Cyclooxygenase-1 and cyclooxygenase-2 selectivity of non-steroidal anti-inflammatory drugs: investigation using human peripheral monocytes

Kato, Miyako; Nishida, Shinichi; Kitasato, Hidero; Sakata, Natsue; Kawai, Shinichi

doi:10.1211/0022357011778070

Cited by 146 publications

(120 citation statements)

References 33 publications

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“…* Ratio of IC50 for COX-1 to IC50 for COX-2 (positively correlated with COX-2 selectivity such that a ratio < 1 indicates COX-1 selectivity and a ratio > 1 indicates COX-2 selectivity). Based on references [33][34][35][36] Biochem Pharmacol. Author manuscript; available in PMC 2012 February 1.…”

Section: Discussionmentioning

confidence: 99%

“…The experiments performed utilized NSAIDs with variable effects on intestinal restitution and variable COX-selectivity, as shown in Table 1 [33][34][35][36]. Drug effects were evaluated over the following ranges of concentrations, as indicated in the text or figure legends: indomethacin (1-100uM); phenylbutazone (1-100uM); NS-398 (1-100uM), SC-560 (10 nM-1uM).…”

Section: Treatment Protocolsmentioning

confidence: 99%

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Depolarization and decreased surface expression of K+ channels contribute to NSAID-inhibition of intestinal restitution

Freeman

Narváez

McCoy

et al. 2007

Biochemical Pharmacology

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Non-steroidal anti-inflammatory drugs (NSAIDs) contribute to gastrointestinal ulcer formation by inhibiting epithelial cell migration and mucosal restitution; however, the drug-affected signaling pathways are poorly defined. We investigated whether NSAID inhibition of intestinal epithelial migration is associated with depletion of intracellular polyamines, depolarization of membrane potential (E m ) and altered surface expression of K + channels. Epithelial cell migration in response to the wounding of confluent IEC-6 and IEC-Cdx2 monolayers was reduced by indomethacin (100 μM), phenylbutazone (100 μM) and NS-398 (100 μM) but not by SC-560 (1 μM). NSAIDinhibition of intestinal cell migration was not associated with depletion of intracellular polyamines. Treatment of IEC-6 and IEC-Cdx2 cells with indomethacin, phenylbutazone and NS-398 induced significant depolarization of E m , whereas treatment with SC-560 had no effect on E m . The E m of IEC-Cdx2 cells was: −38.5±1.8 mV under control conditions; −35.9±1.6 mV after treatment with SC-560; −18.8±1.2 mV after treatment with indomethacin; and −23.7±1.4 mV after treatment with NS-398. Whereas SC-560 had no significant effects on the total cellular expression of K v 1.4 channel protein, indomethacin and NS-398 decreased not only the total cellular expression of K v 1.4, but also the cell surface expression of both K v 1.4 and K v 1.6 channel subunits in IEC-Cdx2. Both K v 1.4 and K v 1.6 channel proteins were immunoprecipitated by K v 1.4 antibody from IEC-Cdx2 lysates, indicating that these subunits co-assemble to form heteromeric K v channels. These results suggest that NSAID inhibition of epithelial cell migration is independent of polyamine-depletion, and is associated with depolarization of E m and decreased surface expression of heteromeric K v 1 channels.

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Section: Discussionmentioning

confidence: 99%

Section: Treatment Protocolsmentioning

confidence: 99%

Depolarization and decreased surface expression of K+ channels contribute to NSAID-inhibition of intestinal restitution

Freeman

Narváez

McCoy

et al. 2007

Biochemical Pharmacology

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“…The C max following the fourth IV dose was 3090 g/ml and 5617 ng/ml, for 18.75 and 37.5 mg, respectively. AUC (0)(1)(2)(3)(4)(5)(6) following the fourth dose of 18.75 and 37.5 mg were 935 and 1839 ngÁhour/ml, respectively. The C max and AUC following the first and fourth doses were similar, suggesting no accumulation of IV HPbCD-diclofenac.…”

Section: Studymentioning

confidence: 95%

“…1,2 Recent studies have further demonstrated that diclofenac opens KCNQ2/3 potassium channels and inhibits sensory neuronal depolarization, resulting in analgesia. 3 Diclofenac has long been approved as safe and effective for both acute and chronic pain through a variety of routes.…”

mentioning

confidence: 99%

Single‐Dose and Multiple‐Dose Pharmacokinetics and Dose Proportionality of Intravenous and Intramuscular HPβCD‐Diclofenac (Dyloject) Compared with Other Diclofenac Formulations

Mermelstein¹,

Hamilton²,

Wright

et al. 2013

Pharmacotherapy

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STUDY OBJECTIVE To evaluate single-and repeated-dose pharmacokinetics (PK) and dose proportionality of hydroxypropyl-b-cyclodextrin (HPbCD)-diclofenac compared with Voltarol after intravenous (IV) and intramuscular (IM) administration. DESIGN Study 1: Single-dose randomized four-way crossover study. Study 2: Multiple-dose randomized three-way crossover study. SETTING Clinical research center. SUBJECTS Healthy adult volunteers. INTERVENTION Study 1: Subjects received HPbCD-diclofenac and Voltarol, IV and IM, with a 5-day washout between treatment periods. Study 2: Subjects received two doses of IV HPbCD-diclofenac and oral Cataflam once every 6 hours for four doses with a 48-hour washout period between treatment periods. MEASUREMENTS AND MAIN RESULTS Study 1: IV HPbCD-diclofenac had a higher peak plasma concentration (C max ) and earlier time to reach maximum plasma concentration (T max ), but equivalent plasma exposure (area under the curve from time zero to t [AUC 0-t ]) to IV Voltarol. The geometric mean ratio of HPbCD-diclofenac (IV) to Voltarol (IV) for AUC 0-t was 106.27%. The geometric mean ratio of HPbCD-diclofenac (IM) to Voltarol (IM) for AUC 0-t was 110.91%. The geometric mean ratio of HPbCD-diclofenac (IV) to HPbCD-diclofenac (IM) for AUC 0-t was 101.25%. The geometric mean ratio of HPbCD-diclofenac (IM) to Voltarol (IV) for AUC 0-t was 104.96%. Study 2: C max for diclofenac was 2904 and 6031 ng/ml after the first IV dose of 18.75 and 37.5 mg HPbCD-diclofenac, respectively, and was 3090 and 5617 ng/ml after the fourth dose, indicating no accumulation. Plasma exposures to 18.75 mg (866 ngÁhour/ml) and 37.5 mg (1843 ngÁhour/ml) IV HPbCD-diclofenac bracketed that of oral Cataflam 50 mg (1473 ngÁhour/ml). CONCLUSIONS Study 1: Bioavailability in terms of AUC after IV administration was equivalent for HPbCD-diclofenac compared with Voltarol and after IM administration of HPbCD-diclofenac and Voltarol. Bioavailability in terms of AUC after IM administration of HPbCD-diclofenac was equivalent to IV administration of HPbCD-diclofenac and IV administration of Voltarol. Study 2: HPbCDdiclofenac showed dose proportionality after single-and multiple-dose administration and no accumulation of HPbCD-diclofenac. HPbCD-diclofenac was safe and well tolerated following IV and IM administration.

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“…Nonsteroidal anti‐inflammatory drugs (NSAIDs) represent a key aspect of such multimodal approaches 1, 3. Diclofenac is an NSAID that exerts analgesic, antipyretic, and anti‐inflammatory effects via cyclooxygenase (COX)‐1 and COX‐2 inhibition; it has been widely prescribed in multiple formulations since its introduction in the United States in 1988 and has demonstrated efficacy and safety in managing acute and chronic pain 4, 5, 6, 7, 8, 9…”

mentioning

confidence: 99%

Pharmacokinetics of Diclofenac and Hydroxypropyl‐β‐Cyclodextrin (HPβCD) Following Administration of Injectable HPβCD‐Diclofenac in Subjects With Mild to Moderate Renal Insufficiency or Mild Hepatic Impairment

Hamilton

Ernst

Kramer

et al. 2017

Clinical Pharm in Drug Dev

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Given their established analgesic properties, nonsteroidal anti‐inflammatory drugs (NSAIDs) represent an important postoperative pain management option. This study investigated: (1) the effects of mild or moderate renal insufficiency and mild hepatic impairment on the pharmacokinetics (PK) of diclofenac and hydroxypropyl‐β‐cyclodextrin (HPβCD) following administration of the injectable NSAID HPβCD‐diclofenac; and (2) the PK of HPβCD following administration of HPβCD‐diclofenac and intravenous itraconazole formulated with HPβCD in healthy adults. Diclofenac clearance (CL) and volume of distribution (Vz) tended to increase with decreasing renal function (moderate insufficiency versus mild insufficiency or healthy controls). Regression analysis demonstrated a significant relationship between Vz (but not CL or elimination half‐life, t½) and renal function. HPβCD CL was significantly decreased in subjects with renal insufficiency, with a corresponding increase in t½. There were no significant differences in diclofenac or HPβCD PK in subjects with mild hepatic impairment versus healthy subjects. Exposure to HPβCD in healthy subjects following HPβCD‐diclofenac administration was ∼12% of that with intravenous itraconazole, after adjusting for dosing schedule and predicted accumulation (<5% without adjustment). With respect to PK properties, these results suggest that HPβCD‐diclofenac might be administered to patients with mild or moderate renal insufficiency or mild hepatic impairment without dose adjustment (NCT00805090).

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Cyclooxygenase-1 and cyclooxygenase-2 selectivity of non-steroidal anti-inflammatory drugs: investigation using human peripheral monocytes

Cited by 146 publications

References 33 publications

Depolarization and decreased surface expression of K+ channels contribute to NSAID-inhibition of intestinal restitution

Depolarization and decreased surface expression of K+ channels contribute to NSAID-inhibition of intestinal restitution

Single‐Dose and Multiple‐Dose Pharmacokinetics and Dose Proportionality of Intravenous and Intramuscular HPβCD‐Diclofenac (Dyloject) Compared with Other Diclofenac Formulations

Pharmacokinetics of Diclofenac and Hydroxypropyl‐β‐Cyclodextrin (HPβCD) Following Administration of Injectable HPβCD‐Diclofenac in Subjects With Mild to Moderate Renal Insufficiency or Mild Hepatic Impairment

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