RESUMO
BACKGROUND: Concentrations of metoprolol in exhaled breath condensate (EBC) have not been investigated. Herein, we aim to determine the metoprolol levels in EBC, plasma, and urine samples. METHODS: Biological samples were collected from 39 patients receiving metoprolol. Metoprolol was determined using liquid chromatography mass spectrometery. The obtained metoprolol levels in biological fluids were investigated for possible inter-correlations. RESULTS: Acceptable linearity was obtained with coefficient of determinations equal to 0.9998, 0.9941, and 0.9963 for EBC, plasma, and urine samples, respectively. The calibration curves were linear in the ranges of 0.6-500, 0.4-500, and 0.7-10,000 µg·L- 1 regarding EBC, plasma, and urine samples, respectively. The detection and quantification limits were (0.18, 0.12, and 0.21 µg·L- 1) and (0.60, 0.40, and 0.70 µg·L- 1) for EBC, plasma, and urine samples, respectively. The relative standard deviations for the intra- and inter-day replications were obtained between 5.2 and 6.1 and 3.3-4.6%, respectively. The obtained mean metoprolol levels in EBC, plasma, and urine samples of 39 patients were 5.35, 70.76, and 1943.1 µg·L- 1. There were correlations between daily dose and plasma and urinary concentrations of metoprolol in the investigated samples, whereas no significant correlation was observed for daily dose and EBC levels. The correlation among plasma-urine levels was significant, however, the non-significant correlation was obtained between plasma and EBC concentrations. CONCLUSION: Metoprolol levels varied widely due to the metabolic pattern of the Azeri population, different dosages received by the patients, formulation effects, age, sex, and interactions with the co-administered drugs. A poor correlation of EBC-plasma concentrations and a significant correlation of plasma-urine concentrations were observed. Further investigations are required to provide the updated services to personalized medicine departments.
Assuntos
Metoprolol , Metoprolol/urina , Metoprolol/farmacocinética , Metoprolol/sangue , Humanos , Feminino , Masculino , Estudos Transversais , Pessoa de Meia-Idade , Adulto , Idoso , Testes Respiratórios/métodos , Cromatografia Líquida/métodos , Antagonistas de Receptores Adrenérgicos beta 1/urina , Antagonistas de Receptores Adrenérgicos beta 1/sangue , Antagonistas de Receptores Adrenérgicos beta 1/farmacocinética , Antagonistas de Receptores Adrenérgicos beta 1/análise , Adulto JovemRESUMO
Atenolol, a cardioselective ß1-blocker, exhibits efficacy in treating cardiovascular diseases. We conducted a single-center, randomized, open, single-dose, 2-preparation, 2-cycle, 2-sequence, double-crossover trial with a 7-day washout period to investigate the pharmacokinetics, bioequivalence (BE), and safety of test and reference atenolol tablets (25 mg) in healthy Chinese volunteers. Forty-eight healthy participants were randomized into the fasting and fed arms. After administering a single oral dose of the test or reference formulation (25 mg), plasma atenolol concentrations were measured using liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were obtained from concentration-time profiles. In total, 23 and 24 individuals were included in the fasting and fed arms, respectively. The mean concentration-time profiles for both formulations were similar, and Cmax, AUC0-t, and AUC0-∞ were within the BE range of 80%-125%. Thirteen adverse events (AEs) were observed in 7 participants in the fasting arm; 1 withdrew from the trial early owing to an AE. In the fed arm, 20 AEs were observed in 8 participants, and none withdrew from the trial. All adverse reactions were grade I, with no serious AEs or deaths. Therefore, the 2 tablets are bioequivalent in healthy Chinese individuals under fasting and fed conditions, supporting their further clinical development.
Assuntos
Área Sob a Curva , Atenolol , Estudos Cross-Over , Jejum , Voluntários Saudáveis , Comprimidos , Equivalência Terapêutica , Humanos , Atenolol/farmacocinética , Atenolol/administração & dosagem , Atenolol/efeitos adversos , Masculino , Adulto , Feminino , Adulto Jovem , Antagonistas de Receptores Adrenérgicos beta 1/farmacocinética , Antagonistas de Receptores Adrenérgicos beta 1/administração & dosagem , Antagonistas de Receptores Adrenérgicos beta 1/efeitos adversos , Povo Asiático , Administração Oral , Interações Alimento-Droga , China , População do Leste AsiáticoRESUMO
The purpose of the current studies was to develop ocular insert of betaxolol hydrochloride (BXH), using arabinoxylan (AX) as a film former. The inserts were prepared by sandwiching I mg of BXH between two films of AX. Six different formulations of ocular inserts were prepared in such a way that first three formulations contained varying concentrations of AX along with glycerol as plasticizer, whereas, rest of the formulations were added with 0.5mg of sodium alginate, sandwiched between two films of AX along with 1mg of BXH. Chemical compatibilities of the ingredients were assessed by using FTIR. Prepared ocular inserts were subjected to various physicochemical characterizations. The dissolution studies showed that ocular inserts containing sodium alginate with the AX showed sustained release effect better than the formulations with AX alone. Addition of sodium alginate resulted in inhibition of sudden release in initial phase and further sustained the release of drug from ocular inserts. Ocular inserts were pH compatible to the eyes as well as there was no interaction among the drug and excipients, suggesting that the selected excipients were suitable for the development of sustained release ocular inserts of BXH.
Assuntos
Antagonistas de Receptores Adrenérgicos beta 1/administração & dosagem , Alginatos , Betaxolol/administração & dosagem , Glicerol , Plantago , Xilanos , Administração Oftálmica , Antagonistas de Receptores Adrenérgicos beta 1/farmacocinética , Betaxolol/farmacocinética , Preparações de Ação Retardada , Liberação Controlada de Fármacos , Glaucoma de Ângulo Aberto/tratamento farmacológicoRESUMO
BACKGROUND: Beta-blocking is important for critically ill patients. Although some patients are required to continue taking beta-blockers after they no longer need critical care, some of these patients have impaired swallowing abilities. Bisoprolol dermal patches have recently been introduced and appear to be a good alternative to oral bisoprolol tablets. However, it is still unclear whether the pharmacodynamics of such patches are affected by edema in patients who have experienced critical care. This study aimed to clarify the effects of systemic edema on beta-blocker absorption from dermal patches in critically ill patients. METHOD: Patients who exhibited tachycardia and impaired swallowing function after critical care were included in this study. They were assigned to either the edema group (nâ=â6) or no edema group (nâ=â6) depending on the presence/absence of edema in the lower extremities. A bisoprolol dermal patch was pasted onto each subject, and the blood bisoprolol concentration was checked at 8 timepoints over the next 24âhours. The area under the serum concentration time curve, maximum concentration observed (Cmax), and time of maximum concentration observed were also examined. RESULT: The mean blood bisoprolol concentrations of the 2 groups were not significantly different at 2, 4, 6, 8, 10, 12, 16, or 24âhours after the patch application. The area under the serum concentration time curve and maximum concentration observed were not different between the groups. The mean heart rates of the 2 groups were not significantly different at 6, 12, or 24âhours after the patch application (Student t test, Pâ=â.0588, Pâ=â.1080, and Pâ=â.2322, respectively). CONCLUSION: In this study, the blood concentration of bisoprolol and its heart rate-reducing effects after bisoprolol dermal patch application might not be affected by systemic edema in the lower extremities.
Assuntos
Antagonistas de Receptores Adrenérgicos beta 1/farmacocinética , Bisoprolol/farmacocinética , Edema/metabolismo , Absorção Cutânea , Administração Cutânea , Antagonistas de Receptores Adrenérgicos beta 1/administração & dosagem , Antagonistas de Receptores Adrenérgicos beta 1/sangue , Idoso , Idoso de 80 Anos ou mais , Bisoprolol/administração & dosagem , Bisoprolol/sangue , Estudos de Casos e Controles , Feminino , Humanos , MasculinoRESUMO
Recent CYP2D6 phenotype standardization efforts by CYP2D6 activity score (AS) are based on limited pharmacokinetic (PK) and pharmacodynamic (PD) data. Using data from two independent clinical trials of metoprolol, we compared metoprolol PK and PD across CYP2D6 AS with the goal of determining whether the PK and PD data support the new phenotype classification. S-metoprolol apparent oral clearance (CLo), adjusted for clinical factors, was correlated with CYP2D6 AS (P < 0.001). The natural log of CLo was lower with an AS of 1 (7.6 ± 0.4 mL/minute) vs. 2-2.25 (8.3 ± 0.6 mL/minute; P = 0.012), similar between an AS of 1 and 1.25-1.5 (7.8 ± 0.5 mL/minute; P = 0.702), and lower with an AS of 1.25-1.5 vs. 2-2.25 (P = 0.03). There was also a greater reduction in heart rate with metoprolol among study participants with AS of 1 (-10.8 ± 5.5) vs. 2-2.25 (-7.1 ± 5.6; P < 0.001) and no significant difference between those with an AS of 1 and 1.25-1.5 (-9.2 ± 4.7; P = 0.095). These data highlight linear trends among CYP2D6 AS and metoprolol PK and PD, but inconsistencies with the phenotypes assigned by AS based on the current standards. Overall, this case study with metoprolol suggests that utilizing CYP2D6 AS, instead of collapsing AS into phenotype categories, may be the most precise approach for utilizing CYP2D6 pharmacogenomics in clinical practice.
Assuntos
Antagonistas de Receptores Adrenérgicos beta 1/farmacocinética , Citocromo P-450 CYP2D6/genética , Genótipo , Metoprolol/farmacocinética , Administração Oral , Antagonistas de Receptores Adrenérgicos beta 1/administração & dosagem , Adulto , Idoso , Pressão Sanguínea/efeitos dos fármacos , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Metoprolol/administração & dosagem , Pessoa de Meia-Idade , Farmacogenética , Fenótipo , Polimorfismo de Nucleotídeo Único , Estudos ProspectivosRESUMO
Although bisoprolol is used widely to treat patients with heart failure (HF), little information is available regarding the association between the dose of bisoprolol administered and the bisoprolol plasma concentration (Bis-PC) in real-world clinical practice.This was a single-center, observational study in 114 patients with HF receiving once-daily bisoprolol. After determination of trough Bis-PC, the relationship between the dose of bisoprolol and Bis-PC was analyzed. In a multiple linear regression model, the dose of bisoprolol and estimated creatinine clearance (reciprocal number) were identified as independent predictors. HF severity and hepatic function were not associated with Bis-PC.Bis-PC was increased by renal dysfunction, which explained most of the discrepancy between the dose of bisoprolol administered and Bis-PC.
Assuntos
Antagonistas de Receptores Adrenérgicos beta 1/farmacocinética , Bisoprolol/farmacocinética , Insuficiência Cardíaca/tratamento farmacológico , Antagonistas de Receptores Adrenérgicos beta 1/administração & dosagem , Antagonistas de Receptores Adrenérgicos beta 1/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Bisoprolol/administração & dosagem , Bisoprolol/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Landiolol hydrochloride, a highly cardio-selective beta-1 blocker with an ultra-short-acting half-life of 4 minutes, was originally approved by Japan for treatment of intraoperative tachyarrhythmias. This review aims to provide an integrated overview of the current state of knowledge of landiolol hydrochloride in the management of arrhythmia in critical settings. METHODS: We searched MEDLINE, EMBASE, and the Cochrane Library to retrieve relevant articles with a total of 65 records identified. RESULTS: The high ß1 selectivity (ß1/ß2 ratio of 255:1) of landiolol causes a more rapid heart rate (HR) decrease compared to esmolol while avoiding decreases in mean arterial blood pressure. Recently, it has been found useful in left ventricular dysfunction patients and fatal arrhythmia requiring emergency treatment. Recent random clinical trials (RCT) have revealed therapeutic and prophylactic effects on arrhythmia, and very low-dose landiolol might be effective for preventing postoperative atrial fibrillation (POAF) and sinus tachycardia. Likewise, landiolol is an optimal choice for perioperative tachycardia treatment during cardiac surgery. The high ß1 selectivity of landiolol is useful in heart failure patients as a first-line therapy for tachycardia and arrhythmia as it avoids the typical depression of cardiac function seen in other ß-blockers. Application in cardiac injury after percutaneous coronary intervention (PCI), protection for vital organs (lung, kidney, etc.) during sepsis, and stabilizing hemodynamics in pediatric patients are becoming the new frontier of landiolol use. CONCLUSION: Landiolol is useful as a first-line therapy for the prevention of POAF after cardiac/non-cardiac surgery, fatal arrhythmias in heart failure patients and during PCI. Moreover, the potential therapeutic effect of landiolol for sepsis in pediatric patients is currently being explored. As positive RCT results continue to be published, new clinical uses and further clinical studies in various settings by cardiologists, intensivists and pediatric cardiologists are being conducted.
Assuntos
Antagonistas de Receptores Adrenérgicos beta 1/uso terapêutico , Antiarrítmicos/uso terapêutico , Arritmias Cardíacas/prevenção & controle , Frequência Cardíaca/efeitos dos fármacos , Morfolinas/uso terapêutico , Ureia/análogos & derivados , Antagonistas de Receptores Adrenérgicos beta 1/efeitos adversos , Antagonistas de Receptores Adrenérgicos beta 1/farmacocinética , Adulto , Antiarrítmicos/efeitos adversos , Antiarrítmicos/farmacocinética , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/fisiopatologia , Cuidados Críticos , Feminino , Humanos , Masculino , Morfolinas/efeitos adversos , Morfolinas/farmacocinética , Fatores de Risco , Resultado do Tratamento , Ureia/efeitos adversos , Ureia/farmacocinética , Ureia/uso terapêutico , Adulto JovemRESUMO
The mechanisms of drug clearance from the aqueous humor are poorly defined. In this study, a cocktail approach was used to simultaneously determine the pharmacokinetics of three ß-blocker agents after intracameral (ic) injection into the rabbit eyes. Aqueous humor samples were collected and analyzed using LC-MS/MS to determine drug concentrations. Pharmacokinetic parameters were obtained using a compartmental fitting approach, and the estimated clearance, volume of distribution, and half-life values were the following: atenolol (6.44 µL/min, 687 µL, and 73.87 min), timolol (19.30 µL/min, 937 µL, and 33.64 min), and betaxolol (32.20 µL/min, 1421 µL, and 30.58 min). Increased compound lipophilicity (atenolol < timolol < betaxolol) resulted in higher clearance and volume of distributions in the aqueous humor. Clearance of timolol and betaxolol is about 10 times higher than the aqueous humor outflow, demonstrating the importance of other elimination routes (e.g., uptake to iris and ciliary body and subsequent elimination via blood flow).
Assuntos
Antagonistas de Receptores Adrenérgicos beta 1/farmacocinética , Atenolol/farmacocinética , Betaxolol/farmacocinética , Injeções Intraoculares/métodos , Timolol/farmacocinética , Animais , Humor Aquoso/química , Humor Aquoso/efeitos dos fármacos , Humor Aquoso/metabolismo , Atenolol/administração & dosagem , Betaxolol/administração & dosagem , Cromatografia Líquida , Combinação de Medicamentos , Meia-Vida , Pressão Intraocular/efeitos dos fármacos , Masculino , Taxa de Depuração Metabólica , Coelhos , Espectrometria de Massas em Tandem , Timolol/administração & dosagem , Distribuição TecidualRESUMO
Introduction: S-amlodipine is main anti-hypertensive active enantiomer of amlodipine. Bisoprolol is a ß-blocker particularly suitable for hypertensive patients with sinus tachycardia. We evaluated the pharmacokinetic interaction between S-amlodipine and bisoprolol in healthy Chinese subjects. Areas covered: Thirty-two subjects were randomly divided into two equal groups. Subjects in group A were administered S-amlodipine 5 mg for 10 days followed by S-amlodipine 5 mg plus bisoprolol 5 mg for 7 days. Subjects in group B were administered bisoprolol 5 mg for 7 days, followed by S-amlodipine 5 mg plus bisoprolol 5 mg for 10 days. Blood samples were collected for evaluation of pharmacokinetic interaction. Tolerability was evaluated by interview, vital signs, 12-lead ECGs, physical examination, and clinical laboratory tests. Expert opinion: The geometric mean ratio (90% CI) for amlodipine AUCτ,ss and Css-max during the monotherapy and combination therapy periods were 1.0389 (0.9879, 1.0926) and 1.0213 (0.9556, 1.0915). For bisoprolol, it was 1.0193 (0.9834, 1.0566) and 0.9989 (0.9133, 1.0925). Most adverse events were mild-moderate. There was high incidence of elevated alanine aminotransferase, aspartate aminotransferase, and triglyceride.This study found no pharmacokinetic interaction between S-amlodipine and bisoprolol. Alanine aminotransferase, aspartate aminotransferase, and triglycerides should be closely monitored.
Assuntos
Antagonistas de Receptores Adrenérgicos beta 1/administração & dosagem , Anlodipino/administração & dosagem , Anti-Hipertensivos/administração & dosagem , Bisoprolol/administração & dosagem , Antagonistas de Receptores Adrenérgicos beta 1/efeitos adversos , Antagonistas de Receptores Adrenérgicos beta 1/farmacocinética , Adulto , Anlodipino/efeitos adversos , Anlodipino/farmacocinética , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/farmacocinética , Área Sob a Curva , Povo Asiático , Bisoprolol/efeitos adversos , Bisoprolol/farmacocinética , Interações Medicamentosas , Quimioterapia Combinada , Humanos , Pessoa de Meia-Idade , Estereoisomerismo , Transaminases/sangue , Triglicerídeos/sangue , Adulto JovemRESUMO
PURPOSE: Preliminary study results have shown that rats with non-alcoholic fatty liver disease (NAFLD) induced by 1% orotic acid-containing diet have decreased hepatic CYP2D activity. This study aims to evaluate the possible pharmacokinetic changes in NAFLD as a result of reduced metabolic activity of CYP2D. METHODS: The pharmacokinetics of metoprolol and its metabolites, O-desmethyl metoprolol (DMM) and α-hydroxy metoprolol (HM), was investigated in NAFLD and control rats following intravenous (1 mg/kg) and oral (2 mg/kg) administration of metoprolol. The hepatic CYP2D expression was also investigated. RESULTS: NAFLD rats had lower CYP2D expression (by 36.6%) and slower intrinsic clearance (CLint) of metoprolol and formation of HM (by 40.1% and 37.2%, respectively). There were no significant changes in the pharmacokinetics of metoprolol and its metabolites following intravenous administration. In contrast, oral administration of metoprolol resulted in significantly increased total area under plasma concentration-time curve (AUC) of metoprolol (by 127%) and decreased metabolite formation ratios (AUCDMM/AUCMetoprolol [by 42.8%], AUCHM/AUCMetoprolol [by 35.0%]) in NAFLD rats. Moreover, these changes were well correlated with severity of steatosis as quantified by hepatic triglyceride contents. CONCLUSIONS: NALFD can lead to a reduction in the hepatic CLint of a drug if it is a substrate of the CYP2D subfamily. The decreased clearance may result in elevated drug concentrations and increased exposure.
Assuntos
Antagonistas de Receptores Adrenérgicos beta 1/farmacocinética , Metoprolol/farmacocinética , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Ácido Orótico/farmacologia , Animais , Família 2 do Citocromo P450/metabolismo , Fígado/metabolismo , Fígado/patologia , Masculino , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Ligação Proteica , Ratos Sprague-DawleyRESUMO
To date, many questions about the extent and cause of pharmacokinetic (PK) variability of even the most widely studied and prescribed ß1-adrenergic receptor blockers, such as metoprolol and bisoprolol, remain unanswered. Given that there are still no published population pharmacokinetic (PopPK) analyses of bisoprolol in routinely treated patients with acute coronary syndrome (ACS), the aim of this study was to determine its PK variability in 71 Serbian patients with ACS. PopPK analysis was conducted using a nonlinear mixed-effects model (NONMEM), version 7.3.0 (Icon Development Solutions). In each patient, the same formulation of bisoprolol was administered once or twice daily at a total daily dose of 0.625-7.5 mg. We separately assessed the effects of 31 covariates on the PKs of bisoprolol, and our results indicated that only 2 covariates could have possible influence on the variability of the clearance of bisoprolol: the mean daily dose of the drug and smoking habits of patients. These findings suggest that possible autoinduction of drug metabolism by higher total daily doses and induction of cytochrome P450 isoform 3A4 (CYP3A4) by cigarette smoke in liver could be the potential causes of increased total clearance of bisoprolol in patients with ACS.
Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Antagonistas de Receptores Adrenérgicos beta 1/farmacocinética , Bisoprolol/farmacocinética , Modelos Biológicos , Síndrome Coronariana Aguda/sangue , Síndrome Coronariana Aguda/diagnóstico , Antagonistas de Receptores Adrenérgicos beta 1/administração & dosagem , Antagonistas de Receptores Adrenérgicos beta 1/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Bisoprolol/administração & dosagem , Bisoprolol/sangue , Citocromo P-450 CYP3A/biossíntese , Indução Enzimática , Feminino , Humanos , Fígado/enzimologia , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Dinâmica não Linear , Sérvia , Fumantes , Fumar/efeitos adversos , Fumar/sangueRESUMO
Background In heart failure (HF) with reduced ejection fraction, 2 clinical trials, the BEST (ß-Blocker Evaluation of Survival Trial) and HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training), have reported an effectiveness interaction between the ADRB1 (ß-1 adrenergic receptor) Arg389Gly polymorphism and ß-blockers (BBs). HF-ACTION additionally reported a dose-related interaction of unclear origin. If confirmed and pharmacogenetically resolved, these findings may have important implications for HF with reduced ejection fraction precision therapy. We used uniform methodology to investigate BB dose-ADRB1 Arg389Gly polymorphism interaction with major clinical end points in BEST/bucindolol and HF-ACTION/other BB databases. Methods This was a retrospective analysis of prospectively designed DNA substudies from BEST (N=1040) and HF-ACTION (N=957). Subjects were genotyped for ADRB1 Arg389Gly and ADRA2C (α2C adrenergic receptor) Ins322-325Del. BB dose was defined as either no/low dose or high dose, according to total daily dose of either bucindolol (BEST subjects) or other BB (HF-ACTION subjects) standardized to carvedilol equivalents. The main outcome of interest was all-cause mortality, and CV mortality/HF hospitalization was a secondary outcome. Results Subjects in each trial had less all-cause mortality with high- versus no/low-dose BB if they had ADRB1 Arg389Arg (BEST: hazard ratio [HR]=0.40, P=0.002; HF-ACTION: HR=0.45, P=0.005) but not Arg389Gly genotype (both P>0.2). Among gene-dose groups, there was a differential favorable treatment effect of 46% for high-dose bucindolol with ADRB1 Arg389Arg versus Gly carrier genotype (HR, 0.54; P=0.018), but not for no/low-dose bucindolol. In contrast, HF-ACTION Arg389Arg genotype subjects taking no/low-dose BB had greater all-cause mortality compared with 389Gly carriers (HR, 1.83; P=0.015), whereas all-cause mortality did not vary by genotype among subjects taking high-dose BB (HR, 0.84; P=0.55). Conclusions The enhanced HF with reduced ejection fraction efficacy of bucindolol in the ADRB1 Arg389Arg versus 389Gly carrier genotypes occurs at high dose. Other BBs taken at low dose have reduced efficacy for Arg389Arg genotype subjects compared with 389Gly carriers, suggesting a greater relative treatment effect at high dose. These data support guideline recommendations to use high, clinical trial target doses of all BBs to treat HF with reduced ejection fraction.
Assuntos
Antagonistas Adrenérgicos beta/administração & dosagem , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/genética , Polimorfismo Genético , Receptores Adrenérgicos/genética , Antagonistas de Receptores Adrenérgicos beta 1/administração & dosagem , Antagonistas de Receptores Adrenérgicos beta 1/farmacocinética , Antagonistas Adrenérgicos beta/farmacocinética , Adulto , Idoso , Substituição de Aminoácidos/genética , Carvedilol/administração & dosagem , Carvedilol/farmacocinética , Causas de Morte , Ensaios Clínicos como Assunto , Estudos de Coortes , Relação Dose-Resposta a Droga , Feminino , Genótipo , Insuficiência Cardíaca/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Mortalidade , Farmacogenética , Testes Farmacogenômicos , Propanolaminas/administração & dosagem , Propanolaminas/farmacocinética , Receptores Adrenérgicos alfa 2/genética , Receptores Adrenérgicos beta 1/genética , Estudos RetrospectivosRESUMO
In the present work the feasibility of using inner layer-embedded contact lenses (CLs) to achieve sustained release of highly water soluble drug, betaxolol hydrochloride (BH) on the ocular surface was investigated. Blend film of cellulose acetate and Eudragit S100 was selected as the inner layer, while silicone hydrogel was used as outer layer to construct inner layer-embedded contact lenses. Influence of polymer ratio in the blend film on in vitro drug release behavior in phosphate buffered solution or simulated tear fluid was studied and drug-polymer interaction, erosion and swelling of the blend film were characterized to better understand drug-release mechanism. Storage stability of the inner layer-embedded contact lenses in phosphate buffer solution was also conducted, with ignorable drug loss and negligible change in drug release pattern within 30â¯days. In vivo pharmacokinetic study in rabbits showed sustained drug release for over 240â¯h in tear fluid, indicating prolonged drug precorneal residence time. In conclusion, cellulose acetate/Eudragit S100 inner layer-embedded contact lenses are quite promising as controlled-release carrier of highly water soluble drug for ophthalmic delivery.
Assuntos
Antagonistas de Receptores Adrenérgicos beta 1/administração & dosagem , Betaxolol/administração & dosagem , Celulose/análogos & derivados , Lentes de Contato , Portadores de Fármacos/administração & dosagem , Ácidos Polimetacrílicos/administração & dosagem , Administração Oftálmica , Antagonistas de Receptores Adrenérgicos beta 1/química , Antagonistas de Receptores Adrenérgicos beta 1/farmacocinética , Animais , Betaxolol/química , Betaxolol/farmacocinética , Celulose/administração & dosagem , Celulose/química , Celulose/farmacocinética , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Liberação Controlada de Fármacos , Olho/efeitos dos fármacos , Concentração de Íons de Hidrogênio , Masculino , Ácidos Polimetacrílicos/química , Ácidos Polimetacrílicos/farmacocinética , Coelhos , SolubilidadeRESUMO
PURPOSE: Cardiac surgery and conventional extracorporeal circulation (CECC) impair the bioavailability of drugs administered by mouth. It is not known whether miniaturized ECC (MECC) or off-pump surgery (OPCAB) affect the bioavailability in similar manner. We evaluated the metoprolol bioavailability in patients undergoing CABG surgery with CECC, MECC, or having OPCAB. METHODS: Thirty patients, ten in each group, aged 44-79 years, scheduled for CABG surgery were administered 50 mg metoprolol by mouth on the preoperative day at 8-10 a.m. and 8 p.m., 2 h before surgery, and thereafter daily at 8 a.m. and 8 p.m. Blood samples were collected up to 12 h after the morning dose on the preoperative day and on first and third postoperative days. Metoprolol concentration in plasma was analyzed using liquid chromatography-mass spectrometry. RESULTS: The absorption of metoprolol was markedly reduced on the first postoperative day in all three groups, but recovered to the preoperative level on the third postoperative day. The geometric means (90% confidence interval) of AUC0-12 on the first and third postoperative days versus the preoperative day were 44 (26-74)% and 109 (86-139)% in the CECC-group, 28 (16-50)% and 79 (59-105)% in the MECC-group, and 26 (12-56)% and 96 (77-119)% in the OPCAB-group, respectively. Two patients in the CECC-group and two in the MECC-group developed atrial fibrillation (AF). The bioavailability and the drug concentrations of metoprolol in patients developing AF did not differ from those who remained in sinus rhythm. CONCLUSION: The bioavailability of metoprolol by mouth was markedly reduced in the early phase after CABG with no difference between the CECC-, MECC-, and OPCAB-groups.
Assuntos
Antagonistas de Receptores Adrenérgicos beta 1/farmacocinética , Ponte de Artéria Coronária , Circulação Extracorpórea , Metoprolol/farmacocinética , Administração Oral , Antagonistas de Receptores Adrenérgicos beta 1/sangue , Adulto , Idoso , Disponibilidade Biológica , Feminino , Humanos , Masculino , Metoprolol/sangue , Pessoa de Meia-IdadeRESUMO
The pharmacokinetics, pharmacodynamics, safety, and tolerability of long-term administration of esmolol and landiolol, a new fast-acting cardioselective ß-blocker, were compared for the first time in Caucasian subjects in a prospective clinical trial. Twelve healthy volunteers received landiolol and esmolol by continuous infusion for 24 hours in a randomized crossover study using a dose-escalation regimen. Blood concentrations of drugs and metabolites, heart rate, blood pressure, ECG parameters, and tolerability were observed for 30 hours and compared. Drug blood concentrations and areas under the curve were dose-proportional. The half life of landiolol (4.5 minutes) was significantly shorter than that of esmolol (6.9 minutes). Volume of distribution and total clearance were lower for landiolol. Heart rate reduction was faster and more pronounced with landiolol and retained throughout the administration period; effects on blood pressure were not different. Landiolol turned out to be superior to esmolol with respect to pharmacokinetic and pharmacodynamic profile and local tolerability.
Assuntos
Antagonistas de Receptores Adrenérgicos beta 1/farmacocinética , Antagonistas Adrenérgicos beta/farmacocinética , Hemodinâmica/efeitos dos fármacos , Morfolinas/farmacocinética , Propanolaminas/farmacocinética , Ureia/análogos & derivados , Adolescente , Antagonistas de Receptores Adrenérgicos beta 1/administração & dosagem , Antagonistas de Receptores Adrenérgicos beta 1/efeitos adversos , Antagonistas Adrenérgicos beta/administração & dosagem , Antagonistas Adrenérgicos beta/efeitos adversos , Adulto , Pressão Sanguínea/efeitos dos fármacos , Estudos Cross-Over , República Tcheca , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Voluntários Saudáveis , Frequência Cardíaca/efeitos dos fármacos , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Morfolinas/administração & dosagem , Morfolinas/efeitos adversos , Propanolaminas/administração & dosagem , Propanolaminas/efeitos adversos , Estudos Prospectivos , Equivalência Terapêutica , Ureia/administração & dosagem , Ureia/efeitos adversos , Ureia/farmacocinética , População Branca , Adulto JovemRESUMO
BACKGROUND: Bisoprolol and metoprolol are moderately lipophilic, beta(1)-selective betablockers reported to cause adverse effects in the central nervous system (CNS), such as sleep disturbance, suggesting that both drugs may reach relevant concentrations in the brain. CNS beta(2)-receptor blockade has been suspected to be related to such effects. The higher molecular size of bisoprolol (325 Dalton) and the higher beta(1)-selectivity compared to metoprolol (267 Dalton) would suggest a lower rate of CNS effects. METHODS: To address the pharmacokinetic background of this assumption, we quantified to which extent these beta(1)-blockers are able to enter the cerebrospinal fluid (CSF) in 9 (bisoprolol group) and 10 (metoprolol group) neurological patients who had received one of the drugs orally for therapeutic purposes prior to lumbar puncture. We quantified their total concentrations by liquid chromatography/tandem mass spectrometry in paired serum and CSF samples. RESULTS: Median (interquartile range) in CSF reached 55% (47-64%) of total serum concentrations for bisoprolol and 43% (27-81%) for metoprolol, corresponding to 78% (67-92%) and 48% (30-91%) of respective unbound serum concentrations. CONCLUSION: The extent of penetration of bisoprolol and metoprolol into the CSF is similar and compatible with the assumption that both drugs may exert direct effects in the CNS.
Assuntos
Antagonistas de Receptores Adrenérgicos beta 1/farmacocinética , Bisoprolol/farmacocinética , Metoprolol/farmacocinética , Antagonistas de Receptores Adrenérgicos beta 1/sangue , Antagonistas de Receptores Adrenérgicos beta 1/líquido cefalorraquidiano , Adulto , Idoso , Idoso de 80 Anos ou mais , Bisoprolol/sangue , Bisoprolol/líquido cefalorraquidiano , Humanos , Metoprolol/sangue , Metoprolol/líquido cefalorraquidiano , Pessoa de Meia-IdadeRESUMO
ß-Blockers reduce mortality and improve symptoms in people with heart disease; however, current clinically available ß-blockers have poor selectivity for the cardiac ß1-adrenoceptor (AR) over the lung ß2-AR. Unwanted ß2-blockade risks causing life-threatening bronchospasm and reduced efficacy of ß2-agonist emergency rescue therapy. Thus, current life-prolonging ß-blockers are contraindicated in patients with both heart disease and asthma. Here, we describe NDD-713 and -825, novel highly ß1-selective neutral antagonists with good pharmaceutical properties that can potentially overcome this limitation. Radioligand binding studies and functional assays that use human receptors expressed in Chinese hamster ovary cells demonstrate that NDD-713 and -825 have nanomolar ß1-AR affinity >500-fold ß1-AR vs ß2-AR selectivity and no agonism. Studies in conscious rats demonstrate that these antagonists are orally bioavailable and cause pronounced ß1-mediated reduction of heart rate while showing no effect on ß2-mediated hindquarters vasodilatation. These compounds also have good disposition properties and show no adverse toxicologic effects. They potentially offer a truly cardioselective ß-blocker therapy for the large number of patients with heart and respiratory or peripheral vascular comorbidities.-Baker, J. G., Gardiner, S. M., Woolard, J., Fromont, C., Jadhav, G. P., Mistry, S. N., Thompson, K. S. J., Kellam, B., Hill, S. J., Fischer, P. M. Novel selective ß1-adrenoceptor antagonists for concomitant cardiovascular and respiratory disease.
Assuntos
Antagonistas de Receptores Adrenérgicos beta 1/farmacologia , Benzamidas/farmacologia , Isoindóis/farmacologia , Antagonistas de Receptores Adrenérgicos beta 1/administração & dosagem , Antagonistas de Receptores Adrenérgicos beta 1/farmacocinética , Animais , Células CHO , Cricetinae , Cricetulus , Relação Dose-Resposta a Droga , Canal de Potássio ERG1/química , Humanos , Masculino , Testes de Mutagenicidade , Ratos , Ratos Sprague-Dawley , Salmonella typhimuriumRESUMO
Pharmacokinetics, pharmacodynamics, safety, and tolerability of long-term administration of landiolol, a fast-acting cardioselective ß-blocker, were investigated for the first time in white subjects in a prospective clinical trial. Blood concentrations of landiolol and its metabolites, heart rate (HR), blood pressure (BP), and electrocardiogram parameters were studied in 12 healthy volunteers receiving continuous infusions of a new 12-mg/mL formulation of landiolol using a dose-escalation regimen (10 µg/kg BW/min for 2 hours, 20 µg/kg BW/min for 2 hours, 40 µg/kg BW/min for 20 hours, 6 hours follow-up). Landiolol blood concentrations were dose proportional. Time until steady state decreased with increasing doses. Pharmacokinetic parameters were t1/2 = 4.5 minutes, VD = 366 mL/kg, and total body clearance = 53 mL·kg·min. Maximal blood concentrations of the inactive main metabolite M1 were 10-fold higher than those of landiolol, with t1/2 = 126 minutes, VD = 811 mL/kg, and total body clearance = 4.5 mL·kg·min. HR reduction from baseline was fast (significant after 16 minutes) and sustained throughout the administration period. Systolic and diastolic BP reductions and electrocardiogram parameter changes were less pronounced and became significant only occasionally. Recovery after discontinuation of infusion was fast with little (HR) or no (BP) rebound. The new formulation showed excellent local and general tolerability.
Assuntos
Antagonistas de Receptores Adrenérgicos beta 1/administração & dosagem , Antagonistas de Receptores Adrenérgicos beta 1/farmacocinética , Morfolinas/administração & dosagem , Morfolinas/farmacocinética , Ureia/análogos & derivados , População Branca , Antagonistas Adrenérgicos beta/administração & dosagem , Antagonistas Adrenérgicos beta/farmacocinética , Adulto , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Eletrocardiografia/efeitos dos fármacos , Eletrocardiografia/métodos , Feminino , Humanos , Infusões Intravenosas , Masculino , Estudos Prospectivos , Ureia/administração & dosagem , Ureia/farmacocinéticaRESUMO
In the current study, we investigated the metoprolol absorption kinetics of an in-house produced oral sustained-release formulation, matrices manufactured via prilling, and two commercially available formulations, ZOK-ZID® (reservoir) and Slow-Lopresor® (matrix) in both New Zealand White rabbits and Beagle dogs, using a population pharmacokinetic analysis approach. The aim of this study was to compare the in vivo pharmacokinetic (PK) profiles of different formulations based on metoprolol, a selective adrenergic ß1-receptor antagonist, in dogs and rabbits and to contrast the observed differences. To that end, metoprolol (50 to 200mg) was administered to 6 Beagle dogs and 6 New Zealand White rabbits as a single intravenous (IV) bolus injection and to 8 dogs and 6 rabbits as an oral modified release formulation. To derive pharmacokinetic parameters from the data, a non-linear mixed-effects model was developed using NONMEM® where the contribution of observations below the limit of detection (BDL, below detection limit) to the parameter estimates was taken into account in the parameter estimation procedure. In both species and for the three modified release formulations, different absorption models were tested to describe the PK of metoprolol following oral dosing. In Beagle dogs, plasma concentration-time profiles were best described using a sequential zero- and first-order absorption model. In rabbits though, the absorption phase was best described using a first-order process only. In both species, the reservoir formulation ZOK-ZID® was behaving quite similarly. In contrast, the absorption properties of both matrix formulations were rather different between species. This study indicates that the PK of the reservoir formulation is similar in both species, even after accounting for the almost completely missed absorption phase in rabbits. The insights gained further illustrate that rabbits are not very well suited to study the PK of the current matrix formulations in view of their less optimal prolonged release characteristics and the resulting fast decline in metoprolol plasma levels.