Fluorine in the pharmaceutical industry: Synthetic approaches and application of clinically approved fluorine-enriched anti-infectious medications.

The strategic integration of fluorine atoms into anti-infectious agents has become a cornerstone in the field of medicinal chemistry, owing to the unique influence of fluorine on the chemical and biological properties of pharmaceuticals. This review examines the synthetic methodologies that enable the incorporation of fluorine into anti-infectious drugs, and the resultant clinical applications of these fluorine-enriched compounds. With a focus on clinically approved medications, the discussion extends to the molecular mechanisms. It further outlines the specific effects of fluorination, which contribute to the heightened efficacy of anti-infective therapies. By presenting a comprehensive analysis of current drugs and their developmental pathways, this review underscores the continuing evolution and significance of fluorine in advancing anti-infectious treatment options. The insights offered extend valuable guidance for future drug design and the development of next-generation anti-infectious agents.

The Pharmaceutical Industry in 2023: An Analysis of FDA Drug Approvals from the Perspective of Molecules.

With the COVID-19 pandemic behind us, the U.S. Food and Drug Administration (FDA) has approved 55 new drugs in 2023, a figure consistent with the number authorized in the last five years (53 per year on average). Thus, 2023 marks the second-best yearly FDA harvest after 2018 (59 approvals) in all the series. Monoclonal antibodies (mAbs) continue to be the class of drugs with the most approvals, with an exceptional 12, a number that makes it the most outstanding year for this class. As in 2022, five proteins/enzymes have been approved in 2023. However, no antibody-drug conjugates (ADCs) have been released onto the market. With respect to TIDES (peptides and oligonucleotides), 2023 has proved a spectacular year, with a total of nine approvals, corresponding to five peptides and four oligonucleotides. Natural products continue to be the best source of inspiration for drug development, with 10 new products on the market. Three drugs in this year's harvest are pegylated, which may indicate the return of pegylation as a method to increase the half-lives of drugs after the withdrawal of peginesatide from the market in 2013. Following the trends in recent years, two bispecific drugs have been authorized in 2023. As in the preceding years, fluorine and/or N-aromatic heterocycles are present in most of the drugs. Herein, the 55 new drugs approved by the FDA in 2023 are analyzed exclusively on the basis of their chemical structure. They are classified as the following: biologics (antibodies, proteins/enzymes); TIDES (peptide and oligonucleotides); combined drugs; pegylated drugs; natural products; nitrogen aromatic heterocycles; fluorine-containing molecules; and other small molecules.

Rapid reaction optimization by robust and economical quantitative benchtop 19F NMR spectroscopy.

The instrumental analysis of reaction mixtures is usually the rate-determining step in the optimization of chemical processes. Traditionally, reactions are analyzed by gas chromatography, HPLC or quantitative NMR spectroscopy on high-field spectrometers. However, chromatographic methods require elaborate work-up and calibration protocols, and high-field NMR spectrometers are expensive to purchase and operate. This protocol describes an inexpensive and highly effective analysis method based on low-field benchtop NMR spectroscopy. Its key feature is the use of fluorine-labeled model substrates that, because of the wide chemical shift range and high sensitivity of 19F, enable separate, quantitative detection of product and by-product signals even on low-field, permanent magnet spectrometers. An external lock/shim device obviates the need for deuterated solvents, permitting the direct, noninvasive measurement of crude reaction mixtures with minimal workup. The low field-strength facilitates a homogeneous excitation over a wide chemical shift range, minimizing systematic integration errors. The addition of the optimal amount of the nonshifting relaxation agent tris(acetylacetonato) iron(III) minimizes relaxation delays at full resolution, reducing the analysis time to 32 s per sample. The correct choice of processing parameters is also crucial. A step-by-step guideline is provided, the influence of all parameters, including adjustments needed when using high-field spectrometers, is discussed and potential pitfalls are highlighted. The wide applicability of the analytical protocol for reaction optimization is illustrated by three examples: a Buchwald-Hartwig amination, a Suzuki coupling and a C-H arylation reaction.

Atypical methods for characterization of used photovoltaic panels during their pre- and Post-Thermal treatment assessment.

The study presents an innovative approach to the analysis of waste silicon photovoltaic panels prior and after thermal treatment. Using laser-induced breakdown spectroscopy (LIBS), the elemental composition of multilayered panel backsheets was determined, identifying a TiO2-containing coating laminate, a polyvinylidene fluoride (PVDF) layer, and an ethylene vinyl acetate (EVA) encapsulant, while also estimating their thickness. Identifying the fluorine-containing layers allowed their selective removal and safe processing of the used panels. Thermal processing parameters such as temperature (400-550 °C), time (5 - 60 min) and orientation of the busbar relative to the heat source were optimized based on contact angle measurements and CIELAB color space analysis, techniques used to detect organic residues in recovered glass and silicone. The decomposition process was examined by thermal analysis coupled with mass spectroscopy, which revealed that there were no volatile fluorine compounds in the gases released, although fluorine was detected on the recovered glass surface by SEM - EDS examination. After the PVDF layer was removed, fluorine compounds were not found in volatile gases or on the surface of recovered inorganic materials. The study indicated that the orientation of the busbars facilitates the decomposition of organic matter. Methods for reusing recovered secondary materials were also provided, suggesting the potential applications and benefits of recycling components from silicon photovoltaic panels.

Glycan Metabolic Fluorine Labeling for In Vivo Visualization of Tumor Cells and In Situ Assessment of Glycosylation Variations.

The abnormality in the glycosylation of surface proteins is critical for the growth and metastasis of tumors and their capacity for immunosuppression and drug resistance. This anomaly offers an entry point for real-time analysis on glycosylation fluctuations. In this study, we report a strategy, glycan metabolic fluorine labeling (MEFLA), for selectively tagging glycans of tumor cells. As a proof of concept, we synthesized two fluorinated unnatural monosaccharides with distinctive 19 F chemical shifts (Ac4 ManNTfe and Ac4 GalNTfa). These two probes could undergo selective uptake by tumor cells and subsequent incorporation into surface glycans. This approach enables efficient and specific 19 F labeling of tumor cells, which permits in vivo tracking of tumor cells and in situ assessment of glycosylation changes by 19 F MRI. The efficiency and specificity of our probes for labeling tumor cells were verified in vitro with A549 cells. The feasibility of our method was further validated with in vivo experiments on A549 tumor-bearing mice. Moreover, the capacity of our approach for assessing glycosylation changes of tumor cells was illustrated both in vitro and in vivo. Our studies provide a promising means for visualizing tumor cells in vivo and assessing their glycosylation variations in situ through targeted multiplexed 19 F MRI.

[Potential Ecological Risk Assessment and Source Analysis of Heavy Metals in Soil-crop System in Xiong'an New District].

In order to evaluate the distribution characteristics of fluorine geochemistry in the surface soil and human health risk in Xiong'an New District, GIS spatial analysis and correlation analysis were used to analyze the depleted and enriched features and influencing factors of soil fluoride and to carry out the soil fluoride health risk assessment. The uncertainty of the health risk assessment results was studied based on the Monte Carlo stochastic simulation. The results showed that the average content of fluorine was 641 mg·kg-1, which was 1.34 times the background value of the national A-layer soil. The excess fluorine and high-grade samples accounted for more than 85%, and the overall soil fluorine content was relatively high. The average content of fluoride of the irrigation water samples was 0.85 mg·L-1, the spatial distribution characteristics of which were affected by the hydrochemical type and flow direction of shallow groundwater. The vertical spatial variation of soil fluoride, mainly affected by the vertical distribution of soil physicochemical properties such as soil organic carbon and texture, was not obvious. The depletion and enrichment of topsoil fluorine was mainly controlled by the geological background, and its spatial distribution was affected by external inputs, such as human factors (agricultural irrigation water, fertilization, and atmospheric dry and wet deposition). The soil fluoride content was significantly correlated with the iconic indicators of the geomorphological environment, including the content of Al2O3, Fe2O3, MgO, K2O, soil organic carbon (Corg.), cation exchange capacity (CEC), clay, and silt (P<0.01). The results of human health risk assessment showed that oral intake was the main exposure risk route of soil fluoride. The non-carcinogenic health risk index HQ of adults was less than 1, and the harm could be ignored. The probability of non-carcinogenic health risk exceeding the threshold for adults and children was 34.3% and 27.6%, respectively, and daily soil intake was the most sensitive parameter.

A simple, low cost and fast sample preparation method for fluorine determination by ISE in leguminous seeds and oilseeds.

This work presents the first report of the application of microwave-induced combustion in disposable vessels (MIC-DV) as a simple and fast sample preparation step for fluoride determination by ion-selective electrode (ISE) in leguminous seeds and oilseeds samples. Several experimental conditions of MIC-DV were evaluated, such as sample mass, absorbing solution, volume of combustion igniter, purging time with oxygen, and the use of successive combustion cycles. The accuracy of MIC-DV/ISE method was evaluated by comparing the results obtained by microwave-induced combustion and determination by ion chromatography, with agreements ranged from 94 to 106%. The method allowed to achieve relatively low limits of quantification (8.3 to 16 µg g-1) comparing to AOAC method (40 µg g-1), besides the use of small amounts of reagents, less handling of digests, making the method greener and with portable features comparing to other methods.

Distribution, enrichment mechanisms, and health risk assessment of high-fluorine groundwater in the Yudong Plain, Henan Province, China.

The Yudong Plain is in the eastern part of Henan Province, China, where there is little rain and high evaporation. Compared to other areas in Henan Province, the groundwater fluorine content is generally high, which affects the health of residents. Based on the systematic analysis of water chemistry data of shallow and mid-depth groundwater samples in the Yudong Plain, the causes of shallow and mid-depth high-fluorine groundwater in the Yudong Plain were explored using mathematical statistics, spatial interpolation, and ion ratios. The results show that the fluorine contents of both shallow and mid-depth groundwater in the study area are high. The shallow samples had fluorine contents ranging from 0.1 to 4.89 mg/L, with an exceedance rate of 48% and an average content of 1.15 mg/L. The fluorine content of mid-depth samples ranged from 0.14 to 3.32 mg/L, with an exceedance rate of 68% and an average content of 1.33 mg/L. The shallow high-fluorine groundwater is mainly distributed in the central low-lying area, and its main hydrochemical type is HCO3-Na·Mg; the mid-depth high-fluorine groundwater is mainly distributed in strips in the north and east of the study area, and its main water chemistry type is HCO3-Na. Fluorine enrichment in shallow groundwater in the study area is controlled by rock weathering, evaporation concentration, and competitive adsorption, while leaching and dissolution of fluorine-containing minerals in sedimentary strata are the main factors influencing fluorine enrichment in mid-depth groundwater. The results of the human health risk assessment (HRA) showed that the mean non-carcinogenic hazard quotients (HQs) in shallow groundwater were 0.95, 0.64, 0.57, and 0.55 for infants, children, teenagers, and adults, respectively, while the mean non-carcinogenic HQs in mid-depth groundwater were 1.11, 0.74, 0.66, and 0.63, respectively. The study provides a scientific basis for the rational development and use of groundwater in the area and offers theoretical support for the prevention and control of groundwater pollution.

The Pharmaceutical Industry in 2022: An Analysis of FDA Drug Approvals from the Perspective of Molecules.

While 2021 ended with the world engulfed in the COVID-19 Omicron wave, 2022 has ended in almost all countries, except China, with COVID-19 being likened to the flu. In this context, the U.S. Food and Drug Administration (FDA) has authorized only 37 new drugs this year compared to an average of 52 in the last four years. Thus 2022 is the second lowest harvest after 2016 in the last six years. This ranking may be transient and will be confirmed in the coming years. In this regard, the reduction in the number of drugs accepted by the FDA this year applies only to the so-called small molecules as there has been no variation in the respective numbers of biologics or TIDES (peptides and oligonucleotides). Monoclonal antibodies (mAbs) continue to be the class with the most drugs authorized (9), while proteins/enzymes (5) and an antibody-drug conjugate complete the biologics harvest. In 2022, five TIDES and seven drugs inspired by natural products have received the green light, thus showing the same tendency as in previous years. Finally, pharmaceutical agents with nitrogen aromatic heterocycles and/or fluorine atoms continue to be predominant among small molecules this year. Furthermore, three drugs have been approved for imaging, reinforcing the trend in recent years for this class of treatments. A keyword in 2022 is bispecificity since four drugs have this property (two mAbs, one protein, and one peptide). Herein, the 37 new drugs approved by the FDA in 2022 are analyzed. On the basis of chemical structure alone, these drugs are classified as the following: biologics (antibodies, antibody-drug conjugates, proteins/enzymes), TIDES (peptide and oligonucleotides), combined drugs, natural products; nitrogen aromatic heterocycles, fluorine-containing molecules, and other small molecules.

Perfluoroalkyl acids in the aquatic environment of a fluorine industry-impacted region: Spatiotemporal distribution, partition behavior, source, and risk assessment.

The present study investigated the temporal and spatial distributions, partition behaviors, sources, and risks of 14 perfluoroalkyl acids (PFAAs) in the aquatic environment of a fluorine industry-impacted region. The total concentrations of 14 PFAAs (ΣPFAAs) were 118.10-2235.4 ng/L, 40.00-2316.1 ng/g dw, and 6.90-180.5 ng/g dw in dissolved, suspended particle matter (SPM), and sedimentary phases, respectively. The predominant pollutants in the dissolved and SPM phases were perfluoroalkyl carboxylic acids (PFCAs) with carbon chain lengths <9, whereas C13 and C14 PFCAs accounted for a large proportion in the sedimentary phase. The dry season exhibited the highest concentration of ΣPFAAs in the dissolved phase (500.9 ± 350.2 ng/L), while the wet season showed the highest concentrations of ΣPFAAs in the SPM and sedimentary phases (591.6 ± 469.1 ng/g dw and 59.7 ± 35.5 ng/g dw, respectively). Significantly higher concentrations of PFAAs have been found in sewage plant and industrial areas. The concentration of PFAAs in the Xupu water source area (XPS) was slightly higher than that in other water source areas of the Yangtze River, which were either not affected or were less affected by the fluorine industry. The log KD-SPM (distribution coefficient between SPM and water), log KD-SED (distribution coefficient between sediment and water), and log KOC-SED (the organic carbon normalized distribution coefficient) of PFAAs showed significant differences between the wet season and dry season, which may also be affected by carbon chain length. Source identification results showed that industries, wastewater discharge, and nonpoint sources were the main sources of PFAAs in this region. The ecological risk posed by long-chain PFAAs in aquatic organisms cannot be ignored, especially in areas with intensive industrial and agricultural activities. Health risks may exist for local toddlers with long-term exposure to perfluorooctanoic acid (PFOA) through drinking water intake and dermal contact.

Non-invasive in vivo assessment of 11ß-hydroxysteroid dehydrogenase type 1 activity by 19F-Magnetic Resonance Spectroscopy.

11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1) amplifies tissue glucocorticoid levels and is a pharmaceutical target in diabetes and cognitive decline. Clinical translation of inhibitors is hampered by lack of in vivo pharmacodynamic biomarkers. Our goal was to monitor substrates and products of 11ß-HSD1 non-invasively in liver via 19Fluorine magnetic resonance spectroscopy (19F-MRS). Interconversion of mono/poly-fluorinated substrate/product pairs was studied in Wistar rats (male, n = 6) and healthy men (n = 3) using 7T and 3T MRI scanners, respectively. Here we show that the in vitro limit of detection, as absolute fluorine content, was 0.625 µmole in blood. Mono-fluorinated steroids, dexamethasone and 11-dehydrodexamethasone, were detected in phantoms but not in vivo in human liver following oral dosing. A non-steroidal polyfluorinated tracer, 2-(phenylsulfonyl)-1-(4-(trifluoromethyl)phenyl)ethanone and its metabolic product were detected in vivo in rat liver after oral administration of the keto-substrate, reading out reductase activity. Administration of a selective 11ß-HSD1 inhibitor in vivo in rats altered total liver 19F-MRS signal. We conclude that there is insufficient sensitivity to measure mono-fluorinated tracers in vivo in man with current dosage regimens and clinical scanners. However, since reductase activity was observed in rats using poly-fluorinated tracers, this concept could be pursued for translation to man with further development.

Health risk assessment of fluoride exposure due to groundwater consumption in Romania.

Fluoride has both beneficial and detrimental effects on human health. Concentrations of fluoride less than 1.0 mg/L in ingested water are beneficial for the rate of tooth decay, especially in children. The aims of the paper are as follows: (i) to monitor fluoride concentrations in drinking water samples (well water and tap water from the rural district of Valea Râmnicului, Romania); (ii) to study and select the optimal buffer solution and the optimal volume used in the analyses and (iii) to validate the potentiometric method for determining fluoride ions with a selective ion electrode. The values of fluoride ion concentrations in the groundwater samples and in tap water varied from 0.01 to 0.138 mg/L. The values for the hazard quotient for the studied samples varied from 0.01 to 0.13.

Occurrence characteristics and health risk assessment of per- and polyfluoroalkyl substances from water in residential areas around fluorine chemical industrial areas, China.

Recently, identifying the contamination status and assessing the health risk of per- and polyfluoroalkyl substances (PFASs) in surface water and groundwater have been of great significance. Eighteen individual PFASs were analyzed in thirty-three surface/groundwater samples during one period in a fluorine chemical park (Park A) and during two periods in Park B. The mean total concentration of 18 PFASs (∑PFASs) in Park A (9104.63 ng·L-1) was significantly higher than that in the wet season (WS) (801.68 ng·L-1) or DS (714.64 ng·L-1) in Park B. The perfluorobutane sulfonate (PFBS) was the predominant substance in the two parks, and the maximum concentration in groundwater exceeded 10,000 ng·L-1. The contamination status in the wet season (WS) was higher than that in the dry season (DS) in Park B. The ∑PFASs in Park A presented an increasing tendency following the groundwater flow direction, whereas this rule was limited to all periods in Park B. Two relative source contributions (RSCs) of 20% or 100% allowed assessing the PFASs risk to different age groups, and the results revealed that some PFASs (4 ≤ C ≤ 7 or 9 ≤ C ≤ 12) were identified as having a low risk quotient (RQ), except for perfluorooctane sulfonate (PFOS) and PFOA (C = 8). The RQmix value mainly relies on PFOA and PFOS, with a larger contribution rate of 80-90%. All assessed cases (case 1, case 2, case 3, and case 4) in all age groups revealed that infants were vulnerable to PFASs influence, followed by children, teenagers, and adults.

18 Fluorine-fluorodeoxyglucose positron emission tomography for assessment of deep digital flexor tendinopathy: An exploratory study in eight horses with comparison to CT and MRI.

Lesions of the deep digital flexor tendon (DDFT) are a cause for foot lameness in horses. Positron emission tomography (PET) could provide valuable information regarding the metabolic activity of these lesions. The aims of this exploratory, prospective, methods comparison study were to assess the ability of 18 fluorine-fluorodeoxyglucose (18 F-FDG) PET to detect DDFT lesions and to compare the PET findings with CT and MRI findings. Eight horses with lameness due to pain localized to the front feet were included. Both front limbs of all horses were imaged with 18 F-FDG PET, noncontrast CT, and arterial contrast-enhanced CT; 11 limbs were also assessed using MRI. Two observers graded independently 18 F-FDG PET, noncontrast CT, arterial contrast CT, T1-weighted (T1-w) MRI, and T2-weighted (T2-w)/STIR MRI. Maximal standardized uptake values were measured. Lesions were found in seven of 16 DDFT on PET, 12 of 16 DDFT on noncontrast CT, six of 15 DDFT on arterial contrast CT, eight of 11 DDFT on T1-w MRI, and six of 11 DDFT on T2-w/STIR MRI. Positron emission tomography was in better agreement with arterial contrast CT (Kappa-weighted 0.40) and T2-w/STIR MRI (0.35) than with noncontrast CT (0.28) and T1-w MRI (0.20). Maximal standardized uptake values of lesions ranged from 1.9 to 4.6 with a median of 3.1. Chronic lesions with scar tissues identified on noncontrast CT or T1-w MRI did not have increased 18 F-FDG uptake. These results demonstrated that 18 F-FDG PET agreed more closely with modalities previously used to detect active tendon lesions, i.e. arterial contrast CT and T2-w/STIR MRI. 18 Fluorine-fluorodeoxyglucose PET can be used to identify metabolically active DDFT lesions in horses.

Evaluación económica de las alternativas terapéuticas en pacientes con hiperestesia dentinaria / Economic evaluation of the therapeutic alternatives in patients with dentin hyperesthesia

Introducción: La hiperestesia dentinaria es una sensación dolorosa de intensidad variable, que va de leve a moderada y, al encontrarse la dentina expuesta, puede convertirse en una molestia constante. Objetivo: Determinar la alternativa menos costosa en el tratamiento de pacientes con hiperestesia dentinaria. Método: Se realizó una evaluación económica completa del tipo minimización de costo, en la Clínica Estomatológica Provincial Docente Mártires del Moncada de Santiago de Cuba, desde enero hasta mayo de 2019. Se revisaron 40 historias clínicas, escogidas a conveniencia, ya que contaban con los datos necesarios para la investigación. Se crearon 2 grupos de estudios, cuyos integrantes fueron tratados con laca flúor y láser, respectivamente. Se analizaron las variables de edad, sexo, efectividad de los tratamientos, costo directo e indirecto y costo unitario. Resultados: En la serie predominaron el grupo etario de 15-24 años (30,0 %), seguido por el de 25- 34 (25,0 %), así como el sexo femenino (70,0 %). El costo unitario del tratamiento con laca flúor fue de $7,77 y con láser de $5,74, para una diferencia de $2,03. Conclusión: La alternativa menos costosa en el tratamiento de pacientes con hiperestesia dentinaria resultó ser la aplicación de láser; mientras que la evaluación económica realizada demostró ser apropiada en materia de eficiencia económica.

Introduction: Dentin hyperesthesia is a painful sensation of variable intensity that goes from light to moderate and, as dentin is exposed, it can become a constant discomfort. Objective: To determine the less expensive alternative in the treatment of patients with dentin hyperesthesia. Method: A complete economic evaluation of the cost minimization type was carried out in Martires del Moncada Teaching Provincial Stomatological Clinic in Santiago de Cuba, from January to May, 2019. Forty medical records were reviewed, chosen of convenience, since they had the necessary data for the investigation. Two groups of studies were created whose members were treated with lacquer fluorine and laser, respectively. The age, sex, effectiveness of the treatments, direct and indirect cost and unitary cost variables were analyzed. Results: In the series there was a prevalence of the 15-24 age group (30.0 %), followed by that of 25-34 (25.0 %), as well as the female sex (70.0 %). The unitary cost of the treatment with lacquer fluorine was of $7.77 and with laser of $5.74, for a difference of $2.03. Conclusion: The less expensive alternative in the treatment of patients with dentin hyperesthesia was the laser application; while the economic evaluation carried out demonstrated to be appropriate as regards economic efficiency.

Dose profiles and x-ray energy optimization for microbeam radiation therapy by high-dose, high resolution dosimetry using Sm-doped fluoroaluminate glass plates and Monte Carlo transport simulation.

Microbeam radiation therapy (MRT) utilizes highly collimated synchrotron generated x-rays to create narrow planes of high dose radiation for the treatment of tumors. Individual microbeams have a typical width of 30-50 µm and are separated by a distance of 200-500 µm. The dose delivered at the center of the beam is lethal to cells in the microbeam path, on the order of hundreds of Grays (Gy). The tissue between each microbeam is spared and helps aid in the repair of adjacent damaged tissue. Radiation interactions within the peak of the microbeam, such as the photoelectric effect and incoherent (atomic Compton) scattering, cause some dose to be delivered to the valley areas adjacent to the microbeams. As the incident x-ray energy is modified, radiation interactions within a material change and affect the probability of interactions, as well as the directionality and energy of ionizing particles (electrons) that deposit energy in the valley regions surrounding the microbeam peaks. It is crucial that the valley dose between microbeams be minimal to maintain the effectiveness of MRT. Using a monochromatic x-ray source with x-ray energies ranging from 30 to 150 keV, a detailed investigation into the effect of incident x-ray energy on the dose profiles of microbeams was performed using samarium doped fluoroaluminate (FA) glass as the medium. All dosimetric measurements were carried out using a purpose-built fluorescence confocal microscope dosimetric technique that used Sm-doped FA glass plates as the irradiated medium. Dose profiles are measured over a very a wide range of x-ray energies at micrometer resolution and dose distribution in the microbeam are mapped. The measured microbeam profiles at different energies are compared with the MCNP6 radiation transport code, a general transport code which can calculate the energy deposition of electrons as they pass through a given material. The experimentally measured distributions can be used to validate the results for electron energy deposition in fluoroaluminate glass. Code validation is necessary for using transport codes in future treatment planning for MRT and other radiation therapies. It is shown that simulated and measured micro beam-profiles are in good agreement, and micrometer level changes can be observed using this high-resolution dosimetry technique. Full width at 10% of the maximum peak (FW@10%) was used to quantify the microbeam width. Experimental measurements on FA glasses and simulations on the dependence of the FW@10% at various energies are in good agreement. Simulations on energy deposited in water indicate that FW@10% reaches a local minimum around energies 140 keV. In addition, variable slit width experiments were carried out at an incident x-ray energy of 100 keV in order to determine the effect of the narrowing slit width on the delivered peak dose. The microbeam width affects the peak dose, which decreases with the width of the microbeam. Experiments suggest that a typical microbeam width for MRT is likely to be between 20-50 µm based on this work.

Distribution and superposed health risk assessment of fluorine co-effect in phosphorous chemical industrial and agricultural sources.

The industrial and agricultural activities based on phosphorous can increase the F content in the surrounding area, causing a widespread adverse effect on the organisms. However, the current information on the superposed health risk posed by the multi-exposure to the F contamination in an area jointly affected by agricultural and industrial activities (DA) is limited. Herein, the F distribution in multi-environmental media and the exposure risk to humans by ingestion, inhalation, and dermal contact pathways are studied in an DA. The content of soil water-soluble fluorine (WF) was higher in the DA than in the area individually affected by agricultural activities (SA). This indicated a superposed contribution of the industrial and agricultural activities to increase the F toxicity in the soil. The correlation of the soil pH and the organic matter content with the soil WF concentration in DA suggested an inter-relationship between the soil physicochemical properties and the toxicity of F in the soil by industrial and agricultural activities. Irrigation water was not a major anthropogenic source of the cropland soil F. The large variation in F concentration in the crops (101.8-195.6%) might have originated from the discrepancies in the soil F content and air F concentration. The air F pollution (0.6-1.6 µg dm-2 d-1) in the area particularly influenced by intensive industrial activities should be important. The exposure of residents to F was mainly from the ingestion of F-enriched crops. The higher exposure of adults to F than that of children could be attributed to more industrial and agricultural outdoor activities, larger exposure area of the skin, and more daily ingestion of F-enriched food by adults. Overall, present insights into the distribution of and the multi-exposure to F may be beneficial for decreasing the adverse F effects on the residents in DAs worldwide.

Health risk assessment of fluorine in fertilizers from a fluorine contaminated region based on the oral bioaccessibility determined by Biomimetic Whole Digestion-Plasma in-vitro Method (BWDPM).

Due to potential adverse effects of excessive fluorine (F), interests regarding considerable accumulation of F in agricultural soils from application of fertilizers are increasing continually. However, less detailed information of hazard and risk of F in fertilizers to human directly by hand-to-mouth pathway can be obtained. Herein, the bioaccessibility of F (Fbio) in fertilizers is determined by Biomimetic Whole Digestion-Plasma in-vitro Method (BWDPM), which is developed to detect the behaviour of bioaccessible F in both the whole digestive system and plasma for the first time. Observations of higher Fbio in small intestinal phases (4.35-56.33%), large intestine (1.01-40.52%) and plasma (8.07-66.70%) yielded them as the major phases which are faced with higher exposure risk of F. Compared with phosphate fertilizer, more bioaccessible F was observed in compound fertilizer. Some studied factors, such as sweat and food, yield insignificant influences on Fbio, whereas can affect the exposure estimations of F considerably. Exposure risks based on Fbio of fertilizers should be highly concerned, especially the occupational exposure to local farmers. In a word, more explicit and realistic information of the potential risk of F on human health could be obtained by the introduction of Fbio.

Applications of fluorine-containing amino acids for drug design.

Fluorine-containing amino acids are becoming increasingly prominent in new drugs due to two general trends in the modern pharmaceutical industry. Firstly, the growing acceptance of peptides and modified peptides as drugs; and secondly, fluorine editing has become a prevalent protocol in drug-candidate optimization. Accordingly, fluorine-containing amino acids represent one of the more promising and rapidly developing areas of research in organic, bio-organic and medicinal chemistry. The goal of this Review article is to highlight the current state-of-the-art in this area by profiling 42 selected compounds that combine fluorine and amino acid structural elements. The compounds under discussion represent pharmaceutical drugs currently on the market, or in clinical trials as well as examples of drug-candidates that although withdrawn from development had a significant impact on the progress of medicinal chemistry and/or provided a deeper understanding of the nature and mechanism of biological action. For each compound, we present features of biological activity, a brief history of the design principles and the development of the synthetic approach, focusing on the source of tailor-made amino acid structures and fluorination methods. General aspects of the medicinal chemistry of fluorine-containing amino acids and synthetic methodology are briefly discussed.

In Vitro Assessment of Fluorine Nanoemulsion-Labeled Hyaluronan-Based Hydrogels for Precise Intrathecal Transplantation of Glial-Restricted Precursors.

PURPOSE: We studied the feasibility of labeling hydrogel scaffolds with a fluorine nanoemulsion for 19F- magnetic resonance imaging (MRI) to enable non-invasive visualization of their precise placement and potential degradation. PROCEDURE: Hyaluronan-based hydrogels (activated hyaluronan, HA) with increasing concentrations of fluorine nanoemulsion (V-sense) were prepared to measure the gelation time and oscillatory stress at 1 h and 7 days after the beginning of gelation. All biomechanical measurements were conducted with an ARES 2 rheometer. Diffusion of fluorine from the hydrogel: Three hydrogels in various Vs to HA volumetric ratios (1:50, 1:10, and 1:5) were prepared in duplicate. Hydrogels were incubated at 37 °C. To induce diffusion, three hydrogels were agitated at 1000 rpm. 1H and 19F MRI scans were acquired at 1, 3, 7 days and 2 months after gel preparation on a Bruker Ascend 750 scanner. To quantify fluorine content, scans were analyzed using Voxel Tracker 2.0. Assessment of cell viability in vitro and in vivo: Luciferase-positive mouse glial-restricted progenitors (GRPs) were embedded in 0:1, 1:50, 1:10, and 1:5 Vs:HA mixtures (final cell concentration  =1 × 107/ml). For the in vitro assay, mixtures were placed in 96-wells plate in triplicate and bioluminescence was measured after 1, 3, 7, 14, 21, and 28 days. For in vivo experiments, Vs/HA mixtures containing GRPs were injected subcutaneously in SCID mice and BLI was acquired at 1, 3, 7, and 14 days post-injection. RESULTS: Mixing of V-sense at increasing ratios of 1:50, 1:10, and 1:5 v/v of fluorine/activated hyaluronan (HA) hydrogel gradually elongated the gelation time from 194 s for non-fluorinated controls to 304 s for 1:5 V-sense:HA hydrogels, while their elastic properties slightly decreased. There was no release of V-sense from hydrogels maintained in stationary conditions over 2 months. The addition of V-sense positively affected in vitro survival of scaffolded GRPs in a dose-dependent manner. CONCLUSIONS: These results show that hydrogel fluorination does not impair its beneficial properties for scaffolded cells, which may be used to visualize scaffolded GRP transplants with 19F MRI.