Disposition of Extended Release Levetiracetam in Normal Healthy Dogs After Single Oral Dosing

Background

Levetiracetam is an anticonvulsant used for control of canine epilepsy. An extended release preparation should improve dosing convenience.

Objectives

To determine the disposition of extended release levetiracetam in normal dogs after single dosing.

Animals

Pharmacokinetic study: 16 healthy, adult dogs.

Methods

Using a partially randomized crossover study, levetiracetam (30 mg/kg) was administered intravenously (IV) and orally (PO) as extended release preparation with or without food. Blood was collected for 24 hours (IV) or 36 hours (PO). Serum levetiracetam was quantitated by immunoassay and data were subjected to noncompartmental analysis.

Results

Pharmacokinetic parameters for fasted versus fed animals, respectively, were (mean ± SEM): C _max = 26.6 ± 2.38 and 30.7 ± 2.88 μ/mL, T _max = 204.3 ± 18.9 and 393.8 ± 36.6 minutes, t _1/2 = 4.95 ± 0.55 and 4.48 ± 0.48 hours, MRT = 9.8 ± 0.72 and 10 ± 0.64 hours, MAT = 4.7 ± 0.38 and 5.6 ± 0.67 hours, and F = 1.04 ± 0.04 and 1.26 ± 0.07%. Significant differences were limited to T _max (longer) and F (greater) in fed compared to fasted animals. Serum levetiracetam concentration remained above 5 μ/mL for approximately 20 hours in both fasted and fed animals.

Conclusions and Clinical Importance

Extended release levetiracetam (30 mg/kg q12h), with or without food, should maintain concentrations above the recommended minimum human therapeutic concentration.     

Effect of Chronic Administration of Phenobarbital,or Bromide,on Pharmacokinetics of Levetiracetam in Dogs with Epilepsy

Background

Levetiracetam (LEV) is a common add‐on antiepileptic drug (AED) in dogs with refractory seizures. Concurrent phenobarbital administration alters the disposition of LEV in healthy dogs.

Hypothesis/Objectives

To evaluate the pharmacokinetics of LEV in dogs with epilepsy when administered concurrently with conventional AEDs.

Animals

Eighteen client‐owned dogs on maintenance treatment with LEV and phenobarbital (PB group, n = 6), LEV and bromide (BR group, n = 6) or LEV, phenobarbital and bromide (PB–BR group, n = 6).

Methods

Prospective pharmacokinetic study. Blood samples were collected at 0, 1, 2, 4, and 6 hours after LEV administration. Plasma LEV concentrations were determined by high‐pressure liquid chromatography. To account for dose differences among dogs, LEV concentrations were normalized to the mean study dose (26.4 mg/kg). Pharmacokinetic analysis was performed on adjusted concentrations, using a noncompartmental method, and area‐under‐the‐curve (AUC) calculated to the last measured time point.

Results

Compared to the PB and PB–BR groups, the BR group had significantly higher peak concentration (C _max) (73.4 ± 24.0 versus 37.5 ± 13.7 and 26.5 ± 8.96 μg/mL, respectively, P < .001) and AUC (329 ± 114 versus 140 ± 64.7 and 98.7 ± 42.2 h*μg/mL, respectively, P < .001), and significantly lower clearance (CL/F) (71.8 ± 22.1 versus 187 ± 81.9 and 269 ± 127 mL/h/kg, respectively, P = .028).

Conclusions and Clinical Importance

Concurrent administration of PB alone or in combination with bromide increases LEV clearance in epileptic dogs compared to concurrent administration of bromide alone. Dosage increases might be indicated when utilizing LEV as add‐on treatment with phenobarbital in dogs.     

Evaluation of a Quality‐of‐Life Tool for Cats with Diabetes Mellitus

Background: Success in management of diabetes mellitus (DM) is defined as improvement of blood glucose concentrations and clinical signs. However, the psychological and social impact of DM and its daily treatment regimen on quality of life (QoL) of both animal and owner is uncertain. Hypothesis/Objectives: To design, validate, and apply a diabetic pet and owner‐centered, individualized measure of impact of DM (DIAQoL‐pet). Animals/Subjects: Two hundred and twenty‐one owners of insulin‐treated diabetic cats were recruited to complete the DIAQoL‐pet. Methods: Discussions and pilot surveys with clinicians and owners of diabetic cats led to the design of 29 specific DM‐associated QoL questions. Owners of diabetic cats completed the finalized survey. Each item was scored according to impact frequency and perceived importance. An item‐weighted impact score (IWIS) for each item was calculated, as was an average‐weighted impact score (AWIS) by averaging all IWISs. Principal component analysis and Cronbach's α calculation assessed the measure's reliability. Two overview questions measured overall QoL and diabetes‐dependent QoL. Results: The DIAQoL‐pet showed high reliability (Cronbach α 0.83). The AWIS was ?1.76 ± 2.4 (mean ± SD). Areas reported as most negatively impacting QoL included: “boarding difficulties” (IWIS ± SD: ?4.67 ± 5.3), “owner wanting more control” (?4.34 ± 4.7), “difficulties leaving cat with friends or family” (?4.21 ± 4.7), “worry” (?4.10 ± 3.9), “worry hypo” (?3.67 ± 3.5), “social life” (?3.48 ± 3.9), “costs” (?3.04 ± 3.8), and “work life” (?3.03 ± 3.7). Forty‐one percent of owners believed their cat's life would be “a little better” without DM. Conclusions and Clinical Importance: The DIAQoL‐pet proved robust and identified specific areas most negatively impacting on diabetic cats and their owners' QoL. This tool warrants further investigation for use in clinical or research settings.     

Pharmacodynamics of Insulin Detemir and Insulin Glargine Assessed by an Isoglycemic Clamp Method in Healthy Cats

Background: Insulin detemir and insulin glargine are synthetic long‐acting insulin analogs. In people, insulin glargine is longer acting and has a relatively flat time‐action profile, while insulin detemir has significantly less within‐subject variability. Insulin detemir is also associated with less undesired weight gain and decreased frequency of hypoglycemic events. Objectives: To compare the pharmacodynamics of insulin detemir and insulin glargine in healthy cats. Animals: Ten young, healthy, neutered, purpose‐bred cats. Methods: Randomized, cross‐over design. Pharmacodynamics of insulin detemir and insulin glargine were determined by the isoglycemic clamp method after a 0.5 U/kg SC injection. Results: The only significant difference in the pharmacodynamics of insulin detemir and insulin glargine was onset of action (1.8 ± 0.8 and 1.3 ± 0.5 hours for insulin detemir and insulin glargine, respectively, P= .03). End of action of insulin detemir was reached at 13.5 ± 3.5 hours and for insulin glargine at 11.3 ± 4.5 hours (P= .18). Time‐to‐peak action of insulin detemir was reached at 6.9 ± 3.1 hours and for insulin glargine at 5.3 ± 3.8 hours (P= .7). The time‐action curves of both insulin analogs varied between relatively flat curves in some cats and peaked curves in others. Conclusion and Clinical Importance: Insulin detemir and insulin glargine have shorter durations of action than in people when assessed by the clamp method, but in some cats these insulin analogs could be useful as once‐a‐day drugs. Peak effects of both insulin analogs are pronounced in some cats.     

鸡单剂量内服替米考星的药代动力学研究

研究了鸡单剂量(20mg／kg)内服替米考星的药代动力学特征;微生物法测定血浆药物浓度,3P87药动学程序处理药时数据,SPSS(12)统计分析;结果:TMS在健康三黄鸡的药时数据符合一级吸收二室模型,主要药动学参数为:T1/2α为(0.662±0.354)h、T1/2β为(36.344±15.204)h、K1／2a为(0.340±0.132)h、V／F为(7.049±4.320)L／kg、Cmax为(1.108±0.523)mg／L、Tp为(0.765±0.163)h、CL为(0.571±0.138)L·h／kg、AUC(56.220±31.933)mg·h／L。表明:替米考星内服吸收快,达峰短,血中药物高,消除半袁期长,体内分布广泛,维持时间长。     

Evaluation of Serum Thyroid‐Stimulating Hormone Concentration as a Diagnostic Test for Hyperthyroidism in Cats

Background

In humans, measurement of serum thyroid‐stimulating hormone (TSH) concentration is commonly used as a first‐line discriminatory test of thyroid function. Recent reports indicate that canine TSH (cTSH) assays can be used to measure feline TSH and results can help diagnose or exclude hyperthyroidism.

Objectives

To investigate the usefulness of cTSH measurements as a diagnostic test for cats with hyperthyroidism.

Animals

Nine hundred and seventeen cats with untreated hyperthyroidism, 32 euthyroid cats suspected of having hyperthyroidism, and 131 clinically normal cats.

Methods

Prospective study. Cats referred to the Animal Endocrine Clinic for suspected hyperthyroidism were evaluated with serum T₄, T₃, free T₄ (fT ₄), and TSH concentrations. Thyroid scintigraphy was used as the gold standard to confirm or exclude hyperthyroidism.

Results

Median serum TSH concentration in the hyperthyroid cats (<0.03 ng/mL) was significantly (P < .001) lower than concentrations in clinically normal cats (0.05 ng/mL) or euthyroid cats with suspected thyroid disease (0.06 ng/mL). Only 18 (2.0%) hyperthyroid cats had measurable TSH concentrations (≥0.03 ng/mL), whereas 114 (69.9%) of the 163 euthyroid cats had detectable concentrations. Combining serum TSH with T₄ or fT ₄ concentrations lowered the test sensitivity of TSH from 98.0 to 97.0%, but markedly increased overall test specificity (from 69.9 to 98.8%).

Conclusions and Clinical Importance

Serum TSH concentrations are suppressed in 98% of hyperthyroid cats, but concentrations are measurable in a few cats with mild‐to‐moderate hyperthyroidism. Measurement of serum TSH represents a highly sensitive but poorly specific test for diagnosis of hyperthyroidism and is best measured in combination with T₄ and fT ₄.     

Antithrombotic Effect of Enoxaparin in Clinically Healthy Cats: A Venous Stasis Model

Background: Systemic arterial thromboembolic events are a serious complication of cardiac disease in cats.
Objectives: To determine if enoxaparin induces an antithrombotic effect in cats at a dosage of 1 mg/kg SC q12h and if this antithrombotic effect is predicted by anti-Xa activity.
Animals: Fourteen clinically healthy cats were divided into 3 groups: control (4 cats), treated and assessed at 4 hours (5 cats), and treated and assessed at 12 hours (5 cats).
Methods: A venous stasis model was used and the extent of thrombus formation estimated by measuring thrombus weight and accretion of ¹²⁵I-fibrinogen. Plasma anti-Xa activity was measured in treated cats.
Results: There was a significant reduction in thrombus formation in the 4 h group compared with control (median weight, 0.000 versus 0.565 mg/mm, P < .01; median %¹²⁵I-fibrinogen accretion, 0.0 versus 42.0%, P < .01). There was a reduction in thrombus formation in the 12 h group (median weight, 0.006 mg/mm, P = .09; median %¹²⁵I-fibrinogen accretion, 3.83%, P = .09) but this reduction was not significant. The median percent thrombus inhibition for treated cats was 100.0% at 4 hours and 91.4% at 12 hours. Plasma anti-Xa activity was not significantly correlated with thrombus formation.
Conclusions and Clinical Importance: This pilot study demonstrates that enoxaparin, when administered at a dosage of 1 mg/kg SC q12h, produces an antithrombotic effect in a venous statsis model in clinically healthy cats. Furthermore, this study demonstrates that anti-Xa activity is a poor predictor of enoxaparin's antithrombotic effect.     

Effect of Feeding an Iodine‐Restricted Diet in Cats with Spontaneous Hyperthyroidism

Background

Exclusive feeding of an iodine‐restricted diet has been proposed as a method for controlling clinical manifestations of hyperthyroidism in hyperthyroid cats.

Objectives

To determine the effect of feeding an iodine‐restricted diet on TT4 concentrations and clinical signs in cats with spontaneous hyperthyroidism.

Animals

Forty‐nine client‐owned cats with spontaneous hyperthyroidism.

Methods

Retrospective case series. Hyperthyroid cats were exclusively fed a commercially available iodine‐restricted diet. Clinical response was assessed by change in weight and heart rate and serum TT4, blood urea nitrogen (BUN), and creatinine concentrations at various times during dietary management (21–60 days, 60–180 days).

Results

Serum TT4 normalized in 20/48 cats (42%) and 39/47 cats (83%) at 21–60 days and 61–180 days, respectively. Cats in which the TT4 concentrations were still above reference range at 21–60 days had a significantly higher starting TT4 than those that normalized their TT4 levels during the same time period (P = .038). Body weight did not significantly increase (P = .34) nor heart rate decrease (P = .64) during the study. There was a significant decrease in serum creatinine (P = .028). Cats in the low reference range for serum TT4 concentrations did not have a significant increase in body weight (P = .41) nor creatinine (P = .54) when compared to those with high reference range.

Conclusions and Clinical Importance

Restricted‐iodine diets were effective at maintaining serum TT4 concentrations within reference ranges for a majority of cats with spontaneous hyperthyroidism over 1 year, although not all clinical signs of hyperthyroidism improved.     

Contrast‐Enhanced Ultrasound Examination for the Assessment of Renal Perfusion in Cats with Chronic Kidney Disease

Background

Contrast‐enhanced ultrasound examination (CEUS) is a functional imaging technique allowing noninvasive assessment of tissue perfusion. Studies in humans show that the technique holds great potential to be used in the diagnosis of chronic kidney disease (CKD). However, data in veterinary medicine are currently lacking.

Objectives

To evaluate renal perfusion using CEUS in cats with CKD.

Animals

Fourteen client‐owned cats with CKD and 43 healthy control cats.

Methods

Prospective case‐controlled clinical trial using CEUS to evaluate renal perfusion in cats with CKD compared to healthy control cats. Time‐intensity curves were created, and perfusion parameters were calculated using off‐line software. A linear mixed model was used to examine differences between perfusion parameters of cats with CKD and healthy cats.

Results

In cats with CKD, longer time to peak and shorter mean transit times were observed for the renal cortex. In contrast, a shorter time to peak and rise time were seen for the renal medulla. The findings for the renal cortex indicate decreased blood velocity and shorter total duration of enhancement, likely caused by increased vascular resistance in CKD. Increased blood velocity in the renal medulla has not been described before and may be because of a different response to regulatory factors in cortex and medulla.

Conclusions and Clinical Importance

Contrast‐enhanced ultrasound examination was capable of detecting perfusion changes in cats with CKD. Further research is warranted to assess the diagnostic capabilities of CEUS in early stage of the disease process.