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.

The Early Awareness and Alert System in Sweden: History and Current Status.

Introduction: Over the past decades, early awareness and alert (EAA) activities and systems have gained importance and become a key early health technology assessment (HTA) tool. While a pioneer in HTA, Sweden had no national level EAA activities until 2010. We describe the evolution and current status of the Swedish EAA System. Methods: This was a historical analysis based on the knowledge and experience of the authors supplemented by a targeted review of published and gray literature as well as documents relating to EAA activities in Sweden. Key milestones and a description of the current state of the Swedish EAA System is presented. Results: Initiatives to establish a system for the identification and assessment of emerging health technologies in Sweden date back to the 1980s. In the 1990s, the Swedish Agency for HTA and Assessment of Social Services (SBU) supported the development of EuroScan as one of its founder members. In the mid-2000s, an independent regional initiative, driven by the Stockholm County Drug and Therapeutics Committee, resulted in the establishment of a regional horizon scanning function. By 2009, this work had expanded to a collaboration between the four biggest counties in Sweden. The following year it was further expanded to the national level and since then the Swedish EAA System has been carrying out identification, filtration and prioritization of new medicines, early assessment of the prioritized medicines, and dissemination of information. In 2015, the EAA System was incorporated into the Swedish national process for managed introduction and follow-up of new medicines. Outputs from the EAA System are now used to select new medicines for inclusion in this process. Conclusions: The Swedish EAA System started as a regional initiative and rapidly grew to become a national level activity. An important feature of the system today is its complete integration into the national process for managed introduction and follow-up of new medicines. The system will continue to evolve as a response both to the changing landscape of health innovations and to new policy initiatives at the regional, national and international level.

Introduction of pharmaceutical expertise in a palliative care team in Sweden.

OBJECTIVE: This paper presents for the first time the inclusion of dispensing pharmacists, a special group of pharmacy professionals, in a Swedish palliative care team. It also presents the drug stock management in the medication room of the clinical area and the improvement of drug logistics. In addition to a dispensing pharmacist, a pharmacist was included in this part of the project as well. SETTING: The palliative care team at ASIH Långbro Park, Sweden. METHOD: The intervention with the dispensing pharmacists as new members of the interdisciplinary palliative team was evaluated by a questionnaire to the staff. An inventory of the different drugs in stock was performed in March 2006 and in April 2007, respectively. The inventory turnover rate was determined and the drug consumption for the last 6 months of 2005 and 2006, respectively, was also analysed. MAIN OUTCOME MEASURES: The questionnaire used rating scales allowing participants to rate the questions/statements. The number of different drugs and drug packages in stock were recorded during the inventories. Drug costs were calculated and the inventory turnover rate was determined by dividing the annual cost of drugs by the value of the inventory. Drug consumption was analysed using the Xplain statistical programme, a statistical tool from Apoteket AB. RESULTS: The overall impression of the dispensing pharmacists was positive. The staff reported advantages in having a dispensing pharmacist present at ASIH not only for the drug logistics, but also for drug-related queries. The inventory of the drug stock and the drug-handling process resulted in a 14% reduction of product numbers and a 36% reduction in the tied-up capital for drugs in stock. The inventory turnover rate increased from 6.7 to 9.5. A 7% reduction of medication costs was also observed when comparing the last 6 months of 2006 with the costs in 2005. CONCLUSION: The principal result of this project is that inclusion of pharmaceutical expertise on a palliative care team can be a valuable asset for the team in pharmaceutical issues and of great benefit for stock management, including cost savings and improvement of drug logistics.

Differences in beliefs between patients and pharmaceutical specialists regarding medications.

OBJECTIVE: To investigate beliefs concerning medication among patients and pharmaceutical specialists (3 or 5 years of higher education). METHOD: The Beliefs about Medicines Questionnaire (BMQ)-General, which assesses beliefs about medicines in general, was used. RESULTS: For the analyses, 141 (response rate 82%) and 136 (response rate 79%) questionnaires from the patients and pharmaceutical specialists, respectively, were included. The results showed a statistical significant difference between patients and pharmaceutical specialists in beliefs about medicines. Whereas the patients expressed a more negative attitude about medicines (stronger beliefs about medicines as being harmful and less favourable) the pharmaceutical specialists expressed the contrary. However, the pharmaceutical specialists had stronger concerns regarding over-use of medicines as compared to the patients. CONCLUSION: Patients and pharmaceutical specialists expressed different views regarding medications. To achieve concordance in the pharmaceutical care process, pharmaceutical specialists need to exchange information about patients' experiences and not take for granted that they share their views regarding medications. PRACTICE IMPLICATIONS: The pharmaceutical specialists should elicit the patient's concerns about the prescribed medications and be aware of that non-adherence is often the result of the patients making rational decisions about their treatment.

Heterocyclic bis-cations as starting hits for design of inhibitors of the bifunctional enzyme histidine-containing protein kinase/phosphatase from Bacillus subtilis.

The main mechanism of carbon catabolite repression/activation in low-guanine and low-cytosine Gram-positive bacteria seems to involve phosphorylation of HPr (histidine-containing protein) at Ser-46 by the ATP-dependent HPr kinase, which in Bacillus subtilis, Lactobacillus casei, and Staphylococcus xylosus also exhibits phosphatase activity and is thus a bifunctional enzyme (HPrK/P). Since deficiency of HPrK/P in S. xylosus, L. casei, and B. subtilis mutants leads to severe growth defects, inhibitors of the enzyme could form a new family of antibiotic drugs. The aim of the study was to screen an in-house chemical library for identification of hits as inhibitors of HPrK/P in B. subtilis and to further extract additional information of structural features from hit optimization using a radioactive in vitro assay. A symmetrical bis-cationic compound LPS 02-10-L-D09 (2a) with a 12-carbon alkyl linker bridging the two 2-aminobenzimidazole moieties was identified as a non-ATP mimetic compound exhibiting an EC(50) value of 10 microM in a kinase assay with HPr as substrate. The substance also inhibited the phosphatase activity of HPrK/P triggered by the addition of inorganic phosphate. Similar results were obtained with 2a and catabolite repression HPr, which, like HPr, can be phosphorylated at Ser-46 by HPrK/P and is involved in catabolite repression. Structure-activity relationship analysis indicated the importance in its structure of a substituted 2-aminobenzimidazole. This typical heterocycle is linked through a C12 alkyl chain to a second scaffold that can bear a cationic or a noncationic moiety but in all cases should present an aromatic ring in its vicinity.

Generation of bis-cationic heterocyclic inhibitors of Bacillus subtilis HPr kinase/phosphatase from a ditopic dynamic combinatorial library.

Ditopic dynamic combinatorial libraries were generated and screened toward inhibition of the bifunctional enzyme HPr kinase/phosphatase from Bacillus subtilis. The libraries were composed of all possible combinations resulting from the dynamic interconversion of 16 hydrazides and five monoaldehyde or dialdehyde building blocks, resulting in libraries containing up to 440 different constituents. Of all possible acyl hydrazones formed, active compounds containing two terminal cationic heterocyclic recognition groups separated by a spacer of appropriate structure could be rapidly identified using a dynamic deconvolution procedure. Thus, parallel testing of sublibraries where one specific component was excluded basically revealed all the essential components. A potent ditopic inhibitor, based on 2-aminobenzimidazole, was identified from the process.

Properties and regulation of the bifunctional enzyme HPr kinase/phosphatase in Bacillus subtilis.

The bifunctional allosteric enzyme HPr kinase/phosphatase (HPrK/P) from Bacillus subtilis is a key enzyme in the main mechanism of carbon catabolite repression/activation (i.e. a means for the bacteria to adapt rapidly to environmental changes in carbon sources). In this regulation system, the enzyme can phosphorylate and dephosphorylate two proteins, HPr/HPr(Ser(P)) and Crh/Crh(Ser(P)), sensing the metabolic state of the cell. To acquire further insight into the properties of HPrK/P, electrospray ionization mass spectrometry, dynamic light scattering, and BIACORE were used to determine the oligomeric state of the protein under native conditions, revealing that the enzyme exists as a hexamer at pH 6.8 and as a monomer and dimer at pH 9.5. Using an in vitro radioactive assay, the influence of divalent cations, pH, temperature, and different glycolytic intermediates on the activity as well as kinetic parameters were investigated. The presence of divalent cations was found to be essential for both opposing activities of the enzyme. Furthermore, pH values equal to the internal pH of vegetative cells seem to favor the kinase activity, whereas lower pH values increased the phosphatase activity. Among the glycolytic intermediates evaluated, fructose 1,6-diphosphate and fructose 2,6-diphosphate were found to be allosteric activators in the kinase assay, whereas high concentrations inhibited the phosphatase activity, except for fructose 1,6-diphosphate in the case of HPr(Ser(P)). Phosphatase activity was induced by inorganic phosphate as well as acetyl phosphate and glyceraldehyde 3-phosphate. Kinetic parameters indicate a preference for binding of HPr compared with Crh to the enzyme and supported a strong positive cooperativity. This work suggests that the oligomeric state of the enzyme is influenced by several effectors and is correlated to the kinase or phosphatase activity. The phosphatase activity is mainly supported by the hexameric form.

Discovery of a 3-amino-6-phenyl-pyridazine derivative as a new synthetic antineuroinflammatory compound.

Excessive glial activation, with overproduction of cytokines and oxidative stress products, is detrimental and a hallmark of neurodegenerative disease pathology. Suppression of glial activation is a potential therapeutic approach, and protein kinases are targets of some antiinflammatory drugs. To address an unmet need for selective inhibitors of glial activation, we developed a novel 3-amino-6-phenylpyridazine derivative that selectively blocks increased IL-1 beta, iNOS, and NO production by activated glia, without inhibition of potentially beneficial glial functions.