mobic and Disease-Models--Animal

This review focuses on the key pharmacological findings with a new NSAID, meloxicam. Unlike established NSAIDs, it preferentially inhibits inducible COX-2 in guinea-pigs peritoneal macrophages and human COX-2 in COS cells. Compared with other NSAIDs, meloxicam is the most potent inhibitor of prostaglandin biosynthesis in pleural and peritoneal exudate, but only a weak inhibitor in the gastric tract and kidney. Ulcerogenicity in the rat stomach is weak in relation to anti-inflammatory potency, resulting in a high therapeutic index. Meloxicam's high anti-inflammatory potency combined with good tolerability can be explained by its preferential inhibition of COX-2. In adjuvant arthritis rats, meloxicam inhibits not only paw swelling, but also bone and cartilage destruction and systemic signs of disease. It inhibits leucocyte migration, but has no effect on leucotriene B4 or C4. Meloxicam shows a long-lasting anti-inflammatory and analgesic effect on inflammatory pain and reduces pyrogen-induced fever, but has no central nervous system effects. The pharmacokinetic profile of meloxicam in the rat is similar to that in man. Metabolites are inactive.

Topics: Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cyclooxygenase Inhibitors; Disease Models, Animal; Drug Tolerance; Humans; Inflammation; Meloxicam; Mice; Rats; Stomach Ulcer; Thiazines; Thiazoles

Because human patients with monkeypox virus (MPXV) infection report painful symptoms, it is reasonable to assume that animals infected with MPXV experience some degree of pain. Understanding whether and how analgesics affect MPXV disease progression is crucial when planning in vivo challenge experiments. In the current study, we challenged prairie dogs with a low dose (4 ×10³ pfu) of MPXV and treated with meloxicam (NSAID) or buprenorphine (opioid); control animals did not receive analgesia or received analgesia without MPXV challenge. Subsets of animals from each group were serially euthanized during the course of the study. Disease progression and viral kinetics were similar between groups, but MXPVinfected, meloxicam-treated animals showed increasing trends of morbidity and mortality compared with other groups. Differences between no-analgesia MPXV-infected control animals and MPXV-infected animals treated with buprenorphine were minimal. The findings in the current study allow more informed decisions concerning the use of analgesics during experimental MPXV challenge studies, thereby improving animal welfare. In light of these findings, we have modified our pain scale for this animal model to include the use of buprenorphine for pain relief when warranted after MPXV challenge.

Topics: Analgesia; Analgesics, Opioid; Animals; Anti-Inflammatory Agents, Non-Steroidal; Buprenorphine; Disease Models, Animal; Female; Meloxicam; Monkeypox virus; Mpox (monkeypox); Pain; Pain Management; Sciuridae

Anterior cruciate ligament (ACL) tear leads to post-traumatic osteoarthritis (PTOA), a significant clinical burden worldwide that currently has no cure. Recent studies suggest a role of subchondral bone adaptations in the development of PTOA. Particularly, microstructural changes in the rod-and-plate microstructure of subchondral bone may precede and contribute to OA progression. In this study, we quantified microstructural changes in subchondral trabecular rods and plates after ACL-transection for the first time in the well-established preclinical canine model of PTOA and investigated the therapeutic potentials of a bisphosphonate (zoledronate) and NSAID treatment (meloxicam). Unilateral hindlimb ACL transection was performed on skeletally-mature (2-year-old, N = 20) and juvenile (10-month-old, N = 20) male beagles. Animals were assigned to 4 groups (N = 5): ACLT, un-operated control, ACLT with zoledronate, and ACLT with meloxicam treatment. Subchondral bone microstructure was evaluated by micro-computed tomography and cartilage integrity was evaluated histologically. We found that ACL-induced subchondral bone changes depended on skeletal maturity of animals. In mature animals, significant loss of trabecular plates that resulted in reduced PR ratio occurred at Month 1 and persisted until Month 8. Zoledronate treatment prevented trabecular plate loss while meloxicam treatment did not. Whether cartilage degeneration is also attenuated warrants further investigation. In juvenile animals that have not reached skeletal maturity, transient changes in trabecular plate and rod microstructure occurred at Month 3 but not Month 9. Neither zoledronate nor meloxicam treatment attenuated bone microstructural changes or cartilage damages. Findings from this study suggest that early inhibition of bone resorption by bisphosphonate after injury may be a promising therapeutic approach to prevent alterations in subchondral bone microstructure associated with PTOA. Our results further demonstrate that pathogenesis of PTOA may differ between adolescent and adult patients and therefore require distinct management strategies.

Topics: Animals; Anterior Cruciate Ligament Injuries; Bone and Bones; Cartilage, Articular; Disease Models, Animal; Dogs; Male; Meloxicam; Osteoarthritis; X-Ray Microtomography; Zoledronic Acid

Microglia-mediated neuroinflammation plays an important role in ischemic stroke (IS). In this work, a series of novel indole and indazole-piperazine pyrimidine derivatives with anti-neuroinflammatory and neuroprotective activities were designed and synthesized for treatment of IS. Among these compounds, 5j displayed the most attractive cytoprotective effect against oxygen-glucose deprivation/reoxygenation (OGD/R)-induced damage in BV2 cells. Meanwhile, it significantly ameliorated the release of inflammatory mediators, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, nitric oxide (NO) and prostaglandin E2 (PGE2), from lipopolysaccharide (LPS)-induced BV2 cells. Moreover, 5j can decrease the release of TNF-α and IL-1β form LPS-induced mouse brain neuroinflammation model. As a potent inhibitor against both cyclooxygenase-2 (COX-2, IC

Topics: Animals; Anti-Inflammatory Agents; Brain Ischemia; Cyclooxygenase 2; Disease Models, Animal; Indazoles; Indoles; Ischemic Stroke; Lipopolysaccharides; Mice; Microglia; Neuroprotection; Neuroprotective Agents; Piperazine; Pyrimidines; Rats; Stroke; Tumor Necrosis Factor-alpha

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).. 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.. Case/control.. Academic medical center.. Mice.. Administration of peripherally restricted kappa receptor agonists and frequent blood sampling to determine hormone release and body temperature.. LH pulse parameters and body temperature.. 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.. 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

An established lipopolysaccharide (LPS) model previously described in Warmbloods, was inconsistent in Standardbred horses, where lameness was not detected despite the presence of synovitis. The present study aimed to determine the dose of LPS from E. coli O55:B5 required to induce mild to moderate lameness following middle carpal joint injection in Standardbred horses and to quantitate the induced lameness over time, with and without anti-inflammatory pre-treatment. In a baseline trial, eight healthy, clinically sound Standardbred horses were used in a rule-based dose-escalation design trial, starting at a dose of 10 endotoxin units (EU). Lameness at trot was evaluated visually and quantitatively (using an inertial-sensor system and pressure plate analysis). Synovial fluid aspirates were analysed for total nucleated cell counts, total protein and prostaglandin E

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Carpal Joints; Dinoprostone; Disease Models, Animal; Escherichia coli; Horse Diseases; Horses; Injections, Intra-Articular; Lameness, Animal; Lipopolysaccharides; Meloxicam; Synovial Fluid; Synovitis

Nonarteritic anterior ischemic optic neuropathy (NAION) commonly causes sudden optic nerve (ON)-related vision loss. The rodent NAION model (rAION) closely resembles NAION in presentation and physiological responses. We identified early rAION-associated optic nerve head (ONH) inflammatory gene expression responses and the anti-inflammatory prostaglandin PGJ

Topics: Animals; Benzodioxoles; Disease Models, Animal; Male; Meloxicam; Neuroprotective Agents; Optic Neuropathy, Ischemic; Piperidines; Prostaglandin Antagonists; Rats; Rats, Sprague-Dawley; Retinal Ganglion Cells

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

In the present study, we investigated whether mood stabilizer lithium (Li) protects against d-amphetamine (AMP)-induced mania-like behaviours via modulating the novel proinflammatory potential. Repeated treatment with AMP resulted in significant increases in proinflammatory cyclooxygenase-2 (COX-2) and indolemaine-2,3-dioxygenase-1 (IDO)-1 expression in the prefrontal cortex (PFC) of mice. However, AMP treatment did not significantly change IDO-2 and 5-lipoxygenase (5-LOX) expression, suggesting that proinflammatory parameters such as COX-2 and IDO-1 are specific for AMP-induced behaviours. AMP-induced initial expression of COX-2 (15 minutes post-AMP) was earlier than that of IDO-1 (1 hour post-AMP). Mood stabilizer Li and COX-2 inhibitor meloxicam significantly attenuated COX-2 expression 15 minutes post-AMP, whereas IDO-1 inhibitor 1-methyl-DL-tryptophan (1-MT) did not affect COX-2 expression. However, AMP-induced IDO-1 expression was significantly attenuated by Li, meloxicam or 1-MT, suggesting that COX-2 is an upstream molecule for the induction of IDO-1 caused by AMP. Consistently, co-immunoprecipitation between COX-2 and IDO-1 was observed at 30 minutes, 1, 3, and 6 hours after the final AMP treatment. This interaction was also significantly inhibited by Li, meloxicam or 1-MT. Furthermore, AMP-induced hyperlocomotion was significantly attenuated by Li, meloxicam or 1-MT. We report, for the first time, that mood stabilizer Li attenuates AMP-induced mania-like behaviour via attenuation of interaction between COX-2 and IDO-1, and that the interaction of COX-2 and IDO-1 may be critical for the therapeutic intervention mediated by mood stabilizer.

Topics: Amphetamine; Animals; Antimanic Agents; Behavior, Animal; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Disease Models, Animal; Indoleamine-Pyrrole 2,3,-Dioxygenase; Lithium Chloride; Locomotion; Male; Mania; Meloxicam; Mice, Inbred C57BL; Prefrontal Cortex; Signal Transduction; Tryptophan

Non-arteritic anterior ischemic optic neuropathy (NAION) causes a sudden loss of vision and lacks effective treatment. Granulocyte colony-stimulating factor (G-CSF) provides neuroprotection against the experimental optic nerve injuries but also induce leukocytosis upon typical administration. We found synergetic neuroprotective effects of meloxicam and low dose G-CSF without leukocytosis in a rat model of anterior ischemic optic neuropathy (rAION). The WBC counts in the low-dose G-CSF-plus meloxicam-treated group were similar to the sham-operated group. Combination treatment of low-dose G-CSF plus meloxicam preserved RGCs survival and visual function, reduced RGC apoptosis and the macrophages infiltration, and promote more M2 phenotype of macrophage/microglial transition than the low-dose GCSF treatment or the meloxicam treatment. Moreover, the combination treatment induced higher serine/threonine kinase 1 (Akt1) expression. The combination treatment of low-dose G-CSF plus meloxicam lessened the leukocytotic side effect and provided neuroprotective effects via Akt1 activation in the rAION model. This approach provides crucial preclinical information for the development of alternative therapy in AION.

Topics: Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Granulocyte Colony-Stimulating Factor; Humans; Leukocyte Count; Leukocytosis; Macrophages; Male; Meloxicam; Neuroprotective Agents; Optic Nerve; Optic Neuropathy, Ischemic; Proto-Oncogene Proteins c-akt; Rats; Retinal Ganglion Cells; Signal Transduction

Background Osteoarthritis (OA) is a chronic disease in the joints. One of the proinflammatory cytokines that is thought to have a major role in the inflammatory process, the emergence of pain, and cartilage damage in OA is tumor necrosis factor α (TNF-α). Meloxicam is a nonsteroidal anti-inflammatory drug class of drugs that is relatively selective in inhibiting the activity of cyclooxygenase 2 (COX-2) formation. This study is conducted to prove the change in TNF-α level in the use of meloxicam with model in animals suffering from OA. Methods The OA rat model was induced with sodium monoiodoacetate intra-articularly. Rats were divided into 5 groups: negative control group, positive control group, and treatment groups with various doses of meloxicam. Hyperalgesia effect was evaluated using a warm plate test, and TNF-α level was determined using enzyme-linked immunosorbent assay. Results The treatment groups that received meloxicam at a dose of 1.0, 3.0, or 10.0 mg/kg body weight (BW) did not show significant differences in rat knee joint diameter (p = 0.99), but showed a significant difference in sensitivity to heat stimulation (p = 0.02) compared to the control group. Osteoarthritis rats experienced a significant reduction in TNF-α level after being given meloxicam at a dose of 10 mg/kg BW compared with the control group. This shows that the 10 mg/kg BW of meloxicam is a potential dose in reducing the TNF-α level in OA rat models. Conclusions Based on these data, it can be concluded that the inhibition of pain and the development of OA by meloxicam in animal models may be assigned to a decreased level of TNF-α.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Disease Models, Animal; Dose-Response Relationship, Drug; Hyperalgesia; Iodoacetic Acid; Male; Meloxicam; Osteoarthritis, Knee; Rats; Tumor Necrosis Factor-alpha

The aim of this study is to determine the effects of alone or combined usage of doxycycline and meloxicam on brain superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), and matrix metalloproteinase (MMP)-9 levels of lipopolysaccharide (LPS)-induced brain inflammation. Totally 78 rats were divided into 5 groups; Healthy control (n=6), LPS (n=18, 0.05μg/μL/rat, intracranially), LPS+D (n=18, LPS 0.05μg/μL/rat, intracranially and doxycycline 40 mg/kg, intraperitoneally), LPS+M (n=18, LPS 0.05 μg/μL/rat, intracranially and meloxicam 2 mg/kg, intraperitoneally), LPS+Combination (n=18, LPS 0.05 μg/μL/rat, intracranially and simultaneously both drug combination) groups. Animals were euthanized at 1, 3 and 6 hours following injections and the brains were removed. Brain SOD, CAT, MDA and MMP-9 levels were determined by ELISA reader. Parameters of LPS groups generally different from Healthy control group. When compared to LPS group, increased SOD level of LPS+D at 3 hours and CAT levels of LPS+M and LPS+D groups were determined (P<0.05) at 3 and 6 hours, respectively. In addition, all treatments statistically significantly (P<0.05) decreased MMP-9 levels at 6 hours. In conclusion, doxycycline and meloxicam may show antioxidant effect via increasing antioxidant enzyme production in the brain; however combined usage of drugs may show more beneficial effect for neuroinflammation. .

Topics: Animals; Anti-Bacterial Agents; Antioxidants; Catalase; Cyclooxygenase 2 Inhibitors; Disease Models, Animal; Doxycycline; Drug Therapy, Combination; Encephalitis; Inflammation; Lipopolysaccharides; Male; Meloxicam; Rats, Wistar; Superoxide Dismutase

To evaluate the effects of the nutraceuticals omega-6/3 and omega-9/6 on endometriosis-associated infertility and pain.. Controlled experimental study, with each group composed of eight female rats. Fertility groups: sham-operated control (0.9% saline solution); control with endometriosis (0.9% saline); omega-6/3 (1.2 g/kg/day); omega-9/6 (1.2 g/kg/day); and meloxicam (0.8 mg/kg/day). Pain groups: sham-operated control (0.9% saline); control with endometriosis (0.9% saline); omega-6/3 (1.2 g/kg/day); omega-9/6 (1.2 g/kg/day); medroxyprogesterone acetate (5 mg/kg/every 3 days); and meloxicam (0.8 mg/kg/day). Peritoneal endometriosis was surgically induced. Pain was evaluated with the writhing test. Fertility was evaluated by counting the number of embryos in the left hemi-uterus.. The mean number of writhings was as follows: sham-operated, 11.1 ± 2.9; control with endometriosis, 49.3 ± 4.4; omega-6/3, 31.5 ± 2.7; omega-9/6, 34.1 ± 4.5; medroxyprogesterone acetate, 2.1 ± 0.8; meloxicam, 1 ± 0.3. There was a significant difference between both controls and all drugs used for treatment. Regarding fertility, the mean values were as follows: sham-operated, 6.8 ± 0.6; control with endometriosis, 4.2 ± 0.7; omega-6/3, 4.7 ± 1; omega-9/6, 3.8 ± 0.9; and meloxicam, 1.8 ± 0.9.. The omega-6/3 and omega-9/6 nutraceuticals decreased pain compared to the controls. There was no improvement in fertility in any of the tested groups.

Topics: Animals; Disease Models, Animal; Endometriosis; Fatty Acids, Omega-3; Female; Fertility; Medroxyprogesterone Acetate; Meloxicam; Pain; Peritoneum; Rats

Although current neuropathic pain treatment guidelines do not recommend the use of nonsteroidal anti-inflammatory drugs (NSAIDs), whether NSAIDs can serve as a useful adjuvant to conventional multimodal therapy remains unclear.. The spared nerve injury (SNI) rats rapidly developed profound and long-lasting spontaneous and evoked pain behaviors, including mechanical and cold allodynia of the ipsilateral hind paw. At day 5, we first characterized the nociceptive responses to ketorolac, tramadol, pregabalin, and their combinations.. We found that tramadol and pregabalin exerted dose-dependent analgesic effects on both spontaneous and evoked behaviors. However, ketorolac alone did not suppress any behaviors regardless of the dose. Ketorolac-tramadol and ketorolac-pregabalin produced variable degrees of additive suppression of spontaneous and evoked behavioral responses. Cold allodynia was profoundly diminished after ketorolac was added to ineffective pregabalin or tramadol. Mechanical allodynia was markedly attenuated by ketorolac-pregabalin but less so by ketorolac-tramadol mixtures.. Our data demonstrated that an NSAID alone failed to relieve spontaneous or evoked pain behaviors in the rat SNI model, but when combined with a weak opioid and α-2-δ-ligand produced a profound synergistic analgesic effect on cold allodynia and discrepant efficacy for mechanical allodynia and spontaneous pain.

Topics: Animals; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Ketorolac; Male; Meloxicam; Neuralgia; Pregabalin; Rats; Rats, Sprague-Dawley; Tramadol

Murine orthotopic cancer models often require surgery, potentially causing pain or distress. However, analgesics are often withheld because they may alter tumour development. Two orthotopically implanted cancers were investigated in mice pre-treated with meloxicam (10 mg/kg), buprenorphine (0.2 mg/kg) or saline (1 ml/kg). Tumours were imaged and welfare was assessed using body weight, behaviour and nociceptive responses. In study 1, BALB/c mice were inoculated with 4T1 mammary carcinoma or saline during surgery or anaesthesia. As pre-treatment with a single buprenorphine dose appeared beneficial to cancer growth consistency, a second cohort of mice additionally received saline or buprenorphine at 12 and 24 h. Surgery resulted in increased mammary tumour growth and lung metastases. These unwanted effects were lessened by buprenorphine pre-treatment, especially when given repeatedly. Mammary tumour-bearing mice became less active and nociceptive thresholds declined over time, indicating some discomfort as tumours grew. In study 2, C57BL/6 mice received B16 melanoma. This non-surgical model was used to determine whether meloxicam or buprenorphine affected cancer seeding of the lungs. While meloxicam reduced B16 lung seeding, buprenorphine did not. Mechanical thresholds decreased as cancer developed in mice bearing melanoma, but the magnitude of this was insufficient to conclude that there were any significant welfare concerns. This study highlights the scientific value in utilising non-surgical models, where possible. When surgery must be performed at the time of tumour inoculation, the effects of this should be controlled with appropriate analgesics to enhance the value and possibly translation of the research.

Topics: Analgesics; Animal Welfare; Animals; Breast Neoplasms; Buprenorphine; Cell Line, Tumor; Disease Models, Animal; Female; Lung Neoplasms; Mammary Neoplasms, Experimental; Melanoma, Experimental; Meloxicam; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Neoplasm Metastasis; Pain; Thiazines; Thiazoles; Xenograft Model Antitumor Assays

Rutin, naturally occurring flavonoid, has reported to cover interesting multiple pharmacological properties. This study evaluated rutin or/and meloxicam effects in paw inflammation induced by formalin in mice. Mice were divided into four groups: I-Formalin group, II-Rutin 60 mg/kg (p.o.), III-Meloxicam 10 mg/kg (p.o.), plus IV-Combined rutin and meloxicam. Therapies were administered once a day for 7 days. The curative effects were assessed on inflammatory, oxidative stress, and apoptosis. Both rutin and/or meloxicam induced marked improvement in paw licking time on the 1st day and by combined treatment only on the 3rd day as well reduction in paw edema% on the 3rd day. Moreover, noticeable progress in liver malondialdehyde content, superoxide dismutase, and sorbitol dehydrogenase activities as well decline in paw interleukin-1β level and extent of apoptosis. The results spot light on the good influence of combined rutin and meloxicam in formalin-induced mice paw inflammation to a better extent than either rutin or meloxicam lonely.

Topics: Acute Pain; Analgesics, Non-Narcotic; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Apoptosis; Behavior, Animal; Cellulitis; Connective Tissue; Disease Models, Animal; Drug Therapy, Combination; Edema; L-Iditol 2-Dehydrogenase; Liver; Male; Meloxicam; Mice; Organ Size; Oxidative Stress; Random Allocation; Rutin; Superoxide Dismutase; Thiazines; Thiazoles

Migraine is the third most common disease in the world (behind dental caries and tension-type headache) with an estimated global prevalence of 15%, yet its etiology remains poorly understood. Recent clinical trials have heralded the potential of therapeutic antibodies that block the actions of the neuropeptide calcitonin gene-related peptide (CGRP) or its receptor to prevent migraine. Calcitonin gene-related peptide is believed to contribute to trigeminal nerve hypersensitivity and photosensitivity in migraine, but a direct role in pain associated with migraine has not been established. In this study, we report that peripherally administered CGRP can act in a light-independent manner to produce spontaneous pain in mice that is manifested as a facial grimace. As an objective validation of the orbital tightening action unit of the grimace response, we developed a squint assay using a video-based measurement of the eyelid fissure, which confirmed a significant squint response after CGRP injection, both in complete darkness and very bright light. These indicators of discomfort were completely blocked by preadministration of a monoclonal anti-CGRP-blocking antibody. However, the nonsteroidal anti-inflammatory drug meloxicam failed to block the effect of CGRP. Interestingly, an apparent sex-specific response to treatment was observed with the antimigraine drug sumatriptan partially blocking the CGRP response in male, but not female mice. These results demonstrate that CGRP can induce spontaneous pain, even in the absence of light, and that the squint response provides an objective biomarker for CGRP-induced pain that is translatable to humans.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antibodies; Calcitonin Gene-Related Peptide; Disease Models, Animal; Facial Pain; Injections, Intraperitoneal; Locomotion; Meloxicam; Mice; Mice, Inbred C57BL; Pain; Serotonin 5-HT1 Receptor Agonists; Sumatriptan

Painful neuropathic injuries are accompanied by robust inflammatory and oxidative stress responses that contribute to the development and maintenance of pain. After neural trauma the inflammatory enzyme cyclooxygenase-2 (COX-2) increases concurrent with pain onset. Although pre-treatment with the COX-2 inhibitor, meloxicam, before a painful nerve root compression prevents the development of pain, the pathophysiological mechanisms are unknown. This study evaluated if pre-treatment with meloxicam prior to painful root injury prevents pain by reducing spinal inflammation and peripheral oxidative stress. Glial activation and expression of the inflammatory mediator secreted phospholipase A

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Astrocytes; Cervical Cord; Disease Models, Animal; Ganglia, Spinal; Inflammation; Male; Meloxicam; Microglia; Neurons; Oxidative Stress; Pain; Peripheral Nervous System Diseases; Radiculopathy; Rats, Sprague-Dawley; Spinal Nerve Roots

This study was designed to investigate the effect of the cortical cyclooxygenase-2 (COX2) pathway on depressive behaviour in rats. Meloxicam, COX2 overexpressed lentivirus and COX2 RNAi lentivirus were administered to Sprague-Dawley rats subjected to chronic unpredictable mild stress (CUMS). Behaviour tests, biochemistry and immunohistochemistry methods, enzyme-linked immunosorbent assays, western blotting and reverse transcription polymerase chain reactions were used to evaluate the changes in rat behaviour and the cortical COX2 pathway. CUMS rats showed depressive-like behaviours. The superoxide dismutase activity and cyclic adenosine monophosphate (cAMP) contents were significantly decreased, the contents of malondialdehyde, prostaglandin E2 (PGE2) and inflammatory cytokines were significantly increased. The expressions of protein kinase A (PKA) and cAMP response element-binding protein (CREB) were decreased, and the levels of brain-derived neurotrophic factor (BDNF) and COX2 were significantly increased. Meloxicam and COX2 RNAi lentivirus significantly alleviated the abnormalities induced by CUMS, while COX2 overexpressed lentivirus aggravated these abnormalities. Our results indicated that the cortical COX2 pathway was activated in CUMS rats. Inhibition of COX2 activity/expression can obviously improve depressive behaviours in CUMS rats. Upregulating COX2 expression can increase the susceptibility of rats to CUMS. An imbalance in the cortical COX2-PGE2-cAMP/PKA-CREB-BDNF signalling pathway participates in the pathogenic mechanism of depression.

Topics: Animals; Behavior, Animal; Brain-Derived Neurotrophic Factor; Cerebral Cortex; Cyclic AMP; Cyclic AMP Response Element-Binding Protein; Cyclic AMP-Dependent Protein Kinases; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Cytokines; Depression; Dinoprostone; Disease Models, Animal; Gene Expression Regulation; Male; Meloxicam; Rats; RNA Interference; Signal Transduction; Superoxide Dismutase; Thiazines; Thiazoles

To investigate the mechanism of cyclooxygenase 2 (COX2) in learning and memory impairments in rats subjected to chronic unpredictable mild stress (CUMS), meloxicam was used intragastrically to inhibit the activity of cyclooxygenase 2. Moreover, cyclooxygenase 2 over-expressing or RNA interfere lentivirus was injected intraventricularly to increase or decrease the enzyme's expression, respectively. The body weights and sucrose consumption were used to analyze depressive behaviors, while the Morris water maze and step-down-type passive avoidance tests were carried out to evaluate the learning-memory functions. The levels of inflammatory cytokines were measured to estimate inflammation and the contents of cyclic adenosine monophosphate (cAMP) were used to measure the levels of the second messenger. Changes in cyclooxygenase 2 mRNA levels were analyzed using reverse transcription polymerase chain reaction. Moreover, the expression of cyclooxygenase 2, brain-derived neurotrophic factor (BDNF), prostaglandins receptor 3 (EP3), protein kinase A (PKA), cAMP response element binding protein (CREB), and phosphorylated CREB were estimated using immunohistochemical staining or western blotting. The results showed that CUMS led to significant depressive-like behaviors and learning and memory dysfunctions. Also, the cAMP levels decreased significantly, while levels of inflammatory cytokines and prostaglandins E2 increased significantly. The expressions of PKA, BDNF, phosphorylated CREB/CREB declined and cyclooxygenase 2 was increased. Meloxicam and cyclooxygenase 2 RNA interfere lentivirus reversed the changes caused by CUMS while cyclooxygenase 2-overexpressing lentivirus worsened these abnormalities. The findings also showed that CUMS increased cyclooxygenase 2 expression, which can cause learning and memory impairments, mainly through activating the hippocampal neuronal cAMP/PKA-CREB-BDNF signaling pathways.

Topics: Animals; Behavior, Animal; Brain-Derived Neurotrophic Factor; Cyclic AMP; Cyclic AMP Response Element-Binding Protein; Cyclic AMP-Dependent Protein Kinases; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cytokines; Disease Models, Animal; Gene Expression Regulation; Hippocampus; Inflammation Mediators; Learning; Meloxicam; Memory; Memory Disorders; Rats; Signal Transduction; Stress, Psychological; Synapses; Thiazines; Thiazoles

Although neck and low-back pain are common sources of neuropathic pain with high societal costs, the pathophysiology of neuropathic pain is not well-defined. Traditionally, most rodent pain studies rely on evoked reflex-based testing to measure pain. However, these testing methods do not reveal spontaneous pain, particularly early after injury. The rat grimace scale (RGS) for quantifying spontaneous pain has been validated after visceral, incisional, orthopedic, and inflammatory insults but not neuropathic pain. The current study used a rat model of radiculopathy to investigate the time course of RGS, the effect of the NSAID meloxicam on RGS, and the reliability and consistency of RGS across testers. RGS values at baseline and at 3, 6, 24, and 48 h after cervical nerve root compression (NRC) that induced robust evoked pain responses were compared with those obtained after sham surgery. The RGS was also evaluated at 6 h after NRC in another set of rats that had received meloxicam treatment prior to surgery. At 6 h, NRC induced higher RGS scores (1.27 ± 0.18) than did sham surgery (0.93 ± 0.20), and scores remained above baseline for as long as 48 h. Treatment with meloxicam before NRC reduced RGS at 6 h to sham levels, which were lower than those of injury without treatment. The RGS was associated with very good interobserver reliability (intraclass correlation coefficient, 0.91) and excellent internal consistency (Cronbach α, 0.87). These findings suggest that RGS is a useful approach to identifying and monitoring acute neuropathic pain in rats.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Disease Models, Animal; Facial Expression; Male; Meloxicam; Neuralgia; Pain Measurement; Radiculopathy; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Thiazines; Thiazoles; Time Factors; Video Recording

Nonsteroidal anti-inflammatory (NSAI) drugs are the most commonly used group of drugs today. Increase in the use of standard NSAI for treating pain and inflammation was restricted by the fact that these drugs were proven to possibly cause gastrointestinal and renal toxicity. Meloxicam is a NSAI that has anti-inflammatory, analgesic, and antipyretic effects. This study aims to investigate the effects of meloxicam on stomach, kidney, and liver of rats under light microscopy level. Based on the light microscopic observations, mononuclear cell infiltration and pseudolobular formation was established in liver samples of animals in the experimental group. Metaplasia in surface and glandular epithelia and atrophy were observed in stomach samples. Glomerular stasis-related hypertrophy and focal interstitial nephritis were found in kidneys. It was concluded in this study that meloxicam might cause hepatotoxicity, nephrotoxicity, and gastric metaplasia in rats at a used dose and duration.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Chemical and Drug Induced Liver Injury; Cyclooxygenase 2; Disease Models, Animal; Dose-Response Relationship, Drug; Inflammation; Kidney; Kidney Diseases; Liver; Meloxicam; Metaplasia; Pain; Rats; Rats, Sprague-Dawley; Stomach; Stomach Diseases; Thiazines; Thiazoles; Toxicity Tests

Studies have shown altered pharmacokinetic patterns (PK) in patient suffering from acute pain. Thus, we aimed to simulate pharmacokinetics of meloxicam and ibuprofen in pain and pain-free states using a physiological based software program to identify the underlining mechanistic changes for the observed differences.. Published in vivo data of meloxicam and ibuprofen were used for the simulations. Two drug formulations were studied: a fast dissolving (FD) and regular release (RR) tablet formulation. The oral bioavailability was compared between these formulations in vagally suppressed rats (gastric dysfunction) and a control group. For ibuprofen additional human data of a control and post dental surgery group were used. All simulations were performed using GastroPlus™. The in vivo drug release and PK of all formulations were estimated for both drugs using the software's immediate release (IR) or gastric release (GR) models.. For meloxicam, the IR model predicted the in vivo absorption in the control group after administration of the FD and RR formulations. When gastric dysfunction was induced, the IR model did not predict absorption while the GR model did for both formulations, FD and RR. For ibuprofen, the predictions were also very close for both formulations, using the IR model for the control group and the GR model for the vagally suppressed condition in rats and humans.. Gastric control of the drug release in pain/disease state was identified as the major factor causing the observed differences in the pharmacokinetics. Computer simulations of disease states can be employed to optimize drug release from dosage forms to overcome the reported shortfalls in the drug absorption.

Topics: Animals; Computer Simulation; Disease Models, Animal; Humans; Ibuprofen; Meloxicam; Rats; Tablets; Thiazines; Thiazoles

The objective of this study was to investigate the effect of meloxicam-loaded nanocapsules (M-NC) on the treatment of the memory impairment induced by amyloid β-peptide (aβ) in mice. The involvement of Na(+), K(+)-ATPase and cyclooxygenase-2 (COX-2) activities in the hippocampus and cerebral cortex was also evaluated. Mice received aβ (3 nmol/ 3 μl/ per site, intracerebroventricular) or vehicle (3 μl/ per site, i.c.v.). The next day, the animals were treated with blank nanocapsules (17 mL/kg) or M-NC (5 mg/kg) or free meloxicam (M-F) (5 mg/kg). Treatments were performed every other day, until the twelfth day. Animals were submitted to the behavioral tasks (open-field, object recognition, Y-maze and step-down inhibitory avoidance tasks) from the twelfth day. Na(+), K(+)-ATPase and COX-2 activities were performed in hippocampus and cerebral cortex. aβ caused a memory deficit, an inhibition of the hippocampal Na(+), K(+)-ATPase activity and an increase in the hippocampal COX-2 activity. M-NC were effective against all behavioral and biochemical alterations, while M-F restored only the COX-2 activity. In conclusion, M-NC were able to reverse the memory impairment induced by aβ, and Na(+), K(+)-ATPase is involved in the effect of M-NC.

Topics: Alzheimer Disease; Animals; Behavior, Animal; Cerebral Cortex; Cyclooxygenase 2; Disease Models, Animal; Hippocampus; Meloxicam; Memory; Memory Disorders; Mice; Nanocapsules; Sodium-Potassium-Exchanging ATPase; Thiazines; Thiazoles

The purpose of this study was to determine the activity of the autonomic nervous system (ANS), using spectral analysis of the heart rate variability (HRV) in the model of partial bladder outlet obstruction (PBOO) in rats treated with selected non-steroidal anti-inflammatory drugs (NSAID): piroxicam (PRX) or meloxicam (MLX), and following administration of PGF2a prostaglandin analogue (Enzaprost F5). Neither the use of PGF2a analogue nor of MLX, caused significant changes in the HRV spectrum (except for HRV spectrum total power reduction with MLX). The use of PRX caused reduction of the total power and powers of all components of the HRV spectrum (except for VLF). Moreover, increased nLF and reduced nHF were observed. The obtained results suggest that the total prostaglandin synthesis block with a non-selective cyclooxygenase inhibitor (PRX) results in reduced ANS total activity, with decreased parasympathetic activity and a relative sympathetic predominance. The preferential cyclooxygenase-2 block (MLX) caused reduction of the total ANS activity as well, however with no clear disproportion of any part of the ANS. Therefore, prostaglandin synthesis inhibition and associated decrease of parasympathetic activity may constitute an additional and favourable feature of NSAID pharmacodynamics in the treatment of BPH.

Topics: Animals; Cyclooxygenase 2 Inhibitors; Dinoprost; Disease Models, Animal; Heart Rate; Meloxicam; Molecular Targeted Therapy; Piroxicam; Prostaglandin Antagonists; Prostaglandins; Prostaglandins, Synthetic; Rats; Rats, Wistar; Thiazines; Thiazoles; Urinary Bladder Neck Obstruction; Urodynamics

Preclinical Research Neuropathic pain is particularly difficult to treat because of its diverse etiologies and underlying pathophysiological mechanisms. Drug combinations have been proposed to effectively treat some neuropathies. In the present study the interaction of five combinations of meloxicam and gabapentin, were studied to assess the possible synergistic antinociceptive response in neuropathic pain using the von Frey and acetone tests in rat models. Coadministration of meloxicam and gabapentin increased the antihyperalgesic or antiallodynic effects as compared with the compounds administered alone. The area under the curve (AUC) of the antihyperalgesic effects produced by the combination of the two drugs was generally similar to the theoretical sum of effects produced by each drug alone. However, the AUC of the antiallodynic effect produced by one combination (meloxicam 1.0 mg/kg + gabapentin 10 mg/kg) was greater than the theoretical sum of the effects produced by each drug alone. The type of final interaction on the drug combinations can be additive or cause potentiation of antinociceptive effects and depends on the proportion of each compound used in dosing. Drug Dev Res 77 : 134-142, 2016. © 2016 Wiley Periodicals, Inc.

Topics: Amines; Analgesics; Animals; Area Under Curve; Cyclohexanecarboxylic Acids; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Gabapentin; gamma-Aminobutyric Acid; Male; Meloxicam; Neuralgia; Rats; Thiazines; Thiazoles; Treatment Outcome

Glycyrrhetinic acid (GA) and paeoniflorin (PF) are the main active ingredients in Chinese peony- Liquorice Decoction, a widely used Traditional Chinese Medicine.. The aim of this work was to investigate the combinatory analgesic effect of GA and PF after percutaneous administration and to define their pharmacokinetic/pharmacodynamic (PK/PD) characteristics.. GA and PF were produced to transdermal patches based on previous research, and the permeation parameters of GA and PF in the patches were investigated with in vitro experiments. Dysmenorrhea model mice were then produced to compare the analgesic effects of the patches with different proportions of GA-PF. In the in vivo assessment, the number of writhes exhibited by the dysmenorrhea mice was recorded at designated time points, and skin, muscle under skin and plasma samples were collected, for assessments of drug distribution, pharmacokinetics parameters and PK/PD characteristics.. In dysmenorrhea mice, GA-PF and meloxicam (the positive control drug) could relieve pain to equal degrees. Specifically, a single dose of the optimized patches (10%GA-10%PF, wt) exerted a steady analgesic effect for 48h in dysmenorrhea mice, but this effect lagged behind the changes in the plasma concentration. Evaluation with the Bliss Independence criterion revealed that the two ingredients displayed a synergistic effect. Then the PK/PD relationship of GA in this compound preparation was defined with this synergistic effect. The preparation might be suitable for topical spasmolysis and anti-inflammatory therapy.

Topics: Administration, Cutaneous; Animals; Anti-Inflammatory Agents; Disease Models, Animal; Drug Synergism; Drugs, Chinese Herbal; Dysmenorrhea; Female; Glucosides; Glycyrrhetinic Acid; Meloxicam; Mice; Monoterpenes; Skin Absorption; Thiazines; Thiazoles; Tissue Distribution; Transdermal Patch

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; Random Allocation; Real-Time Polymerase Chain Reaction; RNA, Messenger; Thiazines; Thiazoles; Treatment Outcome; Zoledronic Acid

Meloxicam (MLX) is a poorly water-soluble non steroidal anti-inflammatory drug (NSAID). The main objective of the present work was to enhance the dissolution of MLX and thus its bioavailability by the aid of additives. The novelty of this work rises from the utilization of spray drying technology to produce micro particulates solid dispersion systems containing MLX in the presence of small amount of additives. Differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FT-IR), and Scan Electron Microscope (SEM) were used for studying the physico-chemical and morphological properties of MLX samples. The dissolution of MLX samples was investigated in two different pH media. The morphology of MLX solid dispersion micro-particles was spherical in shape according to SEM. FT-IR profiles indicated that a complex was formed between MLX and the additives. DSC patterns of the MLX micro-particles suggested a reduction in the crystallinity of MLX and probability of presence of an interaction between MLX and the additives. The rate of dissolution of the spray-dried MLX enhanced as compared with the unprocessed MLX in both acidic and neutral media. It was found that 100% of the added MLX released within 5 min in phosphate buffer dissolution medium (pH 7.4) compared to that of the unprocessed MLX (15% in 60 min). Such increase rate in the dissolution of the spray dried MLX could be attributed to the increase in wettability of MLX particles and the hydrophilic nature of the additives. The anti-inflammatory effect of the spray dried MLX was explored using formalin induced rat paw edema model. The spray-dried samples showed an increase in the anti-inflammatory activity of MLX as compared to the unprocessed MLX. This work reveals that the spray drying technique is suitable for preparation of micro-particles with improved dissolution and anti-inflammatory effect of MLX.

Topics: Aerosols; Animals; Anti-Inflammatory Agents, Non-Steroidal; Buffers; Calorimetry, Differential Scanning; Chemistry, Pharmaceutical; Crystallography, X-Ray; Desiccation; Disease Models, Animal; Excipients; Formaldehyde; Hydrogen-Ion Concentration; Kinetics; Male; Meloxicam; Microscopy, Electron, Scanning; Pain; Particle Size; Rats, Wistar; Solubility; Spectroscopy, Fourier Transform Infrared; Technology, Pharmaceutical; Thiazines; Thiazoles; Water

Little is known about the treatment of bone pain in animal models of bone cancer. In the present study, the orthotopic 143-B human osteosarcoma xenotransplantation model was used to address the following questions: (1) Can repetitive analgesic treatment extend the experimental period by prolonging the time to reach humane endpoints and (2) Does repetitive analgesic treatment affect bone tumour development and metastasis? The analgesics, buprenorphine and meloxicam, were either applied individually or in combination at 12 h intervals as soon as the animals began to avoid using the tumour cell injected leg. While control mice treated with NaCl showed continuous body weight loss, the major criterion previously for terminating the experiments, animals treated with analgesic substances did not. The control mice had to be sacrificed 26 days after tumour cell injection, whereas the groups of animals with the different pain treatments were euthanized after an additional eight days. Importantly, primary intratibial tumour growth was not affected in any of the experimental groups by any of the pain treatment procedures. Between days 26 and 34 after tumour cell injection an increase of about 100% of the number of lung metastases was found for the groups treated with buprenorphine alone or together with meloxicam, but not for the group treated with meloxicam alone. In summary, the results indicated that both buprenorphine and meloxicam are suitable analgesics for prolonging the experimental periods in an experimental intratibial osteosarcoma mouse model.

Topics: Analgesics, Opioid; Animal Welfare; Animals; Anti-Inflammatory Agents, Non-Steroidal; Bone Neoplasms; Buprenorphine; Disease Models, Animal; Drug Therapy, Combination; Female; Injections; Longevity; Lung Neoplasms; Meloxicam; Mice; Mice, SCID; Osteosarcoma; Pain Management; Thiazines; Thiazoles; Tibia

To evaluate the effects of copaiba oil on jaw defects repair in Wistar rats treated with bioglass or adipose tissue.. A jaw defect was randomly created in forty-two rats and filled with bioglass or adipose tissue. The two groups (Gbio and Gcell) were subdivided in three subgroups with seven animals each according to gavage administration: control (distillated water), oil (copaiba oil) and melox (meloxicam). Euthanasia was performed after forty post-operative days. The bone formation was analyzed regarding the histological aspects.. The osteoclasts activity was observed only in four subgroups (p=0.78). Regarding the osteoblasts presence, it was very similar between the subgroups, the difference was due to Gcell-melox (p=0.009) that presented less osteoblastic activity. The inflammatory cells were more evident in Gcell-melox subgroup, however, there was no difference in comparison with the other subgroups (p=0.52). Bone formation was observed in all subgroups, just two animals showed no bone formation even after 40 days. More than 50% of bone matrix mineralization was observed in 56% (23 animals) of the analyzed areas. The bone matrix mineralization was not different between subgroups (p=0.60).. The subgroups that received copaiba oil showed bone repair, although not statistically significant in comparison to subgroups treated with meloxicam or controls. Copaiba oil administered by gavage had no effect on bone repair in this experimental model.

Topics: Adipose Tissue; Animals; Anti-Inflammatory Agents, Non-Steroidal; Bone Regeneration; Bone Substitutes; Ceramics; Disease Models, Animal; Fabaceae; Jaw; Jaw Abnormalities; Male; Meloxicam; Osteoblasts; Osteoclasts; Osteogenesis; Plant Oils; Rats, Wistar; Reproducibility of Results; Thiazines; Thiazoles; Time Factors; Treatment Outcome; Wound Healing

Lung contusion, which can occur in patients with blunt thoracic trauma, is a leading risk factor for development of acute lung injury (ALI) and acute respiratory distress syndrome. Statins are lipid-lowering drugs with many beneficial antiinflammatory and antioxidative effects. We therefore hypothesized that the administration of statins immediately after trauma will inhibit the production of inflammatory mediators, and thereby alleviate the severity of lung injury.. A model of blunt chest injury in rat was employed. The effects of statins (rosuvastatin) and cyclooxygenase-2 (COX-2) inhibitors (meloxicam) on ALI were assessed by measuring inflammatory mediator levels in the serum and in the bronchoalveolar space. Animals were killed at the end of day 3. Histologic evaluation of lung tissue was performed to confirm the presence and severity of lung contusion as well as the effects of statins, nonsteroidal antiinflammatory drugs, and their combination.. Administration of meloxicam after lung contusion decreased the amount of neutrophil infiltration; however, marked hemorrhage and edema were still noticed. Administration of rosuvastatin decreased significantly cytokine levels that were increased after the blunt chest trauma. Rosuvastatin increased the expression of inducible nitric oxide (iNOS), COX-2, heme oxygenase-1 (HO-1), and prostaglandin E2 (PGE-2) in the bronchoalveolar lavage fluid of the rat contused lungs. Coadministration of meloxicam prevented these changes.. Rosuvastatin treatment after lung contusion attenuated several features of ALI. The enhanced activity of iNOS, COX-2, and HO-1 in the lung may reflect the advent of protective processes that took place in the contused lung. To our knowledge, this is the first demonstration that prostaglandin pathways play an essential role in the effects of statins in lung injury.

Topics: Acute Lung Injury; Animals; Bronchoalveolar Lavage Fluid; Contusions; Cyclooxygenase 2; Dinoprostone; Disease Models, Animal; Drug Evaluation, Preclinical; Fluorobenzenes; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lung; Male; Meloxicam; Pyrimidines; Random Allocation; Rats; Rosuvastatin Calcium; Sulfonamides; Thiazines; Thiazoles

Lyme neuroborreliosis (LNB), caused by the spirochete Borrelia burgdorferi (Bb), could result in cognitive impairment, motor dysfunction, and radiculoneuritis. We hypothesized that inflammation is a key factor in LNB pathogenesis and recently evaluated the effects of dexamethasone, a steroidal anti-inflammatory drug, and meloxicam a non-steroidal anti-inflammatory drug (NSAID), in a rhesus monkey model of acute LNB. Dexamethasone treatment significantly reduced the levels of immune mediators, and prevented inflammatory and/or neurodegenerative lesions in the central and peripheral nervous systems, and apoptosis in the dorsal root ganglia (DRG). However, infected animals treated with meloxicam showed levels of inflammatory mediators, inflammatory lesions, and DRG cell apoptosis that were similar to that of the infected animals that were left untreated.. To address the differential anti-inflammatory effects of dexamethasone and meloxicam on neuronal and myelinating cells of the peripheral nervous system (PNS), we evaluated the potential of these drugs to alter the levels of Bb-induced inflammatory mediators in rhesus DRG cell cultures and primary human Schwann cells (HSC), using multiplex enzyme-linked immunosorbent assays (ELISA). We also ascertained the ability of these drugs to modulate cell death as induced by live Bb in HSC using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) viability assay and the potential of dexamethasone to modulate Bb-induced apoptosis in HSC by the TUNEL assay.. Earlier, we reported that dexamethasone significantly reduced Bb-induced immune mediators and apoptosis in rhesus DRG cell cultures. Here, we report that dexamethasone but not meloxicam significantly reduces the levels of several cytokines and chemokines as induced by live Bb, in HSC and DRG cell cultures. Further, meloxicam does not significantly alter Bb-induced cell death in HSC, while dexamethasone protects HSC against Bb-induced cell death.. These data help further explain our in vivo findings of significantly reduced levels of inflammatory mediators, DRG-apoptosis, and lack of inflammatory neurodegenerative lesions in the nerve roots and DRG of Bb-infected animals that were treated with dexamethasone, but not meloxicam. Evaluating the role of the signaling mechanisms that contribute to the anti-inflammatory potential of dexamethasone in the context of LNB could serve to identify therapeutic targets for limiting radiculitis and axonal degeneration in peripheral LNB.

Topics: Animals; Anti-Inflammatory Agents; Apoptosis; Borrelia burgdorferi; Cell Culture Techniques; Cytokines; Dexamethasone; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique; Ganglia, Spinal; Humans; In Situ Nick-End Labeling; Inflammation; Lyme Neuroborreliosis; Macaca mulatta; Meloxicam; Microscopy, Confocal; Neurons; Schwann Cells; Thiazines; Thiazoles

Atherosclerosis is a complex vascular inflammatory disease. In the last decade it was suggested that nonsteroidal anti-inflammatory drugs (NSAIDs) and in particular inhibition of cyclooxygenase (COX)-2 are associated with an increase in cardiovascular morbidity and mortality. Aspirin is known to reduce the incidence and mortality from ischemic heart disease and is a mainstay in the prevention of vascular complications of atherosclerosis.. To examine the effect of meloxicam, a selective COX-2 inhibitor, or low dose aspirin on the development of experimental atherosclerosis in apoE knockout (KO) compared to wild-type (WT) mice. We aimed to test the hypothesis that meloxicam, a potential vasculitis inducer, would exacerbate atherosclerotic lesions while aspirin, which is known to reduce the incidence of thrombosis occlusive events, would increase protection in this model.. We randomly divided 36 male apoE KO and 36 WT mice, 8 weeks old. Mice were treated for 10 weeks with 0.1 mg/ml aspirin, or 0.05 mg/ml meloxicam, dissolved in their drinking water. Control groups received regular drinking water. At sacrifice, the hearts were removed for histochemical staining and plaque size and composition were examined.. Aspirin-treated animals displayed a decreased atherosclerotic lesion area compared to the untreated control mice, while meloxicam had a null effect on the extent of atherosclerosis in Apo E KO mice.. These results suggest that low dose aspirin reduces early atherosclerosis, while inhibition of COX-2 by meloxicam is not associated with an increase in atherosclerotic plaque size in this mouse model.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Apolipoproteins E; Aspirin; Atherosclerosis; Cyclooxygenase 2 Inhibitors; Disease Models, Animal; Dose-Response Relationship, Drug; Male; Meloxicam; Mice; Mice, Inbred C57BL; Mice, Knockout; Plaque, Atherosclerotic; Thiazines; Thiazoles

Some antidepressants are effective for treating neuropathic pain independent of any effect on depression. Selective serotonin reuptake inhibitors (SSRIs) are one of the potential agents to treat neuropathic pain. The aims of this study were to compare the effects of SSRI and non-steroidal anti-inflammatory drugs (NSAIDs) on pain-related behavior and expression of cytokines in a rat model of neuropathic pain.. Spinal surgery was performed to apply nucleus pulposus (NP) to the dorsal root ganglion (DRG). NP animals were treated with saline (NP + S), meloxicam (NP + M), or low-dose or high-dose paroxetine (NP + PL and NP + PH), respectively. Behavioral testing was performed to investigate the mechanical withdrawal thresholds. The numbers of TNF-immunoreactive (IR) neurons in the DRG and of Iba1-IR microglia in the spinal cord (SC) were evaluated using immunohistochemistry. Expression of TNF in the DRG was examined using Western blots.. The thresholds on days 14, 21, and 28 were higher in the drug-treated animals than in the NP + S group (p < 0.05). The number of TNF-IR neurons in DRGs from the NP + M group increased on day 2 and decreased on day 7, and TNF expression in DRGs was significantly higher in the NP + S group than in the NP + M group on days 7, 14. The number of Iba1-IR microglia in the SC was significantly higher in the NP + S group than in the NP + M, NP + PL, and NP + PH groups on days 7 and 14.. An antidepressant might be a potential agent to treat lumbar disc herniation as well as NSAIDs.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Behavior, Animal; Calcium-Binding Proteins; Disease Models, Animal; Ganglia, Spinal; Immunohistochemistry; Meloxicam; Microfilament Proteins; Microglia; Neuralgia; Neurons; Paroxetine; Rats; Rats, Sprague-Dawley; Selective Serotonin Reuptake Inhibitors; Thiazines; Thiazoles; Tumor Necrosis Factor-alpha

The aim of this study was to synthesize three nitro substituted chalcones and to evaluate their anti-inflammatory activity in the model of carrageenan induced edema in rats. The nitro chalcone were prepared by aldol condensation using of mechanical agitation and environmentally friendly solvents with 72-73% yields in approximately 2h. The three structures were evaluated on biological activity at dose of 200mg/kg and they showed anti-inflammatory protective effect by both oral and intraperitoneal administration, this effect was time dependent.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents; Area Under Curve; Chalcone; Disease Models, Animal; Edema; Rats; ROC Curve

This study analyzes how age and inflammation modify the response of the vesicular glutamate transporters (VGLUTs), VGLUT1-3 to global brain ischemia/reperfusion (I/R) in brain areas with different I/R vulnerabilities.. Global ischemia was induced in 3- and 18-month-old male Sprague-Dawley rats and CA1 and CA3 hippocampal areas, dentate gyrus and cerebral cortex of sham-operated and I/R animals were removed 48 h after insult. Real-time PCR analysis revealed that I/R challenge resulted in a significant decrease of the VGLUT mRNA levels in young animals. Western blot assays showed a lessened age-dependent response to the ischemic damage in VGLUT1 and VGLUT3, while VGLUT2 presented an age and structure-dependent response to challenge. The use of the anti-inflammatory agent meloxicam following challenge showed that COX2 inhibition promotes the expression of VGLUTs in both sham and injured animals, which results in a lessened response to I/R injury.. VGLUT1 and VGLUT3 presented an age-dependent response to ischemic damage, while this VGLUT response was age both and structure-dependent. In addition, COX-2 inhibition resulted in an increase of VGLUT1 and VGLUT2 protein amounts both in sham and injured animals together with a lessening of the transporters' response to ischemia.

Topics: Age Factors; Animals; Anti-Inflammatory Agents, Non-Steroidal; Blotting, Western; Brain; Brain Ischemia; Disease Models, Animal; Male; Meloxicam; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Thiazines; Thiazoles; Vesicular Glutamate Transport Proteins

A novel series of 5-arylidene-2,4-thiazolidinediones (TZDs) 2a-p was synthesized from the condensation of 3-((2-phenylthiazol-4-yl)methyl)thiazolidine-2,4-dione with different benzaldehyde derivatives. All the structures were confirmed by their spectral (IR, ¹H NMR, ¹³C NMR and mass) and elemental analytical data. The new molecules were evaluated in vivo as anti-inflammatory agents in an acute experimental inflammation, evaluating the acute phase bone marrow response and phagocyte activity. All compounds, excepting one, reduced the absolute leukocytes count due to the lower neutrophil percentage. Phagocytary index was decreased by the same molecules, while only half of them reduced the phagocytary activity. The effect was superior to meloxicam, the reference anti-inflammatory drug, for the majority of the TZD derivatives. The new molecules were also investigated for their antimicrobial properties on Gram-positive and Gram-negative bacteria and one fungal strain. Two compounds (2e and 2n) manifested growth inhibition capacity on all the tested strains.

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Antifungal Agents; Candida albicans; Disease Models, Animal; Gram-Negative Bacteria; Gram-Positive Bacteria; Inflammation; Magnetic Resonance Spectroscopy; Male; Meloxicam; Phagocytes; Rats; Rats, Wistar; Structure-Activity Relationship; Thiazines; Thiazoles; Thiazolidinediones

Develop a sensitive, functional biomarker of persistent joint pain in a large animal model of experimental osteoarthritis. Evaluate Impulse Ratio as a measure of weight distribution among supporting limbs throughout the early natural history of osteoarthritis and with local anaesthesia and analgesia.. The distribution of weight bearing in the trot of 11 skeletally-mature dogs was analyzed before and after unilateral surgical intervention (cranial cruciate transection or distal femoral focal impact). The short-term effects of two analgesic treatments (intra-articular lidocaine and intra-dermal meloxicam) were then evaluated as an index of pain relief based on the redistribution of weight-bearing impulse between normal and injured limbs.. Impulse Ratio was able to resolve weight redistribution between limbs in both long-term (weekly for over 400 days) and short-term (15 min intervals) joint evaluations. Joint pain relief from lidocaine administration could be reliably tracked over its brief acting time course. Meloxicam administration resulted in ambiguous results, where average weight bearing in the injured limb did not increase, but the variability of limb use changed transiently and reversibly.. Joint function and the role of persistent joint pain in the development of osteoarthritis can be investigated effectively and efficiently in a large animal model through the use of Impulse Ratio. Impulse Ratio can be a functionally relevant and sensitive biomarker of locomotion-related joint pain.

Topics: Anesthetics, Local; Animals; Anterior Cruciate Ligament Injuries; Anti-Inflammatory Agents, Non-Steroidal; Arthralgia; Arthritis, Experimental; Biomarkers; Disease Models, Animal; Dogs; Female; Femoral Fractures; Gait; Injections, Intra-Articular; Injections, Intradermal; Lidocaine; Male; Meloxicam; Osteoarthritis, Knee; Pilot Projects; Thiazines; Thiazoles; Weight-Bearing

The aim of the present investigation was to develop a nanoemulsion (NE) gel formulation for the transdermal delivery of meloxicam (MLX) in order to ensure maximum controlled and sustained drug release capacity.. The MLX containing NE gel was prepared and characterized for particle size, zeta potential, pH, rheology, in vitro drug release, in vitro skin permeation, and in vitro hemolysis. Differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR) of MLX-NE gel treated rat skin was performed to investigate the skin permeation mechanism of meloxicam from NE gel. Skin permeation potential of the developed gel formulation was assessed using confocal laser scanning microscopy (CLSM). The in vivo toxicity of MLX-NE gel was assessed by histopathological examination in rat. The rat paw edema test was performed to evaluate the anti-inflammatory activity of MLX-NE gel.. Percutaneous absorption studies demonstrated a higher permeation of meloxicam from NE gel, than the drug solution. FTIR and DSC studies supported stratum corneum lipid extraction as a possible penetration enhancer mechanism for MLX-NE gel. CLSM studies confirmed the permeation of the NE gel formulation to the deeper layers of the skin (up to 130 μm). MLX-NE gel turned out to be non-irritant, biocompatible, and provided maximum inhibition of paw edema in rats over 24 h in contrast to MLX solution.. The nanoemulsion gel formulation may hold promise as an effective alternative for the transdermal delivery of meloxicam.

Topics: Administration, Cutaneous; Animals; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Chemical Phenomena; Disease Models, Animal; Edema; Female; Gels; Hemolysis; Humans; Male; Meloxicam; Nanotechnology; Particle Size; Rats; Rheology; Skin; Skin Absorption; Surface Properties; Thiazines; Thiazoles

Meloxicam is a cyclo-oxygenase-2 (COX-2) preferential non-steroidal anti-inflammatory drug with very effective analgesic and anti-inflammatory effects in swine. Previous reports in piglets have demonstrated that meloxicam also inhibits COX-1 and reduces production of thromboxane significantly. We use preinjury analgesia in our immature swine (3-5-day-old piglets) model of brain injury using rapid head rotations without impact. In 23 consecutive subjects we found that premedication with meloxicam (n = 6) produced a significantly higher mortality rate (5/6 or 83%) than buprenorphine (n = 17, 1/17 or 6%, P < 0.02). On gross neuropathological examination of the meloxicam-treated swine, we observed massive subdural and subarachnoid bleeding which were not present in buprenorphine-premedicated animals. To our knowledge there are no previous reports in swine of increased bleeding or platelet inhibition associated with meloxicam administration and further research is needed to define mechanisms of action in piglets. We caution the use of meloxicam in swine when inhibition of platelet aggregation might adversely affect refinement of experimental research protocols, such as in stroke, trauma and cardiac arrest models.

Topics: Amyloid beta-Protein Precursor; Animals; Animals, Newborn; Brain; Brain Injuries; Buprenorphine; Cyclooxygenase 2 Inhibitors; Disease Models, Animal; Hematoma, Subdural; Injections, Intramuscular; Meloxicam; Premedication; Subarachnoid Hemorrhage; Survival Rate; Swine; Thiazines; Thiazoles

The objective of present study was to investigate the protective effect of M-NC against aβ (25-35) peptide-induced damage in mice, as the first step to evaluate their potential value for the treatment of AD. Moreover, we compared the effects of M-NC with free meloxicam (M-F). Mice were divided into six groups: (I) sham, (II) aβ, (III) M-NC, (IV) M-F, (V) M-NC+aβ and (VI) M-F+aβ. Mice were pre-treated with M-NC (5mg/kg, by gavage), M-F (5mg/kg, by gavage) or blank nanocapsules (B-NC). Thirty minutes after treatments, aβ peptide (3nmol) or filtered water were i.c.v. injected. Learning and memory were assessed with the Morris water maze (MWM) (days 4-7) and step-down-type passive-avoidance (SDPA) (days 7-8) tasks. At the end of the experimental protocol (day 8), animals were euthanized and brains were removed for biochemical determinations (reactive species (RS), non-protein thiols (NPSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione S-transferase (GST)) and histological examination. Our results confirmed that aβ peptide caused learning and memory deficits in mice. Histological analysis demonstrated neuronal loss, intense cellular accumulation and chromatolysis caused by aβ peptide. Furthermore, this study showed that oxidative stress was increased in mice that received aβ peptide. An important finding of the present study was the protective effect of M-NC in damage induced by aβ peptide. However, M-F did not have protective effect. In summary, the data reported herein clearly demonstrate that meloxicam carried by polymeric nanocapsules protected against learning and memory impairments, loss neuronal and oxidative stress in a mouse model of AD induced by aβ peptide.

Topics: Amyloid beta-Peptides; Analysis of Variance; Animals; Anti-Inflammatory Agents, Non-Steroidal; Avoidance Learning; Behavior, Animal; Body Weight; Brain; Catalase; Disease Models, Animal; Exploratory Behavior; Glutathione; Glutathione Peroxidase; Glutathione Reductase; Glutathione Transferase; Learning Disabilities; Male; Maze Learning; Meloxicam; Memory Disorders; Mice; Nanocapsules; Peptide Fragments; Superoxide Dismutase; Thiazines; Thiazoles; Time Factors

The medial prefrontal cortex (mPFC) is important for extinction of many behaviors including conditioned place preference (CPP). We examined the effects of intra-mPFC inactivation (with bupivacaine) on extinction of ethanol-induced CPP in mice. Injections of both bupivacaine and vehicle impaired extinction whereas no-surgery control mice extinguished normally. Consistent with recently reported effects of mPFC lesions, these data suggest that extinction was impaired by excessive mPFC damage induced by repeated intracranial infusions.

Topics: Analysis of Variance; Anesthetics, Local; Animals; Anti-Inflammatory Agents, Non-Steroidal; Bupivacaine; Central Nervous System Depressants; Conditioning, Operant; Disease Models, Animal; Ethanol; Extinction, Psychological; Learning Disabilities; Male; Meloxicam; Mice; Mice, Inbred DBA; Microinjections; Prefrontal Cortex; Thiazines; Thiazoles; Time Factors

A series of oxicam non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to be neuroprotective against 1-methyl-4-phenyl pyridinium in human neuroblastoma SH-SY5Y cells via the phosphatidylinositol 3-kinase (PI3K)/Akt pathway independent of cyclooxygenase (COX) inhibition. The present study endeavored to establish this novel effect of meloxicam (MLX), an oxicam NSAID, in a mouse Parkinson's disease (PD) model using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Male C57BL/6 mice, which received MPTP (30 mg/kg/day; s.c.) for 5 consecutive days (chronic model) with 10-day follow-up saline administrations, showed significant motor dysfunction in the pole test due to reduced tyrosine hydroxylase (TH) protein levels in the brain on day 16 after MPTP/saline treatment. Daily coadministrations of MLX (10mg/kg/day; i.p.) and MPTP for the first 5 days and follow-up 10 days with MLX administrations alone (MPTP/MLX treatment) significantly ameliorated MPTP-induced behavioral abnormalities in mice. Concomitant decreases of TH protein levels in the striatum and midbrain of MPTP/MLX-treated mice were not only significantly (p<0.01 and p<0.05, respectively) ameliorated but phosphorylated Akt (pAkt473) expression in the midbrain was also significantly (p<0.01) increased in the midbrain when compared with MPTP/saline-treated mice. These results suggest that MLX, an oxicam NSAID, attenuated dopaminergic neuronal death in the experimental MPTP-PD model by maintenance of the Akt-signaling. Oxicam NSAIDs may serve as potential drugs for PD treatment via a novel mechanism of action.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Anti-Inflammatory Agents, Non-Steroidal; Behavior, Animal; Corpus Striatum; Disease Models, Animal; Dopamine; Hypokinesia; Male; Meloxicam; Mesencephalon; Mice; Mice, Inbred C57BL; Nerve Degeneration; Neuroprotective Agents; Parkinson Disease; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Thiazines; Thiazoles; Tyrosine 3-Monooxygenase

To develop a lameness model to assess the efficacy of analgesics for alleviating pain, swelling and systemic signs of inflammation in sheep.. The response to subcutaneous injection of 0.1 or 0.2 mL turpentine in a forelimb pastern (n = 4 ewes per dose) was examined at 0, 3, 6, 24, 48 and 72 h. In a second experiment, responses were measured at 0, 2, 4, 6, 8, 10, 12 and 24 h in ewes receiving 0.1 mL turpentine ± meloxicam 1 mg/kg IV at 0 h (n = 6 per group). Responses measured included forceplate pressure, skin temperature, limb circumference, nociception, leucocyte count, neutrophil : lymphocyte ratio, haptoglobin and daily feed intake.. Turpentine injection caused a decrease in weight borne on the treated limb, increased skin temperature, increased sensitivity at the injection site and leucocytosis by 2 h and increased limb circumference by 4 h. Weight borne and sensitivity of the injected limb returned to control levels after around 24 h, whereas tissue swelling, elevated skin temperature and elevated haptoglobin levels persisted for at least 72 h. Treatment with meloxicam improved weight borne by and tolerance to pressure exerted on the turpentine-injected limb.. The local and systemic signs of inflammation and pain, temporary reduction in function of the affected limb and partial amelioration of some of these changes by the dose of meloxicam used here suggest that injection of turpentine in the lower forelimb provides a suitable model for examining the efficacy of analgesics for alleviation of pain and inflammation in sheep.

Topics: Analysis of Variance; Animals; Anti-Inflammatory Agents, Non-Steroidal; Body Temperature; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Combinations; Irritants; Lameness, Animal; Meloxicam; Pain; Sheep; Sheep Diseases; Thiazines; Thiazoles; Turpentine

Bone marrow mesenchymal stem cells (BMSC)-induced amelioration of experimental autoimmune encephalomyelitis (EAE) was diminished with neuronal differentiantion of BMSC (nBMSC). BMSC secreted large amounts of PGE2, compared to nBMSC, which correlated with higher efficacy to EAE inhibition. EAE mice treated with PGE2 inhibitor, meloxicam showed decreased serum levels of PGE2 and in parallel decreased inhibitory effect on EAE course. In addition, high levels of PGE2 secretion correlated with high expression of indoleamine-2,3-dioxygenase (IDO). Meloxicam blocked IDO expression in BMSC transferred mice indicating functional relation between PGE2 and IDO induction. The current findings demonstrates PGE2 involvement in BMSC-induced inhibition of EAE and provides a mechanistic link between BMSC-derived PGE2 and IDO-dependent immunoregulation of this autoimmune condition.

Topics: Animals; Bone Marrow Transplantation; Cell Differentiation; Cells, Cultured; Cyclooxygenase Inhibitors; Dinoprostone; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Female; Immunomodulation; Indoleamine-Pyrrole 2,3,-Dioxygenase; Meloxicam; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Thiazines; Thiazoles

The goal of the present study was to develop and validate a new canine model of inflammation. The motivation was to make available a scientifically appropriate and ethically acceptable model to conduct pharmacokinetic/pharmacodynamic investigations for testing nonsteroidal anti-inflammatory drugs in dogs. A kaolin-induce paw inflammation model previously developed in cats was adapted to the dog. The paw inflammation developed within a few hours, reached maximum values 24 h and up to 3 days after kaolin administration, and then progressively resolved over 2 months. Five end points of clinical interest (body temperature, creeping time under a tunnel, paw withdrawal latency to a standardized thermal stimulus, lameness score, and vertical force developed during walking on a force plate) were measured regularly over the next 24 h and beyond to characterize the time development of the inflammation either in control conditions (placebo period) or after the administration of meloxicam (test period) according to a crossover design. Pharmacodynamic data were modeled using an indirect response pharmacokinetic/pharmacodynamic model. This model described three effects of meloxicam, namely, classic anti-inflammatory, analgesic, and antipyretic effects. The mean plasma meloxicam IC(50) values were 210 ng/ml for the antipyretic effect, 390 ng/ml for the analgesic effect, and 546 ng/ml for the vertical force exerted by the paw on the ground as measured by force plates. These in vivo IC(50) values require approximately 80 (antipyretic effect) to 90% (all other effects) cyclooxygenase-2 inhibition as calculated ex vivo whole-blood assay data.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Disease Models, Animal; Dogs; Drug Evaluation, Preclinical; Female; Foot; Inflammation; Lameness, Animal; Male; Meloxicam; Pain Measurement; Random Allocation; Reproducibility of Results; Thiazines; Thiazoles

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used drugs for the management of acute and chronic pain. The role of the opioid system in the synergism between NSAIDs is not well characterized. Mice were injected with a 5% formalin solution (20 μl) into the upper right lip to perform an orofacial formalin test. The isobolographic method was used to determine the interaction between dexketoprofen, which is the (S)-(+) enantiomer of ketoprofen, and meloxicam co-administration. Additionally, the non-selective, opioid antagonist naltrexone, the selective δ opioid receptor (DOP) antagonist naltrindole and the selective κ opioid receptor (KOP) antagonist norbinaltorphimine were used to assess the opioid effects on this interaction. Intraperitoneal administration of dexketoprofen or meloxicam induced dose-dependent antinociception with different phase I and phase II potencies in the orofacial formalin test. Meloxicam displayed similar potencies (ED(50)) in phase I (7.20 mg/kg) and phase II (8.60 mg/kg). Dexketoprofen was more potent in phase I (19.96 mg/kg) than in phase II (50.90 mg/kg). The interactions between dexketoprofen and meloxicam were synergistic in both phases. This was determined based on the fixed ratios (1:1) of their ED(50) values, which were determined by isobolographic analysis. Furthermore, this antinociceptive activity does not seem to be modulated by opioid receptor blockers because they did not induce changes in the nature of this interaction. This finding may be relevant with regards to NSAID multi-modal analgesia where an opioid antagonist must be used.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Facial Pain; Formaldehyde; Ketoprofen; Male; Meloxicam; Mice; Naltrexone; Narcotic Antagonists; Stereoisomerism; Thiazines; Thiazoles

The overproduction of reactive oxygen species and resultant damage to cellular proteins or lipids of cell membranes and DNA by free radicals are the underlying mechanisms of many neuropathologies. Cyclooxygenase-2 (COX-2) inhibitors have been suggested to be neuroprotective by reducing prostanoid and free radical synthesis, or by directing arachidonic acid metabolism through alternate pathways. This study investigated the putative neuroprotective effect of the COX-2 inhibitor, meloxicam, in a rat model of diffuse brain injury.. Sprague-Dawley rats were subjected to traumatic brain injury with a weight-drop device using 300 g(-1) m weight-height impact. The groups were: control, meloxicam (2 mg/kg, i.p.), trauma and trauma + meloxicam (2 mg/kg, i.p.). Forty-eight hours after the injury, neurological examination scores were measured, the animals were decapitated and brain tissues were taken. Brain edema and blood-brain barrier (BBB) permeability were evaluated by wet-dry weight method and Evans blue (EB) extravasation respectively. In brain tissues, malonedialdehyde, glutathione, myeloperoxidase and Na/K-ATPase levels were measured.. The neurological examination scores mildly increased in trauma groups 48 hours after the induction of trauma. Meloxicam treatment improved the altered neurological status. The trauma caused a significant increase in brain water content that was partially reversed by meloxicam. Meloxicam also reduced the EB extravasation indicating the preservation of the BBB integrity. Meloxicam treatment also significantly reduced the increase in malondialdehyde and myeloperoxidase levels and restored glutathione content of the brains that had been significantly increased after trauma.. Meloxicam exerts neuroprotective effect by preserving BBB permeability and by reducing brain edema (probably by its anti-inflammatory properties) in the diffuse brain injury model.

Topics: Analysis of Variance; Animals; Blood-Brain Barrier; Brain Chemistry; Brain Injuries; Cyclooxygenase 2 Inhibitors; Disease Models, Animal; Glutathione; Male; Malondialdehyde; Meloxicam; Neurochemistry; Neurologic Examination; Permeability; Peroxidase; Rats; Rats, Sprague-Dawley; Sodium-Potassium-Exchanging ATPase; Thiazines; Thiazoles

A monolithic drug-in-adhesive (MDIA) type patch containing meloxicam (MX) was designed with an acrylic adhesive, a solubility modulator increasing MX solubility, and enhancers. MDIA patches having one adhesive layer between the backing and the release liner give high productivity and improve patient compliance. The biggest problem to prepare MDIA patch including MX was poor solubility of MX. In this research, solubility modulators to increase solubility of MX and acrylic adhesives and skin permeation enhancers were investigated through solubility tests, in vitro skin permeation tests, and stability tests. Consequently, the composition of sodium methoxide (SM), an acrylic adhesive containing poly(vinyl pyrrolidone) blocks (MAS683), polyoxyethylene cetylether (BC-2), and diisopropanolamine (DIPA) made it possible for MX to be contained in an adhesive layer at a concentration of as much as 15 wt% without MX crystal and with high skin permeation over 400 microG/cm(2). Finally, the patch formulation containing MX (MX-patch) selected through our in vitro study was characterized by in vivo using an animal study to acquire pharmacokinetic (PK) parameters and to confirm the anti-inflammatory efficacy of MX-patch. In the animal study, MX-patch was compared with a commercially available piroxicam patch (PX-patch). The amount of MX delivered from MX-patch to the skin surface was believed to be higher than the amount of MX diffused from the skin tissue to circulatory system because the plasma concentration of MX continuously increased up to 32 h, the end time of PK study, although the patch samples were detached at 24 h. PX-patch produced a C(max) at 8 h. MX-patch showed better significant efficacy than PX-patch in adjuvant arthritis model.

Topics: Acrylic Resins; Administration, Cutaneous; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Carrageenan; Chemistry, Pharmaceutical; Diffusion; Disease Models, Animal; Dosage Forms; Drug Compounding; Drug Stability; Edema; Excipients; Freund's Adjuvant; Meloxicam; Mice; Mice, Hairless; Mycobacterium; Osteoarthritis; Permeability; Piroxicam; Povidone; Rats; Rats, Sprague-Dawley; Skin; Skin Absorption; Solubility; Technology, Pharmaceutical; Thiazines; Thiazoles; Tissue Adhesives

Cyclooxygenase isoenzyme is known to be expressed in different regions of brain, and is mainly used for the treatment of pain and inflammation. Recently, it is proposed that cyclooxygenase isoenzyme may also play a key role in the pathophysiology of various brain-related disorders. The present study was aimed to explore the protective effect of cyclooxygenase inhibitors on stress by using an animal model of chronic stress.. The animals were forced to swim individually for a period of 6 min every day for 15 d. Then, the behavior (locomotor activity, anxiety and memory) and biochemical (lipid peroxidation, nitrite level, reduced glutathione, and catalase) alterations were assessed.. Forced swimming for 15 d caused impaired locomotor activity, anxiety-like behavior and decreased percentage of memory retention, as compared to naive mice (without chronic fatigue treatment). Biochemical analysis revealed significant increases in lipid peroxidation and nitrite level, while levels of reduced glutathione and catalase activity were both decreased. Chronic treatment with naproxen (14 mg/kg, i.p.), rofecoxib (5 mg/kg, i.p.), meloxicam (5 mg/kg, i.p.), nimesulide (5 mg/kg, i.p.) and valdecoxib (10 mg/kg, i.p.) significantly attenuated these behavioral and biochemical (oxidative damage) alterations in chronic-stressed mice.. The cyclooxygenase inhibitors could be used in the management of chronic fatigue-like conditions.

Topics: Animals; Anxiety; Catalase; Chronic Disease; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Disease Models, Animal; Glutathione; Isoxazoles; Lactones; Lipid Peroxidation; Male; Meloxicam; Memory; Mice; Motor Activity; Naproxen; Nitrites; Random Allocation; Stress, Psychological; Sulfonamides; Sulfones; Thiazines; Thiazoles

This study describes the effect of global brain ischemia followed by 48 h reperfusion, when delayed neuronal death can be already observed. We quantified the mRNA levels of the N-methyl-D-aspartate receptor (NMDAR) subunits and those of the astroglia (glial fibrilar acidic protein, GFAP) and microglia (CD11b) markers using real time PCR on the cerebral cortex and hippocampus of 3- and 18-month-old Sprague-Dawley rats. Data show an ischemia/reperfusion-induced decrease in the mRNA levels of the NMDAR NR1, NR2A and NR2B subunits genes, which contrasts with the increase in the CD11b and GFAP mRNA levels. These effects are attenuated in all the genes studied in 18-month-old animals, suggesting that this mechanism of response is less efficient in aged animals. Western blot assays of NR1, NR2A and NR2B show parallels with the real time PCR data, indicating that the down-regulation of these genes is controlled at the transcriptional level. We suggest that a decrease in the efficiency in the control of the NMDAR transcription could account for the higher vulnerability in aged animals, but it cannot explain by itself differences in the vulnerability to ischemia in different areas of the brain. In the assays of ischemia/reperfusion followed by a treatment with the anti-inflammatory agent meloxicam, we observed that ischemic insult was unable to elicit changes in the NMDAR transcription, thus suggesting that inflammation plays a crucial role in the transcriptional control of these genes.

Topics: Aging; Animals; Anti-Inflammatory Agents, Non-Steroidal; Brain Ischemia; Disease Models, Animal; Down-Regulation; Male; Meloxicam; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Reperfusion Injury; RNA, Messenger; Thiazines; Thiazoles; Treatment Outcome

To compare the efficacy of cabergoline (Cb2) and meloxicam in curbing vascular endothelial growth factor (VEGF) expression and preventing ovarian hyperstimulation syndrome (OHSS).. Randomized controlled, animal study.. Academic facility.. We used a total of 50 immature Wistar female rats randomly to create an experimental OHSS model.. Ten rats each formed the control group and mild OHSS group. The remaining 30 were separated into three equal groups of severe OHSS. Mild and severe OHSS were induced through ovarian stimulation with gonadotropins. One group with severe OHSS was administered a low-dose 100 microg/kg Cb2 therapy; another group with severe OHSS received 600 microg/kg meloxicam. Body weight, vascular permeability (VP), VEGF expression, ovary weight, and diameter were then compared.. The efficacy of Cb2 and meloxicam for preventing OHSS.. Comparison of the severe OHSS groups with the controls and mild OHSS group revealed significant increases in VEGF expression, VP, ovary weight, and diameter. The increase in VEGF expression was demonstrated to be dependent on human chorionic gonadotropin doses. However, low-dose Cb2 and meloxicam therapies were shown to be ineffective in decreasing VEGF expression and VP, ovary weight, and ovary diameter in severe OHSS.. VEGF elevation played a critical part in OHSS pathogenesis, but the therapies administered failed to curb VEGF expression.

Topics: Analysis of Variance; Animals; Biopsy, Needle; Body Weight; Cabergoline; Chorionic Gonadotropin; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Ergolines; Female; Immunohistochemistry; Injections, Intramuscular; Meloxicam; Organ Size; Ovarian Hyperstimulation Syndrome; Ovary; Ovulation Induction; Pregnancy; Pregnancy, Animal; Probability; Random Allocation; Rats; Rats, Wistar; Thiazines; Thiazoles; Vascular Endothelial Growth Factor A

To determine whether treatment with an antiresorptive drug in combination with an antiinflammatory drug reduces periarticular bone and soft tissue adaptations associated with the progression of posttraumatic secondary osteoarthritis (OA).. We used in vivo microfocal computed tomography (micro-CT) to map bony adaptations and in vivo micro-magnetic resonance imaging (micro-MRI) to examine joint inflammation in a rat model of surgically induced OA secondary to knee triad injury. We examined the arthroprotective effects of the bisphosphonates alendronate and risedronate and the nonsteroidal antiinflammatory drug (NSAID) meloxicam.. Micro-CT revealed reduced levels of periarticular trabecular bone loss in animals with knee triad injury treated with the bisphosphonate drugs alendronate or risedronate, or the NSAID meloxicam, compared with untreated animals. Alendronate treatment reduced bony osteophyte development. While risedronate as a monotherapy did not positively impact osteophytogenesis, combination therapy with risedronate and meloxicam reduced osteophyte severity somewhat. Micro-MRI revealed an increased, diffuse water signal in the epiphyses of untreated rats with knee triad injury 8 weeks after surgery, suggestive of a bone marrow lesion-like stimulus. In contrast, meloxicam-treated rats showed a significant reduction in fluid signal compared with both bisphosphonate-treated groups 8 weeks after surgery. Histologic analysis qualitatively confirmed the chondroprotective effect of both bisphosphonate treatments, showing fewer degradative changes compared with untreated rats with knee triad injury.. Our findings indicate that select combinations of bisphosphonate and NSAID drug therapy in the early stages of secondary OA preserve trabecular bone mass and reduce the impact of osteophytic bony adaptations and bone marrow lesion-like stimulus. Bisphosphonate and NSAID therapy may be an effective disease-modifying drug regimen if administered early after the initial injury.

Topics: Alendronate; Animals; Anti-Inflammatory Agents, Non-Steroidal; Bone Density Conservation Agents; Disease Models, Animal; Drug Therapy, Combination; Epiphyses; Etidronic Acid; Female; Femur; Magnetic Resonance Imaging; Meloxicam; Osteoarthritis, Knee; Osteophyte; Rats; Rats, Sprague-Dawley; Risedronic Acid; Stifle; Thiazines; Thiazoles; Tibia; Tomography, X-Ray Computed; Water

Few studies have investigated the anti-inflammatory properties of ellagic acid and no published studies have examined the effects of ellagic acid in combination with anesthetic adjuvants. In this study, 54 Sprague-Dawley rats were assigned to one of six groups: (1) vehicle; (2) ketorolac and vehicle; (3) meloxicam and vehicle; (4) ellagic acid and vehicle; (5) ellagic acid, ketorolac, and vehicle; and (6) ellagic acid, meloxicam, and vehicle. Groups 5 and 6 investigated interactions between ellagic acid and cyclooxygenase inhibitors. Paw inflammation was induced with 3% carrageenan and was measured with a plethysmometer at 30 minutes and 4, 8, and 24 hours after intraperitoneal injection. All rats received one intraperitoneal injection of equivalent volumes according to group assignment. Analysis of covariance followed by post hoc analysis determined that ketorolac was the only compound to significantly reduce paw edema at 4 hours (P = .019); ellagic acid alone (P = .038) and the combination of ellagic acid and ketorolac (P = .038) were the only compounds to significantly reduce paw edema at 8 hours. At 24 hours, only ellagic acid was effective (P = .01). Our findings suggest that ellagic acid may be effective against inflammation, may have a prolonged onset and duration of action, and may interact with known cyclooxygenase inhibitors.

Topics: Anesthetics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Disease Models, Animal; Drug Interactions; Ellagic Acid; Inflammation; Isoflurane; Ketorolac; Male; Meloxicam; Perioperative Nursing; Rats; Rats, Sprague-Dawley; Thiazines; Thiazoles

This study reports the mRNA levels of some excitatory amino acid transporters (EAATs) in response to ischemia-reperfusion (I/R) in rat hippocampus and cerebral cortex. The study was performed in 3-month-old and 18-month-old animals to analyze the possible role of age in the I/R response of these transporters. The I/R resulted in a reduced transcription of both the neuronal EAAC1 (excitatory amino acid carrier-1) and the neuronal and glial GLT-1 (glial glutamate transporter 1), while the glial GLAST1a (l-glutamate/l-aspartate transporter 1a) transcription increased following I/R. The changes observed were more striking in 3-month-old animals than in 18-month-old animals. We hypothesize that increases in the GLAST1a mRNA levels following I/R insult can be explained by increases in glial cells, while the GLT-1 response to I/R mirrors neuronal changes. GLAST1a transcription increases in 3-month-old animals support the hypothesis that this transporter would be the main mechanism for extracellular glutamate clearance after I/R. Decreases in EAAC1 and GLT-1 mRNA levels would represent either neuronal changes due to the delayed neuronal death or a putative protective down-regulation of these transporters to decrease the amount of glutamate inside the neurons, which would decrease their glutamate release. This study also reports how the treatment with the anti-inflammatory agent meloxicam attenuates the transcriptional response to I/R in 3-month-old rats and decreases the survival of the I/R-injured animals.

Topics: Aging; Analysis of Variance; Animals; Anti-Inflammatory Agents; Cerebral Cortex; Disease Models, Animal; Encephalitis; Excitatory Amino Acid Transporter 2; Excitatory Amino Acid Transporter 3; Hippocampus; Ischemia; Male; Meloxicam; Phosphopyruvate Hydratase; Rats; Rats, Sprague-Dawley; Reperfusion; RNA, Messenger; Thiazines; Thiazoles

Maternal infections are one of the main causes of adverse developmental outcomes including embryonic resorption and preterm labour. In this study a mouse model of inflammation-associated preterm delivery was developed, and used to study the relationship between nitric oxide (NO) and prostaglandins (PGs).. The murine model of preterm labour was achieved by assaying different doses of bacterial lipopolysaccharides (LPS). Once established, it was used to analyse uterine levels of prostaglandins E(2) and F(2α) (by radioimmunoassay), cyclooxygenases (COX) and NOS proteins (by Western blot) and NO synthase (NOS) activity. Effects of inhibitors of COX and NOS on LPS-induced preterm labour were also studied. In vitro assays with a nitric oxide donor (SNAP) were performed to analyse the modulation of prostaglandin production by NO.. Lipopolysaccharide increased uterine NO and PG synthesis and induced preterm delivery. Co-administration of meloxicam, a cyclooxygenase-2 inhibitor, or aminoguanidine, an inducible NOS inhibitor, prevented LPS-induced preterm delivery and blocked the increase in PGs and NO. Notably, the levels of NO were found to determine its effect on PG synthesis; low concentrations of NO reduced PG synthesis whereas high concentrations augmented them.. An infection-associated model of preterm labour showed that preterm delivery can be prevented by decreasing PG or NO production. NO was found to have a dual effect on PG synthesis depending on its concentration. These data contribute to the understanding of the interaction between NO and PGs in pregnancy and parturition, and could help to improve neonatal outcomes.

Topics: Animals; Blotting, Western; Cyclooxygenase 2 Inhibitors; Dinoprost; Dinoprostone; Disease Models, Animal; Enzyme Inhibitors; Female; Guanidines; Inflammation; Lipopolysaccharides; Meloxicam; Mice; Mice, Inbred BALB C; Nitric Oxide; Nitric Oxide Synthase; Obstetric Labor, Premature; Pregnancy; Radioimmunoassay; Thiazines; Thiazoles; Uterus

The purpose of this study was to present the effectiveness of 2 cyclooxygenase-2 inhibitors, meloxicam and parecoxib, in the prevention of heterotopic ossification. Eighteen white mature male rabbits were divided into 3 groups of 6 animals. One was the control group; 1 group was administered meloxicam subcutaneously, and 1 group was administered parecoxib subcutaneously. For the induction of heterotopic new bone, the Michelsson model was used. The extent of heterotopic new bone development was assessed according to Scott's classification. The meloxicam and parecoxib groups developed significantly less heterotopic bone when compared to the control group. There was no significant difference between the meloxicam and parecoxib group. We concluded that meloxicam and parecoxib are capable of preventing the development of heterotopic new bone in rabbits. The clinical relevance of this study is that meloxicam and parecoxib may be helpful in reducing heterotopic ossification in humans.

Topics: Animals; Bone and Bones; Cyclooxygenase 2 Inhibitors; Disease Models, Animal; Indomethacin; Injections, Subcutaneous; Isoxazoles; Male; Meloxicam; Ossification, Heterotopic; Osteogenesis; Rabbits; Radiography; Thiazines; Thiazoles

Inflammation is believed to play an important role in the etiology and pathogenesis of Parkinson's disease (PD). However, experimental and epidemiological evidences from various non-steroidal anti-inflammatory drugs, including cyclooxygenase-2 (COX-2) inhibitors, seem contradictive. Using the intranigral lipopolysaccharide (LPS) rat model, we show that meloxicam, a preferential COX-2 inhibitor, diminishes the activation of OX-42-immunoreactive (ir) microglia and reduces the loss of tyrosine hydroxylase (TH)-ir dopamine (DA) neurons in the substantia nigra pars compacta (SNpc) that is normally induced by exposure to LPS. Double-labelling immunohistochemistry identified that activated microglia rather than intact resting microglia are the main intracellular venues for COX-2 expression. These findings suggest that inhibition of COX-2 activity in activated microglial cells may be potentially neuroprotective for DA neurons in the SNpc.

Topics: Animals; CD11b Antigen; Cyclooxygenase Inhibitors; Disease Models, Animal; Dopamine; Lipopolysaccharides; Male; Meloxicam; Nerve Degeneration; Neurons; Rats; Rats, Wistar; Substantia Nigra; Thiazines; Thiazoles; Tyrosine 3-Monooxygenase

Recent experimental and clinical studies on Parkinson's disease point out the pivotal role of inflammation in the pathogenesis of neurodegeneration and the possible positive effects of nonsteroidal anti-inflammatory drug therapies. Our aim in this study was to investigate the preventive effects of nonsteroidal anti-inflammatory drugs in the 6-hydroxydopamine (6-OHDA) induced rat model of Parkinson's disease.. Twenty-one female Wistar-Albino rats (200-250g) were used in this study. The rats were divided in three groups: Saline group (n: 7, 2 ml), Acetylsalicylic acid group (n: 7, 100 mg/kg), and Meloxicam group (n: 7, 50 mg/kg). An hour after administration, the rats received a unilateral intranigral injection of 6-OHDA to produce the Parkinson model lesion. Rotational tests were performed two weeks later as follow-up. Immunohistochemical tests were performed in all groups to determine the severity of the lesion in the substantia nigra.. Administration of drugs an hour before the lesions were created did not protect the degeneration of dopaminergic neurons in the substantia nigra.. Oral usage of low repeated doses of nonsteroidal anti-inflammatory drugs may possibly slow down the progression of the disease.

Topics: Amphetamines; Animals; Antiparkinson Agents; Apomorphine; Aspirin; Behavior, Animal; Cyclooxygenase Inhibitors; Disease Models, Animal; Female; Immunohistochemistry; Meloxicam; Neuroprotective Agents; Oxidopamine; Parkinsonian Disorders; Rats; Rats, Wistar; Sympatholytics; Thiazines; Thiazoles

Normotensive and hypertensive male Wistar rats were subjected to the 3 h bilateral carotid artery occlusion followed by 72 h of reperfusion. The selective cycloxygenase-2 inhibitor meloxicam was administered intramuscularly after the cerebral reperfusion at a daily dose of 15 mg/kg. Doppler ultrasound was used to evaluate the cerebral blood flow during the reperfusion phase. The level of malondialdehyde (MDA) within the brain tissue homogenate was determined using spectrophotometry. The presence of arterial hypertension caused the altered response of brain tissue to ischemia/reperfusion. The meloxicam treatment significantly decreased the MDA level in normotensive rats subjected to ischemia-reperfusion. The protective effect of meloxicam against cerebral ischemia/reperfusion injury was more pronounced in hypertensive rats as compared to normotensive animals.

Topics: Animals; Blood Pressure; Brain Ischemia; Cerebrovascular Circulation; Disease Models, Animal; Follow-Up Studies; Hypertension; Injections, Intramuscular; Male; Meloxicam; Middle Cerebral Artery; Rats; Rats, Wistar; Reperfusion Injury; Thiazines; Thiazoles; Treatment Outcome; Ultrasonography, Doppler, Transcranial

The effects of anti-inflammatory drugs on ileal 5-hydroxytryptamine (5-HT) metabolic dynamics at 72 h after a single administration of cisplatin were investigated in rats. Cisplatin 5 mg/kg i.p. caused pathological changes, with an inflammatory response occurring 72 h after its administration. The inflammatory response was associated with the induction of cyclooxygenase-2, but not cyclooxygenase-1, in the ileal mucosa at 72 h after the cisplatin administration. Daily treatment with meloxicam 3 mg/kg s.c. ameliorated the cisplatin-induced mucosal damage, whereas dexamethasone 1 mg/kg s.c. did not. Cisplatin administration also caused a significant increase in cyclooxygenase-2 mRNA expression at 72 h after administration, which was blunted by dexamethasone, but not by meloxicam. Cisplatin increased the content of 5-HT and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), but had no effect on 5-HT turnover (5-HIAA/5-HT ratio). Meloxicam and dexamethasone did not significantly decrease 5-HT and 5-HIAA content. Cisplatin significantly decreased monoamine oxidase activity but increased tryptophan hydroxylase (TPH) activity and TPH(1) mRNA expression in ileal tissue. Meloxicam and dexamethasone significantly restored the decreased monoamine oxidase activity and inhibited the cisplatin-induced increase in tryptophan hydroxylase activity toward the control levels. These drugs also decreased the cisplatin-induced increase in TPH(1) mRNA expression. Neither cisplatin nor the anti-inflammatory drugs had significant effect on mRNA expression of the serotonin re-uptake transporter. These results suggest that the inflammatory response associated with cyclooxygenase-2 induction is involved in the opposite change in ileal tryptophan hydroxylase and monoamine oxidase activities in the delayed phase after single administration of cisplatin to rats.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Cisplatin; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Dexamethasone; Disease Models, Animal; Enzyme Induction; Enzyme Repression; Hydroxyindoleacetic Acid; Ileitis; Ileum; Intestinal Mucosa; Male; Meloxicam; Membrane Proteins; Monoamine Oxidase; Rats; Rats, Wistar; RNA, Messenger; Serotonin; Serotonin Plasma Membrane Transport Proteins; Thiazines; Thiazoles; Time Factors; Tryptophan Hydroxylase

To determine the efficacy of meloxicam ophthalmic formulation on COX-2 activity and expression, inflammation-related cytokines expression and inflammation in an ocular inflammation model.. Ocular inflammation was induced in New Zealand rabbits by topical application of croton oil (3%) for 3 h. An ophthalmic solution of 0.03% meloxicam, 0.1% sodium diclofenac or vehicle (Sophisen) was administered every 4 h. Conjunctiva, cornea, aqueous humour and vitreous humour were collected.. In irritated eyes, 72 h of meloxicam treatment downregulated COX-2 expression and activity (mRNA by RT-PCR and PGE2 levels by ELISA, respectively) in a time-dependent manner and reduced inflammation. Meanwhile, diclofenac failed to reduce COX-2 mRNA or PGE2 to basal levels after 7 days of treatment. Meloxicam treatment downregulated IL-6 and IFN-gamma expression in the conjunctiva and IL-1beta and TNF-alpha expression in the cornea. Diclofenac failed to modify these cytokines in both tissues. Meloxicam treatment increased the expression of IL-6 in conjunctiva, and IL-10 in cornea, while diclofenac had no effect on these cytokines.. Meloxicam treatment was more efficient than diclofenac in downregulating the expression and activity of COX-2, reducing inflammation, and modifying the inflammatory-related cytokines.

Topics: Acute Disease; Animals; Anti-Inflammatory Agents, Non-Steroidal; Aqueous Humor; Cornea; Croton Oil; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cytokines; Dinoprostone; Disease Models, Animal; Down-Regulation; Drug Evaluation, Preclinical; Endophthalmitis; Male; Meloxicam; Ophthalmic Solutions; Rabbits; RNA, Messenger; Thiazines; Thiazoles

Cerebral vasospasm influences morbidity and mortality following subarachnoid haemorrhage (SAH). Inflammation is believed to play a role in post-haemorrhagic vasospasm. Meloxicam is a non-steroidal anti-inflammatory drug. We investigated the effect of meloxicam on a rat femoral artery vasospasm model using the radial wall thickness and cross-sectional lumen area as parameters under light, scanning and transmission electron microscopy examination. Rats were randomly separated into SAH, SAH+ meloxicam and control groups. Rats in the SAH+ meloxicam group were given meloxicam at 2 mg/kg daily for 7 days. Femoral arteries were examined by light microscopy and scanning and transmission electron microscopy, and for morphometric analysis. A statistically significant difference (p<0.001) was detected between the SAH and SAH+ meloxicam groups. Meloxicam treatment reduced ultrastructural and morphometric vasospastic changes. These findings support the hypothesis that inflammation may play a role in the pathophysiologyical pathways of post-haemorrhagic cerebral vasospasm.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Disease Models, Animal; Femoral Artery; Meloxicam; Random Allocation; Rats; Rats, Sprague-Dawley; Subarachnoid Hemorrhage; Thiazines; Thiazoles; Vasospasm, Intracranial

The objective of this study was to examine the effects of rofecoxib, meloxicam, both cyclooxygenase-2 (COX-2) inhibitors and aminoguanidine hydrochloride, an inducible nitric oxide synthase (iNOS) inhibitor and their combinations in neuropathic pain in rats.. Neuropathy was induced by chronic constriction injury (CCI) of right sciatic nerve under ketamine anesthesia in rats. Effect of ED(50) of aminoguanidine hydrochloride, rofecoxib and meloxicam administered orally was investigated using behavioral tests. Effect of combinations of aminoguanidine hydrochloride with rofecoxib and meloxicam was also investigated in neuropathic pain employing behavioral tests.. Behavioral tests, mechanical, thermal and cold stimuli confirmed the development of neuropathic pain after CCI. Aminoguanidine hydrochloride, rofecoxib and meloxicam when administered alone, produced significant increase in paw withdrawal threshold to mechanical stimuli at 6 h in ipsilateral hind paw after CCI. Co-administration of aminoguanidine hydrochloride (30 mg/kg) with rofecoxib (1.31 mg/kg) and meloxicam (1.34 mg/kg) was also found to produce significant increase in paw withdrawal latencies to mechanical stimuli at 6 h. Combined administration of aminoguanidine hydrochloride with meloxicam and rofecoxib produced significant rise in pain threshold for mechanical hyperalgesia in ipsilateral hind paw when compared with the groups treated with aminoguanidine hydrochloride, meloxicam and rofecoxib alone.. Co-administration of meloxicam and rofecoxib with aminoguanidine hydrochloride may be an alternative approach for the treatment of neuropathic pain.

Topics: Animals; Cyclooxygenase 2 Inhibitors; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Combinations; Drug Synergism; Guanidines; Hyperalgesia; Lactones; Male; Meloxicam; Neuralgia; Neurons, Afferent; Nitric Oxide; Nitric Oxide Synthase Type II; Nociceptors; Pain Threshold; Peripheral Nervous System Diseases; Physical Stimulation; Rats; Reaction Time; Sciatic Neuropathy; Sulfones; Thiazines; Thiazoles; Treatment Outcome

A murine lung fibrosis model has been induced by challenging male Swiss albino mice with a fibrotic dose of bleomycin (10 mg/kg body weight, s.c.) twice weekly for 6 weeks. The model has been characterized and confirmed biochemically, histologically and morphometrically. Keeping in mind that inflammation is the forerunner of lung fibrosis, we have investigated the possible anti-fibrotic effect of meloxicam; a selective COX-2 inhibitor, in this lung fibrosis paradigm. When administered ahead of bleomycin challenge, meloxicam significantly reduced the lung content of hydroxyproline; the backbone of collagen matrix. This was further confirmed by the lower collagen deposition as revealed by histochemical examination of lung sections. Meloxicam had also anti-oxidant effect as shown by increase in lung reduced glutathione (GSH) level and decreases in lung malonedialdehyde (MDA) content and myeloperoxidase (MPO) activity. Besides, meloxicam has shown an apparent angiostatic activity. Histologically, meloxicam lessened lung inflammation and fibrotic changes induced by bleomycin. Taken together, one could conclude that meloxicam has shown anti-fibrotic effect in the bleomycin lung fibrosis model. Apart from its well-known anti-inflammatory potential, this anti-fibrotic action of meloxicam resides most probably, at least partly, in its anti-oxidant and angiostatic effects.

Topics: Animals; Antioxidants; Bleomycin; Collagen; Cyclooxygenase Inhibitors; Disease Models, Animal; Glutathione; Hydroxyproline; Lipid Peroxidation; Male; Malondialdehyde; Meloxicam; Mice; Neovascularization, Pathologic; Peroxidase; Pulmonary Fibrosis; Superoxide Dismutase; Thiazines; Thiazoles

We have evaluated the effect of the short-term administration of low therapeutic doses of modern COX-2 inhibitors on the healing of fractures. A total of 40 adult male New Zealand rabbits were divided into five groups. A mid-diaphyseal osteotomy of the right ulna was performed and either normal saline, prednisolone, indometacin, meloxicam or rofecoxib was administered for five days. Radiological, biomechanical and histomorphometric evaluation was performed at six weeks. In the group in which the highly selective anti-COX-2 agent, rofecoxib, was used the incidence of radiologically-incomplete union was similar to that in the control group. All the biomechanical parameters were statistically significantly lower in both the prednisolone and indometacin (p = 0.01) and in the meloxicam (p = 0.04) groups compared with the control group. Only the fracture load values were found to be statistically significantly lower (p = 0.05) in the rofecoxib group. Histomorphometric parameters were adversely affected in all groups with the specimens of the rofecoxib group showing the least negative effect. Our findings indicated that the short-term administration of low therapeutic doses of a highly selective COX-2 inhibitor had a minor negative effect on bone healing.

Topics: Analysis of Variance; Animals; Bony Callus; Cyclooxygenase 2 Inhibitors; Disease Models, Animal; Fracture Healing; Fractures, Bone; Indomethacin; Lactones; Male; Meloxicam; Prednisolone; Rabbits; Sulfones; Thiazines; Thiazoles

Meloxicam (MEL), a cyclooxygenase (COX)-2 inhibitor, decreases prostaglandin production and blocks preterm labor in sheep. The objective of this study is to investigate MEL dosage regimens on COX-1, COX-2, and prostaglandin dehydrogenase (PGDH) expression in ovine intrauterine and fetal tissues. Animals in preterm labor received maternal infusions of saline or MEL at maintained high or graded doses (study 1) or acute graded doses (study 2). MEL blocked preterm labor. In study 1, MEL decreased COX-2 expression in the endometrium, myometrium, and amnion but not placenta or fetal tissues. In study 2, COX-2 expression was unchanged. COX-1/PGDH expression was unaffected. While MEL is an effective tocolytic, reductions in COX-2 protein occurred only with maintained MEL exposure. MEL effects are tissue specific and do not affect COX-1 or PGDH expression. Maternal MEL does not affect fetal COX expression in the sheep, possibly contributing to its lack of fetal side effects.

Topics: Animals; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Meloxicam; Obstetric Labor, Premature; Pregnancy; Sheep; Thiazines; Thiazoles; Uterine Contraction; Uterus

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer related mortality worldwide. The incidence is dramatically increasing and no effective systemic treatments are available accentuating the urgent need for novel treatment approaches. A growing body of evidence suggest that COX-2 signaling is implicated in carcinogenesis and this study was conducted to evaluate the potential of selective COX-2 inhibition for the treatment and prevention of HCCs.. The significance of COX-2 inhibition in HCCs was investigated in vitro (HCC cell-lines), in vivo (xenotransplanted tumors in nude mice) and ex vivo (precission-cut tissue sclice-cultures). Apoptosis-signaling was analyzed by means of immunohistochemistry, Western Blot analyses, Caspase-assays, FACS analyses after Nicoletti-staining, death receptor FACS-analysis, determination of mitochondrial membrane potential, and siRNA knockdown of Mcl-1.. Selective COX-2 inhibition led to a marked tumor-specific growth inhibition of human HCCs in vitro, in vivo and ex vivo based on reduction of proliferation and induction of apoptosis. Both, the death receptor (extrinsic)-, as well as the mitochondrial (intrinsic)-apoptotic pathways were involved. COX-2 inhibition led to an increased surface expression of death receptors and a marked down-regulation of Mcl-1, followed by translocation of Bax to mitochondria and a consecutive release of cytochrome c. Of clinical importance, COX-2 inhibition acted synergistically with chemotherapeutic drugs in the induction of apoptosis whereas primary human-hepatocytes were not sensitized towards apoptosis.. COX-2 inhibition offers therapeutic and preventive potential in HCC.

Topics: Animals; Antineoplastic Agents; Carcinoma, Hepatocellular; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Disease Models, Animal; Drug Design; Humans; Liver Neoplasms; Meloxicam; Rats; Thiazines; Thiazoles

Inflammatory bowel diseases are associated with reduced colonic contractility and induction of cyclooxygenase-2. In this study a possible role of cyclooxygenase-2 in and the underlying mechanism of the reduced contractility were investigated in experimental colitis. The effects of meloxicam, a cyclooxygenase-2 selective inhibitor were examined on colonic contractility and MAP kinase p38 and ERK(1/2) expression. Colitis was induced in Sprague-Dawley male rats by intra-colonic instillation of trinitrobenzenesulphonic acid (TNBS; 40 mg/rat in 50 ethanol). The animals were divided into three groups. Group 1 (n=9) received meloxicam (3 mg/kg-day) gavage 1 h before and 1 day (Group 2) after induction of colitis. Group 3 (n=9) received phosphate buffered saline (PBS) in a similar manner and served as colitic control. The non colitic control animals received meloxicam in a similar manner. The animals were sacrificed after 5 days of treatment, colon was cleaned with PBS and colonic smooth muscle was obtained which was used in this study. Meloxicam treatment given 1 h before or 1 day after administration of colitis restored the reduced colonic contractility without affecting the sensitivity to carbachol. The levels of colonic smooth muscle IL-1beta mRNA, PGE(2), ERK(1/2), p38, malondialdehyde, myeloperoxidase activity and colonic mass were increased, whereas the body weight was decreased due to TNBS. The changes except colonic muscle mass and p38 expression were reversed by meloxicam treatment. These findings indicate that restoration of reduced colonic contractility by meloxicam is mediated by ERK(1/2), and that ERK(1/2) may serve as an important anti inflammatory target for treatment of colitis.

Topics: Animals; Blotting, Western; Carbachol; Colitis; Colon; Cyclooxygenase 2 Inhibitors; Disease Models, Animal; Dose-Response Relationship, Drug; Extracellular Signal-Regulated MAP Kinases; Gastrointestinal Motility; Isometric Contraction; Male; Malondialdehyde; Meloxicam; Muscle, Smooth; p38 Mitogen-Activated Protein Kinases; Peroxidase; Rats; Rats, Sprague-Dawley; RNA, Messenger; Thiazines; Thiazoles; Trinitrobenzenesulfonic Acid

Pancreaticobiliary maljunction (PBM) is a high risk factor in biliary tract carcinoma. The chemopreventive action of a cyclooxygenase (COX)-2 inhibitor (meloxicam) on N-nitrosobis (2-oxopropyl) amine (BOP)-induced gallbladder cancer in hamster PBM models was investigated. In 7-week-old female Syrian golden hamsters, the extrahepatic bile duct at the distal end of the common duct was ligated and cholecystoduodenostomy was performed (group I). In group II, the same surgery was performed and from week 4 after surgery, 10 mg/kg of BOP was injected subcutaneously once a week with a 1-week interval. In group III, in addition to the measures employed in group II, 5 mg/kg/day of meloxicam was administered once a day, every weekday. Pathological findings in the gallbladder in week 20 after surgery were as follows. In group I, proper epithelium (PE) was predominant and there was no cancer. In group II, PE was predominant, but there was also hyperplasia and atypical epithelium (AE) recognized in 8 of 11 cases (72.7%); the area of AE was more extensive than that in group I. Carcinoma in situ (CIS) was recognized in 4 of 11 cases (36.4%) in group II. Group III showed the same pathological findings as group I. However, compared with group II, the incidence of AE decreased to 27.3% and no cancerous lesion was observed. In week 20 after surgery, the proliferative cell nuclear antigen labeling index in group III was statistically significantly lower than in group II (P = 0.045). No statistically significant differences were noted among the groups in terms of apoptosis labeling index in week 20 after surgery. In conclusion, it was confirmed that meloxicam suppresses carcinogenesis in hamster PBM models and its mechanism may be based on the suppression of cell growth.

Topics: Animals; Apoptosis; Carcinogens; Carcinoma in Situ; Cell Proliferation; Cell Transformation, Neoplastic; Cricetinae; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Disease Models, Animal; Epithelium; Female; Gallbladder; Gallbladder Neoplasms; Hyperplasia; Meloxicam; Mesocricetus; Nitrosamines; Proliferating Cell Nuclear Antigen; Thiazines; Thiazoles

Very little is known concerning the occurrence of pain in cancer research models. We wished to establish whether a behaviour-based approach, originally developed to assess postoperative pain, could be used to determine positive effects of the analgesics carprofen and meloxicam in rats that might be experiencing pain during tumour development in an orthotopic model of bladder cancer. An invasive but non-metastatic rat bladder cancer cell line was surgically implanted into the bladder wall of 57 inbred Fisher344 rats. The rats underwent daily clinical assessments. When clinical signs consistent with chronic pain were apparent, behavioural data were collected from 44 animals during 2 x 10 min periods, immediately before and one hour after a subcutaneous injection of either physiological saline (0.9%; 0.2 ml/100 g), carprofen (5 mg/kg) or meloxicam (2 mg/kg). Treatment-associated behaviour changes were then compared between groups. The lack of active behaviour, both before and after each treatment, was consistent with established clinical signs of pain. The rats were so inactive following the treatment that the behavioural technique we had previously developed was of comparatively little use in determining either pain severity or analgesic efficacy. One very prominent effect, however, was an increase in ventral abdominal licking in the control (saline) group. As this was absent in rats given meloxicam or carprofen, and has previously been considered to indicate pain emanating from damaged tissue, it was concluded that the analgesic-treated rats gained at least some benefit from the drug treatments, but it was not possible to gauge the extent of this. Handling for examination or treatment may have intensified pain in rats in the control group, and so this should be avoided whenever possible. It is likely that post-surgical pain differs markedly from cancer pain, so a different set of behavioural markers may be needed to assess it effectively. More intensive behaviour monitoring may help to develop a suitable technique for detecting the onset of, and assess the severity of pain that may occur during tumour development.

Topics: Analysis of Variance; Animals; Behavior, Animal; Carbazoles; Disease Models, Animal; Male; Meloxicam; Pain; Pain Measurement; Pain, Postoperative; Rats; Rats, Inbred F344; Thiazines; Thiazoles; Urinary Bladder Neoplasms

The effects of a synthetic peptide analog of thymulin (PAT) were tested on nociceptive behavior in two animal models for peripheral mononeuropathy and in another two models for capsaicin-induced hyperalgesia. Treatment with PAT (0.25-25 microg/rat, i.p.) produced significant reduction of the mechanical allodynia and heat hyperalgesia in rats subjected to either chronic constriction injury (CCI) or spared nerve injury (SNI) models for mononeuropathy. Cold allodynia was moderately reduced in the CCI model. The inhibition of neuropathic manifestations peaked at 1-2 h post-treatment and disappeared in 3-4 h. Daily treatment with PAT, however, produced progressive attenuation of all neuropathic manifestations in the SNI model. On the other hand, pretreatment with similar doses of PAT produced dose-dependent reduction of the hyperalgesia induced by intraplantar injection of capsaicin (10 microg in 50 microl). The highest dose of PAT (50 microg) produced significant reduction of abdominal aversive behavior induced by i.p injection of capsaicin (20 microg in 100 microl). Compared with the effects of treatment with morphine or meloxicam (injected at single doses known to produce analgesia), PAT exerted equal or stronger inhibitory effects on neuropathic manifestations. The reported results suggest a possible direct action of PAT on afferent nerve fibers but its mechanisms remain to be determined.

Topics: Analgesics, Non-Narcotic; Analgesics, Opioid; Animals; Capsaicin; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Hot Temperature; Hyperalgesia; Ligation; Male; Meloxicam; Morphine; Pain; Pain Threshold; Peptides; Peripheral Nervous System Diseases; Rats; Rats, Sprague-Dawley; Reaction Time; Thiazines; Thiazoles; Thymic Factor, Circulating; Time Factors

We have recently demonstrated dose-related analgesic-induced reductions in the occurrence of 7 behavioural activities following midline laparotomy in rats. For these behaviours to be useful in evaluating pain in laboratory rats they must be shown to occur after different types of surgery, and frequently enough to allow rapid scoring of animals. Here, the relevant behaviours were used to test the analgesic efficacy of meloxicam with a variation of our previous laparotomy model. As part of an unrelated project, 57 male Fischer rats were divided into groups to receive either saline (0.2 ml/100g s.c.), meloxicam (0.5, 1 or 2 mg/kg s.c.) or carprofen (2.5, 5, or 10 mg/kg s.c.) 1h before surgery. Behaviour data were collected for 10 min following 25 min of recovery from isoflurane anaesthesia. The cumulative frequencies of back arching, fall/stagger, writhe and poor gait were used to compute a composite behaviour score. Irrespective of whether analyses included only 5 or all 10 min of the observation period, the relevant behaviours occurred significantly more often in rats given saline or low dose meloxicam than in those given 1 or 2 mg/kg of meloxicam, or any dose of carprofen. We conclude that this technique of quantifying post-surgery behaviour is an effective pain scoring method following abdominal surgery in rats, and that 1 mg/kg meloxicam significantly attenuates laparotomy induced pain. Since only a short observation period is required, this approach represents an important practical advance in assessing abdominal pain severity and clinical drug potency.

Topics: Abdominal Pain; Analgesics, Non-Narcotic; Animals; Anti-Inflammatory Agents, Non-Steroidal; Behavior, Animal; Body Weight; Carbazoles; Disease Models, Animal; Exploratory Behavior; Male; Meloxicam; Motor Activity; Pain Measurement; Pain, Postoperative; Rats; Rats, Inbred F344; Thiazines; Thiazoles; Time Factors

To elucidate the pathogenesis of periapical lesion-associated bone resorption, a disease model of Wistar rat molar was employed. After lesion induction, the mRNAs encoding for matrix metalloproteinase-1 (MMP-1), tissue inhibitor of metalloproteinase-1 (TIMP-1), interleukin-6 (IL-6), and cyclooxygenase-2 (COX-2) in the developing lesions were detected by in situ hybridization at day 5, 10, 15 and 20, respectively. At day 5, MMP-1, IL-6 and COX-2 mRNAs appeared predominantly in macrophages. During day 15 to day 20, increased expressions of these mediators were also found in osteoblasts but to a lesser extent compared with those in macrophages. MMP-1 mRNA was also detected in osteoclasts. In contrast, expression of the TIMP-1 gene was noted primarily in osteoblasts and was less pronounced compared with that of MMP-1. The mediator-expressing cells aggregated in the vicinity of bone resorption areas and their numbers increased with time. These data suggest that macrophages and osteoblasts are involved in the development of periapical lesions, and that they promote bone resorption by producing MMP-1, IL-6 and COX-2. In addition, administration of a specific COX-2 inhibitor, meloxicam, reduced the extent of periapical bone resorption by 43% and simultaneously diminished the numbers of cells synthesizing MMP-1 and IL-6 mRNAs. These results further elucidate the significance of COX-2 in disease progression of periapical lesions as it modulates indirectly the production of MMP-1 and IL-6.

Topics: Animals; Bone Resorption; Cell Count; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Disease Models, Animal; Disease Progression; Gene Expression; In Situ Hybridization; Injections, Intraperitoneal; Interleukin-6; Isoenzymes; Macrophages; Mandibular Diseases; Matrix Metalloproteinase 1; Meloxicam; Osteoblasts; Periapical Diseases; Peroxidases; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Wistar; RNA, Messenger; Thiazines; Thiazoles; Time Factors; Tissue Inhibitor of Metalloproteinase-1

To observe the effect of selective cyclooxygenase-2 (COX-2) inhibitor-meloxicam on the progression of tubulointerstitial fibrosis in rats with unilateral ureteral obstruction (UUO).. UUO rats were treated with meloxicam (M), indomethacin (I) or vehicle alone (U) for 4 weeks. Using reverse transcription-polymerase chain reaction (RT-PCR), we examined the mRNA expressions of transforming growth factor (TGF)-beta receptor-1 and 2 in left kidney from rats with UUO. Immuno-precipitation and immunohistochemistry analysis were carried out to investigate the protein level of TGF-beta(1). Tubulointerstitial fibrosis was quantified by Masson's staining. Similar studies were performed in another group of rats with sham operation (C).. mRNA expressions of TGF-beta receptor-1 and 2 were markedly increased in Group U compared with those in Group C. Both meloxicam and indomethacin inhibited their expressions to a different degree (P < 0.01), but the effect of meloxicam was more significant. Meloxicam decreased the protein level of TGF-beta(1) (P < 0.01), while indomethacin had no such effect. Compared with Group C, there appeared tubulointerstitial fibrosis in the kidney of rats with UUO. The lesion was aggravated by indomethacin, but remarkably attenuated by meloxicam.. In summary, selective COX-2 inhibitor-meloxicam has a salutary effect on the tubular and interstitial response to UUO. TGF-beta and its receptor approaches partly explain some of the mechanism.

Topics: Animals; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Disease Models, Animal; Indomethacin; Isoenzymes; Male; Meloxicam; Nephritis, Interstitial; Prostaglandin-Endoperoxide Synthases; Protective Agents; Rats; Rats, Sprague-Dawley; Thiazines; Thiazoles; Ureteral Obstruction

The aim of this study was to evaluate the effect of exercise on apoptosis in rat gastrocnemius and soleus muscle tissue and to determine the effect of meloxicam, a novel non-steroidal anti-inflammatory drug (NSAID), on the ratio of exercise-induced apoptosis. Forty male Wistar rats were used in the experiments. Spontaneous wheel-running was used as an exercise protocol. Rats were divided randomly into four groups. Group A (n = 10) was the control group, in which rats did not perform any exercise. In group B (n = 10), gastrocnemius and soleus muscles were biopsied immediately after exercise. The rats in group C (n = 10) were placed back in their cages after exercise and allowed to rest for 48 h, after which the gastrocnemius and soleus muscles were biopsied. In group D (n = 10), rats were given 11 mg meloxicam (Mobic, Boehringer Ingelheim) per kilogram body weight per day p.o. for 2 days, after which gastrocnemius and soleus muscles were biopsied 48 h after exercise. The terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP)-biotin nick end labelling (TUNEL) technique was used to detect DNA fragmentation in situ. TUNEL-positive nuclei were identified and counted. The apoptosis ratio in gastrocnemius muscle was 0.50x10(-3)+/-0.96x10(-3) in group A, 5.42x10(-3)+/-3.58x10(-3) in group B, 3.55x10(-3)+/-3.23x10(-3) in Group C and 3.52x10(-3)+/-1.00 in Group D; the ratios in soleus muscle were 0.98x10(-3)+/-1.83x10(-3), 3.03x10(-3)+/-2.78x10(-3), 4.48x10(-3)+/-3.32x10(-3) and 2.91x10(-3) 1.98x10(-3), respectively. The differences between the apoptosis ratios in group A and B, Group A and C, and Group A and D were statistically significant (P < 0.05). There was no statistically significant difference between group C and D. In conclusion, exercise increased apoptosis in gastrocnemius and soleus muscle tissue, and the apoptosis ratios were not affected by meloxicam.

Topics: Analysis of Variance; Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Culture Techniques; Disease Models, Animal; Male; Meloxicam; Muscle, Skeletal; Physical Conditioning, Animal; Probability; Random Allocation; Rats; Rats, Wistar; Reference Values; Sensitivity and Specificity; Statistics, Nonparametric; Thiazines; Thiazoles

Animal models simulating acute human pulpitis are still lacking. The rat incisors present a particular situation where most of their innervation is considered to be unmyelinated and concentrated mainly in the tooth pulp. This study reports on a new model for dental pain induced by inflammatory agents applied to the tooth pulps of incisors. In different groups of rats, artificial crowns were fixed on the lower incisors, after cutting 1-2mm of their distal extremities. A volume of 7-10 microl of solutions of saline, capsaicin (1-10mg/ml) or formalin (2.5% or 5%) was injected in the crown cavity, and the nociceptive behaviour was quantitated following a devised scoring method of four scales. Intradental application of capsaicin produced nociceptive scores in the form of one plateau for 1-2h depending on the concentration used. Similar results were obtained with intradental application of formalin 2.5%. The one plateau of nociceptive scores obtained with formalin contrasts with the biphasic aspect of nociceptive behaviour described with the intradermal formalin test. This discrepancy could be attributed to a difference in the types of afferent fibres involved in each situation. Pretreatment with morphine (2 mg/kg) attenuated, in a naloxone-reversible manner, the nociceptive behaviour observed following intradental application of capsaicin. Pretreatment with meloxicam (a cyclo-oxygenase-2 inhibitor) exerted a less pronounced attenuation of the nociceptive scores when compared with morphine. These results provide evidence for the validity of the described model for the simulation of tooth pulp inflammatory pain in awake animals.

Topics: Analgesics, Opioid; Animals; Behavior, Animal; Capsaicin; Crowns; Cyclooxygenase Inhibitors; Dental Pulp Cavity; Disease Models, Animal; Drug Interactions; Female; Formaldehyde; Gingiva; Inflammation; Male; Meloxicam; Morphine; Naloxone; Narcotic Antagonists; Nerve Fibers; Nociceptors; Pain Measurement; Rats; Rats, Sprague-Dawley; Thiazines; Thiazoles; Toothache

1. The common mechanism of action of non-steroidal anti-inflammatory drugs (NSAIDs) is the inhibition of the enzyme cyclo-oxygenase (COX), however, this inhibition is not enough to completely account for the efficacy of these agents in several models of acute pain. 2. It has been demonstrated that cholinergic agents can induce antinociception, but the nature of the interaction between these agents and NSAIDs drugs has not been studied. The present work evaluates, by isobolographic analysis, the interactions between the cholinergic indirect agonist neostigmine (NEO) and NSAIDs drugs, using a chemical algesiometric test. 3. Intraperitoneal (i.p.) or intrathecal (i.t.) administration of NEO and of the different NSAIDs produced dose-dependent antinociception in the acetic acid writhing test of the mouse. 4. The i.p. or i.t. co-administration of fixed ratios of ED(50) fractions of NSAIDs and NEO, resulted to be synergistic or supra-additive for the combinations ketoprofen (KETO) and NEO, paracetamol (PARA) and NEO) and diclofenac (DICLO) and NEO administered i.p. However, the same combinations administered i.t. were only additive. In addition, the combinations meloxicam (MELO) and NEO and piroxicam (PIRO) and NEO, administered either i.p. or i.t., were additive. 5. The results suggest that the co-administration of NEO with some NSAIDs (e.g. KETO, PARA or DICLO) resulted in a synergistic interaction, which may provide evidence of supraspinal antinociception modulation by the increased acetylcholine concentration in the synaptic cleft of cholinergic interneurons. The interaction obtained between neostigmine and the NSAIDs could carry important clinical implications.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cholinesterase Inhibitors; Diclofenac; Disease Models, Animal; Drug Synergism; Ketoprofen; Meloxicam; Mice; Neostigmine; Pain; Pain Measurement; Prostaglandin-Endoperoxide Synthases; Thiazines; Thiazoles

To study the possible role of the isoenzymes of cyclooxygenase COX-1 and COX-2 in the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model of Parkinson's disease we used acetylsalicylic acid, a COX-1/COX-2 inhibitor, in comparison with meloxicam, a preferential COX-2 inhibitor. As markers of protection we determined the effects on MPTP-induced striatal dopamine depletion, locomotor activity, cell loss, and tyrosine hydroxylase immunoreactivity (TH-IR) in the substantia nigra pars compacta. Male C57BL/6 mice (n = 82) were treated with a single dose of acetylsalicylic acid (10, 50, 100 mg/kg i.p.) or meloxicam (2, 7.5, 50 mg/kg i.p.) immediately prior to administration of MPTP (30 mg/kg s.c.) or saline. After 7 days the mice were sacrificed to analyze striatal dopamine and metabolite levels. Nigral sections were processed for Nissl-staining and TH-IR. In the saline-treated MPTP control group striatal dopamine levels were reduced to 15.9% of control values. Dopamine depletion was significantly attenuated to values of 37.1 and 38.6% of saline control values by acetylsalicylic acid (50 and 100 mg/kg) and to values of 36 and 40% by meloxicam (7.5 and 50 mg/kg), respectively. MPTP-induced decrease of locomotor activity was significantly attenuated by acetylsalicylic acid and meloxicam. Remarkably, the MPTP-induced decrease of TH-IR as well as the loss of nigral neurons was nearly completely prevented by acetylsalicylic acid (100 mg/kg) and meloxicam (7.5 and 50 mg/kg). In conclusion, the inhibition of either COX-1/COX-2 by acetylsalicylic acid or preferentially COX-2 by meloxicam provided a clear neuroprotection against MPTP-toxicity on the striatal and nigral levels.

Topics: 1-Methyl-4-phenylpyridinium; 3,4-Dihydroxyphenylacetic Acid; Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Cell Count; Cyclooxygenase 1; Cyclooxygenase 2; Disease Models, Animal; Dopamine; Homovanillic Acid; Isoenzymes; Male; Meloxicam; Membrane Proteins; Mice; Mice, Inbred C57BL; Motor Activity; Neostriatum; Neuroprotective Agents; Parkinsonian Disorders; Prostaglandin-Endoperoxide Synthases; Substantia Nigra; Thiazines; Thiazoles; Tyrosine 3-Monooxygenase

Using the isolated perfused bovine udder as an in-vitro model of skin inflammation, the effects of topically administered arachidonic acid on prostaglandin and leukotriene synthesis have been shown previously. In this study, the effects of indometacin (indomethacin) and clobetasol-17-propionate (administered topically) as well as flunixin meglumine and meloxicam (administered via the perfusion fluid) have been studied. Compared with controls, arachidonic acid caused a significant increase in the dermal prostaglandin E2 (PGE2) and peptidoleukotriene (LTC4/D4/E4) concentration. Topical treatment with indometacin (1.6 mg cm(-2)) and clobetasol-17-propionate (90 microg cm(-2)), which were administered 60 min before arachidonic acid administration, inhibited the inflammatory reaction. Flunixin meglumine (1 microg mL(-1) perfusion fluid) was administered 30 min after and meloxicam (3 microg mL(-1) perfusion fluid) was administered 60 min before arachidonic acid application. Three hours after arachidonic acid administration, a significant inhibition of PGE2 synthesis was induced by flunixin. In contrast, meloxicam showed only a slight effect. The effect of flunixin was comparable with in-vivo results. It is known from animal studies that anti-inflammatory effects of meloxicam are obvious within up to 6 h after treatment. Therefore, the incomplete effect of meloxicam may be explained pharmacokinetically. In conclusion, the described in-vitro model seems to be suitable for studies of pharmacological effects on eicosanoid synthesis in the skin.

Topics: Administration, Topical; Animals; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acid; Cattle; Clobetasol; Clonixin; Culture Techniques; Dinoprostone; Disease Models, Animal; Eicosanoids; Female; Glucocorticoids; Indomethacin; Mammary Glands, Animal; Meloxicam; Skin Physiological Phenomena; Thiazines; Thiazoles

Prostaglandins are implicated in periodontal bone destruction. We investigated the effect of a non-selective cyclooxygenase (COX) inhibitor (indomethacin-IND) or a type 2 COX inhibitor (meloxicam-MLX) in an experimental periodontal disease (EPD) model.. Wistar rats were subjected to placement of a nylon thread ligature around the maxillary molars and sacrificed after 7 days. Alveolar bone loss (ABL) was measured in one quadrant as the distance between the cemento-enamel junction and the alveolar bone. The other quadrant was processed for histopathologic analysis. Daily weight and white blood cell count were recorded. Groups were treated subcutaneously for 7 days with either IND (0.5, 1, or 2 mg/kg) or MLX (0.75, 1.5, or 3 mg/kg). Controls received no treatment. Macroscopic analysis of the gastric mucosa was done. The control group did not receive any manipulation, and a non-treated group consisted of rats subjected to periodontitis that received no pharmacological treatment.. In the non-treated (NT) group, there was significant ABL, severe mononuclear influx, and an increase in osteoclast numbers. Significant neutrophilia and lymphomonocytosis occurred at 6 hours and at 7 days, respectively, as compared to controls. Significant weight loss persisted until the seventh day in the NT group. Both IND and MLX reduced ABL and histopathologic changes. Neutrophilia and lymphomonocytosis were also significantly reversed. Both IND and MLX induced earlier weight recovery. The stomachs of the IND (1 and 2 mg/kg) groups presented hemorrhage and ulcers, whereas in the MLX-treated groups, there were mild petechiae just in the 3 mg/kg group.. COX inhibition prevented ABL in this experimental periodontal disease model. MLX displays similar efficacy and less gastric damage than IND. MLX may provide a better risk/benefit ratio in the treatment of human periodontitis than non-selective COX inhibitors.

Topics: Alveolar Bone Loss; Alveolar Process; Animals; Anti-Inflammatory Agents, Non-Steroidal; Body Weight; Cell Count; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Disease Models, Animal; Indomethacin; Injections, Subcutaneous; Isoenzymes; Leukocyte Count; Leukocytes, Mononuclear; Leukocytosis; Male; Meloxicam; Molar; Neutrophils; Osteoclasts; Periodontitis; Peroxidases; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Wistar; Stomach; Thiazines; Thiazoles; Tooth Cervix

In this study, ischemia-reperfusion produced in rats by clamping the celiac artery for 0.5 h followed by 1 h of reperfusion was used to develop a new model of superficial gastric erosions progressing to deeper ulcers. Ischemia alone resulted in an immediate fall in gastric blood flow but no gross mucosal lesions were observed. When ischemia was followed by reperfusion, gastric erosive lesions occurred, reached a maximum at 12 h and then declined after 24 h. These acute erosions progressed into deeper lesions 24 h after ischemia-reperfusion and reached a peak after 3 days. Gastric blood flow and the mucosal generation of prostaglandin E(2) were significantly suppressed immediately following ischemia-reperfusion, but with the healing of deeper gastric ulcers, both gastric blood flow and prostaglandin E(2) generation were gradually restored. Cyclooxygenase-1 mRNA was detected by reverse transcription-polymerase chain reaction in intact gastric mucosa and throughout the recovery of the mucosa from acute ischemia-reperfusion lesions, whereas cyclooxygenase-2 mRNA, was recorded only after ischemia-reperfusion. NS-398 and rofecoxib, selective inhibitors of cyclooxyganase-2, failed to affect prostaglandin E(2) generation in the non-ulcerated gastric mucosa but inhibited it significantly in the ulcer area. The two cyclooxygenase-2 inhibitors as well as resveratrol, a specific cyclooxygenase-1 inhibitor and indomethacin and meloxicam, non-specific inhibitors of cyclooxygenase, augmented acute gastric erosions induced by ischemia-reperfusion and delayed significantly the progression of these lesions into deeper ulcers at each time interval after ischemia-reperfusion. We conclude that prostaglandins generated by both cyclooxygenase-1 and cyclooxygenase-2 contribute to the healing of gastric lesions induced by ischemia-reperfusion.

Topics: Animals; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprostone; Disease Models, Animal; Gastric Mucosa; Gastrins; Gene Expression Regulation, Enzymologic; Indomethacin; Interleukin-1; Isoenzymes; Lactones; Meloxicam; Membrane Proteins; Nitrobenzenes; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Rats; Regional Blood Flow; Reperfusion Injury; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Stilbenes; Stomach Ulcer; Sulfonamides; Sulfones; Thiazines; Thiazoles; Time Factors

The antipyretic efficacy of meloxicam was evaluated in a feline endotoxin model using a replicated change-over design. Twelve adult cats of both sexes were allocated at random to three experimental groups. At 30 min prior to the intravenous (i.v.) endotoxin challenge (0.5 microgram/kg body weight(b.w.)), 2 animals in each group received an i.v. injection of 0.1, 0.3 or 0.5 mg meloxicam/kg b.w. and the two remaining animals in each group received physiological saline. In a second phase, 21 days later, the meloxicam/placebo treatment was exchanged within each group. The rectal temperature and scores for general demeanour were determined at 30-min intervals from before dosing to 300 min after the endotoxin challenge. Haematological parameters were analysed before and 60 min after administration of endotoxin. The results indicated a significant dose-dependent antipyretic response to meloxicam after endotoxin challenge. The antipyretic response in the medium- and high-dose meloxicam groups did not differ significantly, but both were significantly different from the low-dosage group. The individual effects of endotoxin on general demeanour were rather variable but meloxicam tended to have a beneficial effect. Endotoxin induced a reduction in the white blood cell count but this was not influenced by meloxicam. It was concluded that the pyretic endotoxin model is very suitable for studying new NSAIDs in cats and that the optimum single dose of meloxicam in this model was 0.3 mg/kg b.w.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Behavior, Animal; Body Temperature; Cat Diseases; Cats; Cross-Over Studies; Disease Models, Animal; Dose-Response Relationship, Drug; Endotoxins; Escherichia coli; Female; Fever; Injections, Intravenous; Male; Meloxicam; Thiazines; Thiazoles

The effects of intra-articular injection, on two occasions, 3 weeks apart, of the contrast agent Urografin on the cytological and biochemical characteristics of synovial fluid (SF) were examined in two studies in dogs. The first study provided baseline data in two non-medicated dogs. The second study used a cross-over design whereby 4 dogs received a 7-day oral treatment with either a placebo or meloxicam (0.2 mg/kg body weight daily) with a washout period of 3 weeks, in order to determine the effect of this new non-steroidal anti-inflammatory drug (NSAID) on the response to Urografin injection. SF samples were collected under general anaesthesia prior to and at 24 and 72 h after each Urografin injection. The volume, relative viscosity, white blood cell count and concentrations of protein, lactate dehydrogenase (LDH) and hyaluronic acid of these samples were determined. The results from both studies indicate that intra-articular injection of Urografin provoked a mild local transient inflammatory response, the most dramatic evidence of which was an increase in the white blood cell count in the SF after 24 h. In the second study, comparison of the synovial fluid measurements of the placebo-treated dogs at 24 h after Urografin injection with those prior to injection revealed significant increases in SF volume, white blood cell count, protein concentration and LDH activity and a significant reduction in relative viscosity. At 72 h after injection, only the white blood cell count and relative viscosity were significantly different from the pre-injection values.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Disease; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis; Diatrizoate Meglumine; Disease Models, Animal; Dog Diseases; Dogs; Female; Leukocyte Count; Male; Meloxicam; Shoulder Joint; Synovial Fluid; Thiazines; Thiazoles