Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 3.675
Filtrar
1.
Environ Sci Pollut Res Int ; 28(39): 55029-55040, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34128161

RESUMO

A simple, sensitive, and rapid spectrofluorimetric method was developed for the determination of the ß-blocker pindolol. The native fluorescence of pindolol was measured in different organic solvents and in cyclodextrin aqueous media. The highest fluorescence signal was obtained in 2-propanol at λem = 303 nm with λex = 260 nm. Analytical figures of merit for the spectrofluorimetric determination of pindolol were satisfactory, with wide linear dynamic range (LDR) values of two orders of magnitude, and rather low limit of detection (LOD) values between 0.2 and 8.7 ng/mL. Moreover, the addition of cyclodextrins (HP-ß-CD and ß-CD) in aqueous media enhanced the fluorescence of pindolol. In addition, the inclusion complexes of pindolol with cyclodextrins were investigated and the stability constants of complexes were calculated by means of the method of nonlinear regression (NLR). The method was successfully applied to the analysis of tap water and natural water samples, spiked with pindolol.


Assuntos
Ciclodextrinas , Pindolol , Espectrometria de Fluorescência
2.
Molecules ; 25(24)2020 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-33348734

RESUMO

In this work, we examine methyl nuclear magnetic resonance (NMR) spectra of the methionine ε-[13CH3] labelled thermostabilized ß1 adrenergic receptor from turkey in association with a variety of different effectors, including mini-Gs and nanobody 60 (Nb60), which have not been previously studied in complex with ß1 adrenergic receptor (ß1AR) by NMR. Complexes with pindolol and Nb60 induce highly similar inactive states of the receptor, closely resembling the resting state conformational ensemble. We show that, upon binding of mini-Gs or nanobody 80 (Nb80), large allosteric changes throughout the receptor take place. The conformation of tß1AR stabilized by the native-like mini-Gs protein is highly similar to the conformation induced by the currently used surrogate Nb80. Interestingly, in both cases residual dynamics are present, which were not observed in the resting states. Finally, we reproduce a pharmaceutically relevant situation, where an antagonist abolishes the interaction of the receptor with the mini-G protein in a competitive manner, validating the functional integrity of our preparation. The presented system is therefore well suited for reproducing the individual steps of the activation cycle of a G protein-coupled receptor (GPCR) in vitro and serves as a basis for functional and pharmacological characterizations of more native-like systems in the future.


Assuntos
Proteínas de Ligação ao GTP/metabolismo , Pindolol/metabolismo , Receptores Adrenérgicos beta 1/metabolismo , Anticorpos de Cadeia Única/metabolismo , Anticorpos de Domínio Único/imunologia , Sítios de Ligação , Cristalografia por Raios X , Humanos , Ressonância Magnética Nuclear Biomolecular , Conformação Proteica , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais , Turquia
3.
Angew Chem Int Ed Engl ; 59(51): 23162-23168, 2020 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-32869436

RESUMO

Here, an electrokinetic extraction (EkE) syringe is presented allowing for on-line electrokinetic removal of serum proteins before ESI-MS. The proposed concept is demonstrated by the determination of pharmaceuticals from human serum within minutes, with sample preparation limited to a 5× dilution of the sample in the background electrolyte (BGE) and application of voltage, both of which can be performed in-syringe. Signal enhancements of 3.6-32 fold relative to direct infusion of diluted serum and up to 10.8 fold enhancement, were obtained for basic and acidic pharmaceuticals, respectively. Linear correlations for the basic drugs by EkE-ESI-MS/MS were achieved, covering the necessary clinical range with LOQs of 5.3, 7.8, 6.1, and 17.8 ng mL-1 for clomipramine, chlorphenamine, pindolol, and atenolol, respectively. For the acidic drugs, the EkE-ESI-MS LOQs were 3.1 µg mL-1 and 2.9 µg mL-1 for naproxen and paracetamol, respectively. The EkE-ESI-MS and EkE-ESI-MS/MS methods showed good accuracy (%found of 81 % to 120 %), precision (≤20 %), and linearity (r>0.997) for all the studied drugs in spiked serum samples.


Assuntos
Proteínas Sanguíneas/isolamento & purificação , Seringas , Acetaminofen/sangue , Atenolol/sangue , Proteínas Sanguíneas/química , Clorfeniramina/sangue , Clomipramina/sangue , Humanos , Cinética , Naproxeno/sangue , Pindolol/sangue , Espectrometria de Massas por Ionização por Electrospray
4.
Cochrane Database Syst Rev ; 9: CD010054, 2020 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-32888198

RESUMO

BACKGROUND: Beta-blockers are commonly used in the treatment of hypertension. We do not know whether the blood pressure (BP) lowering efficacy of beta-blockers varies across the day. This review focuses on the subclass of beta-blockers with partial agonist activity (BBPAA). OBJECTIVES: To assess the degree of variation in hourly BP lowering efficacy of BBPAA over a 24-hour period in adults with essential hypertension. SEARCH METHODS: The Cochrane Hypertension Information Specialist searched the following databases for relevant studies up to June 2020: the Cochrane Hypertension Specialised Register; CENTRAL; 2020, Issue 5; MEDLINE Ovid; Embase Ovid; the World Health Organization International Clinical Trials Registry Platform; and ClinicalTrials.gov. We also contacted authors of relevant papers regarding further published and unpublished work. The searches had no language restrictions. SELECTION CRITERIA: We sought to include all randomised and non-randomised trials that assessed the hourly effect of BBPAA by ambulatory monitoring, with a minimum follow-up of three weeks. DATA COLLECTION AND ANALYSIS: Two review authors independently selected the included trials and extracted the data. We assessed the certainty of the evidence using the GRADE approach. Outcomes included in the review were end-point hourly systolic and diastolic blood pressure (SBP and DBP) and heart rate (HR), measured using a 24-hour ambulatory BP monitoring (ABPM) device. MAIN RESULTS: Fourteen non-randomised baseline controlled trials of BBPAA met our inclusion criteria, but only seven studies, involving 121 participants, reported hourly ambulatory BP data that could be included in the meta-analysis. Beta-blockers studied included acebutalol, pindolol and bopindolol. We judged most studies at high or unclear risk of bias for selection bias, attrition bias, and reporting bias. We judged the overall certainty of the evidence to be very low for all outcomes. We analysed and presented data by each hour post-dose. Very low-certainty evidence showed that hourly mean reduction in BP and HR visually showed an attenuation over time. Over the 24-hour period, the magnitude of SBP lowering at each hour ranged from -3.68 mmHg to -17.74 mmHg (7 studies, 121 participants), DBP lowering at each hour ranged from -2.27 mmHg to -9.34 mmHg (7 studies, 121 participants), and HR lowering at each hour ranged from -0.29 beats/min to -10.29 beats/min (4 studies, 71 participants). When comparing between three 8-hourly time intervals that correspond to day, evening, and night time hours, BBPAA was less effective at lowering BP and HR at night, than during the day and evening. However, because we judged that these outcomes were supported by very low-certainty evidence, further research is likely to have an important impact on the estimate of effect and may change the conclusion. AUTHORS' CONCLUSIONS: There is insufficient evidence to draw general conclusions about the degree of variation in hourly BP-lowering efficacy of BBPAA over a 24-hour period, in adults with essential hypertension. Very low-certainty evidence showed that BBPAA acebutalol, pindolol, and bopindolol lowered BP more during the day and evening than at night. However, the number of studies and participants included in this review was very small, further limiting the certainty of the evidence. We need further and larger trials, with accurate recording of time of drug intake, and with reporting of standard deviation of BP and HR at each hour.


Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Ritmo Circadiano/fisiologia , Hipertensão/tratamento farmacológico , Acebutolol/uso terapêutico , Agonistas Adrenérgicos beta/uso terapêutico , Adulto , Viés , Pressão Sanguínea/fisiologia , Ensaios Clínicos Controlados como Assunto , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Pindolol/análogos & derivados , Pindolol/uso terapêutico , Fatores de Tempo
5.
Int J Mol Sci ; 21(18)2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32961980

RESUMO

Several research disciplines require fast, reliable and highly automated determination of pharmaceutically active compounds and their enantiomers in complex biological matrices. To address some of the challenges of Capillary Electrophoresis (CE), such as low concentration sensitivity and performance degradation linked to the adsorption and interference of matrix components, CE in a hydrodynamically closed system was evaluated using the model compounds Pindolol and Propranolol. Some established validation parameters such as repeatability of injection efficiency, resolution and sensitivity were used to assess its performance, and it was found to be broadly identical to that of hydrodynamically opened systems. While some reduction in separation efficiency was observed, this was mainly due to dispersion caused by injection and it had no impact on the ability to resolve enantiomers of model compounds even when spiked into complex biological matrix such as blood serum. An approximately 18- to 23-fold increase in concentration sensitivity due to the employment of wide bore capillaries was observed. This brings the sensitivity of CE to a level similar to that of liquid chromatography techniques. In addition to this benefit and unlike in hydrodynamically opened systems, suppression of electroosmotic flow, which is essential for hydrodynamically closed systems practically eliminates the matrix effects that are linked to protein adsorption.


Assuntos
Eletroforese Capilar/métodos , Soro/química , Eletroforese Capilar/instrumentação , Hidrodinâmica , Preparações Farmacêuticas , Pindolol/análise , Propranolol/análise , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Software , Estereoisomerismo
7.
Behav Brain Res ; 393: 112797, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32649976

RESUMO

Recently, we demonstrated the promising anxiolytic action of 7-chloro-4-(phenylselanyl) quinoline (4-PSQ) in mice. For this reason, the objective of this study was to expand our previous findings by investigating the contribution of serotoninergic and GABAergic systems to the anxiolytic action of this compound. Pretreatment with different serotoninergic antagonists (pindolol, WAY100635 and ketanserin) blocked the anxiolytic effect caused by 4-PSQ (50 mg/kg, per oral) in the elevated plus maze (EPM) test. The contribution of the GABAergic system was investigated by pretreatment with pentylenetetrazole (a GABAA receptor antagonist) (PTZ). 4-PSQ diminished the PTZ-induced anxiety, and did not modify the locomotor, exploratory and motor activities of mice. Later, this group of animals was euthanized and the blood was removed to determine the levels of corticosterone, and cerebral cortex and hippocampus to determine the mRNA expression levels of cAMP response element binding protein (CREB), brain derived neurotrophic factor (BDNF) and nuclear factor kappa B (NF-κB), as well as the Na+, K+ ATPase activity and reactive species (RS) levels. 4-PSQ was able to significantly reverse the increase in RS and corticosterone levels, as well as the decrease of CREB and BDNF expression in the cerebral structures and increase of NF-κB expression in the hippocampus. Finally, 4-PSQ restored the Na+, K+ ATPase activity in the cerebral structures evaluated. Here, we showed that the modulation of serotonergic and GABAergic systems, factors related to neurogenesis, oxidative status and Na+, K+ ATPase activity contributes to the anxiolytic effect of 4-PSQ and reinforces the therapeutical potential of this compound for the treatment of anxiety.


Assuntos
Ansiolíticos/administração & dosagem , Ansiedade/fisiopatologia , Quinolinas/administração & dosagem , Receptores de GABA-A/fisiologia , Selênio/administração & dosagem , Serotonina/fisiologia , Animais , Ansiedade/prevenção & controle , Antagonistas de Receptores de GABA-A/administração & dosagem , Masculino , Camundongos , Pindolol/administração & dosagem , Quinolinas/química , Receptores de GABA-A/administração & dosagem , Selênio/química , Antagonistas da Serotonina/administração & dosagem
8.
J Hazard Mater ; 393: 122490, 2020 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-32197201

RESUMO

In this work, we have investigated the stability of pindolol (PIN), a non-selective ß1-blocker detected in the river and wastewater of hospitals, in water solution under solar irradiation. Further, detailed insights into the stability of PIN were obtained by the density functional theory (DFT) calculations and molecular dynamics simulations. The kinetics of PIN photocatalytic degradation and mineralization has been studied using four commercial photocatalysts ZnO and TiO2 (P25, Hombikat, and Wackherr). It was found that the major role in degradation of PIN play the reactive hydroxyl radicals. The structures of degradation intermediates were suggested by LC-ESI-MS/MS and DFT calculations. Also, DFT calculations were used to refine molecular structures of intermediates and obtain their geometries. Toxicity of PIN and its mixtures formed during photocatalytic degradation were investigated using mammalian cell lines (H-4-II-E, HT-29, and MRC-5). The H-4-II-E cell line was the most sensitive to PIN and its photodegradation mixtures. The computational results were combined with the experimental data on the amounts of degradation intermediates for determination of the intermediates that were principally responsible for the toxicity. Intermediate with two hydroxyl groups, positioned on indole ring in meta and para positions, was proposed as the one with the highest contribution to toxicity.


Assuntos
Pindolol/química , Luz Solar , Titânio/efeitos da radiação , Poluentes Químicos da Água/química , Óxido de Zinco/efeitos da radiação , Animais , Catálise , Linhagem Celular , Humanos , Cinética , Modelos Moleculares , Fotólise , Pindolol/toxicidade , Ratos , Titânio/química , Poluentes Químicos da Água/toxicidade , Óxido de Zinco/química
9.
Am J Obstet Gynecol ; 223(4): 525-537, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32199925

RESUMO

OBJECTIVE DATA: Chronic hypertension is associated with adverse perinatal outcomes, although the optimal treatment is unclear. The aim of this network metaanalysis was to simultaneously compare the efficacy and safety of antihypertensive agents in pregnant women with chronic hypertension. STUDY: Medline, Scopus, CENTRAL, Web of Science, Clinicaltrials.gov, and Google Scholar databases were searched systematically from inception to December 15, 2019. Both randomized controlled trials and cohort studies were held eligible if they reported the effects of antihypertensive agents on perinatal outcomes among women with chronic hypertension. STUDY APPRAISAL AND SYNTHESIS METHODS: The primary outcomes were preeclampsia and small-for-gestational-age risk. A frequentist network metaanalytic random-effects model was fitted. The main analysis was based on randomized controlled trials. The credibility of evidence was assessed by taking into account within-study bias, across-studies bias, indirectness, imprecision, heterogeneity, and incoherence. RESULTS: Twenty-two studies (14 randomized controlled trials and 8 cohorts) were included, comprising 4464 women. Pooling of randomized controlled trials indicated that no agent significantly affected the incidence of preeclampsia. Atenolol was associated with significantly higher risk of small-for-gestational age compared with placebo (odds ratio, 26.00; 95% confidence interval, 2.61-259.29) and is ranked as the worst treatment (P-score=.98). The incidence of severe hypertension was significantly lower when nifedipine (odds ratio, 0.27; 95% confidence interval, 0.14-0.55), methyldopa (odds ratio, 0.31; 95% confidence interval, 0.17-0.56), ketanserin (odds ratio, 0.29; 95% confidence interval, 0.09-0.90), and pindolol (odds ratio, 0.17; 95% confidence interval, 0.05-0.55) were administered compared with no drug intake. The highest probability scores were calculated for furosemide (P-score=.86), amlodipine (P-score=.82), and placebo (P-score=.82). The use of nifedipine and methyldopa were associated with significantly lower placental abruption rates (odds ratio, 0.29 [95% confidence interval, 0.15-0.58] and 0.23 [95% confidence interval, 0.11-0.46], respectively). No significant differences were estimated for cesarean delivery, perinatal death, preterm birth, and gestational age at delivery. CONCLUSION: Atenolol was associated with a significantly increased risk for small-for-gestational-age infants. The incidence of severe hypertension was significantly lower when nifedipine and methyldopa were administered, although preeclampsia risk was similar among antihypertensive agents. Future large-scale trials should provide guidance about the choice of antihypertensive treatment and the goal blood pressure during pregnancy.


Assuntos
Descolamento Prematuro da Placenta/epidemiologia , Anti-Hipertensivos/uso terapêutico , Retardo do Crescimento Fetal/epidemiologia , Hipertensão/tratamento farmacológico , Pré-Eclâmpsia/epidemiologia , Complicações Cardiovasculares na Gravidez/tratamento farmacológico , Anlodipino/uso terapêutico , Atenolol/uso terapêutico , Cesárea/estatística & dados numéricos , Doença Crônica , Feminino , Furosemida/uso terapêutico , Idade Gestacional , Humanos , Hipertensão/fisiopatologia , Incidência , Recém-Nascido Pequeno para a Idade Gestacional , Ketanserina/uso terapêutico , Metildopa/uso terapêutico , Metanálise em Rede , Nifedipino/uso terapêutico , Morte Perinatal , Pindolol/uso terapêutico , Gravidez , Nascimento Prematuro/epidemiologia , Índice de Gravidade de Doença
10.
J Cachexia Sarcopenia Muscle ; 11(2): 594-605, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32067370

RESUMO

BACKGROUND: Cachexia, a common manifestation of malignant cancer, is associated with wasting of skeletal muscle and fat tissue. In this study, we investigated the effects of a new first in class anabolic catabolic transforming agent on skeletal muscle in a rat model of cancer cachexia. METHODS: Young male Wistar Han rats were intraperitoneally inoculated with 108 Yoshida hepatoma AH-130 cells and once daily treated with 0.3 mg kg-1 , 3 mg kg-1 MT-102, or placebo by gavage. RESULTS: Three mg kg-1 d-1 MT-102 not only prevented progressive loss of fat mass (-6 ± 2 g vs -12 ± 1 g; P < 0.001); lean mass (+1 ± 10 g vs. -37 ± 2 g; P < 0.001) and body weight (+1 ± 13 g vs. -60 ± 2 g; P < 0.001) were remained. Quality of life was also improved as indicated by a higher food intake 12.9 ± 3.1 g and 4.3 ± 0.5 g, 3 mg kg-1 d-1 MT-102 vs. placebo, respectively, P < 0.001) and a higher spontaneous activity (52 369 ± 6521 counts/24 h and 29 509 ± 1775 counts/24 h, 3 mg·kg-1 d-1 MT-102 vs. placebo, respectively, P < 0.01) on Day 11. Most importantly, survival was improved (HR = 0.29; 95% CI: 0.16-0.51, P < 0.001). The molecular mechanisms behind these effects involve reduction of overall protein degradation and activation of protein synthesis, assessed by measurement of proteasome and caspase-6 activity or Western blot analysis, respectively. CONCLUSIONS: The present study shows that 3 mg kg-1 MT-102 reduces catabolism, while inducing anabolism in skeletal muscle leading to an improved survival.


Assuntos
Caquexia/tratamento farmacológico , Neoplasias Hepáticas Experimentais/metabolismo , Pindolol/farmacologia , Animais , Composição Corporal , Caquexia/metabolismo , Caquexia/patologia , Modelos Animais de Doenças , Neoplasias Hepáticas Experimentais/patologia , Masculino , Distribuição Aleatória , Ratos , Ratos Wistar , Análise de Sobrevida
11.
Anal Chem ; 92(4): 3006-3013, 2020 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-31971372

RESUMO

Capillary electrophoresis-mass spectrometry is a powerful technique for high-throughput and high efficiency separations combined with structural identification. Electrospray ionization is the primary interface used to couple capillary electrophoresis to mass analyzers; however, improved designs continue to be reported. A new interfacing method based on vibrating sharp-edge spray ionization is presented in this work to overcome the challenges of decoupling applied voltages and to enhance the compatibility with separations performed at near-neutral pH. The versatility and ease of use of this ionization source is demonstrated using ß-blockers, peptides, and proteins. The cationic ß-blocker pindolol was injected electrokinetically, and detected at concentrations ranging from 10 nM to 5 µM, with an estimated detection limit of 2 nM. The vibrating sharp-edge spray ionization functions with flow rates from 70 to 200 nL/min and did not perturb the capillary electrophoresis separation electroosmotic flow as evidenced by the observation that most migration times differed less than 7% (n = 3) across a lab-built system interfaced to mass spectrometry and a commercial system that utilizes absorbance detection. For cationic beta-blockers the theoretical plates achieved in the capillary electrophoresis-mass spectrometry setup were 80%-95% of that observed with a commercial capillary electrophoresis-UV absorbance detection system.


Assuntos
Eletro-Osmose , Pindolol/análise , Eletroforese Capilar/instrumentação , Estrutura Molecular , Espectrometria de Massas por Ionização por Electrospray/instrumentação
12.
Med Hypotheses ; 133: 109407, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31586811

RESUMO

Attention Deficit Hyperactivity Disorder (ADHD) is one of the most common childhood behavioural disorders, the frontline treatments for which are drugs with abuse potential. As a consequence, there is an urgent need to develop non addictive drug treatments with equivalent efficacy. Preclinical evidence suggests that selective serotonin uptake inhibitors (SSRIs) are likely to be effective in ADHD, however clinical reports suggest that SSRIs are of limited therapeutic value for the treatment of ADHD. We propose that this disconnect can be explained by the pattern of drug administration in existing clinical trials (administration for short periods of time, or intermittently) leading to inadequate control of the autoregulatory processes which control 5-HT release, most notably at the level of inhibitory 5-HT1A somatodendritic autoreceptors. These autoreceptors reduce the firing rate of 5-HT neurons (limiting release) unless they are desensitised by a long term, frequent pattern of drug administration. As such, we argue that the participants in earlier trials were not administered SSRIs in a manner which realises any potential benefits of targeting 5-HT in the pharmacotherapy of ADHD. In light of this, we hypothesise that there may be under-researched potential to exploit 5-HT transmission therapeutically in ADHD, either through changing the administration regime, or by pharmacological means. Recent pharmacological research has successfully potentiated the effects of SSRIs in acute animal preparations by antagonising inhibitory 5-HT1A autoreceptors prior to the administration of the SSRI fluoxetine. We suggest that combination therapies linking SSRIs and 5-HT1A antagonists are a potential way forward in the development of efficacious non-addictive pharmacotherapies for ADHD.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Inibidores de Captação de Serotonina/uso terapêutico , Colículos Superiores/fisiopatologia , Animais , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Ensaios Clínicos como Assunto/métodos , Dioxanos/administração & dosagem , Dioxanos/uso terapêutico , Esquema de Medicação , Sinergismo Farmacológico , Quimioterapia Combinada , Humanos , Pindolol/farmacologia , Pindolol/uso terapêutico , Piperazinas/administração & dosagem , Piperazinas/uso terapêutico , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos , Receptor 5-HT1A de Serotonina/fisiologia , Movimentos Sacádicos/fisiologia , Neurônios Serotoninérgicos/efeitos dos fármacos , Neurônios Serotoninérgicos/fisiologia , Serotonina/fisiologia , Antagonistas do Receptor 5-HT1 de Serotonina/administração & dosagem , Antagonistas do Receptor 5-HT1 de Serotonina/farmacologia , Antagonistas do Receptor 5-HT1 de Serotonina/uso terapêutico , Inibidores de Captação de Serotonina/administração & dosagem , Inibidores de Captação de Serotonina/farmacologia , Colículos Superiores/efeitos dos fármacos
13.
J Pharm Pharmacol ; 71(10): 1576-1583, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31347707

RESUMO

OBJECTIVES: Paraoxonase-1 (PON1) enzyme is related to high-density lipoprotein (HDL), which is calcium dependent. It has essential roles such as protecting LDL against oxidation and detoxification of highly toxic substances. It is a significant risk to reduce the levels of this enzyme in patients with diabetes mellitus, cardiovascular diseases, hyperthyroidism and chronic renal failure. METHODS: Here, it was reported that the purification of human serum PON1 using straightforward methods and determination of the interactions between some antihypertension drugs and the enzyme. KEY FINDING: It was found that these drugs exhibit potential inhibitor properties for human serum PON1 with IC50 values in the range of 131.40-369.40 µm and Ki values in the range of 56.24 ± 6.75-286.74 ± 28.28 µm. These drugs showed different inhibition mechanisms. It was determined that midodrine and nadolol were exhibited competitive inhibition, but atenolol and pindolol were exhibited non-competitive inhibition. CONCLUSION: Usage of these drugs would be hazardous in some cases.


Assuntos
Anti-Hipertensivos/farmacologia , Arildialquilfosfatase/sangue , Aterosclerose/sangue , Aterosclerose/tratamento farmacológico , Atenolol/farmacologia , Humanos , Lipoproteínas HDL/sangue , Midodrina/farmacologia , Nadolol/farmacologia , Pindolol/farmacologia
14.
Transl Psychiatry ; 9(1): 134, 2019 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-30975977

RESUMO

Developing positron emission tomography (PET) radioligands for the detection of endogenous serotonin release will enable the investigation of serotonergic deficits in many neuropsychiatric disorders. The present study investigates how acute challenges that aim to increase or decrease cerebral serotonin levels affect binding of the serotonin 2A receptor (5-HT2AR) agonist radioligand [11C]Cimbi-36. In a randomized, double-blind, placebo-controlled, three-arm design, 23 healthy volunteers were PET scanned twice with [11C]Cimbi-36: at baseline and following double-blind assignment to one of three interventions (1) infusion of the selective serotonin reuptake inhibitor (SSRI) citalopram preceded by oral dosing of the 5-HT1AR antagonist pindolol, (n = 8) (2) acute tryptophan depletion (ATD) (n = 7) and (3) placebo (n = 8). Two-sample t-tests revealed no significant group differences in percent change of neocortical [11C]Cimbi-36 binding from baseline to intervention between placebo and citalopram/pindolol (p = 0.4) or between placebo and ATD (p = 0.5). Notably, there was a significantly larger within-group variation in 5-HT2AR binding after intervention with citalopram/pindolol, as compared with placebo (p = 0.007). These findings suggest that neither ATD nor a combination of citalopram and pindolol elicit acute unidirectional changes in serotonin levels sufficient to be detected with [11C]Cimbi-36 PET in neocortex. We suggest that the large interindividual variation in 5-HT2AR binding after citalopram/pindolol reflects that after an acute SSRI intervention, individuals respond substantially different in terms of their brain serotonin levels. Our observation has a potential impact for the understanding of patient responses to SSRI.


Assuntos
Tomografia por Emissão de Pósitrons , Neurônios Serotoninérgicos/fisiologia , Transmissão Sináptica , Benzilaminas , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Radioisótopos de Carbono , Citalopram/farmacologia , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Humanos , Masculino , Fenetilaminas , Pindolol/farmacologia , Serotonina/fisiologia , Inibidores de Captação de Serotonina/farmacologia , Adulto Jovem
15.
Cell Tissue Res ; 377(1): 107-113, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30627806

RESUMO

Major depressive disorder is a severe, disabling disorder that affects around 4.7% of the population worldwide. Based on the monoaminergic hypothesis of depression, monoamine reuptake inhibitors have been developed as antidepressants and nowadays, they are used widely in clinical practice. However, these drugs have a limited efficacy and a slow onset of therapeutic action. Several strategies have been implemented to overcome these limitations, including switching to other drugs or introducing combined or augmentation therapies. In clinical practice, the most often used augmenting drugs are lithium, triiodothyronine, atypical antipsychotics, buspirone, and pindolol, although some others are in the pipeline. Moreover, multitarget antidepressants have been developed to improve efficacy. Despite the enormous effort exerted to improve these monoaminergic drugs, they still fail to produce a rapid and sustained antidepressant response in a substantial proportion of depressed patients. Recently, new compounds that target other neurotransmission system, such as the glutamatergic system, have become the focus of research into fast-acting antidepressant agents. These promising alternatives could represent a new pharmacological trend in the management of depression.


Assuntos
Antidepressivos/farmacologia , Monoaminas Biogênicas/farmacologia , Transtorno Depressivo Maior/tratamento farmacológico , Fármacos Atuantes sobre Aminoácidos Excitatórios/farmacologia , Antipsicóticos/farmacologia , Buspirona/farmacologia , Sinergismo Farmacológico , Humanos , Lítio/farmacologia , Pindolol/farmacologia , Tri-Iodotironina/farmacologia
16.
Addict Biol ; 24(4): 652-663, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30022582

RESUMO

Repeated cycles of binge-like alcohol consumption and abstinence change the activity of several neurotransmitter systems. Some of these changes are consolidated following prolonged alcohol use and are thought to play an important role in the development of dependence. We have previously shown that systemic administration of the dual beta-adrenergic antagonist and 5-HT1A/1B partial agonist pindolol selectively reduces long-term but not short-term binge-like consumption of ethanol and alters excitatory postsynaptic currents in basolateral amygdala (BLA) principal neurons. The aim of this study was to investigate the effects of pindolol microinfusions in the BLA on long-term ethanol intake using the drinking-in-the-dark paradigm in mice. We also microinfused RU24969 (5-HT1A/1B receptor partial agonist) and CGP12177 (ß1/2 adrenergic antagonist) following long-term ethanol intake and determined the densities of 5-HT1A/1B receptors and ß1/2 adrenergic in the BLA following short-term (4 weeks) and long-term ethanol (12 weeks) consumption. We show that intra-BLA infusion of pindolol (1000 pmol/0.5 µl), RU24969 (0.3 and 3 pmol/0.5 µl) and CGP12177 (500 pmol/0.5 µl) produce robust decreases in long-term ethanol consumption. Additionally, we identified reduced ß1/2 adrenergic receptor expression and no change in 5-HT1A/1B receptor density in the BLA of long-term ethanol-consuming mice. Collectively, our data highlight the effects of pindolol on voluntary, binge-like ethanol consumption behavior following long-term intake.


Assuntos
Antagonistas de Receptores Adrenérgicos beta 2/farmacologia , Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos , Depressores do Sistema Nervoso Central/administração & dosagem , Etanol/administração & dosagem , Pindolol/farmacologia , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Animais , Complexo Nuclear Basolateral da Amígdala/metabolismo , Depressores do Sistema Nervoso Central/farmacologia , Agonismo Parcial de Drogas , Etanol/farmacologia , Humanos , Indóis/farmacologia , Camundongos , Norepinefrina/metabolismo , Propanolaminas/farmacologia , Receptor 5-HT1A de Serotonina/efeitos dos fármacos , Receptor 5-HT1A de Serotonina/metabolismo , Receptor 5-HT1B de Serotonina/efeitos dos fármacos , Receptor 5-HT1B de Serotonina/metabolismo , Receptores Adrenérgicos beta 1/efeitos dos fármacos , Receptores Adrenérgicos beta 1/metabolismo , Receptores Adrenérgicos beta 2/efeitos dos fármacos , Receptores Adrenérgicos beta 2/metabolismo , Serotonina/metabolismo
17.
Behav Brain Res ; 357-358: 82-87, 2019 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-29113874

RESUMO

The effects of the 5-HT1A receptor blocker pindolol and the 5-HT releasing and uptake blocking agent d-fenfluramine, both used as indirect serotonin agonists, on flumazenil-induced acute anxiety reactions were studied in panic disorder patients to test the hypothesis that serotonin (5-HT) inhibits neural systems mediating panic attacks. Thirty never treated or drug free PD patients (16 females) aged 22-49 y (mean ±â€¯SD, 32.9 ±â€¯8) received single doses of d-fenfluramine (n = 10; 30 mg, p.o.), pindolol (n = 10; 5 mg, p.o.), or placebo (n = 10) 90 and 45 min before a challenge test with flumazenil (1.5 mg, i.v., in 10 min), under double-blind conditions. Panic attacks occurred in 5 control subjects (placebo-flumazenil group), 5 subjects in the pindolol group and in 7 in the d-fenluramine pre-treated patients. Patients experiencing anxiety attacks following flumazenil reported higher increases in anxiety scores. Respiratory rate increases were not different between patients experiencing or not a panic attack. Despite sample size limitation, this study suggests that flumazenil induced anxiety reaction is not a good pharmacological model of panic attacks, considering the absence of serotonergic modulation of its effects.


Assuntos
Ansiedade/tratamento farmacológico , Fenfluramina/uso terapêutico , Pindolol/uso terapêutico , Antagonistas da Serotonina/uso terapêutico , Inibidores de Captação de Serotonina/uso terapêutico , Adulto , Ansiedade/induzido quimicamente , Ansiedade/etiologia , Feminino , Flumazenil/efeitos adversos , Moduladores GABAérgicos/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Transtorno de Pânico/complicações , Escalas de Graduação Psiquiátrica , Análise de Regressão , Adulto Jovem
18.
J Chromatogr A ; 1568: 214-221, 2018 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-30122164

RESUMO

The present study describes a rapid and effective capillary electrophoresis (CE) method for the enantioseparation of pindolol using single-isomer octa(6-O-sulfo)-γ-cyclodextrin. The complexation parameters were determined under neutral and high pH conditions to identify optimal separation conditions using a theoretical model. Baseline separation of pindolol enantiomers was achieved within 6 min in a sodium/MOPS buffer, pH 7.2, with a selector concentration of 6 mM. The method was validated according to the ICH guidelines using imidazole as an internal standard. Low limits of detection and quantification were found, specifically 1.2 µg/mL and 4 µg/mL (0.6 µg/mL and 2 µg/mL per enantiomer), respectively. The calibration curves showed good linearity, with a coefficient of determination R2 ≥ 0.999 over a 5 - 55 µg/mL concentration range and over a 50 - 300 µg/mL concentration range of the racemic mixture. The relative standard deviations (%RSD) of intra-day and inter-day precision were lower than 8% at LOQ level, lower than 3% at 50 µg/mL level and lower than 1.5% at 300 µg/mL level. Accuracy ranged from 95 to 103% (106% at LOQ level). The proposed method was successfully tested on a medical formulation of Visken® Sandoz intravenous solution and Visken® Teofarma pills for oral use.


Assuntos
Eletroforese Capilar/métodos , Pindolol/isolamento & purificação , Software , gama-Ciclodextrinas/química , Tampões (Química) , Calibragem , Concentração de Íons de Hidrogênio , Limite de Detecção , Reprodutibilidade dos Testes , Estereoisomerismo , Fatores de Tempo
19.
Neuropharmacology ; 135: 63-72, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29505786

RESUMO

Both selective serotonin reuptake inhibitors (SSRIs) and ventromedial prefrontal cortex (vmPFC) deep brain stimulation (DBS) modulate serotonergic activity. We compared the acute (1 day) and long-term (12 days) effects of vmPFC stimulation and fluoxetine on serotonin (5-HT) release and receptor expression in rats. Samples to measure serotonin levels were collected from the hippocampus using microdialysis. Serotonin transporter (SERT), 5-HT1A and 5-HT1B mRNA were measured using in situ hybridization. [3H]8-OH-DPAT and [125I]cyanopindolol autoradiography were used to measure 5-HT1A and 5-HT1B binding. Our results show that after fluoxetine injections serotonin levels were approximately 150% higher than at baseline. Twelve days later, pre-injection 5-HT extracellular concentration was substantially higher than on day 1. In contrast, serotonin levels following DBS were only 50% higher than at baseline. While pre-stimulation 5-HT on day 12 was significantly higher than on treatment day 1, no stimulation-induced 5-HT peak was recorded. SERT expression in the dorsal raphe was increased after acute fluoxetine and decreased following a single day of DBS. Neither fluoxetine nor DBS administered acutely substantially changed 5-HT1A or 5-HT1B binding. Chronic fluoxetine treatment, however, was associated with a decrease in [3H]8-OH-DPAT prefrontal cortex and hippocampus expression. In contrast, chronic DBS induced a significant increase in [125I]cyanopindolol binding in the prefrontal cortex, globus pallidus, substantia nigra and raphe nuclei. mRNA expression of 5-HT1A and 5-HT1B in raphe nuclei was not altered by either treatment. These results suggest that fluoxetine and DBS modulate activity of the serotonergic system but likely exert their effects through different mechanisms.


Assuntos
Estimulação Encefálica Profunda , Fluoxetina/farmacologia , Receptor 5-HT1A de Serotonina/biossíntese , Receptor 5-HT1B de Serotonina/biossíntese , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Serotonina/metabolismo , 8-Hidroxi-2-(di-n-propilamino)tetralina/metabolismo , Animais , Encéfalo/metabolismo , Hipocampo/metabolismo , Radioisótopos do Iodo/metabolismo , Pindolol/análogos & derivados , Pindolol/metabolismo , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiologia , Ensaio Radioligante , Ratos , Fatores de Tempo , Trítio/metabolismo
20.
Sci Rep ; 7: 39905, 2017 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-28051147

RESUMO

Mechanisms underlying ß2-adrenoreceptor (ß2AR) inverse agonist mediated bronchoprotectiveness remain unknown. We incubated ICI118,551, formoterol, budesonide, and formoterol plus budesonide, as well as ICI118,551 or pindolol plus formoterol, ICI118,551 plus forskolin, SQ22,536 or H89 plus formoterol in ASMCs to detect expressions of M3R, PLCß1 and IP3. The level of M3R in the presence of 10-5 mmol/L ICI118,551 were significantly decreased at 12 h, 24 h and 48 h (P < 0.05), and at 24 h were significantly reduced in ICI118,551 with concentration of 10-5 mmol/L, 10-6 mmol/L, 10-7 mmol/L, and 10-8 mmol/L (P < 0.05). The level of IP3 in 10-5 mmol/L ICI118,551 was significantly diminished at 24 h (P < 0.01), except for that at 1 h, neither was in the level of PLCß1. A concentration of 10-5 mmol/L ICI118,551 at 24 h showed a significant reduction of M3R level compared to formoterol (P < 0.01), budesonide (P < 0.01), and formoterol + budesonide (P < 0.05), but significant reduction of PLCß1 and IP3 was only found between 10-5 mmol/L ICI118,551 and formoterol at 24 h, but not in the comparison of budesonide or formoterol + budesonide. Pindolol and H89 could not inhibit the formoterol-induced expression of M3R (P > 0.05), but SQ22,536 significantly antagonized the formoterol-induced M3R expression (P < 0.05). In conclusions, ß2AR inverse agonist, ICI118,551, exerts similar bronchoprotective effects to corticosteroids via decreasing the expression of M3R and inhibiting the production of IP3.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Regulação para Baixo/efeitos dos fármacos , Receptor Muscarínico M3/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Animais , Broncodilatadores/farmacologia , Células Cultivadas , Colforsina/farmacologia , Agonismo Inverso de Drogas , Fumarato de Formoterol/farmacologia , Inositol 1,4,5-Trifosfato/metabolismo , Masculino , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Fosfolipase C beta/metabolismo , Pindolol/farmacologia , Ratos , Ratos Wistar , Receptores Adrenérgicos beta 2/química
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...