Pharmacokinetic-pharmacodynamic modelling of QT interval prolongation following citalopram overdoses

Aims To develop a pharmacokinetic-pharmacodynamic model describing the time-course of QT interval prolongation after citalopram overdose and to evaluate the effect of charcoal on the relative risk of developing abnormal QT and heart-rate combinations. Methods Plasma concentrations and electrocardiograph (ECG) data from 52 patients after 62 citalopram overdose events were analysed in WinBUGS using a Bayesian approach. The reported doses ranged from 20 to 1700 mg and on 17 of the events a single dose of activated charcoal was administered. The developed pharmacokinetic-pharmacodynamic model was used for predicting the probability of having abnormal combinations of QT-RR, which was assumed to be related to an increased risk for torsade de pointes (TdP). Results The absolute QT interval was related to the observed heart rate with an estimated individual heart-rate correction factor [alpha = 0.36, between-subject coefficient of variation (CV) = 29%]. The heart-rate corrected QT interval was linearly dependent on the predicted citalopram concentration (slope = 40 ms l mg(-1), between-subject CV = 70%) in a hypothetical effect-compartment (half-life of effect-delay = 1.4 h). The heart-rate corrected QT was predicted to be higher in women than in men and to increase with age. Administration of activated charcoal resulted in a pronounced reduction of the QT prolongation and was shown to reduce the risk of having abnormal combinations of QT-RR by approximately 60% for citalopram doses above 600 mg. Conclusion Citalopram caused a delayed lengthening of the QT interval. Administration of activated charcoal was shown to reduce the risk that the QT interval exceeds a previously defined threshold and therefore is expected to reduce the risk of TdP.

Acute alcohol consumption and mechanism of injury

Objective: The purpose of this study was to determine whether injury mechanism among injured patients is differentially distributed as a function of acute alcohol consumption (quantity, type, and drinking setting). Method: A cross-sectional study was conducted between October 2000 and October 2001 in the Gold Coast Hospital Emergency Department, Queensland, Australia. Data were collected quarterly over a 12-month period. Every injured patient who presented to the emergency department during the study period for treatment of an injury sustained less than 24 hours prior to presentation was approached for interview. The final sample comprised 593 injured patients (males = 377). Three measures of alcohol consumption in the 6 hours prior to injury were obtained from self-report: quantity, beverage type, and drinking setting. The main outcome measure was mechanism of injury which was categorized into six groups: road traffic crash (RTC), being hit by or against something, fall, cut/piercing, overdose/poisoning, and miscellaneous. Injury intent was also measured (intentional vs unintentional). Results: After controlling for relevant confounding variables, neither quantity nor type of alcohol was significantly associated with injury mechanism. However, drinking setting (i.e., licensed premise) was significantly associated with increased odds of sustaining an intentional versus unintentional injury (odds ratio [OR] = 2.79, 95% confidence interval [CI] = 1.4-5.6); injury through being hit by/against something versus other injury types (OR = 2.59, 95% CI = 1.4-4.9); and reduced odds of sustaining an injury through RTC versus non-RTC (OR = 0.02, 95% CI = 0.004-0.9), compared with not drinking alcohol prior to injury. Conclusions: No previous analytical studies have examined the relationship between injury mechanism and acute alcohol consumption (quantity, type, and setting) across all types of injury and all injury severities while controlling for potentially important confounders (demographic and situational confounders, risk-taking behavior, substance use, and usual drinking patterns). These data suggest that among injured patients, mechanism of injury is not differentially distributed as a function of quantity or type of acute alcohol consumption but may be differentially distributed as a function of drinking setting (i.e., RTC, intentional injury, being hit). Therefore, prevention strategies that focus primarily on the quantity and type of alcohol consumed should be directed generically across injury mechanisms and not limited to particular cause of injury campaigns.

Chronic obstructive pulmonary disease: current burden and future projections

Information about the comparative magnitude of the burden from various diseases and injuries is a critical input into building the evidence base for health policies and programmes. Such information should be based on a critical evaluation of all available epidemiological data using standard and comparable procedures across diseases and injuries, including information on the age at death and the incidence, duration and severity of cases who do not die prematurely from the disease. A summary measure, disability-adjusted life yrs (DALYs), has been developed to simultaneously measure the amount of disease burden due to premature mortality and the amount due to the nonfatal consequences of disease.

Trends in morphine prescriptions, illicit morphine use and associated harms among regular injecting drug users in Australia

This paper examines population trends in morphine prescriptions in Australia, and contrasts them with findings from annual surveys with regular injecting drug users (IDU). Data on morphine prescriptions from 1995 to 2003 were obtained from the Drug Monitoring System (DRUMS) run by the Australian Government Department of Health and Ageing. Data collected from regular IDU as part of the Australian Illicit Drug Reporting System (IDRS) were analysed (2001-2004). The rate of morphine prescription per person aged 15-54 years increased by 89% across Australia between 1995 and 2003 (from 46.3 to 85.9 mg per person). Almost half (46%) of IDU surveyed in 2004 reported illicit morphine use, with the highest rates in jurisdictions where heroin was less available. Recent morphine injectors were significantly more likely to be male, unemployed, out of treatment and homeless in comparison to IDU who had not injected morphine. They were also more likely to have injected other pharmaceutical drugs and to report injection related problems. Among those who had injected morphine recently, the most commonly reported injecting harms were morphine dependence (38%), difficulty finding veins into which to inject (36%) and scarring or bruising (27%). Morphine use and injection is a common practice among regular IDU in Australia. In some cases, morphine may be a substitute for illicit heroin; in others, it may be being used to treat heroin dependence where other pharmacotherapies, such as methadone and buprenorphine, are perceived as being unavailable or undesirable by IDU. Morphine injection appears to be associated with polydrug use, and with it, a range of problems related to drug injection. Further research is required to monitor and reduce morphine diversion and related harms by such polydrug injectors.

Psychotropic medication utilization in a child and adolescent mental health service

Objectives: This study aimed to identify rates and correlates of psychotropic drug utilization in children and adolescents in inpatient and outpatient settings. Methods: A retrospective chart review examined 122 inpatient and 126 outpatient charts from a metropolitan child and youth mental health service in Brisbane, Australia. Results: Inpatients received more psychotropic medication than outpatients (71% vs. 25%; p < 0.01). Patients receiving medication were older, had longer hospital admissions, and more complex presentations, including history of abuse or suicide attempts and more diagnoses (all p < 0.01). Selective serotonin reuptake inhibitors (SSRIs) were the most frequently used drug class (44% inpatients; 14% outpatients), primarily indicated for mood disorders (31%). SSRIs and newer antidepressants (ADs) were used more frequently in patients with a high suicide risk (p < 0.01). Atypical antipsychotics (APs) were also used (inpatients 23%; outpatients 3%), primarily for behavioral disturbances. Half of those receiving medication (51%) received polypharmacy (> 1 concurrent drug), with up to four drugs used at one time. Rates of polypharmacy were highest among patients receiving antipsychotics. Conclusions: Use of psychotropic medication is frequent in this population. Future research should initially focus on inpatients and intensive treatment settings and examine both safety and efficacy of interventions for depression in young people, atypical antipsychotics for behavioral disturbances, and polypharmacy.

Restriction of intramuscular neurite branching and extension is lost in agrin and rapsyn-deficient mice

The phrenic nerve enters the diaphragm at approximately embryonic day 12.5 (E12.5) in the mouse. The secondary nerve trunk advances along the centre of the diaphragm muscle and extends tertiary branches primarily towards the lateral side during normal embryonic development. In the present study we quantified the intramuscular neurite branching in the most ventral region of the diaphragm at E15.5 and E18.5 in wild-type mice, agrin knock-out mice (KOAG) and rapsyn knock-out mice (KORAP). KOAG and KORAP have decreased muscle contraction due to their inability to maintain/form acetylcholine receptor (AChR) clusters during embryonic development. Heterozygote mothers were anaesthetised via an overdose of Nembutal (30 mg; Boeringer Ingelheim, Ridgefield, CT, USA) and killed via cervical dislocation. There were increases in the number of branches exiting the medial side of the phrenic nerve trunk in KOAG and KORAP compared to wild-type mice, but not on the lateral side at E15.5 and E18.5. However, the number of bifurcations in the periphery significantly increased on both the medial and lateral sides of the diaphragm at E15.5 and E18.5 in KOAG and KORAP compared to control mice. Furthermore, neurites extended further on both the medial and lateral sides of the diaphragm at E15.5 and E18.5 in KOAG and KORAP compared to wild-type mice. Together these results show that the restriction of neurite extension and bifurcations from the secondary nerve trunk is lost in both KOAG and KORAP allowing us the opportunity to investigate the factors that restrict motoneuron behaviour in mammalian muscles.

Alogliptin after acute coronary syndrome in patients with type 2 diabetes

Background - To assess potentially elevated cardiovascular risk related to new antihyperglycemic drugs in patients with type 2 diabetes, regulatory agencies require a comprehensive evaluation of the cardiovascular safety profile of new antidiabetic therapies. We assessed cardiovascular outcomes with alogliptin, a new inhibitor of dipeptidyl peptidase 4 (DPP-4), as compared with placebo in patients with type 2 diabetes who had had a recent acute coronary syndrome. Methods - We randomly assigned patients with type 2 diabetes and either an acute myocardial infarction or unstable angina requiring hospitalization within the previous 15 to 90 days to receive alogliptin or placebo in addition to existing antihyperglycemic and cardiovascular drug therapy. The study design was a double-blind, noninferiority trial with a prespecified noninferiority margin of 1.3 for the hazard ratio for the primary end point of a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Results - A total of 5380 patients underwent randomization and were followed for up to 40 months (median, 18 months). A primary end-point event occurred in 305 patients assigned to alogliptin (11.3%) and in 316 patients assigned to placebo (11.8%) (hazard ratio, 0.96; upper boundary of the one-sided repeated confidence interval, 1.16; P<0.001 for noninferiority). Glycated hemoglobin levels were significantly lower with alogliptin than with placebo (mean difference, -0.36 percentage points; P<0.001). Incidences of hypoglycemia, cancer, pancreatitis, and initiation of dialysis were similar with alogliptin and placebo. Conclusions - Among patients with type 2 diabetes who had had a recent acute coronary syndrome, the rates of major adverse cardiovascular events were not increased with the DPP-4 inhibitor alogliptin as compared with placebo. (Funded by Takeda Development Center Americas; EXAMINE ClinicalTrials.gov number, NCT00968708.)

Lack of effect of aspirin in primary CV prevention in type 2 diabetic patients with nephropathy:results from 8 years follow-up of NID-2 study

The risk-to-benefit ratio for the use of low dose of aspirin in primary cardiovascular (CV) prevention in patients with diabetes mellitus remains to be clarified. We assessed the effect of aspirin on risk of CV events in type 2 diabetic patients with nephropathy, in order to verify the usefulness of Guidelines in clinical practice. We carried out a prospective multicentric study in 564 patients with type 2 diabetic nephropathy free of CV disease attending outpatient diabetes clinics. A total of 242 patients received antiplatelet treatment with aspirin 100 mg/day (group A), and 322 were not treated with antiplatelet drugs (group B). Primary end point was the occurrence of total major adverse cardio-vascular events (MACE). Secondary end points were the relative occurrence of fatal MACE. The average follow-up was 8 years. Total MACE occurred in 49 patients from group A and in 52 patients from group B. Fatal MACE occurred in 22 patients from group A and in 20 from group B; nonfatal MACE occurred in 27 patients from group A and in 32 patients from group B. Kaplan-Meier analysis did not show a statistically significant difference of cumulative MACE between the two groups. A not statistically significant difference in the incidence of both fatal (p = 0.225) and nonfatal CV events (p = 0.573) between the two groups was observed. These results were confirmed after adjustment for confounders (HR for MACE 1.11, 95 % CI 0.91-1.35). These findings suggest that low dose of aspirin is ineffective in primary prevention for patients with nephropathy. © 2014 Springer-Verlag Italia.

Exploring the Life-Saving Potential of Naloxone : A Systematic Review and Descriptive Meta-Analysis of Take Home Naloxone (THN) Programmes for Opioid Users

Date of Acceptance: 21/09/2015 This study was funded by NHS Health Scotland. The opinions expressed in this paper as those of the authors alone and are not necessarily those of NHS Health Scotland. The funders had no role in the conduct of the research.

Exploring the Life-Saving Potential of Naloxone : A Systematic Review and Descriptive Meta-Analysis of Take Home Naloxone (THN) Programmes for Opioid Users

Date of Acceptance: 21/09/2015 This study was funded by NHS Health Scotland. The opinions expressed in this paper as those of the authors alone and are not necessarily those of NHS Health Scotland. The funders had no role in the conduct of the research.

Self-cutting and prospective repetition of self-harm: studies of emergency department presentations in Ireland

Background Self-harm places an individual at increased risk of future self-harm and suicide, and indicates distress and maladaptive coping. Those who present to hospital with self-cutting form a significant minority of self-harm patients who are at increased risk of prospective repetition of self-harm and suicide compared with those presenting with intentional overdose. In addition to increased risk, there is emerging evidence of demographic, psychological, clinical, and social differences between those presenting with self-cutting and those presenting with overdose. Aim and Key Objectives The aim of the current doctoral work was to examine in detail the association between presenting with self-cutting and risk of prospective repetition. The objectives were: to identify evidence-based risk factors for repetition of self-harm among those presenting to emergency departments with self-harm; to compare demographic and presentation characteristics and prospective repetition across presentations of self-cutting only, self-cutting plus intentional overdose, and intentional overdose only; to compare prospective repetition and other characteristics within self-cutting presentations based on the type of treatment received; to compare self-cutting and intentional overdose patients on psychological risk and protective factors for repetition; and to examine the lived experience of engaging in repeated overdose and self-cutting. Methods The current doctoral work used a mixed-methods approach and is comprised of one systematic review and four empirical studies. The empirical studies were two registry-based prospective studies of Irish hospital presentations of self-harm, one prospective structured interview study, and one qualitative study using Interpretative Phenomenological Analysis. Results The systematic review identified several consistent and emerging risk factors for repetition of self-harm, compared to which self-cutting had a medium-sized effect. The registry studies demonstrated that the involvement of self-cutting, particularly less medically severe selfcutting, confers an increased risk of 1-month and 12-month repetition among Irish index selfharm presentations. The structured psychological study detected higher hopelessness and lower non-reactivity to inner experience among those presenting with self-cutting, and higher depression among those who repeated self-harm. Repeaters had lower baseline levels of protective psychological factors than non-repeaters and continued to have higher depression and hopelessness at follow-up. Finally, the qualitative study indicated that self-harm is a purposeful action taken in response to an overwhelming situation and is evaluated afterwards in terms of personal and social effects. Chosen method of self-harm seemed to be influenced by the desired outcome of the self-harm act, capability, accessibility and previous experience. Conclusion Despite limitations in terms of recruitment rates, the work presented in this thesis is innovative in examining the issue of the association between self-cutting and repetition from multiple perspectives. No one factor can reliably predict all repetition but self-cutting represents one consistent and easily detected risk factor for repetition. Those who present with self-cutting exhibit significant differences on demographic, clinical, and psychological variables compared with those presenting with intentional overdose, and seem to exhibit a more vulnerable profile. However, those who present with self-cutting do not form a discrete or homogenous group, and self-harm methods and levels of suicidal intent are liable to fluctuate over time.

Factors associated with self-cutting as a method of self-harm: findings from the Irish National Registry of Deliberate Self-Harm

Background: Research suggests that patients presenting to hospital with self-cutting differ from those with intentional overdose in demographic and clinical characteristics. However, large-scale national studies comparing self-cutting patients with those using other self-harm methods are lacking. We aimed to compare hospital-treated self-cutting and intentional overdose, to examine the role of gender in moderating these differences, and examine the characteristics and outcomes of those patients presenting with combined self-cutting and overdose. Methods: Between 2003 and 2010, the Irish National Registry of Deliberate Self-Harm recorded 42,585 self-harm presentations to Irish hospital emergency departments meeting the study inclusion criteria. Data were obtained on demographic and clinical characteristics by independent data registration officers. Results: Compared with overdose only, involvement of self-cutting (with or without overdose) was significantly more common in males than females, with an overrepresentation of males aged <35 years. Independent of gender, involvement of self-cutting (with or without overdose) was significantly associated with younger age, city residence, repetition within 30 days and repetition within a year (females only). Factors associated with self-cutting as the sole method were no fixed abode/living in an institution, presenting outside 9 a.m. to 5 p.m., not consuming alcohol and repetition between 31 days and 1 year (males only). Conclusion: The demographic and clinical differences between self-harm patients underline the presence of different subgroups with implications for service provision and prevention of repeated self-harm. Given the relationship between self-cutting and subsequent repetition, service providers need to ensure that adequate follow-up arrangements and supports are in place for the patient.

Factors associated with hospitalization after suicide spectrum behaviors: results from a multicentre study in Spain

Objectives: to identify factors associated with admission after suicide spectrum behaviors. Methods: Patient's characteristics, the nature of their suicidal behavior, admission rates between centres, and factors associated with admission have been examined in suicide spectrum presentations to emergency departments in three Spanish cities. Results: Intent of the suicidal behavior had the greatest impact on hospitalization. Older age, living alone, self-harm method not involving drug overdose, previous history of suicide spectrum behaviors and psychiatric diagnosis of schizophrenia, mood or personality disorder were independently associated with being admitted. There was a three-fold between-centre difference in the rate of hospitalization. Conclusions: widespread differences in the rate of hospitalization were primarily accounted for by characteristics of the individual patients and their suicidal behavior.

Suicide and deliberate self harm in older Irish adults

Background: Hospital-treated deliberate self harm and suicide among older adults have rarely been examined at a national level. Methods: The Irish Central Statistics Office provided suicide and undetermined death data for 1980-2006. The National Registry of Deliberate Self Harm collected data relating to deliberate self harm presentations made in 2006-2008 to all 40 Irish hospital emergency departments. Results: Rates of female suicide among older adults (over 55 years) were relatively stable in Ireland during 1980-2006 whereas male rates increased in the 1980s and decreased in more recent decades. Respectively, the annual male and female suicide and undetermined death rate was 22.1 and 7.6 per 100,000 in 1997-2006. Male and female deliberate self harm was 3.0 and 11.0 times higher at 67.4 and 83.4 per 100,000, respectively. Deliberate self harm and suicide decreased in incidence with increasing age. Deliberate self harm generally involved drug overdose (male: 72%; female 85%) or self-cutting (male: 15%; female 9%). The most common methods of suicide were hanging (41%) and drowning (29%) for men and drowning (39%) and drug overdose (24%) for women. City and urban district populations had the highest rates of hospital-treated self harm. The highest suicide rates were in urban districts. Conclusions: Older Irish adults have high rates of hospital-treated deliberate self harm but below average rates of suicide. Drowning was relatively common as a method of suicide. Restricting availability of specific medications may reduce both forms of suicidal behavior.

Facilitators and Barriers to Naloxone Kit Use Among Opioid-Dependent Patients Seeking Treatment at Medication Assisted Therapy Clinics in North Carolina, USA

Naloxone – an opioid antagonist that reverses the effects of opioids, including potential death from overdose – is increasingly being distributed in non-medical settings. We conducted a mixed methods study administering a survey to 100 treatment seekers and pursuing observant participation at four methadone/buprenorphine Medication Assisted Therapy (MAT) clinics in North Carolina, USA. Female participants were more likely to have gotten a kit and to carry it with them, whereas male participants were more likely to have witnessed an overdose and to have made use of naloxone. Men discussed the difficulties of carrying the naloxone kits, which are currently too large to fit in a pocket. Public health officials may be relieved to know that naloxone users intend to call emergency services.