RESUMO
Dried Blood Spots (DBS) revolutionize therapeutic drug monitoring using LC-MS for the precise quantification of cardiovascular drugs (CDs), enabling personalized treatment adapted to patient-specific pharmacokinetics with minimal invasiveness. This study aims to achieve simultaneous quantification of eight CDs in DBS, overcoming physicochemical challenges. A two-step protein precipitation method was used for simple and precise sample preparation. The drugs were analyzed using LC-MS/MS in ESI positive-ion mode, showing high sensitivity and linearity, with a correlation coefficient (r2) exceeding 0.999, after being separated on a reversed-phase chromatography by gradient elution of DW-acetonitrile containing 0.1 % formic acid + 2 mM ammonium formate. The validation results indicate good selectivity, with no observed matrix effect and carry-over. The intra- and inter-day accuracy and precision were within 6 % for most drugs, except for digoxin and deslanoside at low therapeutic levels where the variation was within 20 %. Stability tests confirmed suitable DBS handling and storage conditions, indicating drug stability for at least 30 days at room temperature. The analysis of whole spot has demonstrated remarkable precision and reliability in all target drugs. The analysis of 3 mm internal diameter discs, punched in and out of DBS, presumed to contain 3 µL of blood, showed acceptable accuracy for most drugs, with less polar drugs like digoxin and deslanoside showing lower accuracy, indicating a need for further correction due to non-uniform drug distribution. Consequently, the developed LC-MS/MS method enables the quantification of multiple CDs in a single DBS analysis, while suggesting the potential for accuracy-based analysis.
Assuntos
Fármacos Cardiovasculares , Teste em Amostras de Sangue Seco , Espectrometria de Massas em Tandem , Espectrometria de Massas em Tandem/métodos , Teste em Amostras de Sangue Seco/métodos , Humanos , Reprodutibilidade dos Testes , Modelos Lineares , Cromatografia Líquida/métodos , Fármacos Cardiovasculares/sangue , Fármacos Cardiovasculares/farmacocinética , Limite de Detecção , Monitoramento de Medicamentos/métodosRESUMO
This study evaluated the adherence to prescribed cardiovascular therapy medications among cardiovascular disease patients attending clinics in Misan, Amara, Iraq. Mixed methods were used to assess medication adherence comprising the Arabic version of the eight-item Morisky Medication Adherence Scale (MMAS-8) and determination of drug concentrations in patient dried blood spot (DBS) samples by liquid chromatography-high resolution mass spectrometry. Three hundred and three Iraqi patients (median age 53 years, 50.5% female) who had been taking one or more of the nine commonly prescribed cardiovascular medications (amlodipine, atenolol, atorvastatin, bisoprolol, diltiazem, lisinopril, losartan, simvastatin and valsartan) for at least six months were enrolled. For each patient MMAS-8 scores were determined alongside drug concentrations in their dried blood spot samples. Results from the standardized questionnaire showed that adherence was 81.8% in comparison with 50.8% obtained using the laboratory-based microsample analysis. The agreement between the indirect (MMAS-8) and direct (DBS analysis) assessment approaches to assessing medication adherence showed significantly poor agreement (kappa = 0.28, P = 0.001). The indirect and direct assessment approaches showed no significant correlation between nonadherence to prescribed cardiovascular pharmacotherapy and age and gender, but were significantly associated with the number of medications in the patient's treatment regimen (MMAS-8: Odds Ratio (OR) 1.947, 95% CI, P = 0.001; DBS analysis: OR 2.164, 95% CI, P = 0.001). The MMAS-8 results highlighted reasons for nonadherence to prescribed cardiovascular pharmacotherapy in this patient population whilst the objective DBS analysis approach gave valuable information about nonadherence to each medication in the patient's treatment regimen. DBS sampling, due its minimally invasive nature, convenience and ease of transport is a useful alternative matrix to monitor adherence objectively in Iraq to cardiovascular pharmacotherapy. This information combined with MMAS-8 can provide clinicians with an evidence-based novel approach to implement intervention strategies to optimise and personalise cardiovascular pharmacotherapy in the Iraqi population and thereby improve patient health outcomes.
Assuntos
Fármacos Cardiovasculares/sangue , Fármacos Cardiovasculares/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Adesão à Medicação/estatística & dados numéricos , Antagonistas Adrenérgicos beta/uso terapêutico , Adulto , Idoso , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Sistema Cardiovascular/patologia , Teste em Amostras de Sangue Seco/métodos , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Iraque , Masculino , Pessoa de Meia-Idade , Inquéritos e QuestionáriosRESUMO
A sensitive and robust method has been developed using an ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) assay to quantify Tat-K13, a novel interfering peptide for the treatment of ischemic stroke, in human plasma. Automated solid-phase extraction on a Waters Oasis WCX (30 µm, 10 mg) 96-well plate was used to extract Tat-K13 from human plasma and the extracts were separated on a Waters Acquity CSH column (2.1 × 50 mm i.d., 1.7 µm) with a gradient elution method by mobile phase A (nonafluoropentanoic acid-acetic acid-water, 1:2:1000, v/v/v) and B (nonafluoropentanoic acid-acetic acid-water-acetonitrile, 1:2:100:900, v/v/v/v). The method was fully validated following international bioanalytical guidelines and showed good linearity from 2.10 to 1,050 ng/ml. The method was successfully applied to investigate the clinical pharmacokinetics of Tat-K13 in health volunteers. Rapid elimination of Tat-K13 from the body was observed, with half-life ranging from 0.26 to 0.78 h across different dose levels. The exposure of Tat-K13 was approximately dose-dependent in terms of the area under the concentration-time curve and peak concentration.
Assuntos
Fármacos Cardiovasculares , Cromatografia Líquida de Alta Pressão/métodos , AVC Isquêmico/tratamento farmacológico , Peptídeos , Espectrometria de Massas em Tandem/métodos , Adolescente , Adulto , Fármacos Cardiovasculares/sangue , Fármacos Cardiovasculares/farmacocinética , Fármacos Cardiovasculares/uso terapêutico , Humanos , Pessoa de Meia-Idade , Peptídeos/sangue , Peptídeos/farmacocinética , Peptídeos/uso terapêutico , Reprodutibilidade dos Testes , Adulto JovemRESUMO
BACKGROUND: Levamlodipine, a calcium channel blocker, has been show act as a cardiovascular drug. To compare the pharmacokinetic parameters between levamlodipine (test formulation) at a single dose of 5 mg and amlodipine (reference formulation) at a single dose of 10 mg, the bioequivalence study was carried out. METHODS: A single-dose randomized, open-label, two-period crossover study was designed in healthy Chinese subjects. 48 subjects were divided into fasted and fed groups equally. The subjects randomly received the test or reference formulations at the rate of 1:1. Following a 21-day washout period, the alternative formulations were received. The blood samples were collected at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 24, 36, 48, 72, 96, 120, 144, 168 h later. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was applied to determine the plasma concentrations of levamlodipine. Adverse events were recorded. RESULTS: The 90% confidence intervals (CIs) of the ratio of geometric means (GMRs) of Cmax, AUC0-t, and AUC0-∞ under both fasted and fed conditions were within the prespecified bioequivalence limits between 80 ~ 125%. Under fasted conditions, 24 subjects were enrolled and completed the study. The mean Cmax was (2.70 ± 0.49) ng/mL, AUC0-t was (141.32 ± 36.24) ng × h/mL and AUC0-∞ was (157.14 ± 45.65) ng × h/mL after a single dose of 5 mg levamlodipine. The mean Cmax was (2.83 ± 0.52) ng/mL, AUC0-t was (153.62 ± 33.96) ng × h/mL and AUC0-∞ was (173.05 ± 41.78) ng × h/mL after a single dose of 10 mg amlodipine. Under fed conditions, 24 subjects were enrolled and completed the study. The mean Cmax was (2.73 ± 0.55) ng/mL, AUC0-t was (166.93 ± 49.96) ng × h/mL and AUC0-∞ was (190.99 ± 70.89) ng × h/mL after a single dose of 5 mg levamlodipine. The mean Cmax was (2.87 ± 0.81) ng/mL AUC0-t was (165.46 ± 43.58) ng × h/mL and AUC0-∞ was (189.51 ± 64.70) ng × h/mL after a single dose of 10 mg amlodipine. Serious adverse event was not observed. CONCLUSION: The trial confirmed that levamlodipine at a single dose of 5 mg and amlodipine at a single dose of 10 mg were bioequivalent under both fasted condition and fed condition. TRIAL REGISTRATION: Cinicaltrials, NCT04411875 . Registered 3 June 2020 - Retrospectively registered.
Assuntos
Povo Asiático , Fármacos Cardiovasculares/administração & dosagem , Fármacos Cardiovasculares/sangue , Niacina/análogos & derivados , Adulto , Anlodipino/administração & dosagem , Anlodipino/sangue , Estudos Cross-Over , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Niacina/administração & dosagem , Niacina/sangue , Comprimidos , Equivalência Terapêutica , Adulto JovemAssuntos
Antineoplásicos/efeitos adversos , Fármacos Cardiovasculares/sangue , Digoxina/sangue , Monitoramento de Medicamentos , Cardiopatias/tratamento farmacológico , Feniltioidantoína/análogos & derivados , Neoplasias da Próstata/tratamento farmacológico , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Benzamidas , Monitoramento de Medicamentos/efeitos adversos , Monitoramento de Medicamentos/métodos , Cardiopatias/sangue , Humanos , Imunoensaio , Medições Luminescentes , Masculino , Pessoa de Meia-Idade , Nitrilas , Feniltioidantoína/efeitos adversos , Feniltioidantoína/farmacologia , Feniltioidantoína/uso terapêutico , Neoplasias da Próstata/secundárioRESUMO
We studied pharmacokinetics and bioavailability of verapamil, propranolol, and ethacizine in healthy volunteers after single oral administration under normal conditions and on the second day of simulated antiorthostatic hypokinesia modeling some effects of microgravity. Under conditions of antiorthostatic hypokinesia, a tendency to a decrease in half-elimination period, mean retention time, and volume of distribution and an increase in the rate of absorption, ratio of maximum concentrations, and relative rate of absorption of verapamil and propranolol were revealed. For ethacizine, a statistically significant increase in the time of attaining maximum concentration and volume of distribution and a decrease in the maximum concentration, rate of absorption, ratio of maximum concentrations, and relative rate of absorption under conditions of antiorthostatic hypokinesia were found.
Assuntos
Fármacos Cardiovasculares/farmacocinética , Hipocinesia/sangue , Fenotiazinas/farmacocinética , Propranolol/farmacocinética , Verapamil/farmacocinética , Simulação de Ausência de Peso/métodos , Adulto , Área Sob a Curva , Disponibilidade Biológica , Fármacos Cardiovasculares/sangue , Meia-Vida , Humanos , Hipocinesia/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Fenotiazinas/sangue , Propranolol/sangue , Verapamil/sangueRESUMO
In this work, the aim of our study was to assess whether sesamin could influence the pharmacokinetics of ivabradine and its active metabolite N-desmethylivabradine in rats. At the begining, 12 healthy male Sprague-Dawley rats were randomly divided into two groups: The rats were received an oral administration of 1.0mg/kg ivabradine alone (the control group), and the rats were given 1.0mg/kg ivabradine co-administered with 50mg/kg sesamin by gavage (the test group). After that, blood samples were collected from the tail vein of rats, and ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) were used for determing the plasma concentrations of ivabradine and N-desmethylivabradine in rats. Finally, the pharmacokinetic parameters were estimated using DAS 2.0 software. As the results, the pharmacokinetic parameters (t1/2, Cmax, AUC (0-t) and AUC (0-oo)) of ivabradine in the control group were significantly lower than those in the test group (P<0.05). Moreover, sesamin significantly decreased t1/2, Cmax, AUC(0-t) and AUC(0-oo) of N-desmethylivabradine when compared to the control. These results demonstrated that sesamin increases plasma concentration of ivabradine and decreases N-desmethylivabradine conversely. Hence, our data indicated sesamin could influence the pharmacokinetic profile of ivabradine in rats, which might cause food-drug interaction in humans.
Assuntos
Dioxóis/farmacologia , Ivabradina/farmacocinética , Lignanas/farmacologia , Administração Oral , Animais , Área Sob a Curva , Fármacos Cardiovasculares/sangue , Fármacos Cardiovasculares/metabolismo , Fármacos Cardiovasculares/farmacocinética , Cromatografia Líquida de Alta Pressão , Dioxóis/administração & dosagem , Dioxóis/farmacocinética , Ivabradina/sangue , Ivabradina/metabolismo , Lignanas/administração & dosagem , Lignanas/farmacocinética , Masculino , Ratos Sprague-Dawley , Espectrometria de Massas em TandemRESUMO
A dried blood spot (DBS) sampling method was exploited to extract cardiovascular drugs using a small volume of whole blood of human and rodent. Thereafter, an analytical method using liquid chromatography with tandem mass spectrometry (LC-MS/MS) was developed and validated for the determination of 12 cardiovascular drugs. A 6 mm internal diameter disc containing 10 µL of blood was punched from a specifically designed card and analyzed by LC-MS/MS using a gradient elution method with a total run time of 16 min. For sample separation, a universal octadecyl-silica column was used with a flow rate of 0.2 mL/min. The developed method was validated in terms of linearity, accuracy, and precision, which showed satisfactory results. In addition, the matrix effects were closely investigated to confirm the extraction efficiency. Additionally, the stability was tested by storing DBSs at room temperature; the results showed that these drugs were stable for at least 30 days. Accordingly, the proposed LC-MS/MS method is capable to analyze several cardiovascular drugs in a single analysis. It can be applied to therapeutic drug monitoring in patients as well as in the in vivo settings.
Assuntos
Fármacos Cardiovasculares/sangue , Teste em Amostras de Sangue Seco , Cromatografia Líquida , Humanos , Espectrometria de Massas em TandemRESUMO
BACKGROUND: The purpose of this pilot study was to determine if a definitive clinical trial of thiamine supplementation was warranted in patients with acute heart failure. We hypothesized that thiamine, when added to standard of care, would improve dyspnea (primary outcome) in hospitalized patients with acute heart failure. Peak expiratory flow rate, type B natriuretic peptide, free fatty acids, glucose, hospital length of stay, as well as 30-day rehospitalization and mortality were pre-planned secondary outcome measures. METHODS: This was a blinded experimental study at two urban academic hospitals. Consecutive patients admitted from the Emergency Department with a primary diagnosis of acute heart failure were recruited over 2 years. Patients on a daily dietary supplement were excluded. Randomization was stratified by type B natriuretic peptide and diabetes medication categories. Subjects received study drug (100 mg thiamine or placebo) in the evening of their first and second day. Outcome measures were obtained 8 h after study drug infusion. Dyspnea was measured on a 100-mm visual analog scale sitting up on oxygen, sitting up off oxygen, and lying supine off oxygen with 0 indicating no dyspnea. Data were analyzed using mixed-models as well as linear, negative binomial and logistic regression models to assess the impact of group on outcome measures. RESULTS: Of 130 subjects randomized, 118 had evaluable data (55 in the control and 63 in the treatment groups), 89% in both groups were adjudicated to have primarily AHF. Thiamine values increased significantly in the treatment group and were unchanged in the control group. One patient had thiamine deficiency. Only dyspnea measured sitting upright on oxygen differed significantly by group over time. No change was found for the other measures of dyspnea and all of the secondary measures. CONCLUSIONS: In mild-moderate acute heart failure patients without thiamine deficiency, a standard dosing regimen of thiamine did not improve dyspnea, biomarkers, or other clinical parameters. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00680706 , May 20, 2008 (retrospectively registered).
Assuntos
Fármacos Cardiovasculares/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Tiamina/uso terapêutico , Doença Aguda , Idoso , Idoso de 80 Anos ou mais , Fármacos Cardiovasculares/administração & dosagem , Fármacos Cardiovasculares/sangue , Dispneia , Feminino , Insuficiência Cardíaca/fisiopatologia , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Tiamina/administração & dosagem , Tiamina/sangue , Resultado do Tratamento , Escala Visual AnalógicaRESUMO
Meldonium is a metabolic drug whose inclusion in the 2016 List of Prohibited Substances and Methods followed the analysis of data collected under the 2015 World Anti-Doping Agency Monitoring Program. In the early months of 2016, anti-doping laboratories reported an unusually high number of cases in which urine samples contained high concentrations of meldonium. Consequently, the meldonium excretion period in healthy athletes and the substance's long-term urine and blood (plasma) pharmacokinetics became central questions for the anti-doping community to address, to ensure appropriate assessment of the scientific and medical situation, and also fair treatment of athletes from a result management and legal standpoint. At the present time, data on meldonium pharmacokinetics is limited to a few studies, with no known data available on long-term excretion of high oral doses. The primary objective of this open-label study was to determine long-term urine and plasma pharmacokinetic parameters of meldonium in healthy volunteers. Study design included single and repeated functional load testing and assessment of L-carnitine administration on meldonium excretion and pharmacokinetics. Thirty-two volunteers were equally divided into two groups receiving either 1.0 g or 2.0 g of oral meldonium daily for 3 weeks. The study found meldonium takes several days to attain a steady state in blood and displays an elimination period over several months after cessation of treatment. Moreover, findings demonstrate that the daily dose, periodicity and duration of treatment with meldonium are the most important factors to consider in calculating the substance's elimination and complete body clearance.
Assuntos
Fármacos Cardiovasculares/sangue , Fármacos Cardiovasculares/urina , Metilidrazinas/sangue , Metilidrazinas/urina , Administração Oral , Adulto , Atletas , Fármacos Cardiovasculares/administração & dosagem , Dopagem Esportivo , Feminino , Voluntários Saudáveis , Humanos , Masculino , Metilidrazinas/administração & dosagem , Detecção do Abuso de Substâncias , Adulto JovemRESUMO
Stability data of toxics or drugs in gel-based or mechanical separation blood collection tubes are lacking, especially for therapeutic drug monitoring and clinical toxicology procedures. According to ISO 15189 accreditation standard, laboratories need to master the entire preanalytical process including the stability of analytes in a specific tube. Here we explored the impact of BD PST™ II and Barricor™ separator tubes on the stability of 167 therapeutic compounds and common drugs of abuse in plasma samples using LC-MS/MS. Forty drugs were significantly affected by the use of PST™ II tubes, including antidepressants (11/26), neuroleptics (9/13), cardiovascular drugs (5/26), anxiolytics and hypnotics (4/25) and some drugs of abuse (5/26). Six compounds exhibited significant reduction by the mechanical Barricor™ tubes. Ten drugs exhibited low (<85%) but non-significant recoveries due to inter-assay variability. Besides, a logPâ¯>â¯3.3 was determined as a cut-off value to predict a potential lack of stability in PST™ II gel tubes with an 86.4% sensitivity and a 61.4% specificity. As a consequence, determination of drugs with a logPâ¯>â¯3.3 should be carried out with caution in plasma samples withdrawn on PST™ II. The study showed the Barricor™ and non-gel tubes cause less drug interference and are recommended for the drugs studied.
Assuntos
Ansiolíticos/sangue , Antidepressivos/sangue , Coleta de Amostras Sanguíneas , Fármacos Cardiovasculares/sangue , Hipnóticos e Sedativos/sangue , Drogas Ilícitas/sangue , Coleta de Amostras Sanguíneas/normas , Cromatografia Líquida , Avaliação Pré-Clínica de Medicamentos , Monitoramento de Medicamentos , Géis/química , Humanos , Espectrometria de Massas em TandemAssuntos
Fármacos Cardiovasculares/intoxicação , Digoxina/intoxicação , Eletrocardiografia , Frequência Cardíaca/efeitos dos fármacos , Taquicardia Ventricular/induzido quimicamente , Taquicardia Ventricular/diagnóstico , Administração Oral , Idoso de 80 Anos ou mais , Fármacos Cardiovasculares/administração & dosagem , Fármacos Cardiovasculares/sangue , Angiografia Coronária , Diagnóstico Diferencial , Digoxina/administração & dosagem , Digoxina/sangue , Feminino , Humanos , Valor Preditivo dos Testes , Taquicardia Ventricular/fisiopatologia , Taquicardia Ventricular/terapiaRESUMO
The pharmacokinetics and the effects of a single intramuscular (IM) dose of alfaxalone on sedation and cardiopulmonary and echocardiographic variables was studied in dogs. Twelve healthy adult Beagles (3 females, 9 males) were used in this prospective controlled cross-over trial. Echocardiography was performed with and without 4 mg kg-1 alfaxalone IM with a week wash-out interval. Sedation (19-point scale; 0 = no sedation), cardiopulmonary parameters, blood gas analysis and plasma concentration of alfaxalone were assessed every 5 minutes following the injection (T0). The influence of the alfaxalone plasma concentration and time on physiological variables was tested using a linear model whereas echocardiographic measurements were compared between conscious and alfaxalone-administered dogs using paired t-tests. Compared to baseline, alfaxalone administration was followed by an increase in heart rate (HR) from T5 to T30 and a decrease in mean arterial pressure (MAP) at T10, T25 and T30, in stroke volume (SV; 15 ± 5 to 11 ± 3 ml; P<0.0001), and end-diastolic volume (EDV; 24.7 ± 5.7 to 19.4 ± 4.9 ml). Cardiac output (CO) and blood gas analysis did not change significantly throughout. Mean plasma half-life was 29 ± 8 minutes, volume of distribution was 1.94 ± 0.63 L kg-1, and plasma clearance was 47.7 ± 14.1 ml kg-1 minute-1. Moderate to deep sedation was observed from T5 to T35. Ten dogs showed paddling, trembling, nystagmus and strong reaction to sound during the procedure. Although there were no significant changes in CO and oxygenation, the impact of HR, MAP, SV, EDV alterations requires further investigations in dogs with cardiac disease.
Assuntos
Fármacos Cardiovasculares/administração & dosagem , Fármacos Cardiovasculares/farmacocinética , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/farmacocinética , Pregnanodionas/administração & dosagem , Pregnanodionas/farmacocinética , Animais , Gasometria , Fármacos Cardiovasculares/efeitos adversos , Fármacos Cardiovasculares/sangue , Estudos Cross-Over , Cães , Ecocardiografia , Feminino , Coração/efeitos dos fármacos , Coração/fisiologia , Frequência Cardíaca/efeitos dos fármacos , Hipnóticos e Sedativos/efeitos adversos , Hipnóticos e Sedativos/sangue , Injeções Intramusculares , Masculino , Movimento/efeitos dos fármacos , Pregnanodionas/efeitos adversos , Pregnanodionas/sangue , Estudos Prospectivos , Distribuição AleatóriaRESUMO
Bilayer pseudo-stationary phase micellar liquid chromatography (MLC) was developed for simultaneous isocratic isolation of hydrochlorothiazide, as a basic-polar (hydrophilic) cardiovascular drug, as well as triamterene and losartan potassium, as acidic-nonpolar (hydrophobic) cardiovascular drugs. Utilizing a deep eutectic solvent (DES), as a novel green mobile phase additive in combination with acetonitrile (ACN) and acetic acid (ACA), drastically improved the chromatographic behavior of the drugs. Concentration of sodium dodecyl sulphate (SDS), as well as volume percentages of ACN, DES, and ACA were optimized by using a central composite design. The optimal composition of the mobile phase (0.12â¯molâ¯L-1 SDS, 5% ACN, 4% DES, and 2% ACA) was chosen through the desirability function. The chromatographic peaks of both hydrophilic and hydrophobic drugs, respectively, emerged at high and low retention time values in the shortest total analysis time of 20â¯min (at a flow rate of 2â¯mLâ¯min-1). Analytical characterization of the developed approach was investigated through Food and Drug Administration (FDA) guidelines. Applicability of the method was evaluated by analysing of human plasma samples which were directly injected into the system.
Assuntos
Fármacos Cardiovasculares/isolamento & purificação , Hidroclorotiazida/isolamento & purificação , Losartan/isolamento & purificação , Projetos de Pesquisa , Triantereno/isolamento & purificação , Fármacos Cardiovasculares/sangue , Fármacos Cardiovasculares/química , Cromatografia Líquida de Alta Pressão , Humanos , Hidroclorotiazida/sangue , Hidroclorotiazida/química , Interações Hidrofóbicas e Hidrofílicas , Losartan/sangue , Losartan/química , Micelas , Software , Triantereno/sangue , Triantereno/química , Estados Unidos , United States Food and Drug AdministrationRESUMO
In the last few years, a number of studies were conducted which aimed at understanding the mechanisms of cardiovascular drug, metabolism, and there is still the need to determine the metabolites of cardiac drugs for the purpose of metabolism control. In this study, we employ a direct combination of electrochemical oxidation and mass spectrometric (EC-MS) identification for monitoring the oxidation pathway of ten cardiovascular drugs (metoprolol, propranolol, propafenone, mexiletine, oxprenolol, pirbuterol, pindolol, cicloprolol, acebutolol and atenolol). Oxidation was accomplished in an electrochemical thin-layer cell coupled on-line to electrospray ionization mass spectrometry (EC/ESI-MS). For further characterization of electrochemical products, the approach involving liquid chromatography linked to tandem mass spectrometry was used. Appropriate conditions for oxidation and identification processes with such parameters as the potential value, mobile phase (type and pH) and working electrode were optimized. Optimization was performed with the use of central composite design (CCD). Besides electrochemical oxidation of analytes (phase I of metabolic transformation), addition of glutathione (GSH) for follow-up reactions (phase II conjunction) was also investigated. The electrochemical results were compared to in-vivo experiments by analyzing plasma and urine samples from patients who had been administered selected cardiovascular drugs. These results show that electrochemistry coupled to mass spectrometry turned out to be an analytical tool suitable to procure a feasible analytical base for the envisioned in vivo experiments.
Assuntos
Fármacos Cardiovasculares , Técnicas Eletroquímicas , Espectrometria de Massas por Ionização por Electrospray/métodos , Fármacos Cardiovasculares/sangue , Fármacos Cardiovasculares/química , Fármacos Cardiovasculares/farmacocinética , Fármacos Cardiovasculares/urina , Cromatografia Líquida de Alta Pressão , Eletroquímica , Glutationa/química , Humanos , Estrutura Molecular , Oxirredução , Espectrometria de Massas em TandemRESUMO
BACKGROUND: Mitochondrial dysfunction and energy depletion in the failing heart are innovative therapeutic targets in heart failure management. Elamipretide is a novel tetrapeptide that increases mitochondrial energy; however, its safety, tolerability, and therapeutic effect on cardiac structure and function have not been studied in heart failure with reduced ejection fraction. METHODS AND RESULTS: In this double-blind, placebo-controlled, ascending-dose trial, patients with heart failure with reduced ejection fraction (ejection fraction, ≤35%) were randomized to either a single 4-hour infusion of elamipretide (cohort 1 [n=8], 0.005; cohort 2 [n=8], 0.05; and cohort 3 [n=8], 0.25 mg·kg-1·h-1) or placebo control (n=12). Safety and efficacy were assessed by clinical, laboratory, and echocardiographic assessments performed at pre-, mid- and end-infusion and 6-, 8-, 12- and 24-hours postinfusion start. Peak plasma concentrations of elamipretide occurred at end-infusion and were undetectable by 24 hours postinfusion. There were no serious adverse events. Blood pressure and heart rate remained stable in all cohorts. Compared with placebo, a significant decrease in left ventricular end-diastolic volume (-18 mL; P=0.009) and end-systolic volume (-14 mL; P=0.005) occurred at end infusion in the highest dose cohort. CONCLUSIONS: This is the first study to evaluate elamipretide in heart failure with reduced ejection fraction and demonstrates that a single infusion of elamipretide is safe and well tolerated. High-dose elamipretide resulted in favorable changes in left ventricular volumes that correlated with peak plasma concentrations, supporting a temporal association and dose-effect relationship. Further study of elamipretide is needed to determine long-term safety and efficacy. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02388464.
Assuntos
Fármacos Cardiovasculares/administração & dosagem , Metabolismo Energético/efeitos dos fármacos , Insuficiência Cardíaca/tratamento farmacológico , Mitocôndrias Cardíacas/efeitos dos fármacos , Oligopeptídeos/administração & dosagem , Idoso , Bulgária , Fármacos Cardiovasculares/efeitos adversos , Fármacos Cardiovasculares/sangue , Fármacos Cardiovasculares/farmacocinética , Método Duplo-Cego , Ecocardiografia , Feminino , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Mitocôndrias Cardíacas/metabolismo , Oligopeptídeos/efeitos adversos , Oligopeptídeos/sangue , Oligopeptídeos/farmacocinética , Estudos Prospectivos , Volume Sistólico/efeitos dos fármacos , Resultado do Tratamento , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
BACKGROUND: In this double-blind randomized placebo-controlled crossover trial, we investigated whether oral sodium nitrate, when added to existing background medication, reduces exertional ischemia in patients with angina. METHODS AND RESULTS: Seventy patients with stable angina, positive electrocardiogram treadmill test, and either angiographic or functional test evidence of significant ischemic heart disease were randomized to receive oral treatment with either placebo or sodium nitrate (600 mg; 7 mmol) for 7 to 10 days, followed by a 2-week washout period before crossing over to the other treatment (n=34 placebo-nitrate, n=36 nitrate-placebo). At baseline and at the end of each treatment, patients underwent modified Bruce electrocardiogram treadmill test, modified Seattle Questionnaire, and subgroups were investigated with dobutamine stress, echocardiogram, and blood tests. The primary outcome was time to 1 mm ST depression on electrocardiogram treadmill test. Compared with placebo, inorganic nitrate treatment tended to increase the primary outcome exercise time to 1 mm ST segment depression (645.6 [603.1, 688.0] seconds versus 661.2 [6183, 704.0] seconds, P=0.10) and significantly increased total exercise time (744.4 [702.4, 786.4] seconds versus 760.9 [719.5, 802.2] seconds, P=0.04; mean [95% confidence interval]). Nitrate treatment robustly increased plasma nitrate (18.3 [15.2, 21.5] versus 297.6 [218.4, 376.8] µmol/L, P<0.0001) and almost doubled circulating nitrite concentrations (346 [285, 405] versus 552 [398, 706] nmol/L, P=0.003; placebo versus nitrate treatment). Other secondary outcomes were not significantly altered by the intervention. Patients on antacid medication appeared to benefit less from nitrate supplementation. CONCLUSIONS: Sodium nitrate treatment may confer a modest exercise capacity benefit in patients with chronic angina who are taking other background medication. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov/. Unique identifier: NCT02078921. EudraCT number: 2012-000196-17.
Assuntos
Angina Estável/tratamento farmacológico , Fármacos Cardiovasculares/administração & dosagem , Tolerância ao Exercício/efeitos dos fármacos , Nitratos/administração & dosagem , Administração Oral , Idoso , Angina Estável/sangue , Angina Estável/diagnóstico , Angina Estável/fisiopatologia , Fármacos Cardiovasculares/efeitos adversos , Fármacos Cardiovasculares/sangue , Estudos Cross-Over , Método Duplo-Cego , Quimioterapia Combinada , Ecocardiografia sob Estresse , Eletrocardiografia , Teste de Esforço , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nitratos/efeitos adversos , Nitratos/sangue , Nitritos/sangue , Escócia , Inquéritos e Questionários , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Drug-coated balloons (DCBs) are a predominant revascularization therapy for symptomatic femoropopliteal artery disease. Because of the differences in excipients, paclitaxel dose, and coating morphologies, varying clinical outcomes have been observed with different DCBs. We report the results of 2 studies investigating the pharmacokinetic and clinical outcomes of a new DCB to treat femoropopliteal disease. METHODS: In the ILLUMENATE Pivotal Study (Prospective, Randomized, Single-Blind, U.S. Multi-Center Study to Evaluate Treatment of Obstructive Superficial Femoral Artery or Popliteal Lesions With A Novel Paclitaxel-Coated Percutaneous Angioplasty Balloon), 300 symptomatic patients (Rutherford class 2-4) were randomly assigned to DCB (n=200) or standard angioplasty (percutaneous transluminal angioplasty [PTA]) (n=100). The primary safety end point was freedom from device- and procedure-related death through 30 days, and freedom from target limb major amputation and clinically driven target lesion revascularization through 12 months. The primary effectiveness end point was primary patency through 12 months. In the ILLUMENATE PK study (Pharmacokinetic Study of the Stellarex Drug-Coated Angioplasty Balloon), paclitaxel plasma concentrations were measured after last DCB deployment and at prespecified times (at 1, 4, 24 hours and at 7 and 14 days postprocedure) until no longer detectable. RESULTS: In the ILLUMENATE Pivotal Study, baseline characteristics were similar between groups: 50% had diabetes mellitus, 41% were women, mean lesion length was 8.3 cm, and 44% were severely calcified. The primary safety end point was met (92.1% for DCB versus 83.2% for PTA, P=0.025 for superiority) and the primary patency rate was significantly higher with DCB (76.3% for DCB versus 57.6% for PTA, P=0.003). Primary patency per Kaplan-Meier estimates at day 365 was 82.3% for DCB versus 70.9% for PTA (P=0.002). The rate of clinically driven target lesion revascularization was significantly lower in the DCB cohort (7.9% versus 16.8%, P=0.023). Improvements in ankle-brachial index, Rutherford class, and quality of life were comparable, but the PTA cohort required twice as many revascularizations. Pharmacokinetic outcomes showed that all patients had detectable paclitaxel levels after DCB deployment that declined within the first hour (54.4±116.9 ng/mL to 1.4±1.0 ng/mL). CONCLUSIONS: The data demonstrate superior safety and effectiveness of the Stellarex DCB in comparison with PTA, and plasma levels of paclitaxel fall to low levels within 1 hour. CLINICAL TRIAL REGISTRATION: URL: http://clinicaltrials.gov. Unique identifiers: NCT01858428 and NCT01912937.
Assuntos
Angioplastia com Balão , Fármacos Cardiovasculares/administração & dosagem , Materiais Revestidos Biocompatíveis/química , Paclitaxel/administração & dosagem , Doença Arterial Periférica/terapia , Idoso , Fármacos Cardiovasculares/sangue , Fármacos Cardiovasculares/farmacocinética , Fármacos Cardiovasculares/farmacologia , Feminino , Artéria Femoral/patologia , Meia-Vida , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Paclitaxel/sangue , Paclitaxel/farmacocinética , Paclitaxel/farmacologia , Doença Arterial Periférica/mortalidade , Doença Arterial Periférica/patologia , Estudos Prospectivos , Índice de Gravidade de Doença , Método Simples-Cego , Fatores de Tempo , Resultado do Tratamento , Grau de Desobstrução Vascular/efeitos dos fármacosRESUMO
Apelin is an important mammalian peptide hormone with a range of physiological roles, especially in the cardiovascular system. The apelinergic system is a promising target for treatment of disease, but this remains to be realized due to rapid proteolysis of apelin-derived peptides by proteases, including neprilysin (NEP). The synthetic analogues modified within the NEP degradation site ("RPRL" motif) showed improved in vitro proteolytic stability while maintaining receptor-binding affinities, with three candidate peptides retaining full cardiovascular activities for potential therapeutic application. Many such analogues proved physiologically inactive even with relatively conservative modifications, highlighting the importance of this region for full agonist activity of this peptide hormone.
Assuntos
Fármacos Cardiovasculares/síntese química , Peptídeos e Proteínas de Sinalização Intercelular/síntese química , Neprilisina/sangue , Animais , Receptores de Apelina , Pressão Sanguínea/efeitos dos fármacos , Células CHO , Fármacos Cardiovasculares/sangue , Fármacos Cardiovasculares/farmacologia , Cricetulus , Frequência Cardíaca/efeitos dos fármacos , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Camundongos , Isoformas de Proteínas/sangue , Isoformas de Proteínas/síntese química , Isoformas de Proteínas/farmacologia , Ratos , Receptores Acoplados a Proteínas G/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Dried blood spot (DBS) sampling was investigated as a means of obtaining micro-volume blood samples for the quantitative analyses of ten commonly UK prescribed cardiovascular drugs as an indicator of medication adherence. An 8mm disc was punched out from each DBS from calibration, quality control and volunteer samples and extracted using methanol containing the internal standard. Each extract was evaporated to dryness, the residue reconstituted in methanol:water (40:60v/v) containing 0.1% formic acid and analysed by LC-HRMS. Chromatography was performed using gradient elution on a Zorbax Eclipse C18 HD 100mm×2.1mm, 1.8µm pore size column with the column oven temperature at 40°C. Flow rate of the mobile phase was 0.6ml/min with a run time of 2.5min. Electrospray positive ionization was used for MS detection. Drug recoveries from spiked blood spots were 68% for simvastatin and ≥87% for all other target drugs. Compound specificity was obtained operating the MS with a 5ppm mass window. The LC-HRMS method was validated, with results for accuracy and precision within acceptable limits; analytes were stable at room temperature for at least 10 weeks and different blood spot volumes and haematocrit values had no significant effect. The LC-HRMS assay was used to analyse DBS samples from volunteers, some of whom were prescribed one or more of the target drugs. In results from 37 volunteers the assay successfully identified volunteers who were known to be either adherent or nonadherent; confirmed the correct drug/drugs for multiple prescriptions; demonstrated no false positives from other cardiovascular drugs; revealed several examples of unsuspected non-adherence. These results indicated that the developed assay was suitable for trials with patients.