Aromatic photosubstitution reactions

Abstract-In this paper attention is given primarily to substitution reactions of photoexcited aromatic compounds with (non-excited) nucleophiles. At the end a brief discussion is presented on the less-well known, but no less interesting photoinduced electrophilic substitution reactions, followed by a schematic representation of the various possible ways of heterolytic reaction of an electronically excited aromatic molecule. Nucleophilic aromatic photosubstitution nowadays comprises a great number and variety of reactions. Without ignoring traditional photochemical characteristics (singlet vs triplet reaction, ir -irK or pj * excitation etc.) the authors offer a systematization based mainly on the nature and influence of substituents (electron attracting or donating) in the aromatic system and on kinetic features. For certain types of aromatic photosubstitution the results obtained by chemical and spectroscopic investigations permit speculation on their mechanism. The variety and subtlety of the photoinduced aromatic substitutions seem to be no less than that of their thermal counterparts notwithstanding the fact that these reactions generally proceed extremely fast (not far from encounter controlled). As in the field of concerted processes, in heterolytic aromatic substitutions the thermal and the photochemical reactions mutually complement each other in a theoretically intriguing and practically useful way

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

Effect of minimal enteral feeding on recovery in a methotrexate-induced gastrointestinal mucositis rat model

Patients suffering from gastrointestinal mucositis often receive parenteral nutrition as nutritional support. However, the absence of enteral nutrition might not be beneficial for the intestine. We aimed to determine the feasibility of minimal enteral feeding (MEF) administration in a methotrexate (MTX)-induced mucositis rat model and thereby determine the effect of MEF on recovery. Male Wistar rats were attached to swivel systems from day 1 to 5 after 45 mg/kg MTX IV injection. The MTX group continued ad libitum feeding, and the MTX + MEF group continued ad libitum feeding and received from day 1 to 5 continuously MEF. MEF consisted of 20 % of their normal caloric intake. We measured body weight, intake, and plasma citrulline. At day 10, the rats were terminated and villus and crypt length were measured. The administration of MEF caused no increased severity of mucositis phenotype, with comparable caloric intake, body weight, and plasma citrulline during mucositis. The recovery of plasma citrulline levels was not different between both groups. At day 7 and 8, the MTX + MEF group gained significantly more weight (p <0.05 and p <0.01, respectively), and at day 8 and 9 the total caloric intake was significantly increased (p <0.01 and p <0.05, respectively) compared to the MTX group. At day 10, the rats from the MTX + MEF group showed a significant increase in jejunal villus length compared to the MTX group (p <0.05). This is the first study in which the feasibility of MEF administration during chemotherapy-induced mucositis was determined. This study indicates that MEF administration is feasible during mucositis and suggests that MEF accelerates recovery after MTX-induced mucositis

Antibiotic-induced disruption of the microbiome exacerbates chemotherapy-induced diarrhoea and can be mitigated with autologous faecal microbiota transplantation

BACKGROUND: Chemotherapy is well documented to disrupt the gut microbiome, leading to poor treatment outcomes and a heightened risk of adverse toxicity. Although strong associations exist between its composition and gastrointestinal toxicity, its causal contribution remains unclear. Our inability to move beyond association has limited the development and implementation of microbial-based therapeutics in chemotherapy adjuncts with no clear rationale of how and when to deliver them. METHODS/RESULTS: Here, we investigate the impact of augmenting the gut microbiome on gastrointestinal toxicity caused by the chemotherapeutic agent, methotrexate (MTX). Faecal microbiome transplantation (FMT) delivered after MTX had no appreciable impact on gastrointestinal toxicity. In contrast, disruption of the microbiome with antibiotics administered before chemotherapy exacerbated gastrointestinal toxicity, impairing mucosal recovery (P < 0.0001) whilst increasing diarrhoea severity (P = 0.0007) and treatment-related mortality (P = 0.0045). Importantly, these detrimental effects were reversed when the microbiome was restored using autologous FMT (P = 0.03), a phenomenon dictated by the uptake and subsequent expansion of Muribaculaceae. CONCLUSIONS: These are the first data to show that clinically impactful symptoms of gastrointestinal toxicity are dictated by the microbiome and provide a clear rationale for how and when to target the microbiome to mitigate the acute and chronic complications caused by disruption of the gastrointestinal microenvironment. Translation of this new knowledge should focus on stabilising and strengthening the gut microbiome before chemotherapy and developing new microbial approaches to accelerate recovery of the mucosa. By controlling the depth and duration of mucosal injury, secondary consequences of gastrointestinal toxicity may be avoided.Hannah R.Wardill, Stijn A.R.van der Aa, Ana R.da Silva Ferreira, Rick Havinga, Wim J.E.Tissing, Hermie J.M.Harmse