Effect of obesity and feeding on the growth hormone (GH) response to the GH secretagogue L-692,429 in young men.

GH secretion and the response to GH secretagogues are significantly diminished in obese individuals. Previous studies have shown that L-692,429 (L), a nonpeptide mimetic of GH-releasing peptide, selectively stimulates GH release in normal young men and in the elderly, who also have diminished GH secretion. A paired, two-site study examined the effects of L on GH release in 12 healthy obese (part A; mean +/- SD: age, 26.1 +/- 3.3 yr; body mass index, 35.0 +/- 3.1 kg/m2) and 10 nonobese (part B; age, 22.2 +/- 2.3 yr; body mass index, < or = 27.0) young men. In part A, placebo, low dose L (0.2 mg/kg), or high dose L (0.75 mg/kg) was administered iv over 15 min on 3 separate occasions after an overnight fast. Samples for GH, PRL, and cortisol determinations were obtained every 15 min. GH release (mean +/- SE) was significantly increased by both doses of L compared to the effect of placebo: 12.6 +/- 1.8 micrograms/L (low dose), 18.5 +/- 2.7 micrograms/L (high dose), and 0.84 +/- 0.1 microgram/L (placebo), respectively (P < 0.05). In a subset of 6 obese men, in samples collected every 5 min, the GH response to both doses of L was significantly greater than that to 1 microgram/kg GHRH. To compare the response to low dose L in the obese and to determine the effects of feeding on this response, 0.2 mg/kg L was administered as described in part A to nonobese young men after an overnight fast (fasted) or a standardized breakfast (fed; part B). Low dose L was an effective GH secretagogue in nonobese young men; however, this effect was attenuated with feeding [43.6 +/- 7.9 (fasted) vs. 17.7 +/- 4.8 (fed) micrograms/L]. Of note, the response to low dose L in fasted obese individuals was similar to that in fed nonobese individuals. The administration of L was well tolerated in both groups. We conclude that L is an effective GH secretagogue in obese and nonobese young men and may have therapeutic benefits when administered to relative (obese or elderly) or absolute GH-deficient individuals.

Dose-response relationships for alendronate treatment in osteoporotic elderly women. Alendronate Elderly Osteoporosis Study Centers.

Alendronate (ALN) is an aminobisphosphonate employed as an antiresorptive agent in the treatment of osteoporosis. The present study was carried out to determine dose-response relationships, particularly the effects of relatively low doses of ALN, on bone mineral density (BMD), biochemical indexes of bone and mineral metabolism, and bone histology, with particular attention to effects in elderly women. This prospective, randomized, double blind, 2-yr multicenter study compared the effects of placebo with those of 1.0, 2.5, or 5.0 mg ALN daily. All subjects received supplemental calcium (500 mg daily) as the carbonate. We studied 359 women with lumbar spine BMD at least 2.0 SD below the peak young adult mean. Subjects were stratified by age, with 135 aged 60-69 yr and 224 aged 70-85 yr. Histomorphometry was performed on transiliac bone biopsies obtained from 104 subjects after 1 yr and from 83 subjects after 2 yr. This study elucidated the previously uninvestigated lower region of the dose-response curve for ALN in osteoporosis. Over 2 yr, treatment with 1.0, 2.5, or 5.0 mg/day increased lumbar spine BMD, on the average, by 0.65%, 3.54%, and 5.67%, respectively, compared with that in the placebo group (P < 0.001 vs. placebo for the 2.5 and 5 mg groups). Significant dose-related increases were also seen in BMD at appendicular sites and in total body BMD. Dose-dependent reductions in bone turnover to new steady states were indicated by serum and urine biochemical markers as well as by histomorphometry. There was also a dose-related reduction in the proportion of subjects suffering nonvertebral fractures (P < 0.05). Safety profiles were similar for the ALN and placebo groups and for both age strata. Efficacy was similar for both age strata. There was no evidence of impaired mineralization or other histological abnormalities due to ALN treatment. We conclude that treatment with ALN over a period of 2 yr was well tolerated and produced dose-dependent increases in BMD without evidence of a plateau over the dose range of 1.0-5.0 mg daily. One milligram daily did not result in a significant effect on BMD, and 5.0 mg daily produced favorable effects at all sites measured. Other studies have demonstrated somewhat greater effects on 10 mg daily. ALN, was equally effective and well tolerated in osteoporotic women over 70 yr old as in younger women with the same condition.

Inhibition of cholecystokinin-stimulated pancreaticobiliary output in man by the cholecystokinin receptor antagonist MK-329.

MK-329 (formerly L-364,718) is a new nonpeptide antagonist for the peripheral (type-A) cholecystokinin (CCK) receptor, which has proved effective in blocking the actions of both exogenous and endogenous CCK in several species. To evaluate the effect of MK-329 on CCK-stimulated pancreaticobiliary output in man, six normal subjects received 10 mg MK-329 or placebo orally in a randomized, crossover fashion, before a background intravenous infusion of secretin (5 pmol/kg/h) and two doses of CCK-8 (approximately 15 and 40 pmol/kg/h, each for 1 h). Gastric and duodenal juice were aspirated separately via two double-lumen tubes, with 51Cr-ethylene-diaminetetraacetic acid as a duodenal marker. After placebo treatment the background infusion of secretin produced maximum plasma concentrations of secretin similar to postprandial values, averaging about 5 pM. After placebo treatment the low dose CCK-8 infusion (15 pmol/kg/h) increased circulating CCK concentrations from basal levels of 1.8 +/- 0.2 pM to levels similar to those observed postprandially, averaging 9.2 +/- 1.3 pM, and the high dose of CCK-8 (40 pmol/kg/h) induced supraphysiologic levels of CCK, averaging 23.4 +/- 3.2 pM. Plasma concentrations of secretin and CCK were not significantly different during MK-329 treatment. As expected, infusion of CCK-8 at both doses stimulated pancreatic exocrine secretion and gallbladder contraction in placebo controls, as indicated by increases in the output of trypsin, amylase, bicarbonate, and bilirubin. Whereas MK-329 did not significantly reduce basal pancreatic secretion, the integrated incremental output of trypsin, amylase, and bicarbonate in response to stimulation with the low (physiologic) CCK dose was inhibited by 74% (p less than 0.01), 89% (NS), and 75% (p less than 0.05), respectively. Basal bilirubin output was virtually abolished after treatment with MK-329, and the response to the low dose of CCK was reduced by 98% (p less than 0.01), indicating almost complete inhibition of gallbladder contraction at physiologic circulating concentrations of CCK. It is concluded that MK-329 is an orally active antagonist of CCK-stimulated pancreaticobiliary output in man and could thus be utilized to explore the physiologic regulation of the exocrine pancreas and gallbladder by CCK.