1A Agonist Research Articles

A Comparative Study to Evaluate the Efficacy of Dexmedetomidine and Clonidine to Accentuate the Perioperative Analgesia of Caudal 0.25% Isobaric Levobupivacaine in Pediatric Infraumbilical Surgeries

BackgroundCaudal block is an efficient way to offer perioperative analgesia for painful sub-umbilical interventions. It enables early ambulation and periprocedural hemodynamic stability. These are important advantages over general anesthesia, notably in preterm babies and in children with cardiopulmonary comorbidities. In this study, we aimed to compare the effect of dexmedetomidine and clonidine to accentuate the perioperative analgesia of 0.25% isobaric levobupivacaine in pediatric caudal anesthesia.MethodologyA prospective double-blind randomized control study was conducted on 60 patients with the American Society of Anesthesiologists (ASA) physical status I, between the ages of one to six undergoing infraumbilical abdominal surgery under caudal anesthesia in the Department of Anaesthesia, Sardar Patel Medical College, Bikaner. Patients were randomly allocated to the following three groups of 20 each: group L, 1 mL/kg of levobupivacaine 0.25%; group LD, 1 mL/kg of levobupivacaine 0.25% with 0.5 µg/kg of dexmedetomidine; and group LC, 1 mL/kg of levobupivacaine 0.25% with 0.5 µg/kg of clonidine. Intraoperative and postoperative hemodynamic parameters were recorded for 24 hours. Patients’ pain scores, sedation scores, and Bromage scores were recorded. In our study, the main observation was the duration of analgesia and the total analgesic requirement for 24 hours.ResultsThere was a significant difference in the duration of analgesia among the three groups (p < 0.001). Group LC had the highest duration of analgesia of 492.00 (50.01) minutes, followed by group LD 486.00 (54.71) minutes, and the lowest in group L 291.00 (40.25) minutes. There was a significant difference between the three groups in terms of the total dose of analgesics in 24 hours (p < 0.001), with the median total dose of analgesics being the highest in Group L. Three groups differed significantly in terms of motor block, which was limited to up to 180 minutes in groups LC and LD with no residual motor block.ConclusionsThe addition of α2 agonists such as clonidine or dexmedetomidine at a dose of 0.5 µg/kg as an adjuvant to caudal levobupivacaine (0.25%) at 1 mL/kg significantly prolongs the duration of opioid-free analgesia in children undergoing infraumbilical abdominal surgeries without prolonging the motor blockade and any side effects. Moreover, dexmedetomidine does not offer a significant advantage over clonidine regarding the analgesia duration.

Abstract P3054: Alpha-1a Adrenergic Receptor Activation Increases Electron Transport Chain Activity And Preserves Cardiac Contractility Following Myocardial Infarction

Heart failure features decreased electron transport chain (ETC) activity in cardiomyocyte mitochondria. Previous studies have demonstrated that alpha-1A adrenergic receptor (α1A-AR) activation increases cardiac contractility in the failing heart. However, α1A-AR activation as a method of ETC regulation following cardiac injury has not been studied. Here, we assessed the hypothesis that α1A-AR activation increases ETC activity following myocardial infarction (MI) induced by left coronary artery ligation. We measured cardiac contractility using echocardiography at baseline and 7 days after MI in male CL57Bl/6J mice receiving the selective α1A-AR agonist A61603 (10 ng/kg/d) (n = 8) or vehicle (0.9% saline) (n = 9) via subcutaneous osmotic minipumps (Panel A). We then profiled citrate synthase (CS), a key enzyme in the citric acid cycle and common marker for mitochondrial mass, and ETC Complex I-IV activities in ventricular lysates. ETC enzyme activities were normalized to CS to define ETC capacity on a per mitochondrion basis. On Day 0, there were no differences in fractional shortening between groups (Panel B, 46 ± 3% vs. 49 ± 3%, p = 0.27) (mean ± SEM). On Day 7, fractional shortening was preserved in A6-treated mice compared to vehicle controls (Panel B, 24 ± 3% vs. 14 ± 1%, p = 0.01). A6 decreased CS activity compared to vehicle controls (Panel C, 11,024 ± 1,035 vs. 15,966 ± 1,068 nmol/mg/min, p &lt; 0.01). When normalized to CS activity, A6 increased Complex I (16 ± 2% vs. 7 ± 1%, p &lt; 0.01) (1,584 ± 116 vs. 1,106 ± 154 nmol/min/mg), Complex III (82 ± 8% vs. 56 ± 5%, p = 0.01) (8,435 ± 461 vs. 8,542 ± 327 nmol/min/mg), and Complex IV (121 ± 12% vs. 92 ± 9.%, p = 0.04) (12,523 ± 673 vs. 14,174 ± 1,156) activities (Panel D), suggesting enhanced ETC activity on a per mitochondrion basis. In conclusion, we show that a low dose of a selective α1A-AR agonist enhances cardiac contractility following MI. Increased ETC enzyme activity, particularly Complex I, may contribute to this beneficial effect. Ours is the first study in which selective α1A-AR activation has been linked to enhanced cardiac contractility and mitochondrial metabolism following MI. These findings may outline a novel mechanism through which α1A-AR activation preserves cardiac function in the injured and failing heart.

Trace Amine-Associated Receptor 1 Agonists for Schizophrenia

TAAR1 agonists are an emerging drug class in the treatment of schizophrenia as they may offer a novel mechanism of action for symptom management without blocking dopamine D2 receptors, unlike currently available antipsychotic medications that act primarily via D2 binding. Two TAAR1 agonists are currently in clinical development for schizophrenia. The first is ulotaront, a TAAR1 full agonist with 5-hydroxytryptamine 1A agonist activity that is administered orally once daily, and the other is ralmitaront, a TAAR1 partial agonist that is also administered orally once daily. The published clinical trial evidence on TAAR1 agonists currently only pertains to ulotaront, which includes a 4-week, phase II, placebo-controlled randomized trial on patients with acute exacerbation of schizophrenia and a 26-week, open-label extension study of this same trial. These studies demonstrated improvements across disease-specific and global impression scales following treatment with ulotaront, with statistically significant differences compared to placebo, and no increased risk of the side effects (extrapyramidal symptoms and metabolic changes) associated with traditional D2-binding antipsychotic therapies. There is currently no cost information available for TAAR1 agonists. Ulotaront is currently undergoing phase III trials and, though it is not currently approved in any country and the date of Health Canada licensing and marketing in Canada is not yet known, it is expected to be the first TAAR1 agonist for schizophrenia in the Canadian market. Ulotaront received Breakthrough Therapy designation from the FDA in 2019 to expedite its development and the drug’s manufacturer is planning to file a New Drug Application with the FDA in 2023. Ralmitaront is currently in phase II trials, which are expected to be completed in 2023.

Dexmedetomidine-induced polyuria in the intensive care unit: a case report

Abstract Dexmedetomidine is an α2 agonist that is frequently used for sedation in intensive care units (ICUs). Hypotension and bradycardia are common adverse effects observed in clinical practice. In perioperative conditions, polyuria is a rare adverse effect with limited case reports after dexmedetomidine infusion. Similar to this situation, in ICU, there are rare cases. We present the case of a 59-year-old man who developed polyuria secondary to high-dose intravenous dexmedetomidine infusion in the medical ICU.

Diffuse noxious inhibitory controls and conditioned pain modulation: a shared neurobiology within the descending pain inhibitory system?

Diffuse noxious inhibitory controls and conditioned pain modulation: a shared neurobiology within the descending pain inhibitory system?

Midazolam-Dexmedetomidine Combination versus Midazolam Alone for Premedication in Children Undergoing Pediatric Cataract Surgeries: a Double‐Blinded Randomized Controlled Trial

Background: Dexmedetomidine, a selective α2 agonist has shown promising results when used as a premedicant. This prospective randomized study evaluated the efficacy of two different premedication regimens in achieving a smooth conduct of anesthesia and optimum pain relief in pediatric cataract surgeries. Methods: 90 ASA I or II children, aged 1-6 years, scheduled for elective cataract surgeries were randomized to receive either 0.25 mg kg-1oral midazolam and 1μg kg-1 of intranasal dexmedetomidine (Group MD; n=45) or 0.5mg/kg oral midazolam followed by 0.02ml kg-1 intranasal saline drops (Group MS; n=45) 45 min prior to surgery. Drug acceptance, anxiety at parental separation and quality of mask induction was evaluated. Subtenon block was given to all the children. Intraoperative use of narcotics was avoided and used only as rescue drug. Primary outcome of the study was number of patients requiring rescue analgesia over 24-hour period. The secondary outcomes were time to first rescue analgesia, frequency of rescue analgesia, incidence of OCR and PONV. Results: 90% of the children in Group MD achieved MOAA/S ≤ 4 at 30 minutes versus 95% in Group MS. Drug acceptability, parental separation and mask acceptance were similar in both groups. Incidence of PONV and children who required rescue analgesia was less in MD group compared with MS group. There was no event of OCR in both groups. Conclusion: Premedication with combined IND and low dose oral midazolam is superior in decreasing postoperative analgesic requirements when compared to routine oral midazolam premedication alone in pediatric cataract surgeries under general anesthesia.

The selective 5-HT 1A receptor agonist, NLX-112, overcomes tetrabenazine-induced catalepsy and depression-like behavior in the rat.

Tetrabenazine, a preferential inhibitor of the vesicular monoamine transporter type 2, depletes the brain monoamines dopamine, serotonin and norepinephrine. Tetrabenazine and deutetrabenazine (Austedo ®) are used to treat chorea associated with Huntington's disease. However, both compounds are known to aggravate Parkinsonism and depression observed in Huntington's disease patients. NLX-112 (a.k.a. befiradol/F13640) is a highly selective, potent and efficacious serotonin 5-HT 1A agonist. In animal models, it has robust efficacy in combating other iatrogenic motor disorders such as L-DOPA-induced dyskinesia and has marked antidepressant-like activity in rodent tests. In the present study, we investigated, in rats, the efficacy of NLX-112 to counteract tetrabenazine-induced catalepsy (a model of Parkinsonism) and tetrabenazine-induced potentiation of immobility in the forced swim test (FST, a model to detect antidepressant-like activity). The prototypical 5-HT 1A agonist, (±)8-OH-DPAT, and the 5-HT 1A partial agonist/dopamine D2 receptor blocker, buspirone, were used as comparators. Both NLX-112 and (±)8-OH-DPAT (0.16-2.5 mg/kg p.o. or s.c., respectively) abolished catalepsy induced by tetrabenazine (2 mg/kg i.p.). In comparison, buspirone (0.63-5.0 mg/kg p.o.) was ineffective and even tended to potentiate tetrabenazine-induced catalepsy at 0.63 mg/kg. In the FST, NLX-112 and (±)8-OH-DPAT (0.63 mg/kg) strongly reduced immobility when administered alone but also significantly opposed potentiation of immobility induced by tetrabenazine (1.5 mg/kg i.p.). Buspirone (0.63 and 2.5 mg/kg p.o.) had no effect by itself or against tetrabenazine. These results strongly suggest that selective and highly efficacious 5-HT 1A agonists, such as NLX-112, may be useful in combating tetrabenazine-induced Parkinsonism and/or depression in Huntington's disease patients.

CHANGES OF VASCULAR REACTIVITY TO ADENOSINE A1 AND A2A RECEPTOR AGONISTS AFTER HYPERBARIC OXYGENATION

Objective: Hyperbaric oxygenation (HBO) affects vascular reactivitiy, which plays an important role in the pathophysiology of hypertension and other cardiovascular diseases. New data suggest important effects of HBO on oxidative stress and alteration of production of vasoactive metabolites in blood vessels; however, the role of adenosine A1 and A2a receptors is still underinvestigated.This study aimed to determine the functional role of adenosine A1 and A2a receptors in changes of vascular reactivity in isolated middle cerebral arteries (MCA) of Spague-Dawley rats, after acute and intermittent HBO. Design and method: Male and female healthy Sprague-Dawley rats aged 8–10 weeks were divided into 3 groups: CTRL (control non HBO), A-HBO (single animals exposed to HBO for 2 hours) and 4D-HBO (animals exposed to HBO at a pressure od 2 bars for 2 hours daily for 4 days, with vascular experiments conducted on the fifth day). The rats were anesthetized with ketamine-chloride (3 ml/kg) and midazolam (0,5 ml/kg) and decapitated. The MCA were isolated, cannulated and pressurized for 60’at 80 mmHg to assess basal diameter using pressure myograph Danish Myo Technology. A1 adenosin receptor selective agonist CCPA or A2a adenosin receptor agonist CGS in concentrations from 10–5 to 10–10 M were added to the vessel chamber, and blood vessel diameter was measured after incubation of the drug for 15 minutes. Statistical analyses were performed with Two-way ANOVA tests; p &lt; 0.05 was considered significant. Results: The vasoconstriction in response to A1 agonist administration was similar between the CTRL and 4D-HBO group, while it was significantly reduced in A-HBO compared to the CTRL and 4D-HBO groups. The vasodilation in response to A2a stimulation was significantly reduced in rats exposed to A-HBO and I-HBO compared to CTRL at higher drug concentrations (10–7 to 10–5 M). Conclusions: Acute exposure of rats to HBO leads to decrease in the vasoconstrictive response to adenosine A1 receptor stimulation, while acute and intermittent exposure of rats to HBO is associated with a decrease in the vasodilatory response of MCA to adenosine A2a receptor activation, suggesting that HBO alters sensitivity to or expression of receptors.

Design, synthesis and evaluation of amino-3,5-dicyanopyridines and thieno[2,3-b]pyridines as ligands of adenosine A1 receptors for the potential treatment of epilepsy.

Due to the implication of adenosine in seizure suppression, adenosine-based therapies such as adenosine receptor (AR) agonists have been investigated. This study aimed at investigating thieno[2,3-b]pyridine derivatives as non-nucleoside A1 agonists that could be used in pharmaco-resistant epilepsy (PRE). Compound 7c (thieno[2,3-b]pyridine derivative), displayed good binding affinity to the rA1 AR (Ki = 61.9 nM). This could be a breakthrough for further investigation of this heterocyclic scaffold as potential ligand. In silico evaluation of this compound raised bioavailability concerns but performed well on drug-likeness tests. The effect of intramolecular cyclisation that occurs during synthesis of thieno[2,3-b]pyridines from the lead compounds, amino-3,5-dicyanopyridine derivatives (6a-s) in relation to AR binding was also evaluated. A significant loss of activity against rA1/rA2A ARs with cyclisation was revealed. Amino-3,5-dicyanopyridines exhibited greater affinity towards rA1 ARs (Ki < 10 nM) than rA2A. Compound 6c had the best rA1 affinity (Ki = 0.076 nM). Novel compounds (6d, 6k, 6l, 6m, 6n, 6o, 6p) were highly selective towards rA1 AR (Ki between 0.179 and 21.0 nM). Based on their high selectivity for A1 ARs, amino-3,5-dicyanopyridines may be investigated further as AR ligands in PRE with the right structural optimisations and formulations. A decrease in rA1 AR affinity is observed with intramolecular cyclisation that occurs during synthesis of thieno[2,3-b]pyridines (7a, 7d, 7c) from amino-3,5-dicyanopyridine derivatives (6a, 6f, 6g).

The Role of miRNAs in Dexmedetomidine's Neuroprotective Effects against Brain Disorders.

There are limited neuroprotective strategies for various central nervous system conditions in which fast and sustained management is essential. Neuroprotection-based therapeutics have become an intensively researched topic in the neuroscience field, with multiple novel promising agents, from natural products to mesenchymal stem cells, homing peptides, and nanoparticles-mediated agents, all aiming to significantly provide neuroprotection in experimental and clinical studies. Dexmedetomidine (DEX), an α2 agonist commonly used as an anesthetic adjuvant for sedation and as an opioid-sparing medication, stands out in this context due to its well-established neuroprotective effects. Emerging evidence from preclinical and clinical studies suggested that DEX could be used to protect against cerebral ischemia, traumatic brain injury (TBI), spinal cord injury, neurodegenerative diseases, and postoperative cognitive disorders. MicroRNAs (miRNAs) regulate gene expression at a post-transcriptional level, inhibiting the translation of mRNA into functional proteins. In vivo and in vitro studies deciphered brain-related miRNAs and dysregulated miRNA profiles after several brain disorders, including TBI, ischemic stroke, Alzheimer’s disease, and multiple sclerosis, providing emerging new perspectives in neuroprotective therapy by modulating these miRNAs. Experimental studies revealed that some of the neuroprotective effects of DEX are mediated by various miRNAs, counteracting multiple mechanisms in several disease models, such as lipopolysaccharides induced neuroinflammation, β-amyloid induced dysfunction, brain ischemic-reperfusion injury, and anesthesia-induced neurotoxicity models. This review aims to outline the neuroprotective mechanisms of DEX in brain disorders by modulating miRNAs. We address the neuroprotective effects of DEX by targeting miRNAs in modulating ischemic brain injury, ameliorating the neurotoxicity of anesthetics, reducing postoperative cognitive dysfunction, and improving the effects of neurodegenerative diseases.

Nicotinamide improves in vitro lens regeneration in a mouse capsular bag model

BackgroundMammalian lens regeneration holds great potential as a cataract therapy. However, the mechanism of mammalian lens regeneration is unclear, and the methods for optimization remain in question.MethodsWe developed an in vitro lens regeneration model using mouse capsular bag culture and improved the transparency of the regenerated lens using nicotinamide (NAM). We used D4476 and SSTC3 as a casein kinase 1A inhibitor and agonist, respectively. The expression of lens-specific markers was examined by real-time PCR, immunostaining, and western blotting. The structure of the in vitro regenerated lens was investigated using 3,3′-dihexyloxacarbocyanine iodide (DiOC6) and methylene blue staining, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), and transmission electron microscopy.ResultsThe in vitro lens regeneration model was developed to mimic the process of in vivo mammalian lens regeneration in a mouse capsular bag culture. In the early stage, the remanent lens epithelial cells proliferated across the posterior capsule and differentiated into lens fiber cells (LFCs). The regenerated lenses appeared opaque after 28 days; however, NAM treatment effectively maintained the transparency of the regenerated lens. We demonstrated that NAM maintained lens epithelial cell survival, promoted the differentiation and regular cellular arrangement of LFCs, and reduced lens-related cell apoptosis. Mechanistically, NAM enhanced the differentiation and transparency of regenerative lenses partly by inhibiting casein kinase 1A activity.ConclusionThis study provides a new in vitro model for regeneration study and demonstrates the potential of NAM in in vitro mammalian lens regeneration.

Hypoglycosylated Follistatin‐Like 1 Attenuates the Loss of Coronary and Cerebral Vascular Functional Capacity in Ossabaw Swine with Cardiometabolic Heart Failure with Reduced Ejection Fraction

Ischemic heart disease is a leading cause of death, often resulting from heart failure caused by myocardial infarction. Diabetic cardiomyopathy is increasingly problematic clinically, with the combination of metabolic syndrome and chronic inflammation greatly increasing the risk for both coronary and cerebral vascular disease. Follistatin‐like 1 (FSTL1) is a protein that, when non‐glycosylated, displays regenerative properties including pro‐angiogenic effects and prevention of abnormal vascular remodeling. Thus, the objective of the current study was to assess the therapeutic benefit of human recombinant non‐glycosylated FSTL1 protein on both coronary and cerebral vascular function in a pre‐clinical Ossabaw swine model of myocardial infarction (MI). We hypothesized FSTL1 would attenuate the development of coronary and cerebral vascular dysfunction in an experimental setting of cardiometabolic heart failure with reduced ejection fraction (HFrEF). Intact female Ossabaw swine (2 months old) were fed a Western Diet for 4 months to develop metabolic syndrome. At 6 months of age, animals were subjected to 90 minutes ischemia followed by reperfusion (I/R) to induce MI. One month post‐MI, ALZET osmotic pumps were implanted and either vehicle (MI group) or FSTL1 (MI+FSTL1 group) was delivered over two weeks, with terminal vascular experiments performed 2 months post‐MI. In vitroassessment of isolated coronary (n=5‐6 for infarct, border, and remote regions of the left ventricle; 139.5 ± 4.9 μm diameter) and cerebral (n=2‐6 for middle cerebral artery second order pial; 385.3 ± 18.7 μm diameter) arteriole function was examined using pressure myography. Dose response curves for: 1) U46619 (thromboxane A2 agonist); and 2) NS‐1619 (large‐conductance calcium‐activated potassium channel activator; BKCa) were conducted. A 2x2 ANOVA (Group X Dose) was used to determine significance at the p &lt; 0.05 level. Cardiometabolic HFrEF was indicated by a combined ejection fraction of 38 ± 2% and a fasting HOMA‐IR of 3.8 ± 0.4 (vs. 0.6 ± 0.1 historical control). In coronary arterioles, the NS‐1619 induced vasodilatory capacity was increased ~18‐fold in MI+FSTL1 animals relative to MI (100 ± 13% vs. 1832 ± 3% in MI and MI+FSTL1, respectively) in the remote region of the heart (interaction effect), but not the infarct nor border regions. In cerebral arterioles, the vasoconstrictor capacity in response to U46619 was increased ~2‐fold in MI+FSTL1 relative to MI animals (100 ± 19% vs. 213 ± 25% in MI and MI+FSTL1, respectively; interaction effect). In conclusion, FSTL1 partially attenuates the loss of functional capacity in both coronary and cerebral arterioles, demonstrating its potential to improve vascular function in an experimental setting of cardiometabolic HFrEF.

Activation of Nrf2 in Mice Causes Early Microvascular Cyclooxygenase-Dependent Oxidative Stress and Enhanced Contractility.

Nuclear factor erythroid factor E2-related factor 2 (Nrf2) transcribes antioxidant genes that reduce the blood pressure (BP), yet its activation with tert-butylhydroquinone (tBHQ) in mice infused with angiotensin II (Ang II) increased mean arterial pressure (MAP) over the first 4 days of the infusion. Since tBHQ enhanced cyclooxygenase (COX) 2 expression in vascular smooth muscle cells (VSMCs), we tested the hypothesis that tBHQ administration during an ongoing Ang II infusion causes an early increase in microvascular COX-dependent reactive oxygen species (ROS) and contractility. Mesenteric microarteriolar contractility was assessed on a myograph, and ROS by RatioMaster™. Three days of oral tBHQ administration during the infusion of Ang II increased the mesenteric microarteriolar mRNA for p47phox, the endothelin type A receptor and thromboxane A2 synthase, and increased the excretion of 8-isoprostane F2α and the microarteriolar ROS and contractions to a thromboxane A2 (TxA2) agonist (U-46,619) and endothelin 1 (ET1). These were all prevented in Nrf2 knockout mice. Moreover, the increases in ROS and contractility were prevented in COX1 knockout mice with blockade of COX2 and by blockade of thromboxane prostanoid receptors (TPRs). In conclusion, the activation of Nrf2 over 3 days of Ang II infusion enhances microarteriolar ROS and contractility, which are dependent on COX1, COX2 and TPRs. Therefore, the blockade of these pathways may diminish the early adverse cardiovascular disease events that have been recorded during the initiation of Nrf2 therapy.

Comparison of dexmedetomidine and remifentanil infusion in geriatric patients undergoing outpatient cataract surgery: a prospective, randomized, and blinded study.

Dexmedetomidine is an α2 agonist and remifentanil is a short-acting μ opioid agonist. We aimed to compare the dexmedetomidine and remifentanil infusions used for conscious sedation in geriatric patients undergoing outpatient cataract surgery in terms of sedation quality, side effects, and surgeon satisfaction. Eighty patients were allocated into two groups as per the administration of dexmedetomidine (dexmedetomidine group) and remifentanil (remifentanil group) infusion in this randomized, prospective, double-blinded study. In dexmedetomidine group (n = 40), after a loading of 1 μg/kg dexmedetomidine in 10 minutes, 0.4 μg/kg/h infusion was administered. In the remifentanil group (n = 40), remifentanil at a dose of 0.05 μg/kg was administered for 10 minutes, and then 0.05 μg/kg/min infusion was continued. Observer Assessment Warning/Sedation Scale values evaluating sedation quality were lower in the dexmedetomidine group than in the remifentanil group, although it was not statistically significant (P > 0.05). Bispectral Index values evaluating sedation quality were lower in the dexmedetomidine group according to the remifentanil group (P < 0.05). The dexmedetomidine group had lower Verbal Rating Scale and Visual Analogue Scale scores evaluating pain intensity compared with the remifentanil group (P < 0.05). The nausea Visual Analogue Scale values evaluating the severity of postoperative nausea in the dexmedetomidine group were lower than those in the remifentanil group (P < 0.05). The surgeon satisfaction was found to be greater in the dexmedetomidine group compared with the remifentanil group (P = 0.015). In geriatric patients, the targeted sedation and analgesia levels were achieved more easily with dexmedetomidine infusion, without hemodynamic and respiratory side effects, compared to remifentanil infusion.

Serotonin 1A Receptor Pharmacotherapy and Neuroplasticity in Spinal Cord Injury.

Spinal cord injury is associated with damage in descending and ascending pathways between brainstem/cortex and spinal neurons, leading to loss in sensory-motor functions. This leads not only to locomotor reduction but also to important respiratory impairments, both reducing cardiorespiratory engagement, and increasing cardiovascular risk and mortality. Moreover, individuals with high-level injuries suffer from sleep-disordered breathing in a greater proportion than the general population. Although no current treatments exist to restore motor function in spinal cord injury (SCI), serotoninergic (5-HT) 1A receptor agonists appear as pharmacologic neuromodulators that could be important players in inducing functional improvements by increasing the activation of spared motoneurons. Indeed, single therapies of serotoninergic 1A (5-HT1A) agonists allow for acute and temporary recovery of locomotor function. Moreover, the 5-HT1A agonist could be even more promising when combined with other pharmacotherapies, exercise training, and/or spinal stimulation, rather than administered alone. In this review, we discuss previous and emerging evidence showing the value of the 5HT1A receptor agonist therapies for motor and respiratory limitations in SCI. Moreover, we provide mechanistic hypotheses and clinical impact for the potential benefit of 5-HT1A agonist pharmacology in inducing neuroplasticity and improving locomotor and respiratory functions in SCI.

Clinical evaluation of dexmedetomidine versus clonidine as an adjuvant to bupivacaine in subarachnoid block for gynecological procedure

Background and Aim: Clonidine is a partial α2 adrenergic agonist used intrathecally with well-established efficacy and safety profile with effective prolongation of both motor and sensory spinal blockade. Dexmedetomidine, another member of α2 agonist’s family, is recently being introduced in Indian market and is approved as an intravenous sedative and co-analgesic drug. This study examines and compares the usefulness and safety of dexmedetomidine versus clonidine as an adjuvant to bupivacaine in subarachnoid block for gynecological vaginal surgeries. Material and Methods: Hundred patients, aged 30-60 years of ASA Physical status I and II, scheduled for elective gynecological vaginal surgery were enrolled in this study. Patients were randomly allocated to one of the two groups of 50 patients each by distributing sealed envelopes. Group C (n=50) received 0.5% hyperbaric Bupivacaine 2.5ml + 0.5ml distilled water containing 30µgm clonidine intrathecally. Group D (n=50) received 0.5% hyperbaric Bupivacaine 2.5ml +0.5ml distilled water containing 5µg Dexmedetomidine intrathecally. The sensory block was assessed by skin sensation to pin prick. The motor block was assessed according to the Modified Bromage Scale. Hemodynamic variables were recorded at 1, 3, 5, 10, 15, 20, 30 minutes and then at 15 minutes interval throughout the surgical period.

Clinical Pharmacology Of Dobutamine In Infants And Children

Dobutamine resembles dopamine structurally but possess a bulky aromatic substituent on the amino group. The pharmacological effects of dobutamine are due to direct interaction with α and β receptors. Dobutamine possess a centre of asymmetry, the (-) isomer of dobutamine is a potent α1 agonist and can cause marked pressor response. In contrast, (+) dobutamine is a potent α1 receptor antagonist which can block the effect of (-) dobutamine. Both isomers are full agonist at β receptors; the (+) isomer is a more potent β agonist than the (-) isomer by about 10-fold. Dobutamine is indicated for the short-term treatment of cardiac decompensation that may occur after cardiac surgery and dobutamine is used in the treatment of hypotension especially if related to myocardial dysfunction. Dobutamine is administered by continuous intravenous infusion and the initial dose is 5 µg/kg per min in infants and children. Some authors stated that dopamine is more effective than dobutamine in increasing blood pressure whereas other authors observed that dobutamine and dopamine produce similar pressure response. Dobutamine is methylated and is also conjugated with glucuronic acid. The elimination half-life of dobutamine is 25.6 min in infants and children but it ranges in a wide interval. The treatment of infants and children with dobutamine has been extensively studied and some authors observed that dobutamine increase the blood pressure and decreases vascular resistance. The aim of this study is to review the dobutamine dosing, effects, metabolism, pharmacokinetics, and treatment.

The Anxiolytic Drug Buspirone Prevents Rotenone-Induced Toxicity in a Mouse Model of Parkinson's Disease.

A pharmacological and genetic blockade of the dopamine D3 receptor (D3R) has shown to be neuroprotective in models of Parkinson’s disease (PD). The anxiolytic drug buspirone, a serotonin receptor 1A agonist, also functions as a potent D3R antagonist. To test if buspirone elicited neuroprotective activities, C57BL/6 mice were subjected to rotenone treatment (10mg/kg i.p for 21 days) to induce PD-like pathology and were co-treated with increasing dosages of buspirone (1, 3, or 10 mg/kg i.p.) to determine if the drug could prevent rotenone-induced damage to the central nervous system (CNS). We found that high dosages of buspirone prevented the behavioural deficits caused by rotenone in the open field test. Molecular and histological analyses confirmed that 10 mg/kg of buspirone prevented the degeneration of TH-positive neurons. Buspirone attenuated the induction of interleukin-1β and interleukin-6 expression by rotenone, and this was paralleled by the upregulation of arginase-1, brain-derived neurotrophic factor (BDNF), and activity-dependent neuroprotective protein (ADNP) in the midbrain, striatum, prefrontal cortex, amygdala, and hippocampus. Buspirone treatment also improved mitochondrial function and antioxidant activities. Lastly, the drug prevented the disruptions in the expression of two neuroprotective peptides, pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP). These results pinpoint the neuroprotective efficacy of buspirone against rotenone toxicity, suggesting its potential use as a therapeutic agent in neurodegenerative and neuroinflammatory diseases, such as PD.

Reversal of mitochondrial dysfunction and right ventricular failure after chronic treatment with alpha-1A-adrenergic agonist

Recently we reported that right ventricular failure (RVF) was reversed by chronic treatment with the α1A-adrenergic receptor (α1A-AR) agonist A61603 (PMID 30412439). Reversal of RVF involved an increased level of the mitochondrial anti-apoptotic protein Bcl-2, suggesting that protection of mitochondria played a role.

Varenicline improves cognitive impairment in a mouse model of mPFC ischemia: The possible roles of inflammation, apoptosis, and synaptic factors

Ischemia in the medial prefrontal cortex (mPFC) causes cognitive impairment in stroke cases. This study aimed to examine the effects of varenicline as α7 and α4β2 nicotine acetylcholine receptors (nAChRs) agonist, on cognitive impairment, inflammation, apoptosis, and synaptic dysfunction in mPFC ischemia. Mice were divided to three groups of control, sham, or photothrombotic mPFC ischemia model. The control and sham groups received 2 ml/kg of normal saline for a 14-day period. As well, the animals in the ischemia groups received normal saline (2 ml/kg) or varenicline at 0.1, 1, and 3 mg/kg doses for a 14-day period. Anxiety-like behaviors were then assessed by open field (OFT) and elevated plus-maze (EPM) tests. Memory was also evaluated using Morris water maze (MWM) and novel object recognition (NOR) tests. The levels of inflammatory (IL-1β, TNF-α), apoptotic (Bax, caspase3, BCL-2), and synaptic (SYP, PSD-95, and GAP-43) proteins were examined using the western blot method. In addition, the histological evaluation was performed to assess tissue damage. The administration of Varenicline at the dose of 3 mg/kg reduced the IL-1β, TNF-α, Bax, and caspase3 levels. Moreover, it increased BCL-2, SYP, PSD-95, and GAP-43 levels at the same dose and ameliorated memory impairment and anxiety-like behaviors in mPFC ischemic mice. Varenicline improved cognitive impairment by blocking inflammation and apoptosis, improving synaptic factors, and diminishing tissue damage in the mPFC ischemic mice.