Publications by authors named "Ilja Tacheci"

51 Publications

Colorectal anastomosis dehiscence: a call for more detailed morphological classification.

Wideochir Inne Tech Maloinwazyjne 2021 Mar 16;16(1):98-109. Epub 2020 Jul 16.

Department of Oncology and Radiotherapy, Charles University, Medical Faculty Hradec Králové, University Hospital, Hradec Králové, Czech Republic.

Introduction: A proactive approach is recommended in colorectal anastomosis leak treatment, and early diagnosis is very important. Early postoperative endoscopy would allow rapid diagnosis of anastomotic pathologies and consequent prompt intervention according to anastomotic disruption morphology.

Aim: To evaluate the effectiveness of close endoscopic follow-up of all patients (including asymptomatic ones) in improving diagnosis of acute leak (AL) and reducing its complications.

Material And Methods: This study included 124 patients who had undergone rectum resection for rectal cancer with stapled anastomosis. Endoscopy was performed between the 7 and 10 postoperative day and 1 month postoperatively. For defect morphology assessment, a classification system was created based on four levels of severity. Photographic findings were evaluated by an independent, experienced gastroenterologist.

Results: Postoperative endoscopy revealed 28 (22.6%) patients with acute leakage. Initial endoscopy confirmed AL in 18 patients. Six (31.6%) patients were asymptomatic and 13 (68.4%) were symptomatic. The second endoscopy revealed another 9 (32.1%) leaks (4 (44.5%) asymptomatic and 5 (55.5%) symptomatic). Sixteen (57.1%) patients had grade A leakages, 7 (25.0%) had grade B leakages, and 5 (17.9%) had grade C leakages. Furthermore, 22 of 27 (81%) defects were located posterior and posterior-laterally. Fifteen (55.5%) defects were smaller than 1/3 the circumference, 7 (25.9%) affected 1/3-1/2 of the circumference, and 5 (18.5%) affected more than 1/2 of the circumference.

Conclusions: Incorporation of early endoscopy in postoperative management allows rapid diagnosis of AL and allows faster intervention, even in leaks that are clinically silent.
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http://dx.doi.org/10.5114/wiitm.2020.97367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7991942PMC
March 2021

Peutz-Jeghers syndrome.

Curr Opin Gastroenterol 2021 May;37(3):245-254

2nd Department of Internal Medicine - Gastroenterology, Charles University, Faculty of Medicine in Hradec Kralove and University Hospital, Hradec Kralove, Czech Republic.

Purpose Of Review: Peutz-Jeghers syndrome is a rare, autosomal dominant, hereditary polyposis syndrome defined by gastrointestinal hamartomas and mucocutaneous pigmentations, caused by a germline mutation in the serine/ threonine kinase 11 or liver kinase B1 (STK11/LKB1) genes. Hamartomatous polyps located throughout the gastrointestinal tract can be complicated by bleeding and small bowel intussusception, potentially leading to the need for emergency surgery. Individuals suffering from Peutz-Jeghers syndrome have an increased lifetime risk of various forms of cancer (gastrointestinal, pancreatic, lung, breast, uterine, ovarian and testicular). Surveillance should lead to the prevention of complications and thus a reduction in mortality and morbidity of patients.

Recent Findings: A combined approach based on wireless capsule endoscopy, magnetic resonance enterography and device-assisted enteroscopy is effective in reduction of the polyp burden and thus decreasing the risk of bleeding and intussusception. Current guidelines for screening and surveillance are mostly based on expert opinion rather than evidence.

Summary: Peutz-Jeghers syndrome is an emerging disease that significantly affects the quality of life enjoyed by patients. Despite of all the progress in improved early diagnostics, options for advanced endoscopic therapy and elaborate surveillance, acute and chronic complications decrease the life expectancy of patients suffering from Peutz-Jeghers syndrome.
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http://dx.doi.org/10.1097/MOG.0000000000000718DOI Listing
May 2021

Dieulafoys jejunal lesion as a source of lifethreating bleeding.

Vnitr Lek 2020 ;66(6):381-385

Dieulafoy`s lesion is a rare condition characterized by bleeding into gastrointestinal tract from minimaly eroded submucous artery. Mostly is localized in stomach in elderly polymorbid men, but can occure in entire gastrointestinal tract, in both sexes, in every age. It should be thought off as one of possible causes of obscure bleeding. It is often massive, requiring fast diagnostics, treatment and multidisciplinary approach. The case report discusses patient with recurrent hemodynamicaly significant bleeding into jejunum. It pointed to combined diagnostic approach using both endoscopy and angiography. After failing endoscopically and angiografically due to hemodynamic instability, surgical intervention took place. Precise Dieulafoy`s lesion diagnosis has been determined eventually on histologic section. Diagnostic and therapeutic approach should be individual taking patient´s condition and capabilities of department into consideration. Surgical intervention remains golden standard when hemodynamic instability occures or when endoscopy and angiography fail.
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January 2021

Detection of abnormality in wireless capsule endoscopy images using fractal features.

Comput Biol Med 2020 Dec 27;127:104094. Epub 2020 Oct 27.

Artificial Intelligence Lab, Oslo Metropolitan University, 460167, Norway.

One of the most recent non-invasive technologies to examine the gastrointestinal tract is wireless capsule endoscopy (WCE). As there are thousands of endoscopic images in an 8-15 h long video, an evaluator has to pay constant attention for a relatively long time (60-120 min). Therefore the possibility of the presence of pathological findings in a few images (displayed for evaluation for a few seconds only) brings a significant risk of missing the pathology with all negative consequences for the patient. Hence, manually reviewing a video to identify abnormal images is not only a tedious and time consuming task that overwhelms human attention but also is error prone. In this paper, a method is proposed for the automatic detection of abnormal WCE images. The differential box counting method is used for the extraction of fractal dimension (FD) of WCE images and the random forest based ensemble classifier is used for the identification of abnormal frames. The FD is a well-known technique for extraction of features related to texture, smoothness, and roughness. In this paper, FDs are extracted from pixel-blocks of WCE images and are fed to the classifier for identification of images with abnormalities. To determine a suitable pixel block size for FD feature extraction, various sizes of blocks are considered and are fed into six frequently used classifiers separately, and the block size of 7×7 giving the best performance is empirically determined. Further, the selection of the random forest ensemble classifier is also done using the same empirical study. Performance of the proposed method is evaluated on two datasets containing WCE frames. Results demonstrate that the proposed method outperforms some of the state-of-the-art methods with AUC of 85% and 99% on Dataset-I and Dataset-II respectively.
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http://dx.doi.org/10.1016/j.compbiomed.2020.104094DOI Listing
December 2020

The pharmacokinetic parameters and the effect of a single and repeated doses of memantine on gastric myoelectric activity in experimental pigs.

PLoS One 2020 24;15(1):e0227781. Epub 2020 Jan 24.

Department of Toxicology and Military Pharmacy, University of Defence, Faculty of Military Health Sciences, Hradec Kralove, Czech Republic.

Background: Memantine, currently available for the treatment of Alzheimer's disease, is an uncompetitive antagonist of the N-methyl-D-aspartate type of glutamate receptors. Under normal physiologic conditions, these unstimulated receptor ion channels are blocked by magnesium ions, which are displaced after agonist-induced depolarization. In humans, memantine administration is associated with different gastrointestinal dysmotility side effects (vomiting, diarrhoea, constipation, motor-mediated abdominal pain), thus limiting its clinical use. Mechanism of these motility disorders has not been clarified yet. Pigs can be used in various preclinical experiments due to their relatively very similar gastrointestinal functions compared to humans. The aim of this study was to evaluate the impact of a single and repeated doses of memantine on porcine gastric myoelectric activity evaluated by means of electrogastrography (EGG).

Methods: Six adult female experimental pigs (Sus scrofa f. domestica, mean weight 41.7±5.0 kg) entered the study for two times. The first EGG was recorded after a single intragastric dose of memantine (20 mg). In the second part, EGG was accomplished after 7-day intragastric administration (20 mg per day). All EGG recordings were performed under general anaesthesia. Basal (15 minutes) and study recordings (120 minutes) were accomplished using an EGG stand (MMS, Enschede, the Netherlands). Running spectral analysis based on Fourier transform was used. Results were expressed as dominant frequency of gastric slow waves (DF) and power analysis (areas of amplitudes).

Results: Single dose of memantine significantly increased DF, from basic values (1.65±1.05 cycles per min.) to 2.86 cpm after 30 min. (p = 0.008), lasting till 75 min. (p = 0.014). Basal power (median 452; inter-quartile range 280-1312 μV^2) raised after 15 min. (median 827; IQR 224-2769; p = 0.386; NS), lasting next 30 min. Repetitively administrated memantine caused important gastric arrhythmia. Basal DF after single and repeated administration was not different, however, a DF increase in the second part was more prominent (up to 3.18±2.16 after 15 and 30 min., p<0.001). In comparison with a single dose, basal power was significantly higher after repetitively administrated memantine (median 3940; IQR 695-15023 μV^2; p<0.001). Next dose of 20 mg memantine in the second part induced a prominent drop of power after 15 min. (median 541; IQR 328-2280 μV^2; p<0.001), lasting till 120 min. (p<0.001).

Conclusions: Both single and repeated doses of memantine increased DF. Severe gastric arrhythmia and long-lasting low power after repeated administration might explain possible gastric dysmotility side effects in the chronic use of memantine.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0227781PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980640PMC
April 2020

Accuracy of Colon Capsule Endoscopy for Colorectal Neoplasia Detection in Individuals Referred for a Screening Colonoscopy.

Gastroenterol Res Pract 2019 3;2019:5975438. Epub 2019 Sep 3.

Department of Medicine, First Faculty of Medicine, Charles University, Military University Hospital, Prague, CZ 169 02, Czech Republic.

Backround: Capsule colonoscopy might present an alternative to colonoscopy for colorectal neoplasia screening.

Aim: To assess the accuracy of second-generation capsule colonoscopy (CCE2) for colorectal neoplasia detection compared with conventional colonoscopy (CC).

Methods: From 2011-2015, we performed a multicenter, prospective, cross-over study evaluating the use of CCE2 as a possible colorectal cancer (CRC) screening test based on the assessment of the method's characteristics (accuracy) and safety and patient acceptance of the routine. Enrolled participants fulfilled the CRC screening population criteria if they were asymptomatic, were older than 50, and had no personal or familial history of colorectal neoplasia. The primary outcome was accuracy for the detection of polyps ≥ 6 mm. Secondary outcomes were accuracy for all polyps, polyps ≥ 10 mm, adenomas ≥ 10 mm, and cancers, the quality of bowel cleansing, safety, and CCE2 acceptability by the screening population.

Results: A total of 236 individuals were examined; 11 patients (5%) were excluded. Therefore, 225 subjects (95%) were considered in the intention-to-screen (ITS) group. A total of 201 patients (89%) completed both examinations successfully (per protocol group). In the ITS group, polyps were diagnosed during CC in 114 subjects (51%); polyps ≥ 6 mm, polyps ≥ 10 mm, and adenomas ≥ 10 mm were diagnosed in 34 (15%), 16 (7%), and 11 (5%) patients, respectively. The sensitivity of CCE2 for polyps ≥ 6 mm, polyps ≥ 10 mm, and adenomas ≥ 10 mm was 79% (95% confidence interval (CI): 62-91%), 88% (95% CI: 62-98%), and 100% (95% CI: 72-100%), respectively.

Conclusion: Second-generation capsule colonoscopy is a safe, noninvasive, and sensitive method for colorectal neoplasia detection although CC remains the preferred method for considerable proportion of subjects. CCE2 may therefore be accepted as the primary screening test for colorectal cancer screening.
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http://dx.doi.org/10.1155/2019/5975438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6745144PMC
September 2019

Non-conventional mucosal lesions (serrated epithelial change, villous hypermucinous change) are frequent in patients with inflammatory bowel disease-results of molecular and immunohistochemical single institutional study.

Virchows Arch 2020 Feb 2;476(2):231-241. Epub 2019 Aug 2.

The Fingerland Department of Pathology, Charles University Faculty of Medicine and University Hospital Hradec Králové, Sokolská 581, 500 03, Hradec Králové, Czech Republic.

Chronically inflamed mucosa in inflammatory bowel disease (IBD) is associated with an increased risk of cancer. Besides IBD-associated dysplasia, there are non-conventional mucosal changes that may act as potential precursors. The aim of the study was to retrospectively review samples from IBD patients focusing on detection of such lesions with evaluation of their immunohistochemical and molecular properties. Surgical specimens and/or endoscopical biopsy samples of IBD patients examined during a 10-year period were reviewed. Detected mucosal lesions were divided into three groups-group 1 (non-conventional or putative precursor lesions - PPLs) with serrated or villous hypermucinous morphology, group 2 (true serrated polyps fulfilling valid criteria), and group 3 (IBD-associated neoplasia). Lesions from all groups were analyzed with antibodies against MLH1, p53, and MGMT and by molecular testing of KRAS, NRAS, and BRAF mutation. Samples from 309 IBD patients were reviewed. A total of 88 mucosal lesions were found in 51 patients. Most common were lesions from group 1 with superficial serrated epithelial change seen in 41 samples (46.6%) and villous hypermucinous change in 6 (6.8%). Group 2 consisted of 15 true serrated polyps. Six conventional IBD-dysplasia cases and 11 carcinomas were seen in group 3. Six lesions from group 1 were associated with invasive carcinoma whereas two shared the same mutation in KRAS or BRAF. Lesions from group 1 were characterized by loss of MGMT expression in 44.6%, aberrant p53 expression, and by mutations in KRAS gene in 42.9% of cases. This study proves the existence of mucosal changes other than conventional IBD-dysplasia and extends the knowledge about their immunohistochemical and molecular properties and relation to carcinoma further supporting their potential role in IBD-related carcinogenesis.
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http://dx.doi.org/10.1007/s00428-019-02627-4DOI Listing
February 2020

Morphological, immunohistochemical and molecular features of inflammatory bowel disease associated colorectal carcinoma and associated mucosal lesions - Single institution experience.

Pathol Res Pract 2019 Apr 11;215(4):730-737. Epub 2019 Jan 11.

The Fingerland Department of Pathology, Charles University Faculty of Medicine and University Hospital Hradec Králové, Sokolská 581, Hradec Králové, 500 03, Czech Republic. Electronic address:

Background: Patients with inflammatory bowel disease (IBD) - ulcerative colitis (UC) and Crohn's disease (CD) have an elevated risk of developing colorectal carcinoma (CRC). Major risk factor in IBD patients is the continuous chronic inflammation leading to development of dysplasia and carcinoma. Nevertheless, other types of non-conventional but suspicious mucosal changes serrated change/dysplasia, NOS and villous hypermucinous change, have also been reported in IBD patients. Preneoplastic potential of these lesions is still not well elucidated.

Aims: The aim of this study was identification of IBD-associated CRCs focusing on finding related precursor lesions in the surgical specimen or in archival biopsy samples followed by a detailed morphological, immunohistochemical and molecular evaluation. For the purpose of the study the mucosal lesions were divided into conventional IBD-associated dysplasia and non-conventional lesions that were merged under a provisory term of putative preneoplastic lesions (PPL).

Methods: A total of 309 consecutive IBD colectomy specimens diagnosed during a 10-year period were reviewed. Detailed morphological evaluation, immunohistochemical analysis of mismatch repair (MMR) proteins, p53 and O-methylguanine DNA methyltransferase (MGMT) expression and molecular analysis for KRAS, NRAS and BRAF gene mutation were performed in the retrieved CRC cases as well as in the detected dysplasia and PPLs of these patients.

Results: We identified 11 cases of morphologically heterogenous IBD-associated CRCs, occurring in 5 males and 6 females, aged 26-79 years (mean 44 years). A total of 22 mucosal lesions were revealed in 8 CRC patients comprising conventional IBD-associated dysplasia (4 lesions), PPLs as serrated change/dysplasia NOS (11 lesions), villous hypermucinous change (5 lesions), and two true serrated lesions (one sessile serrated adenoma and one traditional serrated adenoma). More than one type of lesion was found in 6 patients. Seven CRC cases harbored mutation of KRAS/NRAS and one case of BRAF. Two patients with KRAS-mutated CRC showed the same mutation in PPL in the same specimen (one serrated change NOS and one TSA with high-grade dysplasia). Similarly, one BRAF-mutated carcinoma case presented the same mutation in serrated change/dysplasia, NOS in the same specimen. Of the CRCs, two showed deficient MMR system profile, six presented with loss of MGMT expression, and six showed aberrant p53 expression. PPLs showed deficient MGMT expression (14 cases) and aberrant p53 (10 cases) as well.

Conclusion: IBD-associated CRCs are very heterogeneous entities. Besides conventional IBD-related dysplasia, other types of mucosal lesions may be associated with long lasting IBD and CRC e.g. villous hypermucinous change and serrated change/dysplasia, NOS. Since these lesions share certain genetic or immunohistochemical changes with the related CRC, a suspicion is raised that these lesions may also have preneoplastic potential. Awareness of these changes is necessary to prevent their missing and under-reporting, and further studies of these lesions should be carried out.
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http://dx.doi.org/10.1016/j.prp.2019.01.010DOI Listing
April 2019

The prevalence and sociodemographic determinants of uninvestigated dyspepsia in the Czech Republic: a multicentre prospective study accomplished 10 years after the first study from the same geographical areas.

Eur J Gastroenterol Hepatol 2018 Jan;30(1):76-82

Second Department of Medicine - Gastroenterology.

Objective: The epidemiology of uninvestigated dyspepsia was studied in the Czech Republic for the first time in 2001. The aim of the current multicenter prospective study was to evaluate dyspepsia using the same methods in a representative sample of general unselected population from the same geographical areas 10 years later.

Participants And Methods: A total of 38 147 individuals comprised the general population for a random two-step selection process. A total of 1836 participants (863 males and 973 females; aged 5-98 years) took part in the questionnaire-based study. Helicobacter pylori status was investigated in all participants by means of C-urea breath test.

Results: The overall prevalence of dyspepsia was 2.6% among children and adolescents aged 5-17 years and 16.0% among adults aged 18-98 years. We did not detect any statistically significant sex differences in the prevalence of total dyspepsia or its subtypes. Overall, 2.4% of H. pylori-negative children and adolescents aged less than 18 years reported dyspepsia, and 16.8% of H. pylori-negative adults reported it. Among H. pylori-positive children and adolescents and adults, dyspepsia was present in 8.3 and 15.8%, respectively. Type A dyspepsia (as the only long-lasting symptom) was statistically significantly associated with H. pylori status among children and adolescents. Among adults aged 18 years or older, we noted a lower prevalence of dyspepsia in adults with elementary education compared with university education. Current use of antibiotics was associated with an increased prevalence of dyspepsia in adults.

Conclusion: Despite the substantial decrease of H. pylori infection in the Czech Republic over the past 10 years, the prevalence and sociodemographic determinants of uninvestigated dyspepsia did not change significantly.
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http://dx.doi.org/10.1097/MEG.0000000000001007DOI Listing
January 2018

Pharmacokinetic profile of promising acetylcholinesterase reactivators K027 and K203 in experimental pigs.

Toxicol Lett 2017 May 23;273:20-25. Epub 2017 Mar 23.

2nd Department of Medicine - Gastroenterology, Charles University Faculty of Medicine and University Hospital, Hradec Kralove, Czech Republic.

Standard treatment of organophosphorus compounds (OPs) poisoning includes administration of an anti-muscarinic (atropine), anticonvulsive (diazepam) and acetylcholinesterase reactivator (oxime). From a wide group of newly synthesized oximes, oxime K027 and oxime K203 seem to be perspective compounds in some specific OPs intoxication. The available in vitro and in vivo preclinical data indicate that both oximes may be considered for potential human use. The main aim of this study was to establish plasmatic concentration curves of both oximes after intramuscular (i.m.) and intragastric (i.g.) application with subsequent pharmacokinetic analysis and study distribution after (i.m.) application on a non-rodent animal model (experimental pigs; 1500mg/animal). According to the results, both oximes had similar C (K027: 106±19μg/mL and K203: 111±8μg/mL) in T 19±5min, respectively, in 22±3min. Bioavailability of oxime K027 calculated as AUC (8389±1024minμg/mL) was halved compared to oxime K203 (16938±795minμg/mL). The highest concentration from peripheral tissues was found in the kidney and lung, but the brain concentrations stay very low, the plasma/brain ratio being approximately 1%. The applied doses were derived from the recommendation where it is possible to use three autoinjectors to save human life. The results provide us with knowledge about the pharmacokinetics and distribution of these new oximes and may help us to better estimate the human pharmacokinetic profile.
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http://dx.doi.org/10.1016/j.toxlet.2017.03.017DOI Listing
May 2017

Automatic blood detection in capsule endoscopy video.

J Biomed Opt 2016 12;21(12):126007

University of Hradec Králové, Center for Basic and Applied Research, Faculty of Informatics and Management, Hradecká 1249, Hradec Králové 500 03, Czech Republic.

We propose two automatic methods for detecting bleeding in wireless capsule endoscopy videos of the small intestine. The first one uses solely the color information, whereas the second one incorporates the assumptions about the blood spot shape and size. The original idea is namely the definition of a new color space that provides good separability of blood pixels and intestinal wall. Both methods can be applied either individually or their results can be fused together for the final decision. We evaluate their individual performance and various fusion rules on real data, manually annotated by an endoscopist.
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http://dx.doi.org/10.1117/1.JBO.21.12.126007DOI Listing
December 2016

The Importance of Wireless Capsule Endoscopy for Research into the Intestin al Absorption Window of 5-Aminosalicylic Acid in Experimental Pigs.

Curr Pharm Des 2017 ;23(12):1873-1876

Department of Internal Medicine - Gastroenterology, University Hospital, Sokolska 581, 500 05 Hradec Kralove. Czech Republic.

Background: Absorption windows in particular segments of the small intestine can contribute to the development of orally administered drug formulations and can limit the bioavailability of released compounds.

Objective: The aim of this study was to evaluate use of wireless capsule enteroscopy regarding the disintegration kinetic process of tablets in the small intestine and its comparison with the levels of the model drug (5- aminosalicylic acid; 5-ASA), and its majority metabolite (N-acetyl-5-aminosalicylic acid; N-acetyl-5-ASA) in blood plasma.

Methods: Tablets were endoscopically introduced into the duodenum and their disintegration was monitored using wireless capsule enteroscopy in anaesthetised pigs. In parallel, blood plasma time profiles of the model drug (5-ASA) released from tablets and its metabolite (N-acetyl-5-ASA) were detected.

Results: The disintegration of tablets was evident in the proximal jejunum (until the 90-minute mark) and culminated at the 3rd hour. The maximum plasmatic concentration of 5-ASA was reached at the 3rd hour and in the case of its metabolite (N-acetyl-5-ASA) at the 4th hour.

Conclusion: The study demonstrated the advantage of combination of wireless capsule enteroscopy and bioanalytical determination of pharmacokinetic parameters in an animal experiment to localise the disintegration site of solid dosage form and following kinetics of intestinal absorption of the released active agent.
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http://dx.doi.org/10.2174/1381612822666161201145247DOI Listing
April 2018

The plausible association of MTHFR and ADORA2A polymorphisms with nodules in rheumatoid arthritis patients treated with methotrexate.

Pharmacogenet Genomics 2017 02;27(2):43-50

aSecond Department of Internal Medicine - Gastroenterology and Rheumatology, Faculty of Medicine bInstitute of Clinical Biochemistry and Diagnostics, University Hospital Departments of cSocial and Clinical Pharmacy dBiophysics and Physical Chemistry ePharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove fInstitute of Physics, Faculty of Mathematics and Physics, Charles University, Prague, Czech Republic.

Objective: The treatment of rheumatoid arthritis (RA) patients with methotrexate (MTX) is linked to the development or progression of rheumatoid nodules. The aim of this study was to determine whether folate and adenosine pathways-related single nucleotide polymorphisms might be predictive of increased nodule formation in RA patients treated with oral MTX.

Methods: A total of 185 Caucasian RA patients were enrolled in this cross-sectional study, all of whom fulfilled the 1987 RA criteria of the American College of Rheumatology; each patient had a history of MTX treatment.

Results: A higher frequency of the MTHFR 1298AA genotype was found in 17 (70.8%) of 24 patients with general nodules [odds ratio (OR)=3.08, 95% confidence interval (CI): 1.20-7.69] and in 14 (73.7%) of 19 patients who developed nodules during MTX treatment (OR=3.55, 95% CI: 1.22-10.32). In contrast, a negative association with nodules during MTX treatment (OR=0.29, 95% CI: 0.08-1.10) was found for 19 (79.2%) patients with the TT genotype (rs2298383) in the adenosine A2a receptor gene (ADORA2A). However, the significance did not remain upon correction for multiple testing. The combination of MTHFR 1298AA along with ADORA2A rs2298383 CC or CT genotypes occurring in one-third of RA patients showed a higher frequency of general nodules 15/59 (25.4%) as well as developing nodules during MTX treatment 13/59 (22.0%) in comparison with the overall studied group: 24/185 (13.0%) and 19/185 (10.3%), respectively.

Conclusion: This exploratory study indicates for the first time a plausible association of adenosine and folate pathways single nucleotide polymorphisms in nodules' etiopathogenesis.
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http://dx.doi.org/10.1097/FPC.0000000000000256DOI Listing
February 2017

Wireless Capsule Enteroscopy in Healthy Volunteers.

Acta Medica (Hradec Kralove) 2016;59(3):79-83. Epub 2016 Sep 8.

Second Department of Internal Medicine - Gastroenterology; Charles University, Faculty of Medicine and University Hospital, Hradec Králové, Czech Republic.

Introduction: The aim of our prospective study was to define endoscopy appearance of the small bowel in healthy volunteers.

Method: Forty-two healthy volunteers underwent wireless capsule endoscopy, clinical investigation, laboratory tests, and completed a health-status questionnaire. All subjects were available for a 36-month clinical follow-up.

Results: Eleven subjects (26%) had fully normal endoscopy findings. Remaining 31 persons (74%), being asymptomatic, with normal laboratory results, had some minor findings at wireless capsule endoscopy. Most of those heterogeneous findings were detected in the small intestine (27/31; 87%), like erosions and/or multiple red spots, diminutive polyps and tiny vascular lesions. During a 36-month clinical follow-up, all these 42 healthy volunteers remained asymptomatic, with fully normal laboratory control.

Conclusions: Significant part of healthy subjects had abnormal findings at wireless capsule endoscopy. These findings had no clinical relevance, as all these persons remained fully asymptomatic during a 36-month follow-up. Such an endoscopic appearance would be previously evaluated as "pathological". This is a principal report alerting that all findings of any control group of wireless capsule endoscopic studies must be evaluated with caution.
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http://dx.doi.org/10.14712/18059694.2016.93DOI Listing
June 2017

Risk Factors of Acute Pancreatitis in Oral Double Balloon Enteroscopy.

Acta Medica (Hradec Kralove) 2016;59(3):84-90. Epub 2016 Sep 1.

2nd Department of Medicine - Gastroenterology, Charles University, Faculty of Medicine in Hradec Králové, University Teaching Hospital, Hradec Králové, Czech Republic.

Double balloon enteroscopy (DBE) was introduced 15 years ago. The complications of diagnostic DBE are rare, acute pancreatitis is most redoubtable one (incidence about 0.3%). Hyperamylasemia after DBE seems to be a rather common condition respectively. The most probable cause seems to be a mechanical straining of the pancreas. We tried to identify patients in a higher risk of acute pancreatitis after DBE. We investigated several laboratory markers before and after DBE (serum cathepsin B, lactoferrin, E-selectin, SPINK 1, procalcitonin, S100 proteins, alfa-1-antitrypsin, hs-CRP, malondialdehyde, serum and urine amylase and serum lipase). Serum amylase and lipase rose significantly with the maximum 4 hours after DBE. Serum cathepsin and procalcitonin decreased significantly 4 hours after DBE compared to healthy controls and patients values before DBE. Either serum amylase or lipase 4 hours after DBE did not correlate with any markers before DBE. There was a trend for an association between the number of push-and-pull cycles and procalcitonin and urine amylase 4 hours after DBE; between procalcitonin and alfa-1-antitrypsin, cathepsin and hs-CRP; and between E-selectin and malondialdehyde 4 hours after DBE. We found no laboratory markers determinative in advance those patients in a higher risk of acute pancreatitis after DBE.
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http://dx.doi.org/10.14712/18059694.2016.95DOI Listing
June 2017

Small intestinal injury in NSAID users suffering from rheumatoid arthritis or osteoarthritis.

Rheumatol Int 2016 Nov 22;36(11):1557-1561. Epub 2016 Aug 22.

Second Department of Internal Medicine - Gastroenterology, Faculty of Medicine at Hradec Králové, University Hospital, Charles University in Prague, Sokolská 581, 50003, Hradec Králové, Czech Republic.

The goal of this prospective study was to assess non-steroidal anti-inflammatory drug (NSAID)-induced enteropathy in patients with rheumatoid arthritis (RA) or osteoarthritis (OA) by means of non-invasive wireless capsule enteroscopy. A total of 143 patients (74 with RA, 69 with OA) treated with NSAIDs (>1 month) and 42 healthy volunteers were included. All subjects underwent capsule endoscopy, laboratory tests and filled in questionnaires. The severity of small bowel injury was graded as: mild (red spots or sporadic erosions), moderate (10-20 erosions) or severe (>20 erosions or ulcers). Capsule endoscopy identified small bowel lesions in 44.8 % of patients (mild 36.4 %, moderate 3.5 % and severe in 4.9 %). Mild non-specific lesions were found in 11.9 % healthy volunteers. There was a significantly higher prevalence of enteropathy in RA (56.8 %) compared to OA (31.9 %, p < 0.01). A significant difference between NSAID users (RA and OA) with and without enteropathy was observed in erythrocytes (p < 0.01), the leucocyte count (p < 0.05), haemoglobin (p < 0.05), haematocrit (p < 0.05), serum albumin (p < 0.01) and erythrocyte sedimentation rate (p < 0.05). No relationship was found between enteropathy and dyspepsia, gender or age. NSAID therapy is associated with a significant risk of small bowel injury. The risk is significantly higher in RA patients suggesting a possible influence of the underlying disease.

Trial Registration Number: DRKS00004940.
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http://dx.doi.org/10.1007/s00296-016-3552-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5055563PMC
November 2016

Epidermal Growth Factor Attenuates Delayed Ionizing Radiation-Induced Tissue Damage in Bone Marrow Transplanted Mice.

Radiat Res 2016 09 18;186(3):264-74. Epub 2016 Aug 18.

a   Radiobiology and.

We examined the effect of epidermal growth factor (EGF) treatment in mice that received bone marrow transplantation (BMT) after 11 Gy whole-body irradiation. C57Bl/6 mice were divided into three treatment groups: 0 Gy; 11 Gy ((60)Co, single dose, 0.51 Gy/min) with BMT (5 × 10(6) bone marrow cells isolated from green fluorescent protein syngeneic mice, 3-4 h postirradiation); and 11 Gy with BMT and EGF (2 mg/kg applied subcutaneously 1, 3 and 5 days postirradiation). Survival data were collected. Bone marrow, peripheral blood count and cytokines, gastrointestine and liver parameters and migration of green fluorescent protein-positive cells were evaluated at 63 days postirradiation. Epidermal growth factor increased survival of irradiated animals that received BMT from 10.7 to 85.7% at 180 days postirradiation. In the BMT group, we found changes in differential bone marrow and blood count, plasma cytokine levels, gastrointestinal tissues and liver at 63 days postirradiation. These alterations were completely or in some parameters at least partially restored by epidermal growth factor. These findings indicate that epidermal growth factor, administered 1, 3 and 5 days postirradiation in combination with bone marrow transplantation, significantly improves long-term prognosis.
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http://dx.doi.org/10.1667/RR14247.1DOI Listing
September 2016

Advanced Studies in Clinical and Experimental Research in Gastroenterology.

Gastroenterol Res Pract 2016 3;2016:4253143. Epub 2016 Feb 3.

Department of Internal Medicine, First Faculty of Medicine of Charles University and Military University Hospital, U Vojenské nemocnice 1200, 169 02 Prague, Czech Republic.

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http://dx.doi.org/10.1155/2016/4253143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4756218PMC
March 2016

Impact of tacrine and 7-methoxytacrine on gastric myoelectrical activity assessed using electrogastrography in experimental pigs.

Neuro Endocrinol Lett 2015 ;36 Suppl 1:150-5

2nd Department of Medicine - Gastroenterology, Charles University in Prague, Faculty of Medicine in Hradec Králové, University Teaching Hospital, Hradec Kralove, Czech Republic.

Objectives: Tacrine was the first acetylcholinesterase inhibitor approved for therapy of Alzheimer's disease. It has currently been withdrawn in some countries mostly due to the risk of hepatotoxicity and might be replaced by its derivate 7-methoxytacrine (7-MEOTA). The aim of this study was to assess the impact of these two compounds on gastric myoelectrical activity by means of surface cutaneous electrogastrography (EGG).

Methods: Twelve pigs (Sus scrofa f. domestica, weighing 30-35 kg) entered the study. A single dose of tacrine (200 mg i.m., n=6) or 7-MEOTA (200 mg i.m., n=6) was administrated. All EGG recordings were performed under general anaesthesia in the morning after 24 hours of fasting. Basal (30 minutes) and study recordings (150 minutes) were accomplished using an EGG stand (MMS, Enschede, the Netherlands). Results were expressed as dominant frequency of gastric slow waves, power analysis (areas of amplitudes) and power ratio assessment (ratio of the areas of amplitudes after and before study drug administration).

Results: Tacrine decreased EGG dominant frequency 10 minutes after its administration (from basal 3.1±0.6 to 2.8±0.6 cycles per minute; p=0.014). Tacrine induced a non-significant 60-minute increase of the power (with maximal value 493±533 μV2 at 20 minutes) and power ratio (with maximal value 2.04±3.4 at 10 minutes). Tacrine caused substantial gastric arrhythmia. 7-MEOTA did not influence dominant frequency of gastric slow waves significantly. 7-MEOTA caused a short-term late increase of the power ratio at 60 minutes (6.3±11.2; p=0.003). Blood cholinesterase activity did not correlate with any EGG parameter either after tacrine or 7-MEOTA at any time.

Conclusions: Tacrine and 7-MEOTA have different impacts on EGG. Tacrine decreased dominant frequency and induced long-lasting gastric arrhythmia. 7-MEOTA caused a short-term late increase of the EGG power in experimental pigs.
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April 2016

Endoscopic treatment of a rectovesical fistula following radical prostatectomy by over-the-scope clip (OTSC).

Wideochir Inne Tech Maloinwazyjne 2015 Sep 14;10(3):486-90. Epub 2015 Sep 14.

Department of Urology, Charles University Hospital, Hradec Kralove, Czech Republic.

The successful management of a rectovesical fistula after radical prostatectomy is difficult. Minimally invasive treatment by over-the-scope clip (OTSC) is a novel method. The authors present results with the use of OTSC. This method was used in 2 patients. The first patient had a rectovesical fistula detected on the fifth day after a prostatectomy. The second patient experienced rectal perforation during prostatectomy and a recurrent fistula after fistulorrhaphy. Both patients had a small fistula located in the vesicourethral anastomosis. Both patients underwent endoscopic OTSC placement. The median follow-up was 26 months. The success rate was 50%. The first patient healed successfully and the second patient had a relapse. The York-Mason procedure was eventually successful. According to our initial experience, the OTSC is suitable for small fistulas detected shortly after a prostatectomy. A more complex fistula, though small, carries a higher recurrence risk.
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http://dx.doi.org/10.5114/wiitm.2015.54101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4653265PMC
September 2015

Attenuation of radiation-induced gastrointestinal damage by epidermal growth factor and bone marrow transplantation in mice.

Int J Radiat Biol 2015 3;91(9):703-14. Epub 2015 Jul 3.

a Department of Radiobiology , Faculty of Military Health Sciences, University of Defence , Trebesska, Hradec Kralove , Czech Republic.

Purpose: We examined the effect of epidermal growth factor (EGF) and bone marrow transplantation (BMT) on gastrointestinal damage after high-dose irradiation of mice.

Material And Methods: C57Black/6 mice were used. Two survival experiments were performed (12 and 13 Gy; (60)Co, 0.59-0.57 Gy/min). To evaluate BMT and EGF action, five groups were established - 0 Gy, 13 Gy, 13 Gy + EGF (at 2 mg/kg, first dose 24 h after irradiation and then every 48 h), 13 Gy + BMT (5 × 10(6) cells from green fluorescent protein [GFP] syngenic mice, 4 h after irradiation), and 13 Gy + BMT + EGF. Survival data, blood cell counts, gastrointestine and liver parameters and GFP positive cell migration were measured.

Results: BMT and EGF (three doses, at 2 mg/kg, administered 1, 3 and 5 days after irradiation) significantly increased survival (13 Gy). In blood, progressive cytopenia was observed with BMT, EGF or their combination having no improving effect early after irradiation. In gastrointestinal system, BMT, EGF and their combination attenuated radiation-induced atrophy and increased regeneration during first week after irradiation with the combination being most effective. Signs of systemic inflammatory reaction were observed 30 days after irradiation.

Conclusions: Our data indicate that BMT together with EGF is a promising strategy in the treatment of high-dose whole-body irradiation damage.
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http://dx.doi.org/10.3109/09553002.2015.1054528DOI Listing
April 2016

HI-6 oxime (an acetylcholinesterase reactivator): blood plasma pharmacokinetics and organ distribution in experimental pigs.

Neuro Endocrinol Lett 2014 ;35 Suppl 2:191-6

Objectives: Oxime HI-6 DMS (dimethanesulfonate) is an asymmetric bis-pyridinium aldoxime and essential acetylcholinesterase (AChE) reactivator. The high effectiveness is due to its wide spectrum of therapeutic activity against different structures of nerve agents. Aim of this study was to compare plasma time profiles and tissue distribution (to delimitation of potential toxicity risks) after its intramuscular (i.m.) and intragastric (i.g.) administration to experimental pigs.

Methods: The study entered female Landrace pigs (Sus scrofa f. domestica), 4-5 months old animals, 29 ± 3.2 kg of body weight. Before the HI-6 DMS administration (i.m. injection or i.g. using a gastric tube), vena auricularis was cannulated (under general anaesthesia) for collection of blood samples. The tissue distribution study was carried out at expected t-max. Concentrations of HI-6 DMS in blood plasma and other tissue samples were detected by means of HPLC method.

Results: Fast absorption after i.m. administration, relatively slow absorption and no even elimination after i.g. administration were found. Tissue distribution showed low accumulation in the liver, but a higher content in the kidneys and high concentrations in the brain and gastrointestinal wall.

Conclusions: Plasma time profiles after i.g. administration has a prolonged pharmacokinetics. Tissue distribution study showed potential side effects to the stomach due to a higher accumulation of HI-6 in this tissue after i.g. administration but not after a standard i.m. administration. Higher content of HI-6 in the kidneys after i.m. administration suggests the main way of the oxime elimination.
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August 2015

Oesophageal Manometry in Experimental Pigs: Methods and Initial Experience.

Acta Medica (Hradec Kralove) 2015 ;58(4):131-4

2nd Department of Internal Medicine - Gastroenterology, Charles University in Praha, Faculty of Medicine at Hradec Králové, University Hospital Hradec Králové, Czech Republic.

The aim of this study project was to prepare our own method of porcine oesophageal manometry. Ten mature experimental pigs entered the study. Conventional water-perfused system was decided for manometry. Porcine resting and relaxed pressures of the lower oesophageal sphincter are fully comparable with healthy human subjects. Evocable swallowing is doable and oesophageal peristalsis is quantifiable. Basic manometric parameters were different in male and female animals. Oesophageal manometry in experimental pigs is feasible. Porcine oesophageal manometry will be usable for preclinical studies in future.
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http://dx.doi.org/10.14712/18059694.2016.5DOI Listing
July 2016

[Epidemiology of dyspepsia].

Vnitr Lek 2014 Jul-Aug;60(7-8):649-56

Epidemiology of uninvestigated dyspepsia was studied in the Czech Republic for the first time in 2001. The aim of our current multi-centre prospective study was to evaluate dyspepsia using the same methods in a representative sample of general unselected population from the same geographical areas 10 years later. A total of 22 centres entered the study. A total of 1,836 subjects (aged 5-98 years) were enrolled. The overall prevalence of dyspepsia was 12 %; namely 3.5 % in subjects aged 5-24 years, 18 % among 25-64-year-old persons and 15 % in subjects 65 years. Despite the substantial decrease of Helicobacter pylori infection in the Czech Republic over the past 10 years, the prevalence and basic socio-demographic determinants of uninvestigated dyspepsia did not change significantly.
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October 2015

Blood pressure and stature in Helicobacter pylori positive and negative persons.

World J Gastroenterol 2014 May;20(19):5625-31

Marcela Kopacova, Miluska Skodova Fendrichova, Stanislav Rejchrt, Tomas Douda, Ilja Tacheci, Jan Bures, 2 Department of Internal Medicine - Gastroenterology, Charles University in Praha, Faculty of Medicine at Hradec Kralove, University Teaching Hospital, 50005 Hradec Kralove, Czech Republic.

To evaluate vital signs and body indices in Helicobacter pylori (H. pylori) positive and negative persons. A total of 22 centres entered the study. They were spread over the whole country, corresponding well to the geographical distribution of the Czech population. A total of 1818 subjects (aged 5-98 years) took part in the study, randomly selected out of 38147 subjects. H. pylori infection was investigated by means of a 13C-urea breath test. Data on height, weight, systolic and diastolic blood pressure and heart rate were collected at the clinics of general practitioners. The overall prevalence of H. pylori infection was 30.4% (402/1321) in adults (≥ 18 year-old) and 5.2% (26/497) in children and adolescents (≤ 17 year-old). Once adjusted for age and gender, only a difference in body mass index remained statistically significant with H. pylori positive adults showing an increase of 0.6 kg/m(2) in body mass index. Once adjusted for age and gender, we found a difference in height between H. pylori positive and H. pylori negative children and adolescents. On further adjustment for place of residence, this difference became statistically significant, with H. pylori positive children and adolescents being on average 3.5 cm shorter. H. pylori positive adults were significantly older compared to H. pylori negative subjects. Once adjusted for age and gender, H. pylori infection had no impact on body weight, body mass index and vital signs either in adults or children and adolescents. Chronic H. pylori infection appeared to be associated with short stature in children. H. pylori infection did not influence blood pressure, body weight and body mass index either in adults or children and adolescents.
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http://dx.doi.org/10.3748/wjg.v20.i19.5625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4024770PMC
May 2014

NSAID-Induced Enteropathy in Rheumatoid Arthritis Patients with Chronic Occult Gastrointestinal Bleeding: A Prospective Capsule Endoscopy Study.

Gastroenterol Res Pract 2013 7;2013:268382. Epub 2013 Dec 7.

Second Department of Internal Medicine-Gastroenterology, Charles University in Prague, Faculty of Medicine in Hradec Králové and University Hospital, Sokolská 581, 500 05 Hradec Králové, Czech Republic.

Background. The purpose of study was to evaluate the diagnostic yield of capsule endoscopy for NSAID-induced enteropathy and clinical, laboratory, and endoscopic characteristics of disease in patients with rheumatoid arthritis. Methods. 37 rheumatoid arthritis patients (30 women; mean age 55) treated with NSAIDs (>1 month), presented with anaemia and/or positive faecal occult blood testing, entered the study and underwent capsule endoscopy (EndoCapsule; Olympus), laboratory tests, and filled in questionnaires. Results. The prevalence of NSAID-induced enteropathy diagnosed by capsule endoscopy was 68% (25/37), classified as mild (red spots or erosions) in 18 (49%), moderate (10-20 erosions) in 4 (11%), and severe enteropathy (>20 erosions or ulcers) in 3 (8%) patients. We did not find statistically significant relationship between the enteropathy and gender, age, haemoglobin, leukocytes, albumin and CRP, or dyspepsia. The difference between subgroups of NSAIDs according to the COX specificity was not statistically significant. Conclusions. Capsule endoscopy is a highly accurate noninvasive method for evaluation of NSAID-induced enteropathy. It was revealed in a substantial section of the patients with rheumatoid arthritis and occult gastrointestinal bleeding, mostly classified as mild damage. No simple clinical or laboratory markers of the presence or severity of NSAID-induced enteropathy were recognised. This trial is registered with DRKS00004940.
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http://dx.doi.org/10.1155/2013/268382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3870618PMC
January 2014

Cryptogenic multifocal ulcerous stenosing enteritis: a review of the literature.

Gastroenterol Res Pract 2013 24;2013:918031. Epub 2013 Nov 24.

2nd Department of Internal Medicine-Gastroenterology, Charles University in Praha, Faculty of Medicine at Hradec Králové, University Teaching Hospital, 500 05 Hradec Králové, Czech Republic.

Cryptogenic multifocal ulcerous stenosing enteritis (CMUSE) is an extremely rare illness characterised by chronic or relapsing subileus status resulting from multiple small intestinal fibrous strictures and multiple shallow ulcers of the small bowel. The etiology is unknown and pathogenesis is not fully understood. Therapy with systemic glucocorticosteroids is the treatment of choice. However, most patients develop corticosteroid dependence. Deep enteroscopy enables precise diagnostic work, possible endoscopic treatment of stenoses; may obviate the need for surgery and prevent excessive small bowel resections.
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http://dx.doi.org/10.1155/2013/918031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3858008PMC
June 2014

Cronkhite-Canada syndrome: review of the literature.

Gastroenterol Res Pract 2013 28;2013:856873. Epub 2013 Nov 28.

2nd Department of Medicine, Charles University in Praha, Faculty of Medicine at Hradec Králové, University Teaching Hospital, Sokolska 581, 500 05 Hradec Králové, Czech Republic.

Cronkhite-Canada syndrome is a rare disease characterised by diffuse polyposis of the gastrointestinal tract, diarrhoea, weight loss, abdominal pain, cutaneous hyperpigmentation, dystrophic changes of fingernails, and alopecia. The etiology is probably autoimmune and diagnosis is based on history, physical examination, endoscopic findings of gastrointestinal polyposis, and histology. The disease is very rare; about 450 cases have been described in the literature so far. We present a review of the literature with our own picture documentation of this rare condition.
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http://dx.doi.org/10.1155/2013/856873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3863521PMC
June 2014

Impact of paraoxon followed by acetylcholinesterase reactivator HI-6 on gastric myoelectric activity in experimental pigs.

Neuro Endocrinol Lett 2013 ;34 Suppl 2:79-83

2nd Department of Internal Medicine - Gastroenterology, Charles University Faculty of Medicine and University Hospital, Hradec Králové, Czech Republic.

Objectives: Organophosphorus compounds represent nerve agents, pesticides and several industrial compounds. Treatment after exposure to organophosphates involves the use of parasympatolytics, acetylcholinesterase (AChE) reactivators/modulators and anticonvulsive drugs. Wider clinical use of several AChE reactivators/modulators might be limited because of possible side effects, including gastrointestinal toxicity. In this study we evaluated the effect of paraoxon and an AChE reactivator (HI-6) on the gastric myoelectric activity in experimental pigs.

Methods: Six female experimental pigs (mean weight 33 kg) entered the study. Intramuscular paraoxon (1.5 g) was administrated after the baseline gastric electrogastrography (EGG) recording, followed by HI-6 dimethansulphonate (1.5 g i.m.) 10 min. later. A further ten 15-minute-interval EGG recordings were performed. Running spectral analysis was used for the elemental evaluation of the EGG. The results were expressed as dominant frequency of slow waves at all intervals of EGG recordings. EGG power analysis was performed in all animals.

Results: Paraoxon induced a non-significant decrease of dominant frequency (2.8±0.6 vs. 2.6±0.5 cycles per min.; p=0.092). Subsequent administration of HI-6 normalised dominant frequency to basal values and increased it significantly within the subsequent 30 minutes (3.0±0.4; p<0.001). Paraoxon administration did not influence the power (within a 10-minute exposure). However, the amplitudes increased significantly 90 minutes after administration of HI-6 (819±109 vs. 5054±732 μV2; p<0.001).

Conclusions: AChE reactivator HI-6 blocked the gastric effect of paraoxon significantly. Subsequent myoelectric changes in the dominant frequency and power were executed by HI-6. The effect of paraoxon was non-significant.
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May 2014

Intravenous application of HI-6 salts (dichloride and dimethansulphonate) in pigs: comparison with pharmacokinetics profile after intramuscular administration.

Neuro Endocrinol Lett 2013 ;34 Suppl 2:74-8

Biomedical Research Center, University Hospital, Hradec Králové, Czech Republic.

Objectives: Oxime HI-6 is an acetylcholinesterase reactivator therapeutically efficient against nerve agents. Because of their physico-chemical properties, oximes are typically applied intramuscularly (i.m.). This route of administration has also some disadvantages, and alternative strategies ought to be examined. We evaluated the pharmacokinetic profiles of two HI-6 salts after their intravenous (i.v.) administration, and compare the results with the known pharmacokinetics after i.m. administration.

Methods: Pigs were administered with HI-6 salts (i.v), either HI-6 dichloride (10.71 mg/kg) or molar equivalent HI-6 dimethansulphonate (13.59 mg/kg). Doses of the HI-6 salts corresponded with a standard HI-6 dichloride dose in one autoinjector (500 mg) and were recalculated for one kilogram of body weight.

Results: The main pharmacokinetic parameters are comparable after i.v. and i.m. HI-6 administration. The compared pharmacokinetic parameters were half-life, terminal rate constant, mean residence time of the molecule in the body, clearance, and the apparent volume in the terminal phase. The bioavailability after i.m. administration was comparable with that of i.v.; these results suggest that the oxime is well released from the muscle depot. Significant differences were found in parameters Cmax and Tmax which are important in cases of emergency when rapidity and bioavailability are paramount for the success of treatment.

Conclusions: I.v. administration should solve the problem of rapid clearance. Infusion or bolus administration may be considered as a logical subsequent step in oxime treatment strategy. The main advantage is in maintenance of an effective therapeutic plasma concentration, a more easily achievable effective therapeutic concentration, and fewer local adverse reactions.
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May 2014