Liposome-encapsulated oxymorphone provides prolonged relief of post-surgical visceral pain in rats

A delayed‐release formulation of liposome‐encapsulated oxymorphone was produced using a novel dehydration–rehydration technique. The purpose of this study was to (i) compare the analgesic properties of this preparation with those of repeated injections of standard oxymorphone in rats with post‐operative visceral pain and (ii) determine whether liposome‐encapsulated oxymorphone differed from standard oxymorphone in duration of the effect. Visceral pain was elicited in approximately 300 g Sprague–Dawley rats by intestinal resection performed under isoflurane anesthesia. Rats were monitored with pulse oximetry; mean anesthesia time (35 ± 10 minutes) did not differ between the groups. Rats were randomly divided into two groups: Group 1 received 1.2 mg kg^?1 liposome‐encapsulated oxymorphone SC once at skin closure and 0.2 mL of saline SC every 4 hours; Group 2 received 0.2 mL liposome‐encapsulated sucrose SC once at skin closure and 0.3 mg kg^?1 standard oxymorphone SC every 4 hours. In both groups, a behavioral ethogram for pain score (grooming, porphyrin staining, body position) was recorded every 4 hours for 48 hours after surgery. Observers were blinded to the treatment. Body weight, food consumption, and urine output were recorded daily for 7 days after anesthetic recovery. Data were analyzed using anova , with significance at p < 0.05. Based on the behavioral pain score, a single injection of liposome‐encapsulated oxymorphone was as effective for relief of post‐surgical visceral pain in rats as multiple (every 4 hours) injections of standard oxymorphone administered over a 48 hour period (p = 0.18). In rats, given one dose of liposome‐encapsulated oxymorphone, the mean body weight change from day 0 to day 7 was +9.4 g, whereas rats given multiple injections of standard oxymorphone had a mean body weight change of ?3.6 g over this time (p < 0.01). Mean daily food consumption was significantly less in rats given multiple injections of standard oxymorphone (p < 0.05). There was no difference between groups in urine production. In conclusion, a single dose of liposome‐encapsulated oxymorphone was effective in treating visceral pain in rats. Rats treated with liposome‐encapsulated oxymorphone had improved recovery, based on body weight changes and food consumption, compared with rats treated with multiple doses of standard oxymorphone. Liposome‐encapsulated oxymorphone offered advantages including provision of effective analgesia, prolonged dosing intervals, and minimal handling stress.     

An outbreak of toe ulcers,sole ulcers and white line disease in a group of dairy heifers immediately after calving

Abstract

CASE HISTORY: An outbreak of severe lameness was reported on a 780-cow spring-calving dairy herd in the Manawatu region within 1–3 weeks of calving, which affected over 90% of a group of 150 dairy heifers. Approximately 3 weeks before the planned start of calving heifers had been fed maize and grass silage on a concrete feed pad for 3–4 h per day, and mixed with a group of adult cows.

CLINICAL FINDINGS: During treatment for lameness, the feet of 28 lame heifers were closely examined. Seventy lesions were recorded in the claws of these heifers. The predominant lesion was severe solar and white line haemorrhage, with much of the haemorrhage focussed at the site at which sole ulcers are normally seen. White line disease was seen in nine claws and sole ulcers in four. Additionally, a lesion which is not commonly recorded in New Zealand, a toe abscess arising from separation of the white line from the sole in the abaxial region of tip of the toe was recorded in 11 claws. The clinical impression was that the soles of the affected heifers were very thin. This was supported by examination of the feet of eight heifers using ultrasonography that indicated heifers with hoof horn haemorrhages had very thin soles (estimated mean 4.1 mm) and that these soles were thinner than those in non-lame heifers without haemorrhages.

DIAGNOSIS: The pattern of disease seen in these heifers closely matched that seen in an outbreak of lameness in heifers in Florida, which was linked to thin soles resulting from excess hoof horn wear. The clinical signs and findings of the examination using ultrasonography strongly implicated thin soles as the underlying cause of lameness on this farm. An on-farm investigation revealed a combination of heifer behaviour and prolonged exposure to wet concrete on the feed pad were the primary causes of excess wear that resulted in thin soles.

CLINICAL RELEVANCE: This was an unusual outbreak of lameness in a group of newly calved heifers. The problem highlights the value of good management during the transition of heifers at pasture to the lactating herd standing on concrete for long periods, in the control of lameness.     

Pregnancies attained after collection and transfer of oocytes from ovaries of five euthanatized mares

After euthanasia, ovaries were removed from 5 horses and shipped to a laboratory where 46 oocytes were collected. The oocytes were cultured for 24 to 30 hours, and 36 oocytes were transferred to 10 recipient mares via flank laparotomies. Recipient mares were inseminated with semen from various stallions. Sixteen days after transfer, 4 of the recipients were pregnant with at least 1 embryonic vesicle. Embryonic death occurred in 3 recipients, whereas a healthy live foal was born from 1 recipient. Ovaries from valuable mares can be a source of viable oocytes after death of the mare. For shipping to a laboratory, fluctuations in temperature should be minimized and the ovaries should not be chilled.     

Serum concentrations across time after subcutaneous administration of liposome-encapsulated or standard oxymorphone in Rhesus macaques

Our lab has developed a slow‐release liposomal formulation of oxymorphone (LEOx). The purpose of this study was to compare serum concentrations of oxymorphone after administration of LEOx and standard oxymorphone (STDOx) to healthy female rhesus macaques. At baseline, 1 mL of blood was drawn from the femoral vein with the animal in a restraint cage. Primates were divided into two groups: (i) LEOx 1.0 mg kg^–1(n = 4); 2) STDOx 0.1 mg kg^–1(n = 4). Unloaded liposomal vehicle (0.5 mL) was used as a control (n = 2). All treatments were given subcutaneously in a shaved area proximal to the right ileal wing. Femoral venous blood was drawn and serum concentrations of drug were measured at 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, and 120 hours. Serum concentrations were measured with ELISA. Serum concentrations were compared between groups and within groups across time with anova . Drug was not detected at any time point in the control group. While sedation was not objectively measured, no animal appeared overly sedate after either treatment. All animals willingly accepted treats and did not appear nauseated or somnolent. Serum concentrations of drug were not significantly different between the two treatment groups from 0 to 2 hours. From 4 hours through 72 hours, however, serum concentrations were significantly higher (p < 0.05) in the animals that received LEOx. By 12 hours, serum concentrations of drug fell below the limit of detection (1.5 ng mL^–1) in animals that received STOx. In animals that received LEOx, serum concentrations at 72 hours were comparable to those measured at 4 hours in animals that received STOx. These results suggest that subcutaneous administration of liposomal oxymorphone yields extended serum levels of drug. These results also suggest that liposomal oxymorphone may provide therapeutic (i.e. analgesic) serum concentrations of drug for 2–3 days after a single subcutaneous administration. Further studies are warranted to assess analgesic efficacy and pharmacokinetics of lipsomal oxymorphone in primates.     

Sedative effects and serum concentrations across time after subcutaneous administration of liposome-encapsulated or standard oxymorphone in healthy dogs

Our lab has developed a slow‐release liposomal formulation of oxymorphone (LEOx). The purpose of this study was to compare sedative effects and serum concentrations of oxymorphone after administration of LEOx and standard oxymorphone (STDOx) to dogs. At baseline, 1 mL of blood was drawn from the cephalic vein and sedation score was recorded. Dogs were divided into four groups (n = 6): (i) LEOx 1.0 mg kg^–1; (ii) LEOx 0.5 mg kg^–1; (iii) STDOx 0.1 mg kg^–1; (iv) STDOx 0.05 mg kg^–1. Unloaded liposomal vehicle (0.5 mL) was used as a control (n = 2). All treatments were given subcutaneously between the scapulae. Sedation score and serum concentration of drug were recorded at 0.5, 1, 2, 4, 8, 12, 16, 24 hours and daily for 5 days. Serum concentrations were measured with ELISA. At all time points, drug was not detected and sedation score was 0 in the control group. Sedation score for group 1 was significantly higher (p < 0.05) at 1 hour than for groups 2,3, and 4. There was no difference in sedation score between treatment groups at any other time. Serum concentrations of drug were significantly higher (p < 0.05) for group 1 at all time points measured after baseline. In groups 2, 3, and 4, serum concentrations of drug fell below the limit of detection (1.5 ng mL^–1) by 24 hours. Serum concentrations after 0.1 mg kg^–1of STDOx were 11.1 ± 3.6 ng mL^–1at 4 hours, which is the recommended time for redosing and presumably reflects the lower end of a therapeutic serum concentration. Serum concentrations were comparable after 1.0 mg kg^–1 of LEOx (10.5 ± 2.4 ng mL^–1) 48 hours after administration. These results suggest that liposomal oxymorphone may provide therapeutic serum concentrations of drug for 2 days after a single subcutaneous administration without undue sedation or other deleterious effects in healthy dogs. Further studies are warranted to assess analgesic efficacy and pharmacokinetics of lipsomal oxymorphone in dogs.     

Electrocardiographic values in Spanish-bred horses of different ages

SUMMARY The duration of electrocardiograph wave forms and intervals were determined in 179 Spanish-bred (Andalusian) horses aged from 1 month to 17 years. The values were compared with those of other breeds, and the relationship between electrocardiographic data and age was examined. High correlation coefficients were found between PR, ST and QT intervals and the age of the horses, and an inverted relation between heart rate and age was found. A multiple range analysis was made and the results suggest that significant changes in duration values and heart rate ocurred at the age of 6 months and in the second year of life.     

Salmonella monitoring programs in Australian feed mills: a retrospective analysis

The availability of safe, commercially prepared stock feed for production animals is an important step in ensuring animal health and welfare and the safety of food animal products for human consumption. Animal feed quality assurance programs include microbiological monitoring of raw materials, mill equipment and finished feed. Over a period of 16 years, 23,963 samples for Salmonella culture and serotyping were collected from 22 stock feed mills. A multivariable generalized linear mixed model (GLMM) was used to identify mill and sample type factors that increase the odds of detecting Salmonella. The odds of detecting a Salmonella positive sample was greatest in samples from raw materials and in mills that processed restricted animal material (RAM). The percentage of positive samples ranged from 7.2% in 2003 to 2.8% in 2017. Of the 1,069 positive samples, 976 were serotyped with 61 different Salmonella serotypes isolated. The serotype most frequently isolated from raw materials was S. Agona, (n = 108) whilst S. Anatum was the serotype most frequently isolated from equipment and finished feed (n = 156). The diversity of Salmonella serotypes differed between mills and different stages of the production line. Microbiological monitoring in the commercial preparation of animal feed in Australian stock feed mills guides the implementation of quality control measures and risk mitigation strategies thereby reducing the prevalence and diversity of potentially zoonotic bacteria such as Salmonella, enhancing food safety for both animal and consumer.     

Transmission studies of Hendra virus (equine morbilli-virus) in fruit bats, horses and cats

Objective To determine the infectivity and transmissibility of Hendra virus (HeV). Design A disease transmission study using fruit bats, horses and cats. Procedure Eight grey-headed fruit bats (Pteropus poliocephalus) were inoculated and housed in contact with three uninfected bats and two uninfected horses. In a second exper iment, four horses were inoculated by subcutaneous injection and intranasal inoculation and housed in contact with three uninfected horses and six uninfected cats. In a third experi ment, 12 cats were inoculated and housed in contact with three uninfected horses. Two surviving horses were inoculated at the conclusion of the third experiment: the first orally and the second by nasal swabbing. All animals were necropsied and examined by gross and microscopic pathological methods, immunoperoxidase to detect viral antigen in formalin-fixed tissues, virus isolation was attempted on tissues and SNT and ELISA methods were used to detect HeV-specific antibody. Results Clinical disease was not observed in the fruit bats, although six of eight inoculated bats developed antibody against HeV, and two of six developed vascular lesions which contained viral antigen. The in-contact bats and horses did not seroconvert. Three of four horses that were inoculated devel oped acute disease, but in-contact horses and cats were not infected. In the third experiment, one of three in-contact horses contracted disease. At the time of necropsy, high titres of HeV were detected in the kidneys of six acutely infected horses, in the urine of four horses and the mouth of two, but not in the nasal cavities or tracheas. Conclusions Grey-headed fruit bats seroconvert and develop subclinical disease when inoculated with HeV. Horses can be infected by oronasal routes and can excrete HeV in urine and saliva. It is possible to transmit HeV from cats to horses. Transmission from P poliocephalus t o horses could not be proven and neither could transmission from horses to horses or horses to cats. Under the experimental conditions of the study the virus is not highly contagious.