• MeSH
• diabetes mellitus 2. typu * diagnóza   farmakoterapie   komplikace   MeSH
• diabetes mellitus diagnóza   farmakoterapie   MeSH
• hypertenze diagnóza   farmakoterapie   MeSH
• indapamid aplikace a dávkování   terapeutické užití   MeSH
• kombinovaná farmakoterapie MeSH
• komplikace diabetu MeSH
• lidé středního věku MeSH
• lidé MeSH
• telmisartan aplikace a dávkování   terapeutické užití   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

Obezita je jednou s častých příčin zvyšujících krevní tlak. Hypertenze u obézních pacientů je často obtížně léčitelná, sůl-senzitivní, provázejí ji častěji orgánové komplikace, zvýšená aktivita sympatiku a renin angiotenzinového systému, také hyperinzulinemie a hyperleptinemie. Fixní kombinace telmisartanu 80 mg a indapamidu 2,5 mg je jednou s možností účinné léčby hypertenze u obézních. Hlavní předností spojení těchto dvou léků je velmi spolehlivý efekt po dobu celých 24 hodin denně, jejich bezpečnost a dobrá tolerance. Další předností je absence negativního metabolického působení, vliv na snížení kolísání krevního tlaku, kardiovaskulární protektivita telmisartanu se současným příznivým ovlivněním inzulinové senzitivity.

Obesity is one of the main causes of arterial hypertension, especially „difficuLt-to-treat" hypertension. The initial therapy of hypertension with 2 antihypertensive agents in a single-pill combination is preferred in most hypertensive patients. The choice of the drugs should consider the cardiovascular protection, the absence of negative metabolic effects, safety, and efficacy in obese patients with impaired renin-angiotensin system, sympathomimetic hyperactivity and hyperinsulinemia a hyperleptinemia. The single-pill combination of telmisartan 80 mg and indapamide 2.5 mg presents suitable option for effective and very well tolerated treatment of hypertension. Telmisartan improves cardiometabolic profile in obese hypertensive patients by improving insulin sensitivity and indapamide is metabolically neutral diuretic. The main advantage of the combination of these two drugs in clinical practice is a very effective blood pressure reduction lasting more than 24 hours, and good tolerance.

• Klíčová slova
• Telmisartan-Indopamid,
• MeSH
• diuretika farmakologie   terapeutické užití   MeSH
• fixní kombinace léků * MeSH
• hypertenze * farmakoterapie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• obezita * komplikace   MeSH
• práce na směny škodlivé účinky   MeSH
• telmisartan farmakologie   terapeutické užití   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH
• práce podpořená grantem MeSH

This study investigated whether sacubitril/valsartan or valsartan are able to prevent left ventricular (LV) fibrotic remodelling and dysfunction in two experimental models of pre-hypertension induced by continuous light (24 hours/day) exposure or by chronic lactacystin treatment, and how this potential protection interferes with the renin-angiotensin-aldosterone system (RAAS). Nine groups of three-month-old male Wistar rats were treated for six weeks as follows: untreated controls (C), sacubitril/valsartan (ARNI), valsartan (Val), continuous light (24), continuous light plus sacubitril/valsartan (24+ARNI) or valsartan (24+Val), lactacystin (Lact), lactacystin plus sacubitil/valsartan (Lact+ARNI) or plus valsartan (Lact+Val). Both the 24 and Lact groups developed a mild but significant systolic blood pressure (SBP) increase, LV hypertrophy and fibrosis, as well as LV systolic and diastolic dysfunction. Yet, no changes in serum renin-angiotensin were observed either in the 24 or Lact groups, though aldosterone was increased in the Lact group compared to the controls. In both models, sacubitril/valsartan and valsartan reduced elevated SBP, LV hypertrophy and fibrosis and attenuated LV systolic and diastolic dysfunction. Sacubitril/valsartan and valsartan increased the serum levels of angiotensin (Ang) II, Ang III, Ang IV, Ang 1-5, Ang 1-7 in the 24 and Lact groups and reduced aldosterone in the Lact group. We conclude that both continuous light exposure and lactacystin treatment induced normal-to-low serum renin-angiotensin models of pre-hypertension, whereas aldosterone was increased in lactacystin-induced pre-hypertension. The protection by ARNI or valsartan in the hypertensive heart in either model was related to the Ang II blockade and the protective Ang 1-7, while in lactacystin-induced pre-hypertension this protection seems to be additionally related to the reduced aldosterone level.

• MeSH
• acetylcystein analogy a deriváty   MeSH
• aldosteron MeSH
• aminobutyráty * MeSH
• bifenylové sloučeniny farmakologie   MeSH
• fibróza MeSH
• fixní kombinace léků MeSH
• hypertenze * farmakoterapie   MeSH
• hypertrofie levé komory srdeční MeSH
• krysa rodu rattus MeSH
• potkani Wistar MeSH
• prehypertenze * MeSH
• renin-angiotensin systém MeSH
• renin MeSH
• srdeční selhání * MeSH
• tepový objem MeSH
• tetrazoly farmakologie   terapeutické užití   MeSH
• valsartan farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Srdeční selhání je závažným zdravotním a také socioekonomickým problémem. Terapie srdečního selhání v poslední době doznala řady změn. U srdečního selhání s redukovanou ejekční frakcí je kromě β-blokátorů, antagonistů mineralokortikoidního receptoru a inhibitorů SGLT2 nedílnou součástí základní terapie také sakubitril/valsartan, který díky svému duálnímu účinku působí na řadu mechanismů v patofyziologii srdečního selhání. Kromě zahájení farmakoterapie je také velmi důležitá další titrace jednotlivých léčiv do maximálně snášených dávek. Díky optimální farmakoterapii můžeme ovlivnit nejenom kvalitu života pacientů, ale také jejich prognózu.

Heart failure is a serious health as well as socio-economic problem. Heart failure therapy has recently undergone a number of changes. In heart failure with a reduced ejection fraction, in addition to beta-blockers, mineralocorticoid receptor antagonists, and SGLT2 inhibitors, sacubitril/ valsartan is also an integral part of basic therapy, which, thanks to its dual effect, acts on a number of mechanisms in the pathophysiology of heart failure. In addition to starting drug therapy, further titration of individual drugs to the maximum tolerated doses is also very important. Thanks to optimal pharmacotherapy, we can influence not only the quality of life of patients, but also their prognosis.

• Klíčová slova
• sakubitril/valsartan,
• MeSH
• aminobutyráty farmakologie   terapeutické užití   MeSH
• antagonisté receptorů pro angiotenzin farmakologie   terapeutické užití   MeSH
• bifenylové sloučeniny farmakologie   terapeutické užití   MeSH
• fixní kombinace léků MeSH
• lidé středního věku MeSH
• lidé MeSH
• srdeční selhání * farmakoterapie   MeSH
• valsartan farmakologie   terapeutické užití   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

Kazuistika je věnovaná zkušenosti s využitím inhibitoru neprilysinu a angiotenzinového receptoru II (sakubitril/valsartanu) v léčbě srdečního selhání se zachovanou systolickou funkcí levé komory (HFpEF), ale s progredující systolickou dysfunkcí pravé komory a trikuspidální regurgitací při dilataci anulu. Doplnění léčby diuretikem a β-blokátorem o sakubitril/valsartan namísto inhibitoru angiotenzin konvertujícího enzymu vedlo ke zmírnění převážně pravostranného srdečního selhání a umožnilo odložení potřebné operace trikuspidální chlopně do doby zvládnutí průvodní hematologické problematiky. Přes příznivý dopad plastiky trikuspidální chlopně zůstal sakubitril/valsartan v nižší dávce potřebnou a přínosnou součástí léčby i v následujícím období. V článku jsou dále diskutovány současné možnosti farmakoterapie HFpEF.

The case report describes the experience with the use of an neprilysin and angiotensin II receptor blocker (sacubitril/valsartan) in the treatment of heart failure with preserved left ventricular systolic function (HFpEF) but with progressive right ventricular systolic dysfunction and tricuspid regurgitation in tricuspid annular dilation. Adding a diuretic and a β-blocker to sacubitril/valsartan instead of an angiotensin-converting enzyme inhibitor resulted in amelioration of the predominantly right-sided heart failure and allowed deferral of the necessary tricuspid valve surgery until the accompanying hematologic issues were managed. Despite the beneficial impact of tricuspid valve surgery, lower-dose of sacubitril/valsartan remained a necessary and beneficial part of treatment in the subsequent period. Current options for pharmacotherapy of HFpEF are also discussed.

• Klíčová slova
• sakubitril/valsartan,
• MeSH
• aminobutyráty farmakologie   terapeutické užití   MeSH
• antagonisté receptorů pro angiotenzin farmakologie   terapeutické užití   MeSH
• bifenylové sloučeniny farmakologie   terapeutické užití   MeSH
• fixní kombinace léků MeSH
• lidé MeSH
• senioři MeSH
• srdeční selhání * farmakoterapie   MeSH
• valsartan farmakologie   terapeutické užití   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• kazuistiky MeSH

Heart failure (HF) is life-threatening disease due to electro-mechanical dysfunction associated with hemodynamic overload, while alterations of extracellular matrix (ECM) along with perturbed connexin-43 (Cx43) might be key factors involved. We aimed to explore a dual impact of pressure, and volume overload due to aorto-caval fistula (ACF) on Cx43 and ECM as well as effect of renin-angiotensin blockade. Hypertensive Ren-2 transgenic rats (TGR) and normotensive Hannover Sprague-Dawley rats (HSD) that underwent ACF were treated for 15-weeks with trandolapril or losartan. Blood serum and heart tissue samples of the right (RV) and left ventricles (LV) were used for analyses. ACF-HF increased RV, LV and lung mass in HSD and to lesser extent in TGR, while treatment attenuated it and normalized serum ANP, BNP-45 and TBARS. Cx43 protein and its ser368 variant along with PKCε were lower in TGR vs HSD and suppressed in both rat strains due to ACF but prevented more by trandolapril. Pro-hypertrophic PKCδ, collagen I and hydroxyproline were elevated in TGR and increased due to ACF in both rat strains. While SMAD2/3 and MMP2 levels were lower in TGR vs HSD and reduced due to ACF in both strains. Findings point out the strain-related differences in response to volume overload. Disorders of Cx43 and ECM signalling may contribute not only to HF but also to the formation of arrhythmogenic substrate. There is benefit of treatment with trandolapril and losartan indicating their pleiotropic anti-arrhythmic potential. It may provide novel input to therapy.

• MeSH
• extracelulární matrix MeSH
• hypertenze * MeSH
• konexin 43 genetika   MeSH
• krevní tlak MeSH
• krysa rodu rattus MeSH
• losartan farmakologie   MeSH
• píštěle * MeSH
• potkani Sprague-Dawley MeSH
• potkani transgenní MeSH
• renin MeSH
• srdeční selhání * MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Sparsentan, a novel, non-immunosuppressive, single-molecule, dual endothelin angiotensin receptor antagonist, significantly reduced proteinuria versus irbesartan, an angiotensin II receptor blocker, at 36 weeks (primary endpoint) in patients with immunoglobulin A nephropathy in the phase 3 PROTECT trial's previously reported interim analysis. Here, we report kidney function and outcomes over 110 weeks from the double-blind final analysis. METHODS: PROTECT, a double-blind, randomised, active-controlled, phase 3 study, was done across 134 clinical practice sites in 18 countries throughout the Americas, Asia, and Europe. Patients aged 18 years or older with biopsy-proven primary IgA nephropathy and proteinuria of at least 1·0 g per day despite maximised renin-angiotensin system inhibition for at least 12 weeks were randomly assigned (1:1) to receive sparsentan (target dose 400 mg oral sparsentan once daily) or irbesartan (target dose 300 mg oral irbesartan once daily) based on a permuted-block randomisation method. The primary endpoint was proteinuria change between treatment groups at 36 weeks. Secondary endpoints included rate of change (slope) of the estimated glomerular filtration rate (eGFR), changes in proteinuria, a composite of kidney failure (confirmed 40% eGFR reduction, end-stage kidney disease, or all-cause mortality), and safety and tolerability up to 110 weeks from randomisation. Secondary efficacy outcomes were assessed in the full analysis set and safety was assessed in the safety set, both of which were defined as all patients who were randomly assigned and received at least one dose of randomly assigned study drug. This trial is registered with ClinicalTrials.gov, NCT03762850. FINDINGS: Between Dec 20, 2018, and May 26, 2021, 203 patients were randomly assigned to the sparsentan group and 203 to the irbesartan group. One patient from each group did not receive the study drug and was excluded from the efficacy and safety analyses (282 [70%] of 404 included patients were male and 272 [67%] were White) . Patients in the sparsentan group had a slower rate of eGFR decline than those in the irbesartan group. eGFR chronic 2-year slope (weeks 6-110) was -2·7 mL/min per 1·73 m2 per year versus -3·8 mL/min per 1·73 m2 per year (difference 1·1 mL/min per 1·73 m2 per year, 95% CI 0·1 to 2·1; p=0·037); total 2-year slope (day 1-week 110) was -2·9 mL/min per 1·73 m2 per year versus -3·9 mL/min per 1·73 m2 per year (difference 1·0 mL/min per 1·73 m2 per year, 95% CI -0·03 to 1·94; p=0·058). The significant reduction in proteinuria at 36 weeks with sparsentan was maintained throughout the study period; at 110 weeks, proteinuria, as determined by the change from baseline in urine protein-to-creatinine ratio, was 40% lower in the sparsentan group than in the irbesartan group (-42·8%, 95% CI -49·8 to -35·0, with sparsentan versus -4·4%, -15·8 to 8·7, with irbesartan; geometric least-squares mean ratio 0·60, 95% CI 0·50 to 0·72). The composite kidney failure endpoint was reached by 18 (9%) of 202 patients in the sparsentan group versus 26 (13%) of 202 patients in the irbesartan group (relative risk 0·7, 95% CI 0·4 to 1·2). Treatment-emergent adverse events were well balanced between sparsentan and irbesartan, with no new safety signals. INTERPRETATION: Over 110 weeks, treatment with sparsentan versus maximally titrated irbesartan in patients with IgA nephropathy resulted in significant reductions in proteinuria and preservation of kidney function. FUNDING: Travere Therapeutics.

• MeSH
• antagonisté receptorů pro angiotenzin škodlivé účinky   MeSH
• chronické selhání ledvin * MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• IgA nefropatie * farmakoterapie   MeSH
• irbesartan škodlivé účinky   MeSH
• lidé MeSH
• proteinurie farmakoterapie   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• randomizované kontrolované studie MeSH

BACKGROUND: An unmet need exists for focal segmental glomerulosclerosis (FSGS) treatment. In an 8-week, phase 2 trial, sparsentan, a dual endothelin-angiotensin receptor antagonist, reduced proteinuria in patients with FSGS. The efficacy and safety of longer-term treatment with sparsentan for FSGS are unknown. METHODS: In this phase 3 trial, we enrolled patients with FSGS (without known secondary causes) who were 8 to 75 years of age; patients were randomly assigned to receive sparsentan or irbesartan (active control) for 108 weeks. The surrogate efficacy end point assessed at the prespecified interim analysis at 36 weeks was the FSGS partial remission of proteinuria end point (defined as a urinary protein-to-creatinine ratio of ≤1.5 [with protein and creatinine both measured in grams] and a >40% reduction in the ratio from baseline). The primary efficacy end point was the estimated glomerular filtration rate (eGFR) slope at the time of the final analysis. The change in eGFR from baseline to 4 weeks after the end of treatment (week 112) was a secondary end point. Safety was also evaluated. RESULTS: A total of 371 patients underwent randomization: 184 were assigned to receive sparsentan and 187 to receive irbesartan. At 36 weeks, the percentage of patients with partial remission of proteinuria was 42.0% in the sparsentan group and 26.0% in the irbesartan group (P = 0.009), a response that was sustained through 108 weeks. At the time of the final analysis at week 108, there were no significant between-group differences in the eGFR slope; the between-group difference in total slope (day 1 to week 108) was 0.3 ml per minute per 1.73 m2 of body-surface area per year (95% confidence interval [CI], -1.7 to 2.4), and the between-group difference in the slope from week 6 to week 108 (i.e., chronic slope) was 0.9 ml per minute per 1.73 m2 per year (95% CI, -1.3 to 3.0). The mean change in eGFR from baseline to week 112 was -10.4 ml per minute per 1.73 m2 with sparsentan and -12.1 ml per minute per 1.73 m2 with irbesartan (difference, 1.8 ml per minute per 1.73 m2; 95% CI, -1.4 to 4.9). Sparsentan and irbesartan had similar safety profiles, and the frequency of adverse events was similar in the two groups. CONCLUSIONS: Among patients with FSGS, there were no significant between-group differences in eGFR slope at 108 weeks, despite a greater reduction in proteinuria with sparsentan than with irbesartan. (Funded by Travere Therapeutics; DUPLEX ClinicalTrials.gov number, NCT03493685.).

• MeSH
• biologické markery MeSH
• dítě MeSH
• dospělí MeSH
• fokálně segmentální glomeruloskleróza * komplikace   farmakoterapie   patofyziologie   MeSH
• hodnoty glomerulární filtrace MeSH
• indukce remise MeSH
• irbesartan * aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• kreatinin MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• proteinurie * farmakoterapie   etiologie   MeSH
• senioři MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• randomizované kontrolované studie MeSH

• Klíčová slova
• sakubitril/valsartan,
• MeSH
• aminobutyráty farmakologie   terapeutické užití   MeSH
• bifenylové sloučeniny farmakologie   terapeutické užití   MeSH
• hypertenze farmakoterapie   MeSH
• klinická studie jako téma metody   MeSH
• lidé MeSH
• srdeční selhání * farmakoterapie   MeSH
• valsartan farmakologie   terapeutické užití   MeSH
• Check Tag
• lidé MeSH

AIMS: Diabetes mellitus is associated with worse outcomes and lower attainment of disease-modifying therapies in patients with heart failure with reduced ejection fraction (HFrEF). This post hoc analysis of TRANSITION compared the patterns of tolerability and uptitration of sacubitril/valsartan in patients with HFrEF stabilized after hospital admission due to acute decompensated HF depending on the presence or absence of diabetes as a co-morbidity. METHODS: TRANSITION, a randomized, open-label study compared sacubitril/valsartan initiation pre-discharge vs. post-discharge (up to14 days) in 991 patients hospitalized for acutely decompensated HFrEF. The impact of diabetes status on tolerability and safety was studied at 10-week and 26-week post-randomization. RESULTS: Among the 991 patients analysed at baseline, 460 (46.4%) had diabetes and exhibited a higher risk profile. At 10 weeks, sacubitril/valsartan target dose (97/103 mg bid) was achieved in a similar proportion of patients in each subgroup, when initiated pre-discharge or post-discharge respectively [diabetes subgroup: 47% (n = 105/226) vs. 50% (n = 115/228); relative risk ratio (RRR), 0.923; P = 0.412; non-diabetes subgroup: 45% (n = 119/267) vs. 51% (n = 133/261); RRR, 0.878; P = 0.155]. The proportions of patients achieving and maintaining either 49/51 mg or 97/103 mg bid [diabetes subgroup: 61.1% (n = 138/226) vs. 67.5% (n = 154/228); RRR, 0.909; P = 0.175; non-diabetes subgroup: 62.9% [n = 168/267] vs 69.3% [n = 181/261]; RRR, 0.906; P = 0.118] or any dose for ≥2 weeks leading to Week 10 [diabetes subgroup: 85% (n = 192/226) vs. 88.2% (n = 201/228); RRR, 0.966; P = 0.356; non-diabetes subgroup: 86.9% (n = 232/267) vs. 90.8% (n = 237/261); RRR, 0.963; P = 0.215] were also similar in each subgroup, when initiated pre-discharge or post-discharge, respectively. At 10 weeks, hypotension and renal dysfunction rates were similar, although hyperkalaemia was higher among patients with diabetes (15.9% vs. 9.5%). The rate of permanent discontinuation due to adverse events was similar in the diabetes and non-diabetes subgroups at 10 weeks, respectively: pre-discharge (7.5% vs. 7.1%) or post-discharge (5.7% vs. 4.2%). Similar patterns of uptitration and tolerability were observed at 26 weeks. Cardiac biomarkers including NT-proBNP (P < 0.005) and hs-TnT (P < 0.005) reduced significantly from baseline levels in both subgroups at Weeks 4 and 10; however, the response was greater among patients without diabetes. Mortality (diabetes vs. non-diabetes subgroups: 3.3% vs 4.0%; P = 0.438) and HF rehospitalization (diabetes vs. non-diabetes subgroups: 36.3% vs. 33.0%; P = 0.295) did not differ between the groups at 26 weeks. CONCLUSIONS: Despite a higher risk profile among patients with diabetes, sacubitril/valsartan initiation either before or shortly after discharge in hospitalized patients with HFrEF resulted in comparable rates of dose up-titration and tolerability as in those without diabetes.

• MeSH
• aminobutyráty terapeutické užití   MeSH
• antagonisté receptorů pro angiotenzin terapeutické užití   MeSH
• bifenylové sloučeniny terapeutické užití   MeSH
• diabetes mellitus * MeSH
• lidé MeSH
• následná péče MeSH
• propuštění pacienta MeSH
• srdeční selhání * MeSH
• tepový objem fyziologie   MeSH
• tetrazoly terapeutické užití   MeSH
• valsartan terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• randomizované kontrolované studie MeSH