• Journal of Pharmaceutical Investigation
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• v.28 no.4
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• pp.241-247
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• 1998

Ketoconazole is an imidazole antifungal agent which inhibits the biosynthesis of fungal cellmembrane ergosterol and has immunosuppressive properties in vitro. Biphenyl dimethyl dicarboxylate (PMC) has been utilized for antioxidative action and for liver-protective purposes. Studies were undertaken to investigate effects of biphenyl dimethyl dicarboxylate (PMC) on the immunosuppression of ketoconazole in ICR mice. In the combination of PMC and ketoconazole, as compared with the treatment of ketoconazole alone, there were significant increases in activities of natural killer (NK) cells and phagocytes along with circulation leukocytes. The elevation of serum glutamic-pyruvic transaminase (S-GPT) and total protein levels caused by ketoconazole were reduced by the combination of PMC and ketoconazole. In addition, lower serum albumin and albumin/globulin (A/G) ratio were also increased to normal level.

• Journal of Pharmaceutical Investigation
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• v.26 no.3
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• pp.193-199
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• 1996

The polymorphism of biphenyl dimethyl dicarboxylate was investigated by DSC. From product five crystal forms. Form 1, Form 2, Form 3, Form 4, and Form 5, were characterized and three crystal forms. Form 6, Form 7, and Form 8, were prepared with the recrystallization method. The dissolution patterns of these eight crystal farms were also studied, but there was practically no difference in dissolution rate.

• Archives of Pharmacal Research
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• v.22 no.3
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• pp.255-261
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• 1999

The effect of biphenyl dimethyl dicarboxylate (PMC) on the cellular and nonspecific immunosuppressions by ketoconazole (KCZ) was investigated in ICR mice. PMC at a dose of 6 mg/kg was administered orally to mice daily for 14 consecutive days. KCZ was suspended in RPMI 1640 medium and orally administered at 160 mg/kg/day 2 hrs after the administration of PMC. Immune responses of the delayed-type hypersensitively (DTH) reaction to sheep red blood cells (SRBC), phagocytic activity and natural killer (NK) cell activity were evaluated. DTH reaction to SRBC was enhanced to normal level by the combination of PMC and KCZ, as compared with treatment of KCZ alone. In the combination of PMC and KCZ, as compared with treatment of KCZ alone, there were also significant increases in activities of natural killer (NK) cells and phagocytes along with circulating leukocytes. These findings indicate that PMC shows a significant restoration from the immunotoixc status induced by KCZ.

• 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.

• Toxicological Research
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• v.11 no.2
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• pp.181-185
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• 1995

To know the mechanism of biphenyl dimethyl dicarboxylate (DDB) in the protection of chemically induced hepatotoxicity, the activity of glutamic pyruvic tran.saminase (GPT) and the level of lipid peroxidation metabolite (malondialdehyde, MDA) and ATP content in hepatocytes were determined in serum and primarily cultured hepatocytes. For in vibo study, rats were pretreated with DDB (300 mg/ kg, p.o.)for 7 days. DDB pretreatment efficiently reduced the elevation of serum GPT activity induced by carbon tetrachloride (1.6 ml/kg, s.c.) and acetaminophen administration (1500 mg/kg, i.p.). In ex vivo study, hepatocytes were isolated from the rats pretreated with DDB (300 mg/kg, p.o.)for 7 days and cultured for 12 hrs before inducing cytotoxicity with chemicals. The MDA formation and the GPT release induced by adriamycin $(1\times10^{-4} mg/ml)$ and cisplatin $(2\times10^{-4} mg/ml)$ were markedly decreased in the hepatocytes from the rats pretreated with DDB as compared to vehicle only. However, DDB pretreatment did not prevent the decrease of ATP contents of hepatocytes induced by cisplatin and adriamycin. In in vitro experiment, DDB was pretreated in primary cultured hepatocytes for 3 days. DDB enhanced the decreases of ATP contents induced by cisplatin and adriamycln. These results suggest that DDB may protect the hepatocytes from injury induced by hepatotoxlcants through inhibiting the lipid peroxidation.

• YAKHAK HOEJI
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• v.44 no.3
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• pp.263-271
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• 2000

In an attempt to develop an injectable form of practically insoluble biphenyl dimethyl dicarboxylate (DDB), the effect of various vehicles, cosolvents and hydrotropic agents was investigated. It was found that polyethylene glycol (PEG) 400 revealed the best solvency toward DDB (17.7 mg/ml at $37^{\circ}C$), and decreasing order of the solubility was as follows: PEG 400>PEG 300>diethylene glycol monoethyl ether (DGME)>PEG-8 glyceryl caprylate/caprate. Among the hydrotropes used, sodium salicylate, sodium benzoate and nicotinamide were effective in increasing the solubility in water. The solubility of DDB in 2 M sodium salicylate, sodium benzoate and nicotinamide solutions was increased 44.3, 23.5 and 44.0 times than that in water, respectively. The addition of sodium salicylate and sodium benzoate to PEG 300-water PEG 400-water and DGME-water cosolvents remarkably increased the solubility of DDB, and significantly retarded precipitate formation when mixed with water Hemolytic properties of DDB injections (2 mg/4~10 ml) in PEG 300-water or DGME-water (60:40 v/v) cosolvents containing sodium benzoate (0.14~0.35 M) were very low. It was concluded from the results that these solutions would be applied to the design of new DDB injections.

• Archives of Pharmacal Research
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• v.26 no.2
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• pp.173-181
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• 2003

A polymeric micelle drug delivery system was developed to enhance the solubility of poorly-water soluble drug, biphenyl dimethyl dicarboxylate, DDB. The block copolymers consisting of poly(D,L-lactide) (PLA) as the hydrophobic segment and methoxy poly(ethylene glycol) (mPEG) as the hydrophilic segment were synthesized and characterized by NMR, DSC and MALDI-TOF mass spectroscopy. The size of the polymeric micelles measured by dynamic light scattering showed a narrow monodisperse size distribution with the average diameter less than 50 nm. The MW of mPEG-PLA, 3000 (MW of mPEG, 2 K; MW of PLA, 1K), and the presence of hydrophilic and hydrophobic segments on the polymeric micelles were confirmed by MALDI-TOF mass spectroscopy and NMR, respectively. Polymeric micelle solutions of DDB were prepared by three different methods, i.e. the matrix method, emulsion method and dialysis method. In the matrix method, DDB solubility was reached to 13.29 mg/mL. The mPEG-PLA 2K-1K micelle system was compared with the poloxamer 407 micelle system for their critical micelle concentration, micelle size, solubilizing capacity, stability in dilution and physical state. DDB loaded-polymeric micelles prepared by the matrix method showed a significantly increased aqueous solubility (＞5000 fold over intrinsic solubility) and were found to be superior to the poloxamer 407 micelles as a drug carrier.

• Journal of Pharmaceutical Investigation
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• v.26 no.1
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• pp.23-28
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• 1996

The dissolution characteristics of DDB were markedly enhanced by preparing solid dispersions of drug with polyethylene glycol 6000. Solid dispersions of various weight fraction were formed by a melting method. And various tablets$(A{\sim}E)$ were prepared from these solid dispersions with excipients (lactose, com starch, Avicel and PVP) by wet granulation method. There were no significant differences in dissolution rates between physical mixture and DDB alone. But dissolution rates of solid dispersions were $1.4{\sim}2.0$ times greater than that of DDB alone and $1.2{\sim}1.8$ times greater than those of a commercial tablet.

• Korean Journal of Clinical Pharmacy
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• v.3 no.1
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• pp.45-53
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• 1993

Biphenyl Dimethyl dicarboxylate(DDB) has been regarded as a safe, effective drug for decreasing serum aminotransferase levels from elevated serum aminotransferase levels, which cause acute or chronic hepatitis and chronic liver diseases. This study was designed to low dose(22.5mg/day) & short-term therapy effectiveness for 4 weeks of DDB in 30 chronic hepatitis patients with elevated serum aminotransferases. The following results were observed. 1. Serum alanine aminotransferase(ALT) levels significantly decresed from 173. $97\pm130.62(U/L)$ of pretreatment level to $32.23\pm19.22(U/L)$ after treatment for 4 weeks(p<0.00l) and normalized patients by $73\%$ 2. Serum aspartate (AST) aminotransferase levels significantly decreased from $94.90\pm49.17(U/L)$ of pretreatment level to $45.30\pm23.25(U/L)4 after treatment(p0<0.01). 3. However, no significant effects in the serum AST & ALT changes by which cause hepatitis and hepatitis duration (p>0.05). 4. No significant adverse effects were observed except for mild epigastric discomfort in one patient during DDB treatment It is suggested that DDB small dosage administration can result effectively decreasing serum aminotransferase levels from chronic hepatitis patients with elevated serum aminotransferase levels.

• Journal of Pharmaceutical Investigation
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• v.27 no.3
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• pp.199-205
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• 1997

In order to formulate biphenyl dimethyl dicarboxylate(DDB) aqueous solutions, the effects of various solubilizing agents such as cosolvents(PG, PEG 400, glycerin, ethanol), surfactants,$(poloxamer\;407,\;Cremophor^{\circledR}\; RH40,\;Solutol^{\circledR},\;Tween\;80,\;sodium\;lauryl\;sulfate)$, complexation agent$(CELDEX^{\circledR}\;CH-20)$ and others(urea, niacinamide, propylene carbonate, HPMC) on the solubility of DDB in water were evaluated. The solubility of DDB in water was about $0.21\;{\mu}g/ml\;at\;20^{\circ}C$, while its solubility in PEG 400 was 5,000 times higher than that in water. 60% PEG 400 aqueous solution was selected as an optimum solvent system, and surfactants or other solubilizing agents were added to prevent DDB from recrystalization. The addition of surfactants in water increased the solubility of DDB from 15- to 34-fold, however, $CELDEX^{\circledR}\;CH-20$ and other agents studied showed negligible effects on the solubility of DDB in water. The 60% PEG 400 aqueous solution containing 5% $Cremophor^{\circledR}$　RH40 was appeared as the formula of choice. It showed acceptable physical stability after stored for 7 days at $4^{\circ}C$.