Comparative efficacy of buparvaquone and imidocarb in inhibiting the in vitro growth of Babesia bovis.

Introduction: B. bovis is an apicomplexan parasite responsible for bovine babesiosis, a tick-borne disease with a worldwide impact. The disease remains inefficiently controlled, and few effective drugs, including imidocarb dipropionate (ID), are currently available in endemic areas. The objective of this study was to evaluate whether buparvaquone (BPQ), a drug currently used to treat cattle infected with the Babesia-related Theileria spp. parasites, could be active against Babesia parasites. Herein, we compared the effect of ID and BPQ on B. bovis growth in vitro erythrocyte culture. Methods: We compared the effect of ID and BPQ on the culture-adapted Texas T2Bo strain of B. bovis. In vitro cultured parasites were incubated with ID and BPQ at two starting parasitemia levels (PPE), 0.2% and 1%. In vitro cultured parasites were treated with ID or BPQ at concentrations ranging from 10 to 300 nM, during 4 consecutive days. Parasitemia levels were daily evaluated using microscopic examination. Data was compared using the independent Student's t-test. Results and discussion: Both ID and BPQ significantly inhibited (p < 0.05) the growth of B. bovis, regardless of the initial parasitemia used. At 1% parasitemia, BPQ had lower calculated inhibitory concentration 50 (IC50: 50.01) values than ID (IC50: 117.3). No parasites were found in wells with 0.2% starting parasitemia, treated previously with 50 nM of BPQ or ID, after 2 days of culture without drugs. At 1% parasitemia, no parasite survival was detected at 150 nM of BPQ or 300 nM of ID, suggesting that both drugs acted as babesiacidals. Conclusion: Overall, the data suggests that BPQ is effective against B. bovis and shows a residual effect that seems superior to ID, which is currently the first-line drug for treating bovine babesiosis globally.

Comparison of serum SDMA and creatinine as a biomarker for the detection of meloxicam-induced kidney injury in cats.

Introduction: Serum symmetric dimethylarginine (SDMA) and creatinine are commonly used biomarkers of renal function in cats. We hypothesize that the serum analytes creatinine and SDMA are equally effective at detecting impaired renal function caused by meloxicam-induced renal injury in cats. Our primary objective was to compare serum concentrations of SDMA and creatinine in cats before, during, and after induction of renal injury from repeated dosages of meloxicam in the context of a small pilot study. Methods: This follow-up study results from data collected in a well-controlled study that included 12 healthy female adult purpose-bred cats. Cats in the treatment group received meloxicam 0.3 mg/kg subcutaneously (SC) every 24 h for 31 days. Cats in the control group received saline (0.1 mL SC). Renal injury was defined as the presence of tubular damage, basement membrane damage, and/or interstitial inflammation in histological sections of kidney tissue. Serum creatinine and SDMA concentration were measured every 4 days. Results: In the control group, no cats developed renal azotemia. In the treatment group, four out of six cats developed elevated serum creatinine and histopathological evidence of renal injury. Three of these cats developed an elevation in serum SDMA. The time to the development of renal azotemia using serum creatinine or SDMA was not significantly different (p > 0.05). Discussion: In this pilot study, there was no evidence that serum SDMA was superior to serum creatinine at detecting impaired renal function caused by meloxicam-induced renal injury in cats.

Application of eprinomectin-containing parasiticides at label doses causes neurological toxicosis in cats homozygous for ABCB11930_1931del TC.

The feline MDR1 mutation (ABCB11930_1931delTC) has been associated with neurological toxicosis after topical application of eprinomectin products labeled for feline use. Information was collected from veterinarians who submitted samples for ABCB11930_1931delTC genotyping. In most cases, the submission form indicated an adverse event involving eprinomectin, in other cases submitting veterinarians were contacted to determine whether the patient had experienced an adverse drug event involving eprinomectin. If so, additional information was obtained to determine whether the case met inclusion criteria. 14 cases were highly consistent with eprinomectin toxicosis. Eight cats were homozygous for ABCB11930_1931del TC (3 died; 5 recovered). Six cats were homozygous wildtype (2 died; 4 recovered). The observed ABCB11930_1931delTC frequency (57%) was higher than the expected frequency (≤1%) in the feline population (Fisher Exact test, p < 0.01). Among wildtype cats, four were concurrently treated with potential competitive inhibitors of P-glycoprotein. Results indicate that topical eprinomectin products, should be avoided in cats homozygous for ABCB11930_1931delTC. This is a serious, preventable adverse event occurring in an identifiable subpopulation treated with FDA-approved products in accordance with label directions. Acquired P-glycoprotein deficiency resulting from drug interactions may enhance susceptibility to eprinomectin-induced neurological toxicosis in any cat, regardless of ABCB1 genotype.

A pilot study investigating plasma pharmacokinetics and tolerance of oral capecitabine in carcinoma-bearing dogs.

BACKGROUND: Capecitabine is an oral prodrug of the active metabolite 5-fluorouracil, which has been used effectively in human colorectal, head and neck, and mammary carcinomas. Capecitabine has several properties that make it an attractive treatment option for dogs: (i) it is relatively inexpensive, (ii) it has a short half-life in humans, allowing for rapid plasma concentration changes to be achieved with dosage adjustments, (iii) it is effective for treating carcinomas in humans, for which there are no widely-effective oral chemotherapy options in dogs, and (iv) it is thought to preferentially target cancer cells due to different expression of thymidine phosphorylase, thereby decreasing the risk of off-target side effects. However, capecitabine has not been widely explored as a chemotherapy agent for dogs. The goal of this study was to determine the plasma disposition of capecitabine in dogs following a single oral dose and to document any adverse events associated with capecitabine administration over the course of 5 weeks. RESULTS: Capecitabine was well tolerated throughout the 5-week study period when administered to 5 dogs with naturally occurring carcinomas at 750 mg/m[Formula: see text] by mouth once daily for 14 consecutive days in a 3-week cycle. No dogs withdrew from the study due to adverse events or other causes. The median AUC[Formula: see text] was 890 h[Formula: see text]ng/ml (range 750-1100 h[Formula: see text]ng/ml); however, the maximum blood concentration and time to reach that concentration of capecitabine was highly variable after a single dose. CONCLUSIONS: Capecitabine appears well-tolerated as an oral chemotherapy agent for dogs with carcinomas, although individualized dosing may be necessary, and further studies are warranted.

Pharmacokinetics of acetaminophen after a single Oral administration of 20 or 40 mg/kg to 7-9 Day-old foals.

Background: Acetaminophen is utilized in human infants for pain management and fever. Neonatal foals might benefit from administration of acetaminophen but effective and safe dosage regimens for neonatal foals remains to be determined. Objective: The objective was to determine the plasma pharmacokinetics of acetaminophen following oral administration of a single dose of 20 mg/kg or 40 mg/kg to neonatal foals. A secondary objective was to evaluate any changes in hematology and biochemistry profiles. Study design: Randomized study. Methods: Eight clinically healthy 7-9-day old Quarter Horse foals (3 colts and 5 fillies) received a single oral dose of acetaminophen either 20 (n = 4) or 40 (n = 4) mg/kg. Hematology and biochemistry profiles were evaluated before and 7 days after drug administration. Blood samples were collected before and 8 times after acetaminophen administration for 48 h to quantify plasma acetaminophen concentrations. Plasma pharmacokinetic parameters were estimated using non- compartmental analysis. Results: The median peak plasma concentrations (and range) occurred at 1.5 (0.5-2) hours, and 1.0 (1-2) hours for the 20 and 40 mg/kg doses. The maximum plasma concentration (and range) was 12 (7.9-17.4) µg/mL for the 20 mg/kg dose and 14 (11-18) µg/mL for 40 mg/kg dose. The median AUC0-∞ ranged from 46 to 100 and 79 to 160 h*-µg/mL for the 20 and 40 mg/kg dose, respectively. Hematology and biochemistry profiles remained within normal limits. Conclusion: Plasma disposition of acetaminophen after oral administration of 20 and 40 mg/kg to neonates is comparable to adult horses. However, safety and the optimal dosage regimen of acetaminophen for treating pain and or pyrexia in neonates in this age group remains to be determined.

Pharmacokinetics of multiple oral doses of acetaminophen in equine neonates.

OBJECTIVE: To determine the pharmacokinetics and clinical safety of acetaminophen after oral administration of 40 mg/kg q 12 hours or 60 mg/kg q 24 hours for 14 days. ANIMALS: 12 healthy light-breed neonatal foals. PROCEDURES: 6 foals received acetaminophen at 40 mg/kg q 12 hours and 6 foals received 60 mg/kg q 24 hours for 14 days. The study dates were January 31 to April 15, 2023. Physical examinations were performed daily. Plasma disposition of acetaminophen was determined after the first, mid-point drug administration. Hematology and biochemistry analysis was performed before the study, day 7, and the last day of drug administration. Plasma acetaminophen concentrations were determined by high-performance liquid chromatography. Plasma pharmacokinetic parameters were estimated using noncompartmental analysis. RESULTS: No statistically significant changes occurred on hematology or biochemistry profiles. Elevations in γ-glutamyl transferase (GGT) and sorbitol dehydrogenase (SDH) were noted in 4 foals at various time points. The maximum plasma concentration (Cmax) occurred within 2 hours for both doses. The 60 mg/kg dose resulted in a larger median Cmax (range) at 28 µg/mL (22-32) than the 40 mg/kg dose at 23 µg/mL (19-27). The median area under the concentration-vs-time curve from 0 to 8 hours (AUC0-8 hour [range]) was 100 h•µg/mL (82-100) at 40 mg/kg and 128 h•µg/mL (120-168) for 60 mg/kg. Trough concentrations decreased over time for both regimens. CLINICAL RELEVANCE: Foals tolerate oral acetaminophen at 40 mg/kg q 12 hours or 60 mg/kg q 24 hours. Further analgesic and antipyretic studies will help to delineate optimal dosage regimens of acetaminophen to treat foals.

Pharmacokinetics of single dose administration of three increasing doses of acetaminophen per os in 1-3-month-old foals.

BACKGROUND: Acetaminophen is a common analgesic and antipyretic drug used in human medicine and might be an alternative to nonsteroidal anti-inflammatory drugs for treating pain and pyrexia in foals. The pharmacokinetics and safety of differing doses of acetaminophen have not been investigated in foals. OBJECTIVES: To determine the plasma pharmacokinetics and any changes in haematology and biochemistry profiles following oral administration of single doses of acetaminophen at 10, 20, and 40 mg/kg to foals. STUDY DESIGN: Randomised cross-over pharmacokinetic study. METHODS: Six Quarter Horse (two colts and four fillies) foals received 10, 20, and 40 mg/kg acetaminophen orally once. Haematology and biochemistry profiles were performed before and 7 days after each drug administration. Blood samples were collected over 64 h after drug administration and were used to quantify plasma acetaminophen concentrations by liquid chromatography. Pharmacokinetic parameters were determined using compartmental analysis. RESULTS: Median (range) acetaminophen plasma concentrations were 4.4 (1.8-5.1), 6.3 (2.6-12.6), and 14 (7.3-18) µg/ml for the 10, 20, and 40 mg/kg doses, respectively. Median acetaminophen area under the concentration versus time curve (AUC)0-∞ ranged from 25 (11-32), 41 (22-74), and 105 (82-142) h × µg/ml for the 10, 20, and 40 mg/kg doses, respectively. Dose-normalised maximal concentrations and AUC0-∞ values were similar across dose concentrations (p > 0.05). Median terminal half-life for all doses was 2.7-2.8 h. Haematology and biochemistry profiles were normal except for blood urea nitrogen and alkaline phosphatase concentrations. MAIN LIMITATIONS: Foals were growing throughout the study, starting at 1 month and ending at 3 months. Deposition of drugs changes with age. The sample size was small and only single doses were evaluated. No liver biopsies were performed. CONCLUSION: Plasma disposition of acetaminophen after a single oral dose of 10, 20, and 40 mg/kg to 1-3-month-old foals varies greatly with the dose. The analgesic and antipyretic effect in foals is unknown.

INTRODUCTION/CONTEXTE: L'acétaminophène est un médicament analgésique et antipyrétique utilisé communément en médecine humaine. Il pourrait représenter une alternative aux médicaments anti-inflammatoires non-stéroïdiens pour le traitement de la douleur et de la fièvre chez les poulains. La pharmacocinétique et la sécurité de différentes doses d'acétaminophène n'ont pas encore été investigués chez les poulains. OBJECTIFS: Déterminer la pharmacocinétique et les modifications aux profils hématologique et biochimique suivant l'administration orale d'une dose singulière d'acétaminophène à 10, 20 ou 40 mg/kg chez des poulains. TYPE D'ÉTUDE: Étude de pharmacocinétique croisée aléatoire. MÉTHODES: Six chevaux Quarter Horse (2 poulains mâles et 4 femelles) ont reçu 10, 20 et 40 mg/kg d'acétaminophène oralement à une reprise. Les profils hématologique et biochimique ont été analysés avant et 7 jours suivant chaque administration. Les échantillons sanguins ont été récoltés plus de 64 heures après l'administration de la médication et ont été utilisés pour quantifier les concentrations plasmatiques d'acétaminophène par chromatographie liquide. Les paramètres pharmacocinétiques ont été déterminés par analyse compartimentale. RÉSULTATS: Les concentrations plasmatiques médianes d'acétaminophène étaient de 4.4 (1.8-5.1), 6.3 (2.6-12.6), et 14 (7.3-18 ug/mL) pour les doses de 10, 20 et 40 mg/kg respectivement. L'aire sous la courbe médiane pour la concentration versus le temps de l'acétaminophène était de 25 (11-32), 41 (22-74) et 105 (82-142)h*ug/mL pour les doses de 10, 20 et 40 mg/kg respectivement. Les concentrations maximales à doses normalisées et les valeurs AUC0-∞ étaient similaires entre les concentrations des doses (p < 0.05). La demi-vie terminale médiane pour toutes les doses était 2.7-2.8 heures. Les profils hématologique et biochimique étaient normaux, à l'exception des concentrations d'azote uréique sanguine et de phosphatase alcaline. LIMITES PRINCIPALES: Les poulains ont grandi durant l'étude, débutant à 1 mois et se terminant à 3 mois d'âge. La déposition des médicaments varie avec l'âge. La taille de l'échantillon était petit et des doses singulières seulement ont été évaluées. Aucune biopsie de foie n'a été recueillie. CONCLUSIONS: Le sort plasmatique de l'acétaminophène suivant une dose singulière de 10, 20 ou 40 mg/kg chez des poulains de 1-3 mois d'âge varie grandement selon la dose. Les effets analgésique et antipyrétique de l'acétaminophène chez les poulains demeurent inconnus.

Gross, computed tomographic, and endoscopic anatomy of the equine carpal extensor tendon sheaths.

OBJECTIVE: (1) To describe the computed tomography (CT) and gross anatomy of the equine extensor carpi radialis sheath (ECRS) and common digital extensor sheath (CDETS); (2) to describe a single-portal endoscopic examination of the ECRS and CDETS. STUDY DESIGN: Ex vivo experimental. SAMPLE POPULATION: Thirty clinically normal cadaver thoracic equine limbs severed at the humeral diaphysis. METHODS: Ten limbs underwent plain and intrathecal contrast CT examinations and gross dissection of the ECRS and CDETS. Single-portal endoscopic examination of ECRS and CDETS was attempted in 4 limbs and endoscopic examination was performed on 16 limbs. Endoscopic video recordings were reviewed by 3 observers for quality of visualization before dissection and examination for iatrogenic damage. Interobserver agreement for ECRS and CDETS visualization was determined with Fleiss' κ agreement. RESULTS: Extensor carpi radialis sheath and CDETS anatomy was consistent between gross dissection and CT examinations. The ECRS endoscopic portal was medial at the level of the intersection between the extensor carpi obliquus and extensor carpi radialis tendon. The CDETS endoscopic portal was lateral, 5 cm proximal to the lateral styloid process of the ulna. The ECRS and CDETS were well visualized and interobserver agreement was substantial (κ = .73; P < .0001) and moderate (κ = .53; P < .0001), respectively. CONCLUSION: Computed tomography examinations provided useful anatomical information, consistent with gross dissection of the ECRS and CDETS. The described single-portal endoscopic techniques allowed consistent tenoscopic examination of the majority of the ECRS and CDETS. CLINICAL SIGNIFICANCE: Awareness of the intrathecal anatomy of the ECRS and CDETS should facilitate the treatment of these tendon sheaths. The proposed portals provide good to excellent single-site endoscopic visualization of the majority of the ECRS and CDETS.

Applying metabolomics to veterinary pharmacology and therapeutics.

Metabolomics is the large-scale study of low-molecular-weight substances in a biological system in a given physiological state at a given time point. Metabolomics can be applied to identify predictors of inter-individual variability in drug response, provide clinicians with data useful for decision-making processes in drug selection, and inform about the pharmacokinetics and pharmacodynamics of a drug. It is, therefore, an exceptional approach for gaining new understanding effects in the field of comparative veterinary pharmacology. However, the incorporation of metabolomics into veterinary pharmacology and toxicology is not yet widespread, and this is probably, at least in part, a result of its highly multidisciplinary nature. This article reviews the potential applications of metabolomics in veterinary pharmacology and therapeutics. It integrates key concepts for designing metabolomics studies and analyzing and interpreting metabolomics data, providing solid foundations for applying metabolomics to the study of drugs in all veterinary species.

Canine orosomucoid (alpha-1 acid glycoprotein) variants and their influence on drug plasma protein binding.

Orosomucoid polymorphisms influence plasma drug binding in humans; however, canine variants and their effect on drug plasma protein binding have not yet been reported. In this study, the orosomucoid gene (ORM1) was sequenced in 100 dogs to identify the most common variant and its allele frequency determined in 1,464 dogs (from 64 breeds and mixed-breed dogs). Plasma protein binding extent of amitriptyline, indinavir, verapamil, and lidocaine were evaluated by equilibrium dialysis using plasma from ORM1 genotyped dogs (n = 12). Free and total drug plasma concentrations were quantified by liquid chromatography-mass spectrometry. From the five polymorphisms identified in canine ORM1, two were nonsynonymous. The most common was c.70G>A (p.Ala24Thr) with an allele frequency of 11.2% (n = 1464). Variant allele frequencies varied by breed, reaching 74% in Shetland Sheepdogs (n = 21). Free drug fractions did not differ significantly (p > .05; Mann-Whitney U) between plasma collected from dogs with c.70AA (n = 4) and those with c.70GG (n = 8) genotypes. While c.70G>A did not affect the extent of plasma protein binding in our study, the potential biological and pharmacological implication of this newly discovered ORM1 variant in dogs should be further investigated.

Plasmodium Impairs Antibacterial Innate Immunity to Systemic Infections in Part Through Hemozoin-Bound Bioactive Molecules.

One complication of malaria is increased susceptibility to invasive bacterial infections. Plasmodium infections impair host immunity to non-Typhoid Salmonella (NTS) through heme-oxygenase I (HO-I)-induced release of immature granulocytes and myeloid cell-derived IL-10. Yet, it is not known if these mechanisms are specific to NTS. We show here, that Plasmodium yoelii 17XNL (Py) infected mice had impaired clearance of systemic Listeria monocytogenes (Lm) during both acute parasitemia and up to 2 months after clearance of Py infected red blood cells that was independent of HO-I and IL-10. Py-infected mice were also susceptible to Streptococcus pneumoniae (Sp) bacteremia, a common malaria-bacteria co-infection, with higher blood and spleen bacterial burdens and decreased survival compared to naïve mice. Mechanistically, impaired immunity to Sp was independent of HO-I, but was dependent on Py-induced IL-10. Splenic phagocytes from Py infected mice exhibit an impaired ability to restrict growth of intracellular Lm, and neutrophils from Py-infected mice produce less reactive oxygen species (ROS) in response to Lm or Sp. Analysis also identified a defect in a serum component in Py-infected mice that contributes to reduced production of ROS in response to Sp. Finally, treating naïve mice with Plasmodium-derived hemozoin containing naturally bound bioactive molecules, excluding DNA, impaired clearance of Lm. Collectively, we have demonstrated that Plasmodium infection impairs host immunity to diverse bacteria, including S. pneumoniae, through multiple effects on innate immunity, and that a parasite-specific factor (Hz+bound bioactive molecules) directly contributes to Plasmodium-induced suppression of antibacterial innate immunity.

Pharmacometabolomics with a combination of PLS-DA and random forest algorithm analyses reveal meloxicam alters feline plasma metabolite profiles.

Repeated administration of meloxicam to cats is often limited by the potential damage to multiple organ systems. Identifying molecules that predict the adverse effects of meloxicam would help to monitor and individualize its administration, maximizing meloxicam's beneficial effects. The objectives of this study were to (a) determine if the repeated administration of meloxicam to cats alters the plasma metabolome and (b) identify plasma metabolites that may serve to monitor during the administration of meloxicam in cats. Purpose bred young adult cats (n = 12) were treated with meloxicam at 0.3 mg/kg or saline subcutaneously once daily for up to 17 days. An untargeted metabolomics approach was applied to plasma samples collected prior to and at designated time points after meloxicam or saline administration. To refine the discovery of biomarkers, the machine-learning algorithms, partial least squares discriminant analysis (PLS-DA) and random forest (RF), were trained and validated using a separate unrelated group of meloxicam- and saline-treated cats (n = 8). A total of 74 metabolites were included in the statistical analysis. Metabolomic analysis shows that the repeated administration of meloxicam alters multiple substances in plasma, including nonvolatile organic acids, aromatic amino acids, monosaccharides, and inorganic compounds as early as four days following administration of meloxicam. Seventeen plasma molecules were able to distinguish meloxicam-treated from saline-treated cats. The metabolomic changes discovered in this study may help to unveil unknown mechanisms of NSAID-induced side effects. In addition, some metabolites could be valuable for individualizing the administration of meloxicam to cats to mitigate adverse effects.

Concentration of dipotassium ethylenediaminetetraacetic acid but not lithium heparin affects total protein determination in equine synovial fluid.

BACKGROUND: Refractometric determination of total protein (TP) in synovial fluid (SF) is commonly used for diagnosis and monitoring of synovial sepsis in horses. Previous studies have shown that elevated concentrations of certain anticoagulants may overestimate refractometric determination of TP concentration. OBJECTIVES: The aim of the study was to evaluate the effect of different concentrations of dipotassium EDTA (K2EDTA) and lithium heparin (LH) on TP determination by using a hand-held refractometer in equine synovial fluid. STUDY DESIGN: Cross-section observational study. METHODS: Thirty samples of synovial fluid obtained from 22 horses with different synovial conditions were collected. Synovial fluid samples were separated into different aliquots and placed in commercially available collection tubes containing K2EDTA or LH at four different concentrations (1.76, 3.52, 7.04 and 17.6 mg/ml for K2EDTA; 16, 32, 64 and 160 IU/ml for LH) . Refractometric TP determination was performed on untreated and K2EDTA and LH aliquots with a hand-held refractometer and by spectophotometric Biuret method as the gold standard. RESULTS: Refractometric TP determination was overestimated in SF samples containing 10 times the recommended K2EDTA concentrations. Lower concentrations of K2EDTA and LH concentrations did not affect refractometric TP determinations. MAIN LIMITATIONS: Limited number of samples mostly obtained from large synovial structures. CONCLUSION: To avoid incorrect TP determination, the use of LH containing collection tubes may be an appropriate alternative when the SF volume available is not enough to fill the K2EDTA collection tube.

Can blood serum amyloid A concentrations in horses differentiate synovial sepsis from extrasynovial inflammation and determine response to treatment?

BACKGROUND: Serum amyloid A (SAA) concentrations in blood and synovial fluid of horses with synovial sepsis have diagnostic value. Studies suggest serial blood SAA measurements could act as a prognostic indicator. This study evaluated the use of serial blood SAA concentrations for monitoring of horses with synovial sepsis. METHODS: A prospective clinical trial was performed of horses referred to a single hospital with synovial sepsis that survived (n=17), synovial sepsis that were euthanised (n=5), non-septic intrasynovial pathologies (n=14) or extensive extrasynovial lacerations (n=5). SAA concentrations were determined on admission and every 24 hours thereafter. The area under the concentration-time curve from 0 to 144 hours of each group was compared by Kruskal-Wallis and post hoc Dunn's tests (P<0.05). RESULTS: Significant difference in mean blood concentration of SAA was found between synovial sepsis that survived and non-septic pathologies in the first 48 hours, as well as between non-septic intrasynovial pathologies and non-responsive sepsis requiring euthanasia. No difference was found between extensive extrasynovial lacerations and any septic group. CONCLUSIONS: While serial blood SAA is useful for monitoring clinical response of intrasynovial septic pathologies, interpretation should consider other clinical findings since blood SAA is not a specific marker for synovial sepsis.

Urinary chemical fingerprint left behind by repeated NSAID administration: Discovery of putative biomarkers using artificial intelligence.

Prediction and early detection of kidney damage induced by nonsteroidal anti-inflammatories (NSAIDs) would provide the best chances of maximizing the anti-inflammatory effects while minimizing the risk of kidney damage. Unfortunately, biomarkers for detecting NSAID-induced kidney damage in cats remain to be discovered. To identify potential urinary biomarkers for monitoring NSAID-based treatments, we applied an untargeted metabolomics approach to urine collected from cats treated repeatedly with meloxicam or saline for up to 17 days. Applying multivariate analysis, this study identified a panel of seven metabolites that discriminate meloxicam treated from saline treated cats. Combining artificial intelligence machine learning algorithms and an independent testing urinary metabolome data set from cats with meloxicam-induced kidney damage, a panel of metabolites was identified and validated. The panel of metabolites including tryptophan, tyrosine, taurine, threonic acid, pseudouridine, xylitol and lyxitol, successfully distinguish meloxicam-treated and saline-treated cats with up to 75-100% sensitivity and specificity. This panel of urinary metabolites may prove a useful and non-invasive diagnostic tool for monitoring potential NSAID induced kidney injury in feline patients and may act as the framework for identifying urine biomarkers of NSAID induced injury in other species.

Plasma disposition of gabapentin after the intragastric administration of escalating doses to adult horses.

BACKGROUND: In humans, gabapentin an analgesic, undergoes non-proportional pharmacokinetics which can alter efficacy. No information exists on the pharmacokinetics of dosages >20 mg/kg, escalating dosages or dose proportionality of gabapentin in horses. HYPOTHESIS AND OBJECTIVES: Gabapentin exposure in plasma would not increase proportionally relative to the dose in horses receiving dosages ≥20 mg/kg. To assess the plasma pharmacokinetics of gabapentin after nasogastric administration of gabapentin at dosages of 10 to 160 mg/kg in adult horses. ANIMALS: Nine clinically healthy adult Arabian and Quarter Horses. METHODS: In a randomized blinded trial, gabapentin was administered by nasogastric intubation to horses at 10, 20 mg/kg (n = 3) and 60, 80, 120, 160 mg/kg (n = 6). Plasma was collected before and at regular times over 64 hours after administration of gabapentin. Gabapentin was quantified using a validated chromatographic method. Dose proportionality was estimated using a power model. Pharmacokinetic parameters were estimated using compartmental pharmacokinetic analysis. RESULTS: Plasma pharmacokinetics parameters of gabapentin were estimated after nasogastric administration at dosages of 10 to 160 mg/kg. Gabapentin plasma concentration increased with dose increments. However, the area under the concentration curve from zero to infinity and maximal plasma concentration did not increase proportionally relative to the dose in horses. CONCLUSIONS AND CLINICAL IMPORTANCE: Gabapentin exposure in plasma is not proportional relative to the dose in horses receiving nasogastric dosages of 10 to 160 mg/kg.

Canine Albumin Polymorphisms and Their Impact on Drug Plasma Protein Binding.

Drug binding to plasma proteins is routinely determined during drug development. Albumin polymorphisms c.1075G>T (p.Ala359Ser) and c.1422A>T (p.Glu474Asp) were previously shown to alter plasma protein binding of a drug candidate (D01-4582, 4-[1-[3-chloro-4-[N'-(2-methylphenyl)ureido]phenylacetyl]-(4S)-fluoro-(2S)-pyrrolidine-2-yl]methoxybenzoic acid) in a colony of Beagles. Our study investigated the hypothesis that drug-protein binding in plasma from dogs with the albumin H1 (reference) allele would be greater than in plasma from dogs with the albumin H2 allele (c.1075G>T and c.1422A>T) (n = 6 per group). The plasma protein binding extent of four drugs (D01-4582, celecoxib, mycophenolic acid, and meloxicam) was evaluated using ultracentrifugation or equilibrium dialysis. Free and total drug concentrations were analyzed by liquid chromatography-mass spectrometry. The albumin gene coding region was sequenced in 100 dogs to detect novel gene variants, and H1/H2 allele frequency was determined in a large and varied population (n = 1446 from 61 breeds and mixed-breed dogs). For meloxicam, H1 allele plasma had statistically significant higher free drug fractions (P = 0.041) than H2 allele plasma. No significant difference was identified for plasma protein binding of D01-4582, celecoxib, or mycophenolic acid. c.1075G>T and c.1422A>T were the most common single nucleotide polymorphisms in canine albumin, present concurrently in most study dogs and occasionally identified independently. Our findings suggest a potential influence of c.1075G>T and c.1422A>T on plasma protein binding. This influence should be confirmed in vivo and for additional drugs. Based on our results, albumin genotyping should be considered for canine research subjects to improve interpretation of pharmacokinetic data generated during the drug development process for humans and dogs.

Pharmacokinetics of mycophenolic acid and its effect on CD4+ and CD8+ T cells after oral administration of mycophenolate mofetil to healthy cats.

BACKGROUND: Mycophenolate mofetil (MMF) is an immunosuppressant used in human and veterinary medicine. Little pharmacokinetic and pharmacodynamic information on MMF is available in cats. OBJECTIVE: To evaluate the plasma disposition of mycophenolic acid (MPA) and assess its effect on total peripheral blood mononuclear cells and CD4+ /CD8+ ratios after PO administration of MMF. ANIMALS: Healthy cats (n = 10). METHODS: Mycophenolate mofetil was administered at a dosage of 10 mg/kg q12h (n = 3), 15 mg/kg q12h (n = 3), and 15 mg/kg q8h (n = 4) for 7 days. Concentrations of MPA and derivatives were determined using ultra-high-performance liquid chromatography. Flow cytometry was used to assess CD4+ /CD8+ T-cell ratios. RESULTS: All cats biotransformed MMF into MPA. Half of the cats (5/10) had adverse effects within 1 week of MMF administration. Area under the curve limit of quantification (AUC0-LOQh ) of MPA ranged from 1.27 to 2.03 hours·µg/mL and from 1.77 to 8.54 hours·µg/mL after the first and last PO dose of 10 mg/kg. The AUC0-loqh of MPA ranged from 2.18 to 31 hours·µg/mL after the first dose of 15 mg/kg of MMF. Before the first dose of MMF, the average total number of PBMC ranged from 1.2 to 9.3 million/mL. At the last dose of MMF, the average total number of PBMC ranged from 3 to 5 million/mL. CONCLUSION: Mycophenolic acid was detected in all cats. The dose 10 mg/kg given q12h for 1 week was tolerated (n = 3). The efficacy of MMF as an immunosuppressant and long-term safety in cats of this dosage regimen is unknown.

Understanding the effect of repeated administration of meloxicam on feline renal cortex and medulla: A lipidomics and metabolomics approach.

Repeated administration of meloxicam can cause kidney damage in cats by mechanisms that remain unclear. Metabolomics and lipidomics are powerful, noninvasive approaches used to investigate tissue response to drug exposure. Thus, the objective of this study was to assess the effects of meloxicam on the feline kidney using untargeted metabolomics and lipidomics approaches. Female young-adult purpose-breed cats were allocated into the control (n = 4) and meloxicam (n = 4) groups. Cats in the control and meloxicam groups were treated daily with saline and meloxicam at 0.3 mg/kg subcutaneously for 17 days, respectively. Renal cortices and medullas were collected at the end of the treatment period. Random forest and metabolic pathway analyses were used to identify metabolites that discriminate meloxicam-treated from saline-treated cats and to identify disturbed metabolic pathways in renal tissue. Our results revealed that the repeated administration of meloxicam to cats altered the kidney metabolome and lipidome and suggest that at least 40 metabolic pathways were altered in the renal cortex and medulla. These metabolic pathways included lipid, amino acid, carbohydrate, nucleotide and energy metabolisms, and metabolism of cofactors and vitamins. This is the first study using a pharmacometabonomics approach for studying the molecular effects of meloxicam on feline kidneys.

Personalized medicine: going to the dogs?

Interindividual variation in drug response occurs in canine patients just as it does in human patients. Although canine pharmacogenetics still lags behind human pharmacogenetics, significant life-saving discoveries in the field have been made over the last 20 years, but much remains to be done. This article summarizes the available published data about the presence and impact of genetic polymorphisms on canine drug transporters, drug-metabolizing enzymes, drug receptors/targets, and plasma protein binding while comparing them to their human counterparts when applicable. In addition, precision medicine in cancer treatment as an application of canine pharmacogenetics and pertinent considerations for canine pharmacogenetics testing is reviewed. The field is poised to transition from single pharmacogene-based studies, pharmacogenetics, to pharmacogenomic-based studies to enhance our understanding of interindividual variation of drug response in dogs. Advances made in the field of canine pharmacogenetics will not only improve the health and well-being of dogs and dog breeds, but may provide insight into individual drug efficacy and toxicity in human patients as well.