New amphiphilic diblock polymer nanotherapeutics serving simultaneously as a drug delivery system and an inhibitor of multidrug resistance were designed, synthesized, and evaluated for their physico-chemical and biological characteristics. The amphiphilic character of the diblock polymer, containing a hydrophilic block based on the N-(2-hydroxypropyl)methacrylamide copolymer and a hydrophobic poly(propylene oxide) block (PPO), caused self-assembly into polymer micelles with an increased hydrodynamic radius (Rh of approximately 15nm) in aqueous solutions. Doxorubicin (Dox), as a cytostatic drug, was bound to the diblock polymer through a pH-sensitive hydrazone bond, enabling prolonged circulation in blood, the delivery of Dox into a solid tumor and the subsequent stimuli-sensitive controlled release within the tumor mass and tumor cells at a decreased pH. The applicability of micellar nanotherapeutics as drug carriers was confirmed by an in vivo evaluation using EL4 lymphoma-bearing C57BL/6 mice. We observed significantly higher accumulation of micellar conjugates in a solid tumor because of the EPR effect compared with similar polymer-drug conjugates that do not form micellar structures or with the parent free drug. In addition, highly increased anti-tumor efficacy of the micellar polymer nanotherapeutics, even at a sub-optimal dose, was observed. The presence of PPO in the structure of the diblock polymer ensured, during in vitro tests on human and mouse drug-sensitive and resistant cancer cell lines, the inhibition of P-glycoprotein, one of the most frequently expressed ATP-dependent efflux pump that causes multidrug resistance. In addition, we observed highly increased rate of the uptake of the diblock polymer nanotherapeutics within the cells. We suppose that combination of unique properties based on MDR inhibition, stimuli sensitiveness (pH sensitive activation of drug), improved pharmacokinetics and increased uptake into the cells made the described polymer micelle a good candidate for investigation as potential drug delivery system.

• Klíčová slova
• EPR effect, HPMA copolymer, Micellar drug conjugate, Multidrug resistance, P-glycoprotein inhibitor, Poly(propylene oxide),
• MeSH
• akrylamidy aplikace a dávkování   chemie   farmakokinetika   terapeutické užití   MeSH
• antibiotika antitumorózní aplikace a dávkování   chemie   farmakokinetika   terapeutické užití   MeSH
• chemorezistence účinky léků   MeSH
• doxorubicin aplikace a dávkování   chemie   farmakokinetika   terapeutické užití   MeSH
• hydrofobní a hydrofilní interakce MeSH
• lidé MeSH
• micely * MeSH
• mnohočetná léková rezistence účinky léků   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory farmakoterapie   metabolismus   patologie   MeSH
• nosiče léků aplikace a dávkování   chemie   farmakokinetika   terapeutické užití   MeSH
• polymery aplikace a dávkování   chemie   farmakokinetika   terapeutické užití   MeSH
• propylenglykoly aplikace a dávkování   chemie   farmakokinetika   terapeutické užití   MeSH
• tumor burden účinky léků   MeSH
• uvolňování léčiv MeSH
• viabilita buněk účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• akrylamidy MeSH
• antibiotika antitumorózní MeSH
• doxorubicin MeSH
• micely * MeSH
• N-(2-hydroxypropyl)methacrylamide MeSH Prohlížeč
• nosiče léků MeSH
• polymery MeSH
• polypropylene glycol MeSH Prohlížeč
• propylenglykoly MeSH

IMPORTANCE: After multiple sclerosis (MS) relapse while a patient is receiving an injectable disease-modifying drug, many physicians advocate therapy switch, but the relative effectiveness of different switch decisions is often uncertain. OBJECTIVE: To compare the effect of the oral immunomodulator fingolimod with that of all injectable immunomodulators (interferons or glatiramer acetate) on relapse rate, disability, and treatment persistence in patients with active MS. DESIGN, SETTING, AND PARTICIPANTS: Matched retrospective analysis of data collected prospectively from MSBase, an international, observational cohort study. The MSBase cohort represents a population of patients with MS monitored at large MS centers. The analyzed data were collected between July 1996 and April 2014. Participants included patients with relapsing-remitting MS who were switching therapy to fingolimod or injectable immunomodulators up to 12 months after on-treatment clinical disease activity (relapse or progression of disability), matched on demographic and clinical variables. Median follow-up duration was 13.1 months (range, 3-80). Indication and attrition bias were controlled with propensity score matching and pairwise censoring, respectively. Head-to-head analyses of relapse and disability outcomes used paired, weighted, negative binomial models or frailty proportional hazards models adjusted for magnetic resonance imaging variables. Sensitivity analyses were conducted. EXPOSURES: Patients had received fingolimod, interferon beta, or glatiramer acetate for a minimum of 3 months following a switch of immunomodulatory therapy. MAIN OUTCOMES AND MEASURES: Annualized relapse rate and proportion of relapse-free patients, as well as the proportion of patients without sustained disability progression. RESULTS: Overall, 379 patients in the injectable group were matched to 148 patients in the fingolimod group. The fingolimod group had a lower mean annualized relapse rate (0.31 vs 0.42; 95% CI, 0.02-0.19; P=.009), lower hazard of first on-treatment relapse (hazard ratio [HR], 0.74; 95% CI, 0.56-0.98; P=.04), lower hazard of disability progression (HR, 0.53; 95% CI, 0.31-0.91; P=.02), higher rate of disability regression (HR, 2.0; 95% CI, 1.2-3.3; P=.005), and lower hazard of treatment discontinuation (HR, 0.55; P=.04) compared with the injectable group. CONCLUSIONS AND RELEVANCE: Switching from injectable immunomodulators to fingolimod is associated with fewer relapses, more favorable disability outcomes, and greater treatment persistence compared with switching to another injectable preparation following on-treatment activity of MS.

• MeSH
• dospělí MeSH
• fingolimod hydrochlorid MeSH
• imunologické faktory aplikace a dávkování   terapeutické užití   MeSH
• imunosupresiva aplikace a dávkování   terapeutické užití   MeSH
• interferon beta aplikace a dávkování   terapeutické užití   MeSH
• kohortové studie MeSH
• lidé MeSH
• magnetická rezonanční tomografie metody   MeSH
• propylenglykoly aplikace a dávkování   terapeutické užití   MeSH
• retrospektivní studie MeSH
• roztroušená skleróza farmakoterapie   MeSH
• sfingosin aplikace a dávkování   analogy a deriváty   terapeutické užití   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• fingolimod hydrochlorid MeSH
• imunologické faktory MeSH
• imunosupresiva MeSH
• interferon beta MeSH
• propylenglykoly MeSH
• sfingosin MeSH

Glutamatergic neurotransmission plays a role in stress hormone release and the development of mood diseases. The aim of these studies was to verify the hypothesis that repeated treatment with felbamate, an antiepileptic drug modulating glutamatergic neurotransmission, affects hormone release in response to chronic stress. A mouse model of repeated social defeat (nonaggressive male mouse repeatedly defeated by aggressive counterparts) was used. The results showed that acute treatment with felbamate reduced hypolocomotion in an open field induced by repeated social conflict. The same stress procedure resulted in increased release of corticosterone and dopamine. Felbamate decreased noradrenaline concentrations and inhibited stress-induced rise in corticosterone and dopamine. It is suggested that modulation of stress hormone release may be induced by the action of felbamate on glutamate neurotransmission, and neuroendocrine changes could contribute to behavioural effects of the drug. Antidepressant action of this mood-stabilizing drug suggested by clinicians needs further verification.

• MeSH
• biogenní monoaminy krev   MeSH
• felbamát MeSH
• fenylkarbamáty MeSH
• hypokineze krev   farmakoterapie   MeSH
• kortikosteron krev   MeSH
• myši inbrední ICR MeSH
• myši MeSH
• pohybová aktivita účinky léků   fyziologie   MeSH
• propylenglykoly farmakologie   terapeutické užití   MeSH
• psychický stres krev   farmakoterapie   MeSH
• sociální chování * MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• biogenní monoaminy MeSH
• felbamát MeSH
• fenylkarbamáty MeSH
• kortikosteron MeSH
• propylenglykoly MeSH

The anticonvulsant action of felbamate (25, 50, 100 and 150 mg/kg i.p.) was tested against motor seizures induced by pentylenetetrazol in five age-groups of rats (7, 12, 18, 25 and 90 days old). In adult rats, felbamate suppressed generalized tonic-clonic seizures leaving intact minimal clonic seizures. In all groups of rat pups felbamate exhibited a specific action against the tonic phase of generalized tonic-clonic seizures. In addition, the highest dose of felbamate was found to suppress minimal seizures in 18-day-old rats. The changes of felbamate action during ontogeny might be due to multiple mechanisms of anticonvulsant action with an uneven developmental profile.

• MeSH
• antikonvulziva terapeutické užití   MeSH
• felbamát MeSH
• fenylkarbamáty MeSH
• konvulzíva MeSH
• krysa rodu Rattus MeSH
• novorozená zvířata růst a vývoj   fyziologie   MeSH
• pentylentetrazol MeSH
• potkani Wistar MeSH
• propylenglykoly terapeutické užití   MeSH
• stárnutí fyziologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• záchvaty chemicky indukované   farmakoterapie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antikonvulziva MeSH
• felbamát MeSH
• fenylkarbamáty MeSH
• konvulzíva MeSH
• pentylentetrazol MeSH
• propylenglykoly MeSH

• MeSH
• antifungální látky * terapeutické užití   MeSH
• benzylalkoholy terapeutické užití   MeSH
• boritany terapeutické užití   MeSH
• hřeben a laloky MeSH
• kandidóza farmakoterapie   MeSH
• kur domácí MeSH
• modely nemocí na zvířatech MeSH
• povrchově aktivní látky terapeutické užití   MeSH
• preklinické hodnocení léčiv metody   MeSH
• propylenglykoly terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antifungální látky * MeSH
• benzylalkoholy MeSH
• boritany MeSH
• povrchově aktivní látky MeSH
• propylenglykoly MeSH

• MeSH
• 1-propanol terapeutické užití   MeSH
• aerosoly MeSH
• hexachlorofen terapeutické užití   MeSH
• kyseliny palmitové terapeutické užití   MeSH
• kyseliny undecylenové terapeutické užití   MeSH
• lidé MeSH
• mykózy farmakoterapie   MeSH
• propylenglykoly terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 1-propanol MeSH
• aerosoly MeSH
• hexachlorofen MeSH
• kyseliny palmitové MeSH
• kyseliny undecylenové MeSH
• propylenglykoly MeSH