Insufficient efficacy and͞or specificity of antisense oligonucleotides limit their in vivo usefulness. We demonstrate here that a highaffinity DNA analog, locked nucleic acid (LNA), confers several desired properties to antisense agents. Unlike DNA, LNA͞DNA copolymers were not degraded readily in blood serum and cell extracts. However, like DNA, the LNA͞DNA copolymers were capable of activating RNase H, an important antisense mechanism of action. In contrast to phosphorothioate-containing oligonucleotides, isosequential LNA analogs did not cause detectable toxic reactions in rat brain. LNA͞DNA copolymers exhibited potent antisense activity on assay systems as disparate as a G-protein-coupled receptor in living rat brain and an Escherichia coli reporter gene. LNA-containing oligonucleotides will likely be useful for many antisense applications.A ntisense oligonucleotides designed according to straightforward base-pairing rules have been useful in functional genomics efforts, and there also has been recent clinical progress in developing antisense drugs (1-5). The key objective in the field, however, remains the identification of oligonucleotide analogs that provide the possibility to achieve high in vivo efficacy in the absence of significant toxicity (1-3).To date, all human antisense studies, as well as the vast majority of studies on other species, have relied on the use of phosphorothioate DNA analogs (where one nonbridging phosphate oxygen has been replaced). Although phosphorothioates are markedly more resistant to degrading enzymes than DNA, their DNA-binding capacity (relating to potency when used as antisense agents) is low, and they are well known to cause nonspecific protein binding, largely because of their polyanionic nature. The latter phenomenon contributes to a toxicity profile that limits many applications (6, 7). For example, when injected into the brain, phosphorothioates can cause severe tissue damage, especially with repeated or prolonged administration schedules (7,8). Such phosphorothioate-induced toxic reactions are thought to be reduced but not absent in second-generation antisense agents, like mixed backbone oligonucleotides (containing phosphorothioates in combination with oligodeoxyribonucleotides or oligoribonucleotides) (9).Interestingly, conformational restriction has been successfully applied in recent years to the design of high-affinity oligonucleotides. Several analogs containing bi-and tricyclic carbohydrate moieties have displayed enhanced duplex stability (10-20) and most notably so locked nucleic acids (LNA) (Fig. 1). LNA induces unprecedented increases in the thermal stability (melting temperature, T m ) of duplexes toward complementary DNA and RNA (⌬T m ͞LNA monomer ϭ ϩ 3 to ϩ 11°C compared with the corresponding DNA reference). By virtue of their bicyclic structure, the furanose ring of the LNA monomers is locked in a 3Ј-endo conformation, thus structurally mimicking the standard RNA monomers. Moreover, LNA͞LNA duplex formation has been shown to constitute the most stable...

ObjectiveTo investigate whether psychotropics are associated with an increased risk of fall injuries, hospitalizations, and mortality in a large general population of older adults.MethodsWe performed a nationwide matched (age, sex, and case event day) case–control study between 1 January and 31 December 2011 based on several Swedish registers (n = 1,288,875 persons aged ≥65 years). We used multivariate conditional logistic regression adjusted for education, number of inpatient days, Charlson co‐morbidity index, dementia and number of other drugs.ResultsAntidepressants were the psychotropic most strongly related to fall injuries (ORadjusted: 1.42; 95% CI: 1.38–1.45) and antipsychotics to hospitalizations (ORadjusted: 1.22; 95% CI: 1.19–1.24) and death (ORadjusted: 2.10; 95% CI: 2.02–2.17). Number of psychotropics was associated with increased the risk of fall injuries, (4 psychotropics vs 0: ORadjusted: 1.53; 95% CI: 1.39–1.68), hospitalization (4 psychotropics vs 0: ORadjusted: 1.27; 95% CI: 1.22–1.33) and death (4 psychotropics vs 0: ORadjusted: 2.50; 95% CI: 2.33–2.69) in a dose–response manner. Among persons with dementia (n = 58,984), a dose–response relationship was found between number of psychotropics and mortality risk (4 psychotropics vs 0: ORadjusted: 1.99; 95% CI: 1.76–2.25).ConclusionsOur findings support a cautious prescribing of multiple psychotropic drugs to older patients. © 2016 The Authors. International Journal of Geriatric Psychiatry Published by John Wiley & Sons, Ltd.

In a recent study, utilizing single cell recording techniques, we have shown that administration of 5-HT1A receptor antagonists, e.g. (S)-UH-301, to rats concomitantly treated, acute or chronically, with the selective serotonin reuptake inhibitor (SSRI) citalopram significantly increases the activity of 5-hydroxytryptamine (5-HT) containing neurons in the dorsal raphe nucleus (DRN). Here we report correlative experiments using microdialysis in freely moving animals to measure extracellular levels of 5-HT and its metabolite 5-hydroxyindole acetic acid (5-HIAA) in the frontal cortex, a major projection area for DRN-5-HT neurons. Acute administration of (S)-UH-301 (2.5 mg/kg s.c.) or citalopram (2.0 mg/kg s.c.) increased 5-HT concentrations with a maximum of about 70% and 185%, respectively, above baseline. However, when (S)-UH-301 was administered 30 min before citalopram the maximal increase in 5-HT levels was approximately 400%. In rats chronically treated with citalopram (20 mg/kg/day i.p. for 14 days) basal 5-HT concentrations in the frontal cortex were significantly increased and 5-HIAA concentrations were decreased when measured 10-12 h, but not 18-20 h, after the last injection of citalopram, as compared to basal 5-HT and 5-HIAA concentrations in chronic saline-treated rats. When (S)-UH-301 (2.5 mg/kg s.c.) was administered 12 h, but not 20 h, after the last dose of citalopram it produced a significantly larger increase in extracellular concentrations of 5-HT than in control rats. However, in rats pretreated with a single, very high dose of citalopram, 20 mg/kg i.p., administration of (S)-UH-301 at 12 h after citalopram did not increase 5-HT levels. The augmentation by (S)-UH-301 of the increase in brain 5-HT output produced by acute administration of citalopram is probably due to antagonism of the citalopram induced feedback inhibition of 5-HT cells in the DRN, as previously suggested. However, the capacity of (S)-UH-301 to further increase the already elevated extracellular concentrations of 5-HT in brain in animals maintained on a chronic citalopram regimen, in which significant tolerance to the initial feedback inhibition of DRN-5-HT cells and developed, represents a novel finding. Generally, the reduced feedback inhibition of 5-HT neurons obtained with chronic citalopram treatment, and the associated elevation of brain 5-HT concentrations, may be related to functional desensitization of somatodendritic 5-HT1A autoreceptors in the DRN. This phenomenon may also largely explain the larger increase in 5-HT output produced by (S)-UH-301 in chronic citalopram treated animals as compared to its effect in control animals. Yet, a contributory factor may be a slight, remaining feedback inhibition of the 5-HT cells caused by residual citalopram at 12, but not 20 h after its last administration. Previous clinical studies suggest that addition of a 5-HT1A receptor antagonist to an SSRI in the treatment of depression may accelerate the onset of clinical effects. Moreover, in therapy-resistant cases maintained on SSRI...

Ah.vtrtrc/: 'The present study was designed to examine I ) functional interactions bctween 5-€IT,, and 5-HTzAic receptors in thcrmoregulation in rats and 2) the specific involvcmenl of 5-HT2, and 5-HT2c receptors in such interactions. The S-H l ' z~, c receptor agonist DO1 (0.025 1.6 mg kg-', subcutaneously) produccd a dose-dependent hyperthermia in rats, which was enhanced by addition of either of two 5-HTIA receptor antagonists, (-)-pindolo1 (0.5-1.0 mg kg ', suhcutaneously) or WAY-100,635 (0.1-0.4 mg kg-.', subcutaneously). Furthermore, the DOI-induced hyperthermia was counteracted by pretreatment with the 5-HTlA receptor agonist 8-OH-DPAT (0.05 mg kg I, subcutaneously). The hyperthermia produced by DOT, alone or in combination with WAY-100,635, was fully antagonized by pretreatment with the S-HTZA/(. receptor antagonist ritanserin ( I .0 mg kg-I, subcutaneously), as well as with the selective S -H T~A receptor antagonist amperozide (2.0 mg k g~ ', subcutaneously). The present results provide evidence for functional interactions between 5-HTIA and S-HT,, rcceptors in temperature regulation in rats, and also suggest an important role for postsynaptic 5-HTLA receptors in the mediation of DOI-induced hyperthermia.

AIMThe aim of the study was to examine mortality risk associated with use of antidepressants and antipsychotics classified with torsades de pointes (TdP) risk in elderly. METHODSA matched case-control register study was conducted in people 65 years and older dying outside hospital from 2008-2013 (n = 286 092) and matched controls (n = 1 430 460). The association between prescription of antidepressants and antipsychotics with various TdP risk according to CredibleMeds (www.crediblemeds.org) and all-cause mortality was studied by multivariate conditional logistic regression adjusted for comorbidity and several other confounders. RESULTSUse of antidepressants classified with known or possible TdP risk, was associated with higher adjusted risk for mortality (OR 1.53, 95% CI 1.51, 1.56 and OR 1.63, 95% CI 1.61, 1.67, respectively) compared with antidepressants classified with conditional TdP risk (OR 1.25, 95% CI 1.22, 1.28) or without TdP classification (OR 0.99, 95% CI 0.94, 1.05). Antipsychotics classified with known TdP risk were associated with higher risk (OR 4.57, 95% CI 4.37, 4.78) than antipsychotics with possible risk (OR 2.58, 95% CI 2.52, 2.64) or without TdP classification (OR 2.14, 95% CI 2.03, 2.65). The following risk ranking was observed for commonly used antidepressants: mirtazapine > citalopram > sertraline > amitriptyline and for antipsychotics: haloperidol > risperidone >olanzapine > quetiapine. CONCLUSIONThe CredibleMeds system predicted drug-associated risk for mortality in the elderly at the risk class level. Among antipsychotics, haloperidol, and among antidepressants, mirtazapine and citalopram, were associated with the highest risks. The results suggest that the TdP risk with

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