Association of medication clusters and subsequent labor market marginalization in refugee and Swedish-born young adults with common mental disorders in Sweden.

Little is known about the association between common mental disorders (CMD) and labor market integration among refugee and Swedish-born young adults. Socially disadvantaged patients such as refugees are more likely to discontinue their medication use prematurely. This study aimed to identify clusters of individuals with similar psychotropic medication patterns; and examine the relationship between cluster membership with labor market marginalization (LMM) in refugee and Swedish-born young adults with CMD. The study uses a longitudinal matched cohort aged 18-24 years with CMD diagnoses from Swedish registers covering 2006-2016. Dispensed psychotropic medications (antidepressants, antipsychotics, anxiolytics, sedative-hypnotics, mood stabilizers) were collected one year before and after CMD diagnosis. Clusters of patients with similar time courses of prescribed dosages were algorithmically identified. The association of cluster membership with subsequent LMM, (long-term sickness absence, SA, disability pension, DP, or long-term unemployment, UE) was assessed using Cox regression. Among 12,472 young adults with CMD, there were 13.9% with SA, 11.9% with DP, and 13.0% with UE during a mean follow-up of 4.1 years (SD 2.3 years). Six clusters of individuals were identified. A cluster with a sustained increase in all medication types yielded the highest hazard ratio (HR [95% CI]) 1.69 [1.34, 2.13] for SA and 2.63 [2.05, 3.38] for DP. The highest HRs of UE give a cluster with a concentrated peak in antidepressants at CMD diagnosis (HR 1.61[1.18, 2.18]). Refugees and Swedish-born showed similar associations between clusters and LMM. To prevent LMM, targeted support and early assessment of CMD treatment are needed for individuals with a sustained increase in psychotropic medication after CMD diagnosis and for refugees in high-risk clusters for UE characterized by a rapid lowering of treatment dosages, which could be an indicator for premature medication discontinuation.

Use of antipsychotics and antidepressants in first-episode psychotic depression: A nationwide register-based study.

BACKGROUND: According to guidelines, psychotic depression should be treated with both antipsychotics and antidepressants, but current practice is largely unknown. We investigated the prevalence of antipsychotic and antidepressant use in first-episode psychotic depression and factors related to antipsychotic use after the diagnosis. METHODS: We identified individuals aged 16-65 with a first-episode diagnosis of psychotic depression (ICD-10 codes F32.3, F33.3) from nationwide data linkage of Finnish healthcare and population registers during 2000-2018. Point prevalence was measured as 2-week time windows every 3 months, investigating whether the individual had a modeled drug use period ongoing during the window or not, censoring to death and end of data linkage. RESULTS: The study population included 18,490 individuals (58.0% women; mean age 39.9 years, standard deviation 14.7). The prevalence of use for antidepressants (75.0%), antipsychotics (56.4%), and both (50.0%) were highest at 3 months after the diagnosis. The prevalence declined to 51.8%, 34.1%, and 28.7%, respectively, at 3 years after the diagnosis. In a logistic regression analysis, younger age (adjusted odds ratio < 25 vs. ≥55, 0.82 [95% confidence interval 0.73-0.91]), eating disorders (0.78 [0.66-0.92]), substance use disorders (0.80 [0.73-0.87]), and occupational inactivity (0.80 [0.73-0.87]) were associated with decreased odds of using antipsychotics at 3 months after diagnosis. Increased odds were found for diagnosis from inpatient care (1.74 [1.62-1.86]), and later year of cohort entry (2010-2014 vs. 2000-2004, 1.56 [1.42-1.70]). CONCLUSION: At most, half of the individuals with newly diagnosed psychotic depression used both antidepressants and antipsychotics. This likely has a negative impact on treatment success.

Comparative effectiveness of mood stabilizers and antipsychotics in the prevention of hospitalization after lithium discontinuation in bipolar disorder.

The aim of the study was to compare the real-world effectiveness of mood stabilizers and antipsychotics in the prevention of psychiatric hospitalizations and treatment failure after lithium discontinuation in a nationwide bipolar cohort. Using health-care registers, we identified everyone in Finland diagnosed with bipolar disorder during 1987-2018 who discontinued lithium after using it for at least one year (n = 4 052, median period of lithium use before discontinuation 2.7 years). The risk of psychiatric hospitalization and treatment failure (psychiatric hospitalization, death or change in medication) were investigated with within-individual Cox regression. Of mood stabilizer monotherapies, the periods of valproate use (HR = 0.83, 95% CI = 0.71 - 0.97) had lower risk of hospitalization than nonuse of mood stabilizers. Of antipsychotic monotherapies, the use of long-acting injectable (LAI) antipsychotics (HR = 0.48, 95% CI = 0.26 - 0.88) and chlorprothixene (HR = 0.62, 95% CI = 0.44 - 0.88) were associated with lower risk and the use of quetiapine (HR = 1.26, 95% CI = 1.07 - 1.48) and oral olanzapine (HR = 1.23, 95% CI = 1.01 - 1.49) with higher risk of psychiatric hospitalizations than nonuse of antipsychotics. Of mood stabilizer monotherapies, lithium use was associated with lower risk of treatment failure (HR = 0.82, 95% CI = 0.76 - 0.88) than valproate use. The results suggest that antipsychotic LAIs are especially effective in the prevention of psychiatric hospitalizations after lithium discontinuation. The need to alter used medications may be the lowest when lithium is restarted.

Prescription opioids among older adults: ten years of data across five countries.

BACKGROUND: Opioid use has increased globally in the recent decade. Although pain remains a significant problem among older adults, susceptibility to opioid-related harms highlights the importance of careful opioid therapy monitoring on individual and societal levels. We aimed to describe the trends of prescription opioid utilisation among residents aged ≥65 in all Nordic countries during 2009-2018. METHODS: We conducted cross-sectional measurements of opioid utilisation in 2009-2018 from nationwide registers of dispensed drugs in Denmark, Finland, Iceland, Norway, and Sweden. The measures included annual opioid prevalence, defined daily doses (DDDs) per 1000 inhabitants per day (DIDs), and morphine milligram equivalents (MMEs) per user per day. RESULTS: From 2009 to 2018, an average of 808,584 of adults aged ≥65 used opioids yearly in all five countries; an average annual prevalence of 17.0%. During this time period, the prevalence decreased in Denmark, Norway, and Sweden due to declining codeine and/or tramadol use. Iceland had the highest opioid prevalence in 2009 (30.2%), increasing to 31.7% in 2018. In the same period, DIDs decreased in all five countries, and ranged from 28.3 in Finland to 58.5 in Denmark in 2009, and from 23.0 in Finland to 54.6 in Iceland in 2018. MMEs/user/day ranged from 4.4 in Iceland to 19.6 in Denmark in 2009, and from 4.6 in Iceland to 18.8 in Denmark in 2018. In Finland, Norway, and Sweden, MMEs/user/day increased from 2009 to 2018, mainly due to increasing oxycodone utilisation. CONCLUSIONS: The stable or decreasing opioid utilisation prevalence among a majority of older adults across the Nordic countries coincides with an increase in treatment intensity in 2009-2018. We found large cross-national differences despite similarities across the countries' cultures and healthcare systems. For the aged population, national efforts should be placed on improving pain management and monitoring future trends of especially oxycodone utilisation.

Trajectories of antidepressant use and characteristics associated with trajectory groups among young refugees and their Swedish-born peers with diagnosed common mental disorders-findings from the REMAIN study.

PURPOSE: This study aimed to (1) identify the trajectories of prescribed antidepressants in refugee youth and matched Swedish-born peers diagnosed with common mental disorder (CMD) and (2) characterize the trajectories according to sociodemographic and medical factors. METHODS: The study population comprised 2,198 refugees and 12,199 Swedish-born individuals with both Swedish-born parents, aged 16-25 years in 2011, residing in Sweden and treated in specialised healthcare for CMD 2009-11. Group-based trajectory modelling was used to identify different trajectory groups of antidepressant use-based on annual defined daily dosages (DDDs). Multinomial logistic regression was applied to investigate the association of sociodemographic and medical characteristics with the identified trajectories. Nagelkerke pseudo-R2 values were estimated to evaluate the strength of these associations. RESULTS: Four trajectory groups of antidepressant use among young refugees were identified with following proportions and DDD levels in 2011: 'low constant' (88%, < 100), 'low increasing' (2%, ≈710), 'medium decreasing' (8%, ≈170) and 'high increasing' (2%, ≈860). Similar trajectories, however, with different proportions were identified in Swedish-born: 67%, 7%, 21% and 5%, respectively. The most influential factors discriminating the trajectory groups among refugees were 'duration of stay in Sweden' (R2 = 0.013), comorbid 'other mental disorders' (R2 = 0.009) and 'disability pension' (R2 = 0.007), while 'disability pension' (R2 = 0.017), comorbid 'other mental disorders' (R2 = 0.008) and 'educational level' (R2 = 0.008) were the most important determinants discriminating trajectory groups among Swedish-born youth. CONCLUSION: The lower use of antidepressants in refugees with CMDs compared to their Swedish-born counterparts warrants health literacy programs for refugees and training in transcultural psychiatry for healthcare professionals.

Trajectories of labour market marginalisation among young adults with newly diagnosed attention-deficit/hyperactivity disorder (ADHD).

AIMS: Labour market marginalisation (LMM), i.e. severe problems in finding and keeping a job, is common among young adults with attention-deficit/hyperactivity disorder (ADHD). This study aimed to disentangle the extent of LMM as well as the heterogeneity in patterns of LMM among young adults with ADHD and what characterises those belonging to these distinct trajectories of LMM. METHODS: This population-based register study investigated all 6287 young adults, aged 22-29 years, who had their first primary or secondary diagnosis of ADHD in Sweden between 2006 and 2011. Group-based trajectory (GBT) models were used to estimate trajectories of LMM, conceptualised as both unemployment and work disability, 3 years before and 5 years after the year of an incident diagnosis of ADHD. Odds ratios (ORs) with 95% confidence intervals (CIs) for the association between individual characteristics and the trajectory groups of LMM were estimated by multinomial logistic regression. RESULTS: Six distinct trajectories of LMM were found: 'increasing high' (21% belonged to this trajectory group) with high levels of LMM throughout the study period, 'rapidly increasing' (19%), 'moderately increasing' (21%), 'constant low' (12%) with low levels of LMM throughout the study period, 'moderately decreasing' (14%) and finally 'fluctuating' (13%), following a reversed u-shaped curve. Individuals with the following characteristics had an increased probability of belonging to trajectory groups of increasing LMM: low educational level (moderately increasing: OR: 1.4; CI: 1.2-1.8, rapidly increasing: OR: 1.7; CI: 1.3-2.1, increasing high: OR: 2.9; CI: 2.3-3.6), single parents (moderately increasing: OR: 1.6; CI: 1.1-2.4, rapidly increasing: OR: 2.0; CI: 1.3-3.0), those born outside the European Union/the Nordic countries (rapidly increasing: OR: 1.7; CI: 1.1-2.5, increasing high: OR: 2.1; CI: 1.4-3.1), persons living in small cities/villages (moderately increasing: OR: 2.4; CI: 1.9-3.0, rapidly increasing: OR: 2.1; CI: 1.6-2.7, increasing high: OR: 2.6; CI: 2.0-3.3) and those with comorbid mental disorders, most pronounced regarding schizophrenia/psychoses (rapidly increasing: OR: 6.7; CI: 2.9-19.5, increasing high: OR: 12.8; CI: 5.5-37.0), autism spectrum disorders (rapidly increasing: OR: 4.6; CI: 3.1-7.1, increasing high: OR: 9.6; CI: 6.5-14.6), anxiety/stress-related disorders (moderately increasing: OR: 1.3; CI: 1.1-1.7, rapidly increasing: OR: 2.0; CI: 1.6-2.5, increasing high: OR: 1.8; CI: 1.5-2.3) and depression/bipolar disorder (moderately increasing: OR: 1.3; CI: 1.0-1.6, rapidly increasing: OR: 1.7; CI: 1.4-2.2, increasing high: OR: 1.5; CI: 1.2-1.9). CONCLUSIONS: About 61% of young adults were characterised by increasing LMM after a diagnosis of ADHD. To avoid marginalisation, attention should especially be given to young adults diagnosed with ADHD with a low educational level, that are single parents and who are living outside big cities. Also, young adults with comorbid mental disorders should be monitored for LMM early in working life.

Detection of medications associated with Alzheimer's disease using ensemble methods and cooperative game theory.

OBJECTIVE: To study the feasibility of evaluating feature importance with Shapley Values and ensemble methods in the context of pharmacoepidemiology and medication safety. METHODS: We detected medications associated with Alzheimer's disease (AD) by examining the additive feature attribution with combined approach of Gradient Boosting and Shapley Values in the Medication use and Alzheimer's disease (MEDALZ) study, a nested case-control study of 70,719 verified AD cases in Finland. Our methodological approach is to do binary classification using Gradient boosting (an ensemble of weak classifiers) in a supervised learning manner. Then we apply Shapley Values (from cooperative game theory) to analyze how feature combinations affect the classification result. Medication use with a five to one year time-window before AD diagnosis was ascertained from Prescription register. RESULTS: Antipsychotics with low or medium dose, antidepressants with medium to high dose, and cardiovascular medications with medium to high dose were identified as the contributing features for separating cases with AD from controls. Medium to high amount of irregularity in the purchase pattern were an indicating feature for separating AD cases from controls. The similarity of medication purchases between AD cases and controls made the feature evaluation challenging. CONCLUSIONS: The combined approach of Gradient Boosting and feature evaluation with Shapley Values identified features that were consistent with findings from previous hypothesis-driven studies. Additionally, the results from the additive feature attribution identified new candidates for future studies on AD risk factors. Our approach also shows promise for studies based on observational studies, where feature identification and interactions in populations are of interest; and the applicability of using Shapley Values for evaluating feature relevance in pattern recognition tasks.

Long-term thiazide use and risk of low-energy fractures among persons with Alzheimer's disease-nested case-control study.

We investigated the association between thiazide use and the risk of low-energy fractures among community dwellers with Alzheimer's disease. Longer use was associated with a decreased risk of low-energy fractures. This study extends the previous knowledge of reduced fracture risk of thiazides to persons with Alzheimer's disease. INTRODUCTION: To investigate the association between thiazide use and the risk of low-energy fractures (LEF), and hip fracture among community dwellers with Alzheimer's disease (AD). No prior study has evaluated the effect of thiazides on LEF risk of AD patients. METHODS: LEF cases were identified from the MEDALZ study, including all community-dwelling persons diagnosed with AD in Finland 2005-2011. During the follow-up from AD diagnoses until the end of 2015, cases with LEF (N = 10,416) and hip fracture (N = 5578) were identified. LEF cases were matched with up to three controls without LEF, according to time since AD diagnosis, age and gender. Thiazide use identified from the Prescription register data was modeled with PRE2DUP method. Current use was defined in 0-30 days' time window before the fracture/matching date, and duration of current use was assessed. The association between thiazide exposure and LEFs was assessed with conditional logistic regression. RESULTS: Current thiazide use was observed in 10.5% of LEF cases and 12.5% of controls. Current thiazide use was associated with a decreased risk of LEF (adjusted OR [aOR] 0.83, 95% CI 0.77-0.88). In terms of the duration of use, no association was observed with short-term use (< 1 year or 1-3 years), while longer use (> 3 years) was associated with a reduced risk of LEF (aOR 0.77, 95% CI 0.71-0.83) and hip fracture (aOR 0.68, 95% CI 0.60-0.78). CONCLUSIONS: Our study extends the previous knowledge of reduced fracture risk of thiazides to persons with AD, a population with significantly increased background risk of fractures.

The risk of Alzheimer's disease associated with benzodiazepines and related drugs: a nested case-control study.

OBJECTIVE: To assess the association between benzodiazepine and related drug (BZDR) use and risk of Alzheimer's disease (AD) with cumulative consumption and duration of use based models. METHOD: A nationwide nested case-control study of all Finnish community-dwelling persons who received clinically verified AD diagnosis in 2005-2011 (N = 70 719) and their matched controls (N = 282 862). AD diagnosis was based on DSM-IV and NINCDS-ADRDA criteria. BZDR purchases were extracted from the Prescription Register since 1995. The association between BZDR use and AD was assessed using conditional logistic regression with 5-year lag time between exposure and outcome. RESULTS: Benzodiazepine and related drug use was associated with modestly increased risk of AD (adjusted OR 1.06, 95% CI 1.04-1.08). A dose-response relationship was observed with both cumulative consumption and duration. Adjustment for other psychotropics removed the cumulative dose-response relationship by attenuating the ORs in the highest dose category. CONCLUSION: Benzodiazepine and related drug use in general was associated with modestly increased risk of AD. No major differences were observed between different subcategories of BZDRs (i.e. benzodiazepines, Z drugs, short-/medium-acting or long-acting BZDRs). As dose-response relationship abolished after adjustment for other psychotropics, it is possible that the association may partially be due to antidepressants and/or antipsychotics, or concomitant use of these medications.

Mortality in schizophrenia: 30-year nationwide follow-up study.

OBJECTIVE: Recent reports suggest that the mortality gap between persons with schizophrenia and the general population is increasing. We investigated the mortality, age at death, and causes of death among persons diagnosed with schizophrenia and the general population in Finland during 1984-2014. METHODS: All persons with schizophrenia in Finland were identified from hospital discharge register, and compared with the Finnish population aged 16 years and older during 1984-2014, based on data from Statistics Finland. Age at death and standardized mortality ratio (SMR) were calculated for each follow-up year. RESULTS: Mean age at death increased from 57.6 years in 1984 to 70.1 years in 2014 in persons with schizophrenia, and from 70.9 to 77.5 years in the general population. All-cause SMR remained stable during the follow-up (2.6 in 1984 and 2.7 in 2014). A major change was observed in SMR for suicides which decreased from 11.0 in 1984 to 6.6 in 2014 (-40%). The SMRs for cardiovascular and cancer deaths showed increasing trends. CONCLUSION: The longevity of persons with schizophrenia is improving at approximately the same rate as the general population but suicide rates have declined substantially. However, there is still a major disparity in mortality compared with general population.

Fifth-year dental students' visions of leadership-A qualitative study.

INTRODUCTION: Leadership skills are important in dentists' work. Leadership education already in undergraduate curriculum is noteworthy. The aim of this qualitative study was to describe dental students' visions of leadership: how they imagined they end up in leadership position, factors supporting either staying in or leaving the position and their future views. MATERIALS AND METHODS: The data were gathered after participants, fifth-year dental students, attended a "Dentist as a Leader" study module. A method of empathy-based stories was utilised. Based on contrasting frame stories, students were divided into two groups and wrote essays about an imagined situation in which they either enjoyed their leadership position ("Stayers") or considered leaving it ("Leavers"). The data were analysed using the content analysis method. RESULTS: The reasons for ending up in a leadership position were similar in the two groups: accidentally drifting into or intentionally heading for it. Factors supporting staying or leaving the leadership position were more diverse and were divided into personal and working community levels. These factors were common and group-specific. Clinical work, personal life and the ability to improve the organisations were common factors. Good working community was a "Stayer"-specific factor. "Leaver"-specific factors included loneliness, stress and lack of public sector resources. Future career plans were similar in both groups emphasising clinical work. CONCLUSIONS: After having attended leadership training, dental students were able to describe their future careers and list factors supporting either staying or leaving an imagined leadership position. These factors can be utilised by organisations to develop better working environments for future dentist leaders. By recognising the factors, students themselves are able to plan their future career choices and prepare to become leaders.

Proton pump inhibitor use and risk of hip fractures among community-dwelling persons with Alzheimer's disease-a nested case-control study.

BACKGROUND: Hip fractures are a major health concern among older persons with Alzheimer's disease, who usually use many concomitant drugs for several diseases. Evidence of the association between proton pump inhibitor use and risk of hip fracture is contradictory. AIM: To investigate whether the long-term use of proton pump inhibitor is associated with risk of hip fractures among community-dwelling persons with Alzheimer's disease. METHODS: In this nested case-control study, the nationwide MEDALZ data were utilised. Community-dwelling persons with Alzheimer's disease who encountered incident hip fracture (N = 4818; mean age 84.1) were included as cases. Four controls were matched for each case at the date of hip fracture (N = 19 235; mean age 84.0). The association between hip fracture and duration of current PPI use (ongoing use during 0-30 days before the index date), and cumulative duration of use during 10 years before was investigated with conditional logistic regression. RESULTS: Long-term or cumulative proton pump inhibitor use was not associated with an increased risk of hip fracture. Current proton pump inhibitor use was associated with an increased risk of hip fracture (adjusted OR 1.12, 95% CI 1.03-1.22). The risk was increased in short-term current use (<1 year) (adjusted OR 1.23, 95% CI 1.10-1.37). CONCLUSIONS: The increased risk of hip fracture was evident only in short-term proton pump inhibitor use, but no association was found for long-term or cumulative use. Thus, our findings do not support previous assumptions that long-term proton pump inhibitor use would be associated with an increased risk of hip fractures.

The association of medications with sedative properties with oral health behaviour in community-dwelling older people.

OBJECTIVES: The objective of this study was to determine whether drugs with sedative properties are related to oral health behaviour-such as frequency of toothbrushing, using toothpaste and dental visits-and oral hygiene, measured by the number of teeth with dental plaque, among community-dwelling older people. METHODS: The study population consisted of 159 community-dwelling, dentate, non-smoking, older people from the Oral Health GeMS study (Geriatric Multidisciplinary Strategy for the Good Care of Older People study). The data were collected by interviews and clinical examinations during 2004-2005. Sedative properties of drugs were assessed using the sedative load (SL) model. Logistic and Poisson regression models were used to estimate odds ratios/relative risks (OR/RR) and 95% confidence intervals (CI). RESULTS: After adjusting for confounding factors, SL associated with infrequent toothbrushing (OR 1.72, CI: 0.61-4.89), toothpaste use less than twice a day (OR 3.34, CI: 1.39-8.12), non-regular dental visits (OR 2.28 CI: 0.91-5.30) and the number of teeth with dental plaque (RR 1.20 CI: 1.04-1.39) compared to participants without a SL. CONCLUSIONS: The results of this study suggest that use of drugs with sedative properties indicates poor oral health behaviour among older people.

Hospital-treated mental and behavioral disorders and risk of Alzheimer's disease: A nationwide nested case-control study.

BACKGROUND: Studies investigating psychiatric disorders as Alzheimer's disease (AD) risk factors have yielded heterogeneous findings. Differences in time windows between the exposure and outcome could be one explanation. We examined whether (1) mental and behavioral disorders in general or (2) specific mental and behavioral disorder categories increase the risk of AD and (3) how the width of the time window between the exposure and outcome affects the results. METHODS: A nationwide nested case-control study of all Finnish clinically verified AD cases, alive in 2005 and their age, sex and region of residence matched controls (n of case-control pairs 27,948). History of hospital-treated mental and behavioral disorders was available since 1972. RESULTS: Altogether 6.9% (n=1932) of the AD cases and 6.4% (n=1784) of controls had a history of any mental and behavioral disorder. Having any mental and behavioral disorder (adjusted OR=1.07, 95% CI=1.00-1.16) or depression/other mood disorder (adjusted OR=1.17, 95% CI=1.05-1.30) were associated with higher risk of AD with 5-year time window but not with 10-year time window (adjusted OR, 95% CI 0.99, 0.91-1.08 for any disorder and 1.08, 0.96-1.23 for depression). CONCLUSIONS: The associations between mental and behavioral disorders and AD were modest and dependent on the time window. Therefore, some of the disorders may represent misdiagnosed prodromal symptoms of AD, which underlines the importance of proper differential diagnostics among older persons. These findings also highlight the importance of appropriate time window in psychiatric and neuroepidemiology research.

Differences in analgesic use in community-dwelling persons with and without Alzheimer's disease.

BACKGROUND: There are conflicting findings about analgesic use among persons with cognitive impairment compared to cognitively intact older persons. The objective of our study was to investigate the prevalence of analgesic use in community-dwelling persons with and without Alzheimer's disease (AD), within six months after AD diagnosis and to find out factors associated with the use of analgesics and specific analgesic groups. METHOD: We utilized data from register based MEDALZ (Medication use and Alzheimer's disease) cohort consisting of all community-dwelling persons diagnosed with AD during 2005-2011 in Finland and their matched comparison persons without AD. Altogether, 67,215 persons with AD and one comparison person for each case were included. Drug use data were collected from the Prescription Register and comorbidities from Special Reimbursement and Hospital Discharge Registers. RESULTS: Statistically significant (p < 0.001) yet mostly small differences were found for analgesics use: analgesics were used by 34.9% and 33.5% of persons with and without AD, respectively. Paracetamol was the most frequently used analgesic both among persons with (25.0%) and without AD (19.1%). Persons with AD used less frequently NSAIDs (Nonsteroidal Anti-inflammatory Drugs) (13.2% vs. 17.3%) and mild opioids (5.0% vs. 7.1%), while the use of strong opioids was more common in comparison to persons without AD (1.3% vs. 1.1%, respectively). Analgesic users were more likely women, aged ≥80 years, had asthma/COPD, cardiovascular disease, diabetes, cancer, hip fracture, osteoporosis, rheumatoid arthritis, and lower socioeconomic position. CONCLUSION: Further studies are needed to evaluate the adequateness of pain relief in older persons with and without AD. SIGNIFICANCE: Persons with Alzheimer's disease (AD) used more frequently paracetamol and less frequently NSAIDs and mild opioids. A decreasing trend of NSAID use was observed among persons with AD during the study period.

A 100-kDa urinary protein is associated with insulin resistance in offspring of type 2 diabetic patients.

AIMS/HYPOTHESIS: One-third of normoalbuminuric type 1 diabetic patients show immunoreactive nephrin in urine. Offspring of type 2 diabetic patients are insulin-resistant and susceptible to the development of diabetes. We investigated whether the offspring of type 2 diabetic patients show nephrin in urine and whether possible nephrinuria is associated with insulin resistance. METHODS: Urinary proteins from timed overnight urine collections from 128 offspring of type 2 diabetic patients and 9 control subjects were analysed by western blotting using an antibody against nephrin. Glucose metabolism was assessed by OGTT and IVGTT and the euglycaemic-hyperinsulinaemic clamp technique. RESULTS: Of the offspring, 12.5% were strongly and 14.1% weakly positive for a 100-kDa urinary protein. All controls were negative. During the first 10 min of an IVGTT, the offspring strongly positive for the urinary protein had a higher insulin response than the offspring without the protein (3,700 vs 2,306 pmol l(-1)min(-1), p=0.007). Insulin sensitivity (the rate of whole-body glucose uptake divided by the steady-state insulin level x 100) was lower among the offspring strongly positive for the urinary protein than among the offspring negative for the protein (11.3 vs 15.8 micromol kg(-1)min(-1)pmol(-1)l(-1), p=0.008). CONCLUSIONS/INTERPRETATION: A 100-kDa urinary protein detectable with a nephrin antibody is associated with insulin resistance in offspring of type 2 diabetic patients.

Synthesis and in-vitro/in-vivo evaluation of orally administered entacapone prodrugs.

Entacapone is a new inhibitor of catechol-O-methyltransferase (COMT) that is used as an adjunct to L-dopa therapy in the treatment of Parkinson's disease. The bioavailability of orally administered entacapone is, however, relatively low (29-46%). In this study we have prepared more lipophilic acyl and acyloxyacyl esters, an acyloxy alkyl ether and an alkyloxycarbonyl ester of entacapone, and we have evaluated them as potential prodrugs to enhance the oral bioavailability of entacapone. All the derivatives fulfilled prodrug criteria and released entacapone in human serum in-vitro. The oral bioavailability of monopivaloyl (1a) and dipivaloyl (1b) esters of entacapone were investigated further in rats. The lipophilicity of 1b was high (log Papp 4.0 at pH 7.4) but its oral bioavailability was low (F = 0.6%), most probably due to its low aqueous solubility. The monopivaloyl ester of entacapone (1a) had a higher lipophilicity (log Papp 0.80) than entacapone (log Papp 0.18) at pH 7.4 while maintaining an aqueous solubility equal to entacapone. However, oral bioavailability was not increased when compared with the parent drug entacapone (F = 7.0% and 10.4%, respectively).

Synthesis of a water-soluble prodrug of entacapone.

Entacapone was reacted with phosphorous oxychloride in dry pyridine to yield a phosphate ester. The phosphate promoiety increased aqueous solubility of the parent drug by more than 1700- and 20-fold at pH 1.2 and 7.4, respectively. The phosphate ester provides adequate stability (t(1/2) = 2227 h; pH 7.4) towards chemical hydrolysis, and allowed for release of the parent drug via enzymatic hydrolysis in liver homogenate.

Piperazinylalkyl prodrugs of naproxen improve in vitro skin permeation.

Novel morpholinyl (4a) and piperazinylalkyl (4b-e) esters were synthesized and evaluated in vitro for their properties as bioreversible topically administered dermal prodrugs of naproxen. These ionizable prodrugs exhibited various aqueous solubilities and lipophilicities, depending on the pH of medium. As indicated by octanol-buffer partition coefficients (logP(app)) at pH 7.4, all of the prodrugs were significantly more lipophilic (logP(app)=0.7-3.9) than naproxen (logP(app)=0.3). Furthermore, the most aqueous of the soluble prodrugs (4b-d) were only 2-3-fold less soluble in an aqueous buffer of pH 7.4 ( approximately 30-50 mM) than was naproxen ( approximately 100 mM). At a pH of 5.0, prodrugs showed a generally higher aqueous solubility and similar logP(app) values, compared to naproxen. The chemical and enzymatic hydrolysis of prodrugs at 37 degrees C was investigated in aqueous buffer solutions (pH 5.0 and 7.4) and in 80% human serum (pH 7.4), respectively. The prodrugs showed moderate chemical stability (t(1/2)=15-150 days at pH 5.0), and they were hydrolyzed enzymatically to naproxen, with half-lives ranging from 0.4 to 77 min. In permeation studies using post-mortem human skin in vitro, the flux of naproxen was 6.5 and 1.6 nmol/cm(2). h in a saturated aqueous buffer vehicle of pH 7.4 and 5.0, respectively. Among the prodrugs, two piperazinyl derivatives (4c and 4d) resulted in a 9- and 4-fold enhancement of permeation, respectively, when compared to naproxen itself at pH 7.4. 4c also resulted in a significantly (4-fold) better permeation than naproxen at pH 5.0. In conclusion, piperazinyl esters improved skin permeation of naproxen and are promising prodrugs of naproxen for topical drug delivery.