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1. Pharmacokinetics of Injectable Meloxicam and Buprenorphine in the Naked Mole-Rat (Heterocephalus glaber)

   Moran, CR; Park, TJ; Buffenstein, R; Chakrabarty, S; Lindeblad, MO; Fortman, JD; Adams, CR (July 2024, Journal of the American Association for Laboratory Animal Science)

   Unique characteristics of the naked mole-rat (NMR) have made it increasingly popular as a laboratory animal model. These rodents are used to study many fields of research including longevity and aging, cancer, circadian rhythm, pain, and metabolism. Currently, the analgesic dosing regimens used in the NMR mirror those used in other rodent species. However, there is no pharmacokinetic (PK) data supporting the use of injectable analgesics in the NMR. Therefore, we conducted two independent PK studies to evaluate two commonly used analgesics in the NMR; meloxicam (2 mg/kg SC) and buprenorphine (0.1 mg/kg SC). In each study, blood was collected at 8 time points after subcutaneous injection of meloxicam or buprenorphine (0 (pre-dose), 0.25, 0.5, 1, 2, 4, 8, and 24 hrs). Three NMRs were used per time point for a total of 24 animals per PK study. Plasma concentrations of meloxicam were highest between 0.5 hrs and 1 hr post-injection. Levels remained above the extrapolated dog and cat therapeutic threshold levels (390-911 ng/mL) for at least 24 hrs. Plasma concentrations of buprenorphine were highest between 0.25 and 0.5 hrs post-injection. Levels remained above the human therapeutic threshold (1 ng/mL) for up to 21 hrs. No skin reactions were seen in association with injection of either drug. In summary, this data supports dosing meloxicam (2 mg/kg SC) once every 24 hrs and buprenorphine (0.1 mg/kg SC) once every 8-12 hrs in the NMR. Further studies should be performed to evaluate the clinical efficacy of these drugs by correlating plasma concentrations with post-operative pain assessments. 

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2. Intranasal diamorphine population pharmacokinetics modeling and simulation in pediatric breakthrough pain

   https://doi.org/10.1002/psp4.13186  

   Cai, Lianjin; Zhai, Jingchen; Ji, Beihong; Han, Fengyang; Niu, Taoyu; Wang, Luxuan; Wang, Junmei (March 2025, CPT: Pharmacometrics & Systems Pharmacology)

   Abstract Intranasal diamorphine (IND), approved for managing breakthrough pain in the UK, has been identified as an acceptable alternative offering effective, expedient, and less traumatic analgesia for children. However, the current dose regimen in pediatric populations relies on clinical expertise while the pharmacokinetics properties are poorly understood. This study aimed to develop diamorphine population pharmacokinetics (pop‐PK) models and simulate the IND dosing in virtual pediatric subjects. An integrated four‐compartment pop‐PK model with first‐order absorption and elimination provided an appropriate fit and characterized publicly available 385 concentration measurements of diamorphine, 6‐monoacetylmorphine, and morphine collected from adults. Body weight allometry and renal function maturation (age) were incorporated into the final model, serving as two covariates. The estimated IND relative bioavailability was around 52% compared with intramuscularly injected diamorphine. Using this final model, the morphine plasma concentrations, as the active metabolite for pain relief, were simulated in virtual subjects. The utility of model extrapolation was supported by external verification with acceptable average fold errors of 1.06 ± 0.30 and 0.83 ± 0.07 for morphine maximum concentration and exposures. Meanwhile, the simulated morphine concentration–time profiles could recover the PK profiles observed in children after a single dose of IND. The model‐based dosing simulations were therefore assessed in four children age groups to match the therapeutic window of morphine concentrations in steady state (10–20 μg/L). Our study demonstrates that the dose regimen of 0.3 mg/kg loading dose plus 0.1 mg/kg hourly maintenance dose is generally appropriate for multiple pediatric populations with breakthrough pain, in the view of PK. 

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3. Genomic and in vitro pharmacodynamic analysis of rifampicin resistance in multidrug‐resistant canine Staphylococcus pseudintermedius isolates

   https://doi.org/10.1111/vde.12959  

   Hicks, Karly; Tan, Yongjun; Cao, Wenqi; Hathcock, Terri; Boothe, Dawn; Kennis, Robert; Zhang, Dapeng; Wang, Xu; White, Amelia (April 2021, Veterinary Dermatology)

   BackgroundAntimicrobial resistance is a growing concern in canineStaphylococcus pseudintermediusdermatitis. Treatment with rifampicin (RFP) is considered only in meticillin‐resistant and multidrug‐resistantS. pseudintermedius(MDR‐MRSP). Hypothesis/ObjectivesTo determine an optimal RFP dosing for MDR‐MRSP treatment without induction of RFP resistance and identify causal mutations for antimicrobial resistance. Methods and materialsTime–kill assays were performed in a control isolate and three MDR‐MRSP isolates at six clinically relevant concentrations [32 to 1,024 × MIC (the minimum inhibitory concentration)]. Whole‐genome resequencing and bioinformatic analysis were performed in the resistant strains developed in this assay. ResultsThe genomic analysis identified nine antimicrobial resistance genes (ARGs) in MDR‐MRSP isolates, which are responsible for resistance to seven classes of antibiotics. RFP activity against all four isolates was consistent with a time‐dependent and bacteriostatic response. RFP resistance was observed in six of the 28 time–kill assays, including concentrations 64 × MIC in MDR‐MRSP1 isolates at 24 h, 32 × MIC in MDR‐MRSP2 at 48 h, 32 × MIC in MDR‐MRSP3 at 48 h and 256 × MIC in MDR‐MRSP3 at 24 h. Genome‐wide mutation analyses in these RFP‐resistant strains discovered the causal mutations in the coding region of therpoBgene. Conclusions and clinical relevanceA study has shown that 6 mg/kg per os results in plasma concentrations of 600–1,000 × MIC ofS. pseudintermedius. Based on our data, this dose should achieve the minimum MIC (×512) to prevent RFP resistance development; therefore, we recommend a minimum daily dose of 6 mg/kg for MDR‐MRSP pyoderma treatment when limited antibiotic options are available. 

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4. A LC–MS/MS method for the simultaneous determination of 6‐cyanodopamine, 6‐nitrodopamine, 6‐nitrodopa, 6‐nitroadrenaline and 6‐bromodopamine in human plasma and its clinical application in patients with chronic kidney disease

   https://doi.org/10.1002/bmc.5896  

   Ribeiro, Luiz_Fernando; Babadopulos, Tainah; de_Oliveira, Mariana_G; Nishimaru, Flávio; Zatz, Roberto; Elias, Rosilene_Motta; Moraes, Odorico; Moraes, Elisabete; Peterson, Larryn_W; De_Nucci, Gilberto (May 2024, Biomedical Chromatography)

   Abstract The aim of this study was to develop a high‐performance liquid chromatography–tandem mass spectrometry method for the determination of 6‐cyanodopamine, 6‐nitrodopamine, 6‐nitrodopa, 6‐nitroadrenaline and 6‐bromodopamine in human plasma samples. Strata‐X 33 μm solid‐phase extraction cartridges were used for the extraction of the catecholamines from human plasma samples. The catecholamines were separated in a 150 × 3 mm Shim‐pack GIST C₁₈‐AQ column with 3 μm particle size, placed in an oven at 40°C and perfused with 82% mobile phase A (acetonitrile–H₂O; 90:10, v/v) + 0.4% acetic acid and 18% mobile phase B (deionized H₂O) + 0.2% formic acid at a flow rate of 340 μl/min in isocratic mode. The injected volume was 4 μl and the run lasted 4 min. The method was linear from 0.1 to 20 ng/ml and the lower limit of quantification was 0.1 ng/ml for all analytes. The method was applied to evaluate the plasma levels of catecholamines in plasma of patients with chronic kidney disease and allowed the detection for the first time of circulating levels of the novel catecholamines 6‐bromodopamine and 6‐cyanodopamine. 

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5. A systematic study of injectable anesthetic agents in the brown anole lizard ( Anolis sagrei  )

   https://doi.org/10.1177/0023677219862841  

   Rasys, Ashley_M; Divers, Stephen_J; Lauderdale, James_D; Menke, Douglas_B (July 2019, Laboratory Animals)

   Anolis lizards have served as important research models in fields ranging from evolution and ecology to physiology and biomechanics. However, anoles are also emerging as important models for studies of embryo development and tissue regeneration. The increased use of anoles in the laboratory has produced a need to establish effective methods of anesthesia, both for routine veterinary procedures and for research procedures. Therefore, we tested the efficacy of different anesthetic treatments in adult female Anolis sagrei. Alfaxalone, dexmedetomidine, hydromorphone, ketamine and tribromoethanol were administered subcutaneously (SC), either alone or combined at varying doses in a total of 64 female anoles. Drug induction time, duration, anesthesia level and adverse effects were assessed. Differences in anesthesia level were observed depending on injection site and drug combination. Alfaxalone/dexmedetomidine and tribromoethanol/dexmedetomidine were the most effective drug combinations for inducing a surgical plane of anesthesia in anoles. Brown anoles injected SC with alfaxalone (30 mg/kg) plus dexmedetomidine (0.1 mg/kg) or with tribromoethanol (400 mg/kg) plus dexmedetomidine (0.1 mg/kg) experienced mean durations of surgical anesthesia levels of 31.2 ± 5.3 and 87.5 ± 19.8 min with full recovery after another 10.9 ± 2.9 and 46.2 ± 41.8 min, respectively. Hydromorphone given with alfaxalone/dexmedetomidine resulted in deep anesthesia with respiratory depression, while ketamine/hydromorphone/dexmedetomidine produced only light to moderate sedation. We determined that alfaxalone/dexmedetomidine or tribromoethanol/dexmedetomidine combinations were sufficient to maintain a lizard under general anesthesia for coeliotomy. This study represents a significant step towards understanding the effects of anesthetic agents in anole lizards and will benefit both veterinary care and research on these animals. 

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