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European Journal of Pharmacology Nov 2023Intestinal ischemia/reperfusion injury (IRI) is a multifactorial, complex pathophysiological process in clinical settings. In recent years, intestinal IRI has received... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Intestinal ischemia/reperfusion injury (IRI) is a multifactorial, complex pathophysiological process in clinical settings. In recent years, intestinal IRI has received increasing attention due to increased morbidity and mortality. To date, there are no effective treatments. Dexmedetomidine (DEX), a highly selective α-adrenergic receptor agonist, has been demonstrated to be effective against intestinal IRI. In this systematic review and meta-analysis, we evaluated the efficacy and potential mechanisms of DEX as a treatment for intestinal IRI in animal models.
METHODS
Five databases (PubMed, Embase, Web of Science, Cochrane Library, and Scopus) were searched until March 15, 2023. Using the SYRCLE risk bias tool, we assessed methodological quality. Statistical analysis was conducted using STATA 12 and R 4.2.2. We analyzed the related outcomes (mucosa damage-related indicators; inflammation-relevant markers, oxidative stress markers) relied on the fixed or random-effects models.
RESULTS
There were 15 articles including 18 studies included, and 309 animals were involved in the studies. Compared to the model groups, DEX improved intestinal IRI. DEX decreased Chiu's score and serum diamine oxidase (DAO) level. DEX reduced the level of inflammation-relevant markers (interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α). DEX also improved oxidative stress (decreased malondialdehyde (MDA), increased superoxide dismutase (SOD)).
CONCLUSIONS
DEX's effectiveness in ameliorating intestinal IRI has been demonstrated in animal models. Antioxidation, anti-inflammation, anti-apoptotic, anti-pyroptosis, anti-ferroptosis, enhancing mitophagy, reshaping the gut microbiota, and gut barrier protection are possible mechanisms. However, in light of the heterogeneity and methodological quality of these studies, further well-designed preclinical studies are warranted before clinical implication.
Topics: Rats; Animals; Dexmedetomidine; Rats, Sprague-Dawley; Adrenergic alpha-2 Receptor Agonists; Reperfusion Injury; Inflammation; Ischemia
PubMed: 37778612
DOI: 10.1016/j.ejphar.2023.176090 -
The Journal of Experimental Biology Oct 2023Adrenaline and noradrenaline, released as hormones and/or neurotransmitters, exert diverse physiological functions in vertebrates, and teleost fishes are widely used as... (Review)
Review
Adrenaline and noradrenaline, released as hormones and/or neurotransmitters, exert diverse physiological functions in vertebrates, and teleost fishes are widely used as model organisms to study adrenergic regulation; however, such investigations often rely on receptor subtype-specific pharmacological agents (agonists and antagonists; see Glossary) developed and validated in mammals. Meanwhile, evolutionary (phylogenetic and comparative genomic) studies have begun to unravel the diversification of adrenergic receptors (ARs) and reveal that whole-genome duplications and pseudogenization events in fishes results in notable distinctions from mammals in their genomic repertoire of ARs, while lineage-specific gene losses within teleosts have generated significant interspecific variability. In this Review, we visit the evolutionary history of ARs (including α1-, α2- and β-ARs) to highlight the prominent interspecific differences in teleosts, as well as between teleosts and other vertebrates. We also show that structural modelling of teleost ARs predicts differences in ligand binding affinity compared with mammalian orthologs. To emphasize the difficulty of studying the roles of different AR subtypes in fish, we collate examples from the literature of fish ARs behaving atypically compared with standard mammalian pharmacology. Thereafter, we focus on specific case studies of the liver, heart and red blood cells, where our understanding of AR expression has benefited from combining pharmacological approaches with molecular genetics. Finally, we briefly discuss the ongoing advances in 'omics' technologies that, alongside classical pharmacology, will provide abundant opportunities to further explore adrenergic signalling in teleosts.
Topics: Animals; Phylogeny; Fishes; Vertebrates; Receptors, Adrenergic; Mammals; Adrenergic Agents; Evolution, Molecular
PubMed: 37823524
DOI: 10.1242/jeb.245859 -
Journal of Pediatric Hematology/oncology Nov 2023Infantile hemangioma (IH) is the most common benign tumor of infancy. For children with IH who require treatment, propranolol and other beta blockers have been shown to...
Infantile hemangioma (IH) is the most common benign tumor of infancy. For children with IH who require treatment, propranolol and other beta blockers have been shown to be safe and effective. Although consensus guidelines for managing IH have been published, anecdotal experience suggests that there remain variations in management. This study was performed to document these variations amongst providers and to identify areas for future research. We conducted an Internet-based survey of clinicians who treat patients with IH. Hypothetical cases and management scenarios were presented. Twenty-nine respondents participated in the survey. Most respondents use generic propranolol in infants with growing IH of the head and neck, with a goal dose of 2 mg/kg/d, until ~1 year of age. A variety of management strategies were documented including which patients should be treated, optimal dose and duration of therapy, how patients should be monitored, which patients should get additional workup, how propranolol should best be discontinued, and how often to see patients in follow-up. This study demonstrates wide practice variations in managing patients with IH. Further research is indicated to address these variations and develop additional/updated evidence-based guidelines.
Topics: Infant; Child; Humans; Propranolol; Hemangioma; Treatment Outcome; Skin Neoplasms; Adrenergic beta-Antagonists
PubMed: 37749794
DOI: 10.1097/MPH.0000000000002759 -
Journal of Perinatology : Official... Feb 2024Opioids and benzodiazepines have historically been employed for pain relief; however, they are associated with detrimental long-term neurodevelopmental consequences.... (Review)
Review
Opioids and benzodiazepines have historically been employed for pain relief; however, they are associated with detrimental long-term neurodevelopmental consequences. Dexmedetomidine, a highly selective alpha-2-adrenoreceptor agonist, has piqued interest as a viable alternative for neonates, owing to its potential analgesic and neuroprotective attributes. We conducted a systematic review to assess the efficacy and safety of dexmedetomidine utilization in neonates. We conducted a comprehensive search of Ovid, MEDLINE, EMBASE, PubMed, Cochrane, and CINAHL, spanning from January 2010 to September 2022. Our review encompassed six studies involving 252 neonates. Overall, dexmedetomidine may be effective in achieving sedation and analgesia. Furthermore, it may reduce the need for adjunctive sedation or analgesia, shorten the time to extubation, decrease the duration of mechanical ventilation, and accelerate the attainment of full enteral feeds. Notably, no significant adverse effects associated with dexmedetomidine were reported. Nevertheless, additional well-designed studies to establish both the efficacy and safety of dexmedetomidine in neonatal care are needed.
Topics: Infant, Newborn; Humans; Dexmedetomidine; Pain; Adrenergic alpha-2 Receptor Agonists; Pain Management; Analgesia
PubMed: 37845426
DOI: 10.1038/s41372-023-01802-5 -
Medicinal Research Reviews Jan 2024Soft tissue damage stimulates sympathetic nerves to release large amounts of catecholamine hormones which bind to β-adrenergic receptors (β-ARs) on the cell membrane... (Review)
Review
Soft tissue damage stimulates sympathetic nerves to release large amounts of catecholamine hormones which bind to β-adrenergic receptors (β-ARs) on the cell membrane surface. It activates the downstream effector molecules and impairs soft tissue wound healing. β-blockers specifically inhibit β-ARs activation in acute/chronic skin lesions and ulcerative hemangiomas. They also accelerate soft tissue wound healing by shortening the duration of inflammation, speeding keratinocyte migration and reepithelialization, promoting wound contraction and angiogenesis, and inhibiting bacterial virulence effects. In addition, β-blockers shorten wound healing periods in patients with severe thermal damage by reducing the hypermetabolic response. While β-blockers promote/inhibit corneal epithelial cell regeneration and restores limbal stem/progenitor cells function, it could well accelerate/delay corneal wound healing. Given these meaningful effects, a growing number of studies are focused on examining the efficacy and safety of β-blockers in soft tissue wound repair, including acute and chronic wounds, severe thermal damage, ulcerated infantile hemangioma, corneal wounds, and other soft tissue disorders. However, an intensive investigation on their acting mechanisms is imperatively needed. The purpose of this article is to summerize the roles of β-blockers in soft tissue wound healing and explore their clinical applications.
Topics: Humans; Adrenergic beta-Antagonists; Wound Healing; Receptors, Adrenergic; Receptors, Adrenergic, beta
PubMed: 37470332
DOI: 10.1002/med.21984 -
International Journal of Molecular... Aug 2023Ranolazine (RN) is a drug used in the treatment of chronic coronary ischemia. Different clinical trials have shown that RN behaves as an anti-diabetic drug by lowering...
Ranolazine (RN) is a drug used in the treatment of chronic coronary ischemia. Different clinical trials have shown that RN behaves as an anti-diabetic drug by lowering blood glucose and glycosylated hemoglobin (HbA1c) levels. However, RN has not been shown to improve insulin (IN) sensitivity. Our study investigates the possible facilitating effects of RN on the actions of IN in the rabbit aorta. IN induced vasodilation of the abdominal aorta in a concentration-dependent manner, and this dilatory effect was due to the phosphorylation of endothelial nitric oxide synthase (eNOS) and the formation of nitric oxide (NO). On the other hand, IN facilitated the vasodilator effects of acetylcholine but not the vasodilation induced by sodium nitroprusside. RN facilitated all the vasodilatory effects of IN. In addition, IN decreased the vasoconstrictor effects of adrenergic nerve stimulation and exogenous noradrenaline. Both effects were in turn facilitated by RN. The joint effect of RN with IN induced a significant increase in the ratio of p-eNOS/eNOS and pAKT/AKT. In conclusion, RN facilitated the vasodilator effects of IN, both direct and induced, on the adrenergic system. Therefore, RN increases vascular sensitivity to IN, thus decreasing tissue resistance to the hormone, a key mechanism in the development of type II diabetes.
Topics: Animals; Rabbits; Ranolazine; Diabetes Mellitus, Type 2; Insulin Resistance; Vasodilator Agents; Aorta, Abdominal; Adrenergic Agents
PubMed: 37686345
DOI: 10.3390/ijms241713532 -
Ophthalmology Sep 2023To investigate the association of commonly used systemic medications with glaucoma and intraocular pressure (IOP) in the European population. (Meta-Analysis)
Meta-Analysis
PURPOSE
To investigate the association of commonly used systemic medications with glaucoma and intraocular pressure (IOP) in the European population.
DESIGN
Meta-analysis of 11 population-based cohort studies of the European Eye Epidemiology Consortium.
PARTICIPANTS
The glaucoma analyses included 143 240 participants and the IOP analyses included 47 177 participants.
METHODS
We examined associations of 4 categories of systemic medications-antihypertensive medications (β-blockers, diuretics, calcium channel blockers [CCBs], α-agonists, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers), lipid-lowering medications, antidepressants, and antidiabetic medications-with glaucoma prevalence and IOP. Glaucoma ascertainment and IOP measurement method were according to individual study protocols. Results of multivariable regression analyses of each study were pooled using random effects meta-analyses. Associations with antidiabetic medications were examined in participants with diabetes only.
MAIN OUTCOME MEASURES
Glaucoma prevalence and IOP.
RESULTS
In the meta-analyses of our maximally adjusted multivariable models, use of CCBs was associated with a higher prevalence of glaucoma (odds ratio [OR], 1.23; 95% confidence interval [CI], 1.08 to 1.39). This association was stronger for monotherapy of CCBs with direct cardiac effects (OR, 1.96; 95% CI, 1.23 to 3.12). No other antihypertensive medications, lipid-lowering medications, antidepressants, or antidiabetic medications were associated with glaucoma. Use of systemic β-blockers was associated with a lower IOP (β coefficient, -0.33 mmHg; 95% CI, -0.57 to -0.08 mmHg). Monotherapy of both selective systemic β-blockers (β coefficient, -0.45 mmHg; 95% CI -0.74 to -0.16 mmHg) and nonselective systemic β-blockers (β coefficient, -0.54 mmHg; 95% CI, -0.94 to -0.15 mmHg) was associated with lower IOP. A suggestive association was found between use of high-ceiling diuretics and lower IOP (β coefficient, -0.30 mmHg; 95% CI, -0.47 to -0.14 mmHg) but not when used as monotherapy. No other antihypertensive medications, lipid-lowering medications, antidepressants, or antidiabetic medications were associated with IOP.
CONCLUSIONS
We identified a potentially harmful association between use of CCBs and glaucoma prevalence. Additionally, we observed and quantified the association of lower IOP with systemic β-blocker use. Both findings potentially are important, given that patients with glaucoma frequently use systemic antihypertensive medications. Determining causality of the CCB association should be a research priority.
FINANCIAL DISCLOSURE(S)
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Topics: Humans; Intraocular Pressure; Antihypertensive Agents; Glaucoma; Adrenergic beta-Antagonists; Calcium Channel Blockers; Diuretics; Hypoglycemic Agents; Lipids
PubMed: 37150298
DOI: 10.1016/j.ophtha.2023.05.001 -
Acta Dermato-venereologica Aug 2023Parents of infants treated with beta-blockers for infantile haemangioma are often concerned about the long-term aesthetic outcome. This cross-sectional study assessed...
Parents of infants treated with beta-blockers for infantile haemangioma are often concerned about the long-term aesthetic outcome. This cross-sectional study assessed the influence on the long-term aesthetic outcome of characteristics of the infantile haemangioma, the beta-blocker treatment, and the infant. The study included 103 children aged 6-12 years, treated with beta-blockers (propranolol or atenolol) for infantile haemangioma during infancy (age at treatment initiation ≤1 year) for ≥6 months. Dermatologists and parents scored the Patient Observer Scar Assessment Scale, and the child scored a visual analogue scale. Dermatologists identified whether telangiectasia, fibrofatty tissue, and atrophic scar tissue were present. The long-term aesthetic outcome of infantile haemangioma was judged more negatively by dermatologists and parents in case of a superficial component, ulceration, older age at treatment initiation, higher cumulative dose, and/or shorter follow-up time. According to children, infantile haemangioma located on the head had better aesthetic outcome than infantile haemangioma located elsewhere. Close monitoring, particularly of infantile haemangioma with a superficial component, is essential for early initiation of treatment, and to prevent or treat ulceration. These outcome data can support parental counselling and guide treatment strategy.
Topics: Child; Infant; Humans; Cicatrix; Cross-Sectional Studies; Prognosis; Hemangioma, Capillary; Adrenergic beta-Antagonists; Esthetics
PubMed: 37649330
DOI: 10.2340/actadv.v103.5286 -
Acta Pharmacologica Sinica Oct 2023Patients with rheumatoid arthritis (RA) have a much higher incidence of cardiac dysfunction, which contributes to the high mortality rate of RA despite anti-arthritic...
Patients with rheumatoid arthritis (RA) have a much higher incidence of cardiac dysfunction, which contributes to the high mortality rate of RA despite anti-arthritic drug therapy. In this study, we investigated dynamic changes in cardiac function in classic animal models of RA and examined the potential effectors of RA-induced heart failure (HF). Collagen-induced arthritis (CIA) models were established in rats and mice. The cardiac function of CIA animals was dynamically monitored using echocardiography and haemodynamics. We showed that cardiac diastolic and systolic dysfunction occurred in CIA animals and persisted after joint inflammation and that serum proinflammatory cytokine (IL-1β, TNF-α) levels were decreased. We did not find evidence of atherosclerosis (AS) in arthritic animals even though cardiomyopathy was significant. We observed that an impaired cardiac βAR-excitation contraction coupling signal was accompanied by sustained increases in blood epinephrine levels in CIA rats. Furthermore, serum epinephrine concentrations were positively correlated with the heart failure biomarker NT-proBNP in RA patients (r = +0.53, P < 0.0001). In CIA mice, treatment with the nonselective βAR blocker carvedilol (2.5 mg·kg·d, for 4 weeks) or the specific GRK2 inhibitor paroxetine (2.5 mg·kg·d, for 4 weeks) effectively rescued heart function. We conclude that chronic and persistent β-adrenergic stress in CIA animals is a significant contributor to cardiomyopathy, which may be a potential target for protecting RA patients against HF.
Topics: Humans; Mice; Rats; Animals; Arthritis, Experimental; Rodentia; Adrenergic Agents; Arthritis, Rheumatoid; Cytokines; Cardiomyopathies; Heart Failure; Epinephrine
PubMed: 37268711
DOI: 10.1038/s41401-023-01099-2 -
Journal of Hepatology Oct 2023β-blockers reduce hepatic venous pressure gradient (HVPG) by decreasing portal inflow, with no reduction in intrahepatic vascular resistance. 5-Methyltetrahydrofolate... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND & AIMS
β-blockers reduce hepatic venous pressure gradient (HVPG) by decreasing portal inflow, with no reduction in intrahepatic vascular resistance. 5-Methyltetrahydrofolate (5-MTHF) can prevent oxidative loss of tetrahydrobiopterin (BH4), a cofactor for endothelial nitric oxide synthase coupling. It also converts homocysteine (tHcy) into methionine and enables the degradation of asymmetric dimethylarginine (ADMA), an inhibitor of endothelial nitric oxide synthase. The aim of this study was to evaluate the effects of 5-MTHF in combination with propranolol on HVPG and nitric oxide bioavailability markers in patients with cirrhosis and portal hypertension.
METHOD
Sixty patients with cirrhosis and HVPG ≥12 mmHg were randomized 1:1 to receive treatment with 5-MTHF+propranolol or placebo+propranolol for 90 days under double-blind conditions. HVPG and markers of nitric oxide bioavailability (BH4, ADMA and tHcy) were measured again at the end of treatment.
RESULTS
Groups were similar in terms of baseline clinical and hemodynamic data and nitric oxide bioavailability markers. HVPG decreased in both groups, but the magnitude of the change was significantly greater in the group treated with 5-MTHF+propranolol compared to placebo+propranolol (percentage decrease, 20 [29-9] vs. 12.5 [22-0], p = 0.028), without differences in hepatic blood flow. At the end of treatment, 5-MTHF+propranolol (vs. placebo+propranolol) was associated with higher BH4 (1,101.4 ± 1,413.3 vs. 517.1 ± 242.8 pg/ml, p <0.001), lower ADMA (109.3 ± 52.7 vs. 139.9 ± 46.7 μmol/L, p = 0.027) and lower tHcy (μmol/L, 11.0 ± 4.6 vs. 15.4 ± 7.2 μmol/L, p = 0.010) plasma levels.
CONCLUSION
In patients with cirrhosis and portal hypertension, 5-MTHF administration significantly enhanced the HVPG reduction achieved with propranolol. This effect appears to be mediated by improved nitric oxide bioavailability in the hepatic microcirculation.
CLINICAL TRIAL EUDRACT NUMBER
2014-002018-21.
IMPACT AND IMPLICATIONS
Currently, the pharmacological prevention of cirrhosis complications due to portal hypertension, such as esophageal varices rupture, is based on the use of β-blockers, but some patients still present with acute variceal bleeding, mainly due to an insufficient reduction of portal pressure. In this study, we sought to demonstrate that the addition of folic acid to β-blockers is more effective in reducing portal pressure than β-blockers alone. This finding could represent the basis for validation studies in larger cohorts, which could impact the future prophylactic management of variceal bleeding in cirrhosis. Enhancing the benefit of β-blockers with a safe, accessible, cost-effective drug could improve clinical outcomes in cirrhosis, which in turn could translate into a reduction in the rates and costs of hospitalization, and ultimately into improved survival.
Topics: Humans; Propranolol; Esophageal and Gastric Varices; Nitric Oxide Synthase Type III; Portal Pressure; Nitric Oxide; Gastrointestinal Hemorrhage; Adrenergic beta-Antagonists; Liver Cirrhosis; Hypertension, Portal
PubMed: 37482222
DOI: 10.1016/j.jhep.2023.06.017