Doses In Horses Research Articles

Pharmacokinetics and clinical efficacy of acetaminophen (paracetamol) in adult horses with mechanically induced lameness.

Acetaminophen has been used clinically in horses alone or combined with traditional non-steroidal anti-inflammatory drugs for treatment of musculoskeletal pain in horses. To determine the pharmacokinetics and efficacy of acetaminophen at two doses in horses with mechanically induced lameness compared with phenylbutazone or placebo control. In vivo experiment. Nine healthy mares with mechanical lameness induced via a reversible sole pressure horseshoe model were treated with acetaminophen (20 mg/kg PO; A20), acetaminophen (30 mg/kg PO; A30), phenylbutazone (2.2 mg/kg, PO; PB) and oral placebo (C) in a randomised four-way Latin square model. Plasma concentrations for A20 and A30 were analysed via LC-MS/MS and noncompartmental pharmacokinetic analysis. Heart rate and heart rate variability were measured using a portable telemetry. Lameness was scored by three blinded boarded equine surgeons using the AAEP and 10-point scales. Mean maximum plasma concentration (Cmax ) for A20 was 20.01 μg/ml within 0.66 h (Tmax ) after administration; The mean Cmax for A30 was 30.02 μg/ml with a Tmax of 0.43 h. Post-treatment heart rate for A30 was significantly lower than A20 at 1 and 7h; lower than PB at 2, 3, 4.5 and 7h; lower than C at 2, 3.5, 4.5, 6, 7 and 8h. 10-point Lameness scores were significantly improved for A30 than C at 2 and 4h post-treatment; PB was significantly improved than C at 8h post treatment. There were no significant differences in lameness between A20, A30 and PB. Small sample size, lack of objective lameness measurement. Acetaminophen at 30 mg/kg produced a more rapid improvement in lameness scores and heart rate compared with other treatments in this model. Further evaluation of the pharmacokinetics and safety of repeated oral dosing of acetaminophen at 30 mg/kg is needed to determine clinical utility.

Improving clinical outcomes via responsible antimicrobial use in horses

SummaryThe growing problem of antimicrobial resistance affects veterinarians on a daily basis. Antimicrobial stewardship and responsible prescribing are essential for a future with effective antimicrobials, as it is unlikely that new antimicrobials will become available for use in horses in the near future. Extended‐spectrum β‐lactamase (ESBL) producing Enterobacteriaceae, methicillin‐resistant Staphylococcus aureus (MRSA) and Salmonella spp. are pathogens of significant concern but there are also other opportunistic pathogens such as Pseudomonas spp., α‐haemolytic Streptococcus spp., Enterococcus spp. and Acinetobacter spp. which, due to their high intrinsic resistance, have limited treatment options in adult horses. It is essential that highest priority critically important antimicrobials such as ceftiofur, enrofloxacin, rifampicin and polymyxin B are used prudently in horses and ideally based on culture and antimicrobial susceptibility testing (AST). For example, the use of polymyxin B at a low anti‐endotoxic dose rather than at a higher antimicrobial dose in horses for the treatment of systemic inflammatory response syndrome is a potential driver for resistance to colistin (polymyxin E), an antimicrobial used as a last resort in the treatment of multidrug resistant (MDR) Enterobacteriaceae infections in humans. Serum procalcitonin levels are used in humans to distinguish noninfectious inflammatory conditions from inflammation caused by bacteria and other infectious agents and are also used to guide cessation of antimicrobial treatment. Although no such studies have been performed in horses, this or other markers may prove to be helpful in guiding antimicrobial treatment decisions in the future. Optimising sampling techniques and good communication with the microbiology laboratory are essential for generating the accurate culture and AST results that underpin appropriate antimicrobial use. Additionally, there is clearly a need for national and international harmonisation of laboratory methods in order to improve the reliability and consistency of results reported by different laboratories.

Plasma disposition of gabapentin after the intragastric administration of escalating doses to adult horses.

BackgroundIn humans, gabapentin an analgesic, undergoes non‐proportional pharmacokinetics which can alter efficacy. No information exists on the pharmacokinetics of dosages >20 mg/kg, escalating dosages or dose proportionality of gabapentin in horses.Hypothesis and ObjectivesGabapentin exposure in plasma would not increase proportionally relative to the dose in horses receiving dosages ≥20 mg/kg. To assess the plasma pharmacokinetics of gabapentin after nasogastric administration of gabapentin at dosages of 10 to 160 mg/kg in adult horses.AnimalsNine clinically healthy adult Arabian and Quarter Horses.MethodsIn a randomized blinded trial, gabapentin was administered by nasogastric intubation to horses at 10, 20 mg/kg (n = 3) and 60, 80, 120, 160 mg/kg (n = 6). Plasma was collected before and at regular times over 64 hours after administration of gabapentin. Gabapentin was quantified using a validated chromatographic method. Dose proportionality was estimated using a power model. Pharmacokinetic parameters were estimated using compartmental pharmacokinetic analysis.ResultsPlasma pharmacokinetics parameters of gabapentin were estimated after nasogastric administration at dosages of 10 to 160 mg/kg. Gabapentin plasma concentration increased with dose increments. However, the area under the concentration curve from zero to infinity and maximal plasma concentration did not increase proportionally relative to the dose in horses.Conclusions and Clinical ImportanceGabapentin exposure in plasma is not proportional relative to the dose in horses receiving nasogastric dosages of 10 to 160 mg/kg.

Antimicrobial labelling in Australia: a threat to antimicrobial stewardship?

Antimicrobial resistance is a public health emergency, placing veterinary antimicrobial use under growing scrutiny. Antimicrobial stewardship, through appropriate use of antimicrobials, is a response to this threat. The need for antimicrobial stewardship in Australian veterinary practices has had limited investigation. A 2016 survey undertaken to investigate antimicrobial usage patterns by Australian veterinarians found that antimicrobial dose rates were varied and often inappropriate. Doses of procaine penicillin in horses and cattle were often low, with 68% and 90% of respondents, respectively, reporting doses that were unlikely to result in plasma concentrations above minimum inhibitory concentrations for common equine and bovine pathogens. Frequency of penicillin administration was also often inappropriate. Gentamicin doses in horses were largely appropriate (89% of dose rates appropriate), but 9% of respondents reported twice daily dosing. Amoxycillin and amoxycillin-clavulanate were administered at the appropriate doses, or above, to dogs and cats by 54% and 70% of respondents, respectively. Here, we explore the potential reasons for inappropriate antimicrobial dose regimens and report that antimicrobial labels often recommend incorrect dose rates and thus may be contributing to poor prescribing practices. Changes to legislation are needed to ensure that antimicrobial drug labels are regularly updated to reflect the dose needed to effectively and safely treat common veterinary pathogens. This will be especially true if changes in legislation restrict antimicrobial use by veterinarians to the uses and doses specified on the label, thus hampering the current momentum towards improved antimicrobial stewardship.

Effect of feeding on the pharmacokinetics of oral minocycline in healthy adult horses.

Minocycline is commonly used to treat bacterial and rickettsial infections in adult horses but limited information exists regarding the impact of feeding on its oral bioavailability. This study's objective was to compare the pharmacokinetics of minocycline after administration of a single oral dose in horses with feed withheld and with feed provided at the time of drug administration. Six healthy adult horses were administered intravenous (2.2mg/kg) and oral minocycline (4mg/kg) with access to hay at the time of oral drug administration (fed) and with access to hay delayed for 2hr after oral drug administration (fasted), with a 7-day washout between treatments. Plasma concentration versus time data was analyzed based on noncompartmental pharmacokinetics. Mean±SD bioavailability (fasted: 38.6%±4.6; fed: 15.7%±2.3) and Cmax (fasted: 1.343±0.418μg/ml; fed: 0.281±0.157μg/ml) were greater in fasted horses compared to fed horses (p<.05 both). Median (range) Tmax (hr) in fasted horses was 2.0 (1.5-3.5) and in fed horses was 5.0 (1.0-8.0) and was not significantly different between groups. Overnight fasting and delaying feeding hay 2hr after oral minocycline administration improve drug bioavailability and thus plasma concentrations.

Plasma and synovial fluid pharmacokinetics of cefquinome following the administration of multiple doses in horses.

The plasma and synovial fluid pharmacokinetics and safety of cefquinome, a 2-amino-5-thiazolyl cephalosporin, were determined after multiple intravenous administrations in sixteen healthy horses. Cefquinome was administered to each horse through a slow i.v. injection over 20min at 1, 2, 4, and 6mg/kg (n=4 horses per dose) every 12h for 7days (a total of 13 injections). Serial blood and synovial fluid samples were collected during the 12h after the administration of the first and last doses and were analyzed by a high-performance liquid chromatography assay. The data were evaluated using noncompartmental pharmacokinetic analyses. The estimated plasma pharmacokinetic parameters were compared with the hypothetical minimum inhibitory concentration (MIC) values (0.125-2μg/mL). The plasma and synovial fluid concentrations and area under the concentration-time curves (AUC) of cefquinome showed a dose-dependent increase. After a first dose of cefquinome, the ranges for the mean plasma half-life values (2.30-2.41h), the mean residence time (1.77-2.25h), the systemic clearance (158-241mL/h/kg), and the volume of distribution at steady-state (355-431mL/kg) were consistent across dose levels and similar to those observed after multiple doses. Cefquinome did not accumulate after multiple doses. Cefquinome penetrated the synovial fluid with AUCsynovial fluid /AUCplasma ratios ranging from 0.57 to 1.37 after first and thirteenth doses, respectively. Cefquinome is well tolerated, with no adverse effects. The percentage of time for which the plasma concentrations were above the MIC was >45% for bacteria, with MIC values of ≤0.25, ≤0.5, and ≤1μg/mL after the administration of 1, 2, and 4 or 6mg/kg doses of CFQ at 12-h intervals, respectively. Further studies are needed to determine the optimal dosage regimes in critically ill patients.

Repeated post-exercise administration with a mixture of leucine and glucose alters the plasma amino acid profile in Standardbred trotters.

BackgroundThe branched chain amino acid leucine is a potent stimulator of insulin secretion. Used in combination with glucose it can increase the insulin response and the post exercise re-synthesis of glycogen in man. Decreased plasma amino acid concentrations have been reported after intravenous or per oral administration of leucine in man as well as after a single per oral dose in horses. In man, a negative correlation between the insulin response and the concentrations of isoleucine, valine and methionine have been shown but results from horses are lacking. This study aims to determine the effect of repeated per oral administration with a mixture of glucose and leucine on the free amino acid profile and the insulin response in horses after glycogen-depleting exercise.MethodsIn a crossover design, after a glycogen depleting exercise, twelve Standardbred trotters received either repeated oral boluses of glucose, 1 g/kg body weight (BW) at 0, 2 and 4 h with addition of leucine 0.1 g/kg BW at 0 and 4 h (GLU+LEU), or repeated boluses of water at 0, 2 and 4 h (CON). Blood samples for analysis of glucose, insulin and amino acid concentrations were collected prior to exercise and over a 6 h post-exercise period. A mixed model approach was used for the statistical analyses.ResultsPlasma leucine, isoleucine, valine, tyrosine and phenylalanine concentrations increased after exercise. Post-exercise serum glucose and plasma insulin response were significantly higher in the GLU+LEU treatment compared to the CON treatment. Plasma leucine concentrations increased after supplementation. During the post-exercise period isoleucine, valine and methionine concentrations decreased in both treatments but were significantly lower in the GLU+LEU treatment. There was no correlation between the insulin response and the response in plasma leucine, isoleucine, valine and methionine.ConclusionsRepeated post-exercise administration with a mixture of leucine and glucose caused a marked insulin response and altered the plasma amino acid profile in horses in a similar manner as described in man. However, the decreases seen in plasma amino acids in horses seem to be related more to an effect of leucine and not to the insulin response as seen in man.

Pharmacokinetics and distribution of minocycline in mature horses after oral administration of multiple doses and comparison with minimum inhibitory concentrations

Minocycline holds great potential for use in horses not only for its antimicrobial effects but also for its anti-inflammatory and neuroprotective properties. However, there are no pharmacokinetic or safety data available regarding the use of oral minocycline in horses. To determine pharmacokinetics, safety and penetration into plasma, synovial fluid, aqueous humour (AH) and cerebral spinal fluid (CSF) of minocycline after oral administration of multiple doses in horses and to determine the minimum inhibitory concentrations (MIC) of minocycline for equine pathogenic bacteria. Six horses received minocycline (4 mg/kg bwt q. 12 h for 5 doses). Thirty-three blood and 9 synovial fluid samples were collected over 96 h. Aqueous humour and CSF samples were collected 1 h after the final dose. Minocycline concentrations were measured using high pressure liquid chromatography. The MIC values of minocycline for equine bacterial isolates were determined. At steady state, the mean ± s.d. peak concentration of minocycline in the plasma was 0.67 ± 0.26 µg/ml and the mean half-life was 11.48 ± 3.23 h. The highest trough synovial fluid minocycline concentration was 0.33 ± 0.12 µg/ml. The AH concentration of minocycline was 0.09 ± 0.03 µg/ml in normal eyes and 0.11 ± 0.04 µg/ml in blood aqueous barrier-disrupted eyes. The mean CSF concentration of minocycline was 0.38 ± 0.09 µg/ml. The MIC values were determined for 301 isolates. Minocycline concentrations were above the MIC(50) and MIC(90) for many gram-positive equine pathogens. This study supports the use of orally administered minocycline at a dose of 4 mg/kg bwt every 12 h for the treatment of nonocular infections caused by susceptible (MIC ≤ 0.25 µg/ml) organisms in horses. Further studies are required to determine the dose that would be effective for the treatment of ocular infections.

Intravenous and sublingual buprenorphine in horses: pharmacokinetics and influence of sampling site

ObjectiveTo describe the pharmacokinetics and adverse effects of intravenous (IV) and sublingual (SL) buprenorphine in horses, and to determine the effect of sampling site on plasma concentrations after SL administration. Study designRandomized crossover experiment; prospective study. AnimalsEleven healthy adult horses between 6 and 20 years of age and weighing 487–592 kg. MethodsIn the first phase; buprenorphine was administered as a single IV or SL dose (0.006 mg kg−1) and pharmacokinetic parameters were determined for each route of administration using a noncompartmental model. In the second phase; the jugular and lateral thoracic veins were catheterized for simultaneous venous blood sampling, following a dose of 0.006 mg kg−1 SL buprenorphine. For both phases, plasma buprenorphine concentrations were measured using ultra-performance liquid chromatography with mass spectrometry. At each sampling period, horses were assessed for behavioral excitement and gastrointestinal motility. ResultsFollowing IV administration, buprenorphine mean ± SD half-life was 5.79 ± 1.09 hours. Systemic clearance (Cl) following IV administration was 6.13 ± 0.86 mL kg−1 minute−1 and volume of distribution at steady-state was 3.16 ± 0.65 L kg−1. Following IV administration, horses showed signs of excitement. Gastrointestinal sounds were decreased following both routes of administration; however, none of the horses exhibited signs of colic. There was a significant discrepancy between plasma buprenorphine concentrations measured in the jugular vein versus the lateral thoracic vein following phase 2, thus pharmacokinetic parameters following SL buprenorphine are not reported. Conclusions and clinical relevanceBuprenorphine has a long plasma half-life and results in plasma concentrations that are consistent with analgesia in other species for up to 4 hours following IV administration of this dose in horses. While buprenorphine is absorbed into the circulation following SL administration, jugular venous sampling gave a false measurement of the quantity absorbed and should not be used to study the uptake from SL administration.

Pharmacokinetics of the calcium‐channel blocker diltiazem after a single intravenous dose in horses1

The pharmacokinetics of diltiazem were determined in eight healthy horses. Diltiazem HCl, 1 mg/kg i.v., was administered over 5 min. Venous blood samples were collected at regular intervals after administration. Plasma concentrations of diltiazem and desacetyldiltiazem were determined by high-performance liquid chromatography. A second, putative metabolite was detected, but could not be identified due to the lack of an authentic standard. Data were analyzed by nonlinear least-squares regression analysis. The median (minimum-maximum) peak plasma concentration of diltiazem was 727 (539-976) ng/mL. Plasma diltiazem concentration vs. time data were best described by a two-compartment model with first-order drug elimination. The distribution half-life was 12 (6-23) min, the terminal half-life was 93 (73-161) min, the mean residence time was 125 (99-206) min, total plasma clearance was 14.4 (10.4-18.6) mL/kg/min, and the volume of distribution at steady-state was 1.84 (1.46-2.51) L/kg. The normalized ratio of the area under the curve (AUC) of desacetyldiltiazem to the AUC of diltiazem was 0.088 (0.062-0.179). The disposition of diltiazem in horses was characterized by rapid distribution and elimination and a terminal half-life shorter than reported in humans and dogs. Because of the reported low pharmacologic activity, plasma diltiazem metabolite concentrations were not considered clinically important.

Pharmacokinetics and tissue distribution of doxycycline after oral administration of single and multiple doses in horses

To determine pharmacokinetics, safety, and penetration into interstitial fluid (ISF), polymorphonuclear leukocytes (PMNLs), and aqueous humor of doxycycline after oral administration of single and multiple doses in horses. 6 adult horses. The effect of feeding on drug absorption was determined. Plasma samples were obtained after administration of single or multiple doses of doxycycline (20 mg/kg) via nasogastric tube. Additionally, ISF, PMNLs, and aqueous humor samples were obtained after the final administration. Horses were monitored for adverse reactions. Feeding decreased drug absorption. After multiple doses, mean +/- SD time to maximum concentration was 1.63 +/- 1.36 hours, maximum concentration was 1.74 +/- 0.3 microg/mL, and elimination half-life was 12.07 +/- 3.17 hours. Plasma protein binding was 81.76 +/- 2.43%. The ISF concentrations correlated with the calculated percentage of non-protein-bound drug. Maximum concentration was 17.27 +/- 8.98 times as great in PMNLs, compared with plasma. Drug was detected in aqueous humor at 7.5% to 10% of plasma concentrations. One horse developed signs of acute colitis and required euthanasia. Results suggest that doxycycline administered at a dosage of 20 mg/kg, PO, every 24 hours will result in drug concentrations adequate for killing intracellular bacteria and bacteria with minimum inhibitory concentration < or = 0.25 microg/mL. For bacteria with minimum inhibitory concentration of 0.5 to 1.0 microg/mL, a dosage of 20 mg/kg, PO, every 12 hours may be required; extreme caution should be exercised with the higher dosage until more safety data are available.

Pharmacokinetics and tissue distribution of doxycycline after oral administration of single and multiple doses in horses

Pharmacokinetics and tissue distribution of doxycycline after oral administration of single and multiple doses in horses

Lower gastric ulcerogenic effect of suxibuzone compared to phenylbutazone when administered orally to horses

The objective was to compare the gastrointestinal and general toxicity of suxibuzone (SBZ) to that of phenylbutazone (PBZ) when administered orally in horses. Fifteen healthy horses were allocated to three treatment groups. One group received a high dose of PBZ for two weeks; the second group was given an equimolecular dosage of SBZ; and a third group received placebo. Horses were daily monitored, and blood samples were collected before and during the study. On day 18, complete post-mortem examinations were performed. One horse treated with PBZ showed clinical signs of NSAID toxicosis. Small oral ulcers were also detected in other two horses from the PBZ group and in two horses from the SBZ group. There were no statistical differences in the blood parameters among groups. Ulcers in the stomach’s glandular mucosa were observed in all horses of the PBZ group, while only two horses of the SBZ group showed ulcerations. PBZ horses had a significant higher ulcerated area, and gastric ulcers were significantly deeper than those in the SBZ and placebo groups. No other lesions were found in any other tissue. In conclusion, SBZ causes significantly lower gastric ulcerogenic effect than PBZ when administered orally at equimolecular doses in horses.

STUDIES ON THE IMMUNIZATION OF HORSES BY HABU SNAKE VENOM TREATED BY FREUND'S ADJUVANT OR DIHYDROTHIOCTIC ACID

It was elucidated that 5mg. or 100mg. of Habu Snake Venom (Trimeresurus flavoviridis) were available as first immunizing doses in horses when it was treated by Freund's incomplete adjuvant or 100mg. of Dihydrothioctic acid. Four weeks after, 1mg. of plain venom was injected subcutaveously into horses, and the dose was then increased duplicatedly in every week. After ten or fifteen times of booster injection, 0.1ml. of the sera showed to neutralize sufficiently the lethal effect and local lesion due to the venom of 300γ or more. The sera were mixed in vitro with the various amounts of venom and injected intramuscularly into the legs of mice. Thus the total amount of venom used for the immunization and the periods of immunization were reduced to one half in compared with the immunization method without adjuvant adopted until now.