Drug-drug interaction between cannabidiol and phenobarbital in healthy dogs.

Objective: To assess drug-drug interactions between cannabidiol (CBD) and phenobarbital (PB) when simultaneously administered to healthy dogs.

Animals: 9 healthy, purpose bred Beagles.

Procedures: A 3-phase prospective, randomized pharmacokinetic (PK) interaction study of CBD and PB was performed as follows: phase 1, CBD PK determination and evaluation of CBD tolerability by 3 single-dose CBD (5 mg/kg, 10 mg/kg, and 20 mg/kg) protocols followed by 2-week CBD dosing; phase 2, a single-dose, 3-way, crossover PK study of CBD (10 mg/kg), PB (4 mg/kg), or CBD (10 mg/kg) administration plus PB (4 mg/kg); and phase 3, evaluation of chronic PB (4 mg/kg, q 30 d) administration followed by single-dose CBD (10 mg/kg) PK study.

A Pharmacokinetic-Pharmacodynamic Study of Intravenous Midazolam and Flumazenil in Adult New Zealand White-Californian Rabbits ().

Flumazenil, a competitive GABA receptor antagonist, is commonly used in rabbits to shorten sedation or postanesthetic recovery after benzodiazepine administration. However, no combined pharmacokinetic (PK) and pharmacodynamic (PD) data are available to guide its administration in this species. In a prospective, randomized, blinded, crossover study design, the efficacy of IV flumazenil (FLU; 0.

Comparative efficacy of oral meloxicam and phenylbutazone in 2 experimental pain models in the horse.

The efficacy of oral phenylbutazone [PBZ; 4.4 mg/kg body weight (BW), q12h], a non-selective non-steroidal anti-inflammatory drug (NSAID), and oral meloxicam (MXM; 0.6 mg/kg BW, q24h), a COX-2 selective NSAID, were evaluated in 2 experimental pain models in horses: the adjustable heart bar shoe (HBS) model, primarily representative of mechanical pain, and the lipopolysaccharide-induced synovitis (SYN) model, primarily representative of inflammatory pain.

Pharmacokinetics and bioequivalence of 2 meloxicam oral dosage formulations in healthy adult horses.

Meloxicam, a non-steroidal anti-inflammatory drug, is approved for use in horses in several countries, but an equine formulation is not available in North America. However, meloxicam is being used in an extra-label manner in horses in Canada. The purpose of this study, therefore, was to assess the bioequivalence of an approved oral meloxicam suspension (Metacam 15 mg/mL for horses; Boehringer Ingelheim Vetmedica GmBH, Ingelheim, Germany) from the European Union with human meloxicam tablets (Meloxicam 15 mg tablets; TEVA Canada, Toronto, Ontario) compounded with molasses to improve palatability and administration.

CYP17, catechol-o-methyltransferase, and glutathione transferase M1 genetic polymorphisms, lifestyle factors, and breast cancer risk in women on Prince Edward Island.

Genetic polymorphisms in enzymes controlling the formation and disposition of estrogens and their metabolites have been shown to influence breast cancer risk. Environmental and lifestyle factors may interact with estrogen metabolism polymorphisms to influence breast cancer risk. We studied the role of lifestyle factors and genetic polymorphisms in estrogen metabolism in women from Prince Edward Island (PEI), a small province of 135,000 people on the east coast of Canada.

Stroke-induced changes in estrogen release and neuronal activity in the parabrachial nucleus of the male rat.

Recent investigations have provided evidence to suggest exogenous estrogen administration into autonomic nuclei prevents or reverses the autonomic dysfunction observed after middle cerebral artery occlusion (MCAO) in male rats. Because estrogen seems to be a potent neuroprotectant against autonomic dysfunction, it is our hypothesis that endogenous estrogen levels within autonomic nuclei will increase in response to stroke. Therefore, in this investigation, in vivo microdialysis was used to simultaneously measure the concentration of estrogen in the plasma and in the parabrachial nucleus (PBN) of male Sprague-Dawley rats after MCAO.

Role of estrogen in central nuclei mediating stroke-induced changes in autonomic tone.

The current investigation examined the role of estrogen in central autonomic regulatory nuclei on the autonomic dysfunction resulting from middle cerebral artery occlusion (MCAO). Experiments were done in anaesthetized male Sprague-Dawley rats. The effect of MCAO on autonomic tone was assessed by monitoring vagal and renal efferent nerve activities before and following systemic administration of either estrogen or saline and the bilateral microinjection of the estrogen receptor antagonist, ICI 182, 780, into several autonomic nuclei (the intrathecal space of the spinal cord, nucleus tractus solitarius, nucleus ambiguus, rostral ventrolateral medulla, parabrachial nucleus, central nucleus of the amygdala or ventral posteromedial thalamus).

Calpain inhibition but not reticulum endoplasmic stress preconditioning protects rat kidneys from p-aminophenol toxicity.

p-Aminophenol (pAP, 225 mg/kg) administration to rats induced renal failure and has been associated with markers of endoplasmic reticulum (ER) stress, as well as calpain and caspase-12 activation in kidneys. To determine the importance of ER stress and calpain during pAP-induced nephrotoxicity, rats were pretreated with low, nontoxic, doses of ER stress inducers or with the selective calpain inhibitor PD150606 (3 mg/kg). Prior ER stress induced by tunicamycin and oxidized dithiothreitol did not result in protection against renal failure, but PD150606 administration was protective and decreased significantly the rise in creatinine and blood urea nitrogen observed after 24-h post-pAP administration.

Cisplatin, gentamicin, and p-aminophenol induce markers of endoplasmic reticulum stress in the rat kidneys.

In vitro evidence of the involvement of the endoplasmic reticulum (ER) during drug-induced renal toxicity is accumulating. ER stress and ER-mediated cell death markers have been reported after exposure of renal cells to model toxicants and nephrotoxic drugs in various in vitro models, but in vivo experiments with clinically relevant nephrotoxic compounds are lacking. In order to determine the relevance of the in vitro findings, markers of ER stress (XBP1 messenger RNA processing and protein expression; GRP78 and GRP94 upregulation) and ER-mediated cell death (caspase-12 and calpain activation) were examined in kidney tissue of rats exposed to nephrotoxic doses of cisplatin (CIS), gentamicin (GEN), and p-aminophenol (PAP), a nephrotoxic metabolite of acetaminophen.

Effect of endoplasmic reticulum stress preconditioning on cytotoxicity of clinically relevant nephrotoxins in renal cell lines.

The cytoprotection of LLC-PK1 cells afforded by endoplasmic reticulum (ER) stress preconditioning suggests that the ER plays an important role during drug-induced renal toxicity. However, in vitro studies have been largely limited to LLC-PK1 cells and model toxins. Therefore, we tested the hypothesis that cytoprotection following ER stress preconditioning is a common property of renal cell lines (LLC-PK1 (pig), NRK-52E (rat), HEK293 (human), MDCK (dog)) and extends to clinically relevant nephrotoxins.

Calpain-induced endoplasmic reticulum stress and cell death following cytotoxic damage to renal cells.

Calpains and endoplasmic reticulum (ER) stress have both been implicated in renal cell death following exposure to reactive chemical toxicants (RCTs). Therefore, we explored the link between ER stress, calpain, and cell death in renal cell injury due to model RCTs (iodoacetamide, menadione, tert-butyl hydroperoxide) and ER stress inducers (tunicamycin [TUN], thapsigargin [THAPS]). The calpain inhibitor, PD150606, significantly reduced the RCT and TUN-induced cell death in the renal cell line LLC-PK1, but not death induced by THAPS.

Role of polymorphic human cytochrome P450 enzymes in estrone oxidation.

Estrogen and its metabolites are believed to play important roles in breast cancer. The influence of genetic polymorphisms in the enzymes responsible for formation and disposition of estrogen on breast cancer risk may shed light on the importance of estrogen metabolites in this disease. However, for such studies to be valid, it is important to correctly identify the enzymes involved in estrogen bioactivation.

Systemic and pituitary pars intermedia antioxidant capacity associated with pars intermedia oxidative stress and dysfunction in horses.

Objective: To determine whether a deficiency in systemic or local (pars intermedia) antioxidant capacity is associated with pituitary pars intermedia oxidative stress and pituitary pars intermedia dysfunction (PPID) in horses.

Sample Population: Blood samples from 20 horses with PPID and 20 healthy client-owned horses, archived paraffin-embedded adrenal gland and substantia nigra tissues from 20 horses, and pituitary gland tissue from 16 horses.

Procedures: Total glutathione, superoxide dismutase, and glutathione peroxidase activities were determined in RBCs.

Agreement in histologic assessments of the pituitary pars intermedia in aged horses.

Objective: To evaluate concordance among veterinary pathologists in the assessment of histologic findings in the pars intermedia of pituitary gland sections from aged horses with mild signs suggestive of pituitary pars intermedia dysfunction (PPID). Sample Population-10 pituitary glands from aged horses.

Procedure: 7 pathologists were provided with signalment, clinical signs, and a single H&E-stained pituitary gland section from 10 aged horses with mild signs suggestive of PPID.

Estrogen in the parabrachial nucleus attenuates the sympathoexcitation following MCAO in male rats.

Recent investigations have provided evidence to suggest systemic estrogen administration prevented or reversed the sympathoexcitation observed following middle cerebral artery occlusion (MCAO) in male rats. The present investigation sought to determine the role of estrogen injected directly into the parabrachial nucleus (PBN) on the MCAO-induced sympathoexcitation as well as the role of the rostral ventrolateral medulla (RVLM) in mediating the sympathoexcitatory response. Male Sprague-Dawley rats were anesthetized with sodium thiobutabarbitol (100 mg/kg) and were instrumented to continuously record blood pressure, heart rate and renal sympathetic nerve activity (RSNA).

The endoplasmic reticulum in xenobiotic toxicity.

The endoplasmic reticulum (ER) is involved in an array of cellular functions that play important roles in xenobiotic toxicity. The ER contains the majority of cytochrome P450 enzymes involved in xenobiotic metabolism, as well as a number of conjugating enzymes. In addition to its role in drug bioactivation and detoxification, the ER can be a target for damage by reactive intermediates leading to cell death or immune-mediated toxicity.

Disruption of the endoplasmic reticulum by cytotoxins in LLC-PK1 cells.

Prior induction of an endoplasmic reticulum stress response results in protection against reactive cytotoxins in the LLC-PK1 cell line. The purpose of this investigation was to determine therefore if the endoplasmic reticulum was disrupted by iodoacetamide, tert-butylhydroperoxide or sulfamethoxazole hydroxylamine. Toxic concentrations of the three toxins caused a dramatic loss of GRP94 protein within 3-8h of exposure, while induction of GRP78 and calreticulin occurred at 8 and 24h following exposure.

Sympathoexcitatory effects of estrogen in the insular cortex are mediated by GABA.

The current investigation examined the effect of estrogen in the insular cortex (IC) on autonomic tone and cardiac baroreceptor reflex function and sought to determine if modulation of neurotransmission was responsible for mediating this effect. Experiments were performed in Inactin-anaesthetized, male Sprague-Dawley rats. Animals were instrumented to record blood pressure, heart rate, vagal parasympathetic and renal sympathetic nerve activities, as well as cardiac baroreflex sensitivity (BRS).

Serum alkaline phosphatase isoenzyme profiles in phenobarbital-treated epileptic dogs.

Background: Serum total alkaline phosphatase (AP) activity commonly is high in dogs receiving phenobarbital. Specific isoenzymes responsible for this increase are not well documented.

Objectives: The purposes of this study were 1) to qualitatively and quantitatively describe serum AP isoenzymes in phenobarbital-treated dogs and 2) to monitor changes in serum AP isoenzyme activities associated with phenobarbital treatment over time.

Effects of season and sample handling on measurement of plasma alpha-melanocyte-stimulating hormone concentrations in horses and ponies.

Objective: To investigate effects of sample handling, storage, and collection time and season on plasma alpha-melanocyte-stimulating hormone (alpha-MSH) concentration in healthy equids.

Animals: 11 healthy Standardbreds and 13 healthy semiferal ponies.

Procedure: Plasma alpha-MSH concentration was measured by use of radioimmunoassay.

Treatment of inflammatory airway disease in young standardbreds with interferon alpha.

The effect of oral treatment with natural or recombinant human interferon alpha (HIA) on inflammatory airway disease in young standardbreds was assessed in a double-blind, randomized clinical trial. A total of 34 horses with nasal discharge, excess mucus in the trachea, and a persistent cough of at least 2 weeks' duration that interfered with training completed the trial. Horses were rested for 1 week and received oral treatment with either a saline placebo, recombinant human interferon alpha (rHIA; 90 U/horse/day), or natural human interferon alpha (nHIA: 50 U/horse/day) for 5 days.

Estrogen attenuates neuronal excitability in the insular cortex following middle cerebral artery occlusion.

The current investigation examined the role of estrogen in the insular cortex (IC) under both normal and ischemic conditions. Experiments were done in anaesthetized male Sprague-Dawley rats. The effect of systemic 17beta-estradiol (estrogen) administration on levels of amino acids and of endogenous estrogen obtained by microdialysis and its effect on neuronal activity of cells located in the insular cortex were measured in the absence of, and following permanent occlusion of, the right middle cerebral artery (MCA).

Estrogen-induced neurochemical and electrophysiological changes in the parabrachial nucleus of the male rat.

Estrogen has previously been shown to significantly change sympathetic and parasympathetic system output via an action within the central nuclei responsible for regulating autonomic tone. These estrogen-induced changes were observed within 30 min of systemic administration and could be blocked by the direct microinjection of the estrogen receptor antagonist, ICI 182780, into the parabrachial nucleus (PBN) of the pons. In the present investigation, we sought to determine the possible mechanism(s) by which estrogen produced these rapid changes in autonomic tone by determining if estrogen modulates neuronal excitability within the PBN.

Urethral pressure profile and hemodynamic effects of phenoxybenzamine and prazosin in non-sedated male beagle dogs.

Prazosin is a readily available alpha-adrenergic antagonist that may be useful in the management of functional urethral obstruction in companion animals. This study used urethral pressure profilometry to evaluate the urethral effects of prazosin and phenoxybenzamine in healthy, non-sedated, male Beagle dogs. Heart rate, indirect systolic, diastolic and mean arterial blood pressures were measured, and saline perfusion urethral pressure profilometry was performed at 0, 10, 20, and 40 min following intravenous administration of prazosin (0.

Novel non-labile covalent binding of sulfamethoxazole reactive metabolites to cultured human lymphoid cells.

Sulfamethoxazole (SMX) causes rare hypersensitivity syndrome reactions characterized by fever and multi-organ toxicity. Covalent binding of SMX reactive metabolites to cellular proteins has been demonstrated but the link between cytotoxicity and targets of covalent binding has not been explored. We therefore investigated the relationship between covalent binding of the reactive SMX-hydroxylamine (SMX-HA) metabolite, and its cytotoxicity to a hystiocytic lymphoma (U937) cell line.