Browsing by Subject "DRUGS"

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  • Gatta, Viviana; Tomašič, Tihomir; Ilaš, Janez; Zidar, Nace; Peterlin Mašič, Lucija; Barančoková, Michaela; Frlan, Rok; Anderluh, Marko; Kikelj, Danijel; Tammela, Päivi (2020)
    Quorum sensing (QS), a bacterial communication strategy, has been recognized as one of the control mechanisms of virulence in bacteria. Thus, targeting QS offers an interesting opportunity to impair bacterial pathogenicity and develop antivirulence agents. Aiming to enhance the discovery of QS inhibitors, we developed a bioreporter Escherichia coli JW5505 pET-Plsrlux and set up a cell-based assay for identifying inhibitors of autoinducer-2 (AI-2)-mediated QS. A comparative study on the performance of target- versus cell-based assays was performed, and 91 compounds selected with the potential to target the ATP binding pocket of LsrK, a key enzyme in AI-2 processing, were tested in an LsrK inhibition assay, providing 36 hits. The same set of compounds was tested by the AI-2-mediated QS interference assay, resulting in 24 active compounds. Among those, six were also found to be active against LsrK, whereas 18 might target other components of the pathway. Thus, this AI-2-mediated QS interference cell-based assay is an effective tool for complementing target-based assays, yet also stands as an independent assay for primary screening.
  • Hanski, Leena; Ausbacher, Dominik; Tiirola, Terttu M.; Strom, Morten B.; Vuorela, Pia M. (2016)
    We demonstrate in the current work that small cationic antimicrobial beta(2,2)-amino acid derivatives (Mw <500 Da) are highly potent against Chlamydia pneumoniae at clinical relevant concentrations (<5 mu M, i.e. <3.4 mu g/mL). C. pneumoniae is an atypical respiratory pathogen associated with frequent treatment failures and persistent infections. This gram-negative bacterium has a biphasic life cycle as infectious elementary bodies and proliferating reticulate bodies, and efficient treatment is challenging because of its long and obligate intracellular replication cycle within specialized inclusion vacuoles. Chlamydicidal effect of the beta(2,2)-amino acid derivatives in infected human epithelial cells was confirmed by transmission electron microscopy. Images of infected host cells treated with our lead derivative A2 revealed affected chlamydial inclusion vacuoles 24 hours post infection. Only remnants of elementary and reticulate bodies were detected at later time points. Neither the EM studies nor resazurin-based cell viability assays showed toxic effects on uninfected host cells or cell organelles after A2 treatment. Besides the effects on early intracellular inclusion vacuoles, the ability of these beta(2,2)-amino acid derivatives to suppress Chlamydia pneumoniae infectivity upon treatment of elementary bodies suggested also a direct interaction with bacterial membranes. Synthetic beta(2,2)-amino acid derivatives that target C. pneumoniae represent promising lead molecules for development of antimicrobial agents against this hard-totreat intracellular pathogen.
  • Hecht, Idan; Karesvuo, Petteri; Achiron, Asaf; Elbaz, Uri; Laine, Ilkka; Tuuminen, Raimo (2020)
    Purpose To assess the role of anti-inflammatory medication following cataract surgery on the formation of posterior capsular opacification. Design Cohort study. Methods A retrospective registry analysis of 25,818 consecutive cases who underwent cataract surgery between the years 2014 and 2018 at Helsinki University Hospital in Finland. Nd:YAG laser capsulotomy rates were compared between patients treated postoperatively with topical steroids, non-steroidal anti-inflammatory medications (NSAIDs), or their combination. Kaplan-Meier and Cox regression analyses were used. A single eye of each patient was included. Main outcomes were confirmed against a second independent dataset. Results 13,368 patients were included in the analysis with a mean age of 73.2±9.7 years and 61.7% were female. Pseudoexfoliation was noted in 10.1% of cases. The mean follow-up time was 22.8±15.7 months. Patients were treated with steroid monotherapy (28.9% of cases), NSAIDs monotherapy (62.2%), or a combination of both (8.9%). Treatment with steroids resulted in significantly lower Nd:YAG capsulotomy rates compared to NSAIDs (HR 0.76, 95% CI 0.62-0.93, P=0.009). Treatment with combination therapy of steroids and NSAIDs showed no added benefit over steroid monotherapy (HR 1.11, 95% CI 0.68-1.80, P=0.674). Cox regression analysis adjusted for patients’ age, gender, pseudoexfoliation, and risk stratification remained significantly predictive for lower capsulotomy rates with steroid treatment over NSAIDs (HR 0.70, 95% CI 0.52-0.88, P=0.001). Conclusions Postoperative treatment with steroids among patients undergoing uncomplicated cataract surgery was associated with lower rates of clinically significant posterior capsule opacification compared to treatment with NSAIDs alone. Combination therapy of steroids and NSAIDs had no added benefit over steroids alone.
  • Ylinen, Petteri; Holmstrom, Emil; Laine, Ilkka; Lindholm, Juha-Matti; Tuuminen, Raimo (2018)
    PurposeTo examine the anti-inflammatory efficacy and tolerance between preservative-free dexamethasone (DEX) and diclofenac (DICL) eye drops, and their combination following cataract surgery. MethodsA randomized, double-blind, prospective single-centre study with 189 eyes of 180 patients undergoing routine cataract surgery. Laser flare meter measurement and spectral-domain optical coherence tomography imaging were conducted before surgery and at the 28-day postoperative visit. Clinical characteristics, surgical parameters and assessment of postoperative symptoms were recorded. ResultsPreoperative flare was 9.00.6pu/ms and central retinal thickness (CRT) 269.6 +/- 1.9m (mean +/- SEM). On day 28, flare was 22.1 +/- 2.9 pu/ms for DEX, 17.4 +/- 2.5pu/ms for DICL and 13.0 +/- 1.6pu/ms (p ConclusionDiclofenac (DICL), as well as the combination of DEX and DICL, were superior to DEX monotherapy in minimizing CRT change and the incidence of PCME. Combination medication showed no added value compared to DICL monotherapy in uneventful cataract surgery.
  • Weichert, I.; Romero-Ortuno, R.; Tolonen, J.; Soe, T.; Lebus, C.; Choudhury, S.; Nadarajah, C. V.; Nanayakkara, P.; Orru, M.; Di Somma, S. (2018)
    What is known and objectiveDrugs with anticholinergic properties increase the risk of falls, delirium, chronic cognitive impairment, and mortality and counteract procholinergic medications used in the treatment of dementia. Medication review and optimisation to reduce anticholinergic burden in patients at risk is recommended by specialist bodies. Little is known how effective this review is in patients who present acutely and how often drugs with anticholinergic properties are used temporarily during an admission. The aim of the study was to describe the changes in the anticholinergic cognitive burden (ACB) in patients admitted to hospital with a diagnosis of delirium, chronic cognitive impairment or falls and to look at the temporary use of anticholinergic medications during hospital stay. MethodsThis is a multi-centre observational study that was conducted in seven different hospitals in the UK, Finland, The Netherlands and Italy. Results and discussion21.1% of patients had their ACB score reduced by a mean of 1.7%, 19.7% had their ACB increased by a mean of 1.6%, 22.8% of DAP naive patients were discharged on anticholinergic medications. There was no change in the ACB scores in 59.2% of patients. 54.1% of patients on procholinergics were taking anticholinergics. Out of the 98 medications on the ACB scale, only 56 were seen. Medications with a low individual burden were accounting for 64.9% of the total burden. Anticholinergic drugs were used temporarily during the admission in 21.9% of all patients. A higher number of DAPs used temporarily during admission was associated with a higher risk of ACB score increase on discharge (OR=1.82, 95% CI for OR: 1.36-2.45, P What is new and conclusionThere was no reduction in anticholinergic cognitive burden during the acute admissions. This was the same for all diagnostic subgroups. The anticholinergic load was predominantly caused by medications with a low individual burden. More than 1 in 5 patients not taking anticholinergics on admission were discharged on them and similar numbers saw temporary use of these medications during their admission. More than half of patients on cholinesterase-inhibitors were taking anticholinergics at the same time on admission, potentially directly counteracting their effects.
  • Hämäläinen, Lasse; Lahti, Emmi (2021)
    Aims: In October 2019, a citizens' initiative to decriminalise cannabis use started a large debate about drug policy in Finland. This study examines online discussions about the initiative to supplement the current knowledge about citizens' drug opinions. The focus is especially on argumentation techniques that are used to support or object to the decriminalisation. Design: Methodologically, the study is based on discourse studies, new rhetoric, and argumentation analysis. The data of 1,092 messages were collected from a popular Finnish anonymous discussion forum Ylilauta. Results: Online discussions about the legal status of cannabis are highly polarised. Decriminalisation is often both supported and resisted in a strong and affective manner, and even hate speech is not rare in the data. Statements made by both discussion parties often lack any argumentation or are based on fallacies, especially ad hominem arguments. Some discussants refer to scientific studies and expert statements, even though such references are usually inaccurate. Cannabis is compared to alcohol more often than to other illegal drugs. Conclusions: The emotional responses and inadequate argumentation might be partially explained by the general nature of online discussions and the culture of the investigated website, but also by the powerful stigma related to illegal drugs and insufficient knowledge on the subject. A future objective is to create a societal atmosphere where the complex question of the legal status of cannabis could be discussed more neutrally and rationally.
  • Räsänen, Riikka-Marjaana; Hieta, Juha-Pekka; Immanen, Juha; Nieminen, Kaisa; Haavikko, Raisa; Yli-Kauhaluoma, Jari; Kauppila, Tiina J. (2019)
    Desorption atmospheric pressure photoionization (DAPPI) is an ambient mass spectrometry (MS) technique that allows the analysis of both polar and nonpolar compounds directly from the surfaces of various sample types. Here, DAPPI was used to study the chemical profiles in different parts of birch and alder tree barks. Four distinct fractions of Betula pendula (silver birch) bark were collected from three different developmental stages of the stem, after which the chemical profiles of the different tissue types were measured. Of special interest were triterpenoids, a class of important defensive substances, which are found in the bark of the silver birch. Additionally, the chemical profiles of lenticels and the surrounding surfaces in the phellem of B. pendula (silver birch), Alnus glutinosa (black alder), and Alnus incana (gray alder) were screened with DAPPI. Another ambient MS technique, laser ablation atmospheric pressure photoionization (LAAPPI), was further used for the mass spectrometry imaging of lenticels on the B. pendula phellem. All the studied birch bark fractions showed individual chemical profiles in DAPPI. The mass spectra from the young apical stem and the transition zone resembled each other more than the mature stem. Instead, the phellem was found to contain a high amount of triterpenoids in all the developmental stages of the stem. The most intense peaks in the DAPPI mass spectra of the birch bark fractions were those of betulin and lupeol. Betulinic and betulonic acid peaks were intense as well, and these compounds were detected especially in the lenticels of the tree samples.
  • Kopra, Jaakko; Villarta-Aguilera, Marian; Savolainen, Mari; Weingerl, Samo; Myohänen, Timo T.; Rannanpää, Saara; Salvatore, Michael E.; Andressoo, Jaan-Olle; Piepponen, T. Petteri (2018)
    Addictive drugs enhance dopamine release in the striatum, which can lead to compulsive drug-seeking after repeated exposure. Glial cell line-derived neurotrophic factor (GDNF) is an important regulator of midbrain dopamine neurons, and may play a mechanistic role in addiction-related behaviors. To elucidate the components of GDNF-signaling that contribute to addiction-related behaviors of place preference and its extinction, we utilized two genetically modified GDNF mouse models in an amphetamine induced conditioned place preference (CPP) paradigm and evaluated how the behavioral findings correlate with dopamine signaling in the dorsal and ventral striatum. We utilized two knock-in mouse strains to delineate contributions of GDNF and Ret signaling using MEN2B mice (constitutively active GDNF receptor Ret), and GDNF hypermorphic mice (enhanced endogenous GDNF expression). The duration of amphetamine-induced CPP was greatly enhanced in MEN2B mice, but not in the GDNF hypermorphic mice. The enhanced duration of CPP was correlated with increased tyrosine hydroxylase (TH) expression and dopamine content in the ventral striatum. Together, our results suggest that downstream components of GDNF signaling, in this case Ret, may mediate persistent drug-seeking behavior through increased TH expression and dopamine levels in the mesolimbic dopamine neurons. (C) 2017 Elsevier Ltd. All rights reserved.
  • Purmonen, Timo; Puolakka, Kari; Mishra, Dinesh; Gunda, Praveen; Martikainen, Janne (2019)
    Aim: This study assesses the cost-effectiveness of secukinumab vs currently licensed biologics for the treatment of ankylosing spondylitis (AS) from the Finnish health care system perspective. Methods: A semi-Markov model compared secukinumab with adalimumab, adalimumab biosimilar, certolizumab pegol, etanercept, etanercept biosimilar, golimumab, and infliximab in a biologic-naive population over a lifetime horizon. The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was used to assess the treatment response. Efficacy inputs were obtained from the network meta-analysis, and other model inputs were obtained from the published literature and Finnish sources. Main study outcomes included quality-adjusted life years (QALYs) gained and incremental cost-effectiveness ratio in terms of cost per QALY gained. Robustness of results was confirmed by sensitivity analyses and alternative scenario analyses. Results: Secukinumab achieved highest QALYs (13.1) at lowest expected lifetime cost (ss279,872) vs other comparators in biologic-naive AS patients in the base case analysis, thus it dominated other biologics. Golimumab had a second highest QALYs (12.9) at the total cost of ss309,551. Results were sensitive to variation in BASDAI 50 response for secukinumab, baseline Bath Ankylosing Spondylitis Functional Index (BASFI) score across all drugs, change in BASDAI and BASFI scores, and discount rates as observed in the one-way sensitivity analyses. Secukinumab was either dominant or cost-effective treatment in different alternative scenarios. Conclusion: Secukinumab presented itself to be the dominant (ie, less costly and more effective) treatment vs other comparators for the biologic-naive patients with AS in Finland.
  • Bazelier, Marloes T.; Eriksson, Irene; de Vries, Frank; Schmidt, Marjanka K.; Raitanen, Jani; Haukka, Jari; Starup-Linde, Jakob; De Bruin, Marie L.; Andersen, Morten (2015)
    PurposeTo identify pharmacoepidemiological multi-database studies and to describe data management and data analysis techniques used for combining data. MethodsSystematic literature searches were conducted in PubMed and Embase complemented by a manual literature search. We included pharmacoepidemiological multi-database studies published from 2007 onwards that combined data for a pre-planned common analysis or quantitative synthesis. Information was retrieved about study characteristics, methods used for individual-level analyses and meta-analyses, data management and motivations for performing the study. ResultsWe found 3083 articles by the systematic searches and an additional 176 by the manual search. After full-text screening of 75 articles, 22 were selected for final inclusion. The number of databases used per study ranged from 2 to 17 (median=4.0). Most studies used a cohort design (82%) instead of a case-control design (18%). Logistic regression was most often used for individual-level analyses (41%), followed by Cox regression (23%) and Poisson regression (14%). As meta-analysis method, a majority of the studies combined individual patient data (73%). Six studies performed an aggregate meta-analysis (27%), while a semi-aggregate approach was applied in three studies (14%). Information on central programming or heterogeneity assessment was missing in approximately half of the publications. Most studies were motivated by improving power (86%). ConclusionsPharmacoepidemiological multi-database studies are a well-powered strategy to address safety issues and have increased in popularity. To be able to correctly interpret the results of these studies, it is important to systematically report on database management and analysis techniques, including central programming and heterogeneity testing. (c) 2015 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons, Ltd.
  • Mesihää, Samuel; Ketola, Raimo A.; Pelander, Anna; Rasanen, Ilpo; Ojanpera, Ilkka (2017)
    Gas chromatography coupled to atmospheric pressure chemical ionization quadrupole time-of-flight mass spectrometry (GC-APCI-QTOFMS) was evaluated for the identification of new psychoactive substances (NPS). An in-house high mass resolution GC-APCI-QTOFMS test library was developed for 29 nitrogen-containing drugs belonging mostly to synthetic stimulants. The library was based on 12 intra-day measurements of each compound at three different collision energies, 10, 20 and 40 eV. The in-house library mass spectra were compared to mass spectra from a commercial library constructed by liquid chromatography-electrospray ionization (LC-ESI) QTOFMS. The reversed library search scores between the in-house GC-APCI library and the commercial LC-ESI library were compared once a week during a 5-week period by using data measured by GC-APCI-QTOFMS. The protonated molecule was found for all drugs in the full scan mode, and the drugs were successfully identified by both libraries in the targeted MS/MS mode. The GC-APCI library score averaged over all collision energies was as high as 94.4/100 with a high repeatability, while the LC-ESI library score was also high (89.7/100) with a repeatability only slightly worse. These results highlight the merits of GC-APCI-QTOFMS in the analysis of NPS even in situations where the reference standards are not immediately available, taking advantage of the accurate mass measurement of the protonated molecule and product ions, and comparison to existing soft-ionization mass spectral libraries.
  • Yrjönen, Teijo; Vuorela, Heikki; Kauppila, Tiina J. (2017)
    Desorption atmospheric pressure photoionization (DAPPI) is an ambient mass spectrometry (MS) technique that can be used for the analysis of polar and nonpolar compounds directly from surfaces. Here, the feasibility of DAPPI-MS in the screening of plant metabolites from dried Peucedanum palustre leaves and umbels was studied. DAPPI-MS requires no prior sample preparation or chromatographic separation, and the analysis can therefore be performed directly from the untreated plant material. P. palustre contains several linear and angular furanocoumarins, some of which are specific for the species. The DAPPI mass spectra of both leaf and umbel samples showed distinct ions at m/z 445 and 443 in positive and negative ion modes, respectively. MS2 analyses of these ions confirmed that the ions were the protonated and deprotonated molecules, respectively, of peulustrin and its isomers, which have only been identified from P. palustre. The direct analysis of dried plant material by DAPPI-MS was shown to provide a fast and reliable means to confirm the identity of plant materials, to study the metabolite profiles of plants, and to screen biologically relevant compounds from plant surfaces.
  • Stukelj, Jernej; Svanback, Sami; Agopov, Mikael; Lobmann, Korbinian; Strachan, Clare J.; Rades, Thomas; Yliruusi, Jouko (2019)
    Amorphous materials exhibit distinct physicochemical properties compared to their respective crystalline counterparts. One of these properties, the increased solubility of amorphous materials, is exploited in the pharmaceutical industry as a way of increasing bioavailability of poorly water-soluble drugs. Despite the increasing interest in drug amorphization, the analytical physicochemical toolbox is lacking a reliable method for direct amorphous solubility assessment. Here, we show, for the first time, a direct approach to measure the amorphous solubility of diverse drugs by combining optics with fluidics, the single particle analysis (SPA) method. Moreover, a comparison was made to a theoretical estimation based on thermal analysis and to a standardized supersaturation and precipitation method. We have found a good level of agreement between the three methods. Importantly, the SPA method allowed for the first experimental measurement of the amorphous solubility for griseofulvin, a fast crystallizing drug, without the use of a crystallization inhibitor. In conclusion, the SPA approach enables rapid and straightforward determination of the supersaturation potential for amorphous materials of less than 0.1 mg, which could prove highly beneficial in the fields of materials science, analytical chemistry, physical chemistry, food science, pharmaceutical science, and others.
  • Andersen, Petter I.; Ianevski, Aleksandr; Lysvand, Hilde; Oksenych, Valentyn; Bjørås, Magnar; Telling, Kaidi; Lutsar, Irja; Dampis, Uga; Irie, Yasuhiko; Tenson, Tanel; Kantele, Anu; Kainov, Denis (2020)
    Viral diseases are one of the leading causes of morbidity and mortality in the world. Virus-specific vaccines and antiviral drugs are the most powerful tools to combat viral diseases. However, broad-spectrum antiviral agents (BSAAs, i.e. compounds targeting viruses belonging to two or more viral families) could provide additional protection of the general population from emerging and re-emerging viral diseases, reinforcing the arsenal of available antiviral options. Here, we review discovery and development of BSAAs and summarize the information on 120 safe-in-man agents in a freely accessible database (https://drugvirus.info/). Future and ongoing pre-clinical and clinical studies will increase the number of BSAAs, expand the spectrum of their indications, and identify drug combinations for treatment of emerging and re-emerging viral infections as well as co-infections. (C) 2020 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.
  • Tapio, H.; Raekallio, M. R.; Mykkänen, A.; Männikkö, S.; Scheinin, M.; Bennett, R. C.; Vainio, O. (2019)
    Background Medetomidine suppresses cardiovascular function and reduces gastrointestinal motility in horses mainly through peripheral alpha(2)-adrenoceptors. Vatinoxan, a peripheral alpha(2)-antagonist, has been shown experimentally to alleviate the adverse effects of some alpha(2)-agonists in horses. However, vatinoxan has not been investigated during constant-rate infusion (CRI) of medetomidine in standing horses. Objectives To evaluate effects of vatinoxan on cardiovascular function, gastrointestinal motility and on sedation level during CRI of medetomidine. Study design Experimental, randomised, blinded, cross-over study. Methods Six healthy horses were given medetomidine hydrochloride, 7 mu g/kg i.v., without (MED) and with (MED+V) vatinoxan hydrochloride, 140 mu g/kg i.v., followed by CRI of medetomidine at 3.5 mu g/kg/h for 60 min. Cardiorespiratory variables were recorded and borborygmi and sedation levels were scored for 120 min. Plasma drug concentrations were measured. The data were analysed using repeated measures ANCOVA and paired t-tests as appropriate. Results Initially heart rate (HR) was significantly lower and mean arterial blood pressure (MAP) significantly higher with MED compared with MED+V. For example at 10 min HR (mean +/- s.d.) was 26 +/- 2 and 31 +/- 5 beats/minute (P = 0.04) and MAP 129 +/- 15 and 103 +/- 13 mmHg (P
  • Mynttinen, Elsi; Wester, Niklas; Lilius, Tuomas; Kalso, Eija; Mikladal, Bjorn; Varjos, Ilkka; Sainio, Sami; Jiang, Hua; Kauppinen, Esko I.; Koskinen, Jari; Laurila, Tomi (2020)
    Oxycodone is a strong opioid frequently used as an analgesic. Although proven efficacious in the management of moderate to severe acute pain and cancer pain, use of oxycodone imposes a risk of adverse effects such as addiction, overdose, and death. Fast and accurate determination of oxycodone blood concentration would enable personalized dosing and monitoring of the analgesic as well as quick diagnostics of possible overdose in emergency care. However, in addition to the parent drug, several metabolites are always present in the blood after a dose of oxycodone, and to date, there is no electrochemical data available on any of these metabolites. In this paper, a single-walled carbon nanotube (SWCNT) electrode and a Nafion-coated SWCNT electrode were used, for the first time, to study the electrochemical behavior of oxycodone and its two main metabolites, noroxycodone and oxymorphone. Both electrode types could selectively detect oxycodone in the presence of noroxycodone and oxymorphone. However, we have previously shown that addition of a Nafion coating on top of the SWCNT electrode is essential for direct measurements in complex biological matrices. Thus, the Nafion/SWCNT electrode was further characterized and used for measuring clinically relevant concentrations of oxycodone in buffer solution. The limit of detection for oxycodone with the Nafion/SWCNT sensor was 85 nM, and the linear range was 0.5-10 mu M in buffer solution. This study shows that the fabricated Nafion/SWCNT sensor has potential to be applied in clinical concentration measurements.
  • Keltanen, Terhi N.; Heikman, Pertti K.; Muhonen, Leea H.; Gunnar, Teemu O.; Ojanperä, Ilkka A. (2019)
    Urine samples were analyzed for lactose to investigate if elevated lactose concentrations indicate recent (<48 hours) intravenous abuse of substances containing lactose as an excipient. Elevated lactose levels were found in samples given by patients who had recently injected substances intravenously, verified by fresh injection marks. Urine lactose assay can support clinical and toxicological findings when assessing substance abuse.
  • Peltonen, Karita; Colis, Laureen; Liu, Hester; Jaamaa, Sari; Moore, Henna M.; Enback, Juulia; Laakkonen, Pirjo; Vaahtokari, Anne; Jones, Richard J.; af Hallstrom, Taija M.; Laiho, Marikki (2010)
  • Taipale, Heidi; Särkilä, Hanna; Tanskanen, Antti; Kurko, Terhi; Taiminen, Tero; Tiihonen, Jari; Sund, Reijo; Tuulio-Henriksson, Annamari; Saastamoinen, Leena; Hietala, Jarmo (2020)
    This cohort study uses national longitudinal data from the Social Insurance Institution of Finland to investigate the incidence of long-term use of benzodiazepines and related drugs among new users and factors associated with development of long-term use. Importance The proportion of patients who develop long-term benzodiazepine use remains controversial, as do the length of time before long-term use develops and the factors associated with long-term use. Objective To investigate the incidence of long-term benzodiazepine and related drug (BZDR) use and factors associated with the development of long-term use implementing a follow-up design with new BZDR users. Design, Setting, and Participants This population-based cohort study used a nationwide cohort of 129x202f;732 new BZDR users in Finland. New users of BZDRs aged 18 years or older were identified from the prescription register maintained by the Social Insurance Institution of Finland as individuals who initiated BZDR use during 2006 and had not used BZDRs from 2004 to 2005. The follow-up continued until death, long-term hospitalization, a gap of 2 years in BZDR use, or December 31, 2015. The population was analyzed according to age at treatment initiation, categorized into younger (= 65 years) subcohorts. Analyses were conducted from May 2019 to February 2020. Exposures Use of BZDRs, modeled from register-based data using the PRE2DUP (from prescriptions to drug use periods) method. Main Outcomes and Measures Long-term BZDR use, defined as continuous use of 180 days or longer, and factors associated with long-term vs short-term use, compared using Cox proportional hazards models. Results Among the 129x202f;732 incident BZDR users, the mean (SD) age was 52.6 (17.7) years, and 78x202f;017 (60.1%) individuals were women. During the follow-up period, 51x202f;099 BZDR users (39.4%) became long-term users. Long-term treatment was more common in the older subcohort (19x202f;103 individuals [54.5%]) than the younger subcohort (31x202f;996 individuals [33.8%]). At 6 months, 28x202f;586 individuals (22.0%) had become long-term users: 11x202f;805 (33.7%) in the older subcohort and 16x202f;781 (17.7%) in the younger subcohort. The largest proportions of initiators who became long-term users were those persons who initiated treatment with nitrazepam (76.4%; 95% CI, 73.6%-79.1%), temazepam (63.9%; 95% CI, 62.9%-65.0%), lorazepam (62.4%; 95% CI, 59.7%-65.1%), or clonazepam (57.5%; 95% CI, 55.9%-59.2%). Factors associated with the development of long-term use included male sex, older age, receipt of social benefits, psychiatric comorbidities, and substance abuse. Conclusions and Relevance The findings of this population-based cohort study conducted in Finland suggest that the incidence of subsequent long-term BZDR use in individuals who initiate use of BZDRs is high, especially among older persons, and that the specific BZDR used initially is associated with the development of long-term BZDR use and should be carefully considered when prescribing BZDRs. The observed factors that appear to be associated with development of long-term BZDR use also should be considered in clinical decision-making when starting and monitoring BZDR treatment. Questions What is the incidence of long-term use of benzodiazepines and related drugs (BZDRs) in persons who start new BZDR treatment, and what factors are associated with the development of long-term use? Findings In a cohort study of 129x202f;732 new BZDR users in Finland, 34% of working-aged persons and 55% of older persons developed long-term use. Higher rates of long-term use were associated with specific drugs, namely, nitrazepam, temazepam, lorazepam, and clonazepam. Meaning Despite guidelines and recommendations, BZDRs are still prescribed frequently for long-term treatment, especially in older persons, and the initial choice of a specific BZDR is associated with development of long-term BZDR use.
  • Michalcova, Jana; Vasut, Karel; Airaksinen, Marja; Bielakova, Katarina (2020)
    Background Falls are common undesirable events for older adults in institutions. Even though the patient's fall risk may be scored on admission, the medication-induced fall risk may be ignored. This study developed a preliminary categorization of fall-risk-increasing drugs (FRIDs) to be added as a risk factor to the existing fall risk assessment tool routinely used in geriatric care units. Methods Medication use data of older adults who had experienced at least one fall during a hospital ward or a nursing home stay within a 2-year study period were retrospectively collected from patient records. Medicines used were classified into three risk categories (high, moderate and none) according to the fall risk information in statutory summaries of product characteristics (SmPCs). The fall risk categorization incorporated the relative frequency of such adverse drug effects (ADEs) in SmPCs that were known to be connected to fall risk (sedation, orthostatic hypotension, syncope, dizziness, drowsiness, changes in blood pressure or impaired balance). Also, distribution of fall risk scores assessed on admission without considering medications was counted. Results The fall-experienced patients (n = 188, 128 from the hospital and 60 from nursing home records) used altogether 1748 medicaments, including 216 different active substances. Of the active substances, 102 (47%) were categorized as high risk (category A) for increasing fall risk. Fall-experienced patients (n = 188) received a mean of 3.8 category A medicines (n = 710), 53% (n = 375) of which affected the nervous and 40% (n = 281) the cardiovascular system. Without considering medication-related fall risk, 53% (n = 100) of the patients were scored having a high fall risk (3 or 4 risk scores). Conclusion It was possible to develop a preliminary categorization of FRIDs basing on their adverse drug effect profile in SmPCs and frequency of use in older patients who had experienced at least one documented fall in a geriatric care unit. Even though more than half of the fall-experienced study participants had high fall risk scores on admission, their fall risk might have been underestimated as use of high fall risk medicines was common, even concomitant use. Further studies are needed to develop the FRID categorization and assess its impact on fall risk.