Current Issue : January - March Volume : 2020 Issue Number : 1 Articles : 5 Articles
Loxoprofen (LOX) is a non-selective cyclooxygenase inhibitor that is widely used for\nthe treatment of pain and inflammation caused by chronic and transitory conditions. Its alcoholic\nmetabolites are formed by carbonyl reductase (CR) and they consist of trans-LOX, which is active,\nand cis-LOX, which is inactive. In addition, LOX can also be converted into an inactive hydroxylated\nmetabolite (OH-LOXs) by cytochrome P450 (CYP). In a previous study, we reported that CYP3A4 is\nprimarily responsible for the formation of OH-LOX in human liver microsomes. Although metabolism\nby CYP3A4 does not produce active metabolites, it can affect the conversion of LOX into trans-/cis-LOX,\nsince CYP3A4 activity modulates the substrate LOX concentration. Although the pharmacokinetics\n(PK) and metabolism of LOX have been well defined, its CYP-related interactions have not been\nfully characterized. Therefore, we investigated the metabolism of LOX after pretreatment with\ndexamethasone (DEX) and ketoconazole (KTC), which induce and inhibit the activities of CYP3A,\nrespectively. We monitored their effects on the PK parameters of LOX, cis-LOX, and trans-LOX in\nmice, and demonstrated that their PK parameters significantly changed in the presence of DEX or\nKTC pretreatment. Specifically, DEX significantly decreased the concentration of the LOX active\nmetabolite formed by CR, which corresponded to an increased concentration of OH-LOX formed\nby CYP3A4. The opposite result occurred with KTC (a CYP3A inhibitor) pretreatment. Thus, we\nconclude that concomitant use of LOX with CYP3A modulators may lead to drugâ??drug interactions\nand result in minor to severe toxicity even though there is no direct change in the metabolic pathway\nthat forms the LOX active metabolite....
A novel polymeric microsphere (MS) containing micronized triamcinolone acetonide (TA)\nin a crystalline state was structured to provide extended drug retention in joints after intra-articular\n(IA) injection. Microcrystals with a median diameter of 1.7 microm were prepared by ultra-sonication\nmethod, and incorporated into poly(lactic-co-glycolic acid)/poly(lactic acid) (PLGA/PLA) MSs using\nspray-drying technique. Cross-sectional observation and X-ray diffraction analysis showed that drug\nmicrocrystals were evenly embedded in the MSs, with a distinctive crystalline nature of TA. In vitro\ndrug release from the novel MSs was markedly decelerated compared to those from the marketed\ncrystalline suspension (Triam inj.®), or even 7.2 microm-sized TA crystals-loaded MSs. The novel system\noffered prolonged drug retention in rat joints, providing quantifiable TA remains over 28 days.\nWhereas, over 95% of IA TA was removed from joints within seven days, after injection of the\nmarketed product. Systemic exposure of the steroidal compound was drastically decreased with the\nMSs, with <50% systemic exposure compared to that with the marketed product. The novel MS was\nphysicochemically stable, with no changes in drug crystallinity and release profile over 12 months.\nTherefore, the TA microcrystals-loaded MS is expected to be beneficial in patients especially with\nosteoarthritis, with reduced IA dosing frequency....
Colorectal cancer (CRC) is one of the most malignant and fatal cancers worldwide.\nAlthough cytoreductive surgery combined with chemotherapy is considered a promising therapy,\nperitoneal adhesion causes further complications after surgery. In this study, oxaliplatin-loaded\nPoly-(d,l-lactide-co-glycolide) (PLGA) microparticles were prepared using a double emulsion method\nand loaded into hyaluronic acid (HA)- and carboxymethyl cellulose sodium (CMCNa)-based\ncross-linked (HC) hydrogels. From characterization and evaluation study PLGA microparticles\nshowed smaller particle size with higher entrapment efficiency, approximately������...
In a previous study, the specific NOX1/2/4 inhibitor Ewha-18278 was confirmed as a possible\ntreatment for osteoporosis both in vitro and in vivo. Here, we investigated the pharmacokinetics\n(PK) of the compound by intravenous (IV) and oral administrations to rats. Dimethyl sulfoxide\n(DMSO)-based and diazepam injection-based formulations were used to dissolve the compound.\nIn the latter formulation applicable to humans, the changes in PK parameters were monitored at\ntwo different concentrations (1 mg/mL and 2 mg/mL). The area under the plasma concentration-time\ncurve from zero time to infinity (AUCinf) of Ewha-18278 was highest in the DMSO-based formulation\n(2 mg/mL). Also, the concentration was increased 1.6-fold at the low concentration of the diazepam\ninjection-based formulation compared to the high concentration. There was no statistical significance\nin the AUCinf of the compound between DMSO-based formulation (2 mg/mL) and diazepam\ninjection-based formulation (1 mg/mL). These results suggest that Ewha-18278 can be delivered\nto humans by both IV and oral routes. In addition, the diazepam injection-based formulation of\nEwha-18278 appears to be a suitable candidate for dosage development for future toxicity test and\nclinical trial....
The purpose was to explore the optimal dosage regimen of colistin using Monte Carlo\nsimulations, for the treatment of carbapenem-resistant Klebsiella pneumoniae and carbapenem-resistant\nEscherichia coli based on PK/PD targets in critically ill patients. A total of 116 carbapenem-resistant\nK. pneumoniae and E. coli were obtained from various clinical specimens at Siriraj Hospital in\nBangkok, Thailand. Minimum inhibitory concentrations (MICs) of colistin were determined by\nbroth microdilution method. Monte Carlo simulation was used to calculate the cumulative fraction\nof response (CFR) for European Medicine Agency (EMA), US-Food and Drug Administration\n(FDA), Nation et al., Siriraj Hospital and our study regimens. The targeted CFR was 90%.\nFor colistin-susceptible K. pneumoniae, all of the dosage regimens achieved greater than equal to90% CFR in patients with\ncreatinine clearance <80 mL/min except the FDA-approved regimens for patients with creatinine\nclearance 51-79 and 11-29mL/min, respectively. While, patients with creatinine clearance greater than equal to80mL/min,\nCFR greater than equal to90% was observed in Siriraj Hospital and our study regimen. For colistin-susceptible E. coli,\nall of the dosage regimens achieved greater than equal to90% CFR regardless of renal function. In contrast, the currently\napproved regimens achieved CFR target in only 10-50% for colistin-resistant isolates subgroup. These\nresults suggest that currently approved regimens still recommended for colistin-susceptible CRE.\nFor colistin-resistant CRE, alternative approaches such as high dose or combination therapy should\nbe considered....
Loading....