Histamine H3 receptor ligands break ground in a remarkable plethora of therapeutic areas

The neurotransmitter histamine exerts its action through four distinct histamine receptors. The histamine H(1) and H(2) receptor are well established drug targets, whereas the histamine H(4) receptor is undergoing rigorous characterisation at present. The histamine H(3) receptor (H(3)R) is a G(i/o)-protein coupled receptor and is mostly expressed in the CNS. A remarkably large and different array of therapeutic areas, in which ligands for the H(3)R may prove useful, has been identified and a massive research undertaking is underway to substantiate the high expectations for H(3)R ligands. At present, several ligands for the H(3)R are being evaluated in clinical studies. In this review, the many potential therapeutic areas for H(3)R antagonists, inverse agonists and agonists is discussed. Promising medicinal chemistry and toxicological developments, as well as the advancement of several H(3)R ligands into the clinic, will be highlighted. This review also describes the problems that have been overcome and the questions that remain in developing H(3)R-related drugs. Considering the tremendous efforts by industry, it can be expected that the first H(3)R drugs will reach the market soon.     

On the effective point of measurement in megavoltage photon beams

This paper presents a numerical investigation of the effective point of measurement of thimble ionization chambers in megavoltage photon beams using Monte Carlo simulations with the EGSNRC system. It is shown that the effective point of measurement for relative photon beam dosimetry depends on every detail of the chamber design, including the cavity length, the mass density of the wall material, and the size of the central electrode, in addition to the cavity radius. Moreover, the effective point of measurement also depends on the beam quality and the field size. The paper therefore argues that the upstream shift of 0.6 times the cavity radius, recommended in current dosimetry protocols, is inadequate for accurate relative photon beam dosimetry, particularly in the build-up region. On the other hand, once the effective point of measurement is selected appropriately, measured depth-ionization curves can be equated to measured depth-dose curves for all depths within +/- 0.5%.     

Iatrogenic mitral stenosis following transcatheter aortic valve replacement (TAVR)

A 57 year old female underwent transcatheter aortic valve replacement (TAVR) for severe aortic stenosis. Mild iatrogenic mitral stenosis was noted intraoperatively. Attempts to reposition the device were hampered by aortic angulation. One year later, severe mitral stenosis was confirmed on transoesophageal echocardiography. It is important to recognise that iatorgenic mitral stenosis due to TAVR may progress over time. Care should be taken to minimise the risk of this rare complication     

Magnetic and Tunable Sound Absorption Properties of an In-Situ Prepared Magnetorheological Foam

Conventional polyurethane foam has non-tunable sound absorption properties. Here, a magneto-induced foam, called magnetorheological (MR) foam, was fabricated with the feature of being able to tune sound absorption properties, primarily from the middle- to higher-frequency ranges. Three different samples of MR foams were fabricated in situ by varying the concentration of Carbonyl Iron Particles (CIPs) (0, 35, and 75 wt.%). The magnetization properties and tunable sound absorption characteristics were evaluated. From the magnetic saturation properties, the results showed very narrow and small coercivity of hysteresis loops relative to the soft magnetic properties of the CIPs. MR foam with 75 wt.% CIPs showed a higher magnetic saturation at 91.350 emu/g compared to MR foam with 35 wt.% CIPs at 63.896 emu/g. For tunable sound absorption testing, the effect of ‘shifting’ to higher frequency was also observed when the magnetic field was applied, which was ~10 Hz for MR foam with 35 wt.% CIPs and ~130 Hz for MR foam with 75 wt.% CIPs. As the latest evolution of semi-active noise control materials, the results from this study are valuable guidance for the advancement of MR-based devices.     

Online Abortion Drug Sales in Indonesia: A Quality of Care Assessment

This study sought to understand the experience of buying misoprostol online for pregnancy termination in Indonesia. We conducted a mystery client study August through October, 2019. Interactions were analyzed quantitatively and qualitatively, along with the contents of the packages. One hundred ten sellers were contacted, from whom mystery clients made 76 purchases and received 64 drug packages. Almost all sellers sold “packets” containing multiple drugs; 73 percent of packets contained misoprostol, and 47 percent contained at least 800 mcg of misoprostol. Thirty-four packets contained insufficient drugs to complete an abortion. When compared to WHO standards, 87 percent of sellers imparted incomplete information about potential physical effects; no seller provided information about possible complications. Women buying misoprostol from informal online drugs sellers will be underprepared for understanding potential side effects and complications. Educational activities are needed to increase women's access to information about safe use of misoprostol as a harm reduction strategy.     

Über die struktur der aus maleinsäureanhydrid in gegenwart organischer basen erhaltenen polymeren

The structure of the dark polymers of maleic anhydride obtained in the presence of triethylamine and pyridine was investigated. A cis-polyvinyleneketoanhydride structure is suggested for the polymer obtained with triethylamine. The polymer obtained with pyridine is a cis-polyvinyleneketoanhydride but other structural units are also present in its chain (cyclopentanone, maleic anhydride). The polymers display the characteristic properties of polyconjugated polymers: dark colour, signal of electron paramagnetic resonance and solubility only in polar solvents.     

4-benzyl-1H-imidazoles with oxazoline termini as histamine H3 receptor agonists

Research on the therapeutic applications of the histamine H3 receptor (H3R) has traditionally focused on antagonists/inverse agonists. In contrast, H3R agonists have received less attention despite their potential use in several disease areas. The lower availability of H3R agonists not only hampers their full therapeutic exploration, it also prevents an unequivocal understanding of the structural requirements for H3R activation. In the light of these important issues, we present our findings on 4-benzyl-1H-imidazole-based H3R agonists. Starting from two high throughput screen hits (10 and 11), the benzyl side chain was altered with lipophilic groups using combinatorial and classical chemical approaches (compounds 12-31). Alkyne- or oxazolino-substituents gave excellent affinities and agonist activities up to the single digit nM range. Our findings further substantiate the growing notion that basic ligand sidechains are not necessary for H 3R activation and reveal the oxazolino group as a hitherto unexplored functional group in H3R research.