The safety of treating newly diagnosed epilepsy

Introduction: Epilepsy is a serious chronic neurological disorder manifested by an enduring symptomatic predisposition to seizures. Newly diagnosed individuals face increased morbidity, mortality, and socioeconomic costs. Anti-epileptic drug therapy is the treatment usually prescribed, which has efficacy in seizure control and mitigating long-term mortality.

Areas covered: Safety of anti-epileptic drug therapy in adults with a focus in newly diagnosed patients. Areas covered include the most commonly experienced adverse drug effects, as well as those with the highest impacts on drug tolerability, quality of life, morbidity and mortality. Evidence was also reviewed to identify clinical strategies to improve the safety of anti-epileptic drug therapy.

Expert opinion: Anti-epileptic drugs (AEDs) are mostly effective and well tolerated. However, a lack of standardised reporting of adverse drug effects in trials and in clinical practice provides an obstacle for evaluation of which adverse drug effects need to be prioritised in management. Improvement in the reporting of cognitive and other effects, as well as improved precision medicine and pharmacogenomics to target the incidence of high-mortality idiosyncratic reactions, will help to reduce the harm of AEDs in people newly diagnosed with epilepsy.     

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.     

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).     

Advances with extended and controlled release formulations of antiepileptics in the elderly

Introduction: As a matter of course, elderly people are more sensitive to both the pharmacological and toxicological effects of pharmacotherapy. A senior’s treatment, therefore, requires more attention compared to younger adults. Extended release (ER) formulations of anti-epileptic drugs (AEDs) have been developed to improve safety, efficacy and long-term adherence. In senior patients, ER AEDs are used to treat epilepsy, psychiatric conditions, and neuropathic pain. However, very limited clinical evidence is available on the use of these ER AEDs in these populations.

Areas covered: The authors of this paper have identified clinical studies of ER AED formulations used in elderly populations through literature searches looking, both, at their use in epileptic and non-epileptic indications. Additionally, immediate release (IR) and ER formulations of AEDs were compared whenever possible.

Expert opinion: The broad use of ER AED formulations in elderly patients with swallowing problems is limited by the fact that ER AED tablets (or capsules) must not be cut, crushed or chewed. The only exception is the ER formulation of valproate or topiramate which can be mixed with soft food. Although, the ER formulations of AEDs seem better tolerated than the IR equivalents, a possibility of numerous interactions with drugs prescribed for other reasons must be carefully considered.     

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.     

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.     

Safety of clinical practice guideline-recommended antiemetic agents for the prevention of acute chemotherapy-induced nausea and vomiting in pediatric patients: a systematic review and meta-analysis

Introduction: Chemotherapy-induced nausea and vomiting (CINV) are among the most distressing and feared treatment-related adverse effects for cancer patients. Selection of antiemetic agents to prevent CINV should be based on an evaluation of their efficacy and safety. This systematic review and meta-analysis describes the adverse effects associated with antiemetic agents recommended for the prevention of acute CINV in children by clinical practice guidelines (CPGs).

Areas covered: A systematic literature search was conducted using four databases to identify papers describing adverse effects in pediatric patients receiving aprepitant, dexamethasone, granisetron, ondansetron, palonosetron, or tropisetron. Meta-analysis was conducted for adverse effects reported in at least three prospective studies with a cumulative incidence of at least 1%.

Expert opinion: Antiemetic agents currently recommended by CPGs are relatively safe to use in children. The presence of patient-specific risk factors for rare adverse effects, especially cardiac arrhythmia, should be evaluated when selecting a patient’s antiemetic therapy. Evaluation of the long-term safety of CPG-recommended antiemetic agents in pediatric cancer patients is needed.     

Guanidine-based disinfectants,polyhexamethylene guanidine-phosphate (PHMG-P), polyhexamethylene biguanide (PHMB), and oligo(2-(2-ethoxy)ethoxyethyl guanidinium chloride (PGH) induced epithelial-mesenchymal transition in A549 alveolar epithelial cells

Objective: The major active ingredient of humidifier disinfectant, polyhexamethylene guanidine-phosphate (PHMG-P), caused hundreds of deaths with pulmonary fibrosis. However, structurally similar guanidine-based disinfectants are still in use in various fields. Moreover, as they are precursors of excellent antimicrobial compounds, new chemicals with guanidine-based structures have been synthesized and introduced. In this study, we evaluated pulmonary fibrotic responses induced by PHMG-P, polyhexamethylene biguanide (PHMB), and oligo(2-(2-ethoxy)ethoxyethyl guanidinium chloride (PGH) and their toxicity mechanisms in type II alveolar epithelial A549 cells.

Materials and methods: Cellular damage was compared by using the cytotoxicity test (WST-1 assay) and plasma membrane toxicity tests (Lactate dehydrogenase leakage detection assay and plasma membrane staining). As a measure of fibrotic response, induction of the epithelial-mesenchymal transition (EMT) was evaluated by measuring E-cadherin and α-smooth muscle actin (α-SMA) protein expression (epithelial and mesenchymal marker, respectively).

Results: All tested compounds showed membrane damage; PHMG-P and PGH induced the highest and lowest damage, respectively. Moreover, they induced EMT when the test chemicals were treated with similar cytotoxic concentrations.

Conclusions: Our study indicates that three guanidine-based disinfectants are potential fibrosis-inducing chemicals that induce EMT through cellular damage. Therefore, use of guanidine-based polymers should be strictly regulated by considering their potential adverse effects on the lungs.     

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.     

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.     

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.     

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     

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.     

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.     

An evaluation of zonisamide,including its long-term efficacy,for the treatment of focal epilepsy

Introduction: About 70 million people worldwide are estimated to suffer from epilepsy. Despite a large variety of old and new antiepileptic drugs on the market, about 30% of people with epilepsy do not become seizure-free with medical treatment. This is a major individual and public health burden. Most of these difficult-to-treat patients are having focal seizures. Zonisamide is effective against focal seizures in adults and children and, thus, a therapeutic option for such patients. Its safety profile needs special attention.

Areas covered: Herein, the authors discuss the pharmacology, clinical efficacy and the adverse effects of zonisamide. The article is derived from clinical trial data, long-term studies, meta-analyses, review articles, text books, webpages, and official license information.

Expert opinion: Zonisamide has proven to be efficacious in focal epilepsy in children and adults, although it is not more effective than carbamazepine or other antiepileptic drugs. It is also effective in generalized epilepsy and in several other conditions of the CNS. Its safety profile may prevent it from becoming a first-line drug for focal epilepsy or any other indication.     

Update on BRAF and MEK inhibition for treatment of melanoma in metastatic,unresectable, and adjuvant settings

Introduction: Selective inhibition of the MAPK pathway with BRAF and MEK inhibitors has emerged as a key component of the treatment of BRAF-mutant unresectable/locally advanced metastatic melanoma.

Areas covered: Current data are presented on the efficacy and safety of BRAFi + MEKi combination therapy (dabrafenib/trametinib, vemurafenib/cobimetinib, and encorafenib/binimetinib) from phase I, II, and III trials in the unresectable/locally advanced metastatic setting, as well as neoadjuvant and adjuvant applications. The theoretical basis, pre-clinical findings, clinical trial results and current ongoing clinical studies of combined BRAF/MEK inhibition with immunotherapy, also known as ‘triplet therapy,’ are also explored.

Expert opinion: Combination therapy with BRAF and MEK inhibitors dramatically improves response rates, progression-free survival and overall survival in patients with BRAF-mutant metastatic melanoma compared to historical treatments such as chemotherapy. Some serious adverse effects, including cutaneous squamous cell carcinoma, are attenuated with combination therapy, while less severe and reversible effects including pyrexia, left ventricular dysfunction, and ocular events can be more common with combination therapy. Existing data are insufficient to recommend triplet therapy, or a particular treatment sequence, with respect to BRAF and MEK inhibitors and immune therapies, though results from multiple ongoing trials are anticipated.     

Oral antineoplastic agents: assessment of safety and dose adjustments in clinical practice

Objectives: Although the safety profile of oral antineoplastic agents (OAAs) is better than that of classic chemotherapy, the rate of severe adverse events (AEs) is high. The objective was to assess the reasons for adjustments to treatment with OAAs during the first 100 days of treatment.

Methods: The authors performed a prospective observational study of cancer outpatients who initiated OAAs between November 2015 and October 2017. Dose reductions and treatment interruptions were closely followed-up during the first 100 days after the beginning of treatment with an OAA. The authors described the different safety profile of different OAA classes.

Results: The authors included 443 patients (31 different OAA assessed), of whom 53.0% required their OAA to be adjusted during the first 100 days of treatment. A total of 151 patients required dose reductions and/or interruptions of OAAs owing to AEs. The authors identified 203 AEs in these patients. Treatment with sorafenib, lower ECOG performance status, and first-line treatment were associated with a higher proportion of treatment adjustments due to AEs.

Conclusion: These results in clinical practice could be a first approach to help healthcare professionals to design patient monitoring programs by identifying priority patients and drugs, and remarks the importance of pharmacovigilance in OAAs.     

Pharmacology of new and developing intravenous therapies for the management of seizures and epilepsy

Introduction: Antiepileptic drugs (AEDs) are administered orally for chronic use. Parenteral formulations might be necessary when the oral route is not feasible (e.g. an impairment of consciousness, trauma, dysphagia, gastrointestinal illness) or for treatment of seizure emergencies. At present, few intravenous (IV) formulations are available on the market.

Areas covered: The purpose of this review is to summarize the pharmacological characteristics and clinical applications of IV medications that have been recently introduced to the armamentarium of epilepsy therapy or are currently being developed. Apart from AEDs, other compounds belonging to different pharmacological classes (e.g. diuretics, anesthetics), which have shown potential effectiveness in seizure control, are taken into consideration, and the pathophysiological premises supporting their use for epilepsy treatment are illustrated. The authors give particular focus to immunomodulatory and immunosuppressive agents, which have become the therapeutic cornerstones for immune-mediated epilepsies, despite regulatory obstacles.

Expert opinion: In several circumstances, especially in the case of seizure-related emergencies, clinical practice seems not match literature-based evidence, and several IV AEDs are still used off-label. Strong evidence derived from randomized clinical trials (RCTs) is needed to support the effectiveness and tolerability of any therapeutic approach, however common and “accepted’ it may be, in order to guarantee patient safety and well-being.     

Antibiotic-related adverse events in paediatrics: unique characteristics

Introduction: Antibiotics have saved and are still saving countless human lives from the burden of infectious diseases. However, as with all other drugs, they can cause adverse events. Generally, these are uncommon, mild and spontaneously resolving. However, in some cases, they can cause relevant clinical problems. Compared with adults, children, particularly in the first years of life, have a higher risk of antibiotic-related adverse events for several reasons.

Areas covered: In this paper, the conditions that can contribute to the elevated risk of antibiotic-related adverse events in children are discussed.

Expert opinion: Antibiotic stewardship can be a solution to limit antibiotic abuse and misuse and consequently the incidence of antibiotic-related adverse events in children. Moreover, most of the antibiotic-associated adverse events can be avoided with more extensive pre-marketing medicine investigations, improved postmarket safety surveillance system, increased transparency throughout the clinical research enterprise, increased training of clinical pharmacologists and paediatric researchers, expanded pool of paediatric patients, and providing additional funding and incentives for paediatric drug development.