Andrea Corsonello

Recommendations to Prescribe in Complex Older Adults: Results of the CRIteria to Assess Appropriate Medication Use Among Elderly Complex Patients (CRIME) Project

The occurrence of several geriatric conditions may influence the efficacy and limit the use of drugs prescribed to treat chronic conditions. Functional and cognitive impairment, geriatric syndromes (i.e. falls or malnutrition) and limited life expectancy are common features of old age, which may limit the efficacy of pharmacological treatments and question the appropriateness of treatment. However, the assessment of these geriatric conditions is rarely incorporated into clinical trials and treatment guidelines. The CRIME (CRIteria to assess appropriate Medication use among Elderly complex patients) project is aimed at producing recommendations to guide pharmacologic prescription in older complex patients with a limited life expectancy, functional and cognitive impairment, and geriatric syndromes, and providing physicians with a tool to improve the quality of prescribing, independent of setting and nationality. To achieve these aims, we performed the following: (i) Existing disease-specific guidelines on pharmacological prescription for the treatment of diabetes, hypertension, congestive heart failure, atrial fibrillation and coronary heart disease were reviewed to assess whether they include specific indications for complex patients; (ii) a literature search was performed to identify relevant articles assessing the pharmacological treatment of complex patients; (iii) A total of 19 new recommendations were developed based on the results of the literature search and expert consensus. In conclusion, the new recommendations evaluate the appropriateness of pharmacological prescription in older complex patients, translating the recommendations of clinical guidelines to patients with a limited life expectancy, functional and cognitive impairment, and geriatric syndromes. These recommendations cannot represent substitutes for careful clinical consideration and deliberation by physicians; the recommendations are not meant to replace existing clinical guidelines, but they may be used to help physicians in the prescribing process.

Leptin increases serotonin turnover by inhibition of brain nitric oxide synthesis

Leptin administration inhibits diencephalic nitric oxide synthase (NOS) activity and increases brain serotonin (5-HT) metabolism in mice. We evaluated food intake, body-weight gain, diencephalic NOS activity, and diencephalic content of tryptophan (TRP), 5-HT, hydroxyindoleacetic acid (5-HIAA), and 5-HIAA/5-HT ratio after intracerebroventricular (ICV) or intraperitoneal (IP) leptin injection in mice. Five consecutive days of ICV or IP leptin injections induced a significant reduction in neuronal NOS (nNOS) activity, and caused a dose-dependent increase of 5-HT, 5-HIAA, and the 5-HIAA/5-HT ratio. Diencephalic 5-HT metabolism showed a significant increase in 5-HT, 5-HIAA, and the 5-HIAA/5-HT ratio 3 hours after a single leptin injection. This effect was maintained for 3 hours and had disappeared by 12 hours after injection. After a single IP leptin injection, the peak for 5-HT, 5-HIAA, and the 5-HIAA/5-HT ratio was achieved at 6 hours. Single injections of ICV or IP leptin significantly increased diencephalic 5-HT content. Leptin-induced 5-HT increase was antagonized by the coadministration of L-arginine only when the latter was ICV injected, whereas D-arginine did not influence leptin effects on brain 5-HT content. Finally, in nNOS-knockout mice, the appetite-suppressant activity of leptin was strongly reduced, and the leptin-induced increase in brain 5-HT metabolism was completely abolished. Our results indicate that the L-arginine/NO pathway is involved in mediating leptin effects on feeding behavior, and demonstrate that nNOS activity is required for the effects of leptin on brain 5-HT turnover.

Age-Related Pharmacokinetic and Pharmacodynamic Changes and Related Risk of Adverse Drug Reactions

Aging is known to be associated with an increased prevalence of multiple chronic diseases, which frequently causes the use of complex therapeutic regimens. The aging process is characterized by relevant changes in drug handling, physiological reserve, and pharmacodynamic response. Hepatic drug clearance of several drugs decreases with aging, mainly due to reduced blood flow, and hepatocyte mass. Renal function also declines with aging, mainly due to sclerotic changes in the glomeruli. Furthermore, due to reduced muscle mass, older subjects frequently have depressed glomerular filtration rate despite normal serum creatinine, and such a concealed renal insufficiency may impact significantly the clearance of hydrosoluble drugs. Changes in pharmacodynamics are also well documented in the cardiovascular and nervous system. Age-related changes in pharmacokinetics and pharmacodynamics, together with comorbidity and polypharmacy, make elderly patients at special risk for adverse drug reactions, which in turn are cause of relevant health burden and costs. Selected measures can assist in preventing or detecting timely such adverse events.

Moving against frailty: does physical activity matter?

Frailty is a common condition in older persons and has been described as a geriatric syndrome resulting from age-related cumulative declines across multiple physiologic systems, with impaired homeostatic reserve and a reduced capacity of the organism to resist stress. Therefore, frailty is considered as a state of high vulnerability for adverse health outcomes, such as disability, falls, hospitalization, institutionalization, and mortality. Regular physical activity has been shown to protect against diverse components of the frailty syndrome in men and women of all ages and frailty is not a contra-indication to physical activity, rather it may be one of the most important reasons to prescribe physical exercise. It has been recognized that physical activity can have an impact on different components of the frailty syndrome. This review will address the role of physical activity on the most relevant components of frailty syndrome, with specific reference to: (i) sarcopenia, as a condition which frequently overlaps with frailty; (ii) functional impairment, considering the role of physical inactivity as one of the strongest predictors of physical disability in elders; (iii) cognitive performance, including evidence on how exercise and physical activity decrease the risk of early cognitive decline and poor cognition in late life; and (iv) depression by reviewing the effect of exercise on improving mood and increasing positive well-being.

Relationship between plasma leptin levels and the tumor necrosis factor-α system in obese subjects

OBJECTIVE: To evaluate the relationship between plasma leptin and the tumor necrosis factor-α (TNFα), TNF receptor p60 (TNF-R1) and TNF receptor p80 (TNF-R2) concentrations in obese subjects.DESIGN: Case-control study.SETTING: Outpatient’s Service for Prevention and Treatment of Obesity at the University Hospital.MEASUREMENTS: Body mass index (BMI), waist circumference, hip circumference, waist-to-hip ratio (WHR), fasting plasma glucose, fasting plasma insulin, homeostasis model assessment of insulin resistance (HOMA IR), plasma leptin, TNF α, TNF-R1 and TNF-R2 concentrations were evaluated in obese subjects (n=42) and in age- and gender-matched, lean healthy controls (n=16).RESULTS: In obese subjects, fasting plasma glucose and insulin, HOMA IR, plasma leptin, TNFα, TNF-R1 and TNF-R2 concentrations were significantly higher than in controls. Furthermore, females showed higher leptin, TNF-R1 and TNF-R2 plasma concentrations compared to males, in both control and obese subjects. In control subjects, plasma leptin concentrations showed a direct correlation with BMI (r=0.74, P<0.001), hip circumference (r=0.94, P<0.001), TNF-R1 (r=0.79, P<0.001) and TNF-R2 (r=0.64, P<0.01), and a negative correlation with WHR (r=−0.58, P<0.05). In obese subjects, we found a direct correlation between plasma leptin concentrations and BMI (r=0.67, P<0.001), hip circumference (r=0.66, P<0.001), fasting glucose (r=0.37, P<0.05), fasting insulin (r=0.31, P<0.05), HOMA IR (r=0.38, P<0.05), TNF-R1 (r=0.71, P<0.001) and TNR-R2 (r=0.66, P<0.001), while a negative correlation was found between circulating leptin and WHR (r=−0.44, P<0.01). In multivariate analysis, plasma leptin concentrations were significantly associated with BMI (P=0.015) and gender (P=0.047) in the control group, while in obese subjects, plasma leptin showed a significant association with BMI (P=0.019) and TNF-R1 (P=0.012).CONCLUSIONS: Our results are consistent with the hypothesis that the TNFα system could be involved in the regulation of plasma leptin concentrations in obese subjects.

Chronic Renal Failure: A Neglected Comorbidity of COPD

BACKGROUND To the best of our knowledge, the association between COPD and chronic renal failure (CRF) has never been assessed. Lean mass is frequently reduced in COPD, and the glomerular filtration rate (GFR) might be depressed in spite of normal serum creatinine (concealed CRF). We investigated the prevalence and correlates of both concealed and overt CRF in elderly patients with COPD. METHODS We evaluated 356 consecutive elderly outpatients with COPD enrolled in the Extrapulmonary Consequences of COPD in the Elderly Study and 290 age-matched outpatients free from COPD. The GFR was estimated using the Modification of Diet in Renal Disease Study Group equation. Patients were categorized as having normal renal function (GFR > or = 60 mL/min/1.73 m(2)), concealed CRF (normal serum creatinine and reduced GFR), or overt CRF (increased serum creatinine and reduced GFR). Independent correlates of CRF were investigated by logistic regression analysis. RESULTS The prevalence of concealed and overt CRF in patients with COPD was 20.8% and 22.2%, respectively. Corresponding figures in controls were 10.0% and 13.4%, respectively. COPD and age were significantly associated with both concealed CRF (COPD: odds ratio [OR] = 2.19, 95% CI = 1.17-4.12; age: OR = 1.06, 95% CI = 1.04-1.09) and overt CRF (COPD: OR = 1.94, 95% CI = 1.01-4.66; age: OR = 1.06, 95% CI = 1.04-1.10). Diabetes (OR = 1.96, 95% CI = 1.02-3.76), hypoalbuminemia (OR = 2.83, 95% CI = 1.70-4.73), and muscle-skeletal diseases (OR = 1.78, 95% CI = 1.01-3.16) were significant correlates of concealed CRF. BMI (OR = 1.05, 95% CI = 1.01-1.10) and diabetes (OR = 2.25, 95% CI = 1.26-4.03) were significantly associated with overt CRF. CONCLUSIONS CRF is highly prevalent in patients with COPD, even with normal serum creatinine, and might contribute to explaining selected conditions such as anemia that are frequent complications of COPD.

Frailty and muscle metabolism dysregulation in the elderly

The frailty syndrome is increasingly recognized by geriatricians to identify elders at an extreme risk of adverse health outcomes. The physiological changes that result in frailty are complex and up to now have been extremely difficult to characterize due to the frequent coexistence of acute and chronic illness. Frailty is characterized by an decline in the functional reserve with several alterations in diverse physiological systems, including lower energy metabolism, decreased skeletal muscle mass and quality, altered hormonal and inflammatory functions. This altered network leads to an extreme vulnerability for disease, functional dependency, hospitalization and death. One of the most important core components of the frailty syndrome is a decreased reserve in skeletal muscle functioning which is clinically characterized by a loss in muscle mass and strength (sarcopenia), in walking performance and in endurance associated with a perception of exhaustion and fatigue. There are a number of physiological changes that occur in senescent muscle tissues that have a critical effect on body metabolism. The causes of sarcopenia are multi-factorial and can include disuse, changing hormonal function, chronic diseases, inflammation, insulin resistance, and nutritional deficiencies. In this review, we will explore the dysregulation of some biological mechanisms that may contribute to the pathophysiology of the frailty syndrome through age-related changes in skeletal muscle mass and function.

Potentially inappropriate drug prescriptions and risk of hospitalization among older, Italian, nursing home residents: the ULISSE project

AbstractBackground Potentially inappropriate medications in older patients increase the risk of adverse drug events, which are an important cause of hospital admission and death among hospitalized patients. Little information is available about the prevalence of potentially inappropriate drug prescriptions (PIDPs) and the related health adverse outcomes among nursing home (NH) residents. Objective To estimate the prevalence of PIDPs and the association with adverse outcomes in NH residents. Methods A total of 1716 long-term residents aged ≥65 years participating in the ULISSE (Un Link Informatico sui Servizi Sanitari Esistenti per l’anziano [A Computerized Network on Health Care Services for Older People]) project were evaluated using a standardized comprehensive geriatric assessment instrument, i.e. the inter Resident Assessment Instrument Minimum Data Set. A thorough evaluation of residents’ drug use, medical diagnoses and healthcare resource utilization was performed. A PIDP was defined according to the most recent update of the Beers criteria. Results Almost one out of two persons (48%) had at least one PIDP and almost one out of five had two or more PIDPs (18%). Residents with a higher number of PIDPs had a higher likelihood of being hospitalized. Compared with residents without PIDPs, those with two or more PIDPs at baseline had a higher probability of being hospitalized (hazard ratio 1.73; 95% CI 1.14, 2.60) during the following 12 months. Risk of PIDP was positively associated with the total number of drugs and diseases, but negatively with age. PIDPs defined according to specific conditions (n = 780; 55%) were slightly more frequent than PIDPs based on single medications irrespective of specific indication (n=639; 45%). Conclusions PIDP is a significant problem among Italian NH residents. There is an urgent need for intervention trials to test strategies to reduce inappropriate drug use and its associated adverse health outcomes.

Original ResearchCOPDChronic Renal Failure: A Neglected Comorbidity of COPD

BACKGROUND To the best of our knowledge, the association between COPD and chronic renal failure (CRF) has never been assessed. Lean mass is frequently reduced in COPD, and the glomerular filtration rate (GFR) might be depressed in spite of normal serum creatinine (concealed CRF). We investigated the prevalence and correlates of both concealed and overt CRF in elderly patients with COPD. METHODS We evaluated 356 consecutive elderly outpatients with COPD enrolled in the Extrapulmonary Consequences of COPD in the Elderly Study and 290 age-matched outpatients free from COPD. The GFR was estimated using the Modification of Diet in Renal Disease Study Group equation. Patients were categorized as having normal renal function (GFR > or = 60 mL/min/1.73 m(2)), concealed CRF (normal serum creatinine and reduced GFR), or overt CRF (increased serum creatinine and reduced GFR). Independent correlates of CRF were investigated by logistic regression analysis. RESULTS The prevalence of concealed and overt CRF in patients with COPD was 20.8% and 22.2%, respectively. Corresponding figures in controls were 10.0% and 13.4%, respectively. COPD and age were significantly associated with both concealed CRF (COPD: odds ratio [OR] = 2.19, 95% CI = 1.17-4.12; age: OR = 1.06, 95% CI = 1.04-1.09) and overt CRF (COPD: OR = 1.94, 95% CI = 1.01-4.66; age: OR = 1.06, 95% CI = 1.04-1.10). Diabetes (OR = 1.96, 95% CI = 1.02-3.76), hypoalbuminemia (OR = 2.83, 95% CI = 1.70-4.73), and muscle-skeletal diseases (OR = 1.78, 95% CI = 1.01-3.16) were significant correlates of concealed CRF. BMI (OR = 1.05, 95% CI = 1.01-1.10) and diabetes (OR = 2.25, 95% CI = 1.26-4.03) were significantly associated with overt CRF. CONCLUSIONS CRF is highly prevalent in patients with COPD, even with normal serum creatinine, and might contribute to explaining selected conditions such as anemia that are frequent complications of COPD.

Regimen complexity and medication nonadherence in elderly patients

Objective: To assess whether the number of daily administrations of individual drugs, as a measure of regimen complexity, contributes to the profile of an elderly patient who adheres poorly to the prescribed therapy. Population: Six hundred ninety patients over 64 years who were consecutively admitted to 11 acute medical care and three long term/rehabilitation wards in Italy. Main outcome measure: Self-reported adherence to drugs taken at home before admission was measured by a single question assessment for each listed drug supplemented with a latter question about the circumstances of the missed administration. For cognitively impaired patients the question was put to patients’ relatives or caregivers. Methods: A structured multidimensional assessment was performed to identify nonadherence and its potential correlates. Correlates of nonadherence were identified by multivariable logistic regression. Results: We recorded 44 cases (6.4%) of nonadherence to at least one drug. Being assisted by foreign caregivers (OR 2.17; 95% CI 1.02–4.63) and the use of at least one multiple daily dosing drug (OR 2.99; 95% CI 1.24–7.17) were significant independent correlates of medication nonadherence, while age, selected indexes of frailty and the cumulative number of prescribed drugs were not. Conclusion: Regimen complexity and type of assistance are independent correlates of medication nonadherence.