Postmenopausal women with established vertebral osteoporosis were studied for 2 years to determine the terminal elimination half-life and the duration of response to treatment with intravenous alendronate (30 mg) given over 4 days. The urinary excretion of alendronate followed a multiexponential decline. Approximately 50% of the total dose was excreted over the first 5 days, and a further 17% was excreted in the succeeding 6 months. Thereafter, there was a much slower elimination phase with an estimated mean terminal half-life of greater than 10 years (n ‫؍‬ 11). Urinary excretion of hydroxyproline and calcium decreased significantly from pretreatment values by day 3, reaching a nadir by 1 week (40% and 67% decrease, respectively). Thereafter, hydroxyproline remained suppressed for the following 2 years. In contrast, urinary calcium excretion returned gradually toward pretreatment values over the first year and during the second year was comparable to pretreatment values. Serum activity of alkaline phosphatase activity decreased over 3 months (23% reduction), increased gradually thereafter, and returned to pretreatment values at month 24. Bone mineral density measured at the spine increased by approximately 5% during the first year and remained significantly higher than pretreatment values at 2 years. We conclude that a short course of high doses of intravenous alendronate is associated with a prolonged skeletal retention of the agent. This open study also suggests that this regimen has a sustained effect on bone turnover persisting for at least 1

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This [C]UCB-J blocking study validated SO as a suitable reference region for non-invasive quantification of SV2A availability and drug occupancy in the human brain. Accurate quantification can be achieved by using either SUVR with a 60-90 min PET acquisition or SRTM BPwith at least 70 min dynamic PET acquisition.

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Ertapenem is a new once-a-day parenteral carbapenem antimicrobial agent. The pharmacokinetics of unbound and total concentrations of ertapenem in plasma were investigated in elderly subjects and compared with historical data from young adults. In a single- and multiple-dose study, healthy elderly males and females (n = 14) 65 years old or older were given a 1-g intravenous (i.v.) dose once daily for 7 days. Plasma and urine samples collected for 24 h on days 1 and 7 following administration of the 1-g doses were analyzed by reversed-phase high-performance liquid chromatography. Areas under the concentration-time curve from 0 h to infinity (AUC(0- infinity )) for elderly females and males were similar following administration of 1-g single i.v. doses, and thus, the genders were pooled in subsequent analyses. Concentrations in plasma and the half-life of ertapenem were generally higher and longer, respectively, in elderly subjects than in young adults. The mean AUC(0- infinity ) of total ertapenem in the elderly was 39% higher than that in young subjects following administration of a 1-g dose. The differences were slightly greater for the mean AUC(0- infinity ) of unbound ertapenem (71%). The unbound fraction of ertapenem in elderly subjects ( approximately 5 to 11%) was generally greater than that in young adults ( approximately 5 to 8%). As in young adults, ertapenem did not accumulate upon multiple dosing in the elderly. The pharmacokinetics of ertapenem in elderly subjects, while slightly different from those in young adults, do not require a dosage adjustment for elderly patients.

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Aims Following intravenous administration of its prodrug, L-758,298, we assessed the pharmacodynamics of L-754,030, a novel and highly selective NK 1 receptor antagonist, by examining systemic haemodynamics and the blood flow responses to intra-arterial substance P infusion. Methods Sixteen healthy male volunteers participated in a double-blind, randomised, placebo controlled crossover trial of L-758 298. Forearm blood flow was measured using venous occlusion plethysmography during intrabrachial substance P infusion (0.125-128 pmol min −1 ). In part 1, eight subjects received substance P infusions before and during placebo, 0.25 mg, 1 mg or 5 mg of L-758 298. In part 2, eight subjects received substance P infusions 24 h after placebo or 1.43 mg of L-758 298.Results L-758 298 caused dose dependent inhibition of substance P induced vasodilatation ( P<0.001). Placebo adjusted differences (95% CI) in baseline forearm blood flow, mean arterial pressure and heart rate showed no relevant changes with 5 mg of L-758 298 (>1400-fold shift in substance P response): 0.00 (−0.49 to +0.49) ml 100 ml −1 min −1 , 1.0 (−3.2 to +5.2) mmHg and 1.9 (−5.9 to +9.7)beats min −1 , respectively. Twenty-four hours after 1.43 mg of L-758,298, there was 34-fold shift in response to substance P induced vasodilatation ( P<0.008) at plasma L-754 030 concentrations of 2-3 ng ml −1 . L-758 298 was generally well tolerated without serious adverse events. Conclusions Substance P induced forearm vasodilatation is mediated by the endothelial cell NK 1 receptor in man but endogenous substance P does not appear to contribute to the maintenance of peripheral vascular tone or systemic blood pressure.Keywords: substance P, neurokinin 1 receptor, endothelium, haemodynamics, blood flow Substance P is a member of the tachykinin family of Introduction peptides and acts through stimulation of the neurokinin receptors, having a particularly high affinity for the Substance P is a widely distributed endecapeptide which is found principally in the neural tissue of the central, type 1 (NK 1 ) receptor [9]. When given intra-arterially, substance P is a potent vasodilator [10][11][12] through an peripheral and enteric nervous systems [1][2][3][4]. The physiological functions of substance P include neuroendothelium dependent mechanism [13] which is partly mediated by nitric oxide release [14, 15]. In animal transmission in primary sensory neurones with particular involvement in nociception and emesis. In addition to studies, this response is induced via stimulation of the endothelial cell NK 1 receptor [9] although, to date, this functioning as a neurotransmitter, it also acts as an inflammatory mediator [5][6][7] and neurohumoral regulator has not been confirmed in vivo in man. Substance P is found in perivascular neural tissue [16] and has been [1, 8].postulated to play a role in the regulation of vascular

A i m W e evaluated the pharmacokmetics and pharniacodynamics of oral MK-462 in comparison with oral sumatriptan in healthy male volunteers. Metlzods 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 t,, 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 5-10mmHg 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 mdd increases in serum growth hormone without any effect on serum prolactin concentrations. T h e most commonly reported symptom following MK-462 was drowsiness. Coriclirsions These results indicate that the novel 5-HT1, agonist, MK-462, is rapidly absorbed following oral administration and warrants further investigation of its utility in the treatment of acute migraine.