Receptor Antagonist Properties Research Articles

Comparison of the Efficacy and Safety of Bilastine 20mg versus Fexofenadine 180mg for Treatment of Perennial Allergic Rhinitis: Randomized Controlled Study.

Antihistamines has always remained the mainstay drug treatment for Allergic Rhinitis (AR). Bilastine is a novel, non-sedative antihistamine with a super-selective H1 receptor antagonist property. Both bilastine and fexofenadine are second generation antihistamine drugs commonly used to manage AR and Chronic Urticaria (CU). Autologous Skin Serum Test (ASST) is a practical test for histamine release in CU. These tests have been studied in AR patients with limited data studies. 114 patients diagnosed with perennial AR were recruited and divided into two groups of 57 each. One group was started Bilastine 20mg once a day and other group, fexofenadine 180mg once a day. Total Nasal Symptom Score (TNSS) was calculated at presentation and two weeks of antihistamine therapy. ASST was hypothesized to be the test for AR and performed at the time of presentation and at two weeks follow-up. Intergroup and Intragroup assessment of TNSS, ASST and its variables were done using unpaired and paired t test respectively. Patients showed reduction in symptoms of AR with both antihistamines. A significant improvement of sneezing and rhinorrhoea was seen in Fexofenadine group as compared to Bilastine group. TNSS showed statistically significant improvement in both the groups. ASST had statistically significant reduction in both the groups. Both Bilastine and fexofenadine were found to be effective in reduction of symptoms of allergic rhinitis. Bilastine was found to be more effective in overall as well as sneezing and rhinorrhoea noted two weeks after therapy. The online version contains supplementary material available at 10.1007/s12070-024-04770-0.

Urinary retention induced by psychotropics: A case report

IntroductionNeurological bladder is considered a functional disability that has a significant impact on the quality of life and psychological state of patients. Psychotropic drugs, in turn, can worsen the urinary dysfunction caused by this disease.ObjectivesOur objective is to illustrate, through the case of a patient suffering from a neurological bladder decompensated by the treatment of a characterized depressive episode, the link between these two pathologies.MethodsWe report the case of Ms. M.W., aged 51, with a history of high blood pressure stabilized under nebivolol and a neurological bladder diagnosed 10 years ago with episodic pollakiuria, admitted to the psychiatric department for repeated suicide attempts. She had never used psychoactive substances and had no family psychiatric history. The patient presented depressive symptoms evolving for 5 months. The diagnosis of a characterized depressive episode with melancholic features was made and the patient was treated with sertraline. From the first intake of the drug, the patient presented acute urinary retention (UR) requiring the placement of a permanent bladder catheter. The urinary symptoms improved upon stopping the treatment. Sertraline was changed to olanzapine and escitalopram. The patient stopped the treatment after one month because of the worsening of urinary symptoms requiring the installation of a suprapubic catheter. The urinary problem, together with the cessation of treatment, were responsible for a worsening of psychiatric symptoms leading to multiple suicide attempts. Given the advanced stage of the neurological bladder demonstrated by the urodynamic tests, our patient was treated with paroxetine, quetiapine and oxazepam along with psychotherapeutic education. The evolution was characterized by improvement in psychiatric symptoms and the urinary symptoms were stable.ResultsThe lack of improvement after treatment discontinuation could be explained by an underlying neurological bladder manifesting with pollakiuria. The current literature on UR induced by psychotropic treatments is quite rare limited in case reports. This effect occurs especially when selective serotonin reuptake inhibitors (SSRIs) are prescribed in combination with other antipsychotics. Unlike first generation antipsychotics, atypical antipsychotics have muscarinic receptor antagonist properties which can induce UR. Among atypical antipsychotics, olanzapine has been shown to have the greatest antimuscarinic effects. Regarding SSRIs, they are associated with a lower risk of UR than other antidepressants and sertraline had the highest risk of UR.ConclusionsSSRIs can induce UR particularly in combination with atypical antipsychotics. Coordination of care across multiple specialties and understanding the side effects of psychotropic medications can enable faster diagnoses and adequate management.Disclosure of InterestNone Declared

Proteomic Characteristics of the Prefrontal Cortex and Hippocampus in Mice with Chronic Ketamine-Induced Anxiety and Cognitive Impairment

Schizophrenia, a complex psychiatric disorder with diverse symptoms, has been linked to ketamine, known for its N-methyl-D-aspartate (NMDA) receptor antagonistic properties. Understanding the distinct roles and mechanisms of ketamine is crucial, especially regarding its induction of schizophrenia-like symptoms. Recent research highlights the impact of ketamine on key brain regions associated with schizophrenia, specifically the prefrontal cortex (PFC) and hippocampus (Hip). This study focused on these regions to explore proteomic changes related to anxiety and cognitive impairment in a chronic ketamine-induced mouse model of schizophrenia. After twelve consecutive days of ketamine administration, brain tissues from these regions were dissected and analyzed. Using tandem mass tag (TMT) labeling quantitative proteomics techniques, 34,797 and 46,740 peptides were identified in PFC and Hip, corresponding to 5,668 and 6,463 proteins, respectively. In the PFC, a total of 113 proteins showed differential expression, primarily associated with the immuno-inflammatory process, calmodulin, postsynaptic density protein, and mitochondrial function. In the Hip, 129 differentially expressed proteins were screened, mainly related to synaptic plasticity proteins and mitochondrial respiratory chain complex-associated proteins. Additionally, we investigated key proteins within the glutamatergic synapse pathway and observed decreased expression levels of phosphorylated CaMKII and CREB. Overall, the study unveiled a significant proteomic signature in the chronic ketamine-induced schizophrenia mouse model, characterized by anxiety and cognitive impairment in both the PFC and Hip, and this comprehensive proteomic dataset may not only enhance our understanding of the molecular mechanisms underlying ketamine-related mental disorders but also offer valuable insights for future disease treatments.

The significance of finerenone as a novel therapeutic option in diabetic kidney disease: a scoping review with emphasis on cardiorenal outcomes of the finerenone phase 3 trials.

This scoping review prepared by endocrinology and nephrology experts aimed to address the significance of finerenone, as a novel therapeutic option, in diabetic kidney disease (DKD), based on the biological prospect of cardiorenal benefit due to non-steroidal mineralocorticoid receptor antagonist (MRA) properties, and the recent evidence from the finerenone phase 3 program clinical trials. The importance of finerenone in slowing DKD progression was critically reviewed in relation to the role of MR overactivation in the pathogenesis of cardiorenal disease and unmet needs in the current practice patterns. The efficacy and safety outcomes of finerenone phase III study program including FIDELIO-DKD, FIGARO-DKD and FIDELITY were presented. Specifically, perspectives on inclusion of patients with preserved estimated glomerular filtration rate (eGFR) or high albuminuria, concomitant use of sodium-glucose co-transporter-2 inhibitor (SGLT2i) or glucagon-like peptide 1 receptor agonist (GLP-1 RA), baseline glycated hemoglobin (HbA1c) level and insulin treatment, clinically meaningful heart failure outcomes and treatment-induced hyperkalemia were addressed. Finerenone has emerged as a new therapeutic agent that slows DKD progression, reduces albuminuria and risk of cardiovascular complications, regardless of the baseline HbA1c levels and concomitant treatments (SGLT2i, GLP-1 RA, or insulin) and with a favorable benefit-risk profile. The evolving data on the benefit of SGLT2is and non-steroidal MRAs in slowing or reducing cardiorenal risk seem to provide the opportunity to use these pillars of therapy in the management of DKD, after a long-period of treatment scarcity in this field. Along with recognition of the albuminuria as a powerful marker to detect those patients at high risk of cardiorenal disease, these important developments would likely to impact standard-of-care options in the setting of DKD.

Xanthine-Dopamine Hybrid Molecules as Multitarget Drugs with Potential for the Treatment of Neurodegenerative Diseases.

Multitarget drugs based on a hybrid dopamine-xanthine core were designed as potential drug candidates for the treatment of neurodegenerative diseases. Monoamine oxidase B (MAO-B) inhibitors with significant ancillary A2A adenosine receptor (A2AAR) antagonistic properties were further developed to exhibit additional phosphodiesterase-4 and -10 (PDE4/10) inhibition and/or dopamine D2 receptor (D2R) agonistic activity. While all of the designed compounds showed MAO-B inhibition in the nanomolar range mostly combined with submicromolar A2AAR affinity, significant enhancement of PDE-inhibitory and D2R-agonistic activity was additionally reached for some compounds through various structural modifications. The final multitarget drugs also showed promising antioxidant properties in vitro. In order to evaluate their potential neuroprotective effect, representative ligands were tested in a cellular model of toxin-induced neurotoxicity. As a result, protective effects against oxidative stress in neuroblastoma cells were observed, confirming the utility of the applied strategy. Further evaluation of the newly developed multitarget ligands in preclinical models of Alzheimer's and Parkinson's diseases is warranted.

Трехмерная структура молекулы бета-лакторфина

Opioid peptides cause pain relief, sedation and sleep, as well as a euphoric state and a number of autonomic reactions. These peptides are of animal and plant origin. A number of exogenous peptides obtained from food have opiate-like properties. This peptides were named exorphins. The discovery of the opioid activity of the peptide components of food has led to the assumption that certain types of food can act on the central nervous system like opiate drugs. A number of milk exorphins have been found that have opioid receptor antagonist properties. These include casoxins A, B, C, human casoxin D, as well as lactoferroxins A, B and C, as well as alpha and beta lactorphins. The possibility of the formation of these peptides during the hydrolysis of the corresponding proteins by peptidases of the gastrointestinal tract has been proven in vitro. Representatives of exorphins are also cytochrophins and hemorphins. It is assumed that these peptides can be formed in vivo during the proteolytic cleavage of cytochrome b and hemoglobin. The beta-lactorphine molecule is a representative of this class. The conformational possibilities of the beta-lactorphine Tyr-Leu-Leu-Phe molecule were studied by the method of theoretical conformational analysis. The potential function of the system is chosen as the sum of non-valence, electrostatic and torsion interactions and the energy of hydrogen bonds. The low-energy conformations of the alpha-lactorphine molecule, the values of the dihedral angles of the main and side chains of the amino acid residues that make up the molecules were found, and the energy of intra- and interresidual interactions was estimated. It has been shown that the spatial structure of the beta-lactorphine molecule can be represented by eight forms of the main chain. The results obtained can be used to elucidate the structural and structural-functional organization of exorphin molecules.

The median effective concentration of propofol with different doses of esketamine during gastrointestinal endoscopy in elderly patients: A randomized controlled trial.

Propofol may result in hypotension, bradycardia and loss of protective reflexes, especially in elderly patients, while esketamine, a N-methyl-D-aspartate receptor antagonist, has analgesic, anaesthetic and sympathomimetic properties and is known to cause less cardiorespiratory depression. We hypothesized that esketamine may reduce the median effective concentration (EC50 ) of propofol and coadministration is less likely to produce hypotension during gastrointestinal endoscopy in elderly patients. Ninety elderly patients, aged 65-89 years, undergoing gastrointestinal endoscopy were randomly assigned into 3 groups: SK0 (control) group (0 mg/kg esketamine); SK0.25 group (0.25 mg/kg esketamine); and SK0.5 group (0.5 mg/kg esketamine). Anaesthesia was achieved by plasma target-controlled infusion of propofol with different bolus doses of esketamine. The EC50 of propofol for gastrointestinal endoscopy was determined by using the up-and-down method of Dixon. The initial plasma target concentration is 2.5 μg/mL and the adjacent concentration gradient is 0.5 μg/mL. Cardiovascular variables were also measured. Propofol EC50 s and its 95% confidence interval for gastrointestinal endoscopy in elderly patients were 3.69 (2.59-4.78), 2.45 (1.85-3.05) and 1.71 (1.15-2.27) μg/mL in the SK0, SK0.25 and SK0.5 groups, respectively (P < .05). The average percent change from baseline mean arterial pressure was -19.7 (7.55), -15.2 (7.14) and -10.1 (6.73), in the SK0, SK0.25 and SK0.5 groups, respectively (P < .001). Combination medication of propofol with esketamine reduced the propofol EC50 during gastrointestinal endoscopy in elderly patients compared with administration of propofol without esketamine. Increasing doses of SK with propofol are less likely to produce hypotension with shorter recovery time.

Neuroleptic Malignant Syndrome Applied with Targeted Temperature Management

Neuroleptic malignant syndrome (NMS) is a life-threatening neurologic emergency associated with the use of dopamine receptor-antagonist properties or the rapid withdrawal of dopaminergic medications. NMS is characterized by refractory hyperpyrexia, altered mental state, dysautonomia, and rigor. If hyperpyrexia persists, it can result in multiorgan failure. Herein, we report a case of NMS occurring after metoclopramide administration in a patient with pontine hemorrhage, which was successfully treated with targeted temperature management using a surface cooling device.

A new class of 5-HT1A receptor antagonists with procognitive and antidepressant properties.

Aims: 5-HT1A receptor antagonists constitute a potential group of drugs in the treatment of CNS diseases. The aim of this study was to search for new procognitive and antidepressant drugs among amide derivatives of aminoalkanoic acids with 5-HT1A receptor antagonistic properties. Materials & methods: Thirty-three amides were designed and evaluated in silico for their drug-likeness. The synthesized compounds were tested in vitro for their 5-HT1A receptor affinity and functional profile. Moreover, their selectivity over 5-HT7, 5-HT2Aand D2 receptors and ability to inhibit phosphodiesterases were evaluated. Results:A selected 5-HT1A receptor antagonist 20 (Ki=35nM, Kb=4.9nM) showed procognitive and antidepressant activity in vivo. Conclusion: Novel 5-HT1A receptor antagonists were discovered and shown as potential psychotropic drugs.

The Multi-Targeting Ligand ST-2223 with Histamine H3 Receptor and Dopamine D2/D3 Receptor Antagonist Properties Mitigates Autism-Like Repetitive Behaviors and Brain Oxidative Stress in Mice.

Autism spectrum disorder (ASD) is a complex heterogeneous neurodevelopmental disorder characterized by social and communicative impairments, as well as repetitive and restricted behaviors (RRBs). With the limited effectiveness of current pharmacotherapies in treating repetitive behaviors, the present study determined the effects of acute systemic treatment of the novel multi-targeting ligand ST-2223, with incorporated histamine H3 receptor (H3R) and dopamine D2/D3 receptor affinity properties, on ASD-related RRBs in a male Black and Tan BRachyury (BTBR) mouse model of ASD. ST-2223 (2.5, 5, and 10 mg/kg, i.p.) significantly mitigated the increase in marble burying and self-grooming, and improved reduced spontaneous alternation in BTBR mice (all p < 0.05). Similarly, reference drugs memantine (MEM, 5 mg/kg, i.p.) and aripiprazole (ARP, 1 mg/kg, i.p.), reversed abnormally high levels of several RRBs in BTBR (p < 0.05). Moreover, ST-2223 palliated the disturbed anxiety levels observed in an open field test (all p < 0.05), but did not restore the hyperactivity parameters, whereas MEM failed to restore mouse anxiety and hyperactivity. In addition, ST-2223 (5 mg/kg, i.p.) mitigated oxidative stress status by decreasing the elevated levels of malondialdehyde (MDA), and increasing the levels of decreased glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) in different brain parts of treated BTBR mice (all p < 0.05). These preliminary in vivo findings demonstrate the ameliorative effects of ST-2223 on RRBs in a mouse model of ASD, suggesting its pharmacological prospective to rescue core ASD-related behaviors. Further confirmatory investigations on its effects on various brain neurotransmitters, e.g., dopamine and histamine, in different brain regions are still warranted to corroborate and expand these initial data.

Design and Synthesis of Novel Aminoalkanamides Targeting Neurodegeneration and Symptoms of Alzheimer's Disease.

There is currently no drug that slows the process of neurodegeneration or alleviates the cognitive and depressive symptoms in patients with Alzheimer's disease. Due to the increasing number of Alzheimer's patients, there is an urgent need to develop novel drugs with neuroprotective, procognitive, and antidepressant properties. The aim of this study was to design, synthesize, and evaluate novel aminoalkanamides with serotonin 5-HT1A/5-HT;7 receptor affinity and phosphodiesterase (PDE) inhibitory activity as a new approach to combat neurodegeneration and symptoms of Alzheimer's disease. The newly designed compounds were synthesized using classical methods of organic chemistry and tested in vitro for their receptor affinity, functional profile, enzyme inhibition, and ADME properties. The neuroprotective effect against H2O2-induced increase of reactive oxygen species level was tested in SH-SY5Y cells. The novel object recognition and forced swimming tests were used to evaluate the procognitive and antidepressant activity, respectively. Synthesized aminoalkanamides were characterized as potent 5-HT1Areceptor antagonists with additional 5-HT7 receptor antagonistic properties and PDE4B inhibitory activity. Selected compound 15 showed neuroprotective, procognitive, and antidepressant properties. In addition, compound 15 revealed suitable ADME properties expressed as good membrane permeability and high metabolic stability. This study revealed a new class of compounds that may be useful in the search for an effective drug in the alleviation of neurodegeneration and symptoms of Alzheimer's disease.

A randomized, double-blind, placebo-controlled study to assess efficacy of mirtazapine for the treatment of diarrhea predominant irritable bowel syndrome

BackgroundAmple evidence indicates the efficacy of serotonin type 3 (5-HT3) receptor antagonists in the treatment of patients with diarrhea-predominant irritable bowel syndrome (IBS-D). Mirtazapine is an atypical antidepressant with a well-known 5-HT3 receptor antagonist property. This study, therefore, was undertaken to investigate whether compared to placebo, mirtazapine would be efficacious and safe in the treatment of patients with IBS-D.MethodsFrom November 2019 until July 2020, 67 patients meeting Rome IV criteria for IBS-D were randomized in a double-blind fashion into either the mirtazapine treatment group (n = 34) or the placebo treatment group (n = 33). Patients started with mirtazapine 15 mg/day at bedtime for one-week; after which the dose was increased to 30 mg/day for an additional 7-week. Outcomes included changes in the total IBS symptom severity score (IBS-SSS), Hospital anxiety and depression scale score (HADS), and IBS Quality of Life. Additionally, changes in the diary-based symptoms scores including pain, urgency of defecation, bloating, stool frequency, and stool consistency based on the 7-point Bristol Stool Form Scale (BSFS), and a number of days per week with pain, urgency, diarrhea, or bloating, once during the 1-week run-in period, and once during the last week of treatment were recorded.ResultsAll analyses were performed on an Intention-to-Treat (ITT) analysis data set. The results showed compared to placebo, mirtazapine is more efficacious in decreasing the severity of IBS symptoms (P-value = 0.002). Further, at the end of the treatment period, all diary-derived symptoms except bloating showed significantly more improvement in the mirtazapine-treated subjects compared to the placebo-treated subjects. While was well-tolerated, mirtazapine also significantly improved the patients’ quality of life (P-value = 0.04) and anxiety symptoms (P-value = 0.005).ConclusionsOverall, mirtazapine seems to have a potential benefit in the treatment of patients with IBS-D, particularly those with concomitant psychological symptoms. However, further studies are warranted to determine whether these findings are replicated.Trial registrationTrial registration: Registration number at Iranian Registry of Clinical Trials: IRCT20120215009014N311. Registration date: 2019-10-21.

This Month in Anesthesiology

This Month in Anesthesiology

Inverse Association between Serotonin 2A Receptor Antagonist Medication Use and Mortality in Severe COVID-19 Infection

Advanced age and medical co-morbidity are strong predictors of mortality in COVID-19 infection. Yet few studies (to date) have specifically addressed risk factors associated with COVID-19 mortality in a high-risk subgroup of older US adults having one or more chronic diseases. Our hypothesis is that medications having 'off-target' anti-inflammatory effects may play a role in modulating the immune response in COVID-19 infection. We analyzed baseline risk factors associated with respiratory failure or death in 55 older adult US military veterans hospitalized for COVID-19 infection during (March-June 2020) the peak of the pandemic in New Jersey. Fifty-three percent (29/55) of patients experienced respiratory failure and thirty-one percent (17/55) died. In adjusted logistic regression analysis, baseline neutrophil to lymphocyte ratio (NLR) (P=0.0035) and body mass index (P=0.03) were significant predictors of the risk for respiratory failure. Age (P=0.05) and non-use (vs. use) of psychotropic medications having serotonin 2A receptor antagonist properties (odds ratio 5.06; 95% confidence intervals 1.18-21.7; P= 0.029) was each a significant predictor of an increased risk of death. There was a significant interaction effect of age and non-use (vs.. use) of psychotropic serotonin 2A receptor antagonist medications on the odds ratio (OR) for death (P=0.011). In selected, ventilator-dependent COVID-19 pneumonia patients treated with psychotropic serotonin 2A receptor antagonist medications to control agitation and ICU delirium, there was an apparent positive association between medication use and significant rise in the absolute lymphocyte count and decrease in the neutrophil: lymphocyte ratio. Taken together, these data are the first to suggest that certain psychotropic medications used in the treatment of chronic psychiatric illness and/or for acute delirium are inversely associated with mortality in severe COVID-19 infection by unknown mechanism which may involve (in part) immunomodulatory effects.

Mirtazapine, an α2 Antagonist-Type Antidepressant, Reverses Pain and Lack of Morphine Analgesia in Fibromyalgia-Like Mouse Models.

Treatment of fibromyalgia is an unmet medical need; however, its pathogenesis is still poorly understood. In a series of studies, we have demonstrated that some pharmacological treatments reverse generalized chronic pain but do not affect the lack of morphine analgesia in the intermittent cold stress (ICS)-induced fibromyalgia-like pain model in mice. Here we report that repeated intraperitoneal treatments with mirtazapine, which is presumed to disinhibit 5-hydroxytriptamine (5-HT) release and activate 5-HT1 receptor through mechanisms of blocking presynaptic adrenergic α2 and postsynaptic 5-HT2 and 5-HT3 receptors, completely reversed the chronic pain for more than 4 to 5 days after the cessation of treatments. The repeated mirtazapine treatments also recovered the morphine analgesia after the return of nociceptive threshold to the normal level. The microinjection of small interfering RNA (siRNA) adrenergic α2a receptor (ADRA2A) into the habenula, which showed a selective upregulation of α2 receptor gene expression after ICS, reversed the hyperalgesia but did not recover the morphine analgesia. However, both reversal of hyperalgesia and recovery of morphine analgesia were observed when siRNA ADRA2A was administered intracerebroventricularly. As the habenular is reported to be involved in the emotion/reward-related pain and hypoalgesia, these results suggest that mirtazapine could attenuate pain and/or augment hypoalgesia by blocking the habenular α2 receptor after ICS. The recovery of morphine analgesia in the ICS model, on the other hand, seems to be mediated through a blockade of α2 receptor in unidentified brain regions. SIGNIFICANCE STATEMENT: This study reports possible mechanisms underlying the complete reversal of hyperalgesia and recovery of morphine analgesia by mirtazapine, a unique antidepressant with adrenergic α2 and serotonergic receptor antagonist properties, in a type of intermittently repeated stress (ICS)-induced fibromyalgia-like pain model. Habenula, a brain region which is related to the control of emotional pain, was found to play key roles in the antihyperalgesia, whereas other brain regions appeared to be involved in the recovery of morphine analgesia in the ICS model.

Electroencephalographic analysis in soman-exposed 21-day-old rats and the effects of midazolam or LY293558 with caramiphen.

Acute nerve agent exposure induces status epilepticus (SE), which can cause brain damage or death. Research aiming at developing effective therapies for controlling nerve agent-induced SE is commonly performed in adult rats. The characteristics of nerve agent-induced SE in young rats are less clear; relevant knowledge is necessary for developing effective pediatric therapies. Here, we have used electroencephalographic (EEG) recordings and analysis to study seizures in postnatal day 21 rats exposed to 1.2 × LD50 of soman, and compared the antiseizure efficacy of midazolam (MDZ)-currently considered by the Food and Drug Administration to replace diazepam for treating SE in victims of nerve agent exposure-with that of LY293558, an AMPA/GluK1 receptor antagonist, administered in combination with caramiphen, an antimuscarinic with N-methyl-d-aspartate receptor antagonistic properties. Prolonged SE developed in 80% of the rats and was reflected in behavioral seizures/convulsions. Both MDZ and LY293558+ caramiphen stopped the SE induced by soman, but there was a significant recurrence of seizures within 24 h postexposure only in the MDZ-treated group, as revealed in the raw EEG data and their representation in the frequency domain using a fast Fourier transform and in spectral analysis over 24 hours. In contrast to the high efficacy of LY293558 + caramiphen, MDZ is not an effective treatment for SE induced by soman in young animals.

Repurposing of Adamantanes with Transmitter Receptor Antagonist Properties for the Prevention/Treatment of COVID-19

Members of the adamantane family of agents in general and two such members, amantadine and memantine, in particular, have established beneficial actions across a wide range of infectious diseases including those caused by coronaviruses. Increasing evidence suggests that the protective effects of these agents is the result of actions on neurotransmitter systems namely the NMDA receptor subclass of the glutamatergic system and by the α7-nACh subclass of nicotinic cholinergic receptor. The potent NMDA receptor antagonist, memantine, prevents motor disabilities and reduces replication of the neuroinvasive/neurotropic human respiratory virus HCoV-OC43 dose-dependently. Moreover, the lysosomotrophic adamantanes amantadine and memantine also limit viral replication. Known lysomotrophic agents such as ammonium chloride inhibit cellular entry of SARS-CoV-2 on laboratory testing. Inhibiting clathrinmediated endocytosis (cellular entry) of the SARS-CoV-2/ACE2 complex by amantadine or rimantadine may block viral entry into vulnerable cellular populations, and also reduce platelet activating factor-priming of Polymorphonuclear [PMN] cells, potentially lessening PMN cell-mediated tissue damage and excess Neutrophil Extracellular Traps [NETs] seen in advanced cases of COVID-19. Rimantadine has inhibitory effects of SARS-CoV-1, a closely-related virus to SARS-CoV-2, which may indicate the need for further evaluation as a treatment for COVID-19. Amantadine increases Dopamine [DA] release and blocks its reuptake, increasing its action on DA receptors on T cells thus activating resting effector T cells and suppressing regulator T cells, which may have a beneficial immunomodulating function in infectious diseases. Proposed adverse effects of smoking on COVID-19 outcomes are attributed to the effects of nicotine via the α7-nACh receptor located on bronchial and alveolar epithelial cells. As an antagonist of this receptor, memantine has the potential to prevent the entry of SARSCoV- 2 into these cells. Independent case reports provide evidence of protective effects of amantadine and/or memantine against COVID-19. Additional epidemiologic studies however indicate a lower incidence of smoking in hospitalized patients, stimulating investigations of nicotine-related aspects, and amino acid sequence analysis indicate homologous sequences with those of neurotoxins seen in snake venoms blocking the α7-nAChR suggesting that COVID-19 may be a disease of the nicotinic cholinergic system; α7-nAChR is involved in the cholinergic anti-inflammatory pathway or reflex. COVID-19 is a biphasic disease, the initial aspect involved with the initial infection and viral replication which stimulates a prominent innate immune response. This then transitions to the adaptive immune response with suppression of infection and recovery, while the innate response is suppressed via the cholinergic anti-inflammatory pathway. Severe disease may occur when the initial innate immune response continues, the cholinergic anti-inflammatory pathway being arrested by the neurotoxin inherent in the viral amino acid sequence, causing a runaway innate immune response. Memantine, being an inhibitor of α7-nACHR, could possibly make COVID-19 worse should it be α7-nACHR inhibitor. Tilorone, a lysosomotrophic agent and α7-nACHR agonist could also have potential as a treatment for COVID-19. Further studies are necessary to determine whether repurposing of adamantanes is beneficial in COVID-19, and for further investigations of pharmacological and pathophysiological properties of SARS-CoV-2.

Decreased serotonin synthesis is involved in seizure-induced respiratory arrest in DBA/1 mice.

A known cause of seizure-induced respiratory arrest is the deficiency in serotonergic neurotransmission. Tryptophan hydroxylase-2 (TPH2) is the rate-limiting enzyme of central serotonin (5-hydroxytryptamine) synthesis which converts l-tryptophan to 5-hydroxytryptophan. A recent study revealed a reduction in TPH2 protein expression in the brainstems of DBA/1 mice that developed recurrent seizure-induced respiratory arrest, whereas the activity of this protein was unexplored. Thus this study aims to investigate the association between intrinsic 5-hydroxytryptamine synthesis in the brainstem and the susceptibility for sudden unexpected death in epilepsy in DBA/1 mice. The effect of LY393558, a potent 5-hydroxytryptamine reuptake inhibitor with 5-HT1B/1D receptor antagonist properties, on seizure-induced respiratory arrest evoked by acoustic stimulation was also examined in DBA/1 mice. ELISA results showed significantly decreased TPH2 activity in the brainstems of untreated DBA/1 mice than that of C57BL/6J mice. Moreover, the concentrations of 5-hydroxytryptamine, 5-hydroxytryptophan and 5-HIAA in the brainstems of DBA/1 mice with or without acoustic stimulation were significantly lower than that of C57BL/6J mice. Acute administration of LY393558 also significantly reduced seizure-induced respiratory arrest in DBA/1 mice. These observations provide novel evidences for the hypothesis that 5-hydroxytryptamine deficiency might be a potential cause of seizure-induced respiratory arrest.

SUN-019 The Selective Progesterone Receptor Modulator Ulipristal Acetate Blocks Glucocorticoid Receptor Transactivation

Progesterone is a crucial regulator of the female reproductive system, but also contributes to the pathogenesis of certain gynecological diseases. As such, selective progesterone receptor modulators (SPRMs) have shown potential for the treatment of such diseases. The SPRM Ulipristal acetate (UPA) offers a much-needed therapeutic option for the clinical management of uterine fibroids. Although UPA initially passed safety evaluations in Europe, post-marketing analysis identified cases of liver injury and hepatic failure, leading to temporary restrictions on UPA use. The structural analysis predicted low glucocorticoid receptor (GR) antagonist properties of UPA, however the anti-glucocorticoid activity of Ulipristal has been demonstrated on reporter constructs in HeLa cells. To determine whether UPA can alter the activity of endogenous GR in various relevant cell types, immortalized human uterine fibroid cells (UtLM) and hepatocytes (HepG2) were treated with the synthetic glucocorticoid dexamethasone and/or UPA. Co-treatment of 100 nM UPA with dexamethasone reduced glucocorticoid-induced expression of PER1, FKBP5, and GILZ in HepG2 and UtLM cells by 30-55%. At 1μM, UPA completely blocked glucocorticoid regulation of these genes in both cell lines. As a comparison, the extent of glucocorticoid inhibition by UPA was comparable to the known PR and GR antagonist RU 486. To discover whether the anti-glucocorticoid activity of UPA was mediated by PR, we knocked down PR expression by siRNA and found that the inhibitory activity of UPA does not require PR, suggesting a direct effect on GR. To determine the mechanism by which UPA inhibits GR activity, we evaluated hallmarks of GR transactivation. As hormone-dependent phosphorylation at S211 is associated with transcriptionally active GR, we evaluated p211 status in response to dexamethasone treatment with and without UPA. In the presence of UPA, dexamethasone-mediated phosphorylation at 211 was significantly diminished. Furthermore, dexamethasone-dependent nuclear translocation of GR was reduced by approximately 70% in both cell lines. Reduced activation of GR resulted in diminished GR recruitment to known regulatory regions in the GILZ promoter in the presence of UPA. We next evaluated the effect of UPA on glucocorticoid-mediated transcription in primary cells. Co-treatment of dexamethasone with UPA blunted glucocorticoid responsiveness in primary human uterine fibroid tissue cultured ex vivo. To determine whether UPA could inhibit endogenous glucocorticoid signaling, mice were treated with vehicle or 2 mg/kg UPA and various tissues were isolated for gene expression analysis. UPA inhibited basal expression of Per1, Fkbp5, and Gilz in the uterus and liver, and lung but not the spleen. These studies suggest that UPA selectively regulates GR activity, which is an important consideration for its use as a long-term therapeutic agent.

Concise review: Therapeutic potential of flupirtine maleate

Flupirtine is a non-opioid analgesic without antipyretic or antiphlogistic properties. Flupirtine is a centrally acting analgesic but the analgesic action of flupirtine does not depend on any central opioid effect. The fact behind this statement is that the pain-relieving property of flupirtine is not reduced by the opioid antagonistic drug naloxone. Flupirtine has been reported for its neuro-protective properties and possess a selective neuronal potassium channel opener that also has NMDA receptor antagonist properties. Flupertine is transformed into two primary derivatives, 4-fluoro-hippuric acid and the Nacetylated analogue D13223. Both derivatives of are flupirtine pharmacologically active with 30% of the analgesic potency of the parent drug and further oxidized and then conjugated with glycine to form inactive metabolites, Recently, Flupirtine maleate has been introduced in Indian market in oral, intravenous and rectal dosage forms. The half life of flupirtine following intravenous administration was 1.8 hours, while the plasma elimination half life in healthy young volunteers following single dose administration of flupirtine by the intravenous, oral and rectal routes was 8.5, 9.6 and 10.7 hours respectively. There is plenty of literature available on the effect of Flupirtine maleate on chronic and acute pain management. These preliminary finding require confirmation in further comparative studies.&#x0D; Keywords: Flupirtine maleate, Naloxone, Opioid, NMDA