Administration Of Meloxicam Research Articles

Recovery of Hematopoiesis and Increased Survival Following Radiological Injury through Modulation of Prostaglandin E2 (PGE2) Signaling.

AbstractAbstract 2638The highly proliferative nature of hematopoietic stem (HSC) and progenitor (HPC) cells, particularly during stress induced hematopoiesis, makes them highly sensitive to radiation, and in extreme circumstances results in the Hematopoietic Syndrome of the Acute Radiation Syndrome (HS-ARS). In addition to the therapeutic use of high dose total body irradiation (TBI), the proliferation of nuclear weapons, increasing use of nuclear power, and worldwide radical terrorism has resulted in a rising need and increased research emphasis on developing countermeasures to a radiological mass casualty event. HS-ARS is characterized by life-threatening neutropenia, thrombocytopenia and lymphocytopenia, and possible death due to infection and/or bleeding. While HSC and HPC are susceptible to radiation exposure, surviving populations of these cells can recover hematopoiesis if given critical time to repair DNA damage, self-renew, expand and differentiate. We previously reported (Hoggatt et al, Blood 2009) that PGE2 increases HSC self-renewal and expression of the anti-apoptotic protein Survivin, resulting in reduced apoptosis and increased HSC number. Since PGE2 production is increased following radiation exposure, and tumors over-producing PGE2 are radioresistant, we hypothesized that PGE2 production may be an endogenous mechanism for recovery from radiation damage, and that enhancement of PGE2 signaling could improve post-irradiation hematopoiesis and survival. Mid-lethally irradiated mice were treated with a single dose of the long-acting PGE2 analog, 16,16 dimethyl PGE2 (dmPGE2) or vehicle 6 hrs post-TBI and morbidity and mortality monitored for 30 days (n=20 mice/group). Treatment with dmPGE2 resulted in 95% survival (P=0.001) compared to only 50% survival in control mice. The number of marrow CFU-GM, BFU-E and CFU-GEMM were significantly higher in surviving mice from the dmPGE2 treated group compared to control mice (2.0±0.1 fold increase in CFC). While PGE2 is beneficial for HSC self-renewal and anti-apoptosis and our data clearly indicate that dmPGE2 treatment enhances hematopoietic recovery and survival post-TBI, we and others have previously shown that PGE2 is inhibitory to myelopoiesis. Therefore, we hypothesized that while exposure to PGE2 early after TBI is beneficial and can increase the number of surviving HSC, sustained exposure to PGE2 is inhibitory to HPC expansion, and may limit hematopoietic recovery. To test this hypothesis, we treated lethally irradiated mice with meloxicam, a cyclooxygenase inhibitor that blocks PGE2 production, for 4 consecutive days, starting either 6 hrs post-irradiation or delayed for 48 hours. While only 5% of control mice survived 30 days post-TBI, 35% of mice treated with meloxicam 6 hrs post-irradiation and 50% of mice receiving delayed meloxicam treatment survived. A faster and more robust recovery of white blood cells (WBC), neutrophils (PMN) and platelets (PLT) was observed at 15 and 30 days post-TBI with delayed meloxicam administration compared to control [15 days: (WBC 4.12 vs 1.15) (PMN 1.25 vs 0.27) (PLT 285 vs 85) x103/ul; 30 days: (WBC 11.3 vs 3.6) (PMN 6.8 vs 1.3) (PLT 819 vs 249) x103/ul], while administration 6 hrs post-irradiation resulted in more modest increases. In addition, analysis of marrow 30 days post-TBI demonstrated a significant enhancement in CFC in both non-delayed and delayed treatment groups compared to control (1.4 and 3.1 fold increase, respectively). These data suggest that inhibition of PGE2 synthesis post-TBI is beneficial for hematopoietic recovery and survival, but that allowing the positive effects of PGE2 on HSC to occur within the first 48 hours of TBI before inhibiting biosynthesis, results in a more efficacious treatment; a model supported by our results demonstrating enhanced recovery and survival with a single treatment of dmPGE2 shortly following TBI. Faced with the complexities of a mass casualty event and difficulty of individual dosimetry and triage, interventions that can mitigate or reduce the severity of exposure, but that are benign to those individuals with limited or no exposure are required. Our results define 2 different treatment modalities which are both highly effective and safe to administer, and can be readily available. In addition, the hematopoietic recovery demonstrated in these studies suggests a potential therapeutic benefit of cyclooxygenase inhibitors in TBI settings. Disclosures:No relevant conflicts of interest to declare.

Pharmacokinetics of meloxicam following intravenous and oral administration in green iguanas (Iguana iguana)

To determine pharmacokinetics of meloxicam in healthy green iguanas following PO and IV administration and assess potential toxicity. 21 healthy green iguanas (Iguana iguana). To assess pharmacokinetics, 13 iguanas were administered a single dose (0.2 mg/kg) of meloxicam PO and, 14 days later, the same dose IV. To assess potential toxicity, 4 iguanas were given meloxicam at a dosage of 1 or 5 mg/kg, PO, every 24 hours for 12 days, and results of histologic examination were compared with results for another 4 iguanas given a single dose of meloxicam (0.2 mg/kg). There were no significant differences between PO and IV administration with regard to terminal half-life (mean ± SD, 12.96 ± 8.05 hours and 9.93 ± 4.92 hours, respectively), mean area under the curve to the last measured concentration (5.08 ± 1.62 μg•h/mL and 5.83 ± 2.49 μg•h/mL), volume of distribution (745 ± 475 mL/kg and 487 ± 266 mL/kg), or clearance (40.17 ± 10.35 mL/kg/h and 37.17 ± 16.08 mL/kg/h). Maximum plasma concentration was significantly greater following IV (0.63 ± 0.17 μg/mL) versus PO (0.19 ± 0.07 μg/mL) administration. Time from administration to maximum plasma concentration and mean residence time were significantly longer following PO versus IV administration. Daily administration of high doses (1 or 5 mg/kg) for 12 days did not induce any histologic changes in gastric, hepatic, or renal tissues. Results suggested that administration of meloxicam at a dose of 0.2 mg/kg IV or PO in green iguanas would result in plasma concentrations > 0.1 μg/mL for approximately 24 hours.

Characterization of a rat model of metastatic prostate cancer bone pain

Purpose:The objectives of this study were to establish and characterize a novel animal model of metastatic prostate cancer-induced bone pain.Methods:Copenhagen rats were injected with 106 MATLyLu (MLL) prostate cancer cells or phosphate-buffered saline by per cutaneous intra femoral injections into the right hind leg distal epiphysis. Over 13 days, rats progressively developed a tumor within the distal femoral epiphysis. On days 3, 7, 10, and 13 post injection, rats were subjected to the incapacitance and Randall–Selitto behavioral tests as they are believed to be indirect reflections of tumor induced pain. Ipsilateral hind limbs were subjected to X-ray and computed tomography (CT) scans and histological sections were stained with hematoxylin and eosin (H&E).Results:Intra femoral injections of MLL cells resulted in the progressive development of a tumor leading to bone destruction and nociceptive behaviors. Tumor development resulted in the redistribution of weight to the contralateral hind leg and significantly reduced the paw withdrawal threshold of the ipsilateral hind paw as observed via the incapacitance and Randall–Selitto tests, respectively. X-ray and computed tomography scans along with H&E stains indicated tumor-associated structural damage to the distal femur. This model was challenged with administration of meloxicam. Compared with vehicle-injected controls, the meloxicam-treated rats displayed smaller nociceptive responses as observed with the incapacitance and Randall–Selitto tests, suggesting that meloxicam was effective in reducing the pain-related symptoms displayed by model animals and that the model behaved in a predictable way to cyclooxygenase-2 treatment.Conclusions:This model is unique from other bone cancer models in that it is a comprehensive model utilizing a competent immune system with a syngeneic tumor. The model establishes a tool that will be useful to investigate mechanisms of cancer pain that are induced by cancer cells.

Effect of seven-day administration of carprofen or meloxicam on renal function in clinically healthy miniature pigs

Carprofen or meloxicam are nonsteroidal anti-inflammatory drugs (NSAIDs), which may elicit a variety of renal disturbances. Prior to this study, the effects of carprofen or meloxicam on renal function in pigs were unknown. A total of 21 clinically healthy Goettingen miniature pigs (36.9 ± 7.22 kg) were divided into three groups based on what they were administered – carprofen, meloxicam or saline. First, blood was collected from the jugular vein and urine by ultrasound-guided cystocentesis. Serum urea (U) and creatinine (CR), fractional clearance of sodium (FCNa), urine gamma-glutamyltransferase (GGT) and alkaline phosphatase (ALP) activities, urine protein/creatinine ratio (UP/UC), urine gamma-glutamyltransferase/creatinine ratio (GGT/CR) and urine alkaline phosphatase/creatinine ratio (ALP/CR) and urine analysis – urine specific gravity (USG) and sediment microscopy were assessed before and seven days after daily intramuscular administration (IM) of saline (1.5 ml per animal), carprofen (2 mg/kg) or meloxicam (0.1 mg/kg). All animals had identical housing, feeding and unlimited water intake and had not undergone surgery or been administered any medication for three months prior to this. All pigs served as control groups for an experimental study of fracture healing using transplantation of mesenchymal stem cells and scaffolds. The data were analyzed using a one way ANOVA and a Mann-Whitney test (P < 0.05). In pigs receiving carprofen, serum urea and creatinine were significantly decreased, compared to the control (P < 0.01) or meloxicam (P < 0.05) groups. In animals receiving meloxicam FCNa was significantly increased (P < 0.05) and urine specific gravity significantly decrease (P < 0.05) compared to the pretreatment values. Two carprofen-treated pigs had a slight increase in renal tubular epithelial cells upon urine sediment examination. Intramuscular administration of carprofen or meloxicam in healthy miniature pigs for seven days causes no clinically important changes in selected renal parameters (without azotemia). However these changes indicate mild damage of renal tubules. Despite these findings, meloxicam or carprofen are recommended for analgesia in healthy pigs.

Pharmacokinetics and pharmacodynamic effects of meloxicam in piglets subjected to a kaolin inflammation model

Fosse, T. K., Spadavecchia, C., Horsberg, T. E., Haga, H. A., Ranheim, B. Pharmacokinetics and pharmacodynamic effects of meloxicam in piglets subjected to a kaolin inflammation model. J. vet. Pharmacol. Therap.34, 367–375. The pharmacokinetics and the analgesic, anti-inflammatory and antipyretic effects of meloxicam were investigated in a placebo controlled study in 2-week-old piglets. Inflammation was induced by a subcutaneous injection of kaolin in the left metacarpus, and 16 h later, meloxicam (0.6 mg/kg) or saline was administered intramuscularly. The absorption half-life was relatively short (0.19 h) and the elimination half-life was 2.6 h. Mechanical nociceptive threshold testing was used to evaluate the analgesic effect, but no significant effect of the meloxicam treatment was found. The skin temperature of the inflamed area increased after the kaolin injection, but no significant decrease in temperature was found after administration of meloxicam. Only limited pyresis was observed after the kaolin injection, and no significant antipyretic effect of meloxicam was found. The results indicated that this dose of meloxicam had very limited anti-inflammatory and analgesic effects in piglets.

Effects of firocoxib, meloxicam, and tepoxalin administration on eicosanoid production in target tissues of healthy cats

To evaluate the effects of firocoxib, meloxicam, and tepoxalin administration in healthy cats by measuring the ability of stimulated tissues to synthesize eicosanoids ex vivo. 8 healthy adult male cats. In a blinded, randomized, crossover study design, cats were treated with firocoxib (1 mg/kg, PO, q 24 h), meloxicam (0.05 mg/kg, PO, q 24 h), tepoxalin (5.0 mg/kg, PO, q 12 h), or a placebo for 8 days. Blood samples and gastric and duodenal mucosal biopsy specimens were collected on days 0 (baseline; immediately before treatment), 3, and 8 of each treatment period. Thromboxane B2 (TXB2) concentrations were measured in serum, and prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) concentrations were measured in plasma. Prostaglandin E1 (PGE1) synthesis, PGE2 synthesis, and LTB4 concentrations were measured in mucosal biopsy specimens. A 21-day minimum washout period was observed between treatments. Repeated-measures analyses were performed. Firocoxib and meloxicam administration resulted in a lower plasma PGE2 concentration than at baseline on days 3 and 8 of administration, whereas tepoxalin administration did not. Tepoxalin administration resulted in a lower serum TXB2 concentration and pyloric and duodenal PGE1 synthesis on both days, compared with baseline and placebo administration. Neither firocoxib nor meloxicam administration altered pyloric or duodenal PGE1 synthesis on either day, compared with placebo administration. Tepoxalin administration also resulted in lower pyloric mucosal LTB4 concentrations on both days, compared with baseline values. Firocoxib and meloxicam administration had no effect on cyclooxygenase-1 activity, whereas tepoxalin administration resulted in inhibition of cyclooxygenase-1 and 5-lipoxygenase.

Depressive psychosis associated with a cyclo oxygenase 2 inhibitor (meloxicam).

We describe a 60 year old man who developed a fluctuating depressive psychosis associated with meloxicam, a non-steroidal anti-inflammatory drug (NSAID). The psychological symptoms observed were temporally related to the administration of meloxicam and occurred in the presence of signs of meloxicam intolerance, such as skin rash and raised blood pressure. The depressive reaction resolved quickly following cessation of meloxicam, recurring on re-exposure. The psychiatric manifestations of NSAID intolerance are rare, however 40% of cases have a history of mental illness. Data from adverse event reporting systems suggest that the newer NSAIDs (COX-2 inhibitors) may have a higher propensity to cause psychiatric adverse effects and should be used with caution in individuals with a history of mental illness. This data may be provocative given current research in to the use of COX-2 inhibitors in augmenting neuroleptic treatment in schizophrenia.

Recommendations for Castration and Dehorning of Cattle

Pain associated with routine husbandry procedures such as dehorning and castration is increasingly being scrutinized by the public. The results of a survey of AABP and AVC members suggest that surgical castration with a scalpel followed by emasculator (>200 lb or 90 kg) or twisting ( <200 lb or 90 kg) is the most common castration method used by practitioners in the United States. Risk of injury to the operator, calf size, handling facilities, and experience were the most important considerations in selecting a castration method. Non-surgical castration is perceived to cause more adverse events than surgical castration. One in five veterinarians currently report using anesthesia or analgesia at the time of castration. Ninety percent of veterinarians vaccinate and dehorn at the time of castration. The Barnes dehorning tool appears to be the most common method of dehorning used in the US. Results of studies that use plasma cortisol or weight gain to determine the optimal timing and method of castration and use of analgesia are often equivocal or conflicting. The preliminary findings of a study using electroencephalography to examine the effect of age at the time of castration on brainwave activity show a more prominent shift toward high-frequency, low-amplitude brain activity in older calves compared with six-week-old calves. Meloxicam tablets administered orally at 0.45 mg/lb (1 mg/kg) may provide a convenient and cost-effective means of providing analgesia in cattle. A mean peak plasma concentration (Cmax) of3.10 ug/mL (Range: 2.64- 3.79 ug/mL) was recorded at 11.64 hours (Range: 10 - 12 hours) with a half-life (T ½ Az) of 27.54 hours (Range: 19.97 - 43.29 hours) after oral meloxicam administration. In recent studies we found that meloxicam administered prior to dehorning at 0.23 mg/lb (0.5 mg/kg) IV significantly increased average daily weight gain in calves after dehorning. A second study found that calves receiving oral meloxicam 24 hours prior to surgical castration tended to have a lower incidence of bovine respiratory disease.

Meloxicam Administration Mitigates Behavioral and Performance Effects of Scoop Dehorning Without Local Anesthesia in Weaned Holstein Calves

This study was conducted to determine the pharmacokinetics of meloxicam and its effect on serum cortisol, heart rate, behavior, and weight gain in calves after scoop dehorning without local anesthesia.

Pre–emptive meloxicam for postoperative analgesia in piglets undergoing surgical castration

ObjectiveTo investigate the effect of preoperative meloxicam administration on postoperative stress and pain induced by surgical castration in piglets. Study designProspective, blinded, randomized clinical trial. AnimalsOne hundred and eighty male piglets of <1 week of age. MethodsCastration was performed on 150 piglets which had received either an intramuscular injection of 0.4 mg kg−1 meloxicam or a placebo 10–30 minutes before the procedure. Blood cortisol and ACTH concentrations were determined at 30 minutes post–castration and haptoglobin was measured at 24 hours post–castration. Presence or absence of foreleg movements, hind leg movements, urine or faeces emission, tremors or other body movements were recorded during the castration procedure. Scores for presence or absence of prostration, tremors, tail movements and isolation were recorded at 30 minutes, and at 1, 2, 4 and 24 hours post–castration and combined in a global behaviour score (GBS). Blood samples were taken from a further 30 piglets which did not undergo castration. ResultsMean blood cortisol and ACTH concentrations at 30 minutes post–castration were both significantly lower in the meloxicam group than in the placebo group (p ≤ 0.01). The mean haptoglobin concentration at 24 hours was not significantly reduced (p = 0.178). The distribution of the GBS during castration was similar in both groups. There were significant differences in the GBS after castration at both 2 and 4 hours post–castration with a greater proportion of piglets in the meloxicam group showing no behavioural alterations (82.7%versus 68.0% at both time points). The score distribution was similar in both groups at 30 minutes, 1 and 24 hours after castration. Conclusion and clinical relevanceThis study suggests that pre–emptive administration of meloxicam is able to produce some postoperative analgesia after surgical castration of young piglets.

Clinical findings and gingival crevicular fluid prostaglandin E2 and interleukin-1-beta levels following initial periodontal treatment and short-term meloxicam administration

Objective: To evaluate the effects of adjunctive meloxicam administration on clinical periodontal measurements and gingival crevicular fluid (GCF) prostaglandin E2 (PGE2) and interleukin-1-beta (IL-1β) levels in chronic periodontitis.Methods: Forty chronic periodontitis patients were randomized to receive either meloxicam 7.5 mg or placebo tablets for 10 days with scaling and root planing (SRP). GCF levels of PGE2 and IL-1β at baseline, day 10 of drug intake and 4 weeks after SRP were determined by enzyme-linked immunosorbent assay. Demographic, clinical periodontal data were analyzed using a repeated measures ANOVA and Bonferroni analysis. GCF PGE2 and IL-1β levels were compared between different evaluation times using the Friedman test. The Mann–Whitney test was used to compare biochemical data between the study groups. Pearson correlation analysis was used to relate clinical and biochemical data.Results: Study groups showed significant reductions in all clinical periodontal measurements and GCF volume (p < 0.05). In both groups, IL-1β was reduced significantly on day 10 and at week 4 compared with baseline (p < 0.01) without significant changes in PGE2 levels (p > 0.05). No significant differences were found between study groups in GCF IL-1β or PGE2 levels (p > 0.05).Conclusion: Adjunctive meloxicam does not seem to provide additional improvement in clinical parameters or GCF PGE2 and IL-1β levels. Larger-scale studies may better clarify potential usage of anti-inflammatory agents in periodontal therapy.

Suppression of Follicular Rupture With Meloxicam, A Cyclooxygenase-2 Inhibitor: Potential for Emergency Contraception

The preferred treatment for emergency contraception at present is the synthetic progestogen levonorgestrel. Although this drug is widely available, women in some countries have little access to it due to restrictions imposed by conservative groups. Recent evidence has shown that levonorgestrel may have no contraceptive effect when taken after the ovulatory process has been triggered; this suggests that contraceptive failures with this drug may result from delayed administration. A number of studies have provided evidence that nonsteroidal anti-inflammatory drugs and specifically, cyclooxygenase-2 (COX-2) inhibitors, can prevent or delay follicular rupture. In a recent placebo controlled, double-blind, crossover study, daily administration of a partially selective COX-2 inhibitor, meloxicam, for 5 days at the onset of the luteinizing hormone (LH) surge significantly delayed follicular rupture. One advantage of using a COX-2 inhibitor to prevent or delay follicular rupture and inhibit the LH surge in comparison with using levonorgestrel is that COX-2 inhibition does not suppress the luteal phase. Accordingly, meloxicam should maintain the normal oscillations of ovarian steroids and preserve normal menstrual cycles. Other benefits of using COX-2 inhibitors include their accessibility over-the-counter in many countries and low cost as well as their improved safety profile with short-term treatment in women of reproductive age compared with steroid hormones. This single center, randomized, Phase I, double-blind, crossover study assessed the efficacy of meloxicam administered during the late follicular phase to prevent or delay follicular rupture when given very close to or after the LH started. The study subjects—27 healthy surgically sterilized volunteers (18―40 years old) with regular menstrual cycles—received oral doses of meloxicam 15 or 30 mg/d for 5 consecutive days starting when the leading follicle had reached 18 mm diameter. The participants underwent 3 cycles—first a drug-treatment cycle, a resting cycle, and then a second drug-treatment cycle. The primary study outcomes were the occurrence of follicular rupture, serum levels of LH, progesterone and estradiol, and the incidence of adverse events. Of the 27 volunteers, 22 completed the study. Dysfunctional ovulation occurred in 50% (11/22) of the cycles in women treated with the 15 mg/d dose and in 91 % of the cycles in women receiving the 30 mg/d dose (P = 0.0068). All women had normal progesterone levels during luteal phase; the mean maximal value was 42 ± 4.1 nmol/L for the 15 mg/d group and 46.8 ± 2.6 nmol/L for the 30 mg/d group. No changes were found in menstrual cycle length or in LH and estradiol levels. Serious adverse events were not observed. The findings of this pilot study suggest that the administration of meloxicam 30 mg/d for 5 consecutive days during the late follicular phase is effective, safe, and may be an alternative to levonorgestrel for emergency contraception.

Effects of aspirin, carprofen, deracoxib, and meloxicam on platelet function and systemic prostaglandin concentrations in healthy dogs

To determine effects of therapeutic dosages of aspirin, carprofen, deracoxib, and meloxicam on platelet function and systemic prostaglandin concentrations in healthy dogs. 10 hound-crossbred dogs. Aspirin (10 mg/kg, PO, q 12 h), carprofen (4.4 mg/kg, PO, q 24 h), deracoxib (2 mg/kg, PO, q 24 h), meloxicam (0.1 mg/kg, PO, q 24 h), and a placebo were administered for 7 days in a random order to each of 10 healthy dogs; there was a 21-day washout period between subsequent treatments. One-stage prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen concentration, and plasma concentrations of thromboxane (TX)B(2) and 6-keto prostaglandin (PG)F(1alpha) were measured before and after treatment administration. Platelet function was assessed by use of a platelet-function analyzer and aggregation. Aspirin, carprofen, and meloxicam did not significantly affect platelet function. Deracoxib caused a mild decrease in platelet aggregation induced by 50microM ADP. Platelet number, Hct, PT, aPTT, and plasma TXB(2) and 6-keto PGF(1alpha) concentrations were unchanged after NSAID administration. Meloxicam administration resulted in a significant decrease in fibrinogen concentration, but results remained within the laboratory reference interval. Oral administration of commonly used NSAIDs at therapeutic dosages in healthy dogs did not alter plasma TXB(2) and 6-keto PGF(1alpha) concentrations. Deracoxib administration resulted in a minor abnormality in platelet aggregation. Anti-inflammatory doses of aspirin did not affect platelet function as measured by use of optical aggregometry and a platelet-function analyzer. Further evaluation of the effects of aspirin and cyclooxygenase-2-selective inhibitors on hemostasis should be performed.

Analgesic effects of intramuscular administration of meloxicam in Hispaniolan parrots (Amazona ventralis) with experimentally induced arthritis

Analgesic effects of intramuscular administration of meloxicam in Hispaniolan parrots (<i>Amazona ventralis</i>) with experimentally induced arthritis

Oral administration of the cyclooxygenase-2 (COX-2) inhibitor meloxicam blocks ovulation in non-human primates when administered to simulate emergency contraception

Prostaglandins produced via cyclooxygenase-2 (COX-2) within the periovulatory follicle are required for successful ovulation. Inhibition of follicular prostaglandin synthesis prevents timely follicle rupture and oocyte release. This study was conducted to determine if a 5-day course of oral administration of the COX-2 inhibitor meloxicam can prevent ovulation while maintaining normal menstrual cycles in non-human primates. Adult female cynomolgus monkeys were studied in each of four sequential menstrual cycles. In Cycle 1, a serum sample was obtained each day and assayed for estradiol, progesterone and luteinizing hormone; first menses was also noted to establish parameters of a normal menstrual cycle for each animal. In Cycle 2, meloxicam was administered orally once each day for 5 days beginning at either mid follicular (n = 4), late follicular (n = 4) or periovulatory (n = 4) phase of the menstrual cycle; daily serum samples and menses were assessed as for Cycle 1. In Cycle 3, the follicle-bearing ovary was removed 2 days after the expected day of ovulation (n = 3-4/treatment group). In Cycle 4, monkeys received the 5-day courses of oral meloxicam as in Cycle 2 (n = 3-4/treatment group), and the remaining ovary was removed. Ovaries were examined for the presence of an oocyte within the follicle. Monkeys had the expected levels of changing reproductive hormones during Cycle 1. Meloxicam treatment in Cycle 2 did not alter hormone levels or the luteal phase length. Follicles of ovaries removed during Cycle 3 did not contain oocytes, indicating successful ovulation. Follicles did contain oocytes after meloxicam treatment beginning in the mid follicular (67%), late follicular (100%) or periovulatory (50%) phase of Cycle 4, indicating failure of ovulation. A 5-day course of oral meloxicam administered around the time of ovulation reduced the rate of oocyte release without alteration of reproductive hormones or menstrual cycle length. Meloxicam may be effective as an emergency contraceptive in women.

Single and Multiple-Dose Pharmacokinetics of Meloxicam After Oral Administration to the Rabbit (Oryctolagus cuniculus)

The nonsteroidal anti-inflammatory drug (NSAID) meloxicam is a very popular anti-inflammatory, analgesic, and antipyretic agent used in veterinary medicine. To determine the pharmacokinetics of this NSAID in rabbits following a single dose and 10-day period of dosing, eight clinically normal, 8-mo-old New Zealand white rabbits (Oryctolagus cuniculus) were administered 0.2 mg/kg meloxicam p.o. daily. Pharmacokinetic analysis of the meloxicam was determined via noncompartmental analysis. After oral administration, mean +/- standard deviation values for area under the curve were 1.8 +/- 0.50 and 2.1 +/- 0.55 microg x h/ml, and maximum plasma concentrations were 0.17 +/- 0.06 and 0.24 +/- 0.07 microg/ml for Day 1 and Day 10, respectively. The half-life was approximately 8 hr. Administration of meloxicam at a dosage of 0.2 to 0.3 mg/kg p.o. every 24 hr is suggested. Although a higher dose may be required for optimum effects, this would require efficacy and safety studies in this species. Meloxicam administered at 0.2 mg/kg p.o. daily for 10 day was well tolerated by the rabbits.

Analgesic effects of intramuscular administration of meloxicam in Hispaniolan parrots (Amazona ventralis) with experimentally induced arthritis

OBJECTIVE-To evaluate the analgesic efficacy of meloxicam in parrots with experimentally induced arthritis, with extent of weight bearing and rotational perch walking used as outcome measures. ANIMALS-15 adult Hispaniolan parrots (Amazona ventralis). PROCEDURES-Arthritis was experimentally induced via intra-articular injection of microcrystalline sodium urate suspension (MSU) into 1 intertarsal joint. Parrots were treated in a crossover design. Five treatments were compared as follows: meloxicam (4 dosages) at 0.05, 0.1, 0.5, and 1.0 mg/kg (IM, q 12 h, 3 times) and 0.03 mL of saline (0.9% NaCl) solution (IM, q 12 h, 3 times). The first treatment was given 6 hours following MSU administration. Lameness was assessed by use of a biomechanical perch to record weight-bearing load and a rotational perch to determine dexterity. Feces were collected to assay for occult blood. RESULTS-Parrots treated with meloxicam at 1.0 mg/kg had significantly better return to normal (baseline) weight bearing on the arthritic pelvic limb, compared with control parrots or parrots treated with meloxicam at 0.05, 0.1, and 0.5 mg/kg. All fecal samples collected from parrots following induction of arthritis and treatment with meloxicam had negative results for occult blood. CONCLUSIONS AND CLINICAL RELEVANCE-Meloxicam administered at 1.0 mg/kg, IM, every 12 hours effectively relieved arthritic pain in parrots.

Population pharmacokinetic modelling and simulation of single and multiple dose administration of meloxicam in cats

The objectives of these investigations were: first, to describe the pharmacokinetic properties of meloxicam in cats following single and multiple oral administration and secondly, to simulate different oral dosage regimes for meloxicam in cats after multiple dose administration to illustrate and evaluate those dosage regimes for the alleviation of inflammation and pain in cats. Six healthy domestic short hair cats were treated orally with various dosage regimes (0.05-0.2 mg/kg/day). Plasma samples were collected at predefined times and quantitatively analysed using liquid/liquid extraction followed by reverse phase HPLC with UV-detection. Meloxicam plasma concentration data were analysed using the population pharmacokinetic approach (software: NONMEM). The final model was used to simulate different dosage regimes. The plasma concentration-time profiles of meloxicam in cats after oral single and multiple dose administration were best described by an open one-compartment model with first-order absorption and first-order elimination. Pharmacokinetic parameters were estimated to be 0.00656 L/h/kg for the total apparent body clearance (CL/F), 0.245 L/kg for the apparent volume of distribution (V/F), 1.26 1/h for the absorption constant (K(A)) and 25.7 h for the mean plasma terminal half-life. Simulations showed that the median trough steady-state concentrations of 228 ng/mL were reached after five, one or 6 days following a single initial dose of 0.05, 0.1 and 0.2 mg/kg each followed by 0.05 mg/kg/day.

Meloxicam inhibits ovulation in non-human primates when administered during the follicular phase of the menstrual cycle to simulate emergency contraception

OBJECTIVE: To determine if a 5 day course of oral administration of the cyclooxygenase inhibitor meloxicam can prevent ovulation while maintaining normal menstrual cycles in nonhuman primates. DESIGN: Adult cynomolgus monkeys were studied in each of 4 menstrual cycles. In cycle 1, serum obtained each day was assayed for estradiol, progesterone, and luteinizing hormone (LH); first menses was also noted. In cycle 2, meloxicam was administered orally once each day for 5 days beginning at either mid follicular, late follicular, or periovulatory stage of the menstrual cycle; serum and menses were assessed as in cycle 1. In cycle 3, the ovary bearing the ovulatory follicle was removed 2 days after the expected day of ovulation. In cycle 4, monkeys received 5 days of oral meloxicam beginning at either mid follicular, late follicular, or periovulatory stage; the remaining ovary was removed 2 days after the expected day of ovulation. Ovarian sections were examined for the presence of an oocyte within the follicle. MATERIALS AND METHODS: Estradiol and progesterone were assessed by immunoassay; LH was assayed by RIA. Hormones levels were compared by ANOVA. Menstrual cycle length was compared by paired t-test. Ovaries were fixed, serial sectioned, and stained. RESULTS: All monkeys showed the expected pattern of changing estradiol, progesterone, and LH levels during cycle 1; meloxicam treatment in cycle 2 did not alter hormone levels or luteal phase length. Ovaries removed in cycle 3 did not contain oocytes within follicles, indicating successful ovulation. In contrast, large follicles did contain oocytes, indicating ovulation failure, after treatment with meloxicam during the mid follicular (67%), late follicular (100%), or periovulatory (50%) stage of cycle 4. CONCLUSIONS: A 5 day course of oral meloxicam can reduce the rate of oocyte release without alteration of reproductive hormones or menstrual cycle length. Meloxicam may be an effective emergency contraceptive.

Multicenter Phase II Trial of Combination Therapy with Meloxicam, a COX-2 Inhibitor, and Natural Interferon- for Metastatic Renal Cell Carcinoma

We conducted a Phase II trial to investigate the efficacy of combined therapy with meloxicam, a cyclooxygenase-2 inhibitor and natural interferon (IFN)-alpha in renal cell carcinoma patients with distant metastasis. The subjects of this study were patients with untreated renal cell carcinoma who were diagnosed from the results of imaging or pathological studies and who had measurable lesions according to the Response Evaluation Criteria in Solid Tumors (RECIST). Patients could be enrolled in the study irrespective of whether nephrectomy had been performed. Treatment involved the subcutaneous injection of natural IFN-alpha at 3 x 10(6) or 5 x 10(6) U three times weekly plus oral administration of meloxicam at 10 mg once daily. A total of 43 patients were enrolled in the present study, included 11 patients without nephrectomy, 23 patients with a high C-reactive protein (CRP) level and 23 patients with extrapulmonary metastasis. Four patients of complete response and 12 patients of partial response were confirmed, given an overall response rate of 37.2% (95% confidence interval, 23.0-53.3%). Stable disease for 6 months or longer was also obtained in 14 patients. The median time to progression was 14 months. Adverse events (AEs) observed were mainly flu-like symptoms due to cytokine. Although the Grade 3 or 4 AEs were fatigue, hepatic dysfunction, arthritis and gastric ulcer, all but one (gastric ulcer) were immediately improved by discontinuation of this combined therapy. The combination of meloxicam and natural IFN-alpha is considered to be an active regimen with tolerable toxicities as a first-line treatment of metastatic renal cell carcinoma.