Cardiac myosin inhibitor, CK-586, minimally reduces systolic function and ameliorates obstruction in feline hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) remains the most common cardiomyopathy in humans and cats with few preclinical pharmacologic interventional studies. Small-molecule sarcomere inhibitors are promising novel therapeutics for the management of obstructive HCM (oHCM) patients and have shown efficacy in left ventricular outflow tract obstruction (LVOTO) relief. The objective of this study was to explore the 6-, 24-, and 48-hour (h) pharmacodynamic effects of the cardiac myosin inhibitor, CK-586, in six purpose-bred cats with naturally occurring oHCM.

Correction: Cook et al. An Optimized Bioassay for Screening Combined Anticoronaviral Compounds for Efficacy against Feline Infectious Peritonitis Virus with Pharmacokinetic Analyses of GS-441524, Remdesivir, and Molnupiravir in Cats. 2022, , 2429.

In the original publication [...

Pharmacokinetics of a Single Transdermal Dose of Mirtazapine in Rhesus Macaques ().

Decreased appetite is a common clinical problem in captive rhesus macaques (). Mirtazapine, a tetracyclic antidepressant originally developed for humans, has shown promise as a safe and effective promoter of weight gain and appetite in several veterinary species including rhesus and cynomolgus macaques. Although mirtazapine is available as oral formulations, transdermal delivery in macaques with reduced appetite would allow quick, painless, topical application.

Effects of pulsatile intravenous follicle-stimulating hormone treatment on ovarian function in women with obesity.

Objective: To establish conditions for effective hypothalamic suppression in women with normal and high body mass index (BMI) and test the hypothesis that intravenous (IV) administration of pulsatile recombinant follicle-stimulating hormone (rFSH) can overcome the clinically evident dysfunctional pituitary-ovarian axis in women with obesity.

Design: Prospective interventional study.

Setting: Academic medical center.

Vinblastine pharmacokinetics in mouse, dog, and human in the context of a physiologically based model incorporating tissue-specific drug binding, transport, and metabolism.

Vinblastine (VBL) is a vinca alkaloid-class cytotoxic chemotherapeutic that causes microtubule disruption and is typically used to treat hematologic malignancies. VBL is characterized by a narrow therapeutic index, with key dose-limiting toxicities being myelosuppression and neurotoxicity. Pharmacokinetics (PK) of VBL is primarily driven by ABCB1-mediated efflux and CYP3A4 metabolism, creating potential for drug-drug interaction.

Microglia-Derived Olfactomedin-like 3 Is a Potent Angiogenic Factor in Primary Mouse Brain Endothelial Cells: A Novel Target for Glioblastoma.

Neoangiogenesis, a hallmark feature of all malignancies, is robust in glioblastoma (GBM). Vascular endothelial growth factor (VEGF) has long been regarded as the primary pro-angiogenic molecule in GBM. However, anti-VEGF therapies have had little clinical efficacy, highlighting the need to explore VEGF-independent mechanisms of neoangiogenesis.

An Optimized Bioassay for Screening Combined Anticoronaviral Compounds for Efficacy against Feline Infectious Peritonitis Virus with Pharmacokinetic Analyses of GS-441524, Remdesivir, and Molnupiravir in Cats.

Feline infectious peritonitis (FIP) is a fatal disease of cats that currently lacks licensed and affordable vaccines or antiviral therapeutics. The disease has a spectrum of clinical presentations including an effusive ("wet") form and non-effusive ("dry") form, both of which may be complicated by neurologic or ocular involvement. The feline coronavirus (FCoV) biotype, termed feline infectious peritonitis virus (FIPV), is the etiologic agent of FIP.

Population pharmacokinetics identifies rapid gastrointestinal absorption and plasma clearance of oral chlorambucil administered to cats with indolent lymphoproliferative malignancies.

Objective: To establish the pharmacokinetics of a single 2-mg oral dose of chlorambucil in cats with indolent lymphoproliferative malignancies.

Animals: 24 client-owned cats.

Procedures: Cats were assigned to 1 of 4 groups, with each group having a total of 3 sample collection time points over 12 hours after receiving a single 2-mg oral dose of chlorambucil.

Effect of standard-dose and high-dose pimobendan on select indices of renal and cardiac function in dogs with American College of Veterinary Internal Medicine stage B2 myxomatous mitral valve disease.

Background: Pimobendan might have favorable effects on renal function but this has not been well-studied in dogs with myxomatous mitral valve disease (MMVD).

Objectives: Determine the effects of standard-dose (SD_pimo) and high-dose pimobendan (HD_pimo) on glomerular filtration rate (GFR) and cardiac size and function in dogs with preclinical MMVD.

Animals: Thirty nonazotemic dogs with stage B2 MMVD.

Fractionated oral dosing and its effect on cyclophosphamide pharmacokinetics in dogs with high-grade multicentric lymphoma.

Cyclophosphamide (CP) is an alkylating agent commonly included in multi-drug treatment protocols for canine cancer. As a prodrug, CP requires hepatic metabolism for activation to the intermediate compound 4-hydroxycyclophosphamide (4-OHCP) which then spontaneously forms alkylating phosphoramide mustard. CP is frequently administered in a fractionated manner, with the total dose given over multiple days.

Pharmacokinetic study comparing doxorubicin concentrations after chemoembolization or intravenous administration in dogs with naturally occurring nonresectable hepatic carcinoma.

Background: Chemoembolization is a viable treatment option for patients with nonresectable hepatic carcinoma (HC) and may allow delivery of chemotherapeutic drugs with decreased systemic toxicity.

Hypothesis/objective: Compare the serum concentrations of doxorubicin after chemoembolization or IV administration in the same patient. We hypothesized that locoregional delivery may result in increased tumor chemotherapeutic drug concentrations, reflected by decreased measurable serum drug concentrations.

Prevalence and Clinicopathologic Features of Canine Metastatic Melanoma Involving the Central Nervous System: A Retrospective Analysis and Comparative Review.

Background: Central nervous system (CNS) involvement is the leading cause of death in malignant melanoma. Rodent models, while vital to mechanistic investigation, have had limited success identifying effective therapies for melanoma brain metastases. The companion dog with melanoma is a promising complementary model for developmental therapeutic investigation, as these tumors occur in an immunologically outbred host that has shared environmental exposures with humans.

Inhaled recombinant human IL-15 in dogs with naturally occurring pulmonary metastases from osteosarcoma or melanoma: a phase 1 study of clinical activity and correlates of response.

Purpose: Although recombinant human interleukin-15 (rhIL-15) has generated much excitement as an immunotherapeutic agent for cancer, activity in human clinical trials has been modest to date, in part due to the risks of toxicity with significant dose escalation. Since pulmonary metastases are a major site of distant failure in human and dog cancers, we sought to investigate inhaled rhIL-15 in dogs with naturally occurring lung metastases from osteosarcoma (OSA) or melanoma. We hypothesized a favorable benefit/risk profile given the concentrated delivery to the lungs with decreased systemic exposure.

Pharmacokinetics of isavuconazole in healthy cats after oral and intravenous administration.

Background: Isavuconazole is a triazole antifungal drug that has shown good efficacy in human patients. Absorption and pharmacokinetics have not been evaluated in cats.

Objectives: To determine the pharmacokinetics of isavuconazole in cats given a single IV or PO dose.

Serum concentrations of gabapentin in cats with chronic kidney disease.

Objectives: The purpose of this study was to assess serum concentrations of gabapentin in cats with chronic kidney disease (CKD) vs clinically healthy cats.

Methods: Five healthy cats were enrolled in a pharmacokinetic study. A single 20 mg/kg dose of gabapentin was administered orally and blood was obtained at 0, 0.

Microglia-Derived Olfactomedin-like 3 Promotes Pro-Tumorigenic Microglial Function and Malignant Features of Glioma Cells.

Under the influence of transforming growth factor-beta (TGFβ), glioma-associated microglia produce molecules that promote glioma growth and invasion. Olfactomedin-like 3 (), a novel, secreted glycoprotein, is known to promote several non-CNS cancers. While it is a direct TGFβ1 target gene in microglia, the role of microglia-derived OLFML3 in glioma progression is unknown.

The interaction between RUNX2 and core binding factor beta as a potential therapeutic target in canine osteosarcoma.

Osteosarcoma remains the most common primary bone tumour in dogs with half of affected dogs unable to survive 1 year beyond diagnosis. New therapeutic options are needed to improve outcomes for this disease. Recent investigations into potential therapeutic targets have focused on cell surface molecules with little clear therapeutic benefit.

Pilot study comparing serum chemotherapy levels after intra-arterial and intravenous administration in dogs with naturally occurring urinary tract tumors.

The proposed advantages of intra-arterial chemotherapy (IAC) are based on the premises of local dose escalation to the tumor and reduced availability of systemic drugs. There is a lack of objective pharmacokinetic data to confirm the advantage of IAC in dogs with naturally occurring urogenital tumors. The objective of this study was to determine if IAC administration in urogenital tumors would result in decreased systemic drug exposure when compared to intravenous routes.

Doxorubicin area under the curve is an important predictor of neutropenia in dogs with naturally occurring cancers.

Doxorubicin (DOX) area-under-the-curve (AUC) was calculated for 40 dogs with spontaneously occurring cancers using a previously validated limited-sampling approach. All dogs were administered a dose of 30 mg/m by intravenous infusion and serum samples were collected at 5, 45 and 60 minutes post-infusion. DOX and its major metabolite, doxorubicinol (doxol), were quantified in serum samples using high-performance liquid chromatography tandem-mass spectrometry.

A genetically engineered microRNA-34a prodrug demonstrates anti-tumor activity in a canine model of osteosarcoma.

Osteosarcoma (OSA) represents the most common primary bone tumor in humans and pet dogs. Little progress has been made with regard to viable treatment options in the past three decades and patients presenting with metastatic disease continue to have a poor prognosis. Recent mouse studies have suggested that microRNA-34a (miR-34a) may have anti-tumor activities in human OSA models.

Simultaneous absolute quantitation of ATP-binding cassette transporters in normal dog tissues by signature peptide analysis using a LC/MS/MS method.

Membrane transport proteins are fundamental components of blood-tissue barriers and affect the absorption, distribution and elimination, and interactions of many of the drugs commonly used in veterinary medicine. A quantitative, simultaneous measurement of these proteins across dog tissues is not currently available, nor is it possible with current immune-based assays such as western blot. In the present study, we aimed to develop a sensitive and specific liquid chromatography tandem-mass spectrometry (LC/MS/MS) based quantitation method that can simultaneously quantitate 14 ATP-binding cassette transporters.

In vivo and in vitro assessment of mirtazapine pharmacokinetics in cats with liver disease.

Background: Liver disease (LD) prolongs mirtazapine half-life in humans, but it is unknown if this occurs in cats with LD and healthy cats.

Hypothesis/objectives: To determine pharmacokinetics of administered orally mirtazapine in vivo and in vitro (liver microsomes) in cats with LD and healthy cats.

Animals: Eleven LD and 11 age-matched control cats.

In vitro and in vivo activity of liposome-encapsulated curcumin for naturally occurring canine cancers.

Curcumin has well-established anti-cancer properties in vitro, however, its therapeutic potential has been hindered by its poor bioavailability. Lipocurc is a proprietary liposome-encapsulated curcumin formulation that enables intravenous delivery and has been shown to reach its highest concentration within lung tissue. The goal of this study was to characterize the anti-cancer and anti-angiogenic activity of Lipocurc in vitro, in addition to evaluating Lipocurc infusions in dogs with naturally occurring cancer.

Pharmacokinetics of cannabidiol administered by 3 delivery methods at 2 different dosages to healthy dogs.

The purpose of this study was to determine the pharmacokinetics of cannabidiol (CBD) in healthy dogs. Thirty, healthy research dogs were assigned to receive 1 of 3 formulations (oral microencapsulated oil beads, oral CBD-infused oil, or CBD-infused transdermal cream), at a dose of 75 mg or 150 mg q12h for 6 wk. Serial cannabidiol plasma concentrations were measured over the first 12 h and repeated at 2, 4, and 6 wk.

Preliminary pharmacokinetics of intravenous and subcutaneous dolasetron and pharmacodynamics of subcutaneous dolasetron in healthy cats.

Objectives The objectives were to evaluate the pharmacokinetics (PK) of subcutaneous (SC) and intravenous (IV) dolasetron and the pharmacodynamics (PD) of SC dolasetron in healthy cats. Methods Five cats with unremarkable complete blood count, serum biochemistry and urinalyses were utilized. In the PK study, cats received 0.