The Activities of the Central Nervous System Following Ethyl Acetate Extract of Mucuna pruriens Seed Administration in Male BALB/c Mice

A number of reports showed the beneficial psychotropic effects of many of the Nigerian medicinal plants, but few scientific studies have been carried out as empirical evidence. This study investigated the possible neurobehavioural effects of ethyl acetate extract of Mucuna pruriens (MP) seed in male BALB/c mice. Male BALB/c mice (2½-3 months old) were grouped into 5 (n=6), treated with normal saline (0.1 mL), n-propanol extract of MP (200, 100, 50 mg/kg) or reference drug haloperidol (HP) or diazepam (DZP); thereafter, subjected to diverse behavioural models to evaluate the central nervous system (CNS) effects of the extract. A bolus of MP (200, 100, and 50 mg/kg) decreased the rectal temperature, exploratory activities (locomotion, rearing and grooming), anxiety-like responses (% open-arms time, open-arm entries, and the total number of enclosed arms times). Additionally, a one-shot of intraperitoneal administration of MP decimated the total score of apomorphine-induced stereotyped behaviours. Latency to hexobarbitone-induced sleep increased significantly in the 200 mg/kg MP, unchanged in the 100 mg/kg MP, and decreased in the 50 mg/kg MP treated groups. There was a marked decrease in the markers of convulsion (tonic flexion, extension, clonic convulsion, stupor, and recovery time) following MP treatment, especially the higher doses (200 mg/kg and 100 mg/kg). In conclusion, the CNS effects of systemic administration of MP seed are not unrelated to its hypothermic, hypnotic, anxiolytic, and anticonvulsant effects.

Central Nervous System Effects of COVID-19 in People with HIV Infection

The convergence of the HIV and SARS-CoV-2 pandemics is an emerging field of interest. In this review, we outline the central nervous system (CNS) effects of COVID-19 in the general population and how these effects may manifest in people with HIV (PWH). We discuss the hypothetical mechanisms through which SARS-CoV-2 could impact the CNS during both the acute and recovery phases of infection and the potential selective vulnerability of PWH to these effects as a result of epidemiologic, clinical, and biologic factors. Finally, we define key research questions and considerations for the investigation of CNS sequelae of COVID-19 in PWH.

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.

Enzyme Replacement Therapy with Pabinafusp Alfa for Neuronopathic Mucopolysaccharidosis II: An Integrated Analysis of Preclinical and Clinical Data

Enzyme replacement therapy (ERT) improves somatic manifestations in mucopolysaccharidoses (MPS). However, because intravenously administered enzymes cannot cross the blood–brain barrier (BBB), ERT is ineffective against the progressive neurodegeneration and resultant severe central nervous system (CNS) symptoms observed in patients with neuronopathic MPS. Attempts to surmount this problem have been made with intrathecal and intracerebroventricular ERT in order to achieve CNS effects, but the burdens on patients are inimical to long-term administrations. However, since pabinafusp alfa, a human iduronate-2-sulfatase fused with a BBB-crossing anti-transferrin receptor antibody, showed both central and peripheral efficacy in a mouse model, subsequent clinical trials in a total of 62 patients with MPS-II (Hunter syndrome) in Japan and Brazil substantiated this dual efficacy and provided an acceptable safety profile. To date, pabinafusp alfa is the only approved intravenous ERT that is effective against both the somatic and CNS symptoms of patients with MPS-II. This article summarizes the previously obtained preclinical and clinical evidence related to the use of this drug, presents latest data, and discusses the preclinical, translational, and clinical challenges of evaluating, ameliorating, and preventing neurodegeneration in patients with MPS-II.

Enzyme Replacement Therapy with Pabinafusp Alfa for Neuronopathic Mucopolysaccharidosis II: an Integrated Analysis of Preclinical and Clinical Data

Enzyme replacement therapy (ERT) improves the somatic manifestations in mucopolysaccharidoses (MPS))．However, because intravenously administered enzymes cannot cross the blood brain barrier (BBB), ERT is ineffective against the progressive neurodegeneration and resultant severe central nervous system (CNS) symptoms observed in patients with neuronopathic MPS. Attempts to surmount this problem have been made with intrathecal and intracerebroventricular ERT intend to achieve CNS effects, but the burdens on patients are inimical to long-term multiple administrations. However, after pabinafusp alfa, a human iduronate-2-sulfatase fused with a BBB-crossing anti-transferrin receptor antibody, showed both central and peripheral efficacy in mice model, subsequent clinical trials in a total of 62 patients with MPS-II (Hunter syndrome) in Japan and Brazil substantiated this dual efficacy and provided an acceptable safety profile. To date, pabinafusp alfa is the only approved intravenous ERT effective against both the somatic and CNS symptoms of patients with MPS-II. This article summarizes the hitherto obtained preclinical and clinical evidence associated with this drug, and discusses the preclinical, translational and clinical challenges of evaluating, ameliorating and preventing the neurodegeneration in patients with MPS-II.

Cellular and Molecular Effects of SARS-CoV-2 Linking Lung Infection to the Brain

In December 2019, a new viral disease emerged and quickly spread all around the world. In March 2020, the COVID-19 outbreak was classified as a global pandemic and by June 2021, the number of infected people grew to over 170 million. Along with the patients’ mild-to-severe respiratory symptoms, reports on probable central nervous system (CNS) effects appeared shortly, raising concerns about the possible long-term detrimental effects on human cognition. It remains unresolved whether the neurological symptoms are caused directly by the SARS-CoV-2 infiltration in the brain, indirectly by secondary immune effects of a cytokine storm and antibody overproduction, or as a consequence of systemic hypoxia-mediated microglia activation. In severe COVID-19 cases with impaired lung capacity, hypoxia is an anticipated subsidiary event that can cause progressive and irreversible damage to neurons. To resolve this problem, intensive research is currently ongoing, which seeks to evaluate the SARS-CoV-2 virus’ neuroinvasive potential and the examination of the antibody and autoantibody generation upon infection, as well as the effects of prolonged systemic hypoxia on the CNS. In this review, we summarize the current research on the possible interplay of the SARS-CoV-2 effects on the lung, especially on alveolar macrophages and direct and indirect effects on the brain, with special emphasis on microglia, as a possible culprit of neurological manifestation during COVID-19.

Exploring CNS effects of American traditional medicines using zebrafish models

: Although American traditional medicine (ATM) has been practiced for millennia, its complex multi-target mechanisms of therapeutic action remain poorly understood. Animal models are widely used to elucidate the therapeutic effects of various ATMs, including their modulation of brain and behavior. Complementing rodent models, the zebrafish (Danio rerio) is a promising novel organism in translational neuroscience and neuropharmacology research. Here, we emphasize the growing value of zebrafish for testing neurotropic effects of ATMs and outline future directions of research in this field. We also demonstrate the developing utility of zebrafish as complementary models for probing CNS mechanisms of ATM action and their potential to treat brain disorders.

RESUME-1: a Phase III study of tolperisone in the treatment of painful, acute muscle spasms of the back

Tolperisone is a nonopioid, centrally acting muscle relaxant in clinical development in the USA for the treatment of symptoms associated with acute, painful muscles spasms of the back. CLN-301, RESUME-1, is a 14-day double-blind, randomized, placebo-controlled, parallel-group Phase III study of the efficacy and safety of tolperisone administered orally three-times daily in 1000 male and female subjects at approximately 70 clinical sites in the USA experiencing back pain due to or associated with muscle spasm of acute onset. Tolperisone is a promising therapeutic for managing acute, painful muscle spasms of the back as it appears to lack the off-target CNS effects often seen with conventional skeletal muscle relaxants. Clinical Trials Registration: NCT04671082

Evaluation of drug-drug interactions in hospitalized patients on medications for OUD

Introduction Medications used to treat OUD have common metabolic pathways and pharmacodynamic properties that can lead to drug-drug interactions (DDIs) that may go unnoticed in the inpatient setting. The purpose of this study was to identify the frequency of DDIs between medications prescribed for OUD and commonly used inpatient medications. Methods This was a retrospective review of orders for buprenorphine, buprenorphine-naloxone, and methadone to identify potential DDIs. Adult inpatients with an order for one of these medications for OUD were included. Medication regimens were evaluated throughout the inpatient stay and on day of discharge for DDIs. DDIs were classified by severity and type of interaction (increased risk of QT prolongation, additive CNS effects/respiratory depression, and opioid withdrawal). The primary endpoint was the number of potential DDIs. Other endpoints included number of each classification/severity of DDI, duration of therapy of interacting medications, and modifications made to OUD medications because of DDIs. Results A total of 102 patients were included, with 215 inpatient interactions and 83 interactions at discharge identified. While inpatient, 85% of patients were on an interacting medication, and 46% of patients were on an interacting medication at discharge. The most common classification of DDI was additive CNS effects/respiratory depression (68.8% inpatient, 50.6% discharge), followed by QT prolongation (24.2% inpatient, 45.8% discharge). The majority of DDIs were classified as requiring close monitoring rather than contraindicated. Discussion There are opportunities to optimize the prescribing practices surrounding OUD medications in both the inpatient setting and at discharge to ensure patient safety.