Adverse event reporting patterns of concomitant botanical dietary supplements with CYP3A4 interactive & CYP3A4 non-interactive anticancer drugs in the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS)

Background: To examine the adverse event (AE) reporting patterns for concomitant Botanical Dietary Supplements (BDS) and anticancer drugs.

Research design and methods: Using the 2004–2015 U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database, AEs involving commonly used BDS and anticancer drugs (categorized into CYP3A4 interactive and CYP3A4 non-interactive) were examined. Disproportionality analyses using reporting odds ratios (RORs) assessed the relative reporting rates of 1) serious AEs (i.e., mortality and morbidity) with concomitant use of BDS (overall and by type) and anticancer drugs compared to anticancer drugs only; and 2) AEs by specific System Organ Classes (SOCs).

Results: A total of 3,264 AEs were reported involving concomitant BDS and CYP3A4 interactives, and 3,885 involving concomitant BDS and non-interactive anticancer drugs. ROR of serious AEs with concomitant all BDS and anticancer drugs compared to anticancer drugs alone showed a potential protective signal (ROR = 0.65, 95% CI = 0.62,0.68), but ROR for açaí and non-interactive anticancer drugs indicated potential risk (ROR = 1.70, 95% CI = 1.01,2.86). Heterogeneity of reporting patterns of AEs related to certain SOCs was observed for use of BDS along with anticancer drugs.

Conclusion: This study identified potential protective and risk signals for AEs with concomitant use of BDS and anticancer drugs.     

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).     

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.     

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.     

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.     

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     

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.     

Emerging therapeutic strategies for transplantation-induced acute kidney injury: protecting the organelles and the vascular bed

Introduction: Renal ischemia-reperfusion injury (IRI) is a significant clinical challenge faced by clinicians in a broad variety of clinical settings such as perioperative and intensive care. Renal IRI induced acute kidney injury (AKI) is a global public health concern associated with high morbidity, mortality, and health-care costs.

Areas covered: This paper focuses on the pathophysiology of transplantation-related AKI and recent findings on cellular stress responses at the intersection of 1. The Unfolded protein response; 2. Mitochondrial dysfunction; 3. The benefits of mineralocorticoid receptor antagonists. Lastly, perspectives are offered to the readers.

Expert opinion: Renal IRI is caused by a sudden and temporary impairment of blood flow to the organ.

Defining the underlying cellular cascades involved in IRI will assist us in the identification of novel interventional targets to attenuate IRI with the potential to improve transplantation outcomes. Targeting mitochondrial function and cellular bioenergetics upstream of cellular damage may offer several advantages compared to targeting downstream inflammatory and fibrosis processes.

An improved understanding of the cellular pathophysiological mechanisms leading to kidney injury will hopefully offer improved targeted therapies to prevent and treat the injury in the future.     

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.     

An updated review of glucocorticoid-related adverse events in patients with rheumatoid arthritis

Introduction: Glucocorticoids represent a cornerstone in the treatment of rheumatoid arthritis. Their effect as a disease-modifying treatment in rheumatoid arthritis is well established. Despite this, the risk of adverse events of glucocorticoids, especially in high doses and over a long time, is constantly highlighted. Data on the prevalence and impact of glucocorticoid-related adverse effects in rheumatoid arthritis is needed, therefore, to be regularly revisited.

Areas covered: In this review, our primary aim was to provide an update of evidence from randomized controlled trials and observational cohort studies on the safety of glucocorticoid treatment in rheumatoid arthritis. Our secondary aim was to provide a critical overview of the concerns raised with both study designs – randomized clinical trials versus nonrandomized observational studies – regarding the assessment of the safety of glucocorticoids in rheumatoid arthritis.

Expert opinion: In the meantime, adherence to recommendations and consensus on standardized methodologies for monitoring and reporting adverse events is essential to improve our knowledge and competence in the best management of glucocorticoids.     

Advances in orally administered pharmacotherapy for the treatment of migraine

Introduction: Migraine is a common and highly disabling neurological disorder whose acute treatment remains problematic and unsatisfactory in a high percentage of cases. Consequently, there remains a need for new symptomatic therapies that can be easily handled by patients (i.e. by oral administration).

Area covered: This review reports on compounds currently under development for the oral treatment of acute migraine attacks, focusing on Calcitonin-Gene-Related-Peptide receptor antagonists, specifically ubrogepant and rimegepant. This article is based on literature obtained from PubMed and publicly available clinical trial data.

Expert opinion: Both reviewed compounds meet the need for rapid and effective pain control, combined with the control of associated bothersome symptoms while also lacking significant adverse events and safety concerns. Though further studies should assess the profile of these compounds comparatively with existing and available treatments (namely triptans), the currently available data points to these new therapies as being very promising new symptomatic oral treatments of migraines.     

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.     

Non-pharmacologic treatments for symptoms of diabetic peripheral neuropathy: a systematic review

Objective: To systematically assess benefits and harm of non-pharmacologic interventions for diabetic peripheral neuropathy (DPN) symptoms.

Methods: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched from 1966 to May 24, 2016 for randomized controlled trials. Two reviewers evaluated studies for eligibility, serially abstracted data, evaluated risk of bias, and graded strength of evidence (SOE) for critical outcomes (pain and quality-of-life).

Results: Twenty-three trials were included. For pain, alpha-lipoic acid was more effective than placebo (moderate SOE) and frequency-modulated electromagnetic stimulation was more effective than sham (low SOE) in the short-term but not the long-term. Electrical stimulation (including transcutaneous) was not effective for pain (low SOE). Spinal cord stimulation was more effective than usual care for pain (low SOE), but had serious complications, and studies had no sham arm. Evidence for cognitive behavioral therapy and acupuncture was insufficient; no exercise or physical therapy trials met inclusion criteria. No interventions reported sufficient evidence on quality-of-life. Most studies were short-term with unclear risk of bias.

Conclusions: Alpha-lipoic acid and spinal cord stimulation were effective for pain; studies were short-term with quality deficits. Spinal cord stimulation had serious adverse events. Further research should address long-term outcomes and other non-pharmacologic treatments.     

A review of dexketoprofen trometamol in acute pain

Objective: Dexketoprofen trometamol is a modified non-selective COX inhibitor with a rapid onset of action that is available as both oral and parenteral formulations. The aim of this narrative review was to assess the efficacy and tolerability/safety of dexketoprofen trometamol in acute pain states using the best available published scientific evidence (randomized controlled clinical trials and systematic reviews/meta-analyses).

Methods: Literature retrieval was performed via Medline, Embase and the Cochrane Library (from inception up to March 2017) using combinations of the terms “randomized controlled trials”, “dexketoprofen”, “celecoxib”, “etoricoxib”, “parecoxib” and “acute pain”.

Results: Single-dose dexketoprofen trometamol provides effective analgesia in the treatment of acute pain, such as postoperative pain (dental and non-dental surgery), renal colic, acute musculoskeletal disorders and dysmenorrhea, and reduces opioid consumption in the postoperative setting. It has a rapid onset of action (within 30?minutes) and is well tolerated during short-term treatment. Direct comparisons with COX-2 inhibitors are lacking; however, the efficacy and tolerability of single-dose dexketoprofen trometamol appears to be consistent with that seen with celecoxib, etoricoxib and parecoxib in the acute pain setting.

Conclusion: In conclusion, dexketoprofen trometamol appears to provide similar analgesic efficacy to COX-2 inhibitors when used to treat acute pain, has a rapid onset of action, is well tolerated, and has an opioid-sparing effect when used as part of a multimodal regimen in the acute pain setting.     

How we use pazopanib in treating soft-tissue sarcoma: experience at our multidisciplinary sarcoma centers

Objective: Soft-tissue sarcomas (STSs) are rare malignant tumors arising from tissues of mesenchymal origin throughout the body with poor prognosis in advanced disease. This commentary describes the current treatment landscape for patients with advanced STS undergoing chemotherapy as well as how pazopanib, a newer multitargeted tyrosine kinase inhibitor, has been incorporated into treatment for different subtypes of STS in our clinical practice.

Methods: PubMed was searched (2010–2015) for articles involving the treatment and management of advanced STS. Key search terms included “soft tissue sarcoma”, “pazopanib”, “chemotherapy”, “doxorubicin”, “ifosfamide”, “trabectedin” and “gemcitabine”. Additionally, ClinicalTrials.gov was searched to identify ongoing studies evaluating pazopanib in STS. Reference citations within relevant articles revealed further sources of value.

Results: Standard treatment for advanced STS is single agent or combination systemic chemotherapy. The efficacy of these treatments varies widely, likely because of tumor heterogeneity and cellular mechanisms of chemoresistance, and adverse effects may be a limiting factor for combination therapy. Pazopanib, approved for the treatment of advanced STS in patients who received prior chemotherapy, has demonstrated clinical benefit in a variety of histologic types of advanced STS where the prognosis is often poor. While pazopanib has a favorable safety profile compared with commonly prescribed chemotherapies, it has several safety concerns and dose-limiting adverse effects. We share our best practice for managing adverse events to ensure patient tolerability.

Conclusions: Use of pazopanib increases the treatment options available to control advanced STS, with management of adverse events through close monitoring, patient education and treatment as necessary.     

Insulin-like growth factor-1 (IGF-1) poly (lactic-co-glycolic acid) (PLGA) microparticles – development,characterisation, and in vitro assessment of bioactivity for cardiac applications

Aim: The aim of this study was to evaluate the formulation of a synthetic IGF-1 (pIGF-1) in PLGA microparticles (MP).

Methods: Poly (lactic-co-glycolic acid) (PLGA) MPs loaded with pIGF-1 were prepared, characterised and evaluated using double emulsion solvent evaporation method.

Results: Spherical MPs showed an average particle size of 2?µm, encapsulation efficiency (EE) of 67% and 50% degradation over 15?days. With a view to enhancing retention in the myocardium, the MP formulation was encapsulated in a cross-linked hyaluronic acid hydrogel. pIGF-1 released from MPs and from MPs suspended in hyaluronic acid hydrogel remained bioactive, determined by a significant increase in cellular proliferation of c-kit⁺ cells.

Conclusion: This formulation has potential for loco-regional delivery to damaged myocardium to promote the survival of cardiomyocytes.     

Lidocaine medicated plaster,an additional potential treatment option for localized post-surgical neuropathic pain: efficacy and safety results of a randomized,placebo-controlled trial

Objective: To assess the efficacy and safety of lidocaine 700?mg medicated plaster (lidocaine plaster) compared to placebo in patients with moderate to severe chronic post-surgical neuropathic pain (PSNP).

Methods: Patients (n?=?363) with a diagnosis of PSNP for a minimum of 3?months to 36?months were randomized (1:1) to lidocaine plaster or placebo for a 12 week double-blind treatment period. Randomization was stratified as “plaster-only” (no concomitant medication for PSNP) or as “add-on” (stable systemic medication for PSNP). The primary efficacy endpoint was the change from baseline in 24?hour average pain intensity at Week 12, assessed by 11?point numerical rating scale (NRS). The trial was registered in ClinicalTrials.gov (NCT01752322) and EudraCT (2012-000347-28).

Results: Treatment with lidocaine or placebo plaster led to a clinically relevant reduction in average pain intensity. Pain reduction (least squares mean [LS mean] standard error [SE], [95% confidence interval, CI]) with lidocaine plaster (?1.70 [0.16], [?2.03, ?1.38]) was numerically higher than with placebo (?1.47 [0.16], [?1.78, ?1.15]) but the difference was not statistically significant (?0.23 [0.23], [?0.69, 0.22]). Pre-specified exploratory subgroup analyses showed the largest differentiation between lidocaine and placebo in patients without concomitant pain medication, and in patients with more than 1?year between surgery and enrollment. Many secondary outcomes showed a numerically larger improvement in favor of lidocaine. The most commonly reported adverse events were administration site reactions linked to topical administration.

Conclusions: A clinically relevant pain reduction was observed with lidocaine plaster in patients with PSNP. The safety and tolerability profile is consistent with current knowledge.     

Assessment of adherence to medication in patients after myocardial infarction treated with percutaneous coronary intervention. Is there a place for newself-reported questionnaires?

Introduction: Non-adherence to medication regimen after myocardial infarction (MI) leads to increased morbidity and mortality and generates additional cost to the healthcare system.

Objectives: The aim of this systematic review was to critically discuss assessment methods of adherence to medication in patients after myocardial infarction treated with percutaneous coronary intervention and the possible application of a new self-reported questionnaire.

Methods: A systematic investigation of all published literature was conducted to minimize the risk of bias. A database search (PubMed, CENTRAL and Google Scholar databases) from January 1998 through December 2017.

Results: Adequate assessment of patient adherence to treatment is necessary to understand the potential for adverse outcomes. Methods developed for adherence evaluation are classified as subjective and objective or as direct and indirect. Direct, objective measures reflect pharmacokinetics and include measurement of the drug or its metabolite concentration, evaluation of the presence of biological markers given with the drug and direct observation of patients’ medication-taking behavior. Several indirect, objective methods are based on evaluation of the availability of prescribed medications assuming that medication is taken exactly as prescribed. Assessment of the effectiveness of treatment, both at the pharmacodynamic and clinical level, indirectly but objectively reflects adherence to treatment. Subjective methods, including patient-kept diaries, patient interviews and self-reported questionnaires, due to their simplicity, real-time feedback and low cost, are often used for adherence evaluation in clinical practice.

Conclusions: In spite of the availability, convenience and variety of methods, measuring adherence still remains a real challenge. Using a well designed questionnaire provides an opportunity to identify patients at increased risk of non-adherence and the obstacles impeding implementation of the treatment plan, allowing implementation of tailored interventions in order to improve patient medication-taking behavior.