- Publikační typ
- abstrakt z konference MeSH
- Publikační typ
- abstrakt z konference MeSH
INTRODUCTION: To date, there is not generally accepted and universal indicator of activity, and functional integrity of the small intestine in patients with coeliac disease. The aim of our study was to investigate whether serum concentrations of the non-essential amino acids citrulline and ornithine might have this function. METHODS: We examined serum citrulline and ornithine concentrations in a subgroup of patients with proven coeliac disease and healthy controls (blood donors). RESULTS: A total of 94 patients with coeliac disease (29 men, mean age 53 ± 18 years; 65 women, mean age 44 ± 14 years) and 35 healthy controls (blood donors) in whom coeliac disease was serologically excluded (10 men, mean age 51 ± 14 years; 25 women, mean age 46 ± 12 years) were included in the study. Significantly lower concentrations of serum ornithine were found in patients with coeliac disease (mean 65 ± 3 μmol/L; median 63 μmol/L, IQR 34 μmol/L, p < 0.001). No statistically nor clinically significant differences were found in the citrulline concentrations between the study and control group. CONCLUSIONS: Serum ornithine (but not citrulline) may be useful for assessing the functional status of the small intestine in uncomplicated coeliac disease. Further studies involving more detailed analysis of dietary and metabolic changes in patients will be needed to reach definitive conclusions.
- MeSH
- celiakie * MeSH
- citrulin * metabolismus MeSH
- dieta MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- ornithin metabolismus MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
At present, therapeutic drug monitoring is the standard in pharmacotherapy using medications with a narrow therapeutic index or showing serious adverse effects, such as in the case of ibrutinib. A technique commonly used for this purpose is liquid chromatography-tandem mass spectrometry combined with isotope dilution in sample processing. Although this method provides a high degree of reliability, its use can be complicated with some specific factors and does not guarantee trouble-free analysis. This paper is focused on investigating issues related to the differential adsorption of ibrutinib and its D4, D5 and 13C6 isotopically labeled analogues combined with instrument-specific carry-over. The results of the research point out the significantly different adsorption behavior of ibrutinib in fluidics of LC-MS compared with that of its D4, D5 and 13C6 stable isotope labeled analogues, showing preferential adsorption of non-labeled compound. The investigation also pointed to a strong affinity of ibrutinib to polymeric surfaces under specific conditions, which has to be taken into consideration during sample preparation and analysis. Our work opens a new field for the discussion of scarcely reported problem related to the use of stable isotope labeled internal standards in LC-MS/MS analysis.
Antidotes against organophosphates often possess physicochemical properties that mitigate their passage across the blood-brain barrier. Cucurbit[7]urils may be successfully used as a drug delivery system for bisquaternary oximes and improve central nervous system targeting. The main aim of these studies was to elucidate the relationship between cucurbit[7]uril, oxime K027, atropine, and paraoxon to define potential risks or advantages of this delivery system in a complex in vivo system. For this reason, in silico (molecular docking combined with umbrella sampling simulation) and in vivo (UHPLC-pharmacokinetics, toxicokinetics; acetylcholinesterase reactivation and functional observatory battery) methods were used. Based on our results, cucurbit[7]urils affect multiple factors in organophosphates poisoning and its therapy by (i) scavenging paraoxon and preventing free fraction of this toxin from entering the brain, (ii) enhancing the availability of atropine in the central nervous system and by (iii) increasing oxime passage into the brain. In conclusion, using cucurbit[7]urils with oximes might positively impact the overall treatment effectiveness and the benefits can outweigh the potential risks.
- MeSH
- atropin chemie MeSH
- hematoencefalická bariéra MeSH
- imidazoly chemie MeSH
- myši MeSH
- oximy chemie MeSH
- paraoxon chemie toxicita MeSH
- počítačová simulace MeSH
- přemostěné cyklické sloučeniny chemie MeSH
- pyridinové sloučeniny chemie MeSH
- reaktivátory cholinesterasy chemie toxicita MeSH
- simulace molekulového dockingu MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
3-Quinuclidinyl benzilate (QNB) is an anticholinergic compound that affects the nervous system. Its hallucinogenic action has led to its potential utility as an incapacitating warfare agent, and it is listed in Schedule 2 by the Organization for the Prohibition of Chemical Weapons. Although this compound has been known for a long time, limited information is available regarding its metabolism and mass spectrometric data of the metabolites, the information that could facilitate the identification of QNB in case of suspected intoxication. To the best of our knowledge, the analytical methods previously described in the literature are based on outdated procedures, which may result in a significantly lower number of observable metabolites. The aim of this work was to obtain deeper insight into QNB biotransformation using a combination of in vitro and in vivo approach. The development of a suitable method for the separation and detection of metabolites using mass spectrometry together with the identification of reliable diagnostic fragments for the unambiguous identification of QNB metabolites in the different biological matrices are also presented in this work. A screening of rat plasma, urine and tissue homogenates revealed 26 new metabolites related to the cytochrome P450 biotransformation pathway, which involves N-oxidation and hydroxylation(s) followed by O-methylation and O-glucuronosylation within phase II of the metabolism. A study showed that the brain is not metabolically active in the case of QNB and that the metabolites do not cross the blood-brain barrier; thus, the toxicodynamic effects are due to QNB itself. In addition, in vitro experiments performed using isolated human liver microsomes revealed N-oxidation as the principal metabolic pathway in human tissue. In light of current global events, the abuse of QNB by terrorists or para-military groups is a real possibility, and our findings may improve the detection systems used in laboratories involved in postexposure investigations.
- MeSH
- biotransformace MeSH
- chinuklidinylbenzilát MeSH
- hmotnostní spektrometrie MeSH
- krysa rodu rattus MeSH
- mozek * MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Being among the top five causes of death in the developed world, Alzheimer's disease represents a major socio-economic issue. We administered a single intramuscular dose of two new hybrid anti-Alzheimer's compounds, with 7-methoxytacrine (7-MEOTA; acetylcholinesterase inhibitor) and tryptophan (inhibitor of amyloid accumulation) in their structure, to rats. Using validated ultra-high-performance liquid chromatography coupled to high-resolution mass spectrometry (UHPLC-HRMS) methods, we uncovered their inability to enter the site of action - the brain. We discuss four possible explanations: i) physico-chemical properties, ii) lack of active/facilitated transport, iii) effective efflux and/or iv) extensive metabolism. High-resolution mass spectrometric analyses proved that the compounds are easily hydrolysed at amide bond between tryptophan and the linker both in vitro and in vivo. Contrary to the parent compounds these metabolites - analogues of 7-MEOTA - can enter the brain in significant amounts.
- MeSH
- Alzheimerova nemoc MeSH
- cholinesterasové inhibitory farmakokinetika MeSH
- hematoencefalická bariéra MeSH
- hydrolýza MeSH
- krysa rodu rattus MeSH
- mozek metabolismus MeSH
- potkani Wistar MeSH
- takrin analogy a deriváty farmakokinetika MeSH
- tandemová hmotnostní spektrometrie MeSH
- tryptofan farmakokinetika MeSH
- vysokoúčinná kapalinová chromatografie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
A combination of tacrine and tryptophan led to the development of a new family of heterodimers as multi-target agents with potential to treat Alzheimer's disease. Based on the in vitro biological profile, compound S-K1035 was found to be the most potent inhibitor of human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE), demonstrating balanced IC50 values of 6.3 and 9.1 nM, respectively. For all the tacrine-tryptophan heterodimers, favorable inhibitory effect on hAChE as well as on hBChE was coined to the optimal spacer length ranging from five to eight carbon atoms between these two pharmacophores. S-K1035 also showed good ability to inhibit Aβ42 self-aggregation (58.6 ± 5.1% at 50 μM) as well as hAChE-induced Aβ40 aggregation (48.3 ± 6.3% at 100 μM). The X-ray crystallographic analysis of TcAChE in complex with S-K1035 pinpointed the utility of the hybridization strategy applied and the structures determined with the two K1035 enantiomers in complex with hBChE could explain the higher inhibition potency of S-K1035. Other in vitro evaluations predicted the ability of S-K1035 to cross blood-brain barrier and to exert a moderate inhibition potency against neuronal nitric oxide synthase. Based on the initial promising biochemical data and a safer in vivo toxicity compared to tacrine, S-K1035 was administered to scopolamine-treated rats being able to dose-dependently revert amnesia.
- MeSH
- acetylcholinesterasa metabolismus MeSH
- Alzheimerova nemoc farmakoterapie metabolismus MeSH
- amyloidní beta-protein antagonisté a inhibitory metabolismus MeSH
- bludiště - učení účinky léků MeSH
- butyrylcholinesterasa metabolismus MeSH
- cholinesterasové inhibitory chemická syntéza chemie farmakologie MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- ligandy MeSH
- molekulární struktura MeSH
- neuroprotektivní látky chemická syntéza chemie farmakologie MeSH
- potkani Wistar MeSH
- proteinové agregáty účinky léků MeSH
- takrin chemie farmakologie MeSH
- tryptofan chemie farmakologie MeSH
- vztah mezi dávkou a účinkem léčiva 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
The objective of this study was to elucidate the pharmacokinetics and metabolite formation of newly developed non-selective AChE/BChE 7-MEOTA-donepezil-like inhibitors for potential therapeutic use in Alzheimer's disease (AD) patients. The chemical structures of metabolites were defined during incubation with human liver microsomes, and subsequently, the metabolization was verified in in vivo study. In vitro metabolic profiling revealed the formation of nine major metabolites in the case of PC-37 and eight metabolites of PC-48. Hydroxylation and the enzymatic hydrolysis of bonds close to the piperazine ring appeared to be the principal metabolic pathways in vitro. Of these metabolites, M1-M7 of PC-37 and M1-M6 of PC-48 were confirmed under in vivo conditions. Pilot pharmacokinetic experiments in rats were focused on the absorption, distribution and elimination of these compounds. Absorption after i.m. application was relatively fast; the bioavailability expressed as AUCtotal was 28179 ± 4691 min.ng/mL for PC-37 and 23374 ± 4045 min.ng/mL for PC-48. Both compounds showed ability to target the central nervous system, with brain concentrations exceeding those in plasma. The maximal brain concentrations are approximately two times higher than the plasma concentrations. The relatively high brain concentrations persisted throughout the experiment until 24 hr after application. Elimination via the kidneys (urine) significantly exceeded elimination via the liver (bile). All these characteristics are crucial for new candidates intended for AD treatment. The principle metabolic pathways that were verified in the in vivo study do not show any evidence for formation of extremely toxic metabolites, but this needs to be confirmed by further studies.
- MeSH
- Alzheimerova nemoc farmakoterapie MeSH
- biologická dostupnost MeSH
- cholinesterasové inhibitory chemická syntéza metabolismus farmakokinetika terapeutické užití MeSH
- hydrolýza MeSH
- hydroxylace MeSH
- jaterní mikrozomy metabolismus MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- metabolické sítě a dráhy MeSH
- mozek účinky léků MeSH
- pilotní projekty MeSH
- piperaziny chemická syntéza metabolismus farmakokinetika terapeutické užití MeSH
- potkani Wistar MeSH
- takrin analogy a deriváty chemická syntéza metabolismus farmakokinetika terapeutické užití MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
