Pharmacokinetic interactions between fexuprazan, a potassium-competitive acid blocker, and nonsteroidal anti-inflammatory drugs in healthy males.

Fexuprazan, a novel potassium-competitive acid blocker, is expected to be used for the prevention of nonsteroidal anti-inflammatory drugs (NSAIDs) induced ulcer. This study aimed to evaluate pharmacokinetic (PK) interactions between fexuprazan and NSAIDs in healthy subjects. A randomized, open-label, multicenter, six-sequence, one-way crossover study was conducted in healthy male subjects. Subjects randomly received one of the study drugs (fexuprazan 40 mg BID, celecoxib 200 mg BID, naproxen 500 mg BID, or meloxicam 15 mg QD) for 5 or 7 days in the first period followed by the combination of fexuprazan and one of NSAIDs for the same days and the perpetrator additionally administered for 1-2 days in the second period. Serial blood samples for PK analysis were collected until 48- or 72-h post-dose at steady state. PK parameters including maximum plasma concentration at steady state (Cmax,ss) and area under plasma concentration-time curve over dosing interval at steady state (AUCτ,ss) were compared between monotherapy and combination therapy. The PKs of NSAIDs were not significantly altered by fexuprazan. For fexuprazan, differences in PK parameters (22% in Cmax, 19% in AUCτ,ss) were observed when co-administered with naproxen, but not clinically significant. The geometric mean ratio (90% confidence interval) of combination therapy to monotherapy for Cmax,ss and AUCτ,ss was 1.22 (1.02-1.46) and 1.19 (1.00-1.43), respectively. There were no significant changes in the systemic exposure of fexuprazan by celecoxib and meloxicam. Fexuprazan and NSAIDs did not show clinically meaningful PK interactions.

Injectable polyamide-amine dendrimer-crosslinked meloxicam-containing poly-γ-glutamic acid hydrogel for prevention of postoperative tissue adhesion through inhibiting inflammatory responses and balancing the fibrinolytic system.

Establishing a physical barrier between the peritoneum and the cecum is an effective method to reduce the risk of postoperative abdominal adhesions. Meloxicam (MX), a nonsteroidal anti-inflammatory drug has also been applied to prevent postoperative adhesions. However, its poor water solubility has led to low bioavailability. Herein, we developed an injectable hydrogel as a barrier and drug carrier for simultaneous postoperative adhesion prevention and treatment. A third-generation polyamide-amine dendrimer (G3) was exploited to dynamically combine with MX to increase the solubility and the bioavailability. The formed G3@MX was further used to crosslink with poly-γ-glutamic acid (γ-PGA) to prepare a hydrogel (GP@MX hydrogel) through the amide bonding. In vitro and in vivo experiments evidenced that the hydrogel had good biosafety and biodegradability. More importantly, the prepared hydrogel could control the release of MX, and the released MX is able to inhibit inflammatory responses and balance the fibrinolytic system in the injury tissues in vivo. The tunable rheological and mechanical properties (compressive moduli: from âˆ¼ 57.31 kPa to âˆ¼ 98.68 kPa;) and high anti-oxidant capacity (total free radical scavenging rate of âˆ¼ 94.56 %), in conjunction with their syringeability and biocompatibility, indicate possible opportunities for the development of advanced hydrogels for postoperative tissue adhesions management.

A 20-Metal Zn(II)-Cd(II)-Eu(III) Nanocluster with Qualitative and Quantitative Luminescence Detection of Meloxicam (an Anti-Inflammatory Drug).

Meloxicam (MLX) is a novel nonsteroidal anti-inflammatory drug, but on the other hand, it has become one of the common microcontaminants in surface waters and sewage. Herein, we report the preparation of a ternary-metal Zn(II)-Cd(II)-Eu(III) nanocluster 1 for the response of MLX through the enhancement of lanthanide luminescence. The luminescence sensing behavior of 1 is expressed by the equation I615nm = 3060 × [MLX] + 46,604, which can be used in the quantitative analysis of MLX concentrations in meloxicam dispersible tablets. Filter paper strips bearing 1 can be used to qualitatively detect MLX by a color change to red under a UV lamp. The luminescence response time is no more than five s, and the detection limit is as low as 2.31 × 10-2 nM.

Long-Acting Drug Delivery Technologies for Meloxicam as a Pain Medicine.

Meloxicam, a selective COX-2 inhibitor, has demonstrated clinical effectiveness in managing inflammation and acute pain. Although available in oral and parenteral formulations such as capsule, tablet, suspension, and solution, frequent administration is necessary to maintain therapeutic efficacy, which can increase adverse effects and patient non-compliance. To address these issues, several sustained drug delivery strategies such as oral, transdermal, transmucosal, injectable, and implantable drug delivery systems have been developed for meloxicam. These sustained drug delivery strategies have the potential to improve the therapeutic efficacy and safety profile of meloxicam, thereby reducing the frequency of dosing and associated gastrointestinal side effects. The choice of drug delivery system will depend on the desired release profile, the target site of inflammation, and the mode of administration. Overall, meloxicam sustained delivery systems offer better patient compliance, and reduce the side effects, thereby improving the clinical applications of this drug. Herein, we discuss in detail different strategies for sustained delivery of meloxicam.

Importance of Considering Fed-State Gastrointestinal Physiology in Predicting the Reabsorption of Enterohepatic Circulation of Drugs.

PURPOSE: The purpose of this study was to develop a simulation model for the pharmacokinetics (PK) of drugs undergoing enterohepatic circulation (EHC) with consideration to the environment in the gastrointestinal tract in the fed state in humans. The investigation particularly focused on the necessity of compensating for the permeability rate constant in the reabsorption process in consideration of drug entrapment in bile micelles. METHODS: Meloxicam and ezetimibe were used as model drugs. The extent of the entrapment of drugs inside bile micelles was evaluated using the solubility ratio of Fed State Simulated Intestinal Fluid version 2 (FeSSIF-V2) to Fasted State Simulated Intestinal Fluid version 2 (FaSSIF-V2). Prediction accuracy was evaluated using the Mean Absolute Percentage Error (MAPE) value, calculated from the observed and predicted oral PK profiles. RESULTS: The solubilization of ezetimibe by bile micelles was clearly observed while that of meloxicam was not. Assuming that only drugs in the free fraction of micelles permeate through the intestinal membrane, PK simulation for ezetimibe was performed in both scenarios with and without compensation by the permeation rate constant. The MAPE value of Zetia® tablet, containing ezetimibe, was lower with compensation than without compensation. By contrast, Mobic® tablet, containing meloxicam, showed a relatively low MAPE value even without compensation. CONCLUSION: For drugs which undergo EHC and can be solubilized by bile micelles, compensating for the permeation rate constant in the reabsorption process based on the free fraction ratio appears an important factor in increasing the accuracy of PK profile prediction.

Machine vision-based non-destructive dissolution prediction of meloxicam-containing tablets.

Machine vision systems have emerged for quality assessment of solid dosage forms in the pharmaceutical industry. These can offer a versatile tool for continuous manufacturing while supporting the framework of process analytical technology, quality-by-design, and real-time release testing. The aim of this work is to develop a digital UV/VIS imaging-based system for predicting the in vitro dissolution of meloxicam-containing tablets. The alteration of the dissolution profiles of the samples required different levels of the critical process parameters, including compression force, particle size and content of the API. These process parameters were predicted non-destructively by multivariate analysis of UV/VIS images taken from the tablets. The dissolution profile prediction was also executed using solely the image data and applying artificial neural networks. The prediction error (RMSE) of the dissolution profile points was less than 5%. The alteration of the API content directly affected the maximum concentrations observed at the end of the dissolution tests. This parameter was predicted with a relative error of less than 10% by PLS models that are based on the color components of UV and VIS images. In conclusion, this paper presents a modern, non-destructive PAT solution for real-time testing of the dissolution of tablets.

Does maropitant provide more effective perioperative pain management than meloxicam in bitches undergoing ovariohysterectomy? The first report on the comparison of visceral algesia-analgesia for ovariohysterectomy.

Ovariohysterectomy (OVH) is a widely used surgical procedure in small animal practice. In developing countries, injectable anesthetics such as ketamine and xylazine are commonly used in veterinary medicine. Pharmacological agents with analgesic activity, such as ketamine and meloxicam, are not sufficiently effective in reducing visceral pain. Therefore, this study aimed to investigate the visceral analgesia and anti-inflammatory effectiveness of maropitant compared with those of meloxicam during and after OVH in bitches. In this study, thirty-six bitches were randomly divided into the maropitant, meloxicam, and control groups. The heart rate (HR), peripheral oxygen saturation, and respiratory rate were monitored during the procedure. Pain scores were assessed using the University of Melbourne pain scale (UMPS). Rescue analgesia was not necessary for any bitch at any time point. Blood samples were collected before anesthesia induction and 24 h after the operation to determine C-reactive protein (CRP) levels. No significant difference was observed in HR between the control and meloxicam groups when the right ovary was removed, and the HR of the maropitant group was significantly (p < 0.05) lower than that of the control group. The pain scores of the maropitant group were significantly (p < 0.05) lower than those of the other groups. However, no significant differences were observed in CRP levels between the groups. In conclusion, compared to meloxicam, maropitant provided more effective visceral analgesia in bitches undergoing OVH, although no significant difference was found in its anti-inflammatory effect.

Development of nanostructured environmentally responsive system containing hydroxypropyl methylcellulose for nose-to-brain administration of meloxicam.

The intranasal administration of drugs using environmentally responsive formulations, employing a combination of hydroxypropyl methylcellulose (HPMC) and poloxamer 407 (P407), can result in release systems that may assist in the treatment of neurological diseases. Meloxicam, considered a potential adjuvant in the treatment of Alzheimer's disease, could be used in these platforms. The aim of this work was to develop a mucoadhesive, thermoresponsive, and nanostructured system containing HPMC for nose-to-brain administration of meloxicam. The initially selected systems were investigated for their rheological, mechanical, and micellar size characteristics. The systems were dilatant at 25 °C and pseudoplastic with a yield value at 37 °C, showing viscoelastic properties at both temperatures. The platform containing HPMC (0.1%, w/w) and P407 (17.5%, w/w) was selected and demonstrated good mucoadhesive properties, along with an appropriate in vitro release profile. HPMC could form a binary system with P407, displaying superior mucoadhesive and thermoresponsive properties for nose-to-brain meloxicam administration, indicating that the selected formulation is worthy of clinical studies.

Nanoformulated meloxicam and rifampin: inhibiting quorum sensing and biofilm formation in Pseudomonas aeruginosa.

Background: We aimed to investigate the simultaneous effects of meloxicam and rifampin nanoformulations with solid lipid nanoparticle (SLN) and nanostructured lipid carrier (NLC) substrates on inhibiting the quorum-sensing system of Pseudomonas aeruginosa and preventing biofilm formation by this bacterium. Methods: Antimicrobial activity of rifampin and meloxicam encapsulated with SLNs and NLCs against P. aeruginosa PAO1 was assessed by disk diffusion, minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC). Results: The SLN formulation was associated with lower doses for the MIC and minimum bactericidal concentration in comparison to NLC. Moreover, our results demonstrated that both nanoformulations were able to produce 100% inhibition of the biofilm formation of P. aeruginosa PAO1. Conclusion: All these findings suggest that meloxicam and rifampin encapsulated with SLNs could be the most effective formulation against P. aeruginosa.

Effect of 2% meloxicam injection in Holstein dairy cows on acute clinical mastitis without systemic symptoms.

This study aimed the efficacy of meloxicam (MX) in treating acute clinical mastitis (ACM) without systemic symptoms in Holstein cows by studying improvement in udder pain, changes in prostaglandin E2(PGE2) and bradykinin (BK) levels in the milk, and milk yield (MY) after healing. Forty-two cows with ACM were randomly assigned to the MX treatment group (T group; n=21) and the control group (C group; n=21). At onset of illness (day 0), the T group received a 0.5 mg/kg subcutaneous (SC) injection of MX whereas the C group received 15 mL SC of saline solution as a placebo. Udder tenderness (UT) was measured, and milk samples were collected on days 0-3. There was little change in the MY of the T group before and after healing, whereas MY in the C group was significantly lower than after healing. UT on day 3 in the T group was significantly lower than that in the C group. PGE2 levels significantly decreased from day 0 to day 3 in both groups. A significant negative correlation between PGE2 and linear score was observed on day 1 in the T group, but not in the C group. In ACM without systemic symptoms, the administration MX may be useful for restoring MY and reducing udder pain after healing.

Refinement of the motorised laminectomy-assisted rat spinal cord injury model by analgesic treatment.

Usage and reporting of analgesia in animal models of spinal cord injury (SCI) have been sparse and requires proper attention. The majority of experimental SCI research uses rats as an animal model. This study aimed to probe into the effects of some commonly used regimens with NSAIDs and opioids on well-being of the rats as well as on the functional outcome of the model. This eight-week study used forty-two female Wistar rats (Crl: WI), randomly and equally divided into 6 treatment groups, viz. I) tramadol (5mg/kg) and buprenorphine (0.05mg/kg); II) carprofen (5mg/kg) and buprenorphine (0.05mg/kg); III) carprofen (5mg/kg); IV) meloxicam (1mg/kg) and buprenorphine (0.05mg/kg); V) meloxicam (1mg/kg); and VI) no analgesia (0.5 ml sterile saline). Buprenorphine was administered twice daily whereas other treatments were given once daily for five days post-operatively. Injections were given subcutaneously. All animals underwent dental burr-assisted laminectomy at the T10-T11 vertebra level. A custom-built calibrated spring-loaded 200 kilodynes force deliverer was used to induce severe SCI. Weekly body weight scores, Rat Grimace Scale (RGS), and dark-phase home cage activity were used as markers for well-being. Weekly Basso Beattie and Bresnahan (BBB) scores served as markers for functionality together with Novel Object Recognition test (NOR) at week 8 and terminal histopathology using area of vacuolisation and live neuronal count from the ventral horns of spinal cord. It was concluded that the usage of analgesia improved animal wellbeing while having no effects on the functional aspects of the animal model in comparison to the animals that received no analgesics.

Simultaneous determination of meloxicam and bupivacaine via a novel modified dual wavelength method and an advanced chemometric approach.

This study presents two spectrophotometric methods; a novel dual wavelength-derivative spectrophotometry and multivariate curve resolution-alternating least squares (MCR-ALS) for the simultaneous determination of a fixed dose combination of bupivacaine (BUP) and meloxicam (MEL) in a ratio of 30:1. The extended UV spectrum of MEL enables its direct determination at λmax 360 nm with no interference from BUP. The determination of BUP was unfeasible directly because the UV spectra of both drugs are moderately overlapped over the wavelength range of 250-450 nm, thus new chemometric based spectrophotometric methods should be developed for its determination. Dual wavelength-derivative method was employed based on using first derivative spectra. The selected dual wavelengths for determination BUP were 274.6 nm and 374.6 nm where the dA/dλ amplitudes differences for MET are equal to zero. MCR-ALS is advanced chemometric tool that enables analysis of multicomponent samples in complex matrices with high resolution based on the decomposition of signal/spectral data into the pure spectra and corresponding concentration profile. The figures of merits for MCR model show that there is a good agreement between the actual and predicted concentrations for MEL and BUP. The methods were validated and statistically compared with a reported HPLC method.

Comparison of firocoxib and meloxicam for pain mitigation in goats undergoing surgical castration.

OBJECTIVE: This study sought to determine whether firocoxib (FIRO) or meloxicam (MEL) was effective at providing analgesia after surgical castration in goats. ANIMALS: 18 intact male crossbred goats (6 to 8 months old) were enrolled with a mean weight of 32.6 (± 2.9) kg. METHODS: Surgical castration was done under injectable anesthesia by a licensed veterinarian. Twelve bucks were surgically castrated and given either FIRO (n = 6) or MEL (n = 6). Six bucks served as controls (CNTLs) and were not castrated. Outcome measurements included visual analogue scale, infrared thermography, plasma cortisol, plasma substance P, and kinetic gait analysis. All outcome measurements were obtained at -24, 4, 8, 24, 48, and 72 hours. RESULTS: All 3 treatments were significantly different from each other at the 24- and 48-hour time points, with MEL animals having lower visual analogue scale scores when compared to FIRO animals; CNTL animals exhibited the lowest plasma cortisol levels (3.19 ng/mL; 95% CI, -1.21 to 7.59 ng/mL) followed by FIRO (7.45 ng/mL; 95% CI, 3.10 to 11.80 ng/mL) and MEL (10.24 ng/mL; 95% CI, 5.87 to 14.60 ng/mL). FIRO had an average mean decrease in gait velocity change (-54.17 cm/s; 95% CI, -92.99 to -15.35 cm/s), while MEL had an increase in gait velocity when compared to baseline values (14.54 cm/s; 95% CI, -24.27 to 53.36 cm/s). Control animals had an average mean of -3.06 cm/s (95% CI, -41.88 to 35.75 cm/s). CLINICAL RELEVANCE: Results from this study showed that there were some analgesic effects from administering MEL when compared to bucks that received a placebo treatment (CNTL).

Effect of meloxicam or robenacoxib administration timing on renal function and postoperative analgesia in cats undergoing ovariohysterectomy: A randomized, blinded, controlled clinical trial.

We evaluated the effect of administration timing of meloxicam and robenacoxib on renal function, platelet cyclo-oxygenase and perioperative analgesia in 60 cats undergoing ovariohysterectomy, in a prospective randomized blinded controlled study. Twelve cats were randomly allocated to one subcutaneous treatment group: meloxicam (0.2 mg/kg) or robenacoxib (2 mg/kg) at admission (MA, RA), at induction (MI, RI) and robenacoxib at the end of surgery (RE). All cats received the same anaesthesia protocol. Plasma renin activity (PRA), plasma creatinine, drug concentrations and serum thromboxane (TxB2) were measured sequentially. Anaesthesia significantly increased PRA, as activity at end of the surgery was higher than 2 h later (mean ± SD: 26.6 ± 2.8 versus 10.0 ± 3.9 ng/mL/h). PRA remained higher at 2 h post-surgery in admission groups compared to induction groups (p = .01). Serum TxB2 was lower with meloxicam than robenacoxib (p = .001), and was lower in the MA than each robenacoxib group at catheter placement. Admission groups (16/24 from RA and MA groups) received earlier rescue analgesia than other groups (p = .033). In conclusion, the renin-angiotensin system was activated during anaesthesia despite cyclo-oxygenase inhibition, possibly due to hypotension or surgical stimulation. There was no effect of drug or timing on the markers of renal function but one cat receiving meloxicam at induction had suspected IRIS grade II acute kidney injury.

Pharmacokinetics of the analgesic and anti-inflammatory drug meloxicam after administration of multiple doses to nursehound sharks (Scyliorhinus stellaris).

OBJECTIVE: To determine the pharmacokinetics of meloxicam in the nursehound shark (Scyliorhinus stellaris) during multiple dose administration. STUDY DESIGN: Prospective experimental trial. ANIMALS: A total of eight clinically healthy adult nursehounds (four males, four females). METHODS: Meloxicam was administered intramuscularly at a dose of 1.5 mg kg-1 once daily for 7 days. Blood samples were collected from the caudal vein for pharmacokinetic analysis at 2.5 hours and 24 hours after drug administration. After a 4 week washout period, meloxicam was administered orally at the same dose at 12 hour intervals for three repeated doses. Blood samples were collected at 1, 2, 4, 6, 8, 12, 24, 36 and 48 hours after the first administration. Sharks were visually monitored during each study and 4 weeks afterwards for side effects or signs of toxicity. Time required to achieve steady state was assessed by visual inspection and statistical comparison of peak and trough concentrations using a Friedman test; comparison between sexes was performed using a Mann-Whitney U test and p-value was set at 0.05. RESULTS: No animal died or showed clinical signs of toxicity during the study. Meloxicam administered orally did not produce detectable concentrations in plasma. After intramuscular administration, steady state was achieved after five doses, and mean trough and peak plasma concentrations at steady state were 1.76 ± 0.21 µg mL-1 and 3.02 ± 0.23 µg mL-1, respectively. Mean peak concentration accumulation ratio was 2.50 ± 0.22. CONCLUSIONS AND CLINICAL RELEVANCE: This study shows that intramuscular posology produces plasma concentrations considered therapeutic for other species. However, meloxicam was not detected in plasma after oral administration. These results suggest that meloxicam administered intramuscularly may be a useful non-steroid anti-inflammatory drug in nursehound sharks. Further pharmacodynamic studies are needed to fully evaluate its clinical use in this species.

Disposition kinetics of meloxicam in green sea turtles (Chelonia mydas) after intravenous and intramuscular administrations.

The pharmacokinetics were described of meloxicam (MLX) in green sea turtles (Chelonia mydas), following a single intravenous (i.v.) and intramuscular (i.m.) administrations at one of two dosages of 0.1 or 0.2 mg/kg body weight (b.w.). The sample of 20 green sea turtles was divided into four groups (n = 5) using a randomization procedure according to a parallel study design. Blood samples were collected at pre-assigned times up to 168 h. MLX in the plasma was cleaned-up and quantified using a validated high-performance liquid chromatography method with UV detection. The concentration of MLX in the experimental green sea turtles with respect to time was pharmacokinetically analyzed using a non-compartment model. MLX plasma concentrations were quantifiable for up to 72 and 120 h after i.v. at dosages of 0.1 and 0.2 mg/kg b.w., respectively, whereas it was measurable for up to 168 h after i.m. administration at both dosages. The long elimination half-life value of MLX (28 h) obtained in green sea turtles after i.v. administration was consistent with the quite slow clearance rate for both dosages. The average maximum concentration (Cmax ) values of MLX were 1.05 µg/mL and 4.26 µg/mL at dosages of 0.1 and 0.2 mg/kg b.w., respectively, with their elimination half-life values being 37.26 h and 30.64 h, respectively, after i.m. administrations. The absolute i.m. bioavailability was approximately 110%. These results suggested that i.m. administration of MLX at a dosage of 0.2 mg/kg b.w. was likely to be effective for clinical use in green sea turtles (Chelonia mydas). However, further studies are needed to determine the pharmacodynamic properties and clinical efficacy of MLX for the treatment of inflammatory disease after single and multiple dosages.

Pharmacokinetics of meloxicam in pre-ruminant calves after intravenous, oral, and subcutaneous administration.

Meloxicam is routinely used for pain alleviation in pre-ruminant calves during husbandry procedures. The pharmacokinetics of a single dose (0.5 mg/kg) of meloxicam was investigated after intravenous (IV), subcutaneous (SC), and oral (PO) administration in 30 pre-ruminant calves. Each group included 10 calves. Oral meloxicam was administered at least 1 h after feeding. Plasma samples were collected for up to 168 h, and the meloxicam concentration was analysed with liquid chromatography and mass spectrometry, followed by a noncompartmental pharmacokinetic analysis. The maximum meloxicam concentrations in plasma were 1.91 ± 0.27 µg/mL and 1.77 ± 0.16 µg/mL after SC and PO routes, respectively. The time of maximum concentration was 7.6 ± 2.8 h after SC and 10.0 ± 5.7 h after PO administration. The approximate bioavailability of meloxicam was 97% for SC and PO routes. The elimination half-lives were 79.2 ± 12.4, 84.6 ± 24.8, and 84.8 ± 22.3 h after IV, SC, and PO routes, respectively. The results suggest that the therapeutic meloxicam concentrations in plasma that are required for pain relief in other species, such as horses, may be maintained for several days following a single dose (0.5 mg/kg) administered IV, SC, or PO in calves.

Phototoxic action of meloxicam contributes to dysregulation of redox homeostasis in normal human skin cells - Molecular and biochemical analysis of antioxidant enzymes in melanocytes and fibroblasts.

The phototoxic effect of meloxicam (MLX) raises the question of the effect of the drug on the redox homeostasis of normal human skin cells. The main objective of the study was to analyze the effect of MLX and/or UVA radiation (UVAR) on the redox homeostasis of human normal skin cells - melanocytes and fibroblasts. MLX was found to affect the activity and expression of enzymes of the antioxidant system differently depending on the cell line used. The drug decreased the activity and expression of superoxide dismutase type 1 and 2 (SOD1 and SOD2), catalase (CAT) and glutathione peroxidase (GPx) in fibroblasts, while increasing the activity of these enzymes in melanocytes. UVA radiation enhanced the effects of the drug. In conclusion, MLX in combination with UVAR induces oxidative stress in melanocytes and fibroblasts, however, the analyses showed that the drug's effect the activity and expression of SOD, CAT and GPx differently, depending on the cell line. The observed dissimilarity between tested cell lines may result from the presence of melanin pigments.