Abstract Genetic variability in the host metabolism of antimalarial drugs influenced by the polymorphisms of cytochrome P450 (CYP) could lead to significant changes in antimalarial treatment response. However, little is known about the frequency of alleles CYP2B6, CYP2C8, and CYP2D6 in an Amazonian population, especially with vivax malaria. Therefore, this study aimed to determine the frequency of CYP alleles CYP2B6*6, CYP2C8*3, and CYP2D6*4 in patients with vivax malaria. The study included 231 patients with vivax malaria treated at a health care reference in Manaus, northern Brazil. A sample of peripheral blood from each subject was collected to perform DNA extraction and genotypic analysis. Genotyping of polymorphisms was performed by allelic discrimination using Real-time polymerase chain reaction. The CYP2D6*4 allele was the most prevalent among patients who developed severe malaria. The frequencies of the CYP2B6*6 and CYP2D6*4 were not different between the severe and uncomplicated malaria. There was a significant association between heterozygous CYP2D6*4 and severe cases of malaria. The results are in agreement with other reports described in the literature for different populations. Future studies are needed to understand the clinical implications of the polymorphisms in patients with vivax malaria.

CNFD (6b,7-dihydro-5H-cyclopenta[b]naphtho[2,1-d]furan-5,6(9aH)-dione) is a semisynthetic naphthoquinone derived from lawsone that has cytotoxic action in different tumor lines and anticancer activity in vivo. Therefore, this molecule is a relevant candidate for drug development, but there is still no information on its human metabolism and systemic elimination. This study aimed to investigate the in vitro metabolism of this naphthoquinone by human liver microsomes. Initially, in order to determine the in vitro enzymatic kinetic parameters, a high performance liquid chromatography (HPLC) method to quantify the CNFD was developed and validated. In addition, the enzymatic kinetic data, the predicted pharmacokinetic in vivo parameters and the phenotyping study were presented. The main metabolism sites and metabolites have been suggested in silico. The developed HPLC method was linear, reproducible, selective, accurate, and stable. The enzymatic kinetic parameters revealed a sigmoidal profile. In vitro to in vivo extrapolation hepatic metabolic clearance was 10.39 mL min-1 kg-1 protein and the liver extraction rate was 51%. The clearance in vivo associated with a hepatic extraction ratio indicates that the hepatic metabolism is the main route of elimination. Although all cytochrome P450 enzymes evaluated metabolized CNFD, CYP2C9 and CYP3A4 showed higher metabolic capacity. For the first time, metabolism studies of CNFD were demonstrated.

RESUMO Muitos alimentos interagem com medicamentos e podem causar alterações nos efeitos farmacológicos do agente terapêutico coadministrado. A enzima CYP3A4, que pertence ao complexo enzimático do citocromo P450, é responsável pelo metabolismo da maioria dos medicamentos atualmente no mercado e está envolvida em muitas interações medicamentosas. Assim, a interação dessa enzima com sucos de algumas frutas, como a toranja, pode afetar a farmacocinética de vários medicamentos. No entanto, frutas nativas da região amazônica ainda não foram alvo desse tipo de pesquisa. Determinamos polifenóis e flavonoides totais dos frutos amazônicos de açaí (Euterpe precatoria), buriti (Mauritia flexuosa), camu-camu (Myrciaria dubia), cubiu (Solanum sessiliflorum), cupuaçu (Theobroma grandiflorum), jenipapo (Genipa americana) e taperebá (Spondias mombin) e avaliamos os efeitos de cada suco de fruta sobre a atividade de CYP3A4, utilizando o suco de carambola (Averrhoa carambola) como controle positivo. O suco de açaí apresentou o maior teor de polifenóis totais e flavonóides (102,6 ± 7,2 µg equivalente de ácido gálico (GAE) por mL e 7,2 ± 0,6 µg equivalente de quercetina (QE) por mL, respectivamente). Todos os sucos foram capazes de inibir a atividade de CYP3A4. Não houve atividade residual da enzima metabolizadora de fármacos para os sucos de açaí, buriti, cubiu, camu-camu e taperebá, enquanto para cupuaçu, jenipapo e o controle positivo, a atividade residual foi de 44,3, 54,3 e 20,2%, respectivamente. Estudos adicionais devem identificar o(s) fitocomposto(s) responsável(is) por esta atividade de inibição, para esclarecer os mecanismos envolvidos neste fenômeno.

ABSTRACT Many foods interact with drugs and may cause changes in the pharmacological effects of the co-administered therapeutic agent. The enzyme CYP3A4, which belongs to the cytochrome P450 enzyme complex, is responsible for the metabolism of most drugs currently on the market and is involved in many drug interactions. Hence, the interaction of this enzyme with juices of some fruits, such as grapefruit, can affect the pharmacokinetics of various drugs. However, native fruits from the Amazon region have not yet been the target of this type of research. We determined total polyphenols and flavonoids of the Amazonian fruits açaí (Euterpe precatoria), buriti (Mauritia flexuosa), camu-camu (Myrciaria dubia), cubiu (Solanum sessiliflorum), cupuaçu (Theobroma grandiflorum), jenipapo (Genipa americana), and taperebá (Spondias mombin) and evaluated the effects of each fruit juice on CYP3A4 activity, using the star fruit (Averrhoa carambola) juice as positive control. Açaí juice presented the highest content of total polyphenols and flavonoids (102.6 ± 7.2 µg gallic acid equivalent (GAE) per mL and 7.2 ± 0.6 µg quercetin equivalent (QE) per mL, respectively). All juices were able to inhibit the activity of CYP3A4. There was no residual activity of the drug-metabolizing enzyme for açai, buriti, cubiu, camu-camu, and taperebá juice, while for cupuaçu, jenipapo and the positive control, the residual activity was 44.3, 54.3 and 20.2%, respectively. Additional studies should identify the phytocompound(s) responsible for this inhibition activity, to clarify the mechanisms involved in this phenomenon.

BACKGROUND The multidrug resistance (MDR) phenotype is frequently observed in Acinetobacter baumannii, the most clinically relevant pathogenic species of its genus; recently, other species belonging to the A. calcoaceticus-A. baumannii complex have emerged as important MDR nosocomial pathogens. OBJECTIVES The present study aimed to verify the occurrence of metallo-β-lactamase genes among distinct Acinetobacter species in a hospital located in the Brazilian Amazon Region. METHODS Antimicrobial susceptibility profiles were determined by broth microdilution. The genetic relationships among these isolates were assessed by pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). Pyrosequencing reads of plasmids carrying the bla NDM-1 gene were generated using the Ion Torrent™ platform sequencing. FINDINGS A total of six isolates carried bla NDM-1: A. baumannii (n = 2), A. nosocomialis (n = 3), and A. pittii (n = 1); three carried bla IMP-1: A. baumannii, A. nosocomialis, and A. bereziniae. Resistance to colistin was observed for an NDM-1-producing A. nosocomialis isolate. Diverse PFGE patterns and sequence types were found among A. nosocomialis and A. baumannii isolates. The bla NDM-1 sequence was inserted in a Tn125 transposon, while the bla IMP-1 was found as a gene cassette of the class 1 integron In86. MAIN CONCLUSIONS To the best of our knowledge, this is the first report describing the dissemination of bla NDM-1 among distinct Acinetobacter species recovered from the same hospital in South America.

ABSTRACT Objectives The aim of this study was to investigate the effects of continuous (48-hour) use of Kinesiotaping (KT) on functional and proprioceptive performance in healthy, physically active men. Method Twenty-six healthy, physically active men (21.8±2.2 years old) were randomly allocated into two groups: 1) Kinesiotaping group (KG, tape applied with 40% tension for rectus femoris activation); 2) Control (CG, tape applied over rectus femoris without additional tension). Subjects attended the laboratory on five separate occasions: 1) familiarization; 2) baseline measurement without tape (BL); 3) immediately post-tape application (T0); 4) 24h (T24); and 5) 48h (T48) post-tape application. The outcomes were distance in the single (SHT) and triple hop tests (THT), vertical jump height (VJH), vertical jump power (VJP), and rate of force development (RFD). A mixed-model ANOVA was applied to verify differences between and within groups. Results No significant (p >0.05) differences were found in the SHT and THT between groups and moments. Likewise, the main effects for VJH, VJP, and RFD were not significant (p >0.05). Conclusion The present study demonstrated no significant immediate or prolonged (48h) effects of KT on functional and proprioceptive performance.

Aim: To describe the off-label and unlicensed utilization patterns of drugs in a Brazilian pediatric hospital. Methods: The research consisted of a descriptive, prospective and cross-sectional study. Results: A total of 1,158 medicines were prescribed for 320 patients, accounting for 65 different drugs. Regarding the classification of drug utilization, the majority of the drugs were prescribed as in-label (57.2%), followed by off-label (36.4%) and by unlicensed (6.3%). The prevalences of unlicensed and off-label utilization of drugs in the studied population were 20.9 and 77.8%, respectively. Polypharmacy was highly associated to both off-label and unlicensed regimen (OR 12.9; 95% CI 3.07-54.2 and OR 3.68; 95% CI 2.02-6.69, respectively) whereas preschool children were less prone to unlicensed prescription (OR 0.39; 95% CI 0.19-0.79). Sex and length of hospitalization were not related to these outcomes. Conclusions: Further studies are necessary to verify the impact of this pattern on the occurrence of adverse drug events.

Objetivo: Describir los patrones de utilización de medicamentos off-label y sin licencia en un hospital pediátrico de Brasil. Métodos: La investigación consistió en un estudio descriptivo, prospectivo y de corte transversal. Resultados: Un total de 1.158 medicamentos fueron prescritos para 320 pacientes, que representan 65 fármacos diferentes. En cuanto a la clasificación de la utilización de medicamentos, la mayoría de los medicamentos fueron prescritos como en la ficha técnica (57,2%), seguido off-label (36,4%) y por sin licencia (6,3%). Las prevalencias de uso sin licencia y off-label de drogas en la población estudiada fueron 20,9 y 77,8%, respectivamente. La polifarmacia fue muy asociada a ambos off-label y el régimen sin licencia (OR 12,9; IC del 95%: 3,07 a 54,2 y OR 3,68; IC del 95%: 2,02 a 6,69, respectivamente), mientras que los niños en edad preescolar fueron menos propensos a prescripción sin licencia (OR 0,39; 95% CI 0,19-,79). El sexo y la duración de la hospitalización no estaban relacionadas con estos resultados. Conclusiones: Son necesarios más estudios para verificar el impacto de este patrón en la ocurrencia de eventos adversos en los medicamentos.

The analysis of drugs and metabolites in biological fluids usually requires extraction procedures to achieve sample clean-up and analyte preconcentration. Commonly, extraction procedures are performed using liquid-liquid extraction or solid-phase extraction. Nevertheless, these extraction techniques are considered to be time-consuming and require a large amount of organic solvents. On this basis, microextraction techniques have been developed. Among them, liquid-phase microextraction has been standing out. This review describes the liquid-phase microextraction technique based on hollow fibers as a novel and promising alternative in sample preparation prior to chromatographic or electrophoretic analysis. The basic concepts related to this technique and its applicability in extraction of drugs are discussed.

Foi realizado um levantamento sobre uso de psicotrópicos entre estudantes da Faculdade de Ciências da Saúde da Universidade Federal do Amazonas, Manaus, Brasil, em uma amostra de 521 alunos. O "uso na vida" de álcool foi relatado por 87,7% dos estudantes (IC95%: 85,34-90,06) e o de tabaco por 30,7% (IC 95%: 27,39-34,01), sendo o último maior entre estudantes do sexo masculino (39,7%; IC95%: 33,33-46,01). As substâncias ilegais mais usadas foram: solventes (11,9%; IC95%: 9,57-14,23), maconha (9,4%; IC95%: 7,30-11,50), anfetamínicos e ansiolíticos (ambos com 9,2%; IC95%: 7,12-11,28), cocaína (2,1%; IC95%: 1,07- 3,13) e alucinógenos (1,2%; IC95%: 0,42-1,98). O principal motivo relatado para o uso de drogas ilegais foi a curiosidade. O "uso na vida" de esteróides anabolizantes foi citado por 2,1% dos estudantes. O uso abusivo de álcool nos últimos 30 dias foi relatado por 12,4% dos universitários. Entre os eventos ocorridos após a ingestão de bebidas alcoólicas, os estudantes citaram envolvimento em briga (4,7%), acidentes (2,4%), faltaà escola (33,7%), falta ao trabalho (11,8%) e condução de veículos (47,3%). A opinião sobre as drogas e o padrão de uso dos estudantes não diferem muito dos estudos semelhantes em outras regiões do Brasil.

A survey was conducted with 521 undergraduate health sciences students from the Federal University in Amazonas, Manaus, Brazil. Lifetime alcohol consumption was reported by 87.7% students, as compared to 30.7% for tobacco, with the latter reported more frequently by males (39.7%). The most common illicit drugs were solvents (11.9%), marijuana (9.4%), amphetamines and anxiolytics (9.2% each), cocaine (2.1%), and hallucinogens (1.2%). The main reason for illicit drug use was curiosity. Lifetime use of anabolic steroids was reported by 2.1% of the students. Alcohol abuse in the previous 30 days was reported by 12.4% of the students. Events following drinking included: fights (4.7%), accidents (2.4%), classroom absenteeism (33.7%), and job absenteeism (11.8%). Another important finding was that 47.3% of students drove after drinking. Opinions on drug abuse and patterns agree with those from similar studies in other regions of Brazil.

Foi realizado um levantamento sobre uso de psicotrópicos entre estudantes da Faculdade de Ciências da Saúde da Universidade Federal do Amazonas, Manaus, Brasil, em uma amostra de 521 alunos. O "uso na vida" de álcool foi relatado por 87,7% dos estudantes (IC95%: 85,34-90,06) e o de tabaco por 30,7% (IC 95%: 27,39-34,01), sendo o último maior entre estudantes do sexo masculino (39,7%; IC95%: 33,33-46,01). As substâncias ilegais mais usadas foram: solventes (11,9%; IC95%: 9,57-14,23), maconha (9,4%; IC95%: 7,30-11,50), anfetamínicos e ansiolíticos (ambos com 9,2%; IC95%: 7,12-11,28), cocaína (2,1%; IC95%: 1,07- 3,13) e alucinógenos (1,2%; IC95%: 0,42-1,98). O principal motivo relatado para o uso de drogas ilegais foi a curiosidade. O "uso na vida" de esteróides anabolizantes foi citado por 2,1% dos estudantes. O uso abusivo de álcool nos últimos 30 dias foi relatado por 12,4% dos universitários. Entre os eventos ocorridos após a ingestão de bebidas alcoólicas, os estudantes citaram envolvimento em briga (4,7%), acidentes (2,4%), faltaà escola (33,7%), falta ao trabalho (11,8%) e condução de veículos (47,3%). A opinião sobre as drogas e o padrão de uso dos estudantes não diferem muito dos estudos semelhantes em outras regiões do Brasil.

A survey was conducted with 521 undergraduate health sciences students from the Federal University in Amazonas, Manaus, Brazil. Lifetime alcohol consumption was reported by 87.7% students, as compared to 30.7% for tobacco, with the latter reported more frequently by males (39.7%). The most common illicit drugs were solvents (11.9%), marijuana (9.4%), amphetamines and anxiolytics (9.2% each), cocaine (2.1%), and hallucinogens (1.2%). The main reason for illicit drug use was curiosity. Lifetime use of anabolic steroids was reported by 2.1% of the students. Alcohol abuse in the previous 30 days was reported by 12.4% of the students. Events following drinking included: fights (4.7%), accidents (2.4%), classroom absenteeism (33.7%), and job absenteeism (11.8%). Another important finding was that 47.3% of students drove after drinking. Opinions on drug abuse and patterns agree with those from similar studies in other regions of Brazil.