Pharmacokinetics and anti-inflammatory effect of naproxen in rats with acute and subacute spinal cord injury.

Previous reports have warned about the influence of spinal cord injury (SCI) on the pharmacokinetics of various drugs. However, the role of SCI in the efficacy and safety of pharmacotherapy remains unknown. Thereby, our aim was to explore the role of SCI on pharmacokinetics and anti-inflammatory effect of naproxen in response to a local inflammatory challenge. Rats received a severe contusive SCI at T9 or sham injury. Pharmacokinetics of a single intravenous dose of naproxen (10 mg kg-1) was studied at days 1 and 15 post-surgery. For the anti-inflammatory assessment, carrageenan was subcutaneously injected in forelimb and hindlimb paws at the same post-surgery periods, and naproxen efficacy was evaluated measuring paw swelling. Plasma protein concentrations and body weight changes were also determined. Plasma naproxen levels and pharmacokinetic parameters were unchanged by acute injury, but subacute injury generated alterations in volume of distribution, clearance, and bioavailability, resulting in significantly reduced plasma naproxen concentrations, in the absence of changes in plasma proteins. Assessment of naproxen anti-inflammatory activity during the acute stage of injury could not be determined because of carrageenan failure to elicit swelling. During the subacute stage, naproxen anti-inflammatory effect on forelimbs (above injury) was similar to that observed in sham-injured animals, while it was almost absent in paralyzed hindlimbs. Under conditions of SCI and peripheral inflammation, pharmacokinetics and anti-inflammatory activity of naproxen vary according to post-injury timing and neurological status of the assessed region.

Effective method for the detection of piroxicam in human plasma using HPLC.

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used by the general population to alleviate inflammation and pain after oral surgeries. Piroxicam is among the most commonly used NSAIDs and excels in controlling pain, swelling, trismus and other common symptoms of inflammation. This study aimed to evaluate different concentrations of piroxicam and its major metabolite, 5'-hydroxypiroxicam, in human plasma samples over time using high performance liquid chromatography (HPLC) after liquid-liquid extraction. Briefly, 10 volunteers participated in this study after approval by the Ethics Committee of Bauru School of Dentistry, Universidade de São Paulo - USP, Brazil. Volunteers received a single dose oral of piroxicam (20 mg) and had blood collected at various times following an established protocol. The methodology of liquid-liquid extraction was effective for determining concentrations of piroxicam in plasma using HPLC in 10 out of 10 volunteers while 5'-hydroxypiroxicam was only detected in 2 out of 10 volunteers.

Enantioselective analysis of etodolac in human plasma by LC-MS/MS: Application to clinical pharmacokinetics.

Etodolac is a non-steroidal anti-inflammatory drug with preferential inhibition of cyclooxigenase-2 and is widely used in the management of pain in patients with inflammatory arthritis. Etodolac is available as a racemic mixture of (-)-(R)-Etodolac and (+)-(S)-Etodolac; cyclooxigenases inhibition is attributed to (+)-(S)-Etodolac. According to our knowledge, this is the first method for determination of etodolac enantiomers in plasma using LC-MS/MS. Plasma extraction were performed with 25µL of plasma and 1mL of n-hexane:ethyl acetate (95:5); racemic ibuprofen was used as internal standard. Resolution of enantiomers were performed in a Chiralcel(®)OD-H column; deprotonated [M-H](-) and their respective ion products were monitored at transitions of 286>242 for etodolac enantiomers and 205>161 for ibuprofen. The quantitation limit was 3.2ng/mL for both enantiomers in plasma. The method was applied to study the pharmacokinetics of etodolac enantiomers after the administration of a 300 and 400mg dose of racemic drug to a healthy volunteer. Analysis of plasma samples showed higher plasma concentration of (-)-(R)-Etodolacfor both doses (300mg dose: AUC(0-∞)49.80 versus 4.55ugh/mL;400mg dose: AUC(0-∞) 63.90 versus 6.00ugh/mL) with an (R)-(+)/(S)-(-) ratio of approximately 11.

Stereoselective Pharmacokinetics of Ketoprofen After Oral Administration of Modified-Release Formulations in Caucasian Healthy Subjects.

BACKGROUND AND OBJECTIVES: Ketoprofen, a potent nonsteroidal anti-inflammatory drug, is clinically administered as a racemic mixture. One of the possible metabolism routes of ketoprofen is the inversion of the R- to S-enantiomer in the gastrointestinal tract. Ketoprofen, as a weak acid drug, might undergo recirculation through pancreatic/intestinal juices. The aim of the work was to investigate if a plasma-gastrointestinal tract recirculation of ketoprofen could explain its R-to-S chiral inversion after the oral administration of two modified-release formulations: a gastro-resistant delayed-release tablet (Reference) and an extended-release-plus-immediate-release bilayer tablet (Test). METHODS: Sixteen healthy Caucasian volunteers (eight women and eight men) participated in a ketoprofen bioequivalence study. Both formulations were administered with and without food. In both cases, standard meals were given throughout the experiment. R- and S-enantiomers were measured separately using a validated HPLC-UV chiral method. Mean concentration-time profiles of ketoprofen enantiomers in plasma were obtained for men and women. Area under the plasma concentration-time curve, maximum ketoprofen plasma concentration, and time-to-peak were also computed for both isomers, both modes of administration, and both sexes. S/R concentration ratio was assessed as an indicator of enantiomer chiral inversion rate. RESULTS: Differences in the pharmacokinetics of S- and R-ketoprofen enantiomers were found after the Test administration. S-Ketoprofen presented a lower plasma exposure compared to R-enantiomer. However, the S/R concentration ratio increased 1 h (in men) and 2 h (in women) after meal intakes. This was related to pancreatic and/or intestinal and/or biliary secretions of the drug, followed by reabsorption and conversion of the R- to the S-isomer. The lower intestinal pH reported for men would lead to a higher oral bioavailability of the Test formulation and a higher reabsorption of both ketoprofen isomers in this sex. Hence, a higher rise of the S/R concentration ratio could be observed in men. No significant differences between isomers exposure were detected in both sexes after the Reference administration. Different lag times were observed after fed and fasting administration of this formulation; however, drug absorption coincided with food ingestion. Then, drug recirculation affected the S/R ratio from the beginning of drug exposure, minimizing the difference between isomers disposition. CONCLUSIONS: R-to-S conversion rate could be mainly associated with several passages of the drug through the intestinal mucosa. The concentration-time profiles of ketoprofen in plasma after the administration of both formulations evidenced R-to-S conversion of recirculating drug following meal intakes.

Effective method for the detection of piroxicam in human plasma using HPLC

Abstract Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used by the general population to alleviate inflammation and pain after oral surgeries. Piroxicam is among the most commonly used NSAIDs and excels in controlling pain, swelling, trismus and other common symptoms of inflammation. This study aimed to evaluate different concentrations of piroxicam and its major metabolite, 5'-hydroxypiroxicam, in human plasma samples over time using high performance liquid chromatography (HPLC) after liquid-liquid extraction. Briefly, 10 volunteers participated in this study after approval by the Ethics Committee of Bauru School of Dentistry, Universidade de São Paulo - USP, Brazil. Volunteers received a single dose oral of piroxicam (20 mg) and had blood collected at various times following an established protocol. The methodology of liquid-liquid extraction was effective for determining concentrations of piroxicam in plasma using HPLC in 10 out of 10 volunteers while 5'-hydroxypiroxicam was only detected in 2 out of 10 volunteers.

Oxidative stress and inflammation in obesity after taurine supplementation: a double-blind, placebo-controlled study.

PURPOSE: Some researchers found decreased levels of plasma taurine in obese subjects and animals, and reduced expression of an important enzyme of taurine synthesis. These evidences, coupled with the metabolic imbalance of obesity and the possible anti-inflammatory and antioxidant effects of taurine, highlighted the use of taurine as a supplement in obesity treatment. The aim of the present study was to investigate whether taurine supplementation, associated with nutritional counseling, modulates oxidative stress, inflammatory response, and glucose homeostasis in obese women. METHODS: A randomized double-blind placebo-controlled study was conducted with 16 women with obesity diagnosis and 8 women in the normal weight range. The obese volunteers were matched by age and body mass index and randomly assigned to either the placebo (3 g/day starch flour) or taurine (3 g/day taurine) group. The study lasted 8 weeks, and the experimental protocol included nutritional assessment and determination of plasma sulfur amino acids, insulin, and adiponectin, serum glycemia, and markers of inflammatory response and oxidative stress. RESULTS: Plasma taurine levels were significantly decreased (41%) in the obese volunteers. Both the placebo and taurine groups showed significant reduction in weight (3%), with no differences between groups. Different from placebo, taurine-supplemented group showed significant increase in plasma taurine (97%) and adiponectin (12%) and significant reduction in the inflammatory marker hs-C-reactive protein (29%) and in the lipid peroxidation marker thiobarbituric acid reactive substances (TBARS) (20%). CONCLUSIONS: Eight weeks of taurine supplementation associated with nutritional counseling is able to increase adiponectin levels and to decrease markers of inflammation (high-sensitivity C-reactive protein) and lipid peroxidation (TBARS) in obese women.

Prevention of liver ischemia reperfusion injury by a combined thyroid hormone and fish oil protocol.

Several preconditioning strategies are used to prevent ischemia-reperfusion (IR) liver injury, a deleterious condition associated with tissue resection, transplantation or trauma. Although thyroid hormone (T3) administration exerts significant protection against liver IR injury in the rat, its clinical application is controversial due to possible adverse effects. Considering that prevention of liver IR injury has also been achieved by n-3 polyunsaturated fatty acid (n-3 PUFA) supplementation to rats, we studied the effect of n-3 PUFA dietary supplementation plus a lower dose of T3 against IR injury. Male Sprague-Dawley rats receiving fish oil (300 mg/kg) for 3 days followed by a single intraperitoneal dose of 0.05 mg T3/kg were subjected to 1 h of ischemia followed by 20 h of reperfusion. Parameters of liver injury (serum transaminases, histology) and oxidative stress (liver contents of GSH and oxidized proteins) were correlated with fatty acid composition, NF-κB activity, and tumor necrosis factor-α (TNF-α) and haptoglobin expression. IR significantly modified liver histology; enhanced serum transaminases, TNF-α response or liver oxidative stress; and decreased liver NF-κB activity and haptoglobin expression. Although IR injury was not prevented by either n-3 PUFA supplementation or T3 administration, substantial decrease in liver injury and oxidative stress was achieved by the combined protocol, which also led to increased liver n-3 PUFA content and decreased n-6/n-3 PUFA ratios, with recovery of NF-κB activity and TNF-α and haptoglobin expression. Prevention of liver IR injury achieved by a combined protocol of T3 and n-3 PUFA supplementation may represent a novel noninvasive preconditioning strategy with potential clinical application.

Preparation, in vitro characterization and in vivo release of naproxen loaded in poly-caprolactone nanoparticles.

Naproxen was loaded in poly-caprolactone (PCL) nanoparticles as an implantable sustained release system to prolong its anti-inflammatory activity. Naproxen-loaded nanoparticles were produced with the following characteristics: Nanometric size (< 300 nm), negative zeta potential, low polydispersity index (< 0.1), satisfactory encapsulation efficiency, low water content (< 1%), and spherical shape. In vitro naproxen release profile was sustained and the kinetic followed the Higuchi model. The PCL nanoparticles containing about 12.5% (w/w) of the naproxen (sample A3) was chosen for complementary studies of stability and in vivo release in rats. Nanoparticles did not suffer alteration during stability studies. In vivo release was sustained by one month. Thus, nanoparticles showed potential to act as an implantable sustained release system for chronic inflammatory diseases use.

Effects of 15d-PGJ2-loaded poly(D,L-lactide-co-glycolide) nanocapsules on inflammation.

BACKGROUND AND PURPOSE: The PPAR-γ agonist 15d-PGJ2 is a potent anti-inflammatory agent but only at high doses. To improve the efficiency of 15d-PGJ2, we used poly(D,L-lactide-co-glycolide) nanocapsules to encapsulate it, and function as a drug carrier system. The effects of these loaded nanocapsules (15d-PGJ2-NC) on inflammation induced by different stimuli were compared with those of free 15d-PGJ2. EXPERIMENTAL APPROACH: Mice were pretreated (s.c.) with either 15d-PGJ2-NC or unloaded 15d-PGJ2 (3, 10 or 30 µg·kg⁻¹), before induction of an inflammatory response by i.p. injection of either endotoxin (LPS), carrageenan (Cg) or mBSA (immune response). KEY RESULTS: The 15d-PGJ2-NC complex did not display changes in physico-chemical parameters or drug association efficiency over time, and was stable for up to 60 days of storage. Neutrophil migration induced by i.p. administration of LPS, Cg or mBSA was inhibited by 15d-PGJ2-NC, but not by unloaded 15d-PGJ2. In the Cg model, 15d-PGJ2-NC markedly inhibited serum levels of the pro-inflammatory cytokines TNF-α, IL-1ß and IL-12p70. Importantly, 15d-PGJ2-NC released high amounts of 15d-PGJ2, reaching a peak between 2 and 8 h after administration. 15d-PGJ 2 was detected in mouse serum after 24 h, indicating sustained release from the carrier. When the same concentration of unloaded 15d-PGJ2 was administered, only small amounts of 15d-PGJ2 were found in the serum after a few hours. CONCLUSIONS AND IMPLICATIONS: The present findings clearly indicate the potential of the novel anti-inflammatory 15d-PGJ2 carrier formulation, administered systemically. The formulation enables the use of a much smaller drug dose, and is significantly more effective compared with unloaded 15d-PGJ2.

The disposition of free and niosomally encapsulated Rac-flurbiprofen in dairy bovines.

Pharmacokinetic parameters were established for flurbiprofen (FBP) after intravenous (i.v.) administration (0.5 mg/kg) of niosomal and nonniosomal formulations in dairy cattle. Niosomes of FBP showed a drug loading of 92.0 +/- 0.7% and the intravenous administration of the FBP niosomes to dairy cattle did not produce any immunological reaction associated to niosomal components. Niosomal FBP was slowly eliminated from plasma and mean residual time (MRT) and AUC(0-->t) and t (1/2) values were significantly higher than those for non niosomal FBP formulations. The results presented in this study indicate that the long circulation of FBP niosomes offers a potential application for improving the pharmacokinetic parameters of short half-life drugs for clinical use. Niosomes offer new promising perspectives of drug delivery modules in bovine therapeutics.

Relative bioavailability of two oral formulations of piroxicam 20 mg: a single-dose, randomized-sequence, open-label, two-period crossover comparison in healthy Mexican adult volunteers.

BACKGROUND: Piroxicam is an NSAID indicated for the treatment of rheumatoid diseases. Although there are generic formulations of oral piroxicam marketed in Mexico, a literature search did not identify published data concerning the bioavailability of these formulations in the Mexican population. OBJECTIVES: The aims of this study were to determine the bioequivalence of a generic (test) and a reference formulation of oral piroxicam 20 mg and to generate data regarding the oral bioavailability of this drug in a Mexican population. METHODS: This single-dose, randomized-sequence, open-label, 2-period crossover study was conducted in healthy Mexican adult volunteers. Subjects were randomly assigned to receive the test formulation followed by the reference formulation, or vice versa, with a 15-day washout period between doses. Study drugs were administered after a 10-hour overnight fast. For pharmacokinetic analysis, blood samples were drawn at 0 (baseline), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 120, and 168 hours after administration. Plasma concentrations of piroxicam were determined using HPLC. The test and reference formulations were to be considered bioequivalent if the 90% CIs for the geometric mean test/reference ratios were within a predetermined range of 80% to 125%. Tolerability was determined using clinical assessment, monitoring of vital signs, laboratory analysis, and subject interviews regarding adverse events (AEs). RESULTS: A total of 28 subjects were enrolled (15 men, 13 women; mean [SD] age, 24 [4] years [range, 19-35 years]; weight, 63.0 [8.9] kg [range, 47.5-81.9 kg]; height, 165 [10] cm [range, 149-179 cm]; and body mass index, 23.2 [1.4] kg/m(2) [range, 20.6-26.0 kg/m(2)]). The 90% CIs for piroxicam C(max), AUC(0-infinity), and AUC(0-infinity)) were 89.98% to 101.04%, 91.46% to 101.19%, and 93.51% to 105.86%, respectively. Thirteen subjects reported a total of 17 AEs during the study. None of the AEs were considered serious or related to the administered formulations. The most common AE was local postvenipuncture ecchymosis, reported in 8 subjects (28.6%). CONCLUSIONS: In this small study in healthy Mexican adult subjects, a single 20-mg dose of the test formulation of orally administered piroxicam met the regulatory requirements to assume bioequivalence, based on the rate and extent of absorption. Both formulations were well tolerated. Mexican national registry code: CE-PEC.0875.

Pharmacokinetic of diclofenac in the presence and absence of glibenclamide in the rat.

PURPOSE: There is evidence that the sulfonylurea antidiabetic agent glibenclamide reduces the analgesic action of non-steroidal anti-inflammatory drugs (NSAIDs), opioids and neuromodulators in animal models. Therefore, in view of the vast clinical uses and interactions of NSAIDs with commonly used therapeutic agents, the interaction of the NSAID diclofenac and glibenclamide was investigated about pharmacokinetic profile and antinociceptive effect in rats. METHODS: Antinociception was assessed using the formalin test. Fifty microliters of diluted formalin was injected s.c. into the dorsal surface of the right hind paw. Nociceptive behavior was quantified as the number of flinches of the injected paw during 60 min after injection. Rats were treated with oral administration of vehicle or increasing doses of diclofenac (3-18 mg/kg) before formalin injection. To determine the pharmacodynamic interaction between diclofenac and glibenclamide, the effect of oral administration of glibenclamide (1-30 mg/kg) on the antinociceptive effect induced by diclofenac (18 mg/kg, p.o.) was assessed. To evaluate the pharmacokinetic interaction between diclofenac and glibenclamide, the effect of glibenclamide (10 mg/kg, p.o.) on the pharmacokinetic of diclofenac (18 mg/kg, p.o.) was studied in the rat. Blood samples were taken over 8 h and analyzed using a validated high-performance liquid chromatography method to generate the pharmacokinetic profile of diclofenac. Pharmacokinetic parameters were estimated using noncompartmental analysis. RESULTS: Systemic administration of diclofenac produced a dose-dependent antinociceptive effect in the formalin test. Systemic treatment with glibenclamide prevented diclofenac-induced antinociception. In pharmacokinetic interaction study, no significant (P>0.05) change in diclofenac concentration-time profiles in the presence of glibenclamide was detected. CONCLUSION: The experimental findings suggest that systemic glibenclamide is able to block the diclofenac-induced antinociception in the rat formalin test. Besides, this antagonism was not produced by diminution in the bioavailability of diclofenac. Likewise, the validated assay had sufficient accuracy and precision for pharmacokinetic determination of diclofenac in the rat.

Quantitation of nimesulide in human plasma by high-performance liquid chromatography with ultraviolet absorbance detection and its application to a bioequivalence study.

A rapid and simple high-performance liquid chromatography-reversed phase (HPLC-RV) method with ultraviolet detection (258 nm) was developed and validated for the quantitation of nimesulide (CAS 51803-78-2) in human plasma. After the plasma samples were extracted with 6.0 ml of dichloromethane containing the internal standard phenacetin 2 microg/ml in methanol, the analysis of the nimesulide level in the plasma samples was carried out using a reverse phase Supelcosil LC-18 (15 cm x 4.6 mm x 5 pm) column. The chromatographic separation was accomplished with an isocratic mobile phase consisting of a mixture of methanolphosphate buffer (pH 3.5; 0.01 mol/l) (55:45, v/v). The inter-assay accuracy ranged from 103.4 to 113.2%, while intra-day ranged from 105.6 to 117.5%. The inter-assay precision ranged from 11.7 to 14.6%, while intra-assay ranged from 3.2 to 9.5%. The recovery of nimesulide was determined as part of the assay validation process and was excellent. The linearity of the nimesulide curves ranged from 0.20 to 15.0 microg/ml (y = 0.3857-0.0081, r = 0.9975). Short-term stability showed that nimesulide is stable in plasma for at least 24 h at room temperature, while long-term stability studies showed that nimesulide is stable in plasma for at least 180 days when stored at -20 degrees C. This validated method was successfully applied to the bioequivalence study of nimesulide in tablets in healthy volunteers.

Oral pharmacokinetics of meloxicam in the rat using a high-performance liquid chromatography method in micro-whole-blood samples.

The pharmacokinetics of meloxicam, a potent analgesic and antiinflammatory drug used in several rheumatic diseases, has been studied in rats that received oral doses of 3.2, 5.6 or 10 mg/kg of meloxicam. Blood samples were obtained at selected times during 24 h after administration, and meloxicam concentrations were determined by a validated high-performance liquid chromatography (HPLC) method, using micro-whole-blood samples, developed in our laboratory. After administration of meloxicam, blood concentrations increased reaching a dose-dependent maximal concentration in about 2 h. Then, concentrations decayed with a half-life of 9 h. An increase in C(max) and AUC as a function of the dose was observed, and no statistically significant difference was observed in AUC/dose or C(max)/dose between doses. However, linearity could not be concluded because of the wide variability observed.

Pharmacokinetics and tissue residues of an oxytetracycline/diclofenac combination in cattle.

Eight male cattle were given a combined dose containing 20 mg/kg oxytetracycline and 0.5 mg/kg diclofenac intramuscularly. Blood samples were drawn at different times until 168 h after administration. Two experimental animals were slaughtered by humane means at weekly intervals up to 28 days after administration. Samples of muscle, injection zone tissue, liver, kidney and fat were obtained. Oxytetracycline and diclofenac concentrations were determined by high performance liquid chromatography. Kinetic analysis was performed by linear regression using the CSTRIP programme. Plasma oxytetracycline concentration showed a maximum (Cmax) of 3.89 +/- 1.48 microg/ml and a prolonged elimination half-life (T1/2beta: 47.73 +/- 18.33 h). The diclofenac plasma profile showed high Cmax (577.62 +/- 238.40 ng/ml), and its T1/2beta was also prolonged (30.48 +/- 9.42 h). Oxytetracycline concentrations were measurable in liver and adipose tissue until day 21 after administration, but all tissue samples were negative for diclofenac at 21 days. The long elimination half-life of diclofenac was an unexpected finding; its T1/2beta in humans is 1.1 h.

Comparative bioavailability of two oral suspensions of naproxen sodium.

The bioavailability of naproxen sodium (CAS 26159-34-2) after administration of two oral suspensions, reference or test (Pactens), was compared in 24 healthy subjects. The volunteers received an oral dose of 250 mg (10 ml) in two separate sessions under fasting conditions according to a randomized cross-over design and blood samples were obtained at selected times for a period of 72 h. Plasma samples were analyzed by a high-performance liquid chromatographic method for determination of naproxen. Individual plasma concentration against time curves were constructed and pharmacokinetic parameters were obtained by non-compartmental techniques. The parameters obtained (mean +/- S.E.M.) were: C(max) 43.93 +/- 1.83 and 44.91 +/- 2.15 microg/ml, t(max) 2.38 +/- 0.21 and 1.83 < or = 0.19 h, AUC(72 h) 721.73 +/- 18.47 and 722.55 +/- 19.07 microg x h/ml for reference and test formulations, respectively. Maximal concentration, AUC(72 h) and AUC(infinity). were log transformed and compared by analysis of variance and ratios; in addition, 90% confidence limits were obtained. As confidence limits were included in the 80-125% range and the probability of exceeding these intervals was always lower than 0.05, it is concluded that the formulations tested are bioequivalent.

Pharmacokinetic parameters of (R)-(-) and (S)-(+)-flurbiprofen in dairy bovines.

The aim of the study was to evaluate the pharmacokinetics of flurbiprofen (FBP) in different age groups and physiological status groups in dairy cattle. Ten Argentine Holstein bovines were divided into three different groups: 3 cows in early lactation, 3 cows in gestation and 4 newborn calves. Based on previous experience, all the animals received racemic FBP (50:50) at a dose of 0.5 mg/kg by intravenous administration. Blood samples were taken at predetermined times after administration of flurbiprofen. Plasma enantiomer concentrations were measured by HPLC. Total body clearance (ClB) of (S)-(+)-FBP was higher in calves than in cows (114.5, 136.4, 121.4, 128.9 microg/ml vs 22.0, 24.2, 46.5 microg/ml and 27.6, 25.3, 34.6 microg/ml). In calves the disposition kinetics showed stereoselective behaviour. Area under the concentration-time curve (AUC) was higher and Cl(B) and steady-state volume of distribution (V(ss)) were lower for (R)-(-)-FBP than for (S)-(+)-FBP. In cows, stereoselectivity was observed in Cl(B) and elimination half-life (t(1)/2) only in the early lactation group. In this study, enantioselective metabolic behaviour of FBP under the physiological situations studied was found. Hence, it is possible that both enantiomers of flurbiprofen may contribute to the drug's therapeutic effects, but further studies with the administration of separate enantiomers will be required to elucidate their metabolism.

Losartan attenuates the antimigratory effect of diclofenac in spontaneously hypertensive rats.

Many patients with hypertension, particularly elderly patients, take nonsteroidal antiinflammatory drugs (NSAIDs) and antihypertensive agents. However, few studies describe the effect of the association of antihypertensive agents with NSAIDs on inflammatory response in hypertension. To investigate this, spontaneously hypertensive rats (SHRs) were treated with either diclofenac alone or diclofenac combined with losartan (an AT1 angiotensin II antagonist). The leukocyte-endothelial interaction was then observed using intravital microscopy. Blood pressure of SHR (169.6+/-3.6) was increased by diclofenac (186.4+/-2.9), reduced by losartan (152.6+/-3.5), and reduced by the combination of the 2 (158.9+/-3.7). All the treatments tested reduced the number of rollers, adherent and migrated leukocytes, and the expression of endothelial intercellular adhesion molecule-1 and P-selectin. The association of losartan reduced the effect of diclofenac on leukocyte migration. Neither treatment tested increased the venular shear rate or modified the venular diameters, number of circulating leukocytes, and L-selectin expression on granulocytes. The reduction of CD11/CD18 expression induced by diclofenac alone was hindered by losartan. A pharmacokinetic interference between losartan and diclofenac was ruled out since no significant differences were observed in the plasma concentrations of each drug when they were associated. In conclusion, although diclofenac does not interfere with the losartan antihypertensive effect, losartan attenuates the effect of diclofenac has on leukocyte behavior and expression of adhesion molecules. Losartan has an antimigratory effect, reducing leukocyte migration by reducing ICAM-1 and P-selectin expression. Losartan may hinder the full expression of the antimigratory effect of diclofenac.