BACKGROUND: Promotion of myelin repair in the context of demyelinating diseases such as multiple sclerosis (MS) still represents a clinical unmet need, given that this disease is not only characterized by autoimmune activities but also by impaired regeneration processes. Hence, this relates to replacement of lost oligodendrocytes and myelin sheaths-the primary targets of autoimmune attacks. Endogenous remyelination is mainly mediated via activation and differentiation of resident oligodendroglial precursor cells (OPCs), whereas its efficiency remains limited and declines with disease progression and aging. Teriflunomide has been approved as a first-line treatment for relapsing remitting MS. Beyond its role in acting via inhibition of de novo pyrimidine synthesis leading to a cytostatic effect on proliferating lymphocyte subsets, this study aims to uncover its potential to foster myelin repair. METHODS: Within the cuprizone mediated de-/remyelination model teriflunomide dependent effects on oligodendroglial homeostasis and maturation, related to cellular processes important for myelin repair were analyzed in vivo. Teriflunomide administration was performed either as pulse or continuously and markers specific for oligodendroglial maturation and mitochondrial integrity were examined by means of gene expression and immunohistochemical analyses. In addition, axon myelination was determined using electron microscopy. RESULTS: Both pulse and constant teriflunomide treatment efficiently boosted myelin repair activities in this model, leading to accelerated generation of oligodendrocytes and restoration of myelin sheaths. Moreover, teriflunomide restored mitochondrial integrity within oligodendroglial cells. CONCLUSIONS: The link between de novo pyrimidine synthesis inhibition, oligodendroglial rescue, and maintenance of mitochondrial homeostasis appears as a key for successful myelin repair and hence for protection of axons from degeneration.
Importance: To our knowledge, the Oral Ponesimod Versus Teriflunomide In Relapsing Multiple Sclerosis (OPTIMUM) trial is the first phase 3 study comparing 2 oral disease-modifying therapies for relapsing multiple sclerosis (RMS). Objective: To compare the efficacy of ponesimod, a selective sphingosine-1-phosphate receptor 1 (S1P1) modulator with teriflunomide, a pyrimidine synthesis inhibitor, approved for the treatment of patients with RMS. Design, Setting, and Participants: This multicenter, double-blind, active-comparator, superiority randomized clinical trial enrolled patients from April 27, 2015, to May 16, 2019, who were aged 18 to 55 years and had been diagnosed with multiple sclerosis per 2010 McDonald criteria, with a relapsing course from the onset, Expanded Disability Status Scale (EDSS) scores of 0 to 5.5, and recent clinical or magnetic resonance imaging disease activity. Interventions: Patients were randomized (1:1) to 20 mg of ponesimod or 14 mg of teriflunomide once daily and the placebo for 108 weeks, with a 14-day gradual up-titration of ponesimod starting at 2 mg to mitigate first-dose cardiac effects of S1P1 modulators and a follow-up period of 30 days. Main Outcomes and Measures: The primary end point was the annualized relapse rate. The secondary end points were the changes in symptom domain of Fatigue Symptom and Impact Questionnaire-Relapsing Multiple Sclerosis (FSIQ-RMS) at week 108, the number of combined unique active lesions per year on magnetic resonance imaging, and time to 12-week and 24-week confirmed disability accumulation. Safety and tolerability were assessed. Exploratory end points included the percentage change in brain volume and no evidence of disease activity (NEDA-3 and NEDA-4) status. Results: For 1133 patients (567 receiving ponesimod and 566 receiving teriflunomide; median [range], 37.0 [18-55] years; 735 women [64.9%]), the relative rate reduction for ponesimod vs teriflunomide in the annualized relapse rate was 30.5% (0.202 vs 0.290; P < .001); the mean difference in FSIQ-RMS, -3.57 (-0.01 vs 3.56; P < .001); the relative risk reduction in combined unique active lesions per year, 56% (1.405 vs 3.164; P < .001); and the reduction in time to 12-week and 24-week confirmed disability accumulation risk estimates, 17% (10.1% vs 12.4%; P = .29) and 16% (8.1% vs 9.9; P = .37), respectively. Brain volume loss at week 108 was lower by 0.34% (-0.91% vs -1.25%; P < .001); the odds ratio for NEDA-3 achievement was 1.70 (25.0% vs 16.4%; P < .001). Incidence of treatment-emergent adverse events (502 of 565 [88.8%] vs 499 of 566 [88.2%]) and serious treatment-emergent adverse events (49 [8.7%] vs 46 [8.1%]) was similar for both groups. Treatment discontinuations because of adverse events was more common in the ponesimod group (49 of 565 [8.7%] vs 34 of 566 [6.0%]). Conclusions and Relevance: In this study, ponesimod was superior to teriflunomide on annualized relapse rate reduction, fatigue, magnetic resonance imaging activity, brain volume loss, and no evidence of disease activity status, but not confirmed disability accumulation. The safety profile was in line with the previous safety observations with ponesimod and the known profile of other S1P receptor modulators. Trial Registration: ClinicalTrials.gov Identifier: NCT02425644.
- MeSH
- dospělí MeSH
- hydroxybutyráty farmakologie MeSH
- imunologické faktory terapeutické užití MeSH
- krotonáty farmakologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- lokální recidiva nádoru farmakoterapie MeSH
- magnetická rezonanční tomografie metody MeSH
- mladiství MeSH
- mladý dospělý MeSH
- nitrily farmakologie MeSH
- progrese nemoci MeSH
- relabující-remitující roztroušená skleróza farmakoterapie MeSH
- thiazoly farmakologie MeSH
- toluidiny farmakologie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
- srovnávací studie MeSH
Complex in vitro characterization of a blended material based on Poly(Lactic Acid), Poly(Hydroxybutyrate), and Thermoplastic Starch (PLA/PHB/TPS) was performed in order to evaluate its potential for application in the field of tissue engineering. We focused on the biological behavior of the material as well as its mechanical and morphological properties. We also focused on the potential of the blend to be processed by the 3D printer which would allow the fabrication of the custom-made scaffold. Several blends recipes were prepared and characterized. This material was then studied in the context of scaffold fabrication. Scaffold porosity, wettability, and cell-scaffold interaction were evaluated as well. MTT test and the direct contact cytotoxicity test were applied in order to evaluate the toxic potential of the blended material. Biocompatibility studies were performed on the human chondrocytes. According to our results, we assume that material had no toxic effect on the cell culture and therefore could be considered as biocompatible. Moreover, PLA/PHB/TPS blend is applicable for 3D printing. Printed scaffolds had highly porous morphology and were able to absorb water as well. In addition, cells could adhere and proliferate on the scaffold surface. We conclude that this blend has potential for scaffold engineering.
- MeSH
- 3D tisk MeSH
- hydroxybutyráty farmakologie terapeutické užití MeSH
- lidé MeSH
- polyestery farmakologie terapeutické užití MeSH
- tkáňové inženýrství metody MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
x
x
- Klíčová slova
- drink spiking, date rape drugs, amorózní chování,
- MeSH
- afrodiziaka klasifikace MeSH
- alkaloidy farmakologie klasifikace MeSH
- anestetika farmakologie klasifikace MeSH
- benzodiazepiny farmakologie klasifikace MeSH
- ethanol farmakologie MeSH
- hydroxybutyráty farmakologie klasifikace MeSH
- ketamin farmakologie MeSH
- lidé MeSH
- nápoje MeSH
- oxytocin farmakologie MeSH
- poruchy spojené s užíváním psychoaktivních látek dějiny MeSH
- propofol farmakologie škodlivé účinky MeSH
- sexuální chování * dějiny účinky léků MeSH
- sexuální delikty MeSH
- významné osobnosti MeSH
- zločin klasifikace prevence a kontrola MeSH
- Check Tag
- lidé MeSH
GHB (γ-hydroxybutyric acid) is a compound endogenous to mammalian brain with high structural resemblance to GABA. GHB possesses nanomolar-micromolar affinity for a unique population of binding sites, but the exact nature of these remains elusive. In this study we utilized the highly selective GHB analogue, 3-hydroxycyclopent-1-enecarboxylic acid (HOCPCA) as a tritiated version (3H-HOCPCA) to radioactively label the specific GHB high-affinity binding site and gain further insight into the density, distribution and developmental profile of this protein. We show that, in low nanomolar concentrations,3H-HOCPCA displays excellent signal-to-noise ratios using rodent brain autoradiography, which makes it a valuable ligand for anatomical quantification of native GHB binding site levels. Our data confirmed that3H-HOCPCA labels only the high-affinity specific GHB binding site, found in high density in cortical and hippocampal regions. The experiments revealed markedly stronger binding at pH 6.0 (Kd73.8 nM) compared to pH 7.4 (Kd2312 nM), as previously reported for other GHB radioligands but similar Bmaxvalues. Using3H-HOCPCA we analyzed the GHB binding protein profile during mouse brain development. Due to the high sensitivity of this radioligand, we were able to detect low levels of specific binding already at E15 in mouse brain, which increased progressively until adulthood. Collectively, we show that3H-HOCPCA is a highly sensitive radioligand, offering advantages over the commonly used radioligand3H-NCS-382, and thus a very suitable in vitro tool for qualitative and quantitative autoradiography of the GHB high-affinity site.
- MeSH
- autoradiografie metody MeSH
- cyklopentany farmakologie MeSH
- hlodavci MeSH
- hydroxybutyráty farmakologie MeSH
- kompetitivní vazba MeSH
- kyseliny karboxylové farmakologie MeSH
- mozek účinky léků metabolismus MeSH
- myši MeSH
- radioligandová zkouška metody MeSH
- vazebná místa MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Gynekolog se může v rámci své profese stát první kontaktní osobou vyšetřující oběť sexuálně motivovaného trestného činu. Článek upozorňuje na aspekt, že by základní vyšetření mělo být vedeno nejenom po linii prohlídky těla a zajištění biologických stop, ale aby byla brána v úvahu i možná úmyslná intoxikace oběti pachatelem. Odhalení a řádné zdokumentování možného medikamentózního ovlivnění kognitivních funkcí oběti by mělo být standardní součástí komplexního vyšetření.
- Klíčová slova
- droga, alkohol, intoxikace,
- MeSH
- amnézie MeSH
- flunitrazepam farmakologie škodlivé účinky MeSH
- hydroxybutyráty aplikace a dávkování farmakologie moč MeSH
- ketamin farmakologie škodlivé účinky MeSH
- kognice účinky léků MeSH
- lidé MeSH
- midazolam farmakologie škodlivé účinky MeSH
- násilí MeSH
- sexuální chování účinky léků MeSH
- toxické psychózy etiologie komplikace MeSH
- znásilnění diagnóza zákonodárství a právo MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
- Klíčová slova
- gama-hydroxybutyrát,
- MeSH
- GABA * analogy a deriváty farmakologie terapeutické užití toxicita MeSH
- hydroxybutyráty * farmakologie toxicita MeSH
- lidé MeSH
- poruchy spojené s užíváním psychoaktivních látek MeSH
- uživatelé drog MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
V článku sa podáva prehľad prác zaoberajúcich sa novými možnosťami farmakoterapie alkoholovej závislosti. Prezentuje sa možné roztriedenie farmák užívaných na liečbu alkoholovej závislosti. Pozornosť sa venuje podrobnejšie naltrexonu a akamprosátu. Kriticky sa hodnotia doterajšie publikácie. Obe liečivá sú nádejné. Naproti tomu o buspirone neexistujú presvedčivé dôkazy o jeho účinnosti pri ovplyvnení základných charakteristík alkoholovej závislosti. Podávajú sa prvé informácie o nalmefene a hydroxybutyráte v tejto indikácii.
The article summarizes new possibilities of alcohol dependence pharmacotherapy. There is also suggested classification of drugs used in the therapy of alcohol addicton. The authors focus mainly on naltrexone and acamprosate. Recent publications are critically rewieved. Both naltrexone and acamprosate may be very helpful to influence basic characteristics of alcohol addiction. On the contrary, there is no sufficient evidence - besed proof of the effectivity of buspirone in alcohol dependence. First information about nalmaphene and hydroxybutyrate in this indication is also mentioned.
- Klíčová slova
- NALMEFEN,
- MeSH
- alkoholismus farmakoterapie MeSH
- buspiron farmakologie MeSH
- hydroxybutyráty farmakologie MeSH
- lidé MeSH
- naltrexon farmakologie MeSH
- odvykací prostředky alkoholu MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
