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1.
Eur J Med Res ; 27(1): 238, 2022 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-36348473

RESUMO

BACKGROUND: To observe the effect and mechanism of alpha-adrenergic receptor inhibitor phentolamine (PTL) in a rabbit model of acute pulmonary embolism (APE) combined with shock. METHODS: Twenty-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. RESULTS: In 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. CONCLUSION: In 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.


Assuntos
Hominidae , Embolia Pulmonar , Choque , Animais , Coelhos , Fentolamina/farmacologia , Embolia Pulmonar/complicações , Embolia Pulmonar/tratamento farmacológico , Receptores Adrenérgicos alfa
2.
BMC Ophthalmol ; 22(1): 402, 2022 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-36209072

RESUMO

PURPOSE: Dim light vision disturbances (DLD) comprise a wide range of symptoms affecting the quality of vision at low illumination including glare, halos, and starbursts. This exploratory study investigated 1.0% phentolamine mesylate ophthalmic solution (PMOS) as a treatment to improve vision and image quality for patients with DLD. METHODS: In this placebo-controlled, randomized, double-masked clinical trial, 24 adult patients with severe DLD were randomized in a 2:1 ratio to receive either one dose of PMOS or placebo. Subjects were eligible if they reported experiencing severe night vision difficulty that was not eliminated by distance spectacle correction and scored ≥0.3 log units below the normal range of contrast sensitivity assessed under mesopic conditions with glare at ≥2 spatial frequencies. Key efficacy outcomes were change from baseline in pupil diameter, contrast sensitivity, and visual acuity. Safety measures including intraocular pressure, conjunctival hyperemia, and systemic effects were also assessed. RESULTS: Eight subjects were randomized to placebo (63% female; mean age 47 years) and 16 were randomized to PMOS (75% female; mean age 42 years). Mean (SD) pupil diameter of PMOS-treated subjects decreased significantly - 1.3 mm (0 to - 2.8 mm) with p < 0.0001. Mean contrast sensitivity with glare in PMOS-treated subjects improved significantly post-treatment at spatial frequencies 3, 6, 12, and 18 cycles per degree (p ≤ 0.03). PMOS also demonstrated improvements in the numbers of letters read for mesopic and photopic, high- and low-contrast visual acuity (LCVA). Importantly, a statistically greater proportion of PMOS-treated eyes registered mesopic LCVA 5 letter (69% vs. 31%, p = 0.029) and 10 letter (34% vs. 6%, p = 0.04) improvement, with a trend at 15 letters (19% vs. 0%, p = 0.16). PMOS was well tolerated with the only reported side effect being a mild increase in conjunctival hyperemia. CONCLUSION: PMOS was well tolerated and effectively reduced pupil size with improvements in contrast sensitivity and visual acuity in adults with severe DLD. Future Phase 3 studies should be conducted to further evaluate its potential to treat DLD. TRIAL REGISTRATION: The trial registration number is NCT04004507 (02/07/2019). Retrospectively registered.


Assuntos
Hiperemia , Cegueira Noturna , Adulto , Sensibilidades de Contraste , Feminino , Ofuscação , Humanos , Masculino , Pessoa de Meia-Idade , Visão Noturna , Soluções Oftálmicas , Fentolamina/uso terapêutico , Transtornos da Visão/tratamento farmacológico
4.
JAMA Netw Open ; 5(10): e2236131, 2022 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-36287566

RESUMO

Importance: Despite being the most common female sexual health complaint worldwide, current treatment options for hypoactive sexual desire disorder (HSDD) are limited in their safety and effectiveness. The hormone kisspeptin is a key endogenous activator of the reproductive hormonal axis with additional emerging roles in sexual and emotional behavior; however, its effects in women with HSDD are unknown. Objective: To test the hypothesis that kisspeptin enhances sexual and attraction brain processing in women with HSDD. Design, Setting, and Participants: This randomized clinical trial was double-masked and placebo controlled with a 2-way crossover. The trial was conducted in a university research setting in the UK from October 2020 to April 2021. Eligible participants were premenopausal women with HSDD. Functional neuroimaging, psychometric, and hormonal analyses were employed to investigate the effects of kisspeptin administration on brain processing, in response to erotic stimuli (erotic videos) and facial attraction (face images of varying attractiveness). Data were analyzed from May to December 2021. Interventions: A 75-minute intravenous infusion of kisspeptin-54 (1 nmol/kg/h) vs equivalent-rate placebo infusion. Main Outcomes and Measures: Blood oxygen level-dependent responses across the whole brain and regions of interest during kisspeptin vs placebo administration in response to erotic and facial attraction stimuli. Results: Of the 40 participants who were randomized, 32 women completed both kisspeptin and placebo visits, with a mean (SE) age of 29.2 (1.2) years. Kisspeptin administration resulted in modulations in sexual and facial attraction brain processing (deactivation of the left inferior frontal gyrus: Z max, 3.76; P = .01; activation of the right postcentral and supramarginal gyrus: Z max, 3.73; P < .001; deactivation of the right temporoparietal junction: Z max 4.08; P = .02). Furthermore, positive correlations were observed between kisspeptin-enhanced hippocampal activity in response to erotic videos, and baseline distress relating to sexual function (r = 0.469; P = .007). Kisspeptin's enhancement of posterior cingulate cortex activity in response to attractive male faces also correlated with reduced sexual aversion, providing additional functional significance (r = 0.476, P = .005). Kisspeptin was well-tolerated with no reported adverse effects. Conclusions and Relevance: These findings lay the foundations for clinical applications for kisspeptin in women with HSDD. Trial Registration: ISRCTN trial registry identifier: ISRCTN17271094.


Assuntos
Libido , Disfunções Sexuais Psicogênicas , Feminino , Masculino , Humanos , Adulto , Kisspeptinas/farmacologia , Kisspeptinas/uso terapêutico , Fentolamina/farmacologia , Fentolamina/uso terapêutico , Disfunções Sexuais Psicogênicas/tratamento farmacológico , Hormônios/farmacologia , Hormônios/uso terapêutico
5.
Clin Sci (Lond) ; 136(20): 1449-1466, 2022 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-36205102

RESUMO

Exposure to low temperatures has been associated with increased gastroesophageal variceal bleeding in patients with cirrhosis and portal hypertension; however, the mechanism remains unclear. Therefore, the aim of the present study was to evaluate the impact of environmental temperature reduction on portal hypertension and the role of adrenergic signaling pathways in this phenomenon. Male Sprague-Dawley rats underwent common bile duct ligation or partial portal vein ligation to induce liver cirrhosis and/or portal hypertension. The impacts of acute or chronic changes in environmental temperature were surveyed. The results showed that acute cooling from 25 to 15°C and 5°C increased the portal pressure by 10.6% and 15.5% in cirrhotic rats, and by 22.2% and 36.1% in portal hypertensive rats, respectively. The transient portal pressure surge started shortly after cooling, reached a peak within 5 min and returned to baseline after 10 min. Systemic vascular resistance, mean arterial pressure and splanchnic blood flow increased significantly at the same time. Plasma epinephrine and norepinephrine concentrations, phospholipase C, protein kinase C activity and myosin phosphorylation of peripheral arteries increased significantly in response to cooling. Phentolamine (an α-blocker) but not propranolol (a non-selective ß-blocker) dose-dependently inhibited the transient portal pressure surge and aforementioned molecular changes. In conclusion, environmental temperature reduction induced peripheral vasoconstriction via α-adrenergic pathways, and redistribution of blood flow to the splanchnic system led to a surge in transient portal pressure. Treatment with α-adrenergic receptor antagonists may exert additional benefits in controlling portal hypertension, especially on exposure to low temperatures.


Assuntos
Varizes Esofágicas e Gástricas , Hipertensão Portal , Ratos , Masculino , Animais , Pressão na Veia Porta , Temperatura , Fentolamina/farmacologia , Circulação Esplâncnica , Ratos Sprague-Dawley , Hemorragia Gastrointestinal , Antagonistas Adrenérgicos beta/farmacologia , Cirrose Hepática , Hemodinâmica , Norepinefrina/farmacologia , Epinefrina/farmacologia , Fosfolipases Tipo C , Proteína Quinase C
6.
Trials ; 23(1): 790, 2022 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-36127739

RESUMO

BACKGROUND: Despite the fast establishment of new therapeutic agents in the management of COVID-19 and large-scale vaccination campaigns since the beginning of the SARS-CoV-2 pandemic in early 2020, severe disease courses still represent a threat, especially to patients with risk factors. This indicates the need for alternative strategies to prevent respiratory complications like acute respiratory distress syndrome (ARDS) associated with COVID-19. Aviptadil, a synthetic form of human vasoactive intestinal peptide, might be beneficial for COVID-19 patients at high risk of developing ARDS because of its ability to influence the regulation of exaggerated pro-inflammatory proteins and orchestrate the lung homeostasis. Aviptadil has recently been shown to considerably improve the prognosis of ARDS in COVID-19 when applied intravenously. An inhaled application of aviptadil has the advantages of achieving a higher concentration in the lung tissue, fast onset of activity, avoiding the hepatic first-pass metabolism, and the reduction of adverse effects. The overall objective of this project is to assess the efficacy and safety of inhaled aviptadil in patients hospitalized for COVID-19 at high risk of developing ARDS. METHODS: This multicenter, placebo-controlled, double-blinded, randomized trial with 132 adult patients hospitalized for COVID-19 and at high risk for ARDS (adapted early acute lung injury score ≥ 2 points) is conducted in five public hospitals in Europe. Key exclusion criteria are mechanical ventilation at baseline, need for intensive care at baseline, and severe hemodynamic instability. Patients are randomly allocated to either inhale 67 µg aviptadil or normal saline (three times a day for 10 days), in addition to standard care, stratified by center. The primary endpoint is time from hospitalization to clinical improvement, defined as either hospital discharge, or improvement of at least two levels on the nine-level scale for clinical status suggested by the World Health Organization. DISCUSSION: Treatment strategies for COVID-19 are still limited. In the context of upcoming new variants of SARS-CoV-2 and possible inefficacy of the available vaccines and antibody therapies, the investigation of alternative therapy options plays a crucial role in decreasing associated mortality and improving prognosis. Due to its unique immunomodulating properties also targeting the SARS-CoV-2 pathways, inhaled aviptadil may have the potential to prevent ARDS in COVID-19. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04536350 . Registered 02 September 2020.


Assuntos
COVID-19 , Síndrome do Desconforto Respiratório , Adulto , Combinação de Medicamentos , Humanos , Estudos Multicêntricos como Assunto , Fentolamina , Ensaios Clínicos Controlados Aleatórios como Assunto , Síndrome do Desconforto Respiratório/diagnóstico , Síndrome do Desconforto Respiratório/tratamento farmacológico , SARS-CoV-2 , Solução Salina , Peptídeo Intestinal Vasoativo
7.
Crit Care Med ; 50(11): 1545-1554, 2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-36044317

RESUMO

OBJECTIVES: Respiratory failure is a lethal complication of COVID-19 that has remained resistant to drug therapy. Vasoactive intestinal peptide (VIP) is shown in nonclinical studies to upregulate surfactant production, inhibit cytokine synthesis, prevent cytopathy, and block replication of the severe acute respiratory syndrome coronavirus 2 virus in pulmonary cells. The study aims to determine whether Aviptadil (synthetic VIP) can improve survival and recovery in patients with COVID-19 respiratory failure compared with placebo and demonstrate biological effects in such patients. DESIGN: A multicenter, placebo-controlled trial. SETTING: Ten U.S. hospitals: six tertiary-care hospitals and four community hospitals. PATIENTS: A total of 196 patients with COVID-19 respiratory failure. INTERVENTIONS: Participants were randomized 2:1 to receive 3 days of IV Aviptadil or placebo. MEASUREMENTS AND MAIN RESULTS: The primary end point (alive and free from respiratory failure at day 60) did not reach statistical significance (odds ratio [OR], 1.6; 95% CI, 0.86-3.11) for patients treated with Aviptadil when controlling for baseline ventilation status as prespecified in the protocol. There was, however, a statistically significant two-fold odds of improved survival (OR, 2.0; 95% CI, 1.1-3.9) at 60 days ( p = 0.035). There was significant improvement in respiratory distress ratio and reduced interleukin 6 cytokine release ( p = 0.02) by day 3.Subgroup analysis identified a statistically significant likelihood of achieving primary end point among those treated with high-flow nasal oxygen at baseline ( p = 0.039). Subjects on mechanical ventilation also experienced a 10-fold increased odds of survival with drug versus placebo ( p = 0.031). CONCLUSIONS: The primary end point did not reach statistical significance, indicating that there was no difference between Aviptadil versus placebo. However, Aviptadil improves the likelihood of survival from respiratory failure at day 60 in critical COVID-19 across all sites of care. Given the absence of drug-related serious adverse events and acceptable safety profile, we believe the benefit versus risk for the use of Aviptadil is favorable for patient treatment.


Assuntos
COVID-19 , Insuficiência Respiratória , COVID-19/tratamento farmacológico , Combinação de Medicamentos , Humanos , Interleucina-6 , Oxigênio , Fentolamina , Insuficiência Respiratória/tratamento farmacológico , Tensoativos , Peptídeo Intestinal Vasoativo/uso terapêutico
8.
Front Endocrinol (Lausanne) ; 13: 824616, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35937820

RESUMO

Aims: Essential hypertension (EHT) is characterized by cardiovascular hyperreactivity to stress but underlying mechanism are not fully understood. Here, we investigated the role of α-adrenergic receptors (α-AR) in the cardiovascular reactivity to a norepinephrine (NE)-stress reactivity-mimicking NE-infusion in essential hypertensive individuals (HT) as compared to normotensive individuals (NT). Methods: 24 male HT and 24 male NT participated in three experimental trials on three separate days with a 1-min infusion followed by a 15-min infusion. Trials varied in infusion-substances: placebo saline (Sal)-infusions (trial-1:Sal+Sal), NE-infusion without (trial-2:Sal+NE) or with non-selective α-AR blockade by phentolamine (PHE) (trial-3:PHE+NE). NE-infusion dosage (5µg/ml/min) and duration were chosen to mimic duration and physiological effects of NE-release in reaction to established stress induction protocols. We repeatedly measured systolic (SBP) and diastolic blood pressure (DBP) as well as heart rate before, during, and after infusions. Results: SBP and DBP reactivity to the three infusion-trials differed between HT and NT (p's≤.014). HT exhibited greater BP reactivity to NE-infusion alone compared to NT (trial-2-vs-trial-1: p's≤.033). Group differences in DBP reactivity to NE disappeared with prior PHE blockade (trial-3: p=.26), while SBP reactivity differences remained (trial-3: p=.016). Heart rate reactivity to infusion-trials did not differ between HT and NT (p=.73). Conclusion: Our findings suggest a mediating role of α-AR in DBP hyperreactivity to NE-infusion in EHT. However, in SBP hyperreactivity to NE-infusion in EHT, the functioning of α-AR seems impaired suggesting that the SBP hyperreactivity in hypertension is not mediated by α-AR.


Assuntos
Adrenérgicos , Hipertensão Essencial , Norepinefrina , Adrenérgicos/farmacologia , Pressão Sanguínea , Hipertensão Essencial/tratamento farmacológico , Humanos , Hipertensão , Infusões Intravenosas , Masculino , Norepinefrina/farmacologia , Fentolamina/farmacologia
9.
Acta Med Okayama ; 76(3): 255-263, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35790355

RESUMO

Mirror image pain (MIP) is a type of extraterritorial pain that results in contralateral pain or allodynia. Glutamate transporter-1 (GLT-1) is expressed in astrocytes and plays a role in maintaining low glutamate levels in the synaptic cleft. Previous studies have shown that GLT-1 dysfunction induces neuropathic pain. Our previous study revealed bilateral GLT-1 downregulation in the spinal cord of a spared nerve injury (SNI) rat. We hypothesized that spinal GLT-1 is involved in the mechanism of MIP. We also previously demonstrated noradrenergic GLT-1 regulation. Therefore, this study aimed to investigate the effect of an α1 adrenergic antagonist on the development of MIP. Rats were subjected to SNI. Changes in pain behavior and GLT-1 protein levels in the SNI rat spinal cords were then examined by intrathecal administration of the α1 adrenergic antagonist phentolamine, followed by von Frey test and western blotting. SNI resulted in the development of MIP and bilateral downregulation of GLT-1 protein in the rat spinal cord. Intrathecal phentolamine increased contralateral GLT-1 protein levels and partially ameliorated the 50% paw withdrawal threshold in the contralateral hind paw. Spinal GLT-1 upregulation by intrathecal phentolamine ameliorates MIP. GLT-1 plays a role in the development of MIPs.


Assuntos
Antagonistas de Receptores Adrenérgicos alfa 1 , Neuralgia , Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Animais , Modelos Animais de Doenças , Neuralgia/tratamento farmacológico , Fentolamina/farmacologia , Ratos , Ratos Sprague-Dawley
10.
Theranostics ; 12(10): 4718-4733, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35832088

RESUMO

Excessive sympathetic activity and norepinephrine (NE) release play crucial roles in the pathogeneses of hypertension. Sympathetic fibers innervate adventitia rather than media of arteries. However, the roles of NE in adventitial fibroblasts (AFs) are unknown. This study investigated the roles of NE in regulating AFs-derived extracellular vesicles (EVs) release and vascular smooth muscle cells (VSMCs) proliferation in hypertension. Methods: AFs and VSMCs were prepared from aorta of Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). AFs were treated with NE (10 µM) for 24 h (every 6 h, 4 times), and cultured in exosomes-depleted medium for 48 h. EVs were isolated from AFs medium with ultracentrifugation for identification and transfer to VSMCs. Results: NE promoted AFs phenotypic transformation and proliferation, which were prevented by α-receptor antagonist phentolamine rather than ß-receptor antagonist propranolol. NE-treated AFs conditioned medium stimulated VSMCs proliferation, which was inhibited by either exosome inhibitor GW4869 or phentolamine. NE increased small EVs number, diameter and angiotensin converting enzyme (ACE) contents. The NE-induced EVs release was abolished by GW4869. The EVs from NE-treated AFs stimulated VSMCs proliferation, which was prevented by angiotensin II type 1 receptor antagonist losartan. The EVs from the ACE knockdown-treated AFs showed lower ACE contents, and lost their roles in stimulating VSMCs proliferation. Conclusion: NE promotes AFs-derived small EVs release and ACE transfer, and then causes VSMCs proliferation in hypertension. Intervention of AFs-derived EVs release may be potential therapeutics for excessive sympathetic activation-related vascular remodeling in hypertension.


Assuntos
Vesículas Extracelulares , Hipertensão , Túnica Adventícia/metabolismo , Animais , Proliferação de Células , Células Cultivadas , Vesículas Extracelulares/metabolismo , Fibroblastos/metabolismo , Hipertensão/metabolismo , Músculo Liso Vascular/metabolismo , Norepinefrina/metabolismo , Norepinefrina/farmacologia , Fentolamina/metabolismo , Fentolamina/farmacologia , Ratos , Ratos Endogâmicos WKY
11.
Biomed Res Int ; 2022: 6554993, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35757477

RESUMO

Objective: Pediatric patients are facing greater difficulties in radial catheterization for anatomic variation and smaller diameter. This study is to investigate the efficacy of phentolamine accompanied by lidocaine subcutaneously under ultrasound guidance on radial catheterization in pediatric patients. Methods: 66 pediatric patients were enrolled and randomly divided into saline group, phentolamine group, and phentolamine+lidocaine group. Baseline characteristics and surgical types were collected. Relevant solutions were subcutaneously injected, and catheterization was subsequently conducted under ultrasound guidance. Radial artery diameter and depth were measured, the success rate of catheterization and procedure time were calculated, and the complications were evaluated with ultrasonography. Results: No significant differences were observed in age, sex, weight, American Society of Anesthesiologists' classification, systolic blood pressure, diastolic blood pressure, heart rate, hemoglobin, and surgical types among three groups. Subcutaneously, the diameter in phentolamine and phentolamine+lidocaine groups increased significantly compared with the saline group. Moreover, the diameter also increased significantly after injection compared with that before injection both in the phentolamine and phentolamine+lidocaine groups. The first-attempt success rates were significantly higher while the procedure times of cannulation were shorter in the phentolamine and phentolamine+lidocaine groups than that in the saline group. Kaplan-Meier analysis showed that the overall procedure time was shorter in the phentolamine and phentolamine+lidocaine groups than the saline group. Overall complications and vasospasm incidence were lower in the phentolamine and phentolamine+lidocaine groups than the saline group. Conclusion: Phentolamine accompanied by lidocaine subcutaneous injection under ultrasound guidance improved the first-attempt success rate and reduced the complication of radial artery catheterization in pediatric patients.


Assuntos
Lidocaína , Artéria Radial , Cateterismo/métodos , Criança , Humanos , Fentolamina/farmacologia , Fentolamina/uso terapêutico , Artéria Radial/diagnóstico por imagem , Artéria Radial/cirurgia , Ultrassonografia , Ultrassonografia de Intervenção/métodos
12.
Sci Rep ; 12(1): 3344, 2022 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-35228612

RESUMO

Incomplete functional recovery after peripheral nerve injury (PNI) often results in devastating physical disabilities in human patients. Despite improved progress in surgical and non-surgical approaches, achieving complete functional recovery following PNI remains a challenge. This study demonstrates that phentolamine may hold a significant promise in treating nerve injuries and denervation induced muscle atrophy following PNI. In a sciatic nerve crush injury mouse model, we found that phentolamine treatment enhanced motor and functional recovery, protected axon myelination, and attenuated injury-induced muscle atrophy in mice at 14 days post-injury (dpi) compared to saline treatment. In the soleus of phentolamine treated animals, we observed the downregulation of phosphorylated signal transducer and activator of transcription factor 3 (p-STAT3) as well as muscle atrophy-related genes Myogenin, muscle ring finger 1 (MuRF-1), and Forkhead box O proteins (FoxO1, FoxO3). Our results show that both nerve and muscle recovery are integral components of phentolamine treatment-induced global functional recovery in mice at 14 dpi. Moreover, phentolamine treatment improved locomotor functional recovery in the mice after spinal cord crush (SCC) injury. The fact that phentolamine is an FDA approved non-selective alpha-adrenergic blocker, clinically prescribed for oral anesthesia reversal, hypertension, and erectile dysfunction makes this drug a promising candidate for repurposing in restoring behavioral recovery following PNI and SCC injuries, axonal neuropathy, and muscle wasting disorders.


Assuntos
Traumatismos dos Nervos Periféricos , Neuropatia Ciática , Animais , Axônios/metabolismo , Humanos , Masculino , Camundongos , Músculo Esquelético/patologia , Atrofia Muscular/patologia , Regeneração Nervosa , Fentolamina/uso terapêutico , Recuperação de Função Fisiológica/fisiologia , Nervo Isquiático/lesões
13.
Hand Surg Rehabil ; 41(3): 311-316, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35065270

RESUMO

Wide awake local anesthetic no tourniquet (WALANT) is gaining popularity amongst hand surgeons. Digital adrenaline use has been shown to be safe in multiple studies and the misconception forbidding it is receding. Phentolamine has been shown to safely reverse the effects of adrenaline should the feared complication of digital ischemia occur. A survey was circulated to 40 specialist practitioners who regularly perform hand procedures at a major tertiary plastic and hand surgery unit. Knowledge and understanding of WALANT, onset and duration of adrenaline effects and reversal was assessed. Whilst the majority of respondents (80%) recognized digital adrenaline use as safe, only 65% were aware of the delay until adrenaline takes full effect. Similarly, only 25% of respondents were aware of the duration of effect of adrenaline. Half of respondents were aware that phentolamine is the established reversal agent for adrenaline with only 20% knowing the correct dose. Given the lack of clinician knowledge surrounding adrenaline and its reversal, we feel that to safely undertake WALANT surgery at our Unit a WALANT protocol must be implemented. Drawing on the successes in the airline industry, a variety of safety frameworks have been established to deliver targeted education for prevention and eventual management of predictable risks. We plan to develop a checklist style protocol targeting the knowledge gaps raised in the survey. This will educate and equip all practitioners working with adrenaline with the knowledge to safely manage complications should they occur. LEVEL OF EVIDENCE: Level 5 (UK Oxford Centre for Evidence based Medicine (CEBM) Levels of Evidence).


Assuntos
Anestesia Local , Anestésicos Locais , Anestesia Local/métodos , Contraindicações , Epinefrina/uso terapêutico , Mãos/cirurgia , Humanos , Fentolamina/uso terapêutico
14.
Environ Sci Pollut Res Int ; 29(6): 8109-8125, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34846667

RESUMO

Vasoactive intestinal peptide (VIP) is a neuropeptide that is produced by the lymphoid cells and plays a major role in immunological functions for controlling the homeostasis of the immune system. VIP has been identified as a potent anti-inflammatory factor, in boosting both innate and adaptive immunity. Since December 2019, SARS-Cov-2 was found responsible for the disease COVID-19 which has spread worldwide. No specific therapies or 100% effective vaccines are yet available for the treatment of COVID-19. Drug repositioning may offer a strategy and several drugs have been repurposed, including lopinavir/ritonavir, remdesivir, favipiravir, and tocilizumab. This paper describes the main pharmacological properties of synthetic VIP drug (Aviptadil) which is now under clinical trials. A patented formulation of vasoactive intestinal polypeptide (VIP), named RLF-100 (Aviptadil), was developed and finally got approved for human trials by FDA in 2001 and in European medicines agency in 2005. It was awarded Orphan Drug Designation in 2001 by the US FDA for the treatment of acute respiratory distress syndrome and for the treatment of pulmonary arterial hypertension in 2005. Investigational new drug (IND) licenses for human trials of Aviptadil was guaranteed by both the US FDA and EMEA. Preliminary clinical trials seem to support Aviptadil's benefit. However, such drugs like Aviptadil in COVID-19 patients have peculiar safety profiles. Thus, adequate clinical trials are necessary for these compounds.


Assuntos
COVID-19 , Peptídeo Intestinal Vasoativo , Combinação de Medicamentos , Humanos , Fentolamina , SARS-CoV-2
15.
Cardiol Young ; 32(7): 1136-1142, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34530952

RESUMO

INTRODUCTION: The effects of alpha-blockade on haemodynamics during and following congenital heart surgery are well documented, but data on patient outcomes, mortality, and hospital charges are limited. The purpose of this study was to characterise the use of alpha-blockade during congenital heart surgery admissions and to determine its association with common clinical outcomes. MATERIALS AND METHODS: A cross-sectional study was conducted using the Pediatric Health Information System database. De-identified data for patients under 18 years of age with a cardiac diagnosis who underwent congenital heart surgery were obtained from 2004 to 2015. Patients were subdivided on the basis of receiving alpha-blockade with either phenoxybenzamine or phentolamine during admission or not. Continuous and categorical variables were analysed using Mann−Whitney U-tests and Fisher exact tests, respectively. Characteristics between subgroups were compared using univariate analysis. Regression analyses were conducted to determine the impact of alpha-blockade on ICU length of stay, hospital length of stay, billed charges, and mortality. RESULTS: Of the 81,313 admissions, 4309 (5.3%) utilised alpha-blockade. Phentolamine was utilised in 4290 admissions. In univariate analysis, ICU length of stay, total length of stay, inpatient mortality, and billed charges were all significantly higher in the alpha-blockade admissions. However, regression analyses demonstrated that other factors were behind these increased. Alpha-blockade was significantly, independently associated with a 1.5 days reduction in ICU length of stay (p < 0.01) and a 3.5 days reduction in total length of stay (p < 0.01). Alpha-blockade was significantly, independently associated with a reduction in mortality (odds ratio 0.8, 95% confidence interval 0.7−0.9). Alpha-blockade was not independently associated with any significant change in billed charges. CONCLUSIONS: Alpha-blockade is used in a subset of paediatric cardiac surgeries and is independently associated with significant reductions in ICU length of stay, hospital length of stay, and mortality without significantly altering billed charges.


Assuntos
Cardiopatias Congênitas , Hospitalização , Adolescente , Criança , Estudos Transversais , Cardiopatias Congênitas/cirurgia , Mortalidade Hospitalar , Humanos , Tempo de Internação , Fentolamina , Estudos Retrospectivos
16.
Front Immunol ; 12: 628065, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34220796

RESUMO

Objective: Hypersympathetic activity is prominent in rheumatoid arthritis, and major life stressors precede onset in ~80% of patients. These findings and others support a link between stress, the sympathetic nervous system and disease onset and progression. Here, we extend previous research by evaluating how selective peripherally acting α/ß2-adrenergic drugs affect joint destruction in adjuvant-induced arthritis. Methods: Complete Freund's adjuvant induced inflammatory arthritis in male Lewis rats. Controls received no treatment. Arthritic rats then received vehicle or twice-daily treatment with the α-adrenergic antagonist, phentolamine (0.5 mg/day) and the ß2-adrenergic agonist, terbutaline (1200 µg/day, collectively named SH1293) from day (D) of disease onset (D12) through acute (D21) and severe disease (D28). Disease progression was assessed in the hind limbs using dorsoplantar widths, X-ray analysis, micro-computed tomography, and routine histology on D14, D21, and D28 post-immunization. Results: On D21, SH1293 significantly attenuated arthritis in the hind limbs, based on reduced lymphocytic infiltration, preservation of cartilage, and bone volume. Pannus formation and sympathetic nerve loss were not affected by SH1293. Bone area and osteoclast number revealed high- and low-treatment-responding groups. In high-responding rats, treatment with SH1293 significantly preserved bone area and decreased osteoclast number, data that correlated with drug-mediated joint preservation. SH1293 suppressed abnormal bone formation based on reduced production of osteophytes. On D28, the arthritic sparing effects of SH1293 on lymphocytic infiltration, cartilage and bone sparing were maintained at the expense of bone marrow adipocity. However, sympathetic nerves were retracted from the talocrural joint. Conclusion and Significance: Our findings support a significant delay in early arthritis progression by treatment with SH1293. Targeting sympathetic neurotransmission may provide a strategy to slow disease progression.


Assuntos
Antagonistas Adrenérgicos alfa/farmacologia , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Artrite Experimental/prevenção & controle , Articulações/efeitos dos fármacos , Fentolamina/farmacologia , Receptores Adrenérgicos alfa/efeitos dos fármacos , Receptores Adrenérgicos beta 2/efeitos dos fármacos , Terbutalina/farmacologia , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Combinação de Medicamentos , Adjuvante de Freund , Articulações/diagnóstico por imagem , Articulações/metabolismo , Articulações/patologia , Masculino , Ratos Endogâmicos Lew , Receptores Adrenérgicos alfa/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Transdução de Sinais
18.
Molecules ; 26(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071269

RESUMO

Vortioxetine is a multimodal antidepressant drug that affects several brain neurochemicals and has the potential to induce various pharmacological effects on the central nervous system. Therefore, we investigated the centrally mediated analgesic efficacy of this drug and the mechanisms underlying this effect. Analgesic activity of vortioxetine (5, 10 and 20 mg/kg, p.o.) was examined by tail-clip, tail-immersion and hot-plate tests. Motor performance of animals was evaluated using Rota-rod device. Time course measurements (30-180 min) showed that vortioxetine (10 and 20 mg/kg) administrations significantly increased the response latency, percent maximum possible effect and area under the curve values in all of the nociceptive tests. These data pointed out the analgesic effect of vortioxetine on central pathways carrying acute thermal and mechanical nociceptive stimuli. Vortioxetine did not alter the motor coordination of mice indicating that the analgesic activity of this drug was specific. In mechanistic studies, pre-treatments with p-chlorophenylalanine (serotonin-synthesis inhibitor), NAN-190 (serotonin 5-HT1A receptor antagonist), α-methyl-para-tyrosine (catecholamine-synthesis inhibitor), phentolamine (non-selective α-adrenoceptor blocker), and naloxone (non-selective opioid receptor blocker) antagonised the vortioxetine-induced analgesia. Obtained findings indicated that vortioxetine-induced analgesia is mediated by 5-HT1A serotonergic, α-adrenergic and opioidergic receptors, and contributions of central serotonergic and catecholaminergic neurotransmissions are critical for this effect.


Assuntos
Analgésicos Opioides/química , Destreza Motora/fisiologia , Receptor 5-HT1A de Serotonina/metabolismo , Receptores Adrenérgicos alfa/metabolismo , Inibidores de Captação de Serotonina/metabolismo , Vortioxetina/farmacologia , Analgesia/métodos , Analgésicos/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Diazepam/farmacologia , Fenclonina/química , Masculino , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos BALB C , Morfina/farmacologia , Naloxona/química , Dor/tratamento farmacológico , Fentolamina/química , Piperazinas/química , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , alfa-Metiltirosina/química
20.
BMJ Case Rep ; 14(4)2021 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-33910787

RESUMO

Increased numbers of adrenaline auto-injectors (AAIs) are in circulation in the UK. The rate of accidental auto-injection injuries has increased during this time. Various treatment strategies are described in the literature. We present the case of a 32-year-old, right-hand-dominant man who sustained an unintentional AAI injury to the volar aspect of his right thumb. On presentation to the emergency department, the thumb was ischaemic. There was no improvement with simple conservative measures (warm soaks). The patient was referred to our tertiary hand surgery service and a digital block using 2% lidocaine promoted reversal of ischaemia within 2 hours with no long-term sequelae. Phentolamine rescue, on standby, was not necessary in this case. In this case report, we highlight the therapeutic challenges associated with managing AAI injury and propose an evidence-based treatment algorithm to prevent risk of severe adverse outcomes such as digital necrosis.


Assuntos
Epinefrina , Lidocaína , Adulto , Algoritmos , Humanos , Isquemia/induzido quimicamente , Isquemia/tratamento farmacológico , Masculino , Fentolamina
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