Pharmacology of drugs used in autoimmune dermatopathies in cats and dogs: A narrative review.

Immunosuppressive drugs are the mainstay of treatment for many feline and canine autoimmune skin diseases, either as monotherapy or in combination with other drugs. Treatment with these drugs is often lifelong and may have long-term consequences on the affected animal's overall quality-of-life. Clinicians need to understand the pharmacology of immunosuppressants in planning and executing the treatment regimen for the best possible clinical outcome, as well as reducing the risk of adverse effects. This review paper will focus on the mechanism of action, pharmacokinetics and pharmacodynamics, clinical uses and adverse effects of immunosuppressive drugs used to treat autoimmune dermatoses in cats and dogs. These include glucocorticoids, ciclosporin A, azathioprine, chlorambucil, mycophenolate mofetil, oclacitinib and Bruton's tyrosine kinase inhibitors.

Les médicaments immunosuppresseurs constituent la base de la thérapeutique de nombreuses dermatoses auto­immunes félines et canines, soit en monothérapie, soit en association avec d'autres médicaments. Le traitement par ces médicaments dure souvent toute la vie et peut avoir des conséquences à long terme sur la qualité de vie globale de l'animal affecté. Les cliniciens doivent comprendre la pharmacologie des immunosuppresseurs afin de planifier et de mettre en place le plan thérapeutique, afin d'obtenir le meilleur résultat clinique possible et de réduire le risque d'effets indésirables. Cet article de synthèse cible le mécanisme d'action, la pharmacocinétique et la pharmacodynamie, les utilisations cliniques et les effets indésirables des médicaments immunosuppresseurs utilisés pour traiter les dermatoses auto­immunes chez les chats et les chiens. Ces médicaments comprennent les glucocorticoïdes, la ciclosporine A, l'azathioprine, le chlorambucil, le mycophénolate mofétil, l'oclacitinib et les inhibiteurs de la tyrosine kinase de Bruton.

Os medicamentos imunossupressores são a base do tratamento para muitas doenças de pele autoimunes felinas e caninas, seja em monoterapia ou em combinação com outros medicamentos. O tratamento com esses medicamentos costuma durar toda a vida e pode ter consequências a longo prazo na qualidade de vida geral do animal afetado. Os clínicos precisam compreender a farmacologia dos imunossupressores para planejar e executar o protocolo de tratamento para se obter o melhor resultado clínico possível, assim como reduzir o risco de efeitos adversos. Este artigo de revisão será focado no mecanismo de ação, farmacocinética e farmacodinâmica, indicações clínicas e efeitos adversos de medicamentos imunossupressores usados para tratar dermatoses autoimunes em cães e gatos. Estes incluem glucocorticóides, ciclosporina A, azatioprina, clorambucil, micofenolato de mofetila, oclacitinib e inibidores da tirosina quinase de Bruton.

Los tratamientos inmunosupresores son la línea de tratamiento principal en muchas enfermedades autoinmunes de la piel de perros y gatos, bien como monoterapia o en combinación con otros fármacos. El tratamiento con estos fármacos es a menudo de larga duración o de por vida y puede tener consecuencias adversas de larga duración en la calidad de vida de los animales. Los veterinarios clínicos tienen que entender la farmacología de los inmunosupresores durante la planificación y ejecución de los tratamientos para obtener los resultados más beneficiosos y reducir los efectos adversos. Este artículo de revisión está enfocado en los mecanismos de acción, farmacocinética, farmacodinámica, usos clínicos y efectos adversos de tratamientos inmunosupresores utilizados en perros y gatos para tratar dermatopatías inmunomediadas de la piel. Se incluyen glucocorticoides, ciclosporina A, azatioprina, clorambucilo, mofetil micofenolato, oclacitinib e inhibidores de la tirosina quinasa de Bruton.

Heparanase Blockade as a Novel Dual-Targeting Therapy for COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused over 5 million deaths worldwide. Pneumonia and systemic inflammation contribute to its high mortality. Many viruses use heparan sulfate proteoglycans as coreceptors for viral entry, and heparanase (HPSE) is a known regulator of both viral entry and inflammatory cytokines. We evaluated the heparanase inhibitor Roneparstat, a modified heparin with minimum anticoagulant activity, in pathophysiology and therapy for COVID-19. We found that Roneparstat significantly decreased the infectivity of SARS-CoV-2, SARS-CoV-1, and retroviruses (human T-lymphotropic virus 1 [HTLV-1] and HIV-1) in vitro. Single-cell RNA sequencing (scRNA-seq) analysis of cells from the bronchoalveolar lavage fluid of COVID-19 patients revealed a marked increase in HPSE gene expression in CD68+ macrophages compared to healthy controls. Elevated levels of HPSE expression in macrophages correlated with the severity of COVID-19 and the expression of inflammatory cytokine genes, including IL6, TNF, IL1B, and CCL2. In line with this finding, we found a marked induction of HPSE and numerous inflammatory cytokines in human macrophages challenged with SARS-CoV-2 S1 protein. Treatment with Roneparstat significantly attenuated SARS-CoV-2 S1 protein-mediated inflammatory cytokine release from human macrophages, through disruption of NF-κB signaling. HPSE knockdown in a macrophage cell line also showed diminished inflammatory cytokine production during S1 protein challenge. Taken together, this study provides a proof of concept that heparanase is a target for SARS-CoV-2-mediated pathogenesis and that Roneparstat may serve as a dual-targeted therapy to reduce viral infection and inflammation in COVID-19. IMPORTANCE The complex pathogenesis of COVID-19 consists of two major pathological phases: an initial infection phase elicited by SARS-CoV-2 entry and replication and an inflammation phase that could lead to tissue damage, which can evolve into acute respiratory failure or even death. While the development and deployment of vaccines are ongoing, effective therapy for COVID-19 is still urgently needed. In this study, we explored HPSE blockade with Roneparstat, a phase I clinically tested HPSE inhibitor, in the context of COVID-19 pathogenesis. Treatment with Roneparstat showed wide-spectrum anti-infection activities against SARS-CoV-2, HTLV-1, and HIV-1 in vitro. In addition, HPSE blockade with Roneparstat significantly attenuated SARS-CoV-2 S1 protein-induced inflammatory cytokine release from human macrophages through disruption of NF-κB signaling. Together, this study provides a proof of principle for the use of Roneparstat as a dual-targeting therapy for COVID-19 to decrease viral infection and dampen the proinflammatory immune response mediated by macrophages.

Potassium penicillin and gentamicin pharmacokinetics in healthy conscious and anesthetized horses.

OBJECTIVE: To determine the effects of general anesthesia on the safety and efficacy of co-administered potassium penicillin G (PEN) and gentamicin (GENT) in horses. STUDY DESIGN: Nonrandomized crossover. ANIMALS: Six adult, Thoroughbred horses. METHODS: Horses were administered PEN (22 000 IU/kg IV) and GENT (6.6 mg/kg IV). Plasma samples were collected over a 6 h period and synovial fluid was collected at 30 min and 6 h respectively. Drug administration and sample collection protocols were repeated after at least a 48 hour washout period and induction of anesthesia using xylazine/ketamine and maintenance with isoflurane gas. Drug concentrations were determined using ultrapressure liquid chromatography with mass spectrometry. A 2-compartment model was used to determine pharmacokinetics and differences were determined between conscious and anesthetized horses using paired t-tests (significance P < .05). RESULTS: Potassium penicillin g and GENT had higher minimum plasma concentrations (PEN 0.44 vs. 0.11 µg/mL, P = .002; GENT 3.0 vs. 1.9 µg/mL, P = .009), longer half lives (PEN 71 vs. 59 min, P = .018; GENT 149 vs. 109 min, P = .038), and slower clearances (PEN 3.41 vs. 5.1 mL/kg/min, P = .005; GENT 1.18 vs. 1.48 mL/kg/min, P = .028) in anesthetized horses vs. conscious horses. The PEN concentrations remained above the breakpoint minimum inhibitory concentration (MIC, 0.5 µg/mL) for 332 min in anesthetized vs. 199 min in conscious horses. The GENT concentrations reached 10 times higher than the breakpoint MIC (2 µg/mL) in all horses and were maintained for 58 vs. 59 min in anesthetized and conscious states, respectively. Synovial fluid concentrations were higher in conscious horses vs. anesthetized horses at 30 min for PEN (7.0 vs. 0.93 µg/mL, P < .001) and 30 (5.3 µg/mL vs. 0.79 µg/mL, P < .001) and 360 min (3.4 vs. 1.82 µg/mL, P < .003) for GENT. CONCLUSION: General anesthesia resulted in lower intrasynovial concentrations and delayed clearance of PEN/GENT in horses. CLINICAL SIGNIFICANCE: Redosing healthy anesthetized horses with PEN prior to 4-5 h is not necessary. When administered to anesthetized horses, intravenous PEN/GENT may not reach adequate intrasynovial concentrations to treat or prevent common pathogens. The doses or dosing intervals of antimicrobials administered to horses undergoing anesthesia may need to be adjusted to ensure maintenance of safe and effective plasma concentrations.

Understanding barriers to prescription retrieval and attitudes toward mental health medications at a university student health services pharmacy.

OBJECTIVES: To describe barriers affecting college students' ability to retrieve prescription medications for mental health conditions from a community pharmacy embedded within a student health center on a university campus and then describe beliefs and attitudes toward the use of those medications. METHODS: We conducted a cross-sectional study of college students who were prescribed a medication(s) for a mental health condition(s) and left the medication(s) unclaimed at the pharmacy for at least 5 days. Eligible participants were identified through routine reminder telephone calls and then provided a link to an online survey via e-mail. The survey collected information on demographics, prescription retrieval barriers, and medication beliefs and attitudes using 2 validated questionnaires. Data were summarized using descriptive statistics and scoring methods specific to the validated questionnaires. RESULTS: A total of 83 e-mails were distributed with 46 usable responses received (55.4% response rate). Participants were undergraduate students (n = 38, 82.6%) and most frequently prescribed a medication(s) for depression (n = 21, 45.7%) or anxiety (n = 16, 34.8%). Forgetting to pick up their medication was the most commonly cited reason for prescription nonretrieval (n = 32, 69.6%) followed by limited pharmacy hours (n = 21, 45.7%). Participants generally viewed the necessity of their medication(s) as outweighing their concerns about their medication(s), and they generally viewed themselves as medication adherent. CONCLUSIONS: University students taking medications for mental health conditions identified forgetfulness and limited pharmacy hours as the most common reasons for not retrieving prescriptions. Students generally viewed their medication(s) as necessary and themselves as medication adherent, suggesting that attitudes and beliefs may play a smaller role in medication use behaviors in this population. Future research is needed to develop and evaluate interventions that improve medication adherence in college students, potentially focused on reminder-based interventions.

Pharmacokinetics and pulmonary distribution of Draxxin® (tulathromycin) in healthy adult horses.

The objective of this study was to determine the pharmacokinetics and tolerability of tulathromycin (Draxxin® ; 2.5 mg/kg once) after intramuscular (IM), subcutaneous (SC), and slow intravenous (IV) administration to six adult horses. A three-phase design and 4-week washout period were used. Drug concentrations in blood and bronchoalveolar lavage (BAL) samples were determined by ultra-performance liquid chromatography tandem mass spectrometry and pharmacokinetic parameters calculated using noncompartmental analysis. Following SC and IM administration, all horses exhibited sweating, discomfort, and periods of recumbency. As signs were more severe after SC administration this route was only used in 3/6 horses. Intravenous administration of tulathromycin was well tolerated in all horses. Mean bioavailability was 99.4% IM and 115% SC. Mean maximum plasma concentration was 645 ng/ml IM and 373 ng/ml SC. Mean half-life was 59.8 h, 54.8 h, and 57.9 h for IV, IM, and SC administration, respectively. Mean clearance was 3.25 ml/kg/min, and mean volume of distribution was 16.8 L/kg following IV administration. Drug was detectable in plasma and BAL samples for 120 h following all routes; however, adverse effects may prevent IM use and SC use is not recommended. Tulathromycin may be a practical and affordable antimicrobial for use in adult equine patients.

Physiological parameter values for physiologically based pharmacokinetic models in food-producing animals. Part III: Sheep and goat.

This report is the third in a series of studies that aimed to compile physiological parameters related to develop physiologically based pharmacokinetic (PBPK) models for drugs and environmental chemicals in food-producing animals including swine and cattle (Part I), chickens and turkeys (Part II), and finally sheep and goats (the focus of this manuscript). Literature searches were conducted in multiple databases (PubMed, Google Scholar, ScienceDirect, and ProQuest), with data on relevant parameters including body weight, relative organ weight (% of body weight), cardiac output, relative organ blood flow (% of cardiac output), residual blood volume (% of organ weight), and hematocrit reviewed and statistically summarized. The mean and standard deviation of each parameter are presented in tables. Equations describing the growth curves of sheep and goats are presented in figures. When data are sufficient, parameter values are reported for different ages or production classes of sheep, including fetal sheep, lambs, and market-age sheep (mature sheep). These data provide a reference database for developing standardized PBPK models to predict drug withdrawal intervals in sheep and goats, and also provide a basis for extrapolating PBPK models from major species such as cattle to minor species such as sheep and goats.

Physiological parameter values for physiologically based pharmacokinetic models in food-producing animals. Part II: Chicken and turkey.

Physiologically based pharmacokinetic (PBPK) models are growing in popularity due to human food safety concerns and for estimating drug residue distribution and estimating withdrawal intervals for veterinary products originating from livestock species. This paper focuses on the physiological and anatomical data, including cardiac output, organ weight, and blood flow values, needed for PBPK modeling applications for avian species commonly consumed in the poultry market. Experimental and field studies from 1940 to 2019 for broiler chickens (1-70 days old, 40 g - 3.2 kg), laying hens (4-15 months old, 1.1-2.0 kg), and turkeys (1 day-14 months old, 60 g -12.7 kg) were searched systematically using PubMed, Google Scholar, ProQuest, and ScienceDirect for data collection in 2019 and 2020. Relevant data were extracted from the literature with mean and standard deviation (SD) being calculated and compiled in tables of relative organ weights (% of body weight) and relative blood flows (% of cardiac output). Trends of organ or tissue weight growth during different life stages were calculated when sufficient data were available. These compiled data sets facilitate future PBPK model development and applications, especially in estimating chemical residue concentrations in edible tissues to calculate food safety withdrawal intervals for poultry.

Physiological parameter values for physiologically based pharmacokinetic models in food-producing animals. Part I: Cattle and swine.

Physiologically based pharmacokinetic (PBPK) models for chemicals in food animals are a useful tool in estimating chemical tissue residues and withdrawal intervals. Physiological parameters such as organ weights and blood flows are an important component of a PBPK model. The objective of this study was to compile PBPK-related physiological parameter data in food animals, including cattle and swine. Comprehensive literature searches were performed in PubMed, Google Scholar, ScienceDirect, and ProQuest. Relevant literature was reviewed and tables of relevant parameters such as relative organ weights (% of body weight) and relative blood flows (% of cardiac output) were compiled for different production classes of cattle and swine. The mean and standard deviation of each parameter were calculated to characterize their variability and uncertainty and to allow investigators to conduct population PBPK analysis via Monte Carlo simulations. Regression equations using weight or age were created for parameters having sufficient data. These compiled data provide a comprehensive physiological parameter database for developing PBPK models of chemicals in cattle and swine to support animal-derived food safety assessment. This work also provides a basis to compile data in other food animal species, including goats, sheep, chickens, and turkeys.

Integration of Food Animal Residue Avoidance Databank (FARAD) empirical methods for drug withdrawal interval determination with a mechanistic population-based interactive physiologically based pharmacokinetic (iPBPK) modeling platform: example for flunixin meglumine administration.

Violative chemical residues in animal-derived food products affect food safety globally and have impact on the trade of international agricultural products. The Food Animal Residue Avoidance Databank program has been developing scientific tools to provide appropriate withdrawal interval (WDI) estimations after extralabel drug use in food animals for the past three decades. One of the tools is physiologically based pharmacokinetic (PBPK) modeling, which is a mechanistic-based approach that can be used to predict tissue residues and WDIs. However, PBPK models are complicated and difficult to use by non-modelers. Therefore, a user-friendly PBPK modeling framework is needed to move this field forward. Flunixin was one of the top five violative drug residues identified in the United States from 2010 to 2016. The objective of this study was to establish a web-based user-friendly framework for the development of new PBPK models for drugs administered to food animals. Specifically, a new PBPK model for both cattle and swine after administration of flunixin meglumine was developed. Population analysis using Monte Carlo simulations was incorporated into the model to predict WDIs following extralabel administration of flunixin meglumine. The population PBPK model was converted to a web-based interactive PBPK (iPBPK) framework to facilitate its application. This iPBPK framework serves as a proof-of-concept for further improvements in the future and it can be applied to develop new models for other drugs in other food animal species, thereby facilitating the application of PBPK modeling in WDI estimation and food safety assessment.

Pharmacokinetics and physiologic/behavioral effects of buprenorphine administered sublingually and intravenously to neonatal foals.

Buprenorphine is absorbed following sublingual administration, which would be a low-stress delivery route in foals. However, the pharmacokinetics/pharmacodynamics are not described in foals. Six healthy foals <21 days of age participated in a blinded, randomized, 3-period, 5-sequence, 3-treatment crossover prospective study. Foals received 0.01-0.02 mg/kg buprenorphine administered SL or IV with an equivalent volume of saline administered by the opposite route. Blood was collected from the cephalic vein for pharmacokinetic analysis. Physiologic parameters (HR, RR, body temperature, GI sounds), locomotion (pedometer), and behavioral data (activity level, nursing time, response to humans) were recorded. Plasma concentration of buprenorphine exceeded a presumed analgesic level (0.6 ng/ml) in five foals in the IV group and one in the SL group but only for a very brief time. Pharmacokinetic analysis following IV administration demonstrated a short elimination half-life (t1/2ß 1.95 ± 0.7 hr), large volume of distribution (6.46 ± 1.54 L/kg), and a high total clearance (55.83 ± 23.75 ml/kg/min), which differs from adult horses. Following SL administration, maximum concentrations reached were 0.61 ± 0.11 ng/ml and bioavailability was 25.1% ± 10.9%. In both groups, there were minor statistical differences in HR, RR, body temperature, locomotion, and time spent nursing. However, these differences were clinically insignificant in this single dose study, and excitement, sedation, or colic did not occur.

Hemadsorption extracorporeal therapy removes cytokines ex vivo in horses.

OBJECTIVE: Plasma cytokine adsorption has shown benefit as an adjunctive therapy in human sepsis but has yet to be investigated in horses. We hypothesized that ex vivo filtration of equine plasma with a novel cytokine adsorption device would significantly reduce concentrations of lipopolysaccharide-stimulated cytokines. We also hypothesized that the device would adsorb medications commonly used to treat sepsis. ANIMALS: 8 horses owned by North Carolina State University. METHODS: Four liters of heparinized whole blood was collected from healthy adult horses (n = 8) and stimulated with lipopolysaccharide (100 ng/mL) for 6 hours (37 °C.) from June 4, 2023, to December 15, 2023. Plasma was filtered through a cytokine adsorption device or sham circuit. Samples were collected at 11 time points for multiplex cytokine analysis. Chemistry analysis was performed before and after filtration. To investigate the impact of the device on medication concentrations, equine plasma containing potassium penicillin, gentamicin, and flunixin meglumine was filtered through the cytokine adsorption device or sham for 6 hours. Drug concentrations before and after filtration were determined by ultra-high-performance liquid chromatography. Prefiltration versus postfiltration sample concentrations were analyzed by Student paired t test using GraphPad Prism 9.0 (P < .05). RESULTS: Filtration of lipopolysaccharide-stimulated equine plasma (n = 8) for 6 hours resulted in significant mean reductions in the cytokines IL-10, IL-5, IL-8, tumor necrosis factor-α (TNF-α), and IL-1ß, as well as albumin. Drug concentrations of potassium penicillin, gentamicin, and flunixin meglumine were also significantly reduced by filtration. CLINICAL RELEVANCE: This work provides proof of concept for further investigation of extracorporeal cytokine adsorption as a potential adjunct treatment for equine sepsis.

The Clinical Pharmacology and Therapeutic Evaluation of Non-Steroidal Anti-Inflammatory Drugs in Adult Horses.

This review firstly examines the underlying pathophysiology of pain and inflammation associated with orthopedic disease and endotoxemia. Then, it reviews the clinical pharmacology (pharmacokinetics and pharmacodynamics) of both conventional and non-conventional NSAIDs in the adult horse, and finally provides an overview of different modalities to evaluate the therapeutic efficacy of NSAIDs in research.

Bead size has a greater effect on in vitro elution from antimicrobial-impregnated calcium sulfate beads than drug concentration.

OBJECTIVE: To compare the elution characteristics of amikacin-impregnated calcium sulfate (CaSO4) beads based on different drug concentrations and bead size configurations. SAMPLE: Six groups of amikacin-impregnated CaSO4 beads and one negative control group. PROCEDURES: Amikacin-impregnated CaSO4 beads were formed with either 500 mg (low-concentration) or 1 g (high-concentration) of amikacin per 15 g CaSO4 hemihydrate powder. The number of beads necessary to approximate 150 mg of amikacin for each of the 3 bead sizes (3 mm, 5 mm, and 7 mm) at both low and high concentrations were placed in 6 mL of phosphate-buffered saline. The saline was sampled at 14 time points over 28 days. Amikacin concentrations were determined using liquid chromatography-mass spectrometry. RESULTS: Smaller beads reached higher mean peak concentrations than larger beads (P < .0006). Peak concentrations for the low- and high-concentration groups were 20.5 mg/mL and 27.4 mg/mL, 13.1 mg/mL and 14.0 mg/mL, and 8.85 mg/mL and 6.75 mg/mL for the 3 mm, 5 mm, and 7 mm beads, respectively. Bead size also affected the length of therapeutic duration, lasting 6 days for the 3 mm and 5 mm beads and 9 days for the 7 mm beads. However, this was only statistically evident among the high-concentration beads (P < .044). Antimicrobial concentration within the same bead sizes did not affect elution. CLINICAL RELEVANCE: Amikacin-impregnated CaSO4 beads achieved extreme supratherapeutic eluent concentrations. While additional studies are needed, bead size significantly affected elution with smaller beads reaching higher peak concentrations and 7 mm, high-concentration beads demonstrating a longer therapeutic duration than smaller beads.

Oral administration of an extended-release formulation of nitrofurantoin results in high concentrations in the urine of dogs.

OBJECTIVE: Sporadic bacterial cystitis in both dogs and humans is often caused by Escherichia coli. In humans, nitrofurantoin is a first-line antimicrobial for the treatment of bacterial cystitis but in dogs a lack of available data may be part of the reason it is only recommended as a second-line treatment. The objective of this preliminary study was to determine the plasma pharmacokinetics and urine concentrations of nitrofurantoin monohydrate-macrocrystalline in dogs. ANIMALS: 8 healthy female hound dogs. PROCEDURES: From July 26 to July 28, 2021, dogs received a single oral dose of nitrofurantoin monohydrate-macrocrystalline 100 mg with food. Blood and urine were collected at predetermined times. Nitrofurantoin concentrations were assayed by UPLC-MS/MS and plasma data were analyzed using noncompartmental methods. RESULTS: Plasma concentrations were low for all dogs with a mean ± SD maximum concentration (Cmax) of 0.242 ± 0.098 µg/mL (range, 0.14 to 0.42 µg/mL) occurring between 2 and 24 hours. Urine concentrations were manyfold higher than for plasma. Cmax in urine was 134 ± 54 µg/mL (range, 49.1 to 218 µg/mL) occurring between 6 and 36 hours. As seen in other species, nitrofurantoin concentrated in urine with concentrations being 500 times higher than the concentration in plasma. CLINICAL RELEVANCE: Results suggested that nitrofurantoin monohydrate-macrocrystalline formulation of nitrofurantoin should be effective in treating bacterial cystitis caused by susceptible uropathogens.

Pharmacokinetics and efficacy of orally administered acetaminophen (paracetamol) in adult horses with experimentally induced endotoxemia.

BACKGROUND: Acetaminophen has been evaluated in horses for treatment of musculoskeletal pain but not as an antipyretic. OBJECTIVES: To determine the pharmacokinetics and efficacy of acetaminophen compared to placebo and flunixin meglumine in adult horses with experimentally induced endotoxemia. ANIMALS: Eight university owned research horses with experimentally induced endotoxemia. METHODS: Randomized placebo controlled crossover study. Horses were treated with acetaminophen (30 mg/kg PO; APAP), flunixin meglumine (1.1 mg/kg, PO; FLU), and placebo (PO; PLAC) 2 hours after administration of LPS. Plasma APAP was analyzed via LC-MS/MS. Serial CBC, lactate, serum amyloid A, heart rate and rectal temperature were evaluated. Serum IL-1ß, IL-6, IL-8, IL-10, and TNF-α were evaluated by an equine-specific multiplex assay. RESULTS: Mean maximum plasma APAP concentration was 13.97 ± 2.74 µg/mL within 0.6 ± 0.3 hour after administration. At 4 and 6 hours after treatment, both APAP (P = <.001, P = .03, respectively) and FLU (P = .0045 and P < .001, respectively) had a significantly greater decrease in rectal temperature compared to placebo. FLU caused greater heart rate reduction than APAP at 4 and 6 hours (P = .004 and P = .04), and PLAC at 4 hours (P = .05) after treatment. CONCLUSIONS AND CLINICAL IMPORTANCE: The pharmacokinetics of acetaminophen in endotoxemic horses differ from those reported by previous studies in healthy horses. Acetaminophen is an option for antipyresis in clinical cases, particularly when administration of traditional NSAIDs is contraindicated.

Pharmacokinetics, tissue residue depletion, and withdrawal interval estimations of florfenicol in goats following repeated subcutaneous administrations.

Florfenicol is a broad-spectrum antibiotic commonly used in the U.S. to treat respiratory and enteric infections in goats in an extra-label manner, which requires scientifically based withdrawal intervals (WDIs) for edible tissues. This study aimed to determine the depletion profiles for florfenicol and florfenicol amine in plasma and tissues samples and to estimate WDIs for goats following subcutaneous injection of 40 mg/kg florfenicol, twice, 96 h apart. The samples were collected up to 50 days after the second dose. Pharmacokinetic parameters were calculated using non-compartmental analysis. Three different pharmacostatistical methods with different operational tolerances were used to calculate WDIs. The plasma half-life was 101.80 h for florfenicol and 207.69 h for florfenicol amine after the second dose. Using the FDA tolerance limit method, WDIs were 202 and 101 days, while the EMA maximum residue limit method estimated 179 and 96 days for the respective tissue concentrations to fall below limits of detection (0.12 µg/g for liver and 0.05 µg/g for kidney). This study characterizes plasma pharmacokinetics and tissue depletion profiles of florfenicol and florfenicol amine in goats following subcutaneous injections and reports estimated WDIs for food safety assessment of florfenicol in goats.

Development and application of an interactive generic physiologically based pharmacokinetic (igPBPK) model for adult beef cattle and lactating dairy cows to estimate tissue distribution and edible tissue and milk withdrawal intervals for per- and polyfluoroalkyl substances (PFAS).

Humans can be exposed to per- and polyfluoroalkyl substances (PFAS) through dietary intake from milk and edible tissues from food animals. This study developed a physiologically based pharmacokinetic (PBPK) model to predict tissue and milk residues and estimate withdrawal intervals (WDIs) for multiple PFAS including PFOA, PFOS and PFHxS in beef cattle and lactating dairy cows. Results showed that model predictions were mostly within a two-fold factor of experimental data for plasma, tissues, and milk with an estimated coefficient of determination (R2) of >0.95. The predicted muscle WDIs for beef cattle were <1 day for PFOA, 449 days for PFOS, and 69 days for PFHxS, while the predicted milk WDIs in dairy cows were <1 day for PFOA, 1345 days for PFOS, and zero day for PFHxS following a high environmental exposure scenario (e.g., 49.3, 193, and 161 ng/kg/day for PFOA, PFOS, and PFHxS, respectively, for beef cattle for 2 years). The model was converted to a web-based interactive generic PBPK (igPBPK) platform to provide a user-friendly dashboard for predictions of tissue and milk WDIs for PFAS in cattle. This model serves as a foundation for extrapolation to other PFAS compounds to improve safety assessment of cattle-derived food products.

Pharmacokinetics and clinical efficacy of acetaminophen (paracetamol) in adult horses with mechanically induced lameness.

BACKGROUND: Acetaminophen has been used clinically in horses alone or combined with traditional non-steroidal anti-inflammatory drugs for treatment of musculoskeletal pain in horses. OBJECTIVES: To determine the pharmacokinetics and efficacy of acetaminophen at two doses in horses with mechanically induced lameness compared with phenylbutazone or placebo control. STUDY DESIGN: In vivo experiment. METHODS: Nine healthy mares with mechanical lameness induced via a reversible sole pressure horseshoe model were treated with acetaminophen (20 mg/kg PO; A20), acetaminophen (30 mg/kg PO; A30), phenylbutazone (2.2 mg/kg, PO; PB) and oral placebo (C) in a randomised four-way Latin square model. Plasma concentrations for A20 and A30 were analysed via LC-MS/MS and noncompartmental pharmacokinetic analysis. Heart rate and heart rate variability were measured using a portable telemetry. Lameness was scored by three blinded boarded equine surgeons using the AAEP and 10-point scales. RESULTS: Mean maximum plasma concentration (Cmax ) for A20 was 20.01 µg/ml within 0.66 h (Tmax ) after administration; The mean Cmax for A30 was 30.02 µg/ml with a Tmax of 0.43 h. Post-treatment heart rate for A30 was significantly lower than A20 at 1 and 7 h; lower than PB at 2, 3, 4.5 and 7 h; lower than C at 2, 3.5, 4.5, 6, 7 and 8 h. 10-point Lameness scores were significantly improved for A30 than C at 2 and 4 h post-treatment; PB was significantly improved than C at 8 h post treatment. There were no significant differences in lameness between A20, A30 and PB. MAIN LIMITATIONS: Small sample size, lack of objective lameness measurement. CONCLUSIONS: Acetaminophen at 30 mg/kg produced a more rapid improvement in lameness scores and heart rate compared with other treatments in this model. Further evaluation of the pharmacokinetics and safety of repeated oral dosing of acetaminophen at 30 mg/kg is needed to determine clinical utility.

CONTEXTO: Acetaminofeno tem sido usado rotineiramente em cavalos com dor musculoesquelética, tanto como terapia solo quanto em associação com outros anti-inflamatórios não esteroides tradicionais. OBJETIVOS: Determinar a farmacocinética e eficácia de duas doses de acetaminofeno em cavalos com claudicação mecanicamente induzida, e comparar com fenilbutazona e placebo. DELINEAMENTO DO ESTUDO: Estudo randomizado, cego e controlado utilizando quadrado latino. METODOLOGIA: Nove éguas adultas com claudicação induzida mecanicamente pelo método de aplicação de pressão na sola através de ferradura foram tratadas com acetaminofeno (20 mg/kg VO; A20), acetaminofeno (30 mg/kg VO; A30), fenilbutazona (2.2 mg/kg, VO; PB) e placebo oral (C) em um estudo quadrado latino de forma randômica. Concentração plasmática dos grupos A20 e A30 foram analisadas pelo método LC-MS/MS e análise farmacocinética não compartimentar. Frequência cardíaca e variação da frequência cardíaca foram mensuradas usando telemetria portátil. O grau de claudicação foi avaliado usando a escala de 10 pontos da AAEP por três cirurgiões especialistas (board-certified) que estavam cegos ao tratamento. RESULTADOS: A média máxima da concentração plasmática (Cmax ) do grupo A20 foi 20.01 µg/ml dentro de 0.66 h (Tmax ) da administração. A média Cmax do grupo A30 foi 30.02 µg/ml dentro da Tmax de 0.43 h. A frequência cardíaca do grupo A30 foi significativamente mais baixa do que a do grupo A20 nos momentos 1 e 7 h; mais baixa do que o grupo PB nos momentos 2, 3, 4.5 e 7 h; e mais baixa do que as do grupo C nos momentos 2, 3.5, 4.5, 6, 7 e 8 h. O grau de claudicação diminuiu significativamente no grupo A30 quando comparado com o grupo C nos momentos 2 e 4 h pós tratamento, e no grupo PB quando comparado com o grupo C no momento 8 h pós tratamento. Não houve diferença significativa em grau de claudicação quando os grupos A20, A30 e PB foram comparados. PRINCIPAIS LIMITAÇÕES: Número pequeno de animais, ausência de mensuração de claudicação objetiva. CONCLUSÕES: A dose de 30 mg/kg de acetaminofeno proporcionou uma superior melhora na escala de claudicação e frequência cardíaca quando comparada com os outros tratamentos avaliados neste estudo. Mais informações sobre a farmacocinética e efeitos da repetida dosagem de 30 mg/kg de acetaminofeno precisam ser avaliadas para determinar a sua aplicabilidade clínica.

Transferrin receptor in primary and metastatic breast cancer: Evaluation of expression and experimental modulation to improve molecular targeting.

BACKGROUND: Conjugation of transferrin (Tf) to imaging or nanotherapeutic agents is a promising strategy to target breast cancer. Since the efficacy of these biomaterials often depends on the overexpression of the targeted receptor, we set out to survey expression of transferrin receptor (TfR) in primary and metastatic breast cancer samples, including metastases and relapse, and investigate its modulation in experimental models. METHODS: Gene expression was investigated by datamining in twelve publicly-available datasets. Dedicated Tissue microarrays (TMAs) were generated to evaluate matched primary and bone metastases as well as and pre and post chemotherapy tumors from the same patient. TMA were stained with the FDA-approved MRQ-48 antibody against TfR and graded by staining intensity (H-score). Patient-derived xenografts (PDX) and isogenic metastatic mouse models were used to study in vivo TfR expression and uptake of transferrin. RESULTS: TFRC gene and protein expression were high in breast cancer of all subtypes and stages, and in 60-85% of bone metastases. TfR was detectable after neoadjuvant chemotherapy, albeit with some variability. Fluorophore-conjugated transferrin iron chelator deferoxamine (DFO) enhanced TfR uptake in human breast cancer cells in vitro and proved transferrin localization at metastatic sites and correlation of tumor burden relative to untreated tumor mice. CONCLUSIONS: TfR is expressed in breast cancer, primary, metastatic, and after neoadjuvant chemotherapy. Variability in expression of TfR suggests that evaluation of the expression of TfR in individual patients could identify the best candidates for targeting. Further, systemic iron chelation with DFO may upregulate receptor expression and improve uptake of therapeutics or tracers that use transferrin as a homing ligand.