A review of the national adverse drug reaction (ADR) & medication errors reporting system of Malta

The overall objectives of Pharmacovigilance include early identification of potential safety hazards, evaluation, monitoring and where appropriate, implementation of regulatory action to maximise benefits and minimise risks associated with medicinal products. Reporting of an ADR associated with use of a medicinal product as well as medication errors is an essential source of necessary information that is required to achieve these objectives. Safety concerns that arise from spontaneous reporting contribute to assessment of the risk benefit balance and hence lead to a regulatory action which could be suspension or revocation of marketing authorization of the product or change in the product information. Furthermore these safety concerns can be communicated to healthcare professionals through Direct Healthcare Professional Communications (DHPCs) and safety circulars and they form the basis of designing Risk Minimisation Measures (RMMs). The establishment of a functional ADR reporting system by law since 2004, not only facilitates participation in the national and EU regulatory process, but also enables Malta to participate in the WHO Programme for International Drug Monitoring, both by contributing to and obtaining data from this extensive information resource.peer-reviewe

Treatment of Leber’s hereditary optic neuropathy : an overview of recent developments

Leber’s hereditary optic neuropathy (LHON) is a rare, maternally-inherited optic neuropathy caused by mitochondrial DNA point mutations and which can cause blindness. Currently, Raxone (idebenone) is the only available medicinal product authorised to treat LHON within the European Union and LHON remains an unmet medical need. The aim of this article was to summarise interventional clinical trials published over the past 5 years (between 2014 and 2019) with the primary purpose of treating LHON. Therapeutic approaches discussed include modulating agents of the mitochondrial electron transport chain such as Raxone, cysteamine bitartrate and KH176, inhibitors of apoptosis such as elamipretide, gene therapy medicinal products such as GS010 and scAAV2P1ND4 and retinal tissue regeneration medicinal products such as bone marrow-derived stem cells.peer-reviewe

Alzheimer's disease and neuroinflammation: will new drugs in clinical trials pave the way to a multi-target therapy?

: Despite extensive research, no disease-modifying therapeutic option, able to prevent, cure or halt the progression of Alzheimer's disease [AD], is currently available. AD, a devastating neurodegenerative pathology leading to dementia and death, is characterized by two pathological hallmarks, the extracellular deposits of amyloid beta (Aβ) and the intraneuronal deposits of neurofibrillary tangles (NFTs) consisting of altered hyperphosphorylated tau protein. Both have been widely studied and pharmacologically targeted for many years, without significant therapeutic results. In 2022, positive data on two monoclonal antibodies targeting Aβ, donanemab and lecanemab, followed by the 2023 FDA accelerated approval of lecanemab and the publication of the final results of the phase III Clarity AD study, have strengthened the hypothesis of a causal role of Aβ in the pathogenesis of AD. However, the magnitude of the clinical effect elicited by the two drugs is limited, suggesting that additional pathological mechanisms may contribute to the disease. Cumulative studies have shown inflammation as one of the main contributors to the pathogenesis of AD, leading to the recognition of a specific role of neuroinflammation synergic with the Aβ and NFTs cascades. The present review provides an overview of the investigational drugs targeting neuroinflammation that are currently in clinical trials. Moreover, their mechanisms of action, their positioning in the pathological cascade of events that occur in the brain throughout AD disease and their potential benefit/limitation in the therapeutic strategy in AD are discussed and highlighted as well. In addition, the latest patent requests for inflammation-targeting therapeutics to be developed in AD will also be discussed

Alzheimer’s disease and neuroinflammation: will new drugs in clinical trials pave the way to a multi-target therapy?

Despite extensive research, no disease-modifying therapeutic option, able to prevent, cure or halt the progression of Alzheimer’s disease [AD], is currently available. AD, a devastating neurodegenerative pathology leading to dementia and death, is characterized by two pathological hallmarks, the extracellular deposits of amyloid beta (Aβ) and the intraneuronal deposits of neurofibrillary tangles (NFTs) consisting of altered hyperphosphorylated tau protein. Both have been widely studied and pharmacologically targeted for many years, without significant therapeutic results. In 2022, positive data on two monoclonal antibodies targeting Aβ, donanemab and lecanemab, followed by the 2023 FDA accelerated approval of lecanemab and the publication of the final results of the phase III Clarity AD study, have strengthened the hypothesis of a causal role of Aβ in the pathogenesis of AD. However, the magnitude of the clinical effect elicited by the two drugs is limited, suggesting that additional pathological mechanisms may contribute to the disease. Cumulative studies have shown inflammation as one of the main contributors to the pathogenesis of AD, leading to the recognition of a specific role of neuroinflammation synergic with the Aβ and NFTs cascades. The present review provides an overview of the investigational drugs targeting neuroinflammation that are currently in clinical trials. Moreover, their mechanisms of action, their positioning in the pathological cascade of events that occur in the brain throughout AD disease and their potential benefit/limitation in the therapeutic strategy in AD are discussed and highlighted as well. In addition, the latest patent requests for inflammation-targeting therapeutics to be developed in AD will also be discussed

European Union pharmacovigilance capabilities : potential for the new legislation

European Directives and Regulations introduced between late 2010 and 2012 have substantially overhauled pharmacovigilance processes across the European Union (EU). In this review, the implementation of the pharmacovigilance legislative framework by EU regulators is examined with the aim of mapping Directive 2010/84/EU and Regulation EC No. 1235/2010 against their aspired objectives of strengthening and rationalizing pharmacovigilance in the EU. A comprehensive review of the current state of affairs of the progress made by EU regulators is presented in this paper. Our review shows that intense efforts by regulators and industry to fulfil legislative obligations have resulted in major positive shifts in pharmacovigilance. Harmonized decision making, transparency in decision processes with patient involvement, information accessibility to the public, patient adverse drug reaction reporting, efforts in communication and enhanced cooperation between member states to maximize resource utilization and minimize duplication of efforts are observed.peer-reviewe

Safety implications of low-dose amitriptyline in neuropathic pain

Background: Treatment guidelines in neuropathic pain list amitriptyline as a first-line option. Modest evidence on efficacy and safety concerns possibly shape the rationale behind dosing recommendations. An observational study was carried out to understand the usefulness of safety monitoring for this established medicine. Methods: Twenty-six (26) subjects were categorized into 2 groups: 13 patients under pain management receiving 10 mg amitriptyline daily for less than 12 months, and 13 patients under psychiatric care receiving a daily dose of 25–75 mg for over 12 months. Dose-related reference ranges were calculated and blood levels were assessed for the case examples presented. Adverse events and ECGs were collated. QT intervals were corrected using Bazett’s and Fridericia’s formulae. Side-effect frequencies were evaluated both within the research groups, and in the broader perspective of spontaneous ADR reporting through EudraVigilance. Results: The applicability of dose-related reference ranges, considering confounding factors such as drug interactions and metabolizer status, is discussed. Patients in both groups reported on average three side-effects, with drowsiness being reported more significantly in the 10 mg group and possibly attenuating with time; an observation not replicated for dry mouth. ADR reports with non-granulated information limit the usefulness of the data retrieved. Comparison of QT corrected with Bazett’s and Fridericia’s formulae suggests that Bazett’s may overestimate the number of patients on amitriptyline with QTc prolongation. Conclusions: This research supports the adoption of evolving research observations to understand the implications of dosing recommendations and safety assessments in attempt of delivering individualized treatment with minimal risk.peer-reviewe

Evidence that heat acclimation training may alter sleep and incidental activity

This randomized cross-over study tested the hypothesis that heat acclimation training would detrimentally affect sleep variables and alter incidental physical activity compared to a thermoneutral training control condition. Eight recreationally trained males (V̇ O2peak 49±4.9 mL. kg-1.min-1) completed two separate interventions separated by at least 31 days: 5 consecutive day training blocks of moderate-intensity cycling (60 min·day-1 at 50% peak power output) in a hot (34.9±0.7 °C and 53±4 % relative humidity) and a temperate (22.2±2.6 °C; 65±8 % relative humidity) environment. Wrist-mounted accelerometers were worn continuously for the length of the training blocks and recorded physical activity, sleep quality and quantity. Data were analysed in a Bayesian framework, with the results presented as the posterior probability that a coefficient was greater or less than zero. Compared to the temperate training environment, heat acclimation impaired sleep efficiency (Pr β0 = .917). Daily sedentary time was, on average, 35 min longer (Pr β>0 = .973) and light physical activity time 18 min shorter (Pr β>0 = .960) during the heat acclimation period. No differences were observed between conditions in sleep duration, subjective sleep quality, or moderate or vigorous physical activity. These findings may suggest that athletes and coaches need to be cognisant that heat acclimation training may alter sleep quality and increase sedentary behaviour

The effects of daily cold-water recovery and postexercise hot-water immersion on training-load tolerance during 5 days of heat-based training

PURPOSE: To examine the effects of daily cold- and hot-water recovery on training load (TL) during 5 days of heat-based training. METHODS: Eight men completed 5 days of cycle training for 60 minutes (50% peak power output) in 4 different conditions in a block counter-balanced-order design. Three conditions were completed in the heat (35°C) and 1 in a thermoneutral environment (24°C; CON). Each day after cycling, participants completed 20 minutes of seated rest (CON and heat training [HT]) or cold- (14°C; HTCWI) or hot-water (39°C; HTHWI) immersion. Heart rate, rectal temperature, and rating of perceived exertion (RPE) were collected during cycling. Session-RPE was collected 10 minutes after recovery for the determination of session-RPE TL. Data were analyzed using hierarchical regression in a Bayesian framework; Cohen d was calculated, and for session-RPE TL, the probability that d > 0.5 was also computed. RESULTS: There was evidence that session-RPE TL was increased in HTCWI (d = 2.90) and HTHWI (d = 2.38) compared with HT. The probabilities that d > 0.5 were .99 and .96, respectively. The higher session-RPE TL observed in HTCWI coincided with a greater cardiovascular (d = 2.29) and thermoregulatory (d = 2.68) response during cycling than in HT. This result was not observed for HTHWI. CONCLUSION: These findings suggest that cold-water recovery may negatively affect TL during 5 days of heat-based training, hot-water recovery could increase session-RPE TL, and the session-RPE method can detect environmental temperature-mediated increases in TL in the context of this study.</p