Alpha 2-adrenoceptor Agonist Research Articles

The alpha2-adrenoceptor agonist clonidine protects against hypoxic-ischemic brain damage in neonatal mice through the Nrf2/NF-κB signaling pathway

Neonatal hypoxic-ischemic brain damage (HIBD) is a severe condition closely associated with neuroinflammation and oxidative stress. Clonidine, a selective α2-adrenergic receptor agonist, is known for its anti-inflammatory and antioxidant properties. Despite these recognized therapeutic benefits, the exact mechanisms by which clonidine exerts its effects in the context of HIBD are not fully understood. This study was designed to thoroughly investigate the impact of clonidine on HIBD-induced neuronal injury and to clarify its underlying mechanism of action. We employed a neonatal mouse model of HIBD to meticulously assess the effects of clonidine on neuronal injury, apoptosis, inflammation, and oxidative stress markers. In addition, we conducted extensive in vitro studies to evaluate the neuroprotective effects of clonidine on primary hippocampal neuronal cells, utilizing advanced techniques such as the Cell Counting Kit-8 (CCK-8), flow cytometry, enzyme-linked immunosorbent assay (ELISA), immunofluorescence assay, and western blotting. Furthermore, we explored the regulatory effects of clonidine on the nuclear factor erythroid 2-related factor (Nrf2)/nuclear factor-κB (NF-κB) signaling pathway through a combination of in vivo and in vitro experiments. The results showed that clonidine significantly reduced cerebral infarction, neuronal damage, and apoptosis in HIBD mice. It also alleviated neuroinflammation and oxidative stress, improved cell viability, and reduced neuronal injury following oxygen-glucose deprivation/reoxygenation (OGD/R). The neuroprotective effects of clonidine were linked to the activation of the Nrf2/heme oxygenase-1 (HO-1) pathway and the inhibition of the NF-κB pathway. Overall, clonidine exhibited neuroprotective properties in HIBD by reducing neuroinflammation and oxidative stress, likely through the modulation of the Nrf2/NF-κB signaling pathway.

Intrathecal Fentanyl versus Intrathecal Dexmedetomidine as an Adjuvant to Isobaric Levobupivacaine 0.5% in Elective Cesarean Sections: A Randomized Control Trial

Background: When a cesarean section is performed, it is crucial to have access to good postoperative analgesia. To achieve this, adjuvants are added along with local anesthetics as it has a synergistic action to improve its duration and quality. Alpha-2 adrenoceptor agonists and opioids such as dexmedetomidine and fentanyl, respectively, are used for their sedative, analgesic, and perioperative sympatholytic and cardiovascular stabilizing effects with reduced anesthetic requirements. The purpose of this research is to evaluate the effects of intrathecal fentanyl versus dexmedetomidine combined with levobupivacaine on postoperative analgesia and hemodynamic changes. Materials and Methods: This is a prospective randomized control trial, among 50 patients undergoing elective cesarean section. Group 1 will receive 0.5% levobupivacaine 2 ml + fentanyl 25 mcg and Group 2 will receive 0.5% levobupivacaine + dexmedetomidine 5 mcg. Duration of analgesia and onset and duration of sensory-motor block, perioperative analgesic requirements, sedation, and hemodynamic stability were compared. The data were entered into Microsoft Excel and analyzed using SPSS 16. Results: The baseline characteristics such as age and gender, weight, height, and body mass index were not statistically significant in both the groups. Duration of analgesia was significantly longer in the dexmedetomidine group than the fentanyl group. The mean time of onset of motor block in the group, for which dexmedetomidine was 14.23 ± 1.85 min and it was found to be much earlier than the local anesthetic group. All the patients in the dexmedetomidine group had a Visual Analog Scale (VAS) score of 0 (no pain) at the end of 4 h. In contrast, only 21 patients in the fentanyl group had a VAS score of 0, and four patients had a VAS score of 2, indicating mild pain requiring no treatment. Conclusion: The study showed that both fentanyl and dexmedetomidine as an adjuvant to levobupivacaine in cesarean section showed a longer duration of analgesia with increased sedation score and lesser pain score. When comparing the both, dexmedetomidine to the levobupivacaine has a more effective effect on postoperative pain management than fentanyl.

Designing Chromane Derivatives as α2A-Adrenoceptor Selective Agonists via Conformation Constraint.

Enhancing the selectivity of alpha2-adrenoceptor (α2A-AR) agonists remains an unresolved issue. Herein, we reported the design of an α2A-AR agonist using the conformation constraint method, beginning with medetomidine. The structure-activity relationship indicated that the 8-substituent of chromane derivatives exerted the most pronounced effect on α2A-AR agonistic activity. Compounds A9 and B9 were identified as the most promising, exhibiting EC50 values of 0.78 and 0.23 nM, respectively. Their selectivity indexes surpassed dexmedetomidine (DMED) by 10-80 fold. In vivo studies demonstrated that both A9 and B9 dose-dependently increased the loss of righting reflex in mice, with ED50 values of 1.54 and 0.138 mg/kg, respectively. Binding mode calculations and mutation studies suggested the indispensability of the hydrogen bond between ASP1283.32 and α2A-AR agonist. In particular, A9 and B9 showed no dual reverse pharmacological effect, a characteristic exhibited by DMED in α2A-AR activation.

Tizanidine: Advances in Pharmacology & Therapeutics and Drug Formulations.

Skeletal muscle relaxants (SMRs) are widely used in treating musculoskeletal conditions. All SMRs, with the exception of baclofen and tizanidine, are on the list of 2023 American Geriatrics Society Beers Criteria® for potentially inappropriate medication use in older adults. In our geriatric practice, off-label use of tizanidine as preemptive analgesia drove us to find recent advances in its pharmacology and therapeutics. An update review of tizanidine was thus presented, aiming to bring the latest knowledge to clinicians and promote further research and practical exploration. Relevant literature up to December 2023 was identified through searches of PubMed, Web of Science, and Embase. Tizanidine, a centrally acting alpha-2 adrenoceptor agonist with both antispastic and antispasmodic activity, shows efficacy in the common indications for all SMRs. From the perspective of drug safety, tizanidine has lower incidences of adverse events (injury, delirium, encephalopathy, falls, and opioid overdose) compared to baclofen, no association with risk of Alzheimer's disease as with orphenadrine, no risk of serotonin syndrome like metaxalone when comedicated with serotonergic drugs, no significant pharmacokinetic changes in CYP2C19 poor metabolizers unlike diazepam and carisoprodol, and no physically addictive or abuse properties like carisoprodol and diazepam. From the perspective of new and potential therapeutic uses, tizanidine has additional benefits (eg, gastroprotection that can improve patient tolerance to nonsteroidal anti-inflammatory agents, anti-neuropathic pain, a key component of multimodal analgesia strategy to reduce early postoperative pain, and anti-tumor effects). New delivery systems of tizanidine are developing to improve the pharmacokinetics of oral products, including buccal patches, transdermal delivery systems, nasal spray, and in situ rectal gel. Tizanidine is an SMR with unique features and may be an optimal initial choice for older adults. There would be more scientific studies, wider therapeutic applications, and new drug formulations in the future.

Novel drug treatments for pain in advanced cancer and serious illness: a focus on neuropathic pain and chemotherapy-induced peripheral neuropathy.

Drugs that are commercially available but have novel mechanisms of action should be explored as analgesics. This review will discuss haloperidol, miragabalin, palmitoylethanolamide (PEA), and clonidine as adjuvant analgesics or analgesics. Haloperidol is a sigma-1 receptor antagonist. Under stress and neuropathic injury, sigma-1 receptors act as a chaperone protein, which downmodulates opioid receptor activities and opens several ion channels. Clinically, there is only low-grade evidence that haloperidol improves pain when combined with morphine, methadone, or tramadol in patients who have cancer, pain from fibrosis, radiation necrosis, or neuropathic pain. Miragabalin is a gabapentinoid approved for the treatment of neuropathic pain in Japan since 2019. In randomized trials, patients with diabetic neuropathy have responded to miragabalin. Its long binding half-life on the calcium channel subunit may provide an advantage over other gabapentinoids. PEA belongs to a group of endogenous bioactive lipids called ALIAmides (autocoid local injury antagonist amides), which have a sense role in modulating numerous biological processes in particular non-neuronal neuroinflammatory responses to neuropathic injury and systemic inflammation. Multiple randomized trials and meta-analyses have demonstrated PEA's effectiveness in reducing pain severity arising from diverse pain phenotypes. Clonidine is an alpha2 adrenoceptor agonist and an imidazoline2 receptor agonist, which is U.S. Federal Drug Administration approved for attention deficit hyperactivity disorder in children, Tourette's syndrome, adjunctive therapy for cancer-related pain, and hypertension. Clonidine activation at alpha2 adrenoceptors causes downstream activation of inhibitory G-proteins (Gi/Go), which inhibits cyclic Adenosine monophosphate (AMP) production and hyperpolarizes neuron membranes, thus reducing allodynia. Intravenous clonidine has been used in terminally ill patients with poorly controlled symptoms, in particular pain and agitation.

Foreign body ingestion due to detachment of pill dispenser tips in cats: a retrospective study of 13 cases.

The aim of this study was to evaluate and describe 13 cases in which a pet piller broke during the administration of medication, and the tip was accidentally ingested by the cat. A total of 15 presentations to the clinic were identified in a private practice database involving 13 cats in which the silicone tip broke. Two of these cats ingested foreign bodies on two separate occasions. Routine radiographic examination enabled the identification of silicone tips in all animals. On 2/15 occasions, the cats did not receive an emetic drug. Intramuscular xylazine (0.2 mg/kg) and dexmedetomidine (6 μg/kg) were administered to 12/15 and 1/15 cats, respectively. The cats were aged 3-17 years (mean age 11.00 ± 4.35 years). Vomiting occurred in 13 cats that received alpha-2 adrenoceptor agonists, although the silicone tip was recovered in only five occurrences. In 9/15 occurrences, endoscopy was performed under general inhalation anesthesia, and the silicone tip was successfully removed. Natural elimination occurred in only one case. The use of pet pillers with detachable silicone tips increases the risk of accidental foreign body ingestion by animals. Therefore, guidelines regarding safety standards for manufacturing would be beneficial. No cat in this series developed clinical signs related to the ingestion of the piller tip, probably because of the quick presentation by the owners and early intervention, including endoscopic retrieval. Surgical intervention was not required in any case, including one in which the foreign body was lodged within the small intestine before being passed naturally by the cat.

Dexmedetomidine alleviates pulmonary fibrosis through the ADORA2B-Mediated MAPK signaling pathway

BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronically progressive fibrotic pulmonary disease characterized by an uncertain etiology, a poor prognosis, and a paucity of efficacious treatment options. Dexmedetomidine (Dex), an anesthetic-sparing alpha-2 adrenoceptor (α2AR) agonist, plays a crucial role in organ injury and fibrosis. However, the underlying mechanisms of IPF remain unknown.MethodsIn our study, the role of Dex in murine pulmonary fibrosis models was determined by Dex injection intraperitoneally in vivo. Fibroblast activation and myofibroblast differentiation were assessed after Dex treatment in vitro. The activation of MAPK pathway and the expression of Adenosine A2B receptor (ADORA2B) were examined in lung myofibroblasts. Moreover, the role of ADORA2B in Dex suppressing myofibroblast differentiation and pulmonary fibrosis was determined using the ADORA2B agonist BAY60-6583.ResultsThe results revealed that Dex could inhibit Bleo-induced pulmonary fibrosis in mice. In vitro studies revealed that Dex suppressed TGF-β-mediated MAPK pathway activation and myofibroblast differentiation. Furthermore, Dex inhibits myofibroblast differentiation and pulmonary fibrosis via downregulating ADORA2B expression.ConclusionsOur findings suggest Dex as a potential therapeutic agent for pulmonary fibrosis. Dex may alleviate lung fibrosis and myofibroblast differentiation through the ADORA2B-mediated MAPK signaling pathway.

The Limited Use Of Dexmedetomidine For Subarachnoid Blocks In Pakistan.

Respected Madam, Dexmedetomidine is a selective alpha-2 adrenoceptor agonist. It acts by binding to the presynaptic alpha-2 adrenoceptors and inhibits the release of norepinephrine. Thereafter, it causes a decrease in the sympathetic tone and terminates the propagation of pain signals. As a result, the haemodynamic and the endocrine stress responses of the body to surgery and anesthesia are attenuated, the blood pressure and heart rate are decreased, and the requirement for other anaesthetic agents is reduced. These effects have meant that dexmedetomidine has been widely used prior to endotracheal intubation to optimize the patients and prevent the likelihood of hemodynamic adverse effects (1). In addition to its use in general anesthesia, peri-operative physicians worldwide are now becoming increasingly aware of the dexmedetomidine’s potential usefor subarachnoid blocks. A few studies have documented the efficacy of intravenous (IV) dexmedetomidine in prolonging the duration of sensory and motor blockade induced by agents such as bupivacaine, prilocaine, and ropivacaine up to 4 hours (2), (3). Recent studies have found that intrathecal administration of dexmedetomidine in combination with the local anesthetic agent yields similar benefits (4). This has been attributed to the activation of presynaptic alpha2-A receptors at locus ceruleus and the termination of pain signal propagation via the medullospinal noradrenergic pathway (4). Therefore, it is no surprise that the use of dexmedetomidine in conjunction with local anesthetics for the subarachnoid block is common practice in peri-operative physicians throughout the globe. While Pakistani peri-operative physicians are aware of the benefits of dexmedetomidine prior to endotracheal intubation (5), the same cannot be said for subarachnoid blocks induced in Pakistan. Peri-operative physicians in Pakistan are either yet to realize the potential benefits the use of dexmedetomidine can provide for subarachnoid blocks or still adhere to conventional spinal anesthesia practices. Since the effects of a conventional subarachnoid block last from 2 to 3 hours, in any case of a surgical adverse event that prolongs the surgery, severe pain, nausea, vomiting, and derangement of the hemodynamic status have been noted in patients. Often times, this results in a shift towards general anesthesia midway through the procedure. Ultimately, the postoperative stay is prolonged which directly impacts the clinical outcome and the quality of life for these patients. ---Continue

0038 Genioglossus muscle (GG) activity evoked by pharmacological stimulation of alpha1-adrenoceptors in pre-hypoglossal region (PHR)

Abstract Introduction The sleep-related withdrawal of noradrenergic excitation and increased cholinergic inhibition of hypoglossal motoneurons (HM), which control the tone of the GG, the largest protruder muscle of the tongue, play a critical role in obstructive sleep apnea pathophysiology. In an animal model of REM sleep, antagonism of alpha1 noradrenergic signaling by microinjections of prazosin into the hypoglossal nucleus (HN) strongly decreased hypoglossal nerve activity. However, a significant delay of this decrease prompted a hypothesis that prazosin must diffuse outside the HN to block alpha1-adrenoceptors that are located on interneurons, which mediate noradrenergic drive to HM. Here, we aimed to map the PHR by microinjecting alpha1 drugs for possible location of these interneurons. Methods Adult C57bl/6J mice (n=28) of both sexes were anesthetized with either ketamine/xylazine (120/20 mg/kg, i.p.) or 1.5-2.0% isoflurane inhaled through a nose mask. Electromyogram electrodes were implanted into GG and diaphragm to record their activity. We microinjected phenylephrine (alpha1-adrenoceptor agonist, 5-10 nl, 1 mM) in both ketamine/xylazine- and isoflurane-anesthetized mice, while prazosin (10 nl, 0.2 mM) was injected only in mice under isoflurane anesthesia. The injection sites were marked with Pontamine Skye Blue. After the completion of experiments, all animals were perfused, and brains removed for histological analysis. Results The activity of GG showed spontaneous phasic inspiratory modulation with minimal tonic component under both anesthesia conditions although its amplitude was markedly lager in animals anesthetized by isoflurane. Effective microinjections of phenylephrine elicited short-lasting (approximately 15 minutes) excitatory GG responses. When injected into the HN, phenylephrine strongly excited GG as compared to injections to the PHR in ketamine/xylazine-anesthetized mice. However, in isoflurane-anesthetized animals, microinjections of phenylephrine into the PHR induced greater activation of GG than injections onto the HN. Microinjections of prazosin in isoflurane-anesthetized mice produced long-lasting disfacilitation of GG activity. However, prazosin injections into the PHR elicited responses with the shortest latencies (0-120 s). Conclusion These results suggest that the putative interneurons that mediate noradrenergic drive to HM are located in the PHR. This finding is important for deciphering the neuronal network that controls the state-dependent activity of GG, which may provide new therapeutic targets for OSA treatment. Support (if any) NIHR01HL133847, NIAR01AG065233.

Comparative evaluation of sedative and anti-nociceptive effects of epidural romifidine, romifidine-lidocaine, and lidocaine in donkeys (Equus asinus).

Local and regional anesthetic procedures are valuable tools in veterinary practice. Caudal epidural administration of local anesthetic agents is widely reported for surgical interventions of the tail, anus, rectum, vulva, vagina, urethra, and bladder in the standing horse. Epidural analgesia is also obtained using various drugs such as alpha-2 adrenoceptor agonists, dissociative anesthetics, and opioids. The present study evaluates the anti-nociceptive and sedative effects of epidural administration of romifidine, a romifidine-lidocaine combination, and lidocaine alone in donkeys. In a randomized prospective study, twenty-four healthy adult donkeys were assigned to four groups (three experimental and one control; n = 6) received either 50 μg/kg of romifidine, 0.30 mg/kg of lidocaine, combined romifidine (50 μg/kg) and lidocaine (0.30 mg/kg) diluted in 0.9% sterile normal saline solution to a total injection volume of 12 ml, or an equivalent volume of sterile saline epidurally. After epidural injection of each treatment, the onset, degree, and duration of sedation and anatomical extension of anti-nociception were documented. Observations began immediately (time 0) pre-administration and at 5, 15, 30, 45, 60, and 30-min intervals subsequently until 210 min after drug injection. Time to onset of perineal analgesia was documented every minute after the epidural injection by evaluating the animal's response to pinpricks. Only romifidine and romifidine-lidocaine induced mild to moderate sedation. Romifidine, romifidine-lidocaine, and lidocaine induced complete bilateral caudal epidural analgesia with loss of sensation in the perineum, tail, inguinal region, caudal aspect of the upper hind limb, chest areas, and extended distally to the dorsal metatarsal area. Sedation lasted longer (p < 0.05) with romifidine (160 ± 15.4 min) than with romifidine-lidocaine (141.6 ± 13.2 min). Longer-lasting analgesia (p < 0.05) was obtained with romifidine (158.3 ± 9.8 min) and romifidine-lidocaine (165 ± 9.4 min) than with lidocaine (75.8 ± 8 min). Epidural administration of a single dose of romifidine or a combination of romifidine-lidocaine produced mild to moderate sedation and complete anti-nociception in the perineal and inguinal regions of donkeys. The clinical usefulness of epidural romifidine or romifidine-lidocaine combinations to perform obstetric procedures in donkeys needs to be assessed.

Tasipimidine, a novel orally administered alpha-2 adrenoceptor agonist, alleviates canine acute anxiety associated with owner departure—A pilot study

Separation anxiety in dogs is a problematic behavior characterized by anxiety that occurs exclusively in the owner's absence or virtual absence, resulting in owner complaints of destructiveness, excessive vocalization, and elimination in the home. The consequences of separation anxiety may include that the owners surrender their dog to a shelter, or even have the dog euthanized. Adrenergic alpha-2 agonists have been shown to be effective in alleviating acute canine fear-based behavior problems at subsedative doses. In this study, the objective was to assess the efficacy of tasipimidine, a novel orally administered adrenergic alpha-2 agonist, in alleviating acute anxiety associated with owner departure in dogs. Twelve clinically healthy privately-owned dogs with a history of separation anxiety were enrolled in a double-blind, placebo-controlled, crossover clinical field study consisting of three 4-day treatment periods in randomized order each followed by a 3-day washout. In each treatment period a different treatment was administered. The three treatments were: placebo, tasipidimine 10ug/kg and tasipidimine 30 ug/kg, all prepared as an oral solution using the same base. At each of the 4-day treatment period study treatment was administered once daily one hour before owner´s departure. Effects of treatment on signs of separation anxiety were assessed by the owner using video recordings. Owner departure related acute anxiety severity score, dog's alertness, usability of the product and adverse events were recorded. Overall, the results showed a statistically significant treatment effect favoring tasipimidine (P= 0.001). When the doses were separately compared to placebo, the dog owners rated the effect of the study treatment more often positively after administering tasipimidine 30 µg/kg compared to placebo (OR 5.40; 95% CI 1.15-25.2; P = 0.032). A statistically significant reduction with the 30 µg/kg dose was seen in destructive/rearranging behavior (P = 0.006) and vocalization (P = 0.036). Most of the dogs were scored to be fully responsive at all time points (66.7%) and able to stand up and walk normally (91.7%), and none of the dogs was scored to be unresponsive or unable to walk. No serious adverse events were reported. The majority of the owners found the product very easy (75.0%) or easy (15.7%) to use. This was a small, cross-over study with one target to select the clinically most suitable dose. Tasipimidine should be further studied in a larger parallel group study to further evaluate its effect as a treatment option for dogs suffering from separation anxiety.

Potential effects of commonly applied drugs on neural stem cell proliferation and viability: A hypothesis-generating systematic review and meta-analysis.

Neural stem cell (NSC) transplantation is an emerging and promising approach to combat neurodegenerative diseases. While NSCs can differentiate into neural cell types, many therapeutic effects are mediated by paracrine, “drug-like” mechanisms. Neurodegenerative diseases are predominantly a burden of the elderly who commonly suffer from comorbidities and thus are subject to pharmacotherapies. There is substantial knowledge about drug-drug interactions but almost nothing is known about a potential impact of pharmacotherapy on NSCs. Such knowledge is decisive for designing tailored treatment programs for individual patients. Previous studies revealed preliminary evidence that the anti-depressants fluoxetine and imipramine may affect NSC viability and proliferation. Here, we derive a hypothesis on how commonly applied drugs, statins and antihypertensives, may affect NSC viability, proliferation, and differentiation. We conducted a systematic review and meta-analysis looking at potential effects of commonly prescribed antihypertensive and antihyperlipidemic medication on NSC function. PubMed and Web of Science databases were searched on according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Publications were assessed against a priori established selection criteria for relevancy. A meta-analysis was then performed on data extracted from publications eligible for full text review to estimate drug effects on NSC functions. Our systematic review identified 1,017 potential studies, 55 of which were eligible for full text review. Out of those, 21 were included in the qualitative synthesis. The meta-analysis was performed on 13 publications; the remainder were excluded as they met exclusion criteria or lacked sufficient data to perform a meta-analysis. The meta-analysis revealed that alpha-2 adrenoceptor agonists, an anti-hypertensive drug class [p < 0.05, 95% confidence intervals (CI) = –1.54; –0.35], and various statins [p < 0.05, 95% CI = –3.17; –0.0694] had an inhibiting effect on NSC proliferation. Moreover, we present preliminary evidence that L-type calcium channel blockers and statins, particularly lovastatin, may reduce NSC viability. Although the data available in the literature is limited, there are clear indications for an impact of commonly applied drugs, in particular statins, on NSC function. Considering the modes of action of the respective drugs, we reveal plausible mechanisms by which this impact may be mediated, creating a testable hypothesis, and providing insights into how future confirmative research on this topic may be conducted.

Intranasal Dexmedetomidine as Sedative for Non-Invasive Pediatric Diagnostic Procedures Outside Operating Room

Background: Children often require sedation for long non-invasive diagnostic procedures. Dexmedetomidine is a highly selective alpha 2-adrenoceptor agonist with sedative, anxiolytic and analgesic properties. It mimics natural sleep and allows patients to easily arouse with minimal effects on respiration and airway patency. Objective: To assess the successful completion of pediatric non-invasive diagnostic procedures with intranasal dexmedetomidine as a sedative agent. Methods: Seventy-nine subjects of age six months to twelve years scheduled for non-invasive diagnostic procedures were included. Dexmedetomidine (4 mcg/kg) was administered intranasally 25 minutes before the scheduled time of procedure. A sedation score of two or above as per the MICHIGAN sedation scale was considered satisfactory for starting the procedure. Results: Seventy-four (95%) out of the seventy-nine subjects were successfully sedated with Intranasal dexmedetomidine (p

Dexmedetomidine-Induced Aortic Contraction Involves Transactivation of the Epidermal Growth Factor Receptor in Rats.

In this study, we examined whether aortic contraction, induced by the alpha-2 adrenoceptor agonist dexmedetomidine, is involved in the transactivation of the epidermal growth factor receptor (EGFR) in isolated endothelium-denuded rat aortas. Additionally, we aimed to elucidate the associated underlying cellular mechanisms. The effects of the alpha-2 adrenoceptor inhibitor rauwolscine, EGFR tyrosine kinase inhibitor AG1478, Src kinase inhibitors PP1 and PP2, and matrix metalloproteinase inhibitor GM6001 on EGFR tyrosine phosphorylation and c-Jun NH2-terminal kinase (JNK) phosphorylation induced by dexmedetomidine in rat aortic smooth muscles were examined. In addition, the effects of these inhibitors on dexmedetomidine-induced contraction in isolated endothelium-denuded rat aorta were examined. Dexmedetomidine-induced contraction was inhibited by the alpha-1 adrenoceptor inhibitor prazosin, rauwolscine, AG1478, PP1, PP2, and GM6001 alone or by a combined treatment with prazosin and AG1478. AG1478 (3 × 10−6 M) inhibited dexmedetomidine-induced contraction in isolated endothelium-denuded rat aortas pretreated with rauwolscine. Dexmedetomidine-induced EGFR tyrosine and JNK phosphorylation were inhibited by rauwolscine, PP1, PP2, GM6001, and AG1478. Furthermore, dexmedetomidine-induced JNK phosphorylation reduced upon EGFR siRNA treatment. Therefore, these results suggested that the transactivation of EGFR associated with dexmedetomidine-induced contraction, mediated by the alpha-2 adrenoceptor, Src kinase, and matrix metalloproteinase, caused JNK phosphorylation and increased calcium levels.

Dexmedetomidine versus propofol sedation in flexible bronchoscopy: a randomized controlled trial

BackgroundDexmedetomidine (DEX), is a highly selective alpha2 adrenoceptor (α2-AR) agonist, successfully used in various procedures including flexible bronchoscopy. Randomized controlled trials (RCTs) evaluating DEX sedation during bronchoscopy report equivocal results regarding respiratory and hemodynamic outcomes.MethodsWe conducted an RCT to evaluate the efficacy and safety of dexmedetomidine compared to propofol for sedation during bronchoscopy. The primary outcome was the number of desaturation events, secondary outcomes were transcutaneous Pco2 level, hemodynamic adverse events and physician and patient satisfaction.ResultsOverall, 63 patients were included, 30 and 33 in the DEX and propofol groups, respectively. The number of desaturation events was similar between groups, median (IQR) 1 (0–1) and 1 (0–2) in the DEX and control groups, respectively (P = 0.29). Median desaturation time was 1 (0–2) and 1 (0–3) minutes in the DEX and control groups, respectively (P = 0.48). Adverse events included hypotension, 33% vs 21.1% in intervention and control groups, respectively (P = 0.04), bradycardia, cough, and delayed recovery from sedation. Total adverse events were 22 and 7 in DEX and propofol groups, respectively (P = 0.009).ConclusionDexmedetomidine sedation during bronchoscopy did not show differences in oxygen saturation and transcutaneous CO2 level in comparison to propofol. Moreover, DEX sedation required a significantly higher number of rescue boluses, due to inadequate sedation and was associated with a higher rate of adverse events.Trial registration NCT04211298, registration date: 26.12.2019.

The first report of clonidine in vivo/in vitro effects on infertile women with polycystic ovary syndrome (in vivo/in vitro study)

The sympathetic nervous system (SNS) is hyperactive in women with polycystic ovary syndrome (PCOS). This study was designed in two sections: in vivo/in vitro with clonidine as the alpha-2 adrenoceptor (ADR-α2) agonist for modulating this hyperactivity. Eighty women with PCO participated in this randomised clinical trial (in vivo). A clonidine (0.1 mg) tablet was given twice a day for two months. Polycystic ovary morphology (PCOM) and pregnancy rate were the main outcome measurements. In the candidates for in vitro fertilisation (IVF), clonidine was added to the culture medium during IVF for two study groups (PCO-clonidine/PCO-without) and two control groups (egg donors-clonidine/egg donors-without). Our results showed that the pregnancy rate significantly was higher in the study group (p = .002). The mRNA expression of ADR-α1 and ADR-β2 in PCO was higher than control group (p value <.001). But ADR-α1 expression in PCO-clonidine group decreased (p value = .042), the same as ADR-α2 expression. The intensity of this effect showed a pattern for ADR-α1<ADR-β2<ADR-α2. Increase of antral follicle count (AFC) growth and pregnancy rate indicate the significant role of ADR-α2 in PCOS. Clonidine reduced gene expression and protein levels, confirming the above results. These results would aid in pharmacological treatments, as well as assisted reproductive technologies (ARTs). Impact Statement What is already known on this subject? In women with PCOS, sympathetic nerve activity is higher than in healthy women. Clonidine is widely used as an alpha-2 presynaptic adrenoceptor (autoreceptor) agonist to modulate the output of the sympathetic nervous system (SNS). Our in vivo/in vitro results showed that the optimal dose of clonidine can increase the oocyte maturity and pregnancy rate in PCO women. This finding was also confirmed by the results in cumulus cell culture. What do the results of this study add? The results of administration of 0.2 mg of clonidine (in vivo) for oocyte maturation and pregnancy rate confirms the in vitro response in the cumulus cell culture of PCO women's follicle. What are the implications of these findings for clinical practice and/or further research? These findings can be used in pharmacological treatment of anovulation and assisted reproductive technology (ART).

Comparison of the anti-nociceptive effect of dexmedetomidine with that of clonidine immediately prior to propofol injection in alleviating propofol injection pain

Background: Propofol is the drug of choice for induction of anaesthesia because of its rapid onset and short duration of action, easy titration, and favourable profile for side effects. But three out of five patients experience pain on injection of propofol. Alleviation of Propofol injection pain (PIP) is thus a major concern and several interventions have been investigated to alleviate the pain associated with propofol injection. Clonidine was found to alleviate the pain of injected propofol effectively. Dexmedetomidine is also an alpha-2 adrenoceptor agonist but is more selective than clonidine and has analgesic and sedative properties. The aim of the study was to compare the anti-nociceptive effect of dexmedetomidine with that of clonidine immediately prior to propofol injection in alleviating propofol injection pain.Methods: A randomized controlled study was conducted on 60 patients admitted in Malla Reddy Institute of Medical Sciences, undergoing elective surgeries under general anaesthesia (GA) for 2 years from October 2015 to September 2017. The patients were randomly divided into two groups (30 each). Group A was administered intravenous injection clonidine 0.5 µg/kg. Group B was administered intravenous injection dexmedetomidine 0.5 µg/kg.Results: In the present study, difference between the study groups in their mean age, mean weight, gender, ASA grading was not found to be statistically significant. The difference between the groups in incidence of pain on propofol injection was found to be significant statistically. The mean baseline heart rate was declining and mean arterial blood pressure was increasing in both the groups but the difference was not found to be statistically significant.Conclusions: Pre-treatment with 0.5 µg/kg of IV dexmedetomidine is more effective as compared to IV clonidine in alleviating propofol injection pain.

Comparing the effects of dexmedetomidine and dexamethasone as perineural adjuvants on peripheral nerve block: A PRISMA-compliant systematic review and meta-analysis.

Dexmedetomidine (Dexm), a selective alpha-2 adrenoceptor agonist, and dexamethasone (Dexa), a very potent and highly selective glucocorticoid, have both been proven effectively to prolong the duration of local anesthetics (LA) in regional anesthesia. However, data comparing the efficacy of Dexm and Dexa as perineural adjuvants are inconsistent. Therefore, this systematic review and meta-analysis of randomized and quasi-randomized controlled trials (RCTs) was conducted to compare the effects of Dexm and Dexa when used as LA adjuvants on peripheral nerve block (PNB). We systematically searched PubMed, Cochrane Library, EMBASE, Web of Science, and ScienceDirect databases up to October, 2020. The primary outcome was the duration of analgesia. Secondary outcomes included incidence of rescue analgesia, cumulative opioid consumption, time required for onset of sensory and motor blockades, duration of sensory and motor blockades, incidence of postoperative nausea and vomiting (PONV), and side effect-associated outcomes (e.g., bradycardia, sedation, hypotension, rates of infection, and neurological complications). The study was registered on PROSPERO, number CRD42020188796. After screening of full-text relevant articles, 13 RCTs that met the inclusion criteria were retrieved for this systematic review. It was revealed that perineural Dexm provided equivalent analgesic duration to perineural Dexa. Besides, the intake of Dexm increased the incidence of rescue analgesia in limbs surgery, as well as the cumulative opioid consumption, and decreased the time required for onset of sensory and motor blockades for long-acting LA (all P < .05). Other analysis revealed insignificant difference between the 2 groups in terms of the incidence of PONV (P > .05). Additionally, 2 studies demonstrated that Dexm possesses more sedative properties than Dexa (P < .05). This meta-analysis indicated that the analgesic duration of Dexm and Dexa as LA adjuvants in PNB is the same. Meanwhile, the effects of perineural Dexm and Dexa on some secondary outcomes, including the incidence of rescue analgesia, cumulative opioid consumption, and time required for onset of sensory and motor blockades, are associated with the surgical site and type of LA.

Early extubation after liver transplantation: Is dexmedetomidine a good option?: A retrospective cohort study.

Dexmedetomidine is a potent and highly selective alpha-2 adrenoceptor agonist with sympatholytic, sedative, anxiolytic and analgesic properties. The aim of this study is to determine the effect of a dexmedetomidine infusion in liver transplant recipients in the early postoperative period on early and smooth extubation. We performed a retrospective chart review of 21 patients undergoing liver transplantation between December 1, 2018 and February 31, 2020. Patients were divided into the dexmedetomidine and midazolam groups. The primary outcome was the extubation time. Secondary outcomes were mean arterial pressure and heart rate before and after extubation. The collected data included the patients' age, gender, surgery time, Model for End-stage Liver Disease score, cold ischemia time, blood transfusion amount and extubation visual analogue scale (VAS) scores. Extubation time was significantly shorter in the dexmedetomidine group than in the midazolam group (median [minimum-maximum], 4 [0-6], 8 [4-13] hours, respectively, P = .000). Extubation VAS scores were statistically significantly lower in dexmedetomidine group (P = .000). Mean arterial pressure values before and after extubation were significantly higher in patients' midazolam group than the dexmedetomidine group (P = .003, P = .005, respectively). Dexmedetomidine infusions provided early and smooth extubation with stable haemodynamics in our patients.

Эффективность и безопасность различных лекарственных форм бримонидина при глаукоме и офтальмогипертензии

Purpose. To present data on the mechanism of action, efficacy, and side effects of various brimonidine dosage forms in the treatment of glaucoma and ocular hypertension. Material and methods. To perform the review, literature sources were searched through the PubMed and Scopus databases up to and including 2021, using the keywords «brimonidine», «efficacy», «safety», «glaucoma medication». A total of 36 articles related to the topic of the review were selected. The beginning of publications on this topic dates back to 1995. Results. Brimonidine, an alpha2-adrenoceptor agonist, effectively reduces intraocular pressure and can be used as monotherapy, adjuvant and replacement therapy. The effectiveness of brimonidine is similar to that of timolol and prevails over betaxolol but inferior to prostaglandin analogues. The new drug formulation brimonidine-purite 0.15% has a more favorable safety and tolerability profile than the original brimonidine 0.2% while maintaining similar efficacy. However, most patients require two or more hypotensive medications to maintain target IOP. In this context, brimonidine is one of the most appropriate drugs because of its pr oven efficacy when combined with other classes of hypotensive drugs. Conclusion. Brimonidine can be used as monotherapy for glaucoma and ophthalmic hypertension. Experimental and clinical studies have shown a potential neuroprotective effect of brimonidine, which is associated with a direct effect on retinal cells, regardless of the effect of the drug on intraocular pressure. Key words: glaucoma, brimonidine, hypotensive drops, intraocular pressure.