Objective: To determine the safety and tolerability of escalating doses of three cannabis oil formulations, containing predominantly CBD, THC, or CBD and THC (1.5:1) vs. placebo in dogs.Design: Randomized, placebo-controlled, blinded, parallel study.Animals: Twenty healthy Beagle dogs (10 males, 10 females).Methods: Dogs were randomly assigned to one of five treatment groups (n = 4 dogs per group balanced by sex): CBD-predominant oil, THC-predominant oil, CBD/THC-predominant oil (1.5:1), sunflower oil placebo, medium-chain triglyceride oil placebo. Up to 10 escalating doses of the oils were planned for administration via oral gavage, with at least 3 days separating doses. Clinical observations, physical examinations, complete blood counts, clinical chemistry, and plasma cannabinoids were used to assess safety, tolerability, and the occurrence of adverse events (AEs). AEs were rated as mild, moderate, or severe/medically significant.Results: Dose escalation of the CBD-predominant oil formulation was shown to be as safe as placebo and safer than dose escalation of oils containing THC (CBD/THC oil or THC oil). The placebo oils were delivered up to 10 escalating volumes, the CBD oil up to the tenth dose (640.5 mg; ∼62 mg/kg), the THC oil up to the tenth dose (597.6 mg; ∼49 mg/kg), and the CBD/THC oil up to the fifth dose (140.8/96.6 mg CBD/THC; ∼12 mg/kg CBD + 8 mg/kg THC). AEs were reported in all dogs across the five groups and the majority (94.9%) were mild. Moderate AEs (4.4% of all AEs) and severe/medically significant AEs (0.8% of all AEs) manifested as constitutional (lethargy, hypothermia) or neurological (ataxia) symptoms and mainly occurred across the two groups receiving oils containing THC (CBD/THC oil or THC oil).Conclusions and clinical significance: Overall, dogs tolerated dose escalation of the CBD oil well, experiencing only mild AEs. The favorable safety profile of 10 escalating doses of a CBD oil containing 18.3-640.5 mg CBD per dose (∼2-62 mg/kg) provides comparative evidence that, at our investigated doses, a CBD-predominant oil formulation was safer and more tolerated in dogs than oil formulations containing higher concentrations of THC.

OBJECTIVE To determine the safety and pharmacokinetics of various doses of plant-derived cannabidiol (CBD) versus placebo following repeated oral administration. ANIMALS 20 healthy adult Beagles. PROCEDURES In a randomized, blinded, placebo-controlled trial, dogs were randomized to 5 groups balanced in body weight and sex (n = 4 dogs/group) and received a CBD (1, 2, 4, or 12 mg/kg; from cannabis extract) or placebo oil formulation PO once daily for 28 days. Outcome variables were assessed through daily health observations, veterinary examinations, CBC, and serum biochemical analysis. Blood samples were collected at various time points to estimate 24-hour pharmacokinetic profiles of CBD and selected metabolites (7-carboxy-CBD and 7-hydroxy-CBD). RESULTS Repeated CBD administration was well tolerated by dogs, with no clinically important changes in measured safety outcomes. Veterinary examinations revealed no clinically important abnormal findings. Adverse events were mild in severity. Relative to placebo administration, CBD administration at 12 mg/kg/d resulted in more gastrointestinal adverse events (mainly hypersalivation) and significantly higher serum alkaline phosphatase activity. Total systemic exposure to CBD increased on a dose-dependent basis following both acute (first dose) and chronic (28 days) administration. Within each CBD dose group, repeated administration increased total systemic exposure to CBD 1.6- to 3.3-fold. The 24-hour trough plasma CBD concentrations were also dose dependent, with a steady state reached following 2 weeks of administration. CONCLUSIONS AND CLINICAL RELEVANCE Repeated, daily oral administration of the CBD formulation led to dose-dependent increases in total systemic exposure to CBD and 24-hour trough plasma concentrations in healthy dogs. These findings could help guide dose selection.

Objectives The aim of this study was to determine the safety and tolerability of escalating doses of orally delivered cannabis oils predominant in cannabidiol (CBD), tetrahydrocannabinol (THC), or both CBD and THC in healthy cats. Methods In this placebo-controlled, blinded study, 20 healthy adult cats were randomized to one of five treatment groups (n = 4 per group): two placebo groups (sunflower oil [SF] or medium-chain triglyceride oil [MCT]), or three plant-derived cannabinoid oil groups (CBD in MCT, THC in MCT or CBD/THC [1.5:1] in SF). Up to 11 escalating doses of each formulation were delivered orally via syringe to fasted subjects, with at least 3 days separating doses. Safety and tolerability were determined from clinical observations, complete blood counts (CBCs) and clinical chemistry. Plasma cannabinoids (CBD, THC) and metabolites (7-COOH-CBD, 11-OH-THC) were assessed. Results Titration to maximum doses of 30.5 mg/kg CBD (CBD oil), 41.5 mg/kg THC (THC oil) or 13.0:8.4 mg/kg CBD:THC (CBD/THC oil) was safely achieved in all subjects. All observed adverse events (AEs) were mild, transient and resolved without medical intervention. Gastrointestinal AEs were more common with formulations containing MCT. Constitutional (lethargy, hypothermia), neurologic (ataxia) and ocular (protrusion membrana nictitans) AEs were more common with oils containing THC (CBD/THC and THC oils). There were no clinically significant changes in CBC or clinical chemistry across treatment groups. Higher plasma levels of the cannabinoids and their metabolites following administration of the CBD/THC combination product are suggestive of a pharmacokinetic interaction. Conclusions and relevance This is the first feline study to explore the safety and tolerability of CBD and THC, alone and in combination, in a controlled research setting. These findings will inform veterinarians of the safety profile of cannabinoids, particularly when considering the potential therapeutic use of CBD in cats or recognizing clinical signs associated with accidental exposure to THC-containing products.

Estrogens have well-recognized and complex cardiovascular effects, including altering myocardial contractility through changes in myofilament function. The presence of multiple estrogen receptor (ER) isoforms in the heart may explain some discrepant findings about the cardiac effects of estrogens. Most studies examining the impact of estrogens on the heart have focused on chronic changes in estrogen levels, and have not investigated rapid, non-genomic pathways. The first objective of this study was to determine how acute activation of ERα impacts cardiac myofilaments. Nongenomic myocardial estrogen signaling is associated with the activation of a variety of signaling pathways. p38 MAPK has been implicated in acute ER signaling in the heart, and is known to affect myofilament function. Thus, the second objective of this study was to determine if acute ERα activation mediates its myofilament effects through p38 MAPK recruitment. Hearts from female C57Bl/6 mice were perfused with the ERα agonist PPT and myofilaments isolated. Activation of ERα depressed actomyosin MgATPase activity and decreased myofilament calcium sensitivity. Inhibition of p38 MAPK attenuated the myofilament effects of ERα activation. ERα stimulation did not affect global myofilament protein phosphorylation, but troponin I phosphorylation at the putative PKA phosphorylation sites was decreased. Changes in myofilament activation did not translate into alterations in whole heart function. The present study provides evidence supporting rapid, non-genomic changes in cardiac myofilament function following acute ERα stimulation mediated by the p38 MAPK pathway.

The combination of antiestrogens and histone deacetylase inhibitors (HDACi) has been found to be antiproliferative in breast cancer models. We designed and synthesized hybrid structures which combined structural features of the pure antiestrogen ICI-164,384 and HDACi's SAHA and entinostat in a single bifunctional molecule. The hybrids retained antiestrogenic and HDACi activity and, in the case of benzamide hybrids, were selective for Class I HDAC3 over Class II HDAC6. The hybrids possessed low micromolar to high nanomolar activity against both ER+ MCF-7 and ER- MDA-MB-231 breast cancer cell models.

The pregnancy hormone relaxin (RLX) is a powerful cardiostimulatory peptide. Despite its well-characterized effects on the heart, the intracellular mechanisms responsible for RLX's positive inotropic effects are unknown. Cardiac myofilaments are the central contractile elements of the heart, and changes in the phosphorylation status of myofilament proteins are known to mediate changes in function. The first objective of this study was to determine whether RLX stimulates myofilament activation and alters the phosphorylation of one or more myofilament proteins. RLX works through a variety of intracellular signaling cascades in different tissue types. Protein kinases A (PKA) and C (PKC) are two common molecules implicated in RLX signaling and are known to affect myofilament function. Thus the second objective of this study was to determine whether RLX mediates its myocardial effects through PKA or PKC activation. Murine myocardium was treated with recombinant H2-RLX, and cardiac myofilaments were isolated. RLX increased cardiac myofilament force development at physiological levels of intracellular Ca 2ϩ without altering myofilament ATP consumption. Myosin binding protein C, troponin T, and troponin I phosphorylation levels were increased with RLX treatment. Immunoblot analysis revealed an increase in myofilament-associated PKC-␦, decreases in PKC-␣ and -␤ II, but no effect on PKC-ε. Inhibition of PKC with chelerythrine chloride or PKC-␦ with rottlerin prevented the RLX-dependent changes in myofilament function and protein phosphorylation. PKA antagonism with H-89 had no effect on the myofilament effects of RLX. This study is the first to show that RLX-dependent changes in myofilament-associated PKC alters myofilament activation in a manner consistent with its cardiostimulatory effects.heart; ventricular myocardium; hormone; phosphorylation; intracellular signaling SINCE ITS DISCOVERY BY HISAW (8), relaxin has been recognized as a hormone of pregnancy. However, nearly 70 years after its role in reproduction was noted, relaxin has emerged as a pleiotropic hormone with profound impact on a variety of physiological systems.Relaxin mediates cardiovascular effects in both health and disease (2, 26). Myocardial contractility is significantly enhanced by relaxin, and its cardiostimulatory effects are even more potent than endothelin, angiotensin II, and isoprenaline (10). It has been suggested that a role of relaxin in pregnancy is its ability to modify the cardiovascular system in the face of increasing demands produced by the developing fetus (27). Some studies have reported that circulating levels of relaxin are elevated in heart failure patients (5, 6), while others have not been able to replicate these findings (13). A significant obstacle in understanding the physiological and pathophysiological roles of relaxin in the cardiovascular system is the general lack of information about its fundamental mechanisms of action.Cardiac myofilaments are the contractile apparatus of the heart, and their interaction with calcium f...

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