Finerenon je vysoce selektivní, nesteroidní antagonista mineralokortikoidního receptoru (MR) s vyšší vazebnou afinitou než spironolakton nebo eplerenon. Na rozdíl od těchto steroidních inhibitorů MR prokázal finerenon jak kardiovaskulární, tak i renální benefit. Finerenon redukuje albuminurii, která představuje časnější a citlivější marker chronického onemocnění ledvin a zvýšeného KV rizika než samotný pokles eGFR (estimated glomerular filtration rate – odhadnutá hodnota glomerulární filtrace). Také u pacientů se srdečním selháním zvyšuje albuminurie riziko progrese srdečního selhání nebo kardiovaskulárního úmrtí. Finerenon je v současnosti indikován u dospělých pacientů k léčbě chronického onemocnění ledvin s albuminurií, spojeného s diabetem mellitem 2. typu. Tito pacienti by měli být léčeni maximální tolerovanou dávkou inhibitorů systému renin-aniotenzin-aldosteronového systému a gliflozinem. Pokud se jedná o pacienta se srdečním selháním, musí mít ejekční frakci levé komory ≥ 40 %. Před zahájením léčby finerenonem je nutné znát eGFR, kalemii a UACR (urine albumin-creatinine ratio – poměr albuminu a kreatininu v moči); léčbu je možno zahájit při eGFR 25–59 ml/min, kalemii pod 5,0 mmol/l a UACR ≥ 3 mg/mmol (≥ 30 mg/g). Po zahájení léčby je nutno v čtyřtýdenním intervalu kontrolovat hladinu kalemie a eGFR. Pokles UACR je možno pozorovat již po 4 měsících léčby a je dobrým markerem adherence pacientů k léčbě. V článku je dále diskutován dopad na hodnoty krevního tlaku, albuminurii a renální funkce. Jsou probírány i možné nežádoucí účinky. Celý článek ilustrativně doplňují dvě kazuistiky pacientů léčených finerenonem.
Finerenone is a highly selective, non-steroidal mineralocorticoid receptor antagonist with high binding affinity (higher than spironolactone and eplerenone). In contrast to the steroidal mineralocorticoid receptor antagonists, finerenone proved cardiovascular and renal benefit. Finerenone reduces albuminuria, which is a sensitive marker of chronic kidney disease and cardiovascular risk. It is an earlier marker than decreased glomerular filtration rate (GFR). Albuminuria is a marker of increased risk of progression of heart failure and cardiovascular death. Currently, finerenone is indicated to adult patients with type 2 diabetes mellitus with chronic kidney disease with albuminuria. These patients should be treated with maximal tolerated doses of renin angiotensin aldosterone system inhibitors and gliflozins. If a patient had a heart failure, the ejection fraction should be above 40 %. Before starting the therapy with finerenone, it is necessary to know the GFR, potassium level in serum and urine albumin-creatinine ratio (UACR). The therapy can be initiated if GFR is 25-59ml/min, potassium level below 5,0 mmol/L and UACR above 3mg/mmol (≥ 30 mg/g). The potassium serum level and GFR should be controlled within a 4 weeks interval after the initiation of the therapy. Decreased UACR can be observed after 4 months of therapy and it is a very good marker of the patient's adherence to the therapy. The article, beside the possible side effects, discusses the impact of finerenone on blood pressure, albuminuria and renal functions. The whole article is well illustrated by two cases of patients treated with finerenon.
- Keywords
- finerenon,
- MeSH
- Biomarkers MeSH
- Renal Insufficiency, Chronic * drug therapy MeSH
- Diabetes Mellitus, Type 2 MeSH
- Hyperkalemia drug therapy MeSH
- Humans MeSH
- Naphthyridines pharmacology therapeutic use MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Check Tag
- Humans MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Case Reports MeSH
Dlouhotrvající subklinický zánět je prokazatelně jedním z faktorů, které ovlivňují progresi aterosklerózy a vedou k destabilizaci aterosklerotických plátů s rizikem komplikací pod obrazem akutního koronárního syndromu. Kromě farmakologického ovlivnění tradičních rizikových faktorů aterosklerózy, jako je dyslipidemie, přináší kontrola prozánětlivého stavu podobné benefity ústící v pokles rizika kardiovaskulárních příhod, což lze monitorovat např. koncentrací vysoce senzitivního C-reaktivního proteinu. Možnosti cíleného ovlivnění subklinického zánětu medikamenty jsou prozatím velmi limitované, lze ovšem využít dostupná léčiva z plejády hypolipidemik, která vedle samotného hypolipidemického účinku umožňují kontrolu prozánětlivého stavu, což ústí v další redukci kardiovaskulárního rizika.
Long-term subclinical inflammation is one of the factors that influence the progression of atherosclerosis and lead to the destabilization of atherosclerotic plaques with increased risk of complications such as acute coronary syndrome. Control of the pro-inflammatory state brings similar benefits as pharmacological management of traditional risk factors of atherosclerosis resulting in lower risk of cardiovascular events. Decreased inflammatory state can be monitored, for example, by the concentration of highly sensitive C-reactive protein. The possibilities of targeted influence of subclinical inflammation are currently limited, but it is possible to use available substances with hypolipidemic effect, which are able to decrease the pro-inflammatory state resulting in a further reduction of cardiovascular risk.
Stres je často opisovaný ako rizikový faktor pre rozvoj širokého spektra ochorení. Pomerne menej preskúmanou oblasťou je však vplyv stresu na hladinu glukózy, a tým potenciálne na riziko rozvoja ochorenia diabetes mellitus 2. typu u všeobecne zdravých mladých jedincov, ktorí sú stresu vystavovaní na pravidelnej báze. Kazuistika opisuje vývoj glykémie v priebehu 14 dní u 23-ročnej študentky medicíny počas prípravy na skúšku ako aj samotnej skúšky z dermatológie. Hodnoty namerané zariadením FreeStyle Libre 2 sa väčšinu času pohybovali vo fyziologickom rozmedzí s očakávanými zvýšeniami po jedle a fyzickej aktivite. Inak mala glykémia relatívne stabilný vývoj v rámci normálnych hodnôt, až na okamih pár hodín pred skúškou, keď začala stúpať. U pozorovanej študentky došlo k zvýšeniu glykémie až na hodnotu 8,2 mmol/l najpravdepodobnejšie v reakcii na akútny stres.
Stress is often described as a risk factor for developing various diseases. However, a relatively less explored area is the effect of stress on glucose levels, and thus potentially on the risk of developing type 2 diabetes mellitus, in generally healthy young individuals who are exposed to stress regularly. This case report describes the glycaemic trends over 14 days in a 23-year-old medical student while preparing for an exam and the dermatology exam itself. Values measured by the FreeStyle Libre 2 device were within the physiological range most of the time, with expected increases after meals and physical activity. Otherwise, glycaemia had a relatively stable trend within expected values, except for a few hours before the exam when it began to rise. The observed student experienced an increase in glycaemia up to 8,2 mmol/l, most likely in response to acute stress.
- MeSH
- Hyperglycemia * etiology MeSH
- Blood Glucose analysis MeSH
- Humans MeSH
- Young Adult MeSH
- Stress, Psychological * MeSH
- Blood Glucose Self-Monitoring MeSH
- Test Anxiety MeSH
- Students, Medical MeSH
- Check Tag
- Humans MeSH
- Young Adult MeSH
- Female MeSH
- Publication type
- Case Reports MeSH
Pokroky ve farmakoterapii přinesly nové možnosti léčby srdečního selhání. Léčba srdečního selhání se sníženou ejekční frakcí má čtyři základní pilíře – základní léky. Aktualizace doporučených postupů rozšířila možnosti léčby pro srdeční selhání s mírně sníženou a zachovalou ejekční frakcí levé komory. Kromě inhibitorů sodíkoglukózového ko-transportéru 2 je novou nadějí pro pacienty se srdečním selháním a ejekční frakcí levé komory nad 40 % selektivní nesteroidní antagonista mineralokortikoidních receptorů – finerenon.
Advances in pharmacotherapy have brought new possibilities in the treatment of heart failure. Therapy of heart failure with reduced ejection fraction has four basic pillars - fundamental drugs. Update of heart failure guidelines extended new options in the treatment of heart failure with preserved and mildly reduced ejection fraction. In additon to sodium glucose co-transporter 2 inhibitors, it is a hope for patients with heart failure and ejection fraction over 40 % selective non-steroideal mineralocorticoid receptro antagonist - finerenon.
- Keywords
- finerenon,
- MeSH
- Sodium-Glucose Transporter 2 Inhibitors pharmacokinetics therapeutic use MeSH
- Humans MeSH
- Naphthyridines pharmacology therapeutic use MeSH
- Heart Failure * drug therapy MeSH
- Check Tag
- Humans MeSH
- Publication type
- Review MeSH
Multiple sclerosis (MS) is a long-term disease that causes inflammation and damage to the nervous system. This study evaluated steroidomic alterations related to MS in 57 female MS patients during the follicular phase and 17 during the luteal phase, as well as in age- and phase-matched controls. The data showed that (1) unconjugated and conjugated steroids were strongly linked between the blood and CSF. (2) MS patients have lower levels of unconjugated steroids compared to controls. However, unchanged levels of conjugated steroids suggest a possible increase in steroid sulfotransferase functioning. (3) MS patients show altered levels of steroids linked to 11β-hydroxylase (CYP11B1) function. While direct enzyme activity was not measured, disrupted cortisol biosynthesis-potentially linked to reduced functioning of both CYP11B1 and 17α-hydroxylase/17,20-lyase-is associated with more severe cases of MS. (4) Reduced levels of 5α/β-steroids and protective GABAergic 3α-hydroxy-5α/β-steroids in MS patients might be linked to the pathophysiology of MS. (5) A potential increase in AKR1C3 function in MS could contribute to inflammation, as this enzyme catalyzes the synthesis of both steroids and prostaglandins. However, direct measurements of enzyme activity are needed to confirm this hypothesis. (6) Lower pregnenolone levels in MS patients might weaken neuroprotection, while higher pregnenolone sulfate levels could support cognitive function. (7) Lower levels of protective pregnenolone, DHEA, and androstenediol were associated with worse MS, suggesting these steroids may help shield against the disease.
- MeSH
- Adult MeSH
- Follicular Phase cerebrospinal fluid MeSH
- Middle Aged MeSH
- Humans MeSH
- Luteal Phase cerebrospinal fluid MeSH
- Young Adult MeSH
- Multiple Sclerosis * cerebrospinal fluid blood MeSH
- Steroids * cerebrospinal fluid blood MeSH
- Case-Control Studies MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Young Adult MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
In a recent Cell article, Baluapuri et al.1 show that loss of the Integrator (INT) complex activates the integrated stress response via double-stranded RNA from incomplete pre-mRNAs, revealing a link to INT-related neurodevelopmental diseases and potential therapeutic targets.
- MeSH
- RNA, Double-Stranded metabolism genetics MeSH
- Stress, Physiological * MeSH
- Humans MeSH
- Neurodevelopmental Disorders * genetics metabolism MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Immune checkpoints are critical in modulating immune responses and maintaining self-tolerance. Cancer cells can exploit these mechanisms to evade immune detection, making immune checkpoints attractive targets for cancer therapy. The introduction of immune checkpoint inhibitors (ICIs) has transformed cancer treatment, with monoclonal antibodies targeting CTLA-4, PD-1, and PD-L1 demonstrating clinical success. However, challenges such as immune-related adverse events, primary and acquired resistance, and high treatment costs persist. To address these challenges, it is essential to explore alternative strategies, including small-molecule and peptide-based inhibitors, aptamers, RNA-based therapies, gene-editing technologies, bispecific and multispecific agents, and cell-based therapies. Additionally, innovative approaches such as lysosome-targeting chimeras, proteolysis-targeting chimeras, and N-(2-hydroxypropyl) methacrylamide copolymers are emerging as promising options for enhancing treatment effectiveness. This review highlights significant advancements in the field, focusing on their clinical implications and successes.
This study aimed to develop a vancomycin population pharmacokinetic model in obese adult patients treated with intermittent haemodialysis and propose a model-based loading dose strategy ensuring attainment of newly recommended AUC-based PK/PD target. Retrospective cross-sectional analysis was performed among obese haemodialysis dependent adult patients treated with intravenous vancomycin. A pharmacokinetic population model was developed using a nonlinear mixed-effects modelling approach and Monte Carlo simulations were used to identify the optimal loading dose for PK/PD target attainment during the first 48 h of treatment. Therapeutic drug monitoring data from 27 patients with a BMI of 30.2-52.9 kg/m2 were analysed. Among all tested variables, only LBM as a covariate of vancomycin Vd significantly improved the model, while vancomycin CL did not correlate with any of the tested variables. The median (IQR) value from the conditional mean of individual estimates of Vd and CL was 68.4 (56.6-84.2) L and 0.86 (0.79-0.90) L/h, respectively. To ensure optimal vancomycin exposure during the first 48 h of therapy, the vancomycin loading dose of 1500, 1750, 2000, 2250, 2500 and 2750 mg should be administered to obese patients with a lean body mass of ˂50, 50-60, 60-70, 70-80, 80-85 and >85 kg, respectively.
- MeSH
- Anti-Bacterial Agents * pharmacokinetics administration & dosage MeSH
- Models, Biological MeSH
- Renal Dialysis * MeSH
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Monte Carlo Method MeSH
- Drug Monitoring MeSH
- Obesity * complications MeSH
- Cross-Sectional Studies MeSH
- Retrospective Studies MeSH
- Aged MeSH
- Vancomycin * pharmacokinetics administration & dosage MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
