Robert Paul Hunter

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 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.

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 patients 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.

The lateral profile of the 6th and 7th cervical spinous processes (CSPs) were examined in four extant species of Equus (n=33); E. caballus (n=26), E. przewalskii (n=3), E. quagga boehmi (n=1), E. asinus (n=3) and compared to pre-domesticated Equus specimens (n=66) representing three known species: E. occidentalis (n=56), E. mosbachensis (n=2), E. curvedins/insulatis (n=1) and unknown Equus species (n=7) from five museums. Six common morphological profiles were revealed: cuneate, curvate, falcate, rudimentary, scalenate, and truncate. For the 6th CSP, the distribution of these morphologies amongst extant Equus is: cuneate, only E. asinus; curvate, E. caballus and E. przewalskii always in combination with ligamentum lamina nuchae (lig. lamina nuchae) attachments from the 2nd through to 7th CSP inclusive; falcate, E. caballus and E. przewalskii always in combination with lig. lamina nuchae attachments from the 2nd through to 7th CSP inclusive; rudimentary, E. caballus always associated with lig. lamina nuchae attachments from the 2nd through to 5th CSP inclusive; scalenate, E. caballus in association with lig. lamina nuchae attachments from the 2nd through to 5th (n=11) or 7th (n=4) CSP inclusive; truncate, not present. The 6th CSP in museum specimens of Equus exhibits one of four profiles: cuneate (n=10), curvate (n=14), scalenate (n=11) and truncate (n=4). For the 7th CSP, the distribution of these morphologies amongst extant Equus is: curvate, E. caballus mostly associated with lig. lamina nuchae attachments from the 2nd through to 5th CSP inclusive, falcate, E. caballus mostly associated with lig. lamina nuchae attachments from the 2nd through to 7th CSP inclusive, scalenate, E. caballus associated with lig. lamina nuchae attachments from the 2nd through to 5th CSP inclusive. Only Rancho La Brea and Tar Pits Museum provided samples suitable for examination of the 7th CSP. These exhibited four profiles: curvate (n=7), falcate (n=11), scalenate (n=2), and truncate (n=7). These findings suggest that the lateral profile of the 6th CSP is of potential use in identification of species; attachments of the lig. lamina nuchae alter the morphology of the 6th and 7th CSP; and that attachments of the lig. lamina nuchae on the 2nd to 7th CSP were likely present in species of Equus prior to domestication.

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 H₂O 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 (C_max) was 3.75 µg/ml with a time to Cmax (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.