Phenolic and flavonoid content and in vitro inhibitory effect of some Amazonian fruit juices on CYP3A4 activity / Conteúdo fenólico e flavonoídico e efeito inibitório in vitro de alguns sucos de frutas da Amazônia sobre a atividade de CYP3A4

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.(AU)

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.(AU)

[Adverse effects of lopinavir/ritonavir in critically ill patients with COVID-19]. / Efectos adversos de lopinavir/ritonavir en enfermedad grave por coronavirus (COVID-19).

During the SARSCoV-2 pandemic many drugs have been used as potential treatments in order to improve the clinical outcome and reduce the mortality. But since it is a currently unknown disease, the evidence about efficacy and safety is built as the drugs are prescribed. In this context, intensive pharmacovigilance allows early detection of adverse events, and thereby infer the safety profile of the indication. We conducted an observational, retrospective, single-center study involving adult patients with severe SARS-CoV-2 infection. All adverse events detected in 23 patients in the Intensive Care Unit between March 15 and June 15, 2020 were registered. We describe type and severity of the adverse events and if treatment suspension was needed. The results show a high rate of adverse events (10/23, 43%) in treatment with lopinavir/ritonavir. In most cases early treatment suspension was required. Even though the limitations of our study derived from the small sample size, these results could help in building evidence about the safety of using lopinavir/ritonavir for severe SARS-CoV-2 infection.

Durante el transcurso de la pandemia causada por el virus SARS-CoV-2 se han utilizado diferentes fármacos como potenciales tratamientos específicos con el objetivo de lograr mejoría clínica y/o disminuir la mortalidad de los afectados, pero al tratarse de una enfermedad hasta ahora desconocida, la evidencia acerca de su seguridad y eficacia se va construyendo a medida que se los prescribe. La farmacovigilancia intensiva en este contexto permite detectar eventos adversos y mediante su reporte y análisis inferir el perfil de seguridad en cada indicación. Se realizó un estudio observacional, retrospectivo, en un único centro, en el cual se relevaron los eventos adversos en 23 pacientes adultos en estado crítico, de los cuales 18 recibieron lopinavir/ritonavir como tratamiento empírico, entre el 15 de marzo y el 15 de junio de 2020, durante su internación en una Unidad de Cuidados Intensivos. Se describe el tipo de eventos adversos, su gravedad y si fueron motivo de suspensión del tratamiento. Los resultados del presente análisis muestran una alta tasa de eventos adversos (10/23, 43%) entre los que recibieron lopinavir/ritonavir, llevando en la mayoría de los casos a la decisión de suspender el mismo antes de completar el tratamiento. Aun con las limitaciones propias del reducido número de casos, la divulgación de dichos resultados aporta evidencia para definir el perfil de seguridad de la combinación lopinavir/ritonavir usado en enfermedad grave por SARS-CoV-2.

Efectos adversos de lopinavir/ritonavir en enfermedad grave por coronavirus (COVID-19) / Adverse effects of lopinavir/ritonavir in critically ill patients with COVID-19

Resumen Durante el transcurso de la pandemia causada por el virus SARS-CoV-2 se han utilizado diferentes fármacos como potenciales tratamientos específicos con el objetivo de lograr mejoría clínica y/o disminuir la mortalidad de los afectados, pero al tratarse de una enfermedad hasta ahora desconocida, la evidencia acerca de su seguridad y eficacia se va construyendo a medida que se los prescribe. La farmacovigilancia intensiva en este contexto permite detectar eventos adversos y mediante su reporte y análisis inferir el perfil de seguridad en cada indicación. Se realizó un estudio observacional, retrospectivo, en un único centro, en el cual se relevaron los eventos adversos en 23 pacientes adultos en estado crítico, de los cuales 18 recibieron lopinavir/ ritonavir como tratamiento empírico, entre el 15 de marzo y el 15 de junio de 2020, durante su internación en una Unidad de Cuidados Intensivos. Se describe el tipo de eventos adversos, su gravedad y si fueron motivo de suspensión del tratamiento. Los resultados del presente análisis muestran una alta tasa de eventos adversos (10/23, 43%) entre los que recibieron lopinavir/ritonavir, llevando en la mayoría de los casos a la decisión de suspender el mismo antes de completar el tratamiento. Aun con las limitaciones propias del reducido número de casos, la divulgación de dichos resultados aporta evidencia para definir el perfil de seguridad de la combinación lopinavir / ritonavir usado en enfermedad grave por SARS-CoV-2.

Abstract During the SARS-CoV-2 pandemic many drugs have been used as potential treatments in order to improve the clinical outcome and reduce the mortality. But since it is a currently unknown disease, the evidence about efficacy and safety is built as the drugs are prescribed. In this context, intensive pharmacovigilance allows early detection of adverse events, and thereby infer the safety profile of the indication. We conducted an observational, retrospective, single-center study involving adult patients with severe SARS-CoV-2 infection. All adverse events detected in 23 patients in the Intensive Care Unit between March 15 and June 15, 2020 were registered. We describe type and severity of the adverse events and if treatment suspension was needed. The results show a high rate of adverse events (10/23, 43%) in treatment with lopinavir/ritonavir. In most cases early treatment suspension was required. Even though the limitations of our study derived from the small sample size, these results could help in building evidence about the safety of using lopinavir/ritonavir for severe SARS-CoV-2 infection.

Clinical Weighting of Drug-Drug Interactions in Hospitalized Elderly.

Adverse drug reactions impact on patient health, effectiveness of pharmacological therapy and increased health care costs. This investigation intended to detect the most critical drug-drug interactions in hospitalized elderly patients, weighting clinical risk. We conducted a cross-sectional study between January and April 2014; all patients 70 years or older, hospitalized for >24 hr and prescribed at least one medication were included in the study. Drug-drug interactions were estimated by combining Stockley's, Hansten and Tatro drug interactions. Drug-drug interactions were weighted using a risk-analysis method based on failure modes, effects and criticality analysis. We calculated a criticality index for each drug involved in the drug-drug interactions based on the severity of the interaction mechanism, the frequency the drug was involved in drug-drug interactions and the risk of drug-drug interactions in patients with impaired renal function. The average number of drugs consumed in the hospital was 6 ± 2.69, involving 160 active ingredients. The most frequent were as follows: Furosemide, followed by Enalapril. Of drug-drug interactions, 2% were classified as contraindicated, 14% advised against and 83% advised caution during the hospital stay. Thirty-four drug-drug interactions were assessed, of which 23 were pharmacodynamic drug-drug interactions and 12 were pharmacokinetic drug-drug interactions (1 was both). The clinical risk calculated for each drug-drug interaction included heparins + non-steroidal anti-inflammatory drugs (NSAIDs) or Digoxin + Calcium Gluconate, cases which are pharmacodynamic drug-drug interactions with agonist effect and clinical risk of bleeding, one of the most common clinical risks in the hospital. An index of clinical risk for drug-drug interactions can be calculated based on severity by the interaction mechanism, the frequency that the drug is involved in drug-drug interactions and the risk of drug-drug interactions in an elderly patient with impaired renal function.