Celecoxib
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Fixní kombinace naproxenu a esomeprazolu představuje inovativní přístup v léčbě bolesti a zánětu u pacientů s osteoartrózou, revmatoidní artritidou a ankylozující spondylitidou. Naproxen jako nesteroidní antirevmatikum s nižším kardiovaskulárním rizikem v kombinaci s esomeprazolem, inhibitorem protonové pumpy přináší účinnou a zároveň bezpečnější variantu terapie, zejména u pacientů s vyšším gastrointestinálním a kardiovaskulárním rizikem. Klinické studie prokázaly srovnatelnou účinnost této kombinace s celekoxibem, ale s nižším výskytem gastrointestinálních nežádoucích účinků. Kombinace nabízí jednoduché dávkování, dobrou toleranci a výhodný bezpečnostní profil, čímž podporuje adherenci pacientů k dlouhodobé terapii. Článek shrnuje dostupná klinická data a přínosy této fixní kombinace v praxi.
The fixed-dose combination of naproxen and esomeprazole represents an innovative approach to managing pain and inflammation in patients with osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis. Naproxen, a nonsteroidal anti-inflammatory drug (NSAID) with a relatively lower cardiovascular risk, combined with esomeprazole, a proton pump inhibitor, offers an effective and safer therapeutic option, particularly for patients at increased gastrointestinal and cardiovascular risk. Clinical studies have demonstrated that this combination provides comparable efficacy to celecoxib, but with a lower incidence of gastrointestinal adverse events. The combination also offers the benefits of simplified dosing, good tolerability, and a favorable safety profile, all of which contribute to improved patient adherence to long-term therapy. This article summarizes the available clinical data and the practical benefits of this fixed combination therapy.
- MeSH
- antiflogistika nesteroidní MeSH
- bolest farmakoterapie MeSH
- esomeprazol * farmakologie terapeutické užití MeSH
- fixní kombinace léků MeSH
- hodnocení léčiv MeSH
- inhibitory protonové pumpy MeSH
- lidé MeSH
- naproxen * farmakologie terapeutické užití MeSH
- revmatické nemoci * farmakoterapie MeSH
- Check Tag
- lidé MeSH
The association and causal role of infectious agents in chronic inflammatory diseases have major implications for public health, treatment, and prevention. Pharmacological treatment of combined infectious and inflammatory diseases requires the administration of multiple drugs, including antibiotics and anti-inflammatory drugs. However, this can cause adverse effects, and therefore, dual-action drugs need to be developed. Anti-inflammatory drugs that have already shown antimicrobial properties appear to be promising candidates. NSAIDs, namely aceclofenac, diclofenac, and ibuprofen, were tested in clinical trials with patients diagnosed with uncomplicated urinary tract infections (UTIs) and cellulitis. The administration of ibuprofen, a drug tested in the highest number of studies, resulted in symptom resolution in patients with UTIs. Additionally, ibuprofen caused a high survival rate in mice infected with Pseudomonas aeruginosa and demonstrated potent in vitro antibacterial effects against Bacillus cereus, Escherichia coli, and Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA) (MIC 0.625-2.5 mg/L). For most anti-inflammatory drugs, only data showing their in vitro and in vivo antimicrobial effects are available. Among these, auranofin caused a high survival rate in mice infected with Enterococcus faecium, S. aureus, and Clostridioides difficile. It also produced a strong in vitro growth-inhibitory effect against Streptococcus agalactiae, S. pneumoniae, S. aureus, S. epidermidis, Bacillus subtilis, C. difficile, E. faecalis, E. faecium, and Mycobacterium tuberculosis (MIC 0.0015-5 mg/L). Similarly, aspirin caused a high survival rate in M. tuberculosis-infected mice and strong to moderate in vitro activity against E. coli, B. cereus, P. aeruginosa, Enterobacter aerogenes, Klebsiella pneumoniae and Salmonella choleraesuis (MIC 1.2-5 mg/L). Moreover, topical application of celecoxib resulted in a high reduction in MRSA burden in mice. However, it only caused moderate in vitro effects against S. epidermidis, S. aureus and Bacillus subitilis (MIC 16-64 mg/L). These data suggest that certain non-steroidal anti-inflammatory drugs (NSAIDs) are promising drug candidates for the development of dual-action drugs for the potential treatment of combined infectious and inflammatory diseases such as tuberculosis, musculoskeletal infections and UTIs. Nevertheless, future clinical trials must be conducted to ascertain the antibacterial effect of these NSAIDs before their practical use.
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Despite currently used intravesical therapies in non-muscle-invasive bladder cancer (NMIBC), the rate of intravesical recurrence remains very high. We aimed to evaluate the effectiveness of adding nonintravesical interventions to standard intravesical therapies to prevent intravesical recurrence. In April 2024, 3 databases were queried for prospective studies evaluating nonintravesical interventions in addition to standard intravesical therapies for NMIBC (CRD42024490988). The primary outcome was intravesical recurrence-free survival (iRFS). Standard pairwise meta-analyses were performed using hazard ratios (HR) and 95% confidence intervals (95% CI) with a random-effects model. We identified 18 eligible studies (14 RCTs and 4 prospective trials) comprising 4,593 NMIBC patients, which investigated pharmacological interventions (eg, selenium, vitamins, Lactobacillus casei, celecoxib, metformin, mistletoe lectin) and lifestyle modifications (diet). The addition of Lactobacillus casei significantly improved iRFS (HR: 0.50; 95% CI: 0.34-0.73; P < .001). A high western diet pattern significantly worsened iRFS (HR:1.48, 95%CI:1.06-2.06, P = .03). The other nonintravesical interventions were not associated with iRFS. Our comprehensive review of the published literature highlights the need for further research into the efficacy of nonvesical interventions for NMIBC. While Lactobacillus was shown to improve iRFS in 2 RCTs, additional high-quality randomized studies are required to evaluate the effectiveness of other interventions.
- MeSH
- aplikace intravezikální MeSH
- celekoxib aplikace a dávkování terapeutické užití MeSH
- Lactobacillus casei MeSH
- lidé MeSH
- lokální recidiva nádoru * prevence a kontrola MeSH
- metformin terapeutické užití aplikace a dávkování MeSH
- nádory močového měchýře * patologie farmakoterapie MeSH
- probiotika aplikace a dávkování terapeutické užití MeSH
- randomizované kontrolované studie jako téma MeSH
- selen aplikace a dávkování terapeutické užití MeSH
- vitaminy aplikace a dávkování terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- metaanalýza MeSH
- přehledy MeSH
- systematický přehled MeSH
Neurozánět hraje důležitou roli v patogenezi epilepsie, a proto je nutné objasnit vliv klasických antiepileptik i adjuvantních látek (např. srdečního glykosidu digoxinu, který již dříve vykazoval jasný antikonvulzivní potenciál) na dráhu cyklooxygenázy a neuron-specifické enolázy v podmínkách chronické epileptogeneze. Cílem článku bylo objasnit vliv digoxinu, natrium-valproátu a celekoxibu samostatně, ale i kombinace digoxinu s natrium-valproátem na obsah cyklooxygenázy 1. a 2. typu, prostaglandinů E2, F2α, I2, tromboxanu B2, 8-isoprostanu a neuron-specifické enolázy v mozku myší na modelu pentylenetetrazolem podnícených záchvatů. Bylo zjištěno, že pouze kombinace natriumvalproátu s digoxinem poskytuje úplný ochranný účinek (absence záchvatů) a vykazuje nejzřetelnější vliv na markery neurozánětu a poškození neuronů ve srovnání s monoterapií každým z těchto léčiv a celekoxibem, který se ukázal jako neúčinné antikonvulzivum. Získané výsledky naznačují, že digoxin je slibným adjuvantním lékem ke klasickým antiepileptikům (především natrium-valproátu) v léčbě epilepsie.
Neuroinflammation plays an important role in the pathogenesis of epilepsy, so it is necessary to clarify the influence of standard antiepileptic drugs as well as adjuvant agents (e.g., cardiac glycoside digoxin, which previously showed a clear anticonvulsant potential) on cyclooxygenase pathway and neuron-specific enolase under the conditions of chronic epileptogenesis. The aim of the article is to determine the effect of digoxin, sodium valproate, and celecoxib per se, as well as the combination of digoxin with sodium valproate on the content of cyclooxygenase 1 and 2 types, prostaglandins E2, F2α, I2, thromboxane B2, 8-isoprostane and neuron-specific enolase in the brain of mice in the pentylenetetrazole-induced kindling model. It was found that only the combination of sodium valproate with digoxin provides a complete protective effect (absence of seizures) and shows the clearest influence on neuroinflammation markers and neuronal damage than monotherapy with each of these drugs and celecoxib, which appeared to be an ineffective anticonvulsant. The obtained results indicate that digoxin is a promising adjuvant drug to classical antiepileptic drugs (mostly sodium valproate) in epilepsy treatment.c
- MeSH
- antikonvulziva * farmakologie terapeutické užití MeSH
- celekoxib aplikace a dávkování farmakologie terapeutické užití MeSH
- cyklooxygenasy účinky léků MeSH
- digoxin aplikace a dávkování terapeutické užití MeSH
- epilepsie chemicky indukované farmakoterapie MeSH
- fosfopyruváthydratasa terapeutické užití MeSH
- kombinovaná farmakoterapie MeSH
- kyselina valproová aplikace a dávkování farmakologie terapeutické užití MeSH
- modely u zvířat MeSH
- neurozánětlivé nemoci * patologie MeSH
- pentylentetrazol farmakologie terapeutické užití MeSH
- potkani Wistar MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
IMPORTANCE: Medulloblastoma recurrence in patients who have previously received irradiation has a dismal prognosis and lacks a standard salvage regimen. OBJECTIVE: To evaluate the response rate of pediatric patients with medulloblastoma recurrence using an antiangiogenic metronomic combinatorial approach (Medulloblastoma European Multitarget Metronomic Anti-Angiogenic Trial [MEMMAT]). DESIGN, SETTING, AND PARTICIPANTS: This phase 2, investigator-initiated, multicenter nonrandomized controlled trial assessed 40 patients with relapsed or refractory medulloblastoma without a ventriculoperitoneal shunt who were younger than 20 years at original diagnosis. Patients were enrolled between April 1, 2014, and March 31, 2021. INTERVENTIONS: Treatment consisted of daily oral thalidomide, fenofibrate, celecoxib, and alternating 21-day cycles of low-dose (metronomic) oral etoposide and cyclophosphamide, supplemented by intravenous bevacizumab and intraventricular therapy consisting of alternating etoposide and cytarabine. MAIN OUTCOMES AND MEASURES: The primary end point was response after 6 months of antiangiogenic metronomic therapy. Secondary end points included progression-free survival (PFS), overall survival (OS), and quality of life. Adverse events were monitored to assess safety. RESULTS: Of the 40 patients (median [range] age at treatment start, 10 [4-17] years; 25 [62.5%] male) prospectively enrolled, 23 (57.5%) achieved disease control after 6 months of treatment, with a response detected in 18 patients (45.0%). Median OS was 25.5 months (range, 10.9-40.0 months), and median PFS was 8.5 months (range, 1.7-15.4 months). Mean (SD) PFS at both 3 and 5 years was 24.6% (7.9%), while mean (SD) OS at 3 and 5 years was 43.6% (8.5%) and 22.6% (8.8%), respectively. No significant differences in PFS or OS were evident based on molecular subgroup analysis or the number of prior recurrences. In patients demonstrating a response, mean (SD) overall 5-year PFS was 49.7% (14.3%), and for patients who remained progression free for the first 12 months of treatment, mean (SD) 5-year PFS was 66.7% (16.1%). Treatment was generally well tolerated. Grade 3 to 4 treatment-related adverse events included myelosuppression, infections, seizures, and headaches. One heavily pretreated patient with a third recurrence died of secondary acute myeloid leukemia. CONCLUSIONS AND RELEVANCE: This feasible and well-tolerated MEMMAT combination regimen demonstrated promising activity in patients with previously irradiated recurrent medulloblastoma. Given these results, this predominantly oral, well-tolerated, and outpatient treatment warrants further evaluation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01356290.
- MeSH
- dítě MeSH
- etoposid MeSH
- kvalita života MeSH
- lidé MeSH
- meduloblastom * farmakoterapie etiologie MeSH
- metronomické podávání léků MeSH
- mladiství MeSH
- nádory mozečku * farmakoterapie etiologie MeSH
- nádory mozku * farmakoterapie MeSH
- předškolní dítě MeSH
- protokoly protinádorové kombinované chemoterapie škodlivé účinky MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky kontrolované MeSH
- multicentrická studie MeSH
Despite the efficacy and potential therapeutic benefits that poly(lactic-co-glycolic acid) (PLGA) nanomedicine formulations can offer, challenges related to large-scale processing hamper their clinical and commercial development. Major hurdles for the launch of a polymeric nanocarrier product on the market are batch-to-batch variations and lack of product consistency in scale-up manufacturing. Therefore, a scalable and robust manufacturing technique that allows for the transfer of nanomedicine production from the benchtop to an industrial scale is highly desirable. Downstream processes for purification, concentration, and storage of the nanomedicine formulations are equally indispensable. Here, we develop an inline sonication process for the production of polymeric PLGA nanomedicines at the industrial scale. The process and formulation parameters are optimized to obtain PLGA nanoparticles with a mean diameter of 150 ± 50 nm and a small polydispersity index (PDI < 0.2). Downstream processes based on tangential flow filtration (TFF) technology and lyophilization for the washing, concentration, and storage of formulations are also established and discussed. Using the developed manufacturing and downstream processing technologies, production of two PLGA nanoformulations encasing ritonavir and celecoxib was achieved at 84 g/h rate. As a measure of actual drug content, encapsulation efficiencies of 49.5 ± 3.2% and 80.3 ± 0.9% were achieved for ritonavir and celecoxib, respectively. When operated in-series, inline sonication and TFF can be adapted for fully continuous, industrial-scale processing of PLGA-based nanomedicines.
- Publikační typ
- časopisecké články MeSH
There is an urgent need for specific antiviral treatments directed against SARS-CoV-2 to prevent the most severe forms of COVID-19. By drug repurposing, affordable therapeutics could be supplied worldwide in the present pandemic context. Targeting the nucleoprotein N of the SARS-CoV-2 coronavirus could be a strategy to impede viral replication and possibly other essential functions associated with viral N. The antiviral properties of naproxen, a non-steroidal anti-inflammatory drug (NSAID) that was previously demonstrated to be active against Influenza A virus, were evaluated against SARS-CoV-2. Intrinsic fluorescence spectroscopy, fluorescence anisotropy, and dynamic light scattering assays demonstrated naproxen binding to the nucleoprotein of SARS-Cov-2 as predicted by molecular modeling. Naproxen impeded recombinant N oligomerization and inhibited viral replication in infected cells. In VeroE6 cells and reconstituted human primary respiratory epithelium models of SARS-CoV-2 infection, naproxen specifically inhibited viral replication and protected the bronchial epithelia against SARS-CoV-2-induced damage. No inhibition of viral replication was observed with paracetamol or the COX-2 inhibitor celecoxib. Thus, among the NSAID tested, only naproxen combined antiviral and anti-inflammatory properties. Naproxen addition to the standard of care could be beneficial in a clinical setting, as tested in an ongoing clinical study.
- MeSH
- antiflogistika nesteroidní farmakologie MeSH
- antivirové látky farmakologie MeSH
- buněčné linie MeSH
- Cercopithecus aethiops MeSH
- COVID-19 MeSH
- farmakoterapie COVID-19 MeSH
- lidé MeSH
- naproxen farmakologie MeSH
- nukleoproteiny antagonisté a inhibitory metabolismus MeSH
- přehodnocení terapeutických indikací léčivého přípravku MeSH
- replikace viru účinky léků MeSH
- SARS-CoV-2 účinky léků fyziologie MeSH
- simulace molekulového dockingu MeSH
- Vero buňky MeSH
- virové proteiny antagonisté a inhibitory metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Combining low-dose chemotherapies is a strategy for designing less toxic and more potent childhood cancer treatments. We examined the effects of combining the novel thiosemicarbazones, di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), or its analog, di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT), with the standard chemotherapies, celecoxib (CX), etoposide (ETO), or temozolomide (TMZ). These combinations were analyzed for synergism to inhibit proliferation of three pediatric tumor cell-types, namely osteosarcoma (Saos-2), medulloblastoma (Daoy) and neuroblastoma (SH-SY5Y). In terms of mechanistic dissection, this study discovered novel thiosemicarbazone targets not previously identified and which are important for considering possible drug combinations. In this case, DpC and Dp44mT caused: (1) up-regulation of a major protein target of CX, namely cyclooxygenase-2 (COX-2); (2) down-regulation of the DNA repair protein, O6-methylguanine DNA methyltransferase (MGMT), which is known to affect TMZ resistance; (3) down-regulation of mismatch repair (MMR) proteins, MSH2 and MSH6, in Daoy and SH-SY5Y cells; and (4) down-regulation in all three cell-types of the MMR repair protein, MLH1, and also topoisomerase 2α (Topo2α), the latter of which is an ETO target. While thiosemicarbazones up-regulate the metastasis suppressor, NDRG1, in adult cancers, it is demonstrated herein for the first time that they induce NDRG1 in all three pediatric tumor cell-types, validating its role as a potential target. In fact, siRNA studies indicated that NDRG1 was responsible for MGMT down-regulation that may prevent TMZ resistance. Examining the effects of combining thiosemicarbazones with CX, ETO, or TMZ, the most promising synergism was obtained using CX. Of interest, a positive relationship was observed between NDRG1 expression of the cell-type and the synergistic activity observed in the combination of thiosemicarbazones and CX. These studies identify novel thiosemicarbazone targets relevant to childhood cancer combination chemotherapy.
- Publikační typ
- časopisecké články MeSH
OBJECTIVE: The objective of this study was to investigate whether diacerein has comparable efficacy with celecoxib in pain reduction for treatment in symptomatic knee OA patients. METHODS: This randomized double-blind multicentre non-inferiority trial evaluated diacerein vs celecoxib treatment in patients with Kellgren-Lawrence grade 2-3 and pain scoring ≥4 (10-cm VAS). Patients were randomized to 6 months of treatment with diacerein 50 mg (n = 187) once daily for 1 month and twice daily thereafter, or celecoxib 200 mg (n = 193) once daily. The primary outcome was the change in WOMAC pain score (0-50 cm) at 6 months, and the secondary outcomes were WOMAC sub-scores, VAS pain score, and the OMERACT-OARSI responder rate. RESULTS: In the per protocol population, the adjusted mean change from baseline in the WOMAC pain score was -11.1 ( 0.9) with diacerein (n = 140) and -11.8 (0.9) with celecoxib (n = 148). The intergroup difference was 0.7 (95% CI: -1.8, 3.2; P = 0.597), meeting the non-inferiority margin. Supportive analysis of the intention-to-treat population gave similar results. Other outcomes showed no significant difference between treatment groups. The incidence of treatment-related adverse events was low and balanced between groups, but a greater incidence of diarrhoea occurred with diacerein (10.2% vs 3.7%). Diarrhoea was considered mild-to-moderate in all but one case with complete resolution. CONCLUSIONS: Diacerein was non-inferior to celecoxib in reducing knee OA pain and improving physical function. Diacerein also demonstrated a good safety profile. TRIAL REGISTRATION: A multicentre study on the effect of DIacerein on Structure and Symptoms vs Celecoxib in Osteoarthritis is a National Institutes of Health (NCT02688400) and European Clinical Trial Database (2015-002933-23) registered phase III (Canada) or IV (Europe) study.
- MeSH
- anthrachinony terapeutické užití MeSH
- antiflogistika nesteroidní terapeutické užití MeSH
- artralgie farmakoterapie MeSH
- artróza kolenních kloubů farmakoterapie MeSH
- celekoxib terapeutické užití MeSH
- dvojitá slepá metoda MeSH
- lidé středního věku MeSH
- lidé MeSH
- měření bolesti MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- hodnocení ekvivalence MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
Background: Oral and topical nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics and intra-articular corticosteroid injections are the recommended first line of treatment for knee osteoarthritis (OA); however, they have serious side effects. Platelet-rich plasma (PRP) has been posited as an effective and safer alternative treatment for knee OA. Hitherto, there is only one study comparing the effectiveness of PRP against an NSAID. Aim of the study: The aim of this study was to determine the effectiveness of PRP against celecoxib in the treatment of early knee OA. Methods: 60 patients with knee OA grade II and III were randomly alocated in two groups. Group 1 received one injection of autologous PRP in each affected knee, with a reinjection after 15 days; Group 2 received 200 mg of oral celecoxib each 24 h for a year. Visual Analogue Scale (VAS), total Western Ontario and McMaster Universities Arthritis Index (WOMAC) and WOMAC subscales for pain, stiffness and function were measured at baseline and at 1, 3, 6 and 12 months after the start of the treatment. Results: At the end of the study PRP was significantly better than celecoxib (p < 0.05) in improving VAS (40.40%), total WOMAC (58.95%) and WOMAC subscales of pain (50.60%), stiffness (34.13%) and function (51.90%). Significant differences remained after adjusting for age, sex or knee OA grade II or III. Conclusions: Intra-articular PRP is significantly better than celecoxib in improving pain, function and stiffness in early knee OA. This significant difference is independent of age, sex or knee OA grade II or III.
