Pharmacokinetic-Pharmacodynamic Modeling of the Inhibitory Effects of Naproxen on the Time-Courses of Inflammatory Pain, Fever, and the Ex Vivo Synthesis of TXB2 and PGE2 in Rats

Krekels, Elke H. J.; Angesjö, Marie; Sjögren, Ingemo; Möller, Kristina Ängeby; Berge, Odd‐Geir; Visser, Sandra A.G.

doi:10.1007/s11095-011-0389-6

Cited by 9 publications

(13 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…No delay in the onset of inhibition was observed, revealing that the effect compartment was located in the central compartment. This result agrees with a previous report that described the use of naproxen [14,23] .…”

Section: Wwwchinapharcom Zhang J Et Alsupporting

confidence: 93%

“…Due to the possibility of repeated measurements and increased reproducibility and sensitivity, PGE 2 could be a suitable alternative endpoint for investigations and comparisons of the time-course and potency of various drug candidates [23] . Several reports have shown the integrated PK-PD modeling of NSAIDs using hyperthermia, hyperalgesia, edema or PGE 2 as pharmacological endpoints [5,11,23] , but little attention has been paid to the impact of the disease status on drug effects [16] . The aim of this study was to characterize the PK-PD modeling of diclofenac in normal and FCA-induced arthritic rats using PGE 2 as a pharmacological endpoint.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Pharmacokinetic-pharmacodynamic modeling of diclofenac in normal and Freund's complete adjuvant-induced arthritic rats

Zhang

Guo

et al. 2012

Acta Pharmacol Sin

View full text Add to dashboard Cite

Aim: To characterize pharmacokinetic-pharmacodynamic modeling of diclofenac in Freund's complete adjuvant (FCA)-induced arthritic rats using prostaglandin E 2 (PGE 2 ) as a biomarker. Methods: The pharmacokinetics of diclofenac was investigated using 20-day-old arthritic rats. PGE 2 level in the rats was measured using an enzyme immunoassay. A pharmacokinetic-pharmacodynamic (PK-PD) model was developed to illustrate the relationship between the plasma concentration of diclofenac and the inhibition of PGE 2 production. The inhibition of diclofenac on lipopolysaccharide (LPS)-induced PGE 2 production in blood cells was investigated in vitro. Results: Similar pharmacokinetic behavior of diclofenac was found both in normal and FCA-induced arthritic rats. Diclofenac significantly decreased the plasma levels of PGE 2 in both normal and arthritic rats. The inhibitory effect on PGE 2 levels in the plasma was in proportion to the plasma concentration of diclofenac. No delay in the onset of inhibition was observed, suggesting that the effect compartment was located in the central compartment. An inhibitory effect sigmoid I max model was selected to characterize the relationship between the plasma concentration of diclofenac and the inhibition of PGE 2 production in vivo. The I max model was also used to illustrate the inhibition of diclofenac on LPS-induced PGE 2 production in blood cells in vitro. Conclusion: Arthritis induced by FCA does not alter the pharmacokinetic behaviors of diclofenac in rats, but the pharmacodynamics of diclofenac is slightly affected. A PK-PD model characterizing an inhibitory effect sigmoid I max can be used to fit the relationship between the plasma PGE 2 and diclofenac levels in both normal rats and FCA-induced arthritic rats.

show abstract

Section: Wwwchinapharcom Zhang J Et Alsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic-pharmacodynamic modeling of diclofenac in normal and Freund's complete adjuvant-induced arthritic rats

Zhang

Guo

et al. 2012

Acta Pharmacol Sin

View full text Add to dashboard Cite

show abstract

“…Ketorolac and naproxen are clinically available NSAIDs that non-selectively inhibit COX enzyme activity and the metabolites like prostaglandin E2 thereby blocking inflammation-induced pain (Buckley and Brogden 1990; Krekels et al 2011). The third part of the studies showed that both ketorolac and naproxen were effective in attenuating carrageenan-induced hyperalgesia in a dose dependent manner.…”

Section: Methodsmentioning

confidence: 99%

Differential effects of opioid-related ligands and NSAIDs in nonhuman primate models of acute and inflammatory pain

et al. 2013

View full text Add to dashboard Cite

Rationale Carrageenan-induced hyperalgesia is a widely used pain model in rodents. However, characteristics of carrageenan-induced hyperalgesia and effects of analgesic drugs under these conditions are unknown in nonhuman primates. Objective The aims of this study were to develop carrageenan-induced hyperalgesia in rhesus monkeys and determine the efficacy and potency of agonists selective for the four opioid receptor subtypes in this model versus acute pain, as compared to NSAIDs. Results Tail-injection of carrageenan produced long-lasting thermal hyperalgesia in monkeys. Systemically administered agonists selective for opioid receptor subtypes i.e. fentanyl (mu/MOP), U-50488H (kappa/KOP), SNC80 (delta/DOP) and Ro 64-6198 (nociceptin/orphanin FQ/NOP) dose-dependently attenuated carrageenan-induced thermal hyperalgesia with different potencies. In absence of carrageenan, these agonists, except SNC80, blocked acute thermal nociception. Opioid-related ligands, especially Ro 64-6198, were much more potent for their antihyperalgesic than antinociceptive effects. Both effects were mediated by the corresponding receptor mechanisms. Only fentanyl produced scratching at antihyperalgesic and antinociceptive doses consistent with its pruritic effects in humans, illustrating a translational profile of MOP agonists in nonhuman primates. Similar to SNC80, systemically administered NSAIDs ketorolac and naproxen dose-dependently attenuated carrageenan-induced hyperalgesia but not acute nociception. Conclusion Using two different pain modalities in nonhuman primates, effectiveness of clinically available analgesics like fentanyl, ketorolac and naproxen was distinguished and their efficacies and potencies were compared with the selective KOP, DOP, and NOP agonists. The opioid-related ligands displayed differential pharmacological properties in regulating hyperalgesia and acute nociception in the same subjects. Such preclinical primate models can be used to investigate novel analgesic agents.

show abstract

“…For example, concentrations of prostaglandin E 2 (PGE 2 ) and thromboxane B 2 (TXB 2 ) are often quantified as indicators for COX-2 and COX-1 activities. 24,25 Proinflammatory cytokines, such as TNFα and IL-1β, are widely used biomarkers for many therapeutic agents. 26–32 Measurement of target cytokine concentrations of anticytokine therapeutics allows direct assessment of their PK/PD.…”

Section: Biomarkers Of Inflammationmentioning

confidence: 99%

“…The first is use of immunoassays, such as enzymelinked immunosorbent assays (ELISAs) 28–31,33–35 and radioimmunoassay (RIA), 36 and the other is ex vivo measurement of enzyme activity. 24,25,37 When measurement of protein concentrations of the mediators is not feasible (usually due to assay insensitivity), mRNA concentrations may be obtained by polymerase chain reaction (PCR) and used as a surrogate. 26,27 …”

Section: Biomarkers Of Inflammationmentioning

confidence: 99%

Pharmacokinetic/Pharmacodynamic Modeling in Inflammation

Lon

Liu

Jusko

2012

Crit Rev Biomed Eng

View full text Add to dashboard Cite

Inflammation is an array of immune responses to infection and injury. It results from a complex immune cascade and is the basis of many chronic diseases such as arthritis, diabetes, and cancer. Numerous mathematical models have been developed to describe the disease progression and effects of anti-inflammatory drugs. This review illustrates the state of the art in modeling the effects of diverse drugs for treating inflammation, describes relevant biomarkers amenable to modeling, and summarizes major advantages and limitations of the published pharmacokinetic/ pharmacodynamic (PK/PD) models. Simple direct inhibitory models are often used to describe in vitro effects of anti-inflammatory drugs. Indirect response models are more mechanism based and have been widely applied to the turnover of symptoms and biomarkers. These, along with target-mediated and transduction models, have been successfully applied to capture the PK/PD of many anti-inflammatory drugs and describe disease progression of inflammation. Biologics have offered opportunities to address specific mechanisms of action, and evolve small systems models to quantitatively capture the underlying physiological processes. More advanced mechanistic models should allow evaluation of the roles of some key mediators in disease progression, assess drug interactions, and better translate drug properties from in vitro and animal data to patients.

show abstract

Pharmacokinetic-Pharmacodynamic Modeling of the Inhibitory Effects of Naproxen on the Time-Courses of Inflammatory Pain, Fever, and the Ex Vivo Synthesis of TXB2 and PGE2 in Rats

Cited by 9 publications

References 37 publications

Pharmacokinetic-pharmacodynamic modeling of diclofenac in normal and Freund's complete adjuvant-induced arthritic rats

Pharmacokinetic-pharmacodynamic modeling of diclofenac in normal and Freund's complete adjuvant-induced arthritic rats

Differential effects of opioid-related ligands and NSAIDs in nonhuman primate models of acute and inflammatory pain

Pharmacokinetic/Pharmacodynamic Modeling in Inflammation

Contact Info

Product

Resources

About