Publications

Although the knowledge base of zoo and wildlife medicine continues to grow rapidly, basic conundrums continue to stymie the clinician seeking to treat nondomestic species. Currently, veterinary-specific breakpoints have been compiled and published in the Clinical Laboratory Standards Institute's VET01S. The premise of veterinary antimicrobial susceptibility testing is that in vitro test results can be used to guide the veterinarian in antimicrobial drug therapeutic decision making when the testing is performed in a standardized and reproducible manner. Zoological medicine practitioners take approved antimicrobials and extrapolate their use to nonapproved species. Before extrapolation of any drug dose, the veterinarian should appreciate the mathematical and physiological assumptions involved and the limitations that are associated with allometry. Oral medications for zoo species are typically hidden in food. Most injectable antimicrobials are given intramuscularly in zoo and wildlife species

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, 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

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.

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.

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.

BACKGROUND: Targeted osmotic lysis (TOL) is a novel technology that involves concomitant stimulation of voltage-gated sodium channels (VGSCs) and the pharmacological blockade of Na+, K+-ATPase causing lysis of highly malignant cancer cells. Hypothesis/Objectives. TOL offers an option for treating advanced carcinomas in companion animals. Animals. Two cats and 2 dogs that presented to veterinary hospitals for evaluation and treatment of one of several forms of carcinoma.

METHODS: Digoxin was administered to achieve steady-state, therapeutic concentrations. The animals were then exposed to pulsed electric field stimulation. Pre- and posttreatment assessments of tumor size and quality of life were compared. The treatment frequency and survivability varied, based on the patient's premorbid functioning and response to treatment.

RESULTS: Regardless of cancer type, TOL consistently increased survival beyond expected, often improving, but without compromising of quality of life. Conclusions and Clinical Importance. TOL warrants consideration as an option for managing advanced carcinomas.

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.