Prophylactic treatment with vitamins C and B2 for methotrexate-induced gastrointestinal mucositis

Mucositis is a common side-effect of chemotherapy treatment, inducing alterations in the composition of the gut microbiota. Redox active compounds, such as vitamins B2 and C, have been shown to reduce inflammation and enhance the growth of anaerobic bacteria in the gut. We therefore aimed to (1) validate the ability of these compounds to promote bacterial cell growth in vitro, and (2) determine their prophylactic efficacy in a rat model of methotrexate (MTX)-induced mucositis. Bacterial growth curves were performed to assess the growth kinetics of bacteria exposed to Vitamins C and B2 (0.5 mM). Male wistar rats (150–200 g) received vitamins B2 (12 mg/day) and C (50 mg/day) via daily oral gavage (from day −1 to day 10). MTX (45 mg/Kg) was administrated via I.V. injection (N = 4–8/group) on day 0. Body weight, water/food consumption and diarrhea were assessed daily. Blood and faecal samples were collected longitudinally to assess citrulline levels (mucositis biomarker) and gut microbiota composition. Vitamins C/B2 enhanced the in vitro growth of anaerobic bacteria Blautia coccoides and Roseburia intestinalis. Contrarily to vitamin B2, in vivo administration of Vitamin C significantly attenuated clinical symptoms of mucositis. Despite their influence on the composition of the gut microbiota, both vitamins did not modulate the course of MTX-induced mucositis, as accessed by plasma citrulline. Vitamins B2 and C enhanced anaerobic bacterial growth in vitro, however their ability to mitigate MTX-induced mucositis was limited.Ana Rita da Silva Ferreira, Hannah R. Wardill, Rick Havinga, Wim J. E. Tissing and Hermie J. M. Harmse

Uso De Práticas Integrativas E Complementares Por Doulas Em Maternidades De Fortaleza (ce) E Campinas (sp)

This study aimed to analyze the Integrative and Complementary Practices (ICP) applied by doulas in the cities of Fortaleza (CE) and Campinas (SP). This is a qualitative study encompassing fifteen doulas: nine from Fortaleza and six from Campinas. The data were collected in the second half of 2010 by conducting semi-structured and pre-organized interviews following the procedures of thematic content analysis. The interpretations of the results were based on the idea that institutionalization of knowledge and practices happen through the conformation of nuclei and fields. The nucleus demarcates the identity of an area of knowledge and the professionals’ practices, and the field demarcates the blurred limits among disciplines that can be submitted to conflicts. We observed that the support offered by doulas permeates a variety of practices framed in traditional medicine as well as in complementary and alternative medicine. ICP was associated with decreases in length of labor, superior pain management, ability of making decision and empowering of women. It is understood that the range of activities offered by doulas and the use of ICP converge to the uniqueness, respect and autonomy of women. Furthermore, it proposes a new model of awareness and practices centered on the importance of the natural process of childbirth. © 2016, UNIV SAOPAULO. All rights reserved.25110812

Nutritional Evaluation Of Children With Chronic Cholestatic Disease

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)To evaluate the nutritional status of children with persistent cholestasis and to compare the anthropometric indices between children with and without liver cirrhosis and children with and without jaundice. Methods Children with persistent cholestasis, i.e. increased direct bilirrubin or changes in the canalicular enzyme gamma-glutamyl transferase (GGT), were included. The anthropometric measures were weight (W), height or length (H), arm circumference (AC), triceps skinfold thickness (TST), arm muscle circumference (AMC), and body mass index (BMI). Results Ninety-one children with cholestasis, with current median age of 12 months, were evaluated. W/age (A) and H/A indices below -2 Z-scores were observed in 33% and 30.8% of patients, respectively. Concerning the W/H index and BMI, only 12% and 16% of patients, respectively, were below -2 Z-scores. Regarding AC, 43.8% of 89 evaluated patients had some depletion. Observing the TST, 64% of patients had depletion, and 71.1% of the 45 evaluated patients had some degree of depletion regarding the ACM index. Conclusion Evaluation using weight in patients with chronic liver diseases may overestimate the nutritional status due to visceromegaly, subclinical edema, or ascites. Indices that correlate weight and height, such as W/H and BMI, may also not show depletion because of the chronic condition in which there are depletion of both weight and height. TST, AC, and ACM are parameters that better estimate nutritional status and should be part of the management of patients with liver diseases and cholestasis. © 2015 Sociedade Brasileira de Pediatria.922197205CNPq, Conselho Nacional de Desenvolvimento Científico e TecnológicoConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq

Does chemotherapy-induced gastrointestinal mucositis affect the bioavailability and efficacy of anti-infective drugs?

Antimicrobial prophylaxis is increasingly being used in patients with hematological malignancies receiving high-dose chemotherapy and hematopoietic stem cell transplantation (HSCT). However, few studies have focused on the potential impact of gastrointestinal mucositis (GI-M), a frequently observed side effect of chemotherapy in patients with cancer that affects the gastrointestinal microenvironment, on drug absorption. In this review, we discuss how chemotherapy leads to an overall loss of mucosal surface area and consequently to uncontrolled transport across the barrier. The barrier function is depending on intestinal luminal pH, intestinal motility, and diet. Another factor contributing to drug absorption is the gut microbiota, as it modulates the bioavailability of orally administrated drugs by altering the gastrointestinal properties. To better understand the complex interplay of factors in GI-M and drug absorption we suggest: (i) the longitudinal characterization of the impact of GI-M severity on drug exposure in patients, (ii) the development of tools to predict drug absorption, and (iii) strategies that allow the support of the gut microbiota. These studies will provide relevant data to better design strategies to reduce the severity and impact of GI-M in patients with cancer.Ana Rita da Silva Ferreira, Anne-Grete Märtson , Alyse de Boer, Hannah R. Wardill, Jan-Willem Alffenaar, Hermie J. M. Harmsen and Wim J. E. Tissin

Exposure of anti-infective drugs and the dynamic changes of the gut microbiota during gastrointestinal mucositis in autologous stem cell transplant patients: a pilot study

Published online: 17 January 2023Gastrointestinal mucositis could potentially compromise drug absorption due to functional loss of mucosa and other pathophysiological changes in the gastrointestinal microenvironment. Little is known about this effect on commonly used anti-infectives. This study aimed to explore the association between different stages of gastrointestinal mucositis, drug exposure, and gut microbiota. A prospective, observational pilot study was performed in HSCT patients aged ≥ 18 years receiving anti-infectives orally. Left-over blood samples and fecal swabs were collected from routine clinical care until 14 days after HSCT to analyze drug and citrulline concentrations and to determine the composition of the gut microbiota. 21 patients with a median age of 58 (interquartile range 54-64) years were included with 252 citrulline, 155 ciprofloxacin, 139 fluconazole, and 76 acyclovir concentrations and 48 fecal swabs obtained. Severe gastrointestinal mucositis was observed in all patients. Due to limited data correlation analysis was not done for valacyclovir and fluconazole, however we did observe a weak correlation between ciprofloxacin and citrulline concentrations. This could suggest that underexposure of ciprofloxacin can occur during severe mucositis. A follow-up study using frequent sampling rather than the use of left-over would be required to investigate the relationship between gastrointestinal mucositis, drug exposure, and gut microbiome.Anne-Grete Märtson, Ana Rita da Silva Ferreira, Anette Veringa, Lei Liu, Hannah R. Wardill, Lenneke A. T. Junier, Tjip S. van der Werf, Hermie J. M. Harmsen, Marieke G. G. Sturkenboom, Lambert F. Span, Wim J. E. Tissing, Jan-Willem C. Alffenaa

Whey-based diet containing medium chain triglycerides modulates the gut microbiota and protects the intestinal mucosa from chemotherapy while maintaining therapy efficacy.

Cytotoxicity (i.e. cell death) is the core mechanism by which chemotherapy induces its anti-cancer effects. Unfortunately, this same mechanism underpins the collateral damage it causes to healthy tissues. The gastrointestinal tract is highly susceptible to chemotherapy’s cytotoxicity, resulting in ulcerative lesions (termed gastrointestinal mucositis, GI-M) that impair the functional capacity of the gut leading to diarrhea, anorexia, malnutrition and weight loss, which negatively impact physical/psychological wellbeing and treatment adherence. Preventing these side effects has proven challenging given the overlapping mechanisms that dictate chemotherapy efficacy and toxicity. Here, we report on a novel dietary intervention that, due to its localized gastrointestinal effects, is able to protect the intestinal mucosal from unwanted toxicity without impairing the anti-tumor effects of chemotherapy. The test diet (containing extensively hydrolyzed whey protein and medium chain triglycerides (MCTs)), was investigated in both tumor-naïve and tumor-bearing models to evaluate its effect on GI-M and chemo-efficacy, respectively. In both models, methotrexate was used as the representative chemotherapeutic agent and the diet was provided ad libitum for 14 days prior to treatment. GI-M was measured using the validated biomarker plasma citrulline, and chemo-efficacy defined by tumor burden (cm3 /g body weight). The test diet significantly attenuated GI-M (P = 0.03), with associated reductions in diarrhea (P < 0.0001), weight loss (P < 0.05), daily activity (P < 0.02) and maintenance of body composition (P < 0.02). Moreover, the test diet showed significant impact on gut microbiota by increasing diversity and resilience, whilst also altering microbial composition and function (indicated by cecal short and brained chain fatty acids). The test diet did not impair the efficacy of methotrexate against mammary adenocarcinoma (tumor) cells. In line with the first model, the test diet minimized intestinal injury (P = 0.001) and diarrhea (P < 0.0001). These data support translational initiatives to determine the clinical feasibility, utility and efficacy of this diet to improve chemotherapy treatment outcomes.Hannah R. Wardill, Ana Rita Da Silva Ferreira, Himanshu Kumar, Emma H. Bateman, Courtney B. Cross, Joanne M. Bowen, Rick Havinga, Hermie J. M. Harmsen, Jan Knol, Bram Dorresteijn, Miriam van Dijk, Jeroen van Bergenhenegouwen, and Wim J. E. Tissin

Star Models with Dark Energy

We have constructed star models consisting of four parts: (i) a homogeneous inner core with anisotropic pressure (ii) an infinitesimal thin shell separating the core and the envelope; (iii) an envelope of inhomogeneous density and isotropic pressure; (iv) an infinitesimal thin shell matching the envelope boundary and the exterior Schwarzschild spacetime. We have analyzed all the energy conditions for the core, envelope and the two thin shells. We have found that, in order to have static solutions, at least one of the regions must be constituted by dark energy. The results show that there is no physical reason to have a superior limit for the mass of these objects but for the ratio of mass and radius.Comment: 20 pages, 1 figure, references and some comments added, typos corrected, in press GR

Rational use of medicines: prescribing indicators at different levels of health care

Este estudo multicêntrico teve como objetivo investigar o padrão de prescrição de medicamentos para pacientes ambulatoriais atendidos em serviços de saúde vinculados a universidades com diferentes níveis de atenção, em oito cidades do sul e centro-oeste do Brasil. As prescrições coletadas foram submetidas à análise de diversos itens, incluindo os indicadores de prescrição propostos pela OMS. No total, 2.411 prescrições foram analisadas e 469 medicamentos foram identificados. O número de medicamentos prescritos por consulta, a frequência de polifarmácia e a porcentagem de consultas com pelo menos um medicamento injetável ou um antimicrobiano prescrito foram maiores em centros de saúde que ofereciam cuidados de atenção básica, em comparação com aqueles que não dispunham desse tipo de atendimento. A maioria dos medicamentos foi prescrita pelo nome genérico (86,1%). Em unidades com cuidados de atenção básica, a acessibilidade foi maior, a prescrição de medicamentos presentes nas Listas Nacional e Municipais de Medicamentos Essenciais foi mais frequente e instruções foram fornecidas aos pacientes mais comumente. Entretanto, advertências e medidas não farmacológicas foram indicadas com menor frequência. Este estudo revela tendências de prescrição de medicamentos em serviços de saúde ligados a universidades, com diferentes níveis de atenção, e indica possíveis áreas de melhoria na prática da prescrição.This multicenter study aimed to investigate prescribing patterns of drugs at different levels of health care delivery in university-affiliated outpatient clinics located in eight cities in the South and Midwest of Brazil. All prescriptions collected were analyzed for various items, including WHO prescribing indicators. A total of 2,411 prescriptions were analyzed, and 469 drugs were identified. The number of drugs prescribed per encounter, the frequency of polypharmacy, and the percentage of encounters with at least one injection or antibiotic prescribed were higher in centers providing primary health care services, compared to those where this type of care is not provided. Most drugs (86.1%) were prescribed by generic name. In centers with primary health care services, drug availability was higher, drugs included in the National and Municipal Lists of Essential Medicines were more frequently prescribed, and patients were given more instructions. However, warnings and non-pharmacological measures were less frequently recommended. This study reveals trends in drug prescribing at different levels of health care delivery in university-affiliated outpatient clinics and indicates possible areas for improvement in prescribing practices