Background and Purpose Nociceptin/orphanin FQ ( N / OFQ ) peptide ( NOP ) receptor antagonists have been proposed as a novel therapeutic approach to P arkinson's disease. Main limitations of previous studies were the use of structurally similar compounds and the evaluation of their acute effects only. We report here on the acute and long‐term antiparkinsonian effects of the novel compound 2‐[3‐[4‐(2‐chloro‐6‐fluoro‐phenyl)‐piperidin‐1‐ylmethyl]‐2‐(morpholine‐4‐carbonyl)‐indol‐1‐yl]‐acetamide ( NiK ‐21273) in comparison with the potent and selective NOP receptor antagonist SB ‐612111. Experimental Approach Basic pharmacological properties of NiK ‐21273 were studied in cell lines and isolated tissues (mouse and rat vas deferens). Antiparkinsonian effects were studied in reserpinized mice and 6‐hydroxydopamine hemilesioned rats under both acute and chronic administration protocols. Key Results In vitro , NiK ‐21273 behaved as a potent ( pA 2 7.7) and selective NOP receptor antagonist. In vivo , it reduced hypokinesia in reserpinized mice at 0.1 and 1 but not 10 mg·kg −1 , whereas SB ‐612111 (0.01–1 mg·kg −1 ) provided a dose‐dependent antiparkinsonian effect. NiK ‐21273 ameliorated motor performance in 6‐hydroxydopamine hemilesioned rats at 0.5 and 5 but not 15 mg·kg −1 . SB ‐612111 replicated these effects in the 0.01–1 mg·kg −1 range without loss of efficacy. Both antagonists synergized with L ‐ DOPA at subthreshold doses. Chronic administration of NiK ‐21273 provided delayed improvement in baseline activity at 0.5 and 1.5 mg·kg −1 , although tolerance to the higher dose was observed. Conversely, SB ‐612111 (1 mg·kg −1 ) maintained its effects over time without modifying baseline activity. Conclusions and Implications NOP receptor antagonists provide motor benefit in parkinsonism models although the ‘therapeutic’ window and long‐term effects may vary between compounds.

Syncope is a common disorder that can lead to serious consequences in the elderly. Tilt-test is a safe, useful specific tool to investigate recurrent syncope also in the elderly. Comorbidities and medication use, widely present in elderly patients, affecting the hemodynamic response, can influence the tilt-test outcome. The aim of this study was to evaluate the influence of these confounding factors on tilt-test results in elderly patients with recurrent syncope. We included in this study a consecutive group of 87 patients > 75 years (82.1 +/- 4.3 years) with unexplained syncope. They underwent passive upright tilt-test. Heart rate an blood pressure were recorded using non-invasive devices. The patients were classified according to the modified Vasovagal Syncope International Study (VASIS). Comorbidities were measured with the geriatric index of comorbidities (GIC), which is a composite score taking into account both the number of diseases and their severity as measured by Greenfield's IDS. The tilt-test was positive in 22 patients. There were no significant differences in clinical characteristics, and medication use between the tilt-test negative and positive patients, except for the GIC score (1.12 +/- 0.5 vs. 2.42 +/- 0.48; p = 0.001) and for a reduced number of medications in the former group (5.7 +/- 3.1 vs. 8.2 +/- 2.4; p = 0.001). This study suggests that comorbidities and the number of medications could influence tilt test outcome.

Today home health care (HHC) programs have been developed in numerous Western countries, in order to answer the questions regarding the care of frail elderly suffering from polypathologies and, therefore, being at high risk of disability. The HHC program of the Israelite Hospital of Rome has been planned as a complementary model, and not as a substitute of hospitalization, being able to offer flexible services, suitable for each elderly patient. The present study has established that taking care of old patients in their home allows us to prevent the deterioration of cognitive performance and functional impairments,as measured by the mini mental state examination (MMSE), the scales of activity of daily living (ADL), and the instrumental activity of daily living (IADL), respectively. We found considerable improvements also in the mood disorders during HHC, as measured by the geriatric depression scale (GDS). All psychometric tests were administered at the beginning of home care and after almost 1 year. Moreover, we formulated some questions regarding the quality of the offered services, and the answers revealed great satisfaction of both the patients and their caregivers.

(-)-cis-1-Methyl-7-[[4-(2,6-dichlorophenyl) piperidin-1-yl]methyl]- 6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (SB-612111) is a novel human opiate receptor-like orphan receptor (ORL-1) antagonist that has high affinity for the clonal human ORL-1 receptor (hORL-1 K-i=0.33 nM), selectivity versus mu-(174-fold), delta-(6391-fold), and kappa (486-fold)opioid receptors and is able to inhibit nociceptin signaling via hORL-1 in a whole cell gene reporter assay. SB-612111 has no measurable antinociceptive effects in vivo in the mouse hot-plate test after intravenous administration but is able to antagonize the antimorphine action of nociceptin [ED50=0.69 mg/kg, 95% confidence limit (CL)=0.34-1.21]. SB-62111 administration can also reverse tolerance to morphine in this model, established via repeated morphine administration. In addition, intravenous SB-612111 can antagonize nociceptin-induced thermal hyperalgesia in a dose-dependent manner (ED50=0.62 mg/kg i.v., 95% CL=0.22-1.89) and is effective per se at reversing thermal hyperalgesia in the rat carrageenan inflammatory pain model. These data show that an ORL-1 receptor antagonist may be a useful adjunct to chronic pain therapy with opioids and can be used to treat conditions in which thermal hyperalgesia is a significant component of the pain response.

Agitated behavior is very common among demented patients and it is one of the main causes of institutionalization of the patients, and of marked distress to families and caregivers. In order to evaluate the efficacy and tolerability of the selective serotonin reuptake inhibitor (SSRI) sertraline-hydrochloride versus small doses of haloperidol for treating agitated behaviors associated with dementia, we performed a randomized, double blind, flexible dose comparison study of sertraline (25-50 mg/day) versus small doses of haloperidol (1-2 mg/day) in 23 institutionalized demented patients (mean age 81.5 +/- 6.7 years) with agitation and behavioral disturbances, according to DSM-IV criteria. Data were collected at start and after 10 weeks of treatment by direct observation performed routinely by trained nurses. Agitation was evaluated by Cohen-Mansfield agitation inventory (CMAI) and the rating scale for extrapyramidal side effects. At start there was no difference in CMAI scores between the two groups of treatment. After taking moderate doses of sertraline and small doses of haloperidol, both groups showed significant improvement in the agitation behaviors (p < 0.05), without significant differences between haloperidol and sertraline groups, whereas significant differences were observed in the incidence of extrapyramidal symptoms. This study confirms the importance of the SSRIs in the treatment of non-cognitive symptoms associated with dementia, and, underlining the relative absence of side effects, suggests an adequate consideration of this drug before initiating a long trial of neuroleptics.

Zinc is an essential element in human biology and it is thought to be involved in several mechanisms of neuronal damage in dementia. The present study was aimed at investigating serum zinc levels in demented institutionalized elderly patients. Thirty patients of mean age 80.5 +/- 6.3 years, affected by dementia (MMSE < 15), as well as 10 age- and sex-matched home resident controls (MMSE > 20) were included. Exclusion criteria were: malignant neoplasms, acute inflammatory diseases, diabetes mellitus, thyroid disease and presence of possible causes of secondary dementia. All subjects underwent a complete biochemical, screening, including serum zinc levels, and geriatric assessment (MMSE, ADL, IADL). Statistical analysis was carried out by linear regression analysis and Mann-Whitney U test. Cognitive and self-sufficiency indicators were statistically different in the two groups (MMSE: 23.1 +/- 2.0 vs. 5.2 +/- 4.3; ADL: 1.9 +/- 2.3 vs. 6.0 +/- 0.0; IADL: 0.9 +/- 1.8 vs. 5.7 +/- 2.1; p < 0.0001 for all pairs). A significantly lower fasting serum zinc concentration was found in the demented patients, than in controls (67.5 +/- 18.5 and 83.2 +/- 10.4 mug/dl, respectively; p < 0.05). Serum zinc levels displayed a positive linear correlation with the MMSE scores (r = 0.630, p < 0.0001). These findings confirm the alteration of zinc metabolism in demented patients, emphasizing the possible role of this element in the pathogenesis of dementia.

In the last decade a number of selective and potent non-peptidic agents became available to explore the usefulness of the delta-opioid receptor in modulation of pain of different origins. As a continuing effort in this field, potent and selective delta-opioid agonists based on the pyrrolomorphinan framework have been designed, synthesised and characterised biologically in our laboratories. In animal models, a selected compound of interest, SB 235863, has proved the concept that selective delta-opioid agonists may have great potential as pain relief agents in inflammatory and neuropathic pain conditions. Importantly, such a compound was free of the unwanted side effects usually associated with narcotic analgesics such as morphine.

There is a large body of evidence that depression is one of the major clinical problems in the elderly. As matter of fact, several studies have addressed their attention on mood disorders in aged subjects, suggesting different etio-pathogenetic factors. Recently growing interest has been concentrated on the role of immunological alterations related to de-pression showing contradictory data. The aim of this study was to evaluate the correlation between depression and alterations of the cytokine network in aged patients. We included 45 elderly subjects (mean age 80.1 + 12.4 years). All subjects underwent a wide bio-chemical assessment, as well as psychological (mini mental state examination: MMSE; geriatric depression scale: GDS) and self-sufficiency (activity of daily living: ADL; instru-mental activity daily living: IADL) examinations. Student's t-test and linear regression analysis were carried out for statistical evaluation. According to international criteria, we defined depressed all subjects with GDS score > 11. (n = 22). They showed higher values of tumor necrosis factor-alpha (TNF-alpha) (47.4 +/- 11.6 vs 8.7 +/- 4.0 pg/ml; p < 0.0001), and lower values of serum iron concentrations (48.3 +/- 12.2 vs 92.5 +/- 16.6 mg/dl; p < 0.0001), than the controls. No significant differences were found in the MMSE scores and serum cholesterol levels of the two groups. Moreover, the depressed subjects were further divided in 2 subgroups, on the basis of their nutritional status: 14 subjects were affected by protein-energy malnutrition (PEM), and 8 of them were well nourished subjects. PEM subjects had higher TNF-alpha, C-reactive protein (CRP) and GDS score, and lower serum iron levels than the well nourished group (p < 0.001). Therefore, our data suggest that depression is closely related to alterations of the cytokine network, particularly in subjects affected by homeostatic balance failure syndrome. Nevertheless, further studies are necessary to establish both the strength and the etio-pathogenetic meaning of this correlation.

INTRODUCTION: The aim of the present study was to evaluate the possible correlation between urinary albumin excretion (UAE), marker of endothelial dysfunction, and C-reactive protein (CRP), marker of chronic in ̄ammation of the arterial wall, in overweight and obese premenopausal women. METHODS: CRP levels and UAE rate were measured in 103 overweight (BMI 25.0 ± 29.9 Kg=m) and obese (BMI 30.0 Kg=m) premenopausal women, aged 18 ± 45 years. Other measurements included central fat accumulation, as evaluated by waist circumference, insulin resistance, as calculated by homeostasis model assessment (HOMAIR), systolic and diastolic blood pressure, and fasting plasma levels of glucose, insulin, and lipids. RESULTS: UAE was positively correlated with BMI (P< 0.01), waist circumference (P< 0.00l), diastolic blood pressure (P<0.01), triglyceride (P< 0.01), HOMAIR (P< 0.05), and CRP levels (P< 0.05), and negatively associated with HDL-cholesterol (P<0.001). After multivariate analysis, diastolic blood pressure, HDL-cholesterol, and CRP levels maintained their signi®cant correlation with UAE (P< 0.05, P< 0.01, and P< 0.01, respectively). Lastly, we observed a gradual increase in CRP plasma levels across the quartiles in which the whole population was divided according to UAE levels (F: 5.67, Pˆ0.001 for linear trend). CONCLUSION: Our study shows a strong relationship between UAE rate and CRP concentrations, irrespective of age and other anthropometric and metabolic variables. On this basis, it can be argued that in ̄ammation of the arterial wall, as indicated by higher CRP plasma levels, and endothelial dysfunction, as shown by higher UAE rate, might represent simultaneous phenomena in the development of atherosclerosis in overweight and obese premenopausal women.

Several non-peptidic opioids have been synthesized recently as part of a program to develop selective δ receptor agonists. In this study, the affinities of a set of compounds for cloned δ and μ opioid receptors expressed in HEK 293 cell lines were determined by competition analysis of [3H]bremazocine binding to membrane preparations. All compounds studied exhibited high affinity and selectivity, with apparent dissociation constants in the range of 0.6–1.7 nM for the δ opioid receptor and 240–1165 nM for the μ opioid receptor. We next sought to determine which domain of the δ receptor was critical for mediating the highly selective binding by analysis of ligand affinities for μ/δ receptor chimeras. Receptor binding profiles suggested that a critical site of receptor/ligand interaction was located between transmembrane domain 5 (TM5) and TM7 of the δ receptor. Substitution of tryptophan 284, located at the extracellular surface of TM6, with lysine, which is found at the equivalent position in the μ opioid receptor, led to a spectrum of effects on affinities, depending on the ligand tested. Affinities of SB 219825 and SB 222941 were particularly sensitive to the substitution, displaying a 50-fold and 70-fold decrease in affinity, respectively. Activities of the δ receptor-selective agonists were tested in two functional assays. Brief exposure of HEK 293 cells expressing δ opioid receptors with selective ligands induced phosphorylation of MAP kinase, although the non-peptidic ligands were less efficacious than the enkephalin derivative DADL (Tyr-d-Ala-Gly-Phe-d-Leu). Similarly, chronic exposure of HEK 293 cells expressing δ opioid receptors with selective, non-peptidic ligands, with the exception of SB 206848, caused receptor down-regulation, however, the SB compounds were less efficacious than DADL.

A continuing effort in the development of non-peptide delta opioid agonists and antagonists has been seen in the last two years. The first non-peptide delta opioid antagonist naltrindole has represented for years the starting point for the design of novel potent and selective delta opioid ligands. Several research groups are still working on the framework of this prototype and have produced a large number of new derivatives with different in vitro and in vivo pharmacological activities. The discovery of TAN-67, BW373U86 and SNC 80 stimulated other lines of research aimed at synthesising analogues with better delta opioid agonist profile and suitable in vivo activity. Chemically unrelated compounds have also been disclosed deriving from the structural comparison of previously identified ligands. These studies have given further insights about the key determinants for the selective interaction with the delta opioid receptor (DOR). The availability of these tool compounds has allowed significant progression in the understanding of the pharmacology associated with the DOR. In addition to the possible use of selective delta opioid agonists as safe and effective pain relief agents, other interesting activities of possible clinical interest have been disclosed e.g., antiviral, cardioprotective and diuretic activity. Furthermore, many scientific reports confirmed the interesting pharmacological activities associated to the selective blockade of the DOR with antagonists e.g., immunosuppression and prevention of substance abuse. This review will focus on the above research activities, highlighting the most relevant literature and patent reports of the last two years. The medicinal chemistry and the competitive scenario related to non-peptide delta opioid ligands will be considered. Emphasis on the therapeutic potential of selective delta opioid ligands will also be discussed throughout the present review.