6 weeks. The disease severity was evaluated and compared according to YMRS and CGI criteria. RESULTS: The mean severity of mania according to YMRS and CGI, at week 0 in comparison with weeks 2, 4 and 6 in both groups was significantly different (p < 0.0001) and the treatment with Aripiprazole at week 2 (p < 0.0001) and 4 (p = 0.0002) was significantly better than the other second-generation antipsychotics. The two groups also showed an overall improvement in CGI-based results at weeks 4 and 6 (p = 0.002). In addition, the efficacy index for aripiprazole at weeks 4 (p = 0.011) and 6 (p < 0.0001) as well as disease improvement in the second (p < 0.0001) and fourth (p = 0.026) weeks after treatment were better than the other second-generation antipsychotics. CONCLUSIONS: Aripiprazole and other second-generation antipsychotics, 2 weeks after initiation of treatment, significantly reduced mania severity in patients with bipolar disorder, however, aripiprazole seems to be more efficient and faster for controlling mania in patients with bipolar disorder.KEY POINTSAripiprazole and other second-generation antipsychotics, 2 weeks after initiation of treatment, significantly reduced mania severity in patients with bipolar disorder.Comparison between the two drugs, aripiprazole showed a more beneficial role in the second and fourth weeks than second-generation antipsychotics.Due to the fact that the possible mechanisms involved in the role of aripiprazole have not been considered compared to other antipsychotics in patients with bipolar disorder, there is a need for more extensive studies in this field.