Acute liver injury induced by drug interaction between dacomitinib and metoprolol due to the inhibition of CYP2D6 by dacomitinib.

INTRODUCTION: In recent years, oral antineoplastic agents are commonly used in antitumor therapy. The interaction between drugs may affect the efficacy of drugs or lead to adverse reactions. We describe the case of a patient who presented acute liver injury, possibly induced by the concomitant use of metoprolol and dacomitinib. CASE REPORT: A 62-year-old male patient with non-small cell lung cancer was admitted for anti-cancer treatment. He regularly took metoprolol tartrate 12.5 mg, 2/day for hypertension. He was treated with dacomitinib according to EGFR Exon21 L858R positive. After 3 days of dacomitinib, the patient's alanine aminotransferase (ALT) and glutathione aminotransferase (AST) increased, and the heart rate and systolic blood pressure of the patient decreased significantly. The patient was diagnosed with acute liver injury. MANAGEMENT AND OUTCOMES: Dacomitinib was discontinued and glutathione, magnesium isoglycyrrhizinate were given to treat acute liver injury. Two days after discontinued dacomitinib, the patient's heart rate increased, but the ALT and AST of the patient elevated again. Metoprolol tartrate was subsequently discontinued and the ALT and AST gradually decreased and the patient discharged from the hospital eight days later with his liver function improved. DISCUSSION: To our knowledge, this is the first case in the literature of acute liver injury possibly induced by the interaction between metoprolol and dacomitinib. The interaction most likely arose because dacomitinib is a CYP2D6 strong inhibitor and could therefore impair the metabolism of metoprolol (a CYP2D6 substrate) and increase its serum concentration. Therefore, hepatic function should be carefully monitored in patients treated with dacomitinib and metoprolol and other inhibitors or inducers of CYP2D6.

Comparison of new-onset post-operative atrial fibrillation between patients receiving carvedilol and metoprolol after off-pump coronary artery bypass graft surgery.

OBJECTIVE: Post-operative atrial fibrillation (POAF) is a common complication of coronary artery bypass graft (CABG) surgery. Previous studies suggest carvedilol is more effective than metoprolol in preventing POAF in on-pump CABG. This study investigated if the same benefit would be seen in off-pump CABG. METHODS: This single-center, retrospective review compared rates of new-onset POAF between adult patients who received carvedilol and metoprolol after off-pump CABG surgery. Safety endpoints included hypotension, bradycardia, dyspnea, and the composite. Multivariate logistic regression was conducted to identify associations between demographics, potential confounders, and beta-blocker dose and POAF. Kaplan-Meier plots and Cox proportional-hazards models examined differences in time-to-event for POAF. RESULTS: 134 patients were included (34 carvedilol and 100 metoprolol). The mean age was 63 years, 70.9% were male, 85% had history of hypertension, 3.7% had history of heart failure with reduced ejection fraction, and 38.8% were taking beta blockers prior to admission. POAF developed in 2 patients (5.8%) in the carvedilol group and 24 patients (24.0%) in the metoprolol group (odds ratio 0.17 [95% CI 0.03-0.83], p = 0.023). Safety endpoints occurred in 10 carvedilol (29.4%) and 44 metoprolol (44.0%) patients (p = 0.134). Hypotension and dyspnea rates were similar between groups; bradycardia occurred more commonly among metoprolol-treated patients (p = 0.040). Time-to-event analyses revealed a hazard ratio = 0.22 (95% CI 0.05-0.93, p = 0.040) for carvedilol use. CONCLUSIONS: In this single-center, retrospective study of off-pump CABG patients, carvedilol was associated with reduced POAF risk and enhanced safety compared to metoprolol.

Co-prescription of metoprolol and CYP2D6-inhibiting antidepressants before and after implementation of an optimized drug interaction database in Norway.

PURPOSE: To compare the co-prescription of metoprolol and potent CYP2D6-inhibiting antidepressants before and during a 10-year period after implementation of an optimized drug interaction database into clinical decision support systems in Norway. METHODS: The study was a retrospective, cross-sequential nationwide analysis of drug-dispensing data retrieved from the Norwegian Prescription Database over a 1-year period before (2007) and two 1-year periods after (2012 and 2017) implementation of a drug interaction database providing recommendations on non-interacting alternative medications. Primary outcome was changes in co-prescription rates of metoprolol and the potent CYP2D6-inhibiting antidepressants fluoxetine, paroxetine, or bupropion relative to alternative antidepressants with no or limited CYP2D6 inhibitory potential. To control for potential secular trend bias, a comparison group consisting of atenolol/bisoprolol users was included. RESULTS: The co-prescription rate of metoprolol with potent CYP2D6 inhibitors declined following implementation of the optimized database, by 21% (P < 0.001) after 5 years and by 40% (P < 0.001) after 10 years. Compared with atenolol/bisoprolol users, patients treated with metoprolol had significantly reduced likelihood of being prescribed a CYP2D6-inhibiting antidepressant in the two post-implementation periods (OR 0.61 (95% CI 0.54-0.69) and OR 0.45 (95% CI 0.40-0.51), respectively, versus OR 0.84 (95% CI 0.74-0.94) prior to implementation). Small and mostly insignificant differences in average daily metoprolol dosage were found between patients treated with the various antidepressants. CONCLUSION: The present study suggests that implementation of a drug interaction database providing recommendations on non-interacting drug alternatives contributes to reduced co-prescribing of drug combinations associated with potentially serious adverse effects.

Comparative effectiveness of metoprolol, ivabradine, and its combination in the management of inappropriate sinus tachycardia in coronary artery bypass graft patients.

BACKGROUND: Inappropriate sinus tachycardia (IST) is an arrhythmic complication observed after coronary artery bypass graft (CABG) surgery which left untreated, commonly increases chances of postoperative stroke. The primary study objective was comparing effectiveness of beta blocker-metoprolol; a specific If blocker-ivabradine and its combination in patients who develop IST as a complication following CABG. MATERIALS AND METHODS: An open-labeled, investigator initiated, clinical study was conducted on 150 patients who developed IST (heart rate [HR] >100 beats/min) following elective CABG surgery. The patients were randomized into three treatment groups. Group I - received ivabradine (5 mg), Group II - metoprolol (25 mg), and Group III - ivabradine (5 mg) and metoprolol (25 mg). Treatment was given orally, twice a day for 7 days in all the three groups postoperatively. Primary endpoints were comparative effectiveness in HR and blood pressure reduction following treatment. RESULTS: IST was diagnosed by an electrocardiogram (12-lead) considering morphological features of P-wave and with 32% increase from baseline HR in all the three groups. Compared to IST arrthymic rate, HR was reduced in all groups following respective treatment (P = 0.05). Reduction in HR was significant (P < 0.05) in combination group followed by ivabradine which was significantly greater than metoprolol treated group. None of the treatments clinically changed the systolic, diastolic and mean blood pressure till discharge. No surgery/treatment-related complications were observed in any groups. CONCLUSION: Ivabradine stands as a pharmacological option for controlling HR and rhythm without associated side effects in postoperative CABG patients with IST.

Segurança, Eficácia e Protocolo de Dose de Metoprolol para Redução de Frequência Cardíaca em Pacientes Pediátricos Externos que Passaram por Angiografia Cardíaca por TC / Safety, Efficacy, and Dose Protocol of Metoprolol for Heart Rate Reduction in Pediatric Outpatients Undergoing Cardiac CT Angiography

Resumo Fundamento Qualidade de imagem e dose de radiação são otimizadas com uma frequência cardíaca (FC) lenta e estável na realização de imagens de artérias coronárias durante a angiografia cardíaca por tomografia computadorizada (CCTA, do inglês cardiac computed tomography angiography) A segurança, a eficácia e o protocolo para a redução da FC com medicamento betabloqueador ainda não foi bem descrita em uma população de pacientes pediátricos. Objetivo Oferecer um protocolo de dose de metoprolol eficiente a ser usado em pacientes pediátricos externos durante a CCTA. Métodos Realizamos uma revisão retrospectiva de todos os pacientes pediátricos externos que receberam o metoprolol durante a CCTA. As características demográficas e clínicas foram resumidas e a redução média em FC foi estimada utilizando-se um modelo de regressão linear multivariada. As imagens foram avaliadas em uma escala de 1 a 4 (1= ideal). Resultados Um total de 78 pacientes externos passaram a uma CCTA com o uso de metoprolol. A média de idade foi de 13 anos, a média de peso foi de 46 kg, e 36 pacientes (46%) eram do sexo masculino. As doses médias de metoprolol foram 1,5 (IQR 1,1; 1,8) mg/kg, e 0,4 (IQR 0,2; 0,7) mg/kg para administrações orais e intravenosas, respectivamente. O produto dose-comprimento por exame foi de 57 (IQR 30, 119) mGy*cm. A redução média da FC foi 19 (IQR 12, 26) batimentos por minuto, ou 23%. Não foram relatadas complicações ou eventos adversos. Conclusão O uso de metoprolol num cenário de pacientes pediátricos externos para redução da FC antes de uma CCTA é seguro e eficiente. Pode-se reproduzir um protocolo de dose de metoprolol quando for necessário atingir uma FC mais lenta, garantindo tempos de aquisição mais rápidos, imagens mais claras e redução na exposição à radiação nessa população. (Arq Bras Cardiol. 2021; 116(1):100-105)

Abstract Background Image quality and radiation dose are optimized with a slow, steady heart rate (HR) when imaging the coronary arteries during cardiac computed tomography angiography (CCTA). The safety, efficacy, and protocol for HR reduction with beta blocker medication is not well described in a pediatric patient population. Objective Provide a safe and efficient metoprolol dose protocol to be used in pediatric outpatients undergoing CCTA. Methods We conducted a retrospective review of all pediatric outpatients who received metoprolol during CCTA. Demographic and clinical characteristics were summarized and the average reduction in HR was estimated using a multivariate linear regression model. Images were evaluated on a 1-4 scale (1= optimal). Results Seventy-eight pediatric outpatients underwent a CCTA scan with the use of metoprolol. The median age was 13 years, median weight of 46 kg, and 36 (46%) were male. The median doses of metoprolol were 1.5 (IQR 1.1, 1.8) mg/kg and 0.4 (IQR 0.2, 0.7) mg/kg for oral and intravenous administrations, respectively. Procedural dose-length product was 57 (IQR 30, 119) mGy*cm. The average reduction in HR was 19 (IQR 12, 26) beats per minute, or 23%. No complications or adverse events were reported. Conclusion Use of metoprolol in a pediatric outpatient setting for HR reduction prior to CCTA is safe and effective. A metoprolol dose protocol can be reproduced when a slower HR is needed, ensuring faster acquisition times, clear images, and associated reduction in radiation exposure in this population. (Arq Bras Cardiol. 2021; 116(1):100-105)

Effect of metoprolol tartrate tablets and recombinant human B-type natriuretic peptide on the sudden cardiac death and malignant arrhythmias in patients with acute myocardial infarction and heart failure.

To explore the effect of metoprolol tartrate tablets and recombinant human natriuretic peptide B (NPPB) on sudden cardiac death and malignant arrhythmias in patients with acute myocardial infarction and patients with heart failure (AMI-HF). A total of 105 AMI-HF patients treatedfrom January 2020 and June 2021 were enrolled and divided into Group I (n=53) and Group II (n=52). Both groups received conventional treatment, and Group II was additionally treated with metoprolol tartrate tablets and NPPB. The clinical observation indicators of the two groups of patients were compared. Group II had better left ventricular end diastolic diameter (LVEDd), left ventricular end systolic diameter (LVESD) and left ventricular ejection fraction (LVEF) (p<0.05). The standard deviation of NN (R-R) interval (SDNN), mean NN (R-R), root mean square of continuous difference (RMSSD) and the percentage of difference between adjacent RR intervals >50ms (pNN50) increased after treatment, with more increase in the Group II (p<0.05). Group II obtained significantly lower levels of B type natriuretic peptide (BNP),N terminal pro B type natriuretic peptide (NT-ProBNP), interleukin (IL)-6 and hs-CRP in contrast to Group I (p<0.05). Markedly higher total response rates were observed in Group II (p<0.05). The combination of metoprolol tartrate tablets and NPPB is effective in treating AMI-HF.

Metoprolol-Induced Pemphigus-Like Reaction.

INTRODUCTION: Pemphigus vulgaris (PV) is a relatively rare, potentially life-threatening autoimmune disease that, in most cases, has an unknown etiology. Medications for hypertension have been linked to the onset and exacerbation of PV-like symptoms. The diagnosis of medication-related PV can be challenging because it has an identical appearance to the clinical and histologic appearance of idiopathic PV and cases may not resolve after discontinuation of the drug. CASE PRESENTATION: We present a case of an elderly patient with gingival and cutaneous erosions, who underwent several medical and dental consultations without an appropriate diagnosis. After biopsy and a thorough review of her medical history, metoprolol was suspected as the offending agent. After consulting with her cardiologist, metoprolol was discontinued, and a complete resolution of all lesions resulted. CONCLUSIONS: To our knowledge, the current case is the first reported case of metoprolol-induced PV in the English-language literature. As such, it highlights the potential of medication involvement in some immune-mediated diseases. Because the oral mucosa is often the first site of involvement in PV, knowledge of drug-related PV is crucial in the diagnosis, treatment, and management of dental patients.

Age Does Not Affect Metoprolol's Effect on Perioperative Outcomes (From the POISE Database).

BACKGROUND: Perioperative ß-blockade reduces the incidence of myocardial infarction but increases that of death, stroke, and hypotension. The elderly may experience few benefits but more harms associated with ß-blockade due to a normal effect of aging, that of a reduced resting heart rate. The tested hypothesis was that the effect of perioperative ß-blockade is more significant with increasing age. METHODS: To determine whether the effect of perioperative ß-blockade on the primary composite event, clinically significant hypotension, myocardial infarction, stroke, and death varies with age, we interrogated data from the perioperative ischemia evaluation (POISE) study. The POISE study randomly assigned 8351 patients, aged ≥45 years, in 23 countries, undergoing major noncardiac surgery to either 200 mg metoprolol CR daily or placebo for 30 days. Odds ratios or hazard ratios for time to events, when available, for each of the adverse effects were measured according to decile of age, and interaction term between age and treatment was calculated. No adjustment was made for multiple outcomes. RESULTS: Age was associated with higher incidences of the major outcomes of clinically significant hypotension, myocardial infarction, and death. Age was associated with a minimal reduction in resting heart rate from 84.2 (standard error, 0.63; ages 45-54 years) to 80.9 (standard error, 0.70; ages >85 years; P < .0001). We found no evidence of any interaction between age and study group regarding any of the major outcomes, although the limited sample size does not exclude any but large interactions. CONCLUSIONS: The effect of perioperative ß-blockade on the major outcomes studied did not vary with age. Resting heart rate decreases slightly with age. Our data do not support a recommendation for the use of perioperative ß-blockade in any age subgroup to achieve benefits but avoid harms. Therefore, current recommendations against the use of ß-blockers in high-risk patients undergoing noncardiac surgery apply across all age groups.

Comparison of effects of losartan and metoprolol on left ventricular and aortic function at rest and during exercise in chronic aortic regurgitation.

Aortic regurgitation (AR) increases the hemodynamic load on both the left ventricle (LV) and the aorta. Vasodilators and beta-blockers both reduce systemic blood pressure, but their relative effects on the LV and aortic function and aortic regurgitant fraction in chronic AR are uncertain. We aimed to compare short-term effects of losartan and metoprolol on LV and aortic function in asymptomatic patients with chronic moderate to severe AR, both at rest and during exercise, using cardiac magnetic resonance (CMR) imaging. 17 chronic AR patients were randomized to 4-6 weeks losartan followed by metoprolol, or vice versa, in a cross-over design. Aortic regurgitant fraction, aortic distensibility, pulse wave velocity and LV function were assessed at rest and after moderate exercise stress (29 ± 7 W, heart rate increase 25 ± 6 bpm) using CMR. Chronic AR patients on metoprolol had a significantly lower mean heart rate, cardiac power index and rate-pressure product, than on losartan (all p < 0.01). However, aortic regurgitant fraction was greater on metoprolol compared to losartan (by 7 ± 11%, p = 0.02). Metoprolol was also associated with a greater reduction in aortic distensibility during exercise than losartan (- 2.4 ± 1.5 × 10-3 vs - 1.7 ± 2.1 × 10-3 mmHg-1 respectively, p = 0.04). End-diastolic volume index was higher on metoprolol than losartan at exercise (difference 6.6 ± 7.8 ml/m2, p < 0.01), as was end-systolic volume index (difference 4.0 ± 5.2 ml/m2, p < 0.01). Losartan and metoprolol have significantly different short-term effects on aortic regurgitation and LV and aortic function in chronic AR. Further research is required to determine the long-term clinical significance of these changes.

Evaluation of the safety and efficacy of metoprolol infusion for children and adolescents with hypertensive crises: a retrospective case series.

BACKGROUND: Acute severe hypertension occurs infrequently in pediatric patients and, consequently, data on the efficacy and safety of most antihypertensive agents, as well as the adverse events associated with these agents, are very limited in this population. In this case series, we evaluated the use of metoprolol infusion in children with hypertensive emergencies. METHODS: The study population comprised children younger than 18 years who had been admitted to the pediatric intensive care unit at King Abdullah University Hospital with blood pressure above the 99th percentile for age, height, and sex and who were symptomatic at the time of presentation. Metoprolol was given as an infusion at a dose of 1-5 mcg/kg/min. The rate of decrease in blood pressure, side effects from the medication, and outcome were assessed. RESULTS: Thirteen patients ranging in age from 2 months to 16 years were included in this study. The initial mean blood pressure was 23-75 mmHg above the 99th percentile for age, height, and sex. Metoprolol was initiated at a dose of 0.5 mcg/kg/min and titrated according to the target blood pressure to a maximum of 5 mcg/kg/min. Mean blood pressure fell by an average of 12.3, 20.4, and 27.1% at 1, 8, and 24 h, respectively, which is consistent with findings on the use of other intravenous medications reported in published studies. The heart rate did not decrease below the normal range for age. There were no significant side effects of the metoprolol infusion. All patients were discharged home with no neurological sequelae secondary to their hypertension. CONCLUSION: An infusion of metoprolol for a hypertensive emergency is a safe and effective treatment for pediatric patients.

The Comparison of the Effects of Nebivolol and Metoprolol on Erectile Dysfunction in the Cases with Coronary Artery Bypass Surgery.

PURPOSE: Beta-blocker use is common in the cases with coronary artery bypass surgery. According to the literature, beta-blockers have positive effects but may cause erectile dysfunction (ED). The most commonly used beta-blockers in ischemic cardiac disease are nebivolol and metoprolol. In our clinic, we aimed to compare the effects of nebivolol and metoprolol succinate on ED in the sexually active cases with coronary artery bypass surgery. METHODS: In our clinic, a total of 119 patients with coronary artery bypass surgery were included in the study. International Index of Erectile Function (IIEF-5) Test was used to evaluate whether the patients had ED and to grade the cases. RESULTS: No significant difference was found in terms of anti-ischemic efficacy between metoprolol succinate and nebivolol in the postoperative period; however, the incidence of any grade ED was %85.96 in Group 1, %83.87 in Group 2. This difference was considered as statistically significant (p = 0.036). CONCLUSION: Beta-blocker use increases the risk of ED in cases with ischemic cardiac disease. We suggest that the complaints of ED could be less frequent with nebivolol use in sexually active cases with ischemic cardiac disease.

Use of flecainide in combination antiarrhythmic therapy in patients with arrhythmogenic right ventricular cardiomyopathy.

BACKGROUND: Antiarrhythmic therapy is commonly used for suppression of arrhythmias in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) in conjunction with implantable cardioverter-defibrillators and catheter ablation. The efficacy of combination flecainide and sotalol/metoprolol therapy for patients refractory to single agents and/or catheter ablation has not been well established. OBJECTIVE: The purpose of this study was to describe our experience with the addition of flecainide in combination with sotalol/metoprolol for treatment of arrhythmias in patients with ARVC. METHODS: We reviewed all patients within our genetic arrhythmia program with a definite diagnosis of ARVC (45 patients) and identified 8 patients treated with a combination of flecainide with sotalol/metoprolol after failure of single-agent therapy and/or catheter ablation. These patients were monitored with at least yearly clinic visits and device interrogations focused on the detection of major ventricular arrhythmias. RESULTS: Of the 8 patients reviewed, 6 demonstrated excellent arrhythmia control after initiation of combination therapy with flecainide and sotalol/metoprolol. These patients have been arrhythmia-free for an average of 35.5 months. Two patients have demonstrated recurrent arrhythmias despite combination therapy and have undergone repeat epicardial and endocardial ablation. Recurrence was noted to occur within 2 months of therapy. Patients were diverse with regard to the severity of disease as well as in the presence of genetic mutations. CONCLUSION: The addition of flecainide in combination with sotalol/metoprolol may be an effective antiarrhythmic strategy for the control of ventricular arrhythmias in patients with ARVC refractory to single-agent therapy and/or catheter ablation.

Metoprolol vs ivabradine in patients with mitral stenosis in sinus rhythm.

BACKGROUND: Severe mitral stenosis is usually symptomatic and is treated by BMV or surgery, whereas mild to moderate mitral stenosis is usually asymptomatic or mildly symptomatic and managed medically. Patients in the later group may become symptomatic during episodes of exercise and increased heart rate. Beta-blockers are frequently used in patients with mitral stenosis to control the heart rate and alleviate exercise-related symptoms. The objective of our study was to investigate the comparative efficacy of ivabradine versus metoprolol in patients with mitral stenosis in sinus rhythm. METHODS: We studied 97 patients of mitral stenosis in sinus rhythm presented with exertional symptoms. The effectiveness of Metoprolol was compared with ivabradine in alleviating these exertional symptoms in a randomized, open label non crossover study. We also assessed various stress ECG parameters, 24 hour Holter parameters and 2D Echo parameters to objectively compare the effects of ivabradine and metoprolol in these patients. RESULTS: Ivabradine and metoprolol both were effective in controlling exertional symptoms. Significant improvement in objective parameters like TMT (work capacity, baseline heart rate and maximal heart rate) and 2D echocardiography (right ventricular systolic pressure) are seen with both drugs. Ivabradine controls the exertional symptoms significantly more than metoprolol. On head to head comparison there was a significant benefit of working capacity and heart rate at maximal exercise in favour of ivabradine. CONCLUSIONS: Ivabradine should be strongly considered in medical management of mitral stenosis patients where beta blockers are contraindicated such as reactive airway disease. The cost of ivabradine is higher than metoprolol which might possess constraints as most of the rheumatic heat disease patients belong to low socio economic status.

Targeting the sympatho-adrenergic link in chronic rheumatic mitral regurgitation: assessing the role of oral beta-blockers.

INTRODUCTION: Chronic mitral regurgitation (MR) is characterized by adverse ventricular remodeling and progressive LV dysfunction leading to heart failure (HF). Beta-blockers (BB) improve LV remodeling and prognosis in patients with HF. As chronic severe MR results in neuroendocrine activation similar to HF, it is likely that BB may also exert favorable effects in these patients. No study has assessed the role of oral BB therapy in chronic rheumatic MR. AIMS: A total of 100 patients of chronic rheumatic MR (mean age 30±13.48 years, NYHA 2.2±0.5) were randomized to BB (Metoprolol, 37±13.5 mg, n=48) vs no BB (n=52) in addition to standard therapy. RESULTS: Baseline BNP and echocardiographic parameters were comparable in the two groups. At 3 months, BB therapy resulted in significantly lower NYHA class (1.97 vs 2.35), BNP (141 vs 207 pg/mL), LV end-systolic (35.89 vs 51.30) and LV end-diastolic volumes (101 vs 128 mL/m(2) ), LV end-systolic stress (81.1 vs 93.3 dyn/cm(2) ), LV mass (122 vs 154 gm/m(2) ), and LV work (737.02 vs 952.82 mm Hg L/min, all P significant). Therapy with BB resulted in a -15.6%, -10.4%,-12.1%, and -7.3% reduction in LV end-systolic and end-diastolic dimensions and LVESVi and LVEDVi, respectively. Following BB therapy, BNP levels, end-systolic stress, indexed LV mass, and LV work also reduced significantly by 27.3%, 15.6%, 8.7%, and 28%, respectively. The control group had no significant change. The MR grade reduced from severe to moderate in 11% of those on BB (controls: no change). At 6 months, the BB group had further improvement in all echocardiographic parameters ranging from +9.1 to -18.2%. CONCLUSION: In this first study of BB in rheumatic MR, targeting the sympatho-adrenergic axis exerted favorable effects on NYHA class, LV volumes, LV end-systolic stress, and LV work. Further studies are required to elucidate the role of BB in rheumatic MR.

Desenvolvimento de sistemas multiparticulados de liberação imediata e modificada para associação de fármacos anti-hipertensivos / Development of immediate and modified release multiparticulate systems for antihypertensive drugs association

Os sistemas multiparticulados são aqueles nos quais a dose do fármaco está dividida em pequenas unidades funcionais, tendo assim, uma série de vantagens sobre os sistemas monolíticos convencionais. Este trabalho teve por objetivo desenvolver formulações multiparticuladas de uso oral para fármacos anti-hipertensivos que serão utilizados na composição de associações. O material está dividido em seis capítulos, sendo inicialmente apresentada uma revisão da literatura a respeito da caracterização física destas pequenas unidades. Ensaios como análise granulométrica, morfologia, densidade, porosidade, avaliação de resistência mecânica e desintegração são os mais empregados para esta finalidade, possibilitando ao formulador conhecer os fatores de maior impacto relacionados às matérias primas e ao processo de fabricação no comportamento das formulações produzidas. Os demais capítulos seguem com o desenvolvimento dos sistemas multiparticulados, que foram embasados em diferentes delineamentos experimentais, seja pela utilização de planejamento fatorial fracionado ou projeto de mistura. Para o metoprolol, fármaco de alta solubilidade, foram produzidas formulações de liberação controlada, sendo a estratégia dividida em três etapas: (I) Produção de minicomprimidos revestidos, nos quais foram avaliadas diferentes combinações do polímero modulador de liberação; (II) otimização do perfil de liberação do fármaco, com avaliação de misturas das formulações produzidas na primeira etapa; (III) Processo de extrusão a quente, no qual diferentes proporções de fármaco e polímero hidrofóbico foram avaliadas. Para os fármacos hidroclorotiazida e olmesartana medoxomila, ambos de baixa solubilidade, a estratégia adotada foi a incorporação de uma dispersão dos fármacos e agentes solubilizantes em grânulos inertes obtidos por extrusão/revestimento. Adicionalmente, também foram produzidas formulações por extrusão a quente de diferentes proporções destes fármacos em polímero hidrofílico. De acordo com os resultados obtidos, foi possível obter formulações de minicomprimidos e grânulos com perfil de dissolução satisfatório, semelhantes aos apresentados pelos medicamentos adotados como referência. Em relação à extrusão a quente foi possível avaliar a influência do processo e polímeros empregados no perfil de dissolução dos grânulos produzidos

Multiparticulate systems are dosage forms in which dose is divided into small functional units presenting some advantages over monolithic conventional systems. The objective of this work was developing multiparticulate formulations for oral use containing antihypertensive drugs to be used in association. The thesis is divided into six issues, been first presented a literature review about physical characterization of multiparticulate systems. Granulometric analysis, morphology, density, porosity, mechanical strength and disintegration are the most used physical characterization tests, enabling formulator knowing the major impact factors related to raw materials and manufacturing process in the performance of the produced formulations. The other issues present the development of the multiparticulate systems based on different statistical experimental design, as fractional factorial design or mixture project. For metoprolol, a highly soluble drug, controlled release formulations were obtained, and the strategy was divided into three steps: (I) coated minitablets production, where different combinations of the controlled release polymer were analyzed; (II) drug release profile optimization, evaluating formulations mixtures produced in the first step; (III) hot melt extrusion process, where different drug: hydrophobic polymer ratios were evaluated. For hydrochlorothiazide and olmesartan medoxomil, both low soluble drugs, the strategy was incorporating a dispersion containing the drugs and solubilizing agents in inert granules obtained by extrusion/coating processes. Additionally, formulations containing different ratios of these drugs and hydrophilic polymers were produced by hot melt extrusion. According to the results, it was possible to obtain minitablets and granules with good dissolution profile, similar to the reference products. Regarding to hot melt extrusion, it was possible to evaluate the influence of process and polymers used in the dissolution profile of the produced granules

Efficacy and safety of out-of-hospital intravenous metoprolol administration in anterior ST-segment elevation acute myocardial infarction: insights from the METOCARD-CNIC trial.

STUDY OBJECTIVE: We seek to examine the efficacy and safety of prereperfusion emergency medical services (EMS)-administered intravenous metoprolol in anterior ST-segment elevation myocardial infarction patients undergoing eventual primary angioplasty. METHODS: This is a prespecified subgroup analysis of the Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction trial population, who all eventually received oral metoprolol within 12 to 24 hours. We studied patients receiving intravenous metoprolol by EMS and compared them with others treated by EMS but not receiving intravenous metoprolol. Outcomes included infarct size and left ventricular ejection fraction on cardiac magnetic resonance imaging at 1 week, and safety by measuring the incidence of the predefined combined endpoint (composite of death, malignant ventricular arrhythmias, advanced atrioventricular block, cardiogenic shock, or reinfarction) within the first 24 hours. RESULTS: From the total population of the trial (N=270), 147 patients (54%) were recruited during out-of-hospital assistance and transferred to the primary angioplasty center (74 intravenous metoprolol and 73 controls). Infarct size was smaller in patients receiving intravenous metoprolol compared with controls (23.4 [SD 15.0] versus 34.0 [SD 23.7] g; adjusted difference -11.4; 95% confidence interval [CI] -18.6 to -4.3). Left ventricular ejection fraction was higher in the intravenous metoprolol group (48.1% [SD 8.4%] versus 43.1% [SD 10.2%]; adjusted difference 5.0; 95% CI 1.6 to 8.4). Metoprolol administration did not increase the incidence of the prespecified safety combined endpoint: 6.8% versus 17.8% in controls (risk difference -11.1; 95% CI -21.5 to -0.6). CONCLUSION: Out-of-hospital administration of intravenous metoprolol by EMS within 4.5 hours of symptom onset in our subjects reduced infarct size and improved left ventricular ejection fraction with no excess of adverse events during the first 24 hours.

[Which is the preferred perioperative beta-blocker?]. / Welke perioperatieve bètablokker heeft de voorkeur?

Guidelines on perioperative cardiovascular evaluation and management of patients undergoing non-cardiac surgery recommend initiation of beta-blocker therapy in at-risk patients who are undergoing intermediate- to high-risk surgery. Continuation of therapy in patients already receiving beta-blockers is also recommended. Recent literature, however, reported an increased risk of perioperative cardiovascular mortality among patients who continued with existing beta-blockade; most patients in this study were using metoprolol. There are important pharmacodynamic and pharmacokinetic differences between various beta-blockers, and these differences may explain the differences in clinical effects. Metoprolol has less beta1 receptor affinity compared with atenolol and bisoprolol, and beta1 receptor polymorphisms affect the clinical effects of metoprolol. Furthermore, metoprolol is dependent on activity of the CYP2D6 liver enzyme, which results in clinically important differences in plasma concentration. It is, therefore, wise to follow the European guidelines and to initiate beta-blocker therapy in the perioperative period with either atenolol or bisoprolol.

Drug-induced pseudo-Sezary syndrome: a case report and literature review.

Pseudo-Sezary syndrome is a benign lymphoproliferative disorder, which clinically and pathologically mimics true Sezary syndrome. In this article, a case of pseudo-Sezary syndrome and review the literature has been reported. The patient was a 51-year-old man who developed erythroderma and palmoplantar keratoderma. The patient's medication history included fosinopril and combination metoprolol/hydrochlorothiazide. Flow cytometry showed a population of 2500 "Sezary-like" CD4726 T cells per microliter in the peripheral blood. Skin biopsy showed numerous atypical lymphocytes with epidermotropism, and there was matching dominant T-cell clonality in the skin and peripheral blood. After stopping all antihypertensive medications, the eruption resolved in its entirety.