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)     

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.     

Plasma and urine nitric oxide concentrations in horses given below a low dose of endotoxin.

OBJECTIVE: To quantify plasma and urine nitric oxide (NO) concentrations before and after low-dose endotoxin infusion in horses. ANIMALS: 11 healthy adult female horses. Procedure-Eight horses were given endotoxin (35 ng/kg of body weight,i.v.) over 30 minutes. Three sentinel horses received an equivalent volume of saline (0.9% NaCl) solution over the same time. Clinical signs of disease and hemodynamic variables were recorded, and urine and plasma samples were obtained to measure NO concentrations prior to endotoxin infusion (t = 0) and every hour until postinfusion hour (PIH) 6, then every 2 hours until PIH 24. Blood for hematologic and metabolic analyses and for serum cytokine bioassays were collected at 0 hour, every hour until PIH 6, every 2 hours through PIH 12, and finally, every 6 hours until PIH 24. RESULTS: Differences in plasma NO concentrations across time were not apparent, but urine NO concentrations significantly decreased at 4 and 20 to 24 hours in endotoxin-treated horses. Also in endotoxin-treated horses, alterations in clinical signs of disease, and hemodynamic, metabolic, and hematologic variables were significant and characteristic of endotoxemia. Serum interleukin-6 (IL-6) activity and tumor necrosis factor (TNF) concentrations were increased above baseline values from 1 to 8 hours and 1 to 2 hours, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Plasma and urine NO concentrations did not increase in horses after administration of a low dose of endotoxin, despite induction of an inflammatory response, which was confirmed by increased TNF and IL-6 values characteristic alterations in clinical signs of disease, and hematologic, hemodynamic and metabolic variables.     

Effects of halothane anesthesia on the clearance of gentamicin sulfate in horses

Inhalation anesthetics decrease the clearance of some drugs that are eliminated by renal excretion. The purpose of the study reported here was to investigate the effects of halothane anesthesia on the pharmacokinetics and urinary excretion of gentamicin sulfate, using the horse as a model. Using a crossover design, pharmacokinetic values after a single IV dose of gentamicin (4 mg/kg) were compared in halothane-anesthetized and unanesthetized horses. Compared with unanesthetized horses, the anesthetized horses had significant decreases in total body clearance (P less than 0.01) and apparent volume of distribution (P less than 0.05), and a significant increase in half-life (P less than 0.05) of gentamicin.     

Bioavailability of gentamicin in dogs after intramuscular or subcutaneous injections

Healthy adult mixed-breed dogs, assigned to 2 groups of 6 dogs each, were given 3 mg of gentamicin sulfate/kg of body weight on 3 injection days 7 days apart. Group 1 was given gentamicin by rapid IV injection, by injection into the belly of the longissimus muscle at the first lumbar vertebrae (IM site 1), and by injection in the belly of the biceps femoris muscle (IM site 2). Group 2 was given gentamicin by rapid IV injection, by SC injection into the space over the cranial angle of the scapula on the midline (SC site 1), and by SC injection just caudal to the crest of the ilium (SC site 2). Pharmacokinetic values (mean +/- SD) from 12 dogs given gentamicin IV were 54.4 +/- 15.4 minutes for the effective half life, 2.29 +/- 0.48 ml/kg/min for clearance, and 172 +/- 25.4 ml/kg for volume of distribution at steady state. Bioavailability (93.92 to 96.65%) and peak plasma gentamicin concentration (9.43 to 10.89 micrograms/ml) were independent of injection site, but time to peak concentration when gentamicin was given at SC site 2 (43.33 minutes) was significantly (P less than 0.05) longer than that when gentamicin was given at IM site 1 (27.50 minutes). Absorption half-life was shorter after injections were given at both IM sites (8.9 and 9.8 minutes) than after injection was given at SC site 2 (18 minutes).     

Induction of the acute-phase cytokine, hepatocyte-stimulating factor/interleukin 6, in the circulation of horses treated with endotoxin.

Because hepatocyte-stimulating factor/interleukin 6 (IL-6) is the principal inducer of acute-phase protein synthesis in the liver, quantification of its activity in blood provides an early and sensitive assessment of the acute-phase response. Circulating IL-6 activity was monitored in 4 adult horses for 72 hours after IV administration of endotoxin. In 4 experiments performed at weekly intervals and in randomized order, each horse was given endotoxin--1,000 30, 1, and 0 ng/kg of body weight. Plasma IL-6 activity was quantified as the ability to promote growth of the IL-6-dependent B-cell hybridoma, B13.29 clone B9. Interleukin-6 activity (171 +/- 10.2 U/ml) was found in all pretreatment plasma samples and was significantly (P less than 0.05) increased above baseline from 2 to 12 hours after 1,000 ng of endotoxin/kg was given and at 3 hours after 30 ng of endotoxin/kg was given. After 1,000- or 30-ng/kgt dosage of endotoxin, peak plasma IL-6 activity (10,128 +/- 4,096 and 1,555 +/- 1,326 U/ml, respectively) was observed for 3 hours. The IL-6 response of endotoxin-treated horses began about 1 hour after tumor necrosis factor appeared in the circulation, and its course closely approximated the endotoxin-induced febrile reaction. Significant increase in plasma IL-6 activity was not detected in horses given 1 ng of endotoxin/kg or control buffer.     

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.     

Flow cytometric analysis of peripheral blood mononuclear cells induced by experimental endotoxemia in horse

Cellular activation and functional cell surface markers were evaluated during experimentally-induced endotoxemia in healthy horses. Eight healthy adult horses were infused a low dose of endotoxin (lipopolysaccharide from Escherichia coli O26: B6, 30 ng/kg of body weight, IV) and five control horses were given an equivalent volume of sterile saline solution. Venous blood samples were collected for flow cytometric analysis of peripheral blood mononuclear cells (PBMCs) and to measure plasma endotoxin concentrations. Clinical signs of endotoxemia were recorded at 10, 20, 30, 40, 50 min, 1, 2, 3, 4, 8, 16, 24 and 48 hr after endotoxin or saline solution administration. Clinical findings characteristic of endotoxemia (tachycardia, tachypnea, increased rectal temperature, and leukopenia) occurred transiently in all horses administered endotoxin; however, plasma endotoxin concentrations were detectable in only 50% (4/8) of the endotoxin-infused horses. The percentage of CD4(+), CD5(+), and CD8(+) cells decreased while the percentage of CD14(+), IgM(+), and MHC class II(+) cells increased significantly after endotoxin infusion. Alterations in the immunophenotype of PBMCs from horses with experimentally-induced endotoxemia were associated with changes in vital signs, indicating that endotoxin altered the immuno balance.     

Theophylline and dyphylline pharmacokinetics in the horse

The pharmacokinetics of theophylline and dyphylline were determined after IV administration in horses. In a preliminary experiment, the usual human dosage (milligram per kilogram) of each drug was given to 1 horse. Results were used to calculate dosages for a cross-over study, using 6 horses for each drug. Theophylline plasma concentrations decreased triexponentially in 5 of 6 healthy horses after IV infusion of 10 mg of aminophylline/kg of body weight for 16 to 32 minutes. In the 6 horses, total body elimination rate constants were variable, and the half-life of theophylline was 9.7 to 19.3 hours. Clearance was 42.3 to 69.2 ml/hr/kg. The initial distribution phase was rapid (t1/2 approx 3.5 to 4 minutes); a 2nd distribution phase was slower (t1/2 approx 1.5 to 2 hours). Plasma concentrations of theophylline were in the assumed effective range (10 to 20 micrograms/ml) from 15 minutes until 40 minutes after time zero. The mean apparent volume of distribution was 1.02 L/kg. After bolus IV injection of dyphylline (20 mg/kg), pharmacokinetics were best described by a 2-compartment open model in 2 horses and by a 3-compartment open model in 4 horses. In the 6 horses, elimination half-life of dyphylline was 1.9 to 2.9 hours, and clearance was 200 to 320 ml/hr/kg. Plasma concentrations (approx 50 micrograms/ml) were observed at 10 minutes after injection without adverse effects. Concentrations greater than 10 micrograms/ml were observed from time zero to about 1.5 hours after injection. Theophylline induced significant increases in heart rate, but dyphylline did not affect heart rate significantly.(ABSTRACT TRUNCATED AT 250 WORDS)     

Synovial fluid pH, cytologic characteristics, and gentamicin concentration after intra-articular administration of the drug in an experimental model of infectious arthritis in horses

Chemical and cytologic effects and bactericidal activity of gentamicin in septic synovial fluid were evaluated in an experimental model of infectious arthritis in horses. Septic arthritis was induced by inoculation of approximately 7.5 X 10(6) colony-forming units of Escherichia coli into 1 antebrachiocarpal joint in each of 16 clinically normal adult horses. Clinical signs of septic arthritis were evident 24 hours after inoculation. Horses were allotted to 3 groups: group-1 horses (n = 5) each were given 150 mg of gentamicin (50 mg/ml; 3 ml) intra-articularly (IA); group-2 horses (n = 5) each were given 2.2 mg of gentamicin/kg of body weight, IV, every 6 hours; and group-3 horses (n = 6) each were given buffered gentamicin, consisting of 3 mEq of sodium bicarbonate (1 mEq/ml; 3 ml) and 150 mg of gentamicin (50 mg/ml; 3 ml), IA. Synovial fluid specimens were obtained at posttreatment hour (PTH) 0, 0.25, 1, 4, 8, 12, and 24 via an indwelling intra-articular catheter. Synovial fluid pH was evaluated at PTH 0, 0.25, and 24. Microbiologic culture and cytologic examination were performed on synovial fluid specimens obtained at PTH 0 and 24, and gentamicin concentration was measured in all synovial fluid specimens. At PTH 0, E coli was isolated from synovial fluid specimens obtained from all horses. Synovial fluid pH was lower (range, 7.08 to 7.16) and WBC count was higher (range, 88,000 to 227,200 cells/microliters) and predominantly neutrophilic (95 to 99%) at PTH 0 than before inoculation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Modulation of arachidonic acid metabolism in endotoxic horses: comparison of flunixin meglumine, phenylbutazone, and a selective thromboxane synthetase inhibitor

Two cyclooxygenase inhibitors (flunixin meglumine and phenylbutazone) and a selective thromboxane synthetase inhibitor were assessed in the management of experimental equine endotoxemia. Drugs or saline solution were administered to 16 horses 15 minutes before administration of a sublethal dose of endotoxin (Escherichia coli 055:B5). Plasma concentrations of thromboxane B2 (TxB2), prostacyclin (6-keto PGF1 alpha), plasma lactate, and hematologic values and clinical appearance were monitored for 3 hours after endotoxin administration. Pretreatment with flunixin meglumine (1 mg/kg of body weight) prevented most of the endotoxin-induced changes and correlated with a significant decrease in plasma TxB2 and 6-keto PGF1 alpha concentrations, compared with concentrations in nontreated horses (ie, pretreated with saline solution). Pretreatment with phenylbutazone (2 mg/kg) attenuated the effects of endotoxin and was associated with a brief, early, significant increase in plasma TxB2 concentrations, but not in plasma 6-keto PGF1 alpha concentrations. Pretreatment with the thromboxane synthetase inhibitor did not appear to clinically benefit the horses involved; however, arachidonic acid metabolism was redirected to prostacyclin production.     

Influence of an omega-3 fatty acid-enriched ration on in vivo responses of horses to endotoxin.

Because certain inflammatory processes are dependent on the fatty acid composition of the cellular membrane, dietary manipulations that replace omega-6 fatty acids with omega-3 fatty acids may modify inflammatory responses. We investigated the effect of supplemental dietary linseed oil, containing the omega-3 fatty acid, alpha-linolenic acid, on in vivo responses of horses to endotoxin. One group of horses (n = 6) was fed a control pelleted ration (0% linseed oil), and another group of horses (n = 6) was fed an 8% linseed oil pelleted ration. After 8 weeks of consuming these rations, all horses were given 0.03 micrograms of Escherichia coli 055:B5 endotoxin/kg of body weight, infused over 30 minutes. Horses were monitored over 24 hours. Compared with baseline values within each ration group, endotoxin infusion caused significant (P less than 0.05) increase in rectal temperature, heart rate, and plasma concentration of thromboxane B2, 6-keto-prostaglandin F1 alpha, and fibrinogen and significant (P less than 0.05) decrease in total WBC count. Compared with baseline values within each ration group, endotoxin infusion failed to cause significant changes in prothrombin, activated partial thromboplastin, thrombin, or whole blood recalcification times, serum concentration of fibrin degradation products, PCV, or plasma total protein concentration. Before and after endotoxin infusion, horses given the linseed oil ration had longer mean whole blood recalcification time and activated partial thromboplastin time than did horses fed the control ration.     

Pharmacokinetic disposition of theophylline in horses after intravenous administration

The pharmacokinetics of theophylline were determined in 6 healthy horses after a single IV administration of 12 mg of aminophylline/kg of body weight (equivalent to 9.44 mg of theophylline/kg). Serum theophylline was measured after the IV dose at 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 15 hours. Serum concentration plotted against time on semilogarithmic coordinates, indicated that theophylline in 5 horses was best described by a 2-compartment open model and in 1 horse by a 1-compartment open model. The following mean pharmacokinetic values were determined; elimination half-life = 11.9 hours, distribution half-life = 0.495 hours, apparent specific volume of distribution = 0.885 +/- 0.075 L/kg, apparent specific volume of central compartment = 0.080 L/kg, and clearance = 51.7 +/- 11.2 ml/kg/hr. Three horses with reversible chronic obstructive pulmonary disease were serially given 1, 3, 6, 9, 12, and 15 mg of aminophylline/kg in single IV doses (equivalent to 0.8, 2.4, 4.7, 7.1, 9.44, and 11.8 mg of theophylline/kg, respectively). The horses were exposed to a dusty barn until they developed clinical signs of respiratory distress and were then given the aminophylline. Effects of increasing doses on different days were correlated with clinical signs, blood pH, and blood gases. The 3 horses had a decrease in the severity of clinical signs after the 9, 12, or 15 mg doses of aminophylline/kg. The horses at 0.5 hour after dosing had a significant decrease in PaCO2 (43.6 +/- 5.5 to 39.4 +/- 6.7 mm of Hg, P less than 0.001) and a significant increase in blood pH (7.38 +/- 0.017 to 7.41 +/- 0.023, P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Endotoxemia in horses: protection provided by antiserum to core lipopolysaccharide

An equine antiserum to core lipopolysaccharide was produced by inoculation of 6 horses with a boiled cell bacterin made from the J-5 mutant of Escherichia coli O111:B4. The antiserum immunoglobulin G titer to J-5 mutant E coli, as determined by enzyme-linked immunosorbent assay, was 1:15,006. Pooled serum prepared before inoculation (preimmune serum) had a J-5 immunoglobulin G titer of 1:350. The J-5 antiserum was tested for its protective efficacy in sublethal endotoxemia in 14 horses. Four horses served as nontreated controls and were given nothing before endotoxin challenge exposure (10 micrograms/kg of body weight, IV). Pooled preimmune serum (3 ml/kg, IV) was administered to 5 horses and J-5 antiserum (3 ml/kg, IV) was administered to 5 other horses 2 to 15 hours before endotoxin challenge exposure. During the 24 hours postendotoxin challenge exposure, endotoxemia was accompanied by significant (P less than 0.05) time-related changes in temperature, heart rate, pulse character, respiratory rate and character, capillary refill time, mucous membrane color, fecal composition, attitude, PCV, total plasma protein, WBC count, platelet count, plasma fibrinogen, prothrombin time, activated partial thromboplastin time, fibrinolytic degradation products, plasma glucose, and plasma lactate in all horses. There were no apparent treatment vs time interactions (P greater than 0.05). Two horses (1 control and 1 given J-5 antiserum) died suddenly from unknown causes immediately after endotoxin challenge exposure. Seemingly, equine antiserum to core lipopolysaccharide did not provide protection from the adverse effects of experimental endotoxemia produced by bolus IV infusion of 10 micrograms of endotoxin/kg.     

Effect of diet on gentamicin-induced nephrotoxicosis in horses.

Gentamicin sulfate-induced nephrotoxicosis was compared in 2 groups of horses fed different rations. Four horses were fed only alfalfa hay, and 4 other horses were fed only whole oats. Seven days after initiation of the diet, all horses were given gentamicin IV (5 mg/kg of body weight) every 12 hours for 22 days. Urinary gamma-glutamyl-transferase to urinary creatinine (UGGT:UCr) ratio was calculated daily, and serum concentration of gentamicin was measured at 1 and 12 hours after drug administration. Results indicated that horses fed oats had greater renal tubular damage than did horses fed alfalfa. Mean UGGT:UCr for horses fed alfalfa was 47.1 +/- 18.8 and was 100.0 +/- 19.0 for horses fed oats (P = 0.007). The UGGT:UCr in horses fed oats was greater than 100 for a total of 54 days; horses fed alfalfa had UGGT:UCr greater than 100 for only 7 days. Two horses not given gentamicin were fed only oats and 2 were fed only alfalfa. These horses had mean UGGT:UCr of 17.6 +/- 2.2 and 30.5 +/- 3.0, respectively. Mean peak and trough concentrations of gentamicin were statistically different for horses fed oats and those fed alfalfa (peak 23.16 +/- 1.87 and 14.07 +/- 1.79 micrograms/ml, respectively [P = 0.0001], and trough, 1.81 +/- 0.69 and 0.71 +/- 0.70 micrograms/ml, respectively [P = 0.0270]). Mean half-lives of gentamicin (estimated from peak and trough concentrations) for horses fed alfalfa (2.58 +/- 0.26 hours) and horses fed oats (2.88 +/- 0.27 hours) were not significantly different. Horses fed only oats had greater degree of gentamicin-induced nephrotoxicosis than did those fed only alfalfa.     

Effect of endotoxin administration on body fluid compartments in the horse

Plasma volume, extracellular fluid volume (ECFV), and total body water (TBW) were measured before and after endotoxin (Escherichia coli) administration in 6 conscious adult horses. Evan's blue dye, sodium thiocyanate, and antipyrine were the test substances used to estimate plasma volume, ECFV, and TBW, respectively. Pharmacokinetic analysis of plasma concentration vs time was used to determine changes in body fluid compartments. The pathophysiologic effects of endotoxin were monitored by clinical evaluation, blood chemical changes, and blood gas determinations. All horses became dyspneic within 15 minutes of endotoxin administration and clinical signs of colic were evident 30 to 45 minutes after endotoxin administration. After endotoxin administration, serum glucose and creatinine concentrations were significantly (P less than 0.05) elevated, and all horses became hypoxic and developed marked metabolic acidosis, and plasma volume decreased approximately 15% (P less than 0.05). A significant change in ECFV or TBW during the 300-minute experimental period was not observed.     

Effect of gentamicin sulfate and sodium bicarbonate on the synovium of clinically normal equine antebrachiocarpal joints

The effect of gentamicin sulfate, unbuffered and buffered with sodium bicarbonate, on synovial fluid and membrane of clinically normal equine joints was evaluated. Thirty-six adult horses with clinically normal antebrachiocarpal joints were allotted to 6 treatment groups of 6 horses each. One antebrachiocarpal joint in each horse was chosen for treatment. Group-1 horses were given gentamicin (3 ml; 50 mg/ml); group-2 horses were given sodium bicarbonate (3 ml; 1 mEq/ml); group-3 horses were given gentamicin (3 ml; 50 mg/ml) and sodium bicarbonate (3 ml; 1 mEq/ml); group-4 horses were not treated; and horses of groups 5 and 6 were given polyionic physiologic solution (3 and 6 ml, respectively). Synovial fluid specimens were obtained from 5 horses of each group for cytologic analysis at postinjection hours (PIH) 0, 24, 72, and 192 and for pH determination at PIH 0, 0.25, 0.5, 1, 4, 8, 24, 72, and 192. The sixth horse of each group was euthanatized at PIH 24, and the synovial membrane of the treated and contralateral (nontreated) antebrachiocarpal joints was examined macroscopically and microscopically. After intra-articular gentamicin administration, the mean synovial fluid pH was lowest (5.98) at PIH 0.25, but by PIH 8, it was not significantly different from the control value (group-5 horses). When sodium bicarbonate was combined with gentamicin before intra-articular administration, the mean synovial fluid pH was lowest (7.07) at PIH 0.25, but by PIH 1, it was not significantly different from the control value (group-6 horses).(ABSTRACT TRUNCATED AT 250 WORDS)     

Gentamicin tissue concentrations in equine small intestine and large colon

Gentamicin sulfate (2.2 mg/kg of body weight, IV) was given to anesthetized horses. Jejunal and large colon tissue samples (1 g), serum, and urine were collected over a 4-hour period. Maximum gentamicin concentrations in serum (10.06 +/- 2.85 micrograms/ml) occurred at 0.25 hours after injection. Maximum gentamicin concentrations in the large colon (4.13 +/- 1.80 micrograms/ml) and jejunum (2.26 +/- 1.35 micrograms/ml) occurred in horses at 0.5 and 0.33 hours, respectively. Tissue concentrations decreased in parallel with serum concentrations and were still detectable at the end of the 4-hour period. During the time that samples were collected, the total amount of gentamicin excreted in the urine ranged from 7.21 +/- 3.11 mg to 11.91 +/- 7.12 mg, with a mean urinary concentration of 57.01 +/- 5.37 micrograms/ml. Over the 4-hour collection period, the fraction of dose that was excreted unchanged in the urine was 4.8 +/- 1.9%. Pharmacokinetic analyses of the serum concentration-time data gave a serum half-life of 2.52 +/- 1.29 hours, volume of distribution of 227 +/- 83 ml/kg, and body clearance of 1.12 +/- 0.26 ml/min/kg. The half-lives of the antibiotic in the jejunum and large colon were 1.32 and 1.33 hours, respectively.     

Effect of experimentally induced endotoxemia on serum interleukin-6 activity in horses.

A study was conducted to determine whether serum interleukin-6 (IL-6) activity increased in horses during experimentally induced endotoxemia and whether serum IL-6 activity correlated to changes in clinical or laboratory data. Six clinically normal horses were given endotoxin IV (30 ng/kg of body weight) in 0.9% NaCl solution over 1 hour. Five of these and 1 additional horse served as controls and were given only 0.9% NaCl solution. Venous blood, for determination of serum IL-6 activity and WBC count, was collected before and at various times through 8 hours after the start of endotoxin or NaCl infusion. Rectal temperature and heart and respiratory rates were recorded throughout the study period. Serum IL-6 activity was determined by bioassay of proliferation of the B13.29 clone B.9 hybridoma cell line. From 1.5 through 5 hours after start of the infusion, serum IL-6 activity was significantly (P less than 0.05) increased in horses given endotoxin. Mean peak serum IL-6 activity was observed between 3 and 4 hours. In response to endotoxin infusion, horses became lethargic, tachycardic, and febrile. Leukopenia developed by 1 hour, followed by leukocytosis at 8 hours. Significant (P less than 0.05) positive association and linear correlation were apparent between mean serum IL-6 activity and mean rectal temperature in the group of horses that were given endotoxin. Changes from baseline were not evident in any of the clinical or laboratory values in horses given only NaCl solution.     

Drug disposition and dosage determination of once daily administration of gentamicin sulfate in horses after abdominal surgery.

OBJECTIVE: To evaluate pharmacokinetics of once daily i.v. administration of gentamicin sulfate to adult horses that had abdominal surgery. DESIGN: Prospective study. ANIMALS: 28 adult horses that underwent abdominal surgery for colic. PROCEDURE: 14 horses were treated with each dosage of gentamicin (i.e., 6.6 or 4 mg/kg, i.v., q 24 h) and blood samples were collected for pharmacokinetic analysis. Plasma gentamicin concentrations were measured by use of a fluorescence polarization immunoassay. Pharmacokinetic analysis measured the elimination half-life, volume of distribution, and gentamicin total systemic clearance. Treatment outcome, CBC, and serum creatinine concentrations were recorded. RESULTS: 1 horse in the high-dosage group died. All other horses successfully recovered, and did not develop bacterial infection or have evidence of drug toxicosis resulting in renal injury. Mean pharmacokinetic variables for gentamicin administration at a high or low dosage (i.e., 6.6 or 4 mg/kg, i.v., q 24 h) were half-life of 1.47 and 1.61 hours, volume of distribution of 0.17 and 0.17 L/kg, and systemic clearance of 1.27 and 1.2 ml/kg/min, respectively. Mean serum creatinine concentration was 1.74 and 1.71 for the high and low dosages, respectively, and serum creatinine concentration was not correlated with gentamicin clearance. CONCLUSIONS AND CLINICAL RELEVANCE: Gentamicin administration at a dosage of 4 mg/kg, i.v., every 24 hours, will result in plasma concentrations that are adequate against susceptible bacteria with a minimum inhibitory concentration (MIC) of < or = 2.0 micrograms/ml. Gentamicin administration at a calculated dosage of 6.8 mg/kg, i.v., every 24 hours will result in optimum plasma concentrations against susceptible bacteria with a MIC of < or = 4.0 micrograms/ml.