Alpha-adrenergic Receptors Research Articles

Electronic medical records-based retrospective, longitudinal, observational study to understand the patient management of benign prostatic hyperplasia with alpha-blockers monotherapy in Indian population.

The present retrospective study evaluates the effectiveness and tolerability of alpha-blockers as monotherapy in patients with benign prostatic hyperplasia associated with lower urinary tract symptoms (LUTS). A total of 335 male patients >50 years were categorized into four groups (Alfuzosin: 166, Silodosin: 67, Tamsulosin: 70, Prazosin: 32). The efficacy evaluated as a change in International Prostate Symptom Score (IPSS), peak flow rate (Qmax), residual urine volume, and relief from LUTS, and tolerability of the various alpha-blockers was assessed across the study group. At baseline, most of the patients in alfuzosin (60%), silodosin (77%), and tamsulosin (90%) groups presented with severe IPSS (20-35), whereas patients in the prazosin group (69%) presented with a moderate score. At the end of the study, the mean IPSS gradually improved to moderate (41%, 62%, 66%, and 28%) and mild (59%, 38%, 28%, and 72%) in the alfuzosin, silodosin, tamsulosin, and prazosin groups, respectively (P = 0.004), with improvement in mean change in residual urine volume and complete relief from LUTS symptoms with no surgical or radiological interventions. Overall, 194 adverse events (AEs) were observed in 38.8% of patients. Of the total AEs, patients in the alfuzosin, silodosin, tamsulosin, and prazosin groups experienced 21%, 22%, 39%, and 18% of AEs, respectively. The nonselective alpha-adrenergic receptor antagonist, alfuzosin, emerged as noninferior in effectiveness and superior in tolerability than other selective alpha-blockers, silodosin, tamsulosin, and prazosin.

Compared Dexmedetomidine and Fentanyl on Sensory-Motor Block in Unilateral Intrathecal Anesthesia of Lower-limbs Orthopedic Surgeries: A Randomized Duble-blind Trials

Background: One of the alternatives for lower-limb orthopedic surgery is spinal anesthesia. It can affect the hemodynamic status and cause the prolonged motor and sensory blocks, as well as urinary retention, which are less common in the unilateral technique. Different drugs are used to improve the quality of the block and reduce its complications. Dexmedetomidine, a selective alpha-2 adrenergic receptor agonist, and fentanyl, an opioid medication, could administration as an adjuvant to increase the intrathecal block quality. Hence, this study aimed to compare unilateral spinal anesthesia with bupivacaine/dexmedetomidine (BD) and bupivacaine/fentanyl (BF) regimes on the sensory-motor block among patients with lower-limb orthopedic surgeries. Materials and Method: This randomized, double-blind clinical trial was performed on 36 patients who underwent lower-limb orthopedic surgeries in Qaem Hospital, Mashhad, Iran. The patients were randomly divided into two groups. Patients who received 5.7 mg hyperbaric bupivacaine 0.5% plus 10 µg fentanyl (BF group) or 5 µg dexmedetomidine (BD group) were administered for inducing unilateral spinal anesthesia. Patients and investigators responsible for data collection were not awarded from allocation groups. The sensory-motor block level, duration, postoperative analgesia, and complications were recorded and compared between the two groups. Results: No significant difference was observed between the two groups in hemodynamic changes (i.e., systolic and diastolic blood pressure and heart rate) before and after the blockage (P˃0.05). Also, there was no difference in the sensory-motor block level and anesthesia-related complications between BF and BD groups (P˃0.05). Conclusion: In patients for whom the use of opioids for unilateral spinal anesthesia is contraindicated, dexmedetomidine could be considered an appropriate alternative.

Dexmedetomidine alleviates intestinal barrier dysfunction and inflammatory response in mice via suppressing TLR4/MyD88/NF-κB signaling in an experimental model of ulcerative colitis.

Ulcerative colitis (UC) is a nonspecific intestinal inflammatory disease. Dexmedetomidine (DEX) is a selective alpha 2-adrenergic receptor agonist commonly used for analgesia and sedation in intensive care units. Herein, the role and mechanism of DEX in dextran sulfate sodium (DSS)-induced colitis was explored. A murine model of DSS-induced colitis was established by adding 3.5% (w/v) DSS in drinking water to C57BL/6J female mice. The severity of colitis was measured by the disease activity index (DAI) score, colon length and body weight of mice. The serum concentration and mRNA levels of inflammatory cytokines in colon tissues were assessed by ELISA and RT-qPCR, respectively. Protein levels of apoptotic markers, tight junction proteins and genes involved in the TLR4/MyD88/NF-κB signaling were quantified utilizing Western blotting. The pathological changes of colon tissues were evaluated by hematoxylin-eosin (HE) staining and histological score. Intestinal permeability in vivo was assessed by fluorescein isothiocyanate (FITC)-dextran (FITC-D) administration. TUNEL assay was used to determine cell apoptosis in the intestinal epithelium. DSS administration resulted in weight loss, shortening of the colon, increased DAI score, histological abnormalities, and increased serum FITC-D levels in mice, all of which were reversed by DEX injection. Moreover, DEX attenuated DSS-triggered inflammatory response, intestinal barrier injury and intestinal epithelial cell apoptosis. Mechanically, DEX inactivated the TLR4/MyD88/NF-κB signaling in the colon tissues. DEX exerts beneficial effects against the intestinal barrier dysfunction, inflammatory response, and apoptosis of intestinal epithelial cells via inactivation of the TLR4/MyD88/NF-κB signaling in mice with DSS-induced colitis.

Alpha adrenergic receptors in clinical practice – Present and future

Abstract In this review we discuss the adrenergic pathways for alpha 1 and alpha 2 receptors and the current as well as potential future medication targeting these receptors. Overall, there is ongoing research into a multitude of directions with a promising outlook for alpha 1 and alpha 2 adrenergic receptors. The alpha 1-adrenergic receptor subfamily is currently modulating only a modest number of nervous system functions due the fact, that only a relatively small number of selective commercial products are available. Chronic stress can affect the long-term depression of alpha 1 receptors. Recent studies are searching for new molecular targets which might act on these receptors. Presynaptic alpha 2 receptors play an important role in modulating release of several neurotransmitters in the central nervous system. The future of alpha 2 adrenergic receptors in clinical practice looks even more promising and versatile than that of alpha 1 adrenergic receptors. Alpha 2 adrenergic receptors show different responses, especially regarding hypertension and heart failure treatment, and current research suggests a genetic component as a cause, which is being explored further.

Treatment of benign prostatic hyperplasia and abnormal ejaculation: live imaging reveals tamsulosin - but not tadalafil - induced dysfunction of prostate, seminal vesicles and epididymis.

One of the most commonly prescribed benign prostatic hyperplasia (BPH) pharmacotherapies, the alpha1-adrenergic blocker tamsulosin, is frequently discontinued, especially by younger patients due to ejaculatory disorders, often without feedback to the attending physician. Using a newly developed ex vivo system simulating sympathetic effects on the most relevant structures for the emission phase of ejaculation, that is seminal vesicles, prostate and the most distal part of the cauda epididymidis, we elucidated that tamsulosin fundamentally disturbed the obligatory noradrenaline-induced contractions in each of these structures which differed to an alternative pharmacotherapy, the PDE5 inhibitor tadalafil. Structures responsible for the emission phase of ejaculation are the seminal vesicles, the most distal part of the cauda epididymidis and the newly characterized prostate excretory ducts. The emission phase is mainly regulated by the sympathetic nervous system through alpha1-adrenergic receptor activation by noradrenaline at the targeted organs. BPH treatment with alpha1A-adrenergic antagonists such as tamsulosin is known to result in ejaculation dysfunction, often leading to discontinuation of therapy. Mechanisms of this disturbance remain unclear. We established a rodent model system to predict drug responses in tissues involved in the emission phase of ejaculation. Imitating the therapeutic situation, prostate ducts, seminal vesicles and the distal cauda epididymal duct were pre-incubated with the smooth muscle cell-relaxing BPH drugs tadalafil, a novel BPH treatment option, and tamsulosin in an ex vivo time-lapse imaging approach. Afterwards, noradrenergic responses in the relevant structures were investigated to simulate sympathetic activation. Noradrenaline-induced strong contractions ultimately lead to secretion in structures without pre-treatment. Contractions were abolished by tamsulosin in prostate ducts and seminal vesicles and significantly decreased in the epididymal duct. Such effects were not observed with tadalafil pre-treatment. Data visualized a serious dysfunction of each organ involved in emission by affecting alpha1-adrenoceptors localized at the relevant structures but not by targeting smooth muscle cell-localized PDE5 by tadalafil. Our model system reveals the mechanism of tamsulosin resulting in adverse effects during ejaculation in patients treated for BPH. These adverse effects on contractility do not apply to tadalafil treatment. This new knowledge translates directly to clinical medicine.

Treatment of ADHD: Drugs, psychological therapies, devices, complementary and alternative methods as well as the trends in clinical trials.

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders having a high influence on social interactions. The number of approved treatments and clinical trials for ADHD have increased markedly during the recent decade. This analytical review provides a quantitative overview of the existing pharmacological and non-pharmacological methods of ADHD treatments investigated in clinical trials during 1999-2021. A total of 695 interventional trials were manually assessed from clinicaltrial.gov with the search term « ADHD», and trial data has been used for analysis. A clear majority of the studies investigated non-pharmacological therapies (∼80%), including many behavioral options, such as social skills training, sleep and physical activity interventions, meditation and hypnotherapy. Devices, complementary and other alternative methods of ADHD treatment are also gaining attention. The pharmacological group accounts for ∼20% of all the studies. The most common drug classes include central nervous system stimulants (e.g., methylphenidate hydrochloride, lisdexamfetamine dimesylate, amphetamine sulfate, mixed amphetamine salts, a combination of dexmethylphenidate hydrochloride and serdexmethylphenidate chloride), selective noradrenaline reuptake inhibitors (atomoxetine, viloxazine), and alpha2 adrenergic receptor agonists (guanfacine hydrochloride, clonidine hydrochloride). Several studies investigated antidepressants (e.g., bupropion hydrochloride, vortioxetine), and atypical antipsychotics (e.g., quetiapine, aripiprazole) but these are yet not approved by the FDA for ADHD treatment. We discuss the quantitative trends in clinical trials and provide an overview of the new drug agents and non-pharmacological therapies, drug targets, and novel treatment options.

Chronic Trazodone and Citalopram Treatments Increase Trophic Factor and Circadian Rhythm Gene Expression in Rat Brain Regions Relevant for Antidepressant Efficacy.

Trazodone is an efficacious atypical antidepressant acting both as an SSRI and a 5HT2A and 5HT2C antagonist. Antagonism to H1-histaminergic and alpha1-adrenergic receptors is responsible for a sleep-promoting action. We studied long-term gene expression modulations induced by chronic trazodone to investigate the molecular underpinning of trazodone efficacy. Rats received acute or chronic treatment with trazodone or citalopram. mRNA expression of growth factor and circadian rhythm genes was evaluated by qPCR in the prefrontal cortex (PFCx), hippocampus, Nucleus Accumbens (NAc), amygdala, and hypothalamus. CREB levels and phosphorylation state were evaluated using Western blotting. BDNF levels were significantly increased in PFCx and hippocampus by trazodone and in the NAc and hypothalamus by citalopram. Likewise, TrkB receptor levels augmented in the PFCx after trazodone and in the amygdala after citalopram. FGF-2 and FGFR2 levels were higher after trazodone in the PFCx. The CREB phosphorylation state was increased by chronic trazodone in the PFCx, hippocampus, and hypothalamus. Bmal1 and Per1 were increased by both antidepressants after acute and chronic treatments, while Per2 levels were specifically augmented by chronic trazodone in the PFCx and NAc, and by citalopram in the PFCx, amygdala, and NAc. These findings show that trazodone affects the expression of neurotrophic factors involved in antidepressant responses and alters circadian rhythm genes implicated in the pathophysiology of depression, thus shedding light on trazodone's molecular mechanism of action.

Impact of intraoperative floppy IRIS syndrome in cataract surgery by phacoemulsification: Analysis of 622 cases

BackgroundSmall pupil syndromes, including IFIS, increase the risk of complications during cataract surgery if proper surgical planning is not performed. Tamsulosin is associated with a very significant increase in the risk of IFIS, due to the prolonged inactivation of alpha-1 adrenergic receptors in the smooth muscle fiber of the iris. Material and methodsSingle-center prospective observational study, carried out at the Hospital de l'Esperança - Parc de Salut Mar. Results622 eyes of 502 patients were included, of which 337 (62%) were women. The mean age of the sample is 74.8 years. 61 cases of IFIS (11%) were observed, of which 13 received treatment with Tamsulosin and 1 with Doxazosin. 23 cases of IFIS were observed in female patients. The female:male ratio was approximately 1:3. 19 cases (3%) of severe IFIS were observed, of which 6 received treatment with alpha-antagonists, with no statistically significant correlation.The mean surgical time was 13.80 min (Standard Deviation - SD: 4.01 min) in patients without IFIS and 16.93 min (SD: 4.32 min) in patients with IFIS. The relationship between the duration of the surgical procedure in minutes and the presence of IFIS was statistically significant, applying a 'two-tailed' or bilateral t-Student test with a p value of 0.01. ConclusionRegardless of the degree of severity, the diagnosis of IFIS lengthens the surgical time in cataract surgery. This represents yet another piece of evidence that supports the use of less selective alpha-1 adrenergic antagonist treatments than Tamsulosin or the performance of cataract surgery before starting these treatments.

Effects and related mechanism of alpha-adrenergic receptor inhibitor phentolamine in a rabbit model of acute pulmonary embolism combined with shock

BackgroundTo observe the effect and mechanism of alpha-adrenergic receptor inhibitor phentolamine (PTL) in a rabbit model of acute pulmonary embolism (APE) combined with shock.MethodsTwenty-four New Zealand rabbits were randomly divided into sham operation group (S group, n = 8), model group (M group, n = 8) and PTL group (n = 8), the model of APE combined with shock was established. Mean pulmonary arterial pressure (MPAP), peripheral mean arterial pressure (MAP) and pulmonary circulation time were evaluated. The expression levels of α1 receptor, α2 receptor and their downstream molecules in pulmonary embolism (PE) and non-pulmonary embolism (non-PE) regions lung tissues were detected and compared, respectively.ResultsIn M group, α receptor-related signaling pathways were significantly activated in both PE and non-PE areas as expressed by up-regulated α1, α2 receptor and phospholipase C (PLC); the expression level of phosphorylated protein kinase A (p-PKA) was significantly down-regulated; myosin light chain kinase (MLCK) and α-smooth muscle actin (α-SMA) levels were up-regulated. PTL treatment significantly improved pulmonary as well as systemic circulation failure: decreased MPAP, restored blood flow in non-PE area, shortened pulmonary circulation time, increased MAP, and restored the circulation failure. PTL induced significantly down-regulated expression of α1 receptor and its downstream molecule PLC in both PE and non-PE area, the expression level of α2 receptor was also down-regulated, the expression level of p-PKA was significantly up-regulated. PTL treatment can inhibit both α1 and α2 receptor-related signaling pathways in whole lung tissues, and inhibit Ca2+ signaling pathways. The expression level of MLCK and α-SMA were significantly down-regulated. Compared with PE area, the changes of expression levels of α receptor and its downstream molecules were more significant in the non-PE region.ConclusionIn this model of APE combined with shock, the sympathetic nerve activity was enhanced in the whole lung, α1 and α2 receptor and their downstream signaling activation might mediate blood flow failure in the whole lung. PTL treatment can effectively restore pulmonary blood flow in non-PE area and improve pulmonary as well as systemic circulation failure possibly through down-regulating α1 and α2 receptor and their downstream signaling pathways.

Comparative Pharmacoepidemiological Assessment of Antihypertensive Drugs Administration Structure in Pregnant Women in Routine Medical Practice in Kursk and Chisinau

Aim. To study the structure of antihypertensive drugs prescription in pregnant women in routine practice in Kursk and Chisinau.Material and methods. The study design was observational descriptive cross-sectional. Authors conducted a survey of doctors in medical organizations in Kursk and Chisinau in 2017-2018.Results. Respondents from Kursk and Chisinau preferred methyldopa in prescriptions of central alpha-adrenergic receptor agonists. Doctors from Chisinau used clonidine in 14.3% of cases. The leading place in the group of calcium channel blockers belonged to short-acting nifedipine. Among beta-blockers in Kursk, doctors most often prescribed bisoprolol (43.3%), metoprolol (21.7%) and nebivolol (13.3%), while in Chisinau the preference was given to metoprolol (32.1%), atenolol (19.6%) and bisoprolol (16.1%). From the group of diuretics, Kursk doctors mainly prescribed hydrochlorothiazide (10%), indapamide (6.7%); in Chisinau, indapamide was the leader (19.6%), hydrochlorothiazide was used less frequently (7,1%). From the class of alpha-blockers, prazosin occupied the leading position among respondents in Kursk, and terazosin in Chisinau.Conclusion. The priority drug classes in both regions were calcium channel blockers, central alpha-adrenergic receptor agonists and beta-blockers. A small number of not recommended drugs prescriptions have been registered. In general, the prescribed treatment corresponded to the current guidelines and protocols for the management of patients with arterial hypertension during pregnancy.

Sympathectomy Ameliorates CFA-Induced Mechanical Allodynia via Modulating Phenotype of Macrophages in Sensory Ganglion in Mice.

The sympathetic nervous system (SNS) is suggested to be involved in some forms of pain, but the mechanisms of which are incompletely known. Moreover, there is a lack of information on the regulatory role of the SNS on macrophages in sensory ganglion, which plays an important role in pain development. The present study aims to investigate the effects of the SNS on orofacial inflammatory pain and examine, if any, how the SNS influences trigeminal ganglion (TG) macrophage responses. Sympathectomy was performed on male C57BL/6 mice before receiving a local injection of Complete Freund's adjuvant (CFA) to induce inflammatory pain. Effects of sympathectomy on orofacial pain were examined by Von Frey test and c-Fos expression. Polarization of TG macrophage was evaluated by immunohistochemistry and the level of norepinephrine (NE) in the TG were determined by liquid chromatography. Sympathetic signaling to TG macrophages were predicted based on single-cell analysis. CFA injection induced a significant increase in mechanical allodynia, the number of c-Fos-positive neuron, and the level of NE in TG, which were largely reduced by sympathectomy. The number of M1 macrophages was markedly increased by CFA and was largely reduced by sympathectomy from 1 to 14 days post-injection. Single-cell RNA sequencing analysis and immunofluorescence staining showed that TG macrophages mainly express β2 adrenergic receptors for NE. Cell-cell communication analysis predicted sympathetic signaling that may modulate macrophage phenotypes, including Colony-stimulating factor-1, Migration inhibitory factor, Pleiotrophin and Nicotinamide phosphoribosyl transferase. The SNS may involve in CFA-induced mechanical allodynia via modulating macrophage phenotypes in the TG. Targeting sympathetic activation might be useful in treating some painful conditions in the orofacial region.

LBMON137 Don't Be Fooled By Normotension Pheo Could Be The Potential

Abstract Introduction Sustained or proximal hypertension is the most common sign of pheochromocytoma, but approximately 5-15% of pts present with normal blood pressure. We report a case of a patient incidentally found to have a catecholamines secreting adrenal tumor, but was normotensive on admission. Case 30-year-old morbidly obese woman incidentally found to have a 4.8 cm left adrenal gland mass while being worked up for sepsis secondary to atypical pneumonia. Initially, the patient presented with dyspnea, chest pain, palpitation, nausea, and vomiting. Her past medical history is significant for preeclampsia, 200 lb wt loss in 1 year, NSTMI a few months prior to admission discharged on dual antiplatelet and metoprolol which she couldn't tolerate due to hypotensive episodes. On arrival to the ED the patient was afebrile, normotensive SBP 90-110 DBP 57-70 mmHg, HR 86 BPM, RR 20, saturating 98% on room air. Her laboratory workup was significant for leukocytosis, elevated D-dimer, hyperkalemia 5.9 mmol/L, mildly elevated liver enzymes, and mildly elevated troponin. MRI abdomen 4.8×4.4×5. 0 cm complex enhancing mass with eccentric necrosis and/or fibrosis arising from the left adrenal gland. Ur Normetanephrine 5867 mcg/24h, Ur Metanephrine 3017 Mcg/24hr, urine dopamine and norepinephrine were within normal limits. Serum Metanephrine 2.64 nmol/L normetanephrine 13.50 nmol/L, aldosterone, renin, and cortisol levels were normal. Discussion Sustained or proximal hypertension is the most common sign of pheochromocytoma, but approximately 5-15% of pts present with normal blood pressure. Other signs and symptoms that may occur include orthostatic hypotension, visual blurring, papilledema, weight loss, polyuria, polydipsia, constipation, increased ESR, insulin resistance, hyperglycemia, leukocytosis, psychiatric disorders, and, rarely, secondary erythrocytosis due to overproduction of erythropoietin. The beta-adrenergic blocker should never be started first because a blockade of vasodilatory peripheral beta-adrenergic receptors with unopposed alpha-adrenergic receptor stimulation can lead to a further elevation in blood pressure. Our patient was normotensive throughout the hospitalization, and before admission was on metoprolol for NSTMI, however, she was unable to tolerate it due to hypotensive episodes. Conclusion Most patients with pheochromocytoma present with hypertension, however, few cases could present with normotension or even hypotension. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

A comparison of efficacy, mechanism, and side effects of clozapine and risperidone in patients with schizophrenia

Schizophrenia is a chronic psychotic disorder characterized by the presence of psychotic symptoms (hallucinations, delusions), negative symptoms (decreased expressiveness), and cognitive symptoms (lack of executive function). The exact etiology of schizophrenia is unknown, although it is thought to be linked to increased dopaminergic activity in the mesolimbic neuronal pathway and decreased dopaminergic activity in the prefrontal cortical pathway. Treatment of schizophrenia includes both pharmacological and psychosocial intervention. Nonpharmacological treatments are effective in treating the negative and cognitive symptoms of schizophrenia and increasing patient adherence to medications. The first-generation “conventional” antipsychotic drugs are high-affinity antagonists of dopamine D2 receptors that are most effective against psychotic symptoms and atypical agents differ pharmacologically from previous antipsychotic agents in their lower affinity for dopamine D2 receptors Clozapine and risperidone both are atypical antipsychotics. Clozapine has weak D2 blocking action. It mainly acts by blocking 5-HT2, alpha-adrenergic, and D4 receptors. Risperidone acts by blocking 5-HT, alpha-adrenergic and D2 receptors. It is a more potent D2 blocker than clozapine and can cause extrapyramidal symptoms at a high dose. Aggravation of seizures more with olanzapine and fewer chances with risperidone. Clozapine is a high potential atypical antipsychotic to cause metabolic side effects, while risperidone is a low potential antipsychotic to cause metabolic side effects. Clozapine is used in the treatment of resistant schizophrenia and risperidone is the most potent atypical antipsychotic agent available in long-acting injectable form.

Floppy iris syndrome associated with specific medication intake: A narrative review.

Intraoperative floppy iris syndrome (IFIS) is a cataract surgery complication that remains a challenge for eye surgeons. It is caused by the antagonism of alfa-1-adrenergic receptors within the dilator muscle of the iris, thus preventing the iris from dilation during a cataract surgery. The long-term blocking alfa-1 adrenergic receptors by the chronic use of a number of systemic medications may lead to permanent anatomical atrophy of the dilator muscle of the iris. The most common drugs associated with the development of IFIS are tamsulosin and other alpha-1 adrenergic receptor antagonists prescribed to patients with low urinary tract symptoms (LUTS). There are other systemic medications that have been reported to have increased risk for IFIS. It is crucial for the ophthalmologist to identify the high-risk patients prone to develop IFIS. Its presence may complicate the course of cataract surgery, ultimately negatively affecting visual outcome. Cataract surgery should be performed by an experienced eye surgeon using alternative pharmacological and surgical techniques. Interdisciplinary cooperation is essential to mitigate potential complications. Patients should be informed by their physicians about the need to report a medication history to their eye specialists, especially before cataract surgery.

The use of tamsulosin in the treatment of 10–15 mm lower ureteral stones in adults: a double-blinded randomized controlled trial

BackgroundThe discovery of alpha-adrenergic receptors in the ureteral smooth muscle cells led to a thorough investigation of the therapeutic potential of alpha-blockers for ureteral calculi. Tamsulosin is a selective blocker of alpha-1A and alpha-1B adrenoceptors. It significantly improved the expulsion of distal ureteral stones measuring 3–10 mm in most randomized trials. To the best of our knowledge, tamsulosin was not tested before in the management of ureteral stones 10–15 mm. Hence, the present study aimed at estimation of the efficacy of tamsulosin in the expulsion of lower ureteral stones 10–15 mm in length compared to placebo in adult patients (primary goal) and the need for ureteral dilatation at scheduled ureteroscopy.MethodsBetween November 2017 and November 2019, 80 patients with distal ureteral stones 10–15 mm were divided into two equal groups. One group received tamsulosin 0.4 mg/day and the other received a placebo. Patients were followed-up for 8 weeks.ResultsSix patients of the tamsulosin group (15%) passed their stones spontaneously compared to none of the placebo group (p = 0.026). Two of the 6 patients who passed the ureteral stones developed urinary retention and required endoscopic treatment of urethral stones. So, the adjusted spontaneous ureteral stone passage ratios for the tamsulosin and the control groups were 10 and 0%, respectively (p = 0.12). Overall, 37.5% reported adverse effects in the tamsulosin group, and 30% in the placebo group (p = 0.7). The most common adverse effect reported in both groups was dizziness, which occurred more frequently with tamsulosin (25%) than placebo (22.5%) (p = 0.9). We noticed increased ejaculatory dysfunction among men in the tamsulosin group versus placebo group [17.9% vs. 3.5% (p = 0.1)]. Among patients who needed ureteroscopy, ureteral dilatation was always needed in the control group versus 85.3% of the tamsulosin group (p = 0.015). Although 23.5% of the treatment group didn’t need stents after ureteroscopy compared to only 12.5% of the control group, this difference was not statistically significant (p = 0.2).ConclusionsAlthough tamsulosin significantly increased spontaneous passage of 10–15 mm lower ureteral stones in adults, it did not decrease the need for operative intervention. Preoperative tamsulosin significantly facilitated ureteral dilations during ureteroscopic management.

MIMICKER OF MYOCARDIAL INFARCTION (MI): PHENYLEPHRINE-ASSOCIATED CORONARY VASOSPASM

MIMICKER OF MYOCARDIAL INFARCTION (MI): PHENYLEPHRINE-ASSOCIATED CORONARY VASOSPASM

A Concise and Useful Guide to Understand How Alpha1 Adrenoceptor Antagonists Work.

Adrenoceptors are the receptors for catecholamines, adrenaline, and noradrenaline. They are divided in α (α1 and α2) and β (β1, β2 and β3). α1-adrenoceptors are subdivided in α1A, α1B and α1D. Most tissues express mixtures of α1-adrenoceptors subtypes, which appear to coexist in different densities and ratios, and in most cases, their responses are probably due to the activation of more than one type. The three subtypes of α1-adrenoceptors are G-protein-coupled receptors (GPCR), specifically coupled to Gq/11. Additionally, the activation of these receptors may activate other signaling pathways or different components of these pathways, which leads to a great variety of possible cellular effects. The first clinically used α1 antagonist was Prazosin for Systemic Arterial Hypertension (SAH). It was followed by its congeners, Terazosin and Doxazosin. Nowadays, there are many classes of α-adrenergic antagonists with different selectivity profiles. In addition to SAH, the α1-adrenoceptors are used to treat Benign Prostatic Hyperplasia (BPH) and urolithiasis. This antagonism may be part of the mechanism of action of tricyclic antidepressants. Moreover, the activation of these receptors may lead to adverse effects such as orthostatic hypotension, similar to what happens with antidepressants and with some antipsychotics. Structure-activity relationships can explain, in part, how antagonists work and how selective they can be for each one of the subtypes. However, it is necessary to develop new molecules which antagonize the α1- adrenoceptors or make chemical modifications in these molecules to improve the selectivity and pharmacokinetic profile and/or reduce the adverse effects of known drugs.

Minimizing Motion Artifacts in Intravital Microscopy Using the Sedative Effect of Dexmedetomidine.

Among intravital imaging instruments, the intravital two-photon fluorescence excitation microscope has the advantage of enabling real-time 3D fluorescence imaging deep into cells and tissues, with reduced photobleaching and photodamage compared with conventional intravital confocal microscopes. However, excessive motion of organs due to involuntary movement such as breathing may result in out-of-focus images and severe fluorescence intensity fluctuations, which hinder meaningful imaging and analysis. The clinically approved alpha-2 adrenergic receptor agonist dexmedetomidine was administered to mice during two-photon fluorescence intravital imaging to alleviate this problem. As dexmedetomidine blocks the release of the neurotransmitter norepinephrine, pain is suppressed, blood pressure is reduced, and a sedation effect is observed. By tracking the quality of focus and stability of detected fluorescence in two-photon fluorescence images of fluorescein isothiocyanate-sensitized liver vasculature in vivo, we demonstrated that intravascular dexmedetomidine can reduce fluorescence fluctuations caused by respiration on a timescale of minutes in mice, improving image quality and resolution. The results indicate that short-term dexmedetomidine treatment is suitable for reducing involuntary motion in preclinical intravital imaging studies. This method may be applicable to other animal models.

2 Dexmedetomidine Sublingual Film for Acute Agitation in Schizophrenia or Bipolar Disorder by Baseline Clinical Global Impression-Severity of Agitation

Dexmedetomidine sublingual film (SF) is a self-administered treatment for acute agitation in patients with schizophrenia (SCZ) or bipolar disorder (BPD). Dexmedetomidine is a selective agonist of alpha-2 adrenergic receptors. A post hoc analysis of pooled Phase 3 clinical trial data investigated the efficacy of dexmedetomidine SF by baseline agitation severity as measured by the clinical global impression- severity (CGI-S) scale.

Efficacy and safety of adrenergic alpha-1 receptor antagonists in older adults: a systematic review and meta-analysis supporting the development of recommendations to reduce potentially inappropriate prescribing

BackgroundAdrenergic alpha-1 receptor antagonists (alpha-1 antagonists) are frequently used medications in the management of lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH) and in the management of therapy-resistant arterial hypertension, two conditions frequently found in older adults. This systematic review aims at presenting a complete overview of evidence over the benefits and risks of alpha-1 antagonist treatment in people ≥ 65 years, and at deriving recommendations for a safe application of alpha-1 antagonists in older adults from the evidence found.MethodsA comprehensive literature search was performed (last update March 25th 2022) including multiple databases (Medline/Pubmed, Embase, the Cochrane Library) and using the PICOS framework to define search terms. The selection of the studies was done by two independent reviewers in a two-step approach, followed by a systematic data extraction. Quality appraisal was performed for each study included using standardised appraisal tools. The studies retrieved and additional literature were used for the development of recommendations, which were rated for strength and quality according to the GRADE methodology.ResultsEighteen studies were included: 3 meta-analyses, 6 randomised controlled trials and 9 observational trials. Doxazosin in the management of arterial hypertension was associated with a higher risk of cardiovascular disease, particularly heart failure, than chlorthalidone. Regarding treatment of LUTS suggestive of BPH, alpha-1 antagonists appeared to be effective in the relief of urinary symptoms and improvement of quality of life. They seemed to be less effective in preventing disease progression. Analyses of the risk profile indicated an increase in vasodilation related adverse events and sexual adverse events for some agents. The risk of falls and fractures as well as the effects of long-term treatment remained unclear. All meta-analyses and 5 out of 6 interventional studies were downgraded in the quality appraisal. 7 out of 9 observational studies were of good quality.ConclusionsIt cannot be recommended to use doxazosin as first-line antihypertensive agent neither in older adults nor in younger patients. In the management of BPH alpha-1 antagonists promise to effectively relieve urinary symptoms with uncertainty regarding their efficacy in preventing long-term progression events.