Study Objective Serotonergic adverse drug events (ADEs) are caused by enhanced intra-synaptic concentrations of 5-hydroxytryptamine (5-HT). No systematic process currently exists for evaluating cumulative 5-HT and off-target toxicity of serotonergic drugs. The primary study aim was to create a Serotonergic Expanded Bioactivity Matrix (SEBM) employing a molecular bioinformatics, poly-pharmacologic approach for assessing the participation of individual 5-HT drugs in serotonin syndrome (SS) reports. Data Sources Publicly available databases including the Food and Drug Association (FDA) Adverse Event Reporting System (FAERS), ChEMBL, DrugBank, PubChem, and Kyoto Encyclopedia of Genes and Genomes (KEGG) were queried for computational and pharmacologic data. Design An in-house bioinformatics TargetSearch program was used to characterize 71 serotonergic drugs interacting at 13 serotonin receptor subtypes, and serotonin re-uptake transporter protein (SERT). Additionally, off-target interactions at norepinephrine transporter (NET), monoamine oxidase (MAO), and muscarinic receptors were included to define 7 poly-pharmacologic drug cohorts. Serotonin syndrome reports for each serotonergic drug were extracted from FAERS using Sternbach’s and Hunter’s criteria. Measurements and Main Results A proportional reporting adverse drug reaction (ADR) ratio (PRR) was calculated from each drug’s total ADEs and SS case reports and aggregated by drug bioactivity cohorts. Triple receptor interactions had a disproportionately higher number of SS cases using both Hunter’s criteria (mean PRR 1.72; 95% C.I. 1.05 to 2.39) and Sternbach’s (mean PRR 1.54, 95% C.I. 1.29 to 1.79). 5-Hydroxtryptamine agonists were associated with a significantly lower proportion of SS cases using Hunter’s and Sternbach’s criteria, respectively (mean PRR 0.49, 95% C.I. 0.17 to 0.81 and mean PRR 0.49, 95% C.I. 0.15 to 0.83). Drugs with disproportionately higher participation in SS vary considerably between the 2 diagnostic criteria. Conclusion The SEBM model suggests a possible poly-pharmacologic role in SS. Although further research is needed, off-target receptor activity may help explain differences in severity of toxicity and clinical presentation.

BackgroundSyzygium jambos has been used as a traditional medicine for the treatment of inflammatory diseases in Bangladesh. The study investigates the high performance liquid chromatography (HPLC) profiling of phenolic compounds, and evaluates the antioxidant and anti-inflammatory activities of ethanol extract of S. jambos available in Bangladesh.MethodsThe extract was subjected to HPLC for the identification and quantification of the major bioactive polyphenols present in S. jambos. Antioxidant activity was determined using 2, 2′-azino bis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS) radical scavenging, reducing power assay, total antioxidant capacity, total phenolic and flavonoid content. Furthermore, the anti-inflammatory effect of the extract in rats for two different test models: carrageenan and histamine-induced paw edema was inspected.ResultsHigh levels of catechin hydrate and rutin hydrate (99.00 and 79.20 mg/100 g extract, respectively) and moderate amounts of ellagic acid and quercetin (59.40 and 69.30 mg/100 g extract, respectively) were quantified in HPLC. Catechin hydrate from this plant extract was determined for the first time through HPLC. For ABTS scavenging assay, the median inhibition concentration (IC50) value of S. jambos was 57.80 µg/ml, which was significant to that of ascorbic acid (12.01 µg/ml). The maximum absorbance for reducing power assay was found to be 0.4934. The total antioxidant capacity, phenolic and flavonoid contents were calculated to be 628.50 mg/g of ascorbic acid, 230.82 mg/g of gallic acid and 11.84 mg/g of quercetin equivalent, respectively. At a dose of 400 mg/kg, a significant acute anti-inflammatory activity (P < 0.01) was observed in rats for both the test models with a reduction in the paw volume of 58.04 and 53.95 %, in comparison to those of indomethacin (62.94 and 65.79 %), respectively.ConclusionsThe results suggest that the phenolic and flavonoid compounds are responsible for acute anti-inflammatory and antioxidant activities of S. jambos.

PEGylation is a widely adopted process to covalently attach a polyethylene glycol (PEG) polymer to a protein drug for the purpose of optimizing drug clinical performance. While the outcomes of PEGylation in imparting pharmacological advantages have been examined through experimental studies, the underlying molecular mechanisms remain poorly understood. Using interferon (IFN) as a representative model system, we carried out comparative molecular dynamics (MD) simulations of free PEGx, apo-IFN, and PEGx-IFN (x ¼ 50, 100, 200, 300) to characterize the molecular-level changes in IFN introduced by PEGylation. The simulations yielded molecular evidence directly linked to the improved protein stability, bioavailability, retention time, as well as the decrease in protein bioactivity with PEG conjugates. Our results indicate that there is a tradeoff between the benefits and costs of PEGylation. The optimal PEG chain length used in PEGylation needs to strike a good balance among the competing factors and maximizes the overall therapeutic efficacy of the protein drug. We anticipate the study will have a broad implication for protein drug design and development, and provide a unique computational approach in the context of optimizing PEGylated protein drug conjugates.

No abstract