Plasma concentrations of LH, testosterone and estradiol-17.BETA. in male beagle dogs.

In cynomolgus macaques, plasma levels of sustained-release formulations of meloxicam meet or exceed efficacious concentrations for 48 to 72 h, thereby allowing less animal handling and providing more consistent efficacy than standard formulations of meloxicam. The goal of this study was to compare the pharmacokinetics of a single subcutaneous dose of a sustained-release formulation of meloxicam (Melox-SR) with those of oral (Melox-PO) and standard subcutaneous (Melox-SC) formulations dosed every 24 h for 3 consecutive days. Dogs (5 or 6 adult male Beagles) each received the following 3 treat- ments: first, Melox-SR (10 mg/mL, 0.6 mg/kg SC once), next Melox-SC (0.2 mg/kg SC once, followed by 0.1 mg/kg SC every 24 h), and finally Melox-PO (same dosage as Melox-SC), with a washout period of at least 2 wk between formulations. Blood was collected at 0 (baseline), 1, 4, 8, 12, 24, 48, and 72 h after the initial administration of each formulation for comparison of meloxicam plasma concentrations. Blood was also collected before administration and at 48 h after Melox-SR injection for CBC and chemistry analysis. Plasma concentrations (mean ± 1 SD) of Melox-SR peaked at the 1-h time point (2180 ± 359 ng/ mL), whereas those of Melox-PO (295 ± 55 ng/mL) and Melox-SC (551 ± 112 ng/mL) peaked at the 4-h time point. Melox-SR yielded significantly higher plasma concentrations than Melox-PO and Melox-SC until the 48 and 72-h time points, respec- tively. Melox-SC plasma concentrations were significantly higher than those of Melox-PO at 4, 8, 12, 24, 48 and 72 h. No lesions were noted at the Melox-SR injection sites, and Melox-SR administration was not associated with changes in the CBC and serum chemistry panels. A single 0.6-mg/kg dose of Melox-SR can yield plasma concentrations that exceed 350 ng/mL for at least 72 h in adult male dogs.

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Pharmacokinetics of Sativex® in Dogs: Towards a Potential Cannabinoid-Based Therapy for Canine Disorders

Biomolecules ◽

10.3390/biom10020279 ◽

2020 ◽

Vol 10 (2) ◽

pp. 279

Author(s):

María Fernández-Trapero ◽

Carmen Pérez-Díaz ◽

Francisco Espejo-Porras ◽

Eva de Lago ◽

Javier Fernández-Ruiz

Keyword(s):

Veterinary Medicine ◽

Single Dose ◽

Multiple Dose ◽

Plasma Concentrations ◽

Beagle Dogs ◽

Blood Samples ◽

Dose Treatment ◽

Pathological Conditions ◽

Sublingual Delivery ◽

Progressive Accumulation

The phytocannabinoid-based medicine Sativex® is currently marketed for the treatment of spasticity and pain in multiple sclerosis patients and is being investigated for other central and peripheral pathological conditions. It may also serve in Veterinary Medicine for the treatment of domestic animals, in particular for dogs affected by different pathologies, including human-like pathological conditions. With the purpose of assessing different dosing paradigms for using Sativex in Veterinary Medicine, we investigated its pharmacokinetics when administered to naïve dogs via sublingual delivery. In the single dose arm of the study, adult Beagle dogs were treated with 3 consecutive sprays of Sativex, and blood samples were collected at 12 intervals up to 24 h later. In the multiple dose arm of the study, Beagle dogs received 3 sprays daily for 14 days, and blood samples were collected for 24 h post final dose. Blood was used to obtain plasma samples and to determine the levels of cannabidiol (CBD), Δ9-tetrahydrocannabinol (Δ9-THC) and its metabolite 11-hydroxy-Δ9-THC. Maximal plasma concentrations of both Δ9-THC (Cmax = 18.5 ng/mL) and CBD (Cmax = 10.5 ng/mL) were achieved 2 h after administration in the single dose condition and at 1 h in the multiple dose treatment (Δ9-THC: Cmax = 24.5 ng/mL; CBD: Cmax = 15.2 ng/mL). 11-hydroxy-Δ9-THC, which is mainly formed in the liver from Δ9-THC, was almost undetected, which is consistent with the use of sublingual delivery. A potential progressive accumulation of both CBD and Δ9-THC was detected following repeated exposure, with maximum plasma concentrations for both cannabinoids being achieved following multiple dose. Neurological status, body temperature, respiratory rate and some hemodynamic parameters were also recorded in both conditions, but in general, no changes were observed. In conclusion, this study demonstrates that single or multiple dose sublingual administration of Sativex to naïve dogs results in the expected pharmacokinetic profile, with maximal levels of phytocannabinoids detected at 1–2 h and suggested progressive accumulation after the multiple dose treatment.

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Pharmacokinetics and Safety of Mitragynine in Beagle Dogs

Planta Medica ◽

10.1055/a-1212-5475 ◽

2020 ◽

Vol 86 (17) ◽

pp. 1278-1285 ◽

Cited By ~ 1

Author(s):

Elizabeth A. Maxwell ◽

Tamara I. King ◽

Shyam H. Kamble ◽

Kanumuri Siva Rama Raju ◽

Erin C. Berthold ◽

...

Keyword(s):

Peak Plasma ◽

Plasma Concentrations ◽

Compartmental Analysis ◽

Ultra Performance Liquid Chromatography ◽

Volume Of Distribution ◽

Pharmacokinetic Studies ◽

Beagle Dogs ◽

Limit Of Quantification ◽

Significant Information ◽

Pharmacokinetic Properties

AbstractMitragynine is the most abundant psychoactive alkaloid derived from the leaves of Mitragyna speciosa (kratom), a tropical plant indigenous to regions of Southeast Asia. Mitragynine displays a moderate affinity to opioid receptors, and kratom is often self-prescribed to treat pain and/or opioid addiction. The purpose of this study was to investigate the safety and pharmacokinetic properties of mitragynine in the dog. Single dose oral (5 mg/kg) and intravenous (0.1 mg/kg) pharmacokinetic studies of mitragynine were performed in female beagle dogs. The plasma concentrations of mitragynine were measured using ultra-performance liquid chromatography coupled with a tandem mass spectrometer, and the pharmacokinetic properties were analyzed using non-compartmental analysis. Following intravenous administration, mitragynine showed a large volume of distribution (Vd, 6.3 ± 0.6 L/kg) and high clearance (Cl, 1.8 ± 0.4 L/h/kg). Following oral mitragynine dosing, first peak plasma (Cmax, 278.0 ± 47.4 ng/mL) concentrations were observed within 0.5 h. A potent mu-opioid receptor agonist and active metabolite of mitragynine, 7-hydroxymitragynine, was also observed with a Cmax of 31.5 ± 3.3 ng/mL and a Tmax of 1.7 ± 0.6 h in orally dosed dogs while its plasma concentrations were below the lower limit of quantification (1 ng/mL) for the intravenous study. The absolute oral bioavailability of mitragynine was 69.6%. Administration of mitragynine was well tolerated, although mild sedation and anxiolytic effects were observed. These results provide the first detailed pharmacokinetic information for mitragynine in a non-rodent species (the dog) and therefore also provide significant information for allometric scaling and dose predictions when designing clinical studies.

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Effects of a [Met]-enkephalin analogue ([d-Ala2,N-Me-Phe4,Met-(O)5-ol]-enkephalin) on canine pituitary function

Journal of Endocrinology ◽

10.1677/joe.0.1270265 ◽

1990 ◽

Vol 127 (2) ◽

pp. 265-271 ◽

Cited By ~ 7

Author(s):

B. P. Meij ◽

A. Rijnberk ◽

J. A. Mol

Keyword(s):

Body Weight ◽

Opioid Receptors ◽

Arginine Vasopressin ◽

Plasma Concentrations ◽

Pituitary Function ◽

Opiate Antagonist ◽

Beagle Dogs ◽

Dose Rates ◽

Dose Dependent ◽

Μ Opioid Receptors

ABSTRACT In adult healthy beagle dogs, plasma concentrations of ACTH, cortisol, α-MSH, GH, prolactin and arginine vasopressin (AVP) were measured after i.v. administration of [d-Ala2,N-Me-Phe4,Met-(O)5-ol]-enkephalin (DAMME) at doses of 0·1, 0·5, 1, 5 and 10 μg/kg body weight. Significant dose-dependent increases occurred for ACTH, cortisol and GH at dose rates of 0·5, 1, 5 and 10 μg/kg body weight. Increments in plasma concentrations of prolactin were significant only at 5 and 10 μg DAMME/kg, and there was no significant effect on plasma concentrations of α-MSH and AVP. Prior i.v. administration of the opiate antagonist naloxone (0·1 mg/kg) attenuated the DAMME (10 μg/kg)-stimulated release of ACTH and cortisol. The results demonstrate that the [Met]-enkephalin analogue DAMME stimulates the release of ACTH, cortisol, GH and prolactin in dogs, and that this stimulation is, at least in part, mediated by μ-opioid receptors. The observations for ACTH and cortisol are different from those in man, where DAMME lowers their basal concentrations. Journal of Endocrinology (1990) 127, 265–271

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Pharmacokinetics and Pharmacodynamics of Immediate- and Modified-Release Mycophenolic Acid Preparations in Healthy Beagle Dogs

Frontiers in Veterinary Science ◽

10.3389/fvets.2020.611404 ◽

2021 ◽

Vol 7 ◽

Author(s):

Michael Klotsman ◽

Sebastien Coquery ◽

Gayatri Sathyan ◽

Vatsala Naageshwaran ◽

Paddy Shivanand ◽

...

Keyword(s):

Cell Proliferation ◽

T Cell ◽

Mycophenolic Acid ◽

Therapeutic Potential ◽

Plasma Concentrations ◽

T Cell Proliferation ◽

Dependent Manner ◽

Modified Release ◽

Beagle Dogs ◽

Immune Mediated

Background: Mycophenolic acid (MPA) is a broad-acting immunomodulating agent that may be therapeutically beneficial for the treatment of immune-mediated diseases in canine patients.Objectives: To determine the suppressive effects of MPA on T-cell proliferation, and to assess the feasibility of a canine-specific q24 h modified-release MPA formulation (OKV-1001b).Animals: Fifteen healthy purpose-bred male beagle dogs.Methods: Two nearly identical open-label fifteen-day studies were conducted in which dogs were randomized to receive mycophenolate mofetil (MMF; 10 mg/kg q12h), or two doses of OKV-1001b (270 mg and 180 mg; q24h). Serial pharmacokinetic (PK) and pharmacodynamic (PD) samples were collected on Days 1, 8, and 15. MPA plasma concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS), while an ex vivo T-cell proliferation assay assessed PD effects. Dogs were continuously monitored for evidence of side effects and gastrointestinal tolerability.Results: MPA induced inhibition of T-cell proliferation was observed following administration of all MPA preparations in a clear concentration-dependent manner. The PK/PD relationship was maintained across all days and time-points. Data generated herein suggest that MPA plasma concentrations above 600 ng/mL achieve at least 50% inhibition of T-cell proliferation.Conclusions and Clinical Importance: MPA holds therapeutic potential for treating dogs with immune-mediated disease, but clinical trials will be necessary to determine its safety and efficacy in naturally occurring disease. Likewise, q24h oral modified release MPA preparations that maintain MPA plasma concentrations between 600 and 1,000 ng/mL are warranted for further studies in client-owned dogs.

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Pharmacokinetic Modeling of Ceftiofur Sodium Using Nonlinear Mixed-Effects in Healthy Beagle Dogs

10.20944/preprints201907.0322.v1 ◽

2019 ◽

Author(s):

Jianzhong Wang ◽

Benjamin Schneider ◽

Jiao Xue ◽

Pan Sun ◽

Jicheng Qiu ◽

...

Keyword(s):

Plasma Concentrations ◽

Companion Animals ◽

Mixed Effects ◽

Absolute Bioavailability ◽

Parameter Estimates ◽

Nonlinear Mixed Effects ◽

Beagle Dogs ◽

First Order ◽

Pharmacologically Active ◽

Ceftiofur Sodium

Ceftiofur (CEF) sodium is a third-generation broad-spectrum cephalosporin commonly used in an extra-label manner in dogs for the treatment of respiratory and urinary system infections. To contribute to the literature supporting CEF use in companion animals, we have developed a compartmental, nonlinear mixed-effects (NLME) model of CEF pharmacokinetics in dogs (PK). We then used the mathematical model to predict (via Monte Carlo simulation) the duration of time for which plasma concentrations of CEF and its pharmacologically active metabolites remained above minimum inhibitory concentrations (respiratory tractEscherichia coli spp). Twelve healthy beagle dogs were administered either 2.2 mg/kg ceftiofur-sodium (CEF-Na) intravenously (I.V) or 2.2 mg/kg CEF-Na subcutaneously (S.C). Plasma samples were collected over a period of 72 hours post-administration. To produce a measurement of total CEF, both CEF and CEF metabolites were derivatized into desfuroylceftiofur acetamide (DCA) before analysis by UPLC-MS/MS. No adverse effects were reported after I.V or S.C dosing. The NLME PK models were parameterized using the stochastic approximation expectation maximization algorithm as implemented in Monolix 2018R2. A two-compartment mamillary model with first-order elimination and first-order S.C absorption best described the available kinetic data. Final parameter estimates indicate that CEF has a low systemic clearance (0.25 L/h/kg) associated with a low global extraction ratio E = 0.02) and a moderate volume of distribution (2.97 L/kg) in dogs. The absolute bioavailability after S.C administration was high (93.7%). Gender was determined to be a significant covariate in explaining the variability of S.C absorption. Our simulations predicted that a dose of 2.2 mg/kg CEF-Na S.C would produce median plasma concentrations of CEF of at least 0.5 µg/mL (MIC50) for approximately 30 hours.

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Chondrotoxicity of ciprofloxacin in immature Beagle dogs: immunohistochemistry, electron microscopy and drug plasma concentrations

Archives of Toxicology ◽

10.1007/s002040050009 ◽

2000 ◽

Vol 73 (10-11) ◽

pp. 564-572 ◽

Cited By ~ 34

Author(s):

R. Stahlmann ◽

S. Kühner ◽

M. Shakibaei ◽

R. Schwabe ◽

J. Flores ◽

...

Keyword(s):

Electron Microscopy ◽

Plasma Concentrations ◽

Beagle Dogs ◽

Drug Plasma Concentrations ◽

Drug Plasma

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Endocrinological effects of single daily ketoconazole administration in male beagle dogs

Acta Endocrinologica ◽

10.1530/acta.0.1070275 ◽

1984 ◽

Vol 107 (2) ◽

pp. 275-281 ◽

Cited By ~ 27

Author(s):

Roland De Coster ◽

Dominiek Beerens ◽

Jef Dom ◽

Gustaaf Willemsens

Keyword(s):

Oral Administration ◽

Plasma Cortisol ◽

Plasma Concentrations ◽

The Other ◽

Plasma Testosterone ◽

Beagle Dogs ◽

Basal Cortisol ◽

High Doses ◽

Daily Oral Administration

Abstract. Some endocrinological effects of single daily oral administration of 150 mg ketoconazole for 15 days were investigated in 4 male beagle dogs. Plasma testosterone fell markedly within 3–4 h and then progressively returned to control concentrations by 10 h after drug administration. On the other hand, plasma 17α-hydroxyprogesterone, progesterone and 17α,20α-dihydroxyprogesterone increased within 3–10 h before returning to basal values after 24 h. Plasma LH did not rise significantly though some high individual levels were noted. Plasma cortisol and oestradiol-17α levels were not significantly modified by the treatment. These results confirm that a high therapeutic dose of ketoconazole, given orally once a day, transiently inhibits in vivo the 17–20 lyase enzyme of the testis, without modifying basal cortisol and oestradiol-17β plasma concentrations and that enzymatic inhibition still occurs after daily treatment for up to 2 weeks but remains transient and parallels the resorption profile of the drug so that normal plasma testosterone levels are observed from 10 to 24 h after drug intake. However, permanent inhibition of androgen biosynthesis might be obtained by the administration of high doses of ketoconazole given several times a day.

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Toxicologic and Inhibitory Receptor Actions of the Etomidate Analog ABP-700 and Its Metabolite CPM-Acid

Anesthesiology ◽

10.1097/aln.0000000000002758 ◽

2019 ◽

Vol 131 (2) ◽

pp. 287-304 ◽

Cited By ~ 1

Author(s):

Beatrijs I. Valk ◽

Megan McGrath ◽

Dario Lehoux ◽

Brad Zerler ◽

John J. A. Marota ◽

...

Keyword(s):

Peak Plasma ◽

Glycine Receptor ◽

Plasma Concentrations ◽

Aminobutyric Acid ◽

High Dose ◽

Glycine Receptors ◽

Beagle Dogs ◽

Response Curves ◽

Involuntary Muscle ◽

Acid Type

Abstract Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background The etomidate analog ABP-700 produces involuntary muscle movements that could be manifestations of seizures. To define the relationship (if any) between involuntary muscle movements and seizures, electroencephalographic studies were performed in Beagle dogs receiving supra-therapeutic (~10× clinical) ABP-700 doses. γ-aminobutyric acid type A (GABAA) and glycine receptor studies were undertaken to test receptor inhibition as the potential mechanism for ABP-700 seizures. Methods ABP-700 was administered to 14 dogs (6 mg/kg bolus followed by a 2-h infusion at 1 mg · kg-1 · min-1, 1.5 mg · kg-1 · min-1, or 2.3 mg · kg-1 · min-1). Involuntary muscle movements were documented, electroencephalograph was recorded, and plasma ABP-700 and CPM-acid concentrations were measured during and after ABP-700 administration. The concentration-dependent modulatory actions of ABP-700 and CPM-acid were defined in oocyte-expressed α1β3γ2L GABAA and α1β glycine receptors (n = 5 oocytes/concentration) using electrophysiologic techniques. Results ABP-700 produced both involuntary muscle movements (14 of 14 dogs) and seizures (5 of 14 dogs). However, these phenomena were temporally and electroencephalographically distinct. Mean peak plasma concentrations were (from lowest to highest dosed groups) 35 μM, 45 μM, and 102 μM (ABP-700) and 282 μM, 478 μM, and 1,110 μM (CPM-acid). ABP-700 and CPM-acid concentration–GABAA receptor response curves defined using 6 μM γ-aminobutyric acid exhibited potentiation at low and/or intermediate concentrations and inhibition at high ones. The half-maximal inhibitory concentrations of ABP-700 and CPM-acid defined using 1 mM γ-aminobutyric acid were 770 μM (95% CI, 590 to 1,010 μM) and 1,450 μM (95% CI, 1,340 to 1,560 μM), respectively. CPM-acid similarly inhibited glycine receptors activated by 1 mM glycine with a half-maximal inhibitory concentration of 1,290 μM (95% CI, 1,240 to 1,330 μM). Conclusions High dose ABP-700 infusions produce involuntary muscle movements and seizures in Beagle dogs via distinct mechanisms. CPM-acid inhibits both GABAA and glycine receptors at the high (~100× clinical) plasma concentrations achieved during the dog studies, providing a plausible mechanism for the seizures.

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