Introduction: Rheumatoid arthritis (RA) is a chronic autoimmune disease with unknown cause. It mainly affects joints and, without proper treatment, negatively impacts their movement, causes painful deformities, and reduces the patients' quality of life. Current treatment options consist of various types of disease-modifying antirheumatic drugs (DMARDs), however 20-30% of patients are partially resistant to them. Therefore, development of new drugs is necessary. Possible option are compounds exhibiting their action via endocannabinoid system, which plays an important role in pain and inflammation modulation. One such compound - cannabidiol (CBD) has already been shown to attenuate synovitis in animal model of RA in in vivo studies. However, it has low bioavailability due to its low water solubility and lipophilicity. This issue can be addressed by preparation of a lipid containing formulation targeting lymphatic system, another route of absorption in the body. Materials and Methods: CBD-containing emulsion was prepared by high-shear homogenization and its droplet size distribution was analysed by optical microscopy. The relative oral bioavailability compared to oil solution as well as total availability of CBD were assessed in a cross-over study in rats and absorption of CBD via lymphatic system was observed. The effect of CBD on the animal model of RA was determined. Results: Compared to oil solution, the emulsion exhibited higher absolute oral bioavailability. Significant lymphatic transport of CBD was observed in all formulations and the concentrations in lymph were calculated. The therapeutic effect of CBD on RA was confirmed as an improvement in clinical symptoms as well as morphological signs of disease activity were observed during the study. Conclusion: In this work, we prepared a simple stable emulsion formulation, determined the pharmacokinetic parameters of CBD and calculated its absolute bioavailability in rats. Moreover, we successfully tested the pharmaceutical application of such a formulation and demonstrated the positive effect of CBD in an animal model of RA.
- MeSH
- aplikace orální MeSH
- bolest farmakoterapie MeSH
- emulze MeSH
- kanabidiol * farmakologie chemie MeSH
- klinické křížové studie MeSH
- krysa rodu rattus MeSH
- kvalita života MeSH
- revmatoidní artritida * farmakoterapie MeSH
- voda MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
This study compared decitabine exposure when administered IV (DEC-IV) at a dose of 20 mg/m2 for 5-days with orally administered decitabine with cedazuridine (DEC-C), as well as the clinical efficacy and safety of DEC-C in patients with acute myeloid leukaemia (AML) who were ineligible for intensive induction chemotherapy. In all, 89 patients were randomised 1:1 to DEC-IV or oral DEC-C (days 1-5 in a 28-day treatment cycle), followed by 5 days of the other formulation in the next treatment cycle. All patients received oral DEC-C for subsequent treatment cycles until treatment discontinuation. Equivalent systemic decitabine exposures were demonstrated (5-day area under the curve ratio between the two decitabine formulations of 99.64 [90% confidence interval 91.23%, 108.80%]). Demethylation rates also were similar (≤1.1% difference). Median overall survival (OS), clinical response and safety profile with oral DEC-C were consistent with those previously observed with DEC-IV. Next-generation sequencing was performed to identify molecular abnormalities that impact OS and TP53 mutations were associated with a poor outcome. These findings support the use of oral DEC-C in patients with AML.
- MeSH
- akutní myeloidní leukemie * farmakoterapie mortalita MeSH
- aplikace orální MeSH
- decitabin * aplikace a dávkování farmakokinetika škodlivé účinky terapeutické užití MeSH
- dospělí MeSH
- intravenózní podání MeSH
- klinické křížové studie MeSH
- lidé středního věku MeSH
- lidé MeSH
- protokoly antitumorózní kombinované chemoterapie * terapeutické užití farmakokinetika škodlivé účinky aplikace a dávkování MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- uridin * analogy a deriváty aplikace a dávkování farmakokinetika škodlivé účinky terapeutické užití MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- randomizované kontrolované studie MeSH
- srovnávací studie MeSH
Práce přináší souhrn informací o sekvenční antibiotické léčbě, tedy přechodu z parenterálního na perorální podávání antibiotik. Cílem tohoto postupu je zlepšení komfortu pacienta, zkrácení délky hospitalizace, omezení komplikací spojených s nitrožilními vstupy a snížení nákladů, a to za stejného výsledku léčby. Jsou uvedeny podmínky na straně pacienta, vhodné klinické situace a dostupná perorální antibiotika.
The article summarizes information on sequential antibiotic therapy, i.e. the transition from parenteral to oral administration of antibiotics. The aim of this approach is to improve patient comfort, reduce the length of hospital stay, limit complications associated with intravenous access, and decrease costs, all while achieving the same treatment outcomes as in parenteral antibiotic therapy. The review also outlines the conditions on the patient's side, suitable clinical situations, and available oral antibiotics.
- Klíčová slova
- sekvenční terapie,
- MeSH
- antibakteriální látky * aplikace a dávkování škodlivé účinky MeSH
- aplikace orální MeSH
- endokarditida farmakoterapie mikrobiologie MeSH
- infekce dýchací soustavy farmakoterapie mikrobiologie MeSH
- infekce močového ústrojí farmakoterapie mikrobiologie MeSH
- intravenózní podání metody škodlivé účinky MeSH
- kvalita života MeSH
- lidé MeSH
- osteomyelitida farmakoterapie mikrobiologie MeSH
- způsoby aplikace léků * MeSH
- Check Tag
- lidé MeSH
BACKGROUND: Short and rare episodes of atrial fibrillation (AF) are commonly detected using implanted devices (device-detected AF) in patients with prior stroke or transient ischemic attack (TIA). The effectiveness and safety of oral anticoagulation in patients with prior stroke or TIA and device-detected AF but with no ECG-documented AF is unclear. METHODS AND RESULTS: This prespecified analysis of the NOAH-AFNET 6 (Non-Vitamin K Antagonist Oral Anticoagulants in Patients With Atrial High Rate Episodes) trial with post hoc elements assessed the effect of oral anticoagulation in patients with device-detected AF with and without a prior stroke or TIA in the randomized, double-blind, double-dummy NOAH-AFNET 6 trial. Outcomes were stroke, systemic embolism, and cardiovascular death (primary outcome) and major bleeding and death (safety outcome). A prior stroke or TIA was found in 253 patients with device-detected AF randomized in the NOAH-AFNET 6 (mean age, 78 years; 36.4% women). There was no treatment interaction with prior stroke or TIA for any of the primary and secondary time-to-event outcomes. In patients with a prior stroke or TIA, 14 out of 122 patients experienced a primary outcome event with anticoagulation (5.7% per patient-year). Without anticoagulation, there were 16 out of 131 patients with an event (6.3% per patient-year). The rate of stroke was lower than expected (anticoagulation: 4 out of 122 [1.6% per patient-year]; no anticoagulation: 6 out of 131 [2.3% per patient-year]). Numerically, there were more major bleeding events with anticoagulation in patients with prior stroke or TIA (8 out of 122 patients) than without anticoagulation (2 out of 131 patients). CONCLUSIONS: Anticoagulation appears to have ambiguous effects in patients with device-detected AF and a prior stroke or TIA in this hypothesis-generating analysis of the NOAH-AFNET 6 in the absence of ECG-documented AF, partially due to a low rate of stroke without anticoagulation.
- MeSH
- antikoagulancia * aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- aplikace orální MeSH
- časové faktory MeSH
- cévní mozková příhoda * prevence a kontrola etiologie MeSH
- dvojitá slepá metoda MeSH
- fibrilace síní * farmakoterapie komplikace diagnóza MeSH
- kardiostimulátor MeSH
- krvácení chemicky indukované MeSH
- lidé MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- tranzitorní ischemická ataka * prevence a kontrola etiologie MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- randomizované kontrolované studie MeSH
BACKGROUND: Belzutifan, a hypoxia-inducible factor 2α inhibitor, showed clinical activity in clear-cell renal-cell carcinoma in early-phase studies. METHODS: In a phase 3, multicenter, open-label, active-controlled trial, we enrolled participants with advanced clear-cell renal-cell carcinoma who had previously received immune checkpoint and antiangiogenic therapies and randomly assigned them, in a 1:1 ratio, to receive 120 mg of belzutifan or 10 mg of everolimus orally once daily until disease progression or unacceptable toxic effects occurred. The dual primary end points were progression-free survival and overall survival. The key secondary end point was the occurrence of an objective response (a confirmed complete or partial response). RESULTS: A total of 374 participants were assigned to belzutifan, and 372 to everolimus. At the first interim analysis (median follow-up, 18.4 months), the median progression-free survival was 5.6 months in both groups; at 18 months, 24.0% of the participants in the belzutifan group and 8.3% in the everolimus group were alive and free of progression (two-sided P = 0.002, which met the prespecified significance criterion). A confirmed objective response occurred in 21.9% of the participants (95% confidence interval [CI], 17.8 to 26.5) in the belzutifan group and in 3.5% (95% CI, 1.9 to 5.9) in the everolimus group (P<0.001, which met the prespecified significance criterion). At the second interim analysis (median follow-up, 25.7 months), the median overall survival was 21.4 months in the belzutifan group and 18.1 months in the everolimus group; at 18 months, 55.2% and 50.6% of the participants, respectively, were alive (hazard ratio for death, 0.88; 95% CI, 0.73 to 1.07; two-sided P = 0.20, which did not meet the prespecified significance criterion). Grade 3 or higher adverse events of any cause occurred in 61.8% of the participants in the belzutifan group (grade 5 in 3.5%) and in 62.5% in the everolimus group (grade 5 in 5.3%). Adverse events led to discontinuation of treatment in 5.9% and 14.7% of the participants, respectively. CONCLUSIONS: Belzutifan showed a significant benefit over everolimus with respect to progression-free survival and objective response in participants with advanced clear-cell renal-cell carcinoma who had previously received immune checkpoint and antiangiogenic therapies. Belzutifan was associated with no new safety signals. (Funded by Merck Sharp and Dohme, a subsidiary of Merck; LITESPARK-005 ClinicalTrials.gov number, NCT04195750.).
- MeSH
- antitumorózní látky * terapeutické užití škodlivé účinky MeSH
- aplikace orální MeSH
- doba přežití bez progrese choroby MeSH
- dospělí MeSH
- everolimus * aplikace a dávkování škodlivé účinky MeSH
- indeny * aplikace a dávkování škodlivé účinky MeSH
- Kaplanův-Meierův odhad MeSH
- karcinom z renálních buněk * farmakoterapie mortalita MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- nádory ledvin * farmakoterapie mortalita MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- transkripční faktory bHLH antagonisté a inhibitory MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- multicentrická studie MeSH
- randomizované kontrolované studie MeSH
- srovnávací studie MeSH
Zásahy do pevných lékových forem (např. drcení či vysypávání obsahu tobolek) je v klinické praxi v lůžkových zdravotnických zařízeních častým jevem. Tyto zásahy jsou u některých léčivých přípravků nevhodné a mohou vést k přímému ohrožení pacienta. Ve sdělení jsou uvedeny příklady dvou pacientů, u nichž tyto nevhodné zásahy vedly k výskytu zdravotních komplikací. V diskuzi jsou navržena opatření, která by mohla vést k minimalizaci rizik plynoucích z těchto zásahů do pevných lékových forem.
Interference in solid dosage forms (e.g., crushing or emptying the contents of capsules) is common in clinical practice in inpatient healthcare settings. These interferences are inappropriate for some medicinal products and may lead to direct patient endangerment. Examples of two patients in whom these inappropriate interventions led to health complications are given in this communication. The measures that could lead to minimising the risks arising from these interventions in solid dosage forms are suggested in the discussion.
- MeSH
- aplikace orální MeSH
- dabigatran aplikace a dávkování farmakologie MeSH
- kyselina valproová aplikace a dávkování farmakologie MeSH
- lékové formy * MeSH
- lidé středního věku MeSH
- lidé MeSH
- metoprolol aplikace a dávkování farmakologie MeSH
- off-label použití léčivého přípravku klasifikace MeSH
- poškození pacienta * klasifikace MeSH
- senioři MeSH
- způsoby aplikace léků MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
- práce podpořená grantem MeSH
PURPOSE: Safety and efficacy of SENS-401, a serotonin type 3 (5-HT3) receptor antagonist and calcineurin inhibitor, in patients with acute sudden sensorineural hearing loss (SSNHL). METHODS: Multicentre randomized, double blind, placebo-controlled trial enrolled adult subjects with sudden sensorineural hearing loss (SSNHL) or unilateral/bilateral acute acoustic trauma leading to SSNHL within 96 h of disease onset. Subjects were randomly assigned to one of the three oral dose groups: 29 mg, 43.5 mg or placebo given twice daily for 28 days. The primary endpoint was the change from baseline in Pure Tone Average (PTA) in the affected ear to the end of treatment visit (day 28). Subjects were further followed up 8 weeks after the end of the treatment period (day 84). RESULTS: A total of 115 subjects were randomized. SENS-401 was well tolerated. Although the primary efficacy endpoint was not met at day 28, post-hoc analyses revealed clinically significant and meaningful efficacy outcomes with SENS-401 when compared to placebo in a substantial group of participants diagnosed with idiopathic SSNHL and who had received corticosteroid treatment. Notable improvements were observed in the PTA change from baseline, the complete hearing recovery rate, and the Word Recognition Score (WRS), particularly at day 84. The responder rate consistently favored treated subjects over those who received the placebo. CONCLUSION: While the primary endpoint was not achieved at the end of the treatment period, the study revealed consistently positive efficacy results of clinical relevance in patients with idiopathic SSNHL who received SENS-401, particularly in the 8-weeks follow-up phase after the completion of the treatment.
- MeSH
- aplikace orální MeSH
- audiometrie čistými tóny MeSH
- dospělí MeSH
- dvojitá slepá metoda MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- náhlá nedoslýchavost * farmakoterapie MeSH
- následné studie MeSH
- percepční nedoslýchavost * farmakoterapie MeSH
- senioři MeSH
- výsledek terapie MeSH
- vztah mezi dávkou a účinkem léčiva 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
- klinické zkoušky, fáze II MeSH
- multicentrická studie MeSH
- randomizované kontrolované studie MeSH
The bioavailability of rivaroxaban at the higher doses (15 and 20 mg) is considerably reduced when the drug is administered on an empty stomach. This can lead to inadequate anticoagulant effect, and therefore, it is recommended to use the higher doses at fed state. However, proper posology may represent a barrier for some patients. Therefore, the aim of this study was to evaluate innovative rivaroxaban-containing formulations designed to eliminate the food effect to ensure reliable absorption and thus to improve patient adherence with the treatment. Three prototypes (Cocrystal, HPMCP and Kollidon) with rivaroxaban were developed and their bioavailability and food effect in comparison to the reference product was tested in open label, randomized, single oral dose, crossover studies, where test products were administered under fasting and fed conditions and the reference product was administered under fed conditions. Comparable bioavailability for all tested prototypes both under fed and fasting conditions was demonstrated as the 90% confidence intervals of the geometric mean ratios for area under the concentration-time curve remained within the standard acceptance range of 80.00%-125.00%. An innovative immediate release form of rivaroxaban with no food effect on drug bioavailability has been developed, which may represent an important step toward increasing adherence, improving treatment outcome and reducing health care costs.
- MeSH
- aplikace orální MeSH
- biologická dostupnost * MeSH
- dospělí MeSH
- inhibitory faktoru Xa farmakokinetika aplikace a dávkování MeSH
- interakce mezi potravou a léky * MeSH
- jídla MeSH
- klinické křížové studie * MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- omezení příjmu potravy * MeSH
- příprava léků metody MeSH
- rivaroxaban * farmakokinetika aplikace a dávkování MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
