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.
- Klíčová slova
- Celecoxib, Diet, Lactobacillus casei, Non-muscle-invasive bladder cancer, Vitamins,
- 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
- Názvy látek
- celekoxib MeSH
- metformin MeSH
- selen MeSH
- vitaminy MeSH
BACKGROUND: Myelodysplastic Syndrome (MDS) is a devastating hematologic malignancy associated with advanced age. Diabetes Mellitus (DM) is one of the most common morbidities worldwide, with metformin serving as the first line therapy for several decades. However, the potential association between previous metformin use and the risk of developing MDS remains uncertain. METHODS: This cross-sectional study addressed the possible association between prior metformin use in DM patients and the subsequent development of MDS. RESULTS: Data from 54,869 DM patients was retrieved from their medical records from a tertiary medical center. Of these, 20,318 patients had been exposed at some point in time to metformin, with 133 (0.7%) subsequently developing MDS. In contrast, among 34,551 DM patients with no prior exposure to metformin, only 154 (0.4%) developed MDS later in life. The Odds Ratio (OR) for MDS development amongst metformin users compared to the entire study population was 1.48 (95% CI 1.17-1.86; p = 0.001). A multivariate analysis adjusting for gender, age, congestive heart failure and chronic kidney disease, past exposure to metformin remained an independent risk factor for MDS development (OR = 1.6, 95% CI 1.26-2.03; p < 0.001). CONCLUSION: Previous exposure to metformin amongst DM patients is associated with an increased risk for MDS development later in life. This is a preliminary, cross-sectional study that show that larger studies in variable MDS patient populations are warranted.
- Klíčová slova
- Biguanides, Cross sectional study, MDS, Metformin, Myelodysplastic syndrome, Odds ratio,
- MeSH
- diabetes mellitus epidemiologie chemicky indukované MeSH
- dospělí MeSH
- hypoglykemika * terapeutické užití škodlivé účinky MeSH
- lidé středního věku MeSH
- lidé MeSH
- metformin * terapeutické užití škodlivé účinky MeSH
- myelodysplastické syndromy * epidemiologie chemicky indukované MeSH
- průřezové studie MeSH
- rizikové faktory MeSH
- senioři nad 80 let MeSH
- senioři 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
- Názvy látek
- hypoglykemika * MeSH
- metformin * MeSH
Proper fetal development requires tight regulation of serotonin concentrations within the fetoplacental unit. This homeostasis is partly maintained by the placental transporter OCT3/SLC22A3, which takes up serotonin from the fetal circulation. Metformin, an antidiabetic drug commonly used to treat gestational diabetes mellitus, was shown to inhibit OCT3. We, therefore, hypothesized that its use during pregnancy could disrupt placental serotonin homeostasis. This hypothesis was tested using three experimental model systems: primary trophoblast cells isolated from the human term placenta, fresh villous human term placenta fragments, and rat term placenta perfusions. Inhibition of serotonin transport by metformin at three concentrations (1 μM, 10 μM, and 100 μM) was assessed in all three models. The OCT3 inhibitor decynium-22 (100 μM) and paroxetine (100 μM), a dual inhibitor of SERT and OCT3, were used as controls. In primary trophoblasts, paroxetine exhibited the strongest inhibition of serotonin uptake, followed by decynium-22. Metformin showed a concentration-dependent effect, reducing serotonin uptake by up to 57 % at the highest concentration. Its inhibitory effect was less pronounced in fresh villous fragments but remained statistically significant at all concentrations. In the perfused rat placenta, metformin demonstrated a concentration-dependent effect, reducing placental serotonin uptake by 44 % at the highest concentration tested. Our findings across all experimental models show inhibition of placental OCT3 by metformin, resulting in reduced serotonin uptake by the trophoblast. This sheds light on mechanisms that may underpin metformin-mediated effects on fetal development.
- Klíčová slova
- OCT3, gestational diabetes mellitus, metformin, placenta, pregnancy, serotonin,
- MeSH
- biologický transport účinky léků MeSH
- hypoglykemika farmakologie MeSH
- krysa rodu Rattus MeSH
- kultivované buňky MeSH
- lidé MeSH
- metformin * farmakologie MeSH
- oktamerní transkripční faktor 3 metabolismus MeSH
- placenta * metabolismus účinky léků MeSH
- potkani Wistar MeSH
- proteiny přenášející organické kationty MeSH
- serotonin * metabolismus MeSH
- těhotenství MeSH
- trofoblasty * metabolismus účinky léků MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- lidé MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- hypoglykemika MeSH
- metformin * MeSH
- oktamerní transkripční faktor 3 MeSH
- proteiny přenášející organické kationty MeSH
- serotonin * MeSH
- solute carrier family 22 (organic cation transporter), member 3 MeSH Prohlížeč
The rising burden of type 2 diabetes mellitus (T2D) poses a significant healthcare challenge on a global scale. The economic impact is also substantial and continually increasing. In Serbia, even though the prevalence is officially around 12 percent, nearly 40 percent of the adult population is estimated to be living with undiagnosed diabetes and more than half the population is obese or overweight. This review comprehensively addresses the present approach to treating T2D, emphasizing the critical role of treatment adherence. We review the various components of T2D treatment, underlining the significance of lifestyle modifications. The pros and cons of medications used in treatment are discussed and factors influencing adherence are analysed. A healthy lifestyle remains the foundation of the treatment, and if not sufficient, early pharmacotherapy is initiated. Medications have been developed to lower blood sugar levels with cardiorenal protection, however, due to their still high cost, metformin remains the drug of first choice for most patients. Adherence to the treatment regimen is often poor. Factors associated with this are diverse and often multiple in a particular patient. Poor adherence is associated with poor glycaemic control, increased risk of disease complications, higher cardiovascular risk, increased mortality, hospitalizations, and healthcare costs. In addition to reducing the complexity of drug therapy and better informing the patient, improved education and motivation could lead to greater adherence. Enhanced communication between the patient and the physician and reduced treatment costs could also have a positive impact. The review concludes that addressing factors affecting adherence can significantly improve T2D outcomes and reduce costs. Further research is needed to identify region-specific risk factors for poor adherence.
- Klíčová slova
- adherence, antidiabetic drugs, compliance, type 2 diabetes mellitus,
- MeSH
- adherence k farmakoterapii MeSH
- diabetes mellitus 2. typu * farmakoterapie MeSH
- hypoglykemika * terapeutické užití MeSH
- lidé MeSH
- metformin terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- hypoglykemika * MeSH
- metformin MeSH
OBJECTIVE: The aim of this study was to: (1) evaluate the anti-inflammatory effects of cannabidiol (CBD) on primary cultures of human gingival fibroblasts (HGFs) and (2) to clinically monitor the effect of CBD in subjects with periodontitis. BACKGROUND: The use of phytocannabinoids is a new approach in the treatment of widely prevalent periodontal disease. MATERIALS AND METHODS: Cannabinoid receptors were analyzed by western blot and interleukin production detected using enzyme immunoassay. Activation of the Nrf2 pathway was studied via monitoring the mRNA level of heme oxygenase-1. Antimicrobial effects were determined by standard microdilution and 16S rRNA screening. In the clinical part, a placebo-control double-blind randomized study was conducted (56 days) in three groups (n = 90) using dental gel without CBD (group A) and with 1% (w/w) CBD (group B) and corresponding toothpaste (group A - no CBD, group B - with CBD) for home use to maintain oral health. Group C used dental gel containing 1% chlorhexidine digluconate (active comparator) and toothpaste without CBD. RESULTS: Human gingival fibroblasts were confirmed to express the cannabinoid receptor CB2. Lipopolysaccharide-induced cells exhibited increased production of pro-inflammatory IL-6 and IL-8, with deceasing levels upon exposure to CBD. CBD also exhibited antimicrobial activities against Porphyromonas gingivalis, with an MIC of 1.5 μg/mL. Activation of the Nrf2 pathway was also demonstrated. In the clinical part, statistically significant improvement was found for the gingival, gingival bleeding, and modified gingival indices between placebo group A and CBD group B after 56 days. CONCLUSIONS: Cannabidiol reduced inflammation and the growth of selected periodontal pathogenic bacteria. The clinical trial demonstrated a statistically significant improvement after CBD application. No adverse effects of CBD were reported by patients or observed upon clinical examination during the study. The results are a promising basis for a more comprehensive investigation of the application of non-psychotropic cannabinoids in dentistry.
- Klíčová slova
- cannabidiol, inflammation, microbiota, oral hygiene, periodontium, phytocannabinoid,
- MeSH
- antiflogistika terapeutické užití farmakologie MeSH
- chlorhexidin terapeutické užití farmakologie analogy a deriváty MeSH
- dospělí MeSH
- dvojitá slepá metoda MeSH
- faktor 2 související s NF-E2 MeSH
- fibroblasty * účinky léků MeSH
- gingiva * účinky léků MeSH
- gingivitida * farmakoterapie MeSH
- hemoxygenasa-1 MeSH
- interleukin-6 analýza MeSH
- interleukin-8 účinky léků MeSH
- kanabidiol * farmakologie terapeutické užití MeSH
- kultivované buňky MeSH
- lidé středního věku MeSH
- lidé MeSH
- parodontitida farmakoterapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- randomizované kontrolované studie MeSH
- Názvy látek
- antiflogistika MeSH
- chlorhexidin MeSH
- chlorhexidine gluconate MeSH Prohlížeč
- faktor 2 související s NF-E2 MeSH
- hemoxygenasa-1 MeSH
- interleukin-6 MeSH
- interleukin-8 MeSH
- kanabidiol * MeSH
- NFE2L2 protein, human MeSH Prohlížeč
Since the outbreak of the COVID-19 pandemic, the use of hand sanitisers has become an inseparable part of our personal hygiene. However, the short-term effect and the need for frequent application are shortcomings that impair the overall protection. Another aspect is that repeated use of some products (typically alcohol-based) may cause skin irritation or eventually more severe health problems. This work proposes spray-drying as a suitable method for the preparation of swellable chitosan carriers, allowing for encapsulation and sustained release of antibacterial chlorhexidine digluconate as a model active substance. After application to hands, micron-sized particles preferentially accommodate space between epidermal ridges, protected against attrition. Thanks to their small size (d < 10 µm), particles are comfortable to carry since they are not recognisable by somatosensory receptors. The performance of formulations with various amounts of chlorhexidine and cross-linker was tested and compared with selected commercial disinfectants available on the Czech market (ethanol gel and alcoholic solution with chlorhexidine) against E. coli and S. epidermidis. The real-life performance was investigated with twelve volunteers performing various activities for up to 2 h. Finally, a replica of the human index finger with accurately captured micro-topology was proposed and compared with volunteers' fingers concerning the total amount of adhered and detached particles.
- MeSH
- chlorhexidin MeSH
- dezinfekční prostředky na mytí rukou * MeSH
- Escherichia coli MeSH
- ethanol MeSH
- lidé MeSH
- pandemie MeSH
- prášky, zásypy, pudry MeSH
- ruka mikrobiologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- chlorhexidin MeSH
- dezinfekční prostředky na mytí rukou * MeSH
- ethanol MeSH
- prášky, zásypy, pudry MeSH
A case study on Sitagliptin drug products and Sitagliptin/Metformin drug products concerning contamination with N-nitrosamines was performed using two newly developed analytical methods for determination of N-nitroso-triazolopyrazine (NTTP; 7-nitroso-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine) and its precursor triazolopyrazine (3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine). The method for determination of triazolopyrazine was previously unpublished, the method for determination of NTTP was published only for analysis of active pharmaceutical ingredient Sitagliptin and not the drug forms. Solving the N-nitrosamine contamination is requested by regulatory authorities all over the world and thus is vital for all pharmaceutical companies. The solution always requires a sensitive analytical method. Both newly developed methods use liquid chromatography coupled with mass spectrometry (single quadrupole analyzer in case of triazolopyrazine and triple quadrupole analyzer in case of NTTP). Separation of triazolopyrazine was achieved on a column Acquity CSH C18 using a mobile phase consisting of aqueous ammonium formate buffered at pH 4.2 and acetonitrile. Detection was performed using positive electrospray and selected ion monitoring at m/z 193. Separation of NTTP was achieved on a column Acquity HSS T3 using a mobile phase consisting of 0.1 % formic acid in water and methanol. Detection was performed using positive electrospray and multiple reaction monitoring at transitions m/z 222.15→42.05 (collision energy 17 eV) and m/z 222.15→192.15 (collision energy 11 eV). Two issues specific to NTTP and triazolopyrazine previously not described in scientific literature were successfully troubleshooted. Spontaneous degradation of Sitagliptin to triazolopyrazine and methyl (R)-3-amino-4-(2,4,5-trifluorophenyl)butanoate was solved by using N,N-dimethylformamide as sample solvent during development of the method for quantitation of triazolopyrazine. A bad peak shape of NTTP due to the presence of rotamers of NTTP was successfully troubleshooted by increasing column temperature. Both methods were used during an optimization study of manufacturing of Sitagliptin and Sitagliptin/Metformin drug products. The goal of the study was to decrease NTTP content in the final drug product under the strict legislative limit set by Federal Drug Agency. The efficacy of several solutions was proven, but could not be fully disclosed due to Intellectual Property Protection policy of Zentiva. Instead, a brief review of recently published strategies to cope with N-nitrosamine contamination is presented.
- Klíčová slova
- NTTP, Nitrites, Nitrosation, Scavengers, Sitagliptin, Triazolopyrazine,
- MeSH
- léčivé přípravky MeSH
- metformin * analýza MeSH
- nitrosaminy * MeSH
- příprava léků MeSH
- pyraziny MeSH
- sitagliptin fosfát MeSH
- vysokoúčinná kapalinová chromatografie metody MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- léčivé přípravky MeSH
- metformin * MeSH
- nitrosaminy * MeSH
- pyraziny MeSH
- sitagliptin fosfát MeSH
The incidence of diseases of affluence, such as diabetes mellitus, cardiovascular diseases, high blood pressure, and high cholesterol has been reported to rise. Consequently, the concentrations of residues of drugs designed to treat these diseases have been rising in water bodies. Moreover, the toxicity of these pharmaceuticals towards fish and other non-target organisms can be even enhanced by microplastic particles that are reportedly present in surface water. Therefore, the aim of this study was to describe the effects of three highly prescribed drugs, in particular metoprolol, enalapril, and metformin on fish early-life stages. Also, it was hypothesized that polystyrene microparticles will increase the toxicity of metoprolol to fish early-life stages. Embryonal acute toxicity tests on Danio rerio and Cyprinus carpio were carried out in order to describe the possible toxic effects of metoprolol, enalapril, and metformin. Also, the acute toxicity of polystyrene microparticles and the combination of metoprolol with polystyrene microparticles were tested on D. rerio embryos. Additionally, a 31-day long embryo-larval subchronic toxicity test was carried out with C. carpio in order to describe the long-term effects of low concentrations of metoprolol. The results of the study show that both metoprolol and enalapril have the potential to disrupt the early development of the heart in the embryonal stages of fish. Also, enalapril and metformin together with polystyrene microparticles seem to possibly disrupt the reproduction cycle and act as endocrine disruptors. Both pure polystyrene microparticles and the combination of them with metoprolol affect inflammatory processes in organisms. Additionally, metformin alters several metabolism pathways in fish early-life stages. The results of the study bring new evidence that even low, environmentally-relevant concentrations of pharmaceuticals have the potential to disrupt the early development of fish, particularly on a molecular level.
- Klíčová slova
- Cyprinus carpio, Danio rerio, Enalapril, Metformin, Metoprolol,
- MeSH
- chemické látky znečišťující vodu * toxicita MeSH
- dánio pruhované MeSH
- enalapril MeSH
- kapři * MeSH
- léčivé přípravky MeSH
- metformin * toxicita MeSH
- metoprolol MeSH
- mikroplasty MeSH
- plastické hmoty MeSH
- polystyreny toxicita MeSH
- voda MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- chemické látky znečišťující vodu * MeSH
- enalapril MeSH
- léčivé přípravky MeSH
- metformin * MeSH
- metoprolol MeSH
- mikroplasty MeSH
- plastické hmoty MeSH
- polystyreny MeSH
- voda MeSH
BACKGROUND: Concomitant medications may potentially affect the outcome of cancer patients. In this sub-analysis of the ARON-2 real-world study (NCT05290038), we aimed to assess the impact of concomitant use of proton pump inhibitors (PPI), statins, or metformin on outcome of patients with metastatic urothelial cancer (mUC) receiving second-line pembrolizumab. METHODS: We collected data from the hospital medical records of patients with mUC treated with pembrolizumab as second-line therapy at 87 institutions from 22 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS), and overall response rate. We carried out a survival analysis by a Cox regression model. RESULTS: A total of 802 patients were eligible for this retrospective study; the median follow-up time was 15.3 months. PPI users compared to non-users showed inferior PFS (4.5 vs. 7.2 months, p = 0.002) and OS (8.7 vs. 14.1 months, p < 0.001). Concomitant PPI use remained a significant predictor of PFS and OS after multivariate Cox analysis. The use of statins or metformin was not associated with response or survival. CONCLUSIONS: Our study results suggest a significant prognostic impact of concomitant PPI use in mUC patients receiving pembrolizumab in the real-world context. The mechanism of this interaction warrants further elucidation.
- Klíčová slova
- ARON-2 study, Immunotherapy, Metformin, Proton pump inhibitors, Statins, Urothelial cancer,
- MeSH
- inhibitory protonové pumpy MeSH
- karcinom z přechodných buněk * MeSH
- lidé MeSH
- metformin * terapeutické užití MeSH
- nádory močového měchýře * MeSH
- retrospektivní studie MeSH
- statiny * terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- inhibitory protonové pumpy MeSH
- metformin * MeSH
- pembrolizumab MeSH Prohlížeč
- statiny * MeSH
BACKGROUND: Despite the improvements in treatment over the last decades, periodontal disease (PD) affects millions of people around the world and the only treatment available is based on controlling microbial load. Diabetes is known to increase the risk of PD establishment and progression, and recently, glucose metabolism modulation by pharmaceutical or dietarian means has been emphasised as a significant modulator of non-communicable disease development. METHODS: The impact of pharmaceutically controlling glucose metabolism in non-diabetic animals and humans (REBEC, UTN code: U1111-1276-1942) was investigated by repurposing Metformin, as a mean to manage periodontal disease and its associated systemic risk factors. RESULTS: We found that glucose metabolism control via use of Metformin aimed at PD management resulted in significant prevention of bone loss during induced periodontal disease and age-related bone loss in vivo. Metformin also influenced the bacterial species present in the oral environment and impacted the metabolic epithelial and stromal responses to bacterial dysbiosis at a single cell level. Systemically, Metformin controlled blood glucose levels and age-related weight gain when used long-term. Translationally, our pilot randomized control trial indicated that systemic Metformin was safe to use in non-diabetic patients and affected the periodontal tissues. During the medication window, patients showed stable levels of systemic blood glucose, lower circulating hsCRP and lower insulin levels after periodontal treatment when compared to placebo. Finally, patients treated with Metformin had improved periodontal parameters when compared to placebo treated patients. CONCLUSION: This is the first study to demonstrate that systemic interventions using Metformin in non-diabetic individuals aimed at PD prevention have oral-systemic effects constituting a possible novel form of preventive medicine for oral-systemic disease management.
- MeSH
- diabetes mellitus 2. typu * MeSH
- hypoglykemika farmakologie terapeutické užití MeSH
- krevní glukóza MeSH
- lidé MeSH
- management nemoci MeSH
- metformin * farmakologie terapeutické užití MeSH
- nemoci parodontu * farmakoterapie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
- Názvy látek
- hypoglykemika MeSH
- krevní glukóza MeSH
- metformin * MeSH
