Comparison of grapiprant and meloxicam for management of postoperative joint pain in dogs: A randomized, double-blinded, prospective clinical trial.

BACKGROUND: Grapiprant is a novel anti-inflammatory drug approved for the treatment of pain associated with osteoarthritis in dogs. OBJECTIVE: Compare the efficacy of grapiprant vs meloxicam for the management of postoperative joint pain in dogs. ANIMALS: Forty-eight dogs presented with cranial cruciate ligament disease and treated by tibial plateau leveling osteotomy (TPLO) between May 2020 and May 2022. METHODS: In this randomized, double blinded, prospective clinical trial, client-owned dogs with naturally occurring unilateral cruciate ligament rupture were enrolled on the day of surgery. The day after surgery, all animals received a subcutaneous injection of 0.2 mg/kg of meloxicam and were randomly assigned to receive either oral grapiprant (2 mg/kg) or meloxicam (0.1 mg/kg), once a day for 14 days, in a blinded manner. The primary endpoint of the study was the pain severity (PSS) and interference (PIS) scores, assessed by the Canine Brief Pain Inventory (CBPI) at day 3, 7, 10 and 15 after the surgery. RESULTS: Three days after surgery, grapiprant treated dogs had lower PSS compared to meloxicam treated dogs with a mean ± SD of 2.76 ± 0.18 vs 3.25 ± 0.23, respectively (difference of -0.49 [95% CI -0.94 to -0.04], P = .032). Pain Interference Score was also lower in grapiprant group at day 3 (4.11 ± 0.18 vs 4.69 ± 0.16 in meloxicam group [difference of -0.58 {95% CI -1.03 to -0.13}, P = .013]) and at day 10 (2.23 ± 0.13 vs 2.72 ± 0.28 [difference of -0.49 {95% CI -0.92 to -0.01}, P = .049]). CONCLUSIONS AND CLINICAL IMPORTANCE: Our study supports the use of grapiprant as an alternative analgesic to meloxicam for management of postoperative joint pain in dogs.

Effects of meloxicam on the welfare of Holstein calves from 6 weeks to 6 months old undergoing amputation dehorning.

Amputation dehorning (AD) is a common practice performed on calves, causing harmful effects such as pain, distress, anxiety, and fear. These effects extend to behavioral, physiological, and hematological responses, prompting serious ethical concerns regarding animal welfare, even when performed with local anesthesia. Meloxicam, a nonsteroidal anti-inflammatory drug, has been widely used to mitigate the side effects of dehorning and disbudding in calves. However, there is a notable gap in research regarding the effects of meloxicam on calves aged 6 wk to 6 mo undergoing AD procedures. This study was designed to assess the effectiveness of co-administering meloxicam with lidocaine, a cornual nerve anesthetic, in alleviating the adverse effects caused by the AD procedure in calves within this age range, compared with the use of lidocaine alone. Thirty Holstein calves were enrolled and randomly divided into 2 groups. The first group received a subcutaneous injection of 5 mL of lidocaine in the horn area and a subcutaneous injection of 0.9% saline at a dose of 0.025 mL/kg in the neck, administered 10 min before the AD procedure. The second group received a combination of lidocaine and meloxicam: a subcutaneous injection of 5 mL of lidocaine in the horn area and a subcutaneous injection of 20 mg/mL meloxicam at a dose of 0.025 mL/kg in the neck, also administered 10 min before the AD procedure. To avoid subjective bias, the researchers were blinded to the treatment groups. Pain-related behaviors, including tail flicking, head shaking, ear flicking, head rubbing, head crossing bar, and kicking, were observed, and physiological parameters, including heart rate, rectal temperature, respiration rate, mechanical nociceptive threshold (MNT), daily active steps, and food intake were monitored. Hematological conditions were determined using enzyme-linked immunosorbent assays and routine blood tests. The data were processed using a generalized linear mixed model. The outcomes demonstrated that the AD procedure increased the frequencies of ear flicking and resulted in rises in the respiration rate, heart rate, rectal temperature, and daily active steps. It also led to decreases in total food intake, forage intake, hay intake, MNT, and increased concentrations of prostaglandin E2 (PgE2), IL-1ß, tumor necrosis factor-α (TNF-α), nitric oxide (NO), and malondialdehyde, as well as glutathione peroxidase activity. However, calves that received meloxicam treatment showed significant improvements in response to the AD procedure, including lower respiration rates, heart rates, and rectal temperatures; higher MNT; and lower intermediate cell ratio. They also had higher red blood counts, hemoglobin levels, hematocrit values; larger mean platelet volumes; and lower concentrations of PgE2, IL-1ß, TNF-α, and NO. These results suggest that co-administration of lidocaine and meloxicam may aid in mitigating the adverse effects induced by the AD procedure on these calves, thereby supporting the use of meloxicam in conjunction with a local anesthetic in AD procedures for calves aged 6 wk to 6 mo.

Tumor Homing Chimeric Peptide Rhomboids to Improve Photodynamic Performance by Inhibiting Therapy-Upregulated Cyclooxygenase-2.

Negative therapeutic feedback of inflammation would extensively attenuate the antitumor effect of photodynamic therapy (PDT). In this work, tumor homing chimeric peptide rhomboids (designated as NP-Mel) are fabricated to improve photodynamic performance by inhibiting PDT-upregulated cyclooxygenase-2 (COX-2). The hydrophobic photosensitizer of protoporphyrin IX (PpIX) and palmitic acid are conjugated onto the neuropilin receptors (NRPs) targeting peptide motif (CGNKRTR) to obtain tumor homing chimeric peptide (Palmitic-K(PpIX)CGNKRTR), which can encapsulate the COX-2 inhibitor of meloxicam. The well dispersed NP-Mel not only improves the drug stability and reactive oxygen species (ROS) production ability, but also increase the breast cancer targeted drug delivery to intensify the PDT effect. In vitro and in vivo studies verify that NP-Mel will decrease the secretion of prostaglandin E2 (PGE2) after PDT treatment, inducing the downregulation of IL-6 and TNF-α expressions to suppress PDT induced inflammation. Ultimately, an improved PDT performance of NP-Mel is achieved without inducing obvious systemic toxicity, which might inspire the development of sophisticated nanomedicine in consideration of the feedback induced therapeutic resistance.

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

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

Comparison of Systemic Extended-release Buprenorphine and Local Extended-release Bupivacaine-Meloxicam as Analgesics for Laparotomy in Mice.

Extended-release (ER) local anesthetics can be used in multi-modal analgesia or in situations in which systemic analgesics may alter animal physiology and thus introduce interpretational confounds. In this study, we compared the analgesic efficacy of an ER buprenorphine formulation with that of a synergistic combination of ER bupivacaine and meloxicam. Female and male CD1 mice were randomly assigned to receive subcutaneous buprenorphine (3.25mg/kg) preemptively, subcutaneous infiltration of bupivacaine???meloxicam (0.03mL at incision closure (bupivacaine, 35mg/kg; meloxicam, 1mg/kg), or saline (10mL/kg SC) after induction of anesthesia. After laparotomy, mice were assessed for changes in daily body weight, rearing frequency, nest consolidation scores, time-to-integrate-nest test (TINT), and response to von Frey testing at 4, 8, 24, 48, and 72h after surgery. Daily weight, nest consolidation scores and rearing frequency were not significantly different among the 3 groups. TINT had fallen significantly response at 24 and 48h after injection in the ER buprenorphine group as compared with the saline and ER bupivacaine-meloxicam groups. Nociceptive thresholds, as assessed with von Frey testing, differed between saline controls and both analgesic groups at 4, 8, 24, 48, and 72 h after surgery. None of the mice in the bupivacaine???meloxicam group developed signs of neurotoxicity, a potential side effect of high-dose local anesthetics. This study demonstrates that local ER bupivacaine???meloxicam may be a useful alternative to systemic, ER buprenorphine for the relief of pain after laparotomy in mice.

Preemptive QP001, a fast-acting meloxicam formulation, provides analgesia and reduces opioid consumption following abdominal surgery: a randomized controlled trial.

BACKGROUND: QP001, a novel meloxicam formulation, has been developed to manage moderate to severe postoperative pain. This study aimed to evaluate the efficacy and safety of QP001 injections for moderate to severe pain following abdominal surgery. METHOD: This prospective, multicenter, randomized, double-blind, placebo-controlled clinical trial enlisted patients experiencing moderate to severe pain following abdominal surgery. These patients were randomized to receive either QP001 injections (30 mg or 60 mg) or a placebo pre-surgery. The primary efficacy endpoint was the total morphine consumption within 24 h after the first administration. RESULTS: A total of 108 patients were enrolled, and 106 patients completed the study. The total morphine consumption in the QP001 30 mg group and 60 mg group, versus placebo group, were significantly lower over the following 24 h (5.11[5.46] vs 8.86[7.67], P = 0.011; 3.11[3.08] vs 8.86[7.67], P < 0.001), respectively. The total morphine consumption in the QP001 30 mg and 60 mg groups, versus placebo group, was also significantly decreased over the following 48 h, including the 24-48 h period (P ≤ 0.001). The QP001 30 mg and 60 mg groups, versus placebo, showed a significant decrease in the area under the curve for pain intensity-time as well as a significant decrease in the effective pressing times of the analgesic pump over the 24 h and 48 h periods (P < 0.05). The QP001 groups, versus placebo, show no significant different in Adverse Events or Adverse Drug Reactions (P > 0.05). CONCLUSION: Preoperative/preemptive QP001 provides analgesia and reduces opioid consumption in patients with moderate to severe pain following abdominal surgery, while maintaining a favorable safety profile.

Randomised, prospective, blinded, clinical trial of opioid-free injectable anaesthesia with or without multimodal analgesia in kittens undergoing ovariohysterectomy.

OBJECTIVES: This study compared an opioid-free injectable anaesthetic protocol with or without multimodal analgesia in kittens undergoing ovariohysterectomy. METHODS: In this prospective, randomised, blinded, clinical trial, 29 healthy kittens (mean ± SD weight 1.55 ± 0.46 kg; aged 10 weeks to 6 months) were included. Anaesthesia was performed with an intramuscular injection of ketamine (4 mg/kg), dexmedetomidine (40 µg/kg) and midazolam (0.25 mg/kg). In the multimodal group (MMG), cats (n = 14) received meloxicam (0.1 mg/kg SC) and intraperitoneal bupivacaine 0.25% (2 mg/kg), whereas the same volume of saline was administered in the control group (CG; n = 15). Atipamezole (0.4 mg/kg IM) was given 15 mins after ovariohysterectomy. Postoperative pain was assessed using the UNESP-Botucatu multidimensional feline pain assessment scale - short form. Rescue analgesia (buprenorphine 0.02 mg/kg IM in MMG/CG and meloxicam 0.1 mg/kg SC in CG) was administered if pain scores were ⩾4/12. Soft food intake (after 2 and 60 mins) was evaluated at specific time points postoperatively. Statistical analyses were performed with linear models and post-hoc pairwise comparison with Benjamini-Hochberg corrections (P <0.05). RESULTS: The prevalence of rescue analgesia was higher in the CG (n = 15/15) than the MMG (n = 1/14; P <0.001). Pain scores at 1 h, 2 h and 4 h postoperatively were higher in the CG (4.1 ± 2.8, 4.8 ± 3.0 and 5.3 ± 1.2, respectively) than in the MMG (1.6 ± 1.0, 1.1 ± 1.0 and 0.9 ± 0.8, respectively; P <0.001). Food intake (%) at 1 h postoperatively was higher in the MMG after 2 and 60 mins (10.4 ± 9 and 71.9 ± 29, respectively) than in the CG (1.4 ± 2 and 13.9 ± 7, respectively; P <0.001). CONCLUSIONS AND RELEVANCE: This opioid-free protocol using multimodal analgesia produced adequate postoperative pain relief, while almost eliminating the need for rescue analgesia in kittens undergoing ovariohysterectomy. Pain decreased food intake.

High-dose Meloxicam Provides Improved Analgesia in Female CD1 Mice: A Pharmacokinetic and Efficacy Study.

Meloxicam is a nonsteroidal anti-inflammatory analgesic drug that is often used in mice. However, doses of 1 to 5 mg/kg given twice daily were recently reported to provide inadequate analgesia. Some studies suggest that doses of up to 20 mg/kg may be necessary for adequate pain management. We investigated the analgesia provided by a high-dose of meloxicam in female CD1 mice. Pharmacokinetic analyses demonstrated that a subcutaneous injection of 10 mg/kg or 20 mg/kg of meloxicam produced therapeutic plasma concentrations for at least 12 h. Ovariectomies via ventral laparotomy were performed to assess analgesic efficacy. Mice were treated immediately before surgery with a high-dose of 10 mg/kg, a low-dose of 2.5 mg/kg, or saline, followed by every 12 h for 36 h. At 3, 6, 12, 24, and 48 h after surgery, mice were assessed for pain based on the following behaviors: distance traveled, time mobile, grooming, rearing, hunched posture, orbital tightening, and von Frey. Initially, some mice received a 20-mg/kg loading dose followed by 10 mg/kg every 12 h. This regimen caused severe morbidity and mortality in 2 mice. Subsequently, this regimen was abandoned, and mice assigned to the high-dose group received 10 mg/kg every 12 h. Mice that received the 10-mg/kg dose after surgery showed less orbital tightening between 3 to 6 h and reduced frequency of hunched posture for 48 h compared with mice that received either the low-dose or saline. However, mice were significantly less mobile for 6 to 12 h after surgery regardless of treatment. These data indicate that a meloxicam dose of 10 mg/kg every 12 h provides better analgesia than a 2.5-mg/kg dose but does not completely alleviate pain.

Meloxicam inhibited oxidative stress and inflammatory response of LPS-stimulated bovine endometrial epithelial cells through Nrf2 and NF-κB pathways.

Meloxicam is a selective cyclooxygenase-2 inhibitor and has been widely used in combination with antibiotics to alleviate uterine inflammation and provide analgesia in postpartum cows. Studies have shown that meloxicam has antioxidant and anti-inflammatory effects. However, the link between meloxicam and uterine inflammation and oxidative stress in dairy cows has not been studied. The purpose of this study was to research the effects of meloxicam (0.5 or 5 µM) on oxidative stress and inflammatory response of primary bovine endometrial epithelial cells (BEEC) stimulated by Escherichia coli lipopolysaccharide (1 µg/mL LPS). As a result, LPS stimulated the production of oxidative stress markers and the expression of inflammatory factors, accompanied by a decrease in the activity and the gene transcription of antioxidant enzymes. Co-treatment of meloxicam and LPS reduced the content of oxidative stress markers and the mRNA levels of the pro-inflammatory genes, and improved antioxidant enzyme activities and the corresponding gene expression as compared with the cells treated with LPS alone. Meloxicam attenuated the inhibitory effect of the Nrf2 pathway and the phosphorylation levels of p65 and IκBα caused by LPS. In conclusion, meloxicam alone had no effect on BEEC, but prevented oxidative stress and inflammatory response in LPS-stimulated BEEC.

Frontal sinus carcinoma in forty-one dogs (2001-2022).

Reports on canine frontal sinus carcinomas (FSCs) are scarce. This retrospective review of 41 dogs with FSC (2001-2022) describes demographic and clinical characteristics of canine FSC and reports the clinical experience and overall survival following treatment with toceranib phosphate (TOC) and meloxicam in 10 cases. Median age at diagnosis was 10.6 years (range: 6.5-15.4 years). There was a male-to-female-ratio of 2.4:1. The most common breeds were Jack Russell Terriers (JRT) (n = 7; 17.1%) and Rottweilers (n = 3, 7.3%). Mesocephalic breeds (70.6%) were most commonly affected, brachycephalics accounted for 8.8%. The most frequent clinical signs included skull deformation dorsomedial to the eye (87.5%), pain/head-shyness (40.0%), ocular (22.5%)/nasal (17.5%) discharge, and exophthalmos (17.5%). Duration of symptoms prior to diagnosis varied from a few days to 9 months. There were no neurological signs at initial presentation despite imaging evidence of osteolysis of the lamina interna of the frontal bone in most dogs (69.4%). In 11.5%, pulmonary changes suggestive of metastasis or concurrent primary pulmonary neoplasia were present. Tumour types included squamous cell carcinoma (58.5%), unspecified carcinoma (29.3%), and adenocarcinoma (9.8%). Ten dogs were treated with TOC (median 2.8 mg/kg EOD or three times per week) and meloxicam (0.1 mg/kg, EOD) (TOC-M), resulting in subjective regression of skull deformity in 8/10 (80.0%) patients. Overall median survival time with TOC-M was 183.5 days (range: 120-434 days). FSCs typically present with skull deformation, but no overt neurological signs. Male dogs and JRT may be overrepresented. The use of TOC-M in FSC appears promising and warrants further prospective evaluation.

Influence of Constant Rate Infusions of Fentanyl Alone or in Combination With Lidocaine and Ketamine on the Response to Surgery and Postoperative Pain in Isoflurane Anesthetized Dogs Undergoing Unilateral Mastectomy: A Randomized Clinical Trial.

The aim of this study was to compare the effects of constant rate infusions (CRI) of fentanyl alone or combined with lidocaine and ketamine (FLK), on physiological parameters, isoflurane requirements and the number of postoperative analgesic rescues in dogs undergoing unilateral mastectomy. Twenty-two dogs were premedicated with acepromazine 0.02 mg/kg and morphine 0.5 mg/kg and anesthetized with propofol and isoflurane. Dogs were randomly assigned to 1 of 2 groups: Fentanyl group (fentanyl 5 µg/kg loading dose [LD] and 9 µg/kg/h CRI; n = 11); FLK group (fentanyl [same doses]; lidocaine 2 mg/kg LD and 3 mg/kg/h CRI; ketamine 1.0 mg/kg LD and 0.6 mg/kg/h CRI; = 11). Intraoperative evaluations were performed before the start of surgery and administration of the treatments (T0); three minutes after the LD (T1); during incision and tissue divulsion (T2); during closure of the surgical wound (T3). Meloxicam (0.1 mg/kg) was administered at T3. Blood samples were collected for determination of plasma concentrations of fentanyl, lidocaine and ketamine. Pain scores and the number of postoperative analgesic rescues with morphine (0.5 mg/kg) were evaluated for 24 hours postoperatively using the short form of the Glasgow Composite Measure Pain Scale. Compared to T0, significant decreases in heart rate (from 84 ± 28 to 53 ± 16 bpm in the Fentanyl group and from 93 ± 16 to 63 ± 15 bpm in FLK) and mean arterial pressure (from 61 ± 5 to 49 ± 10 mmHg in Fentanyl and from 59 ± 3 to 38 ± 6 mmHg in FLK) were observed at T1. Arterial hypotension was transient, with normalization of values at T2 and T3. The expired fraction of isoflurane did not differ significantly between the groups. Plasma concentrations of fentanyl, lidocaine and ketamine remained within the therapeutic range. Postoperatively, the number of dogs requiring analgesic rescue was significantly lower in the FLK (0/11, 0%) than in the Fentanyl group (5/11, 45%). In dogs administered morphine and meloxicam as part of the anesthesia protocol, an intraoperative CRI of FLK abolished the requirement for postoperative analgesic rescue for 24 hours in dogs undergoing mastectomy.

[Comparative analysis of the use of symptomatic slow acting drugs for osteoarthritis containing chondroitin sulfate or affecting its biosynthesis in patients with non-specific low back pain]. / Sravnitel'nyi analiz primeneniya simptomaticheskikh preparatov zamedlennogo deistviya, soderzhashchikh khondroitina sul'fat ili vliyayushchikh na ego biosintez, u patsientov s nespetsificheskoi bol'yu poyasnichno-kresttsovoi lokalizatsii.

OBJECTIVE: Retrospective comparative analysis of the use of SYSADOA preparations containing chondroitin sulfate (Chondroguard, 2 ml, 25 amp., glycosaminoglycan-peptide complex, 1 ml 25 amp., bioactive concentrate of small marine fish, 2 ml, 10 amp.) in patients with chronic non-specific low back pain (LBP) of lumbar and sacral localization caused by spondylosis and osteochondrosis of the lumbar spine, at the stage of outpatient care. MATERIAL AND METHODS: Data of medical records of patients (n=120; men - 32, women - 88, age - 54.1±7.6 years, duration of disease exacerbation 4.0±1.7 months) with nonspecific LBP were systematized according to the inclusion/exclusion criteria. All patients were divided into 4 groups: Group 1 (n=30) received Chondroguard im., 2 ml every other day, the course of treatment was 25 injections, 25 days; Group 2 (n=30) received glycosaminoglycan-peptide complex on the 1st day - 0.3 ml, on the 2nd day - 0.5 ml, and then 3 times a week for 1 ml, course of treatment - 25 injections, 25 days; Group 3 (n=30) received bioactive concentrate of small marine fish, 2 ml im., every other day, the course of treatment was 10 injections; repeated courses of treatment - after 6 months; Group 4 (n=30) received Amelotex (meloxicam) at a dose of 15 mg once a day for 15 days. All patients of the first 3 groups received Amelotex at a dose of 15 mg with the possibility of reducing the dose to 7.5 mg or completely discontinuing the drug if necessary. Retrospectively, dynamic monitoring was performed in the medical records of outpatients after 50 days and 6 months from the start of therapy according to the following parameters: intensity of pain according to VAS, short form of the McGill pain questionnaire, vital signs of patients (Oswestry Disability Index, version 2.1a [Oswestry Disability Index], and Roland-Morris questionnaire), propensity to chronic pain syndrome according to the STarT Back Screening Tool questionnaire, the presence and severity of comorbid fibromyalgia according to the Fibromyalgia Rapid Screening Tool questionnaire, the level of pain catastrophization according to the Pain Catastrophizing Scale, the severity of comorbid anxiety and depression according to the Hospital Anxiety and Depression Scale, the severity comorbid insomnia (Insomnia Severity Index), quality of life according to the SF-36 scale, the effectiveness of drugs according to the patient on a 5-point scale, the need to take NSAIDs and analgesics, tolerability on a 4-point system. The safety of therapy was monitored using the WHO and Naranjo scales. RESULTS: In patients with nonspecific LBP, a greater degree of reduction in the intensity of the pain syndrome, a smaller number of exacerbations of the pain syndrome over 6 months of observation, an improvement in the functional status and life activity, a tendency to a decrease in the severity of anxiety and depression, sleep disturbances and comorbid fibromyalgia, limiting the risk of chronicity and catastrophization of pain, the presence of a structure-modifying effect on IVD and degenerative changes in the facet joints, a significant improvement in the physical and mental components of health, high satisfaction and safety of therapy, which included taking Chondroguard with meloxicam, with a decrease in the need to take the latter by the 50th day observation period compared to other regimens. The effects of Chondroguard and meloxicam turned out to be long-term and were recorded by the 6th month in the absence of Chondroguard, which indicated the preservation of the influence of highly purified cholesterol on the pathogenetic mechanisms of the formation of LBP. CONCLUSION: The study allows us to recommend the use of a parenteral form of cholesterol (Chondroguard, CJSC «PharmFirma «Sotex¼, Russia) for the treatment of nonspecific LBP with moderate or severe pain, chronic relapsing or persistent course, in combination with NSAIDs and their subsequent cancellation or administration on demand.

Organoids of patient-derived medullary thyroid carcinoma: The first milestone towards a new in vitro model in dogs.

Organoid cultures could constitute a valuable in vitro model to explore new treatments for canine (c) medullary thyroid carcinoma (MTC). The study's objectives were to establish and characterize 3D organoid cultures of cMTC using histology and immunohistochemistry (IHC) and to evaluate the effect of antitumor drugs on organoids' viability. Five cMTC tissue samples were used to develop organoid cultures of which one organoid line, named cMTC N°2, could be passaged for an extended period. This cMTC N°2 organoid line was further compared to the primary tumour regarding morphology and IHC expression of thyroid transcription factor-1 (TTF-1), thyroglobulin, calcitonin, synaptophysin, vimentin, Ki-67, cyclooxygenase-2 (COX-2), P-glycoprotein and vascular endothelial growth factor (VEGF). Quality control of the cMTC N°2 organoid line was achieved by a single nucleotide polymorphism (SNP) array of the organoids, primary tumour and healthy blood cells of the same dog. The effect of carboplatin, meloxicam and toceranib phosphate (TOC) on cMTC N°2 organoids' viability was evaluated. The cMTC N°2 organoid line was cultured for 94 days and showed similar histological features with the primary tumour. Immunolabelling for TTF-1, thyroglobulin, calcitonin and VEGF was similar between the primary tumour and cMTC N°2 organoids. Compared to the primary tumour, organoids showed higher immunolabelling for vimentin and Ki-67, and lower immunolabelling for synaptophysin, COX-2 and P-glycoprotein. The SNP genotype was similar for each chromosome between healthy blood cells, primary tumour and cMTC N°2 organoids. Carboplatin, meloxicam and TOC had no effect on cMTC N°2 organoid cell viability within achievable in vivo concentration range. In conclusion, the cMTC N°2 organoid line is a promising first milestone towards an established in vitro organoid model to explore pathophysiology and new treatment modalities in cMTC.

HTX-011 in Combination with Multimodal Analgesic Regimen Minimized Severe Pain and Opioid Use after Total Knee Arthroplasty in an Open-Label Study.

Total knee arthroplasty (TKA) can be associated with significant postoperative pain despite multimodal analgesic (MMA) protocols, and most patients require the use of opioids postoperatively. HTX-011 is a dual-acting local anesthetic containing bupivacaine and low-dose meloxicam in an extended-release polymer. In a prior randomized controlled trial (RCT), HTX-011 reduced pain and opioid use through 72 hours after TKA compared with bupivacaine hydrochloride. This open-label study (NCT03974932) evaluated the efficacy and safety of HTX-011 combined with an MMA regimen in patients undergoing TKA under spinal anesthesia. All patients received intraoperative HTX-011 (400 mg bupivacaine/12 mg meloxicam) in combination with an MMA regimen consisting of preoperative acetaminophen, celecoxib, and pregabalin and postoperative acetaminophen and celecoxib until discharge. Opioid rescue was allowed upon patient request for additional pain control. Pain scores, opioid consumption, discharge readiness, and adverse events were recorded. Fifty-one patients were treated. Compared with the prior RCT, HTX-011 with this MMA regimen further lowered pain scores and reduced opioid use. Mean patient-reported pain scores remained in the mild range, and 82% of patients or more did not experience severe pain at any individual time point through 72 hours after surgery. Mean total opioid consumption was low over 72 hours: 24.8 morphine milligram equivalents (1-2 tablets of oxycodone 10 mg/day). Approximately 60% of patients were ready for discharge by 12 hours, and 39% were discharged without an opioid prescription and did not call back for pain management. The treatment regimen was well tolerated, and no added risk was observed with the addition of MMA. HTX-011 with an MMA regimen reduced postoperative pain and opioid use following TKA.

Bupivacaine/meloxicam ER: A New Dual-acting Extended-Release Local Anesthetic for Opioid-Sparing Postoperative Pain Management.

OBJECTIVE: To review data for bupivacaine/meloxicam extended-release (ER) solution for management of postoperative pain and opioid-sparing effects. DATA SOURCES: Literature search of PubMed (1946 to August 2021) and ProQuest (1946 to August 2021) was performed using the terms: Zynrelef, HTX-011, and "bupivacaine AND meloxicam." Additional information sources include ClinicalTrials.gov, prescribing information, Heron Therapeutics' Clinical and Economic Evidence Dossier, meeting abstracts, and references of identified articles. STUDY SELECTION AND DATA EXTRACTION: Clinical trials and articles evaluating bupivacaine/meloxicam ER for postoperative pain management. DATA SYNTHESIS: Bupivacaine is a short-acting local anesthetic. Its efficacy is negatively impacted by the acidic environment of surgical sites. Meloxicam, a nonsteroidal antiinflammatory, reduces inflammation at the surgical site and increases pH propagating bupivacaine movement into the neurons. In Phase 2 and Phase 3 clinical trials, bupivacaine/meloxicam ER was compared with bupivacaine HCl, bupivacaine ER, and meloxicam ER with and without scheduled nonopioid multimodal analgesia (MMA) in bunionectomies, herniorrhaphies, total knee arthroplasty and abdominoplasty. Postoperative pain was well controlled for 72 hours and consistently superior to placebo, with minimal or no opioid use. Wound healing was not impacted and adverse effects were similar to placebo (most commonly nausea, dizziness, constipation, and headaches). RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Bupivacaine/meloxicam ER is a viable, safe, nonopioid local anesthetic for sustained 72-hour postoperative pain management mitigating opioid consumption. CONCLUSION: Bupivacaine/meloxicam ER is the only dual-acting, extended-release local anesthetic available. It provides effective analgesia in the postoperative setting and successfully reduces or eliminates postoperative opioid consumption.

Early perioperative versus postoperative meloxicam for pain control in patients undergoing orthopedic surgery: a systematic review and Meta-analysis of randomized controlled trials.

OBJECTIVE: Post-orthopaedic operative pain is a serious concern that often requires the administration of analgesics; however, the optimal time of analgesic administration is still inconclusive. Perioperative analgesia is administrating pre-emptive analgesia before and during the surgery followed by postoperative analgesia to decrease the procedure associated nociceptive response. We aim to assess perioperative meloxicam versus postoperative meloxicam for pain control after orthopaedic operations. METHODS: A systematic review and meta-analysis involving randomized controlled trials from PubMed, Embase, Scopus, WOS, and Cochrane until 28th May 2022. We pooled dichotomous outcomes using risk ratio (RR) presented with a 95% confidence interval (CI) and continuous outcomes using mean difference (MD) with 95% CI. We registered our protocol in PROSPERO with ID: CRD42022336046. RESULTS: We included five RCTs with 964 patients. All the included trials showed high risk of performance and detection biases because of lack of blinding. Pooled analysis favored perioperative meloxicam in reducing pain score after six hours (MD: -0.42 with 95% CI [-0.63, -0.21], p = .0001), 12 h (MD: -0.54 with 95% CI [-0.69, -0.39], p = .00001), and 24 h (MD: -0.23 with 95% CI [-0.36, -0.10]. Pooled analysis favored perioperative meloxicam in improving patient global assessment scale after 12 h (MD: -0.66 with 95% CI [-0.86, -0.46], p = .00001), 24 h (MD: -0.30 with 95% CI [-0.49, -0.11, p = .002), and 48 h (MD: -0.17 with 95% CI [-0.33, -0.01], p = .04). Pooled analysis favored perioperative meloxicam in reducing patient-controlled analgesia (MD: -4.25 with 95% CI [-5.96, -2.54], p = .00001). CONCLUSION: Short-term pain management after orthopaedic procedures is better accomplished with perioperative meloxicam than postoperative meloxicam. Before recommending perioperative meloxicam for pain control following orthopaedic surgeries, further multicentre trials are still warranted to examine the impact of perioperative meloxicam in different orthopaedic procedures.

A novel long-acting local anesthetic - HTX-011 (ZYNRELEF™) for postoperative pain control.

INTRODUCTION: Pain following most surgical procedures is expected. However, the treatment and management of postoperative surgical pain have remained challenging. The use of opioid therapy has become increasingly controversial given the limited therapeutic window of these drugs, the adverse side effects, and the potential for abuse. A multimodal approach to the treatment of postoperative pain has been shown to improve pain outcomes after surgery and improve patient satisfaction. Here, we examine a new formulation of bupivacaine and meloxicam extended-release solution HTX-011 (ZYNRELEF®) and its efficacy in postoperative pain control. AREAS COVERED: HTX-011 exists as an extended-release polymer that controls the release of the active ingredients over 72 hours. A systematic approach was taken to review PubMed (Medline) for prospective and retrospective studies related to the use of HTX-011 for the management of postoperative pain. EXPERT OPINION: HTX-011 represents a new tool to help modulate postoperative pain. Although multimodal analgesia has been effective in managing postoperative pain, direct surgical infiltration with local anesthetics has had limited efficacy due to their short duration of action. The HTX-011 formulation provides a long-acting local anesthetic at the surgical site, which provides a longer period of analgesia while maintaining a favorable safety profile.

Inhibiting AKT signaling pathway with cilostazol and meloxicam synergism for suppressing K562 cells in vitro.

Despite advances in cancer treatment, chronic myeloid leukemia (CML) is still one of the leading causes of death in the world. Due to the role of inflammation in cancer promotion and progression, thus use of anti-inflammatory agents may suppress cancer cell growth. In this study, we used two anti-inflammatory drugs, cilostazol and meloxicam, for the treatment of CML. Cell viability was measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and the synergism occurrence was calculated by compusyn software. Annexin V/PI test and Hoechst staining were used to determine the apoptosis rate. To determine the pathway of apoptosis induction, the expression of BCL2 Associated X (Bax) and B-cell lymphoma-2 (Bcl-2) apoptotic genes and caspases activity were evaluated. The cell cycle was analyzed by propidium iodide (PI) staining and flow cytometry. Western blot analysis and immunofluorescence were performed to estimate alterations in Ak strain transforming-1 (AKT-1), phosphprylated AKT-1 (p-AKT-1), adenosine mono-phosphate-kinase (AMPK), and phosphorylated AMPK (p-AMPK) proteins and BCR/ABL and c-Myc distribution, respectively. Results showed that cilostazol, meloxicam, and their combination drug reduced cell viability (p < 0.05). Compared with control, expression of Bax and Bcl-2 decreased in treated cells, respectively (p < 0.05). The caspase-9 activity increased in treated cells compared to control cells (p < 0.001). The applied drugs decreased the protein level of p-AKT-1 while increasing the p-AMPK protein level (p < 0.05). BCR/ABL and c-Myc Protein distribution significantly decreased in treated cells. In conclusion, the combination drug had more cytotoxic effects than cilostazol and meloxicam alone and induced apoptosis by inhibiting AKT-1 activation and c-Myc reduction. Therefore using combination drugs effectively can treat cancers of CML origin.

Three weeks of indomethacin is not superior to 1 week of meloxicam as prophylaxis for heterotopic ossifications after distal biceps tendon repair with a single-incision technique.

BACKGROUND: The aim of this study was to assess the efficacy of 3 weeks of indomethacin, a nonselective nonsteroidal anti-inflammatory drug, in comparison to 1 week of meloxicam as prophylaxis for heterotopic ossifications (HOs) after distal biceps tendon repair. METHODS: A single-center retrospective study was performed on 78 patients undergoing distal biceps tendon repair between 2008 and 2019. From 2008 to 2016, patients received meloxicam 15 mg daily for the period of 1 week as usual care. From 2016 onward, the standard protocol was changed to indomethacin 25 mg 3 times daily for 3 weeks. All patients underwent a single-incision repair with a cortical button technique. The postoperative rehabilitation protocol was similar for all patients. The postoperative radiographs at 8-week follow-up were assessed blindly by 7 independent assessors. If HOs were present, it was classified according to the Ilahi-Gabel classification for size and according to the Gärtner-Heyer classification for density. Statistical analysis was performed to analyze the difference in HO between the patients who were treated with indomethacin and with meloxicam. RESULTS: Seventy-eight patients, with a mean age of 48.8 years (range 30-72) were included. The mean follow-up after surgery was 12 months (range 2-45). Indomethacin (21 days, 25 mg 3 times per day) was prescribed to 26 (33%) patients. The 52 other patients (67%) were prescribed meloxicam 15 mg daily for 7 days. HOs were seen in 19 patients 8 weeks postoperatively. Five of 26 patients treated with indomethacin developed HO, and 14 of 52 patients treated with meloxicam developed HO (P = .5). Two patients had symptomatic HO with minor restrictions in movement; neither patient was treated with indomethacin. Significantly more HOs were seen in patients with a longer time from injury to surgery (P = .01) The intraclass correlation score for reliability between assessors for HO scoring on postoperative radiographs was good to excellent for both classifications. CONCLUSION: In this study, HOs were seen in 24% of postoperative radiographs. Three weeks of indomethacin was not superior to meloxicam for 1 week for the prevention of HO after single-incision distal biceps tendon repair.

Postoperative Acupuncture is as Effective as Preoperative Acupuncture or Meloxicam in Dogs Undergoing Ovariohysterectomy: a Blind Randomized Study.

Background: Acupuncture has the same analgesic effect as non-steroidal antiinflammatory drugs and opioids. It is challenging to perform preoperative acupuncture in unmanageable animals, while the residual postoperative anesthetic effect facilitates the performance of acupuncture postoperatively. Objectives: To compare preoperative acupuncture or meloxicam versus postoperative acupuncture for postoperative analgesia after ovariohysterectomy. Methods: This is a horizontal prospective positive control blind randomized experimental study. Thirty-six dogs were randomly divided into three groups: GA (preemptive acupuncture), GPA (postoperative acupuncture), and GM (meloxicam 0.2 mg/kg IV preoperatively). After sedation with acepromazine (0.05 mg/kg IM), anesthesia was induced with propofol (5.3 ± 0.3 mg/kg) and maintained with isoflurane/O2. Fentanyl (2 µg/kg, IV) was administered immediately before surgery. Bilateral acupuncture was performed at acupoints Large intestine 4, Spleen 6, and Stomach 36 for 20 minutes, before (GA) or immediately after surgery (GPA). Pain was evaluated by an observer blind to the treatment using the Glasgow scale before and for 24 hours after ovariohysterectomy. Dogs with a score ≥ 6 received rescue analgesia with morphine (0.5 mg/kg IM). Nonparametric data were analyzed by the Kruskal-Wallis test, followed by Dunn's test and parametric data by ANOVA followed by Tukey's test. Results: Two GA and one GPA dogs received rescue analgesia once. Two GM dogs received rescue analgesia and one of those was treated again twice. There were no differences in the number of dogs receiving rescue analgesia between groups (p = 0.80). Conclusion: Postoperative acupuncture was as effective as preoperative acupuncture or meloxicam in female dogs undergoing ovariohysterectomy.