Duloxetine 60 mg/day for the prevention of depressive recurrences: post hoc analyses from a recurrence prevention study.

OBJECTIVE: To assess the efficacy of duloxetine 60 mg/day in the prevention of depressive recurrence in patients with major depressive disorder (MDD). METHODS: Patients having at least three episodes of MDD in the past 5 years received open-label (OL) duloxetine 60-120 mg/day for up to 34 weeks. Patients meeting response criteria were then randomised to either duloxetine or placebo for up to 52 weeks of double-blind maintenance treatment. Only patients taking duloxetine 60 mg/day during the OL phase, and randomised to either duloxetine (remained on 60 mg/day dose) or placebo, were included in this post hoc analysis. The primary outcome measure was time to recurrence of a major depressive episode. The 17-item Hamilton Rating Scale for Depression (HAMD(17)) was used to evaluate depressive symptomatology. Global and physical functioning and pain were also assessed. Safety and tolerability were assessed via analysis of treatment-emergent adverse events (TEAEs), vital signs and weight. RESULTS: A total of 124 patients were randomised to duloxetine 60 mg/day (n = 64) or placebo (n = 60). Time to depressive recurrence was significantly longer in duloxetine-treated patients compared with placebo-treated patients (p = 0.001). During the double-blind maintenance phase, 31.7% of placebo-treated patients experienced a depressive recurrence compared with 12.5% of duloxetine-treated patients (p = 0.004). The HAMD(17) total score and most of its subscales as well as the Clinical Global Impression of Severity (CGI-S), significantly worsened in the placebo group compared with the duloxetine 60 mg/day group. There were no significant differences between treatment groups in TEAEs, discontinuations because of adverse events, vital signs or weight. CONCLUSIONS: Treatment with duloxetine 60 mg/day was associated with a longer time to depressive recurrence and a significantly lower recurrence rate compared with placebo.

A non-inferiority comparison of duloxetine and venlafaxine in the treatment of adult patients with generalized anxiety disorder.

The present study is a non-inferiority comparison of duloxetine 60-120 mg/day and venlafaxine extended-release (XR) 75-225 mg/day for the treatment of adults with generalized anxiety disorder (GAD). The non-inferiority test was a prespecified plan to pool data from two nearly identical 10-week, multicentre, randomized, placebo-controlled, double-blind studies of duloxetine 60-120 mg/day and venlafaxine 75-225 mg/ day for the treatment of GAD. An independent expert consensus panel provided six statistical and clinical criteria for determining non-inferiority between treatments. Response was defined as > or =50% reduction in Hamilton Anxiety Rating Scale (HAMA) total score. In the pooled sample, patients were randomly assigned to duloxetine (n = 320), venlafaxine XR (n = 333) or placebo (n = 331). For the non-inferiority analysis, the per-protocol patients who were treated with duloxetine (n = 239) or venlafaxine XR (n = 262) improved significantly more (mean HAMA reductions were -15.4 and -15.2, respectively) than placebo-treated patients (n = 267; -11.6, P < or = 0.001, both comparisons). Response rates were 56%, 58% and 40%, respectively. Discontinuation rate because of AEs was significantly higher for duloxetine (13.4%, P < or = 0.001) and venlafaxine XR (11.4%, P < or = 0.01) groups compared with placebo (5.4%). Duloxetine 60-120 mg/day met all statistical and clinical criteria for non-inferiority and exhibited a similar tolerability profile compared with venlafaxine XR 75-225 mg/day for the treatment of adults with GAD.

The Effect of Conventional and Transparent Surgical Masks on Speech Understanding in Individuals with and without Hearing Loss.

BACKGROUND: It is generally well known that speech perception is often improved with integrated audiovisual input whether in quiet or in noise. In many health-care environments, however, conventional surgical masks block visual access to the mouth and obscure other potential facial cues. In addition, these environments can be noisy. Although these masks may not alter the acoustic properties, the presence of noise in addition to the lack of visual input can have a deleterious effect on speech understanding. A transparent ("see-through") surgical mask may help to overcome this issue. PURPOSE: To compare the effect of noise and various visual input conditions on speech understanding for listeners with normal hearing (NH) and hearing impairment using different surgical masks. RESEARCH DESIGN: Participants were assigned to one of three groups based on hearing sensitivity in this quasi-experimental, cross-sectional study. STUDY SAMPLE: A total of 31 adults participated in this study: one talker, ten listeners with NH, ten listeners with moderate sensorineural hearing loss, and ten listeners with severe-to-profound hearing loss. DATA COLLECTION AND ANALYSIS: Selected lists from the Connected Speech Test were digitally recorded with and without surgical masks and then presented to the listeners at 65 dB HL in five conditions against a background of four-talker babble (+10 dB SNR): without a mask (auditory only), without a mask (auditory and visual), with a transparent mask (auditory only), with a transparent mask (auditory and visual), and with a paper mask (auditory only). RESULTS: A significant difference was found in the spectral analyses of the speech stimuli with and without the masks; however, no more than ∼2 dB root mean square. Listeners with NH performed consistently well across all conditions. Both groups of listeners with hearing impairment benefitted from visual input from the transparent mask. The magnitude of improvement in speech perception in noise was greatest for the severe-to-profound group. CONCLUSIONS: Findings confirm improved speech perception performance in noise for listeners with hearing impairment when visual input is provided using a transparent surgical mask. Most importantly, the use of the transparent mask did not negatively affect speech perception performance in noise.

Estrogen receptor beta agonist LY500307 fails to improve symptoms in men with enlarged prostate secondary to benign prostatic hypertrophy.

BACKGROUND: To assess the efficacy and safety of LY500307, a selective estrogen receptor beta agonist, on lower urinary tract symptoms (LUTS) in patients with enlarged prostate secondary to BPH. METHODS: In a randomized, double-blind, placebo-controlled, parallel phase 2, efficacy and safety study, eligible patients with moderate to severe LUTS and prostatic enlargement (⩾30 ml) were randomized to placebo or LY500307 at 1, 3, 10 and 25 mg once daily for 24 weeks. Primary efficacy end point was change in total International Prostate Symptoms Score (IPSS) after 24 weeks. Secondary end points included changes in total prostate volume (TPV) that served as a proof of concept end point, as well as IPSS quality of life, maximum peak urine flow rate (Qmax) and PSA and safety (adverse events, laboratory test). RESULTS: A total of 414 patients were randomized when the study was terminated because of insufficient TPV reduction, based on a priori defined interim analysis. The IPSS mean change from baseline to end point was -3.4±6.8 in the placebo group and -1.3±6.6, -2.6±7.0, -3.7±6.7 and -4.4±5.7 in the 1, 3, 10 and 25 mg LY500307-treated groups, respectively (P>0.05). Similarly, no treatment effect was observed for any of the secondary efficacy measures. Incidence of adverse events was comparable between treatment groups, and no clinically meaningful changes in laboratory tests were observed. CONCLUSIONS: LY500307 was well tolerated in BPH patients with LUTS at doses up to 25 mg once daily for 24 weeks. The study was terminated early because of inadequate efficacy.

Improvement of psychic and somatic symptoms in adult patients with generalized anxiety disorder: examination from a duloxetine, venlafaxine extended-release and placebo-controlled trial.

BACKGROUND: This study examined the efficacy and tolerability of duloxetine and venlafaxine extended-release (XR) treatment for generalized anxiety disorder (GAD), with a secondary focus on psychic and somatic symptoms within GAD. METHOD: The design was a 10-week, multi-center, double-blind placebo-controlled study of duloxetine (20 mg or 60-120 mg once daily) and venlafaxine XR (75-225 mg once daily) treatment. Efficacy was measured using the Hamilton Anxiety Rating Scale (HAMA), which includes psychic and somatic factor scores. Tolerability was measured by occurrence of treatment-emergent adverse events (TEAEs) and discontinuation rates. RESULTS: Adult out-patients (mean age 42.8 years; 57.1% women) with DSM-IV-defined GAD were randomly assigned to placebo (n=170), duloxetine 20 mg (n=84), duloxetine 60-120 mg (n=158) or venlafaxine XR 75-225 mg (n=169) treatment. Each of the three active treatment groups had significantly greater improvements on HAMA total score from baseline to endpoint compared with placebo (p=0.01-0.001). For the HAMA psychic factor score, both duloxetine treatment arms and venlafaxine XR demonstrated significantly greater improvement compared with placebo (p=0.01-0.001). For the HAMA somatic factor score, the mean improvement in the duloxetine 60-120 mg and venlafaxine XR groups was significantly greater than placebo (p0.05 and p0.01 respectively), whose mean improvement did not differ from the duloxetine 20 mg group (p=0.07). Groups did not differ in study discontinuation rate due to adverse events. CONCLUSIONS: Duloxetine and venlafaxine treatment were each efficacious for improvement of core psychic anxiety symptoms and associated somatic symptoms for adults with GAD.

CHEMLEARN: microcomputer-based training for CHEMLINE, an alternative to formal classroom training.

CHEMLINE (CHEMical Dictionary OnLINE), the National Library of Medicine's online chemical dictionary file, is primarily used by librarians and information scientists to enhance the retrieval of bibliographic information associated with chemical substances. This paper will discuss CHEMLEARN, a microcomputer-based training program designed to provide inexpensive, easily accessible self-instruction as an alternative to formal classroom training in the use of CHEMLINE. CHEMLEARN allows novice users to learn at their own pace and with considerable program feedback. In addition, it provides the skilled searcher with a way to reinforce or recall previously learned search techniques without incurring online charges. CHEMLEARN may be used in place of formal training or as a precursor to or a refresher following formal training.

Acute hazards to young children from residential pesticide exposures.

OBJECTIVES: This study assessed acute hazards to young children from pesticides toxic enough to require child-resistant packaging. METHODS: The names of pesticides meeting acute toxicity criteria were ascertained from the Environmental Protection Agency. Poison Control Center reports identified children younger than 6 years who were exposed to these pesticides. Toxicity category, medical outcome, sex, and age were examined. RESULTS: A higher proportion of children with exposure to the more toxic products had serious medical outcomes. Children 2 years and younger were the predominant age group exposed. CONCLUSIONS: Protective measures--substituting less lethal pesticides, reducing the concentration of the active ingredients, and improving packaging and storage--are recommended.

MEDTUTOR: a microcomputer-based training program for MEDLINE.

MEDTUTOR is an interactive, microcomputer-based training package designed to teach medical and health professionals, as well as librarians and information specialists, how to use MEDLINE effectively. The objective of MEDTUTOR is to provide a comprehensive package for teaching the various commands and search techniques required for utilizing the MEDLINE database through the MEDLARS system. MEDTUTOR's menu-driven design allows novice users to learn about the content and use of MEDLINE, such as author searching, text word searching, MeSH indexing, etc., at their own pace and with considerable program feedback. In addition, MEDTUTOR provides the skilled searcher with a way to reinforce or recall previously-learned search techniques without incurring online charges. MEDTUTOR may be used in place of formal training, as a precursor to or as a refresher following formal training, or for review of a particular concept. It provides inexpensive and easily accessible instruction for searching MEDLINE.

Sequences of three closely related variants of a complex satellite DNA diverge at specific domains.

Major differences among the sequences of the repeat units of a very complex satellite DNA are located in domains which are sensitive to S1 nuclease under torsional stress, indicating that the domains assume unusual secondary or tertiary structures. Repeat units of the satellite, which accounts for 3% of the DNA of a land crab, have been inserted into pBR322 and the primary sequences of three cloned variants determined. The variants selected for sequencing include 1) RU (2089 base pairs (bp) ), representative of the average size of repeat units of cellular satellite; 2) TRU (1674 bp), truncated at an extra EcoRI site; and 3) EXT (2639 bp), extended by a 5-fold amplification of a 142-bp segment, one copy of which is present in RU and TRU (Bonnewell, V., Fowler, R.F., and Skinner, D.M. (1983) Science 221, 862-865). It appears that every copy of the satellite may be different and that the variants do not arise from cloning accidents. Extensive domains, as long as approximately 560 bp, are greater than 95% homologous among RU, TRU, and EXT; these conserved domains are composed of DNA whose base composition and sequences do not have remarkable features. By contrast, the sequences that comprise the divergent domains are unusually rich in 1) tracts of (dG X dC) 13-23 and arrangements of similar but not identical repetitive oligonucleotides or 2) alternating purines and pyrimidines (pu/py).

Agonist-selective endocytosis of mu opioid receptor by neurons in vivo.

Opiate alkaloids are potent analgesics that exert multiple pharmacological effects in the nervous system by activating G protein-coupled receptors. Receptor internalization upon stimulation may be important for desensitization and resensitization, which affect cellular responsiveness to ligands. Here, we investigated the agonist-induced internalization of the mu opioid receptor (MOR) in vivo by using the guinea pig ileum as a model system and immunohistochemistry with an affinity-purified antibody to the C terminus of rat MOR. Antibody specificity was confirmed by the positive staining of human embryonic kidney 293 cells transfected with epitope-tagged MOR cDNA, by the lack of staining of cells transfected with the delta or kappa receptor cDNA, and by the abolition of staining when the MOR antibody was preadsorbed with the MOR peptide fragment. Abundant MOR immunoreactivity (MOR-IR) was localized to the cell body, dendrites, and axonal processes of myenteric neurons. Immunostaining was primarily confined to the plasma membrane of cell bodies and processes. Within 15 min of an intraperitoneal injection of the opiate agonist etorphine, intense MOR-IR was present in vesicle-like structures, which were identified as endosomes by confocal microscopy. At 30 min, MOR-IR was throughout the cytoplasm and in perinuclear vesicles. MOR-IR was still internalized at 120 min. Agonist-induced endocytosis was completely inhibited by the opiate antagonist naloxone. Interestingly, morphine, a high-affinity MOR agonist, did not cause detectable internalization, but it partially inhibited the etorphine-induced MOR endocytosis. These results demonstrate the occurrence of agonist-selective MOR endocytosis in neurons naturally expressing this receptor in vivo and suggest the existence of different mechanisms regulating cellular responsiveness to ligands.