INTRODUCTION: This study explored patient and clinician perspectives on a new fixed-dose combination of macitentan and tadalafil (M/T FDC) in a once-daily single tablet for treatment of pulmonary arterial hypertension (PAH). METHODS: Qualitative semi-structured interviews were conducted during the open-label period of the global, phase 3 A DUE clinical trial that evaluated M/T FDC. A subset of enrolled patients (N = 26) and site investigators (N = 18 clinicians) were interviewed. Patients received four tablets during double-blind treatment and could be in one of three arms (macitentan + placebo; tadalafil + placebo; M/T FDC + placebo) followed by M/T FDC (one tablet) during the open-label period. Patients and clinicians were asked to share their experience of pre-trial PAH medication, double-blind treatment, and open-label M/T FDC. Thematic analysis was conducted on blinded data. RESULTS: Patients preferred the M/T FDC tablet (open-label) over the four tablets during double-blind treatment. Patients were satisfied with M/T FDC, highlighting its positive impact on their psychological well-being, through reducing stress associated with managing multiple pills. All patients indicated that having a single, once-a-day pill for PAH was more convenient and associated with greater treatment adherence. Clinicians highlighted that their patients have a high daily pill burden for PAH and other comorbidities, and prefer treatments with an oral mode of administration that reduce the number of daily pills required. Clinicians felt that M/T FDC would be well received in clinical practice and potentially assist in implementing guideline-recommended combination treatment of PAH. CONCLUSIONS: In this qualitative analysis, all 26 patients and 18 clinicians provided positive feedback on M/T FDC treatment, which was consistent across countries. Reducing the number of pills needed to treat PAH, through use of single-tablet M/T FDC, is highly valued by patients and endorsed by clinicians, who both felt the single-tablet combination therapy could have a positive effect on patients' well-being and increase treatment adherence.

• Klíčová slova
• Clinician interview, Fixed-dose combination, Patient interview, Patient perspective, Polypharmacy, Pulmonary arterial hypertension, Treatment adherence,
• MeSH
• adaptivní klinické zkoušky jako téma MeSH
• antihypertenziva * aplikace a dávkování   terapeutické užití   MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• fixní kombinace léků MeSH
• inhibitory fosfodiesterasy 5 aplikace a dávkování   terapeutické užití   MeSH
• klinické zkoušky, fáze III jako téma MeSH
• kvalitativní výzkum MeSH
• lidé středního věku MeSH
• lidé MeSH
• multicentrické studie jako téma MeSH
• plicní arteriální hypertenze * farmakoterapie   MeSH
• plicní hypertenze * farmakoterapie   MeSH
• pyrimidiny * aplikace a dávkování   terapeutické užití   MeSH
• randomizované kontrolované studie jako téma MeSH
• rozhovory jako téma MeSH
• senioři MeSH
• spokojenost pacientů MeSH
• sulfonamidy * aplikace a dávkování   terapeutické užití   MeSH
• tablety MeSH
• tadalafil * aplikace a dávkování   terapeutické užití   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antihypertenziva * MeSH
• fixní kombinace léků MeSH
• inhibitory fosfodiesterasy 5 MeSH
• macitentan MeSH Prohlížeč
• pyrimidiny * MeSH
• sulfonamidy * MeSH
• tablety MeSH
• tadalafil * MeSH

Pulmonary arterial hypertension (PAH) is a severe and progressive disease with limited survival prospects under currently available therapies. Since the 2022 edition of the European Society of Cardiology and European Respiratory Society guidelines on pulmonary hypertension, substantial clinical evidence has emerged, supporting a new treatment algorithm for PAH as presented at the 7th World Symposium on Pulmonary Hypertension 2024 and the following proceeding papers. Key updates include the introduction of sotatercept as a second-line therapy leading to a revised definition of maximal medical therapy now encompassing agents from four therapeutic groups (phosphodiesterase-5 inhibitors/soluble guanylate cyclase stimulators, endothelin receptor antagonists, prostacyclin pathway agents, and sotatercept), instead of three (phosphodiesterase-5 inhibitors/soluble guanylate cyclase stimulators, endothelin receptor antagonists, prostacyclin pathway agents). Other novelties include the elimination of a distinct pathway for patients with cardiopulmonary comorbidities in favor of an individualized approach, a reduction in the initial patient assessment risk categories from three to two, and a follow-up interval shortened from 3-6 months to 3-4 months post-treatment initiation. This review presents these advancements and emphasizes the need for their widespread implementation in clinical practice. At the end, we present new opportunities and challenges in the treatment of pulmonary arterial hypertension in eight Central and Eastern European countries.

• Klíčová slova
• activin signaling inhibitors, novel therapies, risk assessment, sotatercept, treatment strategy,
• MeSH
• antihypertenziva terapeutické užití   MeSH
• inhibitory fosfodiesterasy 5 terapeutické užití   MeSH
• lidé MeSH
• plicní arteriální hypertenze * farmakoterapie   MeSH
• plicní hypertenze farmakoterapie   terapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• antihypertenziva MeSH
• inhibitory fosfodiesterasy 5 MeSH

INTRODUCTION: The relationship between a poorly functioning thyroid gland and erectile dysfunction (hereinafter, "ED") has been demonstrated in many studies. If a man has thyroid problems, it can negatively affect his ability to achieve or maintain an erection. The thyroid gland produces hormones that affect metabolism and overall body function, including blood circulation. If the thyroid gland is not functioning properly, it can lead to blood circulation disorders, which can affect erectile function. There are also symptoms of thyroid disorders that can contribute to ED. Some of these symptoms include fatigue, depression, and anxiety, which can negatively affect a man's psychological side and affect his sexual performance. OBJECTIVES AND METHODS: In our article, we present a series of patients with ED who were treated in our department and found to have some form of thyroid dysfunction. RESULTS: After treatment for thyroid dysfunction and treatment with 5-phosphodiesterase inhibitors were implemented, erectile function improved in all patients ((Wilcoxon Signed Rank Test; Z = -4.55; p (2-tailed) < 0.001; n = 27) to the level of mild or no ED. Improvement occurred in men with hyper- and hypothyroidism. After one year of treatment, there was no difference between the two groups (t-test; t = 0.75; df = 0.25; p < 0.46). CONCLUSION: This study shows that screening for thyroid dysfunction should be performed in all men with ED and that treating thyroid dysfunction may be an effective way to improve erectile function in men with these health problems.

• MeSH
• dospělí MeSH
• erektilní dysfunkce * farmakoterapie   MeSH
• hypertyreóza * komplikace   farmakoterapie   MeSH
• hypotyreóza * farmakoterapie   komplikace   MeSH
• inhibitory fosfodiesterasy 5 * terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• inhibitory fosfodiesterasy 5 * MeSH

BACKGROUND: Sildenafil, approved for pulmonary arterial hypertension (PAH), has a recommended adult dose of 20 mg TID, with a previously approved 5-mg TID dose by the US Food and Drug Administration. Safety concerns arose because of common off-label use of higher doses, particularly after pediatric data linked higher doses to increased mortality. To assess this, the Food and Drug Administration mandated a study evaluating the effects of various sildenafil doses on mortality in adults with PAH. METHODS: This randomized, double-blind study compared sildenafil at doses of 5, 20, or 80 mg TID in adults with PAH. The primary objective was noninferiority of 80 mg of sildenafil versus 5 mg for all-cause mortality. Secondary end points included time to clinical worsening and change in 6-minute walk distance at 6 months. Interim analyses were planned at 50% and 75% of the anticipated mortality events. Safety and tolerability were assessed in the intention-to-treat population. RESULTS: The study was halted after the first interim analysis, demonstrating noninferiority for 80 mg of sildenafil versus 5 mg. Of 385 patients enrolled across all dose groups, 78 died. The primary analysis showed a hazard ratio of 0.51 (99.7% CI, 0.22-1.21; P<0.001 for noninferiority) for overall survival comparing 80 mg of sildenafil with 5 mg. Time to clinical worsening favored 80 mg of sildenafil compared with 5 mg (hazard ratio, 0.44 [99.7% CI, 0.22-0.89]; P<0.001). Sildenafil at 80 mg improved 6-minute walk distance from baseline at 6 months compared with 5 mg (least square mean change, 18.9 m [95% CI, 2.99-34.86]; P=0.0201). No significant differences were found between 80 mg of sildenafil and 20 mg in mortality, clinical worsening, and 6-minute walk distance. Adverse event-related drug discontinuations were numerically higher with 80 mg of sildenafil. CONCLUSIONS: Sildenafil at 80 mg was noninferior to sildenafil at 5 mg when examining all-cause mortality in adults with PAH. Secondary efficacy end points favored 80 mg of sildenafil over 5 mg. On the basis of these findings, the Food and Drug Administration recently revoked the approval of 5 mg of sildenafil for adults with PAH, reinforced 20 mg TID as the recommended dose, and now allows dose titration up to 80 mg TID, if needed. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02060487.

• Klíčová slova
• mortality, pulmonary arterial hypertension, safety, sildenafil citrate, survival,
• MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• inhibitory fosfodiesterasy 5 aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• plicní arteriální hypertenze farmakoterapie   mortalita   MeSH
• plicní hypertenze farmakoterapie   mortalita   MeSH
• senioři MeSH
• sildenafil citrát * aplikace a dávkování   terapeutické užití   škodlivé účinky   MeSH
• test chůzí MeSH
• vazodilatancia aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• výsledek terapie MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• inhibitory fosfodiesterasy 5 MeSH
• sildenafil citrát * MeSH
• vazodilatancia MeSH

While phosphodiesterase-5 inhibition (PED5i) may prevent hypertrophy and failure in pressure-overloaded heart in an experimental model, the impact of PDE5i on volume-overload (VO)-induced hypertrophy is unknown. It is also unclear whether the hypertrophied right ventricle (RV) and left ventricle (LV) differ in their responsiveness to long-term PDE5i and if this therapy affects renal function. The goal of this study was to elucidate the effect of PDE5i treatment in VO due to aorto-caval fistula (ACF) and to compare PDE5i treatment with standard heart failure (HF) therapy with angiotensin-converting enzyme inhibitor (ACEi). ACF/sham procedure was performed on male HanSD rats aged 8 weeks. ACF animals were randomized for PDE5i sildenafil, ACEi trandolapril, or placebo treatments. After 20 weeks, RV and LV function (echocardiography, pressure-volume analysis), myocardial gene expression, and renal function were studied. Separate rat cohorts served for survival analysis. ACF led to biventricular eccentric hypertrophy (LV: +68%, RV: +145%), increased stroke work (LV: 3.6-fold, RV: 6.7-fold), and reduced load-independent systolic function (PRSW, LV: -54%, RV: -51%). Both ACF ventricles exhibited upregulation of the genes of myocardial stress and glucose metabolism. ACEi but not PDE5i attenuated pulmonary congestion, LV remodeling, albuminuria, and improved survival (median survival in ACF/ACEi was 41 weeks vs. 35 weeks in ACF/placebo, p = .02). PDE5i increased cyclic guanosine monophosphate levels in the lungs, but not in the RV, LV, or kidney. PDE5i did not improve survival rate and cardiac and renal function in ACF rats, in contrast to ACEi. VO-induced HF is not responsive to PDE5i therapy.

• Klíčová slova
• heart failure, phosphodiesterase-5 inhibition, rats, right ventricle, volume overload,
• MeSH
• inhibitory ACE * farmakologie   MeSH
• inhibitory fosfodiesterasy 5 * farmakologie   MeSH
• kardiomegalie farmakoterapie   MeSH
• krysa rodu Rattus MeSH
• remodelace komor * MeSH
• srdeční selhání * farmakoterapie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• inhibitory ACE * MeSH
• inhibitory fosfodiesterasy 5 * MeSH

BACKGROUND: Endothelin receptor antagonist (ERA) and phosphodiesterase 5 inhibitor (PDE5i) combination therapy is recommended for low-/intermediate-risk pulmonary arterial hypertension (PAH) patients. A fixed-dose combination of the ERA macitentan and PDE5i tadalafil (M/T FDC) in a once-daily, single tablet would simplify treatment. OBJECTIVES: The multicenter, double-blind, adaptive phase 3 A DUE study investigated the efficacy and safety of M/T FDC vs macitentan 10 mg and vs tadalafil 40 mg monotherapies in PAH patients, including treatment-naïve and prior ERA or PDE5i monotherapy-treated patients. METHODS: World Health Organization functional class II-III patients were randomized to M/T FDC, macitentan, or tadalafil depending on their PAH treatment (treatment-naïve, ERA, or PDE5i monotherapy) at baseline. The primary endpoint was change in pulmonary vascular resistance (PVR) at week 16. RESULTS: In total, 187 patients were randomized to single-tablet M/T FDC (n = 108), macitentan (n = 35), or tadalafil (n = 44). PVR reduction with M/T FDC was significantly greater vs macitentan (29%; geometric mean ratio 0.71; 95% CL: 0.61-0.82; P < 0.0001) and vs tadalafil (28%; geometric mean ratio 0.72; 95% CL: 0.64-0.80; P < 0.0001). Three patients died in the M/T FDC arm (judged unrelated to treatment). Adverse events (AEs) leading to discontinuation, serious AEs, and those of special interest (anemia, hypotension, and edema) were more frequent with M/T FDC. CONCLUSIONS: Macitentan and tadalafil FDC significantly improved PVR vs monotherapies in PAH patients, with a safety and tolerability profile consistent with the individual components. The A DUE study supports M/T FDC as a once-daily, single-tablet combination for initial therapy and escalation to double combination therapy in patients with PAH. (Clinical Study to Compare the Efficacy and Safety of Macitentan and Tadalafil Monotherapies With the Corresponding Fixed-dose Combination Therapy in Subjects With Pulmonary Arterial Hypertension [PAH]) [A DUE]; NCT03904693).

• Klíčová slova
• macitentan, pulmonary arterial hypertension, randomized controlled trial, single-tablet (fixed-dose) combination therapy, tadalafil,
• MeSH
• antagonisté endotelinového receptoru MeSH
• inhibitory fosfodiesterasy 5 MeSH
• kombinovaná terapie MeSH
• lidé MeSH
• plicní arteriální hypertenze * MeSH
• pyrimidiny * MeSH
• sulfonamidy * MeSH
• tablety MeSH
• tadalafil MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• antagonisté endotelinového receptoru MeSH
• inhibitory fosfodiesterasy 5 MeSH
• macitentan MeSH Prohlížeč
• pyrimidiny * MeSH
• sulfonamidy * MeSH
• tablety MeSH
• tadalafil MeSH

BACKGROUND: Experimental evidence has revealed that phosphodiesterase five inhibitors (PDE5is) increase epithelial barrier function and suppress intestinal carcinogenesis. Few epidemiological studies have investigated the role of PDE5i in increasing the risk of colorectal cancer (CRC); however, these studies have proffered varying conclusions. We therefore aimed to perform a comprehensive review and meta-analysis to investigate whether PDE5i use is associated with the incidence of CRC. METHODS: Databases, namely, PubMed, Scopus, Embase, and Web of Science, were used for literature search. Observational studies (published until January 31, 2021) that assessed the association of PDE5i use with CRC incidence were considered. Pooled relative risk (RR) estimates and corresponding 95% confidence intervals (CIs) were calculated using the DerSimonian-Laird random-effects model. RESULTS: We identified four retrospective studies that involved 965,044 participants and 3,518 CRC cases detected during a mean follow-up of 12.7 years. Pooled results indicated a significantly reduced CRC risk among all PDE5i users (RR, 0.85; 95% CI, 0.76-0.95; P = 0.004, I2 = 63%). Moreover, continuous use of PDE5i was associated with a significantly reduced risk of CRC (RR, 0.63; 95% CI, 0.59-0.68; P < 0.001, I2 = 0.0%). However, the type of PDE5i exhibited no association with the risk of CRC (RR, 1.00; 95% CI, 0.98-1.02; I2 = 84.7%). CONCLUSION: Our findings suggest that continuous use of PDE5i was associated with a significantly reduced risk of CRC development. Future studies with a longitudinal design and adequate control of confounding factors are required to clarify whether a longer duration of PDE5i use alters the risk of CRC.

• Klíčová slova
• Colorectal cancer, Meta-analysis, Pharmacoepidemiology, Phosphodiesterase five inhibitors, Risk, Sildenafil,
• MeSH
• incidence MeSH
• inhibitory fosfodiesterasy 5 * MeSH
• kolorektální nádory * epidemiologie   MeSH
• lidé MeSH
• retrospektivní studie MeSH
• riziko MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• přehledy MeSH
• systematický přehled MeSH
• Názvy látek
• inhibitory fosfodiesterasy 5 * MeSH

BACKGROUND: Riociguat and phosphodiesterase-5 inhibitors (PDE5i), approved for the treatment of pulmonary arterial hypertension (PAH), act on the same pathway via different mechanisms. Riociguat might be an alternative option for patients with PAH who do not respond sufficiently to treatment with PDE5i, but comparisons of the potential benefits of riociguat and PDE5i in these patients are needed. The aim of this trial was to assess the effects of switching to riociguat from PDE5i therapy versus continued PDE5i therapy in patients with PAH at intermediate risk of 1-year mortality. METHODS: Riociguat rEplacing PDE5i therapy evaLuated Against Continued PDE5i thErapy (REPLACE) was an open-label, randomised controlled trial in 81 hospital-based pulmonary hypertension centres in 22 countries. The study enrolled patients aged 18-75 years with symptomatic PAH at intermediate risk of 1-year mortality (based on the European Society for Cardiology-European Respiratory Society guideline thresholds for WHO functional class and 6-min walk distance [6MWD]) who were receiving treatment with a PDE5i with or without an endothelin receptor antagonist for at least 6 weeks before randomisation. Patients were excluded if they had been previously treated with riociguat, had used prostacyclin analogues or prostacyclin receptor agonists within 30 days before randomisation, had clinically significant restrictive or obstructive parenchymal lung disease, or had left heart disease. Patients were randomly assigned (1:1) to remain on PDE5i treatment (oral sildenafil [≥60 mg per day] or oral tadalafil [20-40 mg per day]; the PDE5i group) or to switch to oral riociguat (up to 2·5 mg three times per day; the riociguat group), using an interactive voice and web response system, stratified by cause of PAH. The primary endpoint was clinical improvement by week 24, defined as an absence of clinical worsening and prespecified improvements in at least two of three variables (6MWD, WHO functional class, and N-terminal prohormone of brain natriuretic peptide), analysed using last observation carried forward in all randomly assigned patients with observed values at baseline and week 24 who received at least one dose of study medication (the full analysis set). Secondary endpoints included clinical worsening events. The trial has been completed and is registered with ClinicalTrials.gov, NCT02891850. FINDINGS: Between Jan 11, 2017, and July 31, 2019, 293 patients were screened, of which 226 patients were randomly assigned to the riociguat group (n=111) or to the PDE5i group (n=115). 211 patients completed the study and 14 patients discontinued (seven in each group). One patient assigned to the PDE5i group did not receive treatment, so 225 patients were included in the safety analysis, and one further patient in the PDE5i group had missing components of the composite primary endpoint at baseline, so 224 patients were included in the full analysis set. The primary endpoint was met by 45 (41%) of 111 patients in the riociguat group and 23 (20%) of 113 patients in the PDE5i group; odds ratio [OR] 2·78 (95% CI 1·53-5·06; p=0·0007). Clinical worsening events occurred in one (1%) of 111 patients in the riociguat group (hospitalisation due to worsening PAH) and 10 (9%) of 114 patients in the PDE5i group (hospitalisation due to worsening PAH [n=9]; disease progression [n=1]; OR 0·10 [0·01-0·73]; p=0·0047). The most frequently occurring adverse events were hypotension (15 [14%]), headache (14 [13%]), and dyspepsia (10 [9%]) in the riociguat group, and headache (eight [7%]), cough (seven [6%]), and upper respiratory tract infection (seven [6%]) in the PDE5i group. Serious adverse events were reported in eight (7%) of 111 patients in the riociguat group and 19 (17%) of 114 patients in the PDE5i group. During the study, four patients died in the PDE5i group, one of them during the safety follow-up period. INTERPRETATION: Switching to riociguat from PDE5i treatment, both of which act via the nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate pathway, could be a strategic option for treatment escalation in patients with PAH at intermediate risk of 1-year mortality. FUNDING: Bayer AG, Merck Sharp & Dohme.

• MeSH
• dospělí MeSH
• inhibitory fosfodiesterasy 5 terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• plicní arteriální hypertenze farmakoterapie   MeSH
• prospektivní studie MeSH
• pyrazoly terapeutické užití   MeSH
• pyrimidiny terapeutické užití   MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý 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
• srovnávací studie MeSH
• Názvy látek
• inhibitory fosfodiesterasy 5 MeSH
• pyrazoly MeSH
• pyrimidiny MeSH
• riociguat MeSH Prohlížeč

BACKGROUND: Standard care in severe SARS-CoV-2 pneumonia complicated by severe dyspnea and respiratory failure, consists of symptom reduction, ultimately supported by mechanical ventilation. Patients with severe SARS-CoV-2, a prominent feature of COVID-19, show several similar symptoms to Critical Asthma Syndrome (CAS) patients, such as pulmonary edema, mucus plugging of distal airways, decreased tissue oxygenation, (emergent) exhaustion due to severe dyspnea and respiratory failure. Prior application of elective phosphodiesterase (PDE)3-inhibitors milrinone and enoximone in patients with CAS yielded rapid symptomatic relief and reverted the need for mechanical ventilation, due to their bronchodilator and anti-inflammatory properties. Based on these observations, we hypothesized that enoximone may be beneficial in the treatment of patients with severe SARS-CoV-2 pneumonia and prominent CAS-features. METHODS: In this case report enoximone was administered to four consecutive patients (1 M; 3 F; 46-70 y) with emergent respiratory failure due to SARS-CoV-2 pneumonia. Clinical outcome was compared with three controls who received standard care only. RESULTS: After an intravenous bolus of enoximone 20 mg followed by 10 mg/h via perfusor, a rapid symptomatic relief was observed: two out of four patients recovered within a few hours, the other two (with comorbid COPD GOLD II/III) responded within 24-36 h. Compared to the controls, in the enoximone-treated patients respiratory failure and further COVID-19-related deterioration was reverted and mechanical ventilation was prevented, leading to reduced hospital/ICU time. DISCUSSION: Our preliminary observations suggest that early intervention with the selective PDE3-inhibitor enoximone may help to revert respiratory failure as well as avert mechanical ventilation, and reduces ICU/hospital time in patients with severe SARS-CoV-2 pneumonia. Our findings warrant further research on the therapeutic potential of PDE3-inhibition, alone or in combination with other anti-COVID-19 strategies.

• Klíčová slova
• COVID-19, PDE3-inhibitor, SARS-CoV-2 infection, cytokine storm, enoximone, inflammation, mechanical, ventilation,
• MeSH
• enoximon terapeutické užití   MeSH
• farmakoterapie COVID-19 * MeSH
• inhibitory fosfodiesterasy 3 terapeutické užití   MeSH
• jednotky intenzivní péče MeSH
• lidé středního věku MeSH
• lidé MeSH
• respirační insuficience terapie   MeSH
• SARS-CoV-2 * MeSH
• senioři MeSH
• umělé dýchání * MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• enoximon MeSH
• inhibitory fosfodiesterasy 3 MeSH

To improve the treatment of psoriasiform inflammation, we developed actively targeted nanocarriers loaded with the phosphodiesterase 4 inhibitor AN2728. Methods: Phospholipid-poly(lactic-co-glycolic acid) nanohybrids were prepared and conjugated with monovalent anti-desmoglein 3 antibody to bind keratinocytes. Results: The actively targeted nanohybrids were 229 nm in mean size with a nearly neutral surface charge. Flow cytometry and confocal microscopy showed a 9-fold increase in keratinocyte uptake of targeted nanohybrids relative to non-targeted nanoparticles. The nanoparticles localized mainly in lysosomes after internalization. AN2728-loaded antibody-conjugated nanocarriers inhibited cytokine/chemokine overexpression in activated keratinocytes without affecting cell viability. The targeted nanohybrids also suppressed neutrophil migration by reducing CXCL1 and CXCL2 release from keratinocytes. Following subcutaneous administration in mice, the nanohybrids distributed to the epidermis and hair follicles. In a psoriasis-like skin mouse model, the actively targeted nanoparticles were superior to free drug and non-targeted nanoparticles in mitigating skin inflammation. Intervention with the targeted nanosystem reduced the epidermal thickness of the psoriasiform lesion from 191 to 42 µm, decreased the Psoriasis Area Severity Index by 74%, restored barrier function, and returned chemokine levels to baseline. Conclusions: Our developed nanosystem was safe and demonstrated efficient targeting properties for the treatment of cutaneous inflammation.

• Klíčová slova
• active targeting, desmoglein 3, keratinocyte, lipid-polymer nanohybrid, monovalent antibody, psoriasis,
• MeSH
• bicyklické sloučeniny heterocyklické aplikace a dávkování   farmakologie   MeSH
• buněčné linie keratinocytů HaCaT MeSH
• chemokin CXCL1 účinky léků   imunologie   MeSH
• chemokin CXCL2 účinky léků   imunologie   MeSH
• chemotaxe účinky léků   MeSH
• desmoglein 3 imunologie   MeSH
• epidermis MeSH
• fosfolipidy * MeSH
• imunokonjugáty farmakologie   MeSH
• inhibitory fosfodiesterasy 4 aplikace a dávkování   farmakologie   MeSH
• keratinocyty účinky léků   imunologie   MeSH
• kopolymer kyseliny glykolové a mléčné * MeSH
• lékové transportní systémy MeSH
• lidé MeSH
• lyzozomy metabolismus   ultrastruktura   MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• nanočástice * MeSH
• neutrofily účinky léků   MeSH
• nosiče léků MeSH
• protilátky imunologie   MeSH
• psoriáza imunologie   patologie   MeSH
• sloučeniny boru aplikace a dávkování   farmakologie   MeSH
• vlasový folikul MeSH
• zánět MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• bicyklické sloučeniny heterocyklické MeSH
• chemokin CXCL1 MeSH
• chemokin CXCL2 MeSH
• crisaborole MeSH Prohlížeč
• desmoglein 3 MeSH
• fosfolipidy * MeSH
• imunokonjugáty MeSH
• inhibitory fosfodiesterasy 4 MeSH
• kopolymer kyseliny glykolové a mléčné * MeSH
• nosiče léků MeSH
• protilátky MeSH
• sloučeniny boru MeSH