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2.
J Korean Med Sci ; 30(4): 378-84, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25829804

ABSTRACT

Gaucher disease is a lysosomal storage disease for which enzyme replacement therapy has proven to be effective. A switch-over clinical trial was performed to evaluate the efficacy and safety of Abcertin® (ISU Abxis, Seoul, Korea) in subjects with type 1 Gaucher disease who were previously treated with imiglucerase. Five Korean patients with type 1 Gaucher disease were enrolled. Previous doses of imiglucerase ranged from 30 to 55 U/kg every other week. The same dose of Abcertin® was administered to all patients for 24 weeks. Primary efficacy endpoints were changes in hemoglobin levels and platelet counts, and the secondary efficacy endpoints included changes in liver and spleen volumes, serum biomarkers, skeletal status and bone mineral density (BMD). During the study period, no statistically significant changes were observed in all parameters including hemoglobin levels and platelet counts, liver and spleen volumes, skeletal status and BMD. Abcertin® administration was continued in three patients for another 24 weeks as an extension of the study. Hemoglobin levels and platelet counts were maintained in all three patients. In conclusion, the efficacy and safety of Abcertin® are similar to those of imiglucerase, and Abcertin® is an effective therapeutic agent for patients with type 1 Gaucher disease (Clinical Trial Registry No. NCT02053896 at www.clinicaltrials.gov).


Subject(s)
Biosimilar Pharmaceuticals/therapeutic use , Enzyme Replacement Therapy , Gaucher Disease/drug therapy , Glucosylceramidase/therapeutic use , Recombinant Proteins/therapeutic use , Adolescent , Adult , Biosimilar Pharmaceuticals/adverse effects , Biosimilar Pharmaceuticals/pharmacokinetics , Child , Enzyme Replacement Therapy/adverse effects , Female , Gaucher Disease/blood , Glucosylceramidase/adverse effects , Glucosylceramidase/pharmacokinetics , Humans , Male , Recombinant Proteins/adverse effects , Recombinant Proteins/pharmacokinetics
3.
J Pharmacol Exp Ther ; 333(3): 782-7, 2010 Jun.
Article in English | MEDLINE | ID: mdl-20308330

ABSTRACT

O(6)-methylguanine-DNA methyltransferase (MGMT) plays a crucial role in the defense against the alkylating agent-induced cytotoxic lesion O(6)-alkylguanine in DNA. Although a significant circadian variation in MGMT activity has been found in the liver of mice, the exact mechanism of the variation remains poorly understood. In this study, we present evidence that glucocorticoids were required for the 24-h oscillation of MGMT expression in mouse liver. The exposure of mouse hepatic cells (Hepa1-6) to dexamethasone (DEX) significantly increased the mRNA levels of MGMT in a dose-dependent manner. The DEX-induced increase in MGMT expression was reversed by concomitant treatment with RU486 [11beta-[p-(dimethylamino) phenyl]-17beta-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one], a glucocorticoid receptor antagonist. The mRNA levels of MGMT and its enzymatic activity in the liver of mice showed significant 24-h oscillations, which were not observed in adrenalectomized mice. A single administration of DEX to adrenalectomized mice significantly increased the mRNA levels of MGMT in the liver. These findings suggest that the 24-h oscillation in the hepatic expression of MGMT is caused by the endogenous rhythm of glucocorticoid secretion. Dacarbazine (DTIC), a potent O(6)-guanine-alkylating agent, causes serious hepatotoxicity accompanied by hepatocellular necrosis and hepatic vein thrombosis. DTIC-induced hepatotoxicity in mice was attenuated by administering the drug at the time of day when MGMT expression was abundant. The present findings suggest that glucocorticoid-regulated oscillation in the hepatic MGMT expression is the underlying cause of dosing time-dependent changes in DTIC-induced hepatotoxicity.


Subject(s)
Antineoplastic Agents/toxicity , Chemical and Drug Induced Liver Injury/prevention & control , Dacarbazine/toxicity , Glucocorticoids/pharmacology , O(6)-Methylguanine-DNA Methyltransferase/biosynthesis , O(6)-Methylguanine-DNA Methyltransferase/genetics , Adrenalectomy , Animals , Cells, Cultured , Chemical and Drug Induced Liver Injury/pathology , Circadian Rhythm/drug effects , Corticosterone/blood , Dose-Response Relationship, Drug , Hormone Antagonists/pharmacology , Male , Mice , Mice, Inbred ICR , Mifepristone/pharmacology , Reverse Transcriptase Polymerase Chain Reaction
4.
Biochem Pharmacol ; 78(8): 1075-82, 2009 Oct 15.
Article in English | MEDLINE | ID: mdl-19540206

ABSTRACT

Although Clock gene product, a component of the circadian pacemaker, has been suggested to participate in the regulation of cellular sensitivity to genotoxic stress, the underlying mechanism remains to be fully understood. In this study, we showed that Clock gene mutation modulates the sensitivity of hepatocytes to alkylating agent-induced genotoxic stress through altering the expression of N-methylpurine DNA glycosylase (MPG), the first enzyme in the base excision repair pathway. Neither wild-type nor Clock mutant (Clock/Clock) mice showed a significant 24-h variation in the hepatic expression of MPG. However, the mRNA and protein levels of MPG in the liver of Clock/Clock mice were significantly lower than those in wild-type liver. The cytotoxic effect of methyl methanesulfonate (MMS), a methylating agent, on primary cultured hepatocytes prepared from Clock/Clock mice was more potent than on wild-type hepatocytes, while overexpression of MPG in Clock/Clock hepatocytes restored their MMS sensitivity to the wild-type level. These findings suggest that the product of the Clock gene controls the sensitivity of cells to genotoxic stress through regulating the expression of the MPG gene. Our present findings would provide a molecular link between the circadian clock and DNA repair pathway.


Subject(s)
DNA Damage , DNA Glycosylases/metabolism , Gene Expression Regulation, Enzymologic , Mutation , Trans-Activators/genetics , Animals , Antineoplastic Agents, Alkylating/toxicity , CLOCK Proteins , Cells, Cultured , DNA Glycosylases/genetics , Hepatocytes/drug effects , Hepatocytes/enzymology , Male , Methyl Methanesulfonate/toxicity , Mice , Mice, Mutant Strains , Mutagens/toxicity , RNA, Messenger/genetics , RNA, Messenger/metabolism , RNA, Small Interfering/chemistry , RNA, Small Interfering/metabolism , Sensitivity and Specificity , Trans-Activators/metabolism
5.
Drug Metab Pharmacokinet ; 24(2): 167-74, 2009.
Article in English | MEDLINE | ID: mdl-19430173

ABSTRACT

Concomitant administration of certain fluoroquinolone antimicrobials and nonsteroidal antiinflammatory agents (NSAIDs) induces serious convulsion in humans. There are differences in convulsive activity among fluoroquinolones and in the potentiation of fluoroquinolone-induced convulsion among NSAIDs, but a comprehensive, quantitative comparison has not been carried out. This study evaluates the inhibitory effects of twelve fluoroquinolones (ciprofloxacin, enoxacin, fleroxacin, gatifloxacin, levofloxacin, lomefloxacin, norfloxacin, ofloxacin, pazufloxacin, prulifloxacin, sparfloxacin, and tosufloxacin) alone or in the presence of an NSAID (4-biphenylacetic acid, diclofenac sodium, loxoprofen, lornoxicam or zaltoprofen) on the GABA(A) receptor binding of [(3)H]muscimol in an in vitro study using mice synaptic plasma membrane. The rank order of inhibitory effects of the fluoroquinolones was prulifloxacin asymptotically equal to norfloxacin > ciprofloxacin > or = enoxacin > gatifloxacin > or = ofloxacin asymptotically equal to tosufloxacin asymptotically equal to lomefloxacin > levofloxacin > or = sparfloxacin > or = pazufloxacin asymptotically equal to fleroxacin. 4-Biphenylacetic acid most potently enhanced the inhibitory effects of the fluoroquinolones, while zaltoprofen, loxoprofen, lornoxicam and diclofenac had essentially no effect. The clinical risk of convulsion for each combination was estimated using a pharmacodynamic model based on receptor occupancy using the in vitro data set obtained and pharmacokinetic parameters in humans collected from the literature. The combinations of 4-biphenylacetic acid with prulifloxacin and enoxacin were concluded to be the most hazardous.


Subject(s)
Anti-Bacterial Agents/adverse effects , Anti-Infective Agents/adverse effects , Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Fluoroquinolones/adverse effects , Receptors, GABA-A/analysis , Seizures/chemically induced , Animals , Anti-Infective Agents/pharmacology , Ciprofloxacin/adverse effects , Diclofenac , Dioxolanes , Drug Combinations , Drug Interactions , Enoxacin/adverse effects , Fleroxacin/adverse effects , Gatifloxacin , Levofloxacin , Male , Mice , Microbial Sensitivity Tests , Naphthyridines/adverse effects , Norfloxacin/adverse effects , Norfloxacin/pharmacology , Ofloxacin/adverse effects , Ofloxacin/pharmacology , Oxazines , Phenylacetates , Piperazines
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