An update on heart disease risk associated with testosterone boosting medications

Introduction: The cardiovascular (CV) safety of testosterone replacement therapy (TRT) remains a crucial issue in the management of subjects with late-onset hypogonadism. The authors systematically reviewed and discussed the available evidence focusing our analysis on heart-related issues.

Areas covered: All the available data from prospective observational studies evaluating the role endogenous T levels on the risk of acute myocardial infarction (AMI) were collected and analyzed. In addition, the impact of TRT on heart-related diseases, as derived from pharmaco-epidemiological studies as well as from randomized placebo-controlled trials (RCTs), was also investigated.

Expert opinion: Available evidence indicates that endogenous low T represents a risk factor of AMI incidence and its related mortality. TRT in hypogonadal patients is able to improve angina symptoms in subjects with ischemic heart diseases and exercise ability in patients with heart failure (HF). In addition, when prescribed according to the recommended dosage, TRT does not increase the risk of heart-related events.     

Efficacy of istradefylline for gait disorders with freezing of gait in Parkinson’s disease: A single-arm,open-label,prospective, multicenter study

Background: Gait disorders are common in Parkinson’s disease patients who respond poorly to dopaminergic treatment. Blockade of adenosine A_2A receptors is expected to improve gait disorders. Istradefylline is a first-in-class selective adenosine A_2A receptor antagonist with benefits for motor complications associated with Parkinson’s disease.

Research design and methods: This multicenter, open-label, single-group, prospective interventional study evaluated changes in total gait-related scores of the Part II/III Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) and Freezing of Gait Questionnaire (FOG-Q) in 31 Parkinson’s disease patients treated with istradefylline. Gait analysis by portable gait rhythmogram was performed.

Results: MDS-UPDRS Part III gait-related total scores significantly decreased at Weeks 4–12 from baseline with significant improvements in gait, freezing of gait, and postural stability. Significant decreases in MDS-UPDRS Part II total scores and individual item scores at Week 12 indicated improved daily living activities. At Week 12, there were significant improvements in FOG-Q, new FOG-Q, and overall movement per 48 h measured by portable gait rhythmogram. Adverse events occurred in 7/31 patients.

Conclusions: Istradefylline improved gait disorders in Parkinson’s disease patients complicated with freezing of gait, improving their quality of life. No unexpected adverse drug reactions were identified.

Trial registration: UMIN-CTR (UMIN000020288).     

Routine care interventions with the parents of adult drug and alcohol users

Introduction and aims: To explore routine care interventions which enable parents to support the therapeutic effort of their adult child in drug and alcohol treatment.

Design and methods: Inductive content analysis was used to analyze the experiences of 31 Greek addiction professionals who participated in focus groups.

Findings: Professionals adopted various interventions which included (a) respond to parents quest for help, (b) involvement of the distant parent in treatment, (c) boundary setting, (d) facilitation of parent-child communication, and (e) support of parental changes. These interventions were perceived as necessary, both for motivating and sustaining the client’s change, and for alleviating the parents’ chronic grief and distress over their child’s addiction.

Conclusion: Overall, addiction professionals perceived low intensity interventions, information giving, and non- judgmental informal interactions as catalysts for the parents involvement in addiction treatment.     

An evaluation of peripapillar choroidal thickness in patients receiving systemic isotretinoin treatment

Purpose: Oral isotretinoin (13-cis retinoic acid, 13-cis RA) was approved for severe acne treatment by the FDA in 1982. The ocular side effects associated with oral isotretinoin use are mostly dose-dependent. Numerous ocular pathologies affect peripapillary choroidal layer primarily or indirectly.

Objective: Evaluation of the peripapillary choroidal layer in the patients receiving oral isotretinoin therapy may aid in explaining the pathophysiology of ocular side effects.

Methods: In this study, peripapillary choroidal thickness was assessed in the patients receiving oral isotretinoin treatment via optical coherent tomography technique.

Results: Significant difference was found in the superotemporal and temporal areas.

Conclusion: Oral isotretinoin treatment may affect the thickness of the peripapillary choroidal layer.     

Combining stem cell-derived hepatocytes with impedance sensing to better predict human drug toxicity

Background: The liver plays a central role in human drug metabolism. To model drug metabolism, the major cell type of the liver, the hepatocyte, is commonly used. Hepatocytes can be derived from human and animal sources, including pluripotent stem cells. Cell-based models have shown promise in modeling human drug exposure. The assays used in those studies are normally ‘snap-shot’ in nature, and do not provide the complete picture of human drug exposure.

Research design and methods: In this study, we employ stem cell-derived hepatocytes and impedance sensing to model human drug toxicity. This impedance-based stem cell assay reports hepatotoxicity in real time after treatment with compounds provided by industry.

Results: Using electric cell-substrate impedance Sensing (ECIS), we were able to accurately measure drug toxicity post-drug exposure in real time and more quickly than gold standard biochemical assays.

Conclusions: ECIS is robust and non-destructive methodology capable of monitoring human drug exposure with superior performance to current gold standard ‘snapshot’ assays. We believe that the methodology presented within this article could prove valuable in the quest to better predict off-target effects of drugs in humans.     

Cardiovascular events associated with nicorandil administration prior to primary percutaneous coronary intervention in patients with acute ST-segment elevated myocardial infarction: a systematic review and meta-analysis

Introduction: Nicorandil may exert cardioprotective effects in ischemic heart disease. However, its efficacy in combination with early reperfusion is uncertain. The authors performed a meta-analysis of the short- and long-term clinical outcomes of nicorandil administration at the time of primary percutaneous coronary intervention (PCI) in patients with ST-elevated myocardial infarction (STEMI).

Methods: PubMed, MEDLINE, Embase, and the Cochrane Library databases were systematically searched for eligible randomized controlled studies. The primary endpoint was major adverse cardiovascular events (MACE), both in-hospital and post-discharge. The secondary endpoint was the incidence of no-reflow phenomenon.

Results: Ten studies were included (n = 1105). Mean patient age was 63.0 ± 10.0 years; 76.6% of patients were male. Compared with controls who received primary PCI, combined nicorandil/primary PCI significantly reduced in-hospital MACE (pooled odds ratio [OR] 0.16; 95% confidence interval [CI] 0.09–0.27), follow-up MACE (pooled OR 0.53; 95% CI 0.37–0.75), and total MACE (pooled OR 0.27; 95% CI 0.15–0.49). The combined treatment also reduced the incidence of no-reflow phenomenon (pooled OR 0.34; 95% CI 0.23–0.50).

Conclusion: Nicorandil administration at the time of primary PCI is associated with reduced MACE (both short- and long-term) and no-reflow phenomenon in patients with STEMI.     

Evidence of bioequivalence and positive patient user handling of a tocilizumab autoinjector

Background: The anti–interleukin-6 receptor antibody tocilizumab is approved for subcutaneous injection using a prefilled syringe (PFS). We report results from a bioequivalence study in healthy subjects and a user-handling study in patients with rheumatoid arthritis (RA) using an autoinjector (AI) for tocilizumab.

Methods: A randomized crossover study in healthy subjects (N = 161) examined the bioequivalence, safety, and tolerability of tocilizumab after a single subcutaneous injection by AI versus PFS. A nonrandomized observational, real-life human factors study in RA patients (N = 54) assessed user (RA patients, caregivers, health care providers) ability to administer tocilizumab effectively by AI.

Results: Bioequivalence criteria for tocilizumab AI versus PFS were met for key pharmacokinetic parameters. Safety was comparable between devices and consistent with the established tocilizumab profile. In the real-life human factors study, the proportion of users who successfully performed all essential tasks required to operate the AI to deliver the full dose was 92.3% at first assessment and 98.1% at second assessment, with no safety concerns.

Conclusions: Tocilizumab administration by AI was bioequivalent to administration by PFS. Intended users were successful in performing the tasks required to administer tocilizumab by AI. No new safety signals were observed in either study.

Clinical Trial Registration: NCT02678988, NCT02682823     

Optimisation of the microencapsulation of lavender oil by spray drying

Background: Lavender oil consists of around 100 components and is susceptible to volatilisation and degradation reactions.

Aim: Microencapsulate lavender oil by spray drying using a biocompatible polymeric blend of gum acacia and maltodextrin to protect the oil components. Effect of total polymer content, oil loading, gum acacia, and maltodextrin proportions on the size, yield, loading, and encapsulation efficiency of the microparticles was investigated.

Methods: Morphology and oil localisation within microparticles were assessed by confocal laser scanning electron microscope. Structural preservation and compatibility were assessed using Fourier transform infra-red spectroscopy, differential scanning calorimetry, and gas chromatography–mass spectrometry.

Results: Lavender microparticles of size 12.42?±?1.79?µm prepared at 30 w/w% polymer concentration, 16.67 w/w% oil loading, and 25w/w% gum acacia showed maximum oil protection at high loading (12?mg w/w%), and encapsulation efficiency (77.89 w/w%).

Conclusion: Lavender oil was successfully microencapsulated into stable microparticles by spray drying using gum acacia/maltodextrin polymeric blend.     

Extracts of different pollen species and their effect on human tear fluid and an epithelial cell line

Purpose: Hazelnut and birch pollen are known to destroy tear film components and attack ocular surface cells. We investigated further pollen species from different plant families, whether they show similar effects on human tear fluid and an epithelial cell line in vitro, to provide a broad basis for further research on pollen reactions affecting the tear film and ocular surface.

Materials and methods: Regional pollen species from different plant families (Adoxaceae, Betulaceae, Fagaceae, Juglandaceae, Malvaceae, Oleaceae, Pinaceae, Plantaginaceae, Poaceae, Salicaceae, Sapindaceae) were collected. Their proteolytic activity was evaluated by Zymography. Human tear fluid and cells of an epithelial cell line were incubated with pollen extracts. Tear fluid was analyzed by Polyacrylamide gel electrophoresis (PAGE). Cytomorphology was assessed microscopically and cell viability by proliferation (MTS), water-soluble tetrazolium (WST-1) assay and the impedance-based xCELLigence real-time analysis (RTCA).

Results: Zymography revealed significant protease activity and PAGE showed the degradation of tear proteins by different pollen species. Cells incubated with pollen extracts presented dose- and time-dependent cytomorphological changes. MTS, WST-1, and RTCA revealed cytostatic as well as cytotoxic effects of pollen extracts.

Conclusions: Pollen species from different plant families exert proteolytic activity and degrade human tear fluid as well as epithelial cells, which may play a crucial role in the pathogenesis of allergic and non-allergic reactions affecting the ocular surface.     

Gender,subclinical organ damage and cardiovascular risk stratification in hypertensive patients

Background: The aims of the study were to assess subclinical organ damage in men and women with hypertension and its subsequent effect on cardiovascular risk, and use of new statistical methods for more precise estimation of cardiovascular risk using vascular cardiovascular risk factors: ankle–brachial index (ABI), intima–media thickness (IMT) and pulse wave velocity (PWV).

Methods: We studied 200 patients: 100 hypertensive and 100 normotensive. The parameters we evaluated included: patient age, ABI, IMT, PWV, serum uric acid and serum C-reactive protein (CRP). In addition, the cardiovascular risk according to the SCORE and Framingham scales was assessed.

Results: In the hypertensive group, there were significant correlations between ABI and the Framingham scale in both sexes. In hypertensive women, there were also significant correlations between IMT and the SCORE scale risk, and IMT and the Framingham scale risk.

In normotensive women, there were significant correlations between ABI and the SCORE scale risk, and between ABI and the Framingham scale risk. In normotensive men, there were significant correlations between PWV and the SCORE scale risk, and between PWV and the Framingham scale risk. Lastly, in the group of normotensive men, there were significant correlations between IMT and the SCORE scale risk, and IMT and the Framingham scale risk.

The possibility of correctly classifying a patient into the high-risk category by a logistic regression model using synchronous ABI, IMT and PWV was high – 74% for the risk according to the SCORE scale (66% in men, 88% in women), and 98% for the Framingham scale.

Conclusions: The addition of recognized subclinical target organ damage tests to the estimation of cardiovascular risk can significantly strengthen the prevention of cardiovascular disease.

Cardiovascular risk estimation follow-up with ABI, PWV and IMT increased the probability of correctly classifying people, especially women, into an at least high-risk category according to the SCORE scale, which has valuable therapeutic implications.     

A cross-national comparison of the Twitter feeds of popular alcohol brands in India and Australia

Aims: To evaluate (i) the types of techniques alcohol marketers utilise to facilitate user engagement with content on leading Indian and Australian Twitter alcohol brand pages and (ii) the extent to which users engage with this content in two diverse national contexts.

Methods: The 10 alcohol brands per country with the greatest Twitter presence were identified based on the number of ‘followers’. Number of tweets, photos, and videos were collected and the type of content noted for each brand between 1 January 2016 and 29 February 2016. The data were analysed via an inductive coding approach using NVivo10.

Results: In total, the brands had accumulated up to 150,386 followers (Indian: 110,032; Australian: 40,354). The techniques utilised were a mix of those that differed by country (e.g. India: sexually suggestive content versus Australia: posts related to the brand’s tradition or heritage) and generic approaches (e.g. alcohol sponsorship of sport, music, and fashion; offering consumption suggestions; organising competitions; giveaways; and use of memes).

Conclusions: The flexibility of Twitter, which complements traditional marketing, allows brands to adapt and deliver their online alcohol content in specific national contexts and to capitalise on the cultural meanings users invoke in their interactions with the brands.     

Mesenchymal stem cell-derived exosomes attenuate phosgene-induced acute lung injury in rats

Objective: We have previously found that mesenchymal stem cell (MSC) therapy can ameliorate phosgene-induced acute lung injury (ALI). Moreover, exosomes can be used as a cell-free alternative therapy. In the present study, we aimed to assess the effect of MSC-derived exosomes on phosgene-induced ALI.

Methods: MSC-derived exosomes were isolated from MSCs through ultracentrifugation. Sprague-Dawley (SD) rats were exposed to phosgene at 8.33?g/m³ for 5?min. MSC-derived exosomes were intratracheally administered and rats were sacrificed at the time points of 6, 24 and 48?h.

Results: Compared with the phosgene group, MSC-derived exosomes reversed respiratory function alterations, showing increased levels of TV, PIF, PEF and EF50 as well as decreased levels of RI and EEP. Furthermore, MSC-derived exosomes improved pathological alterations and reduced wet-to-dry ratio and total protein content in BALF. MSC-derived exosomes reduced the levels of TNF-α, IL-1β and IL-6 and increased the IL-10 level in BALF and plasma. MSC-derived exosomes suppressed the MMP-9 level and increased the SP-C level.

Conclusions: MSC-derived exosomes exerted beneficial effects on phosgene-induced ALI via modulating inflammation, inhibiting MMP-9 synthesis and elevating SP-C level.     

Application of disaccharides alone and in combination,for the improvement of stability and particle properties of spray-freeze dried IgG

Purpose: Spray-freeze drying (SFD) is a recently applied method to develop pharmaceutical powders. This study aimed to analyze the competence of Trehalose, Mannitol, Lactose, and Sorbitol instability and aerosolization of Immunoglobulin G (IgG) via SFD.

Methods: Induced soluble aggregates were quantified at 0 and 3?months, and 45?°C using size-exclusion chromatography. Conformation and thermogravimetric assessments were done by Fourier transform infrared spectroscopy and differential scanning calorimetry. Laser light scattering was performed to determine the particle sizes. Aerodynamic features were characterized by twin stage impinger and scanning electron microscopy.

Results: Although sugars/polyols preferably stabilized IgG following the process, storage stabilization was achieved in Trehalose, Trehalose-Lactose, Lactose, and Trehalose-Mannitol-based powders with soluble aggregates <5%. The conformation of antibody was preserved with β sheet content from 66.28% to 76.37%. Particle sizes ranged from 5.23 to 8.12?µm. Mannitol exhibited the best aerodynamic behavior, fine particle fraction (FPF: 70%) but high degree of protein aggregation during storage.

Conclusions: SFD could favorably stabilize antibody using Trehalose and its combination with Lactose and Mannitol, and also, Lactose alone. Sorbitol disturbed IgG powder recovery. Incorporation of other types of excipient is required for efficient respiratory delivery of IgG molecules.     

Animal models of ischemic stroke and their impact on drug discovery

Introduction: Representing the leading cause of long-term disability, ischemic stroke urgently needs further research and drug development. This review summarizes current animal models of ischemic stroke that can be used for drug discovery.

Areas covered: Several reproducible models of permanent and transient focal cerebral ischemia have been established in a variety of animal species including rats and mice, in which a brain-supplying artery, often the middle cerebral artery, is occluded by mechanical devices including sutures, clips and hooks, pharmacological agents or delivery of blot clots. The authors review existing literature about these models, outlining their utility for evaluating acute and post-acute stroke treatments. Since stroke is an age-related disease that strongly affects humans with vascular risk factors and co-morbidities, the authors give focus to strategies replicating risk factors in ischemic stroke models. Furthermore, the authors present models of spontaneous stroke.

Expert opinion: It is important that animal models mimic clinical conditions in a reliable and clinically relevant way, so here, they should replicate the pathophysiology of human stroke, stroke-associated risk factors and doses, times and modes of drug treatment. We propose that risk factor models should more widely be used in early drug discovery, if possible already during the identification of treatment targets.     

Population pharmacokinetics of oxycodone in plasma and cerebrospinal fluid after epidural and intravenous administration

Objectives: To establish the first plasma and cerebrospinal fluid (CSF) oxycodone population pharmacokinetic (PopPK) model after epidural (EPI) and intravenous (IV) oxycodone administration.

Methods: The study was conducted with 30 female subjects undergoing elective gynecological surgery with epidural analgesia. A parallel single dose of EPI oxycodone with IV placebo (EPI group; n = 18) or IV oxycodone with EPI placebo (IV group; n = 12) was administered. An epidural catheter for drug administration was placed at T12/L1 and a spinal catheter for CSF sampling at L3/4. Plasma and CSF for oxycodone analysis were frequently collected. A PopPK model was built using the NONMEM software package.

Results: Plasma and CSF oxycodone concentrations were evaluated using separate central plasma and CSF compartments and separate peripheral plasma and CSF compartments. Epidural space served as a depot compartment with transfer to both the plasma and CSF central compartments. The population parameters for plasma clearance and apparent distribution volumes for central and peripheral compartments for plasma and CSF were 37.4 L/h, 90.2 L, 68.9 L, 0.035 L (fixed based on literature), and 0.039 L, respectively.

Conclusion: A PopPK model was developed and found to precisely and accurately describe oxycodone time-concentration data in plasma and CSF.     

Confidentiality and cultural competence? The realities of engaging young British Pakistanis and Bangladeshis into substance use services

Aims: This paper focuses on the reasons for the under-representation of British South Asians in substance use services. Based on a small-scale evaluation of a substance use service that delivers targeted outreach support within two predominantly Pakistani and Bangladeshi communities in the north west of England, this paper contributes to the debate around how substance use services can best engage with young British Pakistani and Bangladeshi substance users.

Methods: Semi-structured interviews (with six staff members, 18 young Pakistani and Bangladeshi service users, and 18 stakeholders and partner agencies), a detailed ethnographic observation of the service, and an analysis of routinely collected quantitative monitoring data.

Findings: The paper highlights the importance of what Fountain terms low threshold/open access services. Alongside this, the paper argues that the building of trust and confidence in a substance use service is a key when it comes to engaging with young Pakistani and Bangladeshi substance users. Yet this necessary process takes time: something that is at odds with the current trend towards short-term funding regimes and ‘quick wins’.

Conclusions: The paper concludes by advocating the need for, not only a diverse range of engagement strategies, but also a longer term approach when it comes to developing and delivering substance use services aimed at successfully engaging with this particular group of substance users.     

The effectiveness of diversion programmes for offenders using Class A drugs: a systematic review and meta-analysis

Aims: To review existing evidence on effectiveness of community-based diversion programmes for Class A drug-using offenders.

Methods: 31 databases were searched for studies published 1985–2012 (update search 2012–2016) involving community-based Criminal Justice System diversion of Class A drug users via voluntary or court-mandated treatment.

Findings: 16 studies were initially included (US, 10; UK, 4; Canada, 1; Australia, 1). There was evidence for a small impact of diversion to treatment on drug use reduction (primary Class A drug use: OR 1.68, CI 1.12–2.53; other drug use: OR 2.60, 1.70–3.98). Class A drug users were less likely to complete treatment (OR 0.90, 0.87–0.94) than users of other drugs. There was uncertainty surrounding results for offending, which were not pooled due to lack of outcome measure comparability and heterogeneity. Individual studies pointed to a minor effect of diversion on offending. Findings remained unchanged following an update review (evidence up to March 2016: US, 3; Australia, 1).

Conclusions: Treatment accessed via community-based diversion is effective at reducing drug use in Class A drug-using offenders. Evidence of a reduction in offending amongst this group as a result of diversion is uncertain. Poor methodological quality and data largely limited to US methamphetamine users limits available evidence.     

Potentially inappropriate concomitant medicine use with the selective COX-2 inhibitor celecoxib: Analysis and comparison of spontaneous adverse event reports from Australia,Canada and the USA.

Background: To perform an international comparison and analysis of celecoxib spontaneous adverse event reports (AERs) from Canada, Australia and the United States, focusing on gastrointestinal, renal and cardiovascular events. This study also examined concomitant medicines use which may have potentiated the risk of the reported adverse events.

Research, design and methods: Three databases were searched for spontaneous AERs associated with celecoxib, submitted within the past 10 years: Australian Therapeutic Goods Administration Database of Adverse Event Notifications; Canada Vigilance Adverse Reaction Online Database; and the United States Food and Drug Administration Adverse Event Reporting System Database. Analysis of the AERs focussed on the identification of gastrointestinal, cardiovascular and renal adverse events and concomitant medications suspected of potentiating adverse event risks.

Results: A total of 24,232 celecoxib AERs were identified. Gastrointestinal disorders were the most frequently reported adverse events at the system organ class (SOC) level in the AERs. A large number of AERs documented the use of potentially inappropriate concomitant medicines which may have increased the risk of the reported adverse events.

Conclusions: The large number of reports that involved a concomitant medicine that was in contravention with prescribing guidelines indicates an increased need for efforts to support the safe prescribing of celecoxib.     

The quality of spontaneous adverse drug reaction reports from the pharmacovigilance centre in western China

Background: High-quality adverse drug reaction (ADR) reports are essential for conducting drug safety monitoring in pharmacovigilance. The study aim was to assess the current quality of ADR reports in western China, and to identify problems with ADR report quality.

Research design and methods: A sample of 1139 reports received by the Shaanxi ADR Monitoring Center from January 2015 to December 2017 was selected. ADR report quality was evaluated using an ADR report quality evaluation system.

Results: None of the reports were rated as excellent and 1.40% (n = 16) as good. Report quality was better for new and serious reports than for general reports. Medical institutions generated higher quality reports than pharmaceutical manufacturers. Nurses generated higher quality reports than doctors, pharmacists, and other professionals. Reporters of different occupations showed significant differences in the quality of the indicators Reporting time limit, Intervention ADR time, ADR termination time, ADR intervention measures, Original disease, and Cause of medication (P = 0.000).

Conclusions: The ADR data quality was poor in western China, and of lower quality than reported data from previous research in other regions. Improvements in the quality and availability of ADR reports are urgently needed.