Update on relevant equine disorders (Proceedings)

Although the foundations of medical education remain largely unchanged over time, active and continuous research provides new and potentially useful information on various avenues of clinical practice such as new medications that become available, new information on the nature of various disease processes, and new diagnostics that may help the clinician. The purpose of this lecture is to provide some, but certainly not all, of the relevant information that has been recently presented in the veterinary literature.

Pharmacology

Ceftiofur crystalline free acid (Excede) – Impact of route of administration on pharmacokinetics.

·         In order to provide slow time release of drug, this formulation of ceftiofur is in an oil suspension which can result in myositis when administered. The authors compared absorption of drug given as a single injection compared to the same dose split into 2 injections. Splitting of total drug dose into two injection sites did not result in any appreciable differences except for a slightly higher drug concentration at 240 hr when compared to single injection.

·         Conclusions: Acceptable to split the total dose of Excede into two separate injections if deemed necessary.

Ceftiofur Derivates in Endometrial Tissue

·         The best route of administration of ceftiofur (intrauterine or intramuscular) in the treatment of uterine infections is debatable. The authors administered a standard dose of ceftiofur (2.2 mg/kg, IM, once) and measured the ceftiofur concentrations in serum and endometrial tissue. Overall concentrations in uterine tissue were acceptable and exceeded the MIC for S. zooepidemicus at all times sampled and E. coli at 2, 4, and 10 hrs after IM administration.

·         Conclusions: IM ceftiofur reaches acceptable concentrations in uterine tissue for select pathogens.

Amikacin – Dosage in Adult Horses

·         Amikacin is a highly effective antimicrobial effective against many gram-negative bacteria, but the exact dosage in adult horses is debatable and at higher doses, may be cost prohibitive in adult horses. The authors administered 10 mg/kg, IV and demonstrated that this dose is efficacious against numerous microbes and distributes to synovial fluid and peritoneal fluid.

·         Conclusions: Amikacin at 10 mg/kg, IV is an acceptable dose for adult horses.

Telithromycin in Foals – Possible alternative Therapy for R. Equi

·         Some antimicrobial resistance has developed to some of the current macrolides (i.e. erythromycin) used to treat R. equi pneumonia in foals. Telithromycin is a newer macrolide that was administered at a dose of 15 mg/kg via NG tube to 6 foals. This dose provided adequate therapeutic concentrations to R. equi sensitive isolates but was predicted to be adequate for only 2/14 resistant R. equi isolates.  Increasing the dosing frequency to every 12 hours was predicted to treat 50% of macrolide resistant strains of R. equi.

·         Conclusions: Telithromycin at a dose of 15 mg/kg may be effective against sensitive R. equi isolates but more frequent dosing may be necessary for resistant strains.

Valacyclovir in Adult Horses – Oral Bioavailability

·         Acyclovir has been administered to horses with equine herpes myeloencephalopathy but the bioavailability of the drug is questionable. Valacyclovir is a prodrug that is complexed to the amino acid L-valine, which facilitates carrier-mediated transport of the drug into enterocytes, thus improving bioavailability. The authors reported that oral bioavailability was much better when compared to acyclovir and recommended a loading dose of 27 mg/kg, PO, q 8hrs for 2 days followed by a maintenance dose of 18 mg/kg, PO, q 12hrs to exceed target serum concentration of 2 µg/mL.

·         Conclusions: Valacyclovir, at the aforementioned dose, is likely to reach therapeutic concentrations and has better bioavailability then acyclovir.

Deracoxib – COX selective NSAID in Horses

·         Deracoxib (Deramaxx) is a selective COX-2 inhibitor that may potentially be a safer NSAID to administer to horses. A dose of 2 mg/kg was administered PO to horses; the authors demonstrated that the drug was absorbed after oral administration and had a long elimination half-life (mean 12.49 hrs).

·         Conclusions: Deracoxib is absorbed after oral administration and may serve as a COX selective NSAID in the future.

Detomidine Sublingual Administration

·         A sublingual form or detomidine is available and may be helpful to dispense to clients to facilitate routine non-invasive procedures, such as foot trimming and ear clipping, to uncooperative horses. Based on 2 studies, the bioavailability of sublingual detomidine at a dose of 40 µg/kg was 22% with a mean time to onset of sedation of 30 minutes and mean duration of sedation of 183 minutes. After sublingual administration, successful completion of required procedure occurred in 76% of horses.

·         Conclusions: Sublingual administration of detomidine can provide adequate sedation to perform routine, non-invasive procedures.

Esomeprazole – Effects on Gastric pH

·          Occasionally, oral administration of omeprazole is contraindicated (gastric reflux, dysphagia). Administration of the intravenous formulation (0.5 mg/kg), esomeprazole, increased gastric pH to a mean value of 6.43 in healthy adult horses.

·         Conclusions: Esomeprazole can be administered IV to horses in which the oral formulation is not possible.

Pioglitazone – Pharmacokinetics After Oral Dosing

·         Equine metabolic syndrome (EMS) is a relatively new syndrome characterized, in part, by decreased insulin sensitivity. Pioglitazone is administered to people to increase insulin sensitivity. In this study, a dose of 1 mg/kg was administered PO for 11 days. Results suggest that this dose reaches slightly lower therapeutic concentrations observed in people.

·         Conclusions: Pioglitazone was absorbed after oral administration but further study is necessary to determine efficacy in horses with EMS.

Equine metabolic syndrome (EMS)

 EMS is a recently described problem in which, at present, there are more questions than answers. Perhaps one of the best resources that reviews current information on EMS has been put forth as the ACVIM Consensus Statement. In general, horses with EMS are typically characterized by obesity, insulin resistance and laminitis. Obesity can be regional (i.e. cresty neck, fat pads over tail-head, fat accumulation of prepuce, mammary region or behind shoulder) or generalized. Insulin resistance is characterized by hyperinsulinemia or abnormal glycemic and insulinemic responses to exogenously administered glucose/insulin challenges. Finally, clinical or subclinical laminitis develops in the absence of recognized causes (i.e. colic, colitis, retained fetal membranes).

Again, the Consensus Statement proposes pathophysiologic mechanisms of EMS which can be reviewed;  however, the practicing clinician is likely more interested in diagnostic and therapeutic approaches to EMS. Outside of the clinical signs of obesity and laminitis, single blood samples measuring the glucose and insulin is an initial approach. In horses with EMS, blood glucose concentrations are often toward the higher end of reference range indicating partial loss of glycemic control. In addition, hyperinsulinemia (in the absence of factors such as stress or pain) also supports EMS.

A value of 20 µU/mL has been suggested as a general guideline for the upper limit of insulin concentration in healthy horses. Dynamic testing has also been suggested as tissue insensitivity to insulin may only be observed when glycemic control is challenged by induced hyperglycemia. Both oral and IV glucose tolerance tests have been described with full methods found in noted references. Treatment of EMS involves promoting weight loss via dietary management (i.e. reduction of caloric intake, limiting pasture grass from diet, limiting hay intake) and increasing physical activity.

Administration of metformin and levothyroxine may also be beneficial when dietary and activity changes are not sufficient. Metformin enhances the action of insulin within tissues and can be administered at a dose of 15 mg/kg, PO, BID. Levothyroxine can facilitate weight loss and can be given to horses and ponies (>350 kg) at a dose of 48 mg/day while smaller ponies can receive 24 mg/day. Horses should be weaned of levothyroxine once ideal body weight has been achieved.  

Seasonal variation in equine hormones

In light of recent interest in hormonal variations and their relationship in the development of disease, a recent investigation examined the seasonal variation in concentrations of metabolic hormones (ACTH, Cortisol, Insulin, T4) in healthy horses and horses with EMS. No difference was detected in ACTH concentrations between healthy and EMS horses; however, ACTH was higher in August, September and October and lowest in April.

Cortisol and T4 concentrations were within normal ranges throughout all months and did not differ between healthy and EMS horses. This was true for mean glucose concentration as well, although the mean glucose concentration (102.2 mg/dL) was greater than healthy horses (93.7 mg/dL). Insulin concentration was greater in EMS horses throughout several months while mean insulin concentration remained within the reference range throughout the year.

In conclusion, ACTH is most affected by season with highest concentrations noted during August-October. In addition, glucose concentration was generally higher in EMS horses that were hyperinsulinemic.  

Laminitis

The elucidation of the exact pathophysiologic mechanisms leading to the development of laminitis still moves on, but several recent publications have provided possible beneficial therapeutics for this devastating disease. The first study investigated the effects of industrial foam pads on the load distribution in the forefeet of healthy horses. The goals of treatment of laminitis are aimed at halting the biomechanical and physiologic mechanisms of the disease.

In light of this, therapies that decrease the force acting on the laminar junction may help with biomechanical forces that contribute to laminitis. Specifically, in this study, the authors demonstrated that placement of 1.5-inch thick industrial foam insulation sheeting placed on the feet of healthy horses did indeed redistribute the weight of the horse, which is normally borne by the hoof wall, to include the entire palmar surface of the foot for 48 hours.

In turn, the redistribution of body weight to a larger surface area could presumably decrease the amount of weight supported by the laminar structures alone and serve as a means of therapy for acute laminitis. The second set of studies was aimed at decreasing some of the proposed physiologic mechanisms that contribute to the development of laminitis through application of cryotherapy to the feet of horses with induced laminitis. The basis for cryotherapy as a treatment for acute laminitis is that it will induce vasoconstriction to the feet and thus reduce delivery of cytokines, endotoxin and other laminitis triggers to the laminar structures.

In addition, cryotherapy may have a hypometabolic effect to the structures of the equine foot and therefore decrease matrix metalloproteinase activity as well as the metabolic rate to the feet. The authors of these studies were able to demonstrate that the lameness score, histologic damage and MMP-2 expression was significantly decreased in horses in which cryotherapy was applied in a carbohydrate model of laminitis.     

Dexamethasone in fetal development

Premature delivery of the equine fetus can result in significant economic loss due to increased mortality rates and lower discharge rates when compared to foals afflicted with other diseases. Prematurely born foals may have skeletal immaturity as well as organ failure because of maturation failure associated with incomplete development of the hypothalamo-pituitary-adrenal (HPA) axis. In health, a cortisol surge that facilitates cellular differentiation and maturation of numerous organ systems is observed 2-4 days prior to parturition.

In other species, administration of glucocorticoids before birth does indeed accelerate fetal maturation but results in equine fetuses have been inconsistent. In this study, 10 TB mares received either 100 mg dexamethasone IM (5 mares) or 50 mLs of saline IM (5 mares) on Days 315, 316, and 317 of gestation. Gestational length was significantly shorter in dexamethasone treated mares (322 days) compared to control mares (335 days) as was the time interval from last injection to foaling (treated 5.2 days vs control 22.8 days). Treated mares had poor mammary development at foaling when compared to control mares.

There was no statistical difference in body weight at birth between treated (49.4 kg) and control (53.7 kg) foals; however, crown-rump length was decreased in treated foals (94 cm) compared to control foals (100.6 cm). In summary, high doses of dexamethasone shortened gestational length by nearly 2 weeks when compared to control mares. Mammary development and lower colostral quality was observed in treated mares. Of note, a similar regime performed later in gestation (331-347 days) in pony mares caused dystocia and fetal death in one study.     

Equine multinodular pulmonary fibrosis (EMPF)

This recently described disease is characterized by diffuse, multifocal areas of fibrosis within the lung of adult horses and has a possible association with equine herpes virus type 5 (EHV-5) infection. Clinical signs of EMPF that clinicians should look for include tachypnea, increased respiratory rate and effort, cough, abnormal lung sounds on auscultation, weight loss, inappetance and fever. Clinicopathologic abnormalities that support EMPF include anemia, neutrophilic leukocytosis, lymphopenia, hyperfibrinogenemia and hypoxemia.

Radiographic and ultrasonographic examination helps establish the diagnosis with a nodular interstitial lung pattern of varied degree observed.  Transtracheal wash fluid or lung samples have been positive for EHV-5 via PCR in numerous cases suggesting that this viral agent may potentially play a part in the development of disease. Unfortunately, overall prognosis is poor to guarded, although reports of recovery after treatment with steroids ± antivirals have been published.

Lawsonia intracellularis

Proliferative enteropathy is a well described intestinal disease in weanling-age foals that results in hypoproteinemia, peripheral edema, diarrhea and weight loss secondary to inhibited absorptive capacity of the intestine due to marked thickening. However, investigation into the mode of transmission has only been recently described. In a recent study, 3 foals were inoculated with L. intracellularis via intragastric administration; each individual foal was housed with a non-challenged, sentinel foal.

Transient clinical signs of anorexia, lethargy, fever, loose feces, peripheral edema and hypoalbuminemia were observed in 2/3 challenged foals. Fecal shedding of the organism was detected 12-18 post-inoculation and lasted for 1-3 weeks. One sentinel foal demonstrated seroconversion supporting the role of feco-oral transmission. Thus, L. intracellularis is believed to be transmitted via oral exposure, has an incubation period of 2-3 weeks with fecal shedding observed approximately 2 weeks after inoculation.  

Equine protozoal myeloencephalitis – update on diagnostics

Antemortem diagnosis of EPM still remains confusing and is an inexact science but a few recent assays and studies have perhaps provided information that may facilitate more accurate diagnosis. One study examined the use of antibody coefficients (C-value and antibody index) as a means of detecting CNS infection.In theory, proteins, including antibodies, are partitioned between the CSF and plasma at a constant ratio.

With a CNS infection (i.e. EPM) CSF-specific antibodies will be greater than serum-specific antibodies whereas non-CNS infections, the CSF-specific antibodies increase in proportion to serum-specific antibodies. The C-value and Antibody Index are calculated from measured anti-SAG2 antibodies, total protein, albumin and IgG within the serum and CSF. In this specific study, horses with a C-value > 1 were positive in 12/14 EPM horses and negative in 15/15 horses with cervical vertebral myelopathy. 

Thus the C-value may be beneficial in discriminating between seropositive horses with vertebral malformation and horses with EPM. A recent report also noted that serum titers for S. neurona surface antigens (SAG2, SAG3, SAG4) alone were not predictive of EPM diagnosis but rather, CSF titers were correlated strongly with an EPM diagnosis. A serum-to-CSF titer ratio of greater < 100 was observed in 24/29 EPM cases while 93/102 horses with neurologic disease other than EPM had a titer ratio of > 100. Complete details are still pending.     

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