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Caroline de Godoi Rezende Costa Molino, Renata Cavalcanti Carnevale, Aline Teotonio Rodrigues, Marília Berlofa Visacri, Patricia Moriel, Priscila Gava Mazzola Department of Clinical Pathology, Faculty of Medical Sciences (FCM), University of Campinas (UNICAMP), São Paulo, Brazil Background: Substantial complexity has been introduced into treatment regimens for patients with human immunodeficiency virus (HIV) infection. Many drug-related problems (DRPs) are detected in these patients, such as low adherence, therapeutic inefficacy, and safety issues. We evaluated the impact of pharmacist interventions on CD4+ T-lymphocyte count, HIV viral load, and DRPs in patients with HIV infection. Methods: In this 18-month prospective controlled study, 90 outpatients were selected by convenience sampling from the Hospital Dia–University of Campinas Teaching Hospital (Brazil). Forty-five patients comprised the pharmacist intervention group and 45 the control group; all patients had HIV infection with or without acquired immunodeficiency syndrome. Pharmaceutical appointments were conducted based on the Pharmacotherapy Workup method, although DRPs and pharmacist intervention classifications were modified for applicability to institutional service limitations and research requirements. Pharmacist interventions were performed immediately after detection of DRPs. The main outcome measures were DRPs, CD4+ T-lymphocyte count, and HIV viral load. Results: After pharmacist intervention, DRPs decreased from 5.2 (95% confidence interval [CI] =4.1–6.2) to 4.2 (95% CI =3.3–5.1) per patient (P=0.043). A total of 122 pharmacist interventions were proposed, with an average of 2.7 interventions per patient. All the pharmacist interventions were accepted by physicians, and among patients, the interventions were well accepted during the appointments, but compliance with the interventions was not measured. A statistically significant increase in CD4+ T-lymphocyte count in the intervention group was found (260.7 cells/mm3 [95% CI =175.8–345.6] to 312.0 cells/mm3 [95% CI =23.5–40.6], P=0.015), which was not observed in the control group. There was no statistical difference between the groups regarding HIV viral load. Conclusion: This study suggests that pharmacist interventions in patients with HIV infection can cause an increase in CD4+ T-lymphocyte counts and a decrease in DRPs, demonstrating the importance of an optimal pharmaceutical care plan. Keywords: pharmaceutical care, HIV, clinical pharmacy, CD4+ T lymphocyte count, AIDS, pharmacy service

Objective: This study aimed to assess the costs and factors associated with the judicialization of medicines for the municipal Unified Health System in Campinas, São Paulo, Brazil, from 2017 to 2021., Methods: This cross-sectional study used data provided by the Municipal Health Department of Campinas and the Court of Justice of the State of São Paulo., Results: The sample comprised 506 medicines (322 active substances) and 493 legal cases. Of the US$9.270 million disbursed, 67.3% were allocated to purchase medicines. On average, 28.8% of the pharmaceuticals were listed on the National List of Essential Medicines (Rename), of which 52.3% were listed in the specialized component. Expenditures on nonincorporated and oncological medicines accounted for 76% of the total value. Acquisition of brand-specific medicines was predominant (53.7%), of which 75.5% had therapeutic equivalents. ABC curve shows that only 28 active substances corresponded to 79.8% of the expenses incurred to serve 573 plaintiffs. Four factors, when present in legal actions, prevented the rational use of public resources: assumption of responsibilities of other federative entities, acquisition of medicines not incorporated in Rename and oncological drugs, trademark determination, and the requirement to supply the medicine for an indefinite period. Costs associated with these factors caused an increase in expenditure, even with a decrease in legal demands filed against the municipality., Conclusions: Judicialization of medicines in Campinas from 2017 to 2021 required an allocation of US$6.2 million, aimed at treating only 0.068% of the population. Associated factors include legal requirements and internal management challenges that have increased costs., Competing Interests: Author Disclosures Author disclosure forms can be accessed below in the Supplemental Material section., (Copyright © 2024 International Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Objective: This scoping review aims to map studies that applied artificial intelligence (AI) tools to perform health technology assessment tasks in human health care. The review also aims to understand specific processes in which the AI tools were applied and to comprehend the technical characteristics of these tools., Introduction: Health technology assessment is a complex, time-consuming, and labor-intensive endeavor. The development of automation techniques using AI has opened up new avenues for accelerating such assessments in human health settings. This could potentially aid health technology assessment researchers and decision-makers to deliver higher quality evidence., Inclusion Criteria: This review will consider studies that assesses the use of AI tools in any process of health technology assessment in human health. However, publications in which AI is a means of clinical aid, such as diagnostics or surgery will be excluded., Methods: A search for relevant articles will be conducted in databases such as CINAHL (EBSCOhost), Embase (Ovid), MEDLINE (PubMed), Science Direct, Computer and Applied Sciences Complete (EBSCOhost), LILACS, Scopus, and Web of Science Core Collection. A search for gray literature will be conducted in GreyLit.Org, ProQuest Dissertations and Theses, Google Scholar, and the Google search engine. No language filters will be applied. Screening, selection, and data extraction will be performed by 2 independent reviewers. The results will be presented in graphic and tabular format, accompanied by a narrative summary., Details of This Review Can Be Found in Open Science Framework: osf.io/3rm8g., Competing Interests: The authors declare no conflicts of interest, (Copyright © 2024 JBI.)

Objectives: To present an overview of evidence of efficacy, safety, and health-related quality of life of lenalidomide or thalidomide for transplant-ineligible multiple myeloma., Methods: A literature search was performed in 5 databases until July 2022. We included systematic reviews with network meta-analyses of randomized controlled trials on the use of lenalidomide compared with thalidomide for transplant-ineligible multiple myeloma. The A Measurement Tool to Assess Systematic Reviews 2 was used to appraise the quality of included reviews. The results were focused on the lenalidomide + dexamethasone until disease progression (RDc) versus thalidomide + dexamethasone until disease progression (TDc) and induction with melphalan + prednisone + lenalidomide, followed by maintenance with lenalidomide (MPR-R) versus induction with melphalan + prednisone + thalidomide, followed by maintenance with thalidomide (MPT-T) regimens., Results: Nine studies were included. Only 1 study did not show any weakness in critical domains of A Measurement Tool to Assess Systematic Reviews 2. For overall survival, RDc proved to be superior to TDc; however, no study showed significant difference between MPR-R and MPT-T. For progression-free survival, 2 of 3 studies showed that RDc is better than TDc; however, no difference between MPR-R and MPT-T was found. Regarding safety, these lenalidomide-based regimens had a lower risk for neurologic adverse events, with an increased risk of hematologic adverse events. No health-related quality of life meta-analyses were found., Conclusions: These findings suggest that, in terms of efficacy and safety, lenalidomide-based regimen is a good option for treatment of transplant-ineligible multiple myeloma in the public health system of Brazil, especially for those patients who develop severe neuropathy with thalidomide., Competing Interests: Author Disclosures Author disclosure forms can be accessed below in the Supplemental Material section., (Copyright © 2024 International Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

In Brazil, the judicialization of public health for access to medications has resulted in significant challenges to the management of public policies, especially at the municipal level. To evaluate the profile of drug litigations against the Campinas municipal health system from 2017 to 2021, this study analyzed the characteristics of litigants, medicine dispensation, and the timing of court decisions. A quantitative, analytical, and comparative cross-sectional study was conducted using data on the dispensation of 506 types of medications and 493 court cases. The analysis included sociodemographic, procedural, medical-sanitary, and pharmaceutical assistance management variables. The time of court decisions was assessed using the Kruskal‒Wallis test complemented by the Dunn test. The plaintiffs were predominantly adults, females, and self-declared students, and some cases involved nonresidents. Most of the lawsuits were represented by private lawyers, gratuitousness of justice and with decisions favorable to the plaintiff. However, only 43% of the patients obtained a preliminary injunction or early tutelage. The median time needed for a court decision from the date of case filing was 12 days until the granting of a preliminary injunction or early tutelage and 6.5 months until a judgment or dismissal without a decision on the merits. Approximately 32.4% of the medications dispensed by the judicial pharmacy already belonged to the list of the Brazil's Unified Health System in 2020; 46.3% were prescribed by their generic name; 75.5% had therapeutic equivalents, and 94.9% had marketing authorization from the Brazilian National Health Surveillance Agency. Judicialization in Campinas is an alternative way of accessing medications, but it is time-consuming and benefits only a small portion of the population (0.068%). The characteristics of the plaintiffs and judicialized medicines highlight the need to review health policies to promote equitable and efficient access to essential treatments for the population., (© 2024. The Author(s).)

Background: Treating multiple myeloma is complex, and providing supportive care through an interdisciplinary approach is essential., Aim: To report and synthesize pharmacists' clinical activities and impact on the care of patients with multiple myeloma., Method: This was a scoping review that followed the PRISMA-ScR reporting recommendations. A search was conducted in PubMed, Embase, Web of Science, Scopus, and LILACS from the inception of the database until January 10th, 2024. Papers that reported pharmacists' clinical activities in the care of patients with multiple myeloma were included. Descriptive Elements of Pharmacist Intervention Characterization Tool (DEPICT) version 2 was used to characterize the pharmacists' clinical activities. The results are presented as a narrative and tabular synthesis., Results: A total of 2885 records were identified, 10 of which met the inclusion criteria. Pharmacists' clinical activities related to 'direct patient care' (n = 8) and 'medication counseling, education, and training' (n = 7) were the most cited. Most were provided for patients (n = 8), by one-on-one contact (n = 9), and through face-to-face communication method (n = 8), with patient counseling being the main action taken by pharmacists (n = 7). Materials that supported pharmacists' actions were cited in five studies. Integrating pharmacists into interdisciplinary teams led to improved process, clinical, humanistic, and economic outcomes., Conclusion: This scoping review emphasizes pharmacists' clinical activities in improving the care of patients with multiple myeloma. There is a need to develop studies with patient-reported outcomes and comprehensive reporting of pharmacists' clinical activities to ensure reproducibility and effective implementation in clinical practice., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objective: To describe the resident pharmacist's participation in Shared Medical Appointments (SMA) in palliative care., Methods: The resident pharmacist participated in face-to-face SMA with the attending physician, medical and gerontology students, and a nurse., Key Findings: The resident pharmacist supported interdisciplinary discussions and performed pharmaceutical interventions. He helped raise awareness about the effective, safe, and convenient use of medicines, helping improve the quality of life of patients and caregivers., Conclusions: Providing pharmaceutical care to patients in palliative care helped to improve the quality of clinical services offered to these patients, as well as adding value to resident pharmacists' interprofessional practice., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

This systematic review and meta-analysis aimed to verify the association between the genetic variants of adenosine triphosphate (ATP)-binding cassette subfamily B member 1 ( ABCB1 ) and ATP-binding cassette subfamily G member 2 ( ABCG2 ) genes and the presence and severity of gefitinib-associated adverse reactions. We systematically searched PubMed, Virtual Health Library/Bireme, Scopus, Embase, and Web of Science databases for relevant studies published up to February 2024. In total, five studies were included in the review. Additionally, eight genetic variants related to ABCB1 (rs1045642, rs1128503, rs2032582, and rs1025836) and ABCG2 (rs2231142, rs2231137, rs2622604, and 15622C>T) genes were analyzed. Meta-analysis showed a significant association between the ABCB1 gene rs1045642 TT genotype and presence of diarrhea (OR = 5.41, 95% CI: 1.38-21.14, I 2 = 0%), the ABCB1 gene rs1128503 TT genotype and CT + TT group and the presence of skin rash (OR = 4.37, 95% CI: 1.51-12.61, I 2 = 0% and OR = 6.99, 95%CI: 1.61-30.30, I 2 = 0%, respectively), and the ABCG2 gene rs2231142 CC genotype and presence of diarrhea (OR = 3.87, 95% CI: 1.53-9.84, I 2 = 39%). No ABCB1 or ABCG2 genes were positively associated with the severity of adverse reactions associated with gefitinib. In conclusion, this study showed that ABCB1 and ABCG2 variants are likely to exhibit clinical implications in predicting the presence of adverse reactions to gefitinib.

Background: The community of lesbian, gay, bisexual, transgender, queer, intersex, asexual, and other identities (LGBTQIA+), comprising sexual and gender minorities, frequently encounters violence, discrimination, and numerous obstacles in accessing health care services. Pharmacists have the potential to significantly contribute to the health care provision for this community., Objective: To assess pharmacists' perceptions regarding academic preparedness and health care provision for the LGBTQIA+ community in Brazil., Methods: An online cross-sectional survey was conducted from August 2022 to February 2023, focusing on the academic training of pharmacists and the provision of health care to the LGBTQIA+ community in Brazil. Data collection was achieved through a 28-question online questionnaire, comprising both closed-ended questions, and Likert-type items. The study variables were subjected to an exploratory descriptive analysis., Results: We received 261 complete and valid responses. A majority of pharmacists indicated that they provided health care to the LGBTQIA+ community (n = 161, 61.7%); however, they lacked formal education on LGBTQIA+ health care during their pharmacy program (n = 256, 98.1%). Most participants strongly agreed that pharmacists play a crucial role in promoting health care for this community (n = 213, 81.6%). However, only a small percentage felt confident in addressing issues related to the effectiveness and safety of hormone use for transgender patients (n = 38, 14.6%). Furthermore, less than a third believed that the health care provided by pharmacists should be differentiated for patients within and outside of the LGBTQIA+ community (n = 76, 29.1%)., Conclusion: The results of this study underscore the necessity and significance of incorporating this topic both in pharmacy training and continuing education. This approach is crucial to enhance and bolster the clinical practice of pharmacists., Competing Interests: Disclosure The authors declare no relevant conflicts of interest or financial relationships., (Copyright © 2024 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Background: Key performance indicators (KPIs) are a set of indicators that improve the quality of services provided by pharmacists. They enable the monitoring and evaluation of result progress and optimize decision-making for stakeholders. Currently, there is no systematic review regarding KPIs for pharmaceutical services., Objectives: To identify and assess the quality of KPIs developed for pharmaceutical services., Methods: A systematic review was conducted in PubMed, Scopus, EMBASE, and LILACS from the inception of the database until February 5th, 2024. Studies that developed a set of KPIs for pharmaceutical services were included. The indicators were evaluated using the Appraisal of Indicators through Research and Evaluation (AIRE) instrument. Two independent reviewers performed the study selection, data extraction, and quality assessment., Results: Fifteen studies were included. The studies were conducted in different regions, most of which were developed for clinical services in hospitals or ambulatory settings, and used similar domains for the development of KPIs such as medication review, patient safety, and patient counseling. Literature review combined with the Delphi technique was the method most used by the studies, with content validity by inter-rater agreement. Regarding methodological quality, most studies described information on the purpose, definition, and stakeholders' involvement in the set of KPIs. However, little information was observed on the strategy for risk adjustment, instructions for presenting and interpreting the indicator results, the detailed description of the numerator and denominator, evidence scientific, and the feasibility of the set of KPIs. Only one study achieved a high methodological quality in all domains of the AIRE tool., Conclusion: Our findings showed the potential of KPIs to monitor and assess pharmacy practice quality. Future studies should expand KPIs for other settings, explore validity evidence of the existing KPIs, provide detailed descriptions of evidence, formulation, and usage, and test their feasibility in daily practice., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Inc.)

Background: Stakeholders and healthcare professionals have an essential role in the elimination of Hansen's Disease. Of these, pharmacists provide core services that assist the management of these patients with the supply of medicines and clinical actions., Objectives: To summarize evidence on the role of pharmacist in the management of Hansen's Disease., Methods: A literature search was performed in MEDLINE, Embase, Scopus, Web of Sciences, LILACS, and Google Scholar for studies published until September 29th, 2022 without language restriction. Studies that reported actions provided by pharmacists in the management of patients with Hansen's Disease were included. The pharmacist interventions identified in the studies were described based on key domains in DEPICT v.2. Two independent reviewers performed study selection and data extraction and any disagreements were resolved by third and fourth authors., Results: A total of 751 records were identified, of which 8 studies fully met the eligibility criteria. Most of them were conducted in Brazil ( n  = 5), in an ambulatory setting ( n  = 8) and the most common study design was descriptive cross-sectional ( n  = 6). Different roles of pharmacists were identified, such as medication review, therapeutic drug monitoring, patient education, drug information, and dispensing. All studies described pharmacist interventions for patients through one-on-one contact and face-to-face. Pharmacists were responsible for patient counseling ( n  = 8), suggestions for change in therapy ( n  = 2), and monitoring results report (n = 2). The studies reported benefits associated with pharmacist interventions, despite the limited descriptions regarding these actions., Conclusions: Few studies that described the activities of pharmacists in the management of Hansen's Disease were found. As the studies did not offer a satisfactory level of description and quality, further research should be conducted to strengthen this field., Competing Interests: The authors report no conflict of interest., (© 2023 The Authors.)

Background: Pharmacy students are at high risk of developing depressive symptoms that can adversely influence their professional future. However, there are no summarized data on the subject., Objective: To summarize the prevalence and incidence of depressive symptoms in pharmacy students., Methods: A literature search was performed using PubMed, PsycINFO, CINAHL, LILACS, and SCOPUS databases until January 2022. We included observational studies that assessed the prevalence or incidence of depressive symptoms among pharmacy students using a validated screening instrument. Two independent investigators performed the study selection, data extraction, and quality assessment using the Joanna Briggs Institute (JBI) checklist for prevalence studies. The estimate of depressive symptoms was summarized as a narrative synthesis using structured tables., Results: Of the 695 records retrieved in the search, 19 studies met the eligibility criteria. All were cross-sectional studies, published between 2009 and 2022. The number of pharmacy students ranged from 30 to 610. Most studies were conducted in Asia (n = 9) and the Americas (n = 7), and included only public university students (n = 12). The studies used several instruments to screen students for depressive symptoms, mainly Patient Health Questionnaire-9 (n = 7), Beck Depression Inventory (n = 5), and Depression, Anxiety, and Stress Scale 21 (n = 4). Most studies (n = 15) evaluated only the prevalence of depressive symptoms. The estimate of overall, mild, moderate, and severe depressive symptoms ranged from 4.8% to 78.8%, 9.1% to 42.1%, 5.8% to 30.0%, and 0% to 50.0%, respectively. Regarding methodological quality, the score ranged from 4 to 7 out of 9 points according to the JBI checklist., Conclusion: A high proportion of depressive symptoms were observed in pharmacy students. This finding points to the urgent need to develop strategies for screening, early identification of symptoms, and intervention to improve the mental health of students., (Copyright © 2023 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Background: Trazodone hydrochloride is an antidepressant used in clinical practice. As a substrate of cytochrome P450 enzymes that is vulnerable to P-glycoprotein transport, several factors can alter its plasma concentration, and hence, dose adjustment may be required. The aim of this scoping review was to identify genetic polymorphisms that influence the pharmacokinetics of trazodone hydrochloride., Methods: A literature search was performed using PubMed, PubMed Central, BVS/BIREME, EBSCOhost, Web of Science, Embase, Cochrane Library, and Medline databases for studies published until August 2021. The search strategy was based on the following keywords: Trazodone OR "m-chlorophenyl piperazine" AND "Pharmacogenetics" OR "Genetics" OR "Cytochrome P-450 Enzyme System" OR "Polymorphism, Single Nucleotide" OR "Polymorphism, Genetic.", Results: The search retrieved 684 candidate articles; 307 duplicates were eliminated. In total, 377 articles were eligible for the first screen. However, only 4 met the eligibility criteria, and 12 polymorphisms in 5 different genes (CYP2D6, CYP1A2, CYP3A4, CYP3A5, and ABCB1). Notably, only C3435T ABCB1 influenced the pharmacokinetics of trazodone hydrochloride. Individuals with the T/T genotype had lower area under the curve, half-life, and maximum concentration values with a higher clearance rate., Conclusions: Polymorphisms in CYP450 do not seem to directly influence the pharmacokinetics of trazodone hydrochloride or its metabolites. By contrast, genetic polymorphisms in ABCB1 seem to have an important effect on the pharmacokinetics of trazodone hydrochloride by enhancing drug metabolism and elimination., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

PurposeThe emergence of multidrug-resistant (MDR) Gram-negative bacterial infections in the neonatal intensive care unit (NICU) is a major public health threat. Ceftazidime-avibactam (CAZ-AVI) provides a new option for treating infections caused by most beta-lactamase- and carbapenemase-producing Gram-negative bacteria in infants older than three months. However, treatment options are extremely limited, with no safety data available for preterm neonates. Here, we describe our experience regarding the safety and efficacy of off-label use of CAZ-AVI in a NICU in Brazil. Summary: We report a case of a premature infant (born at 29 weeks gestational age) treated with CAZ-AVI due to a bloodstream infection caused by MDR Klebsiella pneumoniae . Conclusion: Treatment with CAZ-AVI was safe and effective in our patient.

Cisplatin is associated with dose-limiting nephrotoxicity, and the timely detection of acute kidney injury (AKI) can affect morbimortality. Therefore, this study aimed to investigate the tools for monitoring renal function in AKI. This was a retrospective, cohort study. Cisplatin-treated patients with head and neck cancer were included. Nephrotoxicity was assessed using serum creatinine, estimated creatinine clearance, serum electrolytic alterations, and plasma kidney injury molecule-1 (KIM-1). The toxicity severity was classified according to Common Terminology Criteria for Adverse Events (CTCAE), and AKI was classified by Risk, Injury, Failure, Loss, and End-stage kidney disease (RIFLE) and Acute Kidney Injury Network (AKIN). A total of 81 participants were included, of whom only 32 did not have AKI. Almost 90% of participants had a decreased estimated glomerular filtration rate five (D5) days after chemotherapy. The AKI estimate differs between AKIN and RIFLE; more participants were diagnosed by the RIFLE at D5, 19.5% versus 2.4% by AKIN, and fifteen had a discordance between these classifications. All laboratory markers showed significant changes on D5. KIM-1 appeared a possible biomarker when considering CTCAE or AKIN classifications (p < 0.05 on D5), but not when RIFLE classification was used (p = 0.0780). Further studies may seek to understand the profiles of different biomarkers together.

Introduction: The safety of BCG revaccination is uncertain and there is no data on its use in patients with COVID-19., Methods: COVID-19 convalescent adults confirmed by SARS-CoV-2 RT-PCR in South-America were 1:1 randomized in the first 14 days of symptoms to BCG intradermal vaccine or placebo and evaluated for adverse events on days 7, 14, 21, and beyond 40 days., Clinical Trial Registration: NCT04369794., Results: 151 placebo and 148 BCG patients were included in the final analysis, with an average age of 40.7 years. No severe adverse event to BCG was reported. On day 7, 130 (87.8%) of the BCG recipients had local reaction, average size of 10.6 ± 6.4 mm, compared to only 2 (1.3%) placebos. Lesions gradually shrunk in size (mean 10.5 mm, 9.7 mm, and 6.8 mm at 14, 21, and beyond 40 days, respectively. The number of symptoms in any of the visits was not different between groups, and anosmia resolved earlier (25.7% vs. 37.1% at 7 days, OR = 1.70, 1.01-2.89, p = 0.035) in the BCG recipients., Conclusion: The BCG revaccination is safe in convalescent COVID-19 adults of a tuberculosis endemic region, regardless of tuberculin or IGRA test results. Local adverse events were similar though occurred earlier to that previously reported in children., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Leonardo O. Reis reports financial support was provided by Coordination of Higher Education Personnel Improvement.]., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Coronavirus disease 2019 (COVID-19) is caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It is known that host microRNAs (miRNAs) can be modulated to favor viral infection or to protect the host. Herein, we report preliminary results of a study aiming at identifying differentially expressed plasmatic miRNAs in Brazilian patients with COVID-19., Methods and Results: miRNAs were extracted from the plasma of eight patients with COVID-19 (four patients with mild COVID-19 and four patients with severe/critical COVID-19) and four healthy controls. Patients and controls were matched for sex and age. miRNA expression levels were detected using high-throughput sequencing. Differential miRNA expression and enrichment analyses were further evaluated. A total of 18 miRNAs were differentially expressed between patients with COVID-19 and controls. miR-4433b-5p, miR-6780b-3p, miR-6883-3p, miR-320b, miR-7111-3p, miR-4755-3p, miR-320c, and miR-6511a-3p were the most important miRNAs significantly involved in the PI3K/AKT, Wnt/β-catenin, and STAT3 signaling pathways. Moreover, 42 miRNAs were differentially expressed between severe/critical and mild patients with COVID-19. miR-451a, miR-101-3p, miR-185-5p, miR-30d-5p, miR-25-3p, miR-342-3p, miR-30e-5p, miR-150-5p, miR-15b-5p, and miR-29c-3p were the most important miRNAs significantly involved in the Wnt/β-catenin, NF-κβ, and STAT3 signaling pathways., Conclusions: If validated by quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR) in a larger number of participants, the miRNAs identified in this study might be used as possible biomarkers for the diagnosis and severity of COVID-19., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Cannabis is used in the treatment of several human conditions; however, its use is still less explored in veterinary medicine. This systematic review aims to summarize the evidence of efficacy and safety of the use of cannabis for the treatment of animal disease. A literature search was performed for studies published until 16 March 2021 in five databases. Randomized clinical trials (RCTs) that reported the efficacy or safety of cannabis in the treatment of animal disease were included. The RoB 2 Tool was used to assess the risk of bias. A total of 2427 records were identified, of which six studies fully met the eligibility criteria. RCTs were conducted in dogs with osteoarthritis ( n = 4), with epilepsy ( n = 1), and with behavioral disorders ( n = 1). All studies used cannabidiol (CBD) oil in monotherapy or in combination with other drugs. Studies used CBD at 2 or 2.5 mg kg -1 twice daily ( n = 4), orally ( n = 5), during 4 or 6 weeks ( n = 3), and compared CBD with placebo ( n = 5). CBD significantly reduced pain and increased activity in dogs with osteoarthritis ( n = 3). Moreover, CBD significantly reduced the frequency of seizures in dogs with epilepsy ( n = 1) and the aggressive behavior of dogs ( n = 1). Although promising results were identified, studies were heterogeneous and presented risks of bias that required caution in the interpretation of findings. Therefore, there was some evidence to support the use of CBD in dogs with osteoarthritis to reduce pain and increased activity, but limited evidence against epilepsy and behavioral problems. In addition, CBD was well tolerated with mild adverse effects. More RCTs with high quality of evidence are needed, including greater numbers of animal subjects, additional species, and clear readout measures to confirm these findings.

Cisplatin (DDP) is a well-known anticancer drug used for the treatment of numerous human cancers in solid organs, including bladder, breast, cervical, head and neck squamous cell, ovarian, among others. Its most important mode of action is the DNA-platinum adducts formation, inducing DNA damage response, silencing or activating several genes to induce apoptosis; these mechanisms result in genetics and epigenetics modifications. The ability of DDP to induce tumor cell death is often challenged by the presence of anti-apoptotic regulators, leading to chemoresistance, wherein many patients who have or will develop DDP-resistance. Cancer cells resist the apoptotic effect of chemotherapy, being a problem that severely restricts the successful results of treatment for many human cancers. In the last 30 years, researchers have discovered there are several types of RNAs, and among the most important are non-coding RNAs (ncRNAs), a class of RNAs that are not involved in protein production, but they are implicated in gene expression regulation, and representing the 98% of the human genome non-translated. Some ncRNAs of great interest are long ncRNAs, circular RNAs, and microRNAs (miRs). Accumulating studies reveal that aberrant miRs expression can affect the development of chemotherapy drug resistance, by modulating the expression of relevant target proteins. Thus, identifying molecular mechanisms underlying chemoresistance development is fundamental for setting strategies to improve the prognosis of patients with different types of cancer. Therefore, this review aimed to identify and summarize miRs that modulate chemoresistance in DDP-resistant in the top five deadliest cancer, both in vitro and in vivo human models., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Loren, Saavedra, Saavedra, De Godoy Torso, Visacri, Moriel and Salazar.)

Objective: We conducted this scoping review to map and summarize scientific evidence on the role of clinical pharmacists in the palliative care of adults and elderly patients with cancer., Data Sources: A literature search was performed in MEDLINE, PubMed Central, Embase, Web of Science, Scopus, and BVS/BIREME for studies published until November 22nd, 2020. Studies that reported work experiences adopted by clinical pharmacists in the palliative care of adults and elderly patients with cancer were included. Two independent authors performed study selection and data extraction. Any disagreements were resolved by discussion with the third and fourth authors. The pharmacist interventions identified in the included studies were described based on key domains in the DEPICT v.2., Data Summary: A total of 586 records were identified, of which 14 studies fully met the eligibility criteria. Most of them were conducted in the United States of America (n  =  5) and Canada (n  =  5) and described the workplace of the pharmacist in clinic/ambulatory (n  =  10). Clinical pharmacists performed several activities and provided services, highlighting medication review (n  =  12), patient and caregivers education (n  =  12), medication histories and-or medication reconciliation (n  =  6). The pharmacist interventions were mostly conducted for patients/caregivers (n  =  13), by one-on-one contact (n  =  14), and by face-to-face (n  =  13). Pharmacists were responsible mainly for change or suggestion for change in therapy (n  =  12) and patient counselling (n  =  12). Pharmacist interventions were well accepted by the clinical team. Overall, studies showed that pharmacists, within an interdisciplinary team, had significant impacts on measured outcomes., Conclusions: In recent years, there have been advances in the role of the pharmacist in palliative care of patients with cancer and there are great opportunities in this field. They play an important role in managing cancer pain and other symptoms, as well as resolving drug related problems. We encourage more research to be carried out to strengthen this field and to benefit patients with advanced cancer with higher quality of life.

Purpose: To summarize the evidence of efficacy and safety of the use of ketamine and esketamine for depression., Methods: A literature search was performed in Medline, the Cochrane Library, LILACS, and CRD until November 2020. We included systematic reviews with meta-analyses of randomized controlled trials on the use of ketamine and esketamine in adult patients with depression. Two authors independently performed the study selection and data extraction. The AMSTAR-2 tool was used to appraise the quality of included reviews., Results: A total of 118 records were identified, and 11 studies fully met the eligibility criteria. Compared to control, ketamine improved the clinical response at 40 min to 1 week and clinical remission at 80 min to 72 h, and esketamine improved both outcomes at 2 h to 4 weeks. Ketamine and esketamine also had a beneficial effect on the depression scales score and suicidality. For adverse events, oral ketamine did not show significant change compared to control, while intranasal esketamine showed difference for any events, such as dissociation, dizziness, hypoesthesia, and vertigo. Most reviews were classified as "critically low quality," and none of them declared the source of funding of the primary studies and assessed the potential impact of risk of bias in primary studies., Conclusion: Ketamine and esketamine showed a significant antidepressant action within a few hours or days after administration; however, the long-term efficacy and safety are lacking. In addition, the methodological quality of the reviews was usually critically low, which may indicate the need for higher quality evidence in relation to the theme., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Capecitabine is an oral anticancer drug which can cause some adverse reactions and the great challenge for its use is to ensure the medication adherence. The aim of this study was to analyze adverse reactions and adherence to capecitabine in patients with gastrointestinal cancer., Methods: A prospective study was performed in a tertiary teaching hospital in Brazil. Outpatients undergoing capecitabine treatment for colorectal or gastric cancer were followed for three cycles of treatment. Patient demographic and clinical characteristics data were collected. Adverse reactions were analyzed using Common Terminology Criteria for Adverse Events (CTCAE) v.4. Adherence to capecitabine were evaluated using Morisky-Green and MedTake tests. Statistical analysis was conducted using Chi-square, Fisher's exact and McNemer tests., Results: One hundred and four patients were enrolled in this study, with a mean age was 58.5 ± 10.9 years; 51.0% were men and 51.0% Caucasian. Nausea and diarrhea were the most frequently reported adverse reactions (82.7% and 62.5%, respectively), followed by vomiting (54.8%), fatigue (54.8%), and hand-foot syndrome (53.9%). Nausea and diarrhea were also the most severe adverse reactions. Most patients were adherent to capecitabine in all cycles of treatment using the Morisky-Green test. Adherence increased significantly between cycle 1 and cycle 2 by MedTake test (p < 0.001). Some demographic and clinical characteristics were associated with adverse reactions (e.g., age and nausea, gender and nausea and vomiting) and capecitabine adherence (e.g., marital status and educational level) as well as some adverse reactions were associated with capecitabine adherence (hand-foot syndrome and nausea)., Conclusions: Clinical oncology pharmacists must provide patient information on the correct use of capecitabine, manage adverse reactions, and monitor adherence to treatment. Strategies to prevent non-adherence to capecitabine must be adopted to ensure the success of pharmacotherapy.

Aim: miRNAs are potential biomarkers of several diseases. This review aimed to identify the miRNAs that could serve as biomarkers of COVID-19. Materials & methods: A literature search of nine databases was carried out for studies published before 13 June 2021 that described dysregulated miRNAs in cells or animals infected by SARS-CoV-2 or in patients with COVID-19. Two independent reviewers selected the studies and extracted data; disagreements were resolved by a third reviewer. Results: Twenty studies were included in this scoping review; results suggested that miR-21-5p, miR-146a, miR-126-3p, miR-144 and miR-155 are the most important dysregulated miRNAs that could serve as biomarkers for diagnosing and indicating the severity of COVID-19. miRNAs appear to play key roles in viral replication, proliferation of infected cells, immune response, inflammation and cardiovascular dysfunction. Conclusion: This review provides insights into the role of miRNAs as biomarkers in COVID-19 and the current status and future directions for research in this field.

The purpose of this systematic review was to map out and summarize scientific evidence on dysregulated microRNAs (miRNAs) that can be possible biomarkers or therapeutic targets for cisplatin nephrotoxicity and have already been tested in humans, animals, or cells. In addition, an in silico analysis of the two miRNAs found to be dysregulated in the majority of studies was performed. A literature search was performed using eight databases for studies published up to 4 July 2021. Two independent reviewers selected the studies and extracted the data; disagreements were resolved by a third and fourth reviewers. A total of 1002 records were identified, of which 30 met the eligibility criteria. All studies were published in English and reported between 2010 and 2021. The main findings were as follows: (a) miR-34a and miR-21 were the main miRNAs identified by the studies as possible biomarkers and therapeutic targets of cisplatin nephrotoxicity; (b) the in silico analysis revealed 124 and 131 different strongly validated targets for miR-34a and miR-21, respectively; and (c) studies in humans remain scarce.

Introduction: It is known that clinical pharmacists intercept prescribing errors and contribute to patient safety in several medical specialties. The aim of this study was to identify, quantify and classify prescribing errors and pharmacist interventions carried out in onco-hematology and bone marrow transplant inpatient units., Methods: This was a prospective and quantitative study, conducted from February 2018 to July 2018 in onco-hematology and bone marrow transplant inpatient units of a tertiary teaching hospital in Brazil. A pharmacist detected prescribing errors and performed interventions. The type and incidence of prescribing errors, error severity, type of pharmacist interventions, potential impact of interventions in patient care, and intervention acceptance rates were evaluated., Results: A total of 1172 prescriptions were evaluated, 9% of them contained errors (total of 135 errors), and the most common error was related to prescribing the wrong dose (31.8%). Wrong dose and omission of drug were the two most frequent errors in onco-hematology, while wrong dose followed by inappropriate dilution were the most frequent in bone marrow transplantation. The pharmacist performed 135 interventions and the most common intervention was related to the treatment regimen (41.5%). Serious errors and very significant pharmacist interventions were the most frequent in both inpatient units. The acceptance rate of pharmacist interventions was high (90%)., Conclusions: Clinical pharmacy improves patient safety and quality of care in onco-hematology and bone marrow transplant inpatient units.

Objectives: The objectives of this study were to analyze adverse drug events (ADEs) related to admissions to a pediatric emergency unit and to identify the associated risk factors., Methods: This was a prospective study. Demographic data and details of medications were collected for each patient admitted. Case studies were performed by clinical pharmacists and the clinical team to discuss whether the admission was due to an ADE and to characterize the ADE. Multivariate logistic regression was used for statistical analysis., Results: In total, 1708 pediatric patients were included in this study. Adverse drug events were the cause of hospital admission in 12.3% of the studied population. The majority of patients presenting with an ADE were in the age group of 0 to 5 years (61.6%), had a mean ± SD age of 4.9 ± 3.9 years, were female (51.2%), were Caucasian (72.0%), and had infectious disorders (49.3%). High frequencies of medication errors (68.8%), use of drugs to treat respiratory disorders (27.7%), and ADEs of mild severity (75.3%) were reported. The risk of being admitted to the pediatric emergency unit for any ADE increased in cases of neurological (odds ratio [OR], 4.63; 95% confidence interval [CI], 2.38-8.99), dermatological (OR, 3.16; 95% CI, 1.93-5.18), and respiratory (OR, 3.02; 95% CI, 1.89-4.83) disorders., Conclusions: A high frequency of ADE-related admissions to the pediatric emergency unit was observed. The risk of being admitted to the pediatric emergency unit for any ADE increased in cases of neurological, dermatological, and respiratory disorders. Clinical pharmacists play an important role in the identification of ADEs and the education of child caregivers and health care providers concerning pediatric medication., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Since the start of the new Coronavirus (COVID-19) outbreak in December 2019, pharmacists worldwide are playing a key role adopting innovative strategies to minimize the adverse impact of the pandemic., Objectives: To identify and describe core services provided by the pharmacist during the COVID-19 pandemic., Methods: A literature search was performed in MEDLINE, Embase, Scopus, and LILACS for studies published between December 1st, 2019 and May 20th, 2020 without language restriction. Studies that reported services provided by pharmacists during the COVID-19 pandemic were included. Two independent authors performed study selection and data extraction with a consensus process. The pharmacist's intervention identified in the included studies were described based on key domains in the DEPICT v.2., Results: A total of 1189 records were identified, of which 11 studies fully met the eligibility criteria. Most of them were conducted in the United States of America (n = 4) and China (n = 4). The most common type of publication were letters (n = 4) describing the workplace of the pharmacist in hospitals (n = 8). These findings showed the different roles of pharmacists during the COVID-19 pandemic, such as disease prevention and infection control, adequate storage and drug supply, patient care and support for healthcare professionals. Pharmacists' interventions were mostly conducted for healthcare professionals and patients (n = 7), through one-to-one contact (n = 11), telephone (n = 6) or video conference (n = 5). The pharmacists' main responsibility was to provide drug information for healthcare professionals (n = 7) as well as patient counseling (n = 8)., Conclusions: A reasonable number of studies that described the role of the pharmacists during the COVID-19 pandemic were found. All studies reported actions taken by pharmacists, although without providing a satisfactory description. Thus, future research with more detailed description as well as an evaluation of the impact of pharmacist intervention is needed in order to guide future actions in this and/or other pandemic., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Radiotherapy and cisplatin lead to cell killing in head and neck squamous cell carcinoma patients, but adverse events and response to treatment are not the same in patients with similar clinicopathological aspects. The aim of this prospective study was to evaluate the roles of TP53 c.215G > C, FAS c.-671A > G, FAS c.-1378G > A, FASL c.-844 C > T, CASP3 c.-1191A > G, and CASP3 c.-182-247G > T single nucleotide variants in toxicity, response rate, and survival of cisplatin chemoradiation-treated head and neck squamous cell carcinoma patients. Genomic DNA was analyzed by polymerase chain reaction for genotyping. Differences between groups of patients were analyzed by chi-square test or Fisher's exact test, multiple logistic regression analysis, and Cox hazards model. One hundred nine patients with head and neck squamous cell carcinoma were enrolled in study. All patients were smokers and/or alcoholics. Patients with FAS c.-671GG genotype, FAS c.-671AG or GG genotype, and FASL c.-844CC genotype had 5.52 (95% confidence interval (CI): 1.42-21.43), 4.03 (95% CI: 1.51-10.79), and 5.77 (95% CI: 1.23-27.04) more chances of presenting chemoradiation-related anemia of grades 2-4, lymphopenia of grade 3 or 4, and ototoxicity of all grades, respectively, than those with the remaining genotypes. FAS c.-671GG genotype was also seen as an independent predictor of shorter event-free survival (hazard ratio (HR): 2.05; P   =  0.007) and overall survival (HR: 1.83; P   =  0.02) in our head and neck squamous cell carcinoma patients. These findings present, for the first time, preliminary evidence that inherited abnormalities in apoptosis pathway, related to FAS c.-671A > G and FASL c.-844 C > T single nucleotide variants, can alter toxicity and survival of tobacco- and alcohol-related head and neck squamous cell carcinoma patients homogeneously treated with cisplatin chemoradiation.

Cisplatin (CDDP) combined with radiotherapy (RT) is employed in head and neck squamous cell carcinoma (HNSCC) with variable toxicities and clinical response. Glutathione S-transferases (GSTs) participate in CDDP excretion from cells, and genes encoding GSTs, GSTM1, GSTT1and GSTP1, are polymorphic in humans. This prospective study aimed to evaluate the roles of GSTM1, GSTT1, and GSTP1 Ile105Val polymorphisms in outcomes of HNSCC patients treated with CDDP chemoradiation. Ninety patients were genotyped by multiplex PCR. Urinary CDDP measurements were performed by HPLC. Treatment side effects and response were analysed by conventional criteria. Patients with GSTT1 genes showed 7.23- and 5.37-fold higher likelihood of presenting vomiting and ototoxicity, lower glomerular filtration rate (GFR), and lower elimination of CDDP in urine relative to patients with deleted genes. Patients harbouring the GSTP1 IleVal or ValVal genotypes showed 4.28-fold higher likelihood of presenting grade 2 or 3 vomiting and lower GFR with treatment than those harbouring the IleIle genotype. In multivariate Cox analysis, patients with the GSTP1 105ValVal genotype had 3.87 more chance of presenting disease progression than those with the IleIle or IleVal genotype (p < 0.01). Our findings provide preliminary evidence that inherited abnormalities in CDDP metabolism, related to GSTT1 and GSTP1 Ile105Val polymorphisms, alter outcomes of HNSCC patients treated with CDDP and RT.

Cisplatin (CDDP) is a highly effective antineoplastic agent, widely used in the treatment of various malignant tumors. However, its major problems are side effects associated to toxicity. Considerable inter-individual differences have been reported for CDDP-induced toxicity due to genetic and epigenetic factors. Genetic causes are well described; however, epigenetic modifications are not fully addressed. In the last few years, many evidences were found linking microRNA to the development of CDDP-mediated toxicity, particularly nephrotoxicity. In this review, we described how genetic and epigenetic modifications can be important determinants for the development of toxicity in patients treated with CDDP, and how these alterations may be interesting biomarkers for monitoring toxicity induced by CDDP. Considering the validation in different studies, we suggest that miR-34a, -146b, -378a, -192, and -193 represent an attractive study group to evaluate potential biomarkers to detect CDDP-related nephrotoxicity., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The protective antioxidant activity of acetylcysteine (NAC) against toxicity due to cisplatin has been reported in experimental models; however, its efficacy in patients has not been elucidated. The aim of this study was to investigate the possible protective effect of NAC on cisplatin-induced toxicity and the effect of NAC on clinical response and oxidative stress in patients treated for head and neck cancer. This was a randomized, double-blind, placebo-controlled trial conducted in patients receiving high-dose cisplatin chemotherapy concomitant to radiotherapy. Patients were randomly assigned to groups and received: (a) 600 mg NAC syrup, orally once daily at night for 7 consecutive days or (b) placebo, administered similarly to NAC. Nephro-, oto-, hepato-, myelo-, and gastrointestinal toxicities, clinical responses, and plasma and cellular markers of oxidative stress were evaluated. Fifty-seven patients were included (n = 28, NAC arm; and n = 29, placebo arm). A high prevalence of most types of toxicities was observed after cisplatin chemotherapy; however, the parameters were similar between the two groups. There was a predominance of partial response to treatment. In the cellular and plasmatic oxidative stress analyses, minor differences were observed. Overall, there was no statistically significant difference between the groups for all outcomes. These findings show that low-dose oral NAC does not protect patients with head and neck cancer from cisplatin-induced toxicities and oxidative stress. The antitumor efficacy of cisplatin was apparently not impaired by NAC., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background The emergence and rapid spread of multidrug-resistant gram-negative bacteria related to nosocomial infections is a growing worldwide problem, and polymyxins have become important due to the lack of new antibiotics. Objectives To evaluate the outcomes and pharmacoeconomic impact of using colistin and polymyxin B to treat nosocomial infections. Setting Neurosurgical, cardiovascular, or transplantation intensive care unit (ICU) at the Clinical Hospital of the University of Campinas (São Paulo, Brazil). Method A retrospective cohort study was conduct in patients in the ICU. The renal function was determined daily during treatment by measuring the serum creatinine. A cost minimization analysis was performed to compare the relative costs of treatment with colistin and polymyxin B. Main outcomes measure The outcomes were 30-day mortality and frequency and onset of nephrotoxicity after beginning treatment. Results Fifty-one patients treated with colistin and 51 with polymyxin B were included. 30-day mortality was observed in 25.49% and 33.33% of patients treated with colistin and polymyxin B, respectively; Nephrotoxicity was observed in 43.14% and 54.90% of patients in colistin and polymyxin B groups, respectively; and onset time of nephrotoxicity was 9.86 ± 13.22 days for colistin and 10.68 ± 9.93 days for polymyxin B group. Colistin treatment had a lower cost per patient compared to the cost for polymyxin B treatment (USD $13,389.37 vs. USD $13,639.16, respectively). Conclusion We found no difference between 30-day mortality and nephrotoxicity between groups; however, colistin proved to be the best option from a pharmacoeconomic point of view.

Objectives: The aim of this study was to report number, type and severity of prescribing errors and pharmacist interventions in high-risk pregnant and postpartum women., Design: A prospective cross-sectional, observational study., Setting: A high-risk obstetric inpatient unit of a Women's Hospital in Brazil., Participants: About 1826 electronic prescriptions for 549 women in the high-risk obstetrics inpatient unit were included., Interventions: When the pharmacist detected potential prescribing errors, interventions were suggested., Main Outcome Measures: Prescriptions were evaluated by clinical pharmacist to identify the type, frequency and severity of prescribing errors and rate of clinical pharmacist intervention acceptance in a high-risk obstetric inpatient., Results: A total of 1826 prescriptions were reviewed with 128 errors (7.0%). The most frequent errors were drug interaction (43.8%), incorrect frequency (21.5%) and improper dose (13.1%). One-hundred and sixty-eight interventions were made by pharmacists, 98.8% of which were accepted by prescribers. Higher maternal age (OR 1.0 (95%CI 1.0-1.1)), higher number of prescribed medications (OR 1.2 (95%CI 1.1-1.3)), obstetric conditions (OR 2.2 (95%CI 1.4-3.3)) and non-breastfeeding postpartum women (OR 3.9 (95% CI 2.5-6.1)) were the independent factors associated with prescribing errors identified through multivariate analysis., Conclusions: The most common prescription errors related to drug interactions, incorrect frequency and higher number of prescribed medications. The rate of pharmacist acceptance intervention was high.

Head and neck squamous cell carcinoma (HNSCC) is treated with cisplatin (CDDP) and radiotherapy (RT), and distinct results are observed among patients with similar clinicopathological aspects. This prospective study aimed to investigate whether MLH1 c.-93G>A (rs1800734), MSH2 c.211+9C>G (rs2303426), MSH3 c.3133G>A (rs26279), EXO1 c.1765G>A (rs1047840), and EXO1 c.2270C>T (rs9350) single nucleotide polymorphisms (SNPs) of the mismatch repair (MMR) pathway change side effects and response rate of 90 HNSCC patients treated with CDDP and RT. DNA from peripheral blood was analyzed by PCR-based methods to obtain genotypes. It was observed 4.27-fold and 4.69-fold increased risks of presenting pronounced nephrotoxicity with treatment in patients with MSH3 GG and EXO1 rs9350 CC genotypes compared with patients with GA or AA and CT or TT genotypes, respectively. MSH3 GG or GA and GT haplotype of EXO1 rs1047840 and rs9350 SNPs conferred to patients 10.29 and 4.00 more chances of presenting pronounced ototoxicity after treatment than MSH3 AA genotype and other EXO1 haplotypes, respectively. Patients with EXO1 rs1047840 GA or AA genotype and AC haplotype of EXO1 rs1047840 and rs9350 SNPs had both 9.55-fold increased risks of achieving partial response or stable disease instead of complete remission after treatment than patients with EXO1 GG genotype and other EXO1 haplotypes, respectively. For the first time, our data show preliminary indication that inherited alterations of DNA MMR pathway, related to MSH3 rs26279, EXO1 rs1047840 and EXO1 rs9350 SNPs, modify toxicity and response to chemoradiation in HNSCC, and may contribute to future personalized treatment of patients., Competing Interests: CONFLICTS OF INTEREST Nothing to report.

Cisplatin is a widely used antineoplastic agent in the treatment of head and neck cancer. However, it is highly nephrotoxic. Oxidative stress is the main mechanism responsible for cisplatin-induced nephrotoxicity. The aim of this study was to characterize cisplatin-induced nephrotoxicity, oxidative stress in peripheral blood mononuclear cells, and the relationship between them. Twenty-four patients were included in the study. Patients had their blood collected prior to cisplatin administration, and 5 and 20 days after initiating therapy, to assess renal function and to determine oxidative stress with MitoSOX™Red, H 2 DCF-DA, and Amplex ® Red tests. Renal function was assessed by measuring serum creatinine, creatinine clearance, and blood urea nitrogen (BUN). Serum creatinine and creatinine clearance were used to grade nephrotoxicity using Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Compared to baseline values, the mean BUN and serum creatinine increased 135 and 100%, respectively, 5 days after cisplatin infusion. Mean creatinine clearance showed a 43% decrease compared to baseline value. Non-statistically significant changes in superoxide anion (O 2 •- ), hydrogen peroxide (H 2 O 2 ), and general reactive oxygen species production occurred. A higher production of H 2 O 2 was correlated with variation in serum creatinine, and was associated with higher grades for serum creatinine increases and creatinine clearance reductions. Linear regression analyses showed an association between H 2 O 2 production and serum creatinine, creatinine clearance, and BUN levels. These results were observed for 5 days following cisplatin administration. In conclusion, H 2 O 2 production was significantly related to changes in all renal parameters that were evaluated, following the cisplatin infusion.

Background: Leukocytoclastic vasculitis is typically mediated by deposition of immune complexes and is related to many causes, including medication. To the best of our knowledge, leukocytoclastic vasculitis related to cisplatin has not yet been described in the scientific literature., Case Presentation: We report a rare case of leukocytoclastic vasculitis after the first cycle of high-dose cisplatin chemotherapy in a patient with larynx carcinoma. A 48-year-old Caucasian man with larynx carcinoma received a high-dose of cisplatin monochemotherapy (100 mg/m 2 every 21 days), along with 70 Gy of radiotherapy divided into 35 sessions, as a therapeutic schedule. Twelve days after the first chemotherapy administration and after 8 sessions of radiotherapy (total of 16 Gy), the patient presented with acute onset of palpable purpura in the lower limbs. The patient was hospitalized for 10 days, and during this period, he underwent several examinations to rule out infectious, autoimmune, and neoplastic disorders. A skin biopsy showed leukocytoclastic vasculitis with a positive pattern for IgM and C3, as detected through direct immunofluorescence. Twenty-five days after cisplatin administration, the chemotherapy regimen was changed to carboplatin AUC 5, and the episodes of purpura ceased, reinforcing the hypothesis of an adverse reaction to cisplatin., Conclusions: Cisplatin can induce leukocytoclastic vasculitis and clinicians should be aware of this potential effect for better case management and diagnosis.

Cisplatin (CDDP) chemotherapy associated with radiation (RT) has been used in advanced head and neck squamous cell carcinoma (HNSCC) patients, and vomiting is a common side effect during treatment. This prospective study aimed to identify the roles of GSTM1 and GSTT1 (presents or nulls), GSTP1 c.313A>G, XPC c.2815A>C, XPD c.934G>A and c.2251A>C, XPF c.2505T>C, ERCC1 c.354C>T, MLH1 c.-93G>A, MSH2 c.211 + 9C>G, MSH3 c.3133G>A, EXO1 c.1765G>A, TP53 c.215G>C, CASP3 c.-1191A>G and c.-1168G>T, CASP9 c.-1339A>G, CASP8 c.-937&#95;-932delAGTAAG, FAS c.-1378G>A and c.-671A>G, and FASL c.-157-687C>T single nucleotide polymorphisms, involved in CDDP metabolism, in vomiting severity in 88 HNSCC patients treated with CDDP and RT. Ondansetron and dexamethasone were administered as anti-emetic therapy. Patients with GSTP1 c.313AG or GG genotype alone and combined with XPD c.934GA or AA, XPF c.2505TC or CC, and CASP9 c.-1339AG or GG genotypes had 4.28, 5.00, 5.45 and 5.38 more chances of presenting moderate/severe vomiting than patients with others genotypes. Our data suggest, for the first time, that inherited abnormality in apoptosis pathway alone or combined with inherited abnormalities in DNA repair pathway, is capable of modulating emesis in HNSCC patients under CDDP chemoradiation and may be used for selecting patients who should receive pre-emptive anti-emetic therapy., (© 2017 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Objective: The aim of this study was to determine the impact of two resolutions to restrict antibiotic use (RDCs no. 44/2010 and 20/2011) in the Campinas metropolitan area (Sao Paulo, Brazil) on antibiotic consumption, resistance rates, and trends in Escherichia coli-causing community-acquired urinary tract infection (UTI)., Methods: The annual retail sale information of antibiotics from drugstores in the Campinas metropolitan area between 2008 and 2012 were obtained through the Intercontinental Medical Statistics Health of Brazil. The daily-defined dose (DDD)/1000 inhabitants/day was calculated from these data to measure consumption. To examine resistance rates, we performed an observational retrospective study in a Campinas teaching hospital, where urinary cultures from outpatients with a clinical suspicion of UTI between October 2009 and September 2015 were analyzed., Results: We observed an increase in rates of antibiotic sales from 2008 to 2011 (cephalosporin: 216.8%, quinolones: 170.9%, aminopenicillins: 140.9%), followed by a decrease in sales in 2012 (cephalosporin: 19.4%, quinolones: 12.7%, aminopenicillins: 11.1%). Sale of nitrofurans, however, did not significantly change during this period. In the retrospective analysis, we observed a significant increasing trend of E. coli resistance for all antibiotic classes, except nitrofurans and folate pathway inhibitors., Conclusions: We found changes in antibiotic consumption, with an initial increase, followed by a decrease in sales after implementation of the resolutions. However, bacterial resistance does not appear to be affected by the RDCs., (Copyright © 2017 International Society for Chemotherapy of Infection and Cancer. Published by Elsevier Ltd. All rights reserved.)

Purpose: The aim of this study is to evaluate the relationship between the CYP450 enzyme family and cisplatin toxicity., Methods: This article examined a collection of studies suggesting that CYP450 enzymes may influence cisplatin toxicity. We performed a narrative mini-review., Results: The studies review showed that CYP450 enzymes have an important role in drug-induced hepatotoxicity and nephrotoxicity, mainly CYP2E1 and CYP4A11. The studies also suggested that the cisplatin and CYP2E1 interaction leads to the generation of reactive oxygen species (ROS) and other oxidants resulting in renal injury; and that ROS generated by both the use of cisplatin and by the CYP2E1 increases tissue damage, induces apoptosis, and causes liver failure., Conclusions: We observed that there is an important relationship between CYP450 and cisplatin, involving increased toxicity. However, the possible mechanisms described for the involvement of CYP450 enzymes in nephrotoxicity and hepatotoxicity induced by cisplatin need to be confirmed by further studies. Therefore, there is a need for a deeper investigation focusing on cisplatin toxicity mediated by CYP450 enzymes, which would undoubtedly contribute to a better understanding of the mechanisms that have been implicated so far.

Introduction  In the pregnancy-puerperal cycle, women may develop complications that require admission to the Intensive Care Unit (ICU). Thus, special attention to pharmacotherapy is necessary, particularly to potential drug interactions (PDIs) and to the effect of the drugs on the fetus and newborn. Objective  The aim of this study was to determine the profile of PDIs and the potential risk of drugs used during pregnancy and breastfeeding among patients admitted to the ICU. Methods  We conducted an observational, cross-sectional and prospective study, including pregnant and breastfeeding women admitted to the ICU at the Women's Hospital of a university in the city of Campinas, Brazil, for one year. Online databases were used to identify and classify the PDIs and the potential risk of the drugs used during pregnancy and breastfeeding. Results  We evaluated 305 prescriptions of 58 women, 31 pregnant and 27 breastfeeding, and 284 (91%) prescriptions presented PDIs. A total of 175 different combinations of PDIs were identified in the prescriptions, and adverse effects caused by the simultaneous use of drugs were not actually observed in the clinical practice. A total of 26 (1.4%) PDIs were classified as contraindicated. We identified 15 (13.8%) drugs prescribed with risk D, and 2 (1.8%) with risk X for pregnant women, as well as 4 (4.9%) drugs prescribed with high risk for breastfeeding women. Conclusions  This study demonstrates that there is a high incidence of PDIs in prescriptions. Most drugs used by pregnant and breastfeeding women at the ICU did not present serious risks to their fetus and newborns, but sometimes drugs with risk D or X are necessary in the course of the treatment., Competing Interests: Declaration of Conflicts of Interest: The authors declare no conflicts of interest with respect to the research, authorship, and/or publication of this article., (Thieme Revinter Publicações Ltda Rio de Janeiro, Brazil.)

Background: Cisplatin is a high-potency anticancer agent; however, it causes significant adverse drug reactions (ADRs). Potential pharmacokinetic markers must be studied to predict or prevent cisplatin-induced ADRs and achieve better prognosis. This study was designed to investigate the relationship between ADRs and kinetics of cisplatin excretion in the urine of patients undergoing high-dose cisplatin chemotherapy and radiotherapy for head and neck cancer., Methods: Outpatients with head and neck cancer received a first cycle of high-dose cisplatin chemotherapy (80-100 mg/m 2 ) concurrent to radiotherapy. ADRs (haematological, renal, and gastrointestinal reactions) were classified based on severity by National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, version 4, grade 0-4). The kinetics of cisplatin excretion in urine was evaluated by high-performance liquid chromatography over three time periods: 0-12, 12-24, and 24-48 h after the administration of cisplatin. Spearman Correlation test and regression analysis were performed to assess the relationship between ADRs and cisplatin excretion in the urine., Results: In total, 59 patients with a mean age of 55.6 ± 9.4 years were analysed; most patients were male (86.4%), white (79.7%), and with pharyngeal tumours in advanced stages (66.1%). The most frequently observed ADRs were anaemia (81.4%), lymphopenia (78%), and nausea (64.4%); mostly grades 1 and 2 of toxicity. The mean cisplatin excretion was 70.3 ± 64.4, 7.3 ± 6.3, and 5 ± 4 μg/mg creatinine at 0-12, 12-24, and 24-48 h, respectively. Statistical analysis showed that the amount of cisplatin excreted did not influence the severity of ADRs., Conclusions: The most frequent ADRs were anaemia, lymphopenia, and nausea. Grades 1 and 2 were the severities for most ADRs. The period over which the highest cisplatin excretion observed was 0-12 h after chemotherapy, and cisplatin excretion could not predict toxicity.

This study aimed to investigate the associations of XPC c.2815A>C, XPD c.934G>A and c.2251A>C, XPF c.2505T>C and ERCC1 c.354C>T single nucleotide polymorphisms (SNPs) of nucleotide excision repair pathway in outcome of head and neck squamous cell carcinoma (HNSCC) patients treated with cisplatin (CDDP) chemoradiation. Patients with XPC c.2815AC or CC and XPD c.934GA or AA genotypes had 0.20 and 0.38 less chances of presenting moderate/severe ototoxicity and nausea, respectively. Patients with XPD c.934AA and c.2251AC or CC genotypes had 8.64, 12.29 and 3.55 more chances of achieving complete response (CR), consistent ototoxicity and nephrotoxicity, respectively. AA haplotype of XPD and ACT haplotype of XPD and ERCC1 SNPs were associated with 9.30 and 3.41 more chances of achieving CR and consistent nephrotoxicity, respectively. At 24 months of follow-up, patients with XPD c.934AA genotype presented lower progression-free survival and overall survival in Kaplan-Meier estimates, and differences between groups remained the same in univariate Cox analysis. Patients with XPD c.934AA genotype had 2.13 and 2.04 more risks of presenting tumor progression and death than others in multivariate Cox analysis. Our data present preliminary evidence that XPC c.2815A>C, XPD c.934G>A and c.2251A>C, and ERCC1 c.354C>T SNPs alter outcome of HNSCC patients treated with CDDP chemoradiation.

Objective: This study aims to evaluate the frequency and severity of nausea and vomiting using two different instruments and relate them to quality of life (QOL) in patients with cancer receiving antineoplastic treatment., Methods: Severity of chemotherapy-induced nausea and vomiting (CINV) was measured by Common Terminology Criteria for Adverse Events (CTCAE) and a numerical scale. QOL was assessed using the Functional Assessment of Cancer Therapy-General questionnaire., Key Findings: Of the 50 patients studied, 60.0% reported nausea (40.0% CTCAE grade 1; 66.7% moderate intensity on numerical scale) and 30.0% reported vomiting (46.7% CTCAE grades 1 and 2, each; 66.7% moderate intensity on numerical scale). CINV did not influence overall QOL., Conclusion: The frequency of CINV was high. There was no association between nausea/vomiting and overall QOL., (© 2015 Royal Pharmaceutical Society.)

Objectives: The aim of this study was to evaluate the quality of life (QOL) of patients with squamous cell carcinoma of the head and neck before and during treatment with high-dose cisplatin and radiotherapy., Methods: This was an observational and longitudinal prospective study conducted from June 2011 to March 2013 at the clinical oncology ambulatory unit of a public teaching hospital in São Paulo, Brazil. The University of Washington Quality of Life Questionnaire was used to measure the QOL of patients before and after each chemotherapy cycle with high-dose cisplatin (80-100 mg/m(2), three cycles) and radiotherapy (2 Gy, 5 days/week for 7 weeks). Data were analyzed using Student t tests, and P < 0.05 was considered statistically significant., Results: Thirty-two patients completed the three cycles of treatment. The study population consisted primarily of white men with a mean age older than 50 years, who had a partner, a low education level, and who were heavy smokers and drinkers, Karnofsky Performance Status of 90% to 100%, pharynx tumors, and stage IV cancer, classified as T4 and N2 stages; the minority of them required interventions such as a feeding tube and tracheostomy. We observed a reduction in QOL after treatment initiation; this reduction was significant after the second chemotherapy cycle and the sixth week of radiotherapy. The abilities to taste, swallow, salivate, and participate in activities and recreation were affected significantly. We also observed a significant improvement in pain and anxiety resulting from the chemoradiation., Conclusions: Healthcare providers need to be aware of the affected domains to provide improved QOL, well-being, and security to cancer patients who are receiving this type of treatment.

Unlabelled: Cisplatin (CDDP) plus radiotherapy (RT) has been used to treat advanced laryngeal squamous cell carcinoma (LSCC) patients. Single nucleotide polymorphisms (SNPs) may be responsible for differences in chemo/radiosensitivity and side effects in those patients. We reported an advanced LSCC patient, who obtained durable complete response and unexpected pronounced toxicity during CDDP and RT, possibly due to SNPs in genes that modulate the effects of this therapeutic modality., Case Presentation: A 30-year-old man with advanced LSCC obtained durable complete response and severe alopecia and pancytopenia after standard and reduced doses of CDDP and RT. Analyses of SNPs revealed that the patient presented GSTT1 deletion, variant MSH3 1045ThrThr, wild GSTP1 105IleIle, and wild BAX -248GG genotypes, which were previously described in association with abnormal detoxification, DNA repair, and damaged cell apoptosis, respectively. Seven other advanced LSCC patients with GSTT1 gene, MSH3 AlaAla or AlaThr, GSTP1 IleVal or ValVal, and BAX GA or AA genotypes served as controls of the study. Only 1 control presented complete response; the other 6 controls obtained partial response of short duration. Four and 3 controls presented grade 1 or 2 and grade 3 anemia or leukopenia during treatment, respectively. The CDDP level in urine collected after CDDP infusion in the reported patient was lower than the median value obtained in controls, suggesting a higher amount of intracellular CDDP in the reported case.The data suggest, for the first time, that inherited abnormalities in intracellular detoxification of CDDP, DNA repair of lesions induced by CDDP and RT, and damaged cell apoptosis may alter treatment response and toxicity in LSCC, but should be confirmed by large pharmacogenomic studies.