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Molecules (Basel, Switzerland) Dec 2021The mechanisms underlying the antineoplastic effects of oxicams have not been fully elucidated. We aimed to assess the effect of classic and novel oxicams on the...
The mechanisms underlying the antineoplastic effects of oxicams have not been fully elucidated. We aimed to assess the effect of classic and novel oxicams on the expression/secretion of macrophage-associated chemokines (RTqPCR/Luminex xMAP) in colorectal adenocarcinoma cells, and on the expression of upstream the non-steroidal anti-inflammatory drug (NSAID)-activated genes , , , and as well as at the chemokine profiling in colorectal tumors. Meloxicam downregulated 9.9-fold, but otherwise the classic oxicams had a negligible/non-significant effect. Novel analogues with a thiazine ring substituted with arylpiperazine and benzoyl moieties significantly modulated chemokine expression to varying degree, upregulated NAG1 and and downregulated . They inhibited and and their effect on and depended on the dose and exposure. The propylene linker between thiazine and piperazine nitrogens and one arylpiperazine fluorine substituent characterized the most effective analogue. Only and were not upregulated in tumors, nor was in tumor-adjacent tissue compared to normal mucosa. Compared to adjacent tissue, and were upregulated, while , and were downregulated in tumors. Tumor and increased along with advancing T and and along with the N stage. The introduction of arylpiperazine and benzoyl moieties into the oxicam scaffold yields effective modulators of chemokine expression, which act by upregulating and interfering with NF-κB signaling.
Topics: Aged; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Caco-2 Cells; Chemokines; Colorectal Neoplasms; Female; HCT116 Cells; Humans; Macrophages; Male; Meloxicam; Piroxicam
PubMed: 34885960
DOI: 10.3390/molecules26237375 -
Journal of Animal Science Mar 2022Hot-iron branding uses thermal injury to permanently identify cattle causing painful tissue damage. The primary objective was to examine the physiological and behavioral...
Hot-iron branding uses thermal injury to permanently identify cattle causing painful tissue damage. The primary objective was to examine the physiological and behavioral effects of oral meloxicam (MEL), compared to a control, administered at the time of hot-iron branding in Angus and Hereford steers and heifers. The secondary objectives were to investigate breed and sex effects on pain biomarkers. A total of 70 yearlings, consisting of 35 heifers and 35 steers (Angus, Hereford, or Angus × Hereford), were enrolled in the study. Animals were blocked by sex, randomized across weight, and assigned to receive MEL (1 mg/kg) or a placebo (CON). Biomarkers were assessed for 48 h after branding and included infrared thermography (IRT), mechanical nociceptive threshold (MNT), accelerometry and a visual analog scale (VAS), and serum cortisol and prostaglandin E2 metabolites (PGEM). Wound healing was assessed for 12 wk. Hair samples to quantify cortisol levels were taken prior to and 30 d post-branding. Responses were analyzed using repeated measures with calf nested in treatment as a random effect, and treatment, time, treatment by time interaction, breed, and sex as fixed effects. There was a treatment by time interaction for PGEM (P < 0.01) with MEL having lower values than CON at 6, 24, and 48 h (MEL: 18.34 ± 3.52, 19.61 ± 3.48, and 22.24 ± 3.48 pg/mL, respectively; CON: 32.57 ± 3.58, 37.00 ± 3.52, and 33.07 ± 3.48 pg/mL; P < 0.01). MEL showed less of a difference in maximum IRT values between the branded (2.27 ± 0.29 °C) and control site (3.15 ± 0.29 °C; P < 0.01). MEL took fewer lying bouts at 0-12 h (4.91 bouts ± 0.56) compared with CON (6.87 bouts ± 0.55; P < 0.01). Compared with Hereford calves, Angus calves exhibited greater serum but lower hair cortisol, greater PGEM, more lying bouts, and less healed wound scores at 3, 4, and 5 wk. Compared with heifers, steers exhibited lower PGEM, lower branding site and ocular IRT, higher MNT, and lower plasma meloxicam levels. Steers spent more time lying, took more lying bouts and had greater VAS pain, and more healed wound scores at 5 wk than heifers. Meloxicam administration at branding reduced branding and control site temperature differences and reduced lying bouts for the first 12 h. Breed and sex effects were observed across many biomarkers. Changes from baseline values for IRT, MNT, lying time, step count, VAS pain, and wound scoring all support that branding cattle is painful.
Topics: Animals; Biomarkers; Cattle; Female; Iron; Meloxicam; Pain; Pain Measurement
PubMed: 35137141
DOI: 10.1093/jas/skac038 -
Toxicology Letters Mar 2021Meloxicam is a thiazole-containing NSAID that was approved for marketing with favorable clinical outcomes despite being structurally similar to the hepatotoxic... (Comparative Study)
Comparative Study
Meloxicam is a thiazole-containing NSAID that was approved for marketing with favorable clinical outcomes despite being structurally similar to the hepatotoxic sudoxicam. Introduction of a single methyl group on the thiazole results in an overall lower toxic risk, yet the group's impact on P450 isozyme bioactivation is unclear. Through analytical methods, we used inhibitor phenotyping and recombinant P450s to identify contributing P450s, and then measured steady-state kinetics for bioactivation of sudoxicam and meloxicam by the recombinant P450s to determine relative efficiencies. Experiments showed that CYP2C8, 2C19, and 3A4 catalyze sudoxicam bioactivation, and CYP1A2 catalyzes meloxicam bioactivation, indicating that the methyl group not only impacts enzyme affinity for the drugs, but also alters which isozymes catalyze the metabolic pathways. Scaling of relative P450 efficiencies based on average liver concentration revealed that CYP2C8 dominates the sudoxicam bioactivation pathway and CYP2C9 dominates meloxicam detoxification. Dominant P450s were applied for an informatics assessment of electronic health records to identify potential correlations between meloxicam drug-drug interactions and drug-induced liver injury. Overall, our findings provide a cautionary tale on assumed impacts of even simple structural modifications on drug bioactivation while also revealing specific targets for clinical investigations of predictive factors that determine meloxicam-induced idiosyncratic liver injury.
Topics: Activation, Metabolic; Anti-Inflammatory Agents, Non-Steroidal; Chemical and Drug Induced Liver Injury; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP2C8; Cytochrome P-450 CYP2C9; Data Mining; Deep Learning; Drug Interactions; Electronic Health Records; Female; Humans; Inactivation, Metabolic; Kinetics; Male; Meloxicam; Microsomes, Liver; Middle Aged; Substrate Specificity; Thiazines
PubMed: 33253783
DOI: 10.1016/j.toxlet.2020.11.015 -
BioMed Research International 2022Transfersomes (TFS) are the promising carriers for transdermal delivery of various low and high molecular weight drugs, owing to their self-regulating and...
Transfersomes (TFS) are the promising carriers for transdermal delivery of various low and high molecular weight drugs, owing to their self-regulating and self-optimizing nature. Herein, we report synthesis and characterization of TFS loaded with meloxicam (MLX), an NSAID, and dexamethasone (DEX), a steroid, for simultaneous transdermal delivery. The different formulations of TFS containing varying amounts of lecithin, Span 80, and Tween 80 (TFS-1 to TFS-6) were successfully prepared by thin-film hydration method. The size of ranged between 248 and 273 nm, zeta potential values covering from -62.6 to -69.5 mV, polydispersity index (PDI) values in between 0.329 and 0.526, and entrapment efficiency of MLX and DEX ranged between 63-96% and 48-81%, respectively. Release experiments at pH 7.4 demonstrated higher cumulative drug release attained with Tween 80 compared to Span 80-based TFS. The scanning electron microscopy (SEM) of selected formulations -1 and TFS-3 revealed spherical shape of vesicles. Furthermore, three optimized transfersomal formulations (based on entrapment efficiency, TFS-1, TFS-3, and TFS-5) were incorporated into carbopol-940 gels coded as TF-G1, TF-G3, and TF-G5. These transfersomal gels were subjected to pH, spreadability, viscosity, homogeneity, skin irritation, drug release, and skin permeation studies, and the results were compared with plain (nontransfersomal) gel having MLX and DEX. TFS released 71.72% to 81.87% MLX in 12 h; whereas, DEX release was quantified as 74.72% to 83.72% in same time. Nevertheless, TF-based gels showed slower drug release; 51.54% to 59.60% for MLX and 48.98% to 61.23% for DEX. The TF-G systems showed 85.87% permeation of MLX (TF-G1), 68.15% (TF-G3), and 68.94% (TF-G5); whereas, 78.59%, 70.54%, and 75.97% of DEX was permeated by TF-G1, TF-G3, and TF-G5, respectively. Kinetic modeling of release and permeation data indicated to follow Korsmeyer-Peppas model showing diffusion diffusion-based drug moment. Conversely, plain gel influx was found mere 26.18% and 22.94% for MLX and DEX, respectively. These results suggest that TF-G loaded with MLX and DEX can be proposed as an alternate drug carriers for improved transdermal flux that will certainly increase therapeutic outcomes.
Topics: Lecithins; Meloxicam; Dexamethasone
PubMed: 36483631
DOI: 10.1155/2022/8170318 -
Veterinary and Comparative Oncology Sep 2015Oral squamous cell carcinoma (OSCC) is common in cats and humans and invades oral bone. We hypothesized that the cyclooxygenase (COX)-2 inhibitor, meloxicam, with the...
Oral squamous cell carcinoma (OSCC) is common in cats and humans and invades oral bone. We hypothesized that the cyclooxygenase (COX)-2 inhibitor, meloxicam, with the bisphosphonate, zoledronic acid (ZOL), would inhibit tumour growth, osteolysis and invasion in feline OSCC xenografts in mice. Human and feline OSCC cell lines expressed COX-1 and COX-2 and the SCCF2 cells had increased COX-2 mRNA expression with bone conditioned medium. Luciferase-expressing feline SCCF2Luc cells were injected beneath the perimaxillary gingiva and mice were treated with 0.1 mg kg(-1) ZOL twice weekly, 0.3 mg kg(-1) meloxicam daily, combined ZOL and meloxicam, or vehicle. ZOL inhibited osteoclastic bone resorption at the tumour-bone interface. Meloxicam was more effective than ZOL at reducing xenograft growth but did not affect osteoclastic bone resorption. Although a synergistic effect of combined ZOL and meloxicam was not observed, combination therapy was well-tolerated and may be useful in the clinical management of bone-invasive feline OSCC.
Topics: Analysis of Variance; Animals; Antineoplastic Combined Chemotherapy Protocols; Bone Density Conservation Agents; Bone Neoplasms; Bone Resorption; Cat Diseases; Cats; Cell Line, Tumor; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Diphosphonates; Disease Models, Animal; Heterografts; Humans; Imidazoles; Male; Meloxicam; Mice; Mice, Nude; Mouth Neoplasms; Neoplasms, Squamous Cell; RNA, Messenger; Random Allocation; Real-Time Polymerase Chain Reaction; Thiazines; Thiazoles; Treatment Outcome; Zoledronic Acid
PubMed: 23651067
DOI: 10.1111/vco.12037 -
Food and Chemical Toxicology : An... Oct 2022Meloxicam is a non-steroidal anti-inflammatory drug (NSAID) commonly used in food-producing animals, including chickens in an extralabel manner. This study aimed to...
Meloxicam is a non-steroidal anti-inflammatory drug (NSAID) commonly used in food-producing animals, including chickens in an extralabel manner. This study aimed to develop a physiologically based pharmacokinetic (PBPK) model for meloxicam in broiler chickens and laying hens to facilitate withdrawal interval (WDI) estimations. The model structure for broiler chickens contained six compartments including plasma, muscle, liver, kidney, fat and rest of body, while an additional compartment of ovary was included for laying hens. The model adequately simulated available pharmacokinetic data of meloxicam in plasma of broiler chickens as well as tissue and egg data of laying hens. The model was converted to a web-based interface and used to predict WDIs following extralabel administrations. The results showed that the estimated WDIs were 50, 44, 11, 3, 3, 22 and 4 days for liver, kidney, muscle, fat, ovary, yolk and white, respectively in laying hens after 14 repeated oral administrations of meloxicam (1 mg/kg) at 24-h intervals. This model provides a useful and flexible tool for risk assessment and management of residues for meat and eggs from chickens treated with meloxicam and will serve as a basis for extrapolation to other NSAID drugs and other poultry species to aid animal-derived food safety assessment.
Topics: Animal Feed; Animals; Anti-Inflammatory Agents, Non-Steroidal; Chickens; Eggs; Female; Internet; Meloxicam
PubMed: 35940329
DOI: 10.1016/j.fct.2022.113332 -
The Journal of Clinical Endocrinology... Jan 2022Recent evidence suggests that vasomotor symptoms (VMS) or hot flashes in the postmenopausal reproductive state and polycystic ovary syndrome (PCOS) in the premenopausal...
CONTEXT
Recent evidence suggests that vasomotor symptoms (VMS) or hot flashes in the postmenopausal reproductive state and polycystic ovary syndrome (PCOS) in the premenopausal reproductive state emanate from the hyperactivity of Kiss1 neurons in the hypothalamic infundibular/arcuate nucleus (KNDy neurons).
OBJECTIVE
We demonstrate in 2 murine models simulating menopause and PCOS that a peripherally restricted kappa receptor agonist (PRKA) inhibits hyperactive KNDy neurons (accessible from outside the blood-brain barrier) and impedes their downstream effects.
DESIGN
Case/control.
SETTING
Academic medical center.
PARTICIPANTS
Mice.
INTERVENTIONS
Administration of peripherally restricted kappa receptor agonists and frequent blood sampling to determine hormone release and body temperature.
MAIN OUTCOME MEASURES
LH pulse parameters and body temperature.
RESULTS
First, chronic administration of a PRKA to bilaterally ovariectomized mice with experimentally induced hyperactivity of KNDy neurons reduces the animals' elevated body temperature, mean plasma LH level, and mean peak LH per pulse. Second, chronic administration of a PRKA to a murine model of PCOS, having elevated plasma testosterone levels and irregular ovarian cycles, suppresses circulating levels of LH and testosterone and restores normal ovarian cyclicity.
CONCLUSION
The inhibition of kisspeptin neuronal activity by activation of kappa receptors shows promise as a novel therapeutic approach to treat both VMS and PCOS in humans.
Topics: Animals; Buprenorphine; Disease Models, Animal; Female; Hot Flashes; Humans; Kisspeptins; Meloxicam; Menopause; Mice; Neurons; Polycystic Ovary Syndrome; Receptors, Opioid, kappa; Vasomotor System
PubMed: 34387319
DOI: 10.1210/clinem/dgab602 -
European Journal of Pharmaceutical... Aug 2022Intranasally administered non-steroidal anti-inflammatory drugs (NSAIDs) offer an innovative opportunity in the field of pain management. Combination of the nasal...
Intranasally administered non-steroidal anti-inflammatory drugs (NSAIDs) offer an innovative opportunity in the field of pain management. Combination of the nasal physiological advantages such as the rich vascularization and large absorption area along with novel nanomedical formulations can fulfill all the necessary criteria of an advanced drug delivery system. Nanoemulsions represent a versatile formulation approach suitable for nasal drug delivery by increasing the absorption and the bioavailability of many drugs for systemic and nose-to-brain delivery due to their stability, small droplet size and optimal solubilization properties. In this study we aimed to develop meloxicam (MX)-loaded mucoadhesive nanoemulsions and to investigate the nasal applicability of the optimized formulations. Our results indicated the optimized nanoemulsion formulation (MX-NE3) had a droplet size of 158.5 nm in monodisperse droplet size distribution (polydispersity index of 0.211). The surface charge was -11.2 mV, which helped with the colloidal stability upon dilution at simulated nasal conditions and storage. The high encapsulation efficiency (79.2%) mediated a 15-fold drug release and a 3-fold permeability increase at nasal conditions compared to the initial MX. Proper wetting properties associated with high mucoadhesion prosper the increased residence time on the surface of the nasal mucosa. No cytotoxic effect of the formulations was observed on NIH/3T3 mouse embryonic fibroblast cell lines, which supports the safe nasal applicability.
Topics: Administration, Intranasal; Animals; Drug Delivery Systems; Emulsions; Fibroblasts; Meloxicam; Mice; Nasal Mucosa; Particle Size
PubMed: 35662634
DOI: 10.1016/j.ejps.2022.106229 -
Journal of Veterinary Science May 2023Meloxicam is used widely for exotic animal analgesia, but its toxicity in common raptor species in Thailand is unclear.
BACKGROUND
Meloxicam is used widely for exotic animal analgesia, but its toxicity in common raptor species in Thailand is unclear.
OBJECTIVES
This study evaluated the single-dose effect of intramuscular meloxicam in common raptor species in Thailand for short-term and long-term periods.
METHODS
Twenty-two raptors were administered a single 1 mg/kg dose of meloxicam individually via intramuscular injection. The following were evaluated: clinical appearance, body weight, body condition score, body temperature, fecal appearance, complete blood cell count, and biochemistry panel before (day 0) and after the injection (1, 7, and 30 days). The collected samples were categorized into three groups: Brahminy kite () (n = 10), adult Barn owl () (n = 4), and juvenile Barn owl (n = 8).
RESULTS
None of the raptors in the study groups showed any abnormalities. The hematological profiles were significantly different in the short-term period (day 1 and day 7). The creatinine, aspartate aminotransferase, and creatinine kinase increased in several groups. On the other hand, the packed cell volume decreased in the Brahminy kite and juvenile Barn owl groups. According to the findings, an intramuscular injection of 1 mg/kg meloxicam affected the blood biochemistry panel of the muscle, but the affected raptors recovered within one week.
CONCLUSIONS
An intramuscular injection of meloxicam at a single 1 mg/kg dose in Brahminy kites and Barn owls was not associated with the morbidity, hepatotoxicity, gastrointestinal toxicity, and nephrotoxicity in the short- and long-term periods.
Topics: Animals; Strigiformes; Meloxicam; Injections, Intramuscular; Creatinine; Raptors; Hematology
PubMed: 37271511
DOI: 10.4142/jvs.23020 -
Veterinary Anaesthesia and Analgesia Jul 2022To investigate the pharmacokinetics of orally and intravenously (IV) administered meloxicam in semi-domesticated reindeer (Rangifer tarandus tarandus).
OBJECTIVE
To investigate the pharmacokinetics of orally and intravenously (IV) administered meloxicam in semi-domesticated reindeer (Rangifer tarandus tarandus).
STUDY DESIGN
A crossover design with an 11 day washout period.
ANIMALS
A total of eight young male reindeer, aged 1.5-2.5 years and weighing 74.3 ± 6.3 kg, mean ± standard deviation.
METHODS
The reindeer were administered meloxicam (0.5 mg kg IV or orally). Blood samples were repeatedly collected from the jugular vein for up to 72 hours post administration. Plasma samples were analysed for meloxicam concentrations with ultraperformance liquid chromatography combined with triple quadrupole mass spectrometry. Noncompartmental analysis for determination of pharmacokinetic variables was performed.
RESULTS
The pharmacokinetic values, median (range), were determined. Elimination half-life (t) with the IV route (n = 4) was 15.2 (13.2-16.8) hours, the volume of distribution at steady state was 133 (113-151) mL kg and clearance was 3.98 (2.63-5.29) mL hour kg. After oral administration (n = 7), the peak plasma concentration (C) was detected at 6 hours, t was 19.3 (16.7-20.5) hours, C 1.82 (1.17-2.78) μg mL and bioavailability (n = 3) 49 (46-73)%. No evident adverse effects were detected after either administration route.
CONCLUSIONS AND CLINICAL RELEVANCE
A single dose of meloxicam (0.5 mg kg IV or orally) has the potential to maintain the therapeutic concentration determined in other species for up to 3 days in reindeer plasma.
Topics: Administration, Oral; Animals; Area Under Curve; Biological Availability; Half-Life; Male; Meloxicam; Reindeer
PubMed: 35659721
DOI: 10.1016/j.vaa.2022.04.005