Palmitoyl-glucosamine co-micronized with curcumin for maintenance of meloxicam-induced pain relief in dogs with osteoarthritis pain.

BACKGROUND: Osteoarthritis (OA) pain is the number one cause of chronic pain in dogs. Multimodal treatment, including combining safe and effective nutritional interventions with non-steroidal anti-inflammatory drugs (NSAIDs), is currently considered one of the most appropriate choices for managing OA pain. Palmitoyl-glucosamine is a feed material belonging to the ALIAmide family, whose parent molecule is the prohomeostatic lipid amide N-palmitoyl-ethanolamine. Curcumin is a promising plant antioxidant. The present study aimed at investigating whether 18-week dietary integration with palmitoyl-glucosamine co-micronized with curcumin was able to maintain pain relief in dogs with OA-associated chronic pain receiving meloxicam (1.5 mg/ml oral suspension) on a tapering regimen (progressive 25% decrease of the original 0.1 mg/kg/day dose, on a biweekly basis) during the first 8 weeks of treatment. Pain was assessed both by the owners and veterinary surgeons, with the first using both subjective evaluation and validated metrology instruments-i.e., Helsinki Chronic Pain Index (HCPI) and Canine Brief Pain Inventory (CBPI)-while the second rating the severity of lameness and pain on palpation on two previously used 5-point scales. RESULTS: A total of fifty-eight dogs with OA chronic pain entered the uncontrolled study. Pain on HCPI was considered severe at baseline (range 18-39). Based on owner's assessment, 90% of dogs who responded to meloxicam at the full-dose regimen could reduce meloxicam up to 25% of the original dose without experiencing pain worsening. Moreover, 75% of dogs was assessed as having no pain increase ten weeks after meloxicam withdrawal. A statistically significant decrease of pain severity as scored by HCPI (P < 0.0001) was observed two and ten weeks after meloxicam withdrawal compared to study entry (17.0 ± 1.05 and 15.1 ± 1.02, respectively, vs 29.0 ± 0.74; mean ± SEM). After meloxicam withdrawal, no statistically significant change in the CBPI scores was recorded. Pain on palpation and lameness significantly changed to less severe distributions along the study period (P < 0.0001). CONCLUSION: The findings appear to suggest that dietary integration with palmitoyl-glucosamine co-micronized with curcumin was able to maintain meloxicam-induced pain relief in dogs with severe OA chronic pain.

Phase I evaluation of CycloSam® (Sm-153-DOTMP) bone seeking radiopharmaceutical in dogs with spontaneous appendicular osteosarcoma.

153 Sm-DOTMP (CycloSam® ) is a newly-patented radiopharmaceutical for bone tumor treatment. DOTMP (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene-phosphonate) is a macrocyclic chelating agent with superior binding properties to 153 Sm when compared with EDTMP (Quadramet™, used for palliative treatment of bone cancer). CycloSam® was administered at 1 mCi/kg (37 MBq/kg) in a prospective pilot study to seven dogs with bone cancer resulting in no myelosuppression. Then, 13 dogs were enrolled in a prospective clinical trial study using traditional 3+3 dose escalation and starting at 1.5 mCi/kg. Baseline evaluation included hematologic and biochemical testing, diagnosis confirmation, thoracic and limb radiographs, technetium-99 m-HDP bone scintigraphy, and 18 F-FDG PET scan (SUVmax). Toxicity (primary endpoint) was assessed through weekly blood counts and adverse events. Dogs received 1.5 mCi/kg (n = 4), 1.75 mCi/kg (n = 6), and 2 mCi/kg (n = 3) of 153 Sm-DOTMP. Dose-limiting neutropenia and thrombocytopenia were seen at 2 mCi/kg. No dose-limiting nonhematologic toxicities occurred. Efficacy (secondary endpoint) was assessed by objective lameness measurement (body-mounted inertial sensors), owner quality-of-life (QoL) questionnaire, and repeat PET scan. Objective lameness measurement improved in four dogs (53%-60% decrease) was equivocal in three dogs, and worsened in four dogs (66%-115% increase); two dogs were not evaluable. Repeat 18 F-FDG PET scan results varied and change in lameness did not consistently correlate with SUVmax changes. QoL score worsened (n = 5) or was improved/stable (n = 7). Carboplatin chemotherapy (300 mg/m2 IV every 3 weeks ×4) started 4 weeks after 153 Sm-DOTMP injection. No dog died of chemotherapy-related complications. All dogs completed study monitoring. The recommended dose for CycloSam® in dogs is 1.75 mCi/kg, which resulted in some pain control with minimal toxicity and was safely combined with chemotherapy.

Pharmacokinetics and pharmacodynamics of intra-articular isoflupredone following administration to horses with lipopolysaccharide-induced synovitis.

BACKGROUND: Intra-articular corticosteroids, such as isoflupredone acetate, are commonly used in the treatment of joint inflammation, especially in performance horses. Following administration in a non-inflamed joints blood concentrations of isoflupredone were low and detectable for only a short period of time post-administration compared to synovial fluid concentrations. For some drugs, inflammation can affect pharmacokinetics, therefore, the goal of the current study was to describe the pharmacokinetics of isoflupredone acetate following intra-articular administration using a model of acute synovitis. Secondarily, pharmacodynamic effects, including effects on joint circumference, joint flexion, and lameness following intra-articular administration of isoflupredone acetate in the experimental model were described. METHODS: Sixteen horses received a single intra-articular dose of 8 mg of isoflupredone acetate or saline 12 h post-administration of lipopolysaccharide. Blood and urine samples were collected up to 72 h and synovial fluid for 28 days post-administration, drug concentrations determined by liquid chromatography- mass spectrometry and pharmacokinetic analysis performed. Joint circumference, maximum angle of pain free joint flexion and lameness were evaluated prior to and post-treatment. RESULTS: The maximum isoflupredone plasma concentration was 2.45 ± 0.61 ng/mL at 2.5 ± 0.75 h and concentrations were less than the limit of quantitation by 72 h. Isoflupredone was below detectable concentrations in urine by 72 h post-administration in all horses and no longer detectable in synovial fluid by 96 h post-administration. Joint circumference was significantly decreased in the isoflupredone treatment group compared to the saline group at 24 and 48 h post drug administration. Pain free joint flexion was significantly different between the saline and isoflupredone treatment groups on day 4 post-treatment. CONCLUSIONS: Synovial fluid concentrations and maximum plasma concentrations of isoflupredone differed slightly between the current study and a previous one describing administration into a non-inflamed joint, however, the detection time of isoflupredone in blood was comparable. Effects of isoflupredone on joint circumference and degree of pain free joint flexion suggest a short duration of effect with respect to alleviation of lipopolysaccharide induced synovitis, however, results of this study support future studies of the anti-inflammatory effects of intra-articular isoflupredone acetate.

Comparison of 2% mepivacaine and a solution of 2% lidocaine/epinephrine administered for median and ulnar nerve blocks in horses with naturally occurring forelimb lameness.

OBJECTIVE: To compare a 2% lidocaine solution containing 5 µg/ml (1:200 000) epinephrine with 2% mepivacaine for reducing lameness in horses after use in proximal nerve blocks. STUDY DESIGN: Experimental randomized crossover. ANIMALS: Six adult horses with naturally occurring forelimb lameness. METHODS: Horses were evaluated using an inertial gait sensor system. Lameness was measured as a vector sum (VS). Following baseline lameness examination, median and ulnar nerve blocks were performed with lidocaine/epinephrine (0.5 mg epinephrine added to 50 ml of 2% lidocaine immediately prior to administration) or an equal volume of 2% mepivacaine. Horses were trotted at 5 min and then at 30 min intervals for 150 min. After 24 h, nerve blocks were repeated using the other local anesthetic. Data were evaluated using linear models. RESULTS: The reduction in the VS did not differ after nerve blocks with lidocaine/epinephrine or mepivacaine (P = .791). Mean time to VS <8.5 mm (n = 5) was 5 and 9.6 min for lidocaine/epinephrine and mepivacaine, respectively. For one horse, VS was not reduced to <8.5 mm with either treatment (this horse had the highest VS before treatments were administered). The decrease in VS to <8.5 mm lasted for 150 min in both treatment groups. CONCLUSION: The outcomes of the median and ulnar nerve blocks performed with 2% lidocaine with epinephrine did not differ from blocks performed with 2% mepivacaine. CLINICAL RELEVANCE: Two percent lidocaine with epinephrine may serve as an adequate replacement for proximal nerve blocks when mepivacaine is unavailable.

Evaluation of the 4-point regional nerve block using 2% lidocaine in sheep.

PURPOSE: To determine whether a single 4-point regional nerve block using 2% lidocaine administered distal to the fetlock of sheep with a single distal limb lameness will result in analgesia of the digits. ANIMALS: Eighteen adult ewes with a single limb lameness originating from distal to the metacarpo/metatarsophalangeal joint were enrolled in the study. PROCEDURES: Digital lameness was confirmed and scored based on clinical examination. Pain associated with digital lesions was assessed in triplicate using a pressure algometer to quantify mechanical nociceptive threshold. The same procedure was repeated on the contralateral limb as a control, and maximum force and time to response recorded. A 4-point regional nerve block was performed using 8 mL of 2% lidocaine. Mechanical nociception was again applied in triplicate to both limbs as described above, by a blinded investigator. Following appropriate medical treatment, the ewe was released and lameness scoring repeated.Median values for pressure and time to withdrawal were determined for affected and control limbs, and differences between pre- and post-lidocaine block measures were compared using Friedman's ANOVA test. The Wilcoxon Signed-Rank test was used to compare lameness score pre- and post-block. Statistical significance was set at α = 0.05. MAIN FINDINGS: Application of the 4-point block resulted in a change in pressure required to elicit withdrawal (F-value 17.7; P < 0.0001) as well as time to withdrawal (F-value 20.4; P < 0.0001), for the affected limb as compared to the control limb. Lameness scores decreased following the block (Signed-rank statistic 85.5; P < 0.0001). PRINCIPAL CONCLUSION: The 4-point nerve block resulted in anesthesia of the distal limb in sheep in this clinical model.

Évaluation du bloc nerveux régional en quatre points avec de la lidocaïne à 2 % chez le mouton. OBJECTIF: Déterminer si un seul bloc nerveux régional en quatre points utilisant de la lidocaïne à 2 % administrée distalement du boulet d'un mouton présentant une boiterie d'un seul membre distal entraînera une analgésie des doigts. ANIMAUX: Dix-huit brebis adultes avec une boiterie d'un seul membre provenant de la partie distale de l'articulation métacarpo/métatarsophalangienne ont été incluses dans l'étude. PROCÉDURES: La boiterie digitale a été confirmée et notée sur la base d'un examen clinique. La douleur associée aux lésions digitales a été évaluée en triple à l'aide d'un algomètre à pression pour quantifier le seuil nociceptif mécanique. La même procédure a été répétée sur le membre controlatéral en tant que témoin, et la force maximale et le temps de réponse ont été enregistrés. Un bloc nerveux régional en quatre points a été réalisé avec 8 ml de lidocaïne à 2 %. La nociception mécanique a de nouveau été appliquée en triple exemplaire aux deux membres comme décrit ci-dessus, par un chercheur en aveugle. Suite à un traitement médical approprié, la brebis a été relâchée et le score de boiterie répété.Les valeurs médianes de la pression et du temps de retrait ont été déterminées pour les membres affectés et les membres témoins, et les différences entre les mesures du bloc avant et après le bloc de lidocaïne ont été comparées à l'aide du test ANOVA de Friedman. Le test de Wilcoxon (signed-rank) a été utilisé pour comparer le score de boiterie avant et après le bloc. Le seuil de signification statistique a été fixé à α = 0,05. PRINCIPAUX RÉSULTATS: L'utilisation du bloc à quatre points a entraîné une modification de la pression requise pour déclencher le retrait (valeur F 17,7; P < 0,0001) ainsi que du temps de retrait (valeur F 20,4; P < 0,0001), pour les membres affectées par rapport au membres témoins. Les scores de boiterie ont diminué après le bloc (statistique de Signed-rank 85,5; P < 0,0001). CONCLUSION PRINCIPALE: Le bloc nerveux en quatre points a entraîné une anesthésie du membre distal chez le mouton dans ce modèle clinique.(Traduit par Dr Serge Messier).

Randomized controlled trial comparison of analgesic drugs for control of pain associated with induced lameness in lactating dairy cattle.

Both the economic loss and welfare implications of lameness affect the dairy industry. Currently no analgesic drugs are approved to alleviate lameness-associated pain in lactating dairy cattle in the United States. In this randomized controlled trial, 48 lactating Holsteins were enrolled to evaluate the effect of oral meloxicam and i.v. flunixin meglumine on induced lameness. Cows were allocated to 1 of 4 treatment groups (n = 12 per group): lameness and flunixin meglumine (LAME + FLU); lameness and meloxicam (LAME + MEL); lameness and placebo (LAME + PLBO); or sham induction and placebo (SHAM + PLBO). Six hours before treatment, arthritis-synovitis was induced in the distal interphalangeal joint with 20 mg of amphotericin B, whereas SHAM cows were given an intra-articular injection of an equal volume (4 mL) of isotonic saline. Cows in LAME + FLU received 2.2 mg/kg flunixin meglumine i.v. and whey protein placebo orally; LAME + MEL were administered 1 mg/kg meloxicam orally and 2 mL/45 kg sterile saline placebo i.v.; LAME + PLBO were administered 2 mL/45 kg sterile saline placebo i.v. and whey protein placebo orally; and SHAM + PLBO received 2 mL/45 kg sterile saline placebo i.v. and whey protein placebo orally. The initial treatment of MEL, FLU, or PLBO was identified as time 0 h and followed by a second dose 24 h later with data collection for 120 h. The methods used to assess analgesic efficacy were electronic pressure mat, visual lameness assessment, visual analog score, plasma cortisol concentration, plasma substance P concentration, mechanical nociception threshold, and infrared thermography imaging. Linear mixed effect modeling was the primary method of statistical analysis. Visual lameness scoring indicated a lower proportion of the FLU + LAME group was lame at the T2 h and T8 h time points in comparison to the positive controls, whereas MEL therapy resulted in a lower proportion of lame cows at the T8 h time point. Cortisol area under the effect curve was lower following FLU therapy compared with LAME + PBLO for the 0-2 h (LSM difference = 35.1 ng·h/mL, 95% CI: 6.8, 63.3 ng·h/mL), 2-8 h (LSM difference = 120.6 ng·h/mL, 95% CI: 77.2, 164.0 ng·h/mL), and 0-24 h (LSM difference = 226.0 ng·h/mL, 95% CI: 103.3, 348.8 ng·h/mL) time intervals. Following MEL therapy, cortisol area under the effect curve was lower than LAME + PLBO for both the 2 to 8 h (LSM difference = 93.6 ng·h/mL, 95% CI: 50.2, 137.0 ng·h/mL) and 0 to 24 h time intervals (LSM difference = 187.6 ng·h/mL, 95% CI: 64.9, 310.4 ng·h/mL). Analysis of data from other assessment modalities failed to discern biologically relevant differences between treatment groups. We conclude that meaningful differences were evident for visual lameness assessment and cortisol from MEL and FLU treatment versus the positive control. Further clinical research is needed toward development of a model that will create reproducible events that are more pronounced in severity and duration of lameness which can be validated as a substitute for naturally occurring lameness cases.

Morphine plasmatic concentration in a pregnant mare and its foal after long term epidural administration.

BACKGROUND: Epidural administration of morphine has been shown to be an effective analgesic strategy in horses; however, the possible occurrence of side effects limits its usage. In order to decrease their frequency, it is important to target the minimal effective plasma concentration and avoid overdosing. As to date species-specific pharmacokinetics data are not available for epidural morphine, the dosing regimen is usually established on the basis of clinical reports and personal experience. In certain physiological conditions, like gestation, the outcome of an empirical dosing scheme can be unpredictable. The aim of this case report is to describe the pharmacological profile of morphine and its metabolites after prolonged epidural administration in a pregnant mare and her foal. CASE PRESENTATION: A 20 years old pregnant mare was presented to our hospital because of severe lameness, 2 months before delivery. Following an ineffective systemic pain treatment, an epidural catheter was inserted and morphine administered (initial dose 0.1 mg/kg every 8 h). Due to its efficacy in controlling pain, it was continued until end of gestation. Plasmatic concentration of morphine and its metabolites were assessed in the mare 6 weeks after starting the treatment, and in both the mare and foal during the first days after delivery. Plasmatic values similar to those previously reported in the literature following morphine short term administration through various routes and not accompanied by side effects were found in the mare, except during an excitatory period. Moreover, no evidence of dangerous drug accumulation or significant milk passage was noticed in the foal. Mild reduction of feces production with no signs of colic and two self-limiting episodes of excitement occurred during treatment in the mare. No side effects occurred during gestation and first phases of life in the foal. CONCLUSION: Prolonged epidural administration of morphine in a pregnant mare allowed good pain control in absence of clinically relevant side effects, in both the mare and her foal. Sudden increase in morphine plasmatic concentration can occur and side effects appear; careful treatment to the lowest effective dose and continuous monitoring of the clinical condition of the treated horse should be performed.

The effects of flunixin meglumine and hoof trimming on lying behavior, locomotion, and milk production in lame and nonlame lactating dairy cows.

Hoof trimming is used to prevent and treat lameness in dairy cows; however, hoof trimming itself increases daily time spent lying down, possibly due to discomfort. We hypothesized that treatment of lame and nonlame cows with an anti-inflammatory analgesic drug at the time of hoof trimming would mitigate discomfort, thereby improving locomotion scores and reducing post-trimming increases in lying time. We further hypothesized that drug treatment would improve post-trimming milk production. Our objective was to determine the effects of treatment with the nonsteroidal anti-inflammatory drug flunixin meglumine (2.2 mg/kg of BW) at the time of hoof trimming on locomotion, lying times, and milk production in lame and nonlame lactating dairy cows. All cows were filmed for locomotion scoring 1 d before and 1, 8, and 28 d after hoof trimming. Daily time spent standing and lying was recorded for 4 d before and 4 wk after hoof trimming, and daily milk production was recorded for 1 wk before and 8 wk after trimming. Thirty minutes before hoof trimming, an intravenous injection of flunixin meglumine (n = 34) or isotonic sterile saline solution (n = 34) was administered to each cow. Then, all cows had their hooves trimmed using the Dutch method. The same treatment was repeated 24 h after hoof trimming. Cows were categorized using baseline locomotion scores as lame (score ≥3/5) or nonlame (score <3/5). Drug treatment did not affect post-trimming changes in locomotion scores, daily lying times, or milk production. In both treatment groups, most cows had the same lameness status (lame or nonlame) at baseline and after treatment, and there was no difference between groups in the number of cows that changed lameness status over time. Lame cows (n = 21) had no significant changes in lying times over the course of the study, whereas nonlame cows (n = 47) had mean daily lying times that were significantly higher than baseline all 4 wk after trimming. Hoof trimming in nonlame cows should be scheduled for a time when increased lying behavior after trimming can be accommodated.

Efficacy of orally administered gabapentin in horses with chronic thoracic limb lameness.

OBJECTIVE: To evaluate the analgesic effects of orally administered gabapentin on horses with chronic thoracic limb lameness. STUDY DESIGN: Randomized, crossover design. ANIMALS: A total of 14 adult horses with chronic thoracic limb lameness. METHODS: Following baseline measurement of lameness, horses were administered each of four treatments orally in grain: treatment G, gabapentin (20 mg kg-1) twice daily for 13 doses; treatment F, firocoxib (171 mg once, then 57 mg once daily for six doses); treatment GF, gabapentin and firocoxib at previously stated doses and frequencies; or treatment C, grain only as a control. Treatments were administered in a randomized, crossover design, separated by 2 weeks. Subjective lameness score (SLS), inertial sensor vector sum (VS) calculations, peak vertical ground reaction force (PVGRF) measurements and vertical impulse (VI) calculations were determined immediately prior to each initial treatment dose and 2-4 hours after the final treatment dose for each treatment. Mean change in SLS, VS, PVGRF and VI for each treatment were compared among treatments. RESULTS: The rank change in SLS of treatment GF was significantly greater than that of treatments C (p = 0.01) and G (p = 0.01) but not of treatment F (p = 0.08). No differences in VS (p = 0.4), PVGRF (p = 0.4) or VI (p = 0.1) were observed among treatments. CONCLUSIONS AND CLINICAL RELEVANCE: Gabapentin, as administered here, did not improve subjective or objective measures of lameness in horses with chronic thoracic limb musculoskeletal pain. Although subjective evaluation identified an improvement in lameness with treatment GF, it was not different from that observed with treatment F. Higher oral dosing and longer treatment regimens of gabapentin may be indicated for the treatment of chronic musculoskeletal pain in horses.

Comparison of lameness outcomes in horses with acute or chronic digital lameness that underwent magnetic resonance imaging.

Aims: To compare the outcome, in terms of lameness score or return to athletic function, of horses with acute vs. chronic digital lameness that underwent magnetic resonance imaging (MRI) of the distal limb and to compare the proportion of horses that received intra-articular therapy of the distal interphalangeal (DIP) joint and pattern of diagnostic analgesia in these groups. Methods: This is a retrospective study of horses (n = 95) with acute (≤12 weeks; n = 46) or chronic (>12 weeks; n = 49) digital lameness that underwent MRI of the distal limb from 2009-2016, at two equine referral centres in the USA. Criteria for inclusion in the study were that a majority of lameness localised distal to the fetlock, and that lameness assessments for ≥12 months following MRI could be obtained from the medical record or the owner could be interviewed regarding their horse's athletic function. Outcome was characterised by an improvement score where 2 = return to work at a previous or higher level or lameness improved by one grade or more, 1 = return to work at a lower level or lameness improved by less than one grade, and 0 = did not return to work or lameness grade worsened. Whether horses had received intra-articular therapy of the DIP joint and the pattern of diagnostic analgesia prior to MRI was also obtained from medical records or by interviewing the owner. Results: There was a difference (p = 0.004) in the proportion of horses assigned to improvement scores of 0, 1 and 2 between horses with acute or chronic lameness. There was no evidence of a difference in the likelihood of having received intra-articular therapy of the DIP joint prior to MRI between horses with chronic or acute lameness (p = 0.085). Similarly, there was no evidence of a difference in the pattern of diagnostic analgesia prior to MRI between the two groups (p = 0.94). Eighty-two percent of owners of horses with acute and 62% of those with horses with chronic lameness had a positive opinion of the utility of MRI as a diagnostic modality. Conclusion: In a population of horses with digital lameness undergoing MRI, a difference in the outcome, in terms of lameness score or return to athletic function was identified between horses with acute lameness compared to those with chronic lameness. Clinical relevance: Horses with digital lameness that undergo MRI when the lameness is acute may have an improved prognosis due to accurate diagnosis and earlier application of appropriate therapy.

Improvement of the clinical signs of gait abnormality after treatment with levothyroxine in a horse with shivering and hypothyroidism.

An 11-year-old Hanoverian gelding used for jumping was evaluated for gait abnormalities and hoof problems in the hindlimbs. Clinical examinations revealed signs consistent with shivers. A thyroid gland enlargement was noticed, baseline serum thyroid hormone (TH) concentrations were low, and a low response to thyrotropin-releasing hormone administration was observed. Hypothyroidism was suspected. The horse was treated with levothyroxine for 1 year. TH concentrations returned to the normal range by week 4 of treatment. Thirty weeks after the initiation of levothyroxine therapy, the gait abnormality improved. Our findings suggest that the assessment of thyroid status and especially of the subclinical thyroid gland disorders in horses affected with shivering, as well as evaluation of the effects of levothyroxine on the improvement of clinical signs could be promising in establishing the aetiopathogenesis and/or treatment of shivering in horses.

Bisphosphonate use in the horse: what is good and what is not?

BACKGROUND: Bisphosphonates (BPs) are a family of molecules characterized by two key properties: their ability to bind strongly to bone mineral and their inhibitory effects on mature osteoclasts and thus bone resorption. Chemically two groups of BPs are recognized, non-nitrogen-containing and nitrogen-containing BPs. Non-nitrogen-containing BPs incorporate into the energy pathways of the osteoclast, resulting in disrupted cellular energy metabolism leading to cytotoxic effects and osteoclast apoptosis. Nitrogen-containing BPs primarily inhibit cholesterol biosynthesis resulting in the disruption of intracellular signaling, and other cellular processes in the osteoclast. BODY: BPs also exert a wide range of physiologic activities beyond merely the inhibition of bone resorption. Indeed, the breadth of reported activities include inhibition of cancer cell metastases, proliferation and apoptosis in vitro. In addition, the inhibition of angiogenesis, matrix metalloproteinase activity, altered cytokine and growth factor expression, and reductions in pain have been reported. In humans, clinical BP use has transformed the treatment of both post-menopausal osteoporosis and metastatic breast and prostate cancer. However, BP use has also resulted in significant adverse events including acute-phase reactions, esophagitis, gastritis, and an association with very infrequent atypical femoral fractures (AFF) and osteonecrosis of the jaw (ONJ). CONCLUSION: Despite the well-characterized health benefits of BP use in humans, little is known regarding the effects of BPs in the horse. In the equine setting, only non-nitrogen-containing BPs are FDA-approved primarily for the treatment of navicular syndrome. The focus here is to discuss the current understanding of the strengths and weaknesses of BPs in equine veterinary medicine and highlight the future utility of these potentially highly beneficial drugs.

Effects of transdermal flunixin meglumine on experimentally induced lameness in adult dairy cattle.

Lameness is a common animal health condition with significant production and welfare implications. The transdermal formulation of flunixin meglumine is the only approved drug for pain control in cattle in the United States. Thirty adult dairy cows were enrolled in a study to determine the effect of transdermal flunixin on cattle with induced lameness. Cows were allocated to 1 of 3 treatment groups, with 10 cows per group: lameness and flunixin (L+F), lameness and placebo (L+P), or sham induction and placebo (S+P). An arthritis-synovitis was induced in the distal interphalangeal joint of the left hind lateral digit, using 20 mg of amphotericin B, 6 h before the application of treatment. Cows enrolled into the sham induction group had 4 mL of isotonic saline injected into the joint. Cows were dosed with transdermal flunixin at 3.33 mg/kg (1 mL/15 kg), or a placebo at 1 mL/15 kg, every 24 h for 3 d. The first treatment of flunixin or placebo was considered the start of the study, identified as time 0 h. Data were collected from all cows for 120 h following the initial treatment application. Outcome measures included plasma cortisol; substance P; visual lameness assessment; mechanical nociception threshold (MNT), presented as difference between left and right feet; infrared thermography (IRT), presented as difference between left and right feet; and gait analysis using a pressure mat. Cortisol concentrations were lower for the L+F group starting at 1.5 h after drug administration. Substance P levels showed no evidence for treatment differences among groups. Differences between the left hind MNT and right hind MNT were detected, with S+P having the lowest difference at -0.04 kilograms-force (kgf; 95% CI: -1.86 to 1.78 kgf), and L+P having the highest at -2.96 kgf (95% CI: 1.55 to 4.36 kgf). The L+F group was intermediate at -2.08 kgf (95% CI: 0.89 to 3.27 kgf). Similarly, when the difference between the maximum temperatures of the coronary band were examined via IRT, the L+P group had the highest difference at 1.64°C (95% CI: 1.02 to 2.26°C), with the L+F and S+P groups measuring 0.57°C (95% CI: 0.06 to 1.08°C) and 0.53°C (95% CI: -0.2 to 1.25°C) respectively. We found no evidence for differences among treatment groups when analyzing force, contact pressure, step impulse, or stride length. Based on differences in MNT, IRT, and cortisol, transdermal flunixin is an effective analgesic agent for induced lameness. Multiple doses of transdermal flunixin may be required to be clinically effective, based on MNT and IRT data. Further investigation of transdermal flunixin and its analgesic effects is warranted in naturally occurring lameness.

Effects of stanozolol on normal and IL-1ß-stimulated equine chondrocytes in vitro.

BACKGROUND: Intra-articular administration of stanozolol has shown promising results by improving the clinical management of lameness associated with naturally-occurring osteoarthritis (OA) in horses, and by decreasing osteophyte formation and subchondral bone reaction in sheep following surgically induced OA. However, there is limited evidence on the anti-inflammatory and modulatory properties of stanozolol on articular tissues. The objective of the current study was to evaluate the effects of stanozolol on chondrocyte viability and gene expression in normal equine chondrocytes and an inflammatory in vitro system of OA (interleukin-1ß (IL-1ß) treated chondrocytes). RESULTS: Chondrocytes from normal metacarpophalangeal joints of skeletally mature horses were exposed to four treatment groups: (1) media only (2) media+IL-1ß (3) media+IL-1ß + stanozolol (4) media+stanozolol. Following exposure, chondrocyte viability and the expression of catabolic, anabolic and structural genes were determined. General linear models with Dunnet's comparisons with Bonferroni's adjustment were performed. Cell viability was similar in all groups. Stanozolol treatment reduced gene expression of MMP-13, MMP-1, IL-6 and COX-2 in both normal and IL-1ß treated chondrocytes. Stanozolol treatment reduced ADAMTS4 gene expression in normal chondrocytes. Stanozolol reduced the expression of COL2A1. CONCLUSIONS: The current study demonstrates stanozolol has chondroprotective effects through downregulation of genes for pro-inflammatory/catabolic cytokines and enzymes associated with OA. However, there is no evidence of increased cartilage stimulation through upregulation of the anabolic and structural genes tested.

Changes in biomarkers in equine synovial fluid two weeks after intra-articular hyaluronan treatment: a randomised double-blind clinical trial.

BACKGROUND: Inflammatory and degenerative activity inside the joint can be studied in vivo via analysis of synovial fluid (SF) biomarkers, which are molecular markers of inflammatory processes and tissue turnover. The aim of this study was to investigate the response of selected biomarkers in the SF after an intra-articular (IA) high-molecular-weight non-animal stabilized hyaluronic acid (NASHA) treatment. Our hypothesis was that prostaglandin E2 (PGE2), substance P, aggrecan chondroitin sulfate 846 epitope (CS846), and carboxypeptide of type II collagen (CPII) concentrations in SF would decrease more in the NASHA than in the placebo group. Twenty-eight clinically lame horses with positive responses to diagnostic IA anaesthesia of the metacarpophalangeal or metatarsophalangeal joints were randomized into treatment (n = 15) and control (n = 13) groups. After collection of baseline SF samples followed by IA diagnostic anaesthesia, horses in the treatment group received 3 ml of a NASHA product IA. Those in the placebo group received an equivalent volume of sterile 0.9% saline solution. The horses were re-evaluated and a second SF sample was obtained after a 2-week period. RESULTS: CS846 concentration decreased in the NASHA group only (P = 0.010). Both PGE2 and CPII concentrations decreased within the groups (PGE2, P = 0.010 for the NASHA group; P = 0.027 for the placebo group; CPII, P < 0.001 for NASHA group; P = 0.009 for placebo group). No significant treatment effect for any biomarker was found between groups. NASHA induced an increase in white blood cell count; this was significant compared with baseline (P = 0.021) and the placebo group (P = 0.045). CONCLUSIONS: Although the SF concentration of the cartilage-derived biomarker CS846 decreased in the NASHA group, no statistically significant treatment effect of any of the biomarkers were observed between treatment groups. The significant increase in SF white blood cell count after IA NASHA may indicate a mild inflammatory response. However, as no clinical adverse effects were observed, we conclude that IA NASHA was well tolerated.

Tiludronate and clodronate do not affect bone structure or remodeling kinetics over a 60 day randomized trial.

BACKGROUND: Tiludronate and clodronate are FDA-approved bisphosphonate drug therapies for navicular disease in horses. Although clinical studies have determined their ability to reduce lameness associated with skeletal disorders in horses, data regarding the effect on bone structure and remodeling is lacking. Additionally, due to off-label use of these drugs in young performance horses, effects on bone in young horses need to be investigated. Therefore, the purpose of this randomized, experimental pilot study was to determine the effect of tiludronate and clodronate on normal bone cells, structure and remodeling after 60 days in clinically normal, young horses. Additionally, the effect of clodronate on bone healing 60 days after an induced defect was investigated. RESULTS: All horses tolerated surgery well, with no post-surgery lameness and all acquired biopsies being adequate for analyses. Overall, tiludronate and clodronate did not significantly alter any bone structure or remodeling parameters, as evaluated by microCT and dynamic histomorphometry. Tiludronate did not extensively impact bone formation or resorption parameters as evaluated by static histomorphometry. Similarly, clodronate did not affect bone formation or resorption after 60 days. Sixty days post-defect, healing was minimally affected by clodronate. CONCLUSIONS: Tiludronate and clodronate do not appear to significantly impact bone tissue on a structural or cellular level using standard dose and administration schedules.

Pharmacokinetics and antinociceptive effects of the soluble epoxide hydrolase inhibitor t-TUCB in horses with experimentally induced radiocarpal synovitis.

This study determined the pharmacokinetics, antinociceptive, and anti-inflammatory effects of the soluble epoxide hydrolase (sEH) inhibitor t-TUCB (trans-4-{4-[3-(4-Trifluoromethoxy-phenyl)-ureido]-cyclohexyloxy}-benzoic acid) in horses with lipopolysaccharide (LPS)-induced radiocarpal synovitis. A total of seven adult healthy mares (n = 4-6/treatment) were administered 3 µg LPS into one radiocarpal joint and t-TUCB intravenously (i.v.) at 0 (control), 0.03, 0.1, 0.3, and 1 mg/kg in a blinded, randomized, crossover design with at least 3 weeks washout between. Two investigators independently assigned pain scores (at rest, walk and trot) and lameness scores before and up to 48 hr after t-TUCB/LPS. Responses to touching the joint skin to assess tactile allodynia, plasma, and synovial fluid (SF) t-TUCB concentrations were determined before and up to 48 hr after t-TUCB/LPS. Blood and SF were collected for clinical laboratory evaluations before and up to 48 hr after t-TUCB/LPS. Areas under the curves of pain and lameness scores were calculated and compared between control and treatments. Data were analyzed using repeated measures ANOVA with Dunnett or Bonferroni post-test. p < .05 was considered significant. Data are mean ± SEM. Compared to control, pain, lameness, and tactile allodynia were significantly lower with 1 mg/kg t-TUCB, but not the other doses. For 0.1, 0.3, and 1 mg/kg t-TUCB treatments, plasma terminal half-lives were 13 ± 3, 13 ± 0.5, and 24 ± 5 hr, and clearances were 68 ± 15, 48 ± 5, and 14 ± 1 ml hr-1  kg-1 . The 1 mg/kg t-TUCB reached the SF at high concentrations. There were no important anti-inflammatory effects. In conclusion, sEH inhibition with t-TUCB may provide analgesia in horses with inflammatory joint pain.

Carnosic acid protects non-alcoholic fatty liver-induced dopaminergic neuron injury in rats.

Non-alcoholic fatty liver disease (NAFLD) has been reported to induce cognitive impairments of hippocampus and may influence central nervous system. In the present study, we investigated whether carnosic acid (CA) ameliorates dopaminergic neuron injury in a rat model of NAFLD. In order to induce NAFLD, rats were fed with high-fat diet (HFD) for 10 weeks. We found that continued CA administration reduced lipid accumulation marked by decreases in alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels, and an increase in high-density lipoprotein cholesterol (HDL-C) level in the serum. H&E staining revealed that feeding CA reduced lipid droplets accumulation, and alleviated oxidative stress by increasing in superoxide dismutase (SOD) level and decreasing in malondialdehyde (MDA) level in the liver. In addition, by measuring several parameters of gait analysis, we demonstrated that CA treatment ameliorated behavioral impairments, as evidenced by decreased duration and maximum variation, accompanied by increased average speed and cadence. Furthermore, CA treated-animals displayed an increase in the contents of dopamine (DA) and its metabolites 3,4-dihydroxyphenylacelic acid (DOPAC) and elevated the expressions of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra (SN) as well as the TH protein in the striatum. Together, these findings suggest that CA may be an effective agent in protecting rats from NAFLD-induced dopaminergic neuron injury.

Short communication: Behavioral evaluation of the analgesic effect of flunixin meglumine in lame dairy cows.

The objective of this study was to evaluate the effect of flunixin meglumine treatment on lameness pain in dairy cows. Twenty-four lactating Holstein cows were enrolled in the study based on visual observation of abnormal locomotion. The primary measurement endpoint was weight-shifting between the rear limbs. Weight-shifting was calculated as the standard deviation of the weight borne on the rear limbs over a 15 min period; this value correlates directly with lameness pain in dairy cows. After collecting baseline weight-bearing data, we randomly assigned cows to 1 of 2 treatment groups: 2.2 mg/kg body weight flunixin meglumine (2 mL/45 kg) or an equivalent volume of isotonic sterile saline solution. Weight-bearing data were collected from each cow at 2, 6, 12, and 24 h after a single intravenous drug treatment. Mean locomotion scores over the 2 d before treatment were 2.38/5 in the flunixin-treated group and 2.43/5 in the saline-treated control group; these values were not significantly different. Weight-shifting values were also not significantly different on either pretreatment day. Cows treated with flunixin meglumine showed significantly less weight-shifting between the rear limbs at 6, 12, and 24 h after treatment compared with saline-treated controls, providing evidence that flunixin meglumine alleviates lameness-associated pain.

Duration of action of mepivacaine and lidocaine in equine palmar digital perineural blocks in an experimental lameness model.

OBJECTIVE: To establish and compare the onset and duration of action of 2 local anesthetics based on objective lameness and skin sensitivity assessment. STUDY DESIGN: Interventional crossover experimental trial with balanced randomization. ANIMALS: Eight horses. METHODS: Reversible forelimb lameness was induced in 8 horses. A palmar digital nerve block (PDNB) was applied with mepivacaine or lidocaine (both 2%). Quantitative lameness and skin sensitivity data were collected with an inertial sensor system and a force gauge, respectively. The times to lameness resolution/skin desensitization (T1), consistent lameness detection/partial return of skin sensitivity (T2), and complete return of lameness/skin sensitivity (T3) were determined and compared between treatments and assessment methods. RESULTS: Mepivacaine blocks resolved lameness in 8/8 horses, compared to 3/8 horses with lidocaine blocks. Both agents led to skin desensitization in 8/8 horses. Skin desensitization occurred sooner than lameness resolution after mepivacaine (P = .047). Duration of action was longer with mepivacaine than lidocaine (mean T3_lameness mepivacaine 366 minutes, lidocaine 113 minutes (P = .038); T3_skin mepivacaine 195 minutes, lidocaine 63 minutes [P ≤ .001]). Skin sensitivity returned sooner than lameness after lidocaine block at T3 (P = .015). CONCLUSION: The use of lidocaine in PDNBs for the purpose of lameness diagnosis should be reassessed, as it may not resolve lameness despite loss of skin sensation. Mepivacaine is superior, with a reliable onset and longer duration of action. Skin desensitization as an indicator for the onset of action or effectiveness of PDNBs for mepivacaine and lidocaine, or as a measure of the duration of action of lidocaine PDNBs should be interpreted with caution.