• Biomolecules & Therapeutics
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• v.10 no.3
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• pp.202-207
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• 2002

The hepato-protective activity of the GODEX (Hepadif-s capsule) has been studied in the rats against $CCl_4$-ethanol induced liver toxicity. The rats were oral1y treated with $CCl_4$ (corn oil/ $CCl_4$ 1:1, 1 mg/kg). And one week passes, $CCl_4$(0.4 mg/kg) administered two times a week for 7 weeks. The drugs have been administered every two days for 4 weeks after $CCl_4$ injection. The experimental groups have consisted of the GODEX (250 mg/kg), Hepadif (200 mg/kg), DDB complex (DDB 50 mg/kg and garlic oil powder 50 mg/kg), DDB (50 mg/kg), and vehicle control respectively. There was a significant decrement on the serum level of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and total bilirubin in all treated groups. Specially, ALT level of GODEX and Hepadif only treated groups was decreased c1early. Also, serum albumin level was significantly enhanced in GODEX treated group compared with control and DDB treated groups. In histological results, hepatocellular vacuolar degeneration, lobular restructure and necrosis of bile duct were severely showed in control. But other treated groups showed centerilobular degeneration and mild hyper-plasia. Hepadif or DDB has a effects of the recovery on serum parameters and structure ill liver injury. When it was compared GODEX to Hepadif alone or DDB complex or DDB, it suggested to have the best activity of the liver recovery.

• YAKHAK HOEJI
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• v.43 no.6
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• pp.827-833
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• 1999

In this study, we have investigated the effect of Biphenyl Dimethyl Dicarboxylate (DDB), a synthetic analogue of Schizandrin C isolated from Schizandrae Fructus on cytochrome $P_450$ lAl and 2Bl, and the protective mechanism against $CCl_4-induced$ hepatotoxicity in rat liver. After DDB was administered into male rats for different periods of time (1~7 days) and with different doses (25, 50, 100 and 200 mg/kg), mRNA levels of CYPlAl were measured by polymearse chain reaction (PCR) and assayed the activities of CYPlAl specific ethoxyresorufin-O-dealkylase (EROD) and CYP2Bl specific benzyloxyresorufin-O-dealkylase (BROD). DDB treatment resulted in increase in CYP2Bl mRNA level and BROD activity, whereas there was no change in CYPlAl mRNA level and EROD activity. This effect of DDB was time-and dose-dependent and reached maximal level by 3 day and 200 mg/kg treatment. In addition, rats were pre-treated with DDB at doses of 25, 50 or 100 mg/kg daily for 4 days, 3-hr after final treatment on the 4th day, $CCl_4$ 0.3ml/kg was intraperitonially injected into the rats to examine the effect of DDB on $CCl_4-induced$ hepatic injury. Serum levels of ALT and AST were determined and histopathological examination was done in rat liver. Furthermore, we have measured hepatic microsomal malondialdehyde(MDA) level, a parameter of lipid peroxidation. Based on serum ALT level and lipid peroxidation, pretreatment of DDB, 50 mg/kg appeared the most protective effect against $CCl_4-induced$ heapatotoxity. These results indicate that DDB stimulates CYP2Bl mRNA level and BROD activity in time and dose dependent manner and suggest that protective effect of DDB on $CCl_4-induced$ hepatotoxicity may be mediated through free radical scavenging.

• The Korean Journal of Pharmacology
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• v.30 no.2
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• pp.217-225
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• 1994

In an attempt to define the effects of Biphenyldimethyl dicarboxylate(DDB) on the lipid peroxidation, oxygen free radical scavenging enzymes activities and hepatic functions in ethanol-induced hepatotoxic rats, we studies malondialdehyde(MDA) level and the activities of catalse, superoxide dismutase(SOD), glutamic-oxaloacetic transaminase(GOT) and glutamic-pyruvic transaminase(GPT) in liver of the rats at 24, 48 and 72 hr after the injection of ethanol and DDB. Sprague-Dalwey albino rats weighing 250 to 280gm were injected intraperitoneally with ethanol(2.5 gm/kg ) only and ethanol plus DDB(300mg/kg ). The result obtained can be summarized as follows : 1) The group treated with ethanol showed significantly higher MDA level and lower catalase and SOD activities at 24, 48 and 72hr after the injection as compared with that of control group. 2) The group treated with ethanol showed significantly higher GOT and GPT activities at 24, 48 and 72hr after the injection as compared with that of control group. 3) The group treated with ethanol plus DDB showed significantly lower MDA level and higher catalase and SOD activities at 24, 48 and 72 hr after the injection as compared with that of ethanol group. 4) The group treated with ethanol plus DDB showed significantly lower GOT and GPT activities at 24, 48 and 72 hr after the injection as compared with that of ethanol group. These results suggest that the excessive oxygen free radicals resulting from the depression of the activities of catalase and superoxide dismutase is an important determinant in pathogenesis of ethanol-induced hepatotoxicity and DDB has antioxidant effects.

• Archives of Pharmacal Research
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• v.29 no.5
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• pp.405-411
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• 2006

Biphenyl dimethyl dicarboxylate (DDB) is a hepatoprotectant, which is used as an adjuvant agent in a treatment for chronic hepatitis. Amantadine is an antiviral agent, which is utilized primarily in the treatment of influenza, but also, occasionally in the treatment of hepatitis C. In a previous study, we reported that DDB, coupled with amantadine, would exert an anti-HBV effect, via the induction of interferon-inducible gene expression in the HepG2 2.2.15 cell line. The primary objective of the present study was to determine whether or not DDB and/or amantadine exhibit anti-HBV properties, and what mechanisms of action might be involved in such properties. In our study, we were able to determine that DDB stimulates Jak/Stat signaling, and induces the expression of interferon alpha $(IFN-\alpha)$ stimulated genes, most notably 6-16 and ISG12. In addition, the antiviral effectors induced by $IFN-\alpha$, PKR, OAS, and MxA, were regulated in the presence of DDB at its optimal concentration $(250{\mu}g/mL)$, to a degree commensurate with the degree of induction associated with the $IFN-\alpha$ treated group. Finally, we determined that the replication of pregenomic RNA and HBeAg was inhibited by DDB treatment, and this inhibition was maximized when coupled with the administration of amantadine $(25{\mu}g/mL)$. In conclusion, the results of this study demonstrated clearly that DDB, as well as the combination of DDB/amantadine, directly inhibited $IFN-\alpha$ signaling-mediated replication of HBV in infected hepatocytes, and thus may represent a novel treatment for chronic hepatitis B, which would be characterized principally by its improved safety over other treatment strategies.

• Biomolecules & Therapeutics
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• v.3 no.3
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• pp.223-228
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• 1995

In an attempt to define the effects of biphenyldimethyl dicarboxylate (DDB) on the lipid peroxidation and oxygen free radical scavenging enzymes activities in mercuric chloride-induced hepatotoxic rats, we studied malondialdehyde (MDA) level and the activities of catalase and superoxide dismutase (SOD) in liver of the rats at 24 hr after the injection of mercuric chloride. Sprague-Dalwey albino rats were injected subcutaneously with mercuric chloride (5 mg/kg) only and mercuric chloride (5 mg/kg) plus. DDB (200 mg/kg/day, p.o) is administered for 4 days prior to 3 days from the injection of mercuric chloride. The group treated with mercuric chloride showed significantly higher MDA level and lower catalase and SOD activities as compared with that of control group. The group treated with mercuric chloride plus DDB showed significantly lower MDA level and catalase activity and higher SOD activity as compared with that of mercuric chloride-treated group. These results suggest that the excessive oxygen free radicals resulting from the depression of superoxide dismutase activity is an important determinant in the pathogenesis of mercuric chloride-induced hepatotoxicity and DDB has antioxidant effects.

• Archives of Pharmacal Research
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• v.24 no.2
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• pp.159-163
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• 2001

The accelerated stability of dimethoxy biphenyl monocarboxylate.HCl (DDB-S) was investigated in 6 mg/mL water solution in the pH ranging 2-10 and the temperature of $45-85^{\circ}C$. The observed rate of degradation followed first-order kinetics. The energy of activation for DDB-S degradation was calculated to be 14.1 and 16.5 $Kcal/mole$ at pH 5 and in distilled watery respectively. The degradation rate constant ($K_{25^{\circ}C}$) obtained by trending line analysis of Arrhenius plots for DDB-S was $5.3{\times}10^{-6}h^{-1}$. The times to degrade 10% ($t_{10}$) and 50% $t_{500}$) at $K_{25^{\circ}C}$ were 829 and 5,416 days, respectively. DDB-S exhibited the fastest degradation at pH 10 and the slowest rate at pH 5. In addition, at $K_{65^{\circ}C}$, degradation rate constants of DDB-S were 0.066, 0.059, 5.460, 32.171, and $1.4{\times}10^{-6}h^{-1}$ at pH 2, 5, 8, 10 and in distilled water, respectively. These observations indicated that the rate-pH profile of DDB-S showed general acid-base catalysis reaction in the range of pH 2-10.

• Archives of Pharmacal Research
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• v.25 no.5
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• pp.655-663
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• 2002

Liver fibrosis is a prepathological state wherein damaged liver tissues in chronic liver diseases, such as hepatitis, are not repaired to normal tissues, but converted to fibrous tissue. 5-(2-Pyrazinyl)-4-methyl-1,2-dithiol-3-thione (oltipraz), a cancer chemopreventive agent, is effective against a wide variety of chemical carcinogens. Recently, we reported that oltipraz inhibits liver fibrogenesis (Kang et al., 2002). In the present study, the effects of oltipraz in combination with dimethyl-4,4'-dimethoxy-5,6,5',6'-dimethylene dioxybiphenyl-2,2'-dicarboxylate (DDb) on dimethylnitrosamine (DMN)-induced liver fibrogenesis were assessed in rats. Oltipraz (30 mg/kg body weight, po, 3 times per week for 4 weeks) was found to inhibit the increases in plasma ALT, AST and bilirubin by DMN, whereas DDB (30 mg/kg body weight, po, 3 times per week for 4 weeks) attenuated the increases in the plasma ALT and bilirubin. The lowered plasma protein and albumin contents in DMN-treated rats were completely restored by oltipraz, but not by DDB. DDB decreases liver cell injury and inflammation through inhibition of nuclear factor-kB. DMN increased the accumulation of liver collagen, as indicated by the increase in the 4-hydroxyproline content in liver homogenates, which was reduced by treatment with oltipraz, but not by DDB. Given the differential effect between oltipraz and DDB, the potential enhancement of antifibrotic efficacy by the drugs was assessed in the animal model. Despite the minimal effect of DDB on DMN-induced fibrogenesis, DDB (5-25 mg/kg), administered together with oltipraz (25-5 mg/kg), showed an additive protective effect against hepatotoxicity and fibrosis induced by DMN, which was shown by the blood chemistry parameters and histopathological analysis. The adequate composition ratio of oltipraz to DDB was 5:1. These results provide information on the pharmaceutical composition, comprising of oltipraz and DDB as the active components, for the treatment and/or prevention of liver fibrosis and cirrhosis.

• Journal of Pharmaceutical Investigation
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• v.27 no.3
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• pp.173-179
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• 1997

A water-soluble DDB derivative (Bis{2-(methylamino)ethyl}-4,4-dimethoxy-5,5',6,6'-dimethylenedioxy-biphenyl-2,2'-dicarboxylate, DDB-S) was synthesized and its therapeutic effects on the liver damage induced by carbon tetrachloride in rats were evaluated. Oral administration of DDB-S reduced the aspartate aminotransferase(AST) and alanine aminotransferase(ALT) activities and increased total protein and albumin contents in the serum of the carbon tetrachloride intoxicated rat. Therapeutic effects of DDB-S by intravenous injection was also investigated using carbon tetrachloride intoxicated rats. Histological studies showed that IV injection of DDB-S had improved the typical necrosis around centrilobular area in liver tissue due to the carbon tetrachloride intoxication and also prevented the elevation of liver weigh/body weight ratio. IV administration of DDB-S to $CCl_4-treated$ rats significantly decreased AST & ALT activities and also prevented the decrease of aniline hydroxylation activity of the liver. These results indicate that i.v. administration of DDB-S is very effective in recovering the liver function in $CCl_4-treated$ rats.

• Proceedings of the Korean Society of Applied Pharmacology
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• 1997.04a
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• pp.118-118
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• 1997

Solid dispersions were used to increase the dissolution rate of biphenyl dimethyl dicarboxylate (DDB) in water, with the ultimate goal of optimizing its bioavailability when incoporated into pharmaceuticals. Carriers used were Kollidon 30, Kollidon VA 64, 2-hydroxypropyl-${\beta}$-cyclodextrin (HPCD), sodium salicylate or sodium benzoate. DDB solid dispersions were prepared at drug to carrier proportions ranging from 1 : 5 to 1 : 20 (w/w) by solvent evaporation method. DDB tablets (7.5 mg) were prepared by compressing the powder mixture composed of solid dispersions, lactose, corn starch, crospovidone and magnesium stearate using a single-punch press. DDB capsules (7.5 mg) were prepared by filing the mixture into empty hard gelatin capsules (size #1). Dissolution studies of DDB from powdered solid dispersions, tablets and capsules were performed in 900 $m\ell$ of water at 100 rpm and 37$^{\circ}C$ by the paddle method. The dissolved amount was assayed by HPLC and expressed as the mean(%)of three determinations.

• Journal of Information Display
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• v.5 no.2
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• pp.39-42
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• 2004

A novel fast-switching LCD with dual-domain bend (DDB) mode is described. DDB alignment is achieved using antiparallel-rubbed cell filled with chiral-doped LC. Initial alignment is mono-domain 180-degree twist. Tilt direction is controlled by oblique electric field to be counter direction in each domain. Twist-to-DDB deformation occurs continuously so that DDB mode does not require high-voltage initialization which is inevitable in Optically Compen sated Bend (OCB) mode. DDB gives wide and symmetric viewing angle in contrast to mono-domain bend formed from 180-degree twist showing strong asymmetry.