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1
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What is the role of cyclic di-GMP signaling within the human gut microbiome?

100%
Rudlaff R. M., Waters C. M.
Microbiome Science and Medicine
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2013
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vol. 1
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issue 1
EN
There is currently little understanding of the role of the bacterial second messenger cyclic di-GMP (c-di-GMP) in the human gut microbiome. C-di-GMP is synthesized by highly conserved diguanylate cyclase (DGC) enzymes and degraded by highly conserved phosphodiesterase (PDE) enzymes. To begin to assess the prevalence of c-di-GMP signaling in the gut microbiome, we found on average 1.0 DGC and 0.8 PDE enzymes per million base pairs of metagenomic DNA derived from stool samples. Specific species encoding substantial numbers of GGDEF and EAL domains were the commensal species Faecalibacterium prausnitzii, Eubacterium rectale, and Mitsuokella multacida. The species Bilophila wadsworthia and Klebsiella oxytoca were identified as gut microbiome members that encode higher numbers of GGDEFs and EALs and are associated with gut dysbiosis and infection. Consistent with this result, genome analysis of several enteric pathogens revealed significantly higher numbers of GGDEFs and EALs per million base pairs compared to the gut microbiome. Our analysis indicates that c-di-GMP signaling is present but minimal in the gut microbiome, and we speculate that the numbers of GGDEFs and EALs in a given genome from a member of the gut microbiome positively correlates with pathogenic potential.
2
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Changes of nitric oxide system and lipid peroxidation parameters in the digestive system of rats under conditions of acute stress, and use of nonsteroidal anti-inflammatory drugs

88%
Fomenko I., Bondarchuk T., Emelyanenko V., Denysenko N., Pavlo S., Ilkiv I., Lesyk R., Sklyarov A.
Current Issues in Pharmacy and Medical Sciences
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2015
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vol. 28
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issue 1
37-41
EN
The use of nonsteroidal anti-inflammatory drugs (NSAIDs) in combination with being physiologically stressed often occurs in in the course of different pathologies. This situation may result in the alteration of digestive system functioning. The effect of stress brings about changes in the activity of nitric oxide synthase (NOS), arginase, cyclooxygenase (COX) and lipid peroxidation, whereas the use of NSAIDs interrupts the multiple functions of the cell via the inhibition of prostaglandins (PGs) synthesis. Taking into account that NOS and COX-systems are connected in their regulation, the aim of the study was to determine the role played by NOS and lipid peroxidation under conditions of the combined action of NSAIDs and stress. In our study, male rats were used. The NSAIDs (naproxen - a non-selective COX inhibitor, celecoxib - a selective COX-2 blocker, and the compound 2A5DHT (which is the active substance of dual COX, and the lipoxygenase (LOX) inhibitor, darbufelone) were all administered at a dose 10 mg/kg, prior to water restraint stress (WRS). WRS brought about an increase of inducible NOS (iNOS) activity in the intestinal mucosal and muscular membranes, as well as in the pancreas. Because of this, constitutive NOS izoform (cNOS) and arginase activities decreased. Moreover, the MDA concentration increased, indicating the development of oxidative stress. In our work, pretreatment with naproxen, as in the WRS model, engendered a decrease in iNOS activity. What is more, administration of Celecoxib did not change iNOS activity, as compared to WRS alone, and it showed a tendency to reduce lipid peroxidation. In addition, 2A5DHT prior WRS brought about a decrease of iNOS activity, with the subsequent rise of cNOS activity. Of note, MDA concentration decreased in all studied organs, indicating the reduction of lipid peroxidation under the action of the darbufelone active substance.
3
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A Prospective Study on Endoscopic Ultrasonography Criteria to Guide Management in Upper GI Submucosal Tumors

88%
Will U., Fueldner F., Mueller A.-K., Meyer F.
Polish Journal of Surgery
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2011
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vol. 83
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issue 2
63-69
EN
Endoscopic ultrasonography (EUS) can differentiate between impression and submucosal tumor (SMT) but it is not known whether EUS criteria can reliably guide management.The aim of this prospective study was to assess an approach to recommend removal versus follow-up investigation based on clinical and EUS criteria, with respect to the predictive values to recognize malignancy versus benign lesions.Material and methods. Over a 7-years time period, all patients referred for the EUS assessment of submucosal upper GI lesions were prospectively enrolled. Extraluminal impressions diagnosed with EUS were not further considered. If submucosal tumors seen with EUS were clearly symptomatic or one of several parameters (tumor size >3 cm, irregular margins, inhomogeneous echotexture and/or enlarged lymph nodes) were found, resection was recommended. The remaining cases were subjected to EUS follow-up.Results. Of cases with 241 submucosal lesions, 65 had impressions and 176 had true submucosal lesions. Of the latter, 29 cases had non-neoplastic lesions (cysts, varices). In 59 cases, removal was deemed necessary due to clinical symptoms and suspicious findings in conventional endoscopy. These subjects underwent either surgical (originating layer, muscularis propria) or endoscopic resection (submucosal origin): 35.6% were malignant, more frequently in the surgical group (41.6% vs 20%). However, in 52.5% (n=31) of the 59 cases with no severe symptoms and true SMT, EUS suggested removal because of their additional criteria. Eighteen patients (12.2%) refused SMT removal and even regular EUS-based follow-up investigation. Clinical follow-up investigation by the family practitioner did not show frank malignancy in these cases (retransferal not registered). Follow-up investigation with EUS was recommended in 70 cases (mean follow-up period, 5 years; range, 1-7 years). The pattern remained unchanged in 67/70, and 2 of the 3 cases with changes underwent surgery for benign leiomyoma (patient refusal, n=1 with no change in the one-year follow-up MRI).Conclusions. An EUS strategy based on defined characteristics to remove SMT with no severe symptoms and suspicious finding in the conventional endoscopy shows a good adherence to the recommended approach and has a reasonable positive predictive value for malignancy (88%). Clinical symptoms alone or with endoscopic finding are frequently too vague to decide for a reasonable SMT resection. The chosen EUS criteria are valuable to: 1) achieve the primary resection of all potentially malignant SMT and 2) avoid to overlook them as shown by the results of the follow-up investigations with no detected malignant lesion.
4
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Safety of oral nifuroxazide – analysis of data from a spontaneous reporting system

88%
Karlowicz-Bodalska K., Głowacka K., Boszkiewicz K., Han S., Wiela-Hojeńska A.
Acta Poloniae Pharmaceutica - Drug Research
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2019
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vol. 76
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issue 4
745-751
EN
Nifuroxazide is a popular chemotherapeutic agent, that is widely used in Poland in acute and chronic bacterial diarrhea treatment. It is available in pharmacies as over-the-counter tablets for adults and a suspension on prescription for children. The aim of the study was to assess the safety of nifuroxazide therapy. Adverse reaction reports from the Regional Pharmacovigilance Center in Wroclaw, the pharmaceutical company PPF Hasco-Lek, and VigiAccess and EudraVigilance databases were analyzed. Based on the analysis of the data collected from the above sources, nifuroxazide have shown a high therapeutic value in the gastrointestinal tract infections, maintaining high safety of usage at the same time. The number of drug application adverse reactions in Poland is not so high primarily due to high safety profile and low patient awareness of the possibility of reporting drug side effects.
5
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Hydrodynamika i naprężenia mechaniczne działające na postać leku w farmakopealnym i niekompendialnym badaniu uwalniania

63%
Wiater M., Hoc D., Paszkowska J., Garbacz G.
Farmacja Polska
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2020
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vol. 76
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issue 4
210-221
EN
The first and an essential step of medication’s path inside the human body is a dissolution of an active pharmaceutical ingridient. A dissolution of oral dosage forms occurs as a result of physicochemical and mechanical stresses which are found in gastrointestinal tract. This results in dissolution of the API, which becomes ready for the next step - absorption. In recent years, diversity and variability of digestive tract parameters has been understood better due to the advances in the research methods that allowed quantification of forces, mechanical stresses and pH gradients acting therein. Dissolution tests are conducted in order to determine the impact of biorelevant factors on the dosage form. These tests are a basic tool for the preclinical prediction of formulations behaviour in gastrointestinal tract, as well as for the quality control and to ensure formulations invariability after technological alterations in production. Pharmacopeia describes the standard procedure of dissolution tests. However, in the light of the research of actual conditions occurring in gastrointestinal tract the compendial methods appear to not fully reflect the hydrodynamic and mechanical stresses. This results in the lack of discriminatory power of pharmacopoeial dissolution tests, whereas differences between formulations occur in vivo. To face the need, simulators for the whole or partial gastrointestinal tract are constructed. These are advanced devices that enable the determination of the impact of the pH gradient, mechanical stresses and forces, enzymes secretion and many others, on the dosage form. The operation of a number of those simulators successfully predicts the behaviour of medication in vivo, which is an indispensable support during the formulation development. In the article there are described the mechanical and hydrodynamic gastrointestinal stresses, hydrodynamics of the most popular pharmacopoeial apparatus and non compendial gastrointestinal simulators, with regard to their ability to mimic biorelevant hydrodynamics.
PL
Dla doustnych postaci leku uwolnienie substancji czynnej zachodzi na skutek działania czynników fizykochemicznych i oddziaływań mechanicznych występujących w przewodzie pokarmowym człowieka. Różnorodność i zmienność parametrów organizmu ludzkiego została w ostatnich latach lepiej poznana dzięki zaawansowanym metodom badawczym, które pozwoliły na ilościowe opisanie sił i naprężeń mechanicznych występujących w przewodzie pokarmowym. Do poznania wpływu biorównoważnych czynników na postać leku prowadzi się badania uwalniania, które są podstawowym narzędziem do przedklinicznej prognozy zachowania się formulacji w przewodzie pokarmowym, ale też kontroli jakości produktu i weryfikacji wpływu zmian technologii produkcji na postać leku. Niestety w świetle odkryć dotyczących rzeczywistych warunków, występujących w przewodzie pokarmowym, metody kompendialne zdają się nie odzwierciedlać w pełni biorównoważnych czynników hydrodynamicznych i naprężeń mechanicznych. Jest to przyczyną, dla której wyniki tradycyjnych badań uwalniania często nie wykazują różnic pomiędzy formulacjami, które z kolei znacząco inaczej wypadają w badaniach in vivo. Aby umożliwić wykrycie różnic między formulacjami in vitro, konstruuje się symulatory całego przewodu pokarmowego, bądź wybranych jego aspektów. Są to zaawansowane urządzenia, pozwalające na badanie wpływu na postać leku takich czynników jak gradient pH, naprężenia i siły mechaniczne, dozowanie enzymów trawiennych i wiele innych. Działanie niektórych z tych aparatów pozwala na trafną predykcję zachowania leku w warunkach in vivo, co jest niezastąpioną pomocą podczas prac formulacyjnych. W niniejszym artykule przedstawiono mechaniczne i hydrodynamiczne warunki panujące w przewodzie pokarmowym, omówiono parametry hydrodynamiczne najpopularniejszych aparatów do uwalniania i przedstawiono modele przewodu pokarmowego, wybrane pod kątem realizacji biorównoważnych naprężeń mechanicznych i sił ścinających oraz zgniatających.
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