Evaluation of metoprolol versus diltiazem for rate control of atrial fibrillation in the emergency department.

OBJECTIVE: The purpose of this study was to compare the effectiveness and safety of the metoprolol and diltiazem administration in the Emergency Department (ED) for rate control of supraventricular tachycardia. METHODS: This was a retrospective cohort study of adult patients who presented to the ED with ventricular rates ≥120 beats per minute (bpm) and who received bolus doses of either intravenous metoprolol or intravenous diltiazem. The primary outcome was achievement of rate control, defined as heart rate < 110 bpm, at two hours after administration of the last bolus dose of metoprolol or diltiazem. Safety outcomes included occurrence of hypotension, defined as systolic blood pressure < 90 mmHg or diastolic blood pressure < 60 mmHg, and bradycardia, defined as heart rate < 60 bpm. RESULTS: There were 166 patients receiving metoprolol and 183 patients receiving diltiazem included in the study. The primary outcome, rate control at two hours after the last bolus dose of metoprolol or diltiazem was similar between the two groups (45.8% vs 42.6%, p = 0.590, respectively). The percentage of patients achieving rate control was also similar (47.0% vs 41.6%, p = 0.333) at one hour. At 0.5 h HR had a significantly greater numerical (diltiazem: 29.3 ± 23.1 bpm vs metoprolol: 21.8 ± 18.9 bpm, p = 0.012) and percent decrease (21.1% vs 15.94%, p = 0.014) in the diltiazem group compared to metoprolol. There was no significant difference in occurrence of bradycardia in the two groups (diltiazem: 3.83% vs metoprolol: 1.2%, p = 0.179). More patients in the diltiazem group compared to the metoprolol group experienced hypotension (39.3% vs 23.5%, p = 0.002). The difference in systolic hypotension events was not significantly different (9.29% vs 5.42%, p = 0.221), while the difference in diastolic hypotension events was significantly different (37.7% vs 22.3%, p = 0.002). CONCLUSION: There was no difference in acute rate control effectiveness two hours after the last bolus dose of diltiazem and metoprolol for supraventricular tachycardias. There was a significantly higher occurrence of hypotension in the diltiazem group which was driven by higher rates of diastolic blood pressures less than 60 mmHg.

Beta-blocker choice and exchangeability in patients with heart failure and chronic obstructive pulmonary disease: an Italian register-based cohort study.

Clinical guidelines suggest that for patients with heart failure and concurrent chronic obstructive pulmonary disease (COPD), metoprolol/bisoprolol/nebivolol should be preferred over carvedilol. However, studies suggest a high proportion of carvedilol usage that remains unexplained. Therefore, we aimed to investigate the predictors of carvedilol choice in patients with heart failure and COPD that were naïve to carvedilol or metoprolol/bisoprolol/nebivolol. Caserta Local Health Unit databases (Italy) were used as data sources. Age, sex, chronic/acute comorbidities, and co-medications were included in a logistic regression model to assess predictors of carvedilol choice. Chronic comorbidities include those defined in the Elixhauser comorbidity index and all hospitalizations within two years prior to the first beta-blocker prescription. Comedications include all redeemed prescriptions within one year prior to the beta-blocker prescription. Kernel density estimations were used to assess the overlap in propensity and preference scores distributions for receiving carvedilol and thereby potential beta-blocker exchangeability. Totally, 10091 patients composed the study population; 2011 were exposed to carvedilol. The overlapping of propensity scores distributions was 57%. Accordingly, the exchangeability was not reached. Atrioventricular block (Odds Ratio, OR 8.20; 95% Confidence Interval, 95% CI 1.30-51.80), cerebrovascular thrombosis (OR 7.06; 95% CI 1.14-43.68), chronic kidney disease (OR 4.32; 95% CI 1.16-16.02), and acute heart failure (OR 1.97; 95% CI 1.28-3.03) hospitalizations were statistically significantly associated with carvedilol choice. Analogously, human insulin (OR 3.00; 95% CI 1.24-7.24), fondaparinux (OR 2.47; 95% CI 1.17-5.21) or strontium ranelate (OR 2.03; 95% CI 1.06-3.90) redeemed prescriptions. In conclusion, this study suggests the absence of beta-blockers exchangeability and a preferential choice of carvedilol in patients with heart failure, COPD and concurrent chronic kidney disease, atrioventricular block, cerebrovascular thrombosis, acute heart failure or redeeming human insulin, fondaparinux or strontium ranelate prescriptions. Therefore, it suggests that choice of prescribing carvedilol over metoprolol/bisoprolol/nebivolol is driven by differences in comorbidities and co-treatments.

Validation of an in-line Raman spectroscopic method for continuous active pharmaceutical ingredient quantification during pharmaceutical hot-melt extrusion.

A calibration model for in-line API determination was developed based on Raman spectra collected during hot-melt extrusion. This predictive model was validated by calculating the accuracy profile based on the analysis results of validation experiments. Furthermore, based on the data of the accuracy profile, the measurement uncertainty was determined. Finally, the robustness of the model was evaluated. A Raman probe was implemented in the die of a twin-screw extruder, to monitor the drug concentration during extrusion of physical mixtures containing 15, 20, 25, 30 and 35% (w/w) metoprolol tartrate (MPT) in Eudragit(®) RS PO, an amorphous copolymer of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups, which are present as salts. Several different calibration models for the prediction of the MPT content were developed, based on the use of single spectra or averaged spectra, and using partial least squares (PLS) regression or multivariate curve resolution (MCR). These predictive models were validated by extruding and monitoring mixtures containing 17.5, 22.5, 25.0, 27.5 and 32.5% (w/w) MPT. Each validated concentration was monitored on three different days, by two different operators. The ß-expectation tolerance intervals were calculated for each model and for each of the validated MPT concentration levels (ß was set at 95%), and acceptance limits were set at 10% (relative bias), indicating that at least 95% of future measurements should not deviate more than 10% from the true value. The only model where these acceptance limits were not exceeded was the MCR model based on averaged Raman spectra. The uncertainty measurements for this model showed that the unknown true value can be found at a maximum of ±7.00% around the measured result, with a confidence level of 95%. The robustness of this model was evaluated via an experimental design varying throughput, screw speed and barrel temperature. The robustness designs showed no significant influence of any of the process settings on the predicted concentration values. Raman spectroscopy proved to be a fast, non-destructive and reliable method for the quantification of MPT during hot-melt extrusion. From the accuracy profile of the MCR model based on averaged spectra, it was concluded that for each MPT concentration in the validated concentration range, 95 out 100 future routine measurements will be included within the acceptance limits (10%).

Simultaneous determination of metoprolol and α-hydroxymetoprolol in human plasma using excitation-emission matrix fluorescence coupled with second-order calibration methods.

BACKGROUND: Metoprolol (MET) is a ß1-adrenoceptor antagonist, which is widely used in the treatment of cardiovascular diseases, and α-hydroxymetoprolol (α-OHM) is its hydroxylated metabolite. Owing to their similar structures, optimization of the condition for the chromatography approach, which is in common use for determination, is both time consuming and laborious. RESULTS: A new and effective strategy that combines the excitation-emission matrix fluorescence with second-order calibration methods was developed for simultaneous determination of MET and α-OHM in human plasma. CONCLUSION: Although the fluorescence spectra of MET and α-OHM overlapped and a large number of unknown and uncalibrated fluorescent components coexisted, the developed method enables accurate concentrations together with reasonable resolution of excitation and emission profiles for the analytes of interest. An additional advantage of the proposed method is that there is no need for separation and sample pretreatment, in addition to lower cost than traditional methods.

[The methods for the protection against counterfeit medications. Part 1. The estimation of the quality of metoprolol succinate substance and tablets from different manufacturers in terms of "identity" and "active ingredient content"].

This paper was designed to report the results of analysis of metoprolol succinate substance and tablets obtained from two manufacturers, Akrikhin (Russia) and AstraZeneca (Sweden). The analysis was performed by spectroscopy in the near IR region and followed by the chemometric treatment of the data obtained. The method was used to confirm the "identity" of metoprolol succinate tablets. The approach to distinguishing the differences between pharmaceutical dosage forms produced by different manufacturers is proposed. Also, the method for the qualitative determination of metoprolol succinate in the pharmaceutical formulations has been developed.

[Methods for the protection against counterfeit medications. Part 2. The assessment of interlot dispersion of the metoprolol succinate tablets fabricated by different manufacturers].

This paper reports the results of analysis of the metoprolol succinate tablets fabricated by two different manufacturers, Akrikhin (Russia) and AstraZeneka (Sweden) by near-IR spectroscopy in the combination with the chemometric processing of the data obtained (discriminative analysis). It is concluded that this method is applicable for the assessment of interlot dispersion of the metoprolol succinate tablets.

Quality control of metoprolol extended-release formulations in the presence of ethanol.

This paper presents in-vitro metoprolol release from four different extended-release (ER) formulations, i.e. Metoprolol GEA® Retard, Logimax® forte, Metoprolol Sandoz® and Seloken ZOC® in the presence of 10 to 40% (v/v%) ethanol at pH 1.2 and pH 6.8. The assay of metoprolol in the dissolution media was performed by reversed phase liquid chromatography (RP-LC) using a mixture of methanol and 100 mM phosphate buffer (pH 3.5) in 40:60 ratio as eluent. The dissolution data showed that the metoprolol contents of Metoprolol Sandoz® and Seloken ZOC® were released fast in the presence of 20% ethanol at the investigated conditions, while the other products demonstrated much more stability against ethanol. Unexpectedly it was discovered that the release of metoprolol from Metoprolol GEA® Retard and to some extent also from Logimax® forte decreased in the ethanol containing media.

Tablet splitting: Product quality assessment of metoprolol succinate extended release tablets.

Metoprolol succinate extended release tablets comprise a multiple unit system containing metoprolol succinate in a multitude of controlled release pellets. Each pellet acts as a separate drug delivery unit and is designed to deliver metoprolol continuously over the dosage interval. Despite the flexibility that controlled release pellets may offer, segregation is one of the challenges that commonly occur during tableting for such drug delivery system. Since all commercial metoprolol succinate extended release tablets are scored, they are deemed suitable for splitting. The present study was aimed at utilizing an innovative technology to determine the dose uniformity for split tablets. Four marketed drug products consisting of innovator and generics were evaluated for effect of splitting on weight, assay and content uniformity. Novel analytical tool such as near infrared (NIR) chemical imaging was used to visualize the distribution of metoprolol succinate and functional excipients on the surfaces of the marketed tablets. The non-homogeneous distribution of directly compressed metoprolol succinate beads on the surface of the tablets as well as the split intersection explained the large variation in the split tablets' weight and content uniformity results. The obtained results indicated the usefulness of NIR chemical imaging to determine the need for content uniformity studies for certain split tablets.

Development and validation of a chiral liquid chromatographic method for the determination of atenolol and metoprolol enantiomers in tablet preparations.

Atenolol (AT) and metoprolol (MT) are predominantly used in the treatment of angina pectoris, certain arrhythmias, systemic hypertension, and several other cardiovascular disorders. Both compounds are produced commercially in the racemic form, although the S-form is responsible for the desired biological effect. This paper describes a simple, rapid, precise, and accurate method for separating the enantiomers of AT and MT. AT isomers are separated by using a Chiralcel OD column (250 x 4.6 mm, 10 microm), hexane-ethanoldiethylamine-acetic acid (60 + 40 + 0.2 + 0.2, v/v/v/v) as the mobile phase, and a flow rate of 1.0 mL/min. MT isomers are separated by using a mobile phase with the same components in the following proportions (40 + 60 + 0.2 + 0.2, v/v/v/v) and a flow rate of 0.8 mL/min. Ultraviolet detection was at 276 nm for both analytes. The coefficients of variation (CVs) and average recoveries (ARs) for the R-enantiomers in samples A, B, C, D, and E were 1.15 and 101.06%, 0.74 and 99.25%, 1.05 and 102.57%, 0.84 and 101.57%, and 0.86 and 98.62%, respectively. The CVs and ARs for the S-enantiomers in samples A, B, C, D, and E were 1.33 and 98.87%, 0.99 and 100.76%, 1.17 and 101.69%, 1.26 and 100.39%, and 1.40 and 99.39%, respectively. The standard curves of R-AT, S-AT, R-MT, and S-MT showed good linearity over the concentration range studied with correlation coefficients of 0.9991, 0.998, 0.9988, and 0.999, respectively.

Retrospective analysis showing less cardiac events in post-myocardial infarction patients treated with metoprolol. Secondary Prevention Group.

This analysis was carried out to clarify the capacity of metoprolol to prevent cardiac events in Japanese post-myocardial infarction patients during a follow-up period of 16.3 months. Cardiac events occurred in 44 of 650 patients treated without beta-blockers (6.8%) and in 13 of 432 patients treated with metoprolol (3.0%), which represents a significant decline in the incidence of cardiac events among patients receiving metoprolol (p<0.01, odds ratio 0.43, 95% confidence interval 0.23-0.80). Because this was a retrospective analysis, there were unavoidable differences in the backgrounds of the patients in the 2 groups. Subgroup analyses, each focusing on a specific patient characteristic, were therefore performed. These showed that metoprolol effectively reduced cardiac events in many subgroups. Furthermore, multivariate analysis carried out to exclude any modification based on the differences in patient background confirmed metoprolol to be effective in reducing subsequent cardiac events in post-myocardial infarction patients. A large, randomized, placebo-controlled clinical trial needs to be performed in the Japanese population to confirm the present result.

Quality of life, side effects and efficacy of lisinopril compared with metoprolol in patients with mild to moderate essential hypertension.

In a double-blind, parallel-group multicentre study in general practice, lisinopril (10-20 mg once daily) was compared with metoprolol (100-200 mg once daily) in 360 patients whose diastolic blood pressure (DBP) was in the range 91-115 mmHg despite diuretic treatment. Following a three week run-in period during which the diuretic was withdrawn, monotherapy with either lisinopril or metoprolol was given for two months with dose doubled after one month if DBP remained greater than 90 mmHg. Quality of life was assessed using established and validated questionnaires at the time of cessation of diuretic treatment and again after two months's active treatment. Both metoprolol and lisinopril achieved statistically significant BP reduction relative to baseline (P less than 0.001). Significantly fewer adverse events were experienced on lisinopril and metoprolol than on diuretic treatment. Frequency of withdrawals due to adverse events were statistically significantly lower on lisinopril than metoprolol P = 0.01. Before treatment approximately 35% of the patients had quality of life problems measured by General Health Questionnaire (GHQ), which was reduced to 17% on lisinopril and 23% on metoprolol. Thus both metoprolol and lisinopril were effective and safe in the treatment of mild to moderate essential hypertension with lisinopril being better tolerated. From patients' self-assessments of quality of life, lisinopril was found to be superior to metoprolol in some aspects of emotional, cognitive and social functioning.