The alphaVbeta3 integrin (vitronectin receptor) plays a pivotal role in bone resorption. We hypothesized that L-000845704, an alphaVbeta3 integrin antagonist, would potently inhibit bone resorption, thereby increasing bone mass as assessed by bone mineral density (BMD) in women with postmenopausal osteoporosis. In a multicenter, randomized, double-blind, placebo-controlled, 12-month study, 227 women (average 63 yr) with low lumbar spine or femoral neck BMD were randomly assigned to receive 100 or 400 mg L-000845704 once daily (qd), 200 mg L-000845704 twice daily (bid), or placebo. L-000845704 increased lumbar spine BMD (2.1, 3.1, and 3.5% for the 100-mg-qd, 400-mg-qd, and 200-mg-bid treatment groups, respectively, vs. -0.1% for placebo; P < 0.01 all treatments vs. placebo). Only 200 mg L-000845704 bid significantly increased BMD at the hip (1.7 vs. 0.3% for placebo; P < 0.03) and femoral neck (2.4 vs. 0.7% for placebo; P < 0.05). No L-000845704 group increased total body BMD. All doses of L-000845704 resulted in a similar approximately 42% decrease from baseline of N-telopeptide cross-links (P < 0.001 vs. placebo). L-000845704 was generally well tolerated; adverse events resulting in discontinuation from the study were relatively infrequent. In conclusion, the antiresorptive effect of the alphaVbeta3 integrin antagonist L-000845704 translated into significant increases in lumbar spine BMD. Furthermore, 200 mg L-000845704 bid provided efficacy at the hip sites. These data suggest that the alphaVbeta3 integrin antagonist L-000845704 could be developed as an effective therapeutic agent for osteoporosis.
The alertness-promoting effect of MK-0249 (10 or 50 mg), a histamine subtype-3 receptor (HRH3) inverse agonist (IA), was evaluated in the stimulant reference sleep deprivation model (SRSDM) using a double-blind, double-dummy, placebo- and modafinil- (200 mg) controlled, four-period crossover design in 24 healthy young men. The two primary hypotheses were related to sleep latency (first appearance of one epoch of stage 2, 3, or 4 or REM sleep, as detected using polysomnography (PSG)) at 8:00 AM on day 2. Statistically significant increases in sleep latency were observed in association with the use of modafinil 200 mg (9.07 min; P < 0.0001), MK-0249 50 mg (5.17 min; P = 0.008), and MK-0249 10 mg (5.45 min; P = 0.005) at the maintenance of wakefulness test (MWT) at 8:00 AM. Sleep latency was higher when averaged over all MWT time points (P < 0.0001 for modafinil and for both doses of MK-0249). The alertness-promoting effect with the use of MK-0249 in the SRSDM suggests that HRH3 IAs may be effective in disorders involving excessive somnolence.
Rationale: Histamine and dopamine contribute to the maintenance of wakefulness.Objective: Exploratory analysis of the effects of 10 and 50 mg of MK-0249, a novel histamine subtype-3 receptor inverse agonist, and 200 mg of modafinil, a presumed dopaminergic compound, on EEG power spectra during sleep deprivation and subsequent recovery sleep. Methods: 25 healthy men were recruited to a double-blind placebocontrolled cross-over design. EEG power spectra, an electrophysiological marker of changes in sleepiness and vigilance, were obtained at the beginning of wake maintenance tests at 2 hourly intervals throughout a night and day of sleep deprivation, which is an established model of excessive sleepiness. Results: After placebo, sleep deprivation was associated with enhancements in delta, theta and reductions in alpha and beta activity.Following dosing at 02:00, MK-0249 and modafinil reduced delta and theta activity and enhanced alpha and beta activity, compared to placebo. During recovery sleep initiated at 21:00 h, latency to sleep onset, and number of awakenings were not different from placebo for any of the active treatments. Wake after sleep onset and stage 1 % was increased and total sleep time, SWS % and REM% were reduced after both doses of MK-0249. Compared to placebo, MK-0249 and the 50 mg dose in particular, reduced activity in some delta and theta/alpha frequencies and enhanced beta activity during NREM sleep and REM sleep.After modafinil, no changes were observed for power spectra during sleep. Conclusion: both MK-0249 and modafinil exert effects on the EEG which are consistent with wake promotion.
The histamine 3 (H3) receptor is a presynaptic autoreceptor in the central nervous system that regulates the synthesis and release of histamine and modulates the release of other major neurotransmitters. H3 receptor inverse agonists (IAs) may be efficacious in the treatment of various central nervous system disorders, including excessive daytime sleepiness, attention deficit hyperactivity disorder, Alzheimer disease, ethanol addiction, and obesity. Methods: Using PET and a novel high-affinity and selective radioligand 11 C-MK-8278, we studied the tracer biodistribution, quantification, and brain H3 receptor occupancy (RO) of MK-0249 and MK-3134, 2 potential IA drugs targeting cerebral H3 receptors, in 6 healthy male subjects (age, 19-40 y). The relationship among H3 IA dose, time on target, and peripheral pharmacokinetics was further investigated in 15 healthy male volunteers (age, 18-40 y) with up to 3 PET scans and 3 subjects per dose level. Results: The mean effective dose for 11 C-MK-8278 was 5.4 6 1.1 mSv/MBq. Human brain kinetics showed rapid high uptake and fast washout. Binding potential values can be assessed using the pons as a reference region, with a test-retest repeatability of 7%. Drug RO data showed low interindividual variability per dose (mean RO SD, 2.1%), and a targeted 90% RO can be reached for both IAs at clinically feasible doses. Conclusion: 11 C-MK-8278 is a useful novel PET radioligand for determination of human cerebral H3 receptor binding and allows highly reproducible in vivo brain occupancy of H3-targeting drugs, hereby enabling the evaluation of novel compounds in early development to select doses and schedules. Hi stamine is an aminergic neurotransmitter that is localized in the central nervous system (CNS) and in peripheral tissues such as the gut, skin, and immune system. In the brain, histaminergic neurons originate in the tuberomammillary nucleus of the hypothalamus and project throughout the CNS, including the thalamus, hypothalamus, cerebral cortex, striatum, medulla oblongata, and spinal cord. There are 4 known G-protein-coupled histamine receptor subtypes (H1-H4). These serve multiple functions in the brain, particularly control of excitability and plasticity. Type 1 and 2 histamine receptor-mediated actions are mostly excitatory. The H3 receptor was discovered in 1983 and cloned at the end of the twentieth century (1) and is mainly expressed in the CNS. H3 receptors predominate in the basal ganglia, with the highest densities in the globus pallidus (2). The H3 receptor is a presynaptic inhibitory autoreceptor that regulates the synthesis and release of histamine and also modulates the release of several other neurotransmitters such as acetylcholine, norepinephrine, serotonin, dopamine, and g aminobutyric acid. Like other G-protein-coupled receptors, H3 receptors signal constitutively, serving to tonically suppress histamine production at baseline. Agonist-induced signaling, such as that which occurs in the presence of elevated histamine levels, further suppresses histamine...
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