Chemistry of Fluorinated Pyrimidines in the Era of Personalized Medicine.

We review developments in fluorine chemistry contributing to the more precise use of fluorinated pyrimidines (FPs) to treat cancer. 5-Fluorouracil (5-FU) is the most widely used FP and is used to treat > 2 million cancer patients each year. We review methods for 5-FU synthesis, including the incorporation of radioactive and stable isotopes to study 5-FU metabolism and biodistribution. We also review methods for preparing RNA and DNA substituted with FPs for biophysical and mechanistic studies. New insights into how FPs perturb nucleic acid structure and dynamics has resulted from both computational and experimental studies, and we summarize recent results. Beyond the well-established role for inhibiting thymidylate synthase (TS) by the 5-FU metabolite 5-fluoro-2'-deoxyuridine-5'-O-monophosphate (FdUMP), recent studies have implicated new roles for RNA modifying enzymes that are inhibited by 5-FU substitution including tRNA methyltransferase 2 homolog A (TRMT2A) and pseudouridylate synthase in 5-FU cytotoxicity. Furthermore, enzymes not previously implicated in FP activity, including DNA topoisomerase 1 (Top1), were established as mediating FP anti-tumor activity. We review recent literature summarizing the mechanisms by which 5-FU inhibits RNA- and DNA-modifying enzymes and describe the use of polymeric FPs that may enable the more precise use of FPs for cancer treatment in the era of personalized medicine.

Corrosive attacks in the UK - Psychosocial perspectives and decontamination strategies.

Acid attacks, or vitriolage, are defined as violent assaults involving the deliberate throwing of an acid or similarly corrosive substance with the intention to "maim, disfigure, torture or kill" [1]. The Acid Survivors Trust International suggest a prevalence of 1500 attacks reported worldwide per annum, although this is likely to be an underestimate by 40% [2]. The UK is thought to have one of the highest of rates of recorded corrosive attacks, with an increase from 228 attacks in 2012 to 601 in 2016. Most were reported by the London Metropolitan police force followed by Northumbria, Cambridgeshire, Hertfordshire, Greater Manchester and Humberside [[2]]. The chemical agents involved include acids, alkalis, oxidising and reducing agents, alkylating and chelating agents and solvents. They cause injury by producing a chemical interaction which can lead to extensive tissue destruction and extreme pain. Herein, we present a review on the changing epidemiology of corrosive attacks in the UK and currently employed management strategies.

The aquaporin-4 inhibitor AER-271 blocks acute cerebral edema and improves early outcome in a pediatric model of asphyxial cardiac arrest.

BACKGROUND: Cerebral edema after cardiac arrest (CA) is associated with increased mortality and unfavorable outcome in children and adults. Aquaporin-4 mediates cerebral water movement and its absence in models of ischemia improves outcome. We investigated early and selective pharmacologic inhibition of aquaporin-4 in a clinically relevant asphyxial CA model in immature rats in a threshold CA insult that produces primarily cytotoxic edema in the absence of blood-brain barrier permeability. METHODS: Postnatal day 16-18 Sprague-Dawley rats were studied in our established 9-min asphyxial CA model. Rats were randomized to aquaporin-4 inhibitor (AER-271) vs vehicle treatment, initiated at return of spontaneous circulation. Cerebral edema (% brain water) was the primary outcome with secondary assessments of the Neurologic Deficit Score (NDS), hippocampal neuronal death, and neuroinflammation. RESULTS: Treatment with AER-271 ameliorated early cerebral edema measured at 3 h after CA vs vehicle treated rats. This treatment also attenuated early NDS. In contrast to rats treated with vehicle after CA, rats treated with AER-271 did not develop significant neuronal death or neuroinflammation as compared to sham. CONCLUSION: Early post-resuscitation aquaporin-4 inhibition blocks the development of early cerebral edema, reduces early neurologic deficit, and blunts neuronal death and neuroinflammation post-CA.

Anti-Adenoviral Activity of 2-(3-Chlorotetrahydrofuran-2-yl)-4-Tosyl-5-(Perfluoropropyl)-1,2,3-Triazole.

Background and objectives: A considerable increase in the levels of adenoviral diseases among both adults and children necessitate the development of effective methods for its prevention and treatment. The synthesis of the new fluorinated 1,2,3-triazoles, and the study of the mechanisms of their action, are promising for the development of efficient antiviral drugs of our time. Materials and Methods: Antiviral activity and cell cytotoxic effect of 2-(3-chlorotetrahydrofuran-2-yl)-4-tosyl-5-(perfluoropropyl)-1,2,3-triazole (G29) were determined by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay. The influence of the compound on the infectivity of human adenovirus type 5 (HAdV-5) was carried out via the cytomorphology method. The influence of the compound on the cell cycle under a condition of adenovirus infection was studied using flow cytometric analysis of propidium iodide-stained cells. Results: It was found that G29 suppressed HAdV-5 reproduction by 50% in concentrations of 37 µg/mL. Furthermore, the compound reduced the titer of virus obtained de novo, and inhibited HAdV-5 inclusion bodies formation by 84⁻90%. The use of fluorinated compounds under the conditions of adenovirus infection decreased the number of apoptotic cells by 11% and the number of cells in S phase by 21⁻42% compared to the profile of infected cells. Conclusions: The fluorinated compound G29 showed moderate activity against HAdV-5 based on several mechanisms. It led to the normalization of the life cycle of cells infected with adenovirus to the level of non-infected cells and caused the obstruction of HAdV-5 reproduction, inducing the formation of non-infectious virus progeny.

Is it time for a change in the approach to chemical burns? The role of Diphoterine® in the management of cutaneous and ocular chemical injuries.

A multitude of household and occupational compounds have the potential to induce chemical burns to the eye and skin. Without prompt intervention, irreversible visual loss and disfigurement may prevail. Diphoterine® and Hexafluorine® are amphoteric and hypertonic chelating solutions used in the management of general chemical and hydrofluoric acid burns, respectively. They rapidly neutralise both acid and alkali agents without heat release and limit diffusion, making them superior to water irrigation alone. However, although Diphoterine® and Hexafluorine® uptake is slowly increasing in industrial workplaces, there is a paucity of education and use in both emergency departments and plastic surgery units worldwide. Herein, we present a case report of combined ocular and cutaneous acid burn treated with Diphoterine®, together with a review of the current supporting literature.

Randomized, within-patient, clinical trial comparing fluorine-synthetic fiber socks with standard cotton socks in improving plantar pustulosis.

BACKGROUND/AIMS: Rubbing the skin may influence the persistence of pustulosis over time. The aim of this study was to assess the impact of a new fabric made with fluorine-synthetic fiber in improving plantar pustulosis. METHODS: A total of 17 patients were randomized to receive on one side a sock made of fluorine-synthetic fiber and on the other a sock made of cotton fabric for 4 weeks. The main outcome was the percentage reduction of lesional area at week 4. RESULTS: The median lesion reduction at week 4 was 42.6% in the fluorine-synthetic fiber arm and 2.7% in the cotton arm (p = 0.148). Among secondary outcomes, the overall reduction over time in the treated areas was significantly in favor of the fluorine-synthetic fiber arm (p = 0.045) as well as the perception of the disease by the patient (p = 0.025). CONCLUSION: Despite the fact that the primary outcome was not reached, there was a tangible reduction in the extension of the treated areas and in the perception of the disease by the patient.

Hypothyroidism in patients with colorectal carcinoma treated with fluoropyrimidines.

Targeted therapy with tyrosine kinase inhibitors, including vascular endothelial growth factor receptors, has been demonstrated to induce hypothyroidism and thyroid dysfunction. Cancer patients with thyroid dysfunction may be underdiagnosed and undertreated. Thyroid function in colorectal cancer patients receiving fluoropyrimidine-based chemotherapy with or without bevacizumab was evaluated at baseline and monthly. In the present study, 3 of 27 (11.1%) patients who received fluoropyrimidine-based chemotherapy developed a thyroid-stimulating hormone (TSH) level >10 µU/ml, and 13 (48.1%) developed an elevation above the upper limit of the normal range. No difference in TSH elevation was noted between the bevacizumab and chemotherapy-alone group (50 vs. 45%; P=1.00, respectively). Three (11.1%) patients developed a TSH level >10 µU/ml and 2 with hypothyroidism were treated with thyroid hormone replacement therapy. We demonstrated that bevacizumab does not affect thyroid function but fluoropyrimidines may induce thyroid dysfunction in patients with colorectal cancer. Further investigation is required to clarify the mechanism of fluoropyrimidine-induced thyroid dysfunction.

Seventy per cent hydrofluoric acid burns: delayed decontamination with hexafluorine® and treatment with calcium gluconate.

This is a case report of decontamination and treatment of a 70% hydrofluoric acid (HF) dermal splash injury. A worker was splashed with 70% HF, sustaining approximately 10% TBSA first- to third-degree chemical skin burns of the face, trunk, and left thigh and leg. Initial decontamination involved water rinsing, removal of contaminated clothing, more water rinsing, topical application of magnesium oxide, and administration of intravenous narcotics for management of severe pain. After a delay of approximately 3 hours, active skin washing with Hexafluorine®, 5 L, was performed, followed by intravenous, intradermal perilesional, and topical inunction administration of calcium gluconate. Pain relief and a cooling sensation were quite prompt after Hexafluorine® decontamination. Surgical debridement and skin grafting of the more severe burns were required. No significant systemic toxicity developed, although this has occurred in previously reported similar concentrated HF dermal splash exposure cases, some of which resulted in fatality. While burns did develop, the patient was released from the intensive care service after 2 days and, after skin grafting, had a good outcome at 90-day follow-up. Even after a long delay, decontamination with Hexafluorine® appeared to be beneficial in this case.

[Significance of urinary uracil measurement following administration of DPD inhibitory fluoropyrimidine(DIF)products].

Individual differences in 5-FU metabolism are mainly attributed to individual differences in the activity of DPD, an enzyme that can metabolize more than 85% of 5-FU. Because urinary uracil is a reflection of DPD activity, it is measured to predict and prevent the occurrence of side effects caused by pyrimidine-type chemotherapeutic agents. From urinary uracil values measured in 84 gastrointestinal cancer patients, 0-60 mmol/g.creatinine was set as a standard. In patients whose urinary uracil values exceeded the standard, 5-FU tended to be accumulated when S-1, a DIF product, was administered and side effects, such as anorexia, vomiting and diarrhea occurred immediately after the start of S-1 administration. If an appropriate DIF product is selected and its dosage set based on the patient's urinary uracil value, the occurrence of side effects would be reduced. Subsequently, a continuation of medication would be possible.

New matrix polymers for photo-activated resin composites using di-alpha-fluoroacrylic acid derivatives.

A novel matrix resin for photo-activated resin composites was developed using alpha-fluoroacrylic acid derivatives. To render resin composites with improved mechanical properties, silica fillers were also used. It was found that the newly developed fluorine-substituted monomer was polymerized quite easily not only by free radical chemical initiators, but also by photoirradiation using free radical photoinitiator system. In particular, the photopolymerization rate of the novel monomer was more than two times faster than that of corresponding methacrylate-based monomer. Composite based on the newly developed matrix resin had higher micro-Vickers hardness and compressive strength values than the methacrylate-based composite, and that it contained only trace residual monomers compared with the methacrylate-based material. The high polymerization conversion of the fluorine-substituted monomer could be attributed to the polar effect or the small steric hindrance of fluorine at the alpha-position.

[Fluorine, an essential element for medicinal chemistry]. / Le fluor: un élément essentiel en chimie médicinale.

Because of the intrinsic properties of the fluorine atom, organic fluoride compounds have unique properties of particular importance in the pharmaceutical industry. The effect of fluorine is illustrated by selected examples of medicinal chemistry.

Selective fluorination in drug design and development: an overview of biochemical rationales.

Several strategies used in the rational design and synthesis of fluorinated compounds as potential therapeutic agents are reviewed. Applications of fluorine substitution in empirical SAR studies for lead development also are discussed, along with the implications with respect to fluorine target interactions that can be derived from biological activities.

Análise crítica da concentraçäo de íons flúor em três águas minerais comercializadas no município de Säo Paulo, e sua importância nos esquemas terapêuticos com os compostos fluorados / Critical analysis of fluoride ions in three mineral waters sold in the city of Säo Paulo and its importance in fluoride therapeutic schedule

O objetivo deste estudo foi mostrar, na situaçäo descrita, o grande risco de fluorese dentária em alunos na idade pré-escolar. Avaliaçäo da concentraçäo de íons flúor em três águas minerais comercializadas no município de Säo Paulo. Imporancia nos esquemas terapêuticos de regiöes onde se faz o uso de água fluorada, e ocorre a ingestäo inadvertida de dentifrícios e suplementos dietéticos fluorados.(au)

Topical treatments for hydrofluoric acid burns: a blind controlled experimental study.

BACKGROUND: Calcium gluconate gel, applied after initial rinsing with water, has a documented effect as first aid treatment for hydrofluoric acid burns. Hexafluorine is a novel liquid compound developed especially for emergency decontamination of hydrofluoric acid eye and skin exposures. However, scientific documentation of the effect of Hexafluorine is insufficient. This study was undertaken to compare Hexafluorine with water rinsing plus topical calcium and with water rinsing alone. METHODS: Thirty-five Sprague-Dawley rats were anesthetized and their backs shaved. Four filter papers 10 mm in diameter were soaked in 50% hydrofluoric acid and applied on the shaved area of each rat for 3 minutes. Thirty seconds later, the acid-exposed skin areas were rinsed with 500 mL Hexafluorine for 3 minutes (group H, n = 10), 500 mL water for 3 minutes (group W, n = 10) or 500 mL water for 3 minutes followed by a single application of 2.5% calcium gluconate gel (group Ca, n = 10), or received no treatment (controls, n = 5). The animals were closely observed for 5 days. Daily at 4 P.M. each of the four burns on every rat was rated on a modified Draize scale graded from 0 to 5 (0 = no visible injury, 1 = diffuse erythema, 2 = distinct erythema, 3 = distinct erythema plus wounds or discolored spots, 4 = distinct erythema plus wounds or discolored areas covering >50% of the burn, 5 = a necrotic wound covering the whole burn). The mean of the four scores was then calculated for each animal and day. The rating procedure was performed by one laboratory assistant who was unaware of the treatment given. Kruskal-Wallis analysis was used to evaluate possible differences between treatment groups on each of the 5 days. If the p-value obtained was <0.05, correction for multiple comparisons was made. RESULTS: The mean severity score in group H was significantly higher than that in group Ca on days 2 and 3. Moreover, Hexafluorine showed a consistent trend towards a worse outcome, both in comparison to water plus topical calcium and to water rinsing alone. CONCLUSION: Based on these observations it is concluded that water rinsing followed by topical calcium should remain the standard first aid treatment for skin exposure to hydrofluoric acid.

Oral fluoropyrimidine-based combination therapy in gastrointestinal cancer.

Significant emphasis has been placed recently on designing more effective fluorouracil (5-FU)-based combination protocols for gastrointestinal cancer. Promising results were seen with 5-FU/leucovorin in combination with irinotecan (Camptosar) or oxaliplatin (Eloxatin), especially in colorectal cancer. Clinical trials of UFT, with or without leucovorin, demonstrate the safety of this regimen and an efficacy comparable to that of bolus 5-FU/leucovorin in the treatment of gastrointestinal tumors. Two large randomized phase III trials of capecitabine (Xeloda) showed that capecitabine also offers a convenient alternative to bolus 5-FU/leucovorin with a superior safety profile and at least equivalent antitumor activity.