Constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are closely related nuclear receptors with overlapping regulatory functions in xenobiotic clearance but distinct roles in endobiotic metabolism. Car activation has been demonstrated to ameliorate hypercholesterolemia by regulating cholesterol metabolism and bile acid elimination, whereas PXR activation is associated with hypercholesterolemia and liver steatosis. Here we show a human CAR agonist/PXR antagonist, MI-883, which effectively regulates genes related to xenobiotic metabolism and cholesterol/bile acid homeostasis by leveraging CAR and PXR interactions in gene regulation. Through comprehensive analyses utilizing lipidomics, bile acid metabolomics, and transcriptomics in humanized PXR-CAR-CYP3A4/3A7 mice fed high-fat and high-cholesterol diets, we demonstrate that MI-883 significantly reduces plasma cholesterol levels and enhances fecal bile acid excretion. This work paves the way for the development of ligands targeting multiple xenobiotic nuclear receptors. Such ligands hold the potential for precise modulation of liver metabolism, offering new therapeutic strategies for metabolic disorders.

• MeSH
• cholesterol metabolismus   krev   MeSH
• cytochrom P-450 CYP3A genetika   metabolismus   MeSH
• dieta s vysokým obsahem tuků škodlivé účinky   MeSH
• hypercholesterolemie * farmakoterapie   metabolismus   etiologie   MeSH
• hypolipidemika * farmakologie   terapeutické užití   MeSH
• játra metabolismus   účinky léků   MeSH
• konstitutivní androstanový receptor MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• pregnanový X receptor * antagonisté a inhibitory   metabolismus   genetika   MeSH
• receptory cytoplazmatické a nukleární * agonisté   metabolismus   genetika   antagonisté a inhibitory   MeSH
• žlučové kyseliny a soli metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cholesterol MeSH
• cytochrom P-450 CYP3A MeSH
• hypolipidemika * MeSH
• konstitutivní androstanový receptor MeSH
• pregnanový X receptor * MeSH
• receptory cytoplazmatické a nukleární * MeSH
• žlučové kyseliny a soli MeSH

OBJECTIVES: The study aims to examine the extent to which the updated ACC/AHA management of blood cholesterol guideline (2018) is implemented in practice and to assess the value of the clinical pharmacist interventions in improving physicians' adherence the guidelines recommendations. METHODS: We utilized in this study an interventional before-after design. The study was conducted on 272 adult patients who visited the study site internal medicine clinics and were candidates for statin therapy based on the 2018 ACC/AHA guidelines for cholesterol management. Adherence to guideline recommendations was measured before and after clinical pharmacists' interventions by calculating the percentage of patients receiving statin therapy as per guideline recommendation, the type and intensity (moderate or high intensity) of statin therapy used, and the need for additional non-statin therapy. RESULTS: Adherence with guideline recommendations was significantly improved from 60.3% to 92.6% (X2 = 79.1, p = 0.0001) after clinical pharmacist interventions. Among patients who were on statin therapy, the percentage of those who were on proper statin intensity increased significantly from 47.6% to 94.4% (X2 = 72.5, p = 0.0001). The combination of statins with non-statin therapies such as ezetimibe and PCSK9 inhibitors increased from 8.5% to 30.6% (X2 = 95, p<0.0001) and from 0.0% to 1.6% (X2 = 6, p = 0.014), respectively. The use of other lipid-lowering agents was diminished from 14.6% to 3.2% (X2 = 19.2, p<0.0001). CONCLUSION: Collaboration between physicians and clinical pharmacists is a crucial strategy to improve patients' treatment and hence, achieve better health outcomes among patients suffering from dyslipidemia.

• MeSH
• cholesterol MeSH
• dodržování směrnic MeSH
• dospělí MeSH
• farmaceuti MeSH
• hypercholesterolemie * farmakoterapie   chemicky indukované   MeSH
• kardiologie * MeSH
• kardiovaskulární nemoci * MeSH
• lidé MeSH
• proproteinkonvertasa subtilisin/kexin typu 9 MeSH
• statiny * terapeutické užití   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Spojené státy americké MeSH
• Názvy látek
• cholesterol MeSH
• PCSK9 protein, human MeSH Prohlížeč
• proproteinkonvertasa subtilisin/kexin typu 9 MeSH
• statiny * 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

PCSK9 inhibitors are modern and effective hypolipidemic drugs for lowering LDL-cholesterol, which belong to the „biological therapy“. Their prescription is limited to specialized centers and to the fulfillment of other conditions set by SÚKL. This article lists the current valid criteria under which they can be indicated for reimbursement from public health insurance, and comments conditions and limitations in terms of the possibility of their fulfillment in clinical practice.

• Klíčová slova
• LDL‑ cholesterol, PCSK9-inhibitors, cardiovascular diseases, cardiovascular risk, diabetes mellitus, familial hypercholesterolemia, mixed dyslipidemia,
• MeSH
• anticholesteremika * terapeutické užití   MeSH
• dyslipidemie * farmakoterapie   MeSH
• hypercholesterolemie * farmakoterapie   MeSH
• hypolipidemika terapeutické užití   MeSH
• LDL-cholesterol MeSH
• lidé MeSH
• PCSK9 inhibitory MeSH
• proproteinkonvertasa subtilisin/kexin typu 9 MeSH
• statiny * terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• anticholesteremika * MeSH
• hypolipidemika MeSH
• LDL-cholesterol MeSH
• PCSK9 inhibitory MeSH
• PCSK9 protein, human MeSH Prohlížeč
• proproteinkonvertasa subtilisin/kexin typu 9 MeSH
• statiny * 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

A new class of drugs known as PCSK9 inhibitors (PCSK9i) provide biological treatment for hypercholesterolemia. These drugs are administered using a subcutaneous injection once in two or four weeks. PCSK9i are not a replacement of the existing hypolipidemics, they just expand the therapeutic spectrum for the critically ill and those who cannot use the standard therapy and do not reach satisfactory target values. There are essentially two indications: (1) hypercholesterolemie and mixed dyslipidemia and (2) secondary prevention of cardiovascular diseases (CVD). Statin intolerance is not the only indication for treatment. However as its presence sometimes plays an essential role as to choosing the treatment, it will be also discussed in the paragraph on reimbursement conditions. Reimbursement conditions (very simplified): the treatment will be provided at selected centres. A list of the centres is included in an annexe to this article. You will find it also on www.interna-cz.eu, on www.kardio-cz.cz and www.athero.cz. The indicative concentration of LDL-cholesterol (LDL-C) from which on PCSK9i can be prescribed as covered from the public health insurance, is the following: (1) familial hypercholesterolemia 4.0 mmol/l, (2) for secondary prevention CVD 3.0 mmol/l - Please note: the presented LDL-C level is one reached under maximum (tolerated) high intensity hypo-lipidemic therapy. High intensity hypolipidemic therapy is defined as atorvastatin 40-80 mg or rosuvastatin 20-40 mg + ezetimibe. In the case of demonstrated intolerance of both the mentioned statins the patient has to be treated with a maximum tolerated dose of statins, in combination with another hypolipidemic drug (ezetimibe). Statin intolerance is defined as intolerance of at least two successive statins, which results in their discontinuation. Statin intolerance alone is not the indication for PCSK9i treatment! The payment criteria must always be complied with. A medical officer can of course be asked to approve such treatment in exceptional cases. Key words: alirocumab - PCSK9 inhibitors centers - center therapy - evolocumab - familial hypercholesterolemia - proprotein konvertase subtilisin kexin 9 inhibitors (PCSK9i) - secondary prevention - statins intolerance.

• Klíčová slova
• alirocumab - PCSK9 inhibitors centers - center therapy - evolocumab - familial hypercholesterolemia - proprotein konvertase subtilisin kexin 9 inhibitors (PCSK9i) - secondary prevention - statins intolerance,
• MeSH
• anticholesteremika * terapeutické užití   MeSH
• hypercholesterolemie * farmakoterapie   MeSH
• konsensus MeSH
• LDL-cholesterol MeSH
• lidé MeSH
• monoklonální protilátky MeSH
• PCSK9 inhibitory MeSH
• proproteinkonvertasa subtilisin/kexin typu 9 * MeSH
• směrnice pro lékařskou praxi jako téma MeSH
• statiny * terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• anticholesteremika * MeSH
• LDL-cholesterol MeSH
• monoklonální protilátky MeSH
• PCSK9 inhibitory MeSH
• PCSK9 protein, human MeSH Prohlížeč
• proproteinkonvertasa subtilisin/kexin typu 9 * MeSH
• statiny * MeSH

The paper provides a brief overview of the key studies focused on PCSK9 inhibitors. It mainly examines positive results of the FOURIER studies on evolocumab, the SPIRE study on boccocizumab and the ODYSSEY Outcomes study on alirocumab. All these studies have not only shown a significant decrease in LDL-cholesterol levels, but also the reduction of cardiovascular events just correlating with these levels. The treatment leading to a dramatic drop in LDL-cholesterol levels was safe and well tolerated by patients. All the studies provided with comments demonstrate a positive impact of biological treatment of hypercholesterolemia on cardiovascular disease and confirm validity of the hypothesis saying “the lower the better”, at least for LDL-cholesterol. In conclusion, Professor Braunwalds hypothesis is mentioned saying that this treatment might eventually lead to as much as eradication of atherothrombotic cardiovascular diseases. Key words: alirocumab - bococizumab - evolocumab - FOURIER - cardiovascular disease - LDL-cholesterol - ODYSSEY Outcomes - SPIRE.

• Klíčová slova
• alirocumab - bococizumab - evolocumab - FOURIER - cardiovascular disease - LDL-cholesterol - ODYSSEY Outcomes - SPIRE,
• MeSH
• anticholesteremika * terapeutické užití   MeSH
• hypercholesterolemie * farmakoterapie   MeSH
• kardiovaskulární nemoci * prevence a kontrola   MeSH
• LDL-cholesterol MeSH
• lidé MeSH
• monoklonální protilátky MeSH
• PCSK9 inhibitory MeSH
• proproteinkonvertasa subtilisin/kexin typu 9 * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• anticholesteremika * MeSH
• LDL-cholesterol MeSH
• monoklonální protilátky MeSH
• PCSK9 inhibitory MeSH
• PCSK9 protein, human MeSH Prohlížeč
• proproteinkonvertasa subtilisin/kexin typu 9 * MeSH

BACKGROUND: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. METHODS: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. RESULTS: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths ( P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events ( P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined with achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend). CONCLUSIONS: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01663402.

• Klíčová slova
• PCSK9 protein, acute coronary syndrome, alirocumab, cholesterol, mortality,
• MeSH
• akutní koronární syndrom krev   farmakoterapie   mortalita   MeSH
• dvojitá slepá metoda MeSH
• humanizované monoklonální protilátky aplikace a dávkování   MeSH
• hypercholesterolemie krev   farmakoterapie   mortalita   MeSH
• injekce subkutánní MeSH
• kombinovaná farmakoterapie MeSH
• LDL-cholesterol antagonisté a inhibitory   krev   MeSH
• lidé středního věku MeSH
• lidé MeSH
• následné studie MeSH
• senioři MeSH
• statiny aplikace a dávkování   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• alirocumab MeSH Prohlížeč
• humanizované monoklonální protilátky MeSH
• LDL-cholesterol MeSH
• statiny MeSH

Hypercholesterolemia is one of the most important risk factors of cardiovascular (CV) disease. Epidemiology follows the prevalence, the incidence and the possibilities of risk factors or diseases intervention. A review of observation epidemiologic studies, pharmacotherapy and treatment perspectives is presented. The first epidemiologic studies, e.g. the Framingham Heart Study or MRFIT showed hyperlipidemia is associated with the incidence of CV disease. The North Karelia Project showed the intervention of CV risk factors is useful on population-based principles. Interventional studies with statins showed the usefulness of LDL cholesterol lowering to decrease CV morbidity and mortality and also total mortality. Anyway, the control of CV risk factors is unsatisfactory.Key words: epidemiology - hypercholesterolemia - intervention.

• MeSH
• anticholesteremika * MeSH
• hypercholesterolemie * farmakoterapie   epidemiologie   MeSH
• kardiovaskulární nemoci * enzymologie   MeSH
• LDL-cholesterol MeSH
• lidé MeSH
• rizikové faktory MeSH
• statiny terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• anticholesteremika * MeSH
• LDL-cholesterol MeSH
• statiny MeSH

Background The risk of cardiovascular disease is closely connected to adipose tissue inflammation. The links between cardiovascular risk predictors and pro and anti-inflammatory macrophages in human adipose tissue were analysed to gain an insight into the pathophysiology of cardiovascular disease. Design Subcutaneous and visceral adipose tissues were obtained from 79 subjects, 52 living kidney donors (during nephrectomy) and 27 patients with peripheral artery disease (during arterial tree reconstruction). Methods Macrophage subsets were isolated from adipose tissues and analysed by flow cytometry using CD14, CD16, CD36 and CD163 monoclonal antibodies. The mutually adjusted differences of phagocytic pro-inflammatory (CD14 + CD16 + CD36high), anti-inflammatory (CD14 + CD16-CD163+) and transitional subsets of macrophages were analysed in relation to cardiovascular predictors (sex, age, body mass index, smoking, hypercholesterolaemia, hypertension and statin treatment). Results Age, male sex and hypercholesterolaemia were closely positively associated with the phagocytic pro-inflammatory macrophage subset in visceral adipose tissues. Interestingly, the proportion of phagocytic pro-inflammatory macrophages was relevantly decreased by statin therapy. A strong positive association of body mass index to the phagocytic pro-inflammatory subset was found in subcutaneous adipose tissues only. A minor transitional subpopulation, CD14 + CD16 + CD36lowCD163+, increased with age in both adipose tissues. This transitional subpopulation was also negatively associated with obesity and hypercholesterolaemia in visceral adipose tissues. Conclusion An effect of cardiovascular risk predictors on adipose tissue macrophage subpopulations was revealed. Interestingly, while age, male sex and hypercholesterolaemia were connected with the pro-inflammatory macrophage subpopulation in visceral adipose tissues, body mass index had a prominent effect in subcutaneous adipose tissues only. A decreasing effect of statins on these pro-inflammatory macrophages was documented.

• Klíčová slova
• Cardiovascular risk factors, adipose tissue, inflammation, macrophage, statins,
• MeSH
• biologické markery krev   MeSH
• dospělí MeSH
• fagocytóza MeSH
• fenotyp MeSH
• hypercholesterolemie krev   farmakoterapie   patologie   MeSH
• index tělesné hmotnosti MeSH
• lidé středního věku MeSH
• lidé MeSH
• makrofágy účinky léků   metabolismus   patologie   MeSH
• mediátory zánětu krev   MeSH
• nitrobřišní tuk účinky léků   metabolismus   patologie   MeSH
• onemocnění periferních arterií krev   patologie   chirurgie   MeSH
• podkožní tuk účinky léků   metabolismus   patologie   MeSH
• prognóza MeSH
• rizikové faktory MeSH
• sexuální faktory MeSH
• statiny terapeutické užití   MeSH
• studie případů a kontrol MeSH
• věkové faktory MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• biologické markery MeSH
• mediátory zánětu MeSH
• statiny MeSH