Reducing the drug burden of sedative and anticholinergic medications in older adults: a scoping review of explicit decision criteria.

OBJECTIVES: To describe the extent, characteristics, and knowledge gaps regarding explicit decision criteria for deprescribing drugs with anticholinergic or sedative properties (Ach/Sed) in older adults. DESIGN: Scoping review. SETTING AND PARTICIPANTS: Original studies, clinical trial protocols, grey literature, and Summaries of Product Characteristics. METHODS: Searches targeting explicit decision criteria for deprescribing Ach/Sed were performed across MEDLINE, EMBASE, CINAHL, and Web of Science, including trial registries (clinicaltrials.gov, ICTRP, EU-CTR, ANZCTR) for pertinent articles, study protocols. Additionally, to encompass non-traditional or 'grey literature' sources, Google searches and relevant agency websites were explored, alongside the summary of product characteristics for Ach/Sed. RESULTS: The initial literature search identified 8,192 unique data sources. After review, 188 original articles or books, 79 internet sources, and 127 SmPCs were included. Examining these sources for explicit criteria for 154 Ach/Sed, overall, 1,271 explicit criteria guidance for identifying clinical scenarios warranting deprescription of Ach/Sed across 145/154 Ach/Sed were identified. These criteria were identified mainly from qualitative research and Summaries of Product Characteristics. Additionally, 455 criteria-based recommendations suggesting approaches for tapering implementation across 76/154 Ach/Sed were identified, mostly from sources classified as expert opinions. Significant heterogeneity was found across the approaches for tapering Ach/Sed. CONCLUSIONS: This scoping review provides a comprehensive overview of the literature providing guidance for clinical scenarios where Ach/Sed should be deprescribed and highlights the existing knowledge gaps regarding comprehensive guidance on tapering these drugs which warranties future research and development.

The Barriers to Deprescription in Older Patients: A Survey of Spanish Clinicians.

BACKGROUND AND OBJECTIVE: There are barriers to deprescription that hinder its implementation in clinical practice. The objective of this study was to analyse the main barriers and limitations of the deprescription process perceived by physicians who care for multipathological patients. MATERIALS AND METHODS: The "deprescription questionnaire of elderly patients" was adapted to an online format and sent to physicians in geriatrics. Question 1 is a reference to establish agreement or disagreement with this practice. The influence of different aspects of deprescription was analysed via the demographic characteristics of the clinicians and perceptions of the various barriers (questions 2-9) by means of bivariate analysis. Based on the latter, a multivariate model was carried out to demonstrate the relationship between barriers and the degree of deprescription agreement among respondents. RESULTS: Of the 72 respondents, 72.2% were in favour of deprescribing. Regarding the analyses, the demographic characteristics did not influence rankings. The deprescription of preventive drugs and consensus with patients were associated with a positive attitude towards deprescribing, while withdrawing drugs prescribed by other professionals, time constraints and patient reluctance emerged as possible barriers. The only factor independently associated with deprescribing was lack of time. CONCLUSIONS: Time was found to be the main barrier to deprescription. Training, the creation of multidisciplinary teams and integrated health systems are key facilitators.

Evidence of Immunomodulatory Food-Protein Derived Peptides in Human Nutritional Interventions: Review on the Outcomes and Potential Limitations.

The immune system is somehow related to all the metabolic pathways, in a bidirectional way, and the nutritional interventions affecting these pathways might have a relevant impact on the inflammatory status of the individuals. Food-derived peptides have been demonstrated to exert several bioactivities by in vitro or animal studies. Their potential to be used as functional food is promising, considering the simplicity of their production and the high value of the products obtained. However, the number of human studies performed until now to demonstrate effects in vivo is still scarce. Several factors must be taken into consideration to carry out a high-quality human study to demonstrate immunomodulatory-promoting properties of a test item. This review aims to summarize the recent human studies published in which the purpose was to demonstrate bioactivity of protein hydrolysates, highlighting the main results and the limitations that can restrict the relevance of the studies. Results collected are promising, although in some studies, physiological changes could not be observed. When responses were observed, they sometimes did not refer to relevant parameters and the immunomodulatory properties could not be clearly established with the current evidence. Well-designed clinical trials are needed in order to evaluate the role of protein hydrolysates in immunonutrition.

Feasibility of the Implementation of LESS-CHRON in Clinical Practice: A Pilot Intervention Study in Older Patients With Multimorbidity.

Background and Objectives: Potentially inappropriate medication refers to the prescription of drugs whose risks outweigh the benefits. There are different pharmacotherapeutic optimization strategies to detect and avoid potentially inappropriate medications (PIMs), namely deprescription. The List of Evidence-Based Deprescribing for Chronic Patients (LESS-CHRON) criteria were designed as a tool to systematize the deprescribing process. LESS-CHRON has established itself as one of the most suitable to be applied in older (≥65 years) multimorbid patients. However, it has not been applied to these patients, to measure the impact on their treatment. For this reason, a pilot study was conducted to analyze the feasibility of implementing this tool in a care pathway. Research Design and Methods: A pre-post quasi-experimental study was conducted. Older outpatients with multimorbidity from the Internal Medicine Unit of a benchmark Hospital were included. The main variable was feasibility in clinical practice, understood as the likelihood that the deprescribing intervention recommended by the pharmacist would be applied to the patient. Success rate, therapeutic, and anticholinergic burden, and other variables related to health care utilization were analyzed. Results: A total of 95 deprescribing reports were prepared. Forty-three were evaluated by the physician who assessed the recommendations made by pharmacists. This translates into an implementation feasibility of 45.3%. The application of LESS-CHRON identified 92 PIMs. The acceptance rate was 76.7% and after 3 months 82.7% of the stopped drugs remained deprescribed. A reduction in anticholinergic burden and enhanced adherence was achieved. However, no improvement was found in clinical or health care utilization variables. Discussion and Implications: The implementation of the tool in a care pathway is feasible. The intervention has achieved great acceptance and deprescribing has been successful in a not insignificant percentage. Future studies with a larger sample size are necessary to obtain more robust results in clinical and health care utilization variables.

Prevalence of Potentially Inappropriate Medications in Patients With Multimorbidity According to LESS-CHRON and STOPPFrail Criteria.

OBJECTIVE: LESS-CHRON (List of Evidence-Based Deprescribing for Chronic Patients) and STOPPFrail (Screening Tool of Older Persons' Prescriptions in Frail adults with limited life expectancy) are criterion-based deprescribing tools. This study aimed to identify the prevalence of potentially inappropriate medications (PIMs) with these tools in an outpatient, polymedicated, older population with multimorbidity. DESIGN: Single-center cross-sectional observational study. SETTING AND PARTICIPANTS: PIMs and criteria subject to deprescribing identified by each tool were collected in patients who were being followed up on outpatient internal medicine consultation. METHODS: PIMs were identified by STOPPFrail and LESS-CHRON criteria reviewing medical histories and pharmacologic treatments of the patients in the electronic health card system. Sociodemographic, clinical, and pharmacologic variables were recorded. A correlation analysis between treatment tools and clinical values was performed using the nonparametric Spearman rho correlation. RESULTS: Eighty-three patients with a median of 14.4 (interquartile range 12-17) prescribed drugs were included. The total number of PIMs identified with LESS-CHRON was 158 vs 127 with STOPPFrail. Eight of the 27 criteria (29.6%) for LESS-CHRON and 15 of the 25 for STOPPFrail were found to be not applicable. A significant correlation was obtained for both tools with the number of prescribed drugs at the time of inclusion. The Profund, Barthel, and Frail-VIG index only showed a significant correlation with LESS-CHRON. CONCLUSION AND IMPLICATIONS: Both tools have shown the capacity to identify PIMs that can be deprescribed in the population studied. However, LESS-CHRON appears to have a greater detection potential in the subgroup of patients analyzed. STOPPFrail brings a certain complementarity in other areas of therapy not covered by LESS-CHRON.

[Cross-cultural adaptation and validation into Spanish of the deprescription questionnaire in the elderly patient]. / Adaptación transcultural y validación al español del cuestionario de desprescripción en el paciente de edad avanzada.

BACKGROUND AND OBJECTIVE: In 2017, a questionnaire was developed in Italian with the aim of determining clinicians' perceptions of deprescription in the elderly population. The objective was to translate and cross-culturally adapt this deprescription questionnaire to Spanish. METHODS: Forward and blind-back translations, followed by a synthesis and adaptation by a third translator. Development of an expert panel to evaluate the adequacy of the translation, the understandability of the translated question and the usefulness of each question. A comprehensibility analysis was carried out on physicians familiar with deprescription. RESULTS: The Spanish version of the questionnaire was obtained, where the average degree of difficulty in the direct and the back-translation was low/moderate. In the first phase of the panel of experts, 4 questions had sections considered "indeterminate" and one question was "doubtful". After the second phase, all the questions were considered "adequate" except for one. CONCLUSIONS: This is the first cross-cultural adaptation to Spanish of this questionnaire, which will provide a tool to assess clinicians' perception of this practice and establish improvements to carry out this activity.

The Predictive Value of Anticholinergic Burden Measures in Relation to Cognitive Impairment in Older Chronic Complex Patients.

Anticholinergic burden (AB) is related to cognitive impairment (CI) and older complex chronic patients (OCCP) are more susceptible. Our objective was to evaluate the predictive value of ten anticholinergic scales to predict a potential CI due to anticholinergic pharmacotherapy in OCCP. An eight-month longitudinal multicentre study was carried out in a cohort of OCCP, in treatment with at least one anticholinergic drug and whose cognition status had been evaluated by Pfeiffer test twice for a period of 6-15 months. CI was considered when the Pfeiffer test increased 2 or more points. AB was detected using ten scales included on the Anticholinergic Burden Calculator. An ROC curve analysis was performed to assess the discriminative capacity of the scales to predict a potential CI and the cut-off point of AB that obtains better validity indicators. 415 patients were included (60.2% female, median age of 85 years (IQR = 11)). 190 patients (45.8%) manifested CI. Only the DBI (Drug Burden Index) showed statistically significant differences in the median AB between patients without CI and with CI (0.5 (1.00) vs. 0.67 (0.65), p = 0.006). At the ROC curve analysis, statistically significant values were obtained only with the DBI (AUC: 0.578 (0.523-0.633), p = 0.006). The cut-off point with the greatest validity selected for the DBI was an AB of 0.41 (moderate risk) (sensitivity = 81%, specificity = 36%, PPV = 51%). The DBI is the scale with the greatest discriminatory power to detect OCCP at risk of CI and the best cut-off point is a load value of 0.41.

Identification and characterisation of deprescribing tools for older patients: A scoping review.

BACKGROUND: Deprescription is the revision of the therapeutic plan with the aim of simplifying it, taking into account patient preferences, prognosis and environment. This strategy is particularly relevant in older patients, mostly polymedicated individuals, since they are exposed to numerous adverse effects and interactions and tend to have less adherence to treatments. OBJECTIVE: To identify the deprescribing tools for older patients available in the scientific literature, classify them according to their design and describe their main features and potential applicability in clinical practice. METHODS: A search was conducted in PubMed and EMBASE for relevant literature published before July 2021. The PRISMA-ScR method was applied, extracting variables related to study and tool characteristics as well as potential clinical applicability. The main inclusion criteria were studies focused on designing or developing deprescribing tools for older patients and those that indicated the features of the deprescribing tool used in detail. RESULTS: Fourteen of 723 papers met the inclusion criteria, and 12 tools were identified: 6 "algorithm-based tools" and 6 "criterion-based tools". Though all tools are aimed at older patients, there are certain peculiarities regarding their design, population, application setting and variables included. Of the 6 criterion-based tools found, 4 used the Delphi method for their design and development. Furthermore, most of them agree on the pharmacological groups that are likely to be deprescribed. CONCLUSIONS: Taking into account the importance of the clinical situation and priorities in the care plan in the deprescribing process, the authors believe that tools which help to evaluate these aspects are the most suitable for application in clinical practice. However, it is necessary to continue studying applicability in real-life clinical scenarios and to obtain health results.

Chronic-pharma: New Platform for Chronic Patients Pharmacotherapy Optimization.

We describe the technological development of a web platform named CHRONIC-PHARMA that integrates three prescription support tools for patients with chronic diseases: Anticholinergic Burden Calculator (ABC), LESS-CHRON criteria and TRIGGER-CHRON. They focus on the optimization and evaluation of pharmacotherapy in patients with chronic diseases, resulting in a useful, single platform that can facilitate the review of pharmacotherapy and improve the safety of chronically ill patients. This is achieved by estimating and reducing the anticholinergic risk (ABC), detecting opportunities for deprescribing drugs and monitoring its success (LESS-CHRON criteria), as well as calculating the risk of adverse drug events (TRIGGER-CHRON). The platform is freely accessible online ( https://chronic-pharma.com/ ) as well as through a mobile application, and therefore easily accessible among the healthcare community.

Concordance Among 10 Different Anticholinergic Burden Scales in At-Risk Older Populations.

OBJECTIVE: The aim of the study was to evaluate the concordance among 10 anticholinergic scales for the measurement of anticholinergic drug exposure in at-risk elderly complex chronic patients in primary care. METHODS: An 8-month cross-sectional, multicenter study was carried out in a cohort of complex chronic patients older than 65 years in treatment with at least 1 drug with anticholinergic activity. Demographic, pharmacological, and clinical data were collected. Anticholinergic burden and risk were detected using the 10 scales included on the anticholinergic burden calculator (http://www.anticholinergicscales.es/). We used κ statistics to evaluated the concordance 2 to 2 (according to risk: high, medium, low or without risk) among the included scales. RESULTS: Four hundred seventy-three patients were recruited (60.3% female, median age of 84 years [interquartile range = 10]). Eighty was the total number of anticholinergic drugs with any scale (1197 prescriptions), with a median of 2 drugs with anticholinergic activity per patient (interquartile range = 2). The κ statistics comparing all the 10 scales ranged from -0.175 (Drug Burden Index versus Chew Scale) to 0.708 (Anticholinergic Activity Scale [AAS] versus Chew Scale). The best concordance was obtained between AAS and Chew Scale (κ = 0.708), followed by Clinician-Rated Anticholinergic Scale and Duran Scale (κ = 0.632) and AAS and Anticholinergic Cognitive Burden Scale (κ = 0.618), being considered substantial strengths of concordance. CONCLUSIONS: The agreement among the 10 scales in elderly patients with complex chronic conditions was highly variable. Great care should be taken when assessing anticholinergic drug exposure using existing scales because of the wide variability among them. The only scales that showed agreement were the AAS-Chew, Clinician-Rated Anticholinergic Scale-Duran, and AAS-Anticholinergic Cognitive Burden Scale pairs. In the rest of the cases, the scales are not interchangeable.

Anticholinergic Exposure in Elderly Complex Chronic Patients: A Cross-Sectional Study.

BACKGROUND: Elderly patients with multiple chronic conditions are closely linked to polymedication, a condition that is also highly associated with the presence of adverse effects, such as those observed by anticholinergic activity. Anticholinergic burden is defined in a very variable way and is described inconsistently using different scores and providing different interpretations of the risk of suffering from anticholinergic adverse effects. OBJECTIVE: The objective is to analyse the anticholinergic risk exposure in elderly complex chronic patients. METHODS: A observational multicentre study was performed for a cohort of complex chronic patients over 65 years who received treatment with at least one drug with anticholinergic activity. Anticholinergic exposure was assessed using ten scales included in the Anticholinergic Burden Calculator. RESULTS: 473 patients were recruited, being 67.7% with excessive polypharmacy. 80 was the total number of anticholinergic drugs with any scale, with a median of 2 drugs with anticholinergic activity per patient (IQR=2). Three scales evaluated more than 70% of the patients (Chew: 79.1%; Drug Burden Index (DBI): 77.8%; Anticholinergic Cognitive Burden (ACB): 75.9%). The percentage of different drugs with anticholinergic properties evaluated ranged from 13.8% (Anticholinergic Burden Classification (ABC)) to 57.5% (DBI) and anticholinergic drugs prescriptions oscillated from 14% (Anticholinergic Risk Scale (ARS)) to 53.3% (DBI). 71.1% of patients were at risk (moderate and high risk) according to DBI vs. 9.7% by ARS at the opposite side. Important differences of anticholinergic risk in patients with excessive polypharmacy were in ACB, ABC and DBI scales. CONCLUSION: This study has highlighted clear differences between the scales used. DBI seems to be the scale that identifies a higher number of elderly chronic complex patients at risk of developing anticholinergic adverse effects.

Association between Anticholinergic Burden and Constipation: A Systematic Review.

The association between anticholinergic burden and constipation is not well defined and documented; for this reason, a systematic review was carried out in five databases (Medline, Embase, Cochrane Central Register of Controlled Trials, CINAHL, and Scopus), including studies assessing the correlation between anticholinergic burden, and constipation between January 2006 and December 2020. Data extraction was conducted independently by two researchers. Abstracts and titles were reviewed to determine eligibility for review with eligible articles read in full. From 2507 identified articles, 11 were selected for this review: six cross-sectional studies, four retrospective cohort studies, and a post hoc analysis of a randomized clinical trial. Overall, nine studies reported at least one statistical association between anticholinergic burden and constipation, finding 13 positive results out of 24 association measurements. A total of 211,921 patients were studied. The association between constipation and anticholinergic burden could be demonstrated in studies including 207,795 patients. Most studies were not designed to find differences in constipation prevalence and did not adjust the results by confounding factors. Our findings suggest that a correlation between anticholinergic burden and constipation exists. Higher quality-evidence studies are needed, including analysis that considers confounding factors, such as other non-pharmacological causes of constipation.

Intervention effectiveness by pharmacists integrated within an interdisciplinary health team on chronic complex patients.

BACKGROUND: Nowadays, it is difficult to establish a specific method of intervention by the pharmacist and its clinical repercussions. Our aim was to identify interventions by pharmacists integrated within an interdisciplinary team for chronic complex patients (CCPs) and determine which of them produce the best results. METHODS: A systematic review (SR) was performed based on PICO(d) question (2008-18): (Population): CCPs; (Intervention): carried out by health system pharmacists in collaboration with an interdisciplinary team; (Comparator): any; (Outcome): clinical and health resources usage outcomes; (Design): meta-analysis, SR and randomized clinical trials. RESULTS: Nine articles were included: one SR and eight randomized clinical trials. The interventions consisted mainly in putting in order the pharmacotherapy and the review of the medication adequacy, medication reconciliation in transition of care and educational intervention for health professionals. Only one showed significant improvements in mortality (27.9% vs. 38.5%; HR = 1.49; P = 0.026), two in health-related quality of life [according to EQ-5D (European Quality of Life-5 Dimensions) and EQ-VAS (European Quality of Life-Visual Analog Scale) tests] and four in other health-related results (subjective self-assessment scales, falls or episodes of delirium and negative health outcomes associated with medication). Significant differences between groups were found in hospital stay and frequency of visits to the emergency department. No better results were observed in hospitalization rate. Otherwise, one study measured cost utility and found a cost of €45 987 per quality-adjusted life year gained due to the intervention. CONCLUSIONS: It was not possible to determine with certainty which interventions produce the best results in CCPs. The clinical heterogeneity of the studies and the short follow-up of most studies probably contributed to this uncertainty.

Therapeutic drug monitoring of infliximab in spondyloarthritis. A review of the literature.

Available evidence indicates that a therapeutic drug monitoring strategy leads to major cost savings related to the anti-tumour necrosis factor-α therapy in both inflammatory bowel disease and rheumatoid arthritis (RA) patients, with no negative impact on efficacy. However, although the systematic use of therapeutic drug monitoring could potentially be beneficial and economically acceptable to drug dose optimization, it is not justifiable for all drugs. Infliximab (IFX) is a chimeric monoclonal immunoglobulin G1 targeting tumour necrosis factor. It has been approved for the treatment of immuno-inflammatory diseases, including RA, ankylosing spondylitis, psoriatic arthritis, Crohn's disease and ulcerative colitis. IFX's pharmacokinetics is highly variable and influences clinical response in chronic inflammatory diseases. Clinical response increases with IFX trough concentrations in RA, ankylosing spondylitis, inflammatory bowel disease and psoriatic patients. Target concentrations predictive of good clinical response were proposed in RA, Crohn's disease and ulcerative colitis. The purpose of this article is to review the current literature surrounding IFX serum concentrations and their related parameters with disease activity in patients with spondyloarthritis. Gathering information about the efficacy of IFX in patients with spondyloarthritis and relating IFX serum concentrations to disease activity were the main goals of this study.

Adherence and preference of intravenous zoledronic acid for osteoporosis versus other bisphosphonates.

OBJECTIVE: To evaluate adherence as well as patient preference and satisfaction of once-yearly intravenous zoledronic acid versus other bisphosphonates treatments. METHODS: In accordance with the PRISMA guidelines, a systematic literature search was conducted in PubMed, Cochrane Library and EMBASE databases, over the date range of 2000-2016. Following the PICO (Population, Interventions, Comparator, Outcomes) elements, eligibility criteria included: (1) participants: adults over 18 with osteoporosis and adults who were at high risk of developing low bone density as a result of chronic use of glucocorticoids; (2) intervention: adherence or patient preference/satisfaction of once-yearly zoledronic acid treatment; (3) comparator: other bisphosphonates; (4) outcome: data about adherence, persistence, compliance, preference and satisfaction criteria. Specific exclusion criteria were also applied. RESULTS: Adherence to zoledronate is only quantified in one study showing that mean proportion of days covered for zoledronic acid was greater than for ibandronate users. Three studies showed 100% of compliance to zoledronate treatment and only one study showed zoledronic acid provided the highest persistence rates. Once-yearly intravenous infusion of zoledronic acid was clearly preferred. Only one article indicated preference for schedules that were once monthly or less frequent and other preference results practically equal between once-yearly intravenous infusion or weekly oral. Although there is little evidence, adherence to osteoporosis treatment is improved with annual intravenous zoledronate regimen. Moreover, patients appear to have preference for less frequent dosing. Switching from oral to intravenous therapy, based on the opportunities offered by an integrated health management area, may allow obtaining better outcomes in adherence to osteoporosis treatment.

[Effectiveness of an intervention strategy in the biosimilar glargine prescription pattern in primary care]. / Efectividad de una estrategia de intervención en el patrón de prescripción del biosimilar glargina en atención primaria.

OBJECTIVES: To examine the effects of specific interventions on biosimilar glargine insulin (BGI) prescribing in general practices and to analyse the influence of prescriber and economic impact. DESIGN: Non randomized controlled study. SETTING: General practices in 2 health areas of Seville, intervention and control group. PARTICIPANTS: 220 general practices (intervention group) and 100 general practices (control group). INTERVENTION: Intervention group received educational seminars on biosimilar drugs, pharmacotherapeutic bulletin and prescribing feedback. The study was carried out from the biosimilar commercialization, October-2015, to February-2016 (pre-intervention) and from February to August 2016 (intervention). MAIN MEASUREMENTS: Percentage of patients and DDD with BGI respect to total glargine before and during intervention for both areas were analysed. Physicians have been analysed by subgroups of age, sex, training, type of contract, years of experience and quota. MAIN RESULTS: Both indicators for intervention group were significantly greater than for control group (P<.0005), with a 95% confidence interval (2.5-4.7). The ratio of the percentage of cumulative increase of both variables between areas was 3.73 times higher after the intervention. No differences were found for the evaluated categories of physicians in the intervention group. CONCLUSIONS: Intervention strategies aimed at training and information, as well as monitoring health professionals, influence the pattern of prescription and can have an economic impact. Our results have not been influenced by the profile of the prescriber.

Association Between Drug Burden Index and Functional and Cognitive Function in Patients with Multimorbidity.

BACKGROUND: Anticholinergic and sedative drugs are associated with adverse events such as cognitive and functional impairment in elderly. The Drug Burden Index (DBI) is a measure of an individual's total exposure to anticholinergic and sedative drugs. Objetive: The study aimed to evaluate the association between the total DBI and cognitive and functional impairment in patients with multimorbidity. SETTING: Patients with multimorbidity enrolled in the IMPACTO project. METHODS: Cross-sectional observational study. MAIN OUTCOME MEASURE: The anticholinergic and sedative exposure was calculated using DBI. The Pfeiffer Test (PT) was used for cognitive status and the Barthel Index (BI) for functional status. RESULTS: 336 patients were included (mean age 77.6 ± 8.7 years, 54.2% men and a mean of 11.5 ± 3.7 prescribed drugs). 180 patients (53.6%) exposed to anticholinergic and/or sedative drugs were identified. The median score obtained in PT was slightly higher in exposed patients (1 (IQR 0-2) and 2 (IQR 0-4), p = 0.082 in "non-exposed" and "exposed", respectively). The bivariate analysis showed an association [0.544 (95% CI 0.044-1.063, p = 0.03)]. The median obtained in the BI analysis was 85.0 (IQR 30.0) and 75.5 (IQR 42.5) p = 0.002, in "nonexposed" and "exposed", respectively. After the adjusted analysis, a relationship was obtained between both the variables [-9,558 (95% CI-15,794; -3,321, p = 0.03)]. CONCLUSION: Higher DBI is associated with the impairment of functional status and, slightly to the deterioration of cognitive function in patients with multimorbidity. DBI should be considered in patients with multimorbidity to optimize the pharmacological treatment of a group of special interest due to its vulnerability.

The flavonol-enriched Cistus albidus chloroform extract possesses in vivo anti-inflammatory and anti-nociceptive activity.

ETHNOPHARMACOLOGICAL RELEVANCE: Cistus albidus L. (Cistaceae) has been traditionally used to treat various inflammatory diseases, but no systematic studies on the anti-inflammatory and anti-nociceptive actions of C. albidus and its putative mechanism have been reported. We aimed to explore the anti-inflammatory and anti-nociceptive effects of this plant and to characterize its polyphenolic composition by liquid chromatography coupled to mass spectrometry (MS). MATERIALS AND METHODS: A chloroform extract derived from C. albidus leaves was obtained by solid-liquid and liquid-liquid extraction. The tail immersion test and acetic-acid-induced writhing test were used to evaluate the anti-nociceptive action, while the experimental λ-carrageenan-induced paw edema model was used to test the anti-inflammatory action. Changes in cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS) expression, as well as the role of mitogen-activated protein kinases (MAPKs) and the nuclear transcription factor kappa B (NF-kB) signaling pathways on lipopolysaccharide (LPS)-stimulated murine peritoneal macrophages were analyzed by western blotting. HPLC with diode array detection coupled to tandem mass spectrometry detection with electrospray ionization (HPLC-DAD-ESI-MS/MS) was performed to determine the phytochemical profile of the extract. RESULTS: Significant anti-nociceptive activity was observed both in the tail immersion (59.63% reduction at 120min) and in the acetic acid (65.94% inhibition) tests at 100mg/kg. The extract (50mg/kg) exhibited a substantial reduction in paw edema (51.6%) and significantly inhibited nitrite generation (72.62%) without affecting cell viability of LPS-stimulated murine peritoneal macrophages. These results were concomitant with a down-regulation of the pro-inflammatory enzymes COX-2 and iNOS in extract-treated macrophages and a decrease in p38 MAPK phosphorylation. HPLC-DAD-ESI-MS/MS analysis revealed that flavonols such as kaempferol and quercetin derivatives were potentially responsible for such effects. CONCLUSION: These results support the widespread use of C. albidus in popular medicine and indicate that this plant has therapeutic potential with analgesic and anti-inflammatory properties based on the presence of flavonol derivatives.