Medicinal Thiols: Current Status and New Perspectives.

The thiol (-SH) functional group is found in a number of drug compounds and confers a unique combination of useful properties. Thiol-containing drugs can reduce radicals and other toxic electrophiles, restore cellular thiol pools, and form stable complexes with heavy metals such as lead, arsenic, and copper. Thus, thiols can treat a variety of conditions by serving as radical scavengers, GSH prodrugs, or metal chelators. Many of the compounds discussed here have been in use for decades, yet continued exploration of their properties has yielded new understanding in recent years, which can be used to optimize their clinical application and provide insights into the development of new treatments. The purpose of this narrative review is to highlight the biochemistry of currently used thiol drugs within the context of developments reported in the last five years. More specifically, this review focuses on thiol drugs that represent the standard of care for their associated conditions, including N-acetylcysteine, 2,3-meso-dimercaptosuccinic acid, British anti-Lewisite, D-penicillamine, amifostine, and others. Reports of novel dosing regimens, delivery strategies, and clinical applications for these compounds were examined with an eye toward emerging approaches to address a wide range of medical conditions in the future.

Capillary-tube package devices for the quantitative performance evaluation of nuclear magnetic resonance spectrometers and pulse sequences.

With the increased sensitivity of modern nuclear magnetic resonance (NMR) spectrometers, the minimum amount needed for chemical-shift referencing of NMR spectra has decreased to a point where a few microliters can be sufficient to observe a reference signal. The reduction in the amount of required reference material is the basis for the NMR Capillary-tube Package (CapPack) platform that utilizes capillary tubes with inner diameters smaller than 150 µm as NMR-tube inserts for external reference standards. It is shown how commercially available electrophoresis capillary tubes with outer diameters of 360 µm are filled with reference liquids or solutions and then permanently sealed by the arc discharge plasma of a commercially available fusion splicer normally employed for joining optical fibers. The permanently sealed capillaries can be used as external references for chemical-shift, signal-to-noise, resolution, and concentration calibration. Combining a number of permanently sealed capillaries to form CapPack devices leads to additional applications such as performance evaluation of NMR spectrometers and NMR pulse sequences. A 10-capillary-tube side-by-side Gradient CapPack device is used in combination with one or two constant gradients, produced by room-temperature shim coils, to monitor the excitation profiles of shaped pulses. One example illustrates the performance of hyperbolic secant (sech) pulses in the EXponentially Converging Eradication Pulse Train (EXCEPT) solvent suppression sequence. The excitation profile of the pulse sequence is obtained in a single gradient NMR experiment. A clustered T 1 CapPack device is introduced consisting of a coaxial NMR-tube insert that holds seven capillary tubes filled with aqueous solutions of different concentrations of the paramagnetic relaxation agent copper(ii) sulfate (CuSO4). The different CuSO4 concentrations lead to spin-lattice relaxation times in the seven capillary tubes that cover a range which extends to more than an order of magnitude. Clustered T 1 CapPack devices are best suited to quantify the effects that relaxation has on magnetizations and coherences during the execution of NMR experiments, which is demonstrated for the order-of-magnitude T 1 insensitivity of signal suppression with EXCEPT.

Predicting the effect of relaxation during frequency-selective adiabatic pulses.

Adiabatic half and full passages are invaluable for achieving uniform, B1-insensitive excitation or inversion of macroscopic magnetization across a well-defined range of NMR frequencies. To accomplish narrow frequency ranges with adiabatic pulses (<100Hz), long pulse durations at low RF power levels are necessary, and relaxation during these pulses may no longer be negligible. A numerical, discrete recursive combination of the Bloch equations for longitudinal and transverse relaxation with the optimized equation for adiabatic angular motion of magnetization is used to calculate the trajectory of magnetization including its relaxation during adiabatic hyperbolic secant pulses. The agreement of computer-calculated data with experimental results demonstrates that, in non-viscous, small-molecule fluids, it is possible to model magnetization and relaxation by considering standard T1 and T2 relaxation in the traditional rotating frame. The proposed model is aimed at performance optimizations of applications in which these pulses are employed. It differs from previous reports which focused on short high-power adiabatic pulses and relaxation that is governed by dipole-dipole interactions, cross polarization, or chemical exchange.

EXponentially Converging Eradication Pulse Train (EXCEPT) for solvent-signal suppression in investigations with variable T(1) times.

Selective presaturation is a common technique for suppressing excessive solvent signals during proton NMR analysis of dilute samples in protic solvents. When the solvent T1 relaxation time constant varies within a series of samples, parameters for the presaturation sequence must often be re-adjusted for each sample. The EXCEPT (EXponentially Converging Eradication Pulse Train) presaturation pulse sequence was developed to eliminate time consuming pulse-parameter re-optimization as long as the variation in the solvent's T1 remains within an order of magnitude. EXCEPT consists of frequency-selective inversion pulses with progressively decreasing interpulse delays. The interpulse delays were optimized to encompass T1 relaxation times ranging from 1 to 10s, but they can be easily adjusted by a single factor for other ranges that fall within an order of magnitude with respect to T1. Sequences with different numbers of inversion pulses were tested to maximize suppression while minimizing the number of pulses and thus the total time needed for suppression. The EXCEPT-16 experiment, where 16 denotes the number of inversion pulses, was found satisfactory for many standard applications. Experimental results demonstrate that EXCEPT provides effective T1-insensitive solvent suppression as predicted by the theory. The robustness of EXCEPT with respect to changes in solvent T1 allows NMR investigations to be carried out for a series of samples without the need for pulse-parameter re-optimization for each sample.