Search Results (209)

This monograph evaluates the scientific and regulatory underpinnings for bioequivalence (BE) waiver of immediate-release (IR) solid oral meloxicam formulations, as a surrogate for in vivo pharmacokinetic trials. In compliance with ICH (The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use), FDA (Food and Drug Administration), and PMDA (Pharmaceuticals and Medical Devices Agency) bioequivalence guidelines, a systematic characterization was performed on meloxicam’s critical attributes, encompassing solubility, permeability, dissolution behavior, pharmacokinetic profiles, therapeutic index, and drug-excipient compatibility. Classified as BCS Class II (low solubility, high permeability), meloxicam nonetheless exhibits a broad therapeutic window and pharmacokinetic characteristics aligning with BE Category I, thus enabling generic product approval via BE waiver with negligible risks of systemic exposure inequivalence. It is noteworthy that current in vitro methodologies are not consistently capable of capturing C_max disparities of BCS Class II weak acids. BE waiver eligibility for meloxicam IR formulations necessitates three prerequisites: (a) excipient composition identical to the reference listed drug and validated by regulatory authorities; (b) ≥85% dissolution within 30 min at pH 1.2, 4.5, and 6.8; (c) comparable dissolution profiles across these pH conditions. Non-adherence mandates a mandatory in vivo BE assessment. Full article

Magnetic nanoparticles represent the next-generation drug delivery systems, enabling drug targeting to specific organs without adverse effects on the body and with a controlled release rate. Their strengths are represented by biocompatibility, low cost, and easy drug loading; some drawbacks are aggregation and poor stability in biological media. In the present work, we synthesized magnetic core–shell structures with a magnetite core coated with layered double hydroxides (LDHs) based on Mg²⁺ or Zn²⁺ and Al³⁺ ions and loaded with meloxicam, a poorly water-soluble anti-inflammatory drug. Several syntheses have been attempted to obtain iron oxides based on the only magnetite phase. The combined use of different characterization techniques allowed us to reveal that the best product, showing the crucial room temperature superparamagnetism and a good level of compositional uniformity, was obtained from co-precipitation in nitrogen flow. The next LDH coating was successful, even if the hybrids showed the occurrence of aggregation. The drug was mainly adsorbed onto the LDH surfaces, as shown by the X-ray diffraction and Infrared Spectroscopy techniques. The loaded meloxicam amount was low, but the subsequent release into simulated body fluid could be prolonged for 4 days. Our study provides a proof of concept about the importance of a thorough characterization of the nanocomposite hybrids and their possible use for tricky drugs, such as those of class II of the Biopharmaceutical Classification System. Full article

Chronic osteoarthritis (COA) is a progressive and degenerative condition that causes joint inflammation and pain, often requiring long-term pharmacological management. Conventional treatments may lead to adverse effects, tolerance, and limited analgesic efficacy. This randomized, double-blind clinical trial evaluated the analgesic potential of a full-spectrum Cannabis sativa oil extract administered orally twice daily over six weeks in dogs with COA. Subjects were assigned to three groups: Cannabis, Placebo, and Control. Pain was assessed using the Canine Brief Pain Inventory (CBPI) and the Canine Osteoarthritis Staging Tool (COAST), which ranges from 0 to 4. The Cannabis extract (46.4 mg/mL) total cannabinoids: Cannabidiol (CBD), Cannabidiolic acid (CBDA), Delta-9-Tetrahydrocannabinol (Δ⁹-THC), and Tetrahydrocannabinolic acid (THCA), were administered using a cautious dose escalation protocol. Treatment began at ~0.1 mg/kg every 12 h, increasing by one drop (1.16 mg) every 72 h. This gradual titration continued until reaching the maximum tolerated dose (2 mg/kg every 12 h), which was maintained for the final two weeks. The protocol was designed to minimize adverse effects and allow close monitoring, especially in geriatric or clinically fragile dogs. By day 28, when the DMT was reached, the Cannabis group showed a 39.6% reduction in CBPI scores, compared to 24.7% in the Placebo group and a 1.6% increase in the Control group. COAST scores improved from level 4 to level 3 in 55.5% of dogs in the Cannabis group, with no changes observed in the other groups. We hypothesize that the co-administration of carprofen, meloxicam, or pregabalin with a full-spectrum Cannabis sativa extract—rich in acidic cannabinoids and terpenes—enhances pain relief and mobility in dogs with COA more effectively than conventional therapies alone. This study aimed to assess the efficacy of an oily full-spectrum Cannabis sativa extract as an adjunctive treatment to NSAIDs in twenty-seven dogs diagnosed with COA, and to compare pain intensity across three treatments groups. Full article

The continuous discharge of pharmaceutical residues into aquatic environments has raised significant environmental concerns due to their persistence and incomplete removal during wastewater treatment. Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most frequently detected pharmaceutical contaminants in industrial effluents. In this study, a sensitive and selective analytical method was developed for the simultaneous determination of ketoprofen (KTP), meloxicam (MEL), and celecoxib (CEL) in pharmaceutical wastewater using micellar electrokinetic chromatography (MEKC) combined with off-line solid-phase extraction (SPE). A high-volume SPE procedure (1000 mL sample) followed by evaporation and reconstitution provided a theoretical enrichment factor of approximately 10,000. Under optimised conditions, complete separation was achieved in less than 10 min. The method exhibited excellent linearity over a range of 0.5–20 µg/mL (r² > 0.999), with limits of detection in wastewater ranging from 14 to 18 ng/L. Accuracy and precision complied with ICH Q2(B) guidelines, and recoveries from spiked wastewater samples ranged from approximately 99% to 101%, indicating efficient extraction and minimal analyte loss. The validated method was successfully applied to real pharmaceutical wastewater samples, demonstrating its suitability for the routine monitoring of trace-level NSAIDs in complex industrial matrices. Full article

Effective pain control after orthopedic surgery is essential in veterinary practice, particularly in small-breed dogs with low physiological reserves. This study aimed to compare the analgesic efficacy and tolerability of five postoperative pain protocols across nine surgical procedures. A retrospective analysis was conducted in 205 small-breed dogs (≤7 kg) undergoing orthopedic surgeries. Dogs were assigned to one of five analgesic protocols: (A) carprofen, (B) tramadol–lidocaine–ketamine continuous-rate infusion, (C) butorphanol continuous-rate infusion, (D) hydromorphone continuous-rate infusion, and (E) multimodal analgesia combining local anesthetics, hydromorphone, and meloxicam. Pain was assessed at 6, 12, 24, 48, and 72 h using the Glasgow Composite Measure Pain Scale—Short Form. Analgesic efficacy was evaluated using pain trajectories, area-under-the-curve analysis, and pain resolution rates, and adverse effects were recorded. Dogs receiving multimodal analgesia achieved the most rapid and sustained pain relief, with all patients reaching pain resolution by 48 h. Hydromorphone alone showed comparable efficacy but was associated with more adverse effects, while tramadol–lidocaine–ketamine showed delayed pain relief and the highest rate of severe side effects. Multimodal analgesia provides superior pain control with acceptable safety in small-breed dogs undergoing orthopedic surgery, supporting its use based on surgical invasiveness and individual patient response. Full article

Feline pulmonary carcinomas are rare and often carry a poor prognosis, particularly when associated with feline lung–digit syndrome. We report a cat with primary pulmonary carcinoma and extensive metastases—including digits, pleura, mandible, scapula, spleen, skeletal muscle, and distant lymph nodes—supporting the broader “MODAL syndrome” concept. Palliative therapy with toceranib phosphate and meloxicam achieved prolonged survival and excellent quality of life, with no adverse effects despite dose escalation. Rapid progression after discontinuation suggests a role for toceranib in delaying tumour growth. Immunohistochemistry revealed c-kit expression in one metastatic lesion but not in the primary tumour or most metastases, highlighting intratumoral heterogeneity and the complexity of targeted therapy. The observed benefit likely reflects toceranib’s multi-target activity (VEGFR2, PDGFR), impacting angiogenesis and tumour progression. This case represents the first report of toceranib phosphate use in feline pulmonary carcinoma and underscores its potential as a palliative option. Full article

Background/Objectives: Meloxicam (MLX) is a nonsteroidal anti-inflammatory drug (NSAID) recommended for treating acute and chronic pain in dogs, frequently administered prophylactically to mitigate postoperative pain; however, its utility is limited by characteristic NSAID-associated adverse effects, such as gastrointestinal side effects. Nanosystems offer the potential to minimize adverse effects by sustaining drug release. Therefore, this study assessed the pharmacokinetics of MLX nanoencapsulation in female dogs undergoing ovariohysterectomy using a population pharmacokinetic (PopPK) modeling approach. Methods: MLX-loaded polymeric nanocapsules (NC-MLX) were prepared using the nanoprecipitation method and characterized by zeta potential, pH, mean diameter, particle size distribution, and drug content. Dogs received 0.2 mg/kg of either NC-MLX or free MLX orally, 4 h before surgery, and plasma samples were analyzed using an HPLC-PDA method. Pharmacokinetics were characterized by non-compartmental analysis and PopPK modeling. Several compartmental structures, variability models, and residual error models were explored, and relevant covariates were investigated. Results: NC-MLX had an average diameter of 326 ± 13 nm, a zeta potential of −26.2 ± 6.4 mV, and drug loading of 99.47% ± 0.01%. NC-MLX showed a significant increase in the t_1/2 (36.99 ± 17.26 h) of MLX compared to the free drug (15.22 ± 4.4 h). The best-fitting PopPK model was a two-compartment model with double extravascular first-order absorption rate constants (Ka₁ and Ka₂), including a lag time for Ka₂ and linear elimination, describing the second peak observed in several animals. The nanoformulation was a significant covariate for Tlag₂, delaying the time for absorption (1.22 and 2.55 h for free MLX and NC-MLX, respectively) and increasing V₂ (0.134 and 0.402 L/kg for free MLX and NC-MLX, respectively). External model validation showed that the final PopPK model accurately predicted plasma concentrations, with MPE% and RMSE values below 15%. Conclusions: Our findings suggest that NC-MLX alters MLX absorption and distribution profiles, supporting its potential as an alternative for postoperative pain management in dogs. Full article

Pain associated with routine husbandry procedures in sheep can persist for several days or even weeks, yet current analgesic options, such as the non-steroidal anti-inflammatory drug (NSAID) meloxicam, typically provide only 24–36 h of analgesia. This mismatch between pain duration and analgesic coverage represents a fundamental limitation of current pain-management strategies in sheep. Sustained-release (SR) formulations are emerging as a promising approach to deliver longer-lasting pain relief from a single dose, reducing the need for repeated handling, and improving both animal welfare and farm efficiency. Emerging evidence highlights both the promise and limitations of different strategies to extend therapeutic coverage beyond 72 h. While preliminary results are encouraging, challenges remain in achieving consistent pharmacokinetic profiles and optimal peak concentrations. Advancing SR meloxicam formulations could support widespread uptake of welfare-focused innovations in the sheep industry. Although not yet widely available, sustained-release meloxicam represent a promising step towards making routine husbandry procedures more humane and efficient. Full article

Background: Local analgesia administered through a wound catheter is widely used for postoperative pain control, yet its effects on wound healing remain incompletely understood. This study examined how levobupivacaine alone or combined with meloxicam or buprenorphine influences inflammatory markers, angiogenesis, apoptosis, and transforming growth factor β1 (TGF-β1) expression during wound healing in rats. Methods: Thirty Sprague Dawley rats were assigned to five groups: control, saline, levobupivacaine (L), levobupivacaine/meloxicam (L/MEL), and levobupivacaine/buprenorphine (L/BUP). Treatments were administered via a wound catheter for three days. Blood and skin samples were collected before surgery and on days 3, 10, and 21. Results: Levobupivacaine combined with meloxicam or buprenorphine caused fluctuations in white blood cell counts, while albumin levels remained stable. Angiogenesis in the L/MEL group was markedly increased compared with the control, saline, and levobupivacaine-only groups, but the newly formed vessels exhibited consistently narrow lumina during the early healing phase. Caspase-3–positive cells were most numerous in L/MEL during inflammatory and proliferative phases, whereas delayed caspase-3 activation was observed in L/BUP. TGF-β1 expression peaked in both adjuvant groups on days 3 and 10. Conclusions: Meloxicam and buprenorphine increased TGF-β1 expression, but their vascular effects differed considerably. Meloxicam induced a marked increase in angiogenesis, but the newly formed vessels were structurally immature, displaying uniformly narrow lumina and poor architectural organisation, which led to their subsequent regression. In contrast, buprenorphine supported the formation of more mature vascular structures, characterised by wider vessel lumina and a more organised vascular network. These findings demonstrate that adjuvants used with levobupivacaine can significantly modify angiogenic and apoptotic responses and should be carefully considered when selecting multimodal local analgesia strategies after surgery. Full article

Background: The minimized pan-coronavirus (CoV) vaccine-1 developed by our laboratory contained pDNA sequences of feline coronavirus serotype-1 (FCoV1) and SARS-CoV2 (SCoV2) spike B-cell epitopes plus FCoV/SCoV2-conserved, CoV-specific polymerase cytotoxic T-lymphocyte (CTL) epitopes formulated in lipid nanoparticle (LNP). Only FCoV2 infects feline cell lines needed for developing native challenge inoculum that causes feline infectious peritonitis (FIP). Hence, Pilot Study 1 evaluated the therapeutic efficacy and safety of the pan-CoV vaccine-1 in feline immunodeficiency virus (FIV)-infected cats, with or without FCoV1 coinfection. Pilot Study 2 evaluated the cross-protective effect of pan-CoV vaccines in specific-pathogen-free (SPF) cats against intranasal challenge with FIP virus serotype 2 (FIPV2). Methods: In Study 1, we vaccinated two FIV-infected cats (one negative and another positive for FCoV1 coinfection) intramuscularly twice with CTL epitopes-LNP vaccine and later twice with pan-CoV vaccine-1. Controls included two unvaccinated FIV-infected cats with or without FCoV1 coinfection. Study 2 assessed the sequential vaccinations of three pan-CoV vaccines in four SPF cats. The first two vaccinations were with pan-CoV vaccine-2, followed by pan-CoV vaccine-3 (twice), and lastly with pan-CoV vaccine-1 (once). Three SPF controls included two cats immunized with LNP and one lacking any immunization. Pan-CoV vaccine-2 contained pDNAs with modified FCoV1/SCoV2 B-cell epitopes plus CTL epitopes in LNP. Pan-CoV vaccine-3 contained only pDNAs with FCoV1 B-cell epitopes plus CTL epitopes in LNP. Results: Study 1 demonstrated no adverse effect with 25 μg and 50 μg CTL epitopes-LNP vaccine and 50 μg pan-CoV vaccine-1. However, 100 μg pan-CoV vaccine-1 caused fever 24 h later, which was resolved by a single Meloxicam treatment. Both vaccinees developed cross-FCoV2 neutralizing antibodies (XNAbs), immunoblot binding antibodies (bAbs) to FCoV1 receptor-binding domain (RBD), and T-cell responses to FCoV1 RBD, whereas one vaccinee also developed bAbs to SCoV2 RBD. Study 2 demonstrated no adverse effects after each vaccination. Three vaccinees developed low-titer XNAbs and bAbs to FCoV2 spike-2 by the fourth vaccination. Upon challenge, all cats developed FCoV2 NAbs and bAbs to FCoV2 nucleocapsid and RBD. High vaccine-induced T-cell responses to FCoV1 RBD and T-cell mitogen responses declined with an increase in responses to FCoV2 RBD at three weeks post-challenge. Two of the three controls died from FIP, whereas one vaccinee, with the lowest vaccine-induced immunity, died from skin vasculitis lesions and detection of FIPV2 infection by semi-nested RT-snPCR in feces. Conclusions: In Pilot Study 1, the pan-CoV vaccine-LNP dose of 50 μg had no adverse effects, but adverse effects were observed at 100 μg dose. In Pilot Study 2, the FCoV1-based B-cell vaccine(s) induced low levels of XNAbs against FIPV2 and delayed challenge infection against high-dose FIPV2. The high-dose FIPV2 infections in the vaccinated and control cats started to clear, by single housing at 23–26 weeks post-challenge, whereas two cats in Pilot Study 1 cleared natural FCoV1 transmission by 26 weeks post-infection. Full article

The therapeutic use of non-steroidal anti-inflammatory drugs (NSAIDs) is limited by gastrointestinal and renal adverse effects caused by non-selective COX-1 and COX-2 inhibition. To address this issue, a new series of naproxen–azetidinone hybrids was rationally designed and synthesized to enhance COX-2 selectivity and reduce off-target toxicity. The synthesis involved esterification, hydrazide formation, Schiff base condensation, and intramolecular cyclization with chloroacetyl chloride. Structural characterization was achieved through FT-IR, ¹H NMR, and ¹³C NMR analyses. In silico ADMET profiling confirmed compliance with Lipinski’s rule and predicted favorable gastrointestinal absorption. Molecular docking revealed high COX-2 binding affinities (−11.93 to −9.72 kcal/mol), while MM/GBSA analysis identified compound N4_c (ΔG = −62.27 kcal/mol) as the most stable complex, surpassing meloxicam and naproxen. DFT (B3LYP/6-31G(d,p)) frontier molecular orbital analysis indicated a narrow HOMO–LUMO gap (ΔE = 2.97 eV) for N4_c, suggesting high electronic reactivity and strong enzyme interaction. Molecular dynamics simulations confirmed complex stability. In vivo anti-inflammatory testing using an egg-white-induced rat paw edema model showed that N4_d, N4_e, and N4_f achieved higher inhibition (19.22%, 16.98%, and 16.98%) than naproxen (4.3%). These results highlight 2-azetidinone–naproxen hybrids as promising selective COX-2 inhibitors with enhanced pharmacokinetic and electronic properties. Full article

Disbudding is a common practice on dairy farms, with the hot iron method (HID) widely used, though it causes considerable pain if no analgesia is provided. This study included two experiments. In Experiment 1, an alternative method using policresulen (POD) was evaluated in 24 Holstein calves randomly assigned to either POD or HID at 21 ± 2 days of age. Calves in the POD group received 0.2 mL of 36% policresulen per horn bud, while those in the HID group were fully cauterized. The cornual nerve was blocked with 5 mL of 2% lidocaine in both treatments, and all calves received meloxicam (0.5 mg/kg body weight) for three days post-procedure. Calves treated with POD exhibited fewer pain-related behaviors, such as scratching the horn buds, rubbing against objects, and head shaking, and showed faster horn bud regression. However, 12-month observations revealed that 9 of 12 POD-treated calves showed horn regrowth, indicating limited long-term effectiveness. Experiment 2 assessed consumer perceptions through a questionnaire and video with 236 participants. Participants with farming experience were more familiar with disbudding and preferred HID. In contrast, individuals with less agricultural contact demonstrated a greater willingness to pay for products from farms implementing animal welfare practices, with 76% favoring POD. Overall, participants experienced in agribusiness prioritized technical knowledge and practicality, while others valued animal welfare and were willing to pay higher prices for welfare-friendly practices. Full article

The primary mechanism of non-steroidal anti-inflammatory drugs (NSAIDs) is inhibition of prostaglandin production mediated by cyclooxygenase. Given the possible association of cyclooxygenase-2, but not cyclooxygenase-1, with membrane lipid rafts, we assessed whether the lipid raft membrane interactivity of NSAIDs correlates with cyclooxygenase-2 selectivity. Lipid raft model membranes and reference membranes were prepared with 1,2-dioleoylphosphatidylcholine/sphingomyelin/cholesterol and 1,2-dipalmitoylphosphatidylcholine, respectively. After treating the membranes with 2–50 μM NSAIDs at pH 7.4, 6.5, and 5.5, fluorescence polarization was measured to determine their membrane interactivity. Conventional NSAIDs (diclofenac, ibuprofen, indomethacin, aspirin, and flurbiprofen) and Coxibs (lumiracoxib, etoricoxib, celecoxib, valdecoxib, and rofecoxib) decreased membrane fluidity, whereas Oxicams (meloxicam, piroxicam, tenoxicam, and lornoxicam) increased. Membrane effects of NSAIDs were so dependent on medium pH that they significantly increased with reducing pH from 7.4 to 5.5. Under inflammatory acidic conditions, the lipid raft membrane interactivity of NSAIDs was more likely to correlate with cyclooxygenase-2 selectivity than the reference membrane interactivity. It is hypothesized that NSAIDs may interact with lipid raft membranes to induce membrane fluidity changes with the potency corresponding to cyclooxygenase-2 inhibition, disrupting the structural and functional integrity of lipid rafts to affect the activity of cyclooxygenase-2 localized in lipid rafts, resulting in cyclooxygenase-2 selective inhibition. Full article

Lopezia racemosa Cav., commonly known as “cancer herb” in indigenous communities, has long been used for its medicinal properties. The biotechnological production of its bioactive compounds through genetic transformation represents a valuable approach for obtaining pharmacologically relevant substances. The initial focus of this study was to identify compounds previously reported in the species; however, phytochemical analysis by HPLC and NMR led to the isolation and identification of two pentacyclic triterpene esters not previously described in L. racemosa: 3-O-[(E)-feruloyl]-maslinic acid (1) and 3-O-[(E)-feruloyl]-corosolic acid (2), identified as constituents of fraction 33. The LRTC3.1 callus line was obtained from hairy roots generated by infecting L. racemosa leaf explants with Agrobacterium rhizogenes strain ATCC15834/pTDT. The crude extract, specific fractions, and the mixture of these compounds demonstrated significant anti-inflammatory and cytotoxic activities. Anti-inflammatory activity was evaluated using the carrageenan-induced mouse paw edema model, where the crude extract achieved 51.02% inhibition of inflammation compared to meloxicam (30.86%). Cytotoxicity was assessed against three human cancer cell lines: breast carcinoma (MCF7), cervical carcinoma (SiHa), and colon carcinoma (HCT-15). Fractions FD (28–29) and 33 exhibited potent cytotoxic effects, with IC₅₀ values of 0.508 and 1.345 µg/mL against SiHa cells, and 0.053 and 2.693 µg/mL against MCF-7 cells, respectively. These findings suggest that transformed L. racemosa cultures represent a promising source of bioactive compounds for potential therapeutic development. Full article

Use of sedation for disbudding is common practice in a number European countries, with United Kingdom (UK) practices adopting its use. This study assessed the effects of disbudding with and without xylazine sedation on growth rates and calf health on a UK calf rearing unit. Data was collected from 485 dairy crossed with beef breed calves between April and August 2024 from a single calf rearing unit in England. Calves were purchased from multiple farms across the UK and arrived on site at approximately 21 days of age. Calves were disbudded—and, in the case of male calves, surgically castrated—at approximately three weeks after arrival on farm. Pens of calves were assigned to undergo disbudding with (SED, n = 238) or without (CTL = 234) xylazine sedation at a dose of 0.2 mg/kg administered intramuscularly. Calves from both groups were provided with local anaesthetic (procaine hydrochloride) as a cornual nerve block and a non-steroidal anti-inflammatory drug (meloxicam). While other studies have demonstrated some behavioural and physiological indicators of pain to be reduced with sedation, this study found that calves in the SED group had a reduced daily liveweight gain (DLWG) of 0.14 kg/day in the short term (mean 20 days) following disbudding (p < 0.001), but there was no difference in growth rates in the medium-term (mean 43 days) post-disbudding (p = 0.30). Some of this difference could be explained by the slightly higher DLWG pre-disbudding in the CTR group, and it is likely that the physiological impacts of sedation accounted for the rest of this difference. This initial reduction in DLWG following disbudding with sedation should be considered by vets, especially on farms where growth rates may already be compromised. In the sedated calves, 19.3% exhibited either some movement or entry into sternal recumbency. Specifically, a light plane of sedation with calves entering sternal recumbency was associated with a reduction in DLWG of 0.89 kg/day compared to 0.98 kg/day for those that remained in lateral recumbency throughout (p = 0.008). The light plane of sedation may have created additional calf stress, impacted feeding behaviours, and impinged welfare, with further work needed to establish the reasons for insufficient sedation. There was no difference in the number of post-disbudding treatment outcomes between calves disbudded with and without sedation (p = 0.97). Full article