No modulatory effect of neurokinin-1 receptor antagonists on serotonin uptake in human and rat brain synaptosomes

Some studies have demonstrated antidepressant activity of neurokinin-1-receptor antagonists (NK-1-RA) in major depressive disorder. However, the underlying mechanisms of this antidepressant effect are largely unknown. Preclinical studies in rats and mice have suggested that NK-1-RA do increase the neuronal release of serotonin (5-HT). This, however, seems to be compensated by an increased 5-HT reuptake, indicating that NK-1-RA have no inhibitory effect on the 5-HT transporter in rodents. Given the possibility that modulation of neurotransmitter release and reuptake may differ between species, with major differences found between rodents and humans, we investigated for the first time the possible modulatory effect of NK-1-RA on 5-HT uptake in human brain synaptosomes and compared it with the situation in rat cortex. We found that the specific human NK-1-RA L-733060, in contrast to the SSRI fluvoxamine (IC₅₀ = 10^− 7.96 M) did not inhibit 5-HT uptake in human brain synaptosomes and did not modulate fluvoxamine-induced 5-HT uptake inhibition at 1 μM. Furthermore, substance P as well as Sar⁹Met(O₂)¹¹SP, as the major agonists at the NK-1-R, did not modulate 5-HT uptake in human brain synaptosomes. Similar results were found in rat cortex synaptosomes by using the rat-specific NK-1-RA WIN51708. These results show that in humans, as in rodents, inhibition of the 5-HT transporter is probably not the underlying mechanism of the assumed antidepressant activity of NK-1-RA.     

Extension of in-use stability of preservative-free nasalia.

Nasal drops and nasal sprays are commonly supplied in multi-dose containers that usually include suitable levels of an appropriate preservative in order to kill or prevent growth of any microorganisms which might enter the dispensing system. Preservatives should both protect the patient from infection and prevent spoilage of the product. Unfortunately, preservatives often cause unwanted side effects; in particular, the nasal mucosa is irritated frequently. Consequently, the use of preservatives in nasal preparations should be avoided. The technical design of the 3K system, a new multi-dose container, combines several microbiological safety features and therefore allows use without preservatives. Earlier tests have shown its safety for 6 weeks after the first opening. In order to test the microbiological safety of this multi-dose system over longer time periods, an in-use stability test was designed. The results revealed that the first dose as well as the contents complied with the requirements of the European Pharmacopoeia. Therefore, from a microbiological point of view for the tested nasalia in the 3K system, the stability after opening could be extended from 6 weeks up to several months without loss of microbiological quality.     

Influence of process parameters in the ASES process on particle properties of budesonide for pulmonary delivery.

Budesonide was micronized by precipitation in supercritical carbon dioxide by using the aerosol solvent extraction system at various process conditions. The process is characterised by spraying an organic solution of budesonide into the supercritical fluid (SCF), precipitation of the drug in the SCF and extraction and recovery of the solvent. The micronized budesonide particles were characterized physico-chemically for their morphology, crystallinity, size distribution and for their aerodynamic behaviour. The particle size distribution of the powder products was similar, regardless of the process conditions used for the crystallization. Also, the morphology of the particles did not differ between the batches. However, the aerodynamic properties of the precipitated batches were significantly different between the batches produced and as compared to a jet-milled budesonide powder. In conclusion, the process conditions in the SCF precipitation may influence the aerodynamic properties, although other physico-chemical parameters appear to be similar.     

Bluetongue Virus Infection of Goats: Re-Emerged European Serotype 8 vs. Two Atypical Serotypes

In recent years, numerous atypical Bluetongue virus (BTV) strains have been discovered all around the world. Atypical BTV strains are phylogenetically distinct from the classical BTV serotypes 1–24 and differ in terms of several biological features. For the first time, the atypical strains BTV-25-GER2018 and BTV-33-MNG3/2016 as well as the re-emerged classical strain BTV-8-GER2018 were evaluated comparatively in a pathogenesis study in goats—the natural host of atypical BTV. A substantial number of in-contact animals were included in this study to detect potential contact transmissions of the virus. After infection, EDTA blood, ocular, nasal and oral swab samples as well as serum were collected regularly and were used for virological and serological analyses, respectively. Our study showed differences in the immunological reaction between the two atypical BTV strains (no group-specific antibody detection) and the classical BTV strain BTV-8-GER2018 (group-specific antibody detection). Furthermore, we observed an increase in the total WBC count (neutrophils and lymphocytes) in goats infected with the atypical BTV strains. No horizontal transmission was seen for all three strains. Our study suggests that the atypical BTVs used in the trial differ from classical BTVs in their immunopathogenesis. However, no evidence of direct contact transmission was found.     

Rhombohedral Phase Formation in Yttria-Stabilized Zirconia Induced by Dental Technical Tools and Its Impact on Dental Applications

In the study the influence of different dental technical tools on the surface temperature and phase composition of fixed dental prostheses (FDPs) made of yttria-partially stabilized zirconia polycrystals (3Y-/4Y-/5Y-PSZ) was investigated. FDPs were fabricated by using computer-aided manufacturing (CAM). The FDPs were treated with a contra-angle handpiece equipped with different burs and polishers. The resulting surface temperatures were measured with a thermographic camera, and the resulting phase transformations were investigated by X-ray diffraction and quantified by Rietveld refinement. Processing with burs resulted in no phase transformation, but a preferred orientation shift. Using coarse polisher induced a phase transformation to the rhombohedral phase, while fine polishers produced no relevant phase transformations and no preferred orientation shift. Compared to the monoclinic phase (ca. 9% theoretical volume increase), which is associated with low-temperature degradation (LTD), the rhombohedral phase is much more voluminous (ca. 15% theoretical volume increase) and distorted and, therefore, has a greater degradation potential.     

Consumption of vegetables and fruits and risk of subtypes of head–neck cancer in the Netherlands Cohort Study

There is limited prospective data on the relationship between consumption of vegetables and fruits and the risk of head–neck cancer (HNC) subtypes [i.e., oral cavity cancer (OCC), oro‐/hypopharyngeal cancer (OHPC) and laryngeal cancer (LC)]. Therefore, we investigated these associations within the Netherlands Cohort Study, in which 120,852 participants completed a 150‐item food frequency questionnaire at baseline in 1986. After 20.3 years of follow‐up, 415 cases of HNC (131 OCC, 88 OHPC, three oral cavity/pharynx unspecified or overlapping and 193 LC) and 3,898 subcohort members were available for case–cohort analysis using Cox proportional hazards models. Total vegetable and fruit consumption was inversely associated with risk of HNC overall [multivariable‐adjusted rate ratios for highest vs. lowest quartile: 0.61, 95% confidence interval (CI) 0.44–0.85, p trend 0.002] and all HNC subtypes, with the strongest associations for OCC. Total vegetable intake and total fruit intake were also associated with a decreased risk of HNC overall and HNC subtypes. No significant interaction was found between vegetable and fruit intake and alcohol consumption or cigarette smoking. In conclusion, in this large‐scale cohort study, consumption of vegetables and fruits was associated with a decreased risk of HNC overall and all subtypes. Consumption of vegetables and fruits (or of specific groups of them) may protect against HNC and its subtypes.     

Uredinorubellins and caeruleoramularin, photodynamically active anthraquinone derivatives produced by two species of the genus ramularia

Both the phytopathogenic fungus Ramularia collo-cygni and the hyperparasite R. uredinicola biosynthesize a number of red and yellow anthraquinone derivatives called rubellins. The new compounds uredinorubellins I and II, which were isolated from R. uredinicola, contribute to understanding the biosynthesis pathway that leads from simple anthraquinones to the rubellins. In addition, we isolated for the first time such simple compounds as chrysophanol and helminthsporin from both Ramularia species. A blue compound isolated from the mycelium of R. collo-cygni was revealed to be a unique 9,4-anthracenedione derivative. Structure elucidation by (1)H and (13)C NMR of the new but unstable compound caeruleoramularin was possible only by feeding the fungus different labeled (13)C acetates. The photodynamic activity of the uredinorubellins was comparable to rubellin D, whereas chrysophanol and caeruleoramularin did not display such activity.