Ivermectin-Loaded Mesoporous Silica and Polymeric Nanocapsules: Impact on Drug Loading, In Vitro Solubility Enhancement, and Release Performance.

Ivermectin (IVM), a widely used drug for parasitic infections, faces formulation and application challenges due to its poor water solubility and limited bioavailability. Pondering the impact of IVM's high partition coefficient value (log P) on its drug release performance, it is relevant to explore whether IVM nanoencapsulation in organic or inorganic nanoparticles would afford comparable enhanced aqueous solubility. To date, the use of inorganic nanoparticles remains an unexplored approach for delivering IVM. Therefore, here we loaded IVM in mesoporous silica particles (IVM-MCM), as inorganic nanomaterial, and in well-known poly(ε-caprolactone) nanocapsules (IVM-NC). IVM-MCM had a well-organized hexagonal mesoporous structure, reduced surface area, and high drug loading of 10% w/w. IVM-NC had a nanometric mean size (196 nm), high encapsulation efficiency (100%), physicochemical stability as an aqueous dispersion, and drug loading of 0.1% w/w. Despite differing characteristics, both nanoencapsulated forms enhance IVM's aqueous intrinsic solubility compared to a crystalline IVM: after 72 h, IVM-MCM and IVM-NC achieve 72% and 78% releases through a dialysis bag, whereas crystalline IVM dispersion achieves only 40% drug diffusion. These results show distinct controlled release profiles, where IVM-NC provides a deeper sustained controlled release over the whole experiment compared to the inorganic nanomaterial (IVM-MCM). Discussing differences, including drug loading and release kinetics, is crucial for optimizing IVM's therapeutic performance. The study design, combined with administration route plans and safety considerations for humans and animals, may expedite the rational optimization of IVM nanoformulations for swift clinical translation.

Environmental enrichment affects behavioral and pharmacological response to antidepressants in CF1 mice.

It has been described that environmental enrichment (EE) exerts beneficial effects on cognitive and emotional performances, dendritic branching, synaptic density, neurogenesis and modulation of neurotrophic systems and neurotransmitters in rodents. However, the influence of EE on pharmacological and behavioral responses in animal models of psychiatric disorders has not been fully established. In this context, the aim of this study was to evaluate the influence of exposure to EE on mice behavior in the open field test (OFT) and forced swimming tests (FST), as well as the response to antidepressant drugs (fluoxetine 30 mg/kg and bupropion 30 mg/kg, p.o.). CF1 mice were exposed to an enriched housing condition at different developmental stages: from mating to postnatal day (PND) 55 (lifelong enrichment), from mating to PND21 (perinatal enrichment) and from PND21 to PND55 (post-weaning enrichment). At PND58 the male offspring were evaluated in the OFT and FST. BDNF gene expression in the hippocampus was determined through qPCR. Mice exposed to perinatal enrichment remained longer in the peripheral zone of the OFT and performed fewer grooming than mice housed under standard condition, and these effects were independent of drug treatment. Post-weaning and lifelong enrichment increased grooming behavior. Bupropion reduced grooming in all groups except in perinatal enriched. In turn, fluoxetine decreased grooming only in post-weaning enriched group. None of the enriched housing conditions altered the immobility time in the FST, which indicates that EE had no antidepressant-like effect. However, all enriched housing conditions abolished the anti-immobility effect of bupropion. None of the EE protocols affected BDNF hippocampal expression. The main conclusion is that mice behavior in the OFT is sensitive to alterations in the housing environment and depends on the developmental stage of exposure. Bupropion and fluoxetine yielded divergent responses depending on the housing condition, which suggests that EE modulates monoaminergic neurotransmission pathways.

Flow cytometry immunophenotyping of healthy platelets and hospitalized patients with suspected platelet dysfunction: Challenges for establishing a cutoff value.

INTRODUCTION AND OBJECTIVE: Flow Cytometry (FC) is one of the techniques, which allows the identification and characterization of platelets. The detection of absent or reduced expression of the glycoproteins is the main objective of this technique. Abnormalities of glycoproteins lead to hemorrhagic syndromes. Among the main diseases, the Bernard-Soulier syndrome (BSS) and Glanzmann thrombasthenia (GT) stand out. We aimed to show a FC-based platelet assessment test for diagnostic use, which measures the expression of markers in normal patients, and evaluate these markers in patients with platelet disorders. METHODS: We examined a control group of 41 healthy adults to establish reference values and assess the variability of the relative expression of platelet markers and subsequently compared these findings to those of 30 patients with suspected platelet dysfunctions. We determined the mean fluorescent intensity (MFI) of the expressed parameters by FC using CD41, CD42a, CD42b and CD61 and SSC/FSC platelet-gated cells. RESULTS: We determined our baseline panel of markers and compared them to suspected platelet dysfunctions. Patients with suspected BSS presented increased levels of the MFI for the GPIIIa (CD61) and GPIIb (CD41). They showed significantly reduced levels of the GPIb (CD42b) and GPIX (CD42a). Patients with suspected GT showed normal expression of the GPIX (CD42a), increased expression of the GPIb (CD42b) and reduced levels of the GPIIIa (CD61). In this case, with reduced levels of only one marker, the GPIIb (CD41), values showed normal expression. CONCLUSIONS: We describe the FC assay to support the diagnosis of different platelet disorders. Our study made it possible to implement a technique that brought benefits to care.

Betulinic Acid-Brosimine B Hybrid Compound Has a Synergistic Effect with Imatinib in Chronic Myeloid Leukemia Cell Line, Modulating Apoptosis and Autophagy.

Chronic myeloid leukemia (CML) is a myeloproliferative disease characterized by the formation of the BCR-ABL (breakpoint cluster region-Abelson) oncoprotein. As many patients display therapeutic resistance, the development of new drugs based on semisynthetic products represents a new potential therapeutic approach for treating the disease. In this study, we investigated the cytotoxic activity, possible mechanism of action of a hybrid compound of betulinic acid (BA) and brosimine B in CML cell lines that are sensitive (K-562) and resistant (K-562R) to imatinib, in addition to evaluating lower doses of imatinib in combination with the hybrid compound. The effects of the compound, and its combination with imatinib, on apoptosis, cell cycle, autophagy and oxidative stress were determined. The compound was cytotoxic in K-562 (23.57 ± 2.87 µM) and K-562R (25.80 ± 3.21 µM) cells, and a synergistic effect was observed when it was associated with imatinib. Apoptosis was mediated by the caspase 3 and 9 intrinsic pathway, and cell cycle evaluation showed arrest at G0/G1. In addition, the hybrid compound increased the production of reactive oxygen species and induced autophagy by increasing LC3II and Beclin-1 mRNA levels. Results suggest that this hybrid compound causes the death of both imatinib-sensitive and -resistant cell lines and may hold potential as a new anticancer treatment against CML.

Comparison of Nonsequencing Techniques for Identification of NPM1 Mutations and Associated Blast Morphology in Patients With Acute Myeloid Leukemia.

CONTEXT.­: Nucleophosmin 1 (NPM1) mutations affect 20% to 30% of all acute myeloid leukemia (AML) patients; several methods are employed to analyze NPM1 mutations, each of them with its advantages and limitations. OBJECTIVE.­: To compare 3 nonsequencing protocols capable of detecting the main NPM1 mutations and to evaluate nuclear morphometric analysis (NMA) as an alternative to cuplike blast detection. DESIGN.­: We selected multiparameter flow cytometry (MFC), amplification refractory mutation system-polymerase chain reaction (ARMS-PCR), and a quantitative PCR (qPCR) kit to identify NPM1 mutations in AML patients at diagnosis. We also evaluated the presence of cuplike blasts and assessed nuclear morphometry using NMA. RESULTS.­: MFC appears as a screening method for NPM1 mutations because of its lower specificity. ARMS-PCR demonstrated specificity similar to that of the qPCR kit, although it was more laborious. qPCR testing, conversely, is relatively fast and easy to standardize. Of these methods, qPCR was the only one capable of identifying the type of NPM1 mutation. With regard to morphology, NMA could be used as an alternative for the evaluation of cuplike blasts in AML smears. CONCLUSIONS.­: qPCR appears to be the best option to identify NPM1 mutations, with ARMS-PCR representing a cheaper alternative. MFC may be used as a screening method, in which results falling within and above the gray zone should be confirmed by molecular testing.

Fixed and on-demand regimens of acetaminophen in periodontal surgery: randomized clinical trial

Aim: to evaluate the clinical efficacy of an acetaminophen analgesic by comparing its prescription in fixed versus ondemand schedules after periodontal surgery. The hypothesis of the study was that the fixed regimen would be more effective than the on-demand regimen for postoperative analgesics following periodontal surgery. Methods: An open randomized clinical trial was conducted. The 68 patients who needed total flap surgery to restore supracrestal tissue attachment or surgical treatment of periodontitis were randomized". Visual Analogue Scale was used to assess pain. The fixed group (n = 34) received 500 mg of acetaminophen every 4 hours for 2 days. The on-demand group (n = 34) was instructed to use the acetaminophen "as needed," at intervals of no less than 4 hours between doses. Ibuprofen was the rescue medication for both groups. Pain scores and medication use were recorded 2, 6, 12, 24 and 48 hours after the surgical procedure. The study was registered at the Brazilian Registry of Clinical Trials under RBR-7wv259. Results: The two groups did not differ in relation to the frequency or the intensity of pain in a 48-hour period (n=20 in the fixed group, and n=22 in the on-demand group), or even in the intention-to-treat (n=34 in each group). Individuals who experienced moderate to severe pain used rescue medication more frequently in both groups. No adverse events were reported. Conclusion: Both regimens were effective in controlling postoperative pain after periodontal surgery

Consumption of benzylpenicillin as a syphilis control indicator

Abstract Syphilis is a disease with compulsory and mandatory notification to the Notifiable Diseases Information System (SINAN), with benzathine benzylpenicillin being the treatment of choice. The aim of the study was to compare the consumption of benzylpenicillin benzathine, from the dispensation, between the health regions of a capital in the southern region of the country, according to the georeferencing of notified cases of syphilis. This is a descriptive, cross-sectional, retrospective study of the use of benzylpenicillin benzathine and of reported cases of syphilis. Data on syphilis cases were obtained from notifications made in SINAN, and drug consumption data were obtained from the Municipal Health Department computerized system for Drug Dispensing from January 1st, 2019 to December 31st, 2019. Notifications and drug consumption were georeferenced according to 8 health regions. From the compilation of data, the rates of cases and consumption in relation to the population of each region were calculated. A total of 3188 notifications and a total of 35191 vials of benzathine benzylpenicillin were analyzed. The ratio of vials by SINAN notifications showed that each patient took 11 vials of the drug, which is a higher value if we consider that the complete treatment is 2 to 6 vials per case.

Conciliação medicamentosa na admissão de pacientes transplantados renais em um hospital universitário / Medication reconciliation in the admission of kidney transplant patients to a university hospital

Introdução:O presente estudo considerou conciliações medicamentosas realizadas na admissão hospitalar de pacientes transplantados renais e intervenções farmacêuticas decorrentes desse processo.Métodos:Trata-se de um estudo transversal realizado no período de julho de 2018 a julho de 2019 no Hospital de Clínicas de Porto Alegre. Foram coletadas as características dos pacientes, as conciliações medicamentosas realizadas pelo farmacêutico clínico, as discrepâncias identificadas pelo mesmo (intencionais e não intencionais) e o resultado das intervenções. Os medicamentos foram classificados de acordo com a Anatomic Therapeutic Chemical (ATC).Resultados:Dos 719 pacientes acompanhados pelo farmacêutico clínico, 175 tiveram a conciliação medicamentosa de admissão realizada, desses, 56 apresentaram discrepâncias não intencionais. Encontramos a média de 2,2 medicamentos omissos por prescrição com desvio padrão de 1,3 medicamentos. No total, foram realizadas 122 intervenções farmacêuticas, sendo que em 61,5% houve adesão por parte da equipe médica. A classe terapêutica com maior ocorrência (43,4%) de discrepâncias não intencionais foi a que atuava sobre o aparelho cardiovascular. As variáveis observadas foram sexo, número de medicamentos nas intervenções (ambas com associação significativa com a adesão médica), idade, tempo de internação, número de medicamentos na internação e número de medicamentos de uso prévio (estas últimas sem associação significativa com a adesão médica). Conclusões:A conciliação medicamentosa previne possíveis erros de medicação, uma vez que a identificação das discrepâncias não intencionais na prescrição médica gera sinalizações que são levadas pelo farmacêutico clínico à equipe assistente, a fim garantir o uso seguro e correto dos medicamentos durante a internação hospitalar.

Introduction:This study considered medication reconciliations performed on hospital admission of kidney transplant patients and pharmaceutical interventions resulting from this process.Methods:This is a cross-sectional study carried out from July 2018 to July 2019 at Hospital de Clínicas de Porto Alegre. The characteristics of the patients, the medication reconciliations performed by the clinical pharmacist, the discrepancies identified by the same (intentional and unintentional) and the result of the interventions were collected. The drugs were classified according to the Anatomic Therapeutic Chemical (ATC). Results:Of the 719 patients monitored by the clinical pharmacist, 175 had medication reconciliation on admission performed, of which 56 had unintentional discrepancies. We found an average of 2.2 missing medications per prescription with a standard deviation of 1.3 medications. In total, 122 pharmaceutical interventions were performed, and in 61.5% there was adherence by the medical team. The therapeutic class with the highest occurrence (43.4%) of unintentional discrepancies was that which acted on the cardiovascular system. The variables observed were gender, number of medications in interventions (both with a significant association with medical adherence), age, length of stay, number of medications in hospitalization and number of medications previously used (the latter without a significant association with medical adherence).Conclusions:Medication reconciliation prevents possible medication errors, since the identification of unintentional discrepancies in the medical prescription generates signals that are taken by the clinical pharmacist to the assistant team, in order to guarantee the safe and correct use of medications during hospitalization.

Aprendizado de máquina nos serviços farmacêuticos: uma revisão integrativa / Machine learning in pharmaceutical services: an integrative review

A crescente digitalização e aplicação de inteligência artificial (IA) em problemas complexos do mundo real, tem potencial de melhorar os serviços de saúde, inclusive da atuação dos farmacêuticos no processo do cuidado. O objetivo deste estudo foi identificar na literatura científica, estudos que testam algoritmos de aprendizado de máquina (Machine Learning ­ ML) aplicados as atividades de farmacêuticos clínicos no cuidado ao paciente. Trata-se de uma revisão integrativa, realizada nas bases de dados, Pubmed, Portal BVS, Cochrane Library e Embase. Artigos originais, relacionados ao objetivo proposto, disponíveis e publicados antes de 31 de dezembro de 2021, foram incluídos, sem limitações de idioma. Foram encontrados 831 artigos, sendo 5 incluídos relacionados as atividades inseridas nos serviços de revisão da farmacoterapia (3) e monitorização terapêutica (2). Foram utilizadas técnicas supervisionadas (3) e não supervisionadas (2) de ML, com variedade de algoritmos testados, sendo todos os estudos publicados recentemente (2019-2021). Conclui-se que a aplicação da IA na farmácia clínica, ainda é discreta, sinalizando os desafios da era digital.

The growing application of artificial intelligence (AI) in complex real-world problems has shown an enormous potential to improve health services, including the role of pharmacists in the care process. Thus, the objective of this study was to identify, in the scientific literature, studies that addressed the use of machine learning (ML) algorithms applied to the activities of clinical pharmacists in patient care. This is an integrative review, conducted in the databases Pubmed, VHL Regional Portal, Cochrane Library and Embase. Original articles, related to the proposed topic, which were available and published before December 31, 2021, were included, without language limitations. There were 831 articles retrieved 5 of which were related to activities included in the pharmacotherapy review services (3) and therapeutic monitoring (2). Supervised (3) and unsupervised (2) ML techniques were used, with a variety of algorithms tested, with all studies published recently (2019­2021). It is concluded that the application of AI in clinical pharmacy is still discreet, signaling the challenges of the digital age.

Adherence and Quality of Life in Non-Valvular Atrial Fibrillation With Direct Oral Anticoagulants Versus Vitamin K Antagonists: A Systematic Review

Abstract Background Direct anticoagulants (DOACs) and vitamin K antagonists (VKAs) differ in pharmacokinetic characteristics, intensity of required laboratory monitoring, and costs. These differences could affect patients' adherence to treatment and quality of life (QoL). Objective To assess whether patients with non-valvular atrial fibrillation (AF) using DOACs have better treatment adherence and QoL when compared to patients using VKAs. Methods We conducted a systematic review in Medline, Embase, LILACS, SciELO, CINAHL, and Cochrane Central, until June 9, 2021. We included studies that estimated and compared treatment adherence and QoL between DOACs and VKAs in adults with non-valvular AF. The methodological quality of the studies was assessed using the Joanna Briggs Institute (JBI) tools. The protocol was registered in the PROSPERO (CRD 42020165238). Results Sixteen studies, including 122,458 patients with non-valvular AF, evaluated adherence, and eleven studies, including 5,687 patients, assessed QoL. A variety of methods was used to measure adherence. Eleven studies showed no difference in adherence between DOACs and VKAs, while three studies favored VKAs over DOACs and two studies favored DOACs over VKAs. QoL was measured by specific (n = 3) or generic questionnaires (n = 8); results favored DOACs over VKAs in four studies, while in the other seven studies the results showed no difference between the groups. Meta-analyses were not performed due to high methodological heterogeneity among studies. Conclusions Available evidence regarding treatment adherence and QoL with DOACs and VKAs is characterized by methodological heterogeneity and conflicting findings.

Fatty acid synthase as a potential new therapeutic target for cervical cancer.

Fatty acid synthase (FASN) is the rate-limiting enzyme for the de novo synthesis of fatty acids in the cytoplasm of tumour cells. Many tumour cells express high levels of FASN, and its expression is associated with a poorer prognosis. Cervical cancer is a major public health problem, representing the fourth most common cancer affecting women worldwide. To date, only a few in silico studies have correlated FASN expression with cervical cancer. This study aimed to investigate in vitro FASN expression in premalignant lesions and cervical cancer samples and the effects of a FASN inhibitor on cervical cancer cells. FASN expression was observed in all cervical cancer samples with increased expression at more advanced cervical cancer stages. The FASN inhibitor (orlistat) reduced the in vitro cell viability of cervical cancer cells (C-33A, ME-180, HeLa and SiHa) in a time-dependent manner and triggered apoptosis. FASN inhibitor also led to cell cycle arrest and autophagy. FASN may be a potential therapeutic target for cervical cancer, and medicinal chemists, pharmaceutical researchers and formulators should consider this finding in the development of new treatment approaches for this cancer type.

Comparative efficacy of amitriptyline, duloxetine and pregabalin for treating fibromyalgia in adults: an overview with network meta-analysis.

Treatment recommendations for fibromyalgia (FM) include a range of predominantly pharmacological treatment options designed to ensure the maintenance of symptoms and improvement in the quality of life of these patients. Our aim is to identify and compare the efficacy of amitriptyline (AMT), duloxetine (DLX), and pregabalin (PGB) for reducing pain intensity by 30% (R30%) and 50% (R50%) in adult patients with fibromyalgia. The review was conducted in the Medline/PubMed, Cochrane Library, and Embase databases up to February 2022. This study included systematic reviews (SR) of randomized clinical trials (RCTs) targeting adult patients over 18 years of age diagnosed with fibromyalgia according to the criteria of scientific societies, which include the basic clinical diagnosis characterized by the presence of pressure sensitivity in at least 11 of the 18 tender points, in addition to the presence of widespread musculoskeletal pain for a period longer than 3 months and a general assessment of the patient's health status. Pregnant women and children or adolescents were excluded. The Rob 2.0 tool from the Cochrane Collaboration was used to assess the risk of bias in RCTs. The quality of evidence of the reviews included was assessed according to the Grading of Recommendations Assessment, Development and Evaluation-GRADE. A meta-analysis for the evidence network was performed using the Bayesian approach, which allows simultaneous comparison of all treatment options (medication and dose). The different treatments were ranked according to the response rate according to the surface under the curve (SUCRA), which was expressed as a percentage. The results were presented in tables and figures. The protocol with the detailed methods was registered in PROSPERO (CRD42021229264). Eight systematic reviews were identified, and, from these, 15 clinical trials comparing AMT (n = 273), DLX (n = 2595), and PGB (n = 3,506) against placebo were selected. For the outcome R30%, PGB 450 mg was superior to DLX 30 mg and PGB 150 mg, while DLX 20 mg and 30 mg were not superior to placebo. For the outcome R50%, AMT 25 mg was superior to all other alternatives evaluated. The calculation of the SUCRA indicated that PGB 450 mg was the best performance option for R30% and AMT 25 mg for R50%. PGB 150 mg was the drug with the worst performance in the two outcomes evaluated. The drugs evaluated showed benefits for pain reduction in patients with fibromyalgia. In the absence of direct comparison studies, indirect comparison meta-analyses are an important resource for assisting in clinical decision-making. Our data only provide an indicator of the effectiveness of the three drugs evaluated, but as with other health conditions, tolerability and safety are important for the decision-making process and clinical management. In this regard, we encourage caution in interpreting our data.

Synthesis and antileukemic activity of an ursolic acid derivative: A potential co-drug in combination with imatinib.

Imatinib, a specific Bcr-Abl tyrosine kinase inhibitor, is the most commonly used drug in the treatment of chronic myeloid leukemia. However, optimal response is not achieved in up to 33% of patients. Therefore, development of novel therapeutic strategies for chronic myeloid leukemia is critical. Betulinic (1) and ursolic (2) acids are natural pentacyclic triterpenes that exhibit antileukemic activities. In this study, we evaluated the effects of pharmacomodulations at the C-3 position of the triterpene moiety of betulinic and ursolic acids on their activity against K562 leukemia cells. Six new derivatives (1a-2c) were synthesized and evaluated for pro-apoptotic and anti-proliferative effects in mammalian and leukemic cells. 2c derivative containing an amine group at the C-3 position of ursolic acid was the most active against leukemia cells with an IC50 value of 5.2 µM after 48 h of treatment. 2c did not exhibit cytotoxic effects against VERO and HepG2 cells and human lymphocytes, showing a good selectivity index for cancer over normal cells. Induced cell death by apoptosis via caspases 3 and 8, and also caused cell cycle arrest as evidenced by accumulation of cells in the G1 phase and decreased cell population in the G2 phase. Furthermore, co-treatment of 2c with imatinib, the chemotherapy drug most commonly used to treat leukemia, resulted in a synergistic effect. Our findings provide a strong rationale for further investigation of combination therapy using the 2c derivative and imatinib in pre-clinical studies.

A three-dimensional microenvironment alters CD73 expression in cervical cancer.

Stem-like cells (CSCs) have a tumour-initiating capacity and play critical role in tumour metastasis, relapse and resistance to therapy. The ectoenzyme CD73, encoded by the NT5E gene, which catalyses the hydrolysis of AMP into adenosine, has been associated to an immunosuppressive tumour microenvironment, tumour cell adhesion and migration. Therefore, we investigated the expression and activity of CD73 in sphere-forming cells from cervical cancer in comparison to monolayer cells in vitro. In addition, in silico analysis was performed to determine the expression of CD73 and other members of purinergic signalling in CSC-like population derived from different tumour types in comparison to monolayer cells. CD73 protein expression levels and functionality in SiHa cells were analysed by flow cytometry and enzymatic assay, respectively. In silico investigation was performed through the analysis of seven datasets from different tumour types using GEO database. In vitro analysis showed a decreased CD73 protein expression and enzymatic activity in cervical spheres, when compared to monolayers. In addition, when sphere-derived cells are re-plated as monolayer culture, the CD73 expression and activity are restored. Supporting the in vitro results, in silico analysis showed that three-dimensional spheres derived from cervical, thyroid and breast cancer presented decreased expression of CD73, when compared to their adherent counterparts. The decreased expression of CD73 in sphere-derived cells or CSC-enriched population reinforce its important role in cell adhesion, tumour spreading ability and metastasis, suggesting CD73 as potential target to be further investigated in cervical cancer.

Natural and Semisynthetic Pentacyclic Triterpenes for Chronic Myeloid Leukemia Therapy: Reality, Challenges and Perspectives.

Chronic myeloid leukemia (CML) is a neoplasm characterized by BCR-ABL1, an oncoprotein with vital role in leukemogenesis. Its inhibition by tyrosine kinase inhibitors represents the main choice of treatment. However, therapeutic failure is worrying given the lack of pharmacological options. Pentacyclic triterpenes are phytochemicals with outstanding antitumoral properties and have also been explored as a basis for the design of potential leads. In this review, we have gathered and discuss data regarding both natural and semisynthetic pentacyclic triterpenes applied to CML cell treatment. We found consistent evidence that the class of pentacyclic triterpenes in general exerts promising pro-apoptotic and antiproliferative activities in sensitive and resistant CML cells, and thus represents a rich source for drug development. We also analyze the predicted drug-like properties of the molecules, discuss the structural changes with biological implications and show the great opportunities this class represents, as well as the perspectives they provide on drug discovery for CML treatment.

Custos diretos e indiretos da fibromialgia: uma revisão de escopo / Direct and indirect costs of fibromyalgia: a scoping review

Objetivo: Identificar os custos médicos diretos e indiretos de pacientes com fibromialgia (FM), bem como elucidar os recursos em saúde utilizados. Métodos: Foi realizada uma revisão de escopo nas bases de dados Medline/PubMed, SciELO e Lilacs, tendo como critérios de inclusão publicações que versavam sobre os custos da FM, publicadas a partir de 2009, disponíveis eletronicamente na íntegra, nos idiomas português, inglês ou espanhol. As buscas foram realizadas entre fevereiro de 2019 e abril de 2021. Resultados: Foram identificados 124 artigos, sendo selecionados 9. Os estudos selecionados foram desenvolvidos na Europa (n=5), América do Norte (n=3) e Ásia (n=1). O número de participantes nos estudos variou de 57 a 2.098, com maior predomínio de pacientes do sexo feminino e idade média variando de 42,6 a 55,2 anos. A média de comorbidades foi de 2,4 a 4,9 por paciente, com um tempo de diagnóstico variando de 4,3 a 6,9 anos. A média do número de consultas médicas variou de 4,68 a 23,3 por paciente/ano, sendo os custos diretos anuais, convertidos para o ano de 2021, de U$ 925,62 a U$ 8.116,59, representando 10,5% a 37,6% dos valores dos custos totais. A média anual de custos indiretos variou de U$ 7.274,98 a U$ 32.294,87, representando 62,4% a 89,5% dos custos totais. Conclusão: Os custos diretos identificados refletiram um panorama do modelo assistencial adotado pelos países que compuseram esta pesquisa e identificamos maior sobrecarga de custos indiretos em relação aos custos totais por paciente, demonstrando maior impacto na comunidade

Objective: To identify the direct and indirect medical costs of patients with fibromyalgia (FM), as well as to elucidate the health resources used. Methods: A scoping review was carried out in the Medline/PubMed, SciELO and Lilacs databases, with the inclusion criteria of publications dealing with the costs of FM, published since 2009, available electronically in full, in Portuguese, English or Spanish. The searches were carried out between February 2019 and April 2021. Results: 124 articles were identified, of which nine were selected. The selected studies were developed in Europe (n=5), North America (n=3) and Asia (n=1). The number of participants in the studies ranged from 57 to 2.098, with a greater predominance of female patients and mean age ranging from 42,6 to 55,2 years. The average of comorbidities was 2,4 to 4,9 per patient, with a time of diagnosis ranging from 4,3 to 6,9 years. The average number of medical consultations ranged from 4,68 to 23,3 per patient/year, with direct annual costs, converted for the year 2021, from U$ 925,62 to U $ 8.116,59, representing 10,5% to 37,6% of the total cost figures. The annual average of indirect costs ranged from U$ 7.274,98 to U$ 32.294,87 representing 62,4% to 89,5% of the total costs. Conclusion: The direct costs identified reflected a panorama of the care model adopted by the countries that composed this research and we identified a greater overhead of indirect costs in relation to the total costs per patient, demonstrating a greater impact on the community

Terapia inalatória em ventilação não-invasiva em pacientes com doença pulmonar obstrutiva crônica / Inhalation therapy during noninvasive ventilation in patients with chronic obstructive pulmonary disease

O objetivo deste estudo é descrever os aspectos técnicos e cuidados a serem observados durante a administração de medicamentos inalatórios contidos em inalador pressurizado (pMDI) em pacientes com doença pulmonar obstrutiva crônica em ventilação não-invasiva (VNI). Trata-se de uma revisão integrativa elaborada em quatro fases: (1) busca na literatura; (2) consulta às sociedades médicas; (3) pesquisaem bulas e monografias dos fármacos inalatórios; e (4) contato com empresas de ventiladores, medicamentos e espaçadores. A busca aos estudos foi conduzida a partir de palavras-chaves e restringida a publicações até 31 de dezembro de 2019, nos idiomas português e inglês. Foram selecionados 9 artigos, sendo 1 estudo primário, 6 estudos de revisão e 2 estudos em modelos experimentais de ventilação. Foram incluídas 2 diretrizes a partir da consulta às sociedades médicas e das 8 empresas contatas, quatro fizeram recomendações quanto à técnica inalatória. Não foram encontradas informações sobre a administração dos fármacos em VNI nas bulas e monografias. Recomenda-se atentar para as medidas que podem aumentar a deposição pulmonar dos fármacos inalatórios, como uso de aerocâmara com pMDI, minimização de escape indesejável de ar, sincronia entre paciente-ventilador, disparo do jato na fase inspiratória e inserção de porta de vazamento na máscara ou circuito. (AU)

The aim of this study is to describe the technical aspects and cautions to be observed during the administration of inhaled medications contained in a pressurized inhaler (pMDI) in patients with chronic obstructive pulmonary disease on noninvasive ventilation. This integrative review consisted of 4 phases: (1) search in the literature; (2) consultation with medical societies; (3) research on package inserts and monographs of inhaled drugs; and (4) contact with ventilator, medication and spacer companies. The search for studies was based on keywords and restricted to articles published until December 31, 2019, written in Portuguese and English. Nine articles were selected, including 1 primary study, 6 review studies and 2 studies on experimental ventilation models. Two guidelines were included from the consultation with medical societies, and of the 8 companies contacted, 4 made recommendations regarding the inhalation technique. No information was found on the administration of noninvasive ventilation drugs in package inserts and monographs. Attention should be given to measures that increase the pulmonary deposition of inhaled drugs, such as the use of an air chamber with pMDI, minimization of undesirable air leakage, patient-ventilator synchronization, jet firing in the inspiratory phase and insertion of a leak port in the mask or circuit. (AU)

Avaliação do perfil de mulheres atendidas em centros de referência em saúde de Porto Alegre/RS e relação de alterações citológicas detectadas no exame citopatológico e a presença do HPV / Profile evaluation of women that attended reference health centers in Porto Alegre/RS and the relationship between cytological alterations detected in cytopathological examination and presence of HPV / Evaluación del perfil de las mujeres atendidas en los centros de referencia de salud de Porto Alegre / RS y la relación de las alteraciones citológicas detectadas en el examen citopatológico con la presencia de VPH

Justificativas e Objetivos: Câncer de colo de útero é considerado um problema de saúde pública mundial. Seu diagnóstico é realizado através do exame citopatológico (EC) e seu desenvolvimento relacionado à infecção pelo papilomavírus humano (HPV). Este estudo objetiva avaliar o perfil de mulheres atendidas em centros de referência em saúde de Porto Alegre, Rio Grande do Sul, assim como a relação de alterações observadas ao EC com presença do HPV. Métodos: Estudo transversal realizado em mulheres atendidas em unidades básicas de saúde e um ambulatório de referência de hospital público terciário, no período de julho de 2014 a janeiro de 2017. Coletaram-se amostras representativas da endo/ectocérvice para realização do EC e investigadas quanto à presença molecular do HPV. Resultados: Foram analisadas 169 mulheres com idade média entre 31 e 40 anos, das quais 125 (74%) informaram que a sexarca ocorreu na faixa de 15-20 anos e 37,9% relatou ter tido de três a cinco parceiros sexuais. Em relação ao EC, 71 (42%) apresentaram resultado negativo para lesão intraepitelial ou malignidade e 98 (58%) alguma anormalidade de células escamosas: 20 (11,8%) atipias; 22 (13%) lesão intraepitelial escamosa de baixo grau e 56 (32,6%) lesão intraepitelial de alto grau (HSIL). Cinquenta (29,6%) apresentaram positividade para HPV, destas 56,4% foram diagnosticadas com HSIL (p<0,01). Conclusão: Os resultados revelam alta frequência de HPV em amostras com alterações citopatológicas, em mulheres jovens e com grau de exposição ao HPV, reforçando a importância do papel da sua identificação precoce na investigação da carcinogênese cervical.(AU)

Background and Objectives: Cervical cancer is considered a worldwide public health problem. Its diagnosis is made through cytopathological examination and its development related to human papillomavirus (HPV) infection. This study aims to evaluate the profile of women treated at reference health centers in Porto Alegre, Rio Grande do Sul, as well as the relation of changes observed to cytopathological examination with the presence of HPV. Methods: This is a cross-sectional study carried out in women treated at basic health units and a referral clinic of a public tertiary hospital, from July 2014 to January 2017. Representative samples of the endo/ectocervix were collected to perform the cytopathological examination and investigated for the molecular presence of HPV. Results: 169 women with mean age between 31 and 40 years were analyzed, of whom 125 (74%) reported that the onset of sexual activity occurred in the 15-20 years age group, and 37.9% reported having had three to five sexual partners. In relation to cytopathological examination, 71 (42%) had a negative result for intraepithelial lesion or malignancy and 98 (58%) some squamous cell abnormality: 20 (11.8%) atypical; 22 (13%) low-grade squamous intraepithelial lesion and 56 (32.6%) high-grade intraepithelial lesion (HSIL). Fifty (29.6%) were positive for HPV, of which 56.4% were diagnosed with HSIL (p < 0.01). Conclusion: The results reveal a high frequency of HPV in samples with cytopathological changes, in young women and with a degree of exposure to HPV, reinforcing the importance of the role of its early identification in the investigation of cervical carcinogenesis.(AU)

Justificación y objetivos: El cáncer de cuello uterino se considera un problema de salud pública en todo el mundo. Su diagnóstico se realiza mediante el examen citopatológico (EC), y su desarrollo está relacionado con la infección por el virus del papiloma humano (VPH). Este estudio objetivó evaluar el perfil de mujeres atendidas en los centros de referencia en salud de Porto Alegre, Rio Grande do Sul (Brasil), así como la relación de las alteraciones observadas en el EC con la presencia del VPH. Métodos: Estudio transversal realizado en las mujeres atendidas por unidades de atención primaria y por una clínica ambulatoria de referencia del hospital público terciario en la ciudad de Porto Alegre, en el período de julio de 2014 a enero de 2017. Se recolectaron muestras representativas de endo/ectocérvice para realizar la CE, las cuales se clasificaron según el sistema Bethesda y se investigaron la presencia molecular del VPH. Resultados: Analizamos 169 mujeres con promedio de edad entre 31 y 40 años, de las cuales 125 (74%) informaron que el sexarche ocurrió en el rango de 15-20 años. La mayoría (37,9%) informó haber tenido de 3 a 5 parejas sexuales; y el 37,3% estaban usando anticonceptivos orales. Con respecto a la EC, 71 (42%) se clasificaron como negativos para lesión intraepitelial o malignidad; y el 98 (58%) tenían alguna anormalidad de células escamosas: 20 (11,8%) de atipias; 22 (13,0%) lesión intraepitelial escamosa de bajo grado y 56 (32,6%) lesión intraepitelial de alto grado (HSIL). La frecuencia de positividad del VPH encontrada fue de 50 (29,6%), de estas un 56,4% fueron diagnosticadas con HSIL (p<0,01). Conclusiones: Estos resultados revelan una alta frecuencia de VPH en muestras con alteraciones citopatológicas presentes en mujeres jóvenes con cierto grado de exposición al VPH, lo que refuerza la importancia de identificarse tempranamente en el análisis de la carcinogénesis cervical.(AU)

Imatinib mesylate affects extracellular ATP catabolism and expression of NTPDases in a chronic myeloid leukemia cell line.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm, characterized by the occurrence of the t(9;22)(q34;q11) translocation. First-line therapy for CML consists of treatment with imatinib mesylate, which selectively inhibits the BCR-ABL protein by competing for its ATP-binding site. Adenine nucleotide signaling is modulated by the ectonucleotidases and this pathway is related to tumorigenic processes. Considering the relationship between ATP and cancer, we aimed to evaluate the influence of imatinib mesylate on the expressions and functions of the NTPDase and ecto-5'-nucleotidase (CD73) enzymes in imatinib-sensitive and -resistant K-562 cell lines. mRNA analysis showed that K-562 cells express all ENTPDs and NT5E. However, when treated with imatinib mesylate for 24 h, the expression of ENTPD1, -2, -3 and -5 increased, leading to a higher nucleotides hydrolysis rate. HPLC analysis identified increased ATP degradation in cells after 24 h of treatment, with consequent ADP and AMP formation, corroborating the increase in gene and protein expression of ectonucleotidases as observed in previous results. On the other hand, we observed that imatinib-resistant K-562 cells presented a decrease in nucleotide hydrolysis and expressions of ENTPD1 and -5. These results suggest an involvement of imatinib in modulating ectonucleotidases in CML that will need further investigation. Since these ectonucleotidases have important catalytic activities in the tumor microenvironment, their modulation in CML cells may represent an important therapeutic approach to regulate levels of extracellular adenine nucleotides.

Betulinic Acid and Brosimine B Hybrid Derivatives as Potential Agents against Female Cancers.

BACKGROUND: Cancer is a multifactorial disease, representing one of the leading causes of death worldwide. On a global estimate, breast cancer is the most frequently occurring cancer in women and cervical cancer, the fourth most common. Both types of cancer remain the major cause of cancer-related mortality in developing countries. A strategy for rational drug design is hybridization, which aims to bring together in one molecule, two or more pharmacophores in order to reach several biological targets. OBJECTIVE: The objective of this work was to develop new hybrids based on natural pharmacophores: Betulinic acid (1) and brosimine b (2), active in female cancer cell lines. METHODS: The coupling reactions were carried out by Steglich esterification. Different compounds were designed for the complete and simplified structural hybridization of molecules. The anticancer activities of the compounds were evaluated in human cervical adenocarcinoma (HeLa), human cervical metastatic epidermoid carcinoma (ME-180), and human breast adenocarcinoma (MCF-7) cell lines. RESULTS: Hybrid 3 presented higher potency (IC50 = 9.2 ± 0.5µM) and SI (43.5) selectively in MCF-7 cells (in relation to Vero cells) with its cytotoxic effect occurring via apoptosis. In addition, compound 6 showed activity in MCF-7 and HeLa cells with intermediate potency, but with high efficacy, acting via apoptosis as well. CONCLUSION: In this context, we showed that the combination of two complex structures generated the development of hybrids with differing inhibitory profiles and apoptotic modes of action, thus representing potential alternatives in female cancer treatment.