Knowledge support for environmental information on pharmaceuticals: experiences among Swedish Drug and Therapeutics Committees.

BACKGROUND: Two publicly available Swedish knowledge support systems, "Pharmaceuticals and Environment" on Janusinfo.se and Fass.se, provide environmental information on pharmaceuticals. Janusinfo is provided by the public healthcare system in Stockholm and Fass is provided by the pharmaceutical industry. The objectives of this study were to investigate the experiences among Swedish Drug and Therapeutics Committees (DTCs) with using the databases, retrieve development proposals for these, and investigate the DTCs' challenges with working with pharmaceuticals in the environment. METHODS: A cross-sectional survey with 21 questions, both closed and open-ended, was distributed electronically in March 2022 to Sweden's 21 DTCs. Descriptive statistics and inductive categorization were used for the analysis. RESULTS: A total of 132 respondents from 18 regions filled out the survey. The average regional response rate was 42%. The DTCs used the knowledge supports to consider environmental aspects of pharmaceuticals in their formularies and in education. Respondents were more familiar with Janusinfo compared to Fass but appreciated the availability of both. The DTCs especially valued the concrete proposals for certain active pharmaceutical ingredients on Janusinfo. Respondents requested that all medicinal products have environmental information on Fass. Challenges included lack of data, lack of transparency from the pharmaceutical industry and difficulties considering the environmental aspect of pharmaceuticals in their healthcare practice. Respondents wanted more knowledge, clear messages, and legislation to support their work to reduce the negative environmental impact of pharmaceuticals. CONCLUSIONS: This study demonstrates that knowledge supports for environmental information on pharmaceuticals are valuable for the DTCs in Sweden, but the respondents experienced challenges in their work in this field. The study can provide insights to those in other countries interested in considering environmental aspects in their formulary decision-making.

Pharmaceuticals and Environment: a web-based decision support for considering environmental aspects of medicines in use.

PURPOSE: The database Pharmaceuticals and Environment is a non-commercial, freely available web-based decision support presenting compiled environmental information for pharmaceutical substances. It was developed by Region Stockholm and launched in 2016 at janusinfo.se. The purpose of this paper is to present the database, report on its current use, and reflect on lessons learned from developing and managing the database. METHODS: A standard operating procedure describes the work and content of the database, e.g., how information is retrieved, processed, and presented. Google Analytics was used for metrics. Issues related to the database have been discussed and handled by a reference group. The experiences from this work are presented. RESULTS: The database contains environmental hazard and risk information, primarily gathered from regulatory authorities and pharmaceutical companies. There are also assessments comparing substances within some groups of pharmaceuticals. The database is used by the Swedish Drug and Therapeutics Committees to include environmental aspects when recommending pharmaceuticals for health care providers. Page views show that users primarily look for information on commonly used substances, e.g., diclofenac and paracetamol/acetaminophen. Major problems for the development of the database are lack of data, lack of transparency, and discrepancies in the available environmental information. CONCLUSION: In the absence of an adequate decision support produced by the regulatory authorities, we find the database Pharmaceuticals and Environment to be useful for Swedish Drug and Therapeutics Committees and health care providers, and it is our belief that the information can be valuable also in other settings.

Patients' knowledge and attitudes to the Wise List - a drug formulary from the Stockholm Drug and Therapeutic committee.

BACKGROUND: Involving patients in decisions about their pharmacotherapy is crucial for a satisfactory treatment outcome. Information and opinions about medicines are available from a variety of sources. The Wise List is the drug formulary of recommended essential medicines for the Stockholm healthcare region and is issued by the Drug and Therapeutics Committee (DTC). To inform the public about treatment for common diseases and the concept of recommended medicines, a patient edition of the Wise List was developed. The aim of this study was to explore patients' knowledge, needs and attitudes to the Wise List, DTC and information about medicines in general. METHODS: To examine patient knowledge about recommended medicines a survey (n = 312) was carried out at four large primary healthcare centres in Stockholm, Sweden. To further elucidate the patients' needs of the information on recommended medicines and medicines in general, three focus group discussions (FGDs) were performed. RESULTS: Of the respondents 57% did not recognise the Wise List, 26% recognised but did not use it and 17% used it. A total of 63% reported that they search for information about medicines. The most common information source was "asking their doctor" (36%) followed by searching the internet (31%). The FGDs revealed that the patients were not interested in medicines in general, only in the medicines they use themselves. They did not understand the aim of the Wise List or how they could benefit from information about recommended medicines. The patients expressed a wish to access all information they need about their own care as well as public healthcare information at one location. CONCLUSION: The intended aim of the DTC with providing information to the public was not achieved as the patients have difficulties to understand the information and how they should use it. The patients were not interested in medicines in general, they wanted information tailored to their specific needs. The findings highlight the importance of creating tools for patients in collaboration with them and evaluate the concept continuously.

Primary care physicians report high trust in and usefulness of the Stockholm drug and therapeutic committee's list of recommended essential medicines (the 'Wise List').

PURPOSE: Inappropriate use of medicines causes increased morbidity, mortality, adverse drug reactions, therapeutic failures and drug resistance as well as wastes valuable resources. Evidence-based cost-effective treatment recommendations of essential medicines are a way of avoiding these. We assessed primary care prescribers' knowledge about and perceptions of an essential medicines formulary, as well as the reasons for adhering to the recommendations. METHODS: We conducted a web based questionnaire survey targeting all physicians working in the primary healthcare of the Stockholm healthcare region (2.3 million inhabitants), regarding the knowledge of, attitudes to and usefulness of the essential medicines formulary of the Stockholm Drug and Therapeutics Committee, the so-called Wise List. RESULTS: Of the 1862 physicians reached by our e-mail invitations, 526 (28%) participated in the survey. All but one respondent knew of the formulary, and 72% used it at least once a week when prescribing. The main reason for using the formulary was evidence-based prescribing; 97% trusted the guidelines, and almost all (98%) found the content easy to understand. At the same time, many prescribers thought that the annual changes of some recommendations were too frequent, and some felt that a national formulary would increase its trustworthiness. CONCLUSIONS: We found that the essential medicines formulary was widely used and trusted by the prescribers. The high uptake of the treatment recommendations could be due to the Stockholm Drug and Therapeutics Committee's transparent process for developing recommendations involving respected experts and clinicians using strict criteria for handling potential conflicts of interest, feedback to prescribers, continuous medical education and minor financial incentives.

High adherence to the 'Wise List' treatment recommendations in Stockholm: a 15-year retrospective review of a multifaceted approach promoting rational use of medicines.

OBJECTIVES: To present the 'Wise List' (a formulary of essential medicines for primary and specialised care in Stockholm Healthcare Region) and assess adherence to the recommendations over a 15-year period. DESIGN: Retrospective analysis of all prescription data in the Stockholm Healthcare Region between 2000 and 2015 in relation to the Wise List recommendations during the same time period. SETTING: All outpatient care in the Stockholm Healthcare Region. PARTICIPANTS: All prescribers in the Stockholm Healthcare Region. MAIN OUTCOME MEASURES: The number of core and complementary substances included in the Wise List, the adherence to recommendations by Anatomic Therapeutic Chemical (ATC) 1st level using defined daily doses (DDDs) adjusted to the DDD for 2015, adherence to recommendations over time measured by dispensed prescriptions yearly between 2002 and 2015. RESULTS: The number of recommended core substances was stable (175-212). Overall adherence to the recommendations for core medicines for all prescribers increased from 75% to 84% (2000 to 2015). The adherence to recommendations in primary care for core medicines increased from 80% to 90% (2005 to 2015) with decreasing range in practice variation (32% to 13%). Hospital prescriber adherence to core medicine recommendations was stable but increased for the combination core and complementary medicines from 77% to 88% (2007 to 2015). Adherence varied between the 4 therapeutic areas studied. CONCLUSIONS: High and increasing adherence to the Wise List recommendations was seen for all prescriber categories. The transparent process for developing recommendations involving respected experts and clinicians using strict criteria for handling potential conflicts of interests, feedback to prescribers, continuous medical education and financial incentives are possible contributing factors. High-quality evidence-based recommendations to prescribers, such as the Wise List, disseminated through a multifaceted approach, will become increasingly important and should be developed further to include recommendations and introduction protocols for new expensive medicines.

Statin-induced myopathy in a usual care setting-a prospective observational study of gender differences.

PURPOSE: The study aims to identify the occurrence and remission of statin-induced myopathy including patient perception and symptom characteristics with a gender perspective. METHODS: The study was designed as a prospective, non-interventional investigation in 192 outpatients receiving statin treatment in usual care with 12 months follow-up. Main outcome measure was myopathy related to statin treatment and classified as probable using WHO criteria for adverse drug reaction (ADR) assessment. RESULTS: Fourteen percent developed myopathy, risk ratio for women 1.52 [95 % CI 1.37; 1.66] as compared to men. The majority graded their pain as "severe." CK values were within normal range. Eighty percent of the women compared to 43 % of the men reported that the muscular symptoms affected their daily life activities to a moderate or severe extent. For those who stopped treatment, mypopathy was the reason for 70 % of the women and 25 % of the men. There was a difference in mean dose between men with and without myopathy, but not in women. Among the patients with myopathy, 76 % reported other ADRs as compared to 21 % of the patients without myopathy (p = 0.002). Twenty-nine percent of the women and 18 % of the men reported other ADRs. CONCLUSION: Women reported a higher frequency of myopathy and other ADRs as well as a larger impact on daily life activities. In men, but not in women, the risk of myopathy was dose-dependent. Patients with myopathy were more susceptible to other statin-induced ADRs which raises the question about common underlying mechanisms.

Low Vitamin D Levels and Genetic Polymorphism in the Vitamin D Receptor are Associated with Increased Risk of Statin-Induced Myopathy.

The main aim of this study was to test the hypothesis whether 25-hydroxyvitamin D (25OHD) levels <50 nmol/L at baseline could predict statin-induced myopathy during the course of treatment. In addition, we analysed the association between a genetic polymorphism in the vitamin D receptor (VDR) and the risk of statin-induced myopathy. We used serum samples from a prospective, observational study in statin-treated patients in Sweden who were thoroughly followed with interviews and questionnaires regarding muscular symptoms (n = 127). In this cohort, 16 developed muscular symptoms and 111 had no muscular symptoms associated with statin treatment during the first year of follow-up. Patients with 25OHD levels <50 nmol/L before starting on statin treatment had four times higher risk of developing muscular symptoms compared with individuals having 25OHD levels >50 nmol/L (RR 4.2; 95% CI 1.7-10.2; p < 0.01). The mean levels of 25OHD at baseline were 50 ± 4 nmol/L among patients developing myopathy and 60 ± 2 nmol/L among patients without myopathy (p < 0.01). Individuals homozygous for the C allele in the VDR polymorphism TaqI (rs731236) had a four times higher risk of developing muscular symptoms; (RR 4.37, 95% CI 1.9-10.1, p < 0.01). In conclusion, 25OHD levels <50 nmol/L might be a useful marker to predict muscular adverse events during statin treatment. In addition, the finding that the VDR polymorphism TaqI was associated with myopathy may indicate a causal relationship between vitamin D function and myopathy, but larger studies are needed before firm conclusions can be drawn.

Evaluation of usage patterns and user perception of the drug-drug interaction database SFINX.

PURPOSE: The aim of the present study was to investigate how prescribers and pharmacists use and perceive the drug-drug interaction database SFINX in their clinical work. METHODS: A questionnaire was developed with questions aimed at the usage of SFINX, and the perceptions of the database. The questionnaire was sent out to all registered users of the web application of SFINX. The anonymous answers from the target users, prescribers and pharmacists were summarized using descriptive statistics. Statistical analysis was performed on age and gender differences for some questions regarding different usage patterns. RESULTS: The questionnaire was sent to 11,763 registered SFINX users. The response rate was 23%, including 1871 answers from prescribers or pharmacists. SFINX was reported to be used at least weekly or more often by 45% of the prescribers and 51% of the pharmacists. Many prescribers reported using the database during the patient consultation (60%) or directly before or after (56%). Among the prescribers, 74% reported that the information received made them change their action at least sometimes. About 20% of the prescribers and 25% of the pharmacists considered the information as irrelevant sometimes or more often. CONCLUSION: Most prescribers and pharmacists reported using SFINX in direct association with a patient consultation. Information received by using SFINX makes prescribers and pharmacists change their handling of patients. DDI databases with relevant information about patient handling might improve drug treatment outcome.

Statin-induced Myopathy and Ubiquinone Levels in Serum - Results from a Prospective, Observational Study.

It has been suggested that an impaired ubiquinone (Q10) synthesis may be responsible for muscular side effects caused by statins. The primary aim of this study was to investigate whether low Q10 levels in serum could be used as a marker to predict the risk of developing statin-induced myopathy. The secondary aim was to compare the change in Q10 levels during statin treatment and differences between men and women. Serum samples from a prospective, observational study in statin-treated patients who were thoroughly followed regarding muscular symptoms were used. In this cohort, 16 developed myopathy and 126 had no muscular symptoms related to statin treatment. Q10 levels were measured with a novel LC-MS method at baseline and after 2 months of statin treatment. Q10 levels showed no correlation with the risk of developing statin-induced myopathy. Individuals with low levels, Q10 < 200 ng/ml, at baseline had no increased risk of developing myopathy. In consistence with earlier reports, we showed that Q10 levels were reduced by 30% during statin treatment. There was no significant difference in the reduction between patients with or without myopathy. Women had approximately 30% lower Q10 levels compared to men both before and after treatment. In this study, there was no association between Q10 levels at baseline and statin-induced muscular side effects during a 2-month follow-up period, and our results indicate that Q10 levels in serum is not a useful marker to predict statin-induced myopathy.

miRNA-27b levels are associated with CYP3A activity in vitro and in vivo.

Previous in vitro studies have shown that microRNA-27b (miR-27b) may regulate mRNA levels of CYP3A4, vitamin D receptor (VDR), and Peroxisome proliferator-activated receptor α (PPAR α) as well as CYP3A4 protein expression and activity. In vitro studies have also shown that vitamin D may affect the expression of CYP3A4. The primary aim of this pilot study was to investigate the association between miR-27b and CYP3A expression and activity. The secondary aim was to investigate the association between 25-hydroxy vitamin D in serum and CYP3A activity. Mi-RNA-27b was quantified using real-time PCR in serum samples (n = 28) and 25-hydroxyvitamin D was measured and correlated with the levels of the endogenous CYP3A activity marker 4ß-hydroxycholesterol. In addition, the correlation between miR-27b and CYP3A activity, measured by dextromethorphan N-demethylation and 6ß-hydroxylation of testosterone and the gene expression of CYP3A4, VDR and PPAR α were assessed in 20 human liver samples. A significant association between circulatory miR-27b levels and 4ß-hydroxycholesterol ratio was found; P = 0.04, and between hepatic miR-27b levels and CYP3A activity, measured by dextromethorphan N-demethylation in human liver (P = 0.04). There was no association between hepatic miR-27b and mRNA levels of CYP3A4, VDR or PPAR α. There was a significant association between serum 25-hydroxyvitamin D levels and 4ß-hydroxycholesterol ratio, P = 0.002. In conclusion, this pilot-study supports the hypothesis that miR-27b levels as well as 25-hydroxyvitamin D may affect CYP3A activity in vivo. The results indicate that miR-27b exerts its inhibitory effect on a translational level rather than affecting mRNA levels.

SFINX-a drug-drug interaction database designed for clinical decision support systems.

OBJECTIVE: The aim was to develop a drug-drug interaction database (SFINX) to be integrated into decision support systems or to be used in website solutions for clinical evaluation of interactions. METHODS: Key elements such as substance properties and names, drug formulations, text structures and references were defined before development of the database. Standard operating procedures for literature searches, text writing rules and a classification system for clinical relevance and documentation level were determined. ATC codes, CAS numbers and country-specific codes for substances were identified and quality assured to ensure safe integration of SFINX into other data systems. Much effort was put into giving short and practical advice regarding clinically relevant drug-drug interactions. RESULTS: SFINX includes over 8,000 interaction pairs and is integrated into Swedish and Finnish computerised decision support systems. Over 31,000 physicians and pharmacists are receiving interaction alerts through SFINX. User feedback is collected for continuous improvement of the content. CONCLUSION: SFINX is a potentially valuable tool delivering instant information on drug interactions during prescribing and dispensing.

Plasma membrane and vesicular glutamate transporter mRNAs/proteins in hypothalamic neurons that regulate body weight.

After synaptic release, glutamate is taken up by the nerve terminal via a plasma membrane-associated protein termed excitatory amino acid transporter 3 (EAAT3). Following entry into the nerve terminal, glutamate is pumped into synaptic vesicles by a vesicular transport system. Three different vesicular glutamate transporter proteins (VGLUT1-3) representing unique markers for glutamatergic neurons were recently characterized. The presence of EAAT3, glutaminase and VGLUT1-3 was examined in mouse, rat and rabbit species at mRNA and protein levels in hypothalamic neurons which are involved in the regulation of body weight using in situ hybridization and immunohistochemistry. EAAT3 and glutaminase mRNAs were demonstrated in all parts of the arcuate nucleus in the dorsomedial and ventromedial hypothalamic nuclei and lateral hypothalamic area. VGLUT1 mRNA was present in the magnocellular lateral hypothalamic nucleus. VGLUT2 mRNA was demonstrated in a subpopulation of neurons in the arcuate nucleus and in the ventromedial and dorsomedial hypothalamic nuclei and lateral hypothalamic area. Few VGLUT3 mRNA expressing neurons were scattered throughout the medial and lateral hypothalamus. EAAT3-like immunoreactivity (-li) was demonstrated in glutamate, neuropeptide Y (NPY), agouti-related peptide (AGRP), pro-opiomelanocortin (POMC), cocaine and amphetamine-regulated transcript (CART), melanin-concentrating hormone and orexin-immunoreactive (-ir) neurons. VGLUT2-li could only be demonstrated in POMC- and CART-ir neurons of the ventrolateral arcuate nucleus. The results show that key neurons involved in regulation of energy balance are glutamatergic and/or densely innervated by glutamatergic nerve terminals. Whereas orexigenic NPY/AGRP neurons situated in the ventromedial part of the arcuate nucleus are mainly GABAergic, it is shown that several anorexigenic POMC/CART neurons of the ventromedial arcuate nucleus are most likely glutamatergic [corrected].