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.     

Clinical profile of the functionally selective glucocorticoid receptor agonist BI 653048 in healthy male subjects

Background: An efficacious anti-inflammatory corticosteroid with reduced side effects has been long sought. We report the pooled results from three clinical proof-of-mechanism Phase I studies of BI 653048 in healthy subjects, a functionally selective, nonsteroidal glucocorticoid (GC).

Research design and methods: Three Phase I trials were conducted: a single rising-dose study and a multiple rising-dose study to evaluate the safety, tolerability, and pharmacokinetics of BI 653048, and a multiple parallel-arm-dose study with intravenous lipopolysaccharide challenge to assess in vivo pharmacodynamics. The pharmacodynamics, efficacy, and safety of BI 653048 and prednisolone were compared.

Results: Treatment with 200 mg BI 653048 was associated with a reduced expression of IL1R2, ITGB3, and SDPR versus 20 mg prednisolone; comparable levels of FKBP5, ZBTB16, and DDIT4 expression were observed. Changes in C-peptide, glucose, insulin, and cortisol were moderate compared with prednisolone. A greater reduction of osteocalcin was observed with 200 mg BI 653048 versus 20 mg prednisolone. Comparable anti-inflammatory efficacy was demonstrated for 200 mg BI 653048 and 20 mg prednisolone. BI 653048 was well tolerated in healthy subjects.

Conclusion: BI 653048 demonstrated the desired anti-inflammatory effects of the nonsteroidal GC; however, the undesirable side-effect profile associated with GC steroids could not be disassociated from BI 653048.

Trial registration: ClinicalTrials.gov identifiers NCT02217644, NCT02217631, and NCT02224105.     

Promising therapies for the treatment of frontotemporal dementia clinical phenotypes: from symptomatic to disease-modifying drugs

Introduction: Frontotemporal dementia (FTD) is a heterogeneous clinical entity that includes several disorders characterized by different cellular mechanisms. Distinctive clinical features in FTD include behavioral, affective, and cognitive symptoms. Unfortunately, little progress has been made over the past 20 years in terms of the development of effective disease-modifying drugs with the currently available symptomatic treatments having limited clinical utility.

Areas covered: This article reviews the principal pharmacological intervention studies for FTD. These are predominantly randomized clinical trials and include symptomatic treatments and potential disease-modifying drugs.

Expert opinion: There is insufficient evidence on effective treatments for FTD and studies with better methodological backgrounds are needed. Most studies reporting therapeutic benefits were conducted with selective serotonin reuptake inhibitors, while anti-dementia drugs have been ineffective in FTD. Since the underlying pathology of FTD mostly consists of abnormal tau protein or TDP-43 aggregates, treatments are being developed to interfere with their aggregation process or with the clearance of these proteins. Furthermore, disease-modifying treatments remain years away as demonstrated by the recent negative Phase III findings of a tau aggregation inhibitor (LMTM) for treating the behavioral variant of FTD. The results from current ongoing Phase I/II trials will hopefully give light to future treatment options.     

Experimental and investigational phosphodiesterase inhibitors in development for asthma

Introduction: Severe, inadequately-controlled asthma remains a clinical challenge. For this reason, clinical trials and preclinical experimental studies on novel agents as an add-on therapies continue emerge. Phosphodiesterases (PDEs) are enzymes that regulate the function of immune cells by hydrolyzing cyclic guanosine monophosphate/cGMP and cyclic adenosine monophosphate/cAMP. PDEs are divided into subfamilies [PDE3, PDE4, PDE5 and PDE7] which are mainly found in the respiratory tract. Inhibitors of PDEs have already been approved for COPD and pulmonary hypertension.

Areas covered: The role of PDE inhibitors in asthma treatment and the possible mechanism of action via their anti-inflammatory and/or bronchodilating effect are discussed.

Expert opinion: Novel PDE inhibitors exhibiting fewer adverse events may have a role as add-on therapies in asthma treatment in the future. More clinical trials are necessary to prove their efficacy and evaluate their safety profile before approval by regulatory bodies is granted.     

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.     

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.     

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.     

Utility of food pellets containing 1-aminobenzotriazole for longer term in vivo inhibition of cytochrome P450 in mice

1. The utility of 1-aminobenzotriazole (ABT), incorporated in food, has been investigated as an approach for longer term inhibition of cytochrome P450 (P450) enzymes in mice.

2. In rats, ABT inhibits gastric emptying, to investigate this potential limitation in mice we examined the effect of ABT administration on the oral absorption of NVS-CRF38. Two hour prior oral treatment with 100?mg/kg ABT inhibited the oral absorption of NVS-CRF38, T_max was 4?hours for ABT-treated mice compared to 0.5?hours in the control group.

3. A marked inhibition of hepatic P450 activity was observed in mice fed with ABT containing food pellets for 1?month. P450 activity, as measured by the oral clearance of antipyrine, was inhibited on day 3 (88% of control), week 2 (83% of control) and week 4 (80% of control).

4. T_max values for antipyrine were comparable between ABT-treated mice and the control group, alleviating concerns about impaired gastric function.

5. Inclusion of ABT in food provides a minimally invasive and convenient approach to achieve longer term inhibition of P450 activity in mice. This model has the potential to enable pharmacological proof-of-concept studies for research compounds which are extensively metabolised by P450 enzymes.     

Safety concerns of biosimilar hormone products

Background: Currently, biotherapeutic medicines are the most effective options for the treatment of many severe and chronic diseases. For faster market entry of biotherapeutic products and their cost reduction, the principles of “biosimilarity” have been developed. Development and licensing of biosimilars is allowed only after the end of patent exclusivity of the original preparation period.

Purpose: Characteristics of the main safety parameters of biosimilar hormone preparations licensed by EMA.

Methods: This paper analyzes the results demonstrating the similarities and differences between biosimilar and reference hormone products indicated in the EPAR (public assessment report) for the examination of materials presented for the licensing of biosimilar products.

Results: During the development of biosimilar hormone medicines, differences in the glycosylation profile between biosimilar and reference preparations are revealed. As biotherapeutical preparations are produced by cells, the differences in glycosylation profile between biosimilar and referent preparation are predictable. While carrying out clinical studies, a high similarity of biosimilar and reference product effectiveness is shown, but some differences between them in the safety profile are revealed.

Conclusions: The study of biosimilar product safety has shown the necessity of further improvement in safety and standard approaches for the assessment of the immunogenicity of biosimilar products.     

Preclinical pharmacokinetics of a novel anti-c-Met antibody–drug conjugate,SHR-A1403, in rodents and non-human primates

1. The in vivo pharmacokinetics (PK) profiles of a novel c-Met antibody–drug conjugate (ADC), SHR-A1403, were investigated and characterized in mice, rats and monkeys.

2. Serum concentrations of ADC and total antibody were detected using validated ELISA methods. The results showed low systemic clearance of both ADC and total antibody in all three species as reflected by gradual decrease in serum concentrations. Half-life (t_1/2) of ADC ranged from 4.6 to 11.3?days in the three species.

3. Tissue distribution study in tumor-bearing mice showed high accumulation of ¹²⁵I-SHR-A1403 in tumor tissues over the other organs/tissues, indicating the favorable safety of SHR-A1403 and characteristics of an ADC drug.

4. Relatively low grade of anti-drug antibody (ADA) in monkeys had no impact on PK profile of the ADC.

5. During discovery stage, undesirable exposure and/or ADA incidence were observed for SHR-A1403 with high or low drug-antibody ratio (DAR), which was DAR?=?5 to 6 and DAR?=?1, respectively, and therefore prompted selection of an appropriate DAR value (DAR?=?2) for SHR-A1403 used in preclinical development and clinical trials.

6. In conclusion, our work demonstrated favorable PK characterization of SHR-A1403, and supported for investigational new drug application (IND) and the ongoing first-in-human trial in the US.     

Pegvaliase: a novel treatment option for adults with phenylketonuria

Objective: In May 2018, the US Food and Drug Administration approved pegvaliase-pqpz (Palynziq*), the first enzyme substitution therapy for the treatment of phenylketonuria (PKU). This article provides an overview of the mechanism of action, pharmacokinetic properties, clinical efficacy, and the safety and tolerability profile of pegvaliase.

Methods: Relevant information was identified through a comprehensive literature search of several databases using the keywords pegvaliase, rAvPAL-PEG, and phenylketonuria. Additional information was gathered from the pegvaliase package insert, posters presented at scientific meetings, and materials provided from the manufacturer, BioMarin.

Results: Pegvaliase is effective in decreasing blood phenylalanine levels, and is associated with a manageable side-effect profile. Phase III clinical trial data demonstrated that 60.7% of patients were able to achieve blood phenylalanine levels less than the guideline recommended 360 µmol/L at 24 months. Brief sub-studies also showed the improvement in inattention symptoms in patients treated with pegvaliase, compared to placebo.

Conclusion: Pegvaliase is a promising new treatment option for adults living with PKU. Further studies are warranted to determine long-term safety and clinical efficacy in sub-populations.     

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.     

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.     

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.     

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.     

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.     

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.