Analgesic Efficacy and Safety of (R)‐ Ketoprofen in Postoperative Dental Pain

Cooper, Stephen A.; Reynolds, D. C.; Reynolds, Beverly; Hersh, Elliot V.

doi:10.1002/j.1552-4604.1998.tb04412.x

Cited by 41 publications

(30 citation statements)

References 22 publications

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“…R-ketoprofen accounts for most of the analgesic activity of ketoprofen and is a promising analgesic without the NSAID side effects. 22,23) Ketoprofen ethyl ester was enantioselectively hydrolyzed to R-ketoprofen in HaCaT keratinocytes by hCE-2, and thus HaCaT keratinocyte are better carriers for synthesizing chiral drugs by biological methods.…”

Section: Discussionmentioning

confidence: 99%

Stereoselective Characteristics and Mechanisms of Epidermal Carboxylesterase Metabolism Observed in HaCaT Keratinocytes

Zhu

Jin-hong

Liu

et al. 2007

Biological & Pharmaceutical Bulletin

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The advantages of transdermal drug delivery over other routes of administration have been well documented, including avoidance of variable absorption rates and first-pass hepatic metabolism with oral delivery and improved therapeutic activity.1) In the past, skin penetration studies usually focused only on the physicochemical factors affecting the transport of drugs across the skin. However, recently, many researchers have also been considering the concurrent epidermal metabolism. Various aspects of the metabolism of xenobiotics in the skin have been reviewed, 2) and it has been demonstrated that skin contains various enzymes including esterase capable of hydrolyzing different esters.3) Ester prodrugs for carboxylic acid-or hydroxyl-containing drugs are widely used for the enhancement of percutaneous absorption and have been noted to show stereoselective hydrolysis in various tissue preparations 4) ; surprisingly, the molecular mechanism of stereoselective hydrolysis in skin has been overlooked.A great deal of the current knowledge on the metabolic clearance of drugs in the skin is based on studies with homogenates of excised tissues, including excised animal skin or human skin. Inherent drawbacks of these models are the doubtful comparability of animal skin versus human skin, the restricted access to human skin, and the potentially high variability of enzyme activity of human skin samples along with the often poorly defined cellular viability of excised tissues. 5)It has been proposed that using cultured HaCaT keratinocytes as a readily available and reproducible in vitro metabolism model may circumvent some of these disadvantages.6) The transformed human HaCaT keratinocyte is a well-established cell model of dermal toxicity and metabolism studies in vitro, because it is easily cultured and has the characteristics of basal epidermal keratinocytes. 7)Carboxylesterase is a group of serine esterases found in numerous animal species and a variety of mammalian tissues. These enzymes hydrolyze many different endogenous and xenobiotic compounds and play a role in the metabolism of numerous drugs. 8) Some researchers have reported the purification and partial characterization of two distinct human carboxylesterases designated human carboxylesterase-1 (hCE-1) and human carboxylesterase-2 (hCE-2).9) These enzymes are expressed in human liver and are both members of the 60-kDalton serine esterase superfamily, but they differ substantially. Sequence homology between the two enzymes is only 48%. hCE-1 is an 180 kDalton trimer with an isoelectric point of 5.8, whereas hCE-2 is a monomer with an isoelectric point of 4.9. Substantial differences in substrate specificity also exist between the two isoforms. 10)Ketoprofen is a nonsteroidal antiinflammatory drug (NSAID) and is used through oral or suppository routes for the treatment of pain and inflammation. Given orally, gastrointestinal side effects are most frequently seen. Therefore percutaneous administration of ketoprofen has been studied to minimize gastrointestinal and o...

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Section: Discussionmentioning

confidence: 99%

Stereoselective Characteristics and Mechanisms of Epidermal Carboxylesterase Metabolism Observed in HaCaT Keratinocytes

Zhu

Jin-hong

Liu

et al. 2007

Biological & Pharmaceutical Bulletin

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“…There is current controversy concerning the pharmacological activity of the R(–) enantiomer of 2‐arylpropionic derivatives, including KTP. Some authors consider that R(–) enantiomers possess analgesic effects ( Brune et al ., 1992 ; Lotsch et al ., 1995 ; Cooper et al ., 1998 ). However, others consider: (a) that all the effects produced after R(–)KTP are a direct and/or indirect consequence of COX inhibition; and (b) that R(–)KTP is pharmacologically inactive, the observed effects being due to the trace presence of the antipode in the administered product or its production by chiral inversion ( Buritova et al ., 1996 ; Carabaza et al ., 1996 ).…”

Section: Discussionmentioning

confidence: 99%

“…Stereoselective pharmacokinetics of KTP has been reported in several animal species ( Rossetti et al ., 1986 ; Abas & Meffin, 1987; Foster et al ., 1988 ; Delatour et al ., 1993 ). In addition, differences in the eudismic ratio of KTP enantiomers, including anti‐inflammatory actions, have been described ( Caldwell et al ., 1988 ; Evans, 1992; Carabaza et al ., 1996 ; Cooper et al ., 1998 ).…”

Section: Introductionmentioning

confidence: 99%

Enantiospecific pharmacokinetics and pharmacodynamics of ketoprofen in sheep

Landoni

Comas²,

Mucci³

et al. 1999

Vet Pharm & Therapeutics

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Pharmacokinetic and pharmacodynamic parameters were established for the enantiomers of the 2-arylpropionic acid (APA) nonsteroidal anti-inflammatory drug (NSAID), ketoprofen (KTP). Each enantiomer was administered separately (1.5 mg/kg) and in a racemic mixture (3 mg/kg) intravenously (i.v.) to a group of eight sheep in a four-way, four-period cross-over study using a tissue cage model of inflammation. Plasma disposition of each KTP enantiomer was similar following separate administration of the pure compounds compared to administration of the racemic mixture. S(+)KTP volume of distribution (Vd(area)) was higher and clearance (ClB) faster than those of R(-)KTP. S(+) and R(-)KTP achieved relatively low concentrations in exudate and transudate. Unidirectional limited chiral inversion of R(-) to S(+)KTP was demonstrated. After R(-)KTP administration S(+)KTP was detected in plasma, but not in either exudate or transudate. Pharmacokinetic/pharmacodynamic (PK/PD) modelling of the data could not be undertaken following R(-)KTP administration because of chiral inversion to S(+)KTP, but the pharmacodynamic parameters, calculated maximum effect (Emax), concentration producing 50% effect (EC50), Hill's coefficient (N), rate constant of elimination of drug effect from the compartment (KeO) and mean equilibration half-life (t1/2KeO) were determined for S(+)KTP after administration of the racemic mixture as well as the pure compound.

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“…In the first case, water in the gel structure was replaced by ethanol exchange; eventually, both the alcogels were subjected to subsequent supercritical drying. Such delivery systems were designed to obtain fast drug release and rapid analgesic effect onset, potentially useful in postoperative pain,28,29 dental surgery,30 renal, and ureteral acute colic 31,32. The effect of formulation conditions and process variables on drug loading, solid state of the drug inside the produced aerogels, micromeritics, and textural properties (surface area, porous structure, etc.)…”

Section: Introductionmentioning

confidence: 99%