Factors influencing the relationship between the dose of amlodipine required for blood pressure control and change in blood pressure in hypertensive cats

BACKGROUND: Hypertension is a common problem in elderly cats. In most cats, systolic blood pressure (SBP) of <160 mmHg is achieved in response to amlodipine besylate at either 0.625 or 1.25 mg q24h. The individual cat factors determining dose requirement dose have not been explored. AIMS: To determine whether individual cat factors influence the dose of amlodipine required to achieve adequate blood pressure control and to determine whether factors other than the prescribed dose of drug alter the achieved plasma amlodipine concentrations. METHODS: Fifty‐nine hypertensive cats that required 0.625 mg (A) and 41 cats that required 1.25 mg (B) amlodipine to reach a target SBP of <160 mmHg were identified, and plasma amlodipine concentrations were determined. Comparisons were made between groups, and multivariable linear regression models were performed to investigate predictors of antihypertensive response. RESULTS: Cats that required a greater dose of amlodipine had significantly higher SBP at diagnosis of hypertension (A: (median [25th, 75th percentile]) 182 [175,192] mmHg; B: 207 [194,217] mmHg, P < .001), but comparable blood pressure was achieved after treatment. Plasma amlodipine concentrations were directly related to the dose of amlodipine administered. At diagnosis, cats in group B had significantly lower plasma potassium concentration (A: 4.1 [3.8,4.5]; B: 3.8 [3.6,4.2] mEq/L, P < .01). Weight did not differ between groups. The decrease in SBP was directly and independently associated with the SBP at diagnosis and the plasma amlodipine concentration. CONCLUSIONS AND CLINICAL IMPORTANCE: Cats with higher blood pressure at diagnosis might require a greater dose of amlodipine to control their blood pressure adequately. Differences in amlodipine pharmacokinetics between cats do not seem to play a role in the antihypertensive response

Development and initial validation of a sensory threshold examination protocol (STEP) for phenotyping canine pain syndromes

Objective To study feasibility and test-retest repeatability of a sensory threshold examination protocol (STEP) and report quantitative sensory threshold distributions in healthy dogs. Study design Prospective, observational, cohort study. Animals Twenty-five healthy client-owned dogs. Methods Tactile sensitivity (TST) (von Frey filaments), mechanical thresholds (MT with 2, 4 and 8 mm probes), heat thresholds (HT) and responsiveness to cold stimulus (CT at 0 °C) were quantitatively assessed for five body areas (BA: tibias, humeri, neck, thoracolumbar region and abdomen) in a randomized order on three different occasions. Linear Mixed Model and Generalised Linear Mixed models were used to evaluate the effects of body weight category, age, sex, BA, occasion, feasibility score and investigator experience. Test-retest repeatability was evaluated with the Intra-class Correlation Coefficient (ICC). Results The STEP lasted 90 minutes without side effects. The BA affected most tests (p = 0.001). Higher thresholds and longer cold latencies were scored in the neck (p = 0.024) compared to other BAs. Weight category affected all thresholds (p = 0.037). Small dogs had lower MT (~1.4 N mean difference) and HT (1.1 0C mean difference) than other dogs (p = 0.029). Young dogs had higher HT than adults (2.2 0C mean difference) (p = 0.035). Gender also affected TST, MT and HT (p < 0.05) (females versus males: TST OR= 0.5, MT= 1.3 N mean difference, HT= 2.2 0C mean difference). Repeatability was substantial to moderate for all tests, but poor for TST. There was no difference in thresholds between occasions, except for CT. Test-retest repeatability was slightly better with the 2 mm MT probe compared to other diameters and improved with operator experience. Conclusions and clinical relevance The STEP was feasible, well tolerated and showed substantial test-retest repeatability in healthy dogs. Further validation is needed in dogs suffering pain

Pharmacokinetic and pharmacodynamic modelling after subcutaneous, intravenous and buccal administration of a high-concentration formulation of buprenorphine in conscious cats

The aim of this study was to describe the joint pharmacokinetic-pharmacodynamic model and evaluate thermal antinociception of a high-concentration formulation of buprenorphine (Simbadol™) in cats

Modeling of Large Pharmacokinetic Data Using Nonlinear Mixed-Effects: A Paradigm Shift in Veterinary Pharmacology. A Case Study With Robenacoxib in Cats

The objective of this study was to model the pharmacokinetics (PKs) of robenacoxib in cats using a nonlinear mixed‐effects (NLME) approach, leveraging all available information collected from cats receiving robenacoxib s.c. and/or i.v.: 47 densely sampled laboratory cats and 36 clinical cats sparsely sampled preoperatively. Data from both routes were modeled sequentially using Monolix 4.3.2. Influence of parameter correlations and available covariates (age, gender, bodyweight, and anesthesia) on population parameter estimates were evaluated by using multiple samples from the posterior distribution of the random effects. A bicompartmental disposition model with simultaneous zero and first‐order absorption best described robenacoxib PKs in blood. Clearance was 0.502 L/kg/h and the bioavailability was high (78%). The absorption constant point estimate (Ka = 0.68 h−1) was lower than beta (median, 1.08 h−1), unveiling flip‐flop kinetics. No dosing adjustment based on available covariates information is advocated. This modeling work constitutes the first application of NLME in a large feline population

Differential pharmacokinetics and pharmacokinetic/pharmacodynamic modelling of robenacoxib and ketoprofen in a feline model of inflammation

Robenacoxib and ketoprofen are acidic nonsteroidal anti‐inflammatory drugs (NSAIDs). Both are licensed for once daily administration in the cat, despite having short blood half‐lives. This study reports the pharmacokinetic/pharmacodynamic (PK/PD) modelling of each drug in a feline model of inflammation. Eight cats were enrolled in a randomized, controlled, three‐period cross‐over study. In each period, sterile inflammation was induced by the injection of carrageenan into a subcutaneously implanted tissue cage, immediately before the subcutaneous injection of robenacoxib (2 mg/kg), ketoprofen (2 mg/kg) or placebo. Blood samples were taken for the determination of drug and serum thromboxane (Tx)B2 concentrations (measuring COX‐1 activity). Tissue cage exudate samples were obtained for drug and prostaglandin (PG)E2 concentrations (measuring COX‐2 activity). Individual animal pharmacokinetic and pharmacodynamic parameters for COX‐1 and COX‐2 inhibition were generated by PK/PD modelling. S(+) ketoprofen clearance scaled by bioavailability (CL/F) was 0.114 L/kg/h (elimination half‐life = 1.62 h). For robenacoxib, blood CL/F was 0.684 L/kg/h (elimination half‐life = 1.13 h). Exudate elimination half‐lives were 25.9 and 41.5 h for S(+) ketoprofen and robenacoxib, respectively. Both drugs reduced exudate PGE2 concentration significantly between 6 and 36 h. Ketoprofen significantly suppressed (>97%) serum TxB2 between 4 min and 24 h, whereas suppression was mild and transient with robenacoxib. In vivoIC50COX‐1/IC50COX‐2 ratios were 66.9:1 for robenacoxib and 1:107 for S(+) ketoprofen. The carboxylic acid nature of both drugs may contribute to the prolonged COX‐2 inhibition in exudate, despite short half‐lives in blood

Major accidents scenarios used for LUP and off-site emergency planning : importance of kinetic description

International audienceThe European States, France in particular, faced with several industrial accidents, like one of the most serious one, the AZF explosion in Toulouse (France) in 2001, which created the trauma of the stakeholders concerned by the chemical risk (industry, authorities and citizen). Learning from this experience, the French Ministry in charge of the Environment, with the help of INERIS, worked on upgrading its chemical risks knowledge and studied to improve new methods on risk assessment. In 2004, INERIS was in charge of developing a new approach to classify accidental scenarios in terms of probability, severity and response time. In this paper, INERIS proposes a prioritisation based on time of occurrence, of development of hazardous phenomena and of effects on targets. Then, INERIS shows a method enabling to integrate, as a second prioritisation criteria, the on-site and off-site response capabilities/abilities as well as the means for population protection in terms of time allowed

Sedative and antinociceptive effects of different combinations of detomidine and methadone in standing horses

Objective To evaluate intravenous (IV) detomidine with methadone in horses to identify a combination which provides sedation and antinociception without adverse effects. Study design Randomized, placebo-controlled, blinded, crossover. Animals A group of eight adult healthy horses aged (mean ± standard deviation) 7 ± 2 years and 372 ± 27 kg. Methods A total of six treatments were administered IV: saline (SAL); detomidine (5 μg kg−1; DET); methadone (0.2 mg kg−1; MET) alone or combined with detomidine [2.5 (MLD), 5 (MMD) or 10 (MHD) μg kg−1]. Thermal, mechanical and electrical nociceptive thresholds were measured, and sedation, head height above ground (HHAG), cardiopulmonary variables and intestinal motility were evaluated at 5, 15, 30, 45, 60, 75, 90, 120 and 180 minutes. Normal data were analyzed by mixed-model analysis of variance and non-normal by Kruskal–Wallis (p < 0.05). Results Nociceptive thresholds in horses administered methadone with the higher doses of detomidine (MMD, MHD) were increased above baseline to a greater degree and for longer duration (MMD: 15–30 minutes, MHD: 30–60 minutes) than in horses administered low dose with methadone or detomidine alone (MLD, DET: 5–15 minutes). No increases in nociceptive thresholds were recorded in SAL or MET. Compared with baseline, HHAG was lower for 30 minutes in MMD and DET, and for 45 minutes in MHD. No significant sedation was observed in SAL, MET or MLD. Intestinal motility was reduced for 75 minutes in MHD and for 30 minutes in all other treatments. Conclusions Methadone (0.2 mg kg−1) potentiated the antinociception produced by detomidine (5 μg kg−1), with minimal sedative effects. Clinical relevance Detomidine (5 μg kg−1) with methadone (0.2 mg kg−1) produced antinociception without the adverse effects of higher doses of detomidine

The importance of measuring skin resistance for electrical nociceptive stimulation in standing horses

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Department of Veterinary Surgery and Anaesthesiology Faculty of Veterinary Medicine and Animal Science UNESP – Univ. Estadual PaulistaDepartments of Clinical Services and Sciences and Comparative Biomedical Sciences Royal Veterinary CollegeTaylor MonroeDepartment of Veterinary Surgery and Anaesthesiology Faculty of Veterinary Medicine and Animal Science UNESP – Univ. Estadual PaulistaFAPESP: 2010/08967-0FAPESP: 2014/00474-

Effect of Cyclooxygenase(COX)-1 and COX-2 inhibition on furosemide-induced renal responses and isoform immunolocalization in the healthy cat kidney

BACKGROUND: The role of cyclooxygenase(COX)-1 and COX-2 in the saluretic and renin-angiotensin responses to loop diuretics in the cat is unknown. We propose in vivo characterisation of isoform roles in a furosemide model by administering non-steroidal anti-inflammatory drugs (NSAIDs) with differing selectivity profiles: robenacoxib (COX-2 selective) and ketoprofen (COX-1 selective). RESULTS: In this four period crossover study, we compared the effect of four treatments: placebo, robenacoxib once or twice daily and ketoprofen once daily concomitantly with furosemide in seven healthy cats. For each period, urine and blood samples were collected at baseline and within 48 h of treatment starting. Plasma renin activity (PRA), plasma and urinary aldosterone concentrations, glomerular filtration rate (GFR) and 24 h urinary volumes, electrolytes and eicosanoids (PGE(2), 6-keto-PGF1(α,) TxB(2)), renal injury biomarker excretions [N-acetyl-beta-D-glucosaminidase (NAG) and Gamma-Glutamyltransferase] were measured. Urine volume (24 h) and urinary sodium, chloride and calcium excretions increased from baseline with all treatments. Plasma creatinine increased with all treatments except placebo, whereas GFR was significantly decreased from baseline only with ketoprofen. PRA increased significantly with placebo and once daily robenacoxib and the increase was significantly higher with placebo compared to ketoprofen (10.5 ± 4.4 vs 4.9 ± 5.0 ng ml(−1) h(−1)). Urinary aldosterone excretion increased with all treatments but this increase was inhibited by 75 % with ketoprofen and 65 % with once daily robenacoxib compared to placebo. Urinary PGE(2) excretion decreased with all treatments and excretion was significantly lower with ketoprofen compared to placebo. Urinary TxB(2) excretion was significantly increased from baseline only with placebo. NAG increased from baseline with all treatments. Immunohistochemistry on post-mortem renal specimens, obtained from a different group of cats that died naturally of non-renal causes, suggested constitutive COX-1 and COX-2 co-localization in many renal structures including the macula densa (MD). CONCLUSIONS: These data suggest that both COX-1 and COX-2 could generate the signal from the MD to the renin secreting cells in cats exposed to furosemide. Co-localization of COX isoenzymes in MD cells supports the functional data reported here. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12917-015-0598-z) contains supplementary material, which is available to authorized users