Search Results (14)

Background and Clinical Significance: Statins are widely prescribed for cardiovascular risk reduction and generally demonstrate a favorable safety profile. While myalgia and elevations in liver enzymes are well-recognized adverse effects, headaches are less commonly reported and often underrecognized in clinical practice. This may result in unnecessary diagnostic evaluations, increased healthcare costs, and delayed identification of the underlying cause. Case Presentation: We describe an adult patient who developed intractable headaches that emerged after many years of statin therapy. The headaches persisted despite conventional analgesic treatment and resolved completely following discontinuation of the statin. Secondary causes were excluded, and comorbid conditions were systematically ruled out. Statin-associated headache is uncommon but clinically relevant. Proposed mechanisms include nitric-oxide-mediated vasodilation, central effects of lipophilic statins, and mitochondrial involvement. In this case, the patient was taking metoprolol succinate, lisinopril, simvastatin, clopidogrel, and tamsulosin. Except for lisinopril, none of the other comedications are strongly linked to new-onset headaches. Holding it did not resolve his headache, making simvastatin the most plausible contributor. This was confirmed by resolution of headache through its discontinuation. Because such headaches may be overlooked, clinicians should consider a statin-related cause when symptoms begin after initiation and may manage this by switching to a hydrophilic statin or using alternative lipid-lowering therapy. Conclusions: Clinicians should remain vigilant about the possibility of statin-induced headache, even in long-term users. Early recognition can prevent unnecessary diagnostic investigations, expedite symptom resolution, and support optimal management of both cardiovascular risk and treatment-related adverse effects. Full article

Aims: Sinus tachycardia after heart transplantation (HTX) due to cardiac graft denervation is associated with reduced post-transplant survival and requires adequate treatment. We analyzed the long-term effects of heart rate control with ivabradine or metoprolol succinate in HTX recipients. Methods: This observational retrospective single-center study analyzed the ten-year results of 110 patients receiving ivabradine (n = 54) or metoprolol succinate (n = 56) after HTX. Analysis included comparison of demographics, medications, heart rates, blood pressure values, echocardiographic features, cardiac catheterization data, cardiac biomarkers, and post-transplant survival including causes of death. Results: Both groups showed no significant differences concerning demographics or medications (except for ivabradine and metoprolol succinate). At 10-year follow-up, HTX recipients with ivabradine showed a significantly lower heart rate (72.7 ± 8.5 bpm) compared to baseline (88.8 ± 7.6 bpm; p < 0.001) and to metoprolol succinate (80.1 ± 8.1 bpm; p < 0.001), a significantly lower NT-proBNP level (588.4 ± 461.4 pg/mL) compared to baseline (3849.7 ± 1960.0 pg/mL; p < 0.001) and to metoprolol succinate (1229.0 ± 1098.6 pg/mL; p = 0.005), a significantly lower overall mortality (20.4% versus 46.4%; p = 0.004), and mortality due to graft failure (1.9% versus 21.4%; p = 0.001). Multivariate analysis showed a significantly decreased risk of death within 10 years after HTX in patients with post-transplant use of ivabradine (HR 0.374, CI 0.182–0.770; p = 0.008). Conclusions: In this single-center trial, patients with ivabradine revealed a significantly more pronounced heart rate reduction, a lower NT-proBNP level, and a superior 10-year survival after HTX. Full article

Metoprolol (MTP), a selective beta-1 adrenergic blocker, is commonly administered in the form of succinate or tartrate salts, depending on the pharmaceutical formulation. It is typically prescribed in oral forms as either immediate-release or extended-release tablets. This study describes a chromatographic method using automated sample clean-up and elution via a reversed-phase mechanism. A TurboFlow approach was applied with a Cyclone P column, and the elution was performed isocratically using a mobile phase of water and acetonitrile (0.1% v/v formic acid) within 4.5 min. Quantification of MTP was achieved using triple quadrupole mass spectrometry, with the transition m/z 268.1 → m/z 130.96 for metoprolol, while bisoprolol fumarate, the internal standard, was detected at m/z 326.3 → m/z 116.2. The method was validated according to bioequivalence guidelines. Selectivity was assessed by checking for potential interferences from blank samples or related compounds formed during sample preparation. Precision and accuracy were evaluated both within and between runs, with a maximum coefficient of variation (CV%) of 10.28 and a maximum relative error (ER%) of 5.38. Linearity was demonstrated over the range of 5 ng/L to 1000 ng/L, with a lower limit of quantification at 0.042 ng/L, made possible by injecting larger sample volumes. A matrix effect of 89% was considered acceptable when compared to standard solutions. Plasma concentrations of MTP were monitored in patients administered either 50 mg or 100 mg doses. For the 50 mg dose, plasma levels reached up to 34 μg/L, while the 100 mg dose produced concentrations ranging from 3.56 to 50.81 μg/L. Although the higher dose generally resulted in elevated plasma levels, significant variability was observed. A strong correlation (r = 0.992) was found between the administered dose and plasma concentration, though variations in absorption rates and patient demographics likely contributed to the observed variability. This method provides a reliable analytical approach suitable for pharmacokinetic and clinical studies involving metoprolol. Full article

Beta-blockers are first-line drugs in the treatment of chronic heart failure (CHF). However, there is no consensus on the specific effects of the beta-blockers of the I-III generation on energy metabolism in CHF. The aim of this study is to conduct a study of beta-blockers of different generations on myocardial energy metabolism in experimental CHF. CHF was modeled in white outbred rats by administering doxorubicin. The study drugs were administered intragastrically—new drug Hypertril (1-(β-phenylethyl)-4-amino-1,2,4-triazolium bromide)-3.5 mg/kg, Metoprolol—15 mg/kg, Nebivolol −10 mg/kg, Carvedilol 50 mg/kg, and Bisoprolol, 10 mg/kg. In the myocardium, the main indices of energy metabolism were determined—ATP, ADP, AMP, malate, lactate, pyruvate, succinate dehydrogenase (SDH) activity, and NAD-dependent malate dehydrogenase (NAD-MDH) activity. Traditional second-generation beta-blockers (Metoprolol and Bisoprolol) did not affect the studied indices of energy metabolism, and third-generation beta-blockers with additional properties—Carvedilol and, especially, Nebivalol and Hypertril—improved myocardial energy metabolism. The obtained results will help to expand our understanding of the effect of beta-blockers of various generations used to treat cardiovascular diseases on energy metabolism, and are also an experimental justification for the practical choice of these drugs in the complex therapy of CHF. Full article

Nowadays, it is a challenge for a bone scaffold to achieve controllable drug release and a porous structure at the same time. Herein, we fabricated hydroxyapatite/poly (butylene succinate)/metoprolol tartrate (HA/PBS/MPT) composites via melt blending, aiming to provide the option of an in situ pore-forming strategy. The introduction of HA not only significantly improved the hydrophilicity of the PBS matrix by reducing the hydrophilic contact angle by approximately 36% at a 10% content, but also damaged the integrity of the PBS crystal. Both were beneficial for the penetration of phosphate-buffered saline solution into matrix and the acceleration of MPT release. Accompanied with MPT release, porous structures were formed in situ, and the HA inside the matrix was exposed. With the increase in HA content, the MPT release rate accelerated and the pore size became larger. The in vitro cytocompatibility evaluation indicated that HA/PBS/MPT composites were conductive to the adhesion, growth, and proliferation of MC3T3-E1 cells due to the HA being exposed around the pores. Thus, the MPT release rate, pore size, and cell induction ability of the HA/PBS/MPT composites were flexibly and effectively adjusted by the composition at the same time. By introducing HA, we innovatively achieved the construction of porous structures during the drug release process, without the addition of pore-forming agents. This approach allows the drug delivery system to combine controllable drug release and biocompatibility effectively, offering a novel method for bone repair material preparation. This work might provide a convenient and robust strategy for the fabrication of bone scaffolds with controllable drug release and porous structures. Full article

The utilized 3D printhead employs an innovative hot-melt extrusion (HME) design approach being fed by drug-loaded polymer granules and making filament strands obsolete. Oscillatory rheology is a key tool for understanding the behavior of a polymer melt in extrusion processes. In this study, small amplitude shear oscillatory (SAOS) rheology was applied to investigate formulations of model antihypertensive drug Metoprolol Succinate (MSN) in two carrier polymers for pharmaceutical three-dimensional printing (3DP). For a standardized printing process, the feeding polymers viscosity results were correlated to their printability and a better understanding of the 3DP extrudability of a pharmaceutical formulation was developed. It was found that the printing temperature is of fundamental importance, although it is limited by process parameters and the decomposition of the active pharmaceutical ingredients (API). Material characterization including differential scanning calorimetry (DSC) and thermogravimetric analyses (TGA) of the formulations were performed to evaluate component miscibility and ensure thermal durability. To assure the development of a printing process eligible for approval, all print runs were investigated for uniformity of mass and uniformity of dosage in accordance with the European Pharmacopoeia (Ph. Eur.). Full article

The development of extended-release dosage forms with adequate drug release is a challenge for pharmaceutical companies, mainly when the drug presents high solubility, as in Biopharmaceutics Classification System (BCS) class I. This study aimed to develop extended-release mini-tablets containing metoprolol succinate (MS), while integrating design of experiments (DOE) and physiologically based biopharmaceutics modeling (PBBM), to predict its absorption and to run virtual bioequivalence (VBE) studies in both fasted and fed states. Core mini-tablet formulations (F1, F2, and F3) were prepared by direct compression and coated using nine coating formulations planned using DOE, while varying the percentages of the controlled-release and the pore-forming polymers. The coated mini-tablets were submitted to a dissolution test; additional formulations were prepared that were optimized by simulating the dissolution profiles, and the best one was submitted to VBE studies using GastroPlus^® software. An optimized formulation (FO) containing a mixture of immediate and extended-release mini-tablets showed to be bioequivalent to the reference drug product containing MS when running VBE studies in both fasted and fed states. The integration of DOE and PBBM showed to be an interesting approach in the development of extended-release mini-tablet formulation containing MS, and can be used to rationalize the development of dosage forms. Full article

The development of new drugs that combine active ingredients for the treatment hypertension is critically essential owing to its offering advantages for both patients and manufacturers. In this study, for the first time, detailed development of a scalable process of film-coated bi-layer tablets containing sustained-release metoprolol succinate and immediate-release amlodipine besylate in a batch size of 10,000 tablets is reported. The processing parameters of the manufacturing process during dry mixing-, drying-, dry mixing- completion stages were systematically investigated, and the evaluation of the film-coated bi-layer tablet properties was well established. The optimal preparation conditions for metoprolol succinate layer were 6 min- dry mixing with a high-speed mixer (120 rpm and 1400 rpm), 30-min drying with a fluid bed dryer, and 5-min- mixing completion at 25 rpm. For the preparation of amlodipine besylate layer, the optimal dry-mixing time using a cube mixer (25 rpm) was found to be 5 min. The average weight of metoprolol succinate layers and bi-layer tablets were controlled at 240–260 mg and 384–416 mg, respectively. Shewhart R chart and $\overline{X}$ charts of all three sampling lots were satisfactory, confirming that the present scalable process was stable and successful. This study confirms that the manufacturing process is reproducible, robust; and it yields a consistent product that meets specifications. Full article

Independent individualization of multiple product attributes, such as dose and drug release, is a crucial overarching requirement of pharmaceutical products for individualized therapy as is the unified integration of individualized product design with the processes and production that drive patient access to such therapy. Individualization intrinsically demands a marked increase in the number of product variants to suit smaller, more stratified patient populations. One established design strategy to provide enhanced product variety is product modularization. Despite existing customized and/or modular product design concepts, multifunctional individualization in an integrated manner is still strikingly absent in pharma. Consequently, this study aims to demonstrate multifunctional individualization through a modular product design capable of providing an increased variety of release profiles independent of dose and dosage form size. To further exhibit that increased product variety is attainable even with a low degree of product modularity, the modular design was based upon a fixed target dosage form size of approximately 200 mm³ comprising two modules, approximately 100 mm³ each. Each module contained a melt-extruded and molded formulation of 40% w/w metoprolol succinate in a PEG1500 and Kollidon^® VA64 erodible hydrophilic matrix surrounded by polylactic acid and/or polyvinyl acetate as additional release rate-controlling polymers. Drug release testing confirmed the generation of predictable, combined drug release kinetics for dosage forms, independent of dose, based on a product’s constituent modules and enhanced product variety through a minimum of six dosage form release profiles from only three module variants. Based on these initial results, the potential of the reconfigurable modular product design concept is discussed for unified integration into a pharmaceutical mass customization/mass personalization context. Full article

The subject of our research is the optimization of direct compression (DC), controlled release drug matrices comprising chitosan/xanthan gum. The foregoing is considered from two main perspectives; the use of low molecular weight chitosan (LCS) with xanthan gum (XG) and the determination of important attributes for direct compression of the mixtures of the two polymers. Powder flow, deformation behaviour, and work of compression parameters were used to characterize powder and tableting properties. Compression pressure and LCS content within the matrix were investigated for their influence on the crushing strength of the tablets produced. Response surface methodology (RSM) was applied to determine the optimum parameters required for DC of the matrices investigated. Results confirm the positive contribution of LCS in enhancing powder compressibility and crushing strength of the resultant compacts. Compactibility of the XG/LCS mixtures was found to be more sensitive to applied compression pressure than LCS content. LCS can be added at concentrations as low as 15% w/w to achieve hard compacts, as indicated by the RSM results. The introduction of the plasticity factor, using LCS, to the fragmenting material XG was the main reason for the high volume reduction and reduced porosity of the polymer mixture. Combinations of XG with other commonly utilized polymers in controlled release studies such as glucosamine, hydroxypropyl methylcellulose (HPMC), Na alginate (ALG), guar gum, lactose and high molecular weight (HMW) chitosan were also used; all the foregoing polymers failed to reduce the matrix porosity beyond a certain compression pressure. Application of the LCS/XG mixture, at its optimum composition, for the controlled release of two model drugs (metoprolol succinate and dyphylline) was examined. The XG/LCS matrix at 15% w/w LCS content was found to control the release of metoprolol succinate and dyphylline. The former preparation confirmed the strong influence of compression pressure on changing the drug release profile. The latter preparation showed the ability of XG/LCS to extend the drug release at a fixed rate for 12 h of dissolution time after which the release became slightly slower. Full article

Phase-separated films of water-insoluble ethyl cellulose (EC) and water-soluble hydroxypropyl cellulose (HPC) can be utilized to tailor drug release from coated pellets. In the present study, the effects of HPC levels and the pH, type, ionic strength and osmolarity of the media on the release profiles of soluble metoprolol succinates from the EC/HPC-coated pellets were investigated, and the differences in drug-release kinetics in multiple media were further elucidated through the HPC leaching and swelling kinetics of the pellets, morphology (SEM) and water uptake of the free films and the interaction between the coating polymers and the media compositions. Interestingly, the drug release rate from the pellets in different media was not in agreement with the drug solubility which have a positive correlation with the drug dissolution rate based on Noyes–Whitney equation law. In particular, the drug release rate in acetate buffer at pH 4.5 was faster than that in other media despite the solubility of drug was relatively lower, regardless of the HPC levels. It may be attributed to the mutual effect between the EC and acetate buffer, which improved the permeability of the film. In contrast, the release of drug in HCl solution was dependent on the HPC levels. Increasing the levels of HPC increased the effects of hydrogen ions on the polymer of HPC, which resulted in a lower viscosity and strength of the gel, forming the larger size of pores in polymer films, thus increasing the drug diffused from the coating film. Further findings in phosphate buffer showed a reduction in the drug release compared to that in other media, which was only sensitive to the osmolarity rather than the HPC level and pH of the buffer. Additionally, a mathematical theory was used to better explain and understand the experimentally measured different drug release patterns. In summary, the study revealed that the effects of the media overcompensated that of the drug solubility to some extent for controlled-release of the coating polymers, and the drug release mechanism in multiple media depend on EC and HPC rather than on HPC alone, which may have a potential to facilitate the optimization of ideally film-coated formulations. Full article

This work is the continuation of a series of studies focused on establishing the relationship between the surface thermodynamic properties of polyelectrolyte matrix tablets and drug release mechanisms. In this case, two model drugs with different polarity features, such as carbamazepine (non-polar) and metoprolol succinate (polar) were used in combination with polymeric material hydroxypropyl-methyl cellulose (HPMC) and two polyelectrolytes derived from maleic anhydride corresponding to the sodium salts of poly(maleic acid-alt-ethylene) and poly(maleic acid-alt-octadecene) named PAM-0Na and PAM-18Na, respectively. The polymers were obtained and characterized as reported previously. Surface studies were performed by the sessile drop method, whilst the surface free energy was determined through Owens, Wendt, Rable and Kaeble (OWRK) semi-empirical model. By contrast, the drug release studies were performed by in vitro dissolution tests, where data were analyzed through dissolution efficiency. The results showed that, depending on the drug polarity, type and polymer proportion, surface properties and drug release processes are significantly affected. Full article

The solubilities of metoprolol succinate (a cardioselective β1 adrenergic receptor) in methanol, ethanol, n-propanol, isopropanol, n-butanol, ethyl acetate, and acetone were measured at temperatures ranging from (278.2 to 318.2) K using a solid–liquid equilibrium method. The solubility of metoprolol succinate increases with increasing temperature. At a fixed temperature, the solubility decreases in the order methanol > ethanol > n-butanol > n-propanol > isopropanol > acetone > ethyl acetate. The enthalpy of fusion and the melting point of metoprolol succinate were determined by differential scanning calorimetry. The thermodynamic properties of the dissolution process, determined by a van’t Hoff analysis, have been obtained and are discussed. The modified Apelblat equation, Wilson model, and non-random two-liquid (NRTL) model were employed to correlate the solubilities of metoprolol succinate in different solvents. Finally, a quantitative structure–property relationship (QSPR) study of physical properties of solvents and density functional theory simulations of hydrogen-bonding structure were carried out to give the explanation for the sequence of solubility in alcohols. The density functional theory (DFT) calculations well illustrated that the solubility of metoprolol succinate in various alcohols can be mainly attributed to the intra- and intermolecular hydrogen bonds in metoprolol succinate-solvent complexes. Full article

Background and objective: Heart rate (HR) ≥70 beats per minute (bpm) increases cardiovascular risk in coronary artery disease (CAD) patients. The objective of the analysis is to characterize HR as well as other clinical parameters in outpatients with stable CAD in Latvia.
Materials and methods: CLARIFY is an ongoing international registry of outpatients with established CAD. Latvian data regarding 120 patients enrolled in CLARIFY and collected at baseline visit during 2009–2010 were analyzed.
Results: The mean HR was 67.7 ± 9.5 and 66.9 ± 10.7 bpm when measured by pulse palpation and electrocardiography, respectively. HR ≤60 bpm and ≥70 bpm was observed in 25% and 35.8% of patients, respectively. When analyzing patients with angina symptoms, 22.8% had HR ≤60 bpm while HR ≥70 bpm was observed in 33.3% of the cases. HR ≥70 bpm was observed in 36.2% of patients with symptoms of chronic heart failure. Beta-blockers were used in 81.7% of the patients. Metoprolol (long acting succinate), bisoprolol, nebivolol and carvedilol in average daily doses 63.8, 5.3, 4.5, and 10.4 mg/d were used in 47, 37, 11 and 3 cases, respectively. Among patients with HR ≥70 bpm 79.1% were using beta-blockers. Medications did not differ significantly between the three groups according to HR level (≤60, 61–69 and ≥70 bpm).
Conclusions: Despite the wide use of beta-blockers, HR is insufficiently controlled in the analyzed sample of stable CAD patients in Latvia. Target HR ≤60 bpm is achieved only in 25% of the patients while more than one third have increased HR ≥70 bpm. Full article