Differential pharmacokinetics and pharmacokinetic/pharmacodynamic modelling of robenacoxib and ketoprofen in a feline model of inflammation

Robenacoxib and ketoprofen are acidic nonsteroidal anti‐inflammatory drugs (NSAIDs). Both are licensed for once daily administration in the cat, despite having short blood half‐lives. This study reports the pharmacokinetic/pharmacodynamic (PK/PD) modelling of each drug in a feline model of inflammation. Eight cats were enrolled in a randomized, controlled, three‐period cross‐over study. In each period, sterile inflammation was induced by the injection of carrageenan into a subcutaneously implanted tissue cage, immediately before the subcutaneous injection of robenacoxib (2 mg/kg), ketoprofen (2 mg/kg) or placebo. Blood samples were taken for the determination of drug and serum thromboxane (Tx)B2 concentrations (measuring COX‐1 activity). Tissue cage exudate samples were obtained for drug and prostaglandin (PG)E2 concentrations (measuring COX‐2 activity). Individual animal pharmacokinetic and pharmacodynamic parameters for COX‐1 and COX‐2 inhibition were generated by PK/PD modelling. S(+) ketoprofen clearance scaled by bioavailability (CL/F) was 0.114 L/kg/h (elimination half‐life = 1.62 h). For robenacoxib, blood CL/F was 0.684 L/kg/h (elimination half‐life = 1.13 h). Exudate elimination half‐lives were 25.9 and 41.5 h for S(+) ketoprofen and robenacoxib, respectively. Both drugs reduced exudate PGE2 concentration significantly between 6 and 36 h. Ketoprofen significantly suppressed (>97%) serum TxB2 between 4 min and 24 h, whereas suppression was mild and transient with robenacoxib. In vivoIC50COX‐1/IC50COX‐2 ratios were 66.9:1 for robenacoxib and 1:107 for S(+) ketoprofen. The carboxylic acid nature of both drugs may contribute to the prolonged COX‐2 inhibition in exudate, despite short half‐lives in blood

The effect of alcohol on the performance of lipase-immobilized enzymatic membrane reactor for esterification of (R,S)-ketoprofen

The effect of alcohols on the performance of lipase-immobilized enzymatic membrane reactor (EMR) for enantioselective esterification of (R,S)-ketoprofen has been studied. In this work, mixed solvent medium was used and the (R)-ketoprofen was reacted with the different alcohols in the presence of immobilized lipase B from Candida antartica, leaving the target product (S)-ketoprofen in its unreacted form. The alcohols involved in the reactions were ethanol, butanol, heptanol and 2-ethoxyethanol. The chain length of alcohol was found to significantly affect the performance of the esterification in EMR. Through the alcohols screening, the esterification reaction using ethanol in EMR showed higher initial rate, conversion, enzyme enantioselectivity, enantiomeric excess of substrate (ees) and enantiomeric excess of product (eep). However the results with butanol showed less inhibition effect on a wider range of temperatur

Effect of Cyclooxygenase(COX)-1 and COX-2 inhibition on furosemide-induced renal responses and isoform immunolocalization in the healthy cat kidney

BACKGROUND: The role of cyclooxygenase(COX)-1 and COX-2 in the saluretic and renin-angiotensin responses to loop diuretics in the cat is unknown. We propose in vivo characterisation of isoform roles in a furosemide model by administering non-steroidal anti-inflammatory drugs (NSAIDs) with differing selectivity profiles: robenacoxib (COX-2 selective) and ketoprofen (COX-1 selective). RESULTS: In this four period crossover study, we compared the effect of four treatments: placebo, robenacoxib once or twice daily and ketoprofen once daily concomitantly with furosemide in seven healthy cats. For each period, urine and blood samples were collected at baseline and within 48 h of treatment starting. Plasma renin activity (PRA), plasma and urinary aldosterone concentrations, glomerular filtration rate (GFR) and 24 h urinary volumes, electrolytes and eicosanoids (PGE(2), 6-keto-PGF1(α,) TxB(2)), renal injury biomarker excretions [N-acetyl-beta-D-glucosaminidase (NAG) and Gamma-Glutamyltransferase] were measured. Urine volume (24 h) and urinary sodium, chloride and calcium excretions increased from baseline with all treatments. Plasma creatinine increased with all treatments except placebo, whereas GFR was significantly decreased from baseline only with ketoprofen. PRA increased significantly with placebo and once daily robenacoxib and the increase was significantly higher with placebo compared to ketoprofen (10.5 ± 4.4 vs 4.9 ± 5.0 ng ml(−1) h(−1)). Urinary aldosterone excretion increased with all treatments but this increase was inhibited by 75 % with ketoprofen and 65 % with once daily robenacoxib compared to placebo. Urinary PGE(2) excretion decreased with all treatments and excretion was significantly lower with ketoprofen compared to placebo. Urinary TxB(2) excretion was significantly increased from baseline only with placebo. NAG increased from baseline with all treatments. Immunohistochemistry on post-mortem renal specimens, obtained from a different group of cats that died naturally of non-renal causes, suggested constitutive COX-1 and COX-2 co-localization in many renal structures including the macula densa (MD). CONCLUSIONS: These data suggest that both COX-1 and COX-2 could generate the signal from the MD to the renin secreting cells in cats exposed to furosemide. Co-localization of COX isoenzymes in MD cells supports the functional data reported here. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12917-015-0598-z) contains supplementary material, which is available to authorized users

Kapasitas jerap niosom terhadap ketoprofen dan prediksi penggunaan transdermal =Niosomes entrapment capacity of prediction transdermal administration ketoprofen ...

Niosomadalah sistem vesikel yang dapat digunakan sebagai pembawa obat lipofilik, hidrofilik dan ampifilik. Ketoprofen adalah salah satu golongan AINSyang sangat sukar larut dalam air dan dapat menyebabkan iritasi lambung pada penggunaan oral. Sistem penghantaran obat secara transdermal sangat penting dikembangkan untuk ketoprofen. Penelitian ini bertujuan untuk memformulasi niosom yang dapat menjerap ketoprofen secara optimal dan dapat menghantarkan ketoprofen melalui rute pemberian transdermal. Penjerapan ketoprofen ke dalam ni\u27Osomdilakukan menggunakan metode hidrasi lapis tipis. Campuran lipid terdiri dari kolesterol dan sorbitan monoester (Span 20, span 60, dan Span 80). Kemampuan niosom menghantarkan ketoprofen melintasi kulit dilakukan dengan mengukur jumlah ketoprofen dalam darah kelinci. Campuran lipid untuk optimasi penjerapan terhadap ketoprofen dipilih berdasarkan jenis sorbitan monoester yang paling banyak menjerap obat. Optimasi penjerapan ketoprofen dilakukan terhadap campuran lipid dengan menaikkan konsentrasi molarnya dengan perbandingan yang tetap 1:1. Penentuan kadar ketoprofen yang mencapai sirkulasi sistemik dilakukan terhadap kelinci jantan dengan mengaplikasikan sediaan gel niosom ketoprofen pada kulit punggung kelinci. Hasil penelitian menunjukkan bahwa niosom dengan penjerapan terbesar terbentuk dari campuran lipid kolesterol dan span 60 dengan penjerapan sebesar 66,16%. Niosom yang terbentuk berukuran 1-6 j.Jm. Niosom mampu menghantarkan ketoprofen mencapai sirkulasi sistemik melalui rute transdermal dengan kadar puncak tercapai pada jam ke-1,5

NOVEL HYDROXYL TERMINATED DENDRIMERS AS POTENTIAL DRUG CARRIERS: SUSTAINED RELEASE, HEMOLYSIS AND CYTOTOXICITY STUDY

Objective: Potential of novel hydroxyl terminated dendrimer generations G1(OH)8, G2(OH)32 and G3(OH)128 as solubility enhancers of model drug ketoprofen was evaluated. G3(OH)128 dendrimer was further explored as the novel carrier for sustained release of ketoprofen. Cytotoxicity and hemolytic potential of G3(OH)128 dendrimer were studied to evaluate toxicity of dendrimer. Methods: Higuchi and Connors method was employed to evaluate improved solubility of ketoprofen at different pH and dendrimer generation. Ketoprofen was loaded into G3(OH)128 dendrimer by inclusion complex method. Ketoprofen loaded dendrimer was characterized by Flourier Transform infrared spectroscopy. Sustained release of ketoprofen from ketoprofen loaded dendrimers was studied and compared to that of free ketoprofen. Cytotoxicity of dendrimers on A-549 cell lines were studied by MTT assay technique. Hemolytic potential of G3 dendrimer was also studied. Results: Solubility of practically insoluble ketoprofen was improved up to 0.77-4.89 mg/ml by dendrimer generations. Solubility of ketoprofen was increased with increase in pH, concentrationand generation number of dendrimer. Ketoprofen was released relatively slowly from ketoprofen loaded dendrimer compared to free ketoprofen. Cytotoxicity and hemolytic assay revealed that dendrimers were less toxic compared to PAMAM dendrimers. Conclusion: Improved solubility of ketoprofen by dendrimer generations, its slow release from G3(OH)128 dendrimer and cytotoxicity and hemolytic assay showed dendrimers have potential as drug carriers. Keywords: Triazine Based Dendrimer, Sustained Release, Cytotoxicity, Hemolysis, Ketoprofen, Encapsulation

<i>In vitro</i> and <i>in vivo</i> studies of artichoke extract (<i>Cynara scolymus</i> L.) as ketoprofen skin penetration enhancer

In this study, the enhancing effect of artichoke extract containing cynaropicrin on the in vitro and in vivo percutaneous absorption of ketoprofen from gels has been investigated

A NANOSCALE DENDRITIC MACROMOLECULES BASED ON ETHANE 1,2-DIAMINE AS POTENTIAL DRUG CARRIERS FOR NSAIDS: SYNTHESIS, CHARACTERIZATION AND APPLICATIONS

Objective: The present work deals with the objective of development and characterization of novel dendritic macromolecules as solubility enhancer and carrier for sustained release of Ketoprofen. Cytotoxicity and hemolytic assay of dendritic macromolecules were also estimated as an objective to evaluate its toxicity and biocompatibility. Methods: Dendritic macromolecules were synthesized using divergent method. Synthesized macromolecules were characterized by spectral techniques such as FTIR, 1H-NMR, 13C-NMR electro-spray ionization mass spectrometry and elemental analysis. Enhanced aqueous solubility of ketoprofen was evaluated with respect to pH, generation number and concentration of dendrimer using Higuchi and Connors method. Sustained release of ketoprofen from ketoprofen loaded dendrimers was measured and compared with that of free ketoprofen. Hemolytic assay and cytotoxicity of G3 dendrimer on A-549 cell lines were studied to evaluate toxicity and biocompatibility of dendrimer. All dendritic macromolecules were fully characterized by spectral techniques. Results: Solubility study revealed that aqueous solubility of ketoprofen by dendrimer increased with increase in pH, concentration and generation of dendrimer. Ketoprofen was released slowly from ketoprofen loaded dendrimer compared to that of free ketoprofen. Dendritic macromolecules were less cytotoxic and showed less hemolytic potential. Conclusion: It can be concluded that dendrimer have high potential as carriers and solubility enhancers of hydrophobic drug. Keywords: Triazine based dendrimer, Ketoprofen, Drug Carrier, Cytotoxicity, Hemolysis

Correlations between electrochemical behaviors and DNA photooxidative properties of non-steroïdal anti-inflammatory drugs and their photoproducts

Alkali-labile lesion to DNA photosensitized, via an electron transfer mechanism, by three non-steroidalanti-inflammatorydrugs (NSAIDs), ketoprofen, tiaprofenic acid and naproxen and their photoproducts during drug photolysis, was investigated using 32P-end labelled synthetic oligonucleotide. These photooxidative damages were correlated with the photophysical and electrochemicalproperties of drugs, appearing as the photosensitizer PS. Photophysical studies provided the excited state energies of the photosensitizer while their redox potentials and the relative stabilities of the PSradical dot− radical-anions were determined by cyclic voltammetry. On the basis of these data, we have calculated the Gibbs energy of photoinduced electron-transfer and evaluated the exergonicity of the oxidative photodamage. Moreover, kinetic control may be invoked according to the stabilities of PSradical dot−. Applied to this NSAIDs family, the photoxidative damages through electron transfer mechanism were analyzed and a good correlation with photoredox and photobiological properties was established