The economic impact of moderate stage Alzheimer's disease in Italy: Evidence from the UP-TECH randomized trial

Background: There is consensus that dementia is the most burdensome disease for modern societies. Few cost-of-illness studies examined the complexity of Alzheimer's disease (AD) burden, considering at the same time health and social care, cash allowances, informal care, and out-of-pocket expenditure by families. Methods: This is a comprehensive cost-of-illness study based on the baseline data from a randomized controlled trial (UP-TECH) enrolling 438 patients with moderate AD and their primary caregiver living in the community. Results: The societal burden of AD, composed of public, patient, and informal care costs, was about �20,000/yr. Out of this, the cost borne by the public sector was �4,534/yr. The main driver of public cost was the national cash-for-care allowance (�2,324/yr), followed by drug prescriptions (�1,402/yr). Out-of-pocket expenditure predominantly concerned the cost of private care workers. The value of informal care peaked at �13,590/yr. Socioeconomic factors do not influence AD public cost, but do affect the level of out-of-pocket expenditure. Conclusion: The burden of AD reflects the structure of Italian welfare. The families predominantly manage AD patients. The public expenditure is mostly for drugs and cash-for-care benefits. From a State perspective in the short term, the advantage of these care arrangements is clear, compared to the cost of residential care. However, if caregivers are not adequately supported, savings may be soon offset by higher risk of caregiver morbidity and mortality produced by high burden and stress. The study has been registered on the website www.clinicaltrials.org (Trial Registration number: NCT01700556). Copyright � International Psychogeriatric Association 2015

High-performance liquid chromatography–tandem mass spectrometry in the identification and determination of phase I and phase II drug metabolites

Applications of tandem mass spectrometry (MS/MS) techniques coupled with high-performance liquid chromatography (HPLC) in the identification and determination of phase I and phase II drug metabolites are reviewed with an emphasis on recent papers published predominantly within the last 6 years (2002–2007) reporting the employment of atmospheric pressure ionization techniques as the most promising approach for a sensitive detection, positive identification and quantitation of metabolites in complex biological matrices. This review is devoted to in vitro and in vivo drug biotransformation in humans and animals. The first step preceding an HPLC-MS bioanalysis consists in the choice of suitable sample preparation procedures (biomatrix sampling, homogenization, internal standard addition, deproteination, centrifugation, extraction). The subsequent step is the right optimization of chromatographic conditions providing the required separation selectivity, analysis time and also good compatibility with the MS detection. This is usually not accessible without the employment of the parent drug and synthesized or isolated chemical standards of expected phase I and sometimes also phase II metabolites. The incorporation of additional detectors (photodiode-array UV, fluorescence, polarimetric and others) between the HPLC and MS instruments can result in valuable analytical information supplementing MS results. The relation among the structural changes caused by metabolic reactions and corresponding shifts in the retention behavior in reversed-phase systems is discussed as supporting information for identification of the metabolite. The first and basic step in the interpretation of mass spectra is always the molecular weight (MW) determination based on the presence of protonated molecules [M+H]+ and sometimes adducts with ammonium or alkali-metal ions, observed in the positive-ion full-scan mass spectra. The MW determination can be confirmed by the [M-H]- ion for metabolites providing a signal in negative-ion mass spectra. MS/MS is a worthy tool for further structural characterization because of the occurrence of characteristic fragment ions, either MSn analysis for studying the fragmentation patterns using trap-based analyzers or high mass accuracy measurements for elemental composition determination using time of flight based or Fourier transform mass analyzers. The correlation between typical functional groups found in phase I and phase II drug metabolites and corresponding neutral losses is generalized and illustrated for selected examples. The choice of a suitable ionization technique and polarity mode in relation to the metabolite structure is discussed as well

Socioeconomic Predictors of the Employment of Migrant Care Workers by Italian Families Assisting Older Alzheimer's Disease Patients: Evidence from the Up-Tech Study

Background: The availability of family caregivers of older people is decreasing in Italy as the number of migrant care workers (MCWs) hired by families increases. There is little evidence on the influence of socioeconomic factors in the employment of MCWs. Method: We analyzed baseline data from 438 older people with moderate Alzheimer's disease (AD), and their family caregivers enrolled in the Up-Tech trial. We used bivariate analysis and multilevel regressions to investigate the association between independent variables - education, social class, and the availability of a care allowance - and three outcomes - employment of a MCW, hours of care provided by the primary family caregiver, and by the family network (primary and other family caregivers). Results: The availability of a care allowance and the educational level were independently associated with employing MCWs. A significant interaction between education and care allowance was found, suggesting that more educated families are more likely to spend the care allowance to hire a MCW. Discussion: Socioeconomic inequalities negatively influenced access both to private care and to care allowance, leading disadvantaged families to directly provide more assistance to AD patients. Care allowance entitlement needs to be reformed in Italy and in countries with similar long-term care and migration systems. � 2015 The Author 2015. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved

An unexpected central hypertensive effect of the new imidazoline compound benazoline

Not availabl

Pilot Test of a New Personal Health System Integrating Environmental and Wearable Sensors for Telemonitoring and Care of Elderly People at Home (SMARTA Project)

Background: The increase in life expectancy is accompanied by a growing number of elderly subjects affected by chronic comorbidities, a health issue which also implies important socioeconomic consequences. Shifting from hospital or community dwelling care towards a home personalized healthcare paradigm would promote active aging with a better quality of life, along with a reduction in healthcare-related costs. Objective: The aim of the SMARTA project was to develop and test an innovative personal health system integrating standard sensors as well as innovative wearable and environmental sensors to allow home telemonitoring of vital parameters and detection of anomalies in daily activities, thus supporting active aging through remote healthcare. Methods: A first phase of the project consisted in the definition of the health and environmental parameters to be monitored (electrocardiography and actigraphy, blood pressure and oxygen saturation, weight, ear temperature, glycemia, home interaction monitoring -water tap, refrigerator, and dishwasher), the feedbacks for the clinicians, and the reminders for the patients. It was followed by a technical feasibility analysis leading to an iterative process of prototype development, sensor integration, and testing. Once the prototype had reached an advanced stage of development, a group of 32 volunteers - including 15 healthy adult subjects, 13 elderly people with cardiac diseases, and 4 clinical operators - was recruited to test the system in a real home setting, in order to evaluate both technical reliability and user perception of the system in terms of effectiveness, usability, acceptance, and attractiveness. Results: The testing in a real home setting showed a good perception of the SMAR-TA system and its functionalities both by the patients and by the clinicians, who appreciated the user interface and the clinical governance system. The moderate system reliability of 65-70% evidenced some technical issues, mainly related to sensor integration, while the patient's user interface showed excellent reliability (100%). Conclusions: Both elderly people and clinical operators considered the SMARTA system a promising and attractive tool for improving patients' healthcare while reducing related costs and preserving quality of life. However, the moderate reliability of the system should prompt further technical developments in terms of sensor integration and usability of the clinical operator's user interface

Pilot Test of a New Personal Health System Integrating Environmental and Wearable Sensors for Telemonitoring and Care of Elderly People at Home (SMARTA Project)

Background: The increase in life expectancy is accompanied by a growing number of elderly subjects affected by chronic comorbidities, a health issue which also implies important socioeconomic consequences. Shifting from hospital or community dwelling care towards a home personalized healthcare paradigm would promote active aging with a better quality of life, along with a reduction in healthcare-related costs. Objective: The aim of the SMARTA project was to develop and test an innovative personal health system integrating standard sensors as well as innovative wearable and environmental sensors to allow home telemonitoring of vital parameters and detection of anomalies in daily activities, thus supporting active aging through remote healthcare. Methods: A first phase of the project consisted in the definition of the health and environmental parameters to be monitored (electrocardiography and actigraphy, blood pressure and oxygen saturation, weight, ear temperature, glycemia, home interaction monitoring-water tap, refrigerator, and dishwasher), the feedbacks for the clinicians, and the reminders for the patients. It was followed by a technical feasibility analysis leading to an iterative process of prototype development, sensor integration, and testing. Once the prototype had reached an advanced stage of development, a group of 32 volunteers-including 15 healthy adult subjects, 13 elderly people with cardiac diseases, and 4 clinical operators-was recruited to test the system in a real home setting, in order to evaluate both technical reliability and user perception of the system in terms of effectiveness, usability, acceptance, and attractiveness. Results: The testing in a real home setting showed a good perception of the SMARTA system and its functionalities both by the patients and by the clinicians, who appreciated the user interface and the clinical governance system. The moderate system reliability of 65-70% evidenced some technical issues, mainly related to sensor integration, while the patient's user interface showed excellent reliability (100%). Conclusions: Both elderly people and clinical operators considered the SMARTA system a promising and attractive tool for improving patients' healthcare while reducing related costs and preserving quality of life. However, the moderate reliability of the system should prompt further technical developments in terms of sensor integration and usability of the clinical operator's user interface

Allyphenyline analogues potentially useful in the management of chronic pain and opioid addiction.

We have previously demonstrated that α2-adrenergic (α2-AR) molecules, related to the non-subtype selective antagonist 1, displayed different activity at α2A-, α2B- and α2C-AR subtypes, depending on the peculiar nature of the ortho substituent in the Ar ring. For example, phenyl and thienyl groups converted 1 into the efficacious agonists 2 (biphenyline) and 3, respectively, activating α2A- and α2C-subtypes. Allyl or cyclopropyl groups of lower steric bulk turned the biological profile of the antagonist 1 only at α2C-subtype: 4 (allyphenyline) and 5 were potent α2C-agonists, whereas efficiently antagonized α2A-AR. From in vivo study 4 significantly enhanced morphine analgesia (due to α2C-AR agonism), was devoid of sedative side effects (due to α2A-AR antagonism) as well as prevented and contrasted morphine tolerance and dependence at very low dose (0.05 mg/Kg) [1]. Encouraged by these results, we prepared and studied compounds 6-12 inspired by 4. They were characterized by ortho substituents of moderate steric bulk and positive or negative σ and π contributions in all the combinations. A molecular modeling study performed on 2-12 highlighted that the desidered α2C-agonism/α2A-antagonism combination was displayed by ligands having favoured extended conformation (i.e. 4 and 5). In contrast, the activation of both α2A- and α2C-subtypes was produced by ligands endowed with favoured folded conformation (i.e. 2 and 3). [1] F. Del Bello et al. J. Med. Chem. 53, 2010, 7825-7835 and references therein

Imidazoline nucleus as a biologically versatile scaffold

Several studies carried out in our laboratories demonstrated the biological versatility of the imidazoline nucleus and the crucial role played by the substituent in position 2 in affecting both the functional behaviour of the ligands and their recognition of a specific biological target. Indeed, suitable chemical manipulations of this substituent provided the antinociceptive agents homoazanicotine [1] or biphenyline [2], activating the α4β2- nicotinic receptor or the α2A-/α2C-adrenoreceptor (AR) subtypes, respectively. Similarly, the α2A-AR antagonist/α2C-AR agonist allyphenyline was obtained. It proved to be an efficacious adjuvant in morphine analgesia and was able to decrease morphine tolerance and dependence. Therefore, it may be considered a novel promising therapeutic tool in pain and opiod addiction management [3]. The imidazoline derivative idazoxan, a potent and non-selective α2-AR antagonist, also interacts with high affinity with I2-imidazoline binding sites (I2-IBS). Nevertheless, unlike other I2-IBS ligands, such as phenyzoline, it does not affect morphine analgesia nor inhibits the development of morphine tolerance [4,5]. Encouraged by our previous results, in the present study we designed some chemical manipulations of the idazoxan molecule with the aim to improve its I2-IBS behavioural profile and to obtain novel α2-AR subtype selective antagonists. Therefore, its quite planar 1,4-benzodioxane scaffold was replaced by the less conformationally constrained 1,4-dioxane nucleus substituted in position 5 or 6 with one phenyl group in both cis or trans stereochemical relationship with the imidazoline ring in position 2 (compounds 1-4). These modifications also allowed us to evaluate the influence of different distances between the aromatic and basic moieties on the biological effects and the stereochemical requirements of the receptor interactions. The obtained results supported the validity of our project. Indeed, compound 2, with a trans stereochemical relationship between 5-phenyl and 2-imidazoline groups, maintained the I2-IBS recognition and was able to antagonize the sole α2A-AR subtype. Interestingly, due to its peculiar behaviour, 2 potently enhanced morphine analgesia, as shown in algesiometric tests. References [1] G. Ferretti, M. Dukat, M. Giannella et al., Bioorg. Med. Chem. Lett., 2000, 10, 2665-2668. [2] F. Gentili, P. Bousquet, L. Brasili et al., J. Med. Chem., 2002, 45, 32-40. [3] F. Del Bello, L. Mattioli, F. Ghelfi et al., J. Med. Chem., 2010, 53, 7825-7835. [4] F. Gentili, C. Cardinaletti, A. Carrieri et al., Eur. J. Pharmacol., 2006, 553, 73-81. [5] F. Gentili, C. Cardinaletti, C. Vesprini, et al., J. Med. Chem., 2008, 51, 5130-5134

Some approaches to the pharmacology of multisubstrate enzyme systems

NRC publication: Ye

Might the observed alpha2A-adrenoreceptor agonism or antagonism of allyphenyline analogues be ascribed to different molecular conformations?

We recently reported that the alpha2-adrenoreceptor (AR) ligand allyphenyline (9) significantly enhanced morphine analgesia (due to its alpha2C-AR agonism), was devoid of sedative side effects (due to its alpha2A-AR antagonism), prevented and reversed morphine tolerance and dependence. To highlight the molecular characteristics compatible with this behaviour and to obtain novel agents potentially useful in chronic pain and opioid addiction management, the allyl group of 9 was replaced by substituents of moderate steric bulk (MR) and positive or negative lipophilic (p) and electronic (r) contributions in all the possible combinations. Effective novel alpha2C-agonists/alpha2A-antagonists (2, 3, 10, 12, and 17) were obtained. This study also demonstrated that contradictory combinations of the physicochemical parameters were similarly able to induce the alpha2A-activation. Since we had previously observed that the absolute configuration affected only the potency, but not the functional profile of the ligands, we hypothesized that the alpha2A-activation was governed by a ligand preferred conformation. From a structural overlay investigation it emerged that an extended conformation appeared to be associated with dual alpha2C-agonism/alpha2A-antagonism, whereas a folded conformation associated with alpha2C-/alpha2A-agonism