Meloxican: Influence on arachidonic acid metabolism: Part 1. In vitro findings

doi:10.1016/0006-2952(95)02111-6

Biochemical Pharmacology

Volume 51, Issue 1, 12 January 1996, Pages 21-28

https://doi.org/10.1016/0006-2952(95)02111-6 Get rights and content

Abstract

Meloxicam is a new nonsteroidal anti-inflammatory drug (NSAID) derived from enolic acid. Meloxicam has shown potent anti-inflammatory activity in animal models together with low gastrointestinal and renal toxicity. Studies were undertaken to compare meloxicam to other NSAIDs in their ability to inhibit either constitutive cyclooxygenase (COX-1) or inducible cyclooxygenase (COX-2). COX-1 was isolated as a cell-free enzyme from bovine seminal vesicles or bovine brain or was present in nonstimulated macrophages derived from the guinea-pig peritoneum. COX-2 was induced in peritoneal macrophages stimulated by lipopolysaccharide (LPS) or isolated as a cell-free enzyme from sheep placenta. Of all NSAIDs tested, meloxicam was the most selective inhibitor of COX-2 in intact cells. In cell-free enzyme preparations, however, meloxicam showed the same activity against COX-1 and COX-2. All other NSAIDs tested were more potent inhibitors of COX-1 than of COX-2. The inducible cyclooxygenase COX-2 has been implicated in the mediation of the inflammatory reaction, whereas the products of the constitutive cyclooxygenase COX-1 have cytoprotective effects in the gastric mucosa, support microcirculation in the kidney, and are antithrombogenic. Therefore, differential inhibitory effects of NSAIDs on COX-1 and COX-2 may have a bearing on the risk-benefit profile displayed in clinical practice. Meloxicam shows a preferential inhibitory effect on COX-2 over COX-1, which may be directly related to the favorable tolerability profile with potent anti-inflammatory effects observed in animal studies.

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Cited by (176)

Evaluation of Targeted Bupivacaine, Bupivacaine-lidocaine-epinephrine, Dexamethasone, and Meloxicam for Reducing Acute Postoperative Pain in Cats Undergoing Routine Ovariohysterectomy
2021, Topics in Companion Animal Medicine
This study compared bupivacaine (BUP), bupivacaine-lidocaine-epinephrine (BLE), dexamethasone (DEX), and meloxicam (MEL) targeted at specific, potentially painful sites for reducing acute postoperative pain in cats undergoing elective ovariohysterectomy. One hundred fifty-one cats were included in a prospective, randomized, double-blinded clinical trial. Anesthesia consisted of a standardized protocol including buprenorphine, ketamine, dexmedetomidine, and isoflurane. A ventral midline ovariohysterectomy was performed, and cats were administered targeted injections of 0.5% bupivacaine (2 mg/kg); a combined 0.25% bupivacaine (1 mg/kg), 1% lidocaine (2 mg/kg), and 1:100,000 epinephrine (0.005 mg/kg); dexamethasone (0.125 mg/kg); or meloxicam (0.2 mg/kg) intraoperatively at the ovarian suspensory ligaments, uterine body, and incisional subcutaneous tissues. A 0-10 Numeric Pain Rating Scale (NRS) was used to assess cats postoperatively, 1 hour and 3 hours after anesthesia recovery prior to a same day discharge. Pain scores among evaluators were in good agreement with an overall Intraclass Correlation Coefficient (ICC) of 0.7897 (95% Confidence Interval 0.795-0.8313). In all groups, overall pain scores 1-hour post anesthesia recovery were significantly higher than scores 3 hours post anesthesia recovery (P < .0001). Averaged pain scores compared among treatment groups did not differ at 1 hour post recovery. At 3-hours post anesthesia recovery, MEL group cats had significantly lower pain scores than the BLE group (P = .018). Study results indicate that early postoperative pain scores were similar for cats receiving local infiltrations of BUP, BLE, DEX, and MEL as part of a multimodal pain therapy for routine ovariohysterectomies. MEL showed somewhat better results 3 hours post anesthesia recovery, gaining significance over the BLE group.
Comparative pharmacokinetics of meloxicam oil suspension in pigs at different dosages following intramuscular administration
2021, Research in Veterinary Science
This study aimed to evaluate the preliminary safety of self-developed meloxicam (MEL) oil suspension and determine the comparative pharmacokinetics of it at 0.8 and 2 mg/kg body weight (b.w.) dosages in pigs following a single intramuscular administration. Six rabbits were used for the study of preliminary safety and six healthy pigs were used for pharmacokinetics study by a crossover design in two periods. The muscle irritation results showed that both of the MEL oil suspension and the conventional injection had no significant changes at the dosage of 0.4 mg/kg b.w.. However, at the dosage of 2 mg/kg b.w., both of the self-developed MEL oil suspension and the MEL conventional injection showed mild irritation to muscle. Plasma concentrations of MEL were measured by ultra performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS). The MEL plasma concentrations were quantified up to 30 h and 72 h after intramuscular administration at the low- and high-dosage, respectively. The difference was statistically significant (P < 0.05) between different dosages in pharmacokinetic parameters of t_1/2λz, C_max, AUC_0-t, AUC_0-μ, MRT, and V_d. The C_max values of MEL were 1.92 ± 0.34 μg/ml and 3.03 ± 1.25 μg/ml at dosages of 0.8 and 2 mg/kg b.w. while the t_max values were 3.25 ± 1.04 h and 4.00 ± 1.26 h, respectively. The pharmacokinetics results of self-developed MEL oil suspension demonstrated that the retention time of it in pigs was prolonged, showing the sustained-release effect. Therefore, Oil suspension was an ideal new drug loading form of MEL.
Cyclooxygenases 1 and 2 inhibition and analgesic efficacy of dipyrone at different doses or meloxicam in cats after ovariohysterectomy
2021, Veterinary Anaesthesia and Analgesia
Citation Excerpt :
The administration of the drugs led to an inhibition of COX-1 activity, as observed by the plasma TXB2 concentration decrease. These results corroborate previous studies on the use of dipyrone (Hinz et al. 2007; Pierre et al. 2007) in other species and meloxicam in other species (Engelhardt et al. 1996a, b; Brideau et al. 2001) and in cats (Giraudel et al. 2005). The COX-1 activity inhibition was greater at both dipyrone doses than meloxicam from 4 hours on.
To evaluate the cyclooxygenases (COX) inhibition, adverse effects and analgesic efficacy of dipyrone or meloxicam in cats undergoing elective ovariohysterectomy.
Prospective, blinded, randomized, clinical study.
A total of 30 healthy young cats.
The cats were randomly assigned to three postoperative groups: D25 (dipyrone 25 mg kg⁻¹ every 24 hours), D12.5 (dipyrone 12.5 mg kg⁻¹ every 12 hours) and M (meloxicam 0.1 mg kg⁻¹ every 24 hours). In the first 24 hours, the drugs were administered intravenously (IV), and then orally for 6 (dipyrone) or 3 days (meloxicam). Prostanoids thromboxane B₂ and prostaglandin E₂ concentrations served as indicators of COX activity and, with physiological variables and pain and sedation scores, were measured for 24 hours after first analgesic administration. Rescue analgesia (tramadol, 2 mg kg⁻¹ IV) was provided if Glasgow feline composite measure pain scale (CMPS-Feline) ≥5. Laboratory tests included symmetric dimethylarginine and adverse effects were evaluated regularly up to 7 and 10 days after surgery, respectively. Parametric and nonparametric data were analyzed with two-way anova and Kruskal-Wallis tests, respectively (p < 0.05).
In the first half hour after analgesic administration, COX-1 activity was close to zero and remained significantly lower than before drug administration for 24 hours in all groups. The inhibition of COX-2 activity was significant for 30 minutes in all groups and up to 4 hours in group M. No alterations in laboratory tests or significant adverse effects were observed. Pain scores and need for rescue analgesia did not differ statistically among groups.
Dipyrone at both doses and meloxicam provided a nonselective inhibition of COX-1 and -2 activities and effective analgesia without causing significant adverse effects or laboratory tests alterations.
Dipyrone at both doses provides equally effective analgesia without causing adverse effects in cats undergoing ovariohysterectomy.
Effects of local or systemic administration of meloxicam on mammary gland inflammatory responses to lipopolysaccharide-induced mastitis in dairy cows
2021, Journal of Dairy Science
Nonsteroidal anti-inflammatory drugs (NSAID) are commonly used in combination with antimicrobial mastitis treatments to reduce pain. Little is known about whether meloxicam, an NSAID designed for the preferential inhibition of cyclooxygenase-2 over cyclooxygenase-1, affects the mammary immune response. The objective of this study was to analyze the mammary immune response to intramammary (local) or intravenous (systemic) administration of meloxicam with or without immune activation by lipopolysaccharide (LPS). We challenged 108 quarters of 30 cows with or without a low or high dose of LPS from Escherichia coli (0.1 or 0.2 µg/quarter), with or without meloxicam via intramammary administration (50 mg/quarter) or intravenous injection (0.5 mg/kg of body weight; ~300 mg/cow). Intramammary administration of meloxicam alone did not trigger an acute inflammatory response, verified by unchanged somatic cell count (SCC) and lactate dehydrogenase (LDH), BSA, and IgG concentrations in milk, which are normally augmented during mastitis due to an opening of the blood–milk barrier. Similarly, intramammary meloxicam did not change the mRNA abundance of inflammatory factors in mammary gland tissue. As expected, quarters challenged with either dose of LPS showed increased leukocyte infiltration (SCC); increased LDH, BSA, IgG, Na, and Cl concentrations; and diminished K concentrations in milk. In contrast to our hypothesis, the addition of intramammary or intravenous meloxicam did not reduce these markers of mastitis in milk. Instead, intramammary meloxicam appeared to accelerate the SCC response to LPS, but only at the lower LPS dose. Moreover, the mRNA expression of inflammatory factors in mammary tissue was not modified by the intramammary application of meloxicam compared with the contralateral quarters that were challenged with LPS only. We demonstrated for the first time that intramammary meloxicam at a dose of 50 mg/quarter did not trigger an immune response in the mammary glands of dairy cows. At the doses we used, meloxicam (intramammary or systemic) did not lower inflammatory responses. The intramammary administration of meloxicam seemed to stimulate leukocyte recruitment into the milk in quarters challenged with a low dose of LPS. The integrity of the blood–milk barrier was not protected by meloxicam in LPS-stimulated quarters. This study provides the first indications that meloxicam does not limit the inflammatory response in the mammary gland, although it does not impair the mammary immune system.
Abcg2 transporter affects plasma, milk and tissue levels of meloxicam
2020, Biochemical Pharmacology
Citation Excerpt :
Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used due to their analgesic, anti-inflammatory and antipyretic properties by inhibition of cyclooxygenase enzymes (COX) [1,2].
ATP-binding cassette (ABCG2) is an efflux transporter that extrudes xenotoxins from cells in liver, intestine, mammary gland, brain and other organs, affecting the pharmacokinetics, brain accumulation and secretion into milk of several compounds, including antitumoral, antimicrobial and anti-inflammatory drugs. The aim of this study was to investigate whether the widely used anti-inflammatory drug meloxicam is an Abcg2 sustrate, and how this transporter affects its systemic distribution. Using polarized ABCG2-transduced cell lines, we found that meloxicam is efficiently transported by murine Abcg2 and human ABCG2. After oral administration of meloxicam, the area under the plasma concentration–time curve in Abcg2^−/− mice was 2-fold higher than in wild type mice (146.06 ± 10.57 µg·h/ml versus 73.80 ± 10.00 µg·h/ml). Differences in meloxicam distribution were reported for several tissues after oral and intravenous administration, with a 20-fold higher concentration in the brain of Abcg2^−/− after oral administration. Meloxicam secretion into milk was also affected by the transporter, with a 2-fold higher milk-to-plasma ratio in wild-type compared with Abcg2^−/− lactating female mice after oral and intravenous administration. We conclude that Abcg2 is an important determinant of the plasma and brain distribution of meloxicam and is clearly involved in its secretion into milk.
Meloxicam affects the inflammatory responses of bovine mammary epithelial cells
2019, Journal of Dairy Science
Nonsteroidal anti-inflammatory drugs are used as supportive therapy with antimicrobial treatments for mastitis in cows to alleviate pain of the inflamed mammary gland. They act mainly by inhibition of cyclooxygenases. Meloxicam (MEL) is a drug designed for cyclooxygenase-2 selectivity, which is upregulated upon inflammation, acting as a key enzyme for the conversion of arachidonic acid to prostaglandins. Although some studies in dairy cows showed positive results in recovery from mastitis when MEL was added to the treatments, direct effects of MEL on the immune system of mastitic cows are unknown. The aim of this study was to investigate effects of MEL on the immune response of bovine mammary epithelial cells (MEC) with or without simultaneous immune stimulation by pathogen-associated molecular patterns of common mastitis pathogens. Mammary epithelial cells from 4 cows were isolated and cultured. To evaluate dose effects of MEL, MEC were challenged with or without 0.2 µg/mL lipopolysaccharide (LPS; serotype O26:B6 from Escherichia coli) with addition of increasing concentrations of MEL (0, 0.25, 0.5, 1.0, 1.5, or 2.0 mg/mL). The addition of MEL prevented the increase of mRNA expression of key inflammatory factors in LPS-challenged MEC in a dose-dependent manner. To investigate the effects of MEL on pathogen-specific immune responses of MEC, treatments included challenges with LPS from E. coli and lipoteichoic acid from Staphylococcus aureus with or without 1.5 mg/mL MEL for 3, 6, and 24 h. Meloxicam prevented the increase of mRNA abundance of key inflammatory mediators in response to LPS and lipoteichoic acid, such as tumor necrosis factor, serum amyloid A, inducible nitric oxide synthase, and the chemokines IL-8 and CXC chemokine ligands 3 and 5. The prostaglandin E₂ synthesis in challenged and nonchallenged cells was reduced by MEL within 24 h. Furthermore, MEL reduced the viability and consequently the total RNA yield of the cells. However, mRNA abundance of apoptosis-related enzymes was not affected by any treatment. Meloxicam had clear dose-dependent effects on the immune response of MEC to pathogen-associated molecular patterns of common mastitis pathogens by preventing increased expression of important factors involved in inflammation. This nonsteroidal anti-inflammatory drug also has detrimental effects on cell viability. How these effects would influence the elimination of pathogens from an infected mammary gland during mastitis therapy with meloxicam needs to be further investigated.

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Research paperMeloxican: Influence on arachidonic acid metabolism: Part 1. In vitro findings

Abstract

J Biol Chem

Lancet

Prostaglandins

Prostaglandins

J Biol Chem

J Biol Chem

Neuron

Antiinflammatory, analgesic, antipyretic and related properties of meloxicam, a new nonsteroidal anti-inflammatory agent

Inflamm Res

Meloxicam, a potent inhibitor of adjuvant arthritis in the rat

Scand J Rheumatol

A double blind placebo controlled study of 7.5 and 15 mg of meloxicam in patients with rheumatoid arthritis (RA)

Scand J Rheumatol

A double blind placebo controlled study of three different doses of meloxicam in patients with osteoarthritis of the knee

Scand J Rheumatol

Mode of action of aspirin and similar compounds

Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs

Nature New Biol

Temporal and pharmacological division of fibroblast cyclooxygenase expression into transcriptional and translational phases

Expression of a mitogen-responsive gene encoding prostaglandin synthase is regulated by RNA splicing

Mitogen-inducible prostaglandin GIH synthase: A new target for nonsteroidal anti-inflammatory drugs

Drug Devel Res

An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation

Nature

Selective inhibition of prostaglandin production in inflammatory exudates and gastric mucosa

Nature

Selectivity of nonsteroidal anti-inflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase

Research paper
Meloxican: Influence on arachidonic acid metabolism: Part 1. In vitro findings