Acetaminophen and the Cyclooxygenase-3 Puzzle: Sorting out Facts, Fictions, and Uncertainties

Kis, Béla; Snipes, James A.; Busija, David W.

doi:10.1124/jpet.105.085431

Cited by 205 publications

(158 citation statements)

References 42 publications

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“…Yet, in vitro studies have demonstrated only weak inhibition of Cox-2 and mPGES-1 by acetaminophen (Mitchell et al, 1993;Thoren and Jakobsson, 2000). Based on this and other observations it has been proposed that acetaminophen targets a brain-specific isoform of Cox, Cox-3, which is a splice variant of the constitutive enzyme Cox-1 (Chandrasekharan et al, 2002), but this idea has been refuted (Kis et al, 2005;Li et al, 2008). It has also been suggested that acetaminophen blocks Cox activity not by binding to its active site but by reducing the active oxidized form of Cox to an inactive form (Ouellet and Percival, 2001), a process that only takes place under conditions with low peroxide activity, such as in the brain (Boutaud et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Acetaminophen reduces lipopolysaccharide-induced fever by inhibiting cyclooxygenase-2

et al. 2013

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Acetaminophen is one of the world's most commonly used drugs to treat fever and pain, yet its mechanism of action has remained unclear. Here we tested the hypothesis that acetaminophen blocks fever through inhibition of cyclooxygenase-2 (Cox-2), by monitoring lipopolysaccharide induced fever in mice with genetic manipulations of enzymes in the prostaglandin cascade. We exploited the fact that lowered levels of a specific enzyme make the system more sensitive to any further inhibition of the same enzyme. Mice were immune challenged by an intraperitoneal injection of bacterial wall lipopolysaccharide and their body temperature recorded by telemetry. We found that mice heterozygous for Cox-2, but not for microsomal prostaglandin E synthase-1 (mPGES-1), displayed attenuated fever, indicating a rate limiting role of Cox-2. We then titrated a dose of acetaminophen that did not inhibit the lipopolysaccharide-induced fever in wild-type mice. However, when the same dose of acetaminophen was given to Cox-2 heterozygous mice, the febrile response to lipopolysaccharide was strongly attenuated, resulting in an almost normalized temperature curve, whereas no difference was seen between wild-type and heterozygous mPGES-1 mice.Furthermore, the fever to intracerebrally injected prostaglandin E 2 was unaffected by acetaminophen treatment. These findings reveal that acetaminophen, similar to aspirin and other non-steroidal anti-inflammatory drugs, is antipyretic by inhibiting cyclooxygenase-2, and not by inhibiting mPGES-1 or signaling cascades downstream of prostaglandin E 2 .

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Section: Introductionmentioning

confidence: 99%

Acetaminophen reduces lipopolysaccharide-induced fever by inhibiting cyclooxygenase-2

et al. 2013

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“…COX-2 is highly inducible in response to cellular activation by hormones, proinflammatory cytokines, growth factors and tumor promoters (41,44) . COX-3, which is encoded by the same gene as the COX-1 isoform, has been demonstrated in vitro in macrophage lines (4,11,24) .…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the immunoexpression of COX-1, COX-2 and p53 in Crohn's disease

Romero

Artigiani

Costa

et al. 2008

Arq. Gastroenterol.

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-Background -Crohn's disease accompanied by nonspecific or idiopathic ulcerative proctocolitis corresponds to a condition called intestinal inflammatory disease. The immunoexpression of cyclooxygenase 2 (COX-2) in Crohn's disease becomes more marked with progression of the disease and the presence of wild-type p53 suppresses the transcription of COX-2. Aims -To investigate the immunoexpression of cyclooxygenase 1 (COX-1), COX-2 and p53 in Crohn's ileocolitis and to correlated this expression with clinical and histopathological parameters. Methods -Forty-five cases of Crohn's disease, 16 cases of actinic colitis (diseased-control group) and 11 cases without a history of intestinal disease (normal control group) were studied. Hematoxylin-eosin-stained sections were submitted to histopathological analysis and the immunohistochemical expression of COX-1, COX-2 and p53 was evaluated by the streptavidin-biotin-peroxidase method. Results -Sixty percent of the Crohn's disease patients were women and 40% were men, with 75.5% whites and 25.5% non-whites. The disease involved the terminal ileum in 44.5% of cases, ileum in 33.3%, colon in 20% and duodenum-ileum in 2.2%. A significant association was observed between COX-2 immunoreactivity and age ≤40 years. Histopathological analysis of Crohn's disease samples showed mild or moderate crypt distortion (57.8% and 35.6% of cases), atrophy (6.6%), mild, moderate and marked chronic inflammation (46.7%, 26.7% and 20%), acute inflammatory activity (93.3%), ulceration (24.4%), mucin depletion (37.8%), Paneth's cells (24.4%), intraepithelial lymphocytes (93.3%), and subepithelial collagen (6.7%). In the CD group, COX-1 immunoreactivity in epithelial and inflammatory cells was observed in 26.7% and 22.2% of cases, respectively.

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“…However, it doesn't affect on thrombocytes compound that cause coagulation like aspirin. Two mechanisms were suggested for how paracetamol works but these are not proved yet [10][11][12][13].…”

Section: Tramadol -Hcl (±Cis-2-[(dimethyl Amino) Methyl]-1-(m-mentioning

confidence: 99%

Simultaneous Determination of Paracetamol and Tramadol in Pharmaceutical Tablets by Derivative UV-Vis Absorption Spectrophotometry

El-Zinati¹,

Abdel-Latif²

2015

TOACJ

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Abstract:A comparative study of the use of first derivative zero order crossing spectra for the resolution of Paracetamol and Tramadol hydrochloride in mixtures has been achieved showing the success of the first derivative method in resolving and quantifying both compounds. Using the first derivative, rather than the second derivative, results in improved signal to noise ratio. The absorption spectra of prepared mixtures were scanned in the range of 200-500 nm. The linear concentration ranges were 25-112 and 6-48 µg mL -1 for paracetamol and Tramadol hydrochloride, respectively. The method has been successfully used for prediction of concentrations of both compounds in mixtures with good selectivity, high sensitivity and extremely low relative error. Statistical comparison was performed using t-test at 95% confidence level. There was no significant statistical difference between the results obtained by the first derivative method and the accepted values for both compounds. Also, the percentage errors were very low which adds to the merits of our work in terms of both sensitivity and accuracy.

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Acetaminophen and the Cyclooxygenase-3 Puzzle: Sorting out Facts, Fictions, and Uncertainties

Cited by 205 publications

References 42 publications

Acetaminophen reduces lipopolysaccharide-induced fever by inhibiting cyclooxygenase-2

Acetaminophen reduces lipopolysaccharide-induced fever by inhibiting cyclooxygenase-2

Evaluation of the immunoexpression of COX-1, COX-2 and p53 in Crohn's disease

Simultaneous Determination of Paracetamol and Tramadol in Pharmaceutical Tablets by Derivative UV-Vis Absorption Spectrophotometry

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