The formation of aminorex in racehorses following levamisole administration. A quantitative and chiral analysis following synthetic aminorex or levamisole administration vs. aminorex-positive samples from the field: a preliminary report

Beginning in 2004, the horseracing industry experienced an epidemic of drug positives for the amphetamine-like drug aminorex. Investigation of the therapeutic treatment of the horses called positive for this drug suggested that its source was from the administration of the anthelmintic levamisole. This study examines the urine concentrations of aminorex as a function of time following administration of synthetic, racemic aminorex. Confirmation of the presence of aminorex in urine samples from the horses known to be treated with levamisole is also presented as are data concerning the concentrations of aminorex in positives called from the field and the corresponding concentrations of levamisole found in the same samples. Furthermore, this study illustrates that the chiral isomer distribution of aminorex found in samples from the field is significantly different from that arising from the administration of synthetic, racemic aminorex and is similar to that observed from aminorex arising from levamisole administration. An examination of the chiral isomer distribution of aminorex and a determination of the presence of levamisole in a sample may be used to assess the source of an aminorex positive, distinguishing it from an intentional synthetic, racemic aminorex administration. The role of levamisole in aminorex formation is also discussed.     

A Retrospective Study of Pemoline Toxicosis in Dogs: 101 Cases (1987–1997)

Pemoline is a central nervous system stimulant commonly used for Attension Deficit Disorder in humans. This study describes the clinical syndrome associated with pemoline ingestion as well as its treatment. Ten years worth (1987–1997) of records from the ASPCa National Animal Poison Control Center involving pemoline ingestion in dogs were reviewed. The data suggests that most dogs ingesting pemoline show signs of central nervous system and cardiovascular stimulation including hyperactivity, tremors, ataxia, seizure, tachycardia, hyperthermia, and mydriasis. Blood chemistry alterations included electrolyte imbalances in some dogs. The minimum dose reported to cause clinical signs was 2.8 mg/kg and the minimum dose reported to have caused death was 10 mg/kg. Dogs generally showed clinical signs within 30 minutes to 24 hours of ingestion. The duration of clinical signs ranged from 15 hours to four days. Ninety-four percent of the dogs recovered with supportive treatment. (Vet. Emerg. & Crit. Care, 9:203–207, 1999)     

湖南地区‘巴劳奈’无花果引种表现及栽培技术

‘巴劳奈’无花果自2016年引入我国进行试栽,试栽表现为果形大,可溶性固形物最高可达25%,产量高且稳定,单株产量可达15~30 kg,是优良的鲜食加工兼用品种。湖南地区目前无花果主栽品种是‘波姬红’和‘布兰瑞克’,现为了扩大湖南地区无花果产业,以湖南省宁乡7月成熟度在60%-80%的‘巴劳奈’夏果为样本,进行引种表现分析,结果表明湖南地区的‘巴劳奈’无花果果形中等,但该品种可溶性固形物在18%以上,含有较高的维生素C和蛋白质,且在湖南地区‘芭劳奈’鲜食果及其加工品价格较‘波姬红’、‘布兰瑞克’等品种高,故可根据本文以湖南省宁乡为基准总结的栽培技术在与该地气候土壤相近的其它中部地区推广栽培。     

Pharmacokinetics and effects of aminorex in horses

OBJECTIVE: To investigate the pharmacokinetics and behavioral effects of aminorex administered IV and PO in horses. ANIMALS: 7 Thoroughbreds. PROCEDURES: In a cross-over design, aminorex (0.03 mg/kg) was administered IV or PO. Plasma and urinary aminorex concentrations were determined via liquid chromatography- mass spectrometry. RESULTS: Decrease of aminorex from plasma following IV administration was described by a 3-compartment pharmacokinetic model. Median (range) values of alpha, beta, and gamma half-lives were 0.04 (0.01 to 0.28), 2.30 (1.23 to 3.09), and 18.82 (8.13 to 46.64) hours, respectively. Total body and renal clearance, the area under the plasma time curve, and initial volume of distribution were 37.26 (28.61 to 56.24) mL x min/kg, 1.25 (0.85 to 2.05) mL x min/kg, 13.39 (8.82 to 17.37) ng x h/mL, and 1.44 (0.10 to 3.64) L/kg, respectively. Oral administration was described by a 2-compartment model with first-order absorption, elimination from the central compartment, and distribution into peripheral compartments. The absorption half-life was 0.29 (0.12 to 1.07) hours, whereas the beta and gamma elimination phases were 1.93 (1.01 to 3.17) and 23.57 (15.16 to 47.45) hours, respectively. The area under the curve for PO administration was 10.38 (4.85 to 13.40) ng.h/mL and the fractional absorption was 81.8% (33.8% to 86.9%). CONCLUSIONS AND CLINICAL RELEVANCE: Aminorex administered IV had a large volume of distribution, initial rapid decrease, and an extended terminal elimination. Following PO administration, there was rapid absorption, rapid initial decrease, and an extended terminal elimination. At a dose of 0.03 mg/kg, the only effects detected were transient and central in origin and were observed only following IV administration.     

Equine herpes myeloencephalopathy

The neurologic form of EHV-1 infection appears to be the result of central nervous system infarction caused by vasculitis, which is initiated in endothelial cells of small blood vessels. The etiologic agent is equine herpesvirus-1, subtype 1. There is some evidence to suggest that the neurologic form of the disease actually results from reactivation of a previous infection. Whether the vasculitis that causes the central nervous system injury is the direct result of the infection or an immune response to the infection has not been determined. The clinical signs are rapid in onset, nonprogressive, and many horses may improve. The diagnosis must often remain tentative, particularly in horses that recover, because there is no single reliable confirmatory test. The prognosis is generally good, although recovery may be slow and incomplete. Supportive therapy is essential, and administration of corticosteroids may be useful. There is no specific therapy for the virus or for the vasculitis. Currently no vaccine can be claimed to protect against the central nervous system form of the disease. Vaccination is recommended, however, to reduce the incidence of respiratory disease, abortion, and neonatal death on the farm. Repeated vaccination is necessary to maintain presumably protective antibody concentrations. Vaccination every 3 to 4 months may decrease the incidence of EHV-1 infection on the farm and therefore may indirectly prevent the occurrence of the neurologic form of the disease.     

Investigation of Single and Paired Measurements of Adrenocorticotropic Hormone for the Diagnosis of Pituitary Pars Intermedia Dysfunction in Horses

Background

Paired measurement of ACTH concentration may be more reliable than a single measurement.

Hypothesis/Objectives

To determine whether the mean of 2 measurements of ACTH concentration is more reliable in assessing pituitary pars intermedia dysfunction (PPID) than a single measurement.

Animals

Paired ACTH measurements were performed on (1) 148 occasions from 124 horses being investigated for PPID, (2) 90 occasions from 76 horses with PPID that were receiving treatment with pergolide, and (3) 63 occasions from 50 horses in which there was no clinical suspicion of PPID. Histologic examination of the pars intermedia was performed in 67 of the untreated horses.

Methods

Outcome of testing using single and the mean of paired samples was compared directly and both methods were compared against histology, which was considered the gold standard.

Results

Paired ACTH measurement altered binary classification as healthy or diseased in 6 of 211 cases, all off which had equivocal initial ACTH concentrations between 20 and 39 pg/mL. Using histology as the gold standard, optimal sensitivity and specificity for diagnosing PPID were 69.4 and 80.9%, respectively, for a single measurement and 72.2 and 76.2%, respectively, for paired measurements. The area under the receiver operating characteristic curve was 0.72 and 0.73 for single and paired measurements compared with histopathologic diagnosis, respectively.

Conclusions and Clinical Importance

Paired measurement of ACTH concentration offers no advantage over a single measurement.     

Equine parvovirus hepatitis

Equine parvovirus hepatitis (EqPV-H) was first described in 2018 in a fatal case of Theiler's disease which followed the administration of an equine-origin biological product. The virus has since been frequently identified in serum and liver tissue of horses affected by Theiler's disease—an acute, severe hepatitis characterised by fulminant hepatic necrosis with a fatal outcome in most cases. EqPV-H is hepatotropic, appears to be associated with subclinical to severe hepatitis in horses, and is a likely cause of Theiler's disease. Although this disease is most frequently reported following the administration of equine-origin biological products, it can also occur among in-contact horses. Horizontal transmission may be iatrogenic, via contaminated equine-origin biological products such as equine serum, botulism or tetanus antitoxin, and mesenchymal stem cells or by means of the oral route of infection. Other horizontal transmission routes, for example, arthropod vectors, warrant further investigation. A worldwide prevalence of EqPV-H antibodies and DNA has been reported in asymptomatic horses. EqPV-H-positive horses suffering from acute, severe hepatitis have reportedly developed clinical signs including icterus, lethargy, inappetence, and neurological abnormalities and have had increased liver-associated biochemistry parameters recorded. The most common histopathological abnormalities of the liver have been hepatocellular necrosis, collapse of the lobular architecture, and lymphocytic infiltration. Most horses infected experimentally with EqPV-H have developed subclinical hepatitis, and close temporal associations between peak viraemia, seroconversion, and the onset of hepatitis have been observed. Based on strong evidence indicating that EqPV-H causes hepatitis in horses, veterinarians should consider this virus an important differential diagnosis in such cases. Potential risks associated with the administration of equine-origin biological products must be emphasised.     

Suspected venous air embolism in three horses

Venous air embolism was suspected in 3 hospitalised horses on the basis of an inadvertently open jugular venous line. Subsequently the 3 horses developed clinical signs including cardiovascular collapse, cardiac dysrhythmia, pulmonary oedema, behavioural abnormalities and neurological signs consistent with central nervous system injury. Treatment included intranasal oxygen therapy, i.v. fluid administration and anti‐inflammatory therapy. Specific therapy aimed at treating air embolism in man is reviewed, with pertinent therapy potentially applicable to horses emphasised.     

Longitudinal study of Australian stringhalt cases in France

Seventy horses with clinical evidence of Australian stringhalt were studied in France from 2003 to 2008. All horses but one had history of bilateral stringhalt and grazed pastures infested with Hypochoeris radicata (L.). They displayed hind limbs hyperflexion and an abnormal gait because of a distal axonopathy with a skeletal muscle denervation and atrophy. Fifty percentage of them recovered spontaneously in 8 months, and only the more affected horses were unable to recover even if they looked healthy on dry and hot days. Clinical troubles revealed also depression or aggressive behaviour, suggesting that central nervous system might be affected. Treatment with phenytoin resulted in a rapid noticeable improvement of stringhalt in some horses but the administration of taurine seems to improve behavioural disorders. Deeply affected horses (grade III and more of Huntington’s classification at the beginning) must be treated with phenytoin when the weather is muddy and damp because they still display stringhalt when they are afraid or at the beginning of the work.     

Heart Rate Variability in Horses Engaged in Equine-Assisted Activities

Although there has been a recent surge in using horses to treat mental and emotional human health issues, the consequences of horse-assisted interventions on the stress response of horses have not been well documented. Assessment of the autonomic nervous system and its regulation of cardiovascular function has been used as an indicator of acute and chronic stress in human beings and horses. Heart rate variability (HRV) is a noninvasive measurement that has been used to assess autonomic nervous system regulation of cardiovascular function. There is evidence to suggest that several factors including the genotype, behavior, environment, temperament, and nutritional status of the horse play a key role in the large inter-individual variations in basal HRV. The present study determined whether 24-hour HRV recordings in horses currently working in equine-assisted therapy (EAT) differ from those previously shown in Thoroughbred horses. Findings from the present study found that in contrast to previous studies in Thoroughbred horses, diurnal and nocturnal low frequency and high frequency powers were not significantly different in horses that are currently engaged in EAT. Future studies are needed to determine the short- and long-term consequences of horses participating in EAT programs. Findings from this study will provide the basis for the development of a physiological/behavioral assessment criteria to determine the consequences of EAT on the well-being of horses as well as to help EAT Centers to improve the beneficial effects of EAT in human beings.     

Exertional heat illness: a review of the syndrome affecting racing Thoroughbreds in hot and humid climates

Metabolic heat produced by Thoroughbred racehorses during racing can rapidly elevate core body temperature (1°C/min). When environmental conditions are hot and humid, the normal physiological cooling mechanisms become ineffective. The heat accumulated may exceed a critical thermal maximum (estimated to be 42°C), which may trigger a complex pathophysiological cascade with potentially lethal consequences. This syndrome has been labelled exertional heat illness (EHI). EHI is described in humans, but has not been well documented in Thoroughbred racehorses. The clinical signs described in racehorses would suggest that the pathophysiological events affecting the central nervous (CNS) and gastrointestinal systems are similar to those described in humans. Clinical signs are progressive and include signs of endotoxaemia and increasing levels of CNS dysfunction. Initially, horses that may be mildly irritable (agitated, randomly kicking out) may progress to unmanageable (disorientation, severe ataxia, falling) and ultimately convulsions, coma and death. Currently, the approach to treatment is largely empirical and involves rapid and effective cooling, administration of drugs to provide sedation, administration of non‐steroidal anti‐inflammatory drugs to ameliorate the effects of endotoxaemia and glucocorticoids to stabilise cell membranes and reduce the effects of inflammation on the CNS. This review provides an overview of the current knowledge about EHI in Thoroughbred racehorses, suggests a likely pathophysiology of the syndrome in horses based on the current literature on heat illness in humans and horses, and outlines current treatment strategies being used to treat racehorses with clinical signs of EHI.     

Equine herpesvirus 1 infection of horses: studies on the experimentally induced neurologic disease.

Experimental infection with equine herpesvirus 1 (rhinopneumonitis) resulted in neurologic disease in 8 of 15 inoculated horses. Nonpregnant animals did not develop clinical disease, and microscopic examination of tissues revealed no changes. In all mares between 3 and 9 months of gestation, a neurologic syndrome appeared 6 to 8 days after inoculation. Mares inoculated when 10 months pregnant did not develop neurologic disorders, but several aborted. The histopathologic change common to both sequelae was vasculitis, involving smaller arteries and veins. Although blood vessel changes were detected in endometrium of all pregnant mares, vascular changes were present in the central nervous system only in mares having neurologic disease. Concomitant degeneration of nervous tissue occurred within the central nervous system and, in many sites, anatomic and temporal relationships of vasculitis and nervous tissue degeneration suggested a cause-effect relationship. This theory was strengthened by the lack of usual histopathologic indications of encephalomyelitis. In cerebrospinal fluid from affected mares, there was an increase in protein but not pleocytosis.     

Effects of intravenously administrated omeprazole on gastric juice pH and gastric ulcer scores in adult horses

The study was performed to evaluate the efficacy of omeprazole powder in sterile water, administered intravenously, on gastric juice pH in adult horses with naturally occurring gastric ulcers. Omeprazole (0.5 mg/kg, IV) was administered once daily for 5 days to 6 adult horses with gastric ulcers. Gastric juice was aspirated through the biopsy channel of an endoscope and pH was measured before and 1 hour after administration of omeprazole on day 1, and then before and after administration of omeprazole on day 5. Gastric ulcer scores were recorded on day 1 before administration of omeprazole and on day 5, 23 hours after the 4th daily dose. Gastric juice pH and ulcer scores were compared between the times. When compared with the pre-injection value (2.01 +/- 0.42), mean +/- SD gastric juice pH was significantly higher when measured 1 hour after administration of the initial dose (4.35 +/- 2.31), and before (5.27 +/- 1.74) and 1 hour after (7.00 +/- 0.25) administration of omeprazole on day 5. Nonglandular gastric ulcer number score significantly decreased from a mean +/- SD of 3.2 +/- 0.80 to 2.0 +/- 1.1, but nonglandular gastric ulcer severity score remained the same. Few glandular ulcers were seen in the study, and scores did not change. Because of its potent and long duration of action on gastric juice pH, this intravenous formulation of omeprazole may show promise for treatment of equine gastric ulcer syndrome (EGUS) in horses with dysphagia, gastric reflux, or other conditions that restrict oral intake of omeprazole paste. Aspiration of gastric juice and measurement of pH can be of use to determine whether the desired pH > 4.0 has been reached after omeprazole treatment.     

Equine stereotypic behaviors: Causation,occurrence, and prevention

There are strong suggestions that equine stereotypies are connected to poor welfare and a suboptimal management and/or stabling environment. Different forms of equine stereotypic behaviors have been described. Crib biting, weaving, and box walking are considered the most prevalent. Several studies have been conducted to establish links between the underlying causes and potential function of such behaviors. Both experimental and epidemiological studies have indicated management factors specifically feeding practices, housing conditions, and weaning method as crucial in the development of stereotypies in stabled horses. Some neurological studies on equine stereotypy demonstrated some forms of central nervous system dysfunction as being associated with the performance of stereotypic behaviors. Different researchers hypothesized that the functional significance of stereotypies is that they reduce stress in captive environments and should thus be considered as a coping mechanism. In contrast, the owner's perspective is often that a stereotypic horse has a “stable vice” that needs to be stopped, and different kinds of methods have been developed to control or regulate stereotypic behaviors. However, if the stress-reducing hypothesis is correct, controlling stereotypic behaviors particularly by physical and surgical approaches without addressing the underlying causes is of great concern to the horse's welfare. Although there is ongoing uncertainty about the exact function, the growing knowledge about causation should be applied: under all circumstances prevention is better than cure.     

Hypercapnic respiratory acidosis: A protective or harmful strategy for critically ill newborn foals?

This paper reviews both the beneficial and adverse effects of permissive hypercapnic respiratory acidosis in critically ill newborn foals. It has been shown that partial carbon dioxide pressure (PCO₂) above the traditional safe range (hypercapnia), has beneficial effects on the physiology of the respiratory, cardiovascular, and nervous system in neonates. In human neonatal critical care medicine permissive hypercapnic acidosis is generally well-tolerated by patients and is more beneficial to their wellbeing than normal carbon dioxide (CO₂) pressure or normocapnia. Even though adverse effects of hypercapnia have been reported, especially in patients with central nervous system pathology and/or chronic infection, critical care clinicians often artificially increase PCO₂ to take advantage of its positive effects on compromised neonate tissues. This is referred to as therapeutic hypercapnia. Hypercapnic respiratory acidosis is common in critically ill newborn foals and has traditionally been considered as not beneficial. A search of online scientific databases was conducted to survey the literature on the effects of hypercapnia in neonates, with emphasis on newborn foals. The dynamic status of safety levels of PCO₂ and data on the effectiveness of different carbon dioxide levels are not available for newborn foals and should be scientifically determined. Presently, permissive hypercapnia should be implemented or tolerated cautiously in compromised newborn foals and its use should be based on relevant data from adult horses and other species.     

Differential expression of TAR DNA-binding protein (TDP-43) in the central nervous system of horses afflicted with equine motor neuron disease (EMND): a preliminary study of a potential pathologic marker

Equine motor neuron disease (EMND) is a neurodegenerative disorder of unknown etiology affecting horses worldwide. Trans-Active Response DNA Binding Protein of 43?kDa (TDP-43) has been reported in the central nervous system (CNS) of several neurodegenerative conditions in humans including Amyotrophic Lateral Sclerosis (ALS) and assumed to play role in the disease. We examined whether horses afflicted with EMND express the TDP-43 in CNS. Ten horses with EMND and 6 controls of different ages and breed we enrolled. Detection of presence of TDP-43 protein in the CNS was analyzed by immunohistochemical staining using rabbit anti-human TARDBP (TDP-43) polyclonal antibody. Formalin fixed neuronal tissues from medulla, cervical, and lumbar spinal cord were harvested from EMND and from control horses. Sections were assigned randomly to TDP-43 treated or rabbit anti-IgG as control. Nuclear staining of TDP-43 was detected in one of the neural tissues of 75?% of EMND-positive and 0 of 0?% of control horses in the central nervous system (medulla, and/or cervical spinal cord and/or lumbar spinal cord). TDP-43 antibody was detected in the nucleus of EMND horses and no cytoplasmic staining was noted. As in ALS, there was no pattern of age clustering associated with the detection of TDP-43. This is the first report on the staining of TDP-43 in neuronal tissues of horses and suggests that TDP-43 may play a role in the pathogenesis of EMND. Further studies are needed to elucidate the etiologic role of this protein in the diseases.     

Lack of local anaesthetic efficacy of fentanyl in the abaxial sesamoid block model

Fentanyl and other opioid drugs have their effect in the central nervous system; however, activity at peripheral sites has also been demonstrated. Pain-suppression activity at peripheral sites raises the possibility of skilled individuals producing local anaesthetic effects with small doses of opioid drugs that would be difficult to detect forensically and could be used to affect the outcome of a race. Therefore, the local pain-suppression effect (peripheral nerve inhibition) of fentanyl was tested using an abaxial sesamoid block/hoof withdrawal model. With this model, fentanyl did not produce significant anaesthesia when tested in eight Thoroughbred horses. This suggests that fentanyl at this or lower doses is unlikely to reduce pain perception when applied directly to sensory neurons. However, the effect of fentanyl and other opioids on joint pain perception of horses, especially inflamed joints, is unknown.     

Efficacy of levamisole alone and in combination with mebendazole against Gongylonema pulchrum infection in rabbits

Gongylonema pulchrum is an important parasite of captive primates. Twelve rabbits were infected with 30 third-stage larvae of G. pulchrum. At 4–7 months post-infection, animals were administered levamisole at a single dose of 12 mg/kg, levamisole at 8 mg/kg three times at 2-day intervals, levamisole at a single dose of 8 mg/kg after administration of mebendazole at 70 mg/kg for 3 days or 8 ml of distilled water for 3 days (control). Necropsy at 14 days after treatment revealed that single and multiple dosages of levamisole reduced nematode burdens by 68.4% and 89.5%, respectively. The combined regimen of mebendazole and levamisole exhibited high efficacy for treating G. pulchrum located widely within the upper digestive tract, with a reduction of 98.2%. These results suggest that this combined chemotherapy treatment may be effective against G. pulchrum infection, including buccal and lingual gongylonemiasis in primates.     

Pathological changes caused by Anoplocephala perfoliata in the equine ileocecal junction

Gastrointestinal motility disorders represent a significant cause of morbidity and mortality in horses. Previously regarded as a non-pathogenic tapeworm, Anoplocephala perfoliata has been recently associated with equine colic. In this study, pathological changes related to A. perfoliata at the ileocecal junction were investigated in 31 slaughtered horses. Our results showed a significant relationship between parasitic burden and grading of histopathological lesions in both the mucosa and submucosa. Moreover, in infested horses, hypertrophy of the circular muscle layer was determined. Finally, an enteric nervous system (ENS) evaluation showed injury to intestinal nervous elements in horses with moderate to high parasitism. In summary, our results on the ENS support a correlation between colic and A. perfoliata infestion in the horse.     

Population Pharmacokinetics of Tobramycin in Horses

Population pharmacokinetics of tobramycin was investigated in 28 healthy horses, with an aim to assess interindividual variability in the disposition of the antibiotic. Additionally, a covariate model for improved prediction of the concentrations in a particular animal was developed. A two-compartmental model best described the data. The final population covariate regression model was based on relationships between body weight and central and peripheral volumes of distribution, and between creatinine clearance and systemic tobramycin clearance. The value of population systemic tobramycin clearance and its interindividual variation (CV) were 0.087 L.hr⁻¹.kg⁻¹ and 6.0%, respectively. The respective values for central and peripheral volumes of distribution were 0.652 L.kg⁻¹ with CV of 17.7% and 1.56 L.kg⁻¹ with CV of 4.5%. In horses with decreased glomerular filtration rate, lower tobramycin clearance is predicted with the population model that requires administration of lower dose than that accepted for treatment of horses with normal kidney function. Population pharmacokinetic analysis allows study of basic disposition of tobramycin in horses with sparse data. The prediction power of the regression model was improved by inclusion of covariables such as body weight and creatinine clearance. This model can be used in direct patient care for the construction of dosing strategy in individual clinical cases.