Metoclopramide induces preparturient, low-level hyperprolactinemia to increase milk production in primiparous sows.

Inadequate milk production by sows often limits the growth of piglets. A successful lactation requires prolactin (PRL)-induced differentiation of the alveolar epithelium within the mammary glands of sows between days 90-110 of gestation. We hypothesized that induction of late gestational hyperprolactinemia in primiparous sows by oral administration of the dopamine antagonist metoclopramide (MET) would enhance mammary epithelial differentiation, milk yield, and piglet growth rate and that these effects would carry over into a subsequent lactation. Twenty-six gilts were assigned to receive either MET (n = 13, 0.8 mg/kg) or vehicle (CON, n = 13) twice daily from days 90-110 of gestation. The same sows were followed into their second lactation without additional treatment. On day 90 of gestation, circulating PRL concentrations peaked 45 min after feeding MET (P < 0.001) and then returned to baseline 3 h later. This response occurred daily out to day 104 of gestation (P < 0.05). Compared with CON, MET-treated gilts had enlarged alveoli on gestation day 110 (P < 0.05). Treatment with MET did not affect feed intake, body weight, or body fatness during pregnancy or lactation. Piglets born to MET-treated sows had both increased body weights and average daily gain on lactation days 14 and 21 (P < 0.05). Milk intake by piglets was estimated from deuterium oxide dilution. Although milk intake by piglets nursing MET sows was not statistically different from those nursing CON sows on day 21 of lactation (P = 0.18), there was a greater increase in milk consumption by piglets born to MET-treated sows between days 9 and 21 of lactation than for those in CON litters (P < 0.001). In one group of second parity sows (n = 11) that were treated with MET during their first gestation, milk yield increased by 21% during their second lactation (P < 0.05) in association with a 14% decline in body fatness across lactation compared with a 7% decline in CON sows (P < 0.05). These findings demonstrate that MET-induced hyperprolactinemia in primiparous sows during late pregnancy can increase milk yield and piglet growth rate, setting the stage for further large-scale studies.

Chronic effects of the novel glucocorticosteroid RPR 106541 administered to beagle dogs by inhalation.

The preclinical safety of RPR 106541, a novel 17-thiosteroid, was evaluated in young adult and mature dogs by inhalation exposure for 26 weeks and 52 weeks, respectively. A dry powder formulation of RPR 106541 in lactose was administered to young adult dogs (approximately 6 months of age at initiation) at doses of 0 (air and placebo controls), 10, 100, or 1,000 microg/kg/d for 26 weeks. A solution-based aerosol formulation was administered to mature dogs (approximately 10 months at initiation) from a pressurized metered dose inhaler at 0 (air and placebo controls), 10, 50, and 150 microg/kg/d for 52 weeks. Clinical evidence of glucocorticosteroid-induced immunosuppression was observed by weeks 20-26 following relatively high dose exposures (100 microg/kg/d and 1,000 microg/kg/d) in young dogs receiving the dry powder formulation for 26 weeks. Classic glucocorticosteroid effects were observed, including adrenocortical atrophy, reduced bone mass with retention of epiphyseal growth plates in long bones, prominence of stromal adipose tissue in bone marrow, and atrophy of lymphoid tissues. Inhalation administration of RPR 106541 to sexually mature dogs facilitated more definitive characterization of endocrine affects of RPR 106541 as compared with administration in younger, sexually immature animals. Significant effects in female reproductive organs included absence of corpora lutea in association with atresia of vesicular follicles within the ovaries, endometrial hyperplasia, and lobular development of mammary tissue. Discordant development of mammary tissue, accumulation of secretory material within hyperplastic endometrial glands, and hypertrophy of uterine lining epithelium in absence of ovulation were consistent with a secondary progestin effect by a potent glucocorticosteroid.

Cardiovascular effects after inhalation of large doses of albuterol dry powder in rats, monkeys, and dogs: a species comparison.

Albuterol is a quickly acting beta-2 adrenergic agonist bronchodilator widely used by asthmatics. Because recent case-control studies have suggested a relationship between the increase in mortality of asthmatics over the past decade and the use of beta 2-adrenergic agonists in the control of asthma, concern has developed regarding the potential cardiotoxicity of beta 2-specific adrenergic agonists, including albuterol. The aim of this investigation was to assess the potential for cardiotoxicity of inhaled albuterol dry powder in rats, monkeys, and dogs. All species were exposed to an aerosol of albuterol 1 h per day, 7 days per week, for at least 2 weeks. Control groups were exposed to filtered conditioned air and handled in the same manner as the albuterol-exposed animals. Plasma concentrations of albuterol confirmed systemic exposure. The daily inhaled dose received by the animals was calculated based on measured respiratory minute volumes, published respiratory tract deposition data, as well as HPLC-determined particle size distribution data and aerosolized albuterol concentrations. Multiples of the maximum daily clinical dose (presentation of 15 micrograms/kg in a 70-kg human) were approximately 0.25- to 2500-fold in the rat, 9- to 100-fold in the monkey, and 0.5- to 90-fold in the dog. No findings attributed to albuterol were observed in the monkey. Tachycardia and transient hypokalemia occurred in rats at multiples of 1.5 times or greater of the maximum clinical dose. Absolute and relative heart weights increased in rats receiving multiples of 47 times or greater of the maximum human dose. In the absence of histopathologic findings, the increases in rat heart weights were considered a physiologic hypertrophic response to tachycardia. In dogs tachycardia and transient hypokalemia occurred at all doses tested. Slight to mild fibrosis in the papillary muscles of the left ventricle of the heart occurred in dogs at multiples > or = 19 times the clinical dose. The cardiovascular effects observed were consistent with the known pharmacologic action of beta 2-adrenergic agonists. Due to the lack of toxicologically relevant findings in rats and monkeys and the wide safety margin in dogs, the findings in this study do not suggest a cardiotoxicity risk in the human population after repeated exposures to clinical doses of albuterol currently used in the treatment of asthma.

Determination of DMP 728, a IIb/IIIa receptor antagonist, in rat and dog plasma by high-performance liquid chromatography with fluorimetric detection.

A specific and sensitive HPLC assay for the determination of DMP 728 in dog and rat plasma has been developed. The method involves solid-phase extraction of DMP 728 and the internal standard from plasma using a C2 column. The extracted compounds are derivatized with benzoin under alkaline conditions. Using a mixture of acetonitrile and 0.1 M potassium phosphate buffer (25:75, v/v, pH 7.4) as mobile phase, the derivatized products are separated on a Regis semipermeable surface C8 column and monitored fluorometrically using 325 nm and 425 nm as excitation and emission wavelengths, respectively. The assay is linear from 2.5 to 1000 ng/ml in dog plasma and from 5 to 1000 ng/ml in rat plasma. The limit of quantitation is 2.5 ng/ml using 0.5 ml of dog plasma and 5 ng/ml using 0.5 ml of rat plasma. The assay has been used in pharmacokinetic studies of DMP 728 in dogs and rats.

Cell-specific processing of preprosomatostatin in cultured neuroendocrine cells.

We have previously found that preprosomatostatin is processed accurately to both somatostatin-14 and somatostatin-28 in pituitary gonadotrophs of transgenic mice. The foreign somatostatin peptides have been shown to enter the regulated secretory pathway of these cells. To determine whether accurate preprosomatostatin processing can occur in any neuroendocrine cell, we introduced preprosomatostatin cDNA expression vectors into several different neuroendocrine cell lines. We found that prosomatostatin was cleaved efficiently to somatostatin-14 and somatostatin-28 in RIN 5F and AtT20 cells, but not in GH4 or PC12 cells. The ability of a particular cell type to process prosomatostatin did not correlate with cellular storage capacity and was independent of the level of biosynthesis of the precursor. These data suggest that prosomatostatin processing requires specific pathways which are present in some neuroendocrine cells, but not in others.