Pharmacokinetic and pharmacodynamic evaluation of intravenous hydromorphone in cats

This study describes the pharmacokinetics of intravenous hydromorphone in cats and the simultaneous measurement of antinociceptive pharmacodynamic effects using a thermal threshold testing system. Following establishment of a baseline thermal threshold, six adult cats were administered 0.1 mg/kg of hydromorphone intravenously. Thermal threshold testing and blood collection were conducted simultaneously at predetermined time points. Plasma hydromorphone concentrations were determined by a liquid chromatographic-mass spectral method and pharmacokinetic analysis was performed by nonlinear least squares regression analysis. Plasma hydromorphone concentrations declined rapidly over time, and were below the limit of quantification of the assay (LOQ = 1.0 ng/mL) by 360 min. In contrast, thermal thresholds rose from a pretreatment value of 40.9 +/- 0.65 degrees C (mean +/- SEM) to instrument cut-out (55 degrees C) within 15 min and remained significantly elevated from 15-450 min after treatment. Inspection of the data revealed no direct correlation between plasma hydromorphone concentrations and the antinociceptive effect of this drug in cats. These findings support the importance of conducting pharmacokinetic studies in parallel with objective measurements of drug effect.     

Pharmacokinetics of gentamicin in cats given Escherichia coli endotoxin

Nineteen cats were given 3 mg of gentamicin sulfate/kg of body weight by rapid IV, SC, or IM injection for baseline values. Serum concentration of gentamicin vs time data were analyzed using a noncompartmental model based on statistical moment theory. One week later, each cat was given 0.5 microgram of Escherichia coli endotoxin/kg, IV. After cats had an increase in rectal temperature of at least 1 C, 3 mg of gentamicin/kg was administered by the same route used the previous week. Serum concentration of gentamicin vs time data were analyzed, and pharmacokinetic values were compared with base-line values. For IV studies, the half-life (t1/2) of gentamicin and the mean residence time were significantly different (P less than 0.05) compared with base line, whereas the total body clearance and apparent volume of distribution at steady state were not. The harmonic mean +/- pseudo SD for the t1/2 of gentamicin after IV administration was 76.8 +/- 12.6 minutes for base line and was 65.2 +/- 12.2 minutes in the same cats given endotoxin. The t1/2 of gentamicin after SC administration was 74.6 +/- 6.2 minutes for base line and was 65.2 +/- 13.6 minutes in the same cats given endotoxin. After IM administration, the t1/2 of gentamicin was 60.3 +/- 10 minutes for base line and was 59.7 +/- 13.6 minutes in the same cats given endotoxin. After IV administration of gentamicin, the arithmetic mean +/- SD for the mean residence time was 102.4 +/- 16.1 minutes for base line vs 79.2 +/- 18.4 minutes in the same cats given endotoxin.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetic interactions between repeated dose phenylbutazone and gentamicin in the horse

This study examined the pharmacokinetics of steady-state phenylbutazone and single bolus intravenous gentamicin when administered together in the horse. The trial design was completed as a cross-over with seven thoroughbred horses. In the first phase each horse received 2.2 mg/kg gentamicin intravenously. After a 2-week washout, each horse received 4.4 mg/kg phenylbutazone intravenously every 24 h for 5 days. On the fourth day each horse received gentamicin as before. Plasma was harvested for gentamicin concentration determination by fluorescence polarization immunoassay and for phenylbutazone concentration determination by high-performance liquid chromatography. All gentamicin data were best approximated by a two-compartment open model using sequential, weighted non-linear regression. Pharmacokinetic parameters were calculated using model-dependent formulae. Phenylbutazone data were analysed by non-compartmental methods. Phenylbutazone induced a 49% increase in the rate of gentamicin return to the central compartment from peripheral tissues (k₂₁) (P<0.05) and there was a trend to a 24% increase in k₁₂ (P = 0.052). The gentamicin elimination half-life was decreased 23% and the V_d(area) was reduced by 26%. No induction by gentamicin of changes in phenylbutazone pharmacokinetics were detected. In summary, phenylbutazone induced changes to the rate and extent of distribution and elimination of gentamicin. Therefore, care should be exercised in the use of aminoglycosides in equine patients concurrently maintained on phenylbutazone.     

Pharmacokinetics of gentamicin after intravenous and subcutaneous injection in obese cats

Six adult domestic shorthair obese cats were given 3-mg/kg gentamicin sulfate by rapid i.v. and by s.c. injection in a cross-over design. The plasma concentration-time data were analyzed using statistical moment theory with no assumption of a specific compartmental model. Means +/- SD for the half-life, which was calculated from the terminal slope of the log concentration-time curve, were 1.37 +/- 0.24 and 1.24 +/- 0.22 h following i.v. and s.c. injection, respectively. The apparent volume of distribution at steady state was 118.55 +/- 19.83 ml/kg, and total body clearance was 1.07 +/- 0.25 ml/kg/min. Bioavailability was 83.58 +/- 14.83% after s.c. administration. The calculated s.c. dose in obese cats to produce an average steady-state concentration of 4 micrograms/ml is 2.5 mg/kg every 8 h compared to 3 mg/kg in normal-weight cats.     

Pathologic changes and tissue gentamicin concentrations after intravenous gentamicin administration in clinically normal and endotoxemic cats

Hematologic and serum biochemical values, tissue gentamicin concentrations, and renal pathologic changes were determined in clinically normal and endotoxemic cats given 3 mg of gentamicin/kg of body weight, IV. Endotoxemia was induced by IV administration of 0.5 microgram of Escherichia coli endotoxin/kg of body weight. In experiment 1, 6 cats were given endotoxin. After rectal temperature increased at least 1 degree C, cats were given gentamicin. Blood samples were collected before and at 1 and 3 hours after administration of gentamicin. With the exception of severe leukopenia, other hematologic changes or changes in serum biochemical values were not observed. In experiment 2, 24 cats were allotted to 4 groups and were given gentamicin, endotoxin, gentamicin plus endotoxin, or neither substance. Three hours later, cats were euthanatized, and tissue and body fluid specimens were obtained and were assayed for gentamicin concentration. Kidney specimens were examined microscopically. Endotoxemic cats had more gentamicin in the renal medulla than did control cats, but none of the cats had detectable renal lesions. The possible nephrotoxic synergism between gentamicin and severe endotoxemia and the lack of major differences in gentamicin concentration in extrarenal tissues indicated that the dosage of gentamicin in endotoxemic cats does not have to exceed the dosage recommended for clinically normal cats. A single dose of gentamicin administered IV did not cause renal damage in mildly endotoxemic cats, but nephrotoxicity ascribed to multiple doses of gentamicin in more severely endotoxemic cats needs to be evaluated.     

The optimal intravenous dose of midazolam after intravenous ketamine in healthy awake cats

The effects of intravenous administration of variable-dose midazolam (0, 0.05, 0.075, 0.1, 0.3 and 0.5 mg/kg) and ketamine (3 mg/kg) were studied in twenty-four healthy unmedicated cats from time of administration until full recovery. End-points were chosen to determine the optimal dose to allow a short period of restraint without noxious stimuli, a short period of restraint with noxious stimuli and endotracheal intubation. Recovery characteristics, as well as undesirable behaviours observed during recovery, were also recorded. The dose of midazolam to achieve lateral recumbency with head down was found to be 0.016 mg/kg in 50% of the population (ED₅₀) and 0.054 mg/kg in 95% (ED₉₅) of the population. A midazolam dose of 0.286 mg/kg was required to prevent conscious perception of a stimulus to the ulnar nerve in 50% of the population and 0.652 mg/kg in 95% of the population. The ED₅₀ and ED₉₅ of midazolam required to prevent swallowing in response to a laryngoscope placed on the back of the tongue were found to be 0.265 mg/kg and 0.583 mg/kg, respectively. The ED₅₀ doses of 0.265 mg/kg for intubation and 0.286 mg/kg for restraint with noxious stimulation were close to the tested dose of 0.3 mg/kg. At that dose, the lack of responses lasted 3.67 ± 2.27 min for laryngoscope and 2.50 ± 2.20 min for ulnar nerve stimulation, with recovery to walking with ataxia taking 41.50 ± 15.18 min and complete recovery taking 3.6 ± 1.3 h. The predominant behavioural pattern during recovery was found to be normal, but some cats also exhibited abnormal behavioural patterns. Nine of the twelve cats exhibited an abnormal arousal state, with 4 being restless and 5 being sedated. Seven of the twelve cats exhibited an abnormal behaviour when approached, with three of the cats being more difficult to approach and four of the cats being easier to approach. Eight of the twelve cats exhibited an abnormal behavioural pattern when restrained, with the cats equally divided between more difficult and easier to restrain. Five of the twelve cats vocalized more during the recovery. The ED₅₀ of 0.042 mg/kg to induce chemical restraint without a noxious stimulus is close to the tested dose of 0.05 mg/kg. At that dose, cats remained lateral with head down for 5.49 ± 4.02 min, took 25.96 ± 5.77 min to walk with ataxia and 1.7 ± 0.4 h for complete recovery. The predominant behavioural patterns during recovery were normal, with several cats exhibiting some abnormal patterns. Two cats were sedated, one cat was more difficult to approach, one cat was easier to restrain and three cats were more vocal.     

Pharmacokinetics of gentamicin following single dose intravenous administration in normal and febrile goats

A pharmacokinetic study of gentamicin (5 mg/kg intravenous (i.v.)) was conducted first in cinically healthy female goats and then in the same goats after induction of fever by Escherichia coli endotoxin (0.2 μg/kg i.v.). Rectal temperature increased 1 to 1.5°C in febrile goats. Differences in the blood serum concentrations of gentamicin were not observed at any time between febrile and normal goats. The disposition kinetics of gentamicin were described by a biex-ponential expression C_P= Ae^-αt+ Be^-β. Median values for the half-lives of gentamicin were 103.6 min in normal and 136.0 min in febrile goats. The apparent volume of distribution (V_d) was 263.3 ml/kg in the febrile goats which was not different from that in the normal goats (240.6 ml/kg). The volume of the central compartment (V_c) was almost identical in normal and febrile goats. The body clearance (Cl_β) was observed to be 1.7 and 1.6 ml/min-kg in normal and febrile goats, respectively. Dosage regimens for gentamicin were calculated on the basis of median kinetic data.     

Pharmacokinetic and pharmacodynamic modelling of intravenous,intramuscular and subcutaneous buprenorphine in conscious cats

ObjectiveTo describe simultaneous pharmacokinetics (PK) and thermal antinociception after intravenous (IV), intramuscular (IM) and subcutaneous (SC) buprenorphine in cats.Study designRandomized, prospective, blinded, three period crossover experiment.AnimalsSix healthy adult cats weighing 4.1 ± 0.5 kg.MethodsBuprenorphine (0.02 mg kg^?1) was administered IV, IM or SC. Thermal threshold (TT) testing and blood collection were conducted simultaneously at baseline and at predetermined time points up to 24 hours after administration. Buprenorphine plasma concentrations were determined by liquid chromatography tandem mass spectrometry. TT was analyzed using anova (p < 0.05). A pharmacokinetic-pharmacodynamic (PK-PD) model of the IV data was described using a model combining biophase equilibration and receptor association-dissociation kinetics.ResultsTT increased above baseline from 15 to 480 minutes and at 30 and 60 minutes after IV and IM administration, respectively (p < 0.05). Maximum increase in TT (mean ± SD) was 9.3 ± 4.9 °C at 60 minutes (IV), 4.6 ± 2.8 °C at 45 minutes (IM) and 1.9 ± 1.9 °C at 60 minutes (SC). TT was significantly higher at 15, 60, 120 and 180 minutes, and at 15, 30, 45, 60 and 120 minutes after IV administration compared to IM and SC, respectively. IV and IM buprenorphine concentration-time data decreased curvilinearly. SC PK could not be modeled due to erratic absorption and disposition. IV buprenorphine disposition was similar to published data. The PK-PD model showed an onset delay mainly attributable to slow biophase equilibration (t_1/2k_e0 = 47.4 minutes) and receptor binding (k_on = 0.011 mL ng^?1 minute^?1). Persistence of thermal antinociception was due to slow receptor dissociation (t_1/2k_off = 18.2 minutes).Conclusions and clinical relevanceIV and IM data followed classical disposition and elimination in most cats. Plasma concentrations after IV administration were associated with antinociceptive effect in a PK-PD model including negative hysteresis. At the doses administered, the IV route should be preferred over the IM and SC routes when buprenorphine is administered to cats.     

Pharmacokinetic interpretation of erythromycin and tylosin activity in serum after intravenous administration of a single dose to cows.

The distribution and elimination kinetics of erythromycin and tylosin, which are macrolide antibiotics, were studied in healthy cows. A single dose (12-5 mg/kg) of drug was administered as an intravenous bolus, and blood samples were collected at precisely timed intervals. The standard cylinder plate bioassay method using Sarcina lutea as test organism was employed to determine antibiotic activity in the serum. The results suggested that these drugs are distributed in at least two kinetically distinct body compartments. By use of established mathematical techniques, values were assigned to the individual rate constants controlling distribution between the central and peripheral compartments and to the rate constant controlling overall elimination (beta) of each drug from the body. The calculated overall tissue to serum drug level ratios (k12/k21) after apparent distribution equilibrium was attained were 2-28 and 2-05 for erythromycin and tylosin, respectively. The half-life (mean+/-SD) of erythromycin was 3-16 h+/-0-44, while that of tylosin was 1-62 h+/-0-17. The total body clearance (ml/kg/min) values were 2-88+/-0-47 for erythromycin and 7-8+/-2-95 for tylosin. Analogue computer simulated curves of the antibiotic levels in the central and tissue compartments as wel as an elimination curve were generated. The tissue level of erythromycin reached a peak of 43 per cent of the dose at 67 min. At 6 h, the percentages of the dose of erythromycin in the central and tissue compartments and eliminated were 6, 19 and 75, respectively. The peak level of tylosin in the tissue compartment (26-5 per cent of the dose) was present at 30 min. At 4 h, 1 and 5 per cent of the dose were contained in the central and peripheral compartments, respectively, while 94 per cent had been eliminated. This single dose study provides information which is essential for the design of a satisfactory dosage regimen.     

Single intravenous and multiple intramuscular dose pharmacokinetics and tissue residue profile of gentamicin in sheep

Single and multiple dose gentamicin regimens were compared in sheep to determine the relevant pharmacokinetic differences. Seven mature sheep were given 10 mg/kg of gentamicin by IV bolus. Serum concentrations were monitored for 19 days. Four weeks after the initial bolus, gentamicin was administered IM (3 mg/kg every 8 hours) for 7 days. Ewes were euthanatized and necropsied at 1, 8, and 15 days after termination of the IM regimen and the tissues were assayed for gentamicin. Serum concentrations were analyzed using a triexponential equation. The IV kinetic studies revealed an alpha half-life (t1/2) of 0.31 +/- 0.14 hours, beta t1/2 of 2.4 +/- 0.5 hours, and gamma t1/2 of 30.4 +/- 18.9 hours. Multiple IM dose kinetic studies revealed a beta t1/2 of 2.8 +/- 0.6 hours and gamma t1/2 of 82.1 +/- 17.8 hours. After multiple dosing, gamma t1/2 was significantly longer than after the single IV bolus (P less than 0.05). Twenty-four hour urine collection accounted for 75% to 80% of the total IV dose. Renal cortical gentamicin concentration reached 224 micrograms/g of tissue and then decreased, with a 90-hour t1/2. Renal medullary gentamicin concentration reached 18 micrograms/g with a 42-day t1/2. After multiple dosing, liver gentamicin concentration reached 11 micrograms/g and skeletal muscle concentrations were less than or equal to 0.6 micrograms/g. Route or duration of administration significantly affected the gamma-phase serum concentrations, which may influence gentamicin nephrotoxicosis. The present study also illustrated the complexities in predicting aminoglycoside withdrawal times for food-producing animals before slaughter.     

Pharmacokinetics of gentamicin C1, C1a and C2 in horses after single intravenous dose

Gentamicin pharmacokinetics has not been studied in horses. Pharmacokinetics of gentamicin C1, C1a and C2 components following i.v. administration of total gentamicin at 6.6 mg/kg bwt to 6 healthy mature horses was determined. Significant differences in clearance, half-life (t 1/2), and mean residence time (MRT) between the gentamicin Cia and the 2 other components were found. The total body clearance (CL) of gentamicin C1a was 1.62 +/- 0.50 ml/min x kg and similar to the glomerular filtration rate (GFR) reported for horses. The CL of gentamicin C1 and C2 were 1.03 +/- 0.08 ml/min x kg and 1.10 +/- 0.15 ml/min x kg, respectively, and significantly slower than that of gentamicin C1a. The values of apparent volume of distribution at steady state were 0.22 +/- 0.05, 0.26 +/- 0.12 and 0.23 +/- 0.05 l/kg for gentamicin C1, C1a and C2, respectively. The MRT values were mean +/- s.d. 3.6 +/- 0.5, 2.7 +/- 0.3 and 3.5 +/- 0.4 h and the t 1/2 values were 3.1 (2.5-4.0), 2.4 (2.0-3.2) and 33 (2.4-4.3) h (harmonic mean and range) for gentamicin C1, C1a and C2, respectively. The MRT and t 1/2 values for gentamicin C1a were significantly shorter than those of gentamicin C1 and C2. It was concluded that the difference in pharmacokinetics between the gentamicin components has potential pharmacological and toxicological implications.     

Hypertrophic cardiomyopathy in a litter of five mixed-breed cats.

A litter of five, 18-month-old, mixed-breed cats were determined to have hypertrophic cardiomyopathy (HCM). Although no overt clinical signs were present in any cat, systolic heart murmurs were present in each. Electrocardiograms were normal, while subjective interpretations of heart enlargement on radiographs were made on four cats. Echocardiographic analyses indicated abnormalities consistent with HCM. Overt clinical signs are absent two years following diagnosis.     

Pharmacokinetic parameters and milk concentrations of ketoprofen after administration as a single intravenous bolus dose to lactating goats

Six clinically normal lactating does were administered ketoprofen (2.2 mg/kg intravenously (i. v.)). Blood and milk samples were collected prior to and for 24 h after drug administration. Drug concentrations in serum and milk were determined by high performance liquid chromatography. Pharmacokinetic parameters from each goat were combined to obtain mean estimates (mean ± SD) of half-life of elimination ( t _½β) of 0.32 ± 0.14 h, systemic clearance ( Cl ) of 0.74 ± 0.12 L/kg· h, and volume of distribution at steady state ( V _ss) of 0.23 ± 0.051 L/kg. In milk, ketoprofen was unmeasurable by the method employed (level of detection 25 ng/mL) for all samples.     

Clinical evaluation of propofol as an intravenous anaesthetic agent in cats and dogs

The clinical efficacy and safety of an emulsion containing 10 mg/ml of the intravenous anaesthetic propofol were evaluated in cats and dogs by veterinary surgeons in eight practices in the United Kingdom. A total of 290 dogs and 207 cats were anaesthetised with propofol either as a single injection for procedures of short duration, or as an induction agent with maintenance provided by further incremental injections or as an induction agent with maintenance by gaseous agents. The mean induction doses of propofol for unpremedicated dogs and cats were respectively 6.55 mg/kg and 8.03 mg/kg. The mean induction doses after premedication with a tranquilliser were 4.5 mg/kg and 5.97 mg/kg for dogs and cats, respectively. Mean recovery times ranged, depending on the method of anaesthesia, from 23 to 40 minutes in dogs and from 27 to 38 minutes in cats; recovery was defined as the time at which the animals were alert and able to stand. Adverse side effects were infrequent, apnoea during induction being the commonest. Acepromazine and atropine were most often used as premedicants although in a few cases diazepam, xylazine and other agents were employed. No clinical incompatibility was observed between propofol and any of the other agents administered during the study. The rapid and usually excitement-free recovery of the animals was a valuable feature of anaesthesia with propofol.     

Clinical evaluation of Alfaxan-CD® as an intravenous anaesthetic in young cats

Objective   To describe and evaluate the use of Alfaxan-CD ® as an intravenous anaesthetic in young cats.
Design   Thirty-five Domestic Short-hair cats aged from 3 to 12 months were admitted into the University Veterinary Teaching Hospital-Sydney for elective surgery. Anaesthesia was induced with Alfaxan-CD® and maintained with isoflurane: 22 cats received no premedication and 13 cats received acepromazine (0.03 mg/kg) and butorphanol (0.3 mg/kg) subcutaneously 30 min prior to induction.
Qualitative and quantitative data for induction and recovery were recorded. Physiological parameters were recorded at 0, 2 and 5 min post induction, and every 5 min thereafter until the end of the procedure.
Results   Intravenous injection of Alfaxan-CD® resulted in rapid induction of anaesthesia with a mean time to intubation of 122 s. The mean dose of Alfaxan-CD® used was 4.2 mg/kg in unpremedicated cats and 2.7 mg/kg in premedicated cats. All cats maintained a heart rate above 95 beats/min. No cat developed hypoxaemia. Hypercapnoea was detected in 4 cats and hypotension was observed in 18 cats. Time to extubation ranged from 1 to 9 min. The mean time to sternal recumbency for premedicated cats was 11 min; 77% of premedicated cats and 23% of unpremedicated cats had a recovery score of 1 or 2.
Conclusion   Alfaxan-CD® is an effective anaesthetic agent in young healthy cats, providing a smooth induction and rapid recovery. Cats that were premedicated with acepromazine and butorphanol prior to induction with Alfaxan-CD® had better recovery scores than those that were not premedicated.     

Hypercalcemia and calcium oxalate urolithiasis in cats: a report of five cases.

Five cats that presented for signs of lower urinary tract disease (i.e., pollakiuria and hematuria) secondary to a calcium oxalate urolithiasis are presented. On evaluation, all five cats had elevations of both serum ionized as well as total serum calcium. The hypercalcemia resolved after discontinuation of urinary acidifying therapy or a dietary change, or both.