Deuterium Isotope Research Articles

Lighting the way to drug labeling

Organic Chemistry It is important during drug development to study how candidate compounds get absorbed and broken down biologically. One common technique for tracking a drug's fate is to label its molecular framework with heavier isotopes of hydrogen (either deuterium or tritium). Loh et al. developed a light-promoted protocol to install these labels on alkyl carbons adjacent to nitrogen. The technique relies on incorporation of the heavy isotope into a thiol from a convenient heavy water source through acid-base chemistry. Next, a photoredox catalyst strips a hydrogen atom equivalent from the carbon, and the thiol engages in radical chemistry to transfer the deuterium or tritium in its place. Science , this issue p. [1182][1] [1]: /lookup/doi/10.1126/science.aap9674

Installing heavy hydrogens with light

To follow the fate of a drug or a drug metabolite as it wends its way through the body, scientists will often label the compound by switching out a hydrogen atom for one of its heavier isotopes—deuterium or tritium. This molecular switcheroo sounds simple, but it can actually be a lot of work, requiring chemists to resynthesize a molecule so it has an atom, usually a halogen, or unsaturated bond where the heavy hydrogen can be swapped in or added. The process can take months. Chemists at Princeton University and Merck & Co. have now come up with a way to switch hydrogen out for deuterium or tritium in a matter of moments. The reaction uses photoredox-mediated hydrogen-atom transfer to replace the hydrogens at C–H bonds adjacent to amines with deuterium or tritium from D2O or T2O (Science 2017, DOI: 10.1126/science.aap9674). Amines are common motifs in biologically active molecules, and

Photoredox-catalyzed deuteration and tritiation of pharmaceutical compounds.

Deuterium- and tritium-labeled pharmaceutical compounds are pivotal diagnostic tools in drug discovery research, providing vital information about the biological fate of drugs and drug metabolites. Herein we demonstrate that a photoredox-mediated hydrogen atom transfer protocol can efficiently and selectively install deuterium (D) and tritium (T) at α-amino sp3 carbon-hydrogen bonds in a single step, using isotopically labeled water (D2O or T2O) as the source of hydrogen isotope. In this context, we also report a convenient synthesis of T2O from T2, providing access to high-specific-activity T2O. This protocol has been successfully applied to the high incorporation of deuterium and tritium in 18 drug molecules, which meet the requirements for use in ligand-binding assays and absorption, distribution, metabolism, and excretion studies.

On the possibility of chiral structure-density submillimeter inhomogeneities existing in water

The existence of stable formations representing submillimeter density inhomogeneities in aqueous solutions was confirmed by using the laser light diffraction (LALLS) method and also the dynamic (DLS) and two-dimensional light scattering methods. The effect of low angle light scattering by giant water clusters depends on the presence of ions or dissolved substances in water solution, and also on the concentration of deuterium (heavy hydrogen isotope). It has been shown that the reduction of deuterium concentration results in the reduction of light scattering ability of protein nanoparticle preparations and water. The formation of long-living discrete water cluster structures possessing chiral properties was substantiated for explaining the manifestation of effects of weak impacts and low concentrations on biological objects.

Multi proxy approach to evaluate and delineate the potential of hot springs in the Kotli District (Kashmir, Pakistan)

Tattapani hot springs are located near the Kotli District of Azad Kashmir, Pakistan. This study evaluates these hot springs based on surface geological information, radon emission measurements, hydro-geochemical and isotopic signatures and potential source mechanisms. Field observations reveal that the hot springs are located at the crest of the Tattapani anticline along the faulted contact of Cambrian carbonates with Paleocene siliciclastics. In addition, remnants of igneous intrusions in the Cambrian carbonates are commonly observed. Spatial distribution of radon emissions (ranging between 2.1 and 29.5KBq m-3) indicates an anomalous zone located over the Cambrian-Paleocene faulted contact. Hydro-geochemical data show sodium-bicarbonate affinity of hot springs. The highest surface temperature of these springs is recorded at 60.8oC. Average reservoir temperatures based on silica and cation geo-thermometers are 101oC and 115oC, respectively. Giggenbach ternary diagram (Na-K-Mg) suggests a non-equilibrium state between fluid and rock, whereas isotopic and chemical data indicate heat loss by conductive cooling and mixing with groundwater during the flow of thermal water up to the surface. Oxygen and deuterium isotopes indicate that thermal water is of meteoric origin, rain and/or snow in the north at higher altitudes providing the potential recharge. Furthermore, absence of tritium in the thermal water suggests a residence time of more than 50 years.

New therapeutic agents marketed in 2017: Part 1

Abstract Objective To provide information on the most important properties of new therapeutic agents marketed in 2017. Data sources Product labeling supplemented selectively with published studies and drug information reference sources. Data synthesis Seven new therapeutic agents marketed in the United States in early 2017 are considered in this first part of a series: ocrelizumab, safinamide mesylate, edaravone, valbenazine tosylate, deutetrabenazine, crisaborole, and dupilumab. Indications, mechanisms of action, and information on dosage and administration for these new agents are reviewed, as are the most important pharmacokinetic properties, adverse events, and other risks and precautions. The new drugs are compared with older drugs marketed for the same indications, and advantages and disadvantages are identified. Summary Ocrelizumab is the first drug shown to be effective in the treatment of primary progressive multiple sclerosis and is more effective than interferon beta-1a in the treatment of relapsing multiple sclerosis. Safinamide is the third monoamine oxidase type B inhibitor for the treatment of patients with Parkinson disease, joining rasagiline and selegilene. Edaravone is only the second drug to be approved for the treatment of amyotrophic lateral sclerosis (ALS), joining riluzole, and has been reported to slow the worsening of ALS symptoms. Valbenazine is the first drug demonstrated to be effective for the treatment of tardive dyskinesia, a neurological disorder that is most often experienced by patients treated for long periods with antipsychotic medications. Deutetrabenazine is the deuterated form of tetrabenazine in which deuterium, the heavy isotope of regular hydrogen, is used instead of hydrogen in two of the substituent groups. Both agents are used to treat chorea associated with Huntington disease, but deutetrabenazine has a longer duration of action, may be administered less frequently, and may be better tolerated. Crisaborole joins the topical corticosteroids and topical calcineurin inhibitors as options for the topical treatment of mild to moderate atopic dermatitis. Dupilumab, which inhibits interleukins 4 and 13, is administered subcutaneously for the treatment of adults with moderate to severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.

Hydrogen Isotope Separation By Using Alkaline Fuel Cell

Introduction The heavy hydrogen isotopes, deuterium (D) and tritium (T) are important materials in the field of nuclear energy. Particularly in recent years, development of new effective separation method is required for the water contaminated by the T. Every day the enormous volume is accumulating in Fukushima Daiichi Nuclear Power Plant. The water electrolysis, which is the industrially most general separation method, has disadvantage that consume energy is tremendous. To solve this point, we have investigated novel hydrogen isotope separation system named Combined Electrolysis Fuel Cell (CEFC) [1]. In this system, hydrogen and oxygen produced by electrolysis is used for power generation in fuel cell. From this, we can save energy and get further isotope effect by electrochemical reaction in fuel cell. Actually we reported that the D isotope was enriched in water phase by fuel cells with anion or cation conducting polymer [2, 3]. Here, we newly focused on another type of fuel cell, Alkaline Fuel Cell (AFC), and investigated the separation mechanism by several electrochemical methods. Experimental The anode was Ru catalyst supported by carbon and the cathode was Pt one. The electrolyte was 30 wt.% KOH solution. Pure H2­­ or D2 gas was supplied to anode and air was did to cathode. The reference electrode was Hg/HgO. Linear sweep amperometry was measured at the scan rate of 20 mA/sec until the cell voltage reached 0.4 V. Simultaneously electrochemical impedance spectroscopy (EIS) was carried out by frequency analyzer. The frequency range was from 0.1 Hz to 1 x 104 Hz. The experimental temperature was 50 ºC. 3．Results Figure 1 shows the cell voltage-current curves of AFC. The same values of cell voltage at 0 A did not clearly demonstrate that the equilibrium potential of hydrogen oxidation reaction depended on the isotopes. The activation overvoltage, which can be detected as the voltage drop when the current was applied, was about 0.2 V for both gases. On the one hand, the cell voltage decreased linearly until the current reached 1400 mA when H2 gas was used. On the other hand, the voltage of D2 result was remarkably fallen at 1160 mA. The difference of the cell voltage was mainly attributed to the anode potential. This result suggested that the H2 gas transportation in the gas diffusion layer was faster than that of D2 probably. In the meeting, we report the separation factor of the D in a ddition to the EIS results. [1] H. Matsushima, T. Nohira, T. Kitabata, Y. Ito, Energy. 30 (2005) 2413. [2] S. Shibuya, H. Matsushima, M. Ueda, J. Electrochem. Soc. 163 (2016) F704 [3] R. Ogawa, H. Matsushima, M. Ueda, Electrochem. Commun. 70 (2016) 5. Figure 1

Long-term data set analysis of stable isotopic composition in German rivers

Stable isotopes oxygen-18 (18O) and deuterium (2H) are commonly used to investigate hydrological processes in catchments. However, only a few isotope studies have been conducted on a large scale and rarely over long time periods. The objective of this study was to identify the spatial and seasonal variability of isotopic composition in river water and how it is affected by geographical and hydrological factors. The stable isotopic composition of river water has been measured in nine large river catchments in Germany for a time period of 12years or 26years. We conducted time series and correlation analyses to identify spatial and temporal patterns of the isotopic composition in the rivers. Further, we compared it to isotopic composition in local precipitation and catchments characteristics. In the majority of the rivers, the spatial and temporal patterns of precipitation were directly reflected in river water. The isotopic signals of the river water were time shifted and show attenuated amplitudes. Further deviations from isotopic compositions in local precipitation were observed in catchments with complex flow systems. These deviations were attributed to catchment processes and influences like evaporation, damming and storage. The seasonality of the isotopic composition was mainly determined by the discharge regimes of the rivers. We found correlations between isotopic long-term averages and catchment altitude as well as latitude and longitude, resulting in a northwest-southeast gradient. Furthermore, it was shown that long-term averages of d-excess were inversely related to flow length and catchment size, which indicates that evaporation enrichment has an impact on the isotopic composition even in catchments of humid climates. This study showed that isotopic composition in rivers can serve as a proxy for the local precipitation and can be utilized as an indicator for hydrological processes even in large river basins. In future, such long time series will help to also understand the impact of changes in the hydrological cycle on the larger scales. They can also be used for calibration and validation of flow and transport models at catchment and sub-catchment scale.

D/H ratio analysis of pyrolysis-released n-alkanes from asphaltenes for correlating oils from different sources

When oil has been greatly altered by severe biodegradation, asphaltene pyrolysis is commonly conducted to obtain intact n-alkanes for carbon isotope analysis, through which oil source characterization and oil–oil correlations can be performed. The ratio of hydrogen isotopes deuterium and hydrogen (D/H ratio) in the individual n-alkanes of oil maltenes has been shown to indicate differences between the depositional environments of the oil sources. The utility of the D/H ratio analysis of n-alkanes from the asphaltene pyrolysis for oil correlation need to be demonstrated. In this study, 18 asphaltene samples from different sources were collected and isothermally pyrolyzed in sealed gold tubes. Effects of the pyrolysis temperature were first illustrated for molecular ratios of alkanes and aromatic compounds and for D/H ratios of pyrolysis-yielded n-alkanes. In the case of n-alkanes in oil maltenes being unavailable for analysis after severe biodegradation, the D/H ratio range of the n-alkanes from the asphaltene pyrolysis was found to be consistent both in normal and biodegraded oils from the same source, indicating that biodegradation has had little effect on their hydrogen isotope signatures. In addition, n-alkanes yielded by asphaltenes from different sources possess clearly different D/H ratios, enabling n-alkane correlation between maltenes that are otherwise very similar. However, relatively large differences of D/H ratios can exist between n-alkanes in the asphaltene pyrolyzates and in maltenes, once the oil was altered by oil mixing formed at different maturity levels. The proposed method is thus helpful in oil–oil correlation for significantly biodegraded oil and oil from a mixed origin.

Initial Results of Density Modulation Experiment for Study of Hydrogen Isotope Effects on Particle Transport in Heliotron J

The effects of hydrogen isotopes (hydrogen and deuterium) were investigated in electron-cyclotron-resonance-heated plasma in the Heliotron J. In order to evaluate particle diffusivity and convection velocity separately, density modulation experiments were performed. Different modulation frequencies (50, 100, and 125 Hz) were applied in order to confirm the results. A smaller diffusion coefficient and a lower inwardly directed convection velocity were obtained at 50 Hz modulation in deuterium-dominant plasma than in hydrogen-dominant plasma, while clear differences were not found at 100 and 125 Hz. The difference in the estimated values is likely to be due to a different spatial response at each frequency. The results suggest that an isotope effect on particle confinement exists in Heliotron J.

Isotope effect on filament dynamics in fusion edge plasmas

The influence of the ion mass on filament propagation in the scrape-off layer of toroidal magnetised plasmas is analysed for various fusion relevant majority species, like hydrogen isotopes and helium, on the basis of a computational isothermal gyrofluid model for the plasma edge. Heavy hydrogen isotope plasmas show slower outward filament propagation and thus improved confinement properties compared to light isotope plasmas, regardless of collisionality regimes. Similarly, filaments in fully ionised helium move more slowly than in deuterium. Different mass effects on the filament inertia through polarisation, finite Larmor radius, and parallel dynamics are identified.

Review of hydrogen isotopes transport parameters and considerations to corresponding experiments

The hydrogen isotopes tritium and deuterium as fuel of future fusion power plants will be in contact with several plant components: Reduced Activation Ferritic Martensitic (RAFM) steel parts of the blanket and austenitic steels used for pipelines and process equipment. Temperatures range from ambient up to 550°C. Since both steel kinds can store and transport hydrogen to a considerable extent, design and safety analyses depend on hydrogen transport parameters for these materials over the full operation temperature range. Therefore, a qualified data base will be necessary for the future work on DEMO.This contribution presents an overview of available transport parameters of different RAFM and austenitic steels, also regarding exothermic hydride generating alloy elements and pure elements. A pre-selection of materials for a planned permeation chamber is discussed on the base of these data.

Hydrogen Isotope Separation By Combined Electrolysis Fuel Cell

The heavy isotopes of hydrogen, deuterium (D) and tritium (T) are materially important in nuclear energy production. In current heavy-water nuclear fission reactors, D is used as a neutron-moderator. Similarly, in nuclear fusion reactors, which are expected to represent the next generation of nuclear power, the reaction of D and T is responsible for the energy production stage. Many researchers have studied various isotope-separation methods, including water distillation, chemical exchange, water electrolysis and combined electrolysis catalytic exchange (CECE). The electrolysis method yields the most effective separation but the process consumes enormous amounts of electricity. This has led to a search for other methods that are more energetically efficient. In an attempt to solve the above problem, we proposed a new concept of hydrogen separation system: the Combined Electrolysis Fuel Cell (CEFC) process [1]. Here, hydrogen and oxygen were produced by electrolysis and used for power generation by fuel cells. Less electricity was consumed by the separation process owing to the implementation of hydrogen energy recycling. More recent works have reported the hydrogen isotope effect in polymer electrolyte fuel cells (PEFCs) [2, 3]. We found that CEFC could reduce 20 % electric energy, comparing with the only electric separation process. Furthermore, CEFC showed the high separation factor (α ≃10) due to the synergistic effect of PEFC and water electrolysis. Here, we will discuss the separation efficiency and the calculation of the total energy consumption by CEFC in several electrolytic and FC conditions. REFERENCES [1] H. Matsushima et al., Energy, 30 (2005) 2413. [2] R. Ogawa et al., Electrochemistry Communications, 70 (2016) 5. [3] S. Shibuya et al., Journal of The Electrochemical Society, 163 (2016) F704

Deuterium retention and desorption properties of ternary beryllide pebbles as advanced neutron multipliers

Beryllium intermetallic compounds (beryllides) such as Be12Ti and Be12V are the most promising advanced neutron multipliers in demonstration (DEMO) power reactors because of their low swelling and high stability at high temperature. In this work, single-phase Be12Ti and Be12V pebbles produced by a novel process combining plasma sintering and rotating electrode methods were successfully fabricated. In parallel to the successful fabrication of binary beryllide pebbles, new research and development on ternary beryllides was begun to determine preferable pebble compositions in terms of mass production and improved properties. The desorption properties and retention of hydrogen isotopes (deuterium) using the newly developed ternary beryllide pebbles indicated that the ternary pebbles exhibited better deuterium desorption properties, such as lower starting-up temperature, total retention, and activation energy for deuterium desorption, than these for beryllium.

QM/MD Simulations on Graphene Hydrogenation/Deuteration: CxH/D Formation Mechanism and Isotope Effect

In this work, we performed QM/MD simulations to investigate the hydrogenation process on quasi-free-standing graphene. We found that, at a lower hydrogen incident energy of 0.4 eV, chemisorption occurred in principle in random positions on the graphene surface with little preference for the adsorption site, causing H-frustrated adsorption patterns over time. However, during prolonged exposure to hydrogen, a para-adsorption pattern emerged, producing 25% maximum coverage. In contrast, at higher incident energies of 1.0 and 1.5 eV, the H-frustration pattern emerged at all times, and a higher hydrogen maximum coverage of ∼50% or 60% was reached. This is because the higher incident energies of 1.0 and 1.5 eV can overcome the barrier of 0.63 eV for continuing hydrogen chemisorption on the C4H structure. Based on potential energy curves for C4H–H with H, hydrogenation on para neighbors is a barrierless reaction, favoring the formation of armchair-like C2H structures. The isotope deuterium increased the coverage...

A study on hydrogen isotopes transport in a liquid metal GaInSn by plasma-driven permeation method

The application of liquid metals such as gallium, tin and lithium as plasma-facing materials is a potential means to resolve the technical issues associated with power exhausting and particle handing in magnetic fusion devices. GaInSn alloy with melting point of 10.5°C, is employed as a modeling material to explore the plasma-driven permeation (PDP) method to study the hydrogen isotopes (hydrogen and deuterium) transport parameters in a liquid metal. Static liquid GaInSn membranes sitting on a mesh sheet are exposed to hydrogen/deuterium plasmas in the linear plasma device VEHICLE-1 with the temperature range of 280–496°C. Hydrogen/deuterium diffusivity are obtained by fitting the time evolutions of permeation fluxes. The dynamic hydrogen/deuterium retention in the liquid GaInSn are found to be low (∼1015D/cm3), which are consistent with the thermal desorption spectroscopy (TDS) measurement following plasma exposure. The hydrogen and deuterium transport parameters are found to be close to each other.

Gyrokinetic characterization of the isotope effect in turbulent transport at the FT-2 tokamak

Isotope effect allows fusion devices to perform better when heavier hydrogen isotopes are used as fuel, but the reason for this improvement is not yet understood. We present the first direct evidence of the isotope effect on particle confinement in the FT-2 tokamak and investigate it via gyrokinetic simulations. Experimental measurements for comparable hydrogen and deuterium discharges show that the particle confinement time increases by 40% for the heavier isotope species. The isotope effect on particle flux is reproduced in global and local gyrokinetic simulations. Global ELMFIRE simulations demonstrate a systemic reduction in particle fluxes across the radial range, showing a ratio of fluxes at the edge and at . Local GENE simulations agree qualitatively with the result. Besides the fluctuation level, smaller scales and a favorable shift in the cross-phase between the turbulent fluctuations are found to contribute to the isotope effect in the simulations.

Capture of heavy hydrogen isotopes in a metal-organic framework with active Cu(I) sites

The production of pure deuterium and the removal of tritium from nuclear waste are the key challenges in separation of light isotopes. Presently, the technological methods are extremely energy- and cost-intensive. Here we report the capture of heavy hydrogen isotopes from hydrogen gas by selective adsorption at Cu(I) sites in a metal-organic framework. At the strongly binding Cu(I) sites (32 kJ mol−1) nuclear quantum effects result in higher adsorption enthalpies of heavier isotopes. The capture mechanism takes place most efficiently at temperatures above 80 K, when an isotope exchange allows the preferential adsorption of heavy isotopologues from the gas phase. Large difference in adsorption enthalpy of 2.5 kJ mol−1 between D2 and H2 results in D2-over-H2 selectivity of 11 at 100 K, to the best of our knowledge the largest value known to date. Combination of thermal desorption spectroscopy, Raman measurements, inelastic neutron scattering and first principles calculations for H2/D2 mixtures allows the prediction of selectivities for tritium-containing isotopologues.

Determination of new anthropometric cut-off values for obesity screening in Indonesian adults.

Body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), and waist-to-stature ratio (WSR) have increasingly been used as screening tools for obesity. However, optimal cut-off values may be different between populations. The current study determined the optimum cut-off values for BMI, WC, WHR, and WSR for obesity screening in Indonesian adults using receiver-operating characteristic (ROC) analysis. Stature, body weight, waist and hip circumferences were measured on 600 Indonesians aged 18-65 years (males, n=292; females, n=308) and BMI, WHR, and WSR calculated. Percentage of body fat (%BF) was determined using the deuterium isotope (D2O) dilution technique. Some existing cut-off points for obesity determination were evaluated for sensitivity and specificity. The existing cutoff values showed low sensitivity in our sample (between 18.4 and 71.1%) and new proposed cut-offs increased the sensitivity to reach 66.7 to 88.5%. The new cut-offs for BMI, WC, WHR, and WSR for determination of obesity were 21.9 (kg/m2), 76.8 (cm), 0.86, and 0.48, respectively, for males and 23.6 (kg/m2), 71.7 (cm), 0.77, and 0.47, respectively, for females. WC and WSR are the most predictive both for males and females, and therefore are considered as better screening tools for obesity in this population.

Determination the Origin of Mineralization in the Coastal Aquifer Northeast Tunisia by Isotopic Method

A geochemical and isotopic techniques were undertaken to characterize groundwater in Northeast Tunisia. Hydrogeochemical investigations demonstrated that groundwater can be classified into different water facies. The Ras Djebel-RafRaf aquifer showed a (Ca-Cl-SO4) and (Na-Cl-NO3) water type. Data inferred from 18O and deuterium isotopes in groundwater samples indicated recharge with modern rainfall. Water characterized by lower δ18O and δ2H values is interpreted as recharged by non-evaporated rainfall originating from Mediterranean air masses from Mediterranean air masses at higher altitude. However, water with relatively enriched δ18O and δ2H contents is thought to reflect the occurrence of an evaporation process related to the long-term practice of flood irrigation.