Effects of ambient temperature on the half-life and dosage regimen of amikacin in the gopher snake

Eight gopher snakes were given amikacin (5 mg/kg of body weight IM) and were housed at ambient temperatures of 25 C or 37 C. Snakes housed at 37 C had a larger volume of distribution, and a more rapid body clearance of amikacin while the apparent half-life was not changed significantly. The minimum inhibitory concentrations of amikacin against isolated snake pathogens were determined at both temperatures. Bacteria were twice as sensitive at 37 C than at 25 C. The data indicated that amikacin should be given IM at a dose schedule of 5 mg/kg (loading dose) followed by 2.5 mg/kg every 72 hours, and that snakes should be housed near the high end of their preferred optimum ambient temperature during treatment.     

Cardiopulmonary effects of a medetomidine-ketamine combination administered intravenously in gopher tortoises

OBJECTIVE: To determine whether IV administration of a combination of medetomidine and ketamine depresses cardiopulmonary function in healthy adult gopher tortoises. DESIGN: Prospective study. ANIMALS: 3 adult male and 3 adult female nonreleasable gopher tortoises. PROCEDURE: Prior to the study, carotid and jugular catheters were surgically placed in each tortoise for blood collection, direct arterial blood pressure monitoring, and drug administration. Heart rate, direct carotid arterial blood pressure, and body temperature were measured before and every 5 minutes for 45 minutes after IV injection of medetomidine (100 microg/kg [45.5 microg/lb]) and ketamine (5 mg/kg [2.3 mg/lb]). Carotid arterial blood samples were collected before and 5, 15, 30, and 45 minutes after medetomidine-ketamine administration to determine pH, PO2, and PCO2. Atipamezole (500 mg/kg [227 microg/lb], IV) was administered 30 minutes after administration of medetomidine-ketamine. RESULTS: The medetomidine-ketamine combination caused a moderate increase in arterial blood pressure, and moderate hypercapnia and hypoxemia. There were no significant changes in heart rate or body temperature. Intravenous administration of atipamezole rapidly induced severe hypotension. CONCLUSIONS AND CLINICAL RELEVANCE: The combination of medetomidine and ketamine administered IV resulted in effective short-term immobilization adequate for minor diagnostic procedures in gopher tortoises. This combination also caused moderate hypoventilation, and it is recommended that a supplemental source of oxygen or assisted ventilation be provided. Atipamezole administration hastens recovery from chemical immobilization but induces severe hypotension. It is recommended that atipamezole not be administered IV for reversal of medetomidine in tortoises and turtles.     

Clinical pharmacokinetics of amikacin in dogs

After IV, IM, and subcutaneous injection of single dosages of amikacin (5, 10, and 20 mg/kg of body weight) in each of 4 dogs, the elimination kinetics of amikacin were determined. The pattern of urinary excretion and cumulative amount excreted unchanged in 24 hours were also determined. Amikacin had a short half-life (approx 1 hour) that was independent of the dosage. Intravenous injection of 10 mg/kg gave apparent volume of distribution of 226 +/- 37 ml/kg and body clearance of 2.64 +/- 0.24 ml/min.kg (mean +/- SD, n = 4). Within 6 hours, greater than 90% of the antibiotic was excreted in the urine, regardless of the route of administration. For isolates of common bacterial species from the canine urinary tract, minimum inhibitory concentrations of amikacin, gentamicin, tobramycin, and kanamycin were determined in vitro. Cumulative percentages were approximately the same for urinary isolates of Escherichia coli, Proteus mirabilis, Pseudomonas aeruginosa, and coagulase-positive staphylococci that were susceptible (minimum inhibitory concentrations less than or equal to 32 micrograms/ml) to increasing concentrations of amikacin, gentamicin, and tobramycin, in vitro. Klebsiella pneumoniae was significantly more susceptible to amikacin than were the other bacteria evaluated. Widest variations in susceptibility to aminoglycosides were found with urinary isolates of streptococcal species. For dogs with normal renal function, an amikacin dosage of 10 mg/kg (IM or subcutaneously) is recommended every 8 hours for treatment of systemic infections, and every 12 hours for treatment of urinary tract infections caused by susceptible bacteria.     

Comparative pharmacokinetics of amikacin in Greyhound and Beagle dogs

The purpose of the study was to compare the pharmacokinetics of amikacin administered i.v., to Greyhound and Beagle dogs and determine amikacin pharmacokinetics administered subcutaneously to Greyhounds. Amikacin was administered i.v. at 10 mg/kg to six healthy Greyhounds and six healthy Beagles. The Greyhounds also received amikacin, 10 mg/kg s.c. Plasma was sampled at predetermined time points and amikacin concentrations determined by a fluorescence polarization immunoassay (FPIA).
The volume of distribution was significantly smaller in Greyhounds (mean = 176.5 mL/kg) compared to Beagles (234.0 mL/kg). The C ₀ and AUC were significantly larger in Greyhounds (86.03 μg/mL and 79.97 h·μg/mL) compared to Beagles (69.97 μg/mL and 50.04 h·μg/mL). The plasma clearance was significantly lower in Greyhounds (2.08 mL/min/kg) compared to Beagles (3.33 mL/min/kg). The fraction of the dose absorbed after s.c. administration to Greyhounds was 0.91, the mean absorption time was 0.87 h, and the mean maximum plasma concentration was 27.40 μg/mL at 0.64 h.
Significant differences in the pharmacokinetics of amikacin in Greyhounds indicate it should be administered at a lower dose compared to Beagles. The dose in Greyhounds to achieve a C _max: AUC  ≥ 8 for bacteria (with an MIC  ≤ 4 μg/mL) is 12 mg/kg q24 h compared to 22 mg/kg q24 in Beagles.     

Comparative pharmacokinetics of amikacin sulphate in calves and sheep

The pharmacokinetics of amikacin sulphate were investigated in calves and sheep. Five animals of each species were given 7.5 mg kg-1 intravenously and intramuscularly. After intravenous administration the pharmacokinetic parameters significantly different (P less than 0.01) between calves (first value) and sheep (second value), were: the initial concentration (87.05, 146.6 micrograms ml-1), the apparent distribution volume (350, 200 ml kg-1), the area under curve (5512, 11,018 min micrograms ml-1) and the clearance (1.5, 0.7 ml min-1 kg-1). After dosing intramuscularly the peak concentration (23.5, 34.36 micrograms ml-1), the peak time (45, 75 min) and the area under curve (5458, 9191 min micrograms ml-1) were significantly different (P less than 0.01). No significant differences were observed in the terminal halflife values, suggesting that elimination rate was independent of both route of administration and animal species. The drug in aqueous solution showed a good bioavailability in both animal species (about 0.87 in sheep and greater than 0.99 in calves) despite the greater serum concentrations always attained in sheep.     

The effect of tropical ambient temperature on growth and metabolism in pigs

Three experiments involving 34 individually fed pigs were conducted in Guadeloupe (16 degrees Lat. N., 61 degrees Long. W.) to determine the effects of environmental temperature (tropical, 22 to 32 degrees C, vs thermoneutral, 17 to 21 degrees C) and feeding method (restricted vs ad libitum) on performance, carcass characteristics and physiological and metabolic responses of pigs at three weight ranges (8 to 25, 29 to 50 and 54 to 79 kg live weight). Compared with the control environment, the tropical climate increased rectal temperature and respiratory rate but depressed growth rate and efficiency of feed utilization. In addition, in the heaviest weight group, feed intake was reduced and body fat increased. Changes in metabolic status, such as increased concentrations of plasma free fatty acids, triglycerides, cholesterol and adipose tissue lipoprotein lipase activity were observed in pigs housed in the tropical environment. Moreover, in these pigs, there was a decreased plasma concentration of thyroid hormones (triiodothyronine and thyroxine). These results indicate that tropical ambient temperature markedly affects the metabolism of pigs and, therefore, probably influences their nutritional requirements.     

A meta-analysis of the effects of high ambient temperature on growth performance of growing-finishing pigs

High ambient temperature (T) is one of the most important climatic factors influencing pig performance. Increased T occurs sporadically during summer heat waves in temperate climates and year round in tropical climates. Results of published experiments assessing the effects of high T on pig performance are surprisingly variable. Thus, a meta-analysis was performed to aggregate our knowledge and attempt to explain differences in the results across studies on the effect of increased T on ADFI and ADG in growing-finishing pigs. Data for ADFI and ADG were extracted from 86 and 80 trials, respectively, from articles published in scientific journals indexed in PubMed, Science Direct, and from proceedings of scientific meetings through November 2009. Data on ADFI and ADG were analyzed using a linear mixed model that included the linear and the quadratic effects of T and BW, and their interactions as continuous, fixed effects variables, and the trial as a random effect factor (i.e., block). In addition, the effects of housing type (2 levels: individual and group housing) and the year of publication (3 levels: 1970 to 1989, 1990 to 1999, and 2000 to 2009) on the intercept and the linear regression term for T (i.e., the slope) were also tested. Results showed that high T had a curvilinear effect on ADFI and ADG and that this effect was more pronounced in heavier pigs. Across T, ADFI was less when pigs were group-housed. The intercept and the regression coefficient (slope) for T were significantly affected by the year of publication. The effect of increased T was greater in more contemporary works, suggesting that modern genotypes could be more sensitive to heat stress than older genotypes of lesser growth potential. In conclusion, pig performance decreases at an accelerating rate as T is increased. The large between-study variability on the effects of high T on pig performance is partially explained by differences in pig BW and to a lesser extent by the year the study was published.     

The pharmacokinetics of ketoconazole and its effects on the pharmacokinetics of midazolam and fentanyl in dogs

KuKanich, B., Hubin, M. The pharmacokinetics of ketoconazole and its effects on the pharmacokinetics of midazolam and fentanyl in dogs. J. vet. Pharmacol. Therap . 33 , 42–49.
Ketoconazole inhibits the Cytochrome P450 3A12 (CYP3A12) metabolizing enzyme as well as the p-glycoprotein efflux pump. The extent and clinical consequence of these effects are poorly understood in dogs. The objective was to assess the pharmacokinetics of ketoconazole after single and multiple doses and the effect of multiple doses of ketoconazole on midazolam (a known CYP3A12 substrate) and the opioid fentanyl. Six greyhound dogs were studied. The study consisted of three phases. Phase 1 consisted of i.v. midazolam (0.23 mg/kg base) and fentanyl (15.71 μg/kg base). Phase 2 consisted of a single oral dose of ketoconazole (mean dose 12.34 mg/kg). Phase 3 consisted of i.v. midazolam (0.23 mg/kg) and fentanyl (10 μg/kg) after 5 days of oral ketoconazole (12.25 mg/kg/day). Ketoconazole significantly inhibited its own elimination with the mean residence time ( MRT ) increasing from 6.24 h in Phase 1 to 12.54 h in Phase 3. Ketoconazole significantly decreased the elimination of midazolam, as expected, with the MRT increasing from 0.81 to 1.49 h. The elimination of fentanyl was not significantly altered by co-administration of ketoconazole with the MRT being 3.90 and 6.35 h. The MRT was the most robust estimate of decreased drug elimination.     

Fluctuating ambient temperature for weaned pigs: effects on performance and immunological and endocrinological functions

Following weaning at 3 wk of age, crossbred barrows and gilts were housed in temperature-controlled rooms for a 5-d adjustment period at 35 degrees C, then assigned to receive constant ambient temperature (CT) or fluctuating ambient temperature (FT) treatment for the nursery phase of the experiment. Pigs in FT received 12 h at 35 degrees C and 12 h at 15 degrees C daily for the initial 2 wk of the experiment, then 12 h at 29 degrees C and 12 h at 9 degrees C daily for the final 2 wk. Pigs in CT received 35 degrees C and 29 degrees C continuously for the first and final 2 wk, respectively. Weekly growth performance, feed intake and feed-conversion efficiency were not affected by treatment. Plasma glucose, serum cortisol, monocyte phagocytic function and antibody response to a commercial E. coli bacterin were similar in pigs exposed to CT and FT treatments. Concentrations of insulin in serum were similar between treatments at 0, 1 and 3 wk but were increased for pigs in FT at 2 (P less than .05) and 4 wk (P less than .01). Numbers of lymphocytes, band neutrophils and monocytes in pigs were not influenced by ambient temperature treatment. However, numbers of mature neutrophils for pigs in FT were increased (P less than .05) at 1 and 3 wk of treatment. Eosinophils were also elevated in FT pigs at 4 wk of treatment. Pairs of littermate pigs that had been given CT and FT treatments were selected randomly to continue on the finishing phase of the experiment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acclimation effects on fed and fasted broiler thermobalance during thermoneutral and high ambient temperature exposure

1. Two experiments were conducted to quantify heat stress (HS) acclimation effects on heat production (H), evaporative heat loss (E), sensible heat loss (S) and change in heat content (HC) of 24 food‐deprived and precision fed broilers.

2. In experiment 1, heat stressed fasted HS acclimated birds (group 1) exhibited lower H (22–6 v. 25–5 kJ/kgW^0.66 per h), E (7.5 v. 8.8 kJ/kgW^0.66 per h), core body temperature (41.8 v. 42.4

C) and respiration rate (129 v. 160 breaths/min) than nonacclimated controls (group 2).

3. In contrast to the first experiment, precision fed HS acclimated birds (group 1) exhibited a higher H (29.3 v. 28.0 kJ/kgW^0.66 per h) and E (10.5 v. 96 kJ/kgW^0.66 per h) during HS and elevated H during thermoneutral periods than their non‐acclimated counterparts (group 2). The elevated H became more pronounced with each successive HS exposure.

4. These results indicate that H increases when broilers are fed, that broilers preferentially dissipate heat as S when environmental conditions permit, and that food and/or energy consumption level markedly influences the bird's capacity to exhibit a HS acclimation response, and in fact has the ability to mask it.     

Population pharmacokinetics of a single intramuscular administration of tulathromycin in adult desert tortoises (Gopherus agassizii)

Tulathromycin, a long acting macrolide antibiotic, has demonstrated efficacy against respiratory pathogens including Mycoplasma bovis and M. hyopneumoniae. A pharmacokinetic study was performed to evaluate the clinical applicability of tulathromycin in desert tortoises following a single intramuscular dose of 5 mg/kg. A single blood sample was collected from 110 different desert tortoises at 0.25, 0.5, 1, 4, 8, 24, 48, 72, 120, and 240 h following drug administration. Plasma concentrations of the parent form of tulathromycin were measured using liquid chromatography/mass spectrometry. As each tortoise was only bled once, pharmacokinetic parameters were initially estimated using a naïve pooled data approach. Given the variability in the data, population‐based compartmental modeling was also performed. Using nonparametric population compartmental modeling, a two‐compartment model with first‐order absorption and elimination best fit the data. An observed C_max of 36.2 ± 29.7 μg/mL was detected at 0.25 h (observed T_max). The elimination half‐life (T_½el) was long (77.1 h) resulting in detectable plasma concentrations 240 h postadministration. This study represents a preliminary step in evaluating the utility of tulathromycin in chelonian species and demonstrates that population data modeling offers advantages for estimating pharmacokinetic parameters where sparse data sampling occurs and there is substantial variability in the data.     

The effects of ketoconazole on the pharmacokinetics of cyclosporine A in cats

OBJECTIVE: To determine the effects of ketoconazole (KC) on the pharmacokinetics of cyclosporine A (CsA) elimination in cats. STUDY DESIGN: Research study and prospective clinical trial. ANIMALS: Five healthy adult cats (pharmacokinetic studies) and 6 client-owned cats with chronic renal failure. METHODS: Blood CsA concentrations were measured after CsA (4 mg/kg i.v.) administration with or without concurrent oral KC (10 mg/kg). Subsequently, a combined CsA-KC immunosuppressive regimen was used in cats after kidney transplantation. Blood CsA concentrations were measured using high performance liquid chromatography. CsA elimination was analyzed using a computerized pharmacokinetics program. RESULTS: KC increased blood CsA concentrations 1.8-fold and 2.2-fold at 12 and 24 hours after CsA administration. KC significantly decreased the mean systemic CsA clearance from 2.73 mL/min/kg to 1.22 mL/min/kg resulting in an increase in the terminal phase half-life from 10.7 to 22.2 hours. The volume of distribution of steady-state of CsA was unaffected by KC. In a series of clinical feline kidney transplant patients, a once-a-day CsA-KC regimen was able to be used in most of the cats and was effective for prevention of allograft rejection in all of these cats. CONCLUSION AND CLINICAL RELEVANCE: KC is an effective adjunct treatment for immunosuppression in feline kidney transplant patients. KC suppresses CsA elimination, which reduces the need for CsA and allows once daily administration of CsA.     

Effect of ambient temperature on mammary gland metabolism in lactating sows

Two groups of three multiparous Large White x Landrace sows were used to investigate the direct effect of ambient temperature on mammary gland metabolism. Sows from the first group were exposed to temperatures of 28 degrees C between d 8 and 14 of lactation, and 20 degrees C between d 15 and 21; treatments were reversed in the second group. Four to six d after farrowing, an ultrasonic blood flow probe was implanted around the right external pudic artery and catheters were fitted in the right anterior mammary vein and in the carotid artery. After surgery all sows were fed 3.8 kg/d of a lactation diet. The arteriovenous (AV, mg/L) plasma samples were obtained every 30 min between 0915 and 1545 on d 5 of exposure to ambient temperature; the same day, milk samples were collected at 1630. Additional arterial samples were obtained between 1000 and 1100 on d 1, 4, and 6 of exposure. Milk yield was estimated from the body weight gain of the litter. Elevated temperature tended to reduce BW loss (2.44 vs 1.82 kg/d, P < 0.10), but did not affect milk yield (11.0 kg/d). Glucagon and leptin arterial concentrations increased (12 and 8%, respectively; P < 0.10), but thyroxin and triiodothyronine concentrations decreased (26 and 16%, respectively; P < 0.01) between 20 and 28 degrees C. Expressed as a percentage of total nutrients, AV difference, glucose, amino acids, triglycerides (TG), free fatty acids, and lactate A-V differences represented 60, 20, 11, 8, and 1%, respectively. Exposure to 28 degrees C increased the extraction rate of glucose, TG, and a-amino acid N (13, 8, and 2.5%, respectively; P < 0.10). The extraction rates of essential and nonessential amino acids were not affected by temperature. The right pudic artery mammary blood flow increased (872 vs 945 mL/min, P < 0.05) between 20 and 28 degrees C, whereas milk yield was unaffected by temperature. It is suggested that this apparent inefficiency of the sow mammary gland in hot conditions could be related to an increase of proportion of blood flow irrigating skin capillaries in order to dissipate body heat.     

Effects of high ambient temperature on plasma metabolomic profiles in chicks

Exposure to high ambient temperature is detrimental to the poultry industry. To understand the influence from a metabolic perspective, we investigated the effects of exposure to high ambient temperature on plasma low‐molecular‐weight metabolite levels in chicks using gas chromatography/mass spectrometry‐based non‐targeted metabolomic analysis. Heat exposure for 4 days suppressed growth and food intake. Of the 92 metabolites identified, the levels of 29 decreased, whereas the levels of nine increased. We performed an enrichment analysis on the identified metabolites and found 35 candidates for metabolic processes affected by heat exposure. Among them, the sulfur amino acid metabolic pathway was clearly detected and the levels of the following related metabolites were decreased: cystathionine, cysteine, cystine, homocysteine and hypotaurine. Changes in the kynurenine pathway in tryptophan metabolism, which is linked to the immune system and oxidative stress, were also observed: kynurenine and quinolinic acid levels increased, whereas nicotinamide levels decreased. These results suggest the possible involvement of various metabolic processes in heat‐exposed chicks. Some of these metabolites would be important to understand the mechanism of biological responses to high ambient temperature in chicks.     

The influence of breed,age, gender,training level and ambient temperature on forelimb and back temperature in racehorses

A previous thermographic study of racehorses identified 13 regions of interest (ROIs) for monitoring the impact of training. However, that investigation did not consider the influence of breed, age, gender or training intensity level on the temperature of ROIs. The present study adopted a multivariate analysis approach to determine whether the aforementioned factors, along with ambient temperature, significantly influenced ROI temperature in the key body regions. Thermography measurements were obtained from 53 racehorses of three breeds. Horses were in regular training for over 10 months, having 13 thermographic examinations in each racing season. Backward stepwise multiple linear regression indicated that ambient temperature and breed contributed significantly to the model for predicting ROI temperature at all 13 ROIs. Training intensity level contributed significantly to the model only at the thoracic vertebrae, the left third metacarpal bone and left fetlock joint. Neither gender nor age contributed to the model significantly at any ROI. Our data suggest that ambient temperature, breed and training level affect racehorse body surface temperature in some areas of the distal parts of the forelimbs and the back. This contributes to a better understanding of the normal range of thermographic findings in racehorses undergoing intensive training.     

Relation between pharmacokinetics of amikacin sulfate and sepsis score in clinically normal and hospitalized neonatal foals.

Pharmacokinetic values after IV administration of amikacin sulfate were determined for clinically normal and hospitalized foals during the first week of life. The relations between drug disposition and sepsis score and serum creatinine concentration also were studied. In clinically normal foals, differences in sepsis score, serum creatinine concentration, and pharmacokinetic variables of amikacin were not found between foals 1 to 3 and 4 to 7 days old. In hospitalized foals, sepsis score, serum creatinine concentration, area under the curve, area under the moment curve, and mean residence time were greater, and total clearance was decreased, compared with values in clinically normal foals. Sepsis score and serum creatinine concentration were inversely correlated to amikacin clearance and appeared to be useful indicators of altered drug disposition.