Central Nervous System Adverse Effects Research Articles

Efficacy and safety of atenolol versus propranolol for treatment of infantile haemangioma: A narrative review.

Infantile haemangiomas (IH) remain the most common benign vascular tumours in childhood. While most IH can be managed conservatively, a proportion of these lesions can cause disfigurement, ulceration or functional impairment, requiring prompt intervention. Propranolol, a lipophilic non-selective beta blocker, has been regarded as first-line therapy, following a serendipitous discovery of its use for IH in 2008. While efficacious, it has been associated with adverse effects such as hypoglycaemia, bronchospasm, sleep disturbances and agitation in infant trials. Hence, atenolol, a hydrophilic beta-1 selective blocker, has demonstrated similar efficacy and potentially greater tolerability, being less likely to cause sleep disturbances given its inability to cross the blood brain barrier, and a decrease in bronchial reactivity. The purpose of this review is to explore and critique the current knowledge on the efficacy and safety of propranolol against atenolol in children with IH. A total of seven studies comparing the two beta-blockers were identified in our search. Atenolol appeared to be as efficacious as propranolol and was associated with fewer central nervous system and bronchial-related adverse events. Further research exploring the optimal dosing for atenolol, particularly for ulcerated or syndromic IH, as well as incidence and management of rebound growth would be beneficial.

The role of oculoplastic surgeons in minimally invasive cosmetic injectables.

In recent years, the field of aesthetic medicine has witnessed a paradigm shift with an increasing demand for minimally invasive cosmetic procedures, including cosmetic injectables. This review aims to delineate the distinctive role played by oculoplastic surgeons in the administration of cosmetic injectables, comparing their expertise to that of nonphysician practitioners. Complications arising from cosmetic injections are discussed, including skin discoloration, inflammation, necrosis, vision loss, retinal pathology, and central nervous system adverse effects. Injector expertise, patient factors, type of filler, location of injection, and management strategies are reviewed. Findings highlight diverse practitioner involvement, common adverse effects like skin necrosis and vision loss, with hyaluronic acid fillers being prominent. Areas at the highest risk for ocular complication include the glabella and nose with potential management involving dissolving fillers and reducing pressure. Emphasis is placed on expert injector selection and patient awareness. The administration of cosmetic injectables requires a profound understanding of facial anatomy, vasculature, and potential complications. In contrast to nonphysician practitioners, oculoplastic and aesthetic surgeons bring a level of anatomical precision and clinical acumen that is essential for navigating the complexities of cosmetic injectables. Emphasis on training and collaboration among practitioners will be essential in advancing the field while prioritizing patient safety and satisfaction.

A Case Report On Metoprolol Induced Nightmares And Hallucinations

Metoprolol is a cardioselective beta-1-adrenergic blocker. It is frequently prescribed for cardiovascular conditions but is associated with potential central nervous system adverse effects, including hallucinations and nightmares. We discuss the case of an 84-year-old female with mixed aortic valve disease who experienced hallucinations and nightmares after starting metoprolol medication. Her symptoms improved after she stopped using metoprolol, indicating a likely causative link. This example emphasizes the significance of rapidly diagnosing and addressing adverse medication reactions, especially in elderly patients who may have underreported symptoms. Understanding the pharmacological properties of lipophilic beta-blockers and their effects on neurological function is critical for improving patient care and reducing negative outcomes

Clinical Pertinence and Determinants of Potential Drug–Drug Interactions in Chronic Kidney Disease Patients: A Cross-sectional Study

Background: Chronic kidney disease (CKD) is one of the major health issues effecting around 15% of world population, and its further complications has raised the need of polypharmacy for management. But this polypharmacy also upsurges the risk of potential drug-drug interactions (pDDIs) in CKD patients, which may further be responsible for increased morbidity and mortality. Objective: The main objective is therefore to evaluate the distribution, severity, causes, associated drug interactions, and clinical relevance of determination of pDDIs in CKD patients. Methods: Medical files of CKD patients examined at nephrology department, Maharishi Markandeshwar Institute of Medical Sciences and Research (MMIMSR), Mullana, between December 2022 and May 2023 were cross-sectionally assessed for this study. Medscape drug interaction checker was used to study patient profiles for pDDIs, and suggestive measures to minimize those pDDIs were studied using DDInter to ensure better clinical decision-making and patient safety. IBM SPSS (version 24) was utilized for statistical analysis. Results: The data reveal that 74.5% of the 200 medical files being evaluated had 839 pDDIs in total, out of which nearly 78.3% of patients had moderate, 15.6% had minor, and 6.07% had serious interactions. The potential adverse outcomes of pDDIs included an irregular heartbeat, hypokalemia, central nervous system (CNS) adverse effects, hypoglycemia, and a decline in therapeutic efficacy. The prevalence of pDDIs was discovered to be substantially correlated with age ≥60 years, (odds ratio [OR] = 0.65; 95% CI = 0.4-0.9; P = 0.040), length of stay ≥10 days (OR = 4.0; 95% CI = 1.29-6.1; P = 0.016), and number of prescribed drugs ≥10 (OR = 5.5; 95% CI = 2.45-10.69; P = 0.004). Conclusion: Patients with CKD have a high incidence of pDDIs (mainly mild to moderate). Older age, duration of hospital stays, and polypharmacy all raise the risk of pDDIs. Healthcare professionals (physicians and clinical pharmacist) should use drug interaction checker software programs like Medscape and DDInter to acquire knowledge about different pDDIS and their alternative measures so that the associated adverse drug reactions (ADRs) can be controlled and rational drug combination can be prescribed for management of CKD ensuring better patient care.

Central nervous system adverse events of immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICI) may trigger immune-related adverse events which rarely affect the central nervous system (CNS-irAEs). Over the past few years, cumulative data have led to the characterization of well defined syndromes with distinct cancer and antibody associations as well as different outcomes. The most frequent CNS-irAE is encephalitis, which includes three main groups: meningoencephalitis, a nonfocal syndrome usually responsive to corticosteroids; limbic encephalitis, associated with high-risk paraneoplastic neurological syndromes (PNS) antibodies (e.g. anti-Hu, anti-Ma2) and neuroendocrine cancers, characterized by poor treatment response and outcomes; and cerebellar ataxia, with variable outcomes (worse when high-risk PNS antibodies are detected). Additionally, a diffuse encephalopathy without inflammatory findings, with poor response to corticosteroids and high mortality has been described. The spectrum of CNS-irAEs also includes meningitis, myelitis, and rarer presentations. A subset of CNS-irAEs (i.e. limbic encephalitis and/or rapidly progressive cerebellar ataxia) is undistinguishable from ICI-naïve PNS. The clinical and outcomes diversity of CNS-irAEs suggests different pathogenic mechanisms, which need to be understood to establish more effective and specific treatment modalities. It is crucial to identify biomarkers able to predict which patients will experience severe CNS-irAEs, to anticipate their diagnosis, and to predict long-term outcomes.

Investigating the Impact of Polypharmacy and Anticholinergic Medication Burden on Objective Cognitive Performance in Adults With Multiple Sclerosis.

Polypharmacy, or the use of 5 or more daily medications, is common in adults with multiple sclerosis (MS), and is often due to various physical, cognitive, and emotional symptoms. However, research regarding the association between polypharmacy and cognitive outcomes in MS is sparse. Furthermore, individuals with MS often use medications with anticholinergic properties, which are commonly associated with cognitive impairment and other central nervous system adverse effects. Currently, the utility of scales measuring anticholinergic burden in MS is unknown. This study aims to investigate the relationship between polypharmacy, anticholinergic burden, and objective cognitive performance in MS. We recruited 90 individuals with MS during routine visits at an MS specialty clinic in Kansas City. Participants completed a brief, virtual cognitive assessment and answered questions about their health. Participants provided their medication lists from which we determined polypharmacy and scores on several anticholinergic burden scales. Statistical analyses included Spearman correlations and linear regression models. Approximately 44% of the individuals surveyed met the criteria for polypharmacy. The number of daily medications was negatively correlated with cognitive performance (rs = -0.45, P < .001). Further, the Drug Burden Index accounted for additional variance in cognitive performance beyond that explained by age, education, MS disease duration, and comorbidities [ΔR2 = .12, F(5, 84) = 7.84, P < .001.]. Clinicians should consider the possible negative consequences of polypharmacy when addressing cognitive concerns in MS. Anticholinergic burden scales may be valuable in this regard. Future investigations could explore behavioral and pharmacological interventions aimed at reducing polypharmacy in MS.

Influence of cytochrome P450 2D6*10/*10 genotype on the risk for tramadol associated adverse effects: a retrospective cohort study.

Background: Tramadol is primarily metabolized by the highly polymorphic CYP2D6 enzyme, leading to a large spectrum of adverse events and clinical response. Ample evidence pointed a reduced CYPD26 activity score in individuals harboring the CYP2D6*10/*10 genotype, nevertheless, there is scarce studies on the impact of CYP2D6*10/*10 genetic polymorphism on long-term tramadol's adverse effects. Aim: To test the correlation between CYP2D6*10/*10 expression and the risk for tramadol-associated adverse effects. Method: Using a database of Leumit Healthcare Services in Israel, we retrospectively assessed the occurrence of adverse events in patients who were prescribed tramadol. A binary logistic regression model was applied to model the relationship between CYP2D6*10/*10 genotype and the occurrence of adverse effects. Results: Data from four hundred ninety-three patients were included in this study. Only 25 (5.1%) patients were heterozygous for the CYP2D6*10 variant, while 56 patients (11%) were tested positive to the CYP2D6*10/*10 genotype. Compared to carriers of other variants, patients with the CYP2D6*10/*10 variant exhibited a higher occurrence of adverse events (odds ratio [OR] = 6.14, 95% confidence interval 3.18-11.83); the odds ratio for central nervous system adverse events and gastrointestinal adverse events were 5.13 (95% CI 2.84-9.28), and 3.25 (95% CI 1.78-5.93), respectively. Conclusion: Among the different CYP2D6 genotypes, CYP2D6*10/*10 genotype carries the higher risk of tramadol related adverse events. Appreciating the frequency of this specific allele it seems prudent to pharmacogenetically screen patients considered for long term tramadol treatment for better tolerability and efficacy outcomes.

New Tic Disorder in a Child With Cystic Fibrosis Treated With Elexacaftor/Tezacaftor/Ivacaftor

The widespread use of highly effective cystic fibrosis transmembrane-conductance regulator ­modulator therapy has dramatically altered the lives of individuals with cystic fibrosis. Clinical trials leading to ­modulator approval by the US Food and Drug Administration demonstrated improvements in major ­outcome measures including pulmonary function, gastrointestinal symptoms, and quality of life. Subsequent clinical experience has confirmed significant improvement across these domains. Adverse effects reported ­during clinical trials included headache and dizziness amongst others including upper respiratory infections, abdominal pain, diarrhea, rash, and elevated serum transaminases. Post marketing clinical experience has suggested that there may be additional central nervous system adverse effects resulting from modulator therapy. Reported events after initiation of cystic fibrosis transmembrane-conductance regulator modulator treatment include headaches and increased prevalence of mental health concerns including anxiety and depression. We report a new tic disorder in a 7-year-old girl with cystic fibrosis treated with elexacaftor/tezacaftor/ivacaftor.

Impact of tramadol and heroin abuse on electroencephalography structure and cognitive functions

BackgroundOpioids, defined as medicines that stimulate opioid receptors, are primarily used in the treatment of moderate to severe pain. They induce central nervous system (CNS) adverse effects. This study aimed to assess the effect of opioids on brain electrical activity, the effect of opioids on cognitive functions, and corroborate whether there was any correlation between changes in brain electrical activity and cognitive functions that may do in opioid addicts.MethodsThis cross-sectional case–control study was performed on 80 cases (divided into two groups 40 cases with tramadol use disorders and 40 cases with heroin use disorders) and 40 age-/sex-matched healthy control. All subjects were subordinated to neuropsychiatric evaluation, assessment of opioid use complaint through history from the case and his relatives, substance monitoring in urine, medicine abuse screening test (DAST), electroencephalography (EEG), and cognitive assessment by Montreal Cognitive Assessment (MOCA).ResultsOpioid dependence convinced global cognitive function impairment, specific cognitive disciplines impairment that included visual-conceptual, visual-motor tracking, visual-constructional skills, language function, attention, memory, and orientation. Additionally, affection of the brain’s electrical activities with significant changes compared with control. Comparison of cognitive impairment substantiated by lower cognitive scores in relation to abnormal EEG changes among studied case groups revealed significant differences.ConclusionsOpioid abusers had a significant impairment of cognitive functions and EEG changes with a significant correlation between changes in brain electrical activity and impairment of cognitive functions.

NCMP-26. PANCEREBELLITIS ASSOCIATED WITH CISPLATIN THERAPY IN A PATIENT WITH OROPHARYNGEAL/ NASOPHARYNGEAL SQUAMOUS CELL CARCINOMA

Abstract Cisplatin, a platinum-based drug, is one of the oldest and most widely used chemotherapeutic agents. It exerts its anti-tumor effect by forming DNA inter-strand and intra-strand cross-links, resulting in lesions that eventually activate apoptotic pathways. Cisplatin remains widely used for the treatment of several solid tumors, though this is often limited by its toxicity which can affect many organ systems, including nephrotoxicity, hepatotoxicity, ototoxicity, and neurotoxicity. A dose-dependent peripheral sensory neuropathy is the most reported cisplatin-induced neurotoxicity. Central nervous system (CNS) toxicity is less common, likely due to the large molecular size of cisplatin preventing its passage through the blood-brain barrier (BBB). There have been reports of cognitive impairment, posterior reversible encephalopathy syndrome, and optic neuritis associated with cisplatin. We present a case of a 38-year-old patient who was treated with concurrent cisplatin and radiation therapy for oropharyngeal/nasopharyngeal squamous cell carcinoma, and around a month after the end of therapy, was found to have imaging findings concerning for pancerebellitis. Extensive workup into infectious causes of cerebellitis was negative. Although there are no reports in the literature of cerebellitis due to cisplatin, it could be the culprit in this case. Animal studies have shown cerebellar dysfunction occurring in the setting of cisplatin exposure. Moreover, it is thought that the drug can reach the CNS if there is a disruption of the BBB, this is supported by the fact that CNS toxicity is more seen in patients who have primary CNS neoplasia, CNS metastatic disease, radiation exposure to the head, among other mechanisms that could potentially disrupt the BBB. Thus, it is important to consider CNS adverse effects, including cerebellitis, in patients receiving cisplatin, especially among those with a potentially compromised BBB.

Revisiting efavirenz in the era of dolutegravir: Low-dose efavirenz, a viable alternative capable of holding its own against dolutegravir-based regimens

ABSTRACT Background: First-line dual NRTI + NNRTI-based ART has shown good virological effectiveness; however, toxicity is common and is often the most common reason for modification of first-line ART. Aims: The purpose of this study is to revisit low-dose efavirenz (EFV) in the era of dolutegravir (DTG) by investigating anti-retroviral therapy (ART) switch strategies for outcomes of virological effectiveness and safety in virologically suppressed Indian persons living with HIV (PLH) on first-line dual nucleoside reverse transcriptase inhibitors (NRTI) + non-NRTI (NNRTI)-based ART. Methods: A phase-IV comparative study of consecutive cases who switched their first-line NNRTI-based ART to either EFV-400 or DTG with a dual NRTI backbone between October 2020 to December 2021 and underwent at least 48 weeks of follow-up. The study is a non-randomised trial, wherein ART regimens were based on physician choice, patient preference and drug availability. Results: A total of 102 [DTG arm: 52; EFV-400 arm: 50; intention-to-treat (ITT) population] participants met the inclusion criteria. At 48-week follow-up, virological failure was not observed in either arm. Virological suppression to &lt; 200 cp/mL was attained in 97.9% (n = 48/49; 95% confidence interval [CI]: 89.1–99.9) and 95.9% (n = 47/49; 95% CI: 86.02–99.5) of patients, respectively, in the DTG and-EFV-400 arm (ITT-populations). There was no significant difference in mean change from baseline in body weight and body mass index between DTG and-EFV-400 arms. The proportion of patients who gained ≥ 10% of their baseline body weight at 24 weeks of exposure to DTG was 16% (n = 8, 95% CI: 5.8 to 26.2) and that to EFV-400 was 10% (n = 5, 95% CI: 1.7 to 18.3) with a difference in proportions: 6.0% (95% CI: −7.1–19.1)]. There was a significant decrease at 24 weeks in mean fasting levels of lipid fractions in the DTG arm as compared to EFV-400 [total cholesterol: − 24.3 mg/dL, 95% CI: −35.2 to − 13.3 vs. −6.9 mg/dL, 95% CI: −17.9–4.1 (P = 0.029) and triglycerides:−35.9 mg/dL, 95% CI: −60.9 to − 10.9 vs. 8.6 mg/dL, 95% CI: −16.6 to 33.8 (P = 0.014)]. Adverse events (AEs) of any grade including laboratory derangements to DTG were experienced by 6% (n = 3, 95% CI: −0.6 to 12.6) and that to EFV-400 by 8% (n = 4, 95% CI: 0.5 to 15.5) with a difference in proportions: 2.0% (95% CI: −7.9 to 11.9). Grades 3–4-AE occurred in two patients, both in the EFV-400 arm. Central nervous system AEs were not observed in the DTG arm and occurred in two patients in the EFV-400 arm. Two patients in the EFV-400 arm discontinued the regimen due to AEs. Conclusion: Both DTG and EFV-400-based first-line ART show good virological effectiveness and safety profiles in patients who are virologically suppressed on dual NRTI + NNRTI-based first-line ART.

Clinical Pharmacokinetics and Pharmacodynamics of the Next Generation Androgen Receptor Inhibitor-Darolutamide.

Darolutamide is a next-generation androgen receptor signaling inhibitor (ARSI) currently approved for the treatment of nonmetastatic castration-resistant prostate cancer (nmCRPC) and metastatic hormone sensitive prostate cancer (mHSPC). Studies suggest that darolutamide also has the potential to be used to treat other stages of prostate cancer (PC), suggesting that its indications will broaden in the near future. Since ARSIs show similar efficacy for the treatment of PC, pharmacokinetic properties of these drugs and patient characteristics could help physicians decide which drug to select. This review provides an overview of the pharmacokinetic and pharmacodynamic properties of darolutamide. One of the most important pharmacological advantages of darolutamide is its low brain distribution and therefore limited seizure potential and central nervous system adverse effects. In addition, darolutamide has little drug-drug interaction potential and is unlikely to alter the exposure of other cytochrome P450 or P-glycoprotein substrates. Nevertheless, it may significantly increase the exposure of breast cancer resistant protein (BCRP) substrates. The limited solubility and bioavailability of darolutamide increases when taken together with food, regardless of the fat content. Darolutamide is excessively metabolized by oxidation and glucuronidation and excreted in the urine and feces. For this reason, dose reduction is required in patients with moderate and severe renal or severe hepatic impairment. Although no exposure-response relationship was observed with darolutamide, less advanced stages of PC showed better PSA response on treatment. Overall, darolutamide has some advantageous pharmacological properties that may lead to its preferred use, when broader registered, in selected patients across different disease stages.

Safety of lorlatinib in ALK-positivenon-small-cell lung cancer and management of central nervous system adverse events.

The use of tyrosine kinase inhibitors has made a breakthrough in the treatment of non-small-cell lung cancer (NSCLC). Recently, lorlatinib, a third-generation tyrosine kinase inhibitor, has demonstrated significant systemic and intracranial activity in both first-line and subsequent-line therapy in ALK-positive NSCLC patients. In this review, general characteristics of lorlatinib, its efficacy in the treatment of ALK-positive NSCLC patients and the safety of lorlatinib, particularly addressing central nervous system adverse events, are discussed. Management of central nervous system adverse events, which seem to be specific to lorlatinib therapy, is outlined.

Curcuma latifolia Roscoe extract reverses inflammatory pain in mice and offers a favorable CNS safety profile

Ethnopharmacological relevanceCurcuma latifolia Roscoe, a plant in the Curcuma genus, has been used as a food additive and folk medicine in Thailand to treat pelvic pain and improve premenstrual syndrome. Although it has been used for centuries, no scientific studies have proved its potential effects on inflammatory pain and central nervous system (CNS) safety profiles.Aim of the study: This study aimed to evaluate the potential effects of the ethanolic extract of C. latifolia rhizome on inflammatory pain in mice, together with its CNS safety profiles. Materials and methodsFirst, network pharmacology was employed to identify the role of bioactive constituents in C. latifolia on inflammatory pain. In addition, in vitro pharmacology was also evaluated to confirm the anti-inflammatory activity of C. latifolia extract at cellular levels in activated macrophages and microglia. Furthermore, the efficacy of the plant extract in attenuating formalin-induced pain-like behaviors in mice was evaluated. Mice were orally administered the extract (125, 250, 500 mg/kg) followed by the measurement of formalin-induced pain-like behaviors. The LABORAS automated behavioral analysis and rotarod test were used to assess potential CNS side effects of C. latifolia extract (500 mg/kg) in mice. ResultsThe results demonstrated that major bioactive constituents present in C. latifolia have the ability to regulate multiple targets, biological processes and pathways associated with inflammatory pain as assessed by network pharmacology. C. latifolia modulated peripheral and central immune cells via reducing proinflammatory mediators (NO, TNF-α, and IL-6). C. latifolia extract improved formalin-induced pain-like behaviors in a dose-dependent manner during phase II of the formalin test. The efficacy of the plant extract at doses of 250 and 500 mg/kg was comparable to that of the positive control (indomethacin 10 mg/kg). Furthermore, the highest therapeutic dose of the extract did not affect motor coordination, exploratory behaviors, general behaviors, and overall well-being of mice, indicating no development of potential CNS adverse effects after administration of the extract. ConclusionThese findings provide novel perspectives on using C. latifolia extract for pain management, considering its therapeutic efficacy and CNS safety.

Chromatographic Data in Statistical Analysis of BBB Permeability Indices.

Blood-brain barrier (BBB) permeability is an essential phenomena when considering the treatment of neurological disorders as well as in the case of central nervous system (CNS) adverse effects caused by peripherally acting drugs. The presented work contains statistical analyses and the correlation assessment of the analyzed group of active pharmaceutical ingredients (APIs) with their BBB-permeability data collected from the literature (such as computational log BB; Kp,uu,brain, and CNS+/- groups). A number of regression models were constructed in order to observe the connections between the APIs' physicochemical properties in combination with their retention data from the chromatographic experiments (TLC and HPLC) and the indices of bioavailability in the CNS. Conducted analyses confirm that descriptors significant in BBB permeability modeling are hydrogen bond acceptors and donors, physiological charge, or energy of the lowest unoccupied molecular orbital. These molecular descriptors were the basis, along with the chromatographic data from the TLC in log BB regression analyses. Normal-phase TLC data showed a significant contribution to the creation of the log BB regression model using the multiple linear regression method. The model using them showed a good predictive value at the level of R2 = 0.87. Models for Kp,uu,brain resulted in lower statistics: R2 = 0.56 for the group of 23 APIs with the participation of k IAM.

Cannabis-based medicines and medical cannabis for adults with cancer pain.

Cannabis-based medicines and medical cannabis for adults with cancer pain.

Orally Induced High Serum Level of Trimethylamine N-oxide Worsened Glial Reaction and Neuroinflammation on MPTP-Induced Acute Parkinson's Disease Model Mice.

Neuroinflammation mediated by brain glial cells is one of the pathological drivers of Parkinson's disease (PD). Recent studies have shown that higher circulating trimethylamine N-oxide (TMAO, a gut microbiota-derived metabolite) can induce neuroinflammation and are strongly related to a variety of central nervous system diseases and adverse brain events. Herein, we explored the effect of pre-existing higher circulating TMAO on dopamine system and neuroinflammation in acute PD model mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydroxypyridine (MPTP). TMAO pretreatment was given by adding 3% (w/v) TMAO to drinking water of mice for 21days to induce higher circulating TMAO status, then mice were administered with MPTP (20mg/kg, i.p) for four times in one day to construct an acute PD model mice and treated with TMAO continuously until the end of the experiment. Results demonstrated that TMAO treatment significantly increased serum TMAO levels. Moreover, high serum TMAO significantly increased activation of microglia and astrocytes both in striatum and in substantia nigra. And strikingly, high serum TMAO significantly promoted the metabolism of striatal dopamine (DA) of PD model mice, although it had no significant effect on the number of dopaminergic neurons or the content of DA. Furthermore, immunofluorescence, ELISA, and RT-qPCR results of the hippocampus also showed that high serum TMAO significantly promoted the activation of microglia and astrocytes in the dentate gyrus, increased the levels of TNF-α and IL-1β, and upregulated gene expression of M1 microglia-related markers (including CD16, CD32, and iNOS) and A2 astrocyte-related markers (including S100a10, Ptx3, and Emp1) in mRNA levels. In summary, we found that pre-existing high serum levels of TMAO worsened the PD-related brain pathology by promoting DA metabolism, aggravating neuroinflammation and regulating glial cell polarization.

A phase 2, randomized, open-label study comparing the effects of darolutamide versus enzalutamide monotherapy on serum testosterone levels in patients with hormone-naive prostate cancer: ARAMON study.

TPS5111 Background: Darolutamide is a structurally distinct and highly potent androgen receptor inhibitor with low blood–brain barrier penetration. In the phase 3 ARAMIS study (NCT02200614) of patients with nonmetastatic castration-resistant prostate cancer, treatment with darolutamide significantly improved metastasis-free survival and overall survival versus placebo, with a favorable safety profile. The incidences of central nervous system adverse events (AEs; e.g. falls, memory impairment, and depression) showed a ≤2% difference between the darolutamide and placebo groups. Fatigue was the only AE with an incidence of &gt; 10% for darolutamide (13.2% vs 8.3% for placebo). In a separate neuroimaging study of healthy volunteers, cerebral blood flow was not altered in patients treated with darolutamide but was significantly reduced in brain areas related to cognition in patients treated with enzalutamide. Furthermore, it is postulated that the low blood–brain barrier penetration of darolutamide may result in lower serum testosterone elevations than those seen with enzalutamide, with the potential of leading to fewer associated feminizing AEs. The objective of ARAMON (NCT05526248) is to compare the effect of darolutamide and enzalutamide monotherapy on post-treatment testosterone levels in patients with hormone-naive prostate cancer experiencing biochemical recurrence after definitive treatment for localized disease. Methods: ARAMON is a two-stage, open-label, phase 2 study of patients with histologically or cytologically confirmed adenocarcinoma of the prostate who have biochemical recurrence after radical primary prostatectomy or radiation therapy, with a prostate-specific antigen (PSA) doubling time of ≤20 months, baseline serum testosterone &gt; 150 ng/dL, and Eastern Cooperative Oncology Group performance status 0/1. During a 52-week lead-in phase, 25 patients will receive darolutamide 600 mg twice daily. If criteria based on serum testosterone increase from baseline to Week 12 are met, the study will proceed to a 52-week randomized phase in which the effects of darolutamide (600 mg twice daily, n = 20) will be compared with the effects of enzalutamide (160 mg once daily, n = 20). The primary endpoint of both phases is the change in serum testosterone level from baseline to Week 12. Secondary endpoints of the randomized phase include the change in serum testosterone levels from baseline to Weeks 24 and 52; PSA at Weeks 4, 12, 24, 36, and 52; changes in blood levels of markers for glucose, lipid metabolism, and endocrine function related to sex hormones; safety; and quality of life. Safety will be assessed through AE monitoring. The first of the 25 planned patients in the lead-in phase was enrolled on January 13, 2023. Clinical trial information: NCT05526248 .

Signal mining and analysis for central nervous system adverse events due to taking oxycodone based on FAERS database.

Central nervous system adverse events (AEs) occur when oxycodone is used in combination with benzodiazepines, antidepressants and anticonvulsants. There have been no reports of central nervous system AEs with oxycodone alone or in combination with oxycodone. Based on USA Food and Drug Administration Adverse Event Reporting System (FAERS) data, this study aims to explore the risk signals of central nervous system AEs with oxycodone alone or in combination with benzodiazepines, antidepressants and anticonvulsants, and to provide a reference for the safe and rational use of this drug. Extracted AEs data from the FAERS for oxycodone alone and in combination with benzodiazepines, antidepressants, and anticonvulsants from Q1 2004 to Q2 2021. The risk signal mining analysis of AEs was performed using the proportional imbalance method and Bayesian method. Number of reports ≥3 and lower 95% CI limit of reporting odds ratio (ROR)>1; number of reports ≥3, proportional reporting ratio (PRR)≥2 and χ2≥4; lower information components (IC) lower 95% CI limit (IC025)>0; empirical Bayes geometric mean (EBGM) lower 95% CI limit (EBGM05)>2, and N>0 were defined as positive signals. A total of 5 793 reports of central nervous system AEs with oxycodone alone were tapped, and 366, 622, and 740 reports of combined benzodiazepines, antidepressants, and anticonvulsants, respectively. Consumers and physicians were the main reporting population. The age distribution of oxycodone alone was mainly from 61 to 80 years old. The age distribution of oxycodone in combination with related drugs was mainly from 46 to 60 years old. The risk of AEs was greater in women than in men, and the United States was the predominant reporting country. Oxycodone alone was strongly associated with myoclonus [ROR=2.92, 95% CI 2.28 to 3.76); PRR=2.92, χ2(77.49); IC=1.52, IC025(0.65); EBGM=2.89, EBGM05(2.33)], delirium [ROR=4.69, 95% CI 4.24 to 5.21; PRR=4.66, χ2(1 052.64); IC=2.17, IC025(1.81); EBGM=4.50, EBGM05 (4.13)], mental disorder [ROR=2.95, 95% CI 2.53 to 3.44; PRR=2.94, χ2(206.93); IC=1.56, IC025(0.96); EBGM=2.95, EBGM05(2.58)], and acute central respiratory depression [ROR=2.87, 95% CI 2.68 to 3.08); PRR=2.82, χ2(971.62); IC=1.52, IC025(1.33), EBGM=2.87, EBGM05 (2.76)]. Combination of benzodiazepines was most strongly associated with mental disorder [ROR=10.08, 95% CI 9.38 to 10.78; PRR=9.90, χ2(64.06); IC=3.33, IC025 (1.65); EBGM=10.08, EBGM05(5.61)], and tremor [ROR=3.09, 95% CI 2.76 to 3.42); PRR=3.08, χ2(48.93); IC=1.63, IC025 (1.17); EBGM=3.09, EBGM05(2.34)]. Combination of antidepressants was most strongly associated with delirium [ROR=13.23, 95% CI 12.23 to 14.23; PRR=12.87, χ2(43.86); IC=3.69, IC025(1.36); EBGM=12.23, EBGM05 (5.32)] and somnolence [ROR=6.74, 95% CI 6.15 to 7.33); PRR=6.73, χ2(53.42); IC=2.75, IC025(1.52); EBGM=6.73, EBGM05(4.10)]. Combination of anticonvulsants was most strongly associated with myoclonus [ROR=17.89, 95% CI 17.46 to 18.32; PRR=17.72, χ2(971.39); IC=4.16, IC025(2.70); EBGM=17.89, EBGM05(12.46)] and delirium [ROR=4.86, 95% CI 4.45 to 5.27); PRR=4.82, χ2(69.49); IC=2.28, IC025 (1.51); EBGM=4.86, EBGM05(3.44)]. Based on pharmacovigilance studies of the FAERS database, clinical medication monitoring of oxycodone alone and in combination with benzodiazepines, antidepressants, and anticonvulsants should be strengthened to be alert to the occurrence of central nervous system-related AEs.

1010. Metronidazole-associated neurologic adverse events: risk factors analysis

Abstract Background Metronidazole is a widely used antibiotic to treat anaerobic and protozoal infections. However, neurologic adverse events associated with metronidazole have been reported in case series and case reports. Previous publications implicated that long-term usage and cumulative dose are risk factors for this adverse event. Still, little is known about the risk factor of the metronidazole-associated neurologic adverse events. Therefore, we conducted a retrospective study to investigate the risk factors for the metronidazole-associated neurologic adverse events through a matched case-control study. Methods This retrospective study enrolled patients prescribed metronidazole from January 2006 to July 2021 at Severance Hospital, a tertiary hospital in South Korea. Case patients were defined as those who developed central nervous system (CNS) adverse events or peripheral nervous system (PNS) adverse events during the study period with causality assessment. In a 1 to 3 ratio, case patients were compared to a control group of the patients without neurologic adverse events, matched on age and cumulative dose of metronidazole. Results 92838 patients were prescribed metronidazole during the study period. Among them, 52 patients showed metronidazole-associated neurologic adverse events (39 patients with CNS, 27 patients with PNS adverse events, and 14 patients with both). The proportion of chronic kidney disease (CKD), solid organ transplantation, liver cirrhosis (LC), intravenous (IV) administration of metronidazole, and concomitant use of a proton pump inhibitor was significantly higher in the case group. The body weight, hemoglobin, and serum albumin levels were lower, and Sequential Organ Failure Assessment scores were higher in the case group. Multivariate conditional logistic regression analysis demonstrated LC, CKD, IV administration, and lower body weight as risk factors for metronidazole-associated neurologic adverse events. Conclusion In this case-control study, LC, CKD, IV administration, and lower body weight were associated with the metronidazole-associated neurologic adverse events. Prolonged metronidazole treatment in patients with the risk factors requires careful examination for these adverse events. Disclosures All Authors: No reported disclosures.