Zolmitriptan (311C90) does not interact with fluoxetine in healthy volunteers.

Zolmitriptan (Zomig, formerly 311C90) is a selective 5-hydroxytryptamine (5-HT)1B/1D-receptor agonist with central and peripheral activity for the acute treatment of migraine. This randomized, placebo-controlled, crossover study investigated the effects of fluoxetine administration on the pharmacokinetics and pharmacodynamics of zolmitriptan. Twenty volunteers were given single doses of fluoxetine 20 mg or an identical placebo daily for 28 days prior to receiving a single 10 mg oral dose of zolmitriptan. Sixteen volunteers completed the two treatment phases. The pharmacokinetic parameters of zolmitriptan and its metabolites were not significantly affected by fluoxetine pretreatment. The pharmacodynamic effects of zolmitriptan were also unaffected by fluoxetine pretreatment. There were small, clinically insignificant increases in blood pressure following zolmitriptan which were unaltered by fluoxetine. Zolmitriptan was well tolerated when given alone or concomitantly with fluoxetine. These results indicate that there is no contraindication to the use of zolmitriptan in patients treated concurrently with selective serotonin reuptake inhibitors and that no adjustment of the zolmitriptan dose is required in these circumstances.

Oral administration of growth hormone (GH) releasing peptide-mimetic MK-677 stimulates the GH/insulin-like growth factor-I axis in selected GH-deficient adults.

To determine the effect of the GH releasing peptide (GHRP)-mimetic, MK-677, on the GH/insulin-like growth factor-I (IGF-I) axis in selected GH-deficient adults, we studied nine severely GH-deficient men [peak serum GH concentration in response to insulin-induced hypoglycemia of 1.2 +/- 1.5 micrograms/L, mean +/- SD (range 0.02-4.79)], age 17-34 yr, height 168 +/- 1.5 cm, body mass index 22.6 +/- 3.3 kg/m2, who had been treated for GH deficiency with GH during childhood. In a double-blind rising-dose design, subjects received once daily oral doses of 10 or 50 mg MK-677 or placebo for 4 days over two treatment periods separated by at least 28 days. Four subjects received placebo and 10 mg/day MK-677 in a cross-over fashion in periods 1 and 2. Five subjects received 10 mg and then 50 mg/day MK-677 in a sequential, rising-dose fashion in periods 1 and 2, respectively. Blood was collected every 20 min for 24 h before treatment and at the end of each period for GH measurement using an ultrasensitive assay. The drug was generally well tolerated, with no significant changes from baseline in circulating concentrations of cortisol, PRL, and thyroid hormones. Serum IGF-i and 24-H mean GH concentrations increased in all subjects after treatment with both 10 and 50 mg/day MK-677 vs. baseline. After treatment with 10 mg MK-677, IGF-I concentrations increased 52 +/- 20% (65 +/- 6 to 99 +/- 9 micrograms/L, geometric mean +/- intrasubject SE, P < or = 0.05 vs. baseline), and 24 h mean GH concentrations increased 79 +/- 19% (0.14 +/- 0.01 to 0.26 +/- 0.02 microgram/L, P < or = 0.05 vs. baseline). Following treatment with 50 mg MK-677, IGF-I concentrations increased 79 +/- 9% (84 +/- 3 to 150 +/- 6 micrograms/L, P < or = 0.05 vs. baseline) and 24-h mean GH concentrations increased 82 +/- 29% (0.21 +/- 0.02 to 0.39 +/- 0.04 microgram/L, P < or = 0.05 vs. baseline), respectively. Serum IGF binding protein-3 concentrations increased with both 10 mg (1.2 +/- 0.1 to 1.7 +/- 0.1 micrograms/L, P < or = 0.05) and 50 mg MK-677 (1.7 +/- 0.1 to 2.2 +/- 0.2 micrograms/L, P < or = 0.05). The GH response to MK-677 was greater in subjects who were the least GH/IGF-I deficient at baseline; by linear regression analysis the increase in 24-h mean GH concentration was positively related to both baseline 24-h mean GH concentration (r = 0.81, P = 0.009) and baseline IGF-I (r = 0.79, P = 0.01) for 10 mg MK-677. IGF-I responses were not significantly related to any baseline measurement. Fasting and postprandial insulin and postprandial glucose increased significantly after MK-677 treatment, and the clinical significance of these changes will need to be assessed in longer term studies. Oral administration of such GHRP-mimetic compounds may have a role in the treatment of GH deficiency of childhood onset.

Initial human experience with MK-462 (rizatriptan): a novel 5-HT1D agonist.

AIMS: We evaluated the pharmacokinetics and pharmacodynamics of oral MK-462 in comparison with oral sumatriptan in healthy male volunteers. METHODS: Sixteen healthy male volunteers were studied in a rising, single dose, alternating panel design with eight subjects per panel. Matching placebo was administered to two of eight study subjects at each dose level of MK-462 in a randomized, double-blind fashion. RESULTS: MK-462 was rapidly absorbed with a median tmax of 1.3 h (range 1-3 h) vs a tmax for sumatriptan of 2.5 h (range 1-4 h, P < 0.001). Administration of either MK-462 or sumatriptan produced maximal mean elevations of 5-10 mmHg in systolic and diastolic blood pressures without effect on heart rate; the changes occurred sooner following MK-462, consistent with more rapid absorption. Both MK-462 and sumatriptan provoked mild increases in serum growth hormone without any effect on serum prolactin concentrations. The most commonly reported symptom following MK-462 was drowsiness. CONCLUSIONS: These results indicate that the novel 5-HT1D agonist, MK-462, is rapidly absorbed following oral administration and warrants further investigation of its utility in the treatment of acute migraine.

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.

Pharmacokinetics and food interaction of MK-462 in healthy males.

A study was conducted to assess the safety, tolerability, and pharmacokinetics of single intravenous (IV) doses of 5-90 micrograms kg-1 of MK-462, and the effect of food on the pharmacokinetics of MK-462 administered orally to healthy males. Results of this study indicate that IV doses of MK-462 from 5 to 90 micrograms kg-1 are well tolerated. The disposition kinetics of MK-462 were linear for IV doses up to and including 60 micrograms kg-1. The values of the plasma clearance (CL), steady-state volume of distribution (Vss), plasma terminal half-life (t1/2), and mean residence time in the body (MRT) of MK-462 averaged 1376 mL min-1, 140 L, 1.8 h, and 1.7 h, respectively, and remained essentially constant over the dosage range of 10-60 micrograms kg-1 of IV MK-462. However, as the dose increased from 60 to 90 micrograms kg-1, the mean value of the apparent CL decreased from 1376 to 807 mL min-1. Thus, elimination of MK-462 was dose dependent in this dosage range. Based on the disposition decomposition analysis (DDA), it was shown that the Vss value of MK-462 remained essentially constant over the dosage range of 10-90 micrograms kg-1 of IV MK-462. The following values of two dose-independent parameters were also calculated by using DDA: distribution clearance (CLd) = 2028 mL min-1, and mean transit time in the peripheral tissues (MTTT) = 0.74 h. The mean values of AUC, Cmax, tmax, and apparent t1/2 of MK-462 in 12 subjects each receiving a 40 mg tablet of MK-462 without breakfast were 330 ng.h mL-1, 77 ng mL-1, 1.6 h, and 1.8 h, respectively. Although administration of a standard breakfast prior to dosing increased the AUC value (by approximately 20%) of MK-462 and delayed its absorption, there were no significant effects of the meal on the values of Cmax and apparent t1/2 of MK-462.

Molecular cloning and nucleotide sequence of cDNA encoding a functional murine low-density-lipoprotein receptor.

The low-density-lipoprotein (LDL) receptor is an important mediator of mammalian cholesterol metabolism; its congenital absence in humans is characterized by hypercholesterolemia, atherosclerosis, and coronary artery disease. We report here the identification and cloning of a cDNA encoding the murine LDL receptor. The cDNA insert is 4467 base pairs in length and the deduced amino acid sequence bears 78.2% homology with the reported human sequence. This murine cDNA was subcloned into a retroviral-based expression vector, LmLSN1, and transfected into 3T3 cells. The production of functional LDL receptor was confirmed by ligand binding of DiI-LDL cholesterol.