Improved Dissolution and Oral Bioavailability of Celecoxib by a Dry Elixir System.

PubMed

Cho, Kwan Hyung; Jee, Jun-Pil; Yang, Da A; Kim, Sung Tae; Kang, Dongjin; Kim, Dae-Young; Sim, Taeyong; Park, Sang Yeob; Kim, Kyeongsoon; Jang, Dong-Jin

2018-02-01

The purpose of this study was to develop and evaluate a dry elixir (DE) system for enhancing the dissolution rate and oral bioavailability of celecoxib. DE system has been used for improving solubility, oral bioavailability of poorly water-soluble drugs. The encapsulated drugs or solubilized drugs in the matrix are rapidly dissolved due to the co-solvent effect, resting in both an enhanced dissolution and bioavailability. DEs containing celecoxib were prepared by spray-drying method and characterized by morphology, drug/ethanol content, drug crystallinity, dissolution rate and oral bioavailability. The ethanol content and drug content in DE system could be easily altered by controlling the spraydrying conditions. The dissolution profile of celecoxib from DE proved to be much higher than that of celecoxib powder due to the nano-structured matrix, amorphous state and encapsulated ethanol. The bioavailability of celecoxib from DEs was compared with celecoxib powder alone and commercial product (Celebrex®) in rats. In particular, blood concentrations of celecoxib form DE formulation were much greater than those of native celecoxib and market product. The data demonstrate that the DE system could provide an useful solid dosage form to enhance the solubility, dissolution rate and oral bioavailability of celecoxib.

Inhibition of cyclooxygenase-2 alleviates liver cirrhosis via improvement of the dysfunctional gut-liver axis in rats.

PubMed

Gao, Jin-Hang; Wen, Shi-Lei; Tong, Huan; Wang, Chun-Hui; Yang, Wen-Juan; Tang, Shi-Hang; Yan, Zhao-Ping; Tai, Yang; Ye, Cheng; Liu, Rui; Huang, Zhi-Yin; Tang, Ying-Mei; Yang, Jin-Hui; Tang, Cheng-Wei

2016-06-01

Inflammatory transport through the gut-liver axis may facilitate liver cirrhosis. Cyclooxygenase-2 (COX-2) has been considered as one of the important molecules that regulates intestinal epithelial barrier function. This study was aimed to test the hypothesis that inhibition of COX-2 by celecoxib might alleviate liver cirrhosis via reduction of intestinal inflammatory transport in thiacetamide (TAA) rat model. COX-2/prostaglandin E2 (PGE2)/EP-2/p-ERK integrated signal pathways regulated the expressions of intestinal zonula occludens-1 (ZO-1) and E-cadherin, which maintain the function of intestinal epithelial barrier. Celecoxib not only decreased the intestinal permeability to a 4-kDa FITC-dextran but also significantly increased expressions of ZO-1 and E-cadherin. When celecoxib greatly decreased intestinal levels of LPS, TNF-α, and IL-6, it significantly enhanced T cell subsets reduced by TAA. As a result, liver fibrosis induced by TAA was significantly alleviated in the celecoxib group. These data indicated that celecoxib improved the integrity of intestinal epithelial barrier, blocked inflammatory transport through the dysfunctional gut-liver axis, and ameliorated the progress of liver cirrhosis. Copyright © 2016 the American Physiological Society.

Celecoxib aggravates cardiac apoptosis in L-NAME-induced pressure overload model in rats: Immunohistochemical determination of cardiac caspase-3, Mcl-1, Bax and Bcl-2.

PubMed

Mosaad, Sarah M; Zaitone, Sawsan A; Ibrahim, Abdelazim; El-Baz, Amani A; Abo-Elmatty, Dina M; Moustafa, Yasser M

2017-06-25

The mechanism of celecoxib cardiovascular adverse events was earlier investigated; yet in-depth investigations are needed to assess the involvement of its pro-apoptotic effect throughout this process. An in-vivo chronic rat model of pressure overload employing Nʷ-nitro-l-arginine methyl ester (L-NAME) was tested at different time intervals to ensure the occurrence of persistent myocardial apoptosis along with pressure overload. Seven groups of male Wistar rats were assigned as (i) distilled water; (ii-iv) L-NAME (60 mg/kg) for 6, 12 or 16 weeks; (v-vii) L-NAME [16 weeks] + celecoxib (25, 50 or 100 mg/kg), from week 13 to week 16. Treatment with L-NAME for 6, 12 or 16 weeks increased systolic blood pressure, serum level of creatine kinase-MB and lactate dehydrogenase. Further, it induced cardiac hypertrophy, detected in terms of greater heart weight index and cardiomyocyte cross-sectional area and produced interstitial and perivascular fibrosis. Moreover, administration of L-NAME increased cardiac immunostaining for activated caspase-3 and Bax/Bcl-2 ratio whereas; immunostaining for Mcl-1 was decreased. Administration of celecoxib (25, 50 or 100 mg/kg) aggravated the L-NAME-induced toxicity. The work results shed the light on the putative pro-apoptotic effect of celecoxib at a risk state of pressure overload comparable to the clinical condition of essential hypertension. Copyright © 2017 Elsevier B.V. All rights reserved.

Controlled release of celecoxib inhibits inflammation, bone cysts and osteophyte formation in a preclinical model of osteoarthritis.

PubMed

Tellegen, A R; Rudnik-Jansen, I; Pouran, B; de Visser, H M; Weinans, H H; Thomas, R E; Kik, M J L; Grinwis, G C M; Thies, J C; Woike, N; Mihov, G; Emans, P J; Meij, B P; Creemers, L B; Tryfonidou, M A

2018-11-01

Major hallmarks of osteoarthritis (OA) are cartilage degeneration, inflammation and osteophyte formation. COX-2 inhibitors counteract inflammation-related pain, but their prolonged oral use entails the risk for side effects. Local and prolonged administration in biocompatible and degradable drug delivery biomaterials could offer an efficient and safe treatment for the long-term management of OA symptoms. Therefore, we evaluated the disease-modifying effects and the optimal dose of polyesteramide microspheres delivering the COX-2 inhibitor celecoxib in a rat OA model. Four weeks after OA induction by anterior cruciate ligament transection and partial medial meniscectomy, 8-week-old female rats (n = 6/group) were injected intra-articular with celecoxib-loaded microspheres at three dosages (0.03, 0.23 or 0.39 mg). Unloaded microspheres served as control. During the 16-week follow-up, static weight bearing and plasma celecoxib concentrations were monitored. Post-mortem, micro-computed tomography and knee joint histology determined progression of synovitis, osteophyte formation, subchondral bone changes, and cartilage integrity. Systemic celecoxib levels were below the detection limit 6 days upon delivery. Systemic and local adverse effects were absent. Local delivery of celecoxib reduced the formation of osteophytes, subchondral sclerosis, bone cysts and calcified loose bodies, and reduced synovial inflammation, while cartilage histology was unaffected. Even though the effects on pain could not be evualated directly in the current model, our results suggest the application of celecoxib-loaded microspheres holds promise as novel, safe and effective treatment for inflammation and pain in OA.

Comparative study of bacterial translocation control with nitric oxide donors and COX2 inhibitor.

PubMed

García-Cenador, María Begoña; Lorenzo-Gómez, María Fernanda; García-Moro, María; García-García, María Inmaculada; Sánchez-Conde, María Pilar; García-Criado, Francisco Javier; García-Sánchez, Enrique; Lozano-Sánchez, Francisco; García-Sánchez, José Elías

2016-10-01

To evaluate the beneficial effects of exogenous NO and an inhibitor of the COX2, and their action levels in a model of SIRS/bacterial translocation (BT) induced by Zymosan A(®). Ninety Wistar rats were submitted to different treatments, and after 12h and 24h they were anaesthetized in order to collect blood, mesenteric lymph nodes, and kidney for subsequent biochemical analyses and microbiological examinations. A nitric oxide donor, Molsidomine(®), was compared with a COX2 inhibitor, Celecoxib(®). Zymosan A(®) was administered to Wistar rats. The animals were divided into 6 groups: one group for survival study, Group (1) No manipulation (BASAL); Group (2) vehicle of Zymosan A(®) given intraperitoneally (SHAM); Group I (control), with Zymosan A(®) (0.6g/kg) intraperitoneally; Group II (Molsidomine), with Molsidomine(®) (4mg/kg) through the penis dorsal vein, 30min prior to administration of the Zy(®) (0.6g/kg); Group III (Celecoxib), with Celecoxib(®) (400mg/kg) orally through a stomach tube, 6h prior to administration of the Zy (0.6g/kg). The parameters survival, bacterial translocation, renal function, neutrophil accumulation, oxygen free radicals (OFR), detoxifying enzymes, and cytokines were measured at different times after Zymosan administration. The model established induced a mortality rate of 100% and generated BT and systemic inflammatory response syndrome (SIRS) in all samples. It also significantly increased all variables, with p<.001 for MPO and all pro-inflammatory cytokines, and p<.01 for all OFR. Treatment with Molsidomine reduced mortality to 0%, decreased BT, MPO, pro-inflammatory cytokines and OFR (p<.001) significantly and increased IL-10 and IL-6 production. Moreover, the Celecoxib(®) showed a lower capacity for SIRS regulation. The exogenous administration of NO prevented BT and controlled SIRS. Therefore these results suggest that Molsidomine could be used as a therapeutic strategy to protect against BT. Copyright © 2016 Elsevier España, S.L.U. and Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

New carboxamide derivatives bearing benzenesulphonamide as a selective COX-II inhibitor: Design, synthesis and structure-activity relationship

PubMed Central

Okoro, Uchechukwu Chris; Ahmad, Hilal

2017-01-01

Sixteen new carboxamide derivatives bearing substituted benzenesulphonamide moiety (7a-p) were synthesized by boric acid mediated amidation of appropriate benzenesulphonamide with 2-amino-4-picoline and tested for anti-inflammatory activity. One compound 7c showed more potent anti-inflammatory activity than celecoxib at 3 h in carrageenan-induced rat paw edema bioassay. Compounds 7g and 7k also showed good anti-inflammatory activity comparable to celecoxib. Compound 7c appeared selectivity index (COX-2/COX-1) better than celecoxib. Compound 7k appeared selectivity index (COX-2/COX-1) a little higher than the half of celecoxib while compound 7g is non-selective for COX-2. The LD50 of compounds 7c, 7g and 7k were comparable to celecoxib. PMID:28922386

Simultaneous Determination of Celecoxib, Erlotinib, and its Metabolite Desmethyl-Erlotinib (OSI-420) in Rat Plasma by Liquid chromatography/Tandem Mass Spectrometry with Positive/Negative Ion-Switching Electrospray Ionisation

PubMed Central

Thappali, Satheeshmanikandan R. S.; Varanasi, Kanthikiran; Veeraraghavan, Sridhar; Arla, Rambabu; Chennupati, Sandhya; Rajamanickam, Madheswaran; Vakkalanka, Swaroop; Khagga, Mukkanti

2012-01-01

A new method for the simultaneous determination of celecoxib, erlotinib, and its active metabolite desmethyl-erlotinib (OSI-420) in rat plasma, by liquid chromatography/tandem mass spectrometry with positive/negative ion-switching electrospray ionization mode, was developed and validated. Protein precipitation with methanol was selected as the method for preparing the samples. The analytes were separated on a reverse-phase C18 column (50mm×4.6mm i.d., 3μ) using methanol: 2 mM ammonium acetate buffer, and pH 4.0 as the mobile phase at a flow rate 0.8 mL/min. Sitagliptin and Efervirenz were used as the internal standards for quantification. The determination was carried out on a Theremo Finnigan Quantam ultra triple-quadrupole mass spectrometer, operated in selected reaction monitoring (SRM) mode using the following transitions monitored simultaneously: positive m/z 394.5→278.1 for erlotinib, m/z 380.3→278.1 for desmethyl erlotinib (OSI-420), and negative m/z −380.1→ −316.3 for celecoxib. The limits of quantification (LOQs) were 1.5 ng/mL for Celecoxib, erlotinib, and OSI-420. Within- and between-day accuracy and precision of the validated method were within the acceptable limits of < 15% at all concentrations. The quantitation method was successfully applied for the simultaneous estimation of celecoxib, erlotinib, and desmethyl erlotinib in a pharmacokinetic study in Wistar rats. PMID:23008811

Celecoxib-induced gastrointestinal, liver and brain lesions in rats, counteraction by BPC 157 or L-arginine, aggravation by L-NAME

PubMed Central

Drmic, Domagoj; Kolenc, Danijela; Ilic, Spomenko; Bauk, Lara; Sever, Marko; Zenko Sever, Anita; Luetic, Kresimir; Suran, Jelena; Seiwerth, Sven; Sikiric, Predrag

2017-01-01

AIM To counteract/reveal celecoxib-induced toxicity and NO system involvement. METHODS Celecoxib (1 g/kg b.w. ip) was combined with therapy with stable gastric pentadecapeptide BPC 157 (known to inhibit these lesions, 10 μg/kg, 10 ng/kg, or 1 ng/kg ip) and L-arginine (100 mg/kg ip), as well as NOS blockade [N(G)-nitro-L-arginine methyl ester (L-NAME)] (5 mg/kg ip) given alone and/or combined immediately after celecoxib. Gastrointestinal, liver, and brain lesions and liver enzyme serum values in rats were assessed at 24 h and 48 h thereafter. RESULTS This high-dose celecoxib administration, as a result of NO system dysfunction, led to gastric, liver, and brain lesions and increased liver enzyme serum values. The L-NAME-induced aggravation of the lesions was notable for gastric lesions, while in liver and brain lesions the beneficial effect of L-arginine was blunted. L-arginine counteracted gastric, liver and brain lesions. These findings support the NO system mechanism(s), both NO system agonization (L-arginine) and NO system antagonization (L-NAME), that on the whole are behind all of these COX phenomena. An even more complete antagonization was identified with BPC 157 (at both 24 h and 48 h). A beneficial effect was evident on all the increasingly negative effects of celecoxib and L-NAME application and in all the BPC 157 groups (L-arginine + BPC 157; L-NAME + BPC 157; L-NAME + L-arginine + BPC 157). Thus, these findings demonstrated that BPC 157 may equally counteract both COX-2 inhibition (counteracting the noxious effects of celecoxib on all lesions) and additional NOS blockade (equally counteracting the noxious effects of celecoxib + L-NAME). CONCLUSION BPC 157 and L-arginine alleviate gastrointestinal, liver and brain lesions, redressing NSAIDs’ post-surgery application and NO system involvement. PMID:28839430

Celecoxib-induced gastrointestinal, liver and brain lesions in rats, counteraction by BPC 157 or L-arginine, aggravation by L-NAME.

PubMed

Drmic, Domagoj; Kolenc, Danijela; Ilic, Spomenko; Bauk, Lara; Sever, Marko; Zenko Sever, Anita; Luetic, Kresimir; Suran, Jelena; Seiwerth, Sven; Sikiric, Predrag

2017-08-07

To counteract/reveal celecoxib-induced toxicity and NO system involvement. Celecoxib (1 g/kg b.w. ip) was combined with therapy with stable gastric pentadecapeptide BPC 157 (known to inhibit these lesions, 10 μg/kg, 10 ng/kg, or 1 ng/kg ip) and L-arginine (100 mg/kg ip), as well as NOS blockade [N(G)-nitro-L-arginine methyl ester (L-NAME)] (5 mg/kg ip) given alone and/or combined immediately after celecoxib. Gastrointestinal, liver, and brain lesions and liver enzyme serum values in rats were assessed at 24 h and 48 h thereafter. This high-dose celecoxib administration, as a result of NO system dysfunction, led to gastric, liver, and brain lesions and increased liver enzyme serum values. The L-NAME-induced aggravation of the lesions was notable for gastric lesions, while in liver and brain lesions the beneficial effect of L-arginine was blunted. L-arginine counteracted gastric, liver and brain lesions. These findings support the NO system mechanism(s), both NO system agonization (L-arginine) and NO system antagonization (L-NAME), that on the whole are behind all of these COX phenomena. An even more complete antagonization was identified with BPC 157 (at both 24 h and 48 h). A beneficial effect was evident on all the increasingly negative effects of celecoxib and L-NAME application and in all the BPC 157 groups (L-arginine + BPC 157; L-NAME + BPC 157; L-NAME + L-arginine + BPC 157). Thus, these findings demonstrated that BPC 157 may equally counteract both COX-2 inhibition (counteracting the noxious effects of celecoxib on all lesions) and additional NOS blockade (equally counteracting the noxious effects of celecoxib + L-NAME). BPC 157 and L-arginine alleviate gastrointestinal, liver and brain lesions, redressing NSAIDs' post-surgery application and NO system involvement.

Exisulind in combination with celecoxib modulates epidermal growth factor receptor, cyclooxygenase-2, and cyclin D1 against prostate carcinogenesis: in vivo evidence.

PubMed

Narayanan, Bhagavathi A; Reddy, Bandaru S; Bosland, Maarten C; Nargi, Dominick; Horton, Lori; Randolph, Carla; Narayanan, Narayanan K

2007-10-01

Nonsteroidal anti-inflammatory drugs mediate anticancer effects by modulating cyclooxygenase-2 (COX-2)-dependent and/or COX-2-independent mechanism(s); however, the toxicity issue is a concern with single agents at higher doses. In this study, we determined the combined effect of celecoxib, a COX-2 inhibitor, along with exisulind (sulindac sulfone/Aptosyn) at low doses in prostate cancer. We used a sequential regimen of N-methyl-N-nitrosourea + testosterone to induce prostate cancer in Wistar-Unilever rats. Following carcinogen treatment, celecoxib and exisulind individually and their combination at low doses were given in NIH-07 diet for 52 weeks. We determined the incidence of prostatic intraepithelial neoplasia, adenocarcinomas, rate of tumor cell proliferation, and apoptosis. Immunohistochemical and Western blot analysis were done to determine COX-2, epidermal growth factor receptor (EGFR), Akt, androgen receptor, and cyclin D1 expression. Serum prostaglandin E2 and tumor necrosis factor-alpha levels were determined using enzyme immunoassay/ELISA assays. The rats that received celecoxib in combination with exisulind at low doses showed a significant decrease in prostatic intraepithelial neoplasia and adenocarcinomas as well as an enhanced rate of apoptosis. An overall decrease in COX-2, EGFR, Akt, androgen receptor, and cyclin D1 expression was found associated with tumor growth inhibition. Reduced serum levels of COX-2 protein, prostaglandin E2, and tumor necrosis factor-alpha indicated anti-inflammatory effects. A strong inhibition of total and phosphorylated form of EGFR (Tyr(992) and Tyr(845)) and Akt (Ser(473)) was significant in rats given with these agents in combination. In this study, we show for the first time that the combination of celecoxib with exisulind at low doses could prevent prostate carcinogenesis by altering key molecular events.

Use of a balanced dual cyclooxygenase-1/2 and 5-lypoxygenase inhibitor in experimental colitis.

PubMed

Pallio, Giovanni; Bitto, Alessandra; Pizzino, Gabriele; Galfo, Federica; Irrera, Natasha; Minutoli, Letteria; Arcoraci, Vincenzo; Squadrito, Giovanni; Macrì, Antonio; Squadrito, Francesco; Altavilla, Domenica

2016-10-15

Cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) play an important role in inflammatory bowel diseases (IBDs). We investigated the effects of flavocoxid, a dual COX/LOX inhibitor, in experimental colitis induced with either dinitrobenzenesulfonic acid (DNBS) or dextrane sulphate sodium (DSS) In the first model, colitis was induced in rats by a single intra-colonic instillation (25mg in 0.8ml 50% ethanol) of DNBS; after 24h animals were randomized to receive orally twice a day, flavocoxid (10mg/kg), zileuton (50mg/kg), or celecoxib (5mg/kg). Sham animals received 0.8ml of saline by a single intra-colonic instillation. Rats were killed 4 days after induction and samples were collected for analysis. In the second model, colitis was induced in rats by the administration of 8% DSS dissolved in drinking water; after 24h animals were randomized to the same above reported treatments. Sham animals received standard drinking water. Rats were killed 5 days after induction and samples were collected for analysis. Flavocoxid, zileuton and celecoxib improved weight loss, reduced colonic myeloperoxydase activity, macroscopic and microscopic damage, and TNF-α serum levels. Flavocoxid and celecoxib also reduced malondialdheyde, 6-keto PGF1α and PGE-2 levels while flavocoxid and zileuton decreased LTB-4 levels. In addition, flavocoxid treatment improved histological features and apoptosis as compared to zileuton and celecoxib; moreover only flavocoxid reduced TXB2, thus avoiding an imbalance in eicosanoids production. Our results show that flavocoxid has protective effect in IBDs and may represents a future safe treatment for inflammatory bowel diseases. Copyright © 2016 Elsevier B.V. All rights reserved.

Physicochemical, Stress Degradation Evaluation and Pharmacokinetic Study of AZGH102, a New Synthesized COX2 Inhibitors after I.V. and Oral Administration in Male and Female Rats.

PubMed

Bahmanof, Hoda; Dadashzadeh, Simin; Zarghi, Afshin; Shafaati, Alireza; Foroutan, Seyed Mohsen

2017-01-01

Coxibs such as celecoxib, rofecoxib, and valdecoxib are introduced as selective COX-2 inhibitors to the market. It has been reported that inhibition of COX-2 beside traditional effects of NSAIDs, reduces the risk of colorectal, breast and lung cancers and also slow the progress of Alzheimer's disease. Zarghi et al. reported 8-benzoyl-2-(4-(methylsulfonyl)phenyl)quinoline-4-carboxylic acid (AZGH 102) as a novel compound with similar IC50 to celecoxib besides improved selectivity index (COX-1/COX-2 inhibitory potency) in comparison with celecoxib. In this study, the physicochemical properties of AZGH 102 such as solubility, log P, and stability were evaluated and the pharmacokinetic characteristics of this compound following intravenous (10 mg/Kg), and oral administration (20 mg/Kg), to male and female Wistar rats were investigated. As the data demonstrated, the AZGH 102 classified as lipophil compound and had suitable stability. This derivative absorbs and distributes faster in female than in male. The AUC 0-∞, absolute bioavailability, Cl and Vd were different in both sexes. According to the obtained data, the AZGH 102 has a sex dependent pharmacokinetic in Wistar rats.

Effects of conventional and hydrogen sulfide-releasing non-steroidal anti-inflammatory drugs in rats with stress-induced and epinephrine-induced gastric damage.

PubMed

Fomenko, Iryna; Sklyarov, Alexander; Bondarchuk, Tetyana; Biletska, Lilya; Panasyuk, Natalia; Wallace, John L

2014-12-01

Mechanisms of gastric defence under conditions of combined influence of acute stress and non-steroidal anti-inflammatory drugs (NSAIDs) are still poorly studied. The aim of this study was to explore the effects of different types of NSAIDs (naproxen, celecoxib and ATB-346) in producing experimental gastric lesions (induced by water-restraint stress (WRS) or by epinephrine (EPN) injection) and to determine the role of lipid peroxidation and the nitric oxide (NO) system in the pathogenesis of the damage. Male rats were used (eight per group) in this work. The NSAIDs were all administered at a dose 10 mg kg(-1) 30 min prior to WRS or EPN injection. Administration of naproxen to the control rats caused development of gastric lesions, whereas administration of a hydrogen sulfide (H2S)-releasing NSAID (ATB-346) or a selective cyclooxygenase-2 inhibitor (celecoxib) did not cause gastric damage. In contrast, lipid peroxidation processes were enhanced in all groups as was the activity of NO synthase (NOS). Pretreatment with naproxen in the WRS model caused an increase in severity of damage and a decrease in NOS activity. ATB-346 displayed beneficial effects, manifested by a decrease in the area of gastric damage, but parameters of lipid peroxidation and the NOS system did not differ substantially from those in the group treated with naproxen. Administration of different NSAIDs under conditions of EPN-induced gastric damage resulted in the decrease in NOS activity and lipid peroxidation. None of the tested NSAIDs exacerbated EPN-induced gastric mucosal injury; indeed, they all reduced the extent of damage.

Characteristics and molecular basis of celecoxib modulation on Kv7 potassium channels

PubMed Central

Du, XN; Zhang, X; Qi, JL; An, HL; Li, JW; Wan, YM; Fu, Y; Gao, HX; Gao, ZB; Zhan, Y; Zhang, HL

2011-01-01

BACKGROUND AND PURPOSE Celecoxib is a selective cyclooxygenase-2 (COX-2) inhibitor used for the treatment of pain and inflammation. Emerging and accumulating evidence suggests that celecoxib can affect cellular targets other than COX, such as ion channels. In this study, we characterized the effects of celecoxib on Kv7 K+ channels and compared its effects with the well-established Kv7 channel opener retigabine. EXPERIMENTAL APPROACH A perforated whole-cell patch technique was used to record Kv7currents expressed in HEK 293 cells and M-type currents from rat superior cervical ganglion neurons. KEY RESULTS Celecoxib enhanced Kv7.2–7.4, Kv7.2/7.3 and Kv7.3/7.5 currents but inhibited Kv7.1 and Kv7.1/KCNE1 currents and these effects were concentration dependent. The IC50 value for inhibition of Kv7.1 channels was approximately 4 µM and the EC50 values for activation of Kv7.2–7.4, Kv7.2/Kv7.3 and Kv7.3/Kv7.5 channels were approximately 2–5 µM. The effects of celecoxib were manifested by increasing current amplitudes, shifting the voltage-dependent activation curve in a more negative direction and slowing the deactivation of Kv7 currents. 2,5-Dimethyl-celecoxib, a celecoxib analogue devoid of COX inhibition activity, has similar but greater effects on Kv7currents. Kv7.2(A235T) and Kv7.2(W236L) mutant channels, which have greatly attenuated responses to retigabine, showed a reversed response to celecoxib, from activation to inhibition. CONCLUSIONS AND IMPLICATIONS These results suggest that Kv7 channels are targets of celecoxib action and provide new mechanistic evidence for understanding the effects of celecoxib. They also provide a new approach to developing Kv7 modulators and for studying the structure–function relationship of Kv7 channels. PMID:21564087

Development and reliability of a multi-modality scoring system for evaluation of disease progression in pre-clinical models of osteoarthritis: celecoxib may possess disease-modifying properties.

PubMed

Panahifar, A; Jaremko, J L; Tessier, A G; Lambert, R G; Maksymowych, W P; Fallone, B G; Doschak, M R

2014-10-01

We sought to develop a comprehensive scoring system for evaluation of pre-clinical models of osteoarthritis (OA) progression, and use this to evaluate two different classes of drugs for management of OA. Post-traumatic OA (PTOA) was surgically induced in skeletally mature rats. Rats were randomly divided in three groups receiving either glucosamine (high dose of 192 mg/kg) or celecoxib (clinical dose) or no treatment. Disease progression was monitored utilizing micro-magnetic resonance imaging (MRI), micro-computed tomography (CT) and histology. Pertinent features such as osteophytes, subchondral sclerosis, joint effusion, bone marrow lesion (BML), cysts, loose bodies and cartilage abnormalities were included in designing a sensitive multi-modality based scoring system, termed the rat arthritis knee scoring system (RAKSS). Overall, an inter-observer correlation coefficient (ICC) of greater than 0.750 was achieved for each scored feature. None of the treatments prevented cartilage loss, synovitis, joint effusion, or sclerosis. However, celecoxib significantly reduced osteophyte development compared to placebo. Although signs of inflammation such as synovitis and joint effusion were readily identified at 4 weeks post-operation, we did not detect any BML. We report the development of a sensitive and reliable multi-modality scoring system, the RAKSS, for evaluation of OA severity in pre-clinical animal models. Using this scoring system, we found that celecoxib prevented enlargement of osteophytes in this animal model of PTOA, and thus it may be useful in preventing OA progression. However, it did not show any chondroprotective effect using the recommended dose. In contrast, high dose glucosamine had no measurable effects. Copyright © 2014 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

CPT-11-Induced Delayed Diarrhea Develops via Reduced Aquaporin-3 Expression in the Colon

PubMed Central

Kon, Risako; Tsubota, Yuika; Minami, Moe; Kato, Saki; Matsunaga, Yukari; Kimura, Hiroshi; Murakami, Yuta; Fujikawa, Tetsuya; Sakurai, Ryoya; Tomimoto, Rei; Machida, Yoshiaki; Ikarashi, Nobutomo; Sugiyama, Kiyoshi

2018-01-01

While irinotecan (CPT-11) has a potent anti-cancer effect, it also causes serious diarrhea as an adverse reaction. In this study, we analyzed the pathogenic mechanism of CPT-11-induced delayed diarrhea by focusing on water channel aquaporin-3 (AQP3) in the colon. When rats received CPT-11, the expression level of AQP3 was reduced during severe diarrhea. It was found that the expression levels of inflammatory cytokines and the loss of crypt cells were increased in the colon when CPT-11 was administered. When celecoxib, an anti-inflammatory drug, was concomitantly administered, both the diarrhea and the reduced expression of AQP3 induced by CPT-11 were suppressed. The inflammation in the rat colon during diarrhea was caused via activated macrophage by CPT-11. These results showed that when CPT-11 is administered, the expression level of AQP3 in the colon is reduced, resulting in delayed diarrhea by preventing water transport from the intestinal tract. It was also suggested that the reduced expression of AQP3 might be due to the inflammation that occurs following the loss of colonic crypt cells and to the damage caused by the direct activation of macrophages by CPT-11. Therefore, it was considered that anti-inflammatory drugs that suppress the reduction of AQP3 expression could prevent CPT-11-induced delayed diarrhea. PMID:29316651

CPT-11-Induced Delayed Diarrhea Develops via Reduced Aquaporin-3 Expression in the Colon.

PubMed

Kon, Risako; Tsubota, Yuika; Minami, Moe; Kato, Saki; Matsunaga, Yukari; Kimura, Hiroshi; Murakami, Yuta; Fujikawa, Tetsuya; Sakurai, Ryoya; Tomimoto, Rei; Machida, Yoshiaki; Ikarashi, Nobutomo; Sugiyama, Kiyoshi

2018-01-06

While irinotecan (CPT-11) has a potent anti-cancer effect, it also causes serious diarrhea as an adverse reaction. In this study, we analyzed the pathogenic mechanism of CPT-11-induced delayed diarrhea by focusing on water channel aquaporin-3 (AQP3) in the colon. When rats received CPT-11, the expression level of AQP3 was reduced during severe diarrhea. It was found that the expression levels of inflammatory cytokines and the loss of crypt cells were increased in the colon when CPT-11 was administered. When celecoxib, an anti-inflammatory drug, was concomitantly administered, both the diarrhea and the reduced expression of AQP3 induced by CPT-11 were suppressed. The inflammation in the rat colon during diarrhea was caused via activated macrophage by CPT-11. These results showed that when CPT-11 is administered, the expression level of AQP3 in the colon is reduced, resulting in delayed diarrhea by preventing water transport from the intestinal tract. It was also suggested that the reduced expression of AQP3 might be due to the inflammation that occurs following the loss of colonic crypt cells and to the damage caused by the direct activation of macrophages by CPT-11. Therefore, it was considered that anti-inflammatory drugs that suppress the reduction of AQP3 expression could prevent CPT-11-induced delayed diarrhea.

Prevention of upper aerodigestive tract cancer in zinc-deficient rodents: Inefficacy of genetic or pharmacological disruption of COX-2

PubMed Central

Fong, Louise Y.Y.; Jiang, Yubao; Riley, Maurisa; Liu, Xianglan; Smalley, Karl J.; Guttridge, Denis C.; Farber, John L.

2009-01-01

Zinc deficiency in humans is associated with an increased risk of upper aerodigestive tract (UADT) cancer. In rodents, zinc deficiency predisposes to carcinogenesis by causing proliferation and alterations in gene expression. We examined whether in zinc-deficient rodents, targeted disruption of the cyclooxygenase (COX)-2 pathway by the COX-2 selective inhibitor celecoxib or by genetic deletion prevent UADT carcinogenesis. Tongue cancer prevention studies were conducted in zinc-deficient rats previously exposed to a tongue carcinogen by celecoxib treatment with or without zinc replenishment, or by zinc replenishment alone. The ability of genetic COX-2 deletion to protect against chemically-induced for-estomach tumorigenesis was examined in mice on zinc-deficient versus zinc-sufficient diet. The expression of 3 predictive bio-markers COX-2, nuclear factor (NF)-κ B p65 and leukotriene A4 hydrolase (LTA4H) was examined by immunohistochemistry. In zinc-deficient rats, celecoxib without zinc replenishment reduced lingual tumor multiplicity but not progression to malignancy. Celecoxib with zinc replenishment or zinc replenishment alone significantly lowered lingual squamous cell carcinoma incidence, as well as tumor multiplicity. Celecoxib alone reduced overexpression of the 3 biomarkers in tumors slightly, compared with intervention with zinc replenishment. Instead of being protected, zinc-deficient COX-2 null mice developed significantly greater tumor multiplicity and forestomach carcinoma incidence than wild-type controls. Additionally, zinc-deficient COX-2−/− forestomachs displayed strong LTA4H immunostaining, indicating activation of an alter-native pathway under zinc deficiency when the COX-2 pathway is blocked. Thus, targeting only the COX-2 pathway in zinc-deficient animals did not prevent UADT carcinogenesis. Our data suggest zinc supplementation should be more thoroughly explored in human prevention clinical trials for UADT cancer. PMID:17985342

Sustained intra-articular release of celecoxib in an equine repeated LPS synovitis model.

PubMed

Cokelaere, Stefan M; Plomp, Saskia G M; de Boef, Esther; de Leeuw, Mike; Bool, Sophie; van de Lest, Chris H A; René van Weeren, P; Korthagen, Nicoline M

2018-05-02

Synovial inflammation is an important characteristic of arthritic disorders like osteoarthritis and rheumatoid arthritis. Orally administered non-steroidal anti-inflammatory drugs (NSAIDs) such as celecoxib are among the most widely prescribed drugs to manage these debilitating diseases. Intra-articular delivery in biodegradable in situ forming hydrogels overcomes adverse systemic effects and prolongs drug retention in the joint. In this study two formulations of celecoxib (40 mg/g and 120 mg/g) in a propyl-capped PCLA-PEG-PCLA triblock copolymer were sequentially evaluated in a multiple LPS challenge equine synovitis model. Intra-articular release and systemic exposure to celecoxib and local changes at joint level were evaluated longitudinally. A single intra-articular injection of the high dose (HCLB)-gel or low dose (LCLB)-gel showed a sustained and controlled intra-articular release in both inflamed and healthy joints together with very low systemic exposure. Synovitis and lameness were moderate respectively very mild in this model due to the low concentration LPS (0.25 ng/joint). Both celecoxib formulations had a mild, transient effect on inflammatory and structural synovial fluid biomarkers but these returned to baseline within one week of administration. The HCLB-gel showed a significant inhibition in peak white blood cell concentration at 8 hours after LPS induction. Elevated levels of celecoxib were observed in the joint for up to 30 days but no overall anti-inflammatory effects could be observed, which was thought to be due to the moderate synovitis. As there were no long-term adverse effects, sustained intra-articular release of celecoxib from in situ forming hydrogels should be evaluated further for its effects on longer-term relief of inflammatory joint pain in humans and animals. Copyright © 2018. Published by Elsevier B.V.

Loxoprofen sodium and celecoxib for postoperative pain in patients after spinal surgery: a randomized comparative study.

PubMed

Sekiguchi, Hiroyuki; Inoue, Gen; Nakazawa, Toshiyuki; Imura, Takayuki; Saito, Wataru; Uchida, Kentaro; Miyagi, Masayuki; Takahira, Naonobu; Takaso, Masashi

2015-07-01

Nonsteroidal anti-inflammatory drugs (NSAIDs) are often used to treat inflammation, pain, and fever, but no criterion standard exists for the management of postoperative pain following spinal surgery. In the present study, we compared the analgesic efficacy of loxoprofen sodium (loxoprofen) and celecoxib for the management of postoperative pain following spinal surgery. One-hundred forty-one patients (mean age 62.2 years) were randomly assigned to two groups before spinal surgery: a loxoprofen group (n = 73, 180 mg/day) and a celecoxib group (n = 68, 200 mg/day). The drugs were administered from 1 day until 7 days after surgery. A numeric rating scale (NRS) was used to evaluate pain at nine predefined times every day and the findings were compared between the two groups. Laboratory data and adverse events were also recorded. There was no significant difference in the maximum and mean NRS scores on each day between loxoprofen and celecoxib, suggesting a comparable analgesic effect for these two NSAIDs. Greater improvement in the NRS score between preadministration (baseline) and 30 min or 2 h after administration was obtained for loxoprofen. This tendency was shown for both slight (NRS score <5 at baseline) and severe pain (NRS score ≥ 5 at baseline). Loxoprofen was discontinued in one patient on day 4 because of renal dysfunction. Celecoxib was discontinued in one patient on day 2 at the patient's request. Both loxoprofen sodium and celecoxib were well tolerated for the relief of acute postoperative pain after spinal surgery. A single administration of loxoprofen showed superior and rapid effectiveness compared with celecoxib for both slight and severe postoperative pain.

Enhanced inhibition of urinary bladder cancer growth and muscle invasion by allyl isothiocyanate and celecoxib in combination

PubMed Central

Zhang, Yuesheng

2013-01-01

Allyl isothiocyanate (AITC) occurs in cruciferous vegetables that are commonly consumed by humans and has been shown to inhibit urinary bladder cancer growth and progression in previous preclinical studies. However, AITC does not significantly modulate cyclooxygenase-2 (Cox-2), whose oncogenic activity has been well documented in bladder cancer and other cancers. Celecoxib is a selective Cox-2 inhibitor and has been widely used for treatment of several diseases. Celecoxib has also been evaluated in bladder cancer patients, but its efficacy against bladder cancer as a single agent remains unclear. In a syngeneic rat model of orthotopic bladder cancer, treatment of the animals with the combination of AITC and celecoxib at low dose levels (AITC at 1mg/kg and celecoxib at 10mg/kg) led to increased or perhaps synergistic inhibition of bladder cancer growth and muscle invasion, compared with each agent used alone. The combination regime was also more effective than each single agent in inhibiting microvessel formation and stimulating microvessel maturation in the tumor tissues. The anticancer efficacy of the combination regime was associated with depletion of prostaglandin E2, a key downstream signaling molecule of Cox-2, caspase activation and downregulation of vascular endothelial growth factor in the tumor tissues. These data show that AITC and celecoxib complement each other for inhibition of bladder cancer and provide a novel combination approach for potential use for prevention or treatment of human bladder cancer. PMID:23946495

Up-regulation of p53 and mitochondrial signaling pathway in apoptosis by a combination of COX-2 inhibitor, Celecoxib and Dolastatin 15, a marine mollusk linear peptide in experimental colon carcinogenesis.

PubMed

Piplani, Honit; Vaish, Vivek; Rana, Chandan; Sanyal, Sankar N

2013-11-01

Programmed cell death, also known as apoptosis, is an active process occurring in eukaryotic cells and it depends on various sets of pro and anti-apoptotic proteins. Chemoprevention of colorectal cancer can be achieved by inducing apoptosis using synthetic compound, Celecoxib and natural peptide, Dolastatin 15 in an effective manner. But the apoptotic signaling by these two drugs remain unclear. The present study was thus focused on the role of Bcl2 family of proteins and their interplay with p53 in rats during the chemoprevention by these two drugs. After treatment for 6 wk with 1, 2-dimethylhydrazine (DMH), animals showed a marked occurrence of multiple plaque lesions. However, a simultaneous treatment with Celecoxib and Dolastatin 15 decreases such number to a significant level. DMH treatment also decreases the number of apoptotic cells in the colonic enterocytes which were corrected to the normal level by Celecoxib and Dolastatin 15. An increased expression of Bcl2 while other proteins like Bax, Apaf-1, cyt c, and caspases in the apoptotic pathway, and the tumor suppressor proteins, p53 and p21 get down-regulated after DMH treatment which were reverted back to normal with Celecoxib and Dolastatin 15. Also, cells having high mitochondrial membrane potential had been seen to increase to significant levels which were reduced after the administration of these anti-inflammatory drugs. In silico molecular docking studies also showed that Dolastatin 15 and Celecoxib may bind to the active site pocket of Bcl2 , thus revealing the direct target of Dolastatin 15 and Celecoxib apart from binding to COX-2. © 2012 Wiley Periodicals, Inc.

Assessment of celecoxib poly(lactic-co-glycolic) acid nanoformulation on drug pharmacodynamics and pharmacokinetics in rats.

PubMed

Harirforoosh, S; West, K O; Murrell, D E; Denham, J W; Panus, P C; Hanley, G A

2016-11-01

Celecoxib (CEL) is a nonsteroidal anti-inflammatory drug (NSAID) showing selective cycloxygenase-2 inhibition. While effective as a pain reducer, CEL exerts some negative influence on renal and gastrointestinal parameters. This study examined CEL pharmacodynamics and pharmacokinetics following drug reformulation as a poly(lactic-co-glycolic) acid nanoparticle (NP). Rats were administered either vehicle (VEH) (methylcellulose solution), blank NP, 40 mg/kg CEL in methylcellulose, or an equivalent NP dose (CEL-NP). Plasma and urine (over 12 hrs) samples were collected prior to and post-treatment. The mean percent change from baseline of urine flow rate along with electrolyte concentrations in plasma and urine were assessed based on 100 g body weight. Using tissues collected 24 hrs post-treatment, gastrointestinal inflammation was estimated through duodenal and gastric prostaglandin E2 (PGE2) and duodenal myeloperoxidase (MPO) levels; while kidney tissue was examined for dilatation and necrosis. CEL concentration was assayed in renal tissue and plasma utilizing high-performance liquid chromatography. Although there were significant changes when comparing CEL and CEL-NP to VEH in plasma sodium concentration and potassium excretion rate, there was no significant variation between CEL and CEL-NP. There was a significant reduction of protective duodenal PGE2 in CEL compared to VEH (p = 0.0088) and CEL-NP (p = 0.02). In the CEL-NP formulation, t1/2, Cmax, AUC0-∞, and Vd/F increased significantly when compared to CEL. At the observed dosage and duration, CEL-NP may not affect CEL-associated electrolyte parameters in either plasma or urine; however, it does provide increased systemic exposure while potentially alleviating some gastrointestinal outcomes related to inflammation.

Single‐dose pharmacokinetics of co‐crystal of tramadol–celecoxib: Results of a four‐way randomized open‐label phase I clinical trial in healthy subjects

PubMed Central

Lahjou, Mounia; Vaqué, Anna; Sust, Mariano; Encabo, Mercedes; Soler, Lluis; Sans, Artur; Sicard, Eric; Gascón, Neus; Encina, Gregorio; Plata‐Salamán, Carlos

2017-01-01

Aims Co‐crystal of tramadol–celecoxib (CTC) is a novel co‐crystal molecule containing two active pharmaceutical ingredients under development by Esteve (E‐58425) and Mundipharma Research (MR308). This Phase I study compared single‐dose pharmacokinetics (PK) of CTC with those of the individual reference products [immediate‐release (IR) tramadol and celecoxib] alone and in open combination. Methods Healthy adults aged 18–55 years were orally administered four treatments under fasted conditions (separated by 7‐day wash‐out period): 200 mg IR CTC (equivalent to 88 mg tramadol and 112 mg celecoxib; Treatment 1); 100 mg IR tramadol (Treatment 2); 100 mg celecoxib (Treatment 3); and 100 mg IR tramadol and 100 mg celecoxib (Treatment 4). Treatment sequence was assigned using computer‐generated randomization. PK parameters were calculated using noncompartmental analysis with parameters for CTC adjusted according to reference product dose (100 mg). Results Thirty‐six subjects (28 male, mean age 36 years) participated. Tramadol PK parameters for Treatments‐1, –2 and –4, respectively, were 263, 346 and 349 ng ml–1 (mean maximum plasma concentration); 3039, 2979 and 3119 ng h ml–1 (mean cumulative area under the plasma concentration–time curve); and 2.7, 1.8 and 1.8 h (median time to maximum plasma concentration). For Treatments 1, 3 and 4, the respective celecoxib PK parameters were 313, 449 and 284 ng ml–1; 2183, 3093 and 2856 ng h ml–1; and 1.5, 2.3 and 3.0 h. No unexpected adverse events were reported. Conclusion PK parameters of each API in CTC were modified by co‐crystallization compared with marketed formulations of tramadol, celecoxib, and their open combination. PMID:28810061

Single-dose pharmacokinetics of co-crystal of tramadol-celecoxib: Results of a four-way randomized open-label phase I clinical trial in healthy subjects.

PubMed

Videla, Sebastián; Lahjou, Mounia; Vaqué, Anna; Sust, Mariano; Encabo, Mercedes; Soler, Lluis; Sans, Artur; Sicard, Eric; Gascón, Neus; Encina, Gregorio; Plata-Salamán, Carlos

2017-12-01

Co-crystal of tramadol-celecoxib (CTC) is a novel co-crystal molecule containing two active pharmaceutical ingredients under development by Esteve (E-58425) and Mundipharma Research (MR308). This Phase I study compared single-dose pharmacokinetics (PK) of CTC with those of the individual reference products [immediate-release (IR) tramadol and celecoxib] alone and in open combination. Healthy adults aged 18-55 years were orally administered four treatments under fasted conditions (separated by 7-day wash-out period): 200 mg IR CTC (equivalent to 88 mg tramadol and 112 mg celecoxib; Treatment 1); 100 mg IR tramadol (Treatment 2); 100 mg celecoxib (Treatment 3); and 100 mg IR tramadol and 100 mg celecoxib (Treatment 4). Treatment sequence was assigned using computer-generated randomization. PK parameters were calculated using noncompartmental analysis with parameters for CTC adjusted according to reference product dose (100 mg). Thirty-six subjects (28 male, mean age 36 years) participated. Tramadol PK parameters for Treatments-1, -2 and -4, respectively, were 263, 346 and 349 ng ml -1 (mean maximum plasma concentration); 3039, 2979 and 3119 ng h ml -1 (mean cumulative area under the plasma concentration-time curve); and 2.7, 1.8 and 1.8 h (median time to maximum plasma concentration). For Treatments 1, 3 and 4, the respective celecoxib PK parameters were 313, 449 and 284 ng ml -1 ; 2183, 3093 and 2856 ng h ml -1 ; and 1.5, 2.3 and 3.0 h. No unexpected adverse events were reported. PK parameters of each API in CTC were modified by co-crystallization compared with marketed formulations of tramadol, celecoxib, and their open combination. © 2017 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Reappraisal of the Therapeutic Role of Celecoxib in Cholangiocarcinoma

PubMed Central

Juang, Horng-Heng; S. Pang, Jong-Hwei; Yu, Chung-Shan; Lin, Kun-Ju; Yeh, Ta-Sen; Jan, Yi-Yin

2013-01-01

Cholangiocarcinoma (CCA), a lethal disease, affects many thousands worldwide yearly. Surgical resection provides the best chance for a cure; however, only one-third of CCA patients present with a resectable tumour at the time of diagnosis. Currently, no effective chemotherapy is available for advanced CCA. Cyclooxygenase-2 (COX-2) is a potential oncogene expressing in human CCA tissues and represents a candidate target for treatment; however, COX-2 inhibitors increase the risk of negative cardiovascular events as application for chemoprevention aim. Here, we re-evaluated the effectiveness and safety of celecoxib, one widely used COX-2 inhibitor, in treating CCA. We demonstrated that celecoxib exhibited an anti-proliferative effect on CGCCA cells via cell cycle arrest at G2 phase and apoptosis induction. Treatment for 5 weeks high dose celecoxib (160 mg/kg) significantly repressed thioacetamide-induced CCA tumour growth in rats as monitored by animal positron emission tomography through apoptosis induction. No obviously observable side effects were noted during the therapeutic period. As retrospectively reviewing 78 intrahepatic mass-forming CCA patients, their survival was strongly and negatively associated with a positive resection margin and high COX-2 expression. Based on our result, we concluded that short-term high dose celecoxib may be a promising therapeutic regimen for CCA. Yet its clinical application still needs more studies to prove its safety. PMID:23922859

Synergistic anti-hyperalgesia of electroacupuncture and low dose of celecoxib in monoarthritic rats: involvement of the cyclooxygenase activity in the spinal cord.

PubMed

Mi, Wen-Li; Mao-Ying, Qi-Liang; Liu, Qiong; Wang, Xiao-Wei; Wang, Yan-Qing; Wu, Gen-Cheng

2008-09-30

Electroacupuncture (EA) can effectively control the exaggerated pain in humans with inflammatory disease and animals with experimental inflammatory pain. However, there have been few investigations on the effect of co-administration of EA and analgesics and the underlying synergistic mechanism. Using behavioral test, RT-PCR analysis, enzyme immunoassay (EIA) and enzyme-linked immunosorbent assay (ELISA), the present study demonstrated that (1) Unilateral intra-articular injection of complete Freund's adjuvant (CFA) produced a constant hyperalgesia and an up-regulation of the prostaglandin E(2) (PGE(2)) level as well as the tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6 levels in the spinal cord; (2) Celecoxib, a selective inhibitor of cyclooxygenase-2 (COX-2), at a dose of 2, 10, and 20 mg/kg (twice daily, p.o.), presented a dose-dependent anti-hyperalgesic effect; (3) Repeated EA stimulation of ipsilateral 'Huan-Tiao' (GB30) and 'Yang-Ling-Quan' (GB34) acupoints significantly suppressed CFA-induced hyperalgesia, and markedly inhibited the CFA-induced increase of the level of PGE(2) as well as IL-1beta, IL-6, and TNF-alpha in the spinal cord; (4) EA combined with low dose of celecoxib (2 mg/kg, twice daily, p.o.) greatly enhanced the anti-hyperalgesic effects of EA, with a synergistic reversing effect on CFA-induced up-regulation of spinal PGE(2), but not on the IL-1beta, IL-6, or TNF-alpha. These data indicated that repeated EA combined with low dose of celecoxib produced synergistic anti-hyperalgesic effect in the CFA-induced monoarthritic rats, which could be made possible by regulating the activity of spinal COX, hence the spinal PGE(2) level. Thus, this combination may provide an effective strategy for pain management.

Effect of celecoxib plus standard chemotherapy on serum levels of vascular endothelial growth factor and cyclooxygenase-2 in patients with gastric cancer.

PubMed

Han, Xiaopeng; Li, Hongtao; Su, Lin; Zhu, Wankun; Xu, Wei; Li, Kun; Zhao, Qingchuan; Yang, Hua; Liu, Hongbin

2014-03-01

Elevated serum levels of vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2) are associated with poor prognosis in patients with gastric cancer. Little is known regarding the clinical benefits of combining celecoxib, a selective inhibitor of COX-2, with standard chemotherapy regimens for the treatment of gastric cancer patients. In this study, we investigated the effect of the combinatorial use of celecoxib with standard chemotherapy on the serum levels of VEGF and COX-2 in patients with gastric cancer. In our study, 80 patients with gastric cancer who underwent laparoscopic radical surgery were randomized into two groups, the combination [celecoxib plus standard oxaliplatin, leucovorin and 5-fluorouracil (FOLFOX4) chemotherapy, n=40] and the FOLFOX4 alone (n=40) groups. In the combination group, celecoxib was orally administered to the patients (400 mg, twice daily). The serum levels of VEGF and COX-2 were measured by ELISA prior to and following surgery. We detected no significant difference in the serum levels of VEGF and COX-2 between the combination and FOLFOX4 alone groups prior to chemotherapy (P>0.05). However, after 6 cycles of chemotherapy, there was a greater decrease in the serum levels of VEGF and COX-2 in the combination group compared to those in the FOLFOX4 group (P<0.01). In addition, the serum levels of VEGF and COX-2 were closely correlated in patients with gastric adenocarcinoma prior to treatment. Our data indicated that, when combined with standard chemotherapy, celecoxib may reduce the serum levels of VEGF and COX-2, suggesting that COX-2 inhibitors may be of therapeutic value through the inhibition of tumor angiogenesis and the prevention of recurrence or metastasis. Thus, celecoxib may be a useful adjuvant agent to standard chemotherapy in patients with advanced gastric cancer.

Efficacy of Celecoxib for Early Postoperative Pain Management in Hip Arthroscopy: A Prospective Randomized Placebo-Controlled Study.

PubMed

Kahlenberg, Cynthia A; Patel, Ronak M; Knesek, Michael; Tjong, Vehniah K; Sonn, Kevin; Terry, Michael A

2017-06-01

To determine whether 400 mg of celecoxib administered 1 hour before hip arthroscopy surgery would reduce pain, provide reduction in overall narcotic consumption, and lead to more rapid discharge from recovery rooms. Ninety-eight patients were randomized to either the celecoxib group (n = 50) or the placebo group (n = 48). An a priori power analysis was done set to detect a difference of 0.50 on the visual analog scale (VAS), based on the senior author's preference. The number of patients planned for recruitment was rounded up to 100 to allow for flexibility in the study. Inclusion criteria were any patient at least 18 years old who underwent hip arthroscopy surgery performed by the senior author. All patients had less than Tönnis grade 2 arthritis. Exclusion criteria were allergy to sulfa-based drugs, prior adverse reaction to celecoxib, or patients who were on chronic narcotics for whom alternative pain management regimens were arranged before surgery. Randomization was performed on a 1:1 basis in blocks of 10 using sealed envelopes stating celecoxib or placebo. One hour before surgery, all patients received either 400 mg celecoxib or placebo. Patients were evaluated using a VAS preoperatively, immediately postoperatively, and at 1 and 2 hours postoperatively. Time from the operating room to "ready for discharge" and number of morphine equivalents of narcotic medication required in the postanesthesia care unit were recorded. Age and preoperative VAS were similar between the celecoxib and placebo control group, with average ages of 34.2 ± 11.9 and 35.8 ± 11.6 (P = .27) and preoperative VAS of 2.1 ± 2.06 and 2.3 ± 1.98 (P = .29), respectively. The celecoxib group had 26 females and 24 males, whereas the placebo group had 29 females and 19 males (P = .42). The most common surgical procedures were labral repair (31 patients in the celecoxib group and 29 patients in the placebo group), and labral repair with acetabular osteoplasty (13 patients in the celecoxib group and 11 patients in the placebo group). There were no significant differences in procedures performed between the 2 groups (P > .05). At 1 hour postoperatively, patients who received celecoxib had a lower pain score that was statistically significant compared with the placebo group (4.6 vs 5.4, P = .03). There was a significant difference in discharge time between patients who received celecoxib and the control group (152.9 minutes vs 172.9 minutes, P = .04). There was no significant difference found in morphine equivalents consumed in the postanesthesia care unit between the 2 groups (15.3 vs 15.4, P = .48). A preoperative dose of 400 mg of celecoxib led to statistically significantly reduced patient-reported pain on the VAS in the acute postoperative period after hip arthroscopy surgery, though the difference is not likely clinically significant. There was a significantly shorter time to discharge in patients who received celecoxib versus placebo. Level I, randomized controlled trial. Copyright © 2017 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.

Antihyperalgesic/antinociceptive effects of ceftriaxone and its synergistic interactions with different analgesics in inflammatory pain in rodents.

PubMed

Stepanovic-Petrovic, Radica M; Micov, Ana M; Tomic, Maja A; Kovacevic, Jovana M; Boškovic, Bogdan D

2014-03-01

The β-lactam antibiotic ceftriaxone stimulates glutamate transporter GLT-1 expression and is effective in neuropathic and visceral pain models. This study examined the effects of ceftriaxone and its interactions with different analgesics (ibuprofen, celecoxib, paracetamol, and levetiracetam) in somatic and visceral pain models in rodents. The effects of ceftriaxone (intraperitoneally/intraplantarly), analgesics (orally), and their combinations were examined in the carrageenan-induced paw inflammatory hyperalgesia model in rats (n = 6-12) and in the acetic acid-induced writhing test in mice (n = 6-10). The type of interaction between ceftriaxone and analgesics was determined by isobolographic analysis. Pretreatment with intraperitoneally administered ceftriaxone (10-200 mg/kg per day) for 7 days produced a significant dose-dependent antihyperalgesia in the somatic inflammatory model. Acute administration of ceftriaxone, via either intraperitoneal (10-200 mg/kg) or intraplantar (0.05-0.2 mg per paw) routes, produced a significant and dose-dependent but less efficacious antihyperalgesia. In the visceral pain model, significant dose-dependent antinociception of ceftriaxone (25-200 mg/kg per day) was observed only after the 7-day pretreatment. Isobolographic analysis in the inflammatory hyperalgesia model revealed approximately 10-fold reduction of doses of both drugs in all examined combinations. In the visceral nociception model, more than 7- and 17-fold reduction of doses of both drugs was observed in combinations of ceftriaxone with ibuprofen/paracetamol and celecoxib/levetiracetam, respectively. Ceftriaxone exerts antihyperalgesia/antinociception in both somatic and visceral inflammatory pain. Its efficacy is higher after a 7-day pretreatment than after acute administration. The two-drug combinations of ceftriaxone and the nonsteroidal analgesics/levetiracetam have synergistic interactions in both pain models. These results suggest that ceftriaxone, particularly in combinations with ibuprofen, celecoxib, paracetamol, or levetiracetam, may provide useful approach to the clinical treatment of inflammation-related pain.

Effect of selective versus non-selective cyclooxygenase inhibitors on ischemia-reperfusion-induced hepatic injury in rats.

PubMed

Abdel-Gaber, Seham A; Ibrahim, Mohamed A; Amin, Entesar F; Ibrahim, Salwa A; Mohammed, Rehab K; Abdelrahman, Aly M

2015-08-01

Ischemia-reperfusion (IR) injury represents an important pathological process of liver injury during major hepatic surgery. The role of cyclooxygenase (COX) enzymes in the pathogenesis of ischemia-reperfusion (IR)-induced liver injury is not clear. This study investigated the effect of a selective COX-2 inhibitor, celecoxib, versus non-selective, indomethacin, on hepatic IR injury in rats. Hepatic IR was induced in adult male rats. The animals were divided into 4 groups: normal control (sham group), IR non-treated group; IR-indomethacin-treated group; and IR-celecoxib-treated group. Liver injury was evaluated by serum alanine aminotransferase (ALT) and a histopathological examination of liver tissues. Hepatic tissue content of oxidative stress parameters glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase, malondialdehyde (MDA), nitric oxide (NO) and the inflammatory marker, tumor necrosis factor-alpha, (TNF-α) were measured. Moreover, the immunohistochemical detection of endothelial NO synthase (eNOS), inducible NO synthase (iNOS), and caspase-3 in the hepatic tissue was performed. Celecoxib, but not indomethacin, significantly attenuated hepatic IR injury as evidenced by reduction in serum ALT as well as by improvement in the histopathological scoring. Such effect was associated with attenuation in oxidative stress and TNF-α, along with modulation of immunohistochemical expression of eNOS, iNOS and caspase-3 in the hepatic tissue. The present study concluded that selective COX-2 inhibition (but not non-selective), is hepatoprotective against liver IR injury; indicating a differential role of COX-1 versus COX-2. Modulation of iNOS, eNOS and caspase-3 might participate in the protective effect of selective COX-2-inhibitors. Copyright © 2015 Elsevier Inc. All rights reserved.

Overexpression of COX-2 in Rat Oral Cancers and Prevention of Oral Carcinogenesis in Rats by Selective and Non-Selective COX Inhibitors

PubMed Central

McCormick, David L.; Phillips, Jonathan M.; Horn, Thomas L.; Johnson, William D.; Steele, Vernon E.; Lubet, Ronald A.

2009-01-01

Oral squamous cell carcinomas induced in rats by 4-nitroquinoline-1-oxide (NQO) demonstrate substantial overexpression of cyclooxygenase-2 (COX-2) when compared to adjacent phenotypically normal oral tissues. By contrast, neither 5-lipoxygenase (5-LOX) nor 12-lipoxygenase (12-LOX) is overexpressed in rat oral cancers. Two chemoprevention studies were performed to test the resulting hypothesis that COX-2 is a useful target for oral cancer chemoprevention in the rat. In both studies, male F344 rats received drinking water exposure to NQO (20 ppm) for 10 weeks, followed by administration of chemopreventive agents from week 10 until study termination at week 26. In the first study, groups of rats were fed basal diet (control), or basal diet supplemented with the selective COX-2 inhibitor, celecoxib (500 or 1500 mg/kg diet); the non-selective COX inhibitor, piroxicam (50 or 150 mg/kg diet); or the 5-LOX inhibitor, zileuton (2000 mg/kg diet). In the second study, rats were fed basal diet (control) or basal diet supplemented with NO-Naproxen (180 or 90 mg/kg diet), a non-selective COX inhibitor that demonstrates reduced gastrointestinal toxicity. When compared to dietary controls, celecoxib decreased oral cancer incidence, cancer invasion score, and cancer-related mortality. Piroxicam decreased cancer-related mortality and cancer invasion score, while NO-naproxen decreased oral cancer incidence and cancer invasion score. By contrast, zileuton demonstrated no chemopreventive activity by any parameter assessed. These data demonstrate that both selective and non-selective inhibitors of COX-2 can prevent NQO-induced oral carcinogenesis in rats. The chemopreventive activity of COX inhibitors may be linked to overexpression of their enzymatic target in incipient oral neoplasms. PMID:20051374

Enhanced release and drug delivery of celecoxib into physiological environment by the different types of nanoscale vehicles

NASA Astrophysics Data System (ADS)

Khazraei, Avideh; Tarlani, Aliakbar; Naderi, Nima; Muzart, Jacques; Abdulhameed (Kaabi), Zahra; Eslami-Moghadam, Mahbube

2017-11-01

Celecoxib (CEL) as the very low water soluble drug was loaded 16 and 50% (w/w) through an impregnation method on varieties of alumina nanostructures such as synthetic sol-gel γ-alumina (Gam-Al), functionalized sol-gel γ-alumina (Gam-Al-NH2), organized nano porous alumina (Onp-Al) and then the results compared with commercial alumina (Com-Al) and SBA-15 (SBA). Analyses of the samples were carried out by FT-IR, X-ray diffraction (XRD) and N2-sorption. in vitro studies were accomplished in simulated body fluid (SBF), simulated gastric fluid (SGF) and simulated intestinal fluid (SIF). In vivo study was carried out on male wistar rats under standard conditions. The N2-sorption revealed the initial pore characteristics of the nanocarriers. XRD patterns showed that the 50% loaded samples contain bulk celecoxib and its solubility in body fluids is lower than that of 16% loaded samples. In the case of 16% loaded samples, the drug solubility in three simulated body fluids drug was found to decrease in the following order: Gam-Al-CEL > Onp-Al-CEL > Com-Al-CEL > SBA-CEL. Gam-Al-CEL showed the highest release (96%) in SBF after 60 min in vivo study showed significant decrease in pain score in rats for Gam-Al-NH2-CEL-16% and Gam-Al-CEL-50%. It could be concluded that the synthetic aluminas have a developing future potential compared to the formal SBA and commercial alumina.

Stability and Ocular Pharmacokinetics of Celecoxib-Loaded Nanoparticles Topical Ophthalmic Formulations.

PubMed

Ibrahim, Mohammed Mostafa; Abd-Elgawad, Abd-Elgawad Helmy; Soliman, Osama Abd-Elazeem; Jablonski, Monica M

2016-12-01

A spontaneous emulsification and/or solvent diffusion method was used for the preparation of celecoxib-loaded nanoparticles (NPs) using polymers, including chitosan (CS), sodium alginate, poly-ε-caprolactone (PCL), poly-l-lactide, and poly-d,l-lactide-co-glycolide. NPs were incorporated into vehicles (eye drops, in situ gelling system, and gel). Formulations were subjected to an accelerated stability study by storing them at elevated temperatures of 30, 35, and 45°C for 6 months. Formulations were evaluated monthly for general appearance, pH, viscosity, particle size, polydispersity index, zeta potential, and drug content. Gels containing CS-NPs and PCL-NPs were selected for an ocular pharmacokinetics study using Sprague-Dawley rats due to their high stability and long shelf lives (24.56 and 33.76 months, respectively). The gel improved NP stability by keeping it inside its network structure, which protected them from aggregation and interacting with water. Our formulations improved celecoxib bioavailability due to their bioadhesivness, thus preventing their rapid removal. Also, NPs acted as drug reservoirs that adhered to eye surface and continuously released the drug. The availability of celecoxib in all eye tissues and its absence in plasma suggests that our formulation could be used for anterior eye disorders and also for treatment of diseases associated with the posterior eye with no systemic side effects. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Dolastatin 15, a mollusk linear peptide, and Celecoxib, a selective cyclooxygenase-2 inhibitor, prevent preneoplastic colonic lesions and induce apoptosis through inhibition of the regulatory transcription factor NF-κB and an inflammatory protein, iNOS.

PubMed

Piplani, Honit; Vaish, Vivek; Sanyal, Sankar Nath

2012-11-01

The marine ecosystem is a unique and enormously rich source of natural products with potential chemopreventive applications in cancer. In the present study, we explored the chemopreventive role and the molecular mechanism of Dolastatin, a linear peptide from an Indian Ocean mollusk, and Celecoxib, a well-established cyclooxygenase-2 (COX-2) inhibitor in an individual as well as in a combination regimen in 1,2-dimethylhydrazine dihydrochloride (DMH)-induced colon carcinogenesis in a rat model. After a 6-week treatment with DMH, morphological analysis revealed a marked occurrence of preneoplastic features in the colonic mucosa, whereas histologically well-characterized dysplasia and hyperplasia were observed in DMH-treated animals. Simultaneous administration of Celecoxib and Dolastatin reduced these features significantly. DMH treatment affected the number of apoptotic cells in colonic enterocytes, which reverted to the normal level with the use of Celecoxib and Dolastatin. Inflammation remains the dominant molecular mechanism in the development of multiple plaque lesions, the carcinogenic lesions in a DMH-induced process that may be mediated by COX-2. Western blot and immunofluorescence analysis revealed a higher expression of COX-2 and nuclear factor-κB, the transcription factors responsible for proinflammatory proteins such as TNFα, and also the inducible nitric oxide synthase in the DMH group, which was further recovered significantly with the use of Celecoxib and Dolastatin. In-silico molecular docking analysis of Dolastatin as a ligand with various regulatory proteins suggests that although the peptide failed to dock to COX-2, it successfully did so with inducible nitric oxide synthase, thereby indicating the potential of this inflammatory protein as a molecular anticancer target in colon carcinogenesis.

Efficacy and safety of additional 200-mg dose of celecoxib in adult patients with postoperative pain following extraction of impacted third mandibular molar: a multicenter, randomized, double-blind, placebo-controlled, phase II study in Japan.

PubMed

Saito, Ken'ichi; Kaneko, Akihiro; Machii, Katsuyuki; Ohta, Hiroyoshi; Ohkura, Masayuki; Suzuki, Makoto

2012-02-01

Although third mandibular molar extraction is a widely used and validated model of acute pain for evaluating analgesic efficacy, a large proportion of patients experience moderate or severe pain following this procedure and require analgesia. Current treatment options have been associated with safety concerns and alternative therapies are sought. Our aim was to assess the efficacy and safety of an additional 200-mg dose of celecoxib, administered 5 to 12 hours after an initial 400-mg dose of the drug for the treatment of moderate or severe acute pain following extraction of an impacted third mandibular molar. This was a multicenter, randomized, double-blind, placebo-controlled, Phase II study. Patients experiencing moderate or severe pain within 1 to 2 hours following extraction of an impacted third mandibular molar received an initial 400-mg dose of celecoxib. Patients requiring additional analgesia were subsequently randomized to receive either an additional 200-mg dose of celecoxib or placebo 5 to 12 hours after the initial dose. The study was designed and conducted by Pfizer Inc. for approval of celecoxib in Japan for the indication of acute pain. The primary end point was the patient's impression of efficacy (4-category global evaluation scale). Secondary efficacy end points included pain intensity on a 4-category pain intensity scale, pain intensity on a 100-mm visual analog scale (VAS), and the pain intensity difference (100-mm VAS). In an exploratory analysis, use of rescue medication was evaluated. Primary and secondary end points were analyzed using the full analysis set. Assessment of the safety profile included a physical examination, measurement of pulse rate and blood pressure, standard 12-lead ECG, and laboratory tests. A total of 69 patients (celecoxib, 42/64 [65.6%]; placebo, 27/58 [46.6%]) received the additional dose of study medication; all completed the study without the need for rescue medication. A significantly higher proportion of patients in the celecoxib 200 mg group (41/64 [64.1%]) compared with the placebo group (15/58 [25.9%]) rated the study medication as "good" or "excellent" ≥ 2 hours after the additional dose (P < 0.0001). Pain intensity (VAS) 2 hours after the additional dose was significantly higher in the placebo group than in the celecoxib 200 mg group (P = 0.0003). The reduction in pain intensity from baseline to 2 hours after the additional dose of study medication was also significantly greater in the celecoxib 200 mg group than in the placebo group (P < 0.0001). The incidence of treatment-related, all-cause adverse events was slightly lower in patients receiving celecoxib 200 mg (20.3%) compared with placebo (31.0%). Overall, an additional 200-mg dose of celecoxib was well tolerated and efficacious in reducing the pain associated with extraction of an impacted third mandibular molar in the study population. ClinicalTrials.gov identifier: NCT01062113. Copyright © 2012 Elsevier HS Journals, Inc. All rights reserved.

Nickel-regulated heart rate variability: The roles of oxidative stress and inflammation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chuang, Hsiao-Chi, E-mail: r92841005@ntu.edu.tw; Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan; Hsueh, Tzu-Wei, E-mail: r95841015@ntu.edu.tw

Heart rate variability (HRV) has been reported to be a putative marker of cardiac autonomic imbalance caused by exposure to ambient particulate matter (PM). Our objective in this study was to determine the effects on HRV from exposure to nickel, an important chemical component of ambient PM that results in oxidative stress and inflammation. HRV data were collected for 72 h before lung exposure (baseline) and 72 h after intratracheal exposure (response) to nickel sulphate (NiSO{sub 4}; 526 μg) in Wistar Kyoto (WKY) and spontaneously hypertensive (SH) rats. The antioxidant N-acetyl-L-cysteine (NAC) and the anti-inflammatory celecoxib were intraperitoneally injected tomore » examine post-exposure oxidative and inflammatory responses. Self-controlled experiments examined the effects of NiSO{sub 4} exposure on average normal-to-normal intervals (ANN), natural logarithm-transformed standard deviation of the normal-to-normal intervals (LnSDNN) and root mean square of successive differences of adjacent normal-to-normal intervals (LnRMSSD); the resulting data were sequentially analysed using the generalised estimating equation model. HRV effects on NiSO{sub 4}-exposed SH rats were greater than those on NiSO{sub 4}-exposed WKY rats. After adjusted the HRV responses in the WKY rats as control, ANN and LnRMSSD were found to be quadratically increased over 72 h after exposure to NiSO{sub 4}. Both NAC and celecoxib mitigated the NiSO{sub 4}-induced alterations in HRV during the exposure period. The results suggest that concurrent Ni-induced oxidative stress and inflammatory responses play important roles in regulating HRV. These findings help bridge the gap between epidemiological and clinical studies on the plausible mechanisms of the cardiovascular consequences induced by chemical components in ambient PM. -- Highlights: ► To determine the effects on HRV from exposure to nickel. ► ANN and LnRMSSD were found to be quadratically increased after exposure to Ni. ► NAC and celecoxib mitigated the Ni-induced alterations in HRV. ► Ni-induced oxidative stress and inflammation play the roles in regulating HRV.« less

Divergent effects of new cyclooxygenase inhibitors on gastric ulcer healing: Shifting the angiogenic balance

PubMed Central

Ma, Li; del Soldato, Piero; Wallace, John L.

2002-01-01

Delayed gastric ulcer healing is a well recognized problem associated with the use of cyclooxygenase (COX) inhibitors. In contrast, NO-releasing COX inhibitors do not interfere with ulcer healing. These divergent effects may in part be due to differences in their effects on platelets, which are known to influence ulcer healing. Therefore, we compared the effects of a nonselective COX inhibitor (flurbiprofen), a nitric oxide-releasing COX inhibitor (HCT-1026), and a selective COX-2 inhibitor (celecoxib) on gastric ulcer healing, angiogenesis, and platelet/serum levels of vascular endothelial growth factor (VEGF) and endostatin. Gastric ulcers were induced in rats by serosal application of acetic acid. Daily treatment with the test drugs was started 3 days later and continued for 1 week. Celecoxib and flurbiprofen impaired angiogenesis and delayed ulcer healing, as well as increasing serum endostatin levels relative to those of VEGF. HCT-1026 did not delay ulcer healing nor impair angiogenesis, and also did not change the ratio of serum endostatin to VEGF. Incubation of human umbilical vein endothelial cells with serum from celecoxib- or flurbiprofen-treated rats resulted in suppressed proliferation and increased apoptosis, effects that were reversed by an antiendostatin antibody. These results demonstrate a previously unrecognized mechanism through which nonsteroidal antiinflammatory drugs can delay ulcer healing, namely, through altering the balance of anti- and proangiogenic factors in the serum. The absence of a delaying effect of HCT-1026 on ulcer healing may be related to the maintenance of a more favorable balance in serum levels of pro- and antiangiogenic growth factors. PMID:12232050

The effectiveness of cyclooxygenase-2 inhibitors and evaluation of angiogenesis in the model of experimental colorectal cancer.

PubMed

Gungor, Hilal; Ilhan, Nevin; Eroksuz, Hatice

2018-06-01

Colorectal cancer (CRC) is an important cause of cancer-related deaths worldwide. Early diagnosis and treatment of CRCs are of importance for improving the survival. In the present study, we studied the effects of nonsteroidal anti-inflammatory drugs (NSAIDs)-induced chemopreventive effects on tumor development incidence and angiogenesis in experimental CRC rats. 1,2-Dimethylhydrazine dihydrochloride (DMH) was used as cancer-inducing agent and two NSAIDs (celecoxib and diclofenac) were given orally as chemopreventive agents. Histopathological and immuno histochemical evaluations were performed in colorectal tissue samples, whereas angiogenesis parameters were studied in blood samples. Histopathological examination showed that adenocarcinoma (62.5%), dysplastic changes (31.25%) and inflammattory changes (6.25%) were detected in DMH group, whereas no pathological change was observed in control rats. In treatment groups, there was marked decrease in adenocarcinoma rate (30% and 10%, respectively). A significant increase was detected in MMP-2, MMP-9 levels and MMP-2/TIMP-2 ratio in DMH group as compared with controls and treatment groups. In immunohistochemical evaluations, there was an increase in intensity and extent of staining of MMP-2 and MMP-9 in DMH group as compared to controls and treatment groups. The decrease in celecoxib group was more prominent. Overall, it was concluded that NSAIDs, particularly cyclooxygenase-2 (COX-2) inhibitors, might have a protective effect on CRC development and slow down progression of tumor in a DMH-induced experimental cancer model. One of the possible mechanisms in the chemoprevention of colon cancer seems to be inhibition of angiogenesis by diclofenac and celecoxib. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Celecoxib exerts protective effects in the vascular endothelium via COX-2-independent activation of AMPK-CREB-Nrf2 signalling.

PubMed

Al-Rashed, Fahad; Calay, Damien; Lang, Marie; Thornton, Clare C; Bauer, Andrea; Kiprianos, Allan; Haskard, Dorian O; Seneviratne, Anusha; Boyle, Joseph J; Schönthal, Alex H; Wheeler-Jones, Caroline P; Mason, Justin C

2018-04-19

Although concern remains about the athero-thrombotic risk posed by cyclo-oxygenase (COX)-2-selective inhibitors, recent data implicates rofecoxib, while celecoxib appears equivalent to NSAIDs naproxen and ibuprofen. We investigated the hypothesis that celecoxib activates AMP kinase (AMPK) signalling to enhance vascular endothelial protection. In human arterial and venous endothelial cells (EC), and in contrast to ibuprofen and naproxen, celecoxib induced the protective protein heme oxygenase-1 (HO-1). Celecoxib derivative 2,5-dimethyl-celecoxib (DMC) which lacks COX-2 inhibition also upregulated HO-1, implicating a COX-2-independent mechanism. Celecoxib activated AMPKα (Thr172) and CREB-1 (Ser133) phosphorylation leading to Nrf2 nuclear translocation. Importantly, these responses were not reproduced by ibuprofen or naproxen, while AMPKα silencing abrogated celecoxib-mediated CREB and Nrf2 activation. Moreover, celecoxib induced H-ferritin via the same pathway, and increased HO-1 and H-ferritin in the aortic endothelium of mice fed celecoxib (1000 ppm) or control chow. Functionally, celecoxib inhibited TNF-α-induced NF-κB p65 (Ser536) phosphorylation by activating AMPK. This attenuated VCAM-1 upregulation via induction of HO-1, a response reproduced by DMC but not ibuprofen or naproxen. Similarly, celecoxib prevented IL-1β-mediated induction of IL-6. Celecoxib enhances vascular protection via AMPK-CREB-Nrf2 signalling, a mechanism which may mitigate cardiovascular risk in patients prescribed celecoxib. Understanding NSAID heterogeneity and COX-2-independent signalling will ultimately lead to safer anti-inflammatory drugs.

The anti-inflammatory effects of Yunnan Baiyao are involved in regulation of the phospholipase A2/arachidonic acid metabolites pathways in acute inflammation rat model.

PubMed

Ren, Xiaobin; Zhang, Mingzhu; Chen, Lingxiang; Zhang, Wanli; Huang, Yu; Luo, Huazhen; Li, Ling; He, Hongbing

2017-10-01

The traditional Chinese medicine Yunnan Baiyao (YNB) has been reported to possess anti‑inflammatory properties, however its mechanism of action remains unclear. It was previously reported that YNB ameliorated depression of arachidonic acid (AA) levels in a rat model of collagen-induced arthritis. In the current study, the capacity of YNB to ameliorate inflammation was compared in carrageenan‑induced and AA‑induced acute inflammation of the rat paw with celecoxib and mizolastine, respectively (n=24 per group). The capacity of YNB to affect the phospholipase A2 (PLA2)/AA pathway (using reverse transcription‑quantitative polymerase chain reaction) and release of inflammatory lipid mediators (by ELISA) were investigated. Celecoxib ameliorated carrageenan‑induced paw edema, and mizolastine ameliorated AA‑induced rat paw edema. YNB alleviated paw edema and inhibited inflammatory cell infiltration in the two models. YNB inhibited production of 5‑LOX AA metabolite leukotriene B4 (LTB4), and suppressed expression of 5‑LOX, cytosolic PLA2 (cPLA2), 5‑LOX‑activating protein, and LTB4 receptor mRNA in the AA‑induced inflammation model (P<0.05). YNB Inhibited the production of the COX‑2 AA metabolite prostaglandin E2 (PGE2) and suppressed expression of COX‑2, cPLA2, PGE2 mRNA in the carrageenan‑induced inflammation mode (P<0.05). Taken together, the data suggest that modulation of COX and LOX pathways in AA metabolism represent a novel anti-inflammatory mechanism of YNB.

Interaction of celecoxib with membranes: the role of membrane biophysics on its therapeutic and toxic effects.

PubMed

Pereira-Leite, Catarina; Nunes, Cláudia; Lima, José L F C; Reis, Salette; Lúcio, Marlene

2012-11-26

The present work provides a biophysical characterization of the interaction of celecoxib, a cyclo-oxigenase-2 selective nonsteroidal anti-inflammatory drug, with membranes using liposomes, constituted by phosphatidylcholines, as membrane model systems. In order to mimic biological conditions, the experiments were performed at physiological pH (7.4); at an acidic pH to mimic the conditions of the inflamed cells (5.0); and at different membrane physical states (gel, ripple, and fluid phase). Important information regarding the celecoxib-membrane interactions was gathered by the complementary biophysical techniques: derivative spectrophotometry was used to determine liposome/water partition coefficient of celecoxib; dynamic light scattering (DLS) measurements were performed to study the influence of celecoxib on lipid main phase transition temperature; fluorescence binding measurements were made to assess the location of celecoxib within the membrane; and small-angle and wide-angle X-ray scattering (SAXS and WAXS) were used to assess the changes in the structure and order of phosphatidylcholine bilayers caused by the presence of celecoxib. The overall results obtained indicate that celecoxib greatly interacts with membranes. Briefly, celecoxib exhibits a high liposome/water partition coefficient that is non-pH-dependent, but the location of celecoxib within the membrane is pH-dependent. In fact, celecoxib is more deeply located inside the membrane at pH 5.0, while it locates closer to the surface at pH 7.4. DLS, SAXS, and WAXS results have shown a high membrane fluidization in the presence of celecoxib, especially at pH 7.4. Overall, the current study can contribute to a biophysical characterization of the celecoxib-membrane interaction. The relevance of the gathered results will be discussed in terms of the reported celecoxib therapeutic and toxic effects.

Caffeine: a potential complexing agent for solubility and dissolution enhancement of celecoxib.

PubMed

Shakeel, Faiyaz; Faisal, Mohammed S

2010-01-01

Complexation of caffeine with the drug celecoxib was used to enhance its solubility as well as in vitro dissolution in the present investigation. Caffeine was extracted from tea leaves using the sublimation method. A molecular complex (1:1) of caffeine-celecoxib was prepared using the solubility method. The solubility of celecoxib in distilled water and the caffeine complex was determined using a HPLC method at a wavelength of 250 nm. Dissolution studies of pure celecoxib, a marketed capsule (Celebrex), and the complex were performed using USP dissolution apparatus I for pure celecoxib and the complex and apparatus II for the capsule in distilled water. The highest solubility (48.32 mg/mL) as well as percent dissolution (90.54%) of celecoxib was obtained with the caffeine-celecoxib complex. The results for solubility and dissolution were highly significant as compared to pure celecoxib and the marketed capsule (p < 0.01). These results suggest that caffeine is a promising complexing agent for solubility as well as dissolution enhancement of the poorly soluble drug celecoxib.

Evening primrose oil or forskolin ameliorates celecoxib-enhanced upregulation of tissue factor expression in mice subjected to lipopolysaccharide-induced endotoxemia.

PubMed

Mosaad, Sarah M; Zaitone, Sawsan A; Ahmed, Amal A M; Abo-Elmatty, Dina M; El-Baz, Amani A; Moustafa, Yasser M

2017-05-01

Celecoxib, a selective cyclooxygenase-2 inhibitor, produces thrombotic events in patients predisposed to cardiovascular risk factors. One theory reported an increase in endothelial expression of tissue factor (TF) as a predisposing factor. This work explored the effect of evening primrose oil (EPO), a source of prostaglandin E1, and forskolin (a cyclic adenosine monophosphate stimulator) against the prothrombotic effect of celecoxib in mice. Lipopolysaccharide mouse model of endotoxemia was used to induce an upregulation of TF activity. Male mice received celecoxib (25 mg/kg), celecoxib plus EPO, or celecoxib plus forskolin for 4 weeks and then subjected to a prothrombotic challenge in the form of an intraperitoneal injection of lipopolysaccharide. Results showed an increase in plasma TF activity, endothelial TF expression, and thrombin-antithrombin (TAT) but lower antithrombin III (ATIII) level in mice that received celecoxib in comparison to those that received the vehicle. Adding EPO or forskolin to celecoxib regimen significantly decreased the prothrombotic effect of celecoxib. A positive correlation (r = 0.8501) was found between TF activity and TAT. Co-administration of EPO or forskolin decreased the activity of TF and mitigated the prothrombotic effect of celecoxib. Therefore, these combinations may have the utility to abrogate the prothrombotic adverse effect of celecoxib in clinical setting.

Withania coagulans Extract Induces Cell Apoptosis and Inhibits COX-2 Expression in a Rat Model of Benign Prostatic Hyperplasia

PubMed Central

Sarbishegi, Maryam; Khajavi, Ozra; Arab, Mohammad Reza

2016-01-01

Background Phytotherapy is a popular treatment option in cases of benign prostatic hyperplasia (BPH), with many different herbal products being used for the treatment of this condition. Withania coagulans (WC) is an herbal medicine that has shown anti-tumoral, anti-inflammatory, and antioxidant effects. Objectives This study examined the effect of Withania coagulans extract (WCE) on prostatic cell apoptosis and cyclooxygenase-2 (COX-2) expression in cases of benign prostatic hyperplasia (BPH) in rats. Methods Forty Wistar rats were equally divided into five groups: control, sham, BPH, BPH + WCE, and BPH + CLX (celecoxib) as a positive control group. The induction of BPH was achieved via the subcutaneous injection of 3 mg/kg of testosterone propionate (TP) daily for 28 days. The animals received WCE, celecoxib, or distilled water by oral gavage accompanied by the TP injection. After four weeks, the prostate glands of the rats were weighed to measure the prostatic index (PI). The ventral lobes of the prostates were dissected and processed with paraffin blocks in order to study the number of mast cells. A TUNEL analysis was performed to evaluate the cell apoptosis, while the expression of COX-2 was examined using immunohistochemistry. Results BPH was obvious in the ventral lobe of the prostate, and the administration of WCE markedly decreased the PI and the number of mast cells (P < 0.001) in the BPH rats. Additionally, the WCE treatment induced prostatic cell apoptosis when compared to the BPH group. Furthermore, following the WCE treatment, the expression of COX-2 in the prostatic tissues was significantly decreased when compared to the BPH groups. Conclusions According to the results of this study, WCE was effective in the treatment of BPH in rats. It may therefore have beneficial effects in the treatment of patients with BPH. PMID:27878112

Mechanism of generation of drug nanocrystals in celecoxib: mannitol nanocrystalline solid dispersion.

PubMed

Bhatt, Varun; Shete, Ganesh; Bansal, Arvind Kumar

2015-11-10

Objective of this work was to understand the mechanism of formation of celecoxib nanocrystals in celecoxib: mannitol nanocrystalline solid dispersion (NSD). Solution of celecoxib and mannitol was spray dried in 1:1 (g:g) proportion to obtain NSD, with average crystallite size of 214.07 ± 45.27 nm. Solubility parameters of celecoxib and mannitol were 23.1 MPa(1/2) and 38.5 MPa(1/2), respectively, hinting their immiscibility. Formation of nanocrystals during NanoCrySP proceeds via intermediate amorphous form of the drug. Earlier work from our lab on hesperetin-mannitol system, had underlined the role of plasticization of amorphous drug by excipient in the formation of nanocrystals. However, in present case, mannitol failed to plasticize amorphous celecoxib and Tg of amorphous celecoxib (56.8°C) showed a negligible change (54.8°C) in presence of mannitol. However, DSC data also suggested crystallization inducing potential of mannitol on amorphous celecoxib. Polarized light microscopy provided evidence that, mannitol facilitated heterogeneous nucleation of amorphous celecoxib at their interface. Transmission electron microscopy analysis suggested that, mannitol acted as a physical barrier to crystal growth of celecoxib crystallites. Thus, though mannitol did not plasticize amorphous celecoxib, it aided in nanocrystal generation by heterogeneous nucleation and providing physical barrier to crystal growth. Copyright © 2015 Elsevier B.V. All rights reserved.

Preparation and evaluation of celecoxib-loaded microcapsules with self-microemulsifying core.

PubMed

Homar, Miha; Dreu, Rok; Kerc, Janez; Gasperlin, Mirjana

2009-09-01

The purpose of this study was to prepare alginate microcapsules with a self-microemulsifying system (SMES) containing celecoxib in the core. An Inotech IE-50 R encapsulator equipped with a concentric nozzle was used to prepare the microcapsules. The encapsulated SMES was shown to increase celecoxib solubility over that of the pure drug more than 400-fold. Microcapsules prepared with a high SMES:celecoxib ratio exhibited distinct core vesicles containing liquid SMES. By modifying the SMES and including an additional chitosan coating, drug loading in the range from 12-40% could be achieved with the degree of encapsulation ranging from 60-82%. Alginate microcapsules loaded with SMES and celecoxib showed increased dissolution rate of celecoxib over that of alginate microcapsules loaded with celecoxib or of the celecoxib alone. Compared to the previous report, drug loading capacity was significantly improved, enabling the formulation of dosage forms which are of suitable size for peroral application.

Use of celecoxib correlates with increased relative risk of acute pancreatitis: a case-control study in Taiwan.

PubMed

Hung, Shih-Chang; Hung, Shih-Rong; Lin, Cheng-Li; Lai, Shih-Wei; Hung, Hung-Chang

2015-10-01

This study evaluated whether there is an association between the use of celecoxib and acute pancreatitis in Taiwan. We conducted a case-control study using the database of the Taiwan National Health Insurance Program. The participants comprised 5,095 subjects, aged 20-84 years, with a first admission episode of acute pancreatitis from 2000 to 2011 as the cases and 20,380 randomly selected sex-matched and age-matched subjects without acute pancreatitis as the controls. The absence of celecoxib prescription was defined as "never used." Current use of celecoxib was defined as subjects who had received at least one prescription for celecoxib within 3 days before diagnosis with acute pancreatitis. A multivariate unconditional logistic regression model was used to calculate the odds ratio (OR) and 95% confidence interval (CI) for acute pancreatitis associated with the use of celecoxib. Compared with subjects who never used celecoxib, the adjusted OR of acute pancreatitis was 5.62 in subjects with current use of celecoxib (95% CI=3.33-9.46). The current use of celecoxib is associated with an increased risk of acute pancreatitis.

Comparison of the effects of treatment with celecoxib, loxoprofen, and acetaminophen on postoperative acute pain after arthroscopic knee surgery: A randomized, parallel-group trial.

PubMed

Onda, Akira; Ogoshi, Atsuko; Itoh, Mieko; Nakagawa, Tomoyuki; Kimura, Masashi

2016-03-01

Selective cyclooxygenase-2 (COX-2) inhibitors, conventional non-selective nonsteroidal anti-inflammatory drugs (NSAIDs), and acetaminophen have been adopted for the relief of mild to moderate acute and chronic pain. However, it remains unclarified whether the therapeutic differences in pain sensation exist among these agents. The aim of this study was to compare the efficacy of different types of analgesic agents for postoperative acute pain management. A single-center, randomized, controlled study was performed in consecutive patients who underwent the second-look procedure with removal of internal fixation after anterior cruciate ligament reconstruction or arthroscopic meniscal repair/meniscectomy. Celecoxib (400 mg for the first dose and then 200 mg), loxoprofen (60 mg), or acetaminophen (600 mg) was orally administered from postoperative 3 h. The pain intensity on a 100-mm VAS scale and subjective assessment of therapeutic pain-relief were compared among these three treatment groups until postoperative 2 days. The acquired data were analyzed according to the per-protocol analysis principle. A total of 432 patients were screened, and 160 were enrolled. The VAS score tended to decrease over time in all groups. There was a significant improvement in the pain score both at rest and on movement, and subjective impression in the celecoxib-treated group compared with acetaminophen at postoperative 2 days. On the other hand, loxoprofen resulted in the benefit only in the pain score at rest in comparison with acetaminophen. Any comparisons between celecoxib and loxoprofen showed insignificant differences throughout observations. No adverse effects were confirmed in each group. These obtained findings in our dose setting conditions suggest that celecoxib and loxoprofen treatments were superior to acetaminophen in pain-relief, though the superiority of loxoprofen over acetaminophen was modest. Overall, selective COX-2 inhibitors including conventional NSAIDs seem to have a possible advantage in acute pain management of relatively less invasive surgery. Copyright © 2015 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.

Dual function of tributyrin emulsion: solubilization and enhancement of anticancer effect of celecoxib.

PubMed

Kang, Sung Nam; Hong, Soon-Seok; Lee, Mi-Kyung; Lim, Soo-Jeong

2012-05-30

Tributyrin, a triglyceride analogue of butyrate, can act as a prodrug of an anticancer agent butyrate after being cleaved by intracellular enzymes. We recently demonstrated that the emulsion containing tributyrin as an inner oil phase possesses a potent anticancer activity. Herein we sought to develop tributyrin emulsion as a carrier of celecoxib, a poorly-water soluble drug with anticancer activity. Combined treatment of human HCT116 colon cancer cells with free celecoxib plus tributyrin emulsion inhibited the cellular proliferation more effectively than that of each drug alone, suggesting the possibility of tributyrin emulsion as a potential celecoxib carrier. The mean droplet size of emulsions tended to increase as the tributyrin content in emulsion increases and the concentration of celecoxib loaded in emulsions was affected by tributyrin content and the initial amount of celecoxib, but not by the total amount of surfactant mixture. The concentration of celecoxib required to inhibit the growth of HCT116 and B16-F10 cancer cells by 50% was 2.6- and 3.1-fold lowered by loading celecoxib in tributyrin emulsions, compared with free celecoxib. These data suggest that the anticancer activity of celecoxib was enhanced by loading in tributyrin emulsions, probably due to the solubilization capacity and anticancer activity of tributyrin emulsion. Copyright © 2012 Elsevier B.V. All rights reserved.

Celecoxib-Induced Cytotoxic Effect Is Potentiated by Inhibition of Autophagy in Human Urothelial Carcinoma Cells

PubMed Central

Ho, I-Lin; Chang, Hong-Chiang; Chuang, Yuan-Ting; Lin, Wei-Chou; Lee, Ping-Yi; Chang, Shih-Chen; Chiang, Chih-Kang; Pu, Yeong-Shiau; Chou, Chien-Tso; Hsu, Chen-Hsun; Liu, Shing-Hwa

2013-01-01

Celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, can elicit anti-tumor effects in various malignancies. Here, we sought to clarify the role of autophagy in celecoxib-induced cytotoxicity in human urothelial carcinoma (UC) cells. The results shows celecoxib induced cellular stress response such as endoplasmic reticulum (ER) stress, phosopho-SAPK/JNK, and phosopho-c-Jun as well as autophagosome formation in UC cells. Inhibition of autophagy by 3-methyladenine (3-MA), bafilomycin A1 or ATG7 knockdown potentiated celecoxib-induced apoptosis. Up-regulation of autophagy by rapamycin or GFP-LC3B-transfection alleviated celecoxib-induced cytotoxicity in UC cells. Taken together, the inhibition of autophagy enhances therapeutic efficacy of celecoxib in UC cells, suggesting a novel therapeutic strategy against UC. PMID:24349176

Effects of celecoxib on proliferation and tenocytic differentiation of tendon-derived stem cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Kairui; Zhang, Sheng; Li, Qianqian

Highlights: • Celecoxib has no effects on TDSCs cell proliferation in various concentrations. • Celecoxib reduced mRNAs levels of tendon associated transcription factor. • Celecoxib reduced mRNAs levels of main tendon associated collagen. • Celecoxib reduced mRNAs levels of tendon associated molecules. - Abstract: NSAIDs are often ingested to reduce the pain and improve regeneration of tendon after tendon injury. Although the effects of NSAIDs in tendon healing have been reported, the data and conclusions are not consistent. Recently, tendon-derived stem cells (TDSCs) have been isolated from tendon tissues and has been suggested involved in tendon repair. Our study aimsmore » to determine the effects of COX-2 inhibitor (celecoxib) on the proliferation and tenocytic differentiation of TDSCs. TDSCs were isolated from mice Achilles tendon and exposed to celecoxib. Cell proliferation rate was investigated at various concentrations (0.1, 1, 10 and 100 μg/ml) of celecoxib by using hemocytometer. The mRNA expression of tendon associated transcription factors, tendon associated collagens and tendon associated molecules were determined by reverse transcription-polymerase chain reaction. The protein expression of Collagen I, Collagen III, Scleraxis and Tenomodulin were determined by Western blotting. The results showed that celecoxib has no effects on TDSCs cell proliferation in various concentrations (p > 0.05). The levels of most tendon associated transcription factors, tendon associated collagens and tendon associated molecules genes expression were significantly decreased in celecoxib (10 μg/ml) treated group (p < 0.05). Collagen I, Collagen III, Scleraxis and Tenomodulin protein expression were also significantly decreased in celecoxib (10 μg/ml) treated group (p < 0.05). In conclusion, celecoxib inhibits tenocytic differentiation of tendon-derived stem cells but has no effects on cell proliferation.« less

Ursodeoxycholic acid counteracts celecoxib in reduction of duodenal polyps in patients with familial adenomatous polyposis: a multicentre, randomized controlled trial

PubMed Central

2013-01-01

Background Due to prophylactic colectomy, mortality in patients with familial adenomatous polyposis (FAP) has changed, with duodenal cancer currently being the main cause of death. Although celecoxib reduces duodenal polyp density in patients with FAP, its long-term use may increase the risk of cardiovascular events and alternatives need to be explored. Preclinical studies suggest that the combination of celecoxib with ursodeoxycholic acid (UDCA) is a potentially effective strategy. We performed a randomized, double-blind, placebo-controlled trial to investigate the effect of celecoxib and UDCA co-treatment on duodenal adenomatosis in patients with FAP. Methods Patients with FAP received celecoxib (400 mg twice daily) and UDCA (1000-2000 mg daily, ~20-30 mg/kg/day, n=19) or celecoxib and placebo (n=18) orally for 6 months. Primary outcome was drug efficacy, assessed by comparing duodenal polyp density at pre- and post-intervention by blinded review of endoscopic recordings. As secondary outcomes, cell proliferation, apoptosis, and COX-2 levels in normal duodenal mucosa were assessed by immunohistochemistry or real-time quantitative polymerase chain reaction. Results In intention-to-treat analysis, deceased polyp density was observed after celecoxib/placebo treatment (p=0.029), whereas increased polyp density was observed after celecoxib/UDCA treatment (p=0.014). The difference in change in duodenal polyp density was statistically significant between the groups (p=0.011). No changes in secondary outcomes were observed. Thirty patients (81%) reported one or more adverse events, 16 patients (84%, Common Toxicity Criteria for Adverse Events version 3.0 (CTCAE) grade 1–3) treated with celecoxib/UDCA and 14 patients (78%, CTCAE grade 1–2) treated with celecoxib/placebo. Nine patients (24%) discontinued intervention prematurely, 5 patients (26%) treated with celecoxib/UDCA and 4 patients (22%) treated with celecoxib/placebo. Conclusions Celecoxib reduces duodenal polyp density in patients with FAP, and unexpectedly, high dose UDCA co-treatment counteracts this effect. The benefit of long term use of celecoxib for duodenal cancer prevention needs to be weighed against the (risk of) adverse events. Trial registration http://ClinicalTrials.gov, identifier NCT00808743 PMID:23919274

Development of spray-dried co-precipitate of amorphous celecoxib containing storage and compression stabilizers.

PubMed

Dhumal, Ravindra S; Shimpi, Shamkant L; Paradkar, Anant R

2007-09-01

The purpose of this study was to obtain an amorphous system with minimum unit operations that will prevent recrystallization of amorphous drugs since preparation, during processing (compression) and further storage. Amorphous celecoxib, solid dispersion (SD) of celecoxib with polyvinyl pyrrollidone (PVP) and co-precipitate with PVP and carrageenan (CAR) in different ratios were prepared by the spray drying technique and compressed into tablets. Saturation solubility and dissolution studies were performed to differentiate performance after processing. Differential scanning calorimetry and X-ray powder difraction revealed the amorphous form of celecoxib, whereas infrared spectroscopy revealed hydrogen bonding between celecoxib and PVP. The dissolution profile of the solid dispersion and co-precipitate improved compared to celecoxib and amorphous celecoxib. Amorphous celecoxib was not stable on storage whereas the solid dispersion and co-precipitate powders were stable for 3 months. Tablets of the solid dispersion of celecoxib with PVP and physical mixture with PVP and carrageenan showed better resistance to recrystallization than amorphous celecoxib during compression but recrystallized on storage. However, tablets of co-precipitate with PVP and carageenan showed no evidence of crystallinity during stability studies with comparable dissolution profiles. This extraordinary stability of spray-dried co-precipitate tablets may be attributed to the cushioning action provided by the viscoelastic polymer CAR and hydrogen bonding interaction between celecoxib and PVP. The present study demonstrates the synergistic effect of combining two types of stabilizers, PVP and CAR, on the stability of amorphous drug during compression and storage as compared to their effect when used alone.

Chemoprevention of Nonmelanoma Skin Cancer With Celecoxib: A Randomized, Double-Blind, Placebo-Controlled Trial

PubMed Central

Viner, Jaye L.; Pentland, Alice P.; Cantrell, Wendy; Bailey, Howard; Kang, Sewon; Linden, Kenneth G.; Heffernan, Michael; Duvic, Madeleine; Richmond, Ellen; Elewski, Boni E.; Umar, Asad; Bell, Walter; Gordon, Gary B.

2010-01-01

Background Preclinical studies indicate that the enzyme cyclooxygenase 2 plays an important role in ultraviolet-induced skin cancers. We evaluated the efficacy and safety of celecoxib, a cyclooxygenase 2 inhibitor, as a chemopreventive agent for actinic keratoses, the premalignant precursor of nonmelanoma skin cancers, and for nonmelanoma skin cancers, including cutaneous squamous cell carcinomas (SCCs) and basal cell carcinomas (BCCs). Methods A double-blind placebo-controlled randomized trial involving 240 subjects aged 37–87 years with 10–40 actinic keratoses was conducted at eight US academic medical centers. Patients were randomly assigned to receive 200 mg of celecoxib or placebo administered orally twice daily for 9 months. Subjects were evaluated at 3, 6, 9 (ie, completion of treatment), and 11 months after randomization. The primary endpoint was the number of new actinic keratoses at the 9-month visit as a percentage of the number at the time of randomization. In an intent-to-treat analysis, the incidence of actinic keratoses was compared between the two groups using t tests. In exploratory analyses, we evaluated the number of nonmelanoma skin cancers combined and SCCs and BCCs separately per patient at 11 months after randomization using Poisson regression, after adjustment for patient characteristics and time on study. The numbers of adverse events in the two treatment arms were compared using χ2 or Fisher exact tests. All statistical tests were two-sided. Results There was no difference in the incidence of actinic keratoses between the two groups at 9 months after randomization. However, at 11 months after randomization, there were fewer nonmelanoma skin cancers in the celecoxib arm than in the placebo arm (mean cumulative tumor number per patient 0.14 vs 0.35; rate ratio [RR] = .43, 95% confidence interval [CI] = 0.24 to 0.75; P = .003). After adjusting for age, sex, Fitzpatrick skin type, history of actinic keratosis at randomization, nonmelanoma skin cancer history, and patient time on study, the number of nonmelanoma skin cancers was lower in the celecoxib arm than in the placebo arm (RR = 0.41, 95% CI = 0.23 to 0.72, P = .002) as were the numbers of BCCs (RR = 0.40, 95% CI = 0.18 to 0.93, P = .032) and SCCs (RR = 0.42, 95% CI = 0.19 to 0.93, P = .032). Serious and cardiovascular adverse events were similar in the two groups. Conclusions Celecoxib may be effective for prevention of SCCs and BCCs in individuals who have extensive actinic damage and are at high risk for development of nonmelanoma skin cancers. PMID:21115882

Levetiracetam interacts synergistically with nonsteroidal analgesics and caffeine to produce antihyperalgesia in rats.

PubMed

Tomić, Maja A; Micov, Ana M; Stepanović-Petrović, Radica M

2013-11-01

Levetiracetam is a novel anticonvulsant with antihyperalgesic efficacy in inflammatory pain. Nonsteroidal analgesics and caffeine, as analgesic adjuvant, are widely used against inflammatory pain. This study characterized the manner in which levetiracetam interacts with analgesics (ibuprofen, celecoxib, and paracetamol) and caffeine to suppress hyperalgesia in a model of localized inflammation. Rat paw inflammation was induced by intraplantar carrageenan (.1 mL, 1%). Hyperalgesia and antihyperalgesic effects of levetiracetam (orally), analgesics (orally), and caffeine (intraperitoneally) alone and 2-drug combinations of levetiracetam with analgesics or caffeine were examined by a modified paw pressure test. The type of interaction between components was determined by isobolographic analysis or by analysis of the log dose-response curves for drug combination and drugs alone. Levetiracetam (10-200 mg/kg), ibuprofen (12.5-100 mg/kg), celecoxib (3.75-30 mg/kg), paracetamol (50-200 mg/kg), caffeine (15-100 mg/kg), and 2-drug combinations of levetiracetam with analgesics/caffeine produced a significant, dose-dependent reduction of inflammatory hyperalgesia. Isobolographic analysis revealed that levetiracetam exerts a synergistic interaction with analgesics, with approximately 7-, 9-, and 11-fold reduction of doses of both drugs in combination of levetiracetam with paracetamol, celecoxib, and ibuprofen, respectively. Analysis of the log dose-response curves for levetiracetam (1-50 mg/kg) in the presence of caffeine (10 mg/kg) and levetiracetam applied alone also revealed a synergistic interaction. Levetiracetam's ED50 in the presence of caffeine was reduced approximately 11-fold. The presented data suggest that 2-drug combinations of levetiracetam and nonsteroidal analgesics or caffeine could be useful in treatment of inflammatory pain. The efficacy and the adverse effects of those mixtures should be explored further in clinical settings. Copyright © 2013 American Pain Society. Published by Elsevier Inc. All rights reserved.

Celecoxib enhances radiosensitivity of hypoxic glioblastoma cells through endoplasmic reticulum stress

PubMed Central

Suzuki, Kenshi; Gerelchuluun, Ariungerel; Hong, Zhengshan; Sun, Lue; Zenkoh, Junko; Moritake, Takashi; Tsuboi, Koji

2013-01-01

Background Refractoriness of glioblastoma multiforme (GBM) largely depends on its radioresistance. We investigated the radiosensitizing effects of celecoxib on GBM cell lines under both normoxic and hypoxic conditions. Methods Two human GBM cell lines, U87MG and U251MG, and a mouse GBM cell line, GL261, were treated with celecoxib or γ-irradiation either alone or in combination under normoxic and hypoxic conditions. Radiosensitizing effects were analyzed by clonogenic survival assays and cell growth assays and by assessing apoptosis and autophagy. Expression of apoptosis-, autophagy-, and endoplasmic reticulum (ER) stress–related genes was analyzed by immunoblotting. Results Celecoxib significantly enhanced the radiosensitivity of GBM cells under both normoxic and hypoxic conditions. In addition, combined treatment with celecoxib and γ-irradiation induced marked autophagy, particularly in hypoxic cells. The mechanism underlying the radiosensitizing effect of celecoxib was determined to be ER stress loading on GBM cells. Conclusion Celecoxib enhances the radiosensitivity of GBM cells by a mechanism that is different from cyclooxygenase-2 inhibition. Our results indicate that celecoxib may be a promising radiosensitizing drug for clinical use in patients with GBM. PMID:23658321

Nitric oxide-releasing aspirin but not conventional aspirin improves healing of experimental colitis

PubMed Central

Zwolinska-Wcislo, Malgorzata; Brzozowski, Tomasz; Ptak-Belowska, Agata; Targosz, Aneta; Urbanczyk, Katarzyna; Kwiecien, Slawomir; Sliwowski, Zbigniew

2011-01-01

AIM: To determine the effect of non-selective cyclooxygenase (COX) inhibitors, selective COX-2 inhibitors and nitric oxide (NO)-releasing aspirin in the healing of ulcerative colitis. METHODS: Rats with 2,4,6 trinitrobenzenesulfon-ic acid (TNBS)-induced colitis received intragastric (ig) treatment with vehicle, aspirin (ASA) (a non-selective COX inhibitor), celecoxib (a selective COX-2 inhibitor) or NO-releasing ASA for a period of ten days. The area of colonic lesions, colonic blood flow (CBF), myeloperoxidase (MPO) activity and expression of proinflammatory markers COX-2, inducible form of nitric oxide synthase (iNOS), IL-1β and tumor necrosis factor (TNF)-α were assessed. The effects of glyceryl trinitrate (GTN), a NO donor, and 2-(4-carboxyphenyl)-4,5-dihydro-4,4,5,5-​tetramethyl-1H-imidazolyl-1-oxy-3-oxide, onopotassium salt (carboxy-PTIO), a NO scavenger, administered without and with ASA or NO-ASA, and the involvement of capsaicin-sensitive afferent nerves in the mechanism of healing the experimental colitis was also determined. RESULTS: Rats with colitis developed macroscopic and microscopic colonic lesions accompanied by a significant decrease in the CBF, a significant rise in colonic weight, MPO activity and plasma IL-1β and TNF-α levels. These effects were aggravated by ASA and 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole (SC-560), but not celecoxib and counteracted by concurrent treatment with a synthetic prostaglandin E2 (PGE2) analog. Treatment with NO-ASA dose-dependently accelerated colonic healing followed by a rise in plasma NOx content and CBF, suppression of MPO and downregulation of COX-2, iNOS, IL-1β and TNF-α mRNAs. Treatment with GTN, the NO donor, significantly inhibited the ASA-induced colonic lesions and increased CBF, while carboxy-PTIO or capsaicin-denervation counteracted the NO-ASA-induced improvement of colonic healing and the accompanying increase in the CBF. These effects were restored by co-treatment with calcitonin gene related peptide (CGRP) and NO-ASA in capsaicin-denervated animals. CONCLUSION: NO-releasing ASA, in contrast to ASA, COX-1 inhibitors, and SC-560, accelerated the healing of colitis via a mechanism involving NO mediated improvement of microcirculation and activation of sensory nerves releasing CGRP. PMID:22039321

Celecoxib increases lung cancer cell lysis by lymphokine-activated killer cells via upregulation of ICAM-1.

PubMed

Schellhorn, Melina; Haustein, Maria; Frank, Marcus; Linnebacher, Michael; Hinz, Burkhard

2015-11-17

The antitumorigenic mechanism of the selective cyclooxygenase-2 (COX-2) inhibitor celecoxib is still a matter of debate. Using lung cancer cell lines (A549, H460) and metastatic cells derived from a lung cancer patient, the present study investigates the impact of celecoxib on the expression of intercellular adhesion molecule 1 (ICAM-1) and cancer cell lysis by lymphokine-activated killer (LAK) cells. Celecoxib, but not other structurally related selective COX-2 inhibitors (i.e., etoricoxib, rofecoxib, valdecoxib), was found to cause a substantial upregulation of ICAM-1 protein levels. Likewise, ICAM-1 mRNA expression was increased by celecoxib. Celecoxib enhanced the susceptibility of cancer cells to be lysed by LAK cells with the respective effect being reversed by a neutralizing ICAM-1 antibody. In addition, enhanced killing of celecoxib-treated cancer cells was reversed by preincubation of LAK cells with an antibody to lymphocyte function associated antigen 1 (LFA-1), suggesting intercellular ICAM-1/LFA-1 crosslink as crucial event within this process. Finally, celecoxib elicited no significant increase of LAK cell-mediated lysis of non-tumor bronchial epithelial cells, BEAS-2B, associated with a far less ICAM-1 induction as compared to cancer cells. Altogether, our data demonstrate celecoxib-induced upregulation of ICAM-1 on lung cancer cells to be responsible for intercellular ICAM-1/LFA-1 crosslink that confers increased cancer cell lysis by LAK cells. These findings provide proof for a novel antitumorigenic mechanism of celecoxib.

Celecoxib increases lung cancer cell lysis by lymphokine-activated killer cells via upregulation of ICAM-1

PubMed Central

Frank, Marcus; Linnebacher, Michael; Hinz, Burkhard

2015-01-01

The antitumorigenic mechanism of the selective cyclooxygenase-2 (COX-2) inhibitor celecoxib is still a matter of debate. Using lung cancer cell lines (A549, H460) and metastatic cells derived from a lung cancer patient, the present study investigates the impact of celecoxib on the expression of intercellular adhesion molecule 1 (ICAM-1) and cancer cell lysis by lymphokine-activated killer (LAK) cells. Celecoxib, but not other structurally related selective COX-2 inhibitors (i.e., etoricoxib, rofecoxib, valdecoxib), was found to cause a substantial upregulation of ICAM-1 protein levels. Likewise, ICAM-1 mRNA expression was increased by celecoxib. Celecoxib enhanced the susceptibility of cancer cells to be lysed by LAK cells with the respective effect being reversed by a neutralizing ICAM-1 antibody. In addition, enhanced killing of celecoxib-treated cancer cells was reversed by preincubation of LAK cells with an antibody to lymphocyte function associated antigen 1 (LFA-1), suggesting intercellular ICAM-1/LFA-1 crosslink as crucial event within this process. Finally, celecoxib elicited no significant increase of LAK cell-mediated lysis of non-tumor bronchial epithelial cells, BEAS-2B, associated with a far less ICAM-1 induction as compared to cancer cells. Altogether, our data demonstrate celecoxib-induced upregulation of ICAM-1 on lung cancer cells to be responsible for intercellular ICAM-1/LFA-1 crosslink that confers increased cancer cell lysis by LAK cells. These findings provide proof for a novel antitumorigenic mechanism of celecoxib. PMID:26513172

Down-Regulation of Glucose-Regulated Protein (GRP) 78 Potentiates Cytotoxic Effect of Celecoxib in Human Urothelial Carcinoma Cells

PubMed Central

Huang, Kuo-How; Kuo, Kuan-Lin; Chen, Shyh-Chyan; Weng, Te-I; Chuang, Yuan-Ting; Tsai, Yu-Chieh; Pu, Yeong-Shiau; Chiang, Chih-Kang; Liu, Shing-Hwa

2012-01-01

Celecoxib is a selective cyclooxygenase-2 (COX-2) inhibitor that has been reported to elicit anti-proliferative response in various tumors. In this study, we aim to investigate the antitumor effect of celecoxib on urothelial carcinoma (UC) cells and the role endoplasmic reticulum (ER) stress plays in celecoxib-induced cytotoxicity. The cytotoxic effects were measured by MTT assay and flow cytometry. The cell cycle progression and ER stress-associated molecules were examined by Western blot and flow cytometry. Moreover, the cytotoxic effects of celecoxib combined with glucose-regulated protein (GRP) 78 knockdown (siRNA), (−)-epigallocatechin gallate (EGCG) or MG132 were assessed. We demonstrated that celecoxib markedly reduces the cell viability and causes apoptosis in human UC cells through cell cycle G1 arrest. Celecoxib possessed the ability to activate ER stress-related chaperones (IRE-1α and GRP78), caspase-4, and CCAAT/enhancer binding protein homologous protein (CHOP), which were involved in UC cell apoptosis. Down-regulation of GRP78 by siRNA, co-treatment with EGCG (a GRP78 inhibitor) or with MG132 (a proteasome inhibitor) could enhance celecoxib-induced apoptosis. We concluded that celecoxib induces cell cycle G1 arrest, ER stress, and eventually apoptosis in human UC cells. The down-regulation of ER chaperone GRP78 by siRNA, EGCG, or proteosome inhibitor potentiated the cytotoxicity of celecoxib in UC cells. These findings provide a new treatment strategy against UC. PMID:22438966

Antitumor effect of the selective COX-2 inhibitor celecoxib on endometrial adenocarcinoma in vitro and in vivo

PubMed Central

XIAO, YITAO; TENG, YINCHENG; ZHANG, RUI; LUO, LAIMIN

2012-01-01

The aim of this study was to investigate the antitumor effect of the selective cyclooxygenase-2 (COX-2) inhibitor celecoxib on endometrial adenocarcinoma in mice. Various amounts of celecoxib were added to HEC-1B cells in vitro for different durations. Cell cycle and apoptosis were analyzed using flow cytometry. HEC-1B cytostasis, invasiveness and COX-2 expression were examined by MTT, transwell cabin and western blot assays, respectively. An in vivo human endometrial adenocarcinoma model was established in BALB/c nude mice using HEC-1B cells. For two weeks, the celecoxib groups were treated with celecoxib 2 or 4 mg/day via oral administration and the control group was treated with saline. Tumor volume, growth curves and the inhibition rate (IR) were recorded. COX-2 expression levels and microvessel density (MVD) were investigated using an immunohistochemical technique. In the celecoxib groups, cell proliferation was significantly inhibited in a concentration- and time-dependent manner. The proportion of cells in the G0/G1 phase increased within 24 h after the addition of celecoxib whereas those in the S and G2/M phases decreased with an increasing apoptosis peak (sub-G1) and apoptosis rate. The microporous Matrigel-coated polycarbonate membrane of the Transwell cabin was traversable for the HEC-1B cells. The invasiveness was attenuated when the celecoxib concentration was increased. The tumor growth was also greatly inhibited when the celecoxib concentration was increased. The tumor IRs were 32.4 and 48.6% following treatment with 2 and 4 mg/day celecoxib, respectively. COX-2 was mainly expressed in the cytoplasm of the tumor cells. In the celecoxib groups, the COX-2 expression levels were concentration-dependent. The COX-2 expression level and MVD decreased when the celecoxib concentration was increased. The results of dependability analysis revealed that the COX-2 expression level was positively correlated with MVD (r=0.921; P<0.01). The antitumor effect of celecoxib on endometrial adenocarcinoma in nude mice may be related to the inhibition of COX-2 expression and microangiogenesis. PMID:23226798

Cardiovascular Safety of Celecoxib, Naproxen, or Ibuprofen for Arthritis.

PubMed

Nissen, Steven E; Yeomans, Neville D; Solomon, Daniel H; Lüscher, Thomas F; Libby, Peter; Husni, M Elaine; Graham, David Y; Borer, Jeffrey S; Wisniewski, Lisa M; Wolski, Katherine E; Wang, Qiuqing; Menon, Venu; Ruschitzka, Frank; Gaffney, Michael; Beckerman, Bruce; Berger, Manuela F; Bao, Weihang; Lincoff, A Michael

2016-12-29

The cardiovascular safety of celecoxib, as compared with nonselective nonsteroidal antiinflammatory drugs (NSAIDs), remains uncertain. Patients who required NSAIDs for osteoarthritis or rheumatoid arthritis and were at increased cardiovascular risk were randomly assigned to receive celecoxib, ibuprofen, or naproxen. The goal of the trial was to assess the noninferiority of celecoxib with regard to the primary composite outcome of cardiovascular death (including hemorrhagic death), nonfatal myocardial infarction, or nonfatal stroke. Noninferiority required a hazard ratio of 1.12 or lower, as well as an upper 97.5% confidence limit of 1.33 or lower in the intention-to-treat population and of 1.40 or lower in the on-treatment population. Gastrointestinal and renal outcomes were also adjudicated. A total of 24,081 patients were randomly assigned to the celecoxib group (mean [±SD] daily dose, 209±37 mg), the naproxen group (852±103 mg), or the ibuprofen group (2045±246 mg) for a mean treatment duration of 20.3±16.0 months and a mean follow-up period of 34.1±13.4 months. During the trial, 68.8% of the patients stopped taking the study drug, and 27.4% of the patients discontinued follow-up. In the intention-to-treat analyses, a primary outcome event occurred in 188 patients in the celecoxib group (2.3%), 201 patients in the naproxen group (2.5%), and 218 patients in the ibuprofen group (2.7%) (hazard ratio for celecoxib vs. naproxen, 0.93; 95% confidence interval [CI], 0.76 to 1.13; hazard ratio for celecoxib vs. ibuprofen, 0.85; 95% CI, 0.70 to 1.04; P<0.001 for noninferiority in both comparisons). In the on-treatment analysis, a primary outcome event occurred in 134 patients in the celecoxib group (1.7%), 144 patients in the naproxen group (1.8%), and 155 patients in the ibuprofen group (1.9%) (hazard ratio for celecoxib vs. naproxen, 0.90; 95% CI, 0.71 to 1.15; hazard ratio for celecoxib vs. ibuprofen, 0.81; 95% CI, 0.65 to 1.02; P<0.001 for noninferiority in both comparisons). The risk of gastrointestinal events was significantly lower with celecoxib than with naproxen (P=0.01) or ibuprofen (P=0.002); the risk of renal events was significantly lower with celecoxib than with ibuprofen (P=0.004) but was not significantly lower with celecoxib than with naproxen (P=0.19). At moderate doses, celecoxib was found to be noninferior to ibuprofen or naproxen with regard to cardiovascular safety. (Funded by Pfizer; ClinicalTrials.gov number, NCT00346216 .).

Celecoxib promotes c-FLIP degradation through Akt-independent inhibition of GSK3.

PubMed

Chen, Shuzhen; Cao, Wei; Yue, Ping; Hao, Chunhai; Khuri, Fadlo R; Sun, Shi-Yong

2011-10-01

Celecoxib is a COX-2 inhibitor that reduces the risk of colon cancer. However, the basis for its cancer chemopreventive activity is not fully understood. In this study, we defined a mechanism of celecoxib action based on degradation of cellular FLICE-inhibitory protein (c-FLIP), a major regulator of the death receptor pathway of apoptosis. c-FLIP protein levels are regulated by ubiquitination and proteasome-mediated degradation. We found that celecoxib controlled c-FLIP ubiquitination through Akt-independent inhibition of glycogen synthase kinase-3 (GSK3), itself a candidate therapeutic target of interest in colon cancer. Celecoxib increased the levels of phosphorylated GSK3, including the α and β forms, even in cell lines, where phosphorylated Akt levels were not increased. Phosphoinositide 3-kinase inhibitors abrogated Akt phosphorylation as expected but had no effect on celecoxib-induced GSK3 phosphorylation. In contrast, protein kinase C (PKC) inhibitors abolished celecoxib-induced GSK3 phosphorylation, implying that celecoxib influenced GSK3 phosphorylation through a mechanism that relied upon PKC and not Akt. GSK3 blockade either by siRNA or kinase inhibitors was sufficient to attenuate c-FLIP levels. Combining celecoxib with GSK3 inhibition enhanced attenuation of c-FLIP and increased apoptosis. Proteasome inhibitor MG132 reversed the effects of GSK3 inhibition and increased c-FLIP ubiquitination, confirming that c-FLIP attenuation was mediated by proteasomal turnover as expected. Our findings reveal a novel mechanism through which the regulatory effects of c-FLIP on death receptor signaling are controlled by GSK3, which celecoxib acts at an upstream level to control independently of Akt.

Celecoxib promotes c-FLIP degradation through Akt-independent inhibition of GSK3

PubMed Central

Chen, Shuzhen; Cao, Wei; Yue, Ping; Hao, Chunhai; Khuri, Fadlo R.; Sun, Shi-Yong

2011-01-01

Celecoxib is a COX2 inhibitor that reduces the risk of colon cancer. However, the basis for its cancer chemopreventive activity is not fully understood. In this study, we defined a mechanism of celecoxib action based on degradation of c-FLIP, a major regulator of the death receptor pathway of apoptosis. c-FLIP protein levels are regulated by ubiquitination and proteasome-mediated degradation. We found that celecoxib controlled c-FLIP ubiquitination through Akt-independent inhibition of GSK3 kinase, itself a candidate therapeutic target of interest in colon cancer. Celecoxib increased the levels of phosphorylated GSK3 (p-GSK3), including the α and β forms, even in cell lines where p-Akt levels were not increased. PI3K inhibitors abrogated Akt phosphorylation as expected but had no effect on celecoxib-induced GSK3 phosphorylation. In contrast, PKC inhibitors abolished celecoxib-induced GSK3 phosphorylation, implying that celecoxib influenced GSK3 phosphorylation through a mechanism relied upon PKC but not Akt. GSK3 blockade either by siRNA or kinase inhibitors was sufficient to attenuate c-FLIP levels. Combining celecoxib with GSK3 inhibition enhanced attenuation of c-FLIP and increased apoptosis. Proteasome inhibitor MG132 reversed the effects of GSK3 inhibition and increased c-FLIP ubiquitination, confirming that c-FLIP attenuation was mediated by proteasomal turnover as expected. Our findings reveal a novel mechanism through which the regulatory effects of c-FLIP on death receptor signaling are controlled by GSK3, which celecoxib acts at an upstream level to control independently of Akt. PMID:21868755

Celecoxib interferes to a limited extent with aspirin‐mediated inhibition of platelets aggregation

PubMed Central

Ruzov, Mark; Rimon, Gilad; Pikovsky, Oleg

2015-01-01

Aims The aim of the study was to analyze the interaction between celecoxib and low dose aspirin for COX‐1 binding and its consequences on the aspirin‐mediated antiplatelet effects. Methods We investigated ex vivo the interaction between celecoxib and aspirin for COX‐1 binding and measured the resulting antiplatelet effects. We applied mechanism‐based pharmacokinetic−pharmacodynamic (PKPD) modelling to analyze these data and to predict in vivo platelet aggregation for different doses and administration schedules of aspirin and celecoxib. Results The predictions of the PK‐PD model were consistent with results from previous studies that investigated interaction between aspirin and celecoxib. The modelling results indicate that celecoxib can attenuate to a limited extent the in vivo antiplatelet effects of low dose aspirin. The extent of this interaction can be substantial (up to 15% increase in platelet aggregation by 200 mg day−1 celecoxib when combined with low dose aspirin) during the first days of aspirin administration in patients who are already treated with celecoxib, and it cannot be prevented by separate administration of the interacting drugs. Conclusions At the recommended therapeutic doses, celecoxib can attenuate to a limited extent the in vivo antiplatelet effects of low dose aspirin. Patients receiving a combination of low dose aspirin and the recommended doses of celecoxib were not identified to have increased risk of cardiovascular and cerebrovascular events due to competition between these drugs for COX‐1 binding. Interaction between low dose aspirin and other COX‐2 inhibitors and its clinical consequences requires further investigation. PMID:26456703

Interaction of celecoxib with different anti-cancer drugs is antagonistic in breast but not in other cancer cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

El-Awady, Raafat A., E-mail: relawady@sharjah.ac.ae; Department of Pharmacology and Pharmaceutics, College of Pharmacy, University of Sharjah, University City road, 27272 Sharjah; Saleh, Ekram M.

Celecoxib, an inhibitor of cyclooxygenase-2, is being investigated for enhancement of chemotherapy efficacy in cancer clinical trials. This study investigates the ability of cyclooxygenase-2 inhibitors to sensitize cells from different origins to several chemotherapeutic agents. The effect of the drug's mechanism of action and sequence of administration are also investigated. The sensitivity, cell cycle, apoptosis and DNA damage of five different cancer cell lines (HeLa, HCT116, HepG2, MCF7 and U251) to 5-FU, cisplatin, doxorubicin and etoposide {+-} celecoxib following different incubation schedules were analyzed. We found antagonism between celecoxib and the four drugs in the breast cancer cells MCF7 followingmore » all incubation schedules and between celecoxib and doxorubicin in all cell lines except for two combinations in HCT116 cells. Celecoxib with the other three drugs in the remaining four cell lines resulted in variable interactions. Mechanistic investigations revealed that celecoxib exerts different molecular effects in different cells. In some lines, it abrogates the drug-induced G2/M arrest enhancing pre-mature entry into mitosis with damaged DNA thus increasing apoptosis and resulting in synergism. In other cells, it enhances drug-induced G2/M arrest allowing time to repair drug-induced DNA damage before entry into mitosis and decreasing cell death resulting in antagonism. In some synergistic combinations, celecoxib-induced abrogation of G2/M arrest was not associated with apoptosis but permanent arrest in G1 phase. These results, if confirmed in-vivo, indicate that celecoxib is not a suitable chemosensitizer for breast cancer or with doxorubicin for other cancers. Moreover, combination of celecoxib with other drugs should be tailored to the tumor type, drug and administration schedule. - Graphical abstract: Display Omitted Highlights: > Celecoxib may enhance effects of anticancer drugs. > Its combination with four drugs was tested in five cancer cell lines. > It antagonized the effects of the four drugs in the breast cancer cell line MCF7. > Doxorubicin's cytotoxic effects were antagonized by celecoxib in four cell lines. > Cell cycle, apoptosis and DNA damage explain the different interactive effects.« less

Celecoxib Monotherapy Maintained Small Intestinal Mucosa Better Compared With Loxoprofen Plus Lansoprazole Treatment: A Double-blind, Randomized, Controlled Trial.

PubMed

Fujimori, Shunji; Hanada, Ryuzo; Hayashida, Mari; Sakurai, Toshiyuki; Ikushima, Ippei; Sakamoto, Choitsu

2016-03-01

The aim of this study was to compare celecoxib with loxoprofen for protection of small intestine. RCT studies report that COX-2 selective inhibitor celecoxib induces fewer small intestinal injuries than nonselective nonsteroidal anti-inflammatory drugs (NSAIDs). Loxoprofen is a prodrug nonselective NSAID developed to protect upper gastrointestinal tract. A total of 150 healthy volunteers (40 to 70 y) were enrolled. After medical checkup including laboratory data, subjects were randomly assigned to celecoxib (200 mg daily) or loxoprofen (180 mg daily) plus lansoprazole (15 mg daily). All drugs were prepared using inactive capsules. After randomization, all subjects were first examined by baseline capsule endoscopy (CE). After 14 days, subjects underwent posttreatment CE. We compared baseline and posttreatment CE findings of the 2 groups. All CE data were evaluated blindly by 3 reviewers. Pretreatment and posttreatment laboratory variables were also compared. A total of 74 subjects (49±6 y, F/M: 36/38) were enrolled in celecoxib group and 76 subjects (49±7 y, F/M: 39/37)in loxoprofen group. Five in celecoxib group and 4 in loxoprofen group were excluded from CE analysis mainly due to incomplete CE. The percentage of subjects with at least 1 posttreatment mucosal break was lower in celecoxib group (10%) than in loxoprofen group (49%) (P<0.0001). A total of 0.3±1.0 posttreatment small intestinal mucosal breaks were detected in the celecoxib group, and 6.8±21.5 in the loxoprofen group (P<0.0001). Posttreatment hemoglobin concentration in loxoprofen group (5.1% reduction) was lower compared with celecoxib group (2.1% reduction) (P=0.006). In terms of protection of small intestine from NSAIDs toxicity, celecoxib monotherapy was superior to loxoprofen+lansoprazole combination therapy (UMIN: 000007936).

The ErbB family and androgen receptor signaling are targets of Celecoxib in prostate cancer.

PubMed

Brizzolara, Antonella; Benelli, Roberto; Venè, Roberta; Barboro, Paola; Poggi, Alessandro; Tosetti, Francesca; Ferrari, Nicoletta

2017-08-01

Inflammation plays a central role in prostate cancer (PCa) development through significant crosstalk between the COX-2-ErbB family receptor network and androgen receptor (AR)-EGFR signaling pathways. The purpose of this work was to determine the ability of the COX-2 inhibitor Celecoxib to modulate the EGFR-AR signaling pathway in androgen-dependent PCa cells and to provide a rationale for its beneficial use in chemopreventive strategies. Functional studies of Celecoxib activity were performed on LNCaP prostate cancer cells. Western blotting, gene expression analysis, dual-luciferase reporter assay and ELISA were applied to assess the Celecoxib mechanisms of action. We found that Celecoxib, through EGF and amphiregulin (AREG) induction, caused EGFR and ErbB2 activation and consequent degradation associated with the inhibition of androgenic signaling. By upregulating the E3 ubiquitin ligase Nrdp1, Celecoxib also efficiently downregulated ErbB3, which is strongly implicated in castration-resistant prostate cancer. Lastly, Celecoxib directly regulated AR transcription and translation independent of ErbB activation by downregulating the RNA binding protein heterogeneous nuclear ribonucleoprotein K (hnRNP K). The simultaneous suppression of ErbB kinases and androgen signaling by Celecoxib represents a novel strategy to interrupt the vicious cycle of AR/ErbB cross-talk with the primary purpose of undermining their resilient signaling in prostate cancer progression. Our data provide important premises for the chemopreventive use of Celecoxib in the clinical management of prostate cancer. Copyright © 2017 Elsevier B.V. All rights reserved.

Celecoxib activates PI-3K/Akt and mitochondrial redox signaling to enhance heme oxygenase-1-mediated anti-inflammatory activity in vascular endothelium.

PubMed

Hamdulay, Shahir S; Wang, Bufei; Birdsey, Graeme M; Ali, Faisal; Dumont, Odile; Evans, Paul C; Haskard, Dorian O; Wheeler-Jones, Caroline P; Mason, Justin C

2010-04-15

Although nonsteroidal anti-inflammatory drugs (NSAIDs) provide important control of pain and inflammation, they have been overshadowed by concerns regarding atherothrombotic complications. However, celecoxib seems to have a relatively good cardiovascular profile and may improve endothelial function in coronary heart disease. This led us to the hypothesis that celecoxib induces the vasculoprotective enzyme heme oxygenase-1 (HO-1). In human umbilical vein and aortic endothelial cells, 24-48 h treatment with celecoxib induced HO-1 mRNA and protein expression and increased HO-1 enzyme activity. This effect was not seen with rofecoxib or indomethacin. Supplementation of culture medium with iloprost or prostaglandin E(2) failed to reverse celecoxib-mediated HO-1 induction, indicating a cyclooxygenase-independent mechanism. Rather, this action of celecoxib involved generation of mitochondria-derived reactive oxygen species, Akt phosphorylation, and nuclear translocation of the transcription factor Nrf2, with N-acetylcysteine, PI-3K antagonist LY290042, and dominant-negative Akt abrogating the effects. Furthermore, celecoxib-induced HO-1 was inhibited by dominant-negative Nrf2. The functional significance of HO-1 induction was revealed by celecoxib-mediated inhibition of VCAM-1 expression, a response reversed by the HO-1 antagonist zinc protoporphyrin. HO-1 induction provides a molecular mechanism for clinical observations indicating relative freedom from atherothrombotic complications in patients taking celecoxib compared to other NSAIDs with comparable anti-inflammatory activity. Copyright 2010 Elsevier Inc. All rights reserved.

Celecoxib Sensitizes Staphylococcus aureus to Antibiotics in Macrophages by Modulating SIRT1

PubMed Central

Annamanedi, Madhavi; Kalle, Arunasree M.

2014-01-01

We have previously shown that celecoxib in combination with an antibiotic, increase the bacterial sensitivity to antibiotics. However, the underlying molecular mechanism remained elusive. Efficacy of the combinatorial treatment of celecoxib and ampicillin in vitro was evaluated on macrophage-phagocytosed S aureus. To elucidate the mechanism, signaling pathway of infection and inflammation involving TLR2, JNK, SIRT1 and NF-κB was studied by FACS, Western blot, ELISA and activity assays. Combinatorial treatment of ampicillin and celecoxib reduced the bacterial load in the macrophages. Further studies clearly suggested the activation of the master regulator of oxidative stress and inflammation SIRT1,, by celecoxib when used alone and/or in combination with ampicillin. Also, the results indicated that celecoxib inhibited JNK phosphorylation thereby stabilizing and activating SIRT1 protein that inhibited the COX-2 gene transcription with a significant decrease in the levels of protein inflammatory cytokines like IL-6, MIP-1α and IL-1β via inhibition of NF-κB. SIRT1 activation by celecoxib also resulted in increase of catalase and peroxidase activity with a decrease in Nitric oxide levels. In conclusion, we demonstrate a novel role of celecoxib in controlling inflammation as an enhancer of antibiotic activity against bacteria by modulating SIRT1. PMID:24950067

Celecoxib sensitizes Staphylococcus aureus to antibiotics in macrophages by modulating SIRT1.

PubMed

Annamanedi, Madhavi; Kalle, Arunasree M

2014-01-01

We have previously shown that celecoxib in combination with an antibiotic, increase the bacterial sensitivity to antibiotics. However, the underlying molecular mechanism remained elusive. Efficacy of the combinatorial treatment of celecoxib and ampicillin in vitro was evaluated on macrophage-phagocytosed S. aureus. To elucidate the mechanism, signaling pathway of infection and inflammation involving TLR2, JNK, SIRT1 and NF-κB was studied by FACS, Western blot, ELISA and activity assays. Combinatorial treatment of ampicillin and celecoxib reduced the bacterial load in the macrophages. Further studies clearly suggested the activation of the master regulator of oxidative stress and inflammation SIRT1, by celecoxib when used alone and/or in combination with ampicillin. Also, the results indicated that celecoxib inhibited JNK phosphorylation thereby stabilizing and activating SIRT1 protein that inhibited the COX-2 gene transcription with a significant decrease in the levels of protein inflammatory cytokines like IL-6, MIP-1α and IL-1β via inhibition of NF-κB. SIRT1 activation by celecoxib also resulted in increase of catalase and peroxidase activity with a decrease in Nitric oxide levels. In conclusion, we demonstrate a novel role of celecoxib in controlling inflammation as an enhancer of antibiotic activity against bacteria by modulating SIRT1.

Effects of celecoxib on cell apoptosis and Fas, FasL and Bcl-2 expression in a BGC-823 human gastric cancer cell line.

PubMed

Li, Qian; Peng, Jie; Liu, Ting; Zhang, Guiying

2017-09-01

Fas, which is an apoptotic-related protein, has an important role in cell apoptosis. Fas ligand (FasL) binds to Fas and activates apoptosis signal transduction. We previously demonstrated that the efficiency of celecoxib inhibited the proliferation and apoptosis of HT-29 colon cancer cell line. The BGC823 cell line was used as an experimental model to evaluate the potential role of celecoxib on gastric cancer cell apoptosis. Inhibitory effects of celecoxib on cell viability were determined by MTT assay. Cell apoptosis was evaluated by flow cytometric analysis and laser confocal microscopy. The results of the present study demonstrated that celecoxib inhibited the viability of BGC823 cells in a concentration- and time-dependent manner. Furthermore, the effect of BGC823 cells apoptosis was increased in a concentration-dependent manner. Western blotting was used to determine the protein expression levels of Fas, FasL, and B-cell lymphoma-2 (Bcl-2). During the celecoxib-induced apoptosis of BGC823 cells, celecoxib upregulated Fas expression and downregulated FasL and Bcl-2 expression in a concentration-dependent manner. These results suggest that celecoxib inhibited the growth and induced apoptosis of BGC823 gastric cancer cells by regulating the protein expression of Fas, FasL and Bcl-2.

Novel celecoxib analogues inhibit glial production of prostaglandin E2, nitric oxide, and oxygen radicals reverting the neuroinflammatory responses induced by misfolded prion protein fragment 90-231 or lipopolysaccharide.

PubMed

Villa, Valentina; Thellung, Stefano; Bajetto, Adriana; Gatta, Elena; Robello, Mauro; Novelli, Federica; Tasso, Bruno; Tonelli, Michele; Florio, Tullio

2016-11-01

We tested the efficacy of novel cyclooxygenase 2 (COX-2) inhibitors in counteracting glia-driven neuroinflammation induced by the amyloidogenic prion protein fragment PrP90-231 or lipopolysaccharide (LPS). In search for molecules with higher efficacy than celecoxib, we focused our study on its 2,3-diaryl-1,3-thiazolidin-4-one analogues. As experimental models, we used the immortalized microglial cell line N9, rat purified microglial primary cultures, and mixed cultures of astrocytes and microglia. Microglia activation in response to PrP90-231 or LPS was characterized by growth arrest, morphology changes and the production of reactive oxygen species (ROS). Moreover, PrP90-231 treatment caused the overexpression of the inducible nitric oxide synthase (iNOS) and COX-2, with the consequent nitric oxide (NO), and prostaglandin E 2 (PGE 2 ) accumulation. These effects were challenged by different celecoxib analogues, among which Q22 (3-[4-(sulfamoyl)phenyl]-2-(4-tolyl)thiazolidin-4-one) inhibited microglia activation more efficiently than celecoxib, lowering both iNOS and COX-2 activity and reducing ROS release. During neurodegenerative diseases, neuroinflammation induced by amyloidogenic peptides causes the activation of both astrocytes and microglia with these cell populations mutually regulating each other. Thus the effects of PrP90-231 and LPS were also studied on mixed glial cultures containing astrocytes and microglia. PrP90-231 treatment elicited different responses in the co-cultures induced astrocyte proliferation and microglia growth arrest, resulting in a differential ability to release proinflammatory molecules with the production of NO and ROS mainly attributable on microglia, while COX-2 expression was induced also in astrocytes. Q22 effects on both NO and PGE 2 secretion were more significant in the mixed glial cultures than in purified microglia, demonstrating Q22 ability to revert the functional interaction between astrocytes and microglia. These results demonstrate that Q22 is a powerful drug able to revert glial neuroinflammatory responses and might represent a lead to explore the chemical space around celecoxib frameworks to design even more effective agents, paving the way to novel approaches to contrast the neuroinflammation-dependent toxicity. Copyright © 2016 Elsevier Ltd. All rights reserved.

Preemptive multimodal pain regimen reduces opioid analgesia for patients undergoing robotic-assisted laparoscopic radical prostatectomy.

PubMed

Trabulsi, Edouard J; Patel, Jitesh; Viscusi, Eugene R; Gomella, Leonard G; Lallas, Costas D

2010-11-01

Minimally invasive surgical techniques have many benefits, including reduced postoperative pain. Despite this, most patients require opioid analgesia, which can have significant side effects and toxicity. We report the first urologic study using multimodal analgesia with pregabalin, a gabapentinoid. The present retrospective study included 60 patients who underwent robotic-assisted laparoscopic radical prostatectomy. Of the 60 patients, 30 received multimodal treatment with pregabalin 150 mg, acetaminophen 975 mg, and celecoxib 400 mg orally 2 hours before the start of the procedure and continued postoperatively. These patients were compared with 30 consecutive previous patients, who had received a standard postoperative analgesic regimen with intravenous ketorolac 15 mg every 6 hours with oxycodone 5 mg and acetaminophen 325 mg, 1 to 2 tablets, every 4 hours as needed for pain. The patients in the multimodal treatment group had a significantly reduced intraoperative opioid requirement, as measured by the mean morphine equivalent dose administered (38.4 ± 2.73 mg vs 49.1 ± 2.65 mg; P < .01). The mean postoperative opioid use was also significantly reduced (10.7 ± 2.82 mg vs 26.2 ± 6.56 mg; P = .034), as was the mean total morphine equivalent dose administered (49.1 ± 2.7 mg vs 75.3 ± 4.6 mg; P < .001). The operative time, estimated operative blood loss, antiemetic use, postoperative creatinine and hemoglobin levels, and length of stay were similar in the 2 groups. No operative or treatment complications occurred in either group. The present retrospective review has indicated that a multimodal analgesic approach with pregabalin and celecoxib administered preoperatively decreases intraoperative and postoperative opioid use in patients undergoing robotic-assisted laparoscopic radical prostatectomy. Copyright © 2010 Elsevier Inc. All rights reserved.

Celecoxib extends C. elegans lifespan via inhibition of insulin-like signaling but not cyclooxygenase-2 activity

PubMed Central

Ching, Tsui-Ting; Chiang, Wei-Chung; Chen, Ching-Shih; Hsu, Ao-Lin

2011-01-01

Summary One goal of aging research is to develop interventions that combat age-related illnesses and slow aging. Although numerous mutations have been shown to achieve this in various model organisms, only a handful of chemicals have been identified to slow aging. Here we report that celecoxib, a non-steroidal anti-inflammatory drug (NSAID) widely used to treat pain and inflammation, extends C. elegans lifespan and delays the age-associated physiological changes, such as motor activity declines. Celecoxib also delays the progression of age-related proteotoxicity as well as tumor growth in C. elegans. Celecoxib was originally developed as a potent COX-2 inhibitor. However, the result from a structural-activity analysis demonstrated that the anti-aging effect of celecoxib might be independent of its COX-2 inhibitory activity, as analogs of celecoxib that lack cyclooxygenase-2 (COX-2) inhibitory activity produces a similar effect on lifespan. Furthermore, we found that celecoxib acts directly on 3’-phosphoinositide-dependent kinase-1 (PDK-1), a component of the insulin/IGF-1 signaling (IIS) cascade to increase lifespan. PMID:21348927

Single dose oral celecoxib for acute postoperative pain in adults

PubMed Central

Derry, Sheena; Moore, R Andrew

2014-01-01

Background This is an update of a review published in The Cochrane Library 2008, Issue 4. Celecoxib is a selective cyclo-oxygenase-2 (COX-2) inhibitor usually prescribed for the relief of chronic pain in osteoarthritis and rheumatoid arthritis. Celecoxib is believed to be associated with fewer upper gastrointestinal adverse effects than conventional non-steroidal anti-inflammatory drugs (NSAIDs). Its effectiveness in acute pain was demonstrated in the earlier reviews. Objectives To assess analgesic efficacy and adverse effects of a single oral dose of celecoxib for moderate to severe postoperative pain. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, the Oxford Pain Database, and ClinicalTrials.gov. The most recent search was to 3 January 2012. Selection criteria We included randomised, double-blind, placebo-controlled trials (RCTs) of adults prescribed any dose of oral celecoxib or placebo for acute postoperative pain. Data collection and analysis Two review authors assessed studies for quality and extracted data. We converted summed pain relief (TOTPAR) or pain intensity difference (SPID) into dichotomous information, yielding the number of participants with at least 50% pain relief over four to six hours, and used this to calculate the relative benefit (RB) and number needed to treat to benefit (NNT) for one patient to achieve at least 50% of maximum pain relief with celecoxib who would not have done so with placebo. We used information on use of rescue medication to calculate the proportion of participants requiring rescue medication and the weighted mean of the median time to use. Main results Eight studies (1380 participants) met the inclusion criteria. We identified five potentially relevant unpublished studies in the most recent searches, but data were not available at this time. The number of included studies therefore remains unchanged. The NNT for celecoxib 200 mg and 400 mg compared with placebo for at least 50% of maximum pain relief over four to six hours was 4.2 (95% confidence interval (CI) 3.4 to 5.6) and 2.5 (2.2 to 2.9) respectively. The median time to use of rescue medication was 6.6 hours with celecoxib 200 mg, 8.4 with celecoxib 400 mg, and 2.3 hours with placebo. The proportion of participants requiring rescue medication over 24 hours was 74% with celecoxib 200 mg, 63% for celecoxib 400 mg, and 91% for placebo. The NNT to prevent one patient using rescue medication was 4.8 (3.5 to 7.7) and 3.5 (2.9 to 4.6) for celecoxib 200 mg and 400 mg respectively. Adverse events were generally mild to moderate in severity, and were experienced by a similar proportion of participants in celecoxib and placebo groups. One serious adverse event probably related to celecoxib was reported. Authors’ conclusions Single-dose oral celecoxib is an effective analgesic for postoperative pain relief. Indirect comparison suggests that the 400 mg dose has similar efficacy to ibuprofen 400 mg. PMID:22419293

Randomized trial of switching from prescribed non-selective non-steroidal anti-inflammatory drugs to prescribed celecoxib: the Standard care vs. Celecoxib Outcome Trial (SCOT)

PubMed Central

MacDonald, Thomas M.; Hawkey, Chris J.; Ford, Ian; McMurray, John J.V.; Scheiman, James M.; Hallas, Jesper; Findlay, Evelyn; Grobbee, Diederick E.; Hobbs, F.D. Richard; Ralston, Stuart H.; Reid, David M.; Walters, Matthew R.; Webster, John; Ruschitzka, Frank; Ritchie, Lewis D.; Perez-Gutthann, Susana; Connolly, Eugene; Greenlaw, Nicola; Wilson, Adam; Wei, Li; Mackenzie, Isla S.

2017-01-01

Background Selective cyclooxygenase-2 inhibitors and conventional non-selective non-steroidal anti-inflammatory drugs (nsNSAIDs) have been associated with adverse cardiovascular (CV) effects. We compared the CV safety of switching to celecoxib vs. continuing nsNSAID therapy in a European setting. Method Patients aged 60 years and over with osteoarthritis or rheumatoid arthritis, free from established CV disease and taking chronic prescribed nsNSAIDs, were randomized to switch to celecoxib or to continue their previous nsNSAID. The primary endpoint was hospitalization for non-fatal myocardial infarction or other biomarker positive acute coronary syndrome, non-fatal stroke or CV death analysed using a Cox model with a pre-specified non-inferiority limit of 1.4 for the hazard ratio (HR). Results In total, 7297 participants were randomized. During a median 3-year follow-up, fewer subjects than expected developed an on-treatment (OT) primary CV event and the rate was similar for celecoxib, 0.95 per 100 patient-years, and nsNSAIDs, 0.86 per 100 patient-years (HR = 1.12, 95% confidence interval, 0.81–1.55; P = 0.50). Comparable intention-to-treat (ITT) rates were 1.14 per 100 patient-years with celecoxib and 1.10 per 100 patient-years with nsNSAIDs (HR = 1.04; 95% confidence interval, 0.81–1.33; P = 0.75). Pre-specified non-inferiority was achieved in the ITT analysis. The upper bound of the 95% confidence limit for the absolute increase in OT risk associated with celecoxib treatment was two primary events per 1000 patient-years exposure. There were only 15 adjudicated secondary upper gastrointestinal complication endpoints (0.078/100 patient-years on celecoxib vs. 0.053 on nsNSAIDs OT, 0.078 vs. 0.053 ITT). More gastrointestinal serious adverse reactions and haematological adverse reactions were reported on nsNSAIDs than celecoxib, but more patients withdrew from celecoxib than nsNSAIDs (50.9% patients vs. 30.2%; P < 0.0001). Interpretation In subjects 60 years and over, free from CV disease and taking prescribed chronic nsNSAIDs, CV events were infrequent and similar on celecoxib and nsNSAIDs. There was no advantage of a strategy of switching prescribed nsNSAIDs to prescribed celecoxib. This study excluded an increased risk of the primary endpoint of more than two events per 1000 patient-years associated with switching to prescribed celecoxib. Clinical Trial Registration https://clinicaltrials.gov/show/NCT00447759; Unique identifier: NCT00447759. PMID:27705888

Celecoxib induces proliferation and Amphiregulin production in colon subepithelial myofibroblasts, activating erk1-2 signaling in synergy with EGFR.

PubMed

Benelli, Roberto; Venè, Roberta; Minghelli, Simona; Carlone, Sebastiano; Gatteschi, Beatrice; Ferrari, Nicoletta

2013-01-01

The COX-2 inhibitor Celecoxib, tested in phase III trials for the prevention of sporadic colon adenomas, reduced the appearance of new adenomas, but was unable to affect the incidence of colon cancer. Moreover the 5years follow-up showed that patients discontinuing Celecoxib treatment had an increased incidence of adenomas as compared to the placebo arm. In the APC(min/+) mouse model short term treatment with Celecoxib reduced gut adenomas, but a prolonged administration of the drug induced fibroblast activation and intestinal fibrosis with a final tumor burden. The way Celecoxib could directly activate human colon myofibroblasts (MF) has not yet been investigated. We found that MF are activated by non toxic doses of Celecoxib. Celecoxib induces erk1-2 and Akt phosphorylation within 5'. This short term activation is apparently insufficient to cause phenotypic changes, but the contemporary triggering of EGFR causes an impressive synergic effect inducing MF proliferation and the neo-expression and release of Amphiregulin (AREG), a well known EGFR agonist involved in colon cancer progression. As a confirm to these observations, the erk inhibitor U0126 and the EGFR inhibitors Tyrphostin and Cetuximab were able to contrast AREG induction. Our data provide evidence that Celecoxib directly activates MF empowering EGFR signaling. According to these results the association with EGFR (or erk1-2) inhibitors could abolish the off-target activity of Celecoxib, possibly extending the potential of this drug for colon cancer prevention. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

The effect of celecoxib on tumor growth in ovarian cancer cells and a genetically engineered mouse model of serous ovarian cancer.

PubMed

Suri, Anuj; Sheng, Xiugui; Schuler, Kevin M; Zhong, Yan; Han, Xiaoyun; Jones, Hannah M; Gehrig, Paola A; Zhou, Chunxiao; Bae-Jump, Victoria L

2016-06-28

Our objective was to evaluate the effect of the COX-2 inhibitor, celecoxib, on (1) proliferation and apoptosis in human ovarian cancer cell lines and primary cultures of ovarian cancer cells, and (2) inhibition of tumor growth in a genetically engineered mouse model of serous ovarian cancer under obese and non-obese conditions. Celecoxib inhibited cell proliferation in three ovarian cancer cell lines and five primary cultures of human ovarian cancer after 72 hours of exposure. Treatment with celecoxib resulted in G1 cell cycle arrest, induction of apoptosis, inhibition of cellular adhesion and invasion and reduction of expression of hTERT mRNA and COX-2 protein in all of the ovarian cancer cell lines. In the KpB mice fed a high fat diet (obese) and treated with celecoxib, tumor weight decreased by 66% when compared with control animals. Among KpB mice fed a low fat diet (non-obese), tumor weight decreased by 46% after treatment with celecoxib. In the ovarian tumors from obese and non-obese KpB mice, treatment with celecoxib as compared to control resulted in decreased proliferation, increased apoptosis and reduced COX-2 and MMP9 protein expression, as assessed by immunohistochemistry. Celecoxib strongly decreased the serum level of VEGF and blood vessel density in the tumors from the KpB ovarian cancer mouse model under obese and non-obese conditions. This work suggests that celecoxib may be a novel chemotherapeutic agent for ovarian cancer prevention and treatment and be potentially beneficial in both obese and non-obese women.

The effect of celecoxib on tumor growth in ovarian cancer cells and a genetically engineered mouse model of serous ovarian cancer

PubMed Central

Suri, Anuj; Sheng, Xiugui; Schuler, Kevin M.; Zhong, Yan; Han, Xiaoyun; Jones, Hannah M.; Gehrig, Paola A.; Zhou, Chunxiao; Bae-Jump, Victoria L.

2016-01-01

Our objective was to evaluate the effect of the COX-2 inhibitor, celecoxib, on (1) proliferation and apoptosis in human ovarian cancer cell lines and primary cultures of ovarian cancer cells, and (2) inhibition of tumor growth in a genetically engineered mouse model of serous ovarian cancer under obese and non-obese conditions. Celecoxib inhibited cell proliferation in three ovarian cancer cell lines and five primary cultures of human ovarian cancer after 72 hours of exposure. Treatment with celecoxib resulted in G1 cell cycle arrest, induction of apoptosis, inhibition of cellular adhesion and invasion and reduction of expression of hTERT mRNA and COX-2 protein in all of the ovarian cancer cell lines. In the KpB mice fed a high fat diet (obese) and treated with celecoxib, tumor weight decreased by 66% when compared with control animals. Among KpB mice fed a low fat diet (non-obese), tumor weight decreased by 46% after treatment with celecoxib. In the ovarian tumors from obese and non-obese KpB mice, treatment with celecoxib as compared to control resulted in decreased proliferation, increased apoptosis and reduced COX-2 and MMP9 protein expression, as assessed by immunohistochemistry. Celecoxib strongly decreased the serum level of VEGF and blood vessel density in the tumors from the KpB ovarian cancer mouse model under obese and non-obese conditions. This work suggests that celecoxib may be a novel chemotherapeutic agent for ovarian cancer prevention and treatment and be potentially beneficial in both obese and non-obese women. PMID:27074576

Study of osteoarthritis treatment with anti-inflammatory drugs: cyclooxygenase-2 inhibitor and steroids.

PubMed

Cho, Hongsik; Walker, Andrew; Williams, Jeb; Hasty, Karen A

2015-01-01

Patients with osteoarthritis (OA), a condition characterized by cartilage degradation, are often treated with steroids, nonsteroidal anti-inflammatory drugs (NSAIDs), and cyclooxygenase-2 (COX-2) selective NSAIDs. Due to their inhibition of the inflammatory cascade, the drugs affect the balance of matrix metalloproteinases (MMPs) and inflammatory cytokines, resulting in preservation of extracellular matrix (ECM). To compare the effects of these treatments on chondrocyte metabolism, TNF-α was incubated with cultured chondrocytes to mimic a proinflammatory environment with increasing production of MMP-1 and prostaglandin E2 (PGE2). The chondrocytes were then treated with either a steroid (prednisone), a nonspecific COX inhibitor NSAID (piroxicam), or a COX-2 selective NSAID (celecoxib). Both prednisone and celecoxib decreased MMP-1 and PGE-2 production while the nonspecific piroxicam decreased only the latter. Both prednisone and celecoxib decreased gene expression of MMP-1 and increased expression of aggrecan. Increased gene expression of type II collagen was also noted with celecoxib. The nonspecific piroxicam did not show these effects. The efficacy of celecoxib in vivo was investigated using a posttraumatic OA (PTOA) mouse model. In vivo, celecoxib increases aggrecan synthesis and suppresses MMP-1. In conclusion, this study demonstrates that celecoxib and steroids exert similar effects on MMP-1 and PGE2 production in vitro and that celecoxib may demonstrate beneficial effects on anabolic metabolism in vivo.

Clinical pharmacokinetics and pharmacodynamics of celecoxib: a selective cyclo-oxygenase-2 inhibitor.

PubMed

Davies, N M; McLachlan, A J; Day, R O; Williams, K M

2000-03-01

Celecoxib, a nonsteroidal anti-inflammatory drug (NSAID), is the first specific inhibitor of cyclo-oxygenase-2 (COX-2) approved to treat patients with rheumatism and osteoarthritis. Preliminary data suggest that celecoxib also has analgesic and anticancer properties. The selective inhibition of COX-2 is thought to lead to a reduction in the unwanted effects of NSAIDs. Upper gastrointestinal complication rates in clinical trials are significantly lower for celecoxib than for traditional nonselective NSAIDs (e.g. naproxen, ibuprofen and diclofenac). The rate of absorption of celexocib is moderate when given orally (peak plasma drug concentration occurs after 2 to 4 hours), although the extent of absorption is not known. Celexocib is extensively protein bound, primarily to plasma albumin, and has an apparent volume of distribution of 455+/-166L in humans. The area under the plasma concentration-time curve (AUC) of celecoxib increases in proportion to increasing oral doses between 100 and 800mg. Celecoxib is eliminated following biotransformation to carboxylic acid and glucuronide metabolites that are excreted in urine and faeces, with little drug (2%) being eliminated unchanged in the urine. Celecoxib is metabolised primarily by the cytochrome P450 (CYP) 2C9 isoenzyme and has an elimination half-life of about 11 hours in healthy individuals. Racial differences in drug disposition and pharmacokinetic changes in the elderly have been reported for celecoxib. Plasma concentrations (AUC) of celecoxib appear to be 43% lower in patients with chronic renal insufficiency [glomerular filtration rate 2.1 to 3.6 L/h (35 to 60 ml/min)] compared with individuals with healthy renal function, with a 47% increase in apparent clearance. Compared with healthy controls, it has been reported that the steady-state AUC is increased by approximately 40% and 180% in patients with mild and moderate hepatic impairment, respectively. Celecoxib does not appear to interact with warfarin, ketoconazole or methotrexate; however, clinically significant drug interactions with fluconazole and lithium have been documented. As celecoxib is metabolised by CYP2C9, increased clinical vigilance is required during the coadministration of other substrates or inhibitors of this enzyme.

Design, synthesis and biological screening of some novel celecoxib and etoricoxib analogs with promising COX-2 selectivity, anti-inflammatory activity and gastric safety profile.

PubMed

Alsayed, Shahinda S R; Elshemy, Heba A H; Abdelgawad, Mohamed A; Abdel-Latif, Mahmoud S; Abdellatif, Khaled R A

2017-02-01

Two new series of 4,6-diaryl-3-cyanopyridine 4a-r and 1,3,5-triaryl-2-pyrazolines 6a-f and were prepared. The new compounds were evaluated for their in vitro COX-2 selectivity and in vivo anti-inflammatory activity. Compounds 4o,r and 6d,f had moderate to high selectivity index (S.I.) compared to celecoxib (selectivity indexes of 4.5, 3.14, 4.79 and 3.21, respectively) and also, showed in vivo anti-inflammatory activity approximately equal to or higher than celecoxib (edema inhibition %=60.5, 64.5, 59.3 and 59.3, after 3h, respectively) and the effective anti-inflammatory doses were (ED 50 =10.1, 7.8, 8.46 and 10.7mg/kg respectively, celecoxib ED 50 =10.8mg/kg) and ulcerogenic liability were determined for these compounds which showed promising activity by being more potent than celecoxib with nearly negligible ulcerogenic liability compared to celecoxib (reduction in ulcerogenic liability versus celecoxib=85, 82, 74 and 67%, respectively). Copyright © 2016 Elsevier Inc. All rights reserved.

The Effect of Gabapentin Plus Celecoxib on Pain and Associated Complications After Laminectomy.

PubMed

Vasigh, Aminolah; Jaafarpour, Molouk; Khajavikhan, Javaher; Khani, Ali

2016-03-01

Prevention and treatment of postoperative pain is a major challenge in postoperative care and well-being of the surgical patient. The multimodal analgesic method has been recommended as an alternative treatment for the management of postoperative pain. To assess the comparative effect of gabapentin versus gabapentin plus celecoxib on pain and associated complications after laminectomy. In this randomized double- blind clinical trial, 114 patients scheduled for elective laminectomy received gabapentin (n=38, 900 mg daily), gabapentin plus celecoxib (n=38, 200 mg celecoxib plus 300mg gabapentin twice a day), and placebo (n=38, capsule containing starch). Visual Analog Scale (VAS) was used to determine the severity of pain. Complications after surgery, anxiety scores before surgery and patient's satisfaction 24 hour after surgery were recorded. The mean pain sevenity score and morphine consumption in the gabapentin plus celecoxib group were less compared to the placebo and gabapentin group respectively at various intervals (p < 0.001). The mean anxiety score, shivering, nausea, vomiting and pruritus in the gabapentin group were significantly lower compared to the placebo and gabapentin plus celecoxib groups respectively (p < 0.001, p < 0.05). The frequencies of drowsiness (42.1%) in the gabapentin group were significantly high compared to the placebo and gabapentin plus celecoxib group respectively (p <0.001, p< 0.05). In the gabapentin plus celecoxib group patient satisfaction was significantly higher compared to the placebo and gabapentin group (p< 0.05). Combination of 300 mg gabapentin plus 200 mg celecoxib twice a day is a good alternative in multimodal analgesia, effective in pain control with lesser side effects seen with gabapentin alone.

Comparison of gastroduodenal ulcer incidence in healthy Japanese subjects taking celecoxib or loxoprofen evaluated by endoscopy: a placebo-controlled, double-blind 2-week study.

PubMed

Sakamoto, C; Kawai, T; Nakamura, S; Sugioka, T; Tabira, J

2013-02-01

Although nonsteroidal anti-inflammatory drugs (NSAIDs) are widely prescribed globally, their chronic use increases the risk of upper gastrointestinal (GI) damage. Cyclooxygenase-2-selective NSAIDs are considered to reduce this risk. Current guidelines in Japan recommend loxoprofen sodium (loxoprofen), a pro-drug in the propionic acid class of nonselective NSAIDs, as first-line therapy in rheumatoid arthritis. To confirm the superiority of celecoxib, a cyclooxygenase-2-selective NSAID, to loxoprofen in the incidence of gastroduodenal (GD) endoscopic ulcers. A randomised, multicentre, placebo-controlled, double-blind, phase IV clinical trial in healthy Japanese volunteers [mean age 57.5 (range: 40-74) years; >70% female], stratified by Helicobacter pylori status at screening (~40% positive) and randomised 2:2:1 to receive celecoxib 100 mg b.d., loxoprofen 60 mg t.d.s. or placebo. Primary end point was incidence of any GD endoscopic ulcers after 2 weeks of treatment. Of 190 randomised subjects, 189 received at least one dose of celecoxib (n = 76), loxoprofen (n = 76), or placebo (n = 37). Incidence of GD ulcers was 1.4%, 27.6% and 2.7% in the celecoxib, loxoprofen and placebo groups respectively (P < 0.0001 in favour of the celecoxib group); incidence of adverse events (AEs) was 34.2%, 51.3% and 21.6% in the celecoxib, loxoprofen and placebo groups respectively. No serious or severe AEs were reported. Celecoxib 100 mg b.d. was superior to loxoprofen 60 mg t.d.s. regarding the incidence of gastro-duodenal endoscopic ulcers over 2 weeks. Celecoxib was well tolerated and no major safety concerns were observed. © 2012 Blackwell Publishing Ltd.

The role of prostaglandins in spinal transmission of the exercise pressor reflex in decerebrate rats

PubMed Central

Stone, Audrey J.; Copp, Steven W.; Kaufman, Marc P.

2014-01-01

Previous studies found that prostaglandins in skeletal muscle play a role in evoking the exercise pressor reflex; however the role played by prostaglandins in the spinal transmission of the reflex is not known. We determined, therefore, whether or not spinal blockade of cyclooxygenase (COX) activity and/or spinal blockade of endoperoxide receptor (EP) 2 or EP4 receptors attenuated the exercise pressor reflex in decerebrate rats. We first established that intrathecal doses of a non-specific COX inhibitor Ketorolac (100ug in 10ul), a COX-2 specific inhibitor Celecoxib (100μg in 10μl), an EP2 antagonist PF-04418948 (10μg in 10μl), and an EP4 antagonist L-161,982 (4μg in 10μl) effectively attenuated the pressor responses to intrathecal injections of Arachidonic Acid (100μg in 10μl), EP2 agonist Butaprost (4ng in 10 μl), and EP4 agonist TCS 2510 (6.25μg in 2.5 μl), respectively. Once effective doses were established, we statically contracted the hindlimb before and after intrathecal injections of Ketorolac, Celecoxib, the EP2 antagonist and the EP4 antagonist. We found that Ketorolac significantly attenuated the pressor response to static contraction (before Ketorolac: 23±5 mmHg, after Ketorolac 14±5 mmHg; p<0.05) whereas Celecoxib had no effect. We also found that 8μg of L-161,982, but not 4 μg of L-161,982, significantly attenuated the pressor response to static contraction (before L-161,982: 21±4 mmHg, after L-161,982 12±3 mmHg; p<0.05), whereas PF-04418948 (10μg) had no effect. We conclude that spinal COX-1, but not COX-2, plays a role in evoking the exercise pressor reflex, and that the spinal prostaglandins produced by this enzyme are most likely activating spinal EP4 receptors, but not EP2 receptors. PMID:25003710

A simple high performance liquid chromatography method for determination of rebamipide in rat urine.

PubMed

Cooper, Dustin L; Harirforoosh, Sam

2014-01-01

Rebamipide is a mucoprotective agent commonly used to prevent nonsteriodal anti-inflammatory drug-induced gastrointenstinal side effects [1]. Human plasma and urine analysis of rebamipide utilizing high performance liquid chromatography (HPLC) have been reported [2]. Recently, we reported on the plasma levels of rebamipide in presense or absence of celecoxib or diclofenac in rats [3] using a modified HPLC method of detection developed by Jeoung et al. [4]. To tailor the method towards use in urinary rebamipide extraction and analysis, the following modifications were made:•To compensate for high concentrations of rebamipide found in urine, a new rebamipide stock solution was prepared with a final concentration of 50,000 ng/mL.•Rat urine calibration standards were obtained within the range of 50-1000 ng/mL and 1000-50,000 ng/mL.•Plasma samples were replaced with urine samples.

Comparative study of the clinical efficacy of the selective cyclooxygenase-2 inhibitor celecoxib compared with loxoprofen in patients with frozen shoulder.

PubMed

Ohta, Satoru; Komai, Osamu; Hanakawa, Hiroyoshi

2014-01-01

This is a randomized comparative study of the efficacy of celecoxib and loxoprofen in patients with frozen shoulder (scapulohumeral periarthritis). Patients with frozen shoulder who presented with pain as the symptom were divided at random into a celecoxib treatment group (100 mg/dose, twice daily; n = 37) and a loxoprofen treatment group (60 mg/dose, 3 times daily; n = 33). Medication was continued for 1-2 weeks in each group. Each patient was asked to rate the pain on a visual analog scale (score 0-5). This score significantly improved (indicating marked alleviation of pain) in both the celecoxib group (from 3.41 ± 0.86 before treatment to 2.30 ± 1.02 after treatment) and the loxoprofen group (from 3.73 ± 0.67 before treatment to 2.76 ± 0.96 after treatment). In the analysis of disappearance of pain, the percentage of patients showing disappearance of nocturnal pain was significantly higher in the celecoxib group (71.4 %) than in the loxoprofen group (36.8 %). The results confirm that celecoxib is comparable to loxoprofen in terms of analgesic efficacy in patients with frozen shoulder. Among other findings, we report that celecoxib was more effective for nocturnal pain than loxoprofen.

Celecoxib increases SMN and survival in a severe spinal muscular atrophy mouse model via p38 pathway activation.

PubMed

Farooq, Faraz; Abadía-Molina, Francisco; MacKenzie, Duncan; Hadwen, Jeremiah; Shamim, Fahad; O'Reilly, Sean; Holcik, Martin; MacKenzie, Alex

2013-09-01

The loss of functional Survival Motor Neuron (SMN) protein due to mutations or deletion in the SMN1 gene causes autosomal recessive neurodegenerative spinal muscle atrophy (SMA). A potential treatment strategy for SMA is to upregulate the amount of SMN protein originating from the highly homologous SMN2 gene, compensating in part for the absence of the functional SMN1 gene. We have previously shown that in vitro activation of the p38 pathway stabilizes and increases SMN mRNA levels leading to increased SMN protein levels. In this report, we explore the impact of the p38 activating, FDA-approved, blood brain barrier permeating compound celecoxib on SMN levels in vitro and in a mouse model of SMA. We demonstrate a significant induction of SMN protein levels in human and mouse neuronal cells upon treatment with celecoxib. We show that activation of the p38 pathway by low doses celecoxib increases SMN protein in a HuR protein-dependent manner. Furthermore, celecoxib treatment induces SMN expression in brain and spinal cord samples of wild-type mice in vivo. Critically, celecoxib treatment increased SMN levels, improved motor function and enhanced survival in a severe SMA mouse model. Our results identify low dose celecoxib as a potential new member of the SMA therapeutic armamentarium.

Effect of Aspirin Coadministration on the Safety of Celecoxib, Naproxen, or Ibuprofen.

PubMed

Reed, Grant W; Abdallah, Mouin S; Shao, Mingyuan; Wolski, Kathy; Wisniewski, Lisa; Yeomans, Neville; Lüscher, Thomas F; Borer, Jeffrey S; Graham, David Y; Husni, M Elaine; Solomon, Daniel H; Libby, Peter; Menon, Venu; Lincoff, A Michael; Nissen, Steven E

2018-04-24

The safety of nonsteroidal anti-inflammatory drug (NSAID) and aspirin coadministration is uncertain. The aim of this study was to compare the safety of combining NSAIDs with low-dose aspirin. This analysis of the PRECISION (Prospective Randomized Evaluation of Celecoxib Integrated Safety Versus Ibuprofen or Naproxen) trial included 23,953 patients with osteoarthritis or rheumatoid arthritis at increased cardiovascular risk randomized to celecoxib, ibuprofen, or naproxen. The on-treatment population was used for this study. Outcomes included composite major adverse cardiovascular events, noncardiovascular death, gastrointestinal or renal events, and components of the composite. Cox proportional hazards models compared outcomes among NSAIDs stratified by aspirin use following propensity score adjustment. Kaplan-Meier analysis was used to compare the cumulative probability of events. When taken without aspirin, naproxen or ibuprofen had greater risk for the primary composite endpoint compared with celecoxib (hazard ratio [HR]: 1.52; 95% confidence interval [CI]: 1.22 to 1.90, p <0.001; and HR: 1.81; 95% CI: 1.46 to 2.26; p <0.001, respectively). Compared with celecoxib, ibuprofen had more major adverse cardiovascular events (p < 0.05), and both ibuprofen and naproxen had more gastrointestinal (p < 0.001) and renal (p < 0.05) events. Taken with aspirin, ibuprofen had greater risk for the primary composite endpoint compared with celecoxib (HR: 1.27; 95% CI: 1.06 to 1.51; p < 0.01); this was not significantly higher with naproxen (HR: 1.18; 95% CI: 0.98 to 1.41; p = 0.08). Among patients on aspirin, major adverse cardiovascular events were similar among NSAIDs, and compared with celecoxib, ibuprofen had more gastrointestinal and renal events (p < 0.05), while naproxen had more gastrointestinal events (p < 0.05), without a difference in renal events. Similar results were seen on adjusted Kaplan-Meier analysis. Celecoxib has a more favorable overall safety profile than naproxen or ibuprofen when taken without aspirin. Adding aspirin attenuates the safety advantage of celecoxib, although celecoxib is still associated with fewer gastrointestinal events than ibuprofen or naproxen and fewer renal events than ibuprofen. (Prospective Randomized Evaluation of Celecoxib Integrated Safety vs Ibuprofen or Naproxen [PRECISION]; NCT00346216). Copyright © 2018 American College of Cardiology Foundation. All rights reserved.

First-dose analgesic effect of the cyclo-oxygenase-2 selective inhibitor lumiracoxib in osteoarthritis of the knee: a randomized, double-blind, placebo-controlled comparison with celecoxib [NCT00267215

PubMed Central

Wittenberg, Ralf H; Schell, Ernest; Krehan, Gerhard; Maeumbaed, Roland; Runge, Hans; Schlüter, Peter; Fashola, Taiwo OA; Thurston, Helen J; Burger, Klaus J; Trechsel, Ulrich

2006-01-01

Cyclo-oxygenase-2 selective inhibitors are frequently used to manage osteoarthritis. We compared the analgesic efficacy of the novel cyclo-oxygenase-2 selective inhibitor lumiracoxib (Prexige®) versus placebo and celecoxib in patients with knee osteoarthritis. This seven day, double-blind, placebo and active comparator controlled, parallel group study included 364 patients aged ≥50 years with moderate-to-severe symptomatic knee osteoarthritis. Patients received lumiracoxib 400 mg/day (four times the recommended chronic dose in osteoarthritis; n = 144), placebo (n = 75), or celecoxib 200 mg twice daily (n = 145). The primary variable was actual pain intensity difference (100 mm visual–analogue scale) between baseline and the mean of three hour and five hour assessments after the first dose. Actual pain intensity difference, average and worst pain, pain relief and functional status (Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC™]) were measured over seven days. Patients also completed a global evaluation of treatment effect at study end or premature discontinuation. For the primary variable, the superiority of lumiracoxib versus placebo, the noninferiority of lumiracoxib versus celecoxib, and the superiority of lumiracoxib versus celecoxib were assessed by closed test procedure adjusting for multiplicity, thereby maintaining the overall 5% significance level. In addition, celecoxib was assessed versus placebo in a predefined exploratory manner to assess trial sensitivity. Lumiracoxib provided better analgesia than placebo 3–5 hours after the first dose (P = 0.004) through to study end. The estimated difference between lumiracoxib and celecoxib 3–5 hours after the first dose was not significant (P = 0.185). Celecoxib was not significantly different from placebo in this analysis (P = 0.069). At study end 13.9% of lumiracoxib-treated patients reported complete pain relief versus 5.5% and 5.3% of celecoxib and placebo recipients, respectively. WOMAC™ total and subscales improved for both active treatments versus placebo except for difficulty in performing daily activities, for which celecoxib just failed to achieve significance (P = 0.056). In the patient's global evaluation of treatment effect, 58.1% of patients receiving lumiracoxib rated treatment as 'excellent' or 'good', versus 48.6% of celecoxib and 25.3% of placebo patients. Lumiracoxib was well tolerated. The overall incidence of adverse events was similar across treatment groups. PMID:16469112

Celecoxib, a specific COX-2 inhibitor, has no significant effect on methotrexate pharmacokinetics in patients with rheumatoid arthritis.

PubMed

Karim, A; Tolbert, D S; Hunt, T L; Hubbard, R C; Harper, K M; Geis, G S

1999-12-01

To determine the effects of celecoxib, a specific inhibitor of cyclooxygenase 2 (COX-2) on the renal clearance and plasma pharmacokinetic profile of stable methotrexate (MTX) doses in patients with rheumatoid arthritis (RA). Fourteen adult female patients with RA taking a stable weekly dose of MTX (5 to 15 mg/wk) for a minimum of 3 months were randomized to receive concomitantly either celecoxib (200 mg BID) or placebo for a period of 7 days in a single blind, 2 period crossover study of MTX pharmacokinetics and renal clearance. The plasma pharmacokinetic profile of MTX did not change significantly when celecoxib or a placebo was coadministered. The mean renal clearance of MTX alone, 7.98+/-2.18 l/h, was virtually unchanged by coadministration of celecoxib (7.94+/-1.61 l/h) or placebo (7.97+/-1.19 l/h). Celecoxib has no significant effect on the pharmacokinetics or renal clearance of MTX in patients with RA, although these results should be confirmed in prospective studies of elderly and renally impaired patients.

Celecoxib or naproxen treatment does not benefit depressive symptoms in persons age 70 and older: findings from a randomized controlled trial.

PubMed

Fields, Cynthia; Drye, Lea; Vaidya, Vijay; Lyketsos, Constantine

2012-06-01

Several lines of evidence suggest that inflammatory mechanisms may be involved in the severity and progression of depression. One pathway implicated is the production of prostaglandins via the enzyme cyclooxygenase (COX). Although late-life depression in particular has been associated with inflammation, we know of no published studies using COX inhibitors, such as nonsteroidal anti-inflammatory drugs (NSAIDs), in the treatment of depressive syndromes in this population. To evaluate the effect of the NSAIDs celecoxib and naproxen on depressive symptoms in older adults. The Alzheimer's Disease Anti-inflammatory Prevention Trial was a randomized, placebo-controlled, double-masked clinical trial conducted at six U.S. memory clinics. Cognitively normal volunteers age 70 and older with a family history of Alzheimer-like dementia were randomly assigned to receive celecoxib 200 mg twice daily, naproxen sodium 220 mg twice daily, or placebo. The 30-item version of the Geriatric Depression Scale (GDS) was administered to all participants at enrollment and at yearly follow-up visits. Participants with a GDS score greater than 5 at baseline were classified as depressed. Of 2,528 participants enrolled, 2,312 returned for at least one follow-up visit. Approximately one-fifth had significant depressive symptoms at baseline. Mean GDS score, and the percentage with significant depressive symptoms, remained similar over time across all three treatment groups. Furthermore, there was no treatment effect on GDS scores over time in the subgroup of participants with significant depressive symptoms at baseline. In longitudinal analysis using generalized estimating equations (GEE) regression, higher baseline GDS scores, a prior psychiatric history, older age, time in the study, and lower cognition interacting with time, but not treatment assignment, were associated with significantly higher GDS scores over time. Treatment with celecoxib or naproxen did not improve depressive symptoms over time compared with placebo. While inflammation has been implicated in late-life depression, these results do not support the hypothesis that inhibition of the COX pathway with these NSAIDs at these doses alleviates depressive symptoms in older adults.

Celecoxib or naproxen treatment does not benefit depressive symptoms in persons aged 70 and over: findings from a randomized controlled trial

PubMed Central

Fields, Cynthia; Drye, Lea; Vaidya, Vijay; Lyketsos, Constantine

2011-01-01

Background Several lines of evidence suggest that inflammatory mechanisms may be involved in the severity and progression of depression. One pathway implicated is the production of prostaglandins via the enzyme cyclooxygenase (COX). Although late life depression in particular has been associated with inflammation, we know of no published studies using COX inhibitors, such as nonsteroidal anti-inflammatory drugs (NSAIDs), in the treatment of depressive syndromes in this population. Objective To evaluate the effect of the NSAIDs celecoxib and naproxen on depressive symptoms in older adults. Methods The Alzheimer’s Disease Anti-inflammatory Prevention Trial (ADAPT) was a randomized, placebo-controlled, double-masked clinical trial conducted at six U.S. memory clinics. Cognitively normal volunteers aged 70 and over with a family history of Alzheimer-like dementia were randomly assigned to receive celecoxib 200mg BID, naproxen sodium 220mg BID, or placebo. The 30-item version of the Geriatric Depression Scale (GDS) was administered to all participants at enrollment and at yearly follow-up visits. Participants with a GDS score >5 at baseline were classified as depressed. Results Of 2,528 participants enrolled 2,312 returned for at least one follow-up visit. Approximately one-fifth had significant depressive symptoms at baseline. Mean GDS score, and the percentage with significant depressive symptoms, remained similar over time across all three treatment groups. Furthermore, there was no treatment effect on GDS scores over time in the subgroup of participants with significant depressive symptoms at baseline. In longitudinal analysis using Generalized Estimating Equations (GEE) regression, higher baseline GDS scores, a prior psychiatric history, older age, time in the study, and lower cognition interacting with time, but not treatment assignment, were associated with significantly higher GDS scores over time. Conclusions Treatment with celecoxib or naproxen did not improve depressive symptoms over time compared with placebo. While inflammation has been implicated in late life depression, these results do not support the hypothesis that inhibition of the cyclooxygenase pathway with these NSAIDs at these doses alleviates depressive symptoms in older adults. PMID:21775876

Comparing Gabapentin and Celecoxib in Pain Management and Complications After Laminectomy: A Randomized Double-Blind Clinical Trial.

PubMed

Vasigh, Aminolah; Najafi, Fatemeh; Khajavikhan, Javaher; Jaafarpour, Molouk; Khani, Ali

2016-02-01

Complications and postoperative pain are major care problems that can affect the quality of health care plan. According to the use of multimodal therapy the current study aimed to compare the efficacy of gabapentin and celecoxib in pain management and complications after laminectomy at Ilam University of Medical Sciences, Ilam, Iran, in 2015. In this randomized double-blind clinical trial, 114 patients scheduled for elective laminectomy with simple random sampling design received gabapentin (n = 38, 900 mg/day), celecoxib (n = 38, 600 mg/day) and placebo (n = 38, capsule contain starch). Visual analog scale (VAS) was used to determine the intensity of pain. Complications after surgery, anxiety scores before surgery and patient's satisfaction 24 hours after the surgery were recorded. The mean pain intensity in the gabapentin group was lower compared to those of the placebo and celecoxib groups respectively at different time durations (P < 0.001). The means of morphine consumption were 11.9 mg, 22.8 mg and 30.1 mg in the gabapentin, celecoxib and placebo groups, respectively (P < 0.001). The prevalence of shivering, nausea, vomiting and pruritus were 10.5%, 12.8%, 10.3% and 18.4% in the gabapentin group vs 31.5%, 29.8%, 32.4% and 28.9% in the celecoxib group and 42.1%, 44.7%, 39.5% and 44.7% in the placebo group (P < 0.001). The mean anxiety score in the gabapentin group was 2.4 vs those of the celecoxib group 3 and placebo group 3.6 (P < 0.001). The frequencies of drowsiness were 42.1%, 13.2% and 5.3% in the gabapentin, celecoxib and placebo groups, respectively (P < 0.001). In the gabapentin group, patient satisfaction was significantly higher compared to those of the placebo and celecoxib groups (P < 0.05). According to the effect of gabapentin on pain management, complications after laminectomy and increased patients satisfaction, it can be regarded as an alter native in multimodal analgesia.

Celecoxib Induced Tumor Cell Radiosensitization by Inhibiting Radiation Induced Nuclear EGFR Transport and DNA-Repair: A COX-2 Independent Mechanism

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dittmann, Klaus H.; Mayer, Claus; Ohneseit, Petra A.

2008-01-01

Purpose: The purpose of the study was to elucidate the molecular mechanisms mediating radiosensitization of human tumor cells by the selective cyclooxygenase (COX)-2 inhibitor celecoxib. Methods and Materials: Experiments were performed using bronchial carcinoma cells A549, transformed fibroblasts HH4dd, the FaDu head-and-neck tumor cells, the colon carcinoma cells HCT116, and normal fibroblasts HSF7. Effects of celecoxib treatment were assessed by clonogenic cell survival, Western analysis, and quantification of residual DNA damage by {gamma}H{sub 2}AX foci assay. Results: Celecoxib treatment resulted in a pronounced radiosensitization of A549, HCT116, and HSF7 cells, whereas FaDu and HH4dd cells were not radiosensitized. The observedmore » radiosensitization could neither be correlated with basal COX-2 expression pattern nor with basal production of prostaglandin E2, but was depended on the ability of celecoxib to inhibit basal and radiation-induced nuclear transport of epidermal growth factor receptor (EGFR). The nuclear EGFR transport was strongly inhibited in A549-, HSF7-, and COX-2-deficient HCT116 cells, which were radiosensitized, but not in FaDu and HH4dd cells, which resisted celecoxib-induced radiosensitization. Celecoxib inhibited radiation-induced DNA-PK activation in A549, HSF7, and HCT116 cells, but not in FaDu and HH4dd cells. Consequentially, celecoxib increased residual {gamma}H2AX foci after irradiation, demonstrating that inhibition of DNA repair has occurred in responsive A549, HCT116, and HSF7 cells only. Conclusions: Celecoxib enhanced radiosensitivity by inhibition of EGFR-mediated mechanisms of radioresistance, a signaling that was independent of COX-2 activity. This novel observation may have therapeutic implications such that COX-2 inhibitors may improve therapeutic efficacy of radiation even in patients whose tumor radioresistance is not dependent on COX-2.« less

Celecoxib and tauro-ursodeoxycholic acid co-treatment inhibits cell growth in familial adenomatous polyposis derived LT97 colon adenoma cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Heumen, Bjorn W.H. van, E-mail: b.vanheumen@mdl.umcn.nl; Roelofs, Hennie M.J.; Morsche, Rene H.M. te

Chemoprevention would be a desirable strategy to avoid duodenectomy in patients with familial adenomatous polyposis (FAP) suffering from duodenal adenomatosis. We investigated the in vitro effects on cell proliferation, apoptosis, and COX-2 expression of the potential chemopreventives celecoxib and tauro-ursodeoxycholic acid (UDCA). HT-29 colon cancer cells and LT97 colorectal micro-adenoma cells derived from a patient with FAP, were exposed to low dose celecoxib and UDCA alone or in combination with tauro-cholic acid (CA) and tauro-chenodeoxycholic acid (CDCA), mimicking bile of FAP patients treated with UDCA. In HT-29 cells, co-treatment with low dose celecoxib and UDCA resulted in a decreased cellmore » growth (14-17%, p < 0.01). A more pronounced decrease (23-27%, p < 0.01) was observed in LT97 cells. Cell growth of HT-29 cells exposed to 'artificial bile' enriched with UDCA, was decreased (p < 0.001), either in the absence or presence of celecoxib. In LT97 cells incubated with 'artificial bile' enriched with UDCA, cell growth was decreased only in the presence of celecoxib (p < 0.05). No clear evidence was found for involvement of proliferating cell nuclear antigen, caspase-3, or COX-2 in the cellular processes leading to the observed changes in cell growth. In conclusion, co-treatment with low dose celecoxib and UDCA has growth inhibitory effects on colorectal adenoma cells derived from a patient with FAP, and further research on this combination as promising chemopreventive strategy is desired. -- Highlights: Black-Right-Pointing-Pointer Celecoxib and UDCA acid co-treatment decreases cell growth in colon tumor cells. Black-Right-Pointing-Pointer UDCA enriched 'artificial bile' decreases LT-97 cell growth only in presence of celecoxib. Black-Right-Pointing-Pointer PCNA, caspase-3, nor COX-2 seem to be involved in the observed changes in cell growth.« less

PDE5 Inhibitors Enhance Celecoxib Killing in Multiple Tumor Types

PubMed Central

BOOTH, LAURENCE; ROBERTS, JANE L.; CRUICKSHANKS, NICHOLA; TAVALLAI, SEYEDMEHRAD; WEBB, TIMOTHY; SAMUEL, PETER; CONLEY, ADAM; BINION, BRITTANY; YOUNG, HAROLD F.; POKLEPOVIC, ANDREW; SPIEGEL, SARAH; DENT, PAUL

2015-01-01

The present studies determined whether clinically relevant phosphodiesterase 5 (PDE5) inhibitors interacted with a clinically relevant NSAID, celecoxib, to kill tumor cells. Celecoxib and PDE5 inhibitors interacted in a greater than additive fashion to kill multiple tumor cell types. Celecoxib and sildenafil killed ex vivo primary human glioma cells as well as their associated activated microglia. Knock down of PDE5 recapitulated the effects of PDE5 inhibitor treatment; the nitric oxide synthase inhibitor L-NAME suppressed drug combination toxicity. The effects of celecoxib were COX2 independent. Over-expression of c-FLIP-s or knock down of CD95/FADD significantly reduced killing by the drug combination. CD95 activation was dependent on nitric oxide and ceramide signaling. CD95 signaling activated the JNK pathway and inhibition of JNK suppressed cell killing. The drug combination inactivated mTOR and increased the levels of autophagy and knock down of Beclin1 or ATG5 strongly suppressed killing by the drug combination. The drug combination caused an ER stress response; knock down of IRE1α/XBP1 enhanced killing whereas knock down of eIF2α/ATF4/CHOP suppressed killing. Sildenafil and celecoxib treatment suppressed the growth of mammary tumors in vivo. Collectively our data demonstrate that clinically achievable concentrations of celecoxib and sildenafil have the potential to be a new therapeutic approach for cancer. PMID:25303541

Randomised clinical trial: gastrointestinal events in arthritis patients treated with celecoxib, ibuprofen or naproxen in the PRECISION trial.

PubMed

Yeomans, N D; Graham, D Y; Husni, M E; Solomon, D H; Stevens, T; Vargo, J; Wang, Q; Wisniewski, L M; Wolski, K E; Borer, J S; Libby, P; Lincoff, A M; Lüscher, T F; Bao, W; Walker, C; Nissen, S E

2018-06-01

To evaluate GI safety of celecoxib compared with 2 nonselective (ns) NSAIDs, as a secondary objective of a large trial examining multiorgan safety. This randomised, double-blind controlled trial analysed 24 081 patients. Osteoarthritis or rheumatoid arthritis patients, needing ongoing NSAID treatment, were randomised to receive celecoxib 100-200 mg b.d., ibuprofen 600-800 mg t.d.s. or naproxen 375-500 mg b.d. plus esomeprazole, and low-dose aspirin or corticosteroids if already prescribed. Clinically significant GI events (CSGIE-bleeding, obstruction, perforation events from stomach downwards or symptomatic ulcers) and iron deficiency anaemia (IDA) were adjudicated blindly. Mean treatment and follow-up durations were 20.3 and 34.1 months. While on treatment or 30 days after, CSGIE occurred in 0.34%, 0.74% and 0.66% taking celecoxib, ibuprofen and naproxen. Hazard ratios (HR) were 0.43 (95% CI 0.27-0.68, P = 0.0003) celecoxib vs ibuprofen and 0.51 (0.32-0.81, P = 0.004) vs naproxen. There was also less IDA on celecoxib: HR 0.43 (0.27-0.68, P = 0.0003) vs ibuprofen; 0.40 (0.25-0.62, P < 0.0001) vs naproxen. Even taken with low-dose aspirin, fewer CSGIE occurred on celecoxib than ibuprofen (HR 0.52 [0.29-0.94], P = 0.03), and less IDA vs naproxen (0.42 [0.23-0.77, P = 0.005]). Corticosteroid use increased total GI events and CSGIE. H. pylori serological status had no influence. Arthritis patients taking NSAIDs plus esomeprazole have infrequent clinically significant gastrointestinal events. Co-prescribed with esomeprazole, celecoxib has better overall GI safety than ibuprofen or naproxen at these doses, despite treatment with low-dose aspirin or corticosteroids. © 2018 John Wiley & Sons Ltd.

Celecoxib enhances the radiosensitivity of HCT116 cells in a COX-2 independent manner by up-regulating BCCIP

PubMed Central

Xu, Xiao-Ting; Hu, Wen-Tao; Zhou, Ju-Ying; Tu, Yu

2017-01-01

It has been reported that celecoxib, a cyclooxygenase-2 (COX-2)-selective nonsteroidal anti-inflammatory drug (NSAID), regulates the radiosensitivity of several cancer cells. BCCIP (BRCA2 and CDKN1A interacting protein) plays a critical role in maintaining the critical functions of p53 in tumor suppression and response to therapy. However, whether the effect of celecoxib on the radiosensitivity of colorectal cancer (CRC) cells is dependent on BCCIP is largely unclear. In this study, we found that celecoxib enhanced the radiosensitivity of HeLa (a human cervical carcinoma cell line), A549 (a human lung carcinoma cell line), and HCT116 cells (a human CRC cells line). Among these cells, COX-2 expression was undetected in HCT116 cells. Treatment with celecoxib significantly increased BCCIP expression in COX-2 negative HCT116 cells. Knockdown of BCCIP obviously abrogated the enhanced radiosensitivity of HCT116 cells induced by celecoxib. A combination of celecoxib and irradiation treatment induced much more γ-H2AX foci formation, higher levels of radiation injury-related proteins phosphorylation, G2/M arrest, apoptosis, and p53 and p21 expression, and lower levels of Cyclin B1 in HCT116 cells than those in cells treated with irradiation alone. However, these changes were undetected in BCCIP-silenced HCT116 cells. Therefore, these data suggest that BCCIP gene may be a radiosensitivity-related gene in CRC. Celecoxib affects the functions of p53 and inhibits the recovery from the irradiation-induced injury by up-regulating the expression of BCCIP, and subsequently regulates the expressions of genes such as p21 and Cyclin B1 to enhance the radiosensitivity of HCT116 cells in a COX-2 independent manner. PMID:28386336

Celecoxib versus ibuprofen in the prevention of heterotopic ossification following total hip replacement: a prospective randomised trial.

PubMed

Saudan, M; Saudan, P; Perneger, T; Riand, N; Keller, A; Hoffmeyer, P

2007-02-01

We examined whether a selective cyclooxygenase-2 (COX-2) inhibitor (celecoxib) was as effective as a non-selective inhibitor (ibuprofen) for the prevention of heterotopic ossification following total hip replacement. A total of 250 patients were randomised to receive celecoxib (200 mg b/d) or ibuprofen (400 mg t.d.s) for ten days after surgery. Anteroposterior radiographs of the pelvis were examined for heterotopic ossification three months after surgery. Of the 250 patients, 240 were available for assessment. Heterotopic ossification was more common in the ibuprofen group (none 40.7% (50), Brooker class I 46.3% (57), classes II and III 13.0% (16)) than in the celecoxib group (none 59.0% (69), Brooker class I 35.9% (42), classes II and III 5.1% (6), p=0.002). Celecoxib was more effective than ibuprofen in preventing heterotopic bone formation after total hip replacement.

Celecoxib Versus Placebo in Tonsillectomy: A Prospective, Randomized, Double-Blind Placebo-Controlled Trial.

PubMed

Van Daele, Douglas J; Bodeker, Kellie L; Trask, Douglas K

2016-10-01

Celecoxib is a cyclooxygenase-2-specific inhibitor indicated to treat acute pain and pain secondary to osteoarthritis and rheumatoid arthritis. Surgical models of acute pain have demonstrated superior pain relief to placebo. The objective of this study was to test the safety and efficacy of celecoxib for pain relief after tonsillectomy compared to placebo. Adult subjects were randomized to 200 mg celecoxib versus placebo with a loading dose the night before surgery then twice daily for 10 days. Subjects were instructed to supplement the study drug with hydrocodone/acetaminophen liquid or acetaminophen for pain as needed. Subjects completed a daily diary regarding their pain, nausea, vomiting, diet, and activity. Seventeen subjects enrolled. Intraoperative blood loss was similar between groups, and no subject had postoperative bleeding. Three patients returned to the emergency department for treatment, and 2 patients could not complete the diaries, all in the placebo group. Subjects in the placebo group required statistically significant (P < .05) higher doses of narcotic and acetaminophen to control pain. Pain and diet rating scores were slightly better in the celecoxib group compared to placebo. In this small cohort, celecoxib reduced postoperative narcotic and acetaminophen requirements compared to placebo without complications. © The Author(s) 2016.

Escaping the Adverse Impacts of NSAIDs on Tooth Movement During Orthodontics: Current Evidence Based on a Meta-Analysis.

PubMed

Fang, Jie; Li, Yifei; Zhang, Keke; Zhao, Zhihe; Mei, Li

2016-04-01

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to relieve pain during orthodontic treatments; however, the possible inhibition of orthodontic tooth movement (OTM) by NSAIDs has been debated. The aim of this study was to evaluate the influence of some commonly used NSAIDs on OTM during orthodontic treatments. A review of the literature identified relevant studies up to August 2014. A meta-analysis was performed following the guidelines of the Cochrane review group and the PRISMA statement. Studies were identified by searching PUBMED, EMBASE, Web of Science, the Cochrane Central Register of Controlled Trials, and the WHO Clinical Trials Registry Platform. Meta-analysis was performed in a fixed/random-effect model using Revman 5.1.1.Five studies, including 128 subjects and 3 main NSAIDs (celecoxib, acetaminophen, and aspirin), were included for quantitative synthesis and analysis. Celecoxib did not inhibit OTM except with middle-term use (2-3 weeks) (95% CI [-6.47 to -0.43], P = 0.03). Acetaminophen did not inhibit OTM except with long-term use (>1 month) and low-dose use (∼100 mg/kg per day), (95% CI [-2.96 to -0.78], P = 0.0008; 95%CI [-2.42, -0.46], P = 0.004; respectively). Aspirin was found to inhibit OTM (95%CI [-2.40 to -0.64], P = 0.0008). Our systematic review with meta-analysis suggests that aspirin might inhibit OTM in rat models, whereas the short-term (<1 week) use of celecoxib and acetaminophen for relieving orthodontic pain would not inhibit OTM. Well-designed human research should be completed before a solid conclusion can be reached.

Differential impairment of aspirin-dependent platelet cyclooxygenase acetylation by nonsteroidal antiinflammatory drugs

PubMed Central

Li, Xuanwen; Fries, Susanne; Li, Ruizhi; Lawson, John A.; Propert, Kathleen J.; Diamond, Scott L.; Blair, Ian A.; FitzGerald, Garret A.; Grosser, Tilo

2014-01-01

The cardiovascular safety of nonsteroidal antiinflammatory drugs (NSAIDs) may be influenced by interactions with antiplatelet doses of aspirin. We sought to quantitate precisely the propensity of commonly consumed NSAIDs—ibuprofen, naproxen, and celecoxib—to cause a drug–drug interaction with aspirin in vivo by measuring the target engagement of aspirin directly by MS. We developed a novel assay of cyclooxygenase-1 (COX-1) acetylation in platelets isolated from volunteers who were administered aspirin and used conventional and microfluidic assays to evaluate platelet function. Although ibuprofen, naproxen, and celecoxib all had the potential to compete with the access of aspirin to the substrate binding channel of COX-1 in vitro, exposure of volunteers to a single therapeutic dose of each NSAID followed by 325 mg aspirin revealed a potent drug–drug interaction between ibuprofen and aspirin and between naproxen and aspirin but not between celecoxib and aspirin. The imprecision of estimates of aspirin consumption and the differential impact on the ability of aspirin to inactivate platelet COX-1 will confound head-to-head comparisons of distinct NSAIDs in ongoing clinical studies designed to measure their cardiovascular risk. PMID:25385584

A parallel-group comparison study of celecoxib with loxoprofen sodium in third mandibular molar extraction patients.

PubMed

Yamashita, Y; Sano, N; Shimohira, D; Danjo, A; Goto, M

2014-12-01

Non-steroidal anti-inflammatory drugs (NSAIDs) are used widely, but they may damage the upper gastrointestinal mucosa owing to their mechanism of action. Selective cyclooxygenase 2 (COX-2) inhibitors are known to have a reduced risk for such damage. In this comparative study, the efficacy and safety of the selective COX-2 inhibitor celecoxib for pain after third mandibular molar extraction were compared with those of loxoprofen sodium. This was a parallel-group comparison study; 107 patients who had undergone third mandibular molar extraction were given celecoxib and 102 were given loxoprofen. The level of pain on a visual analogue scale (VAS) 15 min and 30 min after taking the experimental drug decreased over time, with no significant difference between the two groups. The percentage of patients taking a second dose was 64.5% for celecoxib and 80.4% for loxoprofen. The time to second dose was significantly longer for celecoxib (533.5 min) than for loxoprofen (387.4 min). There was no significant difference in the patients' impression of efficacy between the two groups, with ratings of 'excellent' and 'good' for 77.4% in the loxoprofen group and 74.5% in the celecoxib group. These results demonstrate that celecoxib is of equal clinical value to loxoprofen for acute pain after third mandibular molar extraction. Copyright © 2014 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

Comparing Gabapentin and Celecoxib in Pain Management and Complications After Laminectomy: A Randomized Double-Blind Clinical Trial

PubMed Central

Vasigh, Aminolah; Najafi, Fatemeh; Khajavikhan, Javaher; Jaafarpour, Molouk; Khani, Ali

2016-01-01

Background Complications and postoperative pain are major care problems that can affect the quality of health care plan. Objectives According to the use of multimodal therapy the current study aimed to compare the efficacy of gabapentin and celecoxib in pain management and complications after laminectomy at Ilam University of Medical Sciences, Ilam, Iran, in 2015. Patients and Methods In this randomized double-blind clinical trial, 114 patients scheduled for elective laminectomy with simple random sampling design received gabapentin (n = 38, 900 mg/day), celecoxib (n = 38, 600 mg/day) and placebo (n = 38, capsule contain starch). Visual analog scale (VAS) was used to determine the intensity of pain. Complications after surgery, anxiety scores before surgery and patient’s satisfaction 24 hours after the surgery were recorded. Results The mean pain intensity in the gabapentin group was lower compared to those of the placebo and celecoxib groups respectively at different time durations (P < 0.001). The means of morphine consumption were 11.9 mg, 22.8 mg and 30.1 mg in the gabapentin, celecoxib and placebo groups, respectively (P < 0.001). The prevalence of shivering, nausea, vomiting and pruritus were 10.5%, 12.8%, 10.3% and 18.4% in the gabapentin group vs 31.5%, 29.8%, 32.4% and 28.9% in the celecoxib group and 42.1%, 44.7%, 39.5% and 44.7% in the placebo group (P < 0.001). The mean anxiety score in the gabapentin group was 2.4 vs those of the celecoxib group 3 and placebo group 3.6 (P < 0.001). The frequencies of drowsiness were 42.1%, 13.2% and 5.3% in the gabapentin, celecoxib and placebo groups, respectively (P < 0.001). In the gabapentin group, patient satisfaction was significantly higher compared to those of the placebo and celecoxib groups (P < 0.05). Conclusions According to the effect of gabapentin on pain management, complications after laminectomy and increased patients satisfaction, it can be regarded as an alter native in multimodal analgesia. PMID:27195145

Novel anti-inflammatory and analgesic agents: synthesis, molecular docking and in vivo studies.

PubMed

Ugwu, David Izuchukwu; Okoro, Uchechukwu Christopher; Ukoha, Pius Onyeoziri; Gupta, Astha; Okafor, Sunday N

2018-12-01

Twelve new derivatives of benzothiazole bearing benzenesulphonamide and carboxamide were synthesised and investigated for their in vivo anti-inflammatory, analgesic and ulcerogenic activities. Molecular docking showed an excellent binding interaction of the synthesised compounds with the receptors, with 17c showing the highest binding energy (-12.50 kcal/mol). Compounds 17c and 17i inhibited carrageenan-induced rat paw oedema at 72, 76, and 80% and 64, 73, and 78% at 1 h, 2 h, and 3 h, respectively. In the analgesic activity experiment, compounds 17c, 17 g, and 17i had ED 50 (µM/kg) of 96, 127, and 84 after 0.5 h; 102, 134, and 72 after 1 h and 89, 156, and 69 µM/kg after 2 h, respectively, which were comparable with 156, 72, and 70 µM/kg for celecoxib. The ulcerogenic index of the most active derivatives 17c and 17i were 0.82 and 0.89, respectively, comparable to 0.92 for celecoxib. The physicochemical studies of the new derivatives showed that they will not have oral bioavailability problems.

The refined biomimetic NeuroDigm GEL™ model of neuropathic pain in a mature rat

PubMed Central

Hannaman, Mary R.; Fitts, Douglas A.; Doss, Rose M.; Weinstein, David E.; Bryant, Joseph L.

2017-01-01

Background: Many humans suffering with chronic neuropathic pain have no objective evidence of an etiological lesion or disease. Frequently their persistent pain occurs after the healing of a soft tissue injury. Based on clinical observations over time, our hypothesis was that after an injury in mammals the process of tissue repair could cause chronic neural pain. Our objectives were to create the delayed onset of neuropathic pain in rats with minimal nerve trauma using a physiologic hydrogel, and characterize the rats’ responses to known analgesics and a targeted biologic. Methods: In mature male Sprague Dawley rats (age 9.5 months) a percutaneous implant of tissue-derived hydrogel was placed in the musculofascial tunnel of the distal tibial nerve. Subcutaneous morphine (3 mg/kg), celecoxib (10 mg/kg), gabapentin (25 mg/kg) and duloxetine (10 mg/kg) were each screened in the model three times each over 5 months after pain behaviors developed. Sham and control groups were used in all screenings. A pilot study followed in which recombinant human erythropoietin (200 units) was injected by the GEL™ neural procedure site. Results: The GEL group gradually developed mechanical hypersensitivity lasting months. Morphine, initially effective, had less analgesia over time. Celecoxib produced no analgesia, while gabapentin and duloxetine at low doses demonstrated profound analgesia at all times tested. The injected erythropoietin markedly decreased bilateral pain behavior that had been present for over 4 months, p ≤ 0.001. Histology of the GEL group tibial nerve revealed a site of focal neural remodeling, with neural regeneration, as found in nerve biopsies of patients with neuropathic pain. Conclusion: The refined NeuroDigm GEL™ model induces a neural response resulting in robust neuropathic pain behavior. The analgesic responses in this model reflect known responses of humans with neuropathic pain. The targeted recombinant human erythropoietin at the ectopic neural lesion appears to alleviate the persistent pain behavior in the GEL™ model rodents. PMID:28620451

Celecoxib: a potent cyclooxygenase-2 inhibitor in cancer prevention.

PubMed

Kismet, Kemal; Akay, M Turan; Abbasoglu, Osman; Ercan, Aygün

2004-01-01

Non-steroidal anti-inflammatory drugs (NSAIDs) are the most widely used therapeutic agents in the treatment of pain, inflammation and fever. They may also have a role in the management of cancer prevention, Alzheimer's disease and prophylaxis against cardiovascular disease. These drugs act primarily by inhibiting cyclooxygenase enzyme, which has two isoforms, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). Selective COX-2 inhibitors provide potent anti-inflammatory and analgesic effects without the side effects of gastric and renal toxicity and inhibition of platelet function. Celecoxib is a potent COX-2 inhibitor being developed for the treatment of rheumatoid arthritis and osteoarthritis. Chemoprevention is the use of pharmacological or natural agents to prevent, suppress, interrupt or reverse the process of carcinogenesis. For this purpose, celecoxib is being used for different cancer types. The effects of NSAIDs on tumor growth remain unclear, but are most likely to be multifocal. In this article, we reviewed COX-2 selectivity, the pharmacological properties of celecoxib, the use of celecoxib for cancer prevention and the mechanisms of chemoprevention.

Cyclooxygenase 2 Promotes Parathyroid Hyperplasia in ESRD

PubMed Central

Zhang, Qian; Qiu, Junsi; Li, Haiming; Lu, Yanwen; Wang, Xiaoyun; Yang, Junwei; Wang, Shaoqing; Zhang, Liyin; Gu, Yong; Hao, Chuan-Ming

2011-01-01

Hyperplasia of the PTG underlies the secondary hyperparathyroidism (SHPT) observed in CKD, but the mechanism underlying this hyperplasia is incompletely understood. Because aberrant cyclooxygenase 2 (COX2) expression promotes epithelial cell proliferation, we examined the effects of COX2 on the parathyroid gland in uremia. In patients with ESRD who underwent parathyroidectomy, clusters of cells within the parathyroid glands had increased COX2 expression. Some COX2-positive cells exhibited two nuclei, consistent with proliferation. Furthermore, nearly 78% of COX2-positive cells expressed proliferating cell nuclear antigen (PCNA). In the 5/6-nephrectomy rat model, rats fed a high-phosphate diet had significantly higher serum PTH levels and larger parathyroid glands than sham-operated rats. Compared with controls, the parathyroid glands of uremic rats exhibited more PCNA-positive cells and greater COX2 expression in the chief cells. Treatment with COX2 inhibitor celecoxib significantly reduced PCNA expression, attenuated serum PTH levels, and reduced the size of the glands. In conclusion, COX2 promotes the pathogenesis of hyperparathyroidism in ESRD, suggesting that inhibiting the COX2 pathway could be a potential therapeutic target. PMID:21335517

Celecoxib suppresses fibroblast growth factor-2 expression in pancreatic ductal adenocarcinoma PANC-1 cells.

PubMed

Li, Jing; Luo, Miaosha; Wang, Yan; Shang, Boxin; Dong, Lei

2016-09-01

The inhibition of cyclooxygenase (COX)-2 has been reported to suppress growth and induce apoptosis in human pancreatic cancer cells. Nevertheless, the precise biological mechanism of how celecoxib, a selective COX-2 inhibitor, regulates the growth and invasion of pancreatic tumors is not completely understood. It has been shown that fibroblast growth factor-2 (FGF-2) and its receptor levels correlate with the inhibition of cancer cell proliferation, migration and invasion in pancreatic ductal adenocarcinoma (PDAC). Therefore, the aim of the present study was to examine the hypothesis that the antitumor activity of celecoxib in PDAC may be exerted through modulation of FGF-2 function. In the present study, we evaluated the effects of celecoxib on the proliferation, migration, invasion and apoptosis of the PANC-1 cell line. Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR) were used to examine the expression of FGF-2, FGFR-2, ERK1/2 and MMPs. In the present study, FGF-2 and FGFR-2 were expressed in PANC-1 cells and FGF-2 exerted a stimulatory effect on phosphorylated extracellular signal regulated kinase (p-ERK) expression. Celecoxib treatment suppressed FGF-2 and FGFR-2 expression and decreased MMP-2, MMP-9 and p-ERK expression in the PANC-1 cells. Furthermore, celecoxib treatment caused the resistance of PANC-1 cells to FGF-2 induced proliferation, migration and invasion ability, as well as the increase in their apoptotic rate. Our data provide evidence that targeting FGF-2 with celecoxib may be used as an effective treatment in PDAC.

[Effects of perioperative administration of celecoxib on pain management and recovery of function after total knee replacement].

PubMed

Shen, Bin; Tang, Xin; Yang, Jing; Li, Yong; Zhou, Zong-ke; Kang, Peng-de; Pei, Fu-xing

2009-01-15

To assess the effect of perioperative administration of a selective cyclooxygenase 2 inhibitor (celecoxib) on pain management and recovery of function after total knee arthroplasty (TKA). Randomized, controlled trial conducted from January 2005 through February 2006, 60 patients underwent TKA for osteoarthritis or rheumatoid arthritis were randomly divided into group of perioperative, administration of celecoxib (Study group, n = 30) and postoperative administration of celecoxib (Control group, n = 30). Patients in Study group were given oral celecoxib 3 d before TKA, 200 mg twice daily, and extended to 5 d postoperatively; patients in Control group were given oral celecoxib 2 h after TKA, 200 mg twice daily, and extended to 5 d postoperatively. All operations were finished by the same surgeon group. The postoperative patient-controlled analgesia (PCA) consumption was significantly less in Study group than in Control group [(43 +/- 12) ml vs. (53 +/- 12) ml, P < 0.05]. The pain scores of postoperative 4, 8, 12 h, 1, 2 d in Study group were 6.1 +/- 1.2, 5.0 +/- 1.3, 4.3 +/- 1.1, 3.4 +/- 1.2, significantly less than in Control group (P < 0.05); There were no intergroup significant differences in the pain scores of postoperative 3, 4, 5 d (P > 0.05). There were no intergroup significant differences in respect to the side-effect occurrence, operation time and postoperative drainage, postoperative analgesic consumption (P > 0.05). The time to achieve 90 degrees knee flexion was significantly shorter in Study group than in Control group [(6.2 +/- 1.7) d vs. (8.6 +/- 1.8) d, P < 0.05]. Perioperative administration of the selective Celecoxib holds the effect of preemptive analgesia. Compared with postoperative administration, perioperative administration of celecoxib can alleviate the early postoperative pain score, reduce the consumption of postoperative analgesic, accelerate the recovery of joint motion and thus increase the patient satisfaction.

The economic and clinical burden of early versus late initiation of celecoxib among patients with osteoarthritis

PubMed Central

Shelbaya, Ahmed; Solem, Caitlyn T; Walker, Chris; Wan, Yin; Johnson, Courtney; Cappelleri, Joseph C

2018-01-01

Objective This study aimed to evaluate the characteristics associated with early versus late initiation of celecoxib treatment after osteoarthritis (OA) diagnosis and whether economic and safety outcomes differ between patients with early versus late initiation of celecoxib. Methods Adults (≥18 years) with a confirmed OA diagnosis (International Classification of Diseases, 9th Edition, Clinical Modifications code: 715.XX), ≥12 months of continuous pre- and post-index enrollment, and ≥1 post-index claim for celecoxib were included from the MarketScan® Commercial Claims and Encounter Database (2009–2013). Index date was defined as initial OA diagnosis. Patients were categorized as initiating celecoxib early (within 6 months of index date) or late (≥6 months after index date). Logistic regressions were used to assess characteristics associated with early versus late celecoxib initiation. Key outcomes included health care resource utilization (HCRU) and costs post-index, and adverse event incidence post-celecoxib initiation. Unadjusted and adjusted comparisons (using generalized linear models with a gamma distribution for costs and Poisson distribution for event and resource utilization) were made between early and late celecoxib initiators. Results Of the 62,434 OA patients identified, 27,402 were early and 35,032 were late initiators. Post-index hospital admissions and length of stay did not differ statistically between early versus late initiators after controlling for pre-index event rates and covariates, but early patients had significantly fewer outpatient (incidence rate ratio [IRR]: 0.96; 95% confidence interval [CI]: 0.95, 0.97) and emergency room visits (IRR: 0.89; 95% CI: 0.84, 0.95). After adjustment for key covariates, early initiators (versus late initiators) had lower all-cause (US$12,909 versus US$13,781, P<0.001) and OA-related (US$4,988 versus US$5,178, P=0.015) costs per person-year. Early initiators had no statistically significant difference in the incidence of post-celecoxib cardiovascular (IRR: 0.92; 95% CI: 0.73, 1.14), gastrointestinal (IRR: 1.25; 95% CI: 0.81, 1.92), or renal (IRR: 1.19; 95% CI: 0.65, 2.18) events, controlling for pre-index event rates and covariates when compared to late initiators. Conclusion In this real-world cohort, patients initiated on celecoxib early (versus late) had significantly lower costs and HCRU; this may warrant consideration when making treatment decisions for OA patients. PMID:29670383

Antinociceptive and anti-arthritic properties of hydroethanolic leaf extract of Clausena anisata (Willd.) Hook. f. ex Benth (Rutaceae) in Rodents: possible mechanism of actions.

PubMed

Ishola, Ismail O; Olayemi, Sunday O; Oreagba, Ibrahim A; Ifeanyi, Chikaodili I; Popoola, Temidayo O

2015-12-20

The leaves of Clausena anisata (Willd.) Hook. f. ex Benth (Rutaceae) is used in Traditional African medicine for the treatment of various ailments including arthritis. The present study sought to investigate the antinociceptive and anti-arthritic properties of hydroethanolic leaf extract of Clausena anisata (HeCA). HeCA (100, 200 or 400 mg/kg, p.o.) was administered 1 h before intraplantar injection of formalin 1%v/v in saline to evaluate antinociceptive effect. Moreover, its possible mechanism of antinociceptive action was investigated through pretreatment of mice with antagonists of receptors implicated in nociception. Anti¬inflammatory effect of the extract was investigated using the carrageenan-induced paw oedema and complete Freund's adjuvant (CFA)-induced arthritis models in rats. HeCA (400 mg/kg) treatment significantly reduced the duration of paw licking/biting during both in the early (42.12%) and late (75.79%) phases of formalin-induced nociception. However, the antinociceptive effect elicited by HeCA was reverse by pretreatment of mice with naloxone, prazosin, yohimbine, ketanserin, L-arginine, and parachlorophenylalanine (PCPA). HeCA produced dose-dependent and time course decrease in carrageenan-induced paw oedema. Pre- and post-treatment of rats with HeCA ameliorated CFA-induced arthritis evidenced in the significant decrease in arthritic index comparatively similar to the effect of celecoxib. CFA- induced oxidative and nitrosative stress were attenuated by subchronic treatment with HeCA. Findings from this study shows that C. anisata possesses antinociceptive activity through possible interaction with opioidergic, noradrenergic, L-arginine-nitric oxide and serotonergic pathways as well as anti-arthritic property which could be attributed to its ability to prevent the release of inflammatory mediators and oxidative stress.

Association of Celecoxib Use With Decreased Opioid Requirements After Head and Neck Cancer Surgery With Free Tissue Reconstruction.

PubMed

Carpenter, Patrick S; Shepherd, Hailey M; McCrary, Hilary; Torrecillas, Vanessa; Kull, Amanda; Hunt, Jason P; Monroe, Marcus M; Buchmann, Luke O; Cannon, Richard B

2018-04-18

Head and neck cancer (HNC) surgery with free tissue reconstruction is associated with considerable postoperative pain. Opioids are typically used but can have adverse effects, including respiratory depression and high rates of dependence and addiction. Safe alternative analgesics that minimize opioid requirements are beneficial in HNC surgery. To investigate the association of celecoxib use with opioid requirements in the postoperative setting after HNC surgery with free tissue reconstruction. A retrospective, matched-cohort study of 147 patients who had undergone HNC surgery with free tissue reconstruction between June 2015 and Sept 2017 in an academic cancer hospital. Patients were separated into groups based on whether celecoxib had been used perioperatively or not. These groups were then matched by stage and site resulting in 102 included participants (51 celecoxib, 51 control). Oral, intravenous (IV), and total morphine equivalents used in the postoperative setting per patient per day. There were 51 patients in the celecoxib cohort (19 women and 32 men) and 51 patients in the control cohort (20 women and 31 men) who met inclusion criteria after clinicopathologic data were matched. The mean age of the celecoxib and control cohorts was 61.6 years and 66.1 years, respectively. Treatment with celecoxib in the postoperative setting was associated with decreased mean use of opioids in oral (mean difference, 9.9 mg/d; 95% CI, -1.2 to 21.1), IV (mean difference, 3.9 mg/d; 95% CI, 1.0-6.8), and total (mean difference, 14 mg/d; 95% CI, 2.6-25.4) amount of morphine equivalents per day. When patients were matched to surgical procedure, the effect was more significant. Patients who underwent composite oral resection and received celecoxib had decreased opioid use in oral (mean difference, 25 mg/d; 95% CI, 12.5-25.4), IV (mean difference, 3.4 mg/d; 95% CI, 1.5-5.5), and total (mean difference, 28.4 mg/d; 95% CI, 15.7-41.5) amounts compared with those in the control group. There was no significant difference in complication rates between the 2 cohorts. Use of celecoxib after head and neck cancer surgery and reconstruction with free tissue transfer was associated with a decrease in oral, IV, and total opioid requirements without increasing surgical or flap-related complications.

Combination of a poxvirus-based vaccine with a cyclooxygenase-2 inhibitor (celecoxib) elicits antitumor immunity and long-term survival in CEA.Tg/MIN mice.

PubMed

Zeytin, Hasan E; Patel, Arti C; Rogers, Connie J; Canter, Daniel; Hursting, Stephen D; Schlom, Jeffrey; Greiner, John W

2004-05-15

The present study was designed to determine whether: (a) chronic administration of dietary celecoxib (Celebrex), a potent nonsteroidal anti-inflammatory drug, which targets the cyclooxygenase-2 (COX-2) enzyme, negatively impacts host immunity; and (b) celecoxib can be coupled with a poxvirus-based vaccine to impact tumor burden in a murine tumor model of spontaneous adenomatous polyposis coli. Naive mice fed the celecoxib-supplemented diets developed eosinophilia with lowered plasma prostaglandin E(2) levels and reduced COX-2 mRNA expression levels in their splenic T cells. Responses of splenic T, B, and natural killer cells to broad-based and antigen-specific stimuli were, for the most part, unchanged in those mice as well as COX-2 knockout mice; exceptions included: (a) reduced IFN-gamma production by concanavalin A- or antigen-stimulated T cells; and (b) heightened lipopolysaccharide response of naive B cells from mice fed a diet supplemented with 1000 ppm of celecoxib. When transgenic mice that express the human carcinoembryonic antigen (CEA) gene (CEA transgenic) were bred with mice bearing a mutation in the Apc(Delta850) gene (multiple intestinal neoplasia mice), the progeny (CEA transgenic/multiple intestinal neoplasia) spontaneously develop multiple intestinal neoplasms that overexpress CEA and COX-2. Beginning at 30 days of age, the administration of a diversified prime/boost recombinant CEA-poxvirus-based vaccine regimen or celecoxib (1000 ppm)-supplemented diet reduced the number of intestinal neoplasms by 54% and 65%, respectively. Combining the CEA-based vaccine with the celecoxib-supplemented diet reduced tumor burden by 95% and significantly improved overall long-term survival. Both tumor reduction and improved overall survival were achieved without any evidence of autoimmunity directed at CEA-expressing or other normal tissues. Celecoxib is prescribed for the treatment of familial adenomatous polyposis in humans, and the CEA-based vaccines have been well tolerated and capable of eliciting anti-CEA host immune responses in early clinical studies. The results suggest that the administration of a recombinant poxvirus-based vaccine is compatible with celecoxib, and this combined chemoimmuno-based approach might lead to an additive therapeutic antitumor benefit not only in patients diagnosed with familial adenomatous polyposis but, perhaps, in other preventive settings in which COX-2 overexpression is associated with progression from premalignancy to neoplasia.

Mechanisms underlying the growth inhibitory effects of the cyclo-oxygenase-2 inhibitor celecoxib in human breast cancer cells.

PubMed

Basu, Gargi D; Pathangey, Latha B; Tinder, Teresa L; Gendler, Sandra J; Mukherjee, Pinku

2005-01-01

Inhibitors of cyclo-oxygenase (COX)-2 are being extensively studied as anticancer agents. In the present study we evaluated the mechanisms by which a highly selective COX-2 inhibitor, celecoxib, affects tumor growth of two differentially invasive human breast cancer cell lines. MDA-MB-231 (highly invasive) and MDA-MB-468 (moderately invasive) cell lines were treated with varying concentrations of celecoxib in vitro, and the effects of this agent on cell growth and angiogenesis were monitored by evaluating cell proliferation, apoptosis, cell cycle arrest, and vasculogenic mimicry. The in vitro results of MDA-MB-231 cell line were further confirmed in vivo in a mouse xenograft model. The highly invasive MDA-MB-231 cells express higher levels of COX-2 than do the less invasive MDA-MB-468 cells. Celecoxib treatment inhibited COX-2 activity, indicated by prostaglandin E2 secretion, and caused significant growth arrest in both breast cancer cell lines. In the highly invasive MDA-MB-231 cells, the mechanism of celecoxib-induced growth arrest was by induction of apoptosis, associated with reduced activation of protein kinase B/Akt, and subsequent activation of caspases 3 and 7. In the less invasive MDA-MB-468 cells, growth arrest was a consequence of cell cycle arrest at the G0/G1 checkpoint. Celecoxib-induced growth inhibition was reversed by addition of exogenous prostaglandin E2 in MDA-MB-468 cells but not in MDA-MB-231 cells. Furthermore, MDA-MB-468 cells formed significantly fewer extracellular matrix associated microvascular channels in vitro than did the high COX-2 expressing MDA-MB-231 cells. Celecoxib treatment not only inhibited cell growth and vascular channel formation but also reduced vascular endothelial growth factor levels. The in vitro findings corroborated in vivo data from a mouse xenograft model in which daily administration of celecoxib significantly reduced tumor growth of MDA-MB-231 cells, which was associated with reduced vascularization and increased necrosis in the tumor mass. The disparate molecular mechanisms of celecoxib-induced growth inhibition in human breast cancer cells depends upon the level of COX-2 expression and the invasive potential of the cell lines examined. Data suggest a role for COX-2 not only in the growth of cancer cells but also in activating the angiogenic pathway through regulating levels of vascular endothelial growth factor.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zuo, Chaohui, E-mail: zuochaohui@vip.sina.com; Department of Pathology, Immunology and Laboratory Medicine and Shands Cancer Center, University of Florida, Gainesville, FL; Qiu, Xiaoxin

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. Interferon-alpha (IFN-α) has recently been recognized to harbor therapeutic potential in the prevention and treatment of HCC, but it remains controversial as to whether IFN-α exerts direct cytotoxicity against HCC. Cyclooxygenase-2 (COX-2) is overexpressed in HCC and is considered to play a role in hepatocarcinogenesis. Therefore, we aimed to elucidate the combined effect of a COX-2 inhibitor, celecoxib, and IFN-α on in vitro growth suppression of HCC using the hepatoma cell line HLCZ01 and the in vivo nude mouse xenotransplantation model using HLCZ01 cells. Treatment with celecoxib and IFN-αmore » synergistically inhibited cell proliferation in a dose- and time-dependent manner. Apoptosis was identified by 4',6-diamidino-2-phenylindole dihydrochloride and fluorescent staining. IFN-α upregulated the expression of TRAIL, while celecoxib increased the expression of TRAIL receptors. The combined regimen with celecoxib and IFN-α reduced the growth of xenotransplanted HCCs in nude mice. The regulation of IFN-α- and COX-2 inhibitor-induced cell death is impaired in a subset of TRAIL-resistant cells. The molecular mechanisms of HCC cells resistant to TRAIL-induced apoptosis were explored using molecular biological and immunological methods. Interferon-α and the COX-2 inhibitor celecoxib synergistically increased TRAIL-induced apoptosis in hepatocellular carcinoma. These data suggest that IFN-α and celecoxib may offer a novel role with important implications in designing new therapeutics for TRAIL-resistant tumors. - Highlights: ●The cytotoxic effect of TRAIL on a developed HCC HLCZ01 cells infected with HBV. ●IFN-α and celecoxib induced apoptosis in HLCZ01 cells infected with HBV. ●The combined regime reduced the growth of xenotransplanted HCCs in nude mice model.« less

A multicentre, randomized, placebo- and active-controlled trial comparing the efficacy and safety of topical ketoprofen in Transfersome gel (IDEA-033) with ketoprofen-free vehicle (TDT 064) and oral celecoxib for knee pain associated with osteoarthritis.

PubMed

Conaghan, Philip G; Dickson, John; Bolten, Wolfgang; Cevc, Gregor; Rother, Matthias

2013-07-01

To assess the efficacy and safety of 12-week treatment with ketoprofen in ultradeformable phospholipid vesicles in patients with OA knee pain and to compare the efficacy with that of ketoprofen-free vehicle and celecoxib. METHODS; A multicentre, double-blind controlled study in which patients with knee OA and moderate pain were randomized to one of the six arms: topical ketoprofen 50 or 100 mg in ultradeformable vesicles (IDEA-033), 2.2 or 4.4 g ketoprofen-free vehicle (TDT 064), oral celecoxib 100 mg or matching oral placebo, all bd. The primary outcome was change from baseline in the WOMAC pain subscale at week 12. A total of 1395 patients received treatment. Baseline mean WOMAC pain scores ranged from 4.7 to 4.8 across groups. The mean reduction in WOMAC pain score at week 12 was -1.9 (-40.8%) for ketoprofen 50 mg, -1.9 (-40.9%) for ketoprofen 100 mg, -1.9 (-39.8%) for 2.2 g TDT 064, -1.8 (-37.8%) for 4.4 g TDT 064, -1.9 (-40.4%) for celecoxib and -1.4 (-29.3%) for oral placebo. IDEA-033 was not statistically superior to TDT 064. All topical treatments were statistically superior to oral placebo and non-inferior to celecoxib. The most frequent types of treatment-related adverse events reported were gastrointestinal for oral (15.9% for celecoxib) and dermal for topical applications (12.2% for ketoprofen 100 mg). IDEA-033 was not superior to ketoprofen-free vehicle, but both formulations were superior to oral placebo and non-inferior to celecoxib in reducing OA knee pain. ClinicalTrials.gov, http://clinicaltrials.gov/, NCT00716547.

Coxibs interfere with the action of aspirin by binding tightly to one monomer of cyclooxygenase-1

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rimon, Gilad; Sidhu, Ranjinder S.; Lauver, D. Adam

Pain associated with inflammation involves prostaglandins synthesized from arachidonic acid (AA) through cyclooxygenase-2 (COX-2) pathways while thromboxane A{sub 2} formed by platelets from AA via cyclooxygenase-1 (COX-1) mediates thrombosis. COX-1 and COX-2 are both targets of nonselective nonsteroidal antiinflammatory drugs (nsNSAIDs) including aspirin whereas COX-2 activity is preferentially blocked by COX-2 inhibitors called coxibs. COXs are homodimers composed of identical subunits, but we have shown that only one subunit is active at a time during catalysis; moreover, many nsNSAIDS bind to a single subunit of a COX dimer to inhibit the COX activity of the entire dimer. Here, we reportmore » the surprising observation that celecoxib and other coxibs bind tightly to a subunit of COX-1. Although celecoxib binding to one monomer of COX-1 does not affect the normal catalytic processing of AA by the second, partner subunit, celecoxib does interfere with the inhibition of COX-1 by aspirin in vitro. X-ray crystallographic results obtained with a celecoxib/COX-1 complex show how celecoxib can bind to one of the two available COX sites of the COX-1 dimer. Finally, we find that administration of celecoxib to dogs interferes with the ability of a low dose of aspirin to inhibit AA-induced ex vivo platelet aggregation. COX-2 inhibitors such as celecoxib are widely used for pain relief. Because coxibs exhibit cardiovascular side effects, they are often prescribed in combination with low-dose aspirin to prevent thrombosis. Our studies predict that the cardioprotective effect of low-dose aspirin on COX-1 may be blunted when taken with coxibs.« less

Celecoxib versus a non-selective NSAID plus proton-pump inhibitor: what are the considerations?.

PubMed

Chen, Judy T; Pucino, Frank; Resman-Targoff, Beth H

2006-01-01

Nonsteroidal anti-inflammatory drugs (NSAIDs) are extensively used worldwide. However, associated adverse gastrointestinal effects (NSAID gastropathy) such as bleeding, perforation and obstruction result in considerable morbidity, mortality, and expense. Although it is essential to employ gastroprotective strategies to minimize these complications in patients at risk, controversy remains on whether celecoxib alone or a non-selective NSAID in conjunction with a proton-pump inhibitor (PPI) is a superior choice. Recent concerns regarding potential cardiovascular toxicities associated with cox-2 selective inhibitors may favor non-selective NSAID/PPI co-therapy as the preferred choice. Concomitant use of low-dose aspirin with any NSAID increases the risk of gastrointestinal complications and diminishes the improved gastrointestinal safety profile of celecoxib; whereas use of ibuprofen plus PPI regimens may negate aspirin's antiplatelet benefits. Evidence shows that concurrent use of a non-selective NSAID (such as naproxen) plus a PPI is as effective in preventing NSAID gastropathy as celecoxib, and may be more cost-effective. Patients failing or intolerant to this therapy would be candidates for celecoxib at the lowest effective dose for the shortest duration of time. Potential benefits from using low-dose celecoxib with a PPI in patients previously experiencing bleeding ulcers while taking NSAIDs remains to be proven. An evidence-based debate is presented to assist clinicians with the difficult decision-making process of preventing NSAID gastropathy while minimizing other complications.

An apple oligogalactan potentiates the growth inhibitory effect of celecoxib on colorectal cancer.

PubMed

Li, Yuhua; Niu, Yinbo; Sun, Yang; Mei, Lin; Zhang, Bangle; Li, Qian; Liu, Li; Zhang, Rong; Chen, Jianfa; Mei, Qibing

2014-01-01

Multiple studies have indicated that selective cyclooxygenase-2 (COX-2) inhibitors possess clinically chemopreventive and preclinically anticancer activities. Their long-term use, however, may be limited by the cardiovascular toxicity. This study tried to investigate whether an apple oligogalactan (AOG) could enhance the growth inhibitory effect of celecoxib on colorectal cancer. Caco-2 and HT-29 cell lines were exposed to different concentrations of AOG (0-1 g/L), celecoxib (0-25 μmol/L), and their combination. COX-2 levels were assessed by reverse transcription PCR and Western blot. COX-2 activity was evaluated by measuring prostaglandin E2 concentration. A colitis-associated colorectal cancer (CACC) mouse model was used to determine the effect of the combination in vivo. AOG (0.1-0.5 g/L) could potentiate the inhibitory effect of physiologic doses of celecoxib (5 μmol/L) on cell growth and decrease COX-2 expressions both at RNA and protein levels. In vivo, the combination (2.5% AOG plus 0.04% celecoxib, w/w) prevented against CACC in mice effectively. Our data indicate that AOG could potentiate the growth inhibitory effect of celecoxib on colorectal cancer both in vitro and in vivo through influencing the expression and function of COX-2 and phosphorylation of MAPKs, which suggests a new possible combinatorial strategy in colorectal cancer therapy.

ZD6474, a new treatment strategy for human osteosarcoma, and its potential synergistic effect with celecoxib

PubMed Central

Pan, Changchuan; Zhou, Yi; Du, Wuying; Chen, Jie-min; Zhu, Xiaofeng; Shen, Jingnan; Chen, Shuai; Liu, Ran-yi; Huang, Wenlin

2015-01-01

ZD6474, a small molecule VEGFR and EGFR tyrosine kinase inhibitor, has been considered as a promising tumor-targeted drug in various malignancies. EGFR and cyclooxygenase-2 (COX-2) were found overexpressed in osteosarcoma in previous reports, so here we tried to explore the anti-osteosarcoma effect of ZD6474 alone or combination with celecoxib, a COX-2 inhibitor. The data demonstrated that ZD6474 inhibited the growth of osteosarcoma cells, and promoted G1-phase cell cycle arrest and apoptosis by inhibiting the activity of EGFR tyrosine kinase, and consequently suppressing its downstream PI3k/Akt and MAPK/ERK pathway. Additionally, daily administration of ZD6474 produced a dose-dependent inhibition of tumor growth in nude mice. Celecoxib also significantly inhibited the growth of osteosarcoma cells in dose-dependent manner, while combination of ZD6474 and celecoxib displayed a synergistic or additive antitumor effect on osteosarcoma in vitro and in vivo. The possible molecular mechanisms to address the synergism are likely that ZD6474 induces the down-regulation of COX-2 expression through inhibiting ERK phosphorylation, while celecoxib promotes ZD6474-directed inhibition of ERK phosphorylation. In conclusion, ZD6474 exerts direct anti-proliferative effects on osteosarcoma cells, and the synergistic antitumor effect of the combination of ZD6474 with celecoxib may indicate a new strategy of the combinative treatment of human osteosarcoma. PMID:26050198

Celecoxib plus chemoradiotherapy for locally advanced rectal cancer: a phase II TCOG study.

PubMed

Wang, Ling-Wei; Hsiao, Chin-Fu; Chen, William Tzu-Liang; Lee, Hao-Hsien; Lin, Tzu-Chen; Chen, Hung-Chang; Chen, Hong-Hwa; Chien, Chun-Ru; Lin, Tze-Yi; Liu, Tsang-Wu

2014-05-01

To report the results of a phase II trial combining celecoxib and preoperative chemoradiotherapy (CRT) for locally advanced rectal cancer. Patients with clinical stage II or III rectal cancer were treated with radiotherapy of 44 Gy in 22 fractions. Concurrent chemotherapy consisted of oral tegafur-uracil and folinate on days 1-30 and 38-65. Celecoxib (400 mg/day) given from days 1 to 65. Surgery was done on day 70. The expression of cyclooxygenase 2 (COX-2) in tumor tissues was evaluated microscopically as a prognostic factor. From 2008 to 2011, 53 patients completed CRT+ celecoxib therapy and 47 received radical surgery. Grade 3 diarrhea developed in 5 (9%). Grade 4 anemia was seen in 2 (4%). Pathological complete response (pCR) was seen in 6 (13%). T or N downstaging found in 38 (81%). Sphincter preservation was achieved in 77% of low-positioned tumors. Patients with tumors expressing high-level COX-2 after CRT + celecoxib treatment had inferior pelvic control (P = 0.01), disease-free survival (P = 0.04), and overall survival (P = 0.03) than those with low-level expression. Celecoxib can be safely combined with preoperative CRT for rectal cancer. More intensified adjuvant therapy may be considered for tumors expressing high-level COX-2 after CRT and surgery. © 2013 Wiley Periodicals, Inc.

Anti-tumor effect and mechanism of cyclooxygenase-2 inhibitor through matrix metalloproteinase 14 pathway in PANC-1 cells.

PubMed

Li, Siyuan; Gu, Zhuoyu; Xiao, Zhiwei; Zhou, Ting; Li, Jun; Sun, Kan

2015-01-01

To investigate whether celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, can attenuate proliferation, migration, invasion and MMP-14 expression in pancreatic cancer cells PANC-1 and the possible anti-tumor mechanism of celecoxib. Human pancreatic cancer cell line PANC-1 cells were treated with diverse concentrations of celecoxib (20, 60, 100 μmol/L). Cell proliferation, invasion and migration capabilities were measured by MTT colorimetry, transwell invasion assay, and scratch assay separately. At the same time, the protein expression of COX-2 and MMP-14 was assessed by ELISA. The capabilities of proliferation, invasion and migration in PANC-1 cells were attenuated in a concentration-dependent manner after treated with celecoxib, followed by the down-regulation of the protein expression of COX-2 and MMP-14. In addition, MMP-14 expression was significantly positively correlated with COX-2 expression. COX-2 inhibitor celecoxib can inhibit the proliferation, invasion and migration of PANC-1 cells via down-regulating the expression of MMP-14 in a concentration-dependent manner, thus contributing to its anti-tumor effect in pancreatic cancer.

LY3127760, a Selective Prostaglandin E4 (EP4) Receptor Antagonist, and Celecoxib: A Comparison of Pharmacological Profiles

PubMed Central

Smith, Claire; Hu, Leijun; Coutant, David E.; Whitehurst, Kelly; Phipps, Krista; McNearney, Terry Ann; Yang, Xiao; Ackermann, Bradley; Pottanat, Thomas; Landschulz, William

2017-01-01

Abstract Safety, tolerability, and pharmacology profiles of LY3127760, an EP4 antagonist, were explored in healthy subjects in a subject/investigator‐blind, parallel‐group, multiple‐ascending dose study. Cohorts consisted of 13 patients randomized to LY3127760, celecoxib (400 mg), or placebo (9:2:2 ratio) for 28 days. LY3127760 was well tolerated; the most commonly observed adverse events were gastrointestinal, similar to celecoxib. LY3127760 increased release of ex vivo tumor necrosis factor alpha after lipopolysaccharide/prostaglandin E2 stimulation when compared with placebo, suggesting a dose‐dependent blockade of the EP4 receptor. Compared with placebo, 24‐h urinary excretion of prostaglandin E metabolite was modestly increased; prostacyclin metabolite was inhibited; and thromboxane A2 metabolite was unchanged. Effects on sodium and potassium excretion were similar to those of celecoxib. We conclude that LY3127760 demonstrated similar effects on prostacyclin synthesis and renal sodium retention as celecoxib. These data support exploration of LY3127760 at daily doses of 60 mg to 600 mg in phase II trials. This trial's registration number: NCT01968070. PMID:28857461

Immunomodulatory effect of Celecoxib on HMGB1/TLR4 pathway in a recurrent seizures model in immature rats.

PubMed

Morales-Sosa, Mariana; Orozco-Suárez, Sandra; Vega-García, Angélica; Caballero-Chacón, Sara; Feria-Romero, Iris A

2018-07-01

Epileptic seizures constitute an important problem in pediatric neurology during the developmental period. The frequency and nosological significance of seizures, as well as their association with epileptogenesis, may be related to underlying mechanisms such as neuroinflammation. Those mechanisms of response activate inflammatory molecules induced in the neurons, activated glial cells and endothelial cells via the key HMGB1/TLR4 pathway. In this study, the drug celecoxib (CCX) was used as a blocker of the cyclooxygenase 2 (COX-2) and HMGB1/TLR-4 pathways. The experimental model was implemented in 10-day-old neonatal Sprague Dawley rats to induce recurrent seizures with kainic acid (KA, 1.4 mg/kg). Data were evaluated at early (14 PND) and late (30 PND) time points. The results showed that the CCX and CCX + pentobarbital (PB) groups exhibited a protective effect by significantly increasing the time latency of seizures compared to the KA group at both early (p < 0.01) and late (p < 0.001) times. When the CCX group was compared to the KA group, there was also a significant decrease in the number of HMGB1 and TLR-4 transcripts (p < 0.05) and in COX-2 protein expression (p < 0.05) in the most important areas for seizure generation (the hippocampus and cortex) at both the early and late time points. These results demonstrated that CCX treatment after epileptic seizures has a neuroprotective effect due to the inhibition of proinflammatory proteins and associated signaling pathways and reduces seizure susceptibility. Additionally, the timely intervention of inflammatory pathways will reduce the risk of developing epilepsy in adulthood. Copyright © 2018 Elsevier Inc. All rights reserved.

Tumor-associated down-regulation of 15-lipoxygenase-1 is reversed by celecoxib in colorectal cancer.

PubMed

Heslin, Martin J; Hawkins, Ashley; Boedefeld, William; Arnoletti, J Pablo; Frolov, Andrey; Soong, Richie; Urist, Marshall M; Bland, Kirby I

2005-06-01

To evaluate the role of celecoxib on 15-lipoxygenase-1 (15-LOX-1) expression, protein levels, and rates of apoptosis in colorectal cancer cell lines. Also, to evaluate the expression of 15-LOX-1 in human normal mucosa, adenoma, and carcinoma with correlation to overall survival. The function of 15-LOX-1 is to maintain normal rates of apoptosis (programmed cell death). Decreased apoptosis is one mechanism of cancer growth and dissemination. It is our hypothesis that expression of 15-LOX-1 is reduced in human colorectal cancer (CRC) and the administration of celecoxib can reverse this process and induce apoptosis. Effect of celecoxib in cell culture: The effect of 40 micromol/L celecoxib was compared with untreated controls in tissue culture utilizing HT-29 and DLD-1 CRC cell lines. Expression of 15-LOX-1 protein was measured by immunoblot. Induction of apoptosis was evaluated by annexin V staining. All data are presented as mean +/- SEM, with significance defined as P < 0.05. 15-LOX-1 in human CRC: From February 1998 to January 2002, 126 patients underwent surgical resection of either colorectal adenomas (n = 24) or carcinomas (n = 102), or both (n = 25). Tissue was macrodissected, snap frozen, and stored at -80 degrees C. After tissue processing, RNA was extracted and gene expression of 15-LOX-1 was quantified utilizing ABI prism real-time quantitative RT-PCR. Significance evaluated by the Wilcoxon signed rank test. Effect of celecoxib in cell culture: After 72 hours of treatment with celecoxib, immunoblot demonstrated a 1.5- to 2-fold increase in 15-LOX-1 protein expression in HT-29 and DLD-1 cells, respectively. Celecoxib produced greater than a 2-fold increase in the rate of apoptosis compared with control cells in both cell lines (P < 0.05). 15-LOX-1 in human CRC: The mean age of the patients was 62 +/- 1 years; 78% were white and 48% were female. The mean size of the polyps and cancers were 3.0 +/- 0.4 and 5.0 +/- 0.1 cm, respectively. Expression of 15-LOX-1 relative to S9 was 30 in normal mucosa and significantly down-regulated to 11 in adenomas and 16 in carcinomas (P < 0.05). 15-LOX-1 gene expression is significantly reduced in both human colorectal adenomas and carcinomas and associated with decreased survival. Administration of celecoxib restores 15-LOX-1 protein expression and induces apoptosis. Down-regulation of 15-LOX-1 is an early event in the adenoma to carcinoma sequence, and reversal with celecoxib may represent one mechanism for chemoprevention of polyps or treatment of carcinomas.

Inhibition of bacterial multidrug resistance by celecoxib, a cyclooxygenase-2 inhibitor.

PubMed

Kalle, Arunasree M; Rizvi, Arshad

2011-01-01

Multidrug resistance (MDR) is a major problem in the treatment of infectious diseases and cancer. Accumulating evidence suggests that the cyclooxygenase-2 (COX-2)-specific inhibitor celecoxib would not only inhibit COX-2 but also help in the reversal of drug resistance in cancers by inhibiting the MDR1 efflux pump. Here, we demonstrate that celecoxib increases the sensitivity of bacteria to the antibiotics ampicillin, kanamycin, chloramphenicol, and ciprofloxacin by accumulating the drugs inside the cell, thus reversing MDR in bacteria.

Effect of Formulation Variables on Preparation of Celecoxib Loaded Polylactide-Co-Glycolide Nanoparticles

PubMed Central

Cooper, Dustin L.; Harirforoosh, Sam

2014-01-01

Polymer based nanoparticle formulations have been shown to increase drug bioavailability and/or reduce drug adverse effects. Nonsteroidal anti-inflammatory drugs (e.g. celecoxib) reduce prostaglandin synthesis and cause side effects such as gastrointestinal and renal complications. The aim of this study was to formulate celecoxib entrapped poly lactide-co-glycolide based nanoparticles through a solvent evaporation process using didodecyldimethylammonium bromide or poly vinyl alcohol as stabilizer. Nanoparticles were characterized for zeta potential, particle size, entrapment efficiency, and morphology. Effects of stabilizer concentration (0.1, 0.25, 0.5, and 1% w/v), drug amount (5, 10, 15, and 20 mg), and emulsifier (lecithin) on nanoparticle characterization were examined for formula optimization. The use of 0.1, 0.25, and 0.5% w/v didodecyldimethylammonium bromide resulted in a more than 5-fold increase in zeta potential and a more than 1.5-fold increase in entrapment efficiency with a reduction in particle size over 35%, when compared to stabilizer free formulation. Nanoparticle formulations were also highly influenced by emulsifier and drug amount. Using 0.25% w/v didodecyldimethylammonium bromide NP formulations, peak zeta potential was achieved using 15 mg celecoxib with emulsifier (17.15±0.36 mV) and 20 mg celecoxib without emulsifier (25.00±0.18 mV). Peak NP size reduction and entrapment efficiency was achieved using 5 mg celecoxib formulations with (70.87±1.24 nm and 95.55±0.66%, respectively) and without (92.97±0.51 nm and 95.93±0.27%, respectively) emulsifier. In conclusion, formulations using 5 mg celecoxib with 0.25% w/v didodecyldimethylammonium bromide concentrations produced nanoparticles exhibiting enhanced size reduction and entrapment efficiency. Furthermore, emulsifier free formulations demonstrated improved zeta potential when compared to formulations containing emulsifier (p<0.01). Therefore, our results suggest the use of emulsifier free 5 mg celecoxib drug formulations containing 0.25% w/v didodecyldimethylammonium bromide for production of polymeric NPs that demonstrate enhanced zeta potential, small particle size, and high entrapment efficiency. PMID:25502102

Tomography-guided palisade sacroiliac joint radiofrequency neurotomy versus celecoxib for ankylosing spondylitis: a open-label, randomized, and controlled trial.

PubMed

Zheng, Yongjun; Gu, Minghong; Shi, Dongping; Li, Mingli; Ye, Le; Wang, Xiangrui

2014-09-01

Sacroiliac joint (SIJ) pain is a common symptom in ankylosing spondylitis (AS). Palisade sacroiliac joint radiofrequency neurotomy (PSRN) is a novel treatment for the SIJ pain. In the current clinical trial, we treated AS patients with significant SIJ pain using PSRN under computed tomography guidance and compared the results with the celecoxib treatment. The current study included 155 AS patients. Patients were randomly assigned to receive PSRN or celecoxib treatment (400 mg/day for 24 weeks). The primary endpoint was global pain intensity in visual analog scale, at week 12. Secondary endpoints included pain intensity at week 24, disease activity, functional and mobility capacities, and adverse events at week 24. In comparison with the baseline collected immediately prior to the interventions, global pain intensity was significantly lower at both 12 and 24 weeks after the treatment in both arms. Pain reduction was more robust in the PSRN arm (by more than 1.9 and 2.2 cm at 12 and 24 weeks in comparison with the celecoxib arm, P < 0.0001 for both). The PSRN was also more effective in improving physical function and spinal mobility (P < 0.05 vs. celecoxib for both). Gastrointestional irritation was more frequent in the celecoxib arm than in the PSRN arm (P < 0.05). No severe complications were noted in either arm. PSRN is both efficacious and safe in managing SIJ pain in patients with AS.

Mechanisms underlying the growth inhibitory effects of the cyclo-oxygenase-2 inhibitor celecoxib in human breast cancer cells

PubMed Central

Basu, Gargi D; Pathangey, Latha B; Tinder, Teresa L; Gendler, Sandra J; Mukherjee, Pinku

2005-01-01

Introduction Inhibitors of cyclo-oxygenase (COX)-2 are being extensively studied as anticancer agents. In the present study we evaluated the mechanisms by which a highly selective COX-2 inhibitor, celecoxib, affects tumor growth of two differentially invasive human breast cancer cell lines. Methods MDA-MB-231 (highly invasive) and MDA-MB-468 (moderately invasive) cell lines were treated with varying concentrations of celecoxib in vitro, and the effects of this agent on cell growth and angiogenesis were monitored by evaluating cell proliferation, apoptosis, cell cycle arrest, and vasculogenic mimicry. The in vitro results of MDA-MB-231 cell line were further confirmed in vivo in a mouse xenograft model. Results The highly invasive MDA-MB-231 cells express higher levels of COX-2 than do the less invasive MDA-MB-468 cells. Celecoxib treatment inhibited COX-2 activity, indicated by prostaglandin E2 secretion, and caused significant growth arrest in both breast cancer cell lines. In the highly invasive MDA-MB-231 cells, the mechanism of celecoxib-induced growth arrest was by induction of apoptosis, associated with reduced activation of protein kinase B/Akt, and subsequent activation of caspases 3 and 7. In the less invasive MDA-MB-468 cells, growth arrest was a consequence of cell cycle arrest at the G0/G1 checkpoint. Celecoxib-induced growth inhibition was reversed by addition of exogenous prostaglandin E2 in MDA-MB-468 cells but not in MDA-MB-231 cells. Furthermore, MDA-MB-468 cells formed significantly fewer extracellular matrix associated microvascular channels in vitro than did the high COX-2 expressing MDA-MB-231 cells. Celecoxib treatment not only inhibited cell growth and vascular channel formation but also reduced vascular endothelial growth factor levels. The in vitro findings corroborated in vivo data from a mouse xenograft model in which daily administration of celecoxib significantly reduced tumor growth of MDA-MB-231 cells, which was associated with reduced vascularization and increased necrosis in the tumor mass. Conclusion The disparate molecular mechanisms of celecoxib-induced growth inhibition in human breast cancer cells depends upon the level of COX-2 expression and the invasive potential of the cell lines examined. Data suggest a role for COX-2 not only in the growth of cancer cells but also in activating the angiogenic pathway through regulating levels of vascular endothelial growth factor. PMID:15987447

The hepatic safety and tolerability of the cyclooxygenase-2 selective NSAID celecoxib: pooled analysis of 41 randomized controlled trials.

PubMed

Soni, Paresh; Shell, Briton; Cawkwell, Gail; Li, Chunming; Ma, Hong

2009-08-01

To assess the hepatic safety and tolerability of celecoxib versus placebo and three commonly prescribed nonselective nonsteroidal anti-inflammatory drugs (NSAIDs). This was a retrospective, pooled analysis of a 41-study dataset involving patients with osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, chronic low back pain, and Alzheimer's disease. Criteria for selection of studies were: (1) Randomized, parallel-group design and planned treatment duration of > or =2 weeks (2) > or =1 placebo or NSAID comparator (3) > or =1 arm with celecoxib at total daily dose of > or =200 mg (4) Data available as of October 31, 2004 Data were pooled by treatment and subject from the safety analysis population of included studies. Treatment-emergent hepatobiliary adverse events (AEs) were compared for celecoxib <200 mg/day (943 patients), 200 mg/day (12 008 patients), 400 mg/day (7380 patients), and 800 mg/day (4602 patients); placebo (4057 patients); diclofenac 100-150 mg/day (7639 patients); naproxen 1000 mg/day (2953 patients); and ibuprofen 2400 mg/day (2484 patients). Hepatobiliary laboratory abnormalities were also analyzed. There were no cases of liver failure, treatment-related liver transplant, or treatment-related hepatobiliary death. Incidence of serious hepatic AEs was low, with 13 (0.05%) serious hepatic AEs among 24 933 celecoxib-treated patients, and 16 (0.21%) among 7639 diclofenac-treated patients. No patients receiving celecoxib or any nonselective NSAID met criteria for Hy's rule (alanine aminotransferase [ALT] > or =3 x upper limit of normal [ULN] with bilirubin > or =2 x ULN). The incidence of notable (> or =5 x ULN) and severe (> or =10 x ULN) ALT elevations was similar for all treatment groups except diclofenac. Significantly fewer hepatobiliary AEs were reported for celecoxib (any dose; 1.11%) than for diclofenac (vs. 4.24%, p < 0.0001); for ibuprofen (vs. 1.53%, p = 0.06) and placebo (vs. 0.89%, p = 0.21) the incidence of AEs was comparable to celecoxib. A number of limitations should be considered when evaluating the results: findings were limited by the quality and reporting of the studies selected; difficulty in estimating the incidence of AEs due to the low frequency of events; acetaminophen not included as an active comparator. In this pooled analysis, the incidence of hepatic AEs in patients treated with celecoxib was similar to that for both placebo-treated patients and patients treated with ibuprofen or naproxen, but lower than for diclofenac.

Antiproliferative effect of a novel nitro-oxy derivative of celecoxib in human colon cancer cells: role of COX-2 and nitric oxide.

PubMed

Bocca, Claudia; Bozzo, Francesca; Bassignana, Andrea; Miglietta, Antonella

2010-07-01

It has been shown previously that a novel nitrooxy derivative of celecoxib exerts antiproliferative and pro-apoptotic effects in human colon cancer cells. The aim of this study was to elucidate whether these biological properties depend on COX-2 inhibition and/or NO release. Therefore, the derivative was decomposed into the parent compound celecoxib and the NO donor benzyl nitrate and the biological role of each was tested in COX-2-positive (HT-29) and -negative (SW-480) colon cancer cells. The main findings were that the nitro-oxy derivative behaved like celecoxib in HT-29 cells in terms of COX-2 and ERK/MAPK inhibition, as well as induction of apoptosis, while the benzyl nitrate had no such effects. Interestingly, the beta-catenin system was activated by the nitro-oxy derivative as well as by benzyl nitrate alone more potently than by the parent compound celecoxib, suggesting a possible regulatory role for NO. In SW480 cells, these activities were substantially less pronounced, suggesting the presence of COX-2-dependent mechanisms in the modulation of these parameters.

Celecoxib for the treatment of mild-to-moderate depression due to acute brucellosis: a double-blind, placebo-controlled, randomized trial.

PubMed

Jafari, S; Ashrafizadeh, S-G; Zeinoddini, A; Rasoulinejad, M; Entezari, P; Seddighi, S; Akhondzadeh, S

2015-08-01

Depression is a debilitating complication of brucellosis and how best to treat this is a matter of debate. Inflammatory processes are involved in the pathogenesis of both brucellosis and depression. Therefore, we hypothesized that celecoxib could be beneficial for the treatment of depression due to brucellosis. Forty outpatients with depression due to brucellosis with a Hamilton Depression Rating Scale score (HDRS) <19 participated in a randomized, double-blind, placebo-controlled trial and underwent 8 weeks of treatment with either celecoxib (200 mg bid) or placebo as an adjunctive to antibiotic therapy. Patients were evaluated using HDRS at baseline and weeks 4 and 8. Repeated-measures analysis demonstrated significant effect for time × treatment interaction on the HDRS score [F (1·43, 57·41) = 37·22, P < 0·001]. Significantly greater response to treatment occurred in the celecoxib group than in the placebo group at the study end [10 patients (50%) vs. no patient (0%), respectively, P < 0·001]. No serious adverse event was observed. Celecoxib is a safe and effective treatment for depression due to brucellosis when compared with placebo. © 2015 John Wiley & Sons Ltd.

In-vitro and in-vivo inhibition of melanoma growth and metastasis by the drug combination of celecoxib and dacarbazine.

PubMed

Sadhu, Satya S; Wang, Shenggang; Averineni, Ranjith K; Seefeldt, Teresa; Yang, Yang; Guan, Xiangming

2016-12-01

Celecoxib has been found to be effective in cancer prevention and treatment. Its combination with other chemotherapeutic agents was reported to produce synergistic/additive effects on various cancers. Dacarbazine (DTIC) is one of the most commonly used drugs in the treatment of metastatic melanoma. This investigation aimed to determine the in-vitro and in-vivo effects of the drug combination of celecoxib and DTIC on melanoma growth and metastasis. Melanoma cells B16-F10 and SK-MEL-28, and female C57BL/6 mice were used for the study. Our in-vitro data showed that significant synergistic effects were obtained when celecoxib was used together with various concentrations of DTIC. A study with B16-F10 cells using flow cytometry analysis showed that the drug combination induced significantly more apoptosis than each drug used individually. Our in-vivo results showed that the drug combination was much more effective than each drug used alone for the inhibition of both melanoma growth and metastasis in the B16-F10+C57BL/6 mouse models. For melanoma growth, the median survival rates for phosphate-buffered saline (PBS) (control), celecoxib (30 mg/kg), DTIC-1 (10 mg/kg), DTIC-2 (positive control, 50 mg/kg), and the drug combination (DTIC 10 mg/kg+celecoxib 30 mg/kg) were 6, 6.5, 7.5, 7.5, and 9 days, respectively. For melanoma metastasis, the average number of metastatic tumors in murine lungs was 53.7±10.7, 31.8±18.6, 21.2±21.7, 7.0±9.0, and 0.8±2.0 for PBS, DTIC-1, celecoxib, the drug combination, and DTIC-2. Our results warrant further investigation of the combination as an effective treatment for melanoma patients.

[Specific inhibitors of cyclooxygenase-2 (COX-2): current knowledge and perspectives].

PubMed

Rioda, W T; Nervetti, A

2001-01-01

The Authors summarize the current knowledge on a new class of nonsteroidal anti-inflammatory drugs (NSAIDs), the coxib (celecoxib and rofecoxib), in the treatment of rheumatic diseases. Celecoxib and rofecoxib are selective cyclooxygenase-2 (COX-2) inhibitors which possess the same anti-inflammatory and analgesic activities, but a better gastric tolerability compared to the non-selective COX-1 and COX-2 inhibitors. The Authors also report other possible therapeutic effects of these NSADIs as evidenced by the more recent data of the literature. Celecoxib seems to reduce the incidence of new polyps in patients with familial adenomatous polyposis. It has been suggested the use of celecoxib as a protective drug against the development of colorectal cancer. Other (neoplastic) or pre-neoplastic conditions, such as bladder dysplasia, Barret esophagus, attinic keratosis and Alzheimer's disease seem to have benefit from this class of drugs.

Efficacy of adjunctive celecoxib treatment for patients with major depressive disorder: a meta-analysis.

PubMed

Na, Kyoung-Sae; Lee, Kang Joon; Lee, Ji Sung; Cho, Young Sung; Jung, Han-Yong

2014-01-03

Numerous studies have reported that inflammation is closely associated with depression, and adjunctive non-steroidal anti-inflammatory drug (NSAID) treatment has been suggested as a novel therapeutic approach for depression. We searched electronic databases including Medline, Embase, and the Cochrane Central Register of Controlled Trials. We only included randomized controlled trials comparing adjunctive NSAIDs with placebos for treating depressive episodes. Of the 654 retrieved entries, we identified four relevant studies with a total of 150 patients (75 NSAID patients and 75 placebo patients) with depressive episodes. All four studies used celecoxib as the NSAID. The patients receiving adjunctive celecoxib had significantly higher mean changes in the Hamilton Rating Scale for Depression scores between baseline and endpoint measurements compared with those receiving placebo (weighted mean difference=3.26, 95% confidence interval; CI=1.81 to 4.71). The adjunctive celecoxib group also showed better remission (odds ratio; OR=6.58, 95% CI=2.55 to 17.00) and response rates (OR=6.49, 95% CI=2.89 to 14.55) than the placebo group. The all-cause drop-out rate was more favorable for the celecoxib group than for the placebo group (OR=0.45, 95% CI=0.18 to 1.13), although the statistical significance was not statistically significant (p=0.09). Adjunctive treatment with NSAIDs, particularly celecoxib, can be a promising strategy for patients with depressive disorder. Future studies with a larger sample size and longer study duration are needed to confirm the efficacy and tolerability of NSAIDs for depression. © 2013.

Relative efficacy and tolerability of etoricoxib, celecoxib, and naproxen in the treatment of osteoarthritis : A Bayesian network meta-analysis of randomized controlled trials based on patient withdrawal.

PubMed

Song, Gwan Gyu; Seo, Young Ho; Kim, Jae-Hoon; Choi, Sung Jae; Ji, Jong Dae; Lee, Young Ho

2016-06-01

This study aimed to assess the relative efficacy and tolerability of etoricoxib, celecoxib, and naproxen at recommended dosages in patients with osteoarthritis (OA). Randomized controlled trials (RCTs) examining the efficacy and tolerability of etoricoxib 30-60 mg, celecoxib 200-400 mg, and naproxen 1000 mg, based on the number of patient withdrawals among those with OA, were included in this network meta-analysis. We performed a Bayesian random-effects network meta-analysis to combine direct and indirect evidence from the RCTs. Eight RCTs, including 5,942 patients, met the inclusion criteria. The proportion of patient withdrawals due to lack of efficacy was significantly lower in the etoricoxib 30-60 mg (OR 0.21, 95 % CrI 0.12-0.38), celecoxib 200-400 mg (OR 0.29, 95 % CrI 0.18-0.47), and naproxen 1000 mg (OR 0.31, 95 % CrI 0.18-0.51) groups than in the placebo group. The number of patient withdrawals due to lack of efficacy tended to be lower in the etoricoxib 30-60 mg group than in the naproxen 1000 mg and celecoxib 200-400 mg groups, although they did not reach statistical significance (OR 0.68, 95 % CrI 0.36-1.33 and OR 0.70, 95 % CrI 0.38-1.37, respectively). Ranking probabilities based on the surface under the cumulative ranking curve (SUCRA) indicated that etoricoxib 30-60 mg had the highest probability of being the best treatment based on the number of withdrawals due to lack of efficacy (SUCRA = 0.9168) followed by celecoxib 200-400 mg (SUCRA = 0.5659), naproxen 1000 mg (SUCRA = 0.5171), and placebo (SUCRA = 0.000189). With respect to tolerability, the number of withdrawals due to adverse events was not significantly different among etoricoxib, celecoxib, naproxen, and placebo, although it tended to be lower with etoricoxib and placebo. Etoricoxib 30-60 mg, celecoxib 200-400 mg, and naproxen 1000 mg were more efficacious than placebo. However, there was no significant difference in efficacy and tolerability between the medications.

Tramadol versus Celecoxib for reducing pain associated with outpatient hysteroscopy: a randomized double-blind placebo-controlled trial.

PubMed

Hassan, A; Wahba, A; Haggag, H

2016-01-01

Which is better, Tramadol or Celecoxib, in reducing pain associated with outpatient hysteroscopy? Both Tramadol and Celecoxib are effective in reducing pain associated with outpatient hysteroscopy but Celecoxib may be better tolerated. Pain is the most common cause of failure of outpatient hysteroscopy. A systematic review and meta-analysis showed that local anaesthetics were effective in reducing pain associated with hysteroscopy but there was insufficient evidence to support the use of oral analgesics, opioids and non-steroidal anti-inflammatory drugs, to reduce hysteroscopy-associated pain and further studies were recommended. This was a randomized double-blind placebo-controlled trial with balanced randomization (allocation ratio 1:1:1) conducted in a university hospital from May 2014 to November 2014. Two hundred and ten women who had diagnostic outpatient hysteroscopy were randomly divided into three equal groups: Group 1 received oral Tramadol 100 mg, group 2 received Celecoxib 200 mg and group 3 received an oral placebo. All the drugs were given 1 h before the procedure. A patient's perception of pain was assessed during the procedure, immediately afterwards and 30 min after the procedure with the use of a visual analogue scale (VAS). There was a significant difference in the pain scores among the groups during the procedure, immediately afterwards and 30 min after the procedure (P< 0.001, 0.001, <0.001 respectively). Tramadol had significantly lower pain scores when compared with the placebo during the procedure (mean difference = 1.54, 95% confidence interval (CI) (0.86, 2.22), P < 0.001), immediately after the procedure (mean difference = 1.09; 95% CI (0.5, 1.68), P < 0.001) and 30 min later (mean difference = 0.95, 95% CI (0.48, 1.41), P < 0.001). Celecoxib administration also led to significantly lower pain scores than the placebo during the procedure (mean difference = 1.28, 95% CI (0.62, 1.94), P < 0.001), immediately after the procedure (mean difference = 0.72; 95% CI (0.13, 1.32), P = 0.016) and 30 min later (mean difference = 0.77, 95% CI (0.3, 1.24), P = 0.001). There were no significant differences in pain scores between Tramadol and Celecoxib at any time. Time until no pain differed significantly among the groups (P = 0.01); it was shorter with both Tramadol and Celecoxib groups when compared with placebo (P = 0.002 and 0.046, respectively). The procedure failed to be completed in one patient in the placebo group but no failure to complete the procedure occurred in Tramadol and Celecoxib groups. Four women in the Tramadol group reported nausea but no side effects were reported with Celecoxib group and no complications were reported in any group of patients. All results were based on the subjective perception of pain, which varies among individuals and is related to the individuals' previous pain experience and level of anxiety. Tramadol and Celecoxib are effective in reducing pain in outpatient hysteroscopy. Celecoxib may be better tolerated as no side effects were reported in the study, however further research on a larger sample size is required before drawing firm conclusions about lack of side effects. This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector. All authors declare no conflict of interest. www.clinicaltrials.gov - NCT02071303. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Complexation of tocotrienol with gamma-cyclodextrin enhances intestinal absorption of tocotrienol in rats.

PubMed

Ikeda, Saiko; Uchida, Tomono; Ichikawa, Tomio; Watanabe, Takashi; Uekaji, Yukiko; Nakata, Daisuke; Terao, Keiji; Yano, Tomohiro

2010-01-01

To determine the bioavailability of tocotrienol complex with gamma-cyclodextrin, the effects of tocotrienol/gamma-cyclodextrin complex on tocotrienol concentration in rat plasma and tissues were studied. Rats were administered by oral gavage an emulsion containing tocotrienol, tocotrienol with gamma-cyclodextrin, or tocotrienol/gamma-cyclodextrin complex. At 3 h after administration, the plasma gamma-tocotrienol concentration of the rats administered tocotrienol/gamma-cyclodextrin complex was higher than that of the rats administered tocotrienol and gamma-cyclodextrin. In order to determine the effect of complexation on tocotrienol absorption, rats were injected with Triton WR1339, which prevents the catabolism of triacylglycerol-rich lipoprotein by lipoprotein lipase, and then administered by oral gavage an emulsion containing tocotrienol, tocotrienol with gamma-cyclodextrin, or tocotrienol/gamma-cyclodextrin complex. The plasma gamma-tocotrienol concentration of the Triton-treated rats administered tocotrienol/gamma-cyclodextrin complex was higher than that of the other Triton-treated rats. These results suggest that complexation of tocotrienol with gamma-cyclodextrin elevates plasma and tissue tocotrienol concentrations by enhancing intestinal absorption.

Intracerebroventricular administration of taurine impairs learning and memory in rats.

PubMed

Ito, Koichi; Arko, Matevž; Kawaguchi, Tomohiro; Kikusui, Takefumi; Kuwahara, Masayoshi; Tsubone, Hirokazu

2012-03-01

Taurine is a semi-essential amino acid widely distributed in the body and we take in it from a wide range of nutritive-tonic drinks to improve health. To date, we have elucidated that oral supplementation of taurine does not affect learning and memory in the rat. However, there are few studies concerning the direct effects of taurine in the brain at the behavior level. In this study, we intracerebroventricularly administered taurine to rats and aimed to elucidate the acute effects on learning and memory using the Morris water maze method. Escape latency, swim distance, and distance to zone, which is the integral of the distance between the rats and the platform for every 0.16 seconds, were adopted as parameters of the ability of learning and memory. We also tried to evaluate the effect of intraperitoneal taurine administration. Escape latency, swim distance, and distance to zone were significantly longer in the intracerebroventricularly taurine-administered rats than in the saline-administered rats. Mean swimming velocity was comparable between these two groups, although the physical performance was improved by taurine administration. Probe trials showed that the manner of the rats in finding the platform was comparable. In contrast, no significant differences were found between the intraperitoneally taurine-administered rats and the saline-administered rats. These results indicate that taurine administered directly into the brain ventricle suppresses and delays the ability of learning and memory in rats. In contrast, it is implied that taurine administered peripherally was not involved in learning and memory.

Effectiveness and safety of Glucosamine, chondroitin, the two in combination, or celecoxib in the treatment of osteoarthritis of the knee

PubMed Central

Zeng, Chao; Wei, Jie; Li, Hui; Wang, Yi-lun; Xie, Dong-xing; Yang, Tuo; Gao, Shu-guang; Li, Yu-sheng; Luo, Wei; Lei, Guang-hua

2015-01-01

This study aimed to investigate the effectiveness and safety of glucosamine, chondroitin, the two in combination, or celecoxib in the treatment of knee osteoarthritis (OA). PubMed, Embase and Cochrane Library were searched through from inception to February 2015. A total of 54 studies covering 16427 patients were included. Glucosamine plus chondroitin, glucosamine alone, and celecoxib were all more effective than placebo in pain relief and function improvement. Specifically, celecoxib is most likely to be the best treatment option, followed by the combination group. All treatment options showed clinically significant improvement from baseline pain, but only glucosamine plus chondroitin showed clinically significant improvement from baseline function. In terms of the structure-modifying effect, both glucosamine alone and chondroitin alone achieved a statistically significant reduction in joint space narrowing. Although no significant difference was observed among the five options with respect to the three major adverse effects (withdrawal due to adverse events, serious adverse events and the number of patients with adverse events), the additional classical meta-analysis showed that celecoxib exhibited a higher rate of gastrointestinal adverse effect comparing with the placebo group. The present study provided evidence for the symptomatic efficacy of glucosamine plus chondroitin in the treatment of knee OA. PMID:26576862

Comparison of the anti-proliferation and apoptosis-induction activities of sulindac, celecoxib, curcumin, and nifedipine in mismatch repair-deficient cell lines.

PubMed

Wei, Shu-Chen; Lin, Young-Sun; Tsao, Po-Nien; Wu-Tsai, Jyy-Ji; Wu, C H Herbert; Wong, Jau-Min

2004-08-01

The adenomatous polyposis coli (APC) and mismatch repair (MMR) pathways are both involved in the tumorigenesis of hereditary colorectal cancers. Chemoprevention focuses on the APC pathway in the absence of information concerning MMR targets. This study compared the anticancer effects of sulindac, celecoxib, curcumin, and nifedipine in MMR-deficient cell lines, in order to determine the most appropriate chemopreventive agent for long-term use in patients with hereditary colorectal cancer. Five human colorectal cell lines (SW480, HCT116, LoVo, SW48, and HCT15) and an endometrial cancer cell line (HEC-1-A) were used for susceptibility testing. Tests included assays for growth inhibition, cell-cycle arrest, and apoptosis. Sulindac, celecoxib, curcumin, and nifedipine all displayed dose- and time-dependent anti-proliferation activities. Celecoxib was the most effective anti-proliferative agent, and increased the G0/G1 phase proportion in the cell cycle after treatment more significantly than the other agents in all cell lines. Curcumin displayed a more potent apoptosis-inducing activity than the other agents in treated cells. The tested drugs were effective against colorectal and endometrial cancer cell lines. Celecoxib is more potent with fewer side effects than sulindac. Nifedipine's observed chemopreventive efficacy may complement its known therapeutic application in patients with hypertension.

LY3127760, a Selective Prostaglandin E4 (EP4) Receptor Antagonist, and Celecoxib: A Comparison of Pharmacological Profiles.

PubMed

Jin, Yan; Smith, Claire; Hu, Leijun; Coutant, David E; Whitehurst, Kelly; Phipps, Krista; McNearney, Terry Ann; Yang, Xiao; Ackermann, Bradley; Pottanat, Thomas; Landschulz, William

2018-01-01

Safety, tolerability, and pharmacology profiles of LY3127760, an EP4 antagonist, were explored in healthy subjects in a subject/investigator-blind, parallel-group, multiple-ascending dose study. Cohorts consisted of 13 patients randomized to LY3127760, celecoxib (400 mg), or placebo (9:2:2 ratio) for 28 days. LY3127760 was well tolerated; the most commonly observed adverse events were gastrointestinal, similar to celecoxib. LY3127760 increased release of ex vivo tumor necrosis factor alpha after lipopolysaccharide/prostaglandin E2 stimulation when compared with placebo, suggesting a dose-dependent blockade of the EP4 receptor. Compared with placebo, 24-h urinary excretion of prostaglandin E metabolite was modestly increased; prostacyclin metabolite was inhibited; and thromboxane A2 metabolite was unchanged. Effects on sodium and potassium excretion were similar to those of celecoxib. We conclude that LY3127760 demonstrated similar effects on prostacyclin synthesis and renal sodium retention as celecoxib. These data support exploration of LY3127760 at daily doses of 60 mg to 600 mg in phase II trials. This trial's registration number: NCT01968070. © 2017 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Efficacy of celecoxib in the treatment of CNS lymphomas: an in vivo model.

PubMed

Wang, Weijun; Kardosh, Adel; Su, Yuzhuang S; Schonthal, Axel H; Chen, Thomas C

2006-11-15

The incidence of primary central nervous system lymphomas (PCNSLs) has increased over the past several decades. Unfortunately, even with the most effective therapeutic regimen (that is, methotrexate with wholebrain radiation therapy), PCNSL recurs within a few years in more than half of the treated patients and is eventually fatal. Because PCNSL usually occurs in older patients and in those with acquired immunodeficiency syndrome, combination treatments in which both chemo- and radiation therapy are used is often poorly tolerated and results in a significant reduction in the quality of life. Recently, it has been demonstrated that the selective cyclooxygenase- 2 inhibitor celecoxib (Celebrex), can block the growth of lymphoma cells in vitro. To create an experimental animal model in vivo for the PCNSL study, the authors intracranially injected a human B-cell lymphoma cell line into nude mice. Their data demonstrate that this experimental model is an excellent one for human PCNSL with brain and leptomeningeal involvement. They also evaluated the feasibility of using celecoxib as a therapeutic agent in the treatment of PCNSL. Nude mice with intracranial lymphomas were treated with celecoxib contained in the animal chow. The treated animals demonstrated significantly prolonged survival times compared with the untreated animals. Based on the authors' data, celecoxib may be a promising therapeutic agent for the treatment of PCNSL.

Impact of surfactants on the crystallization of aqueous suspensions of celecoxib amorphous solid dispersion spray dried particles.

PubMed

Chen, Jie; Ormes, James D; Higgins, John D; Taylor, Lynne S

2015-02-02

Amorphous solid dispersions are frequently prepared by spray drying. It is important that the resultant spray dried particles do not crystallize during formulation, storage, and upon administration. The goal of the current study was to evaluate the impact of surfactants on the crystallization of celecoxib amorphous solid dispersions (ASD), suspended in aqueous media. Solid dispersions of celecoxib with hydroxypropylmethylcellulose acetate succinate were manufactured by spray drying, and aqueous suspensions were prepared by adding the particles to acidified media containing various surfactants. Nucleation induction times were evaluated for celecoxib in the presence and absence of surfactants. The impact of the surfactants on drug and polymer leaching from the solid dispersion particles was also evaluated. Sodium dodecyl sulfate and Polysorbate 80 were found to promote crystallization from the ASD suspensions, while other surfactants including sodium taurocholate and Triton X100 were found to inhibit crystallization. The promotion or inhibition of crystallization was found to be related to the impact of the surfactant on the nucleation behavior of celecoxib, as well as the tendency to promote leaching of the drug from the ASD particle into the suspending medium. It was concluded that surfactant choice is critical to avoid failure of amorphous solid dispersions through crystallization of the drug.

Celecoxib:Nicotinamide Dissociation: Using Excipients to Capture the Cocrystal's Potential

DOE Office of Scientific and Technical Information (OSTI.GOV)

Remenar,J.; Peterson, M.; Stephens, P.

2007-01-01

The cocrystal of celecoxib and nicotinamide (Cel:Nic) was crystallized from chloroform in a 1:1 ratio, and the structure has been solved from powder X-ray diffraction data. The dissolution and solubility of Cel:Nic are medium dependent and can be attributed to differences in conversion of Cel:Nic to celecoxib polymorphs I and III (Cel-I and Cel-III). The presence of low concentrations of surfactants facilitates the rapid conversion of neat Cel:Nic to large aggregates of Cel-III that dissolve more slowly than commercial Cel-III into 1% SDS solution. In contrast, combinations of Cel:Nic with both 1-10% solid SDS and PVP wet rapidly and convertmore » to a mixture of amorphous celecoxib and a micron-sized crystalline celecoxib form IV (Cel-IV), which has recently been shown to be up to 4-fold more bioavailable than marketed Cel-III. More than 90% of the suspended material dissolves within 2 min at 37 C when transferred to 1% SDS solution. This example highlights the importance of exploring the form conversion of cocrystals in aqueous media prior to pharmacokinetic studies, and illustrates the potential of simple formulations to overcome the limitations caused by rapid dissociation of cocrystals and recrystallization of poorly soluble forms in aqueous media.« less

Celecoxib: Nicotinamide Dissociateion: Using Excipients to Capture the Cocrystal's Potential

DOE Office of Scientific and Technical Information (OSTI.GOV)

Remenar,J.; Peterson, M.; Stephens, P.

2007-01-01

The cocrystal of celecoxib and nicotinamide (Cel:Nic) was crystallized from chloroform in a 1:1 ratio, and the structure has been solved from powder X-ray diffraction data. The dissolution and solubility of Cel:Nic are medium dependent and can be attributed to differences in conversion of Cel:Nic to celecoxib polymorphs I and III (Cel-I and Cel-III). The presence of low concentrations of surfactants facilitates the rapid conversion of neat Cel:Nic to large aggregates of Cel-III that dissolve more slowly than commercial Cel-III into 1% SDS solution. In contrast, combinations of Cel:Nic with both 1-10% solid SDS and PVP wet rapidly and convertmore » to a mixture of amorphous celecoxib and a micron-sized crystalline celecoxib form IV (Cel-IV), which has recently been shown to be up to 4-fold more bioavailable than marketed Cel-III. More than 90% of the suspended material dissolves within 2 min at 37 C when transferred to 1% SDS solution. This example highlights the importance of exploring the form conversion of cocrystals in aqueous media prior to pharmacokinetic studies, and illustrates the potential of simple formulations to overcome the limitations caused by rapid dissociation of cocrystals and recrystallization of poorly soluble forms in aqueous media.« less

Synergistic anticancer effects of combined gamma-tocotrienol and celecoxib treatment are associated with suppression in Akt and NFkappaB signaling.

PubMed

Shirode, Amit B; Sylvester, Paul W

2010-05-01

The selective cyclooxygenase (COX)-2 inhibitor, celecoxib, and the vitamin E isoform, gamma-tocotrienol, both display potent anticancer activity. However, high dose clinical use of selective COX-2 inhibitors has been limited by gastrointestinal and cardiovascular toxicity, whereas limited absorption and transport of gamma-tocotrienol by the body has made it difficult to obtain and sustain therapeutic levels in the blood and target tissues. Studies were conducted to characterize the synergistic anticancer antiproliferative effects of combined low dose celecoxib and gamma-tocotrienol treatment on mammary tumor cells in culture. The highly malignant mouse +SA mammary epithelial cells were maintained in culture on serum-free defined control or treatment media. Treatment effects on COX-1, COX-2, Akt, NFkappaB and prostaglandin E(2) (PGE(2)) synthesis were assessed following a 3- or 4-day culture period. Treatment with 3-4 microM gamma-tocotrienol or 7.5-10 microM celecoxib alone significantly inhibited +SA cell growth in a dose-responsive manner. However, combined treatment with subeffective doses of gamma-tocotrienol (0.25 microM) and celecoxib (2.5 microM) resulted in a synergistic antiproliferative effect, as determined by isobologram analysis, and this growth inhibitory effect was associated with a reduction in PGE(2) synthesis, and decrease in COX-2, phospho-Akt (active), and phospho-NFkappaB (active) levels. These results demonstrate that the synergistic anticancer effects of combined celecoxib and gamma-tocotrienol therapy are mediated by COX-2 dependent and independent mechanisms. These findings also suggest that combination therapy with these agents may provide enhanced therapeutic response in breast cancer patients, while avoiding the toxicity associated with high-dose COX-2 inhibitor monotherapy. 2009 Elsevier Masson SAS. All rights reserved.

Synergistic anticancer effects of combined γ-tocotrienol and celecoxib treatment are associated with suppression in Akt and NFκB signaling

PubMed Central

Shirode, Amit B.; Sylvester, Paul W.

2009-01-01

The selective cyclooxygenase (COX)-2 inhibitor, celecoxib, and the vitamin E isoform, γ-tocotrienol, both display potent anticancer activity. However, high dose clinical use of selective COX-2 inhibitors has been limited by gastrointestinal and cardiovascular toxicity, whereas limited absorption and transport of γ-tocotrienol by the body has made it difficult to obtain and sustain therapeutic levels in the blood and target tissues. Studies were conducted to characterize the synergistic anticancer antiproliferative effects of combined low dose celecoxib and γ-tocotrienol treatment on mammary tumor cells in culture. The highly malignant mouse +SA mammary epithelial cells were maintained in culture on serum-free defined control or treatment media. Treatment effects on COX-1, COX-2, Akt, NFκB and prostaglandin E2 (PGE2) synthesis was assessed following a 3- or 4-day culture period. Treatment with 3–4 μM γ-tocotrienol or 7.5–10 μM celecoxib alone significantly inhibited +SA cell growth in a dose-responsive manner. However, combined treatment with subeffective doses of γ-tocotrienol (0.25 μM) and celecoxib (2.5 μM) resulted in a synergistic antiproliferative effect, as determined by isobologram analysis, and this growth inhibitor effect was associated with a reduction in PGE2 synthesis, and decrease in COX-2, phospho-Akt (active), and phospho-NFκB (active) levels. These results demonstrate that the synergistic anticancer effects of combined celecoxib and γ-tocotrienol therapy are mediated by COX-2 dependent and independent mechanisms. These findings also suggest that combination therapy with these agents may provide enhanced therapeutic response in breast cancer patients, while avoiding the toxicity associated with high-dose COX-2 inhibitor monotherapy. PMID:19954924

Concurrent use of methotrexate and celecoxib increases risk of silent liver fibrosis in rheumatoid arthritis patients with subclinical reduced kidney function.

PubMed

Park, Jin Su; Park, Min-Chan; Park, Yong-Beom; Lee, Soo-Kon; Lee, Sang-Won

2014-01-01

We evaluated the effects of concurrent use of methotrexate and celecoxib on silent liver and kidney damages in rheumatoid arthritis (RA) patients. We enrolled 92 RA patients with normal laboratory results related to liver and kidney functions, who had received methotrexate and celecoxib concurrently over 6 months. Liver stiffness measurement (LSM) using transient elastography and ultrasonography were performed along with blood and urine tests. Estimated glomerular filtration rate (eGFR) was calculated by both the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and the Modification of Diet in Renal Disease (MDRD) equations. Initial eGFR represented kidney function at the time of the initiation of celecoxib. The cutoff for abnormal LSM values was adopted as 5.3 kPa. The optimal cutoff of each eGFR for abnormal LSM values was also calculated. The median age of patients was 55 years old (74 women). The median LSM was 4.4 kPa and the median eGFRs and median initial eGFRs ranged from 89 to 99 mL/min/1.73 m(2). The cumulative doses of methotrexate and celecoxib and their concurrent administration duration did not affect LSM values and eGFRs. Both eGFRs were significantly associated with LSM values. Patients with initial eGFR(CKD-EPI), initial eGFR(MDRD), and eGFR(CKD-EPI) below each optimal cutoff had significantly high risks for silent liver fibrosis (RR 9.4, 10.3, and 4.4, p < 0.001, respectively). Both initial eGFRs (CKD-EPI and MDRD) and eGFR (CKD-EPI) were significant predictors for the development of silent liver fibrosis in RA patients who had received methotrexate and celecoxib concurrently for at least 6 months.

The Risk of Major NSAID Toxicity with Celecoxib, Ibuprofen, or Naproxen: A Secondary Analysis of the PRECISION Trial.

PubMed

Solomon, Daniel H; Husni, M Elaine; Libby, Peter A; Yeomans, Neville D; Lincoff, A Michael; Lϋscher, Thomas F; Menon, Venu; Brennan, Danielle M; Wisniewski, Lisa M; Nissen, Steven E; Borer, Jeffrey S

2017-12-01

The relative safety of long-term use of nonsteroidal anti-inflammatory drugs is unclear. Patients and providers are interested in an integrated view of risk . We examined the risk of major nonsteroidal anti-inflammatory drug toxicity in the PRECISION trial. We conducted a post hoc analysis of a double-blind, randomized, controlled, multicenter trial enrolling 24,081 patients with osteoarthritis or rheumatoid arthritis at moderate or high cardiovascular risk. Patients were randomized to receive celecoxib 100 to 200 mg twice daily, ibuprofen 600 to 800 mg thrice daily, or naproxen 375 to 500 mg twice daily. All patients were provided with a proton pump inhibitor. The outcome was major nonsteroidal anti-inflammatory drug toxicity, including time to first occurrence of major adverse cardiovascular events, important gastrointestinal events, renal events, and all-cause mortality. During follow-up, 4.1% of subjects sustained any major toxicity in the celecoxib arm, 4.8% in the naproxen arm, and 5.3% in the ibuprofen arm. Analyses adjusted for aspirin use and geographic region found that subjects in the naproxen arm had a 20% (95% CI 4-39) higher risk of major toxicity than celecoxib users and that 38% (95% CI 19-59) higher risk. These risks translate into numbers needed to harm of 135 (95% CI, 72-971) for naproxen and 82 (95% CI, 53-173) for ibuprofen, both compared with celecoxib. Among patients with symptomatic arthritis who had moderate to high risk of cardiovascular events, approximately 1 in 20 experienced a major toxicity over 1 to 2 years. Patients using naproxen or ibuprofen experienced significantly higher risk of major toxicity than those using celecoxib. Copyright © 2017 Elsevier Inc. All rights reserved.

Celecoxib restores angiogenic factor expression at the maternal-fetal interface in the BPH/5 mouse model of preeclampsia.

PubMed

Reijnders, Dorien; Liu, Chin-Chi; Xu, Xinjing; Zhao, Anna M; Olson, Kelsey N; Butler, Scott D; Douglas, Nataki C; Sones, Jenny L

2018-05-01

Preeclampsia (PE), a hypertensive disease of pregnancy, is a leading cause of fetal and maternal morbidity/mortality. Early angiogenic and inflammatory disturbances within the placenta are thought to underlie the development of the maternal PE syndrome and poor pregnancy outcomes. However, the exact etiology remains largely unknown. Here, we use the BPH/5 mouse model of PE to elucidate the way in which inflammation early in pregnancy contributes to abnormal expression of angiogenic factors at the maternal-fetal interface. We have previously described improvement in maternal hypertension and fetal growth restriction in this model after treatment with the anti-inflammatory cyclooxygenase-2 (Cox2) specific inhibitor celecoxib. To further characterize the mechanisms by which celecoxib improves poor pregnancy outcomes in BPH/5 mice, we determined expression of angiogenic factors and complement pathway components after celecoxib. In BPH/5 implantation sites there was increased hypoxia inducible factor-1α ( Hif1α), heme oxygenase-1 ( Ho-1), and stem cell factor ( Scf) mRNA concomitant with elevated prostaglandin synthase 2 ( Ptgs2), encoding Cox2, and elevated VEGF protein. Angiopoietin 1 ( Ang1), tunica interna endothelial cell kinase-2 receptor ( Tie2), complement factor 3 ( C3), and complement factor B ( CfB) were increased in midgestation BPH/5 placentae. Whereas BPH/5 expression levels of VEGF, Ang1, and Tie2 normalized after celecoxib, placental C3 and CfB mRNA remained unchanged. However, celecoxib did reduce the pregnancy-specific circulating soluble fms-like tyrosine kinase-1 (sFlt-1) rise in BPH/5 mice at midgestation. These data show that elevated Cox2 during implantation contributes to placental angiogenic factor imbalances in the BPH/5 mouse model of PE.

Celecoxib enhances the anti-inflammatory effects of farnesylthiosalicylic acid on T cells independent of prostaglandin E(2) production.

PubMed

Mor, Adam; Aizman, Elizabeta; Kloog, Yoel

2012-10-01

Celecoxib (Celebrex(®)), a non-steroidal anti-inflammatory drug and selective cyclooxygenase-2 inhibitor, is widely used to treat arthritis and other inflammatory disorders. Awareness of its anti-proliferative properties has prompted another indication for its use, in preventing colon polyps in high-risk populations. Farnesylthiosalicylic acid (FTS; Salirasib(®)), designed to inhibit oncogenic Ras and currently under evaluation in phase I/II and II clinical trials, was recently shown by our group to exert anti-inflammatory effects on both lymphocytes and mast cells. Here we examined whether celecoxib combined with FTS would enhance this anti-inflammatory activity. While each drug separately inhibited Ras activation in these cells, their combination yielded more marked inhibition as well as further inhibition of ERK phosphorylation, lymphocyte adhesion, and interleukin-2 secretion. The inhibitory effects, moreover, were independent of prostaglandin E(2) secretion. These data point to the promising potential of combined treatment with celecoxib and FTS for inflammatory disorders involving lymphocytes.

Grafting of allylimidazole and n-vinylcaprolactam as a thermosensitive polymer onto magnetic nano-particles for the extraction and determination of celecoxib in biological samples.

PubMed

Morovati, Atefeh; Ahmad Panahi, Homayon; Yazdani, Farzaneh

2016-11-20

In this research, a novel method is reported for the surface grafting of n-vinylcaprolactam as a thermosensitive agent and allylimidazole with affinity toward celecoxib onto magnetic nano-particles. The grafted nano-particles were characterized by Fourier transform infrared spectroscopy, elemental analysis, and thermogravimetric analysis. The surface morphology was studied using Scanning Electron Microscopy. The resulting grafted nano-particles were used for the determination of trace celecoxib in biological human fluids and pharmaceutical samples. The profile of celecoxib uptake by the modified magnetic nano-particles indicated good accessibility of the active sites in the grafted copolymer. It was found that the adsorption behavior could be fitted by the Langmuir adsorption isotherm model. Solid phase extraction for biological fluids such as urine and serum were investigated. In this study, urine extraction recovery of more than 95% was obtained. Copyright © 2016 Elsevier B.V. All rights reserved.

Combined chondroitin sulfate and glucosamine for painful knee osteoarthritis: a multicentre, randomised, double-blind, non-inferiority trial versus celecoxib

PubMed Central

Hochberg, Marc C; Martel-Pelletier, Johanne; Monfort, Jordi; Möller, Ingrid; Castillo, Juan Ramón; Arden, Nigel; Berenbaum, Francis; Blanco, Francisco J; Conaghan, Philip G; Doménech, Gema; Henrotin, Yves; Pap, Thomas; Richette, Pascal; Sawitzke, Allen; du Souich, Patrick; Pelletier, Jean-Pierre

2016-01-01

Objectives To compare the efficacy and safety of chondroitin sulfate plus glucosamine hydrochloride (CS+GH) versus celecoxib in patients with knee osteoarthritis and severe pain. Methods Double-blind Multicentre Osteoarthritis interVEntion trial with SYSADOA (MOVES) conducted in France, Germany, Poland and Spain evaluating treatment with CS+GH versus celecoxib in 606 patients with Kellgren and Lawrence grades 2–3 knee osteoarthritis and moderate-to-severe pain (Western Ontario and McMaster osteoarthritis index (WOMAC) score ≥301; 0–500 scale). Patients were randomised to receive 400 mg CS plus 500 mg GH three times a day or 200 mg celecoxib every day for 6 months. The primary outcome was the mean decrease in WOMAC pain from baseline to 6 months. Secondary outcomes included WOMAC function and stiffness, visual analogue scale for pain, presence of joint swelling/effusion, rescue medication consumption, Outcome Measures in Rheumatology Clinical Trials and Osteoarthritis Research Society International (OMERACT-OARSI) criteria and EuroQoL-5D. Results The adjusted mean change (95% CI) in WOMAC pain was −185.7 (−200.3 to −171.1) (50.1% decrease) with CS+GH and −186.8 (−201.7 to −171.9) (50.2% decrease) with celecoxib, meeting the non-inferiority margin of −40: −1.11 (−22.0 to 19.8; p=0.92). All sensitivity analyses were consistent with that result. At 6 months, 79.7% of patients in the combination group and 79.2% in the celecoxib group fulfilled OMERACT-OARSI criteria. Both groups elicited a reduction >50% in the presence of joint swelling; a similar reduction was seen for effusion. No differences were observed for the other secondary outcomes. Adverse events were low and similarly distributed between groups. Conclusions CS+GH has comparable efficacy to celecoxib in reducing pain, stiffness, functional limitation and joint swelling/effusion after 6 months in patients with painful knee osteoarthritis, with a good safety profile. Trial registration number: NCT01425853. PMID:25589511

Celecoxib as adjunctive treatment to risperidone in children with autistic disorder: a randomized, double-blind, placebo-controlled trial.

PubMed

Asadabadi, Mahtab; Mohammadi, Mohammad-Reza; Ghanizadeh, Ahmad; Modabbernia, Amirhossein; Ashrafi, Mandana; Hassanzadeh, Elmira; Forghani, Saeedeh; Akhondzadeh, Shahin

2013-01-01

Autism is associated with activation of the inflammatory response system. This study aims to assess the efficacy of a cyclooxygenase-2 inhibitor, celecoxib, as adjunctive therapy in the treatment of autism In a 10-week randomized double-blind placebo-controlled study, 40 outpatient children with a Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision clinical diagnosis of autism were randomly allocated to celecoxib plus risperidone or placebo plus risperidone. The dose of risperidone and celecoxib were titrated up to 3 and 300 mg/day, respectively. Patients were assessed at baseline and after 2, 4, 6, and 10 weeks of starting medication using the Aberrant Behavior Checklist-Community (ABC-C) Rating Scale. Primary outcome measure was the change in irritability subscale of ABC-C. Significant time × treatment interaction was observed for Irritability (F (1.658, 63.021) = 13.580, P < 0.001), Lethargy/Social Withdrawal (F (1.948, 74.032) = 16.811, P < 0.001), and Stereotypic Behavior (F(1.742, 66.198) = 12.104, P < 0.001), but not for Hyperactivity/Noncompliance (F (2.564, 97.424) = 1.469, P = 0.232), and Inappropriate Speech subscales (F (1.607, 61.075) = 0.173, P = 0.794). By week 10, patients in the celecoxib group showed significantly greater improvement in the Irritability (P < 0.001), Lethargy/Social Withdrawal (P < 0.001), and Stereotypic Behavior (P < 0.00) but not in Hyperactivity/Noncompliance (P = 0.202) and Inappropriate Speech (P = 0.802) subscales than the placebo group. Complete response was achieved by four (20 %) patients in the placebo group and 11 (55 %) patients in the celecoxib group (χ (2) (1) = 5.227, P = 0.022). Frequency of side effects was similar between the two groups. Combination of risperidone and celecoxib was superior to risperidone alone in treating irritability, social withdrawal, and stereotypy of children with autism. (Registration, www.irct.ir ; IRCT138711091556N2).

Multi-Reservoir Phospholipid Shell Encapsulating Protamine Nanocapsules for Co-Delivery of Letrozole and Celecoxib in Breast Cancer Therapy.

PubMed

Elzoghby, Ahmed O; Mostafa, Shaimaa K; Helmy, Maged W; ElDemellawy, Maha A; Sheweita, Salah A

2017-09-01

In the current work, we propose a combined delivery nanoplatform for letrozole (LTZ) and celecoxib (CXB). Multi-reservoir nanocarriers were developed by enveloping protamine nanocapsules (PRM-NCs) within drug-phospholipid complex bilayer. Encapsulation of NCs within phospholipid bilayer was confirmed by both size increase from 109.7 to 179.8 nm and reduction of surface charge from +19.0 to +7.78 mV. The multi-compartmental core-shell structure enabled biphasic CXB release with initial fast release induced by complexation with phospholipid shell followed by prolonged release from oily core. Moreover, phospholipid coating provided protection for cationic PRM-NCs against interaction with RBCs and serum proteins enabling their systemic administration. Pharmacokinetic analysis demonstrated prolonged circulation and delayed clearance of both drugs after intravenous administration into rats. The superior anti-tumor efficacy of multi-reservoir NCs was manifested as powerful cytotoxicity against MCF-7 breast cancer cells and marked reduction in the mammary tumor volume in Ehrlich ascites bearing mice compared with free LTZ-CXB combination. Moreover, the NCs induced apoptotic caspase activation and marked inhibition of aromatase expression and angiogenic marker, VEGF as well as inhibition of both NFκB and TNFα. Multi-reservoir phospholipid shell coating PRM-NCs could serve as a promising nanocarrier for parenteral combined delivery of LTZ and CXB.

Liquid Crystalline Systems Based on Glyceryl Monooleate and Penetration Enhancers for Skin Delivery of Celecoxib: Characterization, In Vitro Drug Release, and In Vivo Studies.

PubMed

Dante, Mariane de Cássia Lima; Borgheti-Cardoso, Livia Neves; Fantini, Marcia Carvalho de Abreu; Praça, Fabíola Silva Garcia; Medina, Wanessa Silva Garcia; Pierre, Maria Bernadete Riemma; Lara, Marilisa Guimarães

2018-03-01

Celecoxib (CXB) is a widely used anti-inflammatory drug that also acts as a chemopreventive agent against several types of cancer, including skin cancer. As the long-term oral administration of CXB has been associated with severe side effects, the skin delivery of this drug represents a promising alternative for the treatment of skin inflammatory conditions and chemoprevention of skin cancer. We prepared and characterized liquid crystalline systems based on glyceryl monooleate and water containing penetration enhancers which were primarily designed to promote skin delivery of CXB. Analysis of their phase behavior revealed the formation of cubic and hexagonal phases depending on the systems' composition. The systems' structure and composition markedly affected the in vitro CXB release profile. Oleic acid reduced CXB release rate, but association oleic acid/propylene glycol increased the drug release rate. The developed systems significantly reduced inflammation in an aerosil-induced rat paw edema model. The systems' composition and liquid crystalline structure influenced their anti-inflammatory potency. Cubic phase systems containing oleic acid/propylene glycol association reduced edema in a sustained manner, indicating that they modulate CXB release and permeation. Our findings demonstrate that the developed liquid crystalline systems are potential carriers for the skin delivery of CXB. Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Activating PTEN by COX-2 inhibitors antagonizes radiation-induced AKT activation contributing to radiosensitization

DOE Office of Scientific and Technical Information (OSTI.GOV)

Meng, Zhen; Department of Oral & Maxillofacial Surgery, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081; Gan, Ye-Hua, E-mail: kqyehuagan@bjmu.edu.cn

2015-05-01

Radiotherapy is still one of the most effective nonsurgical treatments for many tumors. However, radioresistance remains a major impediment to radiotherapy. Although COX-2 inhibitors can induce radiosensitization, the underlying mechanism is not fully understood. In this study, we showed that COX-2 selective inhibitor celecoxib enhanced the radiation-induced inhibition of cell proliferation and apoptosis in HeLa and SACC-83 cells. Treatment with celecoxib alone dephosphorylated phosphatase and tensin homolog deleted on chromosome ten (PTEN), promoted PTEN membrane translocation or activation, and correspondingly dephosphorylated or inactivated protein kinase B (AKT). By contrast, treatment with radiation alone increased PTEN phosphorylation, inhibited PTEN membrane translocationmore » and correspondingly activated AKT in the two cell lines. However, treatment with celecoxib or another COX-2 selective inhibitor (valdecoxib) completely blocked radiation-induced increase of PTEN phosphorylation, rescued radiation-induced decrease in PTEN membrane translocation, and correspondingly inactivated AKT. Moreover, celecoxib could also upregulate PTEN protein expression by downregulating Sp1 expression, thereby leading to the activation of PTEN transcription. Our results suggested that COX-2 inhibitors could enhance radiosensitization at least partially by activating PTEN to antagonize radiation-induced AKT activation. - Highlights: • COX-2 inhibitor, celecoxib, could enhance radiosensitization. • Radiation induced PTEN inactivation (phosphorylation) and AKT activation. • COX-2 inhibitor induced PTEN expression and activation, and inactivated AKT. • COX-2 inhibitor enhanced radiosensitization through activating PTEN.« less

Efficacy and safety of concurrent chemoradiation with weekly cisplatin ± low-dose celecoxib in locally advanced undifferentiated nasopharyngeal carcinoma: a phase II-III clinical trial.

PubMed

Mohammadianpanah, Mohammad; Razmjou-Ghalaei, Sasan; Shafizad, Amin; Ashouri-Taziani, Yaghoub; Khademi, Bijan; Ahmadloo, Niloofar; Ansari, Mansour; Omidvari, Shapour; Mosalaei, Ahmad; Mosleh-Shirazi, Mohammad Amin

2011-01-01

This is the first study that aimed to determine the efficacy and safety of concurrent chemoradiation with weekly cisplatin ± celecoxib 100 mg twice daily in locally advanced undifferentiated nasopharyngeal carcinoma. Eligible patients had newly diagnosed locally advanced (T3-T4, and/or N2-N3, M0) undifferentiated nasopharyngeal carcinoma, no prior therapy, Karnofsky performance status ≥ 70, and normal organ function. The patients were assigned to receive 7 weeks concurrent chemoradiation (70 Gy) with weekly cisplatin 30 mg/m 2 with either celecoxib 100 mg twice daily, (study group, n = 26) or placebo (control group, n = 27) followed by adjuvant combined chemotherapy with cisplatin 70 mg/m 2 on day 1 plus 5-fluorouracil 750 mg/m 2 /d with 8-h infusion on days 1-3, 3-weekly for 3 cycles. Overall clinical response rate was 100% in both groups. Complete and partial clinical response rates were 64% and 36% in the study group and 44% and 56% in the control group, respectively (P > 0.25). The addition of celecoxib to concurrent chemoradiation was associated with improved 2-year locoregional control rate from 84% to 100% (P = 0.039). The addition of celecoxib 100 mg twice daily to concurrent chemoradiation improved 2-year locoregional control rate.

The addition of celecoxib improves the antitumor effect of cetuximab in colorectal cancer: role of EGFR-RAS-FOXM1-β-catenin signaling axis

PubMed Central

Valverde, Araceli; Peñarando, Jon; Cañas, Amanda; López-Sánchez, Laura M.; Conde, Francisco; Guil-Luna, Silvia; Hernández, Vanessa; Villar, Carlos; Morales-Estévez, Cristina; de la Haba-Rodríguez, Juan; Arand o, Enrique; Rodríguez-Ariza, Antonio

2017-01-01

Here we showed that the addition of the COX-2 inhibitor celecoxib improved the antitumor efficacy in colorectal cancer (CRC) of the monoclonal anti-EGFR antibody cetuximab. The addition of celecoxib augmented the efficacy of cetuximab to inhibit cell proliferation and to induce apoptosis in CRC cells. Moreover, the combination of celecoxib and cetuximab was more effective than either treatment alone in reducing the tumor volume in a mouse xenograft model. The combined treatment enhanced the inhibition of EGFR signaling and altered the subcellular distribution of β-catenin. Moreover, knockdown of FOXM1 showed that this transcription factor participates in this enhanced antitumoral response. Besides, the combined treatment decreased β-catenin/FOXM1 interaction and reduced the cancer stem cell subpopulation in CRC cells, as indicated their diminished capacity to form colonospheres. Notably, the inmunodetection of FOXM1 in the nuclei of tumor cells in human colorectal adenocarcinomas was significantly associated with response of patients to cetuximab. In summary, our study shows that the addition of celecoxib enhances the antitumor efficacy of cetuximab in CRC due to impairment of EGFR-RAS-FOXM1-β-catenin signaling axis. Results also support that FOXM1 could be a predictive marker of response of mCRC patients to cetuximab therapy. PMID:28423516

Outcomes studies of the gastrointestinal safety of cyclooxygenase-2 inhibitors.

PubMed

Scheiman, James M

2002-01-01

Short-term endoscopic studies of the highly selective cyclooxygenase-2 (COX-2) inhibitors (coxibs) rofecoxib and celecoxib have shown that these agents are well tolerated and have efficacy equivalent to nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) with fewer adverse effects on the upper gastrointestinal (GI) tract. These studies are limited, however, as the detection of endoscopic lesions is not well correlated with symptomatic ulcers and ulcer complications. Outcomes studies of the GI safety are, therefore, essential to understanding how coxibs are likely to perform in a clinical practice setting. Four large outcomes studies (Vioxx Gastrointestinal Outcomes Research, VIGOR; Assessment of Difference Between Vioxx and Naproxen to Ascertain Gastrointestinal Tolerability and Effectiveness trial, ADVANTAGE; Celecoxib Long-term Arthritis Safety Study, CLASS; and the Successive Celecoxib Efficacy and Safety Studies, SUCCESS) examined the GI safety of rofecoxib and celecoxib in over 39,000 patients with osteoarthritis or rheumatoid arthritis. Results of these studies showed that patients taking a supratherapeutic dose of rofecoxib or celecoxib had significantly lower rates of GI-related adverse events than those taking a nonselective NSAID (naproxen, ibuprofen, or diclofenac). Reduced risk of upper GI events was seen in patients with multiple risk factors and in patients using low-dose aspirin and corticosteroids concomitantly with a coxib. Results of large outcomes studies provide support for the COX-2 hypothesis and demonstrate the long-term safety and tolerability of coxibs.

Chemical Isotope Labeling LC-MS for Monitoring Disease Progression and Treatment in Animal Models: Plasma Metabolomics Study of Osteoarthritis Rat Model

NASA Astrophysics Data System (ADS)

Chen, Deying; Su, Xiaoling; Wang, Nan; Li, Yunong; Yin, Hua; Li, Liang; Li, Lanjuan

2017-01-01

We report a chemical isotope labeling (CIL) liquid chromatography mass spectrometry (LC-MS) method generally applicable for tracking metabolomic changes from samples collected in an animal model for studying disease development and treatment. A rat model of surgically induced osteoarthritis (OA) was used as an example to illustrate the workflow and technical performance. Experimental duplicate analyses of 234 plasma samples were carried out using dansylation labeling LC-MS targeting the amine/phenol submetabolome. These samples composed of 39 groups (6 rats per group) were collected at multiple time points with sham operation, OA control group, and OA rats with treatment, separately, using glucosamine/Celecoxib and three traditional Chinese medicines (Epimedii folium, Chuanxiong Rhizoma and Bushen-Huoxue). In total, 3893 metabolites could be detected and 2923 of them were consistently detected in more than 50% of the runs. This high-coverage submetabolome dataset could be used to track OA progression and treatment. Many differentiating metabolites were found and 11 metabolites including 2-aminoadipic acid, saccharopine and GABA were selected as potential biomarkers of OA progression and OA treatment. This study illustrates that CIL LC-MS is a very useful technique for monitoring incremental metabolomic changes with high coverage and accuracy for studying disease progression and treatment in animal models.

Chemical Isotope Labeling LC-MS for Monitoring Disease Progression and Treatment in Animal Models: Plasma Metabolomics Study of Osteoarthritis Rat Model

PubMed Central

Chen, Deying; Su, Xiaoling; Wang, Nan; Li, Yunong; Yin, Hua; Li, Liang; Li, Lanjuan

2017-01-01

We report a chemical isotope labeling (CIL) liquid chromatography mass spectrometry (LC-MS) method generally applicable for tracking metabolomic changes from samples collected in an animal model for studying disease development and treatment. A rat model of surgically induced osteoarthritis (OA) was used as an example to illustrate the workflow and technical performance. Experimental duplicate analyses of 234 plasma samples were carried out using dansylation labeling LC-MS targeting the amine/phenol submetabolome. These samples composed of 39 groups (6 rats per group) were collected at multiple time points with sham operation, OA control group, and OA rats with treatment, separately, using glucosamine/Celecoxib and three traditional Chinese medicines (Epimedii folium, Chuanxiong Rhizoma and Bushen-Huoxue). In total, 3893 metabolites could be detected and 2923 of them were consistently detected in more than 50% of the runs. This high-coverage submetabolome dataset could be used to track OA progression and treatment. Many differentiating metabolites were found and 11 metabolites including 2-aminoadipic acid, saccharopine and GABA were selected as potential biomarkers of OA progression and OA treatment. This study illustrates that CIL LC-MS is a very useful technique for monitoring incremental metabolomic changes with high coverage and accuracy for studying disease progression and treatment in animal models. PMID:28091618

Cyclooxgenase-2 Inhibiting Perfluoropoly (Ethylene Glycol) Ether Theranostic Nanoemulsions—In Vitro Study

PubMed Central

Patel, Sravan Kumar; Zhang, Yang; Pollock, John A.; Janjic, Jelena M.

2013-01-01

Cylcooxgenase-2 (COX-2) expressing macrophages, constituting a major portion of tumor mass, are involved in several pro-tumorigenic mechanisms. In addition, macrophages are actively recruited by the tumor and represent a viable target for anticancer therapy. COX-2 specific inhibitor, celecoxib, apart from its anticancer properties was shown to switch macrophage phenotype from tumor promoting to tumor suppressing. Celecoxib has low aqueous solubility, which may limit its tumor inhibiting effect. As opposed to oral administration, we propose that maximum anticancer effect may be achieved by nanoemulsion mediated intravenous delivery. Here we report multifunctional celecoxib nanoemulsions that can be imaged by both near-infrared fluorescence (NIRF) and 19F magnetic resonance. Celecoxib loaded nanoemulsions showed a dose dependent uptake in mouse macrophages as measured by 19F NMR and NIRF signal intensities of labeled cells. Dramatic inhibition of intracellular COX-2 enzyme was observed in activated macrophages upon nanoemulsion uptake. COX-2 enzyme inhibition was statistically equivalent between free drug and drug loaded nanoemulsion. However, nanoemulsion mediated drug delivery may be advantageous, helping to avoid systemic exposure to celecoxib and related side effects. Dual molecular imaging signatures of the presented nanoemulsions allow for future in vivo monitoring of the labeled macrophages and may help in examining the role of macrophage COX-2 inhibition in inflammation-cancer interactions. These features strongly support the future use of the presented nanoemulsions as anti-COX-2 theranostic nanomedicine with possible anticancer applications. PMID:23409048

Cyclooxygenase-2 inhibitor induces apoptosis in breast cancer cells in an in vivo model of spontaneous metastatic breast cancer.

PubMed

Basu, Gargi D; Pathangey, Latha B; Tinder, Teresa L; Lagioia, Michelle; Gendler, Sandra J; Mukherjee, Pinku

2004-11-01

Cyclooxygenase-2 (COX-2) inhibitors are rapidly emerging as a new generation of therapeutic drug in combination with chemotherapy or radiation therapy for the treatment of cancer. The mechanisms underlying its antitumor effects are not fully understood and more thorough preclinical trials are needed to determine if COX-2 inhibition represents a useful approach for prevention and/or treatment of breast cancer. The purpose of this study was to evaluate the growth inhibitory mechanism of a highly selective COX-2 inhibitor, celecoxib, in an in vivo oncogenic mouse model of spontaneous breast cancer that resembles human disease. The oncogenic mice carry the polyoma middle T antigen driven by the mouse mammary tumor virus promoter and develop primary adenocarcinomas of the breast. Results show that oral administration of celecoxib caused significant reduction in mammary tumor burden associated with increased tumor cell apoptosis and decreased proliferation in vivo. In vivo apoptosis correlated with significant decrease in activation of protein kinase B/Akt, a cell survival signaling kinase, with increased expression of the proapoptotic protein Bax and decreased expression of the antiapoptotic protein Bcl-2. In addition, celecoxib treatment reduced levels of proangiogenic factor (vascular endothelial growth factor), suggesting a role of celecoxib in suppression of angiogenesis in this model. Results from these preclinical studies will form the basis for assessing the feasibility of celecoxib therapy alone or in combination with conventional therapies for treatment and/or prevention of breast cancer.

THE FAILURE OF CHLOROFORM ADMINISTERED IN THE DRINKING WATER TO INDUCE RENAL TUBULAR CELL NEOPLASIA IN MALE F344/N RATS

EPA Science Inventory

The failure of chloroform administered in drinking water to induce renal tubular cell neoplasia in male F344/N rats

Chloroform (TCM) has been demonstrated to be a renal carcinogen in the male Osborne-
Mendel rat when administered either by corn oil gavage or in drin...

Neoadjuvant irinotecan, cisplatin, and concurrent radiation therapy with celecoxib for patients with locally advanced esophageal cancer.

PubMed

Cleary, James M; Mamon, Harvey J; Szymonifka, Jackie; Bueno, Raphael; Choi, Noah; Donahue, Dean M; Fidias, Panos M; Gaissert, Henning A; Jaklitsch, Michael T; Kulke, Matthew H; Lynch, Thomas P; Mentzer, Steven J; Meyerhardt, Jeffrey A; Swanson, Richard S; Wain, John; Fuchs, Charles S; Enzinger, Peter C

2016-07-13

Patients with locally advanced esophageal cancer who are treated with trimodality therapy have a high recurrence rate. Preclinical evidence suggests that inhibition of cyclooxygenase 2 (COX2) increases the effectiveness of chemoradiation, and observational studies in humans suggest that COX-2 inhibition may reduce esophageal cancer risk. This trial tested the safety and efficacy of combining a COX2 inhibitor, celecoxib, with neoadjuvant irinotecan/cisplatin chemoradiation. This single arm phase 2 trial combined irinotecan, cisplatin, and celecoxib with concurrent radiation therapy. Patients with stage IIA-IVA esophageal cancer received weekly cisplatin 30 mg/m(2) plus irinotecan 65 mg/m(2) on weeks 1, 2, 4, and 5 concurrently with 5040 cGy of radiation therapy. Celecoxib 400 mg was taken orally twice daily during chemoradiation, up to 1 week before surgery, and for 6 months following surgery. Forty patients were enrolled with stage IIa (30 %), stage IIb (20 %), stage III (22.5 %), and stage IVA (27.5 %) esophageal or gastroesophageal junction cancer (AJCC, 5th Edition). During chemoradiation, grade 3-4 treatment-related toxicity included dysphagia (20 %), anorexia (17.5 %), dehydration (17.5 %), nausea (15 %), neutropenia (12.5 %), diarrhea (10 %), fatigue (7.5 %), and febrile neutropenia (7.5 %). The pathological complete response rate was 32.5 %. The median progression free survival was 15.7 months and the median overall survival was 34.7 months. 15 % (n = 6) of patients treated on this study developed brain metastases. The addition of celecoxib to neoadjuvant cisplatin-irinotecan chemoradiation was tolerable; however, overall survival appeared comparable to prior studies using neoadjuvant cisplatin-irinotecan chemoradiation alone. Further studies adding celecoxib to neoadjuvant chemoradiation in esophageal cancer are not warranted. Clinicaltrials.gov: NCT00137852 , registered August 29, 2005.

A Randomized, Multicenter, Phase III Trial to Evaluate the Efficacy and Safety of Polmacoxib Compared with Celecoxib and Placebo for Patients with Osteoarthritis.

PubMed

Lee, Myungchul; Yoo, Juhyung; Kim, Jin Goo; Kyung, Hee-Soo; Bin, Seong-Il; Kang, Seung-Baik; Choi, Choong Hyeok; Moon, Young-Wan; Kim, Young-Mo; Han, Seong Beom; In, Yong; Choi, Chong Hyuk; Kim, Jongoh; Lee, Beom Koo; Cho, Sangsook

2017-12-01

The aim of this study was to evaluate the safety and analgesic efficacy of polmacoxib 2 mg versus placebo in a superiority comparison or versus celecoxib 200 mg in a noninferiority comparison in patients with osteoarthritis (OA). This study was a 6-week, phase III, randomized, double-blind, and parallel-group trial followed by an 18-week, single arm, open-label extension. Of the 441 patients with knee or hip OA screened, 362 were randomized; 324 completed 6 weeks of treatment and 220 completed the extension. Patients were randomized to receive oral polmacoxib 2 mg (n = 146), celecoxib 200 mg (n = 145), or placebo (n = 71) once daily for 6 weeks. During the extension, all participants received open-label polmacoxib 2 mg. The primary endpoint was the change in Western Ontario and McMaster Universities (WOMAC)-pain subscale score from baseline to week 6. Secondary endpoints included WOMAC-OA Index, OA subscales (pain, stiffness, and physical function) and Physician's and Subject's Global Assessments at weeks 3 and 6. Other outcome measures included adverse events (AEs), laboratory tests, vital signs, electrocardiograms, and physical examinations. After 6 weeks, the polmacoxib-placebo treatment difference was -2.5 (95% confidence interval [CI], -4.4 to -0.6; p = 0.011) and the polmacoxib-celecoxib treatment difference was 0.6 (CI, -0.9 to 2.2; p = 0.425). According to Physician's Global Assessments, more subjects were "much improved" at week 3 with polmacoxib than with celecoxib or placebo. Gastrointestinal and general disorder AEs occurred with a greater frequency with polmacoxib or celecoxib than with placebo. Polmacoxib 2 mg was relatively well tolerated and demonstrated efficacy superior to placebo and noninferior to celecoxib after 6 weeks of treatment in patients with OA. The results obtained during the 18-week trial extension with polmacoxib 2 mg were consistent with those observed during the 6-week treatment period, indicating that polmacoxib can be considered safe for long-term use based on this relatively small scale of study in a Korean population. More importantly, the results of this study showed that polmacoxib has the potential to be used as a pain relief drug with reduced gastrointestinal side effects compared to traditional nonsteroidal anti-inflammatory drugs for OA.

Celecoxib and sulfasalazine had negative association with coronary artery diseases in patients with ankylosing spondylitis

PubMed Central

Wu, Li-Chih; Leong, Pui-Ying; Yeo, Kai-Jieh; Li, Ting-Yu; Wang, Yu-Hsun; Chiou, Jeng-Yuan; Wei, James Cheng-Chung

2016-01-01

Abstract The aim of the study is to assess the effects of celecoxib and sulfasalazine on the risk of coronary artery disease (CAD) in patients with ankylosing spondylitis (AS). Using the claims data of Taiwan National Health Insurance (NHI) database, a nationally representative data that contain the medical records of 23 million Taiwan residents, we randomly selected 1 million cohort from the database, and then we enrolled only patients who were newly diagnosed with AS (n = 4829) between year 2001 and 2010, excluding patients who had CAD (ICD-9- CM codes: 410–414) before the diagnosis of AS (n = 4112). According to propensity score matched 1:2 on age, gender, AS duration, Charlson comorbidity index, hypertension, and hyperlipidemia, 236 and 472 patients were included in the case (AS with CAD) and control (AS without CAD) groups, respectively. We used the WHO defined daily dose (DDD) as a tool to assess the dosage of sulfasalazine and celecoxib exposure. Conditional logistic regression was used to estimate the crude and adjusted odds ratios (ORs) and 95% confidence interval (CI) for the risk of CAD associated with use of sulfasalazine and celecoxib. Among 4112 AS patients, 8.4% (346/4112) developed CAD. CAD in AS patients were positively associated with age of 35 to 65, Charlson comorbidities index (CCI), hypertension, and hyperlipidemia. There was no gender difference between case and control groups. After adjustment for age, gender, CCI, hypertension, and hyperlipidemia, sulfasalazine users with an average daily dose ≥ 0.5 DDD (0.5 gm/day) had negative association with CAD events as compared to sulfasalazine nonusers (OR 0.63; 95% CI, 0.40–0.99, P < 0.05). NSAIDs, including celecoxib, etoricoxib, but no naproxen and diclofenac were negatively associated with CAD. Celecoxib users, with an average daily dose > 1.5 DDD, were negatively associated with CAD events, compared to celecoxib nonusers (OR 0.34; 95% CI, 0.13–0.89; P < 0.05). In this 10-year population-based case-control study, 8.4% of AS patients developed CAD. Sulfasalazine usage at an average dose of ≥ 0.5 gm/day demonstrated negative association with CAD events in patients with AS. PMID:27603385

[Efficiency of different celecoxib regimens in patients with active axial spondyloarthritis: Results of the 4-week pilot open-label comparative single-center study 'AIM'].

PubMed

Gaydukova, I Z; Gamayunova, К A; Dorogoykina, K D; Rebrov, A P

To compare the efficiency and safety of two celecoxib regimens in the short-term treatment of patients with axial spondyloarthritis (axSpA). Examinations were made in 40 patients with axSpA (the 2009 ASAS criteria; age, 38.5±12.1 years; 29 (72.5%) men; axSpA duration, 6.67±5.8 years; BASDAI ≥4.0), who were randomly divided into two groups: 1) 20 patients who received celecoxib 400 mg/day for 30 days; 2) 20 patients who took celecoxib 600 mg/day for 7 days, then the drug was continued at a dose of 200 mg/day for 1 month. High-sensitivity C-reactive protein (CRP) was determined; back pain was assessed using a visual analog scale; ASDAS-CRP scores were calculated at baseline (day 0) and on days 8 and 30. On days 0, 8, and 30 of taking celecoxib 400 mg, the back pain scores were 6.0±3.01, 5.06±2.04, and 5.53±2.35; CRP levels, 24.13±21.46; 27.3±29.3%, and 13.1±21.3 mg/l; erythrocyte sedimentation rate (ESR), 15.25±14.36, 11.85±13.6, and 9.5±6.34 mm/h, respectively (p≥0.05 for all differences in all indicators relative to the baseline values). ASDAS was 3.34±1.02 at baseline, 2.74±1.14 on day 8, and 2.18±1.05 on day 30 (p=0.016 and p=0,000 for differences from the baseline values). In the patients using the dose de-escalation of celecoxib, the back pain scores were 4.95±1.6, 4.11±1.0, and 4.89±2.1 at baseline and on days 8 and 30, respectively (p=0.38 and p=0.065 for the differences from the baseline values); the CRP levels were 15.3±12.5, 12.1±10.8, and 7.5±4.5 mg/l, respectively (p=0.3 and p=0.001); ESR, 13.35±7.2, 15.7±11.6, and 15.16±8.9 mm/h (p≥0.05). At baseline and on days 8 and 30, ASDAS was 3.1±0.6, 2.22±0.7, and 3.47±0.56, respectively (p=0.02 and p=0.000). No differences were found in the rate of adverse events. Different regimens using nonsteroidal anti-inflammatory drugs demonstrated their feasibility, efficiency, and safety in AxSpA patients with high disease activity. The continuous use of celecoxib showed a gradual decrease in clinical and laboratory activity. The de-escalation dose of celecoxib achieved a permanent laboratory activity reduction and pain relief when using 600 mg celecoxib, and after reducing its dose to 200 mg/day, there was a decrease in laboratory disease activity without substantially changing the patients' functional activity. The safety of the comparable regimens was comparable.

Simultaneous determination of celecoxib, hydroxycelecoxib, and carboxycelecoxib in human plasma using gradient reversed-phase liquid chromatography with ultraviolet absorbance detection.

PubMed

Störmer, Elke; Bauer, Steffen; Kirchheiner, Julia; Brockmöller, Jürgen; Roots, Ivar

2003-01-05

A new HPLC method for the simultaneous determination of celecoxib, carboxycelecoxib and hydroxycelecoxib in human plasma samples has been developed. Following a solid-phase extraction procedure, the samples were separated by gradient reversed-phase HLPC (C(18)) and quantified using UV detection at 254 nm. The method was linear over the concentration range 10-500 ng/ml. The intra-assay variability for the three analytes ranged from 4.0 to 12.6% and the inter-assay variability from 4.9 to 14.2%. The achieved limits of quantitation (LOQ) of 10 ng/ml for each analyte allowed the determination of the pharmacokinetic parameters of the analytes after administration of 100 mg celecoxib.

Involvement of hypothalamic cyclooxygenase-2, interleukin-1β and melanocortin in the development of docetaxel-induced anorexia in rats.

PubMed

Yamamoto, Kouichi; Asano, Keiko; Ito, Yui; Matsukawa, Naoki; Kim, Seikou; Yamatodani, Atsushi

2012-12-16

Docetaxel, a taxane derivative, is frequently used for the treatment of advanced breast cancer, non-small cell lung cancer, and metastatic prostate cancer. Clinical reports demonstrated that docetaxel-based chemotherapy often induces anorexia, but the etiology is not completely understood. To elucidate possible mechanisms, we investigated the involvement of central interleukin (IL)-1β, cyclooxygenase (COX)-2, and pro-opiomelanocortin (POMC) in the development of docetaxel-induced anorexia in rats. Rats received docetaxel (10mg/kg, i.p.) with or without pretreatment with selective COX-2 inhibitors, NS-398 (10 and 30 mg/kg, i.g.) or celecoxib (10 and 30 mg/kg, i.g.), and a non-selective COX inhibitor, indomethacin (10mg/kg, i.g.), then food intake was monitored for 24h after administration. We also examined expression of IL-1β, COX-2, and POMC mRNA in hypothalamus of docetaxel-treated rats and the effect of a COX-2 inhibitor on docetaxel-induced POMC mRNA expression. Food consumption in rats was significantly decreased 24h after administration of docetaxel and anorexia was partially reversed by all COX inhibitors. Administration of docetaxel increased IL-1β, COX-2, and POMC mRNA expression in the hypothalamus of rats. The time required to increase these gene expressions was comparable to the latency period of docetaxel-induced anorexia in rats. In addition, pretreatment with COX-2 inhibitors suppressed docetaxel-induced expression of POMC mRNA. These results suggest that IL-1β and COX-2 mRNA expression and subsequent activation of POMC in the hypothalamus may contribute to the development of docetaxel-induced anorexia in rats. Copyright © 2012. Published by Elsevier Ireland Ltd.

Spray Dried Chitosan Microparticles for Intravesical Delivery of Celecoxib: Preparation and Characterization.

PubMed

Lopedota, Angela; Cutrignelli, Annalisa; Laquintana, Valentino; Denora, Nunzio; Iacobazzi, Rosa Maria; Perrone, Mara; Fanizza, Elisabetta; Mastrodonato, Maria; Mentino, Donatella; Lopalco, Antonio; Depalo, Nicoletta; Franco, Massimo

2016-09-01

Chitosan microparticles containing celecoxib (CB), were developed as chemoprevention of bladder cancer. Furthermore two inclusion complexes of CB with methyl-β-cyclodextrin (C1 and C2) were prepared to improve the solubility of the drug. C1 and C2 were obtained by freeze-drying and characterized in the solid state and in solution. Microparticles loaded with CB or C1 or C2 were prepared by spray drying and fully characterized. The yield and encapsulation efficiencies of microparticles depended by both the viscosity and the presence of the inclusion complex in the feed medium nebulised. Generally, the microparticles exhibited a spherical shape with mean diameter of approximately 2 μm which was compatible with local intravesical administration using a catheter. The CB release studies from the microparticles allowed us to identify both immediate release systems (microparticles including the complexes) and prolonged release systems (microparticles including CB alone). The latter exhibited good adhesion to the bladder mucosa, as highlighted by a mucoadhesion study. Histological studies revealed a desquamation of the superficial cells when the bladder mucosa was treated with microparticles loaded with CB, while the morphology of the urothelium did not change when it was treated with microparticles loaded with the inclusion complex. A new CB intravesical formulation than can easily be administered with a catheter and is able to release the drug at the target site for several hours was realized. This new delivery system could be a good alternative to classic oral CB administration.

Ultrasonic vocalization in rats self-administering heroin and cocaine in different settings: evidence of substance-specific interactions between drug and setting.

PubMed

Avvisati, Riccardo; Contu, Laura; Stendardo, Emiliana; Michetti, Caterina; Montanari, Christian; Scattoni, Maria Luisa; Badiani, Aldo

2016-04-01

Clinical and preclinical evidence indicates that the setting of drug use affects drug reward in a substance-specific manner. Heroin and cocaine co-abusers, for example, indicated distinct settings for the two drugs: heroin being used preferentially at home and cocaine preferentially outside the home. Similar results were obtained in rats that were given the opportunity to self-administer intravenously both heroin and cocaine. The goal of the present study was to investigate the possibility that the positive affective state induced by cocaine is enhanced when the drug is taken at home relative to a non-home environment, and vice versa for heroin. To test this hypothesis, we trained male rats to self-administer both heroin and cocaine on alternate days and simultaneously recorded the emission of ultrasonic vocalizations (USVs), as it has been reported that rats emit 50-kHz USVs when exposed to rewarding stimuli, suggesting that these USVs reflect positive affective states. We found that Non-Resident rats emitted more 50-kHz USVs when they self-administered cocaine than when self-administered heroin whereas Resident rats emitted more 50-kHz USVs when self-administering heroin than when self-administering cocaine. Differences in USVs in Non-Resident rats were more pronounced during the first self-administration (SA) session, when the SA chambers were completely novel to them. In contrast, the differences in USVs in Resident rats were more pronounced during the last SA sessions. These findings indicate that the setting of drug taking exerts a substance-specific influence on the ability of drugs to induce positive affective states.

Evaluation of selective cyclooxygenase-2 inhibitor-induced small bowel injury: randomized cross-over study compared with loxoprofen in healthy subjects.

PubMed

Mizukami, Kazuhiro; Murakami, Kazunari; Yamauchi, Mika; Matsunari, Osamu; Ogawa, Ryo; Nakagawa, Yoshifumi; Okimoto, Tadayoshi; Kodama, Masaaki; Fujioka, Toshio

2013-05-01

Non-steroidal anti-inflammatory drugs have the potential to injure the mucosa of the upper digestive tract and small bowel, whereas celecoxib (a selective cyclooxygenase-2 inhibitor) has less influence on the entire digestive tract mucosa. The present study was conducted to compare the extents of small bowel mucosal injury induced by celecoxib and loxoprofen (the most frequently used non-steroidal anti-inflammatory drugs in Japan). Ten healthy adult males were given celecoxib (200 mg/day, Group C) and loxoprofen (180 mg/day, Group L) in a cross-over design for 14 days, and the influence of each drug on small bowel mucosa was evaluated by comparing pre- and post-treatment capsule endoscopy findings. We measured the percentage of patients with small bowel mucosal injury following administration of these drugs as primary endpoint. Additionally, mean number of small bowel mucosal injuries per subject was analyzed as secondary endpoint. The percentage of subjects experiencing small bowel mucosal injury as primary endpoint was 10% in Group C and 70% in Group L after treatment. This magnitude of the difference of between Group C and Group L was statistically significant (P = 0.031). The number of small bowel mucosal injuries as secondary endpoint differed significantly between the two groups, and the influence of celecoxib on small bowel injury was less than that of loxoprofen. These results indicate that celecoxib has less influence on small bowel mucosa than loxoprofen and can be used safely. © 2012 The Authors. Digestive Endoscopy © 2012 Japan Gastroenterological Endoscopy Society.

Destruction of vasculogenic mimicry channels by targeting epirubicin plus celecoxib liposomes in treatment of brain glioma

PubMed Central

Ju, Rui-Jun; Zeng, Fan; Liu, Lei; Mu, Li-Min; Xie, Hong-Jun; Zhao, Yao; Yan, Yan; Wu, Jia-Shuan; Hu, Ying-Jie; Lu, Wan-Liang

2016-01-01

The efficacy of chemotherapy for brain glioma is restricted by the blood–brain barrier (BBB), and surgery or radiotherapy cannot eliminate the glioma cells because of their unique location. Residual brain glioma cells can form vasculogenic mimicry (VM) channels that can cause a recurrence of brain glioma. In the present study, targeting liposomes incorporating epirubicin and celecoxib were prepared and used for the treatment of brain glioma, along with the destruction of their VM channels. Evaluations were performed on the human brain glioma U87MG cells in vitro and on intracranial brain glioma-bearing nude mice. Targeting epirubicin plus celecoxib liposomes in the circulatory blood system were able to be transported across the BBB, and accumulated in the brain glioma region. Then, the liposomes were internalized by brain glioma cells and killed glioma cells by direct cytotoxic injury and the induction of apoptosis. The induction of apoptosis was related to the activation of caspase-8- and -3-signaling pathways, the activation of the proapoptotic protein Bax, and the suppression of the antiapoptotic protein Mcl-1. The destruction of brain glioma VM channels was related to the downregulation of VM channel-forming indictors, which consisted of MMP-2, MMP-9, FAK, VE-Cad, and VEGF. The results demonstrated that the targeting epirubicin plus celecoxib liposomes were able to effectively destroy the glioma VM channels and exhibited significant efficacy in the treatment of intracranial glioma-bearing nude mice. Therefore, targeting epirubicin plus celecoxib liposomes could be a potential nanostructured formulation to treat gliomas and destroy their VM channels. PMID:27042063

IL-1beta suppresses the formation of osteoclasts by increasing OPG production via an autocrine mechanism involving celecoxib-related prostaglandins in chondrocytes.

PubMed

Watanabe, Yusuke; Namba, Aki; Aida, Yukiko; Honda, Kazuhiro; Tanaka, Hideki; Suzuki, Naoto; Matsumura, Hideo; Maeno, Masao

2009-01-01

Elevated interleukin (IL)-1 concentrations in synovial fluid have been implicated in joint bone and cartilage destruction. Previously, we showed that IL-1beta stimulated the expression of prostaglandin (PG) receptor EP4 via increased PGE(2) production. However, the effect of IL-1beta on osteoclast formation via chondrocytes is unclear. Therefore, we examined the effect of IL-1beta and/or celecoxib on the expression of macrophage colony-stimulating factor (M-CSF), receptor activator of NF-kappaB ligand (RANKL), and osteoprotegerin (OPG) in human chondrocytes, and the indirect effect of IL-1beta on osteoclast-like cell formation using RAW264.7 cells. OPG and RANKL expression increased with IL-1beta; whereas M-CSF expression decreased. Celecoxib blocked the stimulatory effect of IL-1beta. Conditioned medium from IL-1beta-treated chondrocytes decreased TRAP staining in RAW264.7 cells. These results suggest that IL-1beta suppresses the formation of osteoclast-like cells via increased OPG production and decreased M-CSF production in chondrocytes, and OPG production may increase through an autocrine mechanism involving celecoxib-related PGs.

Celecoxib plus hormone therapy versus hormone therapy alone for hormone-sensitive prostate cancer: first results from the STAMPEDE multiarm, multistage, randomised controlled trial

PubMed Central

James, Nicholas D; Sydes, Matthew R; Mason, Malcolm D; Clarke, Noel W; Anderson, John; Dearnaley, David P; Dwyer, John; Jovic, Gordana; Ritchie, Alastair WS; Russell, J Martin; Sanders, Karen; Thalmann, George N; Bertelli, Gianfilippo; Birtle, Alison J; O'Sullivan, Joe M; Protheroe, Andrew; Sheehan, Denise; Srihari, Narayanan; Parmar, Mahesh KB

2012-01-01

Summary Background Long-term hormone therapy alone is standard care for metastatic or high-risk, non-metastatic prostate cancer. STAMPEDE—an international, open-label, randomised controlled trial—uses a novel multiarm, multistage design to assess whether the early additional use of one or two drugs (docetaxel, zoledronic acid, celecoxib, zoledronic acid and docetaxel, or zoledronic acid and celecoxib) improves survival in men starting first-line, long-term hormone therapy. Here, we report the preplanned, second intermediate analysis comparing hormone therapy plus celecoxib (arm D) with hormone therapy alone (control arm A). Methods Eligible patients were men with newly diagnosed or rapidly relapsing prostate cancer who were starting long-term hormone therapy for the first time. Hormone therapy was given as standard care in all trial arms, with local radiotherapy encouraged for newly diagnosed patients without distant metastasis. Randomisation was done using minimisation with a random element across seven stratification factors. Patients randomly allocated to arm D received celecoxib 400 mg twice daily, given orally, until 1 year or disease progression (including prostate-specific antigen [PSA] failure). The intermediate outcome was failure-free survival (FFS) in three activity stages; the primary outcome was overall survival in a subsequent efficacy stage. Research arms were compared pairwise against the control arm on an intention-to-treat basis. Accrual of further patients was discontinued in any research arm showing safety concerns or insufficient evidence of activity (lack of benefit) compared with the control arm. The minimum targeted activity at the second intermediate activity stage was a hazard ratio (HR) of 0·92. This trial is registered with ClinicalTrials.gov, number NCT00268476, and with Current Controlled Trials, number ISRCTN78818544. Findings 2043 patients were enrolled in the trial from Oct 17, 2005, to Jan 31, 2011, of whom 584 were randomly allocated to receive hormone therapy alone (control group; arm A) and 291 to receive hormone therapy plus celecoxib (arm D). At the preplanned analysis of the second intermediate activity stage, with 305 FFS events (209 in arm A, 96 in arm D), there was no evidence of an advantage for hormone therapy plus celecoxib over hormone therapy alone: HR 0·98 (95% CI 0·90–1·06). 2-year FFS was 51% (95% CI 46–56) in arm A and 51% (95% CI 43–58) in arm D. There was no evidence of differences in the incidence of adverse events between groups (events of grade 3 or higher were noted at any time in 123 [23%, 95% CI 20–27] patients in arm A and 64 [25%, 19–30] in arm D). The most common grade 3–5 events adverse effects in both groups were endocrine disorders (55 [11%] of patients in arm A vs 19 [7%] in arm D) and musculoskeletal disorders (30 [6%] of patients in arm A vs 15 [6%] in arm D). The independent data monitoring committee recommended stopping accrual to both celecoxib-containing arms on grounds of lack of benefit and discontinuing celecoxib for patients currently on treatment, which was endorsed by the trial steering committee. Interpretation Celecoxib 400 mg twice daily for up to 1 year is insufficiently active in patients starting hormone therapy for high-risk prostate cancer, and we do not recommend its use in this setting. Accrual continues seamlessly to the other research arms and follow-up of all arms will continue to assess effects on overall survival. Funding Cancer Research UK, Pfizer, Novartis, Sanofi-Aventis, Medical Research Council (London, UK). PMID:22452894

Nonsteroidal anti-inflammatory drugs-induced failure of lower esophageal and pyloric sphincter and counteraction of sphincters failure with stable gatric pentadecapeptide BPC 157 in rats.

PubMed

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

2017-04-01

The sphincters failure is a part of NSAIDs-toxicity that can be accordingly counteracted. We used a safe stable gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, MW 1419), LD1 not achieved, since successful in inflammatory bowel disease trials, and counteracts esophagitis, sphincters failure, gastrointestinal ulcer and skin ulcer, external and internal fistulas in rats, and particularly counteracts all NSAIDs-lesions. We assessed lower esophageal sphincter and pyloric sphincter pressure (cmH 2 O) in rats treated with various NSAIDs regimens, at corresponding time points, known to produce stomach, small intestine lesions, hepatotoxicity and encephalopathy. Assessment was after diclofenac (12.5 mg/kg, 40 mg/kg intraperitoneal challenge), ibuprofen (400 mg/day/kg intraperitoneally for 4 weeks), paracetamol (5.0 g/kg intraperitoneal challenge), aspirin (400 mg/kg intraperitoneally or intragastrically), celecoxib (0.5 mg/kg, 1.0 mg/kg intraperitoneally). BPC 157 (10 μg/kg, 10 ng/kg) was given immediately after NSAIDs (intraperitoneally or intragastrically) or given in drinking water. Regularly, in all control NSAIDs fall of pressure occurred in both sphincters rapidly and then persisted. By contrast, in all NSAIDs-rats that received BPC 157, initial fall of pressure was minimized and pressure values restored to normal values. All tested NSAIDs decrease pressure in both sphincters, whilst BPC 157 counteracts their effects and restored both sphincters function.

Inhibition of COX-2 reduces the age-dependent increase of hippocampal inflammatory markers, corticosterone secretion, and behavioral impairments in the rat.

PubMed

Casolini, Paola; Catalani, Assia; Zuena, Anna R; Angelucci, Luciano

2002-05-01

Brain aging as well as brain degenerative processes with accompanying cognitive impairments are generally associated with hyperactivity of the hypothalamus-pituitary-adrenal axis, the end product of which, the glucocorticoid hormone, has been warranted the role of cell damage primum movens ("cascade hypothesis"). However, chronic inflammatory activity occurs in the hippocampus of aged rats as well as in the brain of Alzheimer's disease patients. The concomitant increase in the secretion of the glucocorticoid hormone, the endogenous anti-inflammatory and pro-inflammatory markers, has prompted us to investigate the two phenomena in the aging rat, and to work out its meaning. This study shows that: (I) interleukin-1beta (IL-1beta), tumor necrosis factor alpha (TNFalpha), and prostaglandin E(2) (PGE(2)) increase with age in the rats hippocampus, and (II) chronic oral treatment with celecoxib, a selective cycloxygenase-2 (COX-2) inhibitor, is able to contrast the age-dependent increase in hippocampal levels of pro-inflammatory markers and circulating anti-inflammatory corticosterone, provided that it is started at an early stage of aging. Under these conditions, age-related impairments in cognitive ability may be ameliorated. Taken together, these results indicate that there is a natural tendency to offset the age-dependent increase in brain inflammatory processes via the homeostatic increase of the circulating glucocorticoid hormone. Copyright 2002 Wiley-Liss, Inc.

Dietary anthocyanin-rich Haskap phytochemicals inhibit postprandial hyperlipidemia and hyperglycemia in rats.

PubMed

Takahashi, Azusa; Okazaki, Yukako; Nakamoto, Aika; Watanabe, Sanae; Sakaguchi, Hirohide; Tagashira, Yukari; Kagii, Atsuko; Nakagawara, Shunji; Higuchi, Ohki; Suzuki, Takashi; Chiji, Hideyuki

2014-01-01

Haskap (Lonicera caerulea L.) fruit contains some bioactive phenolic phytochemicals, mainly cyanidin-3-glucoside (cy3-glc) and chlorogenic acid. The purpose of this study was to investigate the effects of anthocyanin-rich phenolic phytochemical (containing 13.2% anthocyanin) purified from a Haskap fruit (named Haskap phytochemical) on postprandial serum triglyceride and blood glucose levels. The Haskap phytochemical (containing cy 3-glc at 300 mg/kg of body weight) was administered orally to rats fasted for 24 h and 30 min later, a corn oil emulsion was administered to these rats. After the administration, serum triglyceride concentration was measured. An increase in serum triglyceride concentration and the AUC significantly lowered in the Haskap phytochemical-administered group than in the saline-administered group. To evaluate the effect of serum glucose levels, the Haskap phytochemical was orally administered to rats fasted for 24 h and sucrose solution (2 g/kg of body weight) was administered to these rats after 30 min. After the administration, blood glucose level was measured. The Haskap phytochemical significantly reduced the increase in blood glucose levels and AUC in the Haskap phytochemical-administered group than in the saline-administered group. Furthermore, to investigate the long-term effects of Haskap phytochemical intake, high-fat diet (HF diet) with 1.5% or 3.0% Haskap phytochemical was administered to rats for four weeks. The investigation of chronological changes in the serum components of the rats fed HF diets in addition to the administration of Haskap phytochemical showed that the increase in serum triglyceride concentrations, total cholesterol concentrations and blood glucose were significantly suppressed compared to the HF diet-fed control (HF-control). These results suggest that the decrease in postprandial blood lipids and blood glucose by short or long-term Haskap phytochemical ingestion is due to anthocyanin and other polyphenols contained in the Haskap phytochemical.

Comparing etoricoxib and celecoxib for preemptive analgesia for acute postoperative pain in patients undergoing arthroscopic anterior cruciate ligament reconstruction: a randomized controlled trial

PubMed Central

2010-01-01

Background The efficacy of selective cox-2 inhibitors in postoperative pain reduction were usually compared with conventional non-selective conventional NSAIDs or other types of medicine. Previous studies also used selective cox-2 inhibitors as single postoperative dose, in continued mode, or in combination with other modalities. The purpose of this study was to compare analgesic efficacy of single preoperative administration of etoricoxib versus celecoxib for post-operative pain relief after arthroscopic anterior cruciate ligament reconstruction. Methods One hundred and two patients diagnosed as anterior cruciate ligament injury were randomized into 3 groups using opaque envelope. Both patients and surgeon were blinded to the allocation. All of the patients were operated by one orthopaedic surgeon under regional anesthesia. Each group was given either etoricoxib 120 mg., celecoxib 400 mg., or placebo 1 hour prior to operative incision. Post-operative pain intensity, time to first dose of analgesic requirement and numbers of analgesic used for pain control and adverse events were recorded periodically to 48 hours after surgery. We analyzed the data according to intention to treat principle. Results Among 102 patients, 35 were in etoricoxib, 35 in celecoxib and 32 in placebo group. The mean age of the patients was 30 years and most of the injury came from sports injury. There were no significant differences in all demographic characteristics among groups. The etoricoxib group had significantly less pain intensity than the other two groups at recovery room and up to 8 hours period but no significance difference in all other evaluation point, while celecoxib showed no significantly difference from placebo at any time points. The time to first dose of analgesic medication, amount of analgesic used, patient's satisfaction with pain control and incidence of adverse events were also no significantly difference among three groups. Conclusions Etoricoxib is more effective than celecoxib and placebo for using as preemptive analgesia for acute postoperative pain control in patients underwent arthroscopic anterior cruciate ligament reconstruction. Trial registration number NCT01017380 PMID:20973952

Effects of heroin on rat prosocial behavior.

PubMed

Tomek, Seven E; Stegmann, Gabriela M; Olive, M Foster

2018-05-04

Opioid use disorders are characterized in part by impairments in social functioning. Previous research indicates that laboratory rats, which are frequently used as animal models of addiction-related behaviors, are capable of prosocial behavior. For example, under normal conditions, when a 'free' rat is placed in the vicinity of rat trapped in a plastic restrainer, the rat will release or 'rescue' the other rat from confinement. The present study was conducted to determine the effects of heroin on prosocial behavior in rats. For 2 weeks, rats were given the opportunity to rescue their cagemate from confinement, and the occurrence of and latency to free the confined rat was recorded. After baseline rescuing behavior was established, rats were randomly selected to self-administer heroin (0.06 mg/kg/infusion i.v.) or sucrose pellets (orally) for 14 days. Next, rats were retested for rescuing behavior once daily for 3 days, during which they were provided with a choice between freeing the trapped cagemate and continuing to self-administer their respective reinforcer. Our results indicate that rats self-administering sucrose continued to rescue their cagemate, whereas heroin rats chose to self-administer heroin and not rescue their cagemate. These findings suggest that rats with a history of heroin self-administration show deficits in prosocial behavior, consistent with specific diagnostic criteria for opioid use disorder. Behavioral paradigms providing a choice between engaging in prosocial behavior and continuing drug use may be useful in modeling and investigating the neural basis of social functioning deficits in opioid addiction. © 2018 Society for the Study of Addiction.

Levels of prostaglandin E metabolite and leukotriene E(4) are increased in the urine of smokers: evidence that celecoxib shunts arachidonic acid into the 5-lipoxygenase pathway.

PubMed

Duffield-Lillico, Anna J; Boyle, Jay O; Zhou, Xi Kathy; Ghosh, Aradhana; Butala, Geera S; Subbaramaiah, Kotha; Newman, Robert A; Morrow, Jason D; Milne, Ginger L; Dannenberg, Andrew J

2009-04-01

Cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LO) play a role in inflammation and carcinogenesis. Biomarkers that reflect tobacco smoke-induced tissue injury are needed. In this study, levels of urinary prostaglandin E metabolite (PGE-M) and leukotriene E(4) (LTE(4)), biomarkers of the COX and 5-LO pathways, were compared in never smokers, former smokers, and current smokers. The effects of celecoxib, a selective COX-2 inhibitor, on levels of PGE-M and LTE(4) were determined. Baseline levels of PGE-M and LTE(4) were positively associated with smoking status; levels of PGE-M and LTE(4) were higher in current versus never smokers. Treatment with 200 mg celecoxib twice daily for 6 +/- 1 days led to a reduction in urinary PGE-M levels in all groups but exhibited the greatest effect among subjects with high baseline PGE-M levels. Thus, high baseline PGE-M levels in smokers reflected increased COX-2 activity. In individuals with high baseline PGE-M levels, treatment with celecoxib led to a significant increase in levels of urinary LTE(4), an effect that was not found in individuals with low baseline PGE-M levels. In conclusion, increased levels of urinary PGE-M and LTE(4) were found in human smokers, a result that may reflect subclinical lung inflammation. In individuals with high baseline levels of PGE-M (elevated COX-2 activity), celecoxib administration shunted arachidonic acid into the proinflammatory 5-LO pathway. Because 5-LO activity and LTE(4) have been suggested to play a role in cardiovascular disease, these results may help to explain the link between use of COX-2 inhibitors and cardiovascular complications.

A Comparative Study on the Efficacy of Ibuprofen and Celecoxib on the Intensity of Perineal Pain Following Episiotomy: A Randomized Clinical Trial

PubMed Central

Suhrabi, Zainab; Taghinejad, Hamid

2013-01-01

Background: Pain is a worldwide problem that often originates from disease process, and diagnostic and treatment procedures such as surgical operations. Objectives: This trial was performed to compare the effectiveness of two analgesics for the management of perineal pain caused by episiotomy. Materials and Methods: A total of 170 nulliparous women who gave birth vaginally with episiotomy between March 2009 and November 2010 were randomly assigned to receive either ibuprofen or celecoxib which were given orally every 6 or 12 hours, respectively. Pain levels were measured before the intervention, and at 1, 2, 4, 8 and 12 hours after providing the first dose on a 10-cm visual analogue scale. Results: The results showed that the two groups had no significant differences regarding demographic characteristics, maternal, neonatal, and post-delivery factors, and mean premedication pain severity. Means of pain severity were different between the two groups as patients in the celecoxib group had lower means than the other group at 1,2,4,8 and 12 hours (4.01 ± 1.8 vs. 4.46 ± 1.9, 3.17 ± 1.9 vs. 3.79 ± 1.7, 2.89 ± 1.3 vs. 2.96 ± 1.5, 2.19 ± 1.8 vs. 2.55 ± 1.4, and 1.98 ± 1.1 vs. 2.45 ± 1.2, respectively) after administration of analgesics. Conclusions: Patients who received celecoxib had lower VAS in comparison with others. Although these differences were not significant, as celecoxib has longer half-life, fewer upper GI symptoms, and is better tolerated based on the previous studies, and this study is in favor of using it. PMID:24693414

[Cost-effectiveness analysis of celecoxib versus non-selective non-steroidal anti-inflammatory drug therapy for the treatment of osteoarthritis in Spain: A current perspective].

PubMed

De Lossada, A; Oteo-Álvaro, Á; Giménez, S; Oyagüez, I; Rejas, J

2016-01-01

To assess the cost-effectiveness of celecoxib and non-selective non-steroidal anti-inflammatory drugs for the treatment of osteoarthritis in clinical practice in Spain. A decision-tree model using distribution, doses, treatment duration and incidence of GI and CV events observed in the pragmatic PROBE-designed «GI-Reasons» trial was used for cost-effectiveness. Effectiveness was expressed in terms of event averted and quality-adjusted life-years (QALY) gained. QALY were calculated based on utility decrement in case of any adverse events reported in GI-Reasons trial. The National Health System perspective in Spain was applied; cost calculations included current prices of drugs plus cost of adverse events occurred. The analysis was expressed as an incremental cost-effectiveness ratio per QALY gained and per event averted. One-way and probabilistic analyses were performed. Compared with non-selective non-steroidal anti-inflammatory drugs, at current prices, celecoxib treatment had higher overall treatment costs €201 and €157, respectively. However, celecoxib was associated with a slight increase in QALY gain and significantly lower incidence of gastrointestinal events (p<.001), with mean incremental cost-effectiveness ratio of €13,286 per QALY gained and €4,471 per event averted. Sensitivity analyses were robust, and confirmed the results of the base case. Celecoxib at current price may be considered as a cost-effective alternative vs. non-selective non-steroidal anti-inflammatory drugs in the treatment of osteoarthritis in daily practice in the Spanish NHS. Copyright © 2015 Sociedad Española de Médicos de Atención Primaria (SEMERGEN). Publicado por Elsevier España, S.L.U. All rights reserved.

Inhibitory effects of oxytocin and oxytocin receptor antagonist atosiban on the activities of carbonic anhydrase and acetylcholinesterase enzymes in the liver and kidney tissues of rats.

PubMed

Kocyigit, Umit M; Taşkıran, Ahmet Şevki; Taslimi, Parham; Yokuş, Ahmet; Temel, Yusuf; Gulçin, İlhami

2017-11-01

The aim of this study was to investigate the effects of oxytocin (OT), atosiban, which is an OT receptor antagonist, and OT-atosiban chemicals injected to rats on the activities of carbonic anhydrase (CA) and acetylcholinesterase (AChE) enzymes in liver and kidney tissues of rats. For this purpose, four different groups, each consisting of six rats (n = 6), were formed (control group, OT administered group, atosiban administered group, and both OT and atosiban administered group). The rats were necropsied 60 min after intraperitoneal injection of chemicals into the rats. Liver tissues of rats were extracted. CA and AChE enzyme activities were measured for each tissue by using hydratase, esterase, and acetylcholiniodide methods. Activity values for each enzyme obtained were statistically calculated. © 2017 Wiley Periodicals, Inc.

Juniperus communis Linn oil decreases oxidative stress and increases antioxidant enzymes in the heart of rats administered a diet rich in cholesterol.

PubMed

Gumral, Nurhan; Kumbul, Duygu Doguc; Aylak, Firdevs; Saygin, Mustafa; Savik, Emin

2015-01-01

It has been asserted that consumption of dietary cholesterol (Chol) raises atherosclerotic cardiovascular diseases and that Chol causes an increase in free radical production. Hypercholesterolemic diet has also been reported to cause changes in the antioxidant system. In our study, different doses of Juniperus communis Linn (JCL) oil, a tree species growing in Mediterranean and Isparta regions and having aromatic characteristics, were administered to rats; and the levels of antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), and thiobarbituric acid reactive substances assay (TBARS) were examined in the heart tissue of rats. In this study, 35 Wistar Albino male adult rats weighing approximately 250-300 g were used. The rats were divided into five groups of seven each. The control group was administered normal pellet chow, and the Chol group was administered pellet chow including 2% Chol, while 50 JCL, 100 JCL, and 200 JCL groups were administered 50, 100, and 200 mg/kg JCL oil dissolved in 0.5% sodium carboxy methyl cellulose, respectively, in addition to the pellet chow containing 2% Chol, by gavage. After 30 days, the experiment was terminated and the antioxidant enzyme activities were examined in the heart tissue of rats. While consumption of dietary Chol decreases the activities of SOD, GSH-Px, and CAT in heart tissue of rats (not significant), administeration of 200 mg/kg JCL oil in addition to Chol led to a significant increase in the activity of antioxidant enzymes. Administering Chol led to a significant increase in TBARS level. Administering 100 and 200 mg/kg JCL oil together with Chol prevented significantly the increase in lipid peroxides. As a result of the study, JCL oil showed oxidant-antioxidant effect in the heart tissue of rats. © The Author(s) 2012.

Pressure application measurement (PAM): a novel behavioural technique for measuring hypersensitivity in a rat model of joint pain.

PubMed

Barton, Nicola J; Strickland, Iain T; Bond, Susan M; Brash, Harry M; Bate, Simon T; Wilson, Alex W; Chessell, Iain P; Reeve, Alison J; McQueen, Daniel S

2007-06-15

Chronic joint pain affects physical well being and can lead to severe psychological and social problems, therefore successful long-term management is highly sought-after. No current behavioural measures of pain used in pre-clinical models mimic the clinical dolorimeter, which provides an objective measure of joint hypersensitivity. In this study we aim to use a novel behavioural readout alongside an established measure to mimic the multifactorial measurements taken in the clinic. Using the pressure application measurement (PAM) device a gradually increasing squeeze was applied across the knee joint of rats until the animal gave an indication of pain or discomfort. PAM and the incapacitance tester were used to detect joint hypersensitivity in a well-established rodent model of adjuvant-induced arthritis. Subsequently, the analgesic effects of prednisolone (1, 3 or 10 mg kg(-1)), morphine (3 mg kg(-1)) and celecoxib (15 mg kg(-1)) were assessed. Both PAM and the incapacitance tester detected a reversal of hypersensitivity 1h post-drug administration. Furthermore, the two readouts were highly correlated, and power analysis indicated that PAM was highly reproducible. In conclusion, PAM provides a novel, accurate behavioural tool for detecting a primary mechanical hypersensitivity in a rat model of chronic inflammatory joint pain.

The level of orally ingested vitamin C affected the expression of vitamin C transporters and vitamin C accumulation in the livers of ODS rats.

PubMed

Sone, Yasuko; Ueta, Etsuko; Kodama, Satoru; Sannoumaru, Yasuko; Miyake, Noriko; Sone, Hirohito; Fujiwara, Yoko; Otsuka, Yuzuru; Kondo, Kazuo; Inagaki, Masahiro; Namba, Eiji; Kurata, Tadao; Suzuki, Emiko

2011-01-01

We investigated the effects of vitamin C administration on vitamin C-specific transporters in ODS/ShiJcl-od/od rat livers. The vitamin C-specific transporter levels increased in the livers of the rats not administered vitamin C and decreased in the livers of those administered vitamin C at 100 mg/d, indicating that these transporter levels can be influenced by the amount of vitamin C administered.

Congenic rats with higher arylamine N-acetyltransferase 2 activity exhibit greater carcinogen-induced mammary tumor susceptibility independent of carcinogen metabolism.

PubMed

Stepp, Marcus W; Doll, Mark A; Samuelson, David J; Sanders, Mary Ann G; States, J Christopher; Hein, David W

2017-03-31

Recent investigations suggest role(s) of human arylamine N-acetyltransferase 1 (NAT1) in breast cancer. Rat NAT2 is orthologous to human NAT1 and the gene products are functional homologs. We conducted in vivo studies using F344.WKY-Nat2 rapid/slow rats, congenic at rat Nat2 for high (rapid) and low (slow) arylamine N-acetyltransferase activity, to assess a possible role for rat NAT2 in mammary tumor susceptibility. Mammary carcinogens, methylnitrosourea (MNU) and 7,12-dimethylbenzanthracene (DMBA) neither of which is metabolized by N-acetyltransferase, were administered to assess mammary tumors. MNU was administered at 3 or 8 weeks of age. DMBA was administered at 8 weeks of age. NAT2 enzymatic activity and endogenous acetyl-coenzyme A (AcCoA) levels were measured in tissue samples and embryonic fibroblasts isolated from the congenic rats. Tumor latency was shorter in rapid NAT2 rats compared to slow NAT2 rats, with statistical significance for MNU administered at 3 and 8 weeks of age (p = 0.009 and 0.050, respectively). Tumor multiplicity and incidence were higher in rapid NAT2 rats compared to slow NAT2 rats administered MNU or DMBA at 8 weeks of age (MNU, p = 0.050 and 0.035; DMBA, p = 0.004 and 0.027, respectively). Recombinant rat rapid-NAT2, as well as tissue samples and embryonic fibroblasts derived from rapid NAT2 rats, catalyzed p-aminobenzoic acid N-acetyl transfer and folate-dependent acetyl-coenzyme A (AcCoA) hydrolysis at higher rates than those derived from rat slow-NAT2. Embryonic fibroblasts isolated from rapid NAT2 rats displayed lower levels of cellular AcCoA than slow NAT2 rats (p < 0.01). A novel role for rat NAT2 in mammary cancer was discovered unrelated to carcinogen metabolism, suggesting a role for human NAT1 in breast cancer.

[Relapsing polychondritis. A case report of a patient treated with methotrexate and celecoxib].

PubMed

Cervera Castillo, Hernando; Torres Caballero, Verónica

2005-01-01

Relapsing polychondritis is a rare illness in which the cartilaginous tissues such as auricles, nose, laryngotracheal structures, joints and others, are affected. Customary treatment is based on corticosteroids and traditional antiinflammatory agents including aspirin and indomethacin. We describe a case of relapsing polychondritis in an 82-year-old man with associated diabetes mellitus and special features treated successfully with alternative therapy based on methotrexate and celecoxib.

Cell Cycle Target-based Therapy for Ovarian Cancer

DTIC Science & Technology

2008-09-01

induces apoptosis in quiescent ovarian cancer cells. Strong inducers of apoptosis included flufenamic acid, flurbiprofen, celebrex and finasteride ...Thus, a whole panel of NSAIDs including Aspirin, Ibuprofen, Exisulind, Acetaminophen, Naproxen, NS-398, Celecoxib, Diclofenac, Finasteride ...Naproxen, 200µM NS-398, 50µM Celecoxib, 200µM Diclofenac, 50µM Finasteride , 200µM Flufenamic acid, 40µM Meloxican, 50µM Ebselen, 20nM Flurbiprofen or

Changes of the peptide YY levels in the intestinal tissue of rats with experimental colitis following oral administration of mesalazine and prednisolone.

PubMed

Hirotani, Yoshihiko; Mikajiri, Kyoko; Ikeda, Kenji; Myotoku, Michiaki; Kurokawa, Nobuo

2008-09-01

Few studies have reported the changes in the peptide YY (PYY) levels in the intestinal tissue of rats with ulcerative colitis (UC) following oral administration of mesalazine and prednisolone. We investigated the effects of these drugs on the intestinal mucosal PYY levels in a rat model of UC. We confirmed that the PYY levels in the rat intestinal mucosal tissue were high in the lower intestinal tract. The leukocyte count and hemoglobin levels approached the normal values after administering mesalazine or prednisolone to rats treated with 3% dextran sulfate sodium (DSS). The PYY levels in the caecum and colon decreased significantly after administering DSS but increased when mesalazine was administered in a tissue-specific manner. Unlike mesalazine, the PYY levels increased in the ileum in addition to the colon and rectum after administering prednisolone. However, neither of the drugs induced any changes in the plasma PYY levels. These findings indicate that changes in the intestinal tissue PYY levels may be partially involved in the improvement of DSS-induced UC in rats following the administration of these drugs.

Adding Celecoxib With or Without Zoledronic Acid for Hormone-Naïve Prostate Cancer: Long-Term Survival Results From an Adaptive, Multiarm, Multistage, Platform, Randomized Controlled Trial

PubMed Central

Mason, Malcolm D.; Clarke, Noel W.; James, Nicholas D.; Dearnaley, David P.; Spears, Melissa R.; Ritchie, Alastair W.S.; Attard, Gerhardt; Cross, William; Jones, Rob J.; Parker, Christopher C.; Russell, J. Martin; Thalmann, George N.; Schiavone, Francesca; Cassoly, Estelle; Matheson, David; Millman, Robin; Rentsch, Cyrill A.; Barber, Jim; Gilson, Clare; Ibrahim, Azman; Logue, John; Lydon, Anna; Nikapota, Ashok D.; O’Sullivan, Joe M.; Porfiri, Emilio; Protheroe, Andrew; Srihari, Narayanan Nair; Tsang, David; Wagstaff, John; Wallace, Jan; Walmsley, Catherine; Parmar, Mahesh K.B.; Sydes, Matthew R.

2017-01-01

Purpose Systemic Therapy for Advanced or Metastatic Prostate Cancer: Evaluation of Drug Efficacy is a randomized controlled trial using a multiarm, multistage, platform design. It recruits men with high-risk, locally advanced or metastatic prostate cancer who were initiating long-term hormone therapy. We report survival data for two celecoxib (Cel)-containing comparisons, which stopped accrual early at interim analysis on the basis of failure-free survival. Patients and Methods Standard of care (SOC) was hormone therapy continuously (metastatic) or for ≥ 2 years (nonmetastatic); prostate (± pelvic node) radiotherapy was encouraged for men without metastases. Cel 400 mg was administered twice a day for 1 year. Zoledronic acid (ZA) 4 mg was administered for six 3-weekly cycles, then 4-weekly for 2 years. Stratified random assignment allocated patients 2:1:1 to SOC (control), SOC + Cel, or SOC + ZA + Cel. The primary outcome measure was all-cause mortality. Results were analyzed with Cox proportional hazards and flexible parametric models adjusted for stratification factors. Results A total of 1,245 men were randomly assigned (Oct 2005 to April 2011). Groups were balanced: median age, 65 years; 61% metastatic, 14% N+/X M0, 25% N0M0; 94% newly diagnosed; median prostate-specific antigen, 66 ng/mL. Median follow-up was 69 months. Grade 3 to 5 adverse events were seen in 36% SOC-only, 33% SOC + Cel, and 32% SOC + ZA + Cel patients. There were 303 control arm deaths (83% prostate cancer), and median survival was 66 months. Compared with SOC, the adjusted hazard ratio was 0.98 (95% CI, 0.80 to 1.20; P = .847; median survival, 70 months) for SOC + Cel and 0.86 (95% CI, 0.70 to 1.05; P =.130; median survival, 76 months) for SOC + ZA + Cel. Preplanned subgroup analyses in men with metastatic disease showed a hazard ratio of 0.78 (95% CI, 0.62 to 0.98; P = .033) for SOC + ZA + Cel. Conclusion These data show no overall evidence of improved survival with Cel. Preplanned subgroup analyses provide hypotheses for future studies. PMID:28300506

Adding Celecoxib With or Without Zoledronic Acid for Hormone-Naïve Prostate Cancer: Long-Term Survival Results From an Adaptive, Multiarm, Multistage, Platform, Randomized Controlled Trial.

PubMed

Mason, Malcolm D; Clarke, Noel W; James, Nicholas D; Dearnaley, David P; Spears, Melissa R; Ritchie, Alastair W S; Attard, Gerhardt; Cross, William; Jones, Rob J; Parker, Christopher C; Russell, J Martin; Thalmann, George N; Schiavone, Francesca; Cassoly, Estelle; Matheson, David; Millman, Robin; Rentsch, Cyrill A; Barber, Jim; Gilson, Clare; Ibrahim, Azman; Logue, John; Lydon, Anna; Nikapota, Ashok D; O'Sullivan, Joe M; Porfiri, Emilio; Protheroe, Andrew; Srihari, Narayanan Nair; Tsang, David; Wagstaff, John; Wallace, Jan; Walmsley, Catherine; Parmar, Mahesh K B; Sydes, Matthew R

2017-05-10

Purpose Systemic Therapy for Advanced or Metastatic Prostate Cancer: Evaluation of Drug Efficacy is a randomized controlled trial using a multiarm, multistage, platform design. It recruits men with high-risk, locally advanced or metastatic prostate cancer who were initiating long-term hormone therapy. We report survival data for two celecoxib (Cel)-containing comparisons, which stopped accrual early at interim analysis on the basis of failure-free survival. Patients and Methods Standard of care (SOC) was hormone therapy continuously (metastatic) or for ≥ 2 years (nonmetastatic); prostate (± pelvic node) radiotherapy was encouraged for men without metastases. Cel 400 mg was administered twice a day for 1 year. Zoledronic acid (ZA) 4 mg was administered for six 3-weekly cycles, then 4-weekly for 2 years. Stratified random assignment allocated patients 2:1:1 to SOC (control), SOC + Cel, or SOC + ZA + Cel. The primary outcome measure was all-cause mortality. Results were analyzed with Cox proportional hazards and flexible parametric models adjusted for stratification factors. Results A total of 1,245 men were randomly assigned (Oct 2005 to April 2011). Groups were balanced: median age, 65 years; 61% metastatic, 14% N+/X M0, 25% N0M0; 94% newly diagnosed; median prostate-specific antigen, 66 ng/mL. Median follow-up was 69 months. Grade 3 to 5 adverse events were seen in 36% SOC-only, 33% SOC + Cel, and 32% SOC + ZA + Cel patients. There were 303 control arm deaths (83% prostate cancer), and median survival was 66 months. Compared with SOC, the adjusted hazard ratio was 0.98 (95% CI, 0.80 to 1.20; P = .847; median survival, 70 months) for SOC + Cel and 0.86 (95% CI, 0.70 to 1.05; P =.130; median survival, 76 months) for SOC + ZA + Cel. Preplanned subgroup analyses in men with metastatic disease showed a hazard ratio of 0.78 (95% CI, 0.62 to 0.98; P = .033) for SOC + ZA + Cel. Conclusion These data show no overall evidence of improved survival with Cel. Preplanned subgroup analyses provide hypotheses for future studies.

Performance on a strategy set shifting task in rats following adult or adolescent cocaine exposure

PubMed Central

Kantak, Kathleen M.; Barlow, Nicole; Tassin, David H.; Brisotti, Madeline F.; Jordan, Chloe J

2014-01-01

Rationale Neuropsychological testing is widespread in adult cocaine abusers, but lacking in teens. Animal models may provide insight into age-related neuropsychological consequences of cocaine exposure. Objectives Determine whether developmental plasticity protects or hinders behavioral flexibility after cocaine exposure in adolescent vs. adult rats. Methods Using a yoked-triad design, one rat controlled cocaine delivery and the other two passively received cocaine or saline. Rats controlling cocaine delivery (1.0 mg/kg) self-administered for 18 sessions (starting P37 or P77), followed by 18 drug-free days. Rats next were tested in a strategy set shifting task, lasting 11–13 sessions. Results Cocaine self-administration did not differ between age groups. During initial set formation, adolescent-onset groups required more trials to reach criterion and made more errors than adult-onset groups. During the set shift phase, rats with adult-onset cocaine self-administration experience had higher proportions of correct trials and fewer perseverative + regressive errors than age-matched yoked-controls or rats with adolescent-onset cocaine self-administration experience. During reversal learning, rats with adult-onset cocaine experience (self-administered or passive) required fewer trials to reach criterion and the self-administering rats made fewer perseverative + regressive errors than yoked-saline rats. Rats receiving adolescent-onset yoked-cocaine had more trial omissions and longer lever press reaction times than age-matched rats self-administering cocaine or receiving yoked-saline. Conclusions Prior cocaine self-administration may impair memory to reduce proactive interference during set shifting and reversal learning in adult-onset but not adolescent-onset rats (developmental plasticity protective). Passive cocaine may disrupt aspects of executive function in adolescent-onset but not adult-onset rats (developmental plasticity hinders). PMID:24800898

Prevention of bone loss in ovariectomized rats: the effect of Salvia miltiorrhiza extracts.

PubMed

Chae, H J; Chae, S W; Yun, D H; Keum, K S; Yoo, S K; Kim, H R

2004-02-01

The preventive effect of Salvia miltiorrhiza extracts (SMEs) on the progress of bone loss induced by ovariectomy (OVX) was studied in rats. We measured body weight and bone histomorphometry in sham, OVX or SMEs-administered OVX rats. From light microscopic analyses, a porous or erosive appearances were observed on the surface of trabecular bone of tibia in OVX rats, whereas those of the same bone in sham rats and in SMEs-administered rats were composed of fine particles. The trabecular bone area and trabecular thickness in OVX rats decreased by 50% from those in sham rats, these decreases were completely inhibited by administration of SMEs for 7 weeks. In this study, the mechanical strength in femur neck was significantly enhanced by the treatment of SMEs for 7 weeks. In OVX rats, free T3 was normal in all cases, whereas free T4 was significantly increased. Although there was no difference between OVX and SMEs-administered rats in T3 level, we have found significant difference between them in T4 level. These results strongly suggest that SMEs are effective in preventing the development of bone loss induced by OVX in rats.

Studies on articular and general toxicity of orally administered ozenoxacin in juvenile rats and dogs.

PubMed

González Borroto, Jorge Ignacio; Awori, Malaika Sharon; Chouinard, Luc; Smith, Susan Y; Tarragó, Cristina; Blazquez, Teresa; Gargallo-Viola, Domingo; Zsolt, Ilonka

2018-05-01

Ozenoxacin is a nonfluorinated quinolone antibacterial approved for topical treatment of impetigo. Because quinolones have known chondrotoxic effects in juvenile animals, the potential toxicity of ozenoxacin was assessed in preclinical studies. Ozenoxacin or ofloxacin (300 mg/kg/day for 5 days, for each compound) was orally administered to juvenile rats, and oral ozenoxacin (10-100 mg/kg/day for 14 days) was administered to juvenile dogs. In juvenile rats, ozenoxacin showed no chondrotoxicity, whereas ofloxacin produced typical quinolone-induced lesions in articular cartilage in three of ten rats. Oral ozenoxacin administration to juvenile dogs showed no chondrotoxicity or toxicologically relevant findings in selected target organs. Ozenoxacin was generally well-tolerated in juvenile rats and dogs, with no evidence of quinolone-induced arthropathy.

A novel three-dimensional large-pore mesoporous carbon matrix as a potential nanovehicle for the fast release of the poorly water-soluble drug, celecoxib.

PubMed

Zhang, Yanzhuo; Wang, Hong; Li, Chuanjun; Sun, Baoxiang; Wang, Yu; Wang, Siling; Gao, Cunqiang

2014-04-01

A novel mesocellular carbon foam (MSU-FC) with a large pore size and a three-dimensional porous structure for the oral delivery of poorly water-soluble drugs was prepared. The goal of this study was to improve in vitro dissolution and in vivo absorption of celecoxib (CEB), a model drug, by means of novel carbon-based nanoparticles prepared from the MSU-FC matrix. The MSU-FC matrix was synthesized by an inverse replica templating method using mesocellular silica template. A solvent immersion/evaporation method was used to load the drug molecules. The drug-loaded nanoparticles were characterized for morphology, surface area, particle size, mesoporous structure, crystallinity, solubility and dissolution. The effect of MSU-FC on cell viability was measured using the MTT conversion assay. Furthermore, the oral bioavailability of CEB-loaded MSU-FC in fasted rats was compared with that of the marketed product. Our results demonstrate that CEB incorporation into the prepared MSU-FC resulted in an approximately 9-fold increase in aqueous solubility in comparison with crystalline CEB. MSU-FC produced accelerated immediate release of CEB in comparison with crystalline CEB (pure CEB powder or marketed formulation) and the drug-loaded conventional mesoporous carbon particles. The relative bioavailability of CEB for CEB-loaded MSU-FC was 172%. In addition, MSU-FC nanoparticles exhibited very low toxicity. The MSU-FC nanomatrix has been shown to be a promising drug delivery vehicle for improving the dissolution and biopharmaceutical characteristics of poorly water-soluble drugs.

Utilisation Pattern of Nonspecific Nonsteroidal Anti-Inflammatory Drugs and COX-2 Inhibitors in a Local Health Service Unit in Northeast Italy.

PubMed

Chiroli, S; Chinellato, A; Didoni, G; Mazzi, S; Lucioni, C

2003-01-01

Nonsteroidal anti-inflammatory drugs (NSAIDs) are prescribed widely in Italy. They include nonspecific NSAIDs (NS-NSAIDs) and the newly marketed cyclo-oxygenase (COX)-2 specific inhibitors (COXIBs) celecoxib and rofecoxib. The objective of this study was to describe the prescribing patterns for NS-NSAIDs and COXIBs in a local Italian area, analysing an administrative database. We extracted from the database information on subjects who had received at least one reimbursed prescription of an NSAID during the period between 1 January 2001 and 31 December 2001, including age, sex, patient identification code, Anatomical Therapeutic Chemical (ATC) classification system code, strength, formulation, number of packs prescribed, prescription date, and prescription of gastroprotective agents (GPAs) on the same day as the prescription of the NSAID. On the basis of the type of NSAID received, we divided the patients into five cohorts: oral NS-NSAIDs only during the observed year, injectable NS-NSAIDs only, celecoxib only, rofecoxib only, and a combination. For descriptive purposes, we defined three age groups: <40 years, 40-64 years, and >64 years. The duration of exposure to NSAID therapy was calculated using the most commonly prescribed dose for the different drugs. Subjects receiving >/=30 doses per year were defined as "regular users". Analyses included mean age, mean duration of exposure, percentage of regular users, and percentage of GPAs co-prescribed in the different cohorts. NSAIDs were prescribed to 62 059 subjects from a resident population of 365 321 inhabitants; 43.8% received oral NS-NSAIDs only, 22.6% injectable NS-NSAIDs only, 7.2% celecoxib only, 5.2% rofecoxib only, and 22% different regimens of different types of NSAIDs. The mean duration of treatment increased with age in all cohorts; the mean age was 56 years in the NS-NSAID cohort, 61 years in the celecoxib cohort, and 62 years in the rofecoxib cohort (p = 0.01, COXIBs vs NS-NSAIDs). The mean duration of therapy was 11.4 days/year for injectable NS-NSAIDs, 43.8 days/year for rofecoxib, 50.5 days/year for oral NS-NSAIDs, and 53.7 days/year for celecoxib. Fifty-four percent of subjects in the oral NS-NSAID cohort were regular users versus 64% in the rofecoxib and 70% in the celecoxib groups (p = 0.001, COXIBs vs NS-NSAIDs). Co-prescription with GPAs was 9.5% for NS-NSAIDs, 8.4% for rofecoxib, and 7.7% for celecoxib. Analysis of an administrative database in Italy showed a trend suggesting that COXIBs are prescribed to an older population and for a longer period of time than NS-NSAIDs, and that their use is less frequently associated with GPAs.

Utilization of non-steroidal anti-inflammatory drugs in Quebec: adherence to the Canadian consensus on prescription guidelines.

PubMed

Moride, Yola; Ducruet, Thierry; Boivin, Jean-François; Lavoie, Frédéric; Rochon, Sophie

2005-01-01

Adverse events associated with the use of non-steroidal anti-inflammatory drugs (NSAIDs) have led to the publication of Canadian prescription guidelines. Prescription practices following the publication of these guidelines and the introduction of COX-2 inhibitors in the Quebec formulary of reimbursed medications remain largely unexplored. To compare the prevalence of contra-indications and selected risk factors for NSAID-toxicity among COX-2 inhibitor users and non-selective NSAID users. A case-control analysis was conducted in a random sample of Quebec adult drug plan members who were treated with celecoxib (n=42,422 cases), rofecoxib (n=25,674 cases), full-dose (anti-inflammatory doses) of non-selective NSAIDs (n=9,673 cases), or low-dose NSAIDs (n=2,745 controls) in the year 2000. Data were obtained from the Quebec prescription and medical services databases (RAMQ). Patients with a history of gastropathy were more likely to be prescribed COX-2 inhibitors than low-dose NSAIDs; the odds ratios were 1.73 (95%CI: 1.56-1.91) and 1.49 (1.33-1.66), respectively for celecoxib and rofecoxib. Corresponding results for concomitant use of anticoagulants were 1.95 (1.34-2.83) for celecoxib and 1.87 (1.26-2.77) for rofecoxib, and for use of corticosteroids they were 1.29 (1.08-1.54) and 1.23 (1.01-1.49). Conversely, patients with the following characteristics were less likely to receive COX-2 inhibitors than low-dose non-selective NSAIDs: age 75+ (OR=0.64; 0.56-0.72 for celecoxib, OR=0.48; 0.76-0.99 for rofecoxib), hypertension (OR=0.83; 0.75-0.92 for celecoxib, OR=0.87; 0.77-0.97 for rofecoxib), and concomitant use of diuretics (OR=0.72; 0.63-0.82 for celecoxib; OR=0.77; 0.66-0.89 for rofecoxib). Patients with risk factors for NSAID gastropathy were more likely prescribed COX-2 inhibitors, while the presence of other contra-indications led to the prescription of low-dose non-selective NSAIDs. However, 12.7% of users of full-dose non-selective NSAIDs were age 75+ and 12.0% had a history of gastropathy, which are considered important risk factors for adverse events.

Possible involvement of mitochondrial energy-producing ability in the development of right ventricular failure in monocrotaline-induced pulmonary hypertensive rats.

PubMed

Daicho, Takuya; Yagi, Tatsuya; Abe, Yohei; Ohara, Meiko; Marunouchi, Tetsuro; Takeo, Satoshi; Tanonaka, Kouichi

2009-09-01

The present study was undertaken to explore the possible involvement of alterations in the mitochondrial energy-producing ability in the development of the right ventricular failure in monocrotaline-administered rats. The rats at the 6th week after subcutaneous injection of 60 mg/kg monocrotaline revealed marked myocardial hypertrophy and fibrosis, that is, severe cardiac remodeling. The time-course study on the cardiac hemodynamics of the monocrotaline-administered rat by the cannula and echocardiographic methods showed a reduction in cardiac double product, a decrease in cardiac output index, and an increase in the right ventricular Tei index, suggesting that the right ventricular failure was induced at the 6th week after monocrotaline administration in rats. The mitochondrial oxygen consumption rate of the right ventricular muscle isolated from the monocrotaline-administered animal was decreased, which was associated with a reduction in myocardial high-energy phosphates. Furthermore, the decrease in mitochondrial oxygen consumption rate was inversely related to the increase in the right ventricular Tei index of the monocrotaline-administered rats. These results suggest that impairment of the mitochondrial energy-producing ability is involved in the development of the right ventricular failure in monocrotaline-induced pulmonary hypertensive rats.

Blood and tissue tocopherol levels in rats following intraperitoneally administered alpha-tocopheryl acetate.

PubMed

McGee, C D; Greenwood, C E; Jeejeebhoy, K N

1990-01-01

The correction or maintenance of blood and tissue alpha-tocopherol (alpha-Toc) levels by intraperitoneally administered all-rac-alpha-tocopheryl acetate (alpha-Tac) was compared with RRR- alpha-tocopherol (alpha-Toc) in vitamin E-depleted and control rats. Rats received 1.3 TE vitamin E daily for 7 days. alpha-Tac was detected in plasma of one-third of alpha-Tac-treated rats 24 hr after the first treatment, although not in subsequent samplings. Both alpha-Tac and alpha-Toc increased tocopherol levels in plasma and liver of E-deprived rats, while little or no change was observed in adipose tissue and brain. Similarly, control rats treated with alpha-Tac or alpha-Toc had significantly greater (p less than 0.05) plasma and liver alpha-Toc levels at day 3 and day 7 than did saline-treated rats. There was no significant difference in adipose alpha-Toc levels among treatment groups of control rats. The results of this study suggest that alpha-Tac is rapidly hydrolyzed to its biologically active alcohol form and results in similar effects to that of intraperitoneally administered alpha-Toc.

Celecoxib Enhances the Efficacy of Low-Dose Antibiotic Treatment against Polymicrobial Sepsis in Mice and Clinical Isolates of ESKAPE Pathogens

PubMed Central

Annamanedi, Madhavi; Varma, Gajapati Y. N.; Anuradha, K.; Kalle, Arunasree M.

2017-01-01

Treatment of multidrug resistant bacterial infections has been a great challenge globally. Previous studies including our study have highlighted the use of celecoxib, a non-steroidal anti-inflammatory drug in combination with antibiotic has decreased the minimal inhibitory concentration to limit Staphylococcus aureus infection. However, the efficacy of this combinatorial treatment against various pathogenic bacteria is not determined. Therefore, we have evaluated the potential use of celecoxib in combination with low doses of antibiotic in limiting Gram-positive and Gram-negative bacteria in vivo in murine polymicrobial sepsis developed by cecum ligation and puncture (CLP) method and against clinically isolated human ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species). The in vivo results clearly demonstrated a significant reduction in the bacterial load in different organs and in the inflammatory markers such as COX-2 and NF-κB via activation of SIRT1 in mice treated with imipenem, a choice of antibiotic for polymicrobial sepsis treatment. Combinatorial treatment of ampicillin and celecoxib was effective on clinical isolates of ESKAPE pathogens, 45% of tested clinical isolates showed more than 50% reduction in the colony forming units when compared to ampicillin alone. In conclusion, this non-traditional treatment strategy might be effective in clinic to reduce the dose of antibiotic to treat drug-resistant bacterial infections. PMID:28533769

Celecoxib Enhances the Efficacy of Low-Dose Antibiotic Treatment against Polymicrobial Sepsis in Mice and Clinical Isolates of ESKAPE Pathogens.

PubMed

Annamanedi, Madhavi; Varma, Gajapati Y N; Anuradha, K; Kalle, Arunasree M

2017-01-01

Treatment of multidrug resistant bacterial infections has been a great challenge globally. Previous studies including our study have highlighted the use of celecoxib, a non-steroidal anti-inflammatory drug in combination with antibiotic has decreased the minimal inhibitory concentration to limit Staphylococcus aureus infection. However, the efficacy of this combinatorial treatment against various pathogenic bacteria is not determined. Therefore, we have evaluated the potential use of celecoxib in combination with low doses of antibiotic in limiting Gram-positive and Gram-negative bacteria in vivo in murine polymicrobial sepsis developed by cecum ligation and puncture (CLP) method and against clinically isolated human ESKAPE pathogens ( Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa , and Enterobacter species). The in vivo results clearly demonstrated a significant reduction in the bacterial load in different organs and in the inflammatory markers such as COX-2 and NF-κB via activation of SIRT1 in mice treated with imipenem, a choice of antibiotic for polymicrobial sepsis treatment. Combinatorial treatment of ampicillin and celecoxib was effective on clinical isolates of ESKAPE pathogens, 45% of tested clinical isolates showed more than 50% reduction in the colony forming units when compared to ampicillin alone. In conclusion, this non-traditional treatment strategy might be effective in clinic to reduce the dose of antibiotic to treat drug-resistant bacterial infections.

Silver-choline chloride modified graphene oxide: Novel nano-bioelectrochemical sensor for celecoxib detection and CCD-RSM model.

PubMed

Parsaee, Zohreh; Karachi, Nima; Abrishamifar, Seyyed Milad; Kahkha, Mohammad Reza Rezaei; Razavi, Razieh

2018-07-01

In this study, silver nanoparticles modified choline chloride functionalized graphene oxide (AgNPs-ChCl-GO) was synthesized using sonochemical method and utilized as a bioelectrochemical sensor for detection of celecoxib (CEL). The characterization studies were ultimately performed in order to acheive a more complete understanding of the morphological and structural features of the AgNPs-ChCl-GO using different techniques including FT-IR, AFM, FE-SEM, EDX, and XRD. AgNPs-ChCl-GO demonstrated a significant improvement in the reduction activity of CEL due to the enhancement in the current response compared to the bare carbon paste electrode (CPE). The optimum experimental conditions, were optimized using central composite design (CCD) methodology. The differential pulse voltammetry (DPVs) showed an expanded linear dynamic ranges of 9.6 × 10 -9 -7.4 × 10 -7  M for celecoxib in Britton-Robinson buffer in pH 5.0 with. LOD (S/N = 3) and LOQ (S/N = 10) were obtained 2.51 × 10 -9  M and 6.58 × 10 -9  M respectively. AgNPs-ChCl-GO-carbon paste electrode exhibited suitable properties and high accuracy determination of celecoxib in the human plasma sample. Copyright © 2018 Elsevier B.V. All rights reserved.

Increase of antioxidative potential of rat plasma by oral administration of proanthocyanidin-rich extract from grape seeds.

PubMed

Koga, T; Moro, K; Nakamori, K; Yamakoshi, J; Hosoyama, H; Kataoka, S; Ariga, T

1999-05-01

The effect of a single oral administration of proanthocyanidins, oligomeric and polymeric polyhydroxyflavan-3-ol units, on the antioxidative potential of blood plasma was studied in rats. Proanthocyanidin-rich extract from grape seeds was administered by intragastric intubation to fasted rats at 250 mg/kg of body weight. The plasma obtained from water- or proanthocyanidin-administered rats was oxidized by incubation with copper sulfate or 2, 2'-azobis(2-amidinopropane) dihydrochloride (AAPH) at 37 degrees C, and the formation of cholesteryl ester hydroperoxides (CE-OOH) was followed. The plasma obtained from proanthocyanidin-administered rats was significantly more resistant against both copper ion-induced and AAPH-induced formation of CE-OOH than that from control rats. The lag phase in the copper ion-induced oxidation of rat plasma was remarkably increased at 15 min after administration of proanthocyanidins and reached a maximum level at 30 min. When the plasma from proanthocyanidin-administered rat was hydrolyzed by sulfatase and beta-glucuronidase following analysis by high-performance liquid chromatography with electrochemical detection, metabolites of proanthocyanidins occurred in rat plasma at 15 min after administration, three peaks of which were identified as gallic acid, (+)-catechin, and (-)-epicatechin. These results suggest that the intake of proanthocyanidins, the major polyphenols in red wine, increases the resistance of blood plasma against oxidative stress and may contribute to physiological functions of plant food including wine through their in vivo antioxidative ability.

In vivo evaluation method of the effect of nattokinase on carrageenan-induced tail thrombosis in a rat model.

PubMed

Kamiya, Seitaro; Hagimori, Masayori; Ogasawara, Masayoshi; Arakawa, Masayuki

2010-01-01

Thrombosis is characterized by congenital and acquired procatarxis. Nattokinase inhibits thrombus formation in vitro. However, in vivo evaluation of the therapeutic efficacy of nattokinase against thrombosis remains to be conducted. Subcutaneous nattokinase injections of 1 or 2 mg/ml were administered to the tails of rats. Subsequently, κ-carrageenan was intravenously administered to the tails at 12 h after nattokinase injections. The mean length of the infarcted regions in the tails of rats was significantly shorter in rats administered 2 mg/ml of nattokinase than those in control rats. Nattokinase exhibited significant prophylactic antithrombotic effects. Previously, the in vitro efficacy of nattokinase against thrombosis had been reported; now our study has revealed the in vivo efficacy of nattokinase against thrombosis. Copyright © 2010 S. Karger AG, Basel.

A cost-effectiveness analysis of celecoxib compared with diclofenac in the treatment of pain in osteoarthritis (OA) within the Swedish health system using an adaptation of the NICE OA model.

PubMed

Brereton, Nicholas; Pennington, Becky; Ekelund, Mats; Akehurst, Ronald

2014-09-01

Celecoxib for the treatment of pain resulting from osteoarthritis (OA) was reviewed by the Tandvårds- och läkemedelsförmånsverket-Dental and Pharmaceutical Benefits Board (TLV) in Sweden in late 2010. This study aimed to evaluate the incremental cost-effectiveness ratio (ICER) of celecoxib plus a proton pump inhibitor (PPI) compared to diclofenac plus a PPI in a Swedish setting. The National Institute for Health and Care Excellence (NICE) in the UK developed a health economic model as part of their 2008 assessment of treatments for OA. In this analysis, the model was reconstructed and adapted to a Swedish perspective. Drug costs were updated using the TLV database. Adverse event costs were calculated using the regional price list of Southern Sweden and the standard treatment guidelines from the county council of Stockholm. Costs for treating cardiovascular (CV) events were taken from the Swedish DRG codes and the literature. Over a patient's lifetime treatment with celecoxib plus a PPI was associated with a quality-adjusted life year (QALY) gain of 0.006 per patient when compared to diclofenac plus a PPI. There was an increase in discounted costs of 529 kr per patient, which resulted in an incremental cost-effectiveness ratio (ICER) of 82,313 kr ($12,141). Sensitivity analysis showed that treatment was more cost effective in patients with an increased risk of bleeding or gastrointestinal (GI) complications. The results suggest that celecoxib plus a PPI is a cost effective treatment for OA when compared to diclofenac plus a PPI. Treatment is shown to be more cost effective in Sweden for patients with a high risk of bleeding or GI complications. It was in this population that the TLV gave a positive recommendation. There are known limitations on efficacy in the original NICE model.

Cost-effectiveness analysis for joint pain treatment in patients with osteoarthritis treated at the Instituto Mexicano del Seguro Social (IMSS): Comparison of nonsteroidal anti-inflammatory drugs (NSAIDs) vs. cyclooxygenase-2 selective inhibitors.

PubMed

Contreras-Hernández, Iris; Mould-Quevedo, Joaquín F; Torres-González, Rubén; Goycochea-Robles, María Victoria; Pacheco-Domínguez, Reyna Lizette; Sánchez-García, Sergio; Mejía-Aranguré, Juan Manuel; Garduño-Espinosa, Juan

2008-11-12

Osteoarthritis (OA) is one of the main causes of disability worldwide, especially in persons >55 years of age. Currently, controversy remains about the best therapeutic alternative for this disease when evaluated from a cost-effectiveness viewpoint. For Social Security Institutions in developing countries, it is very important to assess what drugs may decrease the subsequent use of medical care resources, considering their adverse events that are known to have a significant increase in medical care costs of patients with OA. Three treatment alternatives were compared: celecoxib (200 mg twice daily), non-selective NSAIDs (naproxen, 500 mg twice daily; diclofenac, 100 mg twice daily; and piroxicam, 20 mg/day) and acetaminophen, 1000 mg twice daily. The aim of this study was to identify the most cost-effective first-choice pharmacological treatment for the control of joint pain secondary to OA in patients treated at the Instituto Mexicano del Seguro Social (IMSS). A cost-effectiveness assessment was carried out. A systematic review of the literature was performed to obtain transition probabilities. In order to evaluate analysis robustness, one-way and probabilistic sensitivity analyses were conducted. Estimations were done for a 6-month period. Treatment demonstrating the best cost-effectiveness results [lowest cost-effectiveness ratio $17.5 pesos/patient ($1.75 USD)] was celecoxib. According to the one-way sensitivity analysis, celecoxib would need to markedly decrease its effectiveness in order for it to not be the optimal treatment option. In the probabilistic analysis, both in the construction of the acceptability curves and in the estimation of net economic benefits, the most cost-effective option was celecoxib. From a Mexican institutional perspective and probably in other Social Security Institutions in similar developing countries, the most cost-effective option for treatment of knee and/or hip OA would be celecoxib.

Cost-effectiveness analysis for joint pain treatment in patients with osteoarthritis treated at the Instituto Mexicano del Seguro Social (IMSS): Comparison of nonsteroidal anti-inflammatory drugs (NSAIDs) vs. cyclooxygenase-2 selective inhibitors

PubMed Central

Contreras-Hernández, Iris; Mould-Quevedo, Joaquín F; Torres-González, Rubén; Goycochea-Robles, María Victoria; Pacheco-Domínguez, Reyna Lizette; Sánchez-García, Sergio; Mejía-Aranguré, Juan Manuel; Garduño-Espinosa, Juan

2008-01-01

Background Osteoarthritis (OA) is one of the main causes of disability worldwide, especially in persons >55 years of age. Currently, controversy remains about the best therapeutic alternative for this disease when evaluated from a cost-effectiveness viewpoint. For Social Security Institutions in developing countries, it is very important to assess what drugs may decrease the subsequent use of medical care resources, considering their adverse events that are known to have a significant increase in medical care costs of patients with OA. Three treatment alternatives were compared: celecoxib (200 mg twice daily), non-selective NSAIDs (naproxen, 500 mg twice daily; diclofenac, 100 mg twice daily; and piroxicam, 20 mg/day) and acetaminophen, 1000 mg twice daily. The aim of this study was to identify the most cost-effective first-choice pharmacological treatment for the control of joint pain secondary to OA in patients treated at the Instituto Mexicano del Seguro Social (IMSS). Methods A cost-effectiveness assessment was carried out. A systematic review of the literature was performed to obtain transition probabilities. In order to evaluate analysis robustness, one-way and probabilistic sensitivity analyses were conducted. Estimations were done for a 6-month period. Results Treatment demonstrating the best cost-effectiveness results [lowest cost-effectiveness ratio $17.5 pesos/patient ($1.75 USD)] was celecoxib. According to the one-way sensitivity analysis, celecoxib would need to markedly decrease its effectiveness in order for it to not be the optimal treatment option. In the probabilistic analysis, both in the construction of the acceptability curves and in the estimation of net economic benefits, the most cost-effective option was celecoxib. Conclusion From a Mexican institutional perspective and probably in other Social Security Institutions in similar developing countries, the most cost-effective option for treatment of knee and/or hip OA would be celecoxib. PMID:19014495

Efficacy and safety of epicutaneous ketoprofen in Transfersome (IDEA‐033) versus oral celecoxib and placebo in osteoarthritis of the knee: multicentre randomised controlled trial

PubMed Central

Rother, Matthias; Lavins, Bernard J; Kneer, Werner; Lehnhardt, Klaus; Seidel, Egbert J; Mazgareanu, Stefan

2007-01-01

Objective To compare epicutaneous ketoprofen in Transfersome (ultra‐deformable vesicles, IDEA‐033) versus oral celecoxib and placebo for relief of signs and symptoms in knee osteoarthritis. Methods This was a multicentre, randomised, double‐blind, controlled trial; 397 patients with knee osteoarthritis participated and 324 completed the trial. They were randomly assigned 110 mg epicutaneous ketoprofen in 4.8 g Transfersome plus oral placebo (n = 138), 100 mg oral celecoxib plus placebo gel (n = 132), or both placebo formulations (n = 127) twice daily for 6 weeks. Primary efficacy outcome measures were the changes from baseline to end of the study on the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index pain subscale, physical function subscale and patient global assessment (PGA) of response. Results The mean WOMAC pain subscale scores in the intent to treat population were reduced by 18.2 (95% confidence interval −22.1 to −14.3), 20.3 (−24.3 to −16.2) and 9.9 (−13.9 to −5.8) in the IDEA‐033, celecoxib and placebo groups, respectively, and the physical function subscale score by 14.6 (−18.1 to −11.0), 16.6 (−20.2 to −13.0) and 10.2 (−13.8 to −6.6), respectively. The mean PGA of response scores were 1.8 (1.6 to 2.1), 1.7 (1.5 to 1.9) and 1.3 (1.1 to 1.5), respectively. The differences in change between IDEA‐033 and placebo were statistically significant for pain subscale (p<0.01) and PGA of response (p<0.01). Gastrointestinal adverse events for IDEA‐033 were similar to placebo. Conclusion IDEA‐033 is superior to placebo and comparable with celecoxib in relieving pain associated with an acute flare of knee osteoarthritis. PMID:17363401

BCL-2 and BCL-XL expression are down-regulated in benign prostate hyperplasia nodules and not affected by finasteride and/or celecoxib

PubMed Central

Li, Feng; Pascal, Laura E; Zhou, Jianhua; Zhou, Yibin; Wang, Ke; Parwani, Anil V; Dhir, Rajiv; Guo, Peng; He, Dalin; Nelson, Joel B; Wang, Zhou

2018-01-01

The mechanisms involved in the development of benign prostatic hyperplasia (BPH) are poorly understood. One potential mechanism involved in BPH pathogenesis may involve altered expression of genes related to apoptosis and proliferation because reduced cell death and increased proliferation are thought to contribute to prostatic enlargement. This study examined the expression of B-cell lymphoma 2 (BCL-2) and B-cell lymphoma-extra large (BCL-XL), two important anti-apoptosis factors that are also capable of inhibiting cell proliferation via accelerated G1 arrest or delayed G1/S transition, using immunostaining in simple prostatectomy BPH specimens from patients naïve to androgen manipulation. Since androgens and inflammation are thought to play important roles in BPH pathogenesis, we tested the effect of inhibiting 5a-reductase and/or COX-2 on the expression of BCL-2 and BCL-XL in BPH specimens from prostate cancer patients with BPH. These patients had no prior use of chronic NSAIDs and/or 5a-reductase inhibitors and were treated with celecoxib, finasteride, celecoxib plus finasteride or no treatment for 28 consecutive days prior to surgery. In all specimens, BCL-2 and BCL-XL staining was evident in both luminal and basal epithelial cells, with more intense staining in basal cells. Both luminal and basal cells exhibited decreased BCL-2 and BCL-XL staining in BPH nodules compared to the surrounding normal prostatic tissues. In prostate cancer patients with BPH, celecoxib and/or finasteride did not affect the expression of BCL-2 and BCL-XL in luminal or basal cells in BPH nodules and normal adjacent tissues. These results suggest that BCL-2 and BCL-XL may act as anti-proliferative factors in BPH pathogenesis, and the effect of celecoxib and/or finasteride on BPH is unlikely mediated through modulating BCL-2 and BCL-XL signaling. PMID:29531971

Effect of Urtica dioica Leaf Alcoholic and Aqueous Extracts on the Number and the Diameter of the Islets in Diabetic Rats.

PubMed

Qujeq, Durdi; Tatar, Mohsen; Feizi, Farideh; Parsian, Hadi; Sohan Faraji, Alieh; Halalkhor, Sohrab

2013-01-01

Urtica dioica has been known as a plant that decreases blood glucose. Despite the importance of this plant in herbal medicine, relatively little research has been down on effects of this plant on islets yet. The objective of the current study was to evaluate the effect of dried Urtica dioica leaf alcoholic and aqueous extracts on the number and the diameter of the islets and histological parameters in streptozocin-induced diabetic rats. Six rats were used in each group. Group I: Normal rats were administered saline daily for 8 weeks. Group II: Diabetic rats were administered streptozotocin, 50 mg/kg of body weight; Group III: Diabetic rats were administered dried Urtica dioica leaf aqueous extracts for 8 weeks; Group IV: Diabetic rats were administered dried Urtica dioica leaf alcoholic extracts for 8 weeks. The animals, groups of diabetic and normal, were sacrificed by ether anaesthesia. Whole pancreas was dissected. The tissue samples were formalin fixed and paraffin embedded for microscopic examination. Histologic examination and grading were carried out on hematoxylin-eosin stained sections. The effects of administration of dried Urtica dioica leaf alcoholic and aqueous extracts to diabetic rats were determined by histopathologic examination. The pancreas from control rats showed normal pancreatic islets histoarchitecture. Our results also, indicate that the pancreas from diabetic rats show injury of pancreas tissue while the pancreas from diabetic rats treated with dried Urtica dioica leaf alcoholic and aqueous extracts show slight to moderate rearrangement of islets. According to our findings, dried Urtica dioica leaf alcoholic and aqueous extracts can cause a suitable repair of pancreatic tissue in streptozocin-induced diabetic experimental model.

Effect of Urtica dioica Leaf Alcoholic and Aqueous Extracts on the Number and the Diameter of the Islets in Diabetic Rats

PubMed Central

Qujeq, Durdi; Tatar, Mohsen; Feizi, Farideh; Parsian, Hadi; Sohan Faraji, Alieh; Halalkhor, Sohrab

2013-01-01

Urtica dioica has been known as a plant that decreases blood glucose. Despite the importance of this plant in herbal medicine, relatively little research has been down on effects of this plant on islets yet. The objective of the current study was to evaluate the effect of dried Urtica dioica leaf alcoholic and aqueous extracts on the number and the diameter of the islets and histological parameters in streptozocin-induced diabetic rats. Six rats were used in each group. Group I: Normal rats were administered saline daily for 8 weeks. Group II: Diabetic rats were administered streptozotocin, 50 mg/kg of body weight; Group III: Diabetic rats were administered dried Urtica dioica leaf aqueous extracts for 8 weeks; Group IV: Diabetic rats were administered dried Urtica dioica leaf alcoholic extracts for 8 weeks. The animals, groups of diabetic and normal, were sacrificed by ether anaesthesia. Whole pancreas was dissected. The tissue samples were formalin fixed and paraffin embedded for microscopic examination. Histologic examination and grading were carried out on hematoxylin-eosin stained sections. The effects of administration of dried Urtica dioica leaf alcoholic and aqueous extracts to diabetic rats were determined by histopathologic examination. The pancreas from control rats showed normal pancreatic islets histoarchitecture. Our results also, indicate that the pancreas from diabetic rats show injury of pancreas tissue while the pancreas from diabetic rats treated with dried Urtica dioica leaf alcoholic and aqueous extracts show slight to moderate rearrangement of islets. According to our findings, dried Urtica dioica leaf alcoholic and aqueous extracts can cause a suitable repair of pancreatic tissue in streptozocin-induced diabetic experimental model. PMID:24551786

Alveolar bone dynamics in osteoporotic rats treated with raloxifene or alendronate: confocal microscopy analysis

NASA Astrophysics Data System (ADS)

Ramalho-Ferreira, Gabriel; Faverani, Leonardo Perez; Grossi-Oliveira, Gustavo Augusto; Okamoto, Tetuo; Okamoto, Roberta

2015-03-01

In this study, the characteristics of the alveolar bone of rats with induced osteoporosis were examined. Thirty-two rats were divided into four groups according to the induction of osteoporosis and drugs administered: OG, osteoporotic rats without treatment (negative control); SG, rats which underwent sham surgery ovariectomy (SHAM); alendronate (AG), osteoporotic rats treated with alendronate; and RG, osteoporotic rats treated with raloxifene (RG). On the 8th day after ovariectomy and SHAM surgeries, drug therapy was started with AG or RG. On the 52nd day, 20 mg/kg calcein was administered to all of the rats, and on the 80th day, 20 mg/kg alizarin red was administered. Euthanasia was performed on the 98th day. The bone area marked by fluorochromes was calculated and data were subjected to two-way ANOVA test and Tukey's post-hoc test (p<0.05). The comparison of the induced osteoporosis groups showed no statistically significant differences in bone turnover only between RG and SG (p=0.074) and AG and OG (p=0.138). All other comparisons showed significant differences (p<0.001). The largest bone turnover was observed in RG and SG groups. RG was the medication that improved the dynamics of the alveolar bone of rats with induced osteoporosis, resembling that of healthy rats.

Varenicline decreases nicotine but not alcohol self-administration in genetically selected Marchigian Sardinian alcohol-preferring (msP) rats.

PubMed

Scuppa, Giulia; Cippitelli, Andrea; Toll, Lawrence; Ciccocioppo, Roberto; Ubaldi, Massimo

2015-11-01

Alcohol and nicotine are largely co-abused. Here, we investigated whether concurrent exposure to both addictive drugs influences each other's consumption and whether varenicline attenuates alcohol consumption in the presence of nicotine. Marchigian Sardinian alcohol-preferring (msP) rats trained to simultaneously self-administer oral alcohol (10% v/v) and intravenous nicotine (30μg/kg/inf) were used. Additional groups of rats were trained to self-administer either alcohol or nicotine. Further, msP rats were also trained to self-administer nicotine followed by 22-h/day access to alcohol and water in a two bottle free choice paradigm or water alone. The effects of varenicline (0.0, 0.3, 1.0, 3.0mg/kg, p.o.) on alcohol and nicotine consumption were tested. In a self-administration paradigm, msP rats showed a significantly high level of alcohol and nicotine intake when the drugs were administered alone. However, when access to both drugs occurred concomitantly, the number of nicotine infusions self-administered was significantly decreased. Nicotine self-administration was markedly reduced by varenicline regardless of whether it was self-administered alone or concurrently with alcohol. In a two bottle choice test, varenicline significantly decreased nicotine self-administration but had no influence on alcohol consumption. Varenicline is highly efficacious in decreasing nicotine self-administration either alone or in combination with alcohol. However, varenicline failed to influence both operant responding for alcohol and home-cage alcohol drinking in msP animals. Taken together, our findings suggest that the effects of varenicline could be specific to nicotine under conditions where excessive alcohol drinking is facilitated by genetic factors as in msP rats. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Low direct cytotoxicity of loxoprofen on gastric mucosal cells.

PubMed

Yamakawa, Naoki; Suemasu, Shintaro; Kimoto, Ayumi; Arai, Yasuhiro; Ishihara, Tomoaki; Yokomizo, Kazumi; Okamoto, Yoshinari; Otsuka, Masami; Tanaka, Ken-Ichiro; Mizushima, Tohru

2010-01-01

Pro-drugs of non-steroidal anti-inflammatory drugs (NSAIDs), such as loxoprofen are widely used for clinical purposes because they are not so harmful to the gastrointestinal mucosa. We recently showed that NSAIDs such as indomethacin and celecoxib have direct cytotoxicity (ability to induce necrosis and apoptosis in gastric mucosal cells) due to their membrane permeabilizing activities, which is involved in NSAID-induced gastric lesions. We show here that under conditions where indomethacin and celecoxib clearly induce necrosis and apoptosis, loxoprofen and its active metabolite loxoprofen-OH, do not have such effects in primary culture of guinea pig gastric mucosal cells. Loxoprofen and loxoprofen-OH induced apoptosis more effectively in cultured human gastric cancer cells than in the primary culture. Loxoprofen and loxoprofen-OH exhibited much lower membrane permeabilizing activities than did indomethacin and celecoxib. We thus consider that the low direct cytotoxicity of loxoprofen observed in vitro is involved in its relative safety on production of gastric lesions in clinical situation.

Milk thistle impedes the development of carbontetrachloride-induced liver damage in rats through suppression of bcl-2 and regulating caspase pathway.

PubMed

Aslan, Abdullah; Can, Muhammed İsmail

2014-11-04

The objective of this study was to examine whether MT plays a protective role against the damage in the liver by administering carbontetrachloride (CCl4) to rats. 28 male Wistar albino (n=28, 8weeks old) rats have been used in the study. The rats were distributed into 4 groups according to their live weights. The groups were: (i) negative control (NC): normal water consuming group to which no CCl4 and milk thistle (MT) is administered; (ii) positive control (PC): normal water consuming group to which no CCl4 is administered but MT is administered; (iii) CCl4 group: normal water consuming and group to which CCl4 is administered (2ml/kg live weight, ip); and (iv) CCl4+MT group: CCl4 and MT administered group (2ml/kg live weight, ip). Caspase-3, caspase-9, bax, and bcl-2 protein syntheses were examined via western blotting. MDA determination in liver tissue was made using spectrophotometer. MDA amount has decreased in the CCl4+MT group in comparison to CCl4 group whereas caspase-3 and caspase-9 has increased and bax and bcl-2 has decreased. These results show that MT protects the liver against oxidative damage. Copyright © 2014 Elsevier Inc. All rights reserved.

CARCINOGENICITY OF BROMODICHLOROMETHANE ADMINISTERED IN DRINKING WATER TO THE MALE F344/N RAT AND B6C3F, MOUSE

EPA Science Inventory

CARCINOGENICITY OF BROMODICHLOROMETHANE ADMINISTERED IN DRINKING WATER TO THE MALE F344/N RAT AND B6C3F1 MOUSE.

Bromodichloromethane (BDCM) has been shown to produce kidney and large bowel tumors in both male and female F344/N rats, kidney tumors in male B6C3F 1 mice and ...

VINCLOZOLIN (V) TREATMENT INDUCES REPRODUCTIVE MALFORMATIONS AND INFERTILITY IN F1 MALE RATS WHEN ADMINISTERED DURING SEXUAL BUT NOT GONADAL DIFFERENTIATION. THE EFFECTS ARE NOT TRANSMITTED TO THE SUBSEQUENT GENERATIONS.

EPA Science Inventory

V produces adverse reproductive effects in male rats when administered during sexual differentiation by acting as an androgen-antagonist. It was recently reported that four generations of SD rats, derived from dams dosed via ip injection GD8-15 with 100 mg V/kg/day, displayed pro...

Self-administered nicotine differentially impacts body weight gain in obesity-prone and obesity-resistant rats.

PubMed

Rupprecht, Laura E; Smith, Tracy T; Donny, Eric C; Sved, Alan F

2017-07-01

Obesity and tobacco smoking represent the largest challenges to public health, but the causal relationship between nicotine and obesity is poorly understood. Nicotine suppresses body weight gain, a factor impacting smoking initiation and the failure to quit, particularly among obese smokers. The impact of nicotine on body weight regulation in obesity-prone and obesity-resistant populations consuming densely caloric diets is unknown. In the current experiment, body weight gain of adult male rats maintained on a high energy diet (31.8% kcal from fat) distributed into obesity-prone (OP), obesity-resistant (OR) and an intermediate group, which was placed on standard rodent chow (Chow). These rats were surgically implanted with intravenous catheters and allowed to self-administer nicotine (0 or 60μg/kg/infusion, a standard self-administration dose) in 1-h sessions for 20 consecutive days. Self-administered nicotine significantly suppressed body weight gain but not food intake in OP and Chow rats. Self-administered nicotine had no effect on body weight gain in OR rats. These data suggest that: 1) OR rats are also resistant to nicotine-induced suppression of body weight gain; and 2) nicotine may reduce levels of obesity in a subset of smokers prone to obesity. Copyright © 2017 Elsevier Inc. All rights reserved.

Teratology Studies on Lewisite and Sulfur Mustard Agents: Effects of Sulfur Mustard in Rats and Rabbits

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hackett, P. L.; Rommereim, R. L.; Burton, F. G.

1987-09-30

Sulfur mustard (HD) was administered to rats and rabbits by intragastric intubation. Rats were dosed daily from 6 through 15 days of gestation (dg) with 0. 0.5, 1.0 or 2.0 mg of HD/kg; rabbits were dosed with 0, 0.4, 0.6 or 0.8 mg/kg on 6 through 19 dg. Maternal animals were weighed periodically and, at necropsy, were examined for gross lesions of major organs and reproductive performance; live fetuses were weighed and examined for external, internal and skeletal defects. In rats, reductions in body weights were observed in maternal animals and their female fetuses at the lowest administered dose (0.5more » mg/kg), but the incidence of fetal malformations was not increased. In rabbits the highest administered dose (0.8 mg/kg) induced maternal mortality and depressed body weight measures but did not affect fetal development. These results suggest that orally administered HD is not teratogenic in rats and rabbits since fetal effects were observed only at dose levels that induced frank maternal toxicity. Estimations of dose ranges for "no observable effects levels" in rats and rabbits, respectively, were: < 0.5 and < 0.4 mg/kg in maternal animals and < 0.5 and > 0.8 mg/kg in their fetuses.« less

High-fat Diet-induced Inflammation Accelerates Prostate Cancer Growth via IL6 Signaling.

PubMed

Hayashi, Takuji; Fujita, Kazutoshi; Nojima, Satoshi; Hayashi, Yujiro; Nakano, Kosuke; Ishizuya, Yu; Wang, Cong; Yamamoto, Yoshiyuki; Kinouchi, Toshiro; Matsuzaki, Kyosuke; Jingushi, Kentaro; Kato, Taigo; Kawashima, Atsunari; Nagahara, Akira; Ujike, Takeshi; Uemura, Motohide; Rodriguez Pena, Maria Del Carmen; Gordetsky, Jennifer B; Morii, Eiichi; Tsujikawa, Kazutake; Netto, George J; Nonomura, Norio

2018-05-18

High-fat diet (HFD) could induce prostate cancer progression. The aim of this study is to identify mechanisms of HFD-induced prostate cancer progression, focusing on inflammation. We administered HFD and celecoxib to autochthonous immunocompetent Pb-Cre+; Pten(fl/fl) model mice for prostate cancer. Tumor growth was evaluated by tumor weight and Ki67 stain, and local immune cells were assessed by flow cytometry at 22 weeks of age. Cytokines which correlated with tumor growth were identified, and the changes of tumor growth and local immune cells after inhibition of the cytokine signals were evaluated in the mice. Immunohistochemical analyses using prostatectomy specimens of obese patients were performed. HFD accelerated tumor growth, and increased the myeloid-derived suppressor cells (MDSCs) fraction and M2/M1 macrophage ratio in the model mice. Celecoxib suppressed tumor growth, and decreased both local MDSCs and M2/M1 macrophage ratio in HFD-fed mice. HFD-induced tumor growth was associated with IL6 secreted by prostatic macrophages, as were phosphorylated signal transducer and activator of transcription 3 (pSTAT3)-positive tumor cells. Anti-IL6 receptor antibody administration suppressed tumor growth, and decreased local MDSCs and pSTAT3-positive cell fractions in HFD-fed mice. The tumor-infiltrating CD11b-positive cell count was significantly higher in prostatectomy specimens of obese than those of non-obese prostate cancer patients. HFD increased MDSCs and accelerated prostate cancer tumor growth via IL6/pSTAT3 signaling in the mice. This mechanism could exist in obese prostate cancer patients. IL6-mediated inflammation could be a therapeutic target for prostate cancer. Copyright ©2018, American Association for Cancer Research.

Bioassay of 4'-(chloroacetyl)-acetanilide for possible carcinogenicity.

PubMed

1979-01-01

A bioassay for the possible carcinogenicity of 4'-(chloroacetyl)-acetanilide was conducted using Fischer 344 rats and B6C3F1 mice. 4'-(Chloroacetyl)-acetanilide was administered in the feed, at either of two concentrations, to groups of 50 male and 50 female animals of each species. Twenty animals of each sex and species were placed on test as controls. The high and low dietary concentrations of 4'-(chloroacetyl)-acetanilide were, respectively, 2,000 and 1,000 ppm for rats and 10,000 and 5,000 ppm for mice. The compound was administered for 87 weeks of a 102-week period in rats and for 90 weeks of a 105-week period in mice. Mice were killed at the end of the last week of compound administration, while rats were observed for 1 week after compound administration ceased. There were no significant positive associations between the concentration of 4'-(chloroacetyl)-acetanilide administered and mortality in rats or mice of either sex. Adequate numbers of animals in all groups survived sufficiently long to be at risk from late-developing tumors. Dose-related mean body weight depression was observed for males and females of both species, indicating that the concentrations of 4'-(chloroacetyl)-acetanilide administered to the animals in this bioassay may have approximated the maximum tolerated concentrations. None of the statistical tests for any site in rats of either sex or in male mice indicated a significant positive association between compound administration and tumor incidence. Although there was a significant positive association between the concentration of the compound administered and the incidences of hepatocellular adenomas in female mice, the Fischer exact comparisons were not significant. Under the conditions of this bioassay, 4'-(chloroacetyl)-acetanilide was not carcinogenic when administered in the diet to Fischer 344 rats or B6C3F1 mice of either sex.

Celecoxib sensitizes imatinib-resistant K562 cells to imatinib by inhibiting MRP1-5, ABCA2 and ABCG2 transporters via Wnt and Ras signaling pathways.

PubMed

Dharmapuri, Gangappa; Doneti, Ravinder; Philip, Gundala Harold; Kalle, Arunasree M

2015-07-01

Imatinib mesylate, a tyrosine kinase inhibitor, is very effective in the treatment of chronic myeloid leukemia (CML). However, development of resistance to imatinib therapy is also a very common mechanism observed with long-term administration of the drug. Our previous studies have highlighted the role of cyclooxygenase-2 (COX-2) in regulating the expression of multidrug resistant protein-1 (MDR1), P-gp, in imatinib-resistant K562 cells (IR-K562) via PGE2-cAMP-PKC-NF-κB pathway and inhibition of COX-2 by celecoxib, a COX-2 specific inhibitor, inhibits this pathway and reverses the drug resistance. Studies have identified that not only MDR1 but other ATP-binding cassette transport proteins (ABC transporters) are involved in the development of imatinib resistance. Here, we tried to study the role of COX-2 in the regulation of other ABC transporters such as MRP1, MRP2, MRP3, ABCA2 and ABCG2 that have been already implicated in imatinib resistance development. The results of the study clearly indicated that overexpression of COX-2 lead to upregulation of MRP family proteins in IR-K562 cells and celecoxib down-regulated the ABC transporters through Wnt and MEK signaling pathways. The study signifies that celecoxib in combination with the imatinib can be a good alternate treatment strategy for the reversal of imatinib resistance. Copyright © 2015 Elsevier Ltd. All rights reserved.

Disposition and metabolism of [14C]-levomilnacipran, a serotonin and norepinephrine reuptake inhibitor, in humans, monkeys, and rats

PubMed Central

Brunner, Valérie; Maynadier, Bernadette; Chen, Laishun; Roques, Louise; Hude, Isabelle; Séguier, Sébastien; Barthe, Laurence; Hermann, Philippe

2015-01-01

Levomilnacipran is approved in the US for the treatment of major depressive disorder in adults. We characterized the metabolic profile of levomilnacipran in humans, monkeys, and rats after oral administration of [14C]-levomilnacipran. In vitro binding of levomilnacipran to human plasma proteins was also studied. Unchanged levomilnacipran was the major circulating compound after dosing in all species. Within 12 hours of dosing in humans, levomilnacipran accounted for 52.9% of total plasma radioactivity; the circulating metabolites N-desethyl levomilnacipran N-carbamoyl glucuronide, N-desethyl levomilnacipran, and levomilnacipran N-carbamoyl glucuronide accounted for 11.3%, 7.5%, and 5.6%, respectively. Similar results were seen in monkeys. N-Desethyl levomilnacipran and p-hydroxy levomilnacipran were the main circulating metabolites in rats. Mass balance results indicated that renal excretion was the major route of elimination with 58.4%, 35.5%, and 40.2% of total radioactivity being excreted as unchanged levomilnacipran in humans, monkeys, and rats, respectively. N-Desethyl levomilnacipran was detected in human, monkey, and rat urine (18.2%, 12.4%, and 7.9% of administered dose, respectively). Human and monkey urine contained measurable quantities of levomilnacipran glucuronide (3.8% and 4.1% of administered dose, respectively) and N-desethyl levomilnacipran glucuronide (3.2% and 2.3% of administered dose, respectively); these metabolites were not detected in rat urine. The metabolites p-hydroxy levomilnacipran and p-hydroxy levomilnacipran glucuronide were detected in human urine (≤1.2% of administered dose), and p-hydroxy levomilnacipran glucuronide was found in rat urine (4% of administered dose). None of the metabolites were pharmacologically active. Levomilnacipran was widely distributed with low plasma protein binding (22%). PMID:26150694

Oxaliplatin Alters Expression of T1R2 Receptor and Sensitivity to Sweet Taste in Rats.

PubMed

Ohishi, Akihiro; Nishida, Kentaro; Yamanaka, Yuri; Miyata, Ai; Ikukawa, Akiko; Yabu, Miharu; Miyamoto, Karin; Bansho, Saho; Nagasawa, Kazuki

2016-01-01

As one of the adverse effects of oxaliplatin, a key agent in colon cancer chemotherapy, a taste disorder is a severe issue in a clinical situation because it decreases the quality of life of patients. However, there is little information on the mechanism underlying the oxaliplatin-induced taste disorder. Here, we examined the molecular and behavioral characteristics of the oxaliplatin-induced taste disorder in rats. Oxaliplatin (4-16 mg/kg) was administered to Sprague-Dawley (SD) rats intraperitoneally for 2 d. Expression levels of mRNA and protein of taste receptors in circumvallate papillae (CP) were measured by real-time quantitative polymerase chain reaction (PCR) and immunohistochemistry, respectively. Taste sensitivity was assessed by their behavioral change using a brief-access test. Morphological change of the taste buds in CP was evaluated by hematoxyline-eosin (HE) staining, and the number of taste cells in taste buds was counted by immunohistochemical analysis. Among taste receptors, the expression levels of mRNA and protein of T1R2, a sweet taste receptor subunit, were increased transiently in CP of oxaliplatin-administered rats on day 7. In a brief-access test, the lick ratio was decreased in oxaliplatin-administered rats on day 7 and the alteration was recovered to the control level on day 14. There was no detectable alteration in the morphology of taste buds, number of taste cells or plasma zinc level in oxaliplatin-administered rats. These results suggest that decreased sensitivity to sweet taste in oxaliplatin-administered rats is due, at least in part, to increased expression of T1R2, while these alterations are reversible.

Influence of adrenal hormones in the occurrence and prevention of stress ulcers.

PubMed

Yigiter, Murat; Albayrak, Yavuz; Polat, Beyzagul; Suleyman, Bahadır; Salman, Ahmet Bedii; Suleyman, Halis

2010-11-01

The aim of the study was to examine whether endogenous cortisol and adrenalin have a role in the formation of stress ulcers in intact and adrenalectomized rats. The study was composed of 4 experiments: ulcerated areas in stomachs of adrenalectomized and intact rats were measured, adrenaline (100 μg/kg) and prednisolone (5 mg/kg) were injected intraperitoneally in adrenalectomized rats, metyrapone (200 mg/kg) and metyrosine (200 mg/kg) were administered to intact rats, and metyrapone (200 mg/kg) and metyrosine (200 mg/kg) were administered orally with yohimbine (10 mg/kg) and yohimbine (10 mg/kg) alone were administered to intact rats. After 24-hour restraint stress, ulcerated areas were measured. In the stomach of intact rats, the degree of stress ulcer was 7.25 times more severe than that noted in adrenalectomized rats. Furthermore, stress ulcers in adrenalectomized rats that received adrenaline or prednisolone only were fewer and less severe than rats receiving both adrenaline and prednisolone. Simultaneous administration of adrenaline and prednisolone did not prevent the formation of stress ulcers. However, either of these hormones alone (adrenaline or prednisolone), in the absence of the other, repressed the formation of stress ulcers. This antiulcer activity may be related to α2-adrenergic receptor activity. Copyright © 2010 Elsevier Inc. All rights reserved.

Improvement of neurological disorders in postmenopausal model rats by administration of royal jelly.

PubMed

Minami, A; Matsushita, H; Ieno, D; Matsuda, Y; Horii, Y; Ishii, A; Takahashi, T; Kanazawa, H; Wakatsuki, A; Suzuki, T

2016-12-01

Royal jelly (RJ) from honeybees (Apis mellifera) has estrogenic activity. Estrogen deficiency after menopause leads to a high risk of memory impairment and depression as well as metabolic syndrome and osteoporosis. We here investigated the effect of RJ on memory impairment and depression-like behaviors in ovariectomized (OVX) rats. OVX rats were administered with RJ for 82 days. Hippocampus-dependent spatial memory and depression-like behaviors were assessed by the Morris water maze test and the forced swimming test, respectively. The weights of body, brain and uterus and the contents of protein and myelin galactolipids including galactosylceramide and sulfatide were measured. Memory impairment and depression-like behaviors in OVX rats were recovered to the levels of sham-operated rats by RJ administration. Increased body weight and decreased uterine weight in OVX rats were recovered to the levels of sham-operated rats by 17β-estradiol (E2) administration but not by RJ administration. In contrast, brain weight was slightly increased by RJ administration but not by E2 administration. The contents of protein and myelin galactolipids were higher in the brains of RJ-administered OVX rats than in the brains of E2-administered OVX rats. The results suggest that RJ has a beneficial effect on neurological symptoms of a menopausal disorder.

Antigenotoxic and Antioxidant Activity of Methanol Stem Bark Extract of Napoleona Vogelii Hook & Planch (Lecythidaceae) In Cyclophosphamide-Induced Genotoxicity

PubMed Central

Ikumawoyi, Victor; Agbaje, Esther; Awodele, Olufunsho

2017-01-01

BACKGROUND: Napoleona vogelii is used in traditional medicine for cancer management. AIM: The study was conducted to evaluate the antigenotoxic and antioxidant activities of methanol stem bark extract of N. vogelii in male Sprague Dawley rats. MATERIALS AND METHOD: Thirty male Sprague Dawley rats were randomly divided into group 1 (control) administered 10 mL/kg distilled water, groups 2 and 3 were co-administered 100 mg/kg, 200 mg/kg of N. vogelli and 5 mg/kg cyclophosphamide (CPA) respectively for 7 days p.o. Groups 4 and 5 were administered only 5 mg/kg CPA and 200 mg/kg NV respectively. RESULTS: The LD50 oral was greater than 4 g/kg. There were significant (p < 0.0001) increases in plasma enzymatic and non-enzymatic antioxidant enzymes and significant (p < 0.0001) decrease in percentage micronuclei in bone marrow of extract treated rats compared to rats administered 5 mg/kg CPA alone. There was steatosis pointing to cytotoxic injury in the liver of rats co-administered 200 mg/kg NV and 5 mg/kg CPA. Gas chromatography-mass spectrometry analysis of the extract showed the presence of phytol and unsaturated fatty acids. CONCLUSION: N. vogelii possesses antigenotoxic and antioxidant activities associated with the presence of phytochemicals, phytol and unsaturated fatty acids. PMID:29362611

Wheel running decreases the positive reinforcing effects of heroin.

PubMed

Smith, Mark A; Pitts, Elizabeth G

2012-01-01

The purpose of this study was to examine the effects of voluntary wheel running on the positive reinforcing effects of heroin in rats with an established history of drug self-administration. Rats were assigned to sedentary (no wheel) and exercise (wheel) conditions and trained to self-administer cocaine under positive reinforcement contingencies. Rats acquiring cocaine self-administration were then tested with various doses of heroin during daily test sessions. Sedentary rats self-administered more heroin than exercising rats, and this effect was greatest at low and moderate doses of heroin. These data suggest that voluntary wheel running decreases the positive reinforcing effects of heroin.

Regional heterogeneity for the intracranial self-administration of ethanol within the ventral tegmental area of female Wistar rats.

PubMed

Rodd-Henricks, Z A; McKinzie, D L; Crile, R S; Murphy, J M; McBride, W J

2000-04-01

Because current findings indicate that the selectively bred alcohol-preferring P line of rats self-administers 50-200 mg% ethanol (EtOH) directly into the ventral tegmental area (VTA), whereas the alcohol-nonpreferring NP line does not, it is important to determine whether unselected, common stock rats would self-administer EtOH directly into the VTA. In addition, because neuroanatomical and self-administration studies indicate that the VTA may be functionally heterogeneous, the present study was designed to determine whether there were subregional differences within the VTA for the intracranial self-administration (ICSA) of EtOH. The objective of this study was to employ the ICSA technique to determine whether adult female Wistar rats would self-administer EtOH directly into the VTA, and whether regional heterogeneity existed for EtOH self-infusion within the VTA. Following surgery to implant guide cannulae aimed at either the posterior or anterior VTA, subjects were placed in standard experimental chambers equipped with an 'active lever' [fixed ratio (FR)1 schedule of reinforcement], which caused the delivery of the infusate, and an 'inactive lever', which had no programmed consequence. Subjects were assigned to groups that self-administered either artificial cerebrospinal fluid (aCSF) throughout, or 100-400 mg% EtOH for the first four sessions (acquisition), aCSF in sessions 5 and 6 (extinction), and EtOH again during session 7 (reinstatement). During the four acquisition sessions, rats with posterior VTA placements readily self-administered 200 mg% and 250 mg% EtOH and discriminated between the active and inactive levers. These subjects also demonstrated extinction, when aCSF was substituted for EtOH, and reinstatement when EtOH was reintroduced. Rats with posterior VTA placements self-infused 300 mg% and 400 mg% EtOH, and demonstrated lever discrimination only during the initial acquisition sessions. In contrast, rats with anterior VTA placements did not self-administer EtOH. The findings suggest that EtOH is reinforcing within the posterior VTA of Wistar rats, and the VTA is a functionally heterogeneous structure with regard to EtOH reinforcement.

Effect of naturally mouldy wheat or fungi administration on metallothioneins level in brain tissues of rats.

PubMed

Vasatkova, Anna; Krizova, Sarka; Krystofova, Olga; Adam, Vojtech; Zeman, Ladislav; Beklova, Miroslava; Kizek, Rene

2009-01-01

The aim of this study is to determine level of metallothioneins (MTs) in brain tissues of rats administered by feed mixtures with different content of mouldy wheat or fungi. Selected male laboratory rats of Wistar albino at age of 28 days were used in our experiments. The rats were administered by feed mixtures with different content of vitamins, naturally mouldy wheat or fungi for 28 days. At the very end of the experiment, the animals were put to death and brains were sampled. MT level was determined by differential pulse voltammetry Brdicka reaction. We found that MTs' level in brain tissues from rats administered by standard feed mixtures was significantly higher compared to the level of MTs in rats supplemented by vitamins. Further we studied the effect of supplementation of naturally mouldy wheat on MTs level in rats. In mouldy wheat we detected the presence of following fungi species: Mucor spp., Absidia spp., Penicillium spp., Aspergillus spp. and Fusarium spp. Moreover we also identified and quantified following mycotoxins - deoxynivalenol, zearalenone, T2-toxin and aflatoxins. Level of MTs determined in rats treated with 33 or 66% of mouldy wheat was significantly lower compared to control ones. On the other hand rats treated with 100% of mouldy wheat had less MTs but not significantly. Supplementation of vitamins to rats fed by mouldy wheat had adverse effect on MTs level compared to rats with no other supplementation by vitamins. Moreover vitamins supplementation has no effect on MTs level in brain tissues of rats treated or non-treated with Ganoderma lucidum L. Both mycotoxins and vitamins have considerable effect on level of MTs in brain tissues. It can be assumed that the administered substances markedly influence redox metabolism, which could negatively influence numerous biochemical pathways including those closely related with MTs.

Effects of enterally- and parenterally-administered bombesin on intestinal luminal tryptic activity and protein in the suckling rat.

PubMed

Pollack, P F; Adamson, C; Koldovsky, O

1989-04-15

Because of the presence of bombesin-like immunoreactivity in milk, we investigated if enteral administration of bombesin affects the intestinal luminal content of trypsin and protein in 12-14-day-old rats. Bombesin (40 micrograms/kg), given either orogastrically or subcutaneously, produced a significant elevation in the intestinal content of trypsin activity. Thus, enterally-administered bombesin can produce acute biologic effects in suckling rats.

The effects of prolonged administration of norepinephrine reuptake inhibitors on long-term potentiation in dentate gyrus, and on tests of spatial and object recognition memory in rats.

PubMed

Walling, Susan G; Milway, J Stephen; Ingram, Matthew; Lau, Catherine; Morrison, Gillian; Martin, Gerard M

2016-02-01

Phasic norepinephrine (NE) release events are involved in arousal, novelty detection and in plasticity processes underlying learning and memory in mammalian systems. Although the effects of phasic NE release events on plasticity and memory are prevalently documented, it is less understood what effects chronic NE reuptake inhibition and sustained increases in noradrenergic tone, might have on plasticity and cognitive processes in rodent models of learning and memory. This study investigates the effects of chronic NE reuptake inhibition on hippocampal plasticity and memory in rats. Rats were administered NE reuptake inhibitors (NRIs) desipramine (DMI; 0, 3, or 7.5mg/kg/day) or nortriptyline (NTP; 0, 10 or 20mg/kg/day) in drinking water. Long-term potentiation (LTP; 200 Hz) of the perforant path-dentate gyrus evoked potential was examined in urethane anesthetized rats after 30-32 days of DMI treatment. Short- (4-h) and long-term (24-h) spatial memory was tested in separate rats administered 0 or 7.5mg/kg/day DMI (25-30 days) using a two-trial spatial memory test. Additionally, the effects of chronically administered DMI and NTP were tested in rats using a two-trial, Object Recognition Test (ORT) at 2- and 24-h after 45 and 60 days of drug administration. Rats administered 3 or 7.5mg/kg/day DMI had attenuated LTP of the EPSP slope but not the population spike at the perforant path-dentate gyrus synapse. Short- and long-term memory for objects is differentially disrupted in rats after prolonged administration of DMI and NTP. Rats that were administered 7.5mg/kg/day DMI showed decreased memory for a two-trial spatial task when tested at 4-h. In the novel ORT, rats receiving 0 or 7.5mg/kg/day DMI showed a preference for the arm containing a Novel object when tested at both 2- and 24-h demonstrating both short- and long-term memory retention of the Familiar object. Rats that received either dose of NTP or 3mg/kg/day DMI showed impaired memory at 2-h, however this impairment was largely reversed at 24-h. Animals in the high-dose NTP (20mg/kg/day) group were impaired at both short- and long-term intervals. Activity levels, used as an index of location memory during the ORT, demonstrated that rats receiving DMI were again impaired at retaining memory for location. DMI dose-dependently disrupts LTP in the dentate gyrus of anesthetized rats and also disrupts memory for tests of spatial memory when administered for long periods. Copyright © 2016 Elsevier Inc. All rights reserved.

DEVELOPMENTAL EFFECTS OF TRICHLOROACETONITRILE ADMINISTERED IN CORN OIL TO PREGNANT LONG-EVANS RATS

EPA Science Inventory

Trichloroacetonitrile (TCAN) is a by-product of the chlorine disinfection of water containing natural organic material. When administered by gavage to pregnant Long-Evans rats in a medium-chain triglyceride vehicle, tricaprylin oil (Tricap), at a volume of 10 ml/kg, TCAN induced ...

Effect of the aqueous extract of Psidium guajava on erythromycin-induced liver damage in rats.

PubMed

Sambo, N; Garba, S H; Timothy, H

2009-12-01

The effect of Psidium guajava extract on erythromycin-induced liver damage in albino rats was investigated using 30 normal rats grouped into six. Group I and II served as the normal and treatment controls that were administered with normal saline and 100 mg/kg body weight of erythromycin stearate daily for 14 days respectively. Rats in group III were administered 450 mg/kg body weight of Psidium guajava only for 7 days while rats in groups IV, V and VI were administered Psidium guajava extract for 7 days and 100mg/kg body weight of erythromycin for 14 days. Histopathological investigation of the liver tissues revealed striking oedema and mild periportal mononuclear cell infiltration of hepatic cords in the liver of rats administered 100 mg/kg of erythromycin stearate and 300/450 mg/kg of Psidium guajava extract. Pretreatment with 150 mg/kg of Psidium guajava extract showed a slight degree of protection against the induced hepatic injury caused by 100 mg/kg of erythromycin stearate. Biochemical analysis of the serum obtained revealed a significant increase in serum levels of hepatic enzymes measured in the groups administered with 100 mg/kg of erythromycin stearate and 300/450 mg/kg of Psidium guajava extract compared to the control groups and those pretreated with 150 mg/kg of Psidium guajava extract. This study has shown that the aqueous extract of psidium guajava leaf possesses hepatoprotective property at lower dose and a hepatotoxic property at higher dose but further studies with prolonged duration is recommended.

Reciprocal inhibitory effects of intravenous d-methamphetamine self-administration and wheel activity in rats

PubMed Central

Miller, ML; Vaillancourt, BD; Wright, MJ; Aarde, SM; Vandewater, SA; Creehan, KM; Taffe, MA

2011-01-01

Background Some epidemiological and cessation studies suggest physical exercise attenuates or prevents recreational drug use in humans. Preclinical studies indicate wheel activity reduces cocaine self-administration in rats; this may, however, require the establishment of compulsive wheel activity. Methods Effects of concurrent wheel activity on intravenous d-methamphetamine (METH) self-administration were examined in male Wistar and Sprague Dawley rats with negligible prior wheel experience. Wistar rats self-administered METH (0.05 mg/kg/inf) under a fixed-ratio 1 (FR1) schedule with concurrent access to an activity wheel during sessions 1–14, 8–21 or 15–21. Control rats which did not self-administer METH had access to an activity wheel during sessions 1–14, 8–21 or 15–28. Sprague Dawley rats self-administered METH (0.1 mg/kg/inf) under FR1 for 14 sessions with either concurrent access to a locked or an unlocked activity wheel. Results METH self-administration was lower when the wheel was available concurrently from the start of self-administration training in both strains, even though Sprague Dawley rats self-administered twice as many METH infusions and ran one-sixth as much on the wheel compared to Wistar rats. Wheel access initiated after 7 or 14 days had no effect on METH self-administration in Wistar rats. Wheel activity was significantly reduced in these groups compared with the group with concurrent wheel and METH access for the first 14 sessions. Conclusions These data show METH self-administration is reduced by exercise if initiated from the start of self-administration and that prior METH self-administration experience interferes with the value of exercise as a reinforcer. PMID:21899959

Ibogaine interferes with motivational and somatic effects of naloxone-precipitated withdrawal from acutely administered morphine.

PubMed

Parke, Linda A; Burton, Page; McDonald, Robert V; Kim, Joseph A; Siegel, Shepard

2002-02-01

It has been reported that ibogaine interferes with somatic withdrawal reactions in rats chronically treated with morphine. The present experiments demonstrated that ibogaine also interferes with motivational withdrawal reactions and somatic withdrawal reactions in rats treated with morphine on only two occasions. On each of two conditioning trials, naloxone was administered 24 h following an injection of morphine. Four hours prior to each naloxone administration, rats were injected with either ibogaine or saline. In two experiments, ibogaine interfered with naloxone-precipitated withdrawal. In Experiment 1, ibogaine-treated rats displayed a weaker aversion to the withdrawal-paired chamber, and in Experiment 2, ibogaine-treated rats displayed fewer somatic withdrawal reactions than did saline treated rats.

Sex-dependent effects of fluoxetine and triiodothyronine in the forced swim test in rats.

PubMed

Lifschytz, Tzuri; Shalom, Galit; Lerer, Bernard; Newman, Michael E

2006-02-01

The effects of triiodothyronine (T3) and fluoxetine, administered separately and combined, on behavior of male and female rats in the forced swim test, a procedure for screening antidepressant-like activity, were determined. There were no consistent effects of low doses of fluoxetine (5 mg/kg) or T3 (20 microg/kg), administered daily for 2 weeks. Fluoxetine administered daily at 10 mg/kg for 7 days reduced immobility and increased active behaviors in male rats, but had no effects in female rats. The effects of fluoxetine in male rats were not potentiated by T3. In female rats, T3 at 100 microg/kg given daily for 7 days decreased immobility and increased swimming when these were measured 72 h after the last injection, but not when measurements were performed at an earlier time point. These results provide some support from an animal model for the efficacy of T3 as antidepressant therapy in female patients, but do not provide support for the augmentation and acceleration effects seen clinically when T3 is used in conjunction with established antidepressants such as fluoxetine.

Oxidative stress in rat kidneys due to 3,4-methylenedioxymetamphetamine (ecstasy) toxicity.

PubMed

Ninković, Milica; Selaković, Vesna; Dukić, Mirjana; Milosavljević, Petar; Vasiljević, Ivana; Jovanović, Marina; Malicević, Zivorad

2008-02-01

The mechanism of MDMA (3,4-methylenedioxymethamphetamine)-induced toxicity is believed to be, in part, due to enhanced oxidative stress. As MDMA is eliminated via the kidney, the aim of this study was to investigate whether MDMA created conditions of oxidative stress within rat kidney. Adult male Wistar rats were divided into three groups, control treatment (water), acute MDMA administration (single oral dose: 5, 10, 20 or 40 mg/kg body weight) and subacute MDMA administration (5, 10, or 20 mg/kg body weight per day during 14 days). Animals were sacrificed 8 h after the single oral MDMA administration in the acute MDMA administration group and after the last MDMA administration in the subacute MDMA administration group. Rectal temperature measurements, oxidative stress status parameters and histological examinations were performed. In all MDMA-administered rats, rectal temperature markedly increased peaking approximately 1 h after MDMA ingestion. Superoxide dismutase activity and thiobarbituric acid reactive substances increased after MDMA administration. Histological examinations of the kidney revealed dose-dependent disruption of tissue structure in subacute MDMA-administered rats. The latter was not observed in acute MDMA-administered rats.

Cyanidin-3-glucoside extracted from mulberry fruit can reduce N-methyl-N-nitrosourea-induced retinal degeneration in rats.

PubMed

Lee, Seung Hee; Jeong, Eojin; Paik, Sun-Sook; Jeon, Ji Hyun; Jung, Sung Won; Kim, Hyun-Bok; Kim, Muyan; Chun, Myung-Hoon; Kim, In-Beom

2014-01-01

To investigate the effect of cyanidin-3-O-glucoside (C3G) on a rat retinal degeneration (RD) model. Experimental RD was induced in rats by the intraperitoneal injection of N-methyl-N-nitrosourea (MNU) at 50 mg/kg. C3G extracted from mulberry (Morus alba L.) fruit (50 mg/kg) was orally administered, daily for 1, 2 and 4 weeks after MNU injection. The effects of C3G administration on MNU-induced RD retinas were histologically and functionally assessed by hematoxylin and eosin staining and electroretinography (ERG), respectively. The degree of retinal injury in C3G-administered RD rats was evaluated by immunohistochemistry with an antibody against glial fibrillary acidic protein (GFAP). The preferential protective effect of C3G on scotopic vision was examined by western blot analysis. Marked loss of photoreceptors in the outer nuclear layer (ONL) was observed in RD rats at 2 and 4 weeks after MNU injection, while the ONL in the MNU-induced RD rats given C3G was relatively well preserved. Immunohistochemistry with anti-GFAP showed that retinal injury was also reduced in the retinas of the rats given C3G. Functional assessment by using ERG recordings showed that scotopic ERG responses were significantly increased in RD rats given C3G for 4 weeks (p < 0.01) compared with that of untreated RD rats. In the RD rats given short-term C3G (for 1 and 2 weeks), the increase in ERG responses was not significant. In addition, western blot analysis showed that rhodopsin level in the C3G-administered RD retinas significantly increased compared to that in the non-administered RD retinas (p < 0.05), whereas red/green opsin level did not show any significant difference. Long-term administration of C3G extracted from mulberry fruit could structurally reduce photoreceptor damage and functionally improve scotopic visual functions in the RD rat model induced by MNU.

Efficacy and safety of Postoperative Intravenous Parecoxib sodium Followed by ORal CElecoxib (PIPFORCE) post-total knee arthroplasty in patients with osteoarthritis: a study protocol for a multicentre, double-blind, parallel-group trial

PubMed Central

Zhuang, Qianyu; Bian, Yanyan; Wang, Wei; Jiang, Jingmei; Feng, Bin; Sun, Tiezheng; Lin, Jianhao; Zhang, Miaofeng; Yan, Shigui; Shen, Bin; Pei, Fuxing; Weng, Xisheng

2016-01-01

Introduction Total knee arthroplasty (TKA) has been regarded as a most painful orthopaedic surgery. Although many surgeons sequentially use parecoxib and celecoxib as a routine strategy for postoperative pain control after TKA, high quality evidence is still lacking to prove the effect of this sequential regimen, especially at the medium-term follow-up. The purpose of this study, therefore, is to evaluate efficacy and safety of postoperative intravenous parecoxib sodium followed by oral celecoxib in patients with osteoarthritis (OA) undergoing TKA. The hypothesis is that compared to placebo with opioids as rescue treatment, sequential use of parecoxib and celecoxib can achieve less morphine consumption over the postoperative 2 weeks, as well as better pain control, quicker functional recovery in the postoperative 6 weeks and less opioid-related adverse events during the 12-week recovery phase. Methods and analysis This study is designed as a multicentre, randomised, double-blind, parallel-group and placebo-controlled trial. The target sample size is 246. All participants who meet the study inclusion and exclusion criteria will be randomly assigned in a 1:1 ratio to either the parecoxib/celecoxib group or placebo group. The randomisation and allocation will be study site based. The study will consist of three phases: an initial screening phase; a 6-week double-blind treatment phase; and a 6-week follow-up phase. The primary end point is cumulative opioid consumption during 2 weeks postoperation. Secondary end points consist of the postoperative visual analogue scale score, knee joint function, quality of life, local skin temperature, erythrocyte sedimentation rate, C reactive protein, cytokines and blood coagulation parameters. Safety end points will be monitored too. Ethics and dissemination Ethics approval for this study has been obtained from the Ethics Committee, Peking Union Medical College Hospital, China (Protocol number: S-572) Study results will be available as published manuscripts and presentations at national and international meetings. Trial registration number NCT02198924. PMID:27609846

Efficacy and safety of Postoperative Intravenous Parecoxib sodium Followed by ORal CElecoxib (PIPFORCE) post-total knee arthroplasty in patients with osteoarthritis: a study protocol for a multicentre, double-blind, parallel-group trial.

PubMed

Zhuang, Qianyu; Bian, Yanyan; Wang, Wei; Jiang, Jingmei; Feng, Bin; Sun, Tiezheng; Lin, Jianhao; Zhang, Miaofeng; Yan, Shigui; Shen, Bin; Pei, Fuxing; Weng, Xisheng

2016-09-08

Total knee arthroplasty (TKA) has been regarded as a most painful orthopaedic surgery. Although many surgeons sequentially use parecoxib and celecoxib as a routine strategy for postoperative pain control after TKA, high quality evidence is still lacking to prove the effect of this sequential regimen, especially at the medium-term follow-up. The purpose of this study, therefore, is to evaluate efficacy and safety of postoperative intravenous parecoxib sodium followed by oral celecoxib in patients with osteoarthritis (OA) undergoing TKA. The hypothesis is that compared to placebo with opioids as rescue treatment, sequential use of parecoxib and celecoxib can achieve less morphine consumption over the postoperative 2 weeks, as well as better pain control, quicker functional recovery in the postoperative 6 weeks and less opioid-related adverse events during the 12-week recovery phase. This study is designed as a multicentre, randomised, double-blind, parallel-group and placebo-controlled trial. The target sample size is 246. All participants who meet the study inclusion and exclusion criteria will be randomly assigned in a 1:1 ratio to either the parecoxib/celecoxib group or placebo group. The randomisation and allocation will be study site based. The study will consist of three phases: an initial screening phase; a 6-week double-blind treatment phase; and a 6-week follow-up phase. The primary end point is cumulative opioid consumption during 2 weeks postoperation. Secondary end points consist of the postoperative visual analogue scale score, knee joint function, quality of life, local skin temperature, erythrocyte sedimentation rate, C reactive protein, cytokines and blood coagulation parameters. Safety end points will be monitored too. Ethics approval for this study has been obtained from the Ethics Committee, Peking Union Medical College Hospital, China (Protocol number: S-572) Study results will be available as published manuscripts and presentations at national and international meetings. NCT02198924. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Celecoxib can suppress expression of genes associated with PGE2 pathway in chondrocytes under inflammatory conditions.

PubMed

Sun, Tian-Wen; Wu, Zhi-Hong; Weng, Xi-Sheng

2015-01-01

This study aimed to investigate the effect of a selective cyclooxygenase-2 (COX-2) inhibitor (celecoxib) on the expression of arachidonate-associated inflammatory genes in cultured human normal chondrocytes. Normal chondrocytes were obtained from the cartilage of three different amputated patients without osteoarthritis (OA). Affymetrix Human microarray was used to assess the alterations in gene expression in three groups of cells: untreated cells (negative control group), cells treated with interleukin-1β (IL-1β) (positive control group), and cells treated with IL-1β and celecoxib. The patterns of up-regulation and down-regulation of gene expression were further validated by real-time PCR. A total of 1091 up-regulated genes and 1252 down-regulated genes were identified in the positive control group compared with the negative control group. Among them, PTGS2, ADAMTS5, PTGER2, mPTGES and PTGER4 are known to be involved in chondrocyte inflammation, while VEGFA, BCL2, TRAF1, CYR61, BMP6, DAPK1, DUSP7, IL1RN, MMP13 and TNFSF10 were reported being associated with cytokine and chemokine signaling. 189 up-regulated genes and 177 down-regulated genes were identified in the positive control group compared with intervention group. PTGS1, PTGS2, ADAMTS5, PTGER2, mPTGES and PTGER4 were among the genes down-regulated upon the treatment with celecoxib. Our results demonstrated that the OA chondrocytes are the site of active eicosanoid production. IL-1β can activate inflammation in chondrocytes and trigger the production of various proteins involved in cyclooxygenase pathway. The expression of genes corresponding to these proteins can be down-regulated by celecoxib. The findings indicate that the therapy with prostaglandin E2 (PGE2)-blocking agents may decrease the PGE2 production not only by direct inhibition of COX-2 activity, but also by down-regulating the expression of genes encoding for COX-2, microsomal prostaglandin-endoperoxide synthase 1 (mPGES-1) and prostaglandin E receptors 4 (EP4) in the articular chondrocytes.

TEN- AND NINETY-DAY TOXICITY STUDIES OF 1,2-DICHLOROBENZENE ADMINISTERED BY ORAL GAVAGE TO SPRAGUE-DAWLEY RATS

EPA Science Inventory

Subacute (10-day) and subchronic (90-day) toxicity studies of 1,2-dichlorobenzene (DCB) were conducted in male and female Sprague-Dawley rats. ,2-Dichlorobenzene was administered in corn oil by oral gavage; control animals received corn oil. t time of sacrifice, gross necropsies ...

THE INDUCTION OF ABERRANT CRYPT FOCI (ACF) IN THE COLONS OF RATS BY TRIHALOMETHANES ADMINISTERED IN THE DRINKING WATER

EPA Science Inventory

Bromodichloromethane (BDCM) and bromoform (TBM) had been demonstrated to be colon carcinogens in male and female F344/N rats following administration by corn oil gavage. Our chronic bioassay of BDCM administered in the drinking water failed to demonstrate an enhanced colon cance...

Effect of inhibitors of prostaglandin synthesis on gonadotropin release in the rat.

PubMed

Ojeda, S R; Harms, P G; McCann, S M

1975-10-01

To study the effect of blockade of prostaglandin (PG) synthesis on gonadotropin release in the rat, inhibitors of PG synthesis were injected by various routes in various experimental conditions. The injection of 5-, 8-, 11-, 14-eicosatetraynoic acid (TYA) into the third ventricle (3rd V) significantly decreased plasma LH of ovariectomized (OVX) rats 1, 2, and 4 h following its injection; however, TYA failed to alter plasma LH in OVX rats when administered as a single sc injection and also failed to prevent the post-castration rise in plasma LH when administered sc once daily for 4 days to short-term OVX rats. None of these treatments altered plasma FSH concentrations. Indomethacin (Id) injected into the 3rd V or implanted into the medial basal hypothalamus (MBH) of OVX rats depressed plasma LH 1--6 h later. This effect was no longer observed 24--72 h following its implantation in the MBH. When different doses of Id were administered as single sc injections to OVX rats, plasma LH titers were depressed 24--32 h later, whereas plasma FSH remained either unaltered or was slightly increased. Similarly, the post-castration rise of plasma LH but not that of FSH in male rats was suppressed by a single sc injection of Id given 6 h before orchidectomy. Id administered acutely iv failed to modify the pulsatile release of LH in OVX rats, but it effectively inhibited this release when injected sc 20--30 h before the initiation of blood collection. Moreover, Id blocked the progesterone-induced LH and FSH release in OVX estrogen-primed rats when given sc 24 h before progesterone, but not when it was injected either sc or iv shortly (2 h) before or shortly after (1--3 h) progesterone treatment. Rats treated with Id showed a decrease in BW 24--32 h afters its sc injection. However, the effects of Id on LH release could not be explained by lack of food intake since fasted controls showed LH titers similar to fed rats. Id did not significantly inhibit the LH release in response to synthetic LH-releasing hormone (LHRH) in OVX rats, but partially blocked the response in OVX estrogen, progesterone-treated (OEP) rats. Surprisingly, in OEP rats, Id appeared to potentiate the FSH release in response to LHRH. The results of this study indicate that inhibitors of PG synthesis administered at high doses can inhibit LH release in the rat and that this effect is mainly due to a direct effect of the drug or drugs on the central nervous systen. Consequently, the results of this study give further support to the hypothesis that PGs play a physiological role in the control of gonadotropin secretion.

Synthesis and preliminary in vitro biological evaluation of new carbon-11-labeled celecoxib derivatives as candidate PET tracers for imaging of COX-2 expression in cancer.

PubMed

Gao, Mingzhang; Wang, Min; Miller, Kathy D; Zheng, Qi-Huang

2011-09-01

The enzyme cyclooxygenase-2 (COX-2) is overexpressed in a variety of malignant tumors. This study was designed to develop new radiotracers for imaging of COX-2 in cancer using biomedical imaging technique positron emission tomography (PET). Carbon-11-labeled celecoxib derivatives, [(11)C]4a-c and [(11)C]8a-d, were prepared by O-[(11)C] methylation of their corresponding precursors using [(11)C]CH(3)OTf under basic conditions and isolated by a simplified solid-phase extraction (SPE) method in 52 ± 2% (n = 5) and 57 ± 3% (n = 5) radiochemical yields based on [(11)C]CO(2) and decay corrected to end of bombardment (EOB). The overall synthesis time from EOB was 23 min, the radiochemical purity was >99%, and the specific activity at end of synthesis (EOS) was 277.5 ± 92.5 GBq/μmol (n = 5). The IC(50) values to block COX-2 for known compounds celecoxib (4d), 4a and 4c were 40, 290 and 8 nM, respectively, and preliminary findings from in vitro biological assay indicated that the synthesized new compounds 4b and 8a-d display similar strong inhibitory effectiveness in the MDA-MB-435 human cancer cell line in comparison with the parent compound 4d. These results encourage further in vivo evaluation of carbon-11-labeled celecoxib derivatives as new potential PET radiotracers for imaging of COX-2 expression in cancer. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

Treatment options for rheumatoid arthritis: celecoxib, leflunomide, etanercept, and infliximab.

PubMed

Luong, B T; Chong, B S; Lowder, D M

2000-06-01

To review new pharmacologic agents approved for use in the management of rheumatoid arthritis (RA). A MEDLINE search (1966-January 2000) was conducted to identify English-language literature available on the pharmacotherapy of RA, focusing on celecoxib, leflunomide, etanercept, and infliximab. These articles, relevant abstracts, and data provided by the manufacturers were used to collect pertinent data. All controlled and uncontrolled trials were reviewed. Agents were reviewed with regard to mechanism of action, efficacy, drug interactions, pharmacokinetics, dosing, precautions/contraindications, adverse effects, and cost. Traditional pharmacologic treatments for RA have been limited by toxicity, loss of efficacy, or both. Increasing discoveries into the mechanisms of inflammation in RA have led to the development of new agents in hopes of addressing these limitations. With the development of celecoxib, a selective cyclooxygenase-2 inhibitor, the potential exists to minimize the gastrotoxicity associated with nonsteroidal antiinflammatory drugs. Leflunomide has been shown to be equal to or less efficacious than methotrexate, and may be beneficial as a second-line disease-modifying antirheumatic drug (DMARD). The biologic response modifiers, etanercept and infliximab, are alternatives that have shown benefit alone or in combination with methotrexate. However, they should be reserved for patients who fail to respond to DMARD therapy. Further studies should be conducted to evaluate the long-term safety and efficacy of these agents as well as their role in combination therapy. Celecoxib, leflunomide, etanercept, and infliximab are the newest agents approved for RA. Clinical trials have shown that these agents are beneficial in the treatment of RA; however, long-term safety and efficacy data are lacking.

Effect of Pithecellobium dulce (Roxb.) Benth. fruit extract on cysteamine induced duodenal ulcer in rats.

PubMed

Megala, Jayaraman; Geetha, Arumugam

2015-10-01

The edible fruits of Pithecellobium dulce (Roxb.) Benth. are traditionally used for various gastric complications in India. Here, we investigated the antiulcer activity of hydroalcoholic fruit extract of P. dulce (HAEPD) by applying cysteamine induced duodenal ulcer model in rats. Duodenal ulcer was induced in male albino Wistar rats by oral administration of cysteamine @ 420 mg/kg body wt. as a single dose. The rats were pre-administered orally with HAEPD @ 200 mg/kg body wt. for 30 days prior to ulcer induction. Rats pre-administered with ranitidine @ 30 mg/kg body wt. served as reference drug control. Ulcer score, thiobarbituric acid reactive substances (TBARS), glycoproteins, superoxide dismutase, catalase and glutathione peroxidase and reduced glutathione levels were measured in the duodenum. Rats pre-administered with the HAEPD showed significantly reduced ulcer score comparable to that of ranitidine pretreated rats. The co-administration of HAEPD lowered the TBARS level and also restored the levels of glycoproteins, enzymatic and non-enzymatic antioxidants. Histopathological observations confirmed the presence of inflammation, necrosis and hemorrhagic spots in the duodenum of ulcer control rats which were significantly reduced due to HAEPD treatment. No abnormal alterations were observed in normal rats treated with HAEPD at the dosage studied. The results demonstrated antioxidant and cytoprotective nature of P. dulce, and thereby its significant anti ulcer property.

Baclofen has opposite effects on escalation of cocaine self-administration: increased intake in rats selectively bred for high (HiS) saccharin intake and decreased intake in those selected for low (LoS) saccharin intake

PubMed Central

Holtz, Nathan A.; Carroll, Marilyn E.

2011-01-01

Rats selectively bred for high saccharin intake (HiS) self-administer more cocaine, escalate their cocaine intake during long access, and reinstate cocaine seeking at higher levels than those bred for low saccharin intake (LoS). The present study was conducted to determine if baclofen, an agonist at the GABAb receptor, has differential effects on the escalation of i.v. cocaine intake and reinstatement of cocaine-seeking in HiS and LoS rats. HiS and LoS rats self-administered cocaine during a 2-h daily short-access (ShA) phase for 3 days and then long-access (LgA) sessions for 21 days followed by a second ShA phase. One group of HiS and LoS rats received i.p. injections of 2.5 mg/kg baclofen (HiS+B and LoS+B, respectively), and other groups of HiS and LoS rats received saline (HiS+Sal and LoS+Sal) before each daily session. In a second experiment, HiS and LoS rats self-administered i.v. cocaine during 2-h sessions for 14 days followed by a 21-day extinction period. Baclofen (2.5 mg/kg, i.p.) or saline was administered before saline- or cocaine-primed reinstatement sessions. The HiS+B group escalated their cocaine self-administration and had increased cocaine infusions in the post-LgA ShA phase. The LoS+B group self-administered less cocaine throughout the entire LgA period compared to the LoS+Sal or HiS groups. Baclofen attenuated reinstatement of cocaine seeking in both the HiS and LoS rats with no phenotype differences. Baclofen had opposite effects on cocaine intake in HiS and LoS rats during escalation; HiS increased and LoS decreased intake. These results suggest that treatment effects might vary with individual differences (HiS vs. LoS) and the phase of drug-motivated behavior that is modeled. PMID:21924281

Effects of Diclofenac, L-NAME, L-Arginine, and Pentadecapeptide BPC 157 on Gastrointestinal, Liver, and Brain Lesions, Failed Anastomosis, and Intestinal Adaptation Deterioration in 24 Hour-Short-Bowel Rats.

PubMed

Lojo, Nermin; Rasic, Zarko; Zenko Sever, Anita; Kolenc, Danijela; Vukusic, Darko; Drmic, Domagoj; Zoricic, Ivan; Sever, Marko; Seiwerth, Sven; Sikiric, Predrag

2016-01-01

Stable gastric pentadecapeptide BPC 157 was previously used to ameliorate wound healing following major surgery and counteract diclofenac toxicity. To resolve the increasing early risks following major massive small bowel resectioning surgery, diclofenac combined with nitric oxide (NO) system blockade was used, suggesting therapy with BPC 157 and the nitric oxide synthase (NOS substrate) L-arginine, is efficacious. Immediately after anastomosis creation, short-bowel rats were untreated or administered intraperitoneal diclofenac (12 mg/kg), BPC 157 (10 μg/kg or 10 ng/kg), L-NG-nitroarginine methyl ester (L-NAME, 5 mg/kg), L-arginine (100 mg/kg) alone or combined, and assessed 24 h later. Short-bowel rats exhibited poor anastomosis healing, failed intestine adaptation, and gastrointestinal, liver, and brain lesions, which worsened with diclofenac. This was gradually ameliorated by immediate therapy with BPC 157 and L-arginine. Contrastingly, NOS-blocker L-NAME induced further aggravation and lesions gradually worsened. Specifically, rats with surgery alone exhibited mild stomach/duodenum lesions, considerable liver lesions, and severe cerebral/hippocampal lesions while those also administered diclofenac showed widespread severe lesions in the gastrointestinal tract, liver, cerebellar nuclear/Purkinje cells, and cerebrum/hippocampus. Rats subjected to surgery, diclofenac, and L-NAME exhibited the mentioned lesions, worsening anastomosis, and macro/microscopical necrosis. Thus, rats subjected to surgery alone showed evidence of deterioration. Furtheremore, rats subjected to surgery and administered diclofenac showed worse symptoms, than the rats subjected to surgery alone did. Rats subjected to surgery combined with diclofenac and L-NAME showed the worst deterioration. Rats subjected to surgery exhibited habitual adaptation of the remaining small intestine, which was markedly reversed in rats subjected to surgery and diclofenac, and those with surgery, diclofenac, and L-NAME. BPC 157 completely ameliorated symptoms in massive intestinal resection-, massive intestinal resection plus diclofenac-, and massive intestinal resection plus diclofenac plus L-NAME-treated short bowel rats that presented with cyclooxygenase (COX)-NO-system inhibition. L-arginine ameliorated only L-NAME-induced aggravation of symptoms in rats subjected to massive intestinal resection and administered diclofenac plus L-NAME.

Effects of Diclofenac, L-NAME, L-Arginine, and Pentadecapeptide BPC 157 on Gastrointestinal, Liver, and Brain Lesions, Failed Anastomosis, and Intestinal Adaptation Deterioration in 24 Hour-Short-Bowel Rats

PubMed Central

Lojo, Nermin; Rasic, Zarko; Zenko Sever, Anita; Kolenc, Danijela; Vukusic, Darko; Drmic, Domagoj; Zoricic, Ivan; Sever, Marko; Seiwerth, Sven; Sikiric, Predrag

2016-01-01

Stable gastric pentadecapeptide BPC 157 was previously used to ameliorate wound healing following major surgery and counteract diclofenac toxicity. To resolve the increasing early risks following major massive small bowel resectioning surgery, diclofenac combined with nitric oxide (NO) system blockade was used, suggesting therapy with BPC 157 and the nitric oxide synthase (NOS substrate) L-arginine, is efficacious. Immediately after anastomosis creation, short-bowel rats were untreated or administered intraperitoneal diclofenac (12 mg/kg), BPC 157 (10 μg/kg or 10 ng/kg), L-NG-nitroarginine methyl ester (L-NAME, 5 mg/kg), L-arginine (100 mg/kg) alone or combined, and assessed 24 h later. Short-bowel rats exhibited poor anastomosis healing, failed intestine adaptation, and gastrointestinal, liver, and brain lesions, which worsened with diclofenac. This was gradually ameliorated by immediate therapy with BPC 157 and L-arginine. Contrastingly, NOS-blocker L-NAME induced further aggravation and lesions gradually worsened. Specifically, rats with surgery alone exhibited mild stomach/duodenum lesions, considerable liver lesions, and severe cerebral/hippocampal lesions while those also administered diclofenac showed widespread severe lesions in the gastrointestinal tract, liver, cerebellar nuclear/Purkinje cells, and cerebrum/hippocampus. Rats subjected to surgery, diclofenac, and L-NAME exhibited the mentioned lesions, worsening anastomosis, and macro/microscopical necrosis. Thus, rats subjected to surgery alone showed evidence of deterioration. Furtheremore, rats subjected to surgery and administered diclofenac showed worse symptoms, than the rats subjected to surgery alone did. Rats subjected to surgery combined with diclofenac and L-NAME showed the worst deterioration. Rats subjected to surgery exhibited habitual adaptation of the remaining small intestine, which was markedly reversed in rats subjected to surgery and diclofenac, and those with surgery, diclofenac, and L-NAME. BPC 157 completely ameliorated symptoms in massive intestinal resection-, massive intestinal resection plus diclofenac-, and massive intestinal resection plus diclofenac plus L-NAME-treated short bowel rats that presented with cyclooxygenase (COX)-NO-system inhibition. L-arginine ameliorated only L-NAME-induced aggravation of symptoms in rats subjected to massive intestinal resection and administered diclofenac plus L-NAME. PMID:27627764

Effect of Mucuna pruriens (Linn.) on sexual behavior and sperm parameters in streptozotocin-induced diabetic male rat.

PubMed

Suresh, Sekar; Prakash, Seppan

2012-12-01

Sexual dysfunction is one of the major secondary complications in the diabetic. Mucuna pruriens, a leguminous plant identified for its antidiabetic, aphrodisiac, and improving fertility properties, has been the choice of Indian traditional medicine. Objective of the present study was to analyze the efficacy of M. pruriens on male sexual behavior and sperm parameters in long-term hyperglycemic male rats. Male albino rats were divided as group I control, group II diabetes induced (streptozotocin [STZ] 60 mg/kg of body weight (b.w.) in 0.1 M citrate buffer), group III diabetic rats administered with 200 mg/kg b.w. of ethanolic extract of M. pruriens seed, group IV diabetic rats administered with 5 mg/kg b.w. of sildenafil citrate (SC), group V administered with 200 mg/kg b.w. of extract, and group VI administered with 5 mg/kg b.w. of SC. M. pruriens and SC were administered in single oral dosage per day for a period of 60 days. The animals were subjected to mating behavior analyses, libido, test of potency, and epididymal sperms were analyzed. The mating behavior, libido, test of potency, along with epididymal sperms were studied. The study showed significant reduction in sexual behavior and sperm parameters in group II. Daily sperm production (DSP) and levels of follicular stimulating hormone, luteinizing hormone, and testosterone were significantly reduced in group II, whereas the animals with diabetes administered with seed extract of M. pruriens (group III) showed significant improvement in sexual behavior, libido and potency, sperm parameters, DSP, and hormonal levels when compared to group II. The present work reveals the potential efficacy of ethanolic seed extract of M. pruriens to improve male sexual behavior with androgenic and antidiabetic effects in the STZ-induced diabetic male rats. This study supports the usage of M. pruriens in the Indian system of medicine as sexual invigorator in diabetic condition and encourages performing similar study in men. © 2010 International Society for Sexual Medicine.

Guaifenesin enhances the analgesic potency of ibuprofen, nimesulide and celecoxib in mice.

PubMed

Sliva, Jiri; Dolezal, Tomas; Sykora, David; Vosmanska, Magda; Krsiak, Miloslav

2009-01-01

Previously, we found that guaifenesin enhances analgesia induced by paracetamol. The aim of the present study was to determine whether guaifenesin is able to also increase analgesic activity in the non-steroid anti-inflammatory drugs ibuprofen, nimesulide and celecoxib. In addition we investigated the influence of guaifenesin on plasma levels of nimesulide. A model of visceral pain consisting of intraperitoneal injection of acetic acid (writhing test) was used. Levels of nimesulide in plasma were measured by HPLC. All drugs were given orally and tested in mice. Guaifenesin alone did not produce any antinociceptive effect. Simultaneous administration of guaifenesin (200 mg/kg) and subanalgesic doses of ibuprofen (10 and 30 mg/kg), nimesulide (10 and 20 mg/kg) or celecoxib (1 and 5 mg/kg) resulted in a significant antinociceptive effects. The plasma levels of nimesulide were significantly higher in combination with guaifenesin at 30, 60 and 90 min after oral administration in comparison to nimesulide monotherapy. The present results suggest that guaifenesin might enhance the analgesic activity of various non-steroidal anti-inflammatory drugs.

The effects of chronic testosterone administration on body weight, food intake, and adipose tissue are changed by estrogen treatment in female rats.

PubMed

Iwasa, Takeshi; Matsuzaki, Toshiya; Yano, Kiyohito; Yanagihara, Rie; Tungalagsuvd, Altankhuu; Munkhzaya, Munkhsaikhan; Mayila, Yiliyasi; Kuwahara, Akira; Irahara, Minoru

2017-07-01

In females, estrogens play pivotal roles in preventing excess body weight (BW) gain. On the other hand, the roles of androgens in female BW, appetite, and energy metabolism have not been fully examined. We hypothesized that androgens' effects on food intake (FI) and BW regulation change according to the estrogens' levels. To evaluate this hypothesis, the effects of chronic testosterone administration in ovariectomized (OVX) female rats with or without estradiol supplementation were examined in this study. Chronic testosterone administration decreased BW, FI, white adipose tissue (WAT) weight, and adipocyte size in OVX rats, whereas it increased BW, WAT weight, and adipocyte size in OVX with estradiol-administered rats. In addition, chronic testosterone administration increased hypothalamic CYP19a1 mRNA levels in OVX rats, whereas it did not alter CYP19a1 mRNA levels in OVX with estradiol-administered rats, indicating that conversion of testosterone to estrogens in the hypothalamus may be activated in testosterone-administered OVX rats. Furthermore, chronic testosterone administration decreased hypothalamic TNF-α mRNA levels in OVX rats, whereas it increased hypothalamic IL-1β mRNA levels in OVX with estradiol-administered rats. On the other hand, IL-1β and TNF-α mRNA levels in visceral and subcutaneous WAT and liver were not changed by chronic testosterone administration in both groups. These data indicate that the effects of chronic testosterone administration on BW, FI, WAT weight, and adipocyte size were changed by estradiol treatment in female rats. Testosterone has facilitative effects on BW gain, FI, and adiposity under the estradiol-supplemented condition, whereas it has inhibitory effects in the non-supplemented condition. Differences in the responses of hypothalamic factors, such as aromatase and inflammatory cytokines, to testosterone might underlie these opposite effects. Copyright © 2017 Elsevier Inc. All rights reserved.

DELAYED PREPUTIAL SEPARATION (PPS) AND SP22 MEASUREMENT IN RATS ADMINISTERED BROMOCHLOROACETIC ACID (BCA) IN DRINKING WATER

EPA Science Inventory

Reproductive effects of BCA were determined in a dose range finding study (DRFS) and definitive two-generational study. Adult male and female CD� (SD) rats were administered BCA in drinking water for two weeks in the DRFS (10/sex/group) and ten weeks in the definitive study (25/s...

Effect of early preoperative 5-fluorouracil on the integrity of colonic anastomoses in rats

PubMed Central

Ozel, Leyla; Ozel, M Sefa; Toros, Ahmet Burak; Kara, Melih; Ozkan, Kemal Sırrı; Tellioglu, Gurkan; Krand, Osman; Koyuturk, Meral; Berber, Ibrahim

2009-01-01

AIM: To determine the effect of chemotherapy on wound healing by giving early preoperative 5-fluorouracil (5-FU) to rats with colonic anastomoses. METHODS: Sixty Albino-Wistar male rats (median weight, 235 g) were used in this study. The rats were fed with standard laboratory food and given tap water ad libitum. The animals were divided into three groups: Group 1: Control group (chemotherapy was not administered), Group 2: Intraperitoneally (IP) administered 5-FU group (chemotherapy was administered IP to animals at a dose of 20 mg/kg daily during the 5 d preceeding surgery), Group 3: Intravenously (IV) administered 5-FU group. Chemotherapy was administered via the penil vein, using the same dosing scheme and duration as the second group. After a 3-d rest to minimize the side effects of chemotherapy, both groups underwent surgery. One centimeter of colon was resected 2 cm proximally from the peritoneal reflection, then sutured intermittently and subsequently end-to-end anastomosed. In each group, half the animals were given anaesthesia on the 3rd postoperative (PO) day and the other half on the 7th PO day, for in vivo analytic procedures. The abdominal incisions in the rats were dissected, all the new and old anastomotic segments were clearly seen and bursting pressures of each anastomotic segment, tissue hydroxyproline levels and DNA content were determined to assess the histologic tissue repair process. RESULTS: When the IV group was compared with the IP group, bursting pressures of the anastomotic segments on the 3rd and 7th PO days, were found to be significantly decreased, hydroxyproline levels at the anastomotic segment on the 7th PO day were significantly decreased (P < 0.01). CONCLUSION: In this study, we conclude that early preoperative 5-FU, administered IV, negatively affects wound healing. However, IP administered 5-FU does not negatively affect wound healing. PMID:19725150

Age-dependent effects of systemic administration of oxytetracycline on the viscoelastic properties of rat tail tendons as a mechanistic basis for pharmacological treatment of flexural limb deformities in foals.

PubMed

Wintz, Leslie R; Lavagnino, Michael; Gardner, Keri L; Sedlak, Aleksa M; Arnoczky, Steven P

2012-12-01

To describe the effect of systemically administered oxytetracycline on the viscoelastic properties of rat tail tendon fascicles (TTfs) to provide a mechanistic rationale for pharmacological treatment of flexural limb deformities in foals. TTfs from ten 1-month-old and ten 6-month-old male Sprague-Dawley rats. 5 rats in each age group were administered oxytetracycline (50 mg/kg, IP, q 24 h) for 4 days. The remaining 5 rats in each age group served as untreated controls. Five days after initiation of oxytetracycline treatment, TTfs were collected and their viscoelastic properties were evaluated via a stress-relaxation protocol. Maximum modulus and equilibrium modulus were compared via a 2-way ANOVA. Collagen fibril size, density, and orientation in TTfs were compared between treated and control rats. Viscoelastic properties were significantly decreased in TTfs from 1-month-old oxytetracycline-treated rats, compared with those in TTfs from 1-month-old control rats. Oxytetracycline had no effect on the viscoelastic properties of TTfs from 6-month-old rats. Collagen fibril size, density, and orientation in TTfs from 1-month-old rats did not differ between oxytetracycline-treated and control rats. Results confirmed that systemically administered oxytetracycline decreased the viscoelastic properties of TTfs from 1-month-old rats but not those of TTfs from 6-month-old rats. The decrease in viscoelastic properties associated with oxytetracycline treatment does not appear to be caused by altered collagen fibril diameter or organization. The age-dependent effect of oxytetracycline on the viscoelastic properties of tendons may be related to its effect on the maturation of the extracellular matrix of developing tendons.

The spermatogenic and ovogenic effects of chronically administered Shilajit to rats.

PubMed

Park, Jeong-Sook; Kim, Gee-Young; Han, Kun

2006-10-11

This study examined the possibility of using Shilajit as a fertility agent. The effects of Shilajit on spermatogenesis and ovogenesis were studied using male and female rats. Shilajit was administered orally to 7-week-old rats over a 6-week period. In the male rats, the number of sperms in the testes and epididymides was significant higher than in the control. A histological examination revealed an apparent increase in the number of seminiferous tubular cell layers in the testes of the treated rats. However, there were no significant differences in the weights of heart, spleen, liver, kidney, brain, testes and epididymides. In the female rats, the effect of Shilajit was estimated by the ovulation inducing activity. Over a 5-day, ovulation was induced in seven out of nine rats in the Shilajit administration group and in three out of nine rats in the control. It was estimated that Shilajit had both a spermiogenic and ovogenic effect in mature rats.

[Non-steroidal anti-inflammatory drug induced gastropathy and preventive effects of teprenone on the gastropathy in rats].

PubMed

Ma, Juan; Yuan, Gang; Chen, Min-hu

2006-10-31

To construct the model of non-steroidal anti-inflammatory drug (NSAID) induced gastropathy and observe the preventive effects of Teprenone on it in rats. Ninety-one male Sprague-Dawley (SD) rats were divided into normal saline group, model group (I) and prophylaxis group (II). Group I includes four subgroups (Ia, Ib, Ic, Id) treated by indomethacin (5 mgxkg(-1)xd(-1)), combination of indomethacin (5 mgxkg(-1)xd(-1)) and prednisone (10 mgxkg(-1)xd(-1)), celecoxib (100 mgxkg(-1)xd(-1)) and combination of celecoxib (100 mgxkg(-1)xd(-1)) and prednisone (10 mgxkg(-1)xd(-1)) respectively. Group II also includes four subgroups (IIa, IIb, IIc, IId) pretreated by teprenone (12 mgxkg(-1)xd(-1)) compared with group I. Lesion index (LI), pathohistology index, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) mRNA detected by RT-PCR were observed after 4 days. Compared with normal saline group, LI (11.00 (1.00 - 22.5), 8.50 (0.75 - 14.50), 11.00 (3.50 - 14.75), P < 0.01) of three model subgroups (Ia, Ib, Id), and pathohistology indexes (1.00 (0.00 - 1.25), 2.00 (0.00 - 5.00), 1.00 (0.00 - 3.00), 2.00 (0.00 - 2.00), P < 0.01) of the whole model group increased significantly (P < 0.05). Compared with corresponding model subgroups, LIs (0.00 (0.00 - 0.25), 1.00 (0.00 - 1.50), 0.00 (0.00 - 0.00), 0.00 (0.00 - 1.00), P < 0.05) and pathohistology indexes (0.00 (0.00 - 0.00), 0.00 (0.00 - 0.50), 0.00 (0.00 - 0.25), 0.00 (0.00 - 0.50), P < 0.05) of prophylaxis subgroups were decreased significantly (P < 0.05). There was obvious difference in LI between Ic and Ia as well as between Ic and Id (P < 0.05). Compared with normal saline group, COX-1 mRNA expression of the groups (Ia, Ib, Id, IIa, IIb and IId) increased (0.384 +/- 0.031, 0.354 +/- 0.026, 0.753 +/- 0.049, 0.366 +/- 0.035, 0.381 +/- 0.036, 0.766 +/- 0.401, P < 0.001) while COX-2 mRNA expression of the above groups decreased statistically (0.483 +/- 0.056, 0.448 +/- 0.046, 0.461 +/- 0.050, 0.479 +/- 0.032, P < 0.001). These results suggested gastric mucosa lesions could be resulted from COX-2 inhibitors but better than those induced by traditional NSAID. Prednisone could promote the risk in NSAID induced gastropathy. In addition to COX-1 inhibition, other factors might also involved in NSAID induced gastropathy. Teprenone could prevented from NSAID induced gastropathy but the actions might be not associated with COXs.

The Metabotropic Glutamate 2/3 Receptor Agonist LY379268 Blocked Nicotine-Induced Increases in Nucleus Accumbens Shell Dopamine only in the Presence of a Nicotine-Associated Context in Rats

PubMed Central

D'Souza, Manoranjan S; Liechti, Matthias E; Ramirez-Niño, Ana M; Kuczenski, Ronald; Markou, Athina

2011-01-01

The metabotropic glutamate 2/3 (mGlu2/3) receptor agonist LY379268 ([−]-2-oxa-4-aminobicyclo [3.1.0] hexane-4,6-dicarboxylate) attenuates both nicotine self-administration and cue-induced nicotine seeking in rats. In this study, the effects of LY379268 (1 mg/kg) or saline pretreatment on nicotine-induced increases in nucleus accumbens (NAcc) shell dopamine were evaluated using in vivo microdialysis under different experimental conditions: (i) nicotine (0.4 mg/kg, base) was experimenter-administered subcutaneously to nicotine-naïve rats; (ii) nicotine was experimenter-administered either subcutaneously (0.4 mg/kg) or by a single experimenter-administered infusion (0.06 mg/kg, base) in rats with a history of nicotine self-administration (nicotine experienced) in the absence of a nicotine-associated context (ie, context and cues associated with nicotine self-administration); (iii) nicotine (0.06 mg/kg) was self-administered or experimenter-administered in nicotine-experienced rats in the presence of a nicotine-associated context. In saline-pretreated nicotine-naïve and nicotine-experienced rats, nicotine increased NAcc shell dopamine regardless of the context used for testing. Interestingly, LY379268 pretreatment blocked nicotine-induced increases in NAcc shell dopamine in nicotine-experienced rats only when tested in the presence of a nicotine-associated context. LY379268 did not block nicotine-induced increases in NAcc shell dopamine in nicotine-naïve or -experienced rats tested in the absence of a nicotine-associated context. These intriguing findings suggest that activation of mGlu2/3 receptors negatively modulates the combined effects of nicotine and nicotine-associated contexts/cues on NAcc dopamine. Thus, these data highlight a critical role for mGlu2/3 receptors in context/cue-induced drug-seeking behavior and suggest a neurochemical mechanism by which mGlu2/3 receptor agonists may promote smoking cessation by preventing relapse induced by the combination of nicotine and nicotine-associated contexts and cues. PMID:21654734

Point: From animal models to prevention of colon cancer. Systematic review of chemoprevention in min mice and choice of the model system.

PubMed

Corpet, Denis E; Pierre, Fabrice

2003-05-01

The Apc(Min/+) mouse model and the azoxymethane (AOM) rat model are the main animal models used to study the effect of dietary agents on colorectal cancer. We reviewed recently the potency of chemopreventive agents in the AOM rat model (D. E. Corpet and S. Tache, Nutr. Cancer, 43: 1-21, 2002). Here we add the results of a systematic review of the effect of dietary and chemopreventive agents on the tumor yield in Min mice. The review is based on the results of 179 studies from 71 articles and is displayed also on the internet http://corpet.net/min.(2) We compared the efficacy of agents in the Min mouse model and the AOM rat model, and found that they were correlated (r = 0.66; P < 0.001), although some agents that afford strong protection in the AOM rat and the Min mouse small bowel increase the tumor yield in the large bowel of mutant mice. The agents included piroxicam, sulindac, celecoxib, difluoromethylornithine, and polyethylene glycol. The reason for this discrepancy is not known. We also compare the results of rodent studies with those of clinical intervention studies of polyp recurrence. We found that the effect of most of the agents tested was consistent across the animal and clinical models. Our point is thus: rodent models can provide guidance in the selection of prevention approaches to human colon cancer, in particular they suggest that polyethylene glycol, hesperidin, protease inhibitor, sphingomyelin, physical exercise, epidermal growth factor receptor kinase inhibitor, (+)-catechin, resveratrol, fish oil, curcumin, caffeate, and thiosulfonate are likely important preventive agents.

Vascular brain-derived neurotrophic factor pathway in rats with adjuvant-induced arthritis: Effect of anti-rheumatic drugs.

PubMed

Pedard, Martin; Quirié, Aurore; Totoson, Perle; Verhoeven, Frank; Garnier, Philippe; Tessier, Anne; Demougeot, Céline; Marie, Christine

2018-05-02

In rheumatoid arthritis, the control of both disease activity and standard cardiovascular (CV) risk factors is expected to attenuate the increased CV risk. Evidence that brain-derived neurotrophic factor (BDNF) plays a role in vascular biology led us to investigate the vascular BDNF pathway in arthritis rats as well as the interaction between endothelial nitric oxide (NO) and BDNF production. The aortic BDNF pathway was studied in rats with adjuvant-induced arthritis, (AIA) using Western blot and immunohistochemical analysis. Control of arthritis score was achieved by administration (for 3 weeks) of an equipotent dosage of etanercept, prednisolone, methotrexate, celecoxib or diclofenac. Aortas were exposed to an NO donor or an NO synthase inhibitor and vasoreactivity experiments were performed using LM22A-4 as a TrkB agonist. Vascular BDNF and full length tropomyosin-related kinase B receptor (TrkB-FL) were higher in AIA than in control rats. These changes coincided with decreased endothelial immunoreactivity in BDNF and pTrkB tyr816 and were disconnected from arthritis score. Among anti-rheumatic drugs, only prednisolone and methotrexate prevented AIA-induced vascular BDNF loss. The effect of AIA on aortic BDNF levels was reversed by an NO donor and reproduced by an NOS inhibitor. Finally, LM22A-4 induced both NO-dependent vasodilation and phosphorylation of endothelial NO synthase at serine 1177. Our study identified changes in the BDNF/TrkB pathway as a disease activity-independent component of AIA-associated changes in endothelial phenotype. It provides new perspectives in the understanding and management of the high CV risk reported in rheumatoid arthritis. Copyright © 2018 Elsevier B.V. All rights reserved.

Novel Combination of Sorafenib and Celecoxib Provides Synergistic Anti-Proliferative and Pro-Apoptotic Effects in Human Liver Cancer Cells

PubMed Central

Lampiasi, Nadia; Cusimano, Antonella; Azzolina, Antonina; McCubrey, James A.; Montalto, Giuseppe

2013-01-01

Molecular targeted therapy has shown promise as a treatment for advanced hepatocellular carcinoma (HCC). Sorafenib, a multikinase inhibitor, recently received FDA approval for the treatment of advanced HCC. However, although sorafenib is well tolerated, concern for its safety has been expressed. Celecoxib (Celebrex®) is a selective cyclooxygenase-2 (COX-2) inhibitor which exhibits antitumor effects in human HCC cells. The present study examined the interaction between celecoxib and sorafenib in two human liver tumor cell lines HepG2 and Huh7. Our data showed that each inhibitor alone reduced cell growth and the combination of celecoxib with sorafenib synergistically inhibited cell growth and increased apoptosis. To better understand the molecular mechanisms underlying the synergistic antitumor activity of the combination, we investigated the expression profile of the combination-treated liver cancer cell lines using microarray analysis. Combination treatment significantly altered expression levels of 1,986 and 2,483 transcripts in HepG2 and Huh7 cells, respectively. Genes functionally involved in cell death, signal transduction and regulation of transcription were predominantly up-regulated, while genes implicated in metabolism, cell-cycle control and DNA replication and repair were mainly down-regulated upon treatment. However, combination-treated HCC cell lines displayed specificity in the expression and activity of crucial factors involved in hepatocarcinogenesis. The altered expression of some of these genes was confirmed by semi-quantitative and quantitative RT-PCR and by Western blotting. Many novel genes emerged from our transcriptomic analyses, and further functional analyses may determine whether these genes can serve as potential molecular targets for more effective anti-HCC strategies. PMID:23776502

Intradiscal application of a PCLA-PEG-PCLA hydrogel loaded with celecoxib for the treatment of back pain in canines: What's in it for humans?

PubMed

Tellegen, Anna R; Willems, Nicole; Beukers, Martijn; Grinwis, Guy C M; Plomp, Saskia G M; Bos, Clemens; van Dijk, Maarten; de Leeuw, Mike; Creemers, Laura B; Tryfonidou, Marianna A; Meij, Björn P

2018-03-01

Chronic low back pain is a common clinical problem in both the human and canine population. Current pharmaceutical treatment often consists of oral anti-inflammatory drugs to alleviate pain. Novel treatments for degenerative disc disease focus on local application of sustained released drug formulations. The aim of this study was to determine safety and feasibility of intradiscal application of a poly(ε-caprolactone-co-lactide)-b-poly(ethylene glycol)-bpoly(ε-caprolactone-co-lactide) PCLA-PEG-PCLA hydrogel releasing celecoxib, a COX-2 inhibitor. Biocompatibility was evaluated after subcutaneous injection in mice, and safety of intradiscal injection of the hydrogel was evaluated in experimental dogs with early spontaneous intervertebral disc (IVD) degeneration. COX-2 expression was increased in IVD samples surgically obtained from canine patients, indicating a role of COX-2 in clinical IVD disease. Ten client-owned dogs with chronic low back pain related to IVD degeneration received an intradiscal injection with the celecoxib-loaded hydrogel. None of the dogs showed adverse reactions after intradiscal injection. The hydrogel did not influence magnetic resonance imaging signal at long-term follow-up. Clinical improvement was achieved by reduction of back pain in 9 of 10 dogs, as was shown by clinical examination and owner questionnaires. In 3 of 10 dogs, back pain recurred after 3 months. This study showed the safety and effectiveness of intradiscal injections in vivo with a thermoresponsive PCLA-PEG-PCLA hydrogel loaded with celecoxib. In this set-up, the dog can be used as a model for the development of novel treatment modalities in both canine and human patients with chronic low back pain. Copyright © 2017 John Wiley & Sons, Ltd.

Chemoprevention of Head and Neck Cancer by Simultaneous Blocking of Epidermal Growth Factor Receptor and Cyclooxygenase-2 Signaling Pathways: Preclinical and Clinical Studies

PubMed Central

Shin, Dong M.; Zhang, Hongzheng; Saba, Nabil; Chen, Amy; Nannapaneni, Sreenivas; Amin, A.R.M. Ruhul; Müller, Susan; Lewis, Melinda; Sica, Gabriel; Kono, Scott; Brandes, Johann C.; Grist, William; Moreno-Williams, Rachel; Beitler, Jonathan J.; Thomas, Sufi M.; Chen, Zhengjia; Shin, Hyung Ju C.; Grandis, Jennifer R.; Khuri, Fadlo R.; Chen, Zhuo Georgia

2013-01-01

Purpose We investigated the efficacy and underlying molecular mechanism of a novel chemopreventive strategy combining epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with cyclooxygenase-2 inhibitor (COX-2I). Experimental Design We examined the inhibition of tumor cell growth by combined EGFR-TKI (erlotinib) and COX-2I (celecoxib) treatment using head and neck cancer (HNC) cell lines and a preventive xenograft model. We studied the antiangiogenic activity of these agents and examined the affected signaling pathways by immunoblotting analysis in tumor cell lysates and immunohistochemistry (IHC) and enzyme immunoassay (EIA) analyses on the mouse xenograft tissues and blood, respectively. Biomarkers in these signaling pathways were studied by IHC, EIA, and an antibody array analysis in samples collected from participants in a phase I chemoprevention trial of erlotinib and celecoxib. Results The combined treatment inhibited HNC cell growth significantly more potently than either single agent alone in cell line and xenograft models, and resulted in greater inhibition of cell cycle progression at G1 phase than either single drug. The combined treatment modulated the EGFR and mTOR signaling pathways. A phase I chemoprevention trial of combined erlotinib and celecoxib revealed an overall pathologic response rate of 71% at time of data analysis. Analysis of tissue samples from participants consistently showed downregulation of EGFR, pERK and pS6 levels after treatment, which correlated with clinical response. Conclusion Treatment with erlotinib combined with celecoxib offers an effective chemopreventive approach through inhibition of EGFR and mTOR pathways, which may serve as potential biomarkers to monitor the intervention of this combination in the clinic. PMID:23422093

Treatment of Bartter syndrome. Unsolved issue.

PubMed

Nascimento, Carla Lessa Pena; Garcia, Cecilia Lopes; Schvartsman, Benita Galassi Soares; Vaisbich, Maria Helena

2014-01-01

To describe the results of a long-term follow-up of Bartter syndrome patients treated with different drugs. Patients were diagnosed according to clinical and laboratory data. Treatment protocol was potassium supplementation, sodium, spironolactone, and non-steroidal anti-inflammatory drug. Patients who developed proteinuria were converted to angiotensin conversion enzyme inhibitor. The variables evaluated for each drug were Z-score for weight and stature, proteinuria, creatinine clearance, gastrointestinal complaints, amount of potassium supplementation, serum potassium and bicarbonate levels, and findings of upper digestive endoscopy. 20 patients were included. Follow-up was 10.1 ± 5.2 years. 17 patients received indomethacin for 5.9 ± 5.3 years; 19 received celecoxib, median of 35 months; and five received enalapril, median of 23 months. During indomethacin, a statistically significant increase was observed in the Z-score for stature and weight, without a change in the creatinine clearance. Seven of 17 patients had gastrointestinal symptoms, and upper digestive endoscopy evidenced gastritis in three patients and gastric ulcer in four patients. During celecoxib use, a significant increase was detected in the Z-score for stature and weight and a reduction of hyperfiltration; seven patients presented gastrointestinal symptoms, and upper digestive endoscopy evidenced mild gastritis in three. During enalapril use, no significant changes were observed in the Z-score for stature, weight and creatinine clearance. The conversion to enalapril resulted in a significant reduction in proteinuria. The authors suggest starting the treatment with celecoxib, and replacing by ACEi if necessary, monitoring the renal function. The safety and efficacy of celecoxib need to be assessed in larger controlled studies. Copyright © 2014 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

Combination of an agonistic anti-CD40 monoclonal antibody and the COX-2 inhibitor celecoxib induces anti-glioma effects by promotion of type-1 immunity in myeloid cells and T-cells

PubMed Central

Kosaka, Akemi; Ohkuri, Takayuki

2014-01-01

Malignant gliomas are heavily infiltrated by immature myeloid cells that mediate immuno-suppression. Agonistic CD40 monoclonal antibody (mAb) has been shown to activate myeloid cells and promote antitumor immunity. Our previous study has also demonstrated blockade of cyclooxygenase-2 (COX-2) reduces immunosuppressive myeloid cells, thereby suppressing glioma development in mice. We therefore hypothesized that a combinatory strategy to modulate myeloid cells via two distinct pathways, i.e., CD40/CD40L stimulation and COX-2 blockade, would enhance anti-glioma immunity. We used three different mouse glioma models to evaluate therapeutic effects and underlying mechanisms of a combination regimen with an agonist CD40 mAb and the COX-2 inhibitor celecoxib. Treatment of glioma-bearing mice with the combination therapy significantly prolonged survival compared with either anti-CD40 mAb or celecoxib alone. The combination regimen promoted maturation of CD11b+ cells in both spleen and brain, and enhanced Cxcl10 while suppressing Arg1 in CD11b+Gr-1+ cells in the brain. Anti-glioma activity of the combination regimen was T-cell dependent because depletion of CD4+ and CD8+ cells in vivo abrogated the anti-glioma effects. Furthermore, the combination therapy significantly increased the frequency of CD8+ T-cells, enhanced IFN-γ-production and reduced CD4+CD25+Foxp3+ T regulatory cells in the brain, and induced tumor-antigen-specific T-cell responses in lymph nodes. Our findings suggest that the combination therapy of anti-CD40 mAb with celecoxib enhances anti-glioma activities via promotion of type-1 immunity both in myeloid cells and T-cells. PMID:24878890

Quality by design approach for developing chitosan-Ca-alginate microspheres for colon delivery of celecoxib-hydroxypropyl-β-cyclodextrin-PVP complex.

PubMed

Mennini, N; Furlanetto, S; Cirri, M; Mura, P

2012-01-01

The aim of the present work was to develop a new multiparticulate system, designed for colon-specific delivery of celecoxib for both systemic (in chronotherapic treatment of arthritis) and local (in prophylaxis of colon carcinogenesis) therapy. The system simultaneously benefits from ternary complexation with hydroxypropyl-β-cyclodextrin and PVP (polyvinylpyrrolidone), to increase drug solubility, and vectorization in chitosan-Ca-alginate microspheres, to exploit the colon-specific carrier properties of these polymers. Statistical experimental design was employed to investigate the combined effect of four formulation variables, i.e., % of alginate, CaCl₂, and chitosan and time of cross-linking on microsphere entrapment efficiency (EE%) and drug amount released after 4h in colonic medium, considered as the responses to be optimized. Design of experiment was used in the context of Quality by Design, which requires a multivariate approach for understanding the multifactorial relationships among formulation parameters. Doehlert design allowed for defining a design space, which revealed that variations of the considered factors had in most cases an opposite influence on the responses. Desirability function was used to attain simultaneous optimization of both responses. The desired goals were achieved for both systemic and local use of celecoxib. Experimental values obtained from the optimized formulations were in both cases very close to the predicted values, thus confirming the validity of the generated mathematical model. These results demonstrated the effectiveness of the proposed jointed use of drug cyclodextrin complexation and chitosan-Ca-alginate microsphere vectorization, as well as the usefulness of the multivariate approach for the preparation of colon-targeted celecoxib microspheres with optimized properties. Copyright © 2011 Elsevier B.V. All rights reserved.

Effects of non-steroidal anti-inflammatory drug treatments on cognitive decline vary by phase of pre-clinical Alzheimer disease: findings from the randomized controlled Alzheimer's Disease Anti-inflammatory Prevention Trial.

PubMed

Leoutsakos, Jeannie-Marie S; Muthen, Bengt O; Breitner, John C S; Lyketsos, Constantine G

2012-04-01

We examined the effects of non-steroidal anti-inflammatory drugs on cognitive decline as a function of phase of pre-clinical Alzheimer disease. Given recent findings that cognitive decline accelerates as clinical diagnosis is approached, we used rate of decline as a proxy for phase of pre-clinical Alzheimer disease. We fit growth mixture models of Modified Mini-Mental State (3MS) Examination trajectories with data from 2388 participants in the Alzheimer's Disease Anti-inflammatory Prevention Trial and included class-specific effects of naproxen and celecoxib. We identified three classes: "no decline", "slow decline", and "fast decline", and examined the effects of celecoxib and naproxen on linear slope and rate of change by class. Inclusion of quadratic terms improved fit of the model (-2 log likelihood difference: 369.23; p < 0.001) but resulted in reversal of effects over time. Over 4 years, participants in the slow-decline class on placebo typically lost 6.6 3MS points, whereas those on naproxen lost 3.1 points (p-value for difference: 0.19). Participants in the fast-decline class on placebo typically lost 11.2 points, but those on celecoxib first declined and then gained points (p-value for difference from placebo: 0.04), whereas those on naproxen showed a typical decline of 24.9 points (p-value for difference from placebo: <0.0001). Our results appeared statistically robust but provided some unexpected contrasts in effects of different treatments at different times. Naproxen may attenuate cognitive decline in slow decliners while accelerating decline in fast decliners. Celecoxib appeared to have similar effects at first but then attenuated change in fast decliners. Copyright © 2011 John Wiley & Sons, Ltd.

CARCINOGENICITY OF BROMODICHLOROMETHANE ADMINISTERED IN DRINKING WATER TO MALE F344/N RATS AND B6C3F1 MICE

EPA Science Inventory

A life-time exposure study was conducted to assess the carcinogenicity of bromodichloromethane (BDCM) administered in the drinking water to male F344/N rats and B6C3F1 mice. Mouse: Target concentrations of BDCM (dissolved in deionized water containing 0.25% emulphor) were 0.05, ...

Flavocoxid Inhibits Phospholipase A2, Peroxidase Moieties of the Cyclooxygenases (COX), and 5-Lipoxygenase, Modifies COX-2 Gene Expression, and Acts as an Antioxidant

PubMed Central

Burnett, Bruce P.; Bitto, Alessandra; Altavilla, Domenica; Squadrito, Francesco; Levy, Robert M.; Pillai, Lakshmi

2011-01-01

The multiple mechanisms of action for flavocoxid relating to arachidonic acid (AA) formation and metabolism were studied in vitro. Flavocoxid titrated into rat peritoneal macrophage cultures inhibited cellular phospholipase A2 (PLA2) (IC50 = 60 μg/mL). In in vitro enzyme assays, flavocoxid showed little anti-cyclooxygenase (CO) activity on COX-1/-2 enzymes, but inhibited the COX-1 (IC50 = 12.3) and COX-2 (IC50 = 11.3 μg/mL) peroxidase (PO) moieties as well as 5-lipoxygenase (5-LOX) (IC50 = 110 μg/mL). No detectable 5-LOX inhibition was found for multiple traditional and COX-2 selective NSAIDs. Flavocoxid also exhibited strong and varied antioxidant capacities in vitro and decreased nitrite levels (IC50 = 38 μg/mL) in rat peritoneal macrophages. Finally, in contrast to celecoxib and ibuprofen, which upregulated the cox-2 gene, flavocoxid strongly decreased expression. This work suggests that clinically favourable effects of flavocoxid for management of osteoarthritis (OA) are achieved by simultaneous modification of multiple molecular pathways relating to AA metabolism, oxidative induction of inflammation, and neutralization of reactive oxygen species (ROS). PMID:21765617

Flavocoxid inhibits phospholipase A2, peroxidase moieties of the cyclooxygenases (COX), and 5-lipoxygenase, modifies COX-2 gene expression, and acts as an antioxidant.

PubMed

Burnett, Bruce P; Bitto, Alessandra; Altavilla, Domenica; Squadrito, Francesco; Levy, Robert M; Pillai, Lakshmi

2011-01-01

The multiple mechanisms of action for flavocoxid relating to arachidonic acid (AA) formation and metabolism were studied in vitro. Flavocoxid titrated into rat peritoneal macrophage cultures inhibited cellular phospholipase A2 (PLA(2)) (IC(50) = 60 μg/mL). In in vitro enzyme assays, flavocoxid showed little anti-cyclooxygenase (CO) activity on COX-1/-2 enzymes, but inhibited the COX-1 (IC(50) = 12.3) and COX-2 (IC(50) = 11.3 μg/mL) peroxidase (PO) moieties as well as 5-lipoxygenase (5-LOX) (IC(50) = 110 μg/mL). No detectable 5-LOX inhibition was found for multiple traditional and COX-2 selective NSAIDs. Flavocoxid also exhibited strong and varied antioxidant capacities in vitro and decreased nitrite levels (IC(50) = 38 μg/mL) in rat peritoneal macrophages. Finally, in contrast to celecoxib and ibuprofen, which upregulated the cox-2 gene, flavocoxid strongly decreased expression. This work suggests that clinically favourable effects of flavocoxid for management of osteoarthritis (OA) are achieved by simultaneous modification of multiple molecular pathways relating to AA metabolism, oxidative induction of inflammation, and neutralization of reactive oxygen species (ROS).

Toxicology and carcinogenesis studies of acrylamide (CASRN 79-06-1) in F344/N rats and B6C3F1 mice (feed and drinking water studies).

PubMed

2012-07-01

Acrylamide, a water-soluble α,β-unsaturated amide, is a contaminant in baked and fried starchy foods, including french fries, potato chips, and bread, as a result of Maillard reactions involving asparagine and reducing sugars. Additional sources of acrylamide exposure include cigarettes, laboratory procedures involving polyacrylamide gels, and various occupations (e.g, monomer production and polymerization processes). Acrylamide is carcinogenic in experimental animals. To obtain data for developing quantitative risk assessments for dietary exposures to acrylamide, the Food and Drug Administration nominated acrylamide for an in-depth toxicological evaluation by the National Toxicology Program. As part of this evaluation, male and female B6C3F1/Nctr (C57BL/6N x C3H/HeN MTV-) mice and male and female F344/N Nctr rats were exposed to acrylamide (at least 99.4% pure) in drinking water for 2 years. 2-WEEK STUDY IN RATS: Groups of four male and four female F344/N rats were administered 0, 0.14, 0.35, 0.70, 1.41, 3.52, or 7.03 mM acrylamide in the drinking water (0, 10, 25, 50, 100, 250, or 500 ppm acrylamide) or 0.0, 7.4, 18.5, 37, 74, 185, or 370 mg acrylamide per kg diet for 14 days. One male rat administered 7.03 mM acrylamide in the drinking water died on day 14. Male and female rats receiving 7.03 mM acrylamide weighed 56% and 64% of controls, respectively. Male and female rats fed 370 mg acrylamide per kg diet weighed 74% and 83% of controls, respectively. Female rats receiving 3.52 mM acrylamide in drinking water and male rats fed 185 mg acrylamide per kg diet weighed 85% and 89% of controls, respectively. Rats receiving 7.03 mM acrylamide in drinking water or 370 mg acrylamide per kg diet exhibited hind-leg paralysis on day 14. Mild to moderate dilatation of the urinary bladder was observed in all rats given 370 mg acrylamide per kg diet, and in three of four male rats and all four female rats given 7.03 mM acrylamide in drinking water, and in one of four male rats given 3.52 mM acrylamide in drinking water. Mild to moderate degeneration of the germinal epithelium in the seminiferous tubules of the testes was noted microscopically in all male rats given 7.03 mM acrylamide in drinking water and in two of four male rats fed 370 mg acrylamide per kg diet. 2-WEEK STUDY IN MICE: Groups of four male and four female B6C3F1 mice were administered 0, 0.14, 0.35, 0.70, 1.41, 3.52, or 7.03 mM acrylamide in the drinking water (0, 10, 25, 50, 100, 250, or 500 ppm acrylamide) or 0.0, 7.4, 18.5, 37, 74, 185, or 370 mg acrylamide per kg diet for 14 days. None of the mice administered 7.03 mM acrylamide in the drinking water survived the 14-day study. Mice administered 7.03 mM acrylamide in the drinking water showed marked decreases in body weight (greater than 25% compared to control mice) after seven days of treatment, and two of the mice displayed hind leg paralysis. No significant adverse effects were observed in mice administered 3.52 mM acrylamide in the drinking water for 14 days. Female B6C3F1 mice given 370 mg acrylamide per kg diet for 14 days showed a modest decrease (11%) in body weight. No other significant adverse effects were observed in mice administered any dose of acrylamide in the diet. 3-MONTH STUDY IN RATS: Groups of eight male and eight female F344/N rats were administered 0.0, 0.14, 0.35, 0.70, 1.41, or 3.52 mM acrylamide in the drinking water (0, 10, 25, 50, 100, or 250 ppm acrylamide) or 0.0, 7.4, 18.5, 37, 74, or 185 mg acrylamide per kg diet for 13 weeks. After 13 weeks, male and female rats administered 3.52 mM acrylamide weighed 73% and 71% of the control rats, respectively. Male and female rats fed 185 mg acrylamide per kg diet for 13 weeks weighed 86% and 82% of the control rats, respectively. Hind-leg paralysis was observed in all rats administered 3.52 mM acrylamide in the drinking water or 185 mg acrylamide per kg diet. Four of eight female rats administered 1.41 mM acrylamide also displayed hind-leg paralysis. Radiculoneuropathy (a degenerative lesion) involving the sciatic nerve and lumbar spinal cord was observed in all male and female rats administered 3.52 mM acrylamide or 185 mg acrylamide per kg diet. A low incidence of radiculoneuropathy was also noted in female rats fed 74 mg acrylamide per kg diet. The neuronal degenerative changes were accompanied, at times, by atrophy in skeletal muscle of the hind-limb and luminal dilation of the urinary bladder. All rats treated with 3.52 mM acrylamide displayed increased hemosiderin pigment in their spleens and hyperplasia of red blood cell precursors in their bone marrow. Two of eight male rats fed 185 mg acrylamide per kg diet also had increased hemosiderin pigment in their spleens. Degeneration of the germ cells in the testes was observed in all male rats given 1.41 or 3.52 mM acrylamide, or 185 mg acrylamide per kg diet. A lower incidence of this lesion was also detected in all other doses of acrylamide in the diet. 3-MONTH STUDY IN MICE: Groups of eight male and eight female B6C3F1 mice were administered 0, 0.14, 0.35, 0.70, 1.41, or 3.52 mM acrylamide in the drinking water (0, 10, 25, 50, 100, or 250 ppm acrylamide) or 0.0, 18.5, 37, 74, 185, or 370 mg acrylamide per kg diet. After 13 weeks, the male and female mice given 3.52 mM acrylamide weighed 86% and 94% of their respective control mice; male mice administered 1.41 mM acrylamide weighed 91% of the control male mice; and male and female mice fed 370 mg acrylamide per kg diet weighed 87% and 81% of their respective control groups. Hind-limb paralysis was observed in all mice administered 3.52 mM acrylamide or 370 mg acrylamide per kg diet. Radiculoneuropathy involving the sciatic nerve, lumbar spinal cord, or both was observed in all male and female mice administered 3.52 mM acrylamide. Radiculoneuropathy, involving primarily the sciatic nerve, was also noted in one of eight female mice fed 185 mg acrylamide per kg diet and in mice fed 370 mg acrylamide per kg diet. The neuronal degenerative changes were accompanied, at times, by atrophy in skeletal muscle of the hind-limb and luminal dilation of the urinary bladder. Degeneration of the germ cells in the testes was observed in six of eight male mice given 3.52 mM acrylamide and seven of seven mice fed 370 mg acrylamide per kg diet. 2 YEAR STUDY IN RATS: Groups of 48 male and 48 female F344/N rats were administered acrylamide in the drinking water ad libitum for 2 years. Concentrations of 0.0875, 0.175, 0.35, and 0.70 mM acrylamide (6.25, 12.5, 25, and 50 ppm acrylamide) resulted in an average daily consumption of approximately 0.33, 0.66, 1.32, and 2.71 mg acrylamide per kg body weight in male F344/N rats and 0.44, 0.88, 1.84, and 4.02 mg acrylamide per kg body weight in female F344/N rats. Acrylamide had no effect upon the survival of male F344/N rats. Female F344/N rats administered 0.175, 0.35, or 0.70 mM acrylamide had decreased survival compared to control female F344/N rats. Acrylamide caused significant dose-related decreasing trends in body weight in F344/N rats. At the end of the 2 year period, male and female F344/N rats administered 0.70 mM acrylamide weighed 86% and 85% of their respective control groups. Feed consumption was generally not affected by acrylamide; water consumption in female F344/N rats was increased at later time points. In male F344/N rats, the incidence of epididymis malignant mesothelioma, combined epididymis or testicular tunica malignant mesothelioma, heart malignant incidences of schwannoma, pancreatic islets adenoma, thyroid gland follicular cell carcinoma, and combined thyroid gland follicular cell adenoma or carcinoma was increased significantly in the 0.70 mM acrylamide group. In female F344/N rats, the incidence of clitoral gland carcinoma was increased significantly in the 0.0875, 0.175, and 0.70 mM acrylamide groups. The incidence of mammary gland fibroadenoma was increased significantly at 0.175, 0.35, and 0.70 mM acrylamide. Significant increases in neoplasm incidences were also observed in oral mucosa squamous cell papilloma, combined oral mucosa or tongue squamous cell papilloma or carcinoma, combined skin fibroma, fibrosarcoma, or sarcoma, and combined thyroid gland follicular cell adenoma or carcinoma at 0.70 mM acrylamide. 2-YEAR STUDY IN MICE: Groups of 48 male and 48 female B6C3F1 mice were administered acrylamide in the drinking water ad libitum for 2 years. Concentrations of 0.0875, 0.175, 0.35, and 0.70 mM acrylamide (6.25, 12.5, 25, and 50 ppm acrylamide) resulted in average daily consumption of approximately 1.04, 2.20, 4.11, and 8.93 mg acrylamide per kg body weight in male B6C3F1 mice and 1.10, 2.23, 4.65, and 9.96 mg acrylamide per kg body weight in female B6C3F1 mice. Acrylamide caused dose-related decreasing trends in survival in B6C3F1 mice, with the survival being significantly decreased in male B6C3F1 mice administered 0.70 mM acrylamide and female B6C3F1 mice given 0.35 and 0.70 mM acrylamide. Acrylamide caused only sporadic changes in body weight in B6C3F1 mice, with the magnitude of the change never exceeding 6% of the respective control body weight. Food and water consumption was generally not affected by acrylamide, except for an increased consumption by female B6C3F1 mice in the 0.70 mM acrylamide group toward the end of the study. In male B6C3F1 mice, the incidence of harderian gland adenoma and combined harderian gland adenoma or adenocarcinoma was increased significantly in all acrylamide dose groups. The incidence of lung alveolar/bronchiolar adenoma and combined lung alveolar/bronchiolar adenoma or carcinoma was increased significantly at 0.175 and 0.70 mM acrylamide, and the incidence of stomach (forestomach) squamous cell papilloma and combined stomach (forestomach) squamous cell papilloma or carcinoma was increased significantly at 0.35 and 0.70 mM acrylamide. (ABSTRACT TRUNCATED)

Effect of Nimodipine on Morphine-related Withdrawal Syndrome in Rat Model: An Observational Study

PubMed Central

Mishra, Pravash Ranjan; Barik, Mayadhar; Ray, Subrata Basu

2017-01-01

Objective: To observe the effect of L-type calcium channel blocker like nimodipine on morphine's withdrawal when it was administered continuously along with morphine versus a single bolus dose of nimodipine, which was administered at the end of the experiment before the precipitation of withdrawal reaction in morphine-dependent rats. Materials and Methods: Four groups of adult male Wistar rats were rendered morphine dependent by subcutaneous injections of morphine at a dose of 10 mg/kg for 10 days. Nimodipine 10 mg/kg intraperitoneally (ip) administered to one group once daily before morphine administration in the entire experimental period, and another group received nimodipine only once at the end of the experiment as a single bolus dose 2 mg/kg before the administration of naloxone. Naloxone 3 mg/kg was administered ip to all the groups to precipitate withdrawal reactions. The withdrawal reactions were evaluated and scored as per the Gellert and Holtzman global withdrawal rating scale. Results: Nimodipine when administered as a single bolus dose before naloxone administration in morphine-dependant rats reduced the features of withdrawal reactions more effectively than continuous administration of nimodipine along with morphine throughout the experimental period. Conclusion: We discovered that nimodipine helps in attenuating the severity of morphine withdrawal having potential role encountered during pharmacotherapy with morphine management of opioid dependence, well memory, impairement, cell signaling and phosphorylation of neuron. PMID:28553371

Effect of Nimodipine on Morphine-related Withdrawal Syndrome in Rat Model: An Observational Study.

PubMed

Mishra, Pravash Ranjan; Barik, Mayadhar; Ray, Subrata Basu

2017-01-01

To observe the effect of L-type calcium channel blocker like nimodipine on morphine's withdrawal when it was administered continuously along with morphine versus a single bolus dose of nimodipine, which was administered at the end of the experiment before the precipitation of withdrawal reaction in morphine-dependent rats. Four groups of adult male Wistar rats were rendered morphine dependent by subcutaneous injections of morphine at a dose of 10 mg/kg for 10 days. Nimodipine 10 mg/kg intraperitoneally (ip) administered to one group once daily before morphine administration in the entire experimental period, and another group received nimodipine only once at the end of the experiment as a single bolus dose 2 mg/kg before the administration of naloxone. Naloxone 3 mg/kg was administered ip to all the groups to precipitate withdrawal reactions. The withdrawal reactions were evaluated and scored as per the Gellert and Holtzman global withdrawal rating scale. Nimodipine when administered as a single bolus dose before naloxone administration in morphine-dependant rats reduced the features of withdrawal reactions more effectively than continuous administration of nimodipine along with morphine throughout the experimental period. We discovered that nimodipine helps in attenuating the severity of morphine withdrawal having potential role encountered during pharmacotherapy with morphine management of opioid dependence, well memory, impairement, cell signaling and phosphorylation of neuron.

Effects of orally administered Augmentin on glutamate transporter 1, cystine-glutamate exchanger expression and ethanol intake in alcohol-preferring rats.

PubMed

Hakami, Alqassem Y; Alshehri, Fahad S; Althobaiti, Yusuf S; Sari, Youssef

2017-03-01

Alcohol dependence is associated with deficits in glutamate uptake and impairment of glutamate homeostasis in different brain reward regions. Glutamate transporter subtype 1 (GLT-1), cystine-glutamate exchanger (xCT) and glutamate/aspartate transporter (GLAST) are one of the key players in regulating extracellular glutamate concentration in the brain. Parenteral treatment with ceftriaxone, β-lactam antibiotic, has been reported to attenuate ethanol consumption and reinstatement to cocaine-seeking behavior, in part, by restoring the expression of GLT-1 and xCT in mesocorticolimbic brain regions in rats. In this study, we focused to test Augmentin (amoxicillin/clavulanate), which can be administered orally to subjects. Therefore, we examined the effects of orally administered Augmentin on ethanol intake as well as GLT-1, xCT and GLAST expression in male alcohol-preferring (P) rats. We found that orally administered Augmentin significantly attenuated ethanol consumption in P rats as compared to the vehicle-treated group. Importantly, the attenuation in ethanol consumption was associated with a significant upregulation of GLT-1 and xCT expression in nucleus accumbens (NAc) and prefrontal cortex (PFC). There was no effect of orally administered Augmentin on GLAST expression in either NAc or PFC. These findings present strong evidence that oral administration of Augmentin can be used as an alternative to parenteral treatment. Copyright © 2016 Elsevier B.V. All rights reserved.

Nephro-protective action of P. santalinus against alcohol-induced biochemical alterations and oxidative damage in rats.

PubMed

Bulle, Saradamma; Reddy, Vaddi Damodara; Hebbani, Ananda Vardhan; Padmavathi, Pannuru; Challa, Chandrasekhar; Puvvada, Pavan Kumar; Repalle, Elisha; Nayakanti, Devanna; Aluganti Narasimhulu, Chandrakala; Nallanchakravarthula, Varadacharyulu

2016-12-01

The present study investigated the antioxidant potential of P. santalinus heartwood methanolic extract (PSE) against alcohol-induced nephro-toxicity. The results indicated an increase in the concentration of kidney damage plasma markers, urea and creatinine with a concomitant decrease in the concentration of uric acid in alcohol-administered rats. A significant decrease in plasma electrolytes and mineral levels with increased kidney thiobarbituric acid reactive substances (TBARS) and nitric oxide (NOx) levels was also observed. PSE treatment to alcohol-administered rats effectively prevented the elevation in TBARS and NOx levels. Decreased activity of Na + /K + -ATPase in alcohol administered rats was brought to near normal levels with treatment of PSE. Chronic alcohol consumption affects antioxidant enzymatic activity and reabsorption function of the kidney which is evident from the decreased level of GSH as well as the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR) and glutathione s-transferase (GST). However, treatment with PSE to alcohol-administered rats significantly enhanced these enzymatic activities and reduced glutathione (GSH) content close to normal level. Alcohol-induced organ damage was evident from morphological changes in the kidney. Nevertheless, administration of PSE effectively restored these morphological changes to normal. The flavonoid and tannoid compounds might have protective activity against alcohol-induced oxidative/nitrosative stress mediated kidney damage. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

A rat model of nerve agent exposure applicable to the pediatric population: The anticonvulsant efficacies of atropine and GluK1 antagonists

PubMed Central

Miller, Steven L.; Aroniadou-Anderjaska, Vassiliki; Figueiredo, Taiza H.; Prager, Eric M.; Almeida-Suhett, Camila P.; Apland, James P.; Braga, Maria F.M.

2015-01-01

Inhibition of acetylcholinesterase (AChE) after nerve agent exposure induces status epilepticus (SE), which causes brain damage or death. The development of countermeasures appropriate for the pediatric population requires testing of anticonvulsant treatments in immature animals. In the present study, exposure of 21-day-old (P21) rats to different doses of soman, followed by probit analysis, produced an LD50 of 62 μg/kg. The onset of behaviorally-observed SE was accompanied by a dramatic decrease in brain AChE activity; rats who did not develop SE had significantly less reduction of AChE activity in the basolateral amygdala than rats who developed SE. Atropine sulfate (ATS) at 2 mg/kg, administered 20 min after soman exposure (1.2XLD50), terminated seizures. ATS at 0.5 mg/kg, given along with an oxime within 1 min after exposure, allowed testing of anticonvulsants at delayed time-points. The AMPA/GluK1 receptor antagonist LY293558, or the specific GluK1 antagonist UBP302, administered 1 h post-exposure, terminated SE. There were no degenerating neurons in soman-exposed P21 rats, but both the amygdala and the hippocampus were smaller than in control rats at 30 and 90 days post-exposure; this pathology was not present in rats treated with LY293558. Behavioral deficits present at 30 days post-exposure, were also prevented by LY293558 treatment. Thus, in immature animals, a single injection of atropine is sufficient to halt nerve agent-induced seizures, if administered timely. Testing anticonvulsants at delayed time-points requires early administration of ATS at a low dose, sufficient to counteract only peripheral toxicity. LY293558 administered 1 h post-exposure, prevents brain pathology and behavioral deficits. PMID:25689173

Tributyltin increases the expression of apoptosis- and adipogenesis-related genes in rat ovaries

PubMed Central

Lee, Hyojin; Lim, Sojeong; Yun, Sujin; Yoon, Ayoung; Park, Gayoung

2012-01-01

Objective Tributyltin (TBT), an endocrine disrupting chemical, has been reported to decrease ovarian function by causing apoptosis in the ovary, but the mechanism is not fully understood. Therefore, we examined whether TBT increases the expression of adipogenesis-related genes in the ovary and the increased expression of these genes is associated with apoptosis induction. Methods Three-week-old Sprague-Dawley rats were orally administered TBT (1 or 10 mg/kg body weight) or sesame oil as a control for 7 days. The ovaries were obtained and weighed on day 8, and then they were fixed for terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) or frozen for RNA extraction. Using the total RNA of the ovaries, adipogenesis- and apoptosis-related genes were analyzed by real-time polymerase chain reaction (PCR). Results The ovarian weight was significantly decreased in rats administered 10 mg/kg TBT compared to that in control rats. As determined by the TUNEL assay, the number of apoptotic follicles in ovary was significantly increased in rats administered 10 mg/kg TBT. The real-time PCR results showed that the expression of adipogenesis-related genes such as PPARγ, aP2, CD36, and PEPCK was increased after TBT administration. In addition, apoptosis-related genes such as TNFα and TNFR1 were expressed more in the TBT-administered rats compared with the control rats. Conclusion The present study demonstrates that TBT induces the expression of adipogenesis- and apoptosis-related genes in the ovary leading to apoptosis in the ovarian follicles. These results suggest that the increased expression of adipogenesis-related genes in the ovary by TBT exposure might induce apoptosis resulting in a loss of ovarian function. PMID:22563546

Consequences of Adolescent Exposure to the Cannabinoid Receptor Agonist WIN55,212-2 on Working Memory in Female Rats.

PubMed

Kirschmann, Erin K; McCalley, Daniel M; Edwards, Caitlyn M; Torregrossa, Mary M

2017-01-01

Marijuana is a prevalent illicit substance used by adolescents, and several studies have indicated that adolescent use can lead to long-term cognitive deficits including problems with attention and memory. However, preclinical animal studies that observe cognitive deficits after cannabinoid exposure during adolescence utilize experimenter administration of doses of cannabinoids that may exceed what an organism would choose to take, suggesting that contingency and dose are critical factors that need to be addressed in translational models of consequences of cannabinoid exposure. Indeed, we recently developed an adolescent cannabinoid self-administration paradigm in male rats, and found that prior adolescent self-administration of the cannabinoid receptor agonist WIN55,212-2 (WIN) resulted in improved working memory performance in adulthood. In addition, the doses self-administered were not as high as those that are found to produce memory deficits. However, given known sex differences in both drug self-administration and learning and memory processes, it is possible that cannabinoid self-administration could have different cognitive consequences in females. Therefore, we aimed to explore the effects of self-administered vs. experimenter-administered WIN in adolescent female rats on adult cognitive function. Female rats were trained to self-administer WIN daily throughout adolescence (postnatal day 34-59). A control group self-administered vehicle solution. The acute effects of adolescent WIN self-administration on memory were determined using a short-term spatial memory test 24 h after final SA session; and the long-term effects on cognitive performance were assessed during protracted abstinence in adulthood using a delayed-match-to-sample working memory task. In a separate experiment, females were given daily intraperitoneal (IP) injections of a low or high dose of WIN, corresponding to self-administered and typical experimenter-administered doses, respectively, or its vehicle during adolescence and working memory was assessed under drug-free conditions in adulthood. While self-administration of WIN in adolescence had no significant effects on short-term spatial memory or adult working memory, experimenter administration of WIN resulted in improved adult working memory performance that was more pronounced in the low dose group. Thus, low-dose adolescent WIN exposure, whether self-administered or experimenter-administered, results in either improvements or no change in adult working memory performance in female rats, similar to previous results found in males.

Augmentation of the development of behavioral tolerance to cannabinoid administration through pavlovian conditioning.

PubMed

Hill, Matthew N; Gorzalka, Boris B; Choi, Joyce W

2004-01-01

This investigation examined the effects, in female rats, of a Pavlovian conditioning paradigm on the development of tolerance to hypolocomotion induced by the cannabinoid agonist HU-210. Rats were administered HU-210 and placebo in either an associative or a nonassociative fashion. The results indicated that rats in the associative paradigm developed tolerance significantly faster than those in the nonassociative group (p < 0.03). Subsequently, once tolerance had developed, the associative group of rats was administered HU-210 and placebo in the opposite environments. There were no differences found in locomotion between the CS+ and CS- environments following administration of HU-210. However, when the placebo was administered in the CS+ environment, there was a trend towards increased activity levels (p = 0.06), suggesting withdrawal-like behavior. These findings indicate that the underlying physiological mechanisms of tolerance development in the cannabinoid system are hastened by conditioning, but that these physiological alterations are not contingent upon the associative parameters used for drug administration. Copyright 2004 S. Karger AG, Basel

NTP Renal Toxicity Studies of Selected Halogenated Ethanes Administered by Gavage to F344/N Rats.

PubMed

1996-02-01

The National Cancer Institute and National Toxicology Program have performed 2-year toxicology and carcinogenesis studies with a number of ethanes substituted with chlorine or bromine. A review of the results of studies with these halogenated ethanes has revealed several consistencies between the pattern of halogen substitution and neoplastic responses in some affected organs. One of these consistencies was the finding of a modest increase in the incidence of renal tubule cell neoplasms in male rats administered penta- or hexachloroethane. Certain aspects of the nephropathy also noted in these studies resembled what is now recognized as a distinct hyaline droplet nephropathy typically associated with the accumulation of alpha[alpha]2&mgr;-globulin in renal tubule cells. In an attempt to determine some of the structure activity relationships involved in the induction of hyaline droplet nephropathy by halogenated ethanes, a series of commercially available ethanes substituted with three or more chlorines, four or more bromines, or a combination of chlorines and fluorines was studied in a short-term renal toxicity assessment in male F344/N rats. All chemicals were administered by gavage in corn oil to groups of five male rats once daily for 21 days. The doses selected for study, 0.62 and 1.24 mmol/kg per day, were based on those used in the 2-year pentachloroethane studies. The following chemicals were evaluated: 1,1,1,2- and 1,1,2,2-tetrachloroethane; pentachloroethane; 1,1,2,2-tetrachloro1,2-difluoroethane; 1,1,1-trichloro-2,2,2-trifluoroethane; 1,2-dichloro-1,1-difluoroethane; 1,1,1-trichloroethane; hexachloroethane; 1,1,1,2-and 1,1,2,2-tetrabromoethane; and pentabromoethane. Evaluations included survival, mean body weight gains, clinical signs, organ weights, urinalysis, and histopathologic examination of the right kidney and liver. The kidneys of rats that showed a difference in renal protein droplet accumulation compared to the controls were evaluated for replicative DNA synthesis by staining for proliferating cell nuclear antigen. For most groups, survival was not affected by chemical treatment; however, all rats administered either dose of 1,1,2,2-tetrabromoethane died by Day 11, and all rats administered 1.24 mmol/kg pentabromoethane, 1,1,1,2-tetrabromoethane, or 1,1,2,2-tetrachloroethane died before the end of the study. Rats receiving 0.62 mmol/kg pentabromoethane gained less weight than the controls, and rats in the 0.62 mmol/kg 1,1,1,2-tetrabromoethane group lost weight during the study. Increased kidney weights and signs of renal toxicity, indicated by urinalysis results, were noted in rats in many of the groups administered halogenated ethanes, but these observations were not always coincident with a diagnosis of hyaline droplet nephropathy. Hyaline droplet nephropathy was observed only in rats receiving penta-, hexa-, or 1,1,1,2-tetrachloroethane. The renal tubule cell labeling index was increased, indicating replicative DNA synthesis, in male rats receiving chemicals that induced hyaline droplet nephropathy as well as in males receiving pentabromoethane or 1,1,2,2-tetrachloroethane and in female negative control rats administered pentachloroethane; thus some of the halogenated ethanes appeared to cause significant renal toxicity not associated with hyaline droplet nephropathy. In summary, of the halogenated ethanes studied, the capacity to induce hyaline droplet nephropathy in male rats was restricted to ethanes containing four or more halogens, and only the chlorinated ethanes were active. If the ability to induce hyaline droplet nephropathy is the determining factor in the induction of renal tubule cell neoplasms by halogenated ethanes, then an absence of kidney neoplasms in male rats would be predicted in the event that 2-year studies were performed with the bromo- or chlorofluoroethanes.

[Pituitary function of dysgenesic femal rats. Studies with grafting method].

PubMed

Vanhems, E; Busquet, J

1975-01-01

Misulban administered to pregnant rats on the 15th day of gestation provoked gonadal dysgenesia in the offspring. Study of the pituitary function of dysgenesic female rats, realized by grafting method, showed gonadotrophic hypersecretion.

Polymeric nanoparticles for increased oral bioavailability and rapid absorption using celecoxib as a model of a low-solubility, high-permeability drug.

PubMed

Morgen, Michael; Bloom, Corey; Beyerinck, Ron; Bello, Akintunde; Song, Wei; Wilkinson, Karen; Steenwyk, Rick; Shamblin, Sheri

2012-02-01

To demonstrate drug/polymer nanoparticles can increase the rate and extent of oral absorption of a low-solubility, high-permeability drug. Amorphous drug/polymer nanoparticles containing celecoxib were prepared using ethyl cellulose and either sodium caseinate or bile salt. Nanoparticles were characterized using dynamic light scattering, transmission and scanning electron microscopy, and differential scanning calorimetry. Drug release and resuspension studies were performed using high-performance liquid chromatography. Pharmacokinetic studies were performed in dogs and humans. A physical model is presented describing the nanoparticle state of matter and release performance. Nanoparticles dosed orally in aqueous suspensions provided higher systemic exposure and faster attainment of peak plasma concentrations than commercial capsules, with median time to maximum drug concentration (Tmax) of 0.75 h in humans for nanoparticles vs. 3 h for commercial capsules. Nanoparticles released celecoxib rapidly and provided higher dissolved-drug concentrations than micronized crystalline drug. Nanoparticle suspensions are stable for several days and can be spray-dried to form dry powders that resuspend in water. Drug/polymer nanoparticles are well suited for providing rapid oral absorption and increased bioavailability of BCS Class II drugs.

Modification of the crystal habit of celecoxib for improved processability.

PubMed

Banga, Sheere; Chawla, Garima; Varandani, Deepak; Mehta, B R; Bansal, Arvind K

2007-01-01

Crystallization is often used in the pharmaceutical industry for purification and isolation of drugs, and also as a means of generating polymorphs or isomorphs. The aim of this study was to investigate the role of extrinsic crystallization parameters on the crystallized product, with special emphasis on improving the mechanical properties of acicular celecoxib. Celecoxib isomorphs were prepared using different techniques (solvent crystallization and vapour diffusion) and crystallization conditions (solvents, stirring, degree of supersaturation, crystallization temperature and seeding). Powder X-ray diffractometry, spectroscopic and thermal methods were used to investigate physical characteristics of crystals. Growth kinetics and aggregation dynamics of crystallization in polar and non-polar solvents were simulated using a dynamic light scattering method. The quick appearance of broad peaks over the range of 10-8000 nm in chloroform during crystallization simulation studies indicated faster aggregation in non-polar solvents. Aspect ratio, flow, compressibility and surface area of recrystallized products were also determined. Surface topography was determined by atomic force microscopy and the lath-shaped crystals (aspect ratio of 2-4) exhibited a roughness index of 1.79 in comparison with 2.92 for needles. Overall, the lath-shaped isomorphs exhibited improved flow and better compressibility.

Gabapentin potentiates sensitivity to the interoceptive effects of alcohol and increases alcohol self-administration in rats

PubMed Central

Besheer, Joyce; Frisbee, Suzanne; Randall, Patrick A.; Jaramillo, Anel A.; Masciello, Maria

2016-01-01

Gabapentin, a drug used in the treatment of epileptic seizures and neuropathic pain, has shown efficacy in the treatment of alcohol dependence. Moreover, given that gabapentin is used in the general population (e.g., non-dependent individuals, social drinkers), we sought to utilize preclinical assessments to examine the effects of gabapentin on sensitivity to moderate alcohol doses and alcohol self-administration in rats with a history of moderate drinking. To this end, we assessed whether gabapentin (0, 10, 30, 120 mg/kg, IG) pretreatment alters sensitivity to experimenter- and self-administered alcohol, and whether gabapentin alone has alcohol-like discriminative stimulus effects in rats trained to discriminate a moderate alcohol dose (1 g/kg, IG) vs. water. Second, we assessed whether gabapentin (0, 10, 30, 60 mg/kg, IG) would alter alcohol self-administration in rats with a history of moderate alcohol consumption. Gabapentin pretreatment potentiated the interoceptive effects of both experimenter-administered and self-administered alcohol in discrimination-trained rats. Additionally, the highest gabapentin doses tested (30 and 120 mg/kg) were found to have partial alcohol-like discriminative stimulus effects when administered alone (e.g., without alcohol). In the self-administration trained rats, gabapentin pretreatment (60 mg/kg) resulted in an escalation in alcohol self-administration. Given the importance of interoceptive drug cues in priming and maintaining self-administration, these data define a specific behavioral mechanism (i.e., potentiation of alcohol effects) by which gabapentin may increase alcohol self-administration in non-dependent populations. PMID:26415538

Effects of prior cocaine versus morphine or heroin self-administration on extinction learning driven by overexpectation versus omission of reward.

PubMed

Lucantonio, Federica; Kambhampati, Sarita; Haney, Richard Z; Atalayer, Deniz; Rowland, Neil E; Shaham, Yavin; Schoenbaum, Geoffrey

2015-05-15

Addiction is characterized by an inability to stop using drugs, despite adverse consequences. One contributing factor to this compulsive drug taking could be the impact of drug use on the ability to extinguish drug seeking after changes in expected outcomes. Here, we compared effects of cocaine, morphine, and heroin self-administration on two forms of extinction learning: standard extinction driven by reward omission and extinction driven by reward overexpectation. In experiment 1, we trained rats to self-administer cocaine, morphine, or sucrose for 3 hours per day (limited access). In experiment 2, we trained rats to self-administer heroin or sucrose for 12 hours per day (extended access). Three weeks later, we trained the rats to associate several cues with palatable food reward, after which we assessed extinction of the learned Pavlovian response, first by pairing two cues together in the overexpectation procedure and later by omitting the food reward. Rats trained under limited access conditions to self-administer sucrose or morphine demonstrated normal extinction in response to both overexpectation and reward omission, whereas cocaine-experienced rats or rats trained to self-administer heroin under extended access conditions exhibited normal extinction in response to reward omission but failed to show extinction in response to overexpectation. Here we show that cocaine and heroin can induce long-lasting deficits in the ability to extinguish reward seeking. These deficits were not observed in a standard extinction procedure but instead only affected extinction learning driven by a more complex phenomenon of overexpectation. Published by Elsevier Inc.

Taurine ameliorated thyroid function in rats co-administered with chlorpyrifos and lead.

PubMed

Akande, Motunrayo Ganiyat; Shittu, Muftau; Uchendu, Chidiebere; Yaqub, Lukuman Surakat

2016-12-01

Chlorpyrifos is a widely used organophosphate insecticide for domestic, agricultural and industrial purposes. Lead is a toxic heavy metal and it is used for domestic and industrial purposes. Taurine is a semi essential amino acid with bioprotective properties. The aim of this study was to investigate the effects of taurine on thyroid function in Wistar rats co-administered with chlorpyrifos and lead. The rats were divided into 5 groups of 10 rats each. The first two groups were administered with distilled water and soya oil (1 ml/kg) respectively. The other groups received taurine (50 mg/kg), chlorpyrifos + lead [chlorpyrifos (4.25 mg/kg, 1/20 median lethal dose] and lead (233.25 mg/kg, 1/20 median lethal dose) and taurine + chlorpyrifos + lead respectively. The treatments were administered once daily by oral gavage for 16 weeks. The rats were euthanized after the completion of the study and the thyroid function and thyroid histoarchitecture were evaluated. The results revealed that co-administration of chlorpyrifos and lead to the rats induced perturbations in thyroid function and this was manifested by reductions in the concentrations of triiodothyronine and thyroxine, increased thyroid stimulating hormone concentration and degeneration of the follicular epithelia of the thyroid gland. Taurine alleviated the perturbations in thyroid function and improved thyroid gland histoarchitecture. The beneficial effects of taurine may be attributed to its ability to protect the body from toxicity and oxidative stress. Taurine may be useful for prophylaxis against disruptions in thyroid function in animals that are exposed to environmental chlorpyrifos and lead.

Evaluation of miR-216a and miR-217 as Potential Biomarkers of Acute Exocrine Pancreatic Toxicity in Rats.

PubMed

Wang, Jianying; Huang, Wenhu; Thibault, Stephane; Brown, Thomas P; Bobrowski, Walter; Gukasyan, Hovhannes J; Evering, Winston; Hu, Wenyue; John-Baptiste, Annette; Vitsky, Allison

2017-02-01

Detecting and monitoring exocrine pancreatic damage during nonclinical and clinical testing is challenging because classical biomarkers amylase and lipase have limited sensitivity and specificity. Novel biomarkers for drug-induced pancreatic injury are needed to improve safety assessment and reduce late-stage attrition rates. In a series of studies, miR-216a and miR-217 were evaluated as potential biomarkers of acute exocrine pancreatic toxicity in rats. Our results revealed that miR-216a and miR-217 were almost exclusively expressed in rat pancreas and that circulating miR-216a and miR-217 were significantly increased in rats following administration of established exocrine pancreatic toxicants caerulein (CL) and 1-cyano-2-hydroxy-3-butene (CHB) as well as in rats administered a proprietary molecule known to primarily affect the exocrine pancreas. Conversely, neither microRNA was increased in rats administered a proprietary molecule known to cause a lesion at the pancreatic endocrine-exocrine interface (EEI) or in rats administered an established renal toxicant. Compared with amylase and lipase, increases in miR-216a and miR-217 were of greater magnitude, persisted longer, and/or correlated better with microscopic findings within the exocrine pancreas. Our findings demonstrate that in rats, miR-216a and miR-217 are sensitive and specific biomarkers of acute exocrine pancreatic toxicity that may add value to the measurement of classical pancreatic biomarkers.

Antioxidant mechanism is involved in the gastroprotective effects of ozonized sunflower oil in ethanol-induced ulcers in rats.

PubMed

Zamora Rodríguez, Zullyt B; González Alvarez, Ricardo; Guanche, Dailén; Merino, Nelson; Hernández Rosales, Frank; Menéndez Cepero, Silvia; Alonso González, Yaima; Schulz, Siegfried

2007-01-01

This research was performed in order to determine the potential protective effects of ozonized sunflower oil (OSO) in the injury of rat gastric mucosa induced by absolute ethanol and as well as to elucidate the role of reactive oxygen species (ROS), lipid peroxidation, and some important constituents of antioxidant defense such as superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) in these effects. OSO was administered to rats intragastrically by a cannula and it was applied during four days to animals. The doses of OSO administered daily to each group of rats were 4, 12, and 24 mg/kg, respectively, and one hour after the last treatment, absolute ethanol (1 mL/200 mg body weight) was administered. Our results showed that gastric ulcer index was significantly reduced in rats pretreated with OSO as compared with ethanol-treated controls. However, in rats pretreated with OSO, no significant reduction of TBARS content in gastric mucosa was found as compared to those rats treated with ethanol alone. In contrast, SOD and GSH-Px activities were significantly increased in gastric mucosa of OSO-pretreated rats with respect to those treated with ethanol alone. In summary, our results demonstrate that OSO pretreatment exerts protective effects in ethanol-induced gastric ulcers in rats. Furthermore, these results provide evidence that these protective effects of OSO are mediated at least partially by stimulation of some important antioxidant enzymes such as SOD and GSH-Px, which are scavengers of ROS and therefore prevent gastric injury induced by them.

Antioxidant Mechanism is Involved in the Gastroprotective Effects of Ozonized Sunflower Oil in Ethanol-Induced Ulcers in Rats

PubMed Central

Rodríguez, Zullyt B. Zamora; Álvarez, Ricardo González; Guanche, Dailén; Merino, Nelson; Rosales, Frank Hernández; Cepero, Silvia Menéndez; González, Yaima Alonso; Schulz, Siegfried

2007-01-01

This research was performed in order to determine the potential protective effects of ozonized sunflower oil (OSO) in the injury of rat gastric mucosa induced by absolute ethanol and as well as to elucidate the role of reactive oxygen species (ROS), lipid peroxidation, and some important constituents of antioxidant defense such as superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) in these effects. OSO was administered to rats intragastrically by a cannula and it was applied during four days to animals. The doses of OSO administered daily to each group of rats were 4, 12, and 24 mg/kg, respectively, and one hour after the last treatment, absolute ethanol (1 mL/200 mg body weight) was administered. Our results showed that gastric ulcer index was significantly reduced in rats pretreated with OSO as compared with ethanol-treated controls. However, in rats pretreated with OSO, no significant reduction of TBARS content in gastric mucosa was found as compared to those rats treated with ethanol alone. In contrast, SOD and GSH-Px activities were significantly increased in gastric mucosa of OSO-pretreated rats with respect to those treated with ethanol alone. In summary, our results demonstrate that OSO pretreatment exerts protective effects in ethanol-induced gastric ulcers in rats. Furthermore, these results provide evidence that these protective effects of OSO are mediated at least partially by stimulation of some important antioxidant enzymes such as SOD and GSH-Px, which are scavengers of ROS and therefore prevent gastric injury induced by them. PMID:17497036

The analgesic effect of tramadol in animal models of neuropathic pain and fibromyalgia.

PubMed

Kaneko, Kumi; Umehara, Masato; Homan, Takashi; Okamoto, Ken; Oka, Michiko; Oyama, Tatsuya

2014-03-06

(±)-Tramadol hydrochloride (tramadol) is a widely used analgesic for the treatment of cancer pain and chronic pain. Although many animal studies have shown antinociceptive effects of tramadol in both acute and chronic pain, little is known about the effect of tramadol in putative animal models of fibromyalgia. In this study, we compared the antiallodynic effects of oral administration of tramadol in two kinds of rat chronic pain models, neuropathic pain induced by partial sciatic nerve ligation (PSL) and reserpine-induced myalgia (RIM). In PSL rats, the threshold for responses induced by tactile stimulation with von Frey filaments was significantly decreased seven days after the operation, suggesting that the operation induced tactile allodynia. Orally administered tramadol showed a potent and dose-dependent antiallodynic effect on PSL-induced allodynia. In RIM rats, the threshold was significantly decreased five days after reserpine treatment. Orally administered tramadol also attenuated reserpine-induced tactile allodynia. To explore the mechanism of the antiallodynic effect of tramadol in RIM rats, we investigated the effect of the opioid antagonist naloxone on the tramadol-induced analgesic effect in these rats. The effect of tramadol was partially antagonized by naloxone, suggesting that the opioid receptor is involved at least in part in the antiallodynic effect of tramadol in RIM rats. These data indicate that orally administered tramadol produced improvement in both PSL rats and RIM rats at similar doses and provide evidence that the opioid system is partly involved in the analgesic effect of tramadol in RIM rats. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Colon dysregulation in methamphetamine self-administering HIV-1 transgenic rats

PubMed Central

Bradaric, Brinda D.; Dodiya, Hemraj B.; Ohene-Nyako, Michael; Forsyth, Christopher B.; Keshavarzian, Ali; Shaikh, Maliha; Napier, T. Celeste

2018-01-01

The integrity and function of the gut is impaired in HIV-infected individuals, and gut pathogenesis may play a role in several HIV-associated disorders. Methamphetamine is a popular illicit drug abused by HIV-infected individuals. However, the effect of methamphetamine on the gut and its potential to exacerbate HIV-associated gut pathology is not known. To shed light on this scenario, we evaluated colon barrier pathology in a rat model of the human comorbid condition. Intestinal barrier integrity and permeability were assessed in drug-naïve Fischer 344 HIV-1 transgenic (Tg) and non-Tg rats, and in Tg and non-Tg rats instrumented with jugular cannulae trained to self-administer methamphetamine or serving as saline-yoked controls. Intestinal permeability was determined by measuring the urine content of orally gavaged sugars. Intestinal barrier integrity was evaluated by immunoblotting or immunofluorescence of colon claudin-1 and zonula occludens-1 (ZO-1), two major tight junction proteins that regulate gut epithelial paracellular permeability. Both non-Tg and Tg rats self-administered moderate amounts of methamphetamine. These amounts were sufficient to increase colon permeability, reduce protein level of claudin-1, and reduce claudin-1 and ZO-1 immunofluorescence in Tg rats relative to non-Tg rats. Methamphetamine decreased tight junction immunofluorescence in non-Tg rats, with a similar, but non-significant trend observed in Tg rats. However, the effect of methamphetamine on tight junction proteins was subthreshold to gut leakiness. These findings reveal that both HIV-1 proteins and methamphetamine alter colon barrier integrity, and indicate that the gut may be a pathogenic site for these insults. PMID:29293553

Colon dysregulation in methamphetamine self-administering HIV-1 transgenic rats.

PubMed

Persons, Amanda L; Bradaric, Brinda D; Dodiya, Hemraj B; Ohene-Nyako, Michael; Forsyth, Christopher B; Keshavarzian, Ali; Shaikh, Maliha; Napier, T Celeste

2018-01-01

The integrity and function of the gut is impaired in HIV-infected individuals, and gut pathogenesis may play a role in several HIV-associated disorders. Methamphetamine is a popular illicit drug abused by HIV-infected individuals. However, the effect of methamphetamine on the gut and its potential to exacerbate HIV-associated gut pathology is not known. To shed light on this scenario, we evaluated colon barrier pathology in a rat model of the human comorbid condition. Intestinal barrier integrity and permeability were assessed in drug-naïve Fischer 344 HIV-1 transgenic (Tg) and non-Tg rats, and in Tg and non-Tg rats instrumented with jugular cannulae trained to self-administer methamphetamine or serving as saline-yoked controls. Intestinal permeability was determined by measuring the urine content of orally gavaged sugars. Intestinal barrier integrity was evaluated by immunoblotting or immunofluorescence of colon claudin-1 and zonula occludens-1 (ZO-1), two major tight junction proteins that regulate gut epithelial paracellular permeability. Both non-Tg and Tg rats self-administered moderate amounts of methamphetamine. These amounts were sufficient to increase colon permeability, reduce protein level of claudin-1, and reduce claudin-1 and ZO-1 immunofluorescence in Tg rats relative to non-Tg rats. Methamphetamine decreased tight junction immunofluorescence in non-Tg rats, with a similar, but non-significant trend observed in Tg rats. However, the effect of methamphetamine on tight junction proteins was subthreshold to gut leakiness. These findings reveal that both HIV-1 proteins and methamphetamine alter colon barrier integrity, and indicate that the gut may be a pathogenic site for these insults.

Mitigation of diazinon-induced cardiovascular and renal dysfunction by gallic acid

PubMed Central

Ajibade, Temitayo Olabisi; Omobowale, Temidayo Olutayo; Asenuga, Ebunoluwa Racheal; Afolabi, Jeremiah Moyinoluwa; Adedapo, Adeolu Alex

2016-01-01

Studies of the link between environmental pollutants and cardiovascular dysfunction, neglected for decades, have recently provided new insights into the pathology and consequences of these killers. In this study, rats were divided into four groups, each containing 10 rats. The rats in group one served as controls and were administered normal saline, whereas the rats in group two were orally gavaged with 3 mg/kg of diazinon (DZN) alone for twenty one consecutive days. The rats in groups 3 and 4 were administered respective 60 mg/kg and 120 mg/kg gallic acid (GA) in addition to DZN for twenty one consecutive days. Exposure of rats to diazinon significantly (p<0.05) reduced the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase (GST) and reduced glutathione (GSH) content. Malondialdehyde, hydrogen peroxide (H2O2) and nitric oxide (NO) contents were also significantly (p<0.05) elevated following DZN exposure. DZN further caused a significant (p<0.05) decrease of heart rate and QT interval prolongation. Hematologic analysis revealed significant reduction (p<0.05) in packed cell volume (PCV), hemoglobin concentration (Hb), red blood cell (RBC) count, and total white blood cell count of rats administered only DZN. Observations in this study suggest a modulatory role of gallic acid in diazinon-induced anemia and associated cardiovascular dysfunction in rats. Treatment with gallic acid reversed the oxidative stress markers studied, increased the antioxidant defence system and reduced deleterious effects on hematological parameters in rats. Pathologic findings of the heart and kidney were also found to be lessened. PMID:28652848

A Target-Specific Oral Formulation of Doxorubicin-Protein Nanoparticles: Efficacy and Safety in Hepatocellular Cancer

PubMed Central

Golla, Kishore; Bhaskar, Cherukuvada; Ahmed, Farhan; Kondapi, Anand K.

2013-01-01

Background/Aims: Hepatocellular carcinoma (HCC) also known as malignant hepatoma is a most common liver cancer. Doxorubicin (Doxo) is an anti-cancer drug having activity against a wide spectrum of cancer types. Clinical Utility of doxo has been limited due to its poor bioavailability and toxicity to heart and spleen. Furthermore, cancer chemotherapeutics have limited oral absorption. Transferrin family proteins are highly abundant and plays important role in transport and storage of iron in cells and tissues. Since apotransferrin and lactoferrin receptors are highly expressed on the surface of metabolically active cancer cells, the principal objective of present study is to evaluate efficacy of doxorubicin loaded apotransferrin and lactoferrin nanoparticles (apodoxonano or lactodoxonano) in oral treatment of HCC in rats. Study Design: HCC was induced in rats by supplementing 100 mg/L of diethylnitrosamine (DENA) in drinking water for 8 weeks. A week after the last day of DENA administration, rats were divided into four groups, each group comprising of five animals. Each group was administered with one of the drug viz., saline, doxorubicin (doxo), apodoxonano and lactodoxonano (4 mg/ kg equivalent of drug). In each case, they received 8 doses of the drug orally with six day interval. One week after the last dose, anticancer activity was evaluated by counting the liver nodules, H & E analysis of tissue sections and expression levels of angiogenic and antitumor markers. Results: In rats treated with apodoxonano and lactodoxonano, the number of neoplastic nodules was significantly lower than that of rats administered with saline or with doxo. Apodoxonano and lactodoxonano did not exhibit decrease in mean body weight, which was markedly reduced by 22% in the case of doxo administered rats. In rats treated with nanoformulations, the number of liver nodules was found reduced by >93%. Both nanoformulations showed significantly high localization in liver compared to doxo. Conclusions: Apodoxonano and lactodoxonano showed improved efficacy, bioavailability and safety compared to doxo for treatment of HCC in rats when administered orally. PMID:24155776

Gut vagal afferents are necessary for the eating-suppressive effect of intraperitoneally administered ginsenoside Rb1 in rats.

PubMed

Shen, Ling; Wang, David Q-H; Lo, Chunmin C; Arnold, Myrtha; Tso, Patrick; Woods, Stephen C; Liu, Min

2015-12-01

Ginsenoside Rb1 (Rb1) reduces food intake in both lean and high-fat diet induced-obese rats; however, the sites and/or mediation of the eating-suppressive effect of Rb1 have not previously been identified. We hypothesized that intraperitoneally (ip) administered Rb1 exerts its anorectic action by enhancing sensitivity to satiation signals, such as cholecystokinin (CCK), and/or that it acts through vagal afferent nerves that relay the satiating signaling to the hindbrain. To test these hypotheses, we gave ip bolus doses of Rb1 (2.5-10.0mg/kg) and CCK-8 (0.125-4.0μg/kg) alone or in combination and assessed food intake in rats. Low doses of Rb1 (2.5mg/kg) or CCK-8 (0.125μg/kg) alone had no effect on food intake whereas higher doses did. When these subthreshold doses of Rb1 and CCK-8 were co-administered, the combination significantly reduced food intake relative to saline controls, and this effect was attenuated by lorglumide, a selective CCK1-receptor antagonist. Interestingly, lorglumide blocked food intake induced by an effective dose of CCK-8 alone, but not by Rb1 alone, suggesting that Rb1's anorectic effect is independent of the CCK1 receptor. To determine whether peripherally administered Rb1 suppresses feeding via abdominal vagal nerves, we evaluated the effect of ip Rb1 injection in subdiaphragmatic vagal deafferentation (SDA) and control rats. Rb1's effect on food intake was significantly attenuated in SDA rats, compared with that in SHAM controls. These data indicate that the vagal afferent system is the major pathway conveying peripherally administered Rb1's satiation signal. Copyright © 2015 Elsevier Inc. All rights reserved.

Comparative Analgesic Efficacy of Pregabalin Administered According to Either a Prevention Protocol or an Intervention Protocol in Rats with Cisplatin-induced Peripheral Neuropathy.

PubMed

Han, F Y; Kuo, A; Nicholson, J R; Corradinni, L; Smith, M T

2018-05-21

Chemotherapy-induced peripheral neuropathy (CIPN) is a type of peripheral neuropathic pain that may be dose-limiting in patients administered potentially curative cancer chemotherapy dosing regimens. In cancer survivors, persistent CIPN adversely affects patient quality of life and so adjuvant drugs (anticonvulsants e.g. pregabalin or antidepressants e.g. amitriptyline) are recommended for the relief of CIPN. However, most studies in rodent models of CIPN involve administration of single bolus doses of adjuvant drugs to assess pain-relieving efficacy. Hence this study was designed to assess the efficacy of pregabalin administered to CIPN-rats according to either a prevention or an intervention protocol. Groups of male Sprague-Dawley rats received four single intraperitoneal bolus doses of cisplatin at 3 mg/kg at once-weekly intervals to induce CIPN. For the prevention protocol, oral pregabalin (or vehicle) was administered to CIPN-rats once-daily for 21 consecutive days from day 0 to day 20 inclusive. For the intervention protocol, oral pregabalin was administered once-daily for 21 consecutive days from day 28 to day 48 inclusive. Mechanical allodynia and mechanical hyperalgesia in the bilateral hindpaws were assessed just prior to each dose of cisplatin and at least once-weekly until study completion (day 27, prevention protocol; or day 48, intervention protocol). Mechanical allodynia and mechanical hyperalgesia were also determined at the time of peak effect at ~2 h post- pregabalin/vehicle administration once-weekly until study completion. For the prevention protocol in CIPN-rats, pregabalin alleviated mechanical hyperalgesia but not mechanical allodynia. For the intervention protocol, pregabalin alleviated both mechanical allodynia and mechanical hyperalgesia in the hindpaws. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Gastrointestinal safety of celecoxib versus naproxen in patients with cardiothrombotic diseases and arthritis after upper gastrointestinal bleeding (CONCERN): an industry-independent, double-blind, double-dummy, randomised trial.

PubMed

Chan, Francis K L; Ching, Jessica Y L; Tse, Yee Kit; Lam, Kelvin; Wong, Grace L H; Ng, Siew C; Lee, Vivian; Au, Kim W L; Cheong, Pui Kuan; Suen, Bing Y; Chan, Heyson; Kee, Ka Man; Lo, Angeline; Wong, Vincent W S; Wu, Justin C Y; Kyaw, Moe H

2017-06-17

Present guidelines are conflicting for patients at high risk of both cardiovascular and gastrointestinal events who continue to require non-steroidal anti-inflammatory drugs (NSAIDs). We hypothesised that a cyclooxygenase-2-selective NSAID plus proton-pump inhibitor is superior to a non-selective NSAID plus proton-pump inhibitor for prevention of recurrent ulcer bleeding in concomitant users of aspirin with previous ulcer bleeding. For this industry-independent, double-blind, double-dummy, randomised trial done in one academic hospital in Hong Kong, we screened patients with arthritis and cardiothrombotic diseases who were presenting with upper gastrointestinal bleeding, were on NSAIDs, and require concomitant aspirin. After ulcer healing, an independent staff member randomly assigned (1:1) patients who were negative for Helicobacter pylori with a computer-generated list of random numbers to receive oral administrations of either celecoxib 100 mg twice per day plus esomeprazole 20 mg once per day or naproxen 500 mg twice per day plus esomeprazole 20 mg once per day for 18 months. All patients resumed aspirin 80 mg once per day. Both patients and investigators were masked to their treatments. The primary endpoint was recurrent upper gastrointestinal bleeding within 18 months. The primary endpoint and secondary safety endpoints were analysed in the modified intention-to-treat population. This study was registered with ClinicalTrials.gov, number NCT00153660. Between May 24, 2005, and Nov 28, 2012, we enrolled 514 patients, assigning 257 patients to each study group, all of whom were included in the intention-to-treat population. Recurrent upper gastrointestinal bleeding occurred in 14 patients in the celecoxib group (nine gastric ulcers and five duodenal ulcers) and 31 patients in the naproxen group (25 gastric ulcers, three duodenal ulcers, one gastric ulcer and duodenal ulcer, and two bleeding erosions). The cumulative incidence of recurrent bleeding in 18 months was 5·6% (95% CI 3·3-9·2) in the celecoxib group and 12·3% (8·8-17·1) in the naproxen group (p=0·008; crude hazard ratio 0·44, 95% CI 0·23-0·82; p=0·010). Excluding patients who reached study endpoints, 21 (8%) patients in the celecoxib group and 17 (7%) patients in the naproxen group had adverse events leading to discontinuation of treatment. No treatment-related deaths occurred during the study. In patients at high risk of both cardiovascular and gastrointestinal events who require concomitant aspirin and NSAID, celecoxib plus proton-pump inhibitor is the preferred treatment to reduce the risk of recurrent upper gastrointestinal bleeding. Naproxen should be avoided despite its perceived cardiovascular safety. The Research Grant Council of Hong Kong. Copyright © 2017 Elsevier Ltd. All rights reserved.

Vitamins A and E reverse gasoline vapors-induced hematotoxicity and weight loss in female rats.

PubMed

Uboh, F E; Eteng, M U; Ebong, P E; Umoh, I B

2010-10-01

In this study, gasoline vapors-induced hematotoxicity, growth-depression and weight-loss reversal effect of vitamins A (retinol) and E (α-tocopherol) was assessed in female Wistar albino rats. The rats were exposed to gasoline vapors (17.8 ± 2.6 cm(3)/h/m(3)/day), 6 hours/day, 6 days/week, for 20 weeks. Vitamins A and E at prophylactic dosage (400 and 200 IU/kg/day, respectively) were orally administered to the rats, separately, in the last 2 weeks of exposure. The levels of hemoglobin (Hb), hematocrit or packed cell volume (PCV), red blood cells (RBC), growth rate and weight gain in the rats exposed to the vapors were significantly lower (p < 0.05) compared, respectively, to the levels obtained for control rats. On the other hand, the levels of white blood cells (WBCs) in the test rats were significantly higher (p < 0.05) compared, respectively, with the level obtained for female control rats. These observations indicated that exposure to gasoline vapors may cause hematotoxicity, growth depression and weight loss in female rats. However, administration of vitamins A and E was observed to produce a significant recovery (p < 0.05) in hematotoxicity, growth depression and weight loss observed to be associated with exposure to gasoline vapors, although the rats administered with vitamin E were noted to respond more favorably than those administered with vitamin A. This suggests that although retinol and α-tocopherol may be used to reverse or prevent hematotoxicity, growth depression and weight loss in subjects exposed to gasoline vapors, the reversal potency of α-tocopherol is higher than that of retinol.

Genotoxic evaluation of pirfenidone using erythrocyte rodent micronucleus assay.

PubMed

Alcántar-Díaz, Blanca E; Gómez-Meda, Belinda C; Zúñiga-González, Guillermo M; Zamora-Perez, Ana L; González-Cuevas, Jaime; Alvarez-Rodríguez, Bertha A; Sánchez-Parada, María Guadalupe; García-Bañuelos, Jesús J; Armendáriz-Borunda, Juan

2012-08-01

Pirfenidone is a non-steroidal antifibrotic compound that has been proposed in clinical protocols and experimental studies as a pharmacological treatment for fibroproliferative diseases. The objective of this study was to determine the genotoxicity or cytotoxicity of three doses of pirfenidone using the micronuclei test in peripheral blood erythrocytes of rodent models. Pirfenidone was administered orally to Balb-C mice for 3 days, and also was administered topically to hairless Sprague Dawley rats during the final stage of gestation. Mice were sampled every 24 h over the course of 6 days; pregnant rats were sampled every 24 h during the last 6 days of gestation, and pups were sampled at birth. Blood smears were analyzed and the frequencies of micronucleated erythrocytes (MNEs), micronucleated polychromatic erythrocytes (MNPCEs), and the proportion of polychromatic erythrocytes (PCEs), were recorded in samples from mice, pregnant rats and rat neonates. Increases in MN frequencies (p<0.03) were noted only in the positive control groups. No genotoxic effects or decreased PCE values were observed neither in newborn rats transplacentally exposed to pirfenidone, or in two adult rodent models when pirfenidone was administered orally or topically. Copyright © 2012 Elsevier Ltd. All rights reserved.

Neuroprotective effects of silymarin on ischemia-induced delayed neuronal cell death in rat hippocampus.

PubMed

Hirayama, Koki; Oshima, Hideki; Yamashita, Akiko; Sakatani, Kaoru; Yoshino, Atsuo; Katayama, Yoichi

2016-09-01

We examined the effects of silymarin, which was extracted from Silybum marianum, on delayed neuronal cell death in the rat hippocampus. Rats were divided into four groups: sham-operated rats (sham group), rats which underwent ischemic surgery (control group), rats which were treated with silymarin before and after ischemic surgery (pre group), and rats which were treated with silymarin after ischemic surgery only (post group). We performed the ischemic surgery by occluding the bilateral carotid arteries for 20min and sacrificed the rats one week after the surgery. Silymarin was administered orally at 200mg/kg body weight. Smaller numbers of delayed cell deaths were noted in the rat CA1 region of the pre- and post-groups, and no significant difference was observed between these groups. There were few apoptotic cell deaths in all groups. Compared to the control group, significantly fewer cell deaths by autophagy were found in the pre- and post-group. We concluded that silymarin exerts a preservation effect on delayed neuronal cell death in the rat hippocampus and this effect has nothing to do with the timing of administering of silymarin. Copyright © 2016 Elsevier B.V. All rights reserved.

Biotransformation and mass balance of tipranavir, a nonpeptidic protease inhibitor, when co-administered with ritonavir in Sprague-Dawley rats.

PubMed

Macha, Sreeraj; Chen, Linzhi; Norris, Stephen H; Philip, Elsy; Mao, Yanping; Silverstein, Helga; Struble, Craig; Beers, Wendy

2007-09-01

In this study, tipranavir (TPV) biotransformation and disposition when co-administered with ritonavir (RTV) were characterized in Sprague-Dawley rats. Rats were administered a single intravenous (5 mg kg(-1)) or oral (10 mg kg(-1)) dose of [(14)C]TPV with co-administration of RTV (10 mg kg(-1)). Blood, urine, faeces and bile samples were collected at specified time-points over a period of 168 h. Absorption of TPV-related radioactivity ranged from 53.2-59.6%. Faecal excretion was on average 86.7% and 82.4% (intravenous) and 75.0% and 82.0% (oral) of dosed radioactivity in males and females, respectively. Urinary excretion was on average 4.06% and 6.73% (intravenous) and 9.71% and 8.28% (oral) of dosed radioactivity in males and females, respectively. In bile-duct-cannulated rats, 39.8% of the dose was recovered in bile. After oral administration, unchanged TPV accounted for the majority of the radioactivity in plasma (85.7-96.3%), faeces (71.8-80.1%) and urine (33.3-62.3%). The most abundant metabolite in faeces was an oxidation metabolite R-2 (5.9-7.4% of faecal radioactivity, 4.4-6.1% of dose). In urine, no single metabolite was found to be significant, and comprised <1% of dose. TPV when co-administered with RTV to rats was mainly excreted in feces via bile and the parent compound was the major component in plasma and faeces.

Rubus occidentalis analgesic effect in a rat model of incisional pain.

PubMed

Choi, Geun Joo; Kang, Hyun; Kim, Won Joong; Kwon, Ji Wung; Kim, Beom Gyu; Choi, Yoo Shin; Cha, Young Joo; Ko, Jin Soo

2016-11-01

The purpose of this study was to evaluate the analgesic effect of Rubus occidentalis extract (ROE) in a rat model of incisional pain. The involved mechanisms and proinflammatory cytokine response were also examined. To investigate the analgesic effect, rats were intraperitoneally administered with normal saline or various doses of ROE before or after a plantar incision. To evaluate the involved mechanism, rats were intraperitoneally administered yohimbine, dexmedetomidine, prazosin, naloxone, atropine, or mecamylamine after a plantar incision; ROE was then administered intraperitoneally. The mechanical withdrawal threshold (MWT) was tested with von Frey filaments at various time points. To determine the inflammatory response, serum levels of interleukin (IL)-1β or IL-6 were measured. The MWTs significantly increased at 15 min after postincisional administration of 300 mg/kg ROE when compared with those in the control group. This elevation was observed for up to 45 min. Overall, MWTs increased in proportion to ROE dosage; however, ROEs administered before the incision produced no significant change in the MWT. The analgesic effect of ROE was significantly antagonized by mecamylamine, naloxone, and yohimbine, and agonized by dexmedetomidine. Administration of ROE inhibited the postincisional increase in serum IL-1β and IL-6. Intraperitoneal administration of ROE after surgery induces antinociceptive effects in a rat model of postoperative pain, and its effects on mechanical hyperalgesia may be associated with α 2 -adrenergic, nicotinic cholinergic, and opioid receptors. Copyright © 2016 Elsevier Inc. All rights reserved.

Electroacupuncture prevents endothelial dysfunction induced by ischemia-reperfusion injury via a cyclooxygenase-2-dependent mechanism: A randomized controlled crossover trial

PubMed Central

Park, Jimin; Woo, Jong Shin; Leem, Jungtae; Park, Jun Hyeong; Lee, Sanghoon; Chung, Hyemoon; Lee, Jung Myung; Kim, Jin-Bae; Kim, Woo-Shik; Kim, Kwon Sam; Kim, Weon

2017-01-01

Objective Exploring clinically effective methods to reduce ischemia-reperfusion (IR) injury in humans is critical. Several drugs have shown protective effects, but studies using other interventions have been rare. Electroacupuncture (EA) has induced similar protection in several animal studies but no study has investigated how the effects could be translated and reproduced in humans. This study aimed to explore the potential effect and mechanisms of EA in IR-induced endothelial dysfunction in humans. Methods This is a prospective, randomized, crossover, sham-controlled trial consisting of two protocols. Protocol 1 was a crossover study to investigate the effect of EA on IR-induced endothelial dysfunction. Twenty healthy volunteers were randomly assigned to EA or sham EA (sham). Flow mediated dilation (FMD) of the brachial artery (BA), nitroglycerin-mediated endothelial independent dilation, blood pressure before and after IR were measured. In protocol 2, seven volunteers were administered COX-2 inhibitor celecoxib (200 mg orally twice daily) for five days. After consumption, volunteers underwent FMD before and after IR identical to protocol 1. Results In protocol 1, baseline BA diameter, Pre-IR BA diameter and FMD were similar between the two groups (p = NS). After IR, sham group showed significantly blunted FMD (Pre-IR: 11.41 ± 3.10%, Post-IR: 4.49 ± 2.04%, p < 0.001). However, EA protected this blunted FMD (Pre-IR: 10.96 ± 5.30%, Post-IR: 9.47 ± 5.23%, p = NS, p < 0.05 compared with sham EA after IR). In protocol 2, this protective effect was completely abolished by pre-treatment with celecoxib (Pre-IR: 11.05 ± 3.27%; Post-IR: 4.20 ± 1.68%, p = 0.001). Conclusion EA may prevent IR-induced endothelial dysfunction via a COX-2 dependent mechanism. PMID:28591155

Improved sexual behavior in male rats treated with a Chinese herbal extract: hormonal and neuronal implications.

PubMed

Zanoli, Paola; Benelli, Augusta; Zavatti, Manuela; Rivasi, Marianna; Baraldi, Claudia; Baraldi, Mario

2008-11-01

To investigate the influence of an extract obtained from five Chinese medicinal plants on sexual behavior of adult male rats. The extract was administered at doses of 30, 60 and 120 mg/kg by oral gavage, acutely (one time, 45 min before mating test) or subchronically (daily for 10 days) in sexually potent and sexually sluggish/impotent rats. Sexual behavior, serum levels of luteinizing hormone (LH) and testosterone (T) were evaluated in treated rats and compared with controls receiving vehicle. The effect of the extract on central dopaminergic neurotransmission was assessed in the nucleus accumbens using a microdialysis technique. In sexually potent rats, both acute and subchronic treatment with the extract dosed at 30 and 60 mg/kg reduced mount latency and intromission latency. In sluggish/impotent rats, the acutely administered extract at the dose of 60 mg/kg shortened ejaculation latency, whereas subchronically administered at the doses of 30 and 60 mg/kg, reduced mount, intromission and ejaculation latencies, increasing also the percentage of mounting and ejaculating rats. The extract dosed at 60 mg/kg significantly increased LH and T following acute and subchronic administration and increased 3,4-dihydroxyphenylacetic acid levels in the nucleus accumbens, 30 min after the acute administration. The improvement in both appetitive and consummatory components of sexual behavior observed in male rats treated with the extract could be ascribed to increased serum T level in parallel with the activation of the central dopaminergic system. (c) 2008, Asian Journal of Andrology, SIMM and SJTU. All rights reserved.

A sense oligonucleotide to inducible nitric oxide synthase mRNA increases the survival rate of rats in septic shock.

PubMed

Okuyama, Tetsuya; Nakatake, Richi; Kaibori, Masaki; Okumura, Tadayoshi; Kon, Masanori; Nishizawa, Mikio

2018-01-30

Natural antisense transcripts (asRNAs) that do not encode proteins are transcribed from rat, mouse, and human genes, encoding inducible nitric oxide synthase (iNOS), which catalyzes the production of the inflammatory mediator nitric oxide (NO). In septic shock, NO is excessively produced in hepatocytes and macrophages. The iNOS asRNA interacts with and stabilizes iNOS mRNA. We found that single-stranded 'sense' oligonucleotides corresponding to the iNOS mRNA sequence reduced iNOS mRNA levels by interfering with the mRNA-asRNA interactions in rat hepatocytes. The iNOS sense oligonucleotides that were substituted with phosphorothioate bonds and locked nucleic acids efficiently decreased the levels of iNOS mRNA and iNOS protein. In this study, the gene expression patterns in the livers of two endotoxemia model rats with acute liver failure were compared. Next, we optimized the sequence and modification of the iNOS sense oligonucleotides in interleukin 1β-treated rat hepatocytes. When a sense oligonucleotide was simultaneously administered with d-galactosamine and bacterial lipopolysaccharide (LPS) to rats, their survival rate significantly increased compared to the rats administered d-galactosamine and LPS alone. In the livers of the sense oligonucleotide-administered rats, apoptosis in the hepatocytes markedly decreased. These results suggest that natural antisense transcript-targeted regulation technology using iNOS sense oligonucleotides may be used to treat human inflammatory diseases, such as sepsis and septic shock. Copyright © 2017 Elsevier Inc. All rights reserved.

Successful treatment of an unresectable inflammatory myofibroblastic tumor of the frontal bone using a cyclooxygenase-2 inhibitor and methotrexate.

PubMed

Kusunoki-Nakamoto, Fumiko; Matsukawa, Takashi; Tanaka, Masaki; Miyagawa, Toji; Yamamoto, Tomotaka; Shimizu, Jun; Ikemura, Masako; Shibahara, Junji; Tsuji, Shoji

2013-01-01

Inflammatory myofibroblastic tumor (IMT) is a disease characterized by tumorous lesions consisting of myofibroblastic spindle cells and inflammatory cells that occur primarily in the soft tissues and viscera of children and young adults. Total excision is the most effective therapy. Steroids have been used to treat unresectable lesions with some success. We herein report a case of IMT involving the frontal bone accompanied by pachymeningitis. The tumor was characterized by an aggressive clinical course that was refractory to prednisolone. Performing total excision seemed difficult. Celecoxib and methotrexate were effective treatments. Our experience suggests the efficacy of celecoxib and methotrexate as alternatives for treating unresectable IMT.

Suppression of secondary immune response by antilymphocyte serum: time relationship between immunization and administration of antilymphocyte serum.

PubMed Central

Reuben, C; Sundaram, K; Phondke, G P

1979-01-01

The effect of antilymphocyte serum (ALS) on the secondary humoral immune response to sheep erythrocytes (SRBC) in rats was studied by the Jerne plaque assay technique. Its effect was also studied on the delayed hypersensitivity (DH) response to SRBC by the foot pad swelling test. ALS(N), which was prepared against lymphocytes from normal rats, had no effect on the secondary humoral and cellular response or on the primary cellular response, when administered postantigenically. ALS(I), which was raised against lymph node cells from SRBC immunized rats produced significant immunosuppression of the secondary response to SRBC when administered either before or after the antigenic injections. In the case of DH, ALS(I) behaved just like ALS(N) having no effect on the secondary response and suppressing the primary only when administered prior to the antigen. PMID:369994

Topically applied standardized aqueous extract of Curcuma longa Linn. suppresses endotoxin-induced uveal inflammation in rats.

PubMed

Agarwal, Renu; Gupta, S K; Agarwal, Puneet; Srivastava, Sushma

2013-10-01

Aqueous extract of C. longa when administered 4 h after induction of E. coli lipopolysaccharide-induced uveitis in rats showed significantly suppressed inflammation with a significantly lower mean clinical grade, histopathological grade and aqueous humor (AH) protein level compared to vehicle treated group. Although, prednisolone group showed significantly lower clinical grade, histopathological grades and AH protein levels compared to C. longa group, TNF-alpha levels did not differ significantly. Moreover, when the aqueous extract was administered starting from 3 days before induction of uveitis, the mean clinical and histopathological grade as well as AH protein and TNF-alpha levels were comparable to C. longa group when treatment was administered 4 h after induction of uveitis. It is concluded that topically applied standardized aqueous extract of C. longa suppresses endotoxin-induced uveitis in rats by reducing TNF-alpha activity.

Estrogen rapidly enhances incisional pain of ovariectomized rats primarily through the G protein-coupled estrogen receptor.

PubMed

An, Guanghui; Li, Wenhui; Yan, Tao; Li, Shitong

2014-06-11

It has become increasingly apparent that the pain threshold of females and males varies in an estrogen dependent manner. To investigate the modulation of pain by estrogen and the molecular mechanisms involved in this process. A total of 48 rats were ovariectomized (OVX). At 14 and 20 days after OVX, rats were divided into eight groups: groups 1-4 were administered drugs intravenously (IV); groups 5-8 were administered through intrathecal (IT) catheter. Hind paw incision was made in all animals to determine incisional pain. Paw withdraw threshold (PWT) was tested prior to and 24 h after incision. The test drugs were applied 24 h after the incision. Rats were either IV or IT administered with: 17-β-estradiol (E2), G protein-coupled estrogen receptor (GPER)-selective agonist (G1), GPER-selective antagonist (G15) and E2 (G15+E2), or solvent. Before and 30 min after IV drug administration and 20 min during the IT catheter administration, PWT was tested and recorded. 24 h after incisional surgery, the PWT of all rats significantly decreased. Both in the IV group and IT group: administration of E2 and G1 significantly decreased PWT. Neither administration of G15+E2 nor solvent significantly changed PWT. Estrogen causes rapid reduction in the mechanical pain threshold of OVX rats via GPER.

Rat-bite fever presenting with rash and septic arthritis.

PubMed

Kanechorn Na Ayuthaya, Rajyani; Niumpradit, Nucha

2005-11-01

Rat-bite fever is an uncommon disease known for its endemicity to occur worldwide. Although most patients tend to develop mild symptoms with improvement from conventional antibiotics, it can progress with severe complications with a mortality rate as high as 13% without proper treatment. The authors report a complicated case of rat bite-fever involving a 61-year old woman who presented with fever petechial rash, and septic arthritis following a rat bite. Initially, multiple antibiotics were administered but were not effective. As a consequence, invasive procedures such as arthrotomy and joint debridement were done and prolonged antibiotic was administered until clinical resolution. Since many cases do not have a history of rat bite and may present with fever, rashes, and arthritis it is essential to distinguish it from other diseases. Here, the authors will provide details on the etiology, clinical manifestations, diagnosis, and management to aid prompt detection and treatment of the disease.

Pretreatment with alcoholic extract of Crataegus oxycantha (AEC) activates mitochondrial protection during isoproterenol - induced myocardial infarction in rats.

PubMed

Jayalakshmi, R; Thirupurasundari, C J; Devaraj, S Niranjali

2006-11-01

Crataegus oxycantha (hawthorn) is used in herbal and homeopathic medicine as a cardiotonic. The present study was done to investigate the effect of the alcoholic extract of Crataegus oxycantha (AEC) on mitochondrial function during experimentally induced myocardial infarction in rat. AEC was administered orally to male albino rats (150-200 g), at a dosage of 0.5 ml/100 g body weight/day, for 30 days. At the end of the experimental period, the animals were administered isoproterenol (85 mg/kg body weight, s.c) for 2 days at an interval of 24 h. After 48 h, the rats were anaesthetized and sacrificed. The hearts were homogenized for biochemical and electron microscopic analysis. AEC pretreatment maintained mitochondrial antioxidant status, prevented mitochondrial lipid peroxidative damage and decrease in Kreb's cycle enzymes induced by isoproterenol in rat heart.

The Effect of Lactic Acid Bacteria-fermented Soybean Milk Products on Carrageenan-induced Tail Thrombosis in Rats

PubMed Central

KAMIYA, Seitaro; OGASAWARA, Masayoshi; ARAKAWA, Masayuki; HAGIMORI, Masayori

2013-01-01

Thrombosis is characterized by congenital and acquired procatarxis. Lactic acid bacteria-fermented soybean milk products (FS-LAB) inhibit hepatic lipid accumulation and prevent atherosclerotic plaque formation. However, the therapeutic efficacy of FS-LAB against thrombosis has yet to be investigated. In this study, FS-LAB were administered subcutaneously into the tails of rats, with the subsequent intravenous administration of κ-carrageenan 12 hr after the initial injection. In general, administration of κ-carrageenan induces thrombosis. The length of the infarcted tail regions was significantly shorter in the rats administered a single-fold or double-fold concentration of the FS-LAB solution compared with the region in control rats. Therefore, FS-LAB exhibited significant antithrombotic effects. Our study is the first to characterize the properties of FS-LAB and, by testing their efficacy on an in vivo rat model of thrombosis, demonstrate the potency of their antithrombotic effect. PMID:24936368

THE METABOLISM OF SILICON IN THE RAT AND ITS RELATION TO THE FORMATION OF ARTIFICIAL SILICEOUS CALCULI

PubMed Central

Keeler, Richard F.; Lovelace, Stuart A.

1959-01-01

The urinary excretion of silicon in the rat was found to be enhanced beyond normal levels by the administration of various chemical forms of silicon. The excretion was enhanced to a much greater degree by the administration of ethyl silicate than by magnesium trisilicate, sodium metasilicate, or water glass. The tolerance level of rats to sustained daily doses of ethyl silicate fed via stomach tube was approximately 15 to 30 mg. of silicon per rat per day. Urinary silicon excretion was found to be a straight line function of the concentration of ethyl silicate administered, via stomach tube, with approximately 18 per cent of the administered silicon appearing in the urine at all levels tested. Using sustained dietary additions of ethyl silicate as a means of enhancing urine silicon levels, artificial siliceous urinary calculi were consistently produced on zinc pellets implanted in the bladders of rats. PMID:13654631

Ulva lactuca polysaccharides prevent Wistar rat breast carcinogenesis through the augmentation of apoptosis, enhancement of antioxidant defense system, and suppression of inflammation

PubMed Central

Abd-Ellatef, Gamal-Eldein F; Ahmed, Osama M; Abdel-Reheim, Eman S; Abdel-Hamid, Abdel-Hamid Z

2017-01-01

Background Recently, several research studies have been focused on the isolation and function of the polysaccharides derived from different algal species, which revealed multiple biological activities such as antioxidant and antitumor activities. This study assesses the possible breast cancer chemopreventive properties of common seaweeds, sea lettuce, Ulva lactuca (ulvan) polysaccharides using in vitro bioassays on human breast cancer cell line (MCF-7) and an in vivo animal model of breast carcinogenesis. Methods Cytotoxic effect of ulvan polysaccharides on MCF-7 was tested in vitro. For an in vivo investigation, a single dose of 25 mg/kg body weight 7,12-dimethylbenz[a]anthracene (DMBA) and ulvan polysaccharides (50 mg/kg body weight every other day) for 10 weeks were administered orally to the Wistar rats. Results Deleterious histopathological alterations in breast tissues including papillary cyst adenoma and hyperplasia of ductal epithelial lining with intraluminal necrotic materials and calcifications were observed in the DMBA-administered group. These lesions were prevented in the DMBA-administered group treated with ulvan polysaccharides. The immunohistochemical sections depicted that the treatment of DMBA-administered rats with ulvan polysaccharides markedly increased the lowered pro-apoptotic protein, p53, and decreased the elevated anti-apoptotic marker, bcl2, expression in the breast tissue. The elevated lipid peroxidation and the suppressed antioxidant enzyme activities in DMBA-administered control were significantly prevented by the treatment with ulvan polysaccharides. The elevated levels of inflammatory cytokines tumor necrosis factor-α and nitric oxide were significantly ameliorated in DMBA-administered rats treated with ulvan polysaccharides as compared to DMBA-administered control. Conclusion In conclusion, ulvan polysaccharides at the level of initiation and promotion might have potential chemopreventive effects against breast carcinogenesis. These preventive effects may be mediated through the augmentation of apoptosis, suppression of oxidative stress and inflammation, and enhancement of antioxidant defense system. PMID:28280387

Glaucoma drops control intraocular pressure and protect optic nerves in a rat model of glaucoma.

PubMed

Morrison, J C; Nylander, K B; Lauer, A K; Cepurna, W O; Johnson, E

1998-03-01

To determine whether chronic topical glaucoma therapy can control intraocular pressure (IOP) and protect nerve fibers in a rat model of pressure-induced optic nerve damage. Sixteen adult Brown Norway rats were-administered unilateral episcleral vein injections of hypertonic saline to produce scarring of the aqueous humor outflow pathways. Twice daily applications of either artificial tears (n = 6), 0.5% betaxolol (n = 5), or 0.5% apraclonidine (n = 5) were delivered to both eyes, and awake pressures were monitored with a TonoPen XL tonometer for 17 days before the rats were killed. For animals administered artificial tears, the mean IOP of the experimental eyes was 39 +/- 2 mm Hg compared with 29 +/- 1 mm Hg for the control eyes. This difference was statistically significant (P < 0.001). Mean IOPs in the experimental eyes of animals administered betaxolol and apraclonidine were 29 +/- 7 and 29 +/- 4 mm Hg, respectively, whereas the mean IOP in the control eyes was 28 +/- 1 mm Hg for both groups. There was no statistically significant difference among these values. The mean IOP for the experimental eyes in the betaxolol and apraclonidine groups was lower than that in animals administered artificial tears (P = 0.003). Quantitative histologic analysis of optic nerve damage in experimental eyes showed that four of the six animals administered artificial tears had damage involving 100% of the neural area. This degree of damage appeared in only 3 of 10 animals administered glaucoma therapy. Optic nerve protection was closely correlated with IOP history because damage was limited to less than 10% of the cross-sectional area in all animals in which the maximal IOP was less than or equal to 39 mm Hg, more than 2 SD below the mean value for eyes administered artificial tears. Topical glaucoma therapy in this model can prevent IOP elevation and protect optic nerve fibers.

A choice-based screening method for compulsive drug users in rats.

PubMed

Lenoir, Magalie; Augier, Eric; Vouillac, Caroline; Ahmed, Serge H

2013-07-01

We describe a protocol for screening compulsive drug users among cocaine self-administering rats, the most frequently used animal model in addiction research. Rats are first trained on several alternating days to self-administer either cocaine (i.v.) or saccharin-sweetened water (by mouth)--a potent, albeit nonessential, nondrug reward. Then rats are allowed to choose between the two rewards over several days until the preference stabilizes. Most rats choose to stop using cocaine and pursue the alternative reward. Only a minority of Wistar strain rats (generally 15%) persist in taking the drug, regardless of the severity of past cocaine use and even when made hungry and offered the possibility to relieve their physiological need. Persistence of cocaine use in the face of a high-stakes choice is a core defining feature of compulsion. This choice-based screening method for compulsive drug users is easy to implement, has several important applications, and compares well with other methods in the field. 2013 by John Wiley & Sons, Inc.

Effects of caffeine on alcohol consumption and nicotine self-administration in rats.

PubMed

Rezvani, Amir H; Sexton, Hannah G; Johnson, Joshua; Wells, Cori; Gordon, Karen; Levin, Edward D

2013-09-01

Caffeine, alcohol, and nicotine are 3 of the most widespread self-administered psychoactive substances, which are known to be extensively co-administered. However, little is known about the degree to which they may mutually potentiate each other's consumption. In the current set of studies, we examined in rats the effect of caffeine administration on alcohol drinking and intravenous (i.v.) self-administration of nicotine. In male alcohol-preferring (P) rats, caffeine (5, 10, and 20 mg/kg) or the saline vehicle was administered acutely either by subcutaneous (S.C.) injection or orally (PO) by gavage. In a chronic study, the effect of PO caffeine (5 and 20 mg/kg) on alcohol intake over a 10-day period was tested. In another experiment, the effect of acute PO administration of caffeine (20 mg/kg) or saline on saccharin intake (0.2% solution) was determined in P rats. Effects of 20 mg/kg caffeine on motor activity were also determined in P rats. Finally, the effects of acute PO caffeine administration on nicotine self-administration in Sprague-Dawley rats were also determined. Both routes of administration of caffeine, S.C. and PO, caused a significant dose-related decrease in alcohol intake and preference during free access to alcohol and after 4-day deprivation of alcohol. However, the low dose of 5 mg/kg caffeine increased alcohol intake. Acute PO caffeine also reduced saccharin intake. Acute systemic administration of 20 mg/kg caffeine did not exert a significant effect on motor activity. In Sprague-Dawley rats trained to self-administer i.v. nicotine, acute PO administration of caffeine significantly increased self-administration of nicotine in a dose-related manner. These results suggest that adenosine receptor systems may play a role in both alcohol and nicotine intake and deserve further study regarding these addictions. Copyright © 2013 by the Research Society on Alcoholism.

A rat model of nerve agent exposure applicable to the pediatric population: The anticonvulsant efficacies of atropine and GluK1 antagonists.

PubMed

Miller, Steven L; Aroniadou-Anderjaska, Vassiliki; Figueiredo, Taiza H; Prager, Eric M; Almeida-Suhett, Camila P; Apland, James P; Braga, Maria F M

2015-04-15

Inhibition of acetylcholinesterase (AChE) after nerve agent exposure induces status epilepticus (SE), which causes brain damage or death. The development of countermeasures appropriate for the pediatric population requires testing of anticonvulsant treatments in immature animals. In the present study, exposure of 21-day-old (P21) rats to different doses of soman, followed by probit analysis, produced an LD50 of 62μg/kg. The onset of behaviorally-observed SE was accompanied by a dramatic decrease in brain AChE activity; rats who did not develop SE had significantly less reduction of AChE activity in the basolateral amygdala than rats who developed SE. Atropine sulfate (ATS) at 2mg/kg, administered 20 min after soman exposure (1.2×LD50), terminated seizures. ATS at 0.5mg/kg, given along with an oxime within 1 min after exposure, allowed testing of anticonvulsants at delayed time-points. The AMPA/GluK1 receptor antagonist LY293558, or the specific GluK1 antagonist UBP302, administered 1h post-exposure, terminated SE. There were no degenerating neurons in soman-exposed P21 rats, but both the amygdala and the hippocampus were smaller than in control rats at 30 and 90days post-exposure; this pathology was not present in rats treated with LY293558. Behavioral deficits present at 30 days post-exposure, were also prevented by LY293558 treatment. Thus, in immature animals, a single injection of atropine is sufficient to halt nerve agent-induced seizures, if administered timely. Testing anticonvulsants at delayed time-points requires early administration of ATS at a low dose, sufficient to counteract only peripheral toxicity. LY293558 administered 1h post-exposure, prevents brain pathology and behavioral deficits. Published by Elsevier Inc.

Effects of non-steroidal anti-inflammatory drugs on proliferation, differentiation and migration in equine mesenchymal stem cells.

PubMed

Müller, Maike; Raabe, Oksana; Addicks, Klaus; Wenisch, Sabine; Arnhold, Stefan

2011-03-01

In equine medicine, stem cell therapies for orthopaedic diseases are routinely accompanied by application of NSAIDs (non-steroidal anti-inflammatory drugs). Thus, it has to be analysed how NSAIDs actually affect the growth and differentiation potential of MSCs (mesenchymal stem cells) in vitro in order to predict the influence of NSAIDs such as phenylbutazone, meloxicam, celecoxib and flunixin on MSCs after grafting in vivo. The effects of NSAIDs were evaluated regarding cell viability and proliferation. Additionally, the multilineage differentiation capacity and cell migration was analysed. NSAIDs at lower concentrations (0.1-1 μM for celecoxib and meloxicam and 10-50 μM for flunixin) exert a positive effect on cell proliferation and migration, while at higher concentrations (10-200 μM for celecoxib and meloxicam and 100-1000 μM for flunixin and phenylbutazone), there is rather a negative influence. While there is hardly any influence on the adipogenic as well as on the chondrogenic MSC differentiation, the osteogenic differentiation potential, as demonstrated with the von Kossa staining, is significantly disturbed. Thus, it can be concluded that the effects of NSAIDs on MSCs are largely dependent on the concentrations used. Additionally, for some differentiation lineages, also the choice of NSAID is critical.

Celecoxib-Induced Self-Assembly of Smart Albumin-Doxorubicin Conjugate for Enhanced Cancer Therapy.

PubMed

Shi, Leilei; Xu, Li; Wu, Chenwei; Xue, Bai; Jin, Xin; Yang, Jiapei; Zhu, Xinyuan

2018-03-14

Recent years have witnessed the great contributions that drug combination therapy has made for enhanced cancer therapy. However, because of the complicated pharmacokinetics of combined drug formulations, the majority of combination strategies show severe adverse effects at high dosage and poor biodistribution in vivo. To overcome these deficiencies and achieve enhanced cancer therapy, we put forward a method to construct a smart albumin-based nanoplatform, denoted as K237-HSA-DC, for codelivery of cyclooxygenase-2 (COX-2) inhibitor (celecoxib) and chemotherapeutic agent (doxorubicin, DOX). Both in vitro and in vivo studies indicate that K237-HSA-DC exhibits the best therapeutic efficacy on tumor cells compared with all the other formulations. Moreover, K237-HSA-DC shows fewer side effects on normal organs in contrast to other formulations. To understand the reasons behind the improved drug efficacy in depth, we performed a cell metabonomics-based mechanism study and found that celecoxib could enhance the inhibitory effect of DOX on the transport of glucose into cells and then lead to subsequent significant energy metabolism inhibition. Considering the above-mentioned advantages of K237-HSA-DC, we believe the smart albumin-based nanoplatform can serve as a promising drug delivery system for enhanced cancer therapy.

Continuous low-dose cyclophosphamide and methotrexate combined with celecoxib for patients with advanced cancer

PubMed Central

Khan, O A; Blann, A D; Payne, M J; Middleton, M R; Protheroe, A S; Talbot, D C; Taylor, M; Han, C; Patil, M; Harris, A L

2011-01-01

Background: Combined therapy of metronomic cyclophosphamide, methotrexate and high-dose celecoxib targeting angiogenesis was used in a phase II trial. Methods: Patients with advanced cancer received oral cyclophosphamide 50 mg o.d., celecoxib 400 mg b.d. and methotrexate 2.5 mg b.d. for two consecutive days each week. Response was determined every 8 weeks; toxicity was evaluated according to CTC version 2.0. Plasma markers of inflammation, coagulation and angiogenesis were measured. Results: Sixty-seven of 69 patients were evaluable for response. Twenty-three patients had stable disease (SD) after 8 weeks, but there were no objective responses to therapy. Median time to progression was 57 days. There was a low incidence of toxicities. Among plasma markers, levels of tissue factor were higher in the SD group of patients at baseline, and levels of both angiopoietin-1 and matrix metalloproteinase-9 increased in the progressive disease group only. There were no changes in other plasma markers. Conclusion: This metronomic approach has negligible activity in advanced cancer albeit with minimal toxicity. Analysis of plasma markers indicates minimal effects on endothelium in this trial. These data for this particular regimen do not support basic tenets of metronomic chemotherapy, such as the ability to overcome resistant tumours by targeting the endothelium. PMID:21587257

Continuous low-dose cyclophosphamide and methotrexate combined with celecoxib for patients with advanced cancer.

PubMed

Khan, O A; Blann, A D; Payne, M J; Middleton, M R; Protheroe, A S; Talbot, D C; Taylor, M; Kirichek, O; Han, C; Patil, M; Harris, A L

2011-06-07

Combined therapy of metronomic cyclophosphamide, methotrexate and high-dose celecoxib targeting angiogenesis was used in a phase II trial. Patients with advanced cancer received oral cyclophosphamide 50 mg o.d., celecoxib 400 mg b.d. and methotrexate 2.5 mg b.d. for two consecutive days each week. Response was determined every 8 weeks; toxicity was evaluated according to CTC version 2.0. Plasma markers of inflammation, coagulation and angiogenesis were measured. Sixty-seven of 69 patients were evaluable for response. Twenty-three patients had stable disease (SD) after 8 weeks, but there were no objective responses to therapy. Median time to progression was 57 days. There was a low incidence of toxicities. Among plasma markers, levels of tissue factor were higher in the SD group of patients at baseline, and levels of both angiopoietin-1 and matrix metalloproteinase-9 increased in the progressive disease group only. There were no changes in other plasma markers. This metronomic approach has negligible activity in advanced cancer albeit with minimal toxicity. Analysis of plasma markers indicates minimal effects on endothelium in this trial. These data for this particular regimen do not support basic tenets of metronomic chemotherapy, such as the ability to overcome resistant tumours by targeting the endothelium.

Bone curvature changes can predict the impact of treatment on cartilage volume loss in knee osteoarthritis: data from a 2-year clinical trial.

PubMed

Raynauld, Jean-Pierre; Pelletier, Jean-Pierre; Delorme, Philippe; Dodin, Pierre; Abram, François; Martel-Pelletier, Johanne

2017-06-01

Knee bone curvature assessed by MRI was associated with OA cartilage loss. A recent knee OA trial demonstrated the superiority of chondroitin sulfate over celecoxib (comparator) at reducing cartilage volume loss (CVL) in the medial compartment (condyle). The main objectives were to identify which baseline bone curvature regions of interest (BCROI) best associated with CVL and investigate whether baseline BCROI and 2-year change are correlated with the protective effect of chondroitin sulphate on CVL. This post hoc analysis of a clinical trial used the according-to-protocol population (chondroitin sulphate, n = 57; celecoxib, n = 63) baseline and 2-year MRI to assess bone curvature and CVL. Global optimum search identified the BCROI in the medial condyle using celecoxib as reference. Statistical analyses were performed with Pearson's correlation, Mann-Whitney U -test, Student's t -test and analysis of covariance. The BCROI including the medial posterior condyle and lateral central condyle was found to correlate best with medial condyle CVL at 2 years ( r = 0.33, P = 0.008). In patients with a baseline BCROI value less than the median (more flattened bone), chondroitin sulphate demonstrated a protective effect on CVL compared with celecoxib in the medial compartment (P = 0.037). In patients with 2-year BCROI changes greater than the median (greater severity of bone flattening), chondroitin sulphate protected against CVL in the medial compartment, condyle and central plateau (P ⩽ 0.030). This study is the first to demonstrate the feasibility and usefulness of bone curvature measurements to predict effectiveness of OA treatment on CVL. The results identify bone curvature as a potential novel biomarker for knee OA clinical trials. © The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Need for common internal controls when assessing the relative efficacy of pharmacologic agents using a meta-analytic approach: case study of cyclooxygenase 2-selective inhibitors for the treatment of osteoarthritis.

PubMed

Lee, Chin; Hunsche, Elke; Balshaw, Robert; Kong, Sheldon X; Schnitzer, Thomas J

2005-08-15

To evaluate the role of common internal controls in a meta-analysis of the relative efficacy of cyclooxygenase 2-selective inhibitors (coxibs) in the treatment of osteoarthritis (OA). A systematic search of Medline and US Food and Drug Administration electronic databases was performed to identify randomized, placebo-controlled clinical trials of coxibs (etoricoxib, celecoxib, rofecoxib, valdecoxib) in patients with hip and/or knee OA. The effect size for coxibs and common active internal controls (nonsteroidal antiinflammatory drugs [NSAIDs], naproxen) were determined by the mean changes from baseline in Western Ontario and McMaster Universities Osteoarthritis Index pain subscores as compared with placebo. The effect size for all coxib groups combined (0.44) indicated greater efficacy as compared with placebo, but significant heterogeneity (P < 0.0001) was observed. Rofecoxib at dosages of 12.5 mg/day and 25 mg/day and etoricoxib at a dosage of 60 mg/day had similar effect sizes (0.68 and 0.73, respectively), but these effect sizes were comparatively greater than those for both celecoxib at dosages of 200 mg/day and 100 mg twice daily or valdecoxib at a dosage of 10 mg/day (0.26 and 0.16, respectively). The effect sizes for NSAIDs or naproxen versus placebo, as determined using data from rofecoxib/etoricoxib trials, were consistently higher than the effect sizes derived from trials of celecoxib/valdecoxib. Significant heterogeneity was present in the overall effect size for NSAIDs (P = 0.007) and naproxen (P = 0.04) groups based on data available from all coxib trials. Coxibs and common active internal controls showed larger effect sizes versus placebo in the rofecoxib/etoricoxib trials than in the celecoxib/valdecoxib trials. These findings suggest systematic differences among published coxib trials and emphasize the need for direct-comparison trials. In the absence of such trials, common internal controls should be assessed when performing indirect meta-analytic comparisons.

Oxidative stress of crystalline lens in rat menopausal model.

PubMed

Acer, Semra; Pekel, Gökhan; Küçükatay, Vural; Karabulut, Aysun; Yağcı, Ramazan; Çetin, Ebru Nevin; Akyer, Şahika Pınar; Şahin, Barbaros

2016-01-01

To evaluate lenticular oxidative stress in rat menopausal models. Forty Wistar female albino rats were included in this study. A total of thirty rats underwent oophorectomy to generate a menopausal model. Ten rats that did not undergo oophorectomy formed the control group (Group 1). From the rats that underwent oophorectomy, 10 formed the menopause control group (Group 2), 10 were administered a daily injection of methylprednisolone until the end of the study (Group 3), and the remaining 10 rats were administered intraperitoneal streptozocin to induce diabetes mellitus (Group 4). Total oxidant status (TOS), total antioxidant capacity (TAC), and oxidative stress index (OSI) measurements of the crystalline lenses were analyzed. The mean OSI was the lowest in group 1 and highest in group 4. Nevertheless, the difference between the groups was not statistically significant in terms of OSI (p >0.05). The mean TOS values were similar between the groups (p >0.05), whereas the mean TAC of group 1 was significantly higher than that of the other groups (p <0.001). Our results indicate that menopause may not promote cataract formation.

Nicotine is neuroprotective when administered before but not after nigrostriatal damage in rats and monkeys.

PubMed

Huang, Luping Z; Parameswaran, Neeraja; Bordia, Tanuja; Michael McIntosh, J; Quik, Maryka

2009-05-01

Nicotine reduces dopaminergic deficits in parkinsonian animals when administered before nigrostriatal damage. Here we tested whether nicotine is also beneficial when given to rats and monkeys with pre-existing nigrostriatal damage. Rats were administered nicotine before and after a unilateral 6-hydroxydopamine lesion of the medial forebrain bundle, and the results compared with those in which rats received nicotine only after lesioning. Nicotine pre-treatment attenuated behavioral deficits and lessened lesion-induced losses of the striatal dopamine transporter, and alpha6beta2* and alpha4beta2* nicotinic receptors (nAChRs). By contrast, nicotine administered 2 weeks after lesioning, when 6-hydroxydopamine-induced neurodegenerative effects are essentially complete, did not improve these same measures. Similar results were observed in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned monkeys. Nicotine did not enhance striatal markers when administered to monkeys with pre-existing nigrostriatal damage, in contrast to previous data that showed improvements when nicotine was given to monkeys before lesioning. These combined findings in two animal models suggest that nicotine is neuroprotective rather than neurorestorative against nigrostriatal damage. Receptor studies with (125)I-alpha-conotoxinMII and the alpha-conotoxinMII analog E11A were next performed to determine whether nicotine treatment pre- or post-lesioning differentially affected expression of alpha6alpha4beta2* and alpha6(nonalpha4)beta2* nAChR subtypes in striatum. The observations suggest that protection against nigrostriatal damage may be linked to striatal alpha6alpha4beta2* nAChRs.

Chronic Arachidonic Acid Administration Decreases Docosahexaenoic Acid- and Eicosapentaenoic Acid-Derived Metabolites in Kidneys of Aged Rats.

PubMed

Katakura, Masanori; Hashimoto, Michio; Inoue, Takayuki; Mamun, Abdullah Al; Tanabe, Yoko; Arita, Makoto; Shido, Osamu

2015-01-01

Arachidonic acid (ARA) metabolites produced by cyclo-oxygenase and lipoxygenase are important mediators maintaining physiological renal function. However, the effects of exogenous ARA on kidney function in vivo remain unknown. This study examined the effects of long-term oral ARA administration on normal renal function as well as inflammation and oxidative stress in aged rats. In addition, we measured levels of renal eicosanoids and docosanoids using liquid chromatography-tandem mass spectrometry. Control or ARA oil (240 mg/kg body weight/day) was orally administered to 21-month-old Wistar rats for 13 weeks. Levels of plasma creatinine, blood urea nitrogen, inflammatory and anti-inflammatory cytokines, reactive oxygen species, and lipid peroxidation were not significantly different between the two groups. The ARA concentration in the plasma, kidney, and liver increased in the ARA-administered group. In addition, levels of free-form ARA, prostaglandin E2, and 12- and 15-hydroxyeicosatetraenoic acid increased in the ARA-administered group, whereas renal concentration of docosahexaenoic acid and eicosapentaenoic acid decreased in the ARA-administered group. Levels of docosahexaenoic acid-derived protectin D1, eicosapentaenoic acid-derived 5-, and 18-hydroxyeicosapentaenoic acids, and resolvin E2 and E3 decreased in the ARA-administered group. Our results indicate that long-term ARA administration led to no serious adverse reactions under normal conditions and to a decrease in anti-inflammatory docosahexaenoic acid- and eicosapentaenoic acid-derived metabolites in the kidneys of aged rats. These results indicate that there is a possibility of ARA administration having a reducing anti-inflammatory effect on the kidney.

Chronic Arachidonic Acid Administration Decreases Docosahexaenoic Acid- and Eicosapentaenoic Acid-Derived Metabolites in Kidneys of Aged Rats

PubMed Central

Katakura, Masanori; Hashimoto, Michio; Inoue, Takayuki; Mamun, Abdullah Al; Tanabe, Yoko; Arita, Makoto; Shido, Osamu

2015-01-01

Arachidonic acid (ARA) metabolites produced by cyclo-oxygenase and lipoxygenase are important mediators maintaining physiological renal function. However, the effects of exogenous ARA on kidney function in vivo remain unknown. This study examined the effects of long-term oral ARA administration on normal renal function as well as inflammation and oxidative stress in aged rats. In addition, we measured levels of renal eicosanoids and docosanoids using liquid chromatography–tandem mass spectrometry. Control or ARA oil (240 mg/kg body weight/day) was orally administered to 21-month-old Wistar rats for 13 weeks. Levels of plasma creatinine, blood urea nitrogen, inflammatory and anti-inflammatory cytokines, reactive oxygen species, and lipid peroxidation were not significantly different between the two groups. The ARA concentration in the plasma, kidney, and liver increased in the ARA-administered group. In addition, levels of free-form ARA, prostaglandin E2, and 12- and 15-hydroxyeicosatetraenoic acid increased in the ARA-administered group, whereas renal concentration of docosahexaenoic acid and eicosapentaenoic acid decreased in the ARA-administered group. Levels of docosahexaenoic acid-derived protectin D1, eicosapentaenoic acid-derived 5-, and 18-hydroxyeicosapentaenoic acids, and resolvin E2 and E3 decreased in the ARA-administered group. Our results indicate that long-term ARA administration led to no serious adverse reactions under normal conditions and to a decrease in anti-inflammatory docosahexaenoic acid- and eicosapentaenoic acid-derived metabolites in the kidneys of aged rats. These results indicate that there is a possibility of ARA administration having a reducing anti-inflammatory effect on the kidney. PMID:26485038

Comparing the effects of nebivolol and dexpanthenol on wound healing: an experimental study.

PubMed

Ulger, Burak V; Kapan, Murat; Uslukaya, Omer; Bozdag, Zubeyir; Turkoglu, Ahmet; Alabalık, Ulas; Onder, Akın

2016-06-01

Wound healing is a dynamic, interactive process that is initiated in response to injury. A number of investigations and clinical studies have been performed to determine new approaches for the improvement of wound healing. The aim of this study was to compare the effects of dexpanthenol, a molecule that is widely used for improving wound healing, and nebivolol, a molecule that increases nitric oxide release, on wound healing. A total of 30 rats were divided into three equal groups (n = 10). A linear 2 cm incision was made in the rats' skin. No treatment was administered in the first (control) group. Dexpanthenol cream was administered to the rats in the second group and 5% nebivolol cream was administered to the rats in the third group. The wound areas of all of the rats were measured on certain days. On the 21(st) day, all wounds were excised and histologically evaluated. The wound healing rates of the dexpanthenol and nebivolol groups were higher than those of the control group (P < 0·05). However, the wound healing rates of the dexpanthenol and nebivolol groups were not significantly different. Nebivolol and dexpanthenol have comparable effects on wound healing. © 2014 The Authors. International Wound Journal © 2014 Medicalhelplines.com Inc and John Wiley & Sons Ltd.

Diminished metabolic responses to centrally-administered apelin-13 in diet-induced obese rats fed a high-fat diet.

PubMed

Clarke, K J; Whitaker, K W; Reyes, T M

2009-02-01

The central administration of apelin, a recently identified adipokine, has been shown to affect food and water intake. The present study investigated whether body weight could affect an animal's response to apelin. The effects of centrally-administered apelin-13 on food and water intake, activity and metabolic rate were investigated in adult male diet-induced obese (DIO) rats fed either a high fat (32%) or control diet. Rats were administered i.c.v. apelin-13, 15-30 min prior to lights out, and food and water intake, activity and metabolic rate were assessed. Intracerebroventricular administration of apelin-13 decreased food and water intake and respiratory exchange ratio in DIO rats on the control diet, but had no effect in DIO rats on the high-fat diet. In an effort to identify potential central mechanisms explaining the observed physiological responses, the mRNA level of the apelin receptor, APJ, was examined in the hypothalamus. A high-fat diet induced an up-regulation of the expression of the receptor. Apelin induced a down-regulation of the receptor, but only in the DIO animals on the high-fat diet. In conclusion, we have demonstrated a diminished central nervous system response to apelin that is coincident with obesity.

Anti-inflammatory activity of Polygonum bistorta, Guaiacum officinale and Hamamelis virginiana in rats.

PubMed

Duwiejua, M; Zeitlin, I J; Waterman, P G; Gray, A I

1994-04-01

The aqueous ethanolic extracts of Polygonum bistorta L. Polygonaceae, Guaiacum officinale L. Zygophyllaceae and Hamamelis virginiana L. Hamamelidaceae were screened for anti-inflammatory activity. Administered (100 and 200 mg kg-1, p.o.) before the induction of carrageenan rat paw oedema, extracts of P. bistorta significantly suppressed both the maximal oedema response and the total oedema response (monitored as area under the time course curve). H. virginiana was inactive and G. officinale was only active at 200 mg kg-1. At 200 mg kg-1 administered before the induction of adjuvant arthritis, P. bistorta significantly inhibited both the acute and chronic phases of the adjuvant-induced rat paw swelling, while G. officinale and H. virginiana were only active against the chronic phase. Further studies on P. bistorta (100-800 mg kg-1) revealed a dose-dependent inhibition of the carrageenan-induced rat paw oedema over the dose range 100-400 mg kg-1, the E50 value being approximately 158.5 mg kg-1. The extract (200 mg kg-1), administered after the onset of the inflammatory responses reversed the course of both the carrageenan- and adjuvant-induced rat paw swelling. The results confirm that the extracts of P. bistorta, G. officinale and H. virginiana contain anti-inflammatory substances.

Effect of PPARβ/δ agonist on the placentation and embryo-fetal development in rats.

PubMed

Nishimura, Kyohei; Nakano, Nao; Chowdhury, Vishwajit Sur; Kaneto, Masako; Torii, Mikinori; Hattori, Masa-aki; Yamauchi, Nobuhiko; Kawai, Motoyuki

2013-04-01

The present study was conducted to evaluate the developmental toxicity in the endometrium and placenta due to GW501516 administration by gavage to pregnant rats. GW501516 was orally administered repeatedly to pregnant rats from gestation day (GD) 6 to 17 at a dose of 0, 30, and 100 mg/kg/day. In next study, GW501516 was also orally administered to pregnant rats on GD 7, 8, 9, 10, or 11 at a single dose of 275 or 350 mg/kg. In these studies, caesarean section was performed to examine the pregnancy outcome on GD21. Additionally, GW501516 was orally administered to pregnant rats on GD 10 at a single dose of 275 mg/kg. Placentae were subjected for temporal histological examinations on GD 11, 13, 15, or 17. Placental malformation was induced by repeated administration of GW501516 at a dose of 100 mg/kg/day. Single oral administration of GW501516 at a dose of 275 and/or 350 mg/kg on GD 8, 9, 10, or 11 induced placental malformation, whereas GW501516 administered on GD 10 was the most effective for increasing placental malformation. Histopathologically, single oral administration of GW501516 on GD 10 induced cystic degeneration associated with cellular lysis of glycogen cells started from GD 15 in the basal zone. High frequency of placental malformation was observed by the administration of GW501516. From GD 8 to 11, especially GD 10, is more sensitive period to induce the placental malformation. © 2013 Wiley Periodicals, Inc.

Modification of mortality and tumorigenesis by tocopherol-mono-glucoside (TMG) administered after X irradiation in mice and rats.

PubMed

Ueno, Megumi; Inano, Hiroshi; Onoda, Makoto; Murase, Hironobu; Ikota, Nobuo; Kagiya, Tsutomu V; Anzai, Kazunori

2009-10-01

The effects of TMG [2-(alpha-d-glucopyranosyl) methyl-2,5,7,8-tetramethylchroman-6-ol], a water-soluble vitamin E derivative, administered after irradiation on the mortality of X-irradiated mice and on the development of tumors in the mammary and pituitary glands in rats were investigated. When TMG (650 mg/kg) was administered intraperitoneally (i.p.) to C3H mice immediately after whole-body exposure to 7 Gy radiation, the 30-day survival was significantly higher than that of the control mice. The i.p. administration of TMG at 4 h after irradiation significantly improved survival compared to that of the controls, but administration 8 h after irradiation did not have a significant effect. Subcutaneous administration of TMG immediately after irradiation also decreased mortality significantly. When dams of lactating Wister rats were exposed to 1.5 Gy of X rays at day 21 after parturition and were then treated with diethylstilbestrol as a tumor promoter, the incidence of mammary tumors and pituitary tumors was increased compared to that in the nonirradiated control group. The administration of TMG (600 mg/kg, i.p.) after irradiation significantly reduced the incidence of mammary tumors and pituitary tumors. The number of rats that were free of both mammary and pituitary gland tumors was enhanced fourfold by TMG. These results suggest that TMG is effective in preventing radiation-induced bone marrow death in mice and in reducing mammary and pituitary tumors in rats even when it is administered after irradiation.

Effects of Orally Administered Augmentin on Glutamate Transporter 1, Cystine-glutamate Exchanger Expression as well as Ethanol Intake in Alcohol-Preferring Rats

PubMed Central

Hakami, Alqassem Y.; Alshehri, Fahad S.; Althobaiti, Yusuf S.; Sari, Youssef

2016-01-01

Alcohol dependence is associated with deficits in glutamate uptake and impairment of glutamate homeostasis in different brain reward regions. Glutamate transporter subtype 1 (GLT-1), cystine-glutamate exchanger (xCT) and glutamate/aspartate transporter (GLAST) are the key players in regulating extracellular glutamate concentration in the brain. Parenteral treatment with ceftriaxone, β-lactam antibiotic, has been reported to attenuate ethanol consumption and reinstatement to cocaine-seeking behavior, in part, by restoring the expression of GLT-1 and xCT in mesocorticolimbic brain regions in rats. In this study, we focus to test Augmentin (amoxicillin/clavulanate), which can be administered orally to subjects. Therefore, we examined the effects of orally administered Augmentin on ethanol intake as well as GLT-1, xCT and GLAST expression in alcohol-preferring (P) rats. We found that orally administered Augmentin significantly attenuated ethanol consumption in P rats as compared to the vehicle-treated group. Importantly, the attenuation in ethanol consumption was associated with a significant upregulation of GLT-1 and xCT expression in nucleus accumbens (NAc) and prefrontal cortex (PFC). There was no effect of oral Augmentin on GLAST expression in either NAc or PFC. These findings present strong evidence that oral administration of Augmentin can be used as an alternative to parenteral administration. PMID:27993695

Novelty-induced emotional arousal modulates cannabinoid effects on recognition memory and adrenocortical activity.

PubMed

Campolongo, Patrizia; Morena, Maria; Scaccianoce, Sergio; Trezza, Viviana; Chiarotti, Flavia; Schelling, Gustav; Cuomo, Vincenzo; Roozendaal, Benno

2013-06-01

Although it is well established that cannabinoid drugs can influence cognitive performance, the findings-describing both enhancing and impairing effects-have been ambiguous. Here, we investigated the effects of posttraining systemic administration of the synthetic cannabinoid agonist WIN55,212-2 (0.1, 0.3, or 1.0 mg/kg) on short- and long-term retention of object recognition memory under two conditions that differed in their training-associated arousal level. In male Sprague-Dawley rats that were not previously habituated to the experimental context, WIN55,212-2 administered immediately after a 3-min training trial, biphasically impaired retention performance at a 1-h interval. In contrast, WIN55,212-2 enhanced 1-h retention of rats that had received extensive prior habituation to the experimental context. Interestingly, immediate posttraining administration of WIN55,212-2 to non-habituated rats, in doses that impaired 1-h retention, enhanced object recognition performance at a 24-h interval. Posttraining WIN55,212-2 administration to habituated rats did not significantly affect 24-h retention. In light of intimate interactions between cannabinoids and the hypothalamic-pituitary-adrenal axis, we further investigated whether cannabinoid administration might differently influence training-induced glucocorticoid activity in rats in these two habituation conditions. WIN55,212-2 administered after object recognition training elevated plasma corticosterone levels in non-habituated rats whereas it decreased corticosterone levels in habituated rats. Most importantly, following pretreatment with the corticosterone-synthesis inhibitor metyrapone, WIN55,212-2 effects on 1- and 24-h retention of non-habituated rats became similar to those seen in the low-aroused habituated animals, indicating that cannabinoid-induced regulation of adrenocortical activity contributes to the environmentally sensitive effects of systemically administered cannabinoids on short- and long-term retention of object recognition memory.

Time-dependent decreases in nucleus accumbens AMPA/NMDA ratio and incubation of sucrose craving in adolescent and adult rats.

PubMed

Counotte, Danielle S; Schiefer, Christopher; Shaham, Yavin; O'Donnell, Patricio

2014-04-01

There is evidence that cue-induced sucrose seeking progressively increases after cessation of oral sucrose self-administration (incubation of sucrose craving) in both adolescent and adult rats. The synaptic plasticity changes associated with this incubation at different age groups are unknown. We assessed whether incubation of sucrose craving in rats trained to self-administer sucrose as young adolescents, adolescents, or adults is associated with changes in 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid (AMPA)/N-methyl-D-aspartate (NMDA) ratio (a measure of postsynaptic changes in synaptic strength) in nucleus accumbens. Three age groups initiated oral sucrose self-administration training (10 days) on postnatal day (P) 35 (young adolescents), P42 (adolescents), or P70 (adults). They were then tested for cue-induced sucrose seeking (assessed in an extinction test) on abstinence days 1 and 21. Separate groups of rats were trained to self-administer sucrose or water (a control condition), and assessed for AMPA/NMDA ratio in nucleus accumbens on abstinence days 1-3 and 21. Adult rats earned more sucrose rewards, but sucrose intake per body weight was higher in young adolescent rats. Time-dependent increases in cue-induced sucrose seeking (incubation of sucrose craving) were more pronounced in adult rats, less pronounced in adolescents, and not detected in young adolescents. On abstinence day 21, but not days 1-3, AMPA/NMDA ratio in nucleus accumbens were decreased in rats that self-administered sucrose as adults and adolescents, but not young adolescents. Our data demonstrate age-dependent changes in magnitude of incubation of sucrose craving and nucleus accumbens synaptic plasticity after cessation of sucrose self-administration.

The display of sexual behaviors by female rats administered ICI 182,780.

PubMed

Clark, Ann S; Guarraci, Fay A; Megroz, Alison B; Porter, Donna M; Henderson, Leslie P

2003-04-01

ICI 182,780 (ICI) is a pure antiestrogen that when administered systemically does not cross the blood-brain barrier, thus its actions are limited to the periphery. Four experiments were conducted to test the effects of ICI on the display of sexual behaviors in ovariectomized rats. Experiment 1 examined the effects of three doses of ICI (250, 500, and 750 micro g/rat) on sexual receptivity and paced mating behavior in rats primed with estradiol benzoate (EB) in combination with progesterone (P). Experiments 2 and 3 compared the display of sexual behaviors in rats primed with EB+P or EB alone and administered either 250 micro g ICI (Experiment 2) or 500 micro g ICI (Experiment 3). Experiment 4 tested the effects of ICI (250 and 500 micro g) on the expression of estrogen-induced progestin receptors in the uterus. ICI did not affect the display of sexual receptivity in any experiment. In rats primed with EB+P, paced mating behavior was altered by the 500 and 750 micro g, but not the 250 micro g, doses of ICI. The lowest (250 micro g) dose of ICI did alter paced mating behavior in rats primed with EB alone. The effects of ICI on paced mating behavior were manifested by a substantial lengthening of contact-return latencies following intromissions and ejaculations. The percentage of exits were not affected by ICI. Estrogen stimulation of uterine weight and induction of uterine progestin receptors was suppressed by ICI (250 and 500 micro g). ICI effects on paced mating behavior in hormone-primed female rats are likely to reflect antiestrogenic actions in the periphery, including interference with the estrogen induction of progestin receptors.

Effect of Mucuna pruriens (Linn.) on mitochondrial dysfunction and DNA damage in epididymal sperm of streptozotocin induced diabetic rat.

PubMed

Suresh, Sekar; Prithiviraj, Elumalai; Lakshmi, Nagella Venkata; Ganesh, Mohanraj Karthik; Ganesh, Lakshmanan; Prakash, Seppan

2013-01-09

Mucuna pruriens Linn. (M. pruriens) is a leguminous plant that has been recognized as an herbal medicine for improving fertility and related disorders in the Indian traditional system of medicine, however without proper scientific validations. To study the effect of ethanolic seed extract of M. pruriens on mitochondrial dysfunction and the DNA damage in hyperglycemic rat epididymal spermatozoa. Male Wistar albino rats were divided as control (Sham), diabetes induced [streptozotocin 60 mg/kg of body weight (b.w.) in 0.1M citrate buffer] (STZ), diabetic rats administered with 200mg/kg b.w. of extract (STZ+MP) and normal rats administered with 200mg/kg b.w. of extract (Sham+MP). M. pruriens was administered (gavage) once daily for a period of 60 days. On 60th day animals were sacrificed by cervical dislocation sperm were collected from epididymis and subjected various analysis like antioxidants, ROS, lipid peroxidation (LPO), DNA damage, chromosomal integrity and mitochondrial membrane potential (MMP). Significant reduction in the sperm count, motility, viability and significant increase in the number of abnormal sperm in STZ compared to sham was noticed. STZ rat sperm showed significant increase in LPO and DNA damage. Both the enzymic and non-enzymic were decreased; MMP and the mitochondrial functions were severely affected in STZ group. The diabetic rats supplemented with M. pruriens showed a remarkable recovery in antioxidant levels and reduced LPO with well preserved sperm DNA. MMP and mitochondrial function test were also preserved in STZ+MP rat sperm. The present study has clearly demonstrated the potency of M. pruriens to reduce the diabetic induced sperm damage induced by oxidative stress (OS). These observations are encouraging to perform similar studies in human. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Novelty-Induced Emotional Arousal Modulates Cannabinoid Effects on Recognition Memory and Adrenocortical Activity

PubMed Central

Campolongo, Patrizia; Morena, Maria; Scaccianoce, Sergio; Trezza, Viviana; Chiarotti, Flavia; Schelling, Gustav; Cuomo, Vincenzo; Roozendaal, Benno

2013-01-01

Although it is well established that cannabinoid drugs can influence cognitive performance, the findings—describing both enhancing and impairing effects—have been ambiguous. Here, we investigated the effects of posttraining systemic administration of the synthetic cannabinoid agonist WIN55,212-2 (0.1, 0.3, or 1.0 mg/kg) on short- and long-term retention of object recognition memory under two conditions that differed in their training-associated arousal level. In male Sprague-Dawley rats that were not previously habituated to the experimental context, WIN55,212-2 administered immediately after a 3-min training trial, biphasically impaired retention performance at a 1-h interval. In contrast, WIN55,212-2 enhanced 1-h retention of rats that had received extensive prior habituation to the experimental context. Interestingly, immediate posttraining administration of WIN55,212-2 to non-habituated rats, in doses that impaired 1-h retention, enhanced object recognition performance at a 24-h interval. Posttraining WIN55,212-2 administration to habituated rats did not significantly affect 24-h retention. In light of intimate interactions between cannabinoids and the hypothalamic–pituitary–adrenal axis, we further investigated whether cannabinoid administration might differently influence training-induced glucocorticoid activity in rats in these two habituation conditions. WIN55,212-2 administered after object recognition training elevated plasma corticosterone levels in non-habituated rats whereas it decreased corticosterone levels in habituated rats. Most importantly, following pretreatment with the corticosterone-synthesis inhibitor metyrapone, WIN55,212-2 effects on 1- and 24-h retention of non-habituated rats became similar to those seen in the low-aroused habituated animals, indicating that cannabinoid-induced regulation of adrenocortical activity contributes to the environmentally sensitive effects of systemically administered cannabinoids on short- and long-term retention of object recognition memory. PMID:23340520

Effect of sildenafil citrate on secondary healing in full thickness skin defects in experiment.

PubMed

Cakmak, E; Karasoy Yesilada, A; Sevim, K Z; Sumer, O; Tatlidede, H S; Sakiz, D

2014-01-01

An acceleration of the wound healing process expedites chronic wound patient's return to normal social environments significantly. Sildenafil, a cyclic guanosine monophosphate (cGMP)-dependent phosphodiesterase- 5 inhibitor has been shown to be a potent stimulator of angiogenesis through upregulation of cGMP. In our study, sildenafil was administered orally as a cost-effective supplement in the treatment of full thickness defects and chronic wounds in that manner with low incidence of side effects and morbidity. Randomly selected 72 Wistar-Albino rats were divided into the two groups, 36 rats in each group. Control group (n =36) was divided further into a secondary healing group consisting of 9 rats and a pathology group consisting of 27 rats (pathology group 1: 9 rats, 4th and 7th day of wound healing, pathology group 2: 9 rats, 10th and 14th day of wound healing, pathology group 3: 9 rats, 21st and 28th day of wound healing. Experimental group consisted of 36 rats which received sildenafil citrate (Viagra® Pfizer, Germany) for secondary wound healing to proceed. The average wound healing period in the control group was 17.89 days and in the sildenafil citrate administered group 14.56 days. The difference of the epithelialisation on full thickness defects were more prominent on days 5 and 11 postoperatively. In the sildenafil citrate applied group, on the 7th day, the defect was 25% smaller and on the 13th day, the defect contracted by 38%. In conclusion, we believe that sildenafil citrate administered orally is a cost- effective supplement in the treatment of full thickness defects and chronic wounds in that manner with low incidence of side effects and morbidity (Tab. 4, Fig. 7, Ref. 34).

COMPARATIVE IMMUNOSUPPRESSION OF VARIOUS GLYCOL ETHERS ORALLY ADMINISTERED TO FISCHER 344 RATS

EPA Science Inventory

Oral dosing of adult rats F344 rats with the glycol ether 2-methoxyethanol (ME) or its principal metabolite 2-methoxyacetic acid (MAA) results in the suppression of the primary plaque-forming cell (PFC) response to trinitrophenyl-lipopolysaccharide (TNP_LPS). n the present study,...

Preventive effect of theanine intake on stress-induced impairments of hippocamapal long-term potentiation and recognition memory.

PubMed

Tamano, Haruna; Fukura, Kotaro; Suzuki, Miki; Sakamoto, Kazuhiro; Yokogoshi, Hidehiko; Takeda, Atsushi

2013-06-01

Theanine, γ-glutamylethylamide, is one of the major amino acid components in green tea. On the basis of the preventive effect of theanine intake after birth on mild stress-induced attenuation of hippocamapal CA1 long-term potentiation (LTP), the present study evaluated the effect of theanine intake after weaning on stress-induced impairments of LTP and recognition memory. Young rats were fed water containing 0.3% theanine for 3 weeks after weaning and subjected to water immersion stress for 30min, which was more severe than tail suspension stress for 30s used previously. Serum corticosterone levels were lower in theanine-administered rats than in the control rats even after exposure to stress. CA1 LTP induced by a 100-Hz tetanus for 1s was inhibited in the presence of 2-amino-5-phosphonovalerate (APV), an N-methyl-d-aspartate (NMDA) receptor antagonist, in hippocampal slices from the control rats and was attenuated by water immersion stress. In contrast, CA1 LTP was not significantly inhibited in the presence of APV in hippocampal slices from theanine-administered rats and was not attenuated by the stress. Furthermore, object recognition memory was impaired in the control rats, but not in theanine-administered rats. The present study indicates the preventive effect of theanine intake after weaning on stress-induced impairments of hippocampal LTP and recognition memory. It is likely that the modification of corticosterone secretion after theanine intake is involved in the preventive effect. Copyright © 2013 Elsevier Inc. All rights reserved.

Apocynin prevented inflammation and oxidative stress in carbon tetra chloride induced hepatic dysfunction in rats.

PubMed

Rahman, Md Mizanur; Muse, Awale Yousuf; Khan, D M Isha Olive; Ahmed, Ismaile Hussein; Subhan, Nusrat; Reza, Hasan Mahmud; Alam, Md Ashraful; Nahar, Lutfun; Sarker, Satyajit Dey

2017-08-01

Liver fibrosis is a leading pathway to cirrhosis and a global clinical issue. Oxidative stress mediated tissue damage is one of the prime causes of hepatic dysfunction and fibrosis. Apocynin is one of many strong antioxidants. To evaluate the effect of apocynin in the CCl 4 administered hepatic dysfunction in rats. Female Long Evans rats were administered with CCl 4 orally (1mL/kg) twice a week for 2 weeks and were treated with apocynin (100mg/kg). Both plasma and liver tissues were analyzed for alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase activities. Oxidative stress parameters were also measured by determining malondialdehyde (MDA), nitric oxide (NO), myeloperoxidase (MPO), advanced protein oxidation product (APOP). In addition, antioxidant enzyme activities such as superoxide dismutase (SOD) and catalase activities in plasma and liver tissues were analyzed. Moreover, inflammation and tissue fibrosis were confirmed by histological staining of liver tissue sections. Apocynin significantly reduced serum AST, ALT, and ALP activities in carbon tetrachloride treated rats. It also exhibited a considerable reduction of the oxidative stress markers (MDA, MPO, NO, and APOP level) which was elevated due to CCl 4 administration in rats. Apocynin treatment also restored the catalase and superoxide dismutase activity in CCl 4 treated rats. Histological analysis of liver sections revealed that apocynin prevented inflammatory cells infiltration and fibrosis in CCl 4 administered rats. These results suggest that apocynin protects liver damage induced by CCl 4 by inhibiting lipid peroxidation and stimulating the cellular antioxidant system. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Carvacrol and Pomegranate Extract in Treating Methotrexate-Induced Lung Oxidative Injury in Rats

PubMed Central

Şen, Hadice Selimoğlu; Şen, Velat; Bozkurt, Mehtap; Türkçü, Gül; Güzel, Abdulmenap; Sezgi, Cengizhan; Abakay, Özlem; Kaplan, Ibrahim

2014-01-01

Background This study was designed to evaluate the effects of carvacrol (CRV) and pomegranate extract (PE) on methotrexate (MTX)-induced lung injury in rats. Material/Methods A total of 32 male rats were subdivided into 4 groups: control (group I), MTX treated (group II), MTX+CRV treated (group III), and MTX+PE treated (group IV). A single dose of 73 mg/kg CRV was administered intraperitoneally to rats in group III on Day 1 of the investigation. To group IV, a dose of 225 mg/kg of PE was administered via orogastric gavage once daily over 7 days. A single dose of 20 mg/kg of MTX was given intraperitoneally to groups II, III, and IV on Day 2. The total duration of experiment was 8 days. Malondialdehyde (MDA), total oxidant status (TOS), total antioxidant capacity (TAC), and oxidative stress index (OSI) were measured from rat lung tissues and cardiac blood samples. Results Serum and lung specimen analyses demonstrated that MDA, TOS, and OSI levels were significantly greater in group II relative to controls. Conversely, the TAC level was significantly reduced in group II when compared to the control group. Pre-administering either CRV or PE was associated with decreased MDA, TOS, and OSI levels and increased TAC levels compared to rats treated with MTX alone. Histopathological examination revealed that lung injury was less severe in group III and IV relative to group II. Conclusions MTX treatment results in rat lung oxidative damage that is partially counteracted by pretreatment with either CRV or PE. PMID:25326861

[Prevention of NSAID gastropathy: the difference between a coxibs and the addition of a PPI].

PubMed

Lems, Willem F; Kuipers, Ernst J

2010-01-01

Several strategies are available for the prevention of NSAID gastropathy: the addition of misoprostol or proton pump inhibitors (PPIs) to conventional NSAIDs, or selective use of cyclo-oxygenase 2 inhibitors, the 'coxibs'. The recently published CONDOR study was a randomized trial comparing celecoxib with omeprazole in patients at high risk for NSAID gastropathy. A statistically significant reduction in the primary endpoint was found: hazard ratio: 4.3 (95% CI: 2.6-6.7; p < 0.0001). However, the reduction was largely based on a higher incidence of anaemia in the diclofenac plus omeprazole group. The study has strengths and weaknesses. The most important conclusion is that the nature of the gastro-protective effects of celecoxib and diclofenac/misoprostol are different.

Active vitamin D3, 1,25-(OH)2D3, protects against macrovasculopathy in a rat model of type 2 diabetes mellitus.

PubMed

Ma, R; Deng, X L; Du, G L; Li, C; Xiao, S; Aibibai, Y; Zhu, J

2016-06-03

To investigate the protective effect of the active form of vitamin D3, 1,25-(OH)2D3, on macrovasculopathy in rats with type 2 diabetes mellitus (T2DM), 8-week-old male Sprague-Dawley rats were randomly divided into control group, T2DM group, and treatment group. The T2DM model was established after 6 weeks by administering an intraperitoneal injection of streptozotocin (30 mg/kg). 1,25-(OH)2D3 was administered by gavage to rats in the treatment group, and an equal volume of peanut oil was administered to rats in the T2DM group. Fasting plasma glucose (FPG), triglyceride (TG), total cholesterol (TC), high-density lipoprotein (HDL-C) and low-density lipoprotein (LDL-C) cholesterols were measured in all rats. The morphology of the thoracic aorta was examined, and the expression of tumor necrosis factor alpha (TNF-α), endothelin (ET), endothelial nitric oxide synthase (eNOS), CD54, and CD106 in the thoracic aorta was determined by immunohistochemistry. The expression of FPG, TG, TC, and LDL-C in rats from the T2DM and treatment groups was significantly elevated compared with rats from the control group (P < 0.05). Compared with that in control group, the expression of TNF-α, ET, eNOS, and CD106 was significantly upregulated in the T2DM group and the treatment group, while the expression of CD54 was increased only in the T2DM group (P < 0.05). Moreover, the levels of TNF-α, CD54, and CD106 in rats from the treatment group were lower than those in the T2DM group (P < 0.05). These data suggest that 1,25-(OH)2D3 may protect the macrovessels from injury in T2DM rats by inhibiting the expression of TNF-α, CD54, and CD106.

Influence of several peptidase inhibitors on the pro-inflammatory effects of substance P, capsaicin and collagenase.

PubMed

Damas, J; Bourdon, V; Liégeois, J F; Simmons, W H

1996-11-01

Injection of substance P (SP) in a rat hindpaw induced extravasation of 125I-labelled albumin in both hindpaws and salivation. Intravenous injection of SP dose-dependently increased vascular permeability. This latter effect was increased in rat paws by captopril, an inhibitor of angiotensin-converting enzyme (ACE), administered locally in combination with diprotin A, an inhibitor of an dipeptidyl(amino)peptidase IV (DAP IV) or phosphoramidon, an inhibitor of neutral endopeptidase (NEP). The increase in permeability induced by SP was inhibited by RP 67580, a NK-1-receptor antagonist. Intravenous injection of capsaicin induced labelled albumin extravasation in rat paws. This effect was increased by combination of captopril with diprotin A or phosphoramidon, but not by captopril associated with amastatin, an inhibitor of aminopeptidase M (AmM). It was suppressed by RP 67580. Injection of collagenase in rat paws triggered a swelling and a local plasma exudation. These responses were reduced by RP 67580 but not by RP 68651, its inactive enantiomer. They were increased by combination of captopril with diprotin A or phosphoramidon in normal rats. The potentiating effects of captopril and diprotin A were suppressed by RP 67580 in normal rats but did not develop in kininogen-deficient rats. The oedema induced by collagenase was also increased by lisinopril, another ACE inhibitor, administered locally in combination with apstatin, an inhibitor of aminopeptidase P (AmP). In rats pretreated by methysergide, collagenase-induced oedema was reduced and can be increased by captopril, by lisinopril, administered alone or by lisinopril associated with apstatin. It is concluded that SP is mainly inactivated in rat paws by ACE, DAP IV and NEP. In collagenase-induced oedema, a low amount of SP would be released from afferent nerve terminals by bradykinin formed in low amounts. Bradykinin is inactivated in rat paws by ACE and AmP. In collagenase-oedema, the pro-inflammatory effects of bradykinin are concealed by the effects of the other mediators.

Different effects of vitamin D hormone treatment on depression-like behavior in the adult ovariectomized female rats.

PubMed

Fedotova, Julia; Dudnichenko, Tatyana; Kruzliak, Peter; Puchavskaya, Zhanna

2016-12-01

Vitamine D (VD) has important functions in the human brain and may play a role in affective-related disorders. VD receptors are expressed in multiple brain regions associated with depressive disorders. The aim of the preclinical study was to examine the effects of chronic cholecalciferol administration (1.0, 2.5 or 5.0mg/kg/day,s.c., once daily, for 14days) on the depression-like behavior and corticosterone levels in the blood samples following ovariectomy in female rats. Cholecalciferol was administered to the ovariectomized (OVX) rats and OVX rats treated with 17β-estradiol (17β-E 2 , 0.5μg/rat,s.c., once daily, for 14days). Depression-like behavior and spontaneous locomotor activity were assessed in the forced swimming test (FST) and the open field test (OFT), respectively. The corticosterone levels in the blood serum before and after FST were measured in all experimental groups. Treatment with cholecalciferol in high dose (5.0mg/kg/day,s.c.) significantly decreased the immobility time of OVX rats in the FST. Co-administration of cholecalciferol in high dose with 17β-E 2 exerted a markedly synergistic antidepressant-like effect in the OVX rats on the same model of depression-like behavior testing. Cholecalciferol in high dose (5.0mg/kg/day,s.c.) administered alone or together with 17β-E 2 significantly enhanced frequency of grooming for the OVX rats in the OFT. Moreover, cholecalciferol in high dose administered alone or together with 17β-E 2 significantly decreased the elevated corticosterone levels in the blood serum of OVX rats following the FST. These results indicate that Cholecalciferol in high dose has a marked antidepressant-like effect in the adult female rats with low levels of estrogen. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Effects of heparin fractions on the prevention of skin necrosis resulting from adriamycin extravasation: an experimental study.

PubMed

Askar, Ibrahim; Erbas, M Kemal; Gurlek, Ali

2002-09-01

Extravasation of a chemotherapeutic agent is one of the most frequent complications in cancer patients. Full-thickness skin necrosis often occurs after extravasation. Alternative approaches to treatment are local wound care, elevation, and hypothermia. It was shown that heparin prevents skin necrosis. In this experimental study, the effects of heparin fractions on the prevention of skin necrosis were compared by applying an extravasation model of Adriamycin in rats. Forty Sprague-Dawley male rats weighing 250 to 300 g were used. A total of 0.3 ml doxorubicin hydrochloride was administered subcutaneously to all rats. Ten minutes later, in the control group (group I), 1 ml normal saline was administered subcutaneously. In the first experimental group (group II), 100 U per day heparin sodium was administered in a volume of 1 ml subcutaneously. In the second experimental group (group III), nadroparin calcium (5 anti-Xa U per kilogram per day) was administered. In the third and last experimental group (group IV), dalteparin sodium (5 anti-Xa U per kilogram per day) was administered. All drugs were administered for 2 weeks. Necrotic areas were measured 4 weeks later. Statistical analysis was performed using the Kruskal-Wallis analysis of variance and the Mann-Whitney test. Heparin fractions caused a decreased ulcer rate and size than controls ( < 0.05). There was no superiority among heparin fractions. The authors think that low-molecular weight heparins are preferred, considering the higher risk of bleeding with unfractionated heparin.

Investigation of the Blood Glucose Lowering Potential of the Jamaican Momordica charantia (Cerasee) Fruit in Sprague-Dawley Rats

PubMed Central

Burnett, A; McKoy, M-L; Singh, P

2015-01-01

ABSTRACT The Momordica charantia (MC) fruit has been documented to possess antidiabetic properties. However, these studies were not without controversy surrounding the blood glucose-lowering ability and the mechanism of action in diabetes therapy. In an effort to evaluate such claims in the Jamaican MC species known as cerasee, aqueous extracts of the unripe fruit were studied in normal and diabetic rats. Normal male Sprague-Dawley rats were divided into groups (n = 6) orally administered distilled water, 10% dimethyl sulfoxide (DMSO) solution, the aqueous extract (400 mg/kg body weight) and glibenclamide (15 mg/kg body weight), respectively prior to assessment of fasting blood glucose (FBG) concentration. The oral glucose tolerance test (OGTT) was conducted in normoglycaemic rats orally administered distilled water, 10% DMSO solution, glibenclamide (15 mg/kg body weight) or aqueous extracts of the fruit (200 and 400 mg/kg body weight). Blood glucose concentration was also monitored in streptozotocin-induced diabetic rats administered the aqueous extract (250 mg/kg body weight) or water vehicle after an overnight fast. The aqueous extracts showed no hypoglycaemic or antidiabetic activity. However, the administration of the aqueous extracts (200 and 400 mg/kg body weight) resulted in significant improvement in glucose tolerance of glucose-primed normoglycaemic rats during the OGTT. These data suggest that the glucose-lowering mechanism of the Jamaican MC fruit species likely involves altered glucose absorption across the gastrointestinal tract. PMID:26624580

Effect of artichoke extract (Cynara scolymus L.) on palmitic-1-14C acid oxidation in rats.

PubMed

Juzyszyn, Zygmunt; Czerny, Boguslaw; Pawlik, Andrzej; Drozdzik, Marek

2008-05-01

Studies on the effect of the artichoke extract (AE) on oxidation of palmitic-1-14C acid administered intravenously to rats at a dose 25 and 50 mg/kg bw demonstrated marked enhancement of both 14CO2 expiration rate and 14CO2 recovery in the expired air. The extract suppressed accumulation of palmitic-1-14C acid in serum lipids and epididymal fat pad tissue as well. The effects of the extract on 14CO2 expiration rate, 14CO2 recovery, as well as accumulation of palmitic-1-14C acid were dose dependent. Total14CO2 recovery in expired air during 60 min was elevated by 17.3% (p < 0.05) and 52.1% (p < 0.001) in rats administered the extract at a dose of 25 and 50 mg/kg, respectively. The rats supplemented with the AE at a dose of 25 and 50 mg/kg bw were characterized by 10.0% (not significant) and 19% (p < 0.05) decrease in( 14)C radioactivity of serum lipids as well as reduction of epididymal fat tissue 14C radioactivity by 8.7 and 17.5% (p < 0.05), respectively, in comparison with the control rats. Thus, the results demonstrate that the AE possess stimulatory properties with respect to oxidation of palmitic acid administered to rats, and provide new information on the mechanism of antilipemic activity of the extract associated with activation of lipid oxidation in the organism.

Metabolites of hirsuteine and hirsutine, the major indole alkaloids of Uncaria rhynchophylla, in rats.

PubMed

Nakazawa, Takahiro; Banba, Koh-ichi; Hata, Kazumasa; Nihei, Yutaka; Hoshikawa, Ayumi; Ohsawa, Keisuke

2006-08-01

The metabolic fate of hirsuteine (HT) and hirsutine (HS), the major indole alkaloids of Uncaria rhynchophylla, was investigated using rats. On HPLC analysis, urine from rats orally administered HT were found to contain two metabolites (HT1 and HT2) together with unchanged HT. Similarly HS also was metabolized to two compounds (HS1 and HS2). Metabolite structures were determined to be 11-hydroxyhirsuteine-11-O-beta-D-glucuronide (HT1), 11-hydroxyhirsuteine (HT2), 11-hydroxyhirsutine-11-O-beta-D-glucuronide (HS1) and 11-hydroxyhirsutine (HS2), based on spectroscopic and chemical data. HT1 and HS1 were also detected in bile from rats administered HT and HS, respectively. Total cumulative urinary excretion within 72 h of oral administration was approximately 14% and 26% of the HT and HS doses, respectively, while total cumulative biliary excretion was 35% and 46%, respectively. HT and HS 11-hydroxylation were catalyzed by rat liver microsomes. This 11-hydroxylation activity was inhibited by addition of SKF-525A (a nonselective CYP inhibitor) or cimetidine (a CYP2C inhibitor). These results indicate that orally administered HT and HS are converted to 11-hydroxy metabolites in rats, and that the metabolites are predominantly excreted in bile rather than urine following glucuronidation. Furthermore, the results suggest that CYP2C enzymes are involved, at least in part, in the specific 11-hydroxylation of HT and HS.

A Cocaine Hydrolase Engineered from Human Butyrylcholinesterase Selectively Blocks Cocaine Toxicity and Reinstatement of Drug Seeking in Rats

PubMed Central

Brimijoin, Stephen; Gao, Yang; Anker, Justin J; Gliddon, Luke A; LaFleur, David; Shah, R; Zhao, Qinghai; Singh, M; Carroll, Marilyn E

2008-01-01

Successive rational mutations of human butyrylcholinesterase (BChE) followed by fusion to human serum albumin have yielded an efficient hydrolase that offers realistic options for therapy of cocaine overdose and abuse. This albumin-BChE prevented seizures in rats given a normally lethal cocaine injection (100 mg/kg, i.p.), lowered brain cocaine levels even when administered after the drug, and provided rescue after convulsions commenced. Moreover, it selectively blocked cocaine-induced reinstatement of drug seeking in rats that had previously self-administered cocaine. The enzyme treatment was well tolerated and may be worth exploring for clinical application in humans. PMID:18199998

THE INDUCTION OF ABERRANT CRYPT FOCI (ACF) IN MALE AND FEMALE F344/N RATS BY BROMOCHLOROACETIC ACID (BCA) ADMINISTERED IN THE DRINKING WATER

EPA Science Inventory

The Induction of Aberrant Crypt Foci (ACF) in Male and Female F344/N Rats by Bromochloroacetic Acid (BCA) Administered in the Drinking Water.

M.H. George1, D. Delker1, D.R. Geter1, C.Herbert2, J. Roycroft3, R. Melnick3, D.W.
Rosenberg4, and A.B. DeAngelo1. 1USEPA, Resea...

Effects of endotoxin on monoamine metabolism in the rat.

NASA Technical Reports Server (NTRS)

Pohorecky, L. A.; Wurtman, R. J.; Taam, D.; Fine, J.

1972-01-01

Examination of effects of administered endotoxin on catecholamine metabolism in the rat brain, sympathetic neurons, and adrenal medulla. It is found that endotoxin, administered intraperitoneally, lowers the norepinephrine content in peripheral sympathetic neurons and the brain, and the catecholamine content in the adrenal medulla. It also accelerates the disappearance of H3-norepinephrine from all these tissues. It is therefore suggested that the effects of endotoxin on body temperature may be mediated in part by central non-adrenergic neurons.

Chelation in metal intoxication. VIII. Removal of chromium from organs of potassium chromate administered rats.

PubMed

Behari, J R; Tandon, S K

1980-03-01

Some polyaminocarboxylic acids were examined for their ability to mobilize chromium from certain vital organs, their subcellular fractions, and blood cells of potassium chromate administered rats. Hexamethylene 1,6-diamino tetraacetic acid (TDTA), triethylene tetramine hexaacetic acid (TTHA), and ethylene diamine di (O-hydroxylphenyl acetic acid) (EDDHA) may be useful in preventing or reducing chromate toxicity. No definite relationship could be observed between the structure of the chelating agents and their chromium-removing capacity.

A rat model of nerve agent exposure applicable to the pediatric population: The anticonvulsant efficacies of atropine and GluK1 antagonists

DOE Office of Scientific and Technical Information (OSTI.GOV)

Miller, Steven L., E-mail: stevenmiller17@gmail.com; Program in Neuroscience, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814; Aroniadou-Anderjaska, Vassiliki, E-mail: vanderjaska@usuhs.edu

Inhibition of acetylcholinesterase (AChE) after nerve agent exposure induces status epilepticus (SE), which causes brain damage or death. The development of countermeasures appropriate for the pediatric population requires testing of anticonvulsant treatments in immature animals. In the present study, exposure of 21-day-old (P21) rats to different doses of soman, followed by probit analysis, produced an LD{sub 50} of 62 μg/kg. The onset of behaviorally-observed SE was accompanied by a dramatic decrease in brain AChE activity; rats who did not develop SE had significantly less reduction of AChE activity in the basolateral amygdala than rats who developed SE. Atropine sulfate (ATS)more » at 2 mg/kg, administered 20 min after soman exposure (1.2 × LD{sub 50}), terminated seizures. ATS at 0.5 mg/kg, given along with an oxime within 1 min after exposure, allowed testing of anticonvulsants at delayed time-points. The AMPA/GluK1 receptor antagonist LY293558, or the specific GluK1 antagonist UBP302, administered 1 h post-exposure, terminated SE. There were no degenerating neurons in soman-exposed P21 rats, but both the amygdala and the hippocampus were smaller than in control rats at 30 and 90 days post-exposure; this pathology was not present in rats treated with LY293558. Behavioral deficits present at 30 days post-exposure, were also prevented by LY293558 treatment. Thus, in immature animals, a single injection of atropine is sufficient to halt nerve agent-induced seizures, if administered timely. Testing anticonvulsants at delayed time-points requires early administration of ATS at a low dose, sufficient to counteract only peripheral toxicity. LY293558 administered 1 h post-exposure, prevents brain pathology and behavioral deficits. - Highlights: • The LD{sub 50} of soman was determined in postnatal-day-21 rats. • Rats with no seizures after 1.2XLD{sub 50} soman had less reduction of AChE in the amygdala. • Atropine sulfate (ATS) at 2 mg/kg, given at 20 min after soman, blocked seizures. • With ATS at 0.5 mg/kg, LY293558 or UBP302 at 1 h after exposure terminated seizures. • LY293558 prevented brain pathology and behavioral deficits.« less

The modulating effect of Persea americana fruit extract on the level of expression of fatty acid synthase complex, lipoprotein lipase, fibroblast growth factor-21 and leptin--A biochemical study in rats subjected to experimental hyperlipidemia and obesity.

PubMed

Monika, Padmanabhan; Geetha, Arumugam

2015-09-15

Obesity is a multifactorial disorder which is closely associated with hyperlipidemia. Avocados are edible fruits traditionally consumed for various health benefits including body weight reduction. To determine the hypolipidemic and anti-obesity effect of hydro-alcoholic fruit extract of avocado (HFEA) in rats fed with high fat diet (HFD). Male Sprague Dawley rats were divided into four groups. Groups 1 and 2 rats were fed with normal diet. Groups 3 and 4 rats were fed with HFD for 14 weeks. In addition, Groups 2 and 4 rats were co-administered with 100 mg/kg body weight of HFEA from 3rd week onwards. The HFEA was subjected to HPLC to quantify the major phytonutrients. Body mass index (BMI), adiposity index (ADI), total fat pad mass (TFP), blood lipid levels were determined in all the groups of rats. The mRNA expression of fatty acid synthase (FASN), lipoprotein lipase (LPL), fibroblast growth factor 21 (FGF21) and leptin was also assessed. HFEA was found to contain flavonoids: rutin-141.79, quercetin-5.25, luteolin-165, phenolic compounds: gallic acid-198.57, ellagic acid-238.22, vanillic acid-4.79 and phytosterols: betasitosterol-70, stigmasterol-12.5 (mg/100 g). HFEA reduced BMI, ADI, TFP, blood cholesterol, triglycerides, and LDL in rats fed with HFD. Serum leptin was found reduced in HFEA co-administered rats. The mRNA expression of FASN, LPL, and leptin in subcutaneous and visceral adipose tissue was found to be significantly reduced in HFEA co-administered rats. The gene expression of fibroblast growth factor-21 (FGF21) was found to be significantly increased in HFEA treated rats when compared to HFD control rats. The hypolipidemic effect of HFEA may be partly due to its modulating effect on endogenous fat synthesis and adiponectin formation through the transcription factor FGF21. The results also show that avocado fruit extract has profound influence on leptin activity, which controls satiety and hunger to regulate the food intake. Copyright © 2015 Elsevier GmbH. All rights reserved.

BILIARY EXCRETION AND TISSUE DISTRIBUTION OF CADMIUM-109 ADMINISTERED TO RATS

EPA Science Inventory

The difference in the excretion of cadmium in urine and feces was measured in rats with either ligated or intact bile ducts. Three days following a single oral-administration of cadmium-109 plus stabe cadmium chloride, 0.004 percent of the dose was excreted in the urine of rats w...

Comparison of the Protective Effects of Melatonin and Silymarin Against Gentamicin-Induced Nephrotoxicity in Rats.

PubMed

Ghaznavi, Habib; Mehrzadi, Saeed; Dormanesh, Banafshe; Tabatabaei, Seyyed Mohammad Taghi Hosseini; Vahedi, Habib; Hosseinzadeh, Azam; Pazoki-Toroudi, HamidReza; Rashidian, Amir

2016-10-01

This study compared the possible protective effects of silymarin and melatonin against gentamicin (GEN)-induced nephrotoxicity in rats. Rats were allocated to 6 groups: Group I, control group; Groups II and III, administered with silymarin or melatonin; Group IV, injected with GEN; and Groups V and VI, administered with silymarin or melatonin, and then injected with GEN. Compared with the rats in the control group, all rats injected with GEN significantly presented elevated levels of serum creatinine and urea that was accompanied by an increase in relative kidney weight, increase in renal reactive oxygen species (ROS) and malondialdehyde (MDA) levels, and reduction in renal glutathione (GSH) level and superoxide dismutase (SOD) activity. Silymarin and melatonin pretreatment significantly lowered the elevated serum urea and creatinine concentration, kidney weight, and renal ROS and MDA levels. In addition, silymarin and melatonin significantly enhanced renal GSH level and SOD activity. This study indicates that silymarin and melatonin can attenuate renal injury in rats treated with GEN possibly by reducing the ROS level. © The Author(s) 2015.

Dose-response toxicity studies on tributoxyethyl phosphate orally administered to Sprague-Dawley rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Laham, S.; Szabo, J.; Long, G.

The response of the peripheral nervous system to various dose levels of tributoxyethyl phosphate (TBOP) was investigated in Sprague-Dawley rats. Groups of randomized female and male rats (10 rats/gender/dose level) were administered a single oral dose of TBOP (1.0 to 3.2 g/kg for females;1.0 to 9.0 g/kg for males). Physiological parameters were measured in surviving rats three weeks following TBOP administration. A significant reduction (p<0.05) in caudal nerve conduction velocity (NCV) was observed in both female and male rats. Light and electron microscopic examination of sciatic nerve sections showed degenerative changes in both myelinated and unmyelinated fibers of female (2.0more » g/kg) and male (6.8 g/kg) groups. Advanced degeneration was observed only in the highest dose level of both genders (3.2 g/kg for females; 8.0 and 9.0 g/kg for males). Although similar morphological changes were observed in both genders, females were more susceptible than males to the toxic effects of this compound.« less

A lecithin-based microemulsion of rh-insulin with aprotinin for oral administration: Investigation of hypoglycemic effects in non-diabetic and STZ-induced diabetic rats.

PubMed

Cilek, A; Celebi, N; Tirnaksiz, F; Tay, A

2005-07-14

The aim of this study was to develop a microemulsion formulation providing an improved efficacy of orally administered insulin. The microemulsions were prepared using Labrafil M 1944 CS, Phospholipon 90 G (lecithin), absolute alcohol and bi-distilled water. The microemulsions of recombinant human (rh)-insulin and aqueous solution (200 IU/kg) were administered intragastrically by a canulla to diabetic and non-diabetic rats. Aprotinin (2500 KIU/g) was added as the enzyme inhibitor to the formulation. Upon the administration of intragastric rh-insulin solution (IS) to non-diabetic rats, the plasma glucose and insulin levels were not changed significantly. Therefore, the hypoglycemic effect caused by subcutaneous rh-insulin solution (SC), microemulsion containing rh-insulin (IME) and microemulsion containing rh-insulin and aprotinin (IMEA) were analyzed in diabetic rats. The area above the plasma glucose levels time curves (AAC), minimum glucose concentration (Cmin) and time to Cmin (tmin) were derived from the plasma glucose profiles. IME and IMEA caused approximately 30% decrease in plasma glucose levels. The decrease in the plasma glucose levels continued after the 90th min. The highest AAC value was obtained when IMEA was administered to rats. The maximum plasma insulin concentration (Cmax), time to reach Cmax (tmax), terminal half-life (t(1/2)), area under the plasma concentration-time curve (AUC), mean residence time (MRT) and elimination rate constant (k(el)) values were also calculated. It was observed that t(1/2) values varied between 0.53 and 1.31h. No significant difference could be found between the pharmacokinetic parameters of the IME and IMEA administered groups. Addition of aprotinin to the microemulsion containing rh-insulin increased bioavailability when compared to those not containing it, although the difference is not significant.

Effect of Piper betle leaf extract on alcoholic toxicity in the rat brain.

PubMed

Saravanan, R; Rajendra Prasad, N; Pugalendi, K V

2003-01-01

The protective effect of Piper betle, a commonly used masticatory, has been examined in the brain of ethanol-administered Wistar rats. Brain of ethanol-treated rats exhibited increased levels of lipids, lipid peroxidation, and disturbances in antioxidant defense. Subsequent to the experimental induction of toxicity (i.e., the initial period of 30 days), aqueous P. betle extract was simultaneously administered in three different doses (100, 200, and 300 mg kg(-1)) for 30 days along with the daily dose of alcohol. P. betle coadministration resulted in significant reduction of lipid levels (free fatty acids, cholesterol, and phospholipids) and lipid peroxidation markers such as thiobarbituric acid reactive substances and hydroperoxides. Further, antioxidants, like reduced glutathione, vitamin C, vitamin E, superoxide dismutase, catalase, and glutathione peroxidase, were increased in P. betle-coadministered rats. The higher dose of extract (300 mg kg(-1)) was more effective, and these results indicate the neuroprotective effect of P. betle in ethanol-treated rats.

Confirmation of uterotrophic activity of 3-(4-methylbenzylidine)camphor in the immature rat.

PubMed Central

Tinwell, Helen; Lefevre, Paul A; Moffat, Graeme J; Burns, A; Odum, Jenny; Spurway, T D; Orphanides, George; Ashby, John

2002-01-01

In this study we found that the ultraviolet sunscreen component 3-(4-methylbenzylidine)camphor (4MBC) is uterotrophic in immature rats when administered by either subcutaneous injection or oral gavage. These data confirm earlier reports of uterotrophic activity for this agent when administered to immature rats in the diet or by whole-body immersion; however, they are in contrast to negative unpublished immature rat uterotrophic assay results. Data also indicate that 4MBC binds to isolated rat uterine estrogen receptors and shows activity in a human estrogen receptor yeast transactivation assay; however, we considered both of these effects equivocal. In this study, we confirmed the original observation that 4MBC was active as a mitogen to MCF-7 breast cancer cells. We evaluated and discounted the possibility that the estrogenic activity of 4MBC is related to its bulky camphor group, which is of similar molecular dimensions to that of the weak estrogen kepone. Uncertainty remains regarding the mechanism of the uterotrophic activity of 4MBC. PMID:12003759

A Role for Presynaptic alpha(sub 2)-Adrenoceptors in Angiotensin 2-Induced Drinking in Rats

NASA Technical Reports Server (NTRS)

Fregly, Melvin J.; Rowland, Neil E.; Greenleaf, John E.

1984-01-01

Studies from this laboratory have shown that either central or peripheral administration of clonidine, the alpha(sub 2)-adrenoceptor agonist, can attenuate a variety of dipsogenic stimuli in rats. Further, yohimbine and tolazoline, alpha(sub 2)-adrenoceptor antagonists, augment the drinking response to both peripherally administered isoproterenol and angiotensin 2. Studies reported here establish a dose-inhibition relationship between the dose of clonidine administered (2 to 32 micrograms/kg) intracerebroventricularly (IVT) and inhibition of the drinking response to peripherally administered angiotensin 2 (200 micrograms/kg, SC). DI(sub 50) was approximately 4 micrograms/kg. Yohimbine (300 micrograms/kg, SC) reversed the antidipsogenic effect of centrally administered clonidine (32 micrograms/kg, IVT) on angiotensin 2-induced (200 micrograms/kg, SC) water intake. Phenylephrine, an alpha(sub 2)-adrenoceptor agonist, administered IVT (40 and 80 micrograms/kg) also inhibited angiotensin 2-induced drinking in a dose-related fashion. The antidipsogenic effect of phenylephfine (80 micrograms/kg) was blocked by administration of yohimbine (100 micrograms/kg, SC). Thus, this effect of phenylephrine most likely occurs by way of alpha(sub 2)- adrenoceptors. These results support a role for the pre-synaptic alpha(sub 2)-adrenoceptor in the mediation of drinking in rats. Activation of alpha(sub 2)-adrenoceptors is accompanied by reduced water intake while inhibition of these receptors enhances water intake.

Effects of diabetes on tooth movement and root resorption after orthodontic force application in rats.

PubMed

Arita, K; Hotokezaka, H; Hashimoto, M; Nakano-Tajima, T; Kurohama, T; Kondo, T; Darendeliler, M A; Yoshida, N

2016-05-01

To investigate the effects of diabetes on orthodontic tooth movement and orthodontically induced root resorption in rats. Twenty-three 10-week-old male Sprague-Dawley rats divided into control (n = 7), diabetes (n = 9), and diabetes + insulin (n = 7) groups. Diabetes was induced by administering a single intraperitoneal injection of streptozotocin. Rats with a blood glucose level exceeding 250 mg/dl were assigned to the diabetes group. Insulin was administered daily to the diabetes + insulin group. A nickel-titanium closed-coil spring of 10 g was applied for 2 weeks to the maxillary left first molar in all rats to induce mesial tooth movement. Tooth movement was measured using microcomputed tomography images. To determine the quantity of root resorption, the mesial surfaces of the mesial and distal roots of the first molar were analyzed using both scanning electron microscopy and scanning laser microscopy. After 2 weeks, the amount of tooth movement in the diabetic rats was lower than that in the control rats. Root resorption was also significantly lower in the diabetic rats. These responses of the rats caused by diabetes were mostly diminished by insulin administration. Diabetes significantly reduced orthodontic tooth movement and orthodontically induced root resorption in rats. The regulation of blood glucose level through insulin administration largely reduced these abnormal responses to orthodontic force application. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

GluN2B-containing NMDA receptors blockade rescues bidirectional synaptic plasticity in the bed nucleus of the stria terminalis of cocaine self-administering rats.

PubMed

deBacker, Julian; Hawken, Emily R; Normandeau, Catherine P; Jones, Andrea A; Di Prospero, Cynthia; Mechefske, Elysia; Gardner Gregory, James; Hayton, Scott J; Dumont, Éric C

2015-01-01

Drugs of abuse have detrimental effects on homeostatic synaptic plasticity in the motivational brain network. Bidirectional plasticity at excitatory synapses helps keep neural circuits within a functional range to allow for behavioral flexibility. Therefore, impaired bidirectional plasticity of excitatory synapses may contribute to the behavioral hallmarks of addiction, yet this relationship remains unclear. Here we tracked excitatory synaptic strength in the oval bed nucleus of the stria terminalis (ovBNST) using whole-cell voltage-clamp recordings in brain slices from rats self-administering sucrose or cocaine. In the cocaine group, we measured both a persistent increase in AMPA to NMDA ratio (A:N) and slow decay time of NMDA currents throughout the self-administration period and after withdrawal from cocaine. In contrast, the sucrose group exhibited an early increase in A:N ratios (acquisition) that returned toward baseline values with continued self-administration (maintenance) and after withdrawal. The sucrose rats also displayed a decrease in NMDA current decay time with continued self-administration (maintenance), which normalized after withdrawal. Cocaine self-administering rats exhibited impairment in NMDA-dependent long-term depression (LTD) that could be rescued by GluN2B-containing NMDA receptor blockade. Sucrose self-administering rats demonstrated no impairment in NMDA-dependent LTD. During the maintenance period of self-administration, in vivo (daily intraperitoneally for 5 days) pharmacologic blockade of GluN2B-containing NMDA receptors did not reduce lever pressing for cocaine. However, in vivo GluN2B blockade did normalize A:N ratios in cocaine self-administrating rats, and dissociated the magnitude of ovBNST A:N ratios from drug-seeking behavior after protracted withdrawal. Altogether, our data demonstrate when and how bidirectional plasticity at ovBNST excitatory synapses becomes dysfunctional with cocaine self-administration and that NMDA-mediated potentiation of AMPA receptors in this region may be part of the neural circuits of drug relapse.

Effect of Mucuna pruriens (Linn.) on oxidative stress-induced structural alteration of corpus cavernosum in streptozotocin-induced diabetic rat.

PubMed

Suresh, Sekar; Prakash, Seppan

2011-07-01

Erectile dysfunction is one of the major secondary complications of diabetes. Mucuna pruriens (M. pruriens), a leguminous plant identified for its antidiabetic, aphrodisiac, and fertility enhancing properties, has been the choice of Indian traditional medicine. The objective of the present study was to analyze the efficacy of M. pruriens on free radicals-mediated penile tissue alterations in hyperglycemic male rats. Methods.  Male albino rats were divided as group I (sham) control, group II (STZ) diabetes-induced (streptozotocin 60 mg/kg of body weight [bw] in 0.1 M citrate buffer), group III (STZ + MP) diabetic rats administered with 200 mg/kg bw of ethanolic extract of M. pruriens seed, group IV (STZ + SIL) diabetic rats administered with 5 mg/kg bw of sildenafil citrate, group V (sham + MP) administered with 200 mg/kg bw of extract alone, and group VI (sham + SIL) administered with 5 mg/kg bw of sildenafil citrate. The M. pruriens and sildenafil citrate were given (gavage) once daily for a period of 60 days. At the end of 60 days, the animals were sacrificed and subjected to analysis of reactive oxygen species levels, enzymic and nonenzymic antioxidant levels, levels of NOx, histological, and histomorphometrical study of penile tissue. Remedial use of M. pruriens seed extract on diabetes-induced erectile tissue damage. Significantly high levels of oxidative stress and low levels of antioxidants in the penile tissue seem to contribute to the increased collagen deposition and fibrosis of erectile tissue in STZ rats. Relatively, there was increased damage in STZ + SIL group. Supplementation of M. pruriens in STZ + MP group has revealed the potency to overcome oxidative stress, and good preservation of penile histoarchitecture.  The ethanolic extract of M. pruriens seed significantly recovered or protected erectile tissue from the oxidative stress-induced degeneration by its antioxidant potentials. These findings propound to serve mankind by the treatment of diabetes-induced erectile dysfunction. © 2011 International Society for Sexual Medicine.

Agglomeration of Celecoxib by Quasi Emulsion Solvent Diffusion Method: Effect of Stabilizer.

PubMed

Maghsoodi, Maryam; Nokhodchi, Ali

2016-12-01

Purpose: The quasi-emulsion solvent diffusion (QESD) has evolved into an effective technique to manufacture agglomerates of API crystals. Although, the proposed technique showed benefits, such as cost effectiveness, that is considerably sensitive to the choice of a stabilizer, which agonizes from a absence of systemic understanding in this field. In the present study, the combination of different solvents and stabilizers were compared to investigate any connections between the solvents and stabilizers. Methods: Agglomerates of celecoxib were prepared by QESD method using four different stabilizers (Tween 80, HPMC, PVP and SLS) and three different solvents (methyl acetate, ethyl acetate and isopropyl acetate). The solid state of obtained particles was investigated by differential scanning calorimetry (DSC) and Fourier transform infrared (FT-IR) spectroscopy. The agglomerated were also evaluated in term of production yield, distribution of particles and dissolution behavior. Results: The results showed that the effectiveness of stabilizer in terms of particle size and particle size distribution is specific to each solvent candidate. A stabilizer with a lower HLB value is preferred which actually increased its effectiveness with the solvent candidates with higher lipophilicity. HPMC appeared to be the most versatile stabilizer because it showed a better stabilizing effect compared to other stabilizers in all solvents used. Conclusion: This study demonstrated that the efficiency of stabilizers in forming the celecoxib agglomerates by QESD was influenced by the HLB of the stabilizer and lipophilicity of the solvents.

Nutraceutical inherent of Spinacia oleracea Linn. methanolic leaf extract ameliorates isoproterenol induced myocardial necrosis in male albino Wistar rats via mitigating inflammation.

PubMed

Vutharadhi, Shivaranjani; Jolapuram, Umamaheswari; Kodidhela, Lakshmi Devi

2017-01-01

Cardiovascular diseases (CVDs) remain the principal cause of death in both developed and developing countries. The present study was intended to appraise the nutraceutical inherent of HPLC standardized Spinacia oleracea methanolic leaf extract (SoLE) in isoproterenol (ISO) induced male albino Wistar rats via activation of pro-inflammatory signaling pathway that drives myocardial necrosis. Biochemical analysis of ISO injected rats showed significant alterations in the activities of homocysteine, paraoxonase, lecithin cholesterol acyltransferase, C-reactive protein, myeloperoxidase and caspase-3 which were further confirmed by the histopathological examination. In addition, it also flaunted a significant increase in pro-inflammatory cytokines, such as TNF-α, IL-1β, IL-6 in ISO administered rats when compared with normal control rats. Pretreatment with SoLE (100, 200, and 300mg/kg bw) along with positive control gallic acid, significantly prevented all the adverse effects in ISO administered rats in a dose dependent manner. These results also reiterated the expected amelioration of myocardial necrosis in ISO induced MI rats conveying anti-atherogenic, anti-apoptotic and anti-inflammatory activities of SoLE. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

The effects of Vitamin C on sperm quality parameters in laboratory rats following long-term exposure to cyclophosphamide.

PubMed

Shabanian, Sheida; Farahbod, Farnoosh; Rafieian, Mahmoud; Ganji, Forouzan; Adib, Afshin

2017-01-01

Cyclophosphamide is a widely used medication and can cause oxidative stress. This study was conducted to investigate the effects of Vitamin C on reproductive organs' weight and the quality of sperm parameters in laboratory rats. In this experimental study, 40 rats were randomly assigned into five groups of eight each. Distilled water (DW) group received only food and water, Group 2 was administered with drug solvent (DW) by gavage, Group 3 intraperitoneally administered with 1.6 mg/kg cyclophosphamide, Group 4 gavaged Vitamin C at 0.88 mg/kg, and Group 5 administered with effective doses of Vitamin C and cyclophosphamide by gavage with 1-h intervals. Sperm parameters of the samples were taken from distal epididymis and tissues were studied, and the data were analyzed by SPSS version 22. The lowest weight of testicles and epididymis was seen in cyclophosphamide-exposed rats and the highest weight of testicles and epididymis in Vitamin C-exposed rats ( P < 0.05). The highest motility, progression, viability, and count of sperm were seen in the Vitamin C-treated group and the lowest in the cyclophosphamide-exposed group. The highest proportion of sperm anomalies was seen in the cyclophosphamide-exposed group. Vitamin C, as an antioxidant, can be effective on some of the sperm parameters and can reduce cyclophosphamide-induced complications in animal model.

The effects of Vitamin C on sperm quality parameters in laboratory rats following long-term exposure to cyclophosphamide

PubMed Central

Shabanian, Sheida; Farahbod, Farnoosh; Rafieian, Mahmoud; Ganji, Forouzan; Adib, Afshin

2017-01-01

Cyclophosphamide is a widely used medication and can cause oxidative stress. This study was conducted to investigate the effects of Vitamin C on reproductive organs' weight and the quality of sperm parameters in laboratory rats. In this experimental study, 40 rats were randomly assigned into five groups of eight each. Distilled water (DW) group received only food and water, Group 2 was administered with drug solvent (DW) by gavage, Group 3 intraperitoneally administered with 1.6 mg/kg cyclophosphamide, Group 4 gavaged Vitamin C at 0.88 mg/kg, and Group 5 administered with effective doses of Vitamin C and cyclophosphamide by gavage with 1-h intervals. Sperm parameters of the samples were taken from distal epididymis and tissues were studied, and the data were analyzed by SPSS version 22. The lowest weight of testicles and epididymis was seen in cyclophosphamide-exposed rats and the highest weight of testicles and epididymis in Vitamin C-exposed rats (P < 0.05). The highest motility, progression, viability, and count of sperm were seen in the Vitamin C-treated group and the lowest in the cyclophosphamide-exposed group. The highest proportion of sperm anomalies was seen in the cyclophosphamide-exposed group. Vitamin C, as an antioxidant, can be effective on some of the sperm parameters and can reduce cyclophosphamide-induced complications in animal model. PMID:28516060

NTP Studies of Magnetic Field Promotion (DMBA Initiation) in Female Sprague-Dawley Rats (Whole-body Exposure/Gavage Studies).

PubMed

1999-08-01

Electric and magnetic fields are associated with the production, transmission, and use of electricity; thus, the potential for human exposure is high. These elec-tric and magnetic fields are predominantly of low fre-quency (60 Hz in the United States and 50 Hz in Europe) and generally of low intensity. Because some epidemiology studies and initiation/promotion studies in rats have suggested a potential for increased breast cancer rates with increasing magnetic field exposure, the ability of 50- and 60-Hz magnetic fields to pro-mote mammary gland tumors initiated by the administration of 7,12-dimethylbenz(a)anthracene (DMBA) was examined in female Sprague-Dawley rats in 13- and 26-week whole-body exposure studies. Additional animals were evaluated for changes in pineal gland and serum melatonin concentrations. FIRST 13-WEEK STUDY: Groups of 100 female Sprague-Dawley rats were ad-ministered 20 mg DMBA (four weekly gavage doses of 5 mg in sesame oil) and exposed to 1 G 50-Hz, 5 G 50-Hz, or 1 G 60-Hz magnetic fields for 18.5 hours per day, 7 days per week, for 13 weeks. A group of 100 rats administered 20 mg DMBA served as DMBA controls. A group of 100 vehicle control rats was administered only sesame oil on the same schedule. Additional groups of 10 rats receiving similar treatment were evaluated for pineal gland and serum melatonin concentrations at 4, 8, or 12 weeks. All vehicle control rats survived to the end of the study. Of the animals administered 20 mg DMBA, 6 rats in the DMBA control group, 13 in the DMBA/1 G 50-Hz group, eight in the DMBA/5 G 50-Hz group, and five in the DMBA/1 G 60-Hz group died or were removed from the study prior to the final necropsy. Final mean body weights and body weight gains of the DMBA/1 G 50-Hz and DMBA/1 G 60-Hz groups and the mean body weight gain of the DMBA/5 G 50-Hz group were slightly greater than those of the DMBA control group. Clinical findings including torso masses and ulcers (on the mammary masses) were attributed to DMBA administration. The numbers of palpable mammary gland tumors, tumor sizes, and total tumor areas in DMBA/magnetic field groups were similar to those in the DMBA control group. Relative to the DMBA control group, exposure to magnetic fields did not significantly affect overall incidences of mammary gland neoplasms or nonneoplastic lesions in the DMBA/magnetic field groups. SECOND 13-WEEK STUDY: Groups of 100 female Sprague-Dawley rats were ad-ministered 8 mg DMBA (four weekly gavage doses of 2 mg in sesame oil) and exposed to 1 G 50-Hz or 5 G 50-Hz magnetic fields for 18.5 hours per day, 7 days per week, for 13 weeks. A group of 100 female rats administered 8 mg DMBA served as DMBA controls. Additional groups of 10 rats receiving similar treatment were evaluated for pineal gland and serum melatonin concentrations at 4, 8, or 12 weeks. Except for one rat in the DMBA/5 G 50-Hz group, all rats survived until the end of the study. Final mean body weights of DMBA/magnetic field groups were similar to those of the DMBA control group. Clinical findings including torso masses and ulcers were attributed to DMBA administration. The numbers of palpable mammary gland tumors, tumor sizes, and total tumor areas in DMBA/magnetic field groups were similar to those in the DMBA control group. Relative to the DMBA control group, exposure to magnetic fields did not significantly affect overall incidences of mammary gland neoplasms or nonneoplastic lesions in the DMBA/magnetic field groups. 26-WEEK STUDY: Groups of 100 female Sprague-Dawley rats were administered 10 mg DMBA (in sesame oil) by gavage followed by exposure to 1 G 50-Hz, 5 G 50-Hz, or 1 G 60-Hz magnetic fields for 18.5 hours per day, 7 days per week, for 26 weeks. A group of 100 female rats administered 10 mg DMBA served as DMBA controls. Another 100 vehicle control rats were administered only sesame oil. Additional groups of 10 rats receiving similar treatment were evaluated for pineal gland and serum melatonin concentrations at 4, 8, or 12 weeks. All rats in the vehicle control group survived until the end of the study. Twelve rats in the DMBA control group, 15 in the DMBA/1 G 50-Hz group, 9 in the DMBA/5 G 50-Hz group, and six in the DMBA/1 G 60-Hz group died or were removed during the study. The final mean body weights and body weight gains of the DMBA/1 G 50-Hz and DMBA/5 G 50-Hz groups were significantly greater than those of the DMBA control group. Clinical findings including torso masses, abscesses, and ulcers were attributed to DMBA administration. The pineal gland melatonin concentrations of DMBA/5 G 50-Hz and DMBA/1 G 60-Hz rats were significantly greater than that of the DMBA controls at week 12; however, these data were highly variable between individual animals within each group. The numbers of palpable mammary gland tumors, tumor sizes, and total tumor areas in DMBA/magnetic field groups were similar to those in the DMBA controls. The incidences of mammary gland carci-noma (including multiple) in the DMBA/1 G 60-Hz group were significantly decreased relative to the DMBA control group. CONCLUSIONS: In an initiation/promotion study in which female Sprague-Dawley rats were initiated by four weekly doses of 5 mg DMBA per rat beginning at 50 days of age and exposed to 50-Hz magnetic fields at 1 or 5 G field intensities or to 1 G 60-Hz magnetic fields for 13 weeks, there was no evidence that magnetic fields promoted the development of mammary gland neoplasms. The prevalence and multiplicity of mammary gland carcinomas in all DMBA groups limited the ability of this assay to detect a promoting effect of magnetic fields. In an initiation/promotion study in which female Sprague-Dawley rats were initiated by four weekly doses of 2 mg DMBA per rat beginning at 50 days of age and exposed to 50-Hz magnetic fields at 1 or 5 G field intensities for 13 weeks, there was no evidence that magnetic fields promoted the development of mammary gland neoplasms. In an initiation/promotion study in which female Sprague-Dawley rats were initiated by a single 10 mg DMBA dose at 50 days of age and then exposed to 50-Hz magnetic fields at 1 or 5 G field intensities or to 1 G 60-Hz magnetic fields for 26 weeks, there was no evidence that magnetic fields promoted the development of mammary gland neoplasms.

Combined antiallodynic effect of Neurotropin® and pregabalin in rats with L5-spinal nerve ligation.

PubMed

Okazaki, Ryohei; Namba, Hiroyoshi; Yoshida, Hiroyuki; Okai, Hisashi; Taguchi, Kazuki; Kawamura, Minoru

2013-03-12

In this study, we investigated the combined effect of Neurotropin® and pregabalin for L5-spinal nerve ligation (L5-SNL) model in rats and thiopental-induced sleep in mice. The left fifth lumbar nerve of rats was tightly ligated with silk sutures under pentobarbital anesthesia. The hindpaw withdrawal threshold was measured by application of von Frey filaments. Thiopental sodium was intravenously administered in mice and sleeping time was measured. In L5-SNL rats, an isobolographic analysis was performed to clarify the combined antiallodynic effect of Neurotropin and pregabalin 14 days after ligation in rats. In isobolographic analysis and thiopental-induced sleep test, Neurotropin and pregabalin were orally administered to coincide with the timing of the peak effect of each drug. Neurotropin (50-200 NU/kg) and pregabalin (2.5-10mg/kg) showed a dose-dependent antiallodynic action in L5-SNL rats. The antiallodynic effect of pregabalin was reversed by intrathecal injection of yohimbine or ondansetron. Isobolographic analysis suggested that the combined antiallodynic effect of Neurotropin and pregabalin in L5-SNL rats may have been more than a mere additive effect. Neurotropin (50-400 NU/kg) had no effect on thiopental-induced sleeping time whereas pregabalin (30-100mg/kg) significantly prolonged it. When the dose of pregabalin was 30 mg/kg, Neurotropin (50-400 NU/kg) did not further exacerbate the prolongation effect of pregabalin on thiopental-induced sleep. It was suggested that when Neurotropin was administered in combination with pregabalin, it might provide more effective pain relief than that obtained with each agent alone in neuropathic pain without aggravating adverse effects of pregabalin. Copyright © 2013 Elsevier Inc. All rights reserved.

Absorption, Distribution, Metabolism, and Excretion of the Androgen Receptor Inhibitor Enzalutamide in Rats and Dogs.

PubMed

Ohtsu, Yoshiaki; Gibbons, Jacqueline A; Suzuki, Katsuhiro; Fitzsimmons, Michael E; Nozawa, Kohei; Arai, Hiroshi

2017-08-01

Enzalutamide is an androgen receptor inhibitor that has been approved in several countries. Absorption, distribution, metabolism, and excretion (ADME) data in animals would facilitate understanding of the efficacy and safety profiles of enzalutamide, but little information has been reported in public. The purpose of this study was to clarify the missing ADME profile in animals. ADME of 14 C-enzalutamide after oral administration as Labrasol solution were investigated in non-fasted male Sprague-Dawley rats and beagle dogs. Plasma concentrations of 14 C-enzalutamide peaked in rats and dogs at 6-8 h after a single oral administration. In most tissues, radioactivity concentration peaked at 4 h after administration. Excluding the gastrointestinal tract, tissues with the highest concentration of radioactivity were liver, fat, and adrenal glands. The tissue concentrations of radioactivity declined below the limit of quantitation or <0.89 % of maximum concentration by 168 h post-dose. Two known metabolites (M1 and M2) and at least 15 novel possible metabolites were detected in this study. M1 was the most abundant metabolite in both rats and dogs. Unchanged drug was a minor component in excreta. In intact rats, the mean urinary and fecal excretion of radioactivity accounted for 44.20 and 49.80 % of administered radioactivity, respectively. In intact dogs, mean urinary and fecal excretion was 62.00 and 22.30 % of the administered radioactivity, respectively. Rapid oral absorption was observed in rats and dogs when 14 C-enzalutamide was administered as Labrasol solution. Tissue distribution in rats was clarified. The elimination of enzalutamide is mediated primarily by metabolism. Species differences were observed in excretion route.

Investigation of the Protective Effect of Kefir against Isoproterenol Induced Myocardial Infarction in Rats

PubMed Central

Mert, Handan; Yılmaz, Hikmet; Irak, Kıvanç; Yıldırım, Serkan; Mert, Nihat

2018-01-01

Abstract This study aims to investigate the protective effects of kefir against myocardial infarction induced by isoproterenol (ISO). The rats were randomly divided into 4 groups, each group consisting of 8 rats. The control group, the kefir group (5 mL/kg/d kefir administered to rats as intra-gastric gavage for 60 d), the ISO group (100 mg/kg ISO was administered to rats, s.c. on 61. and 62. d), and kefir+ISO group (5 mL/kg/d kefir was administered to rats intra gastric gavage for 60 days prior to ISO, 100 mg/kg in two doses on day 61 and 62). 12 h after the last ISO dose, all rats were decapitated and their blood samples were collected. Cardiac tissue was reserved for histopathological examination. creatine kinase (CK), alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), triglycerides, total cholesterol,very low density lipoprotein (VLDL), low density lipoprotein (LDL), high density lipoprotein (HDL) and glucose were measured by autoanalyzer, whole blood malondialdehyde (MDA), glutathione (GSH) and plasma advanced oxidation protein products (AOPP) levels were measured spectrophotometrically. It was determined that in the group of kefir+ISO, the levels of AST (p<0.001), CK (p<0.001), LDH (p<0.001), MDA (p<0.001) and AOPP (p<0.001) were decreased, while the GSH (p<0.05) increased, compared to ISO group. There were no significant changes in lipid profile and glucose levels between these two groups. In conclusion, by examining cardiac enzymes and histopathological changes in cardiac tissue, it can be concluded that the administration of kefir in myocardial infarction induced by ISO can protect the heart with its antioxidant characteristic and minimize the toxic damage created by ISO. PMID:29805276

Activation of spinal and supraspinal cannabinoid-1 receptors lead to antinociception in a rat model of neuropathic spinal cord injury pain

PubMed Central

Hama, Aldric; Sagen, Jacqueline

2011-01-01

Activation of CNS cannabinoid subtype-1 (CB1) receptors has been shown to mediate the antinociceptive and other effects of systemically administered CB receptor agonists. The endogenous peptide CB receptor ligand hemopressin (HE) has previously demonstrated an antinociceptive effect in rats with a hind paw inflammation, without exhibiting characteristic CB1 receptor-mediated side-effects. The current study evaluated the effect of intrathecal (i.t.) and intracerebroventricular (i.c.v.) injection of HE in a rat model of neuropathic spinal cord injury (SCI) pain. The non-subtype selective CB receptor agonist WIN 55,212-2 was also centrally administered in SCI rats as a comparator. Four weeks following an acute compression of the mid-thoracic spinal cord, rats displayed markedly decreased hind paw withdrawal thresholds, indicative of below-level neuropathic pain. Central administration of WIN 55,212-2 significantly increased withdrawal thresholds, whereas HE did not. Hemopressin has been reported to block CB1 receptors in vitro, similar to the CB1 receptor antagonist rimonabant. Pretreatment with rimonabant completely blocked the antinociceptive effect of centrally administered WIN 55,212-2, but pretreatment with HE did not. While the data confirm that activation of either supraspinal or spinal CB1 receptors leads to significant antinociception in SCI rats, the current data do not support an antinociceptive effect from an acute blockade of central CB1 receptors, HE’s putative antinociceptive mechanism, in neuropathic SCI rats. Although such a mechanism could be useful in other models of pain with a significant inflammatory component, the current data indicate that activation of CB1 receptors is needed to ameliorate neuropathic SCI pain. PMID:21813113

Serotonin and histamine mediate gastroprotective effect of fluoxetine against experimentally-induced ulcers in rats.

PubMed

Salem Sokar, Samia; Elsayed Elsayad, Mageda; Sabri Ali, Hend

2016-09-01

Research in the treatment of gastric ulcer has involved the investigation of new alternatives, such as anti-depressant drugs. The present study was designed to investigate the gastroprotective effects of fluoxetine against indomethacin and alcohol induced gastric ulcers in rats and the potential mechanisms of that effect. Fluoxetine (20 mg/kg) was administered IP for 14 days. For comparative purposes, other rats were treated with ranitidine (30 mg/kg). Thereafter, after 24 h of fasting, INDO (100 mg/kg) or absolute alcohol (5 ml/kg) was administered to all rats (saline was administered to naïve controls) and rats in each group were sacrificed 5 h (for INDO rats) or 1 h (for alcohol rats) later. Macroscopic examination revealed that both fluoxetine and ranitidine decreased ulcer scores in variable ratios, which was supported by microscopic histopathological examination. Biochemical analysis of fluoxetine- or ranitidine-pre-treated host tissues demonstrated reductions in tumor necrosis factor (TNF)-α and myeloperoxidase (MPO) levels and concomitant increases in gastric pH, nitric oxide (NO) and reduced glutathione (GSH) contents. Fluoxetine, more than ranitidine, also resulted in serotonin and histamine levels nearest to control values. Moreover, immuno-histochemical analysis showed that fluoxetine markedly enhanced expression of cyclo-oxygenases COX-1 and COX-2 in both models; in comparison, ranitidine did not affect COX-1 expression in either ulcer model but caused moderate increases in COX-2 expression in INDO-induced hosts and high expression in alcohol-induced hosts. The results here indicated fluoxetine exhibited better gastroprotective effects than ranitidine and this could be due to anti-secretory, anti-oxidant, anti-inflammatory and anti-histaminic effects of the drug, as well as a stabilization of gastric serotonin levels.

Investigation of the Protective Effect of Kefir against Isoproterenol Induced Myocardial Infarction in Rats.

PubMed

Mert, Handan; Yılmaz, Hikmet; Irak, Kıvanç; Yıldırım, Serkan; Mert, Nihat

2018-04-01

This study aims to investigate the protective effects of kefir against myocardial infarction induced by isoproterenol (ISO). The rats were randomly divided into 4 groups, each group consisting of 8 rats. The control group, the kefir group (5 mL/kg/d kefir administered to rats as intra-gastric gavage for 60 d), the ISO group (100 mg/kg ISO was administered to rats, s.c. on 61. and 62. d), and kefir+ISO group (5 mL/kg/d kefir was administered to rats intra gastric gavage for 60 days prior to ISO, 100 mg/kg in two doses on day 61 and 62). 12 h after the last ISO dose, all rats were decapitated and their blood samples were collected. Cardiac tissue was reserved for histopathological examination. creatine kinase (CK), alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), triglycerides, total cholesterol,very low density lipoprotein (VLDL), low density lipoprotein (LDL), high density lipoprotein (HDL) and glucose were measured by autoanalyzer, whole blood malondialdehyde (MDA), glutathione (GSH) and plasma advanced oxidation protein products (AOPP) levels were measured spectrophotometrically. It was determined that in the group of kefir+ISO, the levels of AST ( p <0.001), CK ( p <0.001), LDH ( p <0.001), MDA ( p <0.001) and AOPP ( p <0.001) were decreased, while the GSH ( p <0.05) increased, compared to ISO group. There were no significant changes in lipid profile and glucose levels between these two groups. In conclusion, by examining cardiac enzymes and histopathological changes in cardiac tissue, it can be concluded that the administration of kefir in myocardial infarction induced by ISO can protect the heart with its antioxidant characteristic and minimize the toxic damage created by ISO.

Hepatoprotective activity of bacoside A against N-nitrosodiethylamine-induced liver toxicity in adult rats.

PubMed

Janani, Panneerselvam; Sivakumari, Kanakarajan; Parthasarathy, Chandrakesan

2009-10-01

N-Nitrosodiethylamine (DEN) is a notorious carcinogen, present in many environmental factors. DEN induces oxidative stress and cellular injury due to enhanced generation of reactive oxygen species; free radical scavengers protect the membranes from DEN-induced damage. The present study was designed to evaluate the protective effect of bacoside A (the active principle isolated from Bacopa monniera Linn.) on carcinogen-induced damage in rat liver. Adult male albino rats were pretreated with 15 mg/kg body weight/day of bacoside A orally (for 14 days) and then intoxicated with single necrogenic dose of N-nitrosodiethylamine (200 mg/kg bodyweight, intraperitonially) and maintained for 7 days. The liver weight, lipid peroxidation (LPO), and activity of serum marker enzymes (aspartate transaminases, alanine transaminases, lactate dehydrogenase, alkaline phosphatase, and gamma-glutamyl transpeptidase) were markedly increased in carcinogen-administered rats, whereas the activities of marker enzymes were near normal in bacoside A-pretreated rats. Activities of antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutatione-S-transferase, and reduced glutathione) in liver also decreased in carcinogen-administered rats, which were significantly elevated in bacoside A-pretreated rats. It is concluded that pretreatment of bacoside A prevents the elevation of LPO and activity of serum marker enzymes and maintains the antioxidant system and thus protects the rats from DEN-induced hepatotoxicity.

Conditional pharmacology/toxicology V: ambivalent effects of thiocyanate upon the development and the inhibition of experimental arthritis in rats by aurothiomalate (Myocrysin®) and metallic silver.

PubMed

Whitehouse, Michael; Butters, Desley; Vernon-Roberts, Barrie

2013-08-01

This article discusses the bizarre and contrary effects of thiocyanate, the major detoxication product of hydrogen cyanide inhaled from tobacco smoke or liberated from cyanogenic foods, e.g. cassava. Thiocyanate both (1) promotes inflammatory disease in rats and (2) facilitates the anti-inflammatory action of historic metal therapies based on gold (Au) or silver (Ag) in three models of chronic polyarthritis in rats. Low doses of nanoparticulate metallic silver (NMS) preparations, i.e. zerovalent silver (Ag°) administered orally, suppressed the mycobacterial ('adjuvant')-induced arthritis (MIA) in rats. Similar doses of cationic silver, Ag(I), administered orally as silver oxide or soluble silver salts were inactive. By contrast, NMS only inhibited the development of the collagen-induced arthritis (CIA) and pristane-induced arthritis (PIA) in rats when thiocyanate was also co-administered in drinking water. These (a) arthritis-selective and (b) thiocyanate-inducible effects of Ag° were also observed in some previous, and now extended, studies with the classic anti-arthritic drug, sodium aurothiomalate (ATM, Myocrisin(®)) and its silver analogue (STM), administered subcutaneously to rats developing the same three forms of polyarthritis. In the absence of either Ag° or ATM, thiocyanate considerably increased the severity of the MIA, CIA and PIA, i.e. acting as a pro-pathogen. Hitherto, thiocyanate was considered relatively harmless. This may not be true in rats/people with immuno-inflammatory stress and concomitant leukocyte activation. Collectively, these findings show how the drug action of a xenobiotic might be determined by the nature (and severity) of the experimental inflammation, as an example of conditional pharmacology. They also suggest that an incipient toxicity, even of normobiotics such as thiocyanate, might likewise be modulated beneficially by well-chosen xenobiotics (drugs, nutritional supplements, etc.), i.e. conditional toxicology (Powanda 1995). Thus, both the disease and the environment may determine (1) the therapeutic action and/or (2) adverse effect(s) of xenobiotics--and even some normobiotics.

Degradation of oxalate in rats implanted with immobilized oxalate oxidase.

PubMed

Raghavan, K G; Tarachand, U

1986-01-20

Accumulation of oxalate leads to hyperoxaluria and calcium oxalate nephrolithiasis in man. Since oxalate is a metabolic end product in mammals, the feasibility of its enzymic degradation has been tested in vivo in rats by administering exogenous oxalate oxidase. Oxalate oxidase, isolated from banana fruit peels, in its native form was found to be non-active at the physiological pH of the recipient animal. However, its functional viability in the recipient animal was ensured by its prior binding with ethylenemaleic anhydride, thus shifting its pH activity curve towards the alkaline range. Rats implanted with dialysis membrane capsules containing such immobilized oxalate oxidase in their peritoneal cavities effectively metabolized intraperitoneally injected [14C]oxalate as well as its precursor [14C]glyoxalate. The implantation of capsules containing coentrapped multienzyme preparations of oxalate oxidase, catalase and peroxidase led to a further degradation of administered [14C]oxalate in rats.

Widespread neuronal degeneration in rats following oral administration of methylmercury during the postnatal developing phase: a model of fetal-type minamata disease.

PubMed

Sakamoto, M; Wakabayashi, K; Kakita, A; Hitoshi Takahashi; Adachi, T; Nakano, A

1998-02-16

The neurotoxicity of methylmercury (MeHg) treatment during the postnatal developing phase in rats was studied. Rats on postnatal day 1 were orally administered 5 mg/kg/day methylmercury chloride (MMC) for more than 30 consecutive days. Body weight loss began 26 days after MMC was administered, and severe paralysis of the hind-limbs and unsteadiness appeared subsequently. Histopathologically, the widespread neuronal degeneration was observed in the cerebral neocortex, neostriatum, red nucleus, brainstem, cerebellum and spinal dorsal root ganglia on day 32. The widespread distribution of the lesions was quite similar to that in fetal cases of MeHg intoxication in Minamata, Japan. These findings suggest that MMC treatment during the postnatal development phase in rats produce a good model of fetal-type Minamata disease. Copyright 1998 Elsevier Science B.V.

[Effect of Shugan Jianpi Recipe on LXRα/FAS signaling pathway mediated hepatocyte fatty deposits in NAFLD rats].

PubMed

Gong, Xiang-Wen; Yang-Qin-He; Yan, Hai-Zhen; Zhang, Yu-Pei; Huang, Jin; Xu, Yong-Jian; Zhang, Jin-Wen; Lin, Chun-Mei

2014-12-01

To explore the effect of Shugan Jianpi Recipe (SJR) on LXRα/FAS signaling pathway mediated hepatocyte fatty deposits in nonalcoholic fatty liver disease (NAFLD) rats. Totally 75 SPF grade male SD rats were randomly divided into 5 groups, i.e., the normal control group, the model group, the Shugan Recipe (SR) treatment groups, the Jianpi Recipe (JR) treatment group, and the SJR group. Except rats in the normal control group, the NAFLD rat model was duplicated using high fat diet (HFD). SR (Chaihu Shugan Powder) was administered to rats in the SR group. JR (Shenlin Baizhu Powder) was administered to rats in the JR group. SJR (Chaihu Shugan Powder plus Shenlin Baizhu Powder) was administered to rats in the SJR group. Changes of liver fat were analyzed using automatic biochemical analyzer. Liver cells were separated by low-speed centrifugation. Their activities and purities were identify using Typan blue and flow cytometry (FCM). Expression levels of LXRα and FAS mRNA in hepatocytes detected by Real-time quantitative PCR. Expression levels of LXRα and FAS protein were detected by Western blot. (1) Pathological results showed in the model group, hepatocytes were swollen with nucleus locating at the cell edge after oil red O staining; unequal sized small vacuoles could be seen inside cytoplasm. Some small vacuoles merged big vacuoles. All these indi- cated a NAFLD rat model was successfully established by high fat diet. Pathological structural changes could be impaired to some degree in all medicated groups, especially in the SR group. (2) Compared with the normal control group, expression levels of LXRα and FAS genes and proteins obviously increased in the model group (P < 0.01). Compared with the model group, their expression levels were obviously down-regulated in the JR group and the SR group (P < 0.01, P < 0.05). LXRα/FAS signaling pathway was an important signaling pathway for mediating lipid metabolism disorders of NAFLD rats. SJR could make hepatocyte fatty deposits tend to repair by adjusting the LXRα/FAS signaling pathway in NAFLD rats, which might be one of important mechanisms for SJR to prevent and cure NAFLD.

Social defeat alters the acquisition of cocaine self-administration in rats: role of individual differences in cocaine-taking behavior.

PubMed

Kabbaj, M; Norton, C S; Kollack-Walker, S; Watson, S J; Robinson, T E; Akil, H

2001-12-01

It is known that social defeat can modulate cocaine self-administration. However, it is unclear whether this psychosocial stressor affects drug-taking behavior to the same extent across all individual animals, particularly those with differing propensities to self-administer psychostimulants. This study examined the effect of social defeat on cocaine self-administration in animals that differ in novelty-seeking behavior that predicts differences in drug self-administration. Male Sprague-Dawley rats were first classified into high-responder (HR) and low-responder (LR) groups. HR and LR rats were categorized based on their locomotor activity in a novel environment, with HR rats exhibiting higher locomotor activity than LR rats. Then, male rats were exposed on four occasions to an aggressive Long Evans male rat over the course of 4 days. Control rats were not exposed to the social defeat. All rats were subsequently implanted with jugular catheters and 3 days later placed into the self-administration box to study the acquisition of cocaine self-administration (0.25 mg per infusion). HR non-defeated animals self-administered more cocaine than the LR non-defeated animals. Following social defeat, the acquisition of cocaine self-administration is significantly delayed in HR rats and enhanced in LR rats. CONCLUSION The unique patterns of responsiveness in the HR and LR animals suggest that social defeat plays a role of equalizer of individual differences in drug-taking behavior.

Bovine and Porcine Transscleral Solute Transport: Influence of Lipophilicity and the Choroid–Bruch’s Layer

PubMed Central

Cheruvu, Narayan P. S.; Kompella, Uday B.

2012-01-01

Purpose To determine the influence of the choroid–Bruch’s layer and solute lipophilicity on in vitro transscleral drug permeability in bovine and porcine eyes. Methods The in vitro permeability of two VEGF inhibitory drugs, budesonide and celecoxib, which are lipophilic and neutral at physiologic pH, and of three marker solutes, 3H-mannitol (hydrophilic, neutral), sodium fluorescein (hydrophilic, anionic), and rhodamine 6G (lipophilic, cationic), were determined across freshly excised scleras, with or without the underlying choroid–Bruch’s layer. Select studies were performed using porcine sclera with and without choroid–Bruch’s layer. Neural retina was removed by exposure of the eyecup to isotonic buffer and wherever required, the retinal pigment epithelial (RPE) layer of the preparation was disrupted and removed by exposure to hypertonic buffer. Because of the poor solubility of celecoxib and budesonide, permeability studies were conducted with 5% wt/vol of hydroxypropyl-β-cyclodextrin (HPβCD). For other solutes, permeability studies were conducted, with and without HPβCD. Partitioning of the solutes into bovine sclera and choroid–Bruch’s layer was also determined. Results The calculated log (distribution coefficient) values were −2.89, −0.68, 2.18, 3.12, and 4.02 for mannitol, sodium fluorescein, budesonide, celecoxib, and rhodamine 6G, respectively. Removal of RPE was confirmed by transmission electron microscopy and differences in the transport of mannitol. The order of the permeability coefficients (Papp) across sclera and sclera–choroid–Bruch’s layers in bovine and porcine models was 3H-mannitol > fluorescein > budesonide > celecoxib > rhodamine 6G, with HPβCD, and 3H-mannitol > fluorescein > rhodamine 6G, without HPβCD. The presence of choroid–Bruch’s layer reduced the bovine scleral permeability by 2-, 8-, 16-, 36-, and 50-fold and porcine tissue permeability by 2-, 7-, 15-, 33-, and 40-fold, respectively, for mannitol, sodium fluorescein, budesonide, celecoxib, and rhodamine 6G. The partition coefficients measured in bovine tissues correlated positively with the log (distribution coefficient) and exhibited a trend opposite that of transport. The partition coefficient ratio of bovine choroid–Bruch’s layer to sclera was ~1, 1.5, 1.7, 2, and 3.5, respectively, for the solutes, as listed earlier. Conclusions The choroid–Bruch’s layer is a more significant barrier to drug transport than is sclera. It hinders the transport of lipophilic solutes, especially a cationic solute, more than hydrophilic solutes and in a more dramatic way than does sclera. The reduction in transport across this layer directly correlates with solute binding to the tissue. Understanding the permeability properties of sclera and underlying layers would be beneficial in designing better drugs for transscleral delivery. PMID:17003447

Azilsartan

MedlinePlus

... It works by blocking the action of certain natural substances that tighten the blood vessels, allowing the ... Advil, Motrin) and naproxen (Aleve, Naprosyn) and selective COX-2 inhibitors such as celecoxib (Celebrex); diuretics ('water pills'); lithium ( ...

Celecoxib

MedlinePlus

... a breakdown of the lining of the joints), rheumatoid arthritis (arthritis caused by swelling of the lining of ... spine). It is also used to treat juvenile rheumatoid arthritis (a type of arthritis that affects children) in ...

A New Orally Active, Aminothiol Radioprotector-Free of Nausea and Hypotension Side Effects at Its Highest Radioprotective Doses

DOE Office of Scientific and Technical Information (OSTI.GOV)

Soref, Cheryl M.; Hacker, Timothy A.; Fahl, William E., E-mail: fahl@oncology.wisc.edu

Purpose: A new aminothiol, PrC-210, was tested for orally conferred radioprotection (rats, mice; 9.0 Gy whole-body, which was otherwise lethal to 100% of the animals) and presence of the debilitating side effects (nausea/vomiting, hypotension/fainting) that restrict use of the current aminothiol, amifostine (Ethyol, WR-2721). Methods and Materials: PrC-210 in water was administered to rats and mice at times before irradiation, and percent-survival was recorded for 60 days. Subcutaneous (SC) amifostine (positive control) or SC PrC-210 was administered to ferrets (Mustela putorius furo) and retching/emesis responses were recorded. Intraperitoneal amifostine (positive control) or PrC-210 was administered to arterial cannulated rats tomore » score drug-induced hypotension. Results: Oral PrC-210 conferred 100% survival in rat and mouse models against an otherwise 100% lethal whole-body radiation dose (9.0 Gy). Oral PrC-210, administered by gavage 30-90 min before irradiation, conferred a broad window of radioprotection. The comparison of PrC-210 and amifostine side effects was striking because there was no retching or emesis in 10 ferrets treated with PrC-210 and no induced hypotension in arterial cannulated rats treated with PrC-210. The tested PrC-210 doses were the ferret and rat equivalent doses of the 0.5 maximum tolerated dose (MTD) PrC-210 dose in mice. The human equivalent of this mouse 0.5 MTD PrC-210 dose would likely be the highest PrC-210 dose used in humans. By comparison, the mouse 0.5 MTD amifostine dose, 400 {mu}g/g body weight (equivalent to the human amifostine dose of 910 mg/m{sup 2}), when tested at equivalent ferret and rat doses in the above models produced 100% retching/vomiting in ferrets and 100% incidence of significant, progressive hypotension in rats. Conclusions: The PrC-210 aminothiol, with no detectable nausea/vomiting or hypotension side effects in these preclinical models, is a logical candidate for human drug development to use in healthy humans in a wide variety of radioprotection settings, including medical radiation, space travel, and nuclear accidents.« less

Short-term effects of highly-bioavailable curcumin for treating knee osteoarthritis: a randomized, double-blind, placebo-controlled prospective study.

PubMed

Nakagawa, Yasuaki; Mukai, Shogo; Yamada, Shigeru; Matsuoka, Masayuki; Tarumi, Eri; Hashimoto, Tadashi; Tamura, Chieko; Imaizumi, Atsushi; Nishihira, Jun; Nakamura, Takashi

2014-11-01

We previously developed a surface-controlled water-dispersible form of curcumin and named it Theracurmin(®) (Theracurmin; Theravalues, Tokyo, Japan). The area under the blood concentration-time curve of Theracurmin in humans was 27-fold higher than that of curcumin powder. We determined the clinical effects of orally administered Theracurmin in patients with knee osteoarthritis during 8 weeks of treatment. Fifty patients with knee osteoarthritis of Kellgren-Lawrence grade II or III and who were aged more than 40 years were enrolled in this randomized, double-blind, placebo-controlled, prospective clinical study. Placebo or Theracurmin containing 180 mg/day of curcumin was administered orally every day for 8 weeks. To monitor adverse events, blood biochemistry analyses were performed before and after 8 weeks of each intervention. The patients' knee symptoms were evaluated at 0, 2, 4, 6, and 8 weeks by the Japanese Knee Osteoarthritis Measure, the knee pain visual analog scale (VAS), the knee scoring system of the Japanese Orthopedic Association, and the need for nonsteroidal anti-inflammatory drugs. At 8 weeks after treatment initiation, knee pain VAS scores were significantly lower in the Theracurmin group than in the placebo group, except in the patients with initial VAS scores of 0.15 or less. Theracurmin lowered the celecoxib dependence significantly more than placebo. No major side effects were observed with Theracurmin treatment. Theracurmin shows modest potential for the treatment of human knee osteoarthritis.

Optimization of cell-based assays to quantify the anti-inflammatory/allergic potential of test substances in 96-well format.

PubMed

Chandrasekaran, C V; Edwin Jothie, R; Kapoor, Preeti; Gupta, Anumita; Agarwal, Amit

2011-06-01

There is an insistent need for robust, reliable, and optimized assays for screening novel drugs targeting the inflammatory/allergic markers. The present study describes about the optimization of eight cell-based assays utilizing mammalian cell lines in 96-well format for quantifying anti-inflammatory/allergic drug candidates. We estimated the inhibitory response of reference compounds: 1400 W dihydrochloride on LPS-induced NO release, celecoxib on LPS-induced PGE(2) production and dexamethasone on LPS-induced pro-inflammatory cytokines IL-1 beta, IL-6, and TNF-alpha production by J774A.1 murine macrophages. Response of acetylsalicylic acid and celecoxib was studied on A23187-induced TXB(2) production; captopril on A23187-stimulated LTB(4) production by HL-60 cells. Effect of ketotifen fumarate was evaluated on A23187-elicited histamine release by RBL-2H3 cells. Each experiment was repeated twice to assess the reproducibility and suitability of the assays by determining appropriate statistical tools viz. %CV, S/B and Z' factor. 1400 W dihydrochloride was capable of inhibiting LPS-induced NO levels (IC(50) = 10.7 μM). Dexamethasone attenuated LPS-induced IL-1 beta (IC(50) = 70 nM), IL-6 (IC(50) = 58 nM) and TNF-alpha (IC(50) = 44 nM) release, whereas celecoxib, a specific COX-2 inhibitor showed marked reduction in LPS-induced PGE(2) (IC(50) = 23 nM) production. Captopril (IC(50) = 48 μM) and ketotifen fumarate (IC(50) = 36.4 μM) demonstrated potent inhibitory effect against A23187-stimulated LTB(4) and histamine levels, respectively. Both acetylsalicylic acid (IC(50) = 5.5 μM) and celecoxib (IC(50) = 7.9 nM) exhibited concentration-dependent decrease in TXB(2) production. Results for all the cell assays from two experiments showed a Z' factor varying from 0.30 to 0.99; the S/B ratio ranged from 2.39 to 24.92; %CV ranged between 1.52 and 20.14. The results proclaim that these cell-based assays can act as ideal tools for screening new anti-inflammatory/anti-allergic compounds.

Krüppel-like factor 5 associates with melamine-cyanurate crystal-induced nephritis in rats.

PubMed

Huang, Hsin-Lei; Yang, Wen-Ying; Pu, Hsiao-Fung; Tsai, Tung-Hu; Lin, Chi-Hung; Chen, Nien-Jung; Tarng, Der-Cherng

2013-10-01

Melamine and cyanuric acid (M/CA), when orally administered together to rats, can induce crystal formation within renal tubules and cause acute kidney injury. To investigate the pathomechanism of crystal-induced nephritis, melamine and/or cyanuric acid were administered to 3-week-old (young) and 8-week-old (adult) rats, respectively. Crystal formation, blood urea nitrogen elevation, tubular cell injury and macrophage infiltration were noted in rats fed with M/CA, but not in rats fed with vehicle, melamine or CA alone. These parameters were significantly higher in young rats than those in adult rats fed with M/CA 200 mg/kg body weight (BW) for 3 days. Krüppel-like factor 5 (KLF5) was expressed on distal tubule cells, especially when crystals deposited within the lumens. Both mRNA and protein levels were higher in young rats than those in adult rats fed with M/CA (200 mg/kg BW). KLF5 expression has been shown to modulate renal tissue cytokine production, and we found that proinflammatory cytokines like monocyte chemoattractant protein-1 and interlukin-6 were increased in kidney tissues of young rats fed with M/CA for 3 days. In contrast, interlukin-10, an anti-inflammatory cytokine, was upregulated in kidneys of adult rats fed with M/CA for 3 days. Crystals are prone to deposition in distal tubules of young rats fed with M/CA. M/CA Crystal-related nephritis might be induced by the KLF5 expression, which modulated macrophage recruitment and proinflammatory cytokine production, subsequently leading to renal tubular injury and interstitial inflammation.

Fructose:Glucose Ratios—A Study of Sugar Self-Administration and Associated Neural and Physiological Responses in the Rat

PubMed Central

Levy, AnneMarie; Marshall, Paul; Zhou, Yan; Kreek, Mary Jeanne; Kent, Katrina; Daniels, Stephen; Shore, Ari; Downs, Tiana; Fernandes, Maria Fernanda; Mutch, David M.; Leri, Francesco

2015-01-01

This study explored whether different ratios of fructose (F) and glucose (G) in sugar can engender significant differences in self-administration and associated neurobiological and physiological responses in male Sprague-Dawley rats. In Experiment 1, animals self-administered pellets containing 55% F + 45% G or 30% F + 70% G, and Fos immunoreactivity was assessed in hypothalamic regions regulating food intake and reward. In Experiment 2, rats self-administered solutions of 55% F + 42% G (high fructose corn syrup (HFCS)), 50% F + 50% G (sucrose) or saccharin, and mRNA of the dopamine 2 (D2R) and mu-opioid (MOR) receptor genes were assessed in striatal regions involved in addictive behaviors. Finally, in Experiment 3, rats self-administered HFCS and sucrose in their home cages, and hepatic fatty acids were quantified. It was found that higher fructose ratios engendered lower self-administration, lower Fos expression in the lateral hypothalamus/arcuate nucleus, reduced D2R and increased MOR mRNA in the dorsal striatum and nucleus accumbens core, respectively, as well as elevated omega-6 polyunsaturated fatty acids in the liver. These data indicate that a higher ratio of fructose may enhance the reinforcing effects of sugar and possibly lead to neurobiological and physiological alterations associated with addictive and metabolic disorders. PMID:26007337

Fructose:glucose ratios--a study of sugar self-administration and associated neural and physiological responses in the rat.

PubMed

Levy, AnneMarie; Marshall, Paul; Zhou, Yan; Kreek, Mary Jeanne; Kent, Katrina; Daniels, Stephen; Shore, Ari; Downs, Tiana; Fernandes, Maria Fernanda; Mutch, David M; Leri, Francesco

2015-05-22

This study explored whether different ratios of fructose (F) and glucose (G) in sugar can engender significant differences in self-administration and associated neurobiological and physiological responses in male Sprague-Dawley rats. In Experiment 1, animals self-administered pellets containing 55% F + 45% G or 30% F + 70% G, and Fos immunoreactivity was assessed in hypothalamic regions regulating food intake and reward. In Experiment 2, rats self-administered solutions of 55% F + 42% G (high fructose corn syrup (HFCS)), 50% F + 50% G (sucrose) or saccharin, and mRNA of the dopamine 2 (D2R) and mu-opioid (MOR) receptor genes were assessed in striatal regions involved in addictive behaviors. Finally, in Experiment 3, rats self-administered HFCS and sucrose in their home cages, and hepatic fatty acids were quantified. It was found that higher fructose ratios engendered lower self-administration, lower Fos expression in the lateral hypothalamus/arcuate nucleus, reduced D2R and increased MOR mRNA in the dorsal striatum and nucleus accumbens core, respectively, as well as elevated omega-6 polyunsaturated fatty acids in the liver. These data indicate that a higher ratio of fructose may enhance the reinforcing effects of sugar and possibly lead to neurobiological and physiological alterations associated with addictive and metabolic disorders.

Pharmacokinetics of the Antiviral Lectin Griffithsin Administered by Different Routes Indicates Multiple Potential Uses.

PubMed

Barton, Christopher; Kouokam, J Calvin; Hurst, Harrell; Palmer, Kenneth E

2016-12-17

Griffithsin (GRFT) is a red alga-derived lectin with demonstrated broad spectrum antiviral activity against enveloped viruses, including severe acute respiratory syndrome-Coronavirus (SARS-CoV), Japanese encephalitis virus (JEV), hepatitis C virus (HCV), and herpes simplex virus-2 (HSV-2). However, its pharmacokinetic profile remains largely undefined. Here, Sprague Dawley rats were administered a single dose of GRFT at 10 or 20 mg/kg by intravenous, oral, and subcutaneous routes, respectively, and serum GRFT levels were measured at select time points. In addition, the potential for systemic accumulation after oral dosing was assessed in rats after 10 daily treatments with GRFT (20 or 40 mg/kg). We found that parenterally-administered GRFT in rats displayed a complex elimination profile, which varied according to administration routes. However, GRFT was not orally bioavailable, even after chronic treatment. Nonetheless, active GRFT capable of neutralizing HIV-Env pseudoviruses was detected in rat fecal extracts after chronic oral dosing. These findings support further evaluation of GRFT for pre-exposure prophylaxis against emerging epidemics for which specific therapeutics are not available, including systemic and enteric infections caused by susceptible enveloped viruses. In addition, GRFT should be considered for antiviral therapy and the prevention of rectal transmission of HIV-1 and other susceptible viruses.

Conditioned stress prevents cue-primed cocaine reinstatement only in stress-responsive rats.

PubMed

Hadad, Natalie A; Wu, Lizhen; Hiller, Helmut; Krause, Eric G; Schwendt, Marek; Knackstedt, Lori A

2016-07-01

Neurobiological mechanisms underlying comorbid posttraumatic stress disorder (PTSD) and cocaine use disorder (CUD) are unknown. We aimed to develop an animal model of PTSD + CUD to examine the neurobiology underlying cocaine-seeking in the presence of PTSD comorbidity. Rats were exposed to cat urine once for 10-minutes and tested for anxiety-like behaviors one week later. Subsequently, rats underwent long-access (LgA) cocaine self-administration and extinction training. Rats were re-exposed to the trauma context and then immediately tested for cue-primed reinstatement of cocaine-seeking. Plasma and brains were collected afterwards for corticosterone assays and real-time qPCR analysis. Urine-exposed (UE; n = 23) and controls not exposed to urine (Ctrl; n = 11) did not differ in elevated plus maze behavior, but UE rats displayed significantly reduced habituation of the acoustic startle response (ASR) relative to Ctrl rats. A median split of ASR habituation scores was used to classify stress-responsive rats. UE rats (n = 10) self-administered more cocaine on Day 1 of LgA than control rats (Ctrl + Coc; n = 8). Re-exposure to the trauma context prevented cocaine reinstatement only in stress-responsive rats. Ctrl + Coc rats had lower plasma corticosterone concentrations than Ctrls, and decreased gene expression of corticotropin releasing hormone (CRH) and Glcci1 in the hippocampus. Rats that self-administered cocaine displayed greater CRH expression in the amygdala that was independent of urine exposure. While we did not find that cat urine exposure induced a PTSD-like phenotype in our rats, the present study underscores the need to separate stressed rats into cohorts based on anxiety-like behavior in order to study individual vulnerability to PTSD + CUD.

Effects of disulfiram on choice behavior in a rodent gambling task: association with catecholamine levels.

PubMed

Di Ciano, Patricia; Manvich, Daniel F; Pushparaj, Abhiram; Gappasov, Andrew; Hess, Ellen J; Weinshenker, David; Le Foll, Bernard

2018-01-01

Gambling disorder is a growing societal concern, as recognized by its recent classification as an addictive disorder in the DSM-5. Case reports have shown that disulfiram reduces gambling-related behavior in humans. The purpose of the present study was to determine whether disulfiram affects performance on a rat gambling task, a rodent version of the Iowa gambling task in humans, and whether any changes were associated with alterations in dopamine and/or norepinephrine levels. Rats were administered disulfiram prior to testing on the rat gambling task or prior to analysis of dopamine or norepinephrine levels in brain homogenates. Rats in the behavioral task were divided into two subgroups (optimal vs suboptimal) based on their baseline levels of performance in the rat gambling task. Rats in the optimal group chose the advantageous strategy more, and rats in the suboptimal group (a parallel to problem gambling) chose the disadvantageous strategy more. Rats were not divided into optimal or suboptimal groups prior to neurochemical analysis. Disulfiram administered 2 h, but not 30 min, before the task dose-dependently improved choice behavior in the rats with an initial disadvantageous "gambling-like" strategy, while having no effect on the rats employing an advantageous strategy. The behavioral effects of disulfiram were associated with increased striatal dopamine and decreased striatal norepinephrine. These findings suggest that combined actions on dopamine and norepinephrine may be a useful treatment for gambling disorders.

THE EFFECT OF ORALLY ADMINISTERED EPSILON AMINOCAPROIC ACID ON THE DEPOSITION AND/OR RETENTION OF RADIOIODINATED FIBRINOGEN AND ANTIBODIES TO FIBRINOGEN IN SUBCUTANEOUS RAT PLASMA CLOTS AND TURPENTINE-INDUCED ABSCESSES OF THE RAT

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mutschler, L.E.

1963-01-25

Treatment of metastatic cancer through the use of highly radioactive labeled tumor-localizing antibodies would have the advantage over conventional radiation therapy techniques of delivering large doses of radiation to areas of malignancy while at the same time sparing vital normal tissue from excessive radiation. Intravenously administered I/sup 131/-labeled rat fibrinogen and antibodies to rat fibrin or fibrinogen were found to localize with considerable specificity in the rat-carried Murphy-Sturm lymphosarcoma. lt was suggested that fibrin deposition in tumors is a phenomenon associated with the growth of these tumors and may be of significance in rapidly growing tumors. An apparent lack ofmore » I/sup 131/-fibrinogen localization was observed in some transplantable rat tumors, such as the Walker carcinoma 256. The hypothesis that fibrin deposition is masked by its subsequent rapid removal by fibrinolytic processes was investigated. Data are presented from an investigation of the in vivo antifibrinolytic properties of epsilon aminocapronic acid (EACA), a potent in vitro fibrinolytic inhibitor. Two basic test systems, both using the rat as an experimental animal, were employed. The first involved measuring the effect of orally administered EACA on the retention of subcutaneous clots labeled with either I/sup 131/-fibrinogen or I/sup 131/-antibody against rat fibrinogen. The second system involved measuring the effect of EACA treatment on the deposition and retention of intravenously injected I/sup 131/-fibrinogen and I/sup 131/- antibody in subcutaneous turpentine-induced abscesses. Data indicate that EACA is a potent in vivo anti-fibrinolytic agent and that the mechanism by which EACA treatment brings about increased tumor localization of I/sup 131/-fibrinogen and I/sup 131/antibody is the inhibition of their subsequent removal by fibrinolytic processes. (C.H.)« less

Object/Context-Specific Memory Deficits Associated with Loss of Hippocampal Granule Cells after Adrenalectomy in Rats

ERIC Educational Resources Information Center

Spanswick, Simon C.; Sutherland, Robert J.

2010-01-01

Chronic adrenalectomy (ADX) causes a gradual and selective loss of granule cells in the dentate gyrus (DG) of the rat. Here, we administered replacement corticosterone to rats beginning 10 wk after ADX. We then tested them in three discrimination tasks based on object novelty, location, or object/context association. Only during testing of the…

Kefir treatment ameliorates dextran sulfate sodium-induced colitis in rats

PubMed Central

Senol, Altug; Isler, Mehmet; Sutcu, Recep; Akin, Mete; Cakir, Ebru; Ceyhan, Betul M; Kockar, M Cem

2015-01-01

AIM: To investigate the preventive effect of kefir on colitis induced with dextran sulfate sodium (DSS) in rats. METHODS: Twenty-four male Wistar-albino rats were randomized into four groups: normal control, kefir-control, colitis, and kefir-colitis groups. Rats in the normal and kefir-control groups were administered tap water as drinking water for 14 d. Rats in the colitis and kefir-colitis groups were administered a 3% DSS solution as drinking water for 8-14 d to induce colitis. Rats in the kefir-control and kefir-colitis groups were administered 5 mL kefir once a day for 14 d while rats in the normal control and colitis group were administered an identical volume of the placebo (skim milk) using an orogastric feeding tube. Clinical colitis was evaluated with reference to the disease activity index (DAI), based on daily weight loss, stool consistency, and presence of bleeding in feces. Rats were sacrificed on the 15th day, blood specimens were collected, and colon tissues were rapidly removed. Levels of myeloperoxidase (MPO), tumor necrosis factor (TNF)-α, interleukin (IL)-10, malondialdehyde, and inducible nitric oxide synthase (iNOS) were measured in colon tissue. RESULTS: The DAI was lower in the kefir-colitis group than in the colitis group (on the 3rd and 5th days of colitis induction; P < 0.01). The DAI was also significantly higher in the colitis group between days 2 and 6 of colitis induction when compared to the normal control and kefir-control groups. The DAI was statistically higher only on the 6th day in the kefir-colitis group when compared to that in the normal control groups. Increased colon weight and decreased colon length were observed in colitis-induced rats. Mean colon length in the colitis group was significantly shorter than that of the kefir-control group. Kefir treatment significantly decreased histologic colitis scores (P < 0.05). MPO activity in the colitis group was significantly higher than in the kefir-control group (P < 0.05). Kefir treatment significantly reduced the DSS colitis-induced TNF-α increase (P < 0.01). No statistically significant differences were observed among groups for IL-10 and MDA levels. Colon tissue iNOS levels in the colitis group were significantly higher than those in the control and kefir-colitis groups (P < 0.05). CONCLUSION: Kefir reduces the clinical DAI and histologic colitis scores in a DSS-induced colitis model, possibly via reduction of MPO, TNF-α, and iNOS levels. PMID:26676086

Kefir treatment ameliorates dextran sulfate sodium-induced colitis in rats.

PubMed

Senol, Altug; Isler, Mehmet; Sutcu, Recep; Akin, Mete; Cakir, Ebru; Ceyhan, Betul M; Kockar, M Cem

2015-12-14

To investigate the preventive effect of kefir on colitis induced with dextran sulfate sodium (DSS) in rats. Twenty-four male Wistar-albino rats were randomized into four groups: normal control, kefir-control, colitis, and kefir-colitis groups. Rats in the normal and kefir-control groups were administered tap water as drinking water for 14 d. Rats in the colitis and kefir-colitis groups were administered a 3% DSS solution as drinking water for 8-14 d to induce colitis. Rats in the kefir-control and kefir-colitis groups were administered 5 mL kefir once a day for 14 d while rats in the normal control and colitis group were administered an identical volume of the placebo (skim milk) using an orogastric feeding tube. Clinical colitis was evaluated with reference to the disease activity index (DAI), based on daily weight loss, stool consistency, and presence of bleeding in feces. Rats were sacrificed on the 15(th) day, blood specimens were collected, and colon tissues were rapidly removed. Levels of myeloperoxidase (MPO), tumor necrosis factor (TNF)-α, interleukin (IL)-10, malondialdehyde, and inducible nitric oxide synthase (iNOS) were measured in colon tissue. The DAI was lower in the kefir-colitis group than in the colitis group (on the 3(rd) and 5(th) days of colitis induction; P < 0.01). The DAI was also significantly higher in the colitis group between days 2 and 6 of colitis induction when compared to the normal control and kefir-control groups. The DAI was statistically higher only on the 6(th) day in the kefir-colitis group when compared to that in the normal control groups. Increased colon weight and decreased colon length were observed in colitis-induced rats. Mean colon length in the colitis group was significantly shorter than that of the kefir-control group. Kefir treatment significantly decreased histologic colitis scores (P < 0.05). MPO activity in the colitis group was significantly higher than in the kefir-control group (P < 0.05). Kefir treatment significantly reduced the DSS colitis-induced TNF-α increase (P < 0.01). No statistically significant differences were observed among groups for IL-10 and MDA levels. Colon tissue iNOS levels in the colitis group were significantly higher than those in the control and kefir-colitis groups (P < 0.05). Kefir reduces the clinical DAI and histologic colitis scores in a DSS-induced colitis model, possibly via reduction of MPO, TNF-α, and iNOS levels.

Regulation of ODC activity in the thymus and liver of rats by adrenal hormones.

PubMed

Zahner, S L; Prahlad, K V; Mitchell, J L

1986-01-01

The activity of L-ornithine decarboxylase (EC 4.1.1.17, ODC) has become a useful indicator of hormone responsiveness. Various regimens of dexamethasone, aldosterone and epinephrine, alone or in combination, were administered to adrenalectomized rats either in acute or chronic doses. In addition, adrenalectomized rats, which were chronically treated with aldosterone and epinephrine, were given a single injection of 50 micrograms dexamethasone and sacrificed at various time intervals after hormone treatment. Hepatic and thymic ODC activity was measured. The expected dexamethasone effect, an increase in hepatic and a decrease in thymic ODC, was observed. This study also revealed that aldosterone induced similar responses in these tissues. Epinephrine had the opposite effect since chronic administration of dexamethasone or aldosterone with epinephrine resulted in control levels of ODC. Furthermore, when aldosterone and epinephrine were chronically administered to adrenalectomized rats, to study the acute effects of dexamethasone on rat thymus and liver, the time course of the response in each tissue was found to be distinct. The influence of the adrenal gland on rat thymus and liver is not restricted only to glucocorticoids, but may also involve other hormones which it secretes.

Topical N-acetylcysteine improves wound healing comparable to dexpanthenol: an experimental study.

PubMed

Oguz, Abdullah; Uslukaya, Omer; Alabalık, Ulas; Turkoglu, Ahmet; Kapan, Murat; Bozdag, Zubeyir

2015-04-01

In this study, we aimed to compare the effects of dexpanthenol and N-acetylcysteine on wound healing. The wound healing process is a multifaceted sequence of activities associated with tissue restoration process. A number of investigations and clinical studies have been performed to determine new approaches for the improvement of wound healing. A total of 30 rats were divided into 3 equal groups. A linear 2-cm incision was made in the rats' skin. No treatment was administered in the first (control) group. Dexpanthenol cream was administered to the rats in the second group and 3% N-acetylcysteine cream was administered to the rats in the third group. The wound areas of all of the rats were measured on certain days. On the 21st day, all wounds were excised and histologically evaluated. The epithelialization and granulation rates between the groups were revealed to be similar in microscopic evaluations. Although the fibrosis was remarkable in the control group as compared with the other groups, it was similar in N-acetylcysteine and dexpanthenol groups. Angiogenesis rate was remarkable in the N-acetylcysteine group compared with the others. In multiple-comparison analysis, Dexpanthenol and N-acetylcysteine groups had similar results in terms of wound healing rates (P < 0.05), which were both higher than in the control group (P > 0.05). The efficacy of N-acetylcysteine in wound healing is comparable to dexpanthenol, and both substances can be used to improve wound healing.

Topical N-Acetylcysteine Improves Wound Healing Comparable to Dexpanthenol: An Experimental Study

PubMed Central

Oguz, Abdullah; Uslukaya, Omer; Alabalık, Ulas; Turkoglu, Ahmet; Kapan, Murat; Bozdag, Zubeyir

2015-01-01

In this study, we aimed to compare the effects of dexpanthenol and N-acetylcysteine on wound healing. The wound healing process is a multifaceted sequence of activities associated with tissue restoration process. A number of investigations and clinical studies have been performed to determine new approaches for the improvement of wound healing. A total of 30 rats were divided into 3 equal groups. A linear 2-cm incision was made in the rats' skin. No treatment was administered in the first (control) group. Dexpanthenol cream was administered to the rats in the second group and 3% N-acetylcysteine cream was administered to the rats in the third group. The wound areas of all of the rats were measured on certain days. On the 21st day, all wounds were excised and histologically evaluated. The epithelialization and granulation rates between the groups were revealed to be similar in microscopic evaluations. Although the fibrosis was remarkable in the control group as compared with the other groups, it was similar in N-acetylcysteine and dexpanthenol groups. Angiogenesis rate was remarkable in the N-acetylcysteine group compared with the others. In multiple-comparison analysis, Dexpanthenol and N-acetylcysteine groups had similar results in terms of wound healing rates (P < 0.05), which were both higher than in the control group (P > 0.05). The efficacy of N-acetylcysteine in wound healing is comparable to dexpanthenol, and both substances can be used to improve wound healing. PMID:25583306

Disposition of [14C]N,N-dimethyl-p-toluidine in F344 rats and B6C3F1 mice.

PubMed

Dix, Kelly J; Ghanbari, Katayoon; Hedtke-Weber, Briana M

2007-05-15

N,N-Dimethyl-p-toluidine (DMPT) is used as a polymerization accelerator, in industrial glues, and as an intermediate in dye and pesticide synthesis. There is potential for human exposure to DMPT. The disposition of oral and intravenous (i.v.) doses of [14C]DMPT in F344 rats and B6C3F1 mice was investigated. A single i.v. (2.5 mg/kg) or oral (2.5, 25, or 250 mg/kg) dose of [14C]DMPT (1-25 microCi) was administered in an aqueous vehicle to male rats and mice. The 25-mg/kg oral dose was administered to females to investigate possible gender differences in disposition. However, no striking gender differences were observed. Since toxicity studies conducted elsewhere used a corn oil vehicle, the 250-mg/kg oral dose also was administered in corn oil to male rats; disposition was not dependent on vehicle. Excreta (through 24 h) and tissues collected at sacrifice were analyzed for total radioactivity. Dose-dependent differences in toxicity and disposition were observed. Toxicity at the 250-mg/kg oral dose to male mice was consistent with acute renal failure. At the same dose, male rats exhibited clinical signs of toxicity through 12 h but were clinically normal by 24 h. At lower oral doses, [14C]DMPT-derived radioactivity was well absorbed and rapidly excreted, primarily in urine.

(-)Ephedrine and caffeine mutually potentiate one another's amphetamine-like stimulus effects.

PubMed

Young, R; Gabryszuk, M; Glennon, R A

1998-10-01

Using rats trained to discriminate 1 mg/kg of (+)amphetamine (ED50 = 0.4 mg/kg) from saline vehicle in a two-lever drug discrimination procedure, it was shown that (-)ephedrine (ED50 = 4.5 mg/kg), but not (+)ephedrine, substitutes for the (+)AMPH stimulus. It was also shown that caffeine (ED50 = 12.9 mg/kg) can substitute for (+)amphetamine in a dose-related fashion. Doses of (-)ephedrine and caffeine, which produced < or = 1% drug-appropriate responding when administered alone, were able to enhance each other's stimulus effects when administered in combination such that there was a twofold leftward shift in their respective dose-response curves. Furthermore, stimulus generalization occurred when a dose of caffeine that produced saline-appropriate responding when administered alone was administered in combination with (+)ephedrine. It would appear that low doses of (-)ephedrine and caffeine may mutually potentiate one another's stimulus effects in (+)AMPH-trained rats, and that a combination of caffeine and (+)ephedrine result in altered stimulus character when compared to comparable doses of either agent administered alone.

Prevention of CCl4-induced liver damage by ginger, garlic and vitamin E.

PubMed

Patrick-Iwuanyanwu, K C; Wegwu, M O; Ayalogu, E O

2007-02-15

The hepatoprotective effects of garlic (Allium sativum), ginger (Zingiber officinale) and vitamin E pre-treatment against carbon tetrachloride (CCl4)-induced liver damage in male wistar albino rats were investigated. Carbon tetrachloride (0.5 mL kg(-1) body weight) was administered after 28 days of feeding animals with diets containing ginger, garlic, vitamin E and various mixtures of ginger and garlic. Serum alanine amino transferase, aspartate amino transferase and alkaline phosphatase levels, 24 h after CCl4 administration, decreased significantly (p < or = 0.05) in rats pre-treated with garlic, ginger, vitamin E and various mixtures of garlic and ginger than in CCl4-treated rats only. Lipid peroxidation expressed by serum malondialdehyde (MDA) concentration was assayed to assess the extent of liver damage by CCl4; including the extent of hepatoprotection by garlic, ginger and vitamin E. MDA concentration was significantly decreased (p < or = 0.05) in rats pretreated with garlic, ginger, vitamin E and various mixtures of garlic and ginger than in rats administered CCl4-alone. Histological examination of the liver revealed severe infiltration of inflammatory cells in rats treated with CCl4 alone. However, the observed alteration in the normal architecture of the hepatic cells decreased remarkably in pre-treated rats.

Vitamin-E reduces the oxidative damage on delta-aminolevulinic dehydratase induced by lead intoxication in rat erythrocytes.

PubMed

Rendón-Ramirez, A; Cerbón-Solórzano, J; Maldonado-Vega, M; Quintanar-Escorza, M A; Calderón-Salinas, J V

2007-09-01

Lead intoxication induces oxidative damage on lipids and proteins. In the present paper we study in vivo and in vitro the antioxidant effect of vitamin-E and trolox, on the oxidative effects of lead intoxication in rat erythrocytes. Vitamin-E simultaneously administered to erythrocytes treated with lead was capable to prevent the inhibition of delta-aminolevulinic dehydratase activity and lipid oxidation. Partial but important protective effects were found when vitamin-E was administered either after or before lead exposure in rats. In vitro, the antioxidant trolox protected delta-ALA-D activity against damage induced by lead or menadione. These results indicate that vitamin-E could be useful in order to protect membrane-lipids and, notably, to prevent protein oxidation produced by lead intoxication.

Celecoxib Inhibits Prion Protein 90-231-Mediated Pro-inflammatory Responses in Microglial Cells.

PubMed

Villa, Valentina; Thellung, Stefano; Corsaro, Alessandro; Novelli, Federica; Tasso, Bruno; Colucci-D'Amato, Luca; Gatta, Elena; Tonelli, Michele; Florio, Tullio

2016-01-01

Activation of microglia is a central event in the atypical inflammatory response occurring during prion encephalopathies. We report that the prion protein fragment encompassing amino acids 90-231 (PrP90-231), a model of the neurotoxic activity of the pathogenic prion protein (PrP(Sc)), causes activation of both primary microglia cultures and N9 microglial cells in vitro. This effect was characterized by cell proliferation arrest and induction of a secretory phenotype, releasing prostaglandin E2 (PGE2) and nitric oxide (NO). Conditioned medium from PrP90-231-treated microglia induced in vitro cytotoxicity of A1 mesencephalic neurons, supporting the notion that soluble mediators released by activated microglia contributes to the neurodegeneration during prion diseases. The neuroinflammatory role of COX activity, and its potential targeting for anti-prion therapies, was tested measuring the effects of ketoprofen and celecoxib (preferential inhibitors of COX1 and COX2, respectively) on PrP90-231-induced microglial activation. Celecoxib, but not ketoprofen significantly reverted the growth arrest as well as NO and PGE2 secretion induced by PrP90-231, indicating that PrP90-231 pro-inflammatory response in microglia is mainly dependent on COX2 activation. Taken together, these data outline the importance of microglia in the neurotoxicity occurring during prion diseases and highlight the potentiality of COX2-selective inhibitors to revert microglia as adjunctive pharmacological approach to contrast the neuroinflammation-dependent neurotoxicity.

Effect of maternal alcohol and nicotine intake, individually and in combination, on fetal growth in the rat

DOE Office of Scientific and Technical Information (OSTI.GOV)

Leichter, J.

1991-03-15

The effect of maternal ethanol and nicotine administration, separately and in combination, on fetal growth of rats was studied. Nicotine was administered by gavage for the entire gestational period. Alcohol was given in drinking water for 4 weeks prior to mating and 30% throughout gestation. Appropriate pair-fed and ad libitum control animals were included to separate the effect of ethanol and nicotine on the outcome of pregnancy from those produced by the confounding variables of malnutrition. Body weights of fetuses exposed to alcohol alone or in combination with nicotine were significantly lower than those of the pair-fed and ad libitummore » controls. However, the difference in fetal body weight between the alcohol plus nicotine and the alcohol alone group was not significant. Similarly, in the rats administered nicotine only, fetal weight was not significantly different compared to control animals. The results of this study indicate that maternal alcohol intake impairs fetal growth and nicotine does not, regardless whether it is administered separately or in combination with alcohol for the entire gestational period.« less

Antinociceptive and pronociceptive effect of levetiracetam in tonic pain model.

PubMed

Cortes-Altamirano, José Luis; Reyes-Long, Samuel; Olmos-Hernández, Adriana; Bonilla-Jaime, Herlinda; Carrillo-Mora, Paul; Bandala, Cindy; Alfaro-Rodriguez, Alfonso

2018-04-01

Levetiracetam (LEV) is a novel anticonvulsant with proven antinociceptive properties. However, the antinociceptive and pronociceptive effect of this drug has not yet been fully elucidated in a tonic pain model. Thirty-six male rats (Wistar) were randomized into six groups and underwent the formalin test as follows: rats in the control group were administered 50μL of 1% formalin in the paw; sham-group rats were administered 50μL of saline in the paw to mimick the application of formalin; the four experimental groups were administered LEV intragastrically (ig) (50, 100, 200 and 300mg/kg), and 40min later 50μL of 1% formalin was injected in the paw. LEV exhibited antinociceptive effect in the 300mg/kg LEV group (p<0.05) and a pronociceptive effect in the 100mg/kg LEV group (p<0.05) and in the 50mg/kg LEV group (p<0.001). The antinociceptive and pronociceptive effect of LEV in a tonic pain model is dose-dependent. Copyright © 2017 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved.

Central effects of corticotropin releasing factor (CRF): evidence for similar interactions with environmental novelty and with caffeine.

PubMed

Britton, D R; Indyk, E

1990-01-01

Centrally administered rat/human corticotropin-releasing factor (rCRF) increases low levels of locomotor activity by rats tested in a familiar environment but suppresses the higher levels of activity associated with exposure of the animals to a novel environment. These opposing responses do not appear to be manifestations of a simple rate-dependent effect, since ICV-administered rCRF did not lower the higher levels of locomotor activity associated with the dark (active) phase of the animal's activity cycle. Caffeine, which has anxiogenic effects in man, produces effects in rats which are similar to those of rCRF. That is, both compounds elevate activity in a familiar environment but lower activity in a novel environment. Furthermore, caffeine appears to substitute for novelty in determining the direction of the locomotor effect of rCRF. Animals made hyperactive by caffeine show decreased activity when co-administered rCRF. These findings are consistent with the view that CRF acts through pathways which also subserve the responsiveness to novelty and to the anxiogenic compound caffeine.

Intravesical application of rebamipide suppresses bladder inflammation in a rat cystitis model.

PubMed

Funahashi, Yasuhito; Yoshida, Masaki; Yamamoto, Tokunori; Majima, Tsuyoshi; Takai, Shun; Gotoh, Momokazu

2014-04-01

We examined the effects of intravesical application of rebamipide (Otsuka Pharmaceutical, Tokyo, Japan) on bladder inflammation and overactivity in a chemically induced cystitis model. Female Sprague Dawley® rats under isoflurane anesthesia were injected with 150 mg/kg cyclophosphamide in the peritoneum, and 1 mM or 10 mM rebamipide or vehicle was administered in the bladder and remained for 1 hour. Control rats were injected with saline in the peritoneum and vehicle was administered in the bladder. The bladder was harvested at 48 hours. Hematoxylin and eosin staining was performed and the inflammation grade was assessed. The amount of myeloperoxidase was measured using enzyme-linked immunosorbent assay. Proinflammatory cytokines were quantified using reverse transcriptase-polymerase chain reaction. Cystometrogram was done in awake rats 48 hours after cyclophosphamide treatment to measure voiding reflex parameters. Histological evaluation revealed that bladder inflammation in cyclophosphamide treated rats was suppressed by rebamipide in a dose dependent manner. Up-regulated myeloperoxidase, IL-1β, IL-6 and TNF-α expression in cyclophosphamide treated rats was also suppressed in rebamipide treated rats. Cystometrogram demonstrated that the intercontraction interval decreased in cyclophosphamide treated rats but was prolonged by rebamipide. Intravesical application of rebamipide suppressed bladder inflammation and overactivity in a dose dependent manner. This may provide a new treatment strategy for chemotherapy associated cystitis. Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Ameliorative potentials of cocoyam (Colocasia esculenta L.) and unripe plantain (Musa paradisiaca L.) on the relative tissue weights of streptozotocin-induced diabetic rats.

PubMed

Eleazu, C O; Iroaganachi, M; Eleazu, K C

2013-01-01

To investigate the ameliorating potentials of cocoyam (Colocasia esculenta L.) and unripe plantain (Musa paradisiaca L.) incorporated feeds on the renal and liver growths of diabetic rats, induced with 55 and 65 mg/kg body weight of Streptozotocin. The blood glucose level of the rats was measured with a glucometer, the protein and glucose and specific gravity (SPGR) in the urine samples of the rats were measured using urine assay strips and urinometer respectively. The chemical composition and antioxidant screening of the test feeds were carried out using standard techniques. Administration of the test feeds for 21 days to the diabetic rats of groups 4 and 5, resulted in 58.75% and 38.13% decreases in hyperglycemia and amelioration of their elevated urinary protein, glucose, SPGR, and relative kidney weights. The diabetic rats administered cocoyam incorporated feeds, had 2.71% and 19.52% increases in weight and growth rates, the diabetic rats administered unripe plantain incorporated feeds had 5.12% and 29.52% decreases in weight and growth rates while the diabetic control rats had 28.69%, 29.46%, 248.9% and 250.14% decreases in weights and growth rates. The cocoyam incorporated feeds contained higher antioxidants, minerals and phytochemicals except alkaloids than unripe plantain feed. Cocoyam and unripe plantain could be useful in the management of diabetic nephropathy.

Taurine Ameliorates Renal Oxidative Damage and Thyroid Dysfunction in Rats Chronically Exposed to Fluoride.

PubMed

Adedara, Isaac A; Ojuade, Temini Jesu D; Olabiyi, Bolanle F; Idris, Umar F; Onibiyo, Esther M; Ajeigbe, Olufunke F; Farombi, Ebenezer O

2017-02-01

Excessive exposure to fluoride poses several detrimental effects to human health particularly the kidney which is a major organ involved in its elimination from the body. The influence of taurine on fluoride-induced renal toxicity was investigated in a co-exposure paradigm for 45 days using five groups of eight rats each. Group I rats received normal drinking water alone, group II rats were exposed to sodium fluoride (NaF) in drinking water at 15 mg/L alone, group III received taurine alone at a dose of 200 mg/kg group IV rats were co-administered with NaF and taurine (100 mg/kg), while group V rats were co-administered with NaF and taurine (200 mg/kg). Administration of taurine significantly reversed the fluoride-mediated decrease in absolute weight and organo-somatic index of the kidney in the exposed rats. Taurine significantly prevented fluoride-induced elevation in plasma urea and creatinine levels in the exposed rats. Moreover, taurine restored fluoride-mediated decrease in the circulatory concentrations of triiodothyronine, thyroxine, and the ratio of triiodothyronine to thyroxine. Taurine ameliorated fluoride-mediated decrease in renal antioxidant status by significantly enhancing the antioxidant enzyme activities as well as glutathione level in the exposed rats. Additionally, taurine inhibited fluoride-induced renal oxidative damage by markedly decreasing the hydrogen peroxide and malondialdehyde levels as well as improved the kidney architecture in the treated rats. Collectively, taurine protected against fluoride-induced renal toxicity via enhancement of thyroid gland function, renal antioxidant status, and histology in rats.

Effects of low doses of americium 241 on animals

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rudnitskaya, E.I.; Moskalev, Yu.I.

1979-10-01

The long term effects of low doses of americium 241 on dogs and rats were investigated. Americium chloride was administered intravenously to dogs and intraperitoneally to rats in varying doses. The biological radiation effects were determined at autopsy. Survival times were reported.

Does caffeine influence the anticholinesterase and antioxidant properties of donepezil? Evidence from in vitro and in vivo studies.

PubMed

Oboh, Ganiyu; Ogunsuyi, Opeyemi Babatunde; Olonisola, Oluwaseyi Emmanuel

2017-04-01

Caffeine is adjudged world's most consumed pharmacologically active food component. With reports of the potential cognitive enhancing properties of caffeine, we sought to investigate if caffeine can influence the anticholinesterase and antioxidant properties of donepezil-a selective acetylcholinesterase (AChE) inhibitor used in the management of Alzheimer's disease (AD). In vitro, we investigated the effect of donepezil (DON), caffeine (CAF) and their various combinations on the activity of AChE in rat brain homogenate, as well as determined their antioxidant properties. In vivo, two rat groups were administered single oral dose of DON (5 mg/kg) and CAF (5 mg/kg) separately, while three groups, each received 5 mg/kg DON plus either 5, 50 or 100 mg/kg CAF for three hours, after which the rats were sacrificed and brain isolated. Results show that CAF concentration dependently and synergistically increased the anticholinesterase properties of DON in vitro. Also, CAF produced a significant influence on investigated in vitro antioxidant properties of DON. Furthermore, rats administered 5 mg/kg CAF and DON produced no significant difference in AChE activity compared to rats administered DON alone. However, co-administration of either 50 or 100 mg/kg CAF with DON lead to higher AChE activity compared to both control and DON groups. In addition, DON, CAF and their various combinations augmented brain antioxidant status in treated rats. We conclude that while low caffeine consumption may improve the antioxidant properties of donepezil without having a significant influence on its anticholinesterase effect, moderate-high caffeine consumption could also improve the antioxidant properties of donepezil but reduce its anticholinesterase effect; nevertheless, a comprehensive clinical trial is essential to fully explore these possibilities in human AD condition.

Profiling the metabolome changes caused by cranberry procyanidins in plasma of female rats using (1) H NMR and UHPLC-Q-Orbitrap-HRMS global metabolomics approaches.

PubMed

Liu, Haiyan; Garrett, Timothy J; Tayyari, Fariba; Gu, Liwei

2015-11-01

The objective was to investigate the metabolome changes in female rats gavaged with partially purified cranberry procyanidins (PPCP) using (1) H NMR and UHPLC-Q-Orbitrap-HRMS metabolomics approaches, and to identify the contributing metabolites. Twenty-four female Sprague-Dawley rats were randomly separated into two groups and administered PPCP or partially purified apple procyanidins (PPAP) for three times using a 250 mg extracts/kg body weight dose. Plasma was collected 6 h after the last gavage and analyzed using (1) H NMR and UHPLC-Q-Orbitrap-HRMS. No metabolome difference was observed using (1) H NMR metabolomics approach. However, LC-HRMS metabolomics data show that metabolome in the plasma of female rats administered PPCP differed from those gavaged with PPAP. Eleven metabolites were tentatively identified from a total of 36 discriminant metabolic features based on accurate masses and/or product ion spectra. PPCP caused a greater increase of exogenous metabolites including p-hydroxybenzoic acid, phenol, phenol-sulphate, catechol sulphate, 3, 4-dihydroxyphenylvaleric acid, and 4'-O-methyl-(-)-epicatechin-3'-O-beta-glucuronide in rat plasma. Furthermore, the plasma level of O-methyl-(-)-epicatechin-O-glucuronide, 4-hydroxy-5-(hydroxyphenyl)-valeric acid-O-sulphate, 5-(hydroxyphenyl)-ϒ-valerolactone-O-sulphate, 4-hydroxydiphenylamine, and peonidin-3-O-hexose were higher in female rats administered with PPAP. The metabolome changes caused by cranberry procyanidins were revealed using an UHPLC-Q-Orbitrap-HRMS global metabolomics approach. Exogenous and microbial metabolites were the major identified discriminate biomarkers. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Distinct Neurochemical Adaptations Within the Nucleus Accumbens Produced by a History of Self-Administered vs Non-Contingently Administered Intravenous Methamphetamine

PubMed Central

Lominac, Kevin D; Sacramento, Arianne D; Szumlinski, Karen K; Kippin, Tod E

2012-01-01

Methamphetamine is a highly addictive psychomotor stimulant yet the neurobiological consequences of methamphetamine self-administration remain under-characterized. Thus, we employed microdialysis in rats trained to self-administer intravenous (IV) infusions of methamphetamine (METH-SA) or saline (SAL) and a group of rats receiving non-contingent IV infusions of methamphetamine (METH-NC) at 1 or 21 days withdrawal to determine the dopamine and glutamate responses in the nucleus accumbens (NAC) to a 2 mg/kg methamphetamine intraperitoneal challenge. Furthermore, basal NAC extracellular glutamate content was assessed employing no net-flux procedures in these three groups at both time points. At both 1- and 21-day withdrawal points, methamphetamine elicited a rise in extracellular dopamine in SAL animals and this effect was sensitized in METH-NC rats. However, METH-SA animals showed a much greater sensitized dopamine response to the drug challenge compared with the other groups. Additionally, acute methamphetamine decreased extracellular glutamate in both SAL and METH-NC animals at both time-points. In contrast, METH-SA rats exhibited a modest and delayed rise in glutamate at 1-day withdrawal and this rise was sensitized at 21 days withdrawal. Finally, no net-flux microdialysis revealed elevated basal glutamate and increased extraction fraction at both withdrawal time-points in METH-SA rats. Although METH-NC rats exhibited no change in the glutamate extraction fraction, they exhibited a time-dependent elevation in basal glutamate levels. These data illustrate for the first time that a history of methamphetamine self-administration produces enduring changes in NAC neurotransmission and that non-pharmacological factors have a critical role in the expression of these methamphetamine-induced neurochemical adaptations. PMID:22030712

The use-dependent, nicotinic antagonist BTMPS reduces the adverse consequences of morphine self-administration in rats in an abstinence model of drug seeking

PubMed Central

Hall, Brandon J.; Pearson, Laura S.; Terry, Alvin V.; Buccafusco, Jerry J.

2011-01-01

In this study, the use-dependent, nicotinic receptor antagonist bis (2, 2, 6, 6-tetramethyl-4-piperidinyl) sebacate (BTMPS) was evaluated for its ability to attenuate the adverse consequences associated with morphine in rats in all three phases of an abstinence model of drug seeking: self-administration, acute withdrawal, and delayed test of drug seeking. Rats were allowed to self-administer morphine (FR1 schedule) with an active response lever, on a 24hr basis inside operant chambers, for 14 days. Each rat was subsequently evaluated for stereotypical behaviors associated with spontaneous morphine withdrawal. Rats were then placed in standard housing cages for a six week period of protracted abstinence from morphine. After this period, each rat was placed back into its respective operant chamber for a 14 day assessment of unrewarded drug seeking responses. BTMPS was administered to the animals in all three clinically relevant phases in three separate sets of experiments. BTMPS treatment during the self-administration phase resulted in up to a 34% reduction of lever responses to morphine when compared to vehicle treated control animals, as well as a 32% reduction in the dose of morphine self-administered. When given during self-administration and acute withdrawal, BTMPS treatment decreased acute withdrawal symptoms (up to 64%) of morphine use and reduced (up to 45%) drug seeking responses after six weeks of protracted withdrawal compared to control animals. BTMPS treatment after six weeks of abstinence from morphine had no effect. These results offer insight into the role of central cholinergic receptors in the onset and maintenance of drug addiction. PMID:21651919

The fate of cyclamate in man and other species

PubMed Central

Renwick, A. G.; Williams, R. T.

1972-01-01

1. 14C-labelled cyclamate has been administered to guinea pigs, rabbits, rats and humans. When given orally to these species on a cyclamate-free diet, cyclamate is excreted unchanged. In guinea pigs some 65% of a single dose is excreted in the urine and 30% in the faeces, the corresponding values for rats being 40 and 50%, for man, 30–50% and 40–60%, and for rabbits, 90 and 5%, the excretion being over a period of 2–3 days. 2. Cyclamate appears to be readily absorbed by rabbits but less readily by guinea pigs, rats and humans. 3. If these animals, including man, are placed on a diet containing cyclamate they develop the ability to convert orally administered cyclamate into cyclohexylamine and consequently into the metabolites of the latter. The extent to which this ability develops is variable, the development occurring more readily in rats than in rabbits or guinea pigs. In three human subjects, one developed the ability quite markedly in 10 days whereas two others did not in 30 days. Removal of the cyclamate from the diet caused a diminution in the ability to convert cyclamate into the amine. 4. In rats that had developed the ability to metabolize orally administered cyclamate, intraperitoneally injected cyclamate was not metabolized and was excreted unchanged in the urine. The biliary excretion of injected cyclamate in rats was very small, i.e. about 0.3% of the dose. 5. The ability of animals to convert cyclamate into cyclohexylamine appears to depend upon a continuous intake of cyclamate and on some factor in the gastrointestinal tract, probably the gut flora. PMID:4655822

Enhancing effect of menthol on nicotine self-administration in rats

PubMed Central

Biswas, Lisa; Harrison, Erin; Gong, Yongzhen; Avusula, Ramachandram; Lee, Jonathan; Zhang, Meiyu; Rousselle, Thomas; Lage, Janice; Liu, Xiu

2016-01-01

Rationale Tobacco smoking is a leading preventable cause of premature death in the United States. Menthol is a significant flavoring additive in tobacco products. Clinical evidence suggests that menthol may promote tobacco smoking and nicotine dependence. However, it is unclear whether menthol enhances the reinforcing actions of nicotine and thus facilitates nicotine consumption. This study employed a rat model of nicotine self-administration to examine the effects of menthol on nicotine-taking behavior. Methods Male Sprague-Dawley rats were trained in daily 1-h sessions to press a lever for intravenous nicotine self-administration under a fixed-ratio 5 schedule of reinforcement. In separate groups, rats self-administered nicotine at four different doses (0.0075, 0.015, 0.03, and 0.06 mg/kg/infusion). Five minutes prior to the two test sessions, menthol (5 mg/kg) or its vehicle was administered intraperitoneally in all rats in a counterbalanced design within each group. In separate rats that self-administered 0.015 mg/kg/infusion nicotine, menthol dose-response function was determined. Menthol was also tested on food self-administration. Results An inverted U-shaped nicotine dose-response curve was observed. Menthol pretreatment shifted the nicotine dose-response curve to the left. The facilitating effect of menthol on the self-administration of 0.015 mg/kg/infusion nicotine was dose-dependent, whereas it produced similar effects at doses above the threshold of 2.5 mg/kg. Menthol tended to suppress the self-administration of food pellets. Conclusions These data demonstrate that menthol enhances the reinforcing effects of nicotine, and the effect of menthol was specific to nicotine. The findings suggest that menthol directly facilitates nicotine consumption, thereby contributing to tobacco smoking. PMID:27473365

Retinoprotective effect of Epithalon in campbell rats of various ages.

PubMed

Khavinson, V Kh; Razumovsky, M I; Trofimova, S V; Razumovskaya, A M

2003-05-01

We studied the retinoprotective effect of Epithalon administered to the offspring of Campbell rats during postnatal ontogeny and to mothers before mating and during pregnancy. After this treatment the morphological structure and functional activity of the retina were preserved for a longer period compared to control rats (by 2 times) and to the animals receiving the peptide only during postnatal ontogeny (by 30%).

Effects of Green Tea Extract on Learning, Memory, Behavior and Acetylcholinesterase Activity in Young and Old Male Rats

ERIC Educational Resources Information Center

Kaur, Tranum; Pathak, C. M.; Pandhi, P.; Khanduja, K. L.

2008-01-01

Objective: To study the effects of green tea extract administration on age-related cognition in young and old male Wistar rats. Methods: Young and old rats were orally administered 0.5% green tea extract for a period of eight weeks and were evaluated by passive avoidance, elevated maze plus paradigm and changes in acetylcholinesterase activity.…

In vivo Studies on the Protective Effect of Propolis on Doxorubicin-Induced Toxicity in Liver of Male Rats.

PubMed

Singla, Shivani; Kumar, Neelima R; Kaur, Jaspreet

2014-05-01

Since anticancer drugs are to be administered for long durations of time and are associated with systemic toxicities, the present studies were conducted to evaluate the protective potential of honey bee propolis against a widely used anticancer drug, doxorubicin (DXR) induced toxicity and oxidative damage in liver tissues of rats. Sixteen male Sprague Dawley rats, weighing between 200-220 g, were used and were divided into four equal groups. Propolis was given orally to rats [250 mg/kg body weight (bw) for 14 consecutive days] and DXR [25 mg/kg bw; intraperitoneally (i.p) was administered on 12(th), 13(th) and 14(th) day of the experiment. All the animals were sacrificed on day 15(th) day by decapitation. Blood and tissue samples were collected for measurement of toxicity and oxidative damage parameters (enzymatic assays and biochemical estimations). Administration of DXR for 3 days at a cumulative dose of 25 mg/kg bw, induced toxicity and oxidative stress in rats as significantly decreased activity of catalase (CAT), superoxide dismutase (SOD), glutathione-S-transferase (GST), glutathione peroxidase (GSH-Px) and glutathione reductase (GR) were observed in rat liver supernatants when compared to control group. Increased activity of serum glutamic pyruvic transaminase (SGPT) and serum glutamic oxaloacetic transaminase (SGOT) was obtained in DXR administered rats. Also there are significantly increased levels of lipid peroxides (measured as malondialdehyde formation) and significantly decreased level of glutathione (GSH) in doxorubicin treated rat liver supernatants as compared to healthy controls. On the other hand, administration of animals with propolis prior to DXR treatment led to significant modulation of the oxidative damage related parameters in liver and hepatotoxicity parameters in blood, when compared to doxorubicin treated group. However results were still not comparable to control group or only propolis group indicating partial protection by propolis at the concentration used against anticancer drug toxicity. Propolis extract was found to have a protective effect against doxorubicin-induced toxicity in rat liver though it was still not normalized. It can be concluded that propolis provides partial protection from toxicity of anticancer drug.

TIME-DEPENDENT NEUROBIOLOGICAL EFFECTS OF COLCHICINE ADMINISTERED DIRECTLY INTO THE HIPPOCAMPUS OF RATS (JOURNAL VERSION)

EPA Science Inventory

Rats were given bilateral injections of colchicine into the dorsal and ventral hippocampus. Behavioral, neurochemical and histopathological measurements were taken up to 12 weeks after surgery. Colchicine produced a consistent increase in spontaneous motor activity, enhanced acou...

Ethanol and Nicotine Interaction within the Posterior Ventral Tegmental Area in Male and Female Alcohol-Preferring Rats: Evidence of Synergy and Differential Gene Activation in the Nucleus Accumbens Shell

PubMed Central

Truitt, William A.; Hauser, Sheketha R.; Deehan, Gerald A.; Toalston, Jamie E.; Wilden, Jessica A.; Bell, Richard L.; McBride, William J.; Rodd, Zachary A.

2015-01-01

Rationale Ethanol and nicotine are frequently co-abused. The biological basis for the high co-morbidity rate is not known. Alcohol-preferring (P) rats will self-administer EtOH or nicotine directly into the posterior ventral tegmental area (pVTA). Objective The current experiments examined whether sub-threshold concentrations of EtOH and nicotine would support the development of self-administration behaviors if the drugs were combined. Methods Rats were implanted with a guide cannula aimed at the pVTA. Rats were randomly assigned to groups that self-administered sub-threshold concentrations of EtOH (50 mg%) or nicotine (1 μM) or combinations of ethanol (25 or 50 mg%) and nicotine (0.5 or 1.0 μM). Alterations in gene expression downstream projections areas (nucleus accumbens shell, AcbSh) were assessed following a single, acute exposure to EtOH (50 mg%), nicotine (1 μM) or ethanol and nicotine (50 mg% + 1 μM) directly into the pVTA. Results The results indicated that P rats would co-administer EtOH and nicotine directly into the pVTA at concentrations that did not support individual self-administration. EtOH and nicotine directly administered into the pVTA resulted in alterations in gene expression in the AcbSh (50.8-fold increase in BDNF, 2.4-fold decrease in GDNF, 10.3-fold increase in Vglut1) that were not observed following microinjections of equivalent concentrations/doses of ethanol or nicotine. Conclusion The data indicate that ethanol and nicotine act synergistically to produce reinforcement and alter gene expression within the mesolimbic dopamine system. The high rate of co-morbidity of alcoholism and nicotine dependence could the result of the interactions of EtOH and nicotine within the mesolimbic dopamine system. PMID:25155311

Tissue distribution and excretion kinetics of orally administered silica nanoparticles in rats

PubMed Central

Lee, Jeong-A; Kim, Mi-Kyung; Paek, Hee-Jeong; Kim, Yu-Ri; Kim, Meyoung-Kon; Lee, Jong-Kwon; Jeong, Jayoung; Choi, Soo-Jin

2014-01-01

Purpose The effects of particle size on the tissue distribution and excretion kinetics of silica nanoparticles and their biological fates were investigated following a single oral administration to male and female rats. Methods Silica nanoparticles of two different sizes (20 nm and 100 nm) were orally administered to male and female rats, respectively. Tissue distribution kinetics, excretion profiles, and fates in tissues were analyzed using elemental analysis and transmission electron microscopy. Results The differently sized silica nanoparticles mainly distributed to kidneys and liver for 3 days post-administration and, to some extent, to lungs and spleen for 2 days post-administration, regardless of particle size or sex. Transmission electron microscopy and energy dispersive spectroscopy studies in tissues demonstrated almost intact particles in liver, but partially decomposed particles with an irregular morphology were found in kidneys, especially in rats that had been administered 20 nm nanoparticles. Size-dependent excretion kinetics were apparent and the smaller 20 nm particles were found to be more rapidly eliminated than the larger 100 nm particles. Elimination profiles showed 7%–8% of silica nanoparticles were excreted via urine, but most nanoparticles were excreted via feces, regardless of particle size or sex. Conclusion The kidneys, liver, lungs, and spleen were found to be the target organs of orally-administered silica nanoparticles in rats, and this organ distribution was not affected by particle size or animal sex. In vivo, silica nanoparticles were found to retain their particulate form, although more decomposition was observed in kidneys, especially for 20 nm particles. Urinary and fecal excretion pathways were determined to play roles in the elimination of silica nanoparticles, but 20 nm particles were secreted more rapidly, presumably because they are more easily decomposed. These findings will be of interest to those seeking to predict potential toxicological effects of silica nanoparticles on target organs. PMID:25565843

Immunohistochemistry of the uterine cervix of rats bearing the Walker 256 tumor treated with copaiba balsam.

PubMed

Botelho, Nara Macedo; Corrêa, Suelen Costa; Lobato, Rodolfo Costa; Teixeira, Renan Kleber Costa; Quaresma, Juarez Antônio Simões

2013-03-01

To investigate the immunohistochemistry of the uterine cervix of 20 Wistar rats (Rattus norvegicus) bearing the Walker 256 tumor, treated with copaiba oil (Copaifera officinalis). The animals were grouped into four subgroups, with five rats each: the GCT and GCopT received distilled water and topically copaiba, respectively, while the GCG and GCopG received distilled water and copaiba by gavage, respectively. The substances were administered for nine days. On the 12th day, after euthanasia, the tumor pieces were sent to the identification of T CD4+, T CD8+ and Natural Killer cells. It was found that the pattern of expression for specific markers of phenotypes of cells involved in tumor immune response was similar in all groups, regardless the administration way of copaiba oil (topical or gavage). Copaiba balsam, administered either topically or by gavage, did not alter the pattern of tumor immune response in rats bearing Walker 256 Tumor.

Tachykinin-induced nasal fluid secretion and plasma exudation in the rat: effects of peptidase inhibition.

PubMed

Lindell, E; Svensjö, M E; Malm, L; Petersson, G

1995-05-01

Substance P (SP) evokes fluid secretion and plasma extravasation when applied to the nasal mucosa of rats. SP and another tachykinin, neurokinin A (NKA), are degraded in vitro by neutral endopeptidase (NEP) and angiotensin-1-converting enzyme (ACE). In this study, NKA or SP were applied locally to the nasal mucosa of rats. Subsequent fluid secretion was measured by a filter paper technique. Plasma exudation was derived as the recovery of intravenous (i.v.) administered 125I-albumin from the fluid-containing filter papers. In order to inhibit enzymatic degradation of the tachykinins by NEP and ACE, the rats were treated with i.v. administered phosphoramidon or captopril respectively or their combination. SP evoked fluid secretion that was augmented by phosphoramidon and further enhanced by adding captopril. NKA evoked nasal fluid secretion less effectively than SP and the effect was unaffected by peptidase inhibition. SP, but not NKA, evoked increased plasma exudation but only after pre-treatment with phosphoramidon.

A Chronic Autoimmune Dry Eye Rat Model with Increase in Effector Memory T Cells in Eyeball Tissue.

PubMed

Hou, Aihua; Bose, Tanima; Chandy, K George; Tong, Louis

2017-06-07

Dry eye disease is a very common condition that causes morbidity and healthcare burden and decreases the quality of life. There is a need for a suitable dry eye animal model to test novel therapeutics to treat autoimmune dry eye conditions. This protocol describes a chronic autoimmune dry eye rat model. Lewis rats were immunized with an emulsion containing lacrimal gland extract, ovalbumin, and complete Freund's adjuvant. A second immunization with the same antigens in incomplete Freund's adjuvant was administered two weeks later. These immunizations were administered subcutaneously at the base of the tail. To boost the immune response at the ocular surface and lacrimal glands, lacrimal gland extract and ovalbumin were injected into the forniceal subconjunctiva and lacrimal glands 6 weeks after the first immunization. The rats developed dry eye features, including reduced tear production, decreased tear stability, and increased corneal damage. Immune profiling by flow cytometry showed a preponderance of CD3 + effector memory T cells in the eyeball.

A Chronic Autoimmune Dry Eye Rat Model with Increase in Effector Memory T Cells in Eyeball Tissue

PubMed Central

Hou, Aihua; Bose, Tanima; Chandy, K. George; Tong, Louis

2017-01-01

Dry eye disease is a very common condition that causes morbidity and healthcare burden and decreases the quality of life. There is a need for a suitable dry eye animal model to test novel therapeutics to treat autoimmune dry eye conditions. This protocol describes a chronic autoimmune dry eye rat model. Lewis rats were immunized with an emulsion containing lacrimal gland extract, ovalbumin, and complete Freund's adjuvant. A second immunization with the same antigens in incomplete Freund's adjuvant was administered two weeks later. These immunizations were administered subcutaneously at the base of the tail. To boost the immune response at the ocular surface and lacrimal glands, lacrimal gland extract and ovalbumin were injected into the forniceal subconjunctiva and lacrimal glands 6 weeks after the first immunization. The rats developed dry eye features, including reduced tear production, decreased tear stability, and increased corneal damage. Immune profiling by flow cytometry showed a preponderance of CD3+ effector memory T cells in the eyeball. PMID:28654074

Comparison of T-2 Toxin and HT-2 Toxin Distributed in the Skeletal System with That in Other Tissues of Rats by Acute Toxicity Test.

PubMed

Yu, Fang Fang; Lin, Xia Lu; Yang, Lei; Liu, Huan; Wang, Xi; Fang, Hua; Lammi, ZMikko J; Guo, Xiong

2017-11-01

Twelve healthy rats were divided into the T-2 toxin group receiving gavage of 1 mg/kg T-2 toxin and the control group receiving gavage of normal saline. Total relative concentrations of T-2 toxin and HT-2 toxin in the skeletal system (thighbone, knee joints, and costal cartilage) were significantly higher than those in the heart, liver, and kidneys (P < 0.05). The relative concentrations of T-2 toxin and HT-2 toxin in the skeletal system (thighbone and costal cartilage) were also significantly higher than those in the heart, liver, and kidneys. The rats administered T-2 toxin showed rapid metabolism compared with that in rats administered HT-2 toxin, and the metabolic conversion rates in the different tissues were 68.20%-90.70%. Copyright © 2017 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.

Identification of sinensetin metabolites in rat urine by an isotope-labeling method and ultrahigh-performance liquid chromatography-electrospray ionization mass spectrometry.

PubMed

Wei, Guor-Jien; Sheen, Jenn-Feng; Lu, Wen-Chien; Hwang, Lucy Sun; Ho, Chi-Tang; Lin, Ching-I

2013-05-29

Sinensetin (SIN), one of the major polymethoxyflavones (PMFs) contained mainly in the citrus peels, has been reported to possess various bioactivities, including antifungal, antimutagenic, anticancer, and anti-inflammatory activities. Although the biotransformation of SIN in fungi and insects has been reported, the information about the metabolism of SIN in mammals is still unclear. In this study, formation of SIN metabolites in rats was investigated. Four isotope-labeled SINs ([4'-D3]SIN, [3'-D3]SIN, [5-D3]SIN, and [6-D3]SIN) were synthesized and administered to rat. The urine samples were collected and main metabolites were monitored by ultrahigh-performance liquid chromatography-electrospray ionization mass spectrometry. The administered compound and four SIN metabolites were detected in rat urine. These metabolites were identified as 4'-hydroxy-5,6,7,3'-tetramethoxyflavone, 5-hydroxy-6,7,3',4'-tetramethoxyflavone, 6-hydroxy-5,7,3',4'-tetramethoxyflavone, and 7-hydroxy-5,6,3',4'-tetramethoxyflavone sulfate.

Traumatic Brain Injury Causes a Tacrolimus-Sensitive Increase in Non-Convulsive Seizures in a Rat Model of Post-Traumatic Epilepsy.

PubMed

Campbell, John N; Gandhi, Anandh; Singh, Baljinderjit; Churn, Severn B

2014-01-01

Epilepsy is a significant but potentially preventable complication of traumatic brain injury (TBI). Previous research in animal models of acquired epilepsy has implicated the calcium-sensitive phosphatase, calcineurin. In addition, our lab recently found that calcineurin activity in the rat hippocampus increases acutely after lateral TBI. Here we use a calcineurin inhibitor test whether an acute increase in calcineurin activity is necessary for the development of late post-traumatic seizures. Adult rats were administered the calcineurin inhibitor Tacrolimus (5mg/kg; i.p.) 1 hour after lateral fluid percussion TBI and then monitored by video-electrocorticography (video-ECoG) for spontaneous seizure activity 5 weeks or 33 weeks later. At 5 weeks post-TBI, we observed epileptiform activity on the video-ECoG of brain injured rats but no seizures. By 33 weeks post-TBI though, nearly all injured rats exhibited spontaneous seizures, including convulsive seizures which were infrequent but lasted minutes (18% of injured rats), and non-convulsive seizures which were frequent but lasted tens of seconds (94% of injured rats). We also identified non-convulsive seizures in a smaller subset of control and sham TBI rats (56%), reminiscent of idiopathic seizures described in other rats strains. Non-convulsive seizures in the brain injured rats, however, were four-times more frequent and two-times longer lasting than in their uninjured littermates. Interestingly, rats administered Tacrolimus acutely after TBI showed significantly fewer non-convulsive seizures than untreated rats, but a similar degree of cortical atrophy. The data thus indicate that administration of Tacrolimus acutely after TBI suppressed non-convulsive seizures months later.

Traumatic Brain Injury Causes a Tacrolimus-Sensitive Increase in Non-Convulsive Seizures in a Rat Model of Post-Traumatic Epilepsy

PubMed Central

Campbell, John N.; Gandhi, Anandh; Singh, Baljinderjit; Churn, Severn B.

2014-01-01

Epilepsy is a significant but potentially preventable complication of traumatic brain injury (TBI). Previous research in animal models of acquired epilepsy has implicated the calcium-sensitive phosphatase, calcineurin. In addition, our lab recently found that calcineurin activity in the rat hippocampus increases acutely after lateral TBI. Here we use a calcineurin inhibitor test whether an acute increase in calcineurin activity is necessary for the development of late post-traumatic seizures. Adult rats were administered the calcineurin inhibitor Tacrolimus (5mg/kg; i.p.) 1 hour after lateral fluid percussion TBI and then monitored by video-electrocorticography (video-ECoG) for spontaneous seizure activity 5 weeks or 33 weeks later. At 5 weeks post-TBI, we observed epileptiform activity on the video-ECoG of brain injured rats but no seizures. By 33 weeks post-TBI though, nearly all injured rats exhibited spontaneous seizures, including convulsive seizures which were infrequent but lasted minutes (18% of injured rats), and non-convulsive seizures which were frequent but lasted tens of seconds (94% of injured rats). We also identified non-convulsive seizures in a smaller subset of control and sham TBI rats (56%), reminiscent of idiopathic seizures described in other rats strains. Non-convulsive seizures in the brain injured rats, however, were four-times more frequent and two-times longer lasting than in their uninjured littermates. Interestingly, rats administered Tacrolimus acutely after TBI showed significantly fewer non-convulsive seizures than untreated rats, but a similar degree of cortical atrophy. The data thus indicate that administration of Tacrolimus acutely after TBI suppressed non-convulsive seizures months later. PMID:25580467

The gastro protective effects of Cibotium barometz hair on ethanol-induced gastric ulcer in Sprague-Dawley rats.

PubMed

Al-Wajeeh, Nahla Saeed; Hajerezaie, Maryam; Noor, Suzita Mohd; Halabi, Mohammed Farouq; Al-Henhena, Nawal; Azizan, Ainnul Hamidah Syahadah; Kamran, Sareh; Hassandarvish, Pouya; Shwter, Abdrabuh N; Karimian, Hamed; Ali, Hapipah Mohd; Abdulla, Mahmood Ameen

2017-01-19

Cibotium barometz is a medical herb used traditionally in the Malaysian peninsula for several ailments, including gastric ulcer. The aim of this study was assessment the anti-ulcer effects of C. barometz hair on ethanol-induced stomach hemorrhagic abrasions in animals. Seven groups of Sprague Dawley (SD) rats were administered 10% Tween 20 in the normal control and ulcer control groups, and omeprazole 20 mg/kg and 62.5, 125, 250, and 500 mg/kg of C. barometz hair extract in the experimental groups. After 60 min, the normal control group of rats was orally administered 10% Tween 20, while absolute ethanol was orally administered to the groups of ulcer control, omeprazole and experimental groups. Stomachs of the rats were examined macroscopically and histologically. Homogenates of stomachs were used to evaluate endogenous antioxidant enzyme activities. Rats pre-fed with plant extract presented a significant decrease in the sore area, increased pH of gastric contents and preserved stomach wall mucus compared to the ulcer group. Histologically, rats pre-fed with C. barometz hair extract showed mild to moderate disruptions of the surface epithelium while animals pre-fed with absolute ethanol showed severe disruptions of the stomach epithelium with edema and leucocyte penetration of the submucosal layer. A Periodic acid Schiff (PAS) staining revealed that each rat pre-treated with the plant extract displayed an intense uptake of stomach epithelial glycoprotein magenta color compared to the ulcer control group. Immunohistochemical analysis revealed that rats pre-fed with the plant extract showed an up-regulation of the heat shock protein 70 (HSP70) and down-regulation of Bax proteins compared to ulcer control rats. Homogenates of the stomach tissue demonstrated significant increases in the endogenous antioxidant enzymatic activity and decreased lipid peroxidation (MDA) in rats pre-treated with C. barometz hair extract compared with the ulcer control rats. In acute toxicity, the liver and kidney revealed no hepatotoxic or nephrotoxic effects histologically. The gastric cytoprotective action of C. barometz hair extract might be attributed to antioxidants, an increase in gastric pH, stomach mucus preservation, increased endogenous antioxidant enzymes, decreased lipid peroxidation, up-regulation of HSP70 and down-regulation of Bax proteins.

Tanshinone IIA exerts neuroprotective effects on hippocampus-dependent cognitive impairments in diabetic rats by attenuating ER stress-induced apoptosis.

PubMed

Chen, Jian; Bi, Yanli; Chen, Lei; Zhang, Qi; Xu, Linhao

2018-08-01

This study aimed to investigate the mechanism by which tanshinone IIA (Tan IIA) suppresses neuronal apoptosis in the hippocampus of diabetic rats. Sprague-Dawley (SD) rats were randomly divided into the following four groups: a control group, a diabetes group and diabetes groups treated with different doses (2 or 4 mg/kg/day) of Tan IIA. Streptozotocin (STZ) was injected into the rats to induce diabetes. Two days after STZ treatment, Tan IIA was intraperitoneally administered to rats in the Tan IIA groups, whereas an equal volume of saline was administered to rats in the control and diabetes groups. After 6 weeks, a one-trial object recognition task and the Morris water maze were applied. The diabetes group displayed notably decreased learning and memory abilities compared with the control group (P < 0.05). Tan IIA rescued hippocampus-dependent memory. Superoxide dismutase (SOD) activity was reduced, and reactive oxygen species (ROS) production, malondialdehyde (MDA) content, and 78-kDa glucose-regulated protein (Grp78), growth arrest and DNA damage-inducible gene 153 (CHOP/GAD153) and cleaved caspase-3 levels were increased in the hippocampus of diabetic rats compared with that of control rats, changes that were accompanied by an increase in neuronal apoptosis in diabetic rats compared with control rats (P < 0.01). However, Tan IIA reduced the MDA content and GRP78 and CHOP expression by inducing SOD activity. Tan IIA attenuated neuronal apoptosis and improved learning and memory by suppressing endoplasmic reticulum (ER) stress activation. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Heterotopic Ossification Following Extremity Blast Amputation: An Animal Model in the Sprague Dawley Rat

DTIC Science & Technology

2012-10-01

Buprenorphine (0.05 mg/kg) and 12 enrofloxacin (5 mg/kg) were administered subcutaneously for preemptive analgesia and 13 prophylactic antibacterial...cage with warmed bedding and was monitored until awakening from anesthesia. 19 Animals received antibiotics ( enrofloxacin , 5 mg/kg administered

Suppressing effect of saikosaponin A, an active ingredient of Bupleurum falcatum, on chocolate self-administration and reinstatement of chocolate seeking in rats.

PubMed

Lorrai, Irene; Maccioni, Paola; Carai, Mauro A M; Capra, Alessandro; Castelli, M Paola; Riva, Antonella; Morazzoni, Paolo; Gessa, Gian Luigi; Colombo, Giancarlo

2017-01-18

Recent lines of experimental evidence have indicated that saikosaponin A (SSA) - a bioactive ingredient of the medicinal plant, Bupleurum falcatum L. - suppressed alcohol, morphine, and cocaine self-administration in rats. The present paper was designed to assess whether the protective properties of SSA on addiction-related behaviors generalize to a hyperpalatable food such as a chocolate-flavored beverage (CFB). To this end, rats were initially trained to lever-respond for CFB [5% (w/v) Nesquik ® powder in water] under fixed ratio (FR) 10 (FR10) schedule of reinforcement. Once lever-responding reached stable levels, rats were treated acutely with two different dose ranges of SSA (0, 0.25, 0.5, and 1mg/kg; 0, 1, 2.5, and 5mg/kg; i.p.) and exposed to the FR10 and progressive ratio (PR) schedules of reinforcement in four independent experiments. The effect of acutely administered SSA (0, 0.25, 0.5, and 1mg/kg; i.p.) on cue-induced reinstatement of seeking behavior for CFB was also assessed. Under the FR and PR schedules of reinforcement, treatment with SSA diminished lever-responding for CFB, amount of self-administered CFB, and breakpoint for CFB. All variables were virtually completely suppressed after treatment with 5mg/kg SSA. Treatment with SSA also suppressed reinstatement of CFB-seeking behavior. No dose of SSA altered rat motor-performance, evaluated exposing all rats to an inverted screen test immediately after the self-administration session. These results demonstrate that acute treatment with SSA potently suppressed several addictive-like behaviors motivated by highly hedonic nourishment. These data extend to a highly rewarding natural stimulus the anti-addictive properties of SSA recently disclosed in rats self-administering alcohol, morphine, and cocaine. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Effects of the hydroethanolic extract of Mucuna pruriens (L.) DC (Fabaceae) on haematological profile in normal and haloperidol treated rats.

PubMed

Akindele, Abidemi J; Busayo, Fadeyibi I

2011-01-01

Mucuna pruriens (L.) DC (Fabaceae) is a climbing plant claimed in traditional medicine to possess anti-anaemic effect. The study is to investigate the effects of the hydroethanolic extract of M. pruriens (MP) on haematological profile in normal and haloperidol treated rats. MP was administered p.o. at doses of 50, 100, 200, and 400 mg/kg to groups of rats daily for 28 days. Control animals received distilled water. Rats were sacrificed on the 28th day and blood samples collected for evaluation of haematological parameters and serum iron. Another set of animals received MP p.o. at same doses but along with haloperidol (0.2 mg/kg, i.p.) daily for 4 days. Three other groups of rats received distilled water, haloperidol, and MP at 400 mg/kg alone. Haematological parameters and serum iron were determined. Extract iron content, phytochemical analysis and acute toxicity studies were also carried out. MP administered to normal rats for 28 days significantly (p < 0.05) reduced the number of platelets and proportion of neutrophils. In haloperidol treated rats, MP significantly reversed the reduction in mean corpuscular haemoglobin (MCH) and mean corpuscular haemoglobin concentration (MCHC) values and increased the red blood cell (RBC) count and packed cell volume (PCV). MP also caused significant reduction in the number of platelets and proportion of neutrophils. Administered alone, MP caused a significant increase in the concentration of haemoglobin. The iron content of MP was found to be 61.20 mg/100 g and it was found to contain alkaloids, cardiac glycosides, saponins and tannins. Given up to 10 g/kg p.o., no deaths and visible signs of toxicity were observed while the LD50 for the i.p. route was estimated to be 1509.46 mg/kg. The findings in the study suggest that the hydroethanolic extract of Mucuna pruriens possibly possess beneficial effects in anaemic conditions especially associated with iron deficiency.

Effects of gonadal hormones on the peripheral cannabinoid receptor 1 (CB1R) system under a myositis condition in rats.

PubMed

Niu, Katelyn Y; Zhang, Youping; Ro, Jin Y

2012-11-01

In this study, we assessed the effects of peripherally administered cannabinoids in an orofacial myositis model, and the role of sex hormones in cannabinoid receptor (CBR) expression in trigeminal ganglia (TG). Peripherally administered arachidonylcyclopropylamide (ACPA), a specific CB1R agonist, significantly attenuated complete Freund's adjuvant (CFA)-induced mechanical hypersensitivity in the masseter muscle in male rats. The ACPA effect was blocked by a local administration of AM251, a specific CB1R antagonist, but not by AM630, a specific CB2R antagonist. In female rats, a 30-fold higher dose of ACPA was required to produce a moderate reduction in mechanical hypersensitivity. CFA injected in masseter muscle significantly upregulated CB1R mRNA expression in TG in male, but not in female, rats. There was a close correlation between the CB1R mRNA levels in TG and the antihyperalgesic effect of ACPA. Interleukin (IL)-1β and IL-6, which are elevated in the muscle tissue following CFA treatment, induced a significant upregulation of CB1R mRNA expression in TG from male rats. The upregulation of CB1R was prevented in TG cultures from orchidectomized male rats, which was restored by the application of testosterone. The cytokines did not alter the CB1R mRNA level in TG from intact as well as ovariectomized female rats. Neither estradiol supplement nor estrogen receptor blockade had any effects on CB1R expression. These data indicate that testosterone, but not estradiol, is required for the regulation of CB1Rs in TG under inflammatory conditions, which provide explanations for the sex differences in the antihyperalgesic effects of peripherally administered cannabinoids. Copyright © 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Review of the cardiovascular safety of COXIBs compared to NSAIDS

PubMed Central

Moodley, I

2008-01-01

Summary Summary There is no doubt that NSAIDs and COXIBS are the mainstay for managing pain and inflammation in arthritis. Overall, at therapeutically equivalent doses, both NSAIDs and COXIBs provide equivalent analgesic and anti-inflammatory efficacy. However, the gastrointestinal risk associated with NSAIDs is considerable. More recently, the cardiovascular risk associated with NSAIDs and COXIBs has become a concern. Most patients, particularly the young, can benefit from NSAIDs without the risk of serious adverse gastrointestinal or cardiovascular events. However, patients with a previous history of serious gastrointestinal complications and the elderly, who could be at risk, do require alternatives. COXIBs have significant benefits over NSAIDs in reducing the incidence of serious gastrointestinal complications (perforations, ulcers and gastric bleeding). Currently two oral COXIBs are available, celecoxib and lumiracoxib, and one parenteral COXIB, parecoxib. Celecoxib has been on the market for longer and has the largest body of evidence. The older NSAIDs, such as meloxicam, with preferential COX-2 inhibition do not have good long-term evidence of reducing the incidence of serious gastrointestinal complications. However, these agents do have evidence of tolerability, ie, reducing the less-serious gastrointestinal effects, mainly dyspepsia. The South African Rheumatoid Arthritis Association’s guidelines, amended in November 2005 recommend COXIBs for elderly patients (> 60 years) with previous gastropathy and those on warfarin and/or corticosteroids, providing they do not have contra-indications. However, caution is advised when prescribing COXIBs for patients with risk factors for heart disease. These recommendations are very similar to those made by the National Institute for Clinical Excellence (NICE). In addition, it should be noted that for those patients without any cardiovascular complications but with gastrointestinal risk factors or on aspirin, it may be necessary to add a proton pump inhibitor (PPI). PPIs, however, provide little benefit for bleeding and ulceration of the lower intestine. One consequence of this low-grade bleeding is anaemia and a general feeling of malaise in patients with rheumatic disease. Current evidence suggests that COXIBs such as rofecoxib and celecoxib do not increase small intestinal permeability and that celecoxib does not cause lower intestinal bleeding and may be of benefit to those patients with lower gastrointestinal complications. In patients at risk for cardiovascular complications, both NSAIDs and COXIBs have been shown to increase the risk of myocardial infarctions (MI), hypertension and heart failure. Studies comparing COXIBs and non-specific NSAIDs should, however, be interpreted with caution. One needs to take into account the underlying baseline cardiovascular risk of the populations being compared. COXIBs appear to be prescribed preferentially to patients who were at an increased risk of cardiovascular events compared with patients prescribed non-specific NSAIDs. When the overall risk of cardiovascular complications is relatively low and an anti-inflammatory agent is required, current evidence suggests that celecoxib is an agent of choice because of its lower cardiovascular toxicity potential compared to NSAIDs and other COXIBs. PMID:18516356

[Effect of duodenal contents of patients with pancreatitis following its introduction into the duodenum of healthy rats].

PubMed

Cherkezova-Kinova, E; Lateva, E; Balutsov, M

1976-01-01

The authors examined 18 rats--6 controls and 12 experimental. After duodenostomy by means of a puncure of the duodenal wall duodenal content from healthy persons was administered in the duodenum of control rats. In the experimental group of animals duodenal content form patients with pancreatitis was administered. Duodenum, pancrea, liver and kidneys were examined histomorphologicaly. The obtained results showed that there were no substantial deviations from the norm in the histomorphological picture of the examined organs after administration of duodenal content. In the organs of the experimental group these changes could be characterized as acute necrotic pancreatitis, acute duodenitis, acute finely dotted dystrophy of liver and slightly, manifested acute renal insufficiency. the authors suggested the occurrence of some toxic substances in the duodenal content in patients with acute pancreatitis.

The Kringle-2 domain of tissue plasminogen activator significantly reduces mortality and brain infarction in middle cerebral artery occlusion rats.

PubMed

Zhang, Haitao; Bi, Feng; Xiao, Chunlan; Liu, Jianxia; Wang, Zhixia; Liu, Jian-Ning; Zhang, Jing

2010-08-01

Tissue plasminogen activator (TPA) showed brain-protective activity within the first 15 min after cerebral ischemia in rats. To understand its molecular mechanism, TPA derivates were intracerebroventricularly administered at 15 min before, and 15, 90, 120 min after middle cerebral artery occlusion (MCAO) in rats. The reduction in mortality and cerebral infarction at 24 h was seen only with TPA administered at 15 min after MCAO. The down-regulation of endogenous TPA by the intracerebroventricular injection of TPA was found to be responsible for the protective effect on the integrity of blood-brain barrier after MCAO, as well as for the reduction in mortality and cerebral infarction. Moreover, for the first time we have found that the Kringle-2 domain is essential for the brain-protective activity of TPA.

Prenatal administration of neuropeptide bombesin promotes lung development in a rat model of nitrofen-induced congenital diaphragmatic hernia.

PubMed

Sakai, Kohei; Kimura, Osamu; Furukawa, Taizo; Fumino, Shigehisa; Higuchi, Koji; Wakao, Junko; Kimura, Koseki; Aoi, Shigeyoshi; Masumoto, Kouji; Tajiri, Tatsuro

2014-12-01

Fetal medical treatment to improve lung hypoplasia in congenital diaphragmatic hernia (CDH) has yet to be established. The neuropeptide bombesin (BBS) might play an important role in lung development. The present study aims to determine whether prenatally administered BBS could be useful to promote fetal lung development in a rat model of nitrofen-induced CDH. Pregnant rats were administered with nitrofen (100mg) on gestation day 9.5 (E9.5). BBS (50mg/kg/day) was then daily infused intraperitoneally from E14, and fetal lungs were harvested on E21. The expression of PCNA was assessed by both immunohistochemical staining and RT-PCR to determine the amount of cell proliferation. Lung maturity was assessed as the expression of TTF-1, a marker of alveolar epithelial cell type II. The lung-body-weight ratio was significantly increased in CDH/BBS(+) compared with CDH/BBS(-) (p<0.05). The number of cells stained positive for PCNA and TTF-1 was significantly decreased in CDH/BBS(+) compared with CDH/BBS(-) (p<0.01). The TTF-1 mRNA expression levels were significantly decreased in CDH/BBS(+) compared with CDH/BBS(-) (p<0.05). Prenatally administered BBS promotes lung development in a rat model of nitrofen-induced CDH. Neuropeptide BBS could help to rescue lung hypoplasia in fetal CDH. Copyright © 2014 Elsevier Inc. All rights reserved.

Effect of heroin-conditioned auditory stimuli on cerebral functional activity in rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Trusk, T.C.; Stein, E.A.

1988-08-01

Cerebral functional activity was measured as changes in distribution of the free fatty acid (1-14C)octanoate in autoradiograms obtained from rats during brief presentation of a tone previously paired to infusions of heroin or saline. Rats were trained in groups of three consisting of one heroin self-administering animal and two animals receiving yoked infusions of heroin or saline. Behavioral experiments in separate groups of rats demonstrated that these training parameters imparts secondary reinforcing properties to the tone for animals self-administering heroin while the tone remains behaviorally neutral in yoked-infusion animals. The optical densities of thirty-seven brain regions were normalized to amore » relative index for comparisons between groups. Previous pairing of the tone to heroin infusions irrespective of behavior (yoked-heroin vs. yoked-saline groups) produced functional activity changes in fifteen brain areas. In addition, nineteen regional differences in octanoate labeling density were evident when comparison was made between animals previously trained to self-administer heroin to those receiving yoked-heroin infusions, while twelve differences were noted when comparisons were made between the yoked vehicle and self administration group. These functional activity changes are presumed related to the secondary reinforcing capacity of the tone acquired by association with heroin, and may identify neural substrates involved in auditory signalled conditioning of positive reinforcement to opiates.« less

Usefulness of real-time elastography strain ratio in the assessment of bile duct ligation-induced liver injury and the hepatoprotective effect of chitosan: an experimental animal study.

PubMed

Dudea, Marina; Clichici, Simona; Olteanu, Diana Elena; Nagy, Andras; Cucoş, Maria; Dudea, Sorin

2015-01-01

The purpose of the study described here was to evaluate the usefulness of the elastographic strain ratio in the assessment of liver changes in an experimental animal setting and the hepatoprotective effects of chitosan. Ultrasonography and Strain Ratio calculation were performed before and after bile duct ligation (BDL) in three groups of Wistar albino rats (n = 10 animals per group): (i) rats subjected to bile duct ligation only; (ii) rats subjected to bile duct ligation and administered chitosan for 14 d; (iii) rats subjected to bile duct ligation and administered chitosan for 7 d. The results were compared with the laboratory data and pathologic findings. Strain ratios revealed an increase in liver stiffness after bile duct ligation (p < 0.05), except in the group with chitosan administered for 7 d, and agreed with laboratory and pathology data. In conclusion, strain ratio can be used as an experimental research instrument in the assessment of liver response to injury. To the best of our knowledge, this is the first study reporting on the usefulness of the sonoelastographic liver-to-kidney strain ratio in assessing the effects of experimentally induced liver lesions. Copyright © 2015 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

Bethanechol-Induced Water Intake in Rats: Possible Mechanisms of Induction

NASA Technical Reports Server (NTRS)

Fregly, Melvin J.; Kikta, Dianne C.; Greenleaf, John E.

1982-01-01

Acute administration of the parasympathomimetic agent, bethanechol, at 2, 4, 8 and 12 mg/kg body wt, IP, induced drinking and increased urine output of rats in a dose-dependent fashion. The first significant increases in both water intake and urine output above that of controls occurred when 4 mg/kg was administered. The drinking and increased urine output in response to administration of 8 mg bethanechol/kg was inhibited by atropine sulfate (3 and 6 mg/kg, IP). In addition, the 0-adrenergic antagonist, propranolol (6 mg/kg, IP, administered 30 min prior to treatment with bethanechol), inhibited bethanechol (8 mg/kg, IP)-induced drinking. Urine output, however, was unaffected by propranolol. Further, the angiotensin I converting enzyme inhibitor, captopril, inhibited significantly the drinking response, but not the increased urine output, accompanying administration of bethanechol (8 mg/kg). The effect of bethanechol and the beta-adrenergic agonist, isoproterenol (25 Ag/kg) separately and in combination, on water intake was also studied. Both compounds increased water intake but they exerted no interactive effect when administered simultaneously. Administration of bethanechol (8 mg/kg) to conscious rats was also accompanied by a significant reduction in both mean blood pressure and heart rate that reached minimal levels within 10 min after treatment. Both responses had returned to control level by one hour after treatment. These results suggest that bethanechol induces drinking in rats by way of the renin-angiotensin system.

NTP toxicity studies of dimethylaminopropyl chloride, hydrochloride (CAS No. 5407-04-5) administered by Gavage to F344/N rats and B6C3F1 mice.

PubMed

Abdo, Km

2007-07-01

Dimethylaminopropyl chloride, hydrochloride is used primarily as an industrial and research organic chemical intermediate acting as an alkylating reagent in Grignard and other types of reactions. It is also used as a pharmaceutical intermediate for the synthesis of many types of drugs, as an agricultural chemical intermediate, as a photographic chemical intermediate, and as a biochemical reagent for enzyme and other studies. Human occupational or other accidental exposure can occur by inhalation, ingestion, or skin absorption. Male and female F344/N rats and B6C3F1 mice received dimethylaminopropyl chloride, hydrochloride (greater than 99% pure) in water by gavage for 2 weeks or 3 months. Genetic toxicology studies were conducted in Salmonella typhimurium and mouse peripheral blood erythrocytes. In the 2-week toxicity studies, groups of five male and five female F344/N rats and B6C3F1 mice were administered doses of 0, 6.25, 12.5, 25, 50, or 100 mg dimethylaminopropyl chloride, hydrochloride/kg body weight in deionized water by gavage, 5 days per week for 16 days. All dosed male and female rats and mice survived until the end of the 2-week study; one vehicle control female mouse died early. Mean body weights of all dosed groups of rats and mice were similar to those of the vehicle control groups. No gross or microscopic lesions were considered related to dimethylaminopropyl chloride, hydrochloride administration. In the 3-month toxicity studies, groups of 10 male and 10 female F344/N rats and B6C3F1 mice were administered doses of 0, 6.25, 12.5, 25, 50, or 100 mg/kg in deionized water by gavage, 5 days per week for 3 months. One male rat in the 50 mg/kg group died during week 12 of the study, and one female mouse in the 100 mg/kg group died during week 9 and another during week 13. The final mean body weights of 50 mg/kg male rats and 50 mg/kg female mice were significantly less than those of the vehicle controls. Possible chemical-related clinical findings in rats included lethargy in one 50 mg/kg male and one 100 mg/kg male, tremors in one 100 mg/kg male, and ataxia in one 50 mg/kg male and two 100 mg/kg males. Absolute lung weights in the 25, 50, and 100 mg/kg groups of female mice were significantly less than those of the vehicle controls. Total serum bile acid concentrations were increased in 50 mg/kg male rats and 100 mg/kg male and female rats. The incidence of goblet cell hypertrophy of the nose was significantly increased in 100 mg/kg male rats compared to the vehicle controls. There were no significant histopathologic findings in mice. Dimethylaminopropyl chloride, hydrochloride was mutagenic in the Salmonella typhimurium base substitution strains TA100 and TA1535, with and without hamster or rat liver S9 activation enzymes; no mutagenic activity was seen in TA97 or TA98. No increase in the frequency of micronucleated erythrocytes was seen in peripheral blood of male or female mice administered dimethylaminopropyl chloride, hydrochloride for 3 months by gavage. In summary, dimethylaminopropyl chloride, hydrochloride caused increased incidences of goblet cell hypertrophy in the nose of male rats and increased serum bile acid concentrations in male and female rats. In mice, dimethylaminopropyl chloride, hydrochloride caused deaths in females administered 100 mg/kg. The estimated no-observed-effect levels were 50 mg/kg per day for male rats and female mice, 100 to 200 mg/kg per day for female rats, and greater than 100 mg/kg per day for male mice. Synonyms: 3-Chloropropyldimethyl-ammonium chloride; (3-chloropropyl)dimethylamine, hydrochloride; N-(3-chloropropyl)-N,N-dimethylammonium chloride; 3-dimethylamino-1-propyl chloride hydrochloride; 3-dimethylaminopropyl chloride hydrochloride; DMPC; 1-propylamine, 3-chloro-N,N-dimethyl-, hydrochloride.

Neuroimmunophilin Ligands Protect Cavernous Nerves after Crush Injury in the Rat: New Experimental Paradigms

PubMed Central

Valentine, Heather; Chen, Yi; Guo, Hongzhi; McCormick, Jocelyn; Wu, Yong; Sezen, Sena F.; Hoke, Ahmet; Burnett, Arthur L.; Steiner, Joseph P.

2009-01-01

Objectives We investigated the effects of the orally bioavailable non-immunosuppressive immunophilin ligand GPI 1046 (GPI) on erectile function and cavernous nerve (CN) histology following unilateral or bilateral crush injury (UCI, BCI, respectively) of the CNs. Methods Adult male Sprague-Dawley rats were administered GPI 15 mg/kg intraperitoneally (ip) or 30 mg/kg orally (po), FK506 1 mg/kg, ip, or vehicle controls for each route of administration just prior to UCI or BCI and daily up to 7 d following injury. At day 1 or 7 of treatment, erectile function induced by CN electrical stimulation was measured, and electron microscopic analysis of the injured CN was performed. Results Intraperitoneal administration of GPI to rats with injured CN protected erectile function, in a fashion similar to the prototypic immunophilin ligand FK506, compared with vehicle-treated animals (93% ± 9% vs. 70% ± 5% vs. 45% ± 1%, p < 0.01, respectively). Oral administration of GPI elicited the same level of significant protection from CN injury. GPI administered PO at 30 mg/kg/d, dosing either once daily or four times daily with 7.5 mg/kg, provided nearly complete protection of erectile function. In a more severe BCI model, PO administration of GPI maintained erectile function at 24 h after CN injury. Ultrastructural analysis of injured CNs indicated that GPI administered at the time of CN injury prevents degeneration of about 83% of the unmyelinated axons at 7 d after CN injury. Conclusions The orally administered immunophilin ligand GPI neuroprotects CNs and maintains erectile function in rats under various conditions of CN crush injury. PMID:17145129

Effects of chronic exposure to triclosan on reproductive and thyroid endpoints in the adult Wistar female rat.

PubMed

Louis, Gwendolyn W; Hallinger, Daniel R; Braxton, M Janay; Kamel, Alaa; Stoker, Tammy E

2017-01-01

Triclosan (TCS), an antibacterial, has been shown to be an endocrine disruptor in the rat. Previously, subchronic TCS treatment to female rats was found to advance puberty and potentiate the effect of ethinyl estradiol (EE) on uterine growth when EE and TCS were co-administered prior to weaning. In the pubertal study, a decrease in serum thyroxine (T 4 ) concentrations with no significant change in serum thyroid-stimulating hormone (TSH) was also observed. The purpose of the present study was to further characterize the influence of TCS on the reproductive and thyroid axes of the female rat using a chronic exposure regimen. Female Wistar rats were exposed by oral gavage to vehicle control, EE (1 μg/kg), or TCS (2.35, 4.69, 9.375 or 37.5 mg/kg) for 8 months and estrous cyclicity monitored. Although a divergent pattern of reproductive senescence appeared to emerge from 5 to 11 months of age between controls and EE-treated females, no significant difference in cyclicity was noted between TCS-treated and control females. A higher % control females displayed persistent diestrus (PD) by the end of the study, whereas animals administered with positive control (EE) were predominately persistent estrus (PE). Thyroxine concentration was significantly decreased in TCS-administered 9.375 and 37.5 mg/kg groups, with no marked effects on TSH levels, thyroid tissue weight, or histology. Results demonstrate that a long-term exposure to TCS did not significantly alter estrous cyclicity or timing of reproductive senescence in females but suppressed T 4 levels at a lower dose than previously observed.

Simvastatin prevents isoproterenol-induced cardiac hypertrophy through modulation of the JAK/STAT pathway

PubMed Central

Al-rasheed, Nouf M; Al-Oteibi, Maha M; Al-Manee, Reem Z; Al-shareef, Sarah A; Al-Rasheed, Nawal M; Hasan, Iman H; Mohamad, Raeesa A; Mahmoud, Ayman M

2015-01-01

Simvastatin (SIM) is a lipid-soluble inhibitor of hydroxy-3-methylglutaryl coenzyme A reductase with multiple reported therapeutic benefits. The present study was designed to investigate the effect of pretreatment with SIM on isoproterenol (ISO)-induced cardiac hypertrophy in rats. Twenty-four male albino Wistar rats weighing 180–200 g were divided into four groups. Groups I and III received normal saline while groups II and IV received SIM (10 mg/kg body weight) for 30 days per gavage. In the last 7 days, rats of groups III and IV were administered ISO (5 mg/kg) intraperitoneally to induce cardiac hypertrophy. Administration of ISO induced an increase in heart-to-body weight (HW/BW) ratio, an increase in serum interleukin-6, and elevated systolic and diastolic blood pressure. Serum levels of lipids, cardiovascular risk indices, and cardiac troponin I and creatine phosphokinase-MB showed significant increase in ISO-induced hypertrophic rats. Histopathological examination of heart tissue revealed focal areas of subendocardium degeneration, mononuclear cellular infiltrations, fibrous tissue deposition, and increased thickness of the myocardium of left ventricle. In addition, ISO-administered rats exhibited significant upregulation of cardiac Janus kinase, phosphorylated signal transducer and activator of transcription, and nuclear factor-kappa B. Pretreatment with SIM significantly prevented ISO-induced cardiac hypertrophy, alleviated the altered biochemical parameters, and improved the heart architecture. In conclusion, our study provides evidence that SIM prevented the development of cardiac hypertrophy via modulation of the Janus kinase/signal transducer and activator of transcription-signaling pathway in the heart of ISO-administered animals. PMID:26150695

The prophylactic effect of Viscum album in streptozotocin-induced diabetic rats

PubMed Central

Turkkan, Asuman; Savas, Hasan Basri; Yavuz, Berire; Yigit, Ayse; Uz, Efkan; Bayram, Nezire Asli; Kale, Banu

2016-01-01

OBJECTIVE: Viscum album (VA) is a species of mistletoe in the family Santalaceae that is thought to have therapeutic properties for several diseases, including diabetes. In the present study, conventional experimental rat model was used with diabetes induced with streptozotocin (STZ) to evaluate effect of VA on lipid peroxidation and antioxidant system. METHODS: Total of 32 adult, male Sprague-Dawley rats were divided into 4 groups of 8 rats: Control group, STZ group, VA group, and group administered VA+STZ. VA extract was 100 mg/kg preparation delivered once a day by oral gavage for 10 days. Single dose of 55 mg/kg STZ citrate buffer (0.1 M, pH 4.5) was administered intraperitoneally to induce diabetes. Fasting blood glucose level was measured and recorded. Animals were sacrificed, and catalase (CAT), malondialdehyde (MDA), and protein present in liver and kidney tissue samples were measured. Activity of CAT, an antioxidant enzyme, was studied according to the Aebi method. MDA, a product of lipid peroxidation, was analyzed using Draper and Hadley spectrophotometric procedure. Protein level was determined using supernatant and extract of tissue homogenates according to Lowry method. Data were assessed using one-way analysis of variance and pairwise comparisons between groups. Post-hoc analysis included Dunnet test, Duncan test, and least significant difference test. P<0.05 was considered significant probability value. RESULTS: Oxidative stress is associated with diabetic complications. VA administered to diabetic rats reduced oxidative stress and improved their general condition. CONCLUSION: Further studies are needed to enhance understanding of potential antidiabetic and antioxidant effects of VA. PMID:28058393

Protective effects of ellagic acid and ozone on rat ovaries with an ischemia/reperfusion injury.

PubMed

Sayar, Ilyas; Bicer, Senol; Gursul, Cebrail; Gürbüzel, Mehmet; Peker, Kemal; Işik, Arda

2016-01-01

This study investigated the effects of the antioxidant agents, ozone (O) and ellagic acid (EA), on ischemia/reperfusion (I/R) injuries developed from an ovarian torsion-detorsion model. Arteries in the left ovaries of rats were clamped for two hours to achieve torsion, and then the clamps were removed for a two-hour detorsion period. Thirty-five female Sprague-Dawley rats were randomly divided into five groups: control: administered only with anesthesia, rats were not subjected to torsion-detorsion; I/R: subjected to torsion and subsequent detorsion, without administering any treatment agent; and I/R + EA, I/R + O and I/R + O + EA: subjected to torsion and detorsion processes and administered with EA, O or EA + O at the 75th minute of torsion. The rats were then sacrificed under general anesthesia and the ovarian tissues were excised. The tissues were homogenized and levels of glutathione reductase, catalase, superoxide dismutase and malondialdehyde (MDA) were analyzed. Tissue damage was evaluated in terms of histopathological parameters, such as hemorrhage, congestion, edema and inflammation. Antioxidant enzyme activity and MDA levels in the ovary tissue increased in the I/R group and decreased in the O, EA and O + EA groups (P < 0.05). Histopathological examination revealed that tissue damage in the O, EA and O + EA groups decreased in comparison with the I/R group (P < 0.05). These biochemical and histopathological findings suggest that EA and O are effective against ovarian I/R injury. © 2015 Japan Society of Obstetrics and Gynecology.

Developmental Injury to the Cerebellar Cortex Following Hydroxyurea Treatment in Early Postnatal Life: An Immunohistochemical and Electron Microscopic Study.

PubMed

Martí, Joaquín; Molina, Vanesa; Santa-Cruz, M C; Hervás, José P

2017-02-01

Postnatal development of the cerebellar cortex was studied in rats administered with a single dose (2 mg/g) of the cytotoxic agent hydroxyurea (HU) on postnatal day (P) 9 and collected at appropriate times ranging from 6 h to 45 days. Quantification of several parameters such as the density of pyknotic, mitotic, BrdU-positive, and vimentin-stained cells revealed that HU compromises the survival of the external granular layer (EGL) cells. Moreover, vimentin immunocytochemistry revealed overexpression and thicker immunoreactive glial processes in HU-treated rats. On the other hand, we also show that HU leads to the activation of apoptotic cellular events, resulting in a substantial number of dying EGL cells, as revealed by TUNEL staining and at the electron microscope level. Additionally, we quantified several features of the cerebellar cortex of rats exposed to HU in early postnatal life and collected in adulthood. Data analysis indicated that the analyzed parameters were less pronounced in rats administered with this agent. Moreover, we observed several alterations in the cerebellar cortex cytoarchitecture of rats injected with HU. Anomalies included ectopic placement of Purkinje cells and abnormities in the dendritic arbor of these macroneurons. Ectopic granule cells were also found in the molecular layer. These findings provide a clue for investigating the mechanisms of HU-induced toxicity during the development of the central nervous system. Our results also suggest that it is essential to avoid underestimating the adverse effects of this hydroxylated analog of urea when administered during early postnatal life.

Simvastatin prevents isoproterenol-induced cardiac hypertrophy through modulation of the JAK/STAT pathway.

PubMed

Al-Rasheed, Nouf M; Al-Oteibi, Maha M; Al-Manee, Reem Z; Al-Shareef, Sarah A; Al-Rasheed, Nawal M; Hasan, Iman H; Mohamad, Raeesa A; Mahmoud, Ayman M

2015-01-01

Simvastatin (SIM) is a lipid-soluble inhibitor of hydroxy-3-methylglutaryl coenzyme A reductase with multiple reported therapeutic benefits. The present study was designed to investigate the effect of pretreatment with SIM on isoproterenol (ISO)-induced cardiac hypertrophy in rats. Twenty-four male albino Wistar rats weighing 180-200 g were divided into four groups. Groups I and III received normal saline while groups II and IV received SIM (10 mg/kg body weight) for 30 days per gavage. In the last 7 days, rats of groups III and IV were administered ISO (5 mg/kg) intraperitoneally to induce cardiac hypertrophy. Administration of ISO induced an increase in heart-to-body weight (HW/BW) ratio, an increase in serum interleukin-6, and elevated systolic and diastolic blood pressure. Serum levels of lipids, cardiovascular risk indices, and cardiac troponin I and creatine phosphokinase-MB showed significant increase in ISO-induced hypertrophic rats. Histopathological examination of heart tissue revealed focal areas of subendocardium degeneration, mononuclear cellular infiltrations, fibrous tissue deposition, and increased thickness of the myocardium of left ventricle. In addition, ISO-administered rats exhibited significant upregulation of cardiac Janus kinase, phosphorylated signal transducer and activator of transcription, and nuclear factor-kappa B. Pretreatment with SIM significantly prevented ISO-induced cardiac hypertrophy, alleviated the altered biochemical parameters, and improved the heart architecture. In conclusion, our study provides evidence that SIM prevented the development of cardiac hypertrophy via modulation of the Janus kinase/signal transducer and activator of transcription-signaling pathway in the heart of ISO-administered animals.

Overview of the arthritis Cost Consequence Evaluation System (ACCES): a pharmacoeconomic model for celecoxib.

PubMed

Pettitt, D; Goldstein, J L; McGuire, A; Schwartz, J S; Burke, T; Maniadakis, N

2000-12-01

Pharmacoeconomic analyses have become useful and essential tools for health care decision makers who increasingly require such analyses prior to placing a drug on a national, regional or hospital formulary. Previous health economic models of non-steroidal anti-inflammatory drugs (NSAIDs) have been restricted to evaluating a narrow range of agents within specific health care delivery systems using medical information derived from homogeneous clinical trial data. This paper summarizes the Arthritis Cost Consequence Evaluation System (ACCES)--a pharmacoeconomic model that has been developed to predict and evaluate the costs and consequences associated with the use of celecoxib in patients with arthritis, compared with other NSAIDs and NSAIDs plus gastroprotective agents. The advantage of this model is that it can be customized to reflect local practice patterns, resource utilization and costs, as well as provide context-specific health economic information to a variety of providers and/or decision makers.

Lemon juice has protective activity in a rat urolithiasis model.

PubMed

Touhami, Mohammed; Laroubi, Amine; Elhabazi, Khadija; Loubna, Farouk; Zrara, Ibtissam; Eljahiri, Younes; Oussama, Abdelkhalek; Grases, Félix; Chait, Abderrahman

2007-10-05

The use of herbal medicines (medicinal plants or phytotherapy) has recently gained popularity in Europe and the United States. Nevertheless the exact mechanism of the preventive effects of these products is still far to be clearly established, being its knowledge necessary to successfully apply these therapies to avoid stone formation. The effect of oral lemon juice administration on calcium oxalate urolithiasis was studied in male Wistar rats. Rats were rendered nephrolithic by providing drinking water containing 0.75% ethylene glycol [v/v] (EG) and 2% ammonium chloride [w/v] (AC) for 10 days. In addition to EG/AC treatment, three groups of rats were also gavage-administered solutions containing 100%, 75% or 50% lemon juice [v/v] (6 microl solution/g body weight). Positive control rats were treated with EG/AC but not lemon juice. Negative control rats were provided with normal drinking water, and were administered normal water by gavage. Each group contained 6 rats. After 10 days, serum samples were collected for analysis, the left kidney was removed and assessed for calcium levels using flame spectroscopy, and the right kidney was sectioned for histopathological analysis using light microscopy. Analysis showed that the rats treated with EG/AC alone had higher amounts of calcium in the kidneys compared to negative control rats. This EG/AC-induced increase in kidney calcium levels was inhibited by the administration of lemon juice. Histology showed that rats treated with EG/AC alone had large deposits of calcium oxalate crystals in all parts of the kidney, and that such deposits were not present in rats also treated with either 100% or 75% lemon juice. These data suggest that lemon juice has a protective activity against urolithiasis.

Beneficial effects of Acer okamotoanum sap on L-NAME-induced hypertension-like symptoms in a rat model.

PubMed

Yang, Hyun; Hwang, Inho; Koo, Tae-Hyoung; Ahn, Hyo-Jin; Kim, Sun; Park, Mi-Jin; Choi, Won-Sil; Kang, Ha-Young; Choi, In-Gyu; Choi, Kyung-Chul; Jeung, Eui-Bae

2012-02-01

The sap of Acer okamotoanum has been termed 'bone-benefit-water' in Korea owing to its mineral and sugar content. In particular, the calcium (Ca) and potassium (K) concentrations of the sap of Acer okamotoanum are 40- and 20-times higher, respectively, than commercial spring water. In the present study, we examined whether Acer okamotoanum sap improves or prevents hypertension-like symptoms in a rat model. Male Sprague-Dawley rats (8-weeks-old) were provided commercial spring water supplemented with 25, 50 or 100% Acer okamotoanum sap, 3% potassium ions (K+) or captopril, and treated daily for 2 weeks with NG-nitro-L-arginine methyl ester (L-NAME; 100 mg/kg/day) by subcutaneous injection, in order to induce hypertensive symptoms. Rats were euthanized 6 h following the final injection. To assess the effect of the sap on hypertension-like symptoms, we examined the mean blood pressure (BP), protein levels and localization of endothelial nitric oxide synthase (eNOS) in the descending aorta of the rats. BP levels were significantly lower in hypertensive rats received 25, 50 and 100% sap compared with rats who were administered only commercial spring water. Protein levels of eNOS were repressed in L-NAME-only-treated rats, but were elevated in the descending aorta of rats administered captopril, K+ water and Acer okamotoanum sap (25, 50 and 100%) up to the level of the sham group provided commercial spring water, and then injected with dimethyl sulfoxide for the same period of time. Localized eNOS protein was abundantly expressed in the perivascular descending aorta adipose tissue of the rats. Taken together, these results demonstrated that the sap of Acer okamotoanum ameliorated high BP induced by L-NAME treatment in a rat model.

Antioxidant activity of Albizzia lebbeck (Linn.) Benth. in alloxan diabetic rats.

PubMed

Resmi, C R; Venukumar, M R; Latha, M S

2006-01-01

There is an increasing demand for natural anti-diabetic drugs, as continuous oral administration of insulin can culminate in many side effects and toxicity. In our endeavour to formulate some cost-effective herbal medicines for diabetes, we undertook this study to evaluate the antioxidant potential of aqueous extract of Albizzia lebbeck (ALL) in diabetic rats. The oxidative stress in alloxan-induced diabetic rats was determined by estimating the levels of thiobarbituric acid reactive substances (TBARS), conjugated dienes (CD) and reduced glutathione (GSH) in liver and kidneys. Activities of antioxidant enzymes, such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX) and glutathione S transferase (GST) were assessed in diabetic as well as rats co-administered with ALL. Oxidative damage in the liver and kidneys of diabetic rats as evidenced by a marked increment in the levels of TBARS and CD, and also a distinct diminution in GSH content was nullified by ALL, as these parameters showed a tendency to retrieve towards normalcy on co-administration of the herbal drug. The antioxidant enzymes registered a decline in activity in diabetic rats thus revealing the damaging effects of free radicals generated due to alloxan exposure. The activities of these enzymes returned to normalcy in ALL-administered rats indicating the antioxidant efficacy of the drug in resisting oxidative insult. The findings provide a rationale for further studies on isolation of active principles and pharmacological evaluation.

Effects of melatonin on aluminium-induced neurobehavioral and neurochemical changes in aging rats.

PubMed

Allagui, M S; Feriani, A; Saoudi, M; Badraoui, R; Bouoni, Z; Nciri, R; Murat, J C; Elfeki, A

2014-08-01

This study aimed to investigate the potential protective effects of melatonin (Mel) against aluminium-induced neurodegenerative changes in aging Wistar rats (24-28months old). Herein, aluminium chloride (AlCl3) (50mg/kg BW/day) was administered by gavage, and melatonin (Mel) was co-administered to a group of Al-treated rats by an intra-peritoneal injection at a daily dose of 10mg/kg BW for four months. The findings revealed that aluminium administration induced a significant decrease in body weight associated with marked mortality for the old group of rats, which was more pronounced in old Al-treated rats. Behavioural alterations were assessed by 'open fields', 'elevated plus maze' and 'Radial 8-arms maze' tests. The results demonstrated that Mel co-administration alleviated neurobehavioral changes in both old and old Al-treated rats. Melatonin was noted to play a good neuroprotective role, reducing lipid peroxidation (TBARs), and enhancing enzymatic (SOD, CAT and GPx) activities in the brain organs of old control and old Al-treated rats. Mel treatment also reversed the decrease of AChE activity in the brain tissues, which was confirmed by histological sections. Overall, the results showed that Mel administration can induce beneficial effects for the treatment of Al-induced neurobehavioral and neurochemical changes in the central nervous system (CNS). Copyright © 2014 Elsevier Ltd. All rights reserved.

Increased expression of proenkephalin and prodynorphin mRNAs in the nucleus accumbens of compulsive methamphetamine taking rats.

PubMed

Cadet, Jean Lud; Krasnova, Irina N; Walther, Donna; Brannock, Christie; Ladenheim, Bruce; McCoy, Michael T; Collector, Daniel; Torres, Oscar V; Terry, Ndeah; Jayanthi, Subramaniam

2016-11-14

Addiction is associated with neuroadaptive changes in the brain. In the present paper, we used a model of methamphetamine self-administration during which we used footshocks to divide rats into animals that continue to press a lever to get methamphetamine (shock-resistant) and those that significantly reduce pressing the lever (shock-sensitive) despite the shocks. We trained male Sprague-Dawley rats to self-administer methamphetamine (0.1 mg/kg/infusion) for 9 hours daily for 20 days. Control group self-administered saline. Subsequently, methamphetamine self-administration rats were punished by mild electric footshocks for 10 days with gradual increases in shock intensity. Two hours after stopping behavioral experiments, we euthanized rats and isolated nucleus accumbens (NAc) samples. Affymetrix Array experiments revealed 24 differentially expressed genes between the shock-resistant and shock-sensitive rats, with 15 up- and 9 downregulated transcripts. Ingenuity pathway analysis showed that these transcripts belong to classes of genes involved in nervous system function, behavior, and disorders of the basal ganglia. These genes included prodynorphin (PDYN) and proenkephalin (PENK), among others. Because PDYN and PENK are expressed in dopamine D1- and D2-containing NAc neurons, respectively, these findings suggest that mechanisms, which impact both cell types may play a role in the regulation of compulsive methamphetamine taking by rats.

Vitamin C modulates lead excretion in rats.

PubMed

Lihm, Hoseob; Kim, Hyun; Chang, Heekyung; Yoon, Myunghee; Lee, Kayoung; Choi, Jongsoon

2013-12-01

Lead, one of the most toxic heavy metals, takes longer time to be excreted from the body than other heavy metals. The purpose of this study is, by measuring lead excretion via urine and feces, to find out the effect of vitamin C in lead chelation. Thirty-six rats were randomly assorted into four groups. All 33 rats except for the control group were administered with lead, before orally administered with different doses of vitamin C per kilogram of body weight. The lead excretion levels in urine and feces as well as the survival rate were then measured for each group. The rats with lead administrations (10/13, 76.9%) with lead administrations only, 10/11 rats (90.9%) with lead administrations and low dose of vitamin C, 9/9 rats (100%) with lead administrations and high dose of vitamin C survived. Among the 29 surviving rats, low vitamin C intake group exhibited higher urinary excretion than the lead only group. The urinary excretion level in high dose vitamin C intakegroup was significantly higher than the lead only group. In addition, fecal lead excretion seemed to be increased in the high dose vitamin C intake group, compared to the group with lead administrations only with statistical significance. Through animal experiment, it was found out that administrating high dose of vitamin C accelerated the excretion of lead in body compared to low dose of vitamin C.

Changes of intestinal mucosal and plasma PYY in a diarrhea model rat and influence of loperamide as the treatment agent for diarrhea.

PubMed

Hirotani, Yoshihiko; Mikajiri, Kyoko; Ikeda, Kenji; Myotoku, Michiaki; Kurokawa, Nobuo

2008-09-01

Peptide YY (PYY) is produced by endocrine cells in the lower gastrointestinal tract. The main functions of PYY are antisecretory effects in the colon and inhibition of gastrointestinal motility. We chose PYY as an index of the intrinsic factor in diarrhea and examined the influence of changes induced in a diarrhea rat model by administration of 4 types of laxative and loperamide hydrochloride (loperamide) as an agent for the treatment of diarrhea. A specific radioimmunoassay was performed to determine plasma and intestinal mucosal PYY concentrations. PYY in the rat intestinal tissue extract was distributed at a high density in the lower intestinal mucosa. In the diarrhea rat model, multiple changes in PYY concentrations in the intestinal mucosa and plasma were observed. In rats administered castor oil and sodium picosulfate, the intestinal mucosal PYY levels significantly decreased in a dose-dependent manner. Plasma PYY levels significantly decreased only in rats administered magnesium citrate. Next, we examined the influence of loperamide administration on the intestinal mucosa and plasma PYY concentrations in these rats. Loperamide administration resulted in multiple changes in plasma and intestinal mucosa PYY concentrations, along with an improvement in the diarrhea. Our research showed that the endocrine hormone PYY is involved in the onset of diarrhea, the course of the condition, and the manifestation of medicinal effects in the lower intestine.

Effects of liraglutide and sibutramine on food intake, palatability, body weight and glucose tolerance in the gubra DIO-rats.

PubMed

Hansen, Gitte; Jelsing, Jacob; Vrang, Niels

2012-02-01

To validate the gubra DIO-rats as a useful animal model of human obesity. The gubra diet-induced obesity (DIO) rat model was based on male Sprague-Dawley rats with ad libitum access to regular chow and a palatable diet rich in fat and sugar. To evaluate the versatility of the gubra DIO-rats as a valid model of human obesity syndrome, the efficacy of 2 weight loss compounds liraglutide and sibutramine with different mechanisms of action were examined in 7-month-old gubra DIO-rats. Liraglutide (200 μg/kg, sc) was administered bi-daily, and sibutramine (5 mg/kg, po) was administered once daily for 23 d. Both the compounds effectively reduced the food intake, body weight and total fat mass as measured by nuclear magnetic resonance. Whereas the 5-HT reuptake inhibitor/5-HT receptor agonist sibutramine reduced the intake of both chow and the gubra-diet, the GLP-1 analogue liraglutide predominantly reduced the intake of the highly palatable diet, indicating a shift in food preference. Sibutramine lowered the insulin sensitivity index, primarily via reductions in glucose-stimulated insulin secretion. This animal model responds well to 2 weight loss compounds with different mechanisms of action. Moreover, the gubra DIO-rat can be particularly useful for the testing of compounds with potential effects on diet preference.

Effects of liraglutide and sibutramine on food intake, palatability, body weight and glucose tolerance in the gubra DIO-rats

PubMed Central

Hansen, Gitte; Jelsing, Jacob; Vrang, Niels

2012-01-01

Aim: To validate the gubra DIO-rats as a useful animal model of human obesity. Methods: The gubra diet-induced obesity (DIO) rat model was based on male Sprague-Dawley rats with ad libitum access to regular chow and a palatable diet rich in fat and sugar. To evaluate the versatility of the gubra DIO-rats as a valid model of human obesity syndrome, the efficacy of 2 weight loss compounds liraglutide and sibutramine with different mechanisms of action were examined in 7-month-old gubra DIO-rats. Liraglutide (200 μg/kg, sc) was administered bi-daily, and sibutramine (5 mg/kg, po) was administered once daily for 23 d. Results: Both the compounds effectively reduced the food intake, body weight and total fat mass as measured by nuclear magnetic resonance. Whereas the 5-HT reuptake inhibitor/5-HT receptor agonist sibutramine reduced the intake of both chow and the gubra-diet, the GLP-1 analogue liraglutide predominantly reduced the intake of the highly palatable diet, indicating a shift in food preference. Sibutramine lowered the insulin sensitivity index, primarily via reductions in glucose-stimulated insulin secretion. Conclusion: This animal model responds well to 2 weight loss compounds with different mechanisms of action. Moreover, the gubra DIO-rat can be particularly useful for the testing of compounds with potential effects on diet preference. PMID:22301859

Depression of home cage wheel running: a reliable and clinically relevant method to assess migraine pain in rats.

PubMed

Kandasamy, Ram; Lee, Andrea T; Morgan, Michael M

2017-12-01

The development of new anti-migraine treatments is limited by the difficulty inassessing migraine pain in laboratory animals. Depression of activity is one of the few diagnostic criteria formigraine that can be mimicked in rats. The goal of the present study was to test the hypothesis thatdepression of home cage wheel running is a reliable and clinically relevant method to assess migraine painin rats. Adult female rats were implanted with a cannula to inject allyl isothiocyanate (AITC) onto the dura to induce migraine pain, as has been shown before. Rats recovered from implantation surgery for 8 days in cages containing a running wheel. Home cage wheel running was recorded 23 h a day. AITC and the migraine medication sumatriptan were administered in the hour prior to onset of the dark phase. Administration of AITC caused a concentration-dependent decrease in wheel running that lasted 3 h. The duration and magnitude of AITC-induced depression of wheel running was consistent following three repeated injections spaced 48 h apart. Administration of sumatriptan attenuated AITC-induced depressionof wheel running when a large dose (1 mg/kg) was administered immediately following AITC administration. Wheel running patterns did not change when sumatriptan was given to naïve rats. These data indicate that home cage wheel running is a sensitive, reliable, and clinically relevant method to assess migraine pain in the rat.

Antioxidant potential properties of mushroom extract (Agaricus bisporus) against aluminum-induced neurotoxicity in rat brain.

PubMed

Waly, Mostafa I; Guizani, Nejib

2014-09-01

Aluminum (Al) is an environmental toxin that induces oxidative stress in neuronal cells. Mushroom cultivar extract (MCE) acted as a potent antioxidant agent and protects against cellular oxidative stress in human cultured neuronal cells. This study aimed to investigate the neuroprotective effect of MCE against Al-induced neurotoxicity in rat brain. Forty Sprague-Dawley rats were divided into 4 groups (10 rats per group), control group, MCE-fed group, Al-administered group and MCE/Al-treated group. Animals were continuously fed ad-libitum their specific diets for 4 weeks. At the end of the experiment, all rats were sacrificed and the brain tissues were homogenized and examined for biochemical measurements of neurocellular oxidative stress indices [glutathione (GSH), Total Antioxidant Capacity (TAC), antioxidant enzymes and oxidized dichlorofluorescein (DCF)]. Al-administration caused inhibition of antioxidant enzymes and a significant decrease in GSH and TAC levels, meanwhile it positively increased cellular oxidized DCF level, as well as Al concentration in brain tissues. Feeding animals with MCE had completely offset the Al-induced oxidative stress and significantly restrict the Al accumulation in brain tissues of Al-administered rats. The results obtained suggest that MCE acted as a potent dietary antioxidant and protects against Al-mediated neurotoxicity, by abrogating neuronal oxidative stress.