Background: Reactive oxygen species (ROS), such as hydrogen peroxide and superoxide, trigger biodegradation of polymer-based nanoparticles (NPs) bearing pinacol-type boronic ester groups. These NPs may selectively release their cargo, in this case paclitaxel (PTX), at the high levels of ROS present in the intracellular environment of inflamed tissues and most tumors. Purpose: The main objective was to determine anti-tumor efficacy of PTX-loaded ROS-sensitive NPs and to examine whether macrophage infiltration had any impact on treatment efficacy. Methods: NPs were synthesized and their characteristics in the presence of H2O2 were demonstrated. Both confocal microscopy as well as flow cytometry approaches were used to determine degradation of ROS-sensitive NPs. HeLa cells were cultured in vitro and used to establish tumor xenografts in nude mice. In vivo experiments were performed to understand toxicity, biodistribution and anti-tumor efficacy of the NPs. Moreover, we performed immunohistochemistry on tumor sections to study infiltration of M1 and M2 subsets of macrophages. Results: We demonstrated that PTX delivered in NPs containing a ROS-sensitive polymer exhibits a better anti-tumor efficacy than PTX in NPs containing ROS-non-sensitive polymer, free PTX or Abraxane® (nab-PTX). The biodistribution revealed that ROS-sensitive NPs exhibit retention in liver, spleen and lungs, suggesting a potential to target cancer metastasizing to these organs. Finally, we demonstrated a correlation between infiltrated macrophage subsets and treatment efficacy, possibly contributing to the efficient anti-tumor effects. Conclusion: Treatment with ROS-sensitive NPs containing PTX gave an improved therapeutic effect in HeLa xenografts than their counterpart, free PTX or nab-PTX. Our data revealed a correlation between macrophage infiltration and efficiency of the different antitumor treatments, as the most effective NPs resulted in the highest infiltration of the anti-tumorigenic M1 macrophages.

• MeSH
• albuminy farmakologie   terapeutické užití   MeSH
• HeLa buňky MeSH
• hydrodynamika MeSH
• lidé MeSH
• makrofágy účinky léků   metabolismus   MeSH
• myši nahé MeSH
• nádorové buněčné linie MeSH
• nádory farmakoterapie   MeSH
• nanočástice terapeutické užití   MeSH
• paclitaxel farmakologie   terapeutické užití   MeSH
• paklitaxel vázaný na albumin terapeutické užití   MeSH
• polymery chemie   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• tkáňová distribuce účinky léků   MeSH
• velikost částic MeSH
• výsledek terapie MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Biodegradable nanoparticles based on stearic acid-modified poly(glycerol adipate) (PGAS) are promising carriers for drug delivery. In order to investigate the impact of the particle interface characteristics on the biological fate, PGAS nanoparticles are covalently and noncovalently coated with N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers. HPMA copolymer-modified PGAS nanoparticles have similar particle sizes, but less negative zeta-potentials. Nanoparticles are double labeled with the fluorescent dyes DiR (noncovalently) and DYOMICS-676 (covalently bound to HPMA copolymer), and their biodistribution is investigated noninvasively by multispectral optical imaging. Both covalent and noncovalent coatings cause changes in the pharmacokinetics and biodistribution in healthy and tumor-bearing mice. In addition to the intended tumor accumulation, high signals of both fluorescent dyes are also observed in other organs, including liver, ovaries, adrenal glands, and bone. The unintended accumulation of nanocarriers needs further detailed and systematic investigations, especially with respect to the observed ovarian and adrenal gland accumulation.

• MeSH
• biologicky odbouratelné plasty chemie   MeSH
• buňky HT-29 MeSH
• fluorescenční barviva chemie   MeSH
• lékové transportní systémy * MeSH
• lidé MeSH
• methakryláty aplikace a dávkování   chemie   MeSH
• myši MeSH
• nádory farmakoterapie   genetika   patologie   MeSH
• nanočástice aplikace a dávkování   chemie   MeSH
• nosiče léků aplikace a dávkování   chemie   MeSH
• polyestery aplikace a dávkování   chemie   MeSH
• tkáňová distribuce účinky léků   MeSH
• xenogenní modely - testy protinádorové aktivity MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

N2-(4-Amino-cyclohexyl)-9-cyclopentyl-N6-(6-furan-2-yl-pyridine-3-ylmethyl)-9H-purine-2,6-diamine (BP-14) and 2-(5-{[2-(4-amino-cyclohexylamino)-9-cyclopentyl-9H-purine-6-ylamino]-methyl}-pyridine-2-yl)-phenol (BP-20) are novel cyclin-dependent kinase inhibitors, structurally related to roscovitine, with significant biological activity. A simple, selective and sensitive liquid chromatography - tandem mass spectrometry method for determining them in rat plasma, using roscovitine as an internal standard, was developed and validated. Chromatographic separation was performed in reversed phase mode on Acquity BEH C18 column (100 × 2.1 mm, 1.7 μm) by gradient elution with mobile phases composed of 15 mM ammonium formate pH 4.0 and methanol at flow rate 0.25 mL/min at 40 °C. The analytes were detected based on their characteristic multiple reaction monitoring transitions in positive electrospray ionization mode m/z 473.07 > 157.93 for BP-14, m/z 499.62 > 184.2 for BP-20 and m/z 355.5 > 90.86 for internal standard. In plasma the method provided good linearity within the entire concentration range: 1-10,000 nmol/L (r2 = 0.9989) for BP-14 and 10-25,000 nmol/L (r2 = 0.9994) for BP-20; the limit of detection was 0.6 nmol/L for BP-14 and 6.1 nmol/L for BP-20. Validation was also performed in bile and urine. The results of validation fit within the acceptance limits following European Medicines Agency guidelines. The method was applied in a pharmacokinetic study of BP-14 and BP-20 in vivo in rats following intravenous and intraduodenal administration including plasma pharmacokinetics, tissue distribution and excretion (renal and biliary). Both compounds showed low bioavailability after intraduodenal administration (0.630 and 1.58% for BP-14 and BP-20, respectively). Distribution into all the analyzed tissues (brain, lungs, liver, kidney, spleen, muscle, adipose tissue) was observed 3 h after single dose administration, the highest and lowest concentrations being reached in the adipose tissue and brain, respectively. The biliary excretion of the parent BP-14 and BP-20 compounds accounted for 4.81% and 10.6% of the doses, respectively, and renal excretion for <0.5% in both cases. The obtained results represent pilot knowledge for further development of a new generation of compounds with strong anticancer activities.

• MeSH
• 2-aminopurin analogy a deriváty   analýza   farmakokinetika   MeSH
• biologická dostupnost MeSH
• cykliny chemie   MeSH
• hepatobiliární exkrece účinky léků   MeSH
• inhibitory proteinkinas aplikace a dávkování   analýza   chemie   farmakokinetika   MeSH
• intravenózní podání metody   MeSH
• kalibrace MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• limita detekce MeSH
• molekulární struktura MeSH
• potkani Wistar MeSH
• protinádorové látky aplikace a dávkování   analýza   chemie   farmakokinetika   MeSH
• reprodukovatelnost výsledků MeSH
• tandemová hmotnostní spektrometrie metody   MeSH
• tkáňová distribuce účinky léků   MeSH
• vysokoúčinná kapalinová chromatografie metody   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

In this review we summarize several synthetic approaches to the advanced synthesis of star-like polymer-based drug carriers. Moreover, their application as nanomedicines for therapy or the diagnosis of neoplastic diseases and their biodistribution are reviewed in detail. From a broad spectrum of star-like systems, we focus only on fully water-soluble systems, mainly based on poly(ethylene glycol) or N-(2-hydroxypropyl)methacrylamide polymer and copolymer arms and polyamidoamine dendrimers serving as the core of the star-like systems.

• MeSH
• lidé MeSH
• methakryláty aplikace a dávkování   chemie   metabolismus   MeSH
• nosiče léků aplikace a dávkování   chemie   metabolismus   MeSH
• polyethylenglykoly aplikace a dávkování   metabolismus   MeSH
• polymery aplikace a dávkování   chemie   metabolismus   MeSH
• tkáňová distribuce účinky léků   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Metabolic and behavioural effects of, and interactions between Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are influenced by dose and administration route. Therefore we investigated, in Wistar rats, effects of pulmonary, oral and subcutaneous (sc.) THC, CBD and THC+CBD. Concentrations of THC, its metabolites 11-OH-THC and THC-COOH, and CBD in serum and brain were determined over 24h, locomotor activity (open field) and sensorimotor gating (prepulse inhibition, PPI) were also evaluated. In line with recent knowledge we expected metabolic and behavioural interactions between THC and CBD. While cannabinoid serum and brain levels rapidly peaked and diminished after pulmonary administration, sc. and oral administration produced long-lasting levels of cannabinoids with oral reaching the highest brain levels. Except pulmonary administration, CBD inhibited THC metabolism resulting in higher serum/brain levels of THC. Importantly, following sc. and oral CBD alone treatments, THC was also detected in serum and brain. S.c. cannabinoids caused hypolocomotion, oral treatments containing THC almost complete immobility. In contrast, oral CBD produced mild hyperlocomotion. CBD disrupted, and THC tended to disrupt PPI, however their combination did not. In conclusion, oral administration yielded the most pronounced behavioural effects which corresponded to the highest brain levels of cannabinoids. Even though CBD potently inhibited THC metabolism after oral and sc. administration, unexpectedly it had minimal impact on THC-induced behaviour. Of central importance was the novel finding that THC can be detected in serum and brain after administration of CBD alone which, if confirmed in humans and given the increasing medical use of CBD-only products, might have important legal and forensic ramifications.

• MeSH
• akustická stimulace MeSH
• analýza rozptylu MeSH
• aplikace inhalační MeSH
• aplikace orální MeSH
• časové faktory MeSH
• fixní kombinace léků MeSH
• injekce subkutánní MeSH
• kanabidiol aplikace a dávkování   farmakokinetika   MeSH
• krysa rodu rattus MeSH
• mozek účinky léků   metabolismus   MeSH
• pátrací chování účinky léků   MeSH
• plynová chromatografie s hmotnostně spektrometrickou detekcí MeSH
• potkani Wistar MeSH
• prepulsní inhibice účinky léků   MeSH
• tetrahydrokanabinol aplikace a dávkování   farmakokinetika   MeSH
• tkáňová distribuce účinky léků   MeSH
• způsoby aplikace léků MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

OBJECTIVE: "Krokodil" is the street name for an impure homemade drug mixture used as a cheap substitute for heroin, containing desomorphine as the main opioid. Abscesses, gangrene, thrombophlebitis, limb ulceration and amputations, jaw osteonecrosis, skin discoloration, ulcers, skin infections, and bleeding are some of the typical reported signs in humans. This study aimed to understand the toxicity of krokodil using Wistar male rats as experimental model. METHODS: Animals were divided into seven groups and exposed subcutaneously to NaCl 0.9% (control), krokodil mixture free of psychotropic substances (blank krokodil), pharmaceutical grade desomorphine 1 mg/kg, and four different concentrations of krokodil (containing 0.125, 0.25, 0.5, and 1 mg/kg of desomorphine) synthesized accordingly to a "domestic" protocol followed by people who inject krokodil (PWIK). Daily injections for five consecutive days were performed, and animals were sacrificed 24 hr after the last administration. Biochemical and histological analysis were carried out. RESULTS: It was shown that the continuous use of krokodil may cause injury at the injection area, with formation of necrotic zones. The biochemical results evidenced alterations on cardiac and renal biomarkers of toxicity, namely, creatine kinase, creatine kinase-MB, and uric acid. Significant alteration in levels of reduced and oxidized glutathione on kidney and heart suggested that oxidative stress may be involved in krokodil-mediated toxicity. Cardiac congestion was the most relevant finding of continuous krokodil administration. CONCLUSIONS: These findings contribute notably to comprehension of the local and systemic toxicological impact of this complex drug mixture on major organs and will hopefully be useful for the development of appropriate treatment strategies towards the human toxicological effects of krokodil.

• MeSH
• injekce subkutánní MeSH
• játra účinky léků   patologie   MeSH
• kodein aplikace a dávkování   analogy a deriváty   toxicita   MeSH
• kožní nemoci chemicky indukované   patologie   MeSH
• krysa rodu rattus MeSH
• ledviny účinky léků   patologie   MeSH
• lidé MeSH
• nekróza chemicky indukované   patologie   MeSH
• opioidní analgetika aplikace a dávkování   toxicita   MeSH
• oxidační stres účinky léků   fyziologie   MeSH
• plíce účinky léků   patologie   MeSH
• potkani Wistar MeSH
• srdce účinky léků   MeSH
• tkáňová distribuce účinky léků   fyziologie   MeSH
• velikost orgánu účinky léků   fyziologie   MeSH
• zakázané drogy toxicita   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Pharmacokinetics of leptin in mammals has received limited attention and only one study has examined more than two time points and this was in ob/ob mice. This study is the first to observe the distribution of leptin over a time course in female mice. A physiologic dose (12 ng) of radiolabelled leptin was injected in adult female mice via the lateral tail vein and tissues were dissected out and measured for radioactivity over a time course up to two hours. Major targets for administered leptin included the liver, kidneys, gastrointestinal tract and the skin while the lungs had high concentrations of administered leptin per gram of tissue. Leptin was also found to enter the lumen of the digestive tract intact from the plasma. Very little of the dose (<1 %) was recovered from the brain at any time. Consequently we confirm that the brain is not a major target for leptin from the periphery, although it may be very sensitive to leptin that does get to the hypothalamus. Several of the major targets (GI tract, skin and lungs) for leptin form the interface for the body with the environment, and given the ability of leptin to modulate immune function, this may represent a priming effect for tissues to respond to damage and infection.

• MeSH
• hypothalamus účinky léků   metabolismus   MeSH
• injekce intravenózní MeSH
• leptin aplikace a dávkování   krev   farmakokinetika   MeSH
• metabolická clearance účinky léků   fyziologie   MeSH
• myši MeSH
• poločas MeSH
• skot MeSH
• tkáňová distribuce účinky léků   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• skot MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Glucose is molecule usually studied in relation to metabolism. Except for this traditional view, it is known that under certain conditions glucose can serve as a signal molecule for the circadian system. The circadian system is entrained by relevant synchronizing cues that can be tissue-dependent. Central oscillator is synchronized mainly by light-dark cycle, while peripheral oscillators can be entrained by food intake. Glucose transport in the organism is controlled by insulin dependent and independent mechanism. Therefore, we employed streptozotocin-induced diabetes to elucidate the influence of metabolic changes on glucose transporter (glut1, glut4) 24-h expression profile in peripheral oscillators in tissues, inside (frontal cortex, cerebellum) and outside (heart) the blood-brain barrier. Diabetes was induced by streptozotocin injection. Seventeen days later, sampling was performed during a 24-h cycle. Gene expression was measured using real-time PCR. We observed down-regulation of glut1 and glut4 expression in the heart of diabetic rats. The expression of glut1 and glut4 in brain areas was not down-regulated, however, we observed trend to phase advance in glut1 expression in the cerebellum. These results may indicate higher glucose levels in diabetic brain, which might influence regulation of clock gene expression in different manner in brain compared to periphery.

• MeSH
• cirkadiánní hodiny * MeSH
• cirkadiánní rytmus * MeSH
• experimentální diabetes mellitus chemicky indukované   metabolismus   MeSH
• glukosa metabolismus   MeSH
• hematoencefalická bariéra metabolismus   MeSH
• krysa rodu rattus MeSH
• potkani Wistar MeSH
• přenašeč glukosy typ 1 metabolismus   MeSH
• přenašeč glukosy typ 4 metabolismus   MeSH
• streptozocin MeSH
• tkáňová distribuce účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• bariatrická chirurgie * škodlivé účinky   MeSH
• kosti a kostní tkáň * metabolismus   patofyziologie   účinky léků   MeSH
• kostní denzita * fyziologie   účinky léků   MeSH
• látky proti obezitě * škodlivé účinky   terapeutické užití   MeSH
• lidé MeSH
• ligand RANK metabolismus   MeSH
• osteokalcin metabolismus   MeSH
• osteonektin metabolismus   MeSH
• osteopontin metabolismus   MeSH
• osteoprotegerin metabolismus   MeSH
• tkáňová distribuce účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• souhrny MeSH

The toxic effect of organophosphates is attributed to irreversible inhibition of acetylcholinesterase (AChE; EC 3.1.1.7), the enzyme that hydrolyses the neurotransmitter acetylcholine. Inhibition potency in vivo of one of the most toxic nerve agents--Russian VX (RVX;N,N-diethyl-2-[methyl-(2-methylpropoxy)phosphoryl]sulfanylethanamine) (1 x LD(50) dose administered intramuscularly, i.m.) was studied in rats. AChE in blood was inhibited by 50%, 3 min after i.m. RVX. Butylcholinesterase (BChE; EC 3.1.1.8) in plasma was inhibited less rapidly and only by 10-20%, 20 min after RVX. AChE and BChE activities in diaphragm were reduced only 35% and 15% at 30 min. While AChE and BChE activities were reduced only about 20% and 15%, respectively, the decline in activity was rapid, occurring within 3 min. These findings indicate that RVX most potently inhibits ChE outside the central nervous system.

• MeSH
• acetylcholinesterasa krev   MeSH
• bránice enzymologie   účinky léků   MeSH
• časové faktory MeSH
• chování zvířat účinky léků   MeSH
• játra enzymologie   účinky léků   MeSH
• krysa rodu rattus MeSH
• LD50 MeSH
• mozek enzymologie   účinky léků   MeSH
• organothiofosforové sloučeniny toxicita   MeSH
• potkani Wistar MeSH
• tkáňová distribuce účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• práce podpořená grantem MeSH