Nowadays, most of the newly developed active pharmaceutical ingredients (APIs) consist of cohesive particles with a mean particle size of <100μm, a wide particle size distribution (PSD) and a tendency to agglomerate, therefore they are difficult to handle in continuous manufacturing (CM) lines. The current paper focuses on the impact of various glidants on the bulk properties of difficult-to-handle APIs. Three challenging powders were included: two extremely cohesive APIs (acetaminophen micronized (APAPμ) and metoprolol tartrate (MPT)) which previously have shown processing issues during different stages of the continuous direct compression (CDC)-line and a spray dried placebo (SD) powder containing hydroxypropylmethyl cellulose (HPMC), known for its sub-optimal flow with a high specific surface area (SSA) and low density. Four flow-enhancing excipients were used: a hydrophilic (Aerosil® 200) and hydrophobic (Aerosil® R972) fumed silica grade, a mesoporous silica grade (Syloid® 244FP), and a calcium phosphate excipient (TRI-CAFOS® 200-7). The APIs and binary API/glidant blends (varied between 0.5-2.75 w/w%) were characterized for their bulk properties relevant for CDC. The results indicated that optimizing different bulk parameters (e.g., density, flow, compressibility..) of an API required varying weight percentages of the glidant (e.g., different surface area coverage (SAC)) depending on the APIs. Moreover, even at similar SAC, the impact of the glidant on the bulk characteristic of the APIs depended on the glidant type properties. While nano-sized silicon dioxide were effective for improving the flowability of a powder, other glidants (mesoporous silica and tricalcium phosphate (TCP)) showed also promise as alternatives. Additionally, an excess of glidant, referred to as oversilication, negatively impacted some bulk parameters, but other characteristics were unaffected. Finally, to determine the appropriate concentration of the different classes of glidants, SAC calculations, an understanding of the glidant's working mechanism, and knowledge about the API's characteristics (i.e., morphology, compressibility, flowability, aeration, density, and wall friction) are required. This study confirmed the necessity of including various material characterization techniques to assess the impact of glidants on the bulk characteristics of APIs.

• Klíčová slova
• Continuous manufacturing, Flow enhancers, Glidant, Material characterization, Rheological properties,
• MeSH
• deriváty hypromelózy * chemie   MeSH
• farmaceutická chemie metody   MeSH
• fosforečnany vápenaté * chemie   MeSH
• hydrofobní a hydrofilní interakce MeSH
• metoprolol * chemie   MeSH
• nerozplněné léky MeSH
• oxid křemičitý chemie   MeSH
• paracetamol * chemie   MeSH
• pomocné látky * chemie   MeSH
• prášky, zásypy, pudry * MeSH
• příprava léků metody   MeSH
• reologie * MeSH
• velikost částic * MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• calcium phosphate MeSH Prohlížeč
• deriváty hypromelózy * MeSH
• fosforečnany vápenaté * MeSH
• metoprolol * MeSH
• nerozplněné léky MeSH
• oxid křemičitý MeSH
• paracetamol * MeSH
• pomocné látky * MeSH
• prášky, zásypy, pudry * MeSH

BACKGROUND: The cardioselective β-1 receptor antagonist metoprolol is used to treat heart failure. It is metabolized in the liver, primarily by cytochrome 2D6. RESEARCH DESIGN AND METHODS: In this study, trough serum concentrations of metoprolol and its metabolite α-hydroxymetoprolol were measured in patients with heart failure with reduced ejection fraction. RESULTS: Concentrations were 1.3-122.9 µg/L for metoprolol and 1.3-125.7 µg/L for α-hydroxymetoprolol, metabolic ratios were 0.11-98.32. The median weight-adjusted apparent clearance of metoprolol was 53.07 (range 3.24-500.0). Metoprolol and α-hydroxymetoprolol concentrations correlated with both daily dose and dose per kilogram of body weight. However, metoprolol concentrations at the same daily dose showed a wide variability. Patients taking 100 mg/day had significantly lower NT-proBNP values than those taking 25 or 50 mg/day. Patients with LVEF ≤ 35% versus > 35% used significantly lower daily doses and doses per kilogram of body weight, although metoprolol concentrations did not differ. A poor cytochrome 2D6 metabolizer phenotype was detected in two patients. CONCLUSIONS: Metoprolol concentrations showed a wide interindividual variability at the same daily dose. Simultaneous determination of metoprolol and α-hydroxymetoprolol concentrations could identify patients at risk of possible accumulation of metoprolol leading to intoxication or, conversely, patients at risk of underdosing. [Figure: see text].

• Klíčová slova
• concentrations, heart failure, metoprolol, variability, α-hydroxymetoprolol,
• MeSH
• antagonisté beta-1-adrenergních receptorů * aplikace a dávkování   MeSH
• cytochrom P-450 CYP2D6 metabolismus   MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• metoprolol * aplikace a dávkování   farmakokinetika   analogy a deriváty   farmakologie   MeSH
• natriuretický peptid typu B * krev   MeSH
• peptidové fragmenty krev   MeSH
• pilotní projekty MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• srdeční selhání * farmakoterapie   patofyziologie   MeSH
• tepový objem * účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva * MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• alpha-hydroxymetoprolol MeSH Prohlížeč
• antagonisté beta-1-adrenergních receptorů * MeSH
• cytochrom P-450 CYP2D6 MeSH
• metoprolol * MeSH
• natriuretický peptid typu B * MeSH
• peptidové fragmenty MeSH
• pro-brain natriuretic peptide (1-76) MeSH Prohlížeč

The incidence of diseases of affluence, such as diabetes mellitus, cardiovascular diseases, high blood pressure, and high cholesterol has been reported to rise. Consequently, the concentrations of residues of drugs designed to treat these diseases have been rising in water bodies. Moreover, the toxicity of these pharmaceuticals towards fish and other non-target organisms can be even enhanced by microplastic particles that are reportedly present in surface water. Therefore, the aim of this study was to describe the effects of three highly prescribed drugs, in particular metoprolol, enalapril, and metformin on fish early-life stages. Also, it was hypothesized that polystyrene microparticles will increase the toxicity of metoprolol to fish early-life stages. Embryonal acute toxicity tests on Danio rerio and Cyprinus carpio were carried out in order to describe the possible toxic effects of metoprolol, enalapril, and metformin. Also, the acute toxicity of polystyrene microparticles and the combination of metoprolol with polystyrene microparticles were tested on D. rerio embryos. Additionally, a 31-day long embryo-larval subchronic toxicity test was carried out with C. carpio in order to describe the long-term effects of low concentrations of metoprolol. The results of the study show that both metoprolol and enalapril have the potential to disrupt the early development of the heart in the embryonal stages of fish. Also, enalapril and metformin together with polystyrene microparticles seem to possibly disrupt the reproduction cycle and act as endocrine disruptors. Both pure polystyrene microparticles and the combination of them with metoprolol affect inflammatory processes in organisms. Additionally, metformin alters several metabolism pathways in fish early-life stages. The results of the study bring new evidence that even low, environmentally-relevant concentrations of pharmaceuticals have the potential to disrupt the early development of fish, particularly on a molecular level.

• Klíčová slova
• Cyprinus carpio, Danio rerio, Enalapril, Metformin, Metoprolol,
• MeSH
• chemické látky znečišťující vodu * toxicita   MeSH
• dánio pruhované MeSH
• enalapril MeSH
• kapři * MeSH
• léčivé přípravky MeSH
• metformin * toxicita   MeSH
• metoprolol MeSH
• mikroplasty MeSH
• plastické hmoty MeSH
• polystyreny toxicita   MeSH
• voda MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• chemické látky znečišťující vodu * MeSH
• enalapril MeSH
• léčivé přípravky MeSH
• metformin * MeSH
• metoprolol MeSH
• mikroplasty MeSH
• plastické hmoty MeSH
• polystyreny MeSH
• voda MeSH

Emerging contaminants and their pervasive presence in freshwater ecosystems have been widely documented, but less is known about their prevalence and the harm they cause in marine ecosystems, particularly in developing countries. This study provides data on the prevalence and risk posed by microplastics, plasticisers, pharmaceuticals and personal care products (PPCPs), and heavy metal(loid)s (HMs) along the Maharashtra coast of India. The sediment and coastal water samples were collected from 17 sampling stations, processed, and subjected to FTIR-ATR, ICP-MS, SEM-EDX, LC-MS/MS, and GC-MS for further analysis. Higher MPs abundance, combined with the pollution load index, indicates that the northern zone is a high-impact zone with pollution concerns. Plasticisers in extracted MPs and HMs adsorption on MPs surface from surrounding waters reveal their roles as a source and vector for contaminants, respectively. The mean concentration of metoprolol (53.7-306 ng L-1), tramadol (16.6-198 ng L-1), venlafaxine (24.6-234 ng L-1), and triclosan (211-433 ng L-1) in Maharashtra's coastal waters were several folds higher than in other water systems, raising major health concerns. The hazard quotient (HQ) scores revealed that >70 % of study sites pose a high to medium (1 > HQ > 0.1) ecological risk to fish, crustaceans and algae, indicating serious concern. Fish and crustaceans (35.3 % each) show a higher level of risk than algae (29.5 %). Metoprolol and venlafaxine could represent greater ecological risks than tramadol. Similarly, HQ suggests that bisphenol A has larger ecological risks than bisphenol S along the Maharashtra coast. To the best of our knowledge, this is the first in-depth investigation into emerging pollutants in Indian coastal regions. This information is crucial for better policy formulation and coastal management in India in general, and Maharashtra in particular.

• Klíčová slova
• Coastal conservation, Ecotoxicology, Heavy metals, Impact zones, Phthalates,
• MeSH
• chemické látky znečišťující vodu * analýza   MeSH
• chromatografie kapalinová MeSH
• ekosystém MeSH
• geologické sedimenty MeSH
• hodnocení rizik MeSH
• kosmetické přípravky * analýza   MeSH
• léčivé přípravky MeSH
• metoprolol MeSH
• mikroplasty analýza   MeSH
• monitorování životního prostředí MeSH
• plastické hmoty analýza   MeSH
• tandemová hmotnostní spektrometrie MeSH
• těžké kovy * analýza   MeSH
• tramadol * MeSH
• venlafaxin hydrochlorid MeSH
• voda analýza   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Indie MeSH
• Názvy látek
• chemické látky znečišťující vodu * MeSH
• kosmetické přípravky * MeSH
• léčivé přípravky MeSH
• metoprolol MeSH
• mikroplasty MeSH
• plastické hmoty MeSH
• těžké kovy * MeSH
• tramadol * MeSH
• venlafaxin hydrochlorid MeSH
• voda MeSH

AIMS: Sub-analysis of a retrospective nation-wide observational analysis of heart failure (HF) epidemiology reported to the Czech National Registry of Reimbursed Health Services between 2012 and 2018 aimed at beta-blockers (BBs) utilization. METHODS AND RESULTS: The beta-blockers were generally used in 81.8% of all patients treated for HF in 2012 (n=52 140); 81.8% in 2013 (n=53 058); 83.1% in 2014 (n=56 221); 82.1% in 2015 (n=57 421); 83.3% in 2016 (n=59 187); 82.2% in 2017 (60 058) and in 81.4% in 2018 (n=60 966). In 2018, the majority of patients treated for HF were prescribed metoprolol (22 974; 30.7%) and bisoprolol (21 001; 28%). Carvedilol was prescribed in 7 331 patients treated for HF (9.8%), nebivolol in 5 392 HF patients. Despite its primary indication, betaxolol was used in 2 341 patients treated for HF (3.1%). All other beta-blockers were used in less than 1% of HF patients. In some of the mostly used BBs, their prescription in patients treated for HF changed in the last years (metoprolol 32.4% in 2012, 30.7% in 2018; bisoprolol 20.3% in 2012, 28% in 2018; carvedilol 18.3% in 2012, 9.8% in 2018; nebivolol 2.5% in 2012, 7.2% in 2018; betaxolol 4.2% in 2012, 3.1% in 2018). CONCLUSION: In an analysis of beta-blockers utilization in all patients treated for heart failure in the given year in the whole country, we have found only slightly lower amount of drug prescription in comparison with specific heart failure registries. This indicates a good translation of current standard of care into common clinical practice. Metoprolol remained the mostly prescribed drug. The prescription of bisoprolol and nebivolol has increased at the expense of carvedilol.

• Klíčová slova
• beta-blockers, heart failure, treatment,
• MeSH
• beta blokátory * terapeutické užití   MeSH
• betaxolol MeSH
• bisoprolol MeSH
• karbazoly MeSH
• karvedilol MeSH
• lidé MeSH
• metoprolol MeSH
• nebivolol MeSH
• propanolaminy * MeSH
• retrospektivní studie MeSH
• srdeční selhání * farmakoterapie   epidemiologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika epidemiologie   MeSH
• Názvy látek
• beta blokátory * MeSH
• betaxolol MeSH
• bisoprolol MeSH
• karbazoly MeSH
• karvedilol MeSH
• metoprolol MeSH
• nebivolol MeSH
• propanolaminy * MeSH

Water from wastewater treatment plants contains concentrations of pharmaceutically active compounds as high as micrograms per liter, which can adversely affect fish health and behavior, and contaminate the food chain. Here, we tested the ability of the common carp hepatic S9 fraction to produce the main metabolites from citalopram, metoprolol, sertraline, and venlafaxine. Metabolism in fish S9 fractions was compared to that in sheep. The metabolism of citalopram was further studied in fish. Our results suggest a large difference in the rate of metabolites formation between fish and sheep. Fish hepatic S9 fractions do not show an ability to form metabolites from venlafaxine, which was also the case for sheep. Citalopram, metoprolol, and sertraline were metabolized by both fish and sheep S9. Citalopram showed concentration-dependent N-desmethylcitalopram formation with Vmax = 1781 pmol/min/mg and Km = 29.7 μM. The presence of ellipticine, a specific CYP1A inhibitor, in the incubations reduced the formation of N-desmethylcitalopram by 30-100% depending on the applied concentration. These findings suggest that CYP1A is the major enzyme contributing to the formation of N-desmethylcitalopram. In summary, the results from the present in vitro study suggest that common carp can form the major metabolites of citalopram, metoprolol, and sertraline.

• Klíčová slova
• citalopram, cytochrome P450, environmental toxicology, metabolite formation, metoprolol, sertraline, venlafaxine,
• MeSH
• citalopram metabolismus   MeSH
• cytochrom P-450 CYP1A1 metabolismus   MeSH
• jaterní mikrozomy metabolismus   MeSH
• kapři MeSH
• léčivé přípravky metabolismus   MeSH
• metoprolol metabolismus   MeSH
• ovce MeSH
• sertralin metabolismus   MeSH
• techniky in vitro MeSH
• venlafaxin hydrochlorid metabolismus   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• citalopram MeSH
• cytochrom P-450 CYP1A1 MeSH
• léčivé přípravky MeSH
• metoprolol MeSH
• sertralin MeSH
• venlafaxin hydrochlorid MeSH

Beta-blockers are chiral compounds with enantiomers that have different bioactivity, which means that while one is active, the other can be inactive or even harmful. Due to their high consumption and incomplete degradation in waste water, they may reach surface waters and affect aquatic organisms. To address this issue we developed a chromatographic method suitable for determining beta-blocker enantiomers in surface waters. It was tested on five beta-blockers (acebutolol, atenolol, bisoprolol, labetalol and metoprolol) and validated on bisoprolol enantiomers. Good enantioseparation of all analysed beta-blockers was achieved on the Chirobiotic V column with the mobile phase composed of methanol/acetic acid/triethylamine (100/0.20/0.15 v/v/v) at a flow rate of 0.5 mL/min and column temperature of 45 °C. Method proved to be linear in the concentration range from 0.075 µg/mL to 5 µg/mL, and showed good recovery. The limits of bisoprolol enantiomer detection were 0.025 µg/mL and 0.026 µg/mL and of quantification 0.075 µg/mL and 0.075 µg/mL. Despite its limitations, it seems to be a promising method for bisoprolol enantiomer analysis in surface water samples. Further research could focus on waste water analysis, where enantiomer concentrations may be high. Furthermore, transferring the method to a more sensitive one such as liquid chromatography coupled with tandem mass spectrometry and using ammonium acetate as the mobile phase additive instead of acetic acid and triethylamine would perhaps yield much lower limits of detection and quantification.

Beta-blokatori su kiralni spojevi s enantiomerima različite bioaktivnosti, dakle, dok je jedan enantiomer aktivan, drugi može biti neaktivan ili čak štetan za organizam. Zbog njihove visoke potrošnje i nepotpune razgradnje u pogonima za preradu otpadnih voda, postoji mogućnost da se pojave u prirodnim vodama i negativno utječu na vodene organizme. Stoga je u ovom radu razvijena kromatografska metoda za određivanje enantiomera beta-blokatora u prirodnim vodama. Metoda je testirana na pet beta-blokatora (acebutolol, atenolol, bisoprolol, labetalol i metoprolol) te validirana za enantiomere bisoprolola. Dobra enantioseparacija svih analiziranih beta-blokatora postignuta je na koloni Chirobiotic V sastava mobilne faze metanol/octena kiselina/trietilamin (100:0,2:0,15 v/v/v) pri protoku od 0,5 mL/min i temperaturi od 45 °C. Metodom je postignuta dobra linearnost u području od 0,075 μg/mL do 5 μg/mL s dobrim analitičkim povratom. Granice detekcije pojedinih enantiomera bisoprolola bile su 0,025 μg/mL i 0,026 μg/mL, a granice kvantifikacije 0,075 μg/ mL za oba enantiomera. Unatoč ograničenjima metode, pokazala se kao obećavajuća metoda analize enantiomera bisoprolola u površinskim vodama. Daljnja istraživanja mogla bi se izvoditi na otpadnim vodama, gdje bi koncentracije enantiomera mogle biti više. Također, korištenjem osjetljivije metode, primjerice vezanoga sustava tekućinske kromatografije i tandemne spektrometrije masa, te korištenjem amonijeva acetata kao aditiva mobilnoj fazi umjesto octene kiseline i trietilamina, mogle bi se postići znatno niže granice detekcije i kvantifikacije.

• Klíčová slova
• Chirobiotic V column, Croatia, Czech Republic, HPLC, acebutolol, atenolol, enantioseparation, labetalol, metoprolol, water analysis,
• MeSH
• acebutolol analýza   MeSH
• atenolol analýza   MeSH
• beta blokátory analýza   MeSH
• bisoprolol analýza   MeSH
• labetalol analýza   MeSH
• metoprolol analýza   MeSH
• voda chemie   MeSH
• vysokoúčinná kapalinová chromatografie metody   MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• acebutolol MeSH
• atenolol MeSH
• beta blokátory MeSH
• bisoprolol MeSH
• labetalol MeSH
• metoprolol MeSH
• voda MeSH

BACKGROUND: Beta-blockers are one of the most important classes of cardiovascular agents and have been considered a cornerstone therapy in heart diseases, such as heart failure (HF) and atrial fibrillation (AF). Among different beta-blockers, metoprolol is a selective beta1-adrenergic antagonist, which has been extensively used since the 1970s. AREAS OF UNCERTAINTY: Although current guidelines include recommendations for the use of controlled-release metoprolol succinate in specific HF and AF indications, and despite extensive clinical experience with metoprolol, comparative evidence on the use of metoprolol succinate compared with other beta-blockers in these indications is limited. DATA SOURCES: We systematically reviewed the data from head-to-head studies directly comparing this compound with other beta-blockers in the treatment of HF or AF. Only clinical trials and observational studies were considered; no other limits were applied. The quality and relevance of retrieved articles were reviewed. RESULTS: A total of 18 articles of the 353 articles identified were selected for inclusion; 12 HF articles and 6 for AF. Additional references were identified from the bibliographies of retrieved articles. The studies show that oral prophylaxis with an appropriate dose of metoprolol may reduce new incidents of AF in high-risk patients. Furthermore, metoprolol succinate is associated with significant mortality and morbidity benefits in the treatment of HF. CONCLUSIONS: Despite the introduction of newer beta-blockers with differing clinical characteristics since its introduction, metoprolol succinate remains a useful drug in both HF and AF.

• MeSH
• alfa-1-adrenergní receptory - antagonisté terapeutické užití   MeSH
• beta blokátory terapeutické užití   MeSH
• fibrilace síní farmakoterapie   MeSH
• lidé MeSH
• metoprolol terapeutické užití   MeSH
• srdeční selhání farmakoterapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• systematický přehled MeSH
• Názvy látek
• alfa-1-adrenergní receptory - antagonisté MeSH
• beta blokátory MeSH
• metoprolol MeSH

• MeSH
• antagonisté beta-1-adrenergních receptorů terapeutické užití   MeSH
• časové faktory MeSH
• kardiovaskulární rehabilitace metody   MeSH
• lidé středního věku MeSH
• lidé MeSH
• metoprolol terapeutické užití   MeSH
• nemoci srdce diagnóza   patofyziologie   rehabilitace   MeSH
• prediktivní hodnota testů MeSH
• reprodukovatelnost výsledků MeSH
• senioři MeSH
• srdeční frekvence účinky léků   MeSH
• terapie cvičením * MeSH
• zátěžový test * MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• dopisy MeSH
• Názvy látek
• antagonisté beta-1-adrenergních receptorů MeSH
• metoprolol MeSH

• MeSH
• amiodaron * MeSH
• lidé MeSH
• metoprolol MeSH
• propafenon MeSH
• septický šok * MeSH
• srdeční arytmie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• dopisy MeSH
• komentáře MeSH
• práce podpořená grantem MeSH
• Názvy látek
• amiodaron * MeSH
• metoprolol MeSH
• propafenon MeSH