To this date, there are no recommendations for personalized stress ulcer prophylaxis (SUP) in critical care that would take the patient's individual genetic predispositions into account. Of drugs used for this purpose, proton pump inhibitors (PPIs) are the first-choice drugs in intensive care unit patients. The degradation of proton pump inhibitors is mediated by cytochrome P450 (CYP) enzymes; in particular, CYP2C19 and, to a lesser extent, CYP3A4 are involved. Expression and metabolic activity of, namely in, CYP2C19 is significantly affected by single nucleotide polymorphisms, the drug metabolization rate varies greatly from ultrarapid to poor and likely influences the optimal dosage. As these CYP2C19 predictive phenotypes via CYP2C19 haplogenotypes (rs12248560/rs4244285) can be relatively easily determined using the current standard equipment of hospital laboratories, we prepared a set of recommendations for personalized PPI-based stress ulcer prophylaxis taking into account the patient's CYP2C19 predictive phenotype determined in this way. These recommendations are valid, in particular, for European, American and African populations, because these populations have the high representations of the CYP2C19*17 allele associated with the overexpression of the CYP2C19 gene and ultrarapid degradation of PPIs. We propose the CYP2C19 gene profiling as a tool for personalized SUP with PPI in critically ill patients.
- Publikační typ
- časopisecké články MeSH
Úvod: Konzervativní léčba refluxní choroby jícnu (GERD - gastroesophageal reflux disease) je v současnosti opřena o skupinu léků, které nejúčinněji potlačují sekreci kyseliny solné v žaludku, a to tzv. inhibitory protonové pumpy (IPP). I když se nejedná o kauzální léčbu onemocnění, jsou považovány a akceptovány jako léky volby „zlatého standardu“. Cílem retrospektivní studie bylo zmapovat medikace pacientů s GERD v různých stupních onemocnění, analyzovat jejich individuální variabilitu v genu kódujícím enzym cytochrom P450 (CYP2C19) a navrhnout metodiku pro jednoduché stanovení genového profilu pacienta s GERD pro zefektivnění terapeutických postupů. Metody: Do studie bylo zařazeno celkem 276 osob s GERD po chirurgickém zákroku se známou farmakologickou anamnézou - 94 pacientů s neerozivní refluxní chorobou, 121 s refluxní ezofagitidou a 61 s Barrettovým jícnem (BE - Barrett´s esophagus) nebo adenokarcinomem jícnu (EAC - esophageal adenocarcinoma). Stanovení genotypů dvou polymorfizmů genu CYP2C19 (*17 rs12248560 a *2 rs4244285) bylo založeno na principu kvantitativní polymerázové řetězové reakce. Výsledky: Více než 90 % pacientů užívalo IPP (omeprazol/lansoprazol/pantoprazol). Ačkoli ve sledované kohortě předepsaná dávkování IPP odpovídala doporučení pro udržovací terapii, u pacientů nebyla zohledněna míra schopnosti účinnou látku metabolizovat. Bylo zjištěno, že nositelé genotypových kombinací obsahujících variantu CYP2C9*17 determinující fenotyp ultrarychlého metabolizátoru (UM) mají nižší pravděpodobnost souběžného výskytu s variantou CYP2C19*2, která kóduje fenotyp intermediárního nebo „špatného“ metabolizátoru (IM nebo PM), než osoby se standardní funkcí enzymu CYP2C19 (p = 0,001). Frekvence kombinací genotypů (tzv. haplogenotypů) a ve výsledku fenotypů UM/IM/PM byla mezi pacienty s GERD 37,3/16,7/1,4 %. Závěr: U pacientů s GERD by měl být před zahájením farmakoterapie IPP definován jejich genový profil, resp. kombinace variant CYP2C19*17 a *2, a to vzhledem k jejich vysoké frekvenci v populaci a funkčnímu metabolickému významu. Předpokládáme, že by toto opatření mohlo vést ke zvýšení efektivity farmakoterapie, a tím ke zlepšení kvality života pacientů a snad i k prevenci rozvoje závažnějších stavů, jakými jsou BE a EAC. Nestandardní schopnost metabolizovat IPP by mohla být jedním z předpokladů k indikaci chirurgického zákroku u pacientů s GERD.
Introduction: Conservative treatment of gastroesophageal reflux disease (GERD) is currently based on a group of drugs that effectively suppress the secretion of hydrochloric acid in the stomach, so-called proton pump inhibitors (PPI). Although these drugs do not target the cause of the disease, they are considered and accepted as the “gold standard“ for the treatment of this disease. The aim of this retrospective study was to map medication of GERD patients in various phases of the disease, to analyze individual variability in the cytochrome P450 (CYP2C19) gene, and to propose an effective method for the simple determination of the gene in GERD patients. Methods: The study included 276 GERD patients with known pharmacological anamnesis who had undergone surgical treatment. The subjects included 94 patients with non-erosive reflux disease, 121 with reflux esophagitis, and 61 with Barrett´s esophagus (BE) or esophageal adenocarcinoma (EAC). Genotypes of two polymorphisms in the CYP2C19 gene (*17 rs12248560 and *2 rs4244285) were determined using quantitative polymerase chain reaction. Results: More than 90% patients were treated with PPI (omeprazole/lansoprazole/pantoprazole). Although the prescribed PPI dosing in the studied cohort was consistent with recommendations for maintenance therapy, the patients´ability to metabolize the active substance was not considered. Carriers of genotype combinations containing the CYP2C9*17 variant, which determines the ultra-rapid metabolizer (UM) phenotype, were less likely to co-occur with the CYP2C19*2 variant, which determines the intermediate or “poor“ metabolizer (IM or PM) phenotype, than individuals with the standard functioning CYP2C19 enzyme (p = 0.001). The frequencies of combinations of genotypes (haplogenotypes) and resulting UM/IM/PM phenotypes were 37.3/16.7/1.4% in GERD patients. Conclusion: Prior to initiating PPI pharmacotherapy in GERD patients, determination of CYP2C19 haplogenotypes (CYP2C19*17 and *2 variants) should be performed due to frequent occurence of these variants in population and their functional metabolic significance. We presume that this approach will increase the effectiveness of pharmacotherapy, improve patient quality of life, and very likely help prevent/reduce the risk of the development of more serious conditions, such as BE and EAC. The non-standard ability to metabolize PPI in GERD patients may be one of the indicators for surgical intervention.
- MeSH
- cytochrom P450 CYP2C19 genetika metabolismus MeSH
- farmakogenetika * MeSH
- gastroezofageální reflux * diagnóza farmakoterapie chirurgie MeSH
- inhibitory protonové pumpy farmakologie metabolismus terapeutické užití MeSH
- interpretace statistických dat MeSH
- lékové interakce MeSH
- lidé MeSH
- polymorfismus genetický MeSH
- polypharmacy MeSH
- retrospektivní studie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
Diplacone (1) and mimulone (2), two geranylated flavanones, have previously shown anti-inflammatory and antiradical activity in vitro. The present study aimed to evaluate their activity in vivo on a model of colitis induced in Wistar rats by an oral administration of dextran sulfate sodium (DSS). Diplacone (1) and mimulone (2) were administered at a bolus dose of 25mg/kg by gastric gavage 48 and 24h prior to the induction of colitis by DSS and every 24h on the following days of the experiment. The effect of the treatment was assessed by monitoring the disease activity index (DAI), histopathological examination, evaluation of the weight and length of the colon and by analysis of the levels and activities of cyclooxygenase-2 (COX-2), matrix metalloproteinase-2 (MMP2), superoxide dismutase-2 (SOD2), and catalase (CAT) in the inflamed tissue. Administration of the test compounds prior and after induction of colitis ameliorated the symptoms of colitis (diarrhea, presence of the blood in the stool) and delayed their onset. The ability of compounds 1 and 2 to reduce the levels of COX-2 and to increase the ratio of pro-MMP2/MMP2 activity correlates with the values of the DAI. The lowering of the levels of the antioxidant enzymes SOD2 and CAT reflects the ability of the test compounds to scavenge reactive oxygen species.
- MeSH
- cyklooxygenasa 2 metabolismus MeSH
- flavanony farmakologie MeSH
- katalasa metabolismus MeSH
- kolitida chemicky indukované farmakoterapie MeSH
- kolon účinky léků patofyziologie MeSH
- matrixová metaloproteinasa 2 metabolismus MeSH
- modely nemocí na zvířatech MeSH
- molekulární struktura MeSH
- potkani Wistar MeSH
- síran dextranu škodlivé účinky MeSH
- superoxiddismutasa metabolismus MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND: Azathioprine [AZA] and mercaptopurine [MP] are recommended for maintenance of steroid-free remission in children with Crohn`s disease [CD]. Azathioprine-induced pancreatitis, an idiosyncratic and major side effect, has been considered as an absolute contraindication for the use of a second thiopurine in IBD patients. MATERIALS AND METHODS: We describe two children with CD in whom MP were successfully trialled after a confirmed azathioprine-induced pancreatitis, being well tolerated in both cases. RESULTS: Two boys [13 and 10 years old] started exclusive enteral nutrition after diagnosis of moderate (Pediatric Crohn's Disease Activity Index [wPCDAI] = 45) and mild [wPCDAI = 35] CD. Both developed an acute mild to moderate pancreatitis after 2 and 3 weeks, respectively, of AZA treatment but recovered fully in hospital after AZA withdrawal. They started on MP treatment without any adverse effect. They were tested for the presence of polymorphisms 238G>C, 460G>A, and 719A>G in the TPMT gene and 94C>A and 21>C in the ITPase. Both patients were wild-type for all tested polymorphisms. CONCLUSIONS: Azathioprine-induced acute pancreatitis should not be considered as an absolute contraindication for the use of MP. Further investigation is required to create a better understanding of the mechanism underlying the adverse events and to allow more possibilities for personalised therapy.
- MeSH
- azathioprin škodlivé účinky terapeutické užití MeSH
- Crohnova nemoc komplikace farmakoterapie MeSH
- dítě MeSH
- imunosupresiva terapeutické užití MeSH
- lidé MeSH
- merkaptopurin terapeutické užití MeSH
- mladiství MeSH
- pankreatitida chemicky indukované MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
Clay minerals have been proposed as very useful materials for modulating drug delivery. These are the commonly used materials in pharmaceutical production both as inorganic carriers or active agents. We focused on the development of suitable long-acting material for local treatment of oral infection where clay minerals act as inorganic drug carriers. Organovermiculites with antibacterial activity were prepared by ion exchange reactions using different concentrations of chlorhexidine diacetate. The samples were characterized by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR) and thermal analysis (TGA). The antibacterial activity was evaluated by finding the minimum inhibitory concentration (MIC). All studied organoclays possessed good antibacterial activity after 24h exposure against Escherichia coli, Enterococcus faecalis and particularly against Staphylococcus aureus. Pseudomonas aeruginosa however proved very resistant as only the sample with the highest concentration of CA that successfully inhibited bacterial growth. Furthermore, clay mineral vermiculite was subjected to in vivo toxicological analysis and its influence on gastrointestinal tract during its oral application was investigated. Tissue samples from buccal mucosa, tongue, esophagus, stomach, terminal duodenum, small intestine, caecum, distal colon and liver were subjected to histological examination, both macroscopically and microscopically. Neither systemic nor local reactions were observed. Therefore the toxicity of vermiculite to a mammal model organism can be excluded.
- MeSH
- antibakteriální látky chemie farmakologie toxicita MeSH
- Bacteria účinky léků MeSH
- chlorhexidin chemie farmakologie MeSH
- gastrointestinální trakt účinky léků MeSH
- krysa rodu rattus MeSH
- nanokompozity chemie toxicita MeSH
- potkani Wistar MeSH
- silikáty hliníku chemie farmakologie toxicita MeSH
- sliznice účinky léků MeSH
- testování materiálů MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Coeliac disease is an autoimmune disorder with genetic predisposition. The aim was to determine the frequency of HLA-DQ2 and HLA-DQ8 in Czech and Slovak patients and the healthy population. The study included 127 patients and 66 healthy volunteers. HLA-DQ2 was identified in 85.03% patients, and 24.24% healthy individuals (P=0.0001; OR17.7632; CI=8.4347-37.4088). HLA-DQ8 was identified in 11.81% patients and 15.5% healthy individuals. HLA-DQ8 occurred more often in HLA-DQ2-negative patients compared to HLA-DQ2-positive patients (P=0.0494; OR3.5; CI 1.0428-11.7468). At least one of the studied HLA-variants was found more often in patients than in healthy individuals (P=0.0001; OR58.8; CI 7.6856-449.8602).
- MeSH
- celiakie genetika patologie MeSH
- etnicita genetika MeSH
- frekvence genu MeSH
- genetická predispozice k nemoci MeSH
- genetické asociační studie MeSH
- haplotypy genetika MeSH
- HLA-DQ antigeny genetika MeSH
- lidé MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Česká republika MeSH
- Slovenská republika MeSH
The primary abnormalities that are associated with a risk of venous thrombosis are the deficiencies of protein C. Protein C (PROC), encoded by the PROC gene, acts through its affinity for binding to its transmembrane endothelial cell protein C receptor (EPCR) encoded by the EPCR gene. The objective of the study was to analyze the link between three polymorphisms in the promoter of PROC gene, the polymorphism in the EPCR gene and the occurrence of venous thrombosis. We genotyped 135 individuals - 51 cases with documented venous thrombosis and 84 healthy volunteers without a history of venous thrombosis. The occurrence of the TAA haplotype of PROC gene was significantly more frequent in the controls (N = 48; 57.1%), compared with the patients (N = 18; 35.3%), (P = 0.0206). The healthy individuals were also significantly often carriers of the TAA haplotype and the standard genotype AA of EPCR gene (50 vs. 25.5%) than the patients (P = 0.0066). The frequency of haplotypes CAA and CGT of PROC gene was insignificantly higher in the patients (15.7 and 21.6%, respectively) than in the control group (9.5 and 13.1%). The combination of haplotype CAA/CAA of PROC gene and variant genotype AG of EPCR gene was confirmed with a higher frequency in the group of patients (3.9 vs. 1.2%).This analysis showed that the PROC haplotype associated with a high protein C level (TAA) and the EPCR AA genotype was significantly more frequent in the healthy volunteers (P = 0.0066). Haplotypes associated with a low production of protein C (CAA or CGT) were more frequent in patients with venous thrombosis.
- MeSH
- CD antigeny genetika MeSH
- dospělí MeSH
- frekvence genu MeSH
- genetická predispozice k nemoci MeSH
- genetické asociační studie MeSH
- genotypizační techniky MeSH
- haplotypy MeSH
- heterozygot MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- polymorfismus genetický * MeSH
- prognóza MeSH
- promotorové oblasti (genetika) * MeSH
- protein C genetika MeSH
- receptory buněčného povrchu genetika MeSH
- rizikové faktory MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- studie případů a kontrol MeSH
- žilní trombóza diagnóza genetika patologie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- Crohnova nemoc farmakoterapie MeSH
- farmakogenetika MeSH
- genotypizační techniky MeSH
- infliximab aplikace a dávkování farmakokinetika farmakologie MeSH
- lidé MeSH
- polymorfismus genetický genetika účinky léků MeSH
- TNF-alfa genetika účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
