A fully validated HPLC-UV method for determination of sulthiame in human serum/plasma samples.

Sulthiame is an old antiepileptic medicine with controversial history, whose effectiveness and safety in use have been stated in some current studies. However, there is still a need for further clinical examinations for confirmation of its usefulness and tolerability in monotherapy and add-on therapy for epilepsy of various etiologies. A fully validated RP HPLC-UV method for determination of sulthiame in serum/plasma samples using desethylatrazine as the internal standard was developed. The biological fluid was prepared for analysis by a simple precipitation method with acetonitrile. The following validation parameters of the method were determined: selectivity/specificity, linearity range (0.2-50.0 µl/ml, R2 > 0.9999), limits of detection (0.19 µl/ml) and quantification (0.58 µl/ml), precision (intra-day CV 1.06% and inter-day CV 1.25%), extraction recovery (~100%), accuracy (bias, -4.61-0.80%), carryover and ruggedness. Moreover, the stability of the medicine in plasma samples under different storage conditions was also tested. The usability of the method for clinical examinations was checked by analysis of serum samples originating from 19 patients treated with sulthiame. The proposed method is appropriate for determination of sulthiame in serum/plasma samples for drug monitoring purposes, as well as for pharmacokinetic studies.

Sultiame pharmacokinetic profile in plasma and erythrocytes after single oral doses: A pilot study in healthy volunteers.

A pilot study was conducted aiming at specifying sultiame's pharmacokinetic profile, completed by in vitro assays evaluating the intraerythrocytic transfer of sultiame and by a pharmacokinetic model assessing its distribution. Single oral doses of sultiame (Ospolot® 50, 100, and 200 mg) were administered in open-label to four healthy volunteers. Serial plasma, whole blood, and urine samples were collected. A spiking experiment was also performed to characterize sultiame's exchanges between plasma and erythrocytes in vitro. Pharmacokinetic parameters were evaluated using standard noncompartmental calculations and nonlinear mixed-effect modeling. The plasma maximal concentrations (Cmax ) showed striking nonlinear disposition of sultiame, with a 10-fold increase while doses were doubled. Conversely, whole blood Cmax increased less than dose proportionally while staying much higher than in plasma. Quick uptake of sultiame into erythrocytes observed in vivo was confirmed in vitro, with minimal efflux. A two-compartment model with first-order absorption, incorporating a saturable ligand to receptor binding, described the data remarkably well, indicating apparent plasma clearance of 10.0 L/h (BSV: 29%) and distribution volume of 64.8 L; saturable uptake into an intracellular compartment of 3.3 L with a maximum binding capacity of 111 mg accounted for nonlinearities observed in plasma and whole blood concentrations. Pharmacokinetic characteristics of sultiame are reported, including estimates of clearance and volume of distribution that were so far unpublished. The noticeable nonlinearity in sultiame disposition should be taken into account for the design of future studies and the interpretation of therapeutic drug monitoring results.

Development and validation of a multiplex UHPLC-MS/MS method for the determination of the investigational antibiotic against multi-resistant tuberculosis macozinone (PBTZ169) and five active metabolites in human plasma.

The emergence of Mycobacterium tuberculosis strains resistant to current first-line antibiotic regimens constitutes a major global health threat. New treatments against multidrug-resistant tuberculosis (MDR-TB) are thus eagerly needed in particular in countries with a high MDR-TB prevalence. In this context, macozinone (PBTZ169), a promising drug candidate with an unique mode of action and highly potent in vitro tuberculocidal properties against MDR Mycobacterium strains, has now reached the clinical phase and has been notably tested in healthy male volunteers in Switzerland. To that endeavor, a multiplex UHPLC-MS/MS method has been developed for the sensitive and accurate human plasma levels determination of PBTZ169 along with five metabolites retaining in vitro anti-TB activity. Plasma protein precipitation with methanol was carried out as a simplified sample clean-up procedure followed by direct injection of the undiluted supernatant for the bioanalysis of the six analytes within 5 min, using 1.8 µm reversed-phase chromatography coupled to triple quadrupole mass spectrometry employing electrospray ionization in the positive mode. Stable isotopically-labelled PBTZ169 was used as internal standard (ISTD), while metabolites could be reliably quantified using two unlabeled chemical analogues selected as ISTD from a large in-house analogous compounds library. The overall methodology was fully validated according to current recommendations (FDA, EMEA) for bioanalytical methods, which include selectivity, carryover, qualitative and quantitative matrix effect, extraction recovery, process efficiency, trueness, precision, accuracy profiles, method and instrument detection limits, integrity to dilution, anticoagulant comparison and short- and long-term stabilities. Stability studies on the reduced metabolite H2-PBTZ169 have shown no significant impact on the actual PBTZ169 concentrations determined with the proposed assay. This simplified, rapid, sensitive and robust methodology has been applied to the bioanalysis of human plasma samples collected within the frame of a phase I clinical study in healthy volunteers receiving PBTZ169.

Evaluating Potential QT Effects of JNJ-54861911, a BACE Inhibitor in Single- and Multiple-Ascending Dose Studies, and a Thorough QT Trial With Additional Retrospective Confirmation, Using Concentration-QTc Analysis.

Nonclinical assays with JNJ-54861911, a ß-secretase 1 inhibitor have indicated that at high concentrations, it may delay cardiac repolarization. A 4-way crossover thorough QT (TQT) study was performed in 64 healthy subjects with 50 and 150 mg JNJ-54861911 once daily for 7 days, placebo, and 400 mg moxifloxacin. Retrospective high-precision QT (HPQT) analysis was performed on serial elecrocardiograms extracted from first-in-human single-ascending dose (SAD) and multiple-ascending dose (MAD) studies to evaluate if early studies could detect and predict QT effect. In the TQT study, a high therapeutic 50 mg dose did not cause QT prolongation, and an effect >10 milliseconds could be excluded at all postdose timepoints. QT prolongation with peak effect on placebo-corrected change from baseline QTcF of 15.5 milliseconds (90%CI, 12.9-18.1 milliseconds) was observed following a supratherapeutic dose (150 mg). No clinically relevant QT changes were observed in earlier studies. However, with SAD/MAD findings by HPQT, the slope of the exposure-response (ER) relationship in the SAD study (doses up to 150 mg) was similar to the TQT study slope, and the estimated QT effect was comparable at high plasma levels. In the MAD study, doses up to 90 mg once daily for 7 days resulted in JNJ-54861911 peak plasma concentrations (Cmax ) comparable to those in the SAD study (∼750 ng/mL), but ER by HPQT failed to detect a QT effect and resulted in negative estimations. Adding a higher dose cohort (150 mg; Cmax , 1125 ng/mL) demonstrated a QT effect, with a slightly lower ER slope than the TQT study. JNJ-54861911 (up to 50 mg) did not cause QT prolongation at clinically relevant plasma concentrations in any studies. Provided sufficiently high plasma concentrations were captured, mild QT prolongation observed postdose with a supratherapeutic dose could be detected (TQT study) and estimated in SAD/MAD studies. Based on population pharmacokinetic modeling and simulation, 5 and 25 mg doses are currently considered for further phase 3 studies and are expected not to cause any relevant QT prolongation.

Quantitative determination of meloxicam in dog plasma by high performance liquid chromatography-tandem mass spectrometry and its application in a pharmacokinetic study.

A rapid, selective and sensitive high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed to determine meloxicam in beagle dog plasma. Sample pretreatment involved a one-step protein precipitation with methanol of 0.1 mL plasma. Analysis was performed on a Venusil ASB-C18 column with mobile phase consisting of methanol-water (containing 0.1% formic acid) (75:25, v/v). The detection was performed on a triple quadrupole tandem mass spectrometer by multiple reaction monitoring mode via electrospray ionization source. Each plasma sample was chromatographed within 4.1 min. The linear calibration curves for meloxicam was obtained in the concentration range of 10.3-4.12 × 103 ng/mL (r ≥ 0.99). The intra- and inter-day precisions (relative standard deviation) were ≤ 15%, and accuracy (relative error) was within ±7.3%. The method herein described was fully validated and successfully applied to the pharmacokinetic study of meloxicam tablets in beagle dog.

Ultrasound-accelerated synthesis of gold nanoparticles modified choline chloride functionalized graphene oxide as a novel sensitive bioelectrochemical sensor: Optimized meloxicam detection using CCD-RSM design and application for human plasma sample.

In this research, gold nanoparticles modified choline chloride functionalized graphene oxide (AuNPs-ChCl-GO) was synthesized through the assistance of ultrasound and fabricated as a novel bioelectrochemical sensor and utilized for the sensitive detection of meloxicam (MEL). The morphological and structural features of the AuNPs-ChCl-GO were characterized using different techniques including FTIR, TEM, FE-SEM, EDX, and XRD. The modified electrode showed a remarkable improvement in the anodic oxidation activity of MEL due to the enhancement in the current response compared to the bare carbon paste electrode (CPE). The biosensor composition and measurement conditions were optimized using an experimental design. The differential pulse voltammetry (DPVs) exhibited expanded linear dynamic in the range of 9.0 × 10-9 to 8.5 × 10-7 M for MEL in Britton-Robinson buffer at pH = 4.0 with a detection limit of 1.008 × 10-9 M. The practical utility of the modified electrode was demonstrated by the accurate detection of MEL in human plasma sample.

Comparison of milk and plasma pharmacokinetics of meloxicam in postpartum versus mid-lactation Holstein cows.

The objective of this study reported here was determine whether differences occurred in meloxicam pharmacokinetics between postpartum cows and mid-lactation cows. Preliminary data from a separate study (P. J. Gorden, unpublished data) in postpartum cows demonstrated elevated plasma and milk concentration profiles compared to previously published data (Malreddy, Coetzee, KuKanich, & Gehring, ). Two different groups were enrolled, each with 10 cows. The treatment group (TRT) was postpartum cows treated with meloxicam, and the positive control (PC) group was cows in mid-lactation treated with meloxicam. Plasma and milk meloxicam concentrations between the TRT and PC group were compared. Significant differences in meloxicam concentration in plasma were determined at all time points from 8 hr to 120 hr post-treatment. In milk, there was a treatment (p = .003), time (p < .001), and treatment by time interaction (p < .001). Significant differences in milk meloxicam concentration were determined at all time points from 8 hr to 96 hr post-treatment, except for the 16-hr time point. The time needed for meloxicam to no longer be detected in milk of the TRT group was longer compared to the PC group, indicating that a longer milk withdrawal is needed. These data suggest higher bioavailability as the underlying mechanism. Further research is needed to determine the mechanisms underlying differences this outcome.

Range of therapeutic prothipendyl and prothipendyl sulfoxide concentrations in clinical blood samples.

Due to a lack of reference blood concentrations in the literature, the forensic evaluation of prothipendyl findings in blood samples is difficult. Interpretations with regard to the assessment of blood concentrations as well as an estimation of the ingested prothipendyl amounts were often vague. To describe a concentration range in clinical samples, prothipendyl and prothipendyl sulfoxide concentrations were determined in serum samples of 50 psychiatric patients receiving 40 mg, 80 mg, or 160 mg doses of prothipendyl. The analyses of prothipendyl and prothipendyl sulfoxide were carried out using validated methods of high performance liquid chromatography coupled to triple quadrupole mass spectrometry (LC-QQQ-MS), respectively. 40 mg doses caused average prothipendyl serum concentrations of 18.0 ng/mL (1 hour after intake) and 7.9 ng/mL (10.5 hours after intake), while 80 mg doses caused averages of 42.6 ng/mL and 15.2 ng/mL at the mentioned times of sampling. Irrespective of the given dose, prothipendyl concentrations below 30 ng/mL were observed in 80% of the patient samples taken 1 hour after ingestion as well as in 90% of the samples collected 10.5 hours after administration. Serum concentrations of the Phase I metabolite prothipendyl sulfoxide averaged 4.3 ng/mL (1 hour after intake) and 3.6 ng/mL (10.5 hours after intake). Possible drug-drug interactions regarding absorption and metabolism of prothipendyl are discussed. Results of the herein presented study are useful for the interpretation of analytical prothipendyl findings in forensic toxicology. The utility of the described concentration range is demonstrated by discussing two death cases involving prothipendyl findings.

Plasma Concentration of Meloxicam in Pediatric Rats.

In this study, we compared the plasma concentrations of meloxicam in pediatric rat pups (ages: 7, 14, 21, and 28 d) with those of young adult rats. Adult rats received 1.34 mg/kg SC meloxicam to determine the target peak plasma concentration (Cmax) for comparison with the pediatric animals. Pediatric rats received 1.34 mg/kg SC meloxicam, and in all age groups, Cmax met or exceeded that in adults (11.5 ±2.7 µg/mL). Plasma concentrations were similar between male and female pups within age groups, and peak plasma concentration was achieved more rapidly in rat pups than adults. The analgesic efficacy of this dose was not evaluated in this study.

Pharmacokinetics of Single-dose Subcutaneous Meloxicam Injections in Black-tailed Prairie Dogs (Cynomys ludovicianus).

This study evaluated the pharmacokinetic profile of a single dose of meloxicam (1.0 mg/kg) administered subcutaneously (n = 6) or intravenously (n = 2) to black-tailed prairie dogs (Cynomys ludovicianus). Blood was collected immediately before (time 0) and at 0.5, 1, 2, 4, 8, 12 and 24 h after drug administration. Plasma meloxicam concentrations were quantified with HPLC-mass spectrometry, and noncompartmental pharmacokinetic analysis was performed. The peak plasma concentrations, time to peak plasma concentration, and terminal half-life of meloxicam after subcutaneous administration (median [minimum-maximum]) were 4.30 (3.00-4.89) µg/mL, 2.00 (0.62-4.00) h, and 11.88 (7.35-18.64) h, respectively. Plasma concentrations of meloxicam for prairie dogs in the present study showed high absorption and slow elimination after drug administration. The results of this study suggest that a 1.0-mg/kg SC dose of meloxicam administered every 24 h might be excessive for prairie dogs, although the ideal therapeutic dose in terms of safety and efficacy is unknown in this species.

In†Vivo Dearomatization of the Potent Antituberculosis Agent BTZ043 via Meisenheimer Complex Formation.

Nitrobenzothiazinones are among the most potent antituberculosis agents. Herein, we disclose an unprecedented in vivo reduction process that affords Meisenheimer complexes of the clinical candidates BTZ043 and PBTZ169. The reduction is reversible, occurs in all mammalian species investigated, has a profound influence on the in vivo ADME characteristics, and has considerable implications for the design and implementation of clinical studies. The reduction was confirmed by chemical studies that enabled the complete characterization of the Meisenheimer complex and its subsequent chemistry. Combination of the in vivo and chemical studies with LC-MS characterization and assay development also provides a basis for rational lead optimization of this very promising class of antituberculosis agents.

The Measurement of Meloxicam and Meloxicam Metabolites in Rat Plasma Using a High-Performance Liquid Chromatography-Ultraviolet Spectrophotometry Method.

A high-performance liquid chromatography-ultraviolet spectrophotometry (HPLC-UV) method for the determination of meloxicam (MEL) and meloxicam metabolites (5'-hydroxy meloxicam (5-HMEL) and 5'-carboxy meloxicam (5-CMEL)) has been developed. After extraction of MEL, 5-HMEL, and 5-CMEL from rat plasma using Oasis HLB cartridges, the extracts were separated with a Luna C18 (2) 100 A column (5 µm, 4.6×150 mm, Phenomenex) using a mobile phase of 50 mM phosphate buffer (pH 2.15, solvent A) and acetonitrile (solvent B) at a flow rate of 0.8 mL/min in a linear gradient. The detection wavelength was 360 nm, and the internal standard (IS) was piroxicam. Each calibration curve was linear in the range of 40 to 1000 ng/mL (r2>0.999). The extraction rates of MEL, 5-HMEL, and 5-CMEL were greater than 86.9%. The intra- and inter-day accuracies were in the range of 95.0 to 119.0%, and the precision was 0.2 to 17.0%. To the best of our knowledge, this is the first report of the quantitative and qualitative measurement of meloxicam and each metabolite using an HPLC-UV method.

PHARMACOKINETIC EVALUATION OF MELOXICAM AFTER INTRAVENOUS AND INTRAMUSCULAR ADMINISTRATION IN NILE TILAPIA (OREOCHROMIS NILOTICUS).

Critically evaluating the pharmacokinetic behavior of a drug in the body provides crucial information about how to effectively treat a patient. Pharmacokinetic studies that exist in fish have primarily focused on drugs used to treat infectious disease, with minimal attention given to analgesic drugs. The objective of this study was to determine the pharmacokinetics of meloxicam (1 mg/kg) in Nile tilapia ( Oreochromis niloticus ) (n = 12). A single dose of meloxicam was administered either i.v. or i.m. Blood samples were obtained at predetermined times after drug injection. Plasma meloxicam concentrations were determined by a validated liquid chromatography/mass spectrometry method, and noncompartmental pharmacokinetic analysis was performed. The mean peak plasma concentration after i.m. injection was 1.95 µg/ml. The mean terminal half-life of meloxicam after i.v. and i.m. administration was 1.36 and 1.8 hr, respectively. The area under the plasma concentration-versus-time curve extrapolated to infinity was 11.26 hr·µg/ml after i.v. administration and 5.72 hr·µg/ml after i.m. administration. Bioavailability of meloxicam after i.m. administration was approximately half that of i.v. administration. Elimination was rapid in both the i.m. and i.v. routes of administration, suggesting that maintaining clinically relevant plasma concentrations may be difficult using this dose. This study represents the first pharmacokinetic evaluation of a nonsteroidal anti-inflammatory drug in a fish species, and further studies evaluating efficacy are needed.

Discovery of S3-Truncated, C-6 Heteroaryl Substituted Aminothiazine ß-Site APP Cleaving Enzyme-1 (BACE1) Inhibitors.

Truncation of the S3 substituent of the biaryl aminothiazine 2, a potent BACE1 inhibitor, led to a low molecular weight aminothiazine 5 with moderate activity. Despite its moderate activity, compound 5 demonstrated significant brain Aß reduction in rodents. The metabolic instability of 5 was overcome by the replacement of the 6-dimethylisoxazole, a metabolic soft spot, with a pyrimidine ring. Thus, truncation of the S3 substituent represents a viable approach to the discovery of orally bioavailable, brain-penetrant BACE1 inhibitors.

Impact of oral meloxicam and long-distance transport on cell-mediated and humoral immune responses in feedlot steers receiving modified live BVDV booster vaccination on arrival.

The objective of this study was to investigate the impact of oral meloxicam (MEL) and long-distance transportation on cell-mediated immunity (CMI) in preconditioned steers receiving a booster vaccination on arrival. We hypothesized that steers treated with MEL at 1mg/kg body weight, 6h before night-time transport, would be less immunocompromised on arrival (day 0) and after 7days, and that CMI following vaccination with a modified live bovine viral diarrhea virus (BVDV) recall antigen would be increased. Brahman crossbreed steers, 13-17 months of age (n=87), were randomly assigned to one of four treatment groups: MEL, transported (MTR) (n=22), MEL, non-transported (MNT) (n=22), lactose placebo, transported (CTR) (n=21), and lactose placebo, non-transported (CNT) (n=22). MTR and CTR steers were transported for approximately 16h non-stop on a truck from Mississippi to Iowa (approximately 1300km), whereas steers in the MNT and CNT groups remained in Mississippi as non-transported controls. Body weight was measured and jugular blood was collected at -1, 0, and 7days from all steers at the same time, regardless of location. Multi-parameter flow cytometry (MP-FCM) was used to identify T-cell subsets and detect the expression of three activation markers (CD25 [interleukin (IL)-2 receptor], intracellular interferon-gamma [IFNγ], and IL-4) after in vitro stimulation with BVDV recall antigen. Plasma cortisol concentration was measured on day -1, 0, and 7 as a marker of transport-associated stress. Serum antibody titer to BVDV was assessed on day -1 and day 7 post-booster vaccination. Whole-blood samples were analyzed using MP-FCM on days 0 and 7. Results were log transformed and analyzed using repeated measures of analysis of variance. Compared with non-transported controls, transport led to an increase in BVDV-induced expression of CD25, IFNγ, and IL-4 in CD4(+), CD8(+), and γδ(+) T-cell subsets (P<0.05). MEL treatment mitigated the transportation-associated increase in CD25 expression by peripheral blood mononuclear cells (PBMCs), CD4(+), and γδ(+) T cells. CMI outputs for the MTR group were less than those of the CTR group (P<0.05); however, the MTR and NT groups did not differ (P>0.10). A treatment*transport interaction was noted for the increase in IL-4 expression by CD8(+) T cells after transport, with a significant difference between the CTR and MTR groups at day 7. In conclusion, the use of oral MEL prior to transport appears to have inhibitory or homeostatic effects, but further research is needed to validate the effect of MEL treatment on specific T-cell subsets in transported cattle.

Postoperative Analgesia Due to Sustained-Release Buprenorphine, Sustained-Release Meloxicam, and Carprofen Gel in a Model of Incisional Pain in Rats (Rattus norvegicus).

Postoperative analgesia in laboratory rats is complicated by the frequent handling associated with common analgesic dosing requirements. Here, we evaluated sustained-release buprenorphine (Bup-SR), sustained-release meloxicam (Melox-SR), and carprofen gel (CG) as refinements for postoperative analgesia. The aim of this study was to investigate whether postoperative administration of Bup-SR, Melox-SR, or CG effectively controls behavioral mechanical and thermal hypersensitivity in a rat model of incisional pain. Rats were randomly assigned to 1 of 5 treatment groups: saline, 1 mL/kg SC BID; buprenorphine HCl (Bup HCl), 0.05 mg/kg SC BID; Bup-SR, 1.2 mg/kg SC once; Melox-SR, 4 mg/kg SC once; and CG, 2 oz PO daily. Mechanical and thermal hypersensitivity were tested daily from day-1 through 4. Bup HCl and Bup-SR attenuated mechanical and thermal hypersensitivity on days 1 through 4. Melox-SR and CG attenuated mechanical hypersensitivity-but not thermal hypersensitivity-on days 1 through 4. Plasma concentrations, measured by using UPLC with mass spectrometry, were consistent between both buprenorphine formulations. Gross pathologic examination revealed no signs of toxicity in any group. These findings suggest that postoperative administration of Bup HCl and Bup-SR-but not Melox-SR or CG-effectively attenuates mechanical and thermal hypersensitivity in a rat model of incisional pain.

Subcutaneous meloxicam suspension pharmacokinetics in mice and dose considerations for postoperative analgesia.

Meloxicam is a cyclooxygenase (COX) inhibitor with a higher selectivity for cyclooxygenase-2 (COX-2) than for cyclooxygenase-1 (COX-1). In the laboratory setting, this nonsteroidal anti-inflammatory drug (NSAID) is commonly selected for analgesia in mice and administered every 24 h. This study characterizes the plasma concentration achieved from a dose of 1.6 mg/kg of meloxicam administered once every 24 h subcutaneously for 72 h in male and female C57BL/6 mice. These values were compared, over time, to reference COX-2 inhibition constants for meloxicam. No significant differences in trough plasma concentrations were noted between genders. The plasma concentrations were below the COX-2 IC50 after 12 h. To maintain a plasma concentration at or above the COX-2 whole blood IC50, the study results suggest an administration frequency of every 12 h when using a dose of 1.6 mg/kg in C57BL/6 mice.

The effect of surgery (Ovariohysterectomy) on the plasma disposition of meloxicam following intravenous administration in dogs.

BACKGROUND: Meloxicam (MLX) is a nonsteroidal anti-inflammatory drug used in the relief of postoperative pain for human and veterinary medicine. This study was designed to investigate the effect of surgery on the plasma disposition of MLX in dogs undergoing ovariohysterectomy following a single intravenous injection at a dose of 0.2 mg/kg bodyweight. Eight crossbred bitches were used in the study. A two-phase experimental design with a 10-day washout period was used. Pre-operative MLX was administered intravenously to 8 bitches about 10 days before surgery (Phase I, control) at a dose of 0.2 mg/kg bodyweight and peri-operative MLX was administered intravenously after anaesthesia and 15 min before the start of surgery (Phase II). Blood samples were collected from all animals at various times between 1 and 96 h after the drug administrations in both phases. The drug concentrations were analysed using high performance liquid chromatography. RESULTS: The volume of plasma MLX distribution at steady-state (Vdss) of the control group (Vdss: 263.0 ml/kg) was significantly greater (P < 0.05) compared to that of the surgery group (Vdss: 149.3 ml/kg). The AUC values were higher (29.5 vs. 23.0 µg.h(2)/ml) and the CL values were lower (7.7 vs. 10.5 ml.h/kg) in the surgery group compared to the control group, respectively, but differences were not significant. CONCLUSIONS: The results of the present study indicated that surgery could alter the plasma disposition of MLX and thus the drug efficacy and side effects such as gastrointestinal ulceration, unusual bleeding and loss of kidney function/failure when repeated doses are used.

Absence of ethnic differences in the pharmacokinetics of moxifloxacin, simvastatin, and meloxicam among three East Asian populations and Caucasians.

AIM: To examine whether strict control of clinical trial conditions could reduce apparent differences of pharmacokinetic (PK) parameters among ethnic groups. METHODS: Open-label, single dose PK studies of moxifloxacin, simvastatin and meloxicam were conducted in healthy male subjects from three East Asian populations (Japanese, Chinese and Koreans) and one Caucasian population as a control. These three drugs were selected because differences in PK parameters have been reported, even though the backgrounds of these East Asian populations are similar. Moxifloxacin (400 mg) was administered orally to 20 subjects, and plasma and urine levels of moxifloxacin and its metabolite (M2) were measured. Simvastatin (20 mg) was given to 40 subjects, and plasma levels of simvastatin and simvastatin acid were measured. Meloxicam (7.5 mg) was given to 30 subjects and its plasma concentration was determined. Intrinsic factors (polymorphism of UGT1A1 for moxifloxacin, SLCO1B1 for simvastatin, and CYP2C9 for meloxicam) were also examined. RESULTS: AUCinf values for moxifloxacin, simvastatin and meloxicam showed no significant differences among the East Asian groups. Cmax values of moxifloxacin and simvastatin, but not meloxicam, showed significant differences. There were no significant differences of data for M2 or simvastatin acid. Genetic analysis identified significant differences in the frequencies of relevant polymorphisms, but these differences did not affect the PK parameters observed. CONCLUSIONS: Although there were some differences in PK parameters among the three East Asian groups, the present study performed under strictly controlled conditions did not reproduce the major ethnic differences observed in previous studies.

Pharmacokinetic profiles of meloxicam in turtles (Trachemys scripta scripta) after single oral, intracoelomic and intramuscular administrations.

Meloxicam is an anti-inflammatory and analgesic drug used to treat many pathological conditions in turtles. With the aim to fill the lack of data about its pharmacokinetic in this species, eighteen turtles (Trachemys scripta scripta) were divided in three groups and treated with a single dose of meloxicam (0.2 mg/kg) by intramuscular, intracoelomic and oral route, respectively. At scheduled time points, blood samples were collected and meloxicam concentrations were determined by HPLC. Pharmacokinetic parameters were calculated from the obtained concentration-time curves. After intramuscular treatment, a plasma peak of meloxicam equal to 1590.03 ± 1845.32 ng/mL (mean ± SD) and a Tmax of 1.17 ± 0.45 h were reached, indicating a quick absorption of the drug. The intracoelomic administration brought to the largest AUC (12621.04 ± 6203.79 h*ng/mL) and to a Cmax and a Tmax equal to 1154.52 ± 662.78 ng/mL and 2.82 ± 1.39 h, respectively. Following oral treatment, the plasma concentrations of meloxicam were very low indicating a scarce absorption. Further studies are warranted to determine the effective plasma concentration of meloxicam in turtles and, consequently, the dosage regimen.