Cannabidiol (CBD)-rich hemp extract use is increasing in veterinary medicine with little examination of serum cannabinoids. Many products contain small amounts of Δ9-tetrahydrocannabinol (THC), and precursor carboxylic acid forms of CBD and THC known as cannabidiolic acid (CBDA) and tetrahydrocannabinolic acid (THCA). Examination of the pharmacokinetics of CBD, CBDA, THC, and THCA on three oral forms of CBD-rich hemp extract that contained near equal amounts of CBD and CBDA, and minor amounts (<0.3% by weight) of THC and THCA in dogs was performed. In addition, we assess the metabolized psychoactive component of THC, 11-hydroxy-Δ9-tetrahydrocannabinol (11-OH-THC) and CBD metabolites 7-hydroxycannabidiol (7-OH-CBD) and 7-nor-7-carboxycannabidiol (7-COOH-CBD) to better understand the pharmacokinetic differences between three formulations regarding THC and CBD, and their metabolism. Six purpose-bred female beagles were utilized for study purposes, each having an initial 7-point, 24-h pharmacokinetic study performed using a dose of 2 mg/kg body weight of CBD/CBDA (~1 mg/kg CBD and ~1 mg/kg CBDA). Dogs were then dosed every 12 h for 2 weeks and had further serum analyses at weeks 1 and 2, 6 h after the morning dose to assess serum cannabinoids. Serum was analyzed for each cannabinoid or cannabinoid metabolite using liquid chromatography and tandem mass spectroscopy (LC-MS/MS). Regardless of the form provided (1, 2, or 3) the 24-h pharmacokinetics for CBD, CBDA, and THCA were similar, with only Form 2 generating enough data above the lower limit of quantitation to assess pharmacokinetics of THC. CBDA and THCA concentrations were 2- to 3-fold higher than CBD and THC concentrations, respectively. The 1- and 2-week steady-state concentrations were not significantly different between the two oils or the soft chew forms. CBDA concentrations were statistically higher with Form 2 than the other forms, showing superior absorption/retention of CBDA. Furthermore, Form 1 showed less THCA retention than either the soft chew Form 3 or Form 2 at weeks 1 and 2. THC was below the quantitation limit of the assay for nearly all samples. Overall, these findings suggest CBDA and THCA are absorbed or eliminated differently than CBD or THC, respectively, and that a partial lecithin base provides superior absorption and/or retention of CBDA and THCA.

Standardized green tea extract was evaluated for exposure and toxicity in Beagle dogs following oral dosing by capsules. The main component (-)-epigallocatechin gallate (EGCG) accounted for 56-72% of the material. A 9-month chronic study (0, 200, 500, and 1000 mg/kg/day) was done in fasted dogs to take advantage of the reported improved catechin bioavailability with fasting. Extensive morbidity, mortality, and pathology of many major organs led to its early termination at 6.5 months and prevented identification of the toxicity mechanisms. A follow-up 13-week study examined the exposure to and toxicity of the extract. In general, toxicities were less severe than in the chronic study during the same interval. Dosing in a fed state resulted in considerably lower and less variable exposure than found under fasted conditions. Toxicity was less frequent and of lesser severity with lower exposure but limited sample size and large variability prevented reaching that definitive conclusion. Differences in mortality and morbidity between the preliminary terminated chronic and follow-up subchronic studies with the same dose of the same drug lot and similar exposure were not fully resolved as there may be other as yet unclear confounding factors.

In the current study, there was a modest but significant increase in risk (1.6- to 2-fold) for miscarriages and/or fetal loss occurring throughout the year in the spouses of applicators who use fungicides. There is a surprisingly significant deficit in the number of male children born to the spouses of fungicide applicators. First-trimester miscarriages occur most frequently in the spring, during the time when herbicides are applied. Use of sulfonylurea (odds ratio OR = 2.1), imidizolinone (OR = 2.6) containing herbicides, and the herbicide combination Cheyenne (OR = 2.9) by male applicators was statistically associated with increased miscarriage risk in the spring. Limited survey data from women who are the spouses of applicators did not show major alterations of long-term endocrinologic status (menarche, menopause, endometriosis). With regard to personal pesticide exposures, only women who engaged in pesticide application where there is direct exposure to these products are at demonstrable risk (OR = 1.8) for miscarriage. It was hypothesized that the overall reproductive toxicity observed in this population is, for the greater part, a male-mediated event. Clarification of exposure events leading to reproductive toxicity through direct measurements of exposure in both men and women is needed to resolve this issue.

No abstract

In a mass casualty radiation event situation, individualized therapy may overwhelm available resources and feasibility issues suggest a need for the development of population-based strategies. To investigate the efficacy of a population-based strategy, Chinese macaques (n = 46) underwent total-body irradiation and received preemptive antibiotics, IV hydration on predetermined postirradiation days and were then compared to macaques (n = 48) that received subject-based care in which blood transfusions, IV hydration, nutritional supplementation and antibiotic supportive measures were provided. Estimated radiation doses for LD30/60, LD50/60 and LD70/60 of animals with subject-based care: 6.83 Gy (6.21, 7.59), 7.44 Gy (6.99, 7.88) and 8.05 Gy (7.46, 8.64), respectively, and for population-based care: 5.61 Gy (5.28, 6.17), 6.62 Gy (6.13, 7.18) and 7.63 Gy (7.21, 8.20), respectively. Analysis of four time periods, 0-9, 10-15, 16-25 and 26-60 days postirradiation, identified significant mortality differences during the period of 10-15 days. A subset analysis of higher radiation doses (6.75-7.20 Gy, n = 32) indicated hydration, nutrition and septic status were not significantly different between treatments. Whole blood transfusion treatment, administered only in subject-supportive care, was associated with significantly higher platelet and absolute neutrophil counts. Median platelet counts greater than 5,670 cells/μl and absolute neutrophil counts greater than 26 cells/μl during this period correlated with survival. We observed that the population-based treatment increased the LD50/60 compared to nontreatment (6.62 Gy vs. 4.92 Gy) and may be further optimized during days 10-15, where strategic blood transfusions or other strategies to achieve increases in neutrophil and platelet counts may further increase survival rates in subjects exposed to high doses of radiation.

Angiotensin I-converting enzyme (ACE, CD143) plays a crucial role in blood pressure regulation, vascular remodeling, and immunity. A wide spectrum of mAbs to different epitopes on the N and C domains of human ACE have been generated and used to study different aspects of ACE biology, including establishing a novel approach-conformational fingerprinting. Here we characterized a novel set of 14 mAbs, developed against human seminal fluid ACE. The epitopes for these novel mAbs were defined using recombinant ACE constructs with truncated N and C domains, species cross-reactivity, ACE mutagenesis, and competition with the previously mapped anti-ACE mAbs. Nine mAbs recognized regions on the N domain, and 5 mAbs-on the C domain of ACE. The epitopes for most of these novel mAbs partially overlap with epitopes mapped onto ACE by the previously generated mAbs, whereas mAb 8H1 recognized yet unmapped region on the C domain where three ACE mutations associated with Alzheimer's disease are localized and is a marker for ACE mutation T877M. mAb 2H4 could be considered as a specific marker for ACE in dendritic cells. This novel set of mAbs can identify even subtle changes in human ACE conformation caused by tissue-specific glycosylation of ACE or mutations, and can detect human somatic and testicular ACE in biological fluids and tissues. Furthermore, the high reactivity of these novel mAbs provides an Isolda A. Popova and Lizelle Lubbe contributed equally.

Hemp based cannabinoids have gained popularity in veterinary medicine due to the potential to treat pain, seizure disorders and dermatological maladies in dogs. Cat owners are also using hemp-based products for arthritis, anxiety and neoplastic disorders with no studies assessing hemp cannabinoids, namely cannabidiol efficacy, for such disorders. Initial twenty-four pharmacokinetic and chronic dosing serum concentration in cats are sparse. The aim of our study was to assess 8 cats physiological and 24 h and 1-week steady state pharmacokinetic response to a cannabidiol (CBD) and cannabidiolic acid (CBDA) rich hemp in a palatable oral paste. Using a standard dose of paste (6.4 mg/CBD + CBDA 5.3 mg/gram) across 8 cats weighing between 4.2 and 5.4 kg showed an average maximal concentration of CBD at 282.0 ± 149.4 ng/mL with a half-life of ~2.1 ± 1.1 h, and CBDA concentrations of 1,011.3 ± 495.4 ng/mL with a half-life of ~2.7 ± 1.4 h, showing superior absorption of CBDA. After twice daily dosing for 1 week the serum concentrations 6 h after a morning dosing showed that the acidic forms of the cannabinoids were approximately double the concentration of the non-acidic forms like CBD and Δ9- tetrahydrocannabinol (THC). The results of this study compared to two other recent studies suggest that the absorption in this specific paste product may be superior to oil bases used previously, and show that the acidic forms of cannabinoids appear to be absorbed better than the non-acidic forms. More importantly, physical and behavioral examinations every morning after dosing showed no adverse events related to neurological function or behavioral alterations. In addition, bloodwork after 1 week of treatment showed no clinically significant serum biochemical alterations as a reflection of hepatic and renal function all remaining within the reference ranges set by the diagnostic laboratory suggesting that short-term treatment was safe.

Cannabinoids hold promise for treating health problems related to inflammation and chronic pain in dogs, in particular cannabidiol (CBD), and its native acid derivative cannabidiolic acid (CBDA). Information regarding systemic delivery of cannabinoids through transdermal routes is sparse. The purpose of this study was to determine pharmacokinetics of transdermal administration of a low‐THC Cannabis sativa extract in healthy dogs. Six purpose‐bred research beagles were treated with a transdermal CBD‐CBDA‐rich extract, and serum concentrations of CBD, CBDA, tetrahydrocannabinol (THC), and its acid derivative tetrahydrocannabinolic acid (THCA) were examined prior to and at the end of weeks 1 and 2. A 4 mg/kg dose of total cannabinoids twice daily resulted in appx 10 ng/ml of CBD, 21–32 ng/ml of CBDA, trace amounts of THCA, and unquantifiable amounts of THC in serum at the end of weeks 1 and 2 of treatment. Results showed that CBDA and THCA were absorbed better systemically than CBD or THC.