A-80426 suppresses CFA-induced inflammatory pain by suppressing TRPV1 activity via NFκB and PI3K pathways in mice

Abstract Objectives Pain is associated with many circumstances, including inflammatory reactions, which arise from modification of the features of signaling pathways. α2-adrenergic receptor antagonists are widely utilized in narcosis. Here, the authors focused on the narcotic effect of A-80426 (A8) on Complete Freund's Adjuvant (CFA) injections-triggered chronic inflammation pain in WT and TRPV1-/- mice and explored whether its antinociceptive impact was modulated via Transient Receptor Potential Vanilloid 1 (TRPV1). Method CFA with or without A8 was co-administered to the mice, which were categorized randomly into four groups: CFA, A8, control, and vehicle. Pain behaviors underwent evaluation through mechanical withdrawal threshold, abdominal withdrawal reflex, and thermal withdrawal latency of WT animals. Results Quantitative polymerase chain reaction revealed that inflammation-promoting cytokines (IL-1β, IL-6, and TNF-α) were upregulated in Dorsal Root Ganglion (DRG) and Spinal Cord Dorsal Horn (SCDH) tissues of WT animals. A8 administration reduced the pain behaviors and production of pro-inflammatory cytokines; however, this effect was significantly reduced in TRPV1-/- mice. Further analysis showed that CFA treatment reduced the TRPV1 expression in WT mice and A8 administration increased its expression and activity. The co-administration of SB-705498, a TRPV1 blocker, did not influence the pain behaviors and inflammation cytokines in CFA WT mice; however, SB-705498 the effect of A8 in WT mice. In addition, the TRPV1 block decreased the NFκB and PI3K activation in the Dorsal Root Ganglia (DRG) and Spinal Cord Dorsal Horn (SCDH) tissues of WT mice. Conclusions Together, A8 exerted a narcotic impact on CFA-supplemented mice via the TRPV1-modulated NFκB and PI3K pathway.

Management of lower ureteral stones using Tamsulosin – A prospective study

Introduction: It has been scientifically established that α1-adrenergic antagonists cause inhibition of the basal tone, peristaltic frequency, and contractions in the lower ureter. Earlier studies have shown promising results with Tamsulosin (α1-adrenergic antagonist) helping in spontaneous passage of Ureteral stones. Hence this prospective randomized double-blind placebo-controlled study is taken up to establish the real impact of Tamsulosin a specific alpha blocker (α1-adrenergic receptors) in expelling distal ureteral stones. This study aimed to include 80 patients with ureteral stones of less than 5 mm and more than 5 mm in size located in the distal ureter. Materials and methods: In the Present study, informed consent was obtained from all 80 patients and the study was conducted after institutional ethical committee approval. Patients are randomized to two groups to receive Tamsulosin and placebo along with analgesics whenever required. Patients were followed up for a period of one month to study the stone expulsion rate, drug side effects and pain episodes. Results: All 80 patients complied with prescribed treatment schedules except 4 patients in placebo group and 2 in study group who were lost to follow up. At the end of 4 weeks, stone expulsion was seen in 30 out of 38 (79% patients in study group and 20 patients out of 36 (56%) in placebo group. The stone expulsion time was shorter in the study group (6.2±3.2 days) and in 9.67±5.4 days for placebo group. No significant impact on the expulsion rate was seen in relation with age, gender and ureteric stones present either in right side or left side. The frequency of pain episodes was almost same and mild in both groups. Conclusion: Tamsulosin is safe and effective drug to enhance spontaneous passage of smaller stones present in distal ureter.

Research progress of intraoperative floppy iris syndrome during phacoemulsification / 国际眼科杂志(Guoji Yanke Zazhi)

? Intraoperative floppy iris syndrome is a particular symptom in phacoemulsification, and it is often occurred in patients with the history of using alpha-1 adrenergic antagonist before cataract surgery. Although the pupil be fully mydriatic before the operation, the progressive constricting of the pupil, the relaxing of iris even the iridoptosis and the unstable anterior chamber still can be found during the phacoemulsification. If treated inappropriately, severe complications and terrible outcomes may happen, which would influenced the surgery effectives. This paper reviewed the epidemiological characteristics, pathogenesis, risk factors, clinical manifestations, complications, and coping strategies of the intraoperative floppy iris syndrome.

Influence of preoperative propranolol on cardiac index during the anhepatic phase of liver transplantation / Influência do propranolol pré-operatório no índice cardíaco durante a fase anepática do transplante hepático / Influencia del propranolol preoperatorio en el índice cardíaco durante la fase anhepática del trasplante hepático

INTRODUCTION: Liver transplantation is the best therapeutic option for end-stage liver disease. Non-selective beta-blocker medications such as propranolol act directly on the cardiovascular system and are often used in the prevention of gastrointestinal bleeding resulting from HP. The effects of propranolol on cardiovascular system of cirrhotic patients during liver transplantation are not known. OBJECTIVE: Evaluate the influence of propranolol used preoperatively on cardiac index during the anhepatic phase of liver transplantation. METHOD: 101 adult patients (73 male [72.2%]) who underwent cadaveric donor orthotopic liver transplantation by piggyback technique with preservation of the retrohepatic inferior vena cava performed at Hospital das Clinicas, Federal University of Minas Gerais were evaluated. There was no difference in severity between groups by the MELD system, p = 0.70. The preoperative use of propranolol and the cardiac index outcome were compared during the anhepatic phase of liver transplantation in 5 groups (I: increased cardiac index, II: cardiac index reduction lower than 16%, III: cardiac index reduction equal to or greater than 16% and less than 31%, IV: cardiac index reduction equal to or greater than 31% and less than 46%, V: cardiac index reduction equal to or greater than 46%). RESULTS: Patients in group I (46.4%) who received propranolol preoperatively were statistically similar to groups II (60%), III (72.7%), IV (50%) and V (30.8%), p = 0.57. CONCLUSION: The use of propranolol before transplantation as prophylaxis for gastrointestinal bleeding may be considered safe, as it was not associated with worsening of cardiac index in anhepatic phase of liver transplantation. .

INTRODUÇÃO: O transplante hepático (TH) é a melhor opção terapêutica para doença hepática em estágio terminal (DHET). As medicações betabloqueadoras não seletivas, como o propranolol, atuam diretamente no sistema cardiovascular (SCV) e são frequentemente usadas na prevenção de hemorragia digestiva decorrente da HP. Os efeitos do propranolol no SCV de cirróticos durante o TH não são conhecidos. OBJETIVO: Avaliar a influência do uso pré-operatório do propranolol no índice cardíaco (IC) durante a fase anepática do TH. MÉTODO: Avaliaram-se 101 pacientes adultos (73 homens, 72,2%) submetidos a transplante ortotópico de fígado doador cadáver, pela técnica de piggyback com preservação da veia cava inferior retro-hepática, feito no Hospital das Clínicas da Universidade Federal de Minas Gerais. Não houve diferença de gravidade pelo sistema MELD entre os grupos, p = 0,70. Foram comparados o uso pré-operatório de propranolol com o desfecho do IC durante a fase anepática do TH em cinco grupos (I: aumento do IC; II: redução do IC inferior a 16%; III: redução do IC igual a ou maior do que 16% e menor do que 31%; IV: redução do IC igual a ou maior do que 31% e menor do que 46%;V: redução do IC igual a ou maior do que 46%). RESULTADOS: Pacientes que fizeram uso pré-operatório de propranolol no grupo I (46,4%) foram estatisticamente semelhantes aos dos grupos II (60%), III (72,7%), IV (50%) e V (30,8%), p = 0,57. CONCLUSÃO: O propranolol no pré-transplante, como profilaxia para hemorragia digestiva, pode ser considerado seguro, pois não se associou à pioria do IC na fase anepática do TH. .

INTRODUCCIÓN: El trasplante hepático (TH) es la mejor opción terapéutica para la enfermedad hepática en estado terminal. Los betabloqueantes no selectivos, como el propranolol, actúan directamente en el sistema cardiovascular y a menudo son usadas en la prevención de la hemorragia digestiva proveniente de la hipertensión portal. Los efectos del propranolol en el sistema cardiovascular de cirróticos durante el TH no se conocen. OBJETIVO: Evaluar la influencia del uso preoperatorio del propranolol en el índice cardíaco (IC) durante la fase anhepática del TH. MÉTODO: Se estudiaron 101 pacientes adultos (73 hombres [72,2%]) sometidos a trasplante ortotópico de hígado de donante cadáver, por la técnica de piggyback con preservación de la vena cava inferior retrohepática, en el Hospital das Clínicas de la Universidad Federal de Minas Gerais. No hubo diferencia respecto a la gravedad por el sistema Meld entre los grupos (p = 0,70). Se comparó el uso preoperatorio del propranolol con el resultado del IC durante la fase anhepática del TH en 5 grupos (i: aumento del IC; ii: reducción del IC < 16%; iii: reducción del IC ≥ 16% y < 31%; iv: reducción del IC ≥ 31% y < 46%;v: reducción del IC ≥ 46%). RESULTADOS: El número de pacientes que usaron el propranolol en el preoperatorio en el grupo i (46,4%) fue estadísticamente similar a los grupos ii (60%), iii (72,7%), iv (50%) y v (30,8%), p = 0,57. CONCLUSIÓN: El propranolol en el pretrasplante, como profilaxis para la hemorragia digestiva, puede ser considerado seguro porque no se asoció con el empeoramiento del IC en la fase anhepática del TH. .

Incidence and Risk Factors of Intraoperative Floppy Iris Syndrome During Cataract Surgery

PURPOSE: To determine the incidence and risk factors of intraoperative floppy iris syndrome (IFIS) in patients undergoing cataract surgery. METHODS: The present study included 981 eyes of 655 patients who underwent cataract surgery and development and grade of IFIS were recorded. Correlation analysis was performed to determine the relationship between the IFIS and risk factors such as alpha1-adrenergic antagonist (tamsulosin, terazosin, alfuzosin), benzodiazepine, 5-alpha-reductase inhibitor, age, gender, hypertension, diabetes and glaucoma. RESULTS: IFIS developed in 178 eyes (18.1%) out of 981 eyes. There was a correlation between the development of the IFIS and alpha1-adrenergic antagonist and benzodiazepine and male gender; however, there was no correlation with 5-alpha-reductase inhibitor, age, gender, hypertension, diabetes and glaucoma. IFIS grade tended to be higher as the cumulative dosage of the alpha1-adrenergic antagonist increased. Odds ratio of the patients using tamsulosin was the highest among the other risk factors, which was 3.8 times higher than the patients using terazosin, 9.0 times higher than the patients using alfuzosin and 11.1 times higher than the patients using benzodiazepine. Among patients who underwent cataract surgery on both eyes and who were confirmed with IFIS in 1 or both eyes, no significant grade differences between the 2 eyes were noted. CONCLUSIONS: Alpha 1-adrenergic antagonist and benzodiazepine were risk factors for the development of the IFIS, and as the cumulative dosage of the alpha1-adrenergic antagonist increased, the probability of developing a higher grade of IFIS increased. Therefore, predicting and preparing for potential IFIS in patients who have the above-mentioned risk factors are necessary before planning cataract surgery. Additionally, the IFIS aspect of the first eye could be utilized as a predictive value for developing IFIS profile of the fellow eye.

Clinical efficacy of non-steroidal anti-inflammatory drugs and α1-adrenergic antagonist on the patients with ureteral stones / 中国综合临床

Objective To investigate the clinical effect of non-steroidal anti-inflammatory drugs and αl-adrenergic antagonist on treating patients with ureteral stones.Methods A total of 128 patients with ureteral colic due to ureteral stones were randomly divided into control and treatment group,and 64 cases in each group.Both two groups were treated with tamsulosin 0.4 mg oral,intravenous injection of saline 1000 mL Patients in treatment group were received intramuscular non-steroidal anti-inflammatory drugs(10 mg) and patients in control group were received pethidine hydrochloride(10 mg).Ultrasound exam were performed after 6-8 h to evaluate the stone expulsive rate.Extracorporeal shock wave lithotripsy and other treatment were underwent when the stone was still not discharge.Results The effective rate of analgesia was 96.9％ (62/64) in treatment group and 100％ (64/64) in control group(x2 =2.03,P =0.50).The stone expulsion rate in treatment group was 28.1％ (18/64),higher than that in control group(12.5％ (8/64),x2 =4.83,P =0.05).Conclusion It is effective to relive ureteral cohc with non-steroidal anti-inflammatory drugs only,and it is better than pethidine in promote stone expulsion when they both used with α1-adrenergic antagonist.

Prazosina de liberação lenta para pacientes com transtorno do estresse pós-traumático resistentes aos ISRS / Slow-release prazosin for SSRI-resistant posttraumatic stress disorder patients

CONTEXTO: Prazosina, um antagonista de receptores alfa-1 adrenérgicos, é utilizada no tratamento de pesadelos e insônia relacionados com TEPT. Apesar das evidências sugerindo sua eficácia também no tratamento de sintomas gerais de TEPT, sua curta meia-vida (2-3 horas) pode limitar seus efeitos terapêuticos.OBJETIVO: Descrever quatro casos de pacientes com TEPT resistentes aos inibidores de recaptação de serotonina ou de serotonina e adrenalina (terapia convencional) tratados com uma apresentação de prazosina de liberação lenta.MÉTODOS: Quatro pacientes com TEPT grave, resistentes à terapia convencional, tiveram a prazosina de liberação lenta (meia-vida de 10,8 horas) adicionada as suas prescrições por pelo menos três meses. Os sintomas de TEPT foram avaliados pela PCL-C e pelos itens referentes a pesadelos e insônia da CAPS, na linha de base e no final do período de observação de cada paciente.RESULTADOS: Dois pacientes mostraram melhora dos sintomas gerais de TEPT (redução de 35,7% e 11,9% nos escores da PCL-C), e três mostraram melhora de pesadelos e insônia (nos escores da CAPS). O único paciente que recebeu doses da prazosina pela manhã e ao deitar-se foi o que mostrou a maior melhora dos sintomas gerais de TEPT.CONCLUSÃO: Possivelmente, a sustentação do bloqueio da atividade noradrenérgica no sistema nervoso central promovida pela prazosina de liberação lenta durante o dia se faz necessária para a melhora de sintomas residuais de TEPT em pacientes em tratamento convencional com antidepressivos.

BACKGROUND: Prazosin is an antagonist of alpha-1 adrenergic receptor used to treat PTSD-related nightmares and insomnia. Although evidence suggests that it is also effective in the treatment of general symptoms of PTSD, its short half-life (2-3 hours) may limit its therapeutic effects.OBJECTIVE: To describe four cases of patients with PTSD resistant to selective serotonin reuptake inhibitors (SSRIs) or selective serotonin/noradrenaline reuptake inhibitor (SNRIs) therapy (conventional therapy) treated with slow-release prazosin presentation.METHODS: Four patients with severe PTSD resistant to conventional therapy received slow-release prazosin (half-life of 10.8 hours) added to their prescription for at least three months. PTSD symptoms were evaluated by the PCL-C, together with nightmares and insomnia items of CAPS, at baseline and at the last observation of each patient.RESULTS: Two patients showed improvement in general symptoms of PTSD (reduction of 35.7% and 11.9% in PCL-C scores), and three showed relief from nightmares and insomnia (CAPS scores). The only patient who received morning and bedtime doses of prazosin showed the greatest improvement in general symptoms of PTSD.DISCUSSION: It is possible that the sustained blockade of noradrenergic activity in the central nervous system provided by slow-release prazosin during the day is necessary to further ameliorate residual PTSD symptoms in patients receiving conventional antidepressant therapy.

Experience of Combination Therapy with Alpha Adrenergic Receptor Antagonist and Anticholinergic Agent in Patients with Lower Urinary Tract Symptoms/Benign Prostatic Hyperplasia: 12 Month Follow-up / 대한남성과학회지

PURPOSE: Through more than 12 months of follow-up, the efficacy and safety of combination therapy with alpha adrenergic receptor antagonist and anticholinergic agent was investigated retrospectively. MATERIALS AND METHODS: This study retrospectively analyzed the data of 84 patients with lower urinary tract symptoms (LUTS)/benign prostatic hyperplasia (BPH) who were managed with an alpha adrenergic receptor antagonist and anticholinergic agent for at least 12 months between Jan 2007 and Dec 2010. On patients' first visit to our department, we obtained the patients' demographic data and information about the prostate total volume, serum prostate specific antigen (sPSA), maximum urinary flow rate (Qmax), International Prostate Symptom Score (IPSS), and postvoid residual (PVR) of each patient. After 12 months, changes in the above factors and the side-effects of anticholinergic agents were investigated. RESULTS: The mean age of the patients was 66.1 years and the total observation period after drug administration was an average 20 months; the total sPSA and prostatic volume of patients was 1.8+/-0.8 ng/dl and 37.3+/-9.5 g, respectively. Qmax in uroflowmetry was improved after 12 months of medication (changed from 9.0+/-3.4 to 13.8+/-4.5 ml/sec; p<0.001). PVR was increased from 35+/-22.2 ml to 49.3+/-37 ml (p<0.001), but the change was not clinically significant, and no acute urinary retention occurred. The total IPSS score decreased from 21.4+/-5.1 to 13.3+/-4.6 (p<0.001), the storage score of IPSS decreased from 9.8+/-2.4 to 5.6+/-2 (p<0.001), and the voiding score was decreased from 11.6+/-3.7 to 7.7+/-3.2 (p<0.001). The QoL with IPSS was improved from 4.2+/-0.8 to 2.8+/-0.7 (p<0.001). During the 12 months there were 34 patients (56 cases) of adverse events. However, no serious adverse events were reported. CONCLUSIONS: Combination therapy with alpha adrenergic receptor antagonist and anticholinergic agent was safe and made an improvement in LUTS in patients with BPH and storage symptoms.

The Changing Pattern of Serum Prostate Specific Antigen in Patients with Benign Prostatic Hyperplasia after Combined Treatment with Finasteride and alpha-blockers: the 3 Year Follow-up Data / 대한비뇨기과학회지

PURPOSE: Some recent studies have demonstrated that finasteride, a well- known 5alpha-reductase inhibitor, can decrease prostate specific antigen (PSA) by approximately 50% during the first 1 year of treatment. We investigated how long-term treatment with finasteride and alpha-blockers impacts on the serum PSA level of men whose final diagnosis was benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: In a retrospective trial, we evaluated a total of 293 men with lower urinary tract symptoms (LUTS) that were suggestive of BPH. These men were divided into two treatment groups: group A was treated with alpha-blockers and group C was treated with a combination of finasteride and alpha-blocker. Comparisons of the two groups were performed by using independent t-tests. The changes in the PSA concentrations from baseline to the time of the final measurements were determined by repeated measures of ANOVA. RESULTS: There was no significant difference in the baseline PSA between the two groups. A statistically significant reduction in the PSA levels was observed at 2 years in C group (p0.05). In group A, the repeatedly measured PSA levels were 2.67, 2.40, 2.41 and 2.42, respectively. In C group, these were 3.22, 2.09, 1.81 and 1.71 respectively. CONCLUSIONS: Our data showed that there was no clinically significant effect of long term treatment with alpha-blocker on the PSA levels. However, finasteride had significant effect on the serum PSA level during first two years of treatment.

Pulmonary Edema following Phenylephrine Intranasal Spray Administration during the Induction of General Anesthesia in a Child

Topical phenylephrine, an agent used to facilitate nasotracheal intubation and prevent nasal mucosal bleeding, can cause severe hypertension in some patients, secondary to its stimulation of alpha-adrenergic receptors. Moreover, a high incidence of pulmonary edema is found in patients whose phenylephrine administration is followed by treatment with beta-blocking agents. We report a case of acute pulmonary edema in a pediatric patient who developed severe hypertension after the inadvertent administration of a large dose of topical nasal phenylephrine, followed by beta-adrenergic antagonists (esmolol).

Hemodynamic Effect of Propofol and Esmolol under Isoflurane Anesthesia in Dogs / 대한마취과학회지

BACKGROUND: Propofol has gained widespread popularity but it should at least be questioned in the presence of heart rate lowering medications such as beta-blockers. Esmolol, due to its ultrashort action and cardioselective properties, has been shown to be safe and effective for use in intraoprative tachycardia and hypertension. The purpose of this study is to evaluate the hemodynamic effects of esmolol and propofol under isoflurane anesthesia in dogs. METHODS: Six-mongrel dogs were induced with thiopental, intubated and ventilated with a mixture of isoflurane (1-1.5 vol%) and oxygen. A pulmonary artery catheter was placed via femoral vein and the femoral artery was cannulated. After stabilization, baseline hemodynamic measurements (HR, MAP, CO, SVR) were obtained. Measurements were repeated 5 and 15 minutes after injection of propofol (2 mg/kg), esmolol (1 mg/kg), and additional esmolol (1 mg/kg) for 30 seconds. Data was analyzed by repeated measurement of ANOVA. P < 0.05 was considered significant. RESULTS: Propofol produced no change in heart rate, MAP, CO and SVR. Heart rate decreased significantly during esmolol administration and remained decreased up to 15 minutes after the injection whereas the MAP, CO and SVR showed no significant changes. CONCLUSIONS: We have demonstrated that the decrease in heart rate continued up to 15 minutes after esmolol administration. These findings suggest that concomittent administration of propofol and esmolol requires monitoring of the heart rate after a bolus intravenous injection of esmolol.

In Vitro Responses of Alpha-adrenergic Antagonist of Rat Detrusor Muscle after Partial Bladder Outlet Obstruction / 대한비뇨기과학회지

PURPOSE: Our experiments were done to determine the effects of alpha-1-adrenergic antagonists which have been commonly used in the treatment of BPH against the partially obstructed detrusor smooth muscle using in-vitro muscle strip study of female rat bladder. MATERIALS AND METHODS: Partial obstruction was created by means of partial ligation of the proximal urethra in 15 female Sprague-Dawley rats. After 6 weeks of obstruction, 1x0.5cm sized each bladder smooth muscle strip was stimulated by field stimulation(FS),(1-32Hz) and bethanechol administration(10(-7)-10(-4)M). After the control stimulations, each strip was pre-treated with doxazosin, tamsulosin, prazosin and atropine for 30 minutes, and then same stimulations were repeated. Seperate strip was pre-treated by propranolol for 30 minutes, and then was stimulated by norepinephrine(10(-4)M) or phenylephrine(10(-4)M). RESULTS: After the administration of doxazosin, percent decreases of maximal tension developed by FS was significantly greater in obstructed(26-50% of the control) than in normal rats(0-12% of the control)(p<0.05). Field stimulated tension were inhibited more in normal(32-40%) than in obstructed rats(p<0.05, 1-32Hz) after the administration of prazosin. Atropine inhibited field stimulated tension to a greater degree in normal(73-63%) than in obstructed(27-43%) rats(p<0.01, 1-32Hz). Complete inhibitory effects of atropine against bethanechol stimulation(10(-7)-10(-4)M) was achieved at 10(-5)M in normal rats. In obstructed rats, complete blockage was achieved at 10-4M of bethanechol. Norepinephrine decreased basal tension both in normal and obstructed rats. After pre-treatment of propranolol, phenylephrine and norepinephrine did not show any increase of basal tension. CONCLUSIONS: Our results suggest that changes of adrenoceptors may be the underlying cause of bladder instability secondary to outflow obstruction as evidenced by significant inhibition of the tension of the detrusor muscle by alpha-1-adrenoceptor blocker(doxazosin but not by tamsulosin) only in obstructed rat bladder. These results also suggest that non-cholinergic components of bladder contraction are much more in obstructed than in normal bladder. It also can be said that doxazosin may have additional effects against bladder instability caused by BPH.

Combination Therapy of Verapamil and Esmolol for the Paroxysmal Supraventricular Tachycardia Recurred during the Central Venous Catheterization: A case report / 대한구급학회지

Combination therapy of beta-blocker and a calcium channel blocker is not recommened because their additive effect on the myocardium and the atrioventricular node may precipitate heart block in susceptible patients. We experienced a 68 years old female patient who had paroxysmal supraventricular tachycardia that was treated with verapamil and esmolol. She had been taking verapamil for 2 years because of her paroxysmal supraventricular tachycardia. She was planned for left ureteronephrectomy due to left ureteral tumor. After epidural catheterization for the postoperative pain control, she was anesthetized with isoflurane and vecuronium. During central venous catheterization, SVT (H.R. from 98 beats per minute to 190 BPM) was suddenly developed with hypotension (B.P. from 120/65 mmHg to 75/42 mmHg) when guide wire was introduced. We treated her with combination therapy of verapamil 7.5 mg and esmolol 18 mg under the monitoring of blood pressure, electrocardiogram, end-tidal CO2 tension, central venous pressure and pulse oximeter. After 20 minutes of vigorous treatment, her heart rate and blood pressure returned to a normal range.