Central Nervous System Adverse Effects Research Articles

Central nervous system adverse events of ceftazidime/avibactam: A retrospective study using Food and Drug Administration Adverse Event Reporting System.

Many antibiotics are well known for being associated with adverse events (AEs) of central nervous system, ceftazidime/avibactam (CAZ/AVI) is a novel β-lactam/β-lactamase inhibitor combinations. In this commentary, we analyzed reports of nervous system disorders associated with CAZ/AVI, meropenem, imipenem, ceftazidime, ceftriaxone, and cefepime in the Food and Drug Administration (FDA) Adverse Event Reporting System database from January 2015 to March 2022. The reporting odds ratios (RORs) method was used to detect the safety signals. Up to 15.62% of CAZ/AVI AEs exhibit nervous system disorders associated with CAZ/AVI. A nervous system disorder signal was detected for CAZ/AVI compared with meropenem, ceftazidime, and ceftriaxone. Compared with meropenem, imipenem, ceftazidime, and ceftriaxone, encephalopathy, myoclonus, reported with CAZ/AVI exhibited significant RORs. This study found that CAZ/AVI showed a relatively stronger sign nervous system disorder than meropenem, ceftazidime, and ceftriaxone in the real world. The poor clinical outcome of these events should attract clinical attention, especially for patients with older than 65 years old and long treatment courses.

Central nervous system adverse events potentially associated with drugs used for COVID-19: scoping reviewEventos adversos en el sistema nervioso central potencialmente relacionados con los medicamentos para tratar la COVID-19: revisión exploratoria

To identify central nervous system (CNS) adverse events potentially associated with prophylaxis or drug treatment for COVID-19, and to describe the characteristic of the individuals affected. A scoping review was performed using a search strategy to retrieve articles from PubMed, EMBASE, SciELO, Scopus, CINAHL and BVS databases. Studies reporting on individuals receiving prophylactic or curative drugs for COVID-19 with at least one CNS adverse event were included. Articles reporting on CNS adverse events associated with medication for other health conditions were excluded. The search retrieved 1 547 articles, eight of which met the inclusion criteria. Seven studies had an observational design. A total of 3 035 individuals were assessed, of whom 1 701 were health care professionals and 1 978 were women. Curative treatment with hydroxychloroquine, chloroquine, lopinavir/ritonavir, and azithromycin was the most frequent (n = 5). The most common adverse events were headache, dizziness, mood disturbances, and drowsiness. Suicide was the most frequent severe event. Six adverse events were unexpected for hydroxychloroquine, chloroquine, and doxycycline. Potential CNS adverse events were unspecific and in general potentially associated with the use of hydroxychloroquine (monotherapy or associated with antibiotics). The data confirm the unfavorable risk/benefit profile of these drugs for the prevention and management of signs and symptoms of SARS-CoV-2 infection.

AML-394 Tagraxofusp in Blastic Plasmacytoid Dendritic Cell Neoplasm With/Without Central Nervous System Involvement and Intrathecal Chemotherapy as Primary Treatment or Prophylaxis: An Italian Experience

The precise frequency of central nervous system (CNS) involvement in blastic plasmacytoid dendritic cell neoplasm (BPDCN) is currently unknown. Recent data suggest it may be ~10% at baseline and 30% at first relapse. CNS is a 'sanctuary' for systemic treatment and can lead to disease recurrence even after the achievement of a complete response (CR) at the medullary and skin level. Ensuring complete meningeal disease clearance is essential, and combining intrathecal (IT) chemotherapy with systemic treatment is a promising approach. Tagraxofusp (TAG, SL-401) is a first-in-class therapy targeting CD123, a molecule that is overexpressed in BPDCN. TAG, available in the US and Europe, is the only approved drug for patients with BPDCN. To determine whether CNS prophylaxis/treatment impacts the prognosis and efficacy of systemic TAG treatment in patients with BPDCN. Retrospective single-center chart review. Patients with BPDCN, with (CNS+) or without (CNS-) CNS involvement. Patients received TAG intravenous infusions at 12 mcg/kg daily on days 1-5 of a 21-day cycle. Intrathecal (IT) chemotherapy (cytarabine and dexamethasone ± methotrexate) was administered in combination with TAG at each cycle as prophylaxis (CNS-) or primary-intention treatment (CNS+). Assessments included CNS response, tumor response, survival, and adverse event (AE) monitoring. Data were collected on 5 patients (n=3 CNS+, n=2 CNS-); all received TAG as first-line therapy. The median number of TAG cycles was 3 (range 1-4). All 3 patients with CNS+ disease achieved CNS complete response (CR), and none reported CNS relapse. In patients receiving CNS prophylaxis, 1 patient received TAG plus HSCT and is in CR after 29 months; another received high-dose chemotherapy, achieved a good partial remission after TAG, and remains alive after 4 months with HSCT shortly planned. No AEs associated with IT chemotherapy were reported. These preliminary results confirm the feasibility of IT chemotherapy in combination with systemic TAG therapy. Baseline CNS involvement did not appear to impact the efficacy or safety profile of TAG. IT chemotherapy and TAG effectively cleared and controlled CNS involvement. IT prophylaxis should be considered in patients with BPDCN who receive CD123-targeted therapies.

Efficacy and Safety of Tramadol for Knee or Hip Osteoarthritis: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.

To examine efficacy and safety of tramadol for knee or hip osteoarthritis (OA). PubMed, Embase, Cochrane Library, and Web of Science were searched up to May 2020 for randomized controlled trials (RCTs) comparing any of the following interventions: tramadol 100 mg/day, 200 mg/day, and 300 mg/day, and placebo for knee or hip OA. Pain and function were measured at or near 12 weeks for efficacy. Gastrointestinal, cardiovascular, and central nervous system (CNS) adverse events (AEs), and withdrawals were measured for safety. Bayesian network meta-analysis was conducted. Six RCTs (3,611 participants) were included. Tramadol 100 mg/day (standardized mean difference [SMD] -0.16 [95% confidence interval (95% CI) -0.34, 0.00]), 200 mg/day (SMD -0.21 [95% CI -0.37, -0.06]), and 300 mg/day (SMD -0.30 [95% CI -0.48, -0.14]) were statistically more effective than placebo in pain relief, but only tramadol 300 mg/day was better than placebo in functional improvement (SMD -0.24 [95% CI -0.47, -0.03]). Tramadol 100 mg/day (relative risk [RR] 2.29 [95% credible interval (CrI) 1.22, 4.25]), 200 mg/day (RR 4.35 [95% CrI 2.31, 8.01]), and 300 mg/day (RR 6.02 [95% CrI 3.22, 11.1]) involved a higher risk of gastrointestinal AEs. Similarly, tramadol 100-300 mg/day showed a higher risk of CNS AEs and withdrawals. However, the risk of cardiovascular AEs remained unclear. Only tramadol 300 mg/day showed minimal improvement in pain and function but with increasing AEs compared with placebo. Tramadol may not be sufficiently recommended for knee or hip OA based on the presented evidence, especially in patients with the risk of gastrointestinal and CNS AEs.

Comparative risk-benefit profiles of weak opioids in the treatment of osteoarthritis: a network meta-analysis of randomized controlled trials

Background Despite their poor tolerance, weak opioids are still the most commonly-prescribed medicine for osteoarthritis (OA)-related pain. The objective of this network meta-analysis was to comparatively examine the efficacy and safety of weak opioids in OA treatment. Methods Databases including PubMed, Embase, Cochrane Library and Web of Science were searched from inception to August 5, 2020 to retrieve randomized controlled trials (RCTs) comparing weak opioids with placebo or between one another in OA patients. Bayesian network meta-analysis was performed on the following outcomes of interest, namely the change-from-baseline score in pain relief, gastrointestinal (GI) adverse events (AEs), central nervous system (CNS) AEs, and total number of AEs (i.e., the number of subjects experiencing any AE for at least once) during follow-up. Results A total of 14 RCTs involving four types of weak opioids were included in this meta-analysis. Compared to placebo, tramadol (standardized mean difference [SMD] = -0.34, 95% credible interval [CrI]: -0.53 to -0.18) and codeine (SMD = -0.39, 95% CrI: -0.79 to -0.04) were effective for pain relief, but involved a higher risk of GI AEs, CNS AEs and total number of AEs. Dextropropoxyphene demonstrated a significantly lower risk of GI AEs (OR = 0.28, 95%CrI: 0.17 to 0.51), CNS AEs (OR = 0.29, 95%CrI: 0.11 to 0.78) and total number of AEs (OR = 0.35, 95%CrI: 0.15 to 0.82) compared to codeine. Dihydrocodeine had a better safety profile in CNS AEs (SUCRA = 64.8%) and total number of AEs (SUCRA = 66.6%). Conclusions The results of the present study confirmed that tramadol and codeine were effective drugs for the treatment of OA, but involved considerable safety issues. Dextropropoxyphene and dihydrocodeine exhibited a relatively good safety profile but their efficacy still warrant further investigation.

Reversibility of Central Nervous System Adverse Events in Course of Art.

The purpose of this study is to evaluate the frequency of central nervous system adverse events (CNS-AE) on dolutegravir (DTG) and non-DTG containing ART, and their reversibility, in the observational prospective SCOLTA cohort. Factors associated with CNS-AE were estimated using a Cox proportional-hazards model. 4939 people living with HIV (PLWH) were enrolled in DTG (n = 1179) and non-DTG (n = 3760) cohorts. Sixty-six SNC-AE leading to ART discontinuation were reported, 39/1179 (3.3%) in DTG and 27/3760 (0.7%) in non-DTG cohort. PLWH naïve to ART, with higher CD4 + T count and with psychiatric disorders were more likely to develop a CNS-AE. The risk was lower in non-DTG than DTG-cohort (aHR 0.33, 95% CI 0.19–0.55, p < 0.0001). One-year follow-up was available for 63/66 PLWH with CNS-AE. AE resolution was reported in 35/39 and 23/24 cases in DTG and non-DTG cohorts, respectively. The probability of AE reversibility was not different based on ART class, sex, ethnicity, CDC stage, or baseline psychiatric disorder. At the same time, a lower rate of event resolution was found in PLWH older than 50 years (p = 0.017). In conclusion, CNS-AE leading to ART discontinuation was more frequent in DTG than non-DTG treated PLWH. Most CNS-AE resolved after ART switch, similarly in both DTG and non-DTG cohorts.

Efficacy, safety, and economic impact of diazepam suppositories with as-needed acetaminophen for prevention of seizure recurrence during the same fever episode in children with suspected simple febrile seizures.

This study was undertaken to evaluate the efficacy, safety, and economic impact of diazepam suppositories with as-needed acetaminophen in comparison with as-needed acetaminophen alone for prevention of seizure recurrence during the same fever episode in suspected pediatric simple febrile seizures (SFS). This single-center, prospective, observational study was conducted from July 29, 2019 to February 15, 2021 at a children's hospital. Children aged 6months to 60months presenting to the emergency department with suspected SFS were included. Participants receiving both diazepam suppositories and as-needed acetaminophen were compared with those receiving as-needed acetaminophen alone. The primary outcome was seizure recurrence during the same fever episode. The secondary outcomes included the incidence of central nervous system (CNS) pathologies, adverse events, and medical costs. Of the 316 participants, 228 (72.2%) had their first febrile seizure. Diazepam (.3-.5mg/kg for up to two doses) was administered to 88 of 316 patients (27.8%). The outcomes were available for 306 patients. The recurrence rate was 3.5% (3/85) in the patients receiving diazepam with as-needed acetaminophen and 12.2% (27/221) in the patients receiving as-needed acetaminophen alone (relative risk = .29, 95% confidence interval [CI] = .09-.93, p=.03). The adjusted odds ratio of diazepam administration against recurrence was .23 (95% CI = .07-.78, p=.02). None of the patients had a CNS pathology. No severe adverse events occurred, although mild ataxia was observed significantly more often in the patients receiving diazepam and as-needed acetaminophen (29.4% vs. 18.7%, p=.04). The median medical cost was US $199 (interquartile range [IQR] = 86-244) for the group receiving both medications and US $202 (IQR = 114-242) for the group receiving as-needed acetaminophen alone. Compared with as-needed acetaminophen alone, diazepam with as-needed acetaminophen may reduce seizure recurrence more during the same fever episode without severe adverse events or additional costs in children with suspected SFS.

Pep19 Has a Positive Effect on Insulin Sensitivity and Ameliorates Both Hepatic and Adipose Tissue Phenotype of Diet-Induced Obese Mice.

Peptide DIIADDEPLT (Pep19) has been previously suggested to improve metabolic parameters, without adverse central nervous system effects, in a murine model of diet-induced obesity. Here, we aimed to further evaluate whether Pep19 oral administration has anti-obesogenic effects, in a well-established high-fat diet-induced obesity model. Male Swiss mice, fed either a standard diet (SD) or high-fat diet (HFD), were orally administrated for 30 consecutive days, once a day, with saline vehicle or Pep19 (1 mg/kg). Next, several metabolic, morphological, and behavioral parameters were evaluated. Oral administration of Pep19 attenuated HFD body-weight gain, reduced in approximately 40% the absolute mass of the endocrine pancreas, and improved the relationship between circulating insulin and peripheral insulin sensitivity. Pep19 treatment of HFD-fed mice attenuated liver inflammation, hepatic fat distribution and accumulation, and lowered plasma alanine aminotransferase activity. The inguinal fat depot from the SD group treated with Pep19 showed multilocular brown-fat-like cells and increased mRNA expression of uncoupling protein 1 (UCP1), suggesting browning on inguinal white adipose cells. Morphological analysis of brown adipose tissue (BAT) from HFD mice showed the presence of larger white-like unilocular cells, compared to BAT from SD, Pep19-treated SD or HFD mice. Pep19 treatment produced no alterations in mice behavior. Oral administration of Pep19 ameliorates some metabolic traits altered by diet-induced obesity in a Swiss mice model.

Perioperative Low-Dose Ketamine for Postoperative Pain Management in Spine Surgery: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Objective Although low-dose ketamine has been shown to be generally beneficial in terms of pain control in a variety of major surgery, there is no consensus regarding the effectiveness of supplemental ketamine analgesic use exclusively in spine surgery. The objective of this systematic review and meta-analysis of randomized controlled trials (RCTs) was to assess the efficacy and safety of perioperative low-dose ketamine for pain management and analgesic consumption in patients undergoing spine surgery. Methods A comprehensive literature search was performed for relevant studies using PubMed, EMBASE, Web of Science, and Cochrane Library. Patients who received perioperative low-dose ketamine were compared to the control group in terms of postoperative pain intensity, opioid consumption, and adverse events. Patients were further categorized by ages and administration times for subgroup analysis. Results A total of 30 RCTs comprising 1,865 patients undergoing elective spine surgery were included. Significantly lower pain intensity and less opioid consumption at 12 h, 24 h, and 48 h postoperatively and lower incidence of postoperative nausea and vomiting (PONV) were observed in the ketamine group (all P < 0.05). There was no significant difference of central nervous system (CNS) adverse events between groups. However, different efficacy of low-dose ketamine was detected when patients were categorized by ages and administration times. Conclusion Perioperative low-dose ketamine demonstrated analgesic and morphine-sparing effect with no increased adverse events after spine surgery. However, this effect was not significant in pediatric patients. Only postoperative or intraoperative and postoperative administration could prolong the analgesic time up to 48 h postoperatively. Further studies should focus on the optimal protocol of ketamine administration and its effect on old age participants.

Central nervous system adverse events after ChAdOx1 vaccination.

IntroductionPost-ChAdOx1 vaccine (AZD1222) adverse events following immunization (AEFI) are uncommon. Recently described neurological events include thrombocytopenia with thrombosis syndrome (TTS) with cerebral venous thrombosis and Guillain-Barré syndrome. There are very few AEFI reports following COVID vaccination from India, because of underreporting or other factors. A few cases of acute transverse myelitis (ATM) and post-vaccinal encephalitis have also been reported.Materials and methodsOver 11 months, in 2 districts of Kerala, India, 8.19 million people were vaccinated with the ChAdOx1 vaccine.ResultsDuring this period, we encountered five cases of autoimmune central nervous system (CNS) AEFI following ChAdOX1 (Oxford/AstraZeneca, Covishield™) vaccination. These included three cases of acute disseminated encephalomyelitis (ADEM), one case of opsoclonus myoclonus ataxia syndrome (OMAS), and one case of limbic encephalitis. The calculated crude incidence of post-ChAdOX1 autoimmune CNS AEFI was approximately 0.24 cases per million for encephalitis and 0.36 per million for ADEM. This was compared to the crude annual incidence of community-acquired ADEM worldwide (3.2–4 per million) and the crude annual incidence of community-acquired encephalitis in India (8.35–10 per million).ConclusionThere was no increase in the incidence of post-vaccination CNS AEFI (ADEM or encephalitis) as compared to the community incidence of ADEM or encephalitis. While this emphasizes the safety of ChAdOX1 nCoV-19 vaccination for COVID-19, it is important to recognize these post-vaccination autoimmune syndromes early to initiate immunosuppressive therapy.

Safety and Tolerability of Fesoterodine in Older Adult Patients with Overactive Bladder

BackgroundOlder patients (> 65 yr) suffering from overactive bladder (OAB) are more likely to have functional impairment and comorbidity than those without OAB. This article reviews available published studies and discusses how fesoterodine might meet the specific needs of the older OAB patient.MethodsA comprehensive literature search was undertaken in order to evaluate fesoterodine safety in older OAB patients.ResultsFesoterodine offers flexible dosing, allowing the clinician to balance risk and benefits according to the symptoms and preferences of the patient. Its balanced affinity for M2 and M3 muscarinic receptors may lead to its benefit on OAB symptoms. Its active metabolite is a P-gp substrate that is actively transported from the central nervous system (CNS), potentially avoiding adverse CNS effects. Fesoterodine can be used in mild or moderate hepatic or renal insufficiency and no dose adjustment is routinely required. Fesoterodine’s benefit has been demonstrated in multiple clinical trials in older and medically vulnerable patients. Fesoterodine was rated as “beneficial” in the LUTS-FORTA classification due to its efficiency and tolerability in older patients.ConclusionHere, the use of fesoterodine in older and vulnerable patients is summarized given the need to approach pharmacotherapy for OAB differently in older adults.

Management of Medication-Induced Psychiatric Disorders.

Management of Medication-Induced Psychiatric Disorders.

Clinical Pharmacology of the Dietary Supplement Kratom (Mitragyna speciosa).

Kratom (Mitragyna speciosa) consists of over 40 alkaloids, with 2 of them, mitragynine and 7-OH-mitragynine (7-OH-MG) being the main psychoactive compounds. Mitragynine and 7-OH-mitragynine each target opioid receptors and have been referred to as atypical opioids. They exert their pharmacologic effects on the mu, delta, and kappa opioid receptors. In addition, they affect adrenergic, serotonergic, and dopaminergic pathways. Kratom has been touted as an inexpensive, legal alternative to standard opioid replacement therapy such as methadone and buprenorphine. Other uses for kratom include chronic pain, attaining a "legal high," and numerous central nervous system disorders, including anxiety, depression, and posttraumatic stress disorder. Kratom induces analgesia and mild euphoria, with a lower risk of respiratory depression or adverse central nervous system effects compared to traditional opioid medications. Nonetheless, kratom has been associated with both physical and psychological dependence, with some individuals experiencing classic opioid withdrawal symptoms upon abrupt cessation. Kratom use has been linked to serious adverse effects, including liver toxicity, seizures, and death. These risks are often compounded by polysubstance abuse. Further, kratom may potentiate the toxicity of coadministered medications through modulation of cytochrome P450, P-glycoprotein, and uridine diphosphate glucuronosyltransferase enzymes. In 2016, the US Drug Enforcement Administration took steps to classify kratom as a federal schedule 1 medication; however, due to public resistance, this plan was set aside. Until studies are conducted that define kratom's role in treating opioid withdrawal and/or other central nervous system conditions, kratom will likely remain available as a dietary supplement for the foreseeable future.

Cardiovascular and renal effects of novel nonpeptide nociceptin opioid peptide receptor agonists.

Partial agonists of the nociceptin opioid peptide (NOP) receptor have potential therapeutic use as antihypertensive and water diuretics (aquaretics). To date, peptide NOP receptor ligands have failed to progress in clinical trials due to poor pharmacokinetics and adverse effects. Nonpeptide, small-molecule NOP receptor ligands may be more suitable as therapeutic agents. This study investigated the cardiovascular and renal responses produced by the novel nonpeptide NOP agonists AT-403, AT-090, AT-127, and AT-039. Changes in mean arterial pressure (MAP), heart rate (HR), renal excretory function and occurrence of sedation and hyperphagia were determined before and after i.v. bolus injection or infusion of the NOP agonists in conscious Sprague-Dawley rats. Additional studies involving (i) measurement of renal sympathetic nerve activity (RSNA) and (ii) renal denervation were conducted to investigate the role of the renal nerves in the cardiorenal responses to AT-039. Bolus i.v. injection of AT-403, AT-090, AT-127 and AT-039 produced significant decreases in MAP and HR and a sodium-sparing diuresis. AT-403, AT-090, and AT-127, but not AT-039, induced sedation and hyperphagia at all doses tested. Infusion i.v. of AT-039 produced hypotension and aquaresis without adverse central nervous system effects or change in HR, responses that were also observed in renal denervated rats. Nonpeptide NOP agonists decrease blood pressure and produce aquaresis in conscious rodents. Due to lack of sedation and hyperphagia, AT-039 represents a novel NOP agonist that may be useful for treatment of hypertension and/or volume overload/hyponatraemic states.

Analysis of anticholinergic adverse effects using two large databases: The US Food and Drug Administration Adverse Event Reporting System database and the Japanese Adverse Drug Event Report database.

IntroductionAnticholinergic adverse effects (AEs) are a problem for elderly people. This study aimed to answer the following questions. First, is an analysis of anticholinergic AEs using spontaneous adverse drug event databases possible? Second, what is the main drug suspected of inducing anticholinergic AEs in the databases? Third, do database differences yield different results?MethodsWe used two databases: the US Food and Drug Administration Adverse Event Reporting System database (FAERS) and the Japanese Adverse Drug Event Report database (JADER) recorded from 2004 to 2020. We defined three types of anticholinergic AEs: central nervous system (CNS) AEs, peripheral nervous system (PNS) AEs, and a combination of these AEs. We counted the number of cases and evaluated the ratio of drug–anticholinergic AE pairs between FAERS and JADER. We computed reporting odds ratios (RORs) and assessed the drugs using Beers Criteria®.ResultsConstipation was the most reported AE in FAERS. The ratio of drug–anticholinergic AE pairs was statistically significantly larger in FAERS than JADER. Overactive bladder agents were suspected drugs common to both databases. Other drugs differed between the two databases. CNS AEs were associated with antidementia drugs in FAERS and opioids in JADER. In the assessment using Beers Criteria®, signals were detected for almost all drugs. Between the two databases, a significantly higher positive correlation was observed for PNS AEs (correlation coefficient 0.85, P = 0.0001). The ROR was significantly greater in JADER.ConclusionsThere are many methods to investigate AEs. This study shows that the analysis of anticholinergic AEs using spontaneous adverse drug event databases is possible. From this analysis, various suspected drugs were detected. In particular, FAERS had many cases. The differences in the results between the two databases may reflect differences in the reporting countries. Further study of the relationship between drugs and CNS AEs should be conducted.

Nalfurafine, a G-Protein-Biased KOR (Kappa Opioid Receptor) Agonist, Enhances the Diuretic Response and Limits Electrolyte Losses to Standard-of-Care Diuretics.

Nalfurafine is a G-protein-biased KOR (kappa opioid receptor) agonist that produces analgesia and lacks central nervous system adverse effects. Here, we examined the cardiovascular and renal responses to intravenous and oral nalfurafine alone and in combination with furosemide, hydrochlorothiazide, or amiloride. We hypothesized that nalfurafine, given its distinct mechanism of vasopressin inhibition, would increase urine output to these diuretics and limit electrolyte loss. Following catheterization, conscious Sprague-Dawley rats received an isotonic saline infusion and were then administered an intravenous bolus of nalfurafine, a diuretic, or a combination. Mean arterial pressure, heart rate, and urine output were recorded for 90 minutes. In another study, rats were placed in metabolic cages and administered drug in an oral volume load. Hourly urine samples were then collected for 5 hours. Intravenous and oral nalfurafine produced a marked diuresis, antinatriuresis, antikaliuresis, and a decrease in mean arterial pressure. Compared with diuretic treatment alone, intravenous coadministration with nalfurafine significantly increased urine output to furosemide and hydrochlorothiazide and decreased sodium and potassium excretion. Notably, mean arterial pressure was reduced with nalfurafine/diuretic combination therapy compared to diuretics alone. Similarly, oral coadministration of nalfurafine significantly increased urine output to hydrochlorothiazide and decreased sodium and potassium excretion, whereas combination with furosemide only limited the amount of sodium excreted. Further, both intravenous and oral coadministration of nalfurafine enhanced the diuresis to amiloride and decreased sodium excretion. Together, these findings demonstrate that nalfurafine enhances the diuresis to standard-of-care diuretics without causing an excessive loss of electrolytes, offering a new approach to treat several cardiovascular conditions.

Abstract P247: Evaluating TRKB activity of novel preclinical brain-penetrant ROS1 and ALK inhibitors

Abstract Oncogenic ROS1 and ALK rearrangements are detected in up to 3% and up to 5% of advanced non-small cell lung cancer (NSCLC), respectively, with up to 40% of patients presenting with brain metastases at diagnosis. Although there are FDA-approved ROS1 and ALK inhibitors, there is a need for next-generation brain-penetrant inhibitors that have activity against drug-resistance mutations while sparing tropomyosin kinase B (TRKB) function in the central nervous system (CNS). TRKB inhibition in the CNS has been implicated in adverse events such as cognitive impairment, mood disorders, sleep effects or sleep disturbances, dizziness, ataxia or gait/motor disturbances, and weight gain, which have been observed with FDA-approved dual TRK/ROS1 inhibitor entrectinib and FDA-approved ALK inhibitor lorlatinib. TRKB-related CNS adverse events present a key challenge for the development of next-generation ROS1 and ALK therapies. We previously reported the discovery of NVL-520 and NVL-655, preclinical inhibitors of ROS1 and ALK, respectively, which have demonstrated activity against common drug-resistance mutations, selectivity versus TRKB, and brain penetrance in preclinical experiments. An important part of the discovery process was generating reliable and relevant TRKB potency measurements to enable structure-activity relationship (SAR) efforts. Here we describe four in vitro TRKB potency assays and explain their utility in guiding selectivity optimization for new inhibitors. These assays include (1) biochemical, (2) cell viability, (3) cellular coupled-enzyme, and (4) direct cellular phosphorylation readouts. Although biological contexts vary, each assay exhibits good cross-correlations, and we recommend multi-assay testing to improve confidence in evaluating TRKB inhibition. Using these assays, we present a multi-assay analysis of the preclinical TRKB potency and selectivity of NVL-520 and NVL-655 alongside FDA-approved or experimental inhibitors of ROS1 (crizotinib, entrectinib, repotrectinib, and taletrectinib) and ALK (crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, and ensartinib). In these preclinical assays, we observed entrectinib and lorlatinib to exhibit poor ROS1-vs-TRKB and ALK G1202R-vs-TRKB selectivity, respectively, which we believe is consistent with their CNS adverse events. In the same experiment, we observed NVL-520 and NVL-655 to exhibit selectivity across all assays, including for ROS1 G2032R and ALK G1202R/L1196M mutations, respectively. In conclusion, we have devised a multi-assay approach to evaluate TRKB inhibition and guide discovery of selective ROS1 and ALK inhibitors, with the goal of minimizing adverse events and driving durable responses for patients. Citation Format: Anupong Tangpeerachaikul, Joshua C. Horan, Henry E. Pelish. Evaluating TRKB activity of novel preclinical brain-penetrant ROS1 and ALK inhibitors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P247.

Abstract P244: NVL-655 exhibits antitumor activity in lorlatinib-resistant and intracranial models of ALK-rearranged NSCLC

Abstract ALK receptor tyrosine kinase can be aberrantly activated by gene rearrangement or point mutation to drive tumor cell proliferation, survival, and metastasis. ALK rearrangements are detected in up to 5% of advanced non-small cell lung cancer (NSCLC), and up to 40% of patients present with brain metastases at diagnosis. Crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib are FDA-approved tyrosine kinase inhibitors for ALK-positive NSCLC. However, durability of response to these treatments is partly limited by mutations in ALK that confer resistance. The G1202R solvent front mutation is commonly observed in patients that have progressed on crizotinib, ceritinib, alectinib, or brigatinib. Patients with tumors harboring G1202R have responded to lorlatinib, but many have relapsed after acquiring compound mutations such as G1202R/L1196M and G1202R/G1269A. Another challenge with lorlatinib is central nervous system (CNS) adverse events attributed to inhibition of tropomyosin receptor kinase B (TRKB), a kinase structurally related to ALK. NVL-655 is a novel preclinical brain-penetrant ALK inhibitor with selectivity over TRKB. We previously reported that NVL-655 inhibits ALK G1202R, G1202R/L1196M, G1202R/G1269A, and G1202R/L1198F in vitro; has favorable kinome and ALK-vs-TRKB selectivity profiles; and shows antitumor activity in a Ba/F3 EML4-ALK variant 1 (v1) G1202R/L1196M xenograft model. Here we report results of a broader preclinical characterization of NVL-655 across ALK models, including an intracranial model. NVL-655 was observed to induce regression in a HIP1-ALK patient-derived xenograft model, an EML4-ALK v1 human cancer cell line-derived model (NCI-H3122), and Ba/F3 xenograft models expressing EML4-ALK v1 G1202R and G1202R/G1269A. Pharmacodynamic (PD) biomarker analyses supported in vivo ALK inhibition by NVL-655. Furthermore, NVL-655 was observed to reduce tumor size and prolong survival by more than 4-fold in a mouse intracranial tumor model of Ba/F3 EML4-ALK v1 G1202R/L1196M luciferase. In conclusion, NVL-655 has a preclinical profile that we believe supports its potential to address a medical need for patients with ALK-positive disease, including those with G1202R compound mutations. We believe the findings presented here support the evaluation of NVL-655 for the treatment of patients with ALK-driven disease. Citation Format: Anupong Tangpeerachaikul, Amit Deshpande, Nancy E. Kohl, Joshua C. Horan, Henry E. Pelish. NVL-655 exhibits antitumor activity in lorlatinib-resistant and intracranial models of ALK-rearranged NSCLC [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P244.

Antinociceptive and Antipruritic Effects of HSK21542, a Peripherally-Restricted Kappa Opioid Receptor Agonist, in Animal Models of Pain and Itch.

Kappa opioid receptor (KOR) agonists have been promising therapeutic candidates, owing to their potential for relieving pain and treating intractable pruritus. Although lacking morphine-like central nervous system (CNS) effects, KOR agonists do elicit sedation, dysphoria and diuresis which seriously impede their development. Peripherally-restricted KOR agonists have a poor ability to penetrate into the CNS system, so that CNS-related adverse effects can be ameliorated or even abolished. However, the only approved peripherally-restricted KOR agonist CR845 remains some frequent CNS adverse events. In the present study, we aim to address pharmacological profiles of HSK21542, with an expectation to provide a safe and effective alternative for patients who are suffering from pain and pruritus. The in vitro experimental results showed that HSK21542 was a selective and potent KOR agonist with higher potency than CR845, and had a brain/plasma concentration ratio of 0.001, indicating its peripheral selectivity. In animal models of pain, HSK21542 significantly inhibited acetic acid-, hindpaw incision- or chronic constriction injury-induced pain-related behaviors, and the efficacy was comparable to CR845 at 15 min post-dosing. HSK21542 had a long-lasting analgesic potency with a median effective dose of 1.48 mg/kg at 24 h post-drug in writhing test. Meanwhile, the antinociceptive activity of HSK21542 was effectively reversed by a KOR antagonist nor-binaltorphimine. In addition, HSK21542 had powerful antipruritic activities in compound 48/80-induced itch model. On the other hand, HSK21542 had a weak ability to produce central antinociceptive effects in a hot-plate test and fewer effects on the locomotor activity of mice. HSK21542 didn’t affect the respiratory rate of mice. Therefore, HSK21542 might be a safe and effective KOR agonist and promising candidate for treating pain and pruritus.

Ixazomib, Daratumumab and Low Dose Dexamethasone in Intermediate-Fit Patients with Newly Diagnosed Multiple Myeloma (NDMM); Results of Induction Treatment of the Phase II HOVON 143 Study

Ixazomib, Daratumumab and Low Dose Dexamethasone in Intermediate-Fit Patients with Newly Diagnosed Multiple Myeloma (NDMM); Results of Induction Treatment of the Phase II HOVON 143 Study