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 steadystate 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, ani- mals 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 H2O 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.

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.

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.

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.

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 H2 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 f1 (difference factor) and f2 (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.

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 (Cmax) was 3.75 µg/ml with a time to Cmax (Tmax) 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.

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. Disciplines Veterinary Medicine | Veterinary Microbiology and Immunobiology | Veterinary Preventive Medicine, Epidemiology, and Public Health Comments This article is published as Martinez, M., Blondeau, J., Cerniglia, C. E., Fink-Gremmels, J., Guenther, S., Hunter, R. P., Li, X.-Z., Papich, M., Silley, P., Soback, S., Toutain, P.-L., Zhang, Q Workshop report: The 2012 Antimicrobial Agents in Veterinary Medicine: exploring the consequences of antimicrobial drug use: a 3-D approach. J. vet. Pharmacol. Therap. 37:e1–e16. doi: 10.1111/jvp.12104. Posted with permission. Rights Works produced by employees of the U.S. Government as part of their official duties are not copyrighted within the U.S. The content of this document is not copyrighted. Authors M. Martinez, J. Blondeau, C. E. Cernigilia, J. Fink-Gremmels, S. Guenther, R. P. Hunter, X.-Z. Li, M. Papich, P. Silley, S. Soback, P.-L. Toutain, and Q. Zhang This article is available at Iowa State University Digital Repository: http://lib.dr.iastate.edu/vmpm_pubs/173 Workshop report: The 2012 Antimicrobial Agents in Veterinary Medicine: exploring the consequences of antimicrobial drug use: a 3-D approach M. MARTINEZ* J. BLONDEAU C. E. CERNIGLIA J. FINK-GREMMELS S. GUENTHER R. P. HUNTER** X.-Z. LI M. PAPICH P. SILLEY S. SOBACK P.-L. TOUTAIN*** & Q. ZHANG *Food and Drug Administration, Center for Veterinary Medicine, Rockville, MD, USA; University of Saskatchewan, Saskatoon, SK, Canada; Division of Microbiology, National Center for Toxicological Research, FDA, Jefferson, AR, USA; Division Pharmacology, Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands; Veterinary Faculty, Institute of Microbiology and Epizootics, Freie Universit€at Berlin, Berlin, Germany; **Elanco Animal Health, Greenfield, IN, USA; Veterinary Drugs Directorate, Health Canada, Ottawa, ON, Canada; College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA; MB Consult Limited, University of Bradford, Bradford, UK; National Residue Control Laboratory, Kimron Veterinary Institute, Ministry of Agriculture, Beit Dagan, Israel; ***UMR1331, INRA, Ecole Nationale V et erinaire de Toulouse, Toulouse, France; College of Veterinary Medicine, Iowa State University, Ames, IA, USA Martinez, M., Blondeau, J., Cerniglia, C. E., Fink-Gremmels, J., Guenther, S., Hunter, R. P., Li, X.-Z., Papich, M., Silley, P., Soback, S., Toutain, P.-L., Zhang, Q. Workshop report: The 2012 Antimicrobial Agents in Veterinary Medicine: exploring the consequences of antimicrobial drug use: a 3-D approach. J. vet. Pharmacol. Therap. 37, e1–e16. 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. (Paper received 9 June 2013; accepted for publication 2 December 2013) Marilyn Martinez, US Food and Drug Administration, Center for Veterinary Medicine, Office of New Animal Drug Evaluation (HFV-100), Rockville, MD 20855, USA. E-mail: Marilyn.Martinez@fda.hhs.gov To view the meeting agenda and to obtain a biographical summary of the keynote speakers and moderators, please go to http://www.aavmconferences.com/2012/

This Stimuli article discusses the approach for the development of a new general chapter on solubility determination for veterinary drug products. Possible procedures are discussed, with emphasis on the shake-flask method. Recommendations are included on the test conditions for products to treat dogs and cattle. The Expert Panel welcomes comments from the public and stakeholders.

ThisStimull article is the first step toward the development of a general chapter addressing solubility criteria for veterinary drug products. The current criteria for classifying drug solubility are based on human gastrointestinal (GI) physiology. These criteria may not be appropriate to the unique conditions encountered within the GI tract of veterinary species. Thus, this article discusses the relationship between the species-specific GI characteristics and the criteria appropriate for describing drug solubility in veterinary species. Initially the discussion focuses on dogs and cattle, the most common veterinary patients in small- and food-animal practices, respectively. Later the discussion will include various other veterinary species of interest.

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.

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.

EDITORIAL article Front. Microbiol., 10 September 2014Sec. Antimicrobials, Resistance and Chemotherapy Volume 5 - 2014 | https://doi.org/10.3389/fmicb.2014.00478

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.

Chapter 38 Antimicrobial Drug Use in Zoological Animals Ellen Wiedner, Ellen WiednerSearch for more papers by this authorRobert P. Hunter, Robert P. HunterSearch for more papers by this author Ellen Wiedner, Ellen WiednerSearch for more papers by this authorRobert P. Hunter, Robert P. HunterSearch for more papers by this author Book Editor(s):Steeve Giguère DVM, PhD, DACVIM, Steeve Giguère DVM, PhD, DACVIM Professor, Large Animal Internal Medicine Marguerite Hodgson Chair in Equine Studies, College of Veterinary Medicine, University of GeorgiaSearch for more papers by this authorJohn F. Prescott MA, VetMB, PhD, John F. Prescott MA, VetMB, PhD Professor Department of Pathobiology, University of GuelphSearch for more papers by this authorPatricia M. Dowling DVM, MS, DACVIM, DACVCP, Patricia M. Dowling DVM, MS, DACVIM, DACVCP Professor, Veterinary Clinical Pharmacology Veterinary Biomedical Sciences, University of SaskatchewanSearch for more papers by this author First published: 16 August 2013 https://doi.org/10.1002/9781118675014.ch38Citations: 2 AboutPDFPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShareShare a linkShare onFacebookTwitterLinked InRedditWechat Summary Results of in vitro susceptibility tests are typically presented to the veterinarian by designating the pathogen as susceptible, intermediate, or resistant. This designation is based on breakpoints established by the Clinical and Laboratory Standards Institute (CLSI). Most injectable antimicrobials are given via the intramuscular route in zoo and wildlife species. Any veterinarian planning to work with wildlife and zoological species should have an understanding of darting equipment and techniques, and its risks, which include stress to the animal, accidental bone fractures or penetration of internal organs and equipment failure, that is, the dart fails to inject its contents either partially or entirely into the animal. An interesting area of antimicrobial research involves wildlife species that actually produce their own antimicrobial substances. Recently, evidence of harmful antibiotic residues in wildlife found causing increased pathology in affected species. Citing Literature Antimicrobial Therapy in Veterinary Medicine, Fifth Edition RelatedInformation

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.).

Martinez, M. N., Hunter, R. P. Introduction to the bioequivalence theme issue. J. vet. Pharmacol. Therap . 35 (Suppl. 1), 1–2. This introduction provides an overview of the veterinary bioequivalence initiative and of the foundational goals and objectives of this theme issue.

Hunter R. P., DeRidder E., Lucas A., Smedley K. O., Yordy D. W. How do you define equivalence of the API of biomass products? J. vet. Pharmacol. Therap. 35 (Suppl. 1), 99–101.

Lees, P., Hunter, R. P., Reeves, P. T., Toutain, P. L. Pharmacokinetics and pharmacodynamics of stereoisomeric drugs with particular reference to bioequivalence determination.J. vet. Pharmacol. Therap.35(Suppl. 1), 17–29.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.