Objective: To determine the utility of oxycodone in the treatment of the restless leg syndrome (RLS). Design: Randomized, double-blind, crossover study employing various dosages of oxycodone. Setting: Patients: Eleven patients (ages 36-74, five men) were recruited from the Lyons VA Medical Center, UMDNJ-Robert Wood Johnson University Hospital, and Columbia Presbyterian Medical Center. All had paresthesia in the legs, motor restlessness, and worsening of symptoms at night and at rest. All patients had periodic limb movements in sleep (PLMS), which are repetitive, stereotypic flexions of the hips, knees, and ankles that recurred during wakefulness while sitting or lying. Other patients, whose restlessness was secondary to other causes such as radiculopathy or drug-addiction, were excluded. Intervention: Patients were tapered off all drugs affecting RLS, had polysomnography, and had symptoms self-rated from 0 to 4 (4 = most severe). Patients were given medication (2.5 mg oxycodone tablet), or placebo, which was gradually increased in dose over 2 weeks to a maximum of 25 mg of oxycodone, or 10 tablets of placebo. The subjects then rated symptoms, had repeat polysomnography, and tapered the medication over 3 days, followed by restart of the other medication (oxycodone or placebo) over the next 2 weeks. Main Outcome Measures: Limb movements during sleep, leg sensations, motor restlessness, arousals/hour during sleep, sleep efficiency, and reports by the patients of their evaluation of their symptoms on a 0-4 scale (0 = none, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe). Main Results: Statistically significant decrements were noted in measures studied including leg sensations (P C 0.009), motor restlessness (P < 0.006), periodic limb movements during sleep per hour (P C 0.004), and arousals during sleep/ hour (P < 0.009). Sleep efficiency and daytime alertness was also improved (P < 0.006). Conclusion:Oxycodone is an effective treatment for restless legs syndrome.

1. Retinal dystrophies (RD) comprise a group of clinically and genetically heterogeneous retinal disorders, which typically result in the degeneration of photoreceptors followed by the impairment or loss of vision. Although age-related macular degeneration (AMD) and retinitis pigmentosa (RP) are among the most common forms of RD, currently, there is no effective treatment for either disorder. 2. Recently, abnormal protein accumulation and aggregation due to protein misfolding and proteasome inhibition have been implicated in the pathogenesis of RD. In this paper we describe effects of several factors on protein aggregation and survival of photoreceptor cells. 3. Expression of rhodopsin carrying P23H mutation causes its accumulation in intracellular inclusion bodies in a perinuclear area of photoreceptor cells. beta- and gamma-synucleins and heat shock protein Hsp-70, but not alpha-synuclein, protect cultured ocular cells from mutant opsin accumulation. This effect might be explained by their chaperonic activity. 4. Knock-out of alpha- and gamma-synucleins does not affect gross retinal morphology, but induces tyrosine hydroxylase in the inner prexiform layer of the retina. Selegiline-a monoamine oxidase inhibitor used for the treatment of Parkinson's disease, reduces apoptosis and increases viability in cultured retinal pigment epithelium cells (APRE-19). 5. These results suggest that chaperones and selegiline may be considered promising candidates for the protection of ocular cells from the accumulation of misfolded and aggregated proteins.

Membrane G protein-coupled receptor kinase 5 (GRK5) deficiency is linked to Alzheimer disease, yet its precise roles in the disease pathogenesis remain to be delineated. We have previously demonstrated that GRK5 deficiency selectively impairs desensitization of presynaptic M2 autoreceptors, which causes presynaptic M2 hyperactivity and inhibits acetylcholine release. Here we report that inactivation of one copy of Grk5 gene in transgenic mice overexpressing ␤-amyloid precursor protein (APP) carrying Swedish mutations (Tg2576 or APPsw) resulted in significantly increased ␤-amyloid (A␤) accumulation, including increased A␤ ؉ plaque burdens and soluble A␤ in brain lysates and interstitial fluid (ISF). In addition, secreted ␤-APP fragment (sAPP␤) also increased, whereas fulllength APP level did not change, suggesting an alteration in favor of ␤-amyloidogenic APP processing in these animals. Reversely, perfusion of methoctramine, a selective M2 antagonist, fully corrected the difference between the control and GRK5-deficient APPsw mice for ISF A␤. In contrast, a cholinesterase inhibitor, eserine, although significantly decreasing the ISF A␤ in both control and GRK5-deficient APPsw mice, failed to correct the difference between them. However, combining eserine with methoctramine additively reduced the ISF A␤ further in both animals. Altogether, these findings indicate that GRK5 deficiency accelerates ␤-amyloidogenic APP processing and A␤ accumulation in APPsw mice via impaired cholinergic activity and that presynaptic M2 hyperactivity is the specific target for eliminating the pathologic impact of GRK5 deficiency. Moreover, a combination of an M2 antagonist and a cholinesterase inhibitor may reach the maximal disease-modifying effect for both amyloid pathology and cholinergic dysfunction.Alzheimer disease (AD 3 ) is a devastating neurodegenerative disorder clinically characterized by progressive loss of memory and other neurological functions. Given that basal forebrain cholinergic neurons are the fundamental basis for memory function, any of the pathological causes in AD, no matter whether they are the hallmark changes of ␤-amyloid (A␤)-enriched senile plaques and neurofibrillary tangles or of the prominent inflammation, have to eventually converge to the extensive basal forebrain cholinergic neuronal loss in AD.Mounting evidence suggests that the excessive accumulation of A␤ is a paramount pathological event leading to AD, either by direct neuronal toxicity or by indirect exacerbation of inflammatory damage to neurons (1, 2). The amyloid precursor protein (APP) can be proteolytically processed either through the ␤-amyloidogenic pathway by ␤-and ␥-secretases or via the non-␤-amyloidogenic pathway by ␣-secretase. The regulation of these two mutually exclusive pathways determines the amount of A␤ production and is thus critically important for the pathogenesis of AD. Previous studies have demonstrated that proteolytic APP processing can be regulated by a variety of G protein-coupled receptors, including cholinergic, se...

Acidosis that occurs under pathological conditions not only affects intracellular signaling molecules, but also directly activates a unique family of ligand-gated ion channels: acid-sensing ion channels (ASICs). ASICs are widely expressed throughout the central and peripheral nervous systems and play roles in pain sensation, learning and memory, and fear conditioning. Overactivation of ASICs contributes to neurodegenerative diseases such as ischemic brain/spinal cord injury, multiple sclerosis, Parkinson’s disease, and Huntington’s disease. Thus, targeting ASICs might be a potential therapeutic strategy for these conditions. This mini-review focuses on the electrophysiology and pharmacology of ASICs and roles of ASICs in neuronal toxicity.

Cyclooxygenase (COX) exists as constitutive (COX-1) and inducible (COX-2) isoforms. Nonsteroidal antiinflammatory drugs (NSAIDs) such as ibuprofen and diclofenac inhibit both COX-1 and COX-2. The role of COX-2 in the genesis of fever in monkeys and humans was examined with use of the specific COX-2 inhibitor rofecoxib. Rofecoxib was administered to monkeys made febrile by 6 microg/kg intravenous lipopolysaccharide. Induced pyrexia was followed by oral rofecoxib (1 or 3 mg/kg), diclofenac (3 mg/kg), or vehicle. Rofecoxib and diclofenac rapidly reversed the elevated temperature (P < .05 versus vehicle for 3 mg/kg rofecoxib and diclofenac at 70 to 90 minutes after dosing). A single-dose, parallel-group, double-blind randomized trial was conducted in 94 patients with fever caused by a viral-type illness. Mean baseline temperature was similar for all groups (-38.5 degrees C). Patients received oral doses of 12.5 mg rofecoxib, 25 mg rofecoxib, 400 mg ibuprofen, or placebo and the mean +/- SE change in oral temperature at 4 hours after dosing was -0.97 degrees C +/- 0.11 degrees C, -1.19 degrees C +/- 0.09 degrees C, -1.20 degrees C +/- 0.11 degrees C, and 0.01 C +/- 0.17 C, respectively (P < .001 for active treatments versus placebo). Specific inhibition of COX-2 by rofecoxib results in antipyretic activity in monkeys and humans comparable to dual COX-1/COX-2 inhibitors such as diclofenac or ibuprofen. The data support the hypothesis that it is the COX-2 isoform that is primarily involved in the genesis of fever in humans.

Iloperidone (HP 873) is a D2 and 5-HT2 receptor-antagonist that is under development as a potential atypical antipsychotic agent. Two studies on iloperidone evaluated its safety and tolerability, made a preliminary pharmacokinetic assessment of single 3- and 5-mg doses, and determined the effect of food on its tolerability and pharmacokinetics in healthy volunteers after single 3-mg doses. Iloperidone was well absorbed orally in fasted subjects. The Cmax occurred approximately 2 to 3 hours after administration of a single 3- or 5-mg dose. The pharmacokinetic parameters increased with the dose between 3 and 5 mg (from 2.2 to 5.2 ng/mL for Cmax, and 16 to 50 ng/mL.h for AUC). Iloperidone was eliminated slowly, with a mean t1/2 of 13.5 to 14.0 hours. Coadministration with food did not significantly affect AUC, tmax, or Cmax. These results indicate that the rate of iloperidone's absorption is decreased, but the overall bioavailability is unchanged, when the drug is taken with food. Orthostatic hypotension, dizziness, and somnolence were the most commonly reported adverse events. Coadministration of food reduced the incidence and severity of these events.

Background: Lorcaserin is a modestly selective agonist for 2C serotonin receptors (5-HT 2C R) approved for weight-loss therapy. This class can attenuate cue-induced responding and drug taking in preclinical studies, but effects in humans have not been reported. Methods and Participants:We evaluated effects of single 10 mg doses of lorcaserin on the subjective and reinforcing effects of cocaine, using a randomized, double-blind, within-subject, cross-over design. Male, non-treatment-seeking, regular cocaine users received either single doses of oral placebo (n = 9) or lorcaserin (n = 9), followed by low-or high-doses of intravenous cocaine (0.23 or 0.46 mg/kg-injection). They were then allowed to self-administer the lower dose of cocaine.Results: Cocaine was well tolerated after lorcaserin pretreatment. Oral lorcaserin did not modify the number of cocaine injections self-administered. However, it prolonged the time over which participants made intravenous choices relative to the duration of monetary (cash) decisions. Lorcaserin increased ratings of 'high' and 'stimulated' after low-dose cocaine or vehicle, but decreased craving for cocaine after intravenous vehicle. It also caused small but significant increases in heart rate following noncontingent injections of intravenous placebo or cocaine. When

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