Effect of Sucralfate on the Relative Bioavailability of Enrofloxacin and Ciprofloxacin in Healthy Fed Dogs

Background: Sucralfate impairs absorption of ciprofloxacin and other fluoroquinolones in humans, but no sucralfate-fluoroquinolone interaction has been reported in dogs. Veterinary formularies recommend avoiding concurrent administration of these medications, which might impact compliance, therapeutic success, and resistance selection from fluoroquinolones. Objectives: To determine whether a drug interaction exists when sucralfate is administered to fed dogs concurrently with ciprofloxacin or enrofloxacin, and whether a 2 hour delay between fluoroquinolone and sucralfate affects fluoroquinolone absorption. Animals: Five healthy Greyhounds housed in a research colony. Methods: This was a randomized crossover study. Treatments included oral ciprofloxacin (C) or oral enrofloxacin (E) alone, each fluoroquinolone concurrently with an oral suspension of sucralfate (CS, ES), and sucralfate suspension 2 hours after each fluoroquinolone (C2S, E2S). Fluoroquinolone concentrations were evaluated using liquid chromatography with mass spectrometry. Results: Drug exposure of ciprofloxacin was highly variable (AUC 5.52-22.47 h ?g/mL) compared to enrofloxacin (AUC 3.86-7.50 h ?g/mL). The mean relative bioavailability for ciprofloxacin and concurrent sucralfate was 48% (range 8-143%) compared to ciprofloxacin alone. Relative bioavailability of ciprofloxacin improved to 87% (range 37-333%) when sucralfate was delayed by 2 hours. By contrast, relative bioavailability for enrofloxacin and concurrent sucralfate was 104% (94-115%).Citation: KuKanich, K., KuKanich, B., Guess, S. and Heinrich, E. (2015), Effect of Sucralfate on the Relative Bioavailability of Enrofloxacin and Ciprofloxacin in Healthy Fed Dogs. Journal of Veterinary Internal Medicine. doi: 10.1111/jvim.1379

Altered Plasma Pharmacokinetics of Ceftiofur Hydrochloride in Cows Affected with Severe Clinical Mastitis

Ceftiofur is the most commonly used antimicrobial in lactating dairy cows. Recently, there has been an increase in the number of violative residues of ceftiofur in the tissues of cull dairy cows. This was the first project in a series of projects we will be completing aimed at characterizing the pharmacokinetics of ceftiofur in disease challenged animals. The results of this study indicate that diseased animals have lower plasma concentrations and altered pharmacokinetics compared to healthy animals. Future work will investigate the influence of altered pharmacokinetics on the presence of violative residues

Systemic and anti-nociceptive effects of prolonged lidocaine, ketamine, and butorphanol infusions alone and in combination in healthy horses

BACKGROUND: Prolonged drug infusions are used to treat horses with severe signs of pain, but can be associated with altered gastrointestinal transit. The purpose of this study was to determine the effects of prolonged constant rate infusions (CRI) of lidocaine (L), butorphanol (B), and ketamine (K) alone and in combination on gastrointestinal transit, behavior, and thermal nociceptive threshold in healthy horses. METHODS: Eight healthy adult horses were used in a randomized, cross-over, blinded, prospective experimental trial. Interventions were saline, L, K, B, LK, LB, BK, and LBK as an intravenous CRI for 96 hours. Drugs were mixed or diluted in saline; following a bolus, CRI rate was 0.15mL/kg/hr with drug doses as follows: L – 1.3 mg/kg then 3 mg/kg/hr; B – 0.018 mg/kg then 0.013 mg/kg/hr; K – 0.55 mg/kg then 0.5 mg/kg/hr. Two-hundred plastic beads were administered intragastrically by nasogastric tube immediately prior to the bolus. Feces were collected every 2 hours, weighed, and beads manually retrieved. Behavior was scored every 2 hours, vital parameters every 6 hours, and thermal nociceptive threshold every 12 hours for 96 hours. Drug concentrations in the LBK solution were tested every 6 hours for 72 hours. RESULTS: Four of 64 trials (3 LBK, 1 BK) were discontinued early due to signs of abdominal discomfort. There were no apparent differences between groups in vital parameters or thermal threshold. Transit time was delayed for LB and LBK with a corresponding decrease in fecal weight that was most severe in the final 24 hours of infusion. Significant changes in behavior scores, vital parameters, or thermal threshold were not observed. The concentration of each drug in the combined solution declined by less than 31% over the sampling period. CONCLUSIONS: Drug combinations containing butorphanol cause an apparent delay in gastrointestinal transit in healthy horses without substantially affecting somatic nociception at the doses studied. Combinations of lidocaine and ketamine may have less impact on gastrointestinal transit than infusions combined with butorphanol. Further work is needed to determine the effects of these drugs in painful or critically ill patients

Parent-Metabolite Pharmacokinetic Models for Tramadol – Tests of Assumptions and Predictions

Allometric principles were used to discern cross-species differences in (±)-tramadol disposition and formation of its primary analgesic metabolite, (±)-O-desmethyl-tramadol (M1). Species differences in formation of M1 may help predict the analgesic effectiveness of tramadol. Tramadol was administered intravenously by a zero-order (constant infusion) process or rapid bolus dose and racemic concentrations of tramadol and M1 measured. Data were pooled to define differences between species (human, rat, cat, dog, goat, donkey and horse). A two-compartment linear disposition model with first-order elimination was used to describe tramadol and M1 disposition. Slow metabolizers were detected in 6% of the population and tramadol clearance to M1 was 16.2% that of extensive metabolizers. Tramadol clearance to M1 was slower and tramadol clearance by other pathways was faster in rats, dogs, and horses compared to humans. There are substantial differences between species in the pharmacokinetics of tramadol and its M1 metabolite, which are not explained by differences in body weight. The hypothesis that volumes of distribution are similar across species was shown not to be true. M1 exposure in the goat, donkey and cat was comparable to humans, which indicates it is likely to be an effective analgesic at typically used doses in these species but not in dogs or horses

Pharmacokinetics of meloxicam in mature swine after intravenous andoral administration

The purpose of this study was to compare the pharmacokinetics of meloxicam in mature swine after intravenous (IV) and oral (PO) administration. Six mature sows (mean bodyweight ± standard deviation = 217.3± 65.68 kg) were administered an IV or PO dose of meloxicam at a target dose of 0.5 mg/kg in a cross-over design. Plasma samples collected up to 48 hours post-administration were analyzed by high pressure liquid chromatography and mass spectrometry (HPLC-MS) followed by non-compartmental pharmacokinetic analysis. Mean peak plasma concentration (CMAX) after PO administration was 1070 ng/ml (645-1749 ng/ml). TMAX was recorded at 2.40 hour (0.50-12.00 hours) after PO administration. Half-life (T ½ λz) for IV and PO administration was 6.15 hours (4.39-7.79 hours) and 6.83 hours (5.18-9.63 hours) respectively. The bioavailability (F) for PO administration was 87% (39-351%). The results of the present study suggest that meloxicam is well absorbed after oral administration

Bioavailability and Pharmacokinetics of Oral Meloxicam in Llamas

South American camelids in the United States have rapidly developed into an important agricultural industry in need of veterinary services. Pain management is challenging in camelids because there are no drugs currently approved by the U.S. Food and Drug Administration for use in these species. Dosage regimens used for many therapeutic drugs have been extrapolated from other ruminants; however, the pharmacokinetics, in camelids, may differ from those of other species. Studies investigating the pharmacokinetics of cyclooxygenase-2 (COX-2) selective non-steroidal anti-inflammatory drugs in camelids are deficient in the published literature. Six adult llamas (121- 168 kg) were administered either a 1 mg/kg dose of oral or a 0.5 mg/kg dose of IV meloxicam in a randomized cross-over design with an 11 day washout period between treatments. Plasma samples collected up to 96 hours post-administration were analyzed by high pressure liquid chromatography and mass spectrometry detection (HPLC-MS) followed by non-compartmental pharmacokinetic analysis. A mean peak plasma concentration (CMAX) of 1.314 μg/mL (Range: 0.826 – 1.776 μg/mL) was recorded at 21.4 hours (Range: 12.0 – 24.0 hours) with a half-life (T ½ λz) of 22.7 hours (Range: 18.0 – 30.8 hours) after oral meloxicam administration. In comparison, a half-life (T ½ λz) of 17.4 hours (Range: 16.2 – 20.7 hours) was demonstrated with IV meloxicam administration. The oral bioavailability (F) of meloxicam (dose normalized) was 76% (Range: 48 – 92%). No adverse effects associated with either treatment modality were observed in the llamas. The mean bioavailability (F) of oral meloxicam was 76% indicating a high degree of gastrointestinal absorption. Plasma meloxicam concentrations >0.2 μg/mL were maintained for up to 72 h after oral administration; >0.2 μg/mL is considered to be the concentration of meloxicam required for analgesic effects in other species such as the horse. These data suggest that a single dosage of oral meloxicam at 1 mg/kg could potentially maintain therapeutic concentrations in plasma for up to 3 days in adult llamas.This article is from BMC Veterinary Research 8 (2012): 85, doi:10.1186/1746-6148-8-85. Posted with permission.</p

Anti-inflammatory salicylate treatment alters the metabolic adaptations to lactation in dairy cattle

Citation:Farney, J. K., Mamedova, L. K., Coetzee, J. F., KuKanich, B., Sordillo, L. M., Stoakes, S. K., … Bradford, B. J. (2013). Anti-inflammatory salicylate treatment alters the metabolic adaptations to lactation in dairy cattle. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 305(2), R110–R117. https://doi.org/10.1152/ajpregu.00152.2013Adapting to the lactating state requires metabolic adjustments in multiple tissues, especially in the dairy cow, which must meet glucose demands that can exceed 5 kg/day in the face of negligible gastrointestinal glucose absorption. These challenges are met through the process of homeorhesis, the alteration of metabolic setpoints to adapt to a shift in physiological state. To investigate the role of inflammation-associated pathways in these homeorhetic adaptations, we treated cows with the nonsteroidal anti-inflammatory drug sodium salicylate (SS) for the first 7 days of lactation. Administration of SS decreased liver TNF-α mRNA and marginally decreased plasma TNF-α concentration, but plasma eicosanoids and liver NF-κB activity were unaltered during treatment. Despite the mild impact on these inflammatory markers, SS clearly altered metabolic function. Plasma glucose concentration was decreased by SS, but this was not explained by a shift in hepatic gluconeogenic gene expression or by altered milk lactose secretion. Insulin concentrations decreased in SS-treated cows on day 7 compared with controls, which was consistent with the decline in plasma glucose concentration. The revised quantitative insulin sensitivity check index (RQUICKI) was then used to assess whether altered insulin sensitivity may have influenced glucose utilization rate with SS. The RQUICKI estimate of insulin sensitivity was significantly elevated by SS on day 7, coincident with the decline in plasma glucose concentration. Salicylate prevented postpartum insulin resistance, likely causing excessive glucose utilization in peripheral tissues and hypoglycemia. These results represent the first evidence that inflammation-associated pathways are involved in homeorhetic adaptations to lactation.the transition from late pregnancy to lactation is a time of great physiological stress, especially for the dairy cow. The decline in feed intake that accompanies parturition, coupled with the rapid increase in energy requirements during lactogenesis, requires a dramatic shift in nutrient fluxes to release stored nutrients and direct them to the mammary gland. This programmed shift in metabolic setpoints is an archetypal example of homeorhesis, defined as the “coordinated changes in metabolism of body tissues necessary to support a physiological state” (4).Mechanisms underlying homeorhetic adaptions to lactation have been described to some extent. The somatotropic axis is decoupled during this time, resulting in dramatic elevations of plasma growth hormone concentrations without the expected rise in insulin-like growth factor 1 secretion (11, 51). Likewise, insulin sensitivity declines substantially from late gestation (5, 48). These endocrine shifts are critical for promoting the mobilization of stored nutrients and sparing glucose for use by the mammary gland. This conservation of glucose is particularly important in ruminants. The microbes that inhabit the rumen ferment most dietary carbohydrate to volatile fatty acids, leaving very little glucose to be absorbed in the small intestine. As a result, lactating cows absorb almost no glucose from the gastrointestinal tract and must synthesize as much as 5 kg of glucose in the liver daily (2).The homeorhetic adaptations that allow cows to increase milk production to 40 kg/day within days after parturition can stress the metabolic system. Rapid lipolysis can increase plasma nonesterified fatty acid (NEFA) concentrations by as much as 10-fold within a few days after parturition (21), and both hypoglycemia and hypocalcemia are common, as nutrients are drawn into the mammary gland. Ketosis and fatty liver (FL) are common metabolic diseases that result during this time; in fact, nearly 90% of all metabolic diseases in dairy cattle occur during the first 4 wk of the 305-day lactation (24).Despite their reliance on mobilized lipid as an energy source, dairy cattle entering lactation with greater adipose mass are at greater risk of developing metabolic diseases (34). It has become clear in the past decade that animals with excessive adiposity exhibit a low-grade inflammation (23), suggesting that perhaps inflammation underlies metabolic disturbances in obese dairy cows. In support of this hypothesis, cows with moderate or severe FL have increased levels of the inflammatory cytokine TNF-α (41). Inflammatory cytokines cause myriad metabolic changes in dairy cattle, including anorexia, lipomobilization, impaired insulin sensitivity, and reduced milk yield (7, 26, 27), all of which are associated with FL and ketosis. Furthermore, daily injection of TNF-α for 7 days increased liver triglyceride content independent of effects on feed intake, and this effect was accompanied by changes in hepatic gene expression consistent with both inflammation and a shift from fatty acid oxidation to triglyceride synthesis (8).These recent findings suggest that exogenous inflammatory agents are sufficient to induce metabolic dysfunction. Whether inflammation is a necessary causative factor in the natural progression of bovine FL and ketosis, however, remains unclear. To address this broad question, we used the nonsteroidal anti-inflammatory drug (NSAID) sodium salicylate (SS). Sodium salicylate is a weak inhibitor of cyclooxygenase (COX)-1 and COX-2 (31), and its probable mode of action is that it inhibits phosphorylation of the NF-κB inhibitor IκB-α (53). Phosphorylation of IκB results in its degradation, allowing NF-κB to be released for translocation into the nucleus and subsequent activation of an inflammatory transcription program (3). The specific hypothesis for this study was that SS would slow liver triglyceride accumulation, promote gluconeogenesis, and limit metabolic disease in dairy cows entering lactation. In contrast, our findings suggest that inflammatory signals may contribute to homeorhetic adaptations to lactation, especially regulation of glucose metabolism and modulation of lipolysis and ketogenesis as animals return to positive energy balance

The effect of timing of oral meloxicam administration on physiological responses in calves after cautery dehorning with local anesthesia.

Abstract Dehorning is a painful husbandry procedure that is commonly performed in dairy calves. Parenteral meloxicam combined with local anesthesia mitigates the physiological and behavioral effects of dehorning in calves. The purpose of this study was to determine the influence of timing of oral meloxicam administration on physiological responses in calves after dehorning. Thirty Holstein bull calves, 8 to 10 wk of age (28–70kg), were randomly assigned to 1 of 3 treatment groups: placebo-treated control group (n=10), calves receiving meloxicam administered orally (1 mg/kg) in powdered milk replacer 12h before cautery dehorning (MEL-PRE; n=10), and calves receiving meloxicam administered as an oral bolus (1 mg/kg) at the time of dehorning (MEL-POST; n=10). Following cautery dehorning, blood samples were collected to measure cortisol, substance P (SP), haptoglobin, ex vivo prostaglandin E 2 (PgE 2 ) production after lipopolysaccharide stimulation and meloxicam concentrations. Maximum ocular temperature and mechanical nociceptive threshold (MNT) were also assessed. Data were analyzed using noncompartmental pharmacokinetic analysis and repeated measures ANOVA models. Mean peak meloxicam concentrations were 3.61±0 0.21 and 3.27±0.14μg/mL with average elimination half-lives of 38.62±5.87 and 35.81±6.26h for MEL-PRE and MEL-POST, respectively. Serum cortisol concentrations were lower in meloxicam-treated calves compared with control calves at 4h postdehorning. Substance P concentrations were significantly higher in control calves compared with meloxicam-treated calves at 120h after dehorning. Prostaglandin E 2 concentrations were lower in meloxicam-treated calves compared with control calves. Mechanical nociceptive threshold was higher in control calves at 1h after dehorning, but meloxicam-treated calves tended to have a higher MNT at 6h after dehorning. No effect of timing of meloxicam administration on serum cortisol concentrations, SP concentrations, haptoglobin concentrations, maximum ocular temperature, or MNT was observed. However, PgE 2 concentrations in MEL-PRE calves were similar to control calves after 12h postdehorning, whereas MEL-POST calves had lower PgE 2 concentrations for 3 d postdehorning. These findings support that meloxicam reduced cortisol, SP, and PgE 2 after dehorning, but only PgE 2 production was significantly affected by the timing of meloxicam administration

Pharmacokinetics of flunixin meglumine in mature swine after intravenous, intramuscular and oral administration

The purpose of this study was to determine intravenous (IV), intramuscular (IM) and oral (PO) FM PK in mature swine. Appropriate pain management for lameness in swine is a critical control point for veterinarians and producers, but science-based guidance on optimal housing, management and treatment of lameness is deficient. Six mature swine (121–168 kg) were administered an IV, IM, or PO dose of flunixin meglumine at a target dose of 2.2 mg/kg in a cross-over design with a 10 day washout period between treatments. Plasma samples collected up to 48 hours post-administration were analyzed by high pressure liquid chromatography and mass spectrometry (HPLC-MS) followed by non-compartmental pharmacokinetic analysis. No adverse effects were observed with flunixin meglumine administration for all routes. Flunixin meglumine was administered at an actual mean dose of 2.21 mg/kg (range: 2.05-2.48 mg/kg) IV, IM and PO. A mean peak plasma concentration (CMAX) for IM and PO administration was 3748 ng/ml (range: 2749–6004 ng/ml) and 946 ng/ml (range: 554–1593 ng/ml), respectively. TMAX was recorded at 1.00 hour (range: 0.50-2.00 hours) and 0.61 hours (range: 0.17-2.00 hours) after PO and IM administration. Half-life (T ½ λz) for IV, IM and PO administration was 6.29 hours (range: 4.84-8.34 hours), 7.49 hours (range: 5.55-12.98 hours) and 7.08 hours (range: 5.29-9.15 hours) respectively. In comparison, bioavailability (F) for PO administration was 22% (range: 11-44%) compared to IM F at 76% (range: 54-92%). The results of the present study suggest that FM oral administration is not the most effective administration route for mature swine when compared to IV and IM. Lower F and Cmax of PO-FM in comparison to IM-FM suggest that PO-FM is less likely to be an effective therapeutic administration route