PURPOSE: The concomitant use of therapeutic drugs may cause potential drug-drug interactions by decreasing or increasing plasma levels of the administered drugs, leading to a suboptimal clinical efficacy or a higher risk of toxicity. Thus, evaluating the inhibitory potential of a new chemical entity, and to clarify the mechanism of inhibition and kinetics in the various CYP enzymes is an important step to predict drug-drug interactions.
STUDY DESIGN: This study was designed to assess the potential inhibitory effects of Alpinia conchigera Griff. rhizomes extract and its active constituent, ACA, on nine c-DNA expressed human cytochrome P450s (CYPs) enzymes using fluorescent CYP inhibition assay.
METHODS/RESULTS: The half maximal inhibitory concentration (IC50) of Alpinia conchigera Griff. rhizomes extract and ACA was determined for CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP3A5. A. conchigera extract only moderately inhibits on CYP3A4 (IC50 = 6.76 ± 1.88µg/ml) whereas ACA moderately inhibits the activities of CYP1A2 (IC50 = 4.50 ± 0.10µM), CYP2D6 (IC50 = 7.50 ± 0.17µM) and CYP3A4 (IC50 = 9.50 ± 0.57µM) while other isoenzymes are weakly inhibited. In addition, mechanism-based inhibition studies reveal that CYP1A2 and CYP3A4 exhibited non-mechanism based inhibition whereas CYP2D6 showed mechanism-based inhibition. Lineweaver-Burk plots depict that ACA competitively inhibited both CYP1A2 and CYP3A4, with a Ki values of 2.36 ± 0.03 µM and 5.55 ± 0.06µM, respectively, and mixed inhibition towards CYP2D6 with a Ki value of 4.50 ± 0.08µM. Further, molecular docking studies show that ACA is bound to a few key amino acid residues in the active sites of CYP1A2 and CYP3A4, while one amino residue of CYP2D6 through predominantly Pi-Pi interactions.
CONCLUSION: Overall, ACA may demonstrate drug-drug interactions when co-administered with other therapeutic drugs that are metabolized by CYP1A2, CYP2D6 or CYP3A4 enzymes. Further in vivo studies, however, are needed to evaluate the clinical significance of these interactions.
MAIN METHODS: Human bone marrow derived MSCs were isolated, expanded in vitro and transfected with adiponectin gene containing plasmid vector. Total RNA was extracted and cDNA was prepared by reverse transcription polymerase chain reaction (RT-PCR). The expression of adiponectin gene and protein in GM-MSCs was analyzed by PCR and Western blotting respectively. The secretion of adiponectin protein from GM-MSCs was analyzed by enzyme-linked immunosorbent assay.
KEY FINDINGS: The expression of adiponectin gene and plasmid DNA was detected in GM-MSCs but not in control group of MSCs. Adiponectin gene expression was detected in GM-MSCs at 2, 7, 14, 21 and 28days after transfection. Western blotting analysis revealed the expression of adiponectin protein only in GM-MSCs. The GM-MSCs stably secreted adiponectin protein into culture media at least for 4weeks.
SIGNIFICANCE: GM-MSCs express and secret adiponectin protein. Therefore, these adiponectin secreting GM-MSCs could be instrumental for the supplementation of adiponectin in the treatment of adiponectin deficiency related diseases.
METHODS: Since 1994, closure of the nose has been undertaken to prevent severe nasal bleeding in patients meeting specific selection criteria. Outcome data collected on this cohort pre- and post-operatively is available for analysis.
RESULTS: From a cohort of 515 HHT patients, 100 have undergone nasal closure, bilateral ab initio in 81%. Fifty patients completed pre- and post-operative epistaxis severity questionnaires and provided information on post-operative problems and 28 completed a Glasgow Benefit Inventory (GBI). Overall most patients derived significant benefit from the procedure with complete cessation of nasal bleeding in 94%, a highly significant improvement in the epistaxis score and a mean GBI score of 53.4. Loss of smell and taste was the most frequent post-operative complaint.
CONCLUSION: HHT can be associated with life-threatening epistaxis significantly affecting patients quality of life. Permanent prevention of airflow is associated with complete or near-total cessation of epistaxis in the majority of patients.