Rapid identification of potential nonsteroidal anti-inflammatory drug overdose-induced liver toxicity and prediction of follow-up exposure: Integrating bioanalytical and population pharmacokinetic assay.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most frequently used drugs that can cause liver toxicity. The aim of this study was to integrate bioanalytical and population pharmacokinetic (PopPK) assay to rapidly screen and quantify the concentrations of NSAIDs in plasma and monitor clinical safety. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the simultaneous quantification of acetaminophen (APAP), flurbiprofen (FLB), aspirin (ASP), and ibuprofen (IBP), four commonly used NSAIDs. The PopPK model of the signature toxicant was analyzed based on the published literature. The LC-MS/MS method was successfully validated and applied to determine NSAID concentrations in patient plasma samples. APAP, ASP, and IBP data were best fitted using a one-compartment model, and FLB data were best fitted using a two-compartment model. Bootstrapping and visual predictive checks suggested that a robust and reliable pharmacokinetic model was developed. A fast, simple, and sensitive LC-MS/MS method was developed and validated for determining APAP, FLB, ASP, and IBP in human plasma. Combined with the PopPK model, this method was applied to rapidly analyze the concentrations of NSAIDs in clinical samples from patients presenting to the emergency department with acute liver dysfunction and monitored NSAIDs clinical safety.

Pharmacokinetic evaluation of oral deracoxib in geese (Anser anser domesticus).

The integration of pain management in veterinary practice, driven by heightened animal welfare concerns, extends to avian species where subtle and nonspecific behavioral signs pose challenges. Given that safety concerns with classical NSAIDs highlight the need for more targeted alternatives in birds, this study explores the pharmacokinetic (PK) properties of Deracoxib (DX), a COX-2 selective NSAID approved for use in dogs, following a single oral administration in geese. Six healthy female geese received 4 mg/kg DX. Blood was drawn from the left wing vein to heparinized tubes at 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, and 24 h. Plasma DX concentrations were measured using HPLC coupled to an UV detector, and the data were pharmacokinetically analyzed using PKanalix™ software in a non-compartmental approach. The results indicated a terminal half-life of 6.3 h and a Tmax of 1 h, with no observed adverse effects. While refraining from claiming absolute safety based on a single dose, it is worth highlighting that further safety studies for DX in geese are warranted, suggesting a possibility for intermittent use. In addition, drawing conclusions on efficacy and suitability awaits further research, particularly in understanding COX-2 selectivity and protein binding characteristics specific to geese.

PHARMACOKINETIC PROFILES OF ORAL PHENYLBUTAZONE, MELOXICAM, AND FIROCOXIB IN SOUTHERN BLACK RHINOCEROS (DICEROS BICORNIS MINOR).

The pharmacokinetic profile of selected NSAIDs in southern black rhinoceros (Diceros bicornis minor) were studied. Phenylbutazone (PBZ), meloxicam (MEL), and firocoxib (FIR) were administered orally to five captive, black rhinoceros, and blood was collected at predetermined time points for NSAID quantification and noncompartmental pharmacokinetic (PK) analysis. Phenylbutazone 4.0 mg/kg PO q12h for three doses, MEL 0.3 mg/kg PO q24h administered twice, and a single oral dose of FIR 0.1 mg/kg, were tested with a minimum washout time of 2 wk. PBZ reached a median (range) peak concentration (Cmax) of 9.42 (2.74-11.5) g/ml at a mean (range) time (Tmax) of 6.00 (4.00 to >12.00) h, and the median (range) elimination half-life (T1/2) was 6.07 (3.95-6.49) h. Phenylbutazone pharmacokinetic parameters for black rhinoceros in this study were similar to domestic horses. Meloxicam reached a median (range) Cmax of 0.576 (0.357-0.655) µg/ml at a median (range) time (Tmax) of 6.00 (4.00-12.00) h; the median (range) T1/2 of MEL was 14.0 (12.4-17.9) h. These results demonstrate that once-daily administration of MEL at 0.3 mg/kg resulted in a serum concentration of greater than 0.200 µg/ml from 2 to 24 h in four animals, which is within the analgesic range (0.200-0.400 µg/ml) for this drug in other species postulated by other studies. A single dose of firocoxib (0.1 mg/kg) reached a median (range) peak concentration (Cmax) of 15.7 (9.65-17.3) ng/ml at a median (range) Tmax of 4.00 (4.00-6.00) h. The median (range) elimination T1/2 of FIR was 4.96 (4.47-6.51) h, which is faster than in the horse. The data suggest that extrapolation from equine FIR dosage recommendations is inappropriate for black rhinoceros.

3D flower-liked Fe3O4/C for highly sensitive magnetic dispersive solid-phase extraction of four trace non-steroidal anti-inflammatory drugs.

A low cost-effective and simple synthesis method was adopted to acquire three-dimensional flower-like structure Fe3O4/C that has large specific area, suitable pore structure and sufficient saturation magnetism. The obtained Fe3O4/C exhibits outstanding preconcentration ability and was applied to extracting non-steroidal anti-inflammatory drugs from complex environmental and biological samples. The parameters of magnetic solid-phase extraction were optimized by univariate and multivariate methods (Box-Behnken design). The high degree of linearity from 2.5 to 1000.0 ng mL-1 (R2 ≥ 0.9976), the limits of detection from 0.25 to 0.5 ng mL- 1 (S/N = 3), and the limits of quantitation from 1.0 to 2.0 ng mL- 1 (S/N = 10) were yielded by adopting this novel method after the optimization. Moreover, the recoveries of non-steroidal anti-inflammatory drugs from 89.6 to 107.0% were acquired in spiked plasma, urine and lake samples. In addition, the adsorption of non-steroidal anti-inflammatory drugs on Fe3O4/C was explored by adsorption isotherms and kinetic studies. Furthermore, the adsorption mechanism for non-steroidal anti-inflammatory drugs by Fe3O4/C was proposed, which was hydrogen bonding and π-π interaction between non-steroidal anti-inflammatory drugs and Fe3O4/C. Graphical abstract.

PHARMACOKINETICS OF ORALLY ADMINISTERED FLUNIXIN MEGLUMINE IN AFRICAN (LOXODONTA AFRICANA) AND ASIAN (ELEPHAS MAXIMUS) ELEPHANTS.

Flunixin meglumine is the most commonly used nonsteroidal anti-inflammatory drug used to treat elephants; however, no pharmacokinetic study for flunixin has yet been conducted in these species, and dosages used range widely. Pharmacokinetic parameters of flunixin were determined in African (Loxodonta africana) and Asian (Elephas maximus) elephants after single-dose oral administration of 0.8 and 1.5 mg/kg flunixin paste in each species. Elephant compliance to oral administration of banamine was occasionally challenging, especially among older, female African elephants. After administration of 0.8 mg/kg flunixin, mean serum concentrations peaked in approximately 1.3 hr at 2.1 ± 0.8 µg/ml for Asian (n = 8) and 2.8 hr at 2.5 ± 0.7 µg/ml for African (n = 8) elephants. Dosages of 1.5 mg/kg flunixin resulted in mean serum concentration peaks of 7.2 ± 1.5 µg/ml in Asian elephants (n = 7) and 4.4 ± 0.7 µg/ml in African elephants (n = 6). However, multiple-dose trials using 1.1 mg/kg flunixin resulted in peak serum concentrations that were again less in Asian than African elephants (2.7 µg/ml versus 4.4 µg/ml, respectively). Asian elephants consistently had lower time to maximal concentration, greater area under the curve, and longer mean residence times compared with African elephants. In other species, flunixin is excreted unchanged primarily via hepatic routes with small amounts in the urine. Asian elephants may engage in some level of enterohepatic recycling of flunixin, as was previously reported for phenylbutazone. This study supports that different oral dosing regimens should be used for Asian (1.0 mg/kg SID) and African (1.2 mg/kg SID) elephants, and oral administration techniques used should ensure complete dosage delivery.

PHARMACOKINETIC BEHAVIOR OF MELOXICAM IN LOGGERHEAD (CARETTA CARETTA), KEMP'S RIDLEY (LEPIDOCHELYS KEMPII), AND GREEN (CHELONIA MYDAS) SEA TURTLES AFTER SUBCUTANEOUS ADMINISTRATION.

The objective of this study was to determine the pharmacokinetics of a single dose of meloxicam administered subcutaneously (SQ) to three species of sea turtles: loggerheads (Caretta caretta), Kemp's ridley (Lepidochelys kempii), and greens (Chelonia mydas). A dose of 1 mg/kg was given to the Kemp's ridleys and greens, whereas the loggerheads received 2 mg/kg. After SQ administration, the half-life (t1/2) of meloxicam administered at 1 mg/kg in the Kemp's ridleys was 5.51 hr but could not be determined in the greens. The half-life of meloxicam administered at 2 mg/kg in the loggerheads was 2.99 hr. The maximum concentration (Cmax) for meloxicam after SQ administration at 1 mg/kg in the Kemp's ridleys was 6.76 µg/ml and in the greens was 9.35 µg/ml. The Cmax in loggerheads for meloxicam after SQ administration at 2 mg/kg was 3.63 µg/mL. Meloxicam administered SQ at a dose of 1 mg/kg to the Kemp's ridley and greens provided measurable plasma concentrations of meloxicam for 48 and 120 hr, respectively, with no adverse side effects. In loggerheads, meloxicam administered SQ at a dose of 2 mg/kg provided measurable plasma levels of meloxicam for only 24 hr. Plasma levels of meloxicam of greater than 0.5 µg/ml are considered to be therapeutic in humans. Results suggested that administration of meloxicam SQ at 1 mg/kg in Kemp's ridleys and greens would result in plasma concentrations greater than 0.5 µg/ml for 12 and 120 hr, respectively. The administration of 2 mg/kg meloxicam to loggerhead turtles resulted in plasma concentrations greater than 0.5 µg/ml for only 4 hr.

Simultaneous determination of moxifloxacin with NSAIDs in API, dosage and serum by reverse phase high-performance liquid chromatography: Application to in vitro drug interactions.

Experimental design is a significant tool for optimization and validation for the development of HPLC methods to determine API in both human serum and pharmaceutical formulations. In this study, RP-HPLC method is developed and validated for the simultaneous determination of moxifloxacin and NSAIDs. In this experiment, Purospher STAR C18 column with optimum assay conditions (10:90, v/v, water: methanol, pH 2.75) used as mobile phase having flow rate of 1.5mL min-1 and screened at 240 nm. The experimental results exhibit reliability through accuracy (98-102%), precision (0.011-1.85%) and linearity (R2>0.999) in range of 0.15-40µgmL-1. The LOD and LOQ limits for moxifloxacin and NSAIDs are found to be 0.015 and 0.046 µgmL-1 respectively. The significant outcomes conclude that the developed method for assay is effectively suitable to human serum and pharmaceutical formulations and there is no interference from excipients of tablets and serum. The proposed method is useful for drug-interaction and investigation of moxifloxacin with NSAIDs.

A study to assess the correlation between plasma, oral fluid and urine concentrations of flunixin meglumine with the tissue residue depletion profile in finishing-age swine.

BACKGROUND: Flunixin meglumine (FM) was investigated for the effectiveness of plasma, oral fluid, and urine concentrations to predict tissue residue depletion profiles in finishing-age swine, along with the potential for untreated pigs to acquire tissue residues following commingled housing with FM-treated pigs. Twenty pigs were housed in groups of three treated and one untreated control. Treated pigs received one 2.2 mg/kg dose of FM intramuscularly. Before treatment and at 1, 3, 6, 12, 24, 36, and 48 h (h) after treatment, plasma samples were taken. At 1, 4, 8, 12 and 16 days (d) post-treatment, necropsy and collection of plasma, urine, oral fluid, muscle, liver, kidney, and injection site samples took place. Analysis of flunixin concentrations using liquid chromatography/tandem mass spectrometry was done. A published physiologically based pharmacokinetic (PBPK) model for flunixin in cattle was extrapolated to swine to simulate the measured data. RESULTS: Plasma concentrations of flunixin were the highest at 1 h post-treatment, ranging from 1534 to 7040 ng/mL, and were less than limit of quantification (LOQ) of 5 ng/mL in all samples on Day 4. Flunixin was detected in the liver and kidney only on Day 1, but was not found 4-16 d post-treatment. Flunixin was either not seen or found less than LOQ in the muscle, with the exception of one sample on Day 16 at a level close to LOQ. Flunixin was found in the urine of untreated pigs after commingled housing with FM-treated pigs. The PBPK model adequately correlated plasma, oral fluid and urine concentrations of flunixin with residue depletion profiles in liver, kidney, and muscle of finishing-age pigs, especially within 24 h after dosing. CONCLUSIONS: Results indicate untreated pigs can be exposed to flunixin by shared housing with FM-treated pigs due to environmental contamination. Plasma and urine samples may serve as less invasive and more easily accessible biological matrices to predict tissue residue statuses of flunixin in pigs at earlier time points (≤24 h) by using a PBPK model.

Safety evaluation of the interchangeable use of robenacoxib in commercially-available tablets and solution for injection in cats.

BACKGROUND: Robenacoxib (Onsior™) is a non-steroidal anti-inflammatory drug developed for canine and feline use for the control of pain and inflammation. It is available as both tablets and solution for injection. The objective of this study was to evaluate the safety of the interchangeable use of commercially available robenacoxib formulations when administered to cats orally using 6 mg tablets and subcutaneously using a solution for injection containing 20 mg/mL. Thirty-four naïve healthy 4-month old cats were enrolled in this 37-day study and were randomized to four groups (three robenacoxib and one control). One robenacoxib group received the maximum recommended dose (MRD) rate of each formulation, while the other two received two and three times this dose rate. The cats underwent three 10-day treatment cycles comprised of seven days of once daily oral administration followed by three days of subcutaneous administration. The third cycle was followed by an additional seven days of oral treatment. The control group received oral empty gelatin capsules or subcutaneous saline injections. Assessment of safety was based on general health observations, clinical observations, physical, ophthalmic, electrocardiographic and neurological examinations, clinical pathology evaluations, food consumption, body weight, and macroscopic and microscopic examinations. Blood samples were collected for toxicokinetic evaluation. RESULTS: Blood concentrations of robenacoxib confirmed systemic exposure of all treated cats. All cats were in good health through study termination and there were no serious adverse events during the study. There were no changes in body weight, food consumption, ophthalmic, physical or neurological examinations during the study. Treatment-related abnormalities were of low occurrence at all doses and included injection site changes (transient edema with minimal or mild, subacute/chronic inflammation histologically) and prolongation of the QT interval. These findings were consistent with previously observed findings in studies with robenacoxib administered separately orally or subcutaneously in cats. Thus, there were no adverse effects that could be attributed specifically to the interchangeable use of oral and injectable robenacoxib. CONCLUSIONS: This 37-day laboratory study supports the safety of interchanging robenacoxib injection at a daily dose of 2 mg/kg with robenacoxib tablets at a daily dose of 1 mg/kg, or vice versa.

Pharmacokinetic profiles of meloxicam after single IV and PO administration in Bilgorajska geese.

The purpose of this study was two-fold: I) to determine the pharmacokinetic profile of meloxicam (MLX) in geese after intravenous (IV) and oral (PO) administration and II) to assess tissue residues in muscle, heart, liver, lung, and kidney. Ten clinically normal female Bilgorajska geese were divided into two groups (treated, n = 8; control, n = 2). Group 1 underwent a 3-phase parallel study with a 1-week washout period. In phase I, animals received MLX (0.5 mg/kg) by IV administration; the blood was collected up to 48 hr. In phases II and III geese were treated orally at the same dosage for the collection of blood and tissue samples, respectively. Group 2 served as control. After the extraction procedure, a validated HPLC method with UV detection was used for plasma and organ analysis. The plasma concentrations were quantifiable up to 24 hr after both the administrations. The elimination phase of MLX from plasma was similar in both the administration groups. The clearance was slow (0.00975 L/hr*Kg), the volume of distribution small (0.0487 L/kg), and the IV half-life was 5.06 ± 2.32 hr. The average absolute PO bioavailability was 64.2 ± 24.0%. Residues of MLX were lower than the LOQ (0.1 µg/kg) in any tested tissue and at any collection time. The dosage used in this study achieved the plasma concentration, which provides analgesia in Hispaniolan Amazon parrots for 5 out of 24 hr after PO administration. MLX tissue concentrations were below the LOD of the assay in tissue (0.03 µg/ml). A more sensitive technique might be necessary to determine likely residue concentrations in tissue.

Impact of lactation on pharmacokinetics of meloxicam in goats.

Use of drug in lactating animal should be carefully considered due to its possibility of changes in pharmacokinetics as well as drug penetration in milk. The aim of this study was to assess the effect of lactation on pharmacokinetics of meloxicam after IV and IM administrations in goats. A crossover design (2 × 2) was used for each lactating and nonlactating group of goats with a 3-week washout period. Meloxicam (0.5 mg/kg) was administered into the jugular vein and upper gluteal muscle by IV and IM routes, respectively. The plasma and milk drug concentrations were determined by high-performance liquid chromatography with diode array detector, and the pharmacokinetic analysis was carried out by noncompartmental analysis. The pharmacokinetic parameters of meloxicam in lactating and nonlactating goats were not significantly different. The IM bioavailability of meloxicam was relatively lower in lactating (75.3 ± 18.6%) than nonlactating goats (103.8 ± 34.7%); however, the difference was not statistically significant. Moreover, AUC ratio between milk and plasma, which represent drug milk penetration, for both IV and IM administrations was less than 1 (about 0.3). In conclusion, pharmacokinetic parameters of meloxicam are not significantly altered by lactation for either the IV or IM routes of administration and this drug does not require a different dosage regimen for lactating animals.

Effect of castration procedure on the pharmacokinetics of meloxicam in goat kids.

The aim of this study was to determine the changes in the pharmacokinetics of meloxicam in goat kids who were castrated following the administration of xylazine. Six goat kids were used for the study. The study was performed in two periods according to a longitudinal study, with a 15-day washout period between periods. In the first period (Control group), 1 mg/kg meloxicam was administered by i.v. route to kids. In the second period (Castration group), the kids were sedated with 0.3 mg/kg xylazine and castration was performed following meloxicam administration. Plasma meloxicam concentration was analyzed using HPLC-UV, and pharmacokinetic parameters were calculated by noncompartmental model. In the control group following the administration of meloxicam, mean elimination half-life (t1/2 ʎz ), area under the concentration-time curve (AUC0-∞ ), total body clearance (ClT ), and volume of distribution at steady-state (Vdss ) were 13.50 ± 0.62 hr, 41.10 ± 2.86 hr µg/ml, 24.43 ± 1.75 ml hr-1  kg-1 , and 0.45 ± 0.03 L/kg, respectively. In the castration group, the t1/2 ʎz of meloxicam prolonged, AUC0-∞ increased, and ClT and Vdss decreased. In conclusion, the excretion of meloxicam from the body slowed and the t1/2 ʎz was prolonged in the castrated goat kids following xylazine administration. However, there is a need to determine the pharmacodynamics of meloxicam in castrated goat kids.

Pharmacokinetics of tolfenamic acid in Hawksbill turtles (Eretmochelys imbricata) after single intravenous and intramuscular administration.

To the best of our knowledge, limited pharmacokinetic information to establish suitable therapeutic plans is available for Hawksbill turtles. Therefore, the present study aimed to assess the pharmacokinetic features of tolfenamic acid (TA) in Hawksbill turtles, Eretmochelys imbricata, after single intravenous (i.v.) and intramuscular (i.m.) administration at dosage 4 mg/kg body weight (b.w.). The study (parallel design) used 10 Hawksbill turtles randomly divided into equal groups. Blood samples were collected at assigned times up to 144 hr. The concentrations of TA in plasma were quantified by a validated liquid chromatography tandem mass spectrometry (LC-ESI-MS/MS). The concentration of TA in the experimental turtles with respect to time was pharmacokinetically analyzed using a noncompartment model. The Cmax values of TA were 89.33 ± 6.99 µg/ml following i.m. administration. The elimination half-life values were 38.92 ± 6.31 hr and 41.09 ± 9.32 hr after i.v. and i.m. administration, respectively. The absolute i.m. bioavailability was 94.46%, and the average binding percentage of TA to plasma protein was 31.39%. TA demonstrated a long half-life and high bioavailability following i.m. administration. Therefore, the i.m. administration is recommended for use in clinical practice because it is both easier to perform and provides similar plasma concentrations to the i.v. administration. However, further studies are needed to determine the clinical efficacy of TA for treatment of inflammatory disease after single and multiple dosages.

Pharmacometabolomics with a combination of PLS-DA and random forest algorithm analyses reveal meloxicam alters feline plasma metabolite profiles.

Repeated administration of meloxicam to cats is often limited by the potential damage to multiple organ systems. Identifying molecules that predict the adverse effects of meloxicam would help to monitor and individualize its administration, maximizing meloxicam's beneficial effects. The objectives of this study were to (a) determine if the repeated administration of meloxicam to cats alters the plasma metabolome and (b) identify plasma metabolites that may serve to monitor during the administration of meloxicam in cats. Purpose bred young adult cats (n = 12) were treated with meloxicam at 0.3 mg/kg or saline subcutaneously once daily for up to 17 days. An untargeted metabolomics approach was applied to plasma samples collected prior to and at designated time points after meloxicam or saline administration. To refine the discovery of biomarkers, the machine-learning algorithms, partial least squares discriminant analysis (PLS-DA) and random forest (RF), were trained and validated using a separate unrelated group of meloxicam- and saline-treated cats (n = 8). A total of 74 metabolites were included in the statistical analysis. Metabolomic analysis shows that the repeated administration of meloxicam alters multiple substances in plasma, including nonvolatile organic acids, aromatic amino acids, monosaccharides, and inorganic compounds as early as four days following administration of meloxicam. Seventeen plasma molecules were able to distinguish meloxicam-treated from saline-treated cats. The metabolomic changes discovered in this study may help to unveil unknown mechanisms of NSAID-induced side effects. In addition, some metabolites could be valuable for individualizing the administration of meloxicam to cats to mitigate adverse effects.

Determination of grapiprant plasma and urine concentrations in horses.

OBJECTIVE: Non-steroidal anti-inflammatory drugs are inhibitors of cyclooxygenase (COX) in tissues and used as therapeutic agents in different species. Grapiprant, a member of the piprant class of compounds, antagonizes prostaglandin receptors. It is a highly selective EP4 prostaglandin E2 receptor inhibitor, thereby limiting the potential for adverse effects caused by wider COX inhibition. The objectives of this study were to determine if the approved canine dose would result in measurable concentrations in horses, and to validate a chromatographic method of analysis for grapiprant in urine and plasma. STUDY DESIGN: Experimental study. ANIMALS: A total of six healthy, adult mixed-breed mares weighing 502 ± 66 (397-600) kg and aged 14.8 ± 5.3 (6-21) years. METHODS: Mares were administered one dose of 2 mg kg-1 grapiprant via nasogastric tube. Blood and urine samples were collected prior to and up to 48 hours after drug administration. Drug concentrations were measured using high-performance liquid chromatography. RESULTS: Grapiprant plasma concentrations ranged from 71 to 149 ng mL-1 with the mean peak concentration (106 ng mL-1) occurring at 30 minutes. Concentrations were below the lower limit of quantification (50 ng mL-1) in four of six horses at 1 hour and in all six horses by 2 hours after drug administration. Grapiprant urine concentrations ranged from 40 to 4077 ng mL-1 and were still detectable at 48 hours after administration. CONCLUSIONS AND CLINICAL RELEVANCE: Currently, there are no published studies looking at the pharmacodynamics of grapiprant in horses. The effective concentration needed to control pain in dogs ranges 114-164 ng mL-1. Oral administration of grapiprant (2 mg kg-1) in horses did not achieve those concentrations. The dose was well tolerated; therefore, studies with larger doses could be conducted.

Pharmacokinetics-based analysis of indomethacin's anti-tumor effect and drug efficacy.

Non-steroidal anti-inflammatory drugs are commonly used anti-inflammatory analgesics in clinic. Indomethacin is a kind of NSAIDs and has anti-tumor effect. It can significantly change the growth cycle of cancer cells, inhibit their proliferation. In this paper, the antineoplastic effect of indomethacin and its pharmacokinetic effect were analysed. The result showed that indomethacin had more metabolic distribution in tumor tissues and reached its peak at 4 hours, after that, the clearance rate was slower than that in the blood, with the clearance rate slowest at 6-12 hours. At the same time, the expression of Bcl-2 protein in cancer cells was significantly reduced and weakened, while the expression of Bax protein did not change significantly. Pharmacodynamic studies have proved that IN (Indomethacin) has a strong anti-tumor effect. It can enter into tumor cells through cell membrane and nuclear membrane to have an anti-tumor effect.

Cyclooxygenase-2, Asymmetric Dimethylarginine, and the Cardiovascular Hazard From Nonsteroidal Anti-Inflammatory Drugs.

BACKGROUND: Large-scale, placebo-controlled trials established that nonsteroidal anti-inflammatory drugs confer a cardiovascular hazard: this has been attributed to depression of cardioprotective products of cyclooxygenase (COX)-2, especially prostacyclin. An alternative mechanism by which nonsteroidal anti-inflammatory drugs might constrain cardioprotection is by enhancing the formation of methylarginines in the kidney that would limit the action of nitric oxide throughout the vasculature. METHODS: Targeted and untargeted metabolomics were used to investigate the effect of COX-2 deletion or inhibition in mice and in osteoarthritis patients exposed to nonsteroidal anti-inflammatory drugs on the l-arginine/nitric oxide pathway. RESULTS: Analysis of the plasma and renal metabolome was performed in postnatal tamoxifen-inducible Cox-2 knockout mice, which exhibit normal renal function and blood pressure. This revealed no changes in arginine and methylarginines compared with their wild-type controls. Moreover, the expression of genes in the l-arginine/nitric oxide pathway was not altered in the renal medulla or cortex of tamoxifen inducible Cox-2 knockout mice. Therapeutic concentrations of the selective COX-2 inhibitors, rofecoxib, celecoxib, and parecoxib, none of which altered basal blood pressure or renal function as reflected by plasma creatinine, failed to elevate plasma arginine and methylarginines in mice. Finally, plasma arginine or methylarginines were not altered in osteoarthritis patients with confirmed exposure to nonsteroidal anti-inflammatory drugs that inhibit COX-1 and COX-2. By contrast, plasma asymmetrical dimethylarginine was increased in mice infused with angiotensin II sufficient to elevate blood pressure and impair renal function. Four weeks later, blood pressure, plasma creatinine, and asymmetrical dimethylarginine were restored to normal levels. The increase in asymmetrical dimethylarginine in response to infusion with angiotensin II in celecoxib-treated mice was also related to transient impairment of renal function. CONCLUSIONS: Plasma methylarginines are not altered by COX-2 deletion or inhibition but rather are elevated coincident with renal compromise.

Increased bioavailability of curcumin using a novel dispersion technology system (LipiSperse®).

PURPOSE: Curcumin has been shown to deliver protective effects against numerous degenerative conditions associated with high levels of inflammation and oxidative stress. Owing to its poor bioavailability when delivered orally, it is difficult to deliver a high concentration therapeutic dose. LipiSperse® is a novel delivery system that uses dispersion technology to enhance bioavailability of hydrophobic agents. In this study, we investigated the pharmacokinetics of a commercially available curcumin extract, with or without the curcumin-LipiSperse® delivery complex. METHODS: Eighteen healthy male and female volunteers participated in this single equivalent dose, randomised, double-blinded study. Seven of those volunteers further participated in the crossover phase of the trial. Plasma concentrations were determined at baseline and at regular intervals over a 24-h period following 750 mg of curcuminoid ingestion. RESULTS: In both the parallel and crossover trial, Curcumin with LipiSperse® delivered significantly higher plasma curcuminoid concentrations compared to the raw curcumin product (807 vs 318 ng/mL in the crossover trial). CONCLUSIONS: The novel delivery system LipiSperse® is safe in humans, and demonstrates superior bioavailability for the supply of curcumin when compared to a standard curcumin extract.

Dose evaluation of intravenous metamizole (dipyrone) in infants and children: a prospective population pharmacokinetic study.

PURPOSE: The prodrug metamizole is prescribed intravenously for postoperative pain in children, including off-label use in infants < 1 year. We aimed to assess the pharmacokinetics of the main metabolites of metamizole in children aged 3-72 months. METHODS: A single dose of 10 mg/kg metamizole was administered intravenously for postoperative analgesia. Pharmacokinetic samples were drawn at predefined time points. Pharmacokinetics of the main active metabolite 4-methylaminoantipyrine and three other metabolites was characterized by both non-compartmental and population pharmacokinetic analysis. AUC0-inf of 4-methylaminoantipyrine was calculated by non-compartmental analysis for two age cohorts (3-23 months, 2-6 years) and compared with the 80-125% range of adult dose-adjusted reference exposure (AUCref). Population pharmacokinetic analysis investigated age and weight dependency of the pharmacokinetics and optimal dosing strategies to achieve equivalent adult exposure. RESULTS: A total of 25 children aged 5 months-5.8 years (7.8-24.8 kg) with at least one concentration sample were included; 19 children had ≥ 5 predefined samples up to 10 h after metamizole dose administration. AUC0-inf of 4-methylaminoantipyrine in children 2-6 years was 29.9 mg/L/h (95% CI 23.4-38.2), significantly lower than AUCref (80-125% range 39.2-61.2 mg/L/h). AUC0-inf of 4-methylaminoantipyrine in infants < 2 years was 43.6 mg/L/h (95% CI 15.8-119.0), comparable with AUCref, while infants < 12 months showed increased exposure. Observed variability could be partially explained by covariates weight and age. CONCLUSIONS: Age-related changes in pharmacokinetics of 4-methylaminoantipyrine requires reduced weight-based IV dosing in infants < 1 year compared with infants and children up to 6 years (5 versus 10-20 mg/kg) to achieve equivalent adult exposure. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02660177 .

Simultaneous determination of piroxicam and norfloxacin in biological fluids by high-performance liquid chromatography with fluorescence detection at zero-order emission mode.

A new highly sensitive high-performance liquid chromatographic method with fluorescence detection (HPLC-FLD) in zero-order emission mode was developed for the first time for the simultaneous determination of piroxicam (PRX) and norfloxacin (NRF) in biological fluids. The fluorescence detector wavelengths were set at 278 nm for excitation and zero-order mode for emission. The zero-order emission mode produced greater sensitivity for the measurement of both drugs than a fixed emission wavelength (446 nm). The new developed method was validated according to International Conference of Harmonization (ICH) guidelines. Linearity was found to be over concentration ranges 0.001-20 µg/ml and 0.00003-0.035 µg/ml for PRX and NRF, respectively. The limits of detection were 4.87 × 10-4 and 1.32 × 10-5 µg/ml for PRX and NRF, and the limits of quantitation were 1.47 × 10-3 and 4.01 × 10-5 µg/ml, respectively. The current fluorescence method was found to be more sensitive than most commonly used analytical methods and was successfully applied for simultaneous determination of PRX and NRF in biological fluids (serum and urine) with recoveries ranging from 91.67% to 100.36% for PRX and from 96.00% to 101.43% for NRF.