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1

Celecoxib confinement within mesoporous silicon for enhanced oral bioavailability

100%

Wang F. , Barnes T. J. , Prestidge C. A.

Mesoporous Biomaterials

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2014

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tom 1

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nr 1

EN

We investigate the physicochemical characteristics of celecoxib (CEL) entrapped within particles of an oxidized porous silicon matrix (pSiox); determine the oral dose response of CEL compared to pure drug and innovator formulation; develop in vivo-in vitro correlation (IVIVC). CEL was loaded into a pSiox matrix by solvent partitioning, with the physical state of the CEL characterized by FTIR, DSC, TGA and XRD, and correlated with in vitro dissolution behavior. Single dose pharmacokinetic parameters of orally dosed CEL were determined in fasted rats for aqueous suspensions of pure CEL, Celebrexr and CEL-pSiox microparticles. Physicochemical testing of CEL-pSiox formulation confirmed the entrapment of CEL within porous nanostructure in an amorphous or non-crystalline form. CEL-pSiox demonstrated superior pharmacokinetics compared with CEL particles or Celebrexr, i.e. increased absolute bioavailability (96.2% vs. 65.2% vs. 88.1%), increased Cmax (0.91 ± 0.09 μg/mL vs. 0.50 ± 0.16 μg/mL vs. 0.73 ± 0.23 μg/mL) and reduced Tmax (1.0 ± 0.0 h vs. 2.8 ± 0.8 h vs. 3.4 ± 1.0 h). Single point correlation was established between in vitro dissolution efficiency (% DE) and in vivo absolute bioavailability or Cmax . Porous silicon microparticles can be formulated as an effective orally dosed solid dispersion preparation for celecoxib

2

Sensitive and validated TLC densitometry method coupled with fluorescence detection for quantitative determination of the newly co-formulated drugs, celecoxib and amlodipine besylate in tablet dosage form

100%

Rizk M. , Toubar S. , Ramzy E. , Helmy M.

Acta Chromatographica

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2022

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tom Vol. 34, no. 2

150--161

EN

New, sensitive, rapid, cost-effective, and validated stability-indicating thin layer chromatographic (TLC) method coupled with fluorescence (FL) detection was developed for the quantitative analysis of celecoxib (CEL) and amlodipine besylate (AMLO) in their laboratory prepared binary mixture using the non-fluorescent TLC silica gel 60 plates. Ethyl acetate: diethylamine: 1-propanol (9:1:0.2, V/V) was used as a developing system. The retention factor (Rf) for each drug was 0.80 ± 0.03 and 0.44 ± 0.01 for CEL and AMLO, respectively. The plates were excited at 264 nm for the simultaneous FL measurement of CEL and AMLO, the calibration curves were linear over a concentration ranges of 30.0–300.0 ng/band and 15.0–150.0 ng/band with mean percentage recoveries of 99.80 ± 0.85 and 99.80 ± 0.77 For CEL and AMLO, respectively. The developed method was applied for the stability studies of the cited drugs in their laboratory prepared binary mixture and the forced degradation products were determined when present in presence of the pure drugs so the method can be considered as a stability-indicating one and it was validated as per ICH guidelines and proved to be accurate and precise.

3

Celecoxib - A Selective Cyclooxygenase-2 Inhibitor Exhibits Dose - Dependent Chemopreventive Activity on an Animal Model of Colorectal Cancer*

86%

Spychalski M. , Dziki Ł. , Buczyński J. , Kulig A. , Sporny S. , Dziki A.

Polish Journal of Surgery

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2008

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tom 80

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nr 5

248-255

EN

Colorectal cancer (CRC) is still one of the unresolved issues in medicine. Despite constant improvements in diagnosis and treatment, the prognosis for CRC is unsatisfactory. In recent years, much attention has been paid to experiments concerning chemoprevention of CRC.The aim of the study was evaluation of the effectiveness of celecoxib, a selective Cyclooxygenase-2 (COX-2) inhibitor of chemically-induced CRC carcinogenesis in Fisher F344 rats.Material and methods. Forty-five four-week old male F344 rats were randomized into four groups. In Groups 1, 2, and 3, we induced the CRC carcinogenesis through two subcutaneous injections of Azoxymethane in doses of 20 mg/kg. Rats from groups 1 and 2 were treated with celecoxib in doses of 10 and 30 mg/kg from the start of the experiment. Group 4 was a negative control. The experiment ended in the 26th week. We assessed the following parameters: the number of Aberrant Crypt Foci (premalignant lesions in colons) and the immunoexpression indexes: COX-2, Vascular Endothelial Growth Factor (VEGF), and c-myc.Results. Celecoxib reduced the ACF number. The ACF reduction was dose-dependent. The median ACF number per field of vision was as follows for each of the groups: 1.7, 0.75, 3.2, and 0.2. Celecoxib, irrespective of the dose, reduced the VEGF immunoexpression index. We did not observe a reduction of COX-2 or c-myc immunoexpression in the celecoxib groups.Conclusions. In this experiment, we proved that celecoxib possessed chemopreventive activity. Carcinogenesis inhibition by selective COX-2 inhibitor was dose-dependent. We demonstrated that celecoxib hidners angiogenesis, expressed as VEGF immunoexpression. We indirectly confirmed the hypothesis of a celecoxib COX-2 independent pathway mechanism of action.

4

Celecoxib increases retinoid sensitivity in human colon cancer cell lines

72%

Liu J. P. , Wei H.-B. , Zheng Z.-H. , Guo W.-P. , Fang J.-F.

Cellular and Molecular Biology Letters

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2010

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tom 15

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nr 3

440-450

EN

Retinoid resistance has limited the clinical application of retinoids as differentiation-inducing and apoptosis-inducing drugs. This study was designed to investigate whether celecoxib, a selective COX-2 inhibitor, has effects on retinoid sensitivity in human colon cancer cell lines, and to determine the possible mechanism of said effects. Cell viability was measured using the MTT assay. Apoptosis was detected via Annexin-V/PI staining and the flow cytometry assay. PGE2 production was measured with the ELISA assay. The expression of RARβ was assayed via western blotting. The results showed that celecoxib enhanced the inhibitory effect of ATRA in both COX-2 high-expressing HT-29 and COX-2 low-expressing SW480 cell lines. Further study showed the ATRA and celecoxib combination induced greater apoptosis, but that the addition of PGE2 did not affect the enhanced growth-inhibitory and apoptosis-inducing effects of the combination. Moreover, NS398 (another selective COX-2 inhibitor) did not affect the inhibitory effects of ATRA in the two cell lines. Western blotting showed that the expression of RARβ in HT-29 cell lines was increased by celecoxib, but not by NS398, and that the addition of PGE2 did not affect the celecoxib-induced expression of the retinoic acid receptor beta. In conclusion, celecoxib increased the expression of RARβ and the level of cellular ATRA sensitivity through COX-2-independent mechanisms. This finding may provide a potential strategy for combination therapy.

5

Pharmacological and dietary factors in prevention of colorectal cancer

72%

Waluga M. , Zorniak M. , Fichna J. , Kukla M. , Hartleb M.

Journal of Physiology and Pharmacology

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2018

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tom 69

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nr 3

6

Nitric oxide (NO)-releasing aspirin exhibits a potent esophagoprotection in experimental model of acute reflux esophagitis. Role of nitric oxide and proinflammatory cytokines

58%

Pawlik M. , Pajdo R. , Kwiecien S. , Ptak-Belowska A. , Sliwowski Z. , Mazurkiewicz-Janik M. , Konturek S. J. , Pawlik W. W. , Brzozowski T.

Journal of Physiology and Pharmacology

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2011

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tom 62

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nr 1

EN

The purpose of this study was to develop an acute animal model of reflux esophagitis, which would be suitable to induce the esophageal damage caused by gastric acid reflux, thus mimicking the esophageal injury of human gastroesophageal reflux disease (GERD). Global research indicates that GERD is rapidly increasing among the world's population. NSAIDs are known to induce gastrointestinal damage and low doses of aspirin (ASA) have been shown to increase the incidences of GERD in humans. Gastric acid and pepsin secretion and enhanced COX-2 expression were implicated in the pathogenesis of reflux esophagitis, but the effect of selective COX-2 inhibitors against lesions induced by the reflux of gastric acid content into esophagus has not been thoroughly studied. Here, we compared the effect of aspirin (ASA) and so called "safe" nitric oxide (NO) derivative of ASA with those of non-selective and selective cyclooxygenase (COX)-1 and COX-2 in rat model of reflux esophagitis. Reflux esophagitis was induced in anesthetized rats by ligating the pylorus and limiting ridge transitional region between the forestomach and the corpus of stomach. Subsequently, the total gastric reservoir to store gastric juice was greatly diminished, resulting in the reflux of this juice into the esophagus. Rats with esophagitis received intragastric (i.g.) pretreatment either with: 1) vehicle (saline), 2) ASA or NO-ASA (100 mg/kg); 3) the non-selective COX inhibitor, indomethacin (5 mg/kg); 4) the selective COX-1 inhibitor, SC-560 (10 mg/kg), and 5) the selective COX-2 inhibitor, celecoxib (5 mg/kg). In a separate series of rats with reflux oesophagitis, the efficacy of ASA combined with a donor of NO, glyceryl trinitrate (GTN; 10 mg/kg i.g.) to prevent esophageal mucosal injury was investigated. Four hours after induction of esophagitis the gross mucosal damage was graded with a macroscopic lesion index (LI) from 0-6. The esophageal blood flow (EBF) was determined by H2-gas clearance technique, the oesophageal mucosal and blood samples were collected for histology and analysis of the RT-PCR expression and release of proinflammatory cytokines IL-1ß, TNF- and IL-6 using specific ELISA. The exposure of the esophagus to reflux of gastric acid time-dependently increased the esophageal LI and morphologic damage, and decreased EBF with the most significant changes observed at 4 hrs after the ligation procedure. The pretreatment with native ASA in the dose that suppressed the generation of mucosal PGE2, enhanced gross and histologic esophageal damage and produced a significant fall in EBF. NO-ASA or ASA coupled with GTN counteracted the aggravation of the damage and accompanying fall in EBF when compared with native ASA applied alone to rats with esophagitis. The proinflammatory cytokines IL-1ß and TNF- were overexpressed in rats with esophagitis and those pretreated with ASA but this effect was significantly attenuated by NO-ASA. Plasma IL-1ß, TNF- and IL-6 were negligible in the intact rats but significantly increased in those with esophagitis, with this effect being further enhanced by non-selective (indomethacin) and selective (SC-560, celecoxib) COX-1 and COX-2 inhibitors. We conclude that conventional NSAID such as aspirin augments esophagitis, while NO-ASA exerts the beneficial protective effect against reflux esophagitis via the enhancement of esophageal microcirculation due to NO release and an inhibitory effect on expression and release of pro-inflammatory cytokines.

7

Inhibitors of cyclooxygenases: mechanisms, selectivity and uses

58%

Botting R. M.

Journal of Physiology and Pharmacology. Supplement

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2006

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tom 57

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nr 5

113-124

EN

The prostaglandins are lipid mediators, discovered in the 1930s by von Euler in Sweden and Goldblatt in the United Kingdom. They are made by the bifunctional enzyme, cyclooxygenase, which has both cyclooxygenase and peroxidase activities in the same molecule. Prostaglandins are involved in physiological functions such as protection of the stomach mucosa, aggregation of platelets and regulation of kidney function. They also have pathological functions such as their involvement in inflammation, fever and pain. Vane in 1971 elegantly showed that the pharmacological actions of aspirin and similar drugs were due to the inhibition of cyclooxygenase. Thus, aspirin-like drugs exert their anti-inflammatory, antipyretic and analgesic effects by inhibition of cyclooxygenase. In 1991, Simmons and his colleagues identified a second cyclooxygenase enzyme, designated cyclooxygenase-2, derived from a separate gene from cyclooxygenase-1. Cyclooxygenase-2 is upregulated by inflammatory mediators and forms prostaglandins which intensify the inflammatory response. Cyclooxygenase-1 is, therefore, a 'housekeeping' enzyme making prostaglandins, which are important for maintaining physiological functions and cyclooxygenase-2 makes prostaglandins which are important in inflammation. The discovery of cyclooxygenase-2 and the establishment of its structure led to the development of selective inhibitors of this enzyme, such as celecoxib and rofecoxib, with potent anti-inflammatory actions but with reduced gastrotoxic effects. A putative cyclooxygenase-3, has also been characterised and cloned. This enzyme is a product of the cyclooxygenase-1 gene, but retains intron 1 after transcription and translates into a cyclooxygenase enzyme with 34 additional amino acids. It is more sensitive to inhibition by paracetamol, aspirin and some other non-steroid anti-inflammatory drugs than cyclooxygenase-1 or cyclooxygenase-2. A cyclooxygenase enzyme induced in cultured cells by some non-steroid anti-inflammatory drugs is also more sensitive to inhibition by paracetamol than cyclooxygenase-2 induced by bacterial lipopolysaccharide

8

Nonsteroidal anti-inflammatory drugs-induced failure of lower esophageal and pyloric sphincter and counteraction of sphincters failure with stable gastric pentadecapeptide BPC157 in rats

58%

Vitaic S. , Stupnisek M. , Drmic D. , Bauk L. , Kokot A. , Klicek R. , Vcev A. , Luetic K. , Seiwerth S. , Sikiric P.

Journal of Physiology and Pharmacology

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2017

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tom 68

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nr 2