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Objective: The objective of this study was to satisfy the US FDA's Center for Devices and Radiological Health regarding the safety of targeted osmotic lysis (TOL), a novel treatment for advanced carcinomas, in Beagle dogs., Methods: 12 intact Beagle dogs, 6 males and 6 females, were divided into 2 treatment groups of 6, each receiving 3 TOL cycles. For each 6-day cycle, digoxin was administered orally at 0.007 mg/kg q 12 h X 6 days to achieve steady-state plasma concentrations. On days 5 and 6 of each cycle, the animals were exposed to pulsed electric field (PEF) stimulation at a field strength of either 18 or 40 V/min for 2 hours. Following the completion of cycles 1 and 2, animals were observed for 7 days. On the day following the end of cycle 3, the animals were euthanized. A complete macroscopic examination was performed, and tissues were collected for microscopic examination., Results: As there were no concurrent untreated control animals, only qualitative comparisons were performed to assess potential differences between group 1, which received the digoxin plus 18 V/min PEF, and group 2, which received digoxin plus 40 V/min PEF. No adverse events related to TOL exposure were observed in either group., Conclusions: Neither group demonstrated gross or microscopic lesions following 3 rounds of exposure to TOL., Clinical Relevance: Due to the lack of toxicity noted in the treated animals, TOL warrants consideration as either a standalone treatment option or as an adjunct to surgery or chemotherapy for managing malignant cancer.

In the United States, a generic Type A medicated article product can gain the FDA approval by demonstrating bioequivalence (BE) to the pioneer product by successfully conducting a blood level, pharmacodynamic, or clinical BE study. A biowaiver can be granted based on several criteria, assuming the dissolution of the test and reference products represents the only factor influencing the relative bioavailability of both products. Monensin is practically insoluble in H 2 O per the USP definition. Previously published data from a comparison study of monensin dissolution profiles from the pioneer product and four generic products using biorelevant media showed that generic monensin products demonstrated different dissolution profiles to the pioneer product in these USP biorelevant rumen media. This follow-up study compared the solubility profiles in simulated intestinal fluid (cFaSSIF, pH 7.5) for the pioneer product and four generic products. The generic monensin products demonstrated different in vitro dissolution profiles to the pioneer product in biorelevant media. The differences demonstrated in solubility and dissolution profiles are of concern regarding the potential efficacy of generic monensin in cattle. There are also additional concerns for the potential development of Eimeria resistance in cattle receiving a sub-therapeutic dose of monensin from a less soluble generic product., (© 2024 John Wiley & Sons Ltd.)

Background: Global plastic use has consistently increased over the past century with several different types of plastics now being produced. Much of these plastics end up in oceans or landfills leading to a substantial accumulation of plastics in the environment. Plastic debris slowly degrades into microplastics (MPs) that can ultimately be inhaled or ingested by both animals and humans. A growing body of evidence indicates that MPs can cross the gut barrier and enter into the lymphatic and systemic circulation leading to accumulation in tissues such as the lungs, liver, kidney, and brain. The impacts of mixed MPs exposure on tissue function through metabolism remains largely unexplored., Objectives: This study aims to investigate the impacts of polymer microspheres on tissue metabolism in mice by assessing the microspheres ability to translocate across the gut barrier and enter into systemic circulation. Specifically, we wanted to examine microsphere accumulation in different organ systems, identify concentration-dependent metabolic changes, and evaluate the effects of mixed microsphere exposures on health outcomes., Methods: To investigate the impact of ingested microspheres on target metabolic pathways, mice were exposed to either polystyrene ( 5 μ m ) microspheres or a mixture of polymer microspheres consisting of polystyrene ( 5 μ m ), polyethylene ( 1 - 4 μ m ), and the biodegradability and biocompatible plastic, poly-(lactic-co-glycolic acid) ( 5 μ m ). Exposures were performed twice a week for 4 weeks at a concentration of either 0, 2, or 4 mg / week via oral gastric gavage. Tissues were collected to examine microsphere ingress and changes in metabolites., Results: In mice that ingested microspheres, we detected polystyrene microspheres in distant tissues including the brain, liver, and kidney. Additionally, we report on the metabolic differences that occurred in the colon, liver, and brain, which showed differential responses that were dependent on concentration and type of microsphere exposure., Discussion: This study uses a mouse model to provide critical insight into the potential health implications of the pervasive issue of plastic pollution. These findings demonstrate that orally consumed polystyrene or mixed polymer microspheres can accumulate in tissues such as the brain, liver, and kidney. Furthermore, this study highlights concentration-dependent and polymer type-specific metabolic changes in the colon, liver, and brain after plastic microsphere exposure. These results underline the mobility within and between biological tissues of MPs after exposure and emphasize the importance of understanding their metabolic impact. https://doi.org/10.1289/EHP13435.

This study evaluated four different formulations of itraconazole and amiodarone. Formulation 1 was Vida's combination tablet containing both active pharmaceutical ingredients (APIs). Formulation 2 was separate, commercially available human generic capsules and tablets of itraconazole and amiodarone, respectively. Formulation 3 was separate, compounded suspensions of itraconazole and amiodarone. Formulation 4 was a compounded chewable tablet of itraconazole. Eight female dogs were dosed with 5 mg/kg of itraconazole and 15 mg/kg amiodarone (except for formulation 4, which only received 5 mg/kg itraconazole) once weekly for 4 weeks using a modified Latin Square design, ensuring that all dogs received all formulations with a 7-day washout between treatments. Animals were fasted overnight prior to each dose administration, with food returned to all animals 4 h post-dose. Blood samples (3 mL) were collected pre-treatment (0) and at appropriate time points over 72 h after each dose for a total of 14 samples per dog per treatment. There was high variability in the serum concentration data within treatment groups for itraconazole. The compounded suspensions were difficult to dose due to the nature of the formulations. The volumes dosed were accurate and consistent, but the suspension was thin and settled immediately when shaking was stopped for both itraconazole and amiodarone. All serum samples following itraconazole chewable tablet administration were not detectable or just above itraconazole's LOQ and thus did not allow for pharmacokinetic determination., (© 2023 John Wiley & Sons Ltd.)

Alzheimer disease (AD) is the leading cause of dementia among older adults. Current AD treatment options are limited, and the absence of appropriate research animals has significantly hindered the development of new AD therapies. Canine cognitive decline (CCD) is a major determinant of morbidity in older animals, with alterations in blood biomarkers, neuropathology, physiology, and behavior comparable to those seen in humans diagnosed with dementia and AD. The one-health goal of achieving optimal health is supported by academics, researchers, and governments. Veterinarians' ability to identify patients in the early stages of CCD is crucial to the successful implementation of interventions that can improve the quality of life of affected dogs. Timely identification of CCD also opens opportunities for innovative interdisciplinary research that will contribute to a better understanding of the underlying mechanisms, early detection, and effective treatments for AD, ultimately benefiting human health as well. Until now, veterinary practitioners have played limited roles as interdisciplinary leaders in the One Health initiative to combat disease. The authors discuss how client-owned animals with spontaneous, naturally occurring CCD can play a significant role as disease-relevant surrogates for translational AD research. The proposed Dogs Overcoming Geriatric Memory and Aging (DOGMA) Study to be conducted in veterinary practices will analyze the relationship between blood biomarkers and biometric behavior in mature and older dogs, with the aim of establishing benchmark CCD data. The DOGMA Study is addressed in the companion Currents in One Health by Hunter et al, AJVR, November 2023.

Treatment options for human dementia remain limited, and additional research is needed to develop and validate translational models. Canine cognitive decline (CCD) is common in older dogs and a major source of morbidity. The decline includes physiological and behavioral changes comparable to those in humans diagnosed with dementia. There are also corresponding changes in plasma neurodegenerative biomarkers and neuropathology. Biomarkers for both human and canine cognitive decline can be used to identify and quantify the onset of behavioral data suggestive of CCD. Successful correlations would provide reference values for the early identification of neurodegeneration in canine patients. This could allow for the subsequent testing of interventions directed at ameliorating CCD and offer translational value leading to safe and effective treatment of dementia in people. Research can help exploit, track, and provide benefits from the rapid progression of spontaneous naturally occurring CCD in a large heterogenous community of companion dogs. Research efforts should work to deliver information using blood biomarkers, comorbidities, and wearable technologies to track and evaluate biometric data associated with neurodegeneration and cognitive decline that can be used by both human and companion animal researchers. The synergistic approach between human and veterinary medicine epitomized in one health underscores the interconnectedness of the well-being of both species. Leveraging the insights gained from studying CCD can not only lead to innovative interventions for pets but will also shed light on the complex mechanisms of human dementia.

Smoke from wildland fires has been shown to produce neuroinflammation in preclinical models, characterized by neural infiltrations of neutrophils and monocytes, as well as altered neurovascular endothelial phenotypes. To address the longevity of such outcomes, the present study examined the temporal dynamics of neuroinflammation and metabolomics after inhalation exposures from biomass-derived smoke. 2-month-old female C57BL/6 J mice were exposed to wood smoke every other day for 2 weeks at an average exposure concentration of 0.5 mg/m 3 . Subsequent serial euthanasia occurred at 1-, 3-, 7-, 14-, and 28-day post-exposure. Flow cytometry of right hemispheres revealed two endothelial populations of CD31 Hi and CD31 Med expressors, with wood smoke inhalation causing an increased proportion of CD31 Hi . These populations of CD31 Hi and CD31 Med were associated with an anti-inflammatory and pro-inflammatory response, respectively, and their inflammatory profiles were largely resolved by the 28-day mark. However, activated microglial populations (CD11b + /CD45 low ) remained higher in wood smoke-exposed mice than controls at day 28. Infiltrating neutrophil populations decreased to levels below controls by day 28. However, the MHC-II expression of the peripheral immune infiltrate remained high, and the population of neutrophils retained an increased expression of CD45, Ly6C, and MHC-II. Utilizing an unbiased approach examining the metabolomic alterations, we observed notable hippocampal perturbations in neurotransmitter and signaling molecules, such as glutamate, quinolinic acid, and 5-α-dihydroprogesterone. Utilizing a targeted panel designed to explore the aging-associated NAD + metabolic pathway, wood smoke exposure drove fluctuations and compensations across the 28-day time course, ending with decreased hippocampal NAD + abundance on day 28. Summarily, these results indicate a highly dynamic neuroinflammatory environment, with potential resolution extending past 28 days, the implications of which may include long-term behavioral changes, systemic and neurological sequalae directly associated with wildfire smoke exposure., (© 2023. BioMed Central Ltd., part of Springer Nature.)

In the United States, a generic Type A medicated article (premix) product can gain government approval by demonstrating in vivo bioequivalence (BE) to the pioneer product in a blood level, pharmacodynamic, or clinical BE study. A biowaiver can be granted based on several criteria including solubility or a dose adjusted method. Monensin is practically insoluble in H 2 O per the USP definition. A comparison was conducted of monensin dissolution profiles from the pioneer product and four generic products using biorelevant media. Dissolution profiles were obtained in both Bovine Simulated Rumen Fluids - High Forage and High Grain diets. Data from twelve vessels (6 vessels per dissolution run × 2) were collected across 8 hrs for each lot and media. Data are reported as % dissolved, based upon the corresponding lot potency (mg/g). With demonstrated acceptable intra-lot variability, data were analyzed using f 1 (difference factor) and f 2 (similarity factor) procedures. The generic monensin products did not demonstrate similar in vitro dissolution profiles to the pioneer product in these USP biorelevant media. Differences in physical parameters (particle size, flow characteristics, and physical composition) were observed between the pioneer and generic products, but these differences had no apparent impact on biorelevant dissolution., (© 2020 Elanco Animal Health. Journal of Veterinary Pharmacology and Therapeutics published by John Wiley & Sons Ltd.)

Pharmacokinetics study of ceftiofur crystalline free acid (CCFA) was conducted in 14 adult captive smooth dogfish ( Mustelus canis ). A single dose of CCFA at 6.6 mg/kg was administered intramuscularly. Blood samples were collected prior to treatment and at 1, 2, 6, 12, 24, 32, 48, 72, 96, 120, 144, and 168 hr posttreatment. Naïve pooling of data from four sharks was used to generate the average plasma drug concentration at each time point. After concluding the study, additional blood samples were opportunistically collected from five randomly selected sharks at 1,920 hr. Plasma ceftiofur and desfuroylceftiofur metabolite concentrations were determined using reversed-phase high performance liquid chromatography (HPLC). Pharmacokinetic analysis was performed using a noncompartmental technique. Peak plasma concentration ( C max ) was 3.75 µg/ml with a time to C max ( T max ) of 96 hr. Ceftiofur plasma concentrations were maintained above 2 µg/ml for at least 168 hr and were still quantifiable at 1,920 hr.

Polypharmacy is a term that describes the inappropriate, concurrent use of multiple drugs in an individual patient. Zoological medicine practitioners must take approved agents (veterinary or human) and extrapolate their use to non-approved species often with little species-specific pharmacological evidence to support their decisions. When considering polypharmacy, even less information exists concerning multi-drug pharmacokinetics, pharmacodynamics, or potential drug-drug interactions in non-domestic species. Unfortunately, captive, zoological species are susceptible, just like their domestic counterparts, to chronic diseases and co-morbidities that may lead to the usage of multiple drugs. Polypharmacy is a recognized and important issue in human medicine, as well as an emerging issue for veterinarians; thus, this paper will discuss the novel, potential risks of polypharmacy in zoological medicine. Hopefully, this discussion will help bring the attention of veterinarians to this issue and serve as an interesting discussion topic for pharmacologists in general.

Particulate matter (PM) is a key indicator of air pollution and a significant risk factor for adverse health outcomes in humans. PM is not a self-contained pollutant but a mixture of different compounds including chemical and biological fractions. While several reviews have focused on the chemical components of PM and associated health effects, there is a dearth of review studies that holistically examine the role of biological and chemical components of inhalable and respirable PM in disease causation. A literature search using various search engines and (or) keywords was done. Articles selected for review were chosen following predefined criteria, to extract and analyze data. The results show that the biological and chemical components of inhalable and respirable PM play a significant role in the burden of health effects attributed to PM. These health outcomes include low birth weight, emergency room visit, hospital admission, respiratory and pulmonary diseases, cardiovascular disease, cancer, non-communicable diseases, and premature death, among others. This review justifies the importance of each or synergistic effects of the biological and chemical constituents of PM on health. It also provides information that informs policy on the establishment of exposure limits for PM composition metrics rather than the existing exposure limits of the total mass of PM. This will allow for more effective management strategies for improving outdoor air quality.

Tuberculosis, caused by Mycobacterium tuberculosis, is a disease of concern in captive Asian elephants (Elephas maximus). Treatment for tuberculosis in elephants utilizes multidrug protocols combining isoniazid, rifampin, pyrazinamide, and/or ethambutol. In this study, a single, coformulated dose of isoniazid 5 mg/kg, rifampin 10 mg/kg, pyrazinamide 30 mg/kg, and ethambutol 30 mg/kg was administered orally to six Asian elephants, and rectally to five elephants using a cross-over design. Blood samples were collected serially over 24 h. Pyrazinamide and ethambutol concentrations were determined using validated gas chromatography assays. Isoniazid and rifampin concentrations were determined using validated high-performance liquid chromatography assays. Rectal isoniazid produced an earlier Tmax compared with oral administration. Oral isoniazid resulted in a comparatively lower Cmax , but higher AUC values compared with rectal isoniazid. Oral rifampin and oral ethambutol were well absorbed while rectal rifampin was not. Oral pyrazinamide produced comparatively higher Cmax and AUC values compared with rectal pyrazinamide. Results of this study indicate that currently recommended therapeutic monitoring sample collection times for rectal isoniazid and oral rifampin do not provide an accurate assessment of exposure for these drugs. This study demonstrates notable individual variability, indicating that dosing of these medications requires individual monitoring and provides additional information to guide the clinician when treating elephants., (© 2014 John Wiley & Sons Ltd.)

Antimicrobial resistance is a global challenge that impacts both human and veterinary health care. The resilience of microbes is reflected in their ability to adapt and survive in spite of our best efforts to constrain their infectious capabilities. As science advances, many of the mechanisms for microbial survival and resistance element transfer have been identified. During the 2012 meeting of Antimicrobial Agents in Veterinary Medicine (AAVM), experts provided insights on such issues as use vs. resistance, the available tools for supporting appropriate drug use, the importance of meeting the therapeutic needs within the domestic animal health care, and the requirements associated with food safety and food security. This report aims to provide a summary of the presentations and discussions occurring during the 2012 AAVM with the goal of stimulating future discussions and enhancing the opportunity to establish creative and sustainable solutions that will guarantee the availability of an effective therapeutic arsenal for veterinary species., (© Published (2014). This article is a U.S. Government work and is in the public domain in the USA.)

Thromboembolic disorders are the leading cause of human mortality. Therefore, development of effective anticoagulant therapy is critical. Factor XIIIA (FXIIIA) protein is a crucial factor in the blood coagulation cascade, and hence it is a vital target for evolution of new antithrombotic agents. Structure-function studies of clotting factor active sites, clot formation, and thrombus structure have gained prominence in the efforts to develop novel anticoagulants. Factor XIIIA was homology modelled with the human transglutaminase-2 crystal structure as a base template for BLAST analysis. Docking and comparative binding site analysis revealed active site residue conservation and inhibitor-protein interactions. Nineteen small molecules possessing suspected anticoagulant properties were successfully docked into the FXIIIA active site following the best CoMFA and CoMSIA prediction values. Dabigatran etexilate was anticipated to be the best FXIIIA inhibitor among the nineteen anticoagulants with the highest binding affinity for the FXIIIA protein and the highest FlexX dock score of -29.8 KJ/mol. Structural properties of FXIIIA inhibitors with increased antithrombotic activity were predicted by this docking study.

Objective: To determine plasma pharmacokinetics of penciclovir following oral and rectal administration of famciclovir to young Asian elephants (Elephas maximus)., Animals: 6 healthy Asian elephants (5 females and 1 male), 4.5 to 9 years old and weighing 1,646 to 2,438 kg., Procedures: Famciclovir was administered orally or rectally in accordance with an incomplete crossover design. Three treatment groups, each comprising 4 elephants, received single doses of famciclovir (5 mg/kg, PO, or 5 or 15 mg/kg, rectally); there was a minimum 12-week washout period between subsequent famciclovir administrations. Serial blood samples were collected after each administration. Samples were analyzed for famciclovir and penciclovir with a validated liquid chromatography-mass spectroscopy assay., Results: Famciclovir was tolerated well for both routes of administration and underwent complete biotransformation to the active metabolite, penciclovir. Mean maximum plasma concentration of penciclovir was 1.3 μg/mL at 1.1 hours after oral administration of 5 mg/kg. Similar results were detected after rectal administration of 5 mg/kg. Mean maximum plasma concentration was 3.6 μg/mL at 0.66 hours after rectal administration of 15 mg/kg; this concentration was similar to results reported for humans receiving 7 mg/kg orally., Conclusions and Clinical Relevance: Juvenile Asian elephants are susceptible to elephant endotheliotropic herpesvirus. Although most infections are fatal, case reports indicate administration of famciclovir has been associated with survival of 3 elephants. In Asian elephants, a dose of 8 to 15 mg of famciclovir/kg given orally or rectally at least every 8 hours may result in penciclovir concentrations that are considered therapeutic in humans.

a) Key issues concerning Premix (Type A medicated articles) Bioequivalence evaluations: 1) This is a complex issue concerning both route of administration and formulation. 2) If the animal is not at the bunk/trough, the animal is not self-administering (eating medicated feed), thus there can be no drug absorption. b) Differing opinions among scientists and regulatory authorities/expert bodies regarding: 1) No harmonization on how to design, conduct, and interpret in vivo studies. 2) Applicability of biowaivers to Type A (premix) products. 3) Why are topdress and complete feed considered differently? Are they different formulations or different routes of administration? 4) Single dose vs. multi-dose studies. 5) What is the final formulation? c) What are the next steps: 1) Harmonize current bioequivalence guidelines through the VICH process. 2) Determine the applicability/non-applicability of the Biopharmaceutical Classification System (BCS). 3) Establish the Total Mixed Ration (i.e. formulation) effects. 4) Define the test subject (individual, pen, etc.)., (© 2012 Blackwell Publishing Ltd.)

Drugs containing one or more chiral centres exist in stereoisomeric molecular forms. Most commonly, drugs containing a single asymmetric carbon atom exist in two enantiomeric forms, designated as eutomer (the more potent) and distomer (the less potent). As well as differences in potency and other pharmacodynamic properties, most members of enantiomeric pairs commonly differ also in their pharmacokinetic profiles. This article reviews factors underlying differences in pharmacological properties of enantiomers. The relevance of such differences for studies designed to evaluate the bioequivalence of products containing chiral drugs is also reviewed., (© 2012 Blackwell Publishing Ltd.)

The intravenous pharmacokinetic profile of tilmicosin is yet to be achieved because of the cardiovascular effects of tilmicosin. This study summarizes two pharmacokinetic studies that provided complete pharmacokinetic profile of tilmicosin in cattle. The first study was a pharmacokinetic study of tilmicosin in beef calves dosed by i.v. infusion over 5 h. The second study was a subcutaneous (s.c.) pharmacokinetic study comparing the pharmacokinetic profile of tilmicosin in light (approximately 170 kg) and heavy (approximately 335 kg) beef cattle and comparing the labeled dose range of 10 or 20 mg/kg dose. The data from the two different studies were used to calculate bioavailability values, which support the assumption that tilmicosin is 100% bioavailable in cattle. The results from the second study showed that the weight of an animal when administered tilmicosin does not have a significant effect on exposure, but did demonstrate that doubling the dose of tilmicosin administered doubles the systemic exposure to tilmicosin., (© 2011 Blackwell Publishing Ltd.)

Products for animal health commercialization follow a structured progression from initial concept through to regulatory approval. Typically, products are developed for use in either food animals or companion animals. These can be for the intention of disease intervention, productivity enhancement or improvement in a quality of life capacity. The animal health industry is a regulated industry, meaning that a government agency is responsible for oversight of products, both pre- and post-approval. There are three primary US government agencies that ensure quality, safety and effectiveness for the approval of new products and post-marketing compliance.

During 2007, a large-scale controlled, multicentre, blinded and randomised field study was conducted in Scotland, England and France to assess the efficacy and safety of monepantel, the first molecule to be developed from the recently discovered amino-acetonitrile derivatives class of anthelmintics, in sheep. Monepantel was administered orally, at a minimum dose of 2.5 mg/kg bodyweight, for the control of gastrointestinal nematodes in sheep maintained at pasture in a range of commercial production systems. Efficacy was measured by faecal egg count (FEC) reduction tests seven days after treatment and was demonstrated to be over 98 per cent against mixed-genus infections. The reduction in FEC of monepantel-treated sheep was statistically significantly greater than in untreated control sheep (P<0.0001). The efficacy of monepantel against mixed-genus natural field infections of the major gastrointestinal nematodes was in agreement with similar studies conducted in Australia and New Zealand. There were no treatment-related adverse events during the study, which included the use of a range of concomitant treatments.

Despite the pharmacological and statistical advances that have occurred since the early days of bioequivalence assessments, there remain many unresolved issues associated with the bioequivalence evaluation of human and veterinary pharmaceuticals. While many of these issues are common to both human and veterinary medicine, there are also challenges specific to veterinary drug products. Examples of complex problems that remain to be resolved include the assessment of drugs associated with complex kinetics (e.g., sustained release formulations that produce multiple peaks), the evaluation of intramammary formulations, uncertainty associated with conditions under which specific enantiomers of metabolites need to be factored into the bioequivalence evaluation, the study design for products and active pharmaceutical ingredients that exhibit highly variable kinetics, equivalence of biomass products, methods for evaluating topical formulations or formulations with very long duration of release, the evaluation of products where destructive sampling is necessary (e.g., aquaculture products), and the evaluation of bioequivalence for Type A medicated articles. This manuscript highlights many of the unresolved challenges currently impacting the evaluation of product bioequivalence in veterinary medicine, and provides a summary of the associated scientific complexities with each of these issues., (© 2010 Blackwell Publishing Ltd.)

Captive Asian elephants (Elephas maximus) are susceptible to lameness resulting from foot and joint pain, including chronic arthritis. In the past, opioid analgesics, such as butorphanol, have been used clinically for pain management. However, dosages used in treating elephants were often extrapolated from data in horses, with no pharmacokinetic information on the specific agents used in elephant species. In this pharmacokinetic study, six adult captive Asian elephants (5 female, 1 male castrate) were administered a 0.015 mg/kg dose of butorphanol by both i.v. and i.m. routes. A complete crossover design was used with a 3-wk washout period between treatments. Serial blood samples were collected immediately prior to butorphanol administration and at 5, 10, 20, and 40 min and 1, 1.5, 2, 3, 4, 5, 6, 8, 10, and 24 h after administration. The butorphanol analysis was performed using a validated liquid chromatography-mass spectrophotometric assay with a limit of quantitation of 0.025 ng/ml. The mean Cmax after i.m. administration was 7.9 ng/ml, with a corresponding Tmax, of 40 min and t(1/3), of 7.1 h. After i.v. administration, the mean Vd(ss) was 1.4 L/kg and the mean Cl(p) was 0.26 L/kg/h. Mean i.m. bioavailability was 37%. The results indicate that butorphanol used at 0.015 mg/kg i.m. or i.v. could be useful in elephants when given for pain control.

Lack of approved pharmaceutical agents and very limited pharmacokinetic data in the scientific literature for exotic, wildlife, and zoo species are a major issue for veterinarians treating these species. There are fewer than 15 compounds approved in the United States for zoo and wildlife species compared to nearly 300 drugs licensed for cattle. Zoo veterinarians are therefore required to extrapolate the use of approved agents (veterinary or human) to nonapproved species, often with little or no scientific basis to support drug or dose schedule selection. In general, species differences in drug absorption, metabolism, distribution, and excretion have been well documented for domestic species. However, there has been limited research to provide similar data for nondomestic species. Consequently, with the possible exception of pet bird species, there is little published information on the pharmacokinetic parameters of drugs in nondomestic species. Additionally, because of the commercial value of many zoo species, the traditional method of "trial and error" for drug and dose selection and related compliance issues is often inappropriate. There is an understandable concern, whereby the zoo veterinarian does not wish to be the first to administer an agent or formulation in an untested species. "One medicine" is a central concept in treating zoo species, in that vertebrate species are generally more similar than dissimilar. However, drug absorption can vary within as well as between species. Considering the anatomical differences between true monogastrics (canine and feline species), hind-gut fermentors (rodents, rabbits, horses, and elephants), fore-gut fermentors (Colobus monkeys and kangaroos), and ruminants (cattle, goats, sheep, and antelope), the potential for differences in pharmacokinetic profiles are marked. Moreover, there are potential differences between organisms in a single class. An example is the ability of several snake species to up- and down-regulate their digestive systems. This renders the time course of oral drug absorption dependent on both body temperature and time after feeding. Plasma protein binding may vary considerably between species and may also be temperature dependent. This is very significant when treating poikilothermic (reptiles, amphibians, and fish) species and when conducting pharmacokinetic studies with highly protein-bound drugs. The large body sizes of some zoo species create additional considerations for treatment with drugs and can place significant limitations on delivery of an effective drug dose.

The nonsteroidal anti-inflammatory drug (NSAID) meloxicam is a very popular anti-inflammatory, analgesic, and antipyretic agent used in veterinary medicine. To determine the pharmacokinetics of this NSAID in rabbits following a single dose and 10-day period of dosing, eight clinically normal, 8-mo-old New Zealand white rabbits (Oryctolagus cuniculus) were administered 0.2 mg/kg meloxicam p.o. daily. Pharmacokinetic analysis of the meloxicam was determined via noncompartmental analysis. After oral administration, mean +/- standard deviation values for area under the curve were 1.8 +/- 0.50 and 2.1 +/- 0.55 microg x h/ml, and maximum plasma concentrations were 0.17 +/- 0.06 and 0.24 +/- 0.07 microg/ml for Day 1 and Day 10, respectively. The half-life was approximately 8 hr. Administration of meloxicam at a dosage of 0.2 to 0.3 mg/kg p.o. every 24 hr is suggested. Although a higher dose may be required for optimum effects, this would require efficacy and safety studies in this species. Meloxicam administered at 0.2 mg/kg p.o. daily for 10 day was well tolerated by the rabbits.

Most drugs indicated for use in dogs are labeled for administration on a mg/kg basis. Such dosing recommendations are grounded on an assumption that total body clearance (Cl) scales in a manner directly proportional to body weight (i.e. that it scales with an allometric exponent of 1). Despite the critical nature of this assumption (the range of normal canine body weights can go from as small as 2 lbs to almost 200 lbs), the validity of this assumption has not been rigorously challenged. Therefore, this manuscript provides an initial assessment of the potential ramifications of this assumption. This objective was accomplished through the following three sets of analysis: (i) examining the observed vs. predicted Cl values across 10 drugs based upon interspecies scaling; (ii) estimating the difference in area under the concentration vs. time curve values if Cl scaled directly in proportion to body weight vs. in a manner consistent with the allometric exponent estimated in the first data analysis; and (iii) exploring the impact of breed differences in drug metabolism that may further confound the problem of exposure assessment. Based upon this assessment, we conclude that if Cl does not scale directly in proportion to body weight, the actual drug exposure in large or small dogs could differ markedly from those concentrations estimated on the basis of studies conducted in beagle-sized dogs.

Peroxidase-mediated oxidation has been proposed as a treatment method for naphthol-contaminated water. However, the impact of solution chemistry on naphthol polymerization and removal has not been documented. This research investigated the impact of pH and ionic strength on peroxidase-mediated removal of 1-naphthol in completely mixed batch reactors. The impact of hydrogen peroxide to 1-naphthol ratio and activity of horseradish peroxidase was also studied. Size exclusion chromatography was used to estimate the molecular weight distribution of oligomeric products, and liquid chromatography/mass spectrometry was used to estimate product structure. Naphthol transformation decreased with ionic strength, and substrate removal was lowest at neutral pHs. Solution pH influenced the size and the composition of the oligomeric products. An equimolar ratio of H(2)O(2):naphthol was sufficient for optimal naphthol removal. Polymerization products included naphthoquinones and oligomers derived from two, three, and four naphthol molecules. Our results illustrate the importance of water chemistry when considering a peroxidase-based approach for treatment of naphthol-contaminated waters.

OBJECTIVE-To determine the pharmacokinetics of marbofloxacin after oral administration every 24 hours to rabbits during a 10-day period. ANIMALS-8 healthy 9-month-old female New Zealand White rabbits. PROCEDURES-Marbofloxacin (5 mg/kg) was administered orally every 24 hours to 8 rabbits for 10 days. The first day of administration was designated as day 1. Blood samples were obtained at 0, 0.17, 0.33, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours on days 1 and 10 of marbofloxacin administration. Plasma marbofloxacin concentrations were quantitated by use of a validated liquid chromatography-mass spectrometry assay. Pharmacokinetic analysis of marbofloxacin was analyzed via noncompartmental methods. RESULTS-After oral administration, mean +/- SD area under the curve was 10.50 +/- 2.00 microg.h/mL and 10.90 +/- 2.45 microg.h/mL, maximum plasma concentration was 1.73 +/- 0.35 microg/mL and 2.56 +/- 0.71 microg/mL, and harmonic mean terminal half-life was 8.0 hours and 3.9 hours for days 0 and 10, respectively. CONCLUSIONS AND CLINICAL RELEVANCE-Marbofloxacin administered orally every 24 hours for 10 days appeared to be absorbed well and tolerated by rabbits. Administration of marbofloxacin at a dosage of 5 mg/kg, PO, every 24 hours is recommended for rabbits to control infections attributable to susceptible bacteria.

Zoologic medicine practitioners take approved agents (veterinary or human) and extrapolate their use to nonapproved species. The decision on dose, duration, and interval is often made with limited species-specific pharmacokinetic information. Because of the monetary value of these animals or their status as endangered species, this method of "trial and error" for therapeutic dosage selection is inappropriate. In zoologic medicine, various methods have been used in an attempt to extrapolate or predict safe and effective dosage regimens. The simplest and typical method of extrapolating a dosage to a nondomestic species is to use a mg/kg dose established for another domestic species or humans. However, this calculation results in a linear increase in the amount of drug administered as body weight increases. Although common, this method tends to overdose large animals and underdose small animals. The second method is similar, except that it takes the approved dose in a specific species and makes an additional assumption that links the dosage to a physiologic function or anatomic feature. Examples are the use of basal metabolic rate or body-surface area as the basis for dosage extrapolation. Allometric scaling of pharmacokinetic parameters is the final method of dosage extrapolation between species. This is commonly used in the pharmaceutical industry to establish the first dosage in human drug investigations. Adaptation of this method for zoologic medicine may enhance our ability to estimate therapeutic dosages for nondomestic species. This review discusses and compares these three methods for dosage selection and provides examples of extrapolation from the literature.

The anti-inflammatory agent, tepoxalin, was administered to eight healthy 6-month-old female New Zealand white rabbits once daily at an oral dose of 10 mg/kg. Blood samples were obtained immediately before and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 h postadministration on days 1 and 10. Tepoxalin and its active metabolite, RWJ 20142, concentrations were determined in plasma by use of high-performance liquid chromatography with mass spectrometry. C(max) of the parent compound was reached between 3 and 8 h of drug administration, with a harmonic mean t(1/2) of 3.6 h. Peak tepoxalin plasma concentrations were 207 +/- 49 ng/mL. After oral administration, the metabolite RWJ 20142 achieved C(max) in plasma 2-8 h after administration, with a t(1/2) of 1.9-4.8 h (harmonic mean 2.8 h). Peak plasma concentrations of RWJ 20142 on day 1 were 2551 +/- 1034 ng/mL.

A highly sensitive and quantitative LC/MS/MS assay for the determination of tilmicosin in serum has been developed and validated. For sample preparation, 0.2 mL of canine serum was extracted with 3 mL of methyl tert-butyl ether. The organic layer was transferred to a new vessel and dried under nitrogen. The sample was then reconstituted for analysis by high performance liquid chromatography-tandem mass spectrometry. A Phenomenex Luna C8(2) analytical column was used for the chromatographic separation. The eluent was subsequently introduced to the mass spectrometer by electrospray ionization. A single range was validated for 50-5000 ng/mL for support of toxicokinetic studies. The inter-day relative error (inaccuracy) for the LLOQ samples ranged from -5.5% to 0.3%. The inter-day relative standard deviations (imprecision) at the respective LLOQ levels were < or =10.1%.

Marbofloxacin is a veterinary only, synthetic, broad spectrum fluoroquinolone antimicrobial agent. In mammals, approximately 40% of the oral dose of marbofloxacin is excreted unchanged in the urine; the remaining is excreted via the bile as unchanged drug in the feces. The Vd ranges from 1.1 (cattle) to 1.3 (dog, goat, swine) L/kg. Because of extra-label use of marbofloxacin in birds and reptiles, this study was designed to determine the profile of metabolites in plasma and compare the circulating metabolite profile between a reptile and an avian species. Six adult ball pythons (Python regius) and 10 blue and gold macaws (Ara ararauna) were used in this study. The macaws were dosed both i.v. and p.o. with a single 2.5 mg/kg administration where as the pythons received a single 10 mg/kg dose both i.v. and p.o. The metabolite profiles of marbofloxacin in the plasma of these species were determined using a high performance liquid chromatography system with a mass spectrometer for detection (LC/MS/MS). Mass spectra data generated from the snake and bird plasma samples were compared with previously reported LC/MS/MS mass spectral data. Evidence does not suggest differences due to route of administration (i.v. vs. p.o.) in either species. Four chromatographic peaks with resulting daughter spectrum were identified and represent 12 possible metabolite structures. All of the proposed metabolites, except for the N-oxide, appear to be unique to macaws. The potential metabolites identified in macaws appear to be very different than those reported for chickens.

Interspecies scaling is a useful tool for the prediction of pharmacokinetic parameters from animals to humans, and it is often used for estimating a first-time in human dose. However, it is important to appreciate the mathematical underpinnings of this scaling procedure when using it to predict pharmacokinetic parameter values across animal species. When cautiously applied, allometry can be a tool for estimating clearance in veterinary species for the purpose of dosage selection. It is particularly valuable during the selection of dosages in large zoo animal species, such as elephants, large cats and camels, for which pharmacokinetic data are scant. In Part I, allometric predictions of clearance in large animal species were found to pose substantially greater risks of inaccuracies when compared with that observed for humans. In this report, we examine the factors influencing the accuracy of our clearance estimates from the perspective of the relationship between prediction error and such variables as the distribution of body weight values used in the regression analysis, the influence of a particular observation on the clearance estimate, and the 'goodness of fit' (R(2)) of the regression line. Ultimately, these considerations are used to generate recommendations regarding the data to be included in the allometric prediction of clearance in large animal species.

Interspecies scaling is a useful tool for the prediction of pharmacokinetic parameters from animals to humans, and it is often used for estimating a first-time in human dose. The knowledge of pharmacokinetics in veterinary species is important for dosage selection, particularly in the treatment of large zoo animal species, such as elephants, giant cats and camels, for which pharmacokinetic data are scant. Therefore, the accuracy in clearance predictions in large animal species, with and without the use of correction factors (rule of exponents), and the impact of species selection in the prediction of clearance in large animal species was examined. Based upon this analysis, it was determined that there is a much larger risk of inaccuracies in the clearance estimates in large animal species when compared with that observed for humans. Unlike in humans, for large animal species, correction factors could not be applied because there was no trend between the exponents of simple allometry and the appropriate correction factor for improving our predictions. Nevertheless, we did see an indication that the exponents of simple allometry may alert us as to when the predicted clearance in the large animal may be underestimated or overpredicted. For example, if a large animal is included in the scaling, the predicted clearance in a large animal should be considered overestimated if the exponent of simple allometry is >1.3. Despite the potential for extrapolation error, the reality is that allometric scaling is needed across many veterinary practice situations, and therefore will be used. For this reason, it is important to consider mechanisms for reducing the risk of extrapolation errors that can seriously affect target animal safety, therapeutic response, or the accuracy of withdrawal time predictions.

The pharmacokinetic parameters of carfentanil and naltrexone were determined in the common eland (Taurotragus oryx). Six adult females were immobilized with xylazine (0.23 +/- 0.03 mg/kg i.m.) and carfentanil (0.0169 +/- 0.0005 mg/kg i.m.) for a 45-min period, during which time routine health care procedures were performed. Heart and respiration rates and body temperatures were monitored throughout the immobilization period. A single intramuscular injection of naltrexone (1.66 +/- 0.08 mg/kg i.m.) was sufficient for reversal. The eland were intermittently restrained in a hydraulic squeeze chute for serial blood sample collection via jugular venipuncture during immobilization and up to 48 hr post-immobilization. The quantification of carfentanil and naltrexone in the plasma was performed by liquid chromatography and mass spectroscopy methods. Carfentanil was rapidly absorbed following administration, with the peak plasma concentration (C(max)) at 13.8 min. Naltrexone was readily absorbed and reached C(max) at 23.4 +/- 16.8 min after administration. All animals stood 2.7 +/- 2.2 min after naltrexone administration. Carfentanil has a half-life of 7.7 hr, whereas naltrexone has a much shorter half-life of 3.7 hr. Although respiratory rates appeared to fluctuate widely among animals, heart rates and body temperature remained stable throughout the immobilization. Renarcotization was not noted as a major complication.

Objective: To determine the pharmacokinetics of marbofloxacin after single IV and orally administered doses in blue and gold macaws., Animals: 10 healthy blue and gold macaws., Procedures: In a crossover study, marbofloxacin (2.5 mg/kg) was administered orally (via crop gavage) to 5 birds and IV to 5 birds. Blood samples were obtained at 0, 0.5, 1, 3, 6, 12, 24, 48, 72, and 96 hours after marbofloxacin administration. After a 4-week washout period, the study was repeated, with the first 5 birds receiving the dose IV and the second 5 birds receiving the dose orally. Serum marbofloxacin concentrations were quantitated by use of a validated liquid chromatography-mass spectrometry assay., Results: After oral administration, mean +/- SD area under the curve was 7.94 +/- 2.08 microg.h/mL, maximum plasma concentration was 1.08 +/- 0.316 microg/mL, and bioavailability was 90.0 +/- 31%. After IV administration of marbofloxacin, the apparent volume of distribution was 1.3 +/- 0.32 L/kg, plasma clearance was 0.29 +/- 0.078 L/h/kg, area under the curve was 9.41 +/- 2.84 microg.h/mL, and the harmonic mean terminal half-life was 4.3 hours., Conclusions and Clinical Relevance: Single IV and orally administered doses of marbofloxacin were well tolerated by blue and gold macaws. The orally administered dose was well absorbed. Administration of marbofloxacin at a dosage of 2.5 mg/kg, PO, every 24 hours may be appropriate to control bacterial infections susceptible to marbofloxacin in this species.

Pharmacokinetics of marbofloxacin in two male and four female adult ball pythons (Python regius) was determined after i.v. and p.o. administration of a single dose. Using a crossover design, each snake was given a single 10 mg/kg dose of marbofloxacin i.v. and p.o. Blood samples were collected prior to and 0.5, 1, 1.5, 3, 6, 12, and 24 hr after marbofloxacin administration. Marbofloxacin was quantitated by use of liquid chromatography-mass spectrometry. Following p.o. administration, marbofloxacin had a peak plasma concentration (Cmax) of 9.40 microg/ml and a time to Cmax (Tmax) of 9.0 hr. Based on the plasma pharmacokinetics generated in this study and pending any further studies to evaluate potential toxicity and multi-dose pharmacokinetics, we suggest a dosage for marbofloxacin in ball pythons of 10 mg/kg p.o. at least every 48 hr, depending on the sensitivity of the pathogen and as a basis for further research.

Azithromycin is classified as an azalide, a subclass of macrolide antimicrobials with a broad spectrum of activity in vitro against many potential bacterial pathogens including spirochetes, anaerobes, and Chlamydia trachomatis. Because of limited data on the use of azithromycin in avian medicine, this study was designed to determine the pharmacokinetics of azithromycin in blue and gold macaws (Ara ararauna), a species commonly seen in clinical practice. Azithromycin (10 mg/kg) was administered via crop lavage to five birds and intravenously to five birds, and blood samples were obtained at 0, 0.5, 1, 3, 6, 12, 24, 48, 72, and 96 hr post-azithromycin administration. Following a 4-wk washout period, the study was repeated with a complete crossover study performed. Concentration of azithromycin in plasma samples was quantified using a validated liquid chromatography/mass spectrometry assay. Pharmacokinetic parameters were determined using noncompartmental analysis. Based on the pharmacokinetic data generated from this study, a starting dose of azithromycin at 10 mg/kg p.o. every 48 hr for susceptible bacterial infections in blue and gold macaws is recommended.

The purpose of this study was to evaluate the multiple dose pharmacokinetics and acute safety of piroxicam and cimetidine alone and in combination in cats. Seven healthy cats were included in this randomized-crossover study. The cats were assigned to groups designated to receive cimetidine alone (15 mg/kg, p.o., q12 h), piroxicam alone (0.3 mg/kg, p.o., q24 h), and piroxicam combined with cimetidine (both at aforementioned doses). The cats were dosed for 10 days followed by at least a 2-week washout period between trials. Serial blood samples were collected following the first and last doses and analyzed utilizing a high-performance liquid chromatography with mass spectrometry detection (LC/MS) assay. Pharmacokinetic parameters were determined using noncompartmental analysis. Endoscopic evaluation of the gastric mucosa was performed and serum urea nitrogen (SUN), creatinine, alkaline phosphatase (ALP), and alanine transaminase (ALT) activities were evaluated. There were not a clinically relevant difference between the pharmacokinetic parameters of piroxicam administered alone or in combination with cimetidine after either the first or last dose. Gastric ulcers were not observed in any cats although gastric erosions were. The SUN, creatinine, ALP, and ALT activities remained within reference ranges for all cats. It appears that once daily, short-term use of piroxicam alone and in combination with cimetidine in cats is relatively safe based on the parameters evaluated in this study. However, further studies are necessary to determine the long-term gastrointestinal safety of piroxicam.

Captive elephants are prone to infections of the feet, lungs, and skin. Often treatment regimens are established with no pharmacokinetic data on the agents being used for treatment in these species. A pharmacokinetic study using ceftiofur (1.1 mg/kg) was conducted in four adult female captive Asian elephants (Elephas maximus) at Busch Gardens in Tampa, Florida. Elephants were given both i.v. and i.m. administrations in a complete crossover design with a 3-week washout period between treatments. Blood samples were collected prior to drug administration and at 0.33, 0.67, 1, 1.5, 2, 4, 8, 12, 24, 48 and 72 h postadministration. Ceftiofur analysis was performed using a validated liquid chromatography/mass spectrophotometric (LC/MS) assay. Plasma concentrations for the i.m. samples were lower than expected. The mean C(max) following i.m. administration was 1.63 microg/mL with a corresponding T(max) of 0.55 h. Following i.v. administration, the median V(d(ss)) was 0.51 L/kg and a median Cl(p) of 0.069 L/kg/h. Mean i.m. bioavailability was 19%. The results indicate that ceftiofur used at 1.1 mg/kg i.m. could be useful in elephants when given two to three times a day or alternatively, 1.1 mg/kg i.v. once daily, depending upon the MIC of the pathogen.