celecoxib, Celebrex
Neuronal expression of cyclooxygenase-2, a pro-inflammatory protein, in the hippocampus of patients with schizophrenia.

Yokota O, Terada S, Ishihara T, Nakashima H, Kugo A, Ujike H, Tsuchiya K, Ikeda K, Saito Y, Murayama S, Ishizu H, Kuroda S.

Department of Neuropsychiatry, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, 700-8558, Japan. oyokota1 yahoo.co.jp

Several types of evidence suggesting that the inflammatory response system is associated with pathophysiology of schizophrenia have been accumulated. Recently, a prospective double-blind study demonstrated that supplementary treatment with celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, produced significantly greater improvement in scores on the Positive and Negative Syndrome Scale (PANSS) and on all subscales during the acute phase in patients with schizophrenia compared with risperidone alone therapy. The therapeutic effect of celecoxib on the psychopathology of schizophrenia is speculated to be based on COX activity inhibition; however, the detailed pharmacological mechanisms are unclear. To clarify whether or not COX-2 expression is altered in schizophrenia, we examined neuronal COX-2 expression in the hippocampus from cases of schizophrenia (n = 17), normal controls (n = 22), and cases of Alzheimer's disease (AD) as a positive control (n = 17). Quantitative immunohistochemical analysis demonstrated that neuronal COX-2 expression was significantly up-regulated in each CA1-4 region in Alzheimer's disease compared with controls, and that the mean COX-2 immunointensity in CA1-4 was significantly correlated with Abeta load in cases of Alzheimer's disease. In contrast, COX-2 expression was not up-regulated in any subdivision of the hippocampus in the schizophrenia group. These results suggest that celecoxib may affect the pathophysiology of schizophrenia through COX-2-independent actions rather than by inhibiting activity of up-regulated COX-2 protein.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15276698&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Safety profile of celecoxib as used in general practice in England: results of a prescription-event monitoring study.

Layton D, Wilton LV, Shakir SA.

Drug Safety Research Unit, Bursledon Hall, Blundell Lane, Southampton, SO31 1AA, UK. deborah.layton dsru.org

AIMS: A post-marketing surveillance study using the technique of Prescription Event Monitoring was undertaken to monitor the safety of celecoxib, a cyclo-oxygenase (COX)-2 inhibitor, as prescribed in primary care in England. METHODS: Patients were identified from dispensed British National Health Service prescription data supplied in confidence by the Prescription Pricing Authority for celecoxib between May and December 2000. Simple questionnaires were sent to the prescribing general practitioner at least 6 months after the date of the first dispensed prescription for each individual patient. Event incidence densities (IDs) [the number of 1st reports per 1000 patient-months of exposure (pme)] were calculated. ID differences for events reported in month 1 (ID1) and months 2-6 (ID2) were examined for temporal changes in event rate. Information on suspected adverse drug reactions (ADRs), reasons for stopping treatment, outcome of pregnancies and cause of death were also requested. Data were gathered on potential gastrointestinal (GI) risk factors [recent use of other non-steroidal anti-inflammatory drugs (NSAIDs), past history of upper GI disorders and concomitant gastro-irritant agents or anti-ulcer drugs]. Crude IDs per 1000 pme and ID ratios were calculated according to potential risk factors, and age (> or = 65 years, < or = 64 years). RESULTS: The cohort comprised of 17,458 patients [median age 62 years (IQR 51,73); 68.3% female]. The most common specified indication was osteoarthritis (28.1%, n = 4905). Not effective was the event with the highest ID1 (139.9 per 1000 pme). The clinical events with the highest ID1 were dyspepsia (25.4 per 1000 pme) followed by abdominal pain (10.6). These were also given frequently as reasons for stopping (551 and 174 of 9126 reports). Of 436 events in 325 patients (1.9% of total cohort) that were reported as ADRs, the most frequent were events within the alimentary system (186 reports). Uncommon events reported during treatment (not necessarily as ADRs) included allergy (0.10%, n = 17), anaphylaxis (0.01%, n = 2), angioneurotic oedema (0.02%, n = 3) and bronchospasm (0.05%, n = 9). There were 103 reports of events associated with thromboembolism and 111 reports of serious GI events [90 GI bleeds (upper and lower); 21 peptic ulcers] received during treatment or within 1 month of stopping. A past history of dyspeptic/other upper GI conditions and use of concomitant gastro-protective drugs were each associated with a significantly increased risk of dyspepsia and abdominal pain. CONCLUSIONS: Frequently reported adverse events were those GI events commonly associated with treatment with other NSAIDS. Stratification by identified risk factors suggested that channelling of high-risk patients is likely. Serious upper and lower GI events, and thromboembolic events did occur during this study, although the incidence was low (< 1%). Doctors should continue to prescribe NSAIDs, including COX-2-specific inhibitors, with caution.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15278327&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Selective COX-2 inhibition prevents progressive dopamine neuron degeneration in a rat model of Parkinson's disease.

Sanchez-Pernaute R, Ferree A, Cooper O, Yu M, Brownell AL, Isacson O.

McLean Hospital/Harvard University Udall Parkinson's Disease Research Center of Excellence, Belmont, Massachusetts, USA. isacson hms.harvard.edu

Several lines of evidence point to a significant role of neuroinflammation in Parkinson's disease (PD) and other neurodegenerative disorders. In the present study we examined the protective effect of celecoxib, a selective inhibitor of the inducible form of cyclooxygenase (COX-2), on dopamine (DA) cell loss in a rat model of PD. We used the intrastriatal administration of 6-hydroxydopamine (6-OHDA) that induces a retrograde neuronal damage and death, which progresses over weeks. Animals were randomized to receive celecoxib (20 mg/kg/day) or vehicle starting 1 hour before the intrastriatal administration of 6-OHDA. Evaluation was performed in vivo using micro PET and selective radiotracers for DA terminals and microglia. Post mortem analysis included stereological quantification of tyrosine hydroxylase, astrocytes and microglia. 12 days after the 6-OHDA lesion there were no differences in DA cell or fiber loss between groups, although the microglial cell density and activation was markedly reduced in animals receiving celecoxib (p < 0.01). COX-2 inhibition did not reduce the typical astroglial response in the striatum at any stage. Between 12 and 21 days, there was a significant progression of DA cell loss in the vehicle group (from 40 to 65%) that was prevented by celecoxib. Therefore, inhibition of COX-2 by celecoxib appears to be able, either directly or through inhibition of microglia activation to prevent or slow down DA cell degeneration.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15285796&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Nitric oxide (NO)-releasing naproxen (HCT-3012 [(S)-6-methoxy-alpha-methyl-2-naphthaleneacetic Acid 4-(nitrooxy)butyl ester]) interactions with aspirin in gastric mucosa of arthritic rats reveal a role for aspirin-triggered lipoxin, prostaglandins, and NO in gastric protection.

Fiorucci S, Di Lorenzo A, Renga B, Farneti S, Morelli A, Cirino G.

Clinica di Gastroenterologia ed Endoscopia Digestiva, Policlinico Monteluce, 06100 Perugia, Italy. fiorucci unipg.it

Administration of selective and nonselective cyclooxygenase (COX)-2 inhibitors to rheumatoid arthritis patients taking low doses of acetylsalicylic acid (ASA) for cardiovascular prevention associates with increased risk of gastrointestinal bleeding. The present study was undertaken to investigate whether administration of HCT-3012 [(S)-6-methoxy-alpha-methyl-2-naphthaleneacetic acid 4-(nitrooxy)butyl ester], a nitric oxide (NO)-releasing derivative of naproxen, exacerbates gastric mucosal injury in arthritic rats administered low doses of ASA. Our results demonstrated that while treating arthritic rats with a dose of 30 mg/kg/day ASA causes detectable mucosal injury, but had no effect on arthritis score and interleukin-6 plasma levels, coadministration of naproxen (10 mg/kg/day) and celecoxib (30 mg/kg/day), in combination with ASA from day 7 to day 21, attenuates arthritis development (P <0.01 versus arthritis alone), but markedly enhanced gastric mucosal damage caused by ASA (P <0.01 versus ASA alone). In contrast, coadministration of HCT-3012 (15 mg/kg/day) significantly attenuated arthritis development, because HCT-3012 was equally or more effective than naproxen and celecoxib in attenuating local and systemic inflammation (P >0.001 versus arthritis) without exacerbating gastric mucosal injury caused by ASA. Arthritis development associates with gastric COX-2 induction, mRNA and protein, and enhanced gastric prostaglandin E2 (PGE2) synthesis (P <0.01 versus control rats). Although all treatments, including celecoxib, were effective in reducing gastric PGE2 synthesis, administering arthritic rats with ASA resulted in a significant increase in gastric content of aspirin-triggered lipoxin (ATL), a COX-2-derived lipid mediator that regulates proinflammatory responses at the neutrophils/endothelial interface. Administering arthritic rats with naproxen and celecoxib abrogates ATL formation induced by ASA although enhanced neutrophils accumulate into the gastric mucosa (P <0.01 versus ASA alone). In contrast, whereas HCT-3012 inhibited ATL formation, it did not increase neutrophil recruitment into the gastric microcirculation. Collectively, these data indicate that HCT-3012 derived from NO has the potential to compensate for inhibition of PGE2 and ATL and to protect the gastric mucosa by limiting the recruitment of neutrophils. These data suggest that HCT-3012 might be a safer alternative to nonsteroidal anti-inflammatory drugs and coxibs in rheumatic patients that take low doses of ASA.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15297470&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Effects of celecoxib on acid-challenged gastric mucosa of rats: comparison with metamizol and piroxicam.

Berenguer B, Alarcon De La Lastra C, Motilva V, La Casa C, Herrerias JM, Pozo D, Calero MJ.

Department of Pharmacology, Faculty of Pharmacy, University of Sevilla, Sevilla, Spain.

Selective COX-2 inhibitors have been shown to produce fewer gastrointestinal adverse reactions than classical NSAIDs. Nevertheless, these new agents may worsen and delay the healing of experimentally induced gastric ulcers in animals. In this study, we compared the effects of a selective COX-2 inhibitor (celecoxib), a preferential COX-1 inhibitor (piroxicam), and a nonnarcotic analgesic (metamizol) on normal gastric mucosa of rats and, on the other hand, in a setting of preexisting acute gastric lesions induced by 0.6 N hydrochloric acid. Under normal conditions, only piroxicam produced appreciable gastric lesions. However, after acid challenge the three assayed drugs induced significant macroscopic and microscopic damage. Myeloperoxidase activity as an index of neutrophil infiltration was elevated with celecoxib and piroxicam on normal gastric mucosa. On inflamed mucosa, celecoxib augmented enzymatic activity at the lower dose, which was parallelled by an increase in the interleukin 1beta level. Acid instillaton produced a significant rise in PGE2 content at 7 hr. Drug treatment after acid challenge decreased prostaglandin values in all cases, although to a lesser extent than after single drug dose administration. COX-2 mRNA expression was visible 1 hr after acid application, whereas COX-2 protein could only be detected at 7 hr. Piroxicam increased both expression levels. All NSAIDs enhanced transforming growth factor alpha and epidermal growth factor receptor immunoreactivity around the acid-induced lesions. It is concluded that selective COX-2 inhibitors, like conventional NSAIDs, impair the healing of gastric damage, and therefore special attention should be paid in patients with gastric pathologies.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15309881&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Efficacy of chitosan microspheres for controlled intra-articular delivery of celecoxib in inflamed joints.

Thakkar H, Sharma RK, Mishra AK, Chuttani K, Murthy RS.

New Drug Delivery System Laboratory, Pharmacy Department, Donor's Plaza, Opp. To University main office, M. S. University of Baroda, Fatehgunj, Vadodara-390 002, India.

The use of polymeric carriers in formulations of therapeutic drug delivery systems has gained widespread application, due to their advantage of being biodegradable and biocompatible. In this study, we aimed to prepare celecoxib-loaded chitosan microspheres for intra-articular administration and to compare the retention of the celecoxib solution and chitosan microspheres in the joint cavity. The microspheres were characterized for entrapment efficiency, particle size and surface morphology by scanning electron microscopy. In-vitro drug release studies of microspheres revealed that the microspheres are able to control the release of celecoxib over a period of 96 h. Biodistribution studies of celecoxib and chitosan microspheres were performed by radiolabelling with( 99m)Tc and injecting intraarticularly in rats. The study indicated that following intra-articular administration the distribution of the drug to the organs, like liver and spleen, is very rapid compared with that of the microspheres. Compared with the drug solution, a 10-fold increase in the concentration of the drug in the joint was observed 24 h post intra-articular injection (P < 0.005) when drug was encapsulated in microspheres.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15324477&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Cyclooxygenase-2 (COX-2) inhibition limits abnormal COX-2 expression and progressive injury in the remnant kidney.

Fujihara CK, Antunes GR, Mattar AL, Andreoli N, Malheiros DM, Noronha IL, Zatz R.

Renal Division, Department of Clinical Medicine, Faculty of Medicine, University of Sao Paulo, Sao Paulo, Brazil.

BACKGROUND: The pathogenesis of progressive nephropathies involves hemodynamic and inflammatory factors. In the 5/6 nephrectomy model, a selective increase of cyclooxygenase-2 (COX-2) expression was shown, whereas treatment with a nonsteroidal anti-inflammatory or a specific COX-2 inhibitor was renoprotective. We investigated in the 5/6 nephrectomy model (1) the renal distribution of COX-2; (2) the hemodynamic and cellular mechanisms by which chronic COX-2 inhibition prevents renal injury. METHODS: After 5/6 nephrectomy, adult male Munich-Wistar rats were subdivided in two groups: 5/6 nephrectomy (N=20), receiving vehicle, and 5/6 nephrectomy + celecoxib (N=19), treated orally with the COX-2 inhibitor, celecoxib, 10 mg/kg/day. Untreated and treated (celecoxib) sham-operated rats were also studied. Renal hemodynamics were examined at 4 weeks, whereas renal morphologic/immunohistochemical studies were carried at 8 weeks. RESULTS: At 4 weeks, 5/6 nephrectomy rats exhibited marked systemic and glomerular hypertension. Celecoxib attenuated both systemic and glomerular hypertension, without affecting glomerular filtration rate (GFR). At 8 weeks, glomerulosclerosis and interstitial expansion were evident in 5/6 nephrectomy rats, and markedly attenuated in 5/6 nephrectomy rats given celecoxib. In both sham-operated and 5/6 nephrectomy rats, COX-2 was expressed at the macula densa. The extent of COX-2 expression at the macula densa was nearly tripled by celecoxib, indicating the existence of a feedback mechanism. In 5/6 nephrectomy rats, COX-2 was also expressed in glomeruli, arterioles, and the cortical interstitium, mostly at inflamed or sclerosing areas. Celecoxib markedly attenuated renal injury, inflammation, and ectopic COX-2 expression in 5/6 nephrectomy rats. CONCLUSION: Chronic COX-2 inhibition attenuated progressive nephropathy by reducing glomerular hypertension, renal inflammation, and ectopic COX-2 expression, indicating a complex contribution of COX-2 to progressive renal injury in 5/6 nephrectomy rats.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14633140&dopt=Abstract celecoxib, Celebrex