Pharmacokinetics of clindamycin HCl administered intravenously, intramuscularly and subcutaneously to dogs

A buffered aqueous solution of clindamycin Hcl (200 mg/mL) was injected intravenously (i.v.) intramuscularly (i.m.) and subcutaneously (s.c.) in a non-randomized, partial cross-over trial involving six male and six female dogs. Blood samples were collected at conventional, predetermined time periods and serum drug concentrations were determined by microbiological assay. Dogs were observed clinically for signs of pain, and activity of serum creatine phosphokinase (CPK) was monitored after i.m. dosing. The i.v. data from five of the dogs best fitted a two-compartment open-system pharmacokinetic model whereas a non-compartment model was most suitable for analysis of the data from the remaining seven dogs. The mean i.v. elimination half-life (t1/2 beta) and the mean residence time (MRT) were 124 and 143 min, respectively. The mean volume of distribution at steady state (Vss) was 0.86 L/kg. Little pain was recorded upon i.m. injection; mean peak serum drug concentration (Cmax) was 4.4 micrograms/mL, the elimination half-life (t1/2el) was 247 min and the calculated bioavailability (F) was 115% of the i.v. dose. Serum CPK activity was elevated to 25-fold the pretreatment level in samples collected 4, 8 and 12 h after i.m. injection. Pain was not recorded after s.c. drug administration; the mean Cmax of 20.8 micrograms/mL was significantly greater than the corresponding value for the i.m. route, and F was 310%. The s.c. route appears to be superior to the i.m. route in terms of local tolerance and serum drug level; a 10 mg/kg SID treatment regimen is suggested for treatment of canine infections due to clindamycin sensitive bacteria.     

Post-operative analgesic effects of butorphanol or firocoxib administered to dogs undergoing elective ovariohysterectomy

ObjectiveTo compare the post-operative analgesic effects of butorphanol or firocoxib in dogs undergoing ovariohysterectomy.Study designProspective, randomized, blinded, clinical trial.AnimalsTwenty-five dogs >1 year of age.MethodsDogs received acepromazine intramuscularly (IM), 0.05 mg kg^?1 and either butorphanol IM, 0.2 mg kg^?1 (BG, n = 12) or firocoxib orally (PO), 5 mg kg^?1 (FG, n = 13), approximately 30 minutes before induction of anesthesia with propofol. Anesthesia was maintained with isoflurane. Ovariohysterectomy was performed by the same surgeon. Pain scores using the dynamic and interactive visual analog scale (DIVAS) were performed before and at 1, 2, 3, 4, 6, 8 and 20 hours after the end of surgery by one observer, blinded to the treatment. Rescue analgesia was provided with morphine (0.5 mg kg^?1) IM and firocoxib, 5 mg kg^?1 (BG only) PO if DIVAS > 50. Groups were compared using paired t-tests and Fisher’s exact test (p < 0.05). Data are presented as mean ± SD.ResultsThe BG required significantly less propofol (BG: 2.6 ± 0.59 mg kg^?1; FG: 5.39 ± 0.7 mg kg^?1) (p < 0.05) but the anesthesia time was longer (BG: 14 ± 6, FG: 10 ± 4 minutes). There were no differences for body weight (BG: 7.9 ± 5.0, FG: 11.5 ± 4.6 kg), sedation scores, and surgery and extubation times (BG: 10 ± 2, 8 ± 5 minutes; FG: 9 ± 3, 8 ± 4 minutes, respectively) (p > 0.05). The FG had significantly lower pain scores than the BG at 1, 2 and 3 hours following surgery (p < 0.05). Rescue analgesia was administered to 11/12 (92%) and 2/13 (15%) dogs in the BG and FG, respectively (p < 0.05).Conclusion and clinical relevanceFirocoxib produced better post-operative analgesia than butorphanol. Firocoxib may be used as part of a multimodal analgesia protocol but may not be effective as a sole analgesic.     

A thermal threshold assay to measure the nociceptive response to morphine sulphate in cattle.

A thermal threshold measurer (TTM) apparatus was developed and tested in 12 dry, nonpregnant, culled cows with the purpose of measuring the thermal nociceptive threshold and of finding the response to morphine sulphate dosages. The cows received a cumulative dose (from 0.00 to 0.40 mg/kg BW) of morphine sulphate through a catheter in the jugular vein. The interval between doses was 20 min, and a nociceptive test was performed 15 min after each injection. The TTM device consisted of a 60 W halogen bulb mounted in a 15 cm PVC tube, with a 0.6 s response time probe attached to its end, connected to a thermocouple. The probe measured the response temperature on the skin over the middle phalanges on the dorsum of the forefoot. The radiating heat stimulus from the bulb was instantaneously terminated with the foot-lift response of the tested animal. The nociceptive response to the 0.00 mg/kg dose was considered the baseline and subsequent measurements were expressed in difference from it. Data were evaluated in a regression analysis using the GLM procedure. A significant elevation (P < 0.0001) in the nociceptive threshold of the cows with cumulative dosing of morphine sulphate was noticed. A high variability (P < 0.0001) in the response among animals was also detected, suggesting that a 2-step dose of morphine sulphate is necessary to achieve a certain degree of induced analgesia in all cows. The nociceptive assay described, using the TTM device, was able to detect an elevation of the thermal threshold of cows due to morphine sulphate induced analgesia. An increase in locomotory behaviour or other side effects due to morphine sulphate were not noticed.     

The steady-state pharmacokinetics and bioequivalence of carprofen administered orally and subcutaneously in dogs

Eighteen male Beagle dogs were randomized to oral (p.o.) or subcutaneous (s.c.) carprofen administration in a two-sequence, two-period crossover design with a 10-day washout between periods. Twenty-five milligrams of carprofen was administered p.o. or s.c. every 12 h for 7 days. Plasma concentrations of carprofen collected after the first and last treatments were determined by high-performance liquid chromatography. Carprofen concentration data were natural log transformed and geometric means were calculated for maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC0--12) following the first dose and Cmax and AUC0--12 following administration of the last dose. Formulations were considered bioequivalent if the 90% confidence interval (CI) of the mean difference for each variable between formulations were within -20% and 25% of the oral formulation. The mean Cmax and AUC0--12 were 16.9 microg/mL and 73.1 microg. h/mL, respectively, following a single oral dose and 8.0 microg/mL and 64.3 microg x h/mL, respectively, following a single s.c. injection. The 90% CI for Cmax (-56.8 to -48.7%) was outside of the bioequivalence criteria whereas the 90% CI for AUC0--12 (-16.3 to -7.5%) was within the bioequivalence criteria. At steady-state, the mean Cmax and AUC0--12 were 18.7 microg/mL and 101.9 microg x h/mL, respectively, following p.o. administration and 14.7 microg/mL and 111.0 microg x h/mL, respectively, following s.c. injection. The 90% CI was outside the bioequivalence criteria for Cmax (-30.8 to -10.8) but within the bioequivalence criteria for AUC0--12 (2.3-15.9%). The results of this study indicate that peak plasma concentrations of carprofen differ when administered p.o. and s.c., but that total drug exposure following a single dose and at steady-state are bioequivalent.     

Use of thermal threshold response to evaluate the antinociceptive effects of butorphanol in cats

OBJECTIVE: To characterize the antinociceptive actions of several doses of butorphanol by use of a thermal threshold testing device specifically designed for cats. ANIMALS: 6 domestic shorthair cats. PROCEDURE: The study was a masked, randomized, crossover design. Thermal thresholds were measured by use of a thermal threshold-testing device specifically developed for cats. A small probe containing a heater element and temperature sensor was held with consistent contact against a shaved area of the cat's skin with an elasticized band. Skin temperature was recorded before each test, prior to activation of the heater. On detection of a response (eg, the cat flinched, turned, or jumped), the stimulus was terminated and the threshold temperature recorded. Three baseline measurements were recorded before IV injection of 0.1, 0.2, 0.4, or 0.8 mg of butorphanol/kg. Each cat received all doses in a randomized order at least 1 week apart. The investigator was unaware of the treatment received. Thermal thresholds were measured every 15 minutes for 6 hours. RESULTS: Mean+/-SD pretreatment threshold temperature for all cats was 40.8+/-2.2 degrees C. There were no dose-related differences among treatments. There was a significant increase in threshold values for all treatments from 15 to 90 minutes after injection. Mydriasis was detected in all cats after treatment with butorphanol and dysphoric behavior was frequently exhibited. CONCLUSIONS AND CLINICAL RELEVANCE: Results obtained by use of a thermal stimulus indicated that the duration of antinociceptive action of butorphanol was 90 minutes and there was no dose-response relationship in cats.     

Pharmacokinetics of subcutaneously administered doramectin in alpacas

The objective of this research was to evaluate comparative pharmacokinetics of doramectin in alpacas, after subcutaneous administration of 0.2 mg/kg dose. Six healthy adult alpacas, mean age of 5 years ± 1, (three female and three gelded males) of mean bodyweight of 62 kg ± 16 kg with an average body condition scored 2.8 ± 1 out of five, were used in this study. Serial blood samples were collected from the jugular vein before the administration until day 21 afterwards to establish the pharmacokinetics of doramectin after its subcutaneous administration at 0.2 mg/kg dose. The blood samples were analysed using high-performance liquid chromatography (HPLC), fluorescence detection method with precolumn derivatisation, validated for alpacas. The pharmacokinetic parameters were calculated using a noncompartmental model, and results showed Cmax (6.05 ± 5.34 ng/ml), Tmax (3.83 ± 2.48 days), AUC (62.12 ± 18.86 ng/ml × d), terminal half-life (6.2 ± 4.9 days) and MRT (11.56 ± 4.43 days). The results of this study showed that the Cmax and AUC were much lower than in cattle and sheep at the same dosage. Tmax remained similar to cattle and sheep. This study presents valuable information about pharmacokinetics of doramectin in alpacas, which can be utilised in its future efficacy studies.     

The pharmacokinetics and analgesic effects of extended‐release buprenorphine administered subcutaneously in healthy dogs

Buprenorphine is a partial μ agonist opioid used for analgesia in dogs. An extended‐release formulation (ER‐buprenorphine) has been shown to provide effective analgesia for 72 hr in rats and mice. Six healthy mongrel dogs were enrolled in a randomized, blinded crossover design to describe and compare the pharmacokinetics and pharmacodynamics of ER‐buprenorphine administered subcutaneous at 0.2 mg/kg (ER‐B) and commercially available buprenorphine for injection intravenously at 0.02 mg/kg (IV‐B). After drug administration, serial blood samples were collected to measure plasma buprenorphine concentrations using liquid chromatography/mass spectrometry detection. Heart rate, respiratory rate, body temperature, sedation score, and thermal threshold latency were recorded throughout the study. Median (range) terminal half‐life, time to maximum concentration, and maximum plasma concentration of ER‐buprenorphine were 12.74 hr (10.43–18.84 hr), 8 hr (4–36 hr), and 5.00 ng/ml (4.29–10.98 ng/ml), respectively. Mild bradycardia, hypothermia, and inappetence were noted in both groups. Thermal threshold latency was significantly prolonged compared to baseline up to 12 hr and up to 72 hr in IV‐B and ER‐B, respectively. These results showed that ER‐buprenorphine administered at a dose of 0.2 mg/kg resulted in prolonged and sustained plasma concentrations and antinociceptive effects up to 72 hr after drug administration.     

Hemodynamic effects of butorphanol in desflurane-anesthetized dogs

ObjectiveTo evaluate the effects of butorphanol on cardiopulmonary parameters in dogs anesthetized with desflurane and breathing spontaneously.Study designProspective, randomized experimental trial.AnimalsTwenty dogs weighing 12 ± 3 kg.MethodsAnimals were distributed into two groups: a control group (CG) and butorphanol group (BG). Propofol was used for induction and anesthesia was maintained with desflurane (10%). Forty minutes after induction, the dogs in the CG received sodium chloride 0.9% (0.05 mL kg^?1 IM), and dogs in the BG received butorphanol (0.4 mg kg^?1 IM). The first measurements of body temperature (BT), heart rate (HR), arterial pressures (AP), cardiac output (CO), cardiac index (CI), central venous pressure (CVP), stroke volume index (SVI), pulmonary arterial occlusion pressure (PAOP), mean pulmonary arterial pressure (mPAP), left ventricular stroke work (LVSW), systemic (SVR) and pulmonary (PVR) vascular resistances, respiratory rate (f_R), and arterial oxygen (PaO₂) and carbon dioxide (PaCO₂) partial pressures were taken immediately before the administration of butorphanol or sodium chloride solution (T0) and then at 15-minute intervals (T15–T75).ResultsIn the BG, HR, AP, mPAP and SVR decreased significantly from T15 to T75 compared to baseline. f_R was lower at T30 than at T0 in the BG. AP and f_R were significantly lower than in the CG from T15 to T75. PVR was lower in the BG than in the CG at T30, while PaCO₂ was higher compared with T0 from T30 to T75 in the BG and significantly higher than in the CG at T30 to T75.Conclusions and clinical relevanceAt the studied dose, butorphanol caused hypotension and decreased ventilation during desflurane anesthesia in dogs. The hypotension (from 86 ± 10 to 64 ± 10 mmHg) is clinically relevant, despite the maintenance of cardiac index.     

Pharmacokinetics of epidural butorphanol in isoflurane-anaesthetized dogs

Sixteen healthy male dogs were used at random in this protocol. The dogs were anaesthetized with isoflurane in oxygen. Eight of the dogs received 0.25 mg/kg of butorphanol (group B) and the others an equal volume of isotonic saline (group S) administered by a catheter inserted in the lumbosacral epidural space. Butorphanol concentrations in plasma and cerebrospinal fluid (CSF) were measured using high-performance liquid chromatography with electrochemical detection. Maximum concentration of butorphanol and time to obtain this concentration were 42.28 ng/mL at 13.88 min in blood, and 18.03 ng/mL at 30 min in CSF. Volume of distribution, clearance, mean distribution and elimination half-lives were respectively 4.39 L/kg, 2.02 L/h.kg, 16.5 min and 189.1 min. Mean isoflurane minimal alveolar concentration values for group B obtained following hind- or forelimb stimulation decreased by 31% after epidural butorphanol. Cutaneous analgesia (to pin-prick test) persisted for 3 h after the end of isoflurane anaesthesia in group B and was in correlation with the plasmatic analgesic dose of butorphanol (9 ng/mL). These results suggested that analgesia was predominantly obtained by action of butorphanol on the supraspinal structures following its vascular systemic absorption.     

The pharmacokinetics of cytarabine administered subcutaneously,combined with prednisone,in dogs with meningoencephalomyelitis of unknown etiology

The objective of this study was to describe the pharmacokinetics (PK) of cytarabine (CA) after subcutaneous (SC) administration to dogs with meningoencephalomyelitis of unknown etiology (MUE). Twelve dogs received a single SC dose of CA at 50 mg/m² as part of treatment of MUE. A sparse sampling technique was used to collect four blood samples from each dog from 0 to 360 min after administration. All dogs were concurrently receiving prednisone (0.5–2 mg kg^?1day^?1). Plasma CA concentrations were measured by HPLC, and pharmacokinetic parameters were estimated using nonlinear mixed‐effects modeling (NLME). Plasma drug concentrations ranged from 0.05 to 2.8 μg/ml. The population estimate (CV%) for elimination half‐life and Tmax of cytarabine in dogs was 1.09 (21.93) hr and 0.55 (51.03) hr, respectively. The volume of distribution per fraction absorbed was 976.31 (10.85%) ml/kg. Mean plasma concentration of CA for all dogs was above 1.0 μg/ml at the 30‐, 60‐, 90‐, and 120‐min time points. In this study, the pharmacokinetics of CA in dogs with MUE after a single 50 mg/m² SC injection in dogs was similar to what has been previously reported in healthy beagles; there was moderate variability in the population estimates in this clinical population of dogs.     

Cardiovascular effects of butorphanol in halothane-anesthetized dogs

Cardiovascular effects of butorphanol (0.2 mg/kg of body weight, IV) and responses associated with subsequent administration of naloxone (0.04 mg/kg, IV) were studied in halothane (1.2% end-tidal concentration)-anesthetized dogs. Transient, but statistically significant (P less than 0.05), decreases in heart rate, mean and diastolic arterial blood pressures, and rate-pressure product were observed after butorphanol administration. Cardiac index, stroke volume, and systemic vascular resistance did not change significantly. Except for the decrease in heart rate, changes in the values of the cardiovascular variables measured after butorphanol administration did not appear to be clinically relevant. Sixty minutes after butorphanol administration, naloxone was given. Statistically significant (P less than 0.05) increases in heart rate, arterial blood pressures, cardiac index, and rate-pressure product, along with dysrhythmias were observed. Stroke volume and systemic vascular resistance remained unchanged after administration of naloxone. Naloxone administration was associated with changes indicative of increased myocardial oxygen consumption.     

Cardiopulmonary effects of butorphanol tartrate in dogs

The effects of butorphanol given (IV) at dose levels of 0.1 and 0.4 mg/kg were evaluated in conscious dogs, n = 5 for each dose. Mild sedation occurred, though it was greater in dogs given the larger dose. Two dogs in each group panted, but PaCO2 was not significantly changed. Small, but significant, decreases in arterial blood pressure, heart rate, and PaO2 occurred (P less than 0.05). Base excess developed a negative trend. The PCV and total protein decreased slightly in dogs given the smaller dose, but were unchanged with the larger dose. Plasma glucose remained within acceptable limits.     

Changes in thermal threshold response in eight cats after administration of buprenorphine, butorphanol and morphine

Thermal thresholds were measured in eight cats after the intramuscular administration of morphine (0.2 mg/kg), buprenorphine (0.01 mg/kg) or butorphanol (0.2 mg/kg), doses commonly used in clinical practice; 0.9 per cent saline (0.3 ml) was injected as a control. Groups of six cats were used and each cat participated in at least two treatments, according to a randomised design. The investigator was blinded to the treatments. The thermal thresholds were measured with a testing device developed specifically for cats, and measurements were made before and five, 30, 45 and 60 minutes and two, four, six, 12 and 24 hours after the injections. There was no significant change in thermal threshold after the injection of saline. With butorphanol, the threshold was increased only at five minutes after the injection and was decreased two hours after the injection; with morphine it was increased from between four and six hours after the injection, and with buprenorphine it was increased from between four and 12 hours after the injection.     

Comparison of the effects of asparaginase administered subcutaneously versus intramuscularly for treatment of multicentric lymphoma in dogs receiving doxorubicin

OBJECTIVE: To determine the effectiveness and safety of asparaginase administered s.c. versus i.m. for treatment of multicentric lymphoma in dogs receiving doxorubicin. DESIGN: Prospective study. ANIMALS: 49 dogs with multicentric lymphoma. PROCEDURE: Dogs were treated with doxorubicin every 3 weeks, for a total of 5 treatments, and were given 3 weekly treatments of asparaginase, s.c. or i.m. Using high-performance liquid chromatography, mean plasma asparagine, aspartic acid, glutamine, and glutamic acid concentrations were determined in dogs before and during treatment with asparaginase (10,000 U/m2 of body surface area, once a week for 3 weeks). Asparaginase was administered s.c. in 23 dogs and i.m. in 26 dogs. Variables evaluated included time to response to chemotherapy, remission and survival times, and clinical and serum biochemical indicators of toxicoses. RESULTS: Using the World Health Organization's staging system for lymphoma, 30 dogs were in clinical stage III and 19 were in clinical stage IV. One week after asparaginase treatment, plasma asparagine concentrations were low and plasma aspartic acid, glutamine, and glutamic acid concentrations were high. Differences in plasma amino acid concentrations were not found between s.c. and i.m. groups. For dogs in clinical stage IV, i.m. administration of asparaginase significantly decreased the number of days to complete remission, compared with s.c. administration (8 vs 17 days, respectively). For dogs in clinical stage III, i.m. administration favorably increased the duration of first remission (191 vs 103 days) and survival time (289 vs 209 days). Overall, dogs treated i.m. had a faster response to chemotherapy (9 vs 15 days), a longer remission (191 vs 109 days), and a longer survival time (286 vs 198 days), compared with all dogs treated s.c. Asparaginase toxicoses were not observed regardless of the route of administration. CLINICAL IMPLICATIONS: For dogs with multicentric lymphoma that are receiving doxorubicin, i.m. treatment with asparaginase is more effective than s.c. treatment.     

Pharmacokinetic evaluation of enrofloxacin administered orally to healthy dogs.

Enrofloxacin was administered orally to 6 healthy dogs at dosages of approximately 2.75, 5.5, and 11 mg/kg of body weight, every 12 hours for 4 days, with a 4-week interval between dosage regimens. Serum and tissue cage fluid (TCF) concentrations of enrofloxacin were measured after the first and seventh treatments. The mean peak serum concentration occurred between 1 and 2.5 hours after dosing. Peak serum concentrations increased with increases in dosage. For each dosage regimen, there was an accumulation of enrofloxacin between the first and seventh treatment, as demonstrated by a significant (P = 0.001) increase in peak serum concentrations. The serum elimination half-life increased from 3.39 hours for the 2.75 mg/kg dosage to 4.94 hours for the 11 mg/kg dosage. Enrofloxacin accumulated slowly into TCF, with peak concentrations being approximately 58% of those of serum. The time of peak TCF concentrations occurred between 3.8 hours and 5.9 hours after drug administration, depending on the dosage and whether it was after single or multiple administrations. Compared with serum concentrations (area under the curve TCF/area under the curve serum), the percentage of enrofloxacin penetration into TCF was 85% at a dosage of 2.75 mg/kg, 83% at a dosage of 5.5 mg/kg, and 88% at a dosage of 11 mg/kg. All 3 dosage regimens of enrofloxacin induced continuous serum and TCF concentrations greater than the minimal concentration required to inhibit 90% (MIC90) of the aerobic and facultative anaerobic clinical isolates tested, except Pseudomonas aeruginosa.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dose-dependent plasma elimination of subcutaneously administered calcium heparin in horses

Pharmacokinetic parameters for subcutaneous low dose heparin in horses have been determined. Four groups of five and one group of eleven mature, healthy horses of various breeds were given single subcutaneous injections of 60, 80, 100, 125, and 150 units of calcium heparin/kg of body weight (U/kg) in the pectoral region. Jugular blood samples were collected prior to, and at hourly intervals for 12 h after injection. Heparin plasma concentrations were measured using a commercially available amidolytic assay. Peak concentrations 4 h after administration were 0.021 +/- 0.016 (mean +/- SD) units of heparin/ml of plasma (U/ml) after 60 U/kg, 0.035 +/- 0.025 U/ml after 80 U/kg, 0.023 +/- 0.004 U/ml after 100 U/kg, 0.034 +/- 0.019 U/ml after 125 U/kg, and 0.053 +/- 0.019 U/ml after 150 U/kg. Data from groups given 60 and 100 U/kg could not be used for kinetic calculations. Elimination constant (l/h), elimination half-life (h), and elimination time (h) calculated to reach base-line values after 80 U/kg were 0.182 +/- 0.041 l/h, 3.8 +/- 0.9 h, and 9.7 +/- 2.2 h. After 125 U/kg, corresponding values were 0.211 +/- 0.019 l/h, 3.3 +/- 0.3 h, 13.4 +/- 1.2 h, and after 150 U/kg 0.098 +/- 0.015 l/h, 7.1 +/- 1.1 h, and 20.6 +/- 3.2 h. Calculated heparin concentrations 12 h after administration of 80, 125, and 150 U/kg were 0.011 +/- 0.002, 0.010 +/- 0.001, and 0.027 +/- 0.004 U/ml.(ABSTRACT TRUNCATED AT 250 WORDS)