Comparison of solubility profiles for pioneer and generic monensin premixes in biorelevant simulated intestinal fluid based on shake flask extractions.

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 H2 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.

The effects of formulation on the pharmacokinetics of itraconazole and amiodarone in dogs after oral administration of a combination product, commercial products, and compounded products.

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.

One-health approach to canine cognitive decline: Dogs Overcoming Geriatric Memory and Aging Initiative for early detection of cognitive decline.

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.

Canine cognitive decline and Alzheimer disease: clinical insights to solve a shared one-health problem.

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.

The Role of Targeted Osmotic Lysis in the Treatment of Advanced Carcinoma in Companion Animals: A Case Series.

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.

Investigation of monensin Type A medicated article dissolution profiles in biorelevant media.

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.

NAÏVE-POOLED PHARMACOKINETICS OF CEFTIOFUR CRYSTALLINE FREE ACID AFTER SINGLE INTRAMUSCULAR ADMINISTRATION IN SMOOTH DOGFISH (MUSTELUS CANIS).

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.

Polypharmacy in Zoological Medicine.

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.

Estimates of the pharmacokinetics of famciclovir and its active metabolite penciclovir in young Asian elephants (Elephas maximus).

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.

Overview of the animal health drug development and registration process: an industry perspective.

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.

Pharmacokinetics and intramuscular bioavailability of a single dose of butorphanol in Asian elephants (Elephas maximus).

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.

Interspecies allometric scaling.

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.

Peroxidase-mediated polymerization of 1-naphthol: impact of solution pH and ionic strength.

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.

Single- and multiple-dose pharmacokinetics of marbofloxacin after oral administration to rabbits.

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.

Single and multiple-dose pharmacokinetics of meloxicam after oral administration to the rabbit (Oryctolagus cuniculus).

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.

Concepts and issues with interspecies scaling in zoological pharmacology.

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.

Quantitative determination of tilmicosin in canine serum by high performance liquid chromatography-tandem mass spectrometry.

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%.