Heat shock protein 90 (Hsp90) is one of the most potential targets in cancer therapy. We have demonstrated using a combination of molecular docking and fast pulling of ligand (FPL) simulations that marine fungi derivatives can be possible inhibitors, preventing the biological activity of Hsp90. The computational approaches were validated and compared with previous experiments. Based on the benchmark of available inhibitors of Hsp90, the GOLD docking package using the ChemPLP scoring function was found to be superior over both Autodock Vina and Autodock4 in the preliminary estimation of the ligand-binding affinity and binding pose with the Pearson correlation, R = −0.62. Moreover, FPL calculations were also indicated as a suitable approach to refine docking simulations with a correlation coefficient with the experimental data of R = −0.81. Therefore, the binding affinity of marine fungi derivatives to Hsp90 was evaluated. Docking and FPL calculations suggest that five compounds including 23, 40, 46, 48, and 52 are highly potent inhibitors for Hsp90. The obtained results enhance cancer therapy research.

Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) are the commonest bacterial causes of sexually transmitted infections in humans with high incidence of co-infection. Treatment with high doses of ceftriaxone (CRO) and cefixime (CFM) is strongly recommended due to the reduced drug susceptibility of NG. However, their safety and efficacy have not been confirmed. We compared the safety and efficacy of a single 1 g intravenous (IV) dose of ceftriaxone (CRO) plus doxycycline (DOX) versus a single 800 mg oral dose of cefixime (CFM) plus DOX for the treatment of NG-CT co-infection. An open-label randomized controlled trial was conducted on 125 individuals aged > 18 years with untreated gonorrhea and chlamydia to compare a single 1 g intravenous dose of CRO + DOX and a single 800 mg oral dose of CFM + DOX. The primary outcome was the clearance of NG from all the initially infected sites. Secondary outcomes included symptom resolution, changes in the serum clearance levels, glomerular filtration rate, and antibiotic minimum inhibitory concentrations. Both regimens were highly effective in treating gonorrhea with success rates of 96.7% (95% confidence interval [CI] 88.8–99.1%) for CRO and 95.3% (95% CI 87.1–98.4%) for CFM. However, CRO + DOX was superior to CFM + DOX for the treatment of NG-CT co-infection (odds ratio 4.41, 95% CI 1.11–25.7). The safety profiles of the two regimens were similar. CRO + DOX was superior to CFM + DOX for the treatment of NG-CT co-infection. CFM + DOX may be indicated in patients with CRO allergy and in settings where CRO is unavailable. Trial registration ClinicalTrials.gov (NCT05216744) on 31/01/22.

Rivaroxaban (RIV; Xarelto; Janssen Pharmaceuticals, Beerse, Belgium) is one of the direct oral anticoagulants. The drug is a strong substrate of cytochrome P450 (CYP) enzymes and efflux transporters. This study aimed to develop a physiologically‐based pharmacokinetic (PBPK) model for RIV. It contained three hepatic metabolizing enzyme reactions (CYP3A4, CYP2J2, and CYP‐independent) and two active transporter‐mediated transfers (P‐gp and BCRP transporters). To illustrate the performance of the developed RIV PBPK model on the prediction of drug–drug interactions (DDIs), carbamazepine (CBZ) was selected as a case study due to the high DDI potential. Our study results showed that CBZ significantly reduces the exposure of RIV. The area under the concentration‐time curve from zero to infinity (AUC_inf) of RIV was reduced by 35.2% (from 2221.3 to 1438.7 ng*h/ml) and by 25.5% (from 2467.3 to 1838.4 ng*h/ml) after the first dose and at the steady‐state, respectively, whereas the maximum plasma concentration (C_max) of RIV was reduced by 37.7% (from 266.3 to 166.1 ng/ml) and 36.4% (from 282.3 to 179.5 ng/ml), respectively. The developed PBPK model of RIV could be paired with PBPK models of other interested perpetrators to predict DDI profiles. Further studies investigating the extent of DDI between CBZ and RIV should be conducted in humans to gain a full understanding of their safety and effects.

One new indole glucoside, 6-methoxyindole-3-carboxylic acid O-β-D-glucopyranosyl ester (1) and ten known alkaloids, fumiquinazoline D (2), fumiquinazoline C (3), fumiquinazoline J (4), bisdethiobis(methylthio)gliotoxin (5), cyclo(L-prolyl-L-tryptophane) (6), tryprostatin B (7), 12,13-dihydroxy-fumitremorgin C (8), 6-methoxyspirotryprostatin B (9), cyclo(L-prolinyl-L-phenylalanine) (10), and cyclo(L-prolinyl-L-valine) (11) were isolated from marine-derived Aspergillus fumigatus M580. Compounds 2, 3, and 7 exhibited significant antimicrobial activity against Gram-positive Enterococcus faecalis with MIC values of 32, 32, and 64 µg/mL, respectively. Compound 4 showed significant cytotoxic activities against Huh7 and HT-29 cancer cell lines with IC50 values of 9.7 ± 0.9 and 10.3 ± 0.9 μM, respectively. Compounds 3 and 10 showed the most α-glucosidase inhibitory activity with inhibitory percentages of 13.6 ± 1.1 and 10.3 ± 0.8 % at the concentration of 100 μg/mL, respectively.

Galgeuntang (GGT), a traditional herbal medicine, is widely co-administered with acetaminophen (AAP) for treatment of the common cold, but this combination has not been the subject of investigation. Therefore, we investigated the herb–drug interaction between GGT and AAP by population pharmacokinetics (PKs) modeling and simulation studies. To quantify PK parameters and identify drug interactions, an open label, three-treatment, three-period, one-sequence (AAP alone, GGT alone, and AAP and GGT in combination) clinical trial involving 12 male healthy volunteers was conducted. Ephedrine (EPD), the only GGT component detected, was identified using a one-compartment model. The PKs of AAP were described well by a one-compartment model and exhibited two-phase absorption (rapid followed by slow) and first-order elimination. The model showed that EPD significantly influenced the PKs of AAP. The simulation results showed that at an AAP dose of 1000 mg × 4 times daily, the area under the concentration versus time curve of AAP increased by 16.4% in the presence of GGT compared to AAP only. In conclusion, the PKs of AAP were affected by co-administration of GGT. Therefore, when AAP is combined with GGT, adverse effects related to overdose of AAP could be induced possibly.