BACKGROUND AND OBJECTIVE: The dual orexin receptor antagonist daridorexant was approved in 2022 for the treatment of insomnia at doses up to 50 mg once per night. This study aimed at investigating the effect of daridorexant 50 mg at steady state on the pharmacokinetics of dabigatran, the active moiety of dabigatran etexilate, and rosuvastatin, sensitive substrates of P-glycoprotein and breast cancer resistance protein, respectively. METHODS: This single-center, open-label, fixed-sequence study enrolled 24 healthy male subjects who were dosed orally with dabigatran etexilate 75 mg on days 1 (Treatment A1) and 9 (Treatment C1) as well as rosuvastatin 10 mg on days 3 (Treatment A2) and 11 (Treatment C2). On days 7-14, daridorexant (50 mg once daily) was administered. Blood samples for the pharmacokinetics of both substrates and the pharmacodynamics of dabigatran, i.e., two coagulation tests, were collected and safety assessments performed. Noncompartmental pharmacokinetic parameters and pharmacodynamic variables were evaluated with geometric mean ratios and 90% confidence intervals of Treatment C1/C2 versus A1/A2. RESULTS: Geometric mean ratios (90% confidence interval) of dabigatran maximum plasma concentration and area under the plasma concentration-time curve were 1.3 (1.0-1.7) and 1.4 (1.1-1.9), respectively, whereas the time to maximum plasma concentration and terminal half-life were comparable between treatments. Pharmacodynamic variables showed a similar pattern as dabigatran pharmacokinetics in both treatments. Rosuvastatin pharmacokinetics were unchanged upon concomitant daridorexant administration. All treatments were well tolerated. CONCLUSIONS: A mild inhibition of P-glycoprotein was observed after administration of daridorexant (50 mg once daily) at steady state, whereas breast cancer resistance protein was not affected. CLINICAL TRIAL REGISTRATION: NCT05480475; date of registration: 29 July, 2022.

• MeSH
• ABC transportér z rodiny G, člen 2 MeSH
• benzimidazoly MeSH
• dabigatran * škodlivé účinky   MeSH
• lidé MeSH
• nádorové proteiny MeSH
• nádory prsu * MeSH
• P-glykoprotein MeSH
• plocha pod křivkou MeSH
• pyridiny škodlivé účinky   MeSH
• rosuvastatin kalcium farmakologie   MeSH
• zdraví dobrovolníci pro lékařské studie MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ABC transportér z rodiny G, člen 2 MeSH
• benzimidazoly MeSH
• dabigatran * MeSH
• daridorexant MeSH Prohlížeč
• nádorové proteiny MeSH
• P-glykoprotein MeSH
• pyridiny MeSH
• rosuvastatin kalcium MeSH

The article analyzes the results of a set of biochemical indicators in the course of treatment with the combined use of rosuvastatin with quercetin in patients with metabolic syndrome (MS) combined with non-alcoholic fatty liver disease. Changes in blood biochemical parameters have been identified and presented with MS, essential for revealing generalbiological mechanisms development and interrelationship between the components of MS and non-alcoholic fatty liver. The effect of an increase in free cholesterol and triglycerides and activation of freeradical oxidation of lipids followed by theaccumulation of oxidative stress products was noted. In the course of long-term hypolipidemic therapy (90 days), 86 patients with non-alcoholic fatty liver disease on the background of metabolic syndrome were previously divided into 2 groups: a comparison group (45 patients), who weretreated with basic therapy - only rosuvastatin, the main group (41 patients) received quercetin together with rosuvastatin -40 mg 3 times a day, clinical and laboratory-instrumental examinations were carried out. On the 90th day of treatment, positive results in the functional state of the liver and lipid spectrum of the blood wereregistered in all patients. A more significant advantage of the therapeutic combination of rosuvastatin with quercetin was proved. The inclusion of quercetin contributed to reducing the intensity of oxidative stress and enhancing antioxidant protection activity, resultingin a decrease in apoptosis of hepatocytes (cytokeratin-18 level was 1.27 times decreased). The studies have shown the feasibility of combined use of quercetin with rosuvastatin for the prevention of the development and progression of metabolic disorders associated with non-alcoholic fatty liver disease.

• Klíčová slova
• NAFLD, apoptosis of hepatocytes, metabolic syndrome, non-alcoholic fatty liver disease, oxidative stress, quercetin,
• MeSH
• lidé MeSH
• metabolický syndrom * komplikace   farmakoterapie   MeSH
• nealkoholová steatóza jater * komplikace   farmakoterapie   MeSH
• quercetin terapeutické užití   MeSH
• rosuvastatin kalcium terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• quercetin MeSH
• rosuvastatin kalcium MeSH

Parallel occurrence of high blood pressure and high plasma cholesterol level is very frequent, in our population in 30 %, and brings multiplicative higher risk for atherosclerotic cardiovascular diseases. On the other hand the contemporary treatment of them reduces that risk synergically. New fixed combination pill of rosuvastatin and ramipril (Kastel) is very felicitous choice for patients with hypercholesterolemia and mild hypertension, in which two antihypertensive drugs are not required immediatelly.

• Klíčová slova
• cardiovascular diasease prevention, hypertension and hypercholesterolemia treatment, the fixed combination of ramipril and rosuvastatin,
• MeSH
• antihypertenziva terapeutické užití   MeSH
• hypercholesterolemie * komplikace   farmakoterapie   MeSH
• hypertenze * komplikace   farmakoterapie   MeSH
• krevní tlak MeSH
• lidé MeSH
• rosuvastatin kalcium farmakologie   terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antihypertenziva MeSH
• rosuvastatin kalcium MeSH

OBJECTIVE: In primary hypercholesterolemia many people treated with statins do not reach their plasma LDL-C goals and are at increased risk of cardiovascular disease (CVD). This study aimed to evaluate efficacy and safety of a new fixed-dose combination (FDC) formulation of rosuvastatin/ezetimibe (R/E) in this population. METHODS: This was a multicenter, multinational, randomized, double-blind, double-dummy, active-controlled, parallel-arm study of FDC R/E in people with primary hypercholesterolemia at very high risk (VHR) or high risk (HR) of CVD, inadequately controlled with 20 mg or 10 mg stable daily dose of rosuvastatin or equipotent dose of another statin. The primary objective was to demonstrate superiority of FDC R/E versus rosuvastatin monotherapy uptitrated to 40 mg (R40) or 20 mg (R20) in reduction of LDL-C after 6 weeks. RESULTS: Randomized VHR participants (n = 244) were treated with R40, R40/E10, or R20/E10; randomized HR participants (n = 208) received R10/E10 or R20. In VHR participants, superiority of R40/E10 and R20/E10 versus R40 was demonstrated on LDL-C percent change from baseline to Week 6 with least squares mean differences (LSMD) of -19.66% (95% CI: -29.48% to -9.84%; P < .001) and -12.28% (95% CI: -22.12% to -2.44%; P = .015), respectively. In HR participants, superiority of R10/E10 over R20 was not demonstrated (LSMD -5.20%; 95% CI: -15.18% to 4.78%; P = .306), despite clinically relevant LDL-C reduction with R10/E10. No unexpected safety findings were reported. CONCLUSIONS: The results from this study suggest that R/E FDCs improve LDL-C reduction and goal achievement in people with primary hypercholesterolemia inadequately controlled with statins and at VHR/HR of CVD.

• Klíčová slova
• cardiovascular disease, ezetimibe, fixed-dose combination, primary hypercholesterolemia, rosuvastatin,
• MeSH
• ezetimib terapeutické užití   MeSH
• hypercholesterolemie * diagnóza   farmakoterapie   MeSH
• kardiovaskulární nemoci * farmakoterapie   MeSH
• LDL-cholesterol MeSH
• lidé MeSH
• rosuvastatin kalcium škodlivé účinky   MeSH
• statiny * terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• ezetimib MeSH
• LDL-cholesterol MeSH
• rosuvastatin kalcium MeSH
• statiny * MeSH

PURPOSE: Statin therapy should be considered in children with familial hypercholesterolemia and sustained high LDL-C levels. There are no data on rosuvastatin exposure in patients <6 years and efficacy/safety can only be derived from case reports. Our aim was to examine developmental changes in pharmacokinetics of rosuvastatin in rats in vivo as a basis for clinical development of formulations for patients < 6 years. METHODS: Rosuvastatin pharmacokinetics was examined in rats aged 1, 4, 7, 10, 14, 21, 28, 35 and 42 days (from birth to sexual maturity). After intraperitoneal dose of 5 mg/kg, blood samples to determine serum rosuvastatin levels were taken at 0.5, 3 and 5 hours. Pharmacokinetic parameters (Vd, CL, AUClast, AUC0-∞) were calculated using pharmacokinecic simulations. RESULTS: Both rosuvastatin CL and Vd started to increase systematically between 2 - 3 weeks of age, which was reflected by decreased total drug exposure. The AUC was up to 13 times higher in the age groups ≤14 days compared with the value at 42 days. CONCLUSIONS: Based on interspecies scaling, a dose reduction could be a feasible way, how to develop appropriate dosing schedule and formulations for children aged 2 - 6 years. However, confirmation in clinical development studies will be needed.

• MeSH
• krysa rodu Rattus MeSH
• metabolická clearance MeSH
• novorozená zvířata MeSH
• plocha pod křivkou MeSH
• pohlavní dospělost MeSH
• rosuvastatin kalcium farmakokinetika   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• rosuvastatin kalcium MeSH

Daridorexant is a dual orexin receptor antagonist in clinical development for the treatment of insomnia. Breast-cancer resistant protein (BCRP) is an efflux pump expressed in intestinal epithelium and hepatocytes, contributing to the absorption, distribution, and elimination of drugs and endogenous compounds. In vitro, daridorexant inhibits BCRP with an IC50 of 3.0 μmol/L. The BCRP substrate rosuvastatin is a cholesterol-lowering drug, recommended for clinical drug-drug interaction (DDI) studies. In order to exclude an inhibitory effect of daridorexant on BCRP, this single-centre, open-label, two-treatment Phase 1 study investigated the effect of daridorexant at steady state on the pharmacokinetics (PK) of single-dose rosuvastatin in 20 healthy male subjects. In addition, safety and tolerability were assessed. A single oral dose of 10 mg rosuvastatin on Day 1 was followed by 96 hours observation. Thereafter, 25 mg daridorexant was administered once daily (o.d.) on Days 5-8 and in combination with 10 mg rosuvastatin on Day 8. On Days 9-12, subjects received 25 mg daridorexant alone. PK sampling was performed up to 120 hours after treatment administration. The results showed that concomitant administration of 25 mg daridorexant o.d. at steady state did not affect the exposure parameters of rosuvastatin in a relevant way, as indicated by the ratios of geometric means (GMRs) ([rosuvastatin + daridorexant]/[rosuvastatin alone]) of 0.93 for both Cmax and AUC0-∞ . Administration of a single dose of 10 mg rosuvastatin, multiple doses of 25 mg daridorexant alone or in combination were well tolerated. Taken together, daridorexant and BCRP substrates can be safely co-administered.

• Klíčová slova
• BCRP, daridorexant, drug-drug interaction, dual orexin receptor antagonist, pharmacokinetics, rosuvastatin,
• MeSH
• ABC transportér z rodiny G, člen 2 * antagonisté a inhibitory   metabolismus   MeSH
• antagonisté orexinových receptorů * farmakokinetika   farmakologie   aplikace a dávkování   MeSH
• dospělí MeSH
• imidazoly MeSH
• lékové interakce * MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• nádorové proteiny * antagonisté a inhibitory   metabolismus   MeSH
• pyrimidiny farmakokinetika   aplikace a dávkování   farmakologie   MeSH
• pyrrolidiny MeSH
• rosuvastatin kalcium * farmakokinetika   aplikace a dávkování   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze I MeSH
• Názvy látek
• ABC transportér z rodiny G, člen 2 * MeSH
• ABCG2 protein, human MeSH Prohlížeč
• antagonisté orexinových receptorů * MeSH
• daridorexant MeSH Prohlížeč
• imidazoly MeSH
• nádorové proteiny * MeSH
• pyrimidiny MeSH
• pyrrolidiny MeSH
• rosuvastatin kalcium * MeSH

Case (description): A 74 years old Caucasian suffering from chronic kidney disease presented with progressive asthenia and diffuse myalgia. It was revealed that the patient used three different rosuvastatin-containing preparations in a total daily dose of 120 mg for 76 days. Laboratory investigations revealed a marked elevation of serum urea, creatinine, myoglobin, creatine kinase (CK) and transaminases. Two serious medication errors have been identified as possible major factors that synergistically contributed to the development of rosuvastatin-induced rhabdomyolysis. First, 40 mg of rosuvastatin dose was prescribed to the patient, although the estimation of glomerular filtration rate (eGFR) declined below 40 ml/min/1.73 m2. Moreover, the patient used 3 different rosuvastatin formulations simultaneously in a total dose of 120 mg/day. The heterozygous CYP2C9*1/*3 genotype and warfarin co-administration could further contribute to the development of rhabdomyolysis. A number of preventive measures, notably in drug policy, are suggested to overcome unintended intoxications. Conclusion: Rosuvastatin-induced myopathy is a rare, but serious adverse effect. This case report highlights the need for a proper treatment and dose adjustment during chronic medical therapy, the need for adequate patient education and application of adequate drug policy measures in the era of fragmented health care delivery and polypragmasia.

• Klíčová slova
• adverse effects, medication errors, rhabdomyolysis, rosuvastatin,
• MeSH
• lidé MeSH
• medikační omyly * MeSH
• rhabdomyolýza chemicky indukované   MeSH
• rosuvastatin kalcium škodlivé účinky   MeSH
• senioři MeSH
• statiny škodlivé účinky   MeSH
• Check Tag
• lidé MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• rosuvastatin kalcium MeSH
• statiny MeSH

Atherosclerotic cardiovascular diseases (ASCVD) play a significant role in morbidity and mortality not only in developed but also increasingly in developing countries. The only causal risk factor (RF) of ASKVO is LDL-cholesterol. The basic pillar of pharmacotherapy of dyslipidaemias are statins, which should be titrated to the maximum (tolerated) dose and then combined with ezetimibe if the LDL-cholesterol targets for the specific categories of CV risk are not reached. Combination therapy is known to be far more effective than increasing the statin dose. Fixed combinations of statins with ezetimibe can be advantageously used to improve adherence.

• Klíčová slova
• CV risk, cardiovascular disease, combination therapy, diabetes mellitus, dyslipidemia, ezetimibe, fixed combination., rosuvastatin,
• MeSH
• anticholesteremika * terapeutické užití   MeSH
• ezetimib MeSH
• kombinovaná farmakoterapie MeSH
• LDL-cholesterol MeSH
• lidé MeSH
• rosuvastatin kalcium MeSH
• statiny * terapeutické užití   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• anticholesteremika * MeSH
• ezetimib MeSH
• LDL-cholesterol MeSH
• rosuvastatin kalcium MeSH
• statiny * MeSH

PURPOSE OF REVIEW: In our pilot study, we aimed to determine how many patients with the statin intolerance history referred to the specialized center for the diagnostics and treatment of lipoprotein metabolism disorders really suffer from a complete statin intolerance. The purpose of the study was to prove that complete statin intolerance is overestimated and overdiagnosed, and with the detailed knowledge of the issue and patient approach, it is possible to find an appropriate statin treatment for the most of patients. RECENT FINDINGS: With the increasing number of statin users worldwide, the issue of statin intolerance has been a frequently discussed topic in recent years. There are many factors that play a role in the manifestation of statin intolerance (predisposing factors as age, sex, and some diseases), genetic factors leading to a different metabolism, drug-drug interactions, psychological reasons, and the negative influence of the mass media. However, it is estimated that true complete statin intolerance, defined by an intolerance of at least three statins at their usual lowest daily doses, occurs in approximately 3-6% of all statin users. In our pilot study, we conducted a retrospective analysis of 300 patients who were referred to the Center of Preventive Cardiology with a history of statin intolerance. During the follow-up treatment, 222 patients (74%) were able to use some statin (rosu-, atorva-, simva-, fluvastatin), and in 21% of the cases (63 patient), the target values according their CV risk level were even achieved. Only 78 patients (26%) were confirmed as being complete statin intolerant following a thorough therapeutic effort. The most tolerated statin was rosuvastatin.

• Klíčová slova
• Complete statin intolerance, Partial statin intolerance, Statin associated muscle symptoms,
• MeSH
• kardiovaskulární nemoci prevence a kontrola   MeSH
• lidé středního věku MeSH
• lidé MeSH
• následné studie MeSH
• pilotní projekty MeSH
• primární prevence MeSH
• retrospektivní studie MeSH
• rosuvastatin kalcium škodlivé účinky   MeSH
• sekundární prevence MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• statiny škodlivé účinky   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• rosuvastatin kalcium MeSH
• statiny MeSH

Prostate cancer is primarily fatal after it becomes metastatic and castration-resistant despite novel combined hormonal and chemotherapeutic regimens. Hence, new therapeutic concepts and drug delivery strategies are urgently needed for the eradication of this devastating disease. Here we report the highly specific, in situ click chemistry driven pretargeted delivery of cytotoxic drug carriers to PSMA(+) prostate cancer cells. Anti-PSMA 5D3 mAb and its F(ab')2 fragments were functionalized with trans-cyclooctene (TCO), labeled with a fluorophore, and used as pretargeting components. Human serum albumin (ALB) was loaded with the DM1 antitubulin agent, functionalized with PEGylated tetrazine (PEG4-Tz), labeled with a fluorophore, and used as the drug delivery component. The internalization kinetics of components and the therapeutic efficacy of the pretargeted click therapy were studied in PSMA(+) PC3-PIP and PSMA(-) PC3-Flu control cells. The F(ab')2 fragments were internalized faster than 5D3 mAb in PSMA(+) PC3-PIP cells. In the two-component pretargeted imaging study, both components were colocalized in a perinuclear location of the cytoplasm of PC3-PIP cells. Better colocalization was achieved when 5D3 mAb was used as the pretargeting component. Consecutively, the in vitro cell viability study shows a significantly higher therapeutic effect of click therapy in PC3-PIP cells when 5D3 mAb was used for pretargeting, compared to its F(ab')2 derivative. 5D3 mAb has a longer lifetime on the cell surface, when compared to its F(ab')2 analogue, enabling efficient cross-linking with the drug delivery component and increased efficacy. Pretargeting and drug delivery components were cross-linked via multiple bioorthogonal click chemistry reactions on the surface of PSMA(+) PC cells forming nanoclusters, which undergo fast cellular internalization and intracellular transport to perinuclear locations.

• Klíčová slova
• PSMA(+) prostate cancer, bioorthogonal click chemistry, drug delivery, nanomedicine, pretargeted therapy,
• MeSH
• albuminy MeSH
• antigeny povrchové imunologie   MeSH
• click chemie metody   MeSH
• cyklooktany chemie   MeSH
• fluorbenzeny chemie   MeSH
• fytogenní protinádorové látky terapeutické užití   MeSH
• glutamátkarboxypeptidasa II imunologie   metabolismus   MeSH
• imunoglobuliny - Fab fragmenty chemie   metabolismus   terapeutické užití   MeSH
• lékové transportní systémy metody   MeSH
• lidé MeSH
• maytansin terapeutické užití   MeSH
• modulátory tubulinu terapeutické užití   MeSH
• monoklonální protilátky chemie   metabolismus   terapeutické užití   MeSH
• nádorové buněčné linie MeSH
• nádory prostaty farmakoterapie   enzymologie   metabolismus   MeSH
• nanomedicína MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Názvy látek
• albuminy MeSH
• AlexaFluor 488 carboxylic acid tetrafluorophenyl ester MeSH Prohlížeč
• antigeny povrchové MeSH
• cyklooktany MeSH
• fluorbenzeny MeSH
• FOLH1 protein, human MeSH Prohlížeč
• fytogenní protinádorové látky MeSH
• glutamátkarboxypeptidasa II MeSH
• imunoglobuliny - Fab fragmenty MeSH
• maytansin MeSH
• modulátory tubulinu MeSH
• monoklonální protilátky MeSH