The role of CYP2C9*2, CYP2C9*3 and VKORC1-1639 variants on the susceptibility of upper gastrointestinal bleeding: A full case-control study.

Purpose: To investigate whether interindividual variability in the CYP2C9 (*2 and *3 alleles) and VKORC1 (rs9923231) genes is associated with increased risk of upper gastrointestinal bleeding (UGIB) in users of non-steroidal anti-inflammatory drugs (NSAIDs) or low-dose aspirin (LDA). Methods: A full case-control study including 200 cases of patients diagnosed with UGIB and 706 controls was conducted in a Brazilian hospital complex. To perform an analysis of NSAIDs dose-effect, the defined daily dose (DDD) for NSAIDs was calculated in the 7-day etiologic window preceding the data index. Three categories of DDD, considering the genotypes of the genetic variants, were established: non-users of NSAIDs (DDD = 0), DDD ≤0.5, and DDD >0.5. Genetic variants and LDA or NSAIDs use synergism was estimated through Synergism Index (SI) and Relative Excess Risk Due To Interaction (RERI). Results: For DDDs of NSAIDs upward of 0.50, a risk of UGIB was identified in carriers of the *3 allele (OR: 15,650, 95% CI: 1.41-174.10) and in carriers of the variant homozygous genotype (TT) of rs9923231 (OR: 38,850, 95% CI: 2.70-556.00). In LDA users, the risk of UGIB was observed to be similar between carriers of the wild type homozygous genotype and carriers of the variant alleles for the CYP2C9 and VKORC1 genes. No synergism was identified. Conclusion: Our findings suggest an increased risk of UGIB in carriers of the variant allele of rs9923231 and in carriers of the *3 allele associated with doses of NSAIDs greater than 0.5. Hence, the assessment of these variants might reduce the incidence of NSAIDs-related UGIB and contribute to the safety of the NSAIDs user.

Cost of adverse drug events related to potentially inappropriate medication use: A systematic review.

BACKGROUND: The use of potentially inappropriate medications (PIMs) for older people is associated with worse health outcomes owing to the occurrence of adverse drug events (ADEs) and drug interactions, leading to increased health care costs. OBJECTIVES: Identify the costs of ADEs related to PIMs use, in addition to the costs predictors. METHODS: A systematic review was conducted in the PubMed and Scopus databases (until February, 2022), and the report of this study was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Interventional and observational studies that reported costs of ADEs regardless of perspective (i.e., payer) were considered. Reporting and methodological quality were assessed using the tool proposed by Larg and Moss for evaluating cost-of-illness studies. RESULTS: A total of 20 (21 publications), published between 2001 and 2020, were included (236,888,744 older people). The ADEs costs related to PIMs use were mostly related to the use of health services (hospitalization [n = 7], health care expenses [n = 7], and emergency department visits [n = 3]). Among the 8 studies that reported P value, 7 identified higher costs for PIM users than non-PIM users. Three studies reported cost predictors, being highest number of PIMs in use, age older than 75 years, male gender, general health status in older people in use of benzodiazepines, and drug interactions in older people diagnosed as having dementia. Regarding to assessment of reporting and methodological quality, all studies had at least one limitation (answer "no"). CONCLUSIONS: Our findings suggest that PIMs use is associated with higher costs of hospitalization, health care expenses, and visits to emergency department owing to ADEs, regardless of PIMs in use, health service, perspective, and screening tools used for PIMs identification. However, these findings should be interpreted with caution because all studies had at least one methodological limitation.

Genetic polymorphisms associated with upper gastrointestinal bleeding: a systematic review.

Non-variceal upper gastrointestinal bleeding (non-variceal UGIB) is a frequent and severe adverse drug reaction. Idiosyncratic responses due to genetic susceptibility to non-variceal UGIB has been suggested. A systematic review was conducted to assess the association between genetic polymorphisms and non-variceal UGIB. Twenty-one publications and 7134 participants were included. Thirteen studies evaluated genetic polymorphism in patients exposed to non-steroidal anti-inflammatory drugs, low-dose aspirin, and warfarin. Eight studies present at least one methodological problem. Only six studies clearly defined that the outcome evaluated was non-variceal UGIB. Genetic polymorphisms involved in platelet activation and aggregation, angiogenesis, inflammatory process, and drug metabolism were associated with risk of non-variceal UGIB (NOS3, COX-1; COX-2; PLA2G7; GP1BA; GRS; IL1RN; F13A1; CDKN2B-AS1; DPP6; TBXA2R; TNF-alpha; VKORC1; CYP2C9; and AGT). Further well-designed studies are needed (e.g., clear restriction to non-variceal UGIB; proper selection of participants; and adjustment of confounding factors) to provide strong evidence for pharmacogenetic and personalized medicine.

Application of trigger tools for detecting adverse drug events in older people: A systematic review and meta-analysis.

OBJECTIVE: To identify trigger tools applied to detect adverse drug events (ADEs) in older people and describe their utility and performance. METHODS: A systematic review was conducted in the PubMed, Lilacs, and Scopus databases (January 2024). Studies that developed, applied, or validated trigger tools and evaluated their utility and/or performance for detecting ADEs in older people were considered. Direct proportion meta-analyses using the inverse-variance method were performed for prevalence of ADEs and positive predictive value (PPV). RESULTS: Twenty-four studies (25 publications) were included. Twelve trigger tools were identified, of which six were developed for detecting ADEs in older population, four developed for general population and modified for older people, and two developed for general population. No tools for detecting ADEs in older people receiving palliative care or hospitalized in intensive or surgical care units were found. The performance of triggers was presented through PPV (11.5-71%), negative predictive values (83.3%), and sensitivity (30-94.8%). The overall PPV was 33.3% (95%CI: 32.5-34.2%). Triggers with good performance were changes in plasma levels of digoxin, glucose, and potassium; changes in international normalized ratio; abrupt medication stop; hypotension; and constipation. The prevalence of ADEs ranged from 2.8 to 66%, with overall prevalence of ADEs of 20% (95%CI: 19.3-20.8%). Preventability ranged from 8.4 to 94.4%. Metabolic or electrolyte disturbances induced by diuretics, constipation induced by opioids, and falls and delirium induced by benzodiazepines were the most prevalent ADEs. CONCLUSION: The trigger tools are flexible and easy to apply, and they can contribute to the detection of ADEs, their associated risk factors, the level of harm, and preventability in different health settings. However, there is no consensus on good or poor values of PPV, which indicate the performance of triggers. Furthermore, there is limited evidence regarding the evaluation of performance through negative predictive value, sensitivity, and specificity. PROSPERO: CRD42022379893.

Use of Antidepressants and the Risk of Upper Gastrointestinal Tract Bleeding: A Case-control Study.

PURPOSE: To investigate the association between the use of antidepressants and the risk of upper gastrointestinal tract bleeding (UGIB). METHODS: A Case-control study was conducted in a Brazilian hospital complex. Cases were defined as patients with a diagnosis of UGIB and controls as patients admitted for reasons unrelated to gastrointestinal bleeding, gastric concerns, or complications associated with low-dose aspirin (LDA) or nonsteroidal anti-inflammatory drugs (NSAIDs) use. Sociodemographic and clinical data, comorbidities, drug therapy in use (long-term use and self-medication), and lifestyle habits were recorded through face-to-face interviews. Two groups were defined: use of antidepressants in general and use of antidepressants according to their affinity for serotonin transporters. The presence of synergism between the concomitant use of antidepressants and LDA or NSAIDs on the risk of UGIB was also explored. FINDINGS: A total of 906 participants were recruited (200 in the case group and 706 in the control group). The use of antidepressants was not associated with the risk of UGIB (odds ratio [OR] = 1.503; 95% CI, 0.78-2.88) or the use of antidepressants with high affinity for serotonin receptors (OR = 1.983; 95% CI, 0.81-4.85). An increased risk of UGIB was observed in concomitant users of antidepressants and LDA (OR = 5.489; 95% CI, 1.60-18.81) or NSAIDs (OR = 18.286; 95% CI, 3.18-105.29). Despite the lack of significance, the use of antidepressants appears to be a positive modifier of UGIB risk in LDA and NSAID users. IMPLICATIONS: These findings indicate an increased risk of UGIB in concomitant users of antidepressants and LDA or NSAIDs, suggesting the need to monitor antidepressant users, especially those most likely to develop UGIB. In addition, further studies with larger sample sizes are needed to confirm these findings.

A comprehensive look at explicit screening tools for potentially inappropriate medication: A systematic scoping review.

OBJECTIVE: To map explicit screening tools to identify potentially inappropriate medication (PIMs), and the characteristics and limitations of these tools. Including PIMs-interactions, therapeutic alternatives and the clinical management of PIMs. METHODS: A systematic scoping review was conducted in PubMed and Scopus (until May 2021). The number of PIMs listed as essential drugs was identified in Model List of Essential Medicines by the World Health Organization (WHO) and National List of Essential Medicines (Brazil). In addition to reporting the therapeutic alternatives and clinical management proposed by explicit screening tools to identify PIMs, we suggested our own alternatives for the PIMs most frequently reported. RESULTS: Fifty-eight tools reported 614 PIMs and 747 PIMs-interactions. Limited overlap between the tools was observed: 123 (69.1%) of 178 therapeutic alternatives proposed by the tools were considered inappropriate by other tools, and 222 (36.1%) of the 614 PIMs identified were named as being inappropriate only once. Only 21 tools were developed by a Delphi panel technique associated with systematic review. The PIMs listed as essential medication in Brazil and by the WHO were 30.6% and 23.3% of the total reported, respectively. For the most-cited PIMs, such as non-steroidal anti-inflammatory drugs, tricyclic antidepressants and benzodiazepines, we suggested the use of non-opioid and opioid analgesics; agomelatine, bupropion or moclobemide; and melatonin, respectively. CONCLUSIONS: The next stages in the development of explicit screening tools to identify PIMs include achieving more consensus between them and improving their applicability across countries. Further, it is recommended that tools include PIMs risks and advice on therapeutic alternatives.

VNTR Polymorphism in Intron 4 of the eNOS Gene and the Risk of Gastrointestinal Bleeding: A Case-control Study.

BACKGROUND AND AIMS: Considering the lack of knowledge regarding the influence of the variable number of repeats of 27 pb in intron 4 (4b/4a VNTR - rs61722009) of the endothelial nitric oxide synthase (eNOS) on the drug response, we assessed the influence of this polymorphism for the risk of upper gastrointestinal bleeding (UGIB). METHODS: A case-control study, including 200 cases and 706 controls, was conducted in a Brazilian hospital complex. Cases were participants with UGIB diagnosis. Controls were participants admitted to surgical procedures not related to gastrointestinal problems. The 4b/4a VNTR was determined through polymerase chain reaction followed by fragment analysis. Conditional logistic regression models were designed. The additive interaction between the presence of the 4b/4a VNTR variant and the use of low-dose aspirin (LDA) and nonsteroidal anti-inflammatory drugs (NSAIDs) was calculated by fitting the Cox regression model through the parameters of Synergism index (S) and Relative Excess Risk Due To Interaction (RERI). RESULTS: The presence of the 4b/4a VNTR variant did not increase the risk of UGIB: carriers of the 4a/4a genotype (OR=0.37, 95%CI: 0.09-1.45) and of the variant allele "4a" (OR=0.91, 95%CI: 0.55-1.51). The risk of UGIB in LDA users carriers of the wild genotype (OR=4.96, 95%CI: 2.04- 2.06) and the variant allele "4a" (OR=3.49, 95%CI: 1.18-10.38) is similar, as well as for NSAID users carriers of the wild genotype (OR=5.73, 95%CI: 2.61-12.60) and variant allele "4a" (OR=5.51, 95%CI: 1.42-15.82). No additive interaction was identified between the presence of the genetic variant and the use of LDA [RERI: -1.44 (95%CI: -6.02-3.14; S: 0.63 (95%CI: -1.97-1.15)] and NSAIDs [RERI: -0.13 (95%CI: -6.79-6.53; S: 0.97 (95%CI: -0.23-4.19)] on the UGIB risk. CONCLUSION: Our data suggests that there is no increase in the magnitude of UGIB risk in LDA and NSAIDs users' carrying the variant allele "4a".

Deficiency and Insufficiency of Vitamin D in Women of Childbearing Age: A Systematic Review and Meta-analysis.

OBJECTIVE: To estimate the prevalence of inadequate vitamin D level and its associated factors for women of childbearing age in Brazil. METHODS: A systematic review was conducted (last updated May 2020). Meta-analyses were performed using the inverse-variance for fixed models with summary proportion calculation by Freeman-Tukey double arcsine. Reporting and methodological quality were assessed using the Joanna Briggs Institute tool for prevalence studies. RESULTS: Our review identified 31 studies, comprising 4,006 participants. All the studies had at least one weakness, mainly due to the use of convenience sampling and small sample size. The overall prevalence of vitamin D deficiency, insufficiency, and both deficiency and insufficiency were 35% (confidence interval, 95%CI: 34-37%), 42% (95%CI: 41-44%), and 72% (95%CI: 71-74%), respectively. CONCLUSION: Although the magnitude of the prevalence of inadequate levels of vitamin D is uncertain, the evidence suggests that presence of vitamin D deficiency or insufficiency in women of reproductive age can cause moderate to severe problems.

OBJETIVO: Estimar a prevalência de níveis inadequados de vitamina D e seus fatores associados para mulheres em idade fértil no Brasil. MéTODOS: Uma revisão sistemática foi realizada (última atualização em maio de 2020). As meta-análises foram realizadas usando o inverso da variância para o modelo fixo com cálculo de proporção sumarizada por transformação arco-seno duplo de Freeman-Tukey. A qualidade metodológica e de reporte foi avaliada usando a ferramenta do Joanna Briggs Institute para estudos de prevalência. RESULTADOS: Nossa revisão identificou 31 estudos, compreendendo 4.006 participantes. Todos os estudos apresentaram pelo menos uma limitação, principalmente devido ao uso de amostra de conveniência e tamanho amostral pequeno. As prevalências gerais de deficiência, insuficiência e deficiência de vitamina D foram 35% (intervalo de confiança, IC 95%: 34­37%), 42% (IC 95%: 41­44%) e 72% (IC 95%: 71­74%), respectivamente. CONCLUSãO: Embora a magnitude da prevalência de níveis inadequados de vitamina D seja incerta, a evidência sugere que presença de deficiência ou insuficiência de vitamina D em mulheres em idade reprodutiva pode causar problemas moderados a graves.

Drug interactions for elderly people with mental and behavioral disorders: a systematic scoping review.

OBJECTIVES: To identify drug interactions of potentially inappropriate medications and mental and behavioral disorders, according to explicit potentially inappropriate medications criteria-based tools. METHODOLOGY: A systematic scoping review was conducted in February 2020. Study characteristics, potentially inappropriate medications, drug interactions, rationale, and therapeutic management proposed were extracted. The commercialization and potentially inappropriate medications standard as essential in Brazil and in the world were identified. Therapeutic management was proposed for the most cited potentially inappropriate medications. RESULTS: 36 tools including 151 drug interactions, in addition to 132 potentially inappropriate medications with concerns related to six mental and behavioral disorders were identified. Cognitive impairment and dementia were the most frequently disorders reported and antipsychotics, anticholinergics, and benzodiazepines were the pharmacological classes more involved in the drug interactions. Despite the tools recommended risperidone and quetiapine when the use of antipsychotics were inevitable; levodopa + carbidopa for Parkinson's disease; and short and intermediate half-life benzodiazepines; the quality of the evidence needs to be assessed. In this review, sleep hygiene; deprescription; medication review; and clinical monitoring of adverse drug reactions are strongly recommended. In addition, to consider agomelatine, bupropion, moclobemide and melatonin as potential safer options for benzodiazepines. CONCLUSION: Knowing the clinical conditions or risk morbidities associated with the use of potentially inappropriate medications and management of these medications for safer therapeutic equivalents or non-pharmacotherapeutic alternatives are relevant for patient safety.

Genetic Variants in PTGS1 and NOS3 Genes Increase the Risk of Upper Gastrointestinal Bleeding: A Case-Control Study.

Objective: To assess the association between PTGS1 and NOS3 variant alleles and the risk to develop upper gastrointestinal bleeding (UGIB) secondary to complicated peptic disease. Methods: A case-control study was conducted in a Brazilian complex hospital from July 2016 to March 2020. Case: Patients with UGIB diagnosis. Control: Patients admitted for surgery not related to gastrointestinal disorders. Variables: UGIB (outcome), genetic variants in PTGS1 and NOS3 genes (independent), and sex, age, schooling, ethnicity, previous history of gastrointestinal disorders, Helicobacter pylori serology, comorbidity, drug therapy, and lifestyle (confounding). The single-nucleotide polymorphisms (SNPs) of the PTSG1 gene (rs1330344, rs3842787, rs10306114, and rs5788) and NOS3 gene (rs2070744 and rs1799983) were determined using the real-time polymerase chain reaction. Helicobacter pylori serology was determined through the chemiluminescence technique. Logistic regression models were built and deviations of allelic frequencies from Hardy-Weinberg equilibrium were verified. Results: 200 cases and 706 controls were recruited. Carriers of the AG genotype of rs10306114 (OR: 2.55, CI 95%: 1.13-5.76) and CA + AA genotypes of rs5788 (OR: 2.53, CI 95%: 1.14-5.59) were associated with an increased risk for the UGIB development. In nonsteroidal anti-inflammatory drugs (NSAIDs) users, the six variants evaluated modified the magnitude of the risk of UGIB, whereas in low-dose aspirin (LDA) users, an increased risk of UGIB was observed for four of them (rs1330344, rs10306114, rs2070744, and rs1799983). Personal ulcer history (p-value: < 0.001); Helicobacter pylori infection (p-value: < 0.011); NSAIDs, LDA, and oral anticoagulant use (p-value: < 0.001); and alcohol intake (p-value: < 0.001) were also identified as independent risk factors for UGIB. Conclusion: This study presents two unprecedented analyses within the scope of the UGIB (rs10306114 and rs2070744), and our findings showing an increased risk of UGIB in the presence of the genetic variants rs10306114 and rs5788, regardless of the drug exposure. Besides, the presence of the evaluated variants might modify the magnitude of the risk of UGIB in LDA/NSAIDs users. Therefore, our data suggest the need for a personalized therapy and drug use monitoring in order to promote patient safety.

EPIDEMIOLOGICAL PROFILE OF PATIENTS WITH NON-VARICEAL UPPER GASTROINTESTINAL BLEEDING SECONDARY TO PEPTIC DISEASE IN A TERTIARY REFERRAL BRAZILIAN HOSPITAL.

BACKGROUND: Non-variceal upper gastrointestinal bleeding (NVUGIB) secondary to peptic ulcer disease is a medical digestive emergency and could be one of the most serious adverse drug reactions. OBJECTIVE: To identify the frequency of diagnosis of NVUGIB secondary to peptic ulcer disease. METHODS: Prospective and epidemiological study conducted in a tertiary referral Brazilian hospital, from July 2016 to December 2019. Upper gastrointestinal endoscopies (UGE) reports were evaluated daily. The diagnosis of NVUGIB secondary to peptic ulcer disease was defined through endoscopic findings of peptic ulcer and erosive gastric lesions, and clinical symptoms. The frequency of diagnosis of NVUGIB secondary to peptic ulcer disease was estimated through the ratio between the number of patients diagnosed and the number of patients underwent UGE in the same period. RESULTS: A total of 2,779 endoscopic reports (2,503 patients) were evaluated, and 178 patients were eligible. The total frequency of diagnosis of NVUGIB secondary to peptic ulcer disease was 7.1%. The annual frequency of diagnosis between 2017 and 2019 ranged from 9.3% to 5.7%. Most patients were men (72.8%); self-declared white (71.8%); older people (56.7%); and, had no familiar or personal history of gastrointestinal diseases (60.1%). 90% of the patients had a peptic ulcer and melena (62.8%). Patients made chronic use of low-dose aspirin (29.3%), other antiplatelet agents (21.9%) and, oral anticoagulants (11.2%); and non-steroidal anti-inflammatories use in the week a prior to the onset of clinical symptoms (25.8%). CONCLUSION: Seven in every 100 patients admitted and underwent UGE in a tertiary hospital were diagnosed with NVUGIB secondary to peptic ulcer disease.

Deficiency of vitamins C and E in women of childbearing age in Brazil: a systematic review and meta-analysis.

BACKGROUND: Despite the several options available for supplements containing vitamins C and E, evidence regarding the prevalence of deficiency or insufficiency of these vitamins is weak. OBJECTIVES: To estimate the prevalence of deficiency or insufficiency of vitamins C and E and associated factors among women of childbearing age, in Brazil. DESIGN AND SETTING: Systematic review and meta-analysis conducted at a Brazilian public university. METHODS: A search from index inception until May 2020 was conducted. Meta-analyses were performed using inverse variance for fixed models, with summary proportions calculation using Freeman-Tukey double arcsine (base case). Reporting and methodological quality were assessed using the Joanna Briggs Institute tool for prevalence studies. RESULTS: Our review identified 12 studies, comprising 1,316 participants, especially breastfeeding women. There was at least one quality weakness in all studies, mainly regarding sampling method (i.e. convenience sampling) and small sample size. The prevalence of vitamin C deficiency ranged from 0% to 40%. Only vitamin E deficiency was synthetized in meta-analyses, with mean prevalences of 6% regardless of the alpha-tocopherol cutoff in plasma, and 5% and 16% for cutoffs of < 1.6-12.0 mmol/l and < 16.2 mmol/l, respectively. The cumulative meta-analysis suggested that a trend to lower prevalence of vitamin E deficiency occurred in recent studies. CONCLUSIONS: Although the studies identified in this systematic review had poor methodological and reporting quality, mild-moderate vitamin C and E deficiencies were identified, especially in breastfeeding women. Thus, designing and implementing policies does not seem to be a priority, because the need has not been properly dimensioned among women of childbearing age in Brazil. REGISTRATION NUMBER IN PROSPERO: CRD42020221605.

Monitoring compliance with Clinical Protocol and Therapeutic Guidelines for Alzheimer's disease.

Dementia is a chronic neurodegenerative disease and Alzheimer's disease (AD) is the most prevalent type. OBJECTIVE: To describe the drug monitoring of patients enrolled in a Clinical Protocol and Therapeutic Guidelines of Alzheimer's Disease (PCDTDA) in Brazil. METHODS: A descriptive study based on interviews conducted in 2017 was performed. Patients diagnosed with Alzheimer's disease (AD) enrolled on the PCDTDA were included. The variables assessed were age, sex, time since diagnosis, clinical parameters of Mini-Mental State Exam (MMSE) and Clinical Dementia Rating (CDR), drug therapy used and AD drug collection. RESULTS: The drug monitoring of 143 patients was evaluated. Observing the requirements of the screening tests for patient enrolment on the PCDTDA, all patients had scores for at least one MMSE and CDR assessment at protocol admission. None of the patients underwent the first reassessment of the effectiveness of AD drug therapy or the semiannual reassessment. CONCLUSION: Although PCDTDA provides the best evidence of AD treatment, the data showed failures in the monitoring of the effectiveness of AD drug therapy at dispensing.

A demência é uma doença crônica e neurodegenerativa, e a doença de Alzheimer (DA) é a mais prevalente. OBJETIVO: Descrever o monitoramento da farmacoterapia de pacientes inseridos no Protocolo Clínico e Diretrizes Terapêuticas da Doença de Alzheimer (PCDTDA), Brasil. MÉTODOS: Estudo descritivo, conduzido por meio de entrevistas em 2017. Foram incluídos pacientes com diagnóstico da doença de Alzheimer (DA) inseridos no PCDTDA. As variáveis foram idade; sexo; tempo de diagnóstico e farmacoterapia da DA; os parâmetros clínicos Mini-exame do estado mental (MEEM) e Clinical Dementia Rating (CDR); e farmacoterapia em uso. RESULTADOS: O monitoramento de 143 pacientes foi avaliado. Considerando a exigência dos testes de rastreio para a inserção do paciente no PCDTDA, observou-se que todos os pacientes tinham pelo menos um escore no MEEM e no CDR na admissão no protocolo. Nenhum paciente foi submetido à primeira reavaliação da efetividade da farmacoterapia da DA e nem à reavaliação semestral. CONCLUSÃO: Apesar do PCDTDA ser a maior evidência do tratamento da DA, dados evidenciam falhas no monitoramento da efetividade da farmacoterapia da DA na dispensação.

Clinical pharmacy services in Brazil, particularly cardiometabolic diseases: a systematic scoping review and meta-analyses.

OBJECTIVE: To map the clinical pharmacy services conducted in Brazil, their characteristics, outcomes, and process measures in general population, as well as the assessment of the clinical impact on people with cardiometabolic diseases (cardiovascular diseases and metabolic diseases). METHODS: A systematic scoping review and meta-analysis were conducted. The electronic searches were re-run in March 2020. To the clinical impact assessment, meta-analyses of cardiometabolic outcomes (i.e., change of systolic (SBP) and diastolic blood pressure (DBP), triglycerides, total cholesterol, glycated hemoglobin (HbA1c), fasting glycemia, LDL-, and HDL-cholesterol) were led. The risk of bias was assessed with the Cochrane Collaboration tools. RESULTS: 71 studies were identified (7,402 patients), being the majority quasi-experimental studies (n=41) and published by research groups of Southeast Brazil (n=33). Medication therapy management (n=62) was the most frequent clinical pharmacy service, performed on outpatient setting (n=45), with adults or elderly people (n=58) with hypertension (n=18) or diabetes (n=10). Process measures (n=58) (e.g. resolution of drug related-problem) were widely used as indicator, followed by clinical (n=44) (e.g. change in SBP), humanistic (n=12) (e.g. change in quality-of-life score assessed by Short-Form 36 Health Survey Questionnaire), and economic outcomes (n=3) (incremental cost-effectiveness ratio for reduction in HbA1c). Regarding the assessment of clinical impact of the services, 20 studies were included in meta-analyses, showing improvement in most cardiometabolic outcomes when considered individual studies. However, the evidence presents high risk of bias, high heterogeneity (median 67-90%) and imprecision, contributing to wide prediction intervals and low reliability. CONCLUSIONS: A predominance of studies on cardiometabolic diseases, process measures, and clinical outcomes were identified. Considering the assessment of the clinical impact of clinical pharmacy services in cardiometabolic diseases, an improvement in most cardiometabolic outcomes was showed, however, with low confidence and wide prediction interval. Therefore, development of larger studies with low risk of bias and major homogeneity is necessary for a better comprehension of clinical pharmacy service characteristics, benefits, and the population groups most benefited.

Risk factors associated with drug therapy among elderly people with Alzheimer's disease: a cross-sectional study.

BACKGROUND: Improving knowledge and establishing strategies and policies for better patient safety are worldwide priorities. OBJECTIVE: To evaluate drug safety among elderly people with Alzheimer's disease (AD). DESIGN AND SETTING: Cross-sectional study among elderly people within the National AD Assistance Protocol (PCDTDA/MS) who were living in the municipality of Araraquara, Brazil, in 2017. METHODS: Through interviews conducted with relatives/caregivers of elderly people with diagnoses of AD, the following variables were evaluated: comorbidities, drug therapy used, use of potentially inappropriate medications for the elderly (PIMs), presence of potentially inappropriate interactions (PIIs) and medication regimen complexity index. Factors associated with AD severity were also evaluated. Multivariate and simple logistic regressions were applied. RESULTS: 143 elderly people enrolled in PCDTDA/MS were analyzed. The majority were women (67.1%); assisted only through the public healthcare system (75.5%); polymedicated (57.4%); using at least one PIM (63.6%); presenting at least one PII (63.6%); and under drug therapy of low to medium complexity (92.2%). No semi-annual monitoring of the effectiveness of PCDTDA/MS drugs was identified. The proportion using AD drug therapy at daily doses differing from those recommended by the World Health Organization was 75.6%. However, these doses were not associated with drug risk. CONCLUSION: The data from this study raise the hypothesis that use of polypharmacy might show a correlation with severity of AD. The drug safety risk may be associated with comorbidities of the metabolic syndrome, anxiety and off-label use of PIMs, such as risperidone and quetiapine, and benzodiazepines (i.e. clonazepam and flunitrazepam).

Harmonization of Pharmacovigilance Regulation in Brazil: Opportunities to Improve Risk Communication.

Brazilian pharmacovigilance regulations involve 3 spheres: health services, Marketing Authorization Holders (MAHs), and sanitary agency. Drug tolerability began to be effectively assessed in Brazil after the founding of the National Agency of Sanitary Surveillance, which developed the Sentinel Network Project. The objective of the Sentinel Network Project is to increase the adverse drug reaction (ADR) reporting rate by health care professionals in the hospital setting. Pharmacovigilance practices became mandatory for MAHs, and patient tolerability issues were considered in drug policy in Brazil only as recently as 2000. However, despite recent events, the regulatory advancements in pharmacovigilance in Brazil are only equivalent to international practices (ie, those of the European Union). The pharmacovigilance system in the European Union integrates the national authorities, the European Commission, and the European Medicines Agency, which is responsible for the scientific evaluation, supervision, and safety monitoring of medicines for human and veterinary use in the European Union. Furthermore, ADR patient reporting is included in the new EU pharmacovigilance regulations. Numerous possible ways are available to improve the Brazilian pharmacovigilance system, mainly through regulations of biosimilar, nanotechnology, and veterinary medicines or by training health care professionals and patients to report nonserious cases and quality deviations. It is necessary to encourage and develop strategies for decentralizing pharmacovigilance actions in the whole country, as is common practice in several EU countries. Motivating and considering ADR reports by patients and improving feedback and audit practices in health care services and MAHs are also necessary measures. With the inclusion of Brazil as a member of the International Conference of Harmonization, significant changes in pharmacovigilance regulation are expected; these updates, which will consider international standards, will improve signal detection and risk communication.

Assessment of the adherence to and costs of the prophylaxis protocol for venous thromboembolism.

OBJECTIVES: Evaluate adherence to the therapeutic prophylaxis protocol for venous thromboembolism (VTE) as well as the costs of this practice. METHODS: A descriptive and cross-sectional study was conducted at a State General Hospital in Brazil through reports of drug dispensions, prescriptions and risk stratification of patients. Adherence to the VTE prophylaxis protocol was monitored. The tests for VTE diagnosis measured the adherence to therapeutic prophylaxis treatment, and the purchase prices of the drugs went into the calculation of drug therapy costs. The level of adherence to prescriptions for VTE prophylaxis in the hospital was classified as "adherence", "non-adherence" and "justified non-adherence" when compared with the protocol. RESULTS: Protocol adherence was observed for 50 (30.9%) patients, and non-adherence was observed for 63 (38.9%) patients, generating an additional cost of $180.40/month. Justified non-adherence in 49 (30.2%) patients generated $514.71/month in savings due to a reduction in the number of daily administrations of unfractionated heparin while still providing an effective method for preventing VTE. Twenty-six patients stratified as having medium to high risk of VTE who did not receive prophylaxis were identified, generating $154.41 in savings. However, these data should be evaluated with caution since the risks and outcomes associated with not preventing VTE outweigh the economy achieved from not prescribing a drug when a patient needs it. The only case of VTE identified during the study period was related to justified non-adherence to the protocol. CONCLUSION: The protocol is based on scientific evidence that describes an effective therapy to prevent VTE. However, the protocol should be updated because the justifications for non-adherence are based on scientific evidence, and this justified non-adherence generates savings and yields effective disease prevention.

Drug administration adjustments for elderly patients with dysphagia: A case report.

An elderly patient, aged 76 years, diagnosed with dysphagia, depression, hypothyroidism, Alzheimer's disease and mild cognitive deficit, was identified with sertraline and levothyroxine- drug-related problems. Medication Therapy Management (MTM) was used to adjust therapy to the patient's needs by macerating sertraline tablets and solubilizing them in 10-30 mL of orange juice. The patient was advised to take levothyroxine after fasting. Six months later, pharmaceutical follow-up identified an increase in the Mini-Mental State Exam score from 22 to 26 and a decrease in the Clinical Dementia Rating (CDR) scale score from 1.0 to 0.5 in conjunction with mood and physical improvements, as well as a significant decrease in aggressiveness and agitation. Cognitive deficit may be a result of poor drug administration procedures, leading to drug ineffectiveness. Optimizing levothyroxine and sertraline administration, based on knowledge of their physicochemical properties, improves their clinical effectiveness, including the cognition of patients with Alzheimer's disease and dysphagia.

Paciente idosa, 76 anos, diagnosticada com disfagia, depressão, hipotireoidismo, doença de Alzheimer e déficit cognitivo leve, foram identificados problemas relacionados com a sertralina e levotiroxina. O Gerenciamento da Terapia Medicamentosa foi usado para ajustar a terapia às necessidades da paciente, macerando comprimidos de sertralina e solubilizando-os em 10-30 mL de suco de laranja. Foi recomendado a paciente tomar levotiroxina após o jejum. Seis meses depois, o seguimento farmacêutico identificou um aumento no score da escala Mini-Mental de 22 para 26 e Avaliação Clínica da Demência (CDR) de 1,0 para 0,5 em conjunto com melhorias físicas e de humor, bem como uma diminuição significativa na agressividade e agitação. O déficit cognitivo pode ser o resultado de procedimentos de administração inadequada de fármacos, levando à ineficácia do fármaco. A otimização da administração de levotiroxina e sertralina, com conhecimento de suas propriedades físico-químicas, melhora sua efetividade clínica, incluindo a cognição do paciente com a doença de Alzheimer e disfagia.

Safety assessment of omeprazole use: a review.

BACKGROUND: Risks regarding hospital admission due to adverse drug reactions and drug interactions from use of omeprazole have been reported. The question guiding the present review was "Which adverse events occur in patients using omeprazole in a Food and Drug Administration-approved and/or off-label manner?" It was also proposed to evaluate the safety of use of omeprazole. DESIGN AND SETTING: Qualitative narrative review with critical evaluation, in a public university. METHODS: The PubMed, SCOPUS, LILACS, SciELO, EMBASE and EBSCO databases were searched on July 31, 2018. Studies evaluating adverse events were screened. RESULTS: 72 articles were included, among which 58 reported on adverse drug events (47, adverse drug reactions; 5, drug interactions; and 6, situations of ineffectiveness). 28 adverse drug reactions not described in compendia and drug leaflets were described in these studies: myocardial infarction (6); stroke (2); spontaneous abortion (1); proliferative changes (1); chills (1); heart failure (1); thrombosis (2); and dementia (1), among others. Severe adverse reactions, for instance cardiac problems, Steven-Johnson syndrome and proliferative changes, were identified. The antiplatelet effects of drugs such as clopidogrel, in patients who underwent heart-related surgery, increased the risk of developing cardiac problems, such as cardiovascular death, myocardial infarction and stroke. In newly transplanted patients, decreased absorption of mycophenolate mofetil occurred, thus leading to rejection of transplanted organs. CONCLUSION: Use of omeprazole should be monitored primarily in patients with heart disorders using antiplatelet agents concomitantly, and in newly transplanted patients using mycophenolic acid, in order to avoid serious adverse reactions.