Concentration-time extrapolation of short-term inhalation exposure levels: dimethyl sulfide, a case study using a chemical-specific toxic load exponent.

OBJECTIVE: Dimethyl sulfide (DMS, CAS 75-18-3) is an industrial chemical. It is both an irritant and neurotoxicant that may be life-threatening because of accidental release. The effects of DMS on public health and associated public health response depend on the exposure concentration and duration. However, currently, public health advisory information exists for only a 1 h exposure duration, developed by the American Industrial Hygiene Association (AIHA). In the present work, the AIHA-reviewed data were computationally extrapolated to other common short-term durations. METHODS: The extrapolation was carried out using the toxic load equation, Cn × t = TL, where C and t are exposure concentration and duration, TL is toxic load, and n is a chemical-specific toxic load exponent derived in the present work using probit meta-analysis. The developed threshold levels were vetted against the AIHA database of clinical and animal health effects induced by DMS. RESULTS: Tier-1 levels were derived based on human exposures that resulted in an easily detectable odor, because DMS is known to have a disagreeable odor that may cause nausea. Tier-2 levels were derived from the lower 95% confidence bounds on a benchmark concentration that caused 10% incidence (BMCL10) of coma in rats during a 15 min inhalation exposure to DMS. Tier-3 levels were based on a BMCL05 for mortality in rats. CONCLUSION: Emergency responders and health assessors may consider these computationally derived threshold levels as a supplement to traditional chemical risk assessment procedures in instances where AIHA developed public health advisory levels do not exist.

Rationale and design of the PLACID study: a randomised trial comparing the efficacy and safety of inhaled loxapine versus IM aripiprazole in acutely agitated patients with schizophrenia or bipolar disorder.

BACKGROUND: The management of acute agitation manifesting in patients with schizophrenia or bipolar disorder requires swift pharmacological intervention to provide rapid symptomatic relief and prevent escalation to aggression and violence. Antipsychotic medications are widely used in this setting and the availability of an inhaled formulation with deep lung absorption of the antipsychotic loxapine has the potential to deliver a faster onset of therapeutic effect than the available intramuscular formulations of antipsychotics. METHODS: The efficacy of inhaled loxapine and the alternative antipsychotic aripiprazole delivered via intramuscular (IM) injection will be compared in the Phase IIIb PLACID study. Adults (18-65 years) with a confirmed diagnosis of schizophrenia or bipolar I disorder presenting with acute agitation will be randomly assigned to open-label treatment in a 1:1 ratio. Clinical evaluation will be conducted by raters blinded to treatment assignment. The primary efficacy endpoint is time to response (defined as a Clinical Global Impression of Improvement [CGI-I] score of 1 [very much improved] or 2 [much improved]). Secondary endpoints will include the percentage of responders at different time points after dosing; the proportion of patients who receive 1 or 2 doses of study drug; time to second dose; time to rescue medication; satisfaction with study drug (evaluated using Item 14 of the Treatment Satisfaction Questionnaire for Medication); and safety and tolerability. Approximately 360 patients will be recruited with an interim analysis conducted once 180 patients have completed the study to decide whether to stop for futility or continue with or without an increase in the sample size up to additional 288 patients. DISCUSSION: The PLACID trial will assess the efficacy and safety of inhaled loxapine with deep lung absorption compared with the IM antipsychotic, aripiprazole, in acutely agitated patients with schizophrenia or bipolar disorder. In the event that the median time to response of inhaled loxapine is significantly shorter than that of the intramuscular aripiprazole, the PLACID study has the potential to support the inhaled antipsychotic therapy as the standard of care in this setting. TRIAL REGISTRATION: The study protocol was registered with the European Clinical Trials Database on the 31 October 2014 (EudraCT number 2014-000456-29 ).

Measurement of Perceived Stress in Age-Related Macular Degeneration.

PURPOSE: To validate the Perceived Stress Scale (PSS) in patients with age-related macular degeneration (AMD) using Rasch analysis. METHODS: Study participants with AMD were recruited from the retina service of the Department of Ophthalmology at the Ohio State University during clinical visits for treatment or observation. Visual acuity with habitual distance correction was assessed. A 10-item version of the PSS was administered in large print or by reading the items to the patient. Rasch analysis was used to investigate the measurement properties of the PSS, including fit to the model, ability to separate between people with different levels of perceived stress, category response structure performance, and unidimensionality. RESULTS: A total of 137 patients with a diagnosis of AMD were enrolled. The mean (±SD) age of participants was 82 ± 9 years. Fifty-four percent were female. Median Early Treatment of Diabetic Retinopathy Study (ETDRS) visual acuity of the better eye was 65 letters (Snellen 20/50), with a range of approximately 20/800 to 20/15. Forty-seven percent of participants were receiving an anti-VEGF injection on the day of the study visit. The response category structure was appropriate. One item, "How often have you felt confident in your ability to handle your personal problems?" was removed due to poor fit statistics. The remaining nine items showed good fit to the model, acceptable measurement precision as assessed by the Rasch person separation statistic, and unidimensionality. There was some evidence of differential item functioning by age and visual acuity. CONCLUSIONS: The Perceived Stress Scale demonstrated acceptable measurement properties and may be useful for the measurement of perceived stress in patients with AMD.

Are women with a history of abuse more vulnerable to perinatal depressive symptoms? A systematic review.

The objective of this paper is to examine the association between maternal lifetime abuse and perinatal depressive symptoms. Papers included in this review were identified through electronic searches of the following databases: Pubmed Medline and Ovid, EMBASE, PsycINFO, and the Cochrane Library. Each database was searched from its start date through 1 September 2011. Keywords such as "postpartum," "perinatal," "prenatal," "depression," "violence," "child abuse," and "partner abuse" were included in the purview of MeSH terms. Studies that examined the association between maternal lifetime abuse and perinatal depression were included. A total of 545 studies were included in the initial screening. Forty-three articles met criteria for inclusion and were incorporated in this review. Quality of articles was evaluated with the Newcastle-Ottawa-Scale (NOS). This systematic review indicates a positive association between maternal lifetime abuse and depressive symptoms in the perinatal period.

Hazard Perception in Visually Impaired Drivers Who Use Bioptic Telescopes.

Purpose: Bioptic telescopic spectacles can allow individuals with central vision impairment to obtain or maintain driving privileges. The purpose of this study was to (1) compare hazard perception ability among bioptic drivers and traditionally licensed controls, (2) assess the impact of bioptic telescopic spectacles on hazard perception in drivers with vision impairment, and (3) analyze the relationships among vision and hazard detection in bioptic drivers. Methods: Visual acuity, contrast sensitivity, and visual field were measured for each participant. All drivers completed the Driving Habits Questionnaire. Hazard perception testing was conducted using commercially available first-person video driving clips. Subjects signaled when they could first identify a traffic hazard requiring a change of speed or direction. Bioptic drivers were tested with and without their bioptic telescopes in alternating blocks. Hazard detection times for each clip were converted to z-scores, converted back to seconds using the average response time across all videos, and then compared among conditions. Results: Twenty-one bioptic drivers and 21 normally sighted controls participated in the study. The hazard response time of bioptic drivers was improved when able to use the telescope (5.4 ± 1.4 seconds vs 6.3 ± 1.8 seconds without telescope); however, it remained significantly longer than for controls (4.0 ± 1.4 seconds). Poorer visual acuity, contrast sensitivity, and superior visual field sensitivity loss were related to longer hazard response times. Conclusions: Drivers with central vision loss had improved hazard response times with the use of bioptic telescopic spectacles, although their responses were still slower than normally sighted control drivers. Translational Relevance: The use of a bioptic telescope by licensed, visually impaired drivers improves their hazard detection speed on a video-based task, lending support to their use on the road.

Stereospecific Cu(I)-Catalyzed C-O Cross-Coupling Synthesis of Acyclic 1,2-Di- and Trisubstituted Vinylic Ethers from Alcohols and Vinylic Halides.

CuI and trans-N,N'-dimethylcyclohexyldiamine catalyze the single-step C-O bond cross-coupling between 1,2-di- and trisubstituted vinylic halides with functionalized alcohols, producing acyclic vinylic ethers. This stereospecific transformation selectively gives each of the (E)- and (Z)-vinylic ether products from the corresponding vinyl halide precursors. This method is compatible with carbohydrate-derived primary and secondary alcohols and several other functional groups. The conditions are mild enough to reliably generate vinylic allylic ethers without promoting Claisen rearrangements.

Use and Perceptions of Advanced Driver Assistance Systems by Older Drivers With and Without Age-Related Macular Degeneration.

Purpose: Advanced driver assistance systems (ADAS) have been reported to improve the safety of elderly and normally sighted drivers. The purpose of this study was to assess exposure to, perceived safety of, comfort level with, and interest in using ADAS among drivers with age-related macular degeneration (AMD). Methods: Current drivers aged 60+ years were recruited at four US sites to complete a survey about ADAS and driving habits. Frequency of use and/or perceptions of eight ADAS were investigated. An avoidance score was generated using questions about difficult driving situations. Results: The survey was completed by 166 participants (80 with AMD vs. 86 without). Participants with AMD had worse self-rated vision than those without (34% vs. 2% poor or fair rating), and drove fewer weekly miles (median [interquartile range [IQR] 30 [15 to 75] vs. 60 [30 to 121] miles, P = 0.002). Participants with AMD reported more avoidance of difficult driving situations (P < 0.001). There was no difference in the number of ADAS used by AMD status (median [IQR for AMD = 2.5 [1 to 5] vs. 3 [2 to 4] without, P = 0.87). Greater reported number of ADAS used was associated with less avoidance of difficult situations (P = 0.02). The majority perceived improved safety with most ADAS. Conclusions: Many drivers with AMD utilize common ADAS, which subjectively improve their road safety and may help to reduce self-imposed restrictions for difficult situations and mileage. Translational Relevance: Drivers with AMD are adopting readily available ADAS, for which they reported potential benefits, such as safety and less restrictive driving.

Codonopsis pilosula Polysaccharides Alleviate Aß 1-40-Induced PC12 Cells Energy Dysmetabolism via CD38/NAD+ Signaling Pathway.

BACKGROUND: Alzheimer's disease (AD) is the most common type of dementia and has a complex pathogenesis with no effective treatment. Energy metabolism disorders, as an early pathological event of AD,have attracted attention as a promising area of AD research. Codonopsis pilosula Polysaccharides are the main effective components of Codonopsis pilosula, which have been demonstrated to regulate energy metabolism. METHODS: In order to further study the roles and mechanisms of Codonopsis pilosula polysaccharides in AD, this study used an Aß1-40-induced PC12 cells model to study the protective effects of Codonopsis pilosula polysaccharides and their potential mechanisms in improving energy metabolism dysfunction. RESULTS: The results showed that Aß1-40 induced a decrease in PC12 cells viability, energy metabolism molecules (ATP, NAD+, and NAD+/NADH) and Mitochondrial Membrane Potential (MMP) and an increase in ROS. Additionally, it was found that Aß1-40 increased CD38 expression related to NAD+ homeostasis, whereas Silent Information Regulation 2 homolog1 (SIRT1, SIRT3), Peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) and SIRT3 activity were decreased. Codonopsis pilosula polysaccharides increased NAD+, NAD+/NADH, SIRT3, SIRT1, and PGC-1α related to NAD+, thus partially recovering ATP. CONCLUSION: Our findings reveal that Codonopsis pilosula polysaccharides protected PC12 cells from Aß1-40-induced damage, suggesting that these components of the Codonopsis pilosula herb may represent an early treatment option for AD patients.

Clinical and serotonergic predictors of non-affective acute remitting psychosis in patients with a first-episode psychosis.

OBJECTIVE: The study aimed to establish clinical predictors of non-affective acute remitting psychosis (NARP) and assess whether these patients showed a distinct serotonergic profile. METHOD: First-episode never treated psychotic patients diagnosed of paranoid schizophrenia (n=35; 21 men and 14 women) or NARP (n=28; 15 men and 13 women) were included. RESULTS: NARP patients showed significantly lower negative symptomatology, better premorbid adjustment, shorter duration of untreated psychosis, more depressive symptomatology and a lower number of 5-HT2A receptors than the paranoid schizophrenia patients. In the logistic regression, the four variables associated with the presence of NARP were: low number of 5-HT2A receptors; good premorbid adjustment; low score in the item 'hallucinatory behaviour' and reduced duration of untreated psychosis. CONCLUSION: Our findings support the view that NARP is a highly distinctive condition different from either affective psychosis or other non-affective psychosis such as schizophrenia, and highlight the need for its validation.

A naturalistic multicenter study of intramuscular olanzapine in the treatment of acutely agitated manic or schizophrenic patients.

BACKGROUND: We conducted a naturalistic, multicenter, 24-hour, nonrandomized, observational study describing for the first time the effectiveness and safety of intramuscular (IM) olanzapine to control agitation and aggression in "real world" patients with psychosis. The data thus obtained was compared with that reported from randomized double-blind clinical trials. METHOD: 92 patients attending psychiatric emergency settings were enrolled. The study subjects were 44 male and 48 female patients with a mean age of 36.5+/-12 years and DSM-IV-TR diagnoses of schizophrenia (48.9%), psychotic disorder not specified (23.9%) or bipolar disorder (27.2%). 10 mg IM olanzapine was administered to all patients. An optional second injection was permitted> or =2 hours later in line with hospital policy. Evaluations (PANSS-EC and CGI-S) were performed at baseline and 2 and 24 hours following the IM injection. RESULTS: Two hours after IM olanzapine was administered, a mean decrease of -9.6 in the PANSS-EC from a baseline score of 26.5 was recorded. At the 24-hour endpoint a statistically and clinically significant reduction in the PANSS-EC scores (11.6+/-5.3) was observed as compared with values at study entry (26.5+/-5.9) and at 2 hours endpoint (16.9+/-9.3), which represent a mean decrease of -14.9 and -5.3, respectively. CONCLUSION: The present naturalistic study provides naturalistic data on the effectiveness of IM olanzapine in the treatment of acute agitation in patients with schizophrenia or bipolar mania that is in line the data obtained in randomized double-blind clinical trials.

Pharmacological management of acutely agitated schizophrenic patients.

Agitation is commonly seen in acute schizophrenic patients and core symptoms include a wide range of symptom. It requires rapid and effective treatment approaches in order to protect patient and caregiver from potential injury. Clinician's decision of pharmacological treatment should be individualized to the needs and circumstances of the patient. Benzodiazepines, typical antipsychotics, and combinations of typical antipsychotics and benzodiazepines have been widely used as treatment options. Atypical antipsychotics have clear advantages over the typical drugs as they generally show a much better safety and tolerability profile, particularly to EPS and related side effects, however clinical perception regarding efficacy in treating acutely agitated psychotic patient is controversial. New intramuscular atypical antipsychotic formulations offer evidence of being at least as effective as typical antipsychotics in controlling agitation. Therefore, they should be considered as first line therapy in agitated schizophrenic patients.

Efficacy of clonidine and of methadone in the rapid detoxification of patients dependent on heroin.

The efficacy of a rapid detoxification schedule (8 to 10 days) with clonidine or methadone was evaluated in 30 patients addicted to heroin. The dose of study drug was preestablished according to the subject's weight and the amount of opioid consumption, and the total daily dose was reduced by approximately 15% during the study. All subjects completed the detoxification program and stayed in the hospital for at least 12 days. Clonidine and methadone therapies proved to be highly effective. There was a marked reduction in anxiety during opioid detoxification, although subjects' experiences differed according to the drug used. On the day of discharge, subjects who had received methadone still had attenuated withdrawal symptoms, whereas there were no such symptoms in the clonidine group. Muscular aching, flatulence, and daily drowsiness were more common among subjects in the methadone group, while subjects in the clonidine group had more sleep disturbances and weeping. Syncopal episodes and bradycardia occurred more frequently in the clonidine group.

Buprenorphine versus heroin dependence: comparison of toxicologic and psychopathologic characteristics.

Sociodemographic, toxicologic, and psychopathologic characteristics of 22 buprenorphine addicts and 45 heroin addicts admitted for inpatient detoxification were compared. Although the buprenorphine addicts were older, clinically significant differences were not apparent. The availability of buprenorphine may be the main reason for its abuse.

Double-blind, placebo-controlled comparison of intramuscular olanzapine and intramuscular haloperidol in the treatment of acute agitation in schizophrenia.

OBJECTIVE: The authors evaluated the comparative efficacy and safety of intramuscular olanzapine, intramuscular haloperidol, and intramuscular placebo for the treatment of acute agitation in schizophrenia. METHOD: Hospitalized patients with schizophrenia received one to three injections of intramuscular olanzapine, 10 mg, intramuscular haloperidol, 7.5 mg, or intramuscular placebo over a 24-hour period. Agitation was measured with the excited component of the Positive and Negative Syndrome Scale and two additional scales. RESULTS: According to scores on the excited component of the Positive and Negative Syndrome Scale, both intramuscular olanzapine and intramuscular haloperidol reduced agitation significantly more than intramuscular placebo 2 and 24 hours following the first injection. Intramuscular olanzapine reduced agitation significantly more than intramuscular haloperidol 15, 30, and 45 minutes following the first injection. No patients treated with intramuscular olanzapine experienced acute dystonia, compared with 7% of those who were treated with intramuscular haloperidol. No significant QT(c) interval changes were observed in any patients. CONCLUSIONS: Intramuscular olanzapine represents a rapid, effective, and safe treatment for acute agitation in schizophrenia.

Consumption of buprenorphine and other drugs among heroin addicts under ambulatory treatment: results from cross-sectional studies in 1988 and 1990.

We assessed the prevalence of consumption of buprenorphine and other drugs among heroin addicts under ambulatory treatment in two cross-sectional studies conducted in 1988 (188 subjects) and in 1990 (197 subjects). Patients were enrolled in one of three different programmes: methadone maintenance programme (MMP), antagonist maintenance programme (AMP) and drug-free programme (DFP). Information given by participants was compared with results of urine screening for drugs. Urine samples were tested using enzyme immunoassay for the detection of heroin, cocaine, dextropropoxyphene, cannabis and benzodiazepines, and radioimmunoassay for buprenorphine. Sixty-six percent of patients in 1988 and 71% of patients in 1990 reported having consumed buprenorphine at some time during their history of drug dependence (period prevalence) and 5.9% and 6.1%, respectively, tested positive to the drug (point prevalence). In over 70% of these patients consumption was by the intravenous route. Consumption of cannabis, cocaine and benzodiazepines was also very high in the study population. Overall, patients in the DFP group consumed the largest number of the drugs tested, while those in the AMP group consumed the smallest number. Abuse of buprenorphine could be more widespread than previously reported.

Use of the Nottingham Health Profile for measuring health status of patients in methadone maintenance treatment.

This study was conducted to assess changes in health-related quality of life over a 3-year follow-up period in a cohort of 135 opioid dependent patients using the Nottingham Health Profile (NHP) questionnaires. Data obtained at 12 months from 80 patients retained in the programme are presented. In summary, opioid addicts in a methadone maintenance programme for a 12-month period experienced an early and substantial improvement in health-related quality of life. The use of the NHP questionnaire to monitor changes in the subjective health of opioid-dependent patients over time provides new insights in the assessment of treatment effectiveness of methadone maintenance programmes.

Cocaine abuse among heroin addicts in Spain.

Abuse of cocaine is becoming a major problem among heroin addicts in Spain. Between 1987 and 1988, 75% of patients admitted as inpatients for detoxification from opiate dependence had consumed cocaine during the 6 months prior to admission and 25% had abused cocaine daily or several times/week. These cocaine abusers showed more toxicologic and psychopathologic problems than opiate addicts who did not abuse cocaine. The opiate addicts who also abused cocaine had begun using illicit drugs earlier and showed a higher frequency of anti-HIV antibodies. They also had more antisocial personality disorders and persistence of depressive symptoms during opiate detoxification than heroin addicts who did not abuse cocaine. Based on these findings, we insist on the need to develop different treatments for detoxifying patients with this dual addiction.

Flunitrazepam consumption among heroin addicts admitted for in-patient detoxification.

The use of benzodiazepines among 973 heroin addicts admitted for inpatient detoxification over a 10-year period was assessed in a cross-sectional study. A total of 780 (80.2%) patients had a history of benzodiazepine use; 666 (68.5%) were consuming benzodiazepines at the time of admission and 419 (43.1%) on an almost daily basis. Seventy-five (7.7%) patients fulfilled criteria for sedative-hypnotic abuse or dependence. Consumption of benzodiazepines began after subjects had become addicted to heroin. Flunitrazepam was ranked first by 68.4% of patients, followed by clorazepate (13%), and diazepam (12.4%). The prevalence of benzodiazepine use, in particular flunitrazepam, among heroin addicts is very high. Specific abuse liability studies are needed to determine whether pharmacologic reasons exist to explain heroin addicts' preference for this compound.

Plasma methadone concentrations as an indicator of opioid withdrawal symptoms and heroin use in a methadone maintenance program.

Plasma methadone concentrations and its main metabolite D,L-2-ethylidiene-1,5-dimethyl-3,5-diphenylpyrrolidine (EDDP) were determined in 93 patients under methadone maintenance treatment to assess their relationship with heroin use and opioid withdrawal symptoms. Neither plasma concentrations of methadone nor EDDP were significantly different when patients that used heroin in last 3 months were compared with those testing negative for this drug (methadone, 355 +/- 217 versus 369 +/- 216 ng/ml, t = 0.29, P = NS; EDDP, 49 +/- 28 versus 54 +/- 40 ng/ml, t = 0.51, P = NS). No correlation between opioid withdrawal scale scores and plasma concentrations of methadone (r = 0.02, P = NS) and EDDP (r = -0.14, P = NS) was found. Therapeutic drug monitoring during methadone maintenance seems to be useful for assessing compliance with treatment but not for predicting heroin use and subjective withdrawal symptoms.

A multicentre study to introduce naltrexone for opiate dependence in Spain.

A multicentre prospective study was performed in eight centres in Spain in order to assess the usefulness of naltrexone in the treatment of opiate dependents and abusers (113 dependents and 37 abusers) non-selected in terms of social class or professional skill. The fundamental criterion for evaluation of clinical outcome was the retention rate. At 6 months this parameter was 40%, i.e. higher than any previously reported for non-selected patients. The adverse effects were mild and did not lead to therapeutic failures. Non-pharmacological factors may have contributed to the good clinical results obtained.