Metabolismus von Psychopharmaka durch das Cytochrom P450-Enzymsystem im Alter

Altern geht mit einer Reihe physiologischer Veränderungen einher. Da in höherem Lebensalter überdurchschnittlich viele Arzneistoffe eingenommen werden und häufig mehrere Erkrankungen gleichzeitig vorliegen, können Auffälligkeiten in den Arzneimittelkonzentrationen im Blut nicht nur altersbedingt, sondern auch krankheitsbedingt oder durch Arzneimittelwechselwirkungen verursacht sein.rnrnDie vorliegende Arbeit untersucht die Fragestellung, ob der Arzneimittelmetabolismus bei Alterspatenten generell, oder nur bei Patienten mit Multimorbidität und –medikation verändert ist, und in welchem Lebensalter diese Veränderungen einsetzen. Im Mittelpunkt stand dabei die Frage, ob die Aktivitäten distinkter Arzneimittel-abbauender Enzyme der Cytochrom P450-Enzym-Familie (CYP) verändert sind. Da viele Psychopharmaka nur bei Patienten im Alter zwischen 18 und 65 Jahren zugelassen sind, wurde die Hypothese geprüft, dass sich Patienten im Alter über und unter 65 Jahren in ihren Medikamentenspiegeln unterscheiden.rnrnFür die Untersuchungen wurde eine Datenbank aus Blutspiegelmessungen erstellt, die im Rahmen des pharmakotherapiebegleitenden TDM erhoben worden waren. Die Blutspiegel stammten von insgesamt 4197 Patienten, die mit Amisulprid, Aripiprazol, Citalopram, Clozapin, Donepezil, Escitalopram, Mirtazapin, Quetiapin, Risperidon, Sertralin, Venlafaxin oder Ziprasidon behandelt wurden. Die Messungen wurden ergänzt mit Angaben aus den TDM-Anforderungsscheinen bezüglich Tagesdosis, Begleitmedikamenten, Schweregrad der Erkrankung, Therapieerfolg und Verträglichkeit der Medikation. Zusätzlich wurden klinische Befunde der Leber- und Nierenfunktion einbezogen, sowie Angaben zur Berechnung des BMI. Die in vivo-CYP-Enzymaktivitäten wurden anhand von metabolischen Ratios (Serumkonzentrationen Metabolit/ Serumkonzentration Muttersubstanz) beurteilt.rnrnIm Mittel stieg der Schweregrad der Erkrankung mit dem Alter und der Therapieerfolg verschlechterte sich. Dies betraf im Einzelnen nur Patienten, die mit Amisulprid oder Clozapin behandelt worden waren. Ältere Patienten litten häufiger an Nebenwirkungen als jüngere.rnUnter Aripiprazol, Quetiapin, Sertralin und Venlafaxin erreichten Alterspatienten mit niedrigeren Tagesdosen gleiche Therapieerfolge wie jüngere Patienten.rnPatienten, die mit Clozapin oder Amisulprid behandelt wurden, zeigten im Alter schlechtere Behandlungserfolge bei gleicher (Clozapin) bzw. niedrigerer (Amisulprid) Tagesdosis.rnTherapieerfolg und mittlere Tagesdosis änderten sich bei Patienten, die Ziprasidon, Donepezil, Citalopram, Escitalopram und Mirtazapin einnahmen, nicht altersabhängig.rnrnAltersabhängige Unterschiede der Serumspiegel zeigten sich für Amisulprid, Aripiprazol, Donepezil, Mirtazapin, Desmethylmirtazapin, Quetiapin und DesmethylsertralinrnAllerdings lagen die Altersgrenzen außer bei Donepezil deutlich niedriger als die gängig angenommene, nämlich bei 35 Jahren (Aripiprazol), 70 Jahren (Donepezil), 55 Jahren (D-Sertralin), 41 Jahren (Amisulprid), 49 Jahren (Quetiapin) und 58 Jahren (Mirtazapin).rnEs bestand kein Zusammenhang zwischen dem Auftreten veränderter Serumspiegel im Alter und dem Verteilungsvolumen, der Plasmaproteinbindung oder der Eliminationshalbwertszeit der untersuchten Wirkstoffe.rnrnBei Patienten ohne Comedikation fand sich in keinem Fall eine altersabhängige Veränderung der Ratio. Es ergab sich daher kein Hinweis auf eine Veränderung der CYP-Aktivität im Alter. Die Einnahme von Comedikation nahm mit dem Alter zu, hierfür ließ sich eine Altersgrenze von 49 Jahren definieren. Unter Polytherapie wurden Veränderungen der CYP-Aktivität beobachtet.rnrnDer Einfluss veränderter Leber- oder Nierenfunktion auf die Biotransformation von Pharmaka wurde anhand von Serumspiegeln von Patienten, die mit Donepezil, Venlafaxin, Citalopram oder Escitalopram behandelt wurden, untersucht. rnBei keinem Wirkstoff wurden unter auffälligen Leber- oder Nierenparametern signifikant veränderte Serumspiegel gemessen.rnEine Abhängigkeit der Serumspiegel vom Körpergewicht wurde nur für Desmethylsertralin gefunden. Die Spiegel waren bei Patienten mit einem Body Mass Index unter 20 signifikant höher als bei Patienten mit einem Index über 20. Aufgrund der kleinen Fallgruppe und der Tatsache, dass der Serumspiegel der Muttersubstanz nicht stieg, konnte nicht zwingend von einem Alterseinfluss aufgrund der veränderten Körperzusammensetzung ausgegangen werden.rnInsgesamt ergaben sich aus den Untersuchungen Hinweise auf moderate altersabhängige Veränderungen der Pharmakokinetik. Es ließen sich allerdings keine allgemeinen Dosierempfehlungen für Alterspatienten ableiten. Es zeigte sich jedoch, dass mit altersabhängigen Veränderungen der Pharmakokinetik bereits nach dem 50. Lebensjahr zu rechnen ist. Weitere Untersuchungen sollten auch den Alterseffekt auf gastrointestinale Transporter einbeziehen, die die aktive Aufnahme von Arzneistoffen ins Blut bewerkstelligen. Unklar ist auch die Rolle des Alterns auf die Aktivität des P-Glykoproteins. rn

Dementia with lewy bodies--diagnosis and treatment

Dementia with Lewy bodies (DLB) accounts for 15-20% of all autopsy confirmed dementias in old age. Characteristic histopathological changes are intracellular Lewy bodies and Lewy neurites, with abundant senile plaques but sparse neurofibrillary tangles. Core clinical features are fluctuating cognitive impairment, persistent visual hallucinations and extrapyramidal motor symptoms (parkinsonism). One of these core features has to be present for a diagnosis of possible DLB, and two for probable DLB. Supportive features are repeated falls, syncope, transient loss of consciousness, neuroleptic sensitivity, delusions and hallucinations in other modalities. DLB is clinically under-diagnosed and frequently misclassified as systemic delirium or dementia due to Alzheimer's disease or cerebrovascular disease. Therapeutic approaches to DLB can pose difficult dilemmas in pharmacological management. Neuroleptic medication is relatively contraindicated because some patients show severe neuroleptic sensitivity, which is associated with increased morbidity and mortality. Antiparkinsonian medication has the potential to exacerbate psychotic symptoms and may be relatively ineffective at relieving extrapyramidal motor symptoms. Recently there is converging evidence that treatment with cholinesterase inhibitors can offer a safe alternative for the symptomatic treatment of cognitive and neuropsychiatric features in DLB. This review will focus on the clinical characteristics of DLB, its differential diagnosis and on possible management strategies.

Persönliche Bilanzierung der Herausforderungen einer Verwitwung im Zeit- und Geschlechtervergleich

Bisherige Forschung hat die Verwitwung entweder primär als soziales oder als individuelles Ereignis untersucht, selten jedoch wurden beide Perspektiven verbunden. Zudem ist wenig darüber bekannt, inwiefern bisherige Forschungsergebnisse Perioden- oder Kohorteneffekte wiederspiegeln. In diesem Beitrag wird die persönliche Bilanzierung nach der Verwitwung älterer Schweizer Frauen und Männer im Geschlechterund Zeitvergleich untersucht1. Die Datenbasis beruht auf Befragungen von 1.197 verwitweten Frauen und Männern (Alter: 65-102 Jahre), welche 1979, 1994 und 2011 durchgeführt wurden. Während sich die wirtschaftlichen und sozialen Rahmenbedingungen nach einer Verwitwung – namentlich bei Frauen – im Zeitvergleich verbessert haben, zeigen sich bezüglich psychischer Herausforderungen einer Verwitwung keine periodenspezifischen Veränderungen. Psychisch bleibt der Partnerverlust auch bei günstigen Sozialbedingungen ein kritisches Lebensereignis, das individualisiert bewältigt werden muss.

Self-esteem development across the life span: A longitudinal study with a large sample from Germany

The authors examined the development of self-esteem across the life span. Data came from a German longitudinal study with 3 assessments across 4 years of a sample of 2,509 individuals ages 14 to 89 years. The self-esteem measure used showed strong measurement invariance across assessments and birth cohorts. Latent growth curve analyses indicated that self-esteem follows a quadratic trajectory across the life span, increasing during adolescence, young adulthood, and middle adulthood, reaching a peak at age 60 years, and then declining in old age. No cohort effects on average levels of self-esteem or on the shape of the trajectory were found. Moreover, the trajectory did not differ across gender, level of education, or for individuals who had lived continuously in West versus East Germany (i.e., the 2 parts of Germany that had been separate states from 1949 to 1990). However, the results suggested that employment status, household income, and satisfaction in the domains of work, relationships, and health contribute to a more positive life span trajectory of self-esteem. The findings have significant implications, because they call attention to developmental stages in which individuals may be vulnerable because of low self-esteem (such as adolescence and old age) and to factors that predict successful versus problematic developmental trajectories.

Tracking the trajectory of shame, guilt, and pride across the life span

The authors examined age differences in shame, guilt, and 2 forms of pride (authentic and hubristic) from age 13 years to age 89 years, using cross-sectional data from 2,611 individuals. Shame decreased from adolescence into middle adulthood, reaching a nadir around age 50 years, and then increased in old age. Guilt increased from adolescence into old age, reaching a plateau at about age 70 years. Authentic pride increased from adolescence into old age, whereas hubristic pride decreased from adolescence into middle adulthood, reaching a minimum around age 65 years, and then increased in old age. On average, women reported experiencing more shame and guilt; Blacks reported experiencing less shame and Asians more hubristic pride than other ethnicities. Across the life span, shame and hubristic pride tended to be negatively related to psychological well-being, and shame-free guilt and authentic pride showed positive relations with well-being. Overall, the findings support the maturity principle of personality development and suggest that as people age they become more prone to experiencing psychologically adaptive self-conscious emotions, such as guilt and authentic pride, and less prone to experiencing psychologically maladaptive ones, such as shame and hubristic pride.

β2-microglobulin is a systemic pro-aging factor that impairs cognitive function and neurogenesis

Aging drives cognitive and regenerative impairments in the adult brain, increasing susceptibility to neurodegenerative disorders in healthy individuals. Experiments using heterochronic parabiosis, in which the circulatory systems of young and old animals are joined, indicate that circulating pro-aging factors in old blood drive aging phenotypes in the brain. Here we identify β2-microglobulin (B2M), a component of major histocompatibility complex class 1 (MHC I) molecules, as a circulating factor that negatively regulates cognitive and regenerative function in the adult hippocampus in an age-dependent manner. B2M is elevated in the blood of aging humans and mice, and it is increased within the hippocampus of aged mice and young heterochronic parabionts. Exogenous B2M injected systemically, or locally in the hippocampus, impairs hippocampal-dependent cognitive function and neurogenesis in young mice. The negative effects of B2M and heterochronic parabiosis are, in part, mitigated in the hippocampus of young transporter associated with antigen processing 1 (Tap1)-deficient mice with reduced cell surface expression of MHC I. The absence of endogenous B2M expression abrogates age-related cognitive decline and enhances neurogenesis in aged mice. Our data indicate that systemic B2M accumulation in aging blood promotes age-related cognitive dysfunction and impairs neurogenesis, in part via MHC I, suggesting that B2M may be targeted therapeutically in old age.

A new class of obesity genes encodes leukocyte adhesion receptors

Obesity is a complex disease, and multiple genes contribute to the trait. The description of five genes (ob, db, tub, Ay, and fat) responsible for distinct syndromes of spontaneous monogenic obesity in mice has advanced our knowledge of the genetics of obesity. However, many other genes involved in the expression of this disease remain to be determined. We report here the identification of an additional class of genes involved in the regulation of adipose tissue mass. These genes encode receptors mediating leukocyte adhesion. Mice deficient in intercellular adhesion molecule-1 became spontaneously obese in old age on normal mouse chow or at a young age when provided with a diet rich in fat. Mice deficient in the counterreceptor for intercellular adhesion molecule-1, the leukocyte integrin αMβ2 (Mac-1), showed a similar obesity phenotype. Since all mice consumed approximately the same amount of food as controls, the leukocyte function appears to be in regulating lipid metabolism and/or energy expenditure. Our results indicate that (i) leukocytes play a role in preventing excess body fat deposition and (ii) defects in leukocyte adhesion receptors can result in obesity.

Empirical laws of survival and evolution: Their universality and implications

Presented analysis of human and fly life tables proves that with the specified accuracy their entire survival and mortality curves are uniquely determined by a single point (e.g., by the birth mortality q0), according to the law, which is universal for species as remote as humans and flies. Mortality at any age decreases with the birth mortality q0. According to life tables, in the narrow vicinity of a certain q0 value (which is the same for all animals of a given species, independent of their living conditions), the curves change very rapidly and nearly simultaneously for an entire population of different ages. The change is the largest in old age. Because probability to survive to the mean reproductive age quantifies biological fitness and evolution, its universal rapid change with q0 (which changes with living conditions) manifests a new kind of an evolutionary spurt of an entire population. Agreement between theoretical and life table data is explicitly seen in the figures. Analysis of the data on basic metabolism reduces it to the maximal mean lifespan (for animals from invertebrates to mammals), or to the maximal mean fission time (for bacteria), and universally scales them with the total number of body atoms only. Phenomenological origin of this unification and universality of metabolism, survival, and evolution is suggested. Their implications and challenges are discussed.

Elements of ergonomics programs : a primer based on workplace evaluations of musculoskeletal disorders /

"March 1997."

Osteoporosis and hip fractures : 1995-2000 /

Hip fracture is the most adverse outcome of osteoporosis. Few surveillance sources exist to estimate the extent of the burden of illness of osteoporosis in Illinois. Because hip fractures are an important proxy measure for the existence of osteoporosis, the Illinois Health Care Cost Containment Council examined hospital use, treatment and outcome measures for hip fracture patients during the years 1995 through 2000. Osteoporosis, as the underlying cause of hip fracture hospitalizations, is investigated for results of treatment and disposition at discharge. In the year 1995, 12,637, discharges for hip fracture patients were reported by Illinois hospitals. In contrast, in the year 2000, 12,311, discharges for hip fracture patients were reported by Illinois hospitals. This study will provide a descriptive analysis of hospital reported discharges during this six-year period, focusing on patient age and gender, cause of injury, treatments, outcomes, billed charges and expected payment source. A significant percentage of hip fractures occurred in people aged 65 and above. Hip fracture rates per thousand persons in females exceeded males in every age group in the study. Females accounted for approximately 75% of all hip fracture discharges during the study period. Facility charges for hip fracture cases in 1995 were over $213.5 million. Comparable charges in 2000 exceeded $270 million. Over 80% of patients in 2000 were discharged to another health care facility for additional care. A review of pathological fractures and reported cases of diagnosed osteoporosis are included to round out the study.

Why many eligible individuals choose not to go on welfare

This article investigates why many eligible for welfare do not participate. We show that on-the-job wage-rising potential is the key factor motivating nonparticipation. Although individuals with very low earnings and little wage-rising potential are typically welfare recipients, those with good wage-rising potential may choose to work, participate in old age, or never participate. Nonparticipation remains the best choice for eligible individuals with large wage-rising potential even if universal old-age social security is available. We will also apply this model to a comprehensive welfare system in Hong Kong.

QUALIDADE DE VIDA, PERCEPÇÃO DE SUPORTE SOCIAL E CONSUMO DE MEDICAMENTOS EM IDOSAS PARTICIPANTES DA UNIVERSIDADE PARA A TERCEIRA IDADE

A presente dissertação de mestrado abordou a qualidade de vida, a percepção de suporte social e o consumo de medicamentos em idosas participantes de um programa da Universidade para a Terceira Idade, no município de São Caetano do Sul - São Paulo - Brasil. O estudo objetivou descrever uma possível relação entre o perfil sociodemografico da amostra, a percepção subjetiva da qualidade de vida, a percepção subjetiva de suporte social, e o consumo de medicamentos, submetendo a testes estatísticos, um conjunto de possíveis relações entre as características sociodemográficas, percepção de qualidade de vida, percepção de suporte social e consumo de medicamentos. Utilizou-se o método descritivo exploratório, de corte transversal, e de caráter quantitativo. Os dados foram coletados entre os meses de agosto a outubro de 2014, através de uma amostra de conveniência, formada por 150 mulheres, com idade média de 66,13 anos. Foram utilizados instrumentos autoaplicáveis: WHOQOL-OLD e WHOQOL-BREF (Word Health Organization Quality of Life Instrument); Escala de Percepção de Suporte Social (EPSS); um questionário sobre a utilização de medicamentos de uso geral, e um questionário contendo os dados sociodemográficos. Dos resultados, 59,3% da amostra concluiu o ensino fundamental, 49,3% é casada, 79,3% não exerce atividade remunerada, e 78,7% não exerce atividades voluntárias. Apresentou boa percepção de Qualidade de Vida Global (82,90%), sendo o domínio com menor valor médio o Funcionamento do Sensório (12,56%), e maior escore médio no domínio Autonomia (14,66%). Sente segurança ao recorrer à rede de suporte social prático (53,08%), e insegurança ao recorrer à sua rede de apoio social emocional (28,88%). A prevalência do uso de medicamentos foi de 3,6%, todos prescritos, e os princípios ativos mais utilizados pertenciam aos tratamentos da hipertensão e sistema cardiovascular. Não foram evidenciadas correlações significativas relevantes entre as variáveis do estudo, do ponto de vista estatístico. Apesar de residirem em um município com elevado Índice de Desenvolvimento Humano, conclui-se que o aumento das possíveis incapacidades físicas das idosas apontam dificuldades de acesso aos recursos do ambiente, onde a amostra estava inserida. Sugere-se a criação de pesquisas e intervenções com idosas, incluindo nos programas de educação continuada, espaços para debate com o tema da finitude e o envelhecimento, bem como a realização de novos estudos de natureza qualitativa, para aprofundar o conhecimento sobre a qualidade de vida, a percepção do suporte social e o consumo de medicamentos nesta população, como também a inclusão de outros grupos sociodemográficos de idosas, em estudos longitudinais.

Dehdyroepiandrosterone sulfate directly activates protein kinase C-β to increase human neutrophil superoxide generation

Dehydroepiandrosterone sulfate (DHEAS) is the most abundant steroid in the human circulation and is secreted by the adrenals in an age-dependent fashion, with maximum levels during the third decade and very low levels in old age. DHEAS is considered an inactive metabolite, whereas cleavage of the sulfate group generates dehydroepiandrosterone (DHEA), a crucial sex steroid precursor. However, here we show that DHEAS, but not DHEA, increases superoxide generation in primed human neutrophils in a dose-dependent fashion, thereby impacting on a key bactericidal mechanism. This effect was not prevented by coincubation with androgen and estrogen receptor antagonists but was reversed by the protein kinase C inhibitor Bisindolylmaleimide 1. Moreover, we found that neutrophils are unique among leukocytes in expressing an organic anion-transporting polypeptide D, able to mediate active DHEAS influx transport whereas they did not express steroid sulfatase that activates DHEAS to DHEA. A specific receptor for DHEAS has not yet been identified, but we show that DHEAS directly activated recombinant protein kinase C-ß (PKC-ß) in a cell-free assay. Enhanced PKC-ß activation by DHEAS resulted in increased phosphorylation of p47phox, a crucial component of the active reduced nicotinamide adenine dinucleotide phosphate complex responsible for neutrophil superoxide generation. Our results demonstrate that PKC-ß acts as an intracellular receptor for DHEAS in human neutrophils, a signaling mechanism entirely distinct from the role of DHEA as sex steroid precursor and with important implications for immunesenescence, which includes reduced neutrophil superoxide generation in response to pathogens.

Interação social e envelhecimento ativo: um estudo em duas praças de Natal/RN

In view of the evident increase in the population group of people over 60 years old, the aging process has raised important discussions on social, political and economical planning that recommend that the increase in longevity must be followed by autonomy and well-being. Faced to these demands, the literature reports that physical activity is a key strategy to promote better living conditions for the elderly. Studies about personenvironment are making efforts to understand the socio physical environment role to encourage old people to make activities in many different environments. Among these, the urban public open space has been reported by many researches as a promising alternative in order to adopt a less sedentary life style. Based on these considerations, this study proposed to investigate the relationship between the social environment support elements and social interaction of seniors in public squares in the city of Natal, RN, using a multimethodological approach that included a experts panel, environmental characteristics analysis of 252 squares, case studies containing collective and individual interviews with elderly users and the spatial representation of their social interactions. The association between physical activities with the socialization practiced by them was identified as the main motivation for their presence in these places. The results indicate that the relationship between the socio-environmental characteristics (concept developed in this study) and the socio-spatial behaviors that include the spatial appropriation, spatial arrangements and interpersonal distances, helps to promote social interactions in carrying out activities, which, according to the assumptions Active Ageing Program, enable the maintenance of an active way of life, with important implications for health, wellness and quality of life in old age

Effects of retirement on cognitive function: A gender and international perspecive

Background: As the global population is ageing, studying cognitive impairments including dementia, one of the leading causes of disability in old age worldwide, is of fundamental importance to public health. As a major transition in older age, a focus on the complex impacts of the duration, timing, and voluntariness of retirement on health is important for policy changes in the future. Longer retirement periods, as well as leaving the workforce early, have been associated with poorer health, including reduced cognitive functioning. These associations are hypothesized to differ based on gender, as well as on pre-retirement educational and occupational experiences, and on post-retirement social factors and health conditions. Methods: A cross-sectional study is conducted to determine the relationship between duration and timing of retirement and cognitive function, using data from the five sites of International Mobility in Aging Study (IMIAS). Cognitive function is assessed using the Leganes Cognitive Test (LCT) scores in 2012. Data are analyzed using multiple linear regressions. Analyses are also done by site/region separately (Canada, Latin America, and Albania). Robustness checks are done with an analysis of cognitive change from 2012 to 2014, the effect of voluntariness of retirement on cognitive function. An instrumental variable (IV) approach is also applied to the cross-sectional and longitudinal analyses as a robustness check to address the potential endogeneity of the retirement variable. Results: Descriptive statistics highlight differences between men and women, as well as between sites. In linear regression analysis, there was no relationship between timing or duration of retirement and cognitive function in 2012, when adjusting for site/region. There was no association between retirement characteristics and cognitive function in site/region/stratified analyses. In IV analysis, longer retirement and on time or late retirement was associated with lower cognitive function among men. In IV analysis, there is no relationship between retirement characteristics and cognitive function among women. Conclusions: While results of the thesis suggest a negative effect of retirement on cognitive function, especially among men, the relationship remains uncertain. A lack of power results in the inability to draw conclusions for site/region-specific analysis and site-adjusted analysis in both linear and IV regressions.