Tamsulosin vs. Tadalafil as medical expulsive therapy for distal ureteral stones: a systematic review and meta-analysis

ABSTRACT Purpose: Medical expulsive therapy (MET) is recommended for distal ureteral stones from 5 to 10 mm. The best drug for MET is still uncertain. In this review, we aim to compare the effectiveness of tadalafil and tamsulosin for distal ureteral stones from 5 to 10 mm in terms of stone expulsion rate (SER), stone expulsion time (SET) and the side effect profile. Materials and methods: A comprehensive literature search was conducted on MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Scopus and Web of Science, from inception until April 2023. Only randomized controlled trials were included in the analysis. Results: Eleven publications with 1,330 patients were included. We observed that tadalafil has a higher SER (OR 0.55, CI 95% 0.38;0.80, p=0.02, I2=52%) and the same efficacy in SET (MD 1.07, CI 95% -0.25; 2.39, p=0.11, I2=84%). No differences were found when comparing side effects as headache, backache, dizziness, and orthostatic hypotension. Conclusion: Tadalafil has a higher stone expulsion rate than tamsulosin as a medical expulsive therapy for patients with distal stones from 5 to 10 mm without differences in side effects.

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.

Discovery of novel α2A adrenergic receptor agonists coupling to Gαi/o proteins by virtual screening / 中国药理学与毒理学杂志

Most α2-AR agonists derived from dexme-detomidine have few structure differences between them and have no selectivity for α2A/2B-AR or Gi/Gs,that can lead to the side effect of drugs.To get novel and potent α2A-AR agonists,we built the homology model for human α 2A-AR and α2B-AR to find α2A-AR agonists with higher selectivity.Compound P300-2342 and its 3 analogs sig-nificantly decreased the locomotor activity of mice(P＜0.05).Furthermore,P300-2342 and its 3 analogs inhibited the binding of[3H]rauwolscine to α 2A-AR and α 2B-AR respectively.In α2A-AR-HEK293 cells,P300-2342 decre-ased forskolinstimulatedcAMPpruductionwithoutincreas-ing cAMP pruduction,that indicated the P300-2342 acti-vating α2A-AR coupling with Gαi/o pathway without Gαs coupling.P300-2342 had no agonistic and antagonistic activities on α 2B-AR.Similar results were shown in 3 analogs of P300-2342.The docking results showed that P300-2342 formed the π-hydrogen bonds with Y394,V114 of α2A-AR,and with V93 of α2B-AR.3 analogs of P300-2342 formed several π-hydrogen bonds with V114,Y196,F390 of α 2A-AR and with V93 of α 2B-AR.We believe that these molecules can serve as leads for fur-ther optimization of α2A-AR agonists with potentially few side effects.

Therapeutic effects of B ultrasound-guided extracorporeal shock wave lithotripsy combined with tamsulosin hydrochloride medication on ureteral calculi / 中国基层医药

Objective:To investigate the therapeutic effects of B ultrasound-guided extracorporeal shock wave lithotripsy combined with tamsulosin hydrochloride medication on ureteral calculi.Methods:The clinical data of 130 patients with ureteral calculi who received treatment in Ninghai First Hospital from March 2019 to June 2020 were retrospectively analyzed. These patients were divided into an observation group and a control group ( n = 65/group) according to the different treatment methods. Patients in the control group received B ultrasound-guided extracorporeal shock wave lithotripsy, and those in the observation group received B ultrasound-guided extracorporeal shock wave lithotripsy combined with tamsulosin hydrochloride medication. Total response rate, stone-free rate after the first treatment, time taken to get rid of stone, treatment times, and Visual Analogue Scale (VAS) score 14 days after the first treatment were compared between the two groups. Renal function indexes (serum creatinine, blood urea nitrogen), mean arterial pressure, VAS score, blood loss, and immunoglobulin G, immunoglobulin M, malondialdehyde, superoxide dismutase levels were determined in the two groups. Results:The total response rate in the control group was significantly lower than that in the observation group [89.23% (58/65) vs. 98.46% (64/65), χ2 = 4.80, P < 0.05]. After 14 days of treatment, the VAS score in the observation group was significantly lower than that in the control group [(3.97 ± 0.36) points vs. (5.59 ± 0.87) points, t = 13.87, P < 0.05). After treatment, the stone-free rate after the first treatment in the control group was significantly lower than that in the observation group [61.54% (40/65) vs. 78.46% (51/65), χ2 = 4.43, P < 0.05). The time taken to get rid of stone and treatment times in the control group were (18.98 ± 3.52) days and (2.53 ± 0.50) times, respectively, which were significantly higher than (12.27 ± 2.77) days and (1.64 ± 0.55) times in the observation group ( t = 12.08, 9.66, both P < 0.05). Urine Kim-1 in the observation group was significantly higher than that in the control group [(89.46 ± 42.46) mmol/L vs. (72.75 ± 17.65) mmol/L, t = 2.93, P < 0.05]. Serum creatinine and blood urea nitrogen levels in the observation group were (101.75 ± 24.53) μmol/L and (348.76 ± 29.84) μmol/L, respectively, which were significantly lower than (139.53 ± 30.56) μmol/L and (397.65 ± 35.64) μmol/L in the control group ( t = 5.82, 8.48, both P < 0.05). After 20-minutes of anesthesia induction, the mean arterial pressure in the observation group was significantly higher than that in the control group [(83.45 ± 12.65) mmHg (1 mmHg=0.133 kPa) vs . (61.68 ± 9.75) mmHg, t = -10.99, P < 0.05]. Intraoperative blood loss in the observation group was significantly lower than that in the control group [(112.65 ± 30.74) mL vs. (170.68 ± 35.67) mL, t = 9.94, P < 0.05]. Serum immunoglobulin G and malondialdehyde levels in the observation group were (8.56 ± 1.74) g/L and (7.74 ± 0.74) mol/L, respectively, which were significantly higher than (7.75 ± 1.68) g/L and (5.21 ± 0.65) mol/L in the control group ( t = 2.70, 20.71, both P < 0.05). Serum immunoglobulin M and superoxide dismutase levels in the observation group were (1.23 ± 0.32) g/L and (71.75 ± 8.57) U/L, which were significantly lower than (1.55 ± 0.45) g/L and (90.64 ± 9.73) U/mL in the control group ( t = -4.67, -11.75, both P < 0.05). Conclusion:B ultrasound-guided extracorporeal shock wave lithotripsy combined with tamsulosin hydrochloride medication is more effective on ureteral calculi than B ultrasound-guided extracorporeal shock wave lithotripsy alone. The combined therapy can effectively reduce pain, increases the treatment efficacy, and is worthy of reference and promotion in clinical practice.

Analysis of factors related to the efficacy of Tamsulosin monotherapy for overactive bladder symptoms in benign prostatic hyperplasia patients with the prostate volume <40 ml / 中华老年医学杂志

Objective:To assess the efficacy of Tamsulosin monotherapy for overactive bladder(OAB)symptoms in benign prostatic hyperplasia(BPH)patients with the prostate volume(PV)<40 ml, and to analyze related factors affecting the efficacy.Methods:300 BPH patients with OAB were enrolled, with an average age of(66.9±7.7)years and the PV<40 ml.Smoking, drinking and other living habits were investigated.Data on the Overactive Bladder Symptom Score(OABSS), International Prostate Symptom Score(IPSS)and Quality of Life Scale(QOLS)were collected before and after 4 weeks of treatment with Tamsulosin 0.2 mg QN.The maximum urine flow rate(Qmax)and bladder residual urine volume(PVR)were measured before and after treatment.OBASS was used as the main assessment parameter to analyze the correlation of efficacy with age, lifestyle, pre-treatment symptom scores, PV, Qmax and PVR.Results:257 patients completed the study, and 169 patients were treated effectively, with an overall effectiveness rate of 65.8%.The effectiveness rates of the mild, moderate and severe OAB groups were 83.6%, 62.4% and 38.5%, respectively, with statistical significance( χ2=13.037, P=0.001).3 patients showed adverse drug reactions, including 2 patients with mild dizziness and 1 patient with nausea.The baseline OABSS score, the proportion of smoking patients and the proportion of drinking patients in the effectively treated OAB group were significantly lower than those in the ineffectively treated group.Multivariate analysis showed that baseline OABSS score( OR=0.735, P<0.001)and smoking( OR=2.111, P=0.029)were correlated with tamsulosin's efficacy in treating BPH patients with OAB with PV<40 ml. Conclusions:The effectiveness rate of Tamsulosin for the treatment of BPH patients with mild OAB with PV<40 ml is high.The baseline OABSS score and smoking are factors affecting the efficacy of Tamsulosin on OAB symptoms in these patients.

Pre-treatment of the beta3-adrenergic receptor agonist BRL37344 reduces in vivo myocardial ischemia/reperfusion injury by improving AMPK and SIRT1 activity and by suppressing mTOR and p70S6K signaling pathways

Abstract This study aimed to investigate the role and signaling pathways of β3-AR in myocardial ischemia/reperfusion (I/R) injury, which is one of the leading causes of death worldwide. 47 male rats were randomly divided into two main groups to evaluate infarct size and molecular parameters. Rats in both groups were randomly divided into 4 groups. Control (sham), I/R (30 min ischemia/120 min reperfusion), BRL37344 (BRL) (A) (5 µg/kg single-dose pre-treatment (preT) before I/R) and BRL (B) (5 µg/kg/day preT for 10 days before I/R). Infarct size was determined with triphenyltetrazolium chloride staining and analyzed with ImageJ program. The levels of AMPK, SIRT1, mTOR, and p70SK6 responsible for cellular energy and autophagy were evaluated by western blot. Infarct size increased in the I/R group (44.84 ± 1.47%) and reduced in the single-dose and 10-day BRL-treated groups (32.22 ± 1.57%, 29.65 ± 0.55%; respectively). AMPK and SIRT1 levels were decreased by I/R but improved in the treatment groups. While mTOR and p70S6K levels increased in the I/R group, they decreased with BRL preT. BRL preT protects the heart against I/R injury. These beneficial effects are mediated in part by activation of AMPK and SIRT1, inhibition of mTOR and p70S6K, and consequently protected autophagy.

Utilidad de la midodrina para controlar el síncope vasovagal: ¿la recomienda la evidencia? / Usefulness of Midodrine for the Control of Recurrent Vasovagal Syncope: Does the Evidence Recommend it? / Utilidade da midodrina no controle da síncope vasovagal: as evidencias a recomendam?

Introducción:El síncope vasovagal es la principal causa de pérdida transitoria de la conciencia, y es un motivo de consulta cada vez más frecuente en pediatría y medicina del adulto. La midodrina es un agonista de los recepto-res alfa, de acción periférica, empleada principalmente en el manejo de la hipotensión ortostática; sin embargo, también se ha evaluado en el síncope vasovagal, con resultados prometedores.Objetivo:Analizar la evidencia más reciente sobre la utilidad de la midodrina para el control y la prevención del síncope vasovagal.Materiales y métodos: Se realizó una búsqueda bibliográfica utilizando términos de búsqueda como Vasovagal Syncope y Midodrine, así como sinónimos, que se combinaron con operadores booleanos, en cinco bases de datos, hasta octubre del 2022. Se incluyeron estudios originales, revisiones sistemáticas y metanálisis, publicados tanto en inglés como en español.Resultados:Ensayos controlados aleatorizados y revisiones sistemáticas y metanálisis difieren ligeramente entre resultados, pero estos demuestran un efecto global protector. La evidencia más reciente y completa indica que utilizar este agente reduce significativamente la positividad al realizar la prueba de la mesa inclinada y que previene la aparición de episodios sincopales.Conclusiones:Aunque la evidencia actual sobre la eficacia de la midodrina respecto a la prevención y control del síncope vasovagal es limitada, se observa un efecto protector significativo, porque disminuye el riesgo de sufrir un episodio sincopal, aproximadamente hasta en un 50 %.Palabras clave: midodrina; síncope vasovagal; síncope; adrenérgicos; medicina basada en la evidencia

Introduction: Vasovagal syncope is the main cause of transient loss of consciousness, being an in-creasingly frequent reason for consultation in pediatrics and adult medicine. Midodrine, a periphe-rally acting alpha-receptor agonist, is mainly used in the management of orthostatic hypotension. However, it has also been evaluated in vasovagal syncope, with promising results. Objective: To analyze the most recent evidence on the usefulness of midodrine for the control and prevention of vasovagal syncope. Materials and Methods: A literature search was performed using search terms such as "Vasovagal Syncope" and "Midodrine," as well as synonyms, which were combined with Boolean operators, in 5 databases until October 2022. Original studies, systematic reviews and meta-analyses, published in both English and Spanish, were included. Results: Randomized controlled trials and systematic reviews and meta-analyses differ slightly between results, but these demonstrate an overall protective effect. The most recent and complete evidence shows that using this agent significantly reduces the probability of positivity when performing the tilt table test and prevents the occurrence of syncopal episodes. Conclusions: Although current evidence on the efficacy of midodrine with respect to the prevention and control of vasovagal syncope is limited, a significant protective effect is observed, reducing the risk of suffering syncopal episode by approximately up to 50%

Introdução: a síncope vasovagal é a principal causa de perda transitória de consciência e é um motivo cada vez mais comum de consulta em pediatria e medicina de adultos. A midodrina é um agonista do receptor alfa de ação periférica usado principalmente no tratamento da hipotensão ortostática; no entanto, ela também foi avaliada na síncope vasovagal, com resultados promissores. Objetivo: Revisar as evidências mais recentes sobre a utilidade da midodrina para o controle e a pre-venção da síncope vasovagal. Materiais e métodos: Foi realizada uma pesquisa na literatura usando termos de pesquisa como Va-sovagal, Syncope e Medodrine, bem como sinônimos, que foram combinados com operadores boo-leanos, em cinco bancos de dados, até outubro de 2022. Foram incluídos estudos originais, revisões sistemáticas e metanálises, publicados em inglês e espanhol. Resultados: Os ensaios clínicos randomizados, as revisões sistemáticas e as metanálises diferem ligei-ramente entre os resultados, mas demonstram um efeito protetor geral. As evidências mais recentes e abrangentes indicam que o uso desse agente reduz significativamente a positividade no teste de inclinação da mesa e evita a ocorrência de episódios de síncope. Conclusões: Embora as evidências atuais sobre a eficácia da midodrina em relação à prevenção e ao controle da síncope vasovagal sejam limitadas, observa-se um efeito protetor significativo, pois ela diminui o risco de sofrer um episódio sincopal em aproximadamente 50%

Comparison of efficacy of three commonly used alpha-blockers as medical expulsive therapy for distal ureter stones: A systematic review and network meta-analysis

ABSTRACT Introduction: The efficacy of alpha-blockers as medical expulsive therapy (MET) is well established. However, it is not known which of the three most commonly used alpha-blockers (tamsulosin, alfuzosin and silodosin) is the most efficacious. With this study we aimed to assess the efficacy of the three commonly used alpha-blockers as MET for distal ureter stones. Materials and Methods: For this review, we searched multiple databases such as PubMed/Medline, Scopus, Embase, OviD SP, CINAHL, and web of science to identify all the relevant randomized studies comparing the efficacy of tamsulosin, alfuzosin, and silodosin. Preferred reporting items for systematic reviews for network meta-analysis (PRISMA-NMA) were followed while conducting this review and the study protocol was registered with PROSPERO (CRD42020175706). Results: In this review, 31 studies with 7077 patients were included. Compared to placebo all the treatment groups were more effective for both stone expulsion rate (SER) and stone expulsion time (SET). For both SER and SET, silodosin had the highest SUCRA (94.8 and 90.4) values followed by alfuzosin (58.8 and 64.9) and tamsulosin (46.2 and 44.5). The incidence of postural hypotension was similar with all the drugs, whereas, the incidence of retrograde ejaculation was significantly higher for silodosin. Overall confidence for each comparison group in this review ranged from "very low" to "moderate" according to the CINeMA approach. Conclusion: Among the three commonly used alpha-blockers silodosin is the most efficacious drug as MET for lower ureter stones followed by alfuzosin and tamsulosin.

Intraoperative adenosine for pheochromocytoma with myocardial infarction and SARS-CoV-2. Case report / Adenosina intraoperatoria para feocromocitoma con infarto miocárdico y SARS-CoV-2. Reporte de caso

Abstract Pheochromocytomas are neuroendocrine tumors capable of synthetizing, storing and releasing catecholaminergic hormones that may lead to lifethreatening hemodynamic instability. The COVID-19 pandemic has increased the risks and perioperative complexity of the patients undergoing pheochromocytoma-associated adrenalectomy. This article discusses the use of adenosine for the management of hypertensive crisis during this intervention, as well as the need to individualize the suitable timing for surgery after recent COVID-19 infection. This article discusses the case of a patient with a finding of right adrenal incidentaloma; further studies determined a metanephrines secreting pheochromocytoma. Following hospital admission for preoperative optimization, the eve of the procedure the patient developed an acute myocardial infarction and subsequently SARS-CoV-2 symptomatic infection. Intraoperatively, hypertensive peaks were managed with continuous adenosine perfusion. The patient was discharged after 48 hours. Preoperative optimization positively influences the intraoperative management of patients with pheochromocytoma. The intraoperative use of adenosine allows for adequate and safe control of hypertensive crises. Each situation must be individualized in patients pending surgery, with a recent COVID-19 infection.

Resumen Los feocromocitomas son tumores neuroendocrinos capaces de sintetizar, almacenar y liberar hormonas catecolaminérgicas que pueden provocar inestabilidad hemodinámica con compromiso vital. La pandemia por COVID-19 ha aumentado los riesgos y la complejidad perioperatoria de los pacientes sometidos a adrenalectomía por feocromocitoma. Describimos el uso de adenosina para manejar las crisis hipertensivas durante esta intervención, así como establecer la necesidad de individualizar el momento quirúrgico idóneo tras infección reciente por COVID-19. Presentamos el caso de un paciente con hallazgo de incidentaloma suprarrenal derecho cuya ampliación de estudio se orientó como feocromocitoma secretor de metanefrinas. Tras ingreso hospitalario para optimización preoperatoria, el día previo al procedimiento presentó un infarto agudo de miocardio y posteriormente una infección sintomática por SARS-CoV-2. Intraoperatoriamente se manejaron los picos hipertensivos con perfusión continua de adenosina. Tras 48 horas recibió el alta hospitalaria. La optimización preoperatoria influye positivamente en el manejo intraoperatorio de los pacientes con feocromocitoma. El uso intraoperatorio de adenosina permite un adecuado y seguro control de las crisis hipertensivas. En pacientes pendientes de cirugía con infección reciente por COVID-19 se requiere individualizar cada situación.

Lactato y catecolaminas: respuesta fisiológica en el paciente crítico / Lactate and catecholamines: a physiological response in critically ill patients

RESUMEN El lactato es un metabolito altamente dinámico que, en condiciones anaerobias, es producido por hipoxia o isquemia; y en condiciones aerobias, es sintetizado por un mecanismo impulsado por la estimulación adrenérgica, a través del receptor β2, que potencia la acción de la bomba sodio-potasio, y por un estado de glicólisis aerobia acelerada. Este metabolito es capaz de intercambiarse entre diferentes células productoras y consumidoras, con lo que asegura la materia prima para obtener energía. El sistema nervioso simpático responde a los estímulos de estrés con la liberación de catecolaminas, que actúan como hormonas y como neurotransmisores en varios tejidos del cuerpo y permiten un aumento del metabolismo que eleva los valores de glucosa y el oxígeno disponible. Existe una relación fisiológica de dependencia entre las catecolaminas y la producción de lactato que predispone al organismo para responder de forma efectiva ante una situación de estrés. Sin embargo, en tejidos sensibles, la respuesta adrenérgica exacerbada puede ocasionar efectos exagerados que pueden incrementar la probabilidad de fallo. En base al conocimiento de estos mecanismos, se plantean estrategias terapéuticas enfocadas en regular la actividad simpática.

ABSTRACT Lactate is a highly dynamic metabolite that is produced, under anaerobic conditions, due to hypoxia or ischemia. Under aerobic conditions, it is synthesized by a mechanism driven by the stimulation of the β2 adrenergic receptor, which increases the activity of the sodium-potassium pump, and by a state of accelerated aerobic glycolysis. This metabolite is capable of being exchanged between different producing and consuming cells, ensuring the raw material for energy production. The sympathetic nervous system responds to stress stimuli through the release of catecholamines, which act as hormones and neurotransmitters in various tissues of the body, allowing an increase in metabolism that raises glucose and available oxygen levels. There is a physiological dependence between catecholamine levels and lactate production, predisposing the body to respond effectively to a stressful situation. However, an exacerbated adrenergic response may cause exaggerated effects on sensitive tissues that increase the probability of failure. Based on the knowledge of these mechanisms, therapeutic strategies focused on regulating the sympathetic activity are proposed.

DNA methylation is involved in the microRNA-886-3p gene expression and plays a potential role in hematopoietic stem and progenitor cell mobilization through affecting SDF-1

The role of the sympathetic nervous system (SNS) in hematopoietic stem and progenitor cell (HSPC) mobilization has been largely investigated. However, there is a critical need for the identification of the underlying contributing factors to improve HSPC yield for transplantation. It has been demonstrated that miR-886-3p targets stromal-derived factor-1 (SDF-1), the central mediator of mobilization, and therefore may play a part in this process. Besides, miR-886-3p expression can be epigenetically regulated through DNA methylation modifications inits gene promoter. Here, to assess the contribution of miR-886-3p and other epigenetic factors in HSPC mobilization, human bone marrow-derived mesenchymal stem cells (MSCs) were treated with the ?-adrenergic agonist of isoprenaline. The expression of miR-886-3p and SDF-1and the gene promoter methylation status of this miRNA were then respectively evaluated through the appropriate PCR techniques. As expected, despite a transient initial increase in SDF-1mRNA level, its expression reduced, and miR-886-3plevel remarkably increased 48 h following treatment. The gene promoter methylation pattern of miR-886-3p also changed from a full methylated state to a partially methylated one. Together, our findings suggest that miR-886-3p can be epigenetically regulated and through suppressing the expression of SDF-1 play an active role in the SNS-mediated HSPC mobilization.

Association between beta-2 adrenergic receptor variants and clinical outcomes in children and adolescents with acute asthma

ABSTRACT Objective To investigate whether different genotypes of p.Arg16Gly, p.Gln27Glu, p.Arg19Cys and p.Thr164Ile variants interfere in response to treatment in children and adolescents with moderate to severe acute asthma. Methods This sample comprised patients aged 2 to 17 years with a history of at least two wheezing episodes and current moderate to severe asthma exacerbation. All patients received multiple doses of albuterol and ipratropium bromide delivered via pressurized metered-dose inhaler with holding chamber and systemic corticosteroids. Hospital admission was defined as the primary outcome. Secondary outcomes were changes in forced expiratory volume in the first second after 1 hour of treatment, and for outpatients, length of stay in the emergency room. Variants were genotyped by sequencing. Results A total of 60 patients were evaluated. Hospital admission rates were significantly higher in carriers of the genotype AA relative to those with genotype AG or GG, within the p.Arg16Gly variant (p=0.03, test χ2, alpha=0.05). Secondary outcomes did not differ between genotypes. Conclusion Hospital admission rates were significantly higher among carriers of the genotype AA within the p.Arg16Gly variant. Trial registration: ClinicalTrials.gov: NCT01323010

Efficacy of inhalation therapy with montelukast sodium, budesonide and formoterol in combination in the treatment of bronchial asthma in adult patients and its effects on cytokines / 中国基层医药

Objective:To investigate the efficacy of combination treatment with montelukast sodium, budesonide and formoterol in the treatment of bronchial asthma in adults and its effects on cytokines.Methods:A total of 100 adult patients with bronchial asthma who received treatment in The First People's Hospital of Yongkang from January 2019 to December 2020 were included in this study. They were randomly assigned to receive either budesonide inhalation alone (control group, n = 50) or combination inhalation of montelukast sodium, budesonide and formoterol (observation group, n = 50) for 12 weeks. Efficacy was compared between the two groups. Lung function [forced expiratory volume in one second (FEV 1), peak expiratory flow (PEF) and FEV 1/forced vital capacity (FVC) ratio], cytokines [interleukin (IL)-2, IL-4, IL-6], Asthma Quality of Life Questionnaire (AQLQ) score, and Asthma Control Test (ACT) score measured before and 12 weeks after treatment were compared between the two groups. Results:Total response rate in the observation group was significantly higher than that in the control group [92.00% (46/50) vs. 72.00% (36/50), χ2 = 6.77, P < 0.05). After 12 weeks of treatment, FEV 1, PEF and FEV1/FVC in the observation group were (2.17 ± 0.23) L, (246.56 ± 17.86) L/s, and (83.86 ± 3.98)%, respectively, which were significantly higher than (1.86 ± 0.17) L, (203.12 ± 20.10) L/s, (74.82 ± 5.67)% in the control group ( t = 7.66, 11.42, 9.22, P < 0.05). Serum IL-2 level in the observation group was significantly higher than that in the control group [(10.85 ± 0.86) ng/L vs. (8.94 ± 1.03) ng/L, t = 10.06, t < 0.05]. Serum IL-4 and IL-6 in the observation group were (24.98 ± 3.08) ng/L and (98.46 ± 9.76) μg/L, respectively, which were significantly lower than (36.75 ± 4.34) ng/L and (125.84 ± 13.19) μg/L in the control group ( t =15.63, 11.79, both P < 0.05). AQLQ score and ACT score in the observation group were (121.03 ± 8.69) points and (22.08 ± 1.35) points, respectively, which were significantly higher than (110.93 ± 7.86) points and (19.74 ± 1.76) points in the control group ( t = 6.095, 7.460, both P < 0.05). Conclusion:Inhalation therapy with montelukast sodium, budesonide and formoterol produces obvious therapeutic effects on bronchial asthma in adult patients and the combined therapy can reduce inflammatory reactions.

Research progress of β-adrenergic receptor antagonists in the treatment of ocular neovascular diseases / 中华眼底病杂志

Ocular neovascularization is a pathological change in various ocular diseases such as diabetic retinopathy, retinopathy of prematurity, central retinal vein occlusion and age-related macular degeneration, which seriously affects patient's vision. β receptors are expressed in conjunctiva, corneal epithelial cells, corneal endothelial cells, extraocular muscles, trabecular meshwork, ciliary muscle, lens and retina. β adrenergic receptor antagonists bind to β receptors to exert anti-angiogenic effects by inhibiting the expression of vascular endothelial growth factor (VEGF), hypoxia-inducible factor-1, interleukin-6 and other angiogenic cytokines; reducing macrophage-related inflammatory response; increasing the expression of anti-angiogenic factors. In the treatment of corneal neovascularization, choroidal neovascularization, and retinopathy of prematurity, it can significantly reduce the area of neovascularization and delay disease progression. Co-administration of anti-VEGF drugs can reduce the frequency of administration of anti-VEGF drugs. At effective therapeutic concentrations, β-adrenergic receptor antagonists are well tolerated; they have broader targets than anti-VEGF drugs, which offers new treatment strategies for ocular neovascularization such as corneal, choroidal and retinal neovascularization.

Experimental study on α1 adrenergic receptor blocker in reducing portal hypertension in rats / 中华消化杂志

Objective:To observe whether α1 adrenergic receptor (α1AR) blocker can reduce and antagonize portal hypertension caused by α1AR activation in rats, and to provide a new approach for the clinical treatment of portal hypertension.Methods:Phenylephrine was chosen as α1AR agonist, and alfuzosin was used as α1AR blocker. The route of administration was portal vein injection, and the pressure was measured by trans-portal vein puncture. According to random number table, 32 male Sprague-Dawley rats were divided into 4 groups: control group, portal hypertension model group, alfuzosin treatment group and alfuzosin prevention group. The portal venous pressure (PVP) was measured in all rats before administration. The rats in the control group were injected with 0.9% sodium chloride solution (1 L/g), and the rats in portal hypertension model group were injected with phenylephrine(1.5 μg/g), and the PVP of the above two groups was measured again at 5 and 10 min after injection. The rats in alfuzosin treatment group were injected with phenylephrine(1.5 μg/g), PVP was measured again at 5 min after administration, and then the rats were given alfuzosin(0.9 μg/g), PVP was measured again at 5 min after administration. The rats in alfuzosin prevention group were injected with alfuzosin(0.9 μg/g), PVP was measured at 1 min after administration, and then the rats were given phenylephrine(1.5 μg/g), PVP was measured again at 1, 5 and 10 min after phenylephrine injection respectively. One way analysis of variance and Dunnett- t test were used for statistical analysis. Results:The portal vein puncture was successfully performed in 4, 6, 8 and 5 rats in the control group, portal hypertension model group, alfuzosin treatment group and alfuzosin prevention group, respectively. The PVP of rats in portal hypertension model group at 5 and 10 min after phenylephrine injection was (18.045±7.636) and (15.515±5.440) mmHg (1 mmHg = 0.133 kPa), respectively, which were both higher than that before administration ((8.452±2.830) mmHg), and the differences were statistically significant ( t=2.89 and 2.82, both P<0.05). At 5 min after alfuzosin injection, the PVP of rats in the alfuzosin treatment group was (10.088±3.743) mmHg, which was lower than that of rats at 5 min after phenylephrine injection ((16.146±4.324) mmHg) and that of portal hypertension model group at 10 min after phenylephrine injection, and the differences were statistically significant ( t=3.00 and 2.22, both P<0.05). There were no significant differences in PVP in the alfuzosin prevention group before administration, at 1 min after injection of alfuzosin, and at 1, 5 and 10 min after injection of phenylephrine (all P > 0.05). Conclusions:α1AR is an important factor involved in the regulation of PVP, and its blockers can reduce and antagonize the portal hypertension caused by α1AR activation, which is of great significance in the prevention and treatment of portal hypertension progression in liver cirrhosis.

Effects of finasteride combined with tamsulosin hydrochloride on glandular microvessel density during the perioperative period in patients with benign prostatic hyperplasia / 中国基层医药

Objective:To investigate the effects of finasteride combined with tamsulosin hydrochloride administered during the perioperative period on glandular microvessel density in patients with benign prostatic hyperplasia.Methods:Ninety patients with benign prostatic hyperplasia who received treatment in Wenzhou Hospital of Integrated Traditional Chinese and Western Medicine from August 2017 to August 2019 were included in this study. They were randomly assigned to receive either oral tamsulosin hydrochloride alone (control group, n = 45) or oral finasteride combined with tamsulosin hydrochloride (observation group, n = 45) during the perioperative period of transurethral resection of the prostate. All patients received 6 weeks of medication. Clinical efficacy, adverse reactions, and urodynamic indexes, glandular microvessel density, International Prostatism Symptom Score, bother score, and urine color/degree of haematuria score pre- and post-treatment were compared between the two groups. Results:The maximum urinary flow rate in each group significantly increased 6 weeks after treatment compared with before treatment. The detrusor pressure and residual urine volume in each group decreased 6 weeks after treatment compared with before treatment. After 6 weeks of treatment, the maximum urinary flow rate was significantly higher in the observation group than in the control group [(15.63 ± 2.26) mL/s vs. (13.14 ± 2.23) mL/s], and residual urine volume was significantly lower in the observation group than in the control group [(29.19 ± 4.81) mL vs. (32.25 ± 5.52) mL, t = 5.26, 2.80, both P < 0.05). International Prostatism Symptom Score measured 6 weeks after treatment and urine color/degree of haematuria score measured 1 week after treatment were (12.09 ± 2.17) points and (1.51 ± 0.27) points, respectively in the observation group, which were significantly lower than those in the control group [(14.28 ± 2.22) points, (2.03 ± 0.38) points, t = 4.73, 7.48, both P < 0.05]. Factor VIII related antigen- and CD34-positive glandular microvessel density values in the observation group were (14.74 ± 3.05) counts/visual field and (19.41 ± 3.07) counts/visual field, respectively, which were significantly lower than those in the control group [(18.08 ± 3.16) counts/visual field, (22.27 ± 3.16) counts/visual field, t = 5.10, 4.35, both P < 0.05]. The incidence of postoperative hematuria was significantly lower in the observation group than in the control group [15.56% (7/45) vs. 35.56% (16/45), χ2 = 4.73, P < 0.05]. Conclusion:Compared with tamsulosin hydrochloride alone, finasteride combined with tamsulosin hydrochloride administered during the perioperative stage can greatly improve the urodynamic indexes of patients with benign prostatic hyperplasia, reduce microvessel density value, International Prostatism Symptom Score, bother score, and decrease the incidence of hematuria. The combined therapy provides a novel idea for preventing perioperative bleeding in patients with benign prostatic hyperplasia.

Effects of gene polymorphisms of β1 adrenergic receptor G1165C and A145G locus on myocardial hypertrophy and the efficacy in patients with hypertension / 中国医师进修杂志

Objective:To investigate the effect of gene polymorphism of β1 adrenergic receptor (β1-AR) G1165C and A145G locus on myocardial hypertrophy and the efficacy in patients with hypertension.Methods:Two hundred and twenty-seven cases of patients with hypertension admitted to Binhai County People′s Hospital from January to December 2019 were enrolled. Among them, there were 113 cases of hypertension with myocardial hypertrophy and 114 cases of hypertension without myocardial hypertrophy. In addition, 115 patients with normal physical examination during the same period were selected as the control group. DNA in the peripheral blood leukocytes was extracted, polymerase chain reaction-restriction fragment length polymorphism method was used to detect β1-AR G1165C and A145G locus gene polymorphism, and the differences in the efficacy of β blockers in hypertensive patients with different genotypes were compared.Results:There was no statistically significant differences in the distribution of β1-AR A145G genotypes among the three groups ( P>0.05). Compared with the healthy control group, the frequency of Gly/Gly genotype carrying β1-AR G1165C locus was higher in hypertension with myocardial hypertrophy group, and the frequency of Gly/Arg and Arg/Arg gene were lower; compared with hypertension without myocardial hypertrophy group, the frequency of Gly/Arg+Gly/Gly gene in hypertension with myocardial hypertrophy group was higher; taking Arg/Arg genotype as the control group, carrying Gly/Gly genotype could increase the risk of cardiac hypertrophy in hypertensive patients by 3.159 times ( OR = 3.159, 95% CI 1.240 - 7.412, P<0.05).The frequency of G1165C allele Arg in the hypertension with myocardial hypertrophy group was significantly lower than that in the control group and the hypertension without myocardial hypertrophy group ( P<0.05); the frequency of G1165C allele Gly was significantly higher than that in the control group and the hypertension without myocardial hypertrophy group ( P<0.05); taking Arg/Arg genotype as the control, carrying Gly/Gly genotype could increase the risk of cardiac hypertrophy in hypertensive ( OR = 3.417, 95% CI 1.357 - 7.965, P<0.05). The left ventricular mass index of Gly/Gly genotype patients was (120.38 ± 28.41) g/m 2, which was significantly higher than (99.76 ± 25.16) g/m 2 and (90.30 ± 19.54) g/m 2 of Gly/Arg and Arg/Arg, with statistically significant differences ( F = 10.89, P<0.01). After the treatment, the resting heart rate, systolic blood pressure, diastolic blood pressure and mean arterial blood pressure of patients with G1165C allele Arg hypertension with myocardial hypertrophy were lower than those with G1165C allele Gly, with statistically significant differences ( P<0.05). Conclusions:β1-AR G1165C gene polymorphism is related to the risk of myocardial hypertrophy in hypertensive patients. Carrying the G1165C allele Gly may increase the risk of susceptibility to cardiac hypertrophy, and β-blockers are more effective in hypertensive patients with myocardial hypertrophy who carry the G1165C allele Arg.

Activating Connexin43 gap junctions primes adipose tissue for therapeutic intervention

Adipose tissue is a promising target for treating obesity and metabolic diseases. However, pharmacological agents usually fail to effectively engage adipocytes due to their extraordinarily large size and insufficient vascularization, especially in obese subjects. We have previously shown that during cold exposure, connexin43 (Cx43) gap junctions are induced and activated to connect neighboring adipocytes to share limited sympathetic neuronal input amongst multiple cells. We reason the same mechanism may be leveraged to improve the efficacy of various pharmacological agents that target adipose tissue. Using an adipose tissue-specific Cx43 overexpression mouse model, we demonstrate effectiveness in connecting adipocytes to augment metabolic efficacy of the β 3-adrenergic receptor agonist Mirabegron and FGF21. Additionally, combing those molecules with the Cx43 gap junction channel activator danegaptide shows a similar enhanced efficacy. In light of these findings, we propose a model in which connecting adipocytes via Cx43 gap junction channels primes adipose tissue to pharmacological agents designed to engage it. Thus, Cx43 gap junction activators hold great potential for combination with additional agents targeting adipose tissue.

Prescription profile of antiarrhythmic drugs in a group of patients in Colombia / Perfil de prescripción de fármacos antiarrítmicos en un grupo de pacientes en Colombia

Abstract Objective: To determine the prescription patterns of antiarrhythmic drugs and variables associated with their use in a population of patients affiliated with the Colombian Health System. Methods: A cross-sectional study was performed on a population database with patients who received antiarrhythmics from March to May 2016. Sociodemographic, pharmacological and comedication variables were included. SPSS-24 was used for data analysis using X2 tests and multivariate analyses. Results: In total, 2772 patients were treated with antiarrhythmics in the evaluated period. The mean age was 70.1 ± 13.1 years, and 51.2% were women. In total, 79.4% used a β-blocker, 58.5% amiodarone and 2.9% a calcium channel blocker. Moreover, 1192 (43.0%) patients were prescribed a single antiarrhythmic, and 1580 (57.0%) received two or more. There were 2603 patients (93.9%) with comedication, including lipid-lowering drugs (62.6%), inhibitors of the renin angiotensin aldosterone system (62.6%) and antiplatelet drugs (42.0%). Age older than 65 years increased the probability of comedication (odds ratio [OR]: 2.48; 95% confidence interval [95% CI]: 1.59-3.85), and the risk was proportional to age. We identified 1364 patients treated with conditional risk medications for QT prolongation (49.2%), 68 with a possible risk (2.5%) and 171 (6.2%) with a known risk. Conclusion: Antiarrhythmic drugs recommended by clinical practice guidelines are mainly used; however, risk interactions interactions of QT prolongation were identified and should be taken into account by physicians to avoid adverse events or complications.

Resumen Objetivo: determinar los patrones de prescripción de fármacos antiarrítmicos y variables asociadas a su utilización en una población de pacientes afiliados al sistema de salud de Colombia. Métodos: estudio de corte transversal sobre una base de datos poblacional con pacientes que recibieron antiarrítmicos entre marzo y mayo de 2016. Se incluyeron variables sociodemográficas, farmacológicas y de comedicación. Para el análisis de datos se utilizó SPSS-24, realizando pruebas X2 y análisis multivariado. Resultados: se encontraron 2 772 pacientes en tratamiento con antiarrítmicos en el periodo evaluado, la edad promedio fue 70,1 ± 13,1 años, 51,2 % eran mujeres. El 79,4% utilizó algún β-bloqueador, 58,5% amiodarona y 2,9 % algún bloqueante de canales de calcio. Al 43 % se les prescribió un solo antiarrítmico y 57 % recibieron dos o más. El 93,9 % tenía con alguna comedicación, especialmente hipolipemiantes (62,6 %), inhibidores del sistema renina angiotensina aldosterona (62,6 %) y antiagregantes (42 %). Ser mayor de 65 años aumentó la probabilidad de comedicación (OR:2,48; IC95 %:1,59-3,85) y el riesgo fue proporcional al incremento de la edad. El 49,2 % (n=1364) estaban tratados con medicamentos de riesgo condicional de prolongación del QT, 2,5 % (n=68) con riesgo posible y 6,2% (n=171) de riesgo conocido. Conclusión: se están utilizando los mismos fármacos recomendados por las guías de práctica clínica; sin embargo, se encontraron interacciones de riesgo de prolongación del intervalo QT que deben ser tenidas en cuenta para evitar eventos o complicaciones en los pacientes.

Como a dexmedetomidina e a clonidina devem ser prescritas no ambiente de terapia intensiva? / How should dexmedetomidine and clonidine be prescribed in the critical care setting?

RESUMO O manejo cardíaco, ventilatório e renal no ambiente de terapia intensiva tem melhorado nas últimas décadas. Cognição e sedação representam dois dos últimos desafios a vencer. Como a sedação convencional não é ideal, e a sedação evocada por agonistas adrenérgicos alfa-2 (sedação "cooperativa" com dexmedetomidina, clonidina ou guanfacina) representa uma alternativa valiosa, este artigo abrange três tópicos práticos para os quais há lacunas na medicina baseada em evidência. O primeiro deles é a mudança de sedação convencional para sedação cooperativa ("mudança"): a resposta curta consiste em retirada abrupta de sedação convencional, implantação imediata de infusão de um agonista alfa-2 e uso de "sedação de resgate" (bolos de midazolam) ou "sedação agressiva" (haloperidol em bolos) para estabilizar a sedação cooperativa. O segundo tópico é a mudança de sedação convencional para sedação cooperativa em pacientes instáveis (por exemplo: delirium tremens refratário, choque séptico, síndrome do desconforto respiratório agudo etc.), pois, para evitar a hipotensão e a bradicardia provocadas por desativadores simpáticos, a resposta curta é manter o volume sistólico por administração de volume, vasopressores e inotrópicos. Por fim, para evitar essas mudanças e dificuldades associadas, os agonistas alfa-2 podem ser sedativos de primeira linha. A resposta curta é administrar agonistas alfa-2 lentamente desde a admissão ou intubação endotraqueal, até estabilização da sedação cooperativa. Dessa forma, conclui-se que os agonistas alfa-2 são, ao mesmo tempo, agentes desativadores simpáticos e sedativos, bem como a desativação simpática implica na manutenção do volume sistólico e na avaliação persistente da volemia. A medicina baseada em evidência deve documentar esta proposta.

ABSTRACT Cardiac, ventilatory and kidney management in the critical care setting has been optimized over the past decades. Cognition and sedation represent one of the last remaning challenges. As conventional sedation is suboptimal and as the sedation evoked by alpha-2 adrenergic agonists ("cooperative" sedation with dexmedetomidine, clonidine or guanfacine) represents a valuable alternative, this manuscript covers three practical topics for which evidence-based medicine is lacking: a) Switching from conventional to cooperative sedation ("switching"): the short answer is the abrupt withdrawal of conventional sedation, immediate implementation of alpha-2 agonist infusion and the use of "rescue sedation" (midazolam bolus[es]) or "breakthrough sedation" (haloperidol bolus[es]) to stabilize cooperative sedation. b) Switching from conventional to cooperative sedation in unstable patients (e.g., refractory delirium tremens, septic shock, acute respiratory distress syndrome, etc.): to avoid hypotension and bradycardia evoked by sympathetic deactivation, the short answer is to maintain the stroke volume through volume loading, vasopressors and inotropes. c) To avoid these switches and associated difficulties, alpha-2 agonists may be considered first-line sedatives. The short answer is to administer alpha-2 agonists slowly from admission or endotracheal intubation up to stabilized cooperative sedation. The "take home" message is as follows: a) alpha-2 agonists are jointly sympathetic deactivators and sedative agents; b) sympathetic deactivation implies maintaining the stroke volume and iterative assessment of volemia. Evidence-based medicine should document our propositions.