Prediction of pharmacokinetic profiles of ampicillin sodium, gentamicin sulfate, and combination ampicillin sodium-gentamicin sulfate in serum and synovia of healthy horses

Pharmacokinetics of ampicillin sodium (11 mg/kg), gentamicin sulfate (2.2 mg/kg), and combination ampicillin sodium-gentamicin sulfate were determined for serum and synovia of healthy horses given single-dose IV injection and were not found to be different from those from other reports; however, a prolonged terminal gamma-phase for gentamicin (8,498 +/- 1,842 minutes) in serum of horses was found to exist. Pharmacokinetic interaction between combination ampicillin sodium-gentamicin sulfate was not observed int he serum or synovia. Prediction of ampicillin sodium or gentamicin sulfate concentrations in synovia, based on serum-based pharmacokinetics, cannot be accomplished solely upon analysis of peripheral-compartment pharmacokinetics. However, once equilibrium is achieved between synovia and extracellular fluid in the peripheral compartment, the decrease in drug concentrations in synovia parallels that in serum. Therefore, after 6 hours, synovial concentrations of gentamicin sulfate can be predicted based on peripheral-compartment pharmacokinetics, using an appropriate correction factor. The significance of these findings need to be correlated with clinical conditions so that a pharmacostatistical model for the prediction of synovial concentrations of drug(s) during treatment of horses with septic arthritis can be developed.     

Effect of probenecid on disposition kinetics of ampicillin in horses.

The effect of an oral dose of probenecid on the disposition kinetics of ampicillin was determined in four horses. An intravenous bolus dose (10 mg/kg) of ampicillin sodium was administered to the horses on two occasions. On the first occasion the antibiotic was administered on its own, and on the second occasion it was administered one hour after an oral dose of 75 mg/kg probenecid. The plasma concentration of probenecid reached a mean (+/- se) maximum concentration (Cmax) of 188-6 +/- 19.3 micrograms/ml after 120.0 +/- 21.2 minutes and concentrations greater than 15 micrograms/ml were present 25 hours after it was administered. The disposition kinetics of ampicillin were altered by the presence of probenecid and as a result the antibiotic had a slower body clearance (ClB; 109.4 +/- 6.71 ml/kg hours compared with 208.9 +/- 26.2 ml/kg hours) a longer elimination half-life (t1/2 beta 1.198 hours compared with 0.701 hours) and consequently a larger area under the plasma concentration versus time curve (AUC 92.3 +/- 5.09 mg/ml hours compared with 35.95 +/- 3.45 mg/ml hours) when compared with animals to which ampicillin was administered alone. The ampicillin concentrations observed suggest that the dosing interval for horses may be increased from between six and eight hours to 12 hours when probenecid is administered in conjunction with the ampicillin.     

Pharmacokinetics of meloxicam in plasma and urine of horses

OBJECTIVE: To determine pharmacokinetic parameters for meloxicam, a nonsteroidal anti-inflammatory drug, in horses. ANIMALS: 8 healthy horses. PROCEDURE: In the first phase of the study, horses were administered meloxicam once in accordance with a 2 x 2 crossover design (IV or PO drug administration; horses fed or not fed). The second phase used a multiple-dose regimen (daily oral administration of meloxicam for 14 days), with meloxicam administered at the recommended dosage (0.6 mg/kg). Plasma and urine concentrations of meloxicam were measured by use of validated methods with a limit of quantification of 10 ng/mL for plasma and 20 ng/mL for urine. RESULTS: Plasma clearance was low (mean +/- SD; 34 +/- 0.5 mL/kg/h), steady-state volume of distribution was limited (0.12 +/- 0.018 L/kg), and terminal half-life was 8.54 +/- 3.02 hours. After oral administration, bioavailability was nearly total regardless of feeding status (98 +/- 12% in fed horses and 85 +/- 19% in nonfed horses). During once-daily administration for 14 days, we did not detect drug accumulation in the plasma. Meloxicam was eliminated via the urine with a urine-to-plasma concentration that ranged from 13 to 18. Concentrations were detected for a relatively short period (3 days) after administration of the final daily dose. CONCLUSIONS AND CLINICAL RELEVANCE: Results of this study support once-daily administration of meloxicam regardless of the feeding status of a horse and suggest a period of at least 3 days before urine concentrations of meloxicam reach concentrations that could be used in drug control programs.     

Determination of grapiprant plasma and urine concentrations in horses

ObjectiveNon-steroidal anti-inflammatory drugs are inhibitors of cyclooxygenase (COX) in tissues and used as therapeutic agents in different species. Grapiprant, a member of the piprant class of compounds, antagonizes prostaglandin receptors. It is a highly selective EP4 prostaglandin E₂ receptor inhibitor, thereby limiting the potential for adverse effects caused by wider COX inhibition. The objectives of this study were to determine if the approved canine dose would result in measurable concentrations in horses, and to validate a chromatographic method of analysis for grapiprant in urine and plasma.Study designExperimental study.AnimalsA total of six healthy, adult mixed-breed mares weighing 502 ± 66 (397–600) kg and aged 14.8 ± 5.3 (6–21) years.MethodsMares were administered one dose of 2 mg kg^–1 grapiprant via nasogastric tube. Blood and urine samples were collected prior to and up to 48 hours after drug administration. Drug concentrations were measured using high-performance liquid chromatography.ResultsGrapiprant plasma concentrations ranged from 71 to 149 ng mL^–1 with the mean peak concentration (106 ng mL^–1) occurring at 30 minutes. Concentrations were below the lower limit of quantification (50 ng mL^–1) in four of six horses at 1 hour and in all six horses by 2 hours after drug administration. Grapiprant urine concentrations ranged from 40 to 4077 ng mL^–1 and were still detectable at 48 hours after administration.Conclusions and clinical relevanceCurrently, there are no published studies looking at the pharmacodynamics of grapiprant in horses. The effective concentration needed to control pain in dogs ranges 114–164 ng mL^–1. Oral administration of grapiprant (2 mg kg^–1) in horses did not achieve those concentrations. The dose was well tolerated; therefore, studies with larger doses could be conducted.     

Phenylbutazone and its metabolites in plasma and urine of thoroughbred horses: population distributions and effects of urinary pH

A survey of plasma and urinary concentrations of phenylbutazone and its metabolites in thoroughbred horses racing in Kentucky was carried out. Post-race blood samples from more than 200 horses running at Latonia Racetrack and Keeneland in the Spring of 1983 were analysed. The modal plasma concentration of phenylbutazone was between 1 and 2 micrograms/ml, the mean concentration was 3.5 micrograms/ml and the range was up to 15 micrograms/ml. Oxyphenbutazone had a modal plasma concentration between 1 and 2 micrograms/ml, a mean concentration of 2.07 micrograms/ml and a range of up to 13 micrograms/ml. gamma OH-phenylbutazone had a modal plasma concentration of less than 1 microgram/ml, a mean level of 1.39 micrograms/ml and a range of up to 7.32 micrograms/ml. All plasma concentration frequency distributions were well fitted by log normal distributions. Urinary concentrations of phenylbutazone yielded modal concentrations of less than 1 microgram/ml, a mean urinary concentration of 2.9 micrograms/ml, with a range of up to 30.5 micrograms/ml. This population fitted a log-normal distribution. For oxyphenbutazone the modal concentration was less than 3 micrograms/ml, the mean concentration was 15.26 micrograms/ml, with a range to 81.5 micrograms/ml. The frequency distribution of these samples was apparently bimodal. For gamma OH-phenylbutazone, the modal concentration was less than 4 micrograms/ml, the mean concentration 21.23 micrograms/ml, with a range of up to 122 micrograms/ml. The population frequency distribution for gamma OH-phenylbutazone was indeterminate. Analysis of the pH of these post-race urine samples showed a bimodal frequency distribution. The pH values observed ranged from 4.9 to 8.7, with peaks at about pH 5.25 and 7.25. This bimodal pattern of urinary pH values is consistent with observations made in England and Japan. Urinary pH influenced the concentrations of phenylbutazone, oxyphenbutazone and gamma OH-phenylbutazone found in the urine samples. The concentration of these metabolites found in alkaline urines were from 32 to 225 times greater than those found in acidic urines. Plasma concentrations of phenylbutazone and its metabolites, however, were unaffected by urinary pH. In interlaboratory experiments, horses running at Hollywood Park were dosed with phenylbutazone at about 2 g/1000 lbs 24 and 48 h before racing, and a mean dose of 0.6 g/1000 lbs at 72 h prior to racing. Post-race plasma samples from these horses showed phenylbutazone concentrations ranging from 0.44 to 9.97 micrograms/ml, with a mean concentration of 4.09 micrograms/ml.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effect of food intake on urine pH in cats

Ninety adult cats were fed an experimental canned meat-based cat food at levels necessary to maintain weight for 11 days. On the 12th day the cats were split into six groups of 15 cats each and fed 0, 20, 40, 60, 80 or 100 per cent of their previous food allotment. Four hours after the food was offered a urine sample was obtained via cysto-centesis. The pH of the urine sample was determined and the sample microscopically evaluated for the presence of struvite crystals. Post prandial urine pH was found to be a linear function of the amount of food consumed: (urine pH = 6–15 + [food intake (g) × 0–015]; P = 0-000). The presence of struvite crystals was dependent on urine pH while amorphous crystals were not. These data suggest that ad libitum feeding (nibble eating) may be beneficial in the management of feline struvite urolithiasis by reducing the magnitude of the post prandial alkaline tide. It also supports the suggestion that struvite crystal formation is largely a function of urinary pH.     

Effect of dose of furosemide on plasma tCO2 changes in standardbred horses

Nine Standardbred horses of similar athletic fitness (six mares, three geldings), ranging from 4 to 11 years of age, were used to determine the effects of 0, 250, or 500 mg intravenously administered furosemide on plasma tCO₂ changes over time. All horses were either currently racing or in advanced stages of race training before entering a qualifying race. Horses were randomly allotted to one of the three treatment levels of furosemide during 3 consecutive weeks. Jugular venous samples were obtained from horses at rest in box stalls before and hourly for 6 hours after administration of furosemide. Body weights of horses ranged from 356 to 456 kg, and the mean was 417 kg. Thus, the dose of furosemide received by each horse ranged from 0.55 to 0.70 mg/kg body weight for the 250-mg injections and from 1.1 to 1.4 mg/kg body weight for the 500-mg injections. Furosemide caused metabolic alkalosis in the horses. Least square means (±SEM) were determined and horses had adjusted plasma tCO₂ of 32.2, 33.9, and 34.7 ± 0.41 for the 0-, 5-, and 10-mL doses of furosemide, respectively. The type 3 tests of hypotheses found that there was a difference (P < .0001) across time, a difference (P = .0016) according to furosemide dose, and a difference (P < .0001) according to treatment × hour. There was no difference (P > .05) according to week or treatment × week. These data suggest that either 250 or 500 mg furosemide given to Standardbred race horses induces statistically similar metabolic alkalosis.     

Effects of intravenously administered esomeprazole sodium on gastric juice pH in adult female horses

Background: Gastric ulcers are common in horses and treatment of horses that cannot be administered oral medication can be problematic. Objectives: To evaluate the efficacy of esomeprazole sodium administered intravenously on gastric juice pH and gastric ulcer scores in horses. Animals: Twelve adult female Quarter Horses. Methods: Esomeprazole sodium (0.5 mg/kg IV) was administered once daily to 8 horses (treatment group) and saline (5 mL IV) was administered to 4 horses (control group) for 13 consecutive days. Gastroscopy was performed and gastric juice pH and gastric ulcer score were recorded before and 1 hour after the administration of esomeprazole sodium or saline on days 1 and 5, then on day 14, 23 hours after the 13th daily dose of esomeprazole sodium or saline. Results: When compared with values before treatment, gastric juice pH was higher in esomeprazole sodium‐treated horses after treatment (4.25 ± 2.39 versus 6.43 ± 1.18; P= .002). Also, gastric juice pH was higher (P= .001) in esomeprazole sodium‐treated horses compared with saline‐treated control horses on day 5 and on day 14 values. Gastric ulcers were seen in 5/12 (43%) horses in the study. Conclusions and Clinical Importance: Esomeprazole sodium shows promise for treatment of gastric ulcers in horses with signs of dysphagia, gastric reflux, or other conditions that restrict oral intake of the current Federal Drug Administration‐approved omeprazole paste.     

Furosemide-induced changes in plasma and blood volume of horses

The effect of furosemide administration (1 mg/kg body weight, i.v.) on plasma and blood volumes in 6 intact and 4 splenectomized horses was measured using Evans blue dye dilution, hematocrit, and hemoglobin and plasma total solids concentrations. Body weight decreased by 33.6 +/- 3.3 and 33.7 +/- 0.8 g/kg 4 h after furosemide administration to intact and splenectomized mares, respectively. Plasma volume, estimated by Evans blue dye dilution, was reduced by 8.3 +/- 3.3% (mean +/- SE) 4 h after furosemide administration. The reduction in plasma volume was first detectable 5-10 min after furosemide administration and was greatest 15-30 min (13.0 +/- 0.8%) after dosing. This study demonstrates that furosemide produces significant and rapid reductions in plasma volume in horses. These decreases in plasma volume only partially resolve 4 h after furosemide administration.     

Pharmacokinetics in pulmonary epithelial lining fluid and plasma of ampicillin and pivampicillin administered to horses

Ampicillin concentrations in pulmonary epithelial lining fluid (PELF) and plasma was studied after single intravenous ampicillin administration (15mg/kg) or single intragastric administration of its prodrug, pivampicillin (19.9mg/kg) to horses and discussed in relation to minimum inhibitory concentrations (MIC) of common equine respiratory pathogens. After intravenous administration, elimination of ampicillin was fast and not detectable in plasma after 12h in three out of six horses. Pivampicillin was absorbed well in non-fasted horses with an oral bioavailability of 36%. The degree of penetration of ampicillin into PELF, as described by the AUC(PELF)/AUC(plasma) ratio from 0 to 12h was 0.40 after intravenous administration and 1.00 after pivampicillin administration. In horses, ampicillin administered either intravenously or orally, in the form of pivampicillin, can provide clinically relevant drug concentrations in PELF for at least 12h, when treating susceptible equine respiratory pathogens (e.g. streptococci). Treatment of other bacterial pathogens requires susceptibility testing and possibly more frequent dosing, depending of minimum inhibitory concentrations (MIC) values.     

Effect of dietary medium chain triacylglycerols on plasma triacylglycerol levels in horses.

The hypothesis tested was that the feeding of medium chain triacylglycerols (MCT) to horses would raise the level of plasma triacylglycerols by increasing the availability of glucose as lipogenic substrate, implying that the MCT effect would be greater with glucose in the diet instead of cellulose. A Latin square experiment was carried out with 4 horses and 4 dietary treatments. The experimental periods lasted 21 d. Blood samples were taken 16 h after feeding. The diets consisted of hay and experimental concentrates, differing in fat source (MCT or soybean oil) and carbohydrate source (corn starch plus glucose or cellulose). The dietary variables, MCT or soybean oil, provided on average 27% of total dietary net energy, while glucose plus constarch or cellulose provided 33%. The feeding of MCT versus soybean oil raised the level of plasma triacylglycerols significantly from 196.7 +/- 30.2 to 427.3 +/- 85.7 mmol/l and that of VLDL cholesterol from 0.028 +/- 0.01 to 0.069 +/- 0.01 mmol/ml. As based on analysis of variance, for the four experimental diets there was no significant effect of carbohydrate source and no fat-carbohydrate interaction. Thus, the hypothesis was rejected. When the diets contained soybean oil, cellulose versus starch plus glucose produced significantly greater increase plasma triacylglycerols. This carbohydrate effect was not seen when horses were fed the MCT diets. The experimental concentrates did not differently influence the concentrations of plasma glucose, total serum cholesterol, phospholipids, insulin, free fatty acids and the activity of post-heparin lipoprotein lipase. We suggest that the MCT-induced increase in plasma triacylglycerols is related to an increase in hepatic VLDL secretion, with the extra substrate for increased synthesis of triacylglycerols being the acetyl-CoA derived from the hepatic oxidation of medium chain fatty acids.     

Fresh and preserved green fodder modify effects of urinary acidifiers on urine pH of horses

Hay stabilises urine pH in horses. It is unknown whether this is an effect of structure or of chemical composition. In this study, four ponies (230–384 kg body weight [BW]) were fed six different diets with either a structure or a composition similar to hay with and without acidifiers in a cross‐over experimental design in amounts to maintain body weight with the following main compounds: Fresh grass (GRASS), alfalfa hay (ALF), grass cobs (COBS), grass silage (SIL), straw (STR) or extruded straw (STRe) for 2 to 10 days. Urine pH was measured in all trials, blood pH, blood base excess and bicarbonate as well as mineral balance were determined in GRASS, ALF, STR and STRe. In the trials with straw and extruded straw, urine pH decreased significantly (STR control: 7.8 ± 0.23, acidifier: 5.2 ± 0.38) when acidifiers were added, whereas in all other diets that were based on fresh or preserved green fodder, pH did not decrease below 7. Blood pH was similarly affected by diet and acidifiers. Acidifiers had little effect on the pre‐prandial blood pH, only in diet STR there was a significant reduction in relation to control. Post‐prandial blood pH was significantly reduced by acidifiers in all diets. Blood bicarbonate and base excess showed corresponding effects. Faecal and renal mineral excretion and apparent mineral digestibility were not systematically affected by diet or acidifiers except for chloride. Chloride added as inorganic chloride salt had an even better apparent digestibility than chloride originating from feed. Because only green plant material stabilised acid base balance, chlorophyll and its metabolites are discussed as potential mediators of the effect of green fodder on acid base balance.     

Effect of sodium bisulfate on skin and hooves of horses

OBJECTIVE: To evaluate the safety of sodium bisulfate for use in horse barn environments by determining its irritant effect on skin and hooves. ANIMALS: 6 female mixed-breed ponies. PROCEDURE: Sodium bisulfate was applied to clipped intact skin of 6 ponies to evaluate its irritant effect after single (48 hours) and repetitive (6 h/d for 10 days) applications; similar areas of skin were used as untreated control sites. In addition, sodium bisulfate was applied to the sole of both front hooves of each pony and covered with wet gauze, and the entire hoof was covered with adhesive tape for 48 hours. RESULTS: Contact with moistened sodium bisulfate for 48 hours had no effect on pony skin. Contact with sodium bisulfate for 6 hours on 10 consecutive days did not cause gross changes but did cause mild to moderate microscopic changes including epidermal necrosis, hyperkeratosis, capillary congestion, edema, and diffuse mixed inflammatory cell infiltrate. All changes were limited to the epidermis and superficial dermis. Gross changes in hoof sole, signs of lameness, and increase in digital pulse pressure or pulse intensity were not detected. CONCLUSIONS AND CLINICAL RELEVANCE: Duration of contact with sodium bisulfate in this study was in excess of that expected under typical husbandry conditions. Despite this fact, gross changes in skin and hooves were not detected. Microscopic lesions were confined to the epidermis and superficial dermis. Results suggest that contact with sodium bisulfate under these conditions is safe.     

HPLC法测定氨苄西林钠可溶性粉中氨苄西林的含量

采用HPLC法测定氨苄西林钠可溶性粉中氨苄西林的含量.色谱柱为WaterssphericalC18(3.9mm×150mm,5μm),流动相为水-乙腈-1mol/L磷酸二氢钾溶液-1mol/L醋酸溶液(909∶80∶10∶1,V/V),检测波长254nm,流速1.0mL/min,柱温30℃,保留时间约4.5min.氨苄西林在0.25～2.0mg/mL范围内具有良好的线性关系(r=0.9999),平均回收率99.6%,RSD为0.3%.     

Effect of sodium hyaluronate in collagenase-induced superficial digital flexor tendinitis in horses.

Superficial digital flexor tendinitis was induced in each forelimb of 8 horses by injecting 4,000 U of collagenase into the midmetacarpal region of the tendon. In each horse, each tendon was treated 24 and 96 hours after the collagenase injection with SC injections of sodium hyaluronate (treated limbs) or an equal volume of 0.9% NaCl solution (control limbs). Exercise was restricted for the first 3 weeks of the study, and a controlled exercise program was instituted for the remainder of the study. Horses were evaluated clinically for lameness, tendon swelling, and midmetacarpal limb circumference. Ultrasonographic examinations were performed regularly (11 examinations/horse) throughout the study, and all horses were euthanatized 12 weeks after collagenase injections. Tendons from 4 horses were harvested for biomechanical testing, and samples were obtained from tendons from the remaining 4 horses for biochemical analysis of collagen. Samples were obtained from all tendons for microscopic evaluation. Significant differences between treated and control tendons were not noticed in any of the variables examined in live horses, although trends toward less lameness in treated limbs and toward better healing on ultrasonographic examination in control limbs were recorded. Significant differences were not noticed in biomechanical or biochemical evaluations, and the only significant (P < 0.05) microscopic finding was more severe inflammation in tendons from treated limbs. This study did not reveal significant benefits of treatment with sodium hyaluronate outside a synovial sheath on tendon repair in collagenase-induced tendinitis.