Studying the impact of a medication use evaluation for polymedicated older patients by the community pharmacist (SIMENON): study protocol.

BACKGROUND: Aged polymedicated patients are particularly vulnerable for drug-related problems. A medication review aims to optimize the medication use of patients and improve health outcomes. In this study, the effect of a pharmacist-led medication use review is investigated for polymedicated ambulatory older patients with the aim of implementing this pharmaceutical care intervention across Belgium. METHODS: This article describes the study protocol of the SIMENON study and reports the results of the feasibility study, which aimed to test and optimize this study protocol. In the SIMENON intervention study, 75 Belgian community pharmacies each recruit 12 patients for a medication use review. For each patient, the identified drug-related problems and subsequent interventions are registered using the PharmDISC classification. In a subset of Dutch speaking patients, a pretest-posttest single group design is used to measure the impact of this review on patient related outcomes using questionnaires. The main outcome of the study is the type and number of drug-related problems and related interventions. A second outcome is the impact of the medication use review on adherence, objectively measured with dispensing data. Evolution in medication related quality of life is another outcome, measured with the Living with Medicines Questionnaire version 3. Other patient reported outcomes include adherence, self-management, patient satisfaction, fall incidents and use of emergency healthcare services. DISCUSSION: The findings of this study can provide data on the effectiveness of a medication use review in the Belgian primary care setting. Furthermore, it will provide insights in which patients benefit most of this intervention and therefore facilitate the implementation of medication review in Belgium. TRIAL REGISTRATION: ClinicalTrials.gov NCT03179722 . Retrospectively registered 7 June 2017.

[The development of clinical practice algorithms for the appropriate use of psychotropic drugs in older persons with high risk of falls]. / Ontwikkeling van algoritmes voor oordeelkundig gebruik van psychofarmaca bij ouderen met verhoogd valrisico.

Psychotropic drugs (hypno-sedatives, antidepressants and antipsychotics) are commonly used in the older population. On the long term, psychotropic drug use in older persons is associated with several negative functional outcomes such as an increased risk of falls. Gradual withdrawal of psychotropic drugs in older persons is feasible and leads to a significant reduction of falls. Both withdrawal of psychotropic drugs as well as the initiation of appropriate treatment with psychotropic drugs requires knowledge, consultation and cooperation between disciplines and a mentality change among healthcare professionals. In order to inform and support healthcare professionals, the Centre of Expertise for Fall and Fracture Prevention Flanders developed three clinical practice algorithms for the appropriate use of psychotropic drugs in older persons with high risk of falls and a fact sheet with background information.

[Frequency and nature of drug related problems with corticosteroids in Belgian community pharmacies]. / Fréquence et nature des problems liés aux corticosteroïdes dans les officines publiques de Belgique.

Aim Aims are: 1] Identify causes of Drug Related Problems (DRPs), interventions performed by pharmacists and results of corticosteroid- related problems and 2] distinguish between problems related to inhaled and general corticosteroids. Methods During 5 days of their internship, 534 final year students of pharmaceutical sciences in six Belgian universities collected DRPs encountered in community pharmacies, as well as related interventions performed by pharmacists and the result of the intervention. The DRPs' electronic registration was done through an adapted tool for Belgium based on the classification of Pharmaceutical Care Network Europe [PCNE- v 6.2]. Findings The frequency of DRPs is 24,8%. 766 DRPs (4,8%) related to corticosteroids, of which 351 were inhaled corticosteroids. The most common causes of corticosteroid-related problems (53- 59%) were technical causes. The most represented category of clinical causes was the inappropriate choice of drug [33-41%]. Pharmacists' intervention was similar for inhaled and general corticosteroids. Pharmacists intervened orally with patients in 38-40% of total interventions, and in writing in 16% of interventions. Pharmacists did not react in 16% of corticosteroid-related problems. 81-83% of PLMS were resolved partially or completely. Conclusion In conclusion, DRPs detected in community pharmacies related to corticosteroid are infrequent (4,8% of DRPs) but 82% of detected problems have been resolved. Furthermore, the study shows the importance for the Belgian health system to introduce an official DRPs classification and software facilitating their documentation in community pharmacies.

[Drug-drug interactions with risk of QT-prolongation. A epidemiological study in Belgian community pharmacies]. / Interactions médicamenteuses comportant in risqué d'allongement de l'interalle QT: étude épidémiologique dans les pharmacies belges.

Introduction Community pharmacists have an important role in the management of drug-drug interactions (DD). One of the interactions that can lead to serious adverse drug events, more specifically Torsade de Pointes and sudden cardiac death, are DDI with risk of CT-prolongation. Many drugs from different therapeutic classes have been linked with the risk of QT-prolongation (as listed in the QT-drug lists of CredibleMeds]. Moreover, patient-specific risk factors should be taken into account. This leads to a complex risk estimation of QT-prolongation for each patient. Aim The aim of this study is to investigate the prevalence of DDI and the management of these interactions in community pharmacies, with special attention for DDI with a risk of QT-prolongation. Method This epidemiological study is based on data of an interuniversity, observational study in 534 Belgian community pharmacies with a last-year pharmacy student (November 2012 - March 2013), in which all drug-related problems (DRP) and associated interventions of the pharmacist were registered for drugs on prescription. In this study, all DRP that were registered as a DDI were selected. The evidence for these DD was verified in four information sources (DelphiCare, Medscape, Drugs.com, handbook 'Commentaren Medicatiebewaking'). Finally, an in-depth analysis was performed for DDI with risk of QT-prolongation. QT-prolonging drugs were identified with the QT-drug lists of CredibleMeds. Results In total, 64.962 prescriptions and 15.952 DRP were registered in the interuniversity study, of which 1858 DRP (11.6%) described as a DDI that was confirmed in at least one of the information sources. Of these interactions, 223 [12.0%] were linked with a risk of QT- prolongation. The majority of the concerned drugs are situated in list 1 of CredibleMeds (known risk of Torsade de Pointes). In 69 CT-prolonging DDI, two drugs of list 1 were involved. The most frequent QT-prolonging DDI was between escitalopram and quetiapine (N=11J. In 69.5% of the QT-prolonging DDI, an intervention was performed by the community pharmacist. In 47.8% of these interventions, the DDI was discussed with the patient. In 28.3% of the QT-prolonging DDI, the pharmacist contacted the physician. However, the proposed intervention was often considered unnecessary by the physician (42.9%). In only 4.5% of the interventions, the involved CT-prolonging drug was replaced by an alternative. Conclusion DDI represent an important part of the DRP in community pharmacies, including DDI with a risk of CT-prolongation (12% of the interactions). In the majority of the QT-prolonging DDI, at least one QT-prolonging drug of list 1 of CredibleMeds [known risk of Torsade de Pointes) was involved. In only 4.5% of the interventions, the involved QT-prolonging drug was replaced by an alternative.

[Drug related problems in Belgian community pharmacies]. / Les problèmes liés aux médicaments dans les officines belges.

INTRODUCTION: The identification, the management and if possible the prevention of drug related problems (DRP), are the main responsibilities of pharmacists. AIM: The aims of the study were 1/to investigate the frequency and nature of drug related problems detected by community pharmacists, 2/to inventories the frequency and nature of the interventions by community pharmacists on prescribed medicines, and 3/to evaluate whether there is a difference between DRP detection at the moment of dispensing versus in a quiet setting (a posteriori detection). METHOD: All trainees of the participating universities of Belgian were asked to contribute to a observational study. Participating pharmacists quantified DRP's and their interventions on prescribed medicines for 5 days. Registrations were made by using a web tool based on an adapted version of the classification list of PCNE. The registration took place in two phases, at the time of delivery as well as in an a posteriori verification of the prescriptions with the pharmaceutical record file of the patients. RESULTS: The study was conducted from November 2012 to April 2013 in 534 community-pharmacies with internship. During this period 9.869 prescriptions (15%) with at least one DRP were detected on a total of 64.962 prescriptions treated by tutor pharmacists. Since there could be more than one problem on a prescription, 15.952 DRP's were registered. 2.597 of the DRP's were detected by a posteriori verification. 75% of all problems had a technical cause and 37% were clinical in nature. Under the technical causes an incomplete prescription was the most common. The most frequently registered clinical causes were a drug interaction, an inopportune time of intake, a too high or too low dose and an unsuitable drug. Participating pharmacists solved almost 3 of the 4 detected DRP's. In more than half of the DRP's, the patient was verbally and/or written informed. In 44% of the a posteriori discovered problems, the pharmacist intervened. CONCLUSION: Pharmacist detected one or more DRP's with 15% of the prescriptions. Analysis of a prescription prior to dispensing the medicines therefore appears necessary. The active intervention of the pharmacist in 83% of the problems indicates that he contributes to the optimization of drug therapy with a potential increase in the quality of life of the patient and a reduction in the cost of healthcare. The a posteriori discovered DRP's demonstrate the need for pharmacist lead meditation reviews possibly together with the physician and/or patient.

[Adherence to chronic medication: also a frequent problem in Belgium!]. / L'observance thérapeutique des traitements chroniques: problématique pour les patients belges aussi!

Medication adherence in chronic conditions such as asthma, type 2 diabetes, heart failure, HIV and cancer appears to be a frequent problem. However, the literature on adherence in patients who use inhaled corticosteroids (ICS), oral hypoglycemic agents, drugs for heart failure, antiretrovirals or oral chemotherapy, contains little or no relevant data for Belgium. In the context of a Master thesis in Pharmaceutical care at KU Leuven, a quantitative study was performed to determine the prevalence of adherence to chronic medication in Belgium. This retrospective, cross-sectional study used a database containing refill data of a regional pharmacists' association (KLAV). Out of the 603 pharmacies affiliated with this association, all 50 pharmacies where HIV medication was delivered, were selected. Dispensing data from the selected pharmacies were collected from 01/07/2008 to 31/12/2009 for five pathologies, i.e.; asthma, type 2 diabetes, heart failure, HIV and cancer. Adherence (TT) was calculated with the Medication Refill Adherence (MRA) method. In order to determine whether there were associations between age, gender, drug class and adherence, Chi-square tests were used. Compared with the other patients, cancer patients were the most adherent in taking their drugs (median adherence rate = 88%). In addition, this was the only group in which the median adherence rate was above the set limit of 80%. The patients who were prescribed inhaled corticosteroids were the least adherent (median adherence rate = 38%). More than 50% of patients with asthma/COPD, heart failure and diabetes were classified as "under-users". Furthermore, the results showed a significant association within asthma patients between gender and adherence. In asthma, type 2 diabetes, heart failure and HIV patients there was a significant relationship between age and adherence and drug class and adherence. As the current study has some limitations, the results should be handled with caution. Nevertheless, the current study shows that also in Belgium there is a problem with medication adherence in chronic conditions, especially in asthma patients.

Factors determining social distance toward people with depression among community pharmacists.

OBJECTIVE: The aim of the present study was to measure stigma among community pharmacists regarding patients with depression, using social distance as a proxy measure. Furthermore, factors influencing stigmatization were identified. METHODS: A survey consisting of questions regarding social distance, cognitive attitude components, stereotypical beliefs and behavioural tendencies towards pharmaceutical care for patients with depression was carried out. The survey was completed by 149 community pharmacists with a response rate of 82%. Multiple linear regression analysis was applied to the results of the survey. RESULTS: Most pharmacists endorsed social distance towards patients with depression. The social distance further increased the more the situation described implied "social closeness". Age, depression care attitude, the stereotypical belief "danger to others" and the level of involvement pharmacists showed towards patients with depression were found to predict social distance. The present model explains 32.3% of the variance in social distance. CONCLUSION: The results showed that community pharmacists have a stigmatizing attitude towards patients with depression. The determinants found to influence these stigmatizing attitudes might be addressed when trying to reduce stigmatization of patients with depression.

[Role of the community pharmacist in the management of drug related problems in home care patients]. / Rôle du pharmacien d'officine dans la gestion des problèmes liès aux médicaments dans le cadre des soins à domicile.

Medication management in home care is an error prone process. In a small pilot project in Flanders, community pharmacists collaborated with physicians and home care nurses through a shared electronic care plan, to optimize the medication management of their home care patients. The pilot project shows that GPs and nurses are positive about the possible contribution of the pharmacist in medication management of home care patients. A larger follow up study is necessary to further identify possible roles of pharmacists in home care and to show related health benefits.

Patient adherence to oral anticancer drugs: an emerging issue in modern oncology.

The steady increase in the use of oral anticancer drugs in modern oncology has created a paradigm shift, challenging traditional attitudes towards cancer care and requiring new concepts of organization of oncology services. Important issues are the prolonged treatment period, management of toxicity, treatment adherence, reimbursement conditions and patient and family education. Although most patients generally prefer oral therapy over intravenous treatment for reasons of convenience, the daily use of oral anticancer drugs can be a challenging commitment for many patients. Reports on adherence and persistence among patients with cancer show that adherence ranges from 16% to 100%, depending on the type of therapy and the measurement/definition of adherence. Apart from demographic, disease and therapy related factors, the determinants that mostly influence (non-)adherence are the satisfaction with care activities performed at the initiation of the drug treatment, and the perceived necessity of treatment. Therefore, patient education addressing these issues is considered the cornerstone of successful oral anticancer treatment. Studies examining the role of different health care providers in the pharmacotherapeutic care of patients with cancer, treated with oral anti-cancer drugs, support the need for a multidisciplinary approach to achieve a maximum benefit for the individual patient and consequently for the whole health system. Limiting adverse events and developing appropriate supportive care are only some aspects that need to be considered in this.

[How to improve the continuity of pharmacotherapy at hospital admission and discharge]. / Comment optimiser la continuité du traitement médicamenteux entre l'hôpital et le domicile?

The continuity of pharmacotherapy is of vital importance when patients move from one health care setting to another. Unfortunately, this continuity is not always guaranteed. The aim of this study is to propose solutions to enhance the continuity of pharmacotherapy at hospital admission and discharge. The study consists of a systematic review of the international literature and an analysis of seamless care initiatives in seven selected countries; a summary of Belgian data on problems as well as solutions with regard to continuity of care; a quantification of the extent of medication changes as a result of a hospital stay in Belgium; and a qualitative analysis of the perception of Belgian health care professionals (HCPs) on approaches to improve seamless care. The literature review yielded 15 papers of sufficient quality. However, this review did not generate definitive conclusions on the clinical impact and the cost-effectiveness of interventions aiming to enhance the continuity of pharmacotherapy. The most important initiatives that have been put in practice in foreign countries include the development and implementation of guidelines for HCPs; national information campaigns; education of HCPs; and the development of information technologies as to share patient and prescription data between settings of care. For Belgium, 66 seamless care initiatives were identified. The high number and variety of projects show the interest for this topic as well as the involvement of various HCPs from diverse settings in the development of solutions. Based on this research, and the solutions discussed in the focus groups, the following elements are proposed to enhance the continuity of pharmacotherapy: a national guideline governing the continuity of pharmacotherapy; a national campaign to sensitize HCPs and patients in this area; the availability of a comprehensive and up to date medication list for each patient; and electronic healthcare infrastructure that facilitates sharing of information.

Determinants of mental health stigma among pharmacy students in Australia, Belgium, Estonia, Finland, India and Latvia.

BACKGROUND: Healthcare professionals commonly exhibit negative attitudes toward people with mental disorders. Few international studies have sought to investigate the determinants of stigma. OBJECTIVE: To conduct an international comparison of pharmacy students' stigma towards people with schizophrenia, and to determine whether stigma is consistently associated with stereotypical attributes of people with schizophrenia. METHOD: Students (n = 649) at eight universities in Australia, Belgium, India, Finland, Estonia and Latvia completed a seven-item Social Distance Scale (SDS) and six items related to stereotypical attributes of people with schizophrenia. RESULTS: Mean SDS scores were 19.65 (+/- 3.97) in Australia, 19.61 (+/- 2.92) in Belgium, 18.75 (+/- 3.57) in India, 18.05 (+/- 3.12) in Finland, and 20.90 (+/- 4.04) in Estonia and Latvia. Unpredictability was most strongly associated with having a high social distance in Australia (beta = -1.285), the perception that people will never recover in India (beta = - 0.881), dangerousness in Finland (beta = -1.473) and the perception of being difficult to talk to in Estonia and Latvia (beta = -2.076). Unpredictability was associated with lower social distance in Belgium (beta = 0.839). CONCLUSION: The extent to which students held stigmatizing attitudes was similar in each country, however, the determinants of stigma were different. Pharmacy education may need to be tailored to address the determinants of stigma in each country.

Thiamine pyrophosphate: an essential cofactor for the alpha-oxidation in mammals--implications for thiamine deficiencies?

The identification of 2-hydroxyphytanoyl-CoA lyase (2-HPCL), a thiamine pyrophosphate (TPP)-dependent peroxisomal enzyme involved in the alpha-oxidation of phytanic acid and of 2-hydroxy straight chain fatty acids, pointed towards a role of TPP in these processes. Until then, TPP had not been implicated in mammalian peroxisomal metabolism. The effect of thiamine deficiency on 2-HPCL and alpha-oxidation has not been studied, nor have possible adverse effects of deficient alpha-oxidation been considered in the pathogenesis of diseases associated with thiamine shortage, such as thiamine-responsive megaloblastic anemia (TRMA). Experiments with cultured cells and animal models showed that alpha-oxidation is controlled by the thiamine status of the cell/tissue/organism, and suggested that some pathological consequences of thiamine starvation could be related to impaired alpha-oxidation. Whereas accumulation of phytanic acid and/or 2-hydroxyfatty acids or their alpha-oxidation intermediates in TRMA patients given a normal supply of thiamine is unlikely, this may not be true when malnourished.

Phytanoyl-CoA hydroxylase: recognition of 3-methyl-branched acyl-coAs and requirement for GTP or ATP and Mg(2+) in addition to its known hydroxylation cofactors.

Phytanoyl-CoA hydroxylase is a peroxisomal alpha-oxidation enzyme that catalyzes the 2-hydroxylation of 3-methyl-branched acyl-CoAs. A polyhistidine-tagged human phytanoyl-CoA hydroxylase was expressed in E. coli and subsequently purified as an active protein. The recombinant enzyme required GTP or ATP and Mg(2+), in addition to its known cofactors Fe(2+), 2-oxoglutarate, and ascorbate. The enzyme was active towards phytanoyl-CoA and 3-methylhexadecanoyl-CoA, but not towards 3-methylhexadecanoic acid. Racemic, R- and S-3-methylhexadecanoyl-CoA were equally well hydroxylated. Hydroxylation of R- and S-3-methylhexadecanoyl-CoA yielded the (2S, 3R) and (2R,3S) isomers of 2-hydroxy-3-methylhexadecanoyl-CoA, respectively. Human phytanoyl-CoA hydroxylase did not show any activity towards 2-methyl- and 4-methyl-branched acyl-CoAs or towards long and very long straight chain acyl-CoAs, excluding a possible role for the enzyme in the formation of 2-hydroxylated and odd-numbered straight chain fatty acids, which are abundantly present in brain. In conclusion, we report the unexpected requirement for ATP or GTP and Mg(2+) of phytanoyl-CoA hydroxylase in addition to the known hydroxylation cofactors. Due to the fact that straight chain fatty acyl-CoAs are not a substrate for phytanoyl-CoA hydroxylase, 2-hydroxylation of fatty acids in brain can be allocated to a different enzyme/pathway.

Purification, molecular cloning, and expression of 2-hydroxyphytanoyl-CoA lyase, a peroxisomal thiamine pyrophosphate-dependent enzyme that catalyzes the carbon-carbon bond cleavage during alpha-oxidation of 3-methyl-branched fatty acids.

In the third step of the alpha-oxidation of 3-methyl-branched fatty acids such as phytanic acid, a 2-hydroxy-3-methylacyl-CoA is cleaved into formyl-CoA and a 2-methyl-branched fatty aldehyde. The cleavage enzyme was purified from the matrix protein fraction of rat liver peroxisomes and identified as a protein made up of four identical subunits of 63 kDa. Its activity proved to depend on Mg(2+) and thiamine pyrophosphate, a hitherto unrecognized cofactor of alpha-oxidation. Formyl-CoA and 2-methylpentadecanal were identified as reaction products when the purified enzyme was incubated with 2-hydroxy-3-methylhexadecanoyl-CoA as the substrate. Hence the enzyme catalyzes a carbon-carbon cleavage, and we propose calling it 2-hydroxyphytanoyl-CoA lyase. Sequences derived from tryptic peptides of the purified rat protein were used as queries to recover human expressed sequence tags from the databases. The composite cDNA sequence of the human lyase contained an ORF of 1,734 bases that encodes a polypeptide with a calculated molecular mass of 63,732 Da. Recombinant human protein, expressed in mammalian cells, exhibited lyase activity. The lyase displayed homology to a putative Caenorhabditis elegans protein that resembles bacterial oxalyl-CoA decarboxylases. Similarly to the decarboxylases, a thiamine pyrophosphate-binding consensus domain was present in the C-terminal part of the lyase. Although no peroxisome targeting signal, neither 1 nor 2, was apparent, transfection experiments with constructs encoding green fluorescent protein fused to the full-length lyase or its C-terminal pentapeptide indicated that the C terminus of the lyase represents a peroxisome targeting signal 1 variant.

Encapsulation of all-trans retinoic acid into wheat ceramides micro vesicles enhanced influence on collagenase and tissue inhibitor of metalloproteinase-1 production by human skin fibroblasts.

The influence of all-trans retinoic acid (RA), either in its free or encapsulated form into wheat ceramides (CER), on the production of collagenase (MMP-1), and tissue inhibitor of metalloproteinase (TIMP-1) by human skin fibroblasts (HSF) at early and late stages of their proliferative life span (PLS) was examined. The level of MMP-1 was elevated and that of TIMP-1 decreased in late as compared to early passage cells. All-trans retinoic acid significantly decreased and increased the secretions of MMP-1 and TIMP-1 respectively, in a dose-dependent manner, from 10-7 m to 10-5 m. Entrapment of RA into CER vesicles potentiated its effect on MMP-1 and TIMP-1 secretions by HSF, independently of cell passages. The extent of variations obtained on MMP-1 and TIMP-1 levels, when HSF culture medium was supplemented with 10-5 m RA, could be obtained using a 100-fold lower concentration of RA encapsulated into CER vesicles. CER had no effect on TIMP-1 and MMP production by HSF in culture, and simultaneous addition of CER and RA did not potentiate the effects of RA alone, indicating that formation of RA-CER liposomes was responsible for the enhancing effects. The rate of internalization of RA into HSF was increased when used in its CER encapsulated form. Therefore, the use of retinoid within CER potentiates its beneficial influence on the MMP-1:TIMP-1 imbalance with fibroblastageing.

Uncoordinate expressions of type I and III collagens, collagenase and tissue inhibitor of matrix metalloproteinase 1 along in vitro proliferative life span of human skin fibroblasts. Regulation by all-trans retinoic acid.

In vitro human skin fibroblasts aging was characterized by a continuous increase of collagenase mRNA levels. On the contrary, TIMP-1 mRNA level decreased only at late passages (> 65% of proliferative life span). Type I and III mRNA levels showed a high variability depending on cell strains studied. However, type I and III collagen expressions varied parallely. All-trans retinoic acid (RA) decreased collagenase expression and stimulated TIMP-1 expression. Under RA action, high variability in mRNAs levels encoding type I and III collagens was observed with HSF passages. However, RA tended to correct variations in collagens expressions observed along HSF life span.

Inhibition of human neutrophil elastase by wheat ceramides.

Synopsis Ceramides, composed of sphingosine N-acyl linked to fatty acids have become widely used in cosmetology. They play several physiological roles in the regulation of skin barrier function. Human neutrophil elastase (HNE) can be inhibited by long-chain fatty acids and their derivatives; it was therefore postulated that plant ceramides could be inhibitors of HNE. Ceramides were extracted from wheat, isolated and characterized. The main fatty acids were 16:0, 18:1, 18:2 and the sphingoid moiety was phytosphingosine. Concentrations necessary to reach 50% inhibition of HNE were, respectively, 33 and 41 mug ml(-1) for non-glycosyl ceramides (CER) and glycosyl ceramides (gly-CER) when using a synthetic specific substrate. Similar extents of inhibition were obtained using a physiological substrate, insoluble elastin. Ex vivo studies showed that CER protected human skin elastic fibres against HNE degradation. Ceramides, being natural non-toxic substances, besides their role in cosmetics, could be of pharmacological interest in dermal inflammatory disorders.