Background: In pharmacotherapy, the achievement of a target clinical outcome requires a certain level of medication intake or adherence. Based on Haynes's early empirical definition of sufficient adherence to antihypertensive medications as taking ≥80% of medication, many researchers used this threshold to distinguish adherent from non-adherent patients. However, we propose that different diseases, medications and patient's characteristics influence the cut-off point of the adherence rate above which the clinical outcome is satisfactory (thereafter medication adherence threshold). Moreover, the assessment of adherence and clinical outcomes may differ greatly and should be taken into consideration. To our knowledge, very few studies have defined adherence rates linked to clinical outcomes. We aimed at investigating medication adherence thresholds in relation to clinical outcomes. Method: We searched for studies that determined the relationship between adherence rates and clinical outcomes in the databases PubMed, Embase^Ⓡ and Web of Science™ until December 2017, limited to English-language. Our outcome measure was any threshold value of adherence. The inclusion criteria of the retrieved studies were (1) any measurement of medication adherence, (2) any assessment of clinical outcomes, and (3) any method to define medication adherence thresholds in relation to clinical outcomes. We excluded articles considered as a tutorial. Two authors (PB and IA) independently screened titles and abstracts for relevance, reviewed full-texts, and extracted items. The results of the included studies are presented qualitatively. Result: We analyzed 6 articles that assessed clinical outcomes linked to adherence rates in 7 chronic disease states. Medication adherence was measured with Medication Possession Ratio (MPR, n = 3), Proportion of Days Covered (PDC, n = 1), both (n = 1), or Medication Event Monitoring System (MEMS). Clinical outcomes were event free episodes, hospitalization, cortisone use, reported symptoms and reduction of lipid levels. To find the relationship between the targeted clinical outcome and adherence rates, three studies applied logistic regression and three used survival analysis. Five studies defined adherence thresholds between 46 and 92%. One study confirmed the 80% threshold as valid to distinguish adherent from non-adherent patients. Conclusion: The analyzed studies were highly heterogeneous, predominantly concerning methods of calculating adherence. We could not compare studies quantitatively, mostly because adherence rates could not be standardized. Therefore, we cannot reject or confirm the validity of the historical 80% threshold. Nevertheless, the 80% threshold was clearly questioned as a general standard.

Patients with polypharmacy are challenged with the management of their daily medication. Medication management strategies for direct oral anticoagulants (DOAC) are especially important to guarantee medication adherence and to prevent thromboembolic events. Patients are often left alone with finding an appropriate strategy. To explore medication management strategies, to measure adherence to DOAC with the aim of deducing recommendations for practice. Face-to-face semi-structured interviews were conducted at the home of outpatients who were taking ≥4 medications daily including a DOAC, and self-managing their medication. A small electronic device (Time4Med™) was given to record medication intake during the four following weeks. During a second home visit, participants saw a graph of their medication intake as dot chart, and obtained a feedback. Interviews were transcribed verbatim and thematically analysed. Medication adherence was calculated with electronic data. Eighteen individuals (61.1% female; median age 77.5 years) were interviewed and reported 30 different medication management strategies, together with triggers, advantages and limitations. They combined at least five strategies, composed of internal (memory-based) and external (packaging-based or intake-based) strategies. The number of strategies was neither associated with the number of medications nor with medication adherence. Taking adherence was <100% for eight patients (44.4%). The inability of any medication management strategy to adapt to ageing and cognitive decline emerged as its most dramatic limitation, especially because individuals would fail to notice when their strategy became unsuited. Elderly patients develop manifold medication management strategies, which can inspire future medication users. Limitations are present such as forgetting medication intake in spite of a management strategy. The moment to adapt the strategy to ageing or cognitive decline is crucial and often goes unnoticed. It is therefore decisive that healthcare professionals regularly re-evaluate the appropriateness of the medication management strategies during counselling or ideally during home visits.

Background: Parkinson disease (PD) is a chronic progressive neurodegenerative disorder leading to motor and non-motor impairment, often resulting in severe loss of quality of life. There are symptomatic treatments without effect on the progression of PD. A disease-modifying treatment that could ideally stop the neurodegenerative process is direly needed. Monosialotetrahexosylganglioside (GM1) is a promising molecule with neuroprotective effects in preclinical models of PD and has yielded encouraging results in patients with PD in a randomized placebo-controlled trial. Talineuren (TLN) is a liposomal formulation of GM1 that has been shown to cross the blood–brain barrier in animals. We assessed the safety and pharmacokinetics (PK) of TLN in patients with PD. Methods and findings: We prospectively enrolled 12 patients with PD into a single-center, open-label phase I trial to assess the safety and tolerability of weekly infusions with TLN. The maximum suitable dose of TLN was determined by dose escalation in three patients. All three patients tolerated the predetermined maximal dose of 720 mg. Subsequently, these and nine additional patients received weekly infusions at the maximum suitable dose of 720 mg TLN over two months (1 patient stopped prematurely). PK were determined for the additional nine patients as a secondary outcome measure. C_max was reached 4 h after infusion start for all but one participant, who reached C_max after 1 h, while the median plasma half-life was reached at 12.6 h. All adverse events were continuously assessed as the primary objective and coded according to the Medical Dictionary for Regulatory Activities (MedDRA). Clinical manifestations of PD were assessed as secondary outcomes using the Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), including a levodopa challenge test at baseline and end. In addition to weekly history taking, scales to measure mood, behavior, quality of life, sleepiness, non-motor symptoms of PD, and cognition were used as further secondary outcomes as well as assessing the Levodopa-Equivalent Daily Dose (LEDD). Overall, 304 adverse events (mean: 25.33; 6–75 events per patient) occurred, 267 of which were mild (mean: 22.25; 3–72 events per patient). 23 were considered related to the study treatment (0–8 events per patient). Very mild-to-severe acute infusion reactions at the second, third, or fourth administration of TLN within the first minutes of the infusion occurred in seven patients. All reported back or neck pain. Other acute infusion reactions were urticaria, plethora, nausea, and chest pain. These adverse reactions disappeared within minutes of stopping the infusion and did not recur when TLN administration was resumed at a very low rate. Beyond the fourth administration, infusions could be given at increased rates up to 370 ml/h, and no acute reaction occurred anymore. The mechanism of this acute infusion reaction remains unclear. Some patients reported mild dizziness for a few hours after TLN following many but not all administrations throughout the study. Non-motor symptoms of PD, motor parkinsonian signs off medication, and quality of life improved significantly during the treatment phase, including the MDS-UPDRS total score (mean decrease −11.09; 95% Confidence Interval [CI]; −18, −4.1; p = 0.006), the Parkinson’s disease Questionnaire-39 (PDQ-39) summary index (mean decrease −2.91; 95% CI; −4.4, −1.4; p = 0.005), and the Non-Motor Symptoms Questionnaire (NMS-Quest) (mean decrease −4.27; 95% CI; −6.5, −2.1; p = 0.009). No statistically significant improvements were seen in the Montreal Cognitive Assessment (MoCA) (mean decrease −0.73; 95% CI; −2.1, 0.62; p = 0.255), Epworth Sleepiness Scale (mean increase 0.09; 95% CI; −2.6, 2.8; p > 0.999), Beck Depression Inventory (BDI) (mean decrease −1.27; 95% CI; −3.8, 1.3; p = 0.257), and the Starkstein Apathy Scale (mean increase 0.36; 95% CI; −1.6, 2.4; p = 0.822). Dopaminergic medications remained stable during the study (LEDD mean increase 8.18; 95% CI; −7.7, 24; p = 0.423). While clinical improvements indicate a benefit associated with TLN treatment, the trial design does not allow for definite conclusions regarding efficacy. A randomized, placebo-controlled trial will be required to corroborate our exploratory findings. Conclusion: TLN is safe and well-tolerated in general. This prospective phase I trial revealed non-allergic habituating acute infusion reactions at the second, third, or fourth treatment that can be prevented by a slower rate of infusion. Importantly, the exploratory results suggest a consistent improvement of signs and symptoms of PD. Trial registration: The NEON trial is registered at the US National Institutes of Health (ClinicalTrials.gov) #NCT04976127 and in the Swiss National Clinical Trials Portal (SNCTP000004631)

Counseling patients on medication adherence could be ameliorated in pharmacy practice. There is a lack of simple and practical strategies to address medication adherence with patients in daily practice. The goal was to develop and test a framework that allows pharmacy teams to define and apply a strategy to address medication adherence in community pharmacies. A framework based on the principles of social marketing was developed. It consisted of 3 items: the target patient (“Who”), the target plan (“How”), and the target goal (“How many”). To test the framework, each participating pharmacy team developed their strategy by defining the 3 items and applied them during one pilot day. A master student observed the encounters between patients and pharmacy team members and used a structured checklist to document the patient's characteristics, counseling content, and strategy use. Pharmacy teams answered a feedback questionnaire at the end of the pilot day. Ten pharmacy teams were included. During a brainstorming session that lasted on average 31 ± 8 min, unique strategies comprised 18 different target patients and 20 different target plans. The planned target goal was a mean of 31 patients (range: 1 to “all”). A total of 325 encounters were observed, of which 208 patients (64%) corresponded to the predefined target patients. Medication adherence was addressed with 73 patients (22.5%), and adherence counseling was performed with 50 patients (15%). The pharmacy teams accepted the framework and judged it feasible and adaptable to their needs. The proposed framework represents a simple tool that enables pharmacy teams to develop a strategy for addressing medication adherence in community pharmacies. Its adoption by pharmacy teams occurred without additional training and its integration into daily practice without difficulties. A further study is now needed to investigate if pharmacy teams can successfully engage patients in discussion on medication adherence and ultimately propose targeted adherence interventions.

Introduction: Calculating patients’ medication availability from dispensing or refill data is a common method to estimate adherence. The most often used measures, such as the medication possession ratio (MPR), average medication supplies over an arbitrary period. Averaging masks the variability of refill behavior over time. Goal: To derive a new absolute adherence estimate from dispensing data. Method: Dispensing histories of patients with 19 refills of direct oral anticoagulants (DOAC) between 1 January 2008 and 31 December 2017 were extracted from 39 community pharmacies in Switzerland. The difference between the calculated and effective refill day (ΔT) was determined for each refill event. We graphed ΔT and its dichotomized version (dΔT) against the MPR, calculated mean ΔT and mean dΔT per refill, and applied cluster analysis. Results: We characterized 2204 refill events from 116 DOAC patients. MPR was high (0.975 ± 0.129) and showed a positive correlation with mean ΔT. Refills occurred on average 17.8 ± 27.9 days “too early”, with a mean of 75.8 ± 20.2 refills being “on time”. Four refill behavior patterns were identified including constant gaps within or at the end of the observation period, which were critical. Conclusion: We introduce a new absolute adherence estimate ΔT that characterizes every refill event and shows that the refill behavior of DOAC patients is dynamic.

Background: Parkinson disease (PD) is a chronic progressive neurodegenerative disorder leading to motor and non- motor impairment often resulting in severe loss of quality of life. There are symptomatic treatments without effect on the progression of PD. A disease-modifying treatment that could ideally stop the neurodegenerative process is direly needed. Monosialotetrahexosylganglioside (GM1) is a promising molecule with neuroprotective effects in preclinical models of PD and has yielded encouraging results in patients with PD in a randomized placebo-controlled trial. Talineuren (TLN) is a liposomal formulation of GM1 that has been shown to cross the blood-brain barrier in animals. We assessed the safety and pharmacokinetics of TLN in patients with PD. Methods and Findings: We prospectively enrolled 12 patients with PD into a single-center, open-label phase I trial to assess the safety and tolerability of weekly infusions with Talineuren. The maximum suitable dose of Talineuren was determined by dose escalation in three patients. Subsequently, these and nine further patients received weekly infusions at the maximum suitable dose of Talineuren over two months (1 patient stopped prematurely). All adverse events were continuously assessed as the primary objective and coded according to the Medical Dictionary for Regulatory Activities (MedDRA®). Clinical manifestations of PD were assessed as secondary outcomes using the Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) including a levodopa challenge test at baseline and end. In addition to weekly history taking, scales to measure mood, behaviour, quality of life, sleepiness, non-motor symptoms of PD, and cognition were used. Dose escalation identified a maximum suitable weekly dose of 720 mg. Overall, 304, mostly mild adverse events occurred. Twenty- three were considered related to the study treatment. Very mild to severe acute infusion reactions at the 2nd, 3rd, or 4th administration of TLN within the first minutes of the infusion occurred in seven patients. All reported back or neck pain. Other acute infusion reactions were urticaria, plethora, nausea, and chest pain. These adverse reactions disappeared within minutes of stopping the infusion and did not recur when Talineuren administration was resumed at a very low rate. Beyond the 4th administration, infusions could be given at increased rates up to 370 ml/h and no acute reaction occurred anymore. The mechanism of this acute infusion reaction remains unclear. Some patients reported mild dizziness for a few hours after Talineuren following many but not all administrations throughout the study. Non-motor symptoms of PD, motor parkinsonian signs off medication, and quality of life improved significantly during the treatment phase, including the MDS-UPDRS total score (mean decrease 11.09±10.47 points; p=0.006) and the PDQ-39 summary index (mean decrease 2.91±2.25 points, p =0.002). Dopaminergic medications remained stable during the study. Conclusion: Talineuren is safe and well-tolerated in general. This prospective phase I trial revealed non-allergic habituating acute infusion reactions at the 2nd, 3rd, or 4th treatment that can be prevented by a slower rate of infusion. Importantly, the exploratory results suggest a consistent improvement of signs and symptoms of PD.