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1.
Sud Med Ekspert ; 66(1): 43-49, 2023.
Artigo em Russo | MEDLINE | ID: mdl-36719313

RESUMO

The purpose of this review is to study the causes of cross-reactions of a number of drugs (mebeverine, phenibut, tropicamide, ramipril, metoprolol, phenylephrine, sertraline, chloropyramine and diphenhydramine) during the preliminary stage of laboratory diagnostics by immunochromatographic method and to propose a possible algorithm for solving this problem. Conducting a hair study in order to identify the fact of the use of psychoactive substances will increase the reliability of analytical diagnostics and reduce the likelihood of false positive results of the analysis. The use of a validated method of enzymatic hydrolysis of hair will eliminate unreliable results of the analysis due to the detection of the native molecule of the toxicant, increase the efficiency and accuracy of the diagnostic procedure.


Assuntos
Metoprolol , Ramipril , Reprodutibilidade dos Testes , Fenilefrina , Cabelo
2.
J Pharm Biomed Anal ; 224: 115191, 2023 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-36512868

RESUMO

In this study, we investigated the effect of type 1 diabetes mellitus on the modulation of the activities of CYP450s in dynamics by a UHPLC-MS/MS method. The diabetic rat model was constructed by an intraperitoneal single injection of streptozotocin. Fasting blood glucose levels > 16.7 mmol/L were considered as diabetic. The rats were given a cocktail of four probe drugs (10 mg/kg phenacetin, 1 mg/kg tolbutamide, 10 mg/kg metoprolol, and 10 mg/kg midazolam) by oral administration for the pharmacokinetic study. Thereafter, the metabolic ratio (MR) of the metabolites to probe substrates were determined. The results indicated that two weeks after diabetes was induced, diabetes increased the MRs of acetaminophen/phenacetin (CYP1A2) and 4-hydroxyl tolbutamide/tolbutamide (CYP2C9); however, it decreased the MRs of α-hydroxy metoprolol/metoprolol (CYP2D6) and 1-hydroxy midazolam/midazolam (CYP3A4). Two months after diabetes was induced, diabetes increased the MRs of acetaminophen/phenacetin and 4-hydroxyl tolbutamide/tolbutamide. The MR of α-hydroxy metoprolol/metoprolol was decreased and the MR of 1-hydroxy midazolam/midazolam was increased but the difference was not significant. According to the results, CYP1A2 and CYP2C9 activities were enhanced in the diabetic rats. and CYP2D6 activity was inhibited in a short period of diabetes; however, the decrease in CYP2D6 activity was not significant in the long period. CYP3A4 activity was decreased in a short period of diabetes and increased in a long period of diabetes but was not significant in the two periods. This study suggests the activity change rule of the CYP450 enzyme system in diabetes mellitus, which can provide a reference for precise clinical medication.


Assuntos
Citocromo P-450 CYP1A2 , Diabetes Mellitus Experimental , Animais , Ratos , Acetaminofen , Cromatografia Líquida de Alta Pressão/métodos , Citocromo P-450 CYP2C9 , Citocromo P-450 CYP2D6 , Citocromo P-450 CYP3A , Sistema Enzimático do Citocromo P-450/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Metoprolol , Midazolam/metabolismo , Fenacetina , Espectrometria de Massas em Tandem/métodos , Tolbutamida
3.
Elife ; 112022 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-36479975

RESUMO

The regeneration potential of the mammalian heart is incredibly limited, as cardiomyocyte proliferation ceases shortly after birth. ß-adrenergic receptor (ß-AR) blockade has been shown to improve heart functions in response to injury; however, the underlying mechanisms remain poorly understood. Here, we inhibited ß-AR signaling in the heart using metoprolol, a cardio-selective ß blocker for ß1-adrenergic receptor (ß1-AR) to examine its role in heart maturation and regeneration in postnatal mice. We found that metoprolol enhanced cardiomyocyte proliferation and promoted cardiac regeneration post myocardial infarction, resulting in reduced scar formation and improved cardiac function. Moreover, the increased cardiomyocyte proliferation was also induced by the genetic deletion of Gnas, the gene encoding G protein alpha subunit (Gαs), a downstream effector of ß-AR. Genome wide transcriptome analysis revealed that the Hippo-effector YAP, which is associated with immature cardiomyocyte proliferation, was upregulated in the cardiomyocytes of ß-blocker treated and Gnas cKO hearts. Moreover, the increased YAP activity is modulated by RhoA signaling. Our pharmacological and genetic studies reveal that ß1-AR-Gαs-YAP signaling axis is involved in regulating postnatal cardiomyocyte proliferation. These results suggest that inhibiting ß-AR-Gαs signaling promotes the regenerative capacity and extends the cardiac regenerative window in juvenile mice by activating YAP-mediated transcriptional programs.


Assuntos
Miócitos Cardíacos , Proteínas de Sinalização YAP , Camundongos , Animais , Miócitos Cardíacos/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Metoprolol/metabolismo , Subunidades alfa de Proteínas de Ligação ao GTP/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo , Proliferação de Células/fisiologia , Mamíferos/metabolismo
4.
Int J Mol Sci ; 23(22)2022 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-36430222

RESUMO

Thermosensitive liquid suppositories (LSs) carrying the model antihypertensive drug metoprolol tartrate (MT) were developed and evaluated. The fundamental purpose of this work was to produce, for the first time, liquid MT suppositories based on biodegradable nanoparticles and optimize their rheological and mechanical properties for prospective rectal administration. The nanoparticle system was based on a biodegradable copolymer synthesized by ring opening polymerization (ROP) of glycolide (GL) and L,L-lactide (LLA). Biodegradable nanoparticles loaded with the model drug were produced by the o/o method at the first stage of the investigation. Depending on the concentration of the drug in the sample, from 66 to 91% of MT was released over 12 h, according to first-order kinetics. Then, thermosensitive LSs with MT-loaded biodegradable nanoparticles were obtained by a cold method and their mechanical and rheological properties were evaluated. To adjust the thermogelling and mucoadhesive properties for rectal administration, the amounts of major formulation components such as poloxamers (P407, P188), Tween 80, hydroxypropylcellulose (HPC), polyvinylpyrrolidone (PVP), and sodium alginate were optimized. The in vitro release results revealed that more than 80% of the MT was released after 12 h, following also first-order kinetics. It was discovered that the diffusion process was dominant. The drug release profile was mainly governed by the rheological and mechanical properties of the developed formulation. Such a novel, thermosensitive formulation might be an effective alternative to hypertension treatment, particularly for unconscious patients, patients with mental illnesses, geriatric patients, and children.


Assuntos
Metoprolol , Nanopartículas , Criança , Humanos , Idoso , Supositórios , Poliglactina 910 , Estudos Prospectivos
5.
Adv Gerontol ; 35(4): 510-517, 2022.
Artigo em Russo | MEDLINE | ID: mdl-36401859

RESUMO

With the ineffectiveness of conservative therapy of chronic rhinosinusitis in all age groups of patients, functional rhinosinusosurgical endoscopic interventions are now often used to do. The minimal bleeding is a necessary condition for their realization. There are reports of the use of beta-blockers for reducing surgical bleeding, but the possibility of their intravenous use in older patients has not been sufficiently studied. The aim of the work was to evaluate the effectiveness of intravenous metoprolol to reduce the bleeding intensity (BI) during rhinosinusosurgical interventions under general anesthesia in elderly and senile patients. The BI was assessed on the Fromme-Boezaart Score scale at different stages of the operation from the 10th to the 60th minute in two groups of patients: without (WM) and using metoprolol (M). It was shown that at the 30th minute of the operation BI was significantly lower in M group. Multivariate analysis of hemodynamic parameters demonstrated a direct relationship between heart rate (HR) and the development of bleeding. In the WM group, the probability of significant bleeding was 8,6 times higher. It has been shown that intraoperative intravenous use of metoprolol reduces the intensity of local bleeding during endoscopic rhinosinusosurgical operations.


Assuntos
Metoprolol , Sinusite , Humanos , Idoso , Sinusite/cirurgia , Perda Sanguínea Cirúrgica , Endoscopia/efeitos adversos , Hemodinâmica
6.
Doc Ophthalmol ; 145(3): 211-219, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36333649

RESUMO

PURPOSE: To investigate ocular safety of intravitreal metoprolol in eyes with central serous chorioretinopathy. METHODS: Five eyes of five patients diagnosed with chronic central serous chorioretinopathy (cCSC) previously treated unsuccessfully with oral spironolactone, micropulse laser and intravitreal anti-vascular endothelial growth factor agents were enrolled and received off-label intravitreal metoprolol (50 µg/0.05 ml). Baseline and follow-up examinations included measurement of best-corrected visual acuity (BCVA), intraocular pressure, anterior chamber cellular/flare scores, vitritis classification, fluorescein and indocyanine green angiography, spectral domain optical coherence tomography and electroretinography (ERG), recorded by means of DTL electrodes and following the standard suggested by the International Society for Clinical Electrophysiology of Vision (ISCEV). The total follow-up period was 4 weeks. RESULTS: There were no significant differences between baseline and follow-up ERG parameters: scotopic or photopic, a- and b-wave amplitude and implicit time, nor oscillatory potentials amplitude, or whatsoever. No intraocular inflammation sign was observed. In addition, BCVA showed small improvement in 4 or kept baseline values in 1 patient. The subretinal and/or intraretinal fluid volume reduced in all patients at 1 month after treatment. CONCLUSION: Patients with refractory cCSC treated with intravitreal 50 µg/0.05 ml metoprolol showed no signs of acute ocular toxicity, along with intraretinal fluid reduction and slight BCVA improvement 1 month after injection. This data suggest that intravitreal metoprolol may be a safe alternative for cCSC.


Assuntos
Coriorretinopatia Serosa Central , Humanos , Coriorretinopatia Serosa Central/diagnóstico , Coriorretinopatia Serosa Central/tratamento farmacológico , Metoprolol/uso terapêutico , Angiofluoresceinografia , Acuidade Visual , Eletrorretinografia , Tomografia de Coerência Óptica , Resultado do Tratamento , Injeções Intravítreas , Estudos Retrospectivos
7.
Int J Mol Sci ; 23(19)2022 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-36232617

RESUMO

Heart failure (HF) carries the highest mortality in the western world and ß-blockers [ß-adrenergic receptor (AR) antagonists] are part of the cornerstone pharmacotherapy for post-myocardial infarction (MI) chronic HF. Cardiac ß1AR-activated ßarrestin2, a G protein-coupled receptor (GPCR) adapter protein, promotes Sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2a SUMO (small ubiquitin-like modifier)-ylation and activity, thereby directly increasing cardiac contractility. Given that certain ß-blockers, such as carvedilol and metoprolol, can activate ßarrestins and/or SERCA2a in the heart, we investigated the effects of these two agents on cardiac ßarrestin2-dependent SERCA2a SUMOylation and activity. We found that carvedilol, but not metoprolol, acutely induces ßarrestin2 interaction with SERCA2a in H9c2 cardiomyocytes and in neonatal rat ventricular myocytes (NRVMs), resulting in enhanced SERCA2a SUMOylation. However, this translates into enhanced SERCA2a activity only in the presence of the ß2AR-selective inverse agonist ICI 118,551 (ICI), indicating an opposing effect of carvedilol-occupied ß2AR subtype on carvedilol-occupied ß1AR-stimulated, ßarrestin2-dependent SERCA2a activation. In addition, the amplitude of fractional shortening of NRVMs, transfected to overexpress ßarrestin2, is acutely enhanced by carvedilol, again in the presence of ICI only. In contrast, metoprolol was without effect on NRVMs' shortening amplitude irrespective of ICI co-treatment. Importantly, the pro-contractile effect of carvedilol was also observed in human induced pluripotent stem cell (hIPSC)-derived cardiac myocytes (CMs) overexpressing ßarrestin2, and, in fact, it was present even without concomitant ICI treatment of human CMs. Metoprolol with or without concomitant ICI did not affect contractility of human CMs, either. In conclusion, carvedilol, but not metoprolol, stimulates ßarrestin2-mediated SERCA2a SUMOylation and activity through the ß1AR in cardiac myocytes, translating into direct positive inotropy. However, this unique ßarrestin2-dependent pro-contractile effect of carvedilol may be opposed or masked by carvedilol-bound ß2AR subtype signaling.


Assuntos
Insuficiência Cardíaca , Células-Tronco Pluripotentes Induzidas , Adenosina Trifosfatases/metabolismo , Antagonistas Adrenérgicos beta/farmacologia , Animais , Carvedilol/farmacologia , Insuficiência Cardíaca/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Metoprolol/metabolismo , Metoprolol/farmacologia , Metoprolol/uso terapêutico , Miócitos Cardíacos/metabolismo , Ratos , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Ubiquitinas/metabolismo , beta-Arrestina 2/metabolismo
8.
Oxid Med Cell Longev ; 2022: 5993459, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36238650

RESUMO

The harm of heart failure mainly causes patients to develop dyspnea, fatigue, fluid retention, and other symptoms, which impair patients' activity tolerance and lead to a dramatic decrease in patients' quality of life. The purpose of this study was to verify whether metoprolol regulates AKAP5 expression and test the role of AKAP5 postinjury in mitigating cardiac infarction-associated tissue remodeling and fibrosis. Sprague-Dawley (SD) rats underwent coronary artery ligation (CAL), which was followed immediately with metoprolol daily. And western blot and coimmunoprecipitation experiments were performed to detect the expression of related proteins in the sham-operated group, model group, and drug-treated group. HW/BW ratio and cardiac expression of COL1 and COL3 were increased in rats following CAL compared with shams. Treatment with metoprolol postinjury was associated with a decrease in HW/BW ratio and COL1/COL3 expression compared to uncontrolled rats. CAL resulted in decreased cardiac AKAP5 expression compared to the control group, while metoprolol treatment restored levels compared to baseline shams. Cardiac expression levels of NFATc3/p-NFATc3 and GATA4 were modest at baseline and increased with injury, whereas metoprolol suppressed gene expression to below injury-associated changes. Immunoprecipitation indicated that AKAP5 could bind and regulate PP2B. In summary, we know that metoprolol alleviates ischemic cardiac remodeling and fibrosis, and the mechanism of alleviating remodeling may improve cardiac AKAP5 expression and AKAP5-PP2B interaction.


Assuntos
Insuficiência Cardíaca , Metoprolol , Proteínas de Ancoragem à Quinase A , Animais , Fibrose , Coração , Metoprolol/farmacologia , Metoprolol/uso terapêutico , Qualidade de Vida , Ratos , Ratos Sprague-Dawley
9.
Biomed Res Int ; 2022: 6098799, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36246960

RESUMO

Diabetic retinopathy (DR) is the most common complication of diabetes and is often characterized by damage to retinal vascular microcirculation, resulting in retinal exudation, hemorrhage, fibrosis, and neovascularization. With the aging of my country's population, the incidence of DR is increasing year by year, and it has become one of the main blinding eye diseases in ophthalmic diseases also tends to be younger. So far, although the pathogenesis of DR is not completely clear, scholars generally believe that DR is based on the disorder of glucose metabolism, causing changes in the microcirculation of ocular tissues, nerves, and blood vessels, resulting in chronic damage to the nutrition and visual function of the eye disease. In order to explore the demand for cardiovascular disease treatment, make up for the lack of chronic diseases affecting people's physical harm, and improve the success rate of cardiovascular disease treatment, a method to observe the efficacy and myocardial remodeling of trimetazidine combined with metoprolol in elderly patients with coronary heart disease and heart failure based on integrated traditional Chinese and Western medicine was proposed. 54 elderly people over 60 years old are afraid of cardiovascular disease and take active protection. A method based on observation of integrated traditional Chinese and Western medicine was proposed, and at the same time, an intelligent medical monitoring system was constructed to better study, observe, and improve the efficacy of trimetazidine combined with metoprolol in elderly patients with coronary heart disease, heart failure, and myocardial impact of refactoring. The results of the study show that trimetazidine has a good clinical effect on ischemic cardiomyopathy heart failure based on the observation of integrated traditional Chinese and Western medicine.


Assuntos
Doenças Cardiovasculares , Doença das Coronárias , Insuficiência Cardíaca , Trimetazidina , Idoso , Doenças Cardiovasculares/complicações , China , Doença das Coronárias/complicações , Doença das Coronárias/tratamento farmacológico , Glucose , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Metoprolol , Pessoa de Meia-Idade , Trimetazidina/uso terapêutico
10.
Acta Dermatovenerol Croat ; 30(2): 116-118, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36254546

RESUMO

Torasemide is a loop diuretic with a molecule that is chemically similar to the sulphonamides described as eosinophilic granulomatosis with polyangiitis (EGPA) triggering drugs. The presented case is probably the first description of torasemide-induced vascular purpura in the course of EGPA. Any diagnosis of vasculitis should be followed by an identification of drugs that may aggravate the disease. A 74-year-old patient was admitted to the Department of Dermatology with purpura-like skin lesions on the upper, and lower extremities, including the buttocks. The lesions had appeared around the ankles 7 days before admission to the hospital and then started to progress upwards. The patient complained on lower limb paresthesia and pain. Other comorbidities included bronchial asthma, chronic sinusitis, ischemic heart disease, mild aortic stenosis, arterial hypertension, and degenerative thoracic spine disease. The woman had previously undergone nasal polypectomy twice. She was on a constant regimen of oral rosuvastatin 5 mg per day, spironolactone 50 mg per day, metoprolol 150 mg per day, inhaled formoterol 12 µg per day, and ipratropium bromide 20 µg per day. Ten days prior to admission, she was commenced on torasemide at a dose of 50 mg per day prescribed by a general practitioner due to high blood pressure. Doppler ultrasound upon admission to the hospital excluded deep venal thrombosis. The laboratory tests revealed leukocytosis (17.1 thousand per mm3) with eosinophilia (38.6%), elevated plasma level of C-reactive protein (119 mg per L) and D-dimers (2657 ng per mm3). Indirect immunofluorescent test identified a low titer (1:80) of antinuclear antibodies, but elevated (1:160) antineutrophil cytoplasmic antibodies (ANCA) in the patient's serum. Immunoblot found them to be aimed against myeloperoxidase (pANCA). A chest X-ray showed increased vascular lung markings, while high-resolution computed tomography revealed peribronchial glass-ground opacities. Microscopic evaluation of skin biopsy taken from the lower limbs showed perivascular infiltrates consisting of eosinophils and neutrophils, fragments of neutrophil nuclei, and fibrinous necrosis of small vessels. Electromyography performed in the lower limbs because of their weakness highlighted a loss of response from both sural nerves, as well as slowed conduction velocity of the right tibial nerve and in both common peroneal nerves. Both clinical characteristics of skin lesions and histopathology suggested a diagnosis of EGPA, which was later confirmed by a consultant in rheumatology. The patient was commenced on prednisone at a dose of 0.5 mg per kg of body weight daily and mycophenolate mofetil at a daily dose of 2 g. The antihypertensive therapy was modified, and torasemide was replaced by spironolactone 25 mg per day. The treatment resulted in a gradual regression of skin lesions within a few weeks. The first report of EGPA dates back to 1951. Its authors were Jacob Churg and Lotte Strauss. They described a case series of 13 patients who had severe asthma, fever, peripheral blood eosinophilia, and granulomatous vasculitis in microscopic evaluation of the skin. Three histopathological criteria were then proposed, and Churg-Strauss syndrome was recognized when eosinophilic infiltrates in the tissues, necrotizing inflammation of small and medium vessels, and the presence of extravascular granulomas were observed together in a patient (1). Only 17.4% of patients met all three histopathological criteria, and the diagnosis of the disease was frequently delayed despite of its overt clinical picture (2). In 1984, Lanham et al. proposed new diagnostic criteria which included the presence of bronchial asthma, eosinophilia in a peripheral blood smear >1.5 thousand per mm3, and signs of vasculitis involving at least two organs other than the lungs (3). Lanham's criteria could also delay the recognition of the syndrome before involvement of internal organs, and the American College of Rheumatology therefore established classification criteria in 1990. These included the presence of bronchial asthma, migratory infiltrates in the lungs as assessed by radiographs, the presence of abnormalities in the paranasal sinuses (polyps, allergic rhinitis, chronic inflammation), mono- or polyneuropathy, peripheral blood eosinophilia (>10% of leukocytes must be eosinophils), and extravascular eosinophilic infiltrates in a histopathological examination. Patients who met 4 out of 6 criteria were classified as having Churg-Strauss syndrome (4). The term EGPA was recommended to define patients with Churg-Strauss syndrome in 2012 (5). EGPA is a condition with low incidence (0.11-2.66 cases per million) and morbidity. It usually occurs in the fifth decade of life (6,7), although 65 cases reports of EGPA in people under 18 years of age could be found in the PubMed and Ovid Medline Database at the end of 2020 (8). The etiopathogenesis of the disease has not been fully explained so far. Approximately 40-60% of patients are positive to pANCA (9), but the role of these antibodies in the pathogenesis of EGPA remains unclear. They are suspected to mediate binding of the Fc receptor to MPO exposed on the surface of neutrophils. Subsequently, this may active neutrophils and contribute to a damage of the vascular endothelium (9,10). Glomerulonephritis, neuropathy, and vasculitis are more common in patients with EGPA who have detectable pANCA when compared with seronegative patients. There are at least several drugs which potentially may EGPA. The strongest association with the occurrence of EGPA was found with the use of leukotriene receptor antagonists (montelukast, zafirlukast, pranlukast), although they are commonly used in the treatment of asthma, which is paradoxically one of the complications of the syndrome (13). Although no relationship has been demonstrated so far between the occurrence of EGPA and the intake of drugs from the groups used by the presented patient, a clear time relationship can be observed between the commencement of torasemide and the onset of symptoms in our patient. To date, only three cases of leukocytoclastic vasculitis have been reported after the administration of torasemide. Both of them developed cutaneous symptoms of the disease within 24 hours of the administration of torasemide in patients with no previous history of drug hypersensitivity, but they disappeared quickly within 8-15 days after drug discontinuation (14,15). The chemical structure of torasemide is similar to the molecule of sulfonamides which were previously found to be a triggering factors for EGPA (12). This drug belongs to the group of loop diuretics classified as sulfonamide derivatives. A comparison of the chemical structure of torasemide and sulphanilamide molecules is presented in Figure 1. The clear time relationship between starting the administration of torasemide and the occurrence of purpura-like lesions suggests that it was an aggravating factor for EGPA in our patient. A coexistence of several disorders (asthma, nasal polyps, symptoms of peripheral neuropathy) in our patient suggest EGPA could have developed in her years before oral intake of torasemide. The sudden onset of skin symptoms shows torasemide to be possible inducing factor for the development of vascular purpura in patients suffering from EGPA but without previous cutaneous involvement.


Assuntos
Asma , Síndrome de Churg-Strauss , Eosinofilia , Granulomatose com Poliangiite , Púrpura , Adolescente , Idoso , Anticorpos Anticitoplasma de Neutrófilos/uso terapêutico , Anticorpos Antinucleares/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Asma/complicações , Proteína C-Reativa/uso terapêutico , Síndrome de Churg-Strauss/complicações , Síndrome de Churg-Strauss/diagnóstico , Síndrome de Churg-Strauss/tratamento farmacológico , Eosinofilia/patologia , Feminino , Fumarato de Formoterol/uso terapêutico , Granulomatose com Poliangiite/complicações , Granulomatose com Poliangiite/diagnóstico , Granulomatose com Poliangiite/terapia , Humanos , Vasculite por IgA , Inflamação/complicações , Ipratrópio/uso terapêutico , Antagonistas de Leucotrienos/uso terapêutico , Metoprolol/uso terapêutico , Ácido Micofenólico/uso terapêutico , Peroxidase/uso terapêutico , Prednisona/uso terapêutico , Receptores Fc/uso terapêutico , Rosuvastatina Cálcica/uso terapêutico , Inibidores de Simportadores de Cloreto de Sódio e Potássio/uso terapêutico , Espironolactona/uso terapêutico , Sulfanilamidas/uso terapêutico , Torasemida/uso terapêutico
11.
Am J Cardiol ; 185: 37-45, 2022 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-36257843

RESUMO

The high early recurrence (ER) rate after radiofrequency catheter ablation (RFCA) seriously affects the prognosis of patients with atrial fibrillation (AF), and there are still controversies regarding the best preventive drugs for postoperative recurrence. A single-center retrospective study was conducted on patients with paroxysmal atrial fibrillation (PAF) who received metoprolol sustained-release tablets combined with dronedarone (observation group) and dronedarone alone (control group) after the first RFCA. A matching cohort was established using a 1:1 propensity score matching method to compare the incidence of ER, cardiac function, inflammation level, quality of life (QoL), and antiarrhythmic drugs (AADs)-related adverse reactions between groups. A total of 56 pairs of patients were successfully matched. The incidence of ER in the observation group was significantly lower than that in the control group (32% vs 14%, p = 0.033); the left atrial diameter in the observation group was significantly lower than that in the control group on Day 90 after RFCA (38 ±4 vs 40 ± 5, p = 0.021), and the QoL of the observation group was significantly improved on the thirtieth and ninetieth days after RFCA compared with the control group (72 ± 5 vs 69 ± 9, p = 0.031; 73 ± 4 vs 70 ± 9, p = 0.025). Multifactorial Cox analysis showed that diabetes mellitus, left atrial diameter >45 mm, ventricular rate >110 beats/min, and postoperative AADs were independent risk factors for ER in patients with PAF. The incidence of sinus bradycardia in the observation group was significantly higher than that in the control group (18% vs 3.6%, p = 0.029), but there was no statistical difference in the overall incidence of AADs-related adverse reactions between groups. Compared with dronedarone alone, dronedarone combined with metoprolol sustained-release tablets can significantly reduce ER after RFCA in patients with PAF and improve cardiac function and QoL, without increasing the AADs-related adverse reactions.


Assuntos
Fibrilação Atrial , Ablação por Cateter , Humanos , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/cirurgia , Dronedarona/uso terapêutico , Metoprolol/uso terapêutico , Qualidade de Vida , Estudos Retrospectivos , Preparações de Ação Retardada/uso terapêutico , Ablação por Cateter/efeitos adversos , Resultado do Tratamento , Recidiva
12.
Am J Emerg Med ; 62: 49-54, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36252310

RESUMO

PURPOSE: Atrial fibrillation (Afib) with rapid ventricular response (RVR) is acutely treated with intravenous push (IVP) metoprolol (MET) or diltiazem (DIL). In heart failure (HF) patients, diltiazem is not recommended due to negative inotropic effects. Studies comparing the treatment of atrial fibrillation often exclude HF. Hirschy et al. evaluated HF patients with concomitant Afib with RVR who received IVP metoprolol or diltiazem to determine their effectiveness and safety. They found similar safety and effectiveness outcomes between the two groups. METHODS: This retrospective, IRB-approved study evaluated patients presenting to the emergency center (EC) with Afib with RVR and HF from January 1, 2018 to July 31, 2021. Included patients were 18 years of age or older, received IVP metoprolol or diltiazem in the EC, and had a recorded baseline ejection fraction (EF). The primary effectiveness outcome was successful heart rate (HR) control 30 min after treatment with either IVP metoprolol or diltiazem, which was defined as HR <100 beats per minute (bpm). Secondary effectiveness outcomes included HR control 60 min post-IVP and at EC discharge or transfer and HR reduction >20% at 30 min after IVP, 60 min after IVP, and at time of discharge or transfer. Other secondary outcomes included the time to adequate HR control, the total dose of IVP metoprolol or diltiazem given, any additional rate-controlling agents given, and crossover between metoprolol and diltiazem. Safety outcomes included bradycardia, hypotension, shortness of breath, increased oxygen requirements, change in EF, acute kidney injury or renal replacement therapy. RESULTS: Of 2580 evaluated, 193 patients were included (134 DIL vs. 59 MET) with age 73.3 ± 12.2 years, 63% female. The average EF was 48.2 ± 14.2% and 30% of patients had heart failure with reduced ejection fraction (HFrEF) while 64% had heart failure with preserved ejection fraction (HFpEF). Effective heart rate control 30 min post-IVP was not different between the two groups (55% DIL vs. 41% MET, p = 0.063). DIL effectively controlled HR quicker than MET (13 [9, 125] DIL vs. 27 [5, 50] MET, min, p = 0.009). DIL resulted in greater HR reductions at 30 min (33.2 ± 25.4 DIL vs. 19.7 ± 19.7 MET, bpm, p < 0.001) and at 60 min (31 ± 23.5 DIL vs. 19.6 ± 19.1 MET, bpm, p = 0.002). DIL also more frequently resulted in a HR reduction of 20% or greater at 30 min (63% DIL vs. 27% MET, p < 0.001), 60 min post-IVP (59% DIL vs. 41% MET, p = 0.019), and at time of patient discharge or transfer from the EC (70% DIL vs. 49% MET, p = 0.005). No differences in safety outcomes were identified. CONCLUSION: Acute management of patients with Afib with RVR and HF is challenging. While successful rate control at 30 min was not significantly different between diltiazem and metoprolol, IVP diltiazem reduced HR more quickly and reduced HR by 20% or greater more frequently than IVP metoprolol with no safety outcome differences. Further studies are needed to evaluate diltiazem's safety in patients with Afib and HF.


Assuntos
Fibrilação Atrial , Insuficiência Cardíaca , Humanos , Feminino , Adolescente , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Masculino , Diltiazem , Metoprolol , Fibrilação Atrial/complicações , Fibrilação Atrial/tratamento farmacológico , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/tratamento farmacológico , Estudos Retrospectivos , Volume Sistólico , Frequência Cardíaca
13.
Int J Mol Sci ; 23(19)2022 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-36233052

RESUMO

Metabolic associated fatty liver disease (MAFLD) is the most common chronic liver disease, with an estimated prevalence of between 20 and 30% worldwide. Observational data supported by in vitro and pre-clinical animal models of MAFLD suggest meaningful differences in drug disposition in MAFLD patients. This study aimed to build a physiologically based pharmacokinetic (PBPK) model reflecting observed changes in physiological and molecular parameters relevant to drug disposition that are associated with MAFLD. A comprehensive literature review and meta-analysis was conducted to identify all studies describing in vivo physiological changes along with in vitro and pre-clinical model changes in CYP 1A2, 2C9, 2C19, 2D6 and 3A4 protein abundance associated with MAFLD. A MAFLD population profile was constructed in Simcyp (version 19.1) by adapting demographic and physiological covariates from the Sim-Healthy population profile based on a meta-analysis of observed data from the published literature. Simulations demonstrated that single dose and steady state area under the plasma concentration time curve (AUC) for caffeine, clozapine, omeprazole, metoprolol, dextromethorphan and midazolam, but not s-warfarin or rosiglitazone, were increased by >20% in the MAFLD population compared to the healthy control population. These findings indicate that MAFLD patients are likely to be experience meaningfully higher exposure to drugs that are primarily metabolized by CYP 1A2, 2C19, 2D6 and 3A4, but not CYP2C9. Closer monitoring of MAFLD patients using drugs primarily cleared by CYP 1A2, 2C19 and 3A4 is warranted as reduced metabolic activity and increased drug exposure are likely to result in an increased incidence of toxicity in this population.


Assuntos
Clozapina , Hepatopatia Gordurosa não Alcoólica , Animais , Cafeína , Citocromo P-450 CYP1A2/genética , Citocromo P-450 CYP1A2/metabolismo , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Dextrometorfano , Metoprolol , Midazolam , Omeprazol , Rosiglitazona , Varfarina/farmacocinética
14.
Environ Sci Technol ; 56(20): 14462-14477, 2022 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-36197061

RESUMO

In shallow, open-water engineered wetlands, design parameters select for a photosynthetic microbial biomat capable of robust pharmaceutical biotransformation, yet the contributions of specific microbial processes remain unclear. Here, we combined genome-resolved metatranscriptomics and oxygen profiling of a field-scale biomat to inform laboratory inhibition microcosms amended with a suite of pharmaceuticals. Our analyses revealed a dynamic surficial layer harboring oxic-anoxic cycling and simultaneous photosynthetic, nitrifying, and denitrifying microbial transcription spanning nine bacterial phyla, with unbinned eukaryotic scaffolds suggesting a dominance of diatoms. In the laboratory, photosynthesis, nitrification, and denitrification were broadly decoupled by incubating oxic and anoxic microcosms in the presence and absence of light and nitrogen cycling enzyme inhibitors. Through combining microcosm inhibition data with field-scale metagenomics, we inferred microbial clades responsible for biotransformation associated with membrane-bound nitrate reductase activity (emtricitabine, trimethoprim, and atenolol), nitrous oxide reduction (trimethoprim), ammonium oxidation (trimethoprim and emtricitabine), and photosynthesis (metoprolol). Monitoring of transformation products of atenolol and emtricitabine confirmed that inhibition was specific to biotransformation and highlighted the value of oscillating redox environments for the further transformation of atenolol acid. Our findings shed light on microbial processes contributing to pharmaceutical biotransformation in open-water wetlands with implications for similar nature-based treatment systems.


Assuntos
Compostos de Amônio , Áreas Alagadas , Atenolol , Biotransformação , Desnitrificação , Emtricitabina/metabolismo , Metoprolol , Nitrato Redutases/metabolismo , Nitrificação , Nitrogênio/metabolismo , Óxido Nitroso , Oxigênio , Preparações Farmacêuticas , Fotossíntese , Trimetoprima , Água
15.
J Emerg Med ; 63(3): 467-476, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36241477

RESUMO

BACKGROUND: Atrial fibrillation (AF) is a common dysrhythmia associated with significant morbidity and mortality. Although many patients have stable AF, some patients can present with a rapid ventricular response (RVR). In these patients, it is important to lower their heart rate. However, there are several options available for rate control in the emergency department setting. CLINICAL QUESTION: What is the most effective agent for rate control for the patient with AF in RVR? EVIDENCE REVIEW: Studies retrieved included two prospective, randomized, double-blind studies and six retrospective cohort studies. These studies provide estimates of the efficacy and safety of calcium channel blockers and ß-blockers for rate control in those with AF with RVR. CONCLUSION: Based upon the available literature, diltiazem likely achieves rate control faster than metoprolol, though both agents seem safe and effective. Clinicians must consider the individual patient, clinical situation, and comorbidities when selecting a medication for rate control.


Assuntos
Fibrilação Atrial , Humanos , Antiarrítmicos/farmacologia , Antiarrítmicos/uso terapêutico , Fibrilação Atrial/complicações , Fibrilação Atrial/tratamento farmacológico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Diltiazem/uso terapêutico , Frequência Cardíaca , Metoprolol/farmacologia , Metoprolol/uso terapêutico , Estudos Prospectivos , Estudos Retrospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto
16.
Beijing Da Xue Xue Bao Yi Xue Ban ; 54(5): 954-960, 2022 Oct 18.
Artigo em Chinês | MEDLINE | ID: mdl-36241239

RESUMO

OBJECTIVE: To analyze the disease spectrums underlying orthostatic intolerance (OI) and sitting intolerance (SI) in Chinese children, and to understand the clinical empirical treatment options. METHODS: The medical records including history, physical examination, laboratory examination, and imagological examination of children were retrospectively studied in Peking University First Hospital from 2012 to 2021. All the children who met the diagnostic criteria of OI and SI were enrolled in the study. The disease spectrums underlying OI and SI and treatment options during the last 10 years were analyzed. RESULTS: A total of 2 110 cases of OI and SI patients were collected in the last 10 years, including 943 males (44.69%) and 1 167 females (55.31%) aged 4-18 years, with an average of (11.34±2.84) years. The overall case number was in an increasing trend over the year. In the OI spectrum, postural tachycardia syndrome (POTS) accounted for 826 cases (39.15%), followed by vasovagal syncope (VVS) (634 cases, 30.05%). The highest proportion of SI spectrum was sitting tachycardia (STS) (8 cases, 0.38%), followed by sitting hypertension (SHT) (2 cases, 0.09%). The most common comorbidity of OI and SI was POTS coexisting with STS (36 cases, 1.71%). The highest proportion of treatment options was autonomic nerve function exercise (757 cases, 35.88%), followed by oral rehydration salts (ORS) (687 cases, 32.56%), metoprolol (307 cases, 14.55%), midodrine (142 cases, 6.73%), ORS plus metoprolol (138 cases, 6.54%), and ORS plus midodrine (79 cases, 3.74%). The patients with POTS coexisting with VVS were more likely to receive pharmacological intervention than the patients with POTS and the patients with VVS (41.95% vs. 30.51% vs. 28.08%, χ2= 20.319, P < 0.01), but there was no significant difference in the proportion of treatment options between the patients with POTS and the patients with VVS. CONCLUSION: POTS and VVS in children are the main underlying diseases of OI, while SI is a new disease discovered recently. The number of children with OI and SI showed an increasing trend. The main treatment methods are autonomic nerve function exercise and ORS. Children with VVS coexisting with POTS were more likely to take pharmacological treatments than those with VVS or POTS only.


Assuntos
Midodrina , Intolerância Ortostática , Síndrome da Taquicardia Postural Ortostática , Síncope Vasovagal , Criança , Eletrólitos , Feminino , Humanos , Masculino , Metoprolol , Intolerância Ortostática/diagnóstico , Intolerância Ortostática/epidemiologia , Intolerância Ortostática/terapia , Síndrome da Taquicardia Postural Ortostática/diagnóstico , Estudos Retrospectivos , Sais , Postura Sentada , Síncope Vasovagal/diagnóstico , Teste da Mesa Inclinada
17.
Medicine (Baltimore) ; 101(35): e30250, 2022 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-36107542

RESUMO

BACKGROUND: This meta-analysis aimed to systematically and comprehensively assess the effectiveness and safety of wenxin granule (WXG) and metoprolol in the treatment of elderly patients with coronary heart disease (CHD) and arrhythmia. METHODS: We searched the electronic databases of the Cochrane Library, PUBMED, EMBASE, CNKI, Wangfang, and CBM from initiation to May 1, 2022, and selected a set of clinical indicators for WXG and metoprolol for CHD and arrhythmia. The methodological quality of the included studies was analyzed using the Cochrane risk-of-bias tool. Data were pooled using a fixed-effects or random-effects model, and a meta-analysis was conducted. RESULTS: Eight randomized controlled trials involving 722 patients with CHD and arrhythmia were included. Our findings showed that WXG and metoprolol showed better effects than metoprolol alone on electrocardiogram change (odds ratio [OR] = 7.21, 95% confidence interval [CI] [1.48, 35.07]), clinical symptom improvement (OR = 5.83, 95% CI [1.52, 22.35]), overall clinical effect (OR = 5.51, 95% CI [2.65, 11.44], P < .001), atrial premature beat (mean difference [MD] = -109.85, 95% CI [-171.25, -48.46], P < .001), ventricular premature beat (MD = -195.43, 95% CI [-334.09, -56.77], P < .001), borderline premature beat (MD = -42.92, 95% CI [-77.18, -8.67], P = .01), short-burst ventricular tachycardia (MD = -35.98, 95% CI [-39.66, -32.30], P < .001), ST segment reduction (MD = -0.47, 95% CI [-0.54, -0.40], P < .001), ST segment decrease duration (MD = -0.76, 95% CI [-0.95, -0.57], P < .001). However, no significant differences were observed in adverse reactions (OR = 0.54, 95% CI [0.27, 1.09], P = .09). CONCLUSION: Compared to metoprolol alone, WXG and metoprolol can more effectively manage patients with CHD and arrhythmia. However, additional large-scale, multicenter, rigorous, and high-quality randomized controlled trials are warranted to verify the present findings.


Assuntos
Doença das Coronárias , Medicamentos de Ervas Chinesas , Complexos Ventriculares Prematuros , Idoso , Doença das Coronárias/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Humanos , Metoprolol/uso terapêutico , Estudos Multicêntricos como Assunto
18.
Vascul Pharmacol ; 146: 107110, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36103993

RESUMO

The mechanisms underlying the success of propranolol in the treatment of infantile hemangioma (IH) remain elusive and do not fully explain the rapid regression of hemangiomatous lesions following drug administration. As autophagy is critically implicated in vascular homeostasis, we determined whether ß-blockers trigger the autophagic flux on infantile hemangioma-derived endothelial cells (Hem-ECs) in vitro. MATERIAL AND METHODS: Fresh tissue specimens, surgically removed for therapeutic purpose to seven children affected by proliferative IH, were subjected to enzymatic digestion. Cells were sorted with anti-human CD31 immunolabeled magnetic microbeads. Following phenotypic characterization, expanded Hem-ECs, at P2 to P6, were exposed to different concentrations (50 µM to 150 µM) of propranolol, atenolol or metoprolol alone and in combination with the autophagy inhibitor Bafilomycin A1. Rapamycin, a potent inducer of autophagy, was also used as control. Autophagy was assessed by Lysotracker Red staining, western blot analysis of LC3BII/LC3BI and p62, and morphologically by transmission electron microscopy. RESULTS: Hem-ECs treated with either propranolol, atenolol or metoprolol displayed positive LysoTracker Red staining. Increased LC3BII/LC3BI ratio, as well as p62 modulation, were documented in ß-blockers treated Hem-ECs. Abundant autophagic vacuoles and multilamellar bodies characterized the cytoplasmic ultrastructural features of autophagy in cultured Hem-ECs exposed in vitro to ß-blocking agents. Importantly, similar biochemical and morphologic evidence of autophagy were observed following rapamycin while Bafilomycin A1 significantly prevented the autophagic flux promoted by ß-blockers in Hem-ECs. CONCLUSION: Our data suggest that autophagy may be ascribed among the mechanisms of action of ß-blockers suggesting new mechanistic insights on the potential therapeutic application of this class of drugs in pathologic conditions involving uncontrolled angiogenesis.


Assuntos
Hemangioma , Propranolol , Antagonistas Adrenérgicos beta/farmacologia , Aminas , Atenolol/farmacologia , Atenolol/uso terapêutico , Autofagia , Proliferação de Células , Criança , Células Endoteliais , Hemangioma/patologia , Humanos , Macrolídeos , Metoprolol/uso terapêutico , Propranolol/farmacologia , Propranolol/uso terapêutico , Sirolimo/farmacologia
19.
Biomolecules ; 12(9)2022 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-36139049

RESUMO

De novo sterol synthesis is a critical homeostatic mechanism in the brain that begins during early embryonic development and continues throughout life. Multiple medications have sterol-biosynthesis-inhibiting side effects, with potentially detrimental effects on brain health. Using LC-MS/MS, we investigated the effects of six commonly used beta-blockers on brain sterol biosynthesis in vitro using cell lines. Two beta-blockers, metoprolol (MTP) and nebivolol, showed extreme elevations of the highly oxidizable cholesterol precursor 7-dehydrocholesterol (7-DHC) in vitro across multiple cell lines. We followed up on the MTP findings using a maternal exposure model in mice. We found that 7-DHC was significantly elevated in all maternal brain regions analyzed as well as in the heart, liver and brain of the maternally exposed offspring. Since DHCR7-inhibiting/7-DHC elevating compounds can be considered teratogens, these findings suggest that MTP utilization during pregnancy might be detrimental for the development of offspring, and alternative beta-blockers should be considered.


Assuntos
Metoprolol , Oxirredutases atuantes sobre Doadores de Grupo CH-CH , Animais , Encéfalo/metabolismo , Colesterol/metabolismo , Cromatografia Líquida , Feminino , Metoprolol/metabolismo , Metoprolol/farmacologia , Camundongos , Nebivolol/metabolismo , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo , Gravidez , Espectrometria de Massas em Tandem , Teratógenos
20.
J Pharm Biomed Anal ; 220: 115022, 2022 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-36063625

RESUMO

As expressed predominantly in cardiac tissue, beta1-adrenoceptor (ß1-AR) is broadly accepted as one of the main targets for drugs against cardiovascular ailments. However, the discovery of ß1-AR ligand is gravely challenged due to the lack of efficient screening method. This work developed a general strategy for pursuing ß1-AR ligands from the herbal extract by immobilizing haloalkane dehalogenase (Halo)-tagged ß1-AR onto microspheres coated with 6-chlorohexanoic acid, and applying the immobilized ß1-AR in the analysis of ligand-receptor interaction. The morphology was characterized by scanning electron microscope (SEM) and X-ray photoelectron spectroscopy (XPS). The chromatographic specificity of the immobilized receptor column was evaluated by determining the association constants of atenolol, esmolol and metoprolol using stepwise frontal analysis plus injection amount-dependent method. The potential ligands binding to ß1-AR was screened by collecting the peak with retention time longer than the void time, and identified the collection by reverse phase liquid chromatography coupled with tandem mass spectrometry. The association constants of the three drugs to ß1-AR were (3.33 ± 0.29)× 106 M-1, (2.33 ± 0.23)× 106 M-1 and (2.06 ± 0.03)× 106 M-1, indicating a desired specificity of the immobilized receptor for recognizing its ligands. Molecular docking showed that van der Waals, hydrogen bonds, and hydrophobic interactions were the principal interaction forces for the receptor-drug complexes. Benzoylmesaconine was screened as the potential ligand of ß1-AR in Radix Aconiti Lateralis Praeparata extract. The association constant of the ligand was (1.06 ± 0.02)× 105 M-1, hinting structural modification may be required before clinical application. The immobilized ß1-AR is possible to provide a rapid method for screening potential ligands in herbal extract.


Assuntos
Aconitum , Medicamentos de Ervas Chinesas , Aconitum/química , Atenolol , Medicamentos de Ervas Chinesas/química , Ligantes , Metoprolol , Simulação de Acoplamento Molecular , Receptores Adrenérgicos
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