RESUMO
Background: Dizziness is a common leading symptom in bilateral vestibulopathy (BVP) and functional dizziness (FD), with significant negative effects on functional ability and quality of life. Vertigoheel is a widely used non-prescription drug for the treatment of vertigo. In order to generate systematic data for Vertigoheel in BVP and FD, we conducted a non-interventional study assessing vertigo symptoms. Methods: This study was conducted as an open-label, prospective, monocentric, non-interventional case series (ClinicalTrials.gov identifier NCT05897853). Patients with BVP and FD received Vertigoheel according to market approval for an observational period of 2 months. Change from baseline after 2 months was assessed for the following endpoints: Dizziness Handicap Inventory (DHI) as the primary endpoint, quality of life (QoL) by EQ-5D-5L, and body sway by static posturography. Patients with FD were additionally assessed for depression and anxiety by PHQ-9 and GAD-7 questionnaires. Patients with BVP were assessed for vestibular function by video head impulse testing and caloric testing. Adverse events and other safety-related observations were evaluated. Results: Of 41 patients with FD and 13 with BVP, two with FD and none with BVP dropped out before the follow-up visit. Both patient groups showed significantly improved disability caused by dizziness after 2 months: In BVP, the DHI decreased on average by 13.2 points from 45.4 to 32.2 (p < 0.001). In FD, the DHI decreased on average by 12.0 points from 46.5 to 34.5 (p < 0.001). In patients with FD, significant improvements were also observed for the secondary endpoints QoL, anxiety, and depression. No significant change was observed for posturography readouts. In patients with BVP, there were no statistically significant improvements for the secondary endpoints QoL, posturography, or vestibular function within the observation period. The study found no evidence of a safety risk. Conclusion: The study provides evidence for Vertigoheel's clinical safety and limited evidence - because of the non-interventional design - for its effectiveness in BVP and FD that are considered disease entities with high medical need for new treatment options. The results may serve as the basis for randomized placebo-controlled trials.
RESUMO
Sulfur-oxidizing prokaryotes (SOP) catalyse a central step in the global S-cycle and are of major functional importance for a variety of natural and engineered systems, but our knowledge on their actual diversity and environmental distribution patterns is still rather limited. In this study we developed a specific PCR assay for the detection of dsrAB that encode the reversely operating sirohaem dissimilatory sulfite reductase (rDSR) and are present in many but not all published genomes of SOP. The PCR assay was used to screen 42 strains of SOP (most without published genome sequence) representing the recognized diversity of this guild. For 13 of these strains dsrAB was detected and the respective PCR product was sequenced. Interestingly, most dsrAB-encoding SOP are capable of forming sulfur storage compounds. Phylogenetic analysis demonstrated largely congruent rDSR and 16S rRNA consensus tree topologies, indicating that lateral transfer events did not play an important role in the evolutionary history of known rDSR. Thus, this enzyme represents a suitable phylogenetic marker for diversity analyses of sulfur storage compound-exploiting SOP in the environment. The potential of this new functional gene approach was demonstrated by comparative sequence analyses of all dsrAB present in published metagenomes and by applying it for a SOP census in selected marine worms and an alkaline lake sediment.
Assuntos
Archaea/classificação , Archaea/enzimologia , Bactérias/classificação , Bactérias/enzimologia , Sulfito de Hidrogênio Redutase/genética , Reação em Cadeia da Polimerase/métodos , Compostos de Enxofre/metabolismo , Archaea/genética , Bactérias/genética , DNA Bacteriano/química , DNA Bacteriano/genética , DNA Ribossômico/química , DNA Ribossômico/genética , Dados de Sequência Molecular , Oxirredução , Filogenia , RNA Ribossômico 16S/genética , Análise de Sequência de DNARESUMO
Sequential cleavage of amyloid precursor protein (APP) by ß- and γ-secretases and the formation of Aß peptides are pivotal for Alzheimer's disease. Therefore, a large number of drugs has been developed targeting APP metabolism. However, many pharmacological compounds have been identified in vitro in immortalized APP overexpressing cell lines rather than in primary neurons. Here, we compared the effect of already characterized secretase inhibitors and modulators on Aß formation in primary chicken telencephalic neurons and in a human neuroglioma cell line (H4) ectopically expressing human APP with the Swedish double mutation. Primary chicken neurons replicated the effects of a ß-secretase inhibitor (ß-secretase inhibitor IV), two γ-secretase inhibitors (DAPM, DAPT), two non-steroidal-anti-inflammatory drugs (sulindac sulfide, CW), and of the calpain inhibitor calpeptin. With the exception of the two γ-secretase inhibitors, all tested compounds were more efficacious in primary chicken telencephalic neurons than in the immortalized H4 cell line. Moreover, H4 cells failed to reproduce the effect of calpeptin. Hence, primary chicken telencephalic neurons represent a suitable cell culture model for testing drugs interfering with APP processing and are overall more sensitive to pharmacological interference than immortalized H4 cells ectopically expressing mutant human APP.
Assuntos
Precursor de Proteína beta-Amiloide/metabolismo , Glioma/metabolismo , Neurônios/metabolismo , Telencéfalo/citologia , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ácido Aspártico Endopeptidases/metabolismo , Calpaína/metabolismo , Linhagem Celular Tumoral , Células Cultivadas , Galinhas , Meios de Cultivo Condicionados/química , Humanos , Modelos Animais , Mutação , Neurônios/citologia , Neurônios/efeitos dos fármacos , Telencéfalo/metabolismoRESUMO
Cerebral accumulation of amyloid-beta (Abeta) is characteristic of Alzheimer disease and of amyloid precursor protein (APP) transgenic mice. Here, we assessed the efficacy of CI-1011, an inhibitor of acyl-coenzyme A:cholesterol acyltransferase, which is suitable for clinical use, in reducing amyloid pathology in both young (6.5 months old) and aged (16 months old) human APP transgenic mice. Treatment of young animals with CI-1011 decreased amyloid plaque load in the cortex and hippocampus and reduced the levels of insoluble Abeta40 and Abeta42 and C-terminal fragments of APP in brain extracts. In aged mice, CI-1011 specifically reduced diffuse amyloid plaques with a minor effect on thioflavin S-positive dense-core plaques. Reduced diffusible amyloid was accompanied by suppression of astrogliosis and enhanced microglial activation. Collectively, these data suggest that CI-1011 treatment reduces amyloid burden in human APP mice by limiting generation and increasing clearance of diffusible Abeta.