Pharmacokinetics and pharmacodynamics of oral acetaminophen in combination with codeine in healthy Greyhound dogs

The purpose of this study was to determine the pharmacokinetic and antinociceptive effects of an acetaminophen/codeine combination administered orally to six healthy greyhounds. Antinociception was assessed using an electronic von Frey (vF) device as a mechanical/pressure model. Acetaminophen was administered at a dose of 600 mg (14.4–23.1 mg/kg) and codeine phosphate at 90 mg (2.1–3.3 mg/kg) equivalent to 67.5 mg codeine base (1.6–2.5 mg/kg). The geometric mean maximum plasma concentrations of acetaminophen, codeine, and codeine‐6‐glucuronide were 7.95 μg/mL, 11.0 ng/mL, and 3819 ng/mL, respectively. Morphine concentrations were <1 ng/mL. The terminal half‐lives of acetaminophen, codeine, and codeine‐6‐glucuronide were 0.94, 1.71, and 3.12 h. There were no significant changes in vF thresholds, except at 12 h which decreased on average by 17% compared to baseline. The decrease in vF thresholds at 12 h could be due to aversion, hyperalgesia, or random variability. The lack of antinociception in this study could be due to a true lack of antinociception, lack of model sensitivity, or specificity. Further studies using different models (including clinical trials), different dog breeds, multiple dose regimens, and a range of dosages are needed prior to recommended use or concluding lack of efficacy for oral acetaminophen/codeine in dogs.     

Serum antibodies against human albumin in critically ill and healthy dogs

OBJECTIVE: To characterize the magnitude and duration of the antibody response against human albumin (HA) in critically ill and healthy dogs. DESIGN: Cohort and cross-sectional study. ANIMALS: Fourteen critically ill dogs that received 25% HA as part of their treatment protocol, 2 healthy dogs with no known previous exposure to HA that received 2 infusions of 25% HA (positive control dogs), and 47 healthy dogs and 21 critically ill dogs with no known exposure to HA (negative control dogs). PROCEDURES: An ELISA to detect IgG against HA was developed. Serum samples were obtained from the critically ill dogs prior to infusion of HA, at the time of hospital discharge, and 4 to 6 weeks and 6 months after HA administration. Serum samples were obtained at 2- to 4-week intervals from both positive control dogs for 101 weeks. A single serum sample was obtained from each of the negative control dogs. RESULTS: All 14 critically ill dogs developed serum IgG against HA. Peak antibody response was detected 4 to 6 weeks after HA administration. In both positive control dogs, IgG against HA was detected 10 days after HA administration and continued past 97 weeks. The peak antibody response was detected at 3 weeks in 1 dog and at 9 weeks in the other. Five of the 68 (7%) negative control dogs had a positive antibody response. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that dogs developed a pronounced IgG response following exposure to HA and that some dogs with no history of HA administration were positive for anti-HA IgG.     

Pre-operative stress in dogs - a preliminary investigation of behavior and heart rate variability in healthy hospitalized dogs

OBJECTIVE: To assess pre-operative behavioral and physiological characteristics of healthy dogs hospitalized for elective surgery. STUDY DESIGN: Open clinical observational study. ANIMALS: Forty-one bitches hospitalized for elective ovariohysterectomy. METHODS: While undisturbed in a hospital cage, the behavior of the dog was recorded using a video camera and recorder. From the video recordings, various behavioral variables were registered. Simultaneous measurements were made on heart rates and heart rate variability (HRV) by use of an ambulatory electrocardiogram. In addition, the dog's response to human approach was noted. RESULTS: Different behavioral patterns were found in the dogs studied. Thirteen individuals were regarded as highly active, and were seen to bark or howl, manipulate the environment or attempt to flee vigorously. In 13 dogs (passive dogs) none of these activities occurred. Panting and displacement behaviors, such as snout licking, were observed in nearly all the animals monitored. In general, heart rates were higher and HRV lower with the most active individuals; however, the presence of physiological arousal could not be excluded in two animals with passive behaviors. To some extent, the behavior of the dog while undisturbed in the cage was reflected in the responses to a person entering the cage. CONCLUSIONS AND CLINICAL RELEVANCE: The different individual responses detected in this study raise an important question concerning their role and existence throughout the entire peri-operative period, especially during the post-anesthetic recovery phase when behavioral characteristics are commonly used to assess patient welfare. The results also emphasize the need for further investigations to explore the effects of pre-operative stressors on canine surgical patients, and the factors contributing to them.     

头孢维星在犬体内的药动学及生物利用度研究

建立了一种头孢维星在犬血浆中的高效液相色谱检测法,并研究了头孢维星在犬体内的药动学特征及生物利用度。选用健康家犬12只,按单剂量(8 mg/kg b.w.)分别静脉注射或皮下注射头孢维星,利用建立的方法对头孢维星在犬血浆中的浓度进行测定,采用Win Nonlin5.2.1程序的非房室模型处理药时数据。结果显示,静脉注射组的主要药动学参数为t1/2β=129.15±35.79 h;MRT=152.56±44.95 h;λz=0.0059±0.0023 h-1;Cl=1.24±0.56 m L/(h·kg);AUC=6942.88±2462.48μg獉h/m L;V=170.20±28.09 m L/kg。皮下注射组的主要药动学参数为t1/2β=136.94±20.96 h;MRT=167.77±28.15 h;Tmax=0.83±0.26 h;Cmax=59.51±7.99μg/m L;λz=0.0052±0.0009 h-1;Cl=1.05±0.21 m L/(h·kg);AUC=7332.58±1118.30μg·h/m L;V=203.81±30.09 m L/kg;F=105.61%。结果表明,头孢维星在家犬体内表现出吸收迅速、消除缓慢、表观分布容积大、生物利用度高等药动学特点。     

Predictive equations of maintenance energy requirement for healthy and chronically ill adult dogs

Maintenance energy requirement (MER) is the energy amount necessary for dogs to maintain their weight and body condition. Some factors can influence the MER, such as gender, age, neutering status and also diseases. The present retrospective study aimed to evaluate MER of adult dogs with several diseases and compare with the MER of healthy adult dogs, observing the influence of parameters such as body condition score (BCS), neutering status, gender, age, diagnosis and type of food on MER of these dogs. A total of 165 adult dogs with weight changes of ≤5% were included and divided in groups according to diagnosis. Mean MER for healthy dogs was 86.09 kcal/BW^0.75, which differed from NRC and FEDIAF recommendations for inactive adult dogs (p = .047). Lowest MERs were of the endocrinopathies (78.52 ± 19.32 kcal/BW^0.75), orthopaedic diseases (59.71 ± 19.30 kcal/BW^0.75) and neurologic diseases (78.83 ± 32.66 kcal/BW^0.75) groups. Gastrointestinal diseases (99.59 ± 20.36 kcal/BW^0.75), orthopaedic diseases (59.71 ± 19.30 kcal/BW^0.75) and neoplasia (95.61 ± 21.02 kcal/BW^0.75) groups were the only groups that differed from the mean MER of healthy adult dogs. Regarding BCS, for each increasing point in a 9-point scale, there was a decrease of 9.8 kcal/BW^0.75 on MER, independent of diagnosis (p < .0001; r² = .55). There was no difference regarding breed size gender and age, but neutered dogs presented lower MER (p = .031). Based on data obtained from the present study, it can be concluded that it is necessary to consider BCS, age, neutering status and diagnosis when calculating MER, both in healthy dogs and chronically ill dogs.     

Serum concentrations of monocyte chemoattractant protein‐1 in healthy and critically ill dogs

Background: The chemokine monocyte chemoattractant protein‐1 (MCP‐1) is a primary regulator of monocyte mobilization from bone marrow, and increased concentrations of MCP‐1 have been associated with sepsis and other inflammatory disorders in critically ill people. The relationship between MCP‐1 and disease in dogs has not been evaluated previously. Objective: The purpose of this study was to assess serum concentrations of MCP‐1 in healthy dogs, dogs in the postoperative period, and critically ill dogs. We hypothesized that MCP‐1 concentrations would be significantly increased in critically ill dogs compared with postoperative or healthy dogs. Methods: Serum concentrations of MCP‐1 were measured in 26 healthy control dogs, 35 postoperative dogs, and 26 critically ill dogs. Critically ill dogs were further subgrouped into dogs with sepsis, parvovirus gastroenteritis, immune‐mediated hemolytic anemia, and severe trauma (n=26). MCP‐1 concentrations were determined using a commercial canine MCP‐1 ELISA. Associations between MCP‐1 concentrations and disease status were evaluated statistically. Results: MCP‐1 concentration was significantly higher in critically ill dogs (median 578 pg/mL, range 144.7–1723 pg/mL) compared with healthy dogs (median 144 pg/mL, range 4.2–266.8 pg/mL) and postoperative dogs (median 160 pg/mL, range 12.6–560.4 pg/mL) (P<.001). All subgroups of critically ill dogs had increased MCP‐1 concentrations with the highest concentrations occurring in dogs with sepsis. However, differences among the 4 subgroups were not statistically significant. Conclusion: Critically ill dogs had markedly increased serum concentrations of MCP‐1 compared with postoperative and healthy dogs. These results indicate that surgery alone is not sufficient to increase MCP‐1 concentrations; thus, measurement of MCP‐1 may be useful in assessing disease severity in critically ill dogs.     

Pharmacokinetics of acetaminophen, codeine, and the codeine metabolites morphine and codeine-6-glucuronide in healthy Greyhound dogs

KuKanich, B. Pharmacokinetics of acetaminophen, codeine, and the codeine metabolites morphine and codeine‐6‐glucuronide in healthy Greyhound dogs. J. vet. Pharmacol. Therap. 33 , 15–21. The purpose of this study was to determine the pharmacokinetics of codeine and the active metabolites morphine and codeine‐6‐glucuronide after i.v. codeine administration and the pharmacokinetics of acetaminophen (APAP), codeine, morphine, and codeine‐6‐glucuronide after oral administration of combination product containing acetaminophen and codeine to dogs. Six healthy Greyhound dogs were administered 0.734 mg/kg codeine i.v. and acetaminophen (10.46 mg/kg mean dose) with codeine (1.43 mg/kg mean dose) orally. Blood samples were collected at predetermined time points for the determination of codeine, morphine, and codeine‐6‐glucuronide plasma concentrations by LC/MS and acetaminophen by HPLC with UV detection. Codeine was rapidly eliminated after i.v. administration (T½ = 1.22 h; clearance = 29.94 mL/min/kg; volume of distribution = 3.17 L/kg) with negligible amounts of morphine present, but large amounts of codeine‐6‐glucuronide (C_max = 735.75 ng/mL) were detected. The oral bioavailability of codeine was 4%, morphine concentrations were negligible, but large amounts of codeine‐6‐glucuronide (C_max = 1952.86 ng/mL) were detected suggesting substantial first pass metabolism. Acetaminophen was rapidly absorbed (C_max = 6.74 μg/mL; T_max = 0.85 h) and eliminated (T½ = 0.96 h). In conclusion, the pharmacokinetics of codeine was similar to other opioids in dogs with a short half‐life, rapid clearance, large volume of distribution, and poor oral bioavailability. High concentrations of codeine‐6‐glucuronide were detected after i.v. and oral administration.     

Bioavailability of oxytetracycline dihydrate tablets in dogs

Plasma oxytetracycline concentrations were studied in four healthy beagles after oral administration of four different commercial preparations of oxytetracycline dihydrate tablets. Although no statistically significant differences were found in the biological availability between the four tablets, assessed by the peak plasma level and the area under the plasma concentration—time curve, there was great variation in the plasma concentrations of oxytetracycline achieved in the sixteen experiments. This variation was not related to the in vitro dissolution properties of the tablets. As the amount of oxytetracycline dihydrate administered in die experiments was almost the maximum recommended dose and the mean peak plasma concentrations were either below or at the lower end of the therapeutic concentration range, it is suggested that higher oral doses than those officially recommended are required to attain effective plasma levels.     

Bioavailability and pharmacokinetics of florfenicol in healthy sheep

A study on bioavailability and pharmacokinetics of florfenicol was conducted in 20 crossbred healthy sheep following a single intravenous (i.v.) and intramuscular (i.m.) doses of 20 and 30 mg/kg body weight (b.w.). Florfenicol concentrations in serum were determined by a validated high-performance liquid chromatography method with UV detection at a wavelength of 223 nm in which serum samples were spiked with chloramphenicol as internal standard. Serum concentration-time data after i.v. administration were best described by a three-compartment open model with values for the distribution half-lives (T(1/2alpha)) 1.51 +/- 0.06 and 1.59 +/- 0.10 h, elimination half-lives (T(1/2beta)) 18.83 +/- 6.76 and 18.71 +/- 1.85 h, total body clearance (Cl(B)) 0.26 +/- 0.03 and 0.25 +/- 0.01 L/kg/h, volume of distribution at steady-state (V(d(ss))) 1.86 +/- 0.11 and 1.71 +/- 0.20 L/kg, area under curve (AUC) 76.31 +/- 9.17 and 119.21 +/- 2.05 microg.h/mL after i.v. injections of 20 and 30 mg/kg b.w. respectively. Serum concentration-time data after i.m. administration were adequately described by a one-compartment open model. The pharmacokinetic parameters were distribution half-lives (T(1/2k(a) )) 0.27 +/- 0.03 and 0.25 +/- 0.09 h, elimination half-lives (T(1/2k(e) )) 10.34 +/- 1.11 and 9.57 +/- 2.84 h, maximum concentrations (C(max)) 4.13 +/- 0.29 and 7.04 +/- 1.61 microg/mL, area under curve (AUC) 67.95 +/- 9.61 and 101.95 +/- 8.92 microg.h/mL, bioavailability (F) 89.04% and 85.52% after i.m. injections of 20 and 30 mg/kg b.w. respectively.     

Bioavailability of a silybin-phosphatidylcholine complex in dogs

Liver dysfunction often is associated with an imbalance in the production and removal of free radicals derived from oxygen and nitrogen and has been managed clinically with antioxidant supplements, including silymarin extract derived from milk thistle. The potential for enhanced bioavailability of a phytosome complex containing phosphatidylcholine and silybin, the primary active flavonolignan in silymarin extract, was tested in dogs. A group of eight beagles (four males, four females) were dosed orally with a silybin-phosphatidylcholine complex (SPC) and a commercially available standardized silymarin extract containing equivalent levels of silybin. Dosing with the SPC resulted in Cmax, Tmax, and AUC0-24 h values (mean+/-SD) for total silybin of 1310+/-880 ng/mL, 2.87+/-2.23 h, and 11,200+/-6520 ng.h/mL, respectively; corresponding values for a standardized silymarin extract were 472+/-383 ng/mL, 4.75+/-2.82 h, and 3720+/-4970 ng.h/mL. A second, separate group of beagles were also dosed with the extract alone, yielding values of 449+/-402 ng/mL, 6.87+/-7.43 h, and 2520+/-2976 ng.h/mL. These data show that a phytosome complex of phosphatidylcholine and silybin markedly enhances bioavailability in dogs.     

美洛昔康片剂在比格犬内的药代动力学及生物利用度研究

本研究以0.1 mg/kg体重的剂量研究美洛昔康片在比格犬中的药代动力学和生物利用度。HPLC分析血浆中的药物浓度,WinNonlin 6.4非房室模型计算药动学参数。比格犬内服美洛昔康片后测得0~48 h美洛昔康的T1/2、Cmax、Tmax和AUC0-t分别为14.55 ± 2.18 h、296.16 ± 74.15 ng·mL-1、6.0 ± 0.00 h和6356.79 ± 1089.78 ng·h·mL-1;比格犬静脉注射美洛昔康溶液后,测得0~48 h美洛昔康的T1/2和AUC0-t分别为11.54 ± 4.18 h和5510.68 ± 1075.29 ng·h·mL-1。内服美洛昔康片剂的绝对生物利用度为115.35%。美洛昔康片在比格犬体内消除速率较慢,消除半衰期较长,在体内滞留时间较长,绝对生物利用度高,药物在体内作用时间较长等药动学特征。     

Bioavailability of three brands of digoxin tablets in dogs

As information on the comparative bioavailability of digoxin tablets in dogs is scarce, three brands of digoxin tablets, commercially available in Belgium, were compared in 6 healthy dogs in a cross-over randomized design. Each dog received 1 mg digoxin on four occasions (once intravenously and 3 times orally). The mean areas under the curve relative to the intravenous value were 80, 71 and 65%. For the 3 oral preparations peak plasma concentrations were reached within 1 hour after dosing and often within 30 minutes. The mean peak concentrations were 11.0, 10.0 and 8.1 ng/ml. The times for 50% dissolution were 4.5, 7.5 and 25 minutes. Although differences between brands were only significant for the dissolution rate, the same ranking order was present for all parameters. It is therefore concluded that it may be advisable not to switch a digitalized dog from one brand to another.     

Comparison of the standard predictive equation for calculation of resting energy expenditure with indirect calorimetry in hospitalized and healthy dogs

OBJECTIVE: To determine the level of clinical agreement between 2 methods for the measurement of resting energy expenditure (REE). DESIGN: Prospective case series. ANIMALS: 77 dogs. PROCEDURE: Oxygen consumption (Vo2) and CO2 production (Vco2) were measured with an open-flow indirect calorimeter in healthy (n = 10) and ill (67) dogs. Measurements were collected at 3 time periods on 2 days. The Vo2 and the Vco2 measurements were then used to calculate the REE values. RESULTS: Mean values of measured (MREE) and predicted (PREE) REEs in healthy dogs and a dog with medical illnesses or trauma were not significantly different. There was a significant difference on day 2 between the MREE and PREE in the group of dogs recovering from major surgery. More importantly, there was significant variation between the PREE and MREE on an individual-dog basis. The PREE only agreed to within +/- 20% of the MREE in 51% to 57% of the dogs. CONCLUSIONS AND CLINICAL RELEVANCE: The level of agreement between these two methods for determining the 24-hour REE was poor in individual dogs. The level of disagreement between the 2 methods indicates that these methods may not be used interchangeably in a clinical setting. Measurement of REE by use of indirect calorimetry may be the only reliable method of determining REE in an individual ill or healthy dog.     

Endostatin concentrations in healthy dogs and dogs with selected neoplasms

Endostatin prevents angiogenesis and tumor growth by inhibiting endothelial cell proliferation and migration. The purpose of this study was to determine serum endostatin concentrations in 53 healthy dogs and in 38 dogs with confirmed malignant neoplasms. Endostatin concentration was determined with a competitive enzymatic immunoassay (EIA) with rabbit polyclonal antibody generated against a recombinant canine endostatin protein. Both the presence of cancer and increasing age were associated with increased serum concentration of endostatin. Endostatin concentration in healthy dogs was 87.7 +/- 3.5 ng/mL. Upper and lower limits of the reference range for serum endostatin concentration in healthy dogs were 60 and 113 ng/mL. Dogs with lymphoma (LSA) and hemangiosarcoma (HSA) had endostatin concentrations of 107 +/- 9.3 ng/mL. In conclusion, this study demonstrates that endostatin can be quantified in dogs and that endostatin concentrations are high in dogs with HSA and LSA.     

Plasma L-carnitine concentration in healthy dogs and dogs with hepatopathy

BACKGROUND: L-Carnitine has an essential role in lipid metabolism. Disturbances of L-carnitine metabolism can influence the energy supply of the organism. L-Carnitine is synthesized exclusively in the liver. Hence, we hypothesized that liver disease can influence L-carnitine metabolism. OBJECTIVES: The goal of this study was to compare plasma L-carnitine concentrations in dogs with different liver diseases of differing severity with the plasma L-carnitine concentrations of healthy dogs. METHODS: Sixteen dogs with inflammatory liver disease and 12 dogs with liver neoplasia were included in the study. Liver disease was diagnosed by clinical chemistry, ultrasonography, and histology of liver biopsy specimens. L-Carnitine concentration was measured in plasma samples using mass spectrometry, and compared among groups using unpaired Student's t-tests. RESULTS: Compared with healthy controls (24.4 +/- 8.4 micromol/L), the plasma L-carnitine concentration in dogs with liver disease (44.2 +/- 23.7 micromol/L) was significantly higher (P<.0001). The difference in L-carnitine concentration between dogs with moderate (n=8; 33.6 +/- 13.7 micromol/L) and severe (n=8; 57.4 +/- 22.9 micromol/L) hepatitis was also significant (P=.02). No difference in plasma L-carnitine concentration was found between dogs with hepatitis and those with liver tumors. CONCLUSIONS: Liver disease in dogs was accompanied by elevated plasma L-carnitine concentration. The severity of hepatitis appears to influence L-carnitine concentration.