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].

• MeSH
• Adrenergic beta-1 Receptor Antagonists * administration & dosage   MeSH
• Cytochrome P-450 CYP2D6 metabolism   MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Metoprolol * administration & dosage   pharmacokinetics   analogs & derivatives   pharmacology   MeSH
• Natriuretic Peptide, Brain * blood   MeSH
• Peptide Fragments blood   MeSH
• Pilot Projects MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Heart Failure * drug therapy   physiopathology   MeSH
• Stroke Volume * drug effects   MeSH
• Dose-Response Relationship, Drug * MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

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.

• MeSH
• Hypromellose Derivatives * chemistry   MeSH
• Chemistry, Pharmaceutical methods   MeSH
• Calcium Phosphates * chemistry   MeSH
• Hydrophobic and Hydrophilic Interactions MeSH
• Metoprolol * chemistry   MeSH
• Bulk Drugs MeSH
• Silicon Dioxide chemistry   MeSH
• Acetaminophen * chemistry   MeSH
• Excipients * chemistry   MeSH
• Powders * MeSH
• Drug Compounding methods   MeSH
• Rheology * MeSH
• Particle Size * MeSH
• Publication type
• Journal Article MeSH

Free radical polymerization technique was used to formulate Poloxamer-188 based hydrogels for controlled delivery. A total of seven formulations were formulated with varying concentrations of polymer, monomer ad cross linker. In order to assess the structural properties of the formulated hydrogels, Fourier Transform Infrared Spectroscopy (FTIR), Thermogravimetric analysis (TGA), Differential Scanning Calorimetry (DSC), Scanning electron microscopy (SEM), and X-ray diffraction (XRD) were carried out. To assess the effect of pH on the release of the drug from the polymeric system, drug release studies were carried in pH 1.2 and 7.4 and it was found that release of the drug was significant in pH 7.4 as compared to that of pH 1.2 which confirmed the pH responsiveness of the system. Different kinetic models were also applied to the drug release to evaluate the mechanism of the drug release from the system. To determine the safety and biocompatibility of the system, toxicity study was also carried out for which healthy rabbits were selected and formulated hydrogels were orally administered to the rabbits. The results obtained suggested that the formulated poloxamer-188 hydrogels are biocompatible with biological system and have the potential to serve as controlled drug delivery vehicles.

• MeSH
• Acrylic Resins * chemistry   MeSH
• Calorimetry, Differential Scanning MeSH
• X-Ray Diffraction MeSH
• Hydrogels * chemistry   MeSH
• Hydrogen-Ion Concentration MeSH
• Rabbits MeSH
• Drug Delivery Systems MeSH
• Delayed-Action Preparations chemistry   pharmacokinetics   MeSH
• Microscopy, Electron, Scanning MeSH
• Drug Carriers chemistry   MeSH
• Poloxamer * chemistry   MeSH
• Spectroscopy, Fourier Transform Infrared MeSH
• Thermogravimetry MeSH
• Timolol * administration & dosage   pharmacokinetics   chemistry   MeSH
• Drug Liberation MeSH
• Animals MeSH
• Check Tag
• Rabbits MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Spektrum cievnych anomálií s rôznym biologickým správaním je veľmi široké. Vaskulárne anomálie sa rozdeľujú na vaskulárne malformácie a vaskulárne nádory – hemangiómy. Hoci mnohé z nich vyzerajú podobne, ich klinická manifestácia je rozmanitá – od nezávažného samolimitujúceho priebehu po život ohrozujúce komplikácie vyžadujúce intenzívny multidisciplinárny terapeutický prístup. Nezriedka sa aj v odbornej praxi všetky cievne anomálie nesprávne nazývajú hemangiómy. Je veľmi dôležité správne klasifikovať a pomenovať cievnu anomáliu, aby sme mohli zvoliť správnu liečbu a zabrániť vzniku závažných komplikácií. Z vaskulárnych nádorov sa u detí najčastejšie vyskytuje infantilný hemangióm (IH). Je to lézia s úplne typickým biologickým správaním a na jej odlíšenie od iných cievnych anomálií zvyčajne stačí dobre odobratá anamnéza. Iba malá časť IH predstavuje pre dieťa riziko a vyžaduje systémovú alebo kombinovanú multimodálnu liečbu. Vaskulárne malformácie predstavujú heterogénnu skupinu zvyčajne vývinových odchýlok cievneho systému a môžu postihovať ktorýkoľvek typ ciev. Často ide o zmiešané cievne lézie. Symptomatické vaskulárne malformácie sú u detí zriedkavé a mnohokrát predstavujú pre lekárov diagnosticko-terapeutickú výzvu. Prinášame kazuistiku nesyndrómového pacienta, u ktorého sa vyskytli dve zriedkavé symptomatické cievne anomálie vyžadujúce multiodborovú starostlivosť. Korešpondenčná autorka: MUDr. Michaela Murgašová Klinika detí a dorastu JLF UK a UNM Kollárova 2 036 01 Martin Slovenská republika murgasovam@zoznam.sk

The spectrum of vascular anomalies with different biological behavior is very wide. They are divided into vascular malformations and vascular tumors – hemangiomas. Although many of them look similar, their clinical manifestation is different – from a mild self-limiting course to life-threatening complications requiring an intensive multidisciplinary therapeutic approach. Frequently, even in professional practice, all vascular anomalies are incorrectly called hemangiomas. It is very important to classify and name the vascular anomaly correctly so that we can choose the right treatment and prevent serious complications. Infantile hemangioma (IH) is the most common vascular tumor in children. It is a lesion with a completely typical biological behavior and a well-taken history is usually sufficient to distinguish it from other vascular anomalies. Only a small part of IH represents a risk to the child and requires systemic or combined multimodal treatment. Vascular malformations represent a heterogeneous group of usually developmental abnormalities of the vascular system and can affect any type of vessels. These are often mixed vascular lesions. Symptomatic vascular malformations are rare in children and often are diagnostic and therapeutic challenge for doctors. We present a case report of a non-syndromic patient with two rare symptomatic vascular anomalies requiring multidisciplinary care.

• MeSH
• Vascular Malformations diagnosis   classification   MeSH
• Child MeSH
• Endovascular Procedures classification   methods   MeSH
• Hemangioma, Capillary * diagnostic imaging   diagnosis   MeSH
• Carotid-Cavernous Sinus Fistula * diagnostic imaging   diagnosis   classification   complications   MeSH
• Infant MeSH
• Humans MeSH
• Magnetic Resonance Angiography methods   MeSH
• Metoprolol pharmacology   therapeutic use   MeSH
• Infant, Newborn MeSH
• Prednisone pharmacology   therapeutic use   MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Male MeSH
• Infant, Newborn MeSH
• Publication type
• Case Reports MeSH

Portosinusoidální vaskulární choroba (PSVD) je málo rozpoznávané onemocnění jater podmíněné postižením malých cév. Diagnóza je definována souborem klinických a/nebo histopatologických kritérií, absolutní podmínkou je vyloučení cirhózy jater biopsií. Klinicky se PSVD obvykle manifestuje komplikací portální hypertenze, ta ale nemusí byt vyjádřena u všech nemocných. V článku popisujeme případ 71letého pacienta se známou, hematologicky nevysvětlenou a dále neprošetřenou splenomegalií, který byl vyšetřen pro těžkou symptomatickou mikrocytární anemii, pravděpodobně sekundární k portální hypertenzi, byť bez deklarovaných krvácivých projevů. Za hospitalizace byla provedena ligace velkých rizikových varixů jícnu, jiný zdroj anemizace prokázán nebyl. U pacienta byla vyloučena pre- nebo posthepatální etiologie portální hypertenze, elastografie jater byla ve fyziologických hodnotách, jaterní testy byly vyjma marginální izolované elevace gama-glutamyltransferázy v normě, funkce jater byla intaktní. V jaterní biopsii byl nález kompatibilní s diagnózou PSVD. U pacienta nebylo rozpoznáno žádné z asociovaných onemocnění, rovněž neužíval rizikovou medikaci, léčba tudíž spočívala pouze v řešení komplikací portální hypertenze, ambulantně byla dokončena eradikace jícnových varixů. Při terapii perorálním preparátem železa došlo k normalizaci hemoglobinu, fyziologické hodnoty přetrvávají i měsíce po ukončení substituční léčby, jaterní funkce je nadále v normě.

Portosinusoidal vascular disease (PSVD) is a rarely recognized liver condition caused by the involvement of small hepatic vessels. The diagnosis is established based on a set of clinical and/or histopathological criteria, with the absolute requirement of excluding liver cirrhosis through biopsy. Clinically, PSVD often presents with complications related to portal hypertension, although not all patients exhibit these signs. This article discusses the case of a 71-year-old patient with known splenomegaly, which had not been fully investigated and lacked a hematological explanation. The patient was evaluated for severe symptomatic microcytic anemia, likely secondary to portal hypertension, despite the absence of overt bleeding symptoms. During hospitalization, ligation of large, high-risk esophageal varices was performed, and no other sources of anemia were identified. Pre- or post-hepatic causes of portal hypertension were ruled out. Liver elastography results were within normal ranges, and liver function tests were normal except for a marginal isolated elevation of gamma-glutamyltransferase. Liver function remained intact. Liver biopsy findings were consistent with a diagnosis of PSVD. The patient did not have any identifiable associated conditions and was not taking any medications known to pose a risk. Therefore, treatment was focused solely on managing the complications of portal hypertension. Outpatient follow-up included the eradication of esophageal varices. Treatment with oral iron supplements led to the normalization of hemoglobin levels, which remained stable for months after the discontinuation of therapy, and liver function tests continued to be normal.

• MeSH
• Antihypertensive Agents therapeutic use   MeSH
• Anemia, Hypochromic diagnosis   drug therapy   MeSH
• Hepatic Veno-Occlusive Disease * diagnosis   therapy   MeSH
• Carvedilol therapeutic use   MeSH
• Humans MeSH
• Hypertension, Portal * diagnosis   drug therapy   MeSH
• Aged MeSH
• Splenomegaly MeSH
• Iron therapeutic use   MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Aged MeSH
• Publication type
• Case Reports MeSH

Hypertenzní nemoc patří mezi nejdůležitější kardiovaskulární rizikové faktory a je těsně spjata se zvýšenou kardiovaskulární morbiditou a mortalitou. Článek pojednává o použití fixní kombinační léčby amlodipinem a bisoprololem v klinické praxi. Tato kombinace vede k úspěšnému dosahování cílových hodnot krevního tlaku a zároveň zlepšuje adherenci pacientů k léčbě. V článku jsou zároveň zohledněny vhodné indikace, u kterých je preparát s výhodou možno použít.

Hypertension is one of the most important cardiovascular risk factors and is closely associated with increased cardiovascular morbidity and mortality. This article discusses the use of fixed combination therapy with amlodipine and bisoprolol in clinical practice. This combination leads to successful achievement of target blood pressure values and also improves patient adherence to treatment. The article also considers suitable indications for which it is preferable to use this drug.

• MeSH
• Medication Adherence MeSH
• Amlodipine * administration & dosage   MeSH
• Bisoprolol * administration & dosage   MeSH
• Adult MeSH
• Drug Combinations MeSH
• Hypertension drug therapy   MeSH
• Blood Pressure MeSH
• Humans MeSH
• Heart Rate MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Female MeSH
• Publication type
• Case Reports MeSH
• Review MeSH

UNLABELLED: PURPOSE : To compare the efficacy and safety of the fixed-dose combination (FDC) of netarsudil 0.02%/latanoprost 0.005% ophthalmic solution (NET/LAT; Roclanda®) with bimatoprost 0.03%/timolol maleate 0.5% (BIM/TIM; Ganfort®) ophthalmic solution in the treatment of open-angle glaucoma (OAG) and ocular hypertension (OHT). METHODS: MERCURY-3 was a 6-month prospective, double-masked, randomized, multicenter, active-controlled, parallel-group, non-inferiority study. Patients (≥ 18 years) with a diagnosis of OAG or OHT in both eyes that was insufficiently controlled with topical medication (IOP ≥ 17 mmHg in ≥ 1 eye and < 28 mmHg in both eyes) were included. Following washout, patients were randomized to once-daily NET/LAT or BIM/TIM for up to 6 months; efficacy was assessed at Week 2, Week 4, and Month 3; safety was evaluated for 6 months. Comparison of NET/LAT relative to BIM/TIM for mean IOP at 08:00, 10:00, and 16:00 h was assessed at Week 2, Week 6, and Month 3. Non-inferiority of NET/LAT to BIM/TIM was defined as a difference of ≤ 1.5 mmHg at all nine time points through Month 3 and ≤ 1.0 mmHg at five or more of nine time points through Month 3. RESULTS: Overall, 430 patients were randomized (NET/LAT, n = 218; BIM/TIM, n = 212), and all received at least one dose of study medication. Efficacy analyses were performed at Month 3 on 388 patients (NET/LAT, n = 184; BIM/TIM, n = 204). NET/LAT demonstrated non-inferiority to BIM/TIM, with a between-treatment difference in IOP of ≤ 1.5 mmHg achieved at all time points and ≤ 1.0 mmHg at the majority of time points (six of nine) through Month 3. Mean diurnal IOP during the study ranged from 15.4 to 15.6 mmHg and 15.2 to 15.6 mmHg in the NET/LAT and BIM/TIM groups respectively, with no between-group statistically significant difference. No significant differences were observed in key secondary endpoints. No serious, treatment-related adverse events (AEs) were observed, and AEs were typically mild/moderate in severity. The most common treatment-related AEs were conjunctival hyperemia (NET/LAT, 30.7%; BIM/TIM, 9.0%) and cornea verticillata (NET/LAT, 11.0%; BIM/TIM, 0%). CONCLUSIONS: Once-daily NET/LAT was non-inferior to BIM/TIM in IOP reduction in OAG and OHT, with AEs consistent with previous findings. NET/LAT offers a compelling alternative FDC treatment option for OAG and OHT.

• MeSH
• Antihypertensive Agents adverse effects   MeSH
• Benzoates * MeSH
• beta-Alanine analogs & derivatives   MeSH
• Bimatoprost therapeutic use   MeSH
• Double-Blind Method MeSH
• Glaucoma, Open-Angle * diagnosis   drug therapy   MeSH
• Latanoprost adverse effects   MeSH
• Humans MeSH
• Intraocular Pressure MeSH
• Ocular Hypertension * diagnosis   drug therapy   MeSH
• Ophthalmic Solutions MeSH
• Prospective Studies MeSH
• Timolol adverse effects   MeSH
• Tonometry, Ocular MeSH
• Treatment Outcome MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Randomized Controlled Trial MeSH

Zásahy do pevných lékových forem (např. drcení či vysypávání obsahu tobolek) je v klinické praxi v lůžkových zdravotnických zařízeních častým jevem. Tyto zásahy jsou u některých léčivých přípravků nevhodné a mohou vést k přímému ohrožení pacienta. Ve sdělení jsou uvedeny příklady dvou pacientů, u nichž tyto nevhodné zásahy vedly k výskytu zdravotních komplikací. V diskuzi jsou navržena opatření, která by mohla vést k minimalizaci rizik plynoucích z těchto zásahů do pevných lékových forem.

Interference in solid dosage forms (e.g., crushing or emptying the contents of capsules) is common in clinical practice in inpatient healthcare settings. These interferences are inappropriate for some medicinal products and may lead to direct patient endangerment. Examples of two patients in whom these inappropriate interventions led to health complications are given in this communication. The measures that could lead to minimising the risks arising from these interventions in solid dosage forms are suggested in the discussion.

• MeSH
• Administration, Oral MeSH
• Dabigatran administration & dosage   pharmacology   MeSH
• Valproic Acid administration & dosage   pharmacology   MeSH
• Dosage Forms * MeSH
• Middle Aged MeSH
• Humans MeSH
• Metoprolol administration & dosage   pharmacology   MeSH
• Off-Label Use classification   MeSH
• Patient Harm * classification   MeSH
• Aged MeSH
• Drug Administration Routes MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Case Reports MeSH
• Research Support, Non-U.S. Gov't MeSH

Zásahy do pevných lékových forem (např. drcení či vysypávání obsahu tobolek) je v klinické praxi v lůžkových zdravotnických zařízeních častým jevem. Tyto zásahy jsou u některých léčivých přípravků nevhodné a mohou vést k přímému ohrožení pacienta. Ve sdělení jsou uvedeny příklady dvou pacientů, u nichž tyto nevhodné zásahy vedly k výskytu zdravotních komplikací. V diskuzi jsou navržena opatření, která by mohla vést k minimalizaci rizik plynoucích z těchto zásahů do pevných lékových forem.

Interference in solid dosage forms (e.g., crushing or emptying the contents of capsules) is common in clinical practice in inpatient healthcare settings. These interferences are inappropriate for some medicinal products and may lead to direct patient endangerment. Examples of two patients in whom these inappropriate interventions led to health complications are given in this communication. The measures that could lead to minimising the risks arising from these interventions in solid dosage forms are suggested in the discussion.

• MeSH
• Administration, Oral MeSH
• Dabigatran administration & dosage   pharmacology   MeSH
• Valproic Acid administration & dosage   pharmacology   MeSH
• Dosage Forms * MeSH
• Middle Aged MeSH
• Metoprolol administration & dosage   pharmacology   MeSH
• Off-Label Use classification   MeSH
• Patient Harm * classification   MeSH
• Aged MeSH
• Drug Administration Routes MeSH
• Check Tag
• Middle Aged MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Case Reports MeSH
• Research Support, Non-U.S. Gov't MeSH

• MeSH
• Diagnosis, Differential MeSH
• Hemangioma, Capillary * diagnosis   drug therapy   pathology   congenital   MeSH
• Humans MeSH
• Infant, Newborn MeSH
• Eyelids * abnormalities   MeSH
• Propranolol therapeutic use   MeSH
• Check Tag
• Humans MeSH
• Infant, Newborn MeSH
• Publication type
• Review MeSH