Docosanol is the only US Food and Drug Administration(FDA)approved over-the-counter topical product for treating recurrent oral-facial herpes simplex labialis.Validated analytical methods for docosanol are required to...Docosanol is the only US Food and Drug Administration(FDA)approved over-the-counter topical product for treating recurrent oral-facial herpes simplex labialis.Validated analytical methods for docosanol are required to demonstrate the bioequivalence of docosanol topical products.A gas chromatography/selected ion monitoring mode mass spectrometry(GC/SIM-MS)method was developed and validated for docosanol determination in biological samples.Docosanol and isopropyl palmitate(internal standard)were separated on a high-polarity GC capillary column with(88%cyanopropy)aryl-polysiloxane employed as the stationary phase.The ions of m/z 83 and 256 were selected to monitor docosanol and isopropyl palmitate,respectively;the total run time was 20 min.The GC/SIM-MS method was validated in accordance with US FDA guidelines,and the results met the US FDA acceptance criteria.The docosanol calibration standards were linear in the 100-10000 ng/mL concentration range(R^(2)>0.994).The recoveries for docosanol from the receptor fluid and skin homogenates were>93.2%and>95.8%,respectively.The validated method was successfully applied to analyze ex vivo human cadaver skin permeation samples.On applying Abreva®cream tube and Abreva®cream pump,the amount of docosanol that penetrated human cadaver skin at 48 h was 21.5±7.01 and 24.0±6.95 ng/mg,respectively.Accordingly,we concluded that the validated GC/SIM-MS was sensitive,specific,and suitable for quantifying docosanol as a quality control tool.This method can be used for routine analysis as a costeffective alternative to other techniques.展开更多
BACKGROUND Cardiac and hepatic functionality are intertwined in a multifaceted relationship.Pathologic processes involving one may affect the other through a variety of mechanisms,including hemodynamic and membrane tr...BACKGROUND Cardiac and hepatic functionality are intertwined in a multifaceted relationship.Pathologic processes involving one may affect the other through a variety of mechanisms,including hemodynamic and membrane transport effects.AIM To better understand the effect of extrahepatic cholestasis on regulations of membrane transporters involving digoxin and its implication for digoxin clearance.METHODS Twelve adult rats were included in this study;baseline hepatic and renal laboratory values and digoxin pharmacokinetic(PK)studies were established before evenly dividing them into two groups to undergo bile duct ligation(BDL)or a sham procedure.After 7 d repeat digoxin PK studies were completed and tissue samples were taken to determine the expressions of cell membrane transport proteins by quantitative western blot and real-time polymerase chain reaction.Data were analyzed using SigmaStat 3.5.Means between pre-surgery and post-surgery in the same experimental group were compared by paired t-test,while independent t-test was employed to compare the means between sham and BDL groups.RESULTS Digoxin clearance was decreased and liver function,but not renal function,was impaired in BDL rats.BDL resulted in significant up-regulation of multidrug resistance 1 expression in the liver and kidney and its down-regulation in the small intestine.Organic anion transporting polypeptides(OATP)1A4 was up-regulated in the liver but down-regulated in intestine after BDL.OATP4C1 expression was markedly increased in the kidney following BDL.CONCLUSION The results suggest that cell membrane transporters of digoxin are regulated during extrahepatic cholestasis.These regulations are favorable for increasing digoxin excretion in the kidney and decreasing its absorption from the intestine to compensate for reduced digoxin clearance due to cholestasis.展开更多
Objective: To synthesize orally bioavailable artemisinin dimers and the evaluation of their in vivo antimalarial activity. Methods: Artemsisin dimers were synthesized and their antimalarial activity was determined in ...Objective: To synthesize orally bioavailable artemisinin dimers and the evaluation of their in vivo antimalarial activity. Methods: Artemsisin dimers were synthesized and their antimalarial activity was determined in in vitro and in vivo studies(administered orally and IP). Results: Dimers5 and 6 provided 100% suppression of parastemia throughout the oral administration study, with all animals surviving up to day 28(the last day of the study). Conclusion: Dimers 4-7 displayed markedly improved in vitro activity against P. falciparum, while the in vivo activity against P. berghei was highly encouraging, with 5 and 6 completely clearing parasitemia from the start of the drug treatment until the end of the study(day 28).展开更多
文摘Docosanol is the only US Food and Drug Administration(FDA)approved over-the-counter topical product for treating recurrent oral-facial herpes simplex labialis.Validated analytical methods for docosanol are required to demonstrate the bioequivalence of docosanol topical products.A gas chromatography/selected ion monitoring mode mass spectrometry(GC/SIM-MS)method was developed and validated for docosanol determination in biological samples.Docosanol and isopropyl palmitate(internal standard)were separated on a high-polarity GC capillary column with(88%cyanopropy)aryl-polysiloxane employed as the stationary phase.The ions of m/z 83 and 256 were selected to monitor docosanol and isopropyl palmitate,respectively;the total run time was 20 min.The GC/SIM-MS method was validated in accordance with US FDA guidelines,and the results met the US FDA acceptance criteria.The docosanol calibration standards were linear in the 100-10000 ng/mL concentration range(R^(2)>0.994).The recoveries for docosanol from the receptor fluid and skin homogenates were>93.2%and>95.8%,respectively.The validated method was successfully applied to analyze ex vivo human cadaver skin permeation samples.On applying Abreva®cream tube and Abreva®cream pump,the amount of docosanol that penetrated human cadaver skin at 48 h was 21.5±7.01 and 24.0±6.95 ng/mg,respectively.Accordingly,we concluded that the validated GC/SIM-MS was sensitive,specific,and suitable for quantifying docosanol as a quality control tool.This method can be used for routine analysis as a costeffective alternative to other techniques.
文摘BACKGROUND Cardiac and hepatic functionality are intertwined in a multifaceted relationship.Pathologic processes involving one may affect the other through a variety of mechanisms,including hemodynamic and membrane transport effects.AIM To better understand the effect of extrahepatic cholestasis on regulations of membrane transporters involving digoxin and its implication for digoxin clearance.METHODS Twelve adult rats were included in this study;baseline hepatic and renal laboratory values and digoxin pharmacokinetic(PK)studies were established before evenly dividing them into two groups to undergo bile duct ligation(BDL)or a sham procedure.After 7 d repeat digoxin PK studies were completed and tissue samples were taken to determine the expressions of cell membrane transport proteins by quantitative western blot and real-time polymerase chain reaction.Data were analyzed using SigmaStat 3.5.Means between pre-surgery and post-surgery in the same experimental group were compared by paired t-test,while independent t-test was employed to compare the means between sham and BDL groups.RESULTS Digoxin clearance was decreased and liver function,but not renal function,was impaired in BDL rats.BDL resulted in significant up-regulation of multidrug resistance 1 expression in the liver and kidney and its down-regulation in the small intestine.Organic anion transporting polypeptides(OATP)1A4 was up-regulated in the liver but down-regulated in intestine after BDL.OATP4C1 expression was markedly increased in the kidney following BDL.CONCLUSION The results suggest that cell membrane transporters of digoxin are regulated during extrahepatic cholestasis.These regulations are favorable for increasing digoxin excretion in the kidney and decreasing its absorption from the intestine to compensate for reduced digoxin clearance due to cholestasis.
文摘Objective: To synthesize orally bioavailable artemisinin dimers and the evaluation of their in vivo antimalarial activity. Methods: Artemsisin dimers were synthesized and their antimalarial activity was determined in in vitro and in vivo studies(administered orally and IP). Results: Dimers5 and 6 provided 100% suppression of parastemia throughout the oral administration study, with all animals surviving up to day 28(the last day of the study). Conclusion: Dimers 4-7 displayed markedly improved in vitro activity against P. falciparum, while the in vivo activity against P. berghei was highly encouraging, with 5 and 6 completely clearing parasitemia from the start of the drug treatment until the end of the study(day 28).
