Skeletal health: primate model of postmenopausal osteoporosis.

Currently, the nonhuman primate is the most widely used large animal model to evaluate the safety and efficacy of new drug entities to treat or prevent estrogen-deficiency-induced bone loss and osteoporosis. Surgical ovariectomy (OVX) induces a state of high bone turnover and rapid bone loss establishing a new steady-state bone mass within 8-9 months. Many systems in the monkey are similar to humans, including skeletal and reproductive physiology and the immune system, making this a plausible model suitable to evaluate the effects of new bone drugs. The long-term sequelae following OVX and withdrawal of monthly exposure to cyclic reproductive hormones in older female monkeys (cynomolgus and rhesus) mimics estrogen depletion and postmenopausal bone loss occurring in women. Characterization of the primate model revealed an apparent limitation to the extent of bone loss. Animals lose bone mass after OVX, but the extent of the bone loss cannot be described as osteoporotic. The small differences between OVX and sham-operated controls in many important bone measurements is overcome by including 15-20 animals per group to provide adequate statistical power. The long-term, at least 16 month, bone safety studies performed to satisfy regulatory guidelines provide an opportunity to study treatment effects for an extended period not covered in shorter-term safety studies. In vivo end-points such as densitometry and biochemical markers translate easily to clinical use, while biomechanical end-points that cannot be measured clinically can be used to predict fracture prevention. To date, the monkey OVX model has been used to support submissions for many new drugs including anabolics, bisphosphonates and selective estrogen receptor modulators. Despite its limitations, the OVX monkey model remains the best characterized of the large animal models of osteopenia and has become integral to osteoporosis drug development.

The influence of the route of administration of 17beta-estradiol, intravenous (pulsed) versus oral, upon DMBA-induced mammary tumour development in ovariectomised rats.

A wide variety of routes of administration and formulations are employed in estrogen replacement therapy. These exhibit differences in the pharmacokinetics and metabolism of estradiol and in the resulting biological effects. This study set out to investigate the effects of pulsed estrogen administration (via the nasal route) compared to oral therapy, as a reference, with regard to breast cancer risk. This was assessed in an experimental model whereby mammary tumours were induced by 7,12-dimetbylbenz(a)anthracene in ovariectomised rats. To mimic a pulsed treatment given via the nasal route doses of estrogen were administered by I.V. route (0.4, 10 and 250 microg/kg). These dosages were predicted to have similar estrogenic activity to doses administered by the oral route (100, 300 and 900 microg/kg). Controls were groups of ovariectomised and SHAM-operated rats and ovarectomised rats administered with either vehicle alone. Two studies were carried out on separate populations of rats and ran in parallel. Tumour appearance (study 1) and tumour growth (study 2) were evaluated. In study I (n = 20/group), treatments with estradiol were conducted for 20 weeks after carcinogen administration; in study 2 (n = 10/group), an 8-week treatment with estradiol was initiated once 7,12-dimethylbenz(a)anthracene-induced tumours appeared. Intravenous dose levels achieved equivalent estrogenicity to corresponding oral dose levels, as assessed by measuring uterus weight. Estrogen deficit was made up by both routes but only the higher doses restored physiological uterus weight. Nevertheless administration via the I.V. route resulted in a lower rate of tumour incidence (p < or = 0.05) than the rate recorded for the oral route. In addition, tumour development was lower with the I.V. route. In conclusion, in this experimental model, pulsed estrogen therapy with 17beta-estradiol administered via the I.V. route resulted in a reduced effect on mammary carcinogenesis when compared to oral administration.

Effect of intraruminally administered, selenium soluble-glass boluses on selenium status in cows and their calves.

Intraruminal selenium soluble-glass boluses were administered by balling gun to 65 of 125 crossbred beef cows (Shorthorn X Charolais) during the last trimester of pregnancy. Elevated (P less than .01) whole blood glutathione peroxidase (GSH-Px) concentrations were observed monthly for the next 10 mo following initiation of treatment, reaching the maximum magnitude (263 vs 41) at the fourth month. Monthly milk samples showed elevated selenium concentrations (P less than .01, April through August; P less than .05 through September). Intraruminal, selenium soluble-glass bolus administration to gestating cows was highly effective in raising the selenium status of their progeny. Although the control calves were in low-selenium status, no acute cases of nutritional muscular dystrophy were observed during this experiment.

Intraruminal selenium pellet for control of nutritional muscular dystrophy in cattle.

Administration of an intraruminal selenium pellet to a herd of pregnant crossbred cows was evaluated for controlling nutritional muscular dystrophy in an area of northern Ontario with numerous losses of calves. Cows were winter-fed grass silage. Each spring cows and calves went to pasture. A single dose of intraruminal selenium pellet was given to 80 cows during last 3 mo of pregnancy the 1st yr only while the remaining 80 were controls. During 3 consecutive years, efficacy of intraruminal selenium pellet was evaluated by selenium status of recipient cows and their offspring as well by the incidence of nutritional muscular dystrophy. Selenium in plasma, as well as glutathione peroxidase in whole blood, in the cows administered intraruminal selenium pellet, were higher than in the deficient controls. Ten months after intraruminal selenium pellet treatment, selenium in tissues was higher in treated than in untreated cows but within normal ranges. Before cows were turned out to pasture the 1st yr, milk selenium of intraruminal selenium pellet cows were higher than controls. This technique of selenium dosing was effective in raising the selenium status of the progeny. There was no evidence of nutritional muscular dystrophy in calves from selenium-dosed cows, while 15 calves born of the untreated cows showed clinical symptoms of nutritional muscular dystrophy.

Neonatal diarrhea of pigs in Quebec: infectious causes of significant outbreaks.

To evaluate the relative importance of the various enteropathogens causing neonatal diarrhea in Quebec farrowing operations, observations were made on 749 diarrheic pigs from 325 outbreaks of diarrhea. They were one to 15 days of age, and were obtained alive for necropsy generally within 48 hours of the onset of diarrhea. Some pigs were from severe, explosive outbreaks of diarrhea with high morbidity and mortality rates, while others were from herds with chronic neonatal diarrhea with lower morbidity and mortality rates. A combination of bacteriological, virological and histological methods were used to study the pigs. Viruses were incriminated in 60%, bacteria in 23% and coccidia in 15.3% of the 325 diarrhea outbreaks. Transmissible gastroenteritis virus was by far the most common enteropathogen with a prevalence of 52%; rotavirus was implicated in 9.2% of the outbreaks while adenovirus was incriminated in 0.30% of the outbreaks. Enterotoxigenic Escherichia coli were involved in 22.4% of the cases while Clostridium perfringens type C was an occasional finding. Coccidia involved in our herds were identified as Isospora suis. The disease was attributed to infection with a single etiologic agent in 590 diarrheic pigs (78%) while combinations of agents were present in only 90 (12%). The age-specific occurrence of the various enteropathogens was evaluated. Transmissible gastroenteritis virus was the most common enteropathogen in all age groups. Colibacillosis was common in pigs which became diarrheic under five days of age; in this age group, the enterotoxigenic E. coli were frequently found alone, but were usually combined with other agents in older pigs. The prevalence of coccidia was high in pigs which became diarrheic between five and 15 days of age. Rotavirus infection was common in diarrheic pigs older than ten days of age. Although individual baby pigs were commonly infected with a single enteropathogen, it was very common to see more than one agent involved in an outbreak of diarrhea, particularly when pigs of different ages were affected. Observations on the occurrence of the enteropathogens according to the seasons were also made. Occurrence of transmissible gastroenteritis was throughout the year with the highest prevalence during the fall, winter and spring months. Colibacillosis and coccidiosis were more common in the summer, fall and early winter months with the lowest prevalence in the spring months.