<i>In Vivo</i> Efficacy of a Synthetic Coumarin Derivative in a Murine Model of Aspergillosis

<div><p>Despite advances in therapeutic modalities, aspergillosis remains a leading cause of mortality. This has necessitated the identification of effective and safe antifungal molecules. In the present study, <i>in vivo</i> safety and antifungal efficacy of a coumarin derivative, <i>N</i>, <i>N, N</i>-Triethyl-11-(4-methyl-2-oxo-2<i>H</i>-benzopyran-7-yloxy)-11-oxoundecan-1-aminium bromide (SCD-1), was investigated. The maximum tolerable dose of compound was determined according to OECD 423 guidelines. The compound could be assigned to category IV of the Globally Harmonized System and its LD₅₀ cut-off was found to be 2000 mg/kg body weight. The survival increased in <i>Aspergillus fumigatus-</i>infected mice treated with a dose of 200 mg/kg, orally or 100 mg/kg body weight, intraperitoneally, of SCD-1 in comparison to infected-untreated animals. The SCD-1 treatment resulted in significant reduction in colony counts in vital organs of the animals. Its protective effect was also observed on day 14 as there was marked reduction in fungal colonies. The treatment with SCD-1 also reduced the levels of serum biochemical parameters with respect to infected-untreated animals. It could be concluded that SCD-1 is a quite safe antifungal compound, which conferred dose dependent protection against experimental aspergillosis. Therefore, SCD-1 holds potential for developing new formulations for aspergillosis.</p></div

Treatment of infected mice with different doses of SCD-1.

<p>Treatment of infected mice with different doses of SCD-1.</p

Survival rate in experimental mice.

<p>The animals were challenged intranasally with conidia of <i>A. fumigatus</i> and treated with different doses of SCD-1, daily, upto 14 days.</p

Body weights of experimental mice.

<p>The daily weight (Mean ± SE) of animals belonging to different groups was recorded daily over a period of 14 days.</p

Fungal burden in different organs of experimental animals.

<p>The number of CFUs (Mean ± SE) were determined on 7^th (A) and 14^th (B) day of infection. Asterisks indicate statistically significant differences. *<i>p</i><0.05, **<i>p</i><0.001.</p

List of proteins discussed in the text with their corresponding protein and gene identifiers.

<p>HGNC: HUGO Gene Nomenclature Committee (<a href="http://www.genenames.org/" target="_blank">http://www.genenames.org/</a>).</p

Event codes and names of events as defined in the EU-ADR project [48], [49].

<p>Event codes and names of events as defined in the EU-ADR project <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002457#pcbi.1002457-Vastrik1" target="_blank">[48]</a>, <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002457#pcbi.1002457-BauerMehren2" target="_blank">[49]</a>.</p

Antipsychotics with low and high risk of producing prolongation of the QT interval (QTPROL) and the results of the substantiation process.

<p>The columns display the risk of producing QTPROL for each drug, the drug name, the ATC code of the drug, the proteins that explain the connection between the drug and the event (Drug-event linking proteins), the clinical events associated with these proteins (Events), as well as p-values. For the drug-event linking proteins, the common protein name is given, and the Gene Symbol and the drug activity values of each drug-event linking protein (pKi or pIC50, average of the multiple values from different sources) are shown in parenthesis.</p

Schematic representation of the signal substantiation process.

<p>The signal substantiation process involves the automatic search for evidences that support the causal inference of the potential signal. A. Signal substantiation through proteins. The profile of targets of the drug and its metabolites is obtained by <i>in silico</i> profiling methods (Drug-Target-Profile). The profile of proteins associated with the clinical event is obtained by mining DisGeNET (Event-Protein Profile). The profiles are compared to find proteins in common in both profiles (Drug-Event Linking Proteins). The evidences that support the association of the drug and event with the Drug-Event Linking proteins are explored to determine if they support the causal inference of the signal. B. Signal substantiation through pathways. Proteins in the Drug-Target-Profile and in the Event-Protein Profile are searched in The Human Protein Atlas database to determine if they are expressed in the same tissue and cell type. Proteins that share expression at both levels (tissue and cell type) are used to query Reactome database, and pathways that contain at least one protein from the Drug-Target-Profile and one protein from the Event-Protein Profile are retrieved. Then, these pathways are explored to determine if they support the causal inference of the signal.</p

Antipsychotics with low and high risk of producing prolongation of the QT interval (QTPROL) analyzed with the filtering workflows (ADR-FM and ADR-FD).

<p>For the ADR-FD, the individual results obtained from the three different sources used (Medline, DailyMed and DrugBank) are shown. The table shows the number of records found in each case. NA: Not Available.</p